Tumor lysis syndrome

Tumor Lysis Syndrome (TLS)

Also known as: Uric acid nephropathy, spontaneous TLS, acute renal failure

1. Description of the problem

• Tumor lysis syndrome (TLS) is defined by the metabolic derangements of hyperuricemia, hyperphosphatemia, hyperkalemia, hypocalcemia and acute renal failure that occur in the setting of rapid tumor destruction.
• When cellular lysis occurs (either spontaneously or following the initiation of immuno-chemotherapy), intracellular contents are released into the bloodstream, overwhelming the pathways that normally maintain their homeostasis.
• The clinical consequences of TLS can range from clinically silent laboratory abnormalities to a life-threatening renal-metabolic emergency. This section will focus on practical strategies to:

• Risk-stratify patients for TLS
• Prevent TLS occurrence
• Recognize TLS
• Treat TLS clinical consequences

Laboratory and Clinical Features of TLS

Laboratory Features of TLS (adopted from Cairo-Bishop definition of TLS):

• Hyperuricemia: Uric acid > 8 mg/dL in adults or 25% increase from baseline
• Hyperkalemia: Potassium > 6 mmol/L or 25% increase from baseline
• Hyperphosphatemia: Phosphorus > 4.5 mg/dl in adults or > 6.5 mg/dl in children or 25% increase from baseline
• Hypocalcemia: Serum calcium < 7 mg/dl or or 25% decrease from baseline

Clinical Features of TLS:

• Acute renal failure (secondary to uric acid nephropathy and/or calcium phosphate nephropathy)
• Cardiac arrhythmia (secondary to electrolyte abnormalities and acidosis)
• Neuromuscular irritability (Ca-related) such as tetany, paresthesias, twitching
• Hypotension or cardiovascular collapse
• Seizure
• Sudden death

Management Strategies: Three Key Concepts

1. Risk stratification: The first step in TLS management is to identify patients at increased risk for its development. This is important so that we may allocate resources appropriately as well as to expose only patients at high risk to preventive measures (which can have their own adverse side effects and clinical consequences). Not all patients with malignancy have the same risk of developing TLS. Risk in part depends on tumor type, bulk of disease, treatment regimen, underlying medical comorbidities and the strategies employed (usually by the treating oncologist) to prevent its occurrence.

TLS risk factors to consider when evaluating a patient:

• Any hematologic malignancy (Burkitt lymphoma, high-grade NHL, acute lymphoblastic leukemia, acute myelogenous leukemia at the highest risk). Case report literature describes TLS in solid tumor malignancies but overall quite rare.
• Intensity of cytoxic chemotherapy or malignant cell sensitivity to treatment
• Preexisting renal disease
• Preexisting cardiac arrhythmias
• Evidence of TLS (spontaneous TLS) prior to the initiation of cytotoxic therapies
• Elevated LDH (surrogate for high cell turnover)
• Inadequate TLS prophylaxis (inadequate IVFs, dehydration prior to treatment initiation, failure to administer uric acid-lowering agents such as allopurinol/urate oxidase)
• Bulky or extensive disease
• Renal infiltration/post renal obstruction by malignancy
• Extramedullary sites of disease

2. TLS monitoring & prophylaxis: The best way to manage this condition is to identify it early on (before a patient develops TLS clinical manifestations) and prevent its clinical consequences by employing an effective preventive regimen (considerations include intravenous crystalloid administration, allopurinol administration, recombinant urate oxidase administration and rarely implementation of hemodialysis prior to or concurrently with the initiation of chemotherapy).

3. TLS Management: Once TLS occurs it is considered to be an
oncologic emergency because it can lead to life-threatening metabolic abnormalities, acute renal failure and death.

Effective treatment of TLS requires a multidisciplinary approach:

• Monitoring strategies: Increased frequency of “TLS panels” (Cr, BUN, K, PO4, Ca, uric acid, LDH levels), telemetry monitoring, possibly a change in level of care from an outpatient facility to a specialized oncology unit, with strong consideration for placement in a intermediate care unit or intensive care unit depending on the clinical severity of TLS
• Clinical consultations: Specialty consultations to consider include nephrology, cardiology, vascular surgery (for HD line placement) and critical care medicine. Not all patients will require specialty service consultation in the management of individual episodes of TLS, but it is critical to consider the advice you will need in the management early on.
• Acute renal failure mangement: Monitoring of renal function / urine output / electrolytes. Increased administration of intravenous crystalloid to maintain renal perfusion. Consideration of renal consultation for hemodialysis.
• Electrolyte management: Recognize and address treatment indications of hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcemia.
• Arrhythmia management (usually secondary to metabolic abnormalities associated with TLS). Primary management includes appropriate monitoring (performing an ECG, telemetry, CCU/ICU placement, cardiology consultation) as well as appropriate management/correction of acid-base status, renal function and electrolyte abnormalities. Arrhythmias to consider include both narrow and wide complex variants.
  Management guidelines of specific secondary cardiac arrhythmias are beyond on the context of this section.

2. Emergency Management

Practical applications

1. TLS monitoring and preventive reccomendations

• Serum chemistry (“TLS panel” including K, PO4, Ca, uric acid, LDH, Cr) should be performed prior to the initiation of cytotoxic therapy.
• 4-6 hours after the start of therapy re-check TLS panel and address abnormalities.
• TLS panels should be performed 1-3 times per 24-hour period during the course of intensive therapy. If they remain without abnormality for several assessments the frequency may be decreased.
• Fluid intake (PO + IV) and urine output should be monitored closely (“strict I & Os”).
• Consider preemptive renal consultation and telemetry monitoring for patients at highest risk of TLS (ie, Burkitt lymphoma) or patients with evidence of spontaneous TLS prior to initiation of treatment. This is also reasonable to consider for patients with an underlying history of renal or cardiac disease.
• IVFs are the mainstay of TLS prevention. IVFs should be titrated to maintain adequate urine output and are typically given (for adults) 2-3 L per 24-hour period. NS is typically used (without additives such as potassium and bicarbonate). Urine alkalinization is controversial and not recommended specifically for TLS prevention (alkalinization may exacerbate precipitation of CaPO4 crystals in the renal tubules and other organs, especially in the settting of hyperphosphatemia). Alkalinization should NOTbe withheld, however, if this is required as part of the treatment regimen (ie, clearance of chemotherapy such as methotrexate).
• Patients at moderate to high risk for TLS should be placed on an agent to prevent hyperuricemia. Oncologists usually select one of two possible choices to achieve this goal:

(1) Allopurinol (xanthine oxidase inhibitor, available PO or IV formulation) should be started for patients at risk for TLS. A standard starting dose for allopurinol (in adults) is 300 mg PO daily for adults with normal renal function. Keep in mind that the dose needs to be adjusted for renal function (see package insert for guidelines). Additionally keep in mind that this medication prevents the formation of uric acid and DOES NOT treat hyperuricemia already present. It should be started at least 48 hours prior to the initiation of cytoxic therapies when clinically possible to maximize its effect.

(2) Rasburicase (urate oxidase inhibitor) should be considered as a component of the TLS preventive (and treatment) regimen for patients at highest risk for TLS (high-grade lymphomas, acute leukemias), patients with high-risk medical comorbidities (such as renal insufficiency at baseline) and patients with marked hyperuricemia prior to the initiation of cytotoxic therapies. The recommended dosing schedule is 0.2 mg/kg IV daily for up to 5 days. Several alternative dosing strategies exist. In our practice we typically administer a flat dose of 6 mg IV daily and re-dose based on serum uric acid levels. KEEP IN MIND THIS DRUG IS CONTRAINDICATED IN PATIENTS WITH G6PD DEFICIENCY. ONCE A PATIENT IS ON THIS MEDICATION MAKE SURE THAT URIC ACID LEVELS ARE COLLECTED ON ICE TO MINIMIZE THE RISK OF FALSELY DEPRESSED URIC ACID LEVELS (The enzyme remains active in the test tube).

2. Practical management of TLS for critically ill patients

Hyperuricemia:

• Increase the IVF rate of crystalloid (and therefore renal perfusion) if clinically possible (keep in mind patient’s ejection fraction and ability to handle excess volume). Consider addition of loop diuretic to increase urine flow (removal of precipitated crystals).
• Addition of rasburicase to TLS regimen if not already given with serial (q4-6 hr) uric acid assessments. KEEP IN MIND THIS DRUG IS CONTRAINDICATED IN PATIENTS WITH G6PD DEFICIENCY. ONCE A PATIENT IS ON THIS MEDICATION MAKE SURE THAT URIC ACID LEVELS ARE COLLECTED ON ICE TO MINIMIZE THE RISK OF FALSELY LOW URIC ACID LEVELS.
• Consider initiation of hemodialysis for refractory hyperuricemia.

Acute renal failure:

• Nephrology consultation
• Change patient’s diet to one with renal restrictions.
• Consider moving the patient to higher-acuity medical floor such as step-down unit or intensive care unit.
• Strict measurement of urine output. Need to know if the patient is becoming oliguric.
• Increase IVF rate (and therefore renal perfusion) if clinically possible.
• Consider implementation of hemodialysis.
• Generally patients can recover renal function if this measure is implemented early in the process of acute renal failure secondary to TLS.

Hyperphosphatemia:

• Restrict phosphate intake.
• Initiate treatment with a phosphate binder.
• Sevelamer, a non-calcium-containing PO4 binder, is a reasonable first choice. In adults it is given 800-1600 mg with each meal.
• Consult nephrology in deciding whether a calcium-containing agent is appropriate.
• Consider implementation of hemodialysis for refractory hyperphosphatemia.

Hypocalcemia: Typically this DOES NOT need to be treated unless the patient has clinical signs/symptoms associated with hypocalcemia. The rationale for not treating this condition in asymptomatic patients is that calcium administration may exacerbate calcium-phosphate crystal deposition in the renal tubules and therefore acute renal failure.

• Perform ECG and place symptomatic patients on telemetry monitoring.
• Serial Ca monitoring. May be more prudent to follow ionized Ca levels in this circumstance.
• Correct PO4 abnoralities first when possible.
• For symptomatic patients, treatment options include use of Ca gluconate or Ca chloride infusion.
• In the setting of ANY cardiac arrhythmia attributed to hypocalcemia, consider cardiac consultation and ACLS guidelines for arrhythmia management.

Hyperkalemia:

• Perform ECG and implement telemetry monitoring.
• Consider renal consultation in setting of severe hyperkalemia, hyperkalemia with any cardiac complications or concomitant acute renal failure.
• Make sure that the patient is NOT receiving excess potassium in the diet, IVFs or as a supplement.
• Serial potassium level assessments every 4-6 hours during acute events
• Consider administration of dextrose +/- insulin, albuterol and/or sodium bicarbonate as temporizing measures.
• Administer sodium polysterene (15-30 grams) orally every 4-6 hours.
• In the setting of ANY cardiac arrhythmia attributed to hyperkalemia, consider cardiac consultation and ACLS guidelines for arrhythmia management.
• Consider implementation of hemodialysis.

3. Diagnosis

Diagnostic criteria

Currently, the most commonly used system employed to define and classify tumor lysis syndrome is the one developed by Cairo and Bishop.

The Cairo-Bishop definition recognizes both the laboratory component of TLS and its clinical consequences.

Laboratory Features of TLS (adopted from Cairo-Bishop definition of TLS):

• Hyperuricemia: Uric acid > 8 mg/dL in adults or 25% increase from baseline
• Hyperkalemia: Potassium > 6 mmol/L or 25% increase from baseline
• Hyperphosphatemia: Phosphorus > 4.5 mg/dl in adults or > 6.5 mg/dl in children or 25% increase from baseline
• Hypocalcemia: Serum calcium < 7 mg/dl or or 25% decrease from baseline

Clinical Features of TLS:

• Acute renal failure: Cr > 1.5 ULN
• Cardiac arrhythmia / sudden death
• Seizure

Keep in mind that NO definition of TLS is perfect and in practice a patient may suffer morbidity / mortality from TLS at ANY level of electrolyte abnormality or renal dysfunction depending on the clinical circumstances. For example, if the patient’s K level has increased from 3.0 mmol/L to 4.9 mmol/L in a short period of time this is not TLS by strict definition, but this is a patient who is at high risk for TLS and its consequences. The lesson here is that a definition can be helpful (especially in the research setting) but it is not a substitute for clinical judgment.

Normal lab values

Laboratory value normal ranges at Hackensack University Medical Center (keep in mind these may vary between different hospital laboratories):

Potassium (K): 3.5-5.2 meq/L

Calcium (Ca): 8.4-10.2 mg/dl

Phosphate (PO4): 2.7-4.3 mg/dl

Uric Acid (UA): 2.5-7.6 mg/dl

Creatinine (Cr): 0.3-1.5 mg/dl

Differential diagnosis

Differential for acute renal failure in oncology patients for whom you are considering the diagnosis of TLS:

• Pre-renal disease (dehydration is common at presentation)
• ATN secondary to renal hypoperfusion
• ATN secondary to toxic injury from medication (consider chemotherapy, NSAIDs, antibiotics, iodinated IV contrast)
• Allergic reaction (AIN)
• Renal tumor infiltration
• Post renal obstruction (tumor)
• Paraneoplastic glomerulonephropathies
• Plasma cell dyscrasias (renal amyloid, light chain deposition, light chain cast nephropathy)
• Sepsis with organ dysfunction (severe sepsis, septic shock)

Confirmatory tests

There are no specific confirmatory tests. The diagnosis of TLS is based on laboratory and clinical features as described.

4. Specific Treatment

Treatment recommendations

Hyperuricemia:

• Increase IVF rate of crystalloid (and therfore renal perfusion) if clinically possible (keep in mind patient’s ejection fraction and ability to handle excess volume). Consider addition of loop diuretic to increase urine flow (removal of precipitated crystals).
• Addition of rasburicase to TLS regimen if not already given with serial (q4-6 hr) uric acid assessments. KEEP IN MIND THIS DRUG IS CONTRAINDICATED IN PATIENTS WITH G6PD DEFICIENCY. ONCE A PATIENT IS ON THIS MEDICATION MAKE SURE THAT URIC ACID LEVELS ARE COLLECTED ON ICE TO MINIMIZE THE RISK OF FALSELY LOW URIC ACID LEVELS.
• Consider initiation of hemodialysis for hyperuricemia in refractory setting.

Acute renal failure:

• Nephrology consultation
• Consider changing patient’s diet to one with renal restrictions.
• Consider moving the patient to higher-acuity medical floor such as step-down unit or intensive care unit.
• Strict measurement of urine output. Need to know if the patient is becoming oliguric.
• Increase IVF rate (and therefore renal perfusion) if clinically possible.
• Consider implementation of hemodialysis. Generally patients can recover renal function if this measure is implemented early in the process of acute renal failure secondary to TLS.

Hyperphosphatemia:

• Restrict phosphate intake.
• Initiate treatment with a phosphate binder.
• Sevelamer, a non-calcium-containing PO4 binder, is a reasonable first choice. In adults is is given 800-1600 mg with each meal.
• Consult nephrology in deciding whether a calcium-containing agent is appropriate.
• Consider implementation of hemodialysis for refractory hyperphosphatemia.

Hypocalcemia: Typically this DOES NOT need to be treated unless the patient has clinical signs / symptoms associated with hypocalcemia. The rationale for not treating this condition in asymptomatic patients is that calcium administration may exacerbate calcium-phosphate crystal deposition in the renal tubules and therefore acute renal failure.

• Perform ECG and place symptomatic patients on telemetry monitoring.
• Serial Ca monitoring. May be more prudent to follow ionized Ca levels in this circumstance.
• Correct PO4 abnormalities first when possible.
• For symptomatic patients, treatment options include use of Ca gluconate or Ca chloride infusion.
• In the setting of ANY cardiac arrhythmia attributed to hypocalcemia, consider cardiac consultation and ACLS guidelines for arrhythmia management.

Hyperkalemia:

• Perform ECG and implement telemetry monitoring.
• Consider renal consultation in setting of severe hyperkalemia, hyperkalemia with any cardiac complications or concomitant acute renal failure.
• Make sure that the patient is NOT receiving excess potassium in the diet, IVFs or as a supplement.
• Serial potassium level assessments every 4-6 hours during acute events
• Consider administration of dextrose +/- insulin, albuterol and/or sodium bicarbonate as temporizing measures.
• Administer sodium polysterene (15-30 grams) orally every 4-6 hours.
• In the setting of ANY cardiac arrhythmia attributed to hyperkalemia, consider cardiac consultation and ACLS guidelines for arrhythmia management.
• Consider implementation of hemodialysis.

Refractory cases

Most cases of TLS do not result in life-threatening renal or metabolic emergencies. However, in the event that a TLS case is refractory to the standard interventions described, always consider (1) transfer to ICU and early involvement of an interventionalist; (2) renal consultation and preparation for hemodialysis; (3) holding future chemotherapy doses (discuss with a hematologist / medical oncologist); (4) transfer to a tertiary care center.

5. Disease monitoring, follow-up and disposition

NA

Pathophysiology

When cellular lysis occurs (either spontaneously or following the initiation of immuno-chemotherapy), intracellular contents are released into the bloodstream, overwhelming the pathways that normally maintain their homeostasis. TLS is defined by the metabolic derangements of hyperuricemia, hyperphosphatemia, hyperkalemia, hypocalcemia and acute renal failure that occur in the setting of rapid tumor destruction.

Acute renal failure:

• Hyperuricemia results from purine catabolism. The enzyme xanthine oxidase catabolizes the oxidation of hypoxanthine to xanthine / uric acid. Unfortunately uric acid is poorly soluble in aqueous solutions (particularly acidic solutions) and can accumulate in the tubules and collecting ducts of the kidney. The deposition of uric acid crystals in the renal tubules / collecting system is one process that can lead to acute renal failure in TLS.
• Calcium phosphate crystal deposition in the renal tubles can also lead to acute renal failure. Hyperphosphatemia can result from rapid cellular lysis. Of note, CaPO4 crystals precipitate more readily in basic solutions. This is the main reason why urine alkalinization in TLS remains controversial and is currently not the standard of care.

What’s the evidence?

DeConti, RC, Calabresi, P. “Use of allopurinol for prevention and control of hyperuricemia in patients with neoplastic disease”. N Engl J Med.. vol. 274. 1966. pp. 481

Conger, JD, Falk, SA. “Intrarenal dynamics in the pathogenesis and prevention of acute urate nephropathy”. J Clin Invest.. vol. 59. 1977. pp. 786

Cairo, MS, Bishop, M. “Tumour lysis syndrome: new therapeutic strategies and classification”. Br J Haematol.. vol. 127. 2004. pp. 3

Cairo, MS, Coiffier, B, Reiter, A, Younes, A. “Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus”. Br J Haematol.. vol. 149. 2010. pp. 578

Howard, SC, Jones, DP, Pui, CH. “The tumor lysis syndrome”. N Engl J Med. vol. 364. 2011. pp. 1844-1854.

Coiffier, B, Mounier, N, Bologna, S, Fermé, C, Tilly, H, Sonet, A, Christian, B, Casasnovas, O, Jourdan, E, Belhadj, K, Herbrecht, R. “Efficacy and safety of rasburicase (recombinant urate oxidase) for the prevention and treatment of hyperuricemia during induction chemotherapy of aggressive non-Hodgkin’s lymphoma: results of the GRAAL1 (Groupe d’Etude des Lymphomes de l’Adulte Trial on Rasburicase Activity in Adult Lymphoma) study”. J Clin Oncol.. vol. 21. 2003. pp. 4402

Jeha, S, Kantarjian, H, Irwin, D, Shen, V, Shenoy, S, Blaney, S, Camitta, B, Pui, CH. “Efficacy and safety of rasburicase, a recombinant urate oxidase (Elitek), in the management of malignancy-associated hyperuricemia in pediatric and adult patients: final results of a multicenter compassionate use trial”. Leukemia.. vol. 19. 2005. pp. 34

Goldman, SC, Holcenberg, JS, Finklestein, JZ, Hutchinson, R, Kreissman, S, Johnson, FL, Tou, C, Harvey, E, Morris, E, Cairo, MS. “A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis”. Blood.. vol. 97. 2001. pp. 2998

Hummel, M, Reiter, S, Adam, K, Hehlmann, R, Buchheidt, D. “Effective treatment and prophylaxis of hyperuricemia and impaired renal function in tumor lysis syndrome with low doses of rasburicase”. Eur J Haematol.. vol. 80. 2008. pp. 331

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