Abstract
Background: Atypical hemolytic uremic syndrome (aHUS), an important cause of acute kidney injury (AKI), is characterized by dysregulation of the alternative complement pathway. Autoantibodies to factor H (FH), a chief regulator of this pathway, account for a distinct subgroup. While high anti-FH titers predict relapse, they do not correlate well with disease activity and their functional characterization is required.Methods: Of 781 patients <18-year-old of aHUS in the nationwide database from 2007 to 2018, 436 (55.8%) had anti-FH antibodies. Clinical features and outcome of patients managed in the last 6-year (n = 317) were compared to before (n = 119). In plasma samples of 44 patients, levels of serial circulating FH immune complexes (CIC), free FH, soluble terminal complement complex (sC5b-9), sheep red blood cell (SRBC) lysis and epitope specificity (n = 8) were examined. Functional renal reserve, ambulatory hypertension, left ventricular hypertrophy (LVH), and proteinuria were evaluated in a subset.Results: Patients presented with markedly elevated anti-FH titers (10,633.2 ± 998.5 AU/ml). Management varied by center, comprising plasma exchange (PEX; 77.5%) and immunosuppression (73.9%). Patients managed in the last 6-year showed better renal survival at mean 28.5 ± 27.3 months (log rank P = 0.022). Mean anti-FH titers stayed 700–1,164 AU/ml during prolonged follow-up, correlating with CIC. Patients with relapse had lower free-FH during remission [Generalized estimating equations (GEE), P = 0.001]; anti-FH levels ≥1,330 AU/ml and free FH ≤440 mg/l predicted relapse (hazards ratio, HR 6.3; P = 0.018). Epitope specificity was similar during onset, remission and relapse. Antibody titer ≥8,000 AU/ml (HR 2.23; P = 0.024), time to PEX ≥14 days (HR 2.09; P = 0.071) and PEX for <14 days (HR 2.60; P = 0.017) predicted adverse renal outcomes. Combined PEX and immunosuppression improved long-term outcomes (HR 0.37; P = 0.026); maintenance therapy reduced risk of relapses (HR 0.11; P < 0.001). At 4.4±2.5 year, median renal reserve was 15.9%; severe ambulatory, masked and pre-hypertension were found in 38, 30, and 18%, respectively. Proteinuria and LVH occurred in 58 and 28% patients, respectively.Conclusion: Prompt recognition and therapy with PEX and immunosuppression, is associated with satisfactory outcomes. Free-FH predicts early relapses in patients with high anti-FH titers. A significant proportion of impaired functional reserve, ambulatory hypertension, proteinuria and LVH highlight the need for vigilant long-term follow-up.
Highlights
METHODSHemolytic uremic syndrome (HUS) is an important cause of acute kidney injury (AKI) in children [1, 2]
From March 2007 to August 2018, 436 (55.8%) of 781 patients from 30 centers in the nationwide database were diagnosed as having anti-factor H (FH) associated atypical hemolytic uremic syndrome (aHUS) (Supplementary Figure 1)
Proportion of patients with anti-FH antibodies younger than 4-year, between 4–11 and 11–18 year at presentation were 20.8, 73.8, and 52.0%, respectively; five patients presented in infancy (Supplementary Figure 2)
Summary
Hemolytic uremic syndrome (HUS) is an important cause of acute kidney injury (AKI) in children [1, 2]. While the majority of patients follow gastrointestinal infection with Shiga toxin associated organisms, abnormalities in the complement and coagulation pathways are associated with atypical hemolytic uremic syndrome (aHUS) [1, 3]. High levels of antibodies at disease onset or relapse are believed to induce functional deficiency of FH; their decline in response to plasmapheresis is associated with disease remission [7, 9, 10]. A dose-response relationship is not established as many patients show high antibody levels even during remission, emphasizing the need to evaluate other markers of complement activation. Atypical hemolytic uremic syndrome (aHUS), an important cause of acute kidney injury (AKI), is characterized by dysregulation of the alternative complement pathway. While high anti-FH titers predict relapse, they do not correlate well with disease activity and their functional characterization is required
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