1. What is tumor lysis syndrome (TLS)?

TLS is a condition in which widespread necrosis of tumor cells releases toxic amounts of intracellular contents into the circulation, resulting in acute hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and acute kidney injury (AKI).

2. What causes TLS?

TLS is usually caused by chemotherapeutic agents in patients with cancer resulting in rapid cell necrosis. Common agents implicated include cisplatin, etoposide, fludarabine, cytosine arabinoside, methotrexate, paclitaxel, rituximab, and corticosteroids. Radiation therapy may rarely cause TLS. Occasionally spontaneous TLS may arise in rapidly growing tumors that outgrow their blood supply.

3. What are the risk factors for the development of TLS?

TLS typically occurs following the chemotherapeutic treatment of hematologic malignancies, in particular Burkitt lymphoma and acute B-cell lymphoblastic leukemia. TLS has only rarely been described following the treatment of solid organ tumors. Specific risk factors for the development of TLS include:

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  Host-related factors

  
  
  
  
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    Volume depletion

    
    
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    Preexisting kidney disease

  
  
  
  
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  Disease-related factors

  
  
  
  
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    Large tumor burden, “bulky” disease, or extensive bone marrow involvement

    
    
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    High tumor proliferation rate

    
    
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    Highly chemo- or radiosensitive tumors

    
    
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    Lactate dehydrogenase (LDH) levels greater than 1500 IU (or twice the upper limit of normal)

    
    
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    Uric acid level greater than 8.0 mg/dL

  
  

4. What laboratory findings are associated with TLS?

Laboratory analysis in TLS typically reveals hyperkalemia, hyperphosphatemia, hypocalcemia, hyperuricemia, and elevated LDH levels. In TLS, the uric acid and LDH levels are often quite elevated. Malignant cells can be very metabolically active, with large amounts of adenosine triphosphate, and can contain up to four times the amount of phosphorus found in normal cells. If AKI develops, decreased kidney clearance of phosphorus and potassium can worsen the hyperphosphatemia and hyperkalemia. Hypocalcemia develops in tumor lysis when calcium complexes with phosphorus.

Hyperuricemia develops in TLS as purine nucleic acids are released from cells that are often rich in nucleic acid material due to their high turnover rates. Purines are sequentially metabolized into hypoxanthine, then xanthine, and finally uric acid ( Fig. 38.1 ). The intracellular enzyme LDH is often increased in TLS. The pretreatment LDH level is a risk factor for developing TLS because it is a marker of increased tumor burden.

Mechanism of uric acid formation.

5. What are the findings on urine microscopy in a patient with TLS?

Urine sediment examination in a patient with acute TLS may reveal uric acid or calcium phosphate crystals, although the lack of crystalluria does not rule out TLS. When AKI develops, there will typically be evidence of tubular injury, with kidney tubular epithelial cells and granular or muddy-brown casts.

6. What is the mechanism of uric acid formation?

As illustrated in Fig. 38.1 , purines from nucleic acids (DNA, RNA) are metabolized to xanthine and hypoxanthine. Xanthine oxidase catalyzes their conversion to uric acid, which is less water soluble, especially in acidic urine. In other species, urate oxidase catalyzes the conversion of uric acid to the much more soluble allantoin, which is readily excreted by the kidneys. In humans and higher primates, a missense mutation in the gene encoding urate oxidase occurred during early hominid evolution, and the nitrogenous waste is excreted as uric acid.