What is tumor lysis syndrome, including its risk factors, pathophysiology, diagnostic criteria, prevention, and management?

Tumor Lysis Syndrome: Comprehensive Overview

Definition and Classification

Tumor lysis syndrome is an oncologic emergency caused by rapid breakdown of malignant cells, releasing massive amounts of intracellular contents (potassium, phosphate, nucleic acids) into the bloodstream, leading to life-threatening metabolic derangements and organ dysfunction. 1

TLS is classified into two categories:

• Laboratory TLS (LTLS): Defined by two or more abnormal serum values (hyperuricemia, hyperkalemia, hyperphosphatemia, or hypocalcemia) within 3 days before or 7 days after initiating anticancer therapy 1
• Clinical TLS (CTLS): Requires laboratory TLS plus one or more clinical complications including renal insufficiency, cardiac arrhythmias, seizures, or death 1

Specific Diagnostic Thresholds

• Hyperuricemia: Uric acid >8 mg/dL in adults and children 1
• Hyperkalemia: Potassium elevation with ECG changes or symptoms 1
• Hyperphosphatemia: Phosphate >1.62 mmol/L 2
• Hypocalcemia: Corrected calcium below normal range 1
• Renal failure: Serum creatinine ≥1.5 times upper normal limit or creatinine clearance <60 mL/min 1

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Pathophysiology

The cascade begins when tumor cells undergo rapid lysis, either spontaneously or following cytotoxic therapy:

• Nucleic acid release: Released DNA and RNA are catabolized to hypoxanthine, then xanthine, and finally to uric acid by xanthine oxidase 1
• Uric acid precipitation: Uric acid crystals precipitate in renal tubules, causing acute tubular obstruction and renal insufficiency 1
• Phosphate-calcium interaction: Hyperphosphatemia drives reciprocal hypocalcemia and calcium-phosphate precipitation in tissues and kidneys, worsening renal injury 3
• Renal vasoconstriction: The metabolic storm triggers renal vasoconstriction, further potentiating acute kidney injury 3

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Risk Factors

Host-Related Factors

• Pre-existing renal impairment or obstructive uropathy 1, 2
• Dehydration and hyponatremia 2
• Advanced age 1
• Baseline hyperuricemia (>8 mg/dL in children, >10 mg/dL in adults) 1, 2

Disease-Related Factors (Highest to Lowest Risk)

Highest Risk Malignancies:

• Burkitt's lymphoma and B-cell ALL: 26.4% TLS rate, representing the absolute highest-risk malignancies 1
• AML with WBC >100 × 10⁹/L: Mortality reaches 83% if clinical TLS develops versus 24% without TLS 1
• High-grade T-cell lymphoblastic NHL 1

Intermediate Risk:

• Diffuse Large B-Cell Lymphoma (DLBCL): Overall TLS rate approximately 6.1%, particularly with bulky disease 1

Lower Risk:

• Chronic Lymphocytic Leukemia (CLL): TLS suspected in only 0.42% of patients 1

Additional Risk Markers:

• Bulky disease (tumor mass >10 cm or massive hepatic metastases) 1, 2
• Elevated LDH >2 times upper normal limit 1, 2
• Extensive bone marrow involvement 1
• High tumor proliferation rate and chemosensitivity 1

Therapy-Related Factors

• Intensive polychemotherapy (cisplatin, cytarabine, etoposide, methotrexate) 2
• Immune checkpoint inhibitors (emerging risk) 4
• Rarely: radiation, corticosteroids, hormonal therapy 5

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Pre-Treatment Evaluation

Before initiating any cytotoxic therapy, perform comprehensive risk stratification: 2

Mandatory Laboratory Assessment

• Renal function: Calculate eGFR using MDRD or Cockcroft-Gault equations—never rely on serum creatinine alone, as it is a delayed and muscle-mass-dependent marker 1
• Baseline metabolic panel: Uric acid, potassium, phosphate, calcium, creatinine, BUN 1, 2
• LDH levels: Marker of tumor burden and cell turnover 1, 2

Imaging

• Renal ultrasound: Perform in all patients to exclude obstructive uropathy before starting chemotherapy 1

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Risk Stratification and Prophylaxis Strategy

High-Risk Patients

Definition: Burkitt's lymphoma, B-ALL, AML with WBC >100 × 10⁹/L, bulky disease, LDH >2× ULN, baseline uric acid >8 mg/dL (children) or >10 mg/dL (adults), pre-existing renal impairment 1, 2

Prophylactic Regimen:

• Aggressive IV hydration through central venous access: 3 L/m²/day, started 48 hours before chemotherapy when possible 1, 2, 6
• Target urine output: ≥100 mL/hour in adults; 3 mL/kg/hour in children <10 kg 2, 6
• Rasburicase 0.20 mg/kg/day IV over 30 minutes for 3-5 days 1, 2, 6
• Inpatient setting with ready access to dialysis 7

Rasburicase is superior to allopurinol in high-risk patients because it enzymatically converts existing uric acid to allantoin (5-10 times more soluble), providing immediate reduction of pre-existing hyperuricemia, whereas allopurinol only prevents new uric acid formation. 2, 6

Intermediate-Risk Patients

Prophylactic Regimen:

• Aggressive hydration: ≥2 L/m²/day 2
• Either allopurinol 300 mg daily OR rasburicase 0.2 mg/kg/day, chosen based on baseline uric acid level and renal function 1, 2

Low-Risk Patients

Prophylactic Regimen:

• Vigorous hydration: ≥2 L/m²/day 1, 2
• Oral allopurinol 100 mg/m² three times daily (maximum 800 mg/day) 1, 2, 6
• In very low-risk cases, prophylactic uric-acid-lowering agents may be omitted if close laboratory monitoring is ensured 2

Critical Pitfall to Avoid

Never administer rasburicase concurrently with allopurinol—this causes xanthine accumulation and eliminates the substrate for rasburicase 1, 2

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Hydration Protocol

• Initiate 48 hours before chemotherapy when possible 1, 2, 6
• Use central venous access for reliable fluid administration in high-risk patients 2, 6
• Add loop diuretics (furosemide) or mannitol if target urine output cannot be achieved, but only after confirming adequate hydration and ruling out obstructive uropathy or hypovolemia 2, 6

Contraindicated Intervention

Urine alkalinization is NOT recommended, especially when rasburicase is used, because it increases the risk of calcium-phosphate precipitation without improving outcomes 2, 6

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Monitoring Protocol

High-Risk Patients (Prophylaxis Phase)

• Every 12 hours for the first 3 days, then every 24 hours: LDH, uric acid, sodium, potassium, creatinine, BUN, phosphorus, calcium, vital signs, urine output 1, 2, 6

Established TLS

• Every 6 hours for the first 24 hours, then daily: Vital signs, serum uric acid, electrolytes, creatinine, BUN 1, 2, 6
• Continuous ECG monitoring for hyperkalemic patients 1, 2, 6

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Management of Established TLS

Immediate Interventions

All patients with clinical TLS or laboratory TLS with worsening parameters require:

• Aggressive IV hydration through central venous access at 3 L/m²/day 1, 6
• Rasburicase 0.20 mg/kg/day IV over 30 minutes immediately 1, 2, 6
• Loop diuretics to maintain urine output if needed 1, 2

Electrolyte Management

Hyperkalemia

Mild (<6 mmol/L, asymptomatic):

• Hydration, loop diuretics, sodium polystyrene 1 g/kg orally or by enema 2, 6

Severe (≥6 mmol/L or symptomatic):

• Rapid insulin 0.1 units/kg plus 25% dextrose 2 mL/kg 2, 6
• Calcium carbonate 100-200 mg/kg/dose to stabilize myocardial membranes 2, 6
• Sodium bicarbonate to correct acidosis 2, 6
• Continuous ECG monitoring is mandatory 1, 2, 6

Hyperphosphatemia

Mild (<1.62 mmol/L):

• No treatment required or aluminum hydroxide 50-100 mg/kg/day divided in 4 doses (oral or nasogastric) 2, 6

Severe or symptomatic:

• Phosphate binders 7
• Consider early dialysis 1, 2

Hypocalcemia

Asymptomatic:

• Do NOT treat—calcium gluconate may increase tissue and renal precipitation of calcium phosphate 2

Symptomatic (tetany, seizures):

• Calcium gluconate 50-100 mg/kg as single IV dose, cautiously repeated if necessary 2, 6

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Clinical Grading System

TLS severity is graded I–IV based on the highest-grade organ complication (renal, cardiac, or neurologic): 1

Grade	Renal (Creatinine/eGFR)	Cardiac Arrhythmia	Seizure
I	Cr ≈1.5× ULN or eGFR 30-45	No intervention needed	None
II	Cr 1.5-3× ULN or eGFR 10-30	Non-urgent intervention	Brief, controlled
III	Cr 3-6× ULN or eGFR 10-20	Symptomatic, incompletely controlled	Poorly controlled
IV	Cr >6× ULN or eGFR <10	Life-threatening with CHF/shock	Status epilepticus

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Indications for Renal Replacement Therapy

Initiate dialysis for: 1, 2, 6

• Severe oliguria or anuria unresponsive to medical management
• Persistent hyperkalemia despite medical therapy
• Hyperphosphatemia with symptomatic hypocalcemia
• Hyperuricemia not responding to rasburicase
• Severe volume overload unresponsive to diuretics 2
• Symptomatic uremia (refractory nausea, vomiting, encephalopathy) 2

In TLS, the threshold for RRT initiation may be lower than in other clinical situations because the process of cell breakdown is ongoing and rapid increases in serum electrolytes cannot be predicted. 7

Hemodialysis effectively removes uric acid (clearance 70-100 mL/min), with plasma uric acid falling approximately 50% with each 6-hour treatment. 1, 6

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Special Considerations

Solid Tumors

• TLS is rare in adult solid tumors but carries 35% mortality when it occurs 1
• Highest risk: metastatic medulloblastoma, bulky small cell lung cancer, massive liver metastases, metastatic germ cell tumors 1, 8
• Precautions should be taken in therapy-sensitive solid tumors with bulky metastatic disease and preexisting risk factors (azotemia, elevated LDH, hyperuricemia) 8

Timing of Chemotherapy

Delaying chemotherapy without addressing TLS risk first results in high mortality (83% for clinical TLS in AML versus 24% without TLS). 1 In high-risk patients, consider cytoreduction before aggressive therapy or gradual dose escalation 7

Rasburicase Advantages

• Allows for earlier administration of chemotherapy due to rapid degradation of uric acid 2
• In randomized trials of children with high-risk hematologic malignancies, rasburicase achieved significantly lower mean uric acid area under the curve compared to allopurinol (p<0.001) 2