C3G Diagnosis: Overlapping Symptoms, Triggers, and Evolving Challenges

Video content above is prompted by the following:

C3G Clinical Insights Summary

This summary captures key points from a discussion between Jonathan Barratt, MBChB, PhD, FRCP,and other panelists regarding C3G.

Triggers and Pathogenesis

• Patients with C3G have underlying genetic predisposition present from birth but disease manifests only after specific triggers
• Common triggers mirror those of atypical hemolytic uremic syndrome:
  • Infections
  • Pregnancy
  • Episodes of kidney injury
• The role of autoantibodies (“intrinsic factors”) that stabilize complement convertases:
  • May develop through molecular mimicry following microbial infections
  • These antibodies inadvertently bind to complement convertases, preventing proper regulation

Diagnostic Challenges

• Clinical presentation is highly variable and can mimic other glomerular diseases:
  • Can present with nephritic or nephrotic patterns
  • May resemble minimal change disease
  • Can mimic IgA nephropathy
  • May present as rapidly progressive glomerulonephritis with acute kidney injury
• Complement testing has limitations:
  • Low serum C3 may provide a clue but is not universal
  • Normal C3 and C4 levels do not rule out C3G
• Kidney biopsy remains essential for definitive diagnosis
• In pediatric patients, C3G often initially resembles postinfectious glomerulonephritis (PIGN)
  • Persistence of glomerulonephritis features beyond expected PIGN resolution time should raise suspicion
  • Some pediatric cases present with pure nephrotic syndrome without hypocomplementemia

C3G must be considered in the differential diagnosis for any glomerular disease presentation, regardless of complement levels, due to its highly variable presentation and overlap with other kidney disorders.