Effect of Colchicine on the Risk of Perioperative Acute Kidney Injury: Clinical Protocol of a Substudy of the Colchicine for the Prevention of Perioperative Atrial Fibrillation Randomized Clinical Trial

Abstract

Acute kidney injury; Colchicine; Noncardiac surgeryLesión renal aguda; Colchicina; Cirugía no cardiacaLesión renal aguda; Colchicina; Cirugía no cardiacaBackground: Inflammation during and after surgery can lead to organ damage including acute kidney injury. Colchicine, an established inexpensive anti-inflammatory medication, may help to protect the organs from pro-inflammatory damage. This protocol describes a kidney substudy of the colchicine for the prevention of perioperative atrial fibrillation (COP-AF) study, which is testing the effect of colchicine versus placebo on the risk of atrial fibrillation and myocardial injury among patients undergoing thoracic surgery. Objective: Our kidney substudy of COP-AF will determine whether colchicine reduces the risk of perioperative acute kidney injury compared with a placebo. We will also examine whether colchicine has a larger absolute benefit in patients with pre-existing chronic kidney disease, the most prominent risk factor for acute kidney injury. Design and Setting: Randomized, superiority clinical trial conducted in 40 centers in 11 countries from 2018 to 2023. Patients: Patients (~3200) aged 55 years and older having major thoracic surgery. Intervention: Patients are randomized 1:1 to receive oral colchicine (0.5 mg tablet) or a matching placebo, given twice daily starting 2 to 4 hours before surgery for a total of 10 days. Patients, health care providers, data collectors, and outcome adjudicators will be blinded to the randomized treatment allocation. Methods: Serum creatinine concentrations will be measured before surgery and on postoperative days 1, 2, and 3 (or until hospital discharge). The primary outcome of the substudy is perioperative acute kidney injury, defined as an increase (from the prerandomization value) in serum creatinine concentration of either ≥26.5 μmol/L (≥0.3 mg/dL) within 48 hours of surgery or ≥50% within 7 days of surgery. The primary analysis (intention-to-treat) will examine the relative risk of acute kidney injury in patients allocated to receive colchicine versus placebo. We will repeat the primary analysis using alternative definitions of acute kidney injury and examine effect modification by pre-existing chronic kidney disease, defined as a prerandomization estimated glomerular filtration rate (eGFR) <60 mL/min per 1.73 m2. Limitations: The substudy will be underpowered to detect small effects on more severe forms of acute kidney injury treated with dialysis. Results: Substudy results will be reported in 2024. Conclusions: This substudy will estimate the effect of colchicine on the risk of perioperative acute kidney injury in older adults undergoing major thoracic surgery.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The Canadian Institutes of Health Research provided an operating grant for the main COP-AF trial. General Research Fund (14121720), Research Grants Council, Hong Kong Special Administrative Region, China. The Department of Medicine at Western University provided additional financial support for this substudy. In addition, the authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: AXG is supported by the Dr Adam Linton Chair in Kidney Health Analytics. PJ Devereaux is supported by a Tier 1 Canada Research Chair in Perioperative Medicine. CP is a member of the advisory board and owns equity in RenalytixAI. He also serves as a consultant for Genfit and is supported by NIH grants R01HL085757, U01DK114866, U01DK106962, U01DK129984, R01DK093770, and P30DK079310. EP is supported by a research grant from Generalitat de Catalunya (PERIS SLT017/20/000089). MKW is supported by the PSI Foundation—Research Trainee Award. D Conen received speaker fees from Servier Canada and BMS/Pfizer, and he received consulting fees from Trimedics and Roche Diagnostics, all outside of the current work. No funding entity had a role in data collection, statistical analysis, article writing, or the decision to publish