What can cause a normal kappa light chain level in the serum and a very high kappa light chain level in the urine in an older adult with possible history of hematological disorders or kidney disease?

Normal Serum Kappa with Very High Urine Kappa: Light Chain Cast Nephropathy

The most likely cause is light chain cast nephropathy (LCCN) with rapid renal clearance of free light chains, where monoclonal kappa light chains are being filtered and excreted in the urine faster than they accumulate in serum, particularly in the setting of preserved glomerular filtration or early acute kidney injury. 1

Primary Mechanism

High urinary free light chain excretion can occur even without proportionally elevated serum levels, as the kidneys rapidly filter and excrete these small proteins (molecular weight ~22-25 kDa) before significant serum accumulation occurs. 1 This pattern is particularly characteristic when:

• Glomerular filtration remains relatively intact in early disease, allowing rapid clearance of light chains into urine 1
• The monoclonal plasma cell clone produces light chains at a rate that matches or is slightly exceeded by renal clearance, preventing serum accumulation 1
• Light chains precipitate in renal tubules (forming casts with Tamm-Horsfall protein), causing tubular obstruction and injury while being excreted in high amounts 1

Diagnostic Considerations

The diagnostic workup must include:

• 24-hour urine collection with electrophoresis and immunofixation to quantify Bence Jones proteinuria, which may show kappa light chains at >200 mg/day even with normal serum levels 1, 2
• Serum free light chain assay to determine the kappa/lambda ratio, which may be abnormal (>1.65) even if absolute kappa levels appear normal 3, 4
• Serum protein electrophoresis (SPEP) and immunofixation (SIFE) to identify any monoclonal protein, though the M-spike may be minimal or absent in pure light chain disease 1, 2
• Renal function assessment including serum creatinine and eGFR, as renal impairment may be developing despite seemingly normal serum light chains 1

A renal biopsy should be strongly considered if the cause of any renal insufficiency is unclear, to assess for light chain cast nephropathy, light chain deposition disease, or AL amyloidosis. 1

Critical Clinical Context

Free light chain levels >150 mg/dL with urine M-spike >200 mg/day and albuminuria <10% strongly suggest light chain cast nephropathy, even if serum levels appear deceptively normal. 4 The key pathophysiologic insight is that high urinary FLC excretion appears necessary for acute kidney injury to occur, not just elevated serum levels. 1

Important Caveats:

• Do not be falsely reassured by "normal" serum kappa levels when urine shows high kappa excretion—this represents active light chain production and renal handling 1
• The kappa/lambda ratio is more informative than absolute values in identifying a monoclonal process 3, 4
• Early intervention is critical: AKI at myeloma diagnosis imposes negative impact on mortality, particularly in the first 6 months 1

Differential Diagnoses to Consider

Light chain myeloma (representing 15-20% of multiple myeloma cases) presents with elevated free light chains without heavy chain expression and may show this pattern. 3

Monoclonal gammopathy of renal significance (MGRS) can cause kidney damage without meeting criteria for multiple myeloma, with light chains causing tubular injury despite low serum levels. 2

Light chain deposition disease (LCDD) shows PAS-negative deposits in tubular basement membranes and may present with high urinary light chains and relatively normal serum levels. 5, 6

AL amyloidosis should be suspected when renal insufficiency or albuminuria is present without high serum light chain levels, as light chains form amyloid fibrils that deposit in organs. 1, 6

Immediate Management Priorities

If light chain cast nephropathy is confirmed or strongly suspected, initiate bortezomib-containing regimens immediately to decrease production of nephrotoxic clonal immunoglobulin. 1, 4, 2

• Bortezomib/dexamethasone can be administered without dose adjustment in severe renal impairment and those on dialysis 1, 4
• Add a third agent that doesn't require dose adjustment: cyclophosphamide, thalidomide, anthracycline, or daratumumab 1, 4
• Goal is rapid reduction of free light chains: minimum 50-60% reduction by day 12 is associated with renal recovery 1, 4

Supportive Care:

• Provide aggressive hydration (target urine output 3 L/day) and consider urine alkalinization 4, 2
• Avoid all nephrotoxic medications, particularly NSAIDs 3, 4, 2
• Treat hypercalcemia if present 4
• Consider therapeutic plasma exchange (TPE) as adjuvant therapy if free light chains are extremely elevated (>15,000-30,000 mg/L) with acute renal injury 4, 7

Monitoring Strategy

• Use the same serum free light chain assay throughout treatment to ensure consistency 4, 2
• Monitor renal function regularly with serum creatinine and eGFR 4, 2
• Repeat 24-hour urine collections to assess treatment response 2
• Assess response after one cycle of therapy, then every other cycle once response trend is observed 4

Recovery of kidney function reverses the negative impact on overall survival, making aggressive early treatment and close monitoring essential. 1