What is the differential diagnosis for a patient presenting with anasarca and low complement levels?

Differential Diagnosis for Anasarca with Low Complement

The differential diagnosis for anasarca with low complement should focus primarily on infection-related glomerulonephritis, lupus nephritis, cryoglobulinemic glomerulonephritis, and ANCA-associated vasculitis with complement consumption. 1

Primary Diagnostic Considerations

Infection-Related Glomerulonephritis

• IgA-dominant infection-related GN presents with low C3 levels and can cause severe nephrotic syndrome with anasarca, particularly in elderly or immunocompromised patients 1
• Bacterial infection-related GN (post-streptococcal, endocarditis-associated, or shunt nephritis) characteristically shows low C3 with normal or low C4, indicating alternative pathway activation 1
• Persistently low C3 beyond 12 weeks after infection suggests C3 glomerulonephritis (C3GN) rather than classic post-infectious GN 1
• Culture evidence from blood, skin, or tonsils should be obtained, along with anti-streptolysin O, anti-DNAse B, and anti-hyaluronidase antibodies 1

Systemic Lupus Erythematosus (SLE)

• Lupus nephritis with low C3 and C4 indicates classical pathway activation and correlates with active renal disease 1, 2, 3
• Patients with fluctuant complement levels have 75% frequency of lupus glomerulonephritis compared to 49% in those with normal complement 3
• Protein-losing enteropathy can be the sole presenting manifestation of SLE with anasarca and low-normal complement levels 2
• Screen with ANA, anti-dsDNA antibodies, and complete complement profile (C3, C4, CH50) 4

Cryoglobulinemic Glomerulonephritis

• Membranoproliferative GN pattern with low complement suggests cryoglobulinemia, particularly when associated with hepatitis C infection 1
• Type I cryoglobulins (monoclonal Ig) can present with intracapillary hyaline thrombi and severe nephrotic syndrome 1
• Serum cryoglobulins, rheumatoid factor, hepatitis C serology, and IgM levels should be measured 1

ANCA-Associated Vasculitis (AAV)

• Low C3c levels correlate with AKI severity in ANCA GN and indicate interstitial vasculitis with intimal arteritis 5
• MPO-ANCA positive patients (30-40% of EGPA cases) frequently show glomerulonephritis, neuropathy, and purpura 1
• Hypocomplementemia occurs in only a minor subset of ANCA GN but when present, indicates more severe tubulointerstitial injury 5
• Test for both MPO-ANCA and PR3-ANCA by ELISA, as P-ANCA by immunofluorescence alone is less specific 1

Secondary Considerations

Crescentic GN Superimposed on Membranous Nephropathy

• Acute renal failure with anasarca in a patient with known membranous GN may represent superimposed crescentic GN 6
• Patients without anti-GBM antibodies have better prognosis than those with antibodies 6
• Early renal biopsy is essential when unexplained acute renal failure develops in nephrotic syndrome 6

C3 Glomerulopathy

• Isolated low C3 with normal C4 suggests alternative pathway dysregulation (C3GN or dense deposit disease) 1
• Membranoproliferative pattern on biopsy with predominant C3 staining and absent or minimal immunoglobulin deposition 1
• Measure factor B antibodies and consider genetic testing for complement regulatory proteins 1

Monoclonal Immunoglobulin-Related GN

• Membranoproliferative pattern with intracapillary pseudothrombi suggests monoclonal Ig deposition 1
• Screen with serum and urine protein electrophoresis, immunofixation, and serum free light chains in adults ≥50 years 4
• IgM kappa staining indicates type 1 cryoglobulinemia (Waldenström macroglobulinemia) 1

Critical Diagnostic Algorithm

Step 1: Measure complement components

• CH50 and AH50 to assess classical and alternative pathways 1
• C3 and C4 levels to determine activation pattern 4, 5
• Low C3 with normal C4 = alternative pathway; Low C3 and C4 = classical pathway 1

Step 2: Infectious workup (most common and immediately treatable cause)

• Blood cultures, throat/skin cultures if infected 1, 4
• Anti-streptolysin O, anti-DNAse B, hepatitis B and C serology 1
• HIV testing in appropriate clinical context 1

Step 3: Autoimmune serologies

• ANA, anti-dsDNA, ANCA (MPO and PR3), anti-GBM antibodies 1, 4
• Cryoglobulins, rheumatoid factor, serum IgA levels 1

Step 4: Kidney biopsy

• Essential when diagnosis remains uncertain or acute renal failure develops 1, 6
• Immunofluorescence pattern distinguishes pauci-immune (ANCA), immune complex (lupus, infection-related), and complement-mediated (C3 glomerulopathy) diseases 1

Common Pitfalls to Avoid

• Never delay infectious workup, as infection is the most common and immediately treatable cause of low complement with anasarca 4
• Do not assume normal complement excludes glomerulonephritis; ANCA GN typically shows normal complement in most cases 5
• Persistently low C3 beyond 12 weeks post-infection mandates kidney biopsy to exclude C3 glomerulopathy 1
• Do not overlook malignancy-associated membranous nephropathy in older adults with unexplained nephrotic syndrome 4
• Isolated P-ANCA positivity without MPO-ANCA can occur in non-vasculitic inflammatory conditions (inflammatory bowel disease); always confirm with MPO-ANCA ELISA 1