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

Membranoproliferative Glomerulonephritis: Clinical Features, Diagnosis, and Treatment

Clinical Features

MPGN typically presents with nephritic syndrome characterized by hematuria, proteinuria (often nephrotic-range), hypertension, and acute kidney injury. 1

Key clinical presentations include:

• Nephrotic syndrome with proteinuria ≥3.5 g/day, hypoalbuminemia, and edema—patients with nephrotic-range proteinuria >3.8 g/day face a 35% risk of end-stage renal disease within 2 years 1
• Nephritic features including glomerular hematuria and acute kidney injury 1
• Hypocomplementemia is common, particularly low C3 levels, though the duration varies by MPGN subtype 2
• Thrombotic complications occur frequently in nephrotic syndrome with 29% incidence of renal vein thrombosis and 17-28% incidence of pulmonary embolism due to loss of anticoagulant proteins 1

Diagnostic Workup

Serum creatinine, urinalysis with quantification of proteinuria, and complement levels (C3 and C4) are mandatory initial tests. 1

Essential Laboratory Testing:

• Complement levels: C3 and C4 to assess alternative pathway activation 1
• Protein electrophoresis to detect monoclonal proteins 1
• Hepatitis C serology, cryoglobulin titers, and antinuclear antibody testing to identify secondary causes 1
• Genetic screening for mutations in C3, complement factors H/I/B, CD46, and CFHR 1-5 is recommended for C3 glomerulopathy in children 1
• Autoantibody testing including C3 nephritic factor (C3Nef) and anti-factor H antibody for C3 glomerulopathy in adults 1

Kidney Biopsy Findings:

Mesangial and/or endocapillary hypercellularity with thickening of capillary walls caused by subendothelial deposits is the characteristic feature. 1

• Lobular accentuation of glomerular tufts with mesangial expansion 1
• GBM changes including double contours ("tram-tracking") 1
• Documentation of the percentage of globally sclerosed glomeruli and extent of tubulointerstitial fibrosis is crucial for prognosis 1

Due to the rarity and complexity of MPGN classification, renal biopsy specimens should be evaluated by experienced nephropathologists. 3

Treatment Approach

Identifying Treatment Candidates:

Patients with idiopathic MPGN with nephrotic syndrome AND progressive decline in kidney function should receive oral cyclophosphamide or mycophenolate mofetil (MMF) plus low-dose alternate-day or daily corticosteroids for less than 6 months. 3, 1

Indications for immunosuppressive therapy include:

• Nephrotic syndrome with or without progressive decline in kidney function 3
• Active nephritic syndrome 3
• Rapidly progressive disease with or without crescents 3

Patients who should NOT receive immunosuppression:

• Normal eGFR with non-nephrotic-range proteinuria (conservative management with close follow-up is appropriate) 3
• Advanced CKD with severe tubulointerstitial fibrosis, small kidney size, or chronic inactive disease 3

Pediatric Treatment:

In children with MPGN and nephrotic syndrome and/or impaired renal function, alternate-day prednisone (40 mg/m²) for 6 to 12 months is warranted as first-line treatment. 3

• One randomized controlled trial showed renal survival at 130 months was 61% with prednisone versus 12% with placebo (P=0.07) 3
• Treatment duration may be extended beyond 12 months if there is clear clinical response 3
• Important caveat: Type III MPGN responds less favorably than Type I, with slower normalization of complement levels, more frequent relapses (24% vs 0%), and greater decline in renal function 2

Adult Treatment:

For adults with MPGN, impaired renal function, and/or nephrotic-range proteinuria, a trial of aspirin (325 mg daily), dipyridamole (75-100 mg three times daily), or combination therapy for 12 months is reasonable. 4

• If no benefit is observed after 12 months, discontinue therapy 4
• Immunosuppression with cyclophosphamide or MMF plus corticosteroids should be reserved for those with progressive disease 3, 1

Secondary MPGN Treatment:

Treatment of the underlying cause is paramount for secondary MPGN:

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

Emerging Therapies:

C5 convertase blockade with eculizumab may reduce proteinuria in select patients with MPGN and terminal complement activation (sC5b-9 >1,000 ng/mL), particularly those without C3 nephritic factors. 5

• In a clinical trial, median proteinuria decreased from 6.03 g/day to 3.74 g/day at 24 weeks (P=0.01) 5
• Three patients achieved partial remission, all with undetectable C3 nephritic factors before treatment 5
• Critical limitation: Benefits were not sustained in all patients, and proteinuria returned during washout periods 5

Conservative Management for All Patients:

Regardless of immunosuppressive therapy decisions, all patients require:

• Blood pressure control with renin-angiotensin-aldosterone system blockade 4
• Agents to reduce proteinuria 4
• Correction of metabolic abnormalities 4
• Close follow-up every 3-4 months monitoring renal function, proteinuria, and urine microscopy 3

Common Pitfalls:

• Failing to distinguish primary from secondary MPGN—always screen for hepatitis C, cryoglobulinemia, monoclonal gammopathies, and infections before initiating immunosuppression 3, 1
• Treating patients with advanced chronic disease—immunosuppression is contraindicated in those with severe tubulointerstitial fibrosis or small kidneys 3
• Not recognizing MPGN pattern without immune deposits—this suggests chronic thrombotic microangiopathy, not true MPGN, and requires different management 3
• Assuming all MPGN subtypes respond similarly to treatment—Type III MPGN has worse outcomes than Type I despite similar therapy 2