Factor H autoantibody is associated with atypical hemolytic uremic syndrome in children in the United Kingdom and Ireland

Vicky Brocklebank,Alan D Salama,Larissa Kerecuk,Caroline Booth,Meredith Kinoshita,Shivaram Hegde,David Kavanagh,Thomas P Sheerin,Atif Awan,Rodney D Gilbert,Sally Johnson,Carol Inward,Amrit Kaur,Kevin J Marchbank,Eric Finlay,Patrick R Walsh,Edwin K.S Wong,Kay Tyerman,Stephen D Marks,Mark Fitzpatrick ,Neil Sheerin ,Timothy H.j Goodship ,Michael Almond ,Nicholas J.a Webb

doi:10.1016/j.kint.2017.04.028

Abstract

Factor H autoantibodies can impair complement regulation, resulting in atypical hemolytic uremic syndrome, predominantly in childhood. There are no trials investigating treatment, and clinical practice is only informed by retrospective cohort analysis. Here we examined 175 children presenting with atypical hemolytic uremic syndrome in the United Kingdom and Ireland for factor H autoantibodies that included 17 children with titers above the international standard. Of the 17, seven had a concomitant rare genetic variant in a gene encoding a complement pathway component or regulator. Two children received supportive treatment; both developed established renal failure. Plasma exchange was associated with a poor rate of renal recovery in seven of 11 treated. Six patients treated with eculizumab recovered renal function. Contrary to global practice, immunosuppressive therapy to prevent relapse in plasma exchange–treated patients was not adopted due to concerns over treatment-associated complications. Without immunosuppression, the relapse rate was high (five of seven). However, reintroduction of treatment resulted in recovery of renal function. All patients treated with eculizumab achieved sustained remission. Five patients received renal transplants without specific factor H autoantibody–targeted treatment with recurrence in one who also had a functionally significant CFI mutation. Thus, our current practice is to initiate eculizumab therapy for treatment of factor H autoantibody–mediated atypical hemolytic uremic syndrome rather than plasma exchange with or without immunosuppression. Based on this retrospective analysis we see no suggestion of inferior treatment, albeit the strength of our conclusions is limited by the small sample size.

Highlights

Factor H autoantibodies can impair complement regulation, resulting in atypical hemolytic uremic syndrome, predominantly in childhood
AHUS is associated with mutations in genes encoding complement regulatory proteins, complement factor H (CFH), complement factor I (CFI), and membrane cofactor protein (CD46)[1] and in genes encoding the complement components complement factor B (CFB) and C3 (C3).[1]
A total of 175 children younger than 16 years of age from the United Kingdom and Ireland who were referred to the UK National Atypical hemolytic uremic syndrome (aHUS) center between 2000 and 2015 were examined for FH autoantibodies

Summary

Introduction

Factor H autoantibodies can impair complement regulation, resulting in atypical hemolytic uremic syndrome, predominantly in childhood. Our current practice is to initiate eculizumab therapy for treatment of factor H autoantibody–mediated atypical hemolytic uremic syndrome rather than plasma exchange with or without immunosuppression. Based on this retrospective analysis we see no suggestion of inferior treatment, albeit the strength of our conclusions is limited by the small sample size. Atypical hemolytic uremic syndrome (aHUS) is commonly a consequence of complement dysregulation[1] and is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury.[1] It is rare, with an incidence of 0.42 per million in the United Kingdom,[2] but associated with significant morbidity and mortality. Anti-FH autoantibodies have been shown to be directed against different epitopes, in some reports exclusively[7,8] but in others predominantly[9,10,11] located at the C-terminal of FH; a polyclonal response to both N and C termini has been reported,[10,12] and functional analyses have demonstrated disruption of complement regulation by multiple mechanisms.[12]

Methods

Results

Conclusion