Tumor lysis syndrome

Did You Know?

• Symptoms of hyperkalemia usually do not manifest until levels exceed 6.5 mmol/L (normal 3.5–5.0 mmol/L) and include palpitations, cardiac conduction abnormalities, arrhythmias, and muscle weakness or paralysis.
• Hypocalcemia symptoms include tetany, paresthesias, muscle cramps, muscle weakness, and sudden changes in mental status such as emotional lability.
• In a registry study of over 28,000 US hospital discharges from 2010–2013, TLS was associated with complications including gastrointestinal bleeding (6%), brain bleed (2%), and cardiac arrest (2%).

Risk factors

Risk factors for tumor lysis syndrome involve tumor, patient, and chemotherapy characteristics. Tumors with high cell turnover, rapid growth, and large bulk are more associated with TLS, particularly poorly differentiated lymphomas such as Burkitt lymphoma, other non-Hodgkin lymphomas, acute lymphoblastic leukemia, and acute myeloid leukemia. Chronic lymphocytic leukemia with lymph node masses greater than 10 cm or greater than 5 cm with lymphocytosis also carries higher risk. Patient-related factors include chronic kidney disease, older age, dehydration, conditions affecting urinary flow or urine acidity, and use of medications such as NSAIDs that may damage kidneys. Chemotherapy characteristics that increase risk include intensive induction chemotherapy, use of anthracycline, cytarabine, or venetoclax. Chemosensitive tumors, such as lymphomas, are at higher risk because they respond more readily to treatment. TLS can also be triggered by steroid treatments or occur spontaneously without any therapy.

Diagnosis

Tumor lysis syndrome should be suspected in cancer patients who develop hyperuricemia, hyperphosphatemia, hyperkalemia, and hypocalcemia with clinical signs of kidney failure, heart arrhythmias, or heart failure within 24 to 72 hours of starting chemotherapy, though it can also occur after radiation, glucocorticoids, or spontaneously. Kidney failure may present as increased creatinine or decreased urine output; urinalysis may show uric acid crystals or amorphous urates, and a urine uric acid–creatinine ratio greater than 1.0 suggests TLS. Laboratory TLS involves two or more abnormalities within three days before or seven days after chemotherapy: uric acid > 8 mg/dL or 25% increase, potassium > 6 meq/L or 25% increase, phosphate > 4.5 mg/dL or 25% increase, calcium < 7 mg/dL or 25% decrease. Clinical TLS requires laboratory TLS plus increased serum creatinine (1.5 times upper limit of normal), cardiac arrhythmia or sudden death, or seizure. A grading scale (0–5) is used; grade 5 is death. In 2011, Howard proposed refinements: two or more electrolyte abnormalities must occur simultaneously to be considered TLS-related, and a 25% change from baseline should not be a criterion unless the value is already outside normal range. Any symptomatic hypocalcemia constitutes clinical TLS.

Prevention

Preventive measures are initiated before, during, and after chemotherapy, as TLS most commonly occurs 24–72 hours after treatment. To prevent acute kidney injury, patients at risk should receive appropriate intravenous hydration to improve renal blood flow and maximize urine output, thereby preventing precipitation of uric acid crystals. A diuretic may be added to increase urine output. Uric acid–lowering therapies include xanthine oxidase inhibitors such as allopurinol or febuxostat, which prevent uric acid formation; rasburicase degrades uric acid into highly soluble allantoin for renal excretion. Concurrent use of allopurinol and rasburicase is not endorsed. Urine alkalinization is not recommended, as it increases calcium phosphate crystal deposition and kidney damage. For hyperkalemia prevention, frequent blood potassium monitoring and cardiac monitoring are important. Strategies include limiting oral potassium intake and using oral sodium polystyrene sulfonate to excrete potassium via the gastrointestinal tract. Insulin with glucose and beta-receptor agonists such as albuterol can shift potassium into cells temporarily, but do not remove it from the body.

Treatment

Treatment targets the specific metabolic disorder. Uric acid–lowering therapy (allopurinol or rasburicase) and intravenous hydration are mainstays for patients with clinical TLS. With widespread use of uric acid–lowering agents, hyperphosphatemia has become the most common cause of kidney damage in TLS. A loop diuretic may be used to maintain urine output. Mild hyperkalemia without symptoms can be treated with a loop diuretic and potassium binders such as sodium zirconium cyclosilicate or sodium polystyrene sulfonate. Severe hyperkalemia may require temporizing agents: rapid-acting insulin with glucose, inhaled beta-agonists such as albuterol, and calcium carbonate to stabilize cardiac membranes. Symptomatic hypocalcemia (e.g., seizures) can be treated with calcium gluconate. Patients may ultimately require renal replacement therapy such as dialysis to quickly normalize electrolytes. Urine alkalinization is no longer recommended, as it is associated with high phosphorus, low calcium, and calcium-phosphate crystal kidney deposits. Frequent blood chemistry monitoring and continuous cardiac monitoring with telemetry and electrocardiograms are necessary to detect life-threatening arrhythmias.