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.

Non-adherence to established dietary guidelines associated with increased mortality: the Copenhagen General Population Study.

AIMS: The relevance of adherence to established dietary guidelines is repeatedly challenged. We hypothesised that non-adherence to established dietary guidelines is associated with an excess risk of cardiovascular, non-cardiovascular and all-cause mortality. METHODS: We studied 100,191 white adult Danes aged 20-100 years recruited in 2003-2015 and followed up until December 2018. During follow-up equalling 865,600 person-years, 9273 individuals died. Participants' diets were assessed at baseline by a food frequency questionnaire focusing on key foods defining a healthy diet according to Danish dietary guidelines. Individuals were divided into five categories ranging from very high to very low adherence to dietary guidelines and studied with Cox and Fine-Gray regression models. At study inclusion, we collected demographic and lifestyle characteristics by questionnaire, made a physical examination and took a blood sample. RESULTS: Cardiovascular, non-cardiovascular and all-cause mortality increased gradually with increasing non-adherence to dietary guidelines. Cardiovascular mortality was 30% higher (95% confidence interval 7-57%), non-cardiovascular mortality 54% higher (32-79%) and all-cause mortality 43% higher (29-59%) in individuals with very low adherence to dietary guidelines compared with those with very high adherence after adjustments for age, sex, education, income, smoking, leisure time physical activity and alcohol intake. Mortality risk estimates were similar in all strata of adjusted variables. CONCLUSION: Non-adherence to Danish food-based dietary guidelines is associated with up to 43% increased all-cause mortality in a dose-response manner. The mortality excess was seen for both cardiovascular and non-cardiovascular causes. The public has good reasons to have confidence in and to adhere to established dietary guidelines.

Global prevalence of protein-energy wasting in kidney disease: A meta-analysis of contemporary observational studies from the international society of renal nutrition and metabolism

Objective: To better define the prevalence of protein-energy wasting (PEW) in kidney disease is poorly defined. Methods: We performed a meta-analysis of PEW prevalence from contemporary studies including more than 50 subjects with kidney disease, published during 2000-2014 and reporting on PEW prevalence by subjective global assessment or malnutrition-inflammation score. Data were reviewed throughout different strata: (1) acute kidney injury (AKI), (2) pediatric chronic kidney disease (CKD), (3) nondialyzed CKD 3-5, (4) maintenance dialysis, and (5) subjects undergoing kidney transplantation (Tx). Sample size, period of publication, reporting quality, methods, dialysis technique, country, geographical region, and gross national income were a priori considered factors influencing between-study variability. Results: Two studies including 189 AKI patients reported a PEW prevalence of 60% and 82%. Five studies including 1776 patients with CKD stages 3-5 reported PEW prevalence ranging from 11% to 54%. Finally, 90 studies from 34 countries including 16,434 patients on maintenance dialysis were identified. The 25th-75th percentiles range in PEW prevalence among dialysis studies was 28-54%. Large variation in PEW prevalence across studies remained even when accounting for moderators. Mixed-effects meta-regression identified geographical region as the only significant moderator explaining 23% of the observed data heterogeneity. Finally, two studies including 1067 Tx patients reported a PEW prevalence of 28% and 52%, and no studies recruiting pediatric CKD patients were identified. Conclusion: By providing evidence-based ranges of PEW prevalence, we conclude that PEW is a common phenomenon across the spectrum of AKI and CKD. This, together with the well-documented impact of PEW on patient outcomes, justifies the need for increased medical attention.

Global Prevalence of Protein-Energy Wasting in Kidney Disease: A Meta-analysis of Contemporary Observational Studies From the International Society of Renal Nutrition and Metabolism.

OBJECTIVE: To better define the prevalence of protein-energy wasting (PEW) in kidney disease is poorly defined. METHODS: We performed a meta-analysis of PEW prevalence from contemporary studies including more than 50 subjects with kidney disease, published during 2000-2014 and reporting on PEW prevalence by subjective global assessment or malnutrition-inflammation score. Data were reviewed throughout different strata: (1) acute kidney injury (AKI), (2) pediatric chronic kidney disease (CKD), (3) nondialyzed CKD 3-5, (4) maintenance dialysis, and (5) subjects undergoing kidney transplantation (Tx). Sample size, period of publication, reporting quality, methods, dialysis technique, country, geographical region, and gross national income were a priori considered factors influencing between-study variability. RESULTS: Two studies including 189 AKI patients reported a PEW prevalence of 60% and 82%. Five studies including 1776 patients with CKD stages 3-5 reported PEW prevalence ranging from 11% to 54%. Finally, 90 studies from 34 countries including 16,434 patients on maintenance dialysis were identified. The 25th-75th percentiles range in PEW prevalence among dialysis studies was 28-54%. Large variation in PEW prevalence across studies remained even when accounting for moderators. Mixed-effects meta-regression identified geographical region as the only significant moderator explaining 23% of the observed data heterogeneity. Finally, two studies including 1067 Tx patients reported a PEW prevalence of 28% and 52%, and no studies recruiting pediatric CKD patients were identified. CONCLUSION: By providing evidence-based ranges of PEW prevalence, we conclude that PEW is a common phenomenon across the spectrum of AKI and CKD. This, together with the well-documented impact of PEW on patient outcomes, justifies the need for increased medical attention.

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.

Cancer risk and mortality after kidney transplantation: a population-based study on differences between Danish centres using standard immunosuppression with and without glucocorticoids.

BACKGROUND: Kidney recipients receive immunosuppression to prevent graft rejection, and long-term outcomes such as post-transplant cancer and mortality may vary according to the different protocols of immunosuppression. METHODS: A national register-based historical cohort study was conducted to examine whether post-transplant cancer and all-cause mortality differed between Danish renal transplantation centres using standard immunosuppressive protocols including steroids (Centres 2, 3, 4) or a steroid-free protocol (Centre 1). The Danish Nephrology Registry, the Danish Civil Registration System, the Danish National Cancer Registry and the Danish National Patient Register were used. A historical cohort of 1450 kidney recipients transplanted in 1995-2005 was followed up with respect to post-transplant cancer and death until 31 December 2011. RESULTS: Compared with Center 1 the adjusted post-transplant cancer risk was 6-39% lower in Centre 3 [hazard ratio (HR) 0.94, 95% confidence interval (CI) 0.67-1.32], in Centre 2 (HR 0.72, 95% CI 0.52-0.98) and in Centre 4 (HR 0.61, 95% CI 0.44-0.83). Compared with Center 1, the adjusted post-transplant mortality was 21-55% higher in Centre 4 (HR 1.21, 95% CI 0.91-1.61), in Centre 3 (HR 1.35, 95% CI 0.98-1.86) and in Centre 2 (HR 1.55, 95% CI 1.17-2.05). On average, post-transplant cancer was associated with a 4-fold increase in the risk of death (HR 4.25, 95% CI 3.36-5.38). CONCLUSIONS: There was a tendency of a higher post-transplant cancer occurrence, but lower all-cause mortality, in the Danish transplantation centre that adhered to a standard steroid-free immunosuppressive protocol.

Historical Study (1986-2014): Improvements in Nutritional Status of Dialysis Patients.

OBJECTIVE: Malnutrition is common in dialysis patients and is associated with adverse clinical outcomes. Despite an increased focus on improved nutrition in dialysis patients, it is claimed that the prevalence of malnutrition in this group of patients has not changed during the last decades. Direct historical comparisons of the nutritional status of dialysis patients have never been published. To directly compare the nutritional status of past and current dialysis patients, we implemented the methodology of a study from 1986 on a population of dialysis patients in 2014. DESIGN: Historical study comparing results of two cross-sectional studies performed in 1986 and 2014. SETTING: We compared the nutritional status of hemodialysis (HD) and peritoneal dialysis (PD) patients attending the dialysis center at Roskilde Hospital, Denmark, in February to June 2014, with that of HD and PD patients treated at the dialysis center at Fredericia Hospital, Denmark, in April 1986. SUBJECTS: Maintenance PD and HD patients (n = 64 in 2014 and n = 48 in 1986). METHODS: We performed anthropometry (body weight, triceps skinfold, and midarm muscle circumferences [MAMCs]) and determined plasma transferrin. MAIN OUTCOME MEASURE: Relative body weight, triceps skinfold, MAMC, body mass index, and prevalence of protein-caloric malnutrition as defined in the original study from 1986. RESULTS: Average relative body weight, triceps skinfold, MAMC, and body mass index were significantly higher in 2014 compared with 1986. The prevalence of protein-caloric malnutrition was significantly lower in 2014 (18%) compared with 1986 (52%). CONCLUSIONS: The nutritional status of maintenance dialysis patients has improved during the last 3 decades. The reason for this improvement could not be identified in the present study, but the most likely contributors are the higher prevalence of obesity in the general population, less predialytic malnutrition, and an improved focus on nutrition in maintenance dialysis patients.

Renal amyloid A amyloidosis as a complication of hidradenitis suppurativa.

Rheumatic disease is the dominant cause of amyloid A (AA) amyloidosis, but other chronic inflammatory diseases may have similar consequences. Hidradenitis suppurativa (HS) is a relatively common, but little known skin disease characterized by chronic inflammation. Here we present a case of chronic HS leading to biopsy-verified severe renal AA amyloidosis and dialysis dependency.

Nutritional Status of Maintenance Dialysis Patients: Low Lean Body Mass Index and Obesity Are Common, Protein-Energy Wasting Is Uncommon.

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.

High-protein diets and renal health.

High-protein diets (i.e., protein content of more than 25% of energy or more than 2 g/kg body weight per day) based on meat and dairy products are repeatedly promoted for weight reduction and better health, but the evidence supporting these notions is quite dubious. As described in the present review, there is a reason to be concerned about adverse effects of such diets, including glomerular hyperfiltration, hypertensive effects of a concomitant increase in dietary sodium, and an increased risk of nephrolithiasis. These diet-induced physiological consequences might lead to an increase in the prevalence of chronic kidney disease in the general population without preexisting kidney disease. Accordingly, we find medical reasons to refrain from promoting high-protein diets, in particular those based on meat and dairy products, until clear-cut evidence for the safety and for the superiority of such diets on human health has been provided.

Nephrogenic systemic fibrosis in Denmark--a nationwide investigation.

BACKGROUND: Nephrogenic systemic fibrosis is a debilitating and painful disorder with an increased stimulation of the connective tissue in the skin and systemic tissues. The disease is associated with exposure to gadolinium-based contrast agent used in magnetic resonance imaging in patients with renal impairment. METHODS: The prevalence of nephrogenic systemic fibrosis has so far never been determined at a national level. In 2009, Denmark was the first country to design a guideline for the tracing of nephrogenic systemic fibrosis patients. The aim of this paper is to communicate the main findings of this quest. RESULTS: The outcome of the nationwide investigation revealed that Denmark had 65 patients with nephrogenic systemic fibrosis and thereby the highest prevalence of nephrogenic systemic fibrosis worldwide with 65 per 5.6 million inhabitants, or 12 per million. CONCLUSIONS: The nationwide investigation in Denmark revealed the highest prevalence of NSF worldwide. This may be rooted in a high level of awareness of NSF both among doctors, politicians and, not least, the media, combined with the fact that a nationwide NSF investigation was initiated.

Plasma concentrations of extracellular matrix protein fibulin-1 are related to cardiovascular risk markers in chronic kidney disease and diabetes.

BACKGROUND: Fibulin-1 is one of a few extracellular matrix proteins present in blood in high concentrations. We aimed to define the relationship between plasma fibulin-1 levels and risk markers of cardiovascular disease. METHODS: Plasma fibulin-1 was determined in subjects with chronic kidney disease (n = 32; median age 62.5, inter-quartile range 51 - 73 years) and 60 age-matched control subjects. Among kidney disease patients serological biomarkers related to cardiovascular disease (fibrinogen, interleukin 6, C-reactive protein) were measured. Arterial applanation tonometry was used to determine central hemodynamic and arterial stiffness indices. RESULTS: We observed a positive correlation of fibulin-1 levels with age (r = 0.38; p = 0.033), glycated hemoglobin (r = 0.80; p = 0.003), creatinine (r = 0.35; p = 0.045), and fibrinogen (r = 0.39; p = 0.027). Glomerular filtration rate and fibulin-1 were inversely correlated (r = -0.57; p = 0.022). There was a positive correlation between fibulin-1 and central pulse pressure (r = 0.44; p = 0.011) and central augmentation pressure (r = 0.55; p = 0.001). In a multivariable regression model, diabetes, creatinine, fibrinogen and central augmentation pressure were independent predictors of plasma fibulin-1. CONCLUSION: Increased plasma fibulin-1 levels were associated with diabetes and impaired kidney function. Furthermore, fibulin-1 levels were associated with hemodynamic cardiovascular risk markers. Fibulin-1 is a candidate in the pathogenesis of cardiovascular disease observed in chronic kidney disease and diabetes.