What is the initial treatment approach for a patient diagnosed with C3 glomerulopathy?

Management of C3 Glomerulopathy

For patients diagnosed with C3 glomerulopathy (C3G), the initial treatment approach should be mycophenolate mofetil (MMF) plus glucocorticoids, especially for moderate-to-severe disease without monoclonal gammopathy. 1

Initial Diagnostic Workup

• Complete a thorough evaluation to identify the underlying cause of C3G, including screening for infections, autoimmune diseases, and monoclonal gammopathies 2
• Perform serum and urine immunoelectrophoresis, immunofixation, and serum free light chain analysis for all adult patients with C3G, especially those over 50 years old 2, 1
• Consider specialized complement testing to identify complement dysregulation, though these tests may require sending samples to specialized laboratories 2
• Rule out infection-related glomerulonephritis or post-infectious glomerulonephritis before confirming C3G diagnosis 1

Treatment Algorithm Based on Disease Severity

For Mild Disease (proteinuria <3.5 g/day, normal eGFR):

• Begin with supportive therapy focusing on renin-angiotensin system (RAS) inhibition 2, 3
• Monitor kidney function and proteinuria every 3-6 months 3

For Moderate-to-Severe Disease:

• First-line therapy: Mycophenolate mofetil (MMF) plus glucocorticoids 1, 4
  • This combination has shown higher rates of remission (79%) and lower probability of kidney failure (14%) compared to other treatment approaches 4
  • Treatment should be continued long-term as relapses occur in approximately 33% of patients after discontinuation 4

For Treatment-Resistant Cases:

• Consider eculizumab for patients who fail to respond to MMF plus glucocorticoids 1, 5
• Response to eculizumab is heterogeneous, with some patients showing improvement within 2 weeks to 6 months after initiation 5
• Pegcetacoplan may be considered for patients who have failed first-line therapy or as part of a clinical trial 1

Special Considerations

Patients with Monoclonal Gammopathy:

• Treatment should focus on controlling the clone of B cells or plasma cells responsible for production of the monoclonal immunoglobulin 2
• Consider hematology consultation for management of the underlying plasma cell or B cell disorder 2

Patients with Rapidly Progressive Disease:

• For crescentic C3G with rapidly progressive glomerulonephritis, treat with high-dose glucocorticoids and cyclophosphamide similar to ANCA-associated vasculitis protocols 2

Monitoring Response to Treatment:

• The main determinant of non-response to MMF plus glucocorticoids is baseline proteinuria level 4, 6
• Patients with pathogenic variants in complement genes may achieve only partial remission, while those with autoantibody-mediated forms more commonly achieve complete remission 4
• Regular monitoring of proteinuria, serum creatinine, and estimated GFR every 3-6 months is recommended 3

Common Pitfalls and Caveats

• Failure to screen for monoclonal gammopathy, especially in patients over 50 years old, may lead to inappropriate treatment selection 2, 1
• Discontinuing MMF treatment too early increases risk of relapse; longer treatment duration is associated with lower relapse rates 4
• Early initiation of therapy may be necessary to prevent disease progression in rapidly progressive cases 5
• C3Nef levels (antibodies against C3 convertase) do not reliably correlate with disease course or therapeutic response 7
• Not accounting for the lag between treatment initiation and reduction in proteinuria can lead to premature treatment changes 3