No Detectable Coagulation Activation After Vitamin K (MK-7) Supplementation in Patients on Dialysis With Functional Vitamin K Deficiency: A One-Year Randomized, Placebo-Controlled Study.

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.

Vitamin K supplementation and bone mineral density in dialysis: results of the double-blind, randomized, placebo-controlled RenaKvit trial.

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.

Vitamin K supplementation and arterial calcification in dialysis: results of the double-blind, randomized, placebo-controlled RenaKvit trial.

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.

Effect of Vitamin D Supplementation on Markers of Vascular Function: A Systematic Review and Individual Participant Meta-Analysis.

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.

Randomized controlled trial of cholecalciferol supplementation in chronic kidney disease patients with hypovitaminosis D.

BACKGROUND: Hypovitaminosis D is common in chronic kidney disease (CKD). Effects of 25-hydroxyvitamin D replenishment in CKD are not well described. METHODS: An 8-week randomized, placebo-controlled, double-blind parallel intervention study was conducted in haemodialysis (HD) and non-HD CKD patients. Treatment consisted of 40,000 IU of cholecalciferol orally per week. Plasma 25-hydroxyvitamin D (25-OHD), plasma 1,25-dihydroxyvitamin D (1,25-diOHD), plasma parathyroid hormone (PTH), serum phosphate, ionized serum calcium and serum fibroblast growth factor 23 (FGF-23) were analysed. We also investigated biomarkers related to cardiovascular disease (plasma D-dimer, plasma fibrinogen, plasma von Willebrand factor antigen and activity, plasma interleukin 6, plasma C-reactive protein, blood pressure, aortic augmentation index, aortic pulse wave velocity and 24-h urinary protein loss). Objective and subjective health variables were assessed (muscle function tests, visual analogue scores and Health Assessment Questionnaire). RESULTS: Fifty-two CKD patients with 25-OHD <50 nmol/L at screening were included. Cholecalciferol supplementation led to a significant increase to a median of 155 nmol/L 25-OHD (interquartile range 137-173 nmol/L) in treated patients (n = 25, P < 0.001). In non-HD patients, we saw a significant increase in 1,25-diOHD (n = 13, P < 0.01) and a lowering of PTH (n = 13, P < 0.001). This was not observed in HD patients. Cholecalciferol supplementation caused a significant increase in serum calcium and FGF-23. CONCLUSIONS: 25-OHD replenishment was effectively obtained with the employed cholecalciferol dosing. In non-HD patients, it had favourable effects on 1,25-diOHD and PTH. Vitamin D-supplemented patients must be monitored for hypercalcaemia. The present study could not identify significant pleiotropic effects of 25-OHD replenishment.

Vitamin d and stage 5 chronic kidney disease: a new paradigm?

Vitamin D receptor agonists (VDRA) are currently recommended for the treatment of secondary hyperparathyroidism in stage 5 CKD. They are considered to be contraindicated in the presence of low or normal (for a dialysis patient) levels of PTH due to the risk of developing adynamic bone disease, with consequent vascular calcification. However, these recommendations are increasingly at odds with the epidemiological evidence, which consistently shows a large survival advantage for patients treated with low-dose VDRAs, regardless of plasma calcium, phosphate, or PTH. A large number of pleiotropic effects of vitamin D have been described, including inhibition of renin activity, anti-inflammation, and suppression of vascular calcification stimulators and stimulation of vascular calcification inhibitors present in the uremic milieu. Laboratory studies suggest that a normal cellular vitamin D level is necessary for normal cardiomyocyte and vascular smooth muscle function. While pharmacological doses of VDRA can be harmful, the present evidence suggests that the level of 1,25-dihydroxycholecalciferol should also be more physiological in stage 5 CKD, and that widespread use of low-dose VDRA would be beneficial. A randomized controlled trial to test this hypothesis is warranted.

No difference between alfacalcidol and paricalcitol in the treatment of secondary hyperparathyroidism in hemodialysis patients: a randomized crossover trial.

Alfacalcidol and paricalcitol are vitamin D analogs used for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease, but have known dose-dependent side effects that cause hypercalcemia and hyperphosphatemia. In this investigator-initiated multicenter randomized clinical trial, we originally intended two crossover study periods with a washout interval in 86 chronic hemodialysis patients. These patients received increasing intravenous doses of either alfacalcidol or paricalcitol for 16 weeks, until parathyroid hormone was adequately suppressed or calcium or phosphate levels reached an upper threshold. Unfortunately, due to a period effect, only the initial 16-week intervention period for 80 patients was statistically analyzed. The proportion of patients achieving a 30% decrease in parathyroid hormone levels over the last four weeks of study was statistically indistinguishable between the two groups. Paricalcitol was more efficient at correcting low than high baseline parathyroid hormone levels, whereas alfacalcidol was equally effective at all levels. There were no differences in the incidence of hypercalcemia and hyperphosphatemia. Thus, alfacalcidol and paricalcitol were equally effective in the suppression of secondary hyperparathyroidism in hemodialysis patients while calcium and phosphorus were kept in the desired range.

Effects of unsaturated fat dietary supplements on blood lipids, and on markers of malnutrition and inflammation in hemodialysis patients.

OBJECTIVE: We examined the effects of commercially available unsaturated fat dietary supplements on blood lipids, and on markers of malnutrition and inflammation, in an adult population of hemodialysis (HD) patients. DESIGN: This was a restricted, randomized (equal blocks), investigator-blinded 2x6 week crossover trial, without a washout interval. SETTING: This study was conducted at the Department of Nephrology, Copenhagen University Hospital Herlev, Herlev, Denmark, in spring 2007. PATIENTS: Participants included 40 (30 males and 10 females) stable, adult patients undergoing regular HD, with a mean age of 64.6 years and a mean body mass index of 23.3kg/m(2). INTERVENTION: In addition to patients' habitual diets, oral unsaturated fat supplements (90mL of Calogen [SHS International, Ltd., Liverpool, UK] and 4 capsules of Pikasol [Dansk Droge, Ishoej, Denmark]) were given in one period, whereas no supplements were given in the other. Dietary supplements contributed 1.8 MJ (430kcal), 47g fat, 26.5g monounsaturated fatty acids, and 3g marine n-3 polyunsaturated fatty acids per day. Blood sampling and nutritional assessments were performed at baseline, after 6 weeks, and after 12 weeks. MAIN OUTCOME MEASURES: Dietary intakes, blood lipids, dry body weight, serum albumin, and serum C-reactive protein comprised our main outcome measures. RESULTS: According to a per-protocol analysis of 14 study completers, fat supplementation resulted in significantly increased total energy intake (+1.6 MJ/day, or 380kcal/day) and an increased dietary fat energy percentage (+9%). We observed no significant changes in blood lipids. Dry body weight (+0.49kg, P=.04) increased, and serum C-reactive protein concentration fell (-1.69mg/L, P=.01), with fat supplementation. Intention-to-treat analysis of 39 participants confirmed the absence of adverse blood-lipid changes. CONCLUSIONS: Unsaturated fat supplementation increased total dietary energy intake to recommended levels, had no adverse impact on blood lipids, improved nutritional status as assessed according to dry body weight, and reduced systemic inflammation as assessed according to C-reactive protein serum concentrations. Adding unsaturated fat to the diet seems to be a safe and effective way to prevent and treat malnutrition in hemodialysis patients.

Vitamin D status in kidney transplant patients: need for intensified routine supplementation.

BACKGROUND: A high prevalence of vitamin D insufficiency has been found in the general population and in patients with chronic kidney disease. OBJECTIVE: The aim was to examine vitamin D status and determinants and metabolic correlates of serum 25-hydroxyvitamin D in a population of adult Danish kidney transplant patients. DESIGN: This was a cross-sectional study of 173 adult kidney transplant patients with a mean (+/-SD) age of 53.4 +/- 11.7 y and a median graft age of 7.4 y (interquartile range: 3.3-12.7 y). Serum concentrations of intact parathyroid hormone (S-PTH), 25-hydroxyvitamin D [S-25(OH)D], and 1,25-dihydroxyvitamin D [S-1,25(OH)(2)D] were measured. Dietary and supplementary intake of vitamin D, avoidance of solar ultraviolet B exposure, and selected lifestyle factors were assessed in a subgroup (n = 97). RESULTS: Fifty-one percent of the patients had vitamin D insufficiency [S-25(OH)D 40-75 nmol/L], and an additional 29% had moderate-to-severe vitamin D deficiency [S-25(OH)D < or = 39 nmol/L]. In multiple regression analysis, sun avoidance (negative association) and vitamin D supplementation (positive association) were independent determinants of S-25(OH)D concentrations. Low S-25(OH)D concentrations were associated with 1) increased S-PTH concentrations (P = 0.0002), independently of S-1,25(OH)(2)D concentrations, and 2) decreased S-1,25(OH)(2)D concentrations (P = 0.002), independently of graft function. CONCLUSIONS: Hypovitaminosis D is common among Danish kidney transplant patients and is associated with reduced concentrations of S-1,25(OH)(2)D and increased S-PTH concentrations. Sun avoidance and vitamin D supplementation are important determinants of vitamin D status. The observed hypovitaminosis D might be corrected by intensified routine vitamin D supplementation as opposed to the current supplementation practice.

Case-control study of gadodiamide-related nephrogenic systemic fibrosis.

BACKGROUND: Nephrogenic systemic fibrosis may be caused by gadolinium (Gd)-containing magnetic resonance imaging contrast agents. Most reported cases were associated with one particular agent, gadodiamide. Yet, unidentified cofactors might explain why only a minority of renal failure patients exposed to gadodiamide develop nephrogenic systemic fibrosis. METHODS: We conducted a case-control study of 19 histologically verified cases and 19 sex- and age-matched controls. All subjects had chronic renal failure when exposed to gadodiamide. Clinical, biochemical and pharmacological data were retrieved from medical records. RESULTS: Cases had been exposed to a mean gadodiamide dose of 0.29 mmol/kg (range 0.18-0.50) shortly before first signs of nephrogenic systemic fibrosis. Controls had been exposed to 0.28 mmol/kg (0.13-0.49). Cumulative gadodiamide exposure while in chronic kidney disease stage 5 was significantly higher among cases compared with controls (0.41 vs 0.31 mmol/kg, P = 0.05) and among severe cases (n = 9) compared with non-severe cases (0.49 vs 0.33 mmol/kg, P = 0.02). Severe cases developed primarily among patients in regular haemodialysis therapy at exposure. Cases had higher serum concentrations of ionized calcium and phosphate than controls and tended to receive higher doses of epoietin-beta than controls at time of exposure. Severe cases were treated with higher doses of epoietin-beta than non-severe cases at exposure (10.8 vs 4.4 10(3) IU/week, P = 0.02). CONCLUSIONS: Increasing cumulative gadodiamide exposure, high-dose epoietin-beta treatment, and higher serum concentrations of ionized calcium and phosphate increase the risk of gadodiamide-related nephrogenic systemic fibrosis in renal failure patients. Severe cases seem to develop primarily among patients in regular haemodialysis therapy at exposure.

Effect of garlic (Allium sativum) powder tablets on serum lipids, blood pressure and arterial stiffness in normo-lipidaemic volunteers: a randomised, double-blind, placebo-controlled trial.

Recent studies have cast doubt on the proposed lipid-lowering and blood pressure-lowering effects of garlic. We tested the effect of dried garlic (Allium sativum) powder on blood lipids, blood pressure and arterial stiffness in a 12-week randomised, double-blind, placebo-controlled trial. Seventy-five healthy, normo-lipidaemic volunteers (men and women aged 40-60 years) were assigned to dried garlic powder tablets (10.8 mg alliin (3-(2-propenylsulfinyl)-L-alanine)/d, corresponding to about three garlic cloves) or placebo. Sixty-two subjects were eligible for the per-protocol analysis. The primary outcome measure was serum total cholesterol concentration. Secondary outcome measures were LDL-cholesterol, HDL-cholesterol and triacylglycerol concentrations, blood pressure and arterial stiffness (assessed by pulse wave velocity). No significant differences between the garlic and placebo groups were detected for any of the outcome measures. However, garlic powder was associated with a near-significant decrease (12 %) in triacylglycerol concentration (P=0.07). In conclusion, garlic powder tablets have no clinically relevant lipid-lowering and blood pressure-lowering effects in middle-aged, normo-lipidaemic individuals. The putative anti-atherosclerotic effect of garlic may be linked to risk markers other than blood lipids.

Effect of fish oil versus corn oil supplementation on LDL and HDL subclasses in type 2 diabetic patients.

OBJECTIVE: The increased risk of coronary heart disease associated with type 2 diabetes may be partially explained by dyslipidemia characterized by high plasma triacylglycerol (TAG), low HDL cholesterol, and a predominance of atherogenic small dense LDLs. Fish oil reduces plasma TAG and has previously been shown to improve the distribution of LDL subclasses in healthy subjects and might, therefore, be a good nonpharmacological treatment for type 2 diabetic patients. In the present study, we investigate the effect of fish oil supplementation on the fasting lipid profile, including LDL and HDL subclasses. RESEARCH DESIGN AND METHODS: A total of 42 type 2 diabetic patients were randomized to supplementation (capsules) with 4 g daily of either fish oil (n = 20) or corn oil (n = 22) for 8 weeks preceded by a 4-week run-in period of corn oil supplementation. Blood was drawn before and after the 8-week intervention period. Plasma lipoproteins, including LDL and HDL subclasses, were separated by ultracentrifugation. RESULTS: Fish oil lowered TAG (group difference: P = 0.025) and raised HDL-2b cholesterol (P = 0.012) and HDL-2a cholesterol (P = 0.007) concentrations as compared with corn oil. We observed no significant effects of fish oil on LDL cholesterol, HDL cholesterol, or the concentration of small dense LDL particles. CONCLUSIONS: Fish oil supplementation may partially correct the dyslipidemia of type 2 diabetic patients. However, the putative very important aspect of diabetic dyslipidemia-the predominance of small dense LDL particles-was unaffected by fish oil.

Different effects of diets rich in olive oil, rapeseed oil and sunflower-seed oil on postprandial lipid and lipoprotein concentrations and on lipoprotein oxidation susceptibility.

Elevated concentrations of fasting and non-fasting triacylglycerol-rich lipoproteins (TRL) as well as oxidative changes of lipoproteins may increase the risk of ischaemic heart disease. To compare the effects of different diets rich in unsaturated fatty acids on the concentrations and in vitro oxidation of fasting and postprandial lipoproteins eighteen males consumed diets enriched with rapeseed oil (RO), olive oil (OO), or sunflower-seed oil (SO) in randomised order for periods of 3 weeks followed by a RO test meal. In the postprandial state the concentrations of cholesterol and triacylglycerol (TAG) in TRL were higher after consumption of OO compared with RO and SO (P<0.04), possibly related to differences in the fasting state. The propagation rates for VLDL and LDL oxidation were higher in the postprandial compared with the fasting state irrespective of diet. In the fasting state, the propagation rates were highest after SO (P<0.001), and in the postprandial state, SO gave rise to a shorter VLDL lag time (P=0.03) and a higher propagation rate than OO consumption (P=0.04). Overall, the SO diet resulted in a higher postprandial propagation rate of LDL (P<0.001) compared with RO and OO, while there was no effect of diet on LDL oxidation lag time. Our results suggest that RO and SO diets lower the postprandial cholesterol and TAG concentrations compared with OO, while RO and OO diets result in similar and lower in vitro susceptibility to oxidation of lipoproteins than SO.