Molecular determinants of STEC-HUS: from complement activation to microvascular thrombosis

Area of Science:

• Nephrology
• Immunology
• Hematology

Background:

• Shiga-like toxin-producing E. coli-induced hemolytic uremic syndrome (STEC-HUS) is a severe condition with no specific treatment and frequent long-term complications.
• Excessive complement activation is implicated in STEC-HUS pathogenesis, but its precise role remains debated.

Purpose of the Study:

• To investigate the involvement of the three complement pathways in STEC-HUS pathogenesis.
• To evaluate the therapeutic potential of targeting the alternative complement pathway.

Main Methods:

• Analysis of patient sera from 37 acute STEC-HUS patients and 24 post-discharge patients.
• Ex-vivo assays using patient sera and microvascular endothelial cells to assess complement deposition and thrombus formation.
• Testing the efficacy of the factor B inhibitor iptacopan and classical/lectin pathway inhibitors.

Main Results:

• Acute-phase sera triggered abnormal C3 and C5b-9 deposition, promoting endothelial thrombus formation.
• Iptacopan effectively blocked complement deposition and thrombus formation, unlike classical or lectin pathway inhibitors.
• Persistent complement activation (C5b-9) was observed in patients after discharge, correlating with incomplete remission and renal abnormalities.

Conclusions:

• The alternative complement pathway is a key driver of microvascular thrombosis in STEC-HUS.
• Targeting the alternative pathway with inhibitors like iptacopan shows therapeutic promise for STEC-HUS.
• Ex-vivo assays can monitor complement activity and clotting, aiding in managing STEC-HUS sequelae.