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

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

The most likely diagnosis in a 6-year-old child presenting with low C3 complement, proteinuria, and hypertension is post-streptococcal glomerulonephritis (PSGN), though C3 glomerulopathy must be urgently excluded if C3 remains low beyond 8-12 weeks. 1

Primary Diagnostic Considerations

Post-Streptococcal Glomerulonephritis (Most Common)

• PSGN is the leading diagnosis when a child presents with the classic triad of hematuria, hypertension, and low C3 following recent pharyngitis or skin infection 2
• The disease manifests as microscopic or gross hematuria, arterial hypertension, edema, and acute kidney injury with a typically self-limiting course 2
• Elevated antistreptolysin O (ASO) titer, low C3, and normal C4 complement factors confirm the diagnosis 2
• Critical timing distinction: C3 levels should normalize within 8-12 weeks in PSGN; persistently low C3 beyond this period is a red flag requiring kidney biopsy to exclude C3 glomerulonephritis 1

C3 Glomerulopathy (Must Be Excluded)

• C3 glomerulopathy should be the primary consideration if C3 remains persistently low, as recommended by the American Academy of Pediatrics and American Society of Nephrology 1
• This encompasses both dense deposit disease (DDD) and C3 glomerulonephritis (C3GN), characterized by C3-positive but immunoglobulin-negative staining on immunofluorescence 1
• C3GN presents with proteinuria, hematuria, hypertension, and renal failure, with chronic deterioration leading to end-stage renal disease within 10 years in 36-50% of patients 3
• Low serum C3 with normal C4 is the hallmark finding, indicating alternative complement pathway dysregulation 3

Lupus Nephritis (Less Likely at Age 6)

• While lupus can present with low C3, proteinuria, and hypertension, it typically affects older children and adolescents
• Both C3 and C4 are usually low in lupus (unlike PSGN or C3GN where C4 is normal) 1

Essential Immediate Workup

First-Line Laboratory Studies

• Obtain comprehensive metabolic panel including serum creatinine, BUN, albumin, and total protein to assess renal function and nephrotic syndrome 1
• Complete complement studies: C3, C4, and factor B to evaluate the alternative complement pathway 1
• Streptococcal serology: ASO titer and anti-DNase B to identify recent streptococcal infection 2
• Urinalysis with microscopy: quantify proteinuria via spot urine protein-to-creatinine ratio and assess for hematuria and red blood cell casts 1

Advanced Complement Testing (If C3 Remains Low)

• C3 nephritic factor (C3NeF) is found in approximately 80% of DDD patients and 45% of C3GN patients 3
• Anti-factor H antibody testing for acquired complement dysregulation 1
• Genetic screening for mutations in C3, complement factors H, I, B, CD46, and CFHR 1-5 should be performed if C3 glomerulopathy is suspected 1

Autoimmune and Infectious Screening

• Antinuclear antibody (ANA) testing to evaluate for systemic lupus erythematosus 1
• Hepatitis B and C serologies to exclude infection-related glomerulonephritis 1

Critical Management Pathway

Immediate Nephrology Referral Criteria

• Immediate pediatric nephrology referral is mandatory for this presentation combining persistent significant proteinuria, hematuria, hypertension, and low C3 1
• The American Academy of Pediatrics recommends urgent referral for children with combined hematuria and proteinuria, edema, or hypertension 1

Timing for Kidney Biopsy

• Kidney biopsy is indicated if C3 remains low beyond 8-12 weeks, as this strongly suggests C3 glomerulopathy rather than self-resolving PSGN 1
• Biopsy should also be considered earlier if there is rapidly progressive renal dysfunction, nephrotic-range proteinuria, or diagnostic uncertainty 4

Blood Pressure Management

• Initiate ACE inhibitor or ARB therapy for hypertension and proteinuria, as these agents provide renoprotection beyond blood pressure control 4
• Target blood pressure below the 75th percentile for age, sex, and height in children with chronic kidney disease 4
• The treatment threshold for initiating antihypertensive therapy is the 90th percentile (approximately 130/85 mmHg for those ≥16 years) 4

Common Pitfalls to Avoid

Timing Errors

• Do not assume PSGN and delay workup if the child lacks a clear history of recent streptococcal infection 2
• Do not wait beyond 12 weeks to pursue kidney biopsy if C3 remains low, as this delay can miss the window for effective treatment of C3 glomerulopathy 1

Incomplete Complement Evaluation

• Always check both C3 and C4 to distinguish between alternative pathway activation (low C3, normal C4) and classical pathway activation (both low) 3
• Failure to obtain C4 levels can lead to misdiagnosis, as lupus nephritis typically shows low C3 and C4 1

Underestimating Disease Severity

• Even with normal initial creatinine, children with C3 glomerulopathy can progress to end-stage renal disease within 10 years 3
• Nephrotic-range proteinuria (>3.5 g/day or spot urine protein-to-creatinine ratio >3.5 g/g) indicates high-risk disease requiring aggressive management 5

Treatment Considerations Based on Diagnosis

If PSGN is Confirmed

• Supportive care with fluid and sodium restriction, antihypertensive therapy, and monitoring for spontaneous resolution 2
• Antibiotics (such as ceftriaxone) if active streptococcal infection is present 2
• Expect C3 normalization within 8-12 weeks and complete clinical recovery 2

If C3 Glomerulopathy is Diagnosed

• Combination immunosuppression with mycophenolate mofetil (600 mg/m² every 12 hours) plus pulse methylprednisolone (30 mg/kg/day IV for 3 days, maximum 1 g) followed by oral prednisolone taper has shown complete renal recovery in pediatric cases 6
• Pegcetacoplan (C3 inhibitor) represents emerging therapy showing rapid clinical improvement within 1 week in treatment-resistant pediatric C3GN 7
• ACE inhibitor therapy should be continued throughout treatment for proteinuria reduction 6