What is the appropriate diagnostic evaluation and management for a patient whose renal biopsy shows dominant complement C3 deposits on immunofluorescence?

Diagnostic Evaluation and Management of C3 Glomerulopathy

When a renal biopsy shows dominant C3 deposits on immunofluorescence, the patient has C3 glomerulopathy until proven otherwise, and you must immediately initiate a comprehensive workup to exclude infection-related glomerulonephritis, masked monoclonal deposits, and to characterize complement dysregulation before considering any immunosuppressive therapy. 1, 2

Confirm the Diagnosis with Precise Immunofluorescence Criteria

• C3 glomerulopathy requires C3 staining that is at least two orders of magnitude (100-fold) more intense than any immunoglobulin (IgG, IgM, IgA) or C1q on immunofluorescence. 3 This stringent criterion captures 88% of true C3 glomerulopathy cases while minimizing false positives. 3

• If frozen tissue is inadequate or if the patient has a circulating monoclonal protein, perform pronase-digestion immunofluorescence on paraffin-embedded tissue immediately to unmask hidden monoclonal immunoglobulin deposits. 1, 2 Approximately 5-10% of apparent C3 glomerulopathy cases with monoclonal gammopathy are actually membranoproliferative glomerulonephritis with masked deposits. 1

• Electron microscopy distinguishes C3 glomerulonephritis (ill-defined mesangial, subepithelial, and subendothelial deposits) from dense deposit disease (highly electron-dense intramembranous "sausage-like" deposits). 1

Mandatory Exclusion of Infection-Related Glomerulonephritis

Rule out active or prior infection before diagnosing primary C3 glomerulopathy. 1, 2 This is critical because infection can trigger complement abnormalities in genetically susceptible patients, and the treatment differs fundamentally. 1

• Test for hepatitis B, hepatitis C, HIV, and evaluate for endocarditis (blood cultures, echocardiography if indicated). 1, 2
• Screen for chronic bacterial, fungal, parasitic, or mycobacterial infections based on clinical context. 1
• If infection is identified, treat the infection first—post-infectious glomerulonephritis typically resolves with antimicrobial therapy and supportive care. 4

Evaluate for Monoclonal Gammopathy of Renal Significance (MGRS)

In all adults with C3 glomerulopathy, especially those ≥50 years old, screen for monoclonal gammopathy because 60-80% have a monoclonal protein at diagnosis. 1, 2

• Obtain serum and urine protein electrophoresis with immunofixation, and serum free light chain analysis. 1, 2
• If a monoclonal protein is detected, pronase-digestion immunofluorescence is mandatory to detect masked deposits. 1, 2
• Involve hematology for evaluation of plasma cell disorders (multiple myeloma, MGUS, lymphoproliferative disorders). 1
• In 30% of C3 glomerulopathy patients with monoclonal gammopathy, the monoclonal protein acts as a C3 nephritic factor or anti-factor H antibody, making this an MGRS-associated disorder requiring clone-directed therapy. 1

Comprehensive Complement Analysis

Perform comprehensive complement testing even in the absence of hypocomplementemia to characterize the underlying complement dysregulation. 1, 2

Standard complement tests (available in most laboratories):

• Serum C3, C4, and CH50 levels. 2
• Persistent isolated low C3 with normal C4 suggests alternative pathway activation. 2

Specialized complement testing (requires reference laboratories):

• Genetic testing: Screen for mutations in C3, complement factors H, I, B, CD46 (membrane cofactor protein), and complement factor H-related proteins (CFHR 1-5). 1, 5
• Autoantibody testing: C3 nephritic factor (C3Nef) and anti-factor H antibodies. 1, 6
• Coordinate early with your clinical laboratory for proper sample collection and storage, as many tests require specialized handling. 2

Exclude Other Causes of C3-Dominant Staining

• Lupus nephritis: Check ANA, anti-dsDNA, complement levels (both C3 and C4 typically low in lupus). 2, 7 "Full house" pattern (IgG, IgM, IgA, C3, C1q) indicates lupus, not C3 glomerulopathy. 7
• Cryoglobulinemia: Test for cryoglobulins, rheumatoid factor, and hepatitis C. 2 Combined low C3 and C4 suggests cryoglobulinemia. 2

Treatment Algorithm Based on Disease Severity and Etiology

If infection-related:

• Treat the underlying infection with appropriate antimicrobials. 4
• Provide supportive care (diuretics, antihypertensives, RAS inhibition). 4
• Reserve corticosteroids only for severe crescentic disease. 4

If MGRS-associated (monoclonal protein driving disease):

• Clone-directed therapy is the primary treatment—work with hematology to target the underlying plasma cell disorder. 1
• Treatment may include bortezomib-based regimens, rituximab, or other agents depending on the clone type. 1

If primary C3 glomerulopathy (no infection, no MGRS):

Mild disease (preserved kidney function, non-nephrotic proteinuria):

• RAS inhibition alone for supportive care. 2
• Avoid immunosuppression in this population. 2

Moderate disease (declining kidney function, nephrotic-range proteinuria):

• First-line: Limited course of glucocorticoids (e.g., prednisone 1 mg/kg/day, maximum 60 mg, tapered over 3-6 months). 2, 7
• If glucocorticoid contraindications exist: Consider mycophenolate mofetil, rituximab, or cyclophosphamide. 2
• Avoid calcineurin inhibitors—long-term use causes immune complex-negative angiopathy and thrombotic microangiopathy. 2

Severe/crescentic disease:

• High-dose corticosteroids (methylprednisolone 500-1000 mg IV for 3 days, then prednisone 1 mg/kg/day). 7
• Add cyclophosphamide (preferred over mycophenolate in severe cases with crescents or rapidly progressive glomerulonephritis). 7
• Consider plasma exchange or complement inhibition (eculizumab, avacopan) in refractory cases, especially if genetic or autoantibody-mediated complement dysregulation is documented. 5, 8, 9

Critical Pitfalls to Avoid

• Never diagnose C3 glomerulopathy without excluding infection and monoclonal gammopathy first. 1, 2 These require fundamentally different treatments.
• Do not rely on "C3 only" immunofluorescence criteria—this captures only 50% of true cases. 3 Use the two-orders-of-magnitude rule. 3
• Do not skip pronase-digestion immunofluorescence in patients with monoclonal proteins—you will miss 5-10% of masked monoclonal deposit cases. 1, 2
• Hypocomplementemia is not required for diagnosis—perform comprehensive complement analysis regardless of serum levels. 1, 2
• Immunofluorescence patterns can change on repeat biopsies in 43% of cases, so clinical correlation is essential. 3

Prognosis and Transplant Planning

• C3 glomerulopathy carries substantial risk for end-stage renal disease and recurrence after transplant (up to 50-80% recurrence rate). 8, 9
• Characterizing the patient's complement profile (genetic vs. autoantibody-mediated) informs transplant risk and guides peri-transplant complement blockade strategies. 6, 8
• A decrease of ≥40% in eGFR over 2-3 years is a poor prognostic sign. 7