Renal ischemic reperfusion (IR) injury contributes significantly to morbidity and mortality in patients undergoing surgery on the kidney or aorta. Renal IR injury induces necrosis which triggers an inflammatory response, which, in turn, triggers even more necrosis. The proximal tubule cell is the cell type most susceptible to IR injury in the kidney due to a precarious balance between oxygen supply and demand. Some clinically used inhalational anesthetics protect against IR injury in the heart, liver and lung by unknown mechanisms. It is also not known if there is a difference among volatile anesthetics in their ability to protect against IR injury. Because renal protection with volatile anesthetics has never been examined, our overall goal utilizing physiological, cellular and molecular techniques is to demonstrate renal protection by volatile anesthetics against IR injury and to understand the mechanism by which this occurs and furthermore, to determine whether differences exist among clinically used volatile anesthetics. Exciting preliminary in vivo and in vitro data generated for this proposal suggest that sevoflurane protects the kidney against IR injury and that this protection is associated with reduced inflammation and necrosis. Additional preliminary studies demonstrate that desflurane exhibits significantly less protection than sevoflurane. Preliminary mechanistic data demonstrate that volatile anesthetics expose phosphatidylserine on renal cell membranes and initiate a potent anti-inflammatory signaling pathway involving TGF-B1 and the phosphatidylserine receptor. These findings lead us to hypothesize that clinically utilized volatile anesthetics differentially protect against IR injury in the kidney by directly reducing necrotic cell death and inflammation. We will quantitate the amount of renal protection afforded by volatile anesthetics against renal necrosis and inflammation after IR injury. Subsequently, we will determine the mechanism of renal protection by volatile anesthetics. We will determine whether volatile anesthetics externalize phosphatidylserine and release TGF-Beta1. We will also examine the role of protein kinase C and mitogen activated protein kinase in volatile anesthetic mediated renal protection. A greater understanding of the ways by which we can modulate necrosis and inflammation may have significant clinical benefit by improving renal outcome following IR injury. Furthermore, it could be clinically important if one can modulate renal cell death by modulating necrosis and inflammation with volatile anesthetics as volatile anesthetics are an intricate component of the perioperative management of these patients.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Cole, Alison E
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Columbia University (N.Y.)
Schools of Medicine
New York
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Rabadi, May; Kim, Mihwa; D'Agati, Vivette et al. (2016) Peptidyl arginine deiminase-4-deficient mice are protected against kidney and liver injury after renal ischemia and reperfusion. Am J Physiol Renal Physiol 311:F437-49
Rabadi, M M; Lee, H T (2015) Adenosine receptors and renal ischaemia reperfusion injury. Acta Physiol (Oxf) 213:222-31
Kim, Mihwa; Ham, Ahrom; Kim, Katelyn Yu-Mi et al. (2014) The volatile anesthetic isoflurane increases endothelial adenosine generation via microparticle ecto-5'-nucleotidase (CD73) release. PLoS One 9:e99950
Ham, Ahrom; Rabadi, May; Kim, Mihwa et al. (2014) Peptidyl arginine deiminase-4 activation exacerbates kidney ischemia-reperfusion injury. Am J Physiol Renal Physiol 307:F1052-62
Ham, Ahrom; Kim, Mihwa; Kim, Joo Yun et al. (2014) Selective deletion of the endothelial sphingosine-1-phosphate 1 receptor exacerbates kidney ischemia-reperfusion injury. Kidney Int 85:807-23
Fukazawa, Kyota; Lee, H Thomas (2014) Volatile anesthetics and AKI: risks, mechanisms, and a potential therapeutic window. J Am Soc Nephrol 25:884-92
Kim, Joo Yun; Kim, Mihwa; Ham, Ahrom et al. (2013) IL-11 is required for A1 adenosine receptor-mediated protection against ischemic AKI. J Am Soc Nephrol 24:1558-70
Lee, H Thomas; Kim, Joo Yun; Kim, Mihwa et al. (2013) Renalase protects against ischemic AKI. J Am Soc Nephrol 24:445-55
Ham, Ahrom; Kim, Mihwa; Kim, Joo Yun et al. (2013) Critical role of interleukin-11 in isoflurane-mediated protection against ischemic acute kidney injury in mice. Anesthesiology 119:1389-401
Fukazawa, Kyota; Lee, H Thomas (2013) Updates on Hepato-Renal Syndrome. J Anesth Clin Res 4:352

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