*Purpose: Eculizumab has revolutionized the management of atypical Hemolytic Uremic Syndrome (aHUS). In 2012, the French aHUS Study Group issued recommendations to advocate the prophylactic use of eculizumab in kidney transplant recipients with high risk of post-transplant aHUS recurrence. Risk stratification was based on the study of post-transplant outcomes in the historical aHUS cohort. This highly-tailored strategy was recently adopted by the 2016 KDIGO guidelines, but has not been assessed so far.

*Methods: A nationwide retrospective multicenter study was conducted, involving 32 centers. Inclusion criteria were the following: 1- aHUS diagnosed before the transplantation; 2- An extensive complement work-up undertaken at the national reference laboratory; 3- At least one adult-onset kidney transplantation performed after January 1^st 2007. High-risk transplantations included those undertaken in patients with previous post-transplant recurrence and/or with pathogenic variants in CFH/C3/CFB. A negative complement screening or a pathogenic variant in CFI were referred to as moderate risk.

*Results: Overall, 126 kidney transplantations, performed in 116 patients were included into the study. In 82 (70.7%) of them immunological and genetic screening identified a dysregulation of the complement alternative pathway. Overall, 58.7 and 33.3% of the transplantations were considered at high risk and moderate risk of aHUS recurrence. Full-blown clinical and subclinical aHUS recurrence occurred in 30 (23.8%) and 12 (9.5%) of the transplantations. Multivariate analysis identified high-risk group (HR=2.94; p=0.003) and prophylactic eculizumab (HR=0.06; p<0.0001) as factors associated independently with an increased and reduced risk of recurrence, respectively. Moreover, aHUS recurrence (HR=3.74; p=0.006) and eculizumab therapy (HR=0.23; p=0.003) were independently associated with increased and decreased risks of graft loss, respectively, while preformed DSA (HR=3.11; p=0.051) fell short of statistical significance. Eculizumab prophylaxis significantly reduced the rates of recurrence in both high- (p<0.001) and moderate-risk (p=0.02) transplantations. More importantly, graft survival was significantly improved by eculizumab prophylaxis in the high-risk transplantation group (p<0.02). Eculizumab discontinuation did not lead to subsequent relapses in the moderate-risk (0/10), unlike in the high-risk (2/7), transplantations group.

*Conclusions: The present study demonstrates that the outcome of kidney transplantation in aHUS patients has dramatically improved since eculizumab approval and supports individualized risk stratification based on complement investigations and medical history.

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