Clinical, epidemiological and molecular aspects of hemolytic uremic syndrome

Abstract: Hemolytic uremic syndrome (HUS) is the most common cause of acute renal failure in children in the western world. HUS is characterized by the triad of hemolytic anemia, thrombocytopenia and renal failure. There are two main subtypes of HUS; typical or D+ (D stands for diarrhea) HUS associated with enterohemorrhagic E. coli (EHEC) infection, which accounts for about 90% of all HUS cases, and atypical HUS. Atypical HUS may be associated with uncontrolled activation of the alternative pathway of complement, and in about 70% of cases mutations are found in complement regulators or proteins. In this thesis an epidemiological investigation of a large outbreak of EHEC infections affecting 30 individuals in southern Sweden in 2002 is described. The source of infection was traced to locally produced contaminated cold-smoked fermented sausage. Studies of whole blood from patients with D+HUS demonstrated the presence of platelet-leukocyte complexes and microparticles bearing tissue factor as well as complement C3 and C9. Platelet-leukocyte complexes and the release of blood-cell derived microparticles bearing tissue factor could be induced by incubation of whole blood with Shiga toxin and O157LPS. Similarly, incubation of whole blood with Shiga toxin and O157LPS induced deposition of C3 and C9 on platelet-leukocyte complexes via the alternative pathway. C3 and C9 were also present on microparticles, particularly those released from platelets and monocytes. Simultaneous incubation with both Shiga toxin and O157LPS increased tissue factor and complement deposition. The release of blood cell-derived microparticles bearing tissue factor and complement components could promote prothrombotic and inflammatory mechanisms and thus contribute to the pathogenesis of D+HUS. Complement mutations were investigated in two kindreds with atypical HUS. A novel C3 mutation (V1636A) with increased affinity for factor B was found. Additional mutations and rare polymorphisms were found in C3, factor H, factor I and MCP. The clinical and pathological phenotypes were described, in which different variants of chronic thrombotic microangiopathy could be attributed to common complement mutations.