[Atypical hemolytic uremic syndrome (aHUS): new insights into pathogenesis leading to novel therapeutic approaches]. / Das atypische hämolytisch-urämische Syndrom (aHUS): neue Erkenntnisse zur Pathogenese mit Implikationen für die Therapie.

The atypical hemolytic-uremic syndrome (aHUS) belongs to the thrombotic mictroangiopathies (TMA). This group of diseases has traditionally been divided on clinical grounds by affected organs into thrombotic-thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS), the latter being termed atypical if not preceeded by diarrhea. Tremendous scientific advances of the last two decases have shown that these clinically overlaping syndromes are caused by distinct molecular mechanisms. The definition of clinical syndromes has therefore been replaced by a TMA-classification on a molecular-mechanistic basis. aHUS is caused by an uncontrolled activation of the alternative complement pathway mostly due to genetic defects. These insights and particularly the development of a specific terminal complement inhibitor have revolutionized the treatment of aHUS and considerably improved its prognosis.

[Pathophysiology of atypical hemolytic uremic syndrome. Ten years of progress, from laboratory to patient]. / Physiopathologie du Syndrome Hémolytique et Urémique atypique. Dix ans de progrès, du laboratoire au patient.

Hemolytic Uremic Syndrome (HUS) is characterized by the triad of hemolytic anemia, thrombocytopenia and acute renal failure. The most frequent form in children is caused by Shiga-toxin producing Escherichia coli. In absence of Shiga-toxin infection, the HUS is called atypical (aHUS). Some HUS are secondary to Streptococcus pneumonia or human immunodeficiency virus infection, cancer, anti-cancer drugs, or cyclosporine. During the last decade, aHUS has been demonstrated to be a disorder of complement alternative pathway regulation. aHUS must be regarded as a complex polygenic disease which results from a combination of genetic risk factors. Approximately 60% of patients have mutations in the genes encoding complement factor H (20-30% of patients), MCP (10-15%), factor I (4-10%), factor B (1-2%) or C3 (5-10%), and 6% have anti-factor H antibodies. Prognosis is severe whereas the clinical features vary according to complement abnormality. aHUS touches both children and adults, but in children very early onset is characteristic of factor H and factor I-HUS, while MCP-HUS is not observed before the age of 1. Half of patients with adult onset have a rapid evolution to end-stage renal disease, but half recover. The best prognosis is in patients with MCP (Membrane Cofactor Protein) mutation and a pediatric onset of the disease, who have a relapsing course, but a risk of end-stage renal disease of only 15-30% at 5 years follow-up. Anti-factor H antibodies-HUS is mainly observed in (pre)adolescents and appears to have a favourable outcome if treated early. There is a high risk of post-transplant recurrence in all groups, except MCP-HUS. These findings have paved the way for innovative therapeutic strategies based on complement blockade, and eculizumab, a monoclonal antibody targeting the human complement component 5, is now widely used to treat aHUS. Mutations in the gene of thrombomodulin and diacylglycerol kinase epsilon (DGKe) have been reported, suggesting the possibility of an alternative or more complex disease-causing mechanism than previously thought.