Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy characterized by intravascular hemolysis, thrombocytopenia, and acute kidney failure. HUS is usually categorized as typical, caused by shiga-toxin producing E. coli (STEC) infection, atypical HUS (aHUS), usually caused by uncontrolled complement activation, or secondary HUS with a coexisting disease. In recent years, a general understanding of the pathogenetic mechanisms driving HUS has increased. Typical (i.e. STEC-HUS) follows a gastrointestinal infection with STEC, while aHUS is associated primarily with mutations or autoantibodies leading to dysregulated complement activation. Amongst the 30-50% of HUS patients with no detectable complement defect, some have either impaired diacylglycerol kinase epsilon activity, cobalamin C deficiency, or plasminogen deficiency. Some have secondary HUS with a coexisting disease or trigger such as autoimmunity, transplantation, cancer, infection, certain cytotoxic drugs, or pregnancy. The common pathogenetic features in STEC-HUS, aHUS, and secondary HUS are simultaneous damage to endothelial cells, intravascular hemolysis, and activation of platelets leading to a procoagulative state, formation of microthrombi, and tissue damage. In this review, the differences and similarities in the pathogenesis of STEC-HUS, aHUS, and secondary HUS are discussed. Common for the pathogenesis seems to be the vicious circle of complement activation, endothelial cell damage and platelet activation, and thrombosis. This process can be stopped by therapeutic complement inhibition in most aHUS patients, but not for example those with a DGKE mutation, and some patients with STEC-HUS or secondary HUS. Therefore, understanding the pathogenesis of the different forms of HUS may prove helpful in clinical practice.
- Submitted November 2, 2016.
- Accepted February 7, 2017.
- Copyright © 2017 American Society of Hematology
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