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Kidney360
Kidney360
KIDNEY
Kidney360
Kidney360
2641-7650
American Society of Nephrology

38814726
K360-2023-000643
10.34067/KID.0000000000000464
00007
3
Clinical Research
Acute Kidney Injury and ICU Nephrology
Evaluation of Cisplatin-Induced Acute Kidney Injury in Patients Coprescribed Serotonin Receptor Antagonists: A Retrospective Analysis
https://orcid.org/0000-0002-8789-9172
Gutgarts Victoria 1 2
Gerardine Supriya 3
Shingarev Roman A. 4
https://orcid.org/0000-0002-0741-2150
Knezevic Andrea 5
https://orcid.org/0000-0002-1402-4498
Zabor Emily C. 6
https://orcid.org/0000-0001-5159-9680
Latcha Sheron 1 2
Joy Melanie S. 7
https://orcid.org/0000-0002-0032-1037
Aleksunes Lauren M. 8
Jaimes Edgar A. 1 2
1 Renal Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
2 Weill Cornell Medical College, New York, New York
3 The Nephrology Group, Visalia, California
4 Kidney Medicine, Cleveland Clinic, Cleveland, Ohio
5 Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
6 Department of Quantitative Health Sciences & Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
7 Division of Nephrology, Cancer Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, School of Medicine, University of Colorado, Denver, Colorado
8 Rutgers, The State University of New Jersey, Piscataway, New Jersey
Correspondence: Dr. Edgar A. Jaimes, email: jaimese@mskcc.org
8 2024
30 5 2024
5 8 10941100
23 8 2023
26 4 2024
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Visual Abstract

Key Points

Serotonin receptor antagonists reduce the incidence of AKI in patients receiving cisplatin as chemotherapy.

New-generation serotonin receptors do not offer any additional advantage in terms of protection from cisplatin induced AKI.

Background

Cisplatin is an effective first-line therapy for a variety of cancers. Cisplatin is highly emetogenic and resulting volume depletion can contribute to AKI. Antiemetic drugs, such as 5-hydroxytryptamine type 3 receptor antagonists (5-HT3RAs), are commonly prescribed to prevent this complication. Preclinical studies suggest first-generation 5-HT3RAs may alter the renal clearance and increase cisplatin toxicity. This retrospective study evaluated whether different 5-HT3RAs modify the risk of AKI in patients receiving cisplatin.

Methods

Patients with cancer who received cisplatin between January 1, 2010, and December 31, 2016, were included. Patients older than 18 years with available data for baseline and post-treatment serum creatinine, cisplatin cumulative dose, and administration of 5-HT3RAs, including first-generation (ondansetron, granisetron, and ramosetron) and second-generation (palonosetron), were analyzed. AKI was defined as 1.5× increase in serum creatinine. Fisher exact and Wilcoxon rank-sum tests were used to assess univariable associations between baseline covariates and AKI and logistic regression for multivariable associations with AKI.

Results

Of 8703 patients identified with cisplatin exposure, 6889 were included. A total of 3881 patients (56.3%) received at least one 5-HT3RA, including palonosetron (3750, 54.4%), ondansetron (1399, 20.3%), and granisetron (11, 0.2%). AKI developed in 1666 patients (24.2%) after cisplatin therapy. Patients who received any 5-HT3RAs were less likely to experience AKI as compared with patients who did not (22.6% versus 26.2%, P = 0.001). Older age, male sex, African ethnicity, and cumulative cisplatin dose were univariably associated with higher risk of AKI (P < 0.001). After adjusting for these variables, use of any of these antiemetic drugs was protective for AKI (odds ratio, 0.84; 95% confidence interval, 0.75 to 0.94; P = 0.003) with no difference detected between type of 5-HT3RA.

Conclusions

Nephrotoxicity continues to be a concern after cisplatin therapy. Given its emetogenic nature, use of antiemetic drugs, such as 5-HT3RAs, can lessen emesis and lower risk of kidney injury. This retrospective analysis supports use of any 5-HT3RAs to lower risk of AKI.

AKI
cancer
cisplatin
drug excretion
National Institute of Health Cancer Center SupportGrants P30CA008748, P30CA072720, and P30CA046934 Not ApplicableNational Institute of Nursing ResearchP30ES00522 Not ApplicableNational Institute of General MedicineR01GM123330 Lauren M. AleksunesNJ Alliance for Clinical ScienceUL1TR003017 Not ApplicableNational Institute of Health Cancer Center SupportGrants P30CA008748, P30CA072720, and P30CA046934 National Institute of Nursing ResearchP30ES00522 National Institute of General MedicineR01GM123330 NJ Alliance for Clinical ScienceUL1TR003017 OPEN-ACCESSTRUE
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pmcIntroduction

Cisplatin is one of the most commonly used platinum-based chemotherapies for the treatment of a variety of solid organ malignancies.1–3 Nephrotoxicity is a well-known side effect of cisplatin, accounting for up to 30% of kidney injury in hospitalized patients with cancer.4–8 The emetogenic nature of cisplatin, classified as a highly emetogenic drug, may increase the risk of AKI by dehydration and intravascular depletion. Antiemetic drugs are coadministered with cisplatin to ameliorate volume losses and reduce the risk of kidney injury.

The American Society of Clinical Oncology guidelines for highly emetogenic chemotherapy includes a four-drug antiemetic regimen consisting of a neurokinin-1 receptor antagonist, a 5-hydroxytryptamine type 3 receptor antagonist (5-HT3Ras), dexamethasone, and olanzapine.9 Experimental and small clinical studies have suggested differences among the different 5-HT3RAs. First-generation drugs, including ondansetron, granisetron, and ramosetron, may be linked to increased cisplatin-related renal adverse effects as compared with second-generation agents, such as palonosetron.10,11 The mechanism for higher risk of renal injury with first-generation 5-HT3RAs is not well understood but is suspected to involve the inhibition of kidney transporters responsible for the renal tubular excretion of cisplatin.12,13 This could manifest as an increased accumulation of cisplatin in the proximal tubule cells and higher risk of AKI.

In this study, we retrospectively evaluated the risk of kidney injury during combined treatment with cisplatin and several 5-HT3RAs. The objectives were to determine whether the use of 5-HT3RAs results in less cisplatin-mediated renal injury and whether the use of second-generation versus first-generation 5-HT3RAs is associated with lower risk of renal injury as suggested by preclinical and smaller clinical studies.11

Methods

Patients at the Memorial Sloan Kettering Cancer Center with any malignancy treated with cisplatin-based therapy from January 1, 2010, to December 31, 2016, were screened for inclusion into the study. Institutional review board approval was obtained before collection and analysis of patient data. Demographic characteristics, including age, sex, and race, were collected from medical records. Laboratory data of interest were baseline serum creatinine defined as the closest measurement within 30 days of starting cisplatin therapy and post-cisplatin creatinine defined as the maximum value recorded within 30 days after the end of cisplatin treatment. Baseline creatinine was defined as abnormal if >1.3 mg/dl on the basis of the upper limit at our institution. Cumulative dose (CD) of cisplatin therapy was included and defined on the basis of previous cisplatin studies.14 The 5-HT3RAs evaluated included ondansetron, palonosetron, and granisetron because they were the most commonly used antiemetics at the Memorial Sloan Kettering Cancer Center. Patients younger than 18 years or who did not have antiemetic or creatinine data available at baseline were excluded from the study.

Outcomes evaluated were (1) the development of AKI defined as an increase in serum creatinine by 1.5× from baseline (pre-cisplatin treatment) to post-cisplatin (maximum value within 30 days after the last dose of cisplatin therapy), (2) effects of 5-HT3RAs coprescribing and risk of AKI, and (3) differences in risk of cisplatin-associated AKI between first and second-generation 5-HT3RAs. Severity of AKI was defined by Kidney Disease Improving Global Outcomes criteria: grade 1 (1.5 to <2-fold), grade 2 (2 to <3-fold), and grade 3 (≥3-fold) baseline.

Statistical Analyses

Fisher's exact and Wilcoxon rank-sum tests were used to assess univariable associations between baseline covariates and the development of AKI after cisplatin exposure. Multivariable associations with AKI were analyzed using logistic regression. The Wilcoxon rank-sum test was used to assess group differences in serum creatinine fold-change from baseline to post-treatment. A P value < 0.05 was considered statistically significant. Statistical analyses were conducted in R version 3.4.1 (R Core Development Team, Vienna, Austria) and SAS version 9.4 (Cary, NC).

Results

We identified 8703 patients with cisplatin exposure, and 6889 of those were included in the study, as shown in Figure 1. The average age was 58 years (range, 18–90). The majority were male (53.6%) and of Caucasian ethnicity (79.5%) (Table 1). The most common malignancy in this study was lung cancer (18%) followed by head and neck cancers (16%), with the additional distributions described in Table 1. The average baseline creatinine was 0.8 mg/dl (range, 0.3–6.5 mg/dl). Abnormal baseline creatinine was observed in 2.7% of patients. The CD of cisplatin ranged from ≤100 to >700 mg/m2. Most patients received a CD of 101–250 mg/m2 (26.6%), 22% received a dose of 251–400 mg/m2, 16.6% received a dose of 401–550 mg/m2, and 24.7% received a dose of >550 mg/m2. The average CD of cisplatin therapy was 342 mg/m2.

Figure 1 Patient screening and selection. 5-HT3RA, 5-hydroxytryptamine type 3 receptor antagonist.

Table 1 Baseline patient characteristics of AKI and no AKI groups

Baseline Characteristics	Overall (N=6889)	No AKI Post-cisplatin (n=5223)	AKI Post-cisplatin (n=1666)	P Valuea	
Age	58 (18–90)	58 (18–90)	60 (19–87)	<0.001b	
Sex				0.039b	
 Female	3197 (46.4)	2387 (45.7)	810 (48.6)		
 Male	3692 (53.6)	2836 (54.3)	856 (51.4)		
Race				<0.001b	
 White	5478 (79.5)	4124 (79)	1354 (81.3)		
 Asian	475 (6.9)	399 (7.6)	76 (4.6)		
 Black	458 (6.6)	316 (6.1)	142 (8.5)		
 Unknown	478 (6.9)	384 (7.4)	94 (5.6)		
Cancer type				<0.001b	
 Lung	1242 (18)	935 (18)	307 (18)		
 Head and neck	1107 (16)	754 (14)	353 (21)		
 Gynecologic	827 (12)	640 (12)	187 (11)		
 Upper gastrointestinal	767 (11)	563 (11)	204 (12)		
 Genitourinary	636 (9)	488 (9)	148 (9)		
 Germ cell tumor	469 (7)	411 (8)	58 (3)		
 Multiple myeloma	149 (2)	132 (3)	17 (1)		
 Skin	94 (1)	63 (1)	31 (2)		
 Other	375 (5)	253 (5)	122 (7)		
 Unknown	1223 (18)	984 (19)	239 (14)		
Baseline laboratory values, median (IQR)					
 Creatinine, mg/dl	0.80 (0.70 to 1.0)	0.80 (0.70–1.0)	0.80 (0.60–0.9)	<0.001b	
 eGFR	96 (81–105)	95 (79–105)	98 (84–106)	<0.001b	
 AST	23 (19–31)	23 (19–30)	24 (19–31)	0.09	
 ALT	23 (17–33)	23 (17–33)	24 (19–31)	0.77	
 BUN	15 (11–18)	15 (12–18)	15 (11–18)	0.01b	
 Albumin	4.2 (3.9–4.5)	4.2 (3.9–4.5)	4.1 (3.8–4.4)	<0.001b	
Cumulative cisplatin dose, mg/m2	342 (7–5097)	330 (9–2347.5)	389 (7–5097)	<0.001b	
ALT, alanine transaminase; AST, aspartate transferase; IQR, interquartile range.

Head and neck includes oropharyngeal, nasopharyngeal, and salivary gland cancers.

Upper gastrointestinal includes gastric, esophageal, gastroesophageal junction, cholangiocarcinoma, biliary tract, pancreatic, and liver cancers.

Genitourinary includes adrenal, bladder, kidney, penile, prostate, and testicular cancers.

a Frequency (%) reported for categorical variables (Chi-square test) and median (interquartile range) for continuous variables (Wilcoxon rank-sum test).

b Significance level of alpha <0.05.

A total of 3881 (56.3%) patients received at least one 5-HT3RA antiemetic. These included ondansetron (n=1399, 20.3%), palonosetron (n=3750, 54.4%), and granisetron (n=11, 0.2%) as shown in Figure 1. Patients may have been on more than one agent or interchanged between 5-HT3RAs during the duration of cisplatin therapy. Among the 3881 patients who received 5-HT3RAs antiemetics, 2479 (63.9%) received palonosetron only, 124 (3.2%) received ondansetron only, and 1267 (32.6%) received both palonosetron and ondansetron.

A total of 1666 (24.2%) patients developed AKI after cisplatin use. This includes AKI grade 1 (1,014, 14.7%), grade 2 (489, 7.1%) and grade 3 (163, 2.4%). Differences in baseline characteristics between patients who developed AKI and had no AKI are shown in Table 1. Patients who received any 5-HT3RA therapies were less likely to experience AKI (22.6%, P = 0.001) as compared with patients who did not (26.4%) (Table 2). When evaluating risk of AKI by 5-HT3RA type, there was less AKI with both the first generation 5-HT3RAs ondansetron (21.9% versus 24.8%, P = 0.03) and the second generation 5-HT3RAs palonosetron (22.8% versus 25.9%, P = 0.003) as shown in Table 2. Compared with patients who received no 5-HT3RA therapy, the rate of AKI was less in those who received palonosetron, only (23.0%), ondansetron, only (17.7%) and both palonosetron and ondansetron (22.3%; P = 0.003). Further, there was no difference observed in serum creatinine fold-change after cisplatin treatment in the palonosetron only and ondansetron only, as shown in Figure 2 (P = 0.32). Given the limited prescribing of granisetron at our institution, it was not possible to assess whether granisetron was also associated with reduced risk for AKI. Major differences between baseline and post cisplatin laboratory values for aspartate transferase, alanine transaminase, BUN, and albumin, were not notable in both the AKI and no AKI groups (Table 3).

Table 2 Univariate analysis between 5-hydroxytryptamine type 3 receptor antagonist use and AKI

5-HT3RA Type	5-HT3RA Status	AKI	P Value	
N=6889	n=1666	
Any 5-HT3RAs	No: 3008	789 (26.2%)	0.001	
Yes: 3881	877 (22.6%)	
Ondansetron	No: 5490	1359 (24.8%)	0.03	
Yes: 1399	307 (21.9%)	
Palonosetron	No: 3139	812 (25.9%)	0.003	
Yes: 3750	854 (22.8%)	
Granisetrona	No: 6878	1664 (24.2%)	1	
Yes: 11	2 (18.2%)	
Combination therapyb	None: 3008	789 (26.2%)	0.003	
Palonosetron, only: 2479	570 (23.0%)	
Ondansetron, only: 124	22 (17.7%)	
Palonosetron+Ondansetron: 1267	283 (22.3%)	
5-HT3RA, 5-hydroxytryptamine type 3 receptor antagonist.

a Granisetron was not used with sufficient frequency to draw statistically significant conclusions.

b Not including 11 patients on granisetron.

Figure 2 Serum creatinine fold-change for patients receiving either palonosetron or ondansetron. No difference was observed in serum creatinine fold-change after cisplatin treatment between patients who received either palonosetron or ondansetron (Wilcoxon P = 0.32).

Table 3 Change in patient laboratory values after cisplatin therapy in the AKI and no AKI groups

Laboratory Values	N	Overall	No AKI	AKI	P Valuea	
AST	5415	1 (−4 to 7)	1 (−4 to 7)	1 (−5 to 7)	0.01	
ALT	5411	2 (−4 to 10)	2 (−4 to 10)	3 (−5 to 12)	0.92	
BUN	6741	−3 (−9 to 1)	−2 (−6 to 2)	−11 (−19 to −5)	<0.001	
Albumin	5401	0.2 (−0.1 to 0.4)	0.2 (−0.1 to 0.4)	0.2 (−0.1 to 0.5)	0.96	
ALT, alanine transaminase; AST, aspartate transferase.

a Wilcoxon rank-sum test.

Multivariable analysis for development of cisplatin-related AKI is shown in Table 4. Older age (HR, 1.03 per 1-year increase [95% confidence interval (CI), 1.02 to 1.03; P < 0.001]), male sex (HR, 1.40 [95% CI, 1.23 to 1.59; P < 0.001]), Black ethnicity (HR, 1.74 [95% CI, 1.4 to 2.16; P < 0.001]), and higher CD of cisplatin, mg/m2 (HR, 1.04 per 50-unit increase [95% CI, 1.03 to 1.05; P < 0.001]) carried higher risk of AKI. After adjusting for age, sex, ethnicity, baseline creatinine value, and cumulative cisplatin dose, the use of any 5-HT3RAs was significantly protective for AKI in the multivariable model. 5-HT3RA use was associated with a 16% reduction in the odds of developing AKI (odds ratio, 0.84; 95% CI, 0.75 to 0.94; P = 0.003). Higher baseline creatinine was associated with lower odds of AKI, in univariate analysis and multivariate analysis.

Table 4 Multivariable analysis for risk factors of AKI post-cisplatin therapy

Variable	OR (95% CI)	P Value	
Age (per 1-yr increase)	1.03 (1.02 to 1.03)	<0.001	
Male sex	1.4 (1.23 to 1.59)	<0.001	
Black	1.74 (1.40 to 2.16)	<0.001	
Use of any 5-HT3RAs	0.84 (0.75 to 0.94)	0.003	
Cumulative cisplatin dose, mg/m2 (per 50-unit increase)	1.04 (1.03 to 1.05)	<0.001	
Baseline creatinine, mg/dl (per one-unit increase)	0.14 (0.10 to 0.19)	<0.001	
5-HT3RA, 5-hydroxytryptamine type 3 receptor antagonist; CI, confidence interval; OR, odds ratio

Discussion

In our study, the largest to date examining the relationship of antiemetic use and kidney function, we investigated whether the use of 5-HT3RA antiemetics reduces the risk of cisplatin-induced AKI and whether second-generation 5-HT3RAs provide an advantage as compared with first-generation. We observed a 16% reduction in the odds of developing AKI in patients who received 5-HT3RA, suggesting that coprescribing of any 5-HT3RAs with cisplatin-containing chemotherapy significantly ameliorates the risk of AKI in these patients. Although these larger groups had overlap and were not mutually exclusive for one type of 5-HT3RA therapy, when we analyzed patients who received palonosetron only and ondansetron only, there remained no difference in serum creatinine fold-changes after cisplatin treatment.

Nephrotoxicity continues to be a common adverse reaction after cisplatin therapy.7,15–17 Although a growing number of novel targeted and cellular therapies are being used to treat solid tumors, cisplatin remains first-line therapy for a number of cancers, either alone or in combination with other agents.17,18 Similar to previous studies,14,19,20 we found a 24% incidence of AKI in this patient population receiving cisplatin and higher risk of AKI in older patients and those who received a higher CD of cisplatin. Interestingly, the risk of AKI was found to be lower in patients with higher baseline creatinine, which may be because of additional hydration outside of our standard protocol described below and less exposure to other nephrotoxic agents not assessed in this retrospective study.

The severity of AKI associated with cisplatin use can be mild to moderate, leading to delays or discontinuation of therapy, reductions in dosing, and changes to potentially less effective chemotherapeutic agents. It can also result in permanent loss of kidney function,14 which can affect suitability for future therapeutic options. Several studies have shown that reductions in dosing and/or duration of treatment is linked to worse oncologic outcomes in patients who are receiving cisplatin as potentially curative therapy (i.e., head and neck, testicular cancers).21

Given the highly emetogenic nature of cisplatin therapy, one purported mechanism for AKI in these patients is volume losses, dehydration, and prerenal azotemia.1 Reduced oral intake as a result of nausea and anorexia is often observed in all patients undergoing chemotherapy. Preventive strategies against prerenal azotemia and ischemic acute tubular toxicity include aggressive hydration protocols.22 At our institution, all patients receiving cisplatin are preemptively given 1 L of normal saline. For patients receiving cisplatin doses >50 mg/m2, an additional 1 L of normal saline is administered afterward. Hydration is continued if urine output is <100 ml/h. In addition, to prevent nausea and vomiting, all patients are given 5-HT3RAs before cisplatin administration. These agents are also given as part of post-treatment care on an individual basis of symptoms. Other agents include amifostine, which was approved for the prevention of cisplatin-associated AKI,23 but is seldom used because its use is associated with hypotension.24 Despite aggressive hydration and careful monitoring of patients prescribed cisplatin, AKI still remains an important clinical problem.

Cisplatin is renally excreted and enters tubular cells from blood by uptake transporters at the basolateral membrane facilitated by efflux transporters at the apical membrane.10 In rat and human cell models, the organic cation transporter 2 mediates the majority of cisplatin basolateral uptake25,26 and increased organic cation transporter 2 expression enhances accumulation of cisplatin in proximal tubular cells.27 Efflux transporters, such as multidrug and toxin extrusion protein 1 (MATE-1) and multidrug and toxin extrusion protein 2, are largely responsible for the excretion of cisplatin into the urinary space.25,28 Nakamura et al. demonstrated that knockout mice lacking the MATE-1 gene had a higher rise in creatinine and urea levels than wild-type mice.29

With respect to AKI risk with generation one versus two 5-HT3RAs, Li et al. showed that ondansetron, a first-generation 5-HT3RA, is a functional inhibitor of multidrug and toxin extrusion transporters and significantly increased renal tissue concentrations of cisplatin in mice.30,31 Furthermore, an uptake study in MATE-1 expressing cells showed that second-generation 5-HT3RAs have weaker MATE-1 inhibitory activity than first-generation, thereby postulating less accumulation of cisplatin and less nephrotoxicity.10,27 A recent small retrospective study of 110 patients who received cisplatin found less AKI in those treated with palonosetron (second-generation) versus ramosetron (first-generation)11 consistent with this experimental observation.

Unlike previous smaller clinical and animal studies, we did not see a difference in the risk of AKI with first-generation versus second-generation 5-HT3RAs. Differences in first and second-generation 5-HT3RAs may not have been seen in our study because of limitations of overlap and coadministration of 5-HT3RAs in this larger though retrospective study. Furthermore, not all patients receiving 5-HT3Ras may have been captured because of the use of paper charts that preceded some of the electronic information collected.

Further studies will be helpful to better delineate best practices in antiemetic administration to lower risk of cisplatin-related AKI. Our finding that any 5-HT3RA lowered risk of AKI suggests that lower volume loss and dehydration from emesis may have a stronger effect on risk of AKI than inhibition of transporters on a cellular level. Prospective studies, underway at our center, that directly investigate pharmacokinetic 5-HT3RA drugs and AKI risk will help to optimize antiemetic guidelines for cisplatin therapy.

Acknowledgments

Data included in this manuscript were presented in abstract form at the Annual Meeting of the American Society of Nephrology in 2019.

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/KN9/A516.

Funding

This work was supported by National Institute of Health Cancer Center Support (Grants P30CA008748, P30CA072720, and P30CA046934), National Institute of Nursing Research (P30ES00522), and NJ Alliance for Clinical Science (UL1TR003017). L.M. Aleksunes: National Institute of General Medicine (R01GM123330).

Author Contributions

Conceptualization: Lauren M. Aleksunes, Victoria Gutgarts, Edgar A. Jaimes, Melanie S. Joy, Roman Shingarev.

Data curation: Supriya Gerardine.

Formal analysis: Andrea Knezevic, Emily C. Zabor.

Methodology: Victoria Gutgarts, Andrea Knezevic, Emily C. Zabor.

Supervision: Edgar A. Jaimes.

Writing – original draft: Supriya Gerardine, Victoria Gutgarts.

Writing – review & editing: Lauren M. Aleksunes, Edgar A. Jaimes, Melanie S. Joy, Sheron Latcha, Roman A. Shingarev.

Data Sharing Statement

All data are included in the manuscript and/or supporting information.

See related editorial, “Are Antiemetics the Next Therapeutic Strategy against Cisplatin-Associated Acute Kidney Injury?,” on pages 1067–1068.
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