What is the differential diagnosis for a 6-year-old child presenting with low C3 (complement) levels and proteinuria?

Differential Diagnosis: Low C3 Complement and Proteinuria in a 6-Year-Old

In a 6-year-old child presenting with low C3 and proteinuria, the primary differential diagnosis is C3 glomerulopathy (C3GN or dense deposit disease), followed by post-infectious glomerulonephritis and membranoproliferative glomerulonephritis (MPGN), with immediate workup including complement studies, renal biopsy, and genetic testing for alternative pathway dysregulation. 1

Primary Diagnostic Considerations

C3 Glomerulopathy (Most Likely in Children)

C3 glomerulopathy is the leading diagnosis when immunofluorescence shows C3-positive but immunoglobulin-negative staining, indicating dysregulation of the alternative complement pathway. 1

• In children, this pattern typically suggests a genetic etiology affecting complement regulation, whereas adults more commonly have autoantibodies 1
• C3 glomerulopathy encompasses both dense deposit disease and C3 glomerulonephritis 1
• Without treatment, approximately 70% of affected children progress to end-stage renal disease within 10 years 2

Post-Infectious Glomerulonephritis

Post-infectious GN should be considered, particularly with history of recent pharyngitis (1-2 weeks prior) or impetigo (4-6 weeks prior). 1

• Low C3 and C4 levels support this diagnosis 1
• Persistently low C3 beyond 12 weeks is a red flag that should prompt kidney biopsy to exclude C3GN 1
• Measure anti-streptolysin O, anti-DNAse B, and anti-hyaluronidase antibodies 1

Immune Complex-Mediated MPGN

If immunofluorescence shows immunoglobulin-positive staining (suggesting immune complex deposition), evaluate for secondary causes of MPGN. 1

In a 6-year-old, relevant secondary causes include: 1

• Infectious: Hepatitis B/C, chronic bacterial infections (including occult infections)
• Autoimmune: Systemic lupus erythematosus (check ANA)
• Miscellaneous: Cystic fibrosis, celiac disease, sickle cell disease

Essential Diagnostic Workup

Initial Laboratory Evaluation

Obtain comprehensive metabolic panel, complement levels (C3, C4), and autoimmune markers to differentiate between diagnostic possibilities. 1, 3

• Complete metabolic panel including serum creatinine, BUN, albumin, and total protein 1
• Complement studies: C3, C4, and factor B 1
• Antinuclear antibody (ANA) testing 1
• Hepatitis B and C serologies 1
• Urine cultures for bacterial or viral pathogens 1

Proteinuria Quantification

Use spot urine protein-to-creatinine ratio (PCR) rather than 24-hour collections in children, as timed collections are impractical and often inaccurate. 3, 4

• Normal PCR is <0.2 g/g 3, 4
• Nephrotic-range proteinuria is PCR >2 g/g 3

Advanced Complement Testing for C3 Glomerulopathy

If C3 glomerulopathy is suspected, obtain specialized testing for alternative pathway dysregulation. 1

Genetic screening for mutations in: 1

• C3
• Complement factors H, I, B
• CD46 (membrane cofactor protein)
• Complement factor H-related proteins (CFHR) 1-5

Acquired factors: 1

• C3 nephritic factor (C3NeF) - antibody to C3 convertase
• Anti-factor H antibody

These specialized tests are available through select research laboratories at University of Iowa and National Jewish Health. 1

Renal Imaging

Renal ultrasound is the first-line imaging modality to assess kidney size and echogenicity. 1

• Echogenic kidneys that are large for age suggest acute glomerulonephritis 1
• Normal or small kidneys may be seen in chronic disease 1

Renal Biopsy Indications

Persistent proteinuria with low C3 requires renal biopsy for definitive diagnosis and to guide treatment. 1, 3

• Biopsy is essential to distinguish between C3 glomerulopathy and immune complex-mediated disease 1
• Specimens should be evaluated by experienced nephropathologists due to the rarity and complexity of MPGN variants 1
• Immunofluorescence pattern determines classification: C3-positive/immunoglobulin-negative indicates C3 glomerulopathy 1

Critical Referral Criteria

Immediate pediatric nephrology referral is warranted for: 1, 3, 5

• Persistent significant proteinuria (PCR >0.2 g/g on three specimens) 1, 3
• Combined hematuria and proteinuria 3, 5
• Edema, hypertension, or signs of nephrotic syndrome 1
• Elevated blood urea nitrogen or creatinine levels 1
• Low C3 persisting beyond 12 weeks (to exclude C3GN) 1

Treatment Considerations Based on Diagnosis

For C3 Glomerulopathy

Treatment options include immunosuppression or complement blockade, with emerging evidence supporting eculizumab in refractory cases. 6, 7, 2, 8

• Mycophenolate mofetil (600 mg/m²/dose every 12 hours) combined with pulse methylprednisolone (30 mg/kg/day IV for 3 days, maximum 1 g) followed by oral prednisolone taper has shown complete remission in pediatric cases 2
• Eculizumab (complement C5 inhibitor) normalized proteinuria within 1-7 months in pediatric C3G patients on native kidneys 7, 8
• Pegcetacoplan (C3/C3b inhibitor) showed rapid clinical improvement within 1 week in a 9-year-old with treatment-resistant C3GN 6
• RAAS blockers (ACE inhibitors or ARBs) should be initiated for proteinuria control 7, 2

For Post-Infectious Glomerulonephritis

Treatment is primarily supportive with management of hypertension and edema; prognosis is generally good with early antibiotic treatment of the underlying infection. 1

• Immunosuppression is generally not indicated and carries substantial risks 1

For Immune Complex-Mediated MPGN

Treatment should target the underlying secondary cause identified through workup. 1

• If no secondary cause is identified and patient has nephrotic syndrome with progressive kidney function decline, consider oral cyclophosphamide or MMF plus low-dose corticosteroids for <6 months 1

Common Pitfalls to Avoid

• Do not assume post-infectious GN if C3 remains low beyond 12 weeks - this mandates biopsy to exclude C3GN 1
• Do not delay genetic testing in children with C3 glomerulopathy - genetic mutations are more common than autoantibodies in pediatric patients and influence prognosis 1, 7
• Do not rely on 24-hour urine collections in children - spot PCR is more practical and reliable 3, 4
• Do not initiate immunosuppression for presumed post-infectious GN without biopsy confirmation if the clinical picture is atypical or C3 remains persistently low 1