Why C3 Glomerulopathy Shows Limited Response to Glucocorticoids
C3 glomerulopathy is fundamentally a complement-driven disease caused by dysregulated alternative pathway activation—not a primary immune-complex or T-cell–mediated process—which explains why glucocorticoids, which primarily suppress adaptive immunity and immune complex formation, demonstrate limited efficacy in most patients. 1, 2
Pathophysiologic Basis for Steroid Resistance
Complement-Mediated Rather Than Immune-Mediated Pathogenesis
C3G results from uncontrolled overactivation of the alternative complement pathway, driven predominantly by acquired autoantibodies (nephritic factors) that stabilize complement convertases, causing continuous C3 cleavage and deposition. 1, 2
The main pathogenic drivers are C3 nephritic factors (C3Nefs), C4Nefs, and C5Nefs—autoantibodies that bind to and stabilize C3 and C5 convertases—rather than traditional immune complexes or T-cell–mediated inflammation that glucocorticoids effectively suppress. 1
Unlike immune complex–mediated glomerulonephritis (where immunoglobulins co-deposit with C3 and respond better to steroids), C3G shows C3-dominant deposition that is ≥100-fold greater than any immunoglobulin, reflecting a fundamentally different disease mechanism. 3
Glucocorticoids Target the Wrong Pathway
Glucocorticoids primarily suppress:
- T-cell activation and cytokine production
- B-cell proliferation and antibody production (to some degree)
- Immune complex formation
- Classical complement pathway activation 4
However, C3G is driven by alternative pathway dysregulation, which operates independently of immune complexes and is not effectively suppressed by standard immunosuppressive doses of glucocorticoids. 2
The alternative pathway activation in C3G is constitutively active due to stabilized convertases, making it resistant to the anti-inflammatory effects of steroids that work primarily on adaptive immunity. 1, 2
Clinical Evidence of Limited Steroid Efficacy
Current Treatment Recommendations Reflect Poor Steroid Response
For moderate-to-severe C3G, the American Journal of Kidney Diseases recommends mycophenolate mofetil (MMF) plus glucocorticoids as first-line therapy, but this combination shows suboptimal response rates, with roughly 50% of patients progressing to end-stage kidney disease within 10 years despite treatment. 5, 6
Treatment with corticosteroids plus mycophenolate has been associated with improved outcomes compared to other regimens, but the benefit likely derives from the combination rather than steroids alone, and overall efficacy remains limited. 4
For crescentic C3G with rapidly progressive glomerulonephritis, high-dose glucocorticoids plus cyclophosphamide may be considered (similar to ANCA-vasculitis protocols), but this represents a specific subset where acute inflammatory injury may be partially steroid-responsive. 5
Emerging Complement-Targeted Therapies Show More Promise
Eculizumab (anti-C5 antibody) demonstrates highly heterogeneous response in C3G, with current clinical indication restricted to rapidly progressive forms, highlighting that even complement-targeted therapy at the C5 level is insufficient for many patients. 5, 4
Pegcetacoplan (C3 inhibitor) is indicated for patients who have failed first-line therapy, reflecting the need for more proximal complement blockade rather than immunosuppression. 5
The limited efficacy of existing complement-targeting treatments underscores that C3G requires therapies directed at the alternative pathway and C3 convertase, not broad immunosuppression. 2
Specific Clinical Scenarios That Modify Steroid Responsiveness
Monoclonal Gammopathy-Associated C3G
In adults ≥50 years with C3G, 60-80% have a monoclonal gammopathy at diagnosis, and treatment should focus on controlling the clone of B cells or plasma cells producing the pathogenic monoclonal immunoglobulin rather than using steroids. 3, 5
Pronase-digestion immunofluorescence should be performed when monoclonal protein is suspected, as masked monoclonal deposits may falsely appear as C3-dominant disease and require anti-clone therapy instead of immunosuppression. 3
Post-Infectious Glomerulonephritis Mimics
Active or prior infections must be excluded before diagnosing primary C3G, as infection-related glomerulonephritis can produce identical C3-dominant patterns but may show better response to supportive care and infection treatment than to steroids. 3, 5
In post-streptococcal glomerulonephritis, C3 levels typically normalize within 8-12 weeks; persistent low C3 beyond 12 weeks suggests true C3G and mandates kidney biopsy with specialized complement studies. 3
Common Pitfalls in Steroid Use for C3G
Pitfall: Assuming C3G will respond to steroids like other glomerulonephritides. Recommendation: Recognize that C3G is complement-driven, not primarily immune-mediated, and requires complement-targeted or combination therapy. 1, 2
Pitfall: Using prolonged high-dose steroids as monotherapy. Recommendation: Limit glucocorticoid courses to <6 months when used, preferably in combination with MMF, and avoid long-term steroid toxicity in a disease with poor steroid response. 5, 4
Pitfall: Failing to screen for monoclonal gammopathy in adults ≥50 years. Recommendation: Perform serum/urine protein electrophoresis, immunofixation, and free light chain analysis, as these patients require anti-clone therapy rather than immunosuppression. 3, 5
Pitfall: Using calcineurin inhibitors for C3G. Recommendation: Avoid these agents, as long-term use is associated with immune complex-negative angiopathy and thrombotic microangiopathy. 3
Algorithmic Approach to C3G Treatment
Complete diagnostic workup to identify underlying cause: screen for infections, autoimmune diseases, and monoclonal gammopathies. 5
For mild disease: Supportive therapy with RAS inhibition alone; avoid immunosuppression. 3
For moderate disease without monoclonal gammopathy: First-line MMF plus limited-course glucocorticoids (<6 months); if contraindications exist, consider rituximab or cyclophosphamide. 3, 5
For monoclonal gammopathy-associated C3G: Hematology consultation for anti-clone therapy targeting the underlying plasma cell or B-cell disorder. 5
For crescentic/rapidly progressive C3G: High-dose glucocorticoids plus cyclophosphamide, with consideration of eculizumab or pegcetacoplan. 5
For refractory disease: Pegcetacoplan or enrollment in clinical trials of novel complement inhibitors. 5, 2