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.