Semin Thromb Hemost 2007; 33(4): 397-407
DOI: 10.1055/s-2007-976175
Copyright © 2007 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Tumor Lysis Syndrome

Ramon V. Tiu1 , 2 , Stavros E. Mountantonakis1 , Andrew J. Dunbar2 , Martin J. Schreiber3  Jr. 
  • 1Internal Medicine, Cleveland Clinic, Cleveland, Ohio
  • 2Experimental Hematology, Cleveland Clinic, Cleveland, Ohio
  • 3Department of Nephrology and Hypertension, Cleveland Clinic, Cleveland, Ohio
Further Information

Publication History

Publication Date:
24 May 2007 (online)

ABSTRACT

Tumor lysis syndrome (TLS) is an important metabolic disorder frequently encountered in the management of a variety of cancers including lymphoma, leukemia, and neuroblastoma. Delayed recognition can result in a variety of biochemical abnormalities resulting in life-threatening complications such as renal failure, arrhythmias, and seizures. Identification of high-risk patients and early recognition of the syndrome is crucial in the early institution of appropriate prophylaxis and treatment. Recent advances in the understanding of urate metabolism, development of new urate-lowering drugs, and the application of biomarkers, calculation methods, and prognostic models to identify high-risk patients will pave the way in improving the management of TLS. We included in this review the new information regarding the urate transporters URAT-1, organic anion transporter 1/3, and MRP4; the urate elimination pathway; a comparison of the old- (allopurinol, native uricase) and new- (febuxostat, Y-700, PEG-uricase, rasburicase) generation urate-lowering agents; and application of new biomarkers (cystatin-C, neutrophil gelatinase-associated lipocalin, kidney injury molecule 1), estimated glomerular filtration rate and calculation methods (modification of diet in renal disease and prognostic model (Penn Predictive Score of Tumor Lysis Syndrome) in the identification of high-risk patients, and alternative unexplored mechanisms (asymmetric dimethylarginine and adenosine) to explain renal injury related to TLS.

REFERENCES

  • 1 Beriwal S, Singh S, Garcia-Young J A. Tumor lysis syndrome in extensive-stage small-cell lung cancer.  Am J Clin Oncol. 2002;  25 474-475
  • 2 Khan J, Broadbent V A. Tumor lysis syndrome complicating treatment of widespread metastatic abdominal rhabdomyosarcoma.  Pediatr Hematol Oncol. 1993;  10 151-155
  • 3 Kushner B H, LaQuaglia M P, Modak S, Cheung N K. Tumor lysis syndrome, neuroblastoma, and correlation between serum lactate dehydrogenase levels and MYCN-amplification.  Med Pediatr Oncol. 2003;  41 80-82
  • 4 Bedrna J, Polcák J. Akuter Harnleiterverschluss nach Bestrahlung chronischer Leukämien mit Röntgenstrahlen.  Med Klin. 1929;  25 1700-1701
  • 5 Crittenden D R, Ackerman G L. Hyperuricemic acute renal failure in disseminated carcinoma.  Arch Intern Med. 1977;  137 97-99
  • 6 Persons D A, Garst J, Vollmer R, Crawford J. Tumor lysis syndrome and acute renal failure after treatment of non-small-cell lung carcinoma with combination irinotecan and cisplatin.  Am J Clin Oncol. 1998;  21 426-429
  • 7 Benekli M, Gullu I H, Savas M C et al.. Acute tumor lysis syndrome following intrathecal methotrexate.  Leuk Lymphoma. 1996;  22 361-363
  • 8 Frame J N, Dahut W L, Crowley S. Fludarabine and acute tumor lysis in chronic lymphocytic leukemia.  N Engl J Med. 1992;  327 1396-1397
  • 9 Abou Mourad Y, Taher A, Shamseddine A. Acute tumor lysis syndrome in large B-cell non-Hodgkin lymphoma induced by steroids and anti-CD 20.  Hematol J. 2003;  4 222-224
  • 10 Fleming D R, Henslee-Downey P J, Coffey C W. Radiation induced acute tumor lysis syndrome in the bone marrow transplant setting.  Bone Marrow Transplant. 1991;  8 235-236
  • 11 Dhingra K, Newcom S R. Acute tumor lysis syndrome in non-Hodgkin lymphoma induced by dexamethasone.  Am J Hematol. 1988;  29 115-116
  • 12 Jasek A M, Day H J. Acute spontaneous tumor lysis syndrome.  Am J Hematol. 1994;  47 129-131
  • 13 Fenaux P, Lai J L, Miaux O et al.. Burkitt cell acute leukaemia (L3 ALL) in adults: a report of 18 cases.  Br J Haematol. 1989;  71 371-376
  • 14 Seftel M D, Bruyere H, Copland M et al.. Fulminant tumour lysis syndrome in acute myelogenous leukaemia with inv(16)(p13;q22).  Eur J Haematol. 2002;  69 193-199
  • 15 Ichida K, Hosoyamada M, Hisatome I et al.. Clinical and molecular analysis of patients with renal hypouricemia in Japan-influence of URAT1 gene on urinary urate excretion.  J Am Soc Nephrol. 2004;  15 164-173
  • 16 Jutabha P, Kanai Y, Hosoyamada M. at al. Identification of a novel voltage-driven organic anion transporter present at apical membrane of renal proximal tubule.  J Biol Chem. 2003;  278 27930-27938
  • 17 Van Aubel R A, Smeets P H, van den Heuvel J J, Russel F G. Human organic anion transporter MRP4 (ABCC4) is an efflux pump for the purine end metabolite urate with multiple allosteric substrate binding sites.  Am J Physiol Renal Physiol. 2005;  288 F327-F333
  • 18 Lipkowitz M S, Leal-Pinto E, Rappoport J Z, Najfeld V, Abramson R G. Functional reconstitution, membrane targeting, genomic structure, and chromosomal localization of a human urate transporter.  J Clin Invest. 2001;  107 1103-1115
  • 19 Enomoto A, Kimura H, Chairoungdua A et al.. Molecular identification of a renal urate anion exchanger that regulates blood urate levels.  Nature. 2002;  417 447-452
  • 20 Hosoyamada M, Ichida K, Enomoto A, Hosoya T, Endou H. Function and localization of urate transporter 1 in mouse kidney.  J Am Soc Nephrol. 2004;  15 261-268
  • 21 Hosoyamada M, Sekine T, Kanai Y, Endou H. Molecular cloning and functional expression of a multispecific organic anion transporter from human kidney.  Am J Physiol. 1999;  276(1 pt 2) F122-F128
  • 22 Xu G, Bhatnagar V, Wen G et al.. Analyses of coding region polymorphisms in apical and basolateral human organic anion transporter (OAT) genes. [OAT1 (NKT), OAT2, OAT3, OAT4, URAT (RST)].  Kidney Int. 2005;  68 1491-1499
  • 23 Oda M, Satta Y, Takenaka O, Takahata N. Loss of urate oxidase activity in hominoids and its evolutionary implications.  Mol Biol Evol. 2002;  19 640-653
  • 24 Ramazzina I, Folli C, Secchi A, Berni R, Percudani R. Completing the uric acid degradation pathway through phylogenetic comparison of whole genomes.  Nat Chem Biol. 2006;  2 144-148
  • 25 Cairo M S, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification.  Br J Haematol. 2004;  127 3-11
  • 26 Mandal A K. Hypokalemia and hyperkalemia.  Med Clin North Am. 1997;  81 611-639
  • 27 Overgaard K, Nielsen O B, Clausen T. Effects of reduced electrochemical Na + gradient on contractility in skeletal muscle: role of the Na+-K+ pump.  Pflugers Arch. 1997;  434 457-465
  • 28 Davidson M B, Thakkar S, Hix J K et al.. Pathophysiology, clinical consequences, and treatment of tumor lysis syndrome.  Am J Med. 2004;  116 546-554
  • 29 Mato A R, Riccio B E, Qin L et al.. A predictive model for the detection of tumor lysis syndrome during AML induction therapy.  Leuk Lymphoma. 2006;  47 877-883
  • 30 Arrambide K, Toto R D. Tumor lysis syndrome.  Semin Nephrol. 1993;  13 273-280
  • 31 Watts R W, Watts J E, Seegmiller J E. Xanthine oxidase activity in human tissues and its inhibition by allopurinol (4-hydroxypyrazolo[3,4-d] pyrimidine).  J Lab Clin Med. 1965t;  66 688-697
  • 32 DeConti R C, Calabresi P. Use of allopurinol for prevention and control of hyperuricemia in patients with neoplastic disease.  N Engl J Med. 1966;  274 481-486
  • 33 Becker M A, Schumacher Jr H R, Wortmann R L et al.. Febuxostat compared with allopurinol in patients with hyperuricemia and gout.  N Engl J Med. 2005;  353 2450-2461
  • 34 Becker M A, Kisicki J, Khosravan R et al.. Febuxostat (TMX-67), a novel, non-purine, selective inhibitor of xanthine oxidase, is safe and decreases serum urate in healthy volunteers.  Nucleosides Nucleotides Nucleic Acids. 2004;  23 1111-1116
  • 35 Yamada I, Fukunari A, Osajima T et al.. Pharmacokinetics/pharmacodynamics of Y-700, a novel xanthine oxidase inhibitor, in rats and man.  Nucleosides Nucleotides Nucleic Acids. 2004;  23 1123-1125
  • 36 Fukunari A, Okamoto K, Nishino T et al.. Y-700 [1-[3-Cyano-4-(2,2-dimethylpropoxy)phenyl]-1H-pyrazole-4-carboxylic acid]: a potent xanthine oxidoreductase inhibitor with hepatic excretion.  J Pharmacol Exp Ther. 2004;  311 519-528
  • 37 Mayer M D, Khosravan R, Vernillet L et al.. Pharmacokinetics and pharmacodynamics of febuxostat, a new non-purine selective inhibitor of xanthine oxidase in subjects with renal impairment.  Am J Ther. 2005;  12 22-34
  • 38 Chanteclair G, Olive D. Acute hyperuricemic kidney failure. Treatment by uricozyme.  Nouv Presse Med. 1975;  4 2274
  • 39 Masera G, Jankovic M, Zurlo M G et al.. Urate-oxidase prophylaxis of uric acid-induced renal damage in childhood leukemia.  J Pediatr. 1982;  100 152-155
  • 40 Pui C H, Mahmoud H H, Wiley J M et al.. Recombinant urate oxidase for the prophylaxis or treatment of hyperuricemia in patients with leukemia or lymphoma.  J Clin Oncol. 2001;  19 697-704
  • 41 Davis S, Park Y K, Abuchowski A, Davis F F. Hypouricaemic effect of polyethyleneglycol modified urate oxidase.  Lancet. 1981;  2 281-283
  • 42 Savoca K V, Davis F F, Palczuk N C. Induction of tolerance in mice by uricase and monomethoxypolyethylene glycol-modified uricase.  Int Arch Allergy Appl Immunol. 1984;  75 58-67
  • 43 Chua C C, Greenberg M L, Viau A T et al.. Use of polyethylene glycol-modified uricase (PEG-uricase) to treat hyperuricemia in a patient with non-Hodgkin lymphoma.  Ann Intern Med. 1988;  109 114-117
  • 44 Bomalaski J S, Holtsberg F W, Ensor C M, Clark M A. Uricase formulated with polyethylene glycol (uricase-PEG 20): biochemical rationale and preclinical studies.  J Rheumatol. 2002;  29 1942-1949
  • 45 Briglia A E. The current state of nonuremic applications for extracorporeal blood purification.  Semin Dial. 2005;  18 380-390
  • 46 Schelling J R, Ghandour F Z, Strickland T J, Sedor J R. Management of tumor lysis syndrome with standard continuous arteriovenous hemodialysis: case report and a review of the literature.  Ren Fail. 1998;  20 635-644
  • 47 Procaccini D A, Querques M, Tappi A, Strippoli P. Peritoneal clearances. Long-term study.  ASAIO Trans. 1988;  34 437-440
  • 48 Descombes E, Perriard F, Fellay G. Diffusion kinetics of urea, creatinine and uric acid in blood during hemodialysis. Clinical implications.  Clin Nephrol. 1993;  40 286-295
  • 49 Levey A S, Bosch J P, Lewis J B et al.. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group.  Ann Intern Med. 1999;  130 461-470
  • 50 Lamb E J, Stowe H J, Simpson D E et al.. Diagnostic accuracy of cystatin C as a marker of kidney disease in patients with multiple myeloma: calculated glomerular filtration rate formulas are equally useful.  Clin Chem. 2004;  50 1848-1851
  • 51 Verhave J C, Fesler P, Ribstein J, du Cailar G, Mimran A. Estimation of renal function in subjects with normal serum creatinine levels: influence of age and body mass index.  Am J Kidney Dis. 2005;  46 233-241
  • 52 Poggio E D, Wang X, Greene T, Van Lente F, Hall P M. Performance of the modification of diet in renal disease and Cockcroft-Gault equations in the estimation of GFR in health and in chronic kidney disease.  J Am Soc Nephrol. 2005;  16 459-466
  • 53 Kopple J D, Berg R, Houser H, Steinman T I, Teschan P. Nutritional status of patients with different levels of chronic renal insufficiency. Modification of Diet in Renal Disease (MDRD) Study Group.  Kidney Int. 1989;  27(suppl) S184-S194
  • 54 Menon V, Wang X, Greene T et al.. Relationship between C-reactive protein, albumin, and cardiovascular disease in patients with chronic kidney disease.  Am J Kidney Dis. 2003;  42 44-52
  • 55 Poge U, Gerhardt T, Stoffel-Wagner B et al.. Prediction of glomerular filtration rate in renal transplant recipients: cystatin C or modification of diet in renal disease equation?.  Clin Transplant. 2006;  20 200-205
  • 56 Madero M, Sarnak M J, Stevens L A. Serum cystatin C as a marker of glomerular filtration rate.  Curr Opin Nephrol Hypertens. 2006;  15 610-616
  • 57 Seronie-Vivien S, Toullec S, Malard L et al.. Contribution of the MDRD equation and of cystatin C for renal function estimates in cancer patients.  Med Oncol. 2006;  23 63-73
  • 58 Thomas F, Seronie-Vivien S, Gladieff L et al.. Cystatin C as a new covariate to predict renal elimination of drugs: application to carboplatin.  Clin Pharmacokinet. 2005;  44 1305-1316
  • 59 Hoppe A, Seronie-Vivien S, Thomas F et al.. Serum cystatin C is a better marker of topotecan clearance than serum creatinine.  Clin Cancer Res. 2005;  11 3038-3044
  • 60 Mishra J, Ma Q, Prada A et al.. Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury.  J Am Soc Nephrol. 2003;  14 2534-2543
  • 61 Han W K, Alinani A, Wu C L et al.. Human kidney injury molecule-1 is a tissue and urinary rumor marker of renal carcinoma.  J Am Soc Nephrol. 2005;  16 1126-1134
  • 62 Matsuguma K, Ueda S, Yamagishi S et al.. Molecular mechanism for elevation of asymmetric dimethylarginine and its role for hypertension in chronic kidney disease.  J Am Soc Nephrol. 2006;  17 2176-2183
  • 63 Busch M, Fleck C, Wolf G, Stein G. Asymmetrical (ADMA) and symmetrical dimethylarginine (SDMA) as potential risk factors for cardiovascular and renal outcome in chronic kidney disease-possible candidates for paradoxical epidemiology?.  Amino Acids. 2006;  30 225-232
  • 64 Kielstein J T, Tsikas D, Fliser D. Effects of asymmetric dimethylarginine (ADMA) infusion in humans.  Eur J Clin Pharmacol. 2006;  62(suppl 13) 39-44
  • 65 Siroka R, Trefil L, Rajdl D et al.. Asymmetric dimethylarginine, homocysteine and renal function-is there a relation?.  Clin Chem Lab Med. 2005;  43 1147-1150
  • 66 Kawamoto R, Tomita H, Oka Y, Ohtsuka N. Relationship between serum uric acid concentration, metabolic syndrome and carotid atherosclerosis.  Intern Med. 2006;  45 605-614
  • 67 Sanchez-Lozada L G, Nakagawa T, Kang D H et al.. Hormonal and cytokine effects of uric acid.  Curr Opin Nephrol Hypertens. 2006;  15 30-33
  • 68 Sanchez-Lozada L G, Tapia E, Santamaria J et al.. Mild hyperuricemia induces vasoconstriction and maintains glomerular hypertension in normal and remnant kidney rats.  Kidney Int. 2005;  67 237-247
  • 69 Weyler S, Fulle F, Diekmann M et al.. Improving potency, selectivity, and water solubility of adenosine A1 receptor antagonists: xanthines modified at position 3 and related pyrimido[1,2,3-cd] purinediones.  ChemMedChem. 2006;  1(8) 891-902
  • 70 Osswald H, Schmitz H J, Kemper R. Tissue content of adenosine, inosine and hypoxanthine in the rat kidney after ischemia and postischemic recirculation.  Pflugers Arch. 1977;  371 45-49
  • 71 Nishiyama A, Miyatake A, Aki Y et al.. Adenosine A(1) receptor antagonist KW-3902 prevents hypoxia-induced renal vasoconstriction.  J Pharmacol Exp Ther. 1999;  291 988-993
  • 72 Yao K, Kusaka H, Sato K, Karasawa A. Protective effects of KW-3902, a novel adenosine A1-receptor antagonist, against gentamicin-induced acute renal failure in rats.  Jpn J Pharmacol. 1994;  65 167-170
  • 73 Yao K, Heyne N, Erley C M, Risler T, Osswald H. The selective adenosine A1 receptor antagonist KW-3902 prevents radiocontrast media-induced nephropathy in rats with chronic nitric oxide deficiency.  Eur J Pharmacol. 2001;  414 99-104

Martin J Schreiber Jr.M.D. 

Department of Nephrology and Hypertension, Cleveland Clinic

9500 Euclid Avenue, Desk A51, Cleveland, Ohio 44195

Email: schreim@ccf.org

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