What is the diagnosis and treatment approach for Membranoproliferative Glomerulonephritis (MPGN)?

Membranoproliferative Glomerulonephritis (MPGN): Etiology, Types, Diagnosis and Treatment

The diagnosis and treatment of MPGN should be directed at the underlying cause, with immunomodulating therapy for immune complex-mediated disease and antiviral therapy for infection-associated cases, particularly HCV-related MPGN. 1

Classification of MPGN

MPGN is now classified based on immunofluorescence findings into three main types:

1. Immune Complex-Mediated MPGN (IC-MPGN)

   • Characterized by immunoglobulin and complement deposits
   • Represents approximately 78% of cases 2

2. Complement-Mediated MPGN (C3G)

   • Includes C3 Glomerulonephritis (C3GN) and Dense Deposit Disease (DDD)
   • Characterized by C3 deposits with minimal or no immunoglobulin deposits
   • Less common, representing about 9% of cases 2

3. Immunofluorescence-Negative MPGN

   • Neither immunoglobulin nor C3 deposits
   • May indicate chronic thrombotic microangiopathy, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, scleroderma, transplant glomerulopathy, antiphospholipid syndrome, or malignant hypertension 3

Etiology

The etiology of MPGN includes:

• Idiopathic: 32% of cases 2
• Infectious causes (25%):
  • Bacterial infections (endocarditis, shunt infections)
  • Viral hepatitis (HCV, HBV)
  • Other infections (malaria, schistosomiasis, mycoplasma) 1
• Autoimmune diseases (14%):
  • Systemic lupus erythematosus
  • Sjögren's syndrome
  • Rheumatoid arthritis 1
• Hematological disorders (10%):
  • Monoclonal gammopathies
  • Lymphoproliferative disorders 2

Diagnostic Approach

1. Renal Biopsy:

   • Essential for diagnosis
   • Requires light microscopy, immunofluorescence, and electron microscopy
   • Should be evaluated by experienced nephropathologists 3

2. Laboratory Evaluation:

   • Renal function assessment (serum creatinine, eGFR)
   • Quantification of proteinuria (24-hour urine)
   • Urinalysis (hematuria, casts)
   • Complement studies (C3, C4, CH50)
   • Evaluation for underlying causes:
     • Viral serologies (HCV, HBV)
     • Autoimmune markers (ANA, RF, anti-dsDNA)
     • Monoclonal protein studies (SPEP, UPEP, immunofixation) 1

3. Complement System Evaluation:

   • Genetic testing for complement factor mutations (H, I, B)
   • Testing for C3 nephritic factor and anti-factor H antibodies 1

Treatment Approach

1. Treatment of Secondary MPGN

• Infection-Related MPGN:

  • Treat the underlying infection with appropriate antimicrobials
  • For HCV-related MPGN:
    • CKD Stages 1-2: Combined antiviral treatment with pegylated interferon and ribavirin 3
    • CKD Stages 3-5 (not on dialysis): Monotherapy with pegylated interferon, with doses adjusted to kidney function 3
    • Consider direct-acting antiviral therapy for viral eradication 1

• Autoimmune Disease-Related MPGN:

  • Treat the underlying autoimmune condition with appropriate immunosuppression 1

• Monoclonal Gammopathy-Related MPGN:

  • Target the B cell or plasma cell clone responsible for monoclonal immunoglobulin production 1

2. Treatment of Idiopathic MPGN

• Immune Complex-Mediated MPGN (IC-MPGN):

  a) With nephrotic syndrome and normal/near-normal serum creatinine:

  • Limited treatment course of glucocorticoids 3
  • If contraindications to glucocorticoids exist or response is inadequate, consider MMF or rituximab 3

  b) With abnormal kidney function (without crescents):

  • Add glucocorticoids and immunosuppressive therapy to supportive care 3
  • Consider mycophenolate mofetil (MMF) as first-line therapy 1

  c) With rapidly progressive crescentic presentation:

  • High-dose glucocorticoids and cyclophosphamide 3
  • Similar regimen to ANCA-associated vasculitis 3

  d) With eGFR <30 ml/min per 1.73 m²:

  • Supportive care alone (unless active necrotizing/crescentic GN) 3

• For children with MPGN:

  • Trial of alternate-day steroids (40 mg/m²) for 6-12 months 3
  • Studies show improved renal survival with this approach 4
  • Type I MPGN responds better to alternate-day prednisone than Type III 4

3. Supportive Care

• Blood pressure control
• Proteinuria management with ACE inhibitors or ARBs
• Cardiovascular risk assessment and management 1

Monitoring and Follow-up

• Regular assessment of kidney function
• Quantification of proteinuria
• Monitoring of complement levels
• Viral load monitoring (in HCV-related cases)
• Evaluation for disease relapse 1

Prognosis

• Prognosis varies based on MPGN type and underlying cause
• Type I MPGN treated with alternate-day prednisone generally has better outcomes than Type III 4
• Persistent hypocomplementemia, particularly in Type III MPGN, may indicate poorer response to therapy 4
• Patients with advanced CKD, severe tubulointerstitial fibrosis, or significant glomerular sclerosis have poorer prognosis 3

Important Considerations

• Due to the rarity of MPGN, renal biopsy specimens should be evaluated by experienced nephropathologists 3
• Avoid long-term use of calcineurin inhibitors as they may be associated with immune complex-negative angiopathy MPGN and thrombotic microangiopathy 3
• Consider clinical trials for patients who fail to respond to standard treatments 3