What are the clinical features, diagnosis, and treatment of Membranoproliferative Glomerulonephritis (GN)?

Membranoproliferative Glomerulonephritis: Clinical Features, Diagnosis, and Treatment

Critical Conceptual Framework

MPGN is not a single disease but a histologic pattern of glomerular injury with multiple distinct etiologies that must be differentiated by immunofluorescence patterns. 1 The classification is based on three immunofluorescence patterns: immune complex-mediated, complement-dominant (C3 glomerulopathy), and immunofluorescence-negative. 1

Clinical Presentation

Common Presentations

• Nephrotic syndrome is the most frequent presentation, characterized by heavy proteinuria (≥3.5 g/day), hypoalbuminemia, and edema. 2
• Nephritic syndrome may occur with hematuria, proteinuria, hypertension, and acute kidney injury. 1
• Asymptomatic urinary abnormalities with microscopic hematuria and non-nephrotic proteinuria can be the initial finding. 2

Age and Demographics

• Primarily affects children and young adults, with average age of onset around 12 years. 3
• Female predominance noted in early-onset disease (before age 10), particularly in Type II MPGN. 3

Associated Systemic Features

• Hypocomplementemia is characteristic across all MPGN types, though mechanisms of complement activation differ. 2
• Type II (dense deposit disease) specifically associates with C3-nephritic factor. 2

Diagnostic Workup

Essential Laboratory Testing

• Serum creatinine, urinalysis with quantification of proteinuria (24-hour collection or protein-to-creatinine ratio). 4
• Complement levels (C3 and C4) are mandatory—low levels help distinguish MPGN from other glomerular diseases. 4
• Protein electrophoresis to detect monoclonal proteins. 4
• Hepatitis C serology, cryoglobulin titers, and antinuclear antibody testing to identify secondary causes. 4

Specialized Testing Based on Immunofluorescence Pattern

• For C3 glomerulopathy in children: genetic screening for mutations in C3, complement factors H/I/B, CD46, and CFHR 1-5. 1
• For C3 glomerulopathy in adults: testing for acquired autoantibodies including C3 nephritic factor (C3Nef) and anti-factor H antibody. 1
• When monoclonal immunoglobulin is detected, specify the MIg type (kappa vs lambda). 1

Kidney Biopsy—Definitive Diagnosis

Light Microscopy Features

• Mesangial and/or endocapillary hypercellularity with thickening of capillary walls caused by subendothelial deposits. 4
• Lobular accentuation of glomerular tufts with mesangial expansion. 4
• GBM changes including double contours ("tram-tracking"). 4
• Document percentage of globally sclerosed glomeruli and extent of tubulointerstitial fibrosis. 4, 1

Immunofluorescence Patterns (Critical for Classification)

• Immune complex-mediated: polyclonal IgG/IgM deposits (e.g., hepatitis C-associated cryoglobulinemic GN). 4
• Complement-dominant (C3 glomerulopathy): isolated or dominant C3 staining. 4
• Monoclonal Ig deposition: IgG or IgM with light chain restriction (kappa or lambda). 4

Electron Microscopy

• Granular deposits predominantly mesangial and subendothelial. 5
• Dense deposit disease (Type II) shows characteristic dense intramembranous deposits. 2

Common Diagnostic Pitfall

Renal biopsy is mandatory in any patient with hepatitis C who has urinary abnormalities or unexplained renal impairment to distinguish MPGN from other HCV-associated glomerular diseases. 1 The three main glomerular patterns from cryoglobulin deposition are diffuse membranoproliferative, mesangial proliferative, and membranous patterns. 1

Treatment Approach

Patients Who Should NOT Receive Immunosuppression

Do not treat patients with advanced CKD, severe tubulointerstitial fibrosis, small kidneys, or chronic inactive disease with immunosuppression. 1 These features predict poor response and increased toxicity risk.

Treatment for Idiopathic MPGN with Nephrotic Syndrome and Progressive Decline

Children

• High-dose alternate-day steroids (40 mg/m² on alternate days) for 6-12 months is the recommended first-line therapy. 6, 2
• If no benefit is observed, discontinue steroids and focus on conservative management. 6

Adults

• For idiopathic MPGN with nephrotic-range proteinuria and/or impaired renal function: oral cyclophosphamide or mycophenolate mofetil (MMF) plus low-dose alternate-day or daily corticosteroids for less than 6 months. 1
• Alternative approach: trial of aspirin (325 mg daily), dipyridamole (75-100 mg three times daily), or combination therapy for 12 months. 6
• If no benefit after 12 months, discontinue antiplatelet therapy. 6

Patients with Normal Renal Function and Asymptomatic Non-Nephrotic Proteinuria

• No specific therapy is necessary. 6
• Close follow-up every 3-4 months monitoring renal function, proteinuria, and blood pressure. 6

Conservative Management (All Patients)

• Aggressive blood pressure control with renin-angiotensin-aldosterone system blockade to reduce proteinuria. 6
• Correction of metabolic abnormalities. 6
• Attention to factors known to delay progression of renal decline. 6

Treatment of Secondary MPGN

• Hepatitis C-associated: Direct-acting antivirals targeting HCV are the primary treatment. 1
• Infection-related: Treat underlying infection (e.g., bacterial endocarditis, cellulitis). 4
• Monoclonal Ig-associated: Treat underlying hematologic disorder (e.g., Waldenström macroglobulinemia). 4

Prognosis and Long-Term Outcomes

Natural History

• MPGN often progresses slowly to end-stage renal disease over years. 2
• Patients with nephrotic-range proteinuria >3.8 g/day have a 35% risk of end-stage renal disease within 2 years. 7
• Clinical outcome appears particularly poor in proliferative GN with monoclonal IgG deposits and membranoproliferative features, with progressive renal decline despite immunosuppressive therapy. 5

Post-Transplant Considerations

• MPGN tends to recur after renal transplantation, especially Type II (dense deposit disease). 2
• Recurrence risk should be discussed with patients considering transplantation. 2

Thrombotic Complications

• Nephrotic syndrome carries significant thrombotic risk with 29% incidence of renal vein thrombosis and 17-28% incidence of pulmonary embolism due to loss of anticoagulant proteins. 7

Critical Clinical Caveat

Early detection through health screenings for blood pressure and urinary dipstick testing (proteinuria and hematuria) plays an important role in identifying MPGN before advanced kidney damage occurs. 3 Female patients with onset before age 10 years, particularly those with Type II MPGN, appear at highest risk for progression to end-stage renal disease. 3