Diagnostics and Therapeutics: Tumor Lysis Syndrome

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Tumor Lysis Syndrome (TLS) is a set of electrolyte derangements that can result from the use of cytotoxic therapies in cancer patients. These can lead to a wide spectrum of emergent complications including but not limited to cardiac dysrhythmias, seizures, and acute renal failure. In this post, we will focus on the risk stratification of these patients, the mechanism of TLS in the context of electrolyte changes, and how to manage the emergent consequences of these derangements (1,2).

Incidence

The overall incidence of Tumor Lysis Syndrome is approximately 4-5% with an associated mortality of 21% (3). However, the incidence of TLS has been difficult to delineate as it varies widely by cancer. Patients with hematologic cancer are at a much higher risk of developing TLS with an incidence of 4-42% (4). This wide range can be attributed to the varying risk between different types of hematologic cancers. Highly proliferative and aggressive blood cancers, such as non-Hodgkin’s Lymphomas, have a TLS incidence of 14%, and a mortality of up to 79% in high-risk AML patients (5). More indolent cancers such as chronic lymphocytic leukemia have lower incidences. It is also worth noting that these aggressive hematologic cancers occur more commonly in children and thus the risk of TLS can be higher in the pediatric population6. For solid cancers, the incidence of TLS is rare with most studies placing them into a low-risk category (6). Hematologic cancer risk for TLS development can be broken down into the following categories (5,7):

Original table recreated by author from information found in references 5 and 7 below.

When to Suspect Tumor Lysis Syndrome

Patient factors that should raise suspicion (2,4,8,9):

  • cytotoxic treatment (radiation, chemotherapy, monoclonal antibodies) within the past 72 hours

  • high-risk hematologic cancer

  • high tumor burden / metastatic disease

  • initial screening labs with leukocytosis > 25,000

  • highly treatment-sensitive cancers

  • high-risk chemotherapy agents (i.e. paclitaxel, doxorubicin, cisplatin)

  • high-risk monoclonal antibody treatments (i.e. dinaciclib, alvocibid, ibrutinib)

  • pre-existing kidney disease

  • dehydration or risk factors for dehydration (nausea, vomiting, sepsis, etc)

  • other nephrotoxic medications and medications that increase baseline uric acid (thiazides, levodopa, alcohol, etc)

  • advanced age

Pathophysiology

The mechanism of tumor lysis syndrome involves the lysis of rapidly proliferating malignant cells resulting in the accumulation of their intracellular products within the bloodstream. The mass lysis of cells involved typically occurs as a byproduct of chemotherapy, radiation, or monoclonal antibody treatment, but can also occur spontaneously and sometimes before the initial diagnosis of cancer (7,10). Uric acid, phosphate, and potassium all reside intracellularly. Upon the death of cells, they are released into the bloodstream and can overwhelm the kidneys and lead to significant electrolyte derangements (7,11). These laboratory changes and associated symptoms typically occur within 24-72 hours of cytotoxic treatment (8).

Uric Acid Metabolism

During a mass lysis of cells, a large amount of DNA is released from the intracellular compartment comprising both purine and pyrimidine nucleotides. The majority of these are broken down into inert products for excretion, but the purine nucleotides are metabolized to hypoxanthine and xanthine, and then converted into uric acid.

 Due to our poor renal excretion of uric acid, the average level of urate in the blood often lives near its solubility limit. Therefore, an acute increase in uric acid in the blood, such as during tumor lysis syndrome, can surpass this limit and lead to monosodium urate (MSU) formation (12).

These crystals typically deposit within the kidney’s collecting tubules due to their lower pH and result in obstructive and pre-renal acute kidney injury. The stones themselves lead to obstruction within the renal collecting ducts while uric acid depletes nitric oxide in the blood through chemical reactions leading to vasoconstriction and ischemia of the kidney (7,13). This initiates a feedback cycle that further deteriorates the kidneys’ filtration rate and ability to excrete uric acid and the other electrolytes mentioned here (10,12).

Pictured below is the normal uric acid metabolism cycle (left) and the metabolism cycle when altered and enhanced by medications to either decrease uric acid production or facilitate its breakdown (right, discussed more below in “Additional Treatments for Severe Electrolyte Derangements”).

Potassium Metabolism

Intracellular potassium constitutes approximately 98% of the human body’s total potassium stores. When there is a mass lysis of cells, intracellular potassium is released and overwhelms the typical avenues of excretion including the liver, muscles, and kidneys (16). This is compounded by the previously mentioned uric acid-induced acute kidney injury. The resulting hyperkalemia can cause muscle weakness, paralysis, and life-threatening arrhythmias that can ultimately lead to cardiac arrest if untreated (10,17).

Phosphate Metabolism

Malignant cells contain up to four times the amount of intracellular phosphate compared to normal cells (5). The majority of systemic phosphate is renally excreted, but this system will become overwhelmed with large amounts of phosphate and in states of acute kidney injury (18). This hyperphosphatemia can lead multiple downstream effects, including the formation of calcium phosphate salts in the renal tubules leading to worsening acute kidney injury during tumor lysis syndrome. Additionally, these salts can deposit in the heart leading to arrhythmias and in the vasculature causing severe arteriosclerosis (5,8).

It is important to note that this hyperphosphatemia is less common in spontaneous tumor lysis syndrome when compared to chemotherapy-induced. There are various discussed mechanisms of this in the existing literature (19).

Calcium Metabolism

As the phosphate levels rise, it will often bind with calcium and effectively chelating the calcium within the blood, causing hypocalcemia. This can often become significant enough to precipitate dysrhythmias, seizures, and tetany (20).

 Work-up and Diagnosis in the Emergency Department

Initial presentation of TLS typically includes generalized symptoms such as gastrointestinal distress, decreased appetite, muscle cramping, palpitations, hematuria / oliguria, and altered mental status. Any of these symptoms in the setting of recent cytotoxic treatment for known blood cancer should raise concern for TLS. Initial work up when suspicious of this process should include ECG, chest x-ray, urinalysis, and the following labs: CBC, CMP, magnesium, phosphate, calcium, uric acid, VBG (for pH), and lactate dehydrogenase (10). When interpreting the lab results of your screening labs, it is important to recognize the difference between laboratory tumor lysis syndrome and clinical tumor lysis syndrome (21).  In recent research, it has been discovered that as high as 42% of adult cancer patients and 70% of pediatric cancer patients suffer from laboratory changes associated with TLS, but have no associated clinical symptoms (9).

Therefore, a classification system was created delineating the two.

Laboratory Tumor Lysis Syndrome (2) (Within three to seven days from cytotoxic therapy, two or more of the following lab value changes):

  • 25% change from baseline potassium, phosphate, calcium, or uric acid

    OR

  • potassium > 6 mg/dl

  • uric acid > 8 mg/dl (nL 1.5-6.0 in females and 2.5-7.0 in males)

  • phosphate > 4.5 mg/dl (adults) and > 6.5 mg/dl (pediatrics)

  • calcium < 7 mg/dl

Clinical Tumor Lysis Syndrome (2) - laboratory TLS + one of the following:

  • cardiac arrhythmia

  • seizure

  • sudden death

  • creatinine > 1.5x upper limit of normal

Management in the Emergency Department

There are slight differences in management depending on if clinical tumor lysis syndrome is present, which are discussed below.

General Management

If the above criteria is met for laboratory or clinical TLS, aggressive intravenous hydration should be initiated to dilute blood concentrations of electrolytes and preserve glomerular filtration and limit kidney injury (8). This will also reduce acidosis and flush out uric acid and calcium phosphate, preventing them from precipitating in the renal tubules (2). This can be achieved with fluid boluses in the emergency department followed by maintenance fluids that average out to twice normal maintenance fluid rates (8). It is important to monitor vitals, volume status, and urine output, especially in patients with known cardiac or renal disease. It may be necessary to cautiously utilize diuretics in these patients to ensure good urine output despite their ability to precipitate more salts in underhydrated patients. Loop diuretics are preferred since they promote potassium secretion (5,7). Additionally, be sure to avoid or discontinue (temporarily) any nephrotoxic medications.

Patients with TLS should be admitted to the hospital with concurrent management from the oncology and renal teams. Electrolyte screening labs should be obtained every four to six hours to observe for any life-threatening derangements (2).

Of note, urine alkalization used to be a cornerstone of the management of TLS, but has fallen out of favor due to the risk for metabolic acidosis and increased xanthine and calcium phosphate precipitation in the renal tubules (5).

Additional Treatments for Severe Electrolyte Derangements

Severe Hyperuricemia

If uric acid  8 mg/dL or 25% increase from baseline develops, then rasburicase should be administered in addition to IV fluid resuscitation. Rasburicase is a recombinant urate oxidase, essentially replacing the enzyme that humans lack to convert uric acid into allantoin, a highly soluble and excretable metabolite.

Uric acid crystals in the urine of a patient with leukemia. From Wikimedia commons https://commons.wikimedia.org/wiki/File:UricAcid_%28cropped%29.jpg under cc attribution SA-3.0, Jan 29, 2025.

Dosing for rasburicase should be 3mg intravenously if uric acid is  8 mg/dL and 6mg intravenously if  12 mg/dL. The onset of rasburicase is rapid with some studies observing marked decreases in uric acid levels within four hours (5). If uric acid levels are not responding to rasburicase then nephrology should be consulted to consider continuous renal replacement therapy (CRRT) (13).

Allopurinol is first line in the prophylactic treatment of hyperuricemia before chemotherapy induction due to its ability to inhibit uric acid formation. However, it is not used to treat emergent hyperuricemia as it cannot reduce existing uric acid levels. Additionally, allopurinol promotes xanthine and hypoxanthine accumulation which can precipitate crystals in the kidney resulting in xanthine nephropathy (5).

Severe Hyperkalemia

If hyperkalemia  6 mg/dL or 25% increase from baseline develops, cardiac monitoring and standard hyperkalemia treatment should be initiated with insulin/dextrose, albuterol nebulization, sodium bicarbonate, and kayexalate.

In this specific hyperkalemia situation, great caution should be taken with administering calcium gluconate as it can worsen calcium phosphate precipitation and acute kidney injury. Therefore, it should only be administered in life-threatening arrhythmia and not simply for peaked t waves on ECG (2,20).

Avoid loop diuretics unless certain that the patient is adequately hydrated. Consider hemodialysis in life-threatening arrhythmia with associated hyperkalemia that is not responding to treatment (2).

Severe Hyperphosphatemia

For phosphate  4.5 mg/dL ( 6.5 mg/dL for children) or 25% increase from baseline, the mainstay of treatment is still aggressive intravenous fluid hydration. In addition, all supplemental phosphate should be avoided and phosphate binders such as oral sevelamer 1600mg can be utilized. Other suitable phosphate binders include calcium acetate, ferric citrate, and lanthanum carbonate (9).

If the phosphate level 7.5, the phosphate is refractory to fluids and phosphate binders, the calcium phosphate product  70, or secondary hypocalcemia develops, then consider hemodialysis. However, some studies report that continuous renal replacement therapy (CRRT) may be more effective at treating this than intermittent hemodialysis.

Severe Hypocalcemia

Since the hypocalcemia in TLS is secondary to hyperphosphatemia, it is typically self-resolving with treatment of the hyperphosphatemia. As mentioned above, be extremely cautious with calcium gluconate due to the risk of increased calcium phosphate precipitation and only administer in cases of symptomatic hypocalcemia. Do not treat to normal lab range, but rather use the minimum dose needed to cease symptoms (50 – 100mg/kg IV calcium gluconate). To lower this risk, also attempt to avoid administering calcium gluconate until after phosphate levels have normalized. Again, consider hemodialysis if hypocalcemia develops, especially if symptomatic, as it is often due to severe hyperphosphatemia (2,9).

Disposition

These patients should be admitted to the ICU for close monitoring of life-threatening arrhythmias, urine output, electrolytes every four to six hours, and aggressive fluid resuscitation (9). Pictured below is an algorithm created for simpler visualization of diagnosis and treatment of TLS in the emergency department.

original document created by author of post. for more information visit https://static1.squarespace.com/static/53c1a2cce4b0e88e61f99b70/t/5e9de2355141403e2a3dc559/1587405366163/AgileMD+-+TLS+v041720.pdf

POST BY Parker maddox, MD

Dr. Maddox is a PGY-1 in Emergency Medicine at the University of Cincinnati

EDITING BY Anita Goel, MD

Dr. Goel is an Assistant Professor in Emergency Medicine at the University of Cincinnati and assistant editor of TamingtheSRU.com

Cite As: Maddox, P., Goel, A. Diagnostics and Therapeutics: Tumor Lysis Syndrome. TamingtheSRU. www.tamingthesru.com/blog/diagnostics/tumor-lysis-syndrome. 2/3/2025.

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