Tumor Lysis Syndrome

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
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 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 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.
KEYWORDS: Tumor lysis syndrome (TLS), xanthine oxidase (XO), urate/anion
exchanger urate transporter 1 (URAT-1), urate oxidase (UOx), allantoin
T
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 significant 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
(ALL) and lymphoma, it has also been described in
solid malignancies—particularly small-cell cancer,1
rhabdomyosarcoma,2 and neuroblastoma.3 The use of
newer, more aggressive cytotoxic therapies has seemingly
increased the incidence of TLS.
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: [email protected].
Hemostatic Dysfunction in Malignant Hematologic Disorders; Guest
Editor, Hau C. Kwaan, M.D., Ph.D.
Semin Thromb Hemost 2007;33:397–407. Copyright # 2007 by
Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY
10001, USA. Tel: +1(212) 584–4662.
DOI 10.1055/s-2007-976175. ISSN 0094-6176.
HISTORY
The first description of TLS was made by two Czech
physicians, Bedrna and Polca´k, in 1929.4 Crittenden
and Ackerman5 made the first clinicopathologic
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SEMINARS IN THROMBOSIS AND HEMOSTASIS/VOLUME 33, NUMBER 4
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,6–8 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
2007
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 [Kþ], 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 flavoprotein called xanthine oxidase (XO). The final
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 efflux 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.
TUMOR LYSIS SYNDROME/TIU ET AL
efflux 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 first
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, sulfinpyrazone, 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 multispecific 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 efflux transporters, namely OATv1 and MRP4,
and are found in the proximal tubules. OATv1 belongs
to the SLC17 glutamate transporter family (first isolated
in porcine kidney), whereas MRP4 is an adenosine
triphosphate (ATP) –dependent unidirectional efflux
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-( þ )-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-defined 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
classification system to help standardize the definition of
TLS. Although an approach that grades severity of TLS
has clinical merit, small changes in serum creatinine
(SCr) may impart significantly greater morbidity risk
than appreciated previously.
HYPERKALEMIA
Kþ is the main intracellular cation regulated through the
Naþ-Kþ 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 defined as serum Kþ 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 Kþ
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
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SEMINARS IN THROMBOSIS AND HEMOSTASIS/VOLUME 33, NUMBER 4
Kþ level of 6 to 7 mEq/L, QRS complex widening
and smaller amplitude of P wave with serum Kþ of 7 to
8 mEq/L, fusion of QRS complex with T wave forming
sine waves with serum Kþ of 8 to 9 mEq/L, and
ultimately atrioventricular dissociation, ventricular
tachycardia, or ventricular fibrillation and death when
the serum Kþ level increases above 9 mEq/L.26 Most
symptoms appear when serum Kþ level are > 6.0 mEq/L.
Coexisting renal failure, metabolic acidosis, and Kþsparing 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 Kþ 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 Kþ measurements
may be a more accurate indicator of the true blood level.28
HYPERPHOSPHATEMIA AND
HYPOCALCEMIA
Hyperphosphatemia is defined as serum phosphate 4.5
mg/dL or 25% increase from baseline, and hypocalcemia
is defined 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 filtration 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.
HYPERURICEMIA
Hyperuricemia is defined 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
2007
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 flow rates. The
low urine flow rates coupled with heavy cell turnover
promotes urate precipitation in the distal nephron during physiologic acidification 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.
MANAGEMENT
The keys to the successful management of TLS include
identification of patients at high risk for developing
TLS, initiation of prevention strategies, and the early
identification 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
flow rates < 100 cm3/mL/h, high-dose loop diuretic
requirements, intravascular volume depletion, or allergies to XO medications.
PREVENTION
Modifiable Risk Factors
HYDRATION STATUS
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 flow rates > 100 to 150 mL/m2/h prior to administration of chemotherapy.
MEDICATIONS
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
TUMOR LYSIS SYNDROME/TIU ET AL
B, and nonsteroidal anti-inflammatory drugs. Other
medications such as angiotensin-converting enzyme
inhibitors, angiotensin receptor blockers, and other
Kþ-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 significant TLS predictors. Subsequent multivariate analysis showed
that SCr levels, serum urate levels, and male gender
remained significant 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 specificity and probability of TLS (0.99
specificity and 78% probability of TLS).29
Nonmodifiable Risk Factors
MALIGNANCIES/URATE TRANSPORTERS
Patients with certain cytogenetic abnormalities associated
with specific 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 specific
urate transporters may also influence 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.
PROGNOSTIC SCORING SYSTEMS
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
TREATMENT
Recent advancements in the treatment options of TLS
have drastically changed the way it is managed. Hydration and effective urine flow 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 efficacious
alternatives for both prophylaxis and primary treatment.
Specific attributes of both old and new agents are
described in Table 1.
Hydration
IV fluid generally is administered 48 hours prior to
chemotherapy. The volume expansion brought about
by hydration helps decrease extracellular phosphate,
Kþ, and urate levels. Hydration also improves the rate
of renal blood flow, 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 efficacious and safer drugs for hyperuricemia, gout, and possibly tumor lysis
syndrome (TLS).
401
IV
IM
IM
IV
dose-dependent
worsen renal failure
Urticaria at infusion site
injection site
longer half life
no allergic reactions;
No antibody formation;
longer half life
no allergic reactions;
longer half life
No antibody formation;
no allergic reactions;
injection site
Local irritation at
No antibody formation;
Local irritation at
antibody formation
hemolysis in G6PD,
Longer half life
allantoin
antibody formation
Allergic reaction, anaphylaxis,
urate into soluble
hemolysis in G6PD,
Effectively transforms
in renal failure
Allergic reaction, anaphylaxis
effect; safe
" CK, " AST
Better hypouricemic
pain, flatulence
Diarrhea, abdominal pain,
headache, gout flare, " CRP,
Safer in renal failure
Abdominal cramps abdominal
manner
uric acid in a
Effectively reduces
Efficacy
acute gouty attack; can
Rash, fever hepatotoxicity,
Side Effects
None
Bomalaski et al,45 2002
Chua et al,44 1988
Pui et al,40 2001;
Masera et al,39 1982
Olive,38 1974;
Chanteclair and
Mayer et al,35 2005
2004 and 2005;
Fukunari et al,37 2004
Becker et al,33,34
Yamada et al,36 2004;
Calabresi,32 1966
De Conti and
Studies
PO, orally; IV, intravenously; CRP, C-reactive protein; CK, creatine kinase; AST, aspartate aminotransferase; G6PD, glucose-6-phosphate dehydrogenase; PEG, polyethylene glycol; IM, intramuscularly.
Puricase
10.5–19.9 d
8d
Uricase
PEG 20
5d
18–24 h
PEG uricase
Pegylated uricase
Rasburicase
IV
PO
PO
PO/IV
Route of
Administration
SEMINARS IN THROMBOSIS AND HEMOSTASIS/VOLUME 33, NUMBER 4
New
uricozyme
Native uricase/
Old
Urate oxidase
1–3 h
1.3–15.8 h
Febuxostat
(TMX-67)
23.5–40.2 h
2 to 3/14–30 h
T1/2
Y700
New
Oxypurinol
Allopurinol/
inhibitors
Old
Xanthine oxidase
Agent
Table 1 Pharmacologic Agents Used in Lowering Urate Levels
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TUMOR LYSIS SYNDROME/TIU ET AL
The choice of IV fluid 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 first 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 efficacy is similar. It
has a variety of drug interactions, including increasing the
levels of cyclophosphamide and warfarin. The first 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 efficacious 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 insufficiency.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 purified from Aspergillus
flavus 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 efficient
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 ¼ 0.0001) in the 65
patients who presented with hyperuricemia, and from
4.3 to 0.5 mg/dL (p ¼ 0.0001) in the remaining 66
patients. SCr levels decreased significantly after 1 day
of treatment in patients with or without hyperuricemia at diagnosis (p ¼ 0.0003 and p ¼ 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% confidence 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 first 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 difficult
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 deficiency.
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.41–44
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SEMINARS IN THROMBOSIS AND HEMOSTASIS/VOLUME 33, NUMBER 4
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 significant tumor burden may
warrant intermittent hemodialysis alone or in conjunction with continuous renal replacement therapy (i.e.,
continuous venovenous hemodialysis [CVVHD] or
continuous venovenous hemofiltration).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 fluids and other conservative measures.45 The
clearance of solutes is highly variable and depends on
the specific prescription for each form of RRT. A
comparative urate clearance in patients with TLS
shows superiority of CVVHD over continuous arteriovenous hemofiltration (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
Identification 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 filtration rate
(GFR). The historical gold standard for assessing
renal function is either inulin or iothalamate clearance. The estimated GFR Modification 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 inflammatory
disease54; and renal transplant recipients.52,55 MDRD
relies on a variety of parameters including the patient’s
SCr, age, sex, and race to estimate GFR.
2007
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 filtered by the glomerulus and almost completely reabsorbed and catabolized by
the proximal tubular cells as opposed to creatinine (filtration 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
gelatinase–associated
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 significantly 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
ASYMMETRIC DIMETHYLARGININES
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 specific 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,
TUMOR LYSIS SYNDROME/TIU ET AL
and is the chief means of ADMA excretion; alternatively, a significant, 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 deficiency.
Elevated ADMA levels increase renal vascular
resistance and reduce renal plasma flow.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.66–68 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 flow 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.
KW-3902
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 flow. 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 flow. When studied in a variety of
clinical setting, KW-3902 has demonstrated renoprotective effects against gentamicin72 and radiocontrast
media.73 This new finding 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 hemofiltration
CKD
chronic kidney disease
CVVHD continuous venovenous hemodialysis
DDAH
dimethylarginine dimethylaminohydrolase
HIU
5-hydroxyisourate
HTN
hypertension
KIM-1
kidney injury molecule 1
MDRD
Modification 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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