Intensive Care Med

https://doi.org/10.1007/s00134-023-07171-z

REVIEW

Precision management of acute kidney

injury in the intensive care unit: current state
of the art
Natalja L. Stanski1 , Camila E. Rodrigues2,3 , Michael Strader4 , Patrick T. Murray4 , Zoltan H. Endre2
and Sean M. Bagshaw5*

© 2023 Springer-Verlag GmbH Germany, part of Springer Nature

Abstract
Acute kidney injury (AKI) is a prototypical example of a common syndrome in critical illness defined by consensus.
The consensus definition for AKI, traditionally defined using only serum creatinine and urine output, was needed to
standardize the description for epidemiology and to harmonize eligibility for clinical trials. However, AKI is not a simple
disease, but rather a complex and multi-factorial syndrome characterized by a wide spectrum of pathobiology. AKI is
now recognized to be comprised of numerous sub-phenotypes that can be discriminated through shared features
such as etiology, prognosis, or common pathobiological mechanisms of injury and damage. The characterization
of sub-phenotypes can serve to enable prognostic enrichment (i.e., identify subsets of patients more likely to share
an outcome of interest) and predictive enrichment (identify subsets of patients more likely to respond favorably
to a given therapy). Existing and emerging biomarkers will aid in discriminating sub-phenotypes of AKI, facilitate
expansion of diagnostic criteria, and be leveraged to realize personalized approaches to management, particularly
for recognizing treatment-responsive mechanisms (i.e., endotypes) and targets for intervention (i.e., treatable traits).
Specific biomarkers (e.g., serum renin; olfactomedin 4 (OLFM4); interleukin (IL)-9) may further enable identification of
pathobiological mechanisms to serve as treatment targets. However, even non-specific biomarkers of kidney injury
(e.g., neutrophil gelatinase-associated lipocalin, NGAL; [tissue inhibitor of metalloproteinases 2, TIMP2]·[insulin like
growth factor binding protein 7, IGFBP7]; kidney injury molecule 1, KIM-1) can direct greater precision management
for specific sub-phenotypes of AKI. This review will summarize these evolving concepts and recent innovations in
precision medicine approaches to the syndrome of AKI in critical illness, along with providing examples of how they
can be leveraged to guide patient care.
Keywords: Acute kidney injury, Biomarker, Phenotype, Endotype, Prognosis, Enrichment, Precision

*Correspondence: bagshaw@ualberta.ca
5
Department of Critical Care Medicine, Faculty of Medicine and Dentistry,
University of Alberta and Alberta Health Services, 2‑124 Clinical Sciences
Building, 8440‑112 ST NW, Edmonton, AB T6G 2B7, Canada
Full author information is available at the end of the article
Introduction
Critical care medicine has long engaged in describing
patient subgroups and disease phenotypes of critical ill-
ness. The most prominently described phenotypes of
critical illness are the syndromes of sepsis, acute res-
piratory distress syndrome (ARDS) and acute kidney
injury (AKI) [1]. These syndromes have been the subject
of consensus definitions, largely driven by simple and
readily available clinical criteria [2–5]. These consensus
definitions have been important for standardizing the
descriptions for epidemiology, outcomes, and prognosis,
and to harmonize eligibility for clinical trials evaluating
various interventions. However, their continued unmodi-
fied application may also be contributing to stalled inno-
vation in therapeutics in critical care.
Traditional methods to identify discrete subgroups
have seldom yielded promising new therapies in clinical
trials and changed practice [1, 6, 7]. Recently, innova-
tive methodologies to identify patient subgroups across
common intensive care unit (ICU) syndromes have been
described [7, 8]. Coupled with the discovery of new
biologic markers of disease (i.e., genomic, transcrip-
tomic, proteomic, metabolomic), these innovations have
advanced our capacity to identify discrete subgroups (i.e.,
sub-phenotypes) of patients with critical illness (e.g., sep-
sis, ARDS, AKI, delirium, pancreatitis) [1, 7–13]. These
methods have been used in specific successful advances
in translational science made in oncology and in other
chronic illnesses and may hold promise to discover treat-
ment-responsive mechanisms (i.e., endotypes) and traits
that can be targeted in AKI-related clinical trials [7, 8].
The promise is to realize personalized diagnostics and
precision-orientated therapies for patients with critical
illness and improved enrichment in clinical trials [7, 8].
In this article, we will summarize these evolving concepts
and the recent innovations in phenotyping the syndrome
of AKI in critical illness and provide illustrative examples.
Clarifying precision medicine concepts:
sub‑phenotypes, endotypes and treatable traits
Despite a growing consensus that heterogeneous syn-
dromes in critical illness like AKI require mechanisms
for further subclassification to move precision care for-
ward [7, 8, 14], a key barrier to operationalizing this con-
cept has undoubtedly been confusion and inconsistency
Take‑home message
Acute kidney injury (AKI) is a syndrome, not a disease, with a wide
spectrum of pathophysiology.
Selected kidney stress and damage biomarkers may enable earlier
detection of kidney injury, facilitate identification of AKI sub-pheno-
types and serve to predictively enrich high-risk patient groups for
specific care pathways or interventions.
The integration of biomarkers with the conventional definition for
AKI, along with selected clinical features, allows for the identification
of AKI sub-phenotypes and enables clustering of patients with simi-
lar prognosis or potential for treatment-responsiveness.
AKI sub-phenotypes have been used to guide targeted manage-
ment of AKI and can accelerate personalized therapeutics in critical
illness. This has been shown in decompensated heart failure and
hepato-renal syndrome with negative kidney damage biomarkers,
and in interleukin (IL)-9 positive acute interstitial nephritis.
in terminology. Building upon recent consensus [7, 8, 14],
Table 1 outlines proposed definitions of phenotype, sub-
phenotype, endotype and treatable trait [8]. Phenotype
refers to a set of clinical features in a group of patients
who share a common syndrome or condition. Cur-
rently, the AKI phenotype is defined by Kidney Disease:
Improving Global Outcomes (KDIGO) consensus crite-
ria, which includes two functional biomarkers (i.e., serum
creatinine and urine output) [4, 21]. Sub-phenotype
describes a subset of clinical features in patients with a
shared phenotype that distinguishes the subgroup from
other subgroups within that phenotype. For patients with
AKI, these sub-phenotypes are characterized by discrete
differences in etiology (i.e., Low perfusion, Inflammation,
Immune, Obstructive, Nephrotoxic [LIION]), shared
risk factors, diagnostic features, mortality risk, and bio-
markers that can be both specific and non-specific for
the underlying pathobiological mechanisms of disease,
or some combination of these. Importantly, it is plausible
that a patient with AKI may have multiple recognizable

Table 1 Proposed definitions for subgrouping patients with AKI [7, 8]

Term Definition

Phenotype A set of clinical features in patients who share a common syndrome or condition
Examples: AKI, ARDS, sepsis, delirium
Sub-phenotype A subset of clinical features in patients with a shared phenotype that distinguishes the group from other groups within
that phenotype
Example: SA-AKI is a sub-phenotype of AKI, and further subgrouping of SA-AKI (i.e., AKI-SP1 and AKI-SP2) can refine that
sub-phenotype [42]
Endotype A subset of patients with a given phenotype that share a distinct biological mechanism of disease
Example: SA-AKI is a sub-phenotype of AKI, and elevated renin may identify an angiotensin II deficient endotype [68,
69]
Treatable trait A subgroup characteristic that can be successfully targeted by an existing, available intervention
Example (sub-phenotype): ADHF associated AKI with a negative tubular injury biomarker and clinical evidence of con-
gestion suggests the patient continue diuretic therapy despite an increasing serum creatinine [53, 63, 65]
Example (endotype): SA-AKI is a sub-phenotype of AKI and elevated renin identifies an angiotensin II deficient endo-
type, which suggests patient treatment with exogenous angiotensin II [68, 69]
ADHF acute decompensated heart failure, AKI acute kidney injury, AKI-SP1 -SP2 AKI sub-phenotypes 1 and 2, determined by endothelial dysfunction/inflammation and
septic shock response to vasopressin, SA-AKI sepsis-associated AKI
 Fig. 1 Disentangling the AKI phenotype, sub-phenotypes, endotypes and treatable traits. The AKI phenotype is defined by the KDIGO consensus
criteria, incorporating the functional biomarkers serum creatinine (sCr) and urine output (UOP), and tubular stress/injury biomarkers, when available.
Once established, unique sub-phenotypes are identified from a myriad of shared clinical features, including (but not limited to) etiology, novel
biomarkers (e.g., transcriptomic, proteomic, metabolomic), clinical risk factors, diagnostic (Dx) features, response to therapy (Tx), trajectory and
outcomes. Based on our current understanding, a single patient with the AKI phenotype may have multiple recognizable and concurrent AKI sub-
phenotypes. Simultaneously, AKI endotypes may also be identified by characterizing distinct pathobiological mechanisms of disease

sub-phenotypes at any given time. Endotype refers to a
subset of patients with a given phenotype that share a
distinct biological mechanism of disease. While previous
articles have defined endotypes as “sub-phenotypes that
share a distinct biological mechanism of disease”, these
terms should be separated which is necessary given the
limited understanding of the underlying pathobiological
mechanisms of AKI. This is key, as multiple endotypes
may exist within a given sub-phenotype and be present
across multiple sub-phenotypes. Finally, treatable trait
is a subgroup characteristic that can be successfully tar-
geted by an existing, available intervention. Within our
current framework, a specific sub-phenotype or endo-
type may represent a treatable trait.
The complexity of critical illness dictates that multiple
inciting pathobiological mechanisms can be (and often
are) at play in critically ill patients with AKI, making it
unlikely that an individual patient will ever be defined
by a single AKI endotype. Second, while acknowledging
that the ultimate goal is the discovery of an underlying
treatable pathobiological mechanism to define a treat-
able trait, there is also sufficient evidence to support
the use of some existing sub-phenotyping strategies to
identify unique treatable traits (e.g., a negative damage
biomarker in the context of AKI associated with acute
decompensated heart failure [ADHF] or hepato-renal
syndrome [HRS]). The complex interplay between these
different classifications is outlined in Fig. 1.
Regardless of the strategy used, subgrouping the AKI
phenotype serves to facilitate prognostic enrichment (i.e.,
identify a subset of patients more likely to experience an
outcome of interest), predictive enrichment (i.e., identify
a subset of patients more likely to respond beneficially
to a given therapy) and more precise management of an
otherwise heterogeneous syndrome.
AKI is a heterogeneous syndrome, not a disease
There are several plausible explanations for the failure
to translate promising and effective therapeutic inter-
ventions from pre-clinical experimental studies into
successful human clinical trials [15, 16]. While current
consensus definitions and delays in the diagnosis of AKI
are likely contributory [17], a fundamental challenge has
been an inability to fully account for the vast heterogene-
ity in patient case-mix and AKI phenotype.
AKI is a complex and multi-factorial syndrome, char-
acterized by a spectrum of pathobiological insults, in
which the course and prognosis are further modified
by patient multi-morbidity and the clinical context of
kidney injury [18, 19] (Table 2). AKI in critical illness
Table 2 Sources of heterogeneity in AKI: susceptibility, presentation, and severity
Characteristic Description and/or potential for biomarker differentiation

Genetic profile IFN-γ gene and kidney transplant rejection

(Gene polymorphisms associated with development of AKI and outcome) Apolipoprotein E, CSA-AKI and mortality
MIF and CSA-AKI
TNF-α, IL-10 and AKI mortality
NADPH oxidase gene variants and RRT requirement and mortality in AKI
ACE and risk of AKI
HLA-DRB1 and RRT requirement
EPO gene promoter and receipt of RRT​
Baseline kidney function CKD as risk factor for AKI: CysC, penKid
(CKD the most important AKI risk factor) Subclinical CKD as risk for AKI: CysC, penKid, KFR
DKK3 as risk for CKD progression and AKI
Multi-morbidity [81–83] Diabetes mellitus
(Associated with higher risk and severity of AKI) Peripheral vascular disease
Heart failure
Cirrhosis
Chronic lung disease
Transplantation
Varying target site of kidney injury Glomerulus: miR-23a-3p
(Different nephron sites might be damaged or the source of biomarkers in Proximal tubule: Pi-GST, KIM-1, miR-192-5p, [TIMP-2]·[IGFBP7]
each AKI episode) TAL: uromodulin, miR-221-3p, miR-222-3p, miR- 210- 3p, OLFM4
Etiology Main causes—LIION classification:
(Causes may associate with prognosis) Low perfusion
Inflammation or Immune-mediated
Obstruction
Nephrotoxicity
Mechanisms of injury Volume status: plasma copeptin, urine PAPPA2
LV failure: urine angiotensinogen, CD14, BNP
Inflammation: plasma procalcitonin, plasma and urine NGAL, plasma and
urine sTREM-1, plasma IL-6, plasma soluble thrombomodulin, plasma
TNFR1/2, plasma IL-8, urine netrin-1, urine IL-18
Endothelial dysfunction: Ang-2/Ang-1
Mitochondrial damage: urine cytochrome C
Apoptosis: urine caspase 3
Cell cycle arrest: urinary [TIMP-2]·[IGFBP7], plasma and urine p21
Presentation Oliguric (vs non-oliguric)
(Some presentations of AKI are associated with worse outcomes) Duration (persistent vs transient)
Recurrent (vs non-recurrent)
ACE angiotensin converting enzyme gene, AKI acute kidney injury, Ang Angiopoietin, APOE apolipoprotein E gene, BNP B-type natriuretic peptide, CD cluster of
differentiation, CKD chronic kidney disease, CysC cystatin C, CSA-AKI Cardiac surgery-associated AKI, DKK3 Dickkopf-3, EPO Erythropoietin gene, HLA-DRB1 human
leukocyte antigen –major histocompatibility complex, class II, DR beta 1 gene, IFN-γ interferon-γ gene, IGFBP7 insulin-like growth factor-binding protein 7, IL
Interleukin, KIM kidney injury molecule 1, KFR kidney functional reserve, LV left ventricle, MIF macrophage migration inhibitory factor gene, miR micro-ribonucleic
acid, NADPH nicotinamide adenosine dinucleotide phosphate gene, NGAL neutrophil gelatinase-associated lipocalin, OLFM4 olfactomedin 4, PAPPA2 pregnancy-
associated plasma protein A2, Pi-GST Pi class-Glutathione S-Transferase, penKid proenkephalin-A, RRT​renal replacement therapy, sTREM-1 soluble triggering receptor
expressed on myeloid cells-1, TAL thick ascending limb of the loop of Henle, TIMP2 tissue inhibitor of metalloproteinases 2, TNF-α tumor necrosis factor α gene, TNFR
tumor necrosis factor receptor

is mediated by wide range of concomitant and com-
peting mechanisms, including a remarkable variety of
adaptive and maladaptive responses to cellular stress
and damage [14, 20]. Key pathobiological changes
may include cellular dysfunction and hypoxia, mito-
chondrial disruption, microvascular changes, and a
spectrum of host-specific inflammatory and immune
signaling patterns [21–25]. Some of these mechanisms
may be identifiable as unique sub-phenotypes or endo-
types characterized by detectable biomarker signatures,
though there may be significant overlap and redun-
dancy with both kidney and remote organ stress, injury,
and damage [20]. The risk of development, progression,
and adverse outcomes associated with AKI is further
contingent on a myriad of additional factors including
patient baseline susceptibility (e.g., genetic profile, age,
multi-morbidity, chronic kidney disease (CKD), kidney
reserve), illness acuity and non-kidney organ dysfunc-
tion (e.g., organ crosstalk), and the underlying features
of the acute kidney insult (i.e., etiology, severity, dura-
tion, frequency) (Table 2).
The current kidney disease
The KDIGO consensus definition for AKI relies on two
crude measures of kidney function (serum creatinine
[SCr] and urine output) and does not comprise exist-
ing and novel serum biomarkers that may reflect early
changes in GFR, like cystatin C and proenkephalin-A
[26, 27]. In addition, this functional definition lacks
any information on the pathobiology of AKI [9, 14, 19].
This is further made challenging by the varying trajec-
tories and temporal phases of the underpinning patho-
biological mechanisms of AKI in critical illness [28–30]
(Table 2). The immense heterogeneity of precipitat-
ing factors captured with this definition, the delayed
diagnosis and the complete absence of information on
treatment-responsive states are key drivers of why clin-
ical trials in AKI have not yielded beneficial and prac-
tice changing results, despite the underlying biologic
rationale and favorable findings in pre-clinical experi-
mental studies [8, 9, 14, 16, 19, 31]. When AKI is classi-
fied with the current consensus definition, patients can
fulfill identical criteria for AKI with similar apparent
severity and duration, however, can have completely
differing and unrelated pathobiology (e.g., AKI in car-
diac surgery, cirrhosis, heart failure, sepsis, cancer
therapy, etc.) [32].
Identification of AKI sub‑phenotypes: strategies,
challenges and limitations
Current approaches to sub‑phenotyping
It is now clear that the syndrome (i.e., phenotype) of
AKI is comprised of numerous sub-phenotypes, which
can be identified and discriminated through shared fea-
tures such as etiology/cause (e.g., LIION, Table 3), and
prognosis (e.g., risk of renal replacement therapy (RRT),
Table 3 AKI sub-phenotypes based on cause: LIION (adapted from [14])
Sub-phenotype (Cause)
Low Perfusion AKI*
Inflammatory/Immune
Obstructive
Nephrotoxic and
Envenomation
*Low Perfusion was previously designated “prerenal” but this alternative terminology is provided to highlight the markedly different management required by the
contributing causes (three “V”s)
AIN acute interstitial nephritis, AKI acute kidney injury, ATI acute tubular injury, CCF congestive cardiac failure, DAMPs damage-associated molecular patterns, HFpEF
heart failure with preserved ejection fraction, HRS hepato-renal syndrome, LVF left ventricular failure, PAMPs pathogen-associated molecular patterns, RVF right
ventricular failure
new CKD, mortality) [9, 14]. Importantly, identified sub-
phenotypes are not clinically or prognostically equiva-
lent, and may behave differently in response to selected
interventions. Classification of AKI sub-phenotypes has
the potential to enable personalised evaluation and com-
parison of variations in “feature-directed” care [33]. This
approach will not, however, necessarily enable evalua-
tion and comparisons of injury-specific “mechanistic-
directed” care (i.e., endotype) [8] (Table 1).
Existing and emerging biomarkers are likely to have
a prominent role in discriminating sub-phenotypes
of AKI directly, if they are specific for a particular sub-
phenotype, or indirectly, if the absence of a detectable
biomarker excludes that sub-phenotype. Expanding the
diagnostic criteria of AKI by integrating biomarkers of
kidney stress/damage will not only embrace the concept
of sub-clinical AKI [17], but can also enable further dif-
ferentiation of sub-phenotypes of AKI; particularly sep-
arating AKI with perturbed function alone from AKI
where there is both active kidney damage and dysfunc-
tion [17, 32]. This has recently been proposed and will
complement conventional approaches to the diagnosis
of AKI [17] (Table 1). For example, an elevated urinary
[tissue inhibitor of metalloproteinases 2, TIMP2]·[insulin
like growth factor binding protein 7, IGFBP7], which
reflects cell cycle arrest, predicts AKI after cardiac and
non-cardiac surgery, serving as a tool for both prognostic
and predictive enrichment in clinical trials and for bed-
side application [34, 35]. Although biomarkers like uri-
nary [TIMP-2]·[IGFBP7] may be non-specific and may
increase due to filtration with impaired proximal tubular
reabsorption rather than in situ kidney tubular damage,
urinary [TIMP-2]·[IGFBP7] remains a validated indicator
of heightened risk of AKI [14, 36]. Similarly, biomarkers
Contributing causes
Vascular—Dilatation: systemic (shock; sepsis), local (HRS); Constriction:
eclampsia, hypertension, rhabdomyolysis, contrast media; Intra-abdomi-
nal pressure: decreased arterial/venous flow
Ventricular—LV and RV dysfunction; HFpEF
Volume—Decreased (dehydration; hypovolemia); Increased (congestion,
hypoproteinemia)
Sepsis—direct (PAMPs), indirect (DAMPs);
Nephritis—acute glomerulonephritis, AIN;
Vasculitis—systemic or kidney specific
Site—dependent sub-phenotypes
Direct—toxin-specific = ATI;
Indirect—AIN
that are more specific for kidney tubular injury, such as
ney injury molecule 1 (KIM-1), and ɑ- and π-glutathione
neutrophil gelatinase-associated lipocalin (NGAL), kid-
s-transferase (GST) among others, are detectable before
changes occur in serum creatinine, and can predict AKI
progression and severity [14, 17]. While biomarker signa-
tures may provide insights into pathobiological mecha-
nisms, serum creatinine will continue to have importance
as a conventional functional measure. Trajectories of
serum creatinine may also discriminate AKI sub-pheno-
types through prediction of persistent AKI or through
patterns of recovery [29, 37]. Conventional measures and
newer biomarkers will likely have complementary roles
for enriching the diagnostic and prognostic assessment
of AKI, and lead to development of a spectrum of com-
panion biomarkers that target therapeutic strategies and
interventions for prevention and management.
Cluster analyses and advanced techniques
As has been done with other heterogeneous syndromes
like ARDS [12, 38, 39] and sepsis [5, 40], cluster anal-
ysis and more advanced data analytic techniques (i.e.,
artificial intelligence/machine learning [AI/ML]) have
been utilized to leverage the large scale clinical and/
or biomarker data that is increasingly available in elec-
tronic health records (EHR) to elucidate unique AKI
sub-phenotypes [41].
In critically ill adults with AKI, two different research
groups have recently utilized latent class analysis (LCA)
to identify two discrete sub-phenotypes of AKI based
on clinical and biomarker data with differences in out-
comes, including mortality and renal recovery [42, 43].
While the biomarkers measured and incorporated into
the sub-phenotypes were not the same in these two
studies, both groups found that the sub-phenotype
more strongly associated with worse outcomes (i.e.,
facilitating prognostic enrichment) was characterized
by increased inflammation, endothelial dysfunction,
and vascular permeability [42, 43]. Moreover, when
Bhatraju et al. applied their two sepsis-associated AKI
(SA-AKI) sub-phenotype classes (AKI-SP1 and AKI-
SP2) to the VASST trial (Vasopressin and Septic Shock
Trial) data, differences in treatment effect were seen
across the two groups, with those patients categorized
to AKI-SP1 showing a survival benefit with receipt of
vasopressin (i.e., potentially aiding predictive enrich-
ment) [42]. While the biomarkers included in these
sub-phenotypes (i.e., those indicative of endothelial
dysfunction) help point to plausible biological under-
pinnings for the observed subgroups, more work is
needed to elucidate the specific AKI endotypes and
treatable traits associated with these sub-phenotypes
[44, 45].
In another example, Chaudhary et al. utilized an
unsupervised deep learning approach of the MIMIC III
clinical database to identify three discrete SA-AKI sub-
phenotypes that demonstrated differences in mortality
and receipt of RRT (i.e., potentially aiding prognostic
enrichment) [41]. In contrast to the LCA methodology
used above (which requires a priori selection of variables
to define subgroups), this approach seeks to harmonize
and leverage massive amounts of routinely captured EHR
data to identify sub-phenotypes. While attractive in prin-
ciple, utilization of this approach should be thoughtfully
employed with consideration of how the identified sub-
phenotypes may further characterize shared pathobiol-
ogy (i.e., endotypes) and identify treatable traits needed
for precision management of AKI. In addition, unsu-
pervised learning techniques usually require thoughtful
interpretation regarding introduction of bias that may
have influenced the AI/ML generation of its results (e.g.,
the dataset it was trained on, or any implicit or explicit
bias). Furthermore, regardless of the approach used,
efforts should be made to harmonize and validate these
sub-phenotyping strategies in additional cohorts to pro-
mote translation of these strategies to the point-of-care.
Challenges and limitations in sub‑phenotyping
The current application of sub-phenotypes and endo-
types is limited, due in part to varying definitions and
analytic methods for characterization. It is also likely that
there is a cross-over and redundancy between sub-phe-
notypes and endotypes, depending on which mechanisms
are active [1]. Biomarkers can provide guidance for iso-
lating a sub-phenotype but can vary depending on how
the markers are obtained (i.e., urine, serum, tissue). The
generalizability of biomarker data is also limited because
studies often exclude patients with multi-morbidity or
advanced chronic disease [46]. In many cases, biomark-
ers are retrospectively analyzed in heterogenous cohorts
with varying patient case-mix, presenting challenges for
interpretation and application of sub-phenotypes [8, 9].
Of the described sub-phenotypes and proposed endo-
types of AKI, nearly all require further prospective exter-
nal validation.
Critical illness is also dynamic, and as such, tempo-
ral changes and trajectory must be considered in AKI
sub-phenotypes [28–30]. For example, a secondary
analysis of the ProCESS (Protocol-based Care for Early
Septic Shock) trial demonstrated that changes in urinary
[TIMP-2]·[IGFBP7] after initial fluid resuscitation during
the first 6 h of sepsis identified patients with differing risk
for adverse outcomes [47]. Specifically, persistent eleva-
tion of urinary [TIMP-2]·[IGFBP7] was strongly associ-
ated with death, receipt of RRT and progression in AKI
 Fig. 2 Proposed management of AKI in the intensive care unit (ICU). AKI definition includes increase in serum creatinine, reduction in urine output
and positivity in kidney damage and stress biomarkers. Several biomarkers, some available at point-of-care, may aid in the detection of AKI, and can
facilitate earlier identification of patients with potential endotypes, treatable traits or suitability for selected preventative approaches. Sub-pheno-
types of AKI, identified by clinical features have already been incorporated into clinical practice (e.g., etiology/causes, AKI stages, severity, duration,
etc.), but sub-phenotypes integrating biomarkers may be more informative and provide predictive and prognostic information. This enhanced
definition of sub-phenotypes differentiates among subgroups of patients with similar outcomes (prognostic enrichment) and/or similar response to
treatments (predictive enrichment). Treatment strategies need further development and refinement, and the nuanced characterization of AKI sub-
phenotypes will evolve with the discovery of new biomarkers and more precise clinical and biomarker-derived sub-phenotypes. ACEi angiotensin
converting enzyme inhibitors, AKI acute kidney injury, ARB angiotensin II receptor blockers, IGFBP-7 insulin-like growth factor-binding protein 7,
KDIGO-AKI acute kidney injury definition according to the Kidney Disease: improving global outcomes guideline (increase in serum creatinine or
decrease in urine output), KIM-1 kidney injury molecule 1, LIION low-perfusion/inflammatory/immune/obstructive/nephrotoxic, NGAL neutrophil
gelatinase-associated lipocalin, PiCCO pulse index continuous cardiac output, RAI renal angina index, RRT​ renal replacement therapy, SAPS simplified
acute physiology score, sCr serum creatinine, TIMP-2 tissue inhibitor of metalloproteinase-2, UOP urine output

severity [47]. The added prognostic value afforded by
serial measurements of these biomarkers highlights the
importance of considering data at multiple time points in
AKI sub-phenotypes.
Additionally, consideration of patient characteristics
in the cohorts in which sub-phenotypes are developed is
important when considering generalizability. For exam-
ple, patient age spectrum (e.g., developmental age) is
an important factor [48, 49]. This is nicely highlighted
in previous work focused on sepsis, where the applica-
tion of pediatric sepsis endotypes A and B to an adult
cohort failed to show the same consistent differences in
mortality between these groups as seen in children [50].
Further, one group has successfully leveraged serum
biomarkers validated to predict mortality in pediatric
sepsis to develop a SA-AKI prediction model, suggest-
ing that the unique inflammatory response to infection
seen in children may be an important contributor to their
AKI sub-phenotype [51]. Taken together, it is likely that
neonates and children exhibit unique AKI sub-pheno-
types that are distinct from their adult counterparts and
require dedicated research efforts to characterize and
integrate into clinical care.
Proposed management approaches for specific
AKI sub‑phenotypes, emerging endotypes
and treatable traits
Recognition of sub-phenotypes associated with an
AKI episode constitutes an important part of gen-
eral management and an opportunity for personalized
targeted therapy (Fig. 2). While etiology/causes (e.g.,
LIION) and clinical features (e.g., severity and dura-
tion) of AKI already serve to guide clinicians in man-
agement, the addition of available biomarkers, such
as [TIMP-2]·[IGFBP7], NGAL, KIM-1 and liver fatty
acid-binding protein (L-FABP), can help facilitate AKI
Table 4 Predictive and prognostic enrichment targets for AKI sub-phenotypes, their potential utility, and existing exam‑
ples
Outcome of interest Proposed use Validated examples

Development of Intensification of supportive care (i.e., KDIGO bundle) Urinary CCL14 [79, 84]
severe persistent Patient/family counseling
AKI (AKI Progres- Enrichment for clinical trials examining novel AKI therapies or mitigation strategies
sion)
Receipt of RRT​ Inform clinical decision-making on suitability and timing of RRT initiation Non-response to furosemide
Enrichment for clinical trials examining acute RRT initiation and strategies stress test [80, 85, 86]
Kidney Non-Recov- Identify patients most likely to benefit from follow-up after AKI No validated sub-phenotypes
ery: Development Patient/family counseling
of AKD and/or CKD Enrichment for clinical trials examining therapies to prevent or mitigate progression
(AKI → AKD → CKD)
All-cause mortality Inform clinical decision-making and risk/benefit assessment of targeted therapies and/or strate- No validated sub-phenotypes
gies
Patient/family counseling
Enrichment for clinical trials examining novel AKI therapies or mitigation strategies, with particu-
lar focus on how such interventions impact mortality (i.e., high pre-test probability)
AKD acute kidney disease, AKI acute kidney injury, CCL14 C–C Motif Chemokine Ligand 14, CKD chronic kidney disease, KDIGO kidney disease improving global
outcomes, RRT​renal replacement therapy

sub-phenotyping. Despite the fact that these biomarkers
are generally non-specific (i.e., detect kidney and sys-
temic stress and damage earlier than serum creatinine
changes but are not sufficiently precise to target specific
pathobiological pathways in AKI), they have been dem-
onstrated to add value in delineating specific AKI sub-
phenotypes for enrichment purposes, some of which
represent treatable traits [35, 42, 51–54]. Some examples
are discussed below.
Importantly, through identifying predictive enrichment
strategies to deliver the right therapy to the right patient
remains the vision of precision medicine, most existing
AKI sub-phenotyping strategies have generally only facil-
itated improved prognostic enrichment [29, 41–44, 47,
51]. To date, these strategies have focused primarily on
differences in all-cause mortality and renal recovery (by
varying definitions) [29, 41–43, 51, 55]. Thus, identifica-
tion and validation of AKI sub-phenotypes to predict (1)
consistently defined endpoints and (2) other meaning-
ful, patient-centered outcomes of interest, are needed to
move precision AKI care forward [56]. Table 4 outlines
proposed enrichment strategies and endpoints of interest
for AKI sub-phenotypes, their potential uses in clinical
practice and research, and existing validated examples,
when available.
Sub‑phenotypes for predictive and prognostic enrichment
Tubular Stress Biomarkers to Guide Post‑Operative Bundled
Care
Positivity for urinary [TIMP-2]·[IGFBP7] after cardiac
surgery successfully and prognostically identifies an at-
risk AKI sub-phenotype [35, 54]. In two single-center
randomized controlled trials, implementation of a
KDIGO care bundle (i.e., optimization of hemodynam-
ics and volume status, harm mitigation, avoidance of
nephrotoxins) in high-risk patients with a post-operative
urinary [TIMP-2]·[IGFBP7] > 0.3, used as a tool for pre-
dictive enrichment, reduced the incidence and severity of
AKI [35, 57]. While the overall incidence of AKI was sim-
ilar in a subsequent open-label multicenter multinational
study, the incidence of moderate to severe AKI was nev-
ertheless reduced in those patients allocated to receive
the post-operative KDIGO care bundle [54].
Tubular injury biomarkers in cirrhosis‑associated AKI
In patients with cirrhosis, differentiating between func-
tional hepato-renal syndrome-associated AKI (HRS-
AKI) and acute tubular injury is challenging. In patients
with cirrhosis and AKI, a negative urinary NGAL could
better discriminate volume-unresponsive HRS from
other sub-phenotypes of AKI in cirrhosis which have
tubular injury (e.g., intrinsic AKI with tubular injury,
allergic interstitial nephritis, glomerulonephritis, bile cast
nephropathy, etc.) [52, 58, 59]. A negative urinary NGAL
in this context (particularly when associated with a low
fractional excretion of sodium [FeNa]) could better target
HRS-specific therapy with terlipressin, rather than addi-
tional fluid therapy or use of vasopressors with minimal
therapeutic potential (and possible iatrogenic harm) [52].
Alternatively, urinary NGAL levels following fluid resus-
citation could provide further discrimination, as 86% of
patients with presumed acute tubular injury were above
a threshold urinary NGAL level of 220 μg/g creatinine,
whereas 88% with HRS-AKI were below this threshold
[60]. Thus, an elevated urinary NGAL in the context of
HRS-AKI would predict a non-beneficial response to
therapy with albumin and terlipressin [59, 61, 62].
Tubular injury biomarkers in acute decompensated heart
failure
In patients with acute decompensated heart failure
(ADHF) treated aggressively with diuretics, a decrease
in GFR estimated by functional markers has often been
defined as worsening renal function (WRF). However,
decongestion in this context is associated with reduced
mortality, despite the apparent functional AKI [63]. Fur-
ther studies have confirmed that WRF in this context
was usually not associated with either an increase in uri-
nary kidney damage biomarkers, such as N-acetyl-β-D-
glucosaminidase (NAG), KIM-1 or NGAL [64] or worse
clinical outcomes such as death or rehospitalization [65].
Thus, in patients with ADHF, negative tubular injury bio-
markers (i.e., the sub-phenotype) adds value by reinforc-
ing a continued strategy of diuretic therapy to achieve
decongestion, despite the changes in functional biomark-
ers suggesting WRF (i.e., “AKI”) [53, 66]. Delineation of
whether an increase in kidney functional biomarkers rep-
resents true AKI or simply reflects concentration due to
diuretic-induced free water removal could be addressed
by interrogation of additional biomarkers (e.g., heart-
type fatty acid binding protein, galectin-3; growth dif-
ferential factor 15) [67], or complemented by serum
natriuretic peptides to confirm the benefits of diuresis
and decongestion.
Endotypes with potential treatable traits
Vasodilatory shock and responsiveness to vasopressors
Few AKI endotypes with clearly delineated shared biology
have been identified, with none validated across patient
cohorts. However, a potential AKI endotype is character-
ized by angiotensin II deficiency or derangement of the
renin–angiotensin–aldosterone system (RAAS). In post
hoc analyses of the Angiotensin II for the Treatment of
High-Output Shock 3 (ATHOS-3) study, some patients
with catecholamine-resistant vasodilatory shock had
high concentrations of serum renin, which was hypoth-
esized as elevated in a setting of reduced angiotensin II
production (as evidenced by high angiotensin I/angio-
tensin II ratios in those patients) [68]. Patients with AKI
and elevated serum renin were more likely to have kidney
recovery after infusion of angiotensin II compared to pla-
cebo [68, 69]. While more work is needed to validate this
endotype, patients in this context with high renin may
represent a treatable trait that could be addressed using
an available therapy, namely angiotensin II.
In patients with SA-AKI, biomarkers can facilitate iden-
tification of sub-phenotypes reflecting varying patho-
physiological mechanisms of AKI and define targeted
treatment pathways [42, 43]. As aforementioned, this was
shown in a post hoc analysis of the VASST trial [70], in
which patients with septic shock within a sub-phenotype
defined by a low angiopoietin-2/angiopoietin-1 ratio and
interleukin-8 levels (sub-phenotype 1, AKI-SP1) showed
survival benefit from the addition of vasopressin to nor-
epinephrine compared with norepinephrine alone [42].
Urinary IL‑9 to identify acute interstitial nephritis
A more specific AKI sub-phenotype that may eventually
qualify as an endotype is identified by urinary interleu-
kin-9 (IL-9). Both urinary IL-9 and tumor necrosis fac-
tor-alpha (TNF-α) were prospectively evaluated in AKI
in scenarios where the differential diagnosis of acute
interstitial nephritis (AIN) included acute tubular injury
(ATI), glomerular diseases, and diabetic kidney disease
[71–73]. Prospective evaluation demonstrated that high
levels of urinary IL-9 and TNF-α were suggestive of a
diagnosis of AIN [73]. Moreover, among the patients
with AIN, those with high urinary IL-9 levels appeared to
benefit from therapy from corticosteroids [72].
Urinary Olfactomedin 4 and Furosemide Responsiveness
Another example is the urinary biomarker olfactomedin
4 (OLFM4), a secreted glycoprotein expressed in stressed
neutrophils and in epithelial cells localized to the loop
of Henle (LOH) and detectable in the urine of children
with sepsis and AKI [74]. Although urinary OLFM4 has
only modest predictive ability for AKI (area under the
curve (AUC) 0.69), evidence suggests OLFM4 localizes
to thick ascending LOH, and may characterize the loca-
tion and extent of kidney stress/damage, with expression
in the lumen and luminal surface together with the Na–
K-CL (NKCC2) receptor, the target for furosemide. This
suggests that urinary OLFM4 may be an actionable bio-
marker to predict furosemide responsiveness [75, 76].
Practical recommendations according to current
evidence
The individual risk of AKI should be considered among
all patients with critical illness supported in ICU set-
tings. While pre-existing CKD and sub-clinical CKD,
defined as chronic kidney injury with fibrosis and a nor-
mal serum creatinine (representing a loss of kidney func-
tional reserve) are important risk factors for AKI, other
chronic diseases, acute illnesses, and exposures during
critical care certainly confer additional risk (Table 2).
Validated measures of illness acuity and burden of organ
dysfunction (e.g., Simplified Acute Physiology Score
[SAPS], Sequential Organ Failure Assessment [SOFA]
score, Renal Angina Index [RAI]) have been shown to
further discriminate patients at heightened risk for AKI
[77, 78] (Fig. 2).
Among patients at heightened risk, guideline-directed
care suggests surveillance with regular assessment of
urine output, serum creatinine and, where available,
selective use of non-specific kidney damage and stress
biomarkers (e.g., [TIMP-2]·[IGFBP7], NGAL, KIM-1
and L-FABP) [4, 17]. Some biomarkers, such as [TIMP-
2]·[IGFBP7] and NGAL, might be available as point-of-
care assays, enabling rapid identification of kidney injury,
diagnosis of AKI and classification within specific AKI
sub-phenotypes. Upon recognition of heightened risk
or overt AKI, further evidence-informed and guideline-
directed measures can be undertaken to avoid or mitigate
additional kidney damage [34, 35, 54]. Alignment within
a specific AKI sub-phenotype can be informed by clinical
features and biomarkers that may enable further specific
therapeutic intervention (Fig. 2). While research to vali-
date relevant sub-phenotypes remains a priority, many
clinical features and biomarkers may provide incremen-
tal prognostic information and support clinical decision-
making (Table 4), such as a trial of furosemide, escalation
to initiation RRT and referral for long-term kidney health
follow-up [79, 80].
Conclusions
The promise to realize personalized care and precision-
orientated therapies for patients with critical illness
and improved predictive enrichment in clinical trials
necessitates further work to discriminate and classify
AKI into sub-phenotypes and endotypes with treat-
able traits [7, 8]. This will demand advances in our cur-
rent diagnostic criteria for AKI, integrating a spectrum
of new biomarkers (i.e., genomics, transcriptomics,
proteomics, metabolomics) that extend the capacity
to detect kidney stress/damage and potentially con-
tribute to improved understanding of the pathobiol-
ogy of human AKI. AKI sub-phenotypes have been
characterized in sepsis, decompensated heart failure,
and hepato-renal syndrome, whereas endotypes have
potentially emerged in the diagnosis and treatment of
catecholamine-resistant shock and acute interstitial
nephritis that show promise in personalizing the care
of patients with these conditions.
Author details
1 Bagshaw SM (2022) Subphenotypes in acute kidney injury: a narrative
Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical
Center, Cincinnati, OH, USA. 2 Department of Nephrology, Prince of Wales
Clinical School, UNSW Medicine, Sydney, NSW, Australia. 3 Nephrology
Department, Hospital das Clínicas, University of São Paulo School of Medicine,
São Paulo, Brazil. 4 Department of Medicine, School of Medicine, University
College Dublin, Dublin, Ireland. 5 Department of Critical Care Medicine, Faculty
of Medicine and Dentistry, University of Alberta and Alberta Health Services,
2‑124 Clinical Sciences Building, 8440‑112 ST NW, Edmonton, AB T6G 2B7,
Canada.
Acknowledgements
SMB is supported by a Canada Research Chair in Critical Care Outcomes and
Systems Evaluation. CER is supported by the Prince of Wales Hospital and
Lewis Foundations and by Fundação de Amparo à Pesquisa do Estado de São
Paulo (FAPESP) (Grant number 2019/19631-7).
Declarations
Conflicts of interest
SMB disclosed fees for scientific advisory from Baxter, Novartis, Sea Star Medi-
cal, BioPorto and SphingoTec. PTM disclosed fees for clinical trial consultancy
(Alexion), scientific advisory board (Renibus Therepeutics) or clinical trial
steering committee membership (AM-Pharma, Novartis). ZHE disclosed assay
support from SphingoTec and scientific advisory board membership (Vifor
Pharmaceuticals).
Publisher’s Note
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Springer Nature or its licensor (e.g. a society or other partner) holds exclusive
rights to this article under a publishing agreement with the author(s) or other
rightsholder(s); author self-archiving of the accepted manuscript version of
this article is solely governed by the terms of such publishing agreement and
applicable law.
Received: 19 April 2023 Accepted: 12 July 2023
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