6-ketoprostaglandin-f1-alpha and Hemolytic-Uremic-Syndrome

The role of prostacyclin (PGI2) in the pathogenesis of haemolytic uraemic syndrome (HUS) is controversial. In part, confusion has been caused by failure to distinguish between two main sub-types of the syndrome: extrinsic, diarrhoea-associated HUS (D+ HUS), usually caused by infection with verocytotoxin-producing Escherichia coli or Shigella dysenteriae, and the heterogeneous group of non-prodromal forms where intrinsic factors predominate (D- HUS). This paper critically reviews data confined to D+ HUS. Two methods have been used to assess PGI2 synthesis; the generation of PGI2 from endothelium in the presence of HUS plasma in vitro and the measurement of stable metabolites in body fluids. No concensus could be reached with regard to the former. The reported increase of PGI2 stable metabolites in plasma may represent reduced clearance or increased carriage by plasma lipids. Apparent differences between studies of urinary excretion of PGI2 metabolites may reflect the way excretion was expressed. If the metabolite concentration is factored for urinary creatinine, it appears that renal excretion and thus renal synthesis of PGI2 is reduced. However, these are insufficient data on which to attribute the pathogenesis of D+ HUS to disordered PGI2 metabolism.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Diarrhea; Endothelium, Vascular; Epoprostenol; Gas Chromatography-Mass Spectrometry; Hemolytic-Uremic Syndrome; Humans; Radioimmunoassay; Rats

Shiga toxin (Stx) and lipopolysaccharide (LPS) both participate in the pathogenesis of post-diarrheal (D+) hemolytic uremic syndrome (HUS), but little is known about factors that modulate the host response to these toxins. Prostacyclin (PGI(2)) is a potent renal vasodilator and inhibitor of platelet aggregation and adhesion. An inability to produce PGI(2) in response to endothelial cell injury could drive the pathogenic cascade. We therefore used a baboon model of HUS to measure PGI(2 )production following the administration of Stx and LPS.. Shiga toxin-1 (Stx-1), with and without LPS, was administered intravenously to baboons in various doses and schedules. 6-keto-PGF(1)alpha, the stable metabolite of PGI(2), was measured by ELISA in the plasma and urine.. Plasma concentrations did not change significantly. Urine values increased significantly in some groups, but not in others, and HUS developed both in animals that did and did not exhibit a significant increase in urinary PGI(2) production.. Renal PGI(2) biosynthesis appears to be affected by the dose and rate of Stx administration, and the timing of LPS infusion. PGI(2) does not protect our primate model from developing HUS.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Disease Models, Animal; Epoprostenol; Hemolytic-Uremic Syndrome; Humans; Kidney; Lipopolysaccharides; Papio; Shiga Toxin 1

The role of prostacyclin in the pathogenesis of haemolytic uraemic syndrome was evaluated in 11 children with acute shigellosis. Plasma concentrations of 6-keto prostaglandin, F1 alpha, a stable metabolite of prostacyclin, were measured by radioimmunoassay during acute illness, early convalescence, and after clinical recovery. Its concentration was low during acute illness in each patient, returning to normal concentrations or above at the time of the last sample. These results suggest that plasma prostacyclin may be involved in the development of the syndrome.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Blood Coagulation; Child; Child, Preschool; Dysentery, Bacillary; Epoprostenol; Female; Hemolytic-Uremic Syndrome; Humans; Infant; Male

We compared the effect of plasma from 19 children with hemolytic uremic syndrome (HUS) on prostacyclin (PGI2) production by fresh rat aortic rings to the effect of plasma from 17 age- and sex-matched normal children, taking into account the PGI2 baseline aortic production (PGI2 release in presence of buffer, 21 determinations). After 10, 20, 30, 40, and 60 minutes incubation of rat aortic tissue with either plasma or buffer, the presence of PGI2 was studied by measuring by radioimmunoassay (RIA) the concentration of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha). 6-keto-PGF1 alpha production increased with time in the two groups of plasma samples and in the presence of buffer, but 6-keto-PGF1 alpha production (ng/mg dried tissue) after 30 minutes incubation and mean 6-keto-PGF1 alpha production (slope of regression line, ng/mg/min) were significantly (P less than 0.01) lower in the presence of normal plasma compared with buffer, and significantly (P less than 0.01) higher in the presence of HUS plasma compared with normal plasma. There was no significant difference between buffer and HUS plasma. We conclude that, under our experimental conditions, normal plasma had an inhibitory activity on 6-keto-PGF1 alpha production by rat aorta. This inhibitory activity was absent in HUS plasma.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Child; Child, Preschool; Epoprostenol; Female; Hemolytic-Uremic Syndrome; Humans; In Vitro Techniques; Infant; Male; Radioimmunoassay; Rats; Rats, Inbred Strains

Evidence supports the hypothesis that plasma prostacyclin activity is deficient in hemolytic-uremic syndrome (HUS). We studied 2 adult patients with HUS. Plasma levels of 6-keto-PGF1 alpha, the stable metabolite of prostacyclin, were measured by radioimmunoassay. Both patients were found to have elevated 6-keto-PGF1 alpha levels. These findings are in contradiction with the prostacyclin deficiency hypothesis and with earlier reports of low or undetectable plasma levels of this metabolite. The patients were treated with IV prostacyclin after a single plasma exchange. The first patient, admitted with advanced renal failure, obtained a rapid remission but renal function did not recover; the second patient, admitted with a less pronounced degree of renal failure, reacted slowly to therapy but renal function partially recovered. We believe that, if any benefit is to be expected from prostacyclin therapy in HUS, it should be started early in the course of the disease.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Epoprostenol; Female; Hemolytic-Uremic Syndrome; Humans; Male; Radioimmunoassay

Reports from Europe suggest that the hemolytic-uremic syndrome is associated with an impaired ability to produce prostacyclin (prostaglandin [PG] I(2)), a potent inhibitor of platelet aggregation and thrombus formation. In comparing the production of PGI(2) by cultured endothelial cells using serum obtained from 22 children with the hemolytic-uremic syndrome with values obtained using serum from 22 normal children, we found that cultured endothelial cells produced less PGF(1alpha) (the stable metabolite of PGI(2)) when incubated with affected serum. The relationship of this observation to the pathogenesis of the hemolytic-uremic syndrome is unclear.

Topics: 6-Ketoprostaglandin F1 alpha; Child; Endothelium; Follow-Up Studies; Hemolytic-Uremic Syndrome; Humans; In Vitro Techniques

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Age Factors; Child; Child, Preschool; Hemolytic-Uremic Syndrome; Humans; Infant; Prostaglandins; Thromboxane B2

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

Topics: 6-Ketoprostaglandin F1 alpha; Aorta; Female; Hemolytic-Uremic Syndrome; Humans; Male; Prostaglandins F; Purpura, Thrombotic Thrombocytopenic