Objective: To characterize genetic findings, clinical phenotypes, kidney outcomes, and eculizumab withdrawal in adults with atypical hemolytic uremic syndrome (aHUS).
Materials and Methods: This single-center, retrospective study reviewed 44 adults who underwent next-generation sequencing (NGS)-based aHUS/thrombotic microangiopathy (TMA) panel testing between 2010 and 2022. After excluding patients with secondary TMA, individuals undergoing asymptomatic donor evaluations, and those with insufficient follow-up, 24 patients were included in the primary cohort. Given the small and unequal genetic subgroups, analyses were descriptive, without formal between-group hypothesis testing.
Results: All 24 patients underwent therapeutic plasma exchange, 15 received eculizumab, and 18 required hemodialysis during the acute phase. Final patient-level genetic classifications were pathogenic/likely pathogenic in 2 patients (8.3%), variants of uncertain significance (VUS) in 6 (25.0%), and benign/likely benign variants or no significant complement variants in 16 (66.7%). During follow-up, 12 patients (50.0%) had an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m², and 7 (29.2%) progressed to end-stage kidney disease. Among the 15 eculizumab-treated patients, 2 had pathogenic/likely pathogenic variants, 5 had VUS, and 8 had benign/likely benign variants or no significant complement variants. Eculizumab was discontinued in all 15 patients. After excluding 5 patients who discontinued treatment because of irreversible kidney dysfunction or nonresponse, 2 of the remaining 10 monitored patients experienced relapse. One patient carried the likely pathogenic CD46 p.Tyr189Asp variant, whereas the other had no pathogenic complement variant but carried the benign/likely benign C3 p.Arg102Gly variant. Eculizumab was restarted in both patients.
Conclusion: Severe kidney outcomes and relapse following treatment withdrawal were not confined to a single genetic category. Genetic findings should inform, but not independently determine, surveillance strategies or decisions regarding complement inhibitor withdrawal. Longitudinal clinical phenotype, kidney recovery, prior disease severity, and the capacity for rapid retreatment remain essential considerations.