When should proliferative glomerulonephritis with monoclonal immunoglobulin deposition (MID) be suspected in patients?

When to Suspect Proliferative Glomerulonephritis with Monoclonal Immunoglobulin Deposits (PGNMID)

PGNMID should be suspected in patients with proteinuria, hematuria, and abnormal renal function who have a membranoproliferative glomerulonephritis (MPGN) pattern on kidney biopsy with monoclonal immunoglobulin deposits, particularly when serum monoclonal protein testing is negative or reveals only small amounts of monoclonal protein. 1

Clinical Presentation

• Proteinuria: Present in virtually all patients (100%), often in nephrotic range
• Hematuria: Present in approximately 60% of cases
• Renal insufficiency: Present in about 80% of patients at diagnosis
• Hypocomplementemia: Present in approximately 40% of patients

Key Diagnostic Features

Kidney Biopsy Findings

• Light microscopy: Predominantly membranoproliferative glomerulonephritis pattern (most common), but can also present as endocapillary proliferative or membranous patterns
• Immunofluorescence: Critical for diagnosis, showing:
  • Monoclonal immunoglobulin deposits (single light chain isotype + single heavy chain subclass)
  • Most commonly IgG3κ (approximately 50% of cases)
  • Other types include IgG1κ, IgG1λ, IgG2λ, and IgG3λ
  • Deposits stain for all three constant domains of gamma heavy chain
• Electron microscopy: Granular electron-dense deposits in mesangial, subendothelial, and sometimes subepithelial locations

Laboratory Findings

• Serum/urine monoclonal protein: Detectable in only about 30-32% of patients 1
• Complement levels: C3 and/or factor B may be low in some patients
• Renal function tests: Often abnormal (mean serum creatinine ~2.8 mg/dL)
• Proteinuria quantification: Mean 5.8 g/day (range 1.9-13.0 g/day)

High-Risk Populations

• Age: More common in adults, but can occur at any age
• No clear gender predilection
• Patients with unexplained MPGN pattern on biopsy
• Patients with recurrent glomerulonephritis after kidney transplantation (90% recurrence rate) 2

Diagnostic Algorithm

1. Initial suspicion: Patient presents with proteinuria, hematuria, and/or renal insufficiency
2. Kidney biopsy: Shows MPGN or other proliferative pattern
3. Immunofluorescence studies: Critical step showing monoclonal immunoglobulin deposits
   • Stain for IgG subclasses (IgG1, IgG2, IgG3, IgG4) and light chains (κ, λ)
   • Look for restriction to a single IgG subclass and light chain
4. Serum/urine studies (even if negative, proceed with diagnosis if biopsy is consistent):
   • Serum protein electrophoresis (SPEP) and immunofixation (SIFE)
   • Urine protein electrophoresis (UPEP) and immunofixation (UIFE)
   • Serum free light chain assay
   • Quantitative immunoglobulins (IgG, IgA, IgM)
5. Bone marrow examination: To identify underlying plasma cell or B-cell clone
   • Aspiration and biopsy with morphological assessment
   • Flow cytometry with extended panels
   • Cytogenetics and FISH studies

Differential Diagnosis

• Immune complex-mediated MPGN: Shows polyclonal immunoglobulin deposits
• C3 glomerulopathy: Shows C3-dominant deposits with minimal or no immunoglobulin
• Monoclonal immunoglobulin deposition disease (MIDD): Linear deposits along basement membranes
• Immunotactoid glomerulonephritis: Organized microtubular deposits
• Fibrillary glomerulonephritis: Usually polyclonal IgG deposits with fibrils
• Cryoglobulinemic glomerulonephritis: Associated with detectable cryoglobulins

Important Clinical Pearls

1. Negative serum/urine monoclonal protein does not exclude PGNMID - approximately 70% of patients have no detectable monoclonal protein 1, 3

2. Serum immunofixation may be more helpful than serum free light-chain assays in diseases associated with intact monoclonal immunoglobulin like PGNMID 1

3. Recurrence after kidney transplantation is common (90%), often occurring within months (median 7 months) 2

4. Progression to end-stage kidney disease occurs in approximately 20% of patients 3

5. When evaluating patients with C3 glomerulopathy over age 50, always consider underlying monoclonal gammopathy as a potential driver 1, 4

6. Treatment should target the underlying B-cell or plasma cell clone when identified, even if small 5

By maintaining a high index of suspicion for PGNMID in patients with unexplained proliferative glomerulonephritis, particularly those with MPGN pattern, early diagnosis and treatment can potentially improve outcomes and prevent progression to end-stage kidney disease.