warfarin and Diabetic-Nephropathies

In this review we present data on prevalence of atrial fibrillation (AF) among patients with type 2 diabetes (T2D), diabetic nephropathy and chronic kidney disease (CKD). Patients with nonvalvular AF and T2D combined with CKD have elevated risk of both bleeding and thromboembolic complications, as well as of all cause death. Efficacy and safety of novel oral anticoagulants (NOAC) depend on comorbidities and can be determined by the presence of T2D and/or diabetic nephropathy. Use of warfarin in CKD in some cases provides no preventive effect relative to risk of stroke and is characterized by increased risk of bleeding because of poor INR control, and possibly development of calcification of arteries. Presence of diabetic nephropathy requires monitoring of renal filtration function for correction of doses or selection of another anticoagulant. Lack of data from randomized controlled trials hampers choice of anticoagulant therapy in patients with terminal CKD on hemodialysis or after renal transplantation.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Humans; Prognosis; Stroke; Warfarin

In this review we present data on prevalence of atrial fibrillation (AF) among patients with type 2 diabetes (T2D), diabetic nephropathy and chronic kidney disease (CKD). Patients with nonvalvular AF and T2D combined with CKD have elevated risk of both bleeding and thromboembolic complications, as well as of all cause death. Efficacy and safety of novel oral anticoagulants (NOAC) depend on comorbidities and can be determined by the presence of T2D and/or diabetic nephropathy. Use of warfarin in CKD in some cases provides no preventive effect relative to risk of stroke and is characterized by increased risk of bleeding because of poor INR control, and possibly development of calcification of arteries. Presence of diabetic nephropathy requires monitoring of renal filtration function for correction of doses or selection of another anticoagulant. Lack of data from randomized controlled trials hampers choice of anticoagulant therapy in patients with terminal CKD on hemodialysis or after renal transplantation.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Humans; Prognosis; Stroke; Warfarin

Nephropathy is one of the most common and severe complications of diabetes mellitus. The mechanism of diabetic nephropathy, however, remains incompletely understood. To elucidate the mechanism of diabetic nephropathy, we focus on the role of a vitamin K-dependent growth factor, growth arrest-specific gene 6 (Gas6), and its receptor Axl in the pathogenesis of diabetic nephropathy. We used streptozotocin (STZ)-induced diabetic rats and mice as a model of diabetic nephropathy and examined the role of Gas6 and Axl in the development of diabetic nephropathy. We also studied signaling mechanisms involved in mesangial hypertrophy characteristic of the early phase of diabetic nephropathy in vitro. After 12 weeks of STZ injection, the glomerular expression of Gas6 and Axl was increased along with the phosphorylation of Akt, p70 S6 kinase, and 4E-BP-1. Administration of warfarin, which inactivates Gas6, inhibited mesangial and glomerular hypertrophy and the increase in albuminuria in STZ-rats. Warfarin treatment also inhibited the phosphorylation of Akt, p70 S6 kinase, and 4E-BP-1. To demonstrate the specific role of Gas6, we showed that these findings were recapitulated in STZ-induced Gas6-knockout mice and confirmed the role of Gas6 in the development of diabetic nephropathy in vivo. In vitro stimulation of mesangial cells with Gas6 resulted in mesangial cell hypertrophy. Stimulation of the cells with 25 mmol/l of glucose increased the expression of Gas6/Axl and mesangial cell size compared with that with 5.6 mmol/l of glucose. LY294002 and rapamycin blocked Gas6-induced activation of the Akt/mTOR pathway and mesangial hypertrophy. Thus, we have found a novel mechanism of glomerular hypertrophy through the Gas6/Axl-mediated pathway in the development of diabetic nephropathy, where the Akt/mTOR pathway is a key signaling cascade in Gas6-mediated mesangial and glomerular hypertrophy. Inhibition of the Gas6/Axl pathway in diabetic patients might be beneficial to slow down the progression of diabetic nephropathy.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Gene Expression; Glomerular Mesangium; Humans; Hypertrophy; Intercellular Signaling Peptides and Proteins; Mice; Mice, Knockout; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Warfarin

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

To investigate the relationship of hypercoagulation and renal dysfunction in patients with diabetic nephropathy(DN).. Forty six diabetes type II patients with nephrotic syndrome were divided into 3 groups according to 24 hr creatinine clearance (Ccr) as high, middle and low groups. Fourteen of the 46 patients received warfarin therapy. The parameters of coagulation and fibrolysis as well as renal function were examined.. Patients with moderate and major renal dysfunction (M group and L group) displayed higher activities of coagulation than those with mild renal dysfunction (H group) did. Warfarin could obviously improve the status of coagulation and fibrolysis in patients with DN and delay the progress of renal dysfunction.. Hypercoa-gulation was one of the causes of renal dysfunction in patients with DN.

Topics: Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Male; Metabolic Clearance Rate; Renal Insufficiency; Thrombophilia; Warfarin

The half-life of fatty acid-conjugated antidiabetic drugs are prolonged through binding to albumin, but this may not occur in diabetic patients with nephropathy complicated with hypoalbuminemia. We previously showed that human serum albumin (HSA) dimerized at the protein's Cys34 by 1,6-bis(maleimido)hexane has longer half-life than the monomer under high permeability conditions. The aim of this study was to investigate the superior ability of this HSA dimer as a plasma-retaining agent for fatty acid conjugated antidiabetic drugs.. The diabetic nephropathy rat model was prepared by administering a single injection of streptozotocin (STZ) intravenously, and the pharmacokinetic properties of HSA monomer and dimer were evaluated. Site-specific fluorescent probe displacement experiments were performed using warfarin and dansylsarcosine as site I and site II specific fluorescent probes, respectively.. The half-life of the HSA dimer in STZ-induced diabetic nephropathy model rats was 1.5 times longer than the HSA monomer. The fluorescent probe displacement experiment results for HSA monomer and dimer were similar, where fatty acid-conjugated antidiabetic drugs displaced dansylsarcosine but not warfarin in a concentration-dependent manner.. The HSA dimer shows potential for use as a plasma-retaining agent for antidiabetic drugs due to its favourable pharmacokinetic properties.

Topics: Animals; Binding Sites; Dansyl Compounds; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Dimerization; Drug Carriers; Fatty Acids; Fluorescent Dyes; Half-Life; Humans; Hypoglycemic Agents; Male; Maleimides; Permeability; Plasma; Protein Binding; Rats; Rats, Sprague-Dawley; Sarcosine; Serum Albumin; Warfarin

Necrotic skin lesions are unfortunately common in patients with end stage renal disease undergoing dialysis therapy. We present a case of a necrotic skin lesion in a peritoneal dialysis patient shortly after the initiation of warfarin therapy for atrial fibrillation. We discuss and contrast distinguishing features of two diagnostic possibilities: warfarin skin necrosis (WSN) and calcific uremic arteriopathy (CUA) in terms of clinical presentation, risk factors and pathology. Lastly, we outline the importance of establishing a diagnosis as treatment regimens differ substantially.

Topics: Anticoagulants; Calciphylaxis; Diabetic Nephropathies; Diagnosis, Differential; Humans; Kidney Failure, Chronic; Male; Middle Aged; Necrosis; Skin Diseases; Warfarin

Many hemodialysis patients receive antiplatelet therapy or warfarin; however, little is known about the effect of this on iron requirements. Given the association of antiplatelet therapy with bleeding we hypothesized that there should be a greater need for iron in such patients, which we tested in this study.. Retrospective 1-year cohort study of 205 chronic hemodialysis patients. The primary outcome variable was total iron dose, which was analyzed according to antiplatelet/warfarin use. Data were also collected on potential confounders, allowing for both unadjusted and adjusted (multiple regression) analysis.. 97/205 patients received antiplatelet/warfarin therapy. This group was older, with a higher incidence of macrovascular disease and diabetes and a higher median C-reactive protein (6.0 vs. 3.75 mg/l). Overall, median iron requirement was 1,300 mg/year. In a multiple regression analysis, antiplatelet/warfarin use was associated with an additional iron requirement of 703 mg (95% confidence interval 188-1,220 mg), with the strongest effect observed in patients with normal inflammatory markers.. We found a high requirement for iron in patients receiving antiplatelet agents/warfarin. We argue that the most likely mechanism for this association is chronic, low-grade blood loss, although further study is required before causality can be established.

Topics: Age Factors; Aged; Anemia, Iron-Deficiency; C-Reactive Protein; Comorbidity; Diabetic Nephropathies; Female; Ferric Compounds; Ferritins; Hemorrhage; Humans; Inflammation; Iron; Iron Deficiencies; Kidney Failure, Chronic; Male; Middle Aged; Nutritional Requirements; Platelet Aggregation Inhibitors; Renal Dialysis; Retrospective Studies; Thrombophilia; Transferrin; Vascular Diseases; Warfarin

Nephropathy is one of the most common complications of diabetes mellitus. Glomerular hypertrophy is a hallmark in the early phase of the nephropathy. The mechanism of glomerular hypertrophy, however, remains incompletely understood. We have reported that Gas6 (growth arrest-specific gene 6) and its receptor, Axl, play a key role in the development of glomerulonephritis. Here we show the important role of Gas6/Axl in the pathogenesis of diabetic glomerular hypertrophy. In streptozotocin (STZ)-induced diabetic rats, mesangial and glomerular hypertrophy and an increase in the glomerular filtration rate (GFR) and albuminuria were observed after 12 weeks of STZ injection. The glomerular expression of Gas6 and Axl was increased in those rats. Administration of warfarin inhibited mesangial and glomerular hypertrophy and the increase in GFR and albuminuria in STZ rats. Moreover, we found less mesangial hypertrophy in STZ-treated Gas6 knockout mice than control mice. In vitro we found that stimulation of mesangial cells with Gas6 resulted in mesangial cell hypertrophy. Thus we have found a novel mechanism of glomerular hypertrophy through the Gas6/Axl-mediated pathway in the development of diabetic nephropathy. Inhibition of the Gas6/Axl pathway in diabetic patients might be beneficial to slow down the progression of diabetic nephropathy.

Topics: Albuminuria; Animals; Axl Receptor Tyrosine Kinase; Blotting, Western; Diabetic Nephropathies; Disease Progression; Flow Cytometry; Glomerular Filtration Rate; Humans; Hypertrophy; Immunohistochemistry; Intercellular Signaling Peptides and Proteins; Kidney; Kidney Diseases; Leucine; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Oncogene Proteins; Proteins; Proto-Oncogene Proteins; Rats; Receptor Protein-Tyrosine Kinases; Recombinant Proteins; Time Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1; Warfarin

We report a patient with diabetic endstage renal disease with an initial platelet count of 17.6 x 10(4)/mm3 who developed type-II heparin-induced thrombocytopenia (HIT) during the induction period of hemodialysis (HD) when unfractionated heparin was used. Because the recognition of the condition and the treatment of this patient with HIT was unsatisfactory, she developed deep venous thrombosis, myocardial infarction, and occlusion of vascular access, at times of platelet counts of 4.1 x 10(4), 7.7 x 10(4), and 6.4 x 10(4)/mm3, respectively, with antibodies to heparin/platelet factor 4 complex. Unfortunately, we misjudged in our belief that the thromboembolic events might be associated with an underlying procoagulant state in diabetic nephrotic syndrome, rather than being associated with the clinical picture of HIT. This case report suggests that the clinician must consider HIT in the differential diagnosis for thromboembolic complications during the induction period of HD, because unfractionated heparin is the major anticoagulant used in HD.

Topics: Anticoagulants; Catheters, Indwelling; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Fibrinolytic Agents; Heparin; Humans; Kidney Failure, Chronic; Middle Aged; Myocardial Infarction; Phlebography; Renal Dialysis; Thrombocytopenia; Ticlopidine; Venous Thrombosis; Warfarin

We present a case of diabetic nephrotic syndrome complicated with cerebral embolism in whom two intracardiac thrombi were found in both right and left ventricles without obvious abnormality echocardiographically. Both thrombi regressed after anticoagulant therapy. This represents an intracardiac thrombotic complication of nephrotic syndrome, presumably with hypercoagulable state as the sole mechanism of intracardiac thrombus formation.

Topics: Adult; Anticoagulants; Diabetic Nephropathies; Female; Heart Ventricles; Humans; Intracranial Embolism and Thrombosis; Nephrotic Syndrome; Thrombosis; Ultrasonography; 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