In situ assessment of glomerular C3/C5 convertases indicates ongoing complement activation in IgA nephropathy

Area of Science:

• Nephrology
• Immunology
• Complement System Biology

Background:

• The complement system plays a role in IgA nephropathy (IgAN) progression, presenting therapeutic targets.
• Current methods for assessing complement activation in IgAN lack precision in distinguishing active from past inflammation.

Purpose of the Study:

• To evaluate the in situ detection of complement convertases in IgA nephropathy (IgAN) kidney biopsies.
• To correlate complement pathway activation with disease severity and clinical outcomes.
• To identify potential biomarkers for guiding complement-targeted therapies in IgAN.

Main Methods:

• Assessed complement deposition (C4d, C5b-9, C3b/iC3b, C1q) in 53 IgAN patient biopsies.
• Utilized in situ proximity ligation assay (Duolink®) to detect classical/lectin (C4b2b) and alternative (C3bBb) pathway convertases in 33 biopsies.
• Quantified convertase signals and correlated them with MEST-C scores, C5b-9 deposition, and renal survival.

Main Results:

• Alternative pathway (C3bBb) and classical/lectin pathway (C4b2b) convertases were detected in a majority of C3c-positive IgAN patients (60.6% and 66.7%, respectively).
• Presence of both convertases was observed in 39.4% of patients; double-negative patients showed better renal survival (P=0.0387).
• C3bBb convertase intensity correlated with C5b-9 deposition (P=0.0011) and was higher in patients with MEST-C scores E1 and S1.

Conclusions:

• In situ convertase detection revealed ongoing complement activation in 87.9% of C3c-positive IgAN patients.
• Alternative pathway activation is linked to specific kidney lesions (E1, S1), C5b-9 deposition, and poorer renal outcomes.
• This technique may improve patient selection for complement-inhibiting therapies in IgAN.