What is the diagnosis and treatment approach for a patient with kidney amyloidosis?

Kidney Amyloidosis: Diagnosis and Treatment

Diagnostic Approach

For suspected kidney amyloidosis, obtain abdominal fat pad aspiration first (69% sensitivity), followed by kidney biopsy if negative, with Congo red staining and mass spectrometry typing mandatory to guide treatment. 1

Clinical Presentation

• Nephrotic syndrome with high-grade proteinuria is the hallmark presentation, occurring in approximately 70% of AL amyloidosis cases 2, 1
• Look specifically for: severe anasarca with marked hypoalbuminemia, progressive renal dysfunction, and paradoxically normal cardiac imaging initially 1
• The classic triad consists of unexplained proteinuria, impaired renal function, and anasarca 1

Diagnostic Testing Algorithm

1. Initial biopsy strategy: Start with abdominal fat pad aspiration as the surrogate site (sensitivity 69%) 1
2. If fat pad negative: Proceed directly to kidney biopsy given nephrotic presentation 1
3. Tissue confirmation: Congo red staining is mandatory to confirm amyloid deposits 1
4. Amyloid typing: Use liquid chromatography with tandem mass spectrometry (LC-MS/MS) to definitively identify the light chain type (kappa vs lambda) 1

Critical Assessment Considerations

• Standard serum creatinine-based eGFR calculations overestimate kidney function due to muscle wasting in amyloidosis patients 3, 4
• Use cystatin C-based GFR estimating equations or 24-hour urine creatinine clearance for accurate assessment 3, 4
• Distinguish AL from ATTR: ATTR rarely causes severe nephrotic syndrome, whereas AL presents with massive proteinuria 1

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Treatment Strategy

Initiate aggressive anti-plasma cell therapy immediately upon AL amyloidosis confirmation to halt light chain production, as kidney function typically stabilizes rather than improves even with successful treatment. 4

Disease-Directed Therapy

First-Line Treatment

• Daratumumab-CyBorD (Daratumumab plus cyclophosphamide, bortezomib, and dexamethasone) is the preferred first-line regimen, achieving very good partial response or better in 78.5% of patients 4
• Goal: Achieve at least 50-60% reduction in free light chains by day 12 of treatment, which correlates with improved outcomes 1

Treatment Modifications for Renal Impairment

• Avoid autologous stem cell transplantation (ASCT) in patients with severe renal impairment and hypoalbuminemia due to prohibitively high treatment-related mortality 4
• Reduce ixazomib starting dose to 3 mg in severe renal impairment or end-stage renal disease requiring dialysis 4

Expected Renal Outcomes

• Proteinuria decreases progressively over months to years after achieving hematologic complete response or very good partial response, and can resolve fully if hematologic response is sustained 3, 4
• GFR usually does not improve but often stabilizes after amyloidogenic light chain production is halted 3, 4
• Renal response occurs in approximately 60% of patients and is associated with improved survival independent of hematologic response 4

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Supportive Renal Management

Volume Management

• Dietary sodium restriction combined with loop diuretics forms the cornerstone of nephrotic syndrome management 3, 4
• Use torsemide or bumetanide over oral furosemide due to greater bioavailability, especially with intestinal wall edema 3
• Consider combination therapy with thiazide diuretics (metolazone) for refractory edema 3
• Intravenous albumin infusions can facilitate diuresis when serum albumin is markedly low (e.g., <1.5-2 g/dL) by increasing intravascular oncotic pressure 3

Anti-Proteinuric Therapy

• ACE inhibitors or angiotensin receptor blockers can be used for anti-proteinuric effects if blood pressure tolerates 3, 4
• Many patients have prohibitively low blood pressure limiting use of these agents 3, 4

Critical Pitfall to Avoid

• Balance fluid removal carefully against kidney perfusion: Aggressive diuresis can reduce GFR through hemodynamic alterations 3, 4
• The management of cardiorenal syndrome requires careful titration between removing excess fluid and maintaining adequate kidney perfusion 3

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Renal Replacement Therapy

Dialysis Modality Selection

• For patients with severe cardiac involvement progressing to end-stage kidney disease, consider peritoneal dialysis, short daily hemodialysis, or long nocturnal hemodialysis 4
• These modalities are better tolerated hemodynamically than conventional thrice-weekly hemodialysis 4

Transplantation

• Kidney transplantation can be considered in carefully selected patients, particularly those achieving sustained hematologic response 4

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Medication Precautions

Drugs to Avoid

• Diflunisal (NSAID and TTR stabilizer) is not recommended for patients with significant kidney impairment (typically eGFR <45 mL/min/1.73 m²) or volume overload due to deleterious effects on kidney hemodynamics, potassium excretion, and sodium excretion 3
• Inotersen (TTR silencer) was associated with crescentic glomerulonephritis in 3% of patients in phase 3 trials; this has not been observed with patisiran or vutrisiran 3

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When Kidney Biopsy Is NOT Helpful

Kidney biopsy is usually not helpful when kidney function declines despite documented eradication of amyloidogenic light chains, as amyloid persists in tissue and it is impossible to distinguish new deposits from pre-existing ones 3, 4

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Multidisciplinary Care Requirements

Nephrologist involvement is essential for managing nephrotic syndrome, cardiorenal syndrome, metabolic complications of chronic kidney disease, and nephrotoxic effects of anti-plasma cell therapies 4