What are the current treatment guidelines for C3 (Complement Component 3) glomerulonephritis?

Treatment Guidelines for C3 Glomerulonephritis

The KDIGO 2021 guidelines recommend mycophenolate mofetil (MMF) plus glucocorticoids as first-line therapy for patients with moderate-to-severe C3 glomerulonephritis, with eculizumab or pegcetacoplan reserved for those who fail initial treatment. 1, 2

Initial Diagnostic Workup Before Treatment

Before initiating any therapy, a comprehensive evaluation must identify underlying causes that fundamentally change management:

• Screen for monoclonal gammopathy in all adults, especially those over 50 years old, using serum/urine protein electrophoresis, immunofixation, and serum free light chain analysis 1, 2, 3
• Exclude active or recent infections (streptococcal, hepatitis B/C, endocarditis) as these can trigger C3G and require infection-directed therapy rather than immunosuppression 1, 2
• Rule out autoimmune diseases (SLE, Sjögren's syndrome) that would necessitate disease-specific immunosuppression 1
• Consider specialized complement testing to identify specific complement dysregulation, though this should not delay treatment 2, 3
• Use pronase digestion on paraffin-embedded tissue if monoclonal protein is detected, as up to 5-10% of apparent C3GN cases are actually masked monoclonal immunoglobulin deposition disease requiring clone-directed therapy 1, 3

Treatment Algorithm Based on Disease Severity

Mild Disease (Preserved GFR, Sub-nephrotic Proteinuria)

• Supportive care alone with RAS inhibition (ACE inhibitors or ARBs) 2, 3
• Avoid immunosuppression in this population 3

Moderate-to-Severe Disease (Declining GFR or Nephrotic-Range Proteinuria)

First-line therapy:

• MMF (mycophenolate mofetil) plus glucocorticoids 1, 2
• Observational data from the Spanish Group for the Study of Glomerular Diseases showed 100% renal survival at 5 years with this regimen, compared to 80% with other immunosuppressives and 72% in untreated patients 4
• A Columbia University series demonstrated 67% remission rate with MMF plus steroids, significantly outperforming other immunosuppressive regimens 5

Second-line therapy if MMF fails:

• Eculizumab (C5 inhibitor) can be tried, though results are variable 1, 2
• Case reports show significant proteinuria reduction (5.3 to 1.3 g/day in one pediatric case), but response is inconsistent 6
• Pegcetacoplan (C3/C3b inhibitor) is emerging as an option for treatment-resistant disease 2, 7
• One pediatric case showed dramatic improvement within 1 week (uPCR from 1.1 to 0.322 g/g within 3 months), allowing discontinuation of all other immunosuppression 7

Crescentic C3GN with Rapidly Progressive Glomerulonephritis

• High-dose glucocorticoids plus cyclophosphamide may be considered, using protocols similar to ANCA-associated vasculitis 2
• This approach is based on limited evidence and should be reserved for severe, rapidly progressive cases 2

Monoclonal Gammopathy-Associated C3G

• Treatment must target the B cell or plasma cell clone producing the monoclonal immunoglobulin 1, 2
• Hematology consultation is essential for clone-directed therapy 2
• Standard immunosuppression for C3G is inappropriate until the underlying clone is addressed 1

Critical Pitfalls to Avoid

The most common error is failing to screen for monoclonal gammopathy in patients over 50 years old, leading to inappropriate immunosuppression when clone-directed therapy is needed 2, 3. Up to 60-80% of adults over 50 with C3G have an underlying monoclonal gammopathy 3.

Avoid calcineurin inhibitors (tacrolimus, cyclosporine) for long-term therapy, as they are associated with immune complex-negative angiopathy and thrombotic microangiopathy 3.

Do not delay treatment waiting for specialized complement testing results, as these often require reference laboratories and take weeks to return 3. Begin appropriate therapy based on clinical presentation and standard workup.

Persistently low C3 beyond 8-12 weeks should prompt re-evaluation for C3G rather than post-infectious glomerulonephritis, but active infection must still be excluded 8, 3.

Supportive Care Measures

Regardless of immunosuppressive strategy, all patients require:

• Dietary sodium restriction to <2.0 g/day to control edema and hypertension 1, 8
• RAS inhibition with ACE inhibitors or ARBs for proteinuria reduction and blood pressure control 3
• Pneumococcal, influenza, and herpes zoster (Shingrix) vaccination before initiating immunosuppression 1
• Screen for tuberculosis, hepatitis B/C, HIV in appropriate patients before immunosuppression 1
• Prophylactic trimethoprim-sulfamethoxazole should be considered with high-dose prednisone or other intensive immunosuppression 1

Monitoring and Follow-up

The KDIGO guidelines emphasize that proteinuria reduction is a key surrogate endpoint, though complete remission may not be achievable in all patients 1. A ≥40% decline in eGFR over 2-3 years suggests progression to kidney failure 1.

Enrollment in clinical trials should be strongly considered given the limited RCT data and unmet therapeutic need in C3G 1, 2. The absence of randomized controlled trial data means current recommendations are based on observational studies and expert consensus 1.