What does an amyloidosis negative SSA (Systemic Sclerosis Associated) result on a renal biopsy signify?

Amyloidosis Negative SSA on Renal Biopsy: Diagnostic Significance

A negative SSA (Serum Amyloid A) result on renal biopsy in a patient with amyloidosis strongly suggests non-AA amyloidosis, most likely AL amyloidosis (light chain amyloidosis) or another rare hereditary form that requires further specialized testing for definitive classification.

Interpretation of Negative SSA in Amyloidosis

• Negative SSA staining on a Congo red-positive renal biopsy indicates that the amyloid deposits are not composed of Serum Amyloid A protein, effectively ruling out AA amyloidosis (secondary amyloidosis) 1

• This finding necessitates further investigation to determine the specific amyloid type, as treatment and prognosis vary significantly depending on the underlying amyloid protein 1

• AL amyloidosis (light chain amyloidosis) is the most common form of non-AA amyloidosis and should be considered as the primary differential diagnosis 2, 3

Recommended Diagnostic Workup

Immunofluorescence and Immunohistochemistry

• Standard immunofluorescence for kappa and lambda light chains should be performed, though it has limited sensitivity (approximately 65%) for AL amyloidosis 2

• If routine immunofluorescence is negative or equivocal, pronase digestion of paraffin-embedded tissue sections should be performed to unmask potentially hidden light chain deposits 1, 4

• Immunohistochemical stains for light chains may also be useful in detecting intracellular monoclonal immunoglobulins when routine studies are negative 1

Mass Spectrometry Analysis

• Mass spectrometric analysis of laser-microdissected kidney tissue containing Congo red-positive deposits is strongly recommended to definitively type the amyloidosis when immunofluorescence/immunohistochemistry results are equivocal 1, 4

• This technique is currently considered the gold standard for accurate diagnosis of amyloidosis, especially in inconclusive cases 5

Hematologic Evaluation

• Comprehensive evaluation for monoclonal gammopathy is essential, including:

  • Serum and urine protein electrophoresis
  • Serum and urine immunofixation
  • Serum free light chain analysis 4, 3

• Bone marrow examination should be considered to evaluate for plasma cell dyscrasia or multiple myeloma 2, 6

Differential Diagnosis of Non-AA Amyloidosis

• AL amyloidosis (light chain amyloidosis): Most common form, associated with plasma cell dyscrasia or multiple myeloma 2, 3

• Hereditary forms of amyloidosis: Consider in patients with negative workup for monoclonal gammopathy or with family history 5

  • Transthyretin amyloidosis (ATTR)
  • Fibrinogen alpha chain amyloidosis
  • Apolipoprotein AI/AII/AIV amyloidosis 3, 7

• ALECT2 amyloidosis: A recently identified form that should be considered, particularly in patients of certain ethnic backgrounds 3, 5

Clinical Implications and Management Considerations

• The specific type of amyloidosis determines treatment approach:

  • AL amyloidosis typically requires chemotherapy targeting the underlying plasma cell disorder 6
  • Hereditary forms do not respond to chemotherapy and may require specific treatments or organ transplantation 5

• Renal staging in AL amyloidosis helps inform prognosis and risk for end-stage kidney disease 6

• A multidisciplinary team approach involving nephrology, hematology, and pathology is essential for optimal management 6

Common Pitfalls to Avoid

• Relying solely on immunofluorescence for typing amyloidosis can lead to misdiagnosis due to its limited sensitivity in AL amyloidosis 2

• Failing to examine the renal medulla can result in missed diagnosis of certain types of amyloidosis, such as AApoAIV amyloidosis, which predominantly affects the medulla 7

• Assuming AA amyloidosis in patients with chronic inflammatory conditions without proper typing can lead to inappropriate treatment 3, 5

• Overlooking the possibility of hereditary amyloidosis, especially in patients with negative workup for monoclonal gammopathy 5