Tumor Lysis Syndrome

Algorithm

%%{init: {"themeVariables": { "lineWidth": "3px", "lineColor": "#000000" } }}%%
graph TD
    %% Node Definitions with Custom Styles
    Start([Patient with Malignancy & Planned Therapy])
    style Start fill:#e3f2fd,stroke:#1565c0,color:#1565c0

    Risk{Risk Stratification}
    style Risk fill:#fff3e0,stroke:#e65100,color:#e65100

    Low[Low Risk: 
WBC < 50k ALL / < 10k AML 
Indolent NHL / Solid Tumors]
    style Low fill:#e8f5e9,stroke:#2e7d32,color:#2e7d32

    Int[Intermediate Risk: 
WBC 50-100k ALL / 10-50k AML 
DLBCL / Bulky Disease]
    style Int fill:#fff8e1,stroke:#fbc02d,color:#fbc02d

    High[High Risk: 
WBC > 100k ALL / > 50k AML 
Burkitt / Lymphoblastic Lymphoma]
    style High fill:#ffebee,stroke:#c62828,color:#c62828

    %% Management Blocks
    MgtLow[Management: 
Close Observation 
Consider IV Hydration]
    style MgtLow fill:#e8f5e9,stroke:#2e7d32,color:#2e7d32

    MgtInt[Management: 
Vigorous IV Hydration 
Allopurinol 300mg/m2/day 
Monitoring q8-12h]
    style MgtInt fill:#fff8e1,stroke:#fbc02d,color:#fbc02d

    MgtHigh[Management: 
Vigorous IV Hydration 
Rasburicase 0.15-0.2mg/kg 
Monitoring q4-6h]
    style MgtHigh fill:#ffebee,stroke:#c62828,color:#c62828

    %% Decision Points
    LabTLS{Lab TLS? 
2+ changes in 
Uric Acid/K/Phos/Ca}
    style LabTLS fill:#f3e5f5,stroke:#7b1fa2,color:#7b1fa2

    ClinicalTLS{Clinical TLS? 
Seizures / Arrhythmia / AKI}
    style ClinicalTLS fill:#fce4ec,stroke:#c2185b,color:#c2185b

    Dialysis[Indication for Dialysis: 
Refractory K > 6 / Phos > 6 
Anuria / Fluid Overload 
Severe Acidosis]
    style Dialysis fill:#212121,stroke:#000000,color:#ffffff

    %% Connections
    Start --> Risk
    Risk --> Low --> MgtLow
    Risk --> Int --> MgtInt
    Risk --> High --> MgtHigh

    MgtLow --> LabTLS
    MgtInt --> LabTLS
    MgtHigh --> LabTLS

    LabTLS -- Yes --> ClinicalTLS
    ClinicalTLS -- Yes --> Dialysis
    ClinicalTLS -- No --> MgtHigh

Introduction And Pathophysiology

• Life-threatening oncologic emergency.
• Arises due to rapid release of intracellular metabolites from dying tumor cells.
• Metabolite release exceeds excretory capacity of kidneys.
• Occurs typically within 12-48 hours of initiating chemotherapy.
• Occurs prior to therapy in patients with massive tumor burden or rapid cell proliferation.
• Infrequently reported in Hodgkin lymphoma, neuroblastoma, and hepatoblastoma.
• Complications include renal insufficiency, cardiac arrhythmias, seizures, disseminated intravascular coagulation, and death.

Mechanisms Of Renal Dysfunction

Multiple mechanisms contribute to acute kidney injury during tumor lysis syndrome (TLS):

• Precipitation of uric acid crystals within renal tubules.
• Precipitation of xanthine crystals. Occurs when urine pH exceeds 7.5 and following initiation of allopurinol.
• Precipitation of calcium phosphate within renal microvasculature and tubular system. Occurs when product of serum calcium and phosphate exceeds 60.
• Massive cytokine release causing systemic inflammation and hypotension.

Diagnostic Criteria

Diagnosis encompasses both laboratory derangements and clinical manifestations.

Laboratory Tumor Lysis Syndrome

Defined as $\ge$ 25% increase from baseline (or absolute value exceeding cut-offs) in $\ge$ 2 of the following serum biochemical parameters:

• Uric Acid: >8 mg/dL.
• Potassium: >6 mEq/L.
• Phosphorus: >6.5 mg/dL.
• Corrected Serum Calcium: <7 mg/dL.

Clinical Tumor Lysis Syndrome

Defined as the presence of laboratory TLS accompanied by specific clinical manifestations:

• Seizures.
• Cardiac arrhythmias.
• Acute kidney injury.

Grading of TLS

Risk Stratification By Malignancy Type

Risk-Based Management Algorithm

Principles Of Prevention And Monitoring

Clinical And Laboratory Surveillance

• Implement strict measurement of fluid intake and urine output.
• Monitor serum electrolytes, calcium, phosphorus, potassium, uric acid, blood urea nitrogen, and creatinine every 4-12 hours.
• Evaluate complete blood counts 1-2 times daily.
• Institute continuous respiratory, central nervous system, and cardiac telemetry monitoring if hyperkalemia or hypocalcemia develops.
• Obtain baseline laboratory values prior to therapy initiation.

Promotion Of Renal Excretion

• Target urine output >100 mL/m²/hour.
• Target urine specific gravity <1.010.
• Administer intravenous hydration at minimum two times maintenance rate.
• Utilize diuretics to augment output only if patient lacks hypotension or hypovolemia.
• First-line diuretic: Furosemide 0.5-1 mg/kg per dose.
• Second-line diuretic: Mannitol 0.5 g/kg per dose.

Management Of Specific Metabolic Derangements

Hyperuricemia

• Pathophysiology: Breakdown of malignant cell nucleic acids. Can cause uric acid nephropathy.
• Allopurinol: Xanthine oxidase inhibitor.
  • Prevents further accumulation of uric acid.
  • Dose: 300 mg/m²/day or 10 mg/kg/day orally (maximum 800 mg/day).
  • Intravenous alternative: 200 mg/m²/day (maximum 600 mg/day).
• Rasburicase: Recombinant urate oxidase enzyme.
  • Actively degrades existing uric acid.
  • Dose: 0.15-0.2 mg/kg/day intravenously.
  • May repeat dose.
  • Indicated for high-risk patients or established hyperuricemia.
  • Contraindications:
    • Assess glucose-6-phosphate dehydrogenase (G6PD) status prior to rasburicase administration.
    • Rasburicase causes severe methemoglobinemia or profound hemolytic anemia in G6PD-deficient patients.
• Urinary Alkalization: Target urine pH 7.0-7.5 to prevent uric acid crystallization. Must discontinue alkalization immediately upon chemotherapy initiation or rasburicase administration. Elevated pH actively promotes dangerous xanthine and calcium phosphate crystal precipitation.

Hyperkalemia

• Pathophysiology: Massive release of intracellular potassium. Causes arrhythmias and cardiac arrest.
• Precaution: Exclude pseudohyperkalemia caused by leukemic cell lysis inside the laboratory collection tube. Avoid any potassium in intravenous fluids unless dangerously low.
• Mild/Asymptomatic: Manage via vigorous hydration and loop diuretics.
• Pharmacologic Clearance: Sodium polystyrene sulfonate (Kayexalate) 1 g/kg every 6 hours combined with sorbitol 50-150 mL. Removes 1 mEq potassium per liter per gram of resin over 24 hours.
• Acute Shift/Stabilization: Sodium bicarbonate, calcium gluconate, glucose, and insulin.

Hyperphosphatemia And Hypocalcemia

• Pathophysiology: Intracellular phosphate release causes hyperphosphatemia. Subsequent precipitation with calcium leads to metastatic calcification, hypocalcemic tetany, photophobia, and pruritus.
• Phosphate Management: Aggressive hydration and forced diuresis. Stop urinary alkalinization. Administer oral aluminum hydroxide (150 mg/kg/day) or sevelamer to bind intestinal phosphate. Implement low-phosphate diet.
• Calcium Management: Treat strictly for symptomatic hypocalcemia (e.g., tetany). Administration of calcium in asymptomatic patients exacerbates calcium phosphate precipitation.
• Calcium Dosing: 10 mg/kg of elemental calcium (0.5-1.0 mL/kg of 10% calcium gluconate). Discontinue immediately upon symptom resolution.
• Contraindication: Never administer calcium in the same intravenous line as sodium bicarbonate.

Indications For Renal Replacement Therapy (Dialysis)

Hemodialysis or hemofiltration represents the definitive intervention for refractory TLS complications. Specific indications include:

• Progressive renal failure accompanied by hyperkalemia, hyperphosphatemia, oliguria, anuria, or volume overload unresponsive to diuretic measures.
• Presence of severe hyperphosphatemia (>6 mg/dL) combined with hypercalcemia (promotes irreversible deposition in renal interstitium and tubular system).
• Estimated glomerular filtration rate falls below 50%.
• Persistent hyperkalemia featuring QRS interval widening on electrocardiogram and/or serum potassium level >6 mEq/L.
• Severe, intractable metabolic acidosis.
• Volume overload absolutely unresponsive to aggressive diuretic therapy.
• Anuria accompanied by overt uremic symptoms (e.g., encephalopathy).
• Severe symptomatic hypocalcemia unresponsive to initial calcium replacement.
• Refractory hypertension (blood pressure >150/90 mmHg) with inadequate urine output persisting 10 hours after treatment initiation.
• Development of congestive heart failure secondary to fluid and metabolic derangements.