Renal prostacyclin biosynthesis is reduced in children with hemolytic- uremic syndrome in the context of systemic platelet activation

Previous studies have reported various abnormalities in prostacyclin (PGI₂) synthesis and metabolism in hemolytic-uremic syndrome (HUS). However, the conclusions of most of these studies are based on in vitro or ex vivo experiments that only give an indirect estimate of the actual biosynthesis in vivo. We studied the urinary excretion of PGI₂ metabolites, taken as a marker of the actual biosynthesis, in six children with HUS during the acute phase of the disease and again when remission was achieved. Eight age- and sex-matched healthy children were studied as controls. Since HUS is also associated with platelet activation and consumption, we also studied the urinary excretion of thromboxane A₂ (TxA₂) metabolites. Urinary PGI₂ and TxA₂ metabolites were assessed by radioimmunoassay after high-performance liquid chromatography (HPLC) purification. Urinary excretion of the PGI₂ hydrolysis product, 6-keto-PGF(1α), was significantly reduced in children with acute HUS as compared with controls, indicating a defective renal synthesis of PGI₂. A significant inverse correlation was found between urinary 6-keto-PGF(1α) and blood urea nitrogen (BUN), as well as plasma creatinine. At remission, urinary 6-keto-PGF(1α) levels increased to values higher than those of controls. By contrast, the urinary excretion of the major PGI₂ β-oxidation product, 2,3-dinor-6-keto-PGF(1α), was comparable to controls, indicating normal systemic PGI₂ biosynthesis. The urinary excretion of both TxA₂ hydrolysis product, TxB₂, and the major β-oxidation metabolite, 2,3-dinor-TxB₂, were lower than normal in the acute phase of HUS if expressed as absolute values. However, when corrected for the platelet number, urinary 2,3-dinor-TxB₂ appeared significantly elevated over the normal range. We conclude that renal, but not systemic, PGI₂ biosynthesis is reduced in the context of systemic platelet activation in HUS of children studied in the acute phase of the disease. Such biochemical alterations may explain the predominant renal localization of the microvascular lesions in children with HUS.