What is the best way to differentiate renal amyloidosis from multiple myeloma–related light‑chain cast nephropathy (myeloma kidney)?

Differentiating Renal Amyloidosis from Myeloma Kidney

Kidney biopsy with Congo red staining, immunofluorescence for light chain restriction, and electron microscopy is the definitive method to distinguish renal amyloidosis from light-chain cast nephropathy (myeloma kidney). 1

Key Histopathologic Distinctions

Light Microscopy Findings

Renal Amyloidosis:

• Amorphous, eosinophilic deposits in glomeruli, interstitium, tubular basement membranes, and vessel walls 1
• Congo red staining shows apple-green birefringence under polarized light 1
• Deposits appear as homogeneous, acellular material 1

Myeloma Kidney (Light Chain Cast Nephropathy):

• Fractured, brittle casts within distal tubules and collecting ducts 2, 3
• Casts typically have sharp, angular edges with surrounding multinucleated giant cell reaction 2
• Congo red staining is negative (though rare exceptions exist with intratubular amyloid casts in 28% of cases) 4
• Tubular atrophy and interstitial inflammation surrounding casts 2

Electron Microscopy Features

Renal Amyloidosis:

• Randomly arranged, non-branching fibrils measuring 8-12 nm in diameter 1
• Fibrils are extracellular and located in mesangium, basement membranes, or interstitium 1

Myeloma Kidney:

• No organized fibrillar structures 2
• Casts appear as electron-dense, amorphous material within tubular lumens 1
• May show crystalline structures in rare light chain crystal cast variants 2

Immunofluorescence Patterns

Both conditions require immunofluorescence to confirm monoclonal light chain restriction (κ or λ dominance). 1

Critical technical consideration: Pronase digestion of paraffin-embedded tissue may be necessary to unmask hidden light chain deposits when routine immunofluorescence is negative or equivocal. 1, 5

Amyloidosis-Specific Testing:

• Mass spectrometry (LC-MS) of laser-microdissected tissue is the gold standard for amyloid typing when immunofluorescence is equivocal, showing equal κ/λ staining, or when distinguishing AL from other amyloid types 1, 5
• LC-MS is essential in approximately 15% of renal amyloidosis cases 1

Clinical and Laboratory Clues

Proteinuria Patterns

Renal Amyloidosis:

• Typically presents with nephrotic-range proteinuria (>3.5 g/day) with predominant albuminuria 3
• Proteinuria often exceeds that seen in myeloma kidney 3

Myeloma Kidney:

• Proteinuria >3.5 g/g creatinine but with low albumin fraction (<10%) 6, 3
• High urine M-spike (>200 mg/day) with predominantly light chains rather than albumin 6

Serum and Urine Free Light Chain Analysis

Myeloma Kidney:

• Extremely high or extremely low κ/λ ratios in urine (markedly abnormal) 3
• Free light chains >150 mg/dL with high urine M-spike strongly suggests cast nephropathy 6

Renal Amyloidosis:

• Moderately elevated κ/λ ratios (less extreme than myeloma kidney) 3
• λ light chain restriction is more characteristic (76% of intratubular amyloid cases) 4

Renal Function at Presentation

• MIDD (monoclonal immunoglobulin deposition disease) presents with worst renal function, followed by myeloma kidney, then AL amyloidosis 3
• Myeloma kidney typically presents with acute kidney injury and rapid decline 6

Important Caveats and Pitfalls

Overlapping Conditions

Intratubular amyloid can coexist with light chain cast nephropathy in 28% of cases, appearing as casts with Congo red-positive margins and amyloid fibrils on electron microscopy. 4 This finding:

• Is more common with λ light chains (76% of cases) 4
• Significantly increases risk of systemic AL amyloidosis (38% vs 0%) 4
• Requires systematic screening with Congo red staining in all myeloma kidney biopsies 4

Multiple pathologies can coexist: Cases of combined light chain deposition disease, cast nephropathy, and amyloid fibrils have been reported, requiring careful examination of all renal compartments. 7, 8

Technical Considerations

• Always perform Congo red staining on all kidney biopsies from patients with monoclonal gammopathy, even when cast nephropathy is suspected 1
• If Congo red is equivocal, mass spectrometry should be performed 1, 5
• Electron microscopy is mandatory to confirm fibril structure and distinguish from other organized deposits 1
• Ultrastructural immunogold labeling can assist when standard techniques are inconclusive 1

Diagnostic Algorithm

1. Obtain kidney biopsy with adequate tissue for light microscopy, immunofluorescence, and electron microscopy 1

2. Perform Congo red staining on all cases with monoclonal gammopathy 1

   • Positive (apple-green birefringence) → Proceed to amyloid typing
   • Negative → Evaluate for cast nephropathy

3. Immunofluorescence for κ and λ light chains 1

   • If negative on frozen tissue, perform pronase digestion on paraffin sections 1, 5
   • Confirm monoclonal restriction pattern

4. Electron microscopy examination 1

   • Look for 8-12 nm randomly arranged fibrils (amyloid) vs amorphous casts
   • Search thoroughly for intratubular crystals or inclusions 1

5. If amyloid confirmed but immunofluorescence equivocal, perform mass spectrometry 1, 5

6. Correlate with serum/urine studies: 6, 3

   • Serum free light chain assay with κ/λ ratio
   • 24-hour urine protein with electrophoresis
   • Urine albumin fraction

7. Screen for systemic involvement if intratubular amyloid detected in cast nephropathy 4