Vitamin D binding protein (DBP) is the major carrier protein of 25-hydroxyvitamin D (25(OH) D) in the circulation, where it may serve roles in maintaining stable levels during times of decreased ...25(OH) availability and in regulating delivery of 25(OH) D to target tissues. Several genetic polymorphisms of DBP have been described that lead to phenotypic changes in the protein that may affect affinity, activity, and concentration. These polymorphisms have been linked with alterations in bone density in several populations. One of the mechanisms by which DBP may alter bone health involves regulating vitamin D bioavailability. DBP-bound vitamin is thought to be relatively unavailable to target tissues, and thus alterations in DBP levels or affinity could lead to changes in vitamin D bioactivity. As a result, functional vitamin D status may differ greatly between individuals with similar total 25(OH) D levels. Additionally, DBP may have independent roles on macrophage and osteoclast activation. This review will summarize recent findings about DBP with respect to measures of bone density and health.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
This study shows that a polymorphism in the vitamin D–binding protein gene that is associated with low levels of vitamin D–binding protein among blacks results in levels of bioavailable vitamin D ...that are similar to those in whites, despite lower levels of total 25-hydroxyvitamin D among blacks.
Low levels of total 25-hydroxyvitamin D, which are more common in black Americans than in white Americans, are associated with negative health outcomes in epidemiologic studies.
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Such studies are responsible for the routine clinical practice of screening for vitamin D deficiency. Among the possible effects of vitamin D deficiency, the strongest evidence is for a role in skeletal disorders,
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but clinical investigations of vitamin D supplementation to decrease the risk of fracture have been inconclusive.
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Because blacks consistently have lower levels of total 25-hydroxyvitamin D than whites, they are frequently given a diagnosis of vitamin D deficiency. . . .
•NURTURE is an ongoing study of nusinersen started in a presymptomatic stage of SMA.•All infants were ≥25 months old, and alive without permanent ventilation.•All infants achieved independent sitting ...and 88% (22/25) were walking alone.•Nusinersen demonstrated durability of effect with a median 2.9 years of follow up.•Nusinersen was well tolerated with no new safety concerns over extended follow up.
Spinal muscular atrophy (SMA) is a neurodegenerative disease associated with severe muscle atrophy and weakness in the limbs and trunk. We report interim efficacy and safety outcomes as of March 29, 2019 in 25 children with genetically diagnosed SMA who first received nusinersen in infancy while presymptomatic in the ongoing Phase 2, multisite, open-label, single-arm NURTURE trial. Fifteen children have two SMN2 copies and 10 have three SMN2 copies. At last visit, children were median (range) 34.8 25.7–45.4 months of age and past the expected age of symptom onset for SMA Types I or II; all were alive and none required tracheostomy or permanent ventilation. Four (16%) participants with two SMN2 copies utilized respiratory support for ≥6 h/day for ≥7 consecutive days that was initiated during acute, reversible illnesses. All 25 participants achieved the ability to sit without support, 23/25 (92%) achieved walking with assistance, and 22/25 (88%) achieved walking independently. Eight infants had adverse events considered possibly related to nusinersen by the study investigators. These results, representing a median 2.9 years of follow up, emphasize the importance of proactive treatment with nusinersen immediately after establishing the genetic diagnosis of SMA in presymptomatic infants and emerging newborn screening efforts.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Acute lung injury (ALI) is a hallmark of systemic inflammation associated with high mortality. Although the vitamin D receptor (VDR) is highly expressed in the lung, its role in lung physiology ...remains unclear. We investigated the effect of VDR deletion on ALI using a lipopolysaccharide (LPS)-induced sepsis model. After LPS challenge VDR-null mice exhibited more severe ALI and higher mortality compared with wild-type (WT) counterparts, manifested by increased pulmonary vascular leakiness, pulmonary edema, apoptosis, neutrophil infiltration, and pulmonary inflammation, which was accompanied by excessive induction of angiopoietin (Ang)-2 and myosin light chain (MLC) phosphorylation in the lung. 1,25-Dihydroxyvitamin D blocked LPS-induced Ang-2 expression by blocking nuclear factor-κB activation in human pulmonary artery endothelial cells. The severity of lung injury seen in VDR-null mice was ameliorated by pretreatment with L1–10, an antagonist of Ang-2, suggesting that VDR signaling protects the pulmonary vascular barrier by targeting the Ang-2-Tie-2-MLC kinase cascade. Severe ALI in VDR-null mice was also accompanied by an increase in pulmonary renin and angiotensin II levels, and pretreatment of VDR-null mice with angiotensin II type 1 receptor blocker losartan partially ameliorated the severity of LPS-induced lung injury. Taken together, these observations provide evidence that the vitamin D-VDR signaling prevents lung injury by blocking the Ang-2-Tie-2-MLC kinase cascade and the renin-angiotensin system.
Ergocalciferol and Cholecalciferol in CKD Nigwekar, Sagar U., MD; Bhan, Ishir, MD, MPH; Thadhani, Ravi, MD, MPH
American journal of kidney diseases,
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Journal Article
Peer reviewed
Open access
The development of chronic kidney disease (CKD) is accompanied by a progressive decrease in the ability to produce 1,25-dihydroxyvitamin D. Pharmacological replacement with active vitamin D therefore ...has been a cornerstone of secondary hyperparathyroidism therapy in the end-stage renal disease population treated by long-term dialysis. Recent evidence suggests that extrarenal conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D may have significant biological roles beyond those traditionally ascribed to vitamin D. Furthermore, low 25-hydroxyvitamin D levels are common in patients with all stages of CKD. This article focuses on the role of nutritional vitamin D replacement in CKD and aims to review vitamin D biology and summarize the existing literature regarding nutritional vitamin D replacement in these populations. Based on the current state of the evidence, we provide suggestions for clinical practice and address areas of uncertainty that need further research.
Background Hyponatremia is associated with increased mortality in chronic diseases. Recent animal studies also implicate hyponatremia in bone abnormalities. However, associations between ...hyponatremia, mineral bone abnormalities, and mortality in incident hemodialysis patients are unknown. Study Design Nonconcurrent prospective cohort study. Setting & Participants Incident hemodialysis patients from the Accelerated Mortality on Renal Replacement (ArMORR) cohort with available serum sodium measurements from the time of dialysis therapy initiation (n = 6,127) were classified as hyponatremic (sodium, <135 mEq/L) or normonatremic (sodium, 135-145 mEq/L) based on glucose-corrected sodium level at the time of dialysis therapy initiation. Patients with sodium levels >145 mEq/L were excluded (n = 74). Predictor Hyponatremia (sodium, <135 mEq/L). Outcomes Mineral bone abnormalities; rates of falls, fractures, and mortality. Measurements Hyponatremia and mineral bone abnormalities were assessed at the time of hemodialysis therapy initiation. Data for other outcomes were collected during a 1-year follow-up. Univariate and multivariable logistic and Cox proportion hazard analyses were conducted to compute ORs and HRs, respectively, with 95% CIs. Results 775 patients were hyponatremic and 5,278 were normonatremic at baseline. In univariate analyses, hyponatremia was associated with hypercalcemia (OR, 1.92; 95% CI, 1.11-3.30), elevated alkaline phosphatase level (OR, 1.36; 95% CI, 1.12-1.66), and hypoparathyroidism (OR, 1.40; 95% CI, 1.18-1.65). Similar relationships were observed in multivariable models. No statistically significant relationships were observed with phosphorus abnormalities, hypovitaminosis D, falls, or fractures. 965 (15.8%) patients had died at the 1-year follow up. Compared with normonatremic patients, hyponatremic patients had higher 1-year mortality in univariate (HR, 1.59; 95% CI, 1.34-1.87) and multivariable analyses (HR, 1.42; 95% CI, 1.19-1.69). Limitations Low rate of falls and fractures, lack of data for bone density and fibroblast growth factor 23. Conclusions In incident hemodialysis patients, hyponatremia is associated with hypercalcemia, elevated alkaline phosphatase levels, hypoparathyroidism, and increased 1-year mortality. Future studies are needed to examine whether treatments to alter hyponatremia have effects on mineral bone abnormalities and mortality.
Background Patients with cirrhosis and refractory ascites have physiologic and hormonal dysregulation that contributes to decreased kidney function. Placement of a transjugular intrahepatic ...portosystemic shunt (TIPS) can reverse these changes and potentially improve kidney function. We sought to evaluate change in estimated glomerular filtration rate (eGFR) following TIPS placement. Study Design Retrospective, matched cohort analysis. Settings & Participants Patients who underwent first-time TIPS placement for refractory ascites in 1995 to 2014. Frequency matching was used to generate a comparator group of patients with cirrhosis and ascites treated with serial large-volume paracentesis (LVP) in a 1:1 fashion. Predictor TIPS placement compared to serial LVP. Outcome Change in eGFR over 90 days’ follow-up. Measurements Multivariable regression stratified by baseline eGFR < 60 versus ≥60 mL/min/1.73 m2 ; analysis of effect modification between TIPS placement and baseline eGFR. Results 276 participants (TIPS, n = 138; serial LVP, n = 138) were analyzed. After 90 days, eGFRs increased significantly after TIPS placement in participants with baseline eGFRs < 60 mL/min/1.73 m2 compared to treatment with serial LVP (21 95% CI, 13-29 mL/min/1.73 m2 ; P < 0.001) and was no different in those with eGFRs ≥ 60 mL/min/1.73 m2 (1 95% CI, −9 to 12 mL/min/1.73 m2 ; P = 0.8). There was significant effect modification between TIPS status and baseline eGFR ( P = 0.001) in a model that included all participants. Limitations Outcomes restricted by clinically recorded data; clinically important differences may still exist between the TIPS and LVP cohorts despite good statistical matching. Conclusions TIPS placement was associated with significant improvement in kidney function. This was most prominent in participants with baseline eGFRs < 60 mL/min/1.73 m2 . Prospective studies of TIPS use in populations with eGFRs < 60 mL/min/1.73 m2 are needed to evaluate these findings.
MedHistory is a web-based software module that graphically displays medication usage (y-axis) against time (x-axis). We set out to examine whether MedHistory would improve clinician’s interactions ...with the medical record system. The authors invited house-officers at our institution to complete a survey about inpatient medication administration before and after using MedHistory. Detailed logs were also kept for 1 year after the study period. Compared to the pre-intervention survey, the post-intervention survey found that reviewing medication history was easier (pre: 13.2% vs post: 32.4%, p = .008), that medication review now fit within resident workflow (38.9% vs 75.7%, p < .001), and that there was increased satisfaction with the electronic health records software (2.6% vs 29.7%, p = .002). Additionally, determining the timing (29% vs 50.1%, p = .045) and dosing history (21.1% vs. 43.2%, p = .036) of inpatient medication administration was easier with MedHistory. Anti-infective agents and drugs requiring frequent adjustments were the most commonly reviewed. A graphical timeline of inpatient medications (MedHistory) was met with favorable response across multiple areas, including efficiency, speed, safety, and workflow.
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