Nora Choi1, Reid Whitlock2, Jessica Klassen3, Michael Zappitelli4, Rakesh C Arora5, Claudio Rigatto6, Julie Ho7. 1. Manitoba Centre for Proteomics & Systems Biology, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada. 2. Department of Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada. 3. Section of Nephrology, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada. 4. Division of Nephrology, Department of Pediatrics, Toronto Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. 5. Department of Surgery, University of Manitoba, Winnipeg, Manitoba, Canada. 6. Department of Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada; Section of Nephrology, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; Chronic Disease Innovation Centre, Seven Oaks Hospital, Winnipeg, Manitoba, Canada. 7. Manitoba Centre for Proteomics & Systems Biology, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada; Section of Nephrology, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada. Electronic address: jho@hsc.mb.ca.
Abstract
OBJECTIVES: Iron regulation is an important modifier of renal ischemia-reperfusion injury, but the role of iron-binding proteins during cardiopulmonary bypass remains unclear. The goal was to characterize iron-binding proteins throughout ischemia-reperfusion injury to determine their association with acute kidney injury development. METHODS: A prospective observational cohort of adult patients who underwent cardiac surgery (n = 301) was obtained, and acute kidney injury was defined by Kidney Disease Improving Global Outcomes. Serum ferritin, transferrin saturation, and urine hepcidin-25 were measured. RESULTS: Intraoperative serum ferritin was lower at the start of cardiopulmonary bypass (P = .005) and 1-hour cardiopulmonary bypass (P = .001) in patients with acute kidney injury versus patients without acute kidney injury. Lower serum ferritin and higher transferrin saturation at 1-hour cardiopulmonary bypass were independent predictors of acute kidney injury (serum ferritin odds ratio, 0.66; 95% confidence interval [CI], 0.48-0.91; transferrin saturation odds ratio, 1.26; 95% CI, 1.02-1.55) and improved model discrimination (area under the curve [AUC], 0.76; 95% CI, 0.67-0.85) compared with clinical prediction alone (AUC, 0.72; 95% CI, 0.62-0.81; ΔAUC and net reclassification index, P = .01). Lower ferritin, higher transferrin saturation at 1-hour cardiopulmonary bypass, and lower urine hepcidin-25 at postoperative day 1 were also independent predictors for acute kidney injury development, and this model demonstrated an AUC of 0.80 (0.72-0.87), which was superior to clinical prediction (ΔAUC P = .002, integrated discrimination improvement and net reclassification index P = .003). CONCLUSIONS: Our findings suggest that lower levels of intraoperative iron-binding proteins may reflect an impaired capacity to rapidly handle catalytic iron released during cardiopulmonary bypass, leading to kidney injury. These data highlight the importance of iron homeostasis in human ischemia-reperfusion injury and suggest it is a potentially modifiable risk during cardiac surgery. Intraoperative detection of incipient acute kidney injury may be feasible and could be used as an enrichment strategy for clinical trials.
OBJECTIVES:Iron regulation is an important modifier of renal ischemia-reperfusion injury, but the role of iron-binding proteins during cardiopulmonary bypass remains unclear. The goal was to characterize iron-binding proteins throughout ischemia-reperfusion injury to determine their association with acute kidney injury development. METHODS: A prospective observational cohort of adult patients who underwent cardiac surgery (n = 301) was obtained, and acute kidney injury was defined by Kidney Disease Improving Global Outcomes. Serum ferritin, transferrin saturation, and urine hepcidin-25 were measured. RESULTS: Intraoperative serum ferritin was lower at the start of cardiopulmonary bypass (P = .005) and 1-hour cardiopulmonary bypass (P = .001) in patients with acute kidney injury versus patients without acute kidney injury. Lower serum ferritin and higher transferrin saturation at 1-hour cardiopulmonary bypass were independent predictors of acute kidney injury (serum ferritin odds ratio, 0.66; 95% confidence interval [CI], 0.48-0.91; transferrin saturation odds ratio, 1.26; 95% CI, 1.02-1.55) and improved model discrimination (area under the curve [AUC], 0.76; 95% CI, 0.67-0.85) compared with clinical prediction alone (AUC, 0.72; 95% CI, 0.62-0.81; ΔAUC and net reclassification index, P = .01). Lower ferritin, higher transferrin saturation at 1-hour cardiopulmonary bypass, and lower urine hepcidin-25 at postoperative day 1 were also independent predictors for acute kidney injury development, and this model demonstrated an AUC of 0.80 (0.72-0.87), which was superior to clinical prediction (ΔAUC P = .002, integrated discrimination improvement and net reclassification index P = .003). CONCLUSIONS: Our findings suggest that lower levels of intraoperative iron-binding proteins may reflect an impaired capacity to rapidly handle catalytic iron released during cardiopulmonary bypass, leading to kidney injury. These data highlight the importance of iron homeostasis in humanischemia-reperfusion injury and suggest it is a potentially modifiable risk during cardiac surgery. Intraoperative detection of incipient acute kidney injury may be feasible and could be used as an enrichment strategy for clinical trials.
Authors: David E Leaf; Mohan Rajapurkar; Suhas S Lele; Banibrata Mukhopadhyay; Emily A S Boerger; Finnian R Mc Causland; Michele F Eisenga; Karandeep Singh; Jodie L Babitt; John A Kellum; Paul M Palevsky; Marta Christov; Sushrut S Waikar Journal: J Am Soc Nephrol Date: 2019-02-08 Impact factor: 10.121