tumor lysis syndrome in malignancies and acute kidney injury diagnosis and management

2. AKI associated with malignancies
 AKI is common in hospitalized patients with cancer and is
associated with increased length of stay and hospital costs
 in a large Danish study including 1.2 million cancer
patients the incidence of AKI was was 17.5% in one year,
and 27% in 5 years
 There are many causes of AKI in cancer patients which
may result from cancer itself, treatment of cancer, or
associated conditions such as sepsis

7. Defenition
 Tumor lysis syndrome (TLS) is an oncologic
emergency caused by massive tumor cell
lysis with the release of large amounts of
potassium, phosphate, and nucleic acids
into the systemic circulation resulting in
hyperkalemia, hyperphosphatemia,
hyperuricemia, hypocalemia, and renal
failure

8. Epidemiology
 The exact incidence of tumor lysis syndrome is unknown. It varies among
different malignancies; bulky, aggressive, treatment-sensitive tumors are
associated with higher incidence of tumor lysis syndrome.
 In patients with intermediate-grade or high-grade non-Hodgkin lymphomas,
laboratory evidence of tumor lysis syndrome occurred in (42%) while
symptomatic clinical syndrome developed in (6%).
 In children with acute leukemia receiving induction chemotherapy,
laboratory evidence of tumor lysis syndrome occurred in 70% of cases, but
clinically significant tumor lysis syndrome occurred in only 3% of cases
 Despite routine urate oxidase therapy, TLS develops in 10–50% of patients with
with high-grad hematological malignancies (acute leukemia, Burkitt’s
lymphoma, or other high-grade non-Hodgkin’slymphoma)

10. Prognosis
 Prognosis in tumor lysis syndrome depends on the underlying malignancy:
 In patients with a hematologic malignancy, the mortality rate for tumor lysis
syndrome is approximately 15%.
 in patients with solid malignancies the mortality is 36%.
 This higher than expected mortality may be secondary to decreased
recognition of the disorder in this patient population leading to reduced
prophylaxis and a delayed initiation of treatment.
 For patients with acute spontaneous tumor lysis syndrome, inpatient
mortality rates exceed 58%.

11. Etiology and risk factors
 Risk factors related to the tumor:
1. High tumor cell proliferation rate
2. Chemosensitivity of the malignancy
3. Large tumor burden, as manifested by bulky disease >10 cm in diameter and/or a
white blood cell count >50,000 per microL, a pretreatment (LDH) more than two
times the upper limit of normal, organ infiltration, or bone marrow involvement
 Risk factors related to the patient:
1. Pretreatment hyperuricemia (serum uric acid >7.5 mg/dL) or hyperphosphatemia
2. A preexisting nephropathy or exposure to nephrotoxins
3. Oliguria and/or acidic urine
4. Dehydration, volume depletion, or inadequate hydration during treatment
 The risk of TLS is greatest in hematologic malignancies especially clinically
aggresine non-Hodgkin lymphoma especially burkitts lymphoma and ALL

15. Clinical picture
 manifestations develop before chemotherapy or more commonly within 72
hours after chemotherapy administration and reflect the underluing
metabolic abnormalities:
• manifestations of hypocalcemia:
anorexia, vomiting, cramps, seizures, spasms, altered mental status,
paresthesia and tetany with positive Chvostek and Trousseau signs, cardiac
arrest
• manifestations of hyperkalemia:
Such as weakness and paralysis, paresthesia and fatal cardiac arrhythmias
• urinary symptoms - Such as dysuria, oliguria, flank pain, and hematuria

16.  Deposition of calcium phosphate in various tissues may be responsible for
the following signs and symptoms:
• Pruritus
• Gangrenous changes of the skin
• Iritis
• Arthritis
► Manifestations of uremia and renal failure:
• Edema, Fluid overload
• Fatigue, weakness, anorexia, nausea, vomiting,
• pruritis, hiccough

18. +1
3 days efore to 7 days after chemotherapy

20. Risk stratification
A risk stratification system for TLS was proposed using the type of malignancy, the burden of disease, treatment,
expected response to treatment, and renal function. The recommended therapy varied according to the risk
category
>5%
1-5%
<1%

21. Prevention

22. Prevention
 IV hydration:
 Aggressive intravenous (IV) hydration is the cornerstone of preventing TLS and
is recommended prior to therapy in all patients at intermediate or high risk
for TLS. The goal of IV hydration is induction of a high urine output to
minimize the likelihood of uric acid precipitation in the tubules.
 However, IV hydration can lead to potentially dangerous fluid overload in
patients with underlying renal insufficiency or cardiac dysfunction particularly
if the patient is in an edematous state Prior to initiation of IV hydration
 A 2008 International Expert Panel on TLS recommended that both children
and adults at risk for TLS initially receive 2 to 3 L/m 2 per day of IV fluid
 Urine output should be monitored closely and maintained within a range of 80
to 100 mL/m 2 per hour
 Diuretics can be used to maintain the urine output, if necessary, but
contraindicated in patient with hypovolemia or obstructive uropathy.

23.  The choice of hydration fluid depends upon the clinical
circumstances:
• . The expert panel suggests the initial use of 5% dextrose one-
quarter normal (isotonic) saline.
• In patients with hyponatremia or volume depletion, isotonic saline
should be the initial hydration fluid.
• Potassium and calcium should be withheld from the hydration
fluids, at least initially, due to the risk of hyperkalemia and
hyperphosphatemia with calcium phosphate precipitation once
tumor breakdown begins

24.  The optimal duration of hydration, should depend on:
• the tumor burden
• the type of chemotherapy used (some regimens induce tumor lysis
syndrome several days later)
• the drug sensitivity of the tumor
• the patient’s ability to drink
• renal function
• IV hydration should be continued at least until:
1. tumor burden is largely resolved (as indicated by blast cell count as well
as liver and spleen size in patients with leukemia, and serum LDH level
or tumor size in those with solid tumors)
2. there is no evidence of significant tumor lysis (as indicated by serum uric
acid and phosphorus level
3. patient can drink adequately with good urine output.

25. Prevention
 Urine alkalinization: The role of urinary alkalinization with either
acetazolamide and/or sodium bicarbonate is unclear and controversial. In the
past, alkalinization to a urine pH of 6.5 to 7.0 or even higher was
recommended to convert uric acid to the more soluble urate salt, thereby
diminishing the likelihood of uric acid precipitation in the tubules. However,
• There are no data demonstrating the efficacy of this approach. In addition,
the only available experimental study suggested that hydration with saline
alone is as effective as alkalinization in minimizing uric acid precipitation
• Alkalinization of the urine promotes calcium phosphate deposition in the
kidney, heart, and other organs in patients who develop marked
hyperphosphatemia once tumor breakdown begins.
► Use of sodium bicarbonate is only indicated in patients with metabolic
acidosis and should be avoided with high phosphate.

26. Hypouricemic agents

27. Allopurinol
 hypoxanthine analog that competitively inhibits xanthine oxidase, blocking the
metabolism of hypoxanthine and xanthine to uric acid. Allopurinol effectively
decreases the formation of new uric acid and reduces the incidence of obstructive
uropathy in patients with malignant disease at risk for TLS. However, there are
several limitations to its use:
• Because it acts by decreasing uric acid formation, allopurinol does not reduce the serum
uric acid concentration before treatment is initiated. Thus, for patients with preexisting
hyperuricemia (serum uric acid ≥7.5 mg/dL [446 micromol/L]), rasburicase is the
preferred hypouricemic agent
• Allopurinol increases serum levels of the purine precursors hypoxanthine and xanthine,
which may lead to xanthinuria, deposition of xanthine crystals in the renal tubules, and
acute renal failure.
• Since allopurinol also reduces the degradation of other purines, dose reductions of 65 to
75 percent are needed in patients being treated with 6-mercaptopurine or azathioprine
• Allopurinol has the potential to interact with a number of other drugs, including
cyclophosphamide , high-dose methotrexate , ampicillin , and thiazide diuretics

28. Allopurinol
 Dose and administration:
 The usual allopurinol dose in adults is 100 mg/m 2 every eight hours
(maximum 800 mg per day). In children, the dose is 50 to 100 mg/m 2 every
eight hours (maximum 300 mg/m 2 per day) or 10 mg/kg per day in divided
doses every eight hours. The dose must be reduced by 50 percent in the
setting of renal failure.
 Among patients who are unable to take oral medications, IV allopurinol can
be administered at a dose of 200 to 400 mg/m 2 per day, in one to three
divided doses (maximum dose 600 mg per day).
 Treatment is generally initiated 24 to 48 hours before the start of induction
chemotherapy. It is continued for up to three to seven days afterward until
there is normalization of serum uric acid and other laboratory evidence of
tumor lysis (eg, elevated serum LDH levels).

29. Rasburicase
 It is recombinant uric acid oxidase that catalyzes oxidation of uric acid to the
much more water-soluble compound allantoin. Urate oxidase is present in
most mammals but not humans.
 Rasburicase is well tolerated, rapidly lowers serum uric acid, and is effective
in preventing and treating hyperuricemia and tumor lysis syndrome (TLS). This
rapid reduction in serum uric acid is in contrast to the effect of allopurinol ,
which decreases uric acid formation and therefore does not acutely reduce
the serum uric acid concentration.
 Unlike allopurinol, uricase does not increase excretion of xanthine and other
purine metabolites; therefore, it does not increase tubule crystallization of
these compounds.

30. Rasburicase
 Dosing and administration
 The EMA and FDA recommend a rasburicase dose of 0.2 mg/kg once daily for
up to five (FDA) or seven (EMA) days. The expert consensus panel provided
alternative dose recommendations based upon risk stratification:
• High-risk patients or a baseline uric acid level >7.5 mg/dL (446 micromol/L) —
rasburicase 0.2 mg/kg
• Intermediate-risk patients with baseline uric acid ≤7.5 mg/dL — rasburicase 0.15
mg/kg
 if tumor lysis is massive, an increase to twice daily dosing may be needed
 The average duration of therapy is two days, but can vary from one to seven
days. There are no guidelines from regulatory agencies or expert groups on
this point, and the length of treatment has generally been based on clinical
judgement, depending on tumor burden, type of cancer and anticancer
treatment, and blood uric acid levels following the first dose.

31.  several small uncontrolled retrospective case series have suggested that lower doses
(0.02 mg/kg to 0.2 mg/kg) and/or shorter duration therapy (even in a single dose)
can be effective in some patients and minimizes cost
 The utility of a single dose of rasburicase was shown in a randomized trial comparing
rasburicase (0.15 mg/kg) given as a single dose versus daily dose for five consecutive
days in 80 adult patients at high to intermediate risk of TLS. Only six (all at high risk)
of the 40 patients randomly assigned to the single dose arm required a second dose of
rasburicase on day 4 because of uric acid levels >7.5 mg/dL, and no patient in either
group developed renal insufficiency.
 Based upon these data, single dose rasburicase may be used in patients at
intermediate risk (0.15 mg/kg or lower) or high risk (0.2 mg/kg) of TLS. However, it is
recommended that these patients receive allopurinol after rasburicase treatment.
Moreover, uric acid levels should be monitored closely and additional doses of
rasburicase given if and when hyperuricemia recurs.

32.  Contraindications and restrictions: The rasburicase label carries a risk of
anaphylaxis, hemolysis, hemoglobinuria, methemoglobinemia, and interference with
serum uric acid measurements
 Rasburicase is CONTRAINDICATED in pregnant or lactating women
 Rasburicase is CONTRAINDICATED in patients with glucose-6-phosphate dehydrogenase
(G6PD) deficiency, because hydrogen peroxide , a byproduct of uric acid breakdown, can
cause severe hemolysis and methemoglobinemia in patients with the enzyme deficiency
 Patients being considered for rasburicase (especially males) who have the potential for
G6PD deficiency (history of prior drug-induced hemolytic anemia or racial/ethnic
background (African-American, Mediterranean, or Southeast Asian descent) should
undergo screening
 Rasburicase within blood samples will cause enzymatic degradation of uric acid ex vivo if
the blood samples are left at room temperature, resulting in falsly low serum uric acid
concentrations, and hence missing the diagnosis of ongoing TLS. Blood samples for
determination of uric acid concentrations should be collected in a prechilled tube,
immediately placed on ice, and the assay completed within four hours, if possible

33. Monitoring guidelines
 Urine output and serial assays of electrolytes and serum uric acid are the key
factors to monitor in patients who are at risk for TLS. Urine output and fluid
balance should be recorded and assessed frequently
 the 2008 International Expert Panel guidelines for monitoring patients at risk of
TLS:
• patients at high risk of developing TLS (particularly those with advanced Burkitt
leukemia/lymphoma) should be in a position to be readily transferred to an ICU
before chemotherapy is started
• Patients at high risk for developing TLS should be tested for laboratory and clinical
TLS parameters (serum concentrations of uric acid, phosphate, potassium,
creatinine, calcium and lactate dehydrogenase [LDH], as well as fluid input and
urine output) four to six hours after the initiation of chemotherapy
• For all patients receiving rasburicase (hence deemed at high risk for TLS), serum
uric acid should be reevaluated four hours after administration of the first dose, and
every 6 to 12 hours (depending on the risk and degree of tumor lysis) thereafter
until normalization of serum LDH and uric acid levels

34.  Adults at intermediate risk for TLS should be monitored for at least 24 hours
after completion of chemotherapy. For multiagent regimens, monitoring
should be maintained for 24 hours after administration of the final agent of
the first cycle of therapy. If rasburicase is not used initially, serum
electrolytes should be measured eight hours after chemotherapy, and the
patient might require a one night hospital stay. If TLS has not occurred within
72 hours of multiagent chemotherapy, the likelihood of TLS is very low.

37. Treatment
 Despite appropriate preventive measures, approximately 3 to 5 percent of
patients develop laboratory and/or clinical evidence of TLS, despite the
prophylactic use of rasburicase . In addition, TLS can occur spontaneously prior
to the onset of chemotherapy, primarily in patients with non-Hodgkin lymphoma
(NHL) or acute leukemia and should be treated as follow:
1. Intensive supportive care with continuous cardiac monitoring and measurement of
electrolytes, creatinine, and uric acid every four to six hours
2. Treatment of specific electrolyte abnormalities
3. The use of rasburicase at 0.2 mg/kg (if it was not given initially) with repeated doses
as necessary
4. Attempting to wash out the obstructing uric acid crystals with fluids with or without a
loop diuretic
5. The appropriate use of renal replacement therapy

38. Management of electrolyte abnormalities
(2008 International Expert Panel guidelines)
 Hyperkalemia is the most dangerous component of TLS because it can
cause sudden death due to cardiac dysrhythmias.
• Patients should limit potassium and phosphate intake during the risk period for
TLS.
• frequent measurement of serum potassium (every four to six hours)
• continuous cardiac monitoring, and the administration of oral sodium
polystyrene sulfonate are recommended in patients with TLS and acute kidney
injury
• Glucose plus insulin or beta-agonists can be used as temporizing measures, and
calcium gluconate may be used to reduce the risk of cardiac dysrhythmia. If
needed, hemodialysis and hemofiltration effectively removes potassium

39.  Symptomatic hypocalcemia should be treated with calcium at the lowest doses
required to relieve symptoms.
 To avoid calcium-phosphate precipitation, most symptomatic acutely hypocalcemic
patients with hyperphosphatemia due to TLS (particularly if the calcium phosphate
product is >60 mg 2 per dL) should not be treated with calcium until
hyperphosphatemia is corrected. In most situations, clinicians should use other oral
phosphate binders. However, patients with severe symptoms of hypocalcemia (eg,
tetany or cardiac arrhythmia) should be considered for calcium replacement
regardless of the phosphate level.
 Asymptomatic patients with hypocalcemia do not require treatment.
 Despite treatment with a hypouricemic agent, hyperphosphatemia remains a major
problem in TLS and can cause acute kidney injury. Strategies aimed at lowering
serum phosphate levels (aggressive hydration and phosphate binder therapy) should
be used in conjunction with control of uric acid in patients who have established TLS
or who are at high risk of developing TLS.
Management of electrolyte abnormalities
(2008 International Expert Panel guidelines)

41. Indications for renal replacement therapy
 The need for renal replacement has significantly reduced since the use of
rasburicase, but about 1.5% of children and 5% of adults require dialysis during
induction therapies
 Indications for renal replacement therapy are similar to those in patients with
other causes of acute kidney injury, although somewhat lower thresholds are used
for patients with TLS because of potentially rapid potassium release and
accumulation, particularly if urine output is low.
 Among the indications for renal replacement therapy in patients with TLS:
• Severe oliguria or anuria and volume overload
• Persistent hyperkalemia and hyperphosphatemia despite treatment
• Hyperphosphatemia-induced symptomatic hypocalcemia
► Because hyperkalemia and hyperphosphatemia can recur after dialysis is
initiated, electrolyte levels must be monitored frequently and dialysis repeated
as needed.

42. ► The prognosis for complete recovery of renal function is excellent if dialysis is
initiated early to rapidly reduce serum uric acid and phosphate
concentrations.
► Oliguria due to acute uric acid nephropathy responds quickly to hemodialysis
with initiation of a diuresis usually occurring as the serum uric acid
concentration falls below 10 mg/dL
► Hemodialysis is efficient in removing uric acid; the clearance is about 70 to
100 mL/min, and serum uric acid levels fall by about 50 percent with each six
hour treatment. Peritoneal dialysis is much less efficient with uric acid
clearances below 10 mL/min.