How should I evaluate and manage a 74-year-old man with hypertension and untreated Waldenström macroglobulinemia who now has impaired renal function, mild proteinuria, pedal edema, and dyspnea on exertion?

Evaluation and Management of Renal Dysfunction and Volume Overload in Waldenström Macroglobulinemia

This patient requires urgent evaluation for WM-related renal disease with kidney biopsy and immediate initiation of WM-directed therapy, as his progressive renal dysfunction with proteinuria and new volume overload symptoms likely represent direct renal involvement by his untreated malignancy.

Immediate Diagnostic Workup

Essential Laboratory Assessment

• Measure serum IgM level immediately to assess disease burden and hyperviscosity risk, as IgM levels >4000 mg/dL require prophylactic plasmapheresis before certain therapies 1
• Check serum viscosity given his dyspnea and edema, as symptomatic hyperviscosity is a medical emergency requiring immediate plasmapheresis 1
• Obtain β2-microglobulin, LDH, and albumin for prognostic stratification using the International Prognostic Scoring System for WM 2, 3
• Assess for cryoglobulins and cold agglutinins, as these IgM-related complications can cause renal injury and require specific management 1

Renal-Specific Evaluation

• Kidney biopsy is strongly recommended to determine the mechanism of renal involvement, as WM can cause membranous nephropathy with IgM deposition, minimal change disease with lymphoid infiltrates, or direct lymphoplasmacytic infiltration 4, 5
• The biopsy finding will guide therapy selection, as direct renal involvement by WM typically responds to WM-directed treatment 4, 5

Cardiac Assessment

• Obtain echocardiogram and BNP/NT-proBNP to distinguish cardiac causes of dyspnea and edema from volume overload secondary to renal dysfunction or hyperviscosity 3
• Rule out cardiac amyloidosis, which can occur with WM and presents with heart failure symptoms 1

Treatment Initiation Criteria Met

This patient clearly meets criteria for immediate WM therapy based on:

• Progressive renal insufficiency (creatinine rising from 1.0 to 1.4) with proteinuria 1
• New symptomatic manifestations (pedal edema and dyspnea on exertion) 1
• These symptoms are attributable to his untreated WM and constitute end-organ damage 1

Recommended First-Line Therapy

Primary Treatment Recommendation

Bortezomib-based therapy (specifically bortezomib-rituximab-dexamethasone, BoRD) is the optimal first-line regimen for this patient because:

• Bortezomib is specifically recommended for WM patients with renal impairment 1
• It provides rapid IgM reduction, which is critical given his symptomatic presentation 1
• Bortezomib should be administered once weekly by subcutaneous route to minimize neuropathy risk 1
• This regimen is safe in elderly patients with renal dysfunction 6, 3

Alternative Regimen Considerations

• Bendamustine-rituximab (BR) is an alternative option, but bendamustine dose must be reduced in renal impairment 1
• DRC (dexamethasone-rituximab-cyclophosphamide) is generally preferred for frail elderly patients but is less ideal when rapid IgM reduction is needed 1, 6
• Zanubrutinib is approved for first-line therapy but may have cardiac toxicity concerns in elderly patients with volume overload 3

Critical Management Considerations

Hyperviscosity Precautions

• If serum IgM is >4000 mg/dL, initiate plasmapheresis immediately before starting any therapy 1
• Avoid rituximab monotherapy in patients with high IgM levels due to risk of IgM flare causing hyperviscosity complications 1, 7
• Plasmapheresis is only temporizing and must be followed by definitive cytoreductive therapy 1

Renal Protection Measures

• Start angiotensin receptor blocker or ACE inhibitor for proteinuria reduction, as demonstrated effective in WM-related membranous nephropathy 4
• Ensure adequate hydration but avoid aggressive fluid administration given volume overload symptoms 5
• Monitor renal function closely during therapy initiation, as improvement typically occurs with WM treatment response 4, 5

Volume Management

• Initiate diuretic therapy cautiously for symptomatic edema, but avoid aggressive diuresis that could worsen renal function 5
• Volume status should be reassessed after determining cardiac function and hyperviscosity status

Monitoring During Treatment

Response Assessment

• Check serum IgM levels monthly during induction therapy to assess treatment response 3
• Monitor renal function (creatinine, urine protein) every 2-4 weeks as improvement should parallel WM response 4, 5
• Reassess symptoms (dyspnea, edema) as these should improve with effective WM therapy 5

Treatment Duration

• Continue induction therapy for approximately 6 months or until maximal response is achieved 6, 3
• Do not stop therapy prematurely even if IgM temporarily increases, as this can occur with certain regimens and does not indicate treatment failure 1

Common Pitfalls to Avoid

• Do not attribute renal dysfunction solely to hypertension without investigating WM-related causes, as direct renal involvement requires WM-specific therapy 4, 5
• Do not delay treatment waiting for biopsy results if hyperviscosity is suspected, as this is a medical emergency 1
• Do not use rituximab monotherapy in this symptomatic patient with potential high IgM burden, as combination therapy is superior 1, 3
• Do not overlook cardiac evaluation before attributing all symptoms to renal disease, as cardiac involvement can occur in WM 3