AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Background

Tumor lysis syndrome (TLS) is a very serious and sometimes life-threatening complication of cancer therapy. It can be defined as a constellation of metabolic abnormalities resulting from spontaneous or treatment-related tumor necrosis or fulminant apoptosis. The metabolic abnormalities observed in patients with tumor lysis syndrome include hyperkalemia, hyperuricemia, and hyperphosphatemia with secondary hypocalcemia. These can lead to acute renal failure (ARF). The main principles of TLS are the identification of high-risk patients, initiation of preventive therapy, and early recognition and intervention of its complications.

Pathophysiology

Tumor lysis syndrome (TLS) can be precipitated before the initiation of therapy and usually lasts up to 3 days after the start of chemotherapy, especially with tumors that have a high growth fraction and high sensitivity to chemotherapy. Burkitt lymphoma and T cell acute lymphoblastic leukemia are most frequently associated with this complication.

TLS has also been observed in association with solid tumors, such as hepatoblastoma and stage IV neuroblastoma. In 1980, Cohen et al identified risk factors that predispose patients to metabolic derangements, such as bulky abdominal disease, elevated pretreatment uric acid level, elevated lactate dehydrogenase level, and poor urine output. Lysis of tumor cells results in rapid release of potassium, purine nucleic acids, and phosphorus, which leads to hyperkalemia, hyperuricemia, and hyperphosphatemia with secondary hypocalcemia. These metabolic abnormalities can subsequently lead to acute renal failure (ARF). These complications may result in multiple organ failureand death.

The kidney is the primary organ involved in the clearance of uric acid, phosphorus, and potassium. Uric acid (pKa = 5.4) is soluble at physiologic pH, but can precipitate in the acidic environment of renal tubules. Hemoconcentration and decreased tubular flow rate within the renal system also contributes to the precipitation of uric acid. Precipitation of uric acid crystals within the collecting ducts and ureters can cause an obstructive uropathy.

The phosphorus content of the lymphoblasts is 3-4 times the content of normal lymphocytes. When these cells lyse as a result of therapy or spontaneous apoptosis, the serum phosphorous rises. The elevated phosphorous can spurn nephrocalcinosis from calcium phosphate crystal precipitation. This occurs in the renal tubules and microvasculature as the in vivo calcium-phosphorus solubility product exceeds 60-70 because of hyperphosphatemia and may be worsened with iatrogenic alkalinization. Symptomatic hypocalcemia may result from hyperphosphatemia.

Frequency

International

Incidence is unknown. Prevalence varies among different malignancies; bulky, aggressive, and treatment-sensitive tumors are associated with higher frequencies of TLS. In studies of frequency in patients with intermediate-grade or high-grade non-Hodgkin lymphomas, laboratory evidence of TLS (42%) occurred much more frequently than the symptomatic clinical syndrome (6%). In children with acute leukemia receiving induction chemotherapy, silent laboratory evidence of TLS occurred in 70% of cases, but clinically significant TLS occurred in only 3%. As advances are made in cancer treatment and more aggressive regimens become in favor, the incidence of TLS may increase and the syndrome emerge in a broader spectrum of malignancies.

Mortality/Morbidity

• ARF: Renal tubule precipitation of uric acid, calcium phosphate, or hypoxanthine causes ARF. This often is oliguric ( <400 mL/d) in nature, leading to volume overload and complications of hypertension and pulmonary edema. High blood urea nitrogen (BUN) levels due to increased protein catabolism and renal impairment can be severe enough to result in pericarditis, platelet dysfunction, and defective cellular immunity. Renal dysfunction can be severe enough to require dialysis, but with prompt supportive measures it usually is reversible.
• Cardiac arrhythmia: Hyperkalemia can lead to ECG changes and life-threatening cardiac arrhythmia, including asystole. Severe potassium elevation can cause ECG alterations such as peaked T waves, flattened P waves, prolonged PR interval, widened QRS complexes, deep S wave, and sine waves. Hypocalcemia can lead to QT interval lengthening, which predisposes patients to ventricular arrhythmia.
• Metabolic acidosis: ARF and liberation of large amounts of endogenous intracellular acids from cellular catabolism result in acidemia. This acidemia causes a decrease in serum bicarbonate concentration and a high anion gap acidosis. Acidemic states can worsen the many electrolyte imbalances already present in TLS; intracellular uptake of potassium is hindered, uric acid solubility is decreased, and extracellular shift of phosphate is promoted. Calcium phosphate solubility, however, improves in acidic conditions. The myriad of metabolic disorders must be assessed and treated rapidly. Proper fluid management, alkalinization of the urine, correction of acidosis, and attention to infections are the mainstays of therapy.

Race

No race predilection exists.

Sex

No sex predilection exists.

Age

Although TLS occurs in all age groups, advanced age is associated with more frequent underlying impaired renal function, which may in turn, predispose patients to clinically significant TLS secondary to decreased ability to dispose of tumor lysis byproducts.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

History

Pertinent historic information should include the following:

• Time of onset of symptoms of malignancy
• Abdominal pain and distension
• Urinary symptoms, such as dysuria, oliguria, flank pain, and hematuria
• Occurrence of any symptoms of hypocalcemia, such as anorexia, vomiting, cramps, seizures, spasms, altered mental status, and tetany
• Symptoms of hyperkalemia, such as weakness and paralysis

Physical

Symptoms reflect the severity of underlying metabolic abnormalities.

• Hyperkalemia can cause paresthesia, weakness, and fatal cardiac arrhythmias.
• Uremia can manifest as fatigue, weakness, malaise, nausea, vomiting, anorexia, metallic taste, hiccups, neuromuscular irritability, difficulty concentrating, pruritus, restless legs, and ecchymoses. As uremia progresses, paresthesia and evidence of pericarditis may develop, as well as signs of drug toxicity for administered medications eliminated by the kidney. Features of volume overload, such as dyspnea, pulmonary rales, edema, and hypertension, may develop.
• Elevated uric acid levels may present with lethargy, nausea, and vomiting. Rapidly increasing uric acid levels may lead to arthralgia and renal colic
• Patients with hypocalcemia may present with carpopedal spasms, tetany with positive Chvostek and Trousseau signs, seizures, anxiety, bronchospasm, and cardiac arrest in extreme cases. Deposition of calcium phosphate in various tissues may be responsible for pruritus, gangrenous changes of the skin, iritis, and arthritis.

Causes

• TLS occurs most often in patients with acute leukemia with high WBC counts and in those with high-grade lymphomas in response to aggressive treatment. TLS may also occur in other hematologic malignancies and in a variety of solid tumors. It has been reported to occur spontaneously, prior to any form of therapy.
• Those at highest risk have bulky, rapidly proliferating tumors that are sensitive to treatment. An elevated pretreatment lactate dehydrogenase (LDH) level, which correlates with high tumor volume, is a strong indicator for developing clinically significant complications of therapy. Presence of renal insufficiency prior to therapy also is correlated with an increased likelihood of TLS.

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Other Problems to be Considered

Patients with cancer are at increased risk of renal failure from etiologies other than TLS. Prerenal causes include volume depletion from anorexia, vomiting, diarrhea, and bleeding. Pelvic or retroperitoneal masses can lead to kidney failure from postrenal urinary tract obstruction. Renal parenchymal diseases include tumor infiltration, myeloma kidney, drug nephrotoxicity from chemotherapeutic agents or antibiotics, radiocontrast nephropathy, vasculitis, and cryoglobulinemic glomerulonephritis. The combination of volume depletion, hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia strongly support the diagnosis of TLS over other causes.

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Lab Studies

• A sample of blood collected by a wide-bore needle or, preferably, an indwelling cannula should be used to obtain a biochemical profile of the patient for biochemical monitoring, which includes serum sodium, potassium, chloride, and bicarbonate.
• Blood chemistry
• • Most patients have laboratory derangements in LDH, potassium, phosphate, calcium, uric acid, and abnormal renal functions, occurring 1-3 days following the initiation of chemotherapy.
  • Hyperkalemia often is the first life-threatening abnormality.
  • High-risk patients should have laboratory monitoring (BUN, creatinine, phosphate, uric acid, LDH, and calcium) prior to therapy and for 48-72 hours after treatment induction. Follow measurements at least twice daily or more often if evidence of TLS develops.
• Urine pH
• • Urine alkalinization prevents renal precipitation of uric acid, but may increase the risks for nephrocalcinosis.
  • If alkaline diuresis is employed, regular determinations of urine pH should guide the extent of therapy.

Imaging Studies

• Radiography of the chest is useful to determine the presence of a large tumor, eg, mediastinal mass.
• Perform ultrasonography or computed tomography scanning of the abdomen and retroperitoneum immediately if mass lesions in the abdomen or renal failure are present. Intravenous contrast may be contraindicated in a patient with renal insufficiency.

Other Tests

• Because increased urine flow rates help to inhibit crystal deposition in renal tubules, close monitoring of urine output is necessary to assess adequacy of hydration. Monitoring urine output for signs of oliguric renal failure is also necessary.
• Frequent cardiac assessment (ECG or continuous cardiac monitoring) is necessary to monitor electrocardiographic changes, which may herald a lethal arrhythmia caused by potassium and calcium disturbances.

Histologic Findings

Pathologic studies demonstrate deposits of uric acid within the distal renal tubule lumina, causing intrarenal hydronephrosis. Uric acid crystals can also be seen within tubular epithelial cells and the medullary microcirculation. Uric acid precipitates may also occur in the renal pelvis and ureters, leading to hydronephrosis and ARF from extrarenal sources.

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Medical Care

• Overview
  • TLS management requires initiation of preventive measures in high-risk patients prior to cancer treatment as well as prompt initiation of supportive care for patients who develop acute TLS during treatment.
  • Patients with evidence of pretreatment acute TLS should be started immediately on TLS treatment. Although it is preferable that all parameters are corrected prior to the initiation of chemotherapy, treatment of the malignancy may be needed sooner. Identify high-risk patients before treatment by assessing the extent of tumor burden, histopathologic findings, and renal function.
• Surveillance
  • Severe manifestations of TLS can be prevented only through meticulous laboratory monitoring and careful clinical observation. Necessary cardiac studies include baseline ECG with follow-up studies or continuous cardiac monitoring during treatment.
  • Appropriate renal surveillance and fluid status determinations require baseline and daily weights, regular vital sign checks, and frequent measurements of both fluid intake and urine output.
  • High-risk patients and those with evidence of TLS should have at least thrice-daily laboratory monitoring of BUN, creatinine, uric acid, potassium, calcium, phosphate. Monitoring should continue for the first 48-72 hours after chemotherapy initiation.
• Control of hyperuricemia
  • Allopurinol is a competitive inhibitor of xanthine oxidase and is given to reduce the conversion of nucleic acid byproducts to uric acid in order to prevent urate nephropathy and subsequent oliguric renal failure. It is usually given orally as 600 mg/d for prophylaxis and 600-900 mg/d (up to a maximum of 500 mg/m²/d) for treatment of TLS. Patients unable to take oral medications can be given intravenous allopurinol. The inhibition of uric acid synthesis promotes an increase of xanthine in both plasma and the renal system. Xanthine, although reported to be rare, has the capacity to precipitate in the renal tubules. Other adverse effects include mild to severe rash, xanthine stone-induced urolithiasis, acute interstitial nephritis, pneumopathy, fever, and eosinophilia. Dose reduction is necessary in renal insufficiency; dose reduction is also necessary if given concomitantly with mercaptopurine, 6-thioguanine, or azathioprine because allopurinol interferes with the metabolism of theseagents.
  • Rasburicase (recombinant urate oxidase) is a newer therapy that can be used when the uric acid levels cannot be lowered sufficiently by standard approaches. It has been shown to be both safe and effective in pediatrics, as well as adults. Rasburicase has emerged as the preferred choice for treatment of hyperuricemia in TLS. Rasburicase has a more rapid onset of action than allopurinol. Some urate oxidase is absent in primates; urate oxidase catalyses the conversion of poorly soluble uric acid to soluble allantoin. By converting uric acid to water-soluble metabolites, it effectively decreases plasma and urinary uric acid levels. Unlike allopurinol, uricase does not increase excretion of xanthine and other purine metabolites; therefore, it does not increase tubule crystallization of these compounds. It is administered by intramuscular injection or intravenous infusion at dosages ranging from 50-100 U/kg/d. It is contraindicated in G-6-PD deficiency and pregnancy.
• Hydration
  • Volume depletion is a major risk factor for TLS and must be corrected vigorously. Aggressive intravenous hydration not only helps correct electrolyte disturbances by diluting extracellular fluid, but it also increases intravascular volume. Increased volume enhances renal blood flow, glomerular filtration rate, and urine volume to decrease the concentration of solutes in the distal nephron and medullary microcirculation.
  • Ideally, IV hydration in high-risk patients should begin 24-48 hours prior to initiation of cancer therapy and continue for 48-72 hours after completion of chemotherapy.
  • Continuous IV infusion rates as high as 4-5 L/d (or 3 L/m²/d) yielding urine volumes of at least 3 L/d should be given unless the patient's cardiovascular status indicates impending volume overload.
• Urinary alkalinization
  • Use of isotonic sodium bicarbonate solutions intravenously to promote alkaline diuresis has the potential benefits of solubilizing, and thus minimizing, intratubular precipitation of uric acid. The goal is to increase urinary pH to 7.0 to maximize uric acid solubility in renal tubules and vessels.
  • Drawbacks to systemic alkaline therapy include magnification of clinical hypocalcemia by shifting ionized calcium to its nonionized form. Increased likelihood of calcium phosphate precipitation in renal tubules is an additional drawback. For these reasons, routine urine alkalinization is controversial, and if it is employed it must include close monitoring of urinary pH, serum bicarbonate, and uric acid levels to both guide therapy and avoid overzealous alkalinization. Consider titrating sodium bicarbonate intravenous fluid solutions to keep the urine pH between 7.0 and 8.0.
  • If urinary alkalinization is not achieved with exogenous bicarbonate solutions despite increasing serum bicarbonate levels, intravenous acetazolamide at doses of 250-500 mg/d (5 mg/kg/d) may be added to decrease proximal tubule bicarbonate reabsorption, thereby increasing urinary pH.
• Control of electrolyte disturbances
  • Aggressively treat and monitor hyperkalemia. Immediately restrict dietary potassium and remove potassium from intravenous fluids. Acute treatment modalities include intravenous infusion of glucose plus insulin to promote redistribution of potassium from the extracellular to intracellular space, and intravenous calcium gluconate as cardioprotection for potassium levels greater than 6.5 mmol/L or for those with ECG alterations. Intravenous hydration with alkaline fluid as already described also can increase intracellular uptake of potassium. Potassium-wasting diuretics may be employed with caution since these may worsen renal precipitation in the volume-contracted patient. Long-term therapy such as oral potassium-exchange resins should be given immediately because of the transient effectiveness of acute treatment modalities. If these measures fail to control serum potassium, dialysis should be initiated promptly.
  • Hyperphosphatemia is managed with oral phosphate binders and the same solution of glucose plus insulin used for control of hyperkalemia. Hyperphosphatemia may lead to hypocalcemia, which usually resolves as phosphate levels are corrected. In some cases, depressed serum 1,25-dihydroxycholecalciferol levels contribute to hypocalcemia, and administration of calcitriol may correct calcium levels. Such therapy, however, should not be undertaken until serum phosphate levels have normalized to avoid metastatic calcium phosphate calcifications. As a rule, do not correct hypocalcemia unless evidence of neuromuscular irritability exists, as indicated by a positive Chvostek or Trousseau sign.
  • Use of furosemide or mannitol for osmotic diuresis has not proven to be beneficial as front-line therapy. In fact, these modalities may contribute to uric acid or calcium phosphate precipitation in renal tubules in a volume-contracted patient. Instead, diuretics should be reserved for well-hydrated patients with insufficient diuresis, and furosemide alone should be considered for the normovolemic patient with hyperkalemia or for the patient with evidence of fluid overload.
  • If the previously mentioned methods fail, consider early initiation of dialysis. Dialysis will avoid irreversible renal failure and other life-threatening complications. Indications for dialysis include persistent hyperkalemia or hyperphosphatemia despite treatment, volume overload, uremia, symptomatic hypocalcemia, and hyperuricemia.
  • Hemodialysis is preferred over peritoneal dialysis because of better phosphate and uric acid clearance rates. Continuous hemofiltration also has been used and is effective in correcting electrolyte abnormalities and fluid overload.
  • Because hyperkalemia can recur after dialysis is initiated and because of the high phosphate burden in some patients with TLS, electrolyte levels must be monitored frequently and dialysis repeated as needed.

Surgical Care

Patients with tumor lysis syndrome may need surgical intervention for central venous line placement or the placement of a dialysis catheter in cases of extreme hyperkalemia or renal failure.

Consultations

• Hospital setting: Cancer patients with acute manifestations of TLS or those at high risk should be treated by personnel who are experienced with TLS complications and treatment. An oncology unit or ICU with readily available continuous cardiac monitoring and hemodialysis capabilities is preferable.
• • If basic supportive care measures are ineffective in controlling electrolyte disturbances or renal function, nephrology and critical care consultants should be accessible to assist in further management.
  • Laboratory turnover time must be rapid so that metabolic derangements can be addressed before life-threatening problems arise.

MEDICATION

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Management of tumor lysis syndrome, other than hydration and alkalinization, necessitates the use of drugs to correct metabolic disturbances. Use of medications must be instituted before the start of chemotherapy; the goal is to achieve optimal metabolic stability.

An alternative to allopurinol for decreasing uric acid load is rasburicase (urate oxidase), which controls hyperuricemia by converting uric acid to water-soluble allantoin. This drug is used widely in Europe and was recently approved by the Food and Drug Administration (FDA) in the United States.

Drug Category: Xanthine oxidase inhibitors

Allopurinol is used to inhibit xanthine oxidase, thereby reducing uric acid. The IV form (Aloprim) may be used for patients unable to tolerate PO administration.

Caution is necessary because of the high uric acid concentration in the urine. In 1986, Andreoli and associates explained some cases of renal failure on the basis of effects of allopurinol in altering purine excretion. In the presence of allopurinol, the excretion of uric acid, xanthine, and hypoxanthine increases several hundred folds, enough to exceed their solubility limit in the renal tubules even at a urinary pH of 7. Also, at a urinary pH higher than 7.5, crystallization of hypoxanthine may occur, which necessitates withdrawal of bicarbonate from IV fluids.

Drug Category: Uric acid oxidizers

These agents metabolize uric acid to a soluble form, thus preventing acute renal failure.

Drug Category: Minerals

Calcium is used to treat arrhythmias due to hyperkalemia or hypocalcemia. Frank or impending renal failure requires additional therapeutic measures. Hyperkalemia is the most common life-threatening emergency. Chemotherapy may have to be discontinued temporarily. The entire potassium intake should be discontinued immediately. The use of calcium does not lower serum potassium levels. It is primarily used to protect the myocardium from the deleterious effects of hyperkalemia (ie, arrhythmias) by antagonizing the membrane actions of potassium.

Drug Category: Intracellular potassium transporters

Sodium bicarbonate, insulin, and glucose cause a transcellular shift of potassium into muscle cells, thereby lowering (temporarily) serum levels of potassium.

Drug Category: Exchange resins

Sodium polystyrene sulfonate is an exchange resin that can be used to treat mild-to-moderate hyperkalemia. Each mEq of potassium is exchanged for 1 mEq of sodium.

Drug Category: Phosphate-binding agents

These agents are used to treat hyperphosphatemia.

FOLLOW-UP

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Further Inpatient Care

• Please refer to Medical Care.

In/Out Patient Meds

• Please refer to Medical Care.

Deterrence/Prevention

• Patients without laboratory evidence of TLS who remain at high risk should have prophylactic measures begun 24-48 hours prior to initiation of cytotoxic therapy. Prophylactic measures include liberal intravenous fluid administration, allopurinol, and urinary alkalinization. Close monitoring of fluid status and blood chemistry is important and should continue until 48-72 hours after chemotherapy initiation. Please refer to the previous section on Medical Care for more information.

Complications

• Potential complications include uremia and oliguric renal failure due to tubule precipitation of uric acid, calcium phosphate, or hypoxanthine.
• Severe electrolyte disturbances, such as hyperkalemia and hypocalcemia, predispose patients to cardiac arrhythmia and seizures.
• Iatrogenic complications, such as pulmonary edema from overly vigorous hydration or metabolic alkalosis from excess exogenous administration of bicarbonate, also can occur and are life threatening if not immediately addressed.

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

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Article Last Updated: Sep 12, 2006