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Tumor Lysis Syndrome

Ramon V. Tiu, M.D.,1,2 Stavros E. Mountantonakis, M.D.,1 Andrew J. Dunbar, B.S.,2 and Martin J. Schreiber, Jr., M.D.3


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. Identication 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 highrisk 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 gelatinaseassociated lipocalin, kidney injury molecule 1), estimated glomerular ltration rate and calculation methods (modication of diet in renal disease and prognostic model (Penn Predictive Score of Tumor Lysis Syndrome) in the identication of high-risk patients, and alternative unexplored mechanisms (asymmetric dimethylarginine and adenosine) to explain renal injury related to TLS.
KEYWORDS: Tumor lysis syndrome (TLS), xanthine oxidase (XO), urate/anion exchanger urate transporter 1 (URAT-1), urate oxidase (UOx), allantoin

umor lysis syndrome (TLS) is a metabolic disorder characterized by hyperuricemia, hyperphosphatemia, hyperkalemia, and hypocalcemia brought about by rapid tumor cell destruction that may result in a variety of musculoskeletal, renal, cardiac, and neurologic manifestations. It is one of the few oncologic emergencies that accounts for a signicant number of morbidity and mortality events if not recognized early and treated appropriately. Although frequently seen after chemotherapy of rapidly proliferating and bulky hematologic malignancies such as acute lymphoblastic leukemia
1 Internal Medicine, Cleveland Clinic, Cleveland, Ohio; 2Experimental Hematology, Cleveland Clinic, Cleveland, Ohio; 3Department of Nephrology and Hypertension, Cleveland Clinic, Cleveland, Ohio. Address for correspondence and reprint requests: Martin J. Schreiber, Jr., M.D., Department of Nephrology and Hypertension, Cleveland Clinic, 9500 Euclid Avenue, Desk A51, Cleveland, Ohio 44195. E-mail:

(ALL) and lymphoma, it has also been described in solid malignanciesparticularly small-cell cancer,1 rhabdomyosarcoma,2 and neuroblastoma.3 The use of newer, more aggressive cytotoxic therapies has seemingly increased the incidence of TLS.

HISTORY The rst description of TLS was made by two Czech k, in 1929.4 Crittenden physicians, Bedrna and Polca 5 and Ackerman made the rst clinicopathologic
Hemostatic Dysfunction in Malignant Hematologic Disorders; Guest Editor, Hau C. Kwaan, M.D., Ph.D. Semin Thromb Hemost 2007;33:397407. Copyright # 2007 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 5844662. DOI 10.1055/s-2007-976175. ISSN 0094-6176.





description of TLS in 1977, when they described a patient with disseminated gastrointestinal carcinoma who developed hyperuricemia, renal failure, and urate crystals in the renal collecting system on autopsy. It has since been described in a variety of clinical situations, either related to therapy (chemotherapy,68 monoclonal antibody,9 radiotherapy,10 corticosteroid therapy11) or not related to therapy (spontaneous)12 for different types of hematologic and solid malignancies.

MOLECULAR MECHANISMS The electrolyte abnormalities and clinical consequences seen in TLS are associated with rapid cellular breakdown in patients with high tumor burden. Various cancers have different growth rates and responsiveness to chemotherapy. Within similar tumor types, variations in tumor behavior are also present. Cytogenetics plays an important role in the prognosis of many cancers and may help stratify more advanced disease within each cancer type. Certain cytogenetic abnormalities are associated with more aggressive disease. For

example, the presence of MYCN gene mutation in neuroblastoma,3 t(8;14)(q24;q32) in L3 type of ALL,13 and inv(16)(p13;q22) in acute myelocytic leukemia (AML)14 are all associated with higher tumor burden and higher incidence of TLS after induction chemotherapy. In TLS, rapid turnover of tumor cells results in a massive release of various intracellular contents (potassium [K], phosphate, nucleic acids, lactate dehydrogenase, etc.) into the systemic circulation. This results in an ionic imbalance within various organs depicted in Fig. 1. Endogenous or exogenous purine nucleotides are catabolized primarily in the liver, but to a lesser extent in the mucosa of the small intestine, and are catalyzed by an iron and molybdenum-containing avoprotein called xanthine oxidase (XO). The nal product of this complex pathway is urate. Urate handling in the renal proximal tubule is composed of a combination of reabsorption, which predominates, and secretion. The recent discovery of various urate transporters including urate/anion exchanger urate transporter 1 (URAT-1),15 efux transporter OATv1,16

Figure 1 Diagram showing urate handling during tumor lysis syndrome as affected by normal human catalytic processes and by pharmacologic interventions. The numerical representation indicates important processes essential in urate production and excretion. (1) Xanthine oxidase (XO) is found in both liver and small intestines. It helps catalyze the conversion of xanthine to urate. This is the primary target of XO inhibitors such as allopurinol, febuxostat, and Y-700. (2) Urate oxidase is found in other animals and converts urate into a more water-soluble form called allantoin. (3) 5-hydroxyisourate hydrolase/2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline (OHCU) decarboxylase are recently elucidated enzymatic pathways leading to the formation of a racemic form of allantoin. (4) Urate/anion exchanger urate transporter 1 (URAT-1) is a newly discovered renal proximal tubule receptor responsible for urate reabsorption. OAT, organic anion transporter.



efux pump MRP4,17 Tamm-Horsfall protein/uromodulin, and UAT/galectin-918 has revolutionized our understanding of urate regulation within the kidney. Among these transporters, URAT-1 is the one best studied in humans. URAT-1, or SLC22A12, is a recently discovered organic protein transporter located in the apical membrane of proximal tubule cells in humans and other mammals that is critical in urate reabsorption. It belongs to the SLC22 family and consists of 555 amino acid residues and 12 predicted transmembrane domains with large hydrophilic loops between the rst and second as well as the sixth and seventh transmembrane domains and intracellular NH2 and COOH terminals. URAT-1 transports urate across the apical membrane in exchange with anions. Certain medications such as losartan, sulnpyrazone, probenecid, benzbromarone, and furosemide use this transporter system to promote uricosuria, whereas medications or substances such as pyrazinamide, nicotinic acid, and lactate inhibit URAT-1, leading to hyperuricemia.15 Urate then moves across the basolateral membrane into the blood by way of the organic anion transporter (OAT).15,19,20 This multispecic OAT, initially isolated from rat kidney, was found to be important in urate reabsorption. The best studied OAT transporters in humans are OAT1 and OAT3, which are both found in the basolateral membrane of the proximal renal tubule, where they participate in organic anion/ dicarboxylate exchange.21,22 New transporters responsible for urate secretion also have been elucidated recently. They come in the form of efux transporters, namely OATv1 and MRP4, and are found in the proximal tubules. OATv1 belongs to the SLC17 glutamate transporter family (rst isolated in porcine kidney), whereas MRP4 is an adenosine triphosphate (ATP) dependent unidirectional efux pump.16 The human counterpart has not been determined for OATv1 but MRP4 is expressed in both human renal proximal apical cells and hepatocytes. Hyperuricemia is a key factor in the pathogenesis of TLS. Similar to the pathophysiology involved in hyperuricemia in gout, the underlying problem relates to underexcreters and overproducers of urate. Mutation of the SLC22A12 transporter can cause idiopathic renal hyperuricosuria and has been implicated in the development of acute hyperuricemic nephropathy after strenuous exercise. The knowledge of newer urate transporters and polymorphisms maybe key in understanding the propensity of certain individuals for TLS, and will allow us to understand better the mechanism of action of various medications in affecting urate metabolism in the molecular level.15 Most mammals, with the exception of humans, retain their ability to convert urate to a more soluble substance in the form of allantoin. This process is catalyzed by urate oxidase (UOx) or uricase. Our inabil-

ity to produce this enzyme stems from a point mutation in a sequence of DNA that results in a stop codon also known as a nonsense mutation in exon 2 of the UOX gene that occurred in our primate ancestor $15 million years ago.23 This evolutionary event helps explain why urate levels in humans are 10 to 50 times higher in comparison to those in other mammals, and thus elucidates our greater propensity to develop gout and even TLS. More recently, two additional pathways leading to the formation of allantoin have paved the way to our understanding of urate metabolism. Through phylogenetic genomic comparison, two genes responsible for encoding proteins that catalyze two sequential steps following urate oxidation to 5-hydroxyisourate (HIU) were discovered. Hydrolysis of HIU results in 2-oxo-4hydroxy-4-carboxy-5-ureidoimidazoline (OHCU) and decarboxylation of OHCU results in S-( )-allantoin. Urate oxidation produces a racemic allantoin that is formed in a time scale of hours by the oxidation of urate, whereas this newly discovered enzymatic pathway produces dextrorotatory allantoin from urate on a time scale of seconds. Although humans are also devoid of the HIU/OHCU pathways from evolutionary-dened inactivating mutations, the importance of such a discovery may facilitate the development of newer enzymatic agents to treat hyperuricemia in gout or TLS.24

CLINICAL EVENTS The majority of the clinical manifestations related to TLS occur as a result of electrolyte imbalance related to tumor cell breakdown. Cairo and Bishop25 devised a classication system to help standardize the denition of TLS. Although an approach that grades severity of TLS has clinical merit, small changes in serum creatinine (SCr) may impart signicantly greater morbidity risk than appreciated previously.

HYPERKALEMIA K is the main intracellular cation regulated through the Na-K ATPase system. Its normal regulation is critical in maintaining the normal resting membrane potential of various cells: skeletal muscle, neural and cardiac muscle.26,27 Hyperkalemia is dened as serum K level > 6.0 mEq/L or 25% increase from baseline 3 days before or 7 days after the initiation of chemotherapy.25 Hyperkalemia causes cardiac arrhythmia, one of the most serious complications related to TLS. It is usually seen 6 -72 hours post-chemotherapy. Neuromuscular and cardiac tissues are most susceptible to changes in K level. Neuromuscular symptoms may include fatigue, muscle cramps, anorexia, paresthesias, and irritability. In the cardiac tissue, depending on the degree of hyperkalemia, a variety of electrocardiographic changes can occur, including peaked T wave (> 5 mm) with serum




K level of 6 to 7 mEq/L, QRS complex widening and smaller amplitude of P wave with serum K of 7 to 8 mEq/L, fusion of QRS complex with T wave forming sine waves with serum K of 8 to 9 mEq/L, and ultimately atrioventricular dissociation, ventricular tachycardia, or ventricular brillation and death when the serum K level increases above 9 mEq/L.26 Most symptoms appear when serum K level are > 6.0 mEq/L. Coexisting renal failure, metabolic acidosis, and Ksparing medications can worsen hyperkalemia and must be observed closely and corrected. Pseudohyperkalemia can also sometimes occur in patients with AML and ALL exhibiting hyperleukocytosis (> 100,000/mL). The falsely elevated K level occurs as a result of mechanical lysis of white blood cells (WBCs) during phlebotomy or ionic shifts following coagulation of blood in the vial. It is a benign process and plasma K measurements may be a more accurate indicator of the true blood level.28

specialized transporters are found within intestinal epithelial cells and vascular smooth muscle cells, and play a minor role in urate elimination. This makes the kidney the main organ affected by high urate levels. One of the most dreaded complications related to TLS is acute kidney injury (AKI) from urate nephropathy. Uric acid has a pKa of 5.5 and is soluble in its ionized form at a pH of 7.0. Dehydration brought about by nausea, vomiting, diarrhea, and diabetes insipidus are commonly caused by the underlying malignancy and chemotherapy, resulting in low urine ow rates. The low urine ow rates coupled with heavy cell turnover promotes urate precipitation in the distal nephron during physiologic acidication at a pH of < 5.5. A urine uric acid to creatinine ratio > 1 is highly suggestive of uric acid nephropathy, whereas values < 0.6 suggest an alternate etiology for AKI.

HYPERPHOSPHATEMIA AND HYPOCALCEMIA Hyperphosphatemia is dened as serum phosphate ! 4.5 mg/dL or 25% increase from baseline, and hypocalcemia is dened as corrected serum calcium level 7.0 mg/dL or 25% decrease from baseline, 3 days before or 7 days after the initiation of chemotherapy.25 Both electrolyte abnormalities usually develop 24 to 48 hours after chemotherapy. Several mechanisms contribute to elevation in phosphate levels in TLS, including increased endogenous release as a result of massive tumor breakdown, impaired glomerular ltration secondary to preceding urate nephropathy/nephrocalcinosis-induced renal failure, and decreased ability of malignant cells to use available endogenous phosphate. Symptoms related to hyperphosphatemia are manifested indirectly through its effect on calcium. Calcium phosphate precipitates when the calcium and phosphate solubility product is exceeded, leading to both hypocalcemia and organ damage related to calcium deposition. Hypocalcemia can result in both neurologic and cardiac symptoms. Neurologic manifestations include muscle cramps, tetany, and/ or seizures. Cardiac manifestations include asymptomatic prolongation of QT interval and depressed cardiac contractility. Calcium phosphate precipitation can lead to acute nephrocalcinosis.

MANAGEMENT The keys to the successful management of TLS include identication of patients at high risk for developing TLS, initiation of prevention strategies, and the early identication of AKI prior to the traditional increase in SCr. All play a role in limiting the extent of TLS-related AKI. A new scoring system for identifying TLS patients in AML patients undergoing induction has been devised and validated.29 Several newer agents currently are available or are undergoing trials that could be potentially useful for the treatment of TLS. Special problems for the treating physician include patients with urine ow rates < 100 cm3/mL/h, high-dose loop diuretic requirements, intravascular volume depletion, or allergies to XO medications.

PREVENTION Modiable Risk Factors


HYPERURICEMIA Hyperuricemia is dened as serum uric acid ! 8.0 mg/d: or 25% increase from baseline 3 days before or 7 days after the initiation of chemotherapy.25 This usually develops 48 to 72 hours after therapy and results in a variety of complications.28 The major route of urate clearance is through the proximal renal tubule, mediated by specialized transporters such as URAT-1.15 Similar

As mentioned, patients with cancers are at high risk for volume depletion. A careful history and physical examination can help identify dehydrated patients and can help guide physicians in appropriate volume replacement. Similarly, patients receiving nephrotoxic chemotherapy such as cisplatin should be well hydrated, with urine ow rates > 100 to 150 mL/m2/h prior to administration of chemotherapy.

The concomitant intake of nephrotoxic agents and other medications that may exacerbate the underlying electrolyte imbalance should be discontinued promptly, if possible. Examples of nephrotoxic drugs include antimicrobials such as aminoglycosides, amphotericin



B, and nonsteroidal anti-inammatory drugs. Other medications such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and other K-sparing diuretics potentially should be discontinued because they may worsen hyperkalemia. Pyrazinamide and nicotinic acid, through inhibition of URAT1, may promote higher tubular urate levels that can lead to crystallization, and therefore must also be avoided.15

dehydrogenase, WBC, male gender, and a background of chronic myelomonocytic leukemia that subsequently transformed to AML are signicant TLS predictors. Subsequent multivariate analysis showed that SCr levels, serum urate levels, and male gender remained signicant predictors and all three variables were used to come up with a scoring system with scores ranging from 0 to 10. The higher the PPS-TLS score, the higher the specicity and probability of TLS (0.99 specicity and 78% probability of TLS).29

Nonmodiable Risk Factors


Patients with certain cytogenetic abnormalities associated with specic malignancies are predisposed to TLS. Examples include the MYCN gene mutation in neuroblastoma,3 t(8,14) in ALL,13 and inv(16) in AML.14 These patients must be observed carefully and administered TLS prophylaxis. Certain polymorphisms of specic urate transporters may also inuence TLS development and may help explain the development of TLS in patients who received appropriate intravenous (IV) hydration and XO inhibitor prophylaxis prior to chemotherapy.

TREATMENT Recent advancements in the treatment options of TLS have drastically changed the way it is managed. Hydration and effective urine ow rates remain a cornerstone of TLS prevention and treatment. As depicted in the Fig. 2, new-generation medications have evolved during the last decade that are safer and more efcacious alternatives for both prophylaxis and primary treatment. Specic attributes of both old and new agents are described in Table 1.

The Penn Predictive Score of Tumor Lysis Syndrome (PPS-TLS) is a recently devised prognostic scoring system based on a single-institution experience of 194 AML patients receiving induction chemotherapy. It demonstrated by univariate analysis that elevated prechemotherapy SCr, serum urate, serum lactate

Hydration IV uid generally is administered 48 hours prior to chemotherapy. The volume expansion brought about by hydration helps decrease extracellular phosphate, K, and urate levels. Hydration also improves the rate of renal blood ow, producing diuresis of 150 to 300 mL/h and protecting against tubular crystallization.28,30

Figure 2 A time line describing the development and clinical application of different types of xanthine oxidase inhibitors and urate oxidase. We made a delineation of old- (allopurinol and native uricase) and new- (febuxostat, Y-700, polyethylene glycol [PEG] -uricase, rasburicase) generation urate-lowering agents based on their original time of development. The delineation is important because it depicts the recent advances in the production of more efcacious and safer drugs for hyperuricemia, gout, and possibly tumor lysis syndrome (TLS).


Table 1 Pharmacologic Agents Used in Lowering Urate Levels

Route of Administration Side Effects Efcacy Studies



Xanthine oxidase

inhibitors Old PO/IV Effectively reduces uric acid in a dose-dependent manner PO PO headache, gout are, " CRP, " CK, " AST pain, atulence Diarrhea, abdominal pain, Abdominal cramps abdominal Safer in renal failure Better hypouricemic effect; safe in renal failure Yamada et al,36 2004; Fukunari et al,37 2004 Becker et al,33,34 2004 and 2005; Mayer et al,35 2005 acute gouty attack; can worsen renal failure Rash, fever hepatotoxicity, De Conti and Calabresi,32 1966


2 to 3/1430 h




23.540.2 h


1.315.8 h


Urate oxidase IV hemolysis in G6PD, antibody formation IV antibody formation IM Local irritation at injection site IM Local irritation at injection site IV Urticaria at infusion site No antibody formation; no allergic reactions; longer half life No antibody formation; no allergic reactions; longer half life No antibody formation; no allergic reactions; longer half life None Bomalaski et al,45 2002 Chua et al,44 1988 Allergic reaction, anaphylaxis, hemolysis in G6PD, Allergic reaction, anaphylaxis Effectively transforms urate into soluble allantoin Longer half life Chanteclair and Olive,38 1974; Masera et al,39 1982 Pui et al,40 2001;


Native uricase/

13 h






1824 h

Pegylated uricase

PEG uricase




PEG 20


10.519.9 d

PO, orally; IV, intravenously; CRP, C-reactive protein; CK, creatine kinase; AST, aspartate aminotransferase; G6PD, glucose-6-phosphate dehydrogenase; PEG, polyethylene glycol; IM, intramuscularly.



The choice of IV uid is still being debated, although the traditional goal is to induce alkaline diuresis through the use of dextrose 5%/0.457 saline plus 50 to 100 mEq of NaHCO3 to help eliminate urate when allopurinol is administered. In certain patients, alkalinization (urine pH 6.5 to 7.5) may increase precipitation of calcium phosphate product in the renal tubules and interfere with renal tubular phosphate reabsorption. Usually alkalinization is not needed when rasburicase is used. AKI in TLS can also result from acute nephrocalcinosis, which can be exacerbated by alkaline diuresis.28

XO INHIBITORS Allopurinol, the earliest and the prototype of all XO inhibitors, was rst approved for clinical use by the U.S. Food and Drug Administration (FDA) in 1966 to treat patients with gout and is still considered as one of the most important drug discoveries in the 20th century.31 An isomer of hypoxanthine, it is rapidly metabolized by XO to its metabolite, oxypurinol. Both allopurinol and oxypurinol irreversibly inhibit XO either by competitive or noncompetitive inhibition. Although it comes in two preparations, oral (PO) and IV, the efcacy is similar. It has a variety of drug interactions, including increasing the levels of cyclophosphamide and warfarin. The rst study looking at its use for TLS was in 1966, in which 33 patients with chronic leukemia, acute leukemia, and lymphoma had a dose-related reduction in uric acid after treatment with allopurinol.32 It has since formed the backbone of both TLS prevention and treatment. More recently, two new investigational agents, namely febuxostat (also known as TEI-6720 or TMX67)33,34 and Y700,35,36 were synthesized and found to be efcacious for patients with hyperuricemia. Febuxostat is a novel nonpurine, selective XO antagonist discovered in 2004. In a clinical trial comparing febuxostat versus allopurinol in patients with hyperuricemia and gout, more patients taking febuxostat (53% for those taking 80 mg PO daily for 52 weeks and 64% for those taking 120 mg PO every day for 52 weeks) reached the primary endpoint of serum urate reduction of less than 6.0 mg/dL (360 mmol/L) in comparison to only 21% for allopurinol. Given that only 0.5 to 1% of either agent undergoes renal clearance, they are both safe in patients with renal insufciency.33,37 This therapy will be ideal in patients at high risk of TLS because AKI as a result of drugs or the primary disease occurs frequently in TLS patients. Similarly, Y700 is another new-generation XO inhibitor that belongs to the 1phenylpyrazol group. It is more potent than allopurinol in reducing urate levels, is similar to febuxostat, and is eliminated primarily through the hepatic system, and thus can be safely used in renal failure.35,36 Both agents are not currently approved by the FDA and have not been investigated in TLS.

URATE OXIDASE The earliest use of uricase puried from Aspergillus avus can be traced back to France and Italy in the 1970s.38 Uricase cDNA was cloned subsequently from the same fungus and subcloned into a more efcient vector in the form of Saccharomyces cerevisiae. The enzyme product from the yeast became known as rasburicase. Rasburicase is a 34-kd tetrameric protein that undergoes elimination independent of the renal and hepatic system through a mechanism called peptide hydrolysis.39 In a study of 131 children, adolescents, and young adults with newly diagnosed leukemia or lymphoma, who either presented with abnormally high plasma uric acid concentrations or had large tumor cell burdens, IV rasburicase at 0.15 or 0.20 mg/kg for 5 to 7 consecutive days produced a rapid and sharp decrease in plasma uric acid concentrations from 9.7 to 1 mg/dL (p 0.0001) in the 65 patients who presented with hyperuricemia, and from 4.3 to 0.5 mg/dL (p 0.0001) in the remaining 66 patients. SCr levels decreased signicantly after 1 day of treatment in patients with or without hyperuricemia at diagnosis (p 0.0003 and p 0.02, respectively).40 In clinical trials, rasburicase is superior to allopurinol. The mean uric acid area under the time concentration curve (0 to 96 hours) was 128 70 mg/ dL/h for the rasburicase group and 329 129 mg/dL/ h for the allopurinol group (p < 0.0001). The rasburicase versus allopurinol group experienced a 2.6-fold (95% condence interval, 2.0 to 3.4) less exposure to uric acid. Patients randomly assigned to rasburicase compared with allopurinol achieved an 86 versus 12% reduction (p < 0.0001) of initial plasma uric acid levels at the rst 4 hours of therapy. Given that rasburicase causes enzymatic degradation of uricase in blood samples at room temperature, uric acid levels may be falsely low. Despite its great potential for TLS, rasburicase and native uricase are highly immunogenic, eliciting formation of antibodies to the enzyme in 17 of 121 patients in one large study, making it difcult to prescribe on a regular basis except in the most mitigating situations.40 Hypersensitivity and anaphylactic reactions have also been reported, which contraindicates its use in patients with asthma, those with a high risk of hypersensitivity reactions, and patients with glucose-6-phosphate dehydrogenase deciency. This limitation has motivated investigators to develop a less antigenic variant of uricase. The products of these investigations are puricase (Savient Pharmaceuticals; East Brunswick, NJ) and uricase PEG 20. Both drugs are covalently conjugated with polyethylene glycol (PEG) to help reduce their antigenicity and also prolong their half-lives. Puricase is derived from a porcine source, whereas uricase PEG 20 comes from Escherichia coli; phase I studies are currently underway for both drugs.4144




RENAL REPLACEMENT THERAPY Early initiation of renal replacement therapy (RRT) has been advocated to control volume status, remove purine byproducts, and decrease the impact of hyperkalemia, hyperphosphatemia (> 15 mg/dL), and hypocalcemia.45 Patients with signicant tumor burden may warrant intermittent hemodialysis alone or in conjunction with continuous renal replacement therapy (i.e., continuous venovenous hemodialysis [CVVHD] or continuous venovenous hemoltration).46 Clinical scenarios meriting RRT include refractory electrolyte imbalance with or without symptoms and presence of comorbidities such as congestive heart failure or underlying chronic kidney disease (CKD) that limit the use of IV uids and other conservative measures.45 The clearance of solutes is highly variable and depends on the specic prescription for each form of RRT. A comparative urate clearance in patients with TLS shows superiority of CVVHD over continuous arteriovenous hemoltration (CAVH; 45 mL/min for CVVHD versus 39 mL/min for CAVH). Peritoneal dialysis (PD)47 is an alternative RRT for patients with TLS,46 but is inferior to HD in clearing urate (70 to 145 mL/min for HD versus 6.7 to 9.5 mL/min for PD) and phosphate.48

NEW INSIGHTS Identication of Patients with Reduced Glomerular Filtration Rate SCr has traditionally been used as the simplest means of assessing renal function. It is, however, unreliable at the extremes of age and glomerular ltration rate (GFR). The historical gold standard for assessing renal function is either inulin or iothalamate clearance. The estimated GFR Modication of Diet on Renal Disease [MDRD] calculation method) may offer a more accurate assessment of renal function versus SCr for patients with GFR > 20 to < 70 mL/ min/1.73 m2. However, this formula is less accurate in hospitalized patients with AKI. Biomarkers are under investigation in a variety of clinical scenarios to determine how well they perform as surrogates of renal function. In the future, biomarkers may facilitate earlier detection of predictable AKI in patients at risk for TLS. The MDRD formula has gained wide acceptance in the estimation of GFR.49 It was found to be superior to the Cockroft-Gault and Nankivell equation in estimating GFR in a variety of settings including patients with multiple myeloma50; those older than 65 years51; patients with CKD,52 malnutrition,53 or inammatory disease54; and renal transplant recipients.52,55 MDRD relies on a variety of parameters including the patients SCr, age, sex, and race to estimate GFR.

Biomarkers Human cystatin C is a 13-kd cysteine protease inhibitor consisting of 120 amino acid residues released by most human nucleated cells. It is freely ltered by the glomerulus and almost completely reabsorbed and catabolized by the proximal tubular cells as opposed to creatinine (ltration and secretion). Cystatin C appears to predict renal function better than creatinine in AKI.56 It was found to be a more sensitive indicator of GFR compared with SCr in cancer patients,57 comparable to SCr for predicting carboplatin clearance,58 superior to SCr in predicting topotecan clearance,59 and equal to MDRD in assessing GFR in kidney transplant recipients. Patients with underlying renal dysfunction or who have reduced renal clearance are at higher risk of developing TLS. There has been little experience in the assessment of cystatin C in the estimation of GFR in patients with bulky tumors undergoing chemotherapy. It may be useful to measure cystatin C as a marker to predict development of TLS. Neutrophil gelatinaseassociated lipocalin (NGAL) is a 25-kd protein bound to gelatinase, and is reabsorbed by the proximal tubule in AKI. NGAL is induced rapidly in the thick ascending limb and can be measured in the urine. The value of urinary NGAL can increase $100-fold in patients with AKI.60 Kidney injury molecule 1 (KIM-1) is an orphan transmembrane receptor, induced to signicantly elevated levels in the proximal tubule after ischemic or nephrotoxic injury. Urinary KIM-1 can distinguish ischemic AKI from prerenal azotemia and CKD.61 Because biomarkers may peak at different points following AKI, a combination of several biomarkers may be needed to predict adequately the development of AKI and monitor renal status with AKI. Additional work in this area is ongoing.

Alternative Pathophysiologic Mechanisms of Renal Injury Related to TLS


Nitric oxide (NO) is important in a variety of physiologic and pathologic processes. It is produced in a multitude of cells, including endothelial cells in blood vessels and renal tubular cells. Reduction in NO causes vasoconstriction and has been implicated in diseases such as coronary artery disease, and pulmonary and renal hypertension (HTN). NO is synthesized from L-arginine through a process catalyzed by nitric oxide synthase (NOS).62,63 In 1992, a specic inhibitor of NOS was discovered in the form of asymmetric dimethylarginine (ADMA). ADMA is synthesized in the nucleolus in virtually all cells in the body through a process catalyzed by protein methyltransferase. A hepatic enzyme called dimethylarginine dimethylaminohydrolase (DDAH) degrades ADMA into citrulline and dimethylamine,



and is the chief means of ADMA excretion; alternatively, a signicant, albeit smaller proportion (50 mm/d), is excreted through the kidneys.63 ADMA levels increase when DDAH is low and when one or more of the following factors is present: diabetes mellitus, tobacco use, hyperhomocysteinemia, preeclampsia, hypothyroidism, end-stage renal disease, oxidative stress, and estrogen deciency. Elevated ADMA levels increase renal vascular resistance and reduce renal plasma ow.64,65 There is growing evidence to suggest that hyperuricemia can cause vascular endothelial injury that predisposes one to essential HTN, renovascular HTN, and cardiovascular disease.6668 The exact mechanism of how urate induces such renovascular processes is currently incompletely understood.67 Given that ADMA is abundant in endothelial cells, it would be valuable to determine whether urate vasculopathy is mediated through ADMA. In TLS, renal failure generally is associated with urate precipitation and acute nephrocalcinosis, but there are cases that cannot be explained purely by either of these processes. Given that HTN is not an uncommon event in TLS, and that there are unclear cases of renal failure in TLS, it may be reasonable to investigate the role of urate in inducing increased renal vascular resistance and decreased renal plasma ow as potential alternative mechanisms of renal injury during TLS. Whether ADMA serves as a mediator of urate injury or is an independent pathogenetic factor in TLS is currently not known. It is important to understand the relationship between ADMA, renal injury, urate levels, and TLS given that targeted therapy for ADMA may pave the way for the prevention of morbidity and mortality related to such pathogenetic processes.

media.73 This new nding is critical in understanding the mechanism of how certain etiologic agents cause renal injury, and in developing compounds that may prevent and treat it. There is no current study examining the role of adenosine in the renal injury that results from TLS and whether KW-3902 will provide renoprotective effects.

ABBREVIATIONS ADMA asymmetric dimethylarginine AKI acute kidney injury AML acute myelocytic leukemia CAVH continuous arteriovenous hemoltration CKD chronic kidney disease CVVHD continuous venovenous hemodialysis DDAH dimethylarginine dimethylaminohydrolase HIU 5-hydroxyisourate HTN hypertension KIM-1 kidney injury molecule 1 MDRD Modication of Diet in Renal Disease (method) NGAL neutrophil gelatinase associated lipocalin NO nitric oxide OAT organic anion transporter OHCU 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline PD peritoneal dialysis PEG polyethylene glycol PPS-TLS Penn Predictive Score of Tumor Lysis Syndrome RRT renal replacement therapy SCr serum creatinine TLS tumor lysis syndrome UOx urate oxidase URAT-1 urate/anion exchanger urate transporter 1 XO xanthine oxidase
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Adenosine is a normal byproduct of ATP hydrolysis and other cellular energy-dependent pathways. The level increases during episodes of low oxygen availability, ultimately leading to vasoconstriction.69,70 In the renal system, adenosine is produced primarily in the renal tubular epithelial cells and reaches the renal vasculature via the interstitial space. During episodes of ischemia, there is a corresponding increase in adenosine levels and decline in renal blood ow. Similarly, adenosine levels seem to increase in conjunction with norepinephrine and angiotensin II during episodes of hypoxia.71 A new compound that selectively antagonizes adenosine A1 receptors was synthesized recently. It currently is known as KW-3902 [8-(noradamantan-3-yl)-1,3-dipropylxanthine]. In animal studies, KW-3902 attenuated hypoxia-induced reduction in renal blood ow. When studied in a variety of clinical setting, KW-3902 has demonstrated renoprotective effects against gentamicin72 and radiocontrast









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