Low levels of serum 25-hydroxy vitamin D are associated with increased arterial stiffness and hypertension. Supplementation with vitamin D precursors has been proposed as a treatment option for these ...conditions. We examined the effect of oral cholecalciferol on arterial stiffness and blood pressure in healthy normotensive adults.
40 healthy adults were randomised in this double-blinded study to either oral cholecalciferol 3000 IU/day or matching placebo and were followed for 16 weeks to examine any effects on pulse wave velocity (PWV), augmentation index (AIx), peripheral and central blood pressure and 24-hour ambulatory blood pressure.
22 subjects in the cholecalciferol arm and 18 subjects in the placebo arm completed the 16 weeks of follow-up. There was no difference in changes in PWV, AIx corrected for heart rate or central or peripheral blood pressure between the two groups. There was no correlation between serum 25-hydroxy vitamin D and any of these parameters.
Oral cholecalciferol 3000 IU/day does not affect arterial stiffness or blood pressure after 16 weeks of treatment in healthy normotensive adults.
ClinicalTrials.gov NCT00952562.
Chronic kidney disease (CKD) is associated with high cardiovascular morbidity and mortality. Recent evidence suggests that increases in both serum and intracellular magnesium (Mg) can slow or even ...prevent the development of vascular calcification seen in CKD. Serum calcification propensity (
) is a novel functional test, which is associated with all-cause mortality in CKD and measures the ability of serum to delay the formation of crystalline nanoparticles. Theoretically, increasing serum Mg should improve
and thereby reduce the propensity towards ectopic calcification.
We conducted a randomized placebo-controlled double-blinded clinical trial to investigate the safety of 2 different doses of oral Mg supplementation in subjects with CKD stages 3 and 4 as well as their effects on intracellular Mg and
. Thirty-six subjects with CKD stages 3 and 4 were randomized to one of 3 groups (placebo, elemental Mg 15 mmol/d or elemental Mg 30 mmol/d) given as slow-release Mg hydroxide and followed for 8 weeks.
Thirty-four subjects completed the trial. Intracellular Mg remained stable throughout the trial despite significant increases in both serum and urine Mg.
increased significantly by 40 min from 256 ± 60 (mean ± SD) to 296 ± 64 minutes (95% confidence interval, 11-70,
< 0.05) in the Mg 30 mmol/d group after 8 weeks. No serious adverse events related to the study medication were reported during the study.
Oral Mg supplementation was safe and well tolerated in CKD stages 3 and 4 and improved
, but did not increase intracellular Mg. Further studies are needed to investigate the long-term effects of Mg supplementation in CKD stage 3 and 4 and whether improvement in calcification propensity is related to clinical endpoints.
Background
Low 25‐hydroxyvitamin D levels are associated with an increased risk of cardiovascular events, but the effect of vitamin D supplementation on markers of vascular function associated with ...major adverse cardiovascular events is unclear.
Methods and Results
We conducted a systematic review and individual participant meta‐analysis to examine the effect of vitamin D supplementation on flow‐mediated dilatation of the brachial artery, pulse wave velocity, augmentation index, central blood pressure, microvascular function, and reactive hyperemia index. MEDLINE, CINAHL, EMBASE, Cochrane Central Register of Controlled Trials, and http://www.ClinicalTrials.gov were searched until the end of 2016 without language restrictions. Placebo‐controlled randomized trials of at least 4 weeks duration were included. Individual participant data were sought from investigators on included trials. Trial‐level meta‐analysis was performed using random‐effects models; individual participant meta‐analyses used a 2‐stage analytic strategy, examining effects in prespecified subgroups. 31 trials (2751 participants) were included; 29 trials (2641 participants) contributed data to trial‐level meta‐analysis, and 24 trials (2051 participants) contributed to individual‐participant analyses. Vitamin D3 daily dose equivalents ranged from 900 to 5000 IU; duration was 4 weeks to 12 months. Trial‐level meta‐analysis showed no significant effect of supplementation on macrovascular measures (flow‐mediated dilatation, 0.37% 95% confidence interval, −0.23 to 0.97; carotid‐femoral pulse wave velocity, 0.00 m/s 95% confidence interval, −0.36 to 0.37); similar results were obtained from individual participant data. Microvascular function showed a modest improvement in trial‐level data only. No consistent benefit was observed in subgroup analyses or between different vitamin D analogues.
Conclusions
Vitamin D supplementation had no significant effect on most markers of vascular function in this analysis.
IntroductionDiabetic kidney disease is a severe complication of diabetes. The diagnosis is based on clinical characteristics such as persistently elevated albuminuria, hypertension and decline in ...kidney function, although this definition is not specific to kidney disease caused by diabetes. The only way to establish an accurate diagnosis—diabetic nephropathy—is by performing a kidney biopsy. The histological presentation of diabetic nephropathy can be associated with a heterogeneous range of histological features with many pathophysiological factors involved demonstrating the complexity of the condition. Current treatment strategies aim to slow disease progression and are not specific to the underlying pathological processes.This study will investigate the prevalence of diabetic nephropathy in individuals with type 2 diabetes (T2D) and severely elevated albuminuria. The deep molecular characterisation of the kidney biopsy and biological specimens may pave the way for improved diagnostic accuracy and a better understanding of the pathological processes involved and may also reveal new targets for individualised treatment.Methods and analysisIn the PRecIsion MEdicine based on kidney TIssue Molecular interrogation in diabetic nEphropathy 2 study, research kidney biopsies will be performed in 300 participants with T2D, urine albumin/creatinine ratio ≥700 mg/g and estimated glomerular filtration ratio >30 mL/min/1.73 m2. Cutting-edge molecular technologies will be applied to the kidney, blood, urine, faeces and saliva samples for comprehensive multi-omics profiling. The associated disease course and clinical outcomes will be assessed by annual follow-up for 20 years.Ethics and disseminationThe Danish Regional Committee on Health Research Ethics and the Knowledge Center on Data Protection (in the Capital Region of Denmark) have granted approval for the study. The results will be published in peer-reviewed journals.Trial registration numberNCT04916132.
IntroductionAtrial fibrillation is highly prevalent in patients on chronic dialysis. It is unclear whether anticoagulant therapy for stroke prevention is beneficial in these patients. Vitamin ...K-antagonists (VKA) remain the predominant anticoagulant choice. Importantly, anticoagulation remains inconsistently used and a possible benefit remains untested in randomised clinical trials comparing oral anticoagulation with no treatment in patients on chronic dialysis. The Danish Warfarin-Dialysis (DANWARD) trial aims to investigate the safety and efficacy of VKAs in patients with atrial fibrillation on chronic dialysis. The hypothesis is that VKA treatment compared with no treatment is associated with stroke risk reduction and overall benefit.Methods and analysisThe DANWARD trial is an investigator-initiated trial at 13 Danish dialysis centres. In an open-label randomised clinical trial study design, a total of 718 patients with atrial fibrillation on chronic dialysis will be randomised in a 1:1 ratio to receive either standard dose VKA targeting an international normalised ratio of 2.0–3.0 or no oral anticoagulation. Principal analyses will compare the risk of a primary efficacy endpoint, stroke or transient ischaemic attack and a primary safety endpoint, major bleeding, in patients allocated to VKA treatment and no treatment, respectively. The first patient was randomised in October 2019. Patients will be followed until 1 year after the inclusion of the last patient.Ethics and disseminationThe study protocol was approved by the Regional Research Ethics Committee (journal number H-18050839) and the Danish Medicines Agency (case number 2018101877). The trial is conducted in accordance with the Helsinki declaration and standards of Good Clinical Practice. Study results will be disseminated to participating sites, at research conferences and in peer-reviewed journals.Trial registration numbersNCT03862859, EUDRA-CT 2018-000484-86 and CTIS ID 2022-502500-75-00.
Increasing levels of magnesium in blood are associated with reduced risk of cardiovascular disease in chronic kidney disease (CKD). Magnesium supplementation may reduce the progression of vascular ...calcification in CKD. The diurnal pattern and effect of fasting on magnesium in blood and urine in CKD is unknown, and knowledge of this may influence management of magnesium supplementation.
We included ten patients with CKD stage four without diabetes mellitus and ten healthy controls. Participants were admitted to our hospital ward for a 24-h study period. Blood and urine samples were collected in a non-fasting state at 8 o'clock in the morning and every third hour hereafter until the final samples in a fasting state at 8 o'clock the following morning.
We found no diurnal variation in plasma magnesium (p = 0.097) in either group, but a significant diurnal variation in urinary excretion of magnesium (p = 0.044) in both CKD and healthy controls with no significant interaction between the two groups, and thus no suggestion that CKD affects diurnal variation of plasma magnesium or urinary magnesium excretion. The levels of plasma magnesium were not significantly different in fasting and non-fasting conditions.
Magnesium in plasma does not display a significant diurnal variation and can be measured at any time of day and in both fasting and non-fasting conditions. Urinary magnesium excretion displays diurnal variation, which is likely related to increased uptake of magnesium during meals and helps maintain a stable concentration of magnesium in blood.
•Magnesium is an important mineral of clinical relevance in chronic kidney disease.•Plasma magnesium does not exhibit a diurnal rhythm in chronic kidney disease.•Plasma magnesium is not influenced by fasting in chronic kidney disease.•Urinary magnesium displays a diurnal rhythm which likely maintains steady plasma magnesium.
Hyperphosphatemia is associated with increased morbidity and mortality in patients with chronic kidney disease. The aim of this study was to assess whether a meal with high phosphorus content would ...affect plasma phosphate in the hours that follow among subjects with end-stage kidney disease on peritoneal dialysis.
This was a single-blinded randomized cross-over trial of 12 subjects on maintenance peritoneal dialysis, in which subjects were randomized to consume a meal with either high or low phosphorus content on 2 separate trial days. On each trial day, plasma phosphate was measured immediately before consumption of the standardized meal and after 1, 2, 3, and 5 hours.
The mean fasting plasma phosphate at baseline was 1.69 ± 0.22 mmol/l. Plasma phosphate was similar between the 2 meals at baseline, as well as at 1, 2, 3, and 5 hours after consumption. The largest observed difference in plasma phosphate between the 2 meals was 0.15 mmol/l, which occurred 5 hours after consumption (high-phosphorus meal 1.75 ± 0.32 mmol/l vs. low-phosphorus meal 1.60 ± 0.14 mmol/l (P = 0.06)). Using summary analyses for repeated measures, we observed a significant difference in the plasma phosphate between the 2 meals (P = 0.03).
Our results show that in subjects with end-stage kidney disease, a meal with high phosphorus content has only a negligible effect on plasma phosphate compared to a meal with low phosphorus content. Thus, large increases in plasma phosphate cannot be accounted for by a high intake of phosphorus in the hours before blood sampling.
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Serum calcification propensity is a novel functional test that quantifies the functionality of the humeral system of calcification control. Serum calcification propensity is measured by T
, the time ...taken to convert from primary to secondary calciprotein particle in the serum. Lower T
represents higher calcification propensity and is associated with higher risk of cardiovascular events and death in patients with ESKD. Increasing magnesium in serum increases T
, but so far, no clinical trials have investigated whether increasing serum magnesium increases serum calcification propensity in subjects with ESKD.
We conducted a single-center, randomized, double-blinded, parallel group, controlled clinical trial, in which we examined the effect of increasing dialysate magnesium from 1.0 to 2.0 mEq/L for 28 days compared with maintaining dialysate magnesium at 1.0 mEq/L on T
in subjects undergoing hemodialysis for ESKD. The primary end point was the value of T
at the end of the intervention.
Fifty-nine subjects were enrolled in the trial, and of these, 57 completed the intervention and were analyzed for the primary outcome. In the standard dialysate magnesium group, T
was 233±81 minutes (mean±SD) at baseline (mean of days -7 and 0) and 229±93 minutes at follow-up (mean of days 21 and 28), whereas in the high dialysate magnesium group, T
was 247±69 minutes at baseline and 302±66 minutes at follow-up. The difference in T
between the two groups at follow-up (primary analysis) was 73 minutes (between-group difference; 95% confidence interval, 30 to 116;
<0.001), and the between-group difference in serum magnesium was 0.88 mg/dl (95% confidence interval, 0.66 to 1.10;
=0.001).
Increasing dialysate magnesium increases T
and hence, decreases calcification propensity in subjects undergoing maintenance hemodialysis.
This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_08_21_CJASNPodcast_18_9_B.mp3.
Abstract
Background
The formation of calciprotein particles (CPPs) may be an important component of the humoral defences against ectopic calcification. Although magnesium (Mg) has been shown to delay ...the transition of amorphous calcium-/phosphate-containing primary CPP (CPP-1) to crystalline apatite-containing secondary CPP (CPP-2) ex vivo, effects on the endogenous CPP pool are unknown.
Methods
We used post hoc analyses from a randomized double-blind parallel-group controlled clinical trial of 28 days treatment with high dialysate Mg of 2.0 mEq/L versus standard dialysate Mg of 1.0 mEq/L in 57 subjects undergoing maintenance hemodialysis for end-stage kidney disease. CPP load, markers of systemic inflammation and bone turnover were measured at baseline and follow-up.
Results
After 28 days of treatment with high dialysate Mg, serum total CPP (−52%), CPP-1 (−42%) and CPP-2 (−68%) were lower in the high Mg group (all P < 0.001) but were unchanged in the standard dialysate Mg group. Tumour necrosis factor-α (−20%) and interleukin-6 (−22%) were also reduced with high dialysate Mg treatment (both P < 0.01). High dialysate Mg resulted in higher levels of bone-specific alkaline phosphatase (a marker of bone formation) (+17%) but lower levels of tartrate-resistant acid phosphatase 5 b (a marker of bone resorption; −33%) (both P < 0.01). Inflammatory cytokines and bone turnover markers were unchanged in the standard dialysate Mg group over the same period.
Conclusions
In this exploratory analysis, increasing dialysate Mg was associated with reduced CPP load and systemic inflammation and divergent changes in markers of bone formation and resorption.
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