What are the five principal causes of renal impairment in patients with multiple myeloma?

Five Principal Causes of Renal Impairment in Multiple Myeloma

The five principal causes of renal impairment in multiple myeloma are: (1) light chain cast nephropathy, (2) direct proximal tubular toxicity from free light chains, (3) light chain deposition disease (LCDD), (4) AL amyloidosis, and (5) contributing factors including hypercalcemia, dehydration, hyperuricemia, infections, and nephrotoxic medications. 1, 2, 3

1. Light Chain Cast Nephropathy (Myeloma Kidney)

• Light chain cast nephropathy is the most common cause, accounting for approximately 90% of myeloma-related renal damage. 1
• This occurs when excess monoclonal free light chains (FLCs) bind to Tamm-Horsfall protein in the loop of Henle and distal tubules, forming obstructive casts that block tubular flow. 1, 2, 3
• The casts cause tubular rupture, which triggers an immune-mediated inflammatory response that further damages the tubules and leads to progressive tubulointerstitial fibrosis. 1, 2, 3
• Cast nephropathy qualifies as a myeloma-defining event (MDE) according to the 2014 International Myeloma Working Group criteria. 1
• Risk increases dramatically when serum FLC concentrations exceed 80-200 mg/dL, though high urinary FLC excretion appears necessary for acute kidney injury to occur, not just elevated serum levels alone. 1, 3, 4

2. Direct Proximal Tubular Toxicity

• Free light chains cause direct injury to proximal tubular cells through multiple toxic mechanisms independent of cast formation. 1, 2
• FLCs activate redox pathways with increased expression of NFκB and MAPK, leading to production of hydrogen peroxide and activation of inflammatory and profibrotic cytokine pathways. 1, 3
• Additional pathogenic pathways include FLC activation of Apoptosis signal-regulating kinase 1 (ASK1) and Janus kinases/STAT pathways, which induce apoptosis, inflammation, and promote tubulointerstitial fibrosis. 1
• This direct tubular cell death mechanism adds to renal dysfunction beyond the obstructive effects of cast formation. 5

3. Light Chain Deposition Disease (LCDD)

• LCDD occurs when monoclonal light chains deposit in kidney tissue without forming amyloid fibrils. 1, 2, 3
• These deposits accumulate in glomeruli, tubular basement membranes, and the interstitium, causing progressive renal dysfunction. 2, 3
• LCDD requires renal biopsy for definitive diagnosis, particularly when albuminuria exceeds 1 g/24 hours. 2, 4
• Unlike cast nephropathy, LCDD may present with more prominent glomerular injury patterns. 4

4. AL Amyloidosis

• AL amyloidosis develops when monoclonal light chains misfold and form amyloid fibrils that deposit in organs including the kidneys. 1, 2, 3
• Amyloid deposits accumulate in glomeruli, interstitium, and blood vessels, causing progressive renal impairment. 1, 2, 3
• Diagnosis requires Congo red staining showing apple-green birefringence under polarized light, with immunofluorescence to identify the light chain type. 4
• Renal biopsy is essential to distinguish AL amyloidosis from cast nephropathy or LCDD when albuminuria is prominent. 2, 4

5. Contributing Factors and Precipitants

• Hypercalcemia causes renal vasoconstriction, reduces glomerular filtration rate, and precipitates acute kidney injury in myeloma patients. 2, 6, 7
• Dehydration concentrates tubular light chains and promotes cast formation, making adequate hydration (minimum 3 liters daily or 2 L/m²/day) essential for prevention. 1, 2, 6
• Hyperuricemia from high tumor burden can cause uric acid nephropathy and requires prompt treatment. 2, 7
• Infections contribute to acute kidney injury through sepsis-related mechanisms and should be treated aggressively. 1, 7
• Nephrotoxic medications including NSAIDs, aminoglycosides, iodinated contrast agents, and bisphosphonates without dose adjustment must be discontinued immediately. 1, 2

Additional Renal Manifestations

• Fanconi syndrome develops when FLCs impair proximal tubule reabsorption capacity, resulting in glucosuria, aminoaciduria, and hypophosphatemia. 1
• Plasma cell infiltration of the kidneys can occur but is less common than the light chain-mediated mechanisms. 7
• Hyperviscosity syndrome from high paraprotein levels can reduce renal blood flow and precipitate acute kidney injury. 7

Clinical Significance

• Renal impairment at diagnosis occurs in 16-31% of patients when defined by serum creatinine >1.4 mg/dL, with 12-17% having eGFR <30 ml/min/1.73 m². 1
• Of the four myeloma-defining events (hypercalcemia, renal impairment, anemia, bone lesions), renal impairment imposes the greatest negative impact on overall survival. 1
• Recovery of kidney function reverses the negative impact on survival, making rapid diagnosis and aggressive treatment essential. 1, 2, 4
• A minimum 50-60% reduction in serum FLC concentration by day 12 of chemotherapy is associated with renal recovery. 1, 3, 4