Characterization of Patients with aHUS and Triggering/Associated Events, with and without Complement Pathogenic Variants or Anti-Cfh Antibodies: A Global aHUS Registry Analysis

Abstract

Background: Atypical hemolytic uremic syndrome (aHUS) is a rare complement-mediated thrombotic microangiopathy (TMA) and can manifest with or without a triggering/associated event. Approximately 50-60% of patients with aHUS present with anti-complement factor H (CFH) autoantibodies or pathogenic variants in genes associated with the complement system, typically impairing regulation of the alternative pathway. This study, using data from the Global aHUS Registry (NCT01522183), assessed the frequency of aHUS triggering/associated events and demographics/characteristics at clinical presentation in patients with or without genetic variants/anti-CFH antibodies. Methods: The Global aHUS Registry collects data on patients with aHUS to develop a greater understanding of the condition and advance disease management. The registry contains information on patients from >100 sites across more than 20 countries. At the time of analysis (June 01, 2022), 1947 patients had been enrolled in the registry since its inception in April 2012. Patients with one triggering/associated event prior and up to aHUS onset and who were within the registry between Apr 2012-Jun 2022 were included in this analysis. Patients with an alternative diagnosis established after enrollment were excluded. Patients were stratified by presence (positive) or absence (negative) of pathogenic genetic variants and/or anti-CFH antibodies; the most frequently assessed genes included C3, CD46, FH, FI, FB, and THBD. Results: Patient demographics, clinical characteristics, and laboratory parameters are presented in Table 1; the frequencies of triggering/associated events are presented in Table 2. In total, 307 patients met inclusion criteria: 90 (29.3%) were positive and 99 (32.2%) were negative for pathogenic genetic variants/anti-CFH antibodies; the other 118 (38.4%) had an unknown genetic status. Median age at aHUS onset was 26.8 years in the positive cohort and 36.5 years in the negative cohort. In the negative population, all 99 patients were tested for pathogenic variants in at least five genes and anti-CFH antibodies, with no variants or antibodies identified. In the positive population, 84 (93.3%) patients had at least one pathogenic variant, while 22 (24.4%) tested positive for anti-CFH antibodies; 16 (17.8%) patients had a pathogenic variant and anti-CFH antibodies. Positive patients were more frequently female and were typically younger at aHUS onset than negative patients, with a greater proportion of pediatric (<18 years) patients observed. Incident trigger type and TMA frequency were comparable between pathogenic variant/anti-CFH antibody positive and negative patients, with similar estimated glomerular filtration rates (eGFR) at aHUS onset, alongside similar numbers of subsequent TMAs and proportions of patients experiencing extra-renal manifestations following aHUS onset. The most common triggering/associated events were pregnancy (19/90, 21.1%), acute infection (15/90, 16.7%), and aHUS occurring ≤30 days from birth (12/90, 13.3%) in the positive cohort, and malignancy (26/99, 26.3%), pregnancy (16/99, 16.2%), and acute infection (15/99, 15.2%) in the negative cohort. Conclusions The similarities in incident trigger type, TMA frequency, clinical presentation and disease severity may potentially arise from the presence of an unknown pathogenic variant, or a less well-established pathogenic mechanism, in negative patients. Further, younger patients with a triggering/associated event were more likely to present with pathogenic variants/anti-CFH antibodies; these patients may be at a higher risk of developing aHUS earlier due to both a genetic predisposition and a subsequent triggering/associated event. The presence of larger proportions of 'birth-triggered' and 'pregnancy-triggered' aHUS patients in the positive cohort may explain the sex and age distribution data. The longer intervals between triggering/associated event and aHUS onset, particularly in the negative cohort, may be explained by the presence of subclinical/undetected disease following the initial triggering/associated event, followed by subsequent clinical identification/presentation. Together, these data reiterate that the presence of triggering/associated events does not exclude the concurrent presence of pathogenic variants and/or anti-CFH antibodies in patients with aHUS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal