thromboxane-b2 and Kidney-Failure--Chronic

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

In a double-blind, randomized, placebo-controlled cross-over study, we investigated in seven patients with chronic renal failure the effect of conjugated estrogens (0.6 mg/kg/day for 5 days) on template bleeding time and on thromboxane A2 (TxA2), beta-thromboglobulin (beta-TG) and prostacyclin (PGI2) concentrations in blood emerging from the template bleeding time incisions. Administration of conjugated estrogens resulted in a significant shortening of the bleeding time in six out of seven patients with a maximum effect 7 and/or 14 days following treatment. Both TxA2 (measured as thromboxane B2, TxB2) and beta-TG release in bleeding time blood were significantly higher following administration of conjugated estrogens as compared to placebo administration. No difference was seen in endothelial PGI2 (measured as 6-keto-prostaglandin F1 alpha) formation when patients were treated with conjugated estrogens as compared to placebo administration over the 28 day observation period. We conclude that in patients with chronic renal failure, infusion of conjugated estrogens results in a significant shortening of the bleeding time together with an increase in platelet reactivity, as indicated by an increase of TxA2 and beta-TG concentration in the microvasculature. No effect was seen on PGI2 production, thereby excluding a major effect on vascular prostaglandin metabolism.

Topics: 6-Ketoprostaglandin F1 alpha; beta-Thromboglobulin; Bleeding Time; Blood Platelets; Double-Blind Method; Estrogens, Conjugated (USP); Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Thromboxane B2

To evaluate the effects of three chemically distinct nonsteroidal anti-inflammatory drugs (NSAIDs) on renal function in patients with asymptomatic, mild but stable chronic renal failure.. Prospectively randomized, triple-crossover study with at least 1-month washout between each of three treatment periods.. Inpatient and outpatient clinical research center of a university teaching hospital.. Convenience sample of 12 women with serum creatinine levels between 130 and 270 mumols/L (1.5 and 3.0 mg/dL). Mean glomerular filtration rate +/- standard error was 0.36 +/- 0.03 mL/s.m2 (37 +/- 3 mL/min.1.73 m2); mean effective renal plasma flow was 1.6 +/- 0.18 mL/s.m2 (166 +/- 19 mL/min.1.73 m2).. Patients received ibuprofen, 800 mg three times daily; piroxicam, 20 mg daily; and sulindac, 200 mg twice daily for 11 days. Treatment was discontinued if serum creatinine rose by 130 mumols/L (1.5 mg/dL) or serum potassium exceeded 6 mmol/L (6 mEq/L).. Three patients met our criteria for stopping ibuprofen by day 8; however, all patients completed piroxicam and sulindac therapy. When the three patients in whom ibuprofen was withdrawn were rechallenged with ibuprofen, 400 mg three times daily, two again developed evidence of acute renal deterioration. All three regimens suppressed renal prostaglandin production.. These findings indicate that a brief course of ibuprofen, a compound widely used on a nonprescription basis, may result in acute renal failure in patients with asymptomatic, mild chronic renal failure. Additional studies are needed to assess the risk of piroxicam and sulindac in patients with more pronounced renal impairment and in patients receiving longer courses of therapy, which, according to our data, may result in drug accumulation.

Topics: Adult; Aged; Creatinine; Female; Glomerular Filtration Rate; Humans; Ibuprofen; Kidney; Kidney Failure, Chronic; Middle Aged; Piroxicam; Prospective Studies; Prostaglandins; Randomized Controlled Trials as Topic; Renal Circulation; Sulindac; Thromboxane B2

Pulmonary hypertension (PHT) has been reported to be high among end-stage renal disease (ESRD) patients. This study evaluated PHT in ESRD patients and the role of arteriovenous fistula (AVF), thromboxane B(2) (TXB(2)) and pro-BNP in this complication.. 45 ESRD patients on regular hemodialysis (HD) (group 1) and 31 ESRD patients on conservative treatment (group 2) underwent clinical and biochemical testing. Pulmonary artery pressure (PAP) was evaluated using Doppler echocardiography. Cardiac assessment by echocardiography and AVF flow measurement by Doppler ultrasound were done. Levels of TXB(2) and N-terminal pro-brain natriuretic peptide (NT-proBNP) in plasma were determined.. PHT was found in 44.4% in group 1 and in 32.3% in group 2. Comparing the two groups shows a significant difference with regard to PAP, proBNP, and TXB(2). Patients with PHT have a significantly higher AVF blood flow, proBNP, and TXB(2). In patients with PHT, 76.7% have left ventricular diastolic dysfunction (LVDD). PAP correlates with AVF flow, proBNP, and TXB(2).. Results show a high prevalence of PHT among patients with ESRD on chronic HD or on conservative treatment. PHT in such patients is related to AVF flow, TXB(2) and NT-proBNP level and LVDD. AVF flow is an important correctable cause of PHT.

Topics: Adult; Aged; Arteriovenous Fistula; Blood Pressure; Echocardiography, Doppler; Female; Humans; Hypertension, Pulmonary; Kidney Failure, Chronic; Male; Middle Aged; Natriuretic Peptide, Brain; Radioimmunoassay; Thromboxane B2

Regular administration of recombinant human erythropoietin (rHuEPO) is frequently associated with a rise in arterial blood pressure in hemodialysis (HD) patients. The aim of this study was to examine the effects of rHuEPO on plasma endothelin (ET)-1 and nitric oxide products (NOx) concentration in HD patients. Fifteen patients on maintenance HD with hematocrit of less than 25% were included in the present study. All patients received 3,000 units of rHuEPO intravenously three times a week at the end of each HD session. Plasma levels of ET-1, NOx, thromboxane B2 (TXB2), prostacyclin (6-keto-PGF1alpha), and cyclic guanosine 3',5'-monophosphate (cGMP) were measured before, 2, and 4 weeks after rHuEPO treatment. Plasma concentrations of ET-1, TXB2, and 6-keto-PGF1alpha were measured by radioimmunoassay. Plasma NOx was measured by high-performance liquid chromatography. An rHuEPO-induced increase in mean arterial blood pressure of over 6 mmHg occurred in 7 patients (hypertensive group), whereas the elevation of mean arterial blood pressure was less than 5 mmHg in 8 patients (nonhypertensive group). Plasma ET-1 levels were elevated in all HD patients. Elevated plasma ET-1 levels remained unchanged after rHuEPO treatment in the hypertensive group, whereas the increase in plasma ET-1 levels was attenuated in the nonhypertensive group. Plasma NOx concentrations were also increased in all HD patients. This increase in plasma NOx levels was lessened in the hypertensive group after rHuEPO administration; however, plasma NOx levels remained increased in the nonhypertensive group. Changes in mean arterial blood pressure were significantly correlated with changes in plasma ET-1/NOx ratio. Plasma levels of TXB2, 6-keto-PGF1alpha, and cGMP were unchanged after rHuEPO administration in the hypertensive and nonhypertensive groups. These results suggest that an increase in ET-1/NOx ratio in blood, probably occurring in vascular endothelial cells, may be associated with rHuEPO-induced hypertension in HD patients.

Topics: 6-Ketoprostaglandin F1 alpha; Biomarkers; Blood Pressure; Cyclic GMP; Endothelin-1; Erythropoietin; Female; Hematocrit; Humans; Hypertension; Japan; Kidney Failure, Chronic; Male; Middle Aged; Nitric Oxide; Recombinant Proteins; Renal Dialysis; Statistics as Topic; Thromboxane B2; Time Factors; Treatment Outcome

Platelets of patients with uremia develop a defective platelet function and have a decreased production of thromboxane B2 (TxB2). Activated platelets generate thromboxane from free arachidonate that is previously released from the membrane phospholipids (PLs) by phospholipases. Phospholipase A2 (PLA2) release up to 70% of the arachidonate in normal platelets, and to date, the activity of this enzyme in uremia is unknown. This work studied the PLA2 activity in the platelets of nine uremic patients and nine healthy volunteers. Washed platelets were labelled with [(14)C]arachidonic acid and activated with calcium ionophore A-23187 (4 microgr/ml). Lipids were resolved by TLC and identified by autoradiography. The distribution of [(14)C]arachidonic acid in the five major platelet phospholipids was found to be normal. Uremic platelets released more radioactivity than normal platelets (19.0 +/- 5.2% versus 11.3 +/- 1.6%, P = 0.001). The production of both, radioactive thromboxane B2 and hydroxyheptadecatrienoic acid was normal (2.6 +/- 1.2% and 3.5 +/- 1.6% of total radioactivity respectively), but the formation of the lipoxygenase metabolite hydroxyeicosatetraenoic acid was increased with respect to the controls (12.9 +/- 4.6% vs 7.0 +/- 1.3% of total radioactivity, P = 0002). In conclusion, platelets of patients with uremia have an increased activity of phospholipase A2 and produce increased amounts of hydroxyeicosatetraenoic acid, an inhibitor of the platelet function.

Topics: Arachidonic Acid; Blood Platelets; Calcimycin; Case-Control Studies; Fatty Acids, Unsaturated; Humans; Kidney Failure, Chronic; Phospholipases A; Phospholipases A2; Platelet Function Tests; Thromboxane B2; Uremia

To investigate the pathophysiological role of vasoactive substances in the progression of chronic renal disease, we measured the 24-hour urinary excretion of prostaglandin 6-keto F1alpha, thromboxane B2, NOx, cGMP and ET-1 in 26 patients with chronic renal failure under conservative treatment and in 40 control subjects. Urinary 6-keto PgF1alpha, TxB2 and cyclic GMP were evaluated by RIA, and ET-1 was assayed by EIA. NOx were evaluated using a colorimetric assay as nitrate/nitrite. Urinary excretion of prostaglandin 6-keto F1alpha averaged 18.1 +/- 20.9 ng/g Ucreat in patients vs. 240.9 +/- 257.3 in controls (p < 0.0001), thromboxane B2 422 +/- 374 ng/g Ucreat in patients vs. 967 +/- 589 in controls (p < 2x 10(-5)), NOx 7.07 +/- 5.54 mg/g Ucreat in patients vs. 9.79 +/- 3.77 in controls (p < 0.01), cGMP 310 +/- 200 pg/g Ucreat in patients vs. 488 +/- 241 in controls (p < 0.001). In contrast, ET-1 urinary excretion was almost doubled in patients (13.45 +/- 5.84 ng/g of Ucreat) in comparison with controls (6.84 +/- 2.81 p < 1x10(-5)). While in control subjects significant correlations between urinary excretions of prostaglandin 6-keto F1alpha and thromboxane B2 (r = 0.69, p < 0.001) or NOx and ET-1 (r = 0.54, p < 0.001) were present, in patients only the relationship between urinary excretions of prostaglandin 6-keto F1alpha and thromboxane B2 (r = 0.53, p < 0.01) was retained. Our data suggest that in the normal kidney a balance between prostaglandin I2 and thromboxane A2, or nitric oxide and endothelin-1 is present, which contributes to hemodynamic regulation and protects this organ from ischemic damage. This balance is abolished in CRF, where a large increment of vasopressor agent endothelin is present, which, joined to a prevalent decrease of prostaglandin I2 synthesis, could contribute to the ischemic and fibrogenetic damage of the kidney, leading to progression of renal disease.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Creatinine; Cyclic GMP; Endothelin-1; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Nitrates; Nitric Oxide; Nitrites; Thromboxane B2; Vasomotor System

Bleeding and platelet dysfunction are prominent features of uremia. Sh ear-induced platelet aggregation (SIPA) involves the interaction of von Willebrand factor (vWF) with platelet membrane glycoproteins (GP) Ib and IIb-IIIa, the same receptor-ligand pair involved in in vivo adhesion and aggregation of platelets in the arterial circulation. We have used a modified rotational cone-plate viscometer to measure SIPA and calcium flux in platelets. Flow cytometric analysis of the surface expression of GP Ib and IIb-IIIa was performed using flourescein isothiocyanate-conjugated monoclonal antibodies CD42b and CD41a, respectively. Uremic patients showed decreased SIPA (controls, 43% +/- 2% [mean +/- SEM]; chronic renal failure patients, 36% +/- 3%; chronic hemodialysis patients, 26% +/- 2%; P < 0.001) along with a decrease in GP IIb-IIIa (controls, chronic renal failure patients, and chronic hemodialysis patients, 840 +/- 25, 649 +/- 42, 661 +/- 38 mean flourescence intensity, respectively; P < 0.0001). Glycoprotein Ib in uremic patients was not significantly different from normal. Chronic hemodialysis patients also demonstrated increased platelet-bound fibrinogen (P < 0.001) and platelet-bound vWF (p < 0.01). Calcium flux and thromboxane B(2) generation during SIPA of uremic platelets was normal. However, uremic plasma showed twice the normal concentration of vWF (P < 0.001) and sodium dodecyl sulfate agarose gel electrophoresis revealed the presence of fibrinogen fragments. Mixing experiments demonstrated an inhibitory effect of uremic plasma on SIPA of normal platelets (decreased from 39% +/- 3% at baseline to 31% +/- 3% after incubation in uremic plasma) along with an activation-independent increase in platelet-bound fibrinogen and platelet-bound vWF. When uremic platelets were incubated in normal plasma, their SIPA increased from 12% +/- 5% at baseline to 18% +/- 4% after incubation in normal plasma; (P = 0.002), although it did not return to normal. These results suggest that the uremic platelet dysfunction results from decreased GP IIb-IIa availability due to receptor occupancy by fibrinogen fragments (and possibly vWF fragments).

Topics: Calcium; Female; Flow Cytometry; Humans; Kidney Failure, Chronic; Male; Middle Aged; Platelet Aggregation; Platelet Glycoprotein GPIIb-IIIa Complex; Receptors, Cytoadhesin; Renal Dialysis; Thromboxane B2; Uremia; von Willebrand Factor

To determine the pathogenic role of serotonin (5-HT), we investigated 5-HT metabolism in undergoing hemodialysis (HD). Mean value of platelet 5-HT in patients undergoing HD was significantly lower than that of normal controls (0.22 + or - 0.16 pmol/10(5) platelets versus 0.35 + or - 0.13 pmol/10(5) platelets, p <0.02). While platelet uptake of 5-HT in normal controls reached a plateau in each experiment after incubation with authentic 5-HT for 60 min, platelet uptake of 5-HT in patients undergoing HD reached various levels. We found significantly lower platelet 5-HT levels in patients with diabetes mellitus (DM) after HD compared with those in patients with chronic glomerulonephritis (p <0.05). The pathogenic role of serotonergic amplifying mechanism especially in patients with DM should be investigated. Second, we investigated plasma 11-dehydro-thromboxane B2 (11-DTXB2) levels in patients undergoing HD. Mean level of plasma 11-DTXB2 concentration in patients after HD was significantly higher than in patients before HD (32.8 + or - 17.0 pg/ml versus 23.7 + or - 7.2 pg/ml, p <0.02). Increased plasma levels of 11-DTXB2 after HD were regarded as an indication of hypercoagulation. Our results provide evidence that several factors such as hypercoagulation, heparin, 5-HT uptake of platelet, or causal diseases of renal failure could be responsible for the lower platelet 5-HT levels in patients undergoing HD.

Topics: Adult; Aged; Blood Platelets; Case-Control Studies; Chromatography, High Pressure Liquid; Diabetic Nephropathies; Female; Glomerulonephritis; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Serotonin; Thromboxane B2

The objective of this study was to assess the effects of flaxseed and flax oil diets in the rat renal ablation model. Flaxseed is a rich source of alpha-linolenic acid, an 18:3n3 omega-3 fatty acid, which has anti-atherogenic and anti-inflammatory properties. Flaxseed, but not flax oil, is also rich in lignans, which are platelet-activating factor-receptor antagonists. Rats were subjected to 5/6 nephrectomy, fed a regular laboratory diet (RLD) for 1 week, then divided into three groups to receive either the RLD (n = 8), a 15% flaxseed diet (n = 8), or a 15% flax oil diet (n = 7). Blood pressure, proteinuria, glomerular filtration rate, and urinary prostaglandins (thromboxane B2 and 6-keto prostaglandin F1 alpha) were measured presurgery and at 1 week (before dietary allotment) and 20 weeks postnephrectomy when blood for plasma lipids and kidneys for histology and tissue-phospholipid analyses were obtained. Blood pressure increased progressively in the RLD group but not in the flax diet groups. Plasma triglycerides and cholesterol increased in all groups, but this increase was significantly attenuated by both flax diets. Proteinuria increased 1 week postsurgery and continued to increase in the RLD group but not in the flax diet groups. Glomerular filtration rate decreased progressively, but this decline in renal function was attenuated significantly by the flax diets. Both of the flax diets prevented glomerulosclerosis and mesangial expansion. Renal alpha-linolenic acid was increased by both the flax diets (flax oil > flaxseed), but eicosapentaenoic acid increased in the flax oil group only. The flaxseed group had greater renal-arachidonic acid levels than the flax oil and RLD groups. The total omega-3 fatty acids increased twofold to threefold in the flax oil group compared with the two other groups. The total saturated fatty acids were lower and the polyunsaturated fatty acids were increased in both flax diet groups. A progressive increase in urinary thromboxane B2 occurred in the RLD group but not in the flaxseed group; the level decreased in the flax oil group. The ratio of prostaglandin F1 alpha/thromboxane B2 was preserved in the flax oil group only. In conclusion, the dietary flax seed and flax oil attenuated the decline in renal function and reduced glomerular injury with favorable effects on blood pressure, plasma lipids, and urinary prostaglandins. While we have not proven any specific synergistic effects of the constituents of the flaxseed diet,

Topics: 6-Ketoprostaglandin F1 alpha; alpha-Linolenic Acid; Analysis of Variance; Animals; Blood Pressure; Disease Models, Animal; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Kidney; Kidney Failure, Chronic; Ligation; Linseed Oil; Lipids; Male; Nephrectomy; Plants, Edible; Proteinuria; Rats; Rats, Sprague-Dawley; Renal Artery; Seeds; Thromboxane B2

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 effect of orally administered Oenothera Biennis L on chronic renal failure was studied in the partially nephrectomized rats. As compared with the control groups, the group treated with Oenothera showed the following features. 1) Urine protein excretion was reduced; 2) Level of serum cholesterol decreased; 3) Scr maintained the same level as before treatment; 4) Level of PGE1 and PGE2 increased both in renal cortex and medulla; 5) 6-keto PGF1 alpha increased in cortex; 6) Increased TXB2 production was only observed 4 weeks after nephrectomy; 7) Glomerular lesions were more severe in control group. It is concluded that Oenothera Biennis L has beneficial effect on the remnant kidney and may be useful as a kind of conservative treatment for chronic renal failure.

Topics: 6-Ketoprostaglandin F1 alpha; Alprostadil; Animals; Dinoprostone; Drugs, Chinese Herbal; Kidney; Kidney Failure, Chronic; Male; Nephrectomy; Proteinuria; Rats; Rats, Wistar; Thromboxane B2

Some of luteinizing hormone (LH) isoforms can stimulate renal growth. The objective of this study is to determine whether the administration of LH modifies subtotal nephrectomy-induced chronic renal failure. Castrated 3/4-nephrectomized male rats were divided into four groups of seven each and fed a low-protein (6%) diet. Ovine LH with renotropic activity (40 micrograms/day) or vehicle only (control) was given for three weeks or six weeks. Compared with controls, remnant kidney weights (% body weight) in LH-treated rats had increased significantly at three weeks (0.385 +/- 0.019 vs 0.443 +/- 0.052, P less than 0.02), but not at six weeks (0.281 +/- 0.004 vs 0.272 +/- 0.013). 24 h creatinine clearance (ml/day/100 g body weight) increased significantly both by three weeks (242 +/- 58 vs 301 +/- 36, P less than 0.05), and six weeks (323 +/- 55 vs 395 +/- 10, P less than 0.01). Urinary thromboxane B2 excretion increased in LH-treated rats, suggesting that hemodynamic changes may play a role in increasing creatinine clearance. Our results suggest that renotropically active oLH stimulated the glomerular function in castrated rats with reduced renal mass. Further study may clarify its clinical usefulness.

Topics: Animals; Castration; Creatinine; Hemodynamics; Kidney Failure, Chronic; Kidney Glomerulus; Luteinizing Hormone; Male; Nephrectomy; Organ Size; Rats; Rats, Inbred Strains; Sheep; Testis; Thromboxane B2

The propensity for renal failure associated with obstructive jaundice and liver disease may be related to enhanced vasoconstriction of the renal vascular bed with resultant decreases in renal blood flow. Renal sympathetic nervous activity may be a mediator of this effect. The increased renal production of prostaglandins which has been observed in previous models of bile duct ligation may serve to counterbalance the effects of such vasoconstricting influences. This study was undertaken to assess the effect of bile duct ligation on renal function and prostaglandin production in the rat. Furthermore, this study was designed to determine if renal sympathetic nerve activity contributes to the development of renal failure after bile duct ligation. Sprague-Dawley rats underwent either sham operation (n = 8), bilateral renal denervation (n = 10), bile duct ligation alone (n = 11), or bile duct ligation and bilateral renal denervation (n = 10). Renal function was assessed before and 4 days after operation. Bile duct ligation resulted in a 46% decrease in creatinine clearance (p less than 0.01), a 33% decrease in urinary sodium excretion (p less than 0.01), a twofold increase in urine flow (p less than 0.01), and twofold increases in urinary excretion of PGE2, 6-keto-PGF1 alpha, and thromboxane B2 (p less than 0.01). Renal denervation did not prevent the decreases in creatinine clearance and sodium excretion seen after bile duct ligation and had no effect on the changes in urine flow and prostaglandin excretion. These findings demonstrate that bile duct ligation in the rat results in impaired renal function, accompanied by increases in renal prostaglandin production. In addition, this study indicates that the perturbations in renal function and renal prostaglandin production induced by bile duct ligation are not mediated by renal sympathetic nerve activity.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Bile Ducts; Cholestasis; Denervation; Dinoprostone; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Ligation; Male; Prostaglandins; Rats; Rats, Inbred Strains; Sympathetic Nervous System; Thromboxane B2

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

Haemostatic activation was measured in patients with either non-diabetic chronic renal failure (CRF) or diabetic nephropathy. We have investigated the relationship between these haemostatic markers and the rate of progression of renal failure. When compared with age- and sex-matched healthy controls, both patient groups showed significantly elevated plasma concentrations of D dimer, von Willebrand factor antigen (vWFAg), and C-reactive protein (CRP) (all P less than 0.001), as well as an increase in spontaneous platelet aggregation (P less than 0.01). Plasma concentration of platelet factor 4 was slightly but not significantly increased. Serum thromboxane was subnormal (P less than 0.01). Multiple regression analysis showed that in non-diabetic CRF proteinuria and serum TxB2 were independently related to the rate of progression of renal failure; in diabetic nephropathy proteinuria and vWFAg were independently related to the rate of progression. In both groups the relationship was stronger with proteinuria (standardised regression coefficients 0.56 and 0.45 respectively) than with serum TxB2 (0.29) or with vWFAg (0.37). We have found haemostatic activation in both non-diabetic and diabetic progressive renal failure. Proteinuria, and also in this study serum TxB2 and vWFAg, appear to be determining factors in the progression of renal failure, and their measurement may have prognostic value.

Topics: Adolescent; Adult; Aged; Antigens; Diabetic Nephropathies; Female; Glomerulosclerosis, Focal Segmental; Hemostasis; Humans; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Platelet Activation; Proteinuria; Thromboxane B2; von Willebrand Factor

Measurement of serum thromboxane B2 (TXB2) and 6-keto-prostaglandins F1 alpha (6-keto-PGF1 alpha) was carried out in 62 patients of renal diseases. The results showed that decrease of TXB2 and 6-Keto-PGF1 alpha values and TXB2/6-Keto-PGF1 alpha ratio was correlated with the decrease of the renal function and was negatively correlated with the level of serum creatinine. The values of TXB2 and 6-Keto-PGF1 alpha were markedly elevated after hemodialysis in 19 patients. It was found that the difference between patients with and without renal hypertension was statistically significant (P less than 0.05). The results indicated that the inbalance of PG value was one of the causes of uremic hemorrhage, PG takes part in the development of renal hypertension.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Aged; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Nephritis; Renal Dialysis; Thromboxane B2

Topics: Adult; Aged; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Piracetam; Pyrrolidinones; Renal Dialysis; 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

Bleeding time and platelet function tests were performed on 31 patients with progressive chronic renal failure (CRF) due to non-immunological (urological) causes, and compared with 22 healthy controls. Patients were classified as mild (plasma creatinine less than 300 mumol/l), moderate (300-600 mumol/l) or severe renal failure (greater than 600 mumol/l). Bleeding time was rarely prolonged in mild and moderate CRF and mean bleeding time significantly elevated only in severe CRF (p less than 0.005). Haematocrit was the only index which correlated with bleeding time (r = -0.40). Platelet counts, collagen stimulated thromboxane generation, and platelet aggregation responses to ADP, collagen and ristocetin were all either normal or increased in all three CRF groups, but thromboxane production in clotting blood was reduced. Plasma fibrinogen, C reactive protein and von Willebrand factor (vWF) were elevated in proportion to CRF. We found no evidence that defects in platelet aggregation or platelet interaction with vWF prolong the bleeding time in patients with progressive CRF.

Topics: Bleeding Time; Blood Platelets; Humans; Kidney Failure, Chronic; Platelet Function Tests; Thromboxane B2

In order to investigate the possible interaction between oral aspirin and antacids in uremic patients on chronic hemodialysis, we administered to 5 uremic patients: (1) aspirin alone; (2) aluminum-magnesium hydroxide with aspirin; (3) aluminum-magnesium hydroxide followed (two hours) by aspirin; (4) calcium carbonate simultaneously with aspirin; and (5) calcium carbonate followed (two hours) by aspirin. In all the occasions, aspirin was given two hours after a standard lunch. Both antacid preparations induced comparable changes in aspirin mean peak plasma concentration (Cmax), if given simultaneously with aspirin, whereas no difference was found in other pharmacokinetic parameters. When antacids were followed (two hours) by aspirin, both Cmax and time of maximum concentration (Tmax) were significantly altered in respect to the value with aspirin alone. No changes in the time course of post aspirin serum thromboxane B2 were detected when aspirin and antacids were administered simultaneously, but the inhibition of serum thromboxane B2 was delayed when antacids were followed (two hours) by aspirin. These results indicate that the administration of antacids to uremic patients interferes with absorption of oral aspirin. This interference can be minimized if aspirin and antacids are given simultaneously.

Topics: Absorption; Adult; Aluminum Hydroxide; Antacids; Aspirin; Calcium Carbonate; Drug Administration Schedule; Drug Combinations; Drug Interactions; Female; Humans; Kidney Failure, Chronic; Magnesium Hydroxide; Male; Middle Aged; Renal Dialysis; Thromboxane B2

We studied the effects of fish oil on the progression of renal insufficiency in rats with subtotal nephrectomy. Five weeks after a 1-2/3 nephrectomy, sixteen rats were fed two different diets which differed only in fat composition. Lipid in the control diet was primarily beef tallow; that of the experimental diet, menhaden oil. Fish oil-fed rats had significant increases in plasma creatinines, decreases in urinary PGE2 and accelerated death rates. An additional twelve rats underwent 1-1/3 nephrectomies, and the same dietary manipulations, followed by renal clearance, histologic and biochemical studies after 12 weeks on the diets. Fish oil-fed rats again did worse, with decreased glomerular filtration rates and filtration fractions, more proteinuria and more glomerular sclerosis. Glomeruli and slices of cortex, medulla and papillae from rats fed fish oil produced much less PGE2 and TXB2 than dietary controls. Fish oil-induced suppression of renal PGE2 may be deleterious in this model and may outweigh the beneficial effect derived from TXA2 suppression. In contrast to fish oil's potentially therapeutic role in cardiovascular and immune-mediated renal disease, this diet is detrimental in rat renoprival nephropathy. This illustrates the importance of examining the effects of fatty acid manipulation individually for each disease entity.

Topics: Animals; Dinoprostone; Female; Fish Oils; Glomerular Filtration Rate; Kidney Failure, Chronic; Kidney Glomerulus; Nephrectomy; Prostaglandins E; Rats; Rats, Inbred Strains; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents, Non-Steroidal; Depression, Chemical; Dogs; Glomerular Filtration Rate; Kidney; Kidney Failure, Chronic; Kidney Glomerulus; Microcirculation; Prostaglandins; Rabbits; Rats; Thromboxane B2

Plasma thromboxane B2 (TXB2) concentration was measured in 7 cases of terminal renal failure before and after haemodialysis. The TXB2 levels were higher in the investigated group than in the control group (p less than 0.05). Haemodialysis induced a further increase in the TXB2 concentration. Increased thromboxane production may play a part in the pathogenesis of accelerated atherosclerosis in uraemic patients treated with chronic haemodialysis.

Topics: Adult; Female; Glomerulonephritis; Humans; Kidney Failure, Chronic; Male; Middle Aged; Pyelonephritis; Renal Dialysis; Thromboxane B2

The peritoneal generation of arachidonic acid metabolites was studied in eight patients with end-stage renal disease undergoing continuous ambulatory peritoneal dialysis (CAPD) during infection-free periods and during bacterial peritonitis. The prostacyclin metabolite 6-keto-PGF1 alpha was found to be the major prostanoid generated by human peritoneal mesothelium (1090 ng (6h)-1, SEM 86, n = 8) followed by lesser amounts of PGE2 (142 ng (6 h)-1, SEM 26, n = 8), PGF2 alpha (162 ng (6 h)-1, SEM 27, n = 8) and TXB2 (59 ng (6 h)-1, SEM 5, n = 8). During peritonitis a significant increase of all prostaglandins and TXB2 occurred (P less than 0.001). The ratio of the vasodilating prostaglandins and their metabolites (PGE2 and 6-keto-PGF1 alpha) to the vasoconstrictors and their metabolites (PGF2 alpha and TXB2) increased from 6.6 to 10.5 during peritoneal inflammation. Augmented peritoneal clearances of creatinin and urea and increased losses of proteins during peritonitis as well as the enhanced peritoneal generation of prostanoids were reduced to basal values by adequate antibiotic therapy. The present results suggest that the increased peritoneal blood flow during peritonitis, probably responsible for the observed changes of peritoneal transport properties, may be induced by a change in the ratio of vasoactive prostaglandins generated by peritoneal mesothelial cells.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Dinoprost; Dinoprostone; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis; Peritoneal Dialysis, Continuous Ambulatory; Peritonitis; Prostaglandins; Prostaglandins E; Prostaglandins F; Thromboxane B2

Whole blood, allowed to clot at 37 degrees C in glass tubes, synthesized thromboxane A2 (TxA2) as determined by radioimmunoassay for thromboxane B2 (TxB2). The time course for TxB2 synthesis showed no further increase after 60 min and the concentration of TxB2 in serum obtained from 60 normal subjects positively correlated with the whole blood platelet count in EDTA anticoagulated blood from the same donor. Patients with chronic renal failure produced less serum TxB2 than age- and sex-matched controls; they also had lower haematocrits. After re-calculating TxB2 production as a function of platelet count and haematocrit all but one of the patients fell in the range of values obtained for controls. These results suggest that chronic renal failure may not be associated with a cyclooxygenase defect and that clotted whole blood TxB2 production should be expressed as a function of platelet count and haematocrit.

Topics: Adult; Female; Hematocrit; Humans; Kidney Failure, Chronic; Kinetics; Male; Platelet Count; Sex Factors; Thromboxane B2; Thromboxanes

Vascular tissues from uremic patients show increased prostaglandin synthesizing capacity while uremic platelets have decreased thromboxane synthesis. It has been suggested that the platelet defects in uremia are partially corrected by hemodialysis and a correlation with the levels of guanidinsuccinic acid, phenolic acid, creatinine or urea has been demonstrated. In our study 6 patients with end-stage renal disease on RHT, underwent, daily and for ten days, two-hours hemoperfusion, in order to obtain lower levels of toxic metabolites such as creatinine (less than 6 mg/dl.). Before and after this intensive treatment we have evaluated BTG plasmatic levels and thromboxane formation by platelets after thrombin and arachidonic acid stimulation. The thromboxane formation was not increased following this treatment, whereas BTG plasmatic levels were significantly diminished.

Topics: Adult; Beta-Globulins; beta-Thromboglobulin; Blood Platelets; Charcoal; Hemoperfusion; Humans; Kidney Failure, Chronic; Middle Aged; Renal Dialysis; Thromboxane B2; Thromboxanes; Uremia

Topics: Dinoprostone; Humans; Kidney Diseases; Kidney Failure, Chronic; Liver Diseases; Prostaglandins E; Syndrome; Thromboxane B2; Thromboxanes

Topics: 6-Ketoprostaglandin F1 alpha; Calcimycin; Humans; Kidney Failure, Chronic; Macrophages; Methacrylates; Peritoneal Dialysis, Continuous Ambulatory; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

The capacity of leukocytes to produce prostacyclin (PGI2) from endogenous and from platelet-derived endoperoxides was tested in whole blood. During the acute phase of the hemolytic uremic syndrome (H.U.S.), the PGI2-production was lower than the controls, whereas the blood from children with chronic renal failure produced higher amounts. Production of PGI2 by blood from children 3/12 to 6 years after the acute phase of H.U.S. was normal, as was the case with blood from their parents. Furthermore, in two H.U.S.-patients studied serially, the decreased PGI2-production capacity normalized 2 1/2 months after the acute phase.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Child; Child, Preschool; Epoprostenol; Hemolytic-Uremic Syndrome; Humans; Infant; Kidney Failure, Chronic; Leukocytes; Prostaglandins; Thromboxane B2

Vasodilatory prostaglandins function to maintain renal perfusion in patients with cirrhosis and ascites. To evaluate the potential contribution of the vasodilator prostaglandin E2 and the vasoconstrictor metabolite thromboxane B2 to the development of the hepatorenal syndrome, we measured urinary excretion of these products in 14 patients with hepatorenal syndrome and in control populations with acute or chronic liver or kidney failure. Radioimmunoassay measurements were confirmed by bioassay and by mass spectrometry. Prostaglandin E2 was decreased compared with healthy controls (2.2 +/- 0.3 vs. 6.3 +/- 0.8 ng/h, p less than 0.01) and compared with acute renal failure (9.6 +/- 2.1 ng/h) and with alcoholic hepatitis (9.2 +/- 3.3 ng/h). Thromboxane B2 concentration was normal in patients with alcoholic hepatitis (0.12 +/- 0.02 vs. 0.15 +/- 0.03 ng/ml) and minimally increased in acute renal failure (0.18 +/- 0.15 ng/ml), but markedly elevated in hepatorenal syndrome (0.69 +/- 0.15 ng/ml, p less than 0.001). Urinary thromboxane B2 concentration fell with improved renal function in 3 patients who survived. These data suggest an imbalance of vasodilator and vasoconstrictor metabolites of arachidonic acid in patients with the hepatorenal syndrome.

Topics: Acute Disease; Acute Kidney Injury; Adolescent; Adult; Biological Assay; Chronic Disease; Dinoprostone; Female; Humans; Kidney Diseases; Kidney Failure, Chronic; Liver Diseases; Male; Mass Spectrometry; Middle Aged; Prostaglandins E; Radioimmunoassay; Syndrome; Thromboxane B2; Thromboxanes

6 patients with end-stage renal disease underwent hemoperfusion with charcoal columns, for 60 min. Blood samples anticoagulated with 2% EDTA/aspirin solution were obtained from arteriovenous fistulas in the basal condition, 5 min after a bolus injection of heparin (7,500 U), at the end of hemoperfusion, and 30 min after. The study was repeated few days later, in the same patients, two hours after 100 mg aspirin by mouth. TXB2 and 6-keto-PGF1 alpha were assayed with RIA in unextracted (U) and extracted (E) and chromatographed platelet poor plasma (PPP). Platelet counts before and after hemoperfusion were also performed. Low levels of the two prostaglandins were found in plasma; this could be related to the procedures for collection and processing of plasma samples; no significant differences were observed between extracted and unextracted samples: there were slightly higher levels of 6-keto-PGF1 alpha in unextracted samples. After charcoal hemoperfusion there was only a slight and not significant increase of TXB2 and 6-keto-PGF1 alpha; low dose aspirin did not modify significantly plasma levels of the two prostaglandins before hemoperfusion but it reduced TXB2 and 6-keto-PGF1 alpha levels after charcoal hemoperfusion. The platelet count fell (-22%) after charcoal hemoperfusion with heparin alone and in similar manner after low-dose aspirin pretreatment (-24%, 7%).

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aspirin; Charcoal; Hemoperfusion; Heparin; Humans; Kidney Failure, Chronic; Middle Aged; Platelet Count; Thromboxane B2; Thromboxanes

We studied prostacyclin as a substitute for heparin in 12 patients who underwent maintenance hemodialysis. All subjects underwent initial hemodialysis with prostacyclin as the sole anticoagulant; 10 of the 12 were restudied during heparin hemodialysis. Few adverse reactions occurred during prostacyclin hemodialysis in the 10 patients in whom dialysis was performed against a bicarbonate-containing dialysate; however, significant hypotension developed in two subjects when an acetate bath was used. Platelet aggregation progressively decreased during prostacyclin hemodialysis (p less than 0.02), but not during heparin hemodialysis, and returned toward control values after hemodialysis. Platelet thromboxane release decreased during both prostacyclin and heparin hemodialysis. Intradialytic percent decrements in serum urea nitrogen and creatinine were greater during prostacyclin than heparin administration (42 +/- 2.9 percent versus 36 +/- 2.6 percent [p less than 0.05] and 33 +/- 2.6 percent versus 29 +/- 2.1 percent [0.05 less than p less than 0.1], respectively). The plasma concentrations of 6-keto-prostaglandin-F1 alpha, a prostacyclin metabolite, reached peak levels by 120 minutes of hemodialysis and declined biexponentially toward predialysis concentrations during 120 minutes after hemodialysis, thereby providing an index of cumulative prostacyclin dosage. We conclude that prostacyclin is not only a safe alternative to heparin anticoagulation during hemodialysis, but that prostacyclin might also increase the efficiency of hemodialysis.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Anticoagulants; Epoprostenol; Female; Heparin; Humans; Kidney Failure, Chronic; Male; Middle Aged; Platelet Aggregation; Prostaglandins; Radioimmunoassay; Renal Dialysis; Thromboxane B2

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