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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