Clinical Use of Eculizumab and Ravulizumab Prof. Fadi Fakhouri Service of Nephrology and Hypertension, CHUV and Lausanne University, Lausanne, Switzerland. Atypical haemolytic uremic syndrome (HUS) is a devastating form of thrombotic microangiopathy (TMA) affecting predominantly the kidney. Untreated, it carries a high risk of end-stage renal disease: 2/3 of adult and half of affected children progress to end-stage kidney disease, at the first episode of atypical HUS or following one or several relapses. A significant body of clinical, experimental and genetic data have helped unravel the pathogenic mechanisms underlying atypical HUS, namely an overactivation of the complement alternative pathway. This breakthrough in our understanding of the pathogenesis of atypical HUS helped designing a specific treatment. C5 blockade, with the first anti-C5 monoclonal antibody, eculizumab, has dramatically changed the perspective in the management and prognosis of atypical HUS. It is currently estimated that C5 blockade reduces the risk of end-stage kidney disease in atypical HUS adult patients from 50-60% to around 10-15%.  Thus, an accurate and rapid diagnosis followed by an early treatment initiation have become crucial for the optimal management of atypical HUS patients. Nevertheless, there is to date no reliable diagnostic test for atypical HUS and the latter remains a diagnosis by exclusion. Furthermore, long-treatment with C5 blockers carries a risk of infectious complications and the burden of repeated infusions. The availability of the long-acting C5 blocker, ravulizumab, allows extending the interval between infusions from 2 weeks to 2 months. However, data on the efficacy of ravulizumab are still limited compared to eculizumab. Finally, a life-long treatment with a C5 blocker is no more a paradigm that applies to all patients with atypical HUS. In patients with no detected complement gene variants, C5 blockade discontinuation is feasible and safe, as the risk of atypical HUS recurrence is below 5%. In carriers of complement gene rare and pathogenic variants, the risk of relapse varies from 25% to 65% and C5 blocker discontinuation has to be discussed on a case-by-case basis.