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:
- Team Diagnosis: Focusing on the challenges of distinguishing C3G from infection-related GN or monoclonal gammopathy.
- 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.
Creators and Guests
Host
Kenar Jhaveri
Chair, ISGD Education Committee. Nephrologist Educator, Rapidly Progressive Glomerular Nephrologist, onconephrologist, cyclist π΄ββοΈ, runner π Editor in chief: ASN Kidney News
Host
Koyal Jain
ISGD Education Committee Co-Chair | PD @UNCkidney | Director of UME @UNCDeptMedicine | Glomerular Diseases and Vasculitis | Medical Education | Tweets are my own
Guest
Matthew Sparks, MD
PD @DukeKidney & @VADurham|@RenalFellowNtwk|@ajkdonline|@NephJC|#NephMadness creator|#NSMC PD|@KIDNEYcon Edu Dir|@kidneynews|@Neph_SIM Ad Board|π³οΈβπally