Clinical bottom line
Atypical hemolytic uremic syndrome (aHUS) is a rare, complement-mediated thrombotic microangiopathy with significant renal involvement and high morbidity. Emerging evidence highlights the therapeutic potential of anti-complement factor B (CFB) therapies targeting dysregulated alternative pathway activation in aHUS patients harboring complement factor B mutations or autoantibodies. Early case reports and mechanistic studies suggest that inhibiting factor B may reduce complement overactivation, ameliorate renal injury, and improve clinical outcomes. However, data remain limited to small cohorts and case series, and the safety and efficacy of anti-factor B agents require validation in larger, controlled studies. Clinicians should consider complement genetic and antibody profiling to identify candidates for these emerging therapies while awaiting robust clinical trial evidence.
What the evidence shows
Atypical HUS is characterized by dysregulation of the alternative complement pathway, often due to genetic mutations or acquired autoantibodies affecting complement regulatory proteins. Complement factor B plays a pivotal role as a component of the C3 convertase complex, and gain-of-function mutations or autoantibodies targeting factor B can drive uncontrolled complement activation and endothelial injury (Bandaru Sai Samyuktha et al., 2022).
Recent case reports have described patients with rare CFB mutations presenting with aHUS and severe renal impairment, where targeted complement inhibition showed promise. For example, Bandaru Sai Samyuktha et al. (2022) reported a rare CFB mutation causing aHUS, highlighting the pathogenic role of factor B dysregulation. Similarly, Pandiyan et al. (2026) described complement-mediated aHUS associated with homozygous CFHR1-CFHR3 deletion and anti-factor H antibodies, underscoring the complexity of complement abnormalities in aHUS and the potential benefit of complement-targeted therapies.
Mechanistic insights from immunobiology studies reveal that anti-factor I and anti-factor B antibodies can exacerbate complement activation, suggesting that neutralizing these factors may restore complement homeostasis (Govindarajan Srinivasavaradan et al., 2020). Moreover, genetic studies implicate calcium-binding domains in complement factor I mutations, which may interact with factor B function, further supporting the rationale for targeting factor B in select patients (Java Anuja et al., 2023).
While eculizumab, a C5 inhibitor, remains the mainstay of treatment for complement-mediated aHUS, it does not directly inhibit factor B. Novel anti-factor B therapies under investigation aim to block the formation or activity of the C3 convertase at an earlier step, potentially offering more precise control of complement activation with fewer off-target effects. However, clinical data on these agents are currently limited to early-phase studies and case reports.
Caveats and uncertainty
The evidence supporting anti-complement factor B therapies in aHUS is preliminary and largely hypothesis-generating. Most data derive from isolated case reports or small case series with heterogeneous patient populations and variable genetic backgrounds (Bandaru Sai Samyuktha et al., 2022; Pandiyan et al., 2026). There is a lack of randomized controlled trials or large observational cohorts to establish efficacy, optimal dosing, and safety profiles.
Complement genetics in aHUS are complex, with multiple interacting mutations and autoantibodies influencing disease phenotype and treatment response (Marinozzi Maria Chiara et al.). The presence of coexisting complement abnormalities, such as anti-factor H antibodies or CFHR deletions, may modulate the effectiveness of anti-factor B therapies and complicate patient selection.
Long-term outcomes and risks of infection or immunosuppression associated with novel complement inhibitors remain uncertain. Additionally, the cost and accessibility of these emerging biologics may limit widespread adoption until further evidence accrues.
How this may change practice
As understanding of complement dysregulation in aHUS deepens, complement factor B emerges as a promising therapeutic target, especially in patients with identified CFB mutations or autoantibodies. Incorporating comprehensive complement genetic and serologic testing into clinical evaluation may help identify candidates who could benefit from anti-factor B therapies.
Pending further validation, clinicians should remain aware of ongoing clinical trials and emerging data on these agents. In refractory or relapsing aHUS cases not fully responsive to C5 inhibition, anti-factor B therapies may represent a future option to tailor complement blockade more precisely.
Multidisciplinary collaboration with nephrologists, hematologists, and immunologists is essential for integrating novel complement-targeted treatments into individualized patient care. Continued research and clinical trial participation will be critical to define the role of anti-factor B therapies in improving renal outcomes and survival in aHUS.