Long-term outcome and management of complement-mediated thrombotic microangiopathy/aHUS

Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening thrombotic microangiopathy characterized by uncontrolled activation of the complement pathway, leading to microangiopathic hemolytic anemia, thrombocytopenia, and organ damage. The advent of complement inhibitors such as eculizumab and ravulizumab has transformed aHUS management, markedly reducing morbidity and mortality. However, long-term therapy presents challenges, including infection risks, economic burden, and the need for indefinite treatment. Discontinuing complement inhibition is a pivotal clinical decision that requires careful risk assessment to prevent relapse. Pathogenic gene variants in complement- regulating proteins, particularly CFH, CFI, MCP/CD46, and C3, significantly increase the risk of relapse, particularly within the first 3 to 12 months after cessation. Patients with multiple pathogenic variants or variants of uncertain significance exhibit heightened vulnerability, necessitating extended monitoring. Clinical predictors such as young age, prior kidney transplantation, and the presence of extrarenal manifestations further stratify relapse risk. Additionally, dynamic biomarkers such as elevated soluble C5b-9 at the time of discontinuation may signal imminent relapse. Comprehensive postdiscontinuation surveillance, including laboratory assessment of kidney function, hemolysis markers, and complement activity, is crucial for early relapse detection. Emerging strategies for personalized risk assessment, including pharmacogenomic profiling and biomarker-guided monitoring, may optimize therapeutic decision-making in aHUS. This review synthesizes current evidence on the long-term management of aHUS, focusing on strategies for anticomplement therapy discontinuation, relapse prediction, and individualized monitoring.