vitamin-k-semiquinone-radical and Renal-Insufficiency--Chronic

This paper summarizes the biochemistry, metabolism, and dietary needs of vitamins in patients with chronic kidney disease (CKD) and kidney transplant recipients. Evidence indicates that the dietary intake, in vivo synthesis, urinary excretion or metabolism of different vitamins may be substantially altered in kidney failure. There are discrepancies in vitamin status assessment depending on whether the assay is functional or measuring the blood vitamin level. Whether vitamin supplements should be routinely prescribed for patients with CKD is controversial. Because low dietary intake and compounds that interfere with vitamin activity are not uncommon in patients with CKD, and water-soluble vitamin supplements appear safe and not costly, the authors recommend that supplements of the water-soluble vitamins should be routinely offered to these individuals. More research is needed to assess vitamin nutrition and function and to determine the daily vitamin needs for all patients with CKD.

Topics: Diet; Dietary Supplements; Humans; Renal Insufficiency, Chronic; Vitamin A; Vitamin K; Vitamins; Water

Although the role of vitamins in the human body is proven, guidelines for patients with chronic kidney disease (CKD) remain unclear. This narrative review summarizes the findings of 98 studies of CKD and the effects of vitamin D, B, C, A, E, and K supplementation on patients on dialysis for CKD, with the aim of summarizing the existing guidelines. The findings are promising, showing the potential effectiveness of vitamin supplementation with, for example, vitamins B, D, or C. However, recommendations are still ambiguous, especially in the case of vitamins A and K, due to the potential toxicity associated with higher doses for patients. Continued research is needed to rigorously evaluate the effectiveness and carefully consider the potential risks of some vitamin supplementation for patients with CKD.

Topics: Dietary Supplements; Humans; Renal Dialysis; Renal Insufficiency, Chronic; Vitamin A; Vitamin D; Vitamin D Deficiency; Vitamin K; Vitamins

Vitamin K (VK) plays many important functions in the body. The most important of them include the contribution in calcium homeostasis and anticoagulation. Vascular calcification (VC) is one of the most important mechanisms of renal pathology. The most potent inhibitor of this process-matrix Gla protein (MGP) is VK-dependent. Chronic kidney disease (CKD) patients, both non-dialysed and hemodialysed, often have VK deficiency. Elevated uncarboxylated matrix Gla protein (ucMGP) levels indirectly reflected VK deficiency and are associated with a higher risk of cardiovascular events in these patients. It has been suggested that VK intake may reduce the VC and related cardiovascular risk. Vitamin K intake has been suggested to reduce VC and the associated cardiovascular risk. The role and possibility of VK supplementation as well as the impact of anticoagulation therapy on VK deficiency in CKD patients is discussed.

Topics: Anticoagulants; Blood Coagulation; Bone and Bones; Calcium; Calcium-Binding Proteins; Cardiovascular Diseases; Extracellular Matrix Proteins; Humans; Matrix Gla Protein; Renal Dialysis; Renal Insufficiency, Chronic; Vascular Calcification; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

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.

Topics: Chronic Kidney Disease-Mineral and Bone Disorder; Female; Fractures, Bone; Humans; Male; Renal Insufficiency, Chronic; Vascular Calcification; Vitamin K

Chronic Kidney Disease (CKD) patients are at high risk of presenting with arterial calcification or stiffness, which confers increased cardiovascular mortality and morbidity. In recent years, it has become evident that VC is an active process regulated by various molecules that may act as inhibitors of vessel mineralization. Matrix Gla Protein (MGP), one the most powerful naturally occurring inhibitors of arterial calcification, requires vitamin K as a co-factor in order to undergo post-translational γ-carboxylation and phosphrorylation and become biologically active. The inactive form of MGP (dephosphorylated, uncarboxylated dp-ucMGP) reflects vitamin K deficiency and has been repeatedly associated with surrogate markers of VC, stiffness, and cardiovascular outcomes in CKD populations. As CKD is a state of progressive vitamin K depletion and VC, research has focused on clinical trials aiming to investigate the possible beneficial effects of vitamin K in CKD and dialysis patients. In this study, we aim to review the current evidence regarding vitamin K supplementation in uremic patients.

Topics: Dietary Supplements; Humans; Renal Dialysis; Renal Insufficiency, Chronic; Vascular Calcification; Vitamin K

Chronic kidney disease (CKD) is commonly associated with vitamin K deficiency. Some of the serious complications of CKD are represented by cardiovascular disease (CVD) and skeletal fragility with an increased risk of morbidity and mortality. A complex pathogenetic link between hormonal and ionic disturbances, bone tissue and metabolism alterations, and vascular calcification (VC) exists and has been defined as chronic kidney disease-mineral and bone disorder (CKD-MBD). Poor vitamin K status seems to have a key role in the progression of CKD, but also in the onset and advance of both bone and cardiovascular complications. Three forms of vitamin K are currently known: vitamin K1 (phylloquinone), vitamin K2 (menaquinone), and vitamin K3 (menadione). Vitamin K plays different roles, including in activating vitamin K-dependent proteins (VKDPs) and in modulating bone metabolism and contributing to the inhibition of VC. This review focuses on the biochemical and functional characteristics of vitamin K vitamers, suggesting this nutrient as a possible marker of kidney, CV, and bone damage in the CKD population and exploring its potential use for promoting health in this clinical setting. Treatment strategies for CKD-associated osteoporosis and CV disease should include vitamin K supplementation. However, further randomized clinical studies are needed to assess the safety and the adequate dosage to prevent these CKD complications.

Topics: Bone and Bones; Cardiovascular Diseases; Chronic Kidney Disease-Mineral and Bone Disorder; Female; Humans; Male; Renal Insufficiency, Chronic; Vascular Calcification; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

This narrative review aimed to summarize the current evidence on the connection between dysbiosis and vitamin K deficiency in patients with chronic kidney disease (CKD). The presence of dysbiosis (perturbations in the composition of the microbiota) has been described in several non-communicable diseases, including chronic kidney disease, and it has been hypothesized that dysbiosis may cause vitamin K deficiency. Patients with CKD present both vitamin K deficiency and gut dysbiosis; however, the relationship between gut dysbiosis and vitamin K deficiency remains to be addressed.. Recently, few studies in animals have demonstrated that a dysbiotic environment is associated with low production of vitamin K by the gut microbiota. Vitamin K plays a vital role in blood coagulation as well as in the cardiovascular and bone systems. It serves as a cofactor for γ-glutamyl carboxylases and thus is essential for the post-translational modification and activation of vitamin K-dependent calcification regulators, such as osteocalcin, matrix Gla protein, Gla-rich protein, and proteins C and S. Additionally, vitamin K executes essential antioxidant and anti-inflammatory functions. Dietary intake is the main source of vitamin K; however, it also can be produced by gut microbiota. This review discusses the effects of uremia on the imbalance in gut microbiota, vitamin K-producing bacteria, and vitamin K deficiency in CKD patients, leading to a better understanding and raising hypothesis for future clinical studies.

Topics: Animals; Dysbiosis; Humans; Renal Insufficiency, Chronic; Uremia; Vitamin K; Vitamin K Deficiency

Atrial fibrillation (AF) and chronic kidney disease (CKD) are closely related conditions with shared risk factors. The growing prevalence of both AF and CKD indicates that more patients will suffer from concurrent conditions. There are various complex interlinking mechanisms with important implications for the management of these patients. Furthermore, there is uncertainty regarding the use of oral anticoagulation (OAC) in AF and CKD that is reflected by a lack of consensus between international guidelines. Therefore, the importance of understanding the implications of co-existing AF and CKD should not be underestimated. In this review, we discuss the pathophysiology and association between AF and CKD, including the underlying mechanisms, risk of thrombo-embolic and bleeding complications, influence on stroke management, and evidence surrounding the use of OAC for stroke prevention.

Topics: Action Potentials; Administration, Oral; Animals; Anticoagulants; Atrial Fibrillation; Blood Coagulation; Heart Conduction System; Heart Rate; Humans; Kidney; Prognosis; Renal Insufficiency, Chronic; Risk Assessment; Risk Factors; Stroke; Thromboembolism; Vitamin K

Pathological calcification is a major cause of cardiovascular morbidities primarily in population with chronic kidney disease (CKD), end stage renal diseases (ERSD) and metabolic disorders. Investigators have accepted the fact that vascular calcification is not a passive process but a highly complex, cell mediated, active process in patients with cardiovascular disease (CVD) resulting from, metabolic insults of bone fragility, diabetes, hypertension, dyslipidemia and atherosclerosis. Over the years, studies have revealed various mechanisms of vascular calcification like induction of bone formation, apoptosis, alteration in Ca-P balance and loss of inhibition. Novel clinical studies targeting cellular mechanisms of calcification provide promising and potential avenues for drug development. The interventions include phosphate binders, sodium thiosulphate, vitamin K, calcimimetics, vitamin D, bisphosphonates, Myoinositol hexaphosphate (IP6), Denosumab and TNAP inhibitors. Concurrently investigators are also working towards reversing or curing pathological calcification. This review focuses on the relationship of vascular calcification to clinical diseases, regulators and factors causing calcification including genetics which have been identified. At present, there is lack of any significant preventive measures for calcifications and hence this review explores further possibilities for drug development and treatment modalities.

Topics: Atherosclerosis; Calcimimetic Agents; Calcium; Denosumab; Diabetes Mellitus; Diphosphonates; Dyslipidemias; Enzyme Inhibitors; Homeostasis; Hypertension; Inositol Phosphates; Phosphorus; Renal Insufficiency, Chronic; Thiosulfates; Vascular Calcification; Vitamin D; Vitamin K

Vitamin K is principally known because it is involved in blood coagulation. Furthermore, epidemiological studies showed that its deficit was associated with increased fragility fractures, vascular calcification and mortality. There are two main types of vitamin K vitamers: Phylloquinone (or PK) and Menaquinones (MKn). Vitamin K acts both as coenzyme of y-glutamyl carboxylase (GGCX) transforming undercarboxylated in carboxylated vitamin K-dependent proteins (e.g., Osteocalcin and Matrix Gla Protein) and as a ligand of the nuclear steroid and xenobiotic receptor (SXR) (in murine species Pregnane X Receptor: PXR), expressed in osteoblasts. It has been highlighted that the uremic state is a condition of greater vitamin K deficiency than the general population with resulting higher prevalence of bone fractures, vascular calcifications and mortality. The purpose of this literature review is to evaluate the protective role of Vitamin K in bone health in CKD patients.

Topics: Animals; Bone and Bones; Fractures, Bone; Humans; Mice; Osteocalcin; Renal Insufficiency, Chronic; Vitamin K

Vitamin K‑dependent proteins (VKDPs) are a group of proteins that need vitamin K to conduct carboxylation. Thus far, scholars have identified a total of 17 VKDPs in the human body. In this review, we summarize three important emerging VKDPs: Growth arrest‑specific protein 6 (Gas 6), Gla‑rich protein (GRP) and periostin in terms of their functions in physiological and pathological conditions. As examples, carboxylated Gas 6 and GRP effectively protect blood vessels from calcification, Gas 6 protects from acute kidney injury and is involved in chronic kidney disease, GRP contributes to bone homeostasis and delays the progression of osteoarthritis, and periostin is involved in all phases of fracture healing and assists myocardial regeneration in the early stages of myocardial infarction. However, periostin participates in the progression of cardiac fibrosis, idiopathic pulmonary fibrosis and airway remodeling of asthma. In addition, we discuss the relationship between vitamin K, VKDPs and cancer, and particularly the carboxylation state of VKDPs in cancer.

Topics: Animals; Cell Adhesion Molecules; Humans; Intercellular Signaling Peptides and Proteins; Myocardial Infarction; Osteoarthritis; Renal Insufficiency, Chronic; Vitamin K

Vitamin K (VK) and vitamin D (VD) deficiency/insufficiency is a common feature of chronic kidney disease (CKD), leading to impaired bone quality and a higher risk of fractures. CKD patients, with disturbances in VK and VD metabolism, do not have sufficient levels of these vitamins for maintaining normal bone formation and mineralization. So far, there has been no consensus on what serum VK and VD levels can be considered sufficient in this particular population. Moreover, there are no clear guidelines how supplementation of these vitamins should be carried out in the course of CKD. Based on the existing results of preclinical studies and clinical evidence, this review intends to discuss the effect of VK and VD on bone remodeling in CKD. Although the mechanisms of action and the effects of these vitamins on bone are distinct, we try to find evidence for synergy between them in relation to bone metabolism, to answer the question of whether combined supplementation of VK and VD will be more beneficial for bone health in the CKD population than administering each of these vitamins separately.

Topics: Adult; Animals; Bone and Bones; Bone Density; Bone Diseases, Metabolic; Bone Remodeling; Dietary Supplements; Drug Therapy, Combination; Female; Humans; Male; Mice; Rats; Renal Insufficiency, Chronic; Vitamin D; Vitamin D Deficiency; Vitamin K; Vitamins

Vascular calcification is a common and important cardiovascular risk factor in patients with chronic kidney disease (CKD). Recent advances in the understanding of the biology of vascular calcification implicate vitamin K-dependent proteins as important regulators in this process. This review highlights recent key advances in vascular biology, epidemiology, and clinical trials in this rapidly evolving field.. Vitamin K deficiency is associated with increasing severity of vascular calcification among patients with CKD, but the relationship with cardiovascular disease and mortality is inconsistent. Vitamin K may reduce calcification propensity by improving the activity of vitamin K-dependent calcification inhibitors or by down-regulating components of the innate immune system to reduce inflammation. However, recent randomized controlled trials in patients with diabetes, CKD, renal transplant, and on hemodialysis have failed to demonstrate improvement in vascular calcification or stiffness after vitamin K treatment.. Current evidence does not support a clinically useful role for vitamin K supplementation to prevent or reverse vascular calcification in patients with CKD. Knowledge gaps remain, particularly whether higher doses of vitamin K, longer duration of supplementations, or use a vitamin K as a part of a package of measures to counteract vascular calcification might be effective.

Topics: Humans; Renal Dialysis; Renal Insufficiency, Chronic; Vascular Calcification; Vitamin K; Vitamin K Deficiency

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Humans; Renal Insufficiency, Chronic; Stroke; Vitamin K

Vitamin K, well known for its role in coagulation, encompasses 2 major subgroups: vitamin K1 is exclusively synthesized by plants, whereas vitamin K2 mostly originates from bacterial synthesis. Vitamin K serves as a cofactor for the enzyme γ-glutamyl carboxylase, which carboxylates and thereby activates various vitamin K-dependent proteins. Several vitamin K-dependent proteins are synthesized in bone, but the role of vitamin K for bone health in chronic kidney disease patients, in particular the prevention of osteoporosis, is still not firmly established. Herein, we focus on another prominent action of vitamin K, in particular vitamin K2 (namely, the activation of matrix γ-carboxyglutamic acid protein, the most potent inhibitor of cardiovascular calcifications). Multiple observational studies link relative vitamin K deficiency or low intake to cardiovascular calcification progress, morbidity, and mortality. Patients with advanced chronic kidney disease are particularly vitamin K deficient, in part because of dietary restrictions but possibly also due to impaired endogenous recycling of vitamin K. At the same time, this population is characterized by markedly accelerated cardiovascular calcifications and mortality. High-dose dietary supplementation with vitamin K2, in particular the most potent form, menaquinone 7, can potently reduce circulating levels of dephosphorylated uncarboxylated (i.e., inactive matrix γ-carboxyglutamic acid protein) in patients with end-stage kidney disease. However, despite this compelling data basis, several randomized controlled trials with high-dose menaquinone 7 supplements in patients with advanced chronic kidney disease have failed to confirm cardiovascular benefits. Herein, we discuss potential reasons and solutions for this.

Topics: Humans; Renal Dialysis; Renal Insufficiency, Chronic; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

Chronic kidney disease (CKD) is a clinical model of premature ageing characterized by cardiovascular disease, persistent uraemic inflammation, osteoporosis muscle wasting and frailty. The accelerated early vascular ageing (EVA) process mediated by medial vascular calcification (VC) is a hallmark of senescence as well as a strong predictor of cardiovascular morbidity and mortality in the CKD population. Current clinical therapeutic strategies and novel treatments for VC have not yet been proven to prevent or reverse VC progression in patients with CKD. Knowledge of the fundamental mechanism underlying EVA is urgently needed to identify and develop novel and efficient therapeutic targets for VC and EVA. An accumulating body of evidence indicates that deoxyribonucleic acid (DNA) damage-induced cellular senescence and 'inflammaging' may largely contribute to such pathological conditions characterized by accelerated EVA. Growing evidence shows that nuclear factor erythroid 2-related factor 2 (NRF2) signalling and vitamin K play a crucial role in counteracting oxidative stress, DNA damage, senescence and inflammaging, whereby NRF2 activation and vitamin K supplementation may provide a novel treatment target for EVA. In this review we discuss the link between senescence and EVA in the context of CKD, with a focus on the role of NRF2 and vitamin K in DNA damage signalling, senescence and inflammaging.

Topics: Cardiovascular Diseases; Cellular Senescence; Disease Progression; DNA Damage; Humans; Inflammation; NF-E2-Related Factor 2; Oxidative Stress; Renal Insufficiency, Chronic; Vascular Calcification; Vitamin K

Chronic kidney disease (CKD) patients have a higher risk of cardiovascular (CVD) morbidity and mortality compared to the general population. The links between CKD and CVD are not fully elucidated but encompass both traditional and uremic-related risk factors. The term CKD-mineral and bone disorder (CKD-MBD) indicates a systemic disorder characterized by abnormal levels of calcium, phosphate, PTH and FGF-23, along with vitamin D deficiency, decreased bone mineral density or altered bone turnover and vascular calcification. A growing body of evidence shows that CKD patients can be affected by subclinical vitamin K deficiency; this has led to identifying such a condition as a potential therapeutic target given the specific role of Vitamin K in metabolism of several proteins involved in bone and vascular health. In other words, we can hypothesize that vitamin K deficiency is the common pathogenetic link between impaired bone mineralization and vascular calcification. However, some of the most common approaches to CKD, such as (1) low vitamin K intake due to nutritional restrictions, (2) warfarin treatment, (3) VDRA and calcimimetics, and (4) phosphate binders, may instead have the opposite effects on vitamin K metabolism and storage in CKD patients.

Topics: Calcium; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hyperparathyroidism; Osteocalcin; Phosphates; Renal Insufficiency, Chronic; Risk Factors; Vascular Calcification; Vitamin K; Vitamin K Deficiency; Warfarin

Direct oral anticoagulants (DOACs) are variably eliminated by the kidneys rendering their use potentially problematic in patients with chronic kidney disease (CKD) or necessitating appropriate dose adjustment.. Both observational and limited randomized trial data for DOACs compared with no treatment or with warfarin for patients with atrial fibrillation on maintenance dialysis were recently published. In a randomized trial in patients on hemodialysis, there was no significant difference in vascular calcification between patients who received rivaroxaban with or without vitamin K2 or vitamin K antagonists. A randomized trial of apixaban versus warfarin was terminated owing to poor enrollment and preliminary results identified no difference in clinical outcomes between groups. However, valuable pharmacodynamic data will be forthcoming from that trial. In observational research, among patients newly diagnosed with atrial fibrillation, there were opposing trends in the associations of apixaban initiation versus no oral anticoagulation with ischemic versus hemorrhagic stroke and no association was present with the overall risk of stroke or embolism. In another study comparing apixaban with warfarin initiation, apixaban was associated with less bleeding. Regular-dose apixaban (5 mg twice daily) associated with reduced rates of ischemic stroke or systemic embolism, whereas no such association was present for those prescribed the reduced dose (2.5 mg twice daily).. DOACs may be used after appropriate dose adjustment for an established clinical indication in patients with advanced CKD. Quality evidence for oral anticoagulation, with any specific agent or dose, for stroke prevention in hemodialysis continues to be lacking.

Topics: Acute Kidney Injury; Administration, Oral; Anticoagulants; Atrial Fibrillation; Glomerular Filtration Rate; Humans; Renal Insufficiency, Chronic; Stroke; Vitamin K

Vascular calcification is a known complication of chronic kidney disease (CKD). The prevalence of vascular calcification in patients with non-dialysis-dependent CKD stages 3-5 has been shown to be as high as 79% (20). Vascular calcification has been associated with increased risk for mortality, hospital admissions, and cardiovascular disease (6, 20, 50, 55). Alterations in mineral and bone metabolism play a pivotal role in the pathogenesis of vascular calcification in CKD. As CKD progresses, levels of fibroblast growth factor-23, parathyroid hormone, and serum phosphorus increase and levels of 1,25-(OH)

Topics: Animals; Anticoagulants; Arteries; Dietary Supplements; Humans; Iatrogenic Disease; Renal Dialysis; Renal Insufficiency, Chronic; Risk Factors; Signal Transduction; Vascular Calcification; Vitamin K; Vitamin K Deficiency; Warfarin

Phosphate toxicity is a well-established phenomenon, especially in chronic kidney disease (CKD), where hyperphosphatemia is a frequent occurrence when CKD is advanced. Many therapeutic efforts are targeted at phosphate, and comprise dietary intervention, modifying dialysis schemes, treating uncontrolled hyperparathyroidism and importantly, phosphate binder therapy. Despite all these interventions, hyperphosphatemia persists in many, and its pathological influence is ongoing. In nephrological care, a somewhat neglected aspect of treatment-when attempts fail to lower exposure to a toxin like phosphate-is to explore the possibility of "anti-dotes". Indeed, quite a long list of factors modify, or are mediators of phosphate toxicity. Addressing these, especially when phosphate itself cannot be sufficiently controlled, may provide additional protection. In this narrative overview, several factors are discussed that may qualify as either such a modifier or mediator, that can be influenced by other means than simply lowering phosphate exposure. A wider scope when targeting phosphate-induced comorbidity in CKD, in particular cardiovascular disease, may alleviate the burden of disease that is the consequence of this potentially toxic mineral in CKD.

Topics: Animals; Calcium; Calcium-Binding Proteins; Extracellular Matrix Proteins; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glucuronidase; Humans; Klotho Proteins; Magnesium; Matrix Gla Protein; Phosphates; Renal Insufficiency, Chronic; Vitamin K

Patients with chronic kidney disease (CKD) are at increased risk of osteoporosis and vascular calcification. Bone demineralization and vascular mineralization go often hand in hand in CKD, similar to as in the general population. This contradictory association is independent of aging and is commonly referred to as the "calcification paradox" or the bone-vascular axis. Various common risk factors and mechanisms have been identified. Alternatively, calcifying vessels may release circulating factors that affect bone metabolism, while bone disease may infer conditions that favor vascular calcification. The present review focuses on emerging concepts and major mechanisms involved in the bone-vascular axis in the setting of CKD. A better understanding of these concepts and mechanisms may identify therapeutics able to target and exert beneficial effects on bone and vasculature simultaneously.

Topics: Adaptor Proteins, Signal Transducing; Animals; Cardiovascular Diseases; Glucuronidase; Humans; Inflammation; Klotho Proteins; Osteoporosis; Osteoprotegerin; Parathyroid Hormone; Renal Insufficiency, Chronic; Signal Transduction; Vascular Calcification; Vitamin K

Accelerated and premature cardiovascular calcification is a hallmark of patients with chronic kidney disease (CKD) or end-stage renal disease (ESRD). The presence and the amount of cardiovascular calcification are among the driving forces of increased morbidity and mortality in renal patients. Cardiovascular calcification occurs at different sites, including the cardiac valves-a location that is of particular importance for both the patient and the treating physician. The correlation between degree of calcification and functional impairment is particularly close at the aortic valve, that is, the amount of calcification predicts the degree of stenosis. Calcific aortic stenosis (CAS) is the most prevalent valvular heart disease in Western societies. CAS is particularly prevalent in patients with underlying CKD or ESRD. CAS increases afterload and hence contributes to the widespread finding of left ventricular hypertrophy in CKD/ESRD patients. Medical treatment options to prevent the development and progression of CAS are limited. Hence, close surveillance and timely referral of patients for heart valve replacement therapy is a mainstay of current therapy. Novel treatment approaches, such as transcatheter aortic valve implantation, offer promising yet challenging options for elderly, comorbid, and often frail patients with CAS in combination with advanced CKD/ESRD.

Topics: Aortic Valve; Aortic Valve Stenosis; Calcinosis; Calcium-Regulating Hormones and Agents; Chelating Agents; Cinacalcet; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Renal Insufficiency, Chronic; Sevelamer; Transcatheter Aortic Valve Replacement; Vitamin K

Vitamin-K antagonists (VKA) have been the standard for oral anticoagulation. However, they carry several problems in older patients: frequent bleeding complications, complex management, risk of interactions with multiple drugs. Two classes of direct oral anticoagulants (DOA) are currently available in France: (a) direct thrombin inhibitors: dabigatran; and (b) direct factor Xa inhibitors: rivaroxaban, apixaban and others. Their management is easier: quickly effective after administration, they are given at fixed doses and do not need regular laboratory monitoring. Several randomized trials have shown that DOA are non-inferior to VKA for treating venous thromboembolic disease (prophylactic or curative treatment) and atrial fibrillation (prevention of associated embolisms). DOA might be also effective for long-term treatment of coronary disease, in some cases. No trial has specifically studied older patients. In the context of atrial fibrillation, subgroup analysis show similar results between patients above and below 75-years-old. Lower doses of dabigatran and apixaban should be used in many older people. All DOA are eliminated at least partly by kidneys. Their dose must be reduced in moderate renal failure (filtration glomerular rate (FGR) 30 to 50mL/min) and they are contraindicated in older patients with severe renal failure (FGR<30mL/min). DOA also have other problems: (a) important drug interactions are still possible, (b) the clinical application of specific coagulation tests need to be defined, (c) their safety in some subgroups of elderly patients, very different from patients included in clinical trials, is not known.

Topics: Acute Coronary Syndrome; Aged; Anticoagulants; Antithrombins; Atrial Fibrillation; Contraindications, Drug; Dose-Response Relationship, Drug; Drug Interactions; Factor Xa Inhibitors; Heart Valve Prosthesis; Hemorrhage; Humans; Renal Insufficiency, Chronic; Risk Factors; Secondary Prevention; Stroke; Thromboembolism; Vitamin K; Warfarin

Vascular calcification is a critical complication in patients with chronic kidney disease (CKD) because it is predictive of cardiovascular events and mortality. In addition to the traditional mechanisms associated with endothelial dysfunction and the osteoblastic transformation of vascular smooth muscle cells (VSMCs), the regulation of calcification inhibitors, such as calciprotein particles (CPPs) and matrix vesicles plays a vital role in uremic vascular calcification in CKD patients because of the high prevalence of vitamin K deficiency. Vitamin K governs the gamma-carboxylation of matrix Gla protein (MGP) for inhibiting vascular calcification, and the vitamin D binding protein receptor is related to vitamin K gene expression. For patients with chronic kidney disease, adequate use of vitamin D supplements may play a role in vascular calcification through modulation of the calciprotein particles and matrix vesicles (MVs).

Topics: Calcium-Binding Proteins; Dietary Supplements; Extracellular Matrix Proteins; Humans; Hyperphosphatemia; Matrix Gla Protein; Myocytes, Smooth Muscle; Renal Insufficiency, Chronic; Vascular Calcification; Vitamin D; Vitamin D Deficiency; Vitamin K; Vitamin K Deficiency

Vitamin K is a composite term referring to a group of fat-soluble vitamins that function as a cofactor for the enzyme γ-glutamyl carboxylase (GGCX), which activates a number of vitamin K-dependent proteins (VKDPs) involved in haemostasis and vascular and bone health. Accumulating evidence demonstrates that chronic kidney disease (CKD) patients suffer from subclinical vitamin K deficiency, suggesting that this represents a population at risk for the biological consequences of poor vitamin K status. This deficiency might be caused by exhaustion of vitamin K due to its high requirements by vitamin K-dependent proteins to inhibit calcification.

Topics: Bone and Bones; Carbon-Carbon Ligases; Dietary Supplements; Humans; Nutritional Status; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Vitamin K; Vitamin K Deficiency; Warfarin

Matrix Gla Protein (MGP), a small Gla vitamin K-dependent protein, is the most powerful natural occurring inhibitor of calcification in the human body. To become biologically active, MGP must undergo vitamin K-dependent carboxylation and phosphorylation. Vitamin K deficiency leads to the inactive uncarboxylated, dephosphorylated form of MGP (dpucMGP). We aimed to review the existing data on the association between circulating dpucMGP and vascular calcification, renal function, mortality, and cardiovascular disease in distinct populations. Moreover, the association between vitamin K supplementation and serum levels of dpucMGP was also reviewed.

Topics: Biological Transport; Calcium-Binding Proteins; Cardiovascular Diseases; Dietary Supplements; Extracellular Matrix Proteins; Gene Expression Regulation; Humans; Matrix Gla Protein; Phosphorylation; Protein Processing, Post-Translational; Renal Insufficiency, Chronic; Survival Analysis; Vascular Calcification; Vascular Stiffness; Vitamin K; Vitamin K Deficiency

The direct oral anticoagulants (DOACs) have emerged as an effective and safe alternative to vitamin K antagonists (VKAs) for stroke and venous thromboembolism (VTE) prevention. However, patients with chronic kidney disease (CKD) experience an increase in the risk of both thromboembolism and bleeding, and the risk-benefit profile of DOACs, particularly in advanced CKD remains a source of ongoing debate. This review summarizes the recent evidence on the effects of DOACs in CKD across a range of clinical indications including newly emerging indications.. Data on early-to-moderate stage CKD derived from pivotal randomized controlled trials in broader atrial fibrillation and VTE populations support the favorable risk-benefit ratio of DOACs compared with VKAs in patients in these groups. However, safety data from observational studies comparing DOACs with VKAs in patients with atrial fibrillation and CKD (moderate to advanced) have been conflicting. Recent trials have evaluated the efficacy of low-dose DOACs on major cardiovascular outcomes, showing promising risk-benefit ratios in high-risk populations with concurrent CKD.. Current data on patients with CKD derived from trials in the broader population suggest that DOACs are an effective alternative to VKAs in patients with early-to-moderate stage CKD. However, studies on patients with advanced CKD are lacking. Further randomized controlled trials, particularly those evaluating the risk of any clinically relevant bleeding as part of a more accurate assessment of the risk-benefit profile of DOACs in people with CKD, are needed.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Humans; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Stroke; Venous Thromboembolism; Vitamin K

Both atrial fibrillation (AF) and chronic kidney disease (CKD) are highly prevalent, especially with increasing age and associated comorbidities, such as hypertension, diabetes, heart failure, and vascular disease. The relationship between both AF and CKD seems to be bidirectional: CKD predisposes to AF while onset of AF seems to lead to progression of CKD. Stroke prevention is the cornerstone of AF management, and AF patients with CKD are at higher risk of stroke, mortality, cardiac events, and bleeding. Stroke prevention requires use of oral anticoagulants, which are either vitamin K antagonists (eg, warfarin), or the nonvitamin K antagonist oral anticoagulants (NOACs). While NOACs have been shown to be effective in mild-to-moderate renal dysfunction, there are a paucity of data regarding NOACs in severe and end-stage renal dysfunction. This review first discusses the evidence for NOACs in CKD. Second, we summarize the current knowledge regarding the efficacy and safety of NOACs to prevent AF-related stroke and systemic embolism in severe and end-stage renal disease.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Comorbidity; Glomerular Filtration Rate; Humans; Prognosis; Renal Insufficiency, Chronic; Thromboembolism; Vitamin K

Topics: Animals; Cardiovascular Diseases; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney; Metabolome; Proteins; Renal Insufficiency, Chronic; Risk Assessment; Risk Factors; Vitamin K; Vitamin K Deficiency

In daily practice, chemical substances called "direct oral anticoagulants" or DOACs are more convenient to administer when set beside vitamin K antagonists (VKA) due to improved pharmacologic properties, fewer drug interactions and rapid onset of action. The objective of this review was to assess whether DOACs are the alternative for VKA in subjects with mild-to-moderate chronic kidney disease (CKD). An analysis of current DOAC trials and studies was performed focusing on subjects with CKD. This review concludes that although DOACS are not recommended in the course of advanced chronic kidney disease (CrCl<30mL/min) or during dialysis, DOACS are a reasonable choice for individuals with mild to moderate CKD.

Topics: Anticoagulants; Hemorrhage; Humans; Renal Insufficiency, Chronic; Stroke; Venous Thrombosis; Vitamin K

Atrial fibrillation (AF) represents the most common arrhythmia in patients with chronic kidney disease (CKD). As in the general population, AF is associated with an increased risk of thromboembolism and stroke, according to progressive decline of glomerular filtration rate (GFR). However, CKD patients, especially those on renal replacement therapy (RRT), also exhibit an increased risk of bleeding, especially from the gastrointestinal tract. Oral anticoagulation is the most effective form of thromboprophylaxis in patients with AF presenting increased risk of stroke. Limited evidence on efficacy, the increased risk of bleeding as well as some concern regarding the use of warfarin in CKD, has often resulted in the underuse of anticoagulation CKD patients. A large body of evidence suggests that non-vitamin K-dependent oral anticoagulant agents (NOACs) significantly reduce the risk of stroke, intracranial hemorrhage, and mortality, with lower to similar major bleeding rates compared with vitamin K antagonist such as warfarin in normal renal function subjects. Hence, they are currently recommended for patients with atrial fibrillation at risk for stroke. However, NOACs metabolism is largely dependent on the kidneys for elimination and little is known in patients with creatinine clearance <25 ml/min who were excluded from all pivotal phase 3 NOACs trials. This review focuses on the current pharmacokinetic, observational, and prospective data on NOACs in patients with advanced chronic kidney disease (creatinine clearance <25 ml/) and those on dialysis.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Humans; Renal Dialysis; Renal Insufficiency, Chronic; Stroke; Thromboembolism; Vitamin K

Anticoagulation in patients with impaired kidney function can be challenging since drugs' pharmacokinetics and bioavailability are altered in this setting. Patients with chronic kidney disease (CKD) treated with conventional anticoagulant agents [vitamin K antagonist (VKA), low-molecular weight heparin (LMWH) or unfractionated heparin (UFH)] are at high risk of bleeding events (both non-major and major clinically relevant bleeding). While anticoagulation reduces the risk of thromboembolic events, the co-existing bleeding risk and the fact that the most commonly used anticoagulation agents are eliminated via the kidneys pose additional challenges. More recently, two classes of direct oral anticoagulant agents (DOACs) have been investigated for the prevention and management of venous thromboembolic events: the direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban, and the direct thrombin inhibitor dabigatran. In this review, we discuss the complex challenges and the practical considerations associated with the management of anticoagulation treatment in patients with CKD, with a special focus on DOACs.

Topics: Administration, Oral; Anticoagulants; Dabigatran; Hemorrhage; Heparin; Humans; Pyrazoles; Pyridones; Renal Insufficiency, Chronic; Rivaroxaban; Thrombosis; Vitamin K

Currently there is lack of head-to-head comparisons between different Non-Vitamin K Antagonist Oral Anticoagulants (NOACs), especially in more risky subgroups, as those with chronic kidney disease (CKD).. We assessed the relative efficacy and safety of the four NOACs on the market in a systematic review and network meta-analysis of patients with atrial fibrillation (AF) and moderate CKD enrolled in the phase 3 randomized trials. A Bayesian framework was used to perform the network meta-analysis. Treatment hierarchy was assessed by surface under the cumulative ranking (SUCRA) curves.. Five randomized trials including 13,878 AF patients with moderate CKD were identified. Full/Single dose NOACs were associated with significant reductions in the odds of stroke/systemic embolism (odd ratio [OR] 0.79, 95% credible intervals [CrI] 0.67-0.94) and major bleeding (OR 0.74, 95% CrI 0.65-0.86) compared with Warfarin. Dabigatran 150 had the highest probability of being ranked first with respect to efficacy (SUCRA 0.96), whereas Apixaban had the second highest (SUCRA 0.67); Dabigatran 110, Rivaroxaban and Edoxaban High-Dose showed similar probabilities of being ranked first for efficacy (SUCRA 0.54, 0.53, 0.51, respectively); with respect to safety, only Apixaban and Edoxaban High Dose had a probability >50% of being ranked first (SUCRA 0.84 and 0.61, respectively).. Indirect comparisons generated the hypothesis that Apixaban and Edoxaban High-Dose might be more likely associated with a better net clinical profile in AF patients with moderate CKD. These findings may potentially guide physicians in selecting the most appropriate NOAC for each patient, while waiting for dedicated evidences.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Humans; Network Meta-Analysis; Renal Insufficiency, Chronic; Thromboembolism; Vitamin K

Patients with chronic kidney disease (CKD) are prone to vascular calcification. Pathogenetic mechanisms of vascular calcifications have been broadly studied and discussed such as the role of hyperphosphatemia, hypercalcemia, parathormone, and vitamin D. In recent years, new insights have been gained pointing to vitamin K as a main actor. It has been discovered that vitamin K is an essential cofactor for the activation of matrix Gla protein (MGP), a calcification inhibitor in the vessel wall. Patients with CKD often suffer from vitamin K deficiency, resulting in low active MGP and eventually a lack of inhibition of vascular calcification. Vitamin K supplementation and switching warfarin to new oral anticoagulants are potential treatments. In addition, MGP may have a role as a non-invasive biomarker for vascular calcification.

Topics: Biomarkers; Dietary Supplements; Humans; Renal Insufficiency, Chronic; Vascular Calcification; Vitamin K; Vitamins

A bidirectional relationship exists between atrial fibrillation (AF) and chronic renal disease. Patients with AF have a higher incidence of renal dysfunction, and the latter predisposes to incident AF. The coexistence of both conditions results in a higher risk for thromboembolic-related adverse events but a paradoxical increased hemorrhagic risk. Oral anticoagulants (both vitamin K antagonists [VKAs] and non-VKA oral anticoagulants [NOACs]) have been demonstrated to be effective in mild to moderate renal dysfunction. Patients with severe renal impairment were excluded from the non-VKA oral anticoagulant trials, so limited data are available. In end-stage renal failure, the net clinical benefit of VKAs in dialysis-dependent patients remains uncertain, although some evidence suggests that such patients may do well with high-quality anticoagulation control. Risk stratification and careful follow-up of such patients are necessary to ensure a net clinical benefit from thromboprophylaxis.

Topics: Administration, Oral; Algorithms; Anticoagulants; Atrial Fibrillation; Hemorrhage; Humans; Renal Insufficiency, Chronic; Risk Assessment; Stroke; Thromboembolism; Vitamin K

The high risk of both stroke and major bleeding in atrial fibrillation (AF) patients with chronic kidney disease (CKD) defines an important population for whom the assessment of the balance between the risk of ischemic stroke and of bleeding is essential. The use of novel oral anticoagulants (NOACs) may be a viable option in this population due to their greater net clinical benefit than warfarin, as demonstrated by the results of the clinical phase III trials. NOACs have been found to have a greater net clinical benefit than warfarin in patients at high risk of either stroke (CHADS2≥1 or CHA2DS2-VASc score≥2) or bleeding (HAS-BLED≥3). Noteworthy, it has been found also a positive net clinical benefit with apixaban and dabigatran 110mg BID in patients with CHADS2 score=0 and HAS-BLED score≥3. At CHA2DS2-VASc score=1, apixaban and both doses of dabigatran were superior to warfarin in terms of the net clinical benefit. Available scientific evidence might help in clinical decision-making regarding the use of NOACs in patients with CKD who are at high risk for both stroke and bleeding. Overall, current findings provide a rationale for the choice of apixaban or rivaroxaban over dabigatran in patients with AF and stage III CKD. Out of the NOACs, only apixaban has been recently approved for the use in patients with end-stage renal dysfunction on hemodialysis (the recommended dose of 5mg twice daily should be halved in patients with body weight of ≤60kg and or age≥80years).

Topics: Anticoagulants; Atrial Fibrillation; Clinical Trials, Phase III as Topic; Humans; Pyrazoles; Pyridones; Renal Insufficiency, Chronic; Severity of Illness Index; Treatment Outcome; Vitamin K

Anticoagulant agents have been approved by international regulatory agencies to prevent and treat venous thromboembolism (VTE). However, chronic kidney disease (CKD) is: (1) highly frequent in VTE patients; (2) strongly linked to VTE; and (3) a risk factor for cardiovascular morbidity/mortality and fatal pulmonary embolism. Therefore, an increasing number of patients are presented with CKD and VTE and more and more physicians must face the questions of the management of these patients and that of the handling of anticoagulant agents in CKD patients because of the pharmacokinetic modifications of these drugs in this population. These modifications may lead to overdosage and dose-related side effects, such as bleeding. It is therefore necessary to screen VTE patients for CKD and to modify the doses of anticoagulants, if necessary.

Topics: Anticoagulants; Cardiovascular Diseases; Drug Overdose; Heparin; Heparin, Low-Molecular-Weight; Humans; Kidney; Pulmonary Embolism; Renal Insufficiency, Chronic; Risk Factors; Venous Thromboembolism; Vitamin K

Novel oral anticoagulants (NOACs) including apixaban, dabigatran and rivaroxaban have been approved by international regulatory agencies to prevent venous thromboembolism as well as treat atrial fibrillation and venous thromboembolism in individuals with chronic kidney disease (CKD). However, alterations in their metabolism in the setting of CKD may impact their efficacy and lead to an increased risk of bleeding. This review summarizes the current literature on the efficacy and safety of these agents in individuals with moderate CKD.. In clinical trials, the use of the NOACs in patients with moderate CKD has demonstrated efficacy and safety similar to those seen with vitamin K antagonists. However, no universal reversal agent for the anticoagulant effect of the NOACs exists in the setting of bleeding. Limited data have demonstrated that hemodialysis has been effectively used to aid in reversing the effects of dabigatran, and the use of prothrombin complex concentrate has also been used for serious and major adverse bleeding events with some success.. As the use of the NOACs in patients with CKD increases, it will be important to monitor their safety, and clinicians who prescribe them should carefully monitor kidney function and recognize the potential for adverse effects.

Topics: Animals; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Fibrinolytic Agents; Humans; Renal Insufficiency, Chronic; Venous Thromboembolism; Vitamin K

Venous thromboembolism (VTE) is a disease state that carries significant morbidity and mortality, and is a known cause of preventable death in hospitalized and orthopedic surgical patients. There are many identifiable risk factors for VTE, yet up to half of VTE incident cases have no identifiable risk factor and carry a high likelihood of recurrence, which may warrant extended therapy. For many years, parenteral unfractionated heparin, low-molecular weight heparin, fondaparinux, and oral vitamin K antagonists (VKAs) have been the standard of care in VTE management. However, limitations in current drug therapy options have led to suboptimal treatment, so there has been a need for rapid-onset, fixed-dosing novel oral anticoagulants in both VTE treatment and prophylaxis. Oral VKAs have historically been challenging to use in clinical practice, with their narrow therapeutic range, unpredictable dose responsiveness, and many drug-drug and drug-food interactions. As such, there has also been a need for novel anticoagulant therapies with fewer limitations, which has recently been met. Dabigatran etexilate is a fixed-dose oral direct thrombin inhibitor available for use in acute and extended treatment of VTE, as well as prophylaxis in high-risk orthopedic surgical patients. In this review, the risks and overall benefits of dabigatran in VTE management are addressed, with special emphasis on clinical trial data and their application to general clinical practice and special patient populations. Current and emerging therapies in the management of VTE and monitoring of dabigatran anticoagulant-effect reversal are also discussed.

Topics: Acute Coronary Syndrome; Anticoagulants; Antithrombins; Comorbidity; Dabigatran; Hemorrhage; Humans; Renal Dialysis; Renal Insufficiency, Chronic; Risk Assessment; Venous Thromboembolism; Vitamin K

The purpose of this paper was to review the literature concerning the treatment of chronic kidney disease-mineral bone disorder (CKD-MBD) in the elderly peritoneal dialysis (PD) patient.. Chronic kidney disease-mineral bone disorder is a major problem in the elderly PD patient, with its associated increased fracture risk, vascular calcification, and accelerated mortality fracture risk. Peritoneal dialysis, however, bears a lower risk than hemodialysis (HD). The approach to CKD-MBD prophylaxis and treatment in the elderly PD patient is similar to other CKD patients, with some important differences. Avoidance of hypercalcemia, hyperphosphatemia, and hyperparathyroidism is important, as in other CKD groups, and is generally easier to attain. Calcium-free phosphate binders are recommended for normocalcemic and hypercalcemic patients. Normalization of vitamin D levels to > 75 nmol/L (> 30 pg/L) and low-dose active vitamin D therapy is recommended for all patients. Hyperparathryoidism is to be avoided by using active vitamin D and cinacalcet. Particular attention should be paid to treating protein malnutrition. Fracture prophylaxis (exercise, use of walkers, dwelling modifications) are important. Hypomagnesemia is common in PD and can be treated with magnesium supplements. Vitamin K deficiency is also common and has been identified as a cause of vascular calcification. Accordingly, warfarin treatment for this age group is problematic.. While treatment principles are similar to other dialysis patient groups, physicians should be aware of the special problems of the elderly group.

Topics: Aged; Aged, 80 and over; Bone Demineralization, Pathologic; Bone Density; Bone Diseases, Metabolic; Calcium; Dietary Supplements; Exercise; Female; Follow-Up Studies; Fractures, Spontaneous; Geriatric Assessment; Humans; Magnesium; Male; Peritoneal Dialysis; Renal Insufficiency, Chronic; Risk Assessment; Treatment Outcome; Vitamin D; Vitamin K

Novel oral anticoagulants (NOACs) (rivaroxaban, dabigatran, apixaban) have been approved by international regulatory agencies to treat atrial fibrillation and venous thromboembolism in patients with kidney dysfunction. However, altered metabolism of these drugs in the setting of impaired kidney function may subject patients with CKD to alterations in their efficacy and a higher risk of bleeding. This article examined the efficacy and safety of the NOACs versus vitamin K antagonists (VKAs) for atrial fibrillation and venous thromboembolism in patients with CKD. A systematic review and meta-analyses of randomized controlled trials were conducted to estimate relative risk (RR) with 95% confidence interval (95% CIs) using a random-effects model. MEDLINE, Embase, and the Cochrane Library were searched to identify articles published up to March 2013. We selected published randomized controlled trials of NOACs compared with VKAs of at least 4 weeks' duration that enrolled patients with CKD (defined as creatinine clearance of 30-50 ml/min) and reported data on comparative efficacy and bleeding events. Eight randomized controlled trials were eligible. There was no significant difference in the primary efficacy outcomes of stroke and systemic thromboembolism (four trials, 9693 participants; RR, 0.64 [95% CI, 0.39 to 1.04]) and recurrent thromboembolism or thromboembolism-related death (four trials, 891 participants; RR, 0.97 [95% CI, 0.43 to 2.15]) with NOACs versus VKAs. The risk of major bleeding or the combined endpoint of major bleeding or clinically relevant nonmajor bleeding (primary safety outcome) (eight trials, 10,616 participants; RR 0.89 [95% CI, 0.68 to 1.16]) was similar between the groups. The use of NOACs in select patients with CKD demonstrates efficacy and safety similar to those with VKAs. Proactive postmarketing surveillance and further studies are pivotal to further define the rational use of these agents.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Hemorrhage; Humans; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Venous Thromboembolism; Vitamin K

The mechanisms of vascular calcifications in chronic renal failure are complex. Apart for clotting factors, vitamin K-dependent proteins include matrix Gla protein. Glutamic acid residues in matrix Gla protein are carboxylated by vitamin K-dependent gamma-carboxylase, which enables it to inhibit calcification. The purpose of this review is to discuss available evidence implicating vitamin K as a modifiable risk factor in the pathogenesis of vascular calcification in renal diseases.

Topics: Effect Modifier, Epidemiologic; Humans; Models, Biological; Nutritional Physiological Phenomena; Renal Insufficiency, Chronic; Risk Factors; Vascular Calcification; Vitamin K; Vitamin K Deficiency

The purpose of this review is to summarize the research to date on vitamin K status in chronic kidney disease (CKD). This review includes a summary of the data available on vitamin K status in patients across the spectrum of CKD as well as the link between vitamin K deficiency in CKD and bone dynamics, including mineralization and demineralization, as well as ectopic mineralization. It also describes two current clinical trials that are underway evaluating vitamin K treatment in CKD patients. These data may inform future clinical practice in this population.

Topics: Bone and Bones; Bone Density; Deficiency Diseases; Humans; Kidney Failure, Chronic; Nutritional Status; Renal Insufficiency, Chronic; Vitamin K; Vitamins

Hepatic vitamin K-dependent proteins (e.g., Factors II, VII, IX and X) form part of the clotting cascade. Factor II (FII)/Prothrombin incorporates 10 Glu residues on the N-terminal region that are γ-carboxylated to Gla residues by the action of γ-glutamyl carboxylase to confer biological activity. Vitamin K is also required for the normal function of Matrix Gla Protein (MGP)--one of several non-clotting-related extra-hepatic vitamin K-dependent proteins. MGP is known to have protective action against vascular calcification--indeed it is a powerful tissue-bound inhibitory mechanism and can be found in blood vessel walls. The mature protein is also dependent on activation by γ-glutamyl carboxylase enzyme to convert Glu residues in its amino acid sequence to Gla. This reaction can only take place when the enzyme is activated in the presence of vitamin K. It is of great potential interest to investigate whether subtle deficiencies of vitamin K may, through its effect on the action of MGP, be a contributing factor to vascular calcification in CKD patients, in whom CV disease is greatly accelerated and in whom vascular calcification is not only common, but progresses aggressively, and is something for which as yet there is no clinically applicable remedy.

Topics: Adult; Aged; Biomarkers; Calcinosis; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Protein Precursors; Prothrombin; Renal Insufficiency, Chronic; Vascular Diseases; Vitamin K; Vitamin K Deficiency

As chronic kidney disease (CKD) is a contraindication to the use of the new anticoagulants, the vitamin K antagonists (VKA) are still valid in patients with CKD, though their use may be harmful. During overanticoagulation, some patients can develop acute kidney injury (AKI), especially those with CKD, by obstruction of the renal tubules and Bowman's spaces by erythrocytes. In addition, VKA increase atherogenesis through vitamin K deficiency, which is essential for the carboxylation of proteins that inhibit calcification of vessels. Eventually, hemodialysed patients under VKA have an increased risk of stroke, especially those over 75 years of age. Therefore anticoagulation with VKA in patients with CKD should be carefully implemented and its monitoring more frequent than in non-CKD patients.

Topics: 4-Hydroxycoumarins; Acute Kidney Injury; Anticoagulants; Atherosclerosis; Blood Coagulation Disorders; Cerebrovascular Disorders; Coumarins; Humans; Indenes; Renal Insufficiency, Chronic; Vitamin K; Warfarin

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Humans; Renal Insufficiency, Chronic; Stroke; Vitamin K

In patients with normal renal function or early stage CKD, the risk-benefit profile of direct oral anticoagulants (DOACs) is superior to that of vitamin K antagonists (VKAs). In patients on hemodialysis, the comparative efficacy and safety of DOACs versus VKAs are unknown.. In the Valkyrie study, 132 patients on hemodialysis with atrial fibrillation were randomized to a VKA with a target INR of 2-3, 10 mg rivaroxaban daily, or rivaroxaban and vitamin K2 for 18 months. Patients continued the originally assigned treatment and follow-up was extended for at least an additional 18 months. The primary efficacy end point was a composite of fatal and nonfatal cardiovascular events. Secondary efficacy end points were individual components of the composite outcome and all-cause death. Safety end points were life-threatening, major, and minor bleeding.. Median (IQR) follow-up was 1.88 (1.01-3.38) years. Premature, permanent discontinuation of anticoagulation occurred in 25% of patients. The primary end point occurred at a rate of 63.8 per 100 person-years in the VKA group, 26.2 per 100 person-years in the rivaroxaban group, and 21.4 per 100 person-years in the rivaroxaban and vitamin K2 group. The estimated competing risk-adjusted hazard ratio for the primary end point was 0.41 (95% CI, 0.25 to 0.68;. In patients on hemodialysis with atrial fibrillation, a reduced dose of rivaroxaban significantly decreased the composite outcome of fatal and nonfatal cardiovascular events and major bleeding complications compared with VKA.. Oral Anticoagulation in Hemodialysis, NCT03799822.

Topics: Aged; Aged, 80 and over; Antifibrinolytic Agents; Atrial Fibrillation; Cardiovascular Diseases; Factor Xa Inhibitors; Female; Hemorrhage; Humans; International Normalized Ratio; Male; Mortality; Renal Dialysis; Renal Insufficiency, Chronic; Rivaroxaban; Vitamin K; Vitamin K 2

Limited data are available on the impact of renal function on the outcome of patients with atrial fibrillation (AF).. AMADEUS was a multicentre, randomized, open-label non-inferiority study that compared fixed-dose idraparinux with conventional anticoagulation by dose-adjusted vitamin K antagonists. We performed a post hoc analysis to assess the impact of renal function on the outcomes of anticoagulated AF patients. The primary efficacy outcome was the composite of stroke/systemic embolism (SE). The principal safety outcome of this analysis was major bleeding. We calculated c-indexes, reflecting the ability for discriminating diseased vs. non-diseased patients, and the net reclassification improvement (NRI, an index of inferior/superior performance of risk estimation scores). Of 4576 patients, 45 strokes and 103 major bleeding events occurred following an average follow-up of 325 ± 164 days. Patients with CrCl >90 mL/min had an annual stroke/SE rate of 0.6% compared with 0.8% for those with CrCl 60-90 mL/min and 2.2% for those with CrCl <60 mL/min (P < 0.001 for linear association). After adjusting for stroke risk factors, patients with CrCl <60 mL/min had more than two-fold higher risk of stroke/SE and almost 60% higher risk of major bleeding compared with those with CrCl ≥60. In patients with the CHA2DS2VASc score 1-2, CrCl <60 mL/min was associated with eight-fold higher stroke risk. When added to the CHA2DS2VASc or CHADS2 scores, CrCl <60 mL/min did not improve the c-indexes for CHADS2 (P = 0.054) or CHA2DS2VASc (P = 0.63) but resulted in significant NRI (0.26, P = 0.02) in this anticoagulated trial cohort.. Renal impairment (CrCl <60 mL/min) doubles the risk of stroke and increased the risk of major bleeding by almost 60% in anticoagulated patients with AF. Renal impairment was additive to stroke risk prediction scores based on a significant NRI, but no significant improvement in discrimination ability (based on c-indexes) for CHA2DS2VASc or CHADS2 was observed.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Hemorrhage; Humans; Kaplan-Meier Estimate; Male; Oligosaccharides; Renal Insufficiency, Chronic; Risk Assessment; ROC Curve; Stroke; Vitamin K

An unmet need exists to reliably predict the risk of intracranial hemorrhage (ICH) in patients with atrial fibrillation (AF) treated with oral anticoagulants (OACs).. An externally validated model improves ICH risk stratification.. Independent factors associated with ICH were identified by Cox proportional hazard modeling, using pooled data from the GARFIELD-AF (Global Anticoagulant Registry in the FIELD-Atrial Fibrillation) and ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) registries. A predictive model was developed and validated by bootstrap sampling and by independent data from the Danish National Patient Register.. In the combined training data set, 284 of 53 878 anticoagulated patients had ICH over a 2-year period (0.31 per 100 person-years; 95% confidence interval [CI]: 0.28-0.35). Independent predictors of ICH included: older age, prior stroke or transient ischemic attack, concomitant antiplatelet (AP) use, and moderate-to-severe chronic kidney disease (CKD). Vitamin K antagonists (VKAs) were associated with a significantly higher risk of ICH compared with non-VKA oral anticoagulants (NOACs) (adjusted hazard ratio: 1.61; 95% CI: 1.25-2.08; p = .0002). The ability of the model to discriminate individuals in the training set with and without ICH was fair (optimism-corrected C-statistic: 0.68; 95% CI: 0.65-0.71) and outperformed three previously published methods. Calibration between predicted and observed ICH probabilities was good in both training and validation data sets.. Age, prior ischemic events, concomitant AP therapy, and CKD were important risk factors for ICH in anticoagulated AF patients. Moreover, ICH was more frequent in patients receiving VKA compared to NOAC. The new validated model is a step toward mitigating this potentially lethal complication.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Humans; Intracranial Hemorrhages; Registries; Renal Insufficiency, Chronic; Risk Factors; Stroke; Vitamin K

Chronic kidney disease (CKD) is accompanied with extensive cardiovascular calcification, in part correlating with functional vitamin K deficiency. Here, we sought to determine causes for vitamin K deficiency beyond reduced dietary intake. Initially, vitamin K uptake and distribution into circulating lipoproteins after a single administration of vitamin K1 plus K2 (menaquinone 4 and menaquinone 7, respectively) was determined in patients on dialysis therapy and healthy individuals. The patients incorporated very little menaquinone 7 but more menaquinone 4 into high density lipoprotein (HDL) and low-density lipoprotein particles than did healthy individuals. In contrast to healthy persons, HDL particles from the patients could not be spiked with menaquinone 7 in vitro and HDL uptake was diminished in osteoblasts. A reduced carboxylation activity (low vitamin K activity) of uremic HDL particles spiked with menaquinone 7 vs. that of controls was confirmed in a bioassay using human primary vascular smooth muscle cells. Kidney menaquinone 4 tissue levels were reduced in 5/6-nephrectomized versus sham-operated C57BL/6 mice after four weeks of a vitamin K rich diet. From the analyzed enzymes involved in vitamin K metabolism, kidney HMG-CoA reductase protein was reduced in both rats and patients with CKD. In a trial on the efficacy and safety of atorvastatin in 1051 patients with type 2 diabetes receiving dialysis therapy, no pronounced vitamin K deficiency was noted. However, the highest levels of PIVKA-II (biomarker of subclinical vitamin K deficiency) were noted when a statin was combined with a proton pump inhibitor. Thus, profound disturbances in lipoprotein mediated vitamin K transport and metabolism in uremia suggest that menaquinone 7 supplementation to patients on dialysis therapy has reduced efficacy.

Topics: Animals; Diabetes Mellitus, Type 2; Humans; Mice; Mice, Inbred C57BL; Rats; Renal Insufficiency, Chronic; Tissue Distribution; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

Vascular calcification contributes to cardiovascular disease (CVD) and mortality in individuals with chronic kidney disease (CKD). Vitamin K-dependent proteins function as calcification inhibitors in vascular tissue.. We sought to determine the association of vitamin K status with mortality and CVD events in adults with CKD.. Plasma dephospho-uncarboxylated matrix gla protein ((dp)ucMGP), which increases when vitamin K status is low, and plasma phylloquinone (vitamin K1), which decreases when vitamin K status is low, were measured in 3066 Chronic Renal Insufficiency Cohort participants (median age = 61 y, 45% female, 41% non-Hispanic black, median estimated glomerular filtration rate [eGFR] = 41 mL/min/1.73m2). The association of vitamin K status biomarkers with all-cause mortality and atherosclerotic-related CVD was determined using multivariable Cox proportional hazards regression.. There were 1122 deaths and 599 atherosclerotic CVD events over the median 12.8 follow-up years. All-cause mortality risk was 21-29% lower among participants with plasma (dp)ucMGP <450 pmol/L (n = 2361) compared with those with plasma (dp)ucMGP ≥450 pmol/L (adjusted HRs [95% CIs]: <300 pmol/L = 0.71 [0.61, 0.83], 300-449 pmol/L = 0.77 [0.66, 0.90]) and 16-19% lower among participants with plasma phylloquinone ≥0.50 nmol/L (n = 2421) compared to those with plasma phylloquinone <0.50 nmol/L (adjusted HRs: 0.50, 0.99 nmol/L = 0.84 [0.72, 0.99], ≥1.00 nmol/L = 0.81 [0.70, 0.95]). The risk of atherosclerotic CVD events did not significantly differ across plasma (dp)ucMGP or phylloquinone categories.. Two biomarkers of vitamin K status were associated with a lower all-cause mortality risk but not atherosclerotic CVD events. Additional studies are needed to clarify the mechanism underlying this association and evaluate the impact of improving vitamin K status in people with CKD.

Topics: Adult; Biomarkers; Cardiovascular Diseases; Female; Humans; Male; Middle Aged; Renal Insufficiency, Chronic; Vitamin K; Vitamin K 1

Vascular calcification is a major manifestation of cardiovascular disease in advanced chronic kidney disease and is inhibited by vitamin K-dependent proteins. Clinical trials of vitamin K supplementation in chronic kidney disease have failed to demonstrate benefits on vascular calcification. Recent laboratory, human, and animal studies have shown that vitamin K handling and metabolism in chronic kidney disease is complex and suggest vitamin K2 subtype supplementation in isolation is unlikely to have significant clinical impact.

Topics: Animals; Brassica; Dietary Supplements; Renal Insufficiency, Chronic; Vascular Calcification; Vitamin K; Vitamin K 2

Topics: Adult; Calcification, Physiologic; Cardiovascular Diseases; Cohort Studies; Female; Humans; Male; Renal Insufficiency, Chronic; Vitamin K

Vascular calcification (VC) is highly prevalent in Chronic Kidney Disease (CKD) patients, progresses gradually with deterioration of kidney function and is a strong, independent predictor of cardiovascular (CV) mortality. Matrix Gla Protein (MGP), the most potent inhibitor of VC, requires vitamin K as a co-factor to become biologically active. Accumulating epidemiological data have associated vitamin K depletion with VC progression and CV outcomes. CKD patients are characterized by poor vitamin K status and at the same time, pronounced CV calcification. In early and advanced CKD, including end-stage kidney disease, exogenous supplementation of vitamin K (especially with menaquinone 7, its most bioavailable form) might decrease the inactive form of MGP (dephosphorylated, uncarboxylated MGP) and probably retard the progression or even reverse VC. Here, we focus and discuss the interventional human studies of vitamin K supplementation in CKD patients and suggest future directions in this area of interest.

Topics: Dietary Supplements; Female; Humans; Male; Renal Dialysis; Renal Insufficiency, Chronic; Vascular Calcification; Vitamin K; Vitamin K Deficiency

Non-vitamin-K dependent oral anti-coagulants (NOAC) are the current therapeutic standard for preventing strokes in patients with atrial fibrillation (AF) and should be preferred over vitamin K antagonists (VKA) in this indication. This recommendation applies also to patients with VHF and concomitant chronic kidney disease (CKD). Real World Evidence (RWE), i. e., structured data from clinical practice, extends and confirms the clinical evidence generated in more formalized clinical trials with NOAC and VKA. In addition, RWE in respect to the indication showed that the superiority of NOAC versus the VKA warfarin can also be extrapolated to phenprocoumon, the commonly used VKA in Germany. Furthermore, data include evidence that the typical progression of CKD appears to be less pronounced in individuals treated with NOAC compared to those treated with VKA.. Die momentanen Leitlinien empfehlen Nicht-Vitamin-K-abhängige orale Antikoagulanzien (NOAK) als Therapiestandard für die Schlaganfallprophylaxe bei Patienten mit Vorhofflimmern (VHF) und sind daher den Vitamin-K-Antagonisten (VKA) vorzuziehen. Diese Empfehlung gilt auch für Patienten mit VHF und chronischer nicht dialysepflichtiger Niereninsuffizienz. Sogenannte Real-World-Evidenz (RWE), also Daten aus der klinischen Praxis, erweitert und bestätigt die zugrunde liegende klinische Evidenz, die in den stärker formalisierten klinischen Prüfungen mit NOAK und VKA, hier ausschließlich Warfarin, gewonnen wurde. Darüber hinaus zeigte die RWE, dass die Überlegenheit der NOAK gegenüber dem VKA Warfarin auch für Phenprocoumon gilt, dem in Deutschland gebräuchlichsten VKA. Auch fanden sich Hinweise, dass bei Patienten mit chronischen Nierenerkrankungen das Fortschreiten der Nierenfunktionsstörung unter Behandlung mit NOAK geringer ausfallen kann als unter VKA.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Female; Fibrinolytic Agents; Humans; Male; Renal Insufficiency, Chronic; Stroke; Vitamin K; Warfarin

Chronic kidney disease (CKD) commonly occurs with vitamin K (VK) deficiency and impaired bone mineralization. However, there are no data explaining the metabolism of endogenous VK and its role in bone mineralization in CKD. In this study, we measured serum levels of phylloquinone (VK1), menaquinone 4 and 7 (MK4, MK7), and VK-dependent proteins: osteocalcin, undercarboxylated osteocalcin (Glu-OC), and undercarboxylated matrix Gla protein (ucMGP). The carboxylated osteocalcin (Gla-OC), Glu-OC, and the expression of genes involved in VK cycle were determined in bone. The obtained results were juxtaposed with the bone mineral status of rats with CKD. The obtained results suggest that the reduced VK1 level observed in CKD rats may be caused by the accelerated conversion of VK1 to the form of menaquinones. The bone tissue possesses all enzymes, enabling the conversion of VK1 to menaquinones and VK recycling. However, in the course of CKD with hyperparathyroidism, the intensified osteoblastogenesis causes the generation of immature osteoblasts with impaired mineralization. The particular clinical significance seems to have a finding that serum osteocalcin and Glu-OC, commonly used biomarkers of VK deficiency, could be inappropriate in CKD conditions, whereas Gla-OC synthesized in bone appears to have an adverse impact on bone mineral status in this model.

Topics: Animals; Biomarkers; Bone and Bones; Minerals; Osteocalcin; Rats; Renal Insufficiency, Chronic; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

The article is an opinion on the problem of venous thromboembolic (VTE) complications in patients with chronic kidney disease (CKD), which is significant and urgent for Russia. Signs of CKD are noted in more than 1/3 of patients with chronic heart failure; a decrease in kidney function is observed in 36% of people over the age of 60, in people of working age, a decrease in function is noted in 16% of cases, and in the presence of cardiovascular diseases increases to 26%. Clinical research data convincingly show that CKD is an independent risk factor for the development of VTE complications. The last decade has given us the opportunity to observe a kind of "revolution" in VTE therapy, which is associated with the appearance on the market of direct oral anticoagulants, including inhibitors of factor IIa (thrombin) and factor Xa. These drugs are approved by the Food and Drug Administration for the treatment of acute thromboembolism. Nevertheless, patients with severe CKD (estimated glomerular filtration rate 30 ml/min) are still limited to the use of unfractionated heparin and vitamin K antagonists, as there is insufficient data to support the use of direct oral anticoagulants in this population.. Статья представляет собой обсуждение проблемы венозных тромбоэмболических осложнений (ВТЭО) у больных хронической болезнью почек (ХБП), которая для нашей страны является значимой и насущной. Признаки ХБП отмечаются более чем у 1/3 пациентов с хронической сердечной недостаточностью; снижение функции почек наблюдается у 36% лиц в возрасте старше 60 лет, у лиц трудоспособного возраста снижение функции отмечается в 16% случаев, а при наличии сердечно-сосудистых заболеваний возрастает до 26%. Данные клинических исследований убедительно показывают, что ХБП является независимым фактором риска развития ВТЭО. Последнее десятилетие дало нам возможность наблюдать некую революцию в терапии ВТЭО, которая связана с появлением на рынке прямых пероральных антикоагулянтов, включающих ингибиторы фактора IIa (тромбина) и фактора Ха. Эти препараты одобрены Управлением по контролю пищевых продуктов и лекарств в США для лечения острой тромбоэмболии. Тем не менее пациенты с тяжелой ХБП (расчетная скорость клубочковой фильтрации 30 мл/мин) по-прежнему ограничены использованием нефракционированного гепарина и антагонистов витамина К, так как недостаточно данных в поддержку использования прямых пероральных антикоагулянтов в этой популяции.

Topics: Anticoagulants; Factor Xa; Heparin; Humans; Prevalence; Renal Insufficiency, Chronic; Thrombin; Venous Thromboembolism; Vitamin K

Topics: Dietary Supplements; Humans; Kidney Transplantation; Renal Insufficiency, Chronic; Vitamin K

Our objectives were to evaluate the risk of adverse events in a 'real-world' vs 'clinical trial' cohort of atrial fibrillation (AF) patients with chronic kidney disease (CKD).. We studied patient-level data for vitamin K antagonist-treated AF patients with a creatinine clearance <60 mL/min from the Murcia AF Project and AMADEUS trial. The study end-points were ischaemic stroke, major bleeding, all-cause mortality, myocardial infarction and intracranial haemorrhage.. This study included 1,108 AF patients with CKD. The annual rate of the composite study outcome of ischaemic stroke, major bleeding and all-cause mortality was higher in the real-world (13.4%) vs AMADEUS (6.6%) cohort with an IRR of 2.04 (95% CI,1.34-3.09), P < .001. Individual annual rates of major bleeding, all-cause mortality and non-cardiovascular mortality were significantly greater in the real-world cohort. Similar findings were demonstrated even after multivariable adjustment, with the composite outcome HR of 2.85 (95% CI,1.74-4.66), P < .001. In a propensity score matched cohort, this risk remained significantly higher in the real-world cohort (IRR 2.95 [95% CI,1.03-10.28], P = .027), as did the risk of major bleeding and all-cause mortality.. Vitamin K antagonist-treated AF patients with CKD are exposed to significant annual rates of major adverse events including all-cause mortality. This risk may be under-appreciated in the idealised environment of randomised controlled trials.

Topics: Anticoagulants; Atrial Fibrillation; Brain Ischemia; Humans; Renal Insufficiency, Chronic; Stroke; Vitamin K

Circulating desphospho-uncarboxylated matrix γ-carboxyglutamate (Gla) protein (dp-ucMGP), a marker of vitamin K status, is associated with renal function and may serve as a potentially modifiable risk factor for incident chronic kidney disease (CKD). We aimed to assess the association between circulating dp-ucMGP and incident CKD.. We included 3969 participants with a mean age of 52.3 ± 11.6 years, of whom 48.0% were male, enrolled in the general population-based Prevention of REnal and Vascular ENd-stage Disease study. Study outcomes were incident CKD, defined as either development of an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or microalbuminuria. Associations of dp-ucMGP with these outcomes were quantified using Cox proportional hazards models and were adjusted for potential confounders.. Median plasma dp-ucMGP was 363 [interquartile range (IQR) 219-532] pmol/L and mean serum creatinine- and serum cystatin C-based eGFR (eGFRSCr-SCys) was 95.4 ± 21.8 mL/min/1.73 m2. During 7.1 years of follow-up, 205 (5.4%) participants developed incident CKD and 303 (8.4%) developed microalbuminuria. For every doubling of plasma dp-ucMGP, hazard ratios for the development of incident CKD and microalbuminuria were 1.85 [95% confidence interval (CI) 1.59-2.16; P < 0.001] and 1.19 (95% CI 1.07-1.32; P = 0.001), respectively. These associations lost significance after adjustment for baseline eGFRSCr-SCys [0.99 (95% CI 0.88-1.12; P = 0.86)] and baseline age [1.03 (95% CI 0.94-1.14; P = 0.50)], respectively.. The associations of plasma dp-ucMGP with incident CKD and microalbuminuria were driven by the respective baseline effects of renal function and age.

Topics: Adult; Biomarkers; Calcium-Binding Proteins; Cohort Studies; Extracellular Matrix Proteins; Humans; Male; Middle Aged; Prospective Studies; Renal Insufficiency, Chronic; Vitamin K

Patients with chronic kidney disease (CKD) suffer from vitamin K deficiency and are at high risk of vascular calcification (VC) and premature death. We investigated the association of functional vitamin K deficiency with all-cause mortality and whether this association is modified by the presence of VC in CKD stage 5 (CKD G5). Plasma dephosphorylated-uncarboxylated matrix Gla-protein (dp-ucMGP), a circulating marker of functional vitamin K deficiency, and other laboratory and clinical data were determined in 493 CKD G5 patients. VC was assessed in subgroups by Agatston scoring of coronary artery calcium (CAC) and aortic valve calcium (AVC). Backward stepwise regression did not identify dp-ucMGP as an independent determinant of VC. During a median follow-up of 42 months, 93 patients died. Each one standard deviation increment in dp-ucMGP was associated with increased risk of all-cause mortality (sub-hazard ratio (sHR) 1.17; 95% confidence interval, 1.01-1.37) adjusted for age, sex, cardiovascular disease, diabetes, body mass index, inflammation, and dialysis treatment. The association remained significant when further adjusted for CAC and AVC in sub-analyses (sHR 1.22, 1.01-1.48 and 1.27, 1.01-1.60, respectively). In conclusion, functional vitamin K deficiency associates with increased mortality risk that is independent of the presence of VC in patients with CKD G5.

Topics: Adult; Aged; Biomarkers; Calcium-Binding Proteins; Cohort Studies; Extracellular Matrix Proteins; Female; Humans; Male; Matrix Gla Protein; Middle Aged; Renal Insufficiency, Chronic; Survival Rate; Vascular Calcification; Vitamin K; Vitamin K Deficiency

Dietary intake modification is important for the treatment of chronic kidney disease (CKD); however, little is known about the association between dietary intake of antioxidant vitamins and kidney function based on gender difference. We examined the relationship of dietary intake of antioxidant vitamins with decreased kidney function according to gender in Japanese subjects. This population-based, cross-sectional study included 936 Japanese participants with the age of 40 years or older. A validated brief self-administered diet history questionnaire was used to measure dietary intakes of vitamin E and its four isoforms, vitamin A and vitamin C. Decreased kidney function was defined as estimated glomerular filtration rate <60 ml/min/1·73 m

Topics: Adult; Aged; Antioxidants; Cross-Sectional Studies; Diet; Female; Humans; Japan; Kidney; Male; Middle Aged; Renal Insufficiency, Chronic; Sex Factors; Vitamin A; Vitamin E; Vitamin K; Vitamins

Oral anticoagulants are the first-line drugs for treating thrombotic disorders related to nonvalvular atrial fibrillation and for treating deep vein thrombosis, diseases that increase in prevalence with age. Older patients have a greater risk of thrombotic and hemorrhagic events and are more prone to drug interactions. Given this backdrop, we wanted to determine the factors associated with the prescription of direct oral anticoagulants and vitamin K antagonists in older patients.. We performed a cross-sectional observational study using a hospital prescription database. The study population consists of 405 older patients who were given oral anticoagulants. The 2 variables of interest were the prescription of 1 of the 2 classes of oral anticoagulants (direct oral anticoagulants vs vitamin K antagonists) and appropriateness of oral anticoagulant prescribing according to Summary of Product Characteristics (potentially inappropriate vs appropriate).. The factors associated with direct oral anticoagulant prescribing were the female gender (odds ratio [OR]: 1.87, 95% confidence interval [CI]: 1.22-2.88) and initiation during hospital stay (OR: 2.56, 95% CI: [1.52-4.32]). Stage 4 and 5 chronic kidney diseases (OR: 0.39, 95% CI: [0.19-0.79] and OR: 0.07, 95% CI: [0.01-0.53]) were factors favoring vitamin K antagonist prescription. Being 90 years of age or more (OR: 2.05, 95% CI: [1.06-3.98]) was a factor for potentially inappropriate anticoagulant prescribing. The gastroenterology department (OR: 2.91, 95% CI: [1.05-8.11]) was associated with potentially inappropriate anticoagulant prescribing.. Direct oral anticoagulants are the drugs of choice for anticoagulant treatment, including in older adults. The female gender and the initiation during hospital stay increased the chances of being prescribed a direct oral anticoagulant in older adults. Stage 4 and 5 chronic kidney disease increased the likelihood of having a vitamin K antagonist prescribed. Our study also revealed a persistence of potentially inappropriate oral anticoagulant prescriptions in older patients.

Topics: Administration, Oral; Age Factors; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Clinical Decision-Making; Cross-Sectional Studies; Databases, Factual; Drug Interactions; Factor Xa Inhibitors; Female; France; Hemorrhage; Humans; Inappropriate Prescribing; Male; Prevalence; Renal Insufficiency, Chronic; Retrospective Studies; Risk Assessment; Risk Factors; Sex Factors; Treatment Outcome; Venous Thrombosis; Vitamin K

Evidence for the efficacy of direct oral anticoagulants (DOACs) to prevent cardiovascular (CV) events and mortality in older individuals with a low estimated glomerular filtration rate (eGFR) is lacking. We sought to characterize the association of oral anticoagulant use with CV morbidity in elderly patients with or without reductions in eGFRs, comparing DOACs with vitamin K antagonists (VKAs).. Population-based retrospective cohort study.. All individuals 66 years or older with an initial prescription for oral anticoagulants dispensed in Ontario, Canada, from 2009 to 2016.. DOACs (apixaban, dabigatran, and rivaroxaban) compared with VKAs by eGFR group (≥60, 30-59, and<30mL/min/1.73m. The primary outcome was a composite of a CV event (myocardial infarction, revascularization, or ischemic stroke) or mortality. Secondary outcomes were CV events alone, mortality, and hemorrhage requiring hospitalization.. High-dimensional propensity score matching of DOAC to VKA users and Cox proportional hazards regression.. 27,552 new DOAC users were matched to 27,552 new VKA users (median age, 78 years; 49% women). There was significantly lower risk for CV events or mortality among DOAC users compared with VKA users (event rates of 79.78 vs 99.77 per 1,000 person-years, respectively; HR, 0.82 [95% CI, 0.75-0.90]) and lower risk for hemorrhage (event rates of 10.35 vs 16.77 per 1,000 person-years, respectively; HR, 0.73 [95% CI, 0.58-0.91]). There was an interaction between eGFR and the association of anticoagulant class with the primary composite outcome (P<0.02): HRs of 1.01 [95% CI, 0.92-1.12], 0.83 [95% CI, 0.75-0.93], and 0.75 [95% CI, 0.51-1.10] for eGFRs of≥60, 30 to 59, and<30mL/min/1.73m. Retrospective observational study design limits causal inference; dosages of DOACs and international normalized ratio values were not available; low event rates in some subgroups limited statistical power.. DOACs compared with VKAs were associated with lower risk for the composite of CV events or mortality, an association for which the strength was most apparent among those with reduced eGFRs. The therapeutic implications of these findings await further study.

Topics: Aged; Aged, 80 and over; Antithrombins; Brain Ischemia; Cause of Death; Comorbidity; Dabigatran; Female; Glomerular Filtration Rate; Hemorrhage; Humans; Male; Mortality; Myocardial Infarction; Myocardial Revascularization; Ontario; Procedures and Techniques Utilization; Propensity Score; Proportional Hazards Models; Pyrazoles; Pyridones; Renal Insufficiency, Chronic; Retrospective Studies; Rivaroxaban; Thrombophilia; Vitamin K

Topics: Bone Diseases, Metabolic; Fractures, Bone; Humans; Kidney Failure, Chronic; Renal Insufficiency, Chronic; Vitamin K

Topics: Humans; Renal Insufficiency, Chronic; Vitamin D Deficiency; Vitamin K

To evaluate the effectiveness and safety of novel oral anticoagulants (NOACs) compared with vitamin K antagonists (VKAs) among patients with non-valvular atrial fibrillation (NVAF), particularly those with chronic kidney disease (CKD).. Population-based matched cohort study.. Over 670 primary care practices in the UK, contributing to the Clinical Practice Research Datalink.. Up to 6818 adult patients newly treated with NOACs between 2011 and 2016, matched 1:1 to new users of VKAs on age, sex and high-dimensional propensity score.. Current exposure to NOACs compared with current exposure to VKAs.. HRs of ischaemic stroke and systemic embolism (SE), major bleeding, gastrointestinal (GI) bleeding, intracranial bleeding, myocardial infarction and all-cause mortality.. In as-treated analyses, the rates of ischaemic stroke/SE were similar between NOACs and VKAs (HR 0.94; 95% CI 0.62 to 1.42), as were the rates of major bleeding (HR 0.86; 95% CI 0.56 to 1.33). NOACs also significantly increased the risk of GI bleeding (HR 1.78; 95% CI 1.27 to 2.48). In patients with NVAF and CKD, NOACs and VKAs remained comparable with respect to the risk of ischaemic stroke/SE (HR 0.79; 95% CI 0.40 to 1.58) and major bleeding (HR 0.88; 95% CI 0.47 to 1.62), with no difference in the risk of GI bleeding (HR 0.99; 95% CI 0.63 to 1.55). Similar results were obtained in on-treatment analyses using a time-dependent exposure definition.. Our results suggest that in the UK primary care, NOACs are overall effective and safe alternatives to VKAs, among patients with NVAF altogether, as well as in patients with NVAF and CKD.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cohort Studies; Comorbidity; Female; Gastrointestinal Hemorrhage; Humans; Male; Middle Aged; Primary Health Care; Regression Analysis; Renal Insufficiency, Chronic; Risk Factors; Stroke; United Kingdom; Vitamin K; Young Adult

Non-vitamin K antagonist oral anticoagulants (NOACs) require renal dose adjustment. The most common estimates of renal function in clinical practice are derived from estimated glomerular filtration rate (eGFR; Modified Diet in Renal Disease [MDRD] or the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]). However, the landmark stroke prevention trials and product monographs recommend the use of the Cockcroft-Gault creatinine clearance equation (eCrCl) for drug eligibility and dose adjustment. We sought to evaluate the agreement in NOAC dosing between these 3 equations in a large population of patients with atrial fibrillation and moderate chronic kidney disease.. We identified 831 patients with non-dialysis-dependent chronic kidney disease and atrial fibrillation (CHA. The use of eGFR resulted in significant misclassification with respect to NOAC dosing. Compared with eCrCl, the MDRD eGFR and CKD-EPI eGFR misclassified 36.2% and 35.8% of patients, respectively. The misclassification resulted in undertreatment (eg, inappropriate dose reduction; 26.9% MDRD, 28.8% CKD-EPI), and to a lesser extent overtreatment (eg, inappropriate use of standard dose; 9.3% MDRD, 7.0% CKD-EPI).. MDRD and CKD-EPI eGFR fail to correctly identify a significant proportion of patients who require NOAC dose adjustment, limiting their clinical utility. Cockcroft-Gault eCrCl should be calculated for all patients in whom a NOAC is being prescribed.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Male; Renal Insufficiency, Chronic; Retrospective Studies; Severity of Illness Index; Thromboembolism; Treatment Outcome; Vitamin K

Chronic kidney disease (CKD) has been related to poor anticoagulation control and an increased risk of bleeding. This study aims to evaluate the association between impaired renal function (eGFR <60 mL/min/1.73 m. This is an ancillary analysis of 1381 patients from the PAULA study, which was a cross-sectional, retrospective and nationwide multicenter study.. Chronic kidney disease is associated with poor anticoagulation control in patients with non-valvular AF taking VKA. The SAMe-TT

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cross-Sectional Studies; Female; Humans; Linear Models; Logistic Models; Male; Middle Aged; Predictive Value of Tests; Renal Insufficiency, Chronic; Retrospective Studies; Treatment Outcome; Vitamin K

Topics: Anticoagulants; Fibrinolytic Agents; Humans; Renal Insufficiency, Chronic; Vitamin K

Topics: Dietary Supplements; Humans; Renal Insufficiency, Chronic; Vitamin K; Vitamin K Deficiency

Patients with chronic kidney disease (CKD) have very high levels of uncarboxylated, inactive, extra-hepatic vitamin K-dependent proteins measured in circulation, putting them at risk for complications of vitamin K deficiency. The major form of vitamin K found in the liver is phylloquinone (K1). Menaquinone-4 (MK-4) is the form of vitamin K that is preferentially found in extra-hepatic tissues.. In the present study, we assessed tissue concentrations of K1 and MK-4 and the expression of vitamin K-related genes in a rat model of adenine-induced CKD.. It was found that rats with both mild and severe CKD had significantly lower amounts of K1 measured in liver, spleen and heart and higher levels of MK-4 measured in kidney cortex and medulla. All animals treated with high dietary K1 had an increase in tissue levels of both K1 and MK-4; however, the relative increase in K1 differed suggesting that the conversion of K1 to MK-4 may be a regulated/limiting process in some tissues. There was a decrease in the thoracic aorta expression of vitamin K recycling (Vkor) and utilization (Ggcx) enzymes, and a decrease in the kidney level of vitamin K1 to MK-4 bioconversion enzyme Ubiad1 in CKD.. Taken together, these findings suggest that CKD impacts vitamin K metabolism, and this occurs early in the disease course. Our findings that vitamin K metabolism is altered in the presence of CKD provides further support that sub-clinical vitamin K deficiency may represent a modifiable risk factor for vascular and bone health in this population.

Topics: Adenine; Animals; Aorta, Thoracic; Carbon-Carbon Ligases; Dimethylallyltranstransferase; Disease Models, Animal; Gene Expression; Kidney; Male; Rats; Real-Time Polymerase Chain Reaction; Renal Insufficiency, Chronic; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Epoxide Reductases

Arteriovenous fistula (AVF) is the common vascular access type for a hemodialysis patient. Its failure is due to neointimal hyperplasia. Vitamin K antagonists are given to lower thrombosis tendency, but have side effects that enhance arterial calcifications. Here, we investigated the effects of vitamin K antagonists and vitamin K2 (K2) treatment on neointimal hyperplasia development and calcification in rats and in arterialized human veins. AVF was generated in female rats while chronic kidney disease (CKD) was induced using an adenine-enriched diet. Arterialization, CKD, and vitamin K antagonists all significantly enhanced venous neointimal hyperplasia. K2 treatment, additional to vitamin K antagonists, significantly reduced neointimal hyperplasia in arterialized veins in healthy rats but not in rats with CKD. Arterialization, CKD, and vitamin K antagonism all significantly increased, whereas K2 supplementation attenuated calcification in healthy rats and rats with CKD. K2 significantly enhanced matrix Gla protein carboxylation in control rats and rats with CKD. Arterialized human vein samples contained inactive matrix Gla protein at calcification and neointimal hyperplasia sites, indicating local vitamin K deficiency. Thus, vitamin K antagonists have detrimental effects on AVF remodeling, whereas K2 reduced neointimal hyperplasia and calcification indicating vasoprotective effects. Hence, K2 administration may be useful to prevent neointimal hyperplasia and calcification in arterialized veins

Topics: Aged; Aged, 80 and over; Animals; Anticoagulants; Arteriovenous Shunt, Surgical; Disease Models, Animal; Female; Femoral Vein; Humans; Hyperplasia; Male; Middle Aged; Neointima; Rats, Sprague-Dawley; Renal Insufficiency, Chronic; Vascular Calcification; Vascular Remodeling; Vitamin K; Vitamin K 2

Following activation by vitamin K (VK), matrix Gla protein (MGP) inhibits arterial calcification, but its role in preserving renal function remains unknown.. In 1166 white Flemish (mean age, 38.2 years) and 714 South Africans (49.2% black; 40.6 years), we correlated estimated glomerular filtration (eGFR [CKD-EPI formula]) and stage of chronic kidney disease (CKD [KDOQI stages 2-3]) with inactive desphospho-uncarboxylated MGP (dp-ucMGP), using multivariable linear and logistic regression.. Among Flemish and white and black Africans, between-group differences in eGFR (90, 100 and 122 mL/min/1.73 m(2)), dp-ucMGP (3.7, 6.5 and 3.2 μg/L), and CKD prevalence (53.5, 28.7 and 10.5%) were significant, but associations of eGFR with dp-ucMGP did not differ among ethnicities (P ≥ 0.075). For a doubling of dp-ucMGP, eGFR decreased by 1.5 (P = 0.023), 1.0 (P = 0.56), 2.8 (P = 0.0012) and 2.1 (P < 0.0001) mL/min/1.73 m(2) in Flemish, white Africans, black Africans and all participants combined; the odds ratios for moving up one CKD stage were 1.17 (P = 0.033), 1.03 (P = 0.87), 1.29 (P = 0.12) and 1.17 (P = 0.011), respectively.. In the general population, eGFR decreases and CKD risk increases with higher dp-ucMGP, a marker of VK deficiency. These findings highlight the possibility that VK supplementation might promote renal health.

Topics: Adult; Biomarkers; Black People; Calcium-Binding Proteins; Extracellular Matrix Proteins; Female; Glomerular Filtration Rate; Humans; Male; Matrix Gla Protein; Middle Aged; Protein Processing, Post-Translational; Renal Insufficiency, Chronic; Vitamin K; White People

Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD), partly due to increased vascular calcification. Vitamin K plays a role in preventing vascular calcification in CKD yet the relationship between vitamin K intake and mortality in CKD patients remains unclear.. This observational cohort study included 3401 participants with CKD from the Third National Health and Nutrition Examination Survey. Vitamin K intake was estimated from 24-h dietary recalls (1988-94). Mortality was determined from the National Death Index records through 2006. Cox-proportional hazards regression was used to estimate Hazard Ratios (HR) by comparing those with adequate intake of vitamin K to those with low intake, adjusting for advanced CKD covariates. For sensitivity analysis, these associations were also examined among those with different renal status.. During a median follow-up of 13.3 years (37,408 person-years), 1815 and 876 participants died from all-cause and CVD causes, respectively. 72% of the participants had vitamin K intake lower than the recommended adequate intake. Participants with vitamin K intake higher than recommended adequate intake for vitamin K were associated with lower risk of all-cause (HR = 0.85; 95%: 0.72-1; P = 0.047) and CVD mortality (HR = 0.78; 95%: 0.64-95; P = 0.016). Sensitivity analyses in subgroups with advanced CKD revealed similar findings.. This observational study suggests that adequate intake of vitamin K may be associated with reduced all-cause and CVD mortality in CKD patients. However, vitamin K may be a marker of a healthy diet; therefore clinical trials may help in clarifying the effect of vitamin K independent of a healthy diet.

Topics: Adult; Aged; Antifibrinolytic Agents; Cardiovascular Diseases; Cohort Studies; Data Collection; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Male; Middle Aged; Observation; Renal Insufficiency, Chronic; Vitamin K; Vitamins

Hypertension is a common comorbidity in patients with chronic kidney disease (CKD). We reported earlier that oral anticoagulants, including warfarin and dabigatran, may induce acute kidney injury. No effects of oral anticoagulants on blood pressure (BP) have been previously reported. The aim of this study was to examine in detail the relationship of anticoagulant therapy and BP in rats.. Sham-operated and 5/6 nephrectomy rats were treated with different doses of oral anticoagulants (warfarin and dabigatran), superoxide scavenger N-acetylcysteine (NAC), vitamin K, and protease activated receptor 1 (PAR-1) inhibitor SCH79797. BP was measured by a tail cuff daily.. Warfarin and dabigatran both increased systolic BP in sham-operated and 5/6 nephrectomy rats in a dose-dependent manner. SCH79797 also increased systolic BP in a dose-dependent manner. Vitamin K prevented warfarin-induced increase in BP but did not affect BP when administered alone. NAC delayed the warfarin-associated increase in BP. Warfarin effects on BP were similar in 5/6 nephrectomy rats with different CKD stages.. Both warfarin and dabigatran increase systolic BP in rats. The mechanism of this effect is not clear, but our data suggest that it is related to decreased thrombin activity associated with anticoagulant treatment. The superoxide scavenger NAC delayed, but did not prevent, warfarin-induced hypertension.

Topics: Acetylcysteine; Animals; Anticoagulants; Antifibrinolytic Agents; Antithrombins; Benzimidazoles; beta-Alanine; Blood Pressure; Dabigatran; Disease Models, Animal; Dose-Response Relationship, Drug; Free Radical Scavengers; Nephrectomy; Pyrroles; Quinazolines; Rats; Receptor, PAR-1; Renal Insufficiency, Chronic; Vitamin K; Warfarin

Topics: Anticoagulants; Diet; Drug Monitoring; Food; Humans; International Normalized Ratio; Potassium; Prothrombin; Renal Insufficiency, Chronic; Vitamin K; Warfarin

Because current rat models used to study chronic kidney disease (CKD)-related vascular calcification show consistent but excessive vascular calcification and chaotic, immeasurable, bone mineralization due to excessive bone turnover, they are not suited to study the bone-vascular axis in one and the same animal. Because vascular calcification and bone mineralization are closely related to each other, an animal model in which both pathologies can be studied concomitantly is highly needed. CKD-related vascular calcification in rats was induced by a 0.25% adenine/low vitamin K diet. To follow vascular calcification and bone pathology over time, rats were killed at weeks 4, 8, 10, 11, and 12. Both static and dynamic bone parameters were measured. Vascular calcification was quantified by histomorphometry and measurement of the arterial calcium content. Stable, severe CKD was induced along with hyperphosphatemia, hypocalcemia as well as increased serum PTH and FGF23. Calcification in the aorta and peripheral arteries was present from week 8 of CKD onward. Four and 8 weeks after CKD, static and dynamic bone parameters were measurable in all animals, thereby presenting typical features of hyperparathyroid bone disease. Multiple regression analysis showed that the eroded perimeter and mineral apposition rate in the bone were strong predictors for aortic calcification. This rat model presents a stable CKD, moderate vascular calcification, and quantifiable bone pathology after 8 weeks of CKD and is the first model that lends itself to study these main complications simultaneously in CKD in mechanistic and intervention studies.

Topics: Animals; Aorta; Bone and Bones; Bone Remodeling; Disease Models, Animal; Disease Progression; Fibroblast Growth Factors; Hypercalcemia; Hyperphosphatemia; Male; Osteogenesis; Parathyroid Hormone; Rats; Rats, Wistar; Regression Analysis; Renal Insufficiency, Chronic; Vascular Calcification; Vitamin K

Renal insufficiency increases the risk of stroke and bleeding in atrial fibrillation patients. Although vitamin K antagonists reduce the risk of stroke in patients with moderate renal dysfunction, this observation is less clear in patients with renal impairment. Moreover, the risk of bleeding with vitamin K antagonists increases as renal function worsens. Maintaining international normalized ratio values within therapeutic targets is more difficult in patients with renal dysfunction, and those agents may cause warfarin-related nephropathy and vascular calcification. Rivaroxaban is the only nonvitamin K oral anticoagulant with a dose specifically tested in patients with moderate renal insufficiency. Rivaroxaban is effective for the prevention of stroke in atrial fibrillation patients with moderate renal dysfunction, with a lower risk of intracranial and fatal bleeding.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Humans; Renal Insufficiency, Chronic; Rivaroxaban; Stroke; Vitamin K; Warfarin

Topics: Humans; Osteoporosis; Renal Insufficiency, Chronic; Vascular System Injuries; Vitamin K; Vitamin K 2

Topics: Hemostatics; Humans; Kidney Failure, Chronic; Renal Insufficiency, Chronic; Vitamin K

Essential information regarding efficacy and safety of vitamin K-antagonists (VKA) treatment for atrial fibrillation (AF) in non-dialysis dependent chronic kidney disease (CKD) is still lacking in current literature. The aim of our study was to compare the risks of stroke or transient ischemic attack (TIA) and major bleeds between patients without CKD (eGFR >60 ml/min), and those with moderate (eGFR 30-60 ml/min), or severe non-dialysis dependent CKD (eGFR <30 ml/min).. We included 300 patients without CKD, 294 with moderate, and 130 with severe non-dialysis dependent CKD, who were matched for age and sex. Uni- and multivariate Cox regression analyses were performed reporting hazard ratios (HRs) for the endpoint of stroke or TIA and the endpoint of major bleeds as crude values and adjusted for comorbidity and platelet-inhibitor use.. Overall, 6.2% (45/724, 1.7/100 patient years) of patients developed stroke or TIA and 15.6% (113/724, 4.8/100 patient years) a major bleeding event. Patients with severe CKD were at high risk of stroke or TIA and major bleeds during VKA treatment compared with those without renal impairment, HR 2.75 (95%CI 1.25-6.05) and 1.66 (95%CI 0.97-2.86), or with moderate CKD, HR 3.93(1.71-9.00) and 1.86 (95%CI 1.08-3.21), respectively. These risks were similar for patients without and with moderate CKD. Importantly, both less time spent within therapeutic range and high INR-variability were associated with increased risks of stroke or TIA and major bleeds in severe CKD patients.. VKA treatment for AF in patients with severe CKD has a poor safety and efficacy profile, likely related to suboptimal anticoagulation control. Our study findings stress the need for better tailored individualised anticoagulant treatment approaches for patients with AF and severe CKD.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Female; Follow-Up Studies; Hemorrhage; Humans; Ischemic Attack, Transient; Male; Middle Aged; Multivariate Analysis; Proportional Hazards Models; Renal Dialysis; Renal Insufficiency, Chronic; Risk Assessment; Risk Factors; Stroke; Treatment Outcome; Vitamin K

Cardiovascular risk factors are associated with the development of chronic kidney disease (CKD), and CKD and vascular disease are etiologically linked. Evidence suggests deficiencies of vitamins D and K may adversely affect the cardiovascular system, but data from longitudinal studies are lacking. We hypothesized that deficiencies of vitamins D and K may be associated with incident CKD and/or incident albuminuria amongst members of the general population.. We analyzed 1,442 Framingham Heart Study participants (mean age 58 years; 50.5% women), free of CKD (eGFR <60 ml/min/1.73 m(2)), with a mean follow-up of 7.8 years in 2005-2008. Incident albuminuria was defined using sex-specific cut-offs of urine albumin-to-creatinine ratio (≥17 mg/g men and ≥25 mg/g women). Baseline log plasma phylloquinone (vitamin K(1)) and 25(OH)D levels, analyzed as continuous variables and by quartile, were related to risk of incident CKD (n = 108) and incident albuminuria (n = 106) using logistic regression models adjusted for standard risk factors.. Participants in the highest phylloquinone quartile (≥1.78 nmol/l) had an increased risk of CKD (multivariable-adjusted OR Q(4) vs. Q(1) 2.39; p = 0.006) and albuminuria at follow-up (multivariable-adjusted OR Q(4) vs. Q(1) 1.95; p = 0.05), whereas no association was observed with continuous phylloquinone levels for either endpoint. Deficiency of 25(OH)D was not associated with incident CKD or albuminuria in either analysis.. Contrary to our hypothesis, higher plasma phylloquinone levels are associated with an increased risk of incident CKD. Whether plasma phylloquinone is a marker for another unmeasured risk factor requires further study. External validation is necessary given the unexpected nature of these results.

Topics: Adult; Aged; Albuminuria; Cohort Studies; Female; Glomerular Filtration Rate; Humans; Incidence; Male; Middle Aged; Regression Analysis; Renal Insufficiency, Chronic; Risk; Treatment Outcome; Vitamin D; Vitamin K; Vitamin K 1