Pediatr Nephrol (2010) 25:305309

DOI 10.1007/s00467-009-1352-1

ORIGINAL ARTICLE

Rasburicase improves hyperuricemia in infants with acute

kidney injury
David J. Hobbs & Julia M. Steinke & Jin Y. Chung &
Gina-Marie Barletta & Timothy E. Bunchman

Received: 2 July 2009 / Revised: 27 August 2009 / Accepted: 10 September 2009 / Published online: 21 November 2009
# IPNA 2009

Abstract Recent data suggest that elevated levels of uric

acid (UA) might contribute to the progression of renal
disease. Rasburicase, recombinant urate oxidase, is a highly
safe and efficacious hypo-uricosuric agent for treatment of
elevated UA levels from tumor lysis. We adopted the use of
rasburicase for management of hyperuricemia in infants
with acute kidney injury (AKI) and, herein, report our
experience. We conducted a retrospective chart review of
infants with hyperuricemia (UA>8 mg/dl) secondary to
AKI (serum creatinine>1.5 mg/dl) treated with rasburicase.
Seven infants (mean age 3455 days, six male), with a
mean weight of 3.21.2 kg, were identified. Rasburicase
was administered intravenously as a single, onetime, bolus
of 0.170.04 mg/kg body weight. Within 24 h, serum UA
had decreased from 13.64.5 mg/dl to 0.90.6 mg/dl
(P<0.05), creatinine had decreased from 3.22.0 mg/dl to
2.01.2 mg/dl (P<0.05), and urinary output had increased
from 2.41.2 ml/kg per hour to 5.91.8 ml/kg per hour
(P<0.05). Continued improvements in UA, creatinine, and
urinary output were observed in the week following
administration of rasburicase, without rebound of the UA.
We observed no treatment-related side effects. All patients
D. J. Hobbs : J. M. Steinke : J. Y. Chung : G.-M. Barletta :
T. E. Bunchman (*)
Pediatric Nephrology, Dialysis and Transplantation,
Helen DeVos Childrens Hospital and Michigan State University
College of Human Medicine,
221 Michigan Street SE, Suite 406,
Grand Rapids, MI 49503, USA
e-mail: Timothy.Bunchman@devoschildrens.org
J. Y. Chung
Michigan State University/Grand Rapids Medical Education
and Research Center (GRMERC/MSU) Pediatric Nephrology
Fellowship Program, GRMERC,
Grand Rapids, MI, USA

demonstrated a normalization of uric acid level without

need of renal replacement therapy. In conclusion, a single
intravenously administered bolus of rasburicase appears to
be a novel treatment for hyperuricemia in infants with AKI.
Keywords Rasburicase . Hyperuricemia . Uric acid .
Acute kidney injury . Dialysis . Pediatrics

Introduction
Acute kidney injury (AKI) is a common problem occurring
in 624% of newborn infants [1]. The etiology of the AKI
is multifactorial, but it is commonly caused by renal
hypoperfusion secondary to intravascular volume depletion,
intrinsic renal disease from prolonged hypoxic ischemic
injury, and often as a component of multiorgan failure as a
consequence of sepsis [25]. Renal replacement therapy
(RRT) remains an important tool in the treatment of AKI
[5, 6].
Recent clinical and animal model data suggest a
pathogenic role for uric acid (UA) in the development and
progression of renal disease [710]. A recent epidemiological
study demonstrated that elevated levels of uric acid
independently increase the risk of chronic kidney disease
[11]. The development of hyperuricemia may also represent
a concomitant factor aggravating pre-existing renal disease
or prolonging recovery from AKI [12, 13].
Standard treatment for hyperuricemia consists of allopurinol, hydration, and urinary alkalinization. Allopurinol
reduces the de novo formation of UA through the inhibition
of xanthine oxidase, which may lead to the accumulation of
nephrotoxic UA precursors such as xanthine and hypoxanthine [14, 15]. Furthermore, allopurinol does not affect preexisting UA and may be slow to normalize UA levels.

Gender

Patient

AA

Race

39

28

27

41

39

41

36

Gestational
age at birth
(weeks)

HIE

Severe
dehydration
(ATN)

HIE, sepsis
with MOF

Placental
abruption

Twintwin
transfusion

HIE

Sepsis

Intrauterine
growth
retardation

HIE

Sepsis

Placental
abruption

Cause
of AKI

Intrauterine
considerations

43

22

155

Age at
injection
(days)

0.14

0.15

0.15

0.13

0.24

0.16

0.20

Dose
(mg/kg)

3.1
16
1.4

1.5
15
0.9

0.6
22
1.5

4.5
29
4.5

2.7
12
0.2

1.1
9

0.9
24

Cr
BUN
UOp
UA
Cr
BUN
UOp
UA
Cr
BUN
UOp
UA
Cr
BUN
UOp
UA
Cr
BUN
UOp
UA
Cr
BUN
UOp

2.1
105
0.7

Day
1

Day
2

UA
Cr
BUN
UOp
UA

Laboratory
tests

5.3
14.7
2.2
31
0.5

3.6
30
3.8
22.4
7.1
172
0.9
10.2
1.7
29
2.5
11.9
1.7
19
1.3
8.2
4.5
29

14.5
1.9
99
1.9
13.6

Day 0
(dose)

4.2
0.5
1.5
21
2.0

3.5
31
4
0.6
1.9
64
8.7
2.2
1.8
43
4.8
1.3
0.8
10
6.4
0.6
3.8
20

0.5
0.9
29
4.8
0.5

Day
1

7.9

1.1
10
4.7

4.3
16
3.7
0.8
1.1
51
4.9

1.8
66
3.6

0.7
3
6.8
1.6

1.6
0.7
8
7.6

Day
2

5.6

0.8
7
2.5

4.2
18
3.0
0.6
1.0
37
2.6
1.6
1.8
78
3.9

0.7
3
4.9
3.3
3.6

0.5
3
10
0.5

Day
3

4.8

3.1

3.4
58
3.7

0.8
28
4.7
3.3
1.6
105
4.8

0.7
6
2.9
4.8
3.7
51

0.6
8
6.7
1.6

Day
5

4.6

2.6
71
4.4

0.9
22
9.8
2.9
1.6
84
5.3

0.5
7
5.3
3.8
3.2
47

1.6
0.5
6
5.6
2.0

Day
7

5.6

0.5
14

0.3
18

3.9
1.1
47

0.7
2

4.8
2.1
7

3.9
0.5
11

2.1

Month
1

0.2
10

1.0
47

1.2
19

0.6
40

Month
6

0.2
19

1.0
37

1.3
18

0.3
6

Month
12

Table 1 Longitudinal data of infants treated intravenously for hyperuricemia with a single bolus of rasburicase on day 0 (M male, F female, C Caucasian, AA African American, HIE hypoxic
ischemic event, MOF multiorgan failure, ATN acute tubular necrosis, UA uric acid (mg/dl), Cr creatinine (mg/dl), BUN blood urea nitrogen (mg/dl), UOp urinary output (ml/kg per hour))

306
Pediatr Nephrol (2010) 25:305309

Pediatr Nephrol (2010) 25:305309

307

Table 2 Group changes after intravenous treatment for hyperuricemia

with a single bolus of rasburicase on day 0. Data are expressed as
means (SDs). Variables were compared (horizontally). BP blood
pressure
Parameter

Day 0 (dose)

Day 1

Uric acid (mg/dl)

Creatinine (mg/dl)
Urinary output (ml/kg per hour)
Blood urea nitrogen (mg/dl)
Phosphorous (mg/dl)

13.6 (4.5)
3.2 (2.0)
2.4 (1.2)
58 (57)
6.0 (1.5)

0.9
2.0
5.9
31
6.4

(0.6)*
(1.2)*
(1.8)*
(18)
(1.5)

3.6
8.5
83
48

(0.8)
(1.4)
(6)
(10)

Potassium (mmol/l)
Calcium (mg/dl)
Systolic BP (mmHg)
Diastolic BP (mmHg)

4.1
8.6
81
44

(0.8)
(1.6)
(12)
(10)

*P<0.05

Rasburicase is a recombinant urate oxidase enzyme that

effectively oxidizes UA to allantoin, which is readily
excretable and highly water-soluble. Rasburicase has
proven to be a safe and highly efficacious hypo-uricosuric
agent in the treatment of children and adults with tumor lysis
syndrome [1618]. We have adopted the use of rasburicase
for the management of hyperuricemia secondary to neonatal
AKI and, herein, report our experience.

Methods
We conducted a retrospective chart review of infants with
hyperuricemia secondary to AKI treated with rasburicase at
Helen DeVos Childrens Hospital, Grand Rapids, Michigan,
USA, between January 2006 and January 2009. Hyperuricemia was defined as serum UA>8 mg/dl, and AKI as
serum creatinine>1.5 mg/dl. Charts were reviewed for
clinical, treatment and laboratory data prior to the administration of rasburicase, throughout the week following
administration of rasburicase, and at 1-month, 6-month
and 12-month follow-up examinations. This study was
approved by the Spectrum Health Institutional Review Board.
A renal ultrasound was performed in all patients to
exclude obstruction and was found to be non-diagnostic.
Prior to treatment with rasburicase, patients underwent
volume reconstitution for 12 days (depending on presentation), with little change in creatinine or urinary output,
after which UA levels were measured and found to be
elevated. The infants were then administered a single,
onetime, bolus of rasburicase intravenously, targeted to
0.150.20 mg/kg, followed by a normal saline solution flush.
Univariate statistical analyses were performed with SAS,
version 9.1 (SAS Institute Inc., Cary, NC, USA). A nonparametric paired t-test, Wilcoxons signed rank sum, was

used to determine significant differences between day 0

(dose) and day 1 measures. Continuous data were expressed
as means standard deviations (SDs). A P value of <0.05
was considered to be statistically significant.

Results
We identified seven hyperuricemic infants with AKI. The
data from individual patients are described in Table 1. The
mean gestational age at birth was 366 weeks. The mean
age of patients at administration of therapy was 3455 days,
and the mean weight was 3.21.2 kg. Six of the seven
infants were male, six of the seven were Caucasian, and one
of the seven was African American. The etiology of the
AKI was as follows: three had a hypoxic ischemic event
(HIE), two had sepsis without multiorgan failure (MOF),
one had sepsis with MOF, and one had acute tubular
necrosis from severe dehydration.
Individual longitudinal changes in uric acid, creatinine,
BUN and urinary output are described in Table 1. Rasburicase
was administered intravenously as a single bolus at a mean
dose of 0.170.04 mg/kg. Within 24 h, all patients had
demonstrated normalization of uric acidmean uric acid
levels decreased from 13.64.5 mg/dl to 0.90.6 mg/dl
(normal<6.5 mg/dl; P<0.05; Table 2). Prior to therapy, four
of five patients demonstrated no change or an increase in
creatinine. Within 24 h of treatment, six of seven showed
improvement in creatininemean creatinine decreased
from 3.22.0 mg/dl to 2.01.2 mg/dl (P<0.05; Table 2).
Similar trends were observed with urinary outputmean
urinary output increased from 2.41.2 ml/kg per hour to
5.91.8 ml/kg per hour (P<0.05; Table 2). We investigated
baseline changes in blood urea nitrogen (BUN), electrolytes,
and blood pressures (Table 2). These parameters either
improved or remained stable throughout the course of the
study, but none attained statistical significance. Repeated
creatinine measurements in four of the seven patients at
1-month, 6-month, and 12-month follow-up examinations
showed continued long-term improvement (Table 1). No
patients underwent RRT.
Rasburicase was well tolerated by all patients, as we
observed no treatment-related adverse events. Two infants
subsequently died from complications secondary to sepsis.
The remaining five children are being followed by our
pediatric nephrology service as outpatients with varying
degrees of chronic kidney disease (CKD).

Discussion
Recent data suggest that uric acid may independently
increase the risk of an individuals developing renal disease

308

and exacerbate pre-existing nephropathy [1113]. Rasburicase is a highly efficacious hypo-uricosuric agent in the
management of tumor lysis [1618]. We adopted rasburicase as a novel treatment for hyperuricemia secondary to
AKI.
We found a onetime, single, bolus of rasburicase,
intravenously administered, to be effective in reducing
serum UA levels. All patients demonstrated normalization
of UA levels within 24 h of administration of rasburicase,
without significant rebound of the UA (Table 1). The
patients also demonstrated improvement in serum creatinine
and urinary output after treatment (Table 1), which is a
finding consistent with those in previous studies [1622].
Our study is, to our knowledge, the first reported use of
rasburicase in hyperuricemic infants with renal failure.
Allopurinol has been used to slow the progression of
renal disease and essential hypertension through the
lowering of UA levels [10, 23], which would also make it
a potential therapy for hyperuricemic infants with AKI. We
use rasburicase because it achieves target UA levels more
rapidly and with less frequent dosing [16]. Furthermore,
a randomized comparison between rasburicase and allopurinol reported that hyperuricemic patients who received
rasburicase demonstrated an improvement in creatinine
levels, whereas those who received allopurinol demonstrated
a worsening [16]. The use of allopurinol may place patients
at risk of developing xanthine nephropathy [14, 15]. Taken
together, this implies that rasburicase may be a superior
therapy for patients with acutely elevated UA levels and
compromised renal function.
Rasburicase was well tolerated by our infant population,
which finding is consistent with those of several single,
multicenter and compassionate use trials [1722, 24, 25].
Newborn infants have, indeed, been represented in compassionate use studies [24, 25] and prospective and randomized
trials [16, 17]. The most frequent adverse reaction in the
North American compassionate use study (total study
n=996) were headache (0.7%), rash (0.4%), fever (0.3%)
and vomiting (0.3%), and ten patients suffered events that
led to withdrawal after a single course of rasburicase [24].
It should be noted that hydrogen peroxide is a byproduct
of uric acid catabolism, and rasburicase should not be
administered to patients with glucose-6-dehydrogenase
(G6PD) deficiency, due to the risk of hemolysis.
Renal replacement therapy is an alternative treatment to
rasburicase and/or allopurinol for hyperuricemia from AKI,
but it is associated with an increased risk of morbidity and
death [3, 5, 6]. In our small study RRT was not prescribed,
due to what we believe is a dramatic effect in response to
this intervention. With improvement of hyperuricemia, we
were able to maximize nutrition and maintain euvolemia for
electrolyte disturbance, and avoid the need for renal
dialysis. Neonatologists and nephrologists who utilize this

Pediatr Nephrol (2010) 25:305309

therapy should continue long-term follow-up examination

of the infant, due to risk of CKD from primary causes of
AKI.
The determination of a potentially beneficial effect on
kidney function from the lowering of UA levels is difficult
from this study. We recognize that the major weakness of
this clinical observation is the lack of a control arm.
Unfortunately, there were no infants with high serum UA
levels, AKI, and similar comorbidity to serve as viable
controls. This study was not powered to determine if
correlations among UA and creatinine and/or urinary output
exist, which would more appropriately assess if reductions
in uric acid resulted in an overall improvement of renal
function and/or reversal of AKI. The lack of a literature or
historic control group and the small sample size may limit
this retrospective study. However, like many clinical
observations, this study describes preliminary data to help
in the design of a prospective investigation of the use of
rasburicase in hyperuricemic AKI patients.

Conclusions
In conclusion, we report rasburicase to be a novel therapy
for the treatment of hyperuricemia in infants with AKI.
Rasburicase was effective in reducing uric acid levels in all
patients within 24 hours of its administration, with no
observed side effects. Patients also demonstrated improvement in serum creatinine and urinary output. Whereas this
was a small retrospective study, it may serve to improve the
management of hyperuricemia in a population that is very
high risk and difficult to treat. A large prospective study of
rasburicase in hyperuricemic infants with AKI may serve to
validate these findings.
Acknowledgements D.J.H. was supported by an American Society
of Nephrology student scholar grant. The authors would like to thank
David P. Weismantel, M.D., M.S., for statistical support. None of the
authors declare a conflict of interest with this research or the
information herein.

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