vitamin-k-semiquinone-radical and Kidney-Failure--Chronic

The prevalence of chronic kidney disease (CKD) is increasing due to the aging of the population and multiplication of risk factors, such as hypertension, arteriosclerosis and obesity. Impaired renal function increases both the risk of bleeding and thrombosis. There are two groups of orally administered drugs to prevent thromboembolic events in patients with CKD who require anticoagulation: vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs). Although VKAs remain the first-line treatment in patients with advanced CKD, treatment with VKAs is challenging due to difficulties in maintaining the appropriate anticoagulation level, tendency to accelerate vascular calcification and faster progression of CKD in patients treated with VKAs. On the other hand, the pleiotropic effect of DOACs, including vascular protection and anti-inflammatory properties along with comparable efficacy and safety of treatment with DOACs, compared to VKAs observed in preliminary reports encourages the use of DOACs in patients with CKD. This review summarizes the available data on the efficacy and safety of DOACs in patients with CKD and provides recommendations regarding the choice of the optimal drug and dosage depending on the CKD stage.

Topics: Administration, Oral; Anticoagulants; Hemorrhage; Humans; Kidney Failure, Chronic; Vitamin K

Patients with end-stage renal disease (ESRD) have high rates of cardiac valvulopathy but can develop contraindications for vitamin K antagonist (VKA) therapy. We explored the evidence for alternative anticoagulation strategies in patients with ESRD with a contraindication for VKA therapy.. A scoping review was completed, searching MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Conference abstracts from inception to March 30, 2021. The study population was patients with ESRD who were on VKA therapy and developed a contraindication to VKA therapy use. All data regarding studies, patient characteristics, anticoagulation strategy, and clinical outcomes were summarized.. Twenty-three articles met inclusion criteria. These articles included 57 patients. Contraindications to VKA therapy included calcific uremic arteriolopathy (CUA) (n = 55) and warfarin-induced skin necrosis (n = 2). All studies were either case reports or case series. There were 10 anticoagulation strategies identified. Continuation of VKA therapy was associated with increased death and decreased rates of CUA resolution (80.0% and 10.0%, respectively), compared to apixaban (24.0% and 70.8%), subcutaneous (SC) low-molecular-weight heparin (LMWH) (14.3%, 85.7%), and SC unfractionated heparin (0.0%, 100.0%). While only 5 patient cases were reported with mechanical heart valves, SC LMWH use has been reported in this context with good outcomes.. In patients with ESRD who develop a contraindication to VKA therapy, several alternative anticoagulation strategies have been reported with superior outcomes to VKA continuation. While outcomes appear superior to continuation of VKA therapy, more data are required before definitive recommendations can be made for the patient with ESRD and a mechanical heart valve.

Topics: Anticoagulants; Contraindications, Drug; Factor Xa Inhibitors; Heart Valve Prosthesis; Heparin; Humans; Kidney Failure, Chronic; Pyrazoles; Pyridones; Renal Dialysis; Vitamin K

In Chronic Kidney Disease, vascular calcification (VC) is highly prevalent even at early stages and is gradually enhanced, along with disease progression to End-Stage Renal Disease (ESRD). The calcification pattern in uremia includes all types of mineralization and contributes to the heavy cardiovascular (CV) burden that is common in these patients. Ectopic mineralization is the result of the imbalance between inhibitors and promoters of vascular calcification, with the latter overwhelming the former. The most powerful, natural inhibitor of calcification is Matrix Gla Protein (MGP), a small vitamin K dependent protein, secreted by chondrocytes and vascular smooth muscle cells. In uremia, MGP was reported as the only molecule able to reverse VC by "sweeping" calcium and hydroxyapatite crystals away from the arterial wall. To become biologically active, this protein needs to undergo carboxylation and phosphorylation, reactions highly dependent on vitamin K status. The inactive form of MGP reflects the deficiency of vitamin K and has been associated with CV events and mortality in ESRD patients. During the past decade, vitamin K status has emerged as a novel risk factor for vascular calcification and CV disease in various populations, including dialysis patients. This review presents evidence regarding the association between vitamin K and CV disease in ESRD patients, which are prone to atherosclerosis and atheromatosis.

Topics: Animals; Blood Vessels; Calcium-Binding Proteins; Extracellular Matrix Proteins; Humans; Kidney Failure, Chronic; Matrix Gla Protein; Risk Factors; Signal Transduction; Treatment Outcome; Vascular Calcification; Vitamin K; Vitamin K Deficiency

The need for anticoagulation in patients with atrial fibrillation (AF) is fundamental to prevent thromboembolic events. Direct oral anticoagulants (DOACs) recently demonstrated to be superior, or at least equal, to Warfarin in reducing the risk for stroke/systemic embolism and preventing major bleeding and intracranial hemorrhages. The AF population often suffers from chronic kidney disease (CKD). Indeed, the relationship between AF and renal function is bidirectional: AF can trigger kidney failure, while kidney impairment can promote alterations able to enhance AF. Therefore, there are concerns regarding prescriptions of anticoagulants to patients with AF and CKD. The worsening in kidney function can be effectively due to anticoagulants administration. Warfarin has been recognized to promote acute kidney injury in case of excessive anticoagulation levels. Nevertheless, further mechanisms can induce the chronic worsening of renal function, thus leading to terminal kidney failure as observed in post-hoc analysis from registration trials and dedicated observational studies. By contrast, DOACs seem to protect kidneys from injuries more efficiently than Warfarin, although they still continue to play a role in promoting some kidney lesions. However, the exact mechanisms remain unknown. This narrative review aimed to discuss the influence of oral anticoagulants on renal impairment as well as to overview potential pathophysiological mechanisms related to this clinical complication.

Topics: Anticoagulants; Atrial Fibrillation; Cytochrome P-450 Enzyme System; Factor Xa Inhibitors; Glomerular Filtration Rate; Hemorrhage; Humans; Kidney; Kidney Diseases; Kidney Failure, Chronic; Oxidative Stress; Patient Acuity; Stroke; Vitamin K

Vascular calcification (VC) is common in advanced chronic kidney disease (CKD), contributes to cardiovascular disease (CVD), and associates with increased mortality. Major risk factors for VC in CKD are increasing age, dialysis vintage, and positive net calcium-phosphate balance. To date, no specific therapy that prevents progression or facilitates regression of VC beyond careful attention to calcium and phosphate balance exists. Accumulating evidence demonstrates that CKD patients may incur subclinical vitamin K deficiency. This deficiency may be induced by exhaustion of vitamin K due to its high requirement by vitamin K-dependent proteins to inhibit VC. This review analyzes the pathophysiological mechanisms and clinical consequences of vitamin K deficiency with emphasis on its involvement on vascular calcification in CKD and end-stage renal disease and its relationship to the bone-vascular axis.

Topics: Humans; Kidney Failure, Chronic; Uremia; Vascular Calcification; Vitamin K; Vitamin K Deficiency

To provide information on the pathogenesis, clinical features, diagnosis, and treatment of calciphylaxis.. This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care.. After participating in this educational activity, the participant should be better able to:1. Recognize the pathogenesis and clinical features of and risk factors for calciphylaxis.2. Explain the diagnosis and management of a patient with calciphylaxis.. Calciphylaxis is a cutaneous ischemic infarct caused by total occlusion of blood vessels initiated by vascular calcification. Until recently, treatments have been limited to controlling its risk factors and optimizing wound care. However, recent advances in clinical understanding of the mechanism of calciphylaxis have identified promising potential therapeutic targets. This article is a narrative review summarizing the clinical features, diagnosis, pathogenesis, and treatment of calciphylaxis.

Topics: Calciphylaxis; Chelating Agents; Humans; Kidney Failure, Chronic; Kidney Transplantation; Pain Management; Renal Dialysis; Risk Factors; Thiosulfates; Thrombosis; Vascular Calcification; Vitamin K; Vitamin K Deficiency; Wound Healing

Patients with end-stage renal disease (ESRD) were excluded from pivotal clinical trials with oral anticoagulants. While such patients are at an increased risk of venous and arterial thromboembolism, their risk of bleeding is also elevated. It is thus of little surprise that stroke prevention with vitamin K antagonists (VKAs) in ESRD patients with atrial fibrillation is controversial, with observational evidence ranging from beneficial to harmful. This uncertainty extends to the less studied use of VKAs for venous thromboembolism in ESRD. The direct oral anticoagulants (DOACs) apixaban and rivaroxaban have now permissive labeling in the United States for atrial fibrillation in patients with ESRD; this expanded labeling has not yet occurred either in Europe or for venous thromboembolism. This review summarizes the current evidence for the pharmacology of DOACs in ESRD as well as their utilization and safety in patients with ESRD and atrial fibrillation.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Humans; Kidney Failure, Chronic; Pyrazoles; Pyridones; Rivaroxaban; United States; Venous Thromboembolism; Vitamin K

The Multimorbid Patient: Use of New Oral Anticoagulants in Patients with Chronic Kidney Disease Abstract. Increasing life expectancy in Western countries is associated with a high prevalence of multiple chronic diseases which is defined by the term "multimorbidity". Many of these patients suffer from chronic kidney disease (CKD) and thrombogenic comorbidities such as atrial fibrillation with the need for oral anticoagulation. For decades vitamin K antagonists have been exclusively prescribed for oral anticoagulation. However, due to altered pharmacokinetics and bioavailability of these drugs in CKD, a significant risk of bleeding exists. The introduction of direct oral anticoagulants as a new and promising alternative to vitamin K antagonists was -especially for CKD patients - highly anticipated. However, data from randomized studies are missing for older patients with advanced CKD. Consequently, a careful evaluation of the risk-benefit ratio is recommended for this sensitive patient population.. Zusammenfassung. Die zunehmende Lebenserwartung in den westlichen Ländern führt zu einer gleichzeitigen Zunahme chronischer Krankheiten, was mit «Multimorbidität» bezeichnet wird. Viele dieser Patienten leiden an chronischer Niereninsuffizienz (CKD) sowie thrombogenen Komorbiditäten wie z.B. Vorhofflimmern, weshalb eine orale Antikoagulation indiziert ist. Für lange Zeit standen lediglich die Vitamin-K-Antagonisten zur Verfügung. Aufgrund der unter anderem veränderten Pharmakokinetik sowie Bioverfügbarkeit dieser Medikamente bei CKD besteht jedoch gleichzeitig ein deutlich erhöhtes Blutungsrisiko. Die Einführung der direkten oralen Antikoagulanzien als neue und vielversprechende Alternative zu Vitamin-K-Antagonisten wurde daher insbesondere für die Population der CKD-Patienten mit grosser Spannung erwartet. Aufgrund der noch nicht ausreichenden Datenlage insbesondere bei älteren Patienten mit fortgeschrittener Niereninsuffizienz sollte das Risiko-Nutzen-Verhältnis vor Therapiebeginn sorgfältig evaluiert werden.

Topics: Anticoagulants; Arterial Occlusive Diseases; Atrial Fibrillation; Comorbidity; Contraindications; Coronary Disease; Dabigatran; Glomerular Filtration Rate; Kidney Failure, Chronic; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thromboembolism; Vitamin K

Direct oral anticoagulants (DOACs) are increasingly prescribed substances in patients with indication for effective anticoagulation. Patients with chronic kidney disease (CKD) have a high burden of cardiovascular risk and are more likely to develop atrial fibrillation (AF) than patients without CKD. Patients with mild to moderate CKD benefit from DOACs, especially when having intolerance to vitamin K-antagonists (VKA). DOACs may in some cases be considered in patients with rare renal disease and hypercoagulabilic state. DOACs are to a large extent eliminated by renal excretion. Since prospective randomised data in CKD patients are sparse, the decision for anticoagulative therapy is challenging especially in patients with severe renal impairment. The direct factor Xa-inhibitors are approved for use even in patients with an estimated glomerular filtration rate (eGFR) between 15 and 30 ml/min. Careful monitoring of renal function on a regular basis is essential before initiation and after start of DOAC, especially for patients at risk for acute renal failure (elderly, diabetics, patients with preexisting kidney disease). None of the DOACs is approved in CKD patients with end-stage-renal-disease (ESRD) with or without dialysis. DOACs are not recommended for kidney transplant patients under immunosuppression with calcineurin inhibitors. In these patients conventional therapy with VKA is the only option, which has to be monitored closely since it has potential adverse effects.. Die direkten oralen Antikoagulantien (DOAK) werden zunehmend häufiger bei Patienten mit einer Indikation für eine effektive Antikoagulation verordnet. Im Vergleich zu Patienten ohne chronische Nierenerkrankung (CKD) haben Patienten mit CKD ein höheres kardiovaskuläres Risiko und eine höhere Wahrscheinlichkeit, Vorhofflimmern zu entwickeln. Die Behandlung mit DOAK ist bei Patienten mit milder bis mäßiger CKD von Vorteil, insbesonde-re wenn eine Unverträglichkeit gegen Vitamin-K-Antagonisten (VKA) besteht. DOAK können in Einzelfällen auch bei Patienten mit seltenen Nierenerkrankungen und Hyperkoagulabilität eingesetzt werden. Die DOAK werden zu einem großen Teil renal eliminiert. Da prospektive, randomisierte Daten zu CKD-Patienten rar sind, ist die Entscheidung für eine Antikoagulation schwierig, insbesondere bei Patienten mit deutlich eingeschränkter Nierenfunktion. Die direkten Faktor-Xa-Hemmer sind auch bei Patienten mit einer geschätzten glomerulären Filtrationsrate (GFR) von 15 bis 30 ml/min zugelassen. Es ist jedoch notwendig, die Nierenfunktion vor und nach Beginn der DOAK sorgfältig und regelmäßig zu evaluieren, besonders bei Patienten mit einem höheren Risiko für ein akutes Nierenversagen (Ältere, Diabetiker, Patienten mit bekannter Nierenerkrankung). Kein DOAK ist bei CKD-Patienten mit terminaler Nierenerkrankung, ob mit oder ohne Dialysetherapie, zugelassen. DOAK sind nicht empfohlen bei nierentransplantierten Patienten, die unter Immunsuppression mit Calcineurin-Hemmern stehen. Bei diesen Patienten ist die konven-tionelle Therapie mit VKA die einzige Möglichkeit und muss aufgrund potenziell uner-wünschter Nebenwirkungen engmaschig kontrolliert werden.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Contraindications; Factor Xa Inhibitors; Humans; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Risk Factors; Venous Thromboembolism; Vitamin K

The use of vitamin K antagonists (VKAs) in hemodialysis patients with atrial fibrillation (AF) is controversial. No randomized trials are available and observational studies have yielded conflicting results, engendering a large clinical practice variability and physician uncertainty. An unresolved but highly relevant question is whether AF poses a true risk of ischemic stroke in hemodialysis and whether any form of oral anticoagulation is therefore warranted.. We conducted a systematic review of studies that compared the incidence of ischemic stroke and bleeding in hemodialysis patients with AF taking VKA and those not taking VKA. When hemodialysis patients had been pooled with peritoneal dialysis, kidney transplant, or stage V chronic kidney disease patients, unpublished outcome data of the hemodialysis subgroup were obtained through personal communication. The main outcome measures were ischemic stroke/thromboembolic events, all-cause mortality, major bleeding, and hemorrhagic stroke. Combined hazard ratios (HRs) and 95% CIs were calculated using a random-effects model.. Twelve prospective or retrospective cohort studies were included in the meta-analysis, totaling 17,380 hemodialysis patients of whom 4,010 (23.1%) received VKA. In VKA-treated patients, mean CHADS. Our meta-analysis revealed a trend for a reduction of the risk of ischemic stroke in hemodialysis patients with AF treated with VKA. The true protective effect may have been underestimated, owing to inclusion of low-risk patients not expected to benefit from anticoagulation and to suboptimal anticoagulation. However, assessment of the overall effect of VKA in hemodialysis patients should also take into account the increased risk of bleeding, in particular of hemorrhagic stroke. Whether new oral anticoagulants provide a better benefit-risk ratio in hemodialysis patients should be the subject of future trials.

Topics: Anticoagulants; Atrial Fibrillation; Cause of Death; Cerebral Hemorrhage; Hemorrhage; Humans; Kidney Failure, Chronic; Mortality; Proportional Hazards Models; Renal Dialysis; Stroke; Thromboembolism; Vitamin K; Warfarin

Non-vitamin K antagonist oral anticoagulants (NOACs) are increasingly used in patients with deep vein thrombosis (DVT), pulmonary embolism (PE) and atrial fibrillation (AF). However, there is insufficient data concerning the periinterventional, perioperative, and intensive care management of patients on NOACs. Therefore, the recommendations regarding this management rely on pharmacokinetics of the particular NOAC in combination with the individual patient's characteristics, bleeding risk of the planned intervention/surgery, and urgency of the procedure. This review summarizes evidence and recommendations regarding the optimal periinterventional/perioperative antithrombotic management of patients on NOACs.

Topics: Antibodies, Monoclonal, Humanized; Anticoagulants; Atrial Fibrillation; Critical Care; Drug Interactions; Half-Life; Hemorrhage; Humans; Kidney Failure, Chronic; Pulmonary Embolism; Risk Factors; Surgical Procedures, Operative; Thromboembolism; Venous Thrombosis; Vitamin K

Cardiovascular mortality of hemodialysis patients remains a major problem. The prevalence and incidence of atrial fibrillation in this population are more important than in the general population. The indication of antivitamin K therapy (AVK) in this context of atrial fibrillation must be weighted against the increased risk of bleeding. Unfortunately, and contrary to the general population, an indication of anticoagulation based on embolic or hemorrhagic risk scores is not as clearly established in the hemodialysis population. No prospective randomized study has investigated the benefit/risk balance of anticoagulant treatment in hemodialysis subjects. This article is a review of the current literature on this topic, showing the prevalence of thromboembolic but also bleeding events in the hemodialysis population. The impact of AVK treatment in this specific population is also reviewed. To the best of our knowledge, the indication of treatment must be individualized.

Topics: Anticoagulants; Atrial Fibrillation; Hemorrhage; Humans; Kidney Failure, Chronic; Renal Dialysis; Stroke; Vitamin K

The purpose of this review article is to summarize the literature on diseases that are documented to have an effect on response to warfarin and other VKAs.. We searched the English literature from 1946 to September 2015 via PubMed, EMBASE, and Scopus for the effect of diseases on response vitamin K antagonists including warfarin, acenocoumarol, phenprocoumon, and fluindione.. Among many factors modifying response to VKAs, several disease states are clinically relevant. Liver disease, hyperthyroidism, and CKD are well documented to increase response to VKAs. Decompensated heart failure, fever, and diarrhea may also elevate response to VKAs, but more study is needed. Hypothyroidism is associated with decreased effect of VKAs, and obese patients will likely require higher initial doses of VKAs.. In order to minimize risks with VKAs while ensuring efficacy, clinicians must be aware of the effect of disease states when prescribing these oral anticoagulants.

Topics: Acenocoumarol; Administration, Oral; Anticoagulants; Cardiovascular Diseases; Diarrhea; Fibrinolytic Agents; Heart Failure; Humans; Hyperthyroidism; Kidney Failure, Chronic; Liver Diseases; Obesity; Phenindione; Phenprocoumon; Vitamin K; Warfarin

Calciphylaxis (calcific uremic arteriolopathy [CUA]) is a threatening disease that increasingly is acknowledged as a challenging condition at the interface of nephrology, dermatology, and cardiology. The primary CUA diagnosis is determined most often in nephrology care units because the vast majority of affected cases are detected in patients with advanced or end-stage renal disease. The typical clinical cascade starts with severe pain in initially often inconspicuous skin areas, which might progress to deep tissue ulcerations. Ulcer development is a severe complication with particularly high morbidity and mortality. Unfortunately, there has been a certain stagnancy regarding the slow progress in our understanding of how and why CUA develops. In addition, several important open issues regarding therapy have not been addressed successfully yet. Therefore, the European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) scientific working group Chronic Kidney Disease-Mineral and Bone Disorders (CKD-MBD) has accepted the challenge and has initiated a call for action by defining calciphylaxis as one of the outstanding research targets for the upcoming years.

Topics: Antioxidants; Biomedical Research; Calciphylaxis; Cinacalcet; Diphosphonates; Humans; Kidney Failure, Chronic; Naphthalenes; Parathyroidectomy; Risk Factors; Thiosulfates; Vitamin K

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

Vascular calcification occurs when calcium accumulates in the intima (associated with atherosclerosis) and/or media layers of the vessel wall. Coronary artery calcification (CAC) reflects the calcium burden within the intima and media of the coronary arteries. In population-based studies, CAC independently predicts cardiovascular disease (CVD) and mortality. A preventive role for vitamin K in vascular calcification has been proposed based on its role in activating matrix Gla protein (MGP), a calcification inhibitor that is expressed in vascular tissue. Although animal and in vitro data support this role of vitamin K, overall data from human studies are inconsistent. The majority of population-based studies have relied on vitamin K intake to measure status. Phylloquinone is the primary dietary form of vitamin K and available supplementation trials, albeit limited, suggest phylloquinone supplementation is relevant to CAC. Yet observational studies have found higher dietary menaquinone, but not phylloquinone, to be associated with less calcification. Vascular calcification is highly prevalent in certain patient populations, especially in those with chronic kidney disease (CKD), and it is plausible vitamin K may contribute to reducing vascular calcification in patients at higher risk. Subclinical vitamin K deficiency has been reported in CKD patients, but studies linking vitamin K status to calcification outcomes in CKD are needed to clarify whether or not improving vitamin K status is associated with improved vascular health in CKD. This review summarizes the available evidence of vitamin K and vascular calcification in population-based studies and clinic-based studies, with a specific focus on CKD patients.

Topics: Adult; Aged; Animals; Calcium-Binding Proteins; Dietary Supplements; Evidence-Based Medicine; Extracellular Matrix Proteins; Female; Humans; Kidney Failure, Chronic; Male; Matrix Gla Protein; Middle Aged; Vascular Calcification; Vitamin K; Vitamin K 1; Vitamins

Atherosclerosis is the main cause of morbidity and mortality in the general population, and premature death in patients with chronic kidney disease (CKD) especially dialysis ones. Besides the typical cardiovascular risk factors there is a considerable vascular calcification of intima media in these patients. Vitamin K - dependent proteins play an essential role in the pathogenesis of mineral and bone disorders related to CKD, including vascular calcification. Vitamin K is a family of vitamins, varying in the number of isoprenoid groups (saturated or unsaturated) connected into 2-methyl-1,4-naphthoquinone ring in C3 position. Vitamin K-dependent proteins require carboxylation (VKDPs) for biological activation. The coagulant factors are the most well-known VKDPs, but the role of the other proteins, like Matrix Gla Protein (MGP), Growth Arrest Specific Gene 6 (Gas-6) and osteocalcin has been recently discovered. MGP prevents vascular calcification and Gas-6 affects vascular smooth muscle cell apoptosis and movement. Carboxylation of osteocalcin promotes bone formation. Additionally vitamin K increases proliferation of osteoblasts and apoptosis of osteoclasts, influencing on bone remodeling. There is few studies indicating for decreased consumption of vitamin K in the general population. The restrictive diet recommended for dialysis patients additionally diminishes its daily supply, increasing the chance for vitamin K deficiency in this population. Clinical consequences of inhibition of epoxide reductase by generally used anticoagulants, that inhibiting vitamin K cycle and preventing gamma-carboxylation of Gla proteins, in the peripheral tissue is hardly known. This paper summaries the state of the art knowledge focused on the role of vitamin K in mineral and bone metabolism disorders in CKD patients.

Topics: Bone and Bones; Bone Remodeling; Humans; Kidney Failure, Chronic; Renal Dialysis; Vascular Calcification; Vitamin K

Morbidity and mortality are massively increased in patients with chronic kidney disease (CKD) and patients with end-stage renale disease (ESRD). Bone disease (renal osteodystrophy) and vascular disease (accelerated arteriosclerosis) are two typical entities contributing to this excess morbidity and mortality. Vitamin K and vitamin K-dependent-proteins play pivotal roles in the physiology of mineralization and in preventing ectopic calcification: two of these vitamin K-dependent-proteins are osteocalcin (regulating bone mineralization) and matrix-Gla protein (MGP, local calcification inhibitor in the vessel wall). Vitamin K deficiency impairs the physiological function of osteocalcin and MGP and, therefore, presumably contributes to bone demineralisation and vascular calcification (the so-called calcification paradox). In this context, the usage of vitamin K antagonists for long-term oral anticoagulation therapy might be risky especially in CKD patients exhibiting a high background level of vascular calcification. We present a summary of data describing the potential role of vitamin K deficiency and supplementation in bone and vascular disease in patients with CKD or ESRD.

Topics: Blood Coagulation Factors; Calcinosis; Calcium-Binding Proteins; Cardiovascular Diseases; Extracellular Matrix Proteins; Humans; Kidney Failure, Chronic; Matrix Gla Protein; Vitamin K

Vitamin K-dependent proteins (VKDPs) require carboxylation to become biologically active. Although the coagulant factors are the most well-known VKDPs, there are many others with important physiologic roles. Matrix Gla Protein (MGP) and Growth Arrest Specific Gene 6 (Gas-6) are two particularly important VKDPs, and their roles in vascular biology are just beginning to be understood. Both function to protect the vasculature; MGP prevents vascular calcification and Gas-6 affects vascular smooth muscle cell apoptosis and movement. Unlike the coagulant factors, which undergo hepatic carboxylation, MGP and Gas-6 are carboxylated within the vasculature. This peripheral carboxylation process is distinct from hepatic carboxylation, yet both are inhibited by warfarin administration. Warfarin prevents the activation of MGP and Gas-6, and in animals, induces vascular calcification. The relationship of warfarin to vascular calcification in humans is not fully known, yet observational data suggest an association. Given the high risk of vascular calcification in those patients with chronic kidney disease, the importance of understanding warfarin's effect on VKDPs is paramount. Furthermore, recognizing the importance of VKDPs in vascular biology will stimulate new areas of research and offer potential therapeutic interventions.

Topics: Animals; Anticoagulants; Blood Vessels; Calcinosis; Calcium-Binding Proteins; Extracellular Matrix Proteins; Humans; Intercellular Signaling Peptides and Proteins; Kidney Failure, Chronic; Matrix Gla Protein; Protein Processing, Post-Translational; Risk Assessment; Risk Factors; Vascular Diseases; Vitamin K; Warfarin

Vascular calcification is highly prevalent and correlated with high rates of cardiovascular mortality in chronic kidney disease patients. Recent evidence suggests that mineral, hormonal, and metabolic imbalances that promote phenotype change in vascular cells as well as deficiencies in specific mineralization inhibitory pathways may be important contributory factors for vascular calcification in these patients. This article reviews current mechanisms proposed for the regulation of vascular calcification and data supporting their potential contribution to this process in chronic kidney disease.

Topics: alpha-2-HS-Glycoprotein; Animals; Antifibrinolytic Agents; Blood Proteins; Bone Density Conservation Agents; Bone Morphogenetic Proteins; Calcinosis; Calcium-Binding Proteins; Chronic Disease; Extracellular Matrix Proteins; Humans; Kidney Diseases; Kidney Failure, Chronic; Matrix Gla Protein; Mice; Parathyroid Hormone; Phosphates; Rats; Vascular Diseases; Vitamin D; Vitamin K

Calcific arteriolopathy (CA), also known as " Calciphylaxis " describes a phenomenon of necrosis, mainly cutaneous and sometimes systemic, due to the obliteration of the arteriole's lumen. Initially there are under-intimal calcium deposits, and then the thrombosis occurs leading to the necrosis. CA affects mainly the renal insufficient hemodialysed patient, but not exclusively. We present 4 cases which illustrate well the etiologic spectrum of CA: terminal renal insufficiency, neoplasia, primary hyperparathyroidism, proteinuria, vitamin K inhibitors. We describe the AC's epidemiology, its cutaneous and systemic clinical presentations, its treatment. We make the hypothesis that CA is a strong risk marker in matter of cardiac mortality and we discuss this point.. In this article we describe the numerous breakthroughs that have been made in matter of research about calcification over the past few years: inhibitors of calcium phosphate deposition, vitamin D and PTH1R, protein-calcium complexes, cell death, induction of bone formation. These data are analysed from a clinical point of view with practical purposes. We present CA not only as a cutaneous disease but as a systemic pathology.. The CA epidemiology is an incentive to more diagnosis suspicion in front of organ infarct involving a patient likely to be concerned by CA. The scientific and therapeutic breakthroughs in matter of calcification enable a better prevention of the disease. Nevertheless it remains very difficult to cure when installed.

Topics: Aged; Arterioles; Biopsy; Calciphylaxis; Calcium; Coronary Artery Disease; Fatal Outcome; Female; Humans; Hyperparathyroidism; Kidney Failure, Chronic; Leg Ulcer; Male; Middle Aged; Neoplasms; Phosphates; Proteinuria; Skin; Vitamin K

Continuous or intermittent use of unfractioned heparin is the anticoagulant of choice to prevent the extracorporeal circulation clotting during the hemodialysis session. However, low molecular weight heparin (LMVH) could be an alternative treatment especially in case of high risk bleeding or during some clinical conditions such as diabetes mellitus, cerebrovascular bleeding, malignant hypertension. LMVH may be given as a single initial bolus injection generally adequate. Heparinization must be lowered or stopped when an effective anticoagulation is previously used.

Topics: Anticoagulants; Contraindications; Extracorporeal Circulation; Hemorrhage; Heparin; Heparin Antagonists; Heparin, Low-Molecular-Weight; Humans; Kidney Failure, Chronic; Protamines; Renal Dialysis; Risk Factors; Thrombosis; Vitamin K

Fat soluble vitamins (except vitamin K) are protein bounded with subsequent storage in the body. It is generally accepted that plasma level of vitamin A is increased in majority of patients with chronic renal insufficiency (CRI) including those on continuous ambulatory peritoneal dialysis (CAPD). Thus, there is no need to supplement this vitamin in CRI patients (pts). Plasma level of vitamin E in CRI pts may be elevated, normal or decreased. It seems to be justified to supplement this vitamin, in spite of its normal plasma level, in case platelet aggregation is increased. Both in dialyzed and nondialyzed CRI pts a normal serum level of vitamin K has been observed. Decreased or extremely low serum level of vitamin D following the gradual loss of renal tissue is to be observed in CRI pts. This deficit is regarded as the main factor leading to the decrease in serum level of calcium, the secondary hyperparathyroidism and bone changes. Treatment with 1.25(OH)2D3 (calcitriol) proved to be most successful in alleviation of symptoms resulting from the deficit of vitamin D3 in the body. Intravenous "pulsating" administration of calcitriol results in rapid normalization of serum PTH level. Treatment with 25(OH)D3 (calcidiol) given orally 3 times a week ("pulsating" method) revealed also fairly good results in this respect. During treatment with vitamin D3 hypercalcemia tends to develop, serum alkaline phosphatase normalizes, elevated PTH serum level decreases. Vitamin D metabolites are less active than 1.25(OH)2D3 being less hypercalcemic.

Topics: Avitaminosis; Calcitriol; Calcium; Humans; Hyperparathyroidism; Kidney Failure, Chronic; Vitamin D; Vitamin E; Vitamin K

Chronic kidney disease and osteoporosis are major public health problems associated with an aging population. Vitamin K insufficiency is prevalent among patients with end-stage renal disease (ESRD). Preliminary data indicate that poor vitamin K status may compromise bone health and that increased inflammation may be in the causal pathway. We performed an ancillary analysis of data collected in the frame of prospective observational cohort studies exploring various aspects of bone health in de novo renal transplant recipients to investigate the association between vitamin K status, inflammation, bone mineral density, and incident clinical fractures. Parameters of mineral metabolism (including biointact PTH and FGF23, sclerostin, calcidiol, calcitriol) and inflammation (CRP and IL-6), osteoprotegerin, bone turnover markers (P1NP, BsAP, and TRAP5B), and dephosphorylated-uncarboxylated Matrix Gla Protein (dp-ucMGP) were assessed on blood samples collected immediately prior to kidney transplantation in 468 patients. Areal bone mineral density (aBMD) was measured at the lumbar spine and femoral neck by dual-energy X-ray absorptiometry within 14 days posttransplant. Poor vitamin K status, defined by dp-ucMGP >500 nmol/L, was highly prevalent (90%). High dp-ucMGP levels independently associated with elevated inflammatory markers and low aBMD. No associations were observed between vitamin K status and bone turnover markers. During a median follow-up of 5.1 years, 33 patients sustained a fragility fracture. In Cox-proportional hazards analysis, a dp-ucMGP above median associated with incident fractures, independent of classical determinants, including age, gender, history of fracture, and aBMD (HR 2.21; 95% CI, 1.00 to 4.91; p < 0.05). In conclusion, poor vitamin K status associates with inflammation and low aBMD in patients with ESRD and confers an increased risk of incident fractures in de novo renal transplant recipients. © 2018 American Society for Bone and Mineral Research.

Topics: Adult; Aged; Biomarkers; Bone Density; Female; Femur Neck; Fibroblast Growth Factor-23; Fractures, Bone; Humans; Kidney Failure, Chronic; Lumbar Vertebrae; Male; Middle Aged; Risk Factors; Vitamin K

Subclinical vitamin K deficiency is prevalent among renal transplant recipients and is associated with an increased risk of cardiovascular disease. However, the association between vitamin K supplementation and improvement of arterial stiffness has not been explored in the renal transplant population. The KING trial (vitamin K2 In reNal Graft) is a single-arm study that evaluated the association between the change in vitamin K status and indices of arterial stiffness following 8 weeks of menaquinone-7 (vitamin K2) supplementation (360 μg once daily) among renal transplant recipients (n = 60). Arterial stiffness was measured using carotid-femoral pulse wave velocity (cfPWV). Subclinical vitamin K deficiency was defined as plasma concentration of dephosphorylated-uncarboxylated matrix Gla protein (dp-ucMGP) >500 pmol/L.At baseline, 53.3% of the study subjects had subclinical vitamin K deficiency. Supplementation was associated with a 14.2% reduction in mean cfPWV at 8 weeks (cfPWV pre-vitamin K2 = 9.8 ± 2.2 m/s vs. cfPWV post-vitamin K2 = 8.4 ± 1.5 m/s; P < .001). Mean dp-ucMGP concentrations were also significantly reduced by 55.1% following menaquinone-7 supplementation with a reduction in the prevalence of subclinical deficiency by 40% (P = .001). When controlled for age, durations of hemodialysis and transplantation, and the change in 24-hour mean arterial pressure, the improvement in arterial stiffness was independently associated with the reduction in dp-ucMGP concentration (P = .014).Among renal transplant recipients with stable graft function, vitamin K2 supplementation was associated with improvement in subclinical vitamin K deficiency and arterial stiffness. (Clinicaltrials.gov: NCT02517580).

Topics: Adult; Biomarkers; Calcium-Binding Proteins; Dietary Supplements; Extracellular Matrix Proteins; Female; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Matrix Gla Protein; Middle Aged; Pilot Projects; Prevalence; Prospective Studies; Pulse Wave Analysis; Renal Dialysis; Treatment Outcome; Vascular Calcification; Vascular Stiffness; Vitamin K; Vitamin K 2; Vitamin K Deficiency; Vitamins

Uncontrolled secondary hyperparathyroidism (sHPT) in patients with ESRD is a risk factor for calcific uremic arteriolopathy (CUA; calciphylaxis).. Adverse event reports collected during the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events trial were used to determine the frequency of CUA in patients receiving hemodialysis who had moderate to severe sHPT, as well as the effects of cinacalcet versus placebo. CUA events were collected while patients were receiving the study drug.. Among the 3861 trial patients who received at least one dose of the study drug, 18 patients randomly assigned to placebo and six assigned to cinacalcet developed CUA (unadjusted relative hazard, 0.31; 95% confidence interval [95% CI], 0.13 to 0.79; P=0.014). Corresponding cumulative event rates (95% CI) at year 4 were 0.011% (0.006% to 0.018%) and 0.005% (0.002% to 0.010%). By multivariable analysis, other factors associated with CUA included female sex, higher body mass index, higher diastolic BP, and history of dyslipidemia or parathyroidectomy. Median (10%, 90% percentile) plasma parathyroid hormone concentrations proximal to the report of CUA were 796 (225, 2093) pg/ml and 410 (71, 4957) pg/ml in patients randomly assigned to placebo and cinacalcet, respectively. Active use of vitamin K antagonists was recorded in 11 of 24 patients with CUA, nine randomly assigned to placebo, and two to cinacalcet, in contrast to 5%-7% at any one time point in patients in whom CUA was not reported.. Cinacalcet appeared to reduce the incidence of CUA in hemodialysis recipients who have moderate to severe sHPT.

Topics: Adult; Aged; Blood Pressure; Body Mass Index; Calcimimetic Agents; Calciphylaxis; Cinacalcet; Dyslipidemias; Female; Humans; Hyperparathyroidism, Secondary; Incidence; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Parathyroidectomy; Renal Dialysis; Risk Factors; Sex Factors; Vitamin K

Topics: Anticoagulants; Humans; Kidney Failure, Chronic; Renal Dialysis; Vitamin K

BACKGROUND Left ventricular thrombus is a serious complication of numerous cardiovascular conditions. Anticoagulation with oral vitamin K antagonists such as warfarin is a standard treatment for left ventricular thrombus and is recommended to reduce the risk of embolization. Patients with cardiac conditions share comorbidities with patients with end-stage renal disease, and patients with advanced kidney disease are predisposed to atherothrombotic and thromboembolic complications. The efficacy of direct oral anticoagulants in patients with left ventricular thrombus has not been well studied. CASE REPORT A 50-year-old man had prior myocardial infarction, heart failure with reduced ejection fraction, diabetes, hypertension, atrial fibrillation, treated hepatitis B infection, and end-stage renal disease on hemodialysis. On regular outpatient follow-up with the cardiology clinic, a transthoracic echocardiogram was requested and revealed akinesia of the mid to apical anterior wall, mid to apical septum, and left ventricular apex, and large apical thrombus measuring 20×15 mm. Apixaban 5 mg orally twice daily was started. A transthoracic echocardiogram was done after 3 months and after 6 months, and the thrombus did not resolve. The apixaban was shifted to warfarin. The international normalized range was maintained at the therapeutic range (INR 2.0-3.0). After 4 months of receiving warfarin, echocardiography showed a resolution of the left ventricular thrombus. CONCLUSIONS We report a case of left ventricular thrombus that was successfully dissolved by warfarin after treatment with apixaban failed. This case challenges the general assumption of apixaban's effectiveness in patients with end-stage renal disease on dialysis.

Topics: Anticoagulants; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Thrombosis; Vitamin K; Warfarin

Calcific Uremic Arteriolopathy (CUA) is a rare disease, causing painful skin ulcers in patients with end stage renal disease. Recommendations for CUA management and treatment are lacking.. We conducted a retrospective cohort study on CUA cases identified in western France, in order to describe its management and outcome in average clinical practices. Selection was based on the Hayashi diagnosis criteria (2013) extended to patients with eGFR < 30 mL/min/1.73m. Eighty-nine CUA cases were identified between 2006 and 2016, including 19 non dialyzed and 70 dialyzed patients. Females with obesity (55.1%) were predominant. Bone mineral disease abnormalities, inflammation and malnutrition (weight loss, serum albumin decrease) preceded CUA onset for 6 months. The multimodal treatment strategy included wound care (98.9%), antibiotherapy (77.5%), discontinuation of Vitamin K antagonists (VKA) (70.8%) and intravenous sodium thiosulfate (65.2%). 40.4% of the patients died within the year after lesion onset, mainly under palliative care. Surgical debridement, distal CUA, localization to the lower limbs and non calcium-based phosphate binders were associated with better survival. Risks factors of developing CUA among dialysis patients were obesity, VKA, weight loss, serum albumin decrease or high serum phosphate in the 6 months before lesion onset.. CUA involved mainly obese patients under VKA. Malnutrition and inflammation preceded the onset of skin lesions and could be warning signs among dialysis patients at risk.. ClinicalTrials.gov identifier NCT02854046, registered August 3, 2016.

Topics: Aged; Calciphylaxis; Case-Control Studies; Chelating Agents; Combined Modality Therapy; Debridement; Female; France; Humans; Kidney Failure, Chronic; Male; Middle Aged; Multivariate Analysis; Obesity; Phosphates; Retrospective Studies; Risk Factors; Sex Distribution; Vitamin K; Weight Loss

Dialysis patients manifest both an increased thrombotic risk and a haemorrhagic tendency. A great number of patients with chronic kidney disease requiring dialysis have cardiovascular comorbidities (coronary artery disease, atrial fibrillation or venous thromboembolism) and different indications for treatment with antithrombotics (primary or secondary prevention). Unfortunately, few randomized controlled trials deal with antiplatelet and/or anticoagulant therapy in dialysis. Therefore cardiology and nephrology guidelines offer ambiguous recommendations and often exclude or ignore these patients. In our opinion, there is a need for an expert consensus that provides physicians with useful information to make correct decisions in different situations requiring antithrombotics. Herein the European Dialysis Working Group presents up-to-date evidence about the topic and encourages practitioners to choose among alternatives in order to limit bleeding and minimize atherothrombotic and cardioembolic risks. In the absence of clear evidence, these clinical settings and consequent therapeutic strategies will be discussed by highlighting data from observational studies for and against the use of antiplatelet and anticoagulant drugs alone or in combination. Until new studies shed light on unclear clinical situations, one should keep in mind that the objective of treatment is to minimize thrombotic risk while reducing bleeding events.

Topics: Algorithms; Anticoagulants; Atrial Fibrillation; Coronary Artery Disease; Drug Therapy, Combination; Evidence-Based Medicine; Fibrinolytic Agents; Hemorrhage; Humans; Kidney Failure, Chronic; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Renal Dialysis; Secondary Prevention; Thrombosis; Venous Thromboembolism; Vitamin K; Warfarin

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

The risk-benefit ratio of vitamin K antagonists for different CHA2DS2-VASc scores in patients with end-stage renal disease treated with dialysis is unknown. The aim of this study was to investigate the association between vitamin K antagonist use and mortality for different CHA2DS2-VASc scores in a cohort of end-stage renal disease patients receiving dialysis treatment.. We prospectively followed 1718 incident dialysis patients. Hazard ratios were calculated for all-cause and cause-specific (stroke, bleeding, cardiovascular and other) mortality associated with vitamin K antagonist use.. Vitamin K antagonist use as compared with no vitamin K antagonist use was associated with a 1.2-fold [95% confidence interval (95% CI) 1.0-1.5] increased all-cause mortality risk, a 1.5-fold (95% CI 0.6-4.0) increased stroke mortality risk, a 1.3-fold (95% CI 0.4-4.2) increased bleeding mortality risk, a 1.2-fold (95% CI 0.9-1.8) increased cardiovascular mortality risk and a 1.2-fold (95% CI 0.8-1.6) increased other mortality risk after adjustment. Within patients with a CHA2DS2-VASc score ≤1, vitamin K antagonist use was associated with a 2.8-fold (95% CI 1.0-7.8) increased all-cause mortality risk as compared with no vitamin K antagonist use, while vitamin K antagonist use within patients with a CHA2DS2-VASc score ≥2 was not associated with an increased mortality risk after adjustment.. Vitamin K antagonist use was not associated with a protective effect on mortality in the different CHA2DS2-VASc scores in dialysis patients. The lack of knowledge on the indication for vitamin K antagonist use could lead to confounding by indication.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Renal Dialysis; Risk Assessment; Risk Factors; Stroke; Survival Rate; Vitamin K

Cardiovascular disease is the leading cause of death in end-stage renal disease and is strongly associated with vascular calcification. Both kidney transplantation and phosphate binders may lower the risk of vascular calcification. Vascular calcification is actively inhibited by vitamin-K-dependent matrix γ-carboxyglutamic acid protein (MGP). Whether kidney transplantation or phosphate binders affect vitamin K status is unknown. Therefore, we studied the influence of kidney transplantation and phosphate binder use on vitamin K status.. We measured plasma desphospho-uncarboxylated MGP (dp-ucMGP), a marker reflecting low vitamin K status, in a cross-sectional study of patients on hemodialysis (n = 82), peritoneal dialysis (n = 31) or who recently received a kidney transplantation (n = 36). By medication inventory, we assessed phosphate binder use. With linear regression, we assessed the influence of kidney transplantation and phosphate binder use on natural-log-transformed dp-ucMGP, adjusting for potential confounders.. Mean age of patients was 52±13 years; 102 (68%) were male. Dp-ucMGP levels were significantly lower in kidney transplant recipients (median 689 pmol/L) compared to patients on dialysis (median 1537 pmol/L, p<0.001). Eighty-nine patients on dialysis used phosphate binders. Using any phosphate binder was not associated with dp-ucMGP levels (median 1637 pmol/L, p = 0.09) compared to no phosphate binders (median 1142 pmol/L). Twenty-six patients used sevelamer monotherapy, which was associated with higher dp-ucMGP levels (median 1740 pmol/L, p = 0.04) after adjusting for age, sex and vitamin K antagonist use.. Recent kidney transplantation is associated with lower dp-ucMGP levels suggesting improved vitamin K status after transplantation. Sevelamer monotherapy is associated with higher dp-ucMGP levels suggesting worsening of vitamin K status. Both findings warrant more attention to vitamin K status in patients on dialysis, as vitamin K is necessary for protection against vascular calcification.

Topics: Calcium-Binding Proteins; Chelating Agents; Cross-Sectional Studies; Extracellular Matrix Proteins; Female; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Matrix Gla Protein; Middle Aged; Prospective Studies; Renal Dialysis; Sevelamer; Vitamin K

Calcific uraemic arteriolopathy (CUA, calciphylaxis) is a rare disease predominantly in dialysis patients and associated with high mortality. Painful skin ulcerations and calcification of cutaneous arterioles characterize calciphylaxis.. We established an observational, Internet-based registry allowing online notification for all German CUA cases. The registry recorded data about patient characteristics, biochemistry and therapies. Blood samples were stored in a central biobank.. Between 2006 and 2015, 253 CUA patients were recorded: median age 70 [interquartile range (IQR) 61-76] years, 60% females and 86% ( n = 207) dialysis patients, translating into an estimated annual incidence rate of 0.04% in German dialysis patients. Fifty-two per cent received vitamin K antagonists (VKAs) prior to CUA. Skin lesions were localized in 71% on the legs or gluteal region. In dialysis CUA patients median total serum calcium was 2.20 (IQR 2.06-2.37) mmol/L, phosphorus 1.67 (IQR 1.35-2.03) mmol/L, intact parathyroid hormone 147 (IQR 72-276) pg/mL and fetuin-A 0.21 (IQR 0.16-0.26) g/L (normal range 0.35-0.95). Median sclerostin, osteoprotegerin, TRAP5b, bone-specific alkaline phosphatase and c-terminal FGF23 levels were all elevated. The most frequently recorded therapeutic procedures in dialysis CUA patients were as follows: wound debridement (29% of cases), stopping VKA (25%), lowering calcium supply (24%), sodium thiosulphate (22%), application of vitamin K (18%), increase of dialysis duration/frequency (17%) and stoping active vitamin D (16%).. Approximately 50% of CUA patients used VKA. Our data suggest that uncontrolled hyperparathyroidism is not the key determinant of calciphylaxis. Therapeutic strategies were heterogeneous. The experience of the German registry will help substantially to initiate a large-scale multinational CUA registry.

Topics: Aged; Calciphylaxis; Female; Fibroblast Growth Factor-23; Humans; Kidney Failure, Chronic; Male; Middle Aged; Registries; Renal Dialysis; Vitamin K

In end-stage renal disease (ESRD), coronary artery calcification (CAC) and inflammation contribute to cardiovascular disease (CVD). Statins do not improve survival in patients with ESRD, and their effect on vascular calcification is unclear. We explored associations between CAC, inflammatory biomarkers, statins and mortality in ESRD.. In 240 patients with ESRD (63% males; median age 56 years) from cohorts including 86 recipients of living donor kidney transplant (LD-Rtx), 96 incident dialysis patients and 58 prevalent peritoneal dialysis patients, associations of CAC score (Agatston Units, AUs), interleukin-6 (IL-6) with high-sensitivity C-reactive protein (hsCRP), tumour necrosis factor (TNF), use of statins and all-cause mortality were analysed. Cardiac CT was repeated in 35 patients after 1·5 years of renal replacement therapy. In vitro, human vascular smooth muscle cells (hVSMCs) were used to measure vitamin K metabolism.. Among 240 patients, 129 (53%) had a CAC score > 100 AUs. Multivariate analysis revealed that independent predictors of 1-SD higher CAC score were age, male gender, diabetes and use of statins. The association between CAC score and mortality remained significant after adjustment for age, gender, diabetes, CVD, use of statins, protein-energy wasting and inflammation. Repeated CAC imaging in 35 patients showed that statin therapy was associated with greater progression of CAC. In vitro synthesis of menaquinone-4 by hVSMCs was significantly impaired by statins.. Elevated CAC score is a mortality risk factor in ESRD independent of inflammation. Future studies should resolve if statins promote vascular calcification and inhibition of vitamin K synthesis in the uremic milieu.

Topics: Adult; Aged; Biomarkers; Coronary Artery Disease; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kaplan-Meier Estimate; Kidney Failure, Chronic; Male; Middle Aged; Muscle, Smooth, Vascular; Vascular Calcification; Vitamin K

Patients with atrial fibrillation requiring maintenance haemodialysis are at increased risk of ischaemic stroke and bleeds. Currently, vitamin K antagonists such as warfarin are predominantly used in these patients as limited data are available on the use of non-vitamin K oral anticoagulants, including dabigatran etexilate (dabigatran). Dabigatran is approximately 85 % renally eliminated, thus, its half-life is prolonged in renal impairment. This study simulated the doseexposure relationship of dabigatran in patients undergoing haemodialysis. Dabigatran exposure was modelled at once- and twice-daily doses of 75 mg, 110 mg and 150 mg and at variations in non-renal clearance and dialysis settings. Resultant dose exposure (area under the curve [AUC]) was compared with values simulated from typical patients in the RE-LY® trial (based on a previously characterised pharmacometric model). In this simulation, all twice-daily dosages resulted in exposures above those simulated from typical RE-LY patients (1.5- to 3.3-fold increase in AUC) and thus may not be optimal for use in haemodialysis patients. However, dabigatran doses of 75 mg or 110 mg once daily produced exposures comparable to those simulated in typical RE-LY patients (-13.3 and +4.4 %, respectively). Of patient and dialysis variables, non-renal clearance had the highest impact on exposure (≤ 30.8 % change). These data could potentially inform dose selection in patients undergoing maintenance haemodialysis and the findings warrant investigation in future clinical trials.

Topics: Administration, Oral; Aged; Anticoagulants; Area Under Curve; Atrial Fibrillation; Brain Ischemia; Computer Simulation; Dabigatran; Humans; Kidney Failure, Chronic; Male; Renal Dialysis; Stroke; Vitamin K

Stroke prevention in dialysis-dependent patients with atrial fibrillation (AF) is an unresolved clinical dilemma. Indeed, no randomized controlled trial evaluating the efficacy and safety of oral anticoagulants in this population, has been conducted so far. Observational research on the use of warfarin in patients on dialysis has shown conflicting results. This uncertainty is mirrored by the wide variations in warfarin prescription patterns across centers. We sought to evaluate the association between the use of vitamin K antagonists (VKAs) and mortality among hemodialysis patient with AF and to assess potential factors affecting the risk-benefit profile of warfarin in this population.. A total of 91,987 patients registered in the European Clinical Dialysis Database® system from January 2004 to January 2015. Of which, 9,238 patients were identified with a diagnosis of AF. After excluding ineligible patients, a 1:1 propensity score matched cohort of 1,324 warfarin users and non-users were assembled.. VKA use was associated with both increased 90-day survival (hazard ratio, HR 0.47, p < 0.01) and 6-year survival (HR 0.76, p < 0.01); however, a trend indicated a stronger early benefit (p for time-interaction <0.01). Moderation analysis showed that patients' age and clinical history of stroke strongly influenced warfarin-related benefits on survival.. VKA may provide an early survival benefit; however, this is partially offset later during the follow-up. In addition, heterogeneous risk-benefit profiles were observed among subgroups of dialysis-dependent patients with AF, further emphasizing the complexities of tailoring stroke prevention strategies in this population.

Topics: Age Factors; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Europe; Humans; Kidney Failure, Chronic; Middle Aged; Mortality; Propensity Score; Registries; Renal Dialysis; Risk Assessment; Stroke; Survival Rate; Time Factors; Vitamin K; Warfarin

Although drug therapy is inherently associated with the risk of adverse drug reactions (ADRs), some of these events are preventable. The estimated proportion of preventable ADRs varies from one study or clinical context to another. Bleeding caused by antithrombotic agents (and particularly vitamin K antagonists, VKAs) constitutes one of the most frequent causes of ADR-related hospitalization.Hence, the objective of the present study was to adapt and validate an ADR preventability score for bleeding due to VKAs and evaluate the preventability of bleeding in 906 consecutive hospitalized, VKA-treated adult patients with a risk of major bleeding (defined as an international normalized ratio ≥5) over a 2-year period. A specific preventability scale for VKA-associated bleeding was developed by adapting a published tool.Overall, 241 of the 906 patients in the study experienced at least 1 VKA-associated bleeding event. The scale's reliability was tested by 2 different evaluators. The inter-rater reliability (evaluated by calculation of Cohen's kappa) ranged from "good" to "excellent." Lastly, the validated scale was used to assess the preventability of the VKA-associated bleeding. We estimated that bleeding was preventable or potentially preventable in 109 of the 241 affected patients (45.2%).We have developed a useful, reliable tool for evaluating the preventability of VKA-associated bleeding. Application of the scale in a prospective study revealed that a high proportion of VKA-associated bleeding events in hospitalized, at-risk adult patients were preventable or potentially preventable.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Algorithms; Anemia; Atrial Fibrillation; Female; Fibrinolytic Agents; Hemorrhage; Humans; Hypertension; International Normalized Ratio; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Reproducibility of Results; Risk Assessment; Severity of Illness Index; Vitamin K; Young Adult

Calciphylaxis is associated with a poor prognosis in dialysis patients, and its pathogenesis remains incompletely understood. Although the use of vitamin K antagonists (VKA) has been implicated, previous reports are conflicting. We aimed to determine if vitamin K antagonists conferred an increased risk of calciphylaxis in patients on dialysis.. We performed a single-centre, retrospective cohort study of 2,234 patients receiving dialysis, and compared the characteristics of those with and without calciphylaxis.. We identified 5 cases of calciphylaxis (all female) between January 2009 and December 2013. Overall, 142 patients (6.4%) were treated with VKA during the study period. Calciphylaxis was more common in the VKA group (4 of 142 patients, OR = 61, 95% CI 6.7-546, p = 0.0001). VKA was withdrawn in all cases and treatment instituted with sodium thiosulphate, cinacalcet and supportive measures. All patients recovered, although there was one sudden cerebrovascular death during follow-up.. Treatment with VKA predisposes to the development of calciphylaxis.

Topics: Adult; Aged; Amputation Stumps; Anticoagulants; Arterioles; Calciphylaxis; Cohort Studies; Diabetes Mellitus, Type 2; Female; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Renal Replacement Therapy; Retrospective Studies; Venous Thrombosis; Vitamin K

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

Topics: Anticoagulants; Aspirin; Atrial Fibrillation; Contraindications; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Humans; Kidney Failure, Chronic; Polysaccharides; Renal Dialysis; Thromboembolism; Vascular Calcification; Vitamin K; Warfarin

Information on recurrent venous thromboembolic events (VTEs) and major bleeding risks during anticoagulant treatment in patients with cancer-associated VTEs and chronic kidney disease (CKD) is scarce, although it is of relevance in establishing better tailored management strategies in these patients.. We compared risks of recurrent VTEs and major bleeds in cancer-associated VTE patients with and without CKD.. A total of 1684 patients diagnosed with a cancer-associated VTE between 2001 and 2011 were followed for 180 days after VTE diagnosis. Patients were treated mainly with low-molecular-weight heparin (LMWH) or vitamin-K antagonists (VKA). Primary outcomes were recurrent VTE and major bleeding. Secondary outcome was fatal bleeding.. Recurrent VTEs occurred in 15.9/100 patient years (py) in patients without CKD (eGFR > 60 mL min(-1) ), 19.5/100 py in those with CKD stage 3A (eGFR 45-60 mL min(-1) ), 14.9/100 py in those with CKD 3B (eGFR 30-45 mL min(-1) ), and 6.8/100 py in patients with CKD 4-5 (eGFR < 30 mL min(-1) ). Major bleeding occurred in 11.4/100 py in patients without CKD, 18.5/100 py in those with CKD stage 3A, 16.0/100 py in those with CKD 3B, and 40.8/100 py in patients with CKD 4-5. Fatal bleeding occurred in 1.1/100 py, 3.4/100 py, 6.3/100 py and 15.7/100 py, respectively. These increased bleeding risks in CKD patients were mainly observed in those on LMWH treatment, not VKA.. The risk of major bleeding was increased in CKD patients with VTE and cancer, and was most prominent in those treated with LMWH and an eGFR < 30 mL min(-1) . These results indicate that LMWH should be used with caution in this specific population.

Topics: Aged; Anticoagulants; Cohort Studies; Female; Follow-Up Studies; Glomerular Filtration Rate; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Kidney Failure, Chronic; Male; Middle Aged; Neoplasms; Recurrence; Registries; Risk; Time Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K

Among the vitamin K antagonists (VKA), indanedione-derived VKA is suspected to induce an immunoallergic risk. One indanedione-derived VKA, fluindione, is still being used in France. The aim of this study was to evaluate the contribution of VKA to acute and chronic nephritis.. Twenty-four cases of biopsy proven acute interstitial nephritis (AIN) were retrospectively selected, based on a first intake of VKA within the previous 12 months as well as an increase of at least 50% of the basal level of serum creatinine. The 24 cases were all treated with fluindione VKA and not with coumarinic VKA.. The subjects studied included 20 men and 4 women, with a mean age of 73.0±9.3 years (range: 44-84). The delay between fluindione introduction and the appearance of an AIN, proven by biopsy when available, was 11.9±6.9 weeks (range: 3-28). Creatinine increased from 123.0±56.4 μmol/L (range: 56-335) at fluindione introduction to 460.7±265.3 μmol/L (range: 109-1200) at the time of AIN discovery. The treatment then consisted of stopping the fluindione and introducing steroids for 21 patients. If a VKA was necessary, fluindione was replaced by a coumarinic VKA. After 6 months, 1 patient died and 15 patients presented severe chronic kidney disease (CKD Stages 4-5). Two patients still required chronic dialysis after 6 months and five patients after 3 years. Patients with pre-existing kidney disease were more prone to develop severe CKD with fluindione.. In this large study, arguments are presented to incriminate fluindione in the induction of acute and chronic nephritis.

Topics: Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Anticoagulants; Coumarins; Drug Hypersensitivity; Female; Follow-Up Studies; France; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Middle Aged; Nephritis, Interstitial; Phenindione; Prognosis; Retrospective Studies; Vitamin K

Vitamin K is essential for activation of γ-carboxyglutamate (Gla)-proteins including the vascular calcification inhibitor matrix Gla-protein (MGP). Insufficient vitamin K intake leads to production of uncarboxylated, mostly inactive proteins and contributes to an increased cardiovascular risk. In kidney transplant recipients, cardiovascular risk is high but vitamin K intake and status have not been defined. We investigated dietary vitamin K intake, vascular vitamin K status and its determinants in kidney transplant recipients. We estimated vitamin K intake in a cohort of kidney transplant recipients (n = 60) with stable renal function (creatinine clearance 61 [42-77] (median [interquartile range]) ml/min), who were 75 [35-188] months after transplantation, using three-day food records and food frequency questionnaires. Vascular vitamin K status was assessed by measuring plasma desphospho-uncarboxylated MGP (dp-ucMGP). Total vitamin K intake was below the recommended level in 50% of patients. Lower vitamin K intake was associated with less consumption of green vegetables (33 vs 40 g/d, p = 0.06) and increased dp-ucMGP levels (621 vs 852 pmol/L, p<0.05). Accordingly, dp-ucMGP levels were elevated (>500 pmol/L) in 80% of patients. Multivariate regression identified creatinine clearance, coumarin use, body mass index, high sensitivity-CRP and sodium excretion as independent determinants of dp-ucMGP levels. In a considerable part of the kidney transplant population, vitamin K intake is too low for maximal carboxylation of vascular MGP. The high dp-ucMGP levels may result in an increased risk for arterial calcification. Whether increasing vitamin K intake may have health benefits for kidney transplant recipients should be addressed by future studies.

Topics: Aged; Calcium-Binding Proteins; Diet; Diet Surveys; Extracellular Matrix Proteins; Female; Humans; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Linear Models; Male; Matrix Gla Protein; Middle Aged; Multivariate Analysis; Vitamin K; Vitamin K Deficiency; Vitamins

Abnormal vitamin K status was documented in patients with chronic kidney diseases (CKD), especially those undergoing hemodialysis. The data related to patients undergoing peritoneal dialysis (PD) are contradictory. Therefore, in the present study we aimed to evaluate vitamin K status in patients with CKD who are treated with continuous ambulatory PD. Twenty-eight patients entered into the study. Dialysis vintage ranged from 3 to 89 months. Vitamin K status was assessed in all subjects using undercarboxylated prothrombin measurement (PIVKA-II). In addition, total protein and albumin levels, total cholesterol, LDL cholesterol, triglyceride, calcium, urea and creatinine concentrations were determined. PIVKA-II concentrations were abnormal in 13 (46.4 %) subjects. BMI values, both total and LDL cholesterol concentrations were significantly higher in patients with than those without vitamin K deficiency. Moreover, PIVKA II levels correlated with BMI values (r = 0.441, p < 0.019), LDL cholesterol (r = 0.434, p < 0.021) and creatinine (r = 0.406, p< 0.032) concentrations. However, through the use of logistic regression analysis and multiple regression analysis, no clinical factor was documented to be the independent risk factor of vitamin K deficiency. In conclusion, vitamin K deficiency is a frequent condition in peritoneally dialyzed patients. Assessment of vitamin K status should become a standard procedure in this group of patients.

Topics: Adult; Aged; Biomarkers; Body Mass Index; Cholesterol, LDL; Creatinine; Female; Humans; Kidney Failure, Chronic; Logistic Models; Male; Middle Aged; Nutritional Status; Peritoneal Dialysis, Continuous Ambulatory; Predictive Value of Tests; Protein Precursors; Prothrombin; Risk Factors; Triglycerides; Vitamin K

Matrix γ-carboxyglutamate (Gla) protein (MGP) is an important local inhibitor of vascular calcification, which can undergo two post-translational modifications: vitamin K-dependent γ-glutamate carboxylation and serine phosphorylation. While carboxylation is thought to have effects upon binding of calcium-ions, phosphorylation is supposed to affect the cellular release of MGP. Since both modifications can be exerted incompletely, various MGP species can be detected in the circulation. MGP levels were measured with two commercially available competitive and two novel sandwich assays in healthy controls, in patients with rheumatic disease, aortic valve disease, and end-stage renal disease, as well as in volunteers after vitamin K supplementation (VKS) and treatment with vitamin K antagonists (VKA). Major differences were found between the MGP assays, including significantly different behaviour with regard to vascular disease and the response to VKA and VKS. The dual-antibody assay measuring non-phosphorylated, non-carboxylated MGP (dp-ucMGP) was particularly sensitive for these changes and would be suited to assess the vascular vitamin K status. We conclude that the different assays for particular circulating MGP species allows the assessment of various aspects of the MGP system.

Topics: Adult; Aged; Antibodies, Monoclonal; Aortic Valve Insufficiency; Arthritis, Rheumatoid; Biomarkers; Calcinosis; Calcium-Binding Proteins; Chondrocalcinosis; Disease Progression; Enzyme-Linked Immunosorbent Assay; Extracellular Matrix Proteins; Feasibility Studies; Humans; Kidney Failure, Chronic; Matrix Gla Protein; Middle Aged; Prognosis; Protein Processing, Post-Translational; Vitamin K

Topics: Acute Kidney Injury; Adult; Biopsy; Blood Urea Nitrogen; Creatinine; Humans; Kidney Failure, Chronic; Kidney Transplantation; Kidney Tubular Necrosis, Acute; Male; Time Factors; Urine; Vitamin K

Deficiencies of water-soluble vitamins may occur in uremic patients mainly because of restricted consumption and of loss during chronic hemo- and peritoneal dialysis. Although the daily requirement for most vitamins is not well defined in chronic renal failure supplementation of the vitamins thiamine, riboflavin, pyridoxine, pantothenic acid, niacin and ascorbic acid, the form of one multivitamin preparation without vitamin A as well as folic acid in dialysis patients after each dialysis is recommended. There is no need for vitamin B12, vitamin A and vitamin E.

Topics: Ascorbic Acid; Avitaminosis; Biotin; Folic Acid; Humans; Kidney Failure, Chronic; Niacin; Pantothenic Acid; Pyridoxine; Riboflavin; Thiamine; Vitamin A; Vitamin B 12; Vitamin E; Vitamin K; Vitamins

Renal toxicosis attributable to vitamin K3 (menadione sodium bisulfite) was suspected in 5 young adult horses in which acute renal failure developed following parenteral administration of vitamin K3 at the manufacturers' recommended dosages. Renal disease was subsequently induced experimentally in 5 of 6 horses by administration of vitamin K3 at manufacturers' recommended dosages. Signs of renal disease in the clinical patients as well as in the horses treated experimentally included renal colic, hematuria, azotemia, and electrolyte abnormalities consistent with acute renal failure. Two clinical patients and 3 experimental horses were subsequently necropsied and found to have lesions of renal tubular nephrosis.

Topics: Acute Kidney Injury; Animals; Female; Hemostatics; Horse Diseases; Horses; Humans; Kidney Failure, Chronic; Kidney Tubular Necrosis, Acute; Male; Mice; Rats; Vitamin K; Vitamin K 3

Topics: Heparin; Humans; Kidney Failure, Chronic; Protamines; Prothrombin Time; Renal Dialysis; Vitamin K

Five patients developed vitamin K-related abnormalities in blood coagulation during treatment with parenteral cephalosporin or cephamycin antibiotics. All the patients had significantly impaired renal function and complicated medical problems. The coagulation defect was corrected with vitamin K therapy.

Topics: Adult; Aged; Cephalosporins; Female; Humans; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Sepsis; Urinary Tract Infections; Vitamin K; Vitamin K Deficiency

The coagulopathy induced by vitamin K deficiency commonly results from our lack of awareness of the clinical setting associated with vitamin K deficiency. Thirteen cases are reviewed to illustrate the clinical correlates most frequently observed. Dietary deficiency was always present, but concomitant antibiotic therapy was not an absolute requirement. The postoperative patient is at high risk, as is the patient with cancer or renal failure. Abnormal bleeding was common, but significant hemorrhage occurred only in postoperative patients. Factor assays were helpful and occasionally necessary to make the diagnosis, but a therapeutic trial with parenteral vitamin K was often enough to provide the right diagnosis. Greater awareness of this deficiency syndrome is necessary to avoid the serious morbidity that often results.

Topics: Adult; Aged; Anti-Bacterial Agents; Blood Coagulation Disorders; Humans; Kidney Failure, Chronic; Male; Middle Aged; Neoplasms; Nutrition Disorders; Preoperative Care; Risk; Surgical Procedures, Operative; Vitamin K; Vitamin K Deficiency