• Tumor lysis syndrome (TLS) is an oncologic emergency referring to the acute release of potentially injurious intracellular contents into the systemic circulation from tumor cell breakdown.
• TLS is a constellation of metabolic disturbances that typically occur in the setting of rapid tumor cell lysis induced by cancer-targeted treatment (chemotherapy and/or other interventions such as embolization or radiation). However, spontaneous tumor cell turnover has produced TLS (i.e., no chemotherapy administration).
• TLS is characterized by hyperuricemia, hyperphosphatemia, hypocalcemia, hyperkalemia, and acute kidney injury (AKI), often with progressive oliguria.^2,3
• In the current classification system by Cairo and Bishop, TLS may be defined by laboratory or clinical parameters (Table E1). Grading of clinical TLS is summarized in Table E2.⁵
  1. Laboratory TLS: Clinically silent; defined by at least two of the following biochemical variables within 3 days before or 7 days after initiation of chemotherapy, despite adequate volume status and uric acid-lowering agents.
     1. Hyperuricemia:
        • Results from the rapid release and catabolism of intracellular nucleic acids.
        • Purine nucleic acids are metabolized to hypoxanthine, xanthine, and finally, uric acid.
        • In an acidic environment, uric acid can precipitate in renal tubules and produce intrarenal obstruction.
     2. Hyperkalemia
     3. Hyperphosphatemia: Phosphate may precipitate with calcium to form calcium phosphate stones in renal tubules
     4. Hypocalcemia: Occurs secondary to precipitation with phosphorus
  2. Clinical TLS occurs when laboratory TLS is complicated by at least one of the following clinical complications that is not attributed to the chemotherapeutic regimen: Severe renal impairment, cardiac arrhythmias, central nervous system toxicity, and/or death.

• TLS

Most commonly occurs in patients with acute leukemias; bulky, solid tumors; or high-grade lymphomas. The pathophysiology of TLS is illustrated in Fig. E1.

• Can occur spontaneously or after antitumor intervention (chemotherapy, radiation, etc.)
• Associated with administration of certain chemotherapeutic agents (whether intravenous, intrathecal, etc.):
  1. Paclitaxel
  2. Hydroxyurea
  3. Etoposide
  4. Fludarabine
• Spontaneous TLS
  1. Rare
  2. Lysis of tumor cells without chemotherapy or in setting of minimal chemotherapy (e.g., steroid monotherapy lymphoma)
  3. Related to rapidity of cell turnover
  4. Associations with pregnancy, fever, and rarely, general anesthesia in predisposed individuals
  5. Hyperphosphatemia may not recur because of the reutilization of released phosphorus for resynthesis of newer tumor cells

Figure E1 Pathophysiology of tumor lysis syndrome (TLS).

Lysis of cancer cells releases DNA, phosphate, potassium, and cytokines. DNA released from the lysed cells is metabolized into adenosine and guanosine, both of which are converted into xanthine. Xanthine is then oxidized by xanthine oxidase, leading to the production of uric acid, which is excreted by the kidneys. When the accumulation of phosphate, potassium, xanthine, or uric acid is more rapid than excretion, tumor lysis syndrome develops. Cytokines cause hypotension, inflammation, and acute kidney injury (AKI), which increases the risk for TLS. The bidirectional dashed line between AKI and tumor lysis syndrome indicates that AKI increases the risk of tumor lysis syndrome by reducing the ability of the kidneys to excrete uric acid, xanthine, phosphate, and potassium. By the same token, development of tumor lysis syndrome can cause AKI by renal precipitation of uric acid, xanthine, and calcium phosphate crystals and by crystal-independent mechanisms. Allopurinol inhibits xanthine oxidase and prevents the conversion of hypoxanthine and xanthine into uric acid but does not remove existing uric acid. In contrast, rasburicase removes uric acid by enzymatically degrading it into allantoin, a highly soluble product that has no known adverse effects on health.

(From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.)

See "Acute Kidney Injury" topic in Section I.

• Early identification of abnormal laboratory values may prevent or reduce complications of TLS.
• Laboratory TLS is defined by the presence of at least two of the following biochemical criteria within 3 days before or 7 days after initiation of chemotherapy despite adequate volume repletion or use of uric acid-lowering agents:
  1. Uric acid: >8.0 mg/dl in adults or above the upper limit of the normal range for age in children
  2. Phosphorus: >4.5 mg/dl in adults or >6.5 mg/dl in children
  3. Potassium: >6.0 mmol/L
  4. Calcium: Corrected calcium <7.0 mg/dl or ionized calcium <1.12 mg/dl (0.66 mmol/L)
• Patients should undergo careful and frequent laboratory and clinical monitoring.
  1. Perform frequent ECGs or continuous cardiac monitoring for arrhythmia detection.
  2. Monitor renal status closely and follow daily weight and fluid intake and output.
  3. Monitor blood urea nitrogen (BUN), creatinine, phosphorus, potassium, calcium, uric acid, and LDH in high-risk patients before and up to 72 h after initiating therapy.
     1. If evidence of TLS develops, laboratory parameters should be checked twice daily.

• Consider abdominal/renal ultrasound if kidney failure is present.
• Consider computed tomography (CT) of the chest/abdomen/pelvis to evaluate for underlying malignancies.

• Prevention is the mainstay of therapy.
• Identify high-risk patients (evaluate extent of tumor burden, kidney function, and pathologic findings) to initiate prophylactic measures in a timely fashion. Delayed treatment may lead to life-threatening complications.
• Optimal treatment involves preservation of renal function and prevention of cardiac dysrhythmias and neuromuscular irritability.
• Metabolic derangements should be corrected before starting cancer therapy.
• Prevention for high-risk patients without TLS:
  1. Prompt, vigorous volume repletion and administration of uricosuric agent are the mainstays of therapy. Box E1 summarizes treatment recommendations for TLS.
     1. Volume repletion:
        • Prevents volume depletion and corrects electrolyte derangement.
        • Fluid intake (whether oral or intravenous) should be maintained at 2 to 3 L/m² per day.
        • Begin 24 to 48 h before initiating cancer treatment and continue for up to 72 h after treatment.
        • If IV fluids are required, isotonic solutions are appropriate (e.g., 0.9% saline or 1 L D₅W plus 3, 50-ml ampules of 1 M NaHCO₃).
        • Maintain urine output at 80 to 100 ml/m² per h.
        • Patients with underlying cardiac or kidney dysfunction should be monitored for volume overload and necessity for loop diuretics.
     2. Hypouricemic agents (e.g., allopurinol, rasburicase, and febuxostat). Uric acid is freely filtered at the glomerulus, and handling in the renal proximal tubule is a combination of reabsorption and secretion mediated by luminal urate/anion exchanger urate transporter 1 (URAT-1) and the basolateral organic anion transporter (OAT). When the capacity to transport luminal uric acid is overwhelmed, there is potential for uric acid to crystallize within the tubular lumen. An acidic urine pH favors this process. Uric acid crystals can cause direct tubular injury by obstruction. Furthermore, intratubular and parenchymatous uric acid precipitations cause renal injury by a granulomatous reaction and necrosis of the distal tubule epithelium through induction of chemokine-mediated inflammation from monocyte chemoattractant protein-1 (MCP-1) and macrophage migration inhibitory factor (MIF). There are also crystal-independent mechanisms, which target hemodynamics. These include increased peritubular capillary pressures, increased vasoconstriction, and decreased blood flow. Uric acid also may prevent recovery from AKI in TLS because it inhibits proximal tubule cell proliferation. These diverse mechanisms are united in their propensity to cause AKI, as reported in Fig. E2.⁶
        • Allopurinol:
          • Xanthine oxidase inhibitor prevents conversion of xanthine and hypoxanthine to uric acid.
          • Prophylactic dose is 200 to 400 mg/m² daily in 1 to 3 divided doses, up to a maximum of 800 mg/day. The treatment dose is 300 to 900 mg/day.
          • In patients with high-grade liquid tumors, allopurinol prophylaxis may cause xanthine nephropathy/nephrolithiasis.
          • Low serum uric acid levels and high urinary xanthine levels aid in diagnosis.
          • Consideration for reduction/cessation of allopurinol therapy should then be considered.
        • Rasburicase:
          • Recombinant urate oxidase is used when uric acid levels cannot be lowered by standard measures.
          • Given by IV or IM route in dosages from 50 to 100 units/kg daily for 1 to 5 days.
          • Should not be administered simultaneously with allopurinol because allopurinol reduces uric acid levels and may reduce rasburicase efficacy.
          • Contraindicated in pregnancy and glucose-6-phosphate dehydrogenase deficiency due to hemolytic concerns.
          • Cost is a limiting factor.
        • Febuxostat dosage is 120 mg/day by mouth. It has fewer drug-drug interactions than allopurinol. Dose requirement in patients with mild-to-moderate renal impairment. Cost is a limiting factor.
     3. Urinary alkalinization:
        • Uric acid is more soluble at urinary alkaline pH.
        • Remains controversial and has fallen out of favor.
        • Contraindicated with hyperphosphatemia because of risk of calcium phosphate deposition leading to stones/nephrocalcinosis.

Figure E2 Principles of therapy for the prevention and treatment of tumor lysis syndrome.

(From Ronco C et al: Critical care nephrology, ed 3, Philadelphia, 2019, Elsevier.)

• Principles:
  1. Early consultations for nephrology and critical care teams
  2. Preventive measures as indicated previously
  3. Aggressive treatment of electrolyte disturbances to prevent cardiac arrhythmias and neuromuscular irritability
     1. Arrhythmias tend to be resistant to conventional therapy
     2. Arrhythmias are a leading cause of death in patients with severe TLS
  4. Treatment of kidney failure
• Management of electrolyte disturbances:
  1. Multiple, coexisting electrolyte abnormalities may make conservative management strategies difficult
     1. Systemic alkalinization may be required for concurrent hyperphosphatemia, hyperuricemia, and acidemia. Alkalinization may worsen hypocalcemia.
  2. Hyperuricemia:
     1. Uric acid-lowering agents including allopurinol or rasburicase
  3. Hyperkalemia:
     1. Low-potassium diet
     2. Intravenous calcium chloride/gluconate for ECG changes indicative of hyperkalemia
     3. Intravenous infusions of glucose and insulin to shift potassium into intracellular compartments
     4. Oral cation exchanger such as Patiromer or sodium zirconium cyclosilicate
     5. Hemodialysis
  4. Hyperphosphatemia:
     1. Low-phosphorus diet
     2. Intravenous infusion of glucose and insulin to shift phosphorus into cells
     3. Oral phosphate binders
  5. Hypocalcemia:
     1. Treat only if neuromuscular irritability is present
     2. Intravenous calcium chloride/gluconate
     3. Calcitriol can be used if the serum phosphorus level is normal but is a relatively slow form of therapy
• Management of kidney failure:
  1. Perform standard workup for kidney failure, including urinalysis, urine microscopy, urinary electrolytes, kidney ultrasound, etc.
  2. Supportive care with intravenous fluids and diuretics (if required).
  3. Consider early dialysis if above methods fail (especially if cardiac abnormalities are present).

• Nephrology
• Critical care

• TLS is an oncologic emergency, which can occur spontaneously, or more commonly, during chemotherapy-related tumor cell lysis.
• TLS is associated with the release of several intracellular contents, including potassium, phosphorus, and uric acid. With concomitant renal failure, these products are retained to pathologic levels, leading to cardiac and neurologic abnormalities.
• Common risk factors for TLS include highly proliferative tumors and large tumor burdens (e.g., high-grade lymphomas and acute leukemias), and preexisting metabolic derangements and renal failure.
• High-risk patients should undergo prophylactic measures initiated 24 to 48 h before initiation of cytotoxic agents.
• Prophylactic measures include aggressive intravenous volume repletion and administration of urate-lowering drugs.
• Frequent laboratory testing and monitoring of vital signs, intakes and outputs, and cardiac/neurologic abnormalities are recommended.
• Complications may include continued electrolyte disturbances, renal failure, uremic complications, cardiac arrhythmias, and pulmonary edema from aggressive volume repletion.