Chapter 13. Tumor Lysis Syndrome

• 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

Disturbances in calcium and phosphorus are common in TLS, and following cytoreductive therapy typically occur within 24–48 hours. The massive phosphorus load to the extracellular compartment as tumor cells lyse can overwhelm the maximal renal phosphaturic threshold thus leading to levels above 4.5 mg/dL, sometimes of great severity (ie, >15 mg/dL). Hypocalcemia, ie, a total calcium level <8.5 mg/dL corrected for albumin or an ionized calcium level <1.08 mmol/L, develops in the setting of hyperphosphatemia as calcium complexes with rising phosphorus levels. These calcium–phosphorus complexes are insoluble at physiologic conditions and precipitate in various tissues and can result in end-organ damage seen in TLS (ie, acute nephrocalcinosis). To a lesser degree, sustained hypocalcemia may also be a result of less 1,25-dihydroxyvitamin D3 (ie, calcitriol) synthesis.

Patients with TLS and disturbances of calcium and phosphorus typically manifest with neuromuscular signs or symptoms related to the hypocalcemia. In particular, patients can present with paresthesias, muscle cramps, tetany (eg, Chvostek's sign or carpopedal spasm), or seizures. Cardiac manifestations may also accompany significant hypocalcemia, most notably prolongation of the QT interval on ECG and depression of cardiac contractility leading to hypotension.

Hyperuricemia

Uric acid is produced in hepatocytes as a byproduct of purine nucleotide catabolism [guanylic acid (GMP), inosinic acid (IMP), and adenylic acid (AMP)] (Figure 13–1). The rate-limiting and final reaction involves the conversion of xanthine to uric acid, driven by the enzyme xanthine oxidase. Further metabolism of uric acid in humans does not occur as the enzyme responsible for its conversion to allantoin, urate oxidase, was lost due to a nonsense mutation during human evolution. The major route of clearance of excessively produced uric acid is through the kidney. In the case of TLS a sudden load of purine nucleotides released from lysed tumor cells results in an acute rise in uric acid production that overwhelms the normal excretory capacity leading to a rise in serum uric acid levels above 7–8 mg/dL, with severe hyperuricemia >15 mg/dL being common. As will be discussed in the following section, the presenting clinical symptoms and signs of hyperuricemia associated with TLS are those associated with oliguria and ARF, which it can induce.

Azotemia and Acute Renal Failure

As stated earlier, a common and potentially serious complication of TLS is acute renal failure. Usually presenting as oliguria associated with a progressive rise in serum creatinine and urea nitrogen, the etiology of ARF is multifactorial. A major mechanism is acute uric acid nephropathy. With a pKa of 5.5, urate is soluble as the ionized form in the blood at a physiologic pH of 7. However, in the distal nephron where the glomerular effluent is acidified to a pH <5.5, under appropriate conditions urate can become protonated and precipitate, especially in the setting of low urine flow rates. When the uric acid load is high enough, such precipitation can lead to intratubular crystal formation and obstruction of urine flow. As a result of this obstruction, the glomerular filtration rate (GFR) drops and clinical ARF ensues. Although rare, the intratubular obstruction can be severe enough to cause collecting system dilation as evidenced by bilateral hydronephrosis on renal ultrasound. Another likely mechanism leading to ARF with TLS is acute nephrocalcinosis. As stated earlier, the precipitous rise in serum phosphorus levels results in the acute formation of calcium–phosphorus complexes, which deposit in tissues. In the kidney this deposition results in tubular toxicity and interstitial inflammation, which further exacerbate the reduction in GFR.

Patients with ARF associated with TLS can present along a spectrum of severity, from asymptomatic azotemia to severe anuria with uremia and volume overload. Particular attention should be paid to volume status (ie, depletion or overload) and electrolyte anomalies (especially potassium and calcium) as disturbances of these can be immediately life threatening and dictate the initial plan of therapy.

Other Studies

Although most often identified in the appropriate clinical setting with compatible laboratory findings, other studies may assist the clinician in the diagnosis of TLS and guide appropriate therapy.

Electrocardiogram

As alluded to earlier, a serious yet treatable complication of TLS is hyperkalemia with associated cardiac conduction defects and arrhythmias. All patients with TLS and laboratory evidence of hyperkalemia should have an ECG performed. Attention should particularly be focused on changes typically indicative of elevated serum potassium levels on cardiac myocyte conduction: T wave peaking, prolongation of the PR and QRS complex, flattened or absent P waves, and atrioventricular blocks or ventricular arrhythmias. The presence of any of these dictates the immediate need for intervention to stabilize the myocardium and lower the serum potassium level.

Urinalysis

As part of an initial evaluation of patients with ARF due to TLS the urinalysis (UA) is indispensable in guiding the clinician to the correct diagnosis. Although their presence does not firmly rule in or their absence rule out TLS, uric acid crystals may be seen on microscopic examination of the urine sediment. These appear as rhomboid or rosette-shaped crystals of yellow or brown color under light microscopy. Other aspects of the UA can aid the clinician during the evaluation of ARF, and, although not specific for TLS, provide useful information. These include an elevated specific gravity indicative of a concentrated urine from concomitant volume depletion, microscopic hematuria, and minimal if any proteinuria in the absence of other renal disease.

Renal Ultrasound

As described above, a major pathophysiologic mechanism of ARF associated with TLS is obstruction of tubular fluid flow by uric acid crystal formation. Although rare, bilateral hydronephrosis has been reported due to presumed extensive tubular obstruction. However, a renal ultrasound can also provide valuable information to help differentiate ARF from TLS from other causes in patients with known malignancies, most notably obstructive uropathy from extrinsic compression of ureters by solid tumors.

Urine Uric Acid/Creatinine Ratio

Although quite sensitive, elevated serum uric acid levels in the setting of ARF are not specific for TLS. Although rarely extremely high, mild to moderate elevations in serum uric acid levels can be seen in ARF from various causes due to impaired renal clearance of normally produced quantities of uric acid as GFR falls. In these cases the uric acid found in the urine results mostly from tubular secretion. Thus the sum total of uric acid excreted is less than normal. This is in contrast to uric acid nephropathy associated with TLS where uric acid production and excretion are greatly increased. Despite the presence of impaired GFR, as long as anuria is not present the net amount of uric acid excreted is higher than the basal state. As such, by measuring the concentration of uric acid in the urine and dividing this value by the urine creatinine concentration to control for the degree of urinary concentration, it is possible to help differentiate ARF due to TLS from other causes. While one study reported that a urinary uric acid/creatinine ratio of >1 was specific for cases of ARF associated with TLS, and a ratio <0.6–0.75 was found in cases of ARF due to other causes, the utility of the urine uric acid/creatinine ratio has not been confirmed in other studies.

The evaluation of electrolyte disturbances and/or ARF can be complex in patients with newly diagnosed malignancies, especially in the setting of recent chemotherapy or radiation treatments. As such it is imperative for the clinician to be mindful of confounding conditions that may mimic TLS, as definitive therapies may be different. Statistically the most common reasons for ARF in hospitalized patients are prerenal azotemia from volume depletion and acute tubular necrosis (ATN). Patients with malignancies are prone to dehydration due to poor oral intake, high gastrointestinal losses of fluid from vomiting or diarrhea, and febrile illnesses with increased rates of insensible fluid loss. However, volume depletion often accompanies TLS. Therefore clinical evidence of prerenal azotemia does not rule out TLS. Regardless, as will be discussed further, intravenous hydration is appropriate and indicated in either scenario.

Hospitalized patients with malignancies are often afflicted by infectious processes requiring evaluations and/or therapies that may be potentially nephrotoxic such as contrast dye, aminoglycoside antibiotics, and amphotericin B. Additionally, significant hypotension may accompany these infections. As a result, ATN from toxins or ischemia is frequently responsible for ARF in this patient population. Although not universally sensitive, dense granular casts on microscopic examination of the urine sediment in cases of ATN can help distinguish it from TLS. Although less common, obstructive uropathy related to direct compression of the ureters and/or urethra by tumors themselves must be part of the differential diagnosis and radiologic evaluation for hydronephrosis is appropriate. Finally, other rare etiologies of ARF in patients with malignancies include acute interstitial nephritis, glomerulonephritis, and microangiopathic hemolytic anemias. However, as these usually present with urine findings not typically seen in TLS (ie, pyuria or significant proteinuria), their differentiation from TLS is not difficult.

Any of these etiologies of ARF can result in electrolyte disturbances as a result of a drop in GFR, including hyperkalemia, hyperphosphatemia/hypocalcemia, and hyperuricemia. However, it is the constellation of all these anomalies together, particularly with very high phosphorus and uric acid levels, in the appropriate clinical setting that clues the clinician toward the correct diagnosis of TLS.

In cases where preventive therapies are not possible and/or when clinically significant TLS develops despite their institution, further treatments may be indicated.

Eliminate Potential Nephrotoxins or Confounders

In situations in which TLS may occur it is prudent to avoid or eliminate any agents that may exacerbate the condition. Most notably the clinician should discontinue any medications that may promote hyperkalemia such as oral or parenteral supplements, β-blockers, and inhibitors of the renin–angiotensin–aldosterone axis [ie, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, potassium-sparing diuretics, and heparin]. Similarly, exogenous phosphate should be avoided, eg, oral supplements and fleets phosphosoda enemas. Given the potential for kidney damage with TLS it is prudent to avoid when possible other potential nephrotoxins including nonsteroidal anti-inflammatory agents, radiocontrast dye, amphotericin-B, and aminoglycoside antibiotics. Finally, prior to chemotherapy patients at risk for TLS should have all uricosuric agents stopped that otherwise impair tubular reabsorption of uric acid and potentially could promote crystallization even further. Such agents include probenecid, aspirin, and thiazide diuretics.

Hydration

As volume depletion can exacerbate the clinical effects of TLS in many different ways, intravenous hydration (eg, 3 L/m2/day) should be initiated 48 hours prior to administration of chemotherapy or as soon as possible if TLS is already present. The goals of this volume expansion are to decrease uric acid, phosphorus, and potassium concentrations in the extracellular compartment. This volume expansion also results in an increased renal blood flow and GFR, thereby inducing a brisk diuresis (>100–150 mL/m2/hour), which can inhibit intratubular uric acid crystallization and obstruction. Forced diuresis with loop diuretics may be necessary if urine flow rates are not high enough with hydration alone, as long as volume depletion is corrected first. Patients should be monitored for signs of volume overload, especially those with established ARF or known preexisting cardiomyopathy. Controversy exists over the type of crystalloid that should be used. As urate is more soluble in the ionized form at physiologic pH, an alkaline diuresis using intravenous sodium bicarbonate (eg, 50–100 mEq of sodium bicarbonate diluted in 1 L of D5 0.45% saline) to maintain a urine pH >7.0–7.5 should help prevent ARF beyond its ability to expand the extracellular volume. However, ARF in TLS is also caused by acute nephrocalcinosis, where calcium-phosphate precipitation is facilitated at a higher pH. Thus bicarbonate administration should be used judiciously and may not offer significant advantages over volume expansion with isotonic saline alone.

Hyperkalemia

Hyperkalemia as part of TLS can be a medical emergency requiring immediate therapy. When cardiac effects of hyperkalemia are present based on ECG findings, membrane stabilization can be temporarily achieved with administration of intravenous calcium (ie, 10% calcium gluconate). Repeat doses may be required if potassium levels cannot be reduced within 15–30 minutes. Simultaneous expansion of the extracellular volume should be initiated to decrease the potassium concentration by dilution. Attempts to shift intracellular potassium are indicated as well by using intravenous insulin with or without glucose, intravenous or inhaled β-agonists, and intravenous bicarbonate. With regard to the latter, caution should be used given the potential for volume overload, exacerbation of hypocalcemia, and facilitation of calcium-phosphate precipitation as mentioned above. Finally, total body potassium can be effected through saline and diuretic-induced kaliuresis, gastrointestinal exchange resins (ie, sodium polystyrene sulfate), and dialysis if needed.

Hyperphosphatemia and Hypocalcemia

Attempts to correct hypocalcemia are contraindicated unless the patient is experiencing neuromuscular symptoms thought to be due to low calcium concentrations. Intravenous calcium administration may potentially facilitate precipitation of calcium and phosphate as long as phosphate levels remain high. The main goal is to correct the underlying hyperphosphatemia as this usually results in concomitant normalization of calcium levels. Beyond expansion of the extracellular volume space, which helps to increase renal phosphate excretion, short courses of non-calcium-containing oral phosphate binders may be initiated such as aluminum hydroxide or carbonate. Dialysis may be necessary for calcium and phosphate correction if these more conservative therapies are not effective and/or if significant ARF is present.

Hyperuricemia

A major focus in the management of TLS is decreasing the elevated serum and urine uric acid concentrations. This may be achieved in different ways. First, volume contraction exacerbates the condition by concentrating the uric acid in the urine, which promotes crystallization. Therefore, volume expansion itself is an effective means of attenuating hyperuricemia. Urine alkalinization to a pH >7 promotes urate to exist almost completely in its ionized form, further decreasing urine crystallization. Although necessary, volume expansion and urine alkalinization are usually not sufficient.

The amount of purine nucleotide precursors released by the lysed tumor cells is not controllable, but it is possible to decrease the conversion of these compounds to uric acid. This is achieved by targeting xanthine oxidase. Allopurinol, along with its active metabolite oxypurinol, acts as a competitive inhibitor of xanthine oxidase. Studies have shown that in cancer patients administered allopurinol at a dose of up to 800 mg daily (usually 200–400 mg/m2/day, intravenous or oral divided two or three times a day), approximately 70% will normalize and 90% will decrease their uric acid levels by at least 1 mg/dL. Intravenous administration is the preferred route, especially if the patient has limited ability to tolerate oral medications, and should be started 24–48 hours prior to chemotherapy if possible along with intravenous hydration. As allopurinol does not affect the amount of uric acid already produced, any decrease in uric acid levels is usually slow due to dependence on renal clearance. An initial effect can be seen within 72 hours of initiation of allopurinol with maximal effect by 7–10 days. As the drug allopurinol and its metabolite oxypurinol are renally cleared, its dose needs to be lowered by over 50% in cases of renal failure.

Finally, newer agents have become available that convert uric acid into the more soluble allantoin, which is easily excreted. Urate oxidase, the enzyme absent in most higher primates including humans, has been utilized since 1975 in Europe in the prophylactic treatment of cancer patients at risk for TLS. Recently a recombinant form of urate oxidase, rasburicase (Elitek, Sanofi-Synthelabo, Inc.), has been approved in the United States. Suggested dosing is 0.05–0.20 mg/kg intravenously each day at the onset of chemotherapy for up to 5 days. In general, given that this enzyme degrades already formed uric acid and is not dependent on renal clearance, uric acid levels decrease quickly within 4 hours of dose administration and to lower levels (ie, <1 mg/dL) compared to allopurinol. No data exist as to whether rasburicase is more effective at preventing ARF associated with TLS. Common side effects of rasburicase include rash and hemolytic anemia due to the generation of hydrogen peroxide during its metabolism. Due to the latter, it is contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency. Potential advantages of rasburicase over allopurinol include a more rapid decline in uric acid levels, which would limit exposure of kidney tissue to high plasma and urine uric acid levels. However, a major drawback to rasburicase is its cost, which is significantly more than allopurinol.

Acute Renal Failure: Role of Renal Replacement Therapy

Renal replacement therapy is indicated in cases of TLS when conservative measures fail to correct the associated metabolic disturbances, when volume overload limits the aggressiveness of conservative measures and/or adversely affects the patient (eg, pulmonary edema), or when patients become symptomatic from uremia. Dialytic therapies not only are capable of restoring metabolic equilibrium, but also offer the advantage of clearing compounds (ie, uric acid and phosphorus) that may otherwise continue to inflict damage on the kidneys. In general, clearance of uric acid and phosphate is greater with hemodialysis compared to peritoneal dialysis, which makes the former the modality of choice when possible.

However, despite high clearance of these solute and volume derangements during each hemodialysis treatment, the limited time exposed to dialysis and the rapid reaccumulation of these compounds and volume excess after the treatment ends may dictate repeated sessions every 12–24 hours. Conversely, although less efficient per unit time, continuous renal replacement therapy over extended periods of hours to days has also proven efficacious in restoring metabolic and volume control in patients with TLS, especially those who are hemodynamically unstable and would not tolerate the intermittent form.

The clinical outcome of patients with TLS varies with the severity of the presentation, the degree to which preventive measures can be instituted, and the extent of the underlying malignant disease. Use of the prophylactic and therapeutic maneuvers described can significantly improve the short-term outcome and prevent fatal complications. In general, ARF associated with TLS is reversible assuming the ability to control the metabolic derangements and limit further renal insults, although renal replacement therapy may be required for a short time.