- Clinically relevant physiology
- Epidemiology & risk factors
- Signs & symptoms
- Questions & discussion
- PDF of this chapter (or create customized PDF)
clinically relevant physiology
- Lysis of tumor cells releases purine nucleotides, which are metabolized as shown above.
- Uric acid and Xanthine are both potentially nephrotoxic, due to precipitation in the renal tubules. Uric acid has a greater tendency to precipitate and to cause renal damage.
- Allopurinol is a medication which inhibits xanthine oxidase.
- i) This will reduce the production of uric acid (which is potentially beneficial).
- ii) This may cause the accumulation of xanthine (which is potentially dangerous, but not as bad as uric acid).
- Rasburicase is the most effective approach to manage purine nucleotide toxicity. It converts uric acid into allantoin, which is harmless. Treatment with rasburicase has the advantage over allopurinol of not leading to accumulation of Xanthine.
- Only Rasburicase can act on uric acid which has allready been generated (allopurinol can prevent generation of additional uric acid, but doesn't affect pre-existing uric acid).
vicious cycle of tumor lysis syndrome
- Tumor lysis may lead to a spiral of progressive renal dysfunction as follows:
- (1) This begins with tumor cells releasing phosphate, potassium, and uric acid.
- (2) Renal failure occurs due to the precipitation of uric acid and calcium phosphate in the kidneys.
- (3) Renal failure then inhibits the excretion of potassium and uric acid, which causes further elevation of potassium and uric acid levels with worsening of tumor lysis syndrome.
- Early dialysis may be needed to break this cycle (more on this below).
the primary problem is now calcium-phosphate
- Tissue damage in tumor lysis syndrome results largely from the precipitation of two substances: uric acid and calcium-phosphate.
- Historically, uric acid was a major concern. This is currently less of an issue because it's relatively easily treated with rasburicase.
- Calcium-phosphate precipitation is becoming the predominant problem:
- The calcium-phosphate product is the calcium concentration (in mg/dL) multiplied by the phosphate concentration (in mg/dL).
- When the calcium-phosphate product rises >60-70, there is a risk of systemic precipitation of calcium phosphate (calciphylaxis)
one minute video to illustrate this better:
epidemiology & risk factors
- Generally 1-5 days after chemotherapy initiation.
- Can occur spontaneously or after radiation therapy.
malignancies with high risk for tumor lysis syndrome
- Burkitt's lymphoma/leukemia.
- Acute leukemia (AML or ALL) with WBC >25,000-100,000.
- High-grade lymphoma with bulky disease (diffuse large B-cell lymphoma and T-cell non-Hodgkins lymphoma).
additional risk factors for tumor lysis syndrome
- Baseline LDH > 1,500 IU/L.
- Pre-treatment hyperuricemia (uric acid >7.5 mg/dL or >446 uM).
- Pre-treatment hyperphosphatemia.
- Baseline renal dysfunction.
- Use of novel and more potent therapies (e.g. biological treatments).
clinical signs & symptoms
symptoms / signs are due to electrolyte abnormalities
- Hyperkalemia (usually first abnormality to emerge)
- Muscle spasms/tetany
- Uric acid:
- Oliguric renal failure
- May see uric acid crystals.
simplified Cairo definition of tumor lysis syndrome
- Laboratory definition = Malignancy plus at least two of the following abnormalities (usually following chemotherapy):
- (1) K >6 mEq/L
- (2) Phosphate >4.5 mg/dL or >1.45 mM
- (3) Uric acid >8 mg/dL or >476 uM
- (4) Calcium <7 mg/dL or <1.75 mM
- Clinical definition
- (1) Laboratory definition plus
- (2) At least one of the following:
- Acute kidney injury (Cr >1.5 times baseline)
- Cardiac arrhythmia
- Sudden death
- Technically, the definition may also be met based on changes in electrolytes over time (e.g. 25% increase in potassium, 25% increase in phosphate). However, in practice such changes are usually not considered (25876990).
differential diagnosis: pseudohyperkalemia
- (1) Pseudohyperkalemia may occur among patients with very high WBC or platelet count.
- Suspect this in patients with elevated potassium, but normal EKG.
- May diagnose this either by:
- (a) Sending STAT potassium to lab on ice using a heparinized tube.
- (b) Measuring potassium at bedside using point-of-care monitor.
- (2) Other sources of tissue necrosis may cause a similar pattern of electrolyte abnormalities
- Acute hepatic necrosis
- Crush injury
prevention of tumor lysis syndrome
(1) purine nucleotide metabolism manipulation
- This decision will typically be made by the hematology/oncology team.
- (1) High risk for tumor lysis syndrome
- Prophylactic rasburicase may be used (18509186). This is expensive, but potentially is the most effective medication for protecting against purine metabolites. This makes the most sense in the context of patients whose uric acid level is already elevated.
- (2) Intermediate risk for tumor lysis syndrome
- Allopurinol may be started 2-3 days before chemotherapy
- The dose is usually 300 mg PO BID, with lower doses in renal dysfunction.
- (3) Low risk for tumor lysis syndrome
- Hydration alone (without allopurinol or rasburicase).
- Fluid selection
- Acidic pH may encourage crystallization of uric acid, so historically urinary alkalinization has been used. More recent evidence indicated that urinary alkalinization isn't beneficial, so this has been abandoned.
- For most patients, balanced crystalloid is a reasonable choice (e.g. LR or Plasmalyte). For patients with significant acidosis due to non anion-gap metabolic acidosis or uremia, isotonic bicarbonate could be considered with a goal of bringing the serum bicarbonate level to a low-normal level (more on pH-guided resuscitation here).
- No clear evidence exists regarding what the ideal fluid and/or rate may be.
- The goal is to render the patient in a euvolemic state with good urine output. Be careful about placing the patient on a high rate of crystalloid if the patient isn't mobilizing infused fluid.
- Ideally, patient will mobilize excess fluid in the urine. However, if the patient is retaining fluid (e.g. due to cardiac or renal dysfunction), then reduce or stop fluid infusion.
(3) stop medications that elevate potassium or phosphate
- Stop potassium or phosphate supplements.
- This includes standing “PRN” potassium orders – it may be wise to allow the potassium to ride a bit low.
- Discontinue medications that increase potassium (e.g. ACEi/ARB, trimethoprim, potassium-sparing diuretics).
(4) renal protection
- Avoid any nephrotoxic medications (e.g. NSAIDs).
- Avoid hypotension/malperfusion of kidneys.
- Patients at intermediate-high risk of tumor lysis syndrome may be monitored with serial labs (electrolytes including Ca/Mg/Phos and uric acid).
- Frequency of monitoring depends on risk level; q6hr labs may be useful for high-risk patients during induction chemotherapy.
- (1) Do #3 and #4 from the last section (if you haven't already).
- (2) Renal diet (potassium & phosphate restricted).
- (3) Consider short-term use of an oral phosphate binder
- Sevelamer (RENAGEL) 800-1600 mg TID with meals may be best choice here (higher dose if phosphate is already elevated >7.5 mg/dL or 2.4 mM)
- Do not treat asymptomatic hypocalcemia (calcium may precipitate with phosphate).
- Symptomatic hypocalcemia may be treated with the lowest dose of calcium possible.
- The ideal treatment for hypocalcemia might be dialysis (with a goal of removing phosphate).
- Hypocalcemia here is really a secondary problem due to hyperphosphatemia, so giving calcium doesn't really fix this.
- Hyperkalemia is often the most life-threatening abnormality in tumor lysis syndrome.
- Overall, treatments for hyperkalemia include the following (discussed further in the hyperkalemia chapter).
- (1) IV calcium to stabilize the myocardium – in profound hyperkalemia.
- (2) IV dextrose and insulin, so shift potassium into cells.
- (3) Removal of potassium from the body – using either diuresis or dialysis (shown above).
- Some minor modifications to the treatment of hyperkalemia in patients with tumor lysis syndrome:
- (a) Avoid acetazolamide (urinary alkalinization could theoretically promote calcium-phosphate precipitation within renal tubules).
- (b) IV calcium should be used only if genuinely necessary (e.g. severe EKG changes, malignant arrhythmias).
- (c) Bicarbonate therapy should be limited to isotonic bicarbonate in patients with metabolic acidosis, with a goal of normalizing the serum bicarbonate (targeting 20-24 mEq/L). Excessive bicarbonate and metabolic alkalosis may encourage calcium-phosphate precipitation in kidneys.
- (d) Overall lower threshold for initiation of dialysis (given that dialysis may benefit many abnormalities encountered in tumor lysis syndrome; see below).
adequate hydration +/- diuresis
- Fluid selection:
- Alkalinizing the urine may reduce the risk of uric acid precipitation, but an alkaline urine will promote precipitation of calcium-phosphate and xanthine.
- If the uric acid level can be controlled with rasburicase, it may be best to avoid urine alkalinization.
- For most patients, a balanced crystalloid may be reasonable (LR or Plasmalyte). In patients with marked acidosis (due to NAGMA or uremic acidosis), isotonic bicarbonate might be considered – but the goal here is to bring the serum bicarbonate to the low-normal range.
- (a) The first and most important step is to establish euvolemia.
- Assess volume status. If hypovolemia is present, treat with crystalloid. (b) Next, provide a generous amount of IV fluid (e.g. 150-200 ml/hr).
- (c) If patient doesn't excrete most of the fluid you're administering, consider judicious administration of diuretic (furosemide and/or thiazide diuretic).
- Both furosemide & thiazide diuretics will help excrete potassium and phosphate.
- Forced diuresis is reasonable, but not proven to be beneficial.
- (d) Carefully monitor fluid status (inputs/outputs)
- Goal is for patient to be euvolemic (err a bit on the wet side, but avoid hypervolemia). If the patient has poor urine output despite diuretic use, then stop fluid administration.
- Goal is for patient to have a high urine output.
- Follow electrolytes and replete potassium and magnesium PRN.
- Enzyme which metabolizes uric acid.
- Effective at reducing uric acid levels within hours. The main drawback is that it's expensive.
- Some retrospective studies suggest that the use of rasburicase may be associated with shorter ICU length of stay (27965022).
- Indications may include:
- Uric acid >8 mg/dL or >476 uM (especially with acute renal failure or refractory to volume resuscitation).
- Contraindications: G6PD deficiency (may cause hemolysis)
- Anaphylaxis, Methemoglobinemia (both rare)
- Spuriously low uric acid measurements due to ex vivo metabolism of uric acid. To prevent this, uric acid levels must be obtained on ice and sent directly to the lab.
- Conventional dosing: 0.2 mg/kg daily for up to 5 days (will work well, but this is probably a higher dose than is necessary).
- Reduced dosing strategy: Give 3 mg (fixed dose), repeat if uric acid level remains elevated 12 hours later (29320954).
- The half-life of rasburicase is ~20 hours. May re-dose daily depending on uric acid levels.
allopurinol is potentially harmful
- Allopurinol reduces the uric acid level, but increases the level of xanthine production. This is a problem for a few reasons:
- 1) Xanthine can precipitate in the kidneys, causing acute kidney injury (xanthine nephropathy).
- 2) Xanthine levels can't be measured clinically – so we cannot know whether this is happening.
- For most patients, it's better to allow purine nucleotides to be metabolized into uric acid, which can then be treated with rasburicase.
- Allopurinol use may impair the efficacy of rasburicase, so the two drugs shouldn't be used together (25876990).
- Allopurinol might be considered in patients who cannot receive rasburicase (due to allergy or G6PD deficiency).
- In general, there is a low threshold for dialysis, because this will resolve numerous problems encountered in tumor lysis syndrome.
- Consider early consultation with nephrology.
- Indications for dialysis may include:
- Volume overload
- Uric acid severely elevated despite rasburicase (e.g. >10 mg/dL)
- Marked hyperphosphatemia, elevated Calcium-Phosphate product (e.g. >70 mg2/dL2), symptomatic hypocalcemia
- Uncontrolled hyperkalemia
- Uremia, acidosis
- Tumor lysis syndrome plus oliguria
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questions & discussion
To keep this page small and fast, questions & discussion about this post can be found on another page here.
- Don't “correct” hypocalcemia unless mandatory, as this may cause calcium-phosphate precipitation.
- Consult nephrology and consider dialysis early.
- Consider the possibility of tumor lysis syndrome in any cancer patient with hyperkalemia or renal failure.
- Don't forget to discontinue allopurinol in patients with established tumor lysis syndrome who are being treated with rasburicase.
- Tumor Lysis Syndrome (WikEM)