REVIEW

Biomarkers for Early Detection of Acute Kidney

Injury

Mahrukh S. Rizvi1 and Kianoush B. Kashani1,2*

Background: Acute kidney injury (AKI) is common in hospitalized patients and is associated with increased
morbidity, mortality, and cost. Currently, AKI is diagnosed after symptoms manifest; available diagnostic
tests (e.g., serum creatinine, urine microscopy, urine output) have limited ability to identify subclinical AKI.
Because of the lack of treatment strategies, AKI typically is managed with supportive measures. However,
strategies exist that may prevent renal insults in critically ill patients; therefore, early recognition of AKI is
crucial for minimizing damage propagation.
Content: Experimental and clinical studies have identified biomarkers that may facilitate earlier recognition
of AKI or even identify patients at risk of AKI. Such biomarkers might aid in earlier implementation of
preventive strategies to slow disease progression and potentially improve outcomes. This review describes
some of the most promising novel biomarkers of AKI, including neutrophil gelatinase-associated lipocalin
(NGAL), kidney injury molecule 1 (KIM-1), interleukin 18 (lL-18), liver-type fatty-acid-binding protein (L-FABP),
insulin-like-growth-factor-binding protein 7 (IGFBP7), and tissue inhibitor of metalloproteinase 2 (TIMP-2).
Summary: We discuss biomarker test characteristics, their strengths and weaknesses, and future direc-
tions of their clinical implementation.

IMPACT STATEMENT
Acute kidney injury (AKI) affects millions of people in the US and increases morbidity, mortality, and
healthcare expenditures. Available laboratory tests for early and accurate diagnosis of AKI have significant
limitations. Novel biomarkers that predict development of AKI earlier are critically needed because they allow
implementation of preventive strategies that potentially improve clinical outcomes. In this report, we review
the most promising biomarkers of AKI that have been investigated during the past 2 decades and present a
model for clinical implementation and areas for future investigation.

1
Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN; 2 Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN.
*Address correspondence to this author at: Division of Nephrology and Hypertension, Mayo Clinic, 200 First St SW, Rochester, MN 55905. Fax
507-266-7891; e-mail kashani.kianoush@mayo.edu.
DOI: 10.1373/jalm.2017.023325
© 2017 American Association for Clinical Chemistry
3
Nonstandard abbreviations: KDIGO, Kidney Disease: Improving Global Outcomes; AKI, acute kidney injury; AKIN, Acute Kidney Injury Network;
AUC-ROC, area under the receiver operating characteristic curve; FDA, Food and Drug Administration; IGFBP7, insulin-like-growth-factor– binding
protein 7; IL, interleukin; KIM-1, kidney injury molecule 1; L-FABP, liver-type fatty-acid– binding protein; NGAL, neutrophil gelatinase-associated
lipocalin; RIFLE, risk, injury, failure, loss, end-stage kidney disease; TIMP2, tissue inhibitor of metalloproteinase 2.
4
Human genes: FABP1, fatty acid binding protein 1.

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Copyright 2017 by American Association for Clinical Chemistry.
REVIEW Acute Kidney Injury Biomarkers

Table 1. AKI definition criteria.

RIFLE AKIN KDIGO

Risk (RIFLE) or stage 1 Increase in serum creatinine
(AKIN/KDIGO) of 50%–99% OR Urine
output of <0.5 mL/kg/h for
6 to 12 h
Injury (RIFLE) or stage 2 Increase in serum creatinine
(AKIN/KDIGO) of 100%–199% OR Urine
output of <0.5 mL/kg/h for
12 to 24 h
Failure (RIFLE) or stage 3 Increase in serum creatinine
(AKIN/KDIGO) of ≥200% OR Increase in
serum creatinine by >0.5
mg/dL to >4.0 mg/dL OR
Urine output of <0.3 mL/kg/
h for >24 h or anuria for
>12 hours OR Initiation of
renal replacement therapy
Loss (RIFLE) Need for renal replacement
therapy for >4 weeks
End stage (RIFLE) Need for renal replacement
therapy for >3 months
Increase in serum creatinine
of ≥0.3 mg/dL or
50%–100% OR Urine
output of <0.5 mL/kg/h for
6 to 12 h
Increase in serum creatinine
of >100 to 200% OR Urine
output of <0.5 mL/kg/h for
12–24 h
Increase in serum creatinine
of >200% OR Increase in
serum creatinine by >0.5
mg/dL to ≥4.0 mg/dL OR
Urine output of <0.3 mL/kg/
h for >24 h or anuria for
>12 hours OR Initiation of
renal replacement therapy
Increase in serum creatinine
of ≥0.3 mg/dL or 50%–99%
OR Urine output of <0.5
mL/kg/h for 6 to 12 h
Increase in serum creatinine
of 100% to 199% OR Urine
output of <0.5 mL/kg/h for
12–24 h
Increase in serum creatinine
of ≥200% OR Increase in
serum of ≥0.3 mg/dL to 4.0
mg/dL ≥ OR Urine output
of <0.3 mL/kg/h for ≥24 h
or anuria for ≥12 h OR
Initiation of renal
replacement therapy

The Kidney Disease: Improving Global Out-
comes (KDIGO)3 most recently defined acute kid-
ney injury (AKI) as an increase in serum Cr by ≥0.3
mg/dL (≥26.5 μmol/L) within 48 h, to ≥1.5 times
baseline within the prior 7 days, or a urine volume
of <0.5 mL/kg/h for 6 hours (Table 1) (1). There are
a broad range of etiologies of AKI in hospitalized
patients, including decreased renal perfusion, in-
trinsic renal disease due to sepsis-associated tu-
bular epithelial cell injury, glomerulonephritis,
nephrotoxic effect of medications, and bladder
outlet obstruction, among others. The incidence of
AKI in hospitalized patients, with use of the KDIGO
equivalent definition of AKI, ranges from 17% to
31%, depending on the sampled population (2–4).
AKI is recognized as an important risk factor for
progression to chronic kidney disease, accelerated
progression to end-stage renal disease, cardiovas-
cular disease, and congestive heart failure (3, 5). It
is also associated with increased short-term mor-
bidity and mortality and with annual healthcare ex-
penditures estimated to be $6.6 billion to $10
billion in the US alone (6–10). The prognosis of pa-
tients with dialysis-requiring AKI has not changed
in the past 50 years, and short- and long-term mor-
tality rates still range from 40% to 80%, despite
advances in extracorporeal renal replacement
techniques (10). Although AKI is associated with
highly detrimental outcomes, recognition of AKI is
unacceptably delayed in up to 43% of hospitalized
patients (11).
Considering the magnitude of the problem and
known delays in diagnosis, early detection of AKI is
crucial for instituting timely precautions that can
potentially impact prognosis. The consensus defi-
nition of AKI has undergone substantial alterations
to improve diagnostic criteria and allow early rec-
ognition. Further efforts have focused on using
electronic health records for automated reporting
of potential AKI to facilitate earlier clinical evalua-
tion and possibly improve outcomes (12, 13). How-
ever, a major hindrance to early and accurate
diagnosis is the low sensitivity and specificity of the
conventional markers of AKI. Although currently
AKI diagnosis is based on changes in serum creat-
inine and urine output, other tests including blood
urea nitrogen, fractional excretion of sodium, and
urine microscopy could be used to guide clinicians

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Acute Kidney Injury Biomarkers
in determination of the extent and underlying
cause of AKI. The use of creatinine as a marker of
AKI has numerous limitations, including poor cor-
relation with glomerular filtration rate during a
dynamic state and variations in its production, se-
cretion, and extrarenal excretion (14–16). Most im-
portantly, creatinine is not a real-time biomarker,
and its levels may not rise until after renal function
is compromised, which could result in a missed
therapeutic window. Urinary output, although a
very sensitive and early marker of kidney dysfunc-
tion, is not a widely used criterion for AKI diagnosis
due to difficulties in collection of urine output data,
frequent use of diuretics, and issues related to in-
dwelling urinary catheters (e.g., early removal of
urinary catheter to avoid catheter-related urinary
tract infection, catheter obstruction, lack of ability
for automated collection of urinary output data
with currently used devices). Other surrogate
markers of kidney injury, including blood urea
nitrogen, fractional excretion of sodium, and
urine microscopy, have their own limitations
with the latter 2 having very low sensitivity and
specificity. Blood urea nitrogen levels vary in-
versely with glomerular filtration rate, however,
and may be falsely increased in subjects with a
high-protein diet, glucocorticoid therapy, tissue
breakdown, gastrointestinal bleeding, total par-
enteral nutrition, and volume depletion, and
falsely decreased in individuals with poor nutri-
tional status or chronic liver disease due to de-
creased urea production.
To improve the outcomes of patients with AKI,
real-time biomarkers must be identified that
facilitate early diagnosis and expedite effective
preventive and therapeutic measures. As such, the
American Society of Nephrology has designated
the identification and standardization of novel bio-
markers of AKI a top priority. The Acute Dialysis
Quality Initiative recommended early integration
of biomarkers in the diagnosis of AKI, suggesting
that earlier diagnosis can potentially improve out-
comes (17). In the US, the only Food and Drug Ad-
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ministration (FDA)-approved biomarkers for early
AKI prediction are the cell-cycle arrest biomarkers
(insulin-like-growth-factor–binding protein 7 [IGFBP7]
and tissue inhibitor metalloproteinases-2 [TIMP-
2]; both described below); the platform to mea-
sure these biomarkers is commercially available
both at the portable and central laboratory forms.
This review aims to appraise the current literature
on the detection and validation of biomarkers of
AKI in various clinical settings.
Biomarkers of AKI
Universal attributes of an ideal biomarker are
as follows: (a) is measurable by a rapid test of
readily available samples (urine or blood); (b) is
measurable by a cost-effective, biologically and
physiologically plausible assay with high sensitivity
and specificity; (c) has dynamic and rapidly chang-
ing levels that correlate with disease progression
or improvement; and (d) has prognostic value (10,
15). Pioneering studies from the past 2 decades
have identified candidate biomarkers of AKI with
considerable potential in translational medicine.
These biomarkers can be subdivided into 5 cate-
gories (Table 2) (15).
Neutrophil gelatinase-associated lipocalin
Neutrophil gelatinase-associated lipocalin (NGAL),
also termed siderocalin or lipocalin-2, is a pro-
tease-resistant, 25-kDa polypeptide of the lipoca-
lin superfamily, initially identified in human
neutrophils (18). It is expressed in trace levels in
various human epithelia, including kidney, trachea,
lungs, stomach, and colon (19). It functions as a
natural siderophore by scavenging the cellular and
pericellular labile iron that is released from organ-
elles during an ischemic or toxic insult. Reducing
available catalytic iron inhibits bacterial growth
and attenuates oxidative stress during organ injury
(20). A decade after its discovery, an elegantly
designed murine study that used a genome-wide
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Table 2. Recently discovered biomarkers.
Biomarker category
Functional biomarker
Urinary low-molecular-weight proteina
Cellular injury/stress-associated protein
Urinary tubular enzyme
Inflammatory mediatorb
a
Undergoes glomerular filtration and is reabsorbed without secretion.
b
Released by renal cells.
interrogation strategy showed that NGAL was one
of the maximally induced genes after initiation of
renal ischemia. It was expressed in renal tubular
cells and upregulated during an ischemic or toxic
insult, and its use as an early urinary biomarker of
AKI was suggested (21, 22).
In 2005, Mishra et al. (23) showed that NGAL was
a robust early biomarker of subclinical AKI in pedi-
atric patients after cardiopulmonary bypass; its el-
evation preceded any increase in serum creatinine
by 1–3 days, and the increase was sustained
throughout the duration of AKI. The area under the
receiver operating characteristic curve (AUC-ROC)
for prediction of AKI on the basis of the consensus
AKI definition was 0.99 and 0.90 for urine and se-
rum NGAL, respectively. A myriad of subsequent
studies evaluated the diagnostic and prognostic
value of urinary NGAL as a biomarker of AKI in var-
ious settings (20, 24–29). A multicenter prospective
study of 1635 patients showed that a single mea-
surement of urinary NGAL in the emergency de-
partment had better discriminatory ability to
predict intrinsic AKI (AUC-ROC of 0.81) than other
biomarkers (kidney injury molecule-1, urinary liver-
type fatty-acid-binding protein, urinary interleukin-
18, and cystatin C) (30). In a metaanalysis of 2538
patients (19 studies from 8 countries) that used a
uniform creatinine-based definition of AKI (defined
as Cr increase >50% within 7 days), the AUC-ROC
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Acute Kidney Injury Biomarkers
Example
Cystatin C, proenkephalin
α1-microglobulin, β2-microglobulin, retinol-binding protein, adenosine
deaminase-binding protein, cystatin C
Neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, liver-type
fatty-acid-binding protein, tissue inhibitor of metalloproteinase 2, and insulin-
like-growth-factor–binding protein 7
Proximal renal tubular epithelial antigen, α-glutathione S-transferase, pi-
glutathione S-transferase, γ-glutamyltranspeptidase, alanine aminopeptidase,
lactate dehydrogenase, N-acetyl-beta-glucosaminidase, alkaline phosphatase
Interleukin-18
of NGAL for predicting AKI across all settings was
0.83 (95% CI, 0.74 – 0.91) when using a median
cutoff value of >150 ng/mL (31, 32). Table 3 sum-
marizes subsequent metaanalyses showing the
diagnostic value of NGAL in specific subgroups
(33–37).
Ultimately, NGAL rises proportionally to the se-
verity and duration of renal injury, is expressed
very early after renal injury (within 1–3 h of renal
insult and 36 –72 h before any increase in creati-
nine), is obtained from a readily available source
(urine or plasma), and can be rapidly assayed. The
studies to compare the performance of NGAL in
urine vs blood are scarce. While it appears both
tests perform reasonably well, it seems urinary
NGAL may carry higher specificity for the AKI. Its
ability to predict AKI before clinical signs are evi-
dent can facilitate implementation of appropriate
preventive measures and improve resource utili-
zation. Although these characteristics make it a
promising biomarker, its performance is discrep-
ant in different settings, and existing studies have
used varying cutoff values that result in varying di-
agnostic accuracy. In addition, there are conflicting
data suggesting that age, race/ethnicity, preexist-
ing renal disease, and sample source (urine vs
plasma) may impact diagnostic accuracy. NGAL is
released by activated neutrophils during bacterial
infection and systemic inflammation and may
 Table 3. Summary of metaanalyses describing performance of the AKI biomarkers.

Patients, Sensitivity Specificity Diagnostic odds

Reference AKI setting No. (95% CI) (95% CI) ratio (95% CI) AUC-ROC Cutoff value
Neutrophil gelatinase-associated lipocalin
Haase et al. (31) All settings 2,538 0.76 (0.63–0.84) 0.89 (0.81–0.93) 18.6 (9.0–38.1) 0.83 (0.74–0.91) >150 ng/mL
Zhang et al. (32) With sepsis 433 0.83 (0.77–0.88) 0.57 (0.54–0.61) 14.72 (6.55–33.10) 0.86 Blood, variable
Acute Kidney Injury Biomarkers

Zhang et al. (32) With sepsis 1263 0.80 (0.77–0.83) 0.80 (0.77–0.83) 24.20 (9.92–59.05) 0.90 Urine, variable
Kim et al. (33) With sepsis 1060 0.88 (0.82–0.92) 0.47 (0.37–0.58) 6.64 (3.80–11.58) 0.88 (0.82–0.92) Blood, 150–400
ng/mL
Wang et al. (34) After contrast 1520 0.83 (0.73–0.91) 0.89 (0.81–0.93) 42.54 (16.74–108.10) 0.93 (0.90–0.95) Blood and urine,
31.9–100.0
ng/mL
Tong et al. (35) After contrast 1310 0.80 (0.74–0.85) 0.83 (0.73–0.90) 20.56 (9.67–43.74) 0.87 (0.84–0.90) Blood, 60–116
ng/mL
Urine, 52.4–100
ng/mL
Zhou et al. (36) After cardiac 4066 0.68 (0.65–0.70) 0.79 (0.77–0.80) 13.05 (7.85–21.70) 0.86 ...
surgery
Kidney injury molecule 1
Shao et al. (37) All settings 2979 0.74 (0.61–0.84) 0.86 (0.74–0.93) 17.43 (6.23–48.74) 0.86 (0.83–0.89) 0.42–2.82 ng/mg
Interleukin 18
Liu et al. (38) All settings 4512 0.58 (0.52–0.64) 0.75 (0.69–0.80) 4.22 (2.90–6.14) 0.70 (0.66–0.74) Urine, variable
Lin et al. (39) All settings 2796 0.51 (. . .) 0.79 (. . .) 5.11 (3.22–8.12) 0.77 (0.71–0.83) Urine, variable
Liver-type fatty-acid-binding protein
Susantitaphong All settings 687 0.74 (0.60–0.84) 0.77 (0.61–0.88) 2.69 (1.63–4.43) ... Urine, variable
et al. (40)
Tissue inhibitor of metalloproteinase 2 and insulin-like-growth-factor–binding protein 7 (combination)
Su et al. (41) All settings 1709 0.84 (0.80–0.88) 0.57 (0.55–0.60) 10.19 (6.23–16.67) 0.88 (0.79–0.97) 0.3–1.07 ng/mL
Abbreviations: AKI, acute kidney injury; AUC-ROC, the area under the receiver operating characteristic curve.

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increase in a graded manner with sepsis severity
(38). Synthesis of the antimicrobial protein NGAL is
dramatically increased in stimulated epithelia (in-
cluding inflamed or malignant colonic epithelium),
serum of patients with bacterial infection, sputum
of patients with asthma or chronic obstructive pul-
monary disease, and bronchial fluid from emphy-
sematous lung (39, 40). As such, optimal cutoff
values are unknown for these different clinical set-
tings, especially given that interference with alter-
native “nonrenal” sources may diminish the test
accuracy for diagnosing AKI. It is currently ap-
proved in Canada and Europe for clinical use
(41, 42).
Kidney injury molecule 1
Kidney injury molecule 1 (KIM-1) is a type-1
transmembrane protein that contains immuno-
globulin, highly O- and N-glycosylated mucin do-
mains in its ectodomain, and a relatively short
cytoplasmic tail (43). It is expressed in trace
amounts in the kidney's proximal tubular cells un-
der normal conditions, but its expression is dra-
matically upregulated in dedifferentiated proximal
tubule cells after an ischemic insult (43, 44). The
KIM-1 ectodomain is present in the urine after an
ischemic insult and is stable for an extended pe-
riod (45). Earlier studies showed increased urinary
KIM-1 levels in patients with biopsy-proven isch-
emic acute tubular necrosis (as compared with
other forms of AKI or chronic kidney disease) (44).
This finding launched the development of rapid
urine immunoassays and clinical studies exploring
its utility in various settings, including cardiopul-
monary bypass, cardiac catheterization, critical ill-
ness, and the emergency department (46, 47). In a
cohort of patients admitted to the intensive care
unit with normal renal function, KIM-1 detected
stage 2 or 3 AKI within 12 h of sample collection,
with an AUC-ROC of 0.69 (30). A recent metaanaly-
sis evaluated the utility of urinary KIM-1 for the
diagnosis of AKI across all settings—assay sensitiv-
ity was 74% (95% CI, 61%– 84%) and specificity was
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86% (95% CI, 74%–93%), with an AUC-ROC of 0.86
(95% CI, 0.83– 0.89) (Table 3) (46). The authors of
this metaanalysis found significant publication bias
and considerable heterogeneity among different
studies.
KIM-1 has clinical promise because of its ability
to detect early subclinical tubular injury with a
rapid and noninvasive test. However, diagnostic
accuracy may vary depending on the type of assay
used, patient age, clinical setting, cutoff used, tim-
ing of measurement, and other factors (46). It dem-
onstrated better sensitivity when an enzyme-
linked immunosorbent assay was used within
2–12 h of clinical insult, in cardiac surgery patients
with acute ischemic tubular necrosis, and in infants
or children as compared to adults (46). Its diagnos-
tic and prognostic value needs to be further vali-
dated in larger trials, and optimal cutoff values for
clinical use currently are undetermined. KIM-1 has
been approved by the US FDA as a biomarker for
preclinical drug development (48).
Interleukin 18
Interleukin 18 (IL 18) is a cytokine in the IL-1 su-
perfamily. It is synthesized by some cells, including
monocytes, macrophages, and proximal tubular
epithelial cells, as a 23-kDa inactive precursor and
is processed into an active 18.3-kDa cytokine by
caspase-1 (49). After being induced in the proximal
tubule, IL18 is released into the urine after cleav-
age by caspase-1 and can be measured in the
urine by use of an enzyme-linked immunosorbent
assay. In early animal models, Melnikov et al. (50)
reported that kidney IL18 increases in the setting
of ischemic AKI and induces tubular necrosis by
mediating ischemia-reperfusion injury and neutro-
phil and monocyte infiltration of the renal paren-
chyma. In a subsequent study, urinary IL18 levels
were shown to be markedly increased in human
subjects with acute tubular necrosis compared
with healthy subjects (51). The predictive accuracy
of IL18 for AKI has since been studied in various
clinical settings, including during cardiac surgery,
Acute Kidney Injury Biomarkers
in intensive care, after cardiac catheterization, and
after organ transplantation. In a multicenter pro-
spective study of 1635 patients, a single measure-
ment of IL18 in the emergency department had
poor discriminatory ability to predict intrinsic AKI
(AUC-ROC, 0.64) compared with other biomarkers
(uNGAL, uIL18, uLFABP, uCysC and uKIM-1) (30). In
a 2013 metaanalysis that included various clinical
settings, the sensitivity and specificity of IL18 to
predict AKI was 0.58 and 0.75, respectively, with
an AUC-ROC of 0.70 (Table 3) (52). IL18 may have
better diagnostic accuracy in children and adoles-
cents after cardiac surgery (52), but the metaanaly-
sis was limited by high heterogeneity, different
definitions of AKI, and different diagnostic cutoffs.
Altogether, the studies suggest that urinary IL18
levels rise early in ischemic kidney injury (approxi-
mately 12 h before clinical AKI) and can be rapidly
and affordably measured. The predictive accuracy
of IL18 may differ depending on age (with better
diagnostic accuracy in adolescents and children),
time of obtainment, and reference range.
However, combining IL18 with other biomarkers
improves its performance in predicting AKI. Fur-
ther appropriately designed studies are warranted
to elucidate the optimal time, cutoff, and setting in
which IL18 would be a useful biomarker for AKI.
Liver-type fatty-acid-binding protein
Liver-type fatty-acid-binding protein (L-FABP),
also termed FABP-1, is part of a family of 14- to
15-kDa cytosolic proteins that function in intracel-
lular lipid trafficking and endogenous cytoprotec-
tion by reducing oxidative stress in ischemia-
reperfusion. It is highly expressed in the liver but is
also expressed in the kidneys, lung, pancreas, and
intestine (53). In the kidney, L-FABP is expressed in
the proximal tubules, where fatty acids are used as
a primary source of energy metabolism (54). Free
fatty acids are filtered through the glomeruli and
reabsorbed into the proximal tubules, where they
bind L-FABP and are transported to mitochondria
or peroxisomes and metabolized through β-
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oxidation (55). The FABP14 gene is responsive to
hypoxic stress, and a rise in urine L-FABP levels
reflects the stress of proximal tubular cells (56). In
a murine model of cisplatin-induced kidney injury,
increased urinary L-FABP levels preceded a rise in
creatinine by 72 h (57). In human studies, L-FABP
was measured in the urine of patients immediately
after reperfusion of living-related kidney trans-
plant, and a significant correlation was observed
between urine L-FABP levels and both peritubular
capillary blood flow and ischemic time of the trans-
planted kidney (54). Among patients undergoing
abdominal aortic aneurysm repair, preoperative
urinary L-FABP levels in endovascular repair and 4
h after open repair predicted AKI with an AUC-ROC
of 0.83 and 0.77, respectively (58). When combined
with NGAL, L-FABP measured 0 –2 h after cardiac
surgery in adults predicted AKI with an AUC-ROC of
0.91– 0.93 (59). A prospective pilot study of pa-
tients with chronic kidney disease undergoing cor-
onary angiography showed that L-FABP levels in
patients who ultimately had AKI were significantly
higher, even before contrast administration, and
were predictive of AKI with an AUC-ROC of 0.70
(60). Similarly, increased baseline L-FABP was
linked with a high risk of AKI after an allogeneic
stem cell transplant (61). In the critical care setting,
urinary L-FABP predicted AKI with an AUC-ROC of
0.75 (62).
Urinary L-FABP levels, which can be tested with
solid-phase enzyme-linked immunosorbent assay
on the basis of the sandwich principle with a work-
ing time of 3.5 h, have a moderate predictive value
for AKI development, with increased levels reflect-
ing underlying ischemic tubular stress. Studies
also demonstrate its ability to predict AKI even be-
fore an ischemic insult (60, 61). However, increased
serum concentrations of L-FABP have recently
been shown with obesity, insulin resistance, and
high blood pressure, all in the absence of acute
tissue injury (63, 64). Studies have also suggested it
could be an early biomarker for lung damage in
moderate acute respiratory failure and a diagnostic
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marker for nonalcoholic hepatic steatosis (65,
66). Although the contribution of serum L-FABP to
urinary L-FABP may be minimal, as suggested by
Kamijo et al. (67), the test needs validation across a
spectrum of clinical settings to determine optimal
cutoff values. It is currently approved in Japan for
clinical use (41).
Tissue inhibitor of metalloproteinase 2 and
insulin-like-growth-factor– binding protein 7
Tissue inhibitor of metalloproteinase 2 (TIMP2)
and insulin-like-growth-factor– binding protein 7
(IGFBP7) are cell-cycle arrest proteins expressed
in renal tubular cells during cellular stress (41). In
addition to inhibiting matrix metalloproteinase,
TIMP2 regulates the cell cycle by directly stimulat-
ing cell division or inducing G1 cell-cycle arrest,
depending on the context (41, 68). IGFBP7 is a se-
creted protein and member of the IGFBP super-
family. It has also been implicated in the G1 cell-
cycle arrest phase, which occurs promptly with
cellular stress. The urinary test for the product of
[TIMP2] [IGFBP7] was the first AKI biomarker ap-
proved by the US FDA after a series of studies re-
vealed promising performance.
Four large premarketing studies were conducted;
the first study (Sapphire study) involved a multi-
center, international, heterogeneous sample of
critically ill patients without evidence of AKI at en-
rollment. Published in 2013, the Sapphire study
(69) was a 2-stage study with discovery and valida-
tion phases. The Discovery study recruited 522
critically ill adults with at least 1 risk factor for AKI
development, and 340 candidate biomarkers were
assessed for their ability to predict AKI. Urine
TIMP2 and IGFBP7 were identified as the best-per-
forming biomarkers, with an AUC-ROC of 0.75 and
0.77, respectively. The product of TIMP2 and
IGFBP7 was superior to all previously described
biomarkers, including NGAL, KIM-1, IL18, and L-
FABP in that specific cohort, with an AUC-ROC of
0.80. The [TIMP2] [IGFBP7] assay was then vali-
dated in the Sapphire cohort. The primary end
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point was stage 2 or 3 AKI (Kidney Disease: Improv-
ing Global Outcomes criteria) within 12 h of enroll-
ment; this end point was reached by 102 out of
728 patients (14%). The test demonstrated a high
sensitivity and negative predictive value with a cut-
off value of 0.3 (ng/mL)2/1000 and a high specificity
with high positive predictive value with a cutoff
value of 2.0 (ng/mL)2/1000. Another multicenter
validation study, Opal, was performed; 154 criti-
cally ill adults were enrolled, and 27 had the pri-
mary end point (stage 2–3 AKI within 12 h) (70).
At the 0.3 (ng/mL)2/1000 cutoff value, the
[TIMP2] [IGFBP7] assay predicted AKI in the next
12 h with a sensitivity of 89% and a negative
predictive value of 97%. At the 2.0 (ng/mL)2/1000
cutoff, the test's specificity was 95%, and the
positive predictive value was 49%. Finally,
the Topaz study further validated the use of
[TIMP2] [IGFBP7] in critically ill adult patients;
the primary end point was stage 2 or 3 AKI within
12 h of enrollment, as determined by 3 AKI ex-
perts (71).
In 2014, these studies led to US FDA approval of
the test (NephroCheck; Astute Medical), which is a
fluorescence lateral flow immunoassay of the urinary
concentrations of [TIMP2] and [IGFBP7], displaying
the result as the product of the 2 proteins as the AKI
risk score [(ng/mL)2/1000]. The turnaround time of
this test is only 20 min. It has since been studied in
various settings, including cardiopulmonary bypass,
high-risk surgery, and pediatrics (72–75). As with
other biomarkers, the studies have reported varying
accuracy, mainly due to heterogeneity in study de-
sign, cutoff values, and clinical settings, with AUC-
ROC ranging from 0.70 – 0.97 (38). Limitations of the
NephroCheck fluorescence immunoassay include
the cost, interference by urine bilirubin (at concen-
tration ≥72 mg/dL) and albumin (at concentrations
≥1250 mg/L), and the relatively rapid decline in levels
after the initial renal insult (instead of a graded rise in
levels with increasing severity of AKI) (41, 76). Cur-
rently, the point-of-care NephroCheck device costs
approximately $5000, with the cartridge for 1 test
 Table 4. Summary of biomarker characteristics.
Biomarker Characteristics
NGAL A protease-resistant, 25-kDa
polypeptide of the lipocalin
superfamily
KIM-1 A 38.7-kDa type-1 transmembrane
protein that contains
immunoglobulin, highly O- and
N-glycosylated mucin domains in
its ectodomain and a relatively
short cytoplasmic tail
IL18 A cytokine of the IL-1 superfamily
with a 23-kDa inactive precursor
processed by caspase-1 into an
active 18.3-kDa cytokine
L-FABP A 14- to 15-kDa cytosolic proteins
[TIMP2] [IGFBP7] TIMP-2 is a 21-kDa protein, and
IGFBP7 is a 29-kDa protein
November 2017 | 02:03 | 000 | JALM
9
.................................................................................................
Advantages
• Rises proportional to severity
and duration of renal injury
expressed early (36–72 h
before clinical AKI)
• Expressed within 1–3 h of
kidney injury
• Approved by the FDA in the
US for preclinical drug
development
• Expressed early (@12 h before • Maybe elevated in urinary tract
clinical AKI)
• Expressed within 0–2 h of
kidney injury
• Highly sensitive early
biomarker of AKI (12 h before
stage 2 and 3 AKI)
• Approved by the FDA for
clinical use
Sample
Limitations type Methodology
Maybe elevated in stimulated epithelia Blood and Immunoassay
(colonic, bronchial), elevated in serum urine Turbidimetric
Acute Kidney Injury Biomarkers
of patients with sepsis and chronic assay
kidney disease. Ideal cutoff value is
unknown
• Diagnostic accuracy may vary Urine Immunoassay
depending on patient age, clinical
setting (best performance in ischemic
ATN), and timing of measurement
from initial insult
• Ideal cutoff value is unknown
Urine Immunoassay
infection, chronic renal insufficiency,
lung injury, and myocardial ischemia
• Maybe elevated in obesity, insulin Urine Immunoassay
resistance, high blood pressure,
nonalcoholic hepatic steatosis, and
moderate acute respiratory failure
• Interference by urine bilirubin (falsely Urine Immunoassay
reduces) and albumin (falsely elevates)
• The decline in levels after initial renal
insult occurs within the first 24–48 h
• High cost
REVIEW
REVIEW Acute Kidney Injury Biomarkers

being approximately $85. The cost– benefit of testing

unknown given the field is yet in its infancy, and there
have not been studies establishing that early recog-
nition of AKI with use of these biomarkers will lead to
reduced disease progression, morbidity, mortality,
or total hospital cost (41). In hospitalized critically ill
patients, a value of 0.3 (ng/mL)2/1000 is associated
with 7 times the risk of developing moderate to se-
vere AKI within 12 h of assessment (71). However,
given the poor specificity at a cutoff value of 0.3 (ng/
mL)2/1000, especially if used by nonexperts in a low-
risk setting, false-positive results would be expected
and could lead to inappropriate use of resources (i.e., Fig. 1. Incorporating the injury biomarkers in
nephrology consultation, renal ultrasound, addi- the definition of acute kidney injury.
tional laboratory evaluation). AKIN, Acute Kidney Injury Network; RIFLE, risk, injury, fail-
ure, loss, end-stage kidney disease.

Other markers
Other potential biomarkers of AKI include mi-
croRNAs, urinary low-molecular-weight proteins,
and urinary tubular enzymes. All of these possible
biomarkers require further study (Table 2).
COMBINING BIOMARKERS TO PREDICT
AKI
An approach that has gained more popularity is
the use of a panel of biomarkers that differ in origin
(within the renal parenchyma) to more accurately
predict AKI. Biomarker panels have been devel-
oped for differentiation and early diagnosis of AKI,
predicting the AKI progress, assessing its severity,
and predicting mortality. In a prospective multi-
center cohort study of 1219 adults and 311 chil-
dren undergoing cardiac surgery, a panel of
biomarkers (KIM-1, IL18, and NGAL, obtained at
distinct time points postoperatively) improved dis-
crimination of AKI compared with individual bio-
markers (48). Similarly, the product of TIMP2 and
IGFBP7 performed better than either entity alone
when predicting AKI in critically ill patients (69). In
adult patients undergoing cardiac surgery, a com-
bination of NGAL and L-FABP (the latter measured
0 –2 h after surgery) performed well, with an AUC-
ROC of 0.91– 0.93 (59). As our knowledge of the
biologic roles of the identified biomarkers improves,
specific panels may be developed that will help dis-
criminate the potential underlying causes of AKI,
progress of AKI, and overall prognosis (77). Table 4
provides a summary of each biomarker characteris-
tics including their advantages and limitations when
they are utilized in the clinical setting.
CLINICAL IMPLEMENTATION OF AKI
BIOMARKERS
Despite the progress that has been made in
identifying AKI biomarkers, their use has not been
widely accepted in clinical practice. Investigators
from the 10th Consensus Conference of the Acute
Dialysis Quality Initiative recommended incorpora-
tion of novel AKI biomarkers within the definition of
AKI (17). They posited that use of biomarkers to de-
termine the extent and location of injury could result
in a more targeted and individualized treatment ap-
proach for each patient with AKI than with current
AKI definitions, including the RIFLE (risk, injury, failure,
loss, end-stage kidney disease) (78) or AKIN (Acute
Kidney Injury Network) criteria (79) (Fig. 1).

....................................................................................................

10 JALM | 000 | 02:03 | November 2017

Acute Kidney Injury Biomarkers
Fig. 2. Incorporating acute kidney injury biomarkers in the clinical practice.
When providers identify individuals with high
AKI risk after clinical evaluation, biomarkers
could then be used to further risk-stratify pa-
tients and efficiently direct resources toward
preventing AKI development or its progression
(Fig. 2).
Conclusion
The past century has seen a shift in the practice
of critical care medicine from anticipatory to pre-
ventive. Early, biomarker-based identification of
patients at risk of AKI development is a fundamen-
tal step toward AKI prevention. The present litera-
ture validating AKI biomarkers is heterogeneous in
study design, in the optimization of the diagnostic
standards, in the test cutoff values, in the time of
obtainment, and in the clinical context; this heter-
ogeneity makes immediate extrapolation of the
data to clinical practice difficult. Moreover, the use
of creatinine as the diagnostic reference criterion
has major shortcomings because it does not de-
tect subclinical AKI and may undermine the speci-
ficity of the tests. Additionally, the performance of
certain biomarkers may be affected by specific
clinical settings (e.g., the use of L-FABP to predict
...................................................................................................
November 2017 | 02:03 | 000 | JALM
REVIEW
AKI in a patient with an underlying metabolic syn-
drome or nonalcoholic hepatic steatosis; or use of
NGAL in patients with sepsis). The pathophysiology
of AKI is very complex, with several distinct patho-
genic mechanisms. As such, a single biomarker
may not hold equal sensitivity and specificity com-
pared with a distinct biomarker profile matched to
the patient's predisposition and exposure history.
As we gain further insights into the biologic func-
tion of biomarkers, development of biomarker
panels to match the distinct disease processes will
help improve test performance.
The future of AKI biomarkers remains exciting,
but further steps are necessary before their clin-
ical use is broadly accepted, including validation
across a spectrum of settings and identification
of discriminatory cutoff values. More research
is needed to validate the benefits and cost-
effectiveness of using biomarkers for early im-
plementation of nephroprotective strategies in
patients at risk. Early recognition of patients at
risk of AKI will allow interventional studies to cor-
roborate whether recognizing these patients
and implementing early nephroprotective care
will improve outcomes such as dialysis require-
ments and mortality rates.
11
REVIEW
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following
4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b)
drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for
all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately
investigated and resolved.
Authors’ Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.
REFERENCES
1. Section 2: AKI Definition. Kidney inter, Suppl. 2012;2(1):
19 –36.
2. Susantitaphong P, Cruz DN, Cerda J, Abulfaraj M,
Alqahtani F, Koulouridis I, et al. World incidence of AKI: a
meta-analysis. Clin J Am Soc Nephrol 2013;8(9):1482–93.
3. Mehta RL, Cerdá J, Burdmann EA, Tonelli M, García-
García G, Jha V, et al. International Society of
Nephrology's 0by25 initiative for acute kidney injury
(zero preventable deaths by 2025): a human rights case
for nephrology. Lancet 2015;385(9987):2616 – 43.
4. Bouchard J, Mehta RL. Acute kidney injury in western
countries. Kidney Diseases 2016;2(3):103–10.
5. Coca SG, Singanamala S, Parikh CR. Chronic kidney
disease after acute kidney injury: a systematic review and
meta-analysis. Kidney Int 2012;81(5):442– 8.
6. Steven GC, Bushra Y, Michael GS, Amit XG, Chirag RP.
Long-term risk of mortality and other adverse outcomes
after acute kidney injury: a systematic review and meta-
analysis. Am J Kidney Dis 2009;53(6):961–73.
7. Lameire NH, Bagga A, Cruz D, De Maeseneer J, Endre Z,
Kellum JA, et al. Acute kidney injury: an increasing global
concern. Lancet 2013;382(9887):170 –9.
8. Cerda J, Lameire N, Eggers P, Pannu N, Uchino S, Wang
H, et al. Epidemiology of acute kidney injury. Clin J Am
Soc Nephrol 2008;3(3):881– 6.
9. Silver SA, Long J, Zheng Y, Chertow GM. Cost of acute
kidney injury in hospitalized patients. J Hosp Med 2017;
12(2):70 – 6.
10. Edelstein C. Biomarkers of kidney disease. Boston (MA):
Elsevier; 2016.
11. MacLeod A. NCEPOD report on acute kidney injury—
must do better. Lancet 2009;374(9699):1405– 6.
12. Sutherland SM, Chawla LS, Kane-Gill SL, Hsu RK, Kramer
AA, Goldstein SL, et al. Utilizing electronic health records
to predict acute kidney injury risk and outcomes:
workgroup statements from the 15th ADQI Consensus
Conference. Can J Kidney Health Dis 2016;3:11.
13. Hoste EAJ, Kashani K, Gibney N, Wilson FP, Ronco C,
Goldstein SL, et al. Impact of electronic-alerting of acute
kidney injury: workgroup statements from the 15th ADQI
Consensus Conference. Can J Kidney Health Dis 2016;
3(1):1–9.
14. Bellomo R, Kellum JA, Ronco C. Defining acute renal
failure: physiological principles. Intensive Care Med 2004;
30(1):33–7.
15. Makris K, Spanou L. Acute kidney injury: diagnostic
....................................................................................................
12 JALM | 000 | 02:03 | November 2017
Acute Kidney Injury Biomarkers
approaches and controversies. Clin Biochem Rev 2016;
37(4):153–75.
16. Kashani K, Cheungpasitporn W, Ronco C. Biomarkers of
acute kidney injury: the pathway from discovery to clinical
adoption. Clin Chem Lab Med. 2017;55(8):1074 – 89.
17. McCullough PA, Bouchard J, Waikar SS, Siew ED, Endre ZH,
Goldstein SL, et al. Implementation of novel biomarkers in
the diagnosis, prognosis, and management of acute kidney
injury: executive summary from the tenth consensus
conference of the Acute Dialysis Quality Initiative (ADQI).
Contrib Nephrol 2013;182:5–12.
18. Kjeldsen L, Johnsen AH, Sengelov H, Borregaard N.
Isolation and primary structure of NGAL, a novel protein
associated with human neutrophil gelatinase. J Biol
Chem 1993;268(14):10425–32.
19. Cowland JB, Borregaard N. Molecular characterization
and pattern of tissue expression of the gene for
neutrophil gelatinase-associated lipocalin from humans.
Genomics 1997;45(1):17–23.
20. Haase M, Devarajan P, Haase-Fielitz A, Bellomo R, Cruz
DN, Wagener G, et al. The outcome of neutrophil
gelatinase-associated lipocalin-positive subclinical acute
kidney injury: a multicenter pooled analysis of
prospective studies. J Am Coll Cardiol 2011;57(17):
1752– 61.
21. Mishra J, Ma Q, Prada A, Mitsnefes M, Zahedi K, Yang J,
et al. Identification of neutrophil gelatinase-associated
lipocalin as a novel early urinary biomarker for ischemic
renal injury. J Am Soc Nephrol 2003;14(10):2534 – 43.
22. Mishra J, Mori K, Ma Q, Kelly C, Yang J, Mitsnefes M, et al.
Amelioration of ischemic acute renal injury by neutrophil
gelatinase-associated lipocalin. J Am Soc Nephrol 2004;
15(12):3073– 82.
23. Mishra J, Dent C, Tarabishi R, Mitsnefes MM, Ma Q, Kelly
C, et al. Neutrophil gelatinase-associated lipocalin (NGAL)
as a biomarker for acute renal injury after cardiac
surgery. Lancet 2005;365(9466):1231– 8.
24. Rostami Z, Nikpoor M, Einollahi B. Urinary neutrophil
gelatinase associated lipocalin (NGAL) for early diagnosis
of acute kidney injury in renal transplant recipients.
Nephrourol Mon 2013;5(2):745–52.
25. Makris K, Markou N, Evodia E, Dimopoulou E,
Drakopoulos I, Ntetsika K, et al. Urinary neutrophil
gelatinase-associated lipocalin (NGAL) as an early marker
of acute kidney injury in critically ill multiple trauma
patients. Clin Chem Lab Med 2009;47(1):79 – 82.
26. Au V, Feit J, Barasch J, Sladen RN, Wagener G. Urinary
Acute Kidney Injury Biomarkers
neutrophil gelatinase-associated lipocalin (NGAL)
distinguishes sustained from transient acute kidney
injury after general surgery. Kidney Int Rep 2016;1(1):
3–9.
27. Feldkamp T, Bienholz A, Kribben A. Urinary neutrophil
gelatinase-associated lipocalin (NGAL) for the detection
of acute kidney injury after orthotopic liver
transplantation. Nephrol Dial Transplant
2011;26(5):1456 – 8.
28. Perrin T, Descombes E, Magnin JL, Gachet M, Hemett
OM, Hayoz D, et al. Urinary neutrophil gelatinase-
associated lipocalin (uNGAL) and contrast-induced acute
kidney injury after coronary angiogram. Swiss Med Wkly
2013;143:w13853.
29. Wagener G, Gubitosa G, Wang S, Borregaard N, Kim M,
Lee HT. Urinary neutrophil gelatinase-associated
lipocalin and acute kidney injury after cardiac surgery.
Am J Kidney Dis 2008;52(3):425–33.
30. Nickolas TL, Schmidt-Ott KM, Canetta P, Forster C, Singer
E, Sise M, et al. Diagnostic and prognostic stratification in
the emergency department using urinary biomarkers of
nephron damage: a multicenter prospective cohort
study. J Am Coll Cardiol 2012;59(3):246 –55.
31. Haase M, Bellomo R, Haase-Fielitz A. Neutrophil
gelatinase-associated lipocalin. Curr Opin Crit Care 2010;
16(6):526 –32.
32. Michael H, Rinaldo B, Prasad D, Peter S, Anja H-F.
Accuracy of neutrophil gelatinase-associated lipocalin
(NGAL) in diagnosis and prognosis in acute kidney injury:
a systematic review and meta-analysis. Am J Kidney Dis
2009;54(6):1012–24.
33. Zhang A, Cai Y, Wang P-F, Qu J-N, Luo Z-C, Chen X-D,
et al. Diagnosis and prognosis of neutrophil gelatinase-
associated lipocalin for acute kidney injury with sepsis: a
systematic review and meta-analysis. Crit Care
2016;20(1):1–13.
34. Kim S, Kim HJ, Ahn HS, Song JY, Um TH, Cho CR, et al. Is
plasma neutrophil gelatinase-associated lipocalin a
predictive biomarker for acute kidney injury in sepsis
patients? A systematic review and meta-analysis. J Crit
Care 2016;33:213–23.
35. Wang K, Duan CY, Wu J, Liu Y, Bei WJ, Chen JY, et al.
Predictive value of neutrophil gelatinase-associated
lipocalin for contrast-induced acute kidney injury after
cardiac catheterization: a meta-analysis. Can J Cardiol.
2016;32(8):1033.e19 –29.
36. Tong J, Li H, Zhang H, Luo Z, Huang Y, Huang J, et al.
Neutrophil gelatinase-associated lipocalin in the
prediction of contrast-induced nephropathy: a systemic
review and meta-analysis. J Cardiovasc Pharmacol 2015;
66(3):239 – 45.
37. Zhou F, Luo Q, Wang L, Han L. Diagnostic value of
neutrophil gelatinase-associated lipocalin for early
diagnosis of cardiac surgery-associated acute kidney
injury: a meta-analysis. Eur J Cardiothoracic Surg 2016;
49(3):746 –55.
38. Dai X, Zeng Z, Fu C, Zhang S, Cai Y, Chen Z. Diagnostic
value of neutrophil gelatinase-associated lipocalin,
...................................................................................................
November 2017 | 02:03 | 000 | JALM
REVIEW
cystatin C, and soluble triggering receptor expressed on
myeloid cells-1 in critically ill patients with sepsis-
associated acute kidney injury. Crit Care 2015;19:223.
39. Keatings VM, Barnes PJ. Granulocyte activation markers
in induced sputum: comparison between chronic
obstructive pulmonary disease, asthma, and normal
subjects. Am J Respir Crit Care Med 1997;155(2):449 –53.
40. Betsuyaku T, Nishimura M, Takeyabu K, Tanino M,
Venge P, Xu S, et al. Neutrophil granule proteins in
bronchoalveolar lavage fluid from subjects with
subclinical emphysema. Am J Respir Crit Care Med 1999;
159(6):1985–91.
41. Vijayan A, Faubel S, Askenazi DJ, Cerda J, Fissell WH,
Heung M, et al. Clinical use of the urine biomarker [TIMP-
2] × [IGFBP7] for acute kidney injury risk assessment. Am
J Kidney Dis 2016;68(1):19 –28.
42. Schinstock CA, Semret MH, Wagner SJ, Borland TM,
Bryant SC, Kashani KB, et al. Urinalysis is more specific
and urinary neutrophil gelatinase-associated lipocalin is
more sensitive for early detection of acute kidney injury.
Nephrol Dial Transplantation 2013;28(5):1175– 85.
43. Ichimura T, Bonventre JV, Bailly V, Wei H, Hession CA,
Cate RL, et al. Kidney injury molecule-1 (KIM-1), a putative
epithelial cell adhesion molecule containing a novel
immunoglobulin domain, is up-regulated in renal cells
after injury. J Biol Chem 1998;273(7):4135– 42.
44. Han WK, Bailly V, Abichandani R, Thadhani R, Bonventre
JV. Kidney injury molecule-1 (KIM-1): a novel biomarker
for human renal proximal tubule injury. Kidney Int 2002;
62(1):237– 44.
45. Vaidya VS, Ramirez V, Ichimura T, Bobadilla NA,
Bonventre JV. Urinary kidney injury molecule-1: a
sensitive quantitative biomarker for early detection of
kidney tubular injury. Am J Physiol 2006;290(2):F517–29.
46. Shao X, Tian L, Xu W, Zhang Z, Wang C, Qi C, et al.
Diagnostic value of urinary kidney injury molecule 1 for
acute kidney injury: a meta-analysis. PLoS One 2014;9(1):
e84131.
47. Vaidya VS, Ford GM, Waikar SS, Wang Y, Clement MB,
Ramirez V, et al. A rapid urine test for early detection of
kidney injury. Kidney Int 2009;76(1):108 –14.
48. Parikh CR, Thiessen-Philbrook H, Garg AX, Kadiyala D,
Shlipak MG, Koyner JL, et al. Performance of kidney injury
molecule-1 and liver fatty acid-binding protein and
combined biomarkers of AKI after cardiac surgery. Clin J
Am Soc Nephrol 2013;8(7):1079 – 88.
49. Lin X, Yuan J, Zhao Y, Zha Y. Urine interleukin-18 in
prediction of acute kidney injury: a systemic review and
meta-analysis. J Nephrol 2015;28(1):7–16.
50. Melnikov VY, Ecder T, Fantuzzi G, Siegmund B, Lucia MS,
Dinarello CA, et al. Impaired IL-18 processing protects
caspase-1-deficient mice from ischemic acute renal
failure. J Clin Invest 2001;107(9):1145–52.
51. Parikh CR, Jani A, Melnikov VY, Faubel S, Edelstein CL.
Urinary interleukin-18 is a marker of human acute tubular
necrosis. Am J Kidney Dis 2004;43(3):405–14.
52. Liu Y, Guo W, Zhang J, Xu C, Yu S, Mao Z, et al. Urinary
13
REVIEW
interleukin 18 for detection of acute kidney injury: a meta-
analysis. Am J Kidney Dis 2013;62(6):1058 – 67.
53. Wang G, Bonkovsky HL, de Lemos A, Burczynski FJ.
Recent insights into the biological functions of liver fatty
acid binding protein 1. J Lipid Res 2015;56(12):2238 – 47.
54. Yamamoto T, Noiri E, Ono Y, Doi K, Negishi K, Kamijo A, et al.
Renal L-type fatty acid binding protein in acute ischemic
injury. J Am Soc Nephrol 2007;18(11):2894 –902.
55. Kamijo-Ikemori A, Kimura K. Urinary liver-type fatty acid
binding protein and chronic kidney disease. Indian J
Nephrol 2015;25(5):263– 4.
56. Susantitaphong P, Siribamrungwong M, Doi K, Noiri E,
Terrin N, Jaber BL. Performance of urinary liver-type fatty
acid-binding protein in acute kidney injury: a meta-
analysis. Am J Kidney Dis 2013;61(3):430 –9.
57. Negishi K, Noiri E, Sugaya T, Li S, Megyesi J, Nagothu K, et al.
A role of liver fatty acid-binding protein in cisplatin-induced
acute renal failure. Kidney Int 2007;72(3):348 –58.
58. Obata Y, Kamijo-Ikemori A, Ichikawa D, Sugaya T, Kimura
K, Shibagaki Y, et al. Clinical usefulness of urinary liver-
type fatty-acid-binding protein as a perioperative marker
of acute kidney injury in patients undergoing
endovascular or open-abdominal aortic aneurysm
repair. J Anesth 2016;30(1):89 –99.
59. Liu S, Che M, Xue S, Xie B, Zhu M, Lu R, et al. Urinary
L-FABP and its combination with urinary NGAL in early
diagnosis of acute kidney injury after cardiac surgery in
adult patients. Biomarkers 2013;18(1):95–101.
60. Manabe K, Kamihata H, Motohiro M, Senoo T, Yoshida S,
Iwasaka T. Urinary liver-type fatty acid-binding protein
level as a predictive biomarker of contrast-induced acute
kidney injury. Eur J Clin Invest 2012;42(5):557– 63.
61. Shingai N, Morito T, Najima Y, Igarashi A, Kobayashi T,
Doki N, et al. Urinary liver-type fatty acid-binding protein
linked with increased risk of acute kidney injury after
allogeneic stem cell transplantation. Biol Blood Marrow
Transplant 2014;20(12):2010 – 4.
62. Doi K, Negishi K, Ishizu T, Katagiri D, Fujita T, Matsubara
T, et al. Evaluation of new acute kidney injury biomarkers
in a mixed intensive care unit. Crit Care Med
2011;39(11):2464 –9.
63. Shi J, Zhang Y, Gu W, Cui B, Xu M, Yan Q, et al. Serum liver
fatty acid binding protein levels correlate positively with
obesity and insulin resistance in Chinese young adults.
PLoS One 2012;7(11):e48777.
64. Ishimura S, Furuhashi M, Watanabe Y, Hoshina K, Fuseya
T, Mita T, et al. Circulating levels of fatty acid-binding
protein family and metabolic phenotype in the general
population. PLoS One 2013;8(11):e81318.
65. Akbal E, Kocak E, Akyurek O, Koklu S, Batgi H, Senes M.
Liver fatty acid-binding protein as a diagnostic marker for
non-alcoholic fatty liver disease. Wien Klin Wochenschr
2016;128(1–2):48 –52.
66. Lachmann RA, Werchan S, Schachtrup C, Haitsma JJ,
Spener F, Lachmann B. Liver-type fatty acid binding
protein in serum and broncho-alveolar lavage in a model
of acute respiratory failure because of surfactant
....................................................................................................
14 JALM | 000 | 02:03 | November 2017
Acute Kidney Injury Biomarkers
depletion—a possible marker for lung damage? Clin
Physiol Funct Imaging 2006;26(6):371–5.
67. Kamijo A, Sugaya T, Hikawa A, Yamanouchi M, Hirata Y,
Ishimitsu T, et al. Urinary liver-type fatty acid binding
protein as a useful biomarker in chronic kidney disease.
Mol Cell Biochem 2006;284(1–2):175– 82.
68. Liu XW, Taube ME, Jung KK, Dong Z, Lee YJ, Roshy S, et al.
Tissue inhibitor of metalloproteinase-1 protects human
breast epithelial cells from extrinsic cell death: a
potential oncogenic activity of tissue inhibitor of
metalloproteinase-1. Cancer Res 2005;65(3):898 –906.
69. Kashani K, Al-Khafaji A, Ardiles T, Artigas A, Bagshaw SM,
Bell M, et al. Discovery and validation of cell cycle arrest
biomarkers in human acute kidney injury. Crit Care 2013;
17(1):R25.
70. Hoste EAJ, McCullough PA, Kashani K, Chawla LS,
Joannidis M, Shaw AD, et al. Derivation and validation of
cutoffs for clinical use of cell cycle arrest biomarkers.
Nephrol Dial Transplantation. 2014;29(11):2054 – 61.
71. Bihorac A, Chawla LS, Shaw AD, Al-Khafaji A, Davison DL,
DeMuth GE, et al. Validation of cell-cycle arrest
biomarkers for acute kidney injury using clinical
adjudication. Am J Respir Crit Care Med 2014;189(8):
932–9.
72. Gunnerson KJ, Shaw AD, Chawla LS, Bihorac A, Al-Khafaji
A, Kashani K, et al. TIMP2*IGFBP7 biomarker panel
accurately predicts acute kidney injury in high-risk
surgical patients. J Trauma Acute Care Surg 2016;80(2):
243–9.
73. Meersch M, Schmidt C, Van Aken H, Martens S, Rossaint
J, Singbartl K, et al. Urinary TIMP-2 and IGFBP7 as early
biomarkers of acute kidney injury and renal recovery
following cardiac surgery. PLoS One 2014;9(3):e93460.
74. Gocze I, Koch M, Renner P, Zeman F, Graf BM, Dahlke
MH, et al. Urinary biomarkers TIMP-2 and IGFBP7 early
predict acute kidney injury after major surgery. PLoS
One 2015;10(3):e0120863.
75. Pilarczyk K, Edayadiyil-Dudasova M, Wendt D,
Demircioglu E, Benedik J, Dohle DS, et al. Urinary [TIMP-
2]*[IGFBP7] for early prediction of acute kidney injury
after coronary artery bypass surgery. Ann Intensive Care
2015;5(1):50.
76. Uettwiller-Geiger DL, Vijayendran R, Kellum JA, Fitzgerald
RL. Analytical characteristics of a biomarker-based risk
assessment test for acute kidney injury (AKI). Clinica
Chimica Acta. 2016;455:93– 8.
77. Lisowska-Myjak B. Serum and urinary biomarkers of
acute kidney injury. Blood Purif 2010;29(4):357– 65.
78. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P.
Acute renal failure— definition, outcome measures,
animal models, fluid therapy and information technology
needs: the Second International Consensus Conference
of the Acute Dialysis Quality Initiative (ADQI) Group. Crit
Care 2004;8(4):R204 –12.
79. Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C,
Warnock DG, et al. Acute Kidney Injury Network: report
of an initiative to improve outcomes in acute kidney
injury. Crit Care 2007;11(2):R31.