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Objective: Patients on dialysis treatment have poor functional vitamin K status, and this may increase the risk of vascular calcification. Vitamin K supplementation may therefore be relevant in patients on dialysis, but the procoagulant effects have not been studied. We evaluated effects of menaquinone-7 (MK-7) supplementation on biomarkers of coagulation in patients on dialysis., Methods: Double-blinded, placebo-controlled study in 123 patients on dialysis randomized to 52 weeks of vitamin K (MK-7, 360 μg/daily, n = 61) or placebo (n = 62). Measurements at baseline and after 52 weeks of intervention included thrombin generation (endogenous thrombin potential, peak thrombin concentration, time to peak, and lag time); clot activities of vitamin K-dependent coagulation factors (F) II, VII, IX, and X; prothrombin fragment 1 + 2 (F1+2); and proteins induced by vitamin K absence II (PIVKA-II). Between-group differences (vitamin K vs. placebo) at 52 weeks were determined with an analysis of covariance. Within-group changes in vitamin K and placebo groups were analyzed with a paired t-test. Vascular adverse events and serious adverse events were registered based on hospital records, laboratory data, and participant interviews and compared between groups using Fisher's exact test or Pearson's Chi-Squared test., Results: A between-group difference at 52 weeks was observed for PIVKA-II (P < .001). PIVKA-II decreased significantly from baseline to 52 weeks in the vitamin K group, but not in the placebo group. We observed no between-group differences or within-group changes for biomarkers of coagulation, except for FVII clot activity which was reduced in the placebo group (P = .04), and no between-group differences in adverse events and serious adverse events., Conclusion: One year of vitamin K supplementation in patients on dialysis has no detectable effects on biomarkers of coagulation activation, clot activities of vitamin K-dependent coagulation factors, and vascular events or death, indicating no procoagulant effects of this treatment., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Extent and progression of coronary artery calcification (CAC) are strong predictors of myocardial infarction and mortality., Objectives: This study aims to investigate if vitamin K2 and D supplementation can reduce CAC progression., Methods: A total of 389 participants were randomized to supplementation with vitamin K2 (720 μg/day) and D (25 μg/day) vs placebo in a multicenter double-blinded randomized controlled trial. The primary endpoint (progression of aortic valve calcification) has been reported. This study reports CAC progression in participants with no ischemic heart disease. CT scans were performed at baseline, 12, and 24 months. ΔCAC and coronary plaque volume were evaluated in the entire group and in 2 subgroups. A safety endpoint was the composite of myocardial infarction, coronary revascularization, and all-cause mortality., Results: In total, 304 participants (male, mean age 71 years) were identified. The intervention and placebo group both increased in mean CAC scores from baseline to 24-month follow-up (Δ203 vs Δ254 AU, P  = 0.089). In patients with CAC scores ≥400 AU, CAC progression was lower by intervention (Δ288 vs Δ380 AU, P  = 0.047). Plaque analyses showed no significant difference in progression of noncalcified plaque volume (Δ-6 vs Δ46 mm 3 , P  = 0.172). Safety events were fewer in participants receiving supplementation (1.9% vs 6.7%, P  = 0.048)., Conclusions: Patients with no prior ischemic heart disease randomized to vitamin K2 and D supplementation had no significant reduction in mean CAC progression over a 2-year follow-up compared to placebo. Although the primary endpoint is neutral, differential responses to supplementation in those with CAC scores ≥400 AU and in safety endpoints are hypothesis-generating for future studies., Competing Interests: Study execution was supported by unrestricted grants from the 10.13039/100007405Danish Heart Foundation (grant No. 17-R116-A7569-22071), the Region of Southern Denmark’s Research Council (grant No. 17/15638), and the 10.13039/501100009708Novo Nordisk Foundation (grant No. NNF17OC0029076). Salary for the investigator Dr Hasific was supported by grants from the Danish Cardiovascular Academy funded by the 10.13039/501100009708Novo Nordisk Foundation (grant No. NNF20SA0067242), the 10.13039/100007405Danish Heart Association, and the Region of Southern Denmark’s Research Council. The study tablets, including placebo, were provided free of charge by Kappa Bioscience, Norway, and Orkla Care, Denmark. The funders had no influence on the design or conduct of the trial and were not involved in data collection or analysis, in the writing of the article, or in the decision to submit for publication. Dr Diederichsen has served as an expert on a Generally Recognized as Safe panel to review the safety of vitamin K2 and its proposed use in foods in the United States. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Background: Vitamin K deficiency is highly prevalent in patients on dialysis and may contribute to their low bone mineral density (BMD) and increased risk of fracture. This study investigated the effect of menaquinone-7 (MK-7) supplementation on BMD in patients on chronic dialysis., Methods: In a multicentre, double-blind, placebo-controlled intervention trial, 123 patients on chronic dialysis were randomised to a daily oral supplement of either MK-7 360 µg or placebo for 2 years. BMD of the distal radius (1/3, mid, ultradistal and total), femoral neck, lumbar spine (L1-L4) and whole body was assessed by dual-energy X-ray absorptiometry. Serum levels of vitamin K1 and MK-7 and plasma levels of total osteocalcin, dephosphorylated-uncarboxylated matrix Gla protein and protein induced by vitamin K absence II were measured to assess vitamin K status., Results: After 2 years, an accelerated BMD loss of the 1/3 distal radius was found with MK-7 supplementation {mean difference of changes relative to placebo -0.023 g/cm2 [95% confidence interval (CI) -0.039 to -0.008]}, whereas the decrease in lumbar spine BMD seen in the placebo group was prevented [mean difference of changes between groups 0.050 g/cm2 (95% CI 0.015-0.085)]. No significant effects were observed at the remaining skeletal sites. Vitamin K status strongly improved in MK-7-supplemented participants., Conclusion: Compared with placebo, an accelerated BMD loss of the 1/3 distal radius was found after 2 years of MK-7 supplementation, whereas a decline in lumbar spine BMD was prevented. As such, MK-7 supplementation might modify BMD site-specifically in patients on dialysis. In aggregate, our findings do not support MK-7 supplementation to preserve bone in patients on dialysis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Background: Arterial calcification is associated with cardiovascular mortality in dialysis patients. Active matrix Gla protein (MGP) is a vitamin K-dependent inhibitor of arterial calcification. Elevated plasma concentrations of inactive MGP, i.e. dephosphorylated-uncarboxylated MGP (dp-ucMGP), are prevalent in dialysis patients. MGP inactivity might contribute to arterial calcification. We investigated whether vitamin K supplementation had an effect on arterial calcification in chronic dialysis patients., Methods: In a 2-year, double-blind, placebo-controlled intervention trial, 48 dialysis patients were randomized to vitamin K [menaquinone-7 (MK-7), 360 µg daily] or placebo. MK-7 in serum and dp-ucMGP in plasma were used to assess vitamin K status. Carotid-femoral pulse wave velocity (cfPWV) and scores of coronary arterial calcification (CAC) and abdominal aortic calcification (AAC) were used to assess arterial calcification., Results: Thirty-seven participants completed Year 1, and 21 completed Year 2. At Year 2, serum MK-7 was 40-fold higher, and plasma dp-ucMGP 40% lower after vitamin K supplementation compared with placebo {mean dp-ucMGP difference: -1380 pmol/L [95% confidence interval (CI) -2029 to -730]}. There was no significant effect of vitamin K supplementation on cfPWV [mean difference at Year 2: 1.2 m/s (95% CI -0.1 to 2.4)]. CAC Agatston score increased significantly in vitamin K supplemented participants, but was not significantly different from placebo [mean difference at Year 2: 664 (95% CI -554 to 1881)]. AAC scores increased in both groups, significantly so within the placebo group at Year 1, but with no significant between-group differences., Conclusions: Vitamin K supplementation improved vitamin K status, but did not hinder or modify the progression of arterial calcification in dialysis patients., (© The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA.)

Introduction: Aortic stenosis is a common heart valve disease, and due to the growing elderly population, the prevalence is increasing. The disease is progressive with increasing calcification of the valve cusps. A few attempts with medical preventive treatment have failed; thus, presently, the only effective treatment of aortic stenosis is surgery. This study will examine the effect of menaquinone-7 (MK-7) supplementation on progression of aortic valve calcification (AVC). We hypothesise that MK-7 supplementation will slow down the calcification process., Methods and Analysis: In this multicenter and double-blinded, placebo-controlled study, 400 men aged 65-74 years with substantial AVC are randomised (1:1) to treatment with MK-7 (720 µg/day) supplemented by the recommended daily dose of vitamin D (25 µg/day) or placebo treatment (no active treatment) for 2 years. Exclusion criteria are treatment with vitamin K antagonist or coagulation disorders. To evaluate AVC score, a non-contrast CT scan is performed at baseline and repeated after 12 and 24 months of follow-up. Primary outcome is difference in AVC score from baseline to follow-up at 2 years. Intention-to-treat principle is used for all analyses., Ethics and Dissemination: There are no reported adverse effects associated with the use of MK-7. The protocol is approved by the Regional Scientific Ethical Committee for Southern Denmark (S-20170059) and the Data Protection Agency (17/19010). It is conducted in accordance with the Declaration of Helsinki. Positive as well as negative findings will be reported., Trial Registration Number: NCT03243890., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: 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., Methods: 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., Results: 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., Conclusions: Oral cholecalciferol 3000 IU/day does not affect arterial stiffness or blood pressure after 16 weeks of treatment in healthy normotensive adults., Trial Registration: ClinicalTrials.gov NCT00952562.

Background and Aims: Maintenance dialysis patients are at increased risk of abnormal nutritional status due to numerous causative factors, both nutritional and non-nutritional. The present study assessed the current prevalence of protein-energy wasting, low lean body mass index and obesity in maintenance dialysis patients, and compared different methods of nutritional assessment., Methods: In a cross-sectional study conducted in 2014 at Roskilde Hospital, Denmark, we performed anthropometry (body weight, skinfolds, mid-arm, waist, and hip circumferences), and determined plasma albumin and normalized protein catabolic rate in order to assess the prevalence of protein-energy wasting, low lean body mass index and obesity in these patients., Results: Seventy-nine eligible maintenance dialysis patients participated. The prevalence of protein-energy wasted patients was 4% (95% CI: 2-12) as assessed by the coexistence of low lean body mass index and low fat mass index. Low lean body mass index was seen in 32% (95% CI: 22-44). Obesity prevalence as assessed from fat mass index was 43% (95% CI: 32-55). Coexistence of low lean body mass index and obesity was seen in 10% (95% CI: 5-19). The prevalence of protein-energy wasting and obesity varied considerably, depending on nutritional assessment methodology., Conclusions: Our data indicate that protein-energy wasting is uncommon, whereas low lean body mass index and obesity are frequent conditions among patients in maintenance dialysis. A focus on how to increase and preserve lean body mass in dialysis patients is suggested in the future. In order to clearly distinguish between shortage, sufficiency and abundance of protein and/or fat deposits in maintenance dialysis patients, we suggest the simple measurements of lean body mass index and fat mass index.

Background: Vitamin D repletion with high doses of vitamin D is often recommended to patients and healthy subjects. The safety, especially concerning changes in urinary calcium excretion is of great importance., Methods: In a double-blinded, placebo-controlled study in 40 healthy volunteers, we examined the changes in mineral metabolism during supplementation with 3000 IU of oral cholecalciferol daily during 4 months., Results: Both 25(OH)vitamin D and 1,25(OH)2vitamin D increased significantly in the active treated group as compared to the placebo group (186% versus 14% (P<0.001) and 28% versus -8% (P<0.001)). No change was observed in urinary calcium excretion in the active group compared to the placebo group (P = 0.891). Fibroblast growth factor 23 increased significantly by 10% (P<0.018) in the active group. However, there was no difference in changes in FGF23 between treatment groups (P = 0.457)., Conclusion: High dose cholecalciferol significantly increases 25(OH)vitamin D and 1,25(OH)2vitamin D levels compared to placebo. No changes in urinary calcium excretion or other measured components of the mineral metabolism were found between groups., Trial Registration: ClinicalTrials.gov NCT00952562.

Background: Peritoneal dialysis is associated with changes in membrane function that can lead eventually to ultrafiltration (UF) failure. Factors driving these changes are thought to include hypertonic glucose exposure, but previously reported associations are confounded by the presence of residual renal function., Methods: Longitudinal membrane function (solute transport and UF capacity) were measured annually in a prospective cohort of 177 functionally anuric patients as part of the European Automated Peritoneal Dialysis Outcomes Study (EAPOS). Subgroup analysis was performed according to glucose exposure and icodextrin use at baseline., Results: The whole cohort experienced an increase in solute transport and reduction in UF capacity at 12 and 24 months that could not be explained by informative censoring. These changes were accelerated and more severe in patients using either 2.27% or 3.86% glucose, or those not using icodextrin at baseline. These differences could not be explained by age, comorbidity score, previous time spent on renal replacement, differential dropout from the study, peritonitis rates, or, by definition, residual renal function. Patients using icodextrin at baseline had worse membrane function and were more likely to be diabetic. There was an association between membrane function changes and achieved 24-hour ultrafiltration over the 2-year study period., Conclusion: Anuric automated peritoneal dialysis (APD) patients experience significant detrimental changes in membrane function over a relatively short time period. Glucose appears to enhance these changes independent of residual renal function. Icodextrin use in these circumstances is associated with less deterioration in membrane function.

Background: In the last 10 years several reports have linked oral 5-aminosalicylic acid (5-ASA) therapy to acute and chronic tubulointerstitial nephritis, but to our knowledge only 2 patients have been reported with terminal end-stage renal disease due to mesalazine (5-ASA). After 1 year of treatment with 5-ASA annual monitoring of serum creatinine is recommended., Results: We report the development of end-stage renal disease in a patient 10 months after the last assessment of serum creatinine, which was normal at 71 micromol/l., Conclusion: Because of this dangerous side effect, we would like to recommend 6-monthly assessment of renal function., (Copyright 2002 S. Karger AG, Basel)

This paper assesses the feasibility of using a double blind controlled clinical trial to evaluate the function of a decision support system by applying such a design to the evaluation of a Diabetes Advisory System (DIAS). DIAS is based on a model of the human carbohydrate metabolism and is designed an interactive clinical tool, which can be used to predict the effects of changes in insulin dose or food intake on the blood glucose concentration in patients with insulin dependent diabetes. It can also be used to identify risk periods for hypoglycaemia. and to provide advice on insulin dose. The latter feature was evaluated in the present study. We believe double blind controlled clinical trials are prerequisites for clinical application of many decision support systems, and conclude that the present double blind controlled clinical trial is a suitable evaluation method for the function of DIAS.

A prospective, randomized, double-blind, placebo-controlled international multicenter trial including 188 newly diagnosed insulin-dependent diabetic (IDDM) patients was undertaken with the aim of investigating whether immunosuppression for one year with ciklosporin (Cs) could induce and maintain clinical remission and improvement of beta-cell function. The relative odds for non-insulin-requiring remission at one year were increased approximately five times in the Cs-treated group. After three months Cs-treated patients achieved more than a doubling of beta-cell function compared to baseline than did placebo-treated patients, and the Cs-treated group maintained this improvement in beta-cell function for 12 months, whereas the placebo-group lost beta-cell function during the same period. Short duration of disease (less than or equal to six weeks of symptoms, less than or equal to two weeks of insulin treatment) was associated positively with remission, as was an elevated proinsulin/C-peptide ratio, especially in patients with the tissue-type HLA-DR 3,4; 4,X and X,X. Cs-treatment inhibited the formation of antibodies against insulin and islet cell components, but islet cell antibody status at entry was not predictive of remission. Cs-treatment caused a reversible decrement of kidney function as measured with serum creatinine and the calculated creatinine clearance, but studies of renal physiology and kidney biopsies performed on a limited subset of patients indicated that Cs treatment in IDDM patients for one year induced a slight chronic nephropathy in some of these.(ABSTRACT TRUNCATED AT 250 WORDS)

Malignant mesenchymoma of the left atrium obstructing the mitral orifice was revealed at autopsy in a 39-year-old woman with a history indicating mitral stenosis. Minor tumour nodules were found in the walls of the right and left ventricle together with a few distant metastases. Clinical findings in primary cardiac tumours and the rarity of primary malignant mesenchymoma of the heart are discussed.

Six patients with Graves' ophthalmopathy (2 with acute and 4 with chronic alterations) were treated with cyclosporin A (10 mg/kg/day) for 5 weeks. This treatment had no effect on either the ocular manifestations (protrusion, eye muscle function) or subjective well-being of the patients. In contrast, creatinine clearance decreased from 83.5 to 55.5 ml/min during treatment, but normalized (94.9 ml/min) after cessation of the drug. A transient increase in serum 4-androstenedione was observed in 3 patients. We conclude that cyclosporin A has no convincing effect in the treatment of Graves' ophthalmopathy, but rather exerts serious renal effects.

A case of primary amyloidosis is presented with diffusely involved the alveolar septa. The lung was studied by light microscopy and by transmission and scanning electron microscopy. The fine structure of the amyloid material showed it to be porous, homogeneous, and an acellular substance consisting of interwoven bundles of amyloid fibrils. The fine structure of the amyloid material was considered to explain the normal gas diffusion across the alveolar respiratory membrane. The diagnosis of amyloidosis was first made from a uterine cervical biopsy specimen.

The contention that cyclosporin A (CyA) nephrotoxicity may be due to renal afferent arteriolar constriction was inferred from rat studies showing CyA to increase renal vascular resistance, to reduce glomerular filtration rate (GFR) and delivery of tubular fluid from the end of the proximal tubule to the loop of Henle (Vprox), and to increase proximal fractional reabsorption. In order to test whether the mechanism of human CyA nephrotoxicity is similar to its rat analogue, and whether CyA treatment causes prolonged renal malfunction after drug withdrawal, renal function was investigated with clearance techniques including lithium clearance (CLi) as a measure of Vprox. The subjects were patients (n = 11) with previously normal renal function, given CyA in the treatment of ocular manifestation of extrarenal disease, or bone-marrow transplant recipients. Nine out of these eleven patients were investigated before and during CyA treatment: GFR (P less than 0.05) and Vprox (P less than 0.005) decreased while proximal fractional reabsorption increased (P less than 0.01). In six patients investigated before CyA was given, and re-examined a mean of 273 days (range 84-384 days) after CyA withdrawal, CLi was reduced (P less than 0.05) while mean GFR was not significantly lowered (0.5 greater than P greater than 0.2). In one of these six patients GFR was reduced to a subnormal value of 26 ml min-1 (1.73 m2 body surface)-1. In conclusion, human and rat CyA nephrotoxicity have the same pattern of renal functional deterioration. Cyclosporin A nephrotoxicity was evident in patients investigated a mean of 9 months after CyA withdrawal.