Brendon Neuen, MD

Panelists discuss how C3 glomerulopathy (C3G) is triggered by factors like infections or pregnancy that activate the alternative pathway in genetically predisposed individuals, presenting with diverse clinical manifestations that often overlap with other glomerular diseases, making diagnosis challenging without kidney biopsy.

C3G Diagnosis: Overlapping Symptoms, Triggers, and Evolving Challenges

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

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:

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

Clinical presentation is highly variable and can mimic other glomerular diseases:

Can present with nephritic or nephrotic patterns

May present as rapidly progressive glomerulonephritis with acute kidney injury

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.

Videos

Panelists discuss how C3 glomerulopathy is an ultrarare glomerular disease characterized by alternative pathway complement dysregulation, which can be caused by either genetic defects or acquired abnormalities like antibodies against regulatory proteins.

Understanding C3G: Pathophysiology and Genetic Factors

C3 Glomerulopathy: Pathophysiology Summary

This summary provides an overview of C3 glomerulopathy (C3G) pathophysiology as described by Jonathan Barratt, MBChB, PhD, FRCP,
during a clinical discussion.

Primary disorder of the alternative pathway of complement activation and regulation

Gain-of-function mutations leading to easier complement system activation

Loss of function in key complement regulatory proteins that normally restrict alternative pathway activation

Antibodies (nephritic factors) that bind to convertase enzymes, preventing proper deactivation

Antibodies against regulatory proteins that inhibit their function

Monoclonal proteins (in monoclonal gammopathy of renal significance) that block regulatory pathways

Kidney biopsy reveals excess C3 complement protein within glomeruli

Characteristic absence of immunoglobulins or immune complexes

Evidence of unilateral alternative pathway complement activation driving glomerular injury

This understanding of C3G pathophysiology highlights the importance of differentiating between acquired and genetic complement abnormalities for proper diagnostic classification and therapeutic approach.

Brendon Neuen, MD

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