REVIEW

C URRENT
OPINION Subphenotypes of acute kidney injury in adults
Suvi T. Vaara a, Lui G. Forni b and Michael Joannidis c

Purpose of review
Acute kidney injury is a heterogeneous syndrome and as such is associated with multiple predisposing
conditions and causes all of which affect outcomes. Such heterogeneity may conceal the potential benefit
of therapies when generally applied to patients with acute kidney injury (AKI). The discovery of
pathophysiology-based subphenotypes could be of benefit in allocating current and future therapies to
specific groups.
Recent findings
Clinical subphenotypes group patients into categories according to predisposing factors, disease severity,
and trajectory. These may be helpful in assessing patient outcomes. Analyses of existing databases have
revealed biological subphenotypes that are characterized by levels of biomarkers indicative of
hyperinflammation and endothelial injury. Patients with increased levels of these biomarkers display higher
mortality rates compared with those with lower levels and there is potential that this group might respond
differently to therapies. However, challenges remain in the validation, generalizability, and application of
these subphenotypes.
Summary
Subphenotyping may help reduce heterogeneity under the umbrella term of acute kidney injury. Despite
challenges remain, the identification of AKI subphenotypes has opened the potential of AKI research
focused on better targeted therapies.
Keywords
acute kidney injury, endothelial injury, inflammation, subphenotypes

INTRODUCTION the presence of biomarker positivity, treatment

Acute kidney injury (AKI) is a frequently encoun-
tered syndrome in the critically ill [1,2] being
defined by increases in plasma creatinine and/or
decreases in urine output [3]. As such, it is an
umbrella term similar to acute respiratory distress
syndrome (ARDS) [4] and sepsis [5] which lacks
granularity when applied to a wide variety of
patients. Markedly different combinations of preex-
response or lack of it, as well as outcomes. Given
this, it follows that there are many potential sub-
phenotypes within a group. Some of these have been
in clinical use for decades, such as the severity score
of AKI [8], whereas recent analyses have revealed
several subphenotypes based on biomarkers that are
suggestive of differing underlying pathophysiolog-
ical processes implying potentially different thera-
&&

isting chronic illnesses, acute risk factors, and the
trajectory of critical illness may lead to AKI that in
turn may manifest with multiple recovery patterns
and outcomes [3]. This existing heterogeneity com-
plicates classification and confounds research
efforts, especially where therapeutic opportunities
are being considered [6].
Recently, the concept of subphenotypes has
emerged in the critical care literature [7]. Subphe-
notypes are distinct groups within a defined pheno-
type, that is, a group of patients with AKI, the overall
phenotype, who share common features that sepa-
rate them from other subphenotypes within the
group [7]. These features may include disease
severity and trajectory, predisposing risk factors,
peutic responses [9 ]. This kind of biologic
a
Division of Intensive Care Medicine, Department of Anesthesiology,
Intensive Care and Pain Medicine, University of Helsinki and Helsinki
University Hospital, Helsinki, Finland, bIntensive Care Unit and Surrey
Perioperative Anaesthesia and Critical Care Collaborative Research
Group, Royal Surrey Hospital NHS Foundation Trust & Department
of Clinical & Experimental Medicine, Faculty of Health Sciences, Uni-
versity of Surrey, Guildford, UK and cDivision of Intensive Care and
Emergency Medicine, Department of Internal Medicine, Medical Uni-
versity of Innsbruck, Innsbruck, Austria
Correspondence to Suvi T. Vaara, Staff Specialist, Intensive Care Unit
M1, Meilahti Hospital, Box 340, 00290 Helsinki, Finland.
Fax: +358 9 471 75678; e-mail: suvi.vaara@helsinki.fi
Curr Opin Crit Care 2022, 28:599–604
DOI:10.1097/MCC.0000000000000970

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Renal system
KEY POINTS
 Subphenotypes are groups within the umbrella term of
AKI which share common features that separate them
from other subphenotypes within the group.
 Biological subphenotyping according to the underlying
pathophysiological process could allow targeting
existing and novel therapeutics to patients who benefit
the most.
 AKI subphenotypes characterized by high levels of
inflammatory and endothelial injury biomarkers and
higher risk for mortality have been discovered.
subphenotyping could allow targeting existing and
novel therapeutics to patients who may benefit the
most from a particular therapeutic approach. In this
narrative review, we will discuss the recent findings
regarding both clinical and biological subpheno-
types as well as associated opportunities and chal-
lenges.
CLINICAL ACUTE KIDNEY INJURY
SUBPHENOTYPES
Whereas significant progress has been made in the
definition and staging of AKI by establishing the
KDIGO criteria 2012 [3], as outlined it remains a
heterogenous syndrome comprising of a variety of
different presentations and causes which require dif-
ferent treatment approaches. Systematic application
of conventional tools, including urine analysis and
microscopy, helping to specify the differential diag-
nosis within the syndrome have been proposed [10]
but are infrequently applied. Consequently, several
approaches have been taken for clinical phenotyping
of AKI over the last decades. AKI has been categorized
using the context of associated organ failure as dis-
criminator resulting in further syndromes, including
cardiorenal syndrome [11], pulmonary renal syn-
drome [12], sepsis-associated AKI [13], and hepato-
renal syndrome [14]. However, all of these suffer from
the same problems with heterogeneity, including
multiple pathophysiological mechanisms, resulting
in limited information regarding the underlying
pathophysiology and resulting treatment.
An alternative approach directed at the pre-
sumed underlying mechanism could be more fruit-
ful. Classically prerenal, intrinsic, and postrenal AKI
have been described although the distinction
between prerenal and intrinsic AKI has become
the focus of intense debate of late as depending
on the duration or ‘prerenal AKI’, it will trigger
pathomechanisms typical for intrinsic AKI
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comprising tubular inflammation, oxygen stress,
and impaired medullary perfusion [15]. Hence,
why the KDIGO definition [3] discourages the use
of the terminology prerenal AKI. Alternatively, cat-
egorization using the trajectories of creatinine have
been proposed as a substitution for prerenal AKI
reflecting a functional reduction of glomerular fil-
tration rate rather than damage. In addition, a pat-
tern of renal recovery has been investigated
resulting in a discrimination between transitory
AKI, with a duration of less than 3 days and persis-
tent AKI [16]. However, persistent AKI has recently
been redefined by the persistence of higher degree of
AKI stage 3 for more than 72 h [17].
Another approach may be according to the
attainment of the criteria of AKI stages. The discrim-
ination of AKI defined by serum creatinine value
versus AKI defined by urine output has significant
implications on the outcome, with the combination
of both criteria showing the worst prognosis [18].
Adding biomarkers to each of the conventional
criteria can add relevant information to the clinical
picture (Fig. 1). However, a decrease in urine output
may represent a pathological or physiological
response [19], and thus may require additional bio-
markers for discrimination [20].
When considering the type of kidney injury and
its associated pathophysiology this may lead to a
specific clinical diagnosis (Table 1) and trigger
immediate intervention(s). For example, reduced
kidney perfusion may result from hypovolemia,
reduced cardiac output, renal vasoconstriction, or
vasoplegic shock. In addition, sepsis exhibiting a
dysregulated host response, as well as the release
of damage-associated molecular patterns may trig-
ger similar inflammatory interstitial reactions in the
kidney as in infection [21]. Other examples
include trauma, burns, and specific insults, such
as infections of the kidney (e.g., pyelonephritis)
and immunologically mediated AKI including glo-
merulonephritis, interstitial nephritis, and vasculi-
tis all of which have specific treatments. Drug-
mediated AKI, which includes both drugs that
impair renal perfusion in general (e.g., calcineurin
inhibitors) or pre and preglomerular vessel tone (i.e.,
nonsteroidal anti-inflammatory drugs, angiotensin-
converting enzyme inhibitors), direct toxins (e.g.,
vancomycin, gentamycin, amphotericin B, non-iso/
low-osmolar radio contrast media) or allergic reac-
tion (e.g., drug-associated interstitial nephritis)
should prompt a critical re-evaluation as to the
continuation of the drug. Finally, obstruction in
the urinary tract should not be missed.
Clinical phenotyping has also been applied to
patients recovering from AKI. In a study on over
16 000 patients with KDIGO stage 2 or 3 AKI patterns
Volume 28  Number 6  December 2022
 Subphenotypes of acute kidney injury in adults Vaara et al.

FIGURE 1. The spectrum of acute kidney injury according to biomarkers of kidney injury, urine output, and serum creatinine.
AKI, acute kidney injury; BM, biomarker; Cr, creatinine; UO, urine output.

of reversal from AKI, defined as survival with no
longer meeting criteria for stage 1, and recovery,
defined as reversal at hospital discharge, were studied
[22]. Five patterns of recovery were identified relating
to the AKI stage. The most common was early reversal
(26.6%) but 26.5% of this cohort had no reversal at all.
Three other phenotypes were described, including
late reversal, early reversal with one or more relapses
but ultimate recovery and relapse without recovery.
In all 58.8% of patients had a complete recovery and
features consistent with this group were patients
undergoing surgery and an increasing urine output.
In those with relapsing AKI sepsis was a strong indi-
cator. Unsurprisingly, outcomes including mortality
and length of hospital stay were associated with sub-
phenotype with individuals recovering late faring
better than those with no recovery and those recov-
ering early having the best outlook. Significantly, in
patients with sepsis and AKI further clinical subphe-
notypes can be recognized and a recent multinational
prospective observational study in children demon-
strated an outcome relationship with clinical pheno-
type based on duration and severity of AKI [23].
BIOLOGICAL ACUTE KIDNEY INJURY
SUBPHENOTYPES
The concept of Biological subphenotypes refers to
groups of patients who share a common underlying
pathophysiological mechanism [7]. Therefore,
finding ways to define biological subphenotypes
could help to allocate therapeutic targets specific
to pathophysiological processes within the correct
population, that is, predictive enrichment. Typi-
cally, these traits may not be identifiable by using
conventional clinical assessment or clinical classi-
fiers such as the severity of AKI.
The current understanding of biological AKI
subphenotypes comes from analyses conducted in
existing observational and randomized controlled
trial (RCT) databases together with biomarker
assays, mostly related to inflammation and endo-
&& &&
thelial injury [9 ,24 ]. These analyses have used
latent class analysis (LCA) to derive subphenotypes.
Briefly, LCA is a mixture modeling technique, with
an assumption of an unobserved categorical variable
existing that separates the patients into mutually
exclusive latent classes [25]. Available observed var-
iables are used to predict the class membership.
Therefore, the results of such an analysis inevitably
depend on the variables that are available which is a
major drawback to this approach.
The first study to discover biological AKI sub-
phenotypes by Bhatraju et al. hypothesized the exis-
tence of subphenotypes based on differences in
inflammatory and endothelial injury biomarkers.
Two subphenotypes were found, and they were
defined by differences in angiopoietin-1 (ANG1),
angiopoietin-2 (ANG2), tumor necrosis factor recep-
tor-1 (TNFR1), and IL-8. Furthermore, in a reanalysis

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Renal system

Table 1. Clinical phenotypes of acute kidney injury

Types of AKI Associated syndromes

Reduced kidney perfusion Low-flow AKI

Hypovolemia Hypovolemic AKI
Reduced cardiac output Cardiac surgery -- AKI, cardiorenal syndrome
Vasoconstriction Hepatorenal syndrome
Vasogenic shock Vasoplegic AKI
Sepsis High-flow AKI
Dysregulated host response Sepsis-associated AKI
Damage-associated molecular pattern triggered inflammatory interstitial reaction Traumatic AKI, burns AKI
(i.e., sepsis, trauma, burns)
Infection Infective AKI
Pyelonephritis Urosepsis
Immunological Autoimmune AKI
Glomerulonephritis Rapidly progressive glomerulonephritis
Interstitial nephritis Acute interstitial nephritis
Vasculitis HUS, TTP, TMA, etc.
Drug associated
Pre and postglomerular vessel tone (i.e., NSAIDs, ACE inhibitors, calcineurin inhibitors) Drug-induced functional AKI
Direct toxins Toxic-AKI (nephrotoxins, rhabdomyolysis)
Allergic reaction Interstitial Nephritis
Outflow obstruction Obstructive AKI

ACE, angiotensin-converting enzyme; AKI, acute kidney injury; HUS, hemolytic-uremic syndrome; TMA, thrombotic microangiopathy; TTP, thrombotic
thrombopenic purpura.

of a randomized trial cohort with a biomarker com-
bination of ANG1, ANG2, and sTNFR1 they discov-
ered that patients belonging to the subphenotype 1
(lower levels of endothelial and inflammatory
markers) responded differently to vasopressin ther-
apy with a lower risk of death compared with the
&&
subphenotype 2 [9 ], whereas the main trial
reported no difference between the treatment
groups [26]. Similarly, endothelial injury biomarkers
&&
were included in another database analysis [24 ]
which demonstrated the largest differences between
heparin-binding protein, neutrophil elastase 2, pro-
teinase 3, and matrix metalloproteinase 8, whereas
ANG2 and IL-6 levels were less discriminatory
between the discovered two subphenotypes. Nota-
bly, patients belonging to subphenotype 2 also had
higher vasopressor requirements and received larger
&&
amounts of fluid therapy [24 ].
As well as a slightly different set of measured
biomarkers, the two analyses also varied regarding
the patient cohort and timing of biomarker meas-
urements, which may explain the later findings
using the same biomarkers by Wiersema et al.
&&
[24 ] where the differences in ANG2 levels between
the discovered subphenotypes were less clear.
Importantly, both analyses support the role of
endothelial injury in the pathophysiology of AKI
associated with worse clinical outcomes. The role of
endothelial injury has been reported in multiple
analyses [27–29] supporting the findings of these
subphenotype analyses. However, the optimal bio-
marker set to define the subphenotype associated
with endothelial injury remains elusive.
Significantly, research regarding biological
ARDS subphenotypes has also revealed patterns of
biomarkers indicative of inflammation and endo-
thelial injury where a defined hyperinflammatory
subphenotype has been associated with higher mor-
tality rates [30]. These biomarkers have included IL-
6, IL-8, sTNFR1, and plasminogen activator inhib-
itor-1 (PAI1) [30]. The application of a parsimonious
algorithm has been validated that uses only three or
four variables to define subphenotypes [31] bringing
the subphenotypes closer to practical clinical use.
Another study recognized so-called uninflamed and
reactive subphenotypes based on an almost corre-
sponding set of endothelial and inflammatory bio-
markers [32]. Notably, the biomarkers defining
hyperinflammatory subphenotypes in AKI partly
correspond to those defining hyperinflammatory
or reactive ARDS subphenotypes (Table 2). Finally,
subphenotypes have also been identified in patients

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 Subphenotypes of acute kidney injury in adults Vaara et al.
who did not yet fulfill the diagnostic criteria for
ARDS [33].
Taken together, it is no surprise that these find-
ings suggest that at least hypoinflammatory and
hyperinflammatory phenotypes exist among ICU
patients. Potentially, these represent the same con-
tinuum of patients, some presenting with AKI, others
with ARDS, and a proportion with both AKI and ARDS
or a subclinical version of these not fulfilling the
current clinical diagnostic criteria. Furthermore, a
concept beyond the syndromic ICU diagnoses has
&&
been proposed [34 ]. Instead of typical ICU syn-
dromes, patients would be grouped based on treatable
traits that reflect underlying pathophysiology and
&&
perhaps would respond to specific treatment [34 ].
Variable insults such as infection or trauma could lead
to the activation of similar pathways leading to these
recognizable traits such as hyperinflammation,
&&
which could be targeted with specific therapies [34 ].
SUBPHENOTYPES AND THERAPEUTIC
POSSIBILITIES
Thus far, the only available data about AKI subphe-
notypes and treatment response come from the anal-
ysis by Bhatraju et al. [9 ]. After discovering and
&&
replication of subphenotypes in observational
cohorts, they developed a parsimonious classification
and applied it to the VASST trial patients. Patients
with subphenotype 1 (and lower levels of the endo-
thelial injury biomarkers) were found to have a ben-
eficial response to vasopressin therapy, in contrast to
&&
the neutral results of the original analysis [9 ].
Research regarding differing therapeutic responses
between the hypoinflammatory and hyperinflamma-
tory subphenotypes of ARDS has revealed interesting
findings. In a reanalysis of a large RCT comparing
simvastatin with placebo, patients with hyperinflam-
matory subphenotype receiving simvastatin had lower
28-day mortality [35]. However, reanalysis of a large
trial comparing rosuvastatin with placebo, no such
benefit for the treatment of a hyperinflammatory
subphenotype could be detected [36]. Significantly,
in the re-analysis of the Fluid and Catheter Treatment
trial, patients with hyperinflammatory subpheno-
types randomized into standard fluid therapy survived
better than patients in the liberal fluid therapy arm,
whereas the original trial reported no survival differ-
ence between treatment arms [37].
These findings among AKI and ARDS patients
strengthen the potential role of subphenotypes in
addressing heterogeneity in therapeutic trials. More-
over, the examples from ARDS patients encourage
further analyses in existing and future AKI trials to
scrutinize whether reducing heterogeneity with
analysis according to subphenotypes would reveal
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treatment benefits for well-defined subgroups. On
the contrary, as most clinical trials are conducted
without biomarker measurements, running even
post-hoc analyses regarding the already discovered
subphenotypes is not possible. Biobanking in trials
would therefore be an important facilitative step to
advance the understanding of heterogeneity in the
trials and the discovery of targeted therapeutics
although this has considerable cost implications.
CHALLENGES AND FUTURE DIRECTIONS
The identification of AKI subphenotypes has opened
a new potential research area; however, multiple
challenges remain especially regarding the biological
subphenotypes. Thus far, the analyses have been
conducted in preexisting databases of observational
cohorts or RCT data with limited variables and bio-
marker data availability, with little external valida-
tion. Therefore, the optimal defining variables as well
as the optimal number of existing subphenotypes
remain unknown. Moreover, in subphenotypes
defined by one or several biomarkers, the timing of
measurement may become a key factor given the
different kinetic profiles. However, Wiersema et al.
&&
[24 ] reported corresponding results regarding sub-
phenotype classification from biomarker levels meas-
ured at ICU admission and 24 h thereafter.
Although the identified subphenotypes come
from analyses that have concentrated on hypotheses
regarding endothelial injury, other subphenotypes
based on different pathophysiological mechanisms
may be discovered. One potential field of research
includes biomarkers found in the urine. Albeit they
have been widely investigated in terms of different
predictive properties, their role of identifying different
pathophysiological pathways, especially in combina-
tion with clinical parameters has not been fully
elucidated yet.
To be useful for the daily care of critically ill
patients in directing future therapeutics to those
who may benefit from them, the subphenotypes
should be easily identifiable also using tools available
in routine clinical work. Thus far, none of the bio-
markers defining the biological subphenotypes of AKI
are routinely available. Therefore, future subpheno-
type studies should also address the development of
tools for bedside subphenotype identification, also
including tools for point-of-care testing. Finally,
machine learning models are likely to play a key role
in the bedside application of subphenotypes [38].
CONCLUSION
Heterogeneity remains a complication of the defi-
nition of AKI. A better understanding of the features
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Renal system
of subphenotypes within the AKI population may
help to discover effective therapies for AKI and to
allocate the right treatment to those who may ben-
efit the most. Analyses in existing databases have
characterized two biological AKI subphenotypes, of
which the hyperinflammatory subphenotype is
defined by increased levels of inflammatory and
endothelial injury biomarkers and associated with
higher mortality rates. Albeit challenges remain, the
identification of AKI subphenotypes has opened a
new avenue of AKI research and the first steps
toward predictive enrichment have been taken.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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