ngal

1. 223International Journal of Critical Illness and Injury Science | Vol. 4 | Issue 3 | Jul-Sep 2014
Role of neutrophil gelatinase‑associated
lipocalin for early detection of acute
kidney injury
Scienthia Sanjeevani, Sonal Pruthi1
, Sarathi Kalra2
, Ashish Goel1
, Om Prakash Kalra
Departments of Nephrology and Internal
Medicine and 1
Internal Medicine,
University College of Medical Sciences
and GTB Hospital, University of Delhi,
New Delhi, India, 2
Department of
Medical Oncology, The University of
Texas, MD Anderson Cancer Center,
Houston, Texas, USA
Address for correspondence:
Prof. Om Prakash Kalra,
Division of Nephrology, University
College of Medical Sciences,
(University of Delhi), Guru Teg Bahadur
Hospital, Dilshad Garden,
Delhi ‑ 110 095, India.
E‑mail: opkalra1@yahoo.com
ABSTRACT
Acute kidney injury (AKI) is characterized by abrupt or rapid decline of renal function
and is usually associated with the development of serious complications as well as an
independent risk of mortality in hospitalized patients. Emergency physicians play a critical
role in recognizing early AKI, preventing iatrogenic injury, and reversing the course of AKI.
Among the various available biomarkers for AKI, reliable and automated assay methods
are commercially available for only cystatin‑C and neutrophil gelatinase‑associated
lipocalin (NGAL). NGAL appears to be a promising marker for early detection of AKI and is
likely to be adapted for wide‑scale clinical use in patient management as a point‑of‑care
test. Use of NGAL along with panel of other renal biomarkers can improve the rate of
early detection of AKI. Large, multicenter studies demonstrate the association between
biomarkers and hard end points such as need for renal replacement therapy (RRT),
cardiovascular events, hospital stay, and death, independent of serum creatinine
concentrations.
Key Words: Acute kidney injury, neutrophil gelatinase-associated lipocalin, point-of-care test
INTRODUCTION
Acute kidney injury (AKI) is characterized by
abrupt or rapid decline of renal function and is
usually associated with the development of serious
complications as well as an independent risk of
mortality in hospitalized patients.[1]
Emergency
physician plays a critical role in recognizing early AKI,
preventing iatrogenic injury, and reversing the course
of AKI. AKI develops in up to 5% of the hospitalized
patients and in up to 30% patients admitted in the
Intensive Care Unit. It is estimated that about 2 million
people die of AKI every year. Those who survive AKI
have a higher risk for later development of chronic
kidney disease (CKD).[2]
In developing countries,
AKI usually develops in younger adults in the setting
of several community‑acquired diseases, affecting
younger and previously healthy individuals and the
spectrum depends on environmental, cultural, and
socioeconomic factors.[2‑5]
Early diagnosis and prompt
treatment can significantly decrease morbidity and
mortality in patients with AKI.
SIGNIFICANCE OF EARLY DIAGNOSIS OF AKI
Despite several advances in the management of critically
ill patients and dialysis techniques during the last few
decades, onceAKI develops, the mortality has continued
to remain unacceptably high. In fact, even minor
elevations of serum creatinine in critically ill patients are
associated with progressive increase in adverse outcomes.
It has been shown that most of the preventive measures
for AKI, which are efficacious in experimental settings,
do not show comparable positive results in the clinical
setting.[6]
Hence, early diagnosis of AKI is of paramount
importance. The lack of reliable biomarkers of early
structural kidney injury results in an unacceptable delay
in the clinical diagnosis, which severely limits prompt
therapeutic approach. Improvement in clinical outcomes
of the patients with acute coronary syndrome in the last
few decades has been aided by the availability of a panel
of biomarkers.Absence of a similar panel inAKI has been
a major impediment in improving clinical outcomes.
AKI is currently diagnosed by functional biomarkers,
such as serum creatinine measurement and estimation
of urine flow rate. However, as creatinine is primarily a
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marker for estimation of glomerular filtration, it cannot be
considered for the estimation of kidney injury, since it is
insensitive and unreliable to diagnose renal tubular injury
in the absence of significant reduction in glomerular
filtration rate (GFR).[7]
An elevation in serum creatinine
is noticed only when GFR has already reduced below
50% of normal. Consequently, more reliable biomarkers
than creatinine are necessary for both an accurate
evaluation of renal function and an early detection ofAKI.
BIOMARKERS FOR AKI
Biomarkers suggested for an accurate and early detection
of AKI are cystatin‑C, neutrophil gelatinase‑associated
lipocalin (NGAL), kidney injury molecule‑1
(KIM‑1), Na+
/H
+ exchanger isoform‑3 (NHE‑3),
N‑acetyl–b‑glucosaminidase, liver‑type fatty acid
binding protein (L‑FABP), Interleukin‑18 (IL‑18), etc.,
Among these, only for cystatin‑C and NGAL, reliable and
automated assay methods are commercially available.[8]
The serendipitous finding that NGAL protein was easily
detected in the urine soon after AKI in animal studies
has prompted an explosion of translational studies to
evaluate NGAL as a non‑invasive biomarker in human
AKI. Early diagnosis of AKI by point‑of‑care testing
for various biomarkers in high‑risk individuals can
significantly help in decreasing morbidity and mortality
in such patients.
BIOCHEMICAL PROPERTIES OF NGAL
NGAL (also known as human neutrophil lipocalin,
lipocalin‑2, siderocalin, 24p3, or LCN) is a small molecule
of 25 kDa having 178 amino acids that belongs to the
superfamilyoflipocalins,whichareproteinsspecializedin
binding and transporting small hydrophobic molecules.[9]
The lipocalins share a molecular organization comprising
eight β‑strands arranged in a complex β‑barrel structure
delineating a calyx shape, which represents their
binding site. NGAL, like the other lipocalins, can
bind some ligands, including the siderophores. After
interaction with these receptors, NGAL is internalized
inside the cell as a protein alone (Apo‑NGAL) or a
complex with iron‑binding siderophores (Holo‑NGAL).
Endosomal vesicles capture Holo‑NGAL inside them
and transport it to the cytoplasm, where it can release the
siderophore‑ironcomplex,thusactivatingiron‑dependent
specific pathways. Conversely, Apo‑NGAL, after being
internalized in the cell, is able to capture cellular iron
and export it to the extracellular space. This results in
depletion of iron cellular pools that, under particular
conditions, may even lead to apoptosis. Due to its specific
binding to bacterial siderophores, NGAL can also exert
a bacteriostatic effect on several strains of bacteria by its
ability to capture siderophores in extracellular space and
to deplete the bacterial iron supply. Therefore, NGAL
represents a critical component of innate immunity to
bacterial infection.
NGAL AS A PROTECTIVE AGENT IN AKI
Injured kidney tubular cells produce and secrete several
biological substances associated with innate and acquired
inflammatory immune responses, including NGAL.
In the kidney, after ischemic injury in animal models,
transcriptome profiling studies identified NGAL to be one
of the most up‑regulated genes, and proteomic analyses
revealed NGAL to be one of the most highly induced
proteins. These studies stimulated several groups of
investigators to evaluate NGAL as a non‑invasive
biomarker in human AKI. Studies in mouse models of
renal ischemia reperfusion showed NGAL production to
be highly up‑regulated at an early stage, and NGAL was
detected in the urine within 2 hours following ischemia.[10]
In response to renal tubular injury, expression of NGAL
rises 1000‑fold in humans and rodents, and it appears so
rapidly in the urine and serum that it may be useful as
an early biomarker of renal failure.
The physiological role of NGAL in this setting may be to
decrease injury by reducing apoptosis and increasing the
normal proliferation of kidney tubule cells. Because of its
abilitytoactasagrowthfactor,NGALhasalsobeenfound
to have a renoprotective effect in acute ischemic renal
injury in an animal model.[11]
In a murine model of renal
ischemia‑reperfusion injury, intravenous administration
of purified recombinant NGAL administered before,
during, or after ischemia resulted in marked amelioration
of the morphologic and functional consequences with a
reduction in the number of apoptotic tubule cells and
an increase in proliferating proximal tubule cells after
ischemic injury.[11]
INDICATIONS FOR MEASUREMENT OF NGAL
Results from various clinical studies suggest that NGAL
measurement (both urine and plasma) might be useful
in early detection of AKI. Measurement of NGAL may
help in timely diagnosis and intervention of AKI to
protect the kidney from further insults in numerous
clinical situations in the Emergency Department and
Intensive Care Unit for management of critical illness,
sepsis and septic shock,[12]
oliguria,[13]
radio‑contrast
procedures,[14,15]
cardiopulmonary bypass (CPB),[16]
polytrauma,[17]
prolonged cardiovascular surgeries, etc.,
Measurement of NGAL might be useful in randomized
control trials assessing efficacy of early intervention for
AKI. Diagnosis of AKI at an early stage might improve
patient selection for such trials. UNGAL level has been
found to be helpful to distinguish patients withAKI from
other morbid conditions with elevated creatinine such
as prerenal azotemia and CKD.[18]
In this study, a single
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measurement of uNGAL in the emergency department
in 635 patients was found to be highly sensitive and
specific (sensitivity 90%, specificity 99%) in diagnosing
AKI. NGAL has also been found to be a useful tool
in disease monitoring in other renal diseases, such as
lupus nephritis,[19]
IgA nephropathy,[20]
and polycystic
kidney disease.[21]
Another relevant area for the clinical
application of NGAL assays is to diagnose delayed graft
function following renal transplantation earlier than rise
in serum creatinine since this may be insensitive in these
settings. Delayed graft function is the main risk factor for
reduced allograft survival.[22]
NGAL IN NON‑RENAL CONDITIONS
NGAL has been found to be a biomarker in many other
non‑renalconditionssuchasbraintumor,[23]
inflammatory
bowel disease,[24]
and pre‑eclampsia.[25]
It has also been
seen that NGAL rises in response to prolonged hypobaric
hypoxia and demonstrates a relationship to the presence
and severity of acute mountain sickness.[26]
NGAL as a predictor of disease severity and outcome
Several clinical studies and systematic reviews indicate
that NGAL should be considered a reliable diagnostic
and prognostic biomarker for kidney injury. Some of
the studies[27‑30]
have been summarized in Table 1. When
compared with the conventional biomarker such as
creatinine, NGAL assay can detect renal injury at an early
stage. A recent multicenter pooled analysis of published
data on 2322 critically ill children and adults revealed the
surprising finding that approximately 20% of patients
displayearlyelevationsinNGALconcentrationsbutnever
develop increases in serum creatinine.[31]
Importantly,
this sub‑group of “NGAL‑positive creatinine‑negative”
subjects encountered a substantial increase in adverse
clinical outcomes, including mortality, dialysis
requirement, ICU stay, and overall hospital stay.[31]
NGAL
assay may be useful as a prognostic tool with regard
to the prediction of renal replacement therapy (RRT)
initiation and in‑hospital mortality. It has been found
to be a useful diagnostic and prognostic biomarker in
the specific setting of cardiorenal syndrome including
patients with chronic or acute heart failure.[32]
Few studies have evaluated the utility of NGAL for
risk stratification and prognosis. Dent et al.[33]
found the
2‑hour postoperative pNGAL level a reliable predictor
of duration of AKI and length of hospital stay, while
the 12‑hour pNGAL level was a predictor of mortality.
Similarly, Bennett et al.[34]
found 2‑hour uNGAL level
a reliable predictor of severity and duration of AKI,
length of hospital stay, requirement for RRT, and
mortality in 196 children undergoing CPB. Single uNGAL
measurement in the Emergency Department was found to
predict the need for nephrology consultation. Zappitelli
et al.[35]
studied uNGAL in 140 critically ill mechanically
ventilated patients. A significant rise (16 times) in levels
of uNGAL occurred 2 days earlier than a 50% increase
in serum creatinine levels. uNGAL levels increased in a
stepwise fashion with worsening RIFLE class.
Estimation of NGAL
The first analytical procedures set up for measurement
of NGAL in blood or urine samples were based on
enzyme‑linked immunosorbent assay (ELISA) or
immunoblotting systems.[16]
In general, these are
manual methods, which are not standardized and not
recommended for clinical practice, but only for research
studies.Theiruseisalsolimitedbytheircostandfeasibility.
The measurement of NGAL in serum, plasma and urine
samples can also be performed by means of commercially
available ELISA kits using both manual procedures and
several auto‑analyzers. Pedersen et al. have recently
evaluated the analytical performance of this ELISA kit,
using the manual procedure for the measurement of
NGAL in both urine and plasma samples and found that
these can be used with acceptable precision for plasma
and urine.[36]
A commercially available point‑of‑care
test (POCT) method is a fluorescence‑based immunoassay
for a rapid measurement (approximately 30 min) of
NGAL in whole blood or plasma samples. This POCT
method has a detection limit at 60 ng/mL and the upper
Table 1: Summary of studies demonstrating the utility of NGAL in point‑of‑care testing for AKI
Author and title No. of patients Objectives Conclusion
Vermi AC, et al. Urinary NGAL as a
predictor of AKI after transcatheter aortic
valve implantation, 2014[27]
34 To investigate the role of NGAL as
urinary biomarker for AKI for TAVI
uNGAL was not found to be a biomarker
of AKI after valve implantation
Patel M, et al. Correlation of serum NGAL
with AKI in hypertensive disorders of
pregnancy, 2013[28]
149 To evaluate AKI in hypertensive
disorders of pregnancy and to examine
the correlation of serum NGAL with AKI
NGAL correlated significantly with
creatinine
Akrawinthawong K, et al. Urine catalytic
iron and NGAL as companion early markers
of AKI after cardiac surgery: A prospective
pilot study, 2013[29]
14 To evaluate the relationship between
urine catalytic iron (unbound iron) and
NGAL over the course of AKI due to
cardiac surgery
Urine catalytic iron appears to rise and
fall in concert with NGAL in patients
undergoing cardiac surgery and may be
indicative of early AKI
Tasanarong A, et al. Urinary NGAL predicts
the severity of contrast‑induced (CI) AKI in
CKD patients undergoing elective coronary
procedures, 2013[30]
130 To know the correlation between
urinary NGAL with severity of
contrast‑induced AKI in CKD patients
undergoing elective coronary procedures
Monitoring of uNGAL levels not only
allows early detection of CI‑AKI but also
predicts its severity in CKD patients
undergoing elective coronary procedures
NGAL: Neutrophil gelatinase-associated lipocalin, AKI: Acute kidney injury, CKD: Chronic kidney disease, CI: Contrast-induced
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limit of the working range at 1300 ng/mL. More recently,
a chemiluminiscent microparticle immunoassay (CMIA)
method has become commercially available, using the
automated platform for the measurement of NGAL in
urine samples.
Both urine and blood samples have their advantages and
limitations. Blood NGAL measurements are invasive and
may potentially reflect the effect of extrarenal disease on
NGAL concentrations. However, samples are readily
available and the measurement can be performed rapidly
on whole blood or plasma (15–20 min) on a point‑of‑care
device. Urine sampling is non‑invasive and there are less
potentially interfering proteins present than in blood
specimens. However, many critically ill patients may be
oligo‑anuric. In addition, urinary NGAL concentrations
may be affected by the status of hydration and diuretic
treatment.
FACTORS INFLUENCING NGAL
MEASUREMENT
In a study on 426 adults undergoing CPB,[37]
UNGAL levels were significantly elevated in all
patients (with or without AKI), suggesting that CPB
may initiate inflammation and activation of neutrophils
leading to increased NGAL levels. In a recentin vitrostudy
by Bobek et al.,[38]
NGAL was found to be ultrafiltered and
adsorbed by polysulfone membranes, reducing its blood
levels.As many patients withAKI undergo hemodialysis,
this finding may be a potentially confounding factor in
the estimation of NGAL.
SIGNIFICANCE OF TESTING PANEL OF
BIOMARKERS FOR AKI
Of the many new biomarkers available, NGAL appears
to be the most promising but it is likely to be most
useful when combined with other markers such as
cystatin C or KIM‑1 to form an “AKI panel”.[39‑41]
Several
studies have examined the use of such biomarkers in
combination.[42,43]
In a study of 100 adult cardiac surgical
patients measuring NGAL and cystatin C as well as urea
and creatinine, the new biomarkers were superior to the
conventional measures in predicting AKI. Blood NGAL
and cystatin C were independent predictors of AKI.[42]
Another study measured KIM‑1, NAG, and NGAL in
90 adults undergoing cardiac surgery.[44]
The AUCs for
KIM‑1 to predict AKI immediately and 3 hours after
operation were 0.68 and 0.65; for NAG were 0.61 and 0.63;
and for NGAL were 0.59 and 0.65. Combining the three
biomarkers enhanced the sensitivity of early detection of
postoperativeAKI compared with individual biomarkers:
The combined AUCs for the three biomarkers were 0.75
and 0.78.
In a large prospective multicenter study of a panel of nine
biomarkers to predict clinical outcomes in 971 emergency
departmentpatientswithsuspectedsepsis,plasmaNGAL
emerged as the strongest predictor of shock and death.[45]
In a secondary analysis of this cohort, an elevated plasma
NGAL level at the time of presentation to the emergency
department predicted severeAKI with anAUC of 0.82.[46]
In a study examining biomarkers for the prediction of
AKI following elective cardiac surgery, urinary NGAL
concentrations measured at the time of admission to the
ICU predicted the subsequent development of AKI with
an AUC of 0.773, and outperformed other biomarkers
including α1‑microglobulin and cystatin C.[47]
In a
similar analysis of multiple urinary biomarkers following
cardiac surgery, the 6‑hour post‑operative NGAL best
predicted severe AKI with an AUC of 0.88.[48]
Serial
measurements of multiple urinary biomarkers after
pediatric cardiac surgery have revealed a sequential
pattern for the appearance of AKI biomarkers,[9]
with
NGAL and L‑FABP being the earliest responders (with
2–4 hours after initiation of cardiopulmonary bypass)
and KIM‑1 and IL‑18 representing the intermediate
responders (increased 6–12 hours after surgery).
Hence, use of a panel of biomarkers for AKI is likely to
improve the early detection of AKI.
LIMITATIONS OF NGAL AS A BIOMARKER FOR
AKI
Despite the optimism in the field, there are important
limitations that exist in the published AKI biomarker
literature that must be acknowledged. First, majority
of studies reported were from single centers and from
homogenous patient populations. Second, most studies
did not include patients with chronic kidney disease.
Third, only a few studies have investigated biomarkers
for the prediction of AKI severity, morbidity, and
mortality. Fourth, use of single biomarker is likely to
have a lower yield; hence, biomarker combinations
are likely to improve our ability to predict AKI and
its outcomes, and these studies are only beginning
to surface. Large multicenter studies are required for
further validation of the use of NGAL in heterogenous
patient populations and for defining cut‑off values for
diagnosis and outcomes of AKI. In addition, various
other factors such as RRT and underlying CKD may
influence its measurement as discussed earlier.
CONCLUSION
NGAL appears to be a promising marker for early
detection ofAKI and is likely to be adapted for wide‑scale
clinical use in patient management as a point‑of‑care test.
Early NGAL measurements can identify patients with
subclinical AKI who have an increased risk of adverse
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outcomes, even in the absence of diagnostic increases in
serum creatinine. Its ability to detectAKI early may allow
clinicians to take corrective and restorative measures
before the kidney damage becomes established and
irreversible. NGAL appears to be an exciting marker of
AKI, but more studies need to be conducted to confirm
its utility in routine clinical practice and to fine tune
the choice of appropriate cut offs for different clinical
settings and populations. Use of NGAL along with a
panel of other renal biomarkers can improve the rate
of early detection of AKI. Large, multicenter studies
demonstrate the association between biomarkers and
hard end points such as need for RRT, cardiovascular
events, hospital stay, and death, independent of serum
creatinine concentrations.
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Source of Support: Nil, Conflict of Interest: None declared.
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