Clinical and Immunological Profile of Anti-factor H Antibody Associated Atypical Hemolytic Uremic Syndrome: A Nationwide Database

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.

Anti-complement factor H (CFH) antibodies and a novel CFH gene mutation in an atypical hemolytic uremic syndrome patient with complement activation of the classical pathway

“…In a different pattern from typical aHUS cases, this case showed the activation of the classical pathway and SLE-like symptoms, which may be caused by immune complexes of multiple autoantibodies that bind the C1q, leading to type 3 hypersensitivity, and consequently SLE-like symptoms, similar to serum disease or type 3 allergy. In fact, the levels of anti-CFH antibody in this patient were higher than those in the previous cases [7,8]. Although we did not measure C1q level and immune complexes binding to C1q, his C4 and C3 levels decreased together and he had multiple autoantibodies, suggesting the activation of the classical pathway rather than the alternative or lectin pathways.…”

Clinical and Genetic Characteristics of Atypical Hemolytic Uremic Syndrome in Children: A Chinese Cohort Study

“…The value is similar to that found in the Indian cohort [29], where more than half of the patients (55.8%) had anti-CFH antibodies. However, the European cohort [30] had a significantly lower antibody-positive ratio, about 10%. This phenomenon cannot be simply attributed to the predisposition of CFHR1/3 deletion among Chinese, as this polymorphism is found in ≤2% of Chinese people, which is lower than 2 and 9% of Europeans and Indians [31].…”

Membrane‐filtration based plasma exchanges for atypical hemolytic uremic syndrome: Audit of efficacy and safety

“…Rates of procedure and access related AE are low, even in young children. Combining PEX with immunosuppression is useful in anti‐FH associated disease . Outcomes do not differ markedly between patients with or without anti‐FH associated aHUS.…”