How should membranoproliferative glomerulonephritis be treated in a child or young adult presenting with nephrotic‑range proteinuria, hematuria, and impaired renal function?

Treatment of Membranoproliferative Glomerulonephritis (MPGN)

Initial Critical Step: Exclude Secondary Causes Before Treatment

Before initiating any immunosuppressive therapy, you must thoroughly evaluate for underlying causes of MPGN, as secondary forms are far more common than idiopathic disease and require treatment of the underlying condition rather than immunosuppression. 1

Mandatory Workup to Exclude Secondary MPGN:

• Infections: Screen for hepatitis B, hepatitis C, bacterial endocarditis, chronic bacterial infections, and other chronic infections 1, 2
• Autoimmune diseases: Check ANA and specific autoantibodies to exclude lupus, rheumatoid arthritis, and other systemic autoimmune conditions 1, 3, 2
• Monoclonal gammopathies (adults): Perform serum and urine immunofixation/immunoelectrophoresis plus serum free light chain analysis to exclude plasma cell dyscrasias 1, 3
• Complement testing: Send C3, C4, complement factors H and I, C3 nephritic factor (C3Nef), and anti-factor H antibody to distinguish immune complex MPGN from C3 glomerulopathy 1

If a secondary cause is identified, treat the underlying condition (e.g., antiviral therapy for hepatitis, antibiotics for endocarditis, chemotherapy for monoclonal gammopathy) rather than proceeding with immunosuppression for idiopathic MPGN. 1, 2

Treatment Algorithm for Idiopathic MPGN in Children and Young Adults

For Patients with Nephrotic Syndrome AND Progressive Decline in Kidney Function:

Treat with oral cyclophosphamide or mycophenolate mofetil (MMF) PLUS low-dose alternate-day or daily corticosteroids, with initial therapy limited to less than 6 months. 1

Specific Corticosteroid Regimen for Children:

• Start prednisone 40 mg/m² on alternate days for 6-12 months (and possibly longer if there is clear clinical response). 1
• This approach is supported by a randomized controlled trial in 80 children showing renal survival of 61% with prednisone versus 12% with placebo at 130 months (P=0.07) 1

For Severe/Crescentic Disease:

• Use IV methylprednisolone 500-1000 mg daily for 3 consecutive days, followed by oral prednisone. 3, 4
• Combine with cyclophosphamide plus corticosteroids for crescentic MPGN, similar to ANCA-associated vasculitis regimen. 4, 2, 5

For Patients with Nephrotic Syndrome WITHOUT Progressive Decline in Kidney Function:

A trial of corticosteroids alone may be warranted as first-line treatment in children, even though the data are not entirely convincing. 1

• Use alternate-day prednisone 40 mg/m² for 6-12 months 1
• If no significant reduction in proteinuria is observed, steroids should be tapered and discontinued 1

For Patients with Normal eGFR and Non-Nephrotic Range Proteinuria:

Treat conservatively with supportive measures only (ACE inhibitors or ARBs for RAS blockade), as long-term outcome is good in this population. 1

• Close follow-up is needed to assess progression based on renal function, proteinuria, and urine microscopy 1

Critical Contraindications to Immunosuppression

Do NOT treat with immunosuppression if any of the following are present: 1

• Advanced chronic kidney disease with severe tubulointerstitial fibrosis
• Small kidney size
• Other findings consistent with chronic inactive disease
• eGFR <30 mL/min/1.73 m² ONLY if biopsy shows extensive glomerulosclerosis or absence of active necrotizing/crescentic lesions 4

Emerging Complement-Targeted Therapy

Pegcetacoplan (EMPAVELI), a C3 inhibitor, is now FDA-approved for C3 glomerulopathy and primary immune complex MPGN in adults and children ≥12 years with proteinuria ≥1 g/day. 6

• Administered as subcutaneous infusion twice weekly 6
• Requires vaccination against S. pneumoniae, N. meningitidis, and H. influenzae type B at least 14 days prior to initiation 6
• Patients must be on stable, optimized doses of ACE inhibitors/ARBs for at least 12 weeks before starting 6
• This represents a targeted approach for complement-mediated disease when traditional immunosuppression has failed or is contraindicated 6, 7

Common Pitfalls to Avoid

• Never use calcineurin inhibitors (tacrolimus, cyclosporine) for MPGN—these cause immune complex-negative angiopathy and thrombotic microangiopathy. 3, 4
• Do not delay treatment in rapidly progressive/crescentic MPGN while waiting for complete workup—treat aggressively with cyclophosphamide and high-dose corticosteroids immediately. 4, 5
• Do not assume all patients with low eGFR should avoid treatment—active crescentic disease warrants aggressive therapy regardless of eGFR if biopsy shows viable renal parenchyma. 4
• Avoid treating patients with advanced chronic changes on biopsy (>50% glomerulosclerosis, extensive fibrosis) as they will not benefit and face only toxicity risk. 1, 4

Strength of Evidence and Nuances

The evidence for MPGN treatment is exceptionally weak, consisting primarily of uncontrolled observational studies and underpowered trials performed before our understanding of complement-mediated versus immune complex-mediated pathogenesis 1. The KDIGO guideline recommendation is graded 2D (weak recommendation, very low-quality evidence) 1. However, in the absence of stronger evidence and given the progressive nature of MPGN leading to end-stage renal disease, immunosuppression is justified in children and young adults with nephrotic syndrome and declining renal function to prevent irreversible kidney damage. 1, 8

The heterogeneity of MPGN—now recognized as a spectrum of complement-mediated and immune complex-mediated diseases rather than distinct entities—explains the variable treatment responses and underscores the importance of thorough pathologic evaluation and complement testing 7, 2, 9.