REVIEW

C URRENT
OPINION Personalized acute kidney injury treatment
Christian Porschen a, Christian Strauss a, Melanie Meersch a
and Alexander Zarbock a,b

Purpose of review
Acute kidney injury (AKI) is a complex syndrome that might be induced by different causes and is
associated with an increased morbidity and mortality. Therefore, it is a very heterogeneous syndrome and
establishing a ‘‘one size fits all’’ treatment approach might not work. This review aims to examine the
potential of personalized treatment strategies for AKI.
Recent findings
The traditional diagnosis of AKI is based on changes of serum creatinine and urine output, but these two
functional biomarkers have several limitations. Recent research identified different AKI phenotypes based
on clinical features, biomarkers, and pathophysiological pathways. Biomarkers, such as Cystatin C, NGAL,
TIMP2IGFBP7, CCL14, and DKK-3, have shown promise in predicting AKI development, renal recovery,
and prognosis. Biomarker-guided interventions, such as the implementation of the KDIGO bundle, have
demonstrated an improvement in renal outcomes in specific patient groups.
Summary
A personalized approach to AKI treatment as well as research is becoming increasingly important as it
allows the identification of distinct AKI phenotypes and the potential for targeted interventions. By utilizing
biomarkers and clinical features, physicians might be able to stratify patients into subphenotypes, enabling
more individualized treatment strategies. This review highlights the potential of personalized AKI treatment,
emphasizing the need for further research and large-scale clinical trials to validate the efficacy of these
approaches.
Keywords
acute kidney injury, acute kidney injury phenotypes, biomarkers, personalized medicine, targeted therapy

INTRODUCTION The underlying susceptibility of the patient also

Acute kidney injury (AKI) is a syndrome, not a influences the occurrence of AKI. Comorbidities,
disease, as it can be triggered by different causes, including chronic kidney disease, diabetes, and
including sepsis, surgery, and nephrotoxic drugs hypertension, are associated with an increased risk
[1,2]. The pathophysiology of this syndrome is com- of AKI. Compared to patients without AKI, patients
plex and still not fully understood. AKI is a common who develop an AKI have an increased mortality rate
complication in critically ill patients, whereas the [7], prolonged stay in the ICU and causes increased
incidence ranges from 20 to 50% and varies between healthcare costs [8].
different patient populations [3,4]. In the past, a In the last decades, several drugs and interven-
standardized definition was lacking, but nowadays tions were investigated to prevent or treat AKI,
the Kidney Disease Improving Global Outcomes unfortunately without success. There is no specific
(KDIGO) definition is used to diagnose and stage therapy available. One reason for the lack of an
AKI. This definition is based on changes of the
serum creatinine (SCr) and/or urine output [5]. a
Klinik f€
ur An€asthesiologie, operative Intensivmedizin und Schmerzther-
However, since AKI biomarkers detect kidney dam-
apie, Universit€ atsklinikum M€unster, M€unster, Germany and bOutcomes
age without loss of function (‘subclinical AKI’) and Research Consortium, Cleveland, Ohio, USA
this damage is associated with a worse long-term Correspondence to Alexander Zarbock, MD, University Hospital
outcome, the Acute Disease Quality Initiative M€unster, Department of Anesthesiology, Intensive Care and Pain Med-
(ADQI) group proposed a new definition of AKI, icine, University Hospital M€
unster, 48149 M€unster, Germany.
combining functional with damage biomarkers Tel: +49 251 83 47252; e-mail: [email protected]
[6]. In addition, the authors also introduced a new Curr Opin Crit Care 2023, 29:551–558
stage (1S) that reflects ‘subclinical AKI’ (1S-AKI). DOI:10.1097/MCC.0000000000001089

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Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.

Renal system

[3,12 –14]. Recent studies have shifted focus

KEY POINTS from decreased renal blood flow due to macrocir-
culatory changes to microcirculatory alterations
 Acute kidney injury (AKI) is a complex syndrome with
in sepsis-associated AKI [15]. Microvascular shunt-
varying causes and outcomes, necessitating a
personalized treatment approach. ing between the afferent and efferent glomerular
arteriole negatively impacts the physiological
 Recent research has identified different AKI phenotypes function of the glomerulus and thereby cause a
based on clinical features, biomarkers, and reduction in GFR [16]. These changes are caused
pathophysiological pathways.
by renal inflammation that is triggered by the
 Biomarkers such as Cystatin C, NGAL, TIMP2IGFBP7, activation of Toll-like receptors [17] and a variety
CCL14, and DKK-3 show promise in predicting AKI of released cytokines that lead to leukocyte activa-
development, renal recovery, and prognosis. tion and recruitment into the inflamed tissue
 AKI treatment interventions, such as implementing the [18,19]. However, recent evidence suggests that
KDIGO bundle, have demonstrated reduced AKI rates histopathological changes in AKI, especially sep-
in specific patient groups. sis-associated AKI, are generally not very pro-
nounced. Nonetheless, if they occur, they are
 Biomarker have shown the potential to guide AKI
often an indicator of persistent renal dysfunction
treatment interventions in the future.
[20]. Microcirculatory alterations due to inflamma-
tion as well as macrovascular hypoperfusion can
lead to the formation of reactive oxygen species,
effective therapy might be that the ‘one size fits all’- which in turn can cause damage to kidney cells via
approach that was used in the past does not DNA damage and consecutive apoptosis or direct
account for the heterogeneity of this complex syn- necrosis [16,21].
drome. Recently, different phenotypes of AKI were
detected [9,10], and based on these new data, it is
unlikely that we find one magic bullet that cures all
PHENOTYPING ACUTE KIDNEY INJURY
cases of AKI. In critically ill patients, several syndromes are
Therefore, a personalized approach, like it is known, including acute respiratory distress syn-
applied in other fields of medicine (e.g., hematol- drome, sepsis, heart failure, delirium, and others.
ogy, or oncology), might reduce the heterogeneity All of the above can be caused by different
of this syndrome and identifies phenotypes of factors, are influenced by different predispositions,
AKI that respond to a given therapy. A diagnostic and can have a multitude of different clinical
approach using novel renal biomarkers promises a expressions, which leads to the opportunity of
timely implementation of preventive measures or phenotyping these syndromes. A phenotype
a specific therapy. can be seen as the observable characteristics of
In this narrative review, we will provide a a disease. In terms of AKI, these would portray
broad overview of phenotypes of AKI as well as most different clinical representations (e.g., oliguria
recent developments in personalized treatment versus a rise in SCr), trajectories, and severities
approaches. [9]. These features offer the opportunity for
further subdividing the group of patients affected
by AKI into subphenotypes, as it has been done for
PATHOPHYSIOLOGY other diseases as well. By this definition, subphe-
AKI is characterized by a sudden decrease of the notypes represent groups of patients, sharing
glomerular filtration rate (GFR) or/and tubular the same clinical features, predispositions such as
injury, which can result from factors such as hypo- epidemiological features, biomarker expressions,
perfusion, nephrotoxins, and inflammatory medi- trajectories, or response to certain interventions
ators [11]. These pathophysiological mechanisms [10].
should not be viewed as separate but as causes of Endotypes, however, refer to specific pathophy-
the same entity, influencing each other. To guide siological pathways of a syndrome, meaning that
personalized treatment opportunities of AKI, it is one phenotype can be caused by different endo-
vital to identify the mechanisms leading to and types. This definition is already well established in
maintaining AKI. In critically ill patients, AKI other syndromes and has been the basis for the
often occurs due to an exacerbated inflammatory development of targeted therapeutics in different
response, commonly triggered by sepsis, trauma, or fields of medicine [22,23]. The complex interdepen-
major surgery. However, sepsis remains the dencies between AKI and its phenotyping process is
most common cause of AKI in the ICU population depicted in Fig. 1.

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 Personalized acute kidney injury treatment Porschen et al.

FIGURE 1. Representation of the complex relationships between biomarkers, AKI and its phenotypes. Patient related factors
impact the development of an AKI, as well as its course. The clinical trajectories of AKI, however, can be included in
phenotype definitions. Biomarkers can on the one hand be used to classify AKI into phenotypes, as well as for prediction of
AKI. In the end, all of these efforts are done to guide treatment for AKI.

OPPORTUNITIES IN SUBPHENOTYPING phenotypes. A recent study identified subpheno-

BASED ON CLINICAL FEATURES types of AKI based on the trajectory of an elevated
The goal of subphenotyping a syndrome should SCr. The authors identified two groups, one group
always be to gain a more granular view on the having a SCr decrease within 72 h and another one
syndrome itself, to deepen the pathophysiological with a SCr elevation lasting for more than 72 h. An
understanding, and to be able to study treatment early renal recovery with a SCr decrease within 72 h
effects on a less heterogenous population. This was associated with a reduced mortality rate [27].
approach is called enrichment and has recently been Kellum et al. [28] identified different subclasses of
reviewed [9]. The current classification of AKI recovery after AKI, based on duration and relapse of
according to KDIGO criteria, based on SCr elevation AKI. Five different patterns of AKI recovery were
and decrease in urine output alone is a generalized identified: early sustained reversal (lasting recovery
classification with the advantage of being easily from AKI after less than 7 days), late reversal (lasting
applicable and fitting a lot of situations. However, recovery from AKI after more than 7 days, but prior
it is not without shortcomings. While encompass- to hospital discharge), relapsing AKI with complete
ing the severity of AKI via classification into three recovery prior to hospital discharge, relapsing AKI
stages, it does not consider temporal aspects of AKI, without complete recovery until hospital discharge,
nor does it factor in the trajectory of renal recovery and no recovery from AKI at all. With an increase in
or recurrent AKI episodes. By focusing only on the AKI duration, the authors were able to show an
increase of the baseline SCr, we might lose impor- increase in mortality. Early sustained reversal had
tant information and apply a too generalized view the best overall survival, while no recovery had the
on AKI. In line with this, multiple studies demon- worst. E.g., in 90 day mortality, early sustained sur-
strated that the early SCr elevation velocity can also vival showed a mortality of 3.5%, late sustained
be used to subphenotype AKI, and the velocity reversal 10.5%, relapse with recovery 13.6%, relapse
increase is associated with a worse outcome without recovery 49.9%, and no reversal 53.4%,
&&
[24,25 ,26,27]. However, not only the early phase which marked a statistical significant difference
of AKI offers opportunities for subclassifying AKI [28]. This finding was subsequently verified by a

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Renal system

follow up study, showing that a longer duration of Biomarkers have also been established to predict
AKI was associated with a more frequent need for renal recovery. Two promising candidates for differ-
renal replacement therapy (RRT), and higher mor- entiating between persistent and transient AKI are
&&
tality compared to shorter episodes of AKI [29 ]. C-C motif chemokine ligand (CCL)14 and dickkopf
The ADQI included this evidence in their recent (DKK)-3. Both molecules are markers of renal fibrosis
consensus report and defined the term transient which has been suspected to be an important factor
(<48 h) and persistent AKI (>48 h) [30]. in renal recovery [51]. Several studies have identified
CCL14 as a potent biomarker to predict persisting
&& &&
AKI [52,53 ,54 ]. Several other biomarkers are cur-
BIOMARKERS FOR SUBPHENOTYPING rently investigated to distinguish between persistent
ACUTE KIDNEY INJURY &
and transient AKI [55,56 ,57,58].
Defining AKI only on clinical features alone would Based on the existing evidence, recommenda-
be highly insufficient as the two function bio- tions on biomarker use have found their way in a
markers, SCr and urine output, have several limita- recent ADQI consensus statement . The recommen-
tions [31]. Endeavors to further classify diseases dations suggest using biomarkers to detect ‘subclin-
based on biomarkers have shown promising results ical AKI’ (stage 1S) in order to detect a kidney
in different fields. Biological and genetic markers in damage without a functional loss. In addition, the
oncology have been well established to guide a more ADQI recommendations suggest to us the bio-
personalized therapy approach [32]. Efforts in markers to further classify AKI into biomarker pos-
adopting this approach in the field of AKI have itive AKI and biomarker negative AKI [6].
generated a large body of research in recent years
&&
[11,15,33 ]. AKI biomarkers of interest are Cystatin
C, neutrophil gelatinase-associated lipocalin LIMITATIONS IN PHENOTYPING ACUTE
(NGAL), kidney molecule (KIM)-1, tissue inhibitor KIDNEY INJURY
of the metalloproteinase (TIMP)-2, insulin-like Biological biomarkers are useful for diagnosing AKI
growth factor binding protein (IGFBP)7, different and identify clinical trajectories. However, there are
interleukins, and other molecules that detect or limitations to consider when using biomarkers for
reflect damage [6,34–37]. Several trials showed that phenotyping. The accuracy of biomarkers can vary,
elevated NGAL levels predict the development of and there is limited research on variations in bio-
AKI, need for RRT, and an increased mortality. How- marker concentrations due to factors like comorbid-
ever, NGAL also has several limitations, since this ities and medications. Research should focus on
marker is also elevated in patients with chronic establishing validated cutoff values and standar-
kidney disease [38,39] and elevated NGAL levels dized assay techniques for consistent and reliable
can also be detected in patients with a systemic results across different care settings as it has been
inflammatory response without kidney damage done for TIMP2-IGFBP7 [49].
[40,41]. In addition, NGAL can also be used to detect Lastly, biomarkers often provide a small window
kidney damage without function loss (‘subclinical of insight into one specific aspect of AKI. However,
AKI’), which is associated with increased mortality AKI is a complex syndrome that can follow different
[42,43]. Cystatin C, also a functional biomarker, is trajectories. Biomarkers should be considered along-
well established and can be used to calculate GFR side clinical presentation and other diagnostic tools.
[44]. Based on the small size of Cystatin C, the
molecule is freely filtered in the glomerulus and
almost completely reabsorbed (99%) in the tubulus PERSONALIZED TREATMENT FOR ACUTE
system. Several studies showed that Cystatin C can KIDNEY INJURY
also be used to predict the development of AKI [45]. Prevention is key in the setting of AKI as no defin-
TIMP2 and IGFBP7 are two markers that are itive causal therapy exists [59]. In the following we
involved in the cell cycle arrest and can be used will explore the question of how this can be done in
to detect kidney stress [34,46]. Several studies have a more personalized approach. A possible future
shown that TIMP2IGFBP7 can be used to predict path of AKI treatment is depicted in Fig. 2.
the development of AKI in different patient
&
cohorts [47,48 ,49]. In contrast to NGAL,
TIMP2IGFBP7 are not influenced by comorbidities. CURRENT STANDARD OF CARE – DOES
Elevated TIMPIGFBP7 levels in patients with an ONE SIZE FIT ALL?
existing AKI are associated with a worse outcome The KDIGO guidelines recommend implementing a
compared to patients with the same AKI severity but bundle of supportive measures in patients at risk for
without elevated TIMP2IGFBP7 levels [36,49–50]. AKI [5]. The recommended measures are close

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 Personalized acute kidney injury treatment Porschen et al.

FIGURE 2. A comparison between a conventional AKI treatment path and novel possible treatment paths in the future. ACE,
angiotensine converting enzyme; AI, artificial intelligence; SCr, serum creatinine; UO, urine output.

monitoring of renal function, optimization of past. The differentiated use of vasopressors is one
hemodynamics and volume status, implementation example in this field. Though norepinephrine is
of a functional hemodynamic monitoring, avoid- widely established as standard vasopressor, it may
ance of hyperglycemia (target range 110–150 mg/ not be adequate in every situation [63]. A recent
dl), and avoidance of nephrotoxic agents if possible study showed that elevated renin levels after cardiac
[5]. However, all these interventions are associated surgery are associated with an increased risk to
with significant potential risks for patients. Stricter develop vasoplegia and AKI. It was hypothesized
limits for glucose levels, for example, bear the risk of that the elevated renin levels are the consequences
potential life-threatening hypoglycemia. The imple- of an endogenous angiotensin II deficiency based on
mentation of an advanced hemodynamic monitor- a reduced angiotensin-converting enzyme (ACE)
ing is associated with an increased infection and activity. Therefore, using exogenous angiotensin II
bleeding rate. Identifying patients at a high risk for as a vasopressor might have a positive effect and
AKI (-progression) may lead to a more targeted treat- prevent vasoplegia and the development of AKI
& &
ment approach and better allocation of resources. [48 ,64 ]. Vasopressin, another clinically available
Although the KDIGO guidelines recommend imple- vasopressor, is another candidate for a more indi-
menting the bundle in patients at high risk for AKI, vidualized treatment approach. Vasopressin has
observational studies demonstrated that the meas- shown promising results in reducing AKI rates after
ures are not implemented in daily practice cardiac surgery [65]. Recent evidence suggests the
& &
[60 ,61,62 ]. existence of different AKI subphenotypes varying in
their response to vasopressin exposure and diverg-
ing in their renal outcomes. The authors built two
A MORE PERSONALIZED APPROACH different subphenotypes of AKI: Subphenotype 1
Several opportunities for a more personalized and 2. The former was characterized by better
approach to AKI treatment have emerged in the renal function, lower rates of sepsis, lower rate of

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Renal system

vasopressor use and lower rates of acute respiratory with AKI including urinary KIM-1, plasma cystatin
distress syndrome, as well as markers of endothelial C, and urinary NGAL [52]. In addition, CCL14 has
activation. The authors were not only able to show also recently been used in combination with the
significant differences between the phenotypes in furosemide stress test (FST) to predict the develop-
terms of renal recovery and mortality (1 having ment of an absolute indication for RRT. The FST is a
higher recovery rates and lower mortality than 2). well established functional test [68]. In this study,
They were also able to show a better response to 1 mg/kg of intravenous furosemide was given to
vasopressin for subphenotype 1 compared to 2 [66]. diuretic-naive patients, while patients pretreated
with diuretics were given 1.5 mg/kg. If urine output
exceeded 200 ml within the consecutive two hours,
BEYOND THE SILVER BULLET – patients were considered FST positive. The authors
COMBINING BIOMARKERS AND demonstrated that a combination of a negative FST
PERSONALIZED ACUTE KIDNEY INJURY test with elevated urinary CCL14 was significantly
THERAPY better in predicting the development of an absolute
&
Finding a ‘‘one size fits all’’ approach in treating AKI indication for RRT than FST or CCL14 alone [69 ].
has been moved out of the focus of research in
recent years, adopting precision medicine
approaches that have been well established in other CONCLUSION
fields. In the field of AKI, several efforts in applying The establishment of more granular approaches to
biomarker-guided, personalized treatment regimens subphenotype syndromes is a well established con-
have been evaluated in recent years and are still cept in different fields of medicine. However, in the
under investigation. The PrevAKI-trials prospec- field of AKI, classifications by using different bio-
tively investigated the biomarker-guided implemen- markers and other tools are not established yet. To
&
tation of the KDIGO bundle [47,48 ]. In these trials, implement AKI subphenotypes into clinical practice
TIMP2IGFBP7 was used to identify cardiac surgery to provide physicians with clinical decision-making
patients at a high risk for AKI. These patients were support tools, large prospective multicenter trials
randomized and received either the standard of care are needed. These studies should show an improve-
(control group) or the KDIGO bundle was imple- ment in patient-centered outcomes, whereas mod-
mented (intervention group). In both trials, it was erate/severe AKI is considered as such an outcome.
shown that the AKI rate was significantly reduced in Although the PrevAKI and the BigpAK trial demon-
&
the intervention group compared to the control strated a reduced moderate/severe AKI [48 ,49], a
group (PrevAKI: primary outcome AKI rate within definitive multicenter trial is required. There is a
72 h after cardia surgery; PrevAKI II trial secondary need for evidence, that the combination of damage
outcome: moderate/severe AKI within 72 h after with functional biomarkers can better characterize
&
cardiac surgery) [47,48 ]. The BigpAK-trial con- AKI and that this new definition translates into a
firmed these findings in patients who underwent better outcome. In the future, one would assume
abdominal surgery. Here, a subgroup analysis of that several damage biomarkers are combined with
patients with TIMP2IGFBP levels between 0.3 functional markers so that a more detailed charac-
and 2.0 showed that patients in the intervention terization of AKI is possible. By applying such
group had a significantly reduced AKI rate compared detailed classification, interventions could then be
to patients of the control group [49]. The BigpAK-2 guided in a more personalized fashion, allocating
trial is now under way, investigating these findings resources more efficiently and providing patients
and validating it in a multicenter randomized con- with the appropriate care models. However, further
&
trolled trial (NCT04647396) [67 ]. clinical studies using these phenotypes to guide
Renal recovery influences the outcome of interventions are needed.
patients with AKI. The RUBY trial showed promising
results in identifying patients at risk for developing
Acknowledgements
persistent severe AKI [52]. In this multicenter pro-
spective observational study, 364 patients were None.
enrolled. Of the biomarkers tested in this study,
urinary C-C motif chemokine ligand 14 (CCL14) Financial support and sponsorship
was the most predictive of persistent stage 3 AKI None.
with an area under the receiver operating character-
istic curve (AUC) (95% confidence interval, 95% CI) Conflicts of interest
of 0.83 (0.78–0.87). This AUC was significantly A.Z. has received consulting fees from Astute-Biomer-
greater than values for other biomarkers associated ieux, Baxter, Bayer, Novartis, Guard Therapeutics, AM

556 www.co-criticalcare.com Volume 29  Number 6  December 2023

Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.

 Personalized acute kidney injury treatment Porschen et al.

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Renal system

50. Fan W, Ankawi G, Zhang J, et al. Current understanding and future directions 61. K€ ullmar M, Wei R, Ostermann M, et al. A multinational observational study
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53. Bagshaw SM, Al-Khafaji A, Artigas A, et al. External validation of urinary C-C This study shows yet again, that the KDIGO bundle of care after AKI is lacking
&& motif chemokine ligand 14 (CCL14) for prediction of persistent acute kidney adherence within clinical practice while showing outcome improvement when the
injury. Crit Care 2021; 25:185. bundle is implemented.
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and builds a basis for its potential clinical implementation into practice. during catecholamine vasopressor therapy: a prospective observational
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&& assay for urinary C-C Motif chemokine ligand 14 (CCL14) for persistent 64. K€ ullmar M, Saadat-Gilani K, Weiss R, et al. Kinetic changes of plasma renin
severe acute kidney injury. Kidney360 2022; 3:1158–1168. & concentrations predict acute kidney injury in cardiac surgery patients. Am J
A very important study showing that CCL14 has the potential to predict persistent Respir Crit Care Med 2021; 203:1119–1126.
severe AKI while using standardized clinical assays. This could be the basis for This is a very important study showing the potential of renin as a functional
implementing CCL14 as a tool in clinical practice. biomarker to predict AKI.
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after contrast media exposure. This could form the basis for new phenotyping & to prevent acute kidney injury after major surgery (BigpAK-2 trial): study
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kidney. Renal Failure 2002; 24:703–723. multicentric approach with a mixed patient cohort, the results of which are highly
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& tective measures to prevent acute kidney injury in septic patients: a retro- chemokine (C-C motif) ligand 14 in a cohort of postsurgical patients. Crit Care
spective cohort study. Anesth Analg 2023. Med 2023; 51:1033–1042.
This study shows the low adherence to the current KDIGO recommendations of This is the first study to combine CCL14 with the furosemide stress test to improve
care after AKI onset in a large intensive care database. prediction capability of both approaches.

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