Nephrol Dial Transplant, 2024, 39, 26–35

https://doi.org/10.1093/ndt/gfad142
Advance access publication date: 3 July 2023

Sepsis-associated acute kidney injury—treatment

TREATMENT STANDARD

standard
Alexander Zarbock1 , Jay L. Koyner 2
, Hernando Gomez3 , Peter Pickkers4 and Lui Forni5 ,6 ; on behalf of the Acute Disease Quality
Initiative group
1
Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital of Münster, Münster, Germany and Outcomes Research Consortium,
Cleveland, OH, USA
2
Section of Nephrology, Department of Medicine, University of Chicago, Chicago, IL, USA
3
Program for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA

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4
Department Intensive Care Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
5
Department of Critical Care, Royal Surrey Hospital Foundation Trust, Guildford, UK
6
Faculty of Health Sciences, University of Surrey, Guildford, UK
Correspondence to: Alexander Zarbock; E-mail: zarbock@uni-muenster.de

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 con-
tributes to ≈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 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 stud-
ies 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 SA-AKI.

Keywords: acute kidney injury, biomarker, renal replacement therapy, sepsis

IN A NUTSHELL

1. The pathophysiology of sepsis-associated acute kidney injury (SA-AKI) 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. haemodynamic optimization and avoidance/minimizing nephrotoxins) in septic pa-
tients at high risk for AKI might prevent AKI development, but no specific therapies are available to treat sepsis-associated
AKI.
4. Renal replacement therapy (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.
5. Preliminary data have suggested that selective subphenotypes of SA-AKI may have a better response to specific vasoactive
drugs (e.g. arginine vasopressin, angiopoietin-2), however, further confirmatory data are needed.

INTRODUCTION Here we discuss the most recent evidence supporting our cur-
rent understanding of the pathophysiology and outcome predic-
Sepsis is characterized by organ dysfunction as a consequence of
tion in patients with SA-AKI. Furthermore, based on the recent
a dysregulated response to infection. Septic shock is character-
recommendations of the Acute Disease Quality Initiative (ADQI)
ized by persistent hypotension despite adequate fluid resuscita-
group [5], we have developed a pragmatic diagnostic and treat-
tion, the need for vasoactive drugs to maintain a mean arterial
ment algorithm for SA-AKI in adults.
pressure (MAP) of at least 65 mmHg and a plasma lactate concen-
tration >2 mmol/L [1].
Up to 60% of patients with sepsis develop acute kidney in- TREATMENT STANDARDS
jury (AKI) [2]. Although the pathophysiology underlying sepsis-
From diagnosis to treatment of SA-AKI
associated AKI (SA-AKI) remains incompletely understood, mul-
Where sepsis is suspected, lactate should be measured, and if el-
tiple mechanisms, including inflammation, complement activa-
evated (>2 mmol/L), measurement should be repeated, with re-
tion, mitochondrial dysfunction and microcirculatory dysfunc-
suscitation guided by lactate levels. Once sepsis is diagnosed, the
tion, are thought to contribute to AKI development [3]. The de-
patient should be treated according to current sepsis guidelines
velopment of AKI carries a significantly increased mortality risk
[1], and before administering antibiotics, blood cultures should be
compared w sepsis alone [4].

Received: May 9, 2023; Editorial decision: June 5, 2023

© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.
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Figure 1: Flow chart of the diagnostic and treatment algorithm.
obtained (Fig. 1). In the presence of sepsis-induced hypoperfusion
(lactate levels ≥2 mmol/L) or septic shock, crystalloid fluid admin-
istration should be initiated and guided based on dynamic param-
eters of fluid responsiveness, along with vasopressors to keep the
MAP >65 mmHg and decrease serum lactate levels. The recom-
mended first-line vasopressor in septic patients is norepinephrine,
as dopamine should not be used in this patient group [1].
Early fluid administration is important to potentially rescue
the macro- and microcirculation in sepsis. The guidelines recom-
mend 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 worse outcome [6], fluid admin-
istration should be individualized and guided by fluid respon-
siveness. The type of fluid used for resuscitation has resulted in
much study and debate, with earlier evidence suggesting that
0.9% saline may cause hyperchloremia, resulting in AKI and worse
patient-centred outcomes [7]. However, more recent studies 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 evidence, the use
of up to 4 L of saline seems to be safe in regard to patient-centred
outcomes [9].
A. Zarbock et al. | 27
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All patients with sepsis should be considered at high risk for
AKI, whereas patients with certain comorbidities, such as chronic
kidney disease, have an even higher risk to develop AKI un-
der these circumstances. Kidney function should be monitored
closely using serum creatinine and urine output for earlier de-
tection 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 base-
line 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 often delayed, particularly in sep-
sis, where the creatinine production rate may be reduced by 50%
and fluid resuscitation may dilute the creatinine concentration
[12]. Although integral to the AKI definition, urine output is non-
specific and is measured accurately only in patients with an in-
dwelling urinary catheter. Interestingly, several observational co-
hort 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].
Early detection of kidney damage is essential, as it may
increase the opportunity for successful interventions [15, 16].
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Figure 2: Optimization of the volume and haemodynamic status. During the optimization, patients will receive functional haemodynamic monitoring
and optimization according to a haemodynamic algorithm: Performance of the passive leg raising test (PLRT). If the cardiac output (CO) increases by
>10%, then volume has to be given. If CO is ≤10%, then proceed with measurement of the cardiac index (CI). If the CI is <2.5 L/min/m2 , then
dobutamine or epinephrine needs to be applied. If the CI is >2.5 L/min/m2 , then proceed with MAP measurement. If the MAP is <65 mmHg, then
norepinephrine needs to be adjusted. If MAP is >65 mmHg, then the goal is achieved. This is checked every 6 hours on the first day and then twice a
day.

Combining damage and functional biomarkers to increase the
sensitivity and specificity of AKI definitions may help [17].
Stage 1S (‘subclinical AKI’), for example, is defined by in-
creased stress/injury biomarker levels despite normal functional
biomarkers (serum creatinine and urine output). In addition, data
from the Protocolized Care for Early Septic Shock (ProCESS) co-
hort demonstrated that biomarker-positive AKI is associated with
lower 30-day survival than biomarker-negative AKI despite the
same functional stage of AKI defined by KDIGO criteria [18].
The concentrations of several serum biomarkers inversely cor-
relate with glomerular filtration rate (GFR) and may provide an
advantage in detecting SA-AKI. Cystatin C and proenkephalin in-
crease earlier than serum creatinine in critically ill patients with
sepsis [19, 20]. Urinary tissue inhibitor of metalloproteinase-2
(TIMP2) and insulin-like growth factor binding protein-7 (IGFBP7),
two markers associated with cell cycle arrest, have very good per-
formance in predicting stage 2 or 3 AKI in critically ill patients
with sepsis (area under the curve 0.84) [21]. Plasma neutrophil
gelatinase-associated lipocalin has been demonstrated to be ele-
vated in septic patients, even in the absence of creatinine or urine
output–based AKI. A higher cut-off value (454 ng/ml) provides a
specificity of 74% and a sensitivity of 72% for detecting AKI [22].
Bedside Doppler ultrasound is a rapid, non-invasive and re-
peatable tool for evaluating renal perfusion and is widely used in
critically ill patients [23]. The Doppler-based renal resistive 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 does not
discriminate between patterns of renal recovery nor modifies risk
stratification for AKI persistence [25]. In addition, several phys-
iological factors, such as intra-abdominal pressure and vascular
compliance, influence RRI. Urinalysis and urine microscopy 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 renal tubule
epithelial cells compared with non-septic AKI. A small trial
demonstrated that a urinalysis score >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 bundle of supportive measures [10] (see also
Fig. 2). Indeed, it has been demonstrated that implementing sup-
portive measures in surgical patients at risk can reduce the oc-
currence 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 re-
ceive all the guideline-recommended measures [28–31]. The bun-
dle that has been shown to reduce AKI in 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 hyperglycaemia,
consideration of alternatives to radiocontrast agents and haemo-
dynamic monitoring with optimization of both volume status and
haemodynamics.
Patients with SA-AKI
The supportive measures should be continued in patients with an
established AKI. However, no evidence shows that the bundle can
positively influence the course of AKI.
Diuretics
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 established [33].
Therefore, the use of diuretics for the prevention or treatment of
SA-AKI is not recommended. However, their use in regulating fluid

Table 1: Supportive measures implemented in patients at high risk for AKI.
Supportive measures
Discontinue all nephrotoxic agents when possible
Optimize volume status and perfusion pressure (Fig. 2)
Consider functional haemodynamic monitoring
Monitor serum creatinine and urine output
Avoid hyperglycaemia
Consider alternatives to radiocontrast procedures
balance and preventing fluid overload fosters their continued use
in critical illness despite their inability to improve renal outcomes.
Bicarbonate
The subgroup analysis of the BICAR-ICU trial, a multicentre,
open-label, controlled phase 3 clinical trial, demonstrated that
treatment with intravenous 4.2% sodium bicarbonate for severe
A. Zarbock et al. | 29
Rationale
Nephrotoxic drugs contribute to AKI in 20–30% of patients. Agents such as antimicrobials
are used in patients already at high risk for AKI (e.g. septic patients), thus it is often
difficult to discern exactly 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
reducing adverse drug events and optimizing kidney health.
Ensuring adequate perfusion pressure and avoiding hypo- or hypervolaemia are crucial
factors for preventing and treating AKI. In addition, fluid management should be guided
by repeated evaluations of fluid status and volume responsiveness, given a higher
cumulative positive fluid balance is associated with AKI and the need for RRT. Balanced
crystalloid solutions are the first choice for fluid replacement and are preferred over
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chloride-rich solutions and synthetic colloids. Given the potentially harmful effects of
synthetic colloids, the use of albumin has been raised as a potentially preferable
alternative. However, to date, no high-quality studies have shown significant benefit to
albumin-containing regimens, so their use can only be recommended in patients who
have received large volumes of crystalloids.
Although the optimum haemodynamic targets are yet to be defined, a MAP >65 mmHg is
usually considered sufficient to maintain organ perfusion. MAP targets >65 mmHg
recommended in sepsis guidelines diminish the RRT rate in patients with pre-existing
hypertension; however, this did not translate into improved survival [35].
Norepinephrine and vasopressin remain first-line agents for the treatment of septic shock.
Venous congestion also plays a pivotal role in the development of SA-AKI. An elevated
central venous pressure (CVP) increases renal venous pressure and subsequently
decreases renal blood flow and GFR. Higher CVP in the first 24 hours of ICU admission
with septic shock was associated with an increased risk for development or persistence of
AKI over the next 5 days [66].
A comprehensive haemodynamic workup is completed by preload and cardiac output
measurements since a low cardiac output state with decreased systemic oxygen delivery
is strongly associated with the development of organ dysfunction. Optimization of stroke
volume and preservation of the cardiac index >3 L/min/m2 was identified to be among the
most important measures to prevent AKI [67].
Close monitoring of renal function based on serum creatinine and urine output is essential
to establish an early diagnosis, classify the 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% confidence interval 0.77–0.94);
P = .001], likely due to improved fluid management and less cumulative volume overload
[13].
High blood glucose levels induce inflammation, apoptosis and 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
glycaemic control have to be balanced against the risk of hypoglycaemia. The 2012 KDIGO
guideline recommends an intermediate corridor between tight and conventional
glycaemic control, targeting plasma glucose of 110–149 mg/dl (6.1–8.3 mmol/L) [10].
A comparable dilemma applies to the use of iodinated radiocontrast agents and the
subsequent development of AKI. Critically ill patients with an inherently increased risk for
AKI are more likely to undergo contrast-enhanced diagnostic procedures involving
radiocontrast agents. However, if required for source detection, the use of contrast media
should not be deferred because of potential risk, which has been shown to be low in
critically ill patients [10]. Almost all studies investigating the effect of contrast agent on
the development of AKI have not shown an increased risk of AKI after contrast exposure.
Therefore the minimal risk of contrast-induced AKI has to be weighed against the benefit
of contrast-enhanced CT, especially in sepsis [68, 69].
metabolic acidaemia (pH <7.20) in critically ill patients with
moderate–severe AKI (Acute Kidney Injury Network 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]. 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
30 | Nephrol Dial Transplant, 2024, Vol. 39, No. 1
population had sepsis at randomization. Therefore the results
cannot be fully extrapolated to patients with SA-AKI.
Blood pressure and vasopressors
Although the arterial blood pressure target in septic patients
is unknown, one trial demonstrated that targeting a MAP
>85 mmHg in patients with pre-existing hypertension reduced
the serum creatinine increase and the need for renal replace-
ment therapy (RRT) [35]. Angiotensin II, an endogenous vasocon-
strictor, preferentially constricts the glomerular efferent arteriole,
thus increasing the GFR. A post hoc analysis of the ATHOS-3 trial
showed that patients with vasodilatory shock on RRT random-
ized to angiotensin II discontinued RRT earlier (38% versus 15% by
day 7, P = .007) and had lower 28-day mortality (30% versus 53%,
P = .012) compared with placebo [36]. Data from a post hoc anal-
ysis suggest that patients with low angiotensin II and high renin
levels benefit from this drug [37, 38]. However, further validation
of these findings data is needed.
RRT
Several recent studies have investigated different aspects of RRT
in the critically ill [39–42], specifically in SA-AKI patients.
Data around the timing of RRT in SA-AKI suggest that there
is no benefit from accelerated RRT initiation [43]. One multi-
centre 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 group [44]. However, 93 (38%) patients in
the delayed arm never received RRT.
Regarding RRT dosing, the evidence supports the recom-
mended delivery dose of 20–25 ml/kg/h [40, 41], partly based
on studies demonstrating no benefit with higher doses or high-
volume haemofiltration [45–47].
In the setting of SA-AKI, large RCTs and meta-analyses have
demonstrated no difference in outcomes between intermittent
versus continuous RRT [48, 49]. However, it might be possible that
haemodynamically unstable patients benefit more from contin-
uous RRT compared with 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 3.9 per week for intermittent dialysis.
Pathophysiology
It is likely that SA-AKI is caused by multiple pathophysiologic
mechanisms that interact with host background susceptibility
factors, the host’s capacity to withstand tissue injury or tolerance
capacity, direct effects related to sepsis and the effect of sepsis-
associated therapies. Future trials to test therapeutic interven-
tions to alleviate SA-AKI will need to embrace this complexity and
likely rely on biomarkers to select patients in whom targeting par-
ticular processes is relevant.
A specific pathophysiologic mechanism proved to induce tubu-
lar injury, therefore AKI is defined as an endotype. In sepsis,
rather than a single endotype, multiple endotypes likely in-
teract and cause injury, thereby inducing SA-AKI. Mechanisms
such as local inflammation, innate immune activation, mitochon-
drial and microvascular dysfunction, oxidative stress, hypoxia,
renin–angiotensin–aldosterone system (RAAS) dysfunction, com-
plement activation and metabolic reprogramming are all sup-
ported by the literature as prominent endotype candidates to ex-
plain the underpinnings of SA-AKI. The evidence supporting the
pre-eminence of these mechanisms is discussed next.
Local innate immune activation, inflammation
and complement activation
The early interaction of damage and pathogen-associated molec-
ular patterns (DAMPs and PAMPs) with the host’s pattern recog-
nition receptors (PRRs) induces the activation of immunity and
complement pathways, leading to a systemic and local renal in-
flammatory response. DAMPs and PAMPs can be filtered through
the glomerulus and engage tubular epithelial cell toll-like recep-
tors (i.e. TLR4). In the tubular system, TLR4 engagement triggers
an oxidative stress outburst [50]. PAMPs and DAMPs can also bind
to PRRs and promote local inflammation [51].
Microvascular dysfunction, oxidative stress, amplification of
the inflammatory response, intrarenal shunting and tissue
hypoxia
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Sepsis is known to cause widespread, systemic microvascular dys-
function, manifested as a decrease in the proportion of capillaries
with continuous flow, an increase in the proportion of capillaries
with intermittent or no flow 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 creatinine increases [53]. In an animal sepsis model,
oxidative stress represented by increased production of reactive
oxygen and nitrogen species occurred in tubular epithelial cells
adjacent to peritubular capillaries with intermittent or stop flow,
suggesting a link between these two injury mechanisms [53]. Slug-
gish peritubular flow can also amplify the inflammatory response
by increasing the exposure time of neighbouring epithelial cells
to activated, cytokine-spilling leucocytes transiting through the
peritubular capillaries [54]. This inflammatory amplification may
explain the association between capillary dysfunction and oxida-
tive stress in the tubular epithelium. A more direct consequence
of microvascular dysfunction may be intrarenal shunting, lead-
ing to the development of areas of tissue hypoxia and to tubular
injury.
RAAS dysfunction
The RAAS modulates vascular tone, fluid and electrolyte bal-
ance and GFR [55]. In critically ill patients, elevated renin levels
are associated with worse survival, major adverse kidney events
(MAKEs) and the need for RRT [56]. In addition, elevated renin
levels are usually found in patients with refractory vasodila-
tory shock [56]. Notably, the inflammatory response can cause
angiotensin-converting enzyme dysfunction, leading to a deficit
in angiotensin II [55].
Mitochondrial dysfunction
The tubular epithelium of the proximal tubules has the daunting,
energetically expensive task of reabsorbing ≈70% of the sodium
contained in the ≈170 L/day of fluid filtered by the glomeru-
lus. Unsurprisingly, the proximal tubule and thick ascending limb
of the loop of Henle are only second to the heart in mitochon-
drial density. Therefore, mitochondrial well-being is critical to
tubular and renal function. Sepsis induces mitochondrial injury
through oxidative damage [57], TLR4-mediated inflammation [58]
and electron transport chain inhibition [59]. It is characterized
by decreased mitochondrial mass, disruption of cristae and vari-
able mitochondrial swelling [60]. In addition, sepsis impairs mi-
tochondrial quality control mechanisms like fission, fusion and
mitophagy, which are critical for protecting and rescuing dysfunc-
tional 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 patient-oriented outcomes like AKI progression,
the need for RRT and mortality.
In samples from >2500 patients with sepsis and septic shock
from the FROG-ICU and ADRENOSS studies, Dépret et al. [61]
showed that in the absence of changes in serum creatinine
and urine output, an elevated proenkephalin level (>80 pmol/L)
at the time of intensive care unit (ICU) arrival was associated
with an increased risk of inpatient mortality. While this elevated
biomarker in the absence of changes in traditional AKI mark-
ers was only present in 6–7% of the population, the associa-
tion between proenkephalin and mortality persisted after ad-
justing for age, sex, comorbidities, ICU diagnosis, creatinine and
diuresis.
In a planned substudy of the ProCESS trial (an early goal-
directed therapy in sepsis randomized control study), pa-
tients who had persistently elevated TIMP2•IGFBP7 levels
[>0.3 [ng/ml]2 /1000) after the first 6 hours of resuscitation with
fluids and vasopressors were at higher risk for a composite end-
point of progression to severe AKI (stage 2 or 3), receipt of dialysis
and mortality [62]. Moreover, the incidence of this composite
endpoint was similar in patients with post-resuscitation elevated
biomarkers regardless of their pre-resuscitation biomarker sta-
tus. Similarly, elevated TIMP2•IGFBP7 levels were associated with
an increased incidence of this composite endpoint regardless of
AKI status based on serum creatinine and urine output [62].
While these studies illustrate that a single biomarker can be
used to risk-stratify patients with sepsis early in their clinical
course, increasingly investigators are using multiple biomarkers
and advanced learning techniques (e.g. machine learning) to iden-
tify patients at 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 pheno-
types had their unique cytokine/biomarker profiles related to dif-
ferent aspects of sepsis (AKI, inflammation, coagulopathy and en-
dothelial dysfunction) as well as their clinical characteristics [pa-
tient demographics, baseline comorbidities and therapeutic expo-
sures (e.g. the need for vasoactive medications)] [63]. Others have
applied similar approaches to large data sets to identify septic pa-
tients at risk for AKI and death [64]. While these phenotypes are
increasingly more prevalent in the literature, their clinical utility
will depend heavily on demonstration that they can be identified
early and efficiently (i.e. using biomarkers) or that they are linked
to an underlying pathophysiologic process that can be targeted or
with a clinically relevant response to a specific therapeutic inter-
vention.
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 SA-AKI involves
early recognition and treatment of the underlying infection, fluid
resuscitation, inotropic or vasopressor agents, diuretics and po-
tentially RRT. Prevention is key and includes early recognition and
treatment of sepsis, avoidance of nephrotoxic agents and appro-
priate dosing of medications.
A. Zarbock et al. | 31
FUNDING
This 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).
AUTHORS’ CONTRIBUTIONS
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 and edited the
manuscript. All authors reviewed the final manuscript before sub-
mission.
DATA AVAILABILITY STATEMENT
No new data were generated or analysed in support of this re-
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search.
CONFLICT OF INTEREST STATEMENT
A.Z. has received consulting fees from Astute-bioMérieux, Baxter,
Bayer, Novartis, Guard Therapeutics, AM Pharma, Paion and Fre-
senius Medical Care; research funding from Astute-bioMérieux,
Fresenius Medical Care and Baxter and speaker fees from Astute-
bioMérieux, Fresenius Medical Care and Baxter. P.P. has received
speaker, travel and consultancy fees as a member of an advisory
board or steering committee for Baxter, EBI, AM-Pharma, Sph-
ingotec, Adrenomed, 4Teen4 and Paion. H.G. serves as a scien-
tific advisor for Novartis and Trilinear BioVentures and has re-
ceived research grants from bioMérieux, Baxter and TES Pharma.
M.J. has received honoraria and research support from Baxter
Healthcare, AM-Pharma, CLS Behring, Fresenius Medical Care
and Novartis. K.K. has received research grants from Philips Re-
search North America and Google, speaker fees from Nikkiso
Critical Care Medical Supplies (Shanghai) and funding from the
National Institute of Diabetes and Digestive and Kidney Dis-
eases (grant R01DK131586) and consulting fees from Baxter (to
the Mayo Clinic). J.L.K. has received consulting fees from Astute-
bioMérieux, Sphingotec, Pfizer, Baxter, Mallinckrodt, Novartis and
Guard Therapeutics; research funding from Astute-bioMérieux,
BioPorto, NxStage Medical, Fresenius Medical Care and Satellite
Healthcare and speaker fees from NxStage Medical. M.M. has re-
ceived lecture fees from bioMérieux, Fresenius Medical Care and
Baxter. T. Reis has received funding for lectures and has been a
consultant or advisory board member for AstraZeneca, B. Braun,
Baxter, bioMeŕieux, Boehringer Ingelheim, Contatti Medical (Cy-
toSorbents), Eurofarma, Fresenius Medical Care, Jafron Biomedi-
cal, Lifepharma and Nova Biomedical. T. Rimmelé serves as a sci-
entific advisor for Jafron Biomedical and Exthera; has received
funding for lectures from B. Braun, Baxter, bioMeŕieux, Exthera,
Fresenius Medical Care, Estor and Jafron Biomedical and has re-
ceived 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 has received fees for sci-
entific advisory from Baxter, Novartis, Sea Star Medical, BioPorto
and SphingoTec. R.B. has received grant money, speaker fees and
advisory board fees from Baxter Acute Care, Jafron Biomedical,
CSL Behring, AM-Pharma, and Paion. V.C. has received lecture
fees from Baxter, Estor-Toray and Aferetica-Cytosorbents. S.L.K.-
G. is an elected member of the Executive Committee (or Coun-
cil) of the Society of Critical Care Medicine (SCCM). The views
presented are those of the author and do not represent the
views of the SCCM. R.L.M. has consulting/advisory relationships
with Baxter, AM-Pharma, bioMeŕieux, Intercept, Mallinckrodt, GE
32 | Nephrol Dial Transplant, 2024, Vol. 39, No. 1
Healthcare, Medtronic, CHF Solutions, Sphingotec, Abiomed, Nova
Biomed, Sanofi, Renasym, Alexion, Fresenius Medical Care, Ab-
bott and Renibus Therapeutics. P.T.M. serves as a scientific advi-
sor for AM-Pharma, Novartis and Renibus Therapeutics. M.O. has
received speaker fees from Fresenius Medical Care, Baxter and
bioMeŕieux and research funding from Fresenius Medical Care,
Baxter and bioMeŕieux. J.R.P. has received research support from
Jafron Biomedical and bioMérieux and consultancy or lecture fees
from Baxter, Nikkiso Europe, Mission Therapeutics and Paion UK.
A.S. has received speaker and/or consulting fees from Fresenius
Medical Care, CytoSorbents, Jafron Biomedical, Medtronics and B.
Braun Avitum and has received grants from the Leenaards Foun-
dation and B. Braun Melsungen. A.T. has received consulting fees
from Baxter and royalties from a 0.5% citrate patent from Baxter.
G.V. has received lecture fees from Baxter. C.R. has been on the
advisory boards or speaker’s bureau for Asahi, Aferetica, Baxter,
bioMérieux, Cytosorbents, B. Braun, GE, Medica, Medtronic, Jafron
Biomedical and AstraZeneca. L.G.F. has received research support
and lecture fees from Ortho Clinical Diagnostics, Baxter, Exthera
and bioMérieux and consulting fees from La Jolla Pharmaceuticals
and Paion. The remaining authors declare no conflicts of interest.
APPENDIX
ADQI group: Mitra K. Nadim (Division of Nephrology and Hy-
pertension, Department of Medicine, Keck School of Medicine,
University of Southern California, Los Angeles, CA, USA), Samira
Bell (Division of Population Health and Genomics, University of
Dundee, Dundee, UK), Michael Joannidis (Division of Intensive
Care and Emergency Medicine, Department of Internal Medicine,
Medical University Innsbruck, Austria), Kianoush Kashani (Di-
vision of Nephrology and Hypertension, Division of Pulmonary
and Critical Care Medicine, Department of Medicine, Mayo Clinic,
Rochester, MN, USA), Neesh Pannu (Department of Medicine, Uni-
versity of Alberta, Edmonton, Alberta, Canada), Melanie Meersch
(Department of Anesthesiology, Intensive Care and Pain Medicine,
University Hospital of Münster, Münster, Germany), Thiago Reis
(D’Or Institute for Research and Education, Division of Kidney
Transplantation, DF Star Hospital, Brasiĺia, Brazil; Laboratory of
Molecular Pharmacology, Faculty of Health Sciences, University
of Brasiĺia, Brasiĺia, Brazil), Thomas Rimmelé (Anesthesiology
and 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, Univer-
sity of Alberta and Alberta Health Services, Edmonton, Alberta,
Canada), Rinaldo Bellomo (Department of Critical Care, Univer-
sity of Melbourne, Parkville, Victoria, Australia; Department of
Intensive Care, Austin Hospital, Melbourne, Victoria, Australia;
Australian and New Zealand Intensive Care Research Centre,
Monash University, Melbourne, Victoria, Australia; Department
of Intensive Care, Royal Melbourne Hospital, Melbourne, Victoria,
Australia), Vicenzo Cantaluppi (Nephrology and Kidney Trans-
plantation Unit, Department of Translational Medicine, University
of Piemonte Orientale, ‘Maggiore della Carità’ University 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, University of Trento, Trento,
Italy; Anesthesia and Intensive Care, Santa Chiara Regional
Hospital, Trento, Italy), Xosé Pérez-Fernández (Servei de Medicina
Intensiva, Hospital Universitari de Bellvitge, L’Hospitalet de
Llobregat, Barcelona, Spain), Faeq Husain-Syed (Department of
Internal Medicine II, University Hospital Giessen and Marburg,
Justus-Liebig-University Giessen, Giessen, Germany), Sandra L.
Kane-Gill (Department of Pharmacy and Therapeutics, School
of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA),
Yvelynne Kelly (Department of Critical Care, Tallaght University
Hospital, Tallaght, Dublin, Ireland; School of Medicine, Trinity
College Dublin, Dublin, Ireland), Ravindra L. Mehta (Department
of Medicine, University of California San Diego, La Jolla, CA,
USA), Patrick T. Murray (School of Medicine, University College
Dublin, Dublin, Ireland), Marlies Ostermann (Department of In-
tensive Care, King’s College London, Guy’s & St Thomas’ Hospital,
London, UK), John Prowle (William Harvey Research Institute,
Faculty of Medicine and Dentistry, Queen Mary University of
London, London, UK), Zaccaria Ricci (Department of Anesthesia
and Critical Care, Meyer Children’s University Hospital, Florence,
Italy; Department of Health Sciences, Section of Anesthesiology
and Intensive Care, University of Florence, Florence, Italy), Emily
Downloaded from https://academic.oup.com/ndt/article/39/1/26/7218568 by guest on 25 December 2023
J. See (Department of Critical Care, University of Melbourne,
Parkville, Victoria, Australia; Department of Intensive Care, Royal
Melbourne Hospital, Melbourne, Victoria, Australia; Department
of Nephrology, Royal Melbourne Hospital, Melbourne, Victoria,
Australia), Antoine Schneider (Adult Intensive Care Unit, Cen-
tre Hospitalier Universitaire Vaudois, Lausanne, Switzerland),
Danielle E. Soranno (Department of Pediatrics, Indiana Univer-
sity 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 Univer-
sitaria Careggi, Florence, Italy), Claudio Ronco (Department of
Medicine, University of Padova, Padua, Italy; International Renal
Research Institute of Vicenza, Vicenza, Italy; Department of
Nephrology, San Bortolo Hospital, Vicenza, Italy).
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