vitamin-k-semiquinone-radical and Uremia

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

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

Topics: Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Transfusion; Hemorrhage; Hemostasis; Heparin; Humans; Liver Diseases; Medical History Taking; Postoperative Complications; Preoperative Care; Surgical Procedures, Operative; Thrombocytopenia; Uremia; Vitamin K

Topics: Administration, Oral; Adrenal Cortex Hormones; Animals; Anti-Bacterial Agents; Anticoagulants; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Factors; Clofibrate; Coumarins; Diuresis; Dogs; Heparin; Humans; Hypnotics and Sedatives; Liver Diseases; Metabolic Diseases; Phenylbutazone; Rats; Salicylates; Sulfonamides; Thrombosis; Uremia; Vitamin K

Vitamin K dependent proteins (VKDP), such as hepatic coagulation factors and vascular matrix Gla protein (MGP), play key roles in maintaining physiological functions. Vitamin K deficiency results in inactive VKDP and is strongly linked to vascular calcification (VC), one of the major risk factors for cardiovascular morbidity and mortality. In this study we investigated how two vitamin K surrogate markers, dephosphorylated-undercarboxylated MGP (dp-ucMGP) and protein induced by vitamin K absence II (PIVKA-II), reflect vitamin K status in patients on hemodialysis or with calcific uremic arteriolopathy (CUA) and patients with atrial fibrillation or aortic valve stenosis. Through inter- and intra-cohort comparisons, we assessed the influence of vitamin K antagonist (VKA) use, vitamin K supplementation and disease etiology on vitamin K status, as well as the correlation between both markers. Overall, VKA therapy was associated with 8.5-fold higher PIVKA-II (0.25 to 2.03 AU/mL) and 3-fold higher dp-ucMGP (843 to 2642 pM) levels. In the absence of VKA use, non-renal patients with established VC have dp-ucMGP levels similar to controls (460 vs. 380 pM), while in HD and CUA patients, levels were strongly elevated (977 pM). Vitamin K supplementation significantly reduced dp-ucMGP levels within 12 months (440 to 221 pM). Overall, PIVKA-II and dp-ucMGP showed only weak correlation (r

Topics: 4-Hydroxycoumarins; Aortic Valve Stenosis; Atrial Fibrillation; Biomarkers; Calcium-Binding Proteins; Cardiovascular Diseases; Cohort Studies; Dietary Supplements; Extracellular Matrix Proteins; Female; Heart Disease Risk Factors; Humans; Indenes; Liver; Male; Matrix Gla Protein; Middle Aged; Nutritional Status; Protein Precursors; Prothrombin; Renal Dialysis; Uremia; Vascular Calcification; Vitamin K; Vitamin K Deficiency

Peripheral artery disease is a common complication among dialyzed patients. Since Vitamin K antagonists promote metastatic calcifications and these are the main determinants of vascular damage, we investigated their role in the development of lower limb ulcers in dialyzed patients. We retrospectively enrolled 316 dialyzed patients, aged 68 ± 15 years, 65% male, 32% diabetic, 43% with ischemic heart disease and followed them for 36 ± 25 months. 60 patients assumed Vitamin K antagonists: they were older, with a higher prevalence of heart disease, at greater risk of death and they developed more ulcers and underwent more lower limb amputations compared to the rest of our cohort. Peripheral artery disease, Vitamin K antagonists and diabetes were independent risk factors for foot lesions. In addition, Vitamin K antagonists were also an independent risk factor for death. Vitamin K antagonists are a potent independent risk factor for the development of the uremic foot syndrome and death.

Topics: Aged; Amputation, Surgical; Anticoagulants; Comorbidity; Diabetes Mellitus, Type 2; Female; Foot Ulcer; Humans; Lower Extremity; Male; Peripheral Arterial Disease; Renal Dialysis; Retrospective Studies; Risk Factors; Uremia; Vitamin K

In chronic kidney disease, vitamin K-dependent proteins, including the calcification inhibitor matrix Gla protein, are largely uncarboxylated indicating that functional vitamin K deficiency may contribute to uremic vascular calcification. Since the effects of uremia on the vitamin K cycle are unknown, we investigated the influence of uremia and vitamin K supplementation on the activity of the vitamin K cycle and extraosseous calcification. Uremia was induced in rats by an adenine-supplemented diet and vitamin K1 or K2 was administered over 4 and 7 weeks. After 4 weeks of adenine diet, the activity of the vitamin K cycle enzyme γ-carboxylase but not the activities of DT-diaphorase or vitamin K epoxide reductase were reduced. Serum levels of undercarboxylated matrix Gla protein increased, indicating functional vitamin K deficiency. There was no light microscopy-detectable calcification at this stage but chemically determined aortic and renal calcium content was increased. Vitamin K treatment reduced aortic and renal calcium content after 4 weeks. Seven weeks of uremia induced overt calcification in the aorta, heart, and kidneys; however, addition of vitamin K restored intrarenal γ-carboxylase activity and overstimulated it in the liver along with reducing heart and kidney calcification. Thus, uremic vitamin K deficiency may partially result from a reduction of the γ-carboxylase activity which possibly contributes to calcification. Pharmacological vitamin K supplementation restored the vitamin K cycle and slowed development of soft tissue calcification in experimental uremia.

Topics: Animals; Aorta; Calcinosis; Calcium-Binding Proteins; Carbon-Carbon Ligases; Extracellular Matrix Proteins; Kidney; Liver; Male; Matrix Gla Protein; NAD(P)H Dehydrogenase (Quinone); Rats; Rats, Wistar; Uremia; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

The vitamin K-dependent proteins (VKDPs) matrix Gla protein and osteocalcin protect from cardiovascular calcifications and bone fractures. A vitamin K recycling system maintains sufficient vitamin K levels for activation of VKDPs through γ-glutamyl carboxylase (GGCX). Kaesler et al. demonstrate that uremia per se can interfere with GGCX activity, contributing to vitamin K deficiency in chronic kidney disease and opening the path to the clinical use of vitamin K, currently tested in randomized trials.

Topics: Animals; Male; Uremia; Vitamin K

Topics: Aged; Blood Coagulation; Cephalosporins; Female; Hemorrhage; Humans; Male; Middle Aged; Prothrombin Time; Uremia; Vitamin K

Vitamin K promotes the formation of gamma-carboxylated glutamic acid (Gla) residues within different protein classes such as vitamin K-dependent clotting factors, bone Gla-protein (BGP or osteocalcin), and atherocalcin. Gla-containing proteins have a high affinity for the Ca2+ ion. In addition to bone and atheromatous plaques they are also regularly found in ectopic calcifications, but not in uncalcified soft tissue. In the present study we investigate the possibility that vitamin K and BGP, in addition to previously recognized factors, may play a role in soft tissue calcification of chronic hemodialysis patients. Patients without radiovisible ectopic calcifications (group A) are compared to patients with such Ca deposits (group B). Both patient groups have comparable values of predialysis plasma Ca, P, alkaline phosphatases, parathyroid hormone (PTH) and 25 hydroxyvitamin D. The CaxP product is slightly higher in group B than in group A patients. Plasma vitamin K1 levels of group B patients are increased to more than twice the values observed in group A patients. Plasma BGP, even though not significantly different, shows a trend towards decreased levels in group B patients. A positive correlation exists between plasma vitamin K1 and BGP for patient group A alone, but not for group B alone. A correlation is also observed between plasma PTH and BGP (all patients) and between serum alkaline phosphatases and plasma BGP (all patients). Taken together, these results favor the hypothesis that in addition to an increased CaxP product a vitamin K excess may induce soft tissue calcification in hemodialysis patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Calcinosis; Calcium; Calcium-Binding Proteins; Connective Tissue Diseases; Female; Humans; Male; Middle Aged; Osteocalcin; Parathyroid Hormone; Renal Dialysis; Uremia; Vitamin K; Vitamin K 1

Topics: Adenosine Triphosphate; Animals; Cytochromes; Electron Transport; Humans; In Vitro Techniques; Liver; Mitochondria; NADP; Oxidative Phosphorylation; Rats; Rotenone; Uremia; Vitamin K

Topics: Antifibrinolytic Agents; Aprotinin; Blood Coagulation Disorders; Blood Coagulation Factors; Fibrinolysis; Humans; Thrombin; Uremia; Vitamin K; Vitamin K Deficiency