Personalised management of atypical haemolytic uraemic syndrome

Abstract

Complement mediated atypical haemolytic uraemic syndrome (CaHUS) is a rare kidney disease in which complement activation occurs on endothelial cell surfaces resulting in thrombotic microangiopathy (TMA), characterized by thrombocytopenia, microangiopathic haemolytic anaemia and acute kidney injury. In 50% of individuals an inherited ( &,͕ &/͕ ϰϲ͕ & and ϯ mutations) or acquired (factor H autoantibodies) complement abnormality is identified. Historically management comprised supportive care and plasma exchange and outcomes were poor. The terminal complement inhibitor eculizumab revolutionised management, but increases the risk of meningococcal infection and is very expensive. I undertook a comprehensive genotypic, phenotypic and outcome study of 2000 individuals referred to the National Specialised aHUS Centre in England with presumed aHUS since the 1990s. I demonstrated that treating with eculizumab significantly improves end stage kidney disease (ESKD) free survival in CaHUS. This includes individuals with Factor H autoantibodies, who are not treated with immunosuppression in the UK. My observational data suggests that eculizumab withdrawal has a favourable safety profile. I demonstrated the importance of noncomplement genes and eculizumab non-response in aHUS. I identified individuals with previously described primary genetic TMAs and found that for '< aHUS TMA episodes resolve regardless of management, and relapses only occur in early childhood. I did not find evidence suggesting a significant role for complement, or treatment with eculizumab. I also identified novel primary genetic TMAs caused by mutations in RNA processing genes as well as genetic secondary TMAs, which are eculizumab non-responsive. I have shown that in the era of complement inhibiting therapy clinical outcomes in aHUS are still contingent on genotype, which predicts both response to treatment and relapse rate upon treatment withdrawal. Precise diagnostic evaluation therefore contributes to the development of a personalised approach to management of atypical haemolytic uraemic syndrome in which the use of complement inhibiting therapy is individualised.