thromboxane-a2 and Kidney-Failure--Chronic

The exact etiology of the conflicting hemostatic disorder in the advanced stage of chronic renal disease, i.e. prothrombotic versus bleeding tendency, is not completely understood. Abnormal platelet function in patients with renal failure is not caused by high concentrations of urea, although the presence of fibrinogen fragments may prevent binding of normal fibrinogen and formation of platelet aggregates. Hemostatic abnormalities in end-stage kidney disease may be affected, to some extent, by the choice of renal replacement therapy. Patients on hemodialysis have an increased risk of thrombotic events, primarily due to the release of thromboxane A2 and adenosine diphosphate into the circulation, as well as platelet degranulation. Some activation of platelets occurs due to the exposure of blood to the roller pump segment, but microbubbles may also play a role. Renal transplantation is the treatment of choice for patients with end-stage renal disease. Immunosuppressive therapy is associated with an increased risk of thromboembolic complications. Additional research is required to identify the potential benefits of different immunosuppressive therapies in relation to platelet aggregation, keeping in mind the long- term need for immunosuppression in renal transplant patients.

Topics: Adenosine Diphosphate; Blood Platelet Disorders; Humans; Kidney Failure, Chronic; Kidney Transplantation; Platelet Aggregation; Renal Dialysis; Renal Replacement Therapy; Risk Factors; Thromboembolism; Thrombosis; Thromboxane A2

Topics: Asthma; Biomarkers; Cardiovascular Diseases; Humans; Immunoenzyme Techniques; Ischemia; Kidney Failure, Chronic; Radioimmunoassay; Reference Values; Specimen Handling; Thrombosis; Thromboxane A2; Thromboxane B2

Topics: beta-Thromboglobulin; Biocompatible Materials; Blood Coagulation; Blood Platelets; Cell Adhesion; Fibrin; Humans; Infections; Kidney Failure, Chronic; Leukocytes; Leukopenia; Lymphocyte Activation; Membranes, Artificial; Platelet Activation; Platelet Adhesiveness; Platelet Factor 4; Polymethyl Methacrylate; Renal Dialysis; Respiratory Burst; Thrombin; Thromboxane A2

to refine a role of free radical oxidation (FRO), anemia, and endothelial dysfunction in the development of cardiovascular events in patients with chronic renal failure (CRF) at diferent stages of the disease.. Eighty-six patients, including 46 (53%) women and 40 (47%) men with Stages II-IV CRF, were examined. The patients' mean age was 43.6 +/- 14 years. Echocardiography, measurements of the blood levels of hemoglobin, albumin, cholesterol, and uric acid, and determination of blood electrolytic composition were made. Blood creatinine concentrations in the group averaged 0.3 mmol/l. Glomerular filtration rate (GFR) calculated from the Cockroft-Goult formula averaged 33.96 +/- 13 ml/min; the duration of CRF was 9.3 +/- 1.6 years. Anemia was detected in 46 (53%) patients. Iron metabolism was estimated from serum ferritin levels. Special studies involved determination of FRO--malondialdehyde (MDA) and the activities of catalase and superoxide dismutase (SOD) in plasma and serum. The plasma concentrations of endohelin-1 (ET-1), thromboxane A2, and prostacyclin were measured by radioimmunoassay. Results. The higher concentrations of MDA and the decreased activities of catalase and SOD, i.e., FRO, correlated with the progression of renal failure. There were also increases in the levels of ET-1 and thromboxane A, and a reduction in the concentration of prostacyclin as blood creatinine levels elevated. Left ventricular hypertrophy was found in 43 (50%) of the 86 patients. Its severity depended on the decrease of creatine phosphokinase and the severity of anemia and arterial hypertension. There was a stable correlation between the changes in left ventricular myocardial mass, MDA levels, and catalase and SOD activities.. The higher level of MDA and the lower activities of catalase and SOD in patients with CRF, which correlate with diminished renal function, confirm that the disease is closely associated with FRO, that, by aggravating anemia and endothelial dysfunction, affects the magnitude of morphological and functional changes in the cardiovascular system in patients with CRF patients.

Topics: Adult; Cardiovascular Diseases; Catalase; Disease Progression; Endothelin-1; Endothelium, Vascular; Female; Follow-Up Studies; Free Radical Scavengers; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Malondialdehyde; Oxidative Stress; Prognosis; Superoxide Dismutase; Thromboxane A2

Dietary supplementation with polyunsaturated fatty acids (PUFAs) alters the course of experimental kidney disease in dogs. In particular, supplementation with omega-6 PUFAs hastens the decline of kidney function, and omega-3 PUFAs are renoprotective. We investigated the early stages of renal insufficiency to determine whether PUFA supplementation altered the magnitude of hypercholesterolemia or glomerular hemodynamics. Two months after 11/12 nephrectomy, dogs were randomly divided into three groups of 6 animals each. Each group of dogs was then fed a low-fat basal diet supplemented with one of three sources of lipid to achieve a final concentration of 15% added fat. Fat sources were rich in omega-3 PUFAs (menhaden fish oil, group FO), omega-6 PUFAs (safflower oil, group SO), or saturated fatty acids (beef tallow, group C). Early in renal insufficiency, before significant kidney damage, group FO had a lower (P<.05) serum cholesterol concentration and tended to have a lower urinary prostaglandin E2 (PGE2) and thromboxane A2 (TxA2) excretion than group C. In contrast, group SO had a higher mean glomerular capillary pressure (P<.05) and more glomerular enlargement (P<.05) and tended to have higher eicosanoid excretion rates than group C. These differences in lipid metabolism, glomerular hypertension and hypertrophy, and urinary eicosanoid metabolism could explain, in part, the beneficial effects of omega-3 PUFAs and the detrimental effects of omega-6 PUFAs when administered on a long-term basis in this model of renal insufficiency.

Topics: Animals; Cholesterol; Dietary Fats, Unsaturated; Dinoprostone; Disease Models, Animal; Dogs; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Fatty Acids, Unsaturated; Female; Hypercholesterolemia; Kidney; Kidney Failure, Chronic; Male; Renal Circulation; Thromboxane A2

Complement activation (plasma levels of the anaphylatoxins C3a and C5a), the aggregation of polymorphonuclear neutrophils (PMN) on 12-O-tetradecanoyl-4 beta-phorbol-13-acetate (TPA) 2.5 microM, A23187 5 microM, arachidonic acid 0.1 mM and TPA-induced thromboxane A2 production by PMN were examined in 10 uraemic patients at times 0, 15 and 240 min after the onset of haemodialysis with Cuprophan (CU) and polyacrylonitrile (PAN) membranes. The rise in plasma C3a and C5a was intense during haemodialysis with CU, but mild with PAN. PMN aggregation in uraemic patients was lower (as compared to normal controls) independently of the agonist used. At 15 min of haemodialysis with CU, PMN aggregation increased and decreased at 240 min, while during haemodialysis on PAN no significant changes in PMN aggregation were noticed. TPA-induced TxA2 synthesis by PMN was decreased in uraemic patients. It was normalized after haemodialysis with PAN, but not with CU. Apparently the mechanisms underlying PMN aggregation and TxA2 synthesis during haemodialysis may not be entirely dependent on complement activation. Evidently, dialysable plasma factors may be responsible for the abnormal PMN function in uraemic patients. Thus, removal of these factors by haemodialysis with an appropriate membrane may improve the PMN functions.

Topics: Acrylic Resins; Adult; Arachidonic Acid; Calcimycin; Cell Aggregation; Cellulose; Complement Activation; Humans; Kidney Failure, Chronic; Membranes, Artificial; Middle Aged; Neutrophils; Renal Dialysis; Tetradecanoylphorbol Acetate; Thromboxane A2; Thromboxane B2

The question of whether pharmacological inhibition of the thromboxane A2 activity prevents cyclosporine-induced chronic renal dysfunction in a Lewis rat model of renal isograft was addressed. Transplanted animals were given a daily oral dose of cyclosporine (20 mg/kg; N = 15), cyclosporine (20 mg/kg) and the thromboxane A2 receptor antagonist GR32191 (3 mg/kg twice daily, by gavage; N = 15), or the vehicle alone (N = 12). Treatments were started the day of kidney transplant, and animals were monitored for 1 year. Cyclosporine-treated animals developed renal insufficiency, as documented by serum creatinine levels of 0.49 +/- 0.09, 0.95 +/- 0.12, and 1.38 +/- 0.15 mg/dL before and after 6 and 12 months of observation, respectively. Cyclosporine and GR32191 used in combination partially but significantly prevented the deterioration of renal function (serum creatinine, basal, 0.52 +/- 0.06; month 6, 0.68 +/- 0.04; month 12, 0.93 +/- 0.10 mg/dL). At the end of the study, GFR, as insulin clearance, was significantly lower in rats given cyclosporine (0.28 +/- 0.09 mL/min/100 g) than in rats given cyclosporine plus GR32191 (0.45 +/- 0.05 mL/min/100 g) or than in vehicle-treated animals (0.56 +/- 0.07 mL/min/100 g). Similar results were obtained for the effective RPF, measured as p-aminohippurate clearance. At the same time points, comparable to whole-blood cyclosporine levels were found in rats receiving cyclosporine alone and in those given cyclosporine plus GR32191. More than 50% of the animals on cyclosporine alone died from uremia before the end of the observation period. By contrast, rats receiving cyclosporine in combination with GR32191 had a prolonged survival.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Biphenyl Compounds; Creatinine; Cyclosporine; Glomerular Filtration Rate; Graft Survival; Heptanoic Acids; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Male; Rats; Rats, Inbred Lew; Receptors, Prostaglandin; Receptors, Thromboxane; Renal Circulation; Thromboxane A2

A recently described method to evaluate the primary haemostatic mechanism under in vivo conditions was utilised to investigate thromboxane A2 (TXA2) and prostacyclin (PGI2) production by platelets and vascular endothelial cells, respectively, in patients with severe chronic renal failure. Unlike some previous studies, a decrease in TXA2 production by uraemic platelets could not be demonstrated. PGI2--produced by microvascular endothelial cells after a standardised injury--was, however, 59% higher in patients than controls (P less than 0.05). An increased local level of this potent platelet inhibitory eicosanoid could play an important role in the bleeding tendency exhibited in chronic renal failure.

Topics: 6-Ketoprostaglandin F1 alpha; Bleeding Time; Blood Platelets; Epoprostenol; Female; Humans; Kidney Failure, Chronic; Male; Microcirculation; Thromboxane A2; Uremia

Intraplatelet serotonin (5-HT), beta-thromboglobulin (beta-TG), and histamine content as well as platelet total thromboxane A2 (TXA2) synthesizing capacity were measured in 53 patients with chronic renal disease: nephrotic syndrome (n = 18); end-stage renal failure (ESRF; n = 13); continuous ambulatory peritoneal dialysis (CAPD; n = 9); hemodialysis (HD; n = 13). These indices of platelet function were correlated with plasma total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) concentrations. When compared with controls, intraplatelet 5-HT was significantly reduced in all patient groups studied and beta-TG was diminished in all patient groups except CAPD. Total platelet TXA2 synthesizing capacity was increased in ESRF and HD groups. Intraplatelet histamine content was not altered in any of the patient groups studied. There was a significant inverse correlation between intraplatelet 5-HT content on the one hand and plasma TC, LDL-C, and TG on the other. The depletion of intraplatelet 5-HT and beta-TG and the increase in total TXA2 synthesizing capacity are consistent with platelet activation in chronic renal disease. The correlation between these indices of platelet activation and TC, LDL-C, HDL-C, and TG suggests that changes in the concentrations of these lipids may contribute to the activation of platelets in these conditions.

Topics: Adolescent; Adult; beta-Thromboglobulin; Blood Platelets; Female; Histamine; Humans; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Nephrotic Syndrome; Peritoneal Dialysis; Renal Dialysis; Serotonin; Thromboxane A2

Overall 14 patients with chronic renal failure treated by hemodialysis were examined. The content of the key metabolites of the arachidonic cascade thromboxane B2, 6-keto-prostaglandin F1 alpha and 12-hydroxyeicosatetraene acid (12-HETE) in blood plasma was reduced in the patients as compared to donors. By the end of hemodialysis, part of the patients showed a tendency towards its normalization, however, no complete recovery was practically recorded. Derangement of the formation of thromboxane A2, prostacyclin and 12-HETE in uremia is likely to be related to reverse inhibition of the function of platelet cyclooxygenase and lipoxygenase by plasma inhibitor. The recovery of the function can be attained after adequate hemodialysis.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; 6-Ketoprostaglandin F1 alpha; Adult; Epoprostenol; Humans; Hydroxyeicosatetraenoic Acids; Kidney Failure, Chronic; Middle Aged; Renal Dialysis; Thromboxane A2; Thromboxane B2; Uremia

To assess the role of altered renal and systemic production of thromboxane A2 and prostacyclin in the hepatorenal syndrome, urinary excretion of their major renal and extrarenal metabolites was measured in patients with compensated and decompensated liver disease, chronic renal failure, and hepatorenal syndrome. Urinary excretion rates of all prostanoids (renal and extrarenal) were increased in subjects with liver disease compared with normal controls. Moreover, they were considerably higher in subjects with severe hepatic decompensation but good renal function compared with those with hepatorenal syndrome. In contrast, the excretion rate of all metabolites was reduced in patients with chronic renal failure. The excretion rate of all metabolites was markedly elevated during the early stages of hepatorenal syndrome and decreased in parallel with creatinine clearance. When corrected for creatinine clearance, there was a strong correlation between prostanoid excretion and serum bilirubin in subjects with liver disease; there was no difference, however, in the excretion of renal and extrarenal prostanoids between hepatorenal syndrome and severe hepatic decompensation. It is concluded that hepatic decompensation is associated with a progressive increase in prostanoid excretion but that changes in production of prostacyclin or thromboxane A2 are unlikely to be major factors in the pathogenesis of the hepatorenal syndrome.

Topics: Adult; Aged; Ascites; Bilirubin; Creatinine; Dinoprost; Epoprostenol; Female; Hepatorenal Syndrome; Humans; Kidney; Kidney Failure, Chronic; Liver Cirrhosis; Liver Diseases; Male; Middle Aged; Thromboxane A2; Thromboxane B2

The formation of prostacyclin (PGI2) and thromboxane A2 and the release of beta-thromboglobulin (beta-TG) at the site of platelet-vessel wall interaction, i.e. in blood emerging from a standardized injury of the microvasculature made to determine bleeding time, was studied in patients with end-stage chronic renal failure undergoing regular haemodialysis and in normal subjects. In the uraemic patients, levels of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) were 1.3-fold to 6.3-fold higher than the corresponding values in the control subjects indicating an increased PGI2 formation in chronic uraemia. Formation of thromboxane B2 (TxB2) at the site of plug formation in vivo and during whole blood clotting in vitro was similar in the uraemic subjects and in the normals excluding a major defect in platelet prostaglandin metabolism in chronic renal failure. Significantly smaller amounts of beta-TG were found in blood obtained from the site of vascular injury as well as after in vitro blood clotting in patients with chronic renal failure indicating an impairment of the alpha-granule release in chronic uraemia. We therefore conclude that the haemorrhagic diathesis commonly seen in patients with chronic renal failure is--at least partially--due to an acquired defect of the platelet alpha-granule release and an increased generation of PGI2 in the microvasculature.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Aged; beta-Thromboglobulin; Bleeding Time; Blood Platelets; Blood Vessels; Child; Epoprostenol; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Thromboxane A2; Thromboxane B2

Topics: Diagnosis, Differential; Hemodynamics; Humans; Kidney; Kidney Failure, Chronic; Liver; Liver Cirrhosis; Natriuretic Agents; Oliguria; Prostaglandins; Renal Circulation; Renin-Angiotensin System; Sympathetic Nervous System; Syndrome; Thromboxane A2

Prostanoids are local cyclooxygenase products, synthesized by mesangial and epithelial cells of the glomerulus as well as by a variety of inflammatory cells and platelets. Prostaglandins and thromboxane have direct vasodilatory and vasoconstrictory effects and can modulate glomerular function. Arachidonic acid, the main substrate for cyclooxygenase, can also be metabolized by the lipoxygenase pathway to leukotrienes, substances which are primarily synthesized in inflammatory cells. In several models induction of immunologic glomerular injury is associated with an increased glomerular formation of cyclooxygenase and lipoxygenase products. The changes in cyclooxygenase products have been shown to account for some hemodynamic changes found in some of these models. Increased renal prostanoid formation is also present in patients with glomerular disease. There is some evidence that increased renal PG-formation in patients with moderate glomerular disease regulates GFR and mediates proteinurie in some of these patients. Leukotrienes are chemotactive substances which modulate the function of inflammatory cells, stimulate the growth of mesangial cells, and constrict mesangial cells in culture. Thus, these compounds might be mediators in the induction of immune mediated glomerular disease.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Eicosanoic Acids; Glomerular Filtration Rate; Glomerulonephritis; Humans; Immune Complex Diseases; Kidney Failure, Chronic; Leukotriene B4; Lipoxygenase; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Prostanoic Acids; Renal Circulation; SRS-A; Thromboxane A2

To study the effects of uremia and hemodialysis on the production rates of antiaggregatory prostacyclin (PGI2) and proaggregatory thromboxane A2 (TxA2), we collected serial plasma samples from eight patients with chronic uremia before, during and after hemodialysis and assayed them for 6-keto-PGF1 alpha and TxB2, the stable metabolites of PGI2 and TxA2, respectively. In addition, the capacity of the platelets to produce TxB2 during spontaneous clotting was studied by measuring the TxB2 levels in serum incubated at +37 degrees C for 60 minutes. The PGI2 production of the uremia patients before hemodialysis was less (P less than 0.001) than that of healthy volunteers. It rose significantly following heparinization and remained elevated during hemodialysis. TxB2 generation by platelets during clotting was diminished in uremia. Plasma TxB2 levels were normal before, but increased during hemodialysis. Thus, profound changes in the PGI2/TxA2-system seem to be associated with uremia and hemodialysis.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Blood Platelets; Epoprostenol; Female; Glomerulonephritis; Heparin; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prostaglandins; Pyelonephritis; Renal Dialysis; Thromboxane A2; Thromboxane B2; Thromboxanes; Uremia

Platelet aggregation and thromboxane B2 production, in response to adenosine diphosphate, were significantly impaired in 7 undialyzed or inadequately dialyzed patients with renal failure when compared to adequately dialyzed individuals or normal subjects. In 1 patient, platelet aggregation and thromboxane synthesis were corrected after adequate hemodialysis. The defect in both platelet aggregation and thromboxane production was induced in normal platelets incubated with uremic platelet-poor plasma. These findings suggest that the uremic platelet defect may be due, in part, to a plasma factor that inhibitors platelet thromboxane synthesis. Further, adequate dialytic therapy may reverse this defect.

Topics: Acute Kidney Injury; Adult; Aged; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Platelet Aggregation; Renal Dialysis; Thromboxane A2; Thromboxane B2; Thromboxanes