Tumor Lysis Syndrome; Causes, Symptoms, Treatment

Tumor lysis syndrome (TLS)








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Tumor lysis syndrome (TLS) is characterized by a massive tumor cell death leading to the development of metabolic derangements and target organ dysfunction. TLS can occur as a result of cancer treatment or spontaneously. Blood cancers constitute the vast majority of TLS cases because of the sensitivity to therapy and rapid division rates.

Tumor lysis syndrome (TLS) is a potentially life-threatening condition that occurs in oncologic and hematologic patients with large tumor burden, either due to cytotoxic therapy or, less commonly, spontaneously because of massive tumor cell lysis. TLS is clinically characterized by acute renal failure, hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. While limited options are available for treating TLS, identifying patients at high risk for developing TLS and prevention in high-risk patients remain an important aspect in the treatment of cancer patients. In general, treatment of TLS consists of intensive hydration, stimulation of diuresis, and, more specifically, in the use of allopurinol and rasburicase.

Tumor lysis syndrome (TLS) describes the pathological sequela of the rapid lysis of tumor cells. The shift of potassium, phosphorus, and nucleic acid material into the extracellular space can rapidly overcome existing homeostatic mechanisms, leading to acute kidney failure, arrhythmia, and death. TLS is the most common oncologic emergency, and although commonly seen in the context of initial chemotherapeutic treatment of hematologic malignancies, increasing recognition is being paid to the occurrence of spontaneous TLS and TLS secondary to treatment of bulky solid tumors.,

Tumor lysis syndrome is a group of metabolic abnormalities that can occur as a complication during the treatment of cancer,[rx] where large amounts of tumor cells are killed off (lysed) at the same time by the treatment, releasing their contents into the bloodstream. This occurs most commonly after the treatment of lymphomas and leukemias. In oncology and hematology, this is a potentially fatal complication, and patients at increased risk for TLS should be closely monitored before, during, and after their course of chemotherapy.

Tumor Lysis Syndrome

Pathophysiology

The pathophysiology of tumor lysis syndrome is complicated. Tumor lysis syndrome is caused by the massive release of intracellular ions such as potassium, phosphorus, and nucleic acids that have been metabolized to uric acid. The main organ is responsible for the excretions of these substances in the kidney. When the compensatory response of the kidney is exhausted as a result of the massive release of intracellular ions, uric acid obstructive uropathy develops which can then progress to acute kidney injury.

Molecules called nucleotides comprise DNA. These nucleotides are units made of a phosphate group, a sugar group, and a nitrogen base. The nitrogen base is adenine, thymine, guanine or cytosine. Adenine and guanine are purines while thymine and cytosine are pyrimidines. Ribonucleic acid, however, is made up of a ribose sugar and a nitrogen base adenine, thymine, and uracil.

The metabolism of the purines adenine and guanine in a stepwise process leads to the production of xanthine. Adenine is metabolized to hypoxanthine whereas guanine is metabolized to xanthine. Xanthine is then further metabolized into uric acid in a reaction that is catalyzed by xanthine oxidase. Most mammals have the enzyme urate oxidase that can transform uric acid to allantoin which is a more soluble substance that can be easily excreted by the kidney. Human beings lack this enzyme.

Due to the rapid turnover of tumor cells, there is an overwhelming production of uric acid which then crystallizes in the renal tubules causing obstructive uropathy from and decreased glomerular filtration rate. In rat models, urate nephropathy causes an increase in both proximal and distal tubule pressure. Peritubular capillary pressure and vascular resistance also increase. Uric acid scavenges nitric oxide which is a potent vasodilator. The scavenging of nitric oxide produces vasoconstriction and kidney ischemia. Uric acid is also a potential pro-inflammatory agent and can cause the release of other cytokine-like tumor necrosis factor-alpha, protein I. These cytokines attract white blood cells and facilitate further injury to the kidney.

Electrolyte Imbalance

Hyperkalemia

The concentration of potassium within the cell is about 120 to 130 meq/L. The lysis of tumorous cells leads to a massive release of intracellular potassium. The excess potassium is usually taken up by the liver and skeletal muscle. The rest is excreted via the gastrointestinal system or the kidney. The obstructive uropathy from uric acid salts can limit the excretion of potassium. Sometimes the hyperkalemia from the solid tumor can reach a potentially life-threatening level. The risk of hyperkalemia is cardiac arrest from arrhythmia.

Hyperphosphatemia

Hyperphosphatemia is another electrolyte imbalance associated with tumor lysis syndrome. The nucleic acid has a phosphate group, and the breakdown of the tumorous cell will lead to the release of a significant amount of phosphorus into the bloodstream. Most of the phosphorus is really excreted. This ability of the kidney to handle a high load of phosphorus is inhibited by acute kidney injury or chronic kidney disease.

Hyperphosphatemia is less common in spontaneous tumor lysis syndrome than those induced by chemotherapy. It leads to the chelation of calcium causing hypocalcemia. Deposition of calcium and phosphorus salts in the kidney and soft tissues can also occur.

Hypocalcemia

Hypocalcemia in tumor lysis syndrome is mostly secondary to the chelation of phosphorus. This condition is more potentially life-threatening than hyperphosphatemia. Possible complications from hypocalcemia include arrhythmia, tetany, seizure, and death. The calcium level might still be relatively low even after the normalization of the phosphorus level because of a deficiency of 1, 25 Vitamin D.

Causes of Tumor Lysis Syndrome

Tumor lysis syndrome is most common in patients diagnosed with leukemia who have a very high white blood cell (WBC) count. It can also be seen in high-grade lymphomas especially after the initiation of aggressive chemotherapy. Other solid tumors that can cause tumor lysis syndrome are hepatoblastoma or neuroblastoma. There are reports of tumor lysis syndrome occurring spontaneously before the initiation of chemotherapy.

An international panel of experts has stratified tumors based on the risk of developing tumor lysis syndrome.

High-Risk Tumors

  • Advanced Burkitt lymphoma
  • Advanced leukemia
  • Early-stage Burkitt lymphoma or leukemia with elevated lactate dehydrogenase
  • Acute lymphocytic leukemia with WBC count greater than 100,000/microliters, or if the baseline increase of lactate dehydrogenase is twice the upper limit of normal
  • Diffuse large B-cell lymphoma and bulky disease with an elevated baseline lactate dehydrogenase of twice the upper limit of normal
  • Acute myeloid leukemia with WBC count greater than or equal to 10,000/microliters

Intermediate-Risk Tumors

  • Acute myeloid leukemia with WBC count between 25,000 and 100,000/microliters
  • Acute lymphocytic leukemia with WBC less than 100,000/microL and lactate dehydrogenase of less than twice the upper limit of normal
  • Diffuse large B-cell lymphoma with a baseline increase in lactate dehydrogenase of twice ULN but the non-bulky disease
  • Early-stage Burkitt lymphoma or leukemia with a lactate dehydrogenase of less than twice the upper limit of normal

Low-Risk Tumors

  • Solid cancers
  • Multiple myelomas
  • Indolent lymphomas
  • Chronic lymphocytic leukemia
  • Chronic myeloid leukemia
  • Acute myelogenous leukemia with a WBC count less than 25,000/microliters and a lactate dehydrogenase elevated to less than twice the upper limit of normal

There are case reports of tumor lysis syndrome associated with the administration of steroids, biological immunomodulators, and monoclonal antibodies. Agents are associated with the development of tumor lysis syndrome include:

  • Thalidomide
  • Bortezomib
  • Hydroxyurea
  • Paclitaxel
  • Fludarabine
  • Etoposide
  • Zoledronic acid

In rare instances, tumor lysis syndrome has been observed in patients under general anesthesia undergoing surgery. Other rare occurrences of tumor lysis syndrome are seen in pregnancy or high fever.

High-Risk Tumors

  • Acute lymphocytic leukemia (5.2% to 23%)
  • Acute myeloid leukemia with a WBC count greater than 75,000 (18 %)
  • B-cell acute lymphoblastic leukemia (26.4%)
  • Burkitt lymphoma (14.9%)

Intermediate-Risk Tumors

  • Acute myeloid leukemia with WBC count between 25,000 and 50,000 (6%)
  • Diffuse large B-cell lymphoma (6%)

Low-risk Tumors

  • Acute myeloid leukemia with WBC count less than 25,000 (1%)
  • Chronic lymphocytic leukemia (0.33%)
  • Chronic myelogenous leukemia (Case reports)
  • A solid tumor (Case reports)

Tumor lysis syndrome is most commonly associated with the initiation of cytotoxic chemotherapy. However, there are case reports of tumor lysis syndrome precipitated by radiation therapy, including the use of thalidomide, dexamethasone therapy, and the use of newer chemotherapeutic agents like rituximab and bortezomib.

Risk Factors for Tumor Lysis Syndrome.

Category of Risk Factor Risk Factor Comments
Cancer mass Bulky tumor or extensive metastasis The larger the cancer mass or the higher the number of cells that will lyse with treatment, the higher the risk of clinical tumor lysis syndrome.
Organ infiltration by cancer cells Hepatomegaly, splenomegaly, and nephromegaly generally represent tumor infiltration into these organs, and therefore a larger tumor burden than that of patients without these findings.
Bone marrow involvement Healthy adults have 1.4 kg of bone marrow. A marrow that has been replaced by leukemic cells contains a cancer mass greater than 1 kg and therefore represents bulky disease.
Renal infiltration or outflow-tract obstruction Cancers that infiltrate the kidney or obstruct urine flow predispose to nephropathy from other causes, such as the tumor lysis syndrome.
Cell lysis potential The high rate of proliferation of cancer cells Lactate dehydrogenase level is a surrogate for tumor proliferation. The higher the level, the greater the risk of the tumor lysis syndrome.
Cancer-cell sensitivity to anticancer therapy Cancers that are inherently more sensitive to therapy have a higher rate of cell lysis and a greater risk of tumor lysis syndrome than the other cancers.
The intensity of initial anticancer therapy The higher the intensity of initial therapy, the greater the rate of cancer-cell lysis and the risk of the tumor lysis syndrome. For example, some protocols for acute lymphoblastic leukemia begin with a week of prednisone monotherapy, and others begin with a combination of a glucocorticoid, vincristine, asparaginase, and daunorubicin. A patient treated on the latter protocol would have a higher risk of tumor lysis syndrome.
Features on patient presentation Nephropathy before a diagnosis of cancer A patient with preexisting nephropathy from hypertension, diabetes, gout, or other causes has a greater risk for acute kidney injury and the tumor lysis syndrome.
Dehydration or volume depletion Dehydration decreases the rate of urine flow through renal tubules and increases the level of solutes (e.g., phosphorus, uric acid) that can crystallize and cause nephropathy.
Acidic urine Uric acid has a lower solubility in acidic urine and therefore crystallizes more rapidly. A patient who presents with acidic urine and hyperuricemia usually already has uric acid crystals or microcrystals in the renal tubules.
Hypotension Hypotension decreases urine flow and increases the level of solutes that can crystallize. Hypotension can also independently cause acute kidney injury.
Exposure to nephrotoxins Vancomycin, aminoglycosides, contrast agents for diagnostic imaging and other potential nephrotoxins increase the risk of acute kidney injury from the lysis of cancer cells.
Supportive care Inadequate hydration Initial boluses of normal saline until the patient is euvolemic followed by infusion of suitable intravenous fluids at two times the maintenance rate (about 180 ml/hr in an adult who can tolerate hyperhydration) increases the rate of urine flow through renal tubules, decreases the level of solutes that can crystallize and cause acute kidney injury, and decreases the time that those solutes remain in the tubules so that even if microcrystals form they may not have time to aggregate into clinically important crystals before removal by the high flow of urine.
Exogenous potassium Unless the patient has severe hypokalemia or a dysrhythmia from hypokalemia, potassium should not be included in the intravenous fluids, and potassium (from food or medications) should be minimized until the risk period for the tumor lysis syndrome has passed.
Exogenous phosphate Restricting dietary phosphate and adding a phosphate binder reduce the exogenous load of phosphate so that the kidneys need only excrete the endogenous load of phosphate released by cancer-cell lysis.
Delayed uric acid removal Allopurinol prevents the formation of new uric acid by inhibiting xanthine oxidase and preventing the conversion of xanthine to uric acid. It does not remove existing uric acid and does increase urinary excretion of xanthine, which can crystallize and cause nephropathy. Rasburicase is an enzyme that rapidly removes uric acid by converting it to allantoin, which is highly soluble and readily excreted in the urine. The longer the uric acid level remains high, the greater the risk of crystal formation and acute kidney injury.

Symptoms of Tumor Lysis Syndrome

Hyperkalemia – Potassium is mainly an intracellular ion. High turnover of tumor cells leads to a spill of potassium into the blood. Symptoms usually do not manifest until levels are high (> 7 mmol/L) [normal 3.5–5.0 mmol/L] and they include

  • cardiac conduction abnormalities (can be fatal)
  • severe muscle weakness or paralysis

Hyperphosphatemia – Like potassium, phosphates are also predominantly intracellular. Hyperphosphatemia causes acute kidney failure in tumor lysis syndrome, because of deposition of calcium phosphate crystals in the kidney parenchyma.

Hypocalcemia – Because of the hyperphosphatemia, calcium is precipitated to form calcium phosphate, leading to hypocalcemia. Symptoms of hypocalcemia include (but are not limited to):

  • Tetany
  • Sudden mental incapacity, including emotional lability
  • Parkinsonian (extrapyramidal) movement disorders
  • Papilledema
  • Myopathy

Hyperuricemia[rx] and hyperuricosuria. Massive cell death and nuclear breakdown generate 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.[rx][rx]
  • 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 for 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 the 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.[rx]

  • Dark urine reduced urine output or flank pain
  • Lack of appetite and fatigue
  • Numbness, seizures, or hallucinations
  • Muscle cramps and spasms
  • Heart palpitations symptoms are generally nonspecific and can include:
  • Kidney failure and death can occur, especially if TLS is left untreated.
  • TLS is diagnosed based on blood tests, along with signs and symptoms. Its onset may be subtle, with only a few abnormal laboratory values, but it can also present with frank kidney and organ failure.
  • Nausea with or without vomiting


Diagnosis of Tumor Lysis Syndrome

Tumor Lysis Syndrome

 

Cairo-Bishop grading of clinical tumor lysis syndrome for adults

Variable Grade 0 Grade I Grade II Grade III Grade IV GradeV
Creatinine None 1.5 times ULN. The rise in creatinine is not attributable to the chemotherapeutic agent(s) > 1.5-3.0 times ULN. The rise in creatinine is not attributable to the chemotherapeutic agent(s) > 3.0-6.0 times ULN. The rise in creatinine is not attributable to the chemotherapeutic agent(s) > 6.0 times ULN. The rise in creatinine is not attributable to the chemotherapeutic agent(s) Death
Cardiac arrhythmia None Intervention not indicated Nonurgent medical intervention indicated. Cardiac arrhythmias not attributable to the chemotherapeutic agent(s) Symptomatic and incompletely controlled medically or controlled with a device (e.g., defibrillator). Cardiac arrhythmias not attributable to the chemotherapeutic agent(s) Life-threatening (e.g., arrhythmia associated with HF, hypotension, syncope, shock). Cardiac arrhythmias not attributable to the chemotherapeutic agent(s) Death
Seizures None One brief, generalized seizure; seizure(s) well controlled by anticonvulsants or infrequent focal motor seizures not interfering with ADL Seizure in which consciousness is altered; poorly controlled seizure disorder; with breakthrough generalized seizures despite medical intervention Seizure of any kind which is prolonged, repetitive or difficult to control (e.g., status epilepticus, intractable epilepsy)

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.

Cairo-Bishop definition

In 2004, Cairo and Bishop defined a classification system for tumor lysis syndrome.[rx]

Laboratory tumor lysis syndrome: abnormality in two or more of the following, occurring within three days before or seven days after chemotherapy.

  • uric acid > 8 mg/dL or 25% increase
  • potassium > 6 meq/L or 25% increase
  • phosphate > 4.5 mg/dL or 25% increase
  • calcium < 7 mg/dL or 25% decrease

Clinical tumor lysis syndrome: laboratory tumor lysis syndrome plus one or more of the following:

  • increased serum creatinine (1.5 times upper limit of normal)
  • cardiac arrhythmia or sudden death
  • seizure

A grading scale (0–5) is used depending on the presence of lab TLS, serum creatinine, arrhythmias, or seizures.

Howard definition

In 2011, Howard proposed a refinement of the standard Cairo-Bishop definition of TLS accounting for 2 limitations:[11]

  • Two or more electrolyte laboratory abnormalities must be present simultaneously to be considered related to TLS. In fact, some patients may present with one abnormality, but later another one may develop that is unrelated to the TLS (e.g., hypocalcemia associated with sepsis).
  • A 25% change from baseline should not be considered a criterion since such increases are rarely clinically important unless the value is already outside the normal range.

Moreover, any symptomatic hypocalcemia should constitute clinical TLS.

History

The history and physical examination of patients with tumor lysis syndrome should be focused on the primary causes of the tumor lysis.

  • Time of onset of malignancy should be elicited with attention to the presence of constitutional symptoms like weight loss or anorexia. Presence of respiratory symptoms dyspnea, orthopnea, and tachypnea can be a sign of airway compression from a primary tumor.
  • Urinary symptoms such as dysuria, flank pain, and hematuria
  • Signs and symptoms that can be associated with hypocalcemia include nausea, vomiting, seizure, tetanic spasm, and change in mental status.
  • Other clinical manifestations of tumor lysis syndrome include, but are not limited to, syncopal attack, palpitation lethargy, pitting edema, facial edema, abdominal distention, and other sign of fluid overload.

Physical Examination

The physical examination should focus on the electrolyte abnormalities that are associated with tumor lysis syndrome. The physical findings associated with these abnormalities are listed below.

Hypocalcemia

Uremia for hyperuricemia and obstructive uropathy

  • Weakness
  • Lethargy
  • Malaise
  • Nausea
  • Vomiting
  • Metallic taste in the mouth
  • Irritability
  • Generalized pruritis
  • Rales and Ronchi from volume overload
  • Muffled heart sound from pericarditis secondary to uremia
  • Joint pain
  • Renal colicky pain
  • Calcium phosphate crystal deposits in the skin
  • Pruritis
  • Gangrene

The signs and symptoms of tumor lysis syndrome can develop spontaneously or about 72 hours after the initiation of chemotherapy.

Evaluation

  • Tumor lysis syndrome is diagnosed based on criteria that were developed by Cairo and Bishop. The criteria established by Cairo and Bishop have several limitations. The most crucial drawback is that the definition of tumor lysis syndrome based on this criterion requires the initiation of chemotherapy.
  • However, in clinical practice, tumor lysis syndrome can develop spontaneously without the initiation of chemotherapy. The second limitation is the use of creatinine level greater than 1.5 the upper limit for age and gender.
  • This is not standard as a patient with CKD (Chronic Kidney Disease) will have elevated creatine in the absence of AKI. The Cairo-Bishop criteria also factor the severity of tumor lysis syndrome based on the severity of illness from grade 0 (asymptomatic) to 4 (death).

Laboratory Diagnosis of Tumor Lysis Syndrome

Requires 2 or more of the following criteria achieved in the same 24-hour period from 3 days before to 7 days after chemotherapy initiation:

  • Uric acid 25% increase from baseline or greater than or equal to 8.0 mg/dL
  • Potassium 25% increase from baseline or greater than or equal to 6.0 mEq/L
  • Phosphorus 25% increase from baseline or greater than or equal to 0.5 mg/dL (greater than or equal to 6.5 mg/dL in children)
  • Calcium 25% decrease from baseline or less than or equal to 7.0 mg/dL

Clinical Diagnosis of Tumor Lysis Syndrome

Laboratory tumor lysis syndrome plus 1 or more of the following:

  • Creatinine greater than 1.5 times the upper limit of normal of an age-adjusted reference range
  • Seizure
  • Cardiac arrhythmia or sudden death

Other origins of AKI should be excluded. In the evaluation of tumor lysis syndrome, the following studies are necessary:

Imaging

  • X-Ray and CT scan of the chest to evaluate the presence of mediastinal mass and the presence of a concomitant pleural effusion
  • CT scan and an ultrasound of the abdomen and retroperitoneal structure if the mass lesion is located in the abdomen or retroperitoneum. Care must be taken with intravenous (IV) contrast because of the presence of AKI in tumor lysis syndrome.

Electrocardiography (ECG)

  • ECG is part of the workup for patients with tumor lysis syndrome to check for findings associated with hyperkalemia and hypocalcemia. Hyperkalemia is a potential cause of fatal arrhythmia in tumor lysis syndrome.

Complete Blood Count (CBC)

  • CBC helps in the diagnosis of malignancy associated with tumor lysis syndrome. The hallmark of most malignancy is leukocytosis with anemia and thrombocytopenia.

Comprehensive Metabolic Panel (CMP)

  • The metabolic derangement associated with tumor lysis syndrome is hyperkalemia, hypocalcemia, hyperphosphatemia, and hyperuricemia. Blood urea nitrogen (BUN), creatinine, and lactate dehydrogenase are also elevated in tumor lysis syndrome. CMP must be monitored between two to three times daily before and after initiation of therapy. Elevated laboratory value might be indicative of the beginning of tumor lysis syndrome.

Urine Analysis

  • Precipitation of uric acid salt can cause obstructive uropathy. In the treatment of tumor lysis syndrome, Alkalinisation of urine with sodium bicarbonate is the standard of care. Frequent urine analysis with an assessment of urine pH, specific gravity and output are mandatory.

Differential Diagnosis

Tumor lysis syndrome should be differentiated  from other clinical conditions that can cause

  • Hyperkalemia
  • Hyperphosphatemia
  • Hyperuricemia

The differential diagnosis of each electrolyte abnormalities are listed below:

Hyperkalemia

  • Hypocalcemia
  • Metabolic acidosis
  • Congenital adrenal hyperplasia
  • Toxicity from digitalis
  • Acute tubular necrosis
  • Electrical burn
  • Head trauma
  • Rhabdomyolysis
  • Thermal burns

 Hyperphosphatemia

  • Monoclonal gammopathy
  • Waldenstrom macroglobulinemia
  • Multiple Myeloma
  • Other differentials to be considered in hyperphosphatemia include:
  • Pseudohypoparathyroidism
  • Rhabdomyolysis
  • Vitamin D intoxication
  • Oral saline laxative (Phospho-soda) abuse
  • Pseudohyperphosphatemia

Hyperuricemia

  • Hyperparathyroidism
  • Hypothyroidism
  • Nephrolithiasis
  • Alcoholic ketoacidosis
  • Diabetic ketoacidosis
  • Gout
  • Pseudogout
  • Type 1 a glycogen storage disease
  • Hemolytic anemia
  • Hodgkins lymphoma
  • Uric acid nephropathy


Treatment of Tumor Lysis Syndrome

Electrolytes imbalances

Hyperkalemia – Intravenous calcium gluconate may be given to stabilize cardiac membranes for severe hyperkalemia or for electrocardiogram changes. For temporary serum reductions in potassium levels, intravenous insulin with dextrose or high dose of inhaled beta-agonists may be used. Oral sodium polystyrene resin, i.e. kayexalate, is recommended for definitive treatment of hyperkalemia. If these measures are insufficient or for severe metabolic derangements, renal replacement therapy should be considered with the consultation of nephrology.

Hyperphosphatemia – Aggressive intravenous fluid resuscitation with the maintenance of high urine output and oral phosphate binders such as sevelamer may be sufficient to improve phosphate levels. Hemodialysis may be required for severe hyperphosphatemia not controlled by these methods.

Hypocalcemia – Hypocalcemia will correct without specific intervention as phosphate levels normalize. With the exception of severe symptomatic hypocalcemia, intravenous calcium gluconate can be considered, however, it is otherwise not recommended due to elevated risk of calcium-phosphate precipitation.

Rapid Expansion of Intravascular Volume

Treatment of tumor lysis syndrome starts with rapid volume expansion. It is recommended to use crystalloids in volume expansion as this will help to increase the glomerular filtration rate (GFR) quickly. Improved GFR helps with the excretion of solutes associated with tumor lysis syndrome. The drawback to this is that the kidney functions should still be intact. Intravenous fluid should be initiated 48 hours before the start of chemotherapy and should be continued for 48 hours after chemotherapy. Hydration with about 3 to 3.5 liters/m2 per day or 4 to 5 liters per day might be needed to provide adequate hydration. This will provide a urine output of about 3 liters per day

Medications

Allopurinol

This is a structural isomer of hypoxanthine. Xanthine oxidase converts allopurinol to oxypurinol. This is the active metabolite, and it is excreted primarily by the kidney. CKD or AKI impair the elimination of oxypurinol. The level of xanthine in the urine and serum can be elevated after the administration of allopurinol because of the inhibition of the conversion of xanthine to uric acid. Xanthine by itself has limited solubility and can crystallize in the renal tubules making the obstructive uropathy associated with tumor lysis syndrome worse.

Allopurinol can decrease the production of uric acid in tumor lysis syndrome but is ineffective in the treatment of hyperuricemia associated with tumor lysis syndrome. Allopurinol is a very useful agent to prevent the development of tumor lysis syndrome.

The use of allopurinol is associated with the development of skin rash, eosinophilia, and acute hepatitis. The combination of these symptoms is called allopurinol hypersensitivity syndrome. In the treatment of tumor lysis syndrome, clinicians should be aware of a potential drug to drug interaction with azathioprine, immunosuppressive drug use in patients with solid organ transplant and autoimmune disorder.

Recombinant Urate Oxidase

A recombinant version of urate oxidase is a drug that is used to treat hyperuricemia in patients with leukemia, lymphoma, and solid tumor who are undergoing chemotherapy.

It is derived from Aspergillus by recombinant technology. The drug’s mechanism of action is the catalyzes of uric acid to allantoin, carbon dioxide, and hydrogen peroxide.

Hydrogen peroxide is a potent oxidizing agent and can cause severe methemoglobinemia or hemolytic anemia in patients with glucose 6 phosphate dehydrogenase G6PD deficiency. The Food and Drug Administration approved recombinant urate oxidase in 2009 This medication can be administered intramuscularly. It can also be given intravenously at doses of between 50 to 100 U/kg per day.

Sodium Bicarbonate for Urine Alkalinisation

The normal urine is acidic with a pH of about 5. The solubility of uric acid in urine is increased about 10-fold with the alkalinization of urine. This can be achieved by adding about 40 to 50 mEq/liter of sodium bicarbonate to the fluid use for hydration in tumor lysis syndrome.

The risk of alkalinization of the urine is a decrease in the level of ionized calcium as there is less bonding of calcium to albumin. This can worsen the hypocalcemia associated with tumor lysis syndrome leading o arrhythmia or tetany. That apart, the alkalinization of urine can favor the precipitation of calcium and phosphate salts in the kidney tubules thus making AKI in tumor lysis syndrome worse.

Therefore, alkalinization of urine with sodium bicarbonate is only advisable if rasburicase is not readily available. Even with that, the level of calcium should be serially monitored.

Calcium

Calcium chloride and calcium gluconate can be administered parenterally to treat hypocalcemia. In tumor lysis syndrome hypocalcemia is secondary to hyperphosphatemia; therefore, administration of calcium can potentiate the deposition of calcium phosphate crystals in soft tissues and the kidney making AKI worse. This might sometimes necessitate the use of hemodialysis.

Hemodialysis

This is an option that is available to use in a dire situation if the level of potassium and phosphorus is too high in the face of tumor lysis syndrome associated AKI. In tumor lysis syndrome, there is an ongoing liberation of intracellular ions. If intermittent hemodialysis is utilized for extracorporeal clearance, rebound hyperkalemia or hyperphosphatemia might develop. Because of this, continuous renal replacement therapy is the best modality for solute removal. This is done with a high flow rate for the dialysate or replacement fluid*-+. For life-threating hyperkalemia, early hemodialysis is recommended. For severe hyperphosphatemcnvmb, is, continuous renal replacement therapy might also be the best treatment modality.

Febuxostat

This medication is also a xanthine oxidase inhibitor that is relatively new to the market. It is more expensive than allopurinol. It does not cause the hypersensitivity reaction that is associated with allopurinol.

In the clinical trial, the Febuxostat for Tumor Lysis Syndrome Prevention in Hematologic Malignancies (FLORENCE), febuxostat provides better control of hyperuricemia of tumor lysis syndrome with a good safety profile and preservation of renal functions.

Alkalinization of urine

Alkalinization of urine was historically recommended in the management of TLS due to the possibility that it may increase the solubility of uric acid in urine. However, recent increasing evidence suggests that urine alkalinization is associated with increased precipitation of calcium phosphate in the renal tubules, particularly in patients with hyperphosphatemia. Therefore, alkalinization of the urine is not recommended in TLS prophylaxis and therapy anymore.

Allopurinol

Allopurinol is available as oral and intravenous formulations and prevents the conversion of hypoxanthine to xanthine and xanthine to uric acid. The renal clearance of hypoxanthine and xanthine are ten times higher than that of uric acid. Allopurinol has several drug-drug interactions, especially with 6-mercaptopurine, thiazide diuretics, azathioprine, cyclosporine, cyclophosphamide, and amoxicillin. It is necessary to adjust the dose or monitor serum levels of these drugs. The drug should be discontinued in case of skin rash due to the possibility of severe hypersensitivity reactions. Indeed, the dose of allopurinol needs to be adjusted in case of renal insufficiency.

Rasburicase

In most mammals, but not in humans, uric acid is oxidized to allantoin using the enzyme urate oxidase. In humans, uric acid is the end product of purine metabolism. Allantoin is ten times more soluble than uric acid and is easily excreted in the urine. Obtained from Aspergillus flavus, a nonrecombinant urate oxidase has been available since 1968.

Hyperkalemia may cause serious cardiac arrhythmias; therefore, potassium should be withheld from hydration fluid. Patients with potassium levels ≥6 mmol/L should be closely monitored and immediate measures should be taken (infusion of calcium gluconate, therapy with β-adrenergic agonists, and intravenous infusion of insulin and glucose).

Treating hyperphosphatemia is difficult, especially if accompanied by AKI. Oral phosphate binders are less effective, and their oral administration could be difficult in these patients. Significant hyperphosphatemia is treated best with renal replacement therapy.

Renal replacement therapy in TLS should be considered for patients with persistent hyperkalemia despite adequate therapy, severe acidosis, and volume overload unresponsive to diuretic therapy.

Volume Expansion

Once TLS has developed, efforts should be made to re-establish normal concentrations of extracellular solutes. Provided that there has not been a complete loss of kidney function, volume expansion, with a goal of increasing kidney excretion of these solutes, is the bedrock of TLS therapy.,

In addition to augmenting potassium, phosphate, and uric acid excretion, a robust urine flow rate will decrease the calcium-phosphate product in the renal tubules, decreasing the risk of crystal formation and micro-obstruction. As we discuss above, we agree with current consensus statements suggesting a target fluid intake of 3 L per day, barring contraindications.

Diuretics

Although the use of diuretics to enhance urinary flow rate may be expected to decrease the risk of tubular calcium-phosphate precipitation, this practice has not been studied. Furthermore, the hemodynamic changes associated with diuretic use may further compromise kidney function in this population. Barring clinically important volume overload, we do not routinely use diuretics in the care of patients with TLS.

Recommendations for the prevention and treatment of tumor lysis syndrome

Low-risk disease Intermediate-risk disease High-risk disease
Diagnostic measures • No specific measures • Daily monitoring of laboratory abnormalities before and during the first 7 days of anticancer therapy • At least twice daily monitoring of laboratory abnormalities before and during the first 7 days of anticancer therapy
Preventive measures • Moderate hydration is recommended • Vigorous hydration
• Keep urinary output >100 mL/h
• Treatment with allopurinol or febuxostat should be started at least 24 hours before initiation of anticancer therapy and should be continued till normalization of uric acid levels and signs of large tumor burden are absent
• Vigorous hydration
• Keep urinary output >100 mL/h
• Single-dose 6 mg of rasburicase. Repeat doses as necessary. In the case of contraindication treatment with febuxostat
Treatment of established tumor lysis syndrome • Admission to intensive care unit with continuous cardiac monitoring and monitoring of laboratory abnormalities every 4–6 hours
• Early nephrology consultation to estimate the indications for renal replacement therapy
• Correction of electrolyte abnormalities
• Vigorous hydration, keep urinary output >100 mL/h
• Single-dose 6 mg of rasburicase. Repeat doses as necessary. In the case of contraindication, treatment with febuxostat

 


References

Tumor lysis syndrome (TLS)

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