Renal Tubular Cell Mitochondrial Dysfunction Occurs Despite Preserved Renal Oxygen Delivery in Experimental Septic Acute Kidney Injury

Objective: To explain the paradigm of significant renal functional impairment despite preserved hemodynamics and histology in sepsis-induced acute kidney injury. Design: Prospective observational animal study. Setting: University research laboratory. Subjects: Male Wistar rats. Intervention: Using a fluid-resuscitated sublethal rat model of fecal peritonitis, changes in renal function were characterized in relation to global and renal hemodynamics, and histology at 6 and 24 hours (n = 6–10). Sham-operated animals were used as comparison (n = 8). Tubular cell mitochondrial function was assessed using multiphoton confocal imaging of live kidney slices incubated in septic serum. Measurements and Main Results: By 24 hours, serum creatinine was significantly elevated with a concurrent decrease in renal lactate clearance in septic animals compared with sham-operated and 6-hour septic animals. Renal uncoupling protein-2 was elevated in septic animals at 24 hours although tubular cell injury was minimal and mitochondrial ultrastructure in renal proximal tubular cells preserved. There was no significant change in global or renal hemodynamics and oxygen delivery/consumption between sham-operated and septic animals at both 6- and 24-hour timepoints. In the live kidney slice model, mitochondrial dysfunction was seen in proximal tubular epithelial cells incubated with septic serum with increased production of reactive oxygen species, and decreases in nicotinamide adenine dinucleotide and mitochondrial membrane potential. These effects were prevented by coincubation with the reactive oxygen species scavenger, 4-hydroxy-2,2,6,6-tetramethyl-piperidin-1-oxyl. Conclusions: Renal dysfunction in sepsis occurs independently of hemodynamic instability or structural damage. Mitochondrial dysfunction mediated by circulating mediators that induce local oxidative stress may represent an important pathophysiologic mechanism. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The in vivo and some of the ex vivo studies were undertaken at University College London, United Kingdom. Light microscopy was undertaken at Hammersmith Hospital, Imperial College, United Kingdom, and electron microscopy was undertaken at the Royal Free Hospital, London, United Kingdom. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://ift.tt/29S62lw). Dr. Arulkumaran received grant support from the Wellcome Trust Clinical Research Training Fellowship (grant in support of this project in part, including Dr. Arulkumaran’s salary). Mr. Pollen is supported by a New investigator award from the U.K. Intensive Care Society, the University College London MBPhD Program, and the Astor Foundation. Dr. Tam is supported by the Diamond Fund from Imperial College Healthcare Charity and Ken and Mary Minton Chair of Renal Medicine. Drs. Arulkumaran and Tam received support for article research from Wellcome Trust/COAF. Dr. Tam’s institution received funding from Wellcome Trust Clinical Research Training Fellowship for Dr Nishkantha Arulkumaran; research project grants from AstraZeneca Limited, Baxter Biosciences, GSK, Roche Palo Alto, Rigel Pharmaceuticals, and MedImmune and has consultancy agreements with MedImmune, Novartis and Rigel Pharmaceuticals; and from Dr. Tam acting as the Chief Investigator of an international clinical trial in IgA nephropathy. Dr. Tam disclosed he is supported by the Diamond Fund from Imperial College Healthcare Charity and Ken and Mary Minton Chair of Renal Medicine, and he has consultancy agreements with Medimmune (ongoing, income to University), Novartis (ongoing, income to university), and Rigel Pharmaceuticals (past: regarding glomerulonephritis: part of income to him, part of income to university). Dr. Unwin’s institution received funding from AstraZeneca, and he received support for article research from Research Councils UK. Dr. Singer disclosed that he is a director of Magnus Oxygen, which is developing a sulfide donor for use in ischemia-reperfusion injury through inhibiting mitochondrial ROS production, and he also sits on an Advisory Board for AM Pharma, which is trialing recombinant alkaline phosphatase therapy for sepsis-induced acute kidney injury. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: nisharulkumaran@doctors.org.uk Copyright © by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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