• Hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, often accompanied by azotemia and oliguric acute renal failure.
  
• Caused by the rapid release of the intracellular contents of tumor cells into the systemic circulation.
  
• Most commonly seen following treatment of hematologic malignancies of high cellular burden and chemosensitivity, such as lymphomas and leukemias.

First described in 1929, tumor lysis syndrome (TLS) defines a well-established constellation of potentially fatal metabolic derangements that can occur most commonly following chemotherapy for certain hematologic malignancies such as acute lymphoblastic leukemia or high-grade non-Hodgkin’s lymphoma (NHL) (Table 13–1). Less commonly, TLS complicates the treatment of other hematologic malignancies such as chronic lymphocytic leukemia, acute myeloid leukemia, plasma cell disorders including multiple myeloma or isolated plasmacytomas, Hodgkin’s lymphoma, and low- or intermediate-grade NHL. Finally, TLS has been reported anecdotally in the setting of solid tumors such as testicular cancer, breast cancer, and lung cancer. Although usually seen after the administration of cytoreductive chemotherapy, TLS can occur spontaneously prior to initiation of any treatment and also may be seen following other therapies such as radiation, corticosteroids, interferon-α, rituximab, and tamoxifen.

This oncologic emergency is characterized by the acute onset of hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia, often associated with acute renal failure (ARF). TLS results from the rapid release of the intracellular contents of tumor cells (ie, uric acid, phosphate, potassium) into the systemic circulation that overwhelms physiologic metabolic pathways that maintain homeostasis. Not all patients with cancer develop TLS, and the incidence varies depending on the patient population studied and exact definition of TLS used. Factors associated with an increased risk of developing TLS include bulky tumors of high cellular burden and rapid proliferation kinetics (such as Burkitt’s lymphoma or acute lymphocytic leukemia), extensive bone marrow involvement, lactate dehydrogenase levels above 1500 IU/mL (a surrogate marker of tumor cellular burden), and tumors with exquisite sensitivity to chemotherapy or radiation.

The clinical consequence of TLS is dependent on the degree of organ damage inflicted by these metabolic derangements, most notably acute kidney, cardiovascular, and neurologic complications. ARF as evidenced by worsening azotemia (usually defined as an increase in serum creatinine greater than 30–50% of baseline) is a serious but potentially reversible entity that commonly accompanies TLS. Renal replacement therapy may be required in up to 30% of cases of ARF associated with TLS. The etiology of ARF as part of this syndrome is multifactorial, but primarily is due to acute obstruction of urine flow by precipitated uric acid crystals within the renal tubules as well as acute nephrocalcinosis with interstitial and tubular damage from calcium–phosphorus complex deposition.

Risk factors associated with ARF accompanying TLS include preexisting chronic kidney disease, volume depletion with a concentrated urine, concomitant nephrotoxic medication use, and an acidic urine pH that can facilitate uric acid crystal formation. ARF is not only a consequence of TLS, but also can exacerbate the metabolic derangements and limit the efficacy of medical therapies to correct it. If left untreated, TLS associated with ARF may lead to dangerous disturbances in potassium, phosphorus, and calcium and lead to severe, life-threatening cardiac arrhythmias, seizures, muscle paralysis, and death.

Although spontaneous cases of TLS occur where preemptive therapy is not possible, the majority of cases of TLS can be predicted based on both tumor and patient-specific risk factors. Thus, imperative in the management of TLS is early and aggressive initiation of preventive measures that may both attenuate the severity of electrolyte disturbances and hopefully prevent any kidney damage as tumor cells begin to lyse.

Symptoms, Signs, and Laboratory Findings

The clinical presentation of patients with TLS is varied and depends on the extent of metabolic derangements present and type of end-organ damage caused by the released intracellular products. A heightened clinical suspicion for TLS should be maintained in those patients with known malignancies associated with high-risk features, especially following tumor reduction therapy.

Hyperkalemia

Hyperkalemia (ie, potassium level >5 mEq/L) develops commonly in TLS and may be seen as early as 6 hours postchemotherapy. The predominant mechanism is a shift of large intracellular stores of potassium into the extracellular fluid (ECF) compartment as tumor cells lyse. In addition, a further shift of potassium out of viable tumor and host cells may occur if metabolic acidosis due to renal failure is present. Finally, the presence of chronic kidney disease prior to TLS and/or ARF developing as a result of TLS impairs renal clearance of this potassium load to the ECF, thereby exacerbating the severity of hyperkalemia and limiting the efficacy of attempts at medical management.

As the ratio of intracellular to extracellular potassium is important in the maintenance of the normal resting membrane potential, the symptoms associated with hyperkalemia most commonly reflect altered neuronal and muscular excitability. Mild elevations in serum potassium can manifest as lethargy, muscle weakness, muscle cramps, and paresthesias. Unfortunately, concomitant hypocalcemia often seen in TLS can further exacerbate the hyperkalemia-induced membrane excitability and neuromuscular symptoms. More progressive hyperkalemia is worrisome due to its effect on the cardiac conduction system, as can be seen during electrocardiogram (ECG) monitoring by peaked T waves, PR and QRS interval prolongation, various atrioventricular blocks, and eventual asystole and cardiac standstill.

In general, serum potassium levels >6.0 mEq/L associated with neuromuscular manifestations or ECG changes require immediate correction. However, one important caveat to consider is pseudohyperkalemia, which is frequently encountered in hematologic malignancies with significant elevations in white blood cell counts (ie, >100,000/mm3). The elevated potassium results from its release from leukocytes mechanically lysed during phlebotomy or as a result of shift following coagulation of blood within the vial. In such cases, the potassium levels returned by the laboratory, sometimes significantly elevated, do not reflect the level in vivo and are not associated with neuromuscular symptoms or ECG changes. By not using tourniquets and measuring plasma (instead of serum) values, potassium values that reliably reflect in vivo levels can be obtained.

Hypocalcemia and Hyperphosphatemia