Accepted Manuscript

Recent advances in pathophysiology and biomarkers of sepsis-induced acute kidney

injury

Ilaria Umbro, Giuseppe Gentile, Francesca Tinti, Paolo Muiesan, Anna Paola
Mitterhofer

PII: S0163-4453(15)00373-4
DOI: 10.1016/j.jinf.2015.11.008
Reference: YJINF 3638

To appear in: Journal of Infection

Received Date: 24 September 2015

Revised Date: 24 November 2015
Accepted Date: 28 November 2015

Please cite this article as: Umbro I, Gentile G, Tinti F, Muiesan P, Mitterhofer AP, Recent advances in
pathophysiology and biomarkers of sepsis-induced acute kidney injury, Journal of Infection (2016), doi:
10.1016/j.jinf.2015.11.008.

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 ACCEPTED MANUSCRIPT
Recent advances in pathophysiology and biomarkers of sepsis-induced acute kidney injury

Running title: Sepsis-induced acute kidney injury

Ilaria Umbroa,b, Giuseppe Gentilec, Francesca Tintia,b, Paolo Muiesana, Anna Paola Mitterhoferb.

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a. The Liver Unit, Queen Elizabeth Hospital Birmingham, Mindelsohn Way, Edgbaston, B15 2GW
Birmingham, United Kingdom

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b. Department of Clinical Medicine, Nephrology and Dialysis B, Sapienza University of Rome, Viale
dell’Università 37, 00185 Rome, Italy

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c. Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Via Benevento 6,
00185 Rome, Italy

Ilaria Umbro: ilaria.umbro@hotmail.it

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Giuseppe Gentile: gentile@bce.uniroma1.it

Francesca Tinti: francesca.tinti@uniroma1.it

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Paolo Muiesan: Paolo.Muiesan@uhb.nhs.uk

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Anna Paola Mitterhofer: annapaola.mitter@uniroma1.it

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Corresponding author: Anna Paola Mitterhofer, Department of Clinical Medicine, Nephrology and Dialysis
B, Sapienza University of Rome, Viale dell’Università 37, 00185 Rome, Italy. Tel.: +39 06 4997 2089. E-mail
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address: annapaola.mitter@uniroma1.it
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Summary

Sepsis is a complex clinical syndrome characterized by a systemic inflammatory response to an infective

insult. This process often leads to widespread tissue injury and multiple organ dysfunction. In particular, the
development of acute kidney injury (AKI) is one of the most frequent complications, which increases the
complexity and cost of care, and is an independent risk factor for mortality. Previous suggestions
highlighting systemic hypotension, renal vasoconstriction and ischaemia–reperfusion injury as the primary
pathophysiological mechanisms involved in sepsis-induced AKI have been challenged. Recently it has been
shown that sepsis-induced AKI occurs in the setting of microvascular dysfunction with release of

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microparticles, inflammation and energetic adaptation of highly metabolic organs to cellular stress. The
intolerable high mortality rate associated with sepsis-induced AKI is partially explained by an incomplete
understanding of its pathophysiology and a delay in diagnosis. The aim of this review is to focus on

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advances in understanding the sepsis pathophysiology, with particular attention to the fundamental
mechanisms of sepsis-induced AKI and the potential diagnostic and prognostic markers involved.

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Keywords: Sepsis; Acute kidney injury; Sepsis-induced acute kidney injury; Sepsis pathophysiology;

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Microparticles; Prognostic markers AN
Introduction

The contact between a host and microorganisms, such as bacteria, viruses or parasites, induces a local
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immune reaction required for host protection. An imbalance between host immune response and
pathogen virulence may produce a systemic reaction called “sepsis” [1].
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1. Definition
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In 1991, the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM)
convened a “Consensus Conference” in the attempt to provide a set of definitions that could be applied to
patients with sepsis and its sequelae [2]. Conference participants, under the chairmanship of Roger C. Bone,
MD, defined “sepsis” as systemic inflammatory response (SIRS) plus infection, “severe sepsis” as sepsis
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associated with organ dysfunction, hypoperfusion or hypotension, and “septic shock” as sepsis with arterial
hypotension, despite adequate fluid resuscitation [2].
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According to the Consensus Conference, SIRS is considered to be present when patients have more than
one of the following clinical findings:
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• body temperature > 38°C or < 36°C;

• heart rate > 90 beats/min;
• hyperventilation evidenced by a respiratory rate of > 20 breaths/min or a PaCO2 < 32 mmHg;
• white blood cell count > 12.000 cells/L or < 4.000 cells/L or with > 10% immature neutrophils.

In 2001 the International Sepsis Definitions Conference, sponsored by the SCCM, the European Society of
Intensive Care Medicine, the ACCP, the American Thoracic Society and the Surgical Infection Society, began
with a view of the strengths and weaknesses of the definitions of sepsis and related conditions. They aimed
to focus on the identification of ways to improve them and to identify methodologies for increasing the
accuracy, reliability, and/or clinical utility of the diagnosis of sepsis. They included a list of possible signs of

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systemic inflammation in response to infection in order to codify the physical and laboratory findings that
prompt an experienced clinician to conclude that an infected patient “looks septic” [3].

The 2001 conference participants convened with the belief that the body of bench work since the 1991
Sepsis Definitions Conference may lead to a major change in the definition of sepsis based on biomarkers.
After a process of evidenced-based review and considerable debate, the participants determined that apart
from expanding the list of signs and symptoms of sepsis to reflect clinical bedside experience, no evidence
exists to support any change in the definitions and that the use of biomarkers for diagnosing sepsis is
premature [3].

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2. Epidemiology

Sepsis is a very complex clinical condition characterized by stimulation of a systemic inflammatory response

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related to an infection [4, 5]. This process often leads to widespread tissue injury that can progress to
multiple organ dysfunction including shock, with significant morbidity and mortality [6]. In the United

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States, an estimated 700.000 cases of sepsis occur each year, resulting in approximately 200.000 annual
deaths; this number accounts for 10% of all deaths annually and exceeds the number of deaths due to
myocardial infarction [7]. The development of acute kidney injury (AKI) is one of the most frequent

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complications of sepsis (about 40% in patients with severe sepsis and septic shock), which increases the
complexity and cost of care, and is an independent risk factor for higher mortality rate, that was
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significantly associated with the severity of AKI [8-11]. Sepsis-induced AKI is a multifactorial, complex
syndrome, associated with longer hospital stay, higher burden of comorbidities, worse outcome (in terms
of renal function and survival) compared to non-septic AKI (70% vs. 45%) or sepsis alone and is regarded as
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a distinct clinical entity [10-12].

Tian et al [13]showed that, according to Acute Kidney Injury Network (AKIN) criteria, the mean 28-day
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mortality was 42.3 % in stage 1 AKI, 66.7 % in stage 2 AKI and 84.6 % in stage 3 AKI, respectively, for
patients in control group and that was 21.7, 38.7 and 67.4 %, respectively, for patients underwent
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continuous renal replacement therapy (CRRT). These results suggest that higher degree of AKIN
classification is related to higher mortality. Despite the increasing ability to support vital organs and
resuscitate patients, the incidence and mortality of sepsis-induced AKI remain high. With the development
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of continuous veno-venous hemofiltration technique, a form of CRRT, the outcome of sepsis-induced AKI
has been significantly improved [13].
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The incidence of sepsis is increasing annually and with the failure of one organ there is a mortality level
approaching 30%, but with three or more organs failing it may exceed 60% [14].
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The intolerable high mortality rate associated with sepsis-induced AKI is partially explained by an
incomplete understanding of its pathophysiology, a delay in diagnosis and, subsequently, in correct
treatment which are crucial for improving sepsis condition [15, 16]. In fact the most recent international
sepsis guidelines entitled “Surviving Sepsis Campaign: International Guidelines for Management of Severe
Sepsis and Septic Shock: 2012” recommend early diagnosis and treatment of sepsis to avoid multiple organ
failure and other adverse outcomes [17]. Therefore, the introduction of new serum and urinary biomarkers
could hypothetically allow earlier diagnosis and better prognostication [18, 19].

Our aim was to review the relevant findings of human studies that were published in the last five years and
that focus on advances in understanding the sepsis pathophysiology, with particular attention to the
fundamental mechanisms of sepsis-induced AKI and the potential diagnostic and prognostic markers
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involved. Literatures related to "sepsis" and "sepsis AND acute kidney injury" were searched using PubMed.
Findings about emerging therapeutic targets and clinical outcomes were not included.

Sepsis

Sepsis is a clinical syndrome characterized by a systemic inflammatory response to an infective insult.

However, this definition lacks precision since the infection may be proven or suspected and the
accompanying non-specific systemic inflammatory response syndrome may also be triggered by non-

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infectious stimuli such as trauma, pancreatitis and cardiopulmonary bypass surgery [20]. In fact, only 60%
of cases are likely to be confirmed microbiologically and there is no correlation between severity of sepsis
and documented infection.

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Sepsis onset may be insidious and in 90% of patients infections are due to either Gram-positive (mainly
staphylococci and streptococci) or Gram-negative bacteria (predominantly Escherichia coli, Pseudomonas

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aeruginosa and Klebsiella species). Fungi, mostly Candida, are the causative agents in nearly 5% patients,
with viral infections and other atypical organisms accounting for the remainder [21]. Most cases of sepsis
are caused by microorganisms responsible for pneumonia with the others arising from infection of the gut,

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urinary tract, soft tissue and intravascular lines [22].
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During sepsis, inflammatory mediators derived from pathogens (macromolecular motifs called Pathogen
Associated Molecular Patterns or PAMPs) and activated immune cells (proteins also known as Damage
Associated Molecular Patterns or DAMPs) mediate host cellular injury [23]. DAMPs and PAMPs, present
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abnormally in a sterile body compartment, can be recognized not only by cells of the immune system, but
also epithelial and parenchymal cells, through a family of transmembrane or intracytoplasmic receptors,
named Pathogen Recognition Receptors or PRRs [24]. This family can be schematically divided on the basis
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of subcellular localization including the Toll-like receptors (TLRs), transmembrane receptors guarding the
extracellular and endosomal compartments, the NOD-like receptors and the retinoic-acid-inducible gene I-
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like helicases (RIG-I-like) scanning the cytoplasmic compartment [25, 26].

Pathogen Recognition Receptors (PRR) engagement leads to immune cell activation characterized by
initiation of microbe-killing systems, production and secretion of pro-inflammatory cytokines (i.e. tumour
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necrosis factor-α or TNF-α, interleukin (IL)-1α and IL-6) and chemokines, enhanced expression of
costimulatory receptors essential for efficient T cell activation, production of arachidonic acid metabolites
and initiator of extrinsic coagulation cascade (i.e. tissue factor, TF) [21].
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In favourable situation, the infection induced immune response is tightly controlled by different
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mechanisms that are triggered by PRR themselves to control the process. These mechanisms include
inhibition of the TLR-related intracellular signalling, production of soluble receptors and antagonists that
neutralize extracellular pro-inflammatory cytokines, production of anti-inflammatory cytokines (i.e. IL-10),
and specific silencing of pro-inflammatory genes [27, 28]. In some patients sepsis is accompanied by a
markedly imbalanced cytokine response, which converts responses that are normally beneficial for fighting
against infections into excessive, damaging inflammation. This leads to activation of the extrinsic system of
coagulation and formation of activated thrombin, further amplifying the thrombotic response via the
intrinsic coagulation cascade [29, 30]. There is also a reduction in some of the natural inhibitors of clotting
(i.e. activated protein C) from increased consumption and endothelial injury. The normal homeostatic
balance of fibrinolysis in the face of thrombosis is also disrupted by increased inhibition from cytokine
induced increases in plasminogen activator inhibitor type 1 and plasmin–antiplasmin complexes. The
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combination of increased thrombosis and reduced fibrinolysis creates microthrombi, which lead to multiple
organ dysfunction and organ failure. The clinical manifestations are seen as the development of, for
example, acute respiratory distress syndrome, disseminated intravascular coagulation or renal failure.

Sepsis-induced acute kidney injury

Sepsis is the most common contributing factor for the development of AKI, accounting for nearly 50% of
cases of AKI in the intensive care unit (ICU), using the latest clinical Kidney Diseases: Improving Global

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Outcomes (KDIGO) criteria based on both serum creatinine and urine output [9, 31-34]. Moreover, AKI is
the leading cause of death in the ICU [35]. In adult, sepsis accounts for 26% to 50% of all AKI in developed
nations, compared with 7% to 10% of AKI associated to primary kidney disease [36-40]. However, the

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pathophysiology of sepsis-induced AKI is still inadequately understood [10, 41]. Although previous studies
highlighted systemic hypotension, renal vasoconstriction and ischaemia–reperfusion injury as the primary

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pathophysiological mechanisms involved in sepsis-induced AKI, recently it has been shown that sepsis-
induced AKI occurs in the setting of renal vasodilatation and increased renal blood flow [42-44].

Thus, other pathophysiological mechanisms which differ from the traditional ischaemia paradigm, leading

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to tubular necrosis, may instead be responsible for septic AKI [45]:
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1- Microcirculatory flow abnormalities
2- Inflammation
3- Cell bioenergetic adaptive responses to injury
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4- Microparticles

1. Microcirculatory flow abnormalities

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Microvascular dysfunction, defined as any damage to the microvascular cellular components, including
endothelial cells, smooth muscle cells, and circulating blood cells, is often detected by altered flow or
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adhesive properties [46].

The fact that the kidney receives 20% of the cardiac output and filters about 120–150 mL of plasma every
minute places it on the front line to be exposed to some mediators. DAMPs and PAMPs can exert their
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effects on the renal tubular cells either via the peritubular microcirculation or they can be filtered at the
glomerulus. These molecules can be recognized by tubular cells through TLR-4 and TLR-2 causing tubular
cell injury [47]. Despite that potentially all nephrons in the kidney could be exposed to these mediators,
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only patches of tubular cells seem to display signs of distress to this danger signal [48]. Microvascular
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dysfunction may play a key role in amplifying the danger signal in specific areas of low flow, exposing the
neighbouring tubular epithelial cells and causing damage in the observed patchy distribution [49]. An
increase in renal perfusion pressure may activate the tubuloglomerular feedback (TGF) that causes afferent
arterial vasoconstriction and reduced hydrostatic pressure in the glomeruli resulting in sustained loss of
filtration with a decrease in the glomerular filtration rate (GFR). The TGF is an intrarenal negative control
mechanism in which NaCl concentration at the macula densa is used as an indicator of changes in filtration,
leading to normalisation of GFR. It limits renal oxygen consumption in a context of inflammatory stress.
[50, 51]

Perfusion to the cortex, mainly containing glomeruli, differs from that to the medulla, mainly containing
tubules. The cortex receives a large amount of blood for the filtration function. In contrast, maintenance of
the cortico medullary osmotic gradients requires low blood flow through the vasa recta. During sepsis, the
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general view has been that renal hypoperfusion is one of the main characteristics of septic AKI and
contributes to the development of renal hypoxia. Conversely, a growing body of evidence shows that sepsis
is not associated with evident renal hypoperfusion but instead is associated with a profound alteration in
microvascular blood flow distribution throughout the body maintaining or even increasing renal blood flow
even in the absence of hyperdynamic circulation [49, 52]. In particular, the renal microcirculation is altered
by several mechanisms such as: blood flow stagnation from altered circulatory cell function, endothelial
and parenchymal cell injury with oxygen utilization abnormalities and mitochondrial dysfunction, increased
coagulopathy [53-55]. In addition, severe capillary leakage can result in interstitial edema exacerbating low

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tissue oxygen perfusion, contributing to hypoxia and multiorgan dysfunction [53, 56, 57].

The progressive systemic haemodinamic deterioration, that characterised sepsis and causes renal
microvascular dysfunction and oxygen homeostasis impairment, leads to oxidative stress and hypoxaemia

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[58]. The microvascular dysfunction may restrict the adequate distribution of the renal oxygenation for the
production of ATP, needed for Na/K pump function and Na reabsorption by the proximal tubule [59]. In this

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context, parenchymal cells switch from aerobic to anaerobic respiration, producing reactive oxygen species.
In an anaerobic state, reactive oxygen species (ROS) are aggressively produced by the mitochondria,
resulting in more cell damage and endothelial cell dysfunction, perpetuating a vicious cycle [60-62].

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A potential role in the genesis of microvascular dysfunction and in the pathophysiology of sepsis-induced
AKI could be also attributed to nitric oxide (NO). Although it is known that sepsis elicits a global increment
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in production of NO, the expression of one of the most important catalyzers of its production, inducible
Nitric Oxide Synthase (iNOS) is heterogeneous [63]. Therefore it is reasonable to consider that
heterogeneous expression of iNOS may result in heterogeneous regional concentrations of NO, which could
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potentially lead to pockets of vascular beds deprived of NO even in the setting of elevated systemic levels.
This is important as it directly relates to the heterogeneous pattern that has been described in sepsis-
induced microvascular dysfunction, and furthermore, may relate to possible pathophysiologic phenomena
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like shunting and hypoxia [64] .

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Oxidative stress and microvascular dysfunction together have an important role in the development of
sepsis-AKI. The relationships between renal microvascular changes and ROS generation have been studied
in preclinical models of sepsis [48, 65, 66]. Nevertheless, the relationship between NO, microvascular
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dysfunction and AKI may not be as straight forward, as sepsis may also cause an iNOS-dependent decrease
in endothelial derived NOS activity (eNOS), which would also result in impaired microvascular homeostasis
[67, 68].
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2. Inflammation
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Sepsis triggers a systemic cytokine-chemokine response. A biphasic profile of immune activation followed
by suppression is shown, and the systemic effects of sepsis have the potential to lead to end-organ injury in
the kidney. Acute tubular necrosis is classically used to describe the cellular effects of sepsis driven by both
ischaemia-reperfusion injury and cytokine-mediated inflammation. However, this terminology is dated and
likely should be supplanted by modern clinical descriptions of AKI [69]. Activation of the endothelium by
circulating inflammatory cytokines leads to increased expression of endothelial adhesion molecules,
including expression of P-selectin, and increased expression of intracellular adhesion molecule-1 (ICAM-1)
and vascular cell adhesion molecule-1 (VCAM-1) in the peritubular capillaries. These molecules lead to
leukocyte activation creating a vicious circle in the inflammatory response [70]. In fact, activated leukocytes
may increase their adherence to the endothelium by up-regulating the expression of integrins, ICAM-1,

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VCAM-1 and selectins [71], within the capillaries. Moreover, they may contribute to microvascular flow
impairment stimulating the release of proinflammatory cytokines, such as IL-6 and IL-8.

Cytokines are also important in inducing a procoagulant effect and, as a consequence, thrombocytopenia
and other coagulation abnormalities are frequent in severe sepsis. Pro-inflammatory cytokines, in particular
IL-1, IL-6 and TNFa, disrupt the main function of vascular endothelial cells which is to maintain the fluidity
of blood. Conversely, some anticoagulant proteins, such as antithrombin, protein C and tissue factor
pathway inhibitor are downregulated. This results in the generation of thrombin that converts fibrinogen
into fibrin. The deposition of fibrin is further enhanced by vasoactive mediators such as histamine, platelet-

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activating factor (PAF) and arachidonic acid metabolites. Both IL-1 and TNFa further enhance clot formation
by impairing the anticoagulant pathway through their inhibition of the production of activated protein C,
which inactivates the procoagulant factors Va and VIIIa [72]. Blood concentrations of activated protein C

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and other inhibitors of coagulation, antithrombin III and thrombomodulin are depressed in sepsis and their
levels are inversely related to mortality [73].

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3. Cell bioenergetic adaptive responses to injury

For optimal function of intracellular organelles, cells require continuous ATP generation. Both oxidative and

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glycolytic pathways produce ATP, but mitochondrial oxidative phosphorylation is more efficient (38
molecules of ATP per mole of glucose vs. 2 molecules of ATP with glycolysis). The kidney derives most of its
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energy from oxidative metabolism (95–99%), and both proximal tubules and thick ascending limb are rich in
mitochondria [74] . They are dynamic organelles able to respond to the changing energy demands of the
cells, and they play a key role in the adaptation to cellular stress in highly metabolic organs. In addition to
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ATP generation by oxidative metabolism, mitochondria play a significant role in the generation and
detoxification of reactive oxygen species, cellular calcium homeostasis, cell survival and death (autophagy
and apoptosis), and other cell signaling pathways [75] . Mitochondria are also the site of production (i.e.
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cortisol) or action (i.e. triiodothyronine, estrogen) of many hormones [76-78], and the biosynthesis of heme
and iron-sulfur clusters [79]. Mitochondrial dysfunction has been actively pursued and strongly implicated
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in the pathophysiology of highly metabolic organs such as the heart, brain, and liver and more recently the
kidney [80].

Mitochondria can be affected in various ways through the systemic inflammatory process:
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- tissue hypoxia leads to insufficient oxygen at the mitochondrial level to drive oxidative
phosphorylation of ADP to ATP [81, 82];
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- excess amounts of NO, carbon monoxide, hydrogen sulfide, and other ROS directly inhibit
mitochondrial respiration, and cause direct damage to mitochondrial protein and other structures
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such as the lipid membrane [83-86];

- hormonal alterations in sepsis affect mitochondrial function and efficiency. For example, thyroid
hormone is thought to predominantly exert its effects via modulating mitochondrial activity [76],
genes transcribing mitochondrial proteins are downregulated early in the inflammatory response.

The inhibition, damage, and decreased turnover of new mitochondrial protein will affect generation of ATP.
This will be compounded by the mitochondrial inhibition/damage induced by the many drugs given as part
of patient management in the critical care setting, including antibiotics, catecholamine inotropes, and
sedatives. If cellular metabolic activity continued in the face of insufficient energy, then ATP levels will drop
and cell death pathways will be activated. Notably this does not appear to be a major feature of sepsis-
induced organ failure because cells may adapt to cope with the falling energy supply. One partial and short-

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term opportunity is an increase in non-mitochondrial ATP production through improved glycolytic activity
[87]. Another possibility is a decline in metabolic activity that may generate a steady-state in which the
reduced energy requirements do not allow ATP levels to drop enough to trigger cell death. This decrease
metabolism in the context of inflammation is likely hibernation. [88]

A decrease in cell functionality will be manifest, if sufficiently severe, as altered physiological and
biochemical functioning of the organ. This is then described as organ “dysfunction” or “failure” but may
actually represent a late-stage adaptive process by the cell/organ/body to deal with the onslaught of a
prolonged and severe inflammatory response [89].

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4. Microparticles

Microvascular dysfunction causes the release of the so called microparticles (MPs) into the systemic

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circulation [90, 91]. Microparticles are intact vesicles derived from the plasma membrane during cellular
activation and apoptosis that promote coagulation and inflammation [92], perpetuating microvascular

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injury. The generation of MPs occurs through an exocytic budding process in several cell types, including
endothelial cells, red blood cells, monocytes, platelets and vascular smooth muscle cells [93].

Microparticles contain proteins and lipids from cell membranes and cytoplasm of their parental cells and

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present cell-specific surface antigens that reflect the parent cell from which they originate at the time of
release. The outer MP membrane contains two procoagulants: a procoagulant phospholipid, and tissue
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factor. Thus, MP subpopulations are heterogeneous with different antigenic profiles and functions which
may depend on their cellular origin and state of activation of the parental cells [94]. Therefore, MPs are
considered as a distributed storage pool of bioactive effectors, exerting proinflammatory [95, 96], and
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prothrombotic properties [97, 98] in the immediate microenvironment of their formation [99].

Microparticles are present at low levels in the blood of healthy individuals, but they are seriously increased
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in a number of pathological states associated with inflammation, activated coagulation, and fibrinolysis
including acute coronary syndrome, metabolic syndrome, cardiopulmonary bypass, antiphospholipid
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syndrome, rheumatoid arthritis, pre-eclampsia, and sepsis [100-102].

Microparticles can directly modulate endothelial cell nitric oxide and prostacyclin productions, stimulate
cytokine release and tissue factor induction, and promote monocyte chemotaxis and adherence to the
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endothelium [103]. Microparticles extracted from whole blood of septic patients exerted pleiotropic and
tissue selective changes in the expression of proinflammatory proteins related to nitrative and oxidative
stresses, changes not seen when MPs were isolated from non septic controls [104].
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Microparticles can also contribute to the prothrombotic state in sepsis by initiating disseminated
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intravascular coagulopathy, a known contributor to multiple-organ dysfunction [95]. In fact tissue factor
present on the surface of MPs is a primary initiator of coagulation.

Microparticles may therefore play a critical role in both the initiation and propagation of sepsis and septic
shock, and possibly in sepsis-induced AKI.

See figure 1.

Novel biomarkers of sepsis-induced acute kidney injury

Many trials have identified potential biomarkers for the diagnosis and prognosis of sepsis-induced AKI
[105].

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1. Alpha 1-microglobulin. Alpha-1-microglobulin (α1m) is a low-molecular weight protein that is synthesized
in the liver, freely filtered by glomeruli and reabsorbed by renal proximal tubular cells where it is
catabolised [106]. Beyond the potential role as a renal biomarker, recent studies revealed that α1m exhibits
several immunosuppressive functions and acts as a radical reductase and scavenger. These findings support
the assumption that α1m may serve as a protector of cells and tissues against apoptotic damage [107-109].
Under normal conditions very little filtered α1m appears in the final excreted urine [110-112]. Therefore,
urine levels above the reference values can indicate proximal tubular damage [113]. Terzi et al [114]
assessed the utility of urine concentrations of α1m as biomarker of early sepsis-induced AKI diagnosis in

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critically ill patients managed in an ICU. They revealed elevated levels of α1m in all septic patients and a
progressive increase of α1m in patients who finally developed sepsis-associated acute kidney injury.

2. Presepsin. Presepsin is a 13-kDa protein that is a fragment of CD14 with truncated N-terminal, the

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receptor for lipopolysaccharide (LPS)/LPS binding protein (LBP) complexes. Recently, presepsin has been
shown to increase in blood in the early stages of sepsis [115]. A multicenter prospective study by Endo et al.

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[116] showed that presepsin is a highly specific marker for diagnosis of bacterial infections in comparison to
other sepsis markers (procalcitonin, IL-6). Nakamura et al [117] attempted to clarify the diagnostic accuracy
of sepsis using the presepsin level according to AKI severity of the patients. They observed that presepsin
was significantly increased in sepsis patients with non-AKI and patients with milder forms of AKI (Risk and

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Injury) compared to non-sepsis groups. Furthermore, the median value of presepsin increased with
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increasing severity of AKI both in the non-sepsis and sepsis groups. Therefore they demonstrated that
blood presepsin level can be a reliable indicator of sepsis not only among non-AKI patients but also patients
with less severe forms of AKI. However, it may not be a reliable indicator of sepsis in patients with a more
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advanced form of AKI, such as those classified under the Risk, Injury, Failure, Loss, End-Stage (RIFLE) criteria
as having failure of kidney function, loss of kidney function and end-stage kidney disease.

3. Procalcitonin. Procalcitonin (PCT), a 13-kDa protein, was first described as a marker elevated in bacterial
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infections in 1993 [118]. In infectious conditions, PCT is released from a lot of tissues including lung, liver,
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kidney, pancreas, spleen, colon, and adipose tissues [119]. Currently, PCT is recognized as one of the
suitable markers for diagnosis of sepsis or severe sepsis. In comparison to other markers which have
traditionally been reported, PCT gives a high rate of specificity for sepsis diagnosis [120]. However, the
concentration of PCT in the human blood is elevated in various conditions, such as in severe trauma,
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surgical invasive procedures, and critical burn injury, which leads to SIRS [121]. In addition, it has been
reported that renal function is a major determinant of PCT levels and thus different thresholds should be
applied according to renal function impairment [122]. There are few studies investigating the relationship
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between PCT and AKI. The purpose of this study by Nakamura et al was to clarify the accuracy of diagnosing
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sepsis using the PCT levels according to AKI severity [123]. They demonstrated that the diagnostic accuracy
of the PCT level of Failure-AKI patients was significantly lower than of non-AKI patients. In addition, there
were significant positive correlation between PCT and Cr, and negative correlation between PCT and eGFR
between each patient. Furthermore, the optimal cut off value of PCT for detecting sepsis is higher in Failure
patients. Therefore, these results suggest that kidney is one of the responsible organs in eliminating PCT
from blood. As a result, PCT may not be a reliable indicator of sepsis in patients with a more advanced form
of AKI, such as those classified under RIFLE criteria as having failure of kidney function. On the other hand,
in septic shock patients, the level of PCT was significantly higher than that in the sepsis and severe sepsis
patients so they suggested that the cause of the rising levels of PCT in sepsis patients was not only AKI but
also sepsis severity.

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4. Neutrophil gelatinase-associated lipocalin. Neutrophil gelatinase-associated lipocalin (NGAL) has been
the most frequently investigated biomarker for early diagnosis of AKI [124]. In humans, three different
forms of NGAL can be found, namely a 25 kDa monomer, a 45 kDa dimer and a 135 kDa heterodimer,
covalently conjugated with gelatinase [125-127]. Up till now, no commercially available immunoassays are
able to make a clear discrimination between the monomer, mainly released from tubular epithelial cells,
and the dimer, originating from neutrophils [126]. Some studies found increased urinary NGAL levels in
patients classified as having transient AKI, suggesting presence of subtle tubular structural injury [128, 129].
Other studies showed a rise in NGAL levels (either in serum or urine) without a rise in serum creatinine or a

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decrease in urinary output. As a result, they speculated on the existence of a new entity called subclinical
AKI [130, 131]. However, serum NGAL levels can be increased in many other conditions beside acute kidney
injury, such as inflammation [132]. As serum NGAL is filtered at the glomerular level, also urinary NGAL can

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potentially be influenced by inflammation [133, 135]. Vanmassenhove et al [136] aimed to characterize the
origin of the raised serum and urine levels of NGAL in septic patients hypothesizing that, as in sepsis
patients, the prevalence of AKI is related to severity of sepsis, which in turn is associated with an increase in

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urinary and serum NGAL levels, a correlation between both urinary and serum NGAL, and severity of illness
could exist, independent of the presence of AKI. They confirmed that the risk for AKI increased with severity
of sepsis. Serum and urinary levels of NGAL increased with severity of illness and inflammation, as assessed

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by APACHE II and CRP. In addition, there was a strong correlation between urinary and serum levels of
NGAL, irrespective of presence of AKI.
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5. Soluble triggering receptor expressed on myeloid cells-1. Urine soluble triggering receptor expressed on
myeloid cells-1 (sTREM-1) is a member of the immunoglobulin superfamily of receptors which is expressed
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on polymorphonuclear granulocytes and mature monocytes [137]. Levels of sTREM-1 has been shown to
increase in body fluid samples during infectious diseases, such as sepsis, pneumonia, septic arthritis,
meningitis, peritonitis, and uterine cavity infection [138]. It has also been reported that serum sTREM-1
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could be used in the assessment of severity or even prognosis of sepsis [139, 140]. While the concentration
of sTREM-1 in normal urine is almost undetectable, it increases in sepsis (30-50 pg/ml) and its dynamic
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change suggests disease progression and/or AKI occurrence or even poor prognosis. Derive and Gibot [141]
demonstrated that the alteration of both plasma and urine sTREM-1 concentration in the non-AKI patient
with sepsis was mild but was very dramatic in the case of AKI. Su et al. suggested that the topical
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inflammatory response of kidney could be involved in the AKI process, not just the systemic inflammatory
response. Thus, sTREM-1 may be produced locally by the endothelial cells, tubular epithelial cells, or
infiltrating inflammatory cells that are recruited during acute tubular necrosis. Consequently, sTREM-1 may
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be released into the blood circulation as a result of alteration in glomerular filtration barrier membrane
pore size and charge.
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6. Others. Powell et al [142] evaluated the association between such markers of inflammation and
endothelial activation at baseline and the risk of future AKI after sepsis. They focused on markers of
inflammation and endothelial cell activation with biologically plausible connections to sepsis and AKI
pathophysiology including IL-6, TNF-α, soluble endothelium selectin (E-Selectin), intercellular adhesion
molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and urinary Albumin-to-creatinine ratio
(ACR). They observed associations between baseline biomarkers E-Selectin and urinary ACR and the risk of
future AKI after sepsis. This association persisted after adjustment for potential confounders. Their
observations supported the hypothesis that before evident renal cellular injury has occurred, there may be
alterations in microcirculation and tissue oxygenation that predispose to renal damage [143]. This concept

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is especially relevant to the septic state, where inflammation and endothelial cell activation are prominent
[144].

Nevertheless, each biomarker has advantages and drawbacks. Sometimes, it may be inappropriate to use
some biomarkers. For example, pre-existing kidney disease may interfere with the NGAL concentration and
septic patients with underlying diseases, such as cancer, chronic kidney disease, immunosuppressed
patients or patients who are or undergoing steroid treatment, may have false-negative results [145-148].

These suggest that not only a single indicator capable of confirming an AKI diagnosis is needed but a

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combination of biomarkers might be more valuable and precise in diagnosing sepsis associated AKI.
Therefore, a large sample size and multicenter study are necessary to validate potential biomarkers in
order to develop a panel of biomarkers to improve the sensitivity and specificity of diagnostic efficacy of

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AKI.

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Conclusion

In conclusion, it seems noticeable that a complex interplay of inflammation and microvascular dysfunction

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characterizes and amplifies the inflammatory signal involved in sepsis-induced AKI. As a consequence,
mitochondria within tubular cells orchestrate a complete metabolic downregulation and reprioritization of
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energy utilization which favors individual cell survival processes (such as mitophagy and cell cycle arrest), at
the expense of kidney function.

Despite marked progresses and profound changes in understanding of the pathophysiology of septic AKI in
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the more recent years, there are still major gaps in our knowledge. It seems reasonable that the
pathophysiological mechanisms involved in sepsis-induced AKI are multiple and more complex than
previously thought and that modern conceptualization of the disease process has abandoned the notion of
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equating sepsis-induced AKI to acute tubular necrosis focusing on renal microvascular alterations.
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Further experimental and human data using the latest standard definitions of sepsis-induced AKI, the
greater application of novel biomarker measurements and molecular biology techniques will likely be
applied to increase our understanding of septic AKI in the next decade.
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Authors’ Contribution
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Ilaria Umbro, Francesca Tinti and Anna Paola Mitterhofer designed and conducted the research; Ilaria
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Umbro analyzed the data and drafted the article; Ilaria Umbro, Giuseppe Gentile, Paolo Muiesan and Anna
Paola Mitterhofer made critical revisions related to important intellectual contents of the manuscript. All
authors had full access to all of the data in the research and approved the final version of the paper.

Conflict of Interests

All authors declare that they have no competing interests regarding the publication of this paper.

Acknowledgments

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This study was supported by a research grant of the Italian Society of Nephrology. The study sponsor
provided logistic support but had no role in the collection and analysis of data or in the writing of the report
and in the decision to submit the paper for publication.

Figure captions

Figure 1. Pathophysiological mechanisms of sepsis-induced acute kidney injury

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DAMPs, Damage Associated Molecular Patterns; PAMPs, Pathogen Associated Molecular Patterns; PRRs,
Pathogen Recognition Receptors; TLR, Toll-like receptors; RIG-I-like receptors, retinoic-acid-inducible gene
I-like helicases receptors; ATN, acute tubular necrosis; NO, Nitric Oxide; iNOS, inducible Nitric Oxide

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Synthase; ROS, reactive oxygen species; DIC, disseminated intravascular coagulation; GFR, glomerular
filtration rate; AKI, acute kidney injury.

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SEPSIS

AFFERENT ARTERIAL VASOCOSTRICTION EFFERENT ARTERIAL VASODILATION

DAMPs/PAMPs
GLOMERULUS

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Tubular epithelial cell

Peritubular capillaries
Tubular lumen
Immune cell activation Circulating DAMPs/PAMPs
Filtered DAMPs/PAMPs /

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Inflammation blood inflammatory mediators
inflammatory mediators
Hypoxia

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PRRs (TLR, NOD-like,
activated leukocytes
RIG-I-like receptors)

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MITOCHONDRIAL and
Proximal tubule

DYSFUNCTION endothelium

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ATP iNOS
NO microvascular
capillary leak activity
dysfunction

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ROS
vasodilatation NO

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apoptosis Cell hibernation
RENAL BLOOD FLOW
Cell cycle arrest

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Tubular HYPOTENSION
Exfoliation into lumen
injury patchy NO
Prostacycline,cytokines
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HYPOXIA
Endothelial dysfunction
MICROPARTICLES (MPs)
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Procoagulant/ proinflammatory
DIC Arachidonic acid properties: Phosphatidylserine,
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ATN metabolities Tissue factor/microhrombi

Tissue oxigenation COAGULATION CASCADE
hypercoagulopathy
Tubuloglomerular feedback GFR
AKI
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Recent advances in pathophysiology and biomarkers of sepsis-induced acute kidney injury

Highlights:

• Acute kidney injury induced by sepsis associated with high mortality rate
• Recent role of microvascular dysfunction inducing acute kidney injury during sepsis
• Release of microparticles, inflammation and energetic adaptation to cellular stress
• Review on pathophysiology of sepsis-induced AKI and diagnostic/prognostic markers

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