A Canadian Study of Cisplatin Metabolomics and Nephrotoxicity (ACCENT): A Clinical Research Protocol

Anshika Jain, Ryan Huang, Jasmine Lee, Natasha Jawa, Yong Jin Lim, Mike Guron, Sharon Abish, Paul C Boutros, Michael Brudno, Bruce Carleton, Geoffrey D E Cuvelier, Lakshman Gunaratnam, Cheryl Ho, Khosrow Adeli, Sara Kuruvilla, Giles Lajoie, Geoffrey Liu, Paul C Nathan, Shahrad Rod Rassekh, Michael Rieder, Sushrut S Waikar, Stephen A Welch, Matthew A Weir, Eric Winquist, David S Wishart, Alexandra P Zorzi, Tom Blydt-Hansen, Michael Zappitelli, Bradley Urquhart, Anshika Jain, Ryan Huang, Jasmine Lee, Natasha Jawa, Yong Jin Lim, Mike Guron, Sharon Abish, Paul C Boutros, Michael Brudno, Bruce Carleton, Geoffrey D E Cuvelier, Lakshman Gunaratnam, Cheryl Ho, Khosrow Adeli, Sara Kuruvilla, Giles Lajoie, Geoffrey Liu, Paul C Nathan, Shahrad Rod Rassekh, Michael Rieder, Sushrut S Waikar, Stephen A Welch, Matthew A Weir, Eric Winquist, David S Wishart, Alexandra P Zorzi, Tom Blydt-Hansen, Michael Zappitelli, Bradley Urquhart

Abstract

Background: Cisplatin, a chemotherapy used to treat solid tumors, causes acute kidney injury (AKI), a known risk factor for chronic kidney disease and mortality. AKI diagnosis relies on biomarkers which are only measurable after kidney damage has occurred and functional impairment is apparent; this prevents timely AKI diagnosis and treatment. Metabolomics seeks to identify metabolite patterns involved in cell tissue metabolism related to disease or patient factors. The A Canadian study of Cisplatin mEtabolomics and NephroToxicity (ACCENT) team was established to harness the power of metabolomics to identify novel biomarkers that predict risk and discriminate for presence of cisplatin nephrotoxicity, so that early intervention strategies to mitigate onset and severity of AKI can be implemented.

Objective: Describe the design and methods of the ACCENT study which aims to identify and validate metabolomic profiles in urine and serum associated with risk for cisplatin-mediated nephrotoxicity in children and adults.

Design: Observational prospective cohort study.

Setting: Six Canadian oncology centers (3 pediatric, 1 adult and 2 both).

Patients: Three hundred adults and 300 children planned to receive cisplatin therapy.

Measurements: During two cisplatin infusion cycles, serum and urine will be measured for creatinine and electrolytes to ascertain AKI. Many patient and disease variables will be collected prospectively at baseline and throughout therapy. Metabolomic analyses of serum and urine will be done using mass spectrometry. An untargeted metabolomics approach will be used to analyze serum and urine samples before and after cisplatin infusions to identify candidate biomarkers of cisplatin AKI. Candidate metabolites will be validated using an independent cohort.

Methods: Patients will be recruited before their first cycle of cisplatin. Blood and urine will be collected at specified time points before and after cisplatin during the first infusion and an infusion later during cancer treatment. The primary outcome is AKI, defined using a traditional serum creatinine-based definition and an electrolyte abnormality-based definition. Chart review 3 months after cisplatin therapy end will be conducted to document kidney health and survival.

Limitations: It may not be possible to adjust for all measured and unmeasured confounders when evaluating prediction of AKI using metabolite profiles. Collection of data across multiple sites will be a challenge.

Conclusions: ACCENT is the largest study of children and adults treated with cisplatin and aims to reimagine the current model for AKI diagnoses using metabolomics. The identification of biomarkers predicting and detecting AKI in children and adults treated with cisplatin can greatly inform future clinical investigations and practices.

Trial registration: ClinicalTrials.gov NCT04442516.

Keywords: acute kidney injury; cisplatin nephrotoxicity; cohort study; metabolomics; pediatrics.

Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

© The Author(s) 2021.

Figures

Figure 1.
Figure 1.
Steering committee, participating centers, and collaborators. Note. The figure demonstrates the individuals involved in each section of the project and their locations. UBC, University of British Columbia; UWO, University of Western Ontario; UofA, University of Alberta; UofM, University of Manitoba; PMH, Princess Margaret Hospital; BU, Boston University. This figure was created with BioRender.com.
Figure 2.
Figure 2.
Schematic of proposed proximal tubule cisplatin toxicity. Note. GST = glutathione S-transferase; GGT = γ glutamyl transpeptidase; APN = aminopeptidase.,,, This figure was created with BioRender.com.
Figure 3.
Figure 3.
Overview of experimental design. Note. DNA is captured only once at the first cisplatin cycle. Both blood and urine are collected 6 times during the study (3 collection time points for each of 2 cisplatin cycles).
Figure 4.
Figure 4.
Sequential overview of the data analysis process. Note. Encompasses data collection, data processing, and multivariate analysis.
Figure 5.
Figure 5.
Timeline of progress to date. Note. Description of progress as of March 2021. This figure was created with BioRender.com.

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