Clinical, epidemiological and molecular aspects of hemolytic uremic syndrome

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.