In a 72‑year‑old man with well‑controlled type 2 diabetes, IgG myeloma status post‑stem‑cell transplant, rising serum creatinine (≈140 → 200 µmol/L), microscopic hematuria, proteinuria (ACR 15‑50 mg/g, protein‑creatinine ratio 34 g/g), whose renal biopsy shows nodular glomerulosclerosis, moderate interstitial fibrosis and tubular atrophy, immunofluorescence with only 1+ granular C3 (negative for IgG, IgA, IgM, kappa, lambda, fibrinogen, albumin) and DNAJB9 negative, and electron microscopy with granular, non‑organized electron‑dense deposits along capillary walls, is this monoclonal immunoglobulin deposition disease (MIDD) or another diagnosis, and how should it be managed?

Diagnostic Assessment: Not Classic MIDD – Consider Diabetic Nephropathy with Masked Monoclonal Deposits or C3 Glomerulopathy

This case does not meet diagnostic criteria for classic monoclonal immunoglobulin deposition disease (MIDD) because immunofluorescence shows only isolated C3 deposition without monoclonal immunoglobulin or light chain restriction. 1 The nodular glomerulosclerosis with isolated C3 and granular electron-dense deposits along capillary walls in a patient with longstanding diabetes and IgG myeloma requires additional workup before finalizing the diagnosis.

Why This Is Not Classic MIDD

MIDD requires demonstration of monotypic immunoglobulin deposits (light chains, heavy chains, or both) by immunofluorescence along glomerular and tubular basement membranes. 1 Your case shows:

• Negative immunofluorescence for IgG, IgA, IgM, kappa, lambda, and fibrinogen [@case presentation]
• Only 1+ granular C3 in mesangium and vessels [@case presentation]
• Granular to powdery electron-dense deposits along capillary walls [@case presentation]

Classic MIDD would show linear punctate deposits of monotypic light chains (most commonly kappa) or heavy chains along both glomerular and tubular basement membranes on immunofluorescence. [@1@, @4@] The absence of monoclonal immunoglobulin staining on standard immunofluorescence makes classic MIDD unlikely.

Critical Next Step: Pronase-Digested Immunofluorescence

You must perform immunofluorescence studies on protease-digested, paraffin-embedded tissue sections before excluding monoclonal immunoglobulin deposition disease. [@2@, 1, @8@] This is essential because:

• 60-80% of patients over 50 years with C3 glomerulopathy have monoclonal gammopathy [@3@, 2]
• Your patient has documented IgG myeloma, making masked monoclonal deposits highly likely [@case presentation]
• Approximately 5-10% of cases appearing as C3 glomerulopathy on routine immunofluorescence actually have membranoproliferative glomerulonephritis with masked monoclonal deposits 2
• Pronase digestion can unmask hidden monoclonal immunoglobulin deposits that are not detected by routine frozen-section immunofluorescence 1, 2

Differential Diagnosis Framework

Most Likely: Diabetic Nephropathy with Concurrent Monoclonal Deposition (Masked)

The nodular glomerulosclerosis pattern in a patient with well-controlled T2DM and IgG myeloma suggests overlapping diabetic nephropathy with masked monoclonal immunoglobulin deposits. 3 This scenario is supported by:

• Nodular glomerulosclerosis is the hallmark of both diabetic nephropathy and MIDD 1, 3, 4
• Light microscopy alone cannot distinguish between diabetic glomerulosclerosis and MIDD 3
• Concurrent diabetic nephropathy and light-and-heavy-chain deposition disease has been documented 3
• The granular electron-dense deposits along capillary walls are consistent with monoclonal immunoglobulin deposition 1

Alternative: C3 Glomerulopathy Associated with Monoclonal Gammopathy

Isolated C3 deposition with monoclonal gammopathy may represent C3 glomerulopathy where the monoclonal protein activates the alternative complement pathway without forming tissue deposits. 1, 2 However:

• The nodular glomerulosclerosis pattern is atypical for primary C3 glomerulopathy 2
• The electron-dense deposits along capillary walls in a "thin band" are more consistent with MIDD than C3 glomerulopathy 1
• C3 glomerulopathy typically shows mesangial and subendothelial deposits, not the linear capillary wall pattern described 1, 2

Less Likely: Heavy-Chain Deposition Disease (HCDD)

IgG heavy-chain deposition disease can present with negative routine immunofluorescence because standard panels do not include IgG subclass staining. 1, 5, 6 HCDD characteristics include:

• Truncated IgG1 (most common in HCDD) lacking the first constant domain may not be detected by routine IgG antibodies 1
• IgG subclass staining is mandatory to detect HCDD 1, 5
• HCDD frequently shows hypocomplementemia and nodular glomerulopathy 4
• Your patient's IgG myeloma makes this diagnosis plausible [@case presentation]

Mandatory Additional Workup

Immediate Biopsy Studies Required

1. Perform pronase-digested paraffin immunofluorescence with full panel (IgG, IgA, IgM, kappa, lambda) 1, 2
2. Add IgG subclass staining (IgG1, IgG2, IgG3, IgG4) to detect heavy-chain restriction 1, 5
3. Consider IgD and IgE immunohistochemistry if pronase immunofluorescence remains negative [@10@]
4. If all immunofluorescence studies remain negative despite electron microscopy deposits, consider laser microdissection with mass spectrometry [@2@, @10@]

Serum and Urine Studies

Correlate biopsy findings with comprehensive monoclonal protein evaluation: [1, @4@, 5]

• Serum protein electrophoresis with immunofixation
• 24-hour urine protein electrophoresis with immunofixation
• Serum free light chain assay with kappa/lambda ratio
• IgG subclass quantification

Complement Workup

Given the isolated C3 deposition, evaluate for complement dysregulation: [@8@]

• Serum C3, C4, CH50 levels
• C3 nephritic factor
• Factor H, Factor I, Factor B levels (if available)

Treatment Algorithm Based on Final Diagnosis

If Pronase IF Confirms Monoclonal Immunoglobulin Deposits (MIDD or HCDD)

Initiate bortezomib-based chemotherapy immediately to target the plasma cell clone. [@5@, @11@, 4] Specific recommendations:

• Bortezomib-based regimens are the gold standard for MIDD treatment 1
• Goal is to achieve at least VGPR (very good partial response) to stabilize or improve renal function 1
• Early treatment with creatinine <5.0 mg/dL (approximately <440 µmol/L) has 67% chance of stabilizing or improving renal function [@12@]
• Your patient's creatinine of ~200 µmol/L makes him an excellent candidate for chemotherapy [@case presentation, 4]
• Consider VCD (bortezomib, cyclophosphamide, dexamethasone) or BMDex (bortezomib, melphalan, dexamethasone) 1

If Pronase IF Remains Negative (C3 Glomerulopathy with Monoclonal Gammopathy)

Treat the underlying plasma cell clone with bortezomib-based therapy, as the monoclonal protein likely drives complement dysregulation. 2, 7 Management includes:

• Clone-directed therapy is essential even without tissue deposits 7
• RAS inhibition for proteinuria control 2
• Avoid long-term calcineurin inhibitors (risk of thrombotic microangiopathy) 2
• Monitor complement levels and renal function closely

If Diabetic Nephropathy Alone (Unlikely Given Myeloma History)

Optimize diabetic nephropathy management with RAS blockade and SGLT2 inhibitors, but maintain high suspicion for concurrent monoclonal deposition given the myeloma history. [@general medical knowledge]

Critical Pitfalls to Avoid

1. Do not accept the diagnosis based on routine immunofluorescence alone in a patient with known monoclonal gammopathy [@2@, 1, @8@]
2. Do not attribute all findings to diabetic nephropathy without excluding monoclonal deposition disease [@9@]
3. Do not delay pronase immunofluorescence – this is the single most important diagnostic step [1, @8@]
4. Do not miss the opportunity for early chemotherapy intervention while renal function is still salvageable [@12@]
5. Do not assume negative routine immunofluorescence excludes MIDD – IgD, IgE, and truncated heavy chains require special staining [1, @10@]

Prognosis and Monitoring

Without treatment, MIDD has poor renal prognosis with mean renal survival of 22 months and patient survival of 54 months. [@12@] However:

• Chemotherapy achieving hematologic response significantly improves renal outcomes [@5@, 4]
• Initial creatinine is the strongest predictor of renal and patient survival 4
• Your patient's relatively preserved renal function (creatinine ~200 µmol/L) is favorable for treatment response [@case presentation, 4]
• Monitor serum free light chains and proteinuria monthly during treatment 1
• Repeat renal biopsy may be considered if renal function deteriorates despite hematologic response 1