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K. El Karoui et al.
ment regulation but also superimposed complement- independent vascular injury.
Interestingly, 12/76 (16%) HE-aHUS patients present- ed with a medical history of long-lasting hypertension or left ventricular hypertrophy suggesting previously undi- agnosed high blood pressure. Among these 12 patients, seven had rare complement genetic variants. Thus, even in the presence of a history of hypertension, patients with HE-aHUS should be studied for rare complement genetic variants. Among HE-aHUS patients, only slight differences in age and platelet count were observed between those with or without rare complement vari- ants. However, low C3 was significantly more frequent in cases with rare complement variant. Thus, patients with HE-aHUS and low C3 levels should be strongly sus- pected of having an underlying complement-mediated disease.
Our results showed that a diagnosis of HE-aHUS is rel- evant from a prognostic standpoint. For the first time, we identified HE at onset as a new clinical factor which could be associated with long-term prognosis. The renal prog- nosis was dramatically better in patients without either HE or complement variants than in all other groups, even in the absence of eculizumab treatment. Similarly, a recent study showed that discontinuation of eculizumab after 6–12 months of treatment seems safe in patients with no documented complement variants.27 Notably, HE-aHUS patients had a severe renal prognosis even in the absence of a rare complement variant, contrary to that of noHE-aHUS patients, in whom renal prognosis was associated with rare complement variants. Furthermore, the dramatic therapeutic effect of eculizumab in noHE- aHUS patients was not observed in HE-aHUS patients, despite a trend to improved prognosis in HE-aHUS patients with a complement variant treated with eculizumab. Overall, our data allow stratification of patients with highly different prognoses according to the presence or absence of HE or rare complement variants: (i) noHE-aHUS patients without rare complement vari- ants have a favorable prognosis even without eculizumab
treatment; (ii) HE-aHUS and noHE-aHUS patients with rare complement variants have a good therapeutic response to eculizumab; and (iii) HE-aHUS patients with no complement variant have a severe prognosis and unclear benefit from eculizumab treatment.
Our study has several limitations. First, our analysis was based on retrospective data. Of greatest concern may be the lack of blood pressure data in 31% of patients from the aHUS registry, who were therefore excluded from this study. Second, major changes in the management of aHUS occurred during the recruitment period. Only patients diagnosed after 2011 were treated with eculizumab and thus were compared to patients diag- nosed before the era of anti-complement therapy. A prospective study is therefore essential in order to evalu- ate the effectiveness of the treatment. Finally, the scope of the current study did not include cases in which the cli- nicians considered patients as having HE only or HUS as a direct consequence of high blood pressure. In these cases, clinicians did not perform complement assessment and patients were not enrolled in this study.
In conclusion, our results show that 40% of patients with HE-aHUS have complement dysregulation with pathogenic rare complement variants. HE and comple- ment genetics allow stratification of patients with highly different renal prognoses and suggest new pathophysio- logical pathways involved in HUS.
Acknowledgments
This work was supported by grants from the SFNDT (Société Francophone de Néphrologie, Dialyse et Transplantation) (to KEK), from the Délégation Régionale à la Recherche Clinique, Assistance Publique – Hôpitaux de Paris (Programme Hospitalier de Recherche Clinique (AOM08198) (to VFB), by the EU FP7 grant 2012-305608 (EURenOmics) (to VFB), the Fondation Du Rein (FRM, Prix 2012 FDR) (to VFB), and the Association pour l’Information et la Recherche dans les Maladies Rénales Génétiques (AIRG France). FP is supported by a CARPEM (CAncer Research for PErsonalized Medicine) doctor- al fellowship.
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