History

Fact Explanation
Symptoms of hyperkalemia Potassium is liberated from lysing tumor cells and usually after 6-72 hours on initiating therapy cause symptoms such as fatigue, generalized muscle weakness, anorexia, paresthesia, and irritability, which ; and if left untreated, it can lead to cardiac arrhythmia (atrioventricular dissociation, ventricular tachycardia, or ventricular fibrillation) and death. The risk of clinically significant hyperkalemia is greatly increased among patients with chronic kidney disease (CKD) or acute kidney injury (AKI) due to the limited potassium clearance. [1] [2] [5]
Symptoms of hyperphosphatemia and secondary hypocalcemia Both electrolyte abnormalities usually develop 24 - 48 hours on initiating chemotherapy. TLS can induce a large phosphate load to the extracellular space because of the relatively high intracellular phosphate concentration. Primarily through chelation with calcium, hyperphosphatemia leads to hypocalcemia, which can precipitate as calcium-phosphate crystals in various organs. Elimination of phosphate by the kidneys is limited by AKI or preexisting CKD. Secondary hypocalcemia of TLS is the more threatening electrolyte disorder than hyperkalemia and hyperphosphatemia. Precipitation of calcium phosphate in the cardiac systems causes serious dysrhythmias, and in the renal tubules leads to acute renal failure. Hypocalcemia may manifest as anxiety, agitation and confused, and in severe cases it can lead to arrhythmia, seizures, tetany, and death. Presumably due to acute deficiencies of 1,25-vitamin D, the hypocalcemia of TLS may persist even after phosphate levels normalize. [1] [2] [4]
Symptoms of hyperuricaemia Usually develops 48 to 72 hours after initiation of chemotherapy, resulting from an enhanced catabolism of large amounts of RNA and DNA. [4] [5] Hyperuricaemia precipitates as uric acid stones, or uric acid nephropathy leading to AKI due to intrarenal crystallization, and also due to crystal-independent mechanisms, such as renal vaso-constriction, impaired autoregulation, decreased renal blood flow, oxidation, and inflammation. [2]
Risk factors Large, rapidly proliferating, advanced metastatic tumors such as rapidly dividing myeloproliferative and lymphoproliferative disorders (classically Burkitts lymphoma in children, and acute lymphoblastic leukaemia in adults) carry the greatest risk. Other malignancies that can develop TLS include chronic leukaemia, breast carcinoma, germ cell rumours, neuroendocrine rumours and small cell lung carcinoma. Chemotherapy is usually associated with TLS, but may also occur with radiotherapy, surgery, endocrine therapy, glucocorticoids, interferon, hyperthermia or spontaneously. Pre-existing nephropathy from hypertension, diabetes, gout, etc. has a higher risk of acute kidney failure and TLS. Exposure to nephrotoxic substances such as non-steroidal anti-inflammatory agents and certain anti-hypertensive medications can also cause TLS. Decreased oral fluid intake and baseline elevations in uric acid and phosphorus may also result in TLS. Increased baseline of lactate dehydrogenase (>2 ULN) and elevated WBC counts (>25,000/µL) also contributes to the risk. TLS may occur without the initiation of cancer therapy in high-grade hematologic malignancies, particularly Burkitt’s lymphoma, which is known as 'spontaneous TLS'. Triggers for spontaneous TLS have not yet been identified. [1] [2] [3] [4]
Features of acute renal failure (ARF) AKI and electrolyte disturbances are the most common forms of renal disease that may occur in a hospitalized patient with cancer, and potentiating prerenal causes include excessive use of diuretics, diabetes insipidus, gastrointestinal losses through diarrhea and vomiting, or reduced oral fluid intake (volume depletion). These patients may be oliguric or nonoliguric. Acute glomerulonephritis may occur in patients with malignancy with almost the same frequency as in the general population; and classically present as hematuria, edema, and hypertension (nephritic syndrome). Exposure to radiographic contrast media, nephrotoxic antibiotics, non-steroidal anti-inflammatory drugs and nephrotoxicity of some of the anti-cancer treatments and certain anaesthetic agents may result in acute tubular necrosis. ARF may occasionally be induced by the infiltration of the parenchyma by lymphoma or leukemic cells, resulting in acute interstitial nephritis. TLS resulting in hyperuricemia, hypocalcemia, and hyperphophatemia may present with ARF. Hyperuricemia can result in intratubular precipitation of uric acid but rarely in formation of uric acid calculi. Most commonly following chemotherapy in hematologic malignancies with bulky tumor loads, hyperphosphatemia leads to the precipitation of calcium phosphate crystals resulting in acute nephrocalcinosis. Tumors themselves are also associated with ARF, e.g. in multiple myeloma where the light chains are nephrotoxic and renal failure can result from either direct toxic effects on cells or through precipitation in the tubules, forming casts. TLS or plasma cell infiltration also can result in ARF. In every case of ARF, urinary tract obstruction (postrenal failure) should be considered, and tumors that may cause urinary tract obstruction are those of the genitourinary tract, lymphomas, retroperitoneal tumors, and metastatic tumors. Patients may have an acute or insidious presentation ,and urine output may vary from anuria to polyuria. [6] [7]
References
  1. WILSON FP, BERNS JS. Tumor Lysis Syndrome: New Challenges and Recent Advances Adv Chronic Kidney Dis [online] 2014 Jan, 21(1):18-26 [viewed 28 November 2014] Available from: doi:10.1053/j.ackd.2013.07.001
  2. HOWARD SC, JONES DP, PUI CH. The Tumor Lysis Syndrome N Engl J Med [online] 2011 May 12, 364(19):1844-1854 [viewed 28 November 2014] Available from: doi:10.1056/NEJMra0904569
  3. MIRRAKHIMOV AE, ALI AM, KHAN M, BARBARYAN A. Tumor Lysis Syndrome in Solid Tumors: An up to Date Review of the Literature Rare Tumors [online] , 6(2):5389 [viewed 28 November 2014] Available from: doi:10.4081/rt.2014.5389
  4. MIKA DENISH, AHMAD SABRINA, GURUVAYOORAPPAN C.. Tumour Lysis Syndrome: Implications for Cancer Therapy. Asian Pacific Journal of Cancer Prevention [online] 2012 August, 13(8):3555-3560 [viewed 02 December 2014] Available from: doi:10.7314/APJCP.2012.13.8.3555
  5. FIRWANA BELAL, HASAN RIM, HASAN NOUR, ALAHDAB FARES, ALNAHHAS IYAD, HASAN SEBA, VARON JOSEPH. Tumor Lysis Syndrome: A Systematic Review of Case Series and Case Reports. Postgrad Med [online] 2012 March, 124(2):92-101 [viewed 03 December 2014] Available from: http://criticalcaremedicine.pbworks.com/w/file/fetch/59412030/Tumor%20Lysis%20Syndrome%20A%20Systematic%20Review.pdf
  6. THOMAS CR JR, DODHIA N. Common emergencies in cancer medicine: metabolic syndromes. J Natl Med Assoc [online] 1991 Sep, 83(9):809-818 [viewed 07 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2627107
  7. LAMEIRE N.. Nephrotoxicity of recent anti-cancer agents. Clinical Kidney Journal [online] December, 7(1):11-22 [viewed 07 December 2014] Available from: doi:10.1093/ckj/sft135

Examination

Fact Explanation
Signs of hyperphosphatemia and secondary hypocalcemia Positive Chvostek and Trousseau signs, carpal and pedal spasms, bronchospasm, seizures, and . papilloedema, cardiomyopathy, hypotension, congestive cardiac failure ,arrhythmias, and cardiac arrest. [1] [2]
Signs of hyperkalemia Paresthesia, weakness, and fatal cardiac arrhythmias. [1] [2]
Signs indicative of uremia Weakness, Fatigue, malaise, nausea, vomiting, anorexia, hiccups, metallic taste, neuromuscular irritability, difficulty concentrating, restless legs, pruritus, and ecchymoses. [1] [2]
References
  1. HOWARD SC, JONES DP, PUI CH. The Tumor Lysis Syndrome N Engl J Med [online] 2011 May 12, 364(19):1844-1854 [viewed 28 November 2014] Available from: doi:10.1056/NEJMra0904569
  2. WILSON FP, BERNS JS. Tumor Lysis Syndrome: New Challenges and Recent Advances Adv Chronic Kidney Dis [online] 2014 Jan, 21(1):18-26 [viewed 28 November 2014] Available from: doi:10.1053/j.ackd.2013.07.001

Differential Diagnoses

Fact Explanation
Isolated electrolyte imbalance Isolated hyperkalemia, hyperuricaemia, hyperphosphataemia or hypocalcaemia can be diagnosed in the presence of differentiating symptoms/signs and differentiating tests, where respective electrolyte abnormalities can be seen, while the others are in the normal ranges. [1] [2] [6]
Acute renal failure EtIologies other than TLS like prerenal causes such as volume depletion from anorexia, vomiting, diarrhea, and bleeding; and postrenal urinary tract obstruction from pelvic or retroperitoneal masses can lead to kidney failure in patients with cancer. The combination of volume depletion, hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia strongly support the diagnosis of TLS over other causes. [1] [2] [3] [4] [5]
References
  1. TRUONG TONY H., BEYENE JOSEPH, HITZLER JOHANN, ABLA OUSSAMA, MALONEY ANNE MARIE, WEITZMAN SHEILA, SUNG LILLIAN. Features at presentation predict children with acute lymphoblastic leukemia at low risk for tumor lysis syndrome. Cancer [online] 2007 October, 110(8):1832-1839 [viewed 03 December 2014] Available from: doi:10.1002/cncr.22990
  2. WILSON F. P., BERNS J. S.. Onco-Nephrology: Tumor Lysis Syndrome. Clinical Journal of the American Society of Nephrology [online] December, 7(10):1730-1739 [viewed 03 December 2014] Available from: doi:10.2215/​CJN.03150312
  3. THOMAS CR JR, DODHIA N. Common emergencies in cancer medicine: metabolic syndromes. J Natl Med Assoc [online] 1991 Sep, 83(9):809-818 [viewed 07 December 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2627107
  4. LORIGAN PC, WOODINGS PL, MORGENSTERN GR, SCARFFE JH. Tumour lysis syndrome, case report and review of the literature. Ann Oncol [online] 1996 Aug, 7(6):631-6 [viewed 28 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/8879379
  5. LAMEIRE N.. Nephrotoxicity of recent anti-cancer agents. Clinical Kidney Journal [online] December, 7(1):11-22 [viewed 07 December 2014] Available from: doi:10.1093/ckj/sft135
  6. HOWARD SCOTT C., JONES DEBORAH P., PUI CHING-HON. The Tumor Lysis Syndrome. N Engl J Med [online] 2011 May, 364(19):1844-1854 [viewed 07 December 2014] Available from: doi:10.1056/NEJMra0904569

Investigations - for Diagnosis

Fact Explanation
Laboratory tests Cairo-Bishop's criteria for classification of laboratory TLS in adults includes the following: (occurrence of any 2 or more of the following 5 laboratory abnormalities defines laboratory TLS) Serum K+ level >6.0 mmol/L or 25% increase from baseline (6-72 hours after treatment) Serum phosphate level ≥4.5 mg/dL or 25% increase from baseline) Serum calcium level ≤7.0mg/dL or 25% decrease from baseline (24-48 hours after treatment) Serum uric acid ≥8.0mg/dL or 25% increase from baseline (48-72 hours after treatment) Creatinine ≥1.5 times the age-defined upper limit of normal [1] [2]
Cairo-Bishop's criteria for classification of clinical tumor lysis syndrome in adults Cardaic dysrhythmia, sudden death, seizures and/or increase in creatinine level of 0.3 mg/dL or presence of oliguria (an average urine output of <0.5 ml/kg/h for 6 h). [1] [2]
References
  1. MIRRAKHIMOV AE, ALI AM, KHAN M, BARBARYAN A. Tumor Lysis Syndrome in Solid Tumors: An up to Date Review of the Literature Rare Tumors [online] , 6(2):5389 [viewed 28 November 2014] Available from: doi:10.4081/rt.2014.5389
  2. MIKA DENISH, AHMAD SABRINA, GURUVAYOORAPPAN C.. Tumour Lysis Syndrome: Implications for Cancer Therapy. Asian Pacific Journal of Cancer Prevention [online] 2012 August, 13(8):3555-3560 [viewed 02 December 2014] Available from: doi:10.7314/APJCP.2012.13.8.3555

Investigations - for Management

Fact Explanation
Central venous pressure and urinary electrolytes Should be assessed in all patients on admission to identify those with fluid depletion. [1]
Patient monitoring Monitoring should be done over the entire period during which the patient is at risk for the TLS i.e. every 4 to 6 hours after the start of cancer therapy in patients at high risk, laboratory monitoring every 8 to 12 hours in patients at intermediate risk , and daily monitoring in patients with low risk for TLS. Intensive nursing care with measurement of urine output, electrolytes, creatinine, and uric acid and continuous cardiac monitoring every 4 to 6 hours is crucial in all patients who have developed TLS and those who are at risk for TLS after initiation of cancer therapy. In patients at high risk TLS where no metabolic aberration exists, monitor electrolytes, urea, creatinine, uric acid, serum calcium and PO4 every 12-24 hours initially; and urine output, blood pressure and CVP at least 4 hourly. [1] [2]
References
  1. LORIGAN PC, WOODINGS PL, MORGENSTERN GR, SCARFFE JH. Tumour lysis syndrome, case report and review of the literature. Ann Oncol [online] 1996 Aug, 7(6):631-6 [viewed 28 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/8879379
  2. HOWARD SC, JONES DP, PUI CH. The Tumor Lysis Syndrome N Engl J Med [online] 2011 May 12, 364(19):1844-1854 [viewed 28 November 2014] Available from: doi:10.1056/NEJMra0904569

Investigations - Screening/Staging

Fact Explanation
Identify individuals at risk of TLS Tumor burden: Bulky lymphatic disease (>10 cm), elevated lactate dehydrogenase (2× upper limit of normal), elevated white blood cell count (>25,000 cells/mm3). Renal function: Baseline creatinine > 1.4 mg/dl. Baseline uric acid: >7.5 mg/dl. Lactate dehydrogenase. Male sex. Chemosensitivity: Variable [1]
References
  1. WILSON F. P., BERNS J. S.. Onco-Nephrology: Tumor Lysis Syndrome. Clinical Journal of the American Society of Nephrology [online] December, 7(10):1730-1739 [viewed 02 December 2014] Available from: doi:10.2215/​CJN.03150312

Management - General Measures

Fact Explanation
Vigorous hydration Adequate hydration is the key for both prevention and treatment of the syndrome. Hyperhydration is recommended in all patients at intermediate or high risk for TLS, at continuous infusion rates of up to 4 to 6 L/d to be initiated 24 to 48 hours prior to cancer therapy and continue for 48 to 72 hours after therapy. [1] Intravenous fluids of 2500 to 3000 ml/m2/d should be given in patients at highest risk for TLS. [3] In addition a loop diuretic agent (e.g., furosemide) can be used in patients who have a low urine output despite adequate hydration. [2]
Prophylaxis Give at least 3 L of oral or intravenous fluid daily before initiation of chemotherapy, provided there are no contraindications to volume expansion. Provide a prophylactic xanthine oxidase inhibitor if there are other risk factors present such as elevated baseline uric acid or LDH, or underlying kidney disease. Recombinant urate oxidase should be given before chemotherapy in patients with high-risk tumor types. Prophylactic use of rasburicase should be given to patients in whom hyperuricemia is delaying initiation of chemotherapy. Avoid using kidney vasoconstrictive substances such as non-steroidal or anti-inflammatory drugs, and iodinated contrast. [2]
Decrease the rate of TLS with a treatment prephase This strategy of giving a low-intensity initial therapy to patients at high risk for the TLS slows down the lysis of the cancer cells allowing renal homeostatic mechanisms to clear metabolites before they accumulate and cause organ damage. In cases of advanced B-cell non-Hodgkin’s lymphoma or Burkitt’s leukemia, treatment with low-dose cyclophosphamide, vincristine, and prednisone can be initiated for a week before the start of intensive chemotherapy; and a week of prednisone monotherapy for childhood acute lymphoblastic leukemia. [3]
References
  1. LORIGAN PC, WOODINGS PL, MORGENSTERN GR, SCARFFE JH. Tumour lysis syndrome, case report and review of the literature. Ann Oncol [online] 1996 Aug, 7(6):631-6 [viewed 28 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/8879379
  2. WILSON FP, BERNS JS. Tumor Lysis Syndrome: New Challenges and Recent Advances Adv Chronic Kidney Dis [online] 2014 Jan, 21(1):18-26 [viewed 28 November 2014] Available from: doi:10.1053/j.ackd.2013.07.001
  3. HOWARD SC, JONES DP, PUI CH. The Tumor Lysis Syndrome N Engl J Med [online] 2011 May 12, 364(19):1844-1854 [viewed 28 November 2014] Available from: doi:10.1056/NEJMra0904569

Management - Specific Treatments

Fact Explanation
Correction of hyperkalemia Infuse 50 ml of 50% glucose and 15U of soluble insulin over 1 hour, intravenous fluids and diuretics. Oral potassium exchange resins such as calcium resonium should be used in the longer term. Serum potassium levels greater than 6.5 mmol/L is a medical emergency and treatment should be commenced with 10-30 ml calcium gluconate (10%) i.v. slowly for cardioprotection, 15 units of soluble insulin and 50 ml 50% glucose i.v. followed by insulin and glucose adjusted according to the blood glucose. Dialysis is required if these measures do not control the serum potassium. [1]
Hypouricemic agents Allopurinol is a xanthine oxidase inhibitor, which prevents the formation of uric acid, and hence it prevents urate crystals from precipitating. It is given to patients at low risk for TSL. Give 500 mg/m2/d, reduce to 200 mg/m2/d after 3 days of chemotherapy. Reduce the dose in renal failure, and if hyperuricaemia is controlled. [1] Rasburicase is a urate oxidase, which makes uric acid more soluble in urine and causes a rapid reduction in uric acid levels, and therefore it is the first line drug given to patients at high risk for TLS rather than allopurinol, after excluding glucose-6 phosphate dehydrogenase deficiency since this medication can lead to severe hemolysis in such patients. In both adults and children start with 1 dose (0.1–0.2 mg/kg) and repeat the dose if necessary. [4] Either allopurinol or rasburicase can be given to patients at intermediate risk for TLS. Patients with clinically established TLS should be managed with aggressive hydration, rasburicase, and hemodialysis in advanced cases. [3] [5]
Intravenous calcium and activated vitamin D Treat hypocalcaemia if symptomatic or in the presence of abnormal ECG. [1]
Urinary alkalinisation Urinary alkalinization increases uric acid solubility but decreases calcium phosphate solubility, and since it is more difficult to correct hyperphosphatemia than hyperuricemia. Therefore, it is not recommended in most cases and it should only be considered in cases of severe hyperuricemia in which recombinant urate oxidase is unavailable. Use isotonic sodium bicarbonate (1.4% w/v), and maintain urinary pH > 7 by adjusting the rate. Discontinue when serum uric acid normalizes. [1]
Renal replacement Therapy Hemodialysis, peritoneal dialysis, and continuous arterial-venous hemodialysis are the last options of treatment that can be done to improve kidney function and persistent electrolyte abnormalities. Indications: Severe oliguria or anuria, persistent hyperkalemia, hyperphosphatemia-induced symptomatic hypocalcemia, calcium-phosphate product ≥70 mg2/dL2, fluid overload or hyperuricaemia. [1] [5]
References
  1. LORIGAN PC, WOODINGS PL, MORGENSTERN GR, SCARFFE JH. Tumour lysis syndrome, case report and review of the literature. Ann Oncol [online] 1996 Aug, 7(6):631-6 [viewed 28 November 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/8879379
  2. HOWARD SC, JONES DP, PUI CH. The Tumor Lysis Syndrome N Engl J Med [online] 2011 May 12, 364(19):1844-1854 [viewed 28 November 2014] Available from: doi:10.1056/NEJMra0904569
  3. MIRRAKHIMOV AE, ALI AM, KHAN M, BARBARYAN A. Tumor Lysis Syndrome in Solid Tumors: An up to Date Review of the Literature Rare Tumors [online] , 6(2):5389 [viewed 28 November 2014] Available from: doi:10.4081/rt.2014.5389
  4. FIRWANA BELAL, HASAN RIM, HASAN NOUR, ALAHDAB FARES, ALNAHHAS IYAD, HASAN SEBA, VARON JOSEPH. Tumor Lysis Syndrome: A Systematic Review of Case Series and Case Reports. Postgrad Med [online] 2012 March, 124(2):92-101 [viewed 03 December 2014] Available from: doi:10.3810/pgm.2012.03.2540