Int Urol Nephrol (2014) 46:17

DOI 10.1007/s11255-013-0448-5

NEPHROLOGY - REVIEW

Current developments in early diagnosis of acute kidney

injury
Nicholas Obermuller Helmut Geiger
Christine Weipert Anja Urbschat

Received: 21 January 2013 / Accepted: 12 April 2013 / Published online: 15 May 2013
Springer Science+Business Media Dordrecht 2013

Abstract Acute kidney injury (AKI) is a very

frequent and serious clinical problem, accounting for
overall high morbidity and mortality. Up to date,
mortality due to AKI is virtually unchanged over the
past 50 years. This may partly be explained due to a
delay in initiating renal protective and appropriate
therapeutic measures since until now there are no
reliable early-detecting biomarkers. The gold standard, serum creatinine, displays poor specificity and
sensitivity with regard to identification of the incipient
phase of AKI, and this is also true for cystatin C. We
aimed to review novel biomarkers of AKI in urine and
serum which have now progressed to the clinical
phase. The main focus refers to their diagnostic and
prognostic value. For this purpose, a web-based
literature search using PubMed was performed comprising the following terms: renal failure, acute kidney
injury and biomarkers. New molecules such as
N. Obermuller (&)
H. Geiger
Division of Nephrology, III Medical Clinic,
Goethe-University Hospital Frankfurt am Main,
Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
e-mail: obermueller@em.uni-frankfurt.de
C. Weipert
Division of Urology and Andrology, Landeskrankenhaus
Hall in Tirol, Milser Str. 10, 6060 Hall in Tirol, Austria
A. Urbschat
Division of Urology and Pediatric Urology,
Goethe-University Hospital Frankfurt am Main,
Theodor-Stern-Kai 7, 60590 Frankfurt, Germany

neutrophil gelatinase-associated lipocalin (NGAL),

kidney injury molecule-1 (KIM-1), N-acetyl-b-D-glucosaminidase (NAG), monocyte chemotactic peptide
(MCP-1), Il-18, liver-type fatty acid-binding protein
(L-FABP) and Netrin-1 are available and represent
promising new markers that, however, need to be
further evaluated in the clinical setting for suitability.
In clinical settings with incipient AKI, not only the
development and the implementation of more sensitive, practicable and accurate biomarkers are required
for well-timed treatment initiation. Just as important is
a substantial improvement of refined and applicable
prophylactic therapeutic options in these situations.
Before full adoption in clinical practice can be
accomplished, adequately powered clinical trials testing a row of biomarkers are strongly warranted.
Keywords Acute kidney injury
Acute renal failure

Biomarker
NGAL
KIM-1

Introduction
The development of acute kidney injury (AKI) that
formally designated acute renal failure (ARF) of any
cause is associated with a high mortality in the
critically ill patient despite significant technical
advances in therapeutic measures including renal
replacement therapy (RRT) such as hemodialysis
[1]. Analyzing publications comprising the period
from January 1970 to December 2004, by which

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mortality rates in patients with AKI during the past

decades have been determined, one can conclude that
despite overall technical progress in the management
of AKI over the last 40 years, the effective mortality
rates remain virtually unchanged until nowadays,
ranging at around 50 % [2]. Fundamental advances in
basic research have explored the pathogenetic mechanisms of AKI and thus have pioneered the way for
successful pharmaco-therapeutic approaches in animal models. Yet, translations of beneficial effects
obtained from animals into humans have provided
rather disappointing results so far [3]. One problem
area which has been widely acknowledged in the
diagnosis of AKI is the continued reliance on markers
which do not reflect acute injury but rather the
functional consequences [4].

Definition and diagnosis

AKI is defined as the abrupt (e.g. within 48 h) and
sustained decrease in renal function, resulting in
retention of nitrogenous (urea and creatinine) and
non-nitrogenous waste products as well as in dysregulation of cellular volume and electrolyte handling. In
clinical practice, the diagnosis of AKI relies on a
decreased glomerular filtration rate, increased serum
creatinine (SCr) with or without oliguria, described by
two principal classifications: the risk, injury, failure,
loss, end-stage (RIFLE) kidney disease [5] and the
acute kidney injury network (AKIN) criteria [6].

Int Urol Nephrol (2014) 46:17

of whether acute kidney injury (AKI) is associated

with ischemia reperfusion injury, sepsis or toxins,
there is a rapid loss of proximal tubular cell cytoskeletal integrity and cell polarity [8]. This occurs mainly
in epithelial cells of the proximal tubules of the outer
medulla, which are most susceptible for ischemia and
toxic influences. Moreover, this S3-segment appears
to be source for supplying (stem) cells that organize
the epithelial reconstitution in the repair phase [9].

Impact of acute kidney injury in the hospital

AKI may be the consequence or the acute manifestation
of a primary kidney disease; in fact, it is by far more
frequently complicating other diseases and is thereby
known to lead to prolonged length of hospital stay,
increased morbidity and mortality and consecutively
generates high medical costs. In this context mortality,
length of stay and costs in hospitalized patients with
acute kidney injury were analyzed retrospectively in
19,982 adults admitted on an internal medical, surgical,
neurology unit, as well as on obstetrics and gynecology
services. Modest increases in SCr were commonly
observed (13 %), and this was significantly positive
associated with mortality, prolonged length of hospital
stay and significantly increased costs, while large
increases in serum creatinine concentration were
observed relatively rarely (1 %). Furthermore, outcomes were related directly to the severity of acute
kidney injury, independently if nominal or percentage
changes in serum creatinine occurred [10].

Pathophysiology
Characteristics and prospects of new biomarkers
Kidney injury can be roughly subclassified into three
categories: prerenal, intrarenal and postrenal forms.
Acute tubular necrosis (ATN) represents the major
(histo) pathological correlate of intrarenal AKI.
Severe prerenal azotemia and acute tubular necrosis
are considered to reflect and to pass into the same
pathophysiological process [7]. The pathophysiology
of acute kidney injury involves a complex network
involving vascular, tubular and inflammatory factors
that act using a repair machinery that can restore
epithelial differentiation and function back to normal
on the one hand or that result in part in progressive
fibrotic remodeling of variable extent, ultimately
leading to chronic kidney disease [8]. Independently

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Renal function in various renal diseases is classically

assessed by the measurement of serum blood urea
nitrogen and creatinine, biomarkers that are not
sufficiently sensitive, especially in the setting of early
diagnosis of AKI. Moreover, changes in serum
creatinine and blood urea nitrogen concentrations
primarily reflect functional changes in filtration
capacity and are not genuine injury markers. In the
clinical setting, AKI biomarkers should not only be
predictive, but also allow non-invasive sample taking.
In addition, samples should be rapidly and reliably
measurable using a standardized testing platform, with
accurate sensitivity and specificity to facilitate early

Int Urol Nephrol (2014) 46:17

detection of AKI. Although there is general agreement

on the need for superior AKI biomarkers, the question
concerning the clinical usefulness and impact still
remains a matter of debate. Since at present a specific
therapy for AKI is not available in all cases, early
detection of AKI might be at some point without
striking consequence because of the general lack of
promising measures to halt its progression. However,
earlier detection might lead to new insights and finally
implement potentially novel and effective therapies.

Diverse biochemical approaches to the diagnosis

of AKI
AKI can be identified in various ways. First, detection
of increased excretion of proximal tubule proteins in the
urine, indicating tubular damage: Of these proteins,
structural proteins (e.g. renal tubular epithelial antigens,
also actin) as well as proximal tubular enzymes (e.g. Nacetylglucosaminidase, alkaline phosphatase and cglutamyltransferase) [11] represent specific molecules.
Second, documentation of proximal tubular cell dysfunction can be assessed by decreased tubular reabsorption of freely filtered low molecular weight proteins
(e.g. b2 microglobin, lysozyme and Cystatin C). Third,
tubular genes and proteins can immediately be upregulated in AKI as a response-to-injury reaction, appearing thereby in the urine, an approach that has received
greatest attention so far. Important examples within this
category are kidney injury molecule-1 (KIM-1) and
neutrophil gelatinase-associated lipocalin (NGAL)
[1214] as well as liver-type fatty acid-binding protein
(L-FABP) [15, 16]. Newly established, complex techniques are used to investigate the urinary excretion of
injury-induced mRNA levels and associated alterations
at their cognate genes (e.g. MCP-1). As yet, the urine
rather than the blood appears to be more promising for
early AKI detection. Important new biomarker characteristics are described in the following.

Arising biomarkers
Neutrophil gelatinase-associated lipocalin
(NGAL)
NGAL is a protein member of the lipocalin family and
is composed of 8 b-strands that form a b-barrel

enclosing calyx [17], being expressed by neutrophils

and epithelial cells including proximal tubule cells. It
has been identified as one of the fastest upregulated
genes in the early phase of the post-ischemic mouse
kidney [18]. So far, NGAL has been investigated
across a broad range of varying clinical settings of
AKI. However, with accumulating experimental and
clinical data, conflicting observations raised some
concerns about the robustness of NGAL as a valid
biomarker. Hence, a meta-analysis of data from 19
studies was carried out to evaluate its potential and
accuracy in the diagnostic and prognostic of AKI.
Putting this data together, NGAL was found to be a
useful early appearing predictor of AKI, with urine or
plasma/serum NGAL levels operating equally well.
Additionally, NGAL level had prognostic value for
clinical endpoints such as initiation of dialysis and
mortality [19]. Disadvantageously, substantial extrarenal NGAL generation in response to systemic stress
can increase urinary NGAL excretion even in the
absence of AKI. Furthermore, NGAL generation
might, although not predictably, arise from chronic
renal disease [1921].
Human kidney injury molecule (KIM-1)
Human kidney injury molecule is a type 1 transmembrane glycoprotein. KIM-1 gene or protein expression
is undetectable in the healthy kidney or urine, and
hence, following injury KIM-1 mRNA is rapidly
synthesized and the protein is generated and localized
at very high levels in the apical membrane of
dedifferentiated proximal tubule cells in human and
rodent kidneys after ischemic or toxic injury [22]. The
soluble form of human KIM-1 can be detected in the
urine of patients with acute tubular necrosis and may
serve as a useful biomarker for renal proximal tubule
injury [23]. Furthermore, high urinary KIM-1 expression was associated with adverse clinical outcome
(death and need for dialysis) in patients with AKI [24]
and was recently evaluated in pre-renal AKI [25] and
following percutaneous coronary intervention [26].
The following characteristics might make it an
attractive biomarker of AKI: absence of KIM-1
expression in the normal kidney, its marked upregulation and insertion into the apical membrane of the
proximal tubule, its persistence in the epithelial cell
until the cell has completely recovered and the ex vivo
room temperature stability of the ectodomain [27].

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N-acetyl-b-D-glucosaminidase (NAG)
NAG is a lysosomal enzyme found predominantly in
proximal tubules. Therefore, increased activity of this
enzyme in the urine may suggest injury to tubular cells
and could serve as a specific urinary marker for tubular
cell function. Filtration of the enzyme is hindered by
glomeruli due to its relatively high molecular weight.
In the course of active kidney disease, urinary NAG
levels remain persistently elevated. The increase in
urinary NAG activity indicates damage to tubular
cells, although it can also reflect increased lysosomal
activity without cellular damage [24]. Increased
urinary NAG excretion has been reported in acute
renal disease of varying etiology, namely induced by
toxic agents, after cardiac surgery and after renal
transplantation [28, 29]. Nevertheless, the utility of
NAG remains limited by the fact that urinary excretion
of the enzyme is also elevated in chronic glomerular
diseases such as diabetic nephropathy [30]. Recently,
NAG was tested in combination with urinary livertype fatty acid-binding protein (L-FABP) after cardiac
surgery, suggesting a combination panel synergism
since L-FABP displayed high sensitivity and NAG
detected AKI with high specificity [31].
Monocyte chemotactic peptide-1 (MCP-1)
Monocyte chemotactic peptide-1 (MCP-1) mRNA has
been found to be upregulated in ischemiareperfusion
injury and was therefore referred to as a biomarker for
mononuclear inflammatory processes that occur after
ischemia-induced acute kidney injury [32]. In further
studies, MCP-1 was found to be a potent chemokine
produced by renal cells, acting as mediator in acute
ischemic and toxic kidney injury. Therefore, MCP-1
protein and MCP-1 mRNA were examined in a mouse
model, by inducing intrarenal, prerenal and postrenal
injury forms. This represented a novel approach
quantifying mRNA levels and corresponding histone
modifications at their cognate genes. This study
revealed an increase in MCP-1 to a greater extent
than NGAL in intrarenal injury. In prerenal and
postrenal injury, NGAL and MCP-1 gene expression
increased comparably. In contrast to this, uremia per
se already induced the NGAL gene in the absence of
renal injury, but not MCP-1, arguing for a better
specificity of MCP-1 for AKI. The potential utility of
MCP-1 as a biomarker was supported by clinical

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Int Urol Nephrol (2014) 46:17

assessments observing increases in urinary MCP-1

protein and mRNA levels without overlap in urine in
patients with AKI. In conclusion, urinary MCP-1 may
be a useful biomarker of AKI, possibly providing
complementary information to that deriving from
NGAL analysis [14].
Interleukin-18 (IL-18)
The proinflammatory cytokine IL-18 is constitutively
expressed in the intercalated cell of the late distal
convoluted tubule, the connecting tubule and the
collecting duct of the healthy human kidney [33].
Urine levels of IL-18 were significantly elevated and
displayed a high sensitivity and specificity for the
diagnosis of acute tubular necrosis in a first crosssectional study in humans with different renal diseases. In detail, patients with prerenal azotemia,
urinary tract infection, chronic kidney disease and
normal renal function were compared with healthy
control subjects [34]. However, considering IL-18
being a pro-inflammatory cytokine that plays an
important role in sepsis, Il-18 measurements may also
be influenced by a number of coexisting variables such
as endotoxemia, inflammatory and autoimmune diseases. Thus, this cytokine seems to be a candidate
biomarker in the setting of AKI, although its proinflammatory properties and its upregulation in inflammatory disease do limit its application in terms of
sensitivity and specificity.
Liver-type fatty acid-binding protein (L-FABP)
L-FABP is a 14-kDa protein, which is mainly
produced in the liver, is expressed in various organs,
filtered via the glomerulus and reabsorbed in the
proximal tubulus [35, 36]. So far, nine types of
L-FABP have been reported. L-FABP binds selectively to free fatty acids (FFA) and accomplishes the
cellular uptake of fatty acid from plasma for transport
to distinct cell components and regulates intracellular
FFA metabolism [36]. Tubulointerstitial damage as
well as AKI was detected to upregulate L-FABP gene
expression and then increase urinary excretion of
L-FABP from the proximal tubules [15, 16]. Urinary
L-FABP was shown to be significantly elevated within
a short time in established AKI of various etiology,
such as acute tubular necrosis, sepsis, nephrotoxin
exposure, contrast-induced AKI and cardiac surgery

Int Urol Nephrol (2014) 46:17

[4, 35, 37, 38], and was therefore attributed as a

powerful early biomarker of AKI. Of note, the serum
L-FABP levels do not influence the urinary L-FABP
levels [15] as this occurs with, for example creatinine.
Altogether, urinary L-FABP provides potential capacity in early AKI diagnosis [39]. However, the impact
of conditions such as liver failure or septic shock on its
renal expression warrants further studies.
Netrin-1
Netrin-1, a multifunctional laminin-related, neuronal
guidance protein, is widely expressed in various
tissues, including the kidney, where it is barely
expressed in tubular epithelial cells of normal kidneys.
However, it was found to be highly expressed and
excreted in the urine after AKI in rodents. Subsequently, urinary Netrin-1 excretion was detected to
increase dramatically in patients with AKI, whereas no
changes were detected in healthy volunteer urine
samples. This led to the conclusion that urinary
Netrin-1 could be a promising early upregulated
biomarker for detection of renal injury [40]. In the
setting of cardiopulmonary bypass operation, a correlation with duration and severity of AKI including
hospital stay was found as well [41]. In further studies,
increased levels of Netrin-1 in the urine were discovered in patients with various forms of AKI, among
them patients with ischemic AKI, radio-contrastinduced AKI, sepsis-induced AKI and drug-induced
AKI in comparison with healthy controls [42].

Conclusion
There are high demands for ideal properties and roles
of biomarkers in early AKI diagnosis. They should be
first of all kidney-specific and highly sensitive for
acute kidney injury. Furthermore, they should be
reliably and easily measurable in uncomplicatedly
accessible samples like plasma or urine and not be
elevated in chronic kidney disease. Desirable would be
additional information on etiology, nature and duration of AKI, in order to provide assistance in
monitoring the course and the response to interventions. It is also possible that some new biomarkers may
support detection of early AKI while others may be
more accurate in tracing the recovery from AKI. The
search for new applicable AKI biomarker is an

ongoing challenge, and yet novel interesting candidates such as cell cycle arrest molecules are currently
under investigation [43].
The future may lie in the application of a combined
urine and plasma marker panel, to increase discrimination and to give hints regarding the underlying
disease origins in order to better treat different
etiologies of AKI as well as to determine prognosis
and severity. It still remains a challenge to evaluate an
evolving marker of renal injury with an established,
but insufficient marker of renal function and renal
injury such as creatinine, since other options are
lacking.
Least, it remains to raise the critical question
regarding the therapeutic consequences and overall
clinical usefulness of implemented biomarkers. Actually, besides avoiding toxic influences and the management of underlying diseases, the treatment of AKI
consists of re-establishing fluid and electrolyte balance, if needed, also renal replacement therapy. Only
prospective, randomized, (pharmaco-) interventional
trials will shed light on the question whether early
biomarker monitoring will predict or influence clinical
outcome of AKI patients.
The above-mentioned simple facts, however, show
that the so-called ideal biomarker for AKI can
probably never be established since a reduced GFR
and the onset of injury are often linked to each other,
however, they do not replace themselves.
Conflict of interest The authors declare that they have no
conflict of interests.

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