ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Pathogenesis and etiology of ischemic acute tubular necrosis

Pathogenesis and etiology of ischemic acute tubular necrosis
Authors:
Mitchell H Rosner, MD
Mark D Okusa, MD
Section Editor:
Paul M Palevsky, MD
Deputy Editor:
John P Forman, MD, MSc
Literature review current through: Nov 2022. | This topic last updated: Oct 19, 2021.

INTRODUCTION — Patients who are hypotensive due to surgery, sepsis, bleeding, or other causes are at risk of developing ischemic acute tubular necrosis (ATN), especially if the impairment in renal perfusion is either severe or prolonged in duration. Patients may also suffer ischemic injury to the kidney due to interruptions in renal blood flow such as from cross-clamping of the renal artery during surgery for removal of renal cell carcinoma. This disorder is characterized by a rising plasma creatinine concentration, elevation in specific urine or serum biomarkers that are indicative of tubular injury such as kidney injury molecule-1 (KIM-1) or neutrophil gelatinase-associated lipocalin (NGAL), a urine volume that may be reduced or normal, and a characteristic set of changes in the urinalysis, including many granular casts and a fractional excretion of sodium above 1 percent and fractional excretion of urea above 35 percent. Serum and urine biomarkers of tubular injury have been proposed as early biomarkers for the diagnosis of ATN [1].

The pathogenesis and etiology of ischemic ATN will be reviewed here [2-4]. The diagnosis of ATN, potential therapies for ischemic ATN, and other causes of ATN are discussed separately:

(See "Possible prevention and therapy of ischemic acute tubular necrosis".)

(See "Etiology and diagnosis of prerenal disease and acute tubular necrosis in acute kidney injury in adults".)

(See "Manifestations of and risk factors for aminoglycoside nephrotoxicity".)

(See "Clinical features and diagnosis of heme pigment-induced acute kidney injury".)

(See "Contrast-associated and contrast-induced acute kidney injury: Clinical features, diagnosis, and management".)

PATHOLOGY AND PATHOGENESIS — The process underlying ischemic ATN occurs in multiple phases, including prerenal (impairment in renal perfusion), initiation of injury, extension of injury, maintenance, and repair [5]. The major histologic changes in ATN are effacement and loss of proximal tubule brush border, patchy loss of tubule cells, focal areas of proximal tubule dilatation, distal tubule casts, and areas of cellular regeneration that appear during the phase of recovery of renal function (picture 1A-B) [6,7].

However, the decline in renal function is usually more prominent than the severity of the histologic changes. In some cases, necrotic cell death is not readily apparent and is restricted to the outer medullary regions (including the S3 segment of the proximal tubule and thick ascending limb of the loop of Henle). In addition to observable tubule obstruction and cell death, other factors may contribute to the decline in glomerular filtration rate (GFR) [6,8]:

Tubules from multiple nephrons drain into a single collecting tubule. As a result, obstruction in a relatively small number of collecting tubules may lead to failure of filtration in a large number of nephrons.

The combination of continued glomerular filtration and impaired proximal and loop reabsorptive function leads to increased sodium chloride delivery to the macula densa in individual nephrons. This activates the tubuloglomerular feedback mechanism, causing afferent arteriolar constriction, which lowers the GFR in an attempt to reduce tubule flow rate [9,10].

Back leak of filtered tubular fluid into the vascular space may occur across the damaged tubule epithelium [11,12].

Apoptosis occurs in both proximal and distal tubule cells [13].

Peritubular capillaries in the outer medulla may be congested with leukocyte accumulation that impairs local renal blood flow [14,15].

A number of processes contribute to the pathogenesis of ATN, including endothelial and epithelial cell injury, intratubular obstruction, changes in local microvascular blood flow, and immunologic or inflammatory processes [2,16].

Endothelial and vascular components of injury — The endothelium of the microcirculation of the kidney contributes to the pathogenesis of ATN [17,18]. In human acute kidney injury (AKI) following renal transplantation, there is a 40 to 50 percent decrease in renal blood flow but a substantially greater decrease in GFR that is not accounted for by the decrease in renal blood flow [19].

In addition, regional blood flow is important in the pathogenesis of AKI. A disproportionate decrease in medullary blood flow relative to total renal blood flow results in medullary ischemia in AKI [20].

Hypotension likely causes global hemodynamic derangements, resulting in a reduction in renal blood flow in sepsis-induced AKI [21]. However, some experimental [22] and human studies [23] suggest an increase in renal blood flow, possibly related to changes in efferent arteriolar vasodilation [24]. In addition, microcirculatory dysfunction reflects intrinsic events, leading to changes in microvascular blood flow, impairment of tissue oxygenation, and ATN, especially in sepsis [25,26]. (See 'Sepsis' below.)

Endothelial cell injury causes disruption in microvascular blood flow, which is important in the initiation and extension phase of ATN [5,27]. A reduction in microvascular blood flow contributes to decreased renal perfusion, renal hypoxia, epithelial cell ischemia, and a resultant decrease in GFR [28]. In particular, reductions in medullary blood flow may worsen the tubule damage caused by the initial ischemic insult. (See 'Epithelial cell injury and dysfunction' below.)

Disruption of the endothelial cell layer may lead to impaired vascular reactivity, increased vascular permeability, and leukocyte recruitment and activation. Activation of the endothelium by ischemic injury leads to upregulation of adhesion molecules such as intracellular adhesion molecule 1 (ICAM-1) and P-selectin [29]. These adhesion molecules facilitate leukocyte-endothelial cell interactions such as macrophage recruitment and elaboration of chemokines [30]. This recruitment of leukocytes serves as one of the early phases of inflammation after ischemia. The endothelial glycocalyx is a network of membrane-bound proteoglycans and glycoproteins that covers the endothelium and contributes to its normal function. Damage to the endothelium results in loss of the glycocalyx and disruption of the actin cytoskeleton [31]. Changes in the local microcirculatory blood flow may result from these changes and cause continued ischemia and tubular damage.

Dysfunction in the endothelial cell permeability barrier at the level of the peritubular capillaries probably contributes to the tubule backleak phenomenon [5,12,32]. Altered endothelial cell-cell contacts resulting in increased intercellular gap formation likely enhance microvascular permeability following ischemic injury [33].

Contributors to endothelial cell injury include the original ischemic insult, leukocyte-endothelial cell interactions, and other inflammatory mediators (such as tumor necrosis factor [TNF]). (See 'Immunologic factors' below.)

Endothelial injury leads to hemodynamic alterations that worsen the initial ischemic insult. There is a local imbalance of vasoactive factors that favors the release of the potent vasoconstrictor, endothelin, along with the reduced release of vasodilatory nitric oxide [34,35].

Endothelial health depends on its interaction with mesenchymal progenitor cells (pericytes) in the interstitial compartment [36,37]. Following ischemia-induced pericyte ablation, endothelial damage enhances focal hypoxia and tubular injury [38,39]. Vascular adhesion protein 1 (VAP-1) is released from pericytes following ischemia, and reperfusion causes H2O2 production in the extracellular space, enhancing the infiltration of neutrophils and worsening injury [40].

Integrins expressed by vascular smooth muscle cells and pericytes bind to ligands that regulate vascular barrier integrity and may play a role in ischemia-reperfusion injury [41].

Altered coagulation and inflammation contribute to ischemic kidney injury. By inhibiting thrombin generation and activating protease-activated receptor-1 (PAR-1), protein C may modulate endothelial dysfunction and protect against kidney injury [42,43].

Thrombomodulin is an important factor in the anticoagulant protein C pathway and has antiinflammatory properties. The administration of soluble thrombomodulin improved microvascular erythrocyte flow rates, reduced microvascular endothelial leukocyte rolling and attachment, minimized endothelial permeability, and reduced renal injury in an ischemic kidney injury model [44].

Endothelial microparticles, which are 0.2 to 2 micrometers in diameter, are components of the endothelial cell membrane that retain cell membrane and intracellular molecules of parental cells including procoagulants and tissue factors [45]. These microparticles are thought to contribute to organ dysfunction in sepsis as adoptive transfer of microparticles from septic rats into healthy rats reproduced inflammatory and other septic characteristics [46].

Epithelial cell injury and dysfunction — The ischemic damage in ATN is generally most severe in the S3 segment of the proximal tubule and in the thick ascending limb of the loop of Henle [8,47]. Early proximal tubule cells appear to be particularly susceptible to ischemia, while the renal medulla normally exists on the brink of hypoxia since the combination of low medullary blood flow and countercurrent exchange of oxygen lowers the pO2 to 10 to 20 mmHg. This sensitivity to hypoxia may be exacerbated by endogenously produced nitric oxide [48].

Poor oxygenation leads to a variety of secondary factors that promote the development of tubule injury, including the intracellular accumulation of calcium, the generation of reactive oxygen species, activation of phospholipases and proteases, depletion of adenosine triphosphate (ATP), and apoptosis (programmed cell death) [49]. The net effect may be either cell death or the sloughing of viable cells into the tubule lumen by impairment of normal cell-to-basement membrane adhesion [50,51]. The latter process involves stress-induced redistribution of integrin receptors from the basolateral membrane, where adhesion to the matrix normally occurs, to the luminal membrane, where luminal integral receptors promote attachment to other dislodged cells causing intratubular obstruction [51].

A variety of other contributors to ischemic tubule injury or dysfunction have been explored in experimental models, but their contribution to human disease is undefined [52-57]:

Ischemia-induced redistribution of membrane proteins – Ischemia disrupts the actin cytoskeleton that anchors the Na-K-ATPase pump to the basolateral membrane, allowing some of the pumps to redistribute onto the luminal membrane [52,53]. This interferes with normal ion transport by pumping sodium back into the tubule lumen. Recovery of function is associated with the return of Na-K-ATPase pumps to the basolateral membrane [52]. As mentioned above, beta-1 integrins are normally polarized to the basal cell membrane, where they maintain cell-substratum adhesion. Ischemic injury results in the redistribution of integrins to the apical membrane, with consequent shedding of tubule cells [58]. The loss of epithelial polarity also leads to the loss of another basolateral membrane surface protein, the complement inhibitor, Crry, which permits activation of the alternative complement pathway, resulting in the recruitment of macrophages and neutrophils [59,60].

Iron-mediated oxidative stress is thought to contribute to ischemia-reperfusion injury. Mislocalized iron in the kidney occurs in experimental ischemia-reperfusion injury. Neutrophil gelatinase-associated lipocalin (NGAL) is a kidney protein that induces renal cell differentiation and binds a siderophore that traps iron with high affinity. NGAL is induced in the kidney after ischemic injury, and the release of unbound iron that occurs as a consequence of ischemic injury can promote the formation of reactive oxygen species. The delivery of a lipocalin-siderophore-iron complex preserves renal histology in mice following ischemic injury [55]. In one study, ferroportin, an iron export protein, contributed to ischemia-reperfusion injury [61]. Hepcidin is an endogenous acute-phase hepatic hormone that binds and degrades ferroportin and attenuates AKI. Furthermore, hepcidin-deficient mice are more susceptible to ischemia-reperfusion injury [61].

Cell death pathways – Cell death following ATN occurs through necrosis or regulated cell death pathways (apoptosis, necroptosis, and pyroptosis) [62].

Necrosis – Epithelial cell necrosis is a nonenergy-dependent process as a result of severe ATP depletion following injury. Necrosis results from an increase in intracellular calcium and activation of membrane phospholipases rather than caspase activation [63].

Apoptosis – Apoptosis is an energy-dependent, "programmed" cell death after injury that results in condensation of nuclear and cytoplasmic material, forming apoptotic bodies. These apoptotic bodies, which are plasma-membrane bound, are rapidly phagocytosed by macrophages and neighboring viable epithelial cells. The caspase family of proteases is an important initiator as well as an effector of apoptosis [64,65].

Necroptosis and ferroptosis – Both necroptosis and ferroptosis are forms of regulated nonapoptotic cell death. In contrast to apoptotic cell death, in necroptosis, the intracellular contents such as ATP, high-mobility group box 1 protein (HMGB1), double-stranded DNA, and RNA components are released. These released molecules are also referred to as damage-associated molecular patterns (DAMPS), leading to necroinflammation [66]. The signaling pathways for necroptosis involve receptor-interacting serine/threonine-protein kinase 1 (RIPK1) [67,68], receptor-interacting serine/threonine-protein kinase 3 (RIPK3) [69], and its substrate mixed-lineage kinase domain-like protein (MLKL) [70].

Ferroptosis – Ferroptosis is a nonapoptotic form of regulated cell death that depends upon iron and is associated with increased lipid peroxidation, due to the lack of activity of glutathione peroxidase 4 (GPX4) [71-73].

Pyroptosis – This regulated form of cell death is highly inflammatory and requires caspase 1, 4/5 for activation [74,75]. Released DAMPS and pathogen-associated molecular patterns (PAMPS) activate NLR family pyrin domain containing 3 (NLRP3) inflammasome, leading to the cleavage of pro-interleukin (IL)-1beta and pro-IL-18, activation of gasdermin D (GSDMD), a pyroptosis executioner, and release of the N terminal fragment (GSDMD-NT) [74]. GSDMD-NT forms a membrane pore and induces cell swelling and cell lysis followed by activation of the innate immunity.

Clearance of apoptotic and necrotic cells – Normally, cells turn over every day due to apoptosis, and their removal by phagocytes is referred to as efferocytosis [76]. This process of efferocytosis is antiinflammatory. Various steps are involved, and a number of different molecules are associated with each step [76]. The natural course of AKI is characterized by an initial phase of injury, followed by a later phase of resolution. The clearance of apoptotic and necrotic cells is necessary to mitigate inflammation and initiate tissue repair. Although this role was thought to be exclusively due to macrophages, kidney injury molecule-1 (KIM-1 or TIM-1), an immunoglobulin superfamily cell-surface protein that is highly upregulated on the surface of injured kidney epithelial cells, has been shown to recognize apoptotic cell surface-specific phosphatidylserine epitopes and confer properties of endogenous phagocytes to kidney epithelial cells [77].

Cellular receptors – Cellular receptors have been implicated in ischemia-reperfusion injury and recovery. Examples of such receptors include [56,78,79]:

Peroxisome proliferator-activated receptor (PPAR) – PPAR beta is a ligand-activated transcription factor that appears to protect against renal ischemia. PPAR beta is ubiquitously expressed in the nephron, particularly in the straight proximal tubule. Mice deficient in PPAR beta are much more susceptible to ischemia, and providing a PPAR beta ligand protects against ischemic renal injury [56]. PPAR gamma agonists, such as fibrates, reduce inflammation and injury following cisplatin administration [80]. PPAR gamma may have an antifibrotic action, possibly mediated by hepatocyte growth factor [78].

Toll-like receptors (TLRs) – TLRs are pattern-recognition receptors implicated in the immune response to pathogens. TLRs are expressed in both immune cells and renal epithelial cells and may serve as targets in the pathogenesis of ischemic injury. TLR 1, 2, 3, 4, and 6 are expressed in kidney epithelial cells [81-84]. The expression of both TLR2 and TLR4 by tubular epithelial cells is increased following ischemia in mice, and the reduction of either TLR2 or 4 expression reduces the generation of ischemia-induced cytokines and preserves renal function following ischemic injury [79,85]. Renal TLR2 RNA is expressed primarily in tubule cells and appears to be linked to the release of cytokines in response to ischemic injury. Mice that are deficient in TLR2 demonstrate a reduction in cytokine release and renal dysfunction compared with mice that express TLR2 [79]. The expression of TLR4 on both immune cells and renal parenchymal cells contributes to AKI [85,86]. The endogenous ligand for TLRs may be heat-shock proteins-60 and -70, mammalian DNA, RNA, interferon alpha, interferon beta, CD40-L, or high mobility group box protein 1 (HMBG1), which are released by necrotic cells and ischemia [87-89].

TLR9, an endosomal class of TLR, which is expressed in the spleen, may also contribute to the pathogenesis of AKI. TLR9 null mice and blockade of TLR9 with antisense oligonucleotides reduce mortality and severity of renal damage in a model of polymicrobial sepsis [90].

Bradykinin receptors – Kinins, a set of hormones produced in the kidney, are vasodilators that may minimize renal ischemia. Support for this hypothesis is provided by the finding that mice without bradykinin B1 and B2 receptors are associated with marked ischemia/reperfusion injury compared with wild-type mice [91].

Release of factors by necrotic or injured cells is likely important in the inflammatory responses that are critical to the extension and maintenance phases of AKI [89]. These factors include: high mobility group 1 protein [92], heat shock proteins [87], and cytokines (IL-1, IL-6, TNF-alfa, IL-18) [93-95]. The chemokine receptor, CX3CR1, and its ligand, fractalkine, may play an early role in AKI [30,96].

In addition to ischemia, other factors may promote renal injury in selected settings:

Endotoxemia may play an important role in the multiple organ failure syndrome. (See 'Etiology' below.)

Complement release during hemodialysis with a bioincompatible membrane may delay renal recovery and increase mortality via neutrophil activation. (See "Dialysis-related factors that may influence recovery of kidney function in acute kidney injury (acute renal failure)".)

Intratubular obstruction — Intratubular obstruction by cells and cellular debris is an important component of ATN [97]. Integrin receptors may contribute to this process as adhesion of tubular epithelial cells to beta1-integrin ligands on the basement membrane may minimize tubule cell detachment and intratubular obstruction [98]. The intraluminal casts are composed, in part, of Tamm-Horsfall protein, which is converted to a gel-like polymer in the setting of high local luminal sodium concentrations that is characteristic of ATN [99].

Immunologic factors — The different arms of the immune system appear to contribute to the pathogenesis of ischemic renal injury [100,101]. Ischemic renal injury is characterized by the appearance of neutrophils, natural killer T cells and macrophages, both components of the innate immune system [30,88,101].

The innate immune system has evolved as a host defense mechanism that recognizes microbial products. TLRs and a limited number of other receptors expressed on dendritic cells and macrophages respond to highly conserved bacterial structures referred to as PAMPs, leading to an immediate and generic response. Pathogens are not the only agents that cause tissue damage. Tissue damage (eg, ischemia reperfusion) is recognized at the cell level via receptor-mediated detection of intracellular proteins released by the dead cells. These proteins are referred to as "alarmin" and include endogenous molecules that signal tissue and cell damage such as mammalian DNA, heat shock proteins, and HMBG1. This model is referred to as the "danger model" [88,89]. Endogenous alarmins and exogenous PAMPs can be considered subgroups of DAMPs. Once activated, dendritic cells activate natural killer T cells [102]; an inflammatory and immune response leads to sequestration of leukocytes in inflamed sites, complement activation, and eradication of pathogens through cytokines, complement/membrane attack complex, and natural killer cells [101].

Complement activation — Complement activation is an early event underlying ischemic kidney injury. It initiates AKI directly through effects on kidney cells or indirectly through effects on innate and adaptive immunity. The anaphylatoxins (C3a and C5a) generated following complement activation bind to C3a and C5a receptors expressed on several types of cells such as leukocytes, endothelial cells, mesangial cells, and tubular epithelial cells, thereby triggering a systemic inflammatory response [103]. During ischemic injury, proximal tubule and kidney mononuclear phagocytes expressing CR5a are markedly upregulated and recruit inflammatory cells. Observations in animal models and humans suggest that the activation of the alternative pathway that forms the membrane attack complex (C5-C9) may contribute to renal injury [104,105]. Several inhibitors of complement activation are present within the mouse kidney, although only complement receptor 1-related protein y (Crry) is present on mouse tubular epithelial cells. Reduced expression of Crry1 in the tubular epithelium increases sensitivity to ischemic injury [59].

The role of the alternative complement pathway is also suggested by the demonstration of C3 deposition along the tubule basement membrane [99]. Upon activation, the complement system generates a number of inflammatory signals that lead to ongoing injury. A few studies have identified a functionally intact intracellular complement system that is important in the immune response [106,107]. This system is present within lymphocytes, epithelial cells, endothelial cells, and other cell types.

Adhesion molecules — Adhesion molecules, such as ICAM-1, may participate in the development of ischemic ATN [108]. The administration of anti-ICAM-1 antibodies preserves renal function and mitigates cell injury in experimental models of AKI, even if given as long as two hours after the ischemic insult. In addition, mutant mice without ICAM-1 are almost completely protected against ischemic renal injury [29]. However, in human trials, the administration of anti-ICAM-1 monoclonal antibody did not prevent ATN in deceased-donor kidney transplant recipients following ischemia [109].

Studies have also suggested a role for other adhesion molecules, such as E- and P-selectins [110-113].

In an animal model of a monoclonal antibody to CD11b/CD18, integrins reduced ischemia-reperfusion injury [114].

Immune cells — Increasing evidence suggests that inflammatory cells may play a role in ischemic renal failure [14,101,115,116]:

ICAM-1 may act in part by promoting neutrophil-endothelial cell interactions [117].

T cells contribute to ischemia-reperfusion injury [118]. Mice deficient in effector CD4+ T cells are protected from ischemic injury [119,120].

The production of interferon gamma from natural killer T cells (a subpopulation of CD4+ cells) contributes to the pathogenesis of acute renal ischemia-reperfusion injury [121].

Mononuclear phagocytes are important in activation of the innate immune response to ischemia-reperfusion injury [122]. Genetic deletion of CCR2 (the chemokine receptor for monocyte chemoattractant protein-1) is associated with decreased ischemic injury due, in part, to lower levels of macrophage activation and renal infiltration [30,123]. Mice depleted of macrophages are protected from ischemic injury [124].

Dendritic cells [125] and natural killer cells [126] contribute to ischemia-reperfusion injury.

Regulatory T cells, in contrast, attenuate ischemia-reperfusion injury [127].

CD4(-)CD8(-) T cells protect against AKI in an animal model [128].

Inflammatory mediators — A wide variety of proinflammatory molecules are released in response to ischemic injury [100,102,129]. These include TNF-alpha, IL-6 and -8, chemokines, and bone morphogenetic protein-7. It is not known whether inhibition of such mediators ameliorates ischemic renal injury [130].

ETIOLOGY — Ischemic ATN is a common complication of severe ischemia (often due to prolonged hypotension), major surgery, or sepsis, particularly in combination with underlying comorbidities (such as chronic kidney disease, atherosclerosis, diabetes mellitus, advanced malignancy, and poor nutrition) [131,132].

Surgery — Postoperative patients are at increased risk for ATN because preoperative intravascular volume depletion, anesthesia-induced hemodynamic changes, and intraoperative fluid losses can lead to reductions in renal blood flow, glomerular filtration rate (GFR; up to 30 to 45 percent), urine volume, and sodium excretion [133-135]. In some cases, surgical techniques require interruption of renal blood flow for short periods of time. Although most patients tolerate these changes well, some develop acute kidney injury (AKI) that is most often due to ATN. The likelihood of tubule injury is increased if there is an additional insult, such as exposure to nephrotoxins (including medications, pigments [hemoglobin or myoglobin]) or repeated hypotensive episodes. Nearly two-thirds of patients who develop ATN have been exposed to more than one nephrotoxic insult. Some data suggest that human kidneys can safely tolerate 30 to 60 minutes of clamp ischemia if other nephrologic insults are not present [136]. This study prospectively analyzed the renal response to clamp ischemia in patients undergoing partial nephrectomy, with the majority of patients experiencing >30 minutes of ischemia [136]. Renal structural changes were much less severe than seen in animal models, and there was only a mild, transient increase in serum creatinine and biomarkers. The rise in these biomarkers did not correlate with the duration of ischemia or changes in renal function data.

There are three surgical procedures that seem to confer the highest risk for ATN:

Abdominal aortic aneurysm surgery, in which there may be periods of total renal ischemia if supra-aortic clamping is required [134,137].

Surgery to correct obstructive jaundice, in which the postoperative reduction in GFR is roughly twice as great (60 versus 30 percent) as that seen with other forms of abdominal surgery [138]. This effect may be related to the absorption of endotoxin from the gut [139]. In normal subjects, endotoxin absorption is limited by the detergent effect of bile salts on the lipopolysaccharide endotoxin molecule; this protection is lost with obstructive jaundice since bile salt secretion is minimal. Preliminary experiments suggest that the administration of bile salts to such patients can prevent both the endotoxemia and the exaggerated renal vasoconstriction [139].

Cardiac surgery, particularly coronary artery bypass graft (CABG) surgery with valve surgery. Important underlying risk factors include underlying renal insufficiency and myocardial dysfunction, combined CABG and valve surgery, and emergency surgery. Off-pump cardiac surgery appears to be associated with a lower risk for AKI in some but not all studies [140]. Issues related to AKI after CABG are discussed separately. (See "Early noncardiac complications of coronary artery bypass graft surgery", section on 'Acute kidney injury'.)

Maintaining adequate systemic and renal hemodynamics during and after surgery, as well as limiting any nephrotoxin exposure, may diminish the risk of ATN in high-risk patients. Thus far, no specific pharmacologic strategy has proven successful in preventing ATN. Strategies have targeted inflammatory pathways, oxidative stress, and renal hemodynamics without effect. (See "Possible prevention and therapy of ischemic acute tubular necrosis".)

Sepsis — Overt or intermittent endotoxemia may play an important role in AKI that is observed as part of the multiple organ dysfunction syndrome [141]. The likelihood of renal tubule injury with sepsis is increased if there are concurrent adverse clinical characteristics, including older age, underlying renal or liver insufficiency, and additional factors [142]. Among the critically ill, sepsis is the most common cause of AKI [143]. (See "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis".)

The mechanism by which endotoxemia leads to AKI is incompletely understood. Systemic hypotension, direct renal vasoconstriction, activation of vasoactive hormones (including renin-angiotensin-aldosterone system and endothelin), induction of nitric oxide synthase, release of cytokines (such as tumor necrosis factor [TNF], interleukin [IL]-1, IL-6, and chemokines), enhanced synthesis of reactive oxygen species, and activation of neutrophils by endotoxin and FMLP (a three-amino acid [fMet-Leu-Phe] chemotactic peptide in the bacterial cell walls) all may contribute to renal injury [21,144-149]. It has been shown, for example, that mild renal ischemia, which alone is not sufficient to cause renal injury, can lead to AKI in the presence of primed neutrophils, as might occur with endotoxemia [150]. The release of elastase and oxidants from neutrophils may also contribute to tubule damage in this setting [145,150].

Hypotension is thought to cause a reduction in renal blood flow in sepsis-induced AKI [21]. This concept has been challenged by experimental [22] and human studies [23] that suggest an increase in renal blood flow, possibly related to changes in efferent arteriolar vasodilation [24]. Changes in microvascular blood flow may also contribute to decreased tissue oxygenation in ATN [25,28].

In addition to ATN, severe sepsis rarely leads to irreversible renal cortical necrosis. In this setting, endotoxin-induced endothelial injury may predispose to intrarenal thrombus formation by directly promoting platelet aggregation by diminishing the release of nitric oxide (endothelium-derived relaxing factor), which normally inhibits platelet aggregation [151], and by increasing the synthesis of plasminogen activator inhibitor type 1, leading to a reduction in fibrinolytic activity [152].

Other — Ischemic ATN can also be seen in patients with severe hypovolemia or acute, severe pancreatitis, in which multiple-organ dysfunction is almost always present [153]. In addition, even moderate degrees of volume depletion can increase the risk of renal failure in the presence of a nephrotoxin, such as an aminoglycoside antibiotic. In this setting, the impairment in cell energetics induced by the aminoglycoside increases the susceptibility to ischemic injury [154]. (See "Etiology, clinical manifestations, and diagnosis of volume depletion in adults" and "Clinical manifestations and diagnosis of acute pancreatitis" and "Manifestations of and risk factors for aminoglycoside nephrotoxicity".)

Other nephrotoxins, such as iodinated radiocontrast material, can also potentiate ischemic injury.

Ischemic ATN may also occur in the absence of overt hypotension in conditions in which renal autoregulation is impaired [155]. This is most commonly observed in patients with chronic kidney disease, liver failure, and longstanding hypertension. The concomitant use of drugs such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or nonsteroidal antiinflammatory drugs can potentiate renal injury by further impairing autoregulation.

BIOMARKERS AND PATHOGENESIS — Serum and urinary biomarkers may allow early diagnosis of acute kidney injury (AKI). These biomarkers may also offer insights into the pathogenesis of AKI and may, in the future, guide therapy. (See "Investigational biomarkers and the evaluation of acute kidney injury", section on 'Diagnostic biomarkers'.)

SUMMARY AND RECOMMENDATIONS

The underlying process of ischemic acute tubular necrosis (ATN) occurs in multiple steps, including prerenal, initiation, extension, maintenance, and repair. This results in a variety of major histologic changes in ATN, including the effacement and loss of proximal tubule brush border, patchy loss of tubule cells, focal areas of proximal tubule dilatation, distal tubule casts, and areas of cellular regeneration that appear during the phase of recovery of renal function. (See 'Pathology and pathogenesis' above.)

A number of processes contribute to the pathogenesis of tubular necrosis. These include endothelial and epithelial cell injury, intratubular obstruction, and immunologic or inflammatory processes. (See 'Pathology and pathogenesis' above.)

ATN is a common complication of severe ischemia (often due to prolonged hypotension), major surgery, or sepsis. ATN frequently occurs in combination with underlying comorbidities. (See 'Etiology' above.)

  1. Alge JL, Arthur JM. Biomarkers of AKI: a review of mechanistic relevance and potential therapeutic implications. Clin J Am Soc Nephrol 2015; 10:147.
  2. Bonventre JV, Yang L. Cellular pathophysiology of ischemic acute kidney injury. J Clin Invest 2011; 121:4210.
  3. Eltzschig HK, Eckle T. Ischemia and reperfusion--from mechanism to translation. Nat Med 2011; 17:1391.
  4. Molitoris BA. Therapeutic translation in acute kidney injury: the epithelial/endothelial axis. J Clin Invest 2014; 124:2355.
  5. Molitoris BA, Sutton TA. Endothelial injury and dysfunction: role in the extension phase of acute renal failure. Kidney Int 2004; 66:496.
  6. Rose BD. Pathophysiology of Renal Disease, 2nd ed., McGraw-Hill, New York 1987. p.84.
  7. Solez K, Morel-Maroger L, Sraer JD. The morphology of "acute tubular necrosis" in man: analysis of 57 renal biopsies and a comparison with the glycerol model. Medicine (Baltimore) 1979; 58:362.
  8. Myers BD, Moran SM. Hemodynamically mediated acute renal failure. N Engl J Med 1986; 314:97.
  9. Mason J, Takabatake T, Olbricht C, Thurau K. The early phase of experimental acute renal failure. III. Tubologlomerular feedback. Pflugers Arch 1978; 373:69.
  10. Schnermann J, Briggs JP, Weber PC. Tubuloglomerular feedback, prostaglandins, and angiotensin in the autoregulation of glomerular filtration rate. Kidney Int 1984; 25:53.
  11. Myers BD, Hilberman M, Spencer RJ, Jamison RL. Glomerular and tubular function in non-oliguric acute renal failure. Am J Med 1982; 72:642.
  12. Donohoe JF, Venkatachalam MA, Bernard DB, Levinsky NG. Tubular leakage and obstruction after renal ischemia: structural-functional correlations. Kidney Int 1978; 13:208.
  13. Lieberthal W, Koh JS, Levine JS. Necrosis and apoptosis in acute renal failure. Semin Nephrol 1998; 18:505.
  14. Friedewald JJ, Rabb H. Inflammatory cells in ischemic acute renal failure. Kidney Int 2004; 66:486.
  15. Awad AS, Rouse M, Huang L, et al. Compartmentalization of neutrophils in the kidney and lung following acute ischemic kidney injury. Kidney Int 2009; 75:689.
  16. Sharfuddin AA, Molitoris BA. Pathophysiology of ischemic acute kidney injury. Nat Rev Nephrol 2011; 7:189.
  17. Verma SK, Molitoris BA. Renal endothelial injury and microvascular dysfunction in acute kidney injury. Semin Nephrol 2015; 35:96.
  18. Sutton TA, Fisher CJ, Molitoris BA. Microvascular endothelial injury and dysfunction during ischemic acute renal failure. Kidney Int 2002; 62:1539.
  19. Alejandro V, Scandling JD Jr, Sibley RK, et al. Mechanisms of filtration failure during postischemic injury of the human kidney. A study of the reperfused renal allograft. J Clin Invest 1995; 95:820.
  20. Karlberg L, Norlén BJ, Ojteg G, Wolgast M. Impaired medullary circulation in postischemic acute renal failure. Acta Physiol Scand 1983; 118:11.
  21. Schrier RW, Wang W. Acute renal failure and sepsis. N Engl J Med 2004; 351:159.
  22. Langenberg C, Wan L, Egi M, et al. Renal blood flow in experimental septic acute renal failure. Kidney Int 2006; 69:1996.
  23. Brenner M, Schaer GL, Mallory DL, et al. Detection of renal blood flow abnormalities in septic and critically ill patients using a newly designed indwelling thermodilution renal vein catheter. Chest 1990; 98:170.
  24. Wan L, Langenberg C, Bellomo R, May CN. Angiotensin II in experimental hyperdynamic sepsis. Crit Care 2009; 13:R190.
  25. De Backer D, Creteur J, Preiser JC, et al. Microvascular blood flow is altered in patients with sepsis. Am J Respir Crit Care Med 2002; 166:98.
  26. Trzeciak S, Cinel I, Phillip Dellinger R, et al. Resuscitating the microcirculation in sepsis: the central role of nitric oxide, emerging concepts for novel therapies, and challenges for clinical trials. Acad Emerg Med 2008; 15:399.
  27. Sheridan AM, Bonventre JV. Cell biology and molecular mechanisms of injury in ischemic acute renal failure. Curr Opin Nephrol Hypertens 2000; 9:427.
  28. Ince C. The central role of renal microcirculatory dysfunction in the pathogenesis of acute kidney injury. Nephron Clin Pract 2014; 127:124.
  29. Kelly KJ, Williams WW Jr, Colvin RB, et al. Intercellular adhesion molecule-1-deficient mice are protected against ischemic renal injury. J Clin Invest 1996; 97:1056.
  30. Li L, Huang L, Sung SS, et al. The chemokine receptors CCR2 and CX3CR1 mediate monocyte/macrophage trafficking in kidney ischemia-reperfusion injury. Kidney Int 2008; 74:1526.
  31. Rubio-Gayosso I, Platts SH, Duling BR. Reactive oxygen species mediate modification of glycocalyx during ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 2006; 290:H2247.
  32. Brodsky SV, Yamamoto T, Tada T, et al. Endothelial dysfunction in ischemic acute renal failure: rescue by transplanted endothelial cells. Am J Physiol Renal Physiol 2002; 282:F1140.
  33. Hörbelt M, Lee SY, Mang HE, et al. Acute and chronic microvascular alterations in a mouse model of ischemic acute kidney injury. Am J Physiol Renal Physiol 2007; 293:F688.
  34. Kohan DE. Endothelins in the kidney: physiology and pathophysiology. Am J Kidney Dis 1993; 22:493.
  35. Schwartz D, Blantz RC. Nitric oxide, sepsis, and the kidney. Semin Nephrol 1999; 19:272.
  36. Caruso RA, Fedele F, Finocchiaro G, et al. Ultrastructural descriptions of pericyte/endothelium peg-socket interdigitations in the microvasculature of human gastric carcinomas. Anticancer Res 2009; 29:449.
  37. Hayden MR, Karuparthi PR, Habibi J, et al. Ultrastructure of islet microcirculation, pericytes and the islet exocrine interface in the HIP rat model of diabetes. Exp Biol Med (Maywood) 2008; 233:1109.
  38. Kramann R, Wongboonsin J, Chang-Panesso M, et al. Gli1(+) Pericyte Loss Induces Capillary Rarefaction and Proximal Tubular Injury. J Am Soc Nephrol 2017; 28:776.
  39. Lemos DR, Marsh G, Huang A, et al. Maintenance of vascular integrity by pericytes is essential for normal kidney function. Am J Physiol Renal Physiol 2016; 311:F1230.
  40. Tanaka S, Tanaka T, Kawakami T, et al. Vascular adhesion protein-1 enhances neutrophil infiltration by generation of hydrogen peroxide in renal ischemia/reperfusion injury. Kidney Int 2017.
  41. McCurley A, Alimperti S, Campos-Bilderback SB, et al. Inhibition of αvβ5 Integrin Attenuates Vascular Permeability and Protects against Renal Ischemia-Reperfusion Injury. J Am Soc Nephrol 2017.
  42. Gupta A, Williams MD, Macias WL, et al. Activated protein C and acute kidney injury: Selective targeting of PAR-1. Curr Drug Targets 2009; 10:1212.
  43. Joyce DE, Gelbert L, Ciaccia A, et al. Gene expression profile of antithrombotic protein c defines new mechanisms modulating inflammation and apoptosis. J Biol Chem 2001; 276:11199.
  44. Sharfuddin AA, Sandoval RM, Berg DT, et al. Soluble thrombomodulin protects ischemic kidneys. J Am Soc Nephrol 2009; 20:524.
  45. Souza AC, Yuen PS, Star RA. Microparticles: markers and mediators of sepsis-induced microvascular dysfunction, immunosuppression, and AKI. Kidney Int 2015; 87:1100.
  46. Mortaza S, Martinez MC, Baron-Menguy C, et al. Detrimental hemodynamic and inflammatory effects of microparticles originating from septic rats. Crit Care Med 2009; 37:2045.
  47. Brezis M, Rosen S, Silva P, Epstein FH. Renal ischemia: a new perspective. Kidney Int 1984; 26:375.
  48. Koivisto A, Pittner J, Froelich M, Persson AE. Oxygen-dependent inhibition of respiration in isolated renal tubules by nitric oxide. Kidney Int 1999; 55:2368.
  49. Kaushal GP, Basnakian AG, Shah SV. Apoptotic pathways in ischemic acute renal failure. Kidney Int 2004; 66:500.
  50. Noiri E, Gailit J, Sheth D, et al. Cyclic RGD peptides ameliorate ischemic acute renal failure in rats. Kidney Int 1994; 46:1050.
  51. Noiri E, Romanov V, Forest T, et al. Pathophysiology of renal tubular obstruction: therapeutic role of synthetic RGD peptides in acute renal failure. Kidney Int 1995; 48:1375.
  52. Molitoris BA, Dahl R, Geerdes A. Cytoskeleton disruption and apical redistribution of proximal tubule Na(+)-K(+)-ATPase during ischemia. Am J Physiol 1992; 263:F488.
  53. Fish EM, Molitoris BA. Alterations in epithelial polarity and the pathogenesis of disease states. N Engl J Med 1994; 330:1580.
  54. Alejandro VS, Nelson WJ, Huie P, et al. Postischemic injury, delayed function and Na+/K(+)-ATPase distribution in the transplanted kidney. Kidney Int 1995; 48:1308.
  55. Mori K, Lee HT, Rapoport D, et al. Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury. J Clin Invest 2005; 115:610.
  56. Letavernier E, Perez J, Joye E, et al. Peroxisome proliferator-activated receptor beta/delta exerts a strong protection from ischemic acute renal failure. J Am Soc Nephrol 2005; 16:2395.
  57. Molitoris BA, Dagher PC, Sandoval RM, et al. siRNA targeted to p53 attenuates ischemic and cisplatin-induced acute kidney injury. J Am Soc Nephrol 2009; 20:1754.
  58. Gailit J, Colflesh D, Rabiner I, et al. Redistribution and dysfunction of integrins in cultured renal epithelial cells exposed to oxidative stress. Am J Physiol 1993; 264:F149.
  59. Thurman JM, Ljubanović D, Royer PA, et al. Altered renal tubular expression of the complement inhibitor Crry permits complement activation after ischemia/reperfusion. J Clin Invest 2006; 116:357.
  60. Thurman JM, Lenderink AM, Royer PA, et al. C3a is required for the production of CXC chemokines by tubular epithelial cells after renal ishemia/reperfusion. J Immunol 2007; 178:1819.
  61. Scindia Y, Dey P, Thirunagari A, et al. Hepcidin Mitigates Renal Ischemia-Reperfusion Injury by Modulating Systemic Iron Homeostasis. J Am Soc Nephrol 2015; 26:2800.
  62. Vanden Berghe T, Linkermann A, Jouan-Lanhouet S, et al. Regulated necrosis: the expanding network of non-apoptotic cell death pathways. Nat Rev Mol Cell Biol 2014; 15:135.
  63. Sogabe K, Roeser NF, Davis JA, et al. Calcium dependence of integrity of the actin cytoskeleton of proximal tubule cell microvilli. Am J Physiol 1996; 271:F292.
  64. Guo R, Wang Y, Minto AW, et al. Acute renal failure in endotoxemia is dependent on caspase activation. J Am Soc Nephrol 2004; 15:3093.
  65. Bonegio R, Lieberthal W. Role of apoptosis in the pathogenesis of acute renal failure. Curr Opin Nephrol Hypertens 2002; 11:301.
  66. Sarhan M, Land WG, Tonnus W, et al. Origin and Consequences of Necroinflammation. Physiol Rev 2018; 98:727.
  67. Holler N, Zaru R, Micheau O, et al. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol 2000; 1:489.
  68. Degterev A, Hitomi J, Germscheid M, et al. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol 2008; 4:313.
  69. Zhang DW, Shao J, Lin J, et al. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 2009; 325:332.
  70. Sun L, Wang H, Wang Z, et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 2012; 148:213.
  71. Yang WS, Stockwell BR. Ferroptosis: Death by Lipid Peroxidation. Trends Cell Biol 2016; 26:165.
  72. Yang WS, Stockwell BR. Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem Biol 2008; 15:234.
  73. Kers J, Leemans JC, Linkermann A. An Overview of Pathways of Regulated Necrosis in Acute Kidney Injury. Semin Nephrol 2016; 36:139.
  74. Tonnus W, Gembardt F, Latk M, et al. The clinical relevance of necroinflammation-highlighting the importance of acute kidney injury and the adrenal glands. Cell Death Differ 2019; 26:68.
  75. Fink SL, Cookson BT. Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells. Infect Immun 2005; 73:1907.
  76. Morioka S, Maueröder C, Ravichandran KS. Living on the Edge: Efferocytosis at the Interface of Homeostasis and Pathology. Immunity 2019; 50:1149.
  77. Ichimura T, Asseldonk EJ, Humphreys BD, et al. Kidney injury molecule-1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells. J Clin Invest 2008; 118:1657.
  78. Li Y, Wen X, Spataro BC, et al. hepatocyte growth factor is a downstream effector that mediates the antifibrotic action of peroxisome proliferator-activated receptor-gamma agonists. J Am Soc Nephrol 2006; 17:54.
  79. Leemans JC, Stokman G, Claessen N, et al. Renal-associated TLR2 mediates ischemia/reperfusion injury in the kidney. J Clin Invest 2005; 115:2894.
  80. Li S, Gokden N, Okusa MD, et al. Anti-inflammatory effect of fibrate protects from cisplatin-induced ARF. Am J Physiol Renal Physiol 2005; 289:F469.
  81. Wolfs TG, Buurman WA, van Schadewijk A, et al. In vivo expression of Toll-like receptor 2 and 4 by renal epithelial cells: IFN-gamma and TNF-alpha mediated up-regulation during inflammation. J Immunol 2002; 168:1286.
  82. Tsuboi N, Yoshikai Y, Matsuo S, et al. Roles of toll-like receptors in C-C chemokine production by renal tubular epithelial cells. J Immunol 2002; 169:2026.
  83. Anders HJ, Banas B, Schlöndorff D. Signaling danger: toll-like receptors and their potential roles in kidney disease. J Am Soc Nephrol 2004; 15:854.
  84. El-Achkar TM, Huang X, Plotkin Z, et al. Sepsis induces changes in the expression and distribution of Toll-like receptor 4 in the rat kidney. Am J Physiol Renal Physiol 2006; 290:F1034.
  85. Wu H, Chen G, Wyburn KR, et al. TLR4 activation mediates kidney ischemia/reperfusion injury. J Clin Invest 2007; 117:2847.
  86. Cunningham PN, Wang Y, Guo R, et al. Role of Toll-like receptor 4 in endotoxin-induced acute renal failure. J Immunol 2004; 172:2629.
  87. Kim BS, Lim SW, Li C, et al. Ischemia-reperfusion injury activates innate immunity in rat kidneys. Transplantation 2005; 79:1370.
  88. Matzinger P. The danger model: a renewed sense of self. Science 2002; 296:301.
  89. Rosin DL, Okusa MD. Dangers within: DAMP responses to damage and cell death in kidney disease. J Am Soc Nephrol 2011; 22:416.
  90. Yasuda H, Leelahavanichkul A, Tsunoda S, et al. Chloroquine and inhibition of Toll-like receptor 9 protect from sepsis-induced acute kidney injury. Am J Physiol Renal Physiol 2008; 294:F1050.
  91. Kakoki M, McGarrah RW, Kim HS, Smithies O. Bradykinin B1 and B2 receptors both have protective roles in renal ischemia/reperfusion injury. Proc Natl Acad Sci U S A 2007; 104:7576.
  92. Andersson U, Wang H, Palmblad K, et al. High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J Exp Med 2000; 192:565.
  93. Thurman JM. Triggers of inflammation after renal ischemia/reperfusion. Clin Immunol 2007; 123:7.
  94. Wu H, Craft ML, Wang P, et al. IL-18 contributes to renal damage after ischemia-reperfusion. J Am Soc Nephrol 2008; 19:2331.
  95. He Z, Lu L, Altmann C, et al. Interleukin-18 binding protein transgenic mice are protected against ischemic acute kidney injury. Am J Physiol Renal Physiol 2008; 295:F1414.
  96. Oh DJ, Dursun B, He Z, et al. Fractalkine receptor (CX3CR1) inhibition is protective against ischemic acute renal failure in mice. Am J Physiol Renal Physiol 2008; 294:F264.
  97. OLIVER J, MacDOWELL M, TRACY A. The pathogenesis of acute renal failure associated with traumatic and toxic injury; renal ischemia, nephrotoxic damage and the ischemic episode. J Clin Invest 1951; 30:1307.
  98. Molina A, Ubeda M, Escribese MM, et al. Renal ischemia/reperfusion injury: functional tissue preservation by anti-activated {beta}1 integrin therapy. J Am Soc Nephrol 2005; 16:374.
  99. Wangsiripaisan A, Gengaro PE, Edelstein CL, Schrier RW. Role of polymeric Tamm-Horsfall protein in cast formation: oligosaccharide and tubular fluid ions. Kidney Int 2001; 59:932.
  100. Bonventre JV, Zuk A. Ischemic acute renal failure: an inflammatory disease? Kidney Int 2004; 66:480.
  101. Li L, Okusa MD. Blocking the immune response in ischemic acute kidney injury: the role of adenosine 2A agonists. Nat Clin Pract Nephrol 2006; 2:432.
  102. Li L, Huang L, Vergis AL, et al. IL-17 produced by neutrophils regulates IFN-gamma-mediated neutrophil migration in mouse kidney ischemia-reperfusion injury. J Clin Invest 2010; 120:331.
  103. Mathern DR, Heeger PS. Molecules Great and Small: The Complement System. Clin J Am Soc Nephrol 2015; 10:1636.
  104. Zhou W, Farrar CA, Abe K, et al. Predominant role for C5b-9 in renal ischemia/reperfusion injury. J Clin Invest 2000; 105:1363.
  105. Thurman JM, Lucia MS, Ljubanovic D, Holers VM. Acute tubular necrosis is characterized by activation of the alternative pathway of complement. Kidney Int 2005; 67:524.
  106. Reis ES, Mastellos DC, Hajishengallis G, Lambris JD. New insights into the immune functions of complement. Nat Rev Immunol 2019; 19:503.
  107. Freeley S, Kemper C, Le Friec G. The "ins and outs" of complement-driven immune responses. Immunol Rev 2016; 274:16.
  108. Molitoris BA, Marrs J. The role of cell adhesion molecules in ischemic acute renal failure. Am J Med 1999; 106:583.
  109. Salmela K, Wramner L, Ekberg H, et al. A randomized multicenter trial of the anti-ICAM-1 monoclonal antibody (enlimomab) for the prevention of acute rejection and delayed onset of graft function in cadaveric renal transplantation: a report of the European Anti-ICAM-1 Renal Transplant Study Group. Transplantation 1999; 67:729.
  110. Singbartl K, Green SA, Ley K. Blocking P-selectin protects from ischemia/reperfusion-induced acute renal failure. FASEB J 2000; 14:48.
  111. Singbartl K, Forlow SB, Ley K. Platelet, but not endothelial, P-selectin is critical for neutrophil-mediated acute postischemic renal failure. FASEB J 2001; 15:2337.
  112. Burne MJ, Rabb H. Pathophysiological contributions of fucosyltransferases in renal ischemia reperfusion injury. J Immunol 2002; 169:2648.
  113. Nemoto T, Burne MJ, Daniels F, et al. Small molecule selectin ligand inhibition improves outcome in ischemic acute renal failure. Kidney Int 2001; 60:2205.
  114. Dehnadi A, Benedict Cosimi A, Neal Smith R, et al. Prophylactic orthosteric inhibition of leukocyte integrin CD11b/CD18 prevents long-term fibrotic kidney failure in cynomolgus monkeys. Nat Commun 2017; 8:13899.
  115. Day YJ, Huang L, McDuffie MJ, et al. Renal protection from ischemia mediated by A2A adenosine receptors on bone marrow-derived cells. J Clin Invest 2003; 112:883.
  116. Lai LW, Yong KC, Igarashi S, Lien YH. A sphingosine-1-phosphate type 1 receptor agonist inhibits the early T-cell transient following renal ischemia-reperfusion injury. Kidney Int 2007; 71:1223.
  117. Caramelo C, Alvarez Arroyo MV. Polymorphonuclear neutrophils in acute renal failure: new insights. Nephrol Dial Transplant 1998; 13:2185.
  118. Ascon M, Ascon DB, Liu M, et al. Renal ischemia-reperfusion leads to long term infiltration of activated and effector-memory T lymphocytes. Kidney Int 2009; 75:526.
  119. Burne MJ, Daniels F, El Ghandour A, et al. Identification of the CD4(+) T cell as a major pathogenic factor in ischemic acute renal failure. J Clin Invest 2001; 108:1283.
  120. Day YJ, Huang L, Ye H, et al. Renal ischemia-reperfusion injury and adenosine 2A receptor-mediated tissue protection: the role of CD4+ T cells and IFN-gamma. J Immunol 2006; 176:3108.
  121. Li L, Huang L, Sung SS, et al. NKT cell activation mediates neutrophil IFN-gamma production and renal ischemia-reperfusion injury. J Immunol 2007; 178:5899.
  122. Huen SC, Cantley LG. Macrophage-mediated injury and repair after ischemic kidney injury. Pediatr Nephrol 2015; 30:199.
  123. Furuichi K, Wada T, Iwata Y, et al. CCR2 signaling contributes to ischemia-reperfusion injury in kidney. J Am Soc Nephrol 2003; 14:2503.
  124. Day YJ, Huang L, Ye H, et al. Renal ischemia-reperfusion injury and adenosine 2A receptor-mediated tissue protection: role of macrophages. Am J Physiol Renal Physiol 2005; 288:F722.
  125. Li L, Okusa MD. Macrophages, dendritic cells, and kidney ischemia-reperfusion injury. Semin Nephrol 2010; 30:268.
  126. Zheng X, Zhang X, Feng B, et al. Gene silencing of complement C5a receptor using siRNA for preventing ischemia/reperfusion injury. Am J Pathol 2008; 173:973.
  127. Kinsey GR, Sharma R, Huang L, et al. Regulatory T cells suppress innate immunity in kidney ischemia-reperfusion injury. J Am Soc Nephrol 2009; 20:1744.
  128. Martina MN, Noel S, Saxena A, et al. Double-Negative αβ T Cells Are Early Responders to AKI and Are Found in Human Kidney. J Am Soc Nephrol 2016; 27:1113.
  129. Menke J, Iwata Y, Rabacal WA, et al. CSF-1 signals directly to renal tubular epithelial cells to mediate repair in mice. J Clin Invest 2009; 119:2330.
  130. Jo SK, Rosner MH, Okusa MD. Pharmacologic treatment of acute kidney injury: why drugs haven't worked and what is on the horizon. Clin J Am Soc Nephrol 2007; 2:356.
  131. Sesso R, Roque A, Vicioso B, Stella S. Prognosis of ARF in hospitalized elderly patients. Am J Kidney Dis 2004; 44:410.
  132. Chawla LS, Abell L, Mazhari R, et al. Identifying critically ill patients at high risk for developing acute renal failure: a pilot study. Kidney Int 2005; 68:2274.
  133. Rose BD. Pathophysiology of Renal Disease, 2nd ed, McGraw-Hill, New York 1987. p.87.
  134. Myers BD, Miller DC, Mehigan JT, et al. Nature of the renal injury following total renal ischemia in man. J Clin Invest 1984; 73:329.
  135. Esson ML, Schrier RW. Diagnosis and treatment of acute tubular necrosis. Ann Intern Med 2002; 137:744.
  136. Parekh DJ, Weinberg JM, Ercole B, et al. Tolerance of the human kidney to isolated controlled ischemia. J Am Soc Nephrol 2013; 24:506.
  137. Gornick CC Jr, Kjellstrand CM. Acute renal failure complicating aortic aneurysm surgery. Nephron 1983; 35:145.
  138. DAWSON JL. POST-OPERATIVE RENAL FUNCTION IN OBSTRUCTIVE JAUNDICE: EFFECT OF A MANNITOL DIURESIS. Br Med J 1965; 1:82.
  139. Cahill CJ. Prevention of postoperative renal failure in patients with obstructive jaundice--the role of bile salts. Br J Surg 1983; 70:590.
  140. Nigwekar SU, Kandula P, Hix JK, Thakar CV. Off-pump coronary artery bypass surgery and acute kidney injury: a meta-analysis of randomized and observational studies. Am J Kidney Dis 2009; 54:413.
  141. Wardle EN. Acute renal failure and multiorgan failure. Nephron 1994; 66:380.
  142. Yegenaga I, Hoste E, Van Biesen W, et al. Clinical characteristics of patients developing ARF due to sepsis/systemic inflammatory response syndrome: results of a prospective study. Am J Kidney Dis 2004; 43:817.
  143. Bagshaw SM, Uchino S, Bellomo R, et al. Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes. Clin J Am Soc Nephrol 2007; 2:431.
  144. Badr KF, Kelley VE, Rennke HG, Brenner BM. Roles for thromboxane A2 and leukotrienes in endotoxin-induced acute renal failure. Kidney Int 1986; 30:474.
  145. Linas SL, Whittenburg D, Repine JE. Role of neutrophil derived oxidants and elastase in lipopolysaccharide-mediated renal injury. Kidney Int 1991; 39:618.
  146. Khan RZ, Badr KF. Endotoxin and renal function: perspectives to the understanding of septic acute renal failure and toxic shock. Nephrol Dial Transplant 1999; 14:814.
  147. Boffa JJ, Just A, Coffman TM, Arendshorst WJ. Thromboxane receptor mediates renal vasoconstriction and contributes to acute renal failure in endotoxemic mice. J Am Soc Nephrol 2004; 15:2358.
  148. Lameire N, Van Biesen W, Vanholder R. Acute renal failure. Lancet 2005; 365:417.
  149. Boffa JJ, Arendshorst WJ. Maintenance of renal vascular reactivity contributes to acute renal failure during endotoxemic shock. J Am Soc Nephrol 2005; 16:117.
  150. Linas SL, Whittenburg D, Parsons PE, Repine JE. Mild renal ischemia activates primed neutrophils to cause acute renal failure. Kidney Int 1992; 42:610.
  151. Shultz PJ, Raij L. Endogenously synthesized nitric oxide prevents endotoxin-induced glomerular thrombosis. J Clin Invest 1992; 90:1718.
  152. Keeton M, Eguchi Y, Sawdey M, et al. Cellular localization of type 1 plasminogen activator inhibitor messenger RNA and protein in murine renal tissue. Am J Pathol 1993; 142:59.
  153. Tran DD, Oe PL, de Fijter CW, et al. Acute renal failure in patients with acute pancreatitis: prevalence, risk factors, and outcome. Nephrol Dial Transplant 1993; 8:1079.
  154. Zager RA. Gentamicin effects on renal ischemia/reperfusion injury. Circ Res 1992; 70:20.
  155. Abuelo JG. Normotensive ischemic acute renal failure. N Engl J Med 2007; 357:797.
Topic 7228 Version 22.0

References