What is the initial approach to treating a patient with an autoimmune condition indicated by a low C3 (complement component 3) marker?

Initial Approach to Low C3 in Autoimmune Conditions

Before initiating any immunosuppressive therapy for a patient with low C3 and suspected autoimmune glomerular disease, you must complete a comprehensive diagnostic workup to identify the underlying etiology, including screening for infections, monoclonal gammopathies (especially in patients ≥50 years), and performing specialized complement testing, as this will fundamentally determine your treatment strategy. 1, 2

Mandatory Initial Diagnostic Evaluation

Rule Out Mimics First

• Exclude active or prior infections before labeling the condition as primary autoimmune C3 glomerulopathy, as infections can trigger complement abnormalities in genetically susceptible patients 1, 3
• Screen specifically for hepatitis B, hepatitis C, bacterial endocarditis, and parasitic infections 1, 4
• Note that prolonged hypocomplementemia (>8 weeks) does not exclude post-infectious glomerulonephritis 4

Essential Laboratory Workup

• Serum and urine immunoelectrophoresis, immunofixation, and serum free light chain analysis are mandatory for all adult patients with C3 glomerulopathy, particularly those ≥50 years old, as 60-80% may have an underlying monoclonal gammopathy 1, 2, 4
• Comprehensive complement analysis including C3, C4, and CH50 levels 4
• Autoimmune serologies: ANA, anti-dsDNA, and ANCA to evaluate for lupus nephritis or ANCA-associated vasculitis 4, 3
• Specialized complement testing (complement regulatory proteins, genetic testing, autoantibodies against complement factors) should be performed even in the absence of hypocomplementemia 1, 4

Renal Biopsy Requirements

• Kidney biopsy with immunofluorescence is essential for pathological classification 4
• If a monoclonal protein is detected, perform immunofluorescence on pronase-digested paraffin-embedded tissue to unmask hidden monoclonal immunoglobulin deposits, as 5-10% of apparent C3 glomerulopathy cases are actually membranoproliferative glomerulonephritis with masked deposits 4

Treatment Algorithm Based on Etiology and Severity

If Monoclonal Gammopathy is Identified

• Treatment must focus on controlling the B-cell or plasma cell clone producing the monoclonal immunoglobulin 2
• Obtain hematology consultation for management of the underlying plasma cell or B cell disorder 2
• This takes precedence over direct immunosuppression of the kidney disease 2

For Idiopathic Immune Complex-Mediated Disease

Mild Disease (proteinuria <3.5 g/day, no nephrotic syndrome, normal eGFR):

• Supportive therapy with RAS inhibition alone 1
• Avoid immunosuppression in this population 1

Moderate Disease (nephrotic syndrome with normal or near-normal creatinine):

• First-line: Limited course of glucocorticoids 1
• If contraindications to glucocorticoids exist, consider mycophenolate mofetil, rituximab (anti-CD20), or cyclophosphamide 1
• Avoid calcineurin inhibitors (CNIs) as long-term use is associated with immune complex-negative angiopathy and thrombotic microangiopathy 1

Severe Disease (nephrotic syndrome with declining kidney function):

• Consider oral cyclophosphamide or mycophenolate mofetil plus low-dose corticosteroids (limited to <6 months) 5

For C3 Glomerulopathy Without Monoclonal Gammopathy

Moderate-to-Severe Disease:

• Initial treatment: Mycophenolate mofetil plus glucocorticoids 2
• If first-line therapy fails, consider eculizumab (C5 inhibitor) 2
• Pegcetacoplan may be considered for patients who have failed first-line therapy or as part of clinical trials 2

Crescentic C3G with Rapidly Progressive Glomerulonephritis:

• Treat with high-dose glucocorticoids and cyclophosphamide, similar to ANCA-associated vasculitis protocols 2

Critical Pitfalls to Avoid

• Failure to screen for monoclonal gammopathy in patients ≥50 years leads to inappropriate treatment selection, as these patients require clone-directed therapy rather than standard immunosuppression 2, 4
• Starting immunosuppression before ruling out infection can worsen outcomes, as infection may be the primary driver or trigger 1, 3
• Using CNIs for long-term management risks inducing additional complement-mediated kidney injury 1
• Assuming C3 glomerulopathy based on standard immunofluorescence alone when monoclonal protein is present—always perform pronase digestion studies to detect masked deposits 4
• Many specialized complement tests require sending samples to reference laboratories; coordinate with your clinical laboratory early for proper collection and storage 1

Special Considerations for Autoimmune Disease Association

• Female patients with C3 glomerulopathy have higher rates of associated autoimmune disorders, particularly those with positive ANA and anti-dsDNA 3
• An autoimmune milieu may act as a trigger for C3 glomerulopathy in genetically susceptible patients with complement pathway variants 3
• Short-term prognosis appears excellent when the autoimmune component is appropriately treated 3