APRIL 2018, VOL. 22 NO. 2 CLINICAL JOURNAL OF ONCOLOGY NURSING.docx

APRIL 2018, VOL. 22 NO. 2 CLINICAL JOURNAL OF
ONCOLOGY NURSING 175CJON.ONS.ORG
C
Nephrotoxicity
Evidence in patients receiving cisplatin therapy
Elizabeth A. Duffy, DNP, RN, CPNP, Wendy Fitzgerald, RN,
MSN, PPCNP-BC, CPON®, Kelley Boyle, MSN, RN, PCNS-
BC, and Radha Rohatgi, PharmD, BCOP
CISPLATIN IS A PLATINUM COMPOUND THAT HAS BEEN
USED as a chemotherapeutic
agent for many different cancers, including ovarian, testicular,
lung, cervical,
and bladder cancers (Ruggiero, Rizzo, Trombatore, Maurizi, &
Riccardi, 2016;
Santoso, Lucci, Coleman, Shafer, & Hannigan, 2003). The
primary dose-
limiting toxicity of cisplatin is nephrotoxicity, a well-known
side effect
(Jones, Spunt, Green, & Springate, 2008; Miller, Tadagavadi,
Ramesh, &
Reeves, 2010). Nephrotoxicity involves glomerular or tubular
dysfunction
of the kidneys after exposure to medications, other treatments,
or toxins
(Skinner, 2011). Nephrotoxicity associated with cisplatin is
related to accu-
mulation of metabolites in the renal proximal tubule cells of the
kidneys,
where about 90% of cisplatin undergoes urinary excretion

(Ruggiero et al.,
2016). Accumulation of these metabolites causes direct
inflammation; the
production of reactive oxygen species, which leads to oxidative
cell damage;
and cell death (Miller et al., 2010; Ruggiero et al., 2016). Many
methods are
available to measure kidney function and define nephrotoxicity
or acute
kidney injury (see Table 1).
Most patients receiving cisplatin experience acute impairment
of glo-
merular and tubular function in varying degrees. Toxicity is
dependent on
individual cisplatin pharmacokinetics and is usually more
severe with high
total cisplatin doses and when other potential nephrotoxic
medications are
given concurrently (Skinner, 2011; Womer, Pritchard, &
Barratt, 1985). In one
study, children aged 10 years or older at treatment had a lower
glomerular
filtration rate 10 years after therapy compared to children aged
younger than
10 years at treatment (Skinner et al., 2009).
Nephrotoxicity can be reversible, but for some individuals, it
can result
in permanent kidney injury, chronic progressive renal failure, or
renal tubule
function impairment (Skinner et al., 2009). Chronic and severe
reductions
of renal function have several sequelae. The immediate impact
may be dose
reduction or cessation of potentially lifesaving nephrotoxic

chemotherapy,
thereby increasing the risk of relapse or progression of the
cancer. In the
event of a disease relapse or progression, changes to renal
function may limit
enrollment in phase 1 or 2 clinical trials because of inclusion
parameters
related to baseline renal function.
Hydration and diuretics have been used in conjunction with
cisplatin
administration for decades to improve the excretion of cisplatin
and reduce
the incidence of nephrotoxicity. One method of promoting this
excretion is
through osmotic diuresis with mannitol (Morgan et al., 2014).
However, the
amount of hydration, the infusion time for hydration, and the
use of diuretics
vary among treatment protocols. The optimal hydration and
diuretic reg-
imen necessary to prevent cisplatin nephrotoxicity is unknown.
KEYWORDS
cisplatin; hydration; nephrotoxicity;
cancer; mannitol; magnesium
DIGITAL OBJECT IDENTIFIER
10.1188/18.CJON.175-183
BACKGROUND: Cisplatin has been used as a
chemotherapeutic agent to treat many different

cancers. A well-known side effect of cisplatin is
nephrotoxicity, which is the primary dose-limiting
toxicity. Hydration in conjunction with appropriate
diuresis can decrease the incidence of nephro-
toxicity.
OBJECTIVES: This article aims to identify best
practices in supportive therapy for patients receiv-
ing cisplatin therapy.
METHODS: A team was assembled to review
research-based evidence and summarize rec-
ommendations to address appropriate hydration
regimens and forced diuresis for patients receiving
cisplatin chemotherapy.
FINDINGS: After a systematic search of the
literature, only one pediatric study was found.
The remaining 22 research-based studies of
adults were synthesized and critically appraised.
Hydration is necessary to prevent nephrotoxicity

with cisplatin administration. In addition, the
administration of magnesium and mannitol may
assist in maintaining renal function and reducing
nephrotoxicity in adults receiving cisplatin. Addi-
tional research is needed to evaluate outcomes of
these interventions in the pediatric population.
✔
176 CLINICAL JOURNAL OF ONCOLOGY NURSING APRIL
2018, VOL. 22 NO. 2 CJON.ONS.ORG
NEPHROTOXICITY
Evidence-Based Guideline Development
Methods
To identify best practices, the current authors conducted a
systematic review to identify optimal hydration and diuretic
reg-
imens to prevent nephrotoxicity in patients receiving cisplatin
therapy. The team included a pediatric nurse practitioner as
team
leader, a pharmacist, two nurses, and a mentor with experience
in
evidence-based reviews.
The team developed the following two clinical questions that
helped identify a population, intervention, and outcome

(Melnyk
& Fineout-Overholt, 2015) to guide the systematic review:
ɐ Among patients receiving cisplatin chemotherapy (including
various doses and infusion duration), what is an appropriate
regimen of hydration and/or forced diuresis to prevent or
decrease the incidence of nephrotoxicity?
various doses and infusion duration), what regimen of hydra-
tion and/or forced diuresis promotes kidney function?
A systematic search of the literature was performed with guid-
ance from a medical librarian. The search included the
following
databases: PubMed, CINAHL®, and the Cochrane Library.
Keywords
and Medical Subject Heading (MeSH) terms consisted of
cisplatin,
nephrotoxicity and nephrotoxicity prevention, mannitol,
hydration,
magnesium, diuresis, mannitol, and furosemide. Limits were set
for
the English language and human studies. None were set
regarding
patient age in an effort to find all evidence related to the topic.
Research studies, meta-analyses, and guidelines were included.
In
addition, the team searched the websites of the American
Society
of Clinical Oncology, the Oncology Nursing Society, and the
Association of Pediatric Hematology/Oncology Nurses, and
Wolters
Kluwer’s UpToDate site for guidelines related to the topic.

The initial search was conducted in March 2015 with no pub-
lication limit identified. A repeat search of the literature was
performed in March 2016 using the same databases, keywords
and
MeSH terms, and limits. A publication date limit of March 2015
to March 2016 was applied to the repeat search and revealed six
new articles. Figure 1 illustrates the literature exclusion
process.
Based on expert consensus of the team, articles that evaluated
oral
fluids as the sole source of hydration were excluded because of
the
improbability of patients tolerating large volumes of oral
hydration
during chemotherapy treatment. In addition, articles including
hypertonic saline were excluded because no clinical indication
sug-
gests the use of this fluid for routine hydration (Platania,
Verzoni,
& Vitali, 2015). Ultimately, 23 articles were identified, which
included all age ranges and which are summarized in the current
evidence-based review. Only one pediatric study was discovered
in
the search, which is summarized. Most of this review consists
of a
synthesis of evidence from studies of adults. The evidence
quality
was graded using the Grading of Recommendations Assessment,
Development, and Evaluation system (Guyatt et al., 2011).
Four clinical practice guidelines were identified from the
search.
One guideline (UpToDate) was not included because of its
paucity
of references; two guidelines from the American Society of
Clinical

Oncology were excluded because they did not include
recommen-
dations regarding hydration or diuresis. The remaining
guideline by
Launay-Vacher, Rey, Isnard-Bagnis, Deray, and Daouphars
(2008)
was evaluated with the Appraisal of Guidelines for Research
and
Evaluation II tool. Because of its low rating, the authors did not
include this guideline in the body of evidence.
Evidence Review
Pediatric Review
Zareifar et al. (2013) evaluated tubular kidney function in a
cohort
of 20 children receiving cisplatin 50–75 mg/m2 every three
weeks for
TABLE 1.
MEASURES OF KIDNEY FUNCTION REPORTED
IN THE EVIDENCE REVIEW
MEASURE MEASUREMENT MODALITY TOXICITY
DEFINITION
Creatinine
clearance
Rate at which creatinine
is cleared from the body;
determined by the amount
of creatinine excreted in the
urine in a given time period
(usually 12 or 24 hours)
compared to the amount

circulating in the blood,
expressed in ml/min/1.73 m2
Decreased level based
on age
CTCAE
Standardized definitions of
toxicities among patients
receiving cancer treatment
Change in serum creatinine
from baseline and if dialysis
is indicated (CTCAE, version
4.03); studies prior to 2010
used 4.0 version.
Glomerular
filtration rate
Plasma or urinary clearance
of exogenously adminis-
tered substance expressed
in ml/min/1.73 m2
on age
RIFLE
Classification for acute
kidney injury based on
assignment of RIFLE disease
determined by urine output,
serum creatinine, and
length of abnormal function

Changes in scores within
7 days
Serum
creatinine
Level of creatinine in the
blood expressed in mg/dl
Increase of a laboratory
determined upper limit
of normal based on age;
increase by more than 25%
over baseline
Urinary
activity
of NAG
Urine test reported as
u/L, u/mmol of creatinine
(normalized)
Increased urinary NAG
excretion correlates with
renal tubular damage.
CTCAE—Common Terminology Criteria for Adverse Events;
min—minute; NAG—N-
acetyl-beta-D-glucosaminidase; RIFLE—Risk, Injury, Failure,
Loss, and End-Stage
Note. Based on information from Bellomo et al., 2007; Murray
et al., 2013; National
Cancer Institute, 2010; Stevens et al., 2006.

CJON.ONS.ORG
treatment of neuroblastoma or germ cell tumors. Children
received
3 L/m2 of hydration and mannitol every 6 hours starting 24
hours
before cisplatin and continuing for one day following cisplatin.
The
children also received magnesium sulfate infusions every 12
hours
for a total of four doses. No significant change in the mean
glomer-
ular function rate was observed before cisplatin treatment
(119.81
ml/minute/1.73 m2, SD = 36.82) compared to the mean after the
third
cisplatin treatment (127.37 ml/minute/1.73 m2, SD = 38.99, p =
0.638).
Hydration
Nephrotoxicity was described in nine studies among adults
receiv-
ing cisplatin therapy by either comparing hydration regimens,
short
versus traditional hydration (n = 4), or evaluating renal
outcomes
with one specific hydration regimen (n = 5). A short hydration
reg-
imen was commonly delivered on an outpatient basis and ranged
from 1,750–4,200 ml of fluid delivered on the day of cisplatin

therapy, whereas a traditional hydration regimen was commonly
delivered on an inpatient basis and consisted of a total of
5,500–
6,300 ml of fluid delivered during multiple days (see Table 2).
No statistically significant difference in renal function or
nephrotoxicity was reported among adults receiving short versus
traditional hydration regimens (Al Bahrani, Moylan, Forouzesh,
Della-Fiorentina, & Goldrick, 2009; Oka et al., 2014; Ouchi,
Asano, Aono, Watanabe, & Kato, 2014). In two of the studies,
serum creatinine (SCR) and creatinine clearance (CRCL) were
stable between both groups (Al Bahrani et al., 2009; Ouchi et
al., 2014); however, one study showed a significant increase in
SCR among the traditional hydration group members, whereas
the SCR of the short hydration group members remained stable
(Sakaida et al., 2016). In addition, no significant differences
were
observed in renal toxicity according to the Common
Terminology
Criteria for Adverse Events (CTCAE), version 4.0, among
individ-
uals receiving traditional versus short hydration regimens (Oka
et
al., 2014; Ouchi et al., 2014). However, grade 2 toxicity was
noted
among one of the 17 adult patients receiving 2.2 L of fluid on
the
day of cisplatin followed with oral hydration (Oka et al., 2014).
Five studies described renal function or nephrotoxicity after
patients received short hydration (from 1,400–3,000 ml) of fluid
on the day of cisplatin administration. Most studies revealed
that
short hydration was safe in preventing renal dysfunction and
tox-
icity (Horinouchi et al., 2013; Hotta et al., 2013; Lavolé et al.,

2012;
Tiseo et al., 2007; Vogl, Zaravinos, Kaplan, & Wollner, 1981).
After
several courses of cisplatin, only 3 of 242 patients had SCR
levels
greater than 2 mg/dl and 1 patient had a SCR level greater than
3
mg/dl (Vogl et al., 1981). Other evidence reported no
significant
change in median SCR or median CRCL among adults receiving
multiple cycles of cisplatin at 75 mg/m2 or greater (Tiseo et al.,
2007). After multiple cisplatin cycles, a grade 2 or higher renal
tox-
icity according to CTCAE, version 4.0, was noted in only 0.3%–
8.6%
of patients receiving 1,450–2,250 ml hydration on the day of
cis-
platin (Horinouchi et al., 2013; Hotta et al., 2013; Lavolé et al.,
2012).
Magnesium
Seven studies evaluated magnesium as an IV supplement, an
additive to IV hydration, and/or an oral supplement. Results
indi-
cated either an increase in CRCL along with a decrease in SCR
(Muraki et al., 2012) or stable CRCL and SCR (Bodnar et al.,
2008; Oka et al., 2014; Willox, McAllister, Sangster, & Kaye,
1986;
Yamamoto et al., 2015) when patients received magnesium sup-
plementation before, during, or after cisplatin therapy. Among
the studies reporting nephrotoxicity according to CTCAE, less
nephrotoxicity was noted in patients who received magnesium
supplements compared to the control groups (Kidera et al.,
2014;
Yoshida et al., 2014). In addition, a lower relative risk of
nephro-

toxicity according to the Risk, Injury, Failure, Loss, and End-
Stage
kidney disease classification was noted among patients
receiving
magnesium compared to patients who did not receive
magnesium
(7% versus 50% risk, p = 0.03) (Yamamoto et al., 2015).
Patients
who did not receive magnesium supplements had a statistically
significant decrease in CRCL and statistically significant
increase
in SCR (Bodnar et al., 2008; Oka et al., 2014). In addition,
multi-
variate analysis revealed that the absence of magnesium
infusion
was a significant independent factor for decreased CRCL (p <
0.001) (Oka et al., 2014). Bodnar et al. (2008) and Willox et al.
(1986) treated patients with magnesium three times per day in
between chemotherapy cycles, but no evidence suggested that
this provided any additional nephroprotection to the regimen.
Furosemide
Three studies examined the role of furosemide in cisplatin-
associated nephrotoxicity. Ostrow et al. (1981) found no signifi-
cant differences in SCR, CRCL, or nephrotoxicity among
patients
receiving furosemide 40 mg immediately prior to cisplatin com-
pared to mannitol 37.5 g by a six-hour infusion with cisplatin.
The
FIGURE 1.
PRISMA DIAGRAM OF SEARCH STRATEGY
PRISMA—Preferred Reporting Items for Systematic Reviews
and Meta-Analyses

Records excluded because of
evaluation of animals, basic
or systematic reviews, or no
evaluation of nephrotoxicity
(n = 293)
Records identified through
database search and
screened after duplicates
removed (n = 326)
Full-text articles assessed for
eligibility (n = 33)
Studies included in evidence
(N = 23)
Full-text articles excluded
because of evaluation of drug
efficacy or dependence on
oral hydration (n = 10)

NEPHROTOXICITY
TABLE 2.
LITERATURE ON HYDRATION AND DIURETIC
SUPPLEMENTATION IN ADULTS RECEIVING CISPLATIN
STUDY SAMPLE AND CISPLATIN DOSE HYDRATION
AND/OR DIURETIC FINDINGS
Short versus traditional hydration
Al Bahrani et al., 2009
145 adults, 88 outpatients on short
hydration and 57 inpatients on traditional
hydration
Outpatient hydration: prehydration 2,000
ml, then cisplatin 1,000 ml, then 100
ml posthydration; inpatient hydration:
same as outpatient except extra 2,000 ml
posthydration
Mean basal serum CRCL (input = 75 ml/
minute, output = 84 ml/minute); no
statistically significant difference between
groups in maximum mean percentage
change from baseline to maximum SCR,
from baseline to 2 months postinfusion
SCR, or with different cisplatin doses
Oka et al., 2014

85 adults, 41 on high volume without
magnesium, 27 on high volume with
magnesium, and 17 on low volume with
magnesium
High volume without magnesium: total
volume 3.55 L on day 1 and 950 ml on days
2 and 3; high volume with magnesium:
total 3.55 L on day 1 and 950 ml on days 2
and 3; low volume with magnesium: total
2.2 L on day 1 and oral hydration only on
days 2 and 3
Maximum toxicity grade according to
SCR; high volume without magnesium:
22 patients with grade 1, 17 with grade 2,
2 with grade 3; high volume with magne-
sium: 26 with grade 1; low volume with
magnesium: 15 with grade 1, 1 with grade 2
Ouchi et al., 2014
30 adults, 13 on short hydration and 17 on
continuous (traditional) hydration
Short hydration: prehydration of 1,000
ml, then cisplatin 500 ml, then 500 ml;
continuous hydration: normal saline or
maintenance solution over 24 hours in
hospital (rate not reported)
No SCR differences (p = 0.32): short hydra-
tion = 0.83 mg/dl, continuous hydration =
0.71 mg/dl; no CRCL differences (p =
0.39): short hydration = 68 ml/minute and
continuous hydration = 73 ml/minute; no

patients had grade 2 or higher toxicity with
short hydration, and 2 had grade 2 or higher
toxicity with continuous hydration.
Sakaida et al., 2016
143 adults, 74 on short hydration and 69
on traditional hydration
Short hydration: 700 ml, then cisplatin
(0–500 ml), then 500 ml followed with
oral hydration only; traditional hydration:
1–1.5 L the day before cisplatin, 2.1 L and
cisplatin (0–500 ml) on day 1, and 1 L on
days 2 and 3
SCR over 4 cycles: short hydration was
stable and traditional hydration increased.
Short hydration
Horinouchi et al., 2013
44 adults; cisplatin 75 mg/m2 or more
every 3 weeks
700 ml prehydration, then cisplatin in 250
ml, then 500 ml posthydration
After cycle 1, no patients had grade 2 or
greater toxicity; after cycle 3, 1 patient had
grade 2 or greater toxicity; post-treatment
SCR median = 0.75, range = 0.4–1.4
Hotta et al., 2013
every 3–4 weeks up to 6 cycles

ml, then 500 ml and patients requested
to drink at least 1 L of water on days 1–3
posthydration
After cycle 1, 2 patients had grade 2 or
greater toxicity; in cumulative cycles, 4 had
grade 2 or greater toxicity
Lavolé et al., 2012 357 adults; cisplatin 75 mg/m2 or more
2 L prehydration, then cisplatin in 250
ml; patients were monitored in clinic for
6 hours, then instructed to drink fluids at
home.
Cumulative cycles: 21 patients had neph-
rotoxicity, 20 had grade 1 toxicity, 1 had
grade 3 toxicity.
Tiseo et al., 2007
every 3 weeks
1 L prehydration, then cisplatin in 500 ml,
then 500 ml posthydration; furosemide
as needed for urine output 100 ml/
hour during the 2 hours before and after
cisplatin
5 patients had renal toxicity, 2 had grade 2,
1 had grade 4, and 2 had toxicity unrelated
to cisplatin; no change in median SCR (p =
0.36, median = 0.9 mg/dl, range = 0.5–1.8);
no change in median CRCL (p = 0.64,
median = 87 ml/minute, range = 40.5–183.5)

Vogl et al., 1981
158 adults; cisplatin 50 mg/m2 every 3–4
weeks
Cisplatin given 30 minutes after starting a
2-hour infusion of 2 L fluid
8 patients had SCR greater than 1.5 mg/dl;
3 patients had SCR greater than 2 mg/dl; 1
patient had SCR greater than 3 mg/dl.
Continued on the next page
TABLE 2. (CONTINUED)
Magnesium
Bodnar et al., 2008
40 adults, 20 with magnesium and 20 with
no magnesium; cisplatin 75 mg/m2
Magnesium sulfate 5 g in prehydration and
oral supplementation with magnesium

subcarbonate 500 mg 3 times per a day
between cycles until three weeks after
last cycle
Patients who received magnesium had no
significant alterations in renal function;
the control group showed significantly
increased SCR (p = 0.0069) and a reduction
in CRCL (p = 0.0077).
Kidera et al., 2014
401 adults, 67 with magnesium and 334
with no magnesium; cisplatin dose greater
than 60 mg/m2
Magnesium group had 2.5 g magnesium
sulfate posthydration
Nephrotoxicity was reported in 4 patients
who received magnesium versus 123
patients who did not receive magnesium
(p < 0.0001).
Muraki et al., 2012
Magnesium group: normal saline,
mannitol, and 8 meq magnesium sulfate;
no magnesium group: normal saline,
mannitol, and furosemide
Patients who received mannitol and
magnesium prior to cisplatin showed a
significantly greater increase in CRCL (p =
0.004) and decrease in SCR (p = 0.0148).

Oka et al., 2014
85 adults, 41 high volume without mag-
nesium, 27 high volume with magnesium,
and 17 low volume with magnesium
days 2 and 3
SCR: high volume without magnesium:
22 patients had grade 1, 17 had grade
2, and 2 had grade 3; high volume with
magnesium: 26 had grade 1; low volume
with magnesium: 15 had grade 1, and 1 had
grade 2; absence of magnesium infusion
was an independent factor for decreased
CRCL (p < 0.001).
Willox et al., 1986
17 adults, 8 with magnesium and 9 with no
magnesium; cisplatin 20 mg/m2 per day
for 5 days
Magnesium sulfate 8 mmol/500 ml and
citrate 10 mmol 3 times a day when IV
infusion was discontinued through the
next cycle
Patients who received magnesium had

significantly reduced renal tubule damage
as measured by NAG (p < 0.01) and fewer
treatment delays. CRCL and SCR did not
differ between the groups.
Yamamoto et al., 2015
no magnesium; cisplatin 40 mg/m2 per
week
Magnesium supplementation group had
prehydration with 15 meq and a daily dose
of 5 meq on days 2 and 3.
No-magnesium arm had a significant
increase (p < 0.05) in SCR (0.58–0.75 mg/
dl) and a significant decrease (p < 0.05)
in glomerular filtration rate (85.1 to 66.5
ml/minute); no significant change in the
magnesium arm; lower relative risk of
nephrotoxicity (according to RIFLE criteria)
in the magnesium group versus other
group (7% versus 50% risk, p = 0.03)
Yoshida et al., 2014
with no magnesium; cisplatin greater than
60 mg/m2
standard hydration, isotonic saline, and 8
meq magnesium sulfate prior to cisplatin;
no-magnesium supplementation group
had standard hydration.
9 patients in the magnesium preloading

group had an SCR grade greater than or
equal to 2; 64 patients in the nonmag-
nesium loading group had an SCR grade
greater than or equal to 2 (p < 0.001);
OR for first cycle = 0.262 (95% CI [0.106,
0.596]); OR during all cycles = 0.234 (95%
CI [0.129, 0.414])
Furosemide
Dumas et al., 1989
20 adults, 10 received furosemide and 10
received diuretic; cisplatin dose 80 mg/m2
Furosemide 20 mg/m2 prior to cisplatin
Mean SCR levels were significantly higher
in patients who received furosemide
versus those who did not (0.95 mg/dl
versus 0.76 mg/dl, p < 0.001), but no
significant differences in CRCL were
observed.
NEPHROTOXICITY

Furosemide (continued)
Muraki et al., 2012
50 adults, 30 received hydration with
furosemide and 20 received hydration
with mannitol and magnesium; cisplatin
75 mg/m2
Patients received either hydration, manni-
tol, and magnesium sulfate; or hydration,
mannitol, and 20 mg furosemide
Patients who received mannitol and mag-
nesium prior to cisplatin administration
showed a significantly greater increase in
CRCL (p = 0.004) and decrease in SCR (p =
0.0148); a hydration protocol supple-
mented with magnesium and mannitol
without furosemide was an independent
factor for the protection of cisplatin-
induced nephrotoxicity (OR = 0.232, 95%
CI [0.055, 0.986], p = 0.039).
Ostrow et al., 1981
22 adults, 10 with mannitol plus hydration
and 12 with furosemide plus hydration;
cisplatin 100 mg/m2
Mannitol 37.5 g plus hydration prior to
cisplatin; furosemide 40 mg plus hydration
before the start of cisplatin

Nephrotoxicity occurred in 28% of
patients who received mannitol and 19%
of patients who received furosemide;
no differences in SCR levels (p > 0.45)
or CRCL levels (p > 0.25) were observed
between the two groups.
Mannitol
Al-Sarraf et al., 1982
67 adults, 34 with mannitol and 33 with no
mannitol; cisplatin 100 mg/m2
Mannitol 12.5 g prior to cisplatin and 25 mg
following cisplatin
Significant renal toxicity after the first
dose of cisplatin was observed in 4% of
patients who received hydration and
mannitol and in 21% of patients who
received hydration alone.
Leu & Baribeault, 2010
92 adults, 46 with mannitol and 46 with
no mannitol; cisplatin dose greater than
40 mg/m2
Mannitol 12.5 g
Average decrease in CRCL between
the two groups; no difference between
hydration plus mannitol and hydration
alone (p = 0.09)
McKibbin et al., 2016

no mannitol; cisplatin 100 mg/m2
Mannitol 12.5 g prior to cisplatin
The addition of mannitol decreased the
incidence of grade 3 acute kidney injury;
nephrotoxicity was listed as a reason for
the discontinuation of therapy in 47% of
patients receiving mannitol compared to
60% of patients receiving saline alone (p =
0.69).
Morgan et al., 2014
143 adults, 85 with mannitol prior to
cisplatin and 58 with furosemide prior to
cisplatin; cisplatin 30–100 mg/m2
Patients who did not receive mannitol
with cisplatin had an increased likelihood
of developing acute kidney injury (OR =
2.646, 95% CI [1.008, 6.944], p = 0.048).
Muraki et al., 2012
mannitol and magnesium, and 30 received
hydration with furosemide; cisplatin 75
mg/m2
Hydration with mannitol and magnesium:
2,700 ml normal saline, 200 ml mannitol,
and 8 meq magnesium sulfate; hydration
with furosemide: 3,100 ml normal saline,

300 ml mannitol, and 20 mg furosemide
magnesium prior to the administration of
cisplatin showed a significantly greater
increase in CRCL (p = 0.004) and decrease
in SCR (p = 0.0148).
Ostrow et al., 1981
cisplatin 100 mg/m2
Mannitol 37.5 g
Nephrotoxicity = CRCL less than 50
and SCR greater than 2; nephrotoxicity
occurred in 19% of patients who received
furosemide and 28% of patients who
received mannitol.
Santoso et al., 2003
49 adults, 17 with saline and mannitol, 17
with saline and furosemide, and 15 with
saline alone; cisplatin 75 mg/m2
Mannitol 50 g
Mannitol arm found to be significantly
nephrotoxic; study was closed prematurely.
CI—confidence interval; CRCL—creatinine clearance; NAG—
N-acetyl-beta-D-glucosaminidase; OR—odds ratio; RIFLE—
Risk, Injury, Failure, Loss, and End-Stage; SCR—serum
creatinine

authors concluded that both diuretics exhibited similar effects.
Other researchers retrospectively evaluated 50 patients to com-
pare the effect of hydration with magnesium sulfate and
mannitol
versus hydration with furosemide 20 mg and mannitol on cispla-
tin-associated nephrotoxicity (Muraki et al., 2012). Hydration
with magnesium and mannitol was an independent factor in
the protection of patients against nephrotoxicity induced by
cisplatin. Finally, mean SCR concentrations were significantly
higher in patients who received furosemide 20 mg/m2 one hour
prior to cisplatin versus those who did not receive furosemide
prior to cisplatin, although no significant differences in CRCL
were observed between groups (Dumas et al., 1989).
Mannitol
Seven studies evaluated the effect of mannitol on cisplatin-
related nephrotoxicity. Three trials found no clear indication
that
mannitol is nephroprotective among adults receiving cisplatin
(Leu & Baribeault, 2010; Ostrow et al., 1981; Santoso et al.,
2003).
In one study of 22 patients receiving cisplatin, 28% of patients
who
received mannitol developed nephrotoxicity compared to 19% of
patients in the furosemide group, with the authors concluding
that
neither mannitol nor furosemide was superior in reducing the
fre-
quency of nephrotoxicity (Ostrow et al., 1981). In another
study, no
significant difference in CRCL was noted among patients
receiving

mannitol and hydration compared to hydration alone (Leu &
Baribeault, 2010). Santoso et al. (2003) found mannitol dosages
of
50 g to be significantly nephrotoxic and terminated the study
pre-
maturely because patients developed nephrotoxicity.
Four studies revealed that mannitol in conjunction with
high-dose cisplatin has a protective effect that allows patients
to
tolerate cisplatin without nephrotoxicity (Al-Sarraf et al., 1982;
McKibbin et al., 2016; Morgan et al., 2014; Muraki et al.,
2012).
Patients who received mannitol and magnesium demonstrated a
significantly greater increase in CRCL (p = 0.004) and decrease
in SCR (p = 0.0148) compared to patients receiving hydration
with mannitol, magnesium, and furosemide (Muraki et al.,
2012).
Morgan et al. (2014) also found improved outcomes in patients
who received mannitol, and reported a 2.6 increased likelihood
of
developing acute kidney injury among adults who did not
receive
mannitol with cisplatin (95% confidence interval [1.008, 6.944],
p = 0.048). They recommended the addition of mannitol with
hydration to prevent cisplatin-induced nephrotoxicity.
Quality of the Evidence
The quality of the hydration evidence was based on nine
research
articles. The evidence consisted of six retrospective studies and
three prospective studies (one nonrandomized, single-center,
phase 2 study; one feasibility study; and one cohort study).
Issues
related to the quality of the evidence included no report of
power

analysis in all studies, inconsistency issues among comparison
groups in two studies, and one potential publication bias
because
of a long lag time from study completion to publication. The
overall body of evidence for hydration was of low quality.
The magnesium evidence was based on seven research articles
consisting of two randomized clinical trials, four retrospective
chart reviews, and one historical prospective cohort study.
Issues
related to the quality of the evidence included lack of reported
power analyses in all studies. The overall body of evidence for
magnesium was of low quality.
The furosemide evidence is based on three research articles
consisting of two randomized, prospective, controlled studies
and
one retrospective chart review. Issues related to the quality of
the
evidence included lack of reported power analyses in all
studies.
The overall body of evidence for furosemide was of low quality.
The mannitol evidence is based on seven research studies. The
designs consisted of four retrospective studies and three
prospec-
tive studies (two randomized, controlled studies and one phase
2 study). Issues related to the quality of the evidence included
lack of reported power analysis in all studies. The overall body
of
evidence for mannitol was of low quality.
Summary of Recommendations
Hydration is necessary to prevent nephrotoxicity with cisplatin
administration; however, the amount, duration, and timing of

hydration for patients cannot be determined from the limited
evidence. In addition, administration of magnesium and
mannitol
may assist in maintaining renal function and reducing nephro-
toxicity in adults receiving cisplatin; however, limited evidence
precludes the ability to provide recommendations for children.
More research is needed to identify best practices for patients.
Limitations
Limitations in the literature review include limited evidence
about
the variation of practice patterns in different settings. There
could
be differences in patient management, particularly hydration
regimens and the use of diuretics, which varies depending on
treat-
ment setting. More research is needed to identify these
differences.
“The optimal
hydration and diuretic
regimen necessary
to prevent cisplatin
nephrotoxicity is
unknown.”
In addition, the literature is limited because of the inclusion
of diverse age groups. Only one pediatric study evaluated neph-
rotoxicity in children receiving cisplatin therapy, requiring
more

evaluation so conclusions can be determined among the
pediatric
population. Also, insufficient literature prevented the authors
from subcategorizing the adult population by age; additional
research should be conducted to evaluate the nephrotoxicity dif-
ferences among young, middle-aged, and older adult patients.
Last, this literature review does not include the effects of
other medications on nephrotoxicity. Researchers should con-
sider investigating the influence of nephrotoxic medications on
people receiving cisplatin therapy.
Implications for Nurses and Conclusion
Cisplatin is an integral component of chemotherapy regimens
for multiple cancers, and nephrotoxicity remains the primary
dose-limiting toxicity of this effective treatment. Hydration has
been shown to maintain renal function and decrease nephrotox-
icity in patients. In addition, magnesium supplementation has
demonstrated nephroprotective effects in adults when included
in
hydration regimens before, during, and after cisplatin.
Additional
research is needed to evaluate outcomes of these interventions
in
the pediatric population.
Research does not currently support the administration of
furosemide to prevent cisplatin-related nephrotoxicity in adults;
however, mannitol may prevent nephrotoxicity. The use of man-
nitol in conjunction with magnesium was an independent factor
in the protection of adults against nephrotoxicity induced by
high-dose cisplatin (Muraki et al., 2012). Additional research is
needed to evaluate these outcomes.
Nurses play a critical role in monitoring patients to prevent
cisplatin-induced nephrotoxicity. The administration of hydra-

tion and the use of medications to aid in diuresis during
cisplatin
therapy is essential. Maintaining accurate weights and intake
and
outputs along with monitoring laboratory values and assessing
for edema will help with early recognition of renal dysfunction.
The provision of patient education focusing on nephrotoxicity
prevention is an important component of the treatment regimen.
Although researchers have evaluated several supportive
strategies to minimize nephrotoxicity in patients receiving cis-
platin therapy, more research is needed. When more evidence is
available, best nephroprotective practices can be developed and
implemented. Until then, nurses should closely monitor kidney
function in all patients receiving cisplatin and immediately
report
abnormalities to the healthcare team.
Elizabeth A. Duffy, DNP, RN, CPNP, is a clinical assistant
professor in the School of
Nursing at the University of Michigan in Ann Arbor; Wendy
Fitzgerald, RN, MSN,
PPCNP-BC, CPON®, is a pediatric nurse practitioner in the
Center for Cancer and
Blood Disorders at the Children’s National Medical Center in
Washington, DC;
Kelley Boyle, MSN, RN, PCNS-BC, is a pediatric BMT nurse
coordinator at the
University of California, San Francisco, Benioff Children’s
Hospital; and Radha Ro-

hatgi, PharmD, BCOP, is a hematology/oncology and bone
marrow clinical phar-
macy specialist at the Children’s National Medical Center.
Duffy can be reached at
[email protected], with copy to [email protected] (Submitted
March
2017. Accepted June 19, 2017.)
The authors take full responsibility for this content. This
research was conducted by a team from
the Children’s Oncology Group Nursing Evidence-Based
Practice Subcommittee. The Children’s
Oncology Group is supported by a National Cancer
Institute/National Clinical Trials Network
Group Operations Center grant (U10CA180886; principal
investigator: Peter C. Adamson).
Fitzgerald serves on a speakers bureau for United Therapeutics.
During the writing of this article,
Rohatgi served on a speakers bureau for the Pediatric Pharmacy
Association. The article has been
reviewed by independent peer reviewers to ensure that it is
objective and free from bias.
REFERENCES
Al Bahrani, B.J., Moylan, E.J., Forouzesh, B., Della-Fiorentina,
S.A., & Goldrick, A.J. (2009). A

short outpatient hydration schedule for cisplatin administration.
Gulf Journal of Oncology,
5, 30–36.
Al-Sarraf, M., Fletcher, W., Oishi, N., Pugh, R., Hewlett, J.S.,
Balducci, L., . . . Padilla, F. (1982).
Cisplatin hydration with and without mannitol diuresis in
refractory disseminated malignant
melanoma: A Southwest Oncology Group study. Cancer
Treatment Reports, 66, 31–35.
Bellomo, R., Kellum, J.A., & Ronco, C. (2007). Defining and
classifying acute renal failure: From
advocacy to consensus and validation of the RIFLE criteria.
Intensive Care Medicine, 33,
409–413. https://doi.org/10.1007/s00134-006-0478-x
Bodnar, L., Wcislo, G., Gasowska-Bodnar, A., Synowiec, A.,
Szarlej-Wcisło, K., & Szczylik, C.
(2008). Renal protection with magnesium subcarbonate and
magnesium sulphate in
patients with epithelial ovarian cancer after cisplatin and
paclitaxel chemotherapy: A
randomised phase II study. European Journal of Cancer, 44,
2608–2614.
Dumas, M., de Gislain, C., d’Athis, P., Chadoint-Noudeau, V.,

Escousse, A., Guerrin, J., &
Autissier, N. (1989). Evaluation of the effect of furosemide on
ultrafilterable platinum
kinetics in patients treated with cis-diamminedichloroplatinum.
Cancer Chemotherapy and
Pharmacology, 23, 37–40. https://doi.org/10.1007/BF00258455
Guyatt, G., Oxman, A.D., Akl, E.A., Kunz, R., Vist, G., Brozek,
J., . . . Schünemann, H.J. (2011).
GRADE guidelines: 1. Introduction—GRADE evidence profiles
and summary of findings tables.
Journal of Clinical Epidemiology, 64, 383–394.
https://doi.org/10.1016/j.jclinepi.2010.04.026
Horinouchi, H., Kubota, K., Itani, H., Taniyama, T.K.,
Nakamichi, S., Wakui, H., . . . Tamura, I.S.T.
(2013). Short hydration in chemotherapy containing cisplatin (≥
75 mg/m2) for patients with
lung cancer: A prospective study. Japanese Journal of Clinical
Oncology, 43, 1105–1109.
Hotta, K., Takigawa, N., Hisamoto-Sato, A., Ichihara, E., Kudo,
K., Uchida, K., . . . Kiura, K. (2013).
Reappraisal of short-term low-volume hydration in cisplatin-
based chemotherapy: Results
of a prospective feasibility study in advanced lung cancer in the
Okayama Lung Cancer

Study Group Trial 1002. Japanese Journal of Clinical Oncology,
43, 1115–1123.
Jones, D.P., Spunt, S.L., Green, D., & Springate, J.E. (2008).
Renal late effects in patients treated
for cancer in childhood: A report from the Children’s Oncology
Group. Pediatric Blood and
Cancer, 51, 724–731. https://doi.org/10.1002/pbc.21695
IMPLICATIONS FOR PRACTICE
ɔ Deliver hydration to patients receiving cisplatin therapy to
maintain
renal function.
ɔ Include magnesium supplementation, which has
nephroprotective
effects in adults, in hydration regimens before, during, and after
cisplatin.
ɔ Add mannitol to hydration to prevent cisplatin-induced
nephrotoxicity in adults.
NEPHROTOXICITY

Kidera, Y., Kawakami, H., Sakiyama, T., Okamoto, K., Tanaka,
K., Takeda, M., . . . Nakagawa,
K. (2014). Risk factors for cisplatin-induced nephrotoxicity and
potential of magnesium
supplementation for renal protection. PLOS ONE, 9(7),
e101902. https://doi.org/10.1371/
journal.pone.0101902
Launay-Vacher, V., Rey, J.-B., Isnard-Bagnis, C., Deray, G., &
Daouphars, M. (2008). Prevention
of cisplatin nephrotoxicity: State of the art and
recommendations from the European
Society of Clinical Pharmacy Special Interest Group on Cancer
Care. Cancer Chemotherapy
and Pharmacology, 61, 903–909.
https://doi.org/10.1007/s00280-008-0711-0
Lavolé, A., Danel, S., Baudrin, L., Gounant, V., Ruppert, A.M.,
Epaud, C., . . . Milleron, B. (2012).
Routine administration of a single dose of cisplatin ≥ 75 mg/m2
after short hydration in an
outpatient lung-cancer clinic. Bulletin du Cancer, 99, E43–E48.
Leu, L., & Baribeault, D. (2010). A comparison of the rates of
cisplatin (cDDP)-induced
nephrotoxicity associated with sodium loading or sodium
loading with forced diuresis as a

preventative measure. Journal of Oncology Pharmacy Practice,
16, 167–171. https://doi
.org/10.1177/1078155209346071
McKibbin, T., Cheng, L.L., Kim, S., Steuer, C.E., Owonikoko,
T.K., Khuri, F.R., . . . Saba, N.F. (2016).
Mannitol to prevent cisplatin-induced nephrotoxicity in patients
with squamous cell cancer
of the head and neck (SCCHN) receiving concurrent therapy.
Supportive Care in Cancer, 24,
1789–1793. https://doi.org/10.1007/s00520-015-2978-0
Melnyk, B.M., & Fineout-Overholt, E. (2015). Evidence-based
practice in nursing and health-
care: A guide to best practice (3rd ed.). Philadelphia, PA:
Lippincott Williams and Wilkins.
Miller, R.P., Tadagavadi, R.K., Ramesh, G., & Reeves, W.B.
(2010). Mechanisms of cisplatin
nephrotoxicity. Toxins, 2, 2490–2518.
https://doi.org/10.3390/toxins2112490
Morgan, K.P., Snavely, A.C., Wind, L.S., Buie, L.W., Grilley-
Olson, J., Walko, C.M., & Weiss, J.
(2014). Rates of renal toxicity in cancer patients receiving
cisplatin with and without manni-
tol. Annals of Pharmacotherapy, 48, 863–869.

https://doi.org/10.1177/1060028014533303
Muraki, K., Koyama, R., Honma, Y., Yagishita, S., Shukuya, T.,
Ohashi, R., . . . Takahashi, K. (2012).
Hydration with magnesium and mannitol without furosemide
prevents the nephrotoxicity
induced by cisplatin and pemetrexed in patients with advanced
non-small cell lung cancer.
Journal of Thoracic Disease, 4, 562–568.
https://doi.org/10.3978/j.issn.2072-1439.2012.10.16
Murray, A.W., Barnfield, M.C., Waller, M.L., Telford, T., &
Peters, A.M. (2013). Assessment of
glomerular filtration rate measurement with plasma sampling: A
technical review. Journal
of Nuclear Medicine Technology, 41, 67–75.
https://doi.org/10.2967/jnmt.113.121004
National Cancer Institute. (2010). Common terminology criteria
for adverse events [v.4.03].
Retrieved from http://bit.ly/2o2Zd4Y
Oka, T., Kimura, T., Suzumura, T., Yoshimoto, N., Nakai, T.,
Yamamoto, N., . . . Hirata, K. (2014).
Magnesium supplementation and high volume hydration reduce
the renal toxicity caused
by cisplatin-based chemotherapy in patients with lung cancer: A
toxicity study. BMC Phar-

macology and Toxicology, 15, 70. https://doi.org/10.1186/2050-
6511-15-70
Ostrow, S., Egorin, M.J., Hahn, D., Markus, S., Aisner, J.,
Chang, P., . . . Wiernik, P.H. (1981).
High-dose cisplatin therapy using mannitol versus furosemide
diuresis: Comparative
pharmacokinetics and toxicity. Cancer Treatment Reports, 65,
73–78.
Ouchi, A., Asano, M., Aono, K., Watanabe, T., & Kato, T.
(2014). Comparison of short and contin-
uous hydration regimen in chemotherapy containing
intermediate- to high-dose cisplatin.
Journal of Oncology, 2014, 767652.
https://doi.org/10.1155/2014/767652
Platania, M., Verzoni, E., & Vitali, M. (2015). Hyponatremia in
cancer patients. Tumori, 101,
246–248. https://doi.org/10.5301/tj.5000257
Ruggiero, A., Rizzo, D., Trombatore, G., Maurizi, P., &
Riccardi, R. (2016). The ability of mannitol
to decrease cisplatin-induced nephrotoxicity in children: Real or
not? Cancer Chemother-
apy and Pharmacology, 77, 19–26.
https://doi.org/10.1007/s00280-015-2913-6

Sakaida, E., Iwasawa, S., Kurimoto, R., Ebata, T., Imai, C.,
Oku, T., . . . Takiguchi, Y. (2016). Safety
of a short hydration method for cisplatin administration in
comparison with a conventional
method—A retrospective study. Japanese Journal of Clinical
Oncology, 46, 370–377.
https://doi.org/10.1093/jjco/hyv203
Santoso, J.T., Lucci, J.A., 3rd, Coleman, R.L., Schafer, I., &
Hannigan, E.V. (2003). Saline, manni-
tol, and furosemide hydration in acute cisplatin nephrotoxicity:
A randomized trial. Cancer
Chemotherapy and Pharmacology, 52, 13–18.
https://doi.org/10.1007/s00280-003-0620-1
Skinner, R. (2011). Nephrotoxicity—What do we know and
what don’t we know? Journal of Pediat-
ric Hematology/Oncology, 33, 128–134.
https://doi.org/10.1097/MPH.0b013e3181f8cac0
Skinner, R., Parry, A., Price, L., Cole, M., Craft, A.W., &
Pearson, A.D.J. (2009). Persistent neph-
rotoxicity during 10-year follow-up after cisplatin or
carboplatin treatment in childhood:
Relevance of age and dose as risk factors. European Journal of
Cancer, 45, 3213–3219.
https://doi.org/10.1016/j.ejca.2009.06.032

Stevens, L.A., Coresh, J., Greene, T., & Levey, A.S. (2006).
Assessing kidney function—
Measured and estimated glomerular filtration rate. New England
Journal of Medicine, 354,
2473–2483. https://doi.org/10.1056/NEJMra054415
Tiseo, M., Martelli, O., Mancuso, A., Sormani, M.P., Bruzzi, P.,
Di Salvia, R., . . . Ardizzoni,
A. (2007). Short hydration regimen and nephrotoxicity of
intermediate to high-dose
cisplatin-based chemotherapy for outpatient treatment in lung
cancer and mesothelioma.
Tumori, 93, 138–144.
Vogl, S.E., Zaravinos, T., Kaplan, B.H., & Wollner, D. (1981).
Safe and effective two-hour
outpatient regimen of hydration and diuresis for the
administration of cis-
diamminedichloroplatinum (II). European Journal of Cancer, 17,
345–350.
Willox, J.C., McAllister, E.J., Sangster, G., & Kaye, S.B.
(1986). Effects of magnesium supplemen-
tation in testicular cancer patients receiving cis-platin: A
randomised trial. British Journal of
Cancer, 54, 19–23.

Womer, R.B., Pritchard, J., & Barratt, T.M. (1985). Renal
toxicity of cisplatin in children. Journal
of Pediatrics, 106, 659–663.
Yamamoto, Y., Watanabe, K., Tsukiyama, I., Matsushita, H.,
Yabushita, H., Matsuura, K., & Wakat-
suki, A. (2015). Nephroprotective effects of hydration with
magnesium in patients with
cervical cancer receiving cisplatin. Anticancer Research, 35,
2199–2204.
Yoshida, T., Niho, S., Toda, M., Goto, K., Yoh, K., Umemura,
S., . . . Ohe, Y. (2014). Protective
effect of magnesium preloading on cisplatin-induced
nephrotoxicity: A retrospective study.
Japanese Journal of Clinical Oncology, 44, 346–354.
https://doi.org/10.1093/jjco/hyu004
Zareifar, S., Jafari, H., Geramizadeh, B., Basiratnia, M.,
Golafshan, H., Cohan, N., . . . Hamidi, R.
(2013). The evaluation of cisplatin effect on tubular function in
children on chemotherapy.
Pediatric Hematology and Oncology, 30, 18–24.
https://doi.org/10.3109/08880018.2012
.737093
CNE ACTIVITY

EARN 0.5 CONTACT HOURS
ONS members can earn free CNE for reading this article and
completing
an evaluation online. To do so, visit cjon.ons.org/cne to link to
this article
and then access its evaluation link after logging in.
Certified nurses can claim no more than 0.5 total ILNA points
for this
program. Up to 0.5 ILNA points may be applied to Symptom
Management
OR Professional Practice. See www.oncc.org for complete
details on
certification.
Copyright of Clinical Journal of Oncology Nursing is the
property of Oncology Nursing
Society and its content may not be copied or emailed to multiple
sites or posted to a listserv
without the copyright holder's express written permission.
However, users may print,
download, or email articles for individual use.

C
Nephrotoxicity
Evidence in patients receiving cisplatin therapy
Elizabeth A. Duffy, DNP, RN, CPNP, Wendy Fitzgerald, RN,
MSN, PPCNP-BC, CPON®, Kelley Boyle, MSN, RN, PCNS-
BC, and Radha Rohatgi, PharmD, BCOP
CISPLATIN IS A PLATINUM COMPOUND THAT HAS BEEN
USED as a chemotherapeutic
agent for many different cancers, including ovarian, testicular,
lung, cervical,
and bladder cancers (Ruggiero, Rizzo, Trombatore, Maurizi, &
Riccardi, 2016;
Santoso, Lucci, Coleman, Shafer, & Hannigan, 2003). The
primary dose-
limiting toxicity of cisplatin is nephrotoxicity, a well-known
side effect
(Jones, Spunt, Green, & Springate, 2008; Miller, Tadagavadi,
Ramesh, &
Reeves, 2010). Nephrotoxicity involves glomerular or tubular
dysfunction
of the kidneys after exposure to medications, other treatments,
or toxins
(Skinner, 2011). Nephrotoxicity associated with cisplatin is
related to accu-
mulation of metabolites in the renal proximal tubule cells of the
kidneys,
where about 90% of cisplatin undergoes urinary excretion
(Ruggiero et al.,
2016). Accumulation of these metabolites causes direct
inflammation; the
production of reactive oxygen species, which leads to oxidative
cell damage;

and cell death (Miller et al., 2010; Ruggiero et al., 2016). Many
methods are
available to measure kidney function and define nephrotoxicity
or acute
kidney injury (see Table 1).
Most patients receiving cisplatin experience acute impairment
of glo-
merular and tubular function in varying degrees. Toxicity is
dependent on
individual cisplatin pharmacokinetics and is usually more
severe with high
total cisplatin doses and when other potential nephrotoxic
medications are
given concurrently (Skinner, 2011; Womer, Pritchard, &
Barratt, 1985). In one
study, children aged 10 years or older at treatment had a lower
glomerular
filtration rate 10 years after therapy compared to children aged
younger than
10 years at treatment (Skinner et al., 2009).
Nephrotoxicity can be reversible, but for some individuals, it
can result
in permanent kidney injury, chronic progressive renal failure, or
renal tubule
function impairment (Skinner et al., 2009). Chronic and severe
reductions
of renal function have several sequelae. The immediate impact
may be dose
reduction or cessation of potentially lifesaving nephrotoxic
chemotherapy,
thereby increasing the risk of relapse or progression of the
cancer. In the
event of a disease relapse or progression, changes to renal
function may limit

enrollment in phase 1 or 2 clinical trials because of inclusion
parameters
related to baseline renal function.
Hydration and diuretics have been used in conjunction with
cisplatin
administration for decades to improve the excretion of cisplatin
and reduce
the incidence of nephrotoxicity. One method of promoting this
excretion is
through osmotic diuresis with mannitol (Morgan et al., 2014).
However, the
amount of hydration, the infusion time for hydration, and the
use of diuretics
vary among treatment protocols. The optimal hydration and
diuretic reg-
imen necessary to prevent cisplatin nephrotoxicity is unknown.
KEYWORDS
cisplatin; hydration; nephrotoxicity;
cancer; mannitol; magnesium
DIGITAL OBJECT IDENTIFIER
10.1188/18.CJON.175-183
BACKGROUND: Cisplatin has been used as a
chemotherapeutic agent to treat many different
cancers. A well-known side effect of cisplatin is
nephrotoxicity, which is the primary dose-limiting

toxicity. Hydration in conjunction with appropriate
diuresis can decrease the incidence of nephro-
toxicity.
OBJECTIVES: This article aims to identify best
practices in supportive therapy for patients receiv-
ing cisplatin therapy.
METHODS: A team was assembled to review
research-based evidence and summarize rec-
ommendations to address appropriate hydration
regimens and forced diuresis for patients receiving
cisplatin chemotherapy.
FINDINGS: After a systematic search of the
literature, only one pediatric study was found.
The remaining 22 research-based studies of
adults were synthesized and critically appraised.
Hydration is necessary to prevent nephrotoxicity
with cisplatin administration. In addition, the
administration of magnesium and mannitol may

assist in maintaining renal function and reducing
nephrotoxicity in adults receiving cisplatin. Addi-
tional research is needed to evaluate outcomes of
these interventions in the pediatric population.
✔
NEPHROTOXICITY
Evidence-Based Guideline Development
Methods
To identify best practices, the current authors conducted a
systematic review to identify optimal hydration and diuretic
reg-
imens to prevent nephrotoxicity in patients receiving cisplatin
therapy. The team included a pediatric nurse practitioner as
team
leader, a pharmacist, two nurses, and a mentor with experience
in
evidence-based reviews.
The team developed the following two clinical questions that
helped identify a population, intervention, and outcome
(Melnyk
& Fineout-Overholt, 2015) to guide the systematic review:
various doses and infusion duration), what is an appropriate

regimen of hydration and/or forced diuresis to prevent or
decrease the incidence of nephrotoxicity?
various doses and infusion duration), what regimen of hydra-
tion and/or forced diuresis promotes kidney function?
A systematic search of the literature was performed with guid-
ance from a medical librarian. The search included the
following
databases: PubMed, CINAHL®, and the Cochrane Library.
Keywords
and Medical Subject Heading (MeSH) terms consisted of
cisplatin,
nephrotoxicity and nephrotoxicity prevention, mannitol,
hydration,
magnesium, diuresis, mannitol, and furosemide. Limits were set
for
the English language and human studies. None were set
regarding
patient age in an effort to find all evidence related to the topic.
Research studies, meta-analyses, and guidelines were included.
In
addition, the team searched the websites of the American
Society
of Clinical Oncology, the Oncology Nursing Society, and the
Association of Pediatric Hematology/Oncology Nurses, and
Wolters
Kluwer’s UpToDate site for guidelines related to the topic.
The initial search was conducted in March 2015 with no pub-
lication limit identified. A repeat search of the literature was
performed in March 2016 using the same databases, keywords
and
MeSH terms, and limits. A publication date limit of March 2015

to March 2016 was applied to the repeat search and revealed six
new articles. Figure 1 illustrates the literature exclusion
process.
Based on expert consensus of the team, articles that evaluated
oral
fluids as the sole source of hydration were excluded because of
the
improbability of patients tolerating large volumes of oral
hydration
during chemotherapy treatment. In addition, articles including
hypertonic saline were excluded because no clinical indication
sug-
gests the use of this fluid for routine hydration (Platania,
Verzoni,
& Vitali, 2015). Ultimately, 23 articles were identified, which
included all age ranges and which are summarized in the current
evidence-based review. Only one pediatric study was discovered
in
the search, which is summarized. Most of this review consists
of a
synthesis of evidence from studies of adults. The evidence
quality
was graded using the Grading of Recommendations Assessment,
Development, and Evaluation system (Guyatt et al., 2011).
Four clinical practice guidelines were identified from the
search.
One guideline (UpToDate) was not included because of its
paucity
of references; two guidelines from the American Society of
Clinical
Oncology were excluded because they did not include
recommen-
dations regarding hydration or diuresis. The remaining
guideline by
Launay-Vacher, Rey, Isnard-Bagnis, Deray, and Daouphars

(2008)
was evaluated with the Appraisal of Guidelines for Research
and
Evaluation II tool. Because of its low rating, the authors did not
include this guideline in the body of evidence.
Evidence Review
Pediatric Review
Zareifar et al. (2013) evaluated tubular kidney function in a
cohort
of 20 children receiving cisplatin 50–75 mg/m2 every three
weeks for
TABLE 1.
MEASURES OF KIDNEY FUNCTION REPORTED
IN THE EVIDENCE REVIEW
MEASURE MEASUREMENT MODALITY TOXICITY
DEFINITION
Creatinine
clearance
Rate at which creatinine
is cleared from the body;
determined by the amount
of creatinine excreted in the
urine in a given time period
(usually 12 or 24 hours)
compared to the amount
circulating in the blood,
expressed in ml/min/1.73 m2
on age

CTCAE
Standardized definitions of
toxicities among patients
receiving cancer treatment
Change in serum creatinine
from baseline and if dialysis
is indicated (CTCAE, version
4.03); studies prior to 2010
used 4.0 version.
Glomerular
filtration rate
Plasma or urinary clearance
of exogenously adminis-
tered substance expressed
in ml/min/1.73 m2
on age
RIFLE
Classification for acute
kidney injury based on
assignment of RIFLE disease
determined by urine output,
serum creatinine, and
length of abnormal function
Changes in scores within
7 days
Serum

creatinine
Level of creatinine in the
blood expressed in mg/dl
Increase of a laboratory
determined upper limit
of normal based on age;
increase by more than 25%
over baseline
Urinary
activity
of NAG
Urine test reported as
u/L, u/mmol of creatinine
(normalized)
Increased urinary NAG
excretion correlates with
renal tubular damage.
CTCAE—Common Terminology Criteria for Adverse Events;
min—minute; NAG—N-
acetyl-beta-D-glucosaminidase; RIFLE—Risk, Injury, Failure,
Loss, and End-Stage
Note. Based on information from Bellomo et al., 2007; Murray
et al., 2013; National
Cancer Institute, 2010; Stevens et al., 2006.

CJON.ONS.ORG
treatment of neuroblastoma or germ cell tumors. Children
received
3 L/m2 of hydration and mannitol every 6 hours starting 24
hours
before cisplatin and continuing for one day following cisplatin.
The
children also received magnesium sulfate infusions every 12
hours
for a total of four doses. No significant change in the mean
glomer-
ular function rate was observed before cisplatin treatment
(119.81
ml/minute/1.73 m2, SD = 36.82) compared to the mean after the
third
cisplatin treatment (127.37 ml/minute/1.73 m2, SD = 38.99, p =
0.638).
Hydration
Nephrotoxicity was described in nine studies among adults
receiv-
ing cisplatin therapy by either comparing hydration regimens,
short
versus traditional hydration (n = 4), or evaluating renal
outcomes
with one specific hydration regimen (n = 5). A short hydration
reg-
imen was commonly delivered on an outpatient basis and ranged
from 1,750–4,200 ml of fluid delivered on the day of cisplatin
therapy, whereas a traditional hydration regimen was commonly
delivered on an inpatient basis and consisted of a total of
5,500–
6,300 ml of fluid delivered during multiple days (see Table 2).

No statistically significant difference in renal function or
nephrotoxicity was reported among adults receiving short versus
traditional hydration regimens (Al Bahrani, Moylan, Forouzesh,
Della-Fiorentina, & Goldrick, 2009; Oka et al., 2014; Ouchi,
Asano, Aono, Watanabe, & Kato, 2014). In two of the studies,
serum creatinine (SCR) and creatinine clearance (CRCL) were
stable between both groups (Al Bahrani et al., 2009; Ouchi et
al., 2014); however, one study showed a significant increase in
SCR among the traditional hydration group members, whereas
the SCR of the short hydration group members remained stable
(Sakaida et al., 2016). In addition, no significant differences
were
observed in renal toxicity according to the Common
Terminology
Criteria for Adverse Events (CTCAE), version 4.0, among
individ-
uals receiving traditional versus short hydration regimens (Oka
et
al., 2014; Ouchi et al., 2014). However, grade 2 toxicity was
noted
among one of the 17 adult patients receiving 2.2 L of fluid on
the
day of cisplatin followed with oral hydration (Oka et al., 2014).
Five studies described renal function or nephrotoxicity after
patients received short hydration (from 1,400–3,000 ml) of fluid
on the day of cisplatin administration. Most studies revealed
that
short hydration was safe in preventing renal dysfunction and
tox-
icity (Horinouchi et al., 2013; Hotta et al., 2013; Lavolé et al.,
2012;
Tiseo et al., 2007; Vogl, Zaravinos, Kaplan, & Wollner, 1981).
After
several courses of cisplatin, only 3 of 242 patients had SCR
levels

greater than 2 mg/dl and 1 patient had a SCR level greater than
3
mg/dl (Vogl et al., 1981). Other evidence reported no
significant
change in median SCR or median CRCL among adults receiving
multiple cycles of cisplatin at 75 mg/m2 or greater (Tiseo et al.,
2007). After multiple cisplatin cycles, a grade 2 or higher renal
tox-
icity according to CTCAE, version 4.0, was noted in only 0.3%–
8.6%
of patients receiving 1,450–2,250 ml hydration on the day of
cis-
platin (Horinouchi et al., 2013; Hotta et al., 2013; Lavolé et al.,
2012).
Magnesium
Seven studies evaluated magnesium as an IV supplement, an
additive to IV hydration, and/or an oral supplement. Results
indi-
cated either an increase in CRCL along with a decrease in SCR
(Muraki et al., 2012) or stable CRCL and SCR (Bodnar et al.,
2008; Oka et al., 2014; Willox, McAllister, Sangster, & Kaye,
1986;
Yamamoto et al., 2015) when patients received magnesium sup-
plementation before, during, or after cisplatin therapy. Among
the studies reporting nephrotoxicity according to CTCAE, less
nephrotoxicity was noted in patients who received magnesium
supplements compared to the control groups (Kidera et al.,
2014;
Yoshida et al., 2014). In addition, a lower relative risk of
nephro-
toxicity according to the Risk, Injury, Failure, Loss, and End-
Stage
kidney disease classification was noted among patients
receiving
magnesium compared to patients who did not receive

magnesium
(7% versus 50% risk, p = 0.03) (Yamamoto et al., 2015).
Patients
who did not receive magnesium supplements had a statistically
significant decrease in CRCL and statistically significant
increase
in SCR (Bodnar et al., 2008; Oka et al., 2014). In addition,
multi-
variate analysis revealed that the absence of magnesium
infusion
was a significant independent factor for decreased CRCL (p <
0.001) (Oka et al., 2014). Bodnar et al. (2008) and Willox et al.
(1986) treated patients with magnesium three times per day in
between chemotherapy cycles, but no evidence suggested that
this provided any additional nephroprotection to the regimen.
Furosemide
Three studies examined the role of furosemide in cisplatin-
associated nephrotoxicity. Ostrow et al. (1981) found no signifi-
cant differences in SCR, CRCL, or nephrotoxicity among
patients
receiving furosemide 40 mg immediately prior to cisplatin com-
pared to mannitol 37.5 g by a six-hour infusion with cisplatin.
The
FIGURE 1.
PRISMA DIAGRAM OF SEARCH STRATEGY
PRISMA—Preferred Reporting Items for Systematic Reviews
and Meta-Analyses
Records excluded because of
evaluation of animals, basic

or systematic reviews, or no
evaluation of nephrotoxicity
(n = 293)
Records identified through
database search and
screened after duplicates
removed (n = 326)
Full-text articles assessed for
eligibility (n = 33)
Studies included in evidence
(N = 23)
Full-text articles excluded
because of evaluation of drug
efficacy or dependence on
oral hydration (n = 10)
NEPHROTOXICITY

TABLE 2.
Short versus traditional hydration
Al Bahrani et al., 2009
145 adults, 88 outpatients on short
hydration and 57 inpatients on traditional
hydration
Outpatient hydration: prehydration 2,000
ml, then cisplatin 1,000 ml, then 100
ml posthydration; inpatient hydration:
same as outpatient except extra 2,000 ml
posthydration
Mean basal serum CRCL (input = 75 ml/
minute, output = 84 ml/minute); no
statistically significant difference between
groups in maximum mean percentage
change from baseline to maximum SCR,
from baseline to 2 months postinfusion
SCR, or with different cisplatin doses
Oka et al., 2014
85 adults, 41 on high volume without
magnesium, 27 on high volume with
magnesium, and 17 on low volume with
magnesium

days 2 and 3
SCR; high volume without magnesium:
22 patients with grade 1, 17 with grade 2,
2 with grade 3; high volume with magne-
sium: 26 with grade 1; low volume with
magnesium: 15 with grade 1, 1 with grade 2
Ouchi et al., 2014
30 adults, 13 on short hydration and 17 on
continuous (traditional) hydration
Short hydration: prehydration of 1,000
ml, then cisplatin 500 ml, then 500 ml;
continuous hydration: normal saline or
maintenance solution over 24 hours in
hospital (rate not reported)
No SCR differences (p = 0.32): short hydra-
tion = 0.83 mg/dl, continuous hydration =
0.71 mg/dl; no CRCL differences (p =
0.39): short hydration = 68 ml/minute and
continuous hydration = 73 ml/minute; no
patients had grade 2 or higher toxicity with
short hydration, and 2 had grade 2 or higher
toxicity with continuous hydration.
Sakaida et al., 2016

143 adults, 74 on short hydration and 69
on traditional hydration
Short hydration: 700 ml, then cisplatin
(0–500 ml), then 500 ml followed with
oral hydration only; traditional hydration:
1–1.5 L the day before cisplatin, 2.1 L and
cisplatin (0–500 ml) on day 1, and 1 L on
days 2 and 3
SCR over 4 cycles: short hydration was
stable and traditional hydration increased.
Short hydration
Horinouchi et al., 2013
every 3 weeks
ml, then 500 ml posthydration
After cycle 1, no patients had grade 2 or
greater toxicity; after cycle 3, 1 patient had
grade 2 or greater toxicity; post-treatment
SCR median = 0.75, range = 0.4–1.4
Hotta et al., 2013
every 3–4 weeks up to 6 cycles
ml, then 500 ml and patients requested
to drink at least 1 L of water on days 1–3
posthydration

After cycle 1, 2 patients had grade 2 or
greater toxicity; in cumulative cycles, 4 had
grade 2 or greater toxicity
Lavolé et al., 2012 357 adults; cisplatin 75 mg/m2 or more
2 L prehydration, then cisplatin in 250
ml; patients were monitored in clinic for
6 hours, then instructed to drink fluids at
home.
Cumulative cycles: 21 patients had neph-
rotoxicity, 20 had grade 1 toxicity, 1 had
grade 3 toxicity.
Tiseo et al., 2007
every 3 weeks
1 L prehydration, then cisplatin in 500 ml,
then 500 ml posthydration; furosemide
as needed for urine output 100 ml/
hour during the 2 hours before and after
cisplatin
5 patients had renal toxicity, 2 had grade 2,
1 had grade 4, and 2 had toxicity unrelated
to cisplatin; no change in median SCR (p =
0.36, median = 0.9 mg/dl, range = 0.5–1.8);
no change in median CRCL (p = 0.64,
median = 87 ml/minute, range = 40.5–183.5)
Vogl et al., 1981
158 adults; cisplatin 50 mg/m2 every 3–4
weeks

Cisplatin given 30 minutes after starting a
2-hour infusion of 2 L fluid
8 patients had SCR greater than 1.5 mg/dl;
3 patients had SCR greater than 2 mg/dl; 1
patient had SCR greater than 3 mg/dl.
Magnesium
Bodnar et al., 2008
Magnesium sulfate 5 g in prehydration and
subcarbonate 500 mg 3 times per a day
between cycles until three weeks after
last cycle
Patients who received magnesium had no

significant alterations in renal function;
the control group showed significantly
increased SCR (p = 0.0069) and a reduction
in CRCL (p = 0.0077).
Kidera et al., 2014
with no magnesium; cisplatin dose greater
than 60 mg/m2
Magnesium group had 2.5 g magnesium
sulfate posthydration
Nephrotoxicity was reported in 4 patients
who received magnesium versus 123
patients who did not receive magnesium
(p < 0.0001).
Muraki et al., 2012
Magnesium group: normal saline,
mannitol, and 8 meq magnesium sulfate;
no magnesium group: normal saline,
mannitol, and furosemide
magnesium prior to cisplatin showed a
significantly greater increase in CRCL (p =
0.004) and decrease in SCR (p = 0.0148).
Oka et al., 2014
85 adults, 41 high volume without mag-
nesium, 27 high volume with magnesium,
and 17 low volume with magnesium

days 2 and 3
SCR: high volume without magnesium:
22 patients had grade 1, 17 had grade
2, and 2 had grade 3; high volume with
magnesium: 26 had grade 1; low volume
with magnesium: 15 had grade 1, and 1 had
grade 2; absence of magnesium infusion
was an independent factor for decreased
CRCL (p < 0.001).
Willox et al., 1986
17 adults, 8 with magnesium and 9 with no
magnesium; cisplatin 20 mg/m2 per day
for 5 days
Magnesium sulfate 8 mmol/500 ml and
citrate 10 mmol 3 times a day when IV
infusion was discontinued through the
next cycle
Patients who received magnesium had
significantly reduced renal tubule damage
as measured by NAG (p < 0.01) and fewer
treatment delays. CRCL and SCR did not
differ between the groups.

Yamamoto et al., 2015
no magnesium; cisplatin 40 mg/m2 per
week
prehydration with 15 meq and a daily dose
of 5 meq on days 2 and 3.
No-magnesium arm had a significant
increase (p < 0.05) in SCR (0.58–0.75 mg/
dl) and a significant decrease (p < 0.05)
in glomerular filtration rate (85.1 to 66.5
ml/minute); no significant change in the
magnesium arm; lower relative risk of
nephrotoxicity (according to RIFLE criteria)
in the magnesium group versus other
group (7% versus 50% risk, p = 0.03)
Yoshida et al., 2014
with no magnesium; cisplatin greater than
60 mg/m2
standard hydration, isotonic saline, and 8
meq magnesium sulfate prior to cisplatin;
no-magnesium supplementation group
had standard hydration.
9 patients in the magnesium preloading
group had an SCR grade greater than or
equal to 2; 64 patients in the nonmag-
nesium loading group had an SCR grade
greater than or equal to 2 (p < 0.001);
OR for first cycle = 0.262 (95% CI [0.106,

0.596]); OR during all cycles = 0.234 (95%
CI [0.129, 0.414])
Furosemide
Dumas et al., 1989
20 adults, 10 received furosemide and 10
received diuretic; cisplatin dose 80 mg/m2
Furosemide 20 mg/m2 prior to cisplatin
Mean SCR levels were significantly higher
in patients who received furosemide
versus those who did not (0.95 mg/dl
versus 0.76 mg/dl, p < 0.001), but no
significant differences in CRCL were
observed.
NEPHROTOXICITY
Furosemide (continued)

Muraki et al., 2012
furosemide and 20 received hydration
with mannitol and magnesium; cisplatin
75 mg/m2
Patients received either hydration, manni-
tol, and magnesium sulfate; or hydration,
mannitol, and 20 mg furosemide
Patients who received mannitol and mag-
nesium prior to cisplatin administration
showed a significantly greater increase in
CRCL (p = 0.004) and decrease in SCR (p =
0.0148); a hydration protocol supple-
mented with magnesium and mannitol
without furosemide was an independent
factor for the protection of cisplatin-
induced nephrotoxicity (OR = 0.232, 95%
CI [0.055, 0.986], p = 0.039).
Ostrow et al., 1981
cisplatin 100 mg/m2
Mannitol 37.5 g plus hydration prior to
cisplatin; furosemide 40 mg plus hydration
before the start of cisplatin
Nephrotoxicity occurred in 28% of
patients who received mannitol and 19%
of patients who received furosemide;
no differences in SCR levels (p > 0.45)

or CRCL levels (p > 0.25) were observed
between the two groups.
Mannitol
Al-Sarraf et al., 1982
67 adults, 34 with mannitol and 33 with no
mannitol; cisplatin 100 mg/m2
Mannitol 12.5 g prior to cisplatin and 25 mg
following cisplatin
Significant renal toxicity after the first
dose of cisplatin was observed in 4% of
patients who received hydration and
mannitol and in 21% of patients who
received hydration alone.
Leu & Baribeault, 2010
no mannitol; cisplatin dose greater than
40 mg/m2
Mannitol 12.5 g
Average decrease in CRCL between
the two groups; no difference between
hydration plus mannitol and hydration
alone (p = 0.09)
McKibbin et al., 2016
no mannitol; cisplatin 100 mg/m2

The addition of mannitol decreased the
incidence of grade 3 acute kidney injury;
nephrotoxicity was listed as a reason for
the discontinuation of therapy in 47% of
patients receiving mannitol compared to
60% of patients receiving saline alone (p =
0.69).
Morgan et al., 2014
143 adults, 85 with mannitol prior to
cisplatin and 58 with furosemide prior to
cisplatin; cisplatin 30–100 mg/m2
Patients who did not receive mannitol
with cisplatin had an increased likelihood
of developing acute kidney injury (OR =
2.646, 95% CI [1.008, 6.944], p = 0.048).
Muraki et al., 2012
mannitol and magnesium, and 30 received
hydration with furosemide; cisplatin 75
mg/m2
Hydration with mannitol and magnesium:
2,700 ml normal saline, 200 ml mannitol,
and 8 meq magnesium sulfate; hydration
with furosemide: 3,100 ml normal saline,
300 ml mannitol, and 20 mg furosemide
magnesium prior to the administration of
cisplatin showed a significantly greater

increase in CRCL (p = 0.004) and decrease
in SCR (p = 0.0148).
Ostrow et al., 1981
cisplatin 100 mg/m2
Mannitol 37.5 g
Nephrotoxicity = CRCL less than 50
and SCR greater than 2; nephrotoxicity
occurred in 19% of patients who received
furosemide and 28% of patients who
received mannitol.
Santoso et al., 2003
49 adults, 17 with saline and mannitol, 17
with saline and furosemide, and 15 with
saline alone; cisplatin 75 mg/m2
Mannitol 50 g
Mannitol arm found to be significantly
nephrotoxic; study was closed prematurely.
CI—confidence interval; CRCL—creatinine clearance; NAG—
N-acetyl-beta-D-glucosaminidase; OR—odds ratio; RIFLE—
Risk, Injury, Failure, Loss, and End-Stage; SCR—serum
creatinine
authors concluded that both diuretics exhibited similar effects.

Other researchers retrospectively evaluated 50 patients to com-
pare the effect of hydration with magnesium sulfate and
mannitol
versus hydration with furosemide 20 mg and mannitol on cispla-
tin-associated nephrotoxicity (Muraki et al., 2012). Hydration
with magnesium and mannitol was an independent factor in
the protection of patients against nephrotoxicity induced by
cisplatin. Finally, mean SCR concentrations were significantly
higher in patients who received furosemide 20 mg/m2 one hour
prior to cisplatin versus those who did not receive furosemide
prior to cisplatin, although no significant differences in CRCL
were observed between groups (Dumas et al., 1989).
Mannitol
Seven studies evaluated the effect of mannitol on cisplatin-
related nephrotoxicity. Three trials found no clear indication
that
mannitol is nephroprotective among adults receiving cisplatin
(Leu & Baribeault, 2010; Ostrow et al., 1981; Santoso et al.,
2003).
In one study of 22 patients receiving cisplatin, 28% of patients
who
received mannitol developed nephrotoxicity compared to 19% of
patients in the furosemide group, with the authors concluding
that
neither mannitol nor furosemide was superior in reducing the
fre-
quency of nephrotoxicity (Ostrow et al., 1981). In another
study, no
significant difference in CRCL was noted among patients
receiving
mannitol and hydration compared to hydration alone (Leu &
Baribeault, 2010). Santoso et al. (2003) found mannitol dosages
of
50 g to be significantly nephrotoxic and terminated the study
pre-

maturely because patients developed nephrotoxicity.
Four studies revealed that mannitol in conjunction with
high-dose cisplatin has a protective effect that allows patients
to
tolerate cisplatin without nephrotoxicity (Al-Sarraf et al., 1982;
McKibbin et al., 2016; Morgan et al., 2014; Muraki et al.,
2012).
Patients who received mannitol and magnesium demonstrated a
significantly greater increase in CRCL (p = 0.004) and decrease
in SCR (p = 0.0148) compared to patients receiving hydration
with mannitol, magnesium, and furosemide (Muraki et al.,
2012).
Morgan et al. (2014) also found improved outcomes in patients
who received mannitol, and reported a 2.6 increased likelihood
of
developing acute kidney injury among adults who did not
receive
mannitol with cisplatin (95% confidence interval [1.008, 6.944],
p = 0.048). They recommended the addition of mannitol with
hydration to prevent cisplatin-induced nephrotoxicity.
Quality of the Evidence
The quality of the hydration evidence was based on nine
research
articles. The evidence consisted of six retrospective studies and
three prospective studies (one nonrandomized, single-center,
phase 2 study; one feasibility study; and one cohort study).
Issues
related to the quality of the evidence included no report of
power
analysis in all studies, inconsistency issues among comparison
groups in two studies, and one potential publication bias
because
of a long lag time from study completion to publication. The

overall body of evidence for hydration was of low quality.
The magnesium evidence was based on seven research articles
consisting of two randomized clinical trials, four retrospective
chart reviews, and one historical prospective cohort study.
Issues
related to the quality of the evidence included lack of reported
power analyses in all studies. The overall body of evidence for
magnesium was of low quality.
The furosemide evidence is based on three research articles
consisting of two randomized, prospective, controlled studies
and
one retrospective chart review. Issues related to the quality of
the
evidence included lack of reported power analyses in all
studies.
The overall body of evidence for furosemide was of low quality.
The mannitol evidence is based on seven research studies. The
designs consisted of four retrospective studies and three
prospec-
tive studies (two randomized, controlled studies and one phase
2 study). Issues related to the quality of the evidence included
lack of reported power analysis in all studies. The overall body
of
evidence for mannitol was of low quality.
Summary of Recommendations
Hydration is necessary to prevent nephrotoxicity with cisplatin
administration; however, the amount, duration, and timing of
hydration for patients cannot be determined from the limited
evidence. In addition, administration of magnesium and
mannitol
may assist in maintaining renal function and reducing nephro-
toxicity in adults receiving cisplatin; however, limited evidence

precludes the ability to provide recommendations for children.
More research is needed to identify best practices for patients.
Limitations
Limitations in the literature review include limited evidence
about
the variation of practice patterns in different settings. There
could
be differences in patient management, particularly hydration
regimens and the use of diuretics, which varies depending on
treat-
ment setting. More research is needed to identify these
differences.
“The optimal
hydration and diuretic
regimen necessary
to prevent cisplatin
nephrotoxicity is
unknown.”
In addition, the literature is limited because of the inclusion
of diverse age groups. Only one pediatric study evaluated neph-
rotoxicity in children receiving cisplatin therapy, requiring
more
evaluation so conclusions can be determined among the
pediatric
population. Also, insufficient literature prevented the authors
from subcategorizing the adult population by age; additional
research should be conducted to evaluate the nephrotoxicity dif-

ferences among young, middle-aged, and older adult patients.
Last, this literature review does not include the effects of
other medications on nephrotoxicity. Researchers should con-
sider investigating the influence of nephrotoxic medications on
people receiving cisplatin therapy.
Implications for Nurses and Conclusion
Cisplatin is an integral component of chemotherapy regimens
for multiple cancers, and nephrotoxicity remains the primary
dose-limiting toxicity of this effective treatment. Hydration has
been shown to maintain renal function and decrease nephrotox-
icity in patients. In addition, magnesium supplementation has
demonstrated nephroprotective effects in adults when included
in
hydration regimens before, during, and after cisplatin.
Additional
research is needed to evaluate outcomes of these interventions
in
the pediatric population.
Research does not currently support the administration of
furosemide to prevent cisplatin-related nephrotoxicity in adults;
however, mannitol may prevent nephrotoxicity. The use of man-
nitol in conjunction with magnesium was an independent factor
in the protection of adults against nephrotoxicity induced by
high-dose cisplatin (Muraki et al., 2012). Additional research is
needed to evaluate these outcomes.
Nurses play a critical role in monitoring patients to prevent
cisplatin-induced nephrotoxicity. The administration of hydra-
tion and the use of medications to aid in diuresis during
cisplatin
therapy is essential. Maintaining accurate weights and intake
and
outputs along with monitoring laboratory values and assessing

for edema will help with early recognition of renal dysfunction.
The provision of patient education focusing on nephrotoxicity
prevention is an important component of the treatment regimen.
Although researchers have evaluated several supportive
strategies to minimize nephrotoxicity in patients receiving cis-
platin therapy, more research is needed. When more evidence is
available, best nephroprotective practices can be developed and
implemented. Until then, nurses should closely monitor kidney
function in all patients receiving cisplatin and immediately
report
abnormalities to the healthcare team.
Elizabeth A. Duffy, DNP, RN, CPNP, is a clinical assistant
professor in the School of
Nursing at the University of Michigan in Ann Arbor; Wendy
Fitzgerald, RN, MSN,
PPCNP-BC, CPON®, is a pediatric nurse practitioner in the
Center for Cancer and
Blood Disorders at the Children’s National Medical Center in
Washington, DC;
Kelley Boyle, MSN, RN, PCNS-BC, is a pediatric BMT nurse
coordinator at the
University of California, San Francisco, Benioff Children’s
Hospital; and Radha Ro-
hatgi, PharmD, BCOP, is a hematology/oncology and bone
marrow clinical phar-
macy specialist at the Children’s National Medical Center.
Duffy can be reached at

[email protected], with copy to [email protected] (Submitted
March
2017. Accepted June 19, 2017.)
The authors take full responsibility for this content. This
research was conducted by a team from
the Children’s Oncology Group Nursing Evidence-Based
Practice Subcommittee. The Children’s
Oncology Group is supported by a National Cancer
Institute/National Clinical Trials Network
Group Operations Center grant (U10CA180886; principal
investigator: Peter C. Adamson).
Fitzgerald serves on a speakers bureau for United Therapeutics.
During the writing of this article,
Rohatgi served on a speakers bureau for the Pediatric Pharmacy
Association. The article has been
reviewed by independent peer reviewers to ensure that it is
objective and free from bias.
REFERENCES
Al Bahrani, B.J., Moylan, E.J., Forouzesh, B., Della-Fiorentina,
S.A., & Goldrick, A.J. (2009). A
short outpatient hydration schedule for cisplatin administration.
Gulf Journal of Oncology,
5, 30–36.

Al-Sarraf, M., Fletcher, W., Oishi, N., Pugh, R., Hewlett, J.S.,
Balducci, L., . . . Padilla, F. (1982).
Cisplatin hydration with and without mannitol diuresis in
refractory disseminated malignant
melanoma: A Southwest Oncology Group study. Cancer
Treatment Reports, 66, 31–35.
Bellomo, R., Kellum, J.A., & Ronco, C. (2007). Defining and
classifying acute renal failure: From
advocacy to consensus and validation of the RIFLE criteria.
Intensive Care Medicine, 33,
409–413. https://doi.org/10.1007/s00134-006-0478-x
Bodnar, L., Wcislo, G., Gasowska-Bodnar, A., Synowiec, A.,
Szarlej-Wcisło, K., & Szczylik, C.
(2008). Renal protection with magnesium subcarbonate and
magnesium sulphate in
patients with epithelial ovarian cancer after cisplatin and
paclitaxel chemotherapy: A
randomised phase II study. European Journal of Cancer, 44,
2608–2614.
Dumas, M., de Gislain, C., d’Athis, P., Chadoint-Noudeau, V.,
Escousse, A., Guerrin, J., &
Autissier, N. (1989). Evaluation of the effect of furosemide on
ultrafilterable platinum

kinetics in patients treated with cis-diamminedichloroplatinum.
Cancer Chemotherapy and
Pharmacology, 23, 37–40. https://doi.org/10.1007/BF00258455
Guyatt, G., Oxman, A.D., Akl, E.A., Kunz, R., Vist, G., Brozek,
J., . . . Schünemann, H.J. (2011).
GRADE guidelines: 1. Introduction—GRADE evidence profiles
and summary of findings tables.
Journal of Clinical Epidemiology, 64, 383–394.
https://doi.org/10.1016/j.jclinepi.2010.04.026
Horinouchi, H., Kubota, K., Itani, H., Taniyama, T.K.,
Nakamichi, S., Wakui, H., . . . Tamura, I.S.T.
(2013). Short hydration in chemotherapy containing cisplatin (≥
75 mg/m2) for patients with
lung cancer: A prospective study. Japanese Journal of Clinical
Oncology, 43, 1105–1109.
Hotta, K., Takigawa, N., Hisamoto-Sato, A., Ichihara, E., Kudo,
K., Uchida, K., . . . Kiura, K. (2013).
Reappraisal of short-term low-volume hydration in cisplatin-
based chemotherapy: Results
of a prospective feasibility study in advanced lung cancer in the
Okayama Lung Cancer
Study Group Trial 1002. Japanese Journal of Clinical Oncology,
43, 1115–1123.
Jones, D.P., Spunt, S.L., Green, D., & Springate, J.E. (2008).

Renal late effects in patients treated
for cancer in childhood: A report from the Children’s Oncology
Group. Pediatric Blood and
Cancer, 51, 724–731. https://doi.org/10.1002/pbc.21695
IMPLICATIONS FOR PRACTICE
ɔ Deliver hydration to patients receiving cisplatin therapy to
maintain
renal function.
ɔ Include magnesium supplementation, which has
nephroprotective
effects in adults, in hydration regimens before, during, and after
cisplatin.
ɔ Add mannitol to hydration to prevent cisplatin-induced
nephrotoxicity in adults.
NEPHROTOXICITY
Kidera, Y., Kawakami, H., Sakiyama, T., Okamoto, K., Tanaka,
K., Takeda, M., . . . Nakagawa,
K. (2014). Risk factors for cisplatin-induced nephrotoxicity and
potential of magnesium

supplementation for renal protection. PLOS ONE, 9(7),
e101902. https://doi.org/10.1371/
journal.pone.0101902
Launay-Vacher, V., Rey, J.-B., Isnard-Bagnis, C., Deray, G., &
Daouphars, M. (2008). Prevention
of cisplatin nephrotoxicity: State of the art and
recommendations from the European
Society of Clinical Pharmacy Special Interest Group on Cancer
Care. Cancer Chemotherapy
and Pharmacology, 61, 903–909.
https://doi.org/10.1007/s00280-008-0711-0
Lavolé, A., Danel, S., Baudrin, L., Gounant, V., Ruppert, A.M.,
Epaud, C., . . . Milleron, B. (2012).
Routine administration of a single dose of cisplatin ≥ 75 mg/m2
after short hydration in an
outpatient lung-cancer clinic. Bulletin du Cancer, 99, E43–E48.
Leu, L., & Baribeault, D. (2010). A comparison of the rates of
cisplatin (cDDP)-induced
nephrotoxicity associated with sodium loading or sodium
loading with forced diuresis as a
preventative measure. Journal of Oncology Pharmacy Practice,
16, 167–171. https://doi
.org/10.1177/1078155209346071

McKibbin, T., Cheng, L.L., Kim, S., Steuer, C.E., Owonikoko,
T.K., Khuri, F.R., . . . Saba, N.F. (2016).
Mannitol to prevent cisplatin-induced nephrotoxicity in patients
with squamous cell cancer
of the head and neck (SCCHN) receiving concurrent therapy.
Supportive Care in Cancer, 24,
1789–1793. https://doi.org/10.1007/s00520-015-2978-0
Melnyk, B.M., & Fineout-Overholt, E. (2015). Evidence-based
practice in nursing and health-
care: A guide to best practice (3rd ed.). Philadelphia, PA:
Lippincott Williams and Wilkins.
Miller, R.P., Tadagavadi, R.K., Ramesh, G., & Reeves, W.B.
(2010). Mechanisms of cisplatin
nephrotoxicity. Toxins, 2, 2490–2518.
https://doi.org/10.3390/toxins2112490
Morgan, K.P., Snavely, A.C., Wind, L.S., Buie, L.W., Grilley-
Olson, J., Walko, C.M., & Weiss, J.
(2014). Rates of renal toxicity in cancer patients receiving
cisplatin with and without manni-
tol. Annals of Pharmacotherapy, 48, 863–869.
https://doi.org/10.1177/1060028014533303
Muraki, K., Koyama, R., Honma, Y., Yagishita, S., Shukuya, T.,
Ohashi, R., . . . Takahashi, K. (2012).

Hydration with magnesium and mannitol without furosemide
prevents the nephrotoxicity
induced by cisplatin and pemetrexed in patients with advanced
non-small cell lung cancer.
Journal of Thoracic Disease, 4, 562–568.
https://doi.org/10.3978/j.issn.2072-1439.2012.10.16
Murray, A.W., Barnfield, M.C., Waller, M.L., Telford, T., &
Peters, A.M. (2013). Assessment of
glomerular filtration rate measurement with plasma sampling: A
technical review. Journal
of Nuclear Medicine Technology, 41, 67–75.
https://doi.org/10.2967/jnmt.113.121004
National Cancer Institute. (2010). Common terminology criteria
for adverse events [v.4.03].
Retrieved from http://bit.ly/2o2Zd4Y
Oka, T., Kimura, T., Suzumura, T., Yoshimoto, N., Nakai, T.,
Yamamoto, N., . . . Hirata, K. (2014).
Magnesium supplementation and high volume hydration reduce
the renal toxicity caused
by cisplatin-based chemotherapy in patients with lung cancer: A
toxicity study. BMC Phar-
macology and Toxicology, 15, 70. https://doi.org/10.1186/2050-
6511-15-70
Ostrow, S., Egorin, M.J., Hahn, D., Markus, S., Aisner, J.,

Chang, P., . . . Wiernik, P.H. (1981).
High-dose cisplatin therapy using mannitol versus furosemide
diuresis: Comparative
pharmacokinetics and toxicity. Cancer Treatment Reports, 65,
73–78.
Ouchi, A., Asano, M., Aono, K., Watanabe, T., & Kato, T.
(2014). Comparison of short and contin-
uous hydration regimen in chemotherapy containing
intermediate- to high-dose cisplatin.
Journal of Oncology, 2014, 767652.
https://doi.org/10.1155/2014/767652
Platania, M., Verzoni, E., & Vitali, M. (2015). Hyponatremia in
cancer patients. Tumori, 101,
246–248. https://doi.org/10.5301/tj.5000257
Ruggiero, A., Rizzo, D., Trombatore, G., Maurizi, P., &
Riccardi, R. (2016). The ability of mannitol
to decrease cisplatin-induced nephrotoxicity in children: Real or
not? Cancer Chemother-
apy and Pharmacology, 77, 19–26.
https://doi.org/10.1007/s00280-015-2913-6
Sakaida, E., Iwasawa, S., Kurimoto, R., Ebata, T., Imai, C.,
Oku, T., . . . Takiguchi, Y. (2016). Safety
of a short hydration method for cisplatin administration in
comparison with a conventional

method—A retrospective study. Japanese Journal of Clinical
Oncology, 46, 370–377.
https://doi.org/10.1093/jjco/hyv203
Santoso, J.T., Lucci, J.A., 3rd, Coleman, R.L., Schafer, I., &
Hannigan, E.V. (2003). Saline, manni-
tol, and furosemide hydration in acute cisplatin nephrotoxicity:
A randomized trial. Cancer
Chemotherapy and Pharmacology, 52, 13–18.
https://doi.org/10.1007/s00280-003-0620-1
Skinner, R. (2011). Nephrotoxicity—What do we know and
what don’t we know? Journal of Pediat-
ric Hematology/Oncology, 33, 128–134.
https://doi.org/10.1097/MPH.0b013e3181f8cac0
Skinner, R., Parry, A., Price, L., Cole, M., Craft, A.W., &
Pearson, A.D.J. (2009). Persistent neph-
rotoxicity during 10-year follow-up after cisplatin or
carboplatin treatment in childhood:
Relevance of age and dose as risk factors. European Journal of
Cancer, 45, 3213–3219.
https://doi.org/10.1016/j.ejca.2009.06.032
Stevens, L.A., Coresh, J., Greene, T., & Levey, A.S. (2006).
Assessing kidney function—
Measured and estimated glomerular filtration rate. New England

Journal of Medicine, 354,
2473–2483. https://doi.org/10.1056/NEJMra054415
Tiseo, M., Martelli, O., Mancuso, A., Sormani, M.P., Bruzzi, P.,
Di Salvia, R., . . . Ardizzoni,
A. (2007). Short hydration regimen and nephrotoxicity of
intermediate to high-dose
cisplatin-based chemotherapy for outpatient treatment in lung
cancer and mesothelioma.
Tumori, 93, 138–144.
Vogl, S.E., Zaravinos, T., Kaplan, B.H., & Wollner, D. (1981).
Safe and effective two-hour
outpatient regimen of hydration and diuresis for the
administration of cis-
diamminedichloroplatinum (II). European Journal of Cancer, 17,
345–350.
Willox, J.C., McAllister, E.J., Sangster, G., & Kaye, S.B.
(1986). Effects of magnesium supplemen-
tation in testicular cancer patients receiving cis-platin: A
randomised trial. British Journal of
Cancer, 54, 19–23.
Womer, R.B., Pritchard, J., & Barratt, T.M. (1985). Renal
toxicity of cisplatin in children. Journal
of Pediatrics, 106, 659–663.

Yamamoto, Y., Watanabe, K., Tsukiyama, I., Matsushita, H.,
Yabushita, H., Matsuura, K., & Wakat-
suki, A. (2015). Nephroprotective effects of hydration with
magnesium in patients with
cervical cancer receiving cisplatin. Anticancer Research, 35,
2199–2204.
Yoshida, T., Niho, S., Toda, M., Goto, K., Yoh, K., Umemura,
S., . . . Ohe, Y. (2014). Protective
effect of magnesium preloading on cisplatin-induced
nephrotoxicity: A retrospective study.
Japanese Journal of Clinical Oncology, 44, 346–354.
https://doi.org/10.1093/jjco/hyu004
Zareifar, S., Jafari, H., Geramizadeh, B., Basiratnia, M.,
Golafshan, H., Cohan, N., . . . Hamidi, R.
(2013). The evaluation of cisplatin effect on tubular function in
children on chemotherapy.
Pediatric Hematology and Oncology, 30, 18–24.
https://doi.org/10.3109/08880018.2012
.737093
CNE ACTIVITY
EARN 0.5 CONTACT HOURS
ONS members can earn free CNE for reading this article and
completing

an evaluation online. To do so, visit cjon.ons.org/cne to link to
this article
and then access its evaluation link after logging in.
Certified nurses can claim no more than 0.5 total ILNA points
for this
program. Up to 0.5 ILNA points may be applied to Symptom
Management
OR Professional Practice. See www.oncc.org for complete
details on
certification.
Copyright of Clinical Journal of Oncology Nursing is the
property of Oncology Nursing
Society and its content may not be copied or emailed to multiple
sites or posted to a listserv
without the copyright holder's express written permission.
However, users may print,
download, or email articles for individual use.

APRIL 2018, VOL. 22 NO. 2 CLINICAL JOURNAL OF ONCOLOGY NURSING.docx

Recommended

Recommended

More Related Content

Similar to APRIL 2018, VOL. 22 NO. 2 CLINICAL JOURNAL OF ONCOLOGY NURSING.docx

Similar to APRIL 2018, VOL. 22 NO. 2 CLINICAL JOURNAL OF ONCOLOGY NURSING.docx (18)

More from festockton

More from festockton (20)

Recently uploaded

Recently uploaded (20)

APRIL 2018, VOL. 22 NO. 2 CLINICAL JOURNAL OF ONCOLOGY NURSING.docx