aHUS, complement, thrombotic microangiopathy, eculizumab, factor H, membrane cofactor protein, ravulizumab. 1. Introduction The hemolytic uremic syndrome (HUS) was first described by Conrad Gasser in 1955. For decades, the term HUS was almost synonymous with diarrheal illness caused by Shiga-toxin-producing E. coli . However, it became evident that a subset of patients—often with a relapsing course, familial clustering, or poor response to supportive care—had a distinct pathophysiology. This variant, now known as atypical HUS (aHUS), represents a disorder of complement dysregulation.
aHUS has an estimated incidence of 0.5–1 per million per year, accounting for approximately 5–10% of all pediatric HUS cases but a higher proportion of adult cases. Without treatment, up to 50% of patients progress to end-stage renal disease (ESRD) or die during the first acute episode. The advent of complement-blocking monoclonal antibodies has transformed aHUS from a disease with guarded prognosis to a manageable chronic condition, yet challenges in diagnosis, cost, and long-term monitoring persist. 2.1 Normal Complement Regulation The alternative pathway (AP) operates as a low-grade, continuous "tickover" system for immediate defense against pathogens. C3 undergoes spontaneous hydrolysis to C3(H₂O), forming a C3 convertase (C3bBb). On host endothelial cells, regulatory proteins such as Factor H (FH) , Factor I (FI) , and Membrane Cofactor Protein (MCP/CD46) rapidly inactivate C3b, preventing amplification. 2.2 The Genetic Lesions in aHUS More than 60% of aHUS patients harbor rare genetic variants in complement genes, though penetrance is incomplete (often ~50%), indicating that a "second hit" (e.g., infection, pregnancy, surgery) is required for disease expression. atypical hemolytic syndrome
| Gene | Protein | Function | % of aHUS | Risk of ESRD without treatment | Recurrence post-transplant | |------|---------|----------|------------|-------------------------------|----------------------------| | CFH | Factor H | Cofactor for FI, decays C3bBb | 20-30% | 70-80% | Very high (>70%) | | MCP | CD46 | Cofactor for FI on cell surface | 10-15% | 30-40% | Low (if kidney alone) | | CFI | Factor I | Cleaves C3b and C4b | 5-10% | 60% | High | | C3 | C3 | Convertase component | 5-10% | 60-70% | High | | CFB | Factor B | Convertase component (gain-of-function) | 1-2% | High | High | | THBD | Thrombomodulin | Enhances FI activation | ~5% | Intermediate | Unknown | For decades, the term HUS was almost synonymous