Pediatr Nephrol

DOI 10.1007/s00467-016-3445-y

ORIGINAL ARTICLE

Predictive ability of urinary biomarkers for outcome

in children with acute kidney injury
Om P. Mishra 1 & Avinash K. Rai 1 & Pradeep Srivastava 4 & Khushaboo Pandey 3 &
Abhishek Abhinay 1 & Rajniti Prasad 1 & Rabindra N Mishra 2 & Franz Schaefer 5

Received: 28 November 2015 / Revised: 16 May 2016 / Accepted: 16 May 2016

# IPNA 2016

Abstract [confidence interval (CI) 0.580–0.920], followed by NAG at

Background Urinary neutrophil gelatinase-associated lipocalin
(NGAL), N-acetyl-beta-D-glucosaminidase (NAG), and inter-
leukin 18 (IL-18) were found to be useful for early detection of
acute kidney injury (AKI). The objective of this study was to
determine the predictive ability of biomarkers for mortality and
variation in levels in relation to different stages of AKI, need
for dialysis, etiologies, and with duration of hospital stay.
Methods Urinary NGAL, NAG, and IL-18 levels were mea-
sured in 50 children with AKI and 30 age- and gender-
matched healthy controls. AKI was classified as per pediatric
Risk, Injury, Failure, Loss, and End-stage (RIFLE) criteria.
Results Median NGAL, NAG, and IL-18 values were signif-
icantly increased in AKI patients compared with controls
(p < 0.001), with significant increase among risk, injury, and
failure stages. Nonsurvivors had significantly higher median
levels of NGAL (p = 0.008) and NAG (p = 0.018) than survi-
vors. NGAL had highest area under the curve (AUC) at 0.750
* Om P. Mishra
opmpedia@yahoo.co.uk
1
Division of Pediatric Nephrology, Department of Pediatrics, Institute
of Medical Sciences, Banaras Hindu University, Varanasi 221005,
India
2
Division of Biostatistics, Department of Community Medicine,
Institute of Medical Sciences,Banaras Hindu University,
Varanasi 221005, India
3
Department of Biochemistry, Institute of Science, Banaras Hindu
University, Varanasi 221005, India
4
School of Biochemical Engineering, Indian Institute of Technology,
Banaras Hindu University, Varanasi 221005, India
5
Division of Pediatric Nephrology, Centre for Pediatrics and
Adolescent Medicine, Heidelberg University Medical Centre, 69120,
Heidelberg, Germany
0.724 (CI 0.541–0.907), with sensitivity and specificity of
75 % each; and IL-18 (AUC 0.688, CI 0.511–0.864), with
sensitivity 62.5 % and specificity 70.8 %, for predicting mor-
tality. Values were significantly higher in patients who re-
quired peritoneal dialysis (PD) than in those in whom it was
not indicated. Levels were comparable among different etiol-
ogies. Only NGAL level was found to be a significant risk
factor associated with longer duration of hospital stay.
Conclusions Urinary NGAL and NAG had modest predictive
ability for mortality. Children requiring dialysis had signifi-
cantly raised levels, and the NGAL level had significant asso-
ciation with duration of hospital stay.
Keywords Acute kidney injury . Biomarkers . Mortality .
Predictive ability . Children
Abbreviations
AKI Acute kidney injury
IL-18 Interleukin 18
NAG N-acetyl-beta-D-glucosaminidase
NAGL Neutrophil gelatinase-associated lipocalin
PD Peritoneal dialysis
Introduction
The incidence of acute kidney injury (AKI) in children ap-
pears to be increasing, and its etiology over recent decades
has shifted from primary renal diseases to being multifactorial
in origin, particularly in hospitalized children. The incidence
varies from 5 % in hospitalized patients to 30–50 % in inten-
sive care units [1]. Acute tubular necrosis, sepsis, hemolytic
uremic syndrome, and glomerulonephritis are the common

etiologies in developing countries [2, 3]. Therapeutic
interventions in AKI have been largely disappointing
due to the complex nature of the pathophysiology.
Despite significant improvements in therapy, the mortal-
ity associated with AKI remains high [3, 4]. Hoste et al.
[5] reported that patients with Risk, Injury, Failure,
Loss, and End-stage (RIFLE) class I or F had signifi-
cantly longer duration of hospital stay and an increased
risk of in-hospital mortality compared with those who
did not progress from class R or those who did not
develop AKI.
Serum creatinine is an unreliable indicator of AKI stage, as
its concentration may not change until about 50 % of the
kidney function has been lost [6]. Certain urinary biomarkers,
such as neutrophil gelatinase-associated lipocalin (NGAL), N-
acetyl-beta-D-glucosaminidase (NAG), and interleukin 18
(IL-18) have been found to be useful in early detection of
AKI [7–10]. NGAL has emerged as one of the earliest proteins
expressed in the kidney after ischemic or nephrotoxic injury in
animal models, being protease resistant and easily detected in
the urine soon after AKI [11, 12]. Urinary NAG activity has
also been detected as a biomarker of kidney injury in the
postoperative period [13].
The level of IL-18, a proinflammatory cytokine, is mark-
edly increased in patients with established AKI, and the initial
value was observed as an independent predictor of mortality
[14]. Liangos et al.[15] found that urinary NAG and kidney
injury molecule-1 levels predicted adverse clinical outcomes
in adult patients with acute renal failure. Xin et al. [16] eval-
uated serum NGAL and IL-18 on the first day of coronary
care unit admission and reported that cumulative survival rates
at 6-months’ follow-up after discharge differed significantly
between patients with and without AKI. Thus, most biomarker
studies have been performed for early detection of AKI, al-
though some evaluated their roles in outcome measures [14,
15, 17–19]. The primary objective of our study was the com-
parative assessment of NGAL, NAG, and IL-18 to predict
mortality in children with AKI, with secondary outcome mea-
sures being variation in levels in relation to different stages
(risk, injury, and failure), dialysis requirement, etiologies, and
duration of hospital stay.
Materials and methods
Patient selection
This was a cross–sectional, hospital-based study of 50 chil-
dren aged 3 months to 14 years of both genders who were
admitted to the Department of Pediatrics from June 2012 to
July 2014 with diagnosis of AKI. Another 30 healthy children
in the same age group who came to the outpatient department
for immunization or routine health checkup served as controls.
Pediatr Nephrol
AKI was defined according to the modified pediatric RIFLE
criteria [20]. The decrease in estimated glomerular filtration
rate (eGFR) from baseline (100 ml/min per 1.73 m2) was
considered to classify Risk, Injury, and Failure stages [21].
The eGFR was calculated by Schwartz formula [22].
Children aged <3 months and > 14 years and having congen-
ital renal malformations, chronic kidney disease, urinary tract
infection, or nephrotic syndrome and those receiving nephro-
toxic drugs such as nonsteroidal anti-inflammatory drugs (ibu-
profen, naproxen, indomethacin), antibiotics (aminoglyco-
sides, vancomycin), or angiotensin-converting enzyme inhib-
itors were excluded from the study. AKI etiology was sepsis,
acute tubular necrosis, severe malaria (caused by Plasmodium
falciparum), hemolytic urea syndrome (HUS) following acute
diarrhea, or postinfectious glomerulonephritis (PIGN) were
categorized on the basis of standard diagnostic criteria.
Blood sample collection and analysis
Blood samples were collected through venipuncture for vari-
ous tests at hospital admission and subsequently to monitor
renal function. Values of different parameters obtained at the
time of hospital admission were used for analysis purposes.
The investigations included hemoglobin; total and differential
leucocyte counts;, platelet counts; peripheral blood smear; se-
rum urea, creatinine, sodium, potassium, total protein, albu-
min, calcium, and phosphate; and arterial blood gases, pH,
bicarbonate (HCO3), and base excess. Other tests performed
were complements C3 and C4, antinuclear antibody, anti-
double-stranded DNA (dsDNA), detection of histidine-rich
protein-2 for P. falciparum by enzyme-linked immunoassay
(ELISA) kit, Widal test, total and differential bilirubin,
antistreptolysin-O titer, C-reactive protein, blood culture, pro-
thrombin time, activated partial thromboplastin time, reticulo-
cyte count, and ultrasonography of the kidneys, ureter, and
bladder, as indicated. AKI patients were managed as per our
hospital standard protocol, including peritoneal dialysis (PD)
when required.
Urine biomarker assay
Urine samples were collected at the time of presentation. In
anuric patients, urine samples were collected when they began
passing urine. One sample from each patient was sent imme-
diately for microscopy examination, culture sensitivity, and
urinary creatinine estimation; another sample of 10 ml was
taken and centrifuged at 1000 rpm for 5 min, and supernatant
was stored at −80 °C until assay for biomarkers (NGAL,
NAG, and IL-18). Measurements of urinary biomarkers were
performed at the School of Biochemical Engineering, Indian
Institute of Technology.
NGAL concentration was measured in urine using ELISA
kit (Abcam, UK) and NAG activity using a kit manufactured
Pediatr Nephrol
by Boehringer Mannheim Biochemica, Mannheim, Germany.
IL-18 level was estimated by ELISA based on double-
antibody sandwich, using a kit manufactured by Hangzhon
East Bio Pharma, China. Urinary NGAL (ng/dl), NAG (U/l),
and IL-18 (pg/ml) were normalized by urine creatinine con-
centration and expressed as nanograms per milligram (ng/
mg), units per gram (U/g), and picograms per milligram (pg/
mg) of urinary creatinine, respectively, before statistical
analysis.
Statistical analysis
Data were analyzed using SPSS software version 16.0
(Chicago, IL, USA). Analysis of variance (ANOVA) was ap-
plied for continuous variables showing normal distribution
and Kruskal–Wallis test for non-Gaussian distribution for
multiple comparisons. Student’s t test was applied for com-
parison of data having normal distribution and Mann–
Whitney U test for non-Gaussian distribution between groups.
Chi-square test was used to compare categorical variables.
Cox proportion hazard model was applied to determine the
relationship between urinary biomarkers and duration of hos-
pital stay. Receiver operating characteristic (ROC) curves
were generated to determine sensitivity, specificity, and areas
under the curve (AUC) for their predictive abilities for mor-
tality. Spearman’s correlation coefficients were calculated be-
tween biomarkers and blood urea and serum creatinine levels.
A p value of <0.05 was considered as significant.
Results
Basic demographic data Twenty-four (48 %) children were
in the 3 months to 5 years age group, 16 (32 %) were 6–
10 years, and the remaining ten (20 %) 11–14 years. Normal
urine output was present in 28 (56 %), oliguria in 20 (40 %),
and anuria in two (4 %) cases. Risk, Injury, and Failure stages
were present in 15 (30 %), 16 (32 %), and 19 (38 %) cases,
respectively. The basic characteristics of controls and patients
with AKI are presented in Table 1. There were 17 (56.7 %)
boys in controls and 37 (74 %) in the AKI group. Fever
(68 %), anemia (44 %), and edema (40 %) were predominant
clinical features at presentation. Six patients (12 %) had he-
maturia. Nine children (18 %) required mechanical ventila-
tion. Patients with AKI in the Failure stage had significantly
higher levels of blood urea, serum creatinine and potassium,
and Pediatric Risk of Mortality (PRISM) score [23], as well as
lower urine creatinine and eGFR when compared with chil-
dren in the Injury and Risk stages.
Out of 50 patients with AKI, four left against medical advice;
outcomes were thus analyzed in 46 patients. Eight children
required PD. PD duration was for a period of 1–8 days
(median 3). Of 46 patients, 17 (36.9 %) died during hospital
stay. Six of eight children who required PD died within 2–
12 days of hospital admission (median 7). A significantly
higher proportion of patients died who required PD, in com-
parison with cases in whom it was not indicated (6/8 vs 11/38,
p = 0.04). Median NGAL, NAG, and IL-18 levels between
survivors and nonsurvivors are presented in Fig. 1a–c. The
nonsurvivors had significantly higher median levels of urinary
NGAL (p = 0.008) and NAG (p = 0.018) than survivors.
Median IL-18 values did not differ significantly between
groups (p = 0.07). ROC curves were generated to determine
cutoff levels of NGAL, NAG, and IL-18 for predicting mor-
tality (Fig. 2). NGAL had the highest AUC, at 0.750 [confi-
dence interval (CI) 0.580–0.920], with sensitivity and speci-
ficity of 75 % each at a cutoff level of 10.2 ng/mg, followed by
NAG (AUC 0.724, CI 0.541–0.907, and sensitivity and spec-
ificity 75 % each) at cutoff level 476.5 U/g and IL-18 (AUC
0.688, CI 0.511–0.864, sensitivity 62.5 %, specificity 70.8 %)
at cutoff level 179.6 pg/mg for predicting mortality.
Urinary NGAL, NAG, and IL-18 levels in patients and
controls are presented in Table 2. NGAL and NAG could be
done in 15 controls and 44 patients and IL-18 in 30 controls
and 50 patients. Median NGAL, NAG, and IL-18 values were
significantly increased in patients compared with controls
(p < 0.001). Further, higher RIFLE stages were associated
with significantly higher median levels of these biomarkers.
The median NGAL (19.7 ng/mg vs 8.2 ng/mg, p = 0.010),
NAG (883 U/g vs 367.5 U/g; p = 0.011) and IL-18
(436.3 pg/mg vs 95.5 pg/mg, p = 0.004) levels were signifi-
cantly higher in patients who required PD.
Etiologies of AKI are shown in Fig. 3. Sepsis and
acute tubular necrosis were found in 15 (30 %) cases
e a c h , f o l l o w e d b y s e v e r e m a l a r i a d u e t o P.
falciparum in 12 (24 %), HUS following gastroenteritis
(D+) in four (8 %), and postinfectious glomerulonephri-
tis in four (8 %) children. Median values of NGAL
(8.2 ng/mg, 10.3 ng/mg, 10.8 ng/mg, 15.7 ng/mg, and
6.3 ng/mg; p = 0.738), NAG (304.5 U/g, 432.0 U/g,
485.0 U/g, 742.2 U/g, and 281.0 U/g; p = 0.809), and
IL-18 (95.3 pg/mg, 237.5 pg/mg, 202.0 pg/mg,
260.2 pg/mg, and 54.1 pg/mg; p = 0.559) were compa-
rable among different etiologies.
Cox proportion hazard model for urinary NGAL, NAG, IL-
18, and serum creatinine was applied to assess the risk for
duration of hospital stay; only urinary NGAL level was a
significant risk for longer duration of hospital stay (Exp. B
1.608, 95 % CI 1.026–2.518; p = 0.038).Correlations of uri-
nary NGAL (r = 0.614, p < 0.001), NAG (r = 0.589,
p < 0.001), and IL-18 (r = 0.483, p < 0.001) with blood urea
was significant in patients with AKI. Relatively higher levels
of correlations were found for these biomarkers with serum
creatinine (r = 0.718, p < 0.001; 0.707, p < 0.001, and 0.683,
p < 0.001, respectively).
 Pediatr Nephrol

Table 1 Basic characteristics of

patients with AKI and controls Parameters Controls AKI P value
n = 30
Total Risk Injury Failure
n = 50 n = 15 n = 16 n = 19

Age (year)a 6.0 6.0 7.0 2.3 6.0 NSb

(3.5–9) (1.4–8.0) (4.0–12.0) (0.7–8.7) (0.9–80)
Gender 17/13 37/13 10/5 12/4 15/4 NSc
(male/female) (56.7 %/43.3 %) (74 %/26 %) (66.7 %/33.3 %) (75 %/25 %) (78.9 %/21.1 %)
Fever – 34 (68 %) 9 (60 %) 11(68.8 %) 14(73.7 %) NSc
Anemia - 22 (44 %) 6 (40 %) 5 (31.3 %) 11(57.9 %) NSc
Edema - 20 (40 %) 6 (40 %) 8 (50 %) 6 (31.6 %) NSc
Hematuria - 6 (12 %) 1 (6.7 %) 2(12.5 %) 3 (15.8 %) NSc
Need for - 9 (18 %) 1 (6.6 %) 2 (12.5 %) 6 (3.15 %) NSc
ventilation
PRISM Scorea - 16.0 12.0 14.0 28.0 <0.01b
(12.0–29.2) (11.0–15.5) (12.0–28.0) (16.0–37.0)
Body mass index 14.6 ± 2.2 14.2 ± 2.8 14.9 ± 2.9 14.7 ± 3.2 13.3 ± 1.9 NSd
(kg/m2)
Systolic BP 93.7 ± 7.2 97.3 ± 21.3 102.5 ± 18.4 91.1 ± 25.0 98.2 ± 20.0 NSd
(mm Hg)
Diastolic BP 64.57 ± 8.2 64.0 ± 15.3 64.3 ± 15.9 63.0 ± 15.9 64.5 ± 15.3 NSd
(mm Hg)
Blood ureaa 29.5 117.3 84.2 111.0 175.0 <0.001b
(mg/dl) (22–34) (83.9–169.0) (66.0–105.6) (86.7–154.6) (143.0–260.0)
Serum creatinine 0.50 ± 0.12 2.90 ± 1.55 1.27 ± 0.16 1.88 ± 0.60 5.05 ± 2.06 <0.001d
(mg/dl)
Serum sodium 137.33 ± 3.79 135.8 ± 9.32 135.3 ± 8.73 132.5 ± 4.8 138.9 ± 11.74 NSd
(mEq/L)
Serum potassium 3.85 ± 0.52 4.8 ± 1.17 4.31 ± 0.70 4.68 ± 1.14 5.31 ± 1.33 <0.001d
(mEq/L)
Urine creatininea 43.2 14.5 23.0 15.7 8.2 <0.001b
(mg/dl) (32.6–51.4) (10.5–22.0) (19.7–42.7) (12.7–21.7) (6.8–12.1)
eGFRa 121.5 23.0 50.3 29.6 11.4 <0.001b
(ml/min/1.73 m2) (105–133.3) (12.0–48.9) (46.2–68.0) (26.2–35.7) (9.9–13.7)

AKI acute kidney injury, BP blood pressure, eGFR estimated glomerular filtration rate, n number of cases, NS not
significant
a
Median (interquartile range)
b
Kruskal–Wallis test
c
Chi-square test
d
Analysis of variance

Discussion we found no significant difference in median levels of

In this study, median urinary NGAL and NAG levels at
hospital admission were significantly raised in AKI
nonsurvivors compared with survivors. Both biomarkers
had modest predictive ability for mortality, with relatively
better performance of NGAL than NAG. The utility of
NGAL in predicting mortality was also found by previous
authors [17, 24]. Liangos et al. [15] analyzed NAG by
stratifying values in different quartiles and found a higher
risk of hospital mortality in the second-, third-, and fourth-
quartile groups when compared with first quartile. Further,
IL-18 between survivors and nonsurvivors. However,
Parikh et al. [14, 17] reported significantly higher urine
IL-18 value in nonsurvivors and concluded it is an inde-
pendent predictor of mortality in patients with acute respi-
ratory distress syndrome in the intensive care unit and
postcardiac surgery pediatric patients who developed
AKI. We found that NGAL, NAG, and IL-18 levels
showed significant increase among Risk, Injury, and
Failure cases, indicating a rise in biomarkers with increas-
ing AKI severity. This is further supported by the fact that
their levels had significant correlations with retention
Pediatr Nephrol
Fig. 1 Median, interquartile range, and cutoff levels of urinary neutrophil
gelatinase-associated lipocalin (NGAL) (a), N-acetyl-beta-D-
glucosaminidase (NAG) (b), and interleukin 18 (IL-18) (c) in survivors
Fig. 2 Receiver operating characteristic curves of urinary neutrophil
gelatinase-associated lipocalin (NGAL), N-acetyl-beta-D-
glucosaminidase (NAG), and interleukin 18 (IL-18) for predicting
mortality
and nonsurvivors. Horizontal thick and thin lines indicate medians and
interquartile ranges, respectively
markers such as blood urea and serum creatinine levels
measured at the time of hospital admission.
Regarding the need for PD in relation to biomarker levels,
we found that patients requiring PD had significantly higher
values than those in whom PD was not indicated. Similarly,
Fan et al. [25] reported significantly higher NGAL level in
patients receiving hemodialysis compared with those who did
not require it. Liangos et al. [15] and Trachtman et al. [26]
observed an increased risk of dialysis in patients with AKI
having raised levels of NGAL. IL-18 has been correlated with
higher risk of requiring dialysis support [17]. Thus, the rela-
tionship of raised biomarker levels and the need of dialytic
support indicates a more severe impairment of function, which
requires renal replacement therapy for recovery.
Raised NGAL value was reported earlier in AKI following
ischemic, nephrotoxic drug injury [8], sepsis [25], and
postcardiac surgery in both pediatric [25, 27] and adult [17,
28] patients. We found no significant alterations in biomarker
level in relation to different AKI etiologies, indicating that a
rise in levels is unaffected by the underlying pathology. It may
 Pediatr Nephrol

Table 2 Urinary NGAL, NAG,

and IL-18 levels in controls and Biomarkers Controls AKI P valuea
patients
Total Risk Injury Failure

NGAL (ng/mg)b 0.13 9.7 2.1 9.1 23.0 <0.001

(0.1, 0.2) (2.5, 16.7) (0.9, 2.5) (6.7, 10.3) (15.9, 28.7)
n = 15 n = 44 n = 15 n = 12 n = 17
NAG (U/g) b 1.4 404 39 383.5 1111.0 <0.001
(1.3–2.1) (48.1–770.2) (17.4–48.1) (301.7–476.5) (724.0–1276)
n = 15 n = 44 n = 15 n = 12 n = 17
IL-18 (pg/mg) b 12.6 136.6 27.9 117.5 401.7 <0.001
(9.9–16.6) (48.0–313.2) (18.9–52.3) (63.8–218.2) (271.0–476.0)
n = 30 n = 50 n = 15 n = 16 n = 19

NGAL neutrophil gelatinase-associated lipocalin, NAG N-acetyl-beta-D-glucosaminidase, IL-18 interleukin 18,

AKI acute kidney injury
a
Kruskal–Wallis test
b
Median with interquartile range in parentheses; units standardized to urine creatinine

be possible that 60 % of our patients had advanced stages of
AKI (injury and failure) at presentation, where almost similar
renal damage occurred, thus reflecting comparable biomarker
levels.
Of the three biomarkers, NGAL correlated relatively better
than NAG and IL-18, with serum urea and creatinine levels
reflecting the severity of renal dysfunction. Thus, patients
took longer to recover. Therefore, urinary NGAL had signif-
icant positive correlation with duration of hospital stay, as
reported previously [17, 25]. Further, Parikh et al. [17] showed
that in patients with ischemic AKI following cardiac surgery,
raised urine IL-18 was associated with longer hospital stay. In
contrast, we found no such association.
This study has limitations in that results cannot be general-
ized for AKI due to nephrotoxic drug injury and the small
sample size, which require evaluation in a larger cohort for
outcome measures. In conclusion, the comparative analysis of
these biomarkers shows modest predictive ability of NGAL
and NAG for mortality. Levels of all three biomarkers showed
significant rise with increasing severity and were significantly

Fig. 3 Etiologies of acute kidney

injury
Pediatr Nephrol
higher in children requiring dialytic support. Only NGAL was
associated with being a significant marker for duration of hos-
pital stay. Therefore, it appears that increased levels at the time
of hospital admission not only indicate severity but also have
prognostic significance.
Author’s contributions OPM, AKR, and AA were involved in the
study design, conduction, data analysis, and manuscript drafting; RP
and RNM helped in data analysis and manuscript drafting; PS and KP
performed estimation of urinary biomarkers; FS helped conceptualize the
study and provide critical revision of the manuscript.
Compliance with ethical standards The study protocol was approved
by the institute's Ethical Committee, and informed consent was taken
from each parent.
Funding The study was supported by the Institutional Grant of School
of Biochemical Engineering, Indian Institute of Technology, Banaras
Hindu University, Varanasi and University Grants Commission (Dr. D.
S. Kothari Post Doctoral Fellowship- F 4-2/2006 (BSR)/13-679/2012
(BSR), New Delhi, India.
Competing interest None
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