IN the current issue of Anesthesiology, an article by Kim et al.  1from the research laboratory of H. Thomas Lee, M.D., Ph.D., investigates strategies to dampen ischemia-driven inflammation of the kidneys and subsequent multiorgan failure using experimental models of acute kidney injury (AKI). In fact, one of the leading causes of morbidity and mortality in surgical patients is perioperative organ failure, such as failure that occurs in the context of AKI, liver failure, intestinal or myocardial ischemia, stroke, or acute lung injury. A common feature of these perioperative diseases is the presence of hypoxia-induced inflammation.2,3The relationship between hypoxia and inflammation under these conditions is interdependent. For example, exposure to ambient hypoxia, as seen during high-altitude mountaineering, is associated with edema of the lungs or brain and systemic inflammatory responses in humans.4,5Similarly, short-term exposure of mice to ambient hypoxia (e.g. , 8% oxygen over 4–8 h) leads to increased inflammatory cytokine concentrations and pulmonary edema.6Moreover, prolonged donor organ exposure to ischemia during organ transplantation is known to enhance graft inflammation and early graft failure.7,8For example, the endotoxin receptor toll-like receptor 4 (TLR4) is expressed in the donor kidney during kidney transplantation, and TLR4 expression concentrations increase with prolonged ischemia time. Donor kidneys with a loss-of-function mutation of the TLR4 receptor show attenuated kidney inflammation and an increased rate of immediate graft function.7Together, these studies indicate that hypoxia represents an inflammatory stimulus (fig. 1) and suggest that targeting hypoxia-elicited inflammation could represent an important therapeutic approach in perioperative medicine.

Although hypoxia can trigger inflammatory responses, inflammation itself is a cause for tissue hypoxia. During active inflammatory disease, metabolic shifts toward hypoxia are severe.2An example for an inflammatory disease characterized by severe tissue hypoxia is acute lung injury. Several factors contribute to pulmonary hypoxia in this context, including attenuated oxygen supply due to airway atelectasis and diminished blood flow to ventilated areas within the lungs. Moreover, the increased metabolic demand by resident cells or recruited inflammatory cells results in profound shifts in the supply/demand ratio of metabolites and oxygen (fig. 1), and hypoxia-driven signaling pathways are activated.9,10Tissue hypoxia during inflammation is more than simply a bystander effect; it can greatly affect the development or attenuation of inflammation through the regulation of oxygen-dependent gene expression.11In fact, studies that target transcriptionally regulated tissue adaptation to hypoxia are an area of intense investigation to prevent hypoxia-induced inflammation and organ failure. For instance, experimental strategies that target hypoxia-driven inflammation have been proposed in the treatment of intestinal, myocardial, or hepatic ischemia; acute lung injury; or AKI.12 

An area in which hypoxia-driven inflammation greatly affects perioperative outcomes is AKI.13AKI is characterized by a decrease in the glomerular filtration rate, occurring over minutes to days.14In hospitalized patients, more than 50% of AKI cases are related to conditions of renal ischemia or more than 80% are related to the critical care setting.14,15A recent study14of hospitalized patients revealed that only a mild increase in the serum creatinine concentration (0.3–0.4 mg/dl) is associated with a 70% greater risk of death than in persons without any increase. Moreover, surgical procedures requiring cross clamping of the aorta and renal vessels are associated with renal failure rates of up to 30%. Similarly, AKI after cardiac surgery occurs in more than 10% of patients under normal circumstances and is associated with dramatic increases in mortality. In addition, AKI and chronic kidney disease are common complications after liver transplantation.16For example, the incidence of AKI after liver transplantation is at least 50%, and 8–17% of patients require renal replacement therapy.17Delayed graft function during kidney transplantation is frequently related to ischemia-associated AKI.18In addition, AKI occurs in approximately 20% of patients diagnosed as having sepsis.15,19 

As shown in the current study by Kim et al. ,1ischemia-induced AKI triggers a downward spiral, leading to subsequent multiorgan failure. The authors elegantly demonstrate that exposure to renal ischemia with concomitant inflammatory activation of the kidneys will result in subsequent gut injury, including breakdown of the intestinal epithelial barrier and massive intestinal inflammation. The intestinal injury will eventually spill over to the liver and cause severe hepatic disease.1It is amazing that this downward spiral is initiated by a local injury to the kidneys (fig. 2). As such, it will be of critical importance to understanding the mechanistic aspects of the cross-talk pathway that connects the kidneys and the intestine during hypoxia-driven renal inflammation and to determining how gut inflammation triggers subsequent hepatic injury and multiorgan failure. The current studies demonstrate that volatile anesthetics dampen kidney inflammation and multiorgan failure initiated by AKI.1In fact, Kim et al.  found that isoflurane protected against AKI and reduced hepatic and intestinal injury via  induction of sphingosine kinase 1 in the gut. By combining pharmacological studies with sphingosine kinase inhibitors, and genetic approaches using knockout mice for sphingosine kinase, they elegantly demonstrated a functional role of this pathway in kidney protection. This is consistent with their previous studies20–22showing kidney protection via  sphingosine kinase and sphingosine-1-phosphate–dependent pathways. Interestingly, other experimental studies from Lee's laboratory indicate that infusion of local anesthetics (e.g. , lidocaine, bupivacaine, or tetracaine) has an opposite effect by potentiating renal dysfunction and kidney inflammation after ischemia–reperfusion injury.23 

The current studies are consistent with previous research from Lee's group demonstrating a protective role of extracellular adenosine signaling during AKI. In the extracellular compartment, adenosine stems from phosphohydrolysis of precursor nucleotides, such as adenosine triphosphate and adenosine monophosphate. In fact, conditions of hypoxia (e.g. , those that occur during AKI) significantly enhance the production of extracellular adenosine.24–26Extracellular adenosine generation and signaling have been strongly implicated in the attenuation of hypoxia-driven inflammation.12As such, genetically altered mice that have defects in the enzymatic generation of extracellular adenosine are more prone to develop kidney inflammation and organ dysfunction when exposed to renal ischemia.27,28Extracellular adenosine can signal through four individual adenosine receptors (ARs): A1AR, A2AAR, A2BAR, and A3AR. In this context, several studies from Lee's research team have demonstrated an important role for A1AR in attenuating renal inflammation and preserving organ function during ischemia. For instance, mice with genetic deletion of A1AR exhibit increased renal injury after ischemia and reperfusion injury.29Moreover, A1AR  −/−mice show increased mortality, renal dysfunction, and hepatic injury when exposed to murine septic peritonitis.30In addition, an elegant proof-of-principle study31using a viral overexpression technique revealed that kidney-specific reconstitution of A1AR in A1AR  −/−mice reduces renal ischemia–reperfusion injury. Consistent with the current studies demonstrating a cross-talk pathway between the kidneys, the intestine, and the liver,1Lee's research team was able to demonstrate that protection against AKI via  A1AR-mediated Akt activation reduces liver injury.32Other studies33have implicated hypoxia-inducible A2BAR in kidney protection from ischemia. Taken together, these studies highlight that endogenous antiinflammatory pathways that are activated by hypoxia-dependent signaling pathways can be targeted to treat renal inflammation induced by ischemia.

Although many experimental studies, including the exciting contributions of Lee's research team, have provided new insight into preventing or treating hypoxia-induced inflammation of the kidney, it remains a challenge to implement those approaches into a clinical setting. In fact, treatment approaches to prevent or treat AKI in the perioperative setting are extremely limited. For instance, several clinical trials involving numerous drugs have shown little or no protective effects. Studies investigating the role of dopamine in the prevention of AKI in a perioperative setting have shown no reduction in mortality or renal outcome. Moreover, studies34investigating loop diuretics (e.g. , furosemide) as a means of kidney protection from AKI observed no reduction in overall mortality. Similarly, studies35on the protective effects of the selective D1-dopamine receptor agonist fenoldopam failed to justify its routine clinical use for perioperative kidney protection. Therefore, future challenges will include systematic approaches to help translate novel experimental approaches of kidney protection from bench to bedside and from mice to human. Moreover, additional mechanistic insights into transcriptionally regulated pathways that dampen hypoxia-elicited kidney inflammation hold the promise for effectively treating hypoxia-driven inflammation. By tapping into endogenous mechanisms of hypoxia-elicited tissue adaptation, such studies could address hypoxia-dependent changes in renal gene expression regulated by micro-RNAs or the direct role of hypoxia sensing and signaling mechanisms in kidney diseases. In fact, I hope that such studies will allow us to further develop therapeutic strategies to dampen inflammation caused by hypoxia while simultaneously increasing ischemia resistance. These therapeutic approaches could be applicable in many perioperative scenarios that involve hypoxia-elicited organ dysfunction, including acute lung injury, organ ischemia, or solid organ transplantation.

Mucosal Inflammation Program, Department of Anesthesiology, University of Colorado Denver, Aurora, Colorado.

The author would like to acknowledge Shelley A. Eltzschig, B.S., B.A., Mucosal Inflammation Program, University of Colorado Denver, Aurora, Colorado, for the artwork included in the article.


Kim M, Park SW, Kim M, D'Agati VD, Lee HT: Isoflurane activates intestinal sphingosine kinase to protect against renal ischemia-reperfusion induced liver and intestine injury. Anesthesiology 2011; 114:363–73
Colgan SP, Taylor CT: Hypoxia: An alarm signal during intestinal inflammation. Nat Rev Gastroenterol Hepatol 2010; 7:281–7
Taylor CT: Interdependent roles for hypoxia inducible factor and nuclear factor-kappaB in hypoxic inflammation. J Physiol 2008; 586:4055–9
Grocott MP, Martin DS, Levett DZ, McMorrow R, Windsor J, Montgomery HE: Arterial blood gases and oxygen content in climbers on Mount Everest. N Engl J Med 2009; 360:140–9
Hartmann G, Tschop M, Fischer R, Bidlingmaier C, Riepl R, Tschop K, Hautmann H, Endres S, Toepfer M: High altitude increases circulating interleukin-6, interleukin-1 receptor antagonist and C-reactive protein. Cytokine 2000; 12:246–52
Rosenberger P, Schwab JM, Mirakaj V, Masekowsky E, Mager A, Morote-Garcia JC, Unertl K, Eltzschig HK: Hypoxia-inducible factor-dependent induction of netrin-1 dampens inflammation caused by hypoxia. Nat Immunol 2009; 10:195–202
Kruger B, Krick S, Dhillon N, Lerner SM, Ames S, Bromberg JS, Lin M, Walsh L, Vella J, Fischereder M, Kramer BK, Colvin RB, Heeger PS, Murphy BT, Schroppel B: Donor Toll-like receptor 4 contributes to ischemia and reperfusion injury following human kidney transplantation. Proc Natl Acad Sci U S A 2009; 106:3390–5
Thabut G, Mal H, Cerrina J, Dartevelle P, Dromer C, Velly JF, Stern M, Loirat P, Leseche G, Bertocchi M, Mornex JF, Haloun A, Despins P, Pison C, Blin D, Reynaud-Gaubert M: Graft ischemic time and outcome of lung transplantation: A multicenter analysis. Am J Respir Crit Care Med 2005; 171:786–91
Eckle T, Grenz A, Laucher S, Eltzschig HK: A2B adenosine receptor signaling attenuates acute lung injury by enhancing alveolar fluid clearance in mice. J Clin Invest 2008; 118:3301–15
Schingnitz U, Hartmann K, Macmanus CF, Eckle T, Zug S, Colgan SP, Eltzschig HK: Signaling through the A2B adenosine receptor dampens endotoxin-induced acute lung injury. J Immunol 2010; 184:5271–9
Karhausen J, Furuta GT, Tomaszewski JE, Johnson RS, Colgan SP, Haase VH: Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis. J Clin Invest 2004; 114:1098–106
Eltzschig HK: Adenosine: An old drug newly discovered. Anesthesiology 2009; 111:904–15
Sadovnikoff N, Gelman S: Perioperative renal protection. Curr Opin Anaesthesiol 1999; 12:337–41
Abuelo JG: Normotensive ischemic acute renal failure. N Engl J Med 2007; 357:797–805
Schrier RW, Wang W: Acute renal failure and sepsis. N Engl J Med 2004; 351:159–69
Jones DR, Lee HT: Perioperative renal protection. Best Pract Res Clin Anaesthesiol 2008; 22:193–208
Yalavarthy R, Edelstein CL, Teitelbaum I: Acute renal failure and chronic kidney disease following liver transplantation. Hemodial Int 2007; 11(suppl 3):S7–12
Parikh CR, Jani A, Mishra J, Ma Q, Kelly C, Barasch J, Edelstein CL, Devarajan P: Urine NGAL and IL-18 are predictive biomarkers for delayed graft function following kidney transplantation. Am J Transplant 2006; 6:1639–45
Jones DR, Lee HT: Protecting the kidney during critical illness. Curr Opin Anaesthesiol 2007; 20:106–12
Kim M, Kim N, D'Agati VD, Emala CW Sr, Lee HT: Isoflurane mediates protection from renal ischemia-reperfusion injury via  sphingosine kinase and sphingosine-1-phosphate-dependent pathways. Am J Physiol Renal Physiol 2007; 293:F1827–35
Song JH, Kim M, Park SW, Chen SW, Pitson SM, Lee HT: Isoflurane via  TGF-beta1 release increases caveolae formation and organizes sphingosine kinase signaling in renal proximal tubules. Am J Physiol Renal Physiol 2010; 298:F1041–50
Birukov KG, Jacobson JR, Flores AA, Ye SQ, Birukova AA, Verin AD, Garcia JG: Magnitude-dependent regulation of pulmonary endothelial cell barrier function by cyclic stretch. Am J Physiol Lung Cell Mol Physiol 2003; 285:L785–97
Lee HT, Krichevsky IE, Xu H, Ota-Setlik A, D'Agati VD, Emala CW: Local anesthetics worsen renal function after ischemia-reperfusion injury in rats. Am J Physiol Renal Physiol 2004; 286:F111–9
Morote-Garcia JC, Rosenberger P, Kuhlicke J, Eltzschig HK: HIF-1-dependent repression of adenosine kinase attenuates hypoxia-induced vascular leak. Blood 2008; 111:5571–80
Morote-Garcia JC, Rosenberger P, Nivillac NM, Coe IR, Eltzschig HK: Hypoxia-inducible factor-dependent repression of equilibrative nucleoside transporter 2 attenuates mucosal inflammation during intestinal hypoxia. Gastroenterology 2009; 136:607–18
Eltzschig HK, Ibla JC, Furuta GT, Leonard MO, Jacobson KA, Enjyoji K, Robson SC, Colgan SP: Coordinated adenine nucleotide phosphohydrolysis and nucleoside signaling in posthypoxic endothelium: Role of ectonucleotidases and adenosine A2B receptors. J Exp Med 2003; 198:783–96
Grenz A, Zhang H, Eckle T, Mittelbronn M, Wehrmann M, Kohle C, Kloor D, Thompson LF, Osswald H, Eltzschig HK: Protective role of ecto-5′-nucleotidase (CD73) in renal ischemia. J Am Soc Nephrol 2007; 18:833–45
Grenz A, Zhang H, Hermes M, Eckle T, Klingel K, Huang DY, Muller CE, Robson SC, Osswald H, Eltzschig HK: Contribution of E-NTPDase1 (CD39) to renal protection from ischemia-reperfusion injury. FASEB J 2007; 21:2863–73
Lee HT, Xu H, Nasr SH, Schnermann J, Emala CW: A1 adenosine receptor knockout mice exhibit increased renal injury following ischemia and reperfusion. Am J Physiol Renal Physiol 2004; 286:F298–306
Gallos G, Ruyle TD, Emala CW, Lee HT: A1 adenosine receptor knockout mice exhibit increased mortality, renal dysfunction, and hepatic injury in murine septic peritonitis. Am J Physiol Renal Physiol 2005; 289:F369–76
Kim M, Chen SW, Park SW, D'Agati VD, Yang J, Lee HT: Kidney-specific reconstitution of the A1 adenosine receptor in A1 adenosine receptor knockout mice reduces renal ischemia-reperfusion injury. Kidney Int 2009; 75:809–23
Park SW, Chen SW, Kim M, Brown KM, D'Agati VD, Lee HT: Protection against acute kidney injury via  A(1) adenosine receptor-mediated Akt activation reduces liver injury after liver ischemia and reperfusion in mice. J Pharmacol Exp Ther 2010; 333:736–47
Grenz A, Osswald H, Eckle T, Yang D, Zhang H, Tran ZV, Klingel K, Ravid K, Eltzschig HK: The reno-vascular A2B adenosine receptor protects the kidney from ischemia. PLoS Med 2008; 5:e137
Bagshaw SM, Delaney A, Haase M, Ghali WA, Bellomo R: Loop diuretics in the management of acute renal failure: A systematic review and meta-analysis. Crit Care Resusc 2007; 9:60–8
Bove T, Landoni G, Calabro MG, Aletti G, Marino G, Cerchierini E, Crescenzi G, Zangrillo A: Renoprotective action of fenoldopam in high-risk patients undergoing cardiac surgery: A prospective, double-blind, randomized clinical trial. Circulation 2005; 111:3230–5