Sepsis-associated acute kidney injury - treatment standard

Alexander Zarbock,1 Jay L. Koyner,2 Hernando Gomez,3 Peter Pickkers,4 Lui Forni5,6 on behalf
of the ADQI group

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Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital of
Münster, Münster, Germany

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Section of Nephrology, Department of Medicine, University of Chicago, Chicago, Illinois,
USA

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Program for Critical Care Nephrology, Department of Critical Care Medicine, University of
Pittsburgh, Pittsburgh, PA, USA

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Department Intensive Care Medicine, Radboud University Medical Centre, Nijmegen, The
Netherlands

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Department of Critical Care, Royal Surrey Hospital Foundation Trust, Guildford, Surrey UK

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Faculty of Health Sciences, University of Surrey, Guildford, Surrey UK
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Correspondence to: Alexander Zarbock; E-mail: zarbock@uni-muenster.de

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© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.
All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
 ABSTRACT
Sepsis is a host's deleterious response to infection, which could lead to life-threatening
organ dysfunction. Sepsis-associated acute kidney injury (SA-AKI) is the most frequent organ
dysfunction and is associated with increased morbidity and mortality. Sepsis contributes to
approximately 50% of all AKI in critically ill adult patients. A growing body of evidence has
unveiled key aspects of the clinical risk factors, pathobiology, response to treatment, and

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elements of renal recovery that have advanced our ability to detect, prevent, and treat SA-
AKI. Despite these advancements, SA-AKI remains a critical clinical condition and a major
health burden, and further studies are needed to diminish the short and long-term
consequences of SA-AKI. We review the current treatment standards and discuss novel
developments in the pathophysiology, diagnosis, outcome prediction, and management of

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SA-AKI.
Keywords: acute kidney injury, biomarker, renal replacement therapy, sepsis

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 "In a nutshell "

1. The pathophysiology of sepsis-associated acute kidney injury is complex and

incompletely understood.
2. Biomarkers can identify patients at high risk for AKI and predict short- and long-
term adverse outcomes.
3. Implementing supportive measures (e.g., hemodynamic optimization and

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avoidance/minimizing nephrotoxins) in septic patients at high risk for AKI might
prevent AKI development, but no specific therapies are available to treat sepsis-
associated acute kidney injury.
4. RRT should be initiated in patients with sepsis who develop medically refractory
complications or persistent AKI, however, a strategy or early pre-emptive RRT is
not associated with improved outcomes.

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5. Preliminary data have suggested that selective subphenotypes of SA-AKI may
better response to specific vasoactives (e.g., AVP, Ang2), however, further
confirmatory data are needed.

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 Introduction
Sepsis is characterized by organ dysfunction as a consequence of a dysregulated response to
infection. Septic shock is characterized by persistent hypotension despite adequate fluid
resuscitation, the need of vasoactive drugs to maintain a mean arterial pressure of at least
65 mm Hg and a plasma lactate concentration above 2 mmol/L.[1]

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Up to 60% of patients with sepsis develop acute kidney injury (AKI).[2] Although the
pathophysiology underlying sepsis-associated AKI (SA-AKI) remains incompletely
understood, multiple mechanisms, including inflammation, complement activation,
mitochondrial dysfunction, and microcirculatory dysfunction, are thought to contribute to
AKI development.[3] The development of AKI carries a significantly increased mortality risk
compared to sepsis alone.[4]

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Here we discuss the most recent evidence supporting our current understanding of the
pathophysiology and outcome prediction in patients with SA-AKI. Furthermore, based on the

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recent recommendations of the Acute Disease Quality Initiative (ADQI) group,[5] we have
developed a pragmatic diagnostic and treatment algorithm for SA-AKI in adults.

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Treatment standards

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From Diagnosis to Treatment of Sepsis-Associated AKI (Figure 1)

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Where sepsis is suspected, lactate should be measured, and if elevated (> 2 mmol/L),
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measurement should be repeated with resuscitation guided by lactate levels. Once sepsis is
diagnosed, the patient should be treated according to current surviving sepsis guidelines,[1]
and before administering antibiotics, blood cultures should be obtained. In the presence of
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sepsis-induced hypoperfusion (lactate levels ≥ 2 mmol/L) or septic shock, crystalloid fluid

administration should be initiated and guided based on dynamic parameters of fluid
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responsiveness, along with vasopressors to keep the mean arterial pressure >65 mmHg and
decrease serum lactate levels. The recommended first line vasopressor in septic patients is
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norepinephrine, whereas dopamine should not be used in this patient group.[1]

Early fluid administration is important to potentially rescue the macro- and microcirculation
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in sepsis. The guidelines recommend an initial 30 ml/kg of crystalloids without adjusting this
volume to the current fluid status of the patient.[1] As volume overload is associated with a
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worse outcome,[6] fluid administration should be individualized and guided by fluid

responsiveness. The type of fluid used for resuscitation has resulted in much study and
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debate with earlier evidence suggesting that 0.9% saline may cause a hyperchloremia
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resulting in AKI and worse patient-centered outcomes.[7] However, more recent studies
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have demonstrated that saline may be used safely without untoward effects.[8] Given the
contradictory evidence this issue remains an area of contention, but based on the current
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evidence, the use of up to 4 l saline seems to be safe in regard to patient-centered

outcomes.[9]
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All patients with sepsis should be considered at high risk for AKI, whereas patients with
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certain comorbidities, like chronic kidney disease, have an even higher risk to develop AKI
 under these circumstances. Kidney function should be monitored closely using serum
creatinine and urine output for earlier detection and staging according to the Kidney Disease
Improving Global Outcomes (KDIGO) guidelines.[10] However, the KDIGO definition of AKI
has several limitations. For example, a baseline serum creatinine value is necessary to
establish an increase, and no consensus method exists to establish a pre-AKI baseline serum
creatinine in the absence of direct data.[11] Furthermore, serum creatinine changes are

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often delayed, particularly in sepsis, where the creatinine production rate may be reduced
by 50%, and fluid resuscitation may dilute creatinine concentration.[12] Although integral to
the AKI definition, urine output is nonspecific and is measured accurately only in patients
with an indwelling urinary catheter. Interestingly, several observational cohort studies show
that the same stage of AKI diagnosed by either serum creatinine or urine output may confer
a differential risk of morbidity and mortality.[13, 14]

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Early detection of kidney damage is essential as it may increase the opportunity for
successful interventions.[15, 16] Combining damage and functional biomarkers to increase

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the sensitivity and specificity of AKI definitions may help.[17] Stage 1S ('subclinical AKI'), for
example, is defined by increased stress/injury biomarker levels despite normal functional

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biomarkers (serum creatinine and urine output). In addition, data from the Protocolized Care
for Early Septic Shock (ProCESS) cohort demonstrated that biomarker-positive AKI was

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associated with lower 30-day survival than biomarker-negative AKI despite the same

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functional stage of AKI defined by KDIGO criteria.[18]

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The concentrations of several serum biomarkers inversely correlate with glomerular
filtration rate (GFR) and may provide an advantage in detecting SA-AKI. Cystatin C and
proenkephalin increase earlier than serum creatinine in critically ill patients with sepsis.[19,
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20] Urinary tissue inhibitor of metalloproteinase-2 and insulin-like growth factor binding
protein-7 (TIMP2•IGFBP7), two markers associated with cell cycle arrest, have a very good
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performance in predicting stage 2 or 3 AKI in critically ill patients with sepsis (AUC of
0.84).[21] Plasma neutrophil gelatinase-associated lipocalin (NGAL) has been demonstrated
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to be elevated in septic patients, even in the absence of creatinine or urine output-based

AKI. A higher cutoff value (454 ng/mL) provides a specificity of 74% and a sensitivity of 72%
for detecting AKI.[22]
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Bedside Doppler ultrasound is a rapid, noninvasive, and repeatable tool for evaluating renal
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perfusion and is widely used in critically ill patients.[23] The Doppler-based renal resistive
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index (RRI) changes before changes in serum creatinine occur during the development of AKI
and RRI has been shown to predict AKI.[24] However, it has been shown that renal doppler
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does not discriminate between patterns of renal recovery nor modifies risk stratification for
acute kidney injury persistence.[25] In addition, several physiological factors, such as intra-
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abdominal pressure and vascular compliance, influence RRI. Urinalysis and urine microscopy
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may contribute to the identification of SA-AKI. Several observational studies evaluated a

urine microscopy score in a cohort of SA-AKI.[26, 27] SA-AKI shows more cast elements and
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renal tubule epithelial cells compared with non-septic AKI. A small trial demonstrated that a
 urinalysis score above 3 was predictive of severe AKI and significantly correlated with
biomarkers of tubular injury.[27]

Patients at high risk for SA-AKI

In patients at high risk for AKI, the KDIGO guidelines recommend implementing a care

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bundle of supportive measures.[10] Indeed, it has been demonstrated that implementing
supportive measures in surgical patients at risk can reduce the occurrence of AKI.[15, 16, 28]
However, this has not been explicitly shown in patients with sepsis. Moreover, despite these
measures being part of routine clinical care, only a minority of patients receive all the
guideline-recommended measures.[28-31] The bundle that has been shown to reduce AKI in

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patients at risk for AKI [15, 16] could be implemented in septic patients at high risk of AKI
and is outlined in Table 1. It includes avoidance of potentially nephrotoxic agents (e.g.,
hydroxyethyl starch), close monitoring of serum creatinine and urine output, avoidance of

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hyperglycemia, consideration of alternatives to radiocontrast agents and hemodynamic
monitoring with optimization of both volume status and hemodynamics.

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Patients with SA-AKI

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The supportive measure should be continued in patients with an established AKI. However,

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no evidence shows that the bundle can positively influence the course of AKI.
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Diuretics
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The prophylactic use of diuretics in patients with a high risk of AKI has been shown to be
unsuccessful in critically ill patients.[32] Similarly, diuretics do not attenuate AKI once it is
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established.[33] Therefore, the use of diuretics for the prevention or treatment of SA-AKI is
not recommended. However, their use in regulating fluid balance and preventing fluid
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overload fosters their continued use in critical illness despite their inability to improve renal
outcomes.
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Bicarbonate
In the subgroup analysis of the BICAR-ICU trial, a multicenter, open-labeled, controlled phase
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3 clinical trial, demonstrated that treatment with intravenous 4.2% sodium bicarbonate for
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severe metabolic acidemia (pH < 7.20) in critically ill patients with moderate-to-severe AKI
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(AKIN stage 2 or 3) reduced the primary composite outcome (death from any cause by day
28 and the presence of at least one organ failure at day 7) and 28-day mortality.[34]
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However, 24% of the control arm received bicarbonate therapy, and these observations may
be subject to considerable type 1 error. Also, only 60% of the trial population had sepsis at
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randomization. Therefore, the results cannot be fully extrapolated to patients with SA-AKI.
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 Blood pressure and vasopressors
Although the arterial blood pressure target in septic patients is unknown, one trial
demonstrated that targeting a mean arterial pressure above 85 mmHg in patients with pre-
existing hypertension reduced the serum creatinine increase and the need for renal
replacement therapy.[35] Angiotensin 2, an endogenous vasoconstrictor, preferentially
constricts the glomerular efferent arteriole, thus increasing the glomerular filtration rate. A

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post-hoc analysis of the ATHOS-3 trial showed that patients with vasodilatory shock on renal
replacement therapy (RRT) randomized to angiotensin 2 discontinued RRT earlier (38% vs.
15% by day 7, p=0.007) and had lower 28-day mortality (30% vs. 53%, p=0.012) compared to
placebo.[36] Data from a post-hoc analysis suggest that patients with low angiotensin 2 and
a high renin levels benefit from this drug.[37, 38] However, further validation of these

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findings data is needed
Renal replacement therapy (RRT)

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Several recent studies have investigated different aspects of RRT in the critically ill,[39-42]
specifically in SA-AKI patients.

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Data around the timing of RRT in SA-AKI suggest that there is no benefit from accelerated

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RRT initiation.[43] One multicenter randomized trial in SA-AKI was stopped early for futility,
with mortality rates of 58% (138/239) in the early group and 54% (128/238) in the delayed

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group.[44] However, 93 (38%) patients in the delayed arm never received RRT.

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Regarding RRT dosing, the evidence supports the recommended delivery dose of 20-25
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mL/kg/h,[40, 41] partly based on studies demonstrating no benefit with higher doses or
high-volume hemofiltration.[45-47]
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In the setting of SA-AKI, large RCTs and meta-analyses have demonstrated no difference in
outcomes between intermittent vs. continuous RRT. [48, 49] However, it might be possible
that hemodynamically unstable patients benefit more from continuous RRT compared to
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intermittent RRT. Therefore, clinicians should start the RRT modality they are most familiar
with, and that achieves a delivered dose of 20-25 mL/ kg/h for continuous RRT or a Kt/V of
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3.9 per week for intermittent dialysis.

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Pathophysiology
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It is likely that SA-AKI is caused by multiple pathophysiologic mechanisms that interact with
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host background susceptibility factors, the host's capacity to withstand tissue injury or
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tolerance capacity, direct effects related to sepsis, and the effect of sepsis-associated
therapies. Future trials to test therapeutic interventions to alleviate SA-AKI will need to
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embrace this complexity and likely rely on biomarkers to select patients in whom the
targeting particular processes is relevant.
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A specific pathophysiologic mechanism proved to induce tubular injury; therefore, AKI is

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defined as an endotype. In sepsis, rather than a single endotype, multiple endotypes likely
interact and cause injury, thereby inducing SA-AKI. Mechanisms such as local inflammation,
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innate immune activation, mitochondrial and microvascular dysfunction, oxidative stress,

 hypoxia, renin-angiotensin-aldosterone axis dysfunction, complement activation, and
metabolic reprogramming are all supported by the literature as prominent endotype
candidates to explain the underpinnings of SA-AKI. The evidence supporting the
preeminence of these mechanisms is discussed next.
Local innate immune activation, inflammation, and complement activation. The early
interaction of damage and pathogen-associated molecular patterns (DAMPs and PAMPs)

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with the host's pattern recognition receptors (PRRs) induces the activation of immunity and
complement pathways, leading to a systemic and local renal inflammatory response. DAMPs
and PAMPs can be filtered through the glomerulus and engage tubular epithelial cell toll-like
receptors (i.e., TLR4). In the tubular system, TLR4 engagement triggers an oxidative stress
outburst.[50] PAMPs and DAMPs can also bind to PRR and promote local inflammation.[51]

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Microvascular dysfunction, oxidative stress, amplification of the inflammatory response,
intrarenal shunting, and tissue hypoxia. Sepsis is known to cause widespread, systemic

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microvascular dysfunction, manifested as a decrease in the proportion of capillaries with
continuous flow, an increase in the proportion of capillaries with intermittent or no flow,

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and an increase in the heterogeneity of blood flow distribution. [52] This also occurs at the
level of the peritubular microvasculature before changes in renal blood flow occur and

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creatinine rises. [53] In an animal sepsis model, oxidative stress represented by increased
production of reactive oxygen and nitrogen species occurred in tubular epithelial cells

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adjacent to peritubular capillaries with intermittent or stop flow, suggesting a link between

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these two injury mechanisms.[53] Sluggish peritubular flow can also amplify the
inflammatory response by increasing the exposure time of neighboring epithelial cells to
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activated, cytokine-spilling leukocytes transiting through the peritubular capillaries.[54] This
inflammatory amplification may explain the association between capillary dysfunction and
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oxidative stress in the tubular epithelium. A more direct consequence of microvascular

dysfunction may be intrarenal shunting, leading to the development of areas of tissue
hypoxia leading to tubular injury.
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RAAS dysfunction. The renin-angiotensin-aldosterone system modulates vascular tone, fluid

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and electrolyte balance, and glomerular filtration rate.[55] In critically ill patients, elevated
renin levels are associated with worse survival, major adverse kidney events (MAKE) and
need for renal replacement therapy.[56] In addition, elevated renin levels are usually found
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in patients with refractory vasodilatory shock.[56] Notably, the inflammatory response can
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cause ACE dysfunction, leading to a deficit in ATII.[55]

Mitochondrial dysfunction. The tubular epithelium of the proximal tubules has the daunting,
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energetically expensive task of reabsorbing ~70% of the sodium contained in the ~170 L/day
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of fluid filtered by the glomerulus. Unsurprisingly, the proximal tubule and thick ascending
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limb of the loop of Henle are only second to the heart in mitochondrial density. Therefore,
mitochondrial well-being is critical to tubular and renal function. Sepsis induces
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mitochondrial injury through oxidative damage, [57] TLR4-mediated inflammation,[58] and

electron transport chain inhibition.[59] It is characterized by decreased mitochondrial mass,
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disruption of cristae, and variable mitochondrial swelling.[60] In addition, sepsis impairs

mitochondrial quality control mechanisms like fission, fusion, and mitophagy, which are
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critical for protecting and rescuing dysfunctional mitochondria. [60]

 Outcome prediction
As discussed above, AKI biomarkers have been used to improve early risk stratification of
patients prone to or already with SA-AKI. In addition, several studies have demonstrated that
blood and urinary biomarkers measured early in the clinical course of sepsis can predict

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patient-oriented outcomes like AKI progression, need for RRT, or mortality.
In samples from over 2,500 patients with sepsis and septic shock from the FROG-ICU and
ADRENOSS studies, Dupret and colleagues showed that in the absence of changes in serum
creatinine and urine output, an elevated proenkephalin level (>80 pmol/L) at the time of ICU
arrival was associated with an increased risk of inpatient mortality.[61] While this elevated

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biomarker in the absence of changes in traditional AKI markers was only present in 6-7% of
the population, the association between proenkephalin and mortality persisted after
adjusting for age, sex, comorbidities, ICU diagnosis, creatinine, and diuresis.

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In a planned sub-study of the ProCESS trial (an early goal-directed therapy in sepsis

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randomized control study), patients who had persistently elevated TIMP2•IGFBP7 levels
(>0.3 [ng/mL]2/1000) after the first 6 hours of resuscitation with fluids and vasopressors

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were at higher risk for a composite endpoint of progression to severe AKI (Stage 2/3), receipt
of dialysis and mortality.[62] Moreover, the incidence of this composite endpoint was similar

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in patients with post-resuscitation elevated biomarkers regardless of their pre-resuscitation

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biomarker status. Similarly, elevated TIMP2•IGFBP7 levels were associated with increased
incidence of this composite endpoint regardless of AKI status based on serum creatinine and
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urine output. [62]
While these studies illustrate that a single biomarker can be used to risk stratify patients
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with sepsis early in their clinical course, increasingly, investigators are using multiple
biomarkers and advanced learning techniques (e.g., machine learning) to identify patients at
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risk for SA-AKI and adverse patient outcomes.[5] In a recent study, four unique sepsis
phenotypes were validated using two large retrospective clinical cohorts. These four
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phenotypes had their unique cytokine/biomarker profiles related to different aspects of

sepsis (AKI, inflammation, coagulopathy, and endothelial dysfunction), as well as their
clinical characteristics (patient demographics, baseline comorbidities, and therapeutic
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exposures - e.g., need for vasoactive medications).[63] Others have applied similar
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approaches to large data sets to identify septic patients at risk for AKI and death.[64] While
these phenotypes are increasingly more prevalent in the literature, their clinical utility will
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depend heavily on the demonstration that they can be identified early and efficiently (i.e.,
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using biomarkers), that they are linked to an underlying pathophysiologic process that can
be targeted or with a clinically relevant response to a specific therapeutic intervention.
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 Conclusions
The pathophysiology of SA-AKI is very complex and still not fully understood. Currently, no
specific therapy exists to prevent or treat this complex syndrome. Management of sepsis-
associated acute kidney injury (SA-AKI) involves early recognition and treatment of the

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underlying infection, fluid resuscitation, inotropic or vasopressor agents, diuretics, and
potentially renal replacement therapy (RRT). Prevention is key and includes early recognition
and treatment of sepsis, avoidance of nephrotoxic agents, and appropriate dosing of
medications.

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 APPENDIX
ADQI group:
Mitra K. Nadim (Division of Nephrology and Hypertension, Department of Medicine, Keck
School of Medicine, University of Southern California, CA, USA), Samira Bell (Division of
Population Health and Genomics, University of Dundee, Dundee, United Kingdom), Michael

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Joannidis (Division of Intensive Care and Emergency Medicine, Department of Internal
Medicine, Medical University Innsbruck, Austria), Kianoush Kashani (Division of Nephrology
and Hypertension, Division of Pulmonary and Critical Care Medicine, Department of
Medicine, Mayo Clinic, Rochester, MN, USA), Neesh Pannu (Department of Medicine,
University of Alberta, Edmonton, Alberta, Canada), Melanie Meersch (Department of
Anesthesiology, Intensive Care and Pain Medicine, University Hospital of Münster, Münster,

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Germany), Thiago Reis (D'Or Institute for Research and Education (IDOR), Division of Kidney
Transplantation, DF Star Hospital, SGAS 914, Asa Sul, 70390-140, Brasília, Brazil; Laboratory

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of Molecular Pharmacology, Faculty of Health Sciences, University of Brasília, Asa Norte,
Campus Darcy Ribeiro, 70910-900, Brasília, Brazil), Thomas Rimmelé (Anesthesiology and

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Critical Care Medicine, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France), Sean
M. Bagshaw (Department of Critical Care Medicine, Faculty of Medicine and Dentistry,

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University of Alberta and Alberta Health Services, Edmonton, Alberta, Canada), Rinaldo
Bellomo (Department of Critical Care, University of Melbourne, Parkville, Australia;

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Department of Intensive Care, Austin Hospital, Melbourne, Victoria, Australia; Australian and

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New Zealand Intensive Care Research Centre, Monash University, Melbourne, Australia;
Department of Intensive Care, Royal Melbourne Hospital, Melbourne, Australia), Vicenzo
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Cantaluppi (Nephrology and Kidney Transplantation Unit, Department of Translational
Medicine, University of Piemonte Orientale (UPO), “Maggiore della Carità” University
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Hospital, Novara, Italy), Akash Deep (Paediatric Intensive Care Unit, King’s College Hospital
NHS Foundation Trust, London, UK), Silvia De Rosa (Centre for Medical Sciences -
CISMed, University of Trento, Trento, Italy; Anesthesia and Intensive Care, Santa Chiara
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Regional Hospital, APSS Trento, Italy), Xose Fernandez-Perez (Servei de Medicina Intensiva,
Hospital Universitari de Bellvitge. L’Hospitalet de Llobregat, Barcelona, Spain), Faeq Husain-
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Syed (Department of Internal Medicine II, University Hospital Giessen and Marburg, Justus-
Liebig-University Giessen, Giessen, Germany), Sandra L. Kane-Gill (Department of Pharmacy
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and Therapeutics, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA), Yvelynne

Kelly (Department of Critical Care, Tallaght University Hospital, Tallaght, Dublin, Ireland;
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School of Medicine, Trinity College Dublin, Ireland), Ravindra L. Mehta (Department of

Medicine, University of California San Diego, La Jolla, CA, USA), Patrick T. Murray (School of
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Medicine, University College Dublin, Dublin, Ireland), Marlies Ostermann (Department of

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Intensive Care, King’s College London, Guy’s & St Thomas’ Hospital, London, UK), John
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Prowle (William Harvey Research Institute, Faculty of Medcicine and Dentistry, Queen Mary
University of London, London, UK), Zaccaria Ricci (Department of Anesthesia and Critical
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Care, Meyer Children’s University Hospital, Florence, Italy; Department of Health Sciences,
Section of Anesthesiology and Intensive Care, University of Florence, Florence, Italy), Emily J.
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See (Department of Critical Care, University of Melbourne, Parkville, Australia; Department

of Intensive Care, Royal Melbourne Hospital, Melbourne, Australia; Department of
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Nephrology, Royal Melbourne Hospital, Melbourne, Victoria, Australia), Antoine Schneider

 (Adult Intensive Care Unit, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne,
Switzerland), Danielle E. Soranno (Department of Pediatrics, Indiana University School of
Medicine, Indianapolis, IN, USA), Ashita Tolwani (Department of Medicine, University of
Alabama at Birmingham, Birmingham, AL, USA), Gianluca Villa (Department of Health
Sciences, Section of Anesthesiology, Intensive Care and Pain Medicine. University of
Florence. Azienda Ospedaliero Universitaria Careggi, Florence, Italy), Claudio Ronco

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(Department of Medicine, University of Padova, Padua, Italy; International Renal Research
Institute of Vicenza (IRRV), Vicenza, Italy; Department of Nephrology, San Bortolo Hospital,
Vicenza, Italy)

FUNDING

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The work was supported by the German Research Foundation (ZA 428/18-2, ZA 428/26-0, ZA
428/21-1, and KFO 342/2 to AZ).

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AUTHORS' CONTRIBUTIONS

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All authors made equal contributions to the discussion of the content. A.Z., J.L.K, H.G., P.P.,
and L.G.F drafted the manuscript and edited for style and length. All authors reviewed the

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final manuscript before submission.

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CONFLICT OF INTEREST STATEMENT
A.Z. has received consulting fees from Astute-Biomerieux, Baxter, Bayer, Novartis, Guard
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Therapeutics, AM Pharma, Paion, Fresenius, research funding from Astute-Biomerieux,

Fresenius, Baxter, and speakers fees from Astute-Biomerieux, Fresenius, Baxter; P.P. has
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received speaker’s honoraria/travel/consultancy reimbursements as a member of an

advisory board or steering committee from Baxter, EBI, AM-Pharma, Sphingotec,
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Adrenomed, 4Teen4, and Paion; H.G. serves as scientific advisor for Novartis and Trilinear
bioventures, and has received research grants from bioMérieux, Baxter and TES Pharma;
M.J. has received honoraria and research support from Baxter Healthcare Corp, AM-Pharma,
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CLS Behring, Fresenius and Novartis; K.K. has received research grants from Philips Research
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North America and Google, speaker’shonorarium from Nikkiso Critical Care Medical Supplies
(Shanghai) Co., Ltd and funding from National Institute of Diabetes and Digestive and Kidney
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Diseases grant (R01DK131586) and consulting fees from Baxter Inc. to Mayo Clinic; J.L.K has
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received consulting fees from Astute-Biomerieux, Sphingotec, Pfizer, Baxter, Mallinckrodt,

Novartis, Guard Therapeutics, research funding from Astute-Biomerieux Medical, Bioporto,
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NxStage, Fresenius, Satellite Healthcare, and speakers fees from NxStage medical; M.M.
received lecture fees from Biomerieux, Fresenius Medical Care and Baxter; T.Reis has
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received funding for lectures, been consultant or advisory board member for AstraZeneca, B.
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Braun, Baxter, bioMérieux, Boehringer Ingelheim, Contatti Medical (CytoSorbents),

Eurofarma, Fresenius Medical Care, Jafron, Lifepharma, and Nova Biomedical; T. Rimmelé
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serves as a scientific advisor for Jafron and Exthera, has received funding for lectures from B.
 Braun, Baxter, bioMérieux, Exthera, Fresenius Medical Care, Estor and Jafron and has
received research grants from Baxter and Fresenius Medical Care; S.M.B. is supported by a
Canada Research Chair in Critical Care Outcomes and Systems Evaluation and SMB has
received fees for Scientific advisory for Baxter, Novartis, Sea Star Medical, BioPorto and
SphingoTec; R.B. has received grant money, speaker's fees, and advisory board fees from
Baxter Acute Care, Jafron Biomedical, CSL Behring, AM Pharma, and Paion; V.C. has received

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lecture fees from Baxter, Estor-Toray and Aferetica-Cytosorbents; S.L.K-G. is an elected
member of the Executive Committee (or Council) of the Society of Critical Care Medicine
(SCCM). The views presented are those of the author and do not represent the views of
SCCM; R.L.M has consulting/advisory relationships with Baxter, AM Pharma, Biomerieux,
Intercept, Mallinckrodt, GE Healthcare; Medtronic,CHF Solutions, Sphingotec, Abiomed,
Nova Biomed, Sanofi, Renasym, Alexion, Fresenius, Abbott, and Renibus; P.T.M. serves as a

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scientific advisor for AM-Pharma, Novartis, and Renibus Therapeutics; M.O. has received
speaker honoraria from Fresenius Medical, Baxter and Biomerieux, and research funding

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from Fresenius Medical, Baxter and Biomerieux; J.R.P has received research support from
Jafron Biomedical Co Ltd and bioMérieux SA and consultancy or lecture fees from Baxter Inc,

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Nikkiso Europe GmbH, Mission Therapeutics Ltd and Paion UK Ltd.; AS has received speaker
and/or consulting honoraria from Fresenius Medical Care, CytoSorbents SA, Jafron,

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Medtronics, and B. Braun Avitum and has received grants from the Leenaards foundation
and B Braun Melsungen; A.T. has received consulting fees from Baxter and royalties from

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0.5% citrate patent from Baxter; G.V. received lecture fees from Baxter; C.R. has been on the

A
advisory boards or speaker’s bureau for Asahi, Aferetica, Baxter, Biomerieux, Cytosorbents,
B.Braun, GE, Medica, Medtronic, Jafron, and AstraZeneca; L.G.F has received research
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support and lecture fees from Ortho Clinical Diagnostics, Baxter, Exthera and Biomerieux and
consulting fees from La Jolla Pharmaceuticals and Paion; The remaining authors declare no
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competing
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DATA AVAILABILITY STATEMENT

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No new data were generated or analysed in support of this research.

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 Table 1: Supportive measures implemented in patients at high risk for AKI

Supportive Rationale
Measures
Discontinue all Nephrotoxic drugs contribute to AKI in 20–30% of patients. Agents
nephrotoxic agents such as antimicrobials are used in patients already at high risk for
when possible AKI (e.g., septic patients) Thus, it is often difficult to discern exactly

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what contribution these agents have on the overall course of AKI.
Nevertheless, limiting exposure whenever possible and weighing the
risk of developing or worsening AKI against the risk associated with
not using the agent is prudent. Recently, consensus has been
obtained for the nephrotoxic potential of various drugs in critically ill
patients.[65] Nephrotoxic stewardship strategies will assist in

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reducing adverse drug events and optimizing kidney health.
Optimize volume Ensuring adequate perfusion pressure and avoiding hypo- or
status and hypervolemia are crucial factors for preventing and treating AKI. In

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perfusion pressure addition, fluid management should be guided by repeated
(Figure 2) evaluations of fluid status and volume responsiveness, given a

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higher cumulative positive fluid balance is associated with AKI and
the need for RRT. Balanced crystalloid solutions are the first choice

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for fluid replacement and are preferred over chloride-rich solutions
and synthetic colloids. Given the potentially harmful effects of

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synthetic colloids, the use of albumin has been raised as a
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potentially preferable alternative. However, to date, no high-quality
studies have shown significant benefit to albumin-containing
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regimens, so their use can only be recommended in patients who
received largo volumes of crystalloids.
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Although the optimum hemodynamic targets have to be defined as

yet, a mean arterial blood pressure of greater than 65 mmHg is
usually considered sufficient to maintain organ perfusion. Mean
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arterial pressure targets higher than the 65 mm Hg recommended in

sepsis guidelines, diminish the RRT rate in patients with pre-existing
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hypertension, however, this did not translate to improved

survival.[35]
Norepinephrine and vasopressin remain first line agents for the
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treatment of septic shock. Venous congestion also plays a pivotal

role in the development of SA-AKI. An elevated central venous
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pressure (CVP) increases renal venous pressure and subsequently

decreases renal blood flow and glomerular filtration rate. Higher
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CVP in the first 24 hours of ICU admission with septic shock was
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associated with increased risk for development or persistence of AKI

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over the next five days.[66]

Consider functional A comprehensive hemodynamic work-up is completed by preload
hemodynamic and cardiac output measurements since a low cardiac output state
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monitoring with decreased systemic oxygen delivery is strongly associated with

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the development of organ dysfunction. Optimization of stroke

volume and preservation of cardiac index above 3 L/min/m 2 was
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identified to be among the most important measures to prevent

 AKI.[67]
Monitor serum Close monitoring of renal function based on serum creatinine and
creatinine and urine output is essential to establish an early diagnosis, classify the
urine output severity and predict the outcome of AKI. Intensive urine output
monitoring is associated with increased detection of AKI and
decreased mortality at day 30 (hazard ratio 0.85; 95% CI, 0.77-

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0.94; P = .001), likely due to improved fluid management and less
cumulative volume overload. [13]
Avoid High blood glucose levels induce inflammation, apoptosis, and
hyperglycemia fibrosis pathways, cause oxidative stress and volume depletion by
osmotic diuresis, and are generally well-recognized for their
contribution to kidney disease. The potential benefits of tight
glycemic control have to be balanced against the risk of

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hypoglycemia. The 2012 KDIGO guideline recommends an
intermediate corridor between tight and conventional glycemic

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control, targeting plasma glucose of 110–149 mg/dl (6.1–8.3
mmol/l).[10]

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Consider A comparable dilemma applies to the use of iodinated radiocontrast
alternatives to agents and the subsequent development of AKI: Critically ill patients
radiocontrast with an inherently increased risk for AKI are more likely to undergo

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procedures contrast-enhanced diagnostic procedures involving radiocontrast

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agents. However if required for source detection the use of contrast
media should not be deferred because of potential risk, which has
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been shown to be low in critically ill patients.[10] However, almost
all studies investigating the effect of contrast agent on the
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development of AKI have not shown an increased risk of AKI after
contrast exposure. Therefore the minimal risk of contrast induced
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AKI has to be weighed against the benefit of contrast-enhanced CT,

especially in sepsis [68, 69].
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Figure 1: Flow chart of diagnostic and treatment algorithm

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Figure 2: Optimization of the volume and hemodynamic status. During the optimization,
patients will receive functional hemodynamic monitoring and optimization according to a
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hemodynamic algorithm: 1) Performance of the passive leg raising test. If the cardiac output
(CO) increases by > 10%, then volume has to be given. If CO is ≤10%, then proceed with
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measurement of the cardiac index (CI). If the CI is < 2.5l/min/m2, then dobutamine or
epinephrine needs to be applied. If CI is > 2.5l/min/m2, then proceed with mean arterial
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pressure (MAP) measurement. If the MAP is < 65mmHg, then norepinephrine needs to be
adjusted. If MAP is > 65mmHg, then the goal is achieved. This is checked every 6 hours on
the first day and then twice a day. Abbreviations: CO, cardiac output; CI, cardiac index; MAP,
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mean arterial pressure; PLRT, passive leg raising test.

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