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We describe the mechanism of action of vitamin K, and its implication in cardiovascular disease, bone fractures, and inflammation to underline its protective role, especially in chronic kidney disease (CKD).Vitamin K acts as a coenzyme of y-glutamyl carboxylase, transforming undercarboxylated in carboxylated vitamin K-dependent proteins. Furthermore, through the binding of the nuclear steroid and xenobiotic receptor, it activates the expression of genes that encode proteins involved in the maintenance of bone quality and bone remodeling. There are three main types of K vitamers: phylloquinone, menaquinones, and menadione. CKD patients, for several conditions typical of the disease, are characterized by lower levels of vitamin K than the general populations, with a resulting higher prevalence of bone fractures, vascular calcifications, and mortality. Therefore, the definition of vitamin K dosage is an important issue, potentially leading to reduced bone fractures and improved vascular calcifications in the general population and CKD patients.

Introduction: The Selective Functional Movement Assessment (SFMA) is a functional movement assessment method to observe movement restrictions in individuals with known musculoskeletal disorders, although it has also been used to evaluate healthy athletes of different sports. Aim: The present paper aimed to evaluate the applicability of SFMA in a clinical setting and to verify whether a student can correctly perform it. Methods: An introductory and explanatory email was sent to the subjects, containing the instructions needed to produce a video with SFMA evaluation movements. SFMA methodology was then used to analyze the received videos. The results between interobserver and intraobserver agreement were compared to the literature, considered the gold standard methods. Results: Twenty-eight subjects (17.71 ± 1.96 years aged) were rated. The functional non-painful scenario (FN) has been assigned more frequently by all raters. The student’s intra-rater reliability proved to be moderate (Kappa coefficient 0.49). Results for inter-rater reliability showed that the reliability degree between the senior physiotherapist and student before and after their educational path is good (Kappa coefficient 0.60 and 0.62, respectively). Conclusions: The results of this study showed SFMA intra-rater reliability to be moderate, while inter-rater reliability can be considered good. These characteristics make it a valuable tool for sport’s needs, even when used by students.

In CKD and in the elderly, Vascular Calcifications (VC) are associated to cardiovascular events and bone fractures. VC scores at the abdominal aorta (AA) from lateral spine radiographs are widely applied (the 0–24 semiquantitative discrete visual score (SV) being the most used). We hypothesised that a novel continuum score based on quantitative computer-assisted tracking of calcifications (QC score) can improve the precision of the SV score. This study tested the repeatability and reproducibility of QC score and SV score. In forty-four patients with VC from an earlier study, five experts from four specialties evaluated the data twice using a dedicated software. Test–retest was performed on eight subjects. QC results were reported in a 0–24 scale to readily compare with SV. The QC score showed higher intra-operator repeatability: the 95% CI of Bland–Altman differences was almost halved in QC; intra-operator R2 improved from 0.67 for SV to 0.79 for QC. Inter-observer repeatability was higher for QC score in the first (Intraclass Correlation Coefficient 0.78 vs. 0.64), but not in the second evaluation (0.84 vs. 0.82), indicating a possible heavier learning artefact for SV. The Minimum Detectable Difference (MDD) was smaller for QC (2.98 vs. 4 for SV, in the 0–24 range). Both scores were insensitive to test–retest procedure. Notably, QC and SV scores were discordant: SV showed generally higher values, and an increasing trend of differences with VC severity. In summary, the new QC score improved the precision of lateral spine radiograph scores in estimating VC. We reported for the first time an estimate of MDD in VC assessment that was 25% lower for the new QC score with respect to the usual SV score. An ongoing study will determine whether this lower MDD may reduce follow-up times to check for VC progression.

Bone Biopsy (BB) with histomorphometric analysis still represents the gold standard for the diagnosis and classification of different forms of renal osteodystrophy. Bone biopsy is the only technique able to provide comprehensive information on all bone parameters, measuring static and dynamic parameters of turnover, cortical and trabecular microarchitecture, and mineralization defects. In nephrological practice, bone biopsy yields relevant indications to support therapeutic choices in CKD, heavily impacting the management and prognosis of uremic patients. Unfortunately, the use of bone biopsy has decreased; a lack of expertise in performing and interpreting, perceived procedure invasiveness and pain, and reimbursement issues have all contributed to this decline. Nevertheless, both bone biomarkers and instrumental images cannot be considered reliable surrogates for histological findings, being insufficiently accurate to properly evaluate underlying mineral and bone disorders. This is a multidisciplinary position paper from the Nephrology and Osteoporosis Italian Scientific Societies with the purpose of restating the role of bone biopsy in CKD patient management and of providing strong solutions to allow diffusion of this technique in Italy, but potentially also in other countries. The Italian approach through the optimization and standardization of bone biopsy procedure, the construction of the Italian Hub and Spoke network, and a request for adjustment and national homogenization of reimbursement to the Italian Health Ministry has led the way to implement bone biopsy and to improve CKD patient management and prognosis. ispartof: NUTRIENTS vol:14 issue:9 ispartof: location:Switzerland status: published

BACKGROUND AND AIMS Vascular calcifications (VCs), a known risk factor for cardiovascular disease and mortality, are strongly linked to vertebral fractures (VFs) [1]. The coronary calcium score from computer tomography (CT) is the gold standard to measure VCs [2], but this implies high radiation doses and costs. Although, several calcifications scores at the abdominal aorta have been developed from lower-dose and low-cost lateral spine RX projections. These scores are widely applied (the 0–24 score): Kauppila Score (KS) [3]. Most RX scores are semi-quantitative implying an error-prone visual assessment. Indeed, so far, repeatability studies could not estimate the minimum detectable difference (MDD). Based on this knowledge, we developed a new RX-based computer-assisted VCs score with the aim to test its precision (repeatability and reproducibility metrics and MDD estimate) compared to KS. METHOD New Quantitative Score (QS), computer-assisted tracking of calcifications, considers both abdominal aorta calcification and column length (range 0–1), then multiplied by 24 to easily compare with the standard score: KS. Dedicated software developed with ALBA framework (https://github.com/IOR-BIC/ALBA) to subsequently record standard and new scores (see Figure 1). We enrolled 44 patients with VCs from an earlier study and the anonymous recorded data were randomized in two series. Five experts from four specialties in two institutions evaluated the data twice, with 1-month interval between series. Additional test-retest evaluation was performed on eight subjects with a second RX within 2 weeks. RESULTS Intra-observer analysis (Bland-Altman plots and regression analysis between series): both scores seem not biased; QS showed higher reproducibility [95% confidence interval (95% CI) of differences almost halved]. Inter-observer [Intra Class Correlation Coefficient (ICC)]: ICC higher for QS in the first series (0.78 versus 0.64); a lower difference was observed in the second evaluation (0.84 versus 0.82). MDD (Standard Error of the Mean): reduced by around 25% for the QS (2.98 versus 4, in the 0–24 scale). Test-retest (Wilcoxon paired test): not significantly different for both scores. Agreement (Bland-Altman plots): scores are discordant. The QS shows significantly higher values and an increasing trend with calcification severity. CONCLUSION Our new quantitative computer-assisted score improved the precision of RX scores in the estimate of VCs. Furthermore, it showed higher intra-observer repeatability than KS and we reported for the first time an estimate of MDD in the VCs assessment. In detail, MDD was 25% lower for the new score. An ongoing study will determine whether this lower MDD may reduce follow-up times to check for VCs progression and whether this new VCs score may act as a risk alert for the development/worsening of VFs.

Objectives Obesity is an important risk factor for morbidity and mortality. Vitamin K2 is involved in the production of bone and matrix amino acid g-carboxy-glutamic acid (Gla) proteins (vitamin K-dependent proteins [VKDPs]), regulating bone and vascular calcification (VC). Bone Gla protein (BGP) is involved both in bone mineralization and VCs. We assessed the relationships between vitamin K levels and body mass index (BMI) according to the hypothesis that the impact of BMI on mortality is partly driven by low vitamin K levels. Methods The Vitamin K Italian (VIKI) study included 387 hemodialysis patients from 18 dialysis centers in Italy. We determined plasma levels of bone markers: vitamin K levels, VKDPs, vitamin 25(OH)D, alkaline phosphatase (ALP), parathyroid hormone (PTH), calcium (Ca), phosphorus (P) and routine biochemistry. BMI was classified into the following categories: underweight (BMI 2), normal weight (18.5 ≤ BMI 2), overweight (25 ≤ BMI 2) and obese (BMI ≥ 30 kg/m2). Results 45.2% of patients were overweight or obese. Stratification by BMI demonstrated lower median menaquinone-7 (MK7)/triglycerides levels in obese patients (0.42 ng/mg [0.19, 0.87], p = 0.005). BGP levels were lower in overweight and obese patients (152 mcg/L [83.2, 251] and 104 mcg/L [62.7, 230], p = Conclusions These data are the first to report an inverse relationship between Vitamin K2 levels and BMI in hemodialysis patients. Further studies are needed to confirm these findings and to determine if lower levels of Vitamin K are related to greater morbidity and mortality in this at-risk population.

Vascular calcification and fragility fractures are associated with high morbidity and mortality, especially in end-stage renal disease. We evaluated the relationship of iliac arteries calcifications (IACs) and abdominal aortic calcifications (AACs) with the risk for vertebral fractures (VFs) in hemodialysis patients. The VIKI study was a multicenter cross-sectional study involving 387 hemodialysis patients. The biochemical data included bone health markers, such as vitamin K levels, vitamin K-dependent proteins, vitamin 25(OH)D, alkaline phosphatase, parathormone, calcium, and phosphate. VF, IACs and AACs was determined through standardized spine radiograms. VF was defined as &gt, 20% reduction of vertebral body height, and VC were quantified by measuring the length of calcium deposits along the arteries. The prevalence of IACs and AACs were 56.1% and 80.6%, respectively. After adjusting for confounding variables, the presence of IACs was associated with 73% higher odds of VF (p = 0.028), whereas we found no association (p = 0.294) for AACs. IACs were associated with VF irrespective of calcification severity. Patients with IACs had lower levels of vitamin K2 and menaquinone 7 (0.99 vs. 1.15 ng/mL, p = 0.003), and this deficiency became greater with adjustment for triglycerides (0.57 vs. 0.87 ng/mL, p &lt, 0.001). IACs, regardless of their extent, are a clinically relevant risk factor for VFs. The association is enhanced by adjusting for vitamin K, a main player in bone and vascular health. To our knowledge these results are the first in the literature. Prospective studies are needed to confirm these findings both in chronic kidney disease and in the general population.

Background Vascular calcification and fragility fractures are common age-related disorders, associated with high morbidity and mortality especially in end-stage renal disease. Skeletal disorders occur in dialysis patients. Few studies have provided data on the prevalence of vertebral fractures (VF) and their association with large artery calcifications. Purpose We evaluated the relationship of iliac arteries calcifications (IACs) and abdominal aorta calcifications (AACs) with the risk for VFs in hemodialysis (HD) patients. Methods The VIKI Study is a cross-sectional study involving 387 HD patients from 18 Italian dialysis centers, assessing demographic, clinical and biochemical data in such patients. Biochemical data included bone health markers such as vitamin K levels, vitamin K-dependent proteins, vitamin 25(OH)D, alkaline phosphatase, parathormone, calcium, phosphate, Bone Gla Protein and Matrix Gla Protein. The presence of VF, IACs and AACs were determined through standardized radiograms of the spine. A >20% reduction of vertebral body height was considered a VF. We quantified vascular calcifications by measuring the length of calcium deposits along the abdominal arteries, classifying the degree of severity for the IACs and AACs with a specific score (mild: 0.1–3 cm; moderate: 3.1–5 cm; and severe >5 cm) previously validated for AACs. Results The prevalence of IACs was 56.1%, and of AACs 80.6%. After adjusting for confounding variables, the presence of IACs was associated with 73% higher odds of VF (p=0.028), whereas we found no association (p=0.294) for AACs. The presence of IACs associated with VF irrespective of calcification severity. Patients with IACs had lower levels of the vitamin K2, menaquinone 7 (0.99 vs 1.15 ng/ml; p=0.003), and deficiency of this marker became greater when adjusting for triglyceride levels (0.57 vs 0.87 ng/ml; p Conclusions The presence of IACs, regardless of their extent, appears to be a clinically relevant risk factor for VFs. The association is further enhanced by including vitamin K, a main player in bone and vascular health, in the model. Prospective studies are needed to confirm these findings both in chronic kidney disease patients and in the general population. Funding Acknowledgement Type of funding sources: None.

Fractures and vascular calcifications (VCs) are common in patients with chronic kidney disease (CKD). They are related to abnormalities in vitamin D metabolism, calcium, phosphorus, parathyroid hormone, and fibroblast growth factor 23 (FGF23)/Klotho that occur with CKD. Impaired vitamin D metabolism and abnormal levels of calcium, phosphate, parathyroid hormone (PTH), and FGF23/Klotho drive bone and vascular changes in CKD. It is unclear if oral calcitriol safely mitigates fracture risk without increasing the burden of calcifications. Therefore, we investigated whether treatment with calcitriol affected the prevalence of fractures and VC progression in hemodialysis (HD) patients. This report is a secondary analysis of the Vitamin K Italian (VIKI) study, a cross-sectional study involving 387 HD patients. We assessed vitamin 25(OH)D, alkaline phosphatase, PTH, calcium, phosphate, osteocalcin or bone Gla protein, matrix Gla protein, and vitamin K levels. Vertebral fractures (VFs) and VCs were determined by spine radiograph. A reduction of >20% of vertebral body height was considered a VF. VCs were quantified by the length of calcific lesions along the arteries. The patients treated with oral calcitriol were 177 of 387 patients (45.7%). The prevalence of VF was lower in patients receiving oral calcitriol than in those untreated (48.6% versus 61.0%, p=0.015), whereas the presence of aortic and iliac calcifications was similar (aortic: 81.9% versus 79.5%, respectively, p=0.552; iliac: 52.0% and 59.5%, respectively, p=0.167). In multivariable logistic regression analysis, oral calcitriol was associated with a 40.2% reduced odds of fracture (OR 0.598; 95% confidence interval [CI], 0.363–0.985; p=0.043). In conclusion, we found a significant association between oral calcitriol and lower VF in HD patients without an increase in the burden of VC. Further prospective and interventional studies are needed to confirm these findings. © 2021 American Society for Bone and Mineral Research (ASBMR).

Long-term treatment with proton pump inhibitors (PPIs) is associated with an increased risk of fractures in the general population. PPIs are widely prescribed to dialysis patients but to date no study has specifically tested, by state-of-art statistical methods, the relationship between use of PPIs and fractures in this patient population. This study aimed to assess whether use of PPIs is associated with bone fractures (ie, hip fractures and fractures other than hip fractures) in a large international cohort of hemodialysis patients. We considered an observational prospective cohort of 27,097 hemodialysis patients from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Data analysis was performed by the Fine and Gray method, considering the competitive risk of mortality, as well as by a cause-specific hazards Cox model with death as a censoring event and matching patients according to the prescription time. Of 27,097 hemodialysis patients, 13,283 patients (49%) were on PPI treatment. Across the follow-up period (median, 19 months), 3.8 bone fractures × 100 person-years and 1.2 hip fractures × 100 person-years occurred. In multiple Cox models, considering the competitive risk of mortality, the incidence rate of bone (subdistribution hazard ratio [SHR] 1.22; 95% CI, 1.10 to 1.36; p < 0.001) and hip fractures (SHR 1.35; 95% CI, 1.13 to 1.62; p = 0.001) was significantly higher in PPI-treated than in PPI-untreated patients. These findings also held true in multiple, cause-specific, hazards Cox models matching patients according to the prescription time (bone fractures: HR 1.47; 95% CI, 1.23 to 1.76; p < 0.001; hip fractures: HR 1.85; 95% CI, 1.37 to 2.50; p < 0.001). The use of PPIs requires caution and a careful evaluation of risks/benefits ratio in hemodialysis patients. © 2019 American Society for Bone and Mineral Research.

Background and Aims In patients with Chronic Kidney Disease (CKD) mineral, bone, and calcific cardiovascular abnormalities are associated to adverse clinical outcomes, including fractures, cardiovascular events and mortality. Vitamin D hormonal system along with alteration levels that occur in calcium, phosphate, PTH, FGF23/Klotho are the main responsible of the bone and vascular metabolism changes, particularly in hemodialysis (HD) patients that experienced the very negative clinical consequences (decreased bone mass, increased fragility fractures and vascular calcification). In the setting of a comparative effectiveness study, we investigated the effect of oral calcitriol on fractures in HD patients taking into account a series of potential confounders. Method We conducted a secondary analysis of the VIKI database, a cross-sectional study involving 387 HD patients from 18 Italian dialysis centers. Routine biochemistry and bone biochemical markers such as vitamin K levels, VKDPs, vitamin 25(OH)D, ALP, PTH, Ca, P, osteocalcin (BGP), Matrix Gla Protein (MGP) were assessed. The presence of Vertebral Fractures (VF) and Vascular Calcification (VC) was determined through spine radiograph. Reduction of >20% of vertebral body height was considered a VF. The severity of the vertebral fractures was estimated as mild, moderate and severe (reduction: 20-25%, 25-40% or >40%, respectively). VC were quantified by measuring the length of calcific deposits along the arteries (mild 0,1-5 cm, moderate 5,1-10 cm and severe >10 cm). Results 177 out 387 patients (45.7%) were treated with oral calcitriol. Oral calcitriol-treated and untreated patients did not differ as for Ca, P, PTH, Albumin, BGP, MGP, and ALP. The prevalence of VF was significantly lower in patients receiving oral calcitriol than in those untreated (48.6% vs 61%, P=0.015), whereas the presence of aortic and iliac calcifications was similar between the two groups (aortic: 81.9% vs 79.5% respectively, P=0.552; iliac: 52.0% and 59.5%, P=0.167). No significant between-groups differences were observed in terms of calcification severity. In a multivariable logistic regression analysis, after adjustment for all potential confounders, oral calcitriol was associated with a marked reduction (-40.2%) of the odds of fractures (OR: 0.598, 95% CI: 0.363-0.985, P=0.043) (see Table). Conclusion A significant association was found between oral calcitriol and lower VF rate in HD patients. Such an effect remained significant also after data adjustment for a large series of potential confounders. Further prospective and interventional studies are needed to confirm these findings.

Little information is available on the beneficial effects of cholecalciferol treatment in comorbid patients hospitalized for COVID-19. The aim of this study was to retrospectively examine the clinical outcome of patients receiving in-hospital high-dose bolus cholecalciferol. Patients with a positive diagnosis of SARS-CoV-2 and overt COVID-19, hospitalized from 15 March to 20 April 2020, were considered. Based on clinical characteristics, they were supplemented (or not) with 400,000 IU bolus oral cholecalciferol (200,000 IU administered in two consecutive days) and the composite outcome (transfer to intensive care unit, ICU and/or death) was recorded. Ninety-one patients (aged 74 &plusmn, 13 years) with COVID-19 were included in this retrospective study. Fifty (54.9%) patients presented with two or more comorbid diseases. Based on the decision of the referring physician, 36 (39.6%) patients were treated with vitamin D. Receiver operating characteristic curve analysis revealed a significant predictive power of the four variables: (a) low (&lt, 50 nmol/L) 25(OH) vitamin D levels, (b) current cigarette smoking, (c) elevated D-dimer levels (d) and the presence of comorbid diseases, to explain the decision to administer vitamin D (area under the curve = 0.77, 95% CI: 0.67&ndash, 0.87, p &lt, 0.0001). Over the follow-up period (14 &plusmn, 10 days), 27 (29.7%) patients were transferred to the ICU and 22 (24.2%) died (16 prior to ICU and six in ICU). Overall, 43 (47.3%) patients experienced the combined endpoint of transfer to ICU and/or death. Logistic regression analyses revealed that the comorbidity burden significantly modified the effect of vitamin D treatment on the study outcome, both in crude (p = 0.033) and propensity score-adjusted analyses (p = 0.039), so the positive effect of high-dose cholecalciferol on the combined endpoint was significantly amplified with increasing comorbidity burden. This hypothesis-generating study warrants the formal evaluation (i.e., clinical trial) of the potential benefit that cholecalciferol can offer in these comorbid COVID-19 patients.

Hyperphosphatemia is a risk factor for vascular calcifications (VCs), which are part of the chronic kidney disease-mineral and bonedisorders (CKD-MBD). Vitamin K-dependent proteins such as matrix Gla protein (MGP) and bone Gla proteins (BGP, or osteocalcin)can inhibit VCs and regulate bone mineralization. In this analysis of the Vitamin K Italian (VIKI) study, the relationship between vitaminK status, vertebral fractures (VFs) and VCs in 387 hemodialysis (HD) patients with (N= 163; 42.1%) or withoutN= 224; 57.9%) seve-lamer was evaluated. Levels of vitamin K vitamers K1 and K2 or menaquinones (MK; MK4–7), total and undercarboxylated (uc) formsfor both BGP and MGP were determined. Although no differences in clinical characteristics were noted, lower levels of MK4 (0.45 ver-sus 0.6 ng/mL,p= .01) and a greater MK4 deficiency was observed in sevelamer-treated patients (13.5% versus 5.4%,p= .005). Mul-tivariate logistic regression revealed that MK4 deficiency was associated with sevelamer use (odds ratio [OR] = 2.64, 95% confidenceinterval [CI] 1.25–5.58,p= .011) and aortic calcification (OR = 8.04, 95% CI 1.07–60.26,p= .04). In the same logistic model, sevelameramplified the effect of total BGP levels on the odds of VFs in patients with total BGP

Vitamin K acts as a coenzyme of carboxylase, catalyzing the carboxylation of several vitamin K dependent proteins. Beyond its well-known effects on blood coagulation, it also exerts relevant effects on bone and the vascular system. In this review, we point out the relevance of an adequate vitamin K intake to obtain sufficient levels of carboxylated (active form) vitamin K dependent proteins (such as Osteocalcin and matrix Gla protein) to prevent bone health. Another bone-related action of Vitamin K is being a ligand of the nuclear steroid and xenobiotic receptor (SXR). We also discuss the recommended intake, deficiency, and assessment of vitamin K. Furthermore, we review the few available studies that have as pre-specified outcome bone fractures, indicating that we need more clinical studies to confirm that vitamin K is a potential therapeutic agent for bone fractures.

The assessment of the vitamin K status and its effects on clinical outcomes in kidney transplantation (KT) patients has sparked interest, but it is still largely unfulfilled. In part, this is due to difficulties in laboratory measurements of vitamin K, especially K2 vitamers. Vitamin K status is currently best assessed by measuring undercarboxylated vitamin-K-dependent proteins. The relative contribution of vitamin K1 and K2 to the health status of the general population and CKD (chronic kidney disease) patients, including KT patients, is also poorly studied. Through a complete and first review of the existing literature, we summarize the current knowledge of vitamin K pathophysiology and its potential role in preventing KT complications and improving organ survival. A specific focus is placed on cardiovascular complications, bone fractures, and the relationship between vitamin K and cancer. Vitamin K deficiency could determine adverse outcomes, and KT patients should be better studied for vitamin K assessment and modalities of effective therapeutic approaches. ispartof: NUTRIENTS vol:12 issue:9 ispartof: location:Switzerland status: published

Background and Aims Two Vitamin K-dependent proteins (VDKPs) link bone and vasculature in CKD-MBD: Bone Gla Protein (BGP) and Matrix Gla Protein (MGP). In ESKD, Vitamin K deficiency is highly prevalent and leads to increased levels of inactive VKDPs (undercaboxylated (ucBGP and dephosphorylated (dp)-uMGP), which are linked to greater risk of fractures and severity of vascular calcification. We hypothesized that kidney transplantation (KT) would improve Vitamin K status and lower levels of inactive VKDPs. Method Between 2014-2017, we conducted a study in 34 patients to assess changes in VKDPs during the 1st year of KT. In a specialized lab we determined VKDPs pre- and 1-year post-KT: total BGP, uc BGP, total MGP, and dp-uc MGP. We determined the prevalence of Vitamin K deficiency based on levels of uc BGP and dp-uc MGP. Results Our cohort had a mean +/- SD age of 48+/-14 years, 32% were female and 97% were Caucasian. 1 year post-KT, there was a decrease in the levels of all VKDPs and the prevalence of Vitamin K deficiency (Table 1 and Figure 1). Patients with greatest severity of Vitamin K deficiency pre-KT had the largest decreases of inactive VDKPs post-KT. Conclusion KT was associated with improvement in Vitamin K status as manifested by decreased levels of inactive VKDPs. These are the first prospective data on VKDPs in CKD patients pre- and post-KT. Studies are needed to assess the impact of improvement in VKDP status after KT on CKD-MBD outcomes.

Background and Aims Sevelamer (S) is a phosphate binding drug used to treat hyperphosphatemia in patients with CKD. Our aim was to evaluate the hypothesis that the use of (S) could interfere with Vitamin K absorption in hemodialysis (HD) patients of VIKI study. Method We tested this hypothesis in VIKI, a cross-sectional study of 387 hemodialysis patients, we established the prevalence of vitamin K deficiency and to assessed the relationship between vitamin K status, vertebral fractures, vascular calcification. We determined serum concentrations of vitamin 25(OH)D; alkaline phosphatase (ALP); vitamers K1, MK4, MK5, MK6, MK7; osteocalcin (BGP) and Matrix Gla Protein (MGP). We highlighted that MK4 deficiency was the strongest predictor of aortic calcification (OR, 2.82; 95% CI, 1.14–7.01) while vitamin K1 deficiency was the strongest predictor of vertebral fractures fractures (OR: 2.94; 95% CI, 1.38–6.26). Results 163 of 387 patients (42.1%) were treated with Sevelamer. There were no differences in levels of 25(OH)D, K1, MK5, MK6 and MK7 among patients treated with and without Sevelamer. Remarkably, the prevalence of MK4 deficiency was higher in Sevelamer treated patients (13.5% vs 5.4%, p=0.005). Sevelamer treated patients also had higher median levels of ALK (89 UI/L vs 77.5 UI/L, p=0.001) and total BGP (210 mcg/L vs 152 mcg/L, p=0.002) and lower median levels of total MGP (16.4 nmol/L vs 20.3 nmol/L, p=0.037) (Table 1 and Figure 1). In multivariable logistic regression, the odds ratio of MK4 deficiency (dependent variable) in patients treated with compared to without Sevelamer was ∼3-fold higher (OR: 2.64, 95% CI: 1.25-5.58, p=0.011) after adjustment for confounders of Vitamin K levels, including older age, previous myocardial infarction, type of HD, ALP, PTH, MGP, BGP, cholesterol and albumin. Conclusion These data support the hypothesis that Sevelamer could interfere with MK4 absorption in HD patients. Longitudinal interventional studies are needed to prove the causal nature of these associations.

Objectives Kidney transplant (KTx) recipients frequently have deficient or insufficient levels of serum vitamin D. Few studies have investigated the effect of cholecalciferol in these patients. We evaluated the efficacy of weekly cholecalciferol administration on parathyroid hormone (PTH) levels in stable KTx patients with chronic kidney disease stage 1–3. Methods In this retrospective cohort study, 48 stable KTx recipients (37 males, 11 females, aged 52 ± 11 years and 26 months post-transplantation) were treated weekly with oral cholecalciferol (7500–8750 IU) for 12 months and compared to 44 untreated age- and gender-matched recipients. Changes in levels of PTH, 25(OH) vitamin D (25[OH]D), serum calcium, phosphate, creatinine and estimated glomerular filtration rate (eGFR) were measured at baseline, 6 and 12 months. Results At baseline, clinical characteristics were similar between treated and untreated patients. Considering the entire cohort, 87 (94.6%) were deficient in vitamin D and 64 (69.6%) had PTH ≥130 pg/mL. Serum calcium, phosphate, creatinine and eGFR did not differ between groups over the follow-up period. However, 25(OH)D levels were significantly higher at both 6 (63.5 vs. 30.3 nmol/L, p Conclusions Weekly administration of cholecalciferol can significantly and stably reduce PTH levels, without any adverse effects on serum calcium and renal function.

Background: Bone Gamma-carboxyglutamic acid (Gla)-protein (BGP or osteocalcin) is a vitamin K-dependent protein involved in the regulation of bone mineralization. Smoking is a risk factor for osteoporosis. Methods: We carried out a secondary analysis of the Vitamin K Italian (VIKI) study to investigate the association between cigarette smoking and BGP levels in patients with end stage renal disease. Data were collected in 370 haemodialysis patients, 37% (136) smokers (or ex-smokers) and 63% (234) nonsmokers. Vascular calcifications and vertebral fractures (quantitative morphometry) were identified on spine radiographs. Results: Smokers had significantly lower BGP levels (152 vs. 204 μg/L, p=0.003). Smokers had lower plasma phosphate levels (4.2 vs. 4.7 mg/dl, p

Vitamin K denotes a group of lipophilic vitamins determining posttranslational modification of proteins. There are two main forms of vitamin K: vitamin K1 (phylloquinone, PK, found in vegetables), and vitamin K2 (menaquinone, MKn, produced by bacteria in the intestine and in fermented foods). Vitamin K1 is principally transported to the liver, regulating the production of coagulation factors. Vitamin K2 is transported to extrahepatic tissues, such as bone and arteries. When considering the issue of adequate vitamin K intake in the general population and in patients affected by bone and mineral abnormalities, specifically osteoporosis and cardiovascular calcification, the distinction between PK and MKn is often underestimated. Although the two forms of vitamin K have similar activity in sustaining the vitamin K cycle and the carboxylation of vitamin K–dependent proteins, their role may be markedly different and therefore their use for the prevention and treatment of bone and mineral abnormalities could follow different pathways and require different doses. We explain in this article that vitamin K2 is a key regulator of clinically relevant molecular processes and propose that its use as a dietary supplement and as a pharmacological treatment for bone and mineral abnormalities should be further explored.

Hyperphosphatemia is a risk factor for vascular calcifications (VCs), which are part of the chronic kidney disease-mineral and bone disorders (CKD-MBD). Vitamin K-dependent proteins such as matrix Gla protein (MGP) and bone Gla proteins (BGP, or osteocalcin) can inhibit VCs and regulate bone mineralization. In this analysis of the Vitamin K Italian (VIKI) study, the relationship between vitamin K status, vertebral fractures (VFs) and VCs in 387 hemodialysis (HD) patients with (N = 163; 42.1%) or without N = 224; 57.9%) sevelamer was evaluated. Levels of vitamin K vitamers K1 and K2 or menaquinones (MK; MK4-7), total and undercarboxylated (uc) forms for both BGP and MGP were determined. Although no differences in clinical characteristics were noted, lower levels of MK4 (0.45 versus 0.6 ng/mL, p = .01) and a greater MK4 deficiency was observed in sevelamer-treated patients (13.5% versus 5.4%, p = .005). Multivariate logistic regression revealed that MK4 deficiency was associated with sevelamer use (odds ratio [OR] = 2.64, 95% confidence interval [CI] 1.25-5.58, p = .011) and aortic calcification (OR = 8.04, 95% CI 1.07-60.26, p = .04). In the same logistic model, sevelamer amplified the effect of total BGP levels on the odds of VFs in patients with total BGP

In chronic kidney disease (CKD), phosphate homoeostasis plays a central role in the development of mineral and bone disorder (MBD) together with decreased serum calcium and elevated serum parathyroid hormone, fibroblast growth factor 23 and sclerostin levels. Today there are only a few data exploring the direct role of abnormal phosphate homoeostasis and hyperphosphataemia in the development of CKD-MBD. On the other hand, several studies have looked at the link between hyperphosphataemia and cardiovascular morbidity and mortality in CKD, but there is a lack of evidence to indicate that lowering phosphate levels improves cardiovascular outcomes in this population. Furthermore, the impact of liberalizing phosphate targets on CKD-MBD progression and bone fracture is currently not known. In this review we discuss the central role of phosphate in the pathogenesis of CKD-MBD and how it may be associated with fracture risk, both in hyper- and hypophosphataemia.

Diabetes mellitus is recognized as one of the major causes of end stage kidney disease. Bone Gla protein (BGP) is a vitamin K-dependent protein involved in bone mineralization and vascular calcifications (VC). Our goal was to characterize BGP and undercarboxylated BGP (ucBGP) in DM patients on HD, compared to HD patients without DM, and their association with vascular and bone disease. 387 HD patients from 18 dialysis centers in Italy. Associations of DM, levels of BGP, vitamin D and VC were evaluated. Time-to-event analysis for all-cause mortality was performed by the Kaplan–Meier. Patients with DM had lower levels of total BGP (139.00 vs. 202.50 mcg/L, p

Fragility fractures (FF) are common in patients with chronic kidney disease (CKD), and they occur at a younger age and with a higher frequency than in the general population, producing significant morbidity, mortality and healthcare costs. The pathogenic mechanisms underlying FF in CKD patients have not been completely understood. Behind CKD-MBD, the uremic toxicity should play a role in their pathogenesis, by affecting bone quality (uremic osteoporosis). There are very few prospective studies investigating risk factors for fragility fractures in CKD patients, and available algorithms for fracture risk prediction (FRAX and DeFRA) have never considered CKD. The diagnosis of vertebral fractures (FV), under-diagnosed in CKD patients as well as in general population, should be performed by Quantitative Vertebral Morphometry (QVM) both with DXA or Spine (D4-L5) x-Ray. A recent KDIGO review has qualified the measurement of the Bone Mineral Density by DXA as a predictive tool for fracture risk assessment in patients with stage G3a-G5D. Furthermore, the Trabecular Bone Score (TBS, software applied to DXA) allows the bone quality evaluation as well as the fracture risk prediction. Other techniques, such as Quantitative Computerized Tomography (QCT), especially High Resolution-peripheral QCT (HR-pQCT), have been shown to be useful, although expensive. Finally, some bone biomarkers (PTH and BAP) demonstrated to be informative for the definition of fracture risk in patients with CKD-MBD. In conclusion, there are several different tools and approaches that demonstrated to be useful for the identification of CKD patients at high risk of fracture, when these are appropriately performed and interpreted by expertise clinicians.

Vitamin K (phylloquinone or vitamin K1and menaquinones or vitamin K2) plays an important role as a cofactor in the synthesis of hepatic blood coagulation proteins, but recently has also aroused an increasing interest for its action in extra-hepatic tissues, in particular in the regulation of bone and vascular metabolism. The accurate measurement of vitamin K status in humans is still a critical issue. Along with indirect assays, such as the undercarboxylated fractions of vitamin K-dependent proteins [prothrombin, osteocalcin (OC), and matrix gla protein], the direct analysis of blood levels of phylloquinone and menaquinones forms might be considered a more informative and direct method for assessing vitamin K status. Different methods for direct quantification of vitamin K serum levels are available. High-performance liquid chromatography (HPLC) methods coupled with post-column reduction procedures and fluorimetric or electrochemical detection are commonly used for food and blood analysis of phylloquinone, but they show some limitations when applied to the analysis of serum menaquinones because of interferences from triglycerides. Recent advancements include liquid chromatography tandem mass spectrometry (LCMS/MS) detection, which assures higher specificity. The optimization and standardization of these methods requires specialized laboratories. The variability of results observed in the available studies suggests the need for further investigations to obtain more accurate analytical results.

Background & aims Vitamin K acts as a coenzyme in the γ-carboxylation of vitamin K-dependent proteins, including coagulation factors, osteocalcin, matrix Gla protein (MGP), and the growth arrest-specific 6 (GAS6) protein. Osteocalcin is a key factor for bone matrix formation. MGP is a local inhibitor of soft tissue calcification. GAS6 activity prevents the apoptosis of vascular smooth muscle cells. Few data on vitamin K intake in chronic kidney disease patients and no data in patients on a Mediterranean diet are available. In the present study, we evaluate the dietary intake of vitamin K1 in a cohort of patients undergoing haemodialysis. Methods In this multi-centre controlled observational study, data were collected from 91 patients aged >18 years on dialysis treatment for at least 12 months and from 85 age-matched control subjects with normal renal function. Participants completed a food journal of seven consecutive days for the estimation of dietary intakes of macro- and micro-nutrients (minerals and vitamins). Results Compared to controls, dialysis patients had a significant lower total energy intake, along with a lower dietary intake of proteins, fats, carbohydrates, fibres, and of all the examined minerals (Ca, P, Fe, Na, K, Zn, Cu, and Mg). With the exception of vitamin B12, vitamins intake followed a similar pattern, with a lower intake in vitamin A, B1, B2, C, D, E, folates, K1 and PP. These finding were confirmed also when normalized for total energy intake or for body weight. In respect to the adequate intakes recommended in the literature, the prevalence of a deficient vitamin K intake was very high (70–90%) and roughly double than in controls. Multivariate logistic model identified vitamin A and iron intake as predictors of vitamin K deficiency. Conclusions Haemodialysis patients had a significantly low intake in vitamin K1, which could contribute to increase the risk of bone fractures and vascular calcifications. Since the deficiency of vitamin K intake seems to be remarkable, dietary counselling to HD patients should also address the adequacy of vitamin K dietary intake and bioavailability. Whether diets with higher amounts of vitamin K1 or vitamin K supplementation can improve clinical outcomes in dialysis patients remains to be demonstrated. © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism

Matrix Gla protein (MGP) and bone Gla protein (BGP) are two vitamin K-dependent proteins (VKDPs) involved in the regulation of vascular calcification (VC). We carried out a secondary analysis of the VIKI study to evaluate associations between drug consumption and VKDP levels in 387 hemodialyzed patients. The VIKI study assessed the prevalence of vitamin K deficiency in hemodialysis patients. We evaluated drug consumption, determined BGP and MGP levels, and verified the presence of any vertebral fractures (VF) and VC by spine radiographs. Total BGP levels were twice as high with calcimimetics versus no calcimimetics (290 vs. 158.5 mcg/L, p < 0.0001) and 69 % higher with vitamin D analogs (268 vs. 159 mcg/L, p < 0.0001). Total MGP was 19 % higher with calcimimetics (21.5 vs. 18.1 mcg/L, p = 0.04) and 54 % higher with calcium acetate (27.9 vs. 18.1 mcg/L, p = 0.003); no difference was found with vitamin D analogs (21.1 vs. 18.3 mcg/L, p = 0.43). Median Total BGP level was 29 % lower in patients with ≥1 VF (151 vs. 213 mcg/L, p = 0.0091) and 36 % lower in patients with VC (164 vs. 262.1 mcg/L, p = 0.0003). In non-survivors, median BGP and MGP were lower, but only for MGP this difference reached the statistical significance (152 vs. 191 mcg/L, p = 0.20 and 15.0 vs. 19.7 mcg/L, p = 0.02, respectively). Pending studies on vitamin K supplementation, calcimimetics, and vitamin D analogs may play a role in preserving vitamin K-dependent protein activity, thus contributing to bone and vascular health in CKD patients.

Background: Warfarin, a widely used anticoagulant, is a vitamin K antagonist impairing the activity of vitamin K-dependent Bone Gla Protein (BGP or Osteocalcin) and Matrix Gla Protein (MGP). Because dabigatran, a new anticoagulant, has no effect on vitamin K metabolism, the aim of this study was to compare the impact of warfarin and dabigatran administration on bone structure and vascular calcification. Methods: Rats with normal renal function received for 6 weeks warfarin, dabigatran or placebo. Bone was evaluated immuno-histochemically and hystomorphometrically after double labelling with declomycin and calcein. Aorta and iliac arteries were examined histologically. Results: Histomorphometric analysis of femur and vertebrae showed significantly decreased bone volume and increased trabecular separation in rats treated with warfarin. Vertebra analysis showed that the trabecular number was higher in dabigatran treated rats. Osteoblast activity and resorption parameters were similar among groups, except for maximum erosion depth, which was higher in warfarin treated rats, suggesting a higher osteoclastic activity. Therefore, warfarin treatment was also associated with higher bone formation rate/bone surface and activation frequency. Warfarin treatment may cause an increased bone turnover characterized by increased remodelling cycles, with stronger osteoclast activity compared to the other groups. There were no differences among experimental groups in calcium deposition either in aortic or iliac arteries. Conclusions: These findings suggest for the first time that dabigatran has a better bone safety profile than warfarin, as warfarin treatment affects bone by reducing trabecular size and structure, increasing turnover and reducing mineralization. These differences could potentially result in a lower incidence of fractures in dabigatran treated patients. This study was supported by a grant form Boehringer-Ingelheim Pharma, Germany (manufacturer of Dabigatran). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.