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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Epidemiology</span><p id="par0005" class="elsevierStylePara elsevierViewall">The incidence of acute renal failure &#40;ARF&#41; in critical patients is variable&#44; depending on the definition used and the population studied&#44; but ranges from 30 to 50&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Sepsis and its most severe presentation&#44; septic shock&#44; are the main causes of ARF in the Intensive Care Unit &#40;ICU&#41;&#44; accounting for up to 50&#37; of all cases&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Mortality due to sepsis remains high&#44; particularly when associated to organ dysfunction such as ARF &#40;with mortality rates of 20&#8211;35&#37;&#41; or in the presence of hemodynamic alterations &#40;mean mortality 60&#37;&#41;&#46; The development of ARF during sepsis is an independent risk factor associated to increased patient mortality<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&#59; in this context&#44; the FRAMI study&#44; involving 43 Spanish ICUs&#44; showed the appearance of ARF in critical patients to be independently associated to increased mortality&#44; with an odds ratio &#40;OR&#41; of 2&#46;51&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Definition</span><p id="par0010" class="elsevierStylePara elsevierViewall">Until recently there was no clear consensus-based definition of ARF in sepsis&#46; The ADQI &#40;Acute Dialysis Quality Initiative&#41; group has proposed a consensus-based diagnostic classification that has been favorably viewed by clinicians&#44; and has made it possible to standardize research work in this field&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The mentioned classification is known as the RIFLE &#40;in reference to Risk&#44; Injury&#44; Failure&#44; Loss&#44; and End-stage renal failure&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Patients are classified according to the loss of glomerular filtration &#40;GF&#41; &#40;with respect to the baseline reference of each patient&#41; and&#47;or urinary flow &#40;UF&#41; into 5 categories &#40;selecting the criterion yielding the poorest classification&#41;&#58; risk &#40;R&#41;&#44; injury &#40;I&#41;&#44; failure &#40;F&#41;&#44; loss &#40;L&#41; or end-stage renal failure &#40;E&#41;&#46; ARF in sepsis is diagnosed in all patients meeting the criteria of sepsis&#44;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> meeting some of the RIFLE criteria&#44; and lacking other conditions or causes capable of accounting for ARF&#44; such as the use of contrast media or nephrotoxic drugs&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">The RIFLE classification has been validated by a number of studies&#46; In a study involving 20&#44;126 patients admitted to a university hospital&#44; 10&#37;&#44; 5&#37; and 3&#46;5&#37; of the subjects reached the maximum R&#44; I and F scores in the RIFLE classification&#44; respectively&#46; Mortality among the patients increased linearly with the severity of the RIFLE score&#44; making it possible to independently predict mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Another study involving 41&#44;972 patients admitted to the ICU reported an ARF incidence of 35&#46;8&#37;&#46; The mortality in the group without ARF was 8&#46;4&#37;&#44; versus 20&#46;9&#37;&#44; 45&#46;6&#37; and 56&#46;8&#37; in those with class R&#44; I and F acute renal failure&#44; respectively&#46; The presence of ARF of any category was found to be an independent mortality risk factor&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">With the purpose of improving sensitivity&#44; the RIFLE criteria were modified by the Acute Kidney Injury Network &#40;AKIN&#41; group&#44; which defined ARF as an increase in serum creatinine of &#8805;0&#46;3<span class="elsevierStyleHsp" style=""></span>mg&#47;dl or a percentage increase of &#8805;1&#46;5 times from baseline as recorded in the previous 48<span class="elsevierStyleHsp" style=""></span>h &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Urine output as a criterion of ARF was maintained&#44; though the glomerular filtration rate and RIFLE L and E scores were excluded&#46; AKIN&#44; in contrast to RIFLE&#44; requires two creatinine measurements spaced 48<span class="elsevierStyleHsp" style=""></span>h apart in order to establish a diagnosis of ARF&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">Some authors have compared RIFLE versus AKIN in patients subjected to heart surgery<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> or admitted to the ICU&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> In general&#44; mortality is comparable with both methods and tends to increase with the severity of ARF&#8211;thus confirming that acute renal damage is correlated to patient mortality&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Pathogenesis</span><p id="par0030" class="elsevierStylePara elsevierViewall">The study of the mechanisms involved in the development of ARF in sepsis is limited by the few histological studies in humans&#44; due to the risk involved in the process and its frequently irreversible nature&#44; and by the impossibility of measuring renal microcirculatory flow values&#46;</p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Renal blood flow in sepsis</span><p id="par0035" class="elsevierStylePara elsevierViewall">The classical position in septic patients is that the principal mechanism underlying ARF is ischemia or hypoperfusion&#8211;suggesting that the decrease in renal blood flow &#40;RBF&#41; and renal vasoconstriction are the characteristic events of sepsis&#46; Furthermore&#44; the main interventions for the management of ARF in sepsis have been volume replacement in already resuscitated patients&#44;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> and the use of renal vasodilators such as dopamine and fenoldapam&#8211;though there is little evidence of their usefulness&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">In effect&#44; the physiopathological processes inherent to sepsis&#44; such as absolute and relative hypovolemia due to vasoplegia &#40;pathological vasodilatation&#41; and capillary leakage&#44; myocardial dysfunction and impaired oxygenation&#44; among other aspects&#44; suggest that decreased oxygen transportation may be a relevant mechanism in ARF&#8211;mainly in the early stages or in sepsis accompanied by cardiogenic shock&#46; However&#44; most studies suggesting an ischemic etiology for ARF in sepsis are derived from animal models of ischemia and reperfusion&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;13</span></a> These models are not consistent with the classical physiopathology of resuscitated sepsis&#44; characterized by high cardiac output &#40;CO&#41; and low peripheral resistance&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The study of RBF in human sepsis is complex&#44; due to the difficulty of measuring it on a continuous basis&#46; Studies in septic animals have yielded contradictory results in relation to RBF&#46; Some studies indicate that during the early phases of sepsis&#44; or after a bolus dose of endotoxin&#44; RBF decreases&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;15</span></a> These models of endotoxemia induce an initial proinflammatory state that is not found in true sepsis&#44; where the increase in inflammatory mediators is gradual rather than explosive as in the mentioned models&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> Other more recent studies underscore the fact that under normal conditions&#44; RBF is several times greater than that required by the actual renal metabolic needs &#8211; since RBF is destined more to glomerular filtration than to renal oxygen transport&#46; These studies show that in resuscitated sepsis&#44; i&#46;e&#46;&#44; where a normal or high cardiac output and systemic vasodilatation are characteristically observed&#44; RBF is normal or even increased&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;18</span></a> A study involving a porcine model of hyperdynamic sepsis found RBF to be generally increased&#44; and particularly increased towards the renal medulla&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> Another study in 8 septic patients in which RBF was estimated invasively via thermodilution showed ARF to develop in the absence of alterations in RBF&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> A systematic review of 160 experimental studies of sepsis and ARF found the principal determinant factor of the normality of RBF in sepsis to be cardiac output &#40;CO&#41;&#46; A high or normal CO is associated to preserved RBF&#44; while a low CO&#8211;i&#46;e&#46;&#44; non-resuscitated sepsis or sepsis associated to cardiogenic shock&#8211;is associated to low RBF&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Thus&#44; even though renal hypoperfusion may play a role in low-flow states such as non-resuscitated sepsis&#44; recent studies show that once the hyperdynamic state characteristic of sepsis has been established&#44; hypoperfusion or renal ischemia are not relevant mechanisms&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Renal histology in sepsis</span><p id="par0055" class="elsevierStylePara elsevierViewall">The renal histological changes observed in sepsis are few and nonspecific&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> A systematic review found only 22&#37; of 184 patients to show evidence of acute tubular necrosis &#40;ATN&#41;&#44; and concluded that the existing experimental and human clinical evidence does not support the idea of ATN as the manifestation or mechanism characteristic of septic ARF&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> The histology of septic ARF is heterogeneous&#8211;relevant findings being leukocyte infiltration &#40;predominantly mononuclear cells&#41;&#44; some degree of tubular cell vacuolization&#44; loss of the brush border&#44; and apoptosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#44;23</span></a> Other described alterations are dysfunction of the intercellular tight junctions&#44; favoring tubular fluid reflux through the epithelium&#44;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> and dysfunction of the basal membrane&#8211;with the consequent detachment of cells into the tubular lumen&#46; This in turn is associated to the appearance of tubular cells or cylinders in the urine sediment&#46; These cellular cylinders produce micro-obstruction of tubular urinary flow &#40;UF&#41;&#44; with cessation of GF in the affected nephron unit&#46; The absence of necrosis in 70&#37; of the patients is compatible with the existing evidence that other mechanisms different from ischemia contribute to the development of ARF during sepsis&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;10</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Apoptosis&#44; or programmed cell death&#44; which in contrast to necrosis does not induce local inflammation&#44;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> has been described as one of the physiopathological phenomena present during ARF in sepsis&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21&#44;22&#44;26</span></a> Apoptosis is observed in 2&#8211;3&#37; of the tubular cells during sepsis&#44; and is more frequent in the distal tubules&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> Tumor necrosis factor-alpha &#40;TNF-&#945;&#41; plays an important role in the induction of renal tubular apoptosis&#59; however&#44; the relevance of apoptosis as a mechanism of ARF <span class="elsevierStyleItalic">in vivo</span> remains the subject of study&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Glomerular filtration in sepsis</span><p id="par0065" class="elsevierStylePara elsevierViewall">Since in most cases of sepsis cardiac output is either normal or elevated&#44; RBF is seen to be normal&#46; A recent study in septic sheep has shown that&#44; in effect&#44; RBF is elevated in association to hyperdynamic CO&#44; though renal vascular resistance &#40;RVR&#41; is decreased&#44; with a secondary reduction in glomerular filtration rate and an associated rise in plasma creatinine concentration&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> The drop in RVR may be explained by an increase in nitric oxide &#40;NO&#41; release&#46; The proinflammatory cascade induces expression of inducible nitric oxide synthetase &#40;iNOS&#41; in the renal medulla&#44;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> in the glomerular mesangial cells and in the endothelial cells of the renal blood vessels<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> &#8211; resulting in intense and prolonged NO release&#46; On the other hand&#44; the acidosis inherent to septic shock&#44; and the decrease in ATP levels in the vascular smooth muscle cells&#44; favor cellular hyperpolarization as a result of potassium release from the cell through ATP-dependent membrane potassium channels&#8211;this in turn contributing to renal vasodilatation through resistance to catecholamines and angiotensin II&#46; Likewise&#44; the recovery of renal function was associated to a recovery of RVR associated to a decrease in RBF&#46; This study suggests that the loss of GF pressure regulation participates as a mechanism of ARF in sepsis&#44; even in the presence of increased RBF&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Glomerular filtration pressure depends on the diameter of the afferent and efferent arterioles&#46; Constriction of the afferent arteriole and&#47;or vasodilatation of the efferent arteriole can give rise to reductions in GF and in UF&#46; Afferent vasodilatation participates as a mechanism of ARF in sepsis&#44; though the efferent arteriole plays an even greater role &#40;hyperemic ARF&#41;&#8211;generating a drop in GF and in UF&#46; However&#44; the lack of direct measurements of RBF in human sepsis limits the drawing of conclusions&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Intrarenal hemodynamics during sepsis</span><p id="par0075" class="elsevierStylePara elsevierViewall">Despite preserved RBF in resuscitated sepsis&#44; the intrarenal distribution of the blood flow may be altered&#44; with a predominance of cortical flow over medullary blood flow&#8211;a situation known as &#8220;corticomedullary redistribution&#8221;&#44; and which is responsible for medullary hypoxia&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> A recent study in animals established differentiated measurements of critical and medullary blood flow using intrarenal laser Doppler flowmetry during sepsis&#46; Both flows remained stable&#44; and the use of noradrenalin&#8211;an adrenergic vasoconstrictor&#8211;significantly increased the flow in both regions&#46; This suggests that the compensation mechanisms are active during hyperdynamic sepsis&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> There probably are modifications in intrarenal blood flow during sepsis&#44; but the evidence suggests that the compensatory mechanisms are active&#44; and that such modifications do not represent a predominant mechanism&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Inflammation and oxidative stress</span><p id="par0080" class="elsevierStylePara elsevierViewall">Other mechanisms&#44; apart from the hemodynamic mechanisms&#44; also participate in the genesis of ARF in sepsis&#46; The inflammatory response inherent to sepsis has been examined as a direct mechanism of ARF&#46; Different mediators implicated in sepsis&#44; together with the neuroendocrine response&#44; participate in the pathogenesis of septic ARF&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">31&#44;32</span></a> The kidneys are particularly sensitive to mediator-induced damage&#46; Both the mesangial cells and the tubular cells are able to express proinflammatory cytokines such as interleukin &#40;IL&#41;-1&#44; IL-6 and TNF-&#945;&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> Both IL-1 and TNF-&#945; have been found to act as inducers of ARF in sepsis&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> Mice with TNF-&#945; receptor deficiency are resistant to the development of endotoxin-mediated ARF&#44; and exhibit less tubular apoptosis and lesser mononuclear cell infiltration&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> However&#44; the use of anti-TNF-&#945; antibodies during sepsis has not been able to improve survival or prevent the development of ARF&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">The mechanisms proposed to explain how IL-1 and TNF-&#945; produce ARF during sepsis include the induction of increased cytokine release&#44; amplifying the inflammatory cascade&#59; favoring of tissue factor expression&#44; which promotes local thrombosis<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a>&#59; the induction of tubular cell apoptosis<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a>&#59; and principally the elevation of regional oxidative stress through an increased production of reactive oxygen species &#40;ROS&#41;&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Oxidative stress in sepsis is related to an increase in the production of ROS&#44; and to the concomitant reduction of antioxidant levels through either consumption or diminished intake&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">39&#8211;41</span></a> The proinflammatory cascade induces the expression of iNOS in the renal medulla&#44;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> in the glomerular mesangial cells&#44; and in the renal vascular endothelial cells<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a>&#8211;with the consequent rise in NO levels during sepsis&#46; NO has both beneficial and deleterious effects during sepsis&#46; Baseline levels of NO are necessary to maintain RBF and intrarenal flow during sepsis&#44; particularly at afferent arteriolar level&#44;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> and to favor cellular mitochondrial biogenesis &#40;re-synthesis&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">42&#44;43</span></a> However&#44; NO is also a free radical&#44; and when produced in excess is able to inhibit the oxidative phosphorylation chain and reduce oxygen consumption&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> NO&#44; moreover&#44; can interact with other ROS to form more toxic reactive species such as peroxynitrite&#44;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">45&#8211;47</span></a> which can cause damage to DNA&#44; proteins and membranes&#8211;resulting in an increase in mitochondrial permeability&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">48&#44;49</span></a> Increased mitochondrial permeability is associated to a decrease in electrochemical gradient and in ATP synthesis&#44; as well as to the activation of apoptosis pathways&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a> The intensity of oxidative damage is correlated to the intensity of mitochondrial damage and to survival&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">48&#44;51</span></a> A number of studies&#44; including one by our own group&#44; have shown that there is not only an increase in ROS during sepsis but also a decrease in antioxidant levels&#44; related to the intensity of the septic process&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">52&#8211;55</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Coagulation and microcirculation</span><p id="par0095" class="elsevierStylePara elsevierViewall">Sepsis is characterized by a prothrombotic and antifibrinolytic state&#44;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a> and the associated microcirculatory dysfunction has been described as a relevant mechanism in the development of multiorgan failure in sepsis&#44; with an association to mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a> Endothelial dysfunction is induced by the inflammatory cascade&#44; and is characterized by an increase in the expression of tissue factor&#8211;which in turn activates the coagulation cascade&#46; At renal level&#44; fibrin deposits have been described in the glomerular capillaries during sepsis&#44; though a recent study has shown that renal arterial&#47;arteriolar thrombosis is not frequent in sepsis&#44; and is not associated to the presence of disseminated intravascular coagulation&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Mitochondrial dysfunction</span><p id="par0100" class="elsevierStylePara elsevierViewall">Mitochondrial dysfunction is described as the incapacity of the cell to maintain its metabolic functions despite adequate oxygen transport&#44; due to the impossibility of using the available oxygen for ATP synthesis&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a> Briefly&#44; mitochondria must couple the transport of energy-rich substrates to the generation of a transmembrane electrochemical gradient allowing the synthesis of ATP&#46; In order for this process to be efficient&#44; there must be adequate function of the oxidative phosphorylation complexes &#40;complexes I&#8211;IV plus ATP synthase&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">59&#44;60</span></a> structural integrity of the mitochondrial membrane &#40;fundamentally the internal membrane&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">61&#44;62</span></a> a sufficient substrate supply&#44;<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">63&#44;64</span></a> and a sufficient number of mitochondria&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">65&#44;66</span></a> Few studies have evaluated cell function in septic ARF&#46; Based on the continuous perfusion of lipopolysaccharide &#40;LPS&#41;&#44; one study observed no alterations in renal mitochondrial function&#44;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a> though a more recent study in pigs with sepsis of intraabdominal origin reported an alteration in renal mitochondrial function&#44; associated to an increase in oxidative stress marker levels&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">68</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Distant damage caused by mechanical ventilation</span><p id="par0105" class="elsevierStylePara elsevierViewall">The use of small tidal volumes &#40;TV&#41; &#40;6<span class="elsevierStyleHsp" style=""></span>ml&#47;kg ideal weight&#41; in mechanical ventilation &#40;MV&#41; during acute respiratory distress syndrome &#40;ARDS&#41; reduces mortality among these patients&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">69</span></a> One of the mechanisms proposed for explaining mortality associated to ARDS and MV is the release of systemic mediators generated at lung level in situations of high TV&#46; An interesting study showed that animals ventilated with high TV values show greater tubular apoptosis and associated renal dysfunction&#46; In fact&#44; on cultivating renal cells <span class="elsevierStyleItalic">in vitro</span> with plasma from animals subjected to high TV&#44; the cells likewise showed a higher apoptosis rate&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">70</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Biomarkers in sepsis and ARF</span><p id="par0110" class="elsevierStylePara elsevierViewall">The use of creatinine and UF for the diagnosis and prognosis of ARF during sepsis &#40;RIFLE and AKIN criteria&#41; poses several limitations&#46; The rise in plasma creatinine is a late phenomenon&#44; and in order for such an elevation to occur&#44; it must be associated with an important decrease in GF capacity&#46; The RIFLE classification does not clearly define the baseline value of patient renal function&#44; in contrast to the AKIN classification&#44; which requires the obtainment of two creatinine measurements spaced 48<span class="elsevierStyleHsp" style=""></span>h apart&#46; On the other hand&#44; UF as a diagnostic criterion of ARF is conditioned by patient volemia and the use of diuretics&#46; Most studies included in the RIFLE and AKIN analyses are retrospective and did not measure UF every 6 or 12<span class="elsevierStyleHsp" style=""></span>h&#59; accordingly&#44; only 12&#37; of them made use of both criteria &#40;increase in creatinine and UF&#41; for diagnosing ARF&#46; The studies that used both criteria reported lesser mortality than those which used only creatinine as diagnostic criterion&#8211;this suggesting that the decrease in UF is more benign and&#47;or reversible than the increase in creatinine&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">The need to establish markers allowing an earlier and more sensitive diagnosis of ARF than creatinine elevation or a decrease in UF has led to the search for biomarkers of renal origin reflecting cellular damage in early stages of the disease&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Neutrophil gelatinase-associated lipocalin &#40;NGAL&#41; is a 24<span class="elsevierStyleHsp" style=""></span>kDa protein normally expressed in low concentrations in different human tissues &#40;kidneys&#44; lungs&#44; stomach and colon&#41;&#44; and is found in the secondary granules of neutrophils&#46; NGAL is released when these cells are activated&#44; particularly in response to bacterial infections&#46; NGAL transcription and release is intensely induced in the presence of epithelial damage&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">In ARF&#44; NGAL is promptly released from the proximal renal tubules following ischemic<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">71</span></a> or toxic damage&#44;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">72</span></a> and its levels can be measured in plasma and urine&#46; A recent review<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">73</span></a> involving over 4000 patients at risk of ARF due to sepsis&#44; heart surgery&#44; exposure to contrast media or transplantation&#44; found NGAL to be significantly elevated in those individuals who develop ARF&#44; and that this elevation significantly precedes the clinical diagnosis of ARF&#46; Elevations in plasma and urine levels of NGAL have also been described in septic patients&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">74</span></a> The plasma and urine concentrations of NGAL are correlated to the degree of renal dysfunction established by the RIFLE or AKIN&#46;<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">75&#44;76</span></a> However&#44; a recent study suggests that urine NGAL elevation is a better predictor of ARF in sepsis than plasma NGAL elevation&#44; which is less specific&#8211;possibly because of the activation of circulating neutrophils&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">74</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Interleukin-18 is a proinflammatory cytokine transcribed and released in the proximal renal tubules&#44; and which can easily be detected in urine following ischemic damage&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">77</span></a> It does not appear to increase under conditions of infection&#44; prerenal ARF or chronic renal failure&#46; This marker was initially described in heart surgery patients in which IL-18 was seen to rise early before the clinical diagnosis of ARF&#44; with an area under the curve &#40;AUC-ROC&#41; of 0&#46;75&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">78</span></a> IL-18 has also been described as a good predictor of ARF in critical patients in general&#44; and in septic patients&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">79</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">KIM-1 &#40;kidney injury molecule-1&#41; is a transmembrane glycoprotein that shows a marked increase in expression on the part of the cell of the proximal renal tubules in response to ischemic or toxic stimuli&#46; Its concentrations can be detected in urine and are seen to increase in patients with ARF&#46; This marker might be useful for predicting the need for dialysis or in-hospital mortality in patients with ARF of different origins and severity&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">80</span></a></p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Treatment</span><p id="par0140" class="elsevierStylePara elsevierViewall">The limitations in establishing a physiopathological model of ARF have delayed the development of successful drug treatments&#44; and at present much of the treatment of ARF in sepsis focuses on the support of kidney function&#46; The management of ARF in septic patients is complicated&#44; due to the existing hemodynamic instability and associated multiorgan dysfunction&#46; As a result&#44; in recent years many&#44; both continuous and intermittent renal replacement therapy &#40;RRT&#41;&#44; techniques have been developed&#8211;though a lack of evidence in favor of one technique over the rest has largely precluded their clinical applicability&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">81&#8211;85</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">The different techniques developed are fundamentally based on two principles&#58; diffusion and convection&#44; or a combination of both&#46; While diffusion techniques &#40;hemodialysis&#41; are preferentially used as non-antiinflammatory replacement therapy&#44; and in hemodynamically stable patients&#44; the convection techniques &#40;hemofiltration&#41; allow greater hemodynamic stability and the achievement of negative water balances&#44; with lesser systemic repercussion&#46;<a class="elsevierStyleCrossRefs" href="#bib0430"><span class="elsevierStyleSup">86&#8211;88</span></a> However&#44; more extended hemodialysis allows the replacement of renal function and the achievement of negative balances even in unstable patients&#46; On the other hand&#44; hemofiltration techniques not only allow renal support but also the possibility of modulating the inflammatory response through the removal of inflammatory compounds &#40;cytokines&#41; of greater molecular weight&#46;<a class="elsevierStyleCrossRefs" href="#bib0445"><span class="elsevierStyleSup">89&#44;90</span></a> Hemofiltration with higher ultrafiltrate doses&#44; referred to as high-volume hemofiltration &#40;ultrafiltration rate &#62;35<span class="elsevierStyleHsp" style=""></span>ml&#47;kg&#47;h&#41;&#44; is mainly associated with a reduction in the need for vasopressors&#44;<a class="elsevierStyleCrossRefs" href="#bib0455"><span class="elsevierStyleSup">91&#8211;93</span></a> though some studies have also related it to improvements in microcirculation<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">94</span></a> and survival&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">92</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">However&#44; although some studies suggest benefits from the use of continuous hemofiltration in hemodynamically unstable patients beyond those offered by intermittent hemodialysis techniques&#44;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">95</span></a> there is still not sufficient evidence of the superiority of continuous RRT over intermittent hemodialysis &#40;IHD&#41; in terms of mortality or the recovery of renal function&#46;<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">96&#44;97</span></a> The use of peritoneal dialysis is related to increased mortality&#44; and thus is not recommended in ARF associated to sepsis&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">98</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conclusions</span><p id="par0155" class="elsevierStylePara elsevierViewall">Acute renal failure associated to sepsis is frequent&#44; and implies increased management complexity and mortality&#46; A series of still poorly understood pathogenic mechanisms are involved&#8211;a fact that has limited the strategies for dealing with the disease&#46; At present&#44; renal support techniques make it possible to replace kidney function efficiently&#44; and there is evidence that they can modulate the inflammatory response&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Financial support</span><p id="par0160" class="elsevierStylePara elsevierViewall">Fondecyt 11100247 &#40;Tomas Regueira&#41;&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflicts of interest</span><p id="par0165" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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          "titulo" => "Epidemiology"
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          "titulo" => "Definition"
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          "titulo" => "Pathogenesis"
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            0 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Renal blood flow in sepsis"
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            1 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Renal histology in sepsis"
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            2 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Glomerular filtration in sepsis"
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              "identificador" => "sec0035"
              "titulo" => "Intrarenal hemodynamics during sepsis"
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              "titulo" => "Inflammation and oxidative stress"
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              "identificador" => "sec0045"
              "titulo" => "Coagulation and microcirculation"
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            6 => array:2 [
              "identificador" => "sec0050"
              "titulo" => "Mitochondrial dysfunction"
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              "identificador" => "sec0055"
              "titulo" => "Distant damage caused by mechanical ventilation"
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            8 => array:2 [
              "identificador" => "sec0060"
              "titulo" => "Biomarkers in sepsis and ARF"
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          "titulo" => "Treatment"
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          "titulo" => "Conclusions"
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          "identificador" => "sec0075"
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    "fechaRecibido" => "2010-12-09"
    "fechaAceptado" => "2011-03-24"
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          "clase" => "keyword"
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          "palabras" => array:3 [
            0 => "Sepsis"
            1 => "Acute renal failure"
            2 => "Renal blood flow"
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          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec10585"
          "palabras" => array:3 [
            0 => "Sepsis"
            1 => "Insuficiencia renal aguda"
            2 => "Flujo sangu&#237;neo renal"
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        "titulo" => "Abstract"
        "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Acute renal failure &#40;ARF&#41; is an independent risk factor associated with increased mortality during sepsis&#46; Recent consensus definitions have allowed the standardization of research on the subject&#46; The understanding of the physiopathology of ARF during sepsis is limited by the scarcity of histological studies and the inability to measure renal microcirculatory flows&#46; Historically&#44; ARF during sepsis has been considered to be a consequence of diminished renal blood flow &#40;RBF&#41;&#46; Indeed&#44; in early stages of sepsis or in sepsis associated to cardiogenic shock&#44; RBF may decrease&#46; However&#44; recent studies have shown that in resuscitated sepsis&#44; in which cardiac output is characteristically normal or even elevated and there is systemic vasodilatation&#44; RBF is normal or even increased&#44; with no associated histological evidence of significant tubular necrosis&#46; Thus&#44; other factors may participate in the genesis of ARF in sepsis&#46; These include apoptosis&#44; glomerular and medullary microcirculatory disorders&#44; cell changes in response to the pro-inflammatory cascade characteristic of sepsis&#44; oxidative stress&#44; mitochondrial dysfunction and damage induced by mechanical ventilation&#44; among others&#46; Sepsis-associated ARF treatment is supportive&#46; In general&#44; renal replacement therapies can be grouped as intermittent or continuous&#44; and as those whose primary objective is the replacement of impaired renal function&#44; versus those whose main objective is to secure hemodynamic stability through the clearing of pro-inflammatory mediators&#46;</p>"
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        "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La insuficiencia renal aguda &#40;IRA&#41; es un factor de riesgo independiente asociado a mayor mortalidad durante la sepsis&#46; Definiciones de consenso recientes han permitido estandarizar los trabajos de investigaci&#243;n en el tema&#46; La comprensi&#243;n de la fisiopatolog&#237;a de la IRA durante la sepsis est&#225; limitada por la escasez de estudios histol&#243;gicos y por la imposibilidad de medir los flujos microcirculatorios renales&#46; Hist&#243;ricamente se ha considerado a la IRA s&#233;ptica como una patolog&#237;a dependiente de la ca&#237;da del flujo sangu&#237;neo renal &#40;FSR&#41;&#46; Efectivamente&#44; en las etapas precoces de la sepsis o en la sepsis acompa&#241;ada de shock cardiog&#233;nico existe compromiso del FSR&#59; sin embargo&#44; estudios recientes han demostrado que en la sepsis reanimada&#44; aquella en que caracter&#237;sticamente se observa un gasto cardiaco normal o alto y vasodilataci&#243;n sist&#233;mica&#44; el FSR es normal o incluso aumentado y no existe evidencia histol&#243;gica significativa de necrosis tubular&#46; Otros factores&#44; distintos al puramente hemodin&#225;mico&#44; participan en la g&#233;nesis de la IRA en la sepsis&#46; Entre &#233;stos est&#225;n la apoptosis celular&#44; los trastornos microcirculatorios glomerulares y medulares&#44; los cambios celulares en respuestas a la cascada proinflamatoria propia de la sepsis&#44; el estr&#233;s oxidativo&#44; la disfunci&#243;n mitocondrial y el da&#241;o a distancia inducido por ventilaci&#243;n mec&#225;nica&#44; entre otros&#46; En la actualidad&#44; el tratamiento de la IRA en la sepsis es de soporte&#46; En general&#44; las terapias de reemplazo renal pueden ser clasificadas como intermitentes o continuas&#44; y en las que buscan primariamente el reemplazo de la funci&#243;n renal deteriorada&#44; frente a aquellas cuyo objetivo principal es lograr la estabilidad hemodin&#225;mica de los pacientes mediante la remoci&#243;n de mediadores proinflamatorios&#46;</p>"
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        "nota" => "<p class="elsevierStyleNotepara">Please cite this article as&#58; Regueira T&#44; et al&#46; Fisiopatolog&#237;a de la insuficiencia renal aguda durante la sepsis&#46; Med Intensiva&#46; 2011&#59;35&#58;424&#8211;32&#46;</p>"
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          "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">GF&#58; glomerular filtrate&#59; UF&#58; urinary flow&#59; ARF&#58; acute renal failure&#59; CRF&#58; chronic renal failure&#59; ESKD&#58; end-stage kidney disease&#46;</p>"
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                  <table border="0" frame="\n
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Category&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">GF criteria&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " rowspan="2" align="left" valign="\n
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                  \t\t\t\t">Risk</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8593; Creatinine<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>1&#46;5 or&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">UF<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;5<span class="elsevierStyleHsp" style=""></span>ml&#47;kg&#47;h<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>6<span class="elsevierStyleHsp" style=""></span>h</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="9" align="left" valign="middle">High sensitivityHigh specificity</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GF decreased &#62;25&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Injury</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8593; Creatinine<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>2 or&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">UF<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;5<span class="elsevierStyleHsp" style=""></span>ml&#47;kg&#47;h<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>12<span class="elsevierStyleHsp" style=""></span>h</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GF decreased &#62;50&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Failure</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8593; Creatinine<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>3 or&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">UF<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;3<span class="elsevierStyleHsp" style=""></span>ml&#47;kg&#47;h<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>24<span class="elsevierStyleHsp" style=""></span>h or anuria<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>12<span class="elsevierStyleHsp" style=""></span>h</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GF decreased &#62;75&#37; or&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ARF over CRF&#58; creatinine &#62;4<span class="elsevierStyleHsp" style=""></span>mg&#47;dl with acute &#8593; &#8805;0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Loss&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
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                  \t\t\t\t">Persistent ARF<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>complete renal function loss &#62;4 weeks</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ESKD &#40;CRF&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">End-stage renal failure &#40;&#62;3 months&#41;</td></tr></tbody></table>
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">RIFLE criteria for classifying acute renal dysfunction&#46;</p>"
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          "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Only one criterion &#40;creatinine or UF&#41; needs to be met to classify a patient&#46; Those receiving renal replacement therapy &#40;RRT&#41; are considered in category 3&#44; independently of the stage in which they are at the time of starting RRT&#46; Categories 1&#44; 2 and 3 correspond to R&#44; I and F of the RIFLE classification&#44; respectively&#46;</p>"
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                  <table border="0" frame="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Category&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " rowspan="2" align="char" valign="\n
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                  \t\t\t\t">1</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8593; Serum creatinine &#8805;0&#46;3<span class="elsevierStyleHsp" style=""></span>mg&#47;dl or&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">UF<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;5<span class="elsevierStyleHsp" style=""></span>ml&#47;kg&#47;h<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>&#62;6<span class="elsevierStyleHsp" style=""></span>h</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t">&#8593; &#8805;150&#8211;200&#37; &#40;1&#46;5&#8211;2 times&#41; from baseline level<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8593; Serum creatinine &#62;200&#8211;300&#37; &#40;&#62;2&#8211;3 times&#41; from baseline level<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">UF<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;5<span class="elsevierStyleHsp" style=""></span>ml&#47;kg&#47;h<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>&#62;12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8593; Serum creatinine &#62;300&#37; &#40;&#62;3 times&#41; from baseline level<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> or serum creatinine &#8805;4&#46;0<span class="elsevierStyleHsp" style=""></span>mg&#47;dl with sharp &#8593; of at least 0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">UF<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;3<span class="elsevierStyleHsp" style=""></span>ml&#47;kg&#47;h<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>&#62;24<span class="elsevierStyleHsp" style=""></span>h or anuria<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">AKIN criteria for classifying acute renal dysfunction&#46;</p>"
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                      "titulo" => "Acute kidney injury in the intensive care unit according to RIFLE"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
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                    0 => array:2 [
                      "doi" => "10.1097/01.CCM.0000277041.13090.0A"
                      "Revista" => array:6 [
                        "tituloSerie" => "Crit Care Med"
                        "fecha" => "2007"
                        "volumen" => "35"
                        "paginaInicial" => "1837"
                        "paginaFinal" => "1843"
                        "link" => array:1 [
                          0 => array:2 [ …2]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Acute renal failure in critically ill patients&#58; a multinational&#44; multicenter study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1001/jama.294.7.813"
                      "Revista" => array:6 [
                        "tituloSerie" => "JAMA"
                        "fecha" => "2005"
                        "volumen" => "294"
                        "paginaInicial" => "813"
                        "paginaFinal" => "818"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
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              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Epidemiology of acute kidney failure in Spanish ICU&#46; Multicenter prospective study FRAMI"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Med Intensiva"
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                        "volumen" => "30"
                        "paginaInicial" => "260"
                        "paginaFinal" => "267"
                        "link" => array:1 [
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Acute renal failure&#8212;definition&#44; outcome measures&#44; animal models&#44; fluid therapy and information technology needs&#58; the Second International Consensus Conference of the Acute Dialysis Quality Initiative &#40;ADQI&#41; Group"
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                          "etal" => false
                          "autores" => array:5 [ …5]
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                    0 => array:2 [
                      "doi" => "10.1186/cc2872"
                      "Revista" => array:6 [
                        "tituloSerie" => "Crit Care"
                        "fecha" => "2004"
                        "volumen" => "8"
                        "paginaInicial" => "R204"
                        "paginaFinal" => "R212"
                        "link" => array:1 [
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              ]
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            4 => array:3 [
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis&#46; The ACCP&#47;SCCM Consensus Conference Committee&#46; American College of Chest Physicians&#47;Society of Critical Care Medicine"
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                          "etal" => true
                          "autores" => array:6 [ …6]
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                        "tituloSerie" => "Chest"
                        "fecha" => "1992"
                        "volumen" => "101"
                        "paginaInicial" => "1644"
                        "paginaFinal" => "1655"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "An assessment of the RIFLE criteria for acute renal failure in hospitalized patients"
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                          "etal" => false
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                      "doi" => "10.1097/01.CCM.0000224227.70642.4F"
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                        "tituloSerie" => "Crit Care Med"
                        "fecha" => "2006"
                        "volumen" => "34"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Acute Kidney Injury Network&#58; report of an initiative to improve outcomes in acute kidney injury"
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                        0 => array:2 [
                          "etal" => true
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Review
Physiopathology of acute renal failure during sepsis
Fisiopatología de la insuficiencia renal aguda durante la sepsis
T. Regueiraa,
Corresponding author
regueira@med.puc.cl

Corresponding author.
, M. Andresena, M. Mercadoa, P. Downeyb
a Departamento de Medicina Intensiva, Hospital Clínico Universidad Católica de Chile, Pontificia Universidad Católica de Chile, Santiago, Chile
b Departamento de Nefrología, Hospital Clínico Universidad Católica de Chile, Pontificia Universidad Católica de Chile, Santiago, Chile
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Epidemiology</span><p id="par0005" class="elsevierStylePara elsevierViewall">The incidence of acute renal failure &#40;ARF&#41; in critical patients is variable&#44; depending on the definition used and the population studied&#44; but ranges from 30 to 50&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Sepsis and its most severe presentation&#44; septic shock&#44; are the main causes of ARF in the Intensive Care Unit &#40;ICU&#41;&#44; accounting for up to 50&#37; of all cases&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Mortality due to sepsis remains high&#44; particularly when associated to organ dysfunction such as ARF &#40;with mortality rates of 20&#8211;35&#37;&#41; or in the presence of hemodynamic alterations &#40;mean mortality 60&#37;&#41;&#46; The development of ARF during sepsis is an independent risk factor associated to increased patient mortality<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&#59; in this context&#44; the FRAMI study&#44; involving 43 Spanish ICUs&#44; showed the appearance of ARF in critical patients to be independently associated to increased mortality&#44; with an odds ratio &#40;OR&#41; of 2&#46;51&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Definition</span><p id="par0010" class="elsevierStylePara elsevierViewall">Until recently there was no clear consensus-based definition of ARF in sepsis&#46; The ADQI &#40;Acute Dialysis Quality Initiative&#41; group has proposed a consensus-based diagnostic classification that has been favorably viewed by clinicians&#44; and has made it possible to standardize research work in this field&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The mentioned classification is known as the RIFLE &#40;in reference to Risk&#44; Injury&#44; Failure&#44; Loss&#44; and End-stage renal failure&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Patients are classified according to the loss of glomerular filtration &#40;GF&#41; &#40;with respect to the baseline reference of each patient&#41; and&#47;or urinary flow &#40;UF&#41; into 5 categories &#40;selecting the criterion yielding the poorest classification&#41;&#58; risk &#40;R&#41;&#44; injury &#40;I&#41;&#44; failure &#40;F&#41;&#44; loss &#40;L&#41; or end-stage renal failure &#40;E&#41;&#46; ARF in sepsis is diagnosed in all patients meeting the criteria of sepsis&#44;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> meeting some of the RIFLE criteria&#44; and lacking other conditions or causes capable of accounting for ARF&#44; such as the use of contrast media or nephrotoxic drugs&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">The RIFLE classification has been validated by a number of studies&#46; In a study involving 20&#44;126 patients admitted to a university hospital&#44; 10&#37;&#44; 5&#37; and 3&#46;5&#37; of the subjects reached the maximum R&#44; I and F scores in the RIFLE classification&#44; respectively&#46; Mortality among the patients increased linearly with the severity of the RIFLE score&#44; making it possible to independently predict mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Another study involving 41&#44;972 patients admitted to the ICU reported an ARF incidence of 35&#46;8&#37;&#46; The mortality in the group without ARF was 8&#46;4&#37;&#44; versus 20&#46;9&#37;&#44; 45&#46;6&#37; and 56&#46;8&#37; in those with class R&#44; I and F acute renal failure&#44; respectively&#46; The presence of ARF of any category was found to be an independent mortality risk factor&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">With the purpose of improving sensitivity&#44; the RIFLE criteria were modified by the Acute Kidney Injury Network &#40;AKIN&#41; group&#44; which defined ARF as an increase in serum creatinine of &#8805;0&#46;3<span class="elsevierStyleHsp" style=""></span>mg&#47;dl or a percentage increase of &#8805;1&#46;5 times from baseline as recorded in the previous 48<span class="elsevierStyleHsp" style=""></span>h &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Urine output as a criterion of ARF was maintained&#44; though the glomerular filtration rate and RIFLE L and E scores were excluded&#46; AKIN&#44; in contrast to RIFLE&#44; requires two creatinine measurements spaced 48<span class="elsevierStyleHsp" style=""></span>h apart in order to establish a diagnosis of ARF&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">Some authors have compared RIFLE versus AKIN in patients subjected to heart surgery<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> or admitted to the ICU&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> In general&#44; mortality is comparable with both methods and tends to increase with the severity of ARF&#8211;thus confirming that acute renal damage is correlated to patient mortality&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Pathogenesis</span><p id="par0030" class="elsevierStylePara elsevierViewall">The study of the mechanisms involved in the development of ARF in sepsis is limited by the few histological studies in humans&#44; due to the risk involved in the process and its frequently irreversible nature&#44; and by the impossibility of measuring renal microcirculatory flow values&#46;</p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Renal blood flow in sepsis</span><p id="par0035" class="elsevierStylePara elsevierViewall">The classical position in septic patients is that the principal mechanism underlying ARF is ischemia or hypoperfusion&#8211;suggesting that the decrease in renal blood flow &#40;RBF&#41; and renal vasoconstriction are the characteristic events of sepsis&#46; Furthermore&#44; the main interventions for the management of ARF in sepsis have been volume replacement in already resuscitated patients&#44;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> and the use of renal vasodilators such as dopamine and fenoldapam&#8211;though there is little evidence of their usefulness&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">In effect&#44; the physiopathological processes inherent to sepsis&#44; such as absolute and relative hypovolemia due to vasoplegia &#40;pathological vasodilatation&#41; and capillary leakage&#44; myocardial dysfunction and impaired oxygenation&#44; among other aspects&#44; suggest that decreased oxygen transportation may be a relevant mechanism in ARF&#8211;mainly in the early stages or in sepsis accompanied by cardiogenic shock&#46; However&#44; most studies suggesting an ischemic etiology for ARF in sepsis are derived from animal models of ischemia and reperfusion&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;13</span></a> These models are not consistent with the classical physiopathology of resuscitated sepsis&#44; characterized by high cardiac output &#40;CO&#41; and low peripheral resistance&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The study of RBF in human sepsis is complex&#44; due to the difficulty of measuring it on a continuous basis&#46; Studies in septic animals have yielded contradictory results in relation to RBF&#46; Some studies indicate that during the early phases of sepsis&#44; or after a bolus dose of endotoxin&#44; RBF decreases&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;15</span></a> These models of endotoxemia induce an initial proinflammatory state that is not found in true sepsis&#44; where the increase in inflammatory mediators is gradual rather than explosive as in the mentioned models&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> Other more recent studies underscore the fact that under normal conditions&#44; RBF is several times greater than that required by the actual renal metabolic needs &#8211; since RBF is destined more to glomerular filtration than to renal oxygen transport&#46; These studies show that in resuscitated sepsis&#44; i&#46;e&#46;&#44; where a normal or high cardiac output and systemic vasodilatation are characteristically observed&#44; RBF is normal or even increased&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;18</span></a> A study involving a porcine model of hyperdynamic sepsis found RBF to be generally increased&#44; and particularly increased towards the renal medulla&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> Another study in 8 septic patients in which RBF was estimated invasively via thermodilution showed ARF to develop in the absence of alterations in RBF&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> A systematic review of 160 experimental studies of sepsis and ARF found the principal determinant factor of the normality of RBF in sepsis to be cardiac output &#40;CO&#41;&#46; A high or normal CO is associated to preserved RBF&#44; while a low CO&#8211;i&#46;e&#46;&#44; non-resuscitated sepsis or sepsis associated to cardiogenic shock&#8211;is associated to low RBF&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Thus&#44; even though renal hypoperfusion may play a role in low-flow states such as non-resuscitated sepsis&#44; recent studies show that once the hyperdynamic state characteristic of sepsis has been established&#44; hypoperfusion or renal ischemia are not relevant mechanisms&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Renal histology in sepsis</span><p id="par0055" class="elsevierStylePara elsevierViewall">The renal histological changes observed in sepsis are few and nonspecific&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> A systematic review found only 22&#37; of 184 patients to show evidence of acute tubular necrosis &#40;ATN&#41;&#44; and concluded that the existing experimental and human clinical evidence does not support the idea of ATN as the manifestation or mechanism characteristic of septic ARF&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> The histology of septic ARF is heterogeneous&#8211;relevant findings being leukocyte infiltration &#40;predominantly mononuclear cells&#41;&#44; some degree of tubular cell vacuolization&#44; loss of the brush border&#44; and apoptosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#44;23</span></a> Other described alterations are dysfunction of the intercellular tight junctions&#44; favoring tubular fluid reflux through the epithelium&#44;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> and dysfunction of the basal membrane&#8211;with the consequent detachment of cells into the tubular lumen&#46; This in turn is associated to the appearance of tubular cells or cylinders in the urine sediment&#46; These cellular cylinders produce micro-obstruction of tubular urinary flow &#40;UF&#41;&#44; with cessation of GF in the affected nephron unit&#46; The absence of necrosis in 70&#37; of the patients is compatible with the existing evidence that other mechanisms different from ischemia contribute to the development of ARF during sepsis&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;10</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Apoptosis&#44; or programmed cell death&#44; which in contrast to necrosis does not induce local inflammation&#44;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> has been described as one of the physiopathological phenomena present during ARF in sepsis&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21&#44;22&#44;26</span></a> Apoptosis is observed in 2&#8211;3&#37; of the tubular cells during sepsis&#44; and is more frequent in the distal tubules&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> Tumor necrosis factor-alpha &#40;TNF-&#945;&#41; plays an important role in the induction of renal tubular apoptosis&#59; however&#44; the relevance of apoptosis as a mechanism of ARF <span class="elsevierStyleItalic">in vivo</span> remains the subject of study&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Glomerular filtration in sepsis</span><p id="par0065" class="elsevierStylePara elsevierViewall">Since in most cases of sepsis cardiac output is either normal or elevated&#44; RBF is seen to be normal&#46; A recent study in septic sheep has shown that&#44; in effect&#44; RBF is elevated in association to hyperdynamic CO&#44; though renal vascular resistance &#40;RVR&#41; is decreased&#44; with a secondary reduction in glomerular filtration rate and an associated rise in plasma creatinine concentration&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> The drop in RVR may be explained by an increase in nitric oxide &#40;NO&#41; release&#46; The proinflammatory cascade induces expression of inducible nitric oxide synthetase &#40;iNOS&#41; in the renal medulla&#44;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> in the glomerular mesangial cells and in the endothelial cells of the renal blood vessels<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> &#8211; resulting in intense and prolonged NO release&#46; On the other hand&#44; the acidosis inherent to septic shock&#44; and the decrease in ATP levels in the vascular smooth muscle cells&#44; favor cellular hyperpolarization as a result of potassium release from the cell through ATP-dependent membrane potassium channels&#8211;this in turn contributing to renal vasodilatation through resistance to catecholamines and angiotensin II&#46; Likewise&#44; the recovery of renal function was associated to a recovery of RVR associated to a decrease in RBF&#46; This study suggests that the loss of GF pressure regulation participates as a mechanism of ARF in sepsis&#44; even in the presence of increased RBF&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Glomerular filtration pressure depends on the diameter of the afferent and efferent arterioles&#46; Constriction of the afferent arteriole and&#47;or vasodilatation of the efferent arteriole can give rise to reductions in GF and in UF&#46; Afferent vasodilatation participates as a mechanism of ARF in sepsis&#44; though the efferent arteriole plays an even greater role &#40;hyperemic ARF&#41;&#8211;generating a drop in GF and in UF&#46; However&#44; the lack of direct measurements of RBF in human sepsis limits the drawing of conclusions&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Intrarenal hemodynamics during sepsis</span><p id="par0075" class="elsevierStylePara elsevierViewall">Despite preserved RBF in resuscitated sepsis&#44; the intrarenal distribution of the blood flow may be altered&#44; with a predominance of cortical flow over medullary blood flow&#8211;a situation known as &#8220;corticomedullary redistribution&#8221;&#44; and which is responsible for medullary hypoxia&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> A recent study in animals established differentiated measurements of critical and medullary blood flow using intrarenal laser Doppler flowmetry during sepsis&#46; Both flows remained stable&#44; and the use of noradrenalin&#8211;an adrenergic vasoconstrictor&#8211;significantly increased the flow in both regions&#46; This suggests that the compensation mechanisms are active during hyperdynamic sepsis&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> There probably are modifications in intrarenal blood flow during sepsis&#44; but the evidence suggests that the compensatory mechanisms are active&#44; and that such modifications do not represent a predominant mechanism&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Inflammation and oxidative stress</span><p id="par0080" class="elsevierStylePara elsevierViewall">Other mechanisms&#44; apart from the hemodynamic mechanisms&#44; also participate in the genesis of ARF in sepsis&#46; The inflammatory response inherent to sepsis has been examined as a direct mechanism of ARF&#46; Different mediators implicated in sepsis&#44; together with the neuroendocrine response&#44; participate in the pathogenesis of septic ARF&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">31&#44;32</span></a> The kidneys are particularly sensitive to mediator-induced damage&#46; Both the mesangial cells and the tubular cells are able to express proinflammatory cytokines such as interleukin &#40;IL&#41;-1&#44; IL-6 and TNF-&#945;&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> Both IL-1 and TNF-&#945; have been found to act as inducers of ARF in sepsis&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> Mice with TNF-&#945; receptor deficiency are resistant to the development of endotoxin-mediated ARF&#44; and exhibit less tubular apoptosis and lesser mononuclear cell infiltration&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> However&#44; the use of anti-TNF-&#945; antibodies during sepsis has not been able to improve survival or prevent the development of ARF&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">The mechanisms proposed to explain how IL-1 and TNF-&#945; produce ARF during sepsis include the induction of increased cytokine release&#44; amplifying the inflammatory cascade&#59; favoring of tissue factor expression&#44; which promotes local thrombosis<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a>&#59; the induction of tubular cell apoptosis<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a>&#59; and principally the elevation of regional oxidative stress through an increased production of reactive oxygen species &#40;ROS&#41;&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Oxidative stress in sepsis is related to an increase in the production of ROS&#44; and to the concomitant reduction of antioxidant levels through either consumption or diminished intake&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">39&#8211;41</span></a> The proinflammatory cascade induces the expression of iNOS in the renal medulla&#44;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> in the glomerular mesangial cells&#44; and in the renal vascular endothelial cells<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a>&#8211;with the consequent rise in NO levels during sepsis&#46; NO has both beneficial and deleterious effects during sepsis&#46; Baseline levels of NO are necessary to maintain RBF and intrarenal flow during sepsis&#44; particularly at afferent arteriolar level&#44;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> and to favor cellular mitochondrial biogenesis &#40;re-synthesis&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">42&#44;43</span></a> However&#44; NO is also a free radical&#44; and when produced in excess is able to inhibit the oxidative phosphorylation chain and reduce oxygen consumption&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> NO&#44; moreover&#44; can interact with other ROS to form more toxic reactive species such as peroxynitrite&#44;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">45&#8211;47</span></a> which can cause damage to DNA&#44; proteins and membranes&#8211;resulting in an increase in mitochondrial permeability&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">48&#44;49</span></a> Increased mitochondrial permeability is associated to a decrease in electrochemical gradient and in ATP synthesis&#44; as well as to the activation of apoptosis pathways&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a> The intensity of oxidative damage is correlated to the intensity of mitochondrial damage and to survival&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">48&#44;51</span></a> A number of studies&#44; including one by our own group&#44; have shown that there is not only an increase in ROS during sepsis but also a decrease in antioxidant levels&#44; related to the intensity of the septic process&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">52&#8211;55</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Coagulation and microcirculation</span><p id="par0095" class="elsevierStylePara elsevierViewall">Sepsis is characterized by a prothrombotic and antifibrinolytic state&#44;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a> and the associated microcirculatory dysfunction has been described as a relevant mechanism in the development of multiorgan failure in sepsis&#44; with an association to mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a> Endothelial dysfunction is induced by the inflammatory cascade&#44; and is characterized by an increase in the expression of tissue factor&#8211;which in turn activates the coagulation cascade&#46; At renal level&#44; fibrin deposits have been described in the glomerular capillaries during sepsis&#44; though a recent study has shown that renal arterial&#47;arteriolar thrombosis is not frequent in sepsis&#44; and is not associated to the presence of disseminated intravascular coagulation&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Mitochondrial dysfunction</span><p id="par0100" class="elsevierStylePara elsevierViewall">Mitochondrial dysfunction is described as the incapacity of the cell to maintain its metabolic functions despite adequate oxygen transport&#44; due to the impossibility of using the available oxygen for ATP synthesis&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a> Briefly&#44; mitochondria must couple the transport of energy-rich substrates to the generation of a transmembrane electrochemical gradient allowing the synthesis of ATP&#46; In order for this process to be efficient&#44; there must be adequate function of the oxidative phosphorylation complexes &#40;complexes I&#8211;IV plus ATP synthase&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">59&#44;60</span></a> structural integrity of the mitochondrial membrane &#40;fundamentally the internal membrane&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">61&#44;62</span></a> a sufficient substrate supply&#44;<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">63&#44;64</span></a> and a sufficient number of mitochondria&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">65&#44;66</span></a> Few studies have evaluated cell function in septic ARF&#46; Based on the continuous perfusion of lipopolysaccharide &#40;LPS&#41;&#44; one study observed no alterations in renal mitochondrial function&#44;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a> though a more recent study in pigs with sepsis of intraabdominal origin reported an alteration in renal mitochondrial function&#44; associated to an increase in oxidative stress marker levels&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">68</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Distant damage caused by mechanical ventilation</span><p id="par0105" class="elsevierStylePara elsevierViewall">The use of small tidal volumes &#40;TV&#41; &#40;6<span class="elsevierStyleHsp" style=""></span>ml&#47;kg ideal weight&#41; in mechanical ventilation &#40;MV&#41; during acute respiratory distress syndrome &#40;ARDS&#41; reduces mortality among these patients&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">69</span></a> One of the mechanisms proposed for explaining mortality associated to ARDS and MV is the release of systemic mediators generated at lung level in situations of high TV&#46; An interesting study showed that animals ventilated with high TV values show greater tubular apoptosis and associated renal dysfunction&#46; In fact&#44; on cultivating renal cells <span class="elsevierStyleItalic">in vitro</span> with plasma from animals subjected to high TV&#44; the cells likewise showed a higher apoptosis rate&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">70</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Biomarkers in sepsis and ARF</span><p id="par0110" class="elsevierStylePara elsevierViewall">The use of creatinine and UF for the diagnosis and prognosis of ARF during sepsis &#40;RIFLE and AKIN criteria&#41; poses several limitations&#46; The rise in plasma creatinine is a late phenomenon&#44; and in order for such an elevation to occur&#44; it must be associated with an important decrease in GF capacity&#46; The RIFLE classification does not clearly define the baseline value of patient renal function&#44; in contrast to the AKIN classification&#44; which requires the obtainment of two creatinine measurements spaced 48<span class="elsevierStyleHsp" style=""></span>h apart&#46; On the other hand&#44; UF as a diagnostic criterion of ARF is conditioned by patient volemia and the use of diuretics&#46; Most studies included in the RIFLE and AKIN analyses are retrospective and did not measure UF every 6 or 12<span class="elsevierStyleHsp" style=""></span>h&#59; accordingly&#44; only 12&#37; of them made use of both criteria &#40;increase in creatinine and UF&#41; for diagnosing ARF&#46; The studies that used both criteria reported lesser mortality than those which used only creatinine as diagnostic criterion&#8211;this suggesting that the decrease in UF is more benign and&#47;or reversible than the increase in creatinine&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">The need to establish markers allowing an earlier and more sensitive diagnosis of ARF than creatinine elevation or a decrease in UF has led to the search for biomarkers of renal origin reflecting cellular damage in early stages of the disease&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Neutrophil gelatinase-associated lipocalin &#40;NGAL&#41; is a 24<span class="elsevierStyleHsp" style=""></span>kDa protein normally expressed in low concentrations in different human tissues &#40;kidneys&#44; lungs&#44; stomach and colon&#41;&#44; and is found in the secondary granules of neutrophils&#46; NGAL is released when these cells are activated&#44; particularly in response to bacterial infections&#46; NGAL transcription and release is intensely induced in the presence of epithelial damage&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">In ARF&#44; NGAL is promptly released from the proximal renal tubules following ischemic<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">71</span></a> or toxic damage&#44;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">72</span></a> and its levels can be measured in plasma and urine&#46; A recent review<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">73</span></a> involving over 4000 patients at risk of ARF due to sepsis&#44; heart surgery&#44; exposure to contrast media or transplantation&#44; found NGAL to be significantly elevated in those individuals who develop ARF&#44; and that this elevation significantly precedes the clinical diagnosis of ARF&#46; Elevations in plasma and urine levels of NGAL have also been described in septic patients&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">74</span></a> The plasma and urine concentrations of NGAL are correlated to the degree of renal dysfunction established by the RIFLE or AKIN&#46;<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">75&#44;76</span></a> However&#44; a recent study suggests that urine NGAL elevation is a better predictor of ARF in sepsis than plasma NGAL elevation&#44; which is less specific&#8211;possibly because of the activation of circulating neutrophils&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">74</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Interleukin-18 is a proinflammatory cytokine transcribed and released in the proximal renal tubules&#44; and which can easily be detected in urine following ischemic damage&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">77</span></a> It does not appear to increase under conditions of infection&#44; prerenal ARF or chronic renal failure&#46; This marker was initially described in heart surgery patients in which IL-18 was seen to rise early before the clinical diagnosis of ARF&#44; with an area under the curve &#40;AUC-ROC&#41; of 0&#46;75&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">78</span></a> IL-18 has also been described as a good predictor of ARF in critical patients in general&#44; and in septic patients&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">79</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">KIM-1 &#40;kidney injury molecule-1&#41; is a transmembrane glycoprotein that shows a marked increase in expression on the part of the cell of the proximal renal tubules in response to ischemic or toxic stimuli&#46; Its concentrations can be detected in urine and are seen to increase in patients with ARF&#46; This marker might be useful for predicting the need for dialysis or in-hospital mortality in patients with ARF of different origins and severity&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">80</span></a></p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Treatment</span><p id="par0140" class="elsevierStylePara elsevierViewall">The limitations in establishing a physiopathological model of ARF have delayed the development of successful drug treatments&#44; and at present much of the treatment of ARF in sepsis focuses on the support of kidney function&#46; The management of ARF in septic patients is complicated&#44; due to the existing hemodynamic instability and associated multiorgan dysfunction&#46; As a result&#44; in recent years many&#44; both continuous and intermittent renal replacement therapy &#40;RRT&#41;&#44; techniques have been developed&#8211;though a lack of evidence in favor of one technique over the rest has largely precluded their clinical applicability&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">81&#8211;85</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">The different techniques developed are fundamentally based on two principles&#58; diffusion and convection&#44; or a combination of both&#46; While diffusion techniques &#40;hemodialysis&#41; are preferentially used as non-antiinflammatory replacement therapy&#44; and in hemodynamically stable patients&#44; the convection techniques &#40;hemofiltration&#41; allow greater hemodynamic stability and the achievement of negative water balances&#44; with lesser systemic repercussion&#46;<a class="elsevierStyleCrossRefs" href="#bib0430"><span class="elsevierStyleSup">86&#8211;88</span></a> However&#44; more extended hemodialysis allows the replacement of renal function and the achievement of negative balances even in unstable patients&#46; On the other hand&#44; hemofiltration techniques not only allow renal support but also the possibility of modulating the inflammatory response through the removal of inflammatory compounds &#40;cytokines&#41; of greater molecular weight&#46;<a class="elsevierStyleCrossRefs" href="#bib0445"><span class="elsevierStyleSup">89&#44;90</span></a> Hemofiltration with higher ultrafiltrate doses&#44; referred to as high-volume hemofiltration &#40;ultrafiltration rate &#62;35<span class="elsevierStyleHsp" style=""></span>ml&#47;kg&#47;h&#41;&#44; is mainly associated with a reduction in the need for vasopressors&#44;<a class="elsevierStyleCrossRefs" href="#bib0455"><span class="elsevierStyleSup">91&#8211;93</span></a> though some studies have also related it to improvements in microcirculation<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">94</span></a> and survival&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">92</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">However&#44; although some studies suggest benefits from the use of continuous hemofiltration in hemodynamically unstable patients beyond those offered by intermittent hemodialysis techniques&#44;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">95</span></a> there is still not sufficient evidence of the superiority of continuous RRT over intermittent hemodialysis &#40;IHD&#41; in terms of mortality or the recovery of renal function&#46;<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">96&#44;97</span></a> The use of peritoneal dialysis is related to increased mortality&#44; and thus is not recommended in ARF associated to sepsis&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">98</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conclusions</span><p id="par0155" class="elsevierStylePara elsevierViewall">Acute renal failure associated to sepsis is frequent&#44; and implies increased management complexity and mortality&#46; A series of still poorly understood pathogenic mechanisms are involved&#8211;a fact that has limited the strategies for dealing with the disease&#46; At present&#44; renal support techniques make it possible to replace kidney function efficiently&#44; and there is evidence that they can modulate the inflammatory response&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Financial support</span><p id="par0160" class="elsevierStylePara elsevierViewall">Fondecyt 11100247 &#40;Tomas Regueira&#41;&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflicts of interest</span><p id="par0165" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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          "titulo" => "Keywords"
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          "titulo" => "Palabras clave"
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        4 => array:2 [
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          "titulo" => "Epidemiology"
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        5 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Definition"
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        6 => array:3 [
          "identificador" => "sec0015"
          "titulo" => "Pathogenesis"
          "secciones" => array:9 [
            0 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Renal blood flow in sepsis"
            ]
            1 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Renal histology in sepsis"
            ]
            2 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Glomerular filtration in sepsis"
            ]
            3 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "Intrarenal hemodynamics during sepsis"
            ]
            4 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Inflammation and oxidative stress"
            ]
            5 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Coagulation and microcirculation"
            ]
            6 => array:2 [
              "identificador" => "sec0050"
              "titulo" => "Mitochondrial dysfunction"
            ]
            7 => array:2 [
              "identificador" => "sec0055"
              "titulo" => "Distant damage caused by mechanical ventilation"
            ]
            8 => array:2 [
              "identificador" => "sec0060"
              "titulo" => "Biomarkers in sepsis and ARF"
            ]
          ]
        ]
        7 => array:2 [
          "identificador" => "sec0065"
          "titulo" => "Treatment"
        ]
        8 => array:2 [
          "identificador" => "sec0070"
          "titulo" => "Conclusions"
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        9 => array:2 [
          "identificador" => "sec0075"
          "titulo" => "Financial support"
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        10 => array:2 [
          "identificador" => "sec0080"
          "titulo" => "Conflicts of interest"
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          "titulo" => "References"
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    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2010-12-09"
    "fechaAceptado" => "2011-03-24"
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec10584"
          "palabras" => array:3 [
            0 => "Sepsis"
            1 => "Acute renal failure"
            2 => "Renal blood flow"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec10585"
          "palabras" => array:3 [
            0 => "Sepsis"
            1 => "Insuficiencia renal aguda"
            2 => "Flujo sangu&#237;neo renal"
          ]
        ]
      ]
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      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Acute renal failure &#40;ARF&#41; is an independent risk factor associated with increased mortality during sepsis&#46; Recent consensus definitions have allowed the standardization of research on the subject&#46; The understanding of the physiopathology of ARF during sepsis is limited by the scarcity of histological studies and the inability to measure renal microcirculatory flows&#46; Historically&#44; ARF during sepsis has been considered to be a consequence of diminished renal blood flow &#40;RBF&#41;&#46; Indeed&#44; in early stages of sepsis or in sepsis associated to cardiogenic shock&#44; RBF may decrease&#46; However&#44; recent studies have shown that in resuscitated sepsis&#44; in which cardiac output is characteristically normal or even elevated and there is systemic vasodilatation&#44; RBF is normal or even increased&#44; with no associated histological evidence of significant tubular necrosis&#46; Thus&#44; other factors may participate in the genesis of ARF in sepsis&#46; These include apoptosis&#44; glomerular and medullary microcirculatory disorders&#44; cell changes in response to the pro-inflammatory cascade characteristic of sepsis&#44; oxidative stress&#44; mitochondrial dysfunction and damage induced by mechanical ventilation&#44; among others&#46; Sepsis-associated ARF treatment is supportive&#46; In general&#44; renal replacement therapies can be grouped as intermittent or continuous&#44; and as those whose primary objective is the replacement of impaired renal function&#44; versus those whose main objective is to secure hemodynamic stability through the clearing of pro-inflammatory mediators&#46;</p>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La insuficiencia renal aguda &#40;IRA&#41; es un factor de riesgo independiente asociado a mayor mortalidad durante la sepsis&#46; Definiciones de consenso recientes han permitido estandarizar los trabajos de investigaci&#243;n en el tema&#46; La comprensi&#243;n de la fisiopatolog&#237;a de la IRA durante la sepsis est&#225; limitada por la escasez de estudios histol&#243;gicos y por la imposibilidad de medir los flujos microcirculatorios renales&#46; Hist&#243;ricamente se ha considerado a la IRA s&#233;ptica como una patolog&#237;a dependiente de la ca&#237;da del flujo sangu&#237;neo renal &#40;FSR&#41;&#46; Efectivamente&#44; en las etapas precoces de la sepsis o en la sepsis acompa&#241;ada de shock cardiog&#233;nico existe compromiso del FSR&#59; sin embargo&#44; estudios recientes han demostrado que en la sepsis reanimada&#44; aquella en que caracter&#237;sticamente se observa un gasto cardiaco normal o alto y vasodilataci&#243;n sist&#233;mica&#44; el FSR es normal o incluso aumentado y no existe evidencia histol&#243;gica significativa de necrosis tubular&#46; Otros factores&#44; distintos al puramente hemodin&#225;mico&#44; participan en la g&#233;nesis de la IRA en la sepsis&#46; Entre &#233;stos est&#225;n la apoptosis celular&#44; los trastornos microcirculatorios glomerulares y medulares&#44; los cambios celulares en respuestas a la cascada proinflamatoria propia de la sepsis&#44; el estr&#233;s oxidativo&#44; la disfunci&#243;n mitocondrial y el da&#241;o a distancia inducido por ventilaci&#243;n mec&#225;nica&#44; entre otros&#46; En la actualidad&#44; el tratamiento de la IRA en la sepsis es de soporte&#46; En general&#44; las terapias de reemplazo renal pueden ser clasificadas como intermitentes o continuas&#44; y en las que buscan primariamente el reemplazo de la funci&#243;n renal deteriorada&#44; frente a aquellas cuyo objetivo principal es lograr la estabilidad hemodin&#225;mica de los pacientes mediante la remoci&#243;n de mediadores proinflamatorios&#46;</p>"
      ]
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        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara">Please cite this article as&#58; Regueira T&#44; et al&#46; Fisiopatolog&#237;a de la insuficiencia renal aguda durante la sepsis&#46; Med Intensiva&#46; 2011&#59;35&#58;424&#8211;32&#46;</p>"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">GF&#58; glomerular filtrate&#59; UF&#58; urinary flow&#59; ARF&#58; acute renal failure&#59; CRF&#58; chronic renal failure&#59; ESKD&#58; end-stage kidney disease&#46;</p>"
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                  \t\t\t\t\tvoid\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Category&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">GF criteria&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">UF criteria&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t">Risk</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8593; Creatinine<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>1&#46;5 or&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">UF<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;5<span class="elsevierStyleHsp" style=""></span>ml&#47;kg&#47;h<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>6<span class="elsevierStyleHsp" style=""></span>h</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="9" align="left" valign="middle">High sensitivityHigh specificity</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">GF decreased &#62;25&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " rowspan="2" align="left" valign="\n
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                  \t\t\t\t">Injury</td><td class="td" title="\n
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                  \t\t\t\t">&#8593; Creatinine<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>2 or&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">UF<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;5<span class="elsevierStyleHsp" style=""></span>ml&#47;kg&#47;h<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>12<span class="elsevierStyleHsp" style=""></span>h</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t">GF decreased &#62;50&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " rowspan="3" align="left" valign="\n
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                  \t\t\t\t">Failure</td><td class="td" title="\n
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                  \t\t\t\t">&#8593; Creatinine<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>3 or&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
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                  \t\t\t\t">UF<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;3<span class="elsevierStyleHsp" style=""></span>ml&#47;kg&#47;h<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>24<span class="elsevierStyleHsp" style=""></span>h or anuria<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>12<span class="elsevierStyleHsp" style=""></span>h</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">GF decreased &#62;75&#37; or&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ARF over CRF&#58; creatinine &#62;4<span class="elsevierStyleHsp" style=""></span>mg&#47;dl with acute &#8593; &#8805;0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Loss&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Persistent ARF<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>complete renal function loss &#62;4 weeks</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t">&#8593; Serum creatinine &#62;300&#37; &#40;&#62;3 times&#41; from baseline level<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> or serum creatinine &#8805;4&#46;0<span class="elsevierStyleHsp" style=""></span>mg&#47;dl with sharp &#8593; of at least 0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&nbsp;\t\t\t\t\t\t\n
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ISSN: 21735727
Original language: English
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