Bence-Jones protein

**Definition:** Bence-Jones protein = monoclonal free immunoglobulin light chains (kappa or lambda, ~22-25 kDa) found in urine. Named after Henry Bence Jones (1847). Historically detected by precipitation when urine is heated to ~50-60°C, which redissolves at ~100°C and reprecipitates on cooling.

**Pathophysiology:** A clonal plasma cell population (or B-cell clone) produces excess light chains relative to heavy chains. Free light chains are small, freely filtered at the glomerulus, and reabsorbed by proximal tubule cells. When the reabsorptive capacity is overwhelmed, they appear in urine (overflow proteinuria).

**Renal complications:** - Cast nephropathy ("myeloma kidney"): light chains bind Tamm-Horsfall protein (uromodulin) in the distal tubule/thick ascending limb, forming obstructing waxy/fractured casts → AKI. Risk is increased by dehydration, hypercalcemia, loop diuretics, NSAIDs, and contrast. - Proximal tubule injury: Fanconi syndrome (type 2 RTA). - AL amyloidosis (lambda more commonly): nephrotic-range proteinuria, Congo red-positive, apple-green birefringence under polarized light. - Light chain deposition disease (kappa more commonly): nodular glomerulosclerosis, non-amyloid, Congo red negative.

**Diagnosis:** - Urine dipstick is primarily sensitive to albumin, so it can be negative or minimally positive despite heavy light chain excretion. Sulfosalicylic acid (SSA) test detects all proteins and will be positive, so a dipstick-negative/SSA-positive discrepancy is a classic clue. - UPEP with immunofixation: confirms monoclonal light chains (a spike on electrophoresis). - Serum free light chain (FLC) assay with abnormal kappa/lambda ratio is the most sensitive; it is also used for monitoring. - SPEP with immunofixation looks for the M-spike (intact immunoglobulin).

**Associated conditions:** - Multiple myeloma (most common; ~15-20% are light-chain-only myeloma, which can have no M-spike on SPEP) - Waldenström macroglobulinemia - MGUS and smoldering myeloma - Primary (AL) amyloidosis - Light chain deposition disease - Other B-cell lymphoproliferative disorders (e.g., CLL), rarely

**Multiple myeloma high-yield:** CRAB features (hyperCalcemia, Renal failure, Anemia, Bone lesions with lytic "punched-out" lesions), rouleaux formation on smear, plasma cells with "fried egg" appearance and clock-face chromatin, ≥10% clonal bone marrow plasma cells (or plasmacytoma) plus myeloma-defining events. Also increased infection risk (hypogammaglobulinemia of normal immunoglobulins), low anion gap (cationic paraprotein), and elevated ESR.

**Management pearls:** Hydration, treat hypercalcemia, avoid nephrotoxins, and treat the underlying plasma cell dyscrasia (proteasome inhibitors such as bortezomib, immunomodulatory agents like lenalidomide, anti-CD38 antibodies like daratumumab, dexamethasone, and autologous stem cell transplant in eligible patients). Bisphosphonates or denosumab for bone disease.

**Exam clue:** Older patient (often Black, male) with back pain, anemia, renal failure, hypercalcemia, and a negative urine dipstick for protein but positive SSA → think Bence-Jones proteinuria/myeloma.