Received: 4 January 2021
DOI: 10.1111/cts.13045|

Revised: 15 March 2021|

Accepted: 16 March 2021

ARTICLE

Effects of 5-­HT₃ receptor antagonists on cisplatin-­induced kidney
injuryMitsuhiro Goda1,2,3 | Masaya Kanda1,2 | Toshihiko Yoshioka1,2 | Ami Yoshida1
Yoichi Murai1 | Yoshito Zamami1,2 | Fuka Aizawa1,2 | Takahiro Niimura1 |Hirofumi Hamano1,2 | Naoto Okada2 | Kenta Yagi3 | Masayuki Chuma4 |Yuki Izawa-­Ishizawa5 | Keisuke Ishizawa1,2
1

Department of Clinical Pharmacology
and Therapeutics, Tokushima University
Graduate School of Biomedical Sciences,
Tokushima, Japan2

Department of Pharmacy, Tokushima
University Hospital, Tokushima, Japan
3

Clinical Research Center for
Developmental Therapeutics, Tokushima
University Hospital, Tokushima, Japan
4

Department of Pharmacy, Asahikawa
Medical University Hospital, Hokkaido,Japan
5

Department of Pharmacology,
Tokushima University Graduate Schoolof Biomedical Sciences, Tokushima,
Japan
Correspondence
Mitsuhiro Goda, Department of ClinicalPharmacology and Therapeutics,
Tokushima University Graduate School of
Biomedical Sciences, 3-­18-­15 Kuramoto,Tokushima 770-­8503, Japan.
Email: mgoda@tokushima-u.ac.jp
Funding information
This research was supported by the Japan
Society for the Promotion of Science(JSPS) KAKENHI (Grant numbers
20K07132 and 20H05799).

|

Abstract
Nausea, vomiting, and renal injury are the common adverse effects associated withcisplatin. Cisplatin is excreted via the multidrug and toxin release (MATE) transporter,and the involvement of the MATE transporter in cisplatin-­induced kidney injury has
been reported. The MATE transporter is also involved in the excretion of ondansetron, but the effects of 5-­HT3 receptor antagonists used clinically for cisplatin-­induced
renal injury have not been elucidated. Therefore, the aim of this study was to investigate the effects of 5-­HT3 receptor antagonists in a mouse model of cisplatin-­induced
kidney injury and to validate the results using medical big data analysis of more than
1.4 million reports and a survey of 3000 hospital medical records. The concomitant
use of a first-­generation 5-­HT3 receptor antagonist (ondansetron, granisetron, or ramosetron) significantly increased cisplatin accumulation in the kidneys and worsened
renal damage. Conversely, the concomitant use of palonosetron had no effect on renal
function compared with the use of cisplatin alone. Furthermore, an analysis of datafrom the US Food and Drug Administration Adverse Event Reporting System andretrospective medical records revealed that the combination treatment of cisplatin anda first-­generation 5-­HT3 receptor antagonist significantly increased the number of reported renal adverse events compared with the combination treatment of cisplatin anda second-­generation 5-­HT3 receptor antagonist. These results suggest that comparedwith the first-­generation antagonists, second-­generation 5-­HT3 receptor antagonists
do not worsen cisplatin-­induced acute kidney injury. The findings should be validated
in a prospective controlled trial before implementation in clinical practice.
Study Highlights

WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
The involvement of the multidrug and toxin release (MATE) transporter in cisplatin-­induced kidney injury has been reported. The MATE transporter is involved in theexcretion of not only cisplatin but also ondansetron, a 5-­HT3 receptor antagonist used
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium,provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.
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| www.cts-journal.com

Clin Transl Sci. 2021;14:1906–1916.

  

EFFECTS OF 5-­HT₃ RAS ON CDDP-­INDUCED AKI| 1907

as an antiemetic; however, the effects of 5-­HT3 receptor antagonists used clinicallyfor cisplatin-­induced renal injury have not been elucidated.
WHAT QUESTION DID THIS STUDY ADDRESS?
The aim of this study was to investigate the effects of 5-­HT3 receptor antagonists ina mouse model of cisplatin-­induced kidney injury and to validate the results using
medical big data analysis of more than 1.4 million reports and a survey of 3000 hospital medical records.
WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
The results suggest that compared with the first-­generation antagonists, second-­
generation 5-­HT3 receptor antagonists do not worsen cisplatin-­induced acute kidney
injury.
HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR
TRANSLATIONAL SCIENCE?
Promoting the use of second-­generation 5-­HT3 receptor antagonists is expected toreduce the number of patients who develop cisplatin-­induced renal damage.

I N T RO D U C T ION
Cisplatin, a platinum-­based anticancer agent, is a key drugin various regimens. However, the adverse effects associated with cisplatin are often problematic in clinical practice,and they include renal impairment, hearing impairment,
nausea, vomiting, and bone marrow suppression.1 Renal
impairment, a dose-­limiting toxicity of cisplatin, occurs inapproximately one-­third of patients treated with cisplatin. It
can cause irreversible damage, thereby reducing the qualityof life of patients and necessitating cisplatin dosage reduction, if treatment for renal impairment is not administered.2
Therefore, it is important to ensure that the renal function ofpatients does not worsen during cisplatin administration tomaintain treatment intensity. Hydration methods are strongly
recommended in the guidelines for renal damage treatment
during anticancer therapy.3 Studies have suggested that thisapproach reduces the frequency of renal damage.4 However,despite prophylactic treatment use, several patients receiving cisplatin experience a decline in renal function.5 There
are no clinically effective therapies for the prophylaxis ortreatment of cisplatin-­induced renal injury, despite the completion of various studies in this regard.1,5,6 Cisplatin is arenally excreted drug, and more than 90% of the drug is excreted in the urine over 24 h after intravenous injection.7 The
concentration of cisplatin in the kidneys is approximately
five-­fold higher than that in the serum and the accumulation of cisplatin in the kidneys significantly contributes tonephrotoxicity.8–­10 Cisplatin-­induced kidney injuries include
severe damage to tubular cells, and nephrotoxicity originatesin the proximal tubules.11 Preclinical studies have elucidated the mechanisms underlying cisplatin-­induced kidney
injury.5–­7 Two transporters implicated in the development of
cisplatin-­induced kidney injury are organic cation transporter

2 (OCT2), located on the basement membrane side of theproximal renal tubules, and multidrug and toxin extrusion(MATE) protein, located on the brush border membrane sideof the proximal renal tubules. Cisplatin is taken up from theblood into the proximal renal tubular cells via OCT2, andthen excreted into the tubules from the proximal renal tubularcells via MATE.12–­14
The cisplatin transport activity of MATE is considerably
lower than that of OCT2, and this difference leads to cisplatinaccumulation in the proximal renal tubules.15,16 Therefore, theinhibition of OCT2 expression may reduce cisplatin accumulation in the tubules, whereas the inhibition of MATE expression
may increase cisplatin accumulation. Notably, cimetidine, asubstrate of OCT2, has been reported to limit cisplatin-­induced
renal damage,17 whereas the MATE inhibitor pyrimethamine
has been reported to exacerbate renal damage.15
Cisplatin is designated as highly emetogenic in the
Guidelines for the Proper Use of Antiemetic Drugs, withnausea and vomiting occurring in more than 90% of patients.18 Nausea and vomiting can be controlled with the appropriate use of antiemetics. Because nausea and vomiting
associated with chemotherapy are caused by the combined
stimulation of 5-­HT₃ receptors in the gastrointestinal tract
and NK-­1 receptors in the chemoreceptor trigger zone, thesereceptor antagonists and steroids are indicated as antiemetic
agents. Notably, a three-­drug combination, comprising anNK-­1 receptor antagonist, a 5-­HT₃ receptor antagonist, and asteroid, has been recommended for use with cisplatin18 andincorporated as a supportive therapy in various regimens.
The 5-­HT₃ receptor antagonists include the first-­generation
agents, ondansetron and granisetron, and second-­generation
agent, palonosetron, and each regimen is used differently.
The 5-­HT₃ receptor antagonists have been reported to be substrates for OCT2 and MATE.19,20 Furthermore, a preclinical

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study using a mouse model of cisplatin-­induced kidney injury demonstrated that ondansetron, a first-­generation drug,
may exacerbate cisplatin-­induced kidney injury by inhibiting
MATE.16 However, the effects of 5-­HT₃ receptor antagonists
used clinically to prevent cisplatin-­induced nausea and vomiting on cisplatin-­induced kidney injury remain unknown.
Therefore, here, we investigated the effects of various 5-­HT₃
receptor antagonists in a mouse model of cisplatin-­induced
kidney injury and validated the results obtained using datafrom retrospective clinical trials and from the analysis of
medical data.

MAT E R IA L S A N D ME T HOD S
Animal model of cisplatin-­induced
nephrotoxicity
All experimental procedures were performed in accordancewith the guidelines of the Animal Research Committee ofTokushima University Graduate School, and the protocol wasapproved by the Institutional Review Board of Tokushima
University Graduate School for Animal Protection (Permit
Number: T30-­85). Nine-­to-­ten-­week-­old C57BL/6 J mice
(weighing 24–­27 g) were purchased from Nippon CLEA
(Tokyo, Japan) and maintained with ad libitum access towater and food (type NMF; Oriental yeast, Tokyo, Japan).
The relative humidity in the breeding room was set at
50% ± 10% and the room temperature was 26°C ± 1°C, witha 12-­h light/dark cycle (lights on at 8:00 a.m., lights off at
8:00 p.m.). The mice were randomly divided into six groups(n = 7–­9 per group): vehicle-­injected, cisplatin-­injected, andfirst-­generation 5-­HT3 receptor antagonists (ondansetron[1 mg/kg], granisetron [30 mg/kg], or ramosetron [1 mg/kg]) or second-­generation 5-­HT3 receptor antagonists (palonosetron [1.5 mg/kg]) administered to the cisplatin-­injectedgroup. The mice were intraperitoneally injected with cisplatin (15 mg/kg) or vehicle. Thirty minutes before cisplatin
injection, the mice were administered various 5-­HT3 receptor antagonists intraperitoneally, including first-­or second-­
generation 5-­HT3 receptor antagonists, or vehicle. At 4, 24,
and 72 h after cisplatin injection, the mice were euthanizedby an overdose of anesthesia, and samples were collected forthe subsequent analysis. The doses were based on those used
as antiemetic agents in animal models.21–­25

Determination of blood and urine creatinine andblood urea nitrogen levels
Blood urea nitrogen (BUN), serum creatinine (serum Cr),and urine creatinine (urine Cr) levels in the serum andurine samples were determined by Oriental Yeast Industries

GODA et al.

(Shiga, Japan). Creatinine clearance (CrCL) was calculated
as follows:
CrCL (ml/min/kg) = urine volume (ml/min/kg) × urine Crconcentration (mg/dl) / serum Cr concentration (mg/dl).

Real-­time polymerase chain reaction using thekidney tissues from mice with cisplatin-­induced
kidney injury
The kidneys were collected from mice with cisplatin-­induced kidney injury. RNA was extracted from the kidneysamples using an RNA extraction solution (NIPPON GENE)
according to the manufacturer’s instructions. The cDNA
was reverse transcribed using the PrimeScript RT Reagent
kit (Takara Bio) and a polymerase chain reaction (PCR)
Thermal Cycler Dice (Takara Bio). The cDNA from eachsample was mixed with forward and reverse primers and
THUNDERBIRD SYBR qPCR Mix (Toyobo); PCR was
performed using an Applied Biosystems StepOnePlus machine (Applied Biosystems). Fold changes in gene expression relative to those of the control group were evaluatedusing mouse glyceraldehyde 3-­
phosphate dehydrogenase
as the internal standard. The primer sets used for PCR are
shown in Table S1.

Histological analysis
Renal tubular injury was assessed as previously described.21
Briefly, the kidney samples were fixed with 4% paraformaldehyde and embedded in paraffin. The samples were cut into4-­μm sections, which were then stained with hematoxylin
and eosin. Tubular damage was scored blindly by 3 or moreindividuals other than the experimenter, according to the percentage of damage (tubular necrosis, brush border loss, castformation, tubular dilation, and tubular degeneration), as follows: 0, normal; 1, less than 25%; 2, 25%–­50%; 3, 50%–­75%;
and 4, greater than 75%. Ten random microscopic fields per
kidney section were used for quantification using the BX53
microscope (Olympus).

Determination of platinum concentration
To determine the concentration of platinum, 20 mg of
the kidney sample or 20 μl of whole blood was incubatedwith 200 μl of 60% nitric acid (Wako) for 1 h at 95°C. The
lysates were centrifuged at 5000 g for 10 min, and 50 μl of
the supernatant was diluted with nitric acid. Platinum concentration was assessed using a polarized Zeeman atomic
absorption spectrophotometer (Model Z-­
5710; Hitachi
High-­
Technologies Co.). The absolute concentration of  

EFFECTS OF 5-­HT₃ RAS ON CDDP-­INDUCED AKI

platinum in the kidneys and whole blood was determinedusing a calibration curve.

Uptake study in HEK293 cells stably
expressing hMATEs
Human embryo kidney cells were obtained from the JapaneseCollection of Research Bioresources Cell Bank (Osaka,
Japan). The cells stably expressing hMATE1 (2.0 × 105 cells/well) were grown in 96-­well plates for 24 h and used in the
DAPI-­update assay. The cells were preincubated with 0.1 ml
of DAPI-­free uptake buffer (130 mM KCl, 2 mM K2HPO4,
1.2 mM MgSO4, 1.0 mM CaCl2, 5 mM glucose, and 20 mM
HEPES; pH 8.0) for 10 min. The uptake assay was initiated by replacing the DAPI-­free uptake buffer with a buffer
containing DAPI (0.5 μM) (0.1 ml) for 10 min. The optimal
experimental conditions were determined after preliminary
experiments based on a previous study.26 All procedures were
performed at 37°C. The reactions were terminated by addingice-­cold DAPI-­free uptake buffer (0.1 ml), and the cells were
washed twice with 0.1 ml of the same buffer. Thereafter,
each well was filled with 0.1 ml of ice-­cold DAPI-­free uptake
buffer, and the intensity of DAPI fluorescence was measured
using a fluorescence plate reader (SpectraMaxi3; Molecular
Devices; 345 nm excitation wavelength and 455 nm emission
wavelength) to evaluate uptake. Cellular protein content wasdetermined as described previously27 using bovine serum
albumin as the standard. The uptake assay was also performed in mock cells, which were transfected with an empty
pcDNA5.1 vector, to determine nonspecific uptake. The half-­
maximal inhibitory concentration (IC50) was calculated using
the probit analysis with SPSS (SPSS Inc.).

Assessing the effects of concomitant drugs
From January 2004 to June 2020, 14,524,065 spontaneousadverse event reports were submitted to the US Food andDrug Administration’s (FDA) Adverse Event Reporting
System (FAERS), and they were downloaded from the FDA
website.28 Duplicate data were excluded in accordance with
the FDA recommendations, and the remaining 12,192,072
reports were used in the analysis. SQLite was used to process
the data, and R version 3.2.1 (R Foundation for StatisticalComputing) was used for statistical analyses. Acute renal
failure was defined using 47 terms of “acute renal failure(SMQ 20000003)” excluding neonatal and pediatric diseases(Table S2) according to Medical Dictionary for Regulatory
Activities (MedDRA) version 23.1.
The risk of adverse events was assessed using the reporting
odds ratio (ROR) and 95% confidence interval (CI). Patients
who received cisplatin were classified into four groups: (1)| 1909patients who used drug A and reported acute renal failure; (2)patients who used drug A and did not report acute renal failure; (3) patients who did not use drug A and reported acuterenal failure; and (4) patients who did not use drug A and did
not report acute renal failure. Based on the following equation, the ROR and 95% CI were calculated.

ROR =

AD
BC

95% CI = exp(ln ROR ± 1.96

√

1 1 1
1
+ + + )A B C D

All tests were two-­tailed, and results with p values lessthan 0.05 were considered statistically significant.

Study design and population
We performed a retrospective case-­control study in patients
who received cisplatin at Tokushima University Hospital, atertiary academic teaching hospital in Tokushima, Japan, between January 1, 2007, and December 31, 2019, under theapproval of the Ethics Committee of Tokushima University
Hospital (reference number 3820). This study was conductedaccording to the principles set forth in the Declaration of
Helsinki. Because the present study was retrospective in nature and used existing information, an opt-­out option was displayed on the institution website as a surrogate for informed
consent for eligible patients according to the Japanese
Governmental guidelines.29 Patients were included if they
had received a single dose of cisplatin greater than or equal to60 mg/m2 during one course of treatment, according to previous studies.30,31 Patients were excluded if they were under
18 years of age, registered in an industry-­initiated clinical
trial, or had insufficient renal function (baseline serum creatinine [SCr] level of ≥1.5 mg/dl and/or estimated glomerular
filtration rate [eGFR] of <60 ml/min/1.73 m2).32,33

Data collection and definitions
We collected baseline data related to physiological conditions,laboratory results, concomitant medication use, and disease history upon the initiation of cisplatin using electronic medical records from Tokushima University Hospital. Cisplatin-­induced
nephrotoxicity (CIN) was defined as an increase in the SCrlevel by greater than or equal to 0.3 mg/dl (26.5 μmol/L) or 50%of the baseline level at 7 days after cisplatin administration.34,35
Data on the proportion of patients using other antiemetic agents,
such as NK1R antagonists, olanzapine, were not obtained because these drugs do not affect renal function in patients with an
eGFR of greater than or equal to 60 ml/min/1.73 m2.36–­39

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|   

TABLE 1
antagonists

GODA et al.

Body weight, kidney weight, and renal function in vehicle-­treated mice and cisplatin-­treated mice with or without 5-­HT₃ receptor

VehicleCDDP

Initial body weight(g)

26.1 ± 0.6

Post body weight (g)CDDP+ ramoCDDP+ palo

CDDP + ond

CDDP + gra

26.4 ± 0.7

26.2 ± 0.3

28.4 ± 0.4

27.6 ± 1.0

26.5 ± 0.3

25.2 ± 0.5

20.7 ± 0.5†

20.3 ± 0.3†

21.9 ± 0.6†

21.1 ± 0.9†

20.9 ± 0.7†

Kidney weight (mg)189.0 ± 7.0

156.9 ± 4.4

171.9 ± 8.0

194.7 ± 5.1

181.0 ± 7.4

173.6 ± 5.0

Urine volume (ml)1.60 ± 0.25

0.95 ± 0.10†

0.85 ± 0.17†

0.92 ± 0.17†

0.85 ± 0.14†

0.93 ± 0.10†

BUN (mg/dl)

21.22 ± 0.69

81.86 ± 5.47†

180.23 ± 21.56 **##

123.80 ± 13.42

123.59 ± 17.6

90.80 ± 19.04

10.89 ± 1.05†

1.29 ± 0.43 **##

1.75 ± 0.20 *#1.58 ± 0.20 *#4.83 ± 0.92

CrCL (ml/min/kg)

4.94 ± 0.70

Note: Data are presented as mean ± SEM.
Abbreviations: BUN, blood urea nitrogen; CrCL, creatinine clearance; CDDP, cisplatin; gra, granisetron; ond, ondansetron; palo, palonosetron; ramo, ramosetron.
†p < 0.05 versus vehicle mice, *p < 0.05 and **p < 0.01 versus CDDP mice. #p < 0.05 and ##p < 0.01 versus CDDP + palonosetron mice; n = 7–­9 in each group.

The eGFR was calculated as follows40:
eGFR (ml/min/1.73 m2) = 194 × serum creatinine -­1.094 × age -­0.287 × 0.739 (if female).

Propensity score matching analysis
As patients in this retrospective case-­
control study were
not randomized as patients treated with the first or second-­
generation antiemetic agents, propensity score matching(PSM) was performed to decrease the variability between
treatment cohorts. Fourteen factors (sex, age, body surface
area [BSA], eGFR, cisplatin dosing/BSA, serum creatinine,
aspartate aminotransferase, alanine aminotransferase, total
bilirubin, serum albumin, and number of patients concomitantly using magnesium sulfate and with chronic heart disease, hypertension, and diabetes mellitus) were selected asfactors associated CIN and/or kidney injury or were deemeda priori to be important demographic characteristics for use
in a logistic regression model, which was used to calculate
propensity scores.41–­43 A 1:1 PSM analysis was performed
using the nearest neighbor matching method with a caliper of
0.20 to reduce the potential bias of patient characteristics.44
Matching was performed without a replacement treatment,
and cases not meeting the matching criteria were excluded.

Statistical analysis
Differences between groups were analyzed using the parametric unpaired t-­test or nonparametric Mann–­Whitney U
test, as applicable. Categorical variables were comparedusing Fisher’s exact test or χ2 test. Results with a p valueof less than 0.05 were considered statistically significant.
Statistical analysis of data of the retrospective case-­control
study was performed using JMP version 15.0 software (SASInstitute Inc.). For comparisons among three or more groups,

a one-­way analysis of variance was performed. Tukey’s test
was also performed as a post hoc analysis. R version 3.2.1 forWindows was used for statistical analyses, and results with atwo-­tailed p value of less than 0.05 were considered statistically significant.

RESULTS
Effects of 5-­HT₃ receptor antagonists on
cisplatin-­induced kidney injury in miceCisplatin-­treated mice presented a decrease in body weight,
but no change in kidney weight (Table 1). Cisplatin-­treatedmice exhibited KIM-­1 and Lcn2 mRNA expression, markers of renal tubular damage, presented elevated plasma BUN,
and showed a significant decrease in CrCL, which indicatedkidney damage (Table 1, Figure 1h,i). Cisplatin in combination with ondansetron, granisetron, or ramosetron exacerbated cisplatin-­induced kidney damage (Table 1, Figure 1h,i);whereas, combination treatment with palonosetron did notexacerbate cisplatin-­induced renal damage.

Histological evaluation
Cisplatin treatment was associated with the degenerationand disruption of renal tissue, including nuclear loss, proximal tubular cell emptying, and tubular dilation. Mice treatedwith the first-­
generation 5-­
HT₃ receptor antagonists presented more extensive damage, such as tubular dilation andtubular cell necrosis, than mice treated with cisplatin alone.
However, there was no difference between the groups thatreceived combination treatment of cisplatin and palonosetronand cisplatin alone (Figure 1g).
The first-­generation 5-­HT₃ receptor antagonist group hada significantly higher score than the cisplatin only group. The

  

EFFECTS OF 5-­HT₃ RAS ON CDDP-­INDUCED AKI

(a)

(b)

(c)

(d)

(e)

(f)

(h)

| 1911(g)(i)

F I G U R E 1 Effects of 5-­HT₃ receptor antagonists on cisplatin-­induced nephrotoxicity. (a–­f) Representative hematoxylin and eosin staining(H&E) of the kidney section of the control mice, cisplatin (CDDP)-­injected mice with vehicle or a 5-­HT₃ receptor antagonist. (a) vehicle, (b)CDDP, (c) CDDP + ondansetron, (d) CDDP + granisetron, (e) CDDP + ramosetron, (f) CDDP + palonosetron. (g) Quantitative analysis of renal
damage scores. Values are expressed as mean ± SEM. ond; ondansetron, gra; granisetron, ramo; ramosetron, palo; palonosetron, †p < 0.05 vs.
vehicle mice, **p < 0.01 versus CDDP mice. ##p < 0.01 versus CDDP + palonosetron mice; n = 7–­9 in each group. (h), (i) The mRNA expression
levels of kidney injury markers (Kim-­1 [h] and Lcn-­2 [i]) in the kidneys of mice in each group. Values are expressed as mean ± SEM. ond;
ondansetron, gra; granisetron, ramo; ramosetron, palo; palonosetron, †p < 0.05 versus vehicle mice, **p < 0.01 versus CDDP mice. ##p < 0.01
versus CDDP + palonosetron mice; n = 7–­9 in each group

score for combination treatment with palonosetron was similar to that for cisplatin alone (Figure 1g).

Effects of 5-­HT3 receptor inhibitorson the platinum concentration in the whole
blood and kidneys
The renal platinum concentration significantly increased in micetreated with ondansetron, granisetron, or ramosetron at 4 h after
cisplatin administration (Figure 2a). In contrast, palonosetron
administration had no effect on the renal platinum concentration (Figure 2a). There was no difference in the platinum concentration in whole blood at 4 h after cisplatin administrationin all groups (Figure 2b). At 24 h after cisplatin administration,

renal accumulation of cisplatin (CDDP only, 14.40 ± 2.74 μg/g,
n = 6) was less than half of that at 4 h, and no effect of concomitant medication was observed (data not shown). These results
suggest that the first-­generation 5-­HT3 receptor inhibitors may
increase platinum accumulation in the kidneys.

Uptake study in HEK293 cells stably
expressing hMATEs
The cis-­inhibition analysis with DAPI revealed that the first-­
generation inhibitors had an IC50 equal to or lower than thatof cimetidine, a typical MATE inhibitor. The first-­generation
inhibitors were found to have a lower IC50 than the second-­
generation inhibitors (Table 2, Figure S1).

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GODA et al.

(a)

(b)

F I G U R E 2 Platinum content in the kidney (a) and whole blood (b) at 4 h after cisplatin (CDDP) treatment. Data are expressed asmean ± SEM. ond; ondansetron, gra; granisetron, ramo; ramosetron, palo; palonosetron, **p < 0.01 versus CDDP mice. ##p < 0.01 versus
CDDP +palonosetron mice, N.S.: not significant; n = 7–­9 in each group
TABLE 2

IC50 value of 5-­HT3 receptor antagonists for hMATE1

Drug

IC50 (µM)

Ondansetron

0.75 ± 0.10

Granisetron

24.70 ± 4.81

Ramosetron

4.42 ± 1.03

Palonosetron

55.79 ± 6.13

Cimetidine

17.94 ± 4.71

Note: Values are expressed as mean ± SEM.
Abbreviation: IC50, half-­maximal inhibitory concentration.

FAERS analysis results
Among 14,524,065 spontaneous adverse event reports submitted from January 2004 to June 2020, 44,678 cases involved cisplatin administration. Based on these reports, the ROR for acuterenal failure was compared among cases reporting combination
treatment with the first-­or second-­generation 5-­HT₃ receptor
antagonists. In total, 8.0% of the patients who received cisplatin reported acute renal failure. The OR of the first-­generation
5-­HT₃ receptor antagonists in combination with cisplatin was
1.26 (95% CI: 1.140–­1.398), and that of the second-­generation
5-­HT₃ receptor antagonists was 0.79 (95% CI: 0.607–­1.02).
The combination of cisplatin with the first-­generation 5-­HT₃
receptor antagonists significantly increased the reported OR for
cisplatin-­related nephropathy (p < 0.01; Table 3).

Patient characteristics
Among 2664 patients treated with CDDP, between January
1, 2007 and December 31, 2019, 53 patients met the inclusion criteria but had insufficient clinical data to allow theevaluation of patient characteristics listed in Table 1; thus,
431 fulfilled the inclusion and exclusion criteria and wereenrolled. CIN occurred in 40 of the 431 enrolled patients(Figure 3). Among these, 126 patients received a concomitant first-­generation antiemetic (first group) and 305 received
a concomitant second-­generation antiemetic (second group).
There was no significant difference in the incidence of CIN
between the groups (first group, 11.9%; second group, 8.2%;
Table 4). Conversely, there was a significant difference inage, eGFR, SCr, serum albumin, and proportion of patientsconcomitantly using magnesium sulfate between the groups.

Propensity score-­adjusted results
The area under the curve of the propensity score for second-­
generation antiemetic treatment, with 14 covariates, was
0.812. We obtained 111 pairs by matching the propensity
score at a caliper value of 0.2. The significant differences inage, eGFR, and percentage of patients using Mg sulfate that
affected CIN development observed in the 111 pairs before
matching were eliminated in the pairs after matching. Afterthe 1:1 PSM analysis, CIN in the first group (15/111, 13.5%)
was significantly lower than that in the second group (6/111,5.4%) in the 111 matched pairs. Patients using antiemetics
with different pharmacokinetics, such as hepatic metabolism
and renal excretion, were included. There were no significant
differences in hepatic and renal functions between the groups
after matching the 111 pairs. The proportion of patients who
received steroids to improve renal function did not differ between the groups in the 111 pairs after PSM matching (firstgroup, 109/111, 98.2%; second group, 111/111, 100.0%, notsignificant). There was no significant difference in other patient characteristics, except for CIN incidence among the 111

  

EFFECTS OF 5-­HT₃ RAS ON CDDP-­INDUCED AKI

TABLE 3

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Effect of 5-­HT₃ receptor antagonists on the occurrence of cisplatin-­induced ARF using the FAERS data analysis

Drug
First-­generation 5-­HT₃ receptor antagonistabSecond-­ generation 5-­HT₃ receptor antagonist

ARF (%) without thedrug

ARF (%) with thedrug

ROR (95% CI)

p value

9.66% (3952/40899)

12.20% (461/3779)

1.26 (1.140–­1.398)<0.001c

9.92% (4350/43870)

7.80% (63/808)

0.79 (0.607–­1.018)

0.072cAbbreviations: ARF, acute renal failure; CI, confidence interval; FAERS, US Food and Drug Administration’s Adverse Event Reporting System; ROR, reporting odds
ratio.
aOndansetron, Granisetron, and Ramosetron.

bcPalonosetron.

Fisher’s exact test.

F I G U R E 3 Flow chart of patient
selection. AKI, acute kidney injury

matched pairs (Table 4). The PSM analysis indicated the efficacy of second-­generation antiemetic drugs for CIN.

DI S C U S S IO N
Our results show that the first-­generation 5-­HT₃ receptor antagonists exacerbate cisplatin-­induced kidney injury by increasing cisplatin accumulation in the kidneys. Conversely,
the second-­generation 5-­HT₃ receptor antagonists do not
adversely affect the kidneys. The results indicate that thehigher inhibitory effect of the first-­generation 5-­HT₃ receptor
antagonists on MATE affects the increase in cisplatin accumulation in the kidneys in response to these agents. A retrospective analysis of reports in an adverse event-­reporting
database revealed a difference in the effects between thefirst-­ and second-­generation 5-­HT₃ receptor antagonists on
cisplatin-­induced kidney injury. A retrospective chart review
of clinical patient data suggested that patients receiving thesecond-­generation 5-­HT₃ receptor antagonists may be at alower risk of exacerbation of cisplatin-­induced kidney injury
than those receiving the first-­generation drugs. Therefore, thesecond-­generation 5-­HT₃ receptor antagonists may be useful as antiemetic agents as they do not exacerbate cisplatin-­induced kidney injury.
Considerable progress has been made in cancer treatment.
New anticancer agents with novel action mechanisms, such as
tyrosine kinase inhibitors and immune checkpoint inhibitors,
have been developed and used in clinical practice. However,
several anticancer therapies with proven effectiveness continue to be used, including cisplatin, a platinum-­based agent
used in chemotherapy for various malignant solid tumors.
Renal impairment is a dose-­limiting toxicity of cisplatin andis a challenge to manage in clinical practice. Despite several
studies, there are no clinically effective drugs for the prevention and treatment of cisplatin-­induced renal impairment;
therefore, it is important to ensure that the renal function does
not worsen during cisplatin treatment in order to maintaintreatment intensity. Cisplatin is classified as a drug with ahigh emetogenic risk, and guidelines recommend the concomitant use of antiemetic agents. Previous studies in mousemodels have reported that ondansetron exacerbates cisplatin-­induced kidney injury. Therefore, 5-­HT₃ receptor antagonists
currently used in clinical practice may affect the incidence of

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TABLE 4

GODA et al.

Patient characteristics of the overall series and propensity score matched pairs at baseline
Before propensity score matching

After propensity score matching

Variable

1st (n = 126)

2nd (n = 305)

p value

1st (n = 111)

2nd (n = 111)

p
value

CIN incidence (%)

15 (11.9)

25 (8.2)

0.273

15 (13.5)

6 (5.4)0.039

Sex (male/female)

92/34

238/67

0.264

83/28

85/26

0.876

Age (year)

61.0 (9.2)

63.6 (9.5)

0.009

61.5 (9.1)

63.0 (10.1)

0.247

Body weight (kg)58.0 (11.6)

59.4 (11.4)

0.238

58.7 (11.7)

58.2 (11.8)

0.763

Height (cm)

162.3 (8.8)

163.7 (8.2)

0.112

162.5 (8.8)

162.5 (8.7)

0.999

BSA (m2)

1.61 (0.18)

1.64 (0.18)

0.149

1.62 (0.19)

1.61 (0.19)

0.815

2

Cisplatin dosing (mg/m /course)78.2 [70.8–­79.9]

76.9 [70.0–­79.9]

0.650

78.2 [70.8–­79.9]

74.9 [68.8–­79.4]

0.826

eGFR (ml/min/1.73 m2)

84.4 [74.4–­97.4]

79.8 [70.6–­90.4]

0.001

83.3 [73.8–­96.5]

81.2 [73.6–­91.0]

0.475

Serum creatinine (mg/dl)

0.68 [0.59–­0.76]

0.73 [0.62–­0.84]

0.003

0.69 [0.60–­0.76]

0.72 [0.60–­0.78]

0.527

AST (IU/L)

23.0 (15.4)

24.4 (13.2)

0.343

23.9 (16.1)

23.2 (12.9)

0.754

ALT (IU/L)

21.5 (19.1)

21.8 (16.8)

0.903

22.5 (20.0)

21.4 (19.4)

0.678

Total bilirubin (mg/dl)

0.64 (0.29)

0.64 (0.25)

0.965

0.63 (0.29)

0.64 (0.26)

0.941

Serum albumin (g/dl)

3.4 (0.6)

3.6 (0.5)

0.012

3.4 (0.6)

3.5 (0.6)

0.504

Concomitant use of magnesium
sulfate (%)

10 (7.9)

153 (50.2)<0.00110 (9.0)

8 (7.2)0.807

Chronic heart disease (%)

0 (0.0)7 (2.3)

0.112

0

0

NA

Hypertension (%)

26 (20.6)

65 (21.3)

1.000

24 (21.6)

25 (22.5)

1.000

Diabetes mellitus (%)

40 (31.8)

111 (36.4)

0.377

39 (35.1)

34 (30.6)

0.568

Comorbidities

Note: Data are presented as mean (SD), median [interquartile range], or number of patients (%).
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BSA, body surface area; CIN, cisplatin-­induced nephrotoxicity; eGFR, estimatedglomerular filtration rate; NA, not applicable.

cisplatin-­induced renal injury. In a mouse model of cisplatin-­induced renal injury, combination treatment with cisplatin
and a first-­generation 5-­HT₃ receptor antagonist exacerbatedrenal damage. Histological evaluation of the renal sections
revealed extensive proximal tubular cell necrosis.
To determine the cause of cisplatin-­induced renal damage exacerbated by the concomitant use of first-­generation
5-­HT₃ receptor antagonists, we measured cisplatin accumulation in the kidneys at 4 or 8 h after cisplatin administration.
The concomitant use of a first-­generation 5-­HT₃ receptor
antagonist significantly increased the renal cisplatin accumulation; however, there was no difference in accumulation
between animals that received combination therapy withpalonosetron and those that received cisplatin monotherapy.
Combination treatment with first-­and second-­generation
agents did not affect the blood levels of cisplatin. Thus, thefirst-­generation 5-­HT₃ receptor antagonists altered cisplatin accumulation in the kidneys without affecting cisplatin
pharmacokinetics.
The excretion of cisplatin from renal tubular cells is
mediated by MATE1, which has been reported to be involved in the CIN development.45 Ondansetron is a MATE

transporter inhibitor.46,47 Ondansetron inhibited MATE andexacerbated cisplatin-­induced kidney injury in mice.16 Li
et al.16 showed that ondansetron inhibits MATE activity invitro and increases the blood concentration and renal accumulation of metformin, a substrate of MATE transporters, in vivo, suggesting a correlation between the inhibitionof MATE transporters and inhibition of renal excretion of
MATE substrates. It has also been reported that there isan association between transporter inhibitory activity, as
determined in vitro, and clinical symptoms.48 Thus, a comparison of the MATE inhibitory activity of various 5-­HT₃
receptor antagonists revealed that the second-­generation
inhibitor palonosetron had weaker MATE inhibitory activity than the three first-­generation agents. Furthermore,
the most notable difference between palonosetron and thefirst-­generation drugs is their affinity for 5-­HT₃ receptors(~ 10-­fold lower inhibition constant values than those of
ondansetron). In addition, the half-­life is significantly increased, to ~ 35 h compared with 5 h for the first-­generation
drugs. Therefore, the difference in pharmacokinetics canbe attributed to a difference in elimination competition
with cisplatin.

EFFECTS OF 5-­HT₃ RAS ON CDDP-­INDUCED AKI

There were some limitations to this study. First, theresults of the experiments conducted in cells and animals
do not fully reflect the effect in humans. Second, theFAERS database accumulates spontaneous reports, which
may be subject to bias such as under-­or over-­reporting.
Therefore, we conducted a retrospective study using electronic medical records, which provide detailed patient
information. The results suggest that the first-­generation
5-­HT₃ receptor antagonists may increase the incidence of
cisplatin-­induced kidney injury. Our retrospective study
using medical electronic records involved a small number of patients, and we could not obtain data about somepotential factors of CIN, such as other antiemetics, othernephrotoxins, and hydration status. Additionally, palonosetron is a more efficacious antiemetic than the first-­
generation 5-­HT₃ receptor antagonists and, therefore, thehydration status may be improved. Consequently, our results may not be fully generalizable without further prospective study in a larger population. Thus, although eachmethod has its limitations, they can be overcome using
multiple methods and information obtained through databases. The results of basic experiments can be validated
for drug efficacy using clinical data to predict clinicaleffects and safety. The results suggest that the concomitant use of first-­generation 5-­HT₃ receptor antagonists
may be a risk factor for cisplatin-­induced renal damage.
However, second-­generation 5-­HT₃ receptor antagonists
appeared to have less effect. Therefore, renal injury
risk in high-­r isk patients may be reduced by selecting asecond-­generation 5-­HT₃ receptor antagonist if the use ofantiemetic agents is necessary.
CONFLICT OF INTEREST
All authors declared no competing interests for this work.
AUTHOR CONTRIBUTIONS
M.G. and Y.I. wrote the manuscript. M.G., Y.I., and K.I. designed the research. M.K., T.Y., A.Y., Y.M., T.N., and M.C.
performed the research. M.G., Y.Z., F.A., H.H., N.O., K.Y.,
and M.C. analyzed the data.
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SUPPORTING INFORMATION
Additional supporting information may be found online in
the Supporting Information section.

How to cite this article: Goda M, Kanda M, Yoshioka
T, et al. Effects of 5-­HT₃ receptor antagonists on
cisplatin-­induced kidney injury. Clin Transl Sci.
2021;14:1906–1916. https://doi.org/10.1111/cts.13045