title: Application of new acute kidney injury biomarkers in human randomized controlled trials.
abstract: The use of novel biomarkers of acute kidney injury (AKI) in clinical trials may help evaluate treatments for AKI. Here we explore potential applications of biomarkers in simulated clinical trials of AKI using data from the TRIBE-AKI multicenter, prospective cohort study of patients undergoing cardiac surgery. First, in a hypothetical trial of an effective therapy at the time of acute tubular necrosis to prevent kidney injury progression, use of an indirect kidney injury marker such as creatinine compared to a new direct biomarker of kidney injury reduces the proportion of true acute tubular necrosis cases enrolled. The result is a lower observed relative risk reduction with the therapy, and lower statistical power to detect a therapy effect at a given sample size. Second, the addition of AKI biomarkers (interleukin-18 and NGAL) to clinical risk factors as eligibility criteria for trial enrollment in early AKI has the potential to increase the proportion of patients who will experience AKI progression and reduce trial cost. Third, we examine AKI biomarkers as outcome measures for the purposes of identifying therapies that warrant further testing in larger, multicenter, multi-country trials. In the hypothetical trial of lower cardiopulmonary bypass time to reduce the risk of postoperative AKI, the sample size required to detect a reduction in AKI is lower if new biomarkers are used to define AKI rather than serum creatinine. Thus, incorporation of new biomarkers of AKI has the potential to increase statistical power, decrease the sample size, and lower the cost of AKI trials.
authors.affiliation: Program of Applied Translational Research, Department of Medicine, Yale University, New Haven, Connecticut, USA; Veterans Affairs Medical Center, West Haven, Connecticut, USA. Electronic address: Chirag.Parikh@Yale.edu.
authors.forename: Chirag R
authors.initials: CR
authors.lastname: Parikh
authors.affiliation: Program of Applied Translational Research, Department of Medicine, Yale University, New Haven, Connecticut, USA.
authors.forename: Dennis G
authors.initials: DG
authors.lastname: Moledina
authors.affiliation: Section of Nephrology, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Coca
authors.affiliation: Program of Applied Translational Research, Department of Medicine, Yale University, New Haven, Connecticut, USA.
authors.forename: Heather R
authors.initials: HR
authors.lastname: Thiessen-Philbrook
authors.affiliation: Department of Medicine, Western University, London, Ontario, Canada; Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada.
authors.forename: Amit X
authors.initials: AX
authors.lastname: Garg
mesh_terms: D058186:Acute Kidney Injury / Q000097:blood* / Q000628:therapy; D015415:Biomarkers / Q000097:blood; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D003404:Creatinine / Q000097:blood*; D018450:Disease Progression; D006801:Humans; D020382:Interleukin-18 / Q000097:blood*; D007677:Kidney Function Tests / Q000379:methods*; D007683:Kidney Tubular Necrosis, Acute / Q000097:blood / Q000628:therapy; D000071068:Lipocalin-2 / Q000097:blood*; D011446:Prospective Studies; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors
chemical_list: D015415:Biomarkers; D020382:Interleukin-18; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D003404:Creatinine
keywords: acute kidney injury; cardiovascular disease; proteomic analysis