Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening thrombotic microangiopathy (TMA) distinct from Shiga toxin-producing Escherichia coli (STEC)-related HUS. It is primarily driven by genetic or acquired dysregulation of the complement system, with pathogenic variants in complement factor H (CFH), factor I (CFI), membrane cofactor protein (MCP/CD46), factor B (CFB), and C3 identified in nearly 60% of patients. The resulting uncontrolled activation of the alternative complement pathway leads to endothelial damage, platelet activation, and microvascular thrombosis, most prominently affecting renal function. Clinically, aHUS is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and organ injury, most commonly renal but often involving extra-renal systems such as cardiovascular, neurological, dermatological, and gastrointestinal organs. Diagnosis is challenging, requiring exclusion of other TMAs such as thrombotic thrombocytopenic purpura (TTP) and typical HUS. Early and accurate identification is essential to prevent irreversible organ damage.

Diagnostic workup integrates clinical, laboratory, and genetic testing. ADAMTS13 activity measurement is critical to exclude TTP, while Shiga toxin assays help differentiate typical HUS. Complement biomarkers, including soluble C5b-9 and factor Ba, are under investigation for their diagnostic and prognostic utility. Genetic testing, employing next-generation sequencing and MLPA, provides prognostic insights and guides therapy, though penetrance remains incomplete and environmental triggers (infections, pregnancy, transplantation) play a pivotal role.

Therapeutically, plasma exchange was historically the first-line option, but outcomes were poor with high rates of end-stage renal disease (ESRD). The advent of complement inhibitors has revolutionized management. Eculizumab, a monoclonal antibody targeting C5, effectively halts terminal complement activation, resulting in rapid hematologic normalization and renal recovery, especially when initiated early. Ravulizumab, a long-acting C5 inhibitor requiring infusions every 8 weeks, offers comparable efficacy with improved quality of life. Real-world studies confirm their sustained safety and effectiveness, though concerns regarding meningococcal infections necessitate vaccination and antibiotic prophylaxis. The duration of therapy remains debated; relapse occurs in 20–30% after discontinuation, particularly in carriers of CFH and CFI mutations. Emerging biomarkers and genetic stratification may enable more personalized discontinuation strategies.

Despite therapeutic advances, significant challenges remain. Complement inhibitors impose a lifelong economic burden, raising questions of cost-effectiveness and accessibility. Health-economic analyses highlight the need for balanced strategies between clinical benefit and financial sustainability. Furthermore, gaps persist in standardized diagnostic criteria, access to genetic testing, and long-term outcome data for ravulizumab. Ongoing research focuses on refining biomarkers for risk stratification, identifying novel complement targets, and developing more affordable therapies. Special considerations arise in pregnancy-associated aHUS, post-transplant recurrence, and pediatric populations, where individualized management is critical.

In conclusion, aHUS exemplifies a paradigm shift in the treatment of rare complement-mediated diseases. Early recognition, integration of genomic data, and targeted complement inhibition have transformed its prognosis. Future research must focus on optimizing therapeutic duration, expanding access to novel agents, and achieving a cost-effective, precision medicine approach for this devastating disorder.