warfarin and Uremia

Topics: Apazone; Bilirubin; Binding Sites; Carrier Proteins; Diazepam; Digitoxin; Fatty Acids, Nonesterified; Half-Life; Humans; Hydrogen-Ion Concentration; Indoles; Kidney Diseases; Kidney Failure, Chronic; Kinetics; Ligands; Liver; Methods; Protein Binding; Protein Conformation; Renal Dialysis; Serum Albumin; Toxins, Biological; Uremia; Warfarin

Calcific uremic arteriopathy (CUA), termed calciphylaxis, is a rare but highly fatal clinical syndrome. There is no clearly laboratory diagnostic criteria for CUA. The medium and small arterial calcification and microthrombosis discovered by skin biopsy, radiologic imaging，bone scan and the evidence of activation of the bone morphogenetic protein signal (BMPs) transduction pathway are useful for early diagnosis of this disease. The common therapies (including intravenous sodium thiosulfate (STS) and bisphosphonates, hyperbaric oxygen therapy and other symptomatic supports) are used for the management of wounds, pain, nutrition, dialysis and so on. Controlling the chronic kidney disease-mineral and bone disorder (CKD-MBD) and some complications of dialysis and drugs (such as warfarin, active vitamin D) can prevent CUA. However, CUA patients still have poor prognosis and high mortality. Since some patients progress rapidly, it is of great importance to make early diagnosis and provide effective treatments with multidisciplinary management.. 钙性尿毒症性小动脉病(calcific uremic arteriolopathy，CUA)又称钙化防御，是一种少见但具有高病死率的临床综合征。CUA目前缺乏明确的实验室诊断标准，皮肤活检有中小动脉中膜钙化及微血栓形成，放射性检查、骨扫描及骨形态蛋白信号通路激活的证据均能早期提示该病。CUA常通过静脉注射硫代硫酸钠、双磷酸盐，高压氧疗及其他对症支持治疗来进行伤口、疼痛、营养、透析等方面的综合管理。CUA的早期防控主要通过合理控制慢性肾病-矿物质与骨异常，减少透析并发症/合并症，慎用某些药物(如华法林、活性维生素D等)来实现。CUA患者预后差，病死率高，部分患者病情进展迅速，早期诊断并制订有效的多学科协作治疗方案极为重要。.

Topics: Calciphylaxis; Early Diagnosis; Humans; Renal Dialysis; Uremia; Warfarin

We herein present the first reported case of severe proptosis caused by ocular and periocular hemorrhages in a continuous ambulatory peritoneal dilaysis patient without previous history of trauma. The bleeding tendency caused by uremia and the use of warfarin during uncontrolled high blood pressure were most likely responsible for her ocular and periocular hemorrhages. Appropriate control of blood pressure and adequate self-care education are important for the prevention and treatment of any bleeding complications in uremic patients receiving both maintenance anticoagulation therapy and peritoneal dialysis.

Topics: Adult; Exophthalmos; Eye; Female; Hemorrhage; Humans; Hypertension; Peritoneal Dialysis, Continuous Ambulatory; Uremia; Warfarin

Matrix Gla protein (MGP) is an inhibitor of vascular calcification but its mechanism of action and pathogenic role are unclear. This was examined in cultured rat aortas and in a model of vascular calcification in rats with renal failure. Both carboxylated (GlaMGP) and uncarboxylated (GluMGP) forms were present in aorta and disappeared during culture with warfarin. MGP was also released into the medium and removed by ultracentrifugation, and similarly affected by warfarin. In a high-phosphate medium, warfarin increased aortic calcification but only in the absence of pyrophosphate, another endogenous inhibitor of vascular calcification. Although GlaMGP binds and inactivates bone morphogenic protein (BMP)-2, a proposed mediator of vascular calcification through up-regulation of the osteogenic transcription factor runx2, neither warfarin, BMP-2, nor the BMP-2 antagonist noggin altered runx2 mRNA content in aortas, and noggin did not prevent warfarin-induced calcification. Aortic content of MGP mRNA was increased 5-fold in renal failure but did not differ between calcified and noncalcified aortas. Immunoblots showed increased GlaMGP in noncalcified (5-fold) and calcified (20-fold) aortas from rats with renal failure, with similar increases in GluMGP. We conclude that rat aortic smooth muscle produces both GlaMGP and GluMGP in tissue-bound and soluble, presumably vesicular, forms. MGP inhibits calcification independent of BMP-2-driven osteogenesis and only in the absence of pyrophosphate, consistent with direct inhibition of hydroxyapatite formation. Synthesis of MGP is increased in renal failure and deficiency of GlaMGP is not a primary cause of medial calcification in this condition.

Topics: Animals; Anticoagulants; Aorta; Bone Morphogenetic Protein 2; Calcinosis; Calcium-Binding Proteins; Core Binding Factor Alpha 1 Subunit; Durapatite; Extracellular Matrix Proteins; Male; Matrix Gla Protein; Models, Biological; Muscle, Smooth, Vascular; Organ Culture Techniques; Osteogenesis; Protein Binding; Rats; Rats, Sprague-Dawley; Renal Insufficiency; RNA, Messenger; Up-Regulation; Uremia; Warfarin

The type of coagulation factors and proteins in cryoprecipitate determine the appropriate indications for its use. To determine the pattern of use at a tertiary care medical center, we performed a retrospective audit of cryoprecipitate utilization. A total of 51 patients received 88 pools of cryoprecipitate. In 39 patients, cryoprecipitate was transfused for appropriate indications: hypofibrinogenemia (n = 19), tissue plasminogen activator reversal (n = 1), management of massive transfusion (n = 7), correction of uremic bleeding (n = 2), and for making fibrin sealant (n = 10). Overall, these patients used approximately 80% of the cryoprecipitate transfused. In 12 other patients, cryoprecipitate was transfused inappropriately to attempt reversal of the anticoagulant effects of warfarin therapy (n = 6), to treat impaired surgical hemostasis in the absence of hypofibrinogenemia (n = 4), and to treat hepatic coagulopathy with multiple factor deficiencies (n = 2). The patterns of misuse, involving 24% of all cryoprecipitate orders, suggest a widespread misunderstanding and need for focused education about the coagulation factors and proteins present in cryoprecipitate and appropriate indications for its use.

Topics: Adult; Afibrinogenemia; Aged; Aged, 80 and over; Blood Loss, Surgical; Blood Transfusion; Factor VIII; Fibrin Tissue Adhesive; Fibrinogen; Hemorrhage; Humans; Liver Neoplasms; Medical Audit; Middle Aged; Retrospective Studies; Tissue Plasminogen Activator; Uremia; Warfarin

The study was performed for clarifying the mechanism of interaction between indoxyl sulfate (IS), a typical uremic toxin bound to site II, and site I-ligands when bound to human serum albumin (HSA). The effect of the N to B transition on the interactions was also examined.. Quantitative investigation of the relations between ligands bound to HSA was performed by equilibrium dialysis, and the binding data were analyzed on the basis of a theoretical model for simultaneous binding of two ligands.. The high-affinity binding constants for the site I-ligands warfarin (WF) and dansyl-L-asparagine (DNSA) increased with increasing pH, whereas those for the site II-ligands IS and dansylsarcosine (DNSS) were hardly affected by pH. Mutual displacement experiments showed that even though IS binds to site II it influenced binding of DNSA at the azapropazone binding area in site I. By contrast, it is unlikely that IS affects the WF binding area of site I. Furthermore, pH-profiles showed that the interaction between IS and DNSA was very sensitive to the N to B transition: "competitive-like" strong allosteric regulation was observed for binding of the two ligands to the N conformer (pH 6.5), whereas in the B conformation (pH 8.5) binding of these molecules was nearly "independent".. The present data provide useful information for elucidating a potential mechanism of interaction between drugs and endogenous substances including uremic toxins.

Topics: Anticoagulants; Asparagine; Binding Sites; Dansyl Compounds; Fluorescent Dyes; Humans; Hydrogen-Ion Concentration; Indican; Ligands; Serum Albumin; Toxins, Biological; Uremia; Warfarin

The interaction of uremic toxins including indole-3-acetic acid (IA), indoxyl sulfate (IS), hippuric acid (HA) and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) with human serum albumin (HSA) has been investigated by three methods of fluorescent probe displacement, ultrafiltration and equilibrium dialysis. The binding parameter of CMPF was found to have the strongest affinity (10(7)M-1) among all the uremic toxins studied. Competitive experiment based on the method of Kragh-Hansen suggested that IA, IS and HA bind to site II, whereas CMPF binds to site I. The present limited data indicated that the four uremic toxins caused inhibition to any endo- or exogenous substances on HSA.

Topics: Binding Sites; Dansyl Compounds; Furans; Hippurates; Humans; Indoleacetic Acids; Indoles; Propionates; Sarcosine; Serum Albumin; Uremia; Warfarin

Impaired binding of anionic drugs to serum albumin in patients with uremia is thought to be due to the accumulation of endogenous substances that bind to albumin. In this study the displacement by the anionic drugs diazepam, warfarin, and salicylic acid, which are known to be representative drugs for the binding sites on the albumin molecule, of several endogenous ligands that bind to albumin in uremic serum was examined. The free fractions of the ligands bound to albumin were separated by ultrafiltration in the presence and the absence of test drugs and assayed by high-performance liquid chromatography. Diazepam displaced indoxyl sulfate (IS), hippuric acid (HA), and indole-3-acetic acid (IAA), and warfarin displaced IS, HA, ISAA, and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid from serum albumin. However, salicylic acid did not displace the substance examined. The methods reported here are useful for determining the binding sites of the endogenous ligands on albumin and to clarify the drug-ligand interaction on albumin molecule in uremic serum.

Topics: Binding Sites; Furans; Hippurates; Humans; Indican; Indoleacetic Acids; Propionates; Protein Binding; Salicylates; Salicylic Acid; Serum Albumin; Uremia; Warfarin

A method for determination of reserve albumin equivalent for binding of warfarin as previously described [1] has been used for assessing the influence of non-esterified fatty acid concentration (NEFA) on binding of warfarin to human serum albumin (HSA). Reserve albumin concentration can be used for calculation of the expected fraction of bound warfarin in serum. It is shown in vitro that binding of warfarin increases with added oleate up to 4 mol of oleate per mol of albumin and then decreases. Twenty-four patients on permanent warfarin treatment showed no correlation of serum albumin and reserve albumin concentrations (r = 0.10, P greater than 0.50) indicating that warfarin binding is governed by other factors. However, in the same patients there was a significant correlation between reserve albumin concentration and NEFA/HSA (r = 0.54, P less than 0.01). In one human volunteer changes of NEFA were provoked by strenuous work and it was found that reserve albumin concentration increased with NEFA concentration as expected from the in vitro findings (r = 0.90, P less than 0.001). Five uraemic patients on permanent warfarin treatment showed increasing reserve albumin concentration with increasing NEFA concentration induced by heparin. These findings indicate that, both in vitro and in vivo, the reserve albumin concentration for binding of warfarin and hence the free warfarin concentration is markedly influenced by NEFA concentration. This may add to the understanding of warfarin dose requirement during anticoagulant therapy.

Topics: Adult; Aged; Fatty Acids, Nonesterified; Female; Humans; In Vitro Techniques; Male; Middle Aged; Oleic Acid; Oleic Acids; Physical Exertion; Protein Binding; Serum Albumin; Uremia; Warfarin

Decreased binding of aromatic acidic drugs and endogenous metabolites to plasma proteins of patients with severe renal failure appears to be due to accumulation of unknown solutes. Both the warfarin and indole binding sites of albumin, the principal binding protein for these ligands, are affected. We used a large number of endogenous aromatic acids and synthetic congeners as displacers (a) better to characterize the chemical requirements for binding to each site and (b) to derive clues to the chemical structure of the undefined binding inhibitors in uremic plasma. 14C-tryptophan, 14C-warfarin and 14C-salicylate were used as bound ligands. Numerous indoles, quinolines and phenyl derivatives were moderate to strong displacers with several structural correlates. Increasing apolar side chain length enhanced displacing potency. A hydroxyl group at the 5 position of indoles and at the para position of phenyl derivatives severely reduced activity. The two ends of amphophilic molecules showed opposite requirements for displacement of tryptophan: the greater the polarity at the hydrophilic end, the greater the tryptophan displacing potency. Conversely, the greater the total hydrophobic mass of the remainder of the molecule, the more potent the inhibition of binding. The dipeptides l-tryptophyl-l-tryptophan and l-tryptophyl-l-phenylalanine were potent displacers. Computer-assisted analysis of warfarin binding in the presence of xanthurenic acid revealed inhibition by a mechanism other than simple competition, probably via a third albumin binding locus. We conclude that decreased binding in uremic plasma is most likely the summation effect of a number of retained aromatic acids, peptides, or both types of ligands.

Topics: Amino Acids; Blood Proteins; Hippurates; Humans; Indoles; Kynurenic Acid; Protein Binding; Quinolines; Salicylates; Salicylic Acid; Serum Albumin; Structure-Activity Relationship; Tryptophan; Uremia; Warfarin; Xanthurenates

We confirmed our previously reported findings that subcutaneous administration of heparin (200 U q 12 hr) in rats with experimental partial renal infarction prevents the development of progressive renal failure and hypertension, as well as the glomerular abnormalities which occur in the remaining viable renal tissue. In the present study, heparin, in the dosage used to prevent progressive renal failure, caused a marked and sustained prolongation of the activated partial thromboplastin time and prothrombin time, as well as a transient prolongation of the bleeding time. Administration of coumadin at doses which caused a significant prolongation of the prothrombin time and bleeding time also inhibited the development of progressive hypertension and uremia in rats with experimental partial renal infarction. These findings indicate that inhibition of blood coagulation effectively protects rats with experimentally decreased renal mass from the development of progressive renal failure and hypertension and support the concept that the glomerular thrombosis plays an important role in the pathogenesis of these complications.

Topics: Animals; Anticoagulants; Cardiomegaly; Female; Hemostasis; Heparin; Hypertension; Infarction; Kidney; Kidney Glomerulus; Rats; Rats, Inbred Strains; Uremia; Warfarin

Warfarin was administered intravenously twice at an interval of six months to rabbits with surgically-induced impairment of renal function and to control animals. Pharmacokinetic analysis showed that the elimination rate of warfarin was significantly decreased in the uraemic group after 2 weeks duration of uraemia and was even further decreased at the second examination 6 months later. No significant changes in the volumes of distribution were found. Renal function tests indicated stable renal function between the two examinations.

Topics: Animals; Chromium Radioisotopes; Edetic Acid; Kinetics; Male; Models, Biological; Rabbits; Time Factors; Uremia; Warfarin

A number of compounds known to accumulate in the blood of uremic patients were added to serum from healthy normal volunteers. It was observed that both hippuric acid and indican were capable of increasing substantially the serum f of both diazepam and warfarin. Furthermore, a mixture of nine different accumulation products (many of which did not measurably increase f when added alone) caused an even greater increase in the f of diazepam. Serum from uremic patients and from normal volunteers, with and without the addition of the compounds known to accumulate in uremia, wee treated by standard procedures (i.e., prolonged dialysis, charcoal treatment, pH alteration) to remove associated small molecules. The results of such treatments suggest that at least part of the diminished binding of drugs seen in the presence of uremia is due to the accumulation of low-molecular-weight endogenous competitors.

Topics: Blood Proteins; Charcoal; Dialysis; Diazepam; Humans; Hydrogen-Ion Concentration; Protein Binding; Uremia; Warfarin

Topics: Animals; Blood Protein Electrophoresis; Cattle; Cyanates; Humans; In Vitro Techniques; Protein Binding; Serum Albumin, Bovine; Time Factors; Uremia; Warfarin

The addition to charcoal treated normal and charcoal treated uremic plasma of four metabolites which accumulate during uremia--uric acid, beta -phenylpyruvic acid, guanidinosuccinic acid, and p-hydroxyphenylacetic acid--failed to produce a warfarin binding defect. Charcoal treatment corrected the warfarin binding defect in uremic plasma, however it diminished the extent of warfarin binding to normal plasma. These observations rule out the possibility that uric acid, beta -phenylpyruvic acid, guanidinosuccinic acid, or p-hydroxyphenylacetic acid contribute to the warfarin binding defect in uremia, and suggest that free fatty acids have no role in the warfarin binding defect.

Topics: Blood Proteins; Charcoal; Humans; In Vitro Techniques; Protein Binding; Uremia; Warfarin

Topics: Adenosine Triphosphate; Animals; Blood Platelets; Humans; Lactates; Liver Cirrhosis; Lupus Erythematosus, Systemic; Neuraminic Acids; Neuraminidase; Platelet Adhesiveness; Purpura, Thrombocytopenic; Rabbits; Time Factors; Uremia; von Willebrand Diseases; Warfarin

Topics: Aspirin; Blood Coagulation; Complement System Proteins; Diabetic Nephropathies; Dipyridamole; Fibrin; Fibrinogen; Glomerulonephritis; Hemolytic-Uremic Syndrome; Heparin; Humans; Iodine Radioisotopes; Kidney; Kidney Diseases; Kidney Glomerulus; Kidney Transplantation; Plasminogen; Proteinuria; Thrombosis; Transplantation, Homologous; Uremia; Warfarin

Topics: Animals; Blood Flow Velocity; Blood Urea Nitrogen; Carbon Dioxide; Charcoal; Chlorides; Creatinine; Heparin; Hydrogen-Ion Concentration; Injections, Intravenous; Inulin; Kidneys, Artificial; Manometry; Nephrectomy; Potassium; Renal Dialysis; Sheep; Sodium; Temperature; Time Factors; Ultrafiltration; Uremia; Uric Acid; Warfarin

Topics: Blood Coagulation; Blood Coagulation Disorders; Humans; Kidneys, Artificial; Perfusion; Polyurethanes; Silicone Elastomers; Surface Properties; Thrombosis; Uremia; Warfarin; Water