Version May 2024
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 kidney 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.
ATN is one of the most common etiologies of acute kidney injury (AKI). It is characterized by a rising plasma creatinine concentration, 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.
Biomarkers indicative of tubular injury such as kidney injury molecule 1 (KIM-1), tissue inhibitor of metalloproteinase 2 (TIMP-2), insulin-like growth factor binding protein 7 (IGFBP-7), or neutrophil gelatinase-associated lipocalin (NGAL) may be detected in serum or urine.
The pathogenesis and etiology of ischemic ATN will be reviewed here [1-3]. 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 "Manifestations of and risk factors for aminoglycoside nephrotoxicity".)
●(See "Clinical features and diagnosis of heme pigment-induced acute kidney injury".)
PATHOLOGY AND PATHOGENESIS — The process underlying ischemic ATN occurs in multiple phases, including prerenal (impairment in kidney perfusion), initiation of injury, extension of injury, maintenance, and repair [4]. 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 kidney function (picture 1A-B) [5,6].
However, the decline in kidney 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) and concomitant rise in serum creatinine [5,7]:
●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 [8,9].
●Back leak of filtered tubular fluid into the vascular space may occur across the damaged tubule epithelium [10,11].
●Apoptosis occurs in both proximal and distal tubule cells [12].
●Peritubular capillaries in the outer medulla may be congested with leukocyte accumulation that impairs local renal blood flow [13,14].
●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 [1,15].
Endothelial and vascular components of injury — The endothelium of the microcirculation of the kidney contributes to the pathogenesis of ATN [16,17]. In human acute kidney injury (AKI) following kidney 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 [18].
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 [19].
Hypotension likely causes global hemodynamic derangements, resulting in a reduction in renal blood flow in sepsis-induced AKI [20]. However, some experimental [21] and human studies [22] suggest an increase in renal blood flow, possibly related to changes in efferent arteriolar vasodilation [23]. The kidney also has arteriovenous shunt pathways that, when enhanced during sepsis, lead to further medullary hypoxia [24,25]. In addition, microcirculatory dysfunction reflects intrinsic events, leading to changes in microvascular blood flow, impairment of tissue oxygenation, local microenvironmental redox stress, and ATN, especially in sepsis [26-28]. (See 'Sepsis' below.)
Endothelial cell injury causes disruption in microvascular blood flow, which is important in the initiation and extension phase of ATN [4,29]. A reduction in microvascular blood flow contributes to decreased kidney perfusion, renal hypoxia, epithelial cell ischemia, and a resultant decrease in GFR [30]. 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 [31,32]. These adhesion molecules facilitate leukocyte-endothelial cell interactions such as macrophage recruitment and elaboration of chemokines [33]. 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, which exposes adhesion molecules facilitating leukocyte adhesion and causes disruption of the actin cytoskeleton [34-36]. 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 [4,11,37]. Altered endothelial cell-cell contacts resulting in increased intercellular gap formation likely enhance microvascular permeability following ischemic injury [38].
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 [39,40].
Endothelial health depends on its interaction with mesenchymal progenitor cells (pericytes) in the interstitial compartment [41,42]. Following ischemia-induced pericyte ablation, endothelial damage enhances focal hypoxia and tubular injury [43,44]. 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 [45].
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 [46].
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 [47,48].
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 kidney injury in an ischemic kidney injury model [49].
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 [50]. 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 [51].
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 [7,52]. 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 [53].
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) [54]. 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 [55,56]. 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 [56].
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 [57-62]:
●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 [57,58]. 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 [57]. 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 [63]. 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 [64,65].
●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 kidney 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 kidney histology in mice following ischemic injury [60]. In one study, ferroportin, an iron export protein, contributed to ischemia-reperfusion injury [66]. 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 [66].
●Local control of adenosine metabolism contributes to ischemia-perfusion injury. Proximal tubules abundantly express 5'-ectonucleotidase (CD73), which converts adenosine monophosphate (AMP) into adenosine, an antiinflammatory molecule, by binding to A2A adenosine receptors [67]. Proximal tubules deficient of CD73 render them exquisitely sensitive to ischemia-reperfusion injury [67]. Additionally, pannexin-1 channels that release ATP are activated in ischemia-reperfusion and thought to contribute to injury [68]. Pharmacologic inhibition of pannexin-1 channels or tissue-specific deletion of proximal tubule or endothelial pannexin-1 channels leads to enhanced injury [68].
●Cell death following ATN occurs through necrosis or regulated cell death pathways (apoptosis, necroptosis, and pyroptosis) [69].
•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 [70].
•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 [71,72].
•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 [73]. The signaling pathways for necroptosis involve receptor-interacting serine/threonine-protein kinase 1 (RIPK1) [74,75], receptor-interacting serine/threonine-protein kinase 3 (RIPK3) [76], and its substrate mixed-lineage kinase domain-like protein (MLKL) [77].
•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) [78-80].
•Pyroptosis – This regulated form of cell death is highly inflammatory and requires caspase 1, 4/5 for activation [81,82]. 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) [81]. GSDMD-NT forms a membrane pore and induces cell swelling and cell lysis followed by activation of the innate immunity.
●Normally, cells turn over every day due to apoptosis, and their removal by phagocytes is referred to as efferocytosis [83]. This process of efferocytosis is antiinflammatory. Various steps are involved, and a number of different molecules are associated with each step [83]. 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 [84].
●Cellular receptors have been implicated in ischemia-reperfusion injury and recovery. Examples of such receptors include [61,85,86]:
•Peroxisome proliferator-activated receptor (PPAR) – PPAR beta is a ligand-activated transcription factor that appears to protect against kidney 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 kidney injury [61]. PPAR gamma agonists, such as fibrates, reduce inflammation and injury following cisplatin administration [87]. PPAR gamma may have an antifibrotic action, possibly mediated by hepatocyte growth factor [85].
•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 [88-91]. 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 kidney function following ischemic injury [86,92]. 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 kidney dysfunction compared with mice that express TLR2 [86]. The expression of TLR4 on both immune cells and kidney parenchymal cells contributes to AKI [92,93]. 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 [94-96].
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 kidney damage in a model of polymicrobial sepsis [97].
•Bradykinin receptors – Kinins, a set of hormones produced in the kidney, are vasodilators that may minimize kidney 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 [98].
●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 [96]. These factors include: high mobility group 1 protein [99], heat shock proteins [94], and cytokines (IL-1, IL-6, TNF-alfa, IL-18) [100-102]. The chemokine receptor, CX3CR1, and its ligand, fractalkine, may play an early role in AKI [33,103].
In addition to ischemia, other factors may promote kidney 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 kidney function 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 [104]. 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 [105]. 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 [106].
Immunologic factors — The different arms of the immune system appear to contribute to the pathogenesis of ischemic kidney injury [107,108]. Ischemic kidney injury is characterized by the appearance of neutrophils, natural killer T cells and macrophages, both components of the innate immune system [33,95,108].
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" [95,96]. Endogenous alarmins and exogenous PAMPs can be considered subgroups of DAMPs. Once activated, dendritic cells activate natural killer T cells [109]; 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 [108].
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 [110]. 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 kidney injury [111,112]. 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 [64].
The role of the alternative complement pathway is also suggested by the demonstration of C3 deposition along the tubule basement membrane [106]. 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 [113,114]. 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 [115]. The administration of anti-ICAM-1 antibodies preserves kidney 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 kidney injury [31]. However, in human trials, the administration of anti-ICAM-1 monoclonal antibody did not prevent ATN in deceased-donor kidney transplant recipients following ischemia [116].
Studies have also suggested a role for other adhesion molecules, such as E- and P-selectins [117-120].
In an animal model of a monoclonal antibody to CD11b/CD18, integrins reduced ischemia-reperfusion injury [121].
Immune cells — Increasing evidence suggests that inflammatory cells may play a role in ischemic kidney failure [13,108,122,123]:
●ICAM-1 may act in part by promoting neutrophil-endothelial cell interactions [124].
●T cells contribute to ischemia-reperfusion injury [125]. Mice deficient in effector CD4+ T cells are protected from ischemic injury [126,127].
●The production of interferon gamma from natural killer T cells (a subpopulation of CD4+ cells) contributes to the pathogenesis of acute kidney ischemia-reperfusion injury [128].
●Mononuclear phagocytes are important in activation of the innate immune response to ischemia-reperfusion injury [129]. 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 [33,130]. Mice depleted of macrophages are protected from ischemic injury [131].
●Dendritic cells [132] and natural killer cells [133] contribute to ischemia-reperfusion injury.
●Regulatory T cells, in contrast, attenuate ischemia-reperfusion injury [134].
●CD4(-)CD8(-) T cells protect against AKI in an animal model [135].
Inflammatory mediators — A wide variety of proinflammatory molecules are released in response to ischemic injury [107,109,136]. 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 kidney injury [137].
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) [138,139].
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 [140-142]. 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 [143]. This study prospectively analyzed the kidney response to clamp ischemia in patients undergoing partial nephrectomy, with the majority of patients experiencing >30 minutes of ischemia [143]. 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 kidney 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 kidney ischemia if supra-aortic clamping is required [141,144].
●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 [145]. This effect may be related to the absorption of endotoxin from the gut [146]. 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 [146].
●Cardiac surgery, particularly coronary artery bypass graft (CABG) surgery with valve surgery. Important underlying risk factors include underlying kidney function impairment 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 [147]. 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".)
Intraoperative and postoperative fluid management is discussed separately. (See "Intraoperative fluid management" and "Overview of postoperative fluid therapy in adults".)
Sepsis — Overt or intermittent endotoxemia may play an important role in AKI that is observed as part of the multiple organ dysfunction syndrome [148]. The likelihood of renal tubule injury with sepsis is increased if there are concurrent adverse clinical characteristics, including older age, underlying kidney function impairment or liver insufficiency, and additional factors [149]. Among the critically ill, sepsis is the most common cause of AKI [150]. (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 [20,151-156]. It has been shown, for example, that mild kidney ischemia, which alone is not sufficient to cause kidney injury, can lead to AKI in the presence of primed neutrophils, as might occur with endotoxemia [157]. The release of elastase and oxidants from neutrophils may also contribute to tubule damage in this setting [152,157].
Hypotension is thought to cause a reduction in renal blood flow in sepsis-induced AKI [20]. This concept has been challenged by experimental [21] and human studies [22] that suggest an increase in renal blood flow, possibly related to changes in efferent arteriolar vasodilation [23]. Changes in microvascular blood flow may also contribute to decreased tissue oxygenation in ATN [26,30].
In addition to ATN, severe sepsis rarely leads to irreversible kidney 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 [158], and by increasing the synthesis of plasminogen activator inhibitor type 1, leading to a reduction in fibrinolytic activity [159].
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 [160]. In addition, even moderate degrees of volume depletion can increase the risk of kidney 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 [161]. (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 [162]. 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 kidney 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 kidney 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.)
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