Dysproteinaemias and Light Chain Diseases

Question 1

What is myeloma?
Haematologic malignancy of __
Preclinical disease __
Onset

2 cardinal features

Commonest class of Ig involvement

Answer 1

Excesssive clonally expanded cytogenetically heterogenous bone marrow-derived plasma cells

Preclinical disease: MGUS (monoclonal gammopathy of unknown significance)

Onset: elderly (median age > 65 years old)

2 cardinal features:
1. Monoclonal immunoglobulin (paraprotein or M protein) and/or associated light chains (kappa, lambda)
2. Bone destruction (osteolytic lesions)

Commonest class of Ig involvement:
IgG > IgA > IgD

Question 2

Multiple myeloma causes __ in nearly half of patients, with _ requiring __
Commonest in __ and __

MM causes AKI via 6 pathogenesis
__ is required to distinguish potential etiologies and guide therapy

Answer 2

Kidney damage, 10% requiring urgent dialysis from severe kidney failure
Commonest in IgD and LC myeloma

MM causes AKI via 6 pathogenesis:
1. Cast nephropathy
2. Hypercalcaemia-induced volume delpetion
3. Monoclonal immunoglobulin deposition disease (MIDD)
4. Amyloidosis
5. Proximal tubulopathy / Fanconi syndrome
6. Cryoglobulinaemia

Kidney biospy required to distinguish etiologies and guide therapy

Question 3

Diagnosis of myeloma

Answer 3

1. Clonal expansion of bone marrow plasma cells > 10%

Additional ONE myeloma-defining event (CRAB):
- Calcium (hypercalcaemia)
- Renal insufficiency
- Anaemia
- Bone lesion

Question 4

Cast nephropathy is the most common histologic findings characterised by __, with __ in distal tubules and collecting ducts +/- proximal tubules.
There is also __, __ and __ of lumina.

Casts are surrounded by inflammatory cells such as __, __, __.

There is __ and __ which later progresses to __ in late stage.

Cast usually stained for __
Usually __

Answer 4

Eosinophilic acellular fractured casts

Brittle cracks in distal tubules, collecting ducts, proximal tubules

Epithelial cell necrosis, thinning and dilatation of lumina

Cast surrounded by macrophages, multinucleated giant cells and PMN neutrophils

Interstitial oedema and inflammation -> progresses to interstitial fibrosis

Stained for monoclonal LC
Usually Kappa IgG

Question 5

What precipitates AKI in myeloma?

Answer 5

Factors that cause volume depletion or sudden reductions in GFR - increases exposure of tubules to LC concentrations

1. Hypercalcaemia - volume depletion, vasoconstriction
2. NSAIDs, intravenous contrast
3. Sepsis

Question 6

Light chains are filtered at __ and reabsorbed at __.
In MM, high LC levels overwhelm capacity and function of proximal tubules, inducing __, continued and pass to __ where LC interact with __ to form __ that __, __ and induce __

Answer 6

Filtered at glomerulus, reabsorbed at proximal tubules

Proximal tubular injuies, pass down to distal tubule

LC interacts with uromodulin to form insoluble casts
Obstructs tubule, rupture basement membrane, induce inflammatory response

Question 7

Investigations of MM

Answer 7

1. FBC: anaemia, thrombocytopenia, pancytopenia
   - Marrow invasion by plasma cells
2. Normal calcium or hypercalcaemia
3. Immunoparesis
4. Increased globulin fraction
5. UFEME
6. Urine electrophoresis and immunofixation
7. sFLC ratio

Question 8

What specific laboratory diagnostic tests are used for diagnosis of myeloma?

Answer 8

1. Serum protein electrophoresis (SPE)
   - Can only detect very high levels (1-5g/dL) of LC-only myeloma
   - Semi quantitative
2. Serum immunofixation electrophoresis (IFE)
   - 10 times more sensitive for Igs and LC
   - Not quantitative
3. Urine IFE
   - Requires concentrated urine samples
   - Can detect low levels of FC
   (Historically named Bence Jones proteins as he invented primitive technique of boiling nad precipitating the proteins)