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.

Keywords: atypical hemolytic uremic syndrome; factor H; plasma exchange; renal reserve; thrombotic microangiopathy.

Figure 1

Anti-factor H antibodies (shown as mean titers, ▴) at onset and 6–12 monthly follow-up over 10 years remain detectable (>150 AU/ml) despite remission. Boxes depict median and interquartile range; whiskers show range of antibody titers at each follow-up visit.

Figure 2

(A) Mean anti-factor H (FH) antibody titers, and (B) Free FH during remission in patients with or without subsequent relapse. Relapses were seen in 12 of 182 (A) and 10 of 44 (B) patients. Generalized estimating equations approach was used on log transformed data. In patients with relapse, the last anti-FH titer and free FH was estimated at median of 1 (0.7–2) months and 5 (2–6.9) months before relapse, respectively. Anti-FH antibody titers ≥1,330 AU/ml or free FH ≤ 440 mg/l predict later relapse.

Figure 3

Probability of renal survival in patients with anti-factor H antibody associated HUS. Patients diagnosed and managed from 2007 to 12 showed 70.8, 59.8, and 59.8% renal survival at 1-, 5-years and at last follow up (interrupted line). Corresponding renal survival in patients managed during 2013-18 (continuous line) was 78.7, 77.1, and 77.1% (log rank P = 0.022).