Neutrophil Gelatinase-Associated Lipocalin

Curve and Neutrophil Gelatinase-Associated Lipocalin

Extended-Range Assay: A New Biomarker Approach in the
Early Diagnosis of Acute Kidney Injury and Cardio-Renal Syndrome

Claudio Ronco, MD,* Dinna Cruz, MD,* and Brian W. Noland, PhD†

Summary: Cardio-Renal syndrome (CRS) is a common and complex clinical condition in which multiple causative
factors are involved. The time window between renal insult and development of acute kidney injury (AKI) in acute
heart failure (AHF) can be varied in different patients and AKI often is diagnosed too late, only when the effects
of the insult become evident with a loss or decline of renal function. For this reason, pharmaceutical interventions
for AKI that have been shown to be renoprotective or beneficial when tested in experimental conditions do not
display similar results in the clinical setting. In most cases patients with AHF are admitted with clinical signs and
symptoms of congestion and fluid overload. Loop diuretics, typically used to induce an enhanced diuresis in these
congested patients, often are associated with a subsequent significant decrease in glomerular filtration rate and
cause a creatinine increase that is apparent within 72 hours. Early detection of AKI is not possible with the use of
serum creatinine and there is a need for a timely diagnostic tool able to address renal damage while it is
happening. We need to define the diagnosis of both AHF and AKI in the early phases of CRS type 1 by coupling
a kidney damage marker such as neutrophil gelatinase-associated lipocalin (NGAL) with B-type natriuretic peptide
(BNP). Indeed, it would be ideal to make available a panel including whole blood or plasma cardiac and renal
biomarkers building specific, pathophysiologically based, molecular profiles. Based on current knowledge and
consensus, we can use kidney damage biomarkers such as plasma NGAL for an early diagnosis of AKI. However,
differences in individual patient values and uncertainties about the ideal cut-off values may currently limit the
application of these biomarkers. We propose that NGAL may increase its usefulness in the diagnosis and
prevention of CRS if a curve of plasma values rather than a single plasma measurement is determined. To apply
the concept of measuring an NGAL curve in AHF patients, however, assay performance in the lower-range values
becomes a critical factor. For this reason, we propose the use of the new extended-range plasma NGAL assay that
may contribute to remarkably improve the sensitivity of AKI diagnosis in AHF and lead to more effective
intervention strategies.
Semin Nephrol 32:121-128 © 2012 Elsevier Inc. All rights reserved.
Keywords: Acute kidney injury, cardio-renal syndrome, fluid overload, biomarkers, NGAL

G reat interest recently has developed in the clini-

cal importance of cardio-renal syndromes (CRS)
and their pathophysiological mechanisms. In
particular, the attention of clinicians has been driven by
the high frequency of acute kidney injury (AKI) in acute
heart failure (AHF) and its management. Frequently, in
fact, the most important mechanism behind CRS type 1 is
indeed an iatrogenic derangement caused by inappropri-
ate use of diuretics or other strategies to alleviate con-
gestion such as extracorporeal ultrafiltration.1 In the at-
*Department of Nephrology Dialysis and Transplantation, Interna-
tional Renal Research Institute, St. Bortolo Hospital, Vicenza, Italy.
†Alere Inc., San Diego, CA.
Financial support for this work: none.
Financial disclosure and conflict of interest statement: Dr. Claudio
Ronco receives speaking honoraria from Alere, Abbot, Gambro and
Pfizer.
Address reprint requests to Claudio Ronco, MD, Department of Ne-
phrology Dialysis and Transplantation, International Renal Re-
search Institute, St. Bortolo Hospital, Viale Rodolfi 37, 36100 Vi-
cenza, Italy. E-mail: cronco@goldnet.it
0270-9295/ - see front matter
© 2012 Elsevier Inc. All rights reserved.
doi:10.1016/j.semnephrol.2011.11.015
tempt to remove fluid overload, severe hemodynamic
consequences may lead to renal hypoperfusion and AKI.
In these circumstances, the importance of sensitive,
specific, but most of all early criteria to diagnose AKI
have clearly emerged. The main issue is to characterize
the type of renal injury separating functional disorders
from tubular damage. In this field, creatinine has been
proven useful as a biomarker for AKI although it repre-
sents a late diagnostic tool serving as a surrogate marker
for a decrease in glomerular filtration rate.2 When glo-
merular filtration rate is declining the damage often al-
ready has occurred and very little can be done to prevent
or to protect the kidney from further damage. In this area,
several molecules have been proven to be useful diag-
nostic tools to detect the presence of early kidney damage
and to describe the level of its severity.3 Among them,
neutrophil gelatinase-associated lipocalin (NGAL) is the
most carefully and extensively studied molecule. Be-
cause of its ability to discriminate between volume-re-
sponsive functional changes and true kidney damage,
NGAL has emerged as the most attractive and reliable
candidate biomarker.4 In some studies, however, the area
under the receiver operating characteristic curve has been
suboptimal compared with other reports in the litera-

Seminars in Nephrology, Vol 32, No 1, January 2012, pp 121-128 121

122
ture.5,6 Because of the dynamic nature of the marker
kinetics, the current uncertainties pertaining to the opti-
mal cut-off point and the timing in which the measure-
ment should be made, despite some interesting results7,8
it may be that in certain settings the predictive capacity of
a single NGAL measurement could be somewhat limited.
Furthermore, when AKI is in its early phases, the levels
of NGAL in blood may still be quite low and difficult to
discriminate with a single absolute cut-off value across
individual patients. For these reasons, an approach may
be required that includes a clear definition of a con-
tinuous scale of NGAL values in the low range and a
repeated series of measurements while the clinical
situation is evolving. In this article we present a new
way to use NGAL for the early diagnosis of AKI and
a new expanded-range plasma assay capable of dis-
crete measurement even in the range below the classic
lower limit of detection.
NGAL AND ITS CURRENT APPLICATIONS
NGAL was first characterized as a protein complexed
with MMP-9 isolated from neutrophils in response to
specific stimuli.9 NGAL is also known as lipocalin-2, as
well as siderocalin, and is known to play a role in fighting
bacterial infections by recovery through specific binding
of siderophore-chelated iron earmarked for bacterial im-
portation.10 The association between NGAL and kidney
injury was first identified using the ischemia reperfusion
model in rodents in which NGAL messenger RNA
showed a marked increase and resultant NGAL protein
increases in the plasma and urine within a few hours after
ischemia reperfusion model, 24 to 48 hours preceding
serum creatinine increase.11 Similar results with early
increase of NGAL ahead of creatinine were obtained
using cisplatin nephrotoxic injury models in animals.11,12
NGAL is therefore one of the most reliable early
biomarkers for ischemic and nephrotoxic kidney injury
(acute tubular necrosis [ATN], contrast induced nephrop-
athy [CIN], and intensive care unit [ICU] setting). It
increases significantly in AKI patients but not in controls
24 to 48 hours before the increase of creatinine.13 NGAL
levels on the day of transplant predict delayed graft
function and dialysis requirement (2-4 days later).14
NGAL predicts the severity of AKI and dialysis require-
ment in children and in adults.13,15-18 This biomarker has
been proven useful in several clinical settings especially
after cardiopulmonary bypass in children and adults, in
pediatric and adult ICUs, in trauma patients, in contrast-
induced nephropathy, and in toxic AKI.13-23 This allows
the phases of the AKI continuum to be matched with the
potential applications for biomarkers in the different ep-
ochs of AKI syndrome (Fig. 1).
Measurements may be influenced by co-existing vari-
ables such as systemic or urinary tract infections and
pre-existing renal diseases, but, nevertheless, NGAL has
displayed remarkable specificity and sensitivity.24-26 Re-
cently, one important study showed that NGAL allows an
C. Ronco and B. Noland
early diagnosis of AKI, distinguishing between kidney
damage AKI and functional volume-responsive renal dis-
orders.4
CRS TYPE 1
CRS type 1 is defined by an acute heart disease (eg,
AHF) leading to AKI.1 The clinical importance of AKI as
far as the outcome is concerned has emerged clearly in
recent years. AKI diagnosed by RIFLE or AKIN criteria
is associated with adverse clinical outcome. Worsening
of renal function in patients with heart failure represents
an extremely important risk factor and often results in an
accelerated decline of the clinical picture.27 For this rea-
son, the questions to be answered in the immediate future
are as follows: is it possible to prevent AKI in AHF
patients or is it at least possible to make the diagnosis in
the very early stages when a mitigation of the severe
consequences is still conceivable? How can we manage
HF patients without harming their kidneys? Why have
our previous attempts to prevent AKI failed even in
the presence of promising experimental results? To an-
swer these questions one must analyze the pathophysiol-
ogy of renal damage in CRS. First, in contrast to exper-
imental models of AKI, in clinical practice AKI is
diagnosed quite late and so the interventions that have
seemed to have a beneficial and protective action in the
experimental setting may not present similar results in
the real world because they probably are applied too late.
If we could have an earlier indicator of kidney damage,
the application of various protective molecules might
occur earlier within a window of potential clinical ben-
efit. If we could diagnose AKI early enough, we likely
could rewrite completely the chapter of renal prevention/
protection with new or pre-existing drug molecules. Sec-
ond, in AHF many mechanisms play an important role in
the development of AKI and the most important among
them should be addressed and considered in a more
timely fashion. We may identify hemodynamic changes,
neurohormonal derangements, associated exogenous fac-
tors and toxic effects, embolic episodes, and important
immunomediated effects such as inflammation-derived
necrosis and apoptosis in the target organ. Even assuming
the co-existence of risk factors such as obesity, subclin-
ical inflammation, endothelial dysfunction and acceler-
ated atherosclerosis, anemia, and previous chronic kid-
ney disease we cannot neglect the paramount importance
of two main factors such as renal hypoperfusion and
renal congestion.
NGAL CURVE IN THE DIAGNOSIS OF CRS
Most patients admitted to the hospital for AHF present
with a status of congestion and are definitely fluid over-
loaded.27 In such patients the RAA axis is activated and
a nonosmotic release of vasopressin determines an inap-
propriate renal vasoconstriction mediated by the V1 re-
ceptors and a significant free water reabsorption medi-
NGAL curve in the diagnosis of AKI 123

AKI CONTINUUM AND RELEVANT BIOMARKERS

Renal
Hypovolemic? Renal (damage +
(
i
(funconal)
l) (d
(damage)) funconal)

Normal ↑Risk Damage ↓GFR Failure Death

damage +
Funconal Damage funconal
Biomarkers Biomarkers Biomarkers
Figure 1. The spectrum of conditions from normal renal function to severe AKI represent a continuum in which, in the early phases, the
functional, hypovolemic AKI may be detected by an increase in serum creatinine not related to damage. In this condition NGAL has been shown
to remain unaffected. In the subsequent steps of the continuum, parenchymal damage may occur and biomarkers such as NGAL may increase
even in the presence of normal functional biomarkers such as creatinine. In the later phases of AKI, functional biomarkers such as creatinine
increase owing to a significant decrease in glomerular filtration rate (GFR). NGAL may remain high, be increasing, or even decrease, depending
on the presence or absence of ongoing insult.

ated by the V2 receptors present in the distal segment of
the nephrons. Such hemodynamic and pathophysiologi-
cal changes are worsened by a significant venous con-
gestion that in the presence of a decreased perfusion of
the glomerular tuft leads to a marked decrease in the
glomerular transcapillary pressure gradient. This results
in severe status of oliguria, water and sodium retention,
worsening congestion, and peripheral edema. In these
circumstances, besides the pharmacologic therapy and
the often overlooked dietary recommendations, the cor-
nerstone of immediate management is represented by
diuretics. Patients are squeezed with loop diuretics often
at very high doses because a “status of diuretic resis-
tance” is often occurring with limited polyuric response
to increasing doses of the drug. In some cases diuretics
become ineffective and the only method to resolve the
clinical impasse is the use of extracorporeal ultrafiltra-
tion. In all cases, however, the clinician has little or no
idea of the level of overhydration, and especially of the
target body weight and hydration that the patient should
reach. In recent studies, the use of bioimpedance vecto-
rial analysis (BIVA) has been advocated as a tool to be
used in conjunction with BNP to modulate therapy and to
define criteria for hospital discharge.28 In particular, al-
though BNP is useful in identifying when the patient
should be discharged, BNP ⫹ BIVA may help to opti-
mize the fluid status of the patient at discharge, reducing
the number of subsequent rehospitalizations for AHF.
These two parameters, however, do not contribute to
better understanding of the renal response to diuretic
and fluid removal strategies and especially do not
allow the detection of possible renal insults caused by
excessive fluid removal and iatrogenic renal hypoper-
fusion. In fact, more than a third of these patients
display a significant increase in creatinine 48 to 72
hours after the beginning of the intensive diuretic or
ultrafiltration therapy.29,30 In these circumstances we
suggest the use of NGAL determination in blood as a
biomarker of early renal damage. NGAL has been
shown to predict AKI 24 to 48 hours before a creati-
124
Figure 2. Didactic representation of a time course of BNP, diuresis,
and creatinine over several days after hospitalization for acute de-
compensated heart failure (ADHF) and the beginning of a high-dose
diuretic regimen.
nine increase is observed. However, because the man-
agement of AHF patients often may be performed over
several days, it is unclear when the NGAL should be
measured. We believe that defining an NGAL curve
could be a useful tool and would be determined by
taking blood samples every 12 to 24 hours as it has
been performed in the past for other biomarkers such
as troponin, myoglobin, and so forth. To support this
approach, we report our experience in some cases that
may prove extremely didactic and explanatory.
In Figure 2, we describe a typical case of a patient
hospitalized for AHF. The patient displayed high values
of BNP at admission and severe fluid overload. The
BIVA analysis suggested a moderate status of overhy-
dration with a slight condition of malnutrition. The pa-
tient presented with typical signs of congestion with
shortness of breath and oliguria. Treatment with high-
dose diuretics produced a significant increase of diuresis
already after 24 hours with partial relief of symptoms. In
the subsequent days the progressive increase in diuresis
was coupled with a parallel reduction of BNP levels (wet
BNP) until both diuresis and BNP stabilized (dry BNP
level). By day 3, BIVA, which is performed serially in
these patients, displayed a moderate status of dehydration
whereas creatinine started to increase, reaching the con-
dition of AKI (RIFLE R). Further increase of creatinine
in the subsequent days led to RIFLE I class of AKI. The
diagnosis of such condition is typically CRS type 1.
In Figure 3, a similar patient was hospitalized for AHF
and a pharmacologic approach similar to the previous
case was undertaken. However, in this case, a close
monitoring of plasma NGAL was performed together
with BNP, diuresis, and BIVA. After 24 hours NGAL
values were more than double compared with baseline.
At 48 hours BIVA displayed a significant reduction of
the overhydration with values close to normal, whereas
C. Ronco and B. Noland
NGAL was more than four times higher than the baseline
value at hospital admission. The NGAL warning trig-
gered the treating physician to stop the diuretic therapy
and stabilize the patient for the days that followed. Di-
uresis and BNP values remained stable whereas NGAL
showed a trend toward reduction. The values of creati-
nine remained stable throughout the hospital admission.
In this case, we may speculate that CRS type 1 was
prevented by modifying the treatment strategy based on
the NGAL warning. This approach is possible only if a
series of NGAL measurements are made. In particular,
the use of the NGAL curve may allow the treating
physician to overcome the limitations caused by uncer-
tainties about the cut-off value, and may create a more
personalized evaluation in the single patient considering
baseline values and subsequent changes in NGAL values
over time. However, a potential limitation to this ap-
proach in the AHF population may be presented by the
relatively low NGAL levels expected in these patients in
light of the lower limit of detection of the first-generation
plasma NGAL assay and the expected variation at the
extreme low end of competitive immunoassays. For this
reason we may speculate that the novel extended-range
plasma NGAL assay may allow for the better exploita-
tion of the potential of the NGAL curve, offering quan-
titative determinations of the NGAL levels even in the
low range. As in the case of CRP and troponin, we may
consider that NGAL values in a single subject are a
continuum in which significant variations within the low
range or even below the previous assay detection limit
represent a significant event from the clinical point of
view. For this reason the development of the extended-
range assay represents a step forward for the early diag-
nosis of AKI in AHF, especially if used in conjunction
with the curve concept.
Figure 3. Didactic representation of a time course of BNP, diuresis,
and creatinine over several days after hospitalization for ADHF and
the beginning of a high-dose diuretic regimen. The management is
modified based on the NGAL curve.
NGAL curve in the diagnosis of AKI 125

THE EXTENDED-RANGE ASSAY FOR NGAL
Plasma NGAL was first described as a putative novel
marker of AKI in clinical samples in 2005 by Mishra et
al,13 who studied this marker in pediatric cardiopulmo-
nary bypass patients. At this time, the clinically relevant
range of NGAL in adult populations was not yet well
known, nor was much known about the various states in
which NGAL might exist in the plasma and the associ-
ated clinical importance of these forms. The competitive
Triage NGAL Test (Alere Inc, San Diego, CA) was
designed to rapidly and quantitatively measure all forms
of NGAL across an assay range from 60 to 1,300 ng/mL
in human blood or plasma, which was shown to ade-
quately cover the expected NGAL values for a cohort of
adult ICU patients.17,18 The competitive Triage NGAL
test comprises recombinant, bacterially expressed NGAL
antigen covalently conjugated to an immobilized latex
nanoparticle and an NGAL-specific antibody conjugated
to a fluorescently labeled latex nanoparticle as a detection
reagent (Fig. 4A). As the sample moves through the
device, it resuspends the detection reagent. After a short
engineered delay, the sample then flows down the diag-
nostic lane zone and over the immobilized NGAL anti-
gen. Unbound detection particles bind to the immobilized
NGAL antigen whereas bound NGAL particles and ex-
cess detection reagent flow past this zone. The remainder
of the sample serves to wash away the unbound detection
reagent. The fluorescent signal at the capture zone is
therefore indirectly proportional to the concentration of
NGAL in the sample (Fig. 4C).
The advantage of this competitive NGAL assay design
is that it will never display a high-dose hook effect,

Figure 4. Comparison of attributes of competitive and sandwich NGAL immunoassays on the triage platform. (A and D) Cartoon representation
of the competitive and sandwich Triage NGAL immunoassays, respectively. (B and E) Dependence of signal-to-concentration %CV conversion
factors as a function of NGAL concentration for the competitive and sandwich formats, respectively. (C and F) Normalized dose-response
characteristics for the competitive and sandwich immunoassay formats, respectively. The filled circles represent averaged measurements from
multiple Triage device replicates. The solid black line through the measured points is a nonlinear least-squares fit of those data to a 5-parameter
asymmetric sigmoid model. The vertical dashed grey line represents the lower assay cut-off value per the product package inserts.
126 C. Ronco and B. Noland

which can be useful for the measurement of NGAL in ward this end, Alere embarked on a development pro-
samples from individuals with relatively high blood gram that would extend the quantifiable range of NGAL
NGAL (eg, patients in the ICU with AKI resulting from to include all apparently healthy samples to the same
acute infections). Some disadvantages of the competitive upper limit as the existing competitive product. The final
approach are a somewhat limited quantitative range and design was a sandwich format immunoassay that uses
the indiscriminant measure of the total NGAL pool. The two antibodies separate from the one used in the com-
competitive Triage NGAL test was designed to quanti- petitive format as well as a different sized detection
tatively measure NGAL from the median of normal en- particle (Fig. 4A and D). In the initial competitive format,
dogenous NGAL (approximately 60 ng/mL) to 1,300 immunization, antibody selection, capture chemistry, and
ng/mL. In competitive assays, the range of quantitation calibration material all were derived from recombinant
tends to be smaller than corresponding sandwich immu- NGAL cloned and expressed in bacteria. The resulting
noassays because of the typical rectangular hyperbolic assay was capable of measuring total NGAL, regardless
r-shape of their dose-response curves. As is typical of all of whether the antigen was free or in a covalent complex
immunoassays, at the extremes of the NGAL dose-re- with matrix metalloproteinase (MMP)9. The redesigned
sponse curve the assay imprecision increases. This can be sandwich assay used the same NGAL construct but ex-
seen in the exaggerated parabolic dependence of the pressed in mammalian cells, which imparts post-transla-
conversion factors for signal-to-concentration percent co- tional modifications in the form of glycosylations. This
efficient of variation (%CV) factors in Figure 1B. The mammalian cell– expressed NGAL was used for immu-
zone where the best concentration precision is achieved nization, antibody selection, and final calibration. In ad-
for the competitive Triage NGAL test is aligned with the dition, the antibodies used in the sandwich immunoassay
intended use in the aid in diagnosis of AKI in ICU have been selected to target the free form of NGAL, not
patients. NGAL in the covalent homodimeric form or heterodi-
meric complexes with MMP9. It is believed that this free
THE EXTENDED-RANGE
form of NGAL is associated more closely with AKI.31
SANDWICH TRIAGE NGAL TEST Beyond new antibodies, the size of the detection par-
The Conformité Européenne (CE)-marked competitive ticle is a major determinant of assay dose-response curve
Triage NGAL test has proven useful in the diagnosis of shape in the new NGAL sandwich immunoassay. This
AKI in ICU patients as designed.17,18 However, many can be partially explained by the fact that reducing the
other indications in which NGAL may prove useful such diameter of the detection sphere from 500 to 68 nm
as contrast-induced nephropathy, worsening renal func- greatly increases the surface-to-volume ratio. At equiva-
tion in the background of heart failure, and AKI in lent percentage solids there is an approximately 400-fold
chronic kidney disease require improved precision within increase in the total number of particles and a 7.4-fold
the apparently healthy NGAL concentration range. To- increase in detection of particle surface area. The amount

50

45 Sandwich
Assay Limit

40 Compeve

35
Lower A
FFrequency

30

25
95th Percenttile
95th Percenttile

20
ower Assay Limit

15

10

5
Lo

0
10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200

NGAL Concentraon (ng/mL)

Figure 5. Comparison of the standard and the high-sensitivity assays in different samples at different concentrations. This shows that the new
extended-range sandwich immunoassay for plasma NGAL is capable of quantitatively measuring the full range of expected values from
apparently healthy donor populations.
NGAL curve in the diagnosis of AKI
of available surface area is directly proportional to the
amount of antibody that can be applied by conjugation.
This increase in total detection antibody serves to par-
tially detune the assay. In addition, the smaller particles
show better passive resuspension than larger ones and the
diffusion and flow properties were shown to be more
advantageous than large ones when subjected to laminar
flow in computational fluid dynamic simulations (data
not shown). Smaller-diameter detection particles yield
less total fluorescence than larger ones in proportion to
their respective volumes. However, the NGAL analyte
yields a high slope in calibration and correspondingly
sensitive limits of detection, presumably from higher
capture efficiency owing to the improved resuspension
and diffusion properties of smaller particles. This permit-
ted the decreasing of the lower limit of NGAL assay
detection from 60 ng/mL in the competitive format to 15
ng/mL in the sandwich immunoassay. As such, the new
sandwich assay has the ability to make quantitative mea-
surements of NGAL over the entire range of expected
NGAL values from a nondiseased apparently healthy
population.
The properties cited earlier taken together give rise to
a broader dynamic range in the sandwich NGAL immu-
noassay as compared with the competitive format (Fig.
4C and E). This, in turn, yields a much broader range in
which relatively lower concentration CVs can be ob-
tained (Fig. 4B and D). This becomes important as the
concentration of NGAL approaches the endogenous
NGAL levels observed in apparently healthy, normal
patient samples and in the additional indications of in-
terest cited previously. The effect can be shown if one
considers an example in which both assays measure an
NGAL concentration of 80 ng/mL with a fluorescence
signal CV of 7%. At 80 ng/mL the signal-to-concentra-
tion conversion factors are 2.8 and 1.6 for the competi-
tive and the sandwich immunoassays, respectively (Fig.
4B and E). The 7% signal CV then corresponds to an
NGAL concentration CV of 19.6% and 11.2% for the
competitive and sandwich formats, respectively.
To characterize the lower limits of the measurable
range of the two assay formats, plasma samples from
apparently healthy donors were tested side-by-side on the
sandwich and competitive Triage NGAL test devices.
The extended detection range of the sandwich immuno-
assay allowed for quantitative measurement of all appar-
ently healthy donor samples and identified a minimum
sample NGAL concentration of 18 ng/mL. In 40% of
these samples the NGAL concentration measured on the
extended range sandwich immunoassay was less than the
lower limit of detection of the competitive immunoassay
(ie, 60 ng/mL). In the case of samples at or greater than
60 ng/mL NGAL, the distribution of assay results for the
two immunoassays was comparable, as can be seen in
Figure 5. This is further illustrated in the 95th percentile
NGAL concentrations determined for the two formats:
154 ng/mL and 138 ng/mL for the sandwich and com-
127
petitive immunoassays, respectively. This result showed
that the new extended-range sandwich immunoassay for
plasma NGAL is capable of quantitatively measuring the
full range of expected values from apparently healthy
donor populations.
CONCLUSIONS
CRS is a complex clinical condition with potentially
severe consequences. AKI in heart failure patients often
is caused by iatrogenic hemodynamic derangement after
inappropriate fluid status assessment and management.
Based on current knowledge, we can use early biomark-
ers such as NGAL for an early diagnosis of AKI. How-
ever, differences in individual response and uncertainties
about cut-off values may limit the application of these
new biomarkers. We propose that plasma NGAL may
increase its usefulness in the diagnosis and prevention of
CRS if a curve of plasma values rather than a single
plasma measurement is determined. Even in the case of a
curve, however, limitations of the first-generation assay
in measuring the lower-range values may affect the
meaning of results significantly. For this reason, the new
high-sensitivity assay for plasma NGAL may contribute
to a remarkable improvement in the sensitivity of the
diagnosis, leading to more effective intervention strate-
gies.
ACKNOWLEDGEMENTS
The authors would like to kindly thank Fred Sundquist, PhD, and
Gillian Parker for their contributions to this article.
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