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Education  |   May 2012
Acute Kidney Injury and Extrarenal Organ Dysfunction: New Concepts and Experimental Evidence
Author Affiliations & Notes
  • Steven C. Yap, M.D.
    *
  • H. Thomas Lee, M.D., Ph.D.
  • *Postdoctoral Research Fellow, Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York. Professor, Department of Anesthesiology, College of Physicians and Surgeons of Columbia University.
Article Information
Education / Cardiovascular Anesthesia / Gastrointestinal and Hepatic Systems / Renal and Urinary Systems / Electrolyte Balance
Education   |   May 2012
Acute Kidney Injury and Extrarenal Organ Dysfunction: New Concepts and Experimental Evidence
Anesthesiology 5 2012, Vol.116, 1139-1148. doi:10.1097/ALN.0b013e31824f951b
Anesthesiology 5 2012, Vol.116, 1139-1148. doi:10.1097/ALN.0b013e31824f951b
ACUTE kidney injury (AKI) frequently occurs in the critically ill with 5%–20% of patients experiencing an episode during their intensive care unit stay.1 AKI in the intensive care unit is rarely an isolated event and frequently occurs within a broader spectrum of disease including sepsis and respiratory insufficiency, and often progresses into multiorgan dysfunction syndrome.2 Despite recent advancements in renal replacement therapy, mortality among patients who sustain AKI complicated by multiorgan dysfunction appears to have remained unchanged and is estimated at approximately 50%.3 Recent clinical evidence suggests that AKI is not only an indicator for severity of illness, but that it also leads to earlier onset of multiorgan dysfunction with profound effects on mortality rates.4,5 Therefore, understanding the specific extrarenal effects of AKI in propagating or exacerbating multiorgan dysfunction is vital because it may identify therapeutic interventions to decrease mortality after AKI (fig. 1). The goals of this brief review are to assess the clinical evidence associating AKI with multiorgan dysfunction and present recent progress in understanding the mechanism using animal models of renal injury.
Fig. 1. Deleterious effects of acute kidney injury (AKI) on distant organs. AKI results in remote organ injury to the heart, lungs, liver, intestines, and brain and leads to an increase in cytokines, leukocyte trafficking, organ dysfunction, apoptosis, and necrosis. GFAP = glial fibrillary acidic protein; ICAM-1 = intercellular adhesion molecule-1; IL = interleukin; LV = left ventricular; TNF-α = tumor necrosis factor-α.
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Fig. 1. Deleterious effects of acute kidney injury (AKI) on distant organs. AKI results in remote organ injury to the heart, lungs, liver, intestines, and brain and leads to an increase in cytokines, leukocyte trafficking, organ dysfunction, apoptosis, and necrosis. GFAP = glial fibrillary acidic protein; ICAM-1 = intercellular adhesion molecule-1; IL = interleukin; LV = left ventricular; TNF-α = tumor necrosis factor-α.
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Clinical Relevance of AKI
Until recently, the lack of a standard definition for AKI resulted in large variations in reported incidence and mortality.6 In 2004, the Acute Dialysis Quality Initiative Group (ADQI) proposed the RIFLE criteria, which aimed to provide a uniform diagnosis and staging of patients with “acute renal failure” based on changes in serum creatinine, glomerular filtration rate, or urine output.7 Subsequent studies, including a prospective observational study by Lassnigg et al.  , showed that a subtle change in creatinine as small as 0.3 mg/dl was associated with increased mortality.8 Consequently, the Acute Kidney Injury Network proposed the term “acute kidney injury” to supplant the usage of “acute renal failure” in recognition that clinically significant kidney injury occurs over a wide spectrum of severity.9 
Simultaneous with these developments, new evidence in both basic science and clinical research began to transform the viewpoint of AKI as a single organ failure into one in which the kidneys play an active role in the evolution of multiorgan dysfunction. In the first prospective multicenter study that epidemiologically characterized AKI, Liano et al.  found an “attributable mortality” rate of 56% among intensive care patients who sustain AKI that could not be explained by other comorbid conditions and was thus attributed specifically to the effects of kidney injury.10 In addition, Levy et al.  found increased mortality after AKI despite controlling for severity of illness by comparing patients with similar comorbid conditions and physiologic severity score, and by multivariate analysis.5 Furthermore, renal failure preceded other conditions such as sepsis, respiratory failure, mental status changes, and bleeding, suggesting that AKI occurs early in the course of multiorgan failure. More recently, a larger multicenter case-controlled study confirmed these results with a mortality rate that was doubled among patients requiring renal replacement therapy compared with control patients.11 Although there may be residual “unmeasured” severity of illness, these studies make a compelling argument that patients in whom AKI develops are at increased risk of death due to kidney injury itself apart from severity of illness.
Why does AKI lead to earlier onset of multiorgan dysfunction and worsened mortality? Pulmonary insufficiency is perhaps one of the most clinically apparent and studied distant organ effects of kidney injury. AKI was found to delay recovery of injured lungs, with increased difficulty weaning from mechanical ventilation (41 days in AKI group vs.  21 days in non-AKI group).12 Difficulty weaning from mechanical ventilation was also present in the nonoliguric AKI subgroup, suggesting that kidney injury apart from volume status increases mortality. Volume status, management of which is made more difficult by compromised kidney function, also has an effect on mortality. Payen et al.  found in an observational cohort study that positive fluid balance was associated with increased mortality.13 However, the Veterans Administration/National Institutes of Health Acute Renal Failure Trial Network study, a multicenter, randomized trial, demonstrated that intensive renal replacement therapy did not decrease mortality or multiorgan failure compared with less intensive therapy.14 
Animal Models of AKI
The scope of clinical studies in this nascent area of research remains limited because of inherent difficulties in studying a complex disease process whose occurrence is closely interrelated with comorbid conditions. Animal models of renal injury have been instrumental in defining the pathophysiology of remote organ dysfunction after AKI by reducing the complexity and experimental limitations associated with human studies while allowing for isolation of variables to gain mechanistic understanding. Of the various animal models, renal ischemia reperfusion and nephrectomy are the most commonly studied because they are simple, reproducible, and can easily achieve a graded injury response. Renal ischemia reperfusion involves transient occlusion of the renal artery and has clinical relevance in suprarenal aortic aneurysm repair,15 partial nephrectomy,16 renal transplantation,17 contrast-induced nephropathy,18 shock, and cardiac arrest. The postreperfusion syndrome is a distinct feature with the injured renal tubules serving as a major source of cytokines and chemokines. In addition, reduction in renal blood flow up to 50% persists after reperfusion19 because of an imbalance between vasoactive mediators and endothelial dysfunction, leading to interstitial edema and leukocyte trafficking.20 In contrast, unilateral and bilateral nephrectomies are of interest as they demonstrate the effects of decreased or absent renal function that is a fundamental characteristic of AKI, but without the effects of the reperfusion syndrome.
Other models of kidney injury, including nephrotoxic injury and sepsis, are less studied especially with regard to remote organ effects (table 1). Although these models are clinically relevant, they do not reliably induce AKI in mice, limiting their empirical usefulness. For example, studies of contrast-induced nephropathy often require previous exposure to combined renal insults such as ischemia and nephrotoxic drugs, as it is difficult to induce nephrotoxic injury with contrast medium alone.21 Similarly, nephrotoxic studies of gentamicin are often conducted in the presence of other insults such as gram-negative sepsis.22,23 
Table 1. Limitations of Animal Models of Kidney Injury
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Table 1. Limitations of Animal Models of Kidney Injury
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Animal models of kidney injury have limitations due to interspecies differences. In humans, hypotension and shock lead to hypoperfusion of the kidneys, which often results in ischemic tubular necrosis. However, severe and prolonged hypotension in rats does not typically induce renal injury and is therefore not suitable for use as a “single insult” animal model.22 In contrast, renal ischemia reperfusion in humans leads to subtle and focal histologic changes but similar insult in rats results in diffuse and extensive necrosis of the proximal tubules.24,25 Finally, the use of “single insult” models of AKI including renal ischemia reperfusion and nephrectomy fail to reflect the multifactorial causes of AKI that is thought to occur in the clinical setting.
Despite these challenges and limitations, animal models of AKI have been instrumental in demonstrating that AKI is not an isolated event and that it results in remote organ dysfunction to the lungs (table 2), heart, liver, intestines, and brain (table 3) through a proinflammatory mechanism that involves neutrophil migration, cytokine expression, and increased oxidative stress26,27 (fig. 2). Neutrophil extravasation into target end organs is characteristic of the innate immune response in acute inflammation28 and is associated with up-regulated cytokine expression,29 which directly leads to end organ injury that is often assessed by increase in vascular permeability. This is demonstrated by injection of Evans blue dye, which has a high binding affinity for albumin, which remains predominantly intravascular but extravasates with disruption of vascular integrity.30 Furthermore, activated neutrophils at sites of inflammation augment this injury by producing reactive oxygen species and depleting antioxidant capacity.
Table 2. Summary of Experimental Studies on Pulmonary Effects of AKI
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Table 2. Summary of Experimental Studies on Pulmonary Effects of AKI
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Table 3. Summary of Experimental Studies on Gastrointestinal, Brain, and Heart Effects of AKI
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Table 3. Summary of Experimental Studies on Gastrointestinal, Brain, and Heart Effects of AKI
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Fig. 2. Global mechanism of distal organ injury. Acute kidney injury leads to distant organ injury through a combination of proinflammatory and oxidative stress-mediated mechanisms. Serum and distal organ cytokine levels increase in conjunction with leukocyte trafficking and increased oxidative stress. In addition, sodium-water channel dysregulation in the lungs aggravates pulmonary edema. IL = interleukin; TNF-α = tumor necrosis factor-α.
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Fig. 2. Global mechanism of distal organ injury. Acute kidney injury leads to distant organ injury through a combination of proinflammatory and oxidative stress-mediated mechanisms. Serum and distal organ cytokine levels increase in conjunction with leukocyte trafficking and increased oxidative stress. In addition, sodium-water channel dysregulation in the lungs aggravates pulmonary edema. IL = interleukin; TNF-α = tumor necrosis factor-α.
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Pulmonary Dysfunction and AKI
The remote effects of AKI in the lungs are due to two distinct mechanisms: uncontrolled inflammatory cascade leading to increased membrane permeability, and down-regulation of sodium-potassium pump and water channels.31 Increased concentrations of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) (fig. 3) originating from either injured renal tubule cells after renal ischemia reperfusion or extrarenal cells (e.g.  , T lymphocytes)32,33 after nephrectomy play key roles in inducing the acute phase response34 and injury to distal organs including the lungs, heart, and liver by promoting an injurious inflammatory response.35 TNF-α and IL-6 have also been shown to increase vascular permeability, leukocyte trafficking, and edema.36,37 
Fig. 3. Plasma interleukin-6 (IL-6) increases after acute kidney injury. Plasma IL-6 measured with mouse-specific enzyme-linked immunosorbent assay (in log scale) increased at 5 h and 24 h after unilateral nephrectomy, bilateral nephrectomy, or 30-min renal ischemia reperfusion.
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Fig. 3. Plasma interleukin-6 (IL-6) increases after acute kidney injury. Plasma IL-6 measured with mouse-specific enzyme-linked immunosorbent assay (in log scale) increased at 5 h and 24 h after unilateral nephrectomy, bilateral nephrectomy, or 30-min renal ischemia reperfusion.
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Increased proinflammatory cytokines directly mediate pulmonary injury after AKI. IL-6 deficient mice and wild-type mice administered neutralizing antibody for IL-6 were protected against pulmonary injury after renal ischemia reperfusion or bilateral nephrectomy with findings of decreased neutrophil infiltration, microvascular permeability, myeloperoxidase activity, and pulmonary edema.31 Conversely, when IL-6 is administered directly to wild-type mice, pulmonary injury ensues as demonstrated by increased myeloperoxidase activity.
The uncontrolled inflammatory response after AKI leads to increased pulmonary vascular permeability, as demonstrated by extravasation of Evans blue dye.38 Impaired vascular integrity results in accumulation of fluid within interstitial lung tissue, leading to pulmonary edema and compromised lung mechanics.39 Extravasation of fluid into alveoli also inactivates surfactant, causing further compromise in lung compliance. Impaired vascular permeability appears to be mediated by macrophages as CNI-1493, a macrophage pacifant, attenuated increase in vascular permeability.38 
The intrinsic compensatory mechanism for interstitial lung edema is dependent on active sodium-potassium pump with passive diffusion of water across aquaporin channels.40 However, ischemic AKI not only causes interstitial pulmonary edema, but it also down-regulates both sodium potassium pump and aquaporin, effectively nullifying this compensatory mechanism.38,41 Furthermore, animal models of reduced aquaporin activity demonstrate a predisposition for ventilator induced lung injury.42 
Histologic changes seen in the lungs after renal ischemia reperfusion, but not bilateral nephrectomy, include enhanced pulmonary endothelial and epithelial cell apoptosis.41 In addition, pulmonary edema, alveolar hemorrhage, and leukocyte trafficking were identified. However, in a later study, Klein et al.  identified septal edema and neutrophil infiltration after both ischemic AKI and bilateral nephrectomy.31 
Gastrointestinal Dysfunction and AKI
The liver and small intestines are interconnected by the portal circulation and work in tandem to propagate multiorgan dysfunction after AKI. The intestines have important immunologic and barrier functions that prevent the large concentration of intraluminal proinflammatory antigens such as Toll-like receptor ligands, cytokines, and bacterial antigens from entering the bloodstream via  the portal circulation.43,44 Thus, loss of intestinal barrier integrity may initiate or propagate hepatic injury, which has severe clinical implications as the liver plays a vital metabolic role in critical illness including protein synthesis, drug metabolism, and detoxification.
Renal ischemia reperfusion and bilateral nephrectomy result in uncontrolled expression of interleukin-17A (IL-17A) in the small intestines.45 IL-17A is a pro-inflammatory cytokine that has an important role in the allergic response by recruiting neutrophils, activating T cells, and inducing expression of other cytokines and chemokines such as TNF-α and IL-6. Indeed, AKI in mice resulted in a significant influx of neutrophils, macrophages (fig. 4), and T-lymphocytes in the small intestinal epithelium and vasculature after AKI in mice.45,46 This proinflammatory process leads to disruption of intestinal barrier integrity as demonstrated by extravasation of Evans blue dye and results in further exacerbation of the inflammatory cascade from penetration of intraluminal antigens into the portal circulation. Histologic changes to the villous lining of the intestines are consistent with loss of intestinal barrier integrity and include apoptosis of the villous endothelium, necrosis of villous epithelium, congestion of villous capillaries, and blunting of intestinal villi. Increased apoptosis within the villi was confirmed with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, particularly among perivascular endothelial cells.
Fig. 4. Proposed mechanism of acute kidney injury (AKI)-induced liver dysfunction. AKI increases small intestinal expression of interleukin-17A (IL-17A) and causes small intestinal injury (impaired vascular permeability, villous endothelial apoptosis and epithelial necrosis, leukocyte infiltration with subsequent cytokine flow into the liver). These events result in hepatic injury (inflammation, apoptosis and necrosis) and increased generation and release of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) into systemic circulation causing further multiorgan injury.
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Fig. 4. Proposed mechanism of acute kidney injury (AKI)-induced liver dysfunction. AKI increases small intestinal expression of interleukin-17A (IL-17A) and causes small intestinal injury (impaired vascular permeability, villous endothelial apoptosis and epithelial necrosis, leukocyte infiltration with subsequent cytokine flow into the liver). These events result in hepatic injury (inflammation, apoptosis and necrosis) and increased generation and release of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) into systemic circulation causing further multiorgan injury.
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IL-17A generated in the intestines drain into the portal circulation and subsequently causes increased hepatic expression of TNF-α and IL-6, as demonstrated by increased TNF-α and IL-6 messenger RNA in liver tissue (fig. 5).45 This is followed by hepatic injury, as demonstrated by increased aspartate transaminase and alanine transaminase concentrations. Liver histology after AKI due to either renal ischemia reperfusion or nephrectomy demonstrates hepatic injury with neutrophil infiltration, hepatocyte vacuolization, and periportal necrosis (fig. 6).45,46 Remarkably, mice deficient in IL-17A, TNF-α, or IL-6, or mice treated with IL-17A, TNF-α, or IL-6 neutralizing antibodies were protected from liver injury after AKI, suggesting that small intestine generation of IL-17A and hepatic expression of TNF-α and IL-6 after AKI directly potentiates liver injury.
Fig. 5. Increased small intestinal macrophage infiltration after acute kidney injury (AKI). Representative photomicrograph (×400) of macrophages (dark brown stain  indicated by arrows  ) in small intestinal tissue harvested from mice subjected to sham surgery (A  ) or bilateral nephrectomy (B  ) 5 h prior.
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Fig. 5. Increased small intestinal macrophage infiltration after acute kidney injury (AKI). Representative photomicrograph (×400) of macrophages (dark brown stain  indicated by arrows  ) in small intestinal tissue harvested from mice subjected to sham surgery (A  ) or bilateral nephrectomy (B  ) 5 h prior.
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Fig. 6. Hepatic injury after acute kidney injury (AKI). Hepatic injury with increased hepatic necrosis and vacuolization after renal ischemia reperfusion. Representative photomicrograph of liver (×400, hematoxylin and eosin staining) of mice subjected to sham surgery (A  ) or to 30 min of renal ischemia and 24 h of reperfusion (B  ). Ischemic AKI rapidly caused nuclear and cytoplasmic degenerative changes, periportal venous hepatocyte necrosis (arrows  ), and marked hepatic vacuolization and congestion.
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Fig. 6. Hepatic injury after acute kidney injury (AKI). Hepatic injury with increased hepatic necrosis and vacuolization after renal ischemia reperfusion. Representative photomicrograph of liver (×400, hematoxylin and eosin staining) of mice subjected to sham surgery (A  ) or to 30 min of renal ischemia and 24 h of reperfusion (B  ). Ischemic AKI rapidly caused nuclear and cytoplasmic degenerative changes, periportal venous hepatocyte necrosis (arrows  ), and marked hepatic vacuolization and congestion.
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Increased oxidative stress and production of reactive oxygen species in the liver are also thought to play a key role in triggering and maintaining the inflammatory response. Malondialdehyde, an index of lipid peroxidation, was found to be increased in the liver after both renal ischemia reperfusion and bilateral nephrectomy.46 In addition, hepatic glutathione, an important endogenous free radical scavenger with protective effects on the liver, was decreased. Administration of glutathione before renal ischemia reperfusion decreased histologic evidence of liver injury, decreased malondialdehyde concentrations, and reduced transaminitis. In addition, renal ischemia reperfusion leads to decreased concentrations of antioxidant enzymes including myeloperoxidase, superoxide dismutase, and catalase.47 
A two-hit model of combined kidney-liver ischemia reperfusion demonstrated that mice subjected to ischemic, unilateral, or bilateral nephrectomy AKI in addition to hepatic ischemia reperfusion had significantly worsened liver injury compared with mice subjected to sham kidney surgery with hepatic ischemia reperfusion.45 This finding may provide an explanation for worsened clinical outcomes when AKI is combined with hepatic complications.4 
Finally, antiinflammatory agents may play a vital role in protection against AKI-induced intestinal as well as hepatic injury. Isoflurane, a volatile anesthetic with potent antiinflammatory effects, was protective in mice against renal ischemia reperfusion with reduced intestinal and hepatic injury in mice compared to pentobarbital, which has minimal antiinflammatory effects.48 This was shown to be mediated directly via  sphingosine-1-phosphate, a G-protein coupled lysophospholipid ligand well known for its ability to promote cell growth and survival, and inhibition of apoptosis.
Cardiac Dysfunction and AKI
Cardiorenal syndrome is characterized by the combination of heart and kidney failure, with one of the organs usually being the primary organ of failure.49 In particular, cardiorenal syndrome type 3 defines heart failure that occurs after AKI. Several mechanisms have been suggested for cardiac dysfunction after AKI, including fluid overload contributing to pulmonary edema, acidemia causing pulmonary vasoconstriction, untreated uremia resulting in pericarditis and decreased myocardial contractility, and hyperkalemia giving rise to arrhythmias.50,51 Even in the absence of these conditions, which are often treatable, cardiac dysfunction may still occur in the setting of AKI.
There is increasing basic science and clinical evidence that inflammatory cytokines have negative consequences on cardiac outcome. The Framingham study found that patients with increased TNF-α and IL-6 concentrations were at increased risk for developing congestive heart failure.52 Patients with increased C-reactive protein concentrations greater than 5 mg/dl also have a 2.8-fold increased risk of developing congestive heart failure. Furthermore, patients with increased concentrations of all three markers had even higher risk of congestive heart failure (hazards ratio 4.07). Among patients with symptomatic heart failure, increased concentrations of TNF-α correlate directly with worsening severity of disease, higher New York Heart Association class, and are prognostic of worsened clinical outcomes.53  56 Patients with congestive heart failure exhibit many features observed in chronic inflammatory conditions. Indeed, patients with severe congestive heart failure have increased concentrations of TNF-α that correlated significantly with features of cachexia.57 –58 
The role of cytokines in the pathogenesis of congestive heart failure is further strengthened by experimental studies suggesting that TNF-α and IL-6, acting concomitantly with neurohormones that lead to salt and water retention, are involved with progressive left ventricular dysfunction, pulmonary edema, left ventricular remodeling, myocyte hypertrophy, and apoptosis.54 Transgenic mice that overexpress TNF-α were found to have left ventricular dilatation and hypertrophy that led to premature death. In addition, these mice were found to have bilateral pleural effusion, myocyte apoptosis, and transmural myocarditis. Transgenic mice that overexpress both IL-6 and its receptor, IL-6R were also found to have ventricular hypertrophy.59 
Cytokine-mediated cardiac dysfunction secondary to AKI has been demonstrated in animal models. Renal ischemia reperfusion in rats resulted in increased TNF-α, IL-1, and intercellular adhesion molecule messenger RNA and myeloperoxidase activity in the heart.60 Within 48 h after renal ischemia reperfusion, significant increases in left ventricular end diastolic diameter, left ventricular end systolic diameter, and decreased fractional shortening were demonstrated by echocardiography. Renal ischemia reperfusion, but not bilateral nephrectomy, resulted in myocardial apoptosis. TNF-α was directly implicated in cardiac dysfunction after AKI as administration of TNF-α blocking antibody significantly decreased cardiomyocyte apoptosis. More recently, heme oxygenase-1, an isoform of an enzyme that catalyzes the degradation of heme and is inducible by oxidative stress and hypoxia, was demonstrated to exert cytoprotective effects.61 Heme oxygenase-1 knockout (HO-1−/−) mice were found to have exacerbated decrease in glomerular filtration rate with marked induction of IL-6 messenger RNA and increased mortality in response to renal ischemia reperfusion.
In contrast with more significant renal injury, mild renal ischemia reperfusion has been found to provide protection against subsequent myocardial ischemia. Research into remote ischemic preconditioning began after observations that occlusion of a specific coronary artery provided myocardial protection beyond its area of perfusion.62,63 Gho et al.  first demonstrated that mice subjected to renal ischemia for 15 min under hypothermic conditions (30°C) were found to have decreased ischemic myocardial area after coronary artery occlusion.64 Several potential mechanisms have been proposed. The ability of hexamethonium, a ganglionic blocker, to abolish remote ischemic preconditioning effects suggests the possibility of a neuronal pathway. In addition, transfusion of blood from a rabbit subjected to combined heart and kidney ischemia reperfusion into an otherwise untreated rabbit was found to provide cardioprotection, providing basis for a humoral mechanism. Finally, myocardial ischemic protection may be due to an antiinflammatory and antiapoptotic systemic response.64,65 However, remote ischemic preconditioning is not specific to the kidneys and has also been demonstrated in ischemia reperfusion of skeletal muscle, brain and liver.
Cerebral Dysfunction and AKI
In animal models of AKI, neurotransmitters have recently been demonstrated to play a role in uremic encephalopathy. Decreased dopamine turnover in the striatum, mesencephalon, and hypothalamus were noted 48 h after bilateral renal ischemia reperfusion, but it is not certain whether this effect is directly caused by AKI or uremia.66 In addition, cerebral inflammation and functional changes were demonstrated after AKI. In mice, renal ischemia reperfusion was found to result in increased neuronal pyknosis and microgliosis in the hippocampus, which plays a substantial role in learning, memory, anxiety, and depression.67 Pyknosis, the irreversible condensation of chromatin in the nucleus, is found in cells undergoing necrosis or apoptosis. Microglial cells, the resident macrophages in the central nervous system, are key mediators of the neuroinflammatory cascade. Furthermore, increased glial fibrillary acidic protein, a marker for cellular inflammation, was noted. Extravasation of Evans blue dye into the brain suggests disruption of the blood-brain barrier in mice after renal ischemia reperfusion. This finding is of clinical importance as disruption of the blood-brain barrier not only results in cerebral edema, but also allows metabolites and toxins that are normally impermeable to the blood brain barrier to produce central nervous system changes. In behavioral testing, mice subjected to renal ischemia reperfusion or bilateral nephrectomy had moderate to severe declines in locomotor activity.67 
Conclusions
Recent clinical studies demonstrate earlier onset of multiorgan failure and increased mortality after AKI that cannot be explained by increased severity of comorbid conditions alone. In animal models of renal ischemia reperfusion or bilateral nephrectomy, it is increasingly clear that AKI is not an isolated event and that it engenders distant organ injury to the lungs, heart, liver and brain through a mechanism that involves neutrophil migration, increased cytokine concentrations, and oxidative stress. However, therapeutic options for treatment of renal failure, especially when complicated by multiorgan failure, continue to be limited with poor efficacy. Hence, understanding the mechanism behind AKI-induced distal organ injury is important as it may reveal new therapeutic targets.
References
Simmons EM, Himmelfarb J, Sezer MT, Chertow GM, Mehta RL, Paganini EP, Soroko S, Freedman S, Becker K, Spratt D, Shyr Y, Ikizler TA, PICARD Study Group: Plasma cytokine levels predict mortality in patients with acute renal failure. Kidney Int 2004; 65:1357–65
Bellomo R, Kellum JA, Ronco C: Defining and classifying acute renal failure: From advocacy to consensus and validation of the RIFLE criteria. Intensive Care Med 2007; 33:409–13
Ympa YP, Sakr Y, Reinhart K, Vincent JL: Has mortality from acute renal failure decreased? A systematic review of the literature. Am J Med 2005; 118:827–32
De Mendona A, Vincent JL, Suter PM, Moreno R, Dearden NM, Antonelli M, Takala J, Sprung C, Cantraine F: Acute renal failure in the ICU: Risk factors and outcome evaluated by the SOFA score. Intensive Care Med 2000; 26:915–21
Levy EM, Viscoli CM, Horwitz RI: The effect of acute renal failure on mortality. A cohort analysis. JAMA 1996; 275:1489–94
Swaminathan M, Stafford-Smith M: Renal dysfunction after vascular surgery. Curr Opin Anaesthesiol 2003; 16:45–51
Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P, Acute Dialysis Quality Initiative workgroup: Acute renal failure-definition, outcome measures, animal models, fluid therapy and information technology needs: The Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004; 8:R204–12
Lassnigg A, Schmidlin D, Mouhieddine M, Bachmann LM, Druml W, Bauer P, Hiesmayr M: Minimal changes of serum creatinine predict prognosis in patients after cardiothoracic surgery: A prospective cohort study. J Am Soc Nephrol 2004; 15:1597–605
Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, Levin A: Acute Kidney Injury Network: Report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007; 11:R31
Liano F, Junco E, Pascual J, Madero R, Verde E: The spectrum of acute renal failure in the intensive care unit compared with that seen in other settings. The Madrid Acute Renal Failure Study Group. Kidney Int Suppl 1998; 66:S16–24
Metnitz PG, Krenn CG, Steltzer H, Lang T, Ploder J, Lenz K, Le Gall JR, Druml W: Effect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients. Crit Care Med 2002; 30:2051–8
Vieira JM Jr, Castro I, Curvello-Neto A, Demarzo S, Caruso P, Pastore L Jr, Imanishe MH, Abdulkader RC, Deheinzelin D: Effect of acute kidney injury on weaning from mechanical ventilation in critically ill patients. Crit Care Med 2007; 35:184–91
Payen D, de Pont AC, Sakr Y, Spies C, Reinhart K, Vincent JL: A positive fluid balance is associated with a worse outcome in patients with acute renal failure. Crit Care 2008; 12:R74
VA/NIH Acute Renal Failure Trial Network, Palevsky PM, Zhang JH, O'Connor TZ, Chertow GM, Crowley ST, Choudhury D, Finkel K, Kellum JA, Paganini E, Schein RM, Smith MW, Swanson KM, Thompson BT, Vijayan A, Watnick S, Star RA, Peduzzi P: Intensity of renal support in critically ill patients with acute kidney injury. N Engl J Med 2008; 359:7–20
Kashyap VS, Cambria RP, Davison JK, L'Italien GJ: Renal failure after thoracoabdominal aortic surgery. J Vasc Surg 1997; 26:949–55; discussion 955–7
Shekarriz B, Shah G, Upadhyay J: Impact of temporary hilar clamping during laparoscopic partial nephrectomy on postoperative renal function: A prospective study. J Urol 2004; 172:54–7
Tilney NL, Guttmann RD: Effects of initial ischemia/reperfusion injury on the transplanted kidney. Transplantation 1997; 64:945–7
Wong GT, Irwin MG: Contrast-induced nephropathy. Br J Anaesth 2007; 99:474–83
Arendshorst WJ, Finn WF, Gottschalk CW: Pathogenesis of acute renal failure following temporary renal ischemia in the rat. Circ Res 1975; 37:558–68
Legrand M, Mik EG, Johannes T, Payen D, Ince C: Renal hypoxia and dysoxia after reperfusion of the ischemic kidney. Mol Med 2008; 14:502–16
Wang YX, Jia YF, Chen KM, Morcos SK: Radiographic contrast media induced nephropathy: Experimental observations and the protective effect of calcium channel blockers. Br J Radiol 2001; 74:1103–8
Zager RA: Partial aortic ligation: A hypoperfusion model of ischemic acute renal failure and a comparison with renal artery occlusion. J Lab Clin Med 1987; 110:396–405
Zager RA: Endotoxemia, renal hypoperfusion, and fever: Interactive risk factors for aminoglycoside and sepsis-associated acute renal failure. Am J Kidney Dis 1992; 20:223–30
Jones DB: Ultrastructure of human acute renal failure. Lab Invest 1982; 46:254–64
Olsen TS, Hansen HE: Ultrastructure of medullary tubules in ischemic acute tubular necrosis and acute interstitial nephritis in man. APMIS 1990; 98:1139–48
Li X, Hassoun HT, Santora R, Rabb H: Organ crosstalk: The role of the kidney. Curr Opin Crit Care 2009; 15:481–7
Grams ME, Rabb H: The distant organ effects of acute kidney injury. Kidney Int 2011; doi: 10.1038/ki.2011.241 [epub ahead of print]
Jones SA: Directing transition from innate to acquired immunity: Defining a role for IL-6. J Immunol 2005; 175:3463–8
Witko-Sarsat V, Rieu P, Descamps-Latscha B, Lesavre P, Halbwachs-Mecarelli L: Neutrophils: Molecules, functions and pathophysiological aspects. Lab Invest 2000; 80:617–53
Jancs N, Jancs-Gbor A, Szolcsnyi J: The role of sensory nerve endings in neurogenic inflammation induced in human skin and in the eye and paw of the rat. Br J Pharmacol Chemother 1968; 33:32–41
Klein CL, Hoke TS, Fang WF, Altmann CJ, Douglas IS, Faubel S: Interleukin-6 mediates lung injury following ischemic acute kidney injury or bilateral nephrectomy. Kidney Int 2008; 74:901–9
Kielar ML, John R, Bennett M, Richardson JA, Shelton JM, Chen L, Jeyarajah DR, Zhou XJ, Zhou H, Chiquett B, Nagami GT, Lu CY: Maladaptive role of IL-6 in ischemic acute renal failure. J Am Soc Nephrol 2005; 16:3315–25
Donnahoo KK, Meng X, Ayala A, Cain MP, Harken AH, Meldrum DR: Early kidney TNF-alpha expression mediates neutrophil infiltration and injury after renal ischemia-reperfusion. Am J Physiol 1999; 277:R922–9
Heinrich PC, Castell JV, Andus T: Interleukin-6 and the acute phase response. Biochem J 1990; 265:621–36
Nechemia-Arbely Y, Barkan D, Pizov G, Shriki A, Rose-John S, Galun E, Axelrod JH: IL-6/IL-6R axis plays a critical role in acute kidney injury. J Am Soc Nephrol 2008; 19:1106–15
Maruo N, Morita I, Shirao M, Murota S: IL-6 increases endothelial permeability in vitro  . Endocrinology 1992; 131:710–4
Royall JA, Berkow RL, Beckman JS, Cunningham MK, Matalon S, Freeman BA: Tumor necrosis factor and interleukin 1 alpha increase vascular endothelial permeability. Am J Physiol 1989; 257:L399–410
Kramer AA, Postler G, Salhab KF, Mendez C, Carey LC, Rabb H: Renal ischemia/reperfusion leads to macrophage-mediated increase in pulmonary vascular permeability. Kidney Int 1999; 55:2362–7
Miserocchi G, Negrini D, Passi A, De Luca G: Development of lung edema: Interstitial fluid dynamics and molecular structure. News Physiol Sci 2001; 16:66–71
Dematte JE, Sznajder JI: Mechanisms of pulmonary edema clearance: From basic research to clinical implication. Intensive Care Med 2000; 26:477–80
Hassoun HT, Lie ML, Grigoryev DN, Liu M, Tuder RM, Rabb H: Kidney ischemia-reperfusion injury induces caspase-dependent pulmonary apoptosis. Am J Physiol Renal Physiol 2009; 297:F125–37
Hales CA, Du HK, Volokhov A, Mourfarrej R, Quinn DA: Aquaporin channels may modulate ventilator-induced lung injury. Respir Physiol 2001; 124:159–66
Pabst R: The anatomical basis for the immune function of the gut. Anat Embryol. (Berl) 1987; 176:135–44
Cario E: Bacterial interactions with cells of the intestinal mucosa: Toll-like receptors and NOD2. Gut 2005; 54:1182–93
Park SW, Chen SW, Kim M, Brown KM, Kolls JK, D'Agati VD, Lee HT: Cytokines induce small intestine and liver injury after renal ischemia or nephrectomy. Lab Invest 2011; 91:63–84
Park SW, Kim M, Chen S, Brown K, Kolls J, Lee HT: Paneth cell activation after acute kidney injury causes liver and intestine injury and systemic inflammation in mice. J Immunol 2010; 184:35.9
Golab F, Kadkhodaee M, Zahmatkesh M, Hedayati M, Arab H, Schuster R, Zahedi K, Lentsch AB, Soleimani M: Ischemic and non-ischemic acute kidney injury cause hepatic damage. Kidney Int 2009; 75:783–92
Serteser M, Koken T, Kahraman A, Yilmaz K, Akbulut G, Dilek ON: Changes in hepatic TNF-alpha levels, antioxidant status, and oxidation products after renal ischemia/reperfusion injury in mice. J Surg Res 2002; 107:234–40
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
Ronco C, Chionh CY, Haapio M, Anavekar NS, House A, Bellomo R: The cardiorenal syndrome. Blood Purif 2009; 27:114–26
Figueras J, Stein L, Diez V, Weil MH, Shubin H: Relationship between pulmonary hemodynamics and arterial pH and carbon dioxide tension in critically ill patients. Chest 1976; 70:466–72
Blake P, Hasegawa Y, Khosla MC, Fouad-Tarazi F, Sakura N, Paganini EP: Isolation of “myocardial depressant factor(s)” from the ultrafiltrate of heart failure patients with acute renal failure. ASAIO J 1996; 42:M911–5
Vasan RS, Sullivan LM, Roubenoff R, Dinarello CA, Harris T, Benjamin EJ, Sawyer DB, Levy D, Wilson PW, D'Agostino RB, Framingham Heart Study: Inflammatory markers and risk of heart failure in elderly subjects without prior myocardial infarction: The Framingham Heart Study. Circulation 2003; 107:1486–91
Deswal A, Petersen NJ, Feldman AM, Young JB, White BG, Mann DL: Cytokines and cytokine receptors in advanced heart failure: An analysis of the cytokine database from the Vesnarinone trial (VEST). Circulation 2001; 103:2055–9
Baumgarten G, Knuefermann P, Mann DL: Cytokines as emerging targets in the treatment of heart failure. Trends Cardiovasc Med 2000; 10:216–23
Ferrari R, Bachetti T, Confortini R, Opasich C, Febo O, Corti A, Cassani G, Visioli O: Tumor necrosis factor soluble receptors in patients with various degrees of congestive heart failure. Circulation 1995; 92:1479–86
Rauchhaus M, Doehner W, Francis DP, Davos C, Kemp M, Liebenthal C, Niebauer J, Hooper J, Volk HD, Coats AJ, Anker SD: Plasma cytokine parameters and mortality in patients with chronic heart failure. Circulation 2000; 102:3060–7
McMurray J, Abdullah I, Dargie HJ, Shapiro D: Increased concentrations of tumour necrosis factor in “cachectic” patients with severe chronic heart failure. Br Heart J 1991; 66:356–8
Levine B, Kalman J, Mayer L, Fillit HM, Packer M: Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 1990; 323:236–41
Hirota H, Yoshida K, Kishimoto T, Taga T: Continuous activation of gp130, a signal-transducing receptor component for interleukin 6-related cytokines, causes myocardial hypertrophy in mice. Proc Natl Acad Sci USA 1995; 92:4862–6
Kelly KJ: Distant effects of experimental renal ischemia/reperfusion injury. J Am Soc Nephrol 2003; 14:1549–58
Tracz MJ, Juncos JP, Croatt AJ, Ackerman AW, Grande JP, Knutson KL, Kane GC, Terzic A, Griffin MD, Nath KA: Deficiency of heme oxygenase-1 impairs renal hemodynamics and exaggerates systemic inflammatory responses to renal ischemia. Kidney Int 2007; 72:1073–80
Przyklenk K, Bauer B, Ovize M, Kloner RA, Whittaker P: Regional ischemic ‘preconditioning’ protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation 1993; 87:893–9
Gho BC, Schoemaker RG, van den Doel MA, Duncker DJ, Verdouw PD: Myocardial protection by brief ischemia in noncardiac tissue. Circulation 1996; 94:2193–200
Peralta C, Fernndez L, Pans J, Prats N, Sans M, Piqu JM, Gelp E, Rosell-Catafau J: Preconditioning protects against systemic disorders associated with hepatic ischemia-reperfusion through blockade of tumor necrosis factor-induced P-selectin up-regulation in the rat. Hepatology 2001; 33:100–13
Konstantinov IE, Arab S, Li J, Coles JG, Boscarino C, Mori A, Cukerman E, Dawood F, Cheung MM, Shimizu M, Liu PP, Redington AN: The remote ischemic preconditioning stimulus modifies gene expression in mouse myocardium. J Thorac Cardiovasc Surg 2005; 130:1326–32
Adachi N, Lei B, Deshpande G, Seyfried FJ, Shimizu I, Nagaro T, Arai T: Uraemia suppresses central dopaminergic metabolism and impairs motor activity in rats. Intensive Care Med 2001; 27:1655–60
Rabb H, Wang Z, Nemoto T, Hotchkiss J, Yokota N, Soleimani M: Acute renal failure leads to dysregulation of lung salt and water channels. Kidney Int 2003; 63:600–6
Deng J, Hu X, Yuen PS, Star RA: Alpha-melanocyte-stimulating hormone inhibits lung injury after renal ischemia/reperfusion. Am J Respir Crit Care Med 2004; 169:749–56
Kim do J, Park SH, Sheen MR, Jeon US, Kim SW, Koh ES, Woo SK: Comparison of experimental lung injury from acute renal failure with injury due to sepsis. Respiration 2006; 73:815–24
Zarbock A, Schmolke M, Spieker T, Jurk K, Van Aken H, Singbartl K: Acute uremia but not renal inflammation attenuates aseptic acute lung injury: A critical role for uremic neutrophils. J Am Soc Nephrol 2006; 17:3124–31
Hassoun HT, Grigoryev DN, Lie ML, Liu M, Cheadle C, Tuder RM, Rabb H: Ischemic acute kidney injury induces a distant organ functional and genomic response distinguishable from bilateral nephrectomy. Am J Physiol Renal Physiol 2007; 293:F30–40
Hoke TS, Douglas IS, Klein CL, He Z, Fang W, Thurman JM, Tao Y, Dursun B, Voelkel NF, Edelstein CL, Faubel S: Acute renal failure after bilateral nephrectomy is associated with cytokine-mediated pulmonary injury. J Am Soc Nephrol 2007; 18:155–64
Awad AS, Rouse M, Huang L, Vergis AL, Reutershan J, Cathro HP, Linden J, Okusa MD: Compartmentalization of neutrophils in the kidney and lung following acute ischemic kidney injury. Kidney Int 2009; 75:689–98
Miyazawa S, Watanabe H, Miyaji C, Hotta O, Abo T: Leukocyte accumulation and changes in extra-renal organs during renal ischemia reperfusion in mice. J Lab Clin Med 2002; 139:269–78
Liu M, Liang Y, Chigurupati S, Lathia JD, Pletnikov M, Sun Z, Crow M, Ross CA, Mattson MP, Rabb H: Acute kidney injury leads to inflammation and functional changes in the brain. J Am Soc Nephrol 2008; 19:1360–70
Nath KA, Grande JP, Croatt AJ, Frank E, Caplice NM, Hebbel RP, Katusic ZS: Transgenic sickle mice are markedly sensitive to renal ischemia-reperfusion injury. Am J Pathol 2005; 166:963–72
Takaoka A, Nakae I, Mitsunami K, Yabe T, Morikawa S, Inubushi T, Kinoshita M: Renal ischemia/reperfusion remotely improves myocardial energy metabolism during myocardial ischemia via  adenosine receptors in rabbits: Effects of “remote preconditioning.” J Am Coll Cardiol 1999; 33:556–64
Pell TJ, Baxter GF, Yellon DM, Drew GM: Renal ischemia preconditions myocardium: Role of adenosine receptors and ATP-sensitive potassium channels. Am J Physiol 1998; 275:H1542–7
Fig. 1. Deleterious effects of acute kidney injury (AKI) on distant organs. AKI results in remote organ injury to the heart, lungs, liver, intestines, and brain and leads to an increase in cytokines, leukocyte trafficking, organ dysfunction, apoptosis, and necrosis. GFAP = glial fibrillary acidic protein; ICAM-1 = intercellular adhesion molecule-1; IL = interleukin; LV = left ventricular; TNF-α = tumor necrosis factor-α.
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Fig. 1. Deleterious effects of acute kidney injury (AKI) on distant organs. AKI results in remote organ injury to the heart, lungs, liver, intestines, and brain and leads to an increase in cytokines, leukocyte trafficking, organ dysfunction, apoptosis, and necrosis. GFAP = glial fibrillary acidic protein; ICAM-1 = intercellular adhesion molecule-1; IL = interleukin; LV = left ventricular; TNF-α = tumor necrosis factor-α.
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Fig. 2. Global mechanism of distal organ injury. Acute kidney injury leads to distant organ injury through a combination of proinflammatory and oxidative stress-mediated mechanisms. Serum and distal organ cytokine levels increase in conjunction with leukocyte trafficking and increased oxidative stress. In addition, sodium-water channel dysregulation in the lungs aggravates pulmonary edema. IL = interleukin; TNF-α = tumor necrosis factor-α.
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Fig. 2. Global mechanism of distal organ injury. Acute kidney injury leads to distant organ injury through a combination of proinflammatory and oxidative stress-mediated mechanisms. Serum and distal organ cytokine levels increase in conjunction with leukocyte trafficking and increased oxidative stress. In addition, sodium-water channel dysregulation in the lungs aggravates pulmonary edema. IL = interleukin; TNF-α = tumor necrosis factor-α.
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Fig. 3. Plasma interleukin-6 (IL-6) increases after acute kidney injury. Plasma IL-6 measured with mouse-specific enzyme-linked immunosorbent assay (in log scale) increased at 5 h and 24 h after unilateral nephrectomy, bilateral nephrectomy, or 30-min renal ischemia reperfusion.
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Fig. 3. Plasma interleukin-6 (IL-6) increases after acute kidney injury. Plasma IL-6 measured with mouse-specific enzyme-linked immunosorbent assay (in log scale) increased at 5 h and 24 h after unilateral nephrectomy, bilateral nephrectomy, or 30-min renal ischemia reperfusion.
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Fig. 4. Proposed mechanism of acute kidney injury (AKI)-induced liver dysfunction. AKI increases small intestinal expression of interleukin-17A (IL-17A) and causes small intestinal injury (impaired vascular permeability, villous endothelial apoptosis and epithelial necrosis, leukocyte infiltration with subsequent cytokine flow into the liver). These events result in hepatic injury (inflammation, apoptosis and necrosis) and increased generation and release of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) into systemic circulation causing further multiorgan injury.
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Fig. 4. Proposed mechanism of acute kidney injury (AKI)-induced liver dysfunction. AKI increases small intestinal expression of interleukin-17A (IL-17A) and causes small intestinal injury (impaired vascular permeability, villous endothelial apoptosis and epithelial necrosis, leukocyte infiltration with subsequent cytokine flow into the liver). These events result in hepatic injury (inflammation, apoptosis and necrosis) and increased generation and release of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) into systemic circulation causing further multiorgan injury.
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Fig. 5. Increased small intestinal macrophage infiltration after acute kidney injury (AKI). Representative photomicrograph (×400) of macrophages (dark brown stain  indicated by arrows  ) in small intestinal tissue harvested from mice subjected to sham surgery (A  ) or bilateral nephrectomy (B  ) 5 h prior.
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Fig. 5. Increased small intestinal macrophage infiltration after acute kidney injury (AKI). Representative photomicrograph (×400) of macrophages (dark brown stain  indicated by arrows  ) in small intestinal tissue harvested from mice subjected to sham surgery (A  ) or bilateral nephrectomy (B  ) 5 h prior.
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Fig. 6. Hepatic injury after acute kidney injury (AKI). Hepatic injury with increased hepatic necrosis and vacuolization after renal ischemia reperfusion. Representative photomicrograph of liver (×400, hematoxylin and eosin staining) of mice subjected to sham surgery (A  ) or to 30 min of renal ischemia and 24 h of reperfusion (B  ). Ischemic AKI rapidly caused nuclear and cytoplasmic degenerative changes, periportal venous hepatocyte necrosis (arrows  ), and marked hepatic vacuolization and congestion.
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Fig. 6. Hepatic injury after acute kidney injury (AKI). Hepatic injury with increased hepatic necrosis and vacuolization after renal ischemia reperfusion. Representative photomicrograph of liver (×400, hematoxylin and eosin staining) of mice subjected to sham surgery (A  ) or to 30 min of renal ischemia and 24 h of reperfusion (B  ). Ischemic AKI rapidly caused nuclear and cytoplasmic degenerative changes, periportal venous hepatocyte necrosis (arrows  ), and marked hepatic vacuolization and congestion.
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Table 1. Limitations of Animal Models of Kidney Injury
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Table 1. Limitations of Animal Models of Kidney Injury
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Table 2. Summary of Experimental Studies on Pulmonary Effects of AKI
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Table 2. Summary of Experimental Studies on Pulmonary Effects of AKI
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Table 3. Summary of Experimental Studies on Gastrointestinal, Brain, and Heart Effects of AKI
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Table 3. Summary of Experimental Studies on Gastrointestinal, Brain, and Heart Effects of AKI
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