Episode 11: Nephmadness Special! Matt Sparks and Aarushi Varshney on C3G

In this episode, hosts Dr. Kenar Jhaveri and Dr. Koyal Jain are joined by Dr. Matt Sparks (co-creator of NephMadness) and Dr. Aarushi Varshney to discuss the evolving landscape of C3 Glomerulopathy (C3G). The conversation highlights the shift from traditional electron microscopy-based classifications to modern immunofluorescence-based diagnosis, as well as the groundbreaking arrival of two new FDA-approved targeted therapies.

The NephMadness Matchup

This episode focuses on the C3G bracket pitting two critical aspects of C3G against each other:

1. Team Diagnosis: Focusing on the challenges of distinguishing C3G from infection-related GN or monoclonal gammopathy.
2. Team Treatment: Highlighting the new era of factor B and C3 inhibitors that are revolutionizing patient outcomes.

Key Takeaways

1. Challenges in Diagnosis

• The "Two Orders of Magnitude" Rule: Modern diagnosis is based on immunofluorescence (IF) showing C3 deposition that is at least two orders of magnitude greater than any other immunoglobulin.
• C3G vs. PIGN: It can be difficult to distinguish C3G from Post-Infectious Glomerulonephritis (PIGN). Clinical clues include patient age, the persistence of low C3 levels after infection resolution, and the presence (or absence) of sub-epithelial humps on pathology.
• The Role of Monoclonal Gammopathy: In older patients, it is critical to rule out monoclonal gammopathy (using SPEP and free light chain assays) as a driver of complement activation.

2. The New Therapeutic Era

The panel discussed two landmark drugs that have recently shifted the C3G treatment paradigm:

• Iptacopan: An oral factor B inhibitor that showed a 30% reduction in proteinuria at six months in the APPEAR trial.
• Pegcetacoplan: A subcutaneous infusion (twice weekly) C3 inhibitor that demonstrated a nearly 70% reduction in proteinuria and stabilization of eGFR in the VALIANT trial.
• A "Hammer" Approach: Pegcetacoplan is described as a "larger hammer" because it acts at the crux of all three complement pathways (Classical, Lectin, and Alternative).

3. Safety & Monitoring

• Vaccination: Because these drugs inhibit the complement cascade, patients MUST be vaccinated against Neisseria meningitidis and Streptococcus pneumoniae at least two weeks before starting therapy.
• Prophylaxis: If urgent treatment is required, patients should start prophylactic antibiotics (such as Penicillin, Augmentin, or Ciprofloxacin).

Resources & Studies Mentioned

• NephMadness: The annual educational "tournament" in nephrology that inspired this discussion.
• The APPEAR Trial (Iptacopan): Investigated the efficacy of the oral factor B inhibitor in patients with C3G.
• The VALIANT Trial (Pegcetacoplan): Evaluated the C3 inhibitor in patients with C3G and primary immune complex MPGN, including post-transplant patients.

The hosts and guests of this GN in 10 episode do not have any disclosures to make relevant to the content of this episode.