Introduction:

• It represents myriad of metabolic and electrolyte abnormalities that result from the release of intracellular products by rapidly dividing tumor cells prior to therapy or from the lysis of sensitive tumor cells during the therapy.

Pathogenesis:

1

Intense lysis of blasts with release of nucleic acids

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Excess purine catabolism (Adenosine and Guanine)

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Increased hypoxanthine

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Conversion of hypoxanthine to xanthine by xanthineoxidase

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Conversion of xanthine to uric acid by xanthineoxidase

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Hypoxanthine and xanthine crystallize at high pH in kidney tubules (So avoid excess alkalization of urine during treatment)

Uric acid forms insoluble urate crystals at pH 5-6 (So moderate alkalization of urine is required during treatment)

2

Intense lysis of blasts with release of potassium

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Hyperkalemia, which is most frequent immediate life threatening complication

3

Intense lysis of blasts with release ofphosphates

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Hyperphosphatemia

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Phosphate binds to calcium in blood

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1. Depletion of calcium causing hypocalcemia

2. Formation of calcium phosphate which precipitates in renal tubules causing acute renal failure

(Acidic pH enhances crystallization, hence "compromise" urine pH during treatment is 7-7.5)

Factors enhancing TLS

• Higher responsiveness to anti-leukemia treatment
• Higher tumor burden
• High proliferative index Ex: ALL, Burkitt's lymphoma, T-NHL, DLBCL, AML with WBC >1lac/cmm
• LDH- >1500
• Volume contraction
• Pre-existing renal dysfunction
• Infiltration of kidney by tumor
• Post treatment ARF
• Acidic/ concentrated urine
• Sepsis/ DIC
• Exogenous potassium/ phosphorous/ purines
• Nephrotoxic/ Uricosuric drugs
• Agents with hyperkalemic effects

Presentation:

• Hyperkalemia
• Hypocalcemia
• Hyperuricemia
• Hyperphosphatemia
• All of the above can lead to
  • Cardiac arrythmias
  • Seizures
• Renal failure

Cairo Bishop definition of TLS:

• Laboratory TLS
  • Presence of 2 or more of the following abnormalities in a patient of cancer or undergoing treatment of cancer, within 3 days prior to or up to 7 days after initiation of treatment
    • Uric acid ≥8mg/dL (≥ 176 micromol/L) or 25% increase from baseline
    • Potassium ≥6 mmol/L (≥6mEq/L) or 25% increase from baseline
    • Phosphate 
      • Children- ≥ 6.5mg/dL (≥ 2.1mmol/L) or 25% increase from baseline
      • Adults- >4.5mg/dl (≥1.45 mmol/L) or 25% increase from baseline
    • Calcium- ≤7mg/dL (≤1.75 mmol/L) or 25% decrease from baseline
• Clinical TLS
  • A patient with laboratory TLS and at least one of the following
    • Creatinine ≥1.5xULN 
    • Cardiac arrythmias
    • Seizures
    • Sudden death

TLS Prophylaxis (Prevention) -Should be started at least 6hrs prior to starting treatment

• T. Allopurinol- 300mg/m² /day in 3 divided doses- for 3-8 days
• Intravenous hyperhydration- 3000-5000ml/m²/day- 
  • This should be started after correcting Hemoglobin by PRBC transfusion
  • No additional potassium should be added
  • Check Input/Output strictly and maintain urine output >100-250ml/m²/hr (Infants- >4ml/kg/hr)
  • For inadequate urine output Furosemide- 1-10mg/kg/day can be given
  • Controlled sodium bicarbonate supply to maintain urine pH between 7-7.5 (Although there is no clear evidence)
• Rasburicase
  • Start if uric acid >8mg/dL/ Very large tumor burden
  • Dose- 0.15- 0.2 units/kg IV in 50ml NS over 30 min 
  • 1mg= 18 units
  • Vial of 1.5mg/ day as a fixed dose is also effective
  • Contraindicated in G6PD deficiency
  • Blood specimens for lab tests must be sent on ice if Rasburicase is given
• Lab tests (12-24hrly)- CBC, Electrolytes, Calcium, Phosphorous, Uric acid, Creatinine

Treatment

• Continue all measures of TLS prophylaxis
• Hyperkalemia- Refer "electrolyte imbalances" section
• Hyperphosphatemia
  • Exclude phosphates in diet
  • Phosphate binders: Sevelamer- 800mg-1600mg- TDS- PO with meals/ Aluminum hydroxide- 0.1gm/kg (Avoid if there is renal dysfunction)
  • Top hyperhydration provided excretion is normal
  • Urine pH not to exceed 7
  • Hypertonic glucose 1gm/kg + 0.3units/kg regular insulin- infused over 30min
  • Hemodialysis
• Hypocalcemia- Refer "electrolyte imbalances" section
  • Treat only if patient is symptomatic, with prior correction of hyperphosphatemia
  • Avoid calcium gluconate if patient has hyperphosphatemia
• Indications for hemodialysis
  • Potassium >7mEq/L or >67mEq/L  and increasing in spite of forced diuresis
  • Phosphorous >15mg/dL (>5mmol/dL)
  • Calcium X Phosphorous- >60mg²/dl² (6.4mmol²/dl²)
  • Uric acid >10mg/dL (>600micromol/L)
  • Creatinine- >10times the upper limit of normal for the age
  • Oliguria/ Anuria- Urine output <50ml/m²/hr in spite of fluid input of 130-200ml/m²/hr with IV. Frusemide as high as 10mg/kg/day
  • High grade bilateral urinary tract obstruction