Tumor lysis syndrome

• Hyperkalemia. Potassium is mainly an intracellular ion. High turnover of tumor cells leads to spill of potassium into the blood. Symptoms usually do not manifest until levels are high (> 6.5 mmol/L) [normal 3.5–5.0 mmol/L] and they include[8]
  • palpitations, cardiac conduction abnormalities, and arrhythmias (can be fatal)
  • muscle weakness or paralysis
• Hyperphosphatemia. Like potassium, phosphates are also predominantly intracellular. Hyperphosphatemia causes acute kidney injury in tumor lysis syndrome, because of deposition of calcium phosphate crystals in the kidney parenchyma.[2]
• Hypocalcemia. Because of the hyperphosphatemia, calcium is precipitated to form calcium phosphate, leading to hypocalcemia.[2] Symptoms of hypocalcemia include (but are not limited to):[9]
  • tetany
  • paresthesias
  • muscle cramps
  • muscle weakness
  • sudden changes in mental status, including emotional lability
  • Parkinsonian (extrapyramidal) movement disorders
  • papilledema
• Hyperuricemia[10] and hyperuricosuria. Massive cell death and nuclear breakdown generates large quantities of nucleic acids. Of these, the purines (adenine and guanine) are converted to uric acid via the purine degradation pathway and excreted in the urine. However, at the high concentrations of uric acid generated by tumor lysis, uric acid is apt to precipitate as monosodium urate crystals.

Acute uric acid nephropathy (AUAN) due to hyperuricosuria has been a dominant cause of acute kidney failure but with the advent of effective treatments for hyperuricosuria, AUAN has become a less common cause than hyperphosphatemia. Two common conditions related to excess uric acid, gout and uric acid nephrolithiasis, are not features of tumor lysis syndrome.

• Lactic acidosis.[11][12]
• Pretreatment spontaneous tumor lysis syndrome. This entity is associated with acute kidney failure due to uric acid nephropathy prior to the institution of chemotherapy and is largely associated with lymphoma and leukemia. The important distinction between this syndrome and the post-chemotherapy syndrome is that spontaneous TLS is not associated with hyperphosphatemia. One suggestion for the reason of this is that the high cell turnover rate leads to high uric acid levels through nucleobase turnover but the tumor reuses the released phosphate for growth of new tumor cells. In post-chemotherapy TLS, tumor cells are destroyed and no new tumor cells are being synthesized. TLS is most common during cytotoxic treatment of hematologic neoplasms.[13]

Risk factors for tumor lysis syndrome depend on several different characteristics of the patient, the type of cancer, and the type of chemotherapy used.[14]

Tumor Characteristics: Tumors with a high cell turnover rate, rapid growth rate, and high tumor bulk tend to be more associated with the development of tumor lysis syndrome. The most common tumors associated with this syndrome are poorly differentiated lymphomas (such as Burkitt's lymphoma), other Non-Hodgkin Lymphomas (NHL), acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML).[3] Other cancers (such as melanoma) have also been associated with TLS but are less common.

Patient Characteristics: Certain patient-related factors can affect the development of clinical tumor lysis syndrome. These factors include elevated baseline serum creatinine, kidney failure, dehydration, and other issues affecting urinary flow or the acidity of urine.[14]

Chemotherapy Characteristics: Chemo-sensitive tumors, such as lymphomas, carry a higher risk for the development of tumor lysis syndrome. Those tumors that are more responsive to a chemotherapy agent carry a higher TLS risk.[7] Usually, the precipitating medication regimen includes combination chemotherapy, but TLS can be triggered in cancer patients by steroid treatment alone, and sometimes without any treatment—in this case the condition is referred to as "spontaneous tumor lysis syndrome".[13]

TLS should be suspected in patients with large tumor burden who develop acute kidney failure along with hyperuricemia (> 15 mg/dL) or hyperphosphatemia (> 8 mg/dL). (Most other acute kidney failure occurs with uric acid < 12 mg/dL and phosphate < 6 mg/dL). Acute uric acid nephropathy is associated with little or no urine output. The urinalysis may show uric acid crystals or amorphous urates. The hypersecretion of uric acid can be detected with a high urine uric acid - creatinine ratio > 1.0, compared to a value of 0.6–0.7 for most other causes of acute kidney failure.

It is important to prevent life-threatening manifestations associated with TLS which include acute kidney injury, hyperkalemia (which may cause cardiac arrhythmias), and or hypocalcemia (which may cause cardiac arrhythmias and neuromuscular irritability).[2]

Acute Kidney Injury: Patients at risk for developing TLS (e.g. patients about to receive chemotherapy for a cancer with a high cell turnover rate, especially lymphomas and leukemias) should receive appropriate intravenous hydration in order to improve blood flow to the kidneys, maximize urine output, and ultimately prevent precipitation of uric acid crystals that can led to acute kidney injury.[2][4] A diuretic may also be indicated to further increase urine output in addition to intravenous hydration.[2][4] Another approach to prevent damage to the kidneys is to prevent the build up of uric acid during TLS, and this can be accomplished with use of allopurinol or rasburicase.[2] Allopurinol (a xanthine oxidase inhibitor, which inhibits uric acid production) works by preventing the formation of uric acid following tumor cell lysis.[4][13] Rasburicase is a synthetic urate oxidase enzyme and acts by degrading uric acid.[16][17] It is not recommended to alkalinize urine in the management of TLS.[2][4]

Hyperkalemia: Monitoring potassium levels in the blood frequently and cardiac monitoring (given the risk of cardiac arrhythmias) are important components in the prevention of adverse consequences in TLS.[2] Other strategies include limiting oral intake of potassium and excreting potassium through the gastrointestinal tract using agents such as oral sodium polystyrene sulfonate can be beneficial.[2][4] Insulin therapy (in conjunction with glucose administration) as well as beta-receptor agonists (such as albuterol) can also be used but are temporary interventions[2] and potassium is not excreted from the body. Hemodialysis and hemofiltration can also be used as options to remove potassium from the bloodstream when hyperkalemia is present.[2]

Hypocalcemia: Hyperphosphatemia is a common finding in TLS and high phosphorus levels can itself contribute to hypocalcemia and therefore phosphate binders may be beneficial in preventing this form of hypocalcemia.[2]

Treatment is first targeted at the specific metabolic disorder.

In general, rasburicase and hydration are the mainstays of treatment in patients with clinical evidence of tumor lysis syndrome.[18] A loop diuretic may also be indicated to maintain appropriate production of urine by the kidneys.[18] Further treatment is targeted towards the specific metabolic abnormalities present in patients with TLS (see "main articles" linked above). Mild hyperkalemia without symptoms can be treated with a loop diuretic and sodium polystirene, while a temporizing agent such as rapid acting insulin (in conjunction with glucose) and an agent to stabilize cardiac membranes such as calcium carbonate may be given in cases of severe hyperkalemia.[18] Concerning symptoms related to hypocalcemia (e.g. seizures) in TLS patients can be treated with calcium gluconate.[18] Tumor lysis patients patients may ultimately also require renal replacement therapy such as through hemodialysis if indicated.[18]

The rate of mortality from tumor lysis syndrome may vary widely depending on the type of underlying malignancy.[19] However, the occurrence of acute kidney injury is concerning given the high mortality that is generally associated with it.[2]