What are the differential diagnoses for a child or young adult presenting with suspected Post-Streptococcal Glomerulonephritis (PSGN) with a recent history of streptococcal infection?

Differential Diagnoses for Post-Streptococcal Glomerulonephritis

When evaluating a patient with suspected PSGN, the key differentials to exclude are IgA-dominant infection-related glomerulonephritis, C3 glomerulonephritis, lupus nephritis, ANCA-associated vasculitis, anti-GBM disease, and cryoglobulinemic glomerulonephritis—all distinguished primarily by complement patterns, serologic markers, and timing of C3 normalization. 1

Primary Differential Diagnoses

Infection-Related Glomerulonephritis (Non-PSGN)

• IgA-dominant infection-related GN is increasingly common in older patients with staphylococcal infections, presenting with similar nephritic features but different immunofluorescence patterns on biopsy 2
• The histology has evolved beyond classic PSGN, with entities showing neutrophilic infiltrate but IgA dominance rather than the traditional subepithelial humps 2
• Consider this diagnosis particularly in adults with concurrent staphylococcal infections (skin, endocarditis, or other deep-seated infections) 2

C3 Glomerulonephritis (C3GN)

• This is the critical differential if C3 remains low beyond 12 weeks, as PSGN should normalize C3 by 8-12 weeks 1
• Both PSGN and C3GN present with low C3 and normal C4, making early differentiation challenging 1
• Kidney biopsy is mandatory if C3 fails to normalize by 12 weeks to distinguish between resolving PSGN and C3GN, which requires different management 1
• C3GN represents complement dysregulation rather than infection-triggered disease and has worse long-term prognosis 1

Lupus Nephritis

• Distinguished by low C3 AND low C4 (unlike PSGN where C4 is normal) 1
• Check ANA and anti-dsDNA antibodies—these should be negative in PSGN 1
• Lupus nephritis typically presents with more systemic features (rash, arthritis, serositis) beyond isolated glomerular disease 1

ANCA-Associated Vasculitis

• Check PR3-ANCA and MPO-ANCA—these should be negative in PSGN 1
• ANCA vasculitis typically presents with normal complement levels, distinguishing it from PSGN 1
• Consider this particularly if there are pulmonary-renal syndrome features or systemic vasculitis manifestations 1

Anti-GBM Disease (Goodpasture Syndrome)

• Check anti-GBM antibodies—these should be negative in PSGN 1
• Anti-GBM disease presents with rapidly progressive glomerulonephritis and normal complement levels 1
• Pulmonary hemorrhage may be present, creating pulmonary-renal syndrome 1

Cryoglobulinemic Glomerulonephritis

• Check cryoglobulins and rheumatoid factor—these should be negative in PSGN 1
• Often associated with hepatitis C infection 1
• May present with palpable purpura, arthralgias, and peripheral neuropathy 1

Diagnostic Algorithm to Differentiate

Initial Serologic Workup

• Streptococcal serology: Measure ASO, anti-DNAse B, and anti-hyaluronidase antibodies 2, 1
• ASO may be normal in up to 27% of cases, particularly with skin infections—anti-DNAse B is more sensitive for impetigo-associated PSGN 1
• Complement studies: C3 should be low, C4 should be normal in PSGN 1

Exclusion Panel

• ANA and anti-dsDNA (to exclude lupus) 1
• PR3-ANCA and MPO-ANCA (to exclude ANCA vasculitis) 1
• Anti-GBM antibodies (to exclude Goodpasture) 1
• Cryoglobulins and rheumatoid factor (to exclude cryoglobulinemia) 1

Timing-Based Differentiation

• Recheck C3 at 8-12 weeks: Complete normalization confirms PSGN 1
• Persistently low C3 beyond 12 weeks mandates kidney biopsy to exclude C3GN or other chronic complement-mediated diseases 1

When to Perform Kidney Biopsy

Kidney biopsy is indicated when: 2, 1

• Diagnosis remains uncertain despite serologic workup
• Atypical presentation (e.g., nephrotic-range proteinuria, absence of hypertension)
• C3 remains low beyond 12 weeks
• Rapidly progressive glomerulonephritis with crescentic features
• Need to assess prognosis in severe cases
• Culture evidence of infection is elusive but clinical suspicion remains high

Common Pitfalls to Avoid

• Do not rely solely on ASO titers—they are less sensitive for skin infections; always check anti-DNAse B and anti-hyaluronidase 1
• Do not assume PSGN if C4 is also low—this suggests lupus or cryoglobulinemia instead 1
• Do not delay biopsy if C3 remains low at 12 weeks—this is the critical timepoint for distinguishing PSGN from C3GN 1
• Do not forget that bacterial infection-related GN can be triggered by organisms other than streptococcus (particularly staphylococcus in adults), which may present with different histologic patterns 2
• Do not overlook that some immune-mediated kidney diseases can be unmasked or triggered by infections, making the distinction between primary glomerular disease and true infection-related GN challenging 2