What are the renal complications of multiple myeloma and how are they managed?

Renal Complications of Multiple Myeloma

Multiple myeloma patients with renal impairment must be treated as a medical emergency with immediate bortezomib-based therapy, aggressive hydration, and correction of hypercalcemia to prevent irreversible kidney damage and reduce early mortality. 1, 2

Incidence and Pathophysiology

Renal impairment occurs in 20-25% of multiple myeloma patients at diagnosis and affects 40-50% during disease course. 1, 3 The primary mechanism involves monoclonal free light chains (FLCs) causing tubulointerstitial damage through multiple pathways 1:

• Cast nephropathy (approximately 90% of cases) occurs when excess FLCs bind to Tamm-Horsfall protein in the distal tubules, forming obstructive casts that cause tubular rupture, atrophy, and progressive interstitial inflammation and fibrosis 1, 2

• Direct proximal tubular toxicity results from FLC-induced activation of NFκB and MAPK pathways, generating hydrogen peroxide and inflammatory cytokines that cause tubular cell death 1, 2

• Light chain deposition disease (LCDD) and AL amyloidosis occur when monoclonal light chains deposit in kidney tissue or form amyloid fibrils in glomeruli, interstitium, and vessels 1, 4

• Fanconi syndrome develops when FLCs impair proximal tubule reabsorption, causing glucosuria, aminoaciduria, and hypophosphatemia 1

Critical risk thresholds: Serum FLC concentrations >50 mg/dL significantly increase acute kidney injury risk, with dramatic escalation when FLC exceeds 80-200 mg/dL 2

Contributing Factors Beyond Light Chains

Additional nephrotoxic processes compound renal damage 1:

• Dehydration
• Hypercalcemia
• Hyperuricemia
• Infections
• Nephrotoxic medications (NSAIDs, aminoglycosides, IV contrast, bisphosphonates without dose adjustment) 5, 6

Common pitfall: Bisphosphonates like zoledronic acid can cause focal segmental glomerulosclerosis or acute tubular necrosis when used without renal dose adjustment 5

Diagnostic Assessment

Use the MDRD or CKD-EPI equation to estimate GFR, not serum creatinine alone, as creatinine poorly reflects actual kidney function. 1, 2 The CKD-EPI-cystatin C equation provides superior prognostic value 1

Renal impairment definition: eGFR <40 mL/min/1.73 m² or serum creatinine >2 mg/dL (the "R" in CRAB criteria) 1, 2

Essential Diagnostic Workup 1, 4:

• Serum creatinine and eGFR (MDRD or CKD-EPI formula)
• 24-hour urine collection with protein electrophoresis and immunofixation to quantify Bence Jones proteinuria
• Serum free light chain assay measuring κ and λ independently with κ:λ ratio (normal 0.26-1.65; in CKD stage 5: 0.34-3.10)
• Serum protein electrophoresis (SPEP) and immunofixation (SIFE)

When to Perform Renal Biopsy 1, 4:

• Proteinuria with albuminuria >1 g/24h (suggests glomerular injury from AL amyloidosis or LCDD rather than cast nephropathy)
• Absence of light chain proteinuria (consider alternative diagnosis)
• Coexisting conditions (diabetes, chronic hypertension) where etiology is unclear

For suspected AL amyloidosis: Subcutaneous fat pad or rectal biopsy with Congo red staining may demonstrate amyloid deposits before proceeding to renal biopsy 1, 4

Diagnostic clue: FLC levels >150 mg/dL with urine M-spike >200 mg/day and albuminuria <10% strongly suggests light chain cast nephropathy 4

Immediate Management Protocol

Supportive Measures (Initiate Simultaneously) 1:

• Aggressive hydration: Minimum 3 liters daily or 2 L/m²/day to reduce urine FLC concentration
• Urine alkalinization to decrease cast formation
• Correct hypercalcemia immediately
• Discontinue all nephrotoxic medications (NSAIDs, aminoglycosides, IV contrast) 5
• Treat hyperuricemia if present

Critical timing: Every day of delay in starting effective antimyeloma therapy allows continued light chain production and progressive tubular damage that may become irreversible 5

Antimyeloma Therapy: First-Line Approach

Bortezomib-based regimens are the standard of care for multiple myeloma with renal impairment because bortezomib requires no dose adjustment in renal failure or dialysis and is not nephrotoxic. 2, 7, 8, 9

Recommended regimen: Bortezomib plus dexamethasone, with consideration of adding a third agent that doesn't require dose adjustment (cyclophosphamide, thalidomide, anthracycline, or daratumumab) 4

Treatment goals 2, 5:

• Minimum 50-60% reduction in serum FLC is associated with renal recovery
• Achieve serum FLC <50 mg/dL by end of cycle 1 improves renal recovery
• Earlier FLC reduction (by day 12 vs. day 21) correlates with better kidney function recovery

Alternative Agents in Renal Impairment

Thalidomide: Can be used without dose adjustment in renal impairment, though experience is limited 7, 8

Lenalidomide: Effective but requires careful dose reduction based on renal function with close monitoring for toxicity 7, 8 Major pitfall: Using lenalidomide without appropriate dose reduction causes severe toxicity and treatment discontinuation, preventing adequate disease control 5

High-dose melphalan (140 mg/m²) with autologous stem cell transplantation: Should be limited to younger patients (<65 years) with chemosensitive disease and considered cautiously in severe renal insufficiency (GFR <30 mL/min) 7, 8

Role of Plasma Exchange

Therapeutic plasma exchange (TPE) remains controversial but may be considered as adjuvant therapy in acute kidney injury with extremely high FLC levels (>150 mg/dL) to promote rapid FLC reduction 1, 4, 7 The evidence does not definitively support routine use 1

Renal Replacement Therapy

Hemodialysis indications: Severe acute kidney injury and end-stage renal disease 7

Use high-flux or high cut-off membranes because routine hemodialysis cannot effectively remove serum free light chains 7, 3 However, high cut-off hemodialysis membranes do not appear to offer significant additive effects beyond antimyeloma therapy 3

Monitoring Strategy

Serial serum free light chain measurements are essential to confirm adequate reduction (target >50-60% by day 12) 2, 5

Use the same serum free light chain assay throughout treatment to ensure consistency 4

Monitor for light chain escape (switch from intact immunoglobulin to free light chain production during treatment), which increases nephrotoxic burden 5

Assess response after one cycle of therapy, then every other cycle once a response trend is observed 4

Critical monitoring pitfall: Relying solely on serum creatinine without assessing urine protein electrophoresis misses ongoing light chain excretion 5

Prognostic Factors

Factors associated with lower probability of renal recovery 5, 8, 9:

• Severe renal impairment at presentation (creatinine >4 mg/dL or dialysis requirement) - only 40-50% achieve improvement
• Failure to achieve 50-60% FLC reduction by day 12
• Continued high urinary FLC excretion (>200 mg/day)
• Extensive tubular atrophy and interstitial fibrosis from prolonged light chain exposure before treatment
• Large amount of proteinuria at baseline

Recovery of kidney function reverses the negative impact on overall survival, making aggressive early treatment essential. 4 Acute kidney injury at myeloma diagnosis imposes negative impact on mortality, particularly in the first 6 months 4