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Tumor lysis syndrome and how to avoid

Definition
  • Combination of metabolic and electrolyte abnormalities that occurs in patients with cancer, usually after the initiation of cytotoxic treatment but also spontaneously
  • Characterised by excessive cell lysis resulting in hyperuricaemia, hyperphosphataemia, hyperkalaemia, and hypocalcaemia
  • TLS is most common with lymphomas and leukaemias, in particular Burkitt's lymphoma and acute lymphoblastic leukaemia
  • It is also associated with other haematological malignancies and solid tumours.
Risk Factors
  • haematological malignancy
  • large tumour burden
  • chemosensitive tumours
  • recent chemotherapy
  • renal impairment
  • dehydration
Differential diagnosis
  • Isolated hyperuricaemia
    • Also associated with malignancy, particularly haematological tumours
    • May be asymptomatic or present with nephrolithiasis or gout
  • Isolated hyperkalaemia
    • Can present with fatigue, weakness, paraesthesia, palpitations, or life-threatening arrhythmias
    • Patient may be taking potassium-sparing medication, systemic heparin, or NSAIDs
    • Renal failure and frequent blood transfusions can contribute
  • Isolated hyperphosphataemia
    • History of dehydration and volume depletion, pulmonary embolism, bone metastases, or advanced renal failure
    • Use of bisphosphonates, laxatives, and antacids may contribute
    • Symptoms such as tetany and cramping relate to hypocalcaemia caused by hyperphosphataemia.
  • Isolated hypocalcaemia
    • Perioral numbness or tingling, paraesthesia of hands and feet, positive Trousseau or Chvostek sign.
Epidemiology
  • Approximate incidence:
    • 6.1% in non-Hodgkin's lymphoma (NHL)
    • 5.2% in acute lymphocytic leukaemia
    • 3.4% in acute myeloid leukaemia
Aetiology
  • TLS appears in haematological malignancies characterised by a high proliferating rate
    • In particular non-Hodgkin's lymphoma, acute lymphocytic leukaemia, and acute myeloid leukaemia
  • Less frequently, TLS appears in other haematological malignancies such as chronic lymphocytic leukaemia and multiple myeloma
  • It is rarely associated with solid tumours, but to date it has been described in a number of primary cancers, including breast cancer, small cell lung cancer, and testicular cancer
  • The risk of developing TLS is increased if the tumour consists of rapidly dividing cells, if the bulk of the disease is high, and if response to treatment is good
  • Pre-existing renal impairment and/or dehydration are predisposing factors that may be modifiable and should be identified prior to treatment initiation
  • High serum lactate dehydrogenase and white blood cell count correlate with high tumour volume and are associated with a high likelihood of TLS
  • Although there is a correlation between advanced age and TLS, age is not an independent risk factor
    • The increased likelihood of developing TLS is most likely related to a reduction in glomerular filtration rate
Clinical features
  • History of haematological malignancy
  • Pre-existing renal compromise
  • Syncope/chest pain/dyspnoea
  • Seizures
  • Nausea and vomiting
  • Anorexia
  • Diarrhoea 
  • Muscle weakness
  • Muscle cramps
  • Lethargy
  • Paraesthesia 
  • Lymphadenopathy
  • Splenomegaly 
  • Hypertension/hypotension
  • Oliguria/anuria/haematuria
Pathophysiology
  • Malignant cells have a high turnover rate
    • => Produce a greater amount of nucleic acid products (which transform to uric acid) and phosphate (approximately 4 times the amount carried by a normal lymphocyte)
  • TLS is caused by the rapid destruction of tumour cells, usually in response to chemotherapy
    • The release of intracellular contents into the bloodstream results in an elevation in serum levels of uric acid, potassium, and phosphate, and a reduction in the level of calcium
  • The ability of the kidney to eliminate these large amounts of byproducts becomes saturated.
  • Hyperuricaemia, in combination with acidic urine and reduced urinary flow, may result in precipitation of uric acid crystals, renal tubular obstruction, and a decline in renal function
    • This is the most common mechanism of acute renal failure in TLS.
  • Hyperphosphataemia may lead to the formation of calcium phosphate crystals and precipitation, resulting in nephrocalcinosis and urinary obstruction.
  • Secondary hypocalcaemia has been reported as a consequence of hyperphosphataemia, which may be symptomatic if severe.
  • Hyperkalaemia is related to the massive cell degradation but may be exacerbated by the development of acute renal failure or lactic acidosis
  • The clinical manifestations of TLS are directly related to these pathophysiological abnormalities
    • Hyperkalaemia, hyperphosphataemia, and hypocalcaemia may result in cardiac arrhythmias and sudden death
    • Hypocalcaemia can lead to muscle cramps, tetany, and seizures
    • Acute renal failure may lead to fluid overload and pulmonary oedema
Investigations
  • Serum uric acid
  • Serum phosphate
  • Serum potassium
  • Serum calcium
  • Full blood count
    • High levels of pretreatment WBC increase the likelihood of developing laboratory and clinical TLS
  • Lactate dehydrogenase
    • High pretreatment levels increase the likelihood of developing laboratory and clinical TLS
  • Serum creatinine
    • A sign of clinical TLS
  • Serum urea
    • Consistent with renal impairment and acute renal failure, or may be raised with dehydration
  • Urine pH
    • Uric acid is poorly soluble in water and becomes less soluble in an acidic environment (urine pH <5)
    • Uric acid crystals can precipitate in renal tubules and cause tubular obstruction and nephropathy
  • ECG
    • Abnormalities with hyperkalaemia include peaked T waves, prolongation of PR and QRS intervals, and flattening of P waves
    • This might be followed by atrioventricular conduction blocks and ventricular fibrillation or asystole
    • In hypocalcaemia, QT prolongation may be seen, which predisposes to ventricular arrhythmias. arrhythmia with hyperkalaemia, hyperphosphataemia, or hypocalcaemia
Management

a) conservative
  • Patients with indolent non-Hodgkin's lymphoma or low proliferating malignancies are at low risk
    • These patients can be observed with regular monitoring of blood biochemistry and regular assessment of fluid balance and vital signs
  • Nephrotoxic agents such as NSAIDs, aminoglycoside antibiotics, and intravenous contrast should be avoided in patients with haematological malignancy undergoing chemotherapy
b) medical
  • Prechemotherapy intravenous hydration
    • Two days before the initiation of systemic cytotoxic therapy, patients should receive intravenous hydration with isotonic sodium chloride
    • Maintain a high urinary output of 100 mL/hour (3 mL/kg/hour in children <10 kg body weight).
  • Phosphate binder
    • Phosphate-binding agents such as aluminium antacids are given to reduce bowel absorption of phosphate
    • Aluminium may cause constipation, whereas magnesium is more likely to cause diarrhoea
    • A combination antacid may reduce colonic adverse effects
  • Allopurinol
    • Can prevent formation of uric acid but cannot destroy the uric acid already present
    • It has been shown to reduce the incidence of urate nephropathy related to uric acid crystal precipitation
    • When used with purine-based chemotherapeutic agents such as mercaptopurine or azathioprine, dose reductions of these agents are required
  • Rasburicase
    • Initial management with a single dose of rasburicase (recombinant urate-oxidase enzyme) may be considered in paediatric patients
    • Rasburicase may be initiated in adults if treatment with allopurinol fails to treat hyperuricaemia
  • Loop diuretic
    • A high glomerular filtration rate results in a reduction of uric acid, phosphate, and potassium in the bloodstream by improving the elimination of uric acid and phosphate
    • Aggressive hydration improves intravascular volume and enhances renal blood flow
    • If urine output is not satisfactory despite volume repletion, then loop diuretics may be used
    • Loop diuretics may cause precipitation of uric acid and calcium phosphate in the tubules and should therefore be avoided in patients with renal obstruction or volume depletion
c) surgical
  • n/a
Prognosis
  • There are no data on prognosis of TLS following successful treatment or prevention
  • Since the introduction of rasburicase, acute renal failure requiring dialysis has been significantly reduced
  • Increased understanding of the pathophysiology and awareness of TLS among physicians has led to better management and better outcomes
    • Official management guidelines have yet to be formulated, but efforts are in progress
  • The outcome and duration of inpatient stay may vary if complications such as cardiac arrhythmias, seizures, or acute renal failure develop
    • Most of these complications can be managed successfully in large specialist centres.
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