Jain Anshika, Huang Ryan, Lee Jasmine, Jawa Natasha, Lim Yong Jin, Guron Mike, Abish Sharon, Boutros Paul C, Brudno Michael, Carleton Bruce, Cuvelier Geoffrey D E, Gunaratnam Lakshman, Ho Cheryl, Adeli Khosrow, Kuruvilla Sara, Lajoie Giles, Liu Geoffrey, Nathan Paul C, Rod Rassekh Shahrad, Rieder Michael, Waikar Sushrut S, Welch Stephen A, Weir Matthew A, Winquist Eric, Wishart David S, Zorzi Alexandra P, Blydt-Hansen Tom, Zappitelli Michael, Urquhart Bradley
Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, ON, Canada.
Temerty Faculty of Medicine, University of Toronto, ON, Canada.
Can J Kidney Health Dis. 2021 Nov 17;8:20543581211057708. doi: 10.1177/20543581211057708. eCollection 2021.
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.
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.
Observational prospective cohort study.
Six Canadian oncology centers (3 pediatric, 1 adult and 2 both).
Three hundred adults and 300 children planned to receive cisplatin therapy.
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.
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.
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.
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.
顺铂是一种用于治疗实体瘤的化疗药物，可导致急性肾损伤（AKI），这是慢性肾病和死亡的已知风险因素。AKI的诊断依赖于生物标志物，而这些生物标志物只有在肾脏损伤发生且功能损害明显后才能测量；这阻碍了AKI的及时诊断和治疗。代谢组学旨在识别与疾病或患者因素相关的细胞组织代谢中涉及的代谢物模式。加拿大顺铂代谢组学与肾毒性研究（ACCENT）团队成立的目的是利用代谢组学的力量，识别预测顺铂肾毒性风险并区分其存在的新型生物标志物，以便能够实施减轻AKI发作和严重程度的早期干预策略。
描述ACCENT研究的设计和方法，该研究旨在识别和验证尿液和血清中与儿童和成人顺铂介导的肾毒性风险相关的代谢组学特征。
观察性前瞻性队列研究。
六个加拿大肿瘤中心（3个儿科、1个成人和2个兼具儿科和成人患者的中心）。
计划接受顺铂治疗的300名成人和300名儿童。
在两个顺铂输注周期中，将检测血清和尿液中的肌酐和电解质以确定是否发生AKI。在基线和整个治疗过程中，将前瞻性收集许多患者和疾病变量。将使用质谱法对血清和尿液进行代谢组学分析。将采用非靶向代谢组学方法分析顺铂输注前后的血清和尿液样本，以识别顺铂AKI的候选生物标志物。候选代谢物将使用独立队列进行验证。
患者将在第一个顺铂周期之前招募。在第一次输注和顺铂治疗后期癌症治疗期间的特定时间点采集血液和尿液。主要结局是AKI，采用基于传统血清肌酐的定义和基于电解质异常的定义。顺铂治疗结束3个月后将进行病历审查，以记录肾脏健康状况和生存率。
在使用代谢物谱评估AKI预测时，可能无法对所有测量和未测量的混杂因素进行调整。跨多个地点收集数据将是一项挑战。
ACCENT是对接受顺铂治疗的儿童和成人进行的最大规模研究，旨在利用代谢组学重新构想当前的AKI诊断模型。识别预测和检测接受顺铂治疗的儿童和成人AKI的生物标志物可为未来的临床研究和实践提供重要信息。
