Timor lysis syndrome
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Tumor Lysis Syndrome (TLS)
Definition
TLS is a metabolic crisis caused by massive cytolysis and the sudden release of intracellular contents — potassium, phosphate, nucleic acids (metabolized to uric acid), and proteins — into the systemic circulation, overwhelming the kidneys' excretory capacity.
Pathophysiology
When tumor cells lyse rapidly, four key intracellular substances flood the circulation:
| Released substance | Consequence |
|---|---|
| Potassium | Hyperkalemia → cardiac dysrhythmias, cardiac arrest |
| Phosphate | Hyperphosphatemia → binds ionized Ca²⁺ → hypocalcemia; calcium-phosphate crystals precipitate in renal tubules |
| Purine nucleotides | Metabolized by xanthine oxidase → uric acid → insoluble at low tubular pH → intratubular obstruction + vasoconstriction + oxidative injury → AKI |
| Proteins/cytokines | Cytokine release contributes to AKI |
Lymphoblasts contain four times more phosphate than normal lymphocytes, explaining the severity of hyperphosphatemia in leukemia/lymphoma.
Uric acid nephropathy causes AKI through both crystal-dependent (tubular obstruction) and crystal-independent mechanisms (renal vasoconstriction, oxidative injury).
— Brenner and Rector's The Kidney, Comprehensive Clinical Nephrology 7th Ed., Tintinalli's Emergency Medicine
Precipitants & Risk Factors
Most common triggers:
- Initiation of chemotherapy (most common)
- Spontaneous TLS — in tumors that have outgrown their blood supply (rare)
High-risk malignancies:
- Burkitt lymphoma (prototype)
- Acute lymphoblastic leukemia (ALL), especially with hyperleukocytosis
- Other high-grade non-Hodgkin lymphomas
- Acute myeloid leukemia
- Solid tumors — uncommon
Patient-level risk factors:
- Bulky, rapidly proliferating tumors
- Pre-existing CKD
- Volume depletion
- Acidic urine (promotes uric acid precipitation)
Cairo-Bishop Diagnostic Criteria
Laboratory TLS
Requires ≥2 of the following within 3 days before or 7 days after initiating chemotherapy:
| Lab | Threshold |
|---|---|
| Uric acid | ≥8 mg/dL or ≥25% increase from baseline |
| Potassium | ≥6.0 mEq/L or ≥25% increase from baseline |
| Phosphorus (adults) | ≥4.5 mg/dL or ≥25% increase from baseline |
| Phosphorus (children) | ≥6.5 mg/dL |
| Calcium | ≤7 mg/dL or ≥25% decrease from baseline |
Clinical TLS
Laboratory TLS plus one or more of:
- Acute kidney injury (creatinine ≥1.5× ULN)
- Cardiac dysrhythmia or sudden death
- Seizure
— Brenner and Rector's The Kidney
Clinical Features
| System | Manifestations |
|---|---|
| Renal | Oliguria/anuria, AKI (often oliguric); elevated LDH is a clue |
| Cardiac | Dysrhythmias (from hyperkalemia), cardiac arrest |
| Neuromuscular | Seizures, tetany, muscle cramps, paresthesias (from hypocalcemia) |
| GI | Nausea, vomiting |
Hyperkalemia is the most immediate life threat — treat aggressively even without ECG changes.
Management
Monitoring
- Repeat labs (electrolytes, creatinine, uric acid, calcium, phosphate, LDH) every 4–8 hours in high-risk patients
- Continuous cardiac monitoring (ECG)
- ICU admission for established TLS
1. IV Fluid Resuscitation (cornerstone)
- Aggressive hydration at >2× maintenance to increase urine flow and dilute intratubular solutes, counteracting uric acid and calcium-phosphate crystal precipitation
- Use loop diuretics only if the patient is volume-replete (forced diuresis without adequate hydration is dangerous)
2. Hyperuricemia
| Agent | Dose | Notes |
|---|---|---|
| Allopurinol | 100 mg/m² | Xanthine oxidase inhibitor; prophylactic use |
| Rasburicase | 0.2 mg/kg IV | Recombinant urate oxidase; converts existing uric acid to allantoin (soluble); used in established TLS |
Rasburicase is contraindicated in G6PD deficiency — risk of hemolytic anemia and methemoglobinemia.
Urinary alkalinization is no longer recommended — while it increases uric acid solubility, it promotes calcium phosphate precipitation in the tubules, worsening AKI.
3. Hyperkalemia
Standard treatment: β-adrenergic agonists, sodium bicarbonate, dextrose + insulin.
- Avoid calcium unless cardiovascular instability (ventricular dysrhythmias, wide QRS) or neuromuscular irritability is present — supplemental calcium risks metastatic calcium-phosphate precipitation in the setting of hyperphosphatemia.
4. Hyperphosphatemia
- Phosphate binders (limited effect)
- Dextrose + insulin
- Dialysis if refractory
5. Hypocalcemia
- Only treat symptomatic hypocalcemia (tetany, seizures, cardiac instability) with calcium gluconate
- Do not treat asymptomatic hypocalcemia aggressively — risks calcium-phosphate deposition
6. Renal Replacement Therapy
- Emergent hemodialysis for established AKI with refractory electrolyte disturbances
- Large phosphate burden may require repeated or prolonged sessions, or continuous renal replacement therapy (CRRT)
- Avoidance of rectal Kayexalate in neutropenic patients (increased bacteremia risk)
Prevention
In high-risk patients before chemotherapy:
- Aggressive IV hydration
- Allopurinol prophylaxis
- Consider rasburicase in very high-risk cases (e.g., bulky Burkitt lymphoma, hyperleukocytosis)
- Close electrolyte monitoring during the first week of chemotherapy
Key Pearls
- TLS can occur spontaneously (without chemotherapy) in rapidly growing tumors
- LDH elevation is an early clue to massive cell lysis
- The combination of very high phosphate + very high uric acid + oliguria in a patient with hematologic malignancy is diagnostic until proven otherwise
- Calcium supplementation in TLS can worsen AKI by promoting nephrocalcinosis — give only for symptomatic hypocalcemia
- Urinary alkalinization was historically used but is now abandoned due to risk of calcium-phosphate precipitation
— Tintinalli's Emergency Medicine, Brenner and Rector's The Kidney, Comprehensive Clinical Nephrology 7th Ed., National Kidney Foundation Primer on Kidney Diseases 8e
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