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

doi:10.1177/20543581211057708

Canadian Journal of Kidney Health and Disease (Nov 2021)

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

Affiliations

Anshika Jain: Temerty Faculty of Medicine, University of Toronto, ON, Canada
Ryan Huang: Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, ON, Canada
Jasmine Lee: Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, ON, Canada
Natasha Jawa: Division of Nephrology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada
Yong Jin Lim: Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada
Mike Guron: Department of Pediatrics, BC Children’s Hospital, The University of British Columbia, Vancouver, Canada
Sharon Abish: Division of Hematology and Oncology, Montreal Children’s Hospital, McGill University Health Centre, Montreal, QC, Canada
Paul C. Boutros: Department of Medical Biophysics, University of Toronto, ON, Canada
Michael Brudno: Canada Centre for Computational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
Bruce Carleton: BC Children’s Hospital Research Institute, Vancouver, Canada
Geoffrey D. E. Cuvelier: CancerCare Manitoba, University of Manitoba, Winnipeg, Canada
Lakshman Gunaratnam: Division of Nephrology, Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
Cheryl Ho: Medical Oncology, BC Cancer, The University of British Columbia, Vancouver, Canada
Khosrow Adeli: University of Toronto, ON, Canada, Canada
Sara Kuruvilla: Division of Medical Oncology, Department of Oncology, Western University, London, ON, Canada
Giles Lajoie: Department of Biochemistry, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada
Geoffrey Liu: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
Paul C. Nathan: Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada
Shahrad Rod Rassekh: Department of Pediatrics, Division of Hematology/Oncology/Bone Marrow Transplantation, BC Children’s Hospital, The University of British Columbia, Vancouver, Canada
Michael Rieder: Department of Pediatrics, Western University, London, ON, Canada
Sushrut S. Waikar: Boston Medical Center, MA, USA
Stephen A. Welch: Division of Medical Oncology, Department of Oncology, Western University, London, ON, Canada
Matthew A. Weir: Division of Nephrology, Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
Eric Winquist: Division of Medical Oncology, Department of Oncology, Western University, London, ON, Canada
David S. Wishart: Department of Biochemistry, University of Alberta, Edmonton, Canada
Alexandra P. Zorzi: Division of Hematology/Oncology, Department of Pediatrics, Children’s Hospital, Western University, London, ON, Canada
Tom Blydt-Hansen: Department of Pediatrics, BC Children’s Hospital, The University of British Columbia, Vancouver, Canada
Michael Zappitelli: Division of Nephrology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada
Bradley Urquhart: Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada

DOI: https://doi.org/10.1177/20543581211057708
Journal volume & issue: Vol. 8

Abstract

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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.

Published in Canadian Journal of Kidney Health and Disease

ISSN: 2054-3581 (Online)
Publisher: SAGE Publishing
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the genitourinary system. Urology
Website: https://journals.sagepub.com/home/cjk

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