Primary Treatment Approach for C3 Glomerulonephritis
Mycophenolate mofetil (MMF) plus glucocorticoids is the first-line treatment for patients with moderate-to-severe C3 glomerulonephritis. 1
Critical Pre-Treatment Evaluation
Before initiating immunosuppression, you must exclude conditions that would fundamentally change your treatment approach:
Screen all adults for monoclonal gammopathy (especially those >50 years old) using serum/urine protein electrophoresis, immunofixation, and serum free light chain analysis—if positive, treatment must target the B cell or plasma cell clone producing the monoclonal immunoglobulin rather than using standard immunosuppression 1
Rule out active or recent infections (streptococcal, hepatitis B/C, endocarditis) as these trigger C3G and require infection-directed therapy, not immunosuppression 1
Exclude autoimmune diseases (SLE, Sjögren's syndrome) that would necessitate disease-specific immunosuppression protocols 1
Consider pronase digestion on paraffin-embedded tissue if monoclonal protein is detected, as 5-10% of apparent C3GN cases are actually masked monoclonal immunoglobulin deposition disease requiring clone-directed therapy 1
Treatment Algorithm by Disease Severity
First-Line Therapy: MMF Plus Glucocorticoids
For moderate-to-severe C3GN without monoclonal gammopathy, initiate MMF plus glucocorticoids as your primary regimen 1. This recommendation comes from observational data showing MMF decreased progression to kidney failure compared to other immunosuppressives 2.
Second-Line Therapy: Eculizumab
If MMF fails, eculizumab (C5 inhibitor) can be tried, though results are variable 2, 1. One pediatric case demonstrated significant proteinuria reduction (5.3 to 1.3 g/day) with eculizumab, and transient interruption caused rapid proteinuria rise to 9.3 g/day 3. The limitation is that eculizumab blocks terminal complement activation but doesn't address upstream C3 dysregulation 4.
Emerging Therapy: Pegcetacoplan
Pegcetacoplan (C3/C3b inhibitor) is emerging as an option for treatment-resistant disease 1. A recent pediatric case showed rapid clinical improvement within 1 week (C3 normalized from 30 to 142 mg/dL, uPCR decreased from 1.1 to 0.422 g/g within 3 months), allowing discontinuation of all immunosuppressive and antihypertensive medications 5. This represents a more targeted approach than eculizumab by directly inhibiting C3 activation 6.
Crescentic C3GN with RPGN
For crescentic C3GN with rapidly progressive glomerulonephritis, consider high-dose glucocorticoids plus cyclophosphamide similar to ANCA-associated vasculitis protocols 1, 7.
Essential Supportive Care
Regardless of immunosuppressive choice, implement these measures:
Maximize RAS inhibition with ACE inhibitors or ARBs titrated to maximally tolerated dose for proteinuria reduction and blood pressure control, targeting systolic BP <120 mmHg 2, 1
Restrict dietary sodium to <2.0 g/day to control edema and hypertension 1
Vaccinate before immunosuppression: pneumococcal, influenza, and herpes zoster (Shingrix) 1
Screen for latent infections: tuberculosis, hepatitis B/C, HIV in appropriate patients 1
Consider prophylactic trimethoprim-sulfamethoxazole with high-dose prednisone or intensive immunosuppression 1
Monitoring Strategy
Proteinuria reduction is your key surrogate endpoint, though complete remission may not be achievable in all patients 1
A ≥40% decline in eGFR over 2-3 years signals progression to kidney failure 1
Strongly consider enrollment in clinical trials given the limited RCT data and unmet therapeutic need in C3G 2, 1
Critical Pitfalls to Avoid
The most dangerous error is failing to screen for monoclonal gammopathy in patients >50 years old, as this leads to inappropriate immunosuppression when clone-directed therapy is needed 7. The second major pitfall is initiating aggressive immunosuppression without excluding infection-triggered C3G, which would resolve with infection treatment alone 1. The 2021 KDIGO guidelines emphasize a more nuanced approach than the 2012 version, recommending restraint in treating patients aggressively and tailoring therapy to severity of disease presentation and histology 2.