ORIGINAL ARTICLE
Analysis of Risk Factors for Hyponatremia During or
Following Chemotherapy in Children With Cancer:
A Hospital-based, Retrospective Cohort Study
Kenji Kishimoto, MD, Ryoji Kobayashi, MD, Hirozumi Sano, MD,
Daisuke Suzuki, MD, Kazue Yasuda, MD, and Kunihiko Kobayashi, MD
Summary: Hyponatremia is the most common electrolyte abnor-
mality in hospitalized patients. The objective of this study was to
identify risk factors for hyponatremia during chemotherapy in
children. A total of 111 consecutive pediatric patients (age, 0 to
18 y) with hematological malignancy (n = 87) or solid tumor
(n = 24) who received chemotherapy in our hospital between 2010
and 2014 were enrolled. The number of chemotherapy cycles
reviewed was 472, with a median of 3 (range, 1 to 8) per patient.
Hyponatremia was defined as a serum sodium level of <135 mmol/
L. Hyponatremia was observed in 80 of 111 (72%) patients, and
138 of 472 (29%) cycles. Neurological sequelae were seen in 2 of
111 (2%) patients, and 2 of 472 (0.4%) cycles. Multivariate logistic
regression identified age 10 to 18 years (odds ratio [OR] = 3.24,
95% confidence interval [CI], 2.07-5.07), total parenteral nutrition
(OR = 8.15, 95% CI, 2.17-30.5), first or second chemotherapy
cycle (OR = 1.74, 95% CI, 1.12-2.70) as independent risk factors
for hyponatremia. Clinical conditions of patients and chemo-
therapeutic agents may have a profound impact on the develop-
ment of hyponatremia. Patients with these factors should be
managed carefully to prevent severe symptoms and sequelae caused
by hyponatremia.
Key Words: hyponatremia, chemotherapy, children, incidence, risk
factor
(J Pediatr Hematol Oncol 2015;00:000–000)
H yponatremia is the most common electrolyte abnormality
in hospitalized patients.1 Symptoms of hyponatremia
range widely from mild to potentially life threatening.2 The
incidence of hyponatremia is higher in hospitalized patients
with cancer than in those without cancer.3 Several reports
have suggested that hyponatremia is associated with increased
mortality in patients with malignancies.3,4 Hospital-acquired
hyponatremia is also increasingly recognized as a cause of
morbidity and mortality in children.5,6 Among hospi-
talized children, children with hematologic and oncologic
diseases have been reported to have a greater risk of
hyponatremia.7
Ectopic production of hormones, gastrointestinal
sodium loss, central nervous system (CNS) disease, drugs,
and excessive water intake are suggested causes for hypo-
natremia in cancer treatment.8 Although patients with
Received for publication June 26, 2015; accepted October 13, 2015.
From the Department of Pediatrics, Sapporo Hokuyu Hospital,
Shiroishi-ku, Sapporo, Hokkaido, Japan.
The authors declare no conflict of interest.
Reprints: Kenji Kishimoto, MD, Department of Pediatrics, Sapporo
Hokuyu Hospital, Higashi-Sapporo 6-6, Shiroishi-ku, Sapporo,
Hokkaido 003-0006, Japan (e-mail: ken@yacht.ocn.ne.jp).
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
J Pediatr Hematol Oncol  Volume 00, Number 00, ’’ 2015
Copyright r 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
cancer are at increased risk for hyponatremia, little infor-
mation is available on the predictors for hyponatremia
during cancer treatment. Moreover, few studies have
investigated the incidence of hyponatremia during chemo-
therapy to date. The objectives of this study were to analyze
the incidence of hyponatremia during chemotherapy and to
identify the risk factors for hyponatremia during chemo-
therapy in children. We performed a retrospective cohort
analysis of children who receive chemotherapy for cancers.
MATERIALS AND METHODS
Patients
A total of 111 consecutive pediatric patients (age
range, 0 to 18 y) with hematological malignancy (n = 87)
or solid tumor (n = 24) who received chemotherapy at
Sapporo Hokuyu Hospital between January 2012 and
December 2014 were enrolled. Patients with primary
intracranial tumors were excluded because of their known
high risk of hyponatremia.9 Patients who died within 14
days after initiation of chemotherapy were also excluded.
The number of chemotherapy cycles reviewed was 472, with
a median of 3 (range, 1 to 8) per patient. High-dose che-
motherapy as part of conditioning regimens for stem cell
transplantation (SCT) was excluded from the analysis.
Informed consent was obtained from the patients or their
parents, and the study was approved by the Institutional
Review Board of Sapporo Hokuyu Hospital.
Definitions
Hyponatremia was defined as a serum sodium level
<135 mmol/L in at least 2 consecutive timepoints in a
chemotherapy cycle. The severity of hyponatremia was
classified into 3 groups based on the recent guideline10: mild
(serum sodium level 130 to 134 mmol/L); moderate (125 to
129 mmol/L); and severe (< 125 mmol/L). Symptomatic
hyponatremia was defined as hyponatremic episodes with
symptoms that were potentially related to hyponatremia.
Neurological complications were defined as symptoms of
hyponatremia if they occurred concurrently with the
development of hyponatremia and they improved with
resolution of hyponatremia. A past history of surgery was
defined as previous surgery for intrathoracic, intra-
peritoneal, retroperitoneal, head and neck, or orthopedic
disease. Renal injury was defined as a 50% increase in
serum creatinine from baseline, or an absolute increase in
serum creatinine of Z0.3 mg/dL, or a documented oliguria
<0.5 mL/kg/h for >6 hours, based on the Acute Kidney
Injury Network classification.11 CNS disease was defined as
the presence of neuroimaging abnormalities including brain
metastases or the presence of tumor cells in the
1 www.jpho-online.com |
 Kishimoto et al
cerebrospinal fluid. Diagnosis of infection was based on a
positive culture or a combination of clinical, serological,
and radiologic findings.
Data Collection
The baseline characteristics of the patients including
demographic information (sex, age, weight, height, and
performance status [PS]), clinical information (diagnosis,
treatment history, and comorbidity), and serum bio-
chemical values, were collected. The PS of the patients was
assessed using the Eastern Cooperative Group PS scale.12
Serum sodium values were prospectively monitored closely
during treatment. Clinical records were reviewed retro-
spectively to identify hyponatremia.
Statistical Analysis
Univariate analysis was performed by Mann Whitney
U test and unpaired t test for quantitative variables, and w2
test and Fisher exact test for qualitative variables. Risk
factors for overall hyponatremia and moderate to severe
hyponatremia were identified through chemotherapy cycle–
based analysis. The most discriminative cut-off points for
the variables were determined by univariate analysis.
Potential risk factors with P values of <0.15 on univariate
analysis were included in a stepwise logistic regression
model to identify the risk factors. In the multivariate
logistic regression model, significant variables were identi-
fied by a backward stepwise procedure. For all models, the
number of covariates examined was determined by the
number of outcome events with 10 events required for 1
covariate.13 Multicollinearity was examined using an
explanatory variable correlation matrix. Odds ratios (ORs)
and 95% confidence intervals (CIs) were calculated for
predictors retained in the final models. A P value of <0.05
was considered statistically significant; all tests were 2-
tailed. All statistical analyses were conducted using Dr
SPSS II for Windows (release 11.0.1J; SPSS Japan, Tokyo,
Japan).
RESULTS
Incidence of Hyponatremia
The baseline characteristics of the patients are shown
in Table 1. All patients received hypotonic intravenous
fluids at the initiation of the chemotherapy cycle for sup-
portive treatment. The mean and SD of parenteral fluid
volume were 74 and 31 mL/kg/d, respectively (Table 2).
Hyponatremia was observed in 80 of 111 (72%) patients.
Of these 80 patients, 35 patients (32%) developed hypo-
natremia in >2 cycles. The median age was significantly
higher in patients with than without hyponatremia (11 vs.
2 y, P < 0.001), and in patients with than without moderate
to severe hyponatremia (12 vs. 5 y, P = 0.001). In the che-
motherapy cycle–based analysis, hyponatremia was
observed in 138 of 472 (29%) cycles: mild hyponatremia in
108 cycles (23%); moderate hyponatremia in 26 cycles
(6%); and severe hyponatremia in 4 cycles (1%). Hypona-
tremia at the initiation of the chemotherapy cycle was
observed in 7 of 472 (1%) cycles, all of which were mild
hyponatremia. The median onset of hyponatremia occurred
8 days (range, 1 to 34 d) after the initiation of chemo-
therapy. In 69 of 138 (50%) cycles with hyponatremia,
patients developed hyponatremia within the first week of
the chemotherapy. There was no significant relation
between severity of hyponatremia and the timing of
2 | www.jpho-online.com Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright r 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
J Pediatr Hematol Oncol  Volume 00, Number 00, ’’ 2015
hyponatremia. Parenteral fluid volume and sodium con-
centration were also not associated the onset of hypona-
tremia. Among 80 patients with hyponatremia, 49 (44%)
experienced symptomatic hyponatremia. The most com-
mon symptom among the patients with hyponatremia was
nausea and vomiting (55%). Seizure and altered mental
status were observed in 1 (0.9%) and 3 patients (3%),
respectively. The median duration of hyponatremia was 8
days (range, 2 to 35 d). Treatment for symptomatic hypo-
natremia (water restriction and/or 3% hypertonic saline)
was required in 11 of 111 (11%) patients, and in 12 of 472
(3%) cycles. Neurological sequelae were seen in 2 of 111
(2%) patients, and in 2 of 472 (0.4%) cycles: resting tremor
in one patient and altered mental status in another patient.
Risk Factor Analysis for Developing
Hyponatremia
Table 2 presents the characteristics of chemotherapy
cycles with overall hyponatremia and moderate to severe
hyponatremia episodes. In univariate analysis, the risk of
hyponatremia was significantly increased in patients with
higher PS score (P = 0.001), total parenteral nutrition (TPN)
(P < 0.001), first or second chemotherapy cycle (P < 0.001),
past history of SCT (P = 0.040), renal injury (P < 0.001), CNS
disease (P = 0.020), and infection (P = 0.022). Other risk fac-
tors for hyponatremia included administration of carboplatin
(P = 0.001), daunorubicin (P < 0.001), dexamethasone
(P = 0.001), ifosfamide (P = 0.012), irinotecan (P = 0.032),
L-asparaginase (P < 0.001), pirarubicin (P = 0.015), pre-
dnisolone (P < 0.001), and vincristine (P < 0.001). Neither
initial serum sodium level nor the volume of parenteral fluid
was shown to be a significant predictor for hyponatremia. The
mean sodium concentration of parenteral fluid was higher in
cycles with than without hyponatremia (55 vs. 50 mmol/L,
P = 0.002), and in cycles with than without moderate to
severe hyponatremia (60 vs. 51 mmol/L, P < 0.001). Renal
injury (P < 0.001), and administration of cyclophosphamide
(P = 0.007), dexamethasone (P = 0.001), and vincristine
(P < 0.001) were strongly associated with moderate to severe
hyponatremia. The administration of daunorubicin, L-aspar-
aginase, or prednisolone was excluded from the multivariate
analysis because a strong correlation was observed between
their administration and the administration of vincristine.
Similarly, administration of dexamethasone was excluded due
to its correlation with cyclophosphamide. Multivariate analysis
identified age 10 to 18 years (OR = 3.24, 95% CI, 2.07-5.07),
TPN (OR = 8.15, 95% CI, 2.17-30.5), first or second chemo-
therapy cycle (OR = 1.74, 95% CI, 1.12-2.70), administration
of carboplatin (OR = 6.51, 95% CI, 2.43-17.5), and admin-
istration of vincristine (OR = 3.56, 95% CI, 2.25-5.63) as
independent risk factors for overall hyponatremia. Renal injury
(OR = 5.38, 95% CI, 2.15-13.5), administration of ifosfamide
(OR = 8.03, 95% CI, 1.83-35.2), and administration of vin-
cristine (OR = 5.90, 95% CI, 2.24-15.5) were also identified as
independent risk factors for moderate to severe hyponatremia
(Table 3). The magnitude of correlations among the variables
was also assessed, and there was no evidence of multi-
collinearity.
DISCUSSION
In the present study, the risk of hyponatremia during
chemotherapy was significantly dependent on the clinical
conditions of patients, such as age, PS, past history, and
comorbidities, as well as on the chemotherapeutic agents.
 J Pediatr Hematol Oncol  Volume 00, Number 00, ’’ 2015 Analysis of Risk Factors for Hyponatremia

TABLE 1. Baseline Characteristics of the Total Population and the Subgroups With Hyponatremia and With Moderate to Severe
Hyponatremia
Baseline Characteristics Total (n = 111) Hyponatremia (n = 80) P* Moderate to Severe Hyponatremia (n = 24) Pw
Age (median [range]) (y) 7 (0-18) 11 (0-18) < 0.001 12 (2-18) 0.001
Male/female 59/52 43/37 0.840 12/12 0.727
Treatment history (n [%])
Chemotherapy 18 (16) 15 (19) 0.245 5 (21) 0.535
SCT 8 (7) 7 (9) 0.439 3 (13) 0.367
Surgery 23 (21) 18 (23) 0.457 6 (25) 0.576
Comorbidity (n [%])
Renal injury 13 (12) 12 (15) 0.106 6 (25) 0.033
CNS disease 9 (8) 7 (9) 1.0 3 (13) 0.403
Infection 5 (5) 5 (6) 0.319 1 (4) 1.0
Diagnosis (n [%])
Hematological malignancy 87 (78) 62 (78) 0.718 19 (79) 0.916
ALL 50 (45) 37 (46) 14 (58)
AML 24 (22) 14 (18) 1 (4)
NHL 9 (8) 8 (10) 3 (13)
Other 4 (4) 3 (4) 0.316 1 (4) 0.101
Solid tumor 24 (22) 18 (23) 0.718 5 (21) 0.916
Neuroblastoma 8 (7) 7 (9) 2 (8)
Hepatoblastoma 5 (5) 4 (5) 1 (4)
Other 11 (10) 7 (9) 0.475 2 (8) 0.936
Disease status (n [%])
Newly diagnosed 93 (84) 65 (81) 19 (79)
Relapsed 18 (16) 15 (19) 0.245 5 (21) 0.535
*P value for comparison of hyponatremia versus none.
wP value for comparison of moderate to severe hyponatremia versus none.
ALL indicates acute lymphoblastic leukemia; AML, acute myeloid leukemia; CNS, central nervous system; NHL, non-Hodgkin lymphoma; SCT, stem cell
transplantation.

To the best of our knowledge, this study is the first to
describe the risk factors for hyponatremia during chemo-
therapy. The present study showed that hyponatremia
during chemotherapy was common in children with cancer.
We previously reported the incidence of the syndrome of
inappropriate secretion of antidiuretic hormone (SIADH)
as 40% in 140 pediatric patients who underwent SCT.14
The high incidence of hyponatremia in our studies seems to
be similar to that reported in a previous study of 63 children
who received chemotherapy or SCT.15 Comparisons of
hyponatremia incidence are difficult, however, because
there have been considerable differences in the definitions of
hyponatremia among the previous studies.3–5,7,14,15 It
should be noted, that although about one half of patients
with hyponatremia were asymptomatic in the present study,
several patients developed severe neurological symptoms
and sequelae. In the present study, all patients received
hypotonic intravenous fluids, and a lower sodium concen-
tration of parenteral fluid was not shown to be a risk factor
for hyponatremia. It has been suggested, however, that use
of hypotonic fluids itself may be a potential risk factor for
hospital-acquired hyponatremia.5–7 We considered that our
results did not support the routine use of parenteral fluid
with lower sodium concentration in children with cancer
because there was no comparison between isotonic and
hypotonic fluids in the present study. Moreover, recent
clinical evidence suggests that isotonic parenteral main-
tenance fluids offer more effective prophylaxis against
hyponatremia than hypotonic fluids in hospitalized chil-
dren.16,17 The optimal fluid therapy should be established
for children with cancer, who have a greater risk of
hyponatremia.7
Several drugs used in chemotherapy, such as vinka
alkaloids, platinum compounds, and alkylating agents,
have been reported to cause hyponatremia.18–21 Most of the
previous literature consists of case reports or small case
series, however, and the precise incidence of hyponatremia
induced by these agents remains unknown. We actually
confirmed that these drugs were significant risk factors for
hyponatremia during chemotherapy. A previous study
reported an estimated rate of hyponatremia and/or SIADH
of 1.3/100,000 vincristine-treated patients,19 which is clearly
lower than the present result. This marked difference may
be attributed to the difference in regimens and patient
populations between the studies.
Besides chemotherapy agents, age, PS, need for TPN,
past history, and comorbidities were also found to be
important factors in the development of hyponatremia during
chemotherapy. We revealed that adolescents are at higher risk
of hyponatremia during chemotherapy. An increased inci-
dence of some chemotherapy-related toxicities in older ado-
lescents was reported in patients with acute lymphoblastic
leukemia,22,23 suggesting that they are more susceptible to
treatment-related toxicity than younger children. Supple-
mental nutrition and infection have been reported as risk
factors for hyponatremia in children undergoing surgery for
intracranial tumors.9 We identified renal injury as one of the
most important risk factors for developing hyponatremia,
especially for moderate to severe hyponatremia. Renal injury
is common in patients with cancer,24 and its cause is multi-
factorial, including nephrotoxic agents, cancer infiltration,
extrarenal obstruction, and infection.25 Renal salt wasting
syndrome induced by cisplatin has been described in previous
reports.20 In the present study, hyponatremia was also
observed in patients with renal injury from causes other than
cisplatin. The present results suggest that renal injury, as well
as SIADH, the definition of which includes normal renal
function,26 plays a critical role in the etiology of hyponatremia

Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. 3 www.jpho-online.com |
Copyright r 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
 Kishimoto et al J Pediatr Hematol Oncol  Volume 00, Number 00, ’’ 2015

TABLE 2. Characteristics of the Total Population and the Subgroups With Hyponatremia and With Moderate to Severe Hyponatremia:
Chemotherapy Cycle–based Comparison
Characteristic at the Initiation of the Total Hyponatremia Moderate to Severe Hyponatremia
Chemotherapy Cycle (n = 472) (n = 138) P* (n = 30) Pw
Age (median [range]) (y) 7 (0-18) 11 (0-18) < 0.001 13 (2-18) < 0.001
Male (n [%]) 242 (51) 72 (52) 0.801 13 (43) 0.369
PS score 2-4 (n [%]) 48 (10) 24 (17) 0.001 5 (17) 0.214
TPN (n [%]) 16 (3) 12 (9) < 0.001 2 (7) 0.270
No. chemotherapy cycle (n [%])
1-2 210 (44) 73 (53) 17 (57)
Z3 262 (56) 65 (47) 0.018 13 (43) 0.166
Serum sodium (mean ± SD) (mmol/L) 140 ± 3 139 ± 4 0.228 140 ± 3 0.477
Past history (n [%])
SCT 39 (8) 17 (12) 0.040 4 (13) 0.297
Surgery 116 (25) 42 (30) 0.057 10 (33) 0.250
Comorbidity (n [%])
Renal injury 34 (7) 23 (17) < 0.001 9 (30) < 0.001
CNS disease 29 (6) 14 (10) 0.020 4 (13) 0.103
Infection 24 (5) 12 (9) 0.022 3 (10) 0.190
Diagnosis (n [%])
Hematological malignancy 357 (76) 98 (71) 0.133 21 (70) 0.457
ALL 217 (46) 58 (42) 15 (50)
AML 92 (19) 22 (16) 1 (3)
NHL 38 (8) 13 (9) 3 (10)
Other 10 (2) 5 (4) 0.255 2 (7) 0.044
Solid tumor 115 (24) 40 (29) 0.133 9 (30) 0.457
Neuroblastoma 39 (8) 11 (8) 4 (13)
Hepatoblastoma 26 (6) 10 (7) 2 (7)
Other 50 (11) 19 (14) 0.569 3 (10) 0.759
Disease status (n)
Newly diagnosed 407 (86) 113 (82) 23 (77)
Relapsed 65 (14) 25 (18) 0.078 7 (23) 0.164
Chemotherapy agent (n [%])
Actinomycin D 19 (4) 8 (6) 0.208 0 (0) 0.624
Bleomycin 11 (2) 4 (3) 0.738 0 (0) 1.0
Carboplatin 23 (5) 14 (10) 0.001 1 (3) 1.0
Cisplatin 65 (14) 19 (14) 0.999 7 (23) 0.164
Cyclophosphamide 204 (43) 66 (48) 0.194 20 (67) 0.007
Cytarabine 209 (44) 44 (32) < 0.001 6 (20) 0.006
Daunorubicin 59 (13) 35 (25) < 0.001 11 (37) < 0.001
Dexamethasone 108 (23) 45 (33) 0.001 14 (47) 0.001
Doxorubicin 16 (3) 6 (4) 0.576 2 (7) 0.270
Etoposide 147 (31) 42 (30) 0.831 6 (20) 0.173
Fludarabine 8 (2) 2 (1) 1.0 0 (0) 1.0
Idarubicin 36 (8) 9 (7) 0.561 2 (7) 1.0
Ifosfamide 18 (4) 10 (7) 0.012 3 (10) 0.099
Irinotecan 14 (3) 8 (6) 0.032 0 (0) 1.0
L-asparaginase 117 (25) 52 (38) < 0.001 15 (50) 0.001
Mercaptopurine 36 (8) 7 (5) 0.179 2 (7) 1.0
Methotrexate 68 (14) 10 (7) 0.004 3 (10) 0.600
Mitoxantrone 46 (10) 17 (12) 0.226 2 (7) 0.756
Nelarabine 16 (3) 2 (1) 0.169 0 (0) 0.614
Pirarubicin 162 (34) 36 (26) 0.015 10 (33) 0.906
Prednisolone 99 (21) 45 (33) < 0.001 11 (37) 0.029
Rituximab 5 (1) 1 (1) 1.0 0 (0) 1.0
Vincristine 190 (40) 77 (56) < 0.001 23 (73) < 0.001
Vindesine 4 (1) 1 (1) 1.0 1 (3) 0.232
Parenteral fluid
Volume (mean ± SD) (mL/kg/d) 74 ± 31 74 ± 28 0.849 80 ± 33 0.321
Sodium concentration (mean ± SD) 52 ± 15 55 ± 15 0.002 60 ± 12 < 0.001
(mmol/L)
*P value for comparison of hyponatremia versus none.
wP value for comparison of moderate to severe hyponatremia versus none.
ALL indicates acute lymphoblastic leukemia; AML, acute myeloid leukemia; CNS, central nervous system; NHL, non-Hodgkin lymphoma; PS, per-
formance status; SCT, stem cell transplantation; TPN, total parenteral nutrition.

4 | www.jpho-online.com Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright r 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
 J Pediatr Hematol Oncol  Volume 00, Number 00, ’’ 2015
TABLE 3. Multivariate Analysis of Risk Factors for Hyponatremia
Overall Hyponatremia
Variables OR (95% CI) P OR (95% CI)
Age (y)
0-9 1.0
10-18 3.24 (2.07-5.07) < 0.001
TPN 8.15 (2.17-30.5) 0.002
Renal injury — 5.38 (2.15-13.5)
No. chemotherapy cycle
1-2 1.74 (1.12-2.70) 0.014
Z3 1.0
Chemotherapy agent
Carboplatin 6.51 (2.43-17.5) < 0.001
Ifosfamide — —
Vincristine 3.56 (2.25-5.63) < 0.001
CI indicates confidence interval; OR, odds ratio; TPN, total parenteral nutrition.
in patients with cancer. Taken together, these findings suggest
that there are at least 2 possible mechanisms of hyponatremia
during or after chemotherapy: SIADH and renal injury.
The present study had several inherent limitations. The
first limitation of this study is the relatively small patient
number, which may limit the power to detect statistical
differences. Second, the hospital-based population and the
fluid therapy given to all the patients make it hard to pre-
dict whether the findings are common in all children with
cancer. Third, the present study was not designed to iden-
tify the potential causes of hyponatremia observed in the
patients. Despite these limitations, this study provides novel
and clinically important information on hyponatremia in
patients with cancer. Most of the previous studies that
showed a poor prognostic impact of hyponatremia involved
adult patients.3,4 Further studies are needed to evaluate the
prognostic value of hyponatremia in children with cancer.
In conclusion, several risk factors for hyponatremia
during or after chemotherapy were identified in children
with cancer. The clinical conditions of patients at the ini-
tiation of the chemotherapy cycle as well as chemo-
therapeutic agents may have a profound impact on the
development of hyponatremia. Patients with these risk
factors should be managed carefully to prevent severe
symptoms and sequelae caused by hyponatremia.
REFERENCES
1. Upadhyay A, Jaber BL, Madias NE. Epidemiology of
hyponatremia. Semin Nephrol. 2009;29:227–238.
2. Adrogue HJ. Consequences of inadequate management of
hyponatremia. Am J Nephrol. 2005;25:240–249.
3. Doshi SM, Shah P, Lei X, et al. Hyponatremia in hospitalized
cancer patients and its impact on clinical outcomes. Am J Kid
Dis. 2012;59:222–228.
4. Hampshire PA, Welch CA, McCrossan LA, et al. Admission
factors associated with hospital mortality in patients with
haematological malignancy admitted to UK adult, general
critical care units: a secondary analysis of the ICNARC Case
Mix Programme Database. Crit Care. 2009;13:R137.
5. Hoorn EJ, Geary D, Robb M, et al. Acute hyponatremia related
to intravenous fluid administration in hospitalized children: an
observational study. Pediatrics. 2004;113:1279–1284.
6. Moritz ML, Ayus JC. New aspects in the pathogenesis,
prevention, and treatment of hyponatremic encephalopathy
in children. Pediatr Nephrol. 2010;25:1225–1238.
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright r 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Analysis of Risk Factors for Hyponatremia
Moderate to Severe Hyponatremia
P
—
—
—
< 0.001
—
—
—
8.03 (1.83-35.2) 0.006
5.90 (2.24-15.5) < 0.001
7. Carandang F, Anglemyer A, Longhurst CA, et al. Association
between maintenance fluid tonicity and hospital-acquired
hyponatremia. J Pediatr. 2013;163:1646–1651.
8. Castillo JJ, Vincent M, Justice E. Diagnosis and management
of hyponatremia in cancer patients. Oncologist. 2012;17:
756–765.
9. Williams CN, Belzer JS, Riva-Cambrin J, et al. The incidence
of postoperative hyponatremia and associated neurological
sequelae in children with intracranial neoplasms. J Neurosurg
Pediatr. 2014;13:283–290.
10. Spasovski G, Vanholder R, Allolio B, et al. Clinical practice
guideline on diagnosis and treatment of hyponatraemia. Eur J
Endocrinol. 2014;170:G1–G47.
11. Mehta RL, Kellum JA, Shah SV, et al. Acute Kidney Injury
Network: report of an initiative to improve outcomes in acute
kidney injury. Crit Care. 2007;11:R31.
12. Oken MM, Creech RH, Tormey DC, et al. Toxicity and
response criteria of the Eastern Cooperative Oncology Group.
Am J Clin Oncol. 1982;5:649–655.
13. Peduzzi P, Concato J, Kemper E, et al. A simulation study of
the number of events per variable in logistic regression
analysis. J Clin Epidemiol. 1996;49:1373–1379.
14. Kobayashi R, Iguchi A, Nakajima M, et al. Hyponatremia and
syndrome of inappropriate antidiuretic hormone secretion
complicating stem cell transplantation.. Bone Marrow Trans-
plant. 2004;34:975–979.
15. Lim YJ, Park EK, Koh HC, et al. Syndrome of inappropriate
secretion of antidiuretic hormone as a leading cause
of hyponatremia in children who underwent chemotherapy
or stem cell transplantation. Pediatr Blood Cancer. 2010;54:
734–737.
16. Choong K, Arora S, Cheng J, et al. Hypotonic versus isotonic
maintenance fluids after surgery for children: a randomized
controlled trial. Pediatrics. 2011;128:857–866.
17. Wang J, Xu E, Xiao Y. Isotonic versus hypotonic maintenance
IV fluids in hospitalized children: a meta-analysis. Pediatrics.
2014;133:105–113.
18. Berghmans T. Hyponatremia related to medical anticancer
treatment. Support Care Cancer. 1996;4:341–350.
19. Hammond IW, Ferguson JA, Kwong K, et al. Hyponatremia
and syndrome of inappropriate anti-diuretic hormone reported
with the use of Vincristine: an over-representation of Asians?
Pharmacoepidemiol Drug Saf. 2002;11:229–234.
20. Hamdi T, Latta S, Jallad B, et al. Cisplatin-induced renal salt
wasting syndrome. South Med J. 2010;103:793–799.
21. Lee YC, Park JS, Lee CH, et al. Hyponatraemia induced by
low-dose intravenous pulse cyclophosphamide. Nephrol Dial
Transplant. 2010;25:1520–1524.
22. Nachman JB, La MK, Hunger SP, et al. Young adults with
acute lymphoblastic leukemia have an excellent outcome with
chemotherapy alone and benefit from intensive postinduction
5 www.jpho-online.com |
 Kishimoto et al J Pediatr Hematol Oncol  Volume 00, Number 00, ’’ 2015

treatment: a report from the children’s oncology group. J Clin
Oncol. 2009;27:5189–5194.
23. Pui CH, Pei D, Campana D, et al. Improved prognosis for
older adolescents with acute lymphoblastic leukemia. J Clin
Oncol. 2011;29:386–391.
24. Launay-Vacher V, Oudard S, Janus N, et al. Prevalence of
renal insufficiency in cancer patients and implications for
anticancer drug management: the renal insufficiency and
anticancer medications (IRMA) study. Cancer. 2007;110:
1376–1384.
25. Darmon M, Ciroldi M, Thiery G, et al. Clinical review: specific
aspects of acute renal failure in cancer patients. Crit Care.
2006;10:211.
26. Bartter FC, Schwartz WB. The syndrome of inappropriate
secretion of antidiuretic hormone. Am J Med. 1967;42:
790–806.

6 | www.jpho-online.com Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright r 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.