Physiopathologie du Syndrome Hémolytique et Urémique atypique

Abstract

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.

Critical appraisal of eculizumab for atypical hemolytic uremic syndrome

“…Despite case reports of “good” outcomes with plasma therapy (three and five patients, respectively), 21 , 22 in a recent report from the French group (n=214 patients), the mortality rate was higher in children than adults (8% vs 2%) after 4 years of followup, with fatal outcomes, despite initial plasma therapy. 23 , 24 Cataland et al, 25 in a retrospective registry analysis of 19 patients diagnosed with aHUS, found that only six of the 16 patients treated with PE/PI had a complete hematologic and kidney recovery (and in contrast to seven of the nine patients treated with eculizumab). Although the genotype–phenotype correlation data indicate that MCP mutations are associated with a better prognosis than CFH mutations, this is not always straightforward, since there are patients who present severe and life-threatening manifestations with different degrees of response to plasma therapy independently of having an identifiable mutation or not.…”