vitamin-k-semiquinone-radical and Kidney-Diseases

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

Vitamin K is a cofactor for the function of the enzyme γ-glutamyl carboxylase, necessary for the activation of multiple vitamin K dependent-proteins. Vitamin K dependent-proteins (VKDPs) have important roles in bone health, vascular health, metabolism, reproduction as well as in cancer progression. Vitamin K deficiency is common in different conditions, including kidney disease, and it may influence the activity of VKDPs. This review discusses vitamin K status in human health and the physiologic and pathologic roles of VKDPs, beyond the established effects in skeletal and cardiovascular health.

Topics: Humans; Kidney Diseases; Vitamin K; Vitamins

Patients with chronic kidney disease (CKD) have an increased risk of developing vascular calcifications, as well as bone dynamics impairment, leading to a poor quality of life and increased mortality. Certain vitamin K dependent proteins (VKDPs) act mainly as calcification inhibitors, but their involvement in the onset and progression of CKD are not completely elucidated. This review is an update of the current state of knowledge about the relationship between CKD and four extrahepatic VKDPs: matrix Gla protein, osteocalcin, growth-arrest specific protein 6 and Gla-rich protein. Based on published literature in the last ten years, the purpose of this review is to address fundamental aspects about the link between CKD and circulating VKDPs levels as well as to raise new topics about how the interplay between molecular weight and charge could influence the modifications of circulating VKDPs at the glomerular level, or whether distinct renal etiologies have effect on VKDPs. This review is the output of a systematic literature search and may open future research avenues in this niche domain.

Topics: Animals; Humans; Kidney Diseases; Proteins; Renal Dialysis; Vitamin K

Atrial fibrillation (AF) is associated with an increased risk of ischemic stroke or systemic embolism compared with normal sinus rhythm. These strokes may efficiently be prevented in patients with risk factors using oral anticoagulant therapy, with either vitamin K antagonists (VKAs) or non-vitamin K antagonist oral anticoagulants (NOACs) (i.e., direct thrombin inhibitors or direct factor Xa inhibitors). Owing to their specific risk profiles, some AF populations may have increased risks of both thromboembolic and bleeding events. These AF patients may be denied oral anticoagulants, whilst evidence shows that the absolute benefits of oral anticoagulants are greatest in patients at highest risk. NOACs are an alternative to VKAs to prevent stroke in patients with "non-valvular AF", and NOACs may offer a greater net clinical benefit compared with VKAs, particularly in these high-risk patients. Physicians have to learn how to use these drugs optimally in specific settings. We review concrete clinical scenarios for which practical answers are currently proposed for use of NOACs based on available evidence for patients with kidney disease, elderly patients, women, patients with diabetes, patients with low or high body weight, and those with valve disease.

Topics: Administration, Oral; Aging; Anticoagulants; Antithrombins; Atrial Fibrillation; Body Weight; Diabetes Mellitus; Factor Xa Inhibitors; Heart Valve Diseases; Hemorrhage; Humans; Kidney Diseases; Risk Factors; Stroke; Vitamin K

The current treatment of thrombotic APS patients includes long-term anticoagulation with oral vitamin K antagonists (VKAs), with warfarin being the one most commonly used. However, the use of VKAs can be challenging, especially in patients with APS. VKAs monitoring in patients with aPL is complicated by the heterogeneous responsiveness to LAs of reagents used in the International Normalized Ratio test, potentially resulting in instability of anticoagulation. For decades, VKAs were the only available oral anticoagulants. However, non-VKA oral anticoagulants, including a direct thrombin inhibitor (dabigatran etexilate) and direct anti-Xa inhibitors (rivaroxaban, apixaban and edoxaban), are currently available. The use of these agents may represent a major step forward since, unlike VKAs, they have few reported drug interactions and they do not interact with food or alcohol intake, thereby resulting in more stable anticoagulant intensity. Most importantly, monitoring their anticoagulant intensity is not routinely required due to their predictable anticoagulant effects. In this review, we discuss the clinical and laboratory aspects of non-VKA oral anticoagulants, focusing on the available evidence regarding their use in patients with APS.

Topics: Administration, Oral; Anticoagulants; Antiphospholipid Syndrome; Antithrombins; Breast Feeding; Factor Xa Inhibitors; Female; Food-Drug Interactions; Hemorrhage; Humans; Kidney Diseases; Liver Diseases; Lupus Coagulation Inhibitor; Pregnancy; Pregnancy Complications; Thrombosis; Vitamin K

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; Dabigatran; Elective Surgical Procedures; Emergencies; Factor Xa Inhibitors; Hemorrhage; Humans; Kidney Diseases; Morpholines; Orthopedic Procedures; Postoperative Complications; Premedication; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Risk; Rivaroxaban; Thiophenes; Thrombophilia; Vitamin K

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

The product of growth arrest-specific gene 6 (Gas6) is a unique vitamin K-dependent autocrine growth factor for mesangial cells, and warfarin inhibits mesangial cell proliferation by interfering with the activation process of Gas6. A recent series of studies has revealed the in vivo roles of Gas6 and its receptor Axl in the progression of acute and chronic glomerulonephritis, diabetic nephropathy, chronic allograft rejection, and human kidney diseases. This review summarizes these studies and discusses the possible interventions targeting the Gas6/Axl pathway to prevent the progression of kidney diseases.

Topics: Animals; Diabetic Nephropathies; DNA-Binding Proteins; Glomerular Mesangium; Glomerulonephritis; Graft Rejection; Humans; Intercellular Signaling Peptides and Proteins; Kidney Diseases; Mice; Mice, Knockout; Signal Transduction; STAT3 Transcription Factor; Trans-Activators; Vitamin K; Warfarin

Topics: Aging; Anti-Bacterial Agents; Biomarkers; Chromatography, High Pressure Liquid; Electrochemistry; Humans; Kidney Diseases; Neoplasms; Protein Precursors; Prothrombin; Reference Values; Risk Factors; Specimen Handling; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Deficiency

Topics: Age Factors; Anemia; Anticoagulants; Antifibrinolytic Agents; Bacterial Infections; Child; Child, Preschool; Disseminated Intravascular Coagulation; Fibrinolysis; Fibrinolytic Agents; Humans; Infant; Infant, Newborn; Infant, Newborn, Diseases; Kidney Diseases; Leukemia; Purpura; Shock; Virus Diseases; Vitamin K; Wounds and Injuries

Topics: Anticoagulants; Blood Coagulation; Drug Antagonism; Endocrine System Diseases; Humans; Kidney Diseases; Liver Diseases; Pharmacogenetics; Vitamin K

Kidney transplant recipients (KTRs) experience substantial survival benefit compared with dialysis patients. However, their mortality and graft failure risk remain high. KTRs are often low in micronutrient status, including vitamins D and K. We investigated the association of both vitamins D and K status, and vitamin D treatment with all-cause mortality and death-censored graft failure.. We studied 461 KTRs from a single-centre study at median 6.1 years after transplantation. At baseline, vitamins D and K concentrations were measured by 25-hydroxyvitamin D [25(OH)D] and dephosphorylated uncarboxylated matrix gla protein (dp-ucMGP) and patients were categorized into: 25(OH)D <50/≥50 nmol/L and median dp-ucMGP <1057/≥1057 pmol/L.. Mean age was 52 ± 12 years, and 122 KTRs (26%) had low vitamins D and K status. During median 9.8 years follow-up, 128 patients (28%) died and 48 (10%) developed death-censored graft failure. Low vitamins D and K status was associated with 2.33 (1.26-4.30) [hazard ratio (95% confidence interval)] increased mortality risk and 3.25 (1.17-9.08) increased graft failure risk compared with KTR with 25(OH)D ≥50 nmol/L and dp-ucMGP <1057 pmol/L. Dp-ucMGP was strongly associated with mortality (per 500 pmol/L increase): 1.41 (1.08-1.41) for vitamin D treatment versus no treatment 1.07 (0.97-1.18), and graft failure 1.71 (1.17-2.49) for vitamin D treatment versus 1.19 (1.05-1.36) no treatment, P-interaction <0.07 for vitamin D treatment (n = 44).. Combined vitamins D and K deficiency are highly prevalent and are associated with increased mortality and graft failure risk compared with high vitamins D and K status. Low vitamin K status was strongly associated with an increased risk of premature mortality and graft failure for patients treated with vitamin D versus no vitamin D treatment.

Topics: Female; Graft Rejection; Graft Survival; Humans; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prognosis; Prospective Studies; Survival Rate; Vitamin D; Vitamin K; Vitamin K Deficiency

Venous thromboembolism (VTE) is a common and serious complication in patients with cancer; treatment guidelines recommend extended therapy of ≥6 months with low-molecular-weight heparin (LMWH) for treatment and prevention of recurrent VTE (rVTE) in this population. This post hoc analysis used data from the CLOT study-a phase III, randomized, open-label, controlled study (N = 676)-to compare the efficacy and safety of dalteparin, a LMWH, versus vitamin K antagonist (VKA) for prevention of rVTE in patients with cancer and renal impairment (creatinine clearance <60 ml/min). Overall, 162/676 (24 %) patients had renal impairment at baseline. Patients received subcutaneous dalteparin 200 IU/kg once daily during month 1, followed by 150 IU/kg once daily for months 2-6; or VKA once daily for 6 months, with initial overlapping subcutaneous dalteparin 200 IU/kg once daily for ≥5 days until international normalized ratio was 2.0-3.0 for 2 consecutive days. Endpoints included the rates of rVTE (primary) and bleeding events. Overall, fewer dalteparin-treated patients (2/74 [2.7 %]) experienced ≥1 adjudicated symptomatic rVTE compared with VKA-treated patients (15/88 [17.0 %]; hazard ratio = 0.15 [95 % confidence interval 0.03-0.65]; p = 0.01). Bleeding event rates for both treatments were similar (p = 0.47). In summary, compared with VKA, dalteparin significantly reduced risk of rVTE in patients with cancer and renal impairment (p = 0.01) while exhibiting a comparable safety profile. This analysis supports dosing patients with renal impairment in accordance with patients with normal renal function; however, anti-Xa monitoring could be considered to further support safety in selected patients, particularly those with very severe renal impairment.

Topics: Acenocoumarol; Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Dalteparin; Female; Humans; Kidney Diseases; Male; Middle Aged; Neoplasms; Venous Thromboembolism; Vitamin K; Warfarin

Information on utilization of oral anticoagulants (OACs) in nursing homes is scarce. This study aimed to (i) describe OAC use in German nursing home residents, (ii) examine factors influencing whether treatment is initiated with vitamin K antagonists (VKAs) or non-VKA oral anticoagulants (NOACs) and (iii) assess which conditions predict switching to NOAC instead of continuing VKA.. Using claims data (2010-2014), we studied a cohort of new nursing home residents aged ≥65 years receiving OAC. Further, OAC use in patients with atrial fibrillation (AF) was examined over the years.. Overall, 16 804 patients (median age: 85 years, 75% female, 44% with renal disease) were included. The majority received phenprocoumon as first OAC (58.0%), followed by rivaroxaban (28.1%). Over the study period, NOAC use increased substantially. Initiating NOAC instead of VKA was predicted by a previous stroke (adjusted odds ratio: 1.76; 95% confidence interval: 1.49-2.08). In contrast, renal disease predicted VKA initiation (0.66; 0.59-0.75) as did the presence of a prosthetic heart valve. Switching from VKA to NOAC was predicted by a stroke (2.55; 2.00-3.24), bleeding events and a recent hospitalization. During 2010-2014, the proportion of AF patients with a CHADS2 score ≥2 receiving OAC increased from 27% to 46%.. NOACs are increasingly used in German nursing homes, both for initial anticoagulation but also in VKA pre-treated patients. Switching from VKA to NOAC was substantially influenced by aspects such as intended higher effectiveness and safety but probably also practicability due to less blood monitoring.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cohort Studies; Drug Monitoring; Female; Germany; Hemorrhage; Humans; Kidney Diseases; Male; Nursing Homes; Phenprocoumon; Rivaroxaban; Stroke; Vitamin K

Topics: Anticoagulants; Fibrinolytic Agents; Humans; Kidney Diseases; Vitamin K

We aimed to compare the efficacy and safety between non-vitamin K antagonist oral anticoagulants (NOACs) and warfarin in atrial fibrillation (AF) patients according to renal dysfunction.. We analysed 1319 patients who had been taken oral anticoagulants. They were classified into patients taking NOACs (n = 326) and warfarin (n = 993). Renal dysfunction was defined as the estimated glomerular filtration rate <60 mL/min by using the Chronic Kidney Disease Epidemiology Collaboration equation. The composite clinical outcomes were defined as the composite of death, hospitalization, and new-onset strokes. Safety outcomes were composed of major and minor bleeding. Subgroup analyses for clinical and safety outcomes were performed according to renal dysfunction during median 596 (506-612) follow-up days. The prevalence of renal dysfunction was similar between the two groups. The incidences of death, hospitalization, and strokes were not different between the two groups. However, the incidences of major bleeding was significantly higher in patients taking warfarin. In the subgroup analysis with renal dysfunction, the use of NOACs significantly improved the composite clinical outcomes (adjusted hazard ratio, HR, 0.30, 95% confidence interval, CI, 0.11-0.77, interaction P = 0.018) and major bleeding (adjusted HR 0.18, 95% CI 0.07-0.45, interaction P = 0.199) even after the covariate adjustment. However, in patients without renal dysfunction, there were no differences in the incidences of the composite clinical outcomes between the two groups.. The benefit of NOACs was more prominent in AF patients with renal dysfunction than without renal dysfunction. These results suggest that NOACs as the first choice oral anticoagulant in AF patients with renal dysfunction.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Causality; Comorbidity; Female; Hemorrhage; Humans; Kidney Diseases; Male; Prevalence; Republic of Korea; Retrospective Studies; Risk Factors; Survival Rate; Thromboembolism; Treatment Outcome; Vitamin K; Warfarin

A 65-year-old man, who had been treated with dabigatran for 66 days prior to electrical cardioversion, developed extensive intestinal, renal and cerebral thromboembolism five days after cardioversion. There is limited information available on the treatment of thromboembolism in patients being treated with dabigatran. Routine biochemical monitoring is not available. As is the case for vitamin K antagonists, anticoagulation with dabigatran is not without risks.

Topics: Aged; Antithrombins; Benzimidazoles; beta-Alanine; Cerebral Infarction; Dabigatran; Electric Countershock; Humans; Ileus; Kidney Diseases; Male; Risk Factors; Thromboembolism; Tomography, X-Ray Computed; Vitamin K

Vitamin K antagonists (VKA) therapy is increasingly used in elderly for prevention of venous thromboembolism (VTE) and of stroke in atrial fibrillation (AF). Glomerular filtration rate (GFR), usually estimated from different equations, decreases progressively with age and it is a risk factor for bleeding. In the frame of the EPICA study, a multicentre prospective observational study including 4,093 patients ≥80 years naïve to VKA treated for AF or after VTE, we performed this ancillary study to evaluate the prevalence of chronic kidney diseases (CKD) by estimated GFR (eGFR). Incidence of bleedings was recorded and bleeding risk was evaluated in relation to eGFR calculated by Cockroft-Gault (C-G); Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas. In addition, the agreement among the three eGFR formulas was evaluated. We recorded 179 major bleedings (rate 1.87 x100 patient-years [py]), 26 fatal (rate 0.27 x100 py). Moderate CKD was detected in 69.3%, 59.3% and 47.0% and severe CKD in 5.8%, 7.4% and 10.0% of cases by C-G, MDRD and CKD-EPI, respectively. Bleeding risk was higher in patients with severe CKD irrespective of the applied equation. This study confirms that CKD represents an independent risk factor for bleeding and that a wide proportion of elderly on VKA had severe or moderate CKD, suggesting the need for frequent monitoring. Although the different available equations yield different eGFR, all appear to similarly predict the risk of major bleeding.

Topics: Age Factors; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Blood Coagulation; Chronic Disease; Female; Glomerular Filtration Rate; Hemorrhage; Humans; Incidence; Italy; Kidney; Kidney Diseases; Male; Odds Ratio; Prevalence; Proportional Hazards Models; Prospective Studies; Risk Assessment; Risk Factors; Severity of Illness Index; Stroke; Treatment Outcome; Venous Thromboembolism; Vitamin K

Topics: Anticoagulants; Atrial Fibrillation; Female; Glomerular Filtration Rate; Hemorrhage; Humans; Kidney; Kidney Diseases; Male; Stroke; Venous Thromboembolism; Vitamin K

Vitamin K, vitamin K-dependent proteins, and vitamin D may be involved in the regulation of calcification in chronic kidney disease (CKD).. Vitamin K and D status was measured as dietary intake, plasma phylloquinone, serum percent uncarboxylated osteocalcin (%ucOC), proteins induced by vitamin K absence (PIVKA-II), Vitamin K Epoxide Reductase single-nucleotide polymorphism, apolipoprotein E genotype, and plasma 25-hydroxyvitamin D (25(OH)D) in 172 subjects with stage 3 to 5 CKD. Nutritional status was determined by subjective global assessment.. Subclinical vitamin K deficiency criteria was met by 6% (phylloquinone), 60% (%ucOC), and 97% (PIVKA-II) of subjects, whereas 58.3% and 8.6% had 25(OH)D insufficiency and deficiency, respectively. Dietary vitamin K intake was associated with higher phylloquinone and lower PIVKA-II. There were positive correlations between phylloquinone and the presence of stable weight, and the absence of subcutaneous fat loss or muscle wasting. 25(OH)D levels were positively associated with stable weight and albumin (P < 0.001). PIVKA-II levels were associated with apolipoprotein E genotype. Higher %ucOC and lower 25(OH)D were similarly associated with CKD stage, parameters of mineral metabolism, and urine albumin to creatinine ratio.. These data indicate that a suboptimal vitamin K and D status is prevalent in patients with CKD. Sufficiency of both vitamins K and D was similarly predicted by measures of overall improved nutritional status. Proteinuria was associated with both a suboptimal vitamin D status as well as worse peripheral vitamin K status.

Topics: Adult; Aged; Aged, 80 and over; Apolipoproteins E; Biomarkers; Chronic Disease; Cross-Sectional Studies; Diet; Female; Genetic Markers; Genotype; Humans; Kidney Diseases; Linear Models; Male; Middle Aged; Mixed Function Oxygenases; Nutritional Status; Osteocalcin; Polymorphism, Single Nucleotide; Protein Precursors; Proteinuria; Prothrombin; Vitamin D; Vitamin D Deficiency; Vitamin K; Vitamin K 1; Vitamin K Deficiency; Vitamin K Epoxide Reductases; Young Adult

Topics: Administration, Oral; Animals; Anticoagulants; Aortic Valve; Biomarkers; Calcinosis; Calcium-Binding Proteins; Chronic Disease; Down-Regulation; Extracellular Matrix Proteins; Glomerular Filtration Rate; Heart Valve Diseases; Humans; Kidney Diseases; Matrix Gla Protein; Prognosis; Vascular Diseases; Vitamin K

Matrix gamma-carboxyglutamic acid protein (MGP), a vitamin K-dependent protein, is involved in regulation of tissue calcification. We previously reported that 9-cis retinoic acid (RA) mitigates 1alpha,25-dihydroxycholecalciferol [1,25(OH)(2)D3]-induced renal calcification in a 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung cancer A/J male mouse model. This raised the question if the mechanism(s) underlying this calcification involves vitamin K. We assessed expression and vitamin K dependent gamma-carboxylation of MGP and vitamin K concentrations [phylloquinone (PK), as well as its conversion product, menaquinone-4 (MK-4)] in tissues obtained from NNK-injected A/J male mice fed 1,25(OH)(2)D3 (2.5 microg/kg diet; D group) +/- RA (15 mg/kg diet) for 20 wk. Renal calcification was only observed in the D group (2/10; 20% of the group). Renal MGP mRNA and uncarboxylated MGP (ucMGP) increased in response to D (P < 0.05) but not in response to RA or RA + D. In contrast, gamma-carboxylated MGP increased to 2.2-fold of the control in response to D+RA (P < 0.05) but not in response to RA or D alone. Although all diets contained equal amounts of PK, the kidney MK-4 concentration was higher in the D group (P < 0.05) and lower in the RA group (P < 0.05) compared with the RA+D or control groups. Renal PK concentrations were lower in the RA and RA+D groups than in the control and D groups (P < 0.05). These data suggest that 9-cis RA mitigated 1,25(OH)(2)D3-induced renal calcification by modifying the 1,25(OH)(2)D3-induced increase in ucMGP. The mechanisms by which 9-cis RA and 1,25(OH)(2)D3 alter vitamin K concentrations warrant further investigation.

Topics: Alitretinoin; Animals; Base Sequence; Calcinosis; Calcitriol; Calcium-Binding Proteins; Carbon-Carbon Ligases; Carcinogens; Dietary Supplements; DNA Primers; Extracellular Matrix Proteins; Kidney Diseases; Liver; Male; Matrix Gla Protein; Mice; Mice, Inbred A; Nitrosamines; RNA, Messenger; Tretinoin; Vitamin K

Because proliferation of mesangial cells is a hallmark of glomerular diseases, understanding the regulatory mechanism of mesangial proliferation is important for the treatment. Warfarin has long been used to treat glomerular diseases, although its mechanism of effect on mesangial proliferation has remained unknown. Therefore, this study was conducted to examine whether warfarin can inhibit mouse mesangial cell proliferation by focusing on Gas6, which has been shown to be activated by vitamin K-dependent gamma-carboxylation. In mesangial cells, Gas6 and its receptor Axl were expressed. In addition, exogenous Gas6 phosphorylated Axl, activated extracellular signal-regulated kinase, and stimulated [3H]-thymidine incorporation in mouse mesangial cells. This study also examined whether endogenous Gas6 stimulates mesangial proliferation. Conditioned medium (CM) from serum-starved mesangial cells could stimulate [3H]-thymidine incorporation and phosphorylate extracellular signal-regulated kinase, whereas CM in the presence of warfarin could not. Simultaneous administration of vitamin K could cancel the inhibitory effect of warfarin. These results suggest that vitamin K-dependent growth factors in the CM are critical for mesangial proliferation. Addition of the extracellular domain of Axl to the CM inhibited its mitogenic effect on mesangial cells, suggesting that this vitamin K-dependent growth factor is Gas6. It is concluded that Gas6 is an endogenous mitogen in mesangial cells, and warfarin inhibits mesangial proliferation possibly by inhibiting gamma-carboxylation of Gas6. This study sheds light on the regulation of mesangial proliferation and may lead to a new therapeutic strategy for glomerular diseases.

Topics: Animals; Axl Receptor Tyrosine Kinase; Cell Division; Cells, Cultured; Culture Media, Conditioned; Glomerular Mesangium; Humans; Intercellular Signaling Peptides and Proteins; Kidney Diseases; Mice; Mitogen-Activated Protein Kinases; Mitogens; Oncogene Proteins; Phosphorylation; Proteins; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; Vitamin K; Warfarin

Redox cycling leading to oxidative stress has been proposed as the mechanism by which adriamycin induces glomerular toxicity in rats. The present study compares the extent of the oxidative stress and cytotoxicity induced by adriamycin to menadione (a model redox cycling quinone) in freshly isolated rat glomeruli. Adriamycin and menadione (25 microM) decreased de novo protein synthesis (measured by 3H-proline incorporation into acid-precipitable glomerular protein) by 50 and 85%, respectively, in 2 h. By contrast, menadione at 25 microM reduce glomerular membrane integrity (as assessed by lactate dehydrogenase leakage), adriamycin reduced membrane integrity at 500 microM adriamycin. Reactive oxygen species (ROS) were measured by the oxidation of dihydrodichlorofluorescein. Menadione (25 microM) and adriamycin (25 microM) increased ROS formation to 260 and 156% of controls after 30 min incubation, respectively. Oxidative stress was assessed by measuring the intracellular level of reduced glutathione (GSH) and the decrease of the NADPH/NADP- ratio which stimulates the pentose phosphate pathway (PPP): (a) menadione (25-100 microM) reduced glomerular GSH to 10-20% of controls, adriamycin (25-100 microM) had no effect; (b) menadione (10 microM) increased PPP activity 6-fold, while adriamycin (125 microM) had only a 2-fold effect. Although adriamycin and menadione generate extensive ROS and decrease protein synthesis, there was no correlation between the extent of oxidative stress and cytotoxicity in glomeruli exposed to adriamycin. These results suggest that oxidative stress may not be the primary mechanisms by which adriamycin induces selective glomerular toxicity.

Topics: Animals; Antibiotics, Antineoplastic; Doxorubicin; Glutathione; Hemostatics; Kidney Diseases; Kidney Glomerulus; L-Lactate Dehydrogenase; Male; Membrane Fluidity; Oxidative Stress; Pentose Phosphate Pathway; Protein Biosynthesis; Rats; Rats, Wistar; Reactive Oxygen Species; Vitamin K

Twelve patient cell lines with biochemically proven complex I deficiency were compared for clinical presentation and outcome, together with their sensitivity to galactose and menadione toxicity. Each patient had elevated lactate to pyruvate ratios demonstrable in fibroblast cultures. Each patient also had decreased rotenone-sensitive NADH-cytochrome c reductase (complexes I and III) with normal succinate cytochrome c reductase (complexes II and III) and cytochrome oxidase (complex IV) activity in cultured skin fibroblasts, indicating a deficient NADH-coenzyme Q reductase (complex I) activity. The patients fell into five categories: severe neonatal lactic acidosis; Leigh disease; cardiomyopathy and cataracts; hepatopathy and tubulopathy; and mild symptoms with lactic acidaemia. Cell lines from 4 out of the 12 patients were susceptible to both galactose and menadione toxicity and 3 of these also displayed low levels of ATP synthesis in digitonin-permeabilized skin fibroblasts from a number of substrates. This study highlights the heterogeneity of complex I deficiency at the clinical and biochemical level.

Topics: Acidosis, Lactic; Adenosine Triphosphate; Cardiomyopathies; Cataract; Cell Line; Child; Child, Preschool; Fibroblasts; Galactose; Hepatomegaly; Humans; Infant; Infant, Newborn; Kidney Diseases; Leigh Disease; NAD(P)H Dehydrogenase (Quinone); Phenotype; Vitamin K

The short-term toxicity of 2-hydroxy-1,4-naphthoquinone (lawsone) and 2-methyl-1,4-naphthoquinone (menadione) has been compared in rats. 2-Methyl-1,4-naphthoquinone has been shown previously to cause haemolytic anaemia in animals, and this was confirmed in the present experiment. 2-Hydroxyl-1,4-naphthoquinone was found also to cause haemolysis, in a dose-dependent manner, as reflected by decreased blood packed cell volumes and haemoglobin levels and by histopathological changes in spleen, liver and kidney. With both naphthoquinones, the haemolysis was of the oxidative type, characterized by the presence of Heinz bodies within erythrocytes. Haemolysis was the only toxic change identified in rats dosed with 2-methyl-1,4-naphthoquinone. In contrast, 2-hydroxyl-1,4-naphthoquinone was not only a haemolytic agent but also a nephrotoxin, causing renal enlargement, elevated plasma levels of urea and creatinine and histologically-identified tubular necrosis, largely confined to the distal segment of the proximal convoluted tubules. The relationship between the in vivo toxic effects of these naphthoquinones and previously-reported data on their in vitro cytotoxic action is discussed.

Topics: Animals; Female; Hemolysis; Kidney Diseases; Naphthoquinones; Rats; Rats, Inbred Strains; Time Factors; Vitamin K

Ten patients (two with normal, eight with impaired renal function) on their usual diet were treated with cefodizime (HR 221) for seven days. The dosage was 4 g/day, adapted to renal function as appropriate. Platelet function, plasma coagulation and vitamin K metabolism were investigated before and on day 7 of therapy. Platelet function and plasma coagulation remained unchanged, regardless of the size of the serum antibiotic trough levels, in both normal and impaired renal function. Vitamin K1 metabolism remained unaffected, since no increase in vitamin K1 2,3 epoxide in the circulation was observed during the therapy. Cefodizime (HR 221), a parenteral aminothiazole cephalosporin, does not affect hemostasis.

Topics: Adult; Aged; Bacterial Infections; Bleeding Time; Blood Coagulation; Cefotaxime; Chemical Phenomena; Chemistry; Female; Hemostasis; Humans; Kidney Diseases; Male; Middle Aged; Platelet Aggregation; Platelet Count; Vitamin K

Topics: Bacteria; Cephalosporins; Cephamycins; Humans; Hypoprothrombinemias; Intestines; Kidney Diseases; Moxalactam; Nephrectomy; 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

Topics: Adipose Tissue; Adolescent; Biopsy; Brain Diseases; Fatty Liver; Female; Hepatitis; Humans; Kidney Diseases; Liver; Virus Diseases; Vitamin K

Topics: Adipose Tissue; Adolescent; Ammonia; Anti-Bacterial Agents; Anticonvulsants; Aspartate Aminotransferases; Blood Glucose; Brain Diseases; Child; Child, Preschool; Consciousness; Electroencephalography; Fatty Liver; Female; Glucocorticoids; Glucose; Hepatitis; Humans; Insulin; Intracranial Pressure; Kidney Diseases; Male; Prognosis; Seizures; Vitamin K

Topics: Adult; Antibodies, Anti-Idiotypic; Anticoagulants; Antigen-Antibody Reactions; Biopsy; Female; Fibrinogen; Fluorescent Antibody Technique; Glomerulonephritis; Humans; Immune Sera; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Kidney; Kidney Diseases; Kidney Glomerulus; Male; Nephrotic Syndrome; Pregnancy; Vitamin K

Topics: Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Child; Child, Preschool; Diagnosis, Differential; Disseminated Intravascular Coagulation; Hemolytic-Uremic Syndrome; Hemostasis; Heparin; Humans; Kidney Diseases; Liver Diseases; Protease Inhibitors; Vitamin K; Vitamin K Deficiency; Vitamin K Deficiency Bleeding

Topics: Adipose Tissue; Blood Coagulation Disorders; Brain Diseases; Fatty Liver; Female; Hepatitis; Humans; Infant; Kidney Diseases; Virus Diseases; Vitamin K

Topics: Child; Child, Preschool; Humans; Kidney Diseases; Vitamin K; Vitamin K Deficiency

Topics: Acenocoumarol; Acute Disease; Blood Coagulation Disorders; Chemical and Drug Induced Liver Injury; Child, Preschool; Factor VII; Factor VIII; Factor X; Hemorrhage; Humans; Kidney Diseases; Kidney Function Tests; Liver Function Tests; Male; Medication Errors; Prothrombin; Prothrombin Time; Vitamin K

Topics: Adipose Tissue; Blood Coagulation Disorders; Brain Diseases; Child, Preschool; Fatty Liver; Glucose; Hepatitis; Humans; Insulin; Kidney Diseases; Male; Mannitol; Peritoneal Dialysis; Remission, Spontaneous; Vitamin K

Topics: Alanine Transaminase; Anti-Bacterial Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Cortisone; Coumarins; Humans; Kidney Diseases; Liver Diseases; Liver Function Tests; Middle Aged; Vitamin K; Water-Electrolyte Balance

Topics: Anemia; Celiac Disease; Diet Therapy; Dwarfism; Edema; Glutens; Humans; Hypocalcemia; Hypokalemia; Hypoproteinemia; Hypoprothrombinemias; Kidney Diseases; Malabsorption Syndromes; Osteomalacia; Vitamin K

Topics: Humans; Kidney; Kidney Diseases; Vitamin A; Vitamin K; Vitamins