What is the management approach for patients with cardiac amyloidosis and proteinuria?

Management of Cardiac Amyloidosis with Proteinuria

The management of patients with cardiac amyloidosis and proteinuria requires a disease-specific approach based on amyloid type, with careful attention to renal manifestations which significantly impact prognosis and treatment options. 1

Amyloid Type Determination

• First step: Determine amyloid type (AL vs. ATTR) through:
  • Tissue biopsy with Congo red staining
  • Immunohistochemistry
  • Mass spectrometry (gold standard for typing)
  • Serum free light chain assay
  • Cardiac imaging (echocardiography, nuclear imaging, cardiac MRI)

Renal Assessment in Cardiac Amyloidosis

AL Amyloidosis

• Kidney involvement in ~70% of AL amyloidosis patients 1
• Typically presents with:
  • Nephrotic syndrome
  • High-grade proteinuria (>500 mg/day)
  • Hypoalbuminemia
  • Progressive kidney dysfunction

ATTR Amyloidosis

• Direct kidney involvement is usually subclinical 1
• Kidney dysfunction primarily due to:
  • Cardiorenal syndrome
  • Autonomic nervous system involvement affecting renal hemodynamics

Diagnostic Considerations

• Proteinuria ≥500 mg/day indicates significant renal involvement 1
• Random urine protein-to-creatinine ratio ≥715 mg/g has 91.8% sensitivity and 95.5% specificity for detecting renal involvement 2
• Standard creatinine-based GFR estimates may be inaccurate due to muscle wasting 1
• Better assessment methods:
  • Cystatin C-based GFR estimation
  • 24-hour urine collection for creatinine clearance

Treatment Approach

For AL Cardiac Amyloidosis with Proteinuria

1. First-line therapy: Daratumumab combined with cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) 3

   • Achieves high rates of deep hematologic responses
   • Monitor for cardiac toxicities (heart failure in 6.4%, LVEF reduction in 23%)

2. Alternative options:

   • CyBorD alone for patients who cannot tolerate daratumumab
   • High-dose melphalan with autologous stem cell transplantation for eligible patients without significant cardiac involvement

3. Response monitoring:

   • Monthly: CBC, biochemistry, NT-proBNP, troponin, serum free light chain quantification
   • Goal: Complete hematologic response or very good partial response
   • Proteinuria typically decreases progressively over months to years after hematologic response 1
   • GFR usually stabilizes rather than improves after treatment

For ATTR Cardiac Amyloidosis with Proteinuria

1. First-line therapy: Tafamidis (80 mg VYNDAQEL or 61 mg VYNDAMAX daily) 3, 4

   • FDA-approved for ATTR cardiomyopathy
   • Reduces mortality and cardiovascular hospitalizations
   • Impact on kidney outcomes not specifically established 1

2. Avoid diflunisal in patients with:

   • eGFR <45 mL/min/1.73 m²
   • Volume overload
   • Due to potential adverse effects on renal hemodynamics, potassium and sodium excretion 1

3. TTR silencers consideration:

   • Inotersen has been associated with crescentic glomerulonephritis (3% of patients) 1
   • Patisiran or vutrisiran may be safer options for renal function

Supportive Management

1. Fluid management:

   • Dietary sodium restriction
   • Judicious use of loop diuretics
   • Consider combination with thiazide diuretics (e.g., metolazone) for resistant cases 1

2. Medication considerations:

   • Use β-blockers, calcium channel blockers, ACE inhibitors/ARBs with caution
   • Careful monitoring of renal function with medication adjustments

3. Anticoagulation:

   • Indicated for atrial fibrillation, embolic stroke/TIA, or intracardiac thrombus
   • Balance benefits against increased bleeding risk in amyloid angiopathy 3

Advanced Therapies

1. Heart transplantation:

   • Proteinuria ≥500 mg/day is a contraindication to heart transplantation 1
   • Consider in select patients without significant extracardiac manifestations

2. Mechanical circulatory support:

   • Temporary support (intra-aortic balloon pump, percutaneous microaxial catheter-based pump) may be considered as bridge to transplantation 1
   • Durable support has worse outcomes compared to other cardiomyopathies

Palliative Care Integration

• Integrate palliative care early for symptom management and quality of life improvement 1, 3
• Especially important when physical symptoms (heart failure, neuropathy, orthostasis, GI distress) or emotional/spiritual distress interfere with quality of life

Monitoring Approach

• Monthly assessment of hematologic parameters and cardiac biomarkers
• Regular evaluation of proteinuria and kidney function
• Echocardiography with strain measurements every 6 months
• Holter ECG monitoring every 6 months

Pitfalls to Avoid

1. Diagnostic pitfalls:

   • Relying solely on serum creatinine to estimate GFR in patients with muscle wasting
   • Failing to assess for proteinuria in cardiac amyloidosis patients

2. Treatment pitfalls:

   • Using NSAIDs (including diflunisal) in patients with significant kidney impairment
   • Delaying hematologic therapy in AL amyloidosis
   • Overlooking the need for careful fluid management

3. Monitoring pitfalls:

   • Not distinguishing between cardiorenal syndrome and direct renal involvement
   • Failing to monitor for treatment toxicities affecting kidney function