What is the cause of an elderly male patient with Waldenstrom's macroglobulinemia (WM) developing wheeze, cough, and impaired renal function?

Differential Diagnosis: Wheeze, Cough, and Acute Kidney Injury in Waldenstrom's Macroglobulinemia

The most likely cause is AL (light chain) amyloidosis with cardiac and renal involvement, which is an infrequent but serious complication of WM that requires urgent evaluation with cardiac biomarkers, echocardiography, and tissue diagnosis. 1

Primary Diagnostic Considerations

AL Amyloidosis (Most Likely)

• AL amyloidosis is an infrequent complication of WM that most commonly affects kidneys, heart, liver, and peripheral nerves 1
• The combination of respiratory symptoms (wheeze/cough suggesting cardiac involvement with pulmonary congestion) and acute renal deterioration strongly suggests multi-organ amyloid deposition 1
• Absence of fever makes infection less likely and points toward a disease-related complication 1

Hyperviscosity Syndrome (Alternative Consideration)

• Hyperviscosity can present with respiratory symptoms and contribute to renal dysfunction, though wheeze is less typical 1
• However, the classic triad includes neurological symptoms (headaches, blurred vision, confusion) and bleeding manifestations (epistaxis), which are not mentioned here 1

Cast Nephropathy from Light Chains

• Acute rise in creatinine may reflect light chain cast nephropathy, particularly if there is concurrent dehydration or other renal insult 1
• This can occur even without overt hyperviscosity 1

Essential Immediate Workup Required

For Amyloidosis Diagnosis

• Serum free light chain (FLC) assay is recommended in situations of suspected AL amyloidosis or renal failure 1
• Fat aspirate and bone marrow biopsy evaluation with Congo red staining to establish amyloidosis diagnosis 1
• Cardiac assessment with echocardiography or cardiac MRI, plus cardiac biomarkers (NT-proBNP, troponins) 1
• Renal markers including 24-hour proteinuria and estimated GFR 1
• Urine protein electrophoresis and immunofixation to exclude abnormal renal immunoglobulin secretion 1

For Hyperviscosity Assessment

• Serum IgM quantification by nephelometry 1
• Fundoscopic examination for venous engorgement ("sausaging") of retinal veins, which is more reliable than serum viscosity measurement 1
• Serum viscosity measurement may be considered but does not correlate well with clinical severity 1

Additional Critical Tests

• Complete blood count with differential to assess for cytopenias 1
• Serum protein electrophoresis and immunofixation 1
• β2-microglobulin level as a prognostic marker 1
• Chest imaging (CT or X-ray) to evaluate for pulmonary edema, pleural effusions, or infiltrative disease 1
• Testing for cryoglobulins if there are symptoms of hyperviscosity or acrocyanosis 1

Critical Clinical Pitfalls

Common Diagnostic Errors

• In patients with renal failure, evaluation of free light chains may be challenging due to impaired clearance 1
• Do not assume respiratory symptoms are simply from infection without fever; consider cardiac amyloidosis with restrictive cardiomyopathy causing pulmonary congestion 1
• The presence of cold agglutinins or cryoglobulins may affect the determination of IgM levels, leading to falsely low or high readings 1

Urgent Management Considerations

• If AL amyloidosis is confirmed, treatment options include proteasome inhibitor-based therapy (BDR, VR) or bendamustine/rituximab 1
• If hyperviscosity is present, plasmapheresis should be used immediately and concomitantly with systemic therapy 1
• Proteasome inhibitor-based therapy (bortezomib) is specifically recommended for patients with amyloidosis and renal impairment 1

Information Still Needed

Clinical History Details

• Presence of neurological symptoms (headaches, visual changes, confusion) to assess for hyperviscosity 1
• History of peripheral neuropathy, which is common in WM and may suggest anti-MAG antibody-associated disease or amyloidosis 1, 2
• Constitutional symptoms (fever, night sweats, weight loss, fatigue) which are indications for therapy 1
• Bleeding manifestations (epistaxis, easy bruising) suggesting acquired von Willebrand disease or hyperviscosity 1
• Orthostatic symptoms or autonomic dysfunction suggesting amyloid neuropathy 2

Physical Examination Findings

• Fundoscopic examination for retinal vein engorgement 1
• Presence of hepatosplenomegaly or lymphadenopathy 1
• Signs of volume overload (peripheral edema, jugular venous distension, pulmonary rales) 1
• Skin examination for purpura or periorbital ecchymoses (raccoon eyes) suggesting amyloidosis 1
• Macroglossia, which is pathognomonic for amyloidosis 1

Laboratory Values Needed

• Baseline IgM level to determine if patient has high IgM (>4000 mg/dL or >60 g/L) at risk for hyperviscosity 1
• Hemoglobin level and platelet count to assess for cytopenias 1
• Albumin level as a prognostic factor 1
• LDH level to assess for aggressive disease or transformation 3
• Baseline creatinine to determine acuity of renal dysfunction 1