What is the pathophysiology, recommended diagnostic work‑up, and first‑line treatment for membranous glomerulonephritis in children, and how does it differ from adults?

Membranous Glomerulonephritis in Pediatrics and Adults

Pathophysiology

Membranous nephropathy is fundamentally an autoimmune disease caused by antibodies targeting podocyte antigens, leading to immune complex deposition along the glomerular basement membrane. 1

• In primary disease, the M-type phospholipase A2 receptor (PLA2R) is the target antigen in most adult cases, with circulating anti-PLA2R antibodies driving the pathology 2
• Anti-PLA2R antibodies can occur in adolescents as young as 12 years, though this is less common than in adults 1
• In young children (especially under 5 years), an exogenous antigen—cationic bovine serum albumin (BSA) from cow's milk—has been implicated as a trigger 1
• Secondary causes are more common in children than adults and must be actively excluded: hepatitis B infection, lupus (even without positive ANA), CMV infection, and medications like D-penicillamine 1, 2, 3
• The immune complexes form subepithelial deposits with characteristic granular IgG and C3 on immunofluorescence, creating the "spike and dome" appearance on electron microscopy 4

Diagnosis

Kidney biopsy is the gold standard for diagnosis and should be performed in all pediatric cases to confirm the diagnosis and exclude secondary causes. 1

Diagnostic Work-Up:

• Measure anti-PLA2R antibodies in adolescents and adults—high levels predict progression and poor prognosis, while low/absent levels suggest higher probability of spontaneous remission 5, 2
• Screen aggressively for secondary causes in children: hepatitis B surface antigen, ANA, complement levels (C3, C4), and consider testing for BSA antibodies in very young children 1, 2
• Lupus should be strongly considered in young women even with negative ANA if biopsy features suggest secondary disease 1
• Assess proteinuria using first morning protein-creatinine ratio rather than 24-hour collection in children 6
• Calculate eGFR using the modified Schwartz equation in pediatric patients 6
• Examine urine sediment for microscopic hematuria (present in 80% of pediatric cases) 4

Key Pitfall:

Do not assume membranous nephropathy in children is idiopathic—secondary causes are proportionally more common than in adults, and missing a treatable underlying condition (like hepatitis B or BSA exposure) can lead to unnecessary immunosuppression 1, 2

Treatment Approach

Children with Non-Nephrotic Proteinuria:

Conservative management without immunosuppression is appropriate for children with non-nephrotic range proteinuria, as they have low risk of progressive renal disease. 1

• Provide supportive care with ACE inhibitors or ARBs for antiproteinuric effect 5
• Restrict sodium to <2.0 g/day 5
• Monitor closely for progression 1

Children with Nephrotic Syndrome:

For pediatric membranous nephropathy with nephrotic syndrome, use a shortened cyclophosphamide regimen (2 mg/kg/day for 12 weeks with alternate-day steroids) to limit cumulative exposure. 1

• This provides total cyclophosphamide dose of approximately 200 mg/kg, substantially less than adult protocols 1
• Do not use more than one course of cyclical corticosteroid/alkylating agent regimen in children due to toxicity concerns 1
• Alternative: Some clinicians trial corticosteroid monotherapy first, though this is ineffective in adults 1
• Calcineurin inhibitors (cyclosporine or tacrolimus) are acceptable alternatives for children who cannot tolerate alkylating agents 1
• In very young children with BSA-related disease, eliminate cow's milk and beef products from the diet 1

Adults with Nephrotic Syndrome:

Initiate immunosuppression in adults only if proteinuria persists >4 g/day after 6 months of optimal supportive care, or if there is ≥30% increase in serum creatinine. 5

• First-line: Modified Ponticelli protocol with alternating monthly cycles of methylprednisolone IV (1 g/day × 3 days) followed by oral prednisone (0.5 mg/kg/day × 27 days), alternating with oral cyclophosphamide (2.5 mg/kg/day adjusted for renal function) for 6 months total 5
• This reduces risk of death or ESRD (RR 0.44) and increases remission rates (RR 1.46) 5
• Alternative: Calcineurin inhibitors (cyclosporine or tacrolimus) for patients with contraindications to alkylating agents 5
• Monitor anti-PLA2R antibody levels during treatment—declining levels predict clinical remission 5, 2

Universal Supportive Care (All Patients):

All patients require aggressive supportive therapy regardless of whether immunosuppression is used. 5

• ACE inhibitors or ARBs at maximally tolerated doses, even without hypertension 6, 5
• Target blood pressure <130/80 mmHg in adults; ≤50th percentile for age/sex/height in children 6, 5
• Sodium restriction to <2.0 g/day 6, 5
• Statin therapy for dyslipidemia 5
• Prophylactic anticoagulation with warfarin if serum albumin <2.5 g/dL due to high thromboembolism risk (membranous nephropathy has highest thrombotic risk among glomerular diseases) 1, 5

Prognosis and Monitoring

• In children treated with corticosteroids plus cyclophosphamide, 75% achieve complete remission and 17% achieve partial remission 7
• Complete remission is significantly associated with absence of chronic histological changes on biopsy 7
• Monitor proteinuria, renal function, and anti-PLA2R antibodies (when applicable) to assess treatment response 5
• Complete remission = proteinuria <0.3 g/day with stable renal function 5
• Partial remission = proteinuria <3.5 g/day with ≥50% reduction from baseline 5

Key Difference Between Pediatric and Adult Disease:

Pediatric membranous nephropathy is NOT the same disease as in adults—children have higher rates of secondary causes, different antigen triggers (BSA vs. PLA2R), and require modified treatment protocols with lower cumulative immunosuppression exposure to minimize long-term toxicity. 1, 2