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

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.

Keywords: acute kidney injury; atypical hemolytic uremic syndrome; complement; factor H autoantibodies; thrombotic microangiopathy.

Figure 1

Age and sex at first presentation of factor H autoantibody-associated atypical hemolytic uremic syndrome. The median age at presentation was 8 years (range, 1–15 years). There was a male predominance: 65% male, 35% female.

Figure 2

(a) Initial titers of factor H autoantibody and circulating immune complexes of factor H/autoantibody. In all patients the initial FH autoantibody titer was above the international consensus positive threshold of 100 relative units (dashed line). In some, but not all patients, circulating immune complexes were detected. (b) Initial factor H level. The dashed line represents the lower limit of the normal range. Fifteen patients (88%) had a normal FH level. Two patients (12%) had a low FH level, and neither had a CFH rare genetic variant. The patient with a rare genetic variant in CFH had a normal FH level. aFH, FH autoantibody; CiC, circulating immune complexes; FH, factor H; RU, relative units.

Figure 3

Changes in factor H autoantibody titers over time for 10 patients. In 10 patients, anti–FH autoantibody titer measurements at multiple time points up to 163 months after the first presentation were available. In 1 patient, the titer fell below the international standard. The maintenance treatment received by each patient is shown. E, on eculizumab; FH, factor H; HD, hemodialysis; N, no specific maintenance treatment; T, transplanted (immunosuppressed).

Figure 4

Autoantibody reactivity with short factor H fragments. Autoantibody binding to FH fragments (corresponding to SCRs 1–7, 8–15, 16–18, and 19–20) and a FH–related protein 1 fragment (SCR 4–5). In 31% of patients the antibodies were polyclonal. In 69% of patients the antibodies were monoclonal, and in 91% of these the binding was to SCRs 19–20. Two of the 3 patients with 2 copies of CFHR1 had antibodies that bound predominantly to SCRs 1–7. FHR1, factor H–related protein 1; ID, identification; NCL, Newcastle; RU, relative units; SCR, short consensus repeat.

Figure 5

Evolution of first episode according to treatment. In children managed supportively, ERF did not develop; treatment with PEX was associated with a high rate of relapse if ERF did not occur, and ERF did not develop in any patient treated with eculizumab or no patient experienced relapse. No patient was treated with immunosuppression at the initial presentation. *Includes PEX alone (n = 8), PEX plus i.v. IgG (n = 2), PEX plus corticosteroids (n = 1). **Defined as recurrence >1 month after presentation and >15 days after disease remission. ^†One patient (patient 10) experienced multiple relapses and was maintained on regular PEX. ERF, established renal failure; PEX, plasma exchange.