How to manage AL (Amyloid Light-chain) amyloidosis with impaired renal function?

Management of AL Amyloidosis with Renal Failure

The primary goal is aggressive anti-plasma cell therapy to halt light chain production, combined with supportive renal management, recognizing that kidney function typically stabilizes rather than improves even with successful hematologic response. 1

Disease-Directed Treatment Strategy

First-Line Therapy Selection

For most patients with AL amyloidosis and renal impairment, Daratumumab-CyBorD (daratumumab, cyclophosphamide, bortezomib, dexamethasone) is the preferred first-line treatment, achieving very good partial response or better in 78.5% of patients. 2 This regimen targets the underlying plasma cell clone responsible for producing amyloidogenic light chains.

Autologous Stem Cell Transplantation (ASCT) Considerations

ASCT should be avoided in patients with severe renal impairment (eGFR <40 mL/min/1.73 m²) and hypoalbuminemia (<2.5 g/dL) due to prohibitively high treatment-related mortality. 1 The presence of both risk factors confers a 44% risk of requiring dialysis within 30 days of ASCT, with associated treatment-related mortality of 44.4%—six-fold higher than patients without these risk factors. 1

For carefully selected patients with preserved renal function (eGFR ≥40 mL/min/1.73 m²) and albumin ≥2.5 g/dL, high-dose melphalan followed by ASCT remains an option, potentially preceded by bortezomib-based induction therapy. 1, 2

Alternative Regimens for ASCT-Ineligible Patients

• CyBorD (cyclophosphamide, bortezomib, dexamethasone) without daratumumab is an acceptable alternative 1, 2
• Melphalan-dexamethasone (MDex): 0.22 mg/kg melphalan plus 40 mg dexamethasone on days 1-4 of a 28-day cycle 1
• Bortezomib-melphalan-dexamethasone (BMDex) 1

Critical Drug Dosing Adjustments in Renal Failure

For severe renal impairment or end-stage renal disease requiring dialysis, reduce ixazomib starting dose to 3 mg (from standard 4 mg) when used in proteasome inhibitor-based regimens. 3

Nephrotoxicity Monitoring

Close monitoring is essential for treatment-related kidney injury, including:

• Lenalidomide-associated acute kidney injury: 66% of AL amyloidosis patients develop worsening kidney function during lenalidomide treatment, with 32% experiencing severe dysfunction (≥100% increase in serum creatinine) 1, 4
• Proteasome inhibitor-associated thrombotic microangiopathy or interstitial nephritis 1
• ASCT-associated acute kidney injury 1

Supportive Renal Management

Volume and Proteinuria Management

Dietary sodium restriction combined with loop diuretics (torsemide or bumetanide preferred over oral furosemide) forms the cornerstone of nephrotic syndrome management. 1 For severe intestinal wall edema, intravenous loop diuretics demonstrate superior bioavailability. 1

Intravenous albumin infusions facilitate diuresis when serum albumin is markedly reduced (<1.5-2 g/dL) by increasing intravascular oncotic pressure and enhancing loop diuretic delivery to the tubular lumen. 1

Consider adding thiazide diuretics (metolazone) in combination with loop diuretics for refractory edema. 1 Compression stockings reduce peripheral edema and improve diuretic tolerability, though use may be challenging with autonomic neuropathy. 1

Anti-Proteinuric Therapy

ACE inhibitors or angiotensin receptor blockers can be used for anti-proteinuric effects if blood pressure tolerates, though many patients have prohibitively low blood pressure. 1 SGLT2 inhibitors have not been studied in amyloid-associated kidney dysfunction and cannot be recommended. 1

Medications to Avoid

NSAIDs should be avoided in patients with significant kidney impairment (eGFR <45 mL/min/1.73 m²) or volume overload due to deleterious effects on renal hemodynamics, potassium excretion, and sodium excretion. 1

Anticoagulation is not recommended specifically for amyloidosis-associated nephrotic syndrome in the absence of other indications (such as atrial fibrillation). 1

Accurate Assessment of Renal Function

Standard serum creatinine-based eGFR calculations overestimate kidney function in AL amyloidosis due to muscle wasting. 1 Better assessments include:

• Cystatin C-based GFR estimating equations (independent of muscle mass) 1
• 24-hour urine creatinine clearance 1
• Serum cystatin C concentrations 1

Expected Renal Outcomes with Treatment

Proteinuria Response

Proteinuria typically decreases progressively over many months to several years after achieving hematologic complete response or very good partial response, and can resolve fully if hematologic response is sustained. 1 Median time to renal response is approximately 12 months. 5

Renal Function Trajectory

GFR usually does not improve but often stabilizes after amyloidogenic light chain production is halted. 1 Renal response (≥50% reduction in proteinuria with <25% decline in renal function) occurs in approximately 60% of patients and is associated with improved survival independent of hematologic response. 5

Complete recovery from advanced chronic kidney disease is uncommon but possible with ongoing intensive therapy. 6

Renal Replacement Therapy

Dialysis Modality Selection

For patients progressing to end-stage kidney disease, kidney replacement options include:

For patients with severe cardiac involvement, peritoneal dialysis, short daily hemodialysis, or long nocturnal hemodialysis are better tolerated hemodynamically than conventional thrice-weekly hemodialysis. 1

Kidney Transplantation

Kidney transplantation can be considered in carefully selected patients, particularly those achieving sustained hematologic response. 1 Sequential living donor kidney transplantation followed by autologous stem cell transplantation is feasible for selected patients with end-stage renal disease due to AL amyloidosis. 7

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. 1 Nephrologists should be involved in:

• Interpreting serum free light chain concentrations in kidney impairment 1
• Interpreting cardiac biomarkers in kidney impairment 1
• Risk-stratifying for stem cell transplantation 1
• Dosing drugs based on kidney function 1
• Determining need for kidney biopsy 1
• Assessing suitability for kidney transplantation 1
• Preparing for dialysis initiation and modality selection 1

Common Pitfalls

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. 1

The balance between removing excess fluid and maintaining adequate kidney perfusion requires careful titration, as aggressive diuresis can reduce GFR through hemodynamic alterations. 1

Standard heart failure medications (beta blockers, calcium channel blockers, ACE inhibitors) often cannot be used due to restrictive cardiomyopathy and should be avoided in acute decompensation. 1