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Yangtze Medicine, 2019, 3, 183-194
http://www.scirp.org/journal/ym
ISSN Online: 2475-7349
ISSN Print: 2475-7330
DOI:
10.4236/ym.2019.33019 Jun. 28, 2019 183 Yangtze
Medicine
Urinary NGAL and KIM-1 Are the Early
Detecting Biomarkers of Preterm Infants with
Acute Kidney Injury
Hongzhu Lu1,2, Qihong Fan1,2, Lu Wang1, Nipun Shrestha1, Sijan Thapa1
1Department of Pediatrics, The First Clinical College, Yangtze University, Jingzhou, China
2Pediatric Research Institute of Yangtze University, Jingzhou, China
Abstract
Background
: Acute kidney injury (AKI) is common in neonates. However,
early diagnosis is difficult. Different biomarkers for early diagnosis of AKI,
such as NGAL, KIM-1, Cys-C, IL-18,
β
2-microglobulin have been proposed.
But regarding premature infant, there is very little research that has been re-
ported.
Objectives
: To investigate the role of urinary NGAL and Kim-1 bio-
markers for early diagnosis of AKI in premature neonates.
Methods
:
Eighty
cases were divided into experimental group (60 cases) and controls group (20
cases). Of 60 cases,
24 patients met the criteria for AKI group; the remaining
36 were non-AKI group. Blood and urine samples, 1 ml each, were
collected
from all subjects at first day, second day, third day and seventh day of life.
Urine NGAL and KIM-1 were measured by ELISA.
Results: The urinary
NGAL and KIM-1 are significantly higher in AKI group than Non-A
KI group
and normal control group in the first three days. They present earlier than
classical Scr.
Conclusion:
Urinay NGAL and Kim-1 are beneficial
biomarkers
for the early diagnosis of AKI in preterm neonates.
Keywords
Neonate, Acute Kidney Injury, NGAL, KIM-1
1. Introduction
Acute Kidney Injury (AKI), formerly known as Acute Renal Failure (ARF), is
one of the numbers of conditions that affect kidney function and structure. AKI
is currently defined as reduction in kidney function, including decreased glo-
merular filtration rate (GFR) and kidney failure. The change in serum creatinine
How to cite this paper:
Lu, H.Z.,
Fan,
Q.H.,
Wang, L., Shrestha, N. and Thapa, S.
(201
9) Urinary NGAL and KIM-
1 Are the
Early Detecting Biomarkers of Preterm
Infants with Acute Kidney Injury
.
Yangtze
Medicine
,
3
, 183-194.
https://doi.org/10.4236/ym.2019.33019
Received:
December 20, 2018
Accepted:
June 25, 2019
Published:
June 28, 2019
Copyright © 201
9 by author(s) and
Scientific
Research Publishing Inc.
This work is licensed under the Creative
Commons Attribution International
License (CC BY
4.0).
http://creativecommons.org/licenses/by/4.0/
Open Access
H. Z. Lu et al.
DOI:
10.4236/ym.2019.33019 184
Yangtze Medicine
(SCr) and urine output are the classical parameter used to diagnose severity and
stage of AKI. The RIFLE criteria have been proposed by the Acute Dialysis
Quality Initiative (ADQI) group, aid in the staging of patients with AKI [1] [2].
According to World Health Organization statistics, 28% of all neonatal deaths
are due to premature birth. In the past 20 years, some developed countries have
preterm birth rates ranging from 5% to 7% [3]. In recent years, a series of studies
have found that mortality of preterm infants is closely related to preterm infants
with renal impairment [4] [5]. Premature infants are at unique risk for develop-
ing AKI due to incomplete nephrogenesis, early exposure to nephrotoxic medi-
cations (
i.e.
Indomethacin, Ibuprofen, cefotaxime, aminoglycosides), and coex-
isting conditions such as patent ductus arteriosus (PDA) and respiratory distress
syndrome (RDS). AKI prevention and therapy have as of yet been rather unsuc-
cessful and unsatisfactory [6] [7]. Serum creatinine concentrations are influ-
enced by many factors. A significant disadvantage of these tests is the time delay
between injury and detection, making the tests insensitive and unreliable for di-
agnostic and prognostic measurements [6]. It is suggested to use other markers
which are stable over time and are not affected by muscle mass or tubular reab-
sorption and secretion. Specific proteins excreted in the urine after injury to par-
ticular segments of the nephron can serve as biomarkers for assessing the site
and severity of renal damage [7]. Currently, for adults and children, many ex-
perts and scholars have proposed different biomarkers for early diagnosis of AKI
[8], such as NGAL, KIM-1, Cys-C, etc. But regarding premature infant, there is
very little research that has been reported. NGAL is a 25-kDa protein that be-
longs to lipocalin group which is highly expressed in proximal tubular epithelial
cells and has role in renal tubular epithelial cells formation and repair. It is ex-
pressed in neutrophils and in low levels in the kidney, prostate, and epithelia of
the respiratory and alimentary tracts [9] [10]. When AKI occurs, tubular epi-
thelial cell is damaged and blood and urine NGAL are abundantly expressed
[11]. KIM-1 belongs to immunoglobulin super family. It is a type 1transmembrane
glycoprotein, the mucin, immunoglobulins composition, an adhesion molecule
[12]. We investigate the role of urinary NGAL and Kim-1 biomarkers for early
diagnosis of AKI in premature neonates.
2. Materials and Methods
2.1. Patients
Eighty cases were divided into experimental group (60 cases, gastational age less
than 34 weeks) and controls group (20 cases, gastational age more than 37
weeks), excluding infection, congenital malformation of the urinary system, cas-
es of medication during pregnancy by the mother. The control group was with-
out risk factors like abnormal pregnancy or use of nephrotoxic medication or
trauma, asphyxia, congenital uninary tract malformation. Families of preterm
infants involved in all the cases were informed about the study and the consent
was signed. The approval of the hospital ethics committee was obtained. Record
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of all selected cases infants and their mother was maintained like inpatient
number, name, sex, gestational age, birth weight, Apgar scores, gravidity and
parity. Case-control data analysis was performed.
Of the 80 cases, 60 cases were the experimental group and 20 cases were the
control group, according to the diagnostic criteria for acute kidney injury in
2007 the United States AKIN (within 48 hours, SCr increased to more than 26.5
μmol/L; or percentage increase in SCr by more than or equal to 50%; or reduc-
tion in urine output less than 0.5 ml/kg/hour over six hours), the experimental
group was divided into AKI group, the non-AKI group. Out of 60 cases, 24 pa-
tients met the criteria for AKI group; the remaining 36 were non-AKI group; the
other 20 cases without any other risk factors were full-term newborns grouped
as normal controls.
Blood and urine samples, 1 ml each, was collected from all subjects at first
day, second day, third day and seventh day of life. The samples were immediate-
ly centrifuged (room temperature 18˚C, 3500 rpm, 5 min), (low speed automatic
balance centrifuge, LDE5-2, Beijing, China). After centrifugation, the superna-
tant (serum) 100 μl was kept in hospital central laboratory at −80˚C tempera-
ture. Blood samples were collected by conventional tube, urine specimens were
collected in urine tube.
2.2. Detection of Samples
Nissan OLYMPUS AU5400 automatic biochemical analyzer available in our
hospital laboratory was used for serum creatinine.
Urine NGAL and KIM-1 were measured by enzyme-linked immunosorbent
assay (ELISA), the kit provided by Shanghai Biological Technology Co., Ltd.
(SEB388Hu 96T). The procedure was followed strictly according to the kit in-
structions.
2.3. Statistical Analysis
Measurement data were expressed as mean ± standard deviation. The compari-
son between the groups was done using the F test. Correlation between the index
and serum creatinine were evaluated using linear regression. Each index sensi-
tivity and specificity was evaluated with the area under the ROC curve. Statistical
analysis was done using SPSS19.0.
3. Results
3.1. Eighty Neonates Was Enrolled
We investigated gestational ages, birth weight, and Apgar score of all cases. The
summary clinical data of all neonates is illustrated in Table 1.
3.2. AKI Group, the Non-AKI Group, Control Group of Preterm
Infants of Different Age and Scr
From Table 2, Figure 1, it is seen that for the same-day-old premature children,
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Figure 1. Changes of Scr in premature infants with different age groups.
Table 1. 80 cases of neonatal clinical data.
Clinical data Number of cases
Gender Male/Female 42/38
Gestational Age
≤34 Week 18
34 - 36 Week 42
≥37 Week 20
Birth Weight
≤1.5 kg 7
1.5 kg - 2 kg (Including 2 kg) 17
2 kg - 3 kg (Including 3 kg) 39
>3 kg 24
Apgar 1 minute
0 - 3 Score (Including 3 score) 1
4 - 7 Score (Including 7 score) 13
>7 Score 66
Mode of Delivery
Birth 13
Caesarean section 67
Table 2. Changes in Scr in preterm infants of different age groups (μmol/L) (
X
± S).
n Day 1 Day 2 Day 3 Day 7
AKI Group ① 26 52.5 ± 30.3 56.2 ± 27.5 98.4 ± 36.1 65.3 ± 27.5
Non AKI Group ② 34 46.0 ± 9.4 47.1 ± 10.2 57.3 ± 18.5 42.2 ± 14.3
Normal control group ③ 20 39.1 ± 8.1 37.8 ± 7.4 36.5 ± 8.3 38.7 ± 8.8
F value 2.869 6.319 4.292 15.109
P value 0.063 0.003 <0.001 <0.001
① ② compare P value 0.186 0.052 <0.001 <0.001
① ③ compare P value 0.019 0.001 <0.001 <0.001
② ③ compare P value 0.201 0.061 0.003 0.512
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Scr is significantly high in AKI group compared to control group. This differ-
ence is statically significant. It is seen that in AKI and control group, for Scr at
day 1, 2, 3 and 7, P < 0.05 and the difference is statically significant. For the
Same-day-old premature children on the first day and second day, P > 0.05 in
AKI and non-AKI groups, the difference is not statistically significant. At 3rd
day and 7th day, P < 0.05 in AKI group and non-AKI group comparison, the
difference is statistically significant. Comparing Non-AKI group and normal
control, first 1, 2, 7 days P > 0.05, the first three days P < 0.05.
In the AKI group, there is no significant change in Scr in first and second day
and then increases with increasing age and again decreases by seventh day. In
case of Non-AKI group, each time the reading is slightly higher than those in the
control group, the first decline is seen in seventh days. In the control group,
from day 1 to day 7, Scr is basically unchanged.
3.3. Changes of NGAL in Preterm Children of Different Age Group
in AKI Group, the Non-AKI Group and Control Group
Table 3 and Figure 2 show that NGAL is significantly high in AKI group and
Non-AKI group when compared to control group of the preterm child of same
age. This difference is statistically significant. AKI group and non-AKI group, on
days 1 to 3, P < 0.05 difference was statistically significant. AKI group and the
normal control group, at day 1, 2, 3, 7 days, P < 0.05 and the difference was sta-
tistically significant. Non-AKI group and normal control group, who was born
the first 1, 2, 3, 7 days, P < 0.05 difference was again statistically significant. For
AKI group and non-AKI group preterm children, NGAL increased with age.
NGAL was on rise during the first three days and the first decline was seen
slightly on the seventh day. AKI group compared with non-AKI group and
normal control group, the first day there is a clear upward rise on the first two
days, significantly increased on the first three days and decreased on seventh
day.
Table 3. Changes in NGAL in preterm children of different age group (ng/ml) (
X
± S).
N Day 1 Day 2 Day 3 Day 7
AKI Group ① 26 2.1 ± 1.4 2.23 ± 1.49 2.58 ± 1.51 1.48 ± 1.33
Non AKI Group ② 34 1.72 ± 1.19 1.81 ± 1.37 1.87 ± 1.38 1.44 ± 1.17
Control ③ 20 0.54 ± 0.28 0.66 ± 0.45 0.83 ± 0.90 0.67 ± 0.60
F value 11.494 9.302 9.892 3.731
P value <0.001 <0.001 <0.001 0.028
① ② compare P 0.039 0.041 0.042 0.035
① ③ compare P <0.001 <0.001 <0.001 0.017
② ③ compare P <0.001 0.002 0.007 0.016
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Figure 2. Changes of NGAL in preterm at different ages.
3.4. KIM-1 in AKI Group, Non-AKI Group, Control Group of
Preterm Infants Different Ages
Table 4 and Figure 3 show that KIM-1 is significantly high in AKI group and
Non-AKI group when compared to control group of the preterm child of same
age. This difference is statistically significant. AKI group and non-AKI group, on
days 1 to 7, P < 0.05 difference was statistically significant. AKI group and the
normal control group, at day 1, 2, 3, 7 days, P < 0.05 and the difference was sta-
tistically significant. Non-AKI group and normal control group, was born the
first 1, 2, 3, 7 days, P > 0.05 difference was statistically not significant.
For AKI group and non-AKI group preterm children, KIM-1 increased with
age. KIM-1 was on rise during the first three days and then decline was seen
slightly on the seventh day. AKI group compared with non-AKI group and
normal control group, the first day there is a clear upward rise on the first two
days, significantly increased on the first three days and decreased on seventh
day.
4. Discussion
The potential role of urine protein biomarkers to detect kidney damage are an
area of active investigation. The present study showed that the urinary NGAL
and KIM-1 are significantly higher in AKI group than Non-AKI group and
normal control group in the first three days. They present earlier than classical
Scr. So the urinay NGAL and Kim-1 are benifical biomarkers for the early diag-
nosis of AKI in preterm neonates.
In the case of AKI, NGAL is secreted in high levels into the blood and urine
within 2 hours of injury [13]. Urinary NGAL appears to be the most promising
AKI biomarker and it is the most strikingly upregulated gene and overexpressed
protein in the kidney after ischemia [14].
The NGAL level measured in an individual is proportional to the severity of
the AKI [15]. Renal expression of NGAL increases in the kidneys after injury for
a variety of reasons. Many studies have evaluated urinary and serum NGAL
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Figure 3. Changes of KIM-1 in premature infants of different age groups.
Table 4. Preterm children of different age groups and KIM-1 (ng/ml) (
X
± S).
n Day 1 Day 2 Day 3 Day 7
AKI Group ① 26 574.1 ± 562.1 583 ± 896.4 807.3 ± 1344 592.5 ± 806.2
Non AKI Group ② 34 276 ± 306 299 ± 328.2 473.9 ± 688.4 265.4 ± 294.3
Control ③ 20 95.96 ± 59.17 106.2 ± 80.9 114.0 ± 69.5 143.6 ± 106.6
F value 9.553 4.346 3.445 5.216
P value <0.001 0.016 0.037 0.008
① ② compare P 0.003 0.045 0.048 0.014
① ③ Compare P <0.001 0.005 0.011 0.004
② ③ Compare P 0.096 0.221 0.155 0.391
capacity to predict AKI in both adults [16] [17] and older children [18] [19].
NGAL in children and newborn range has been relatively a widespread concern.
A study on children with pediatric cardiopulmonary bypass operations showed
that urinary NGAL concentrations above 50 ng/mL in 2 hours after surgery and
serum creatinine levels 50% over basal values. Normally, children tend to have
almost undetectable levels of NGAL [20]. Hundreds of clinical studies demon-
strate that NGAL measures kidney injury but the studies are mainly done in
adult population and very few studies were done in pediatric population. Lavery
et al.
[21] studied 20 children with low birth weight, weighing from 500 g to
1500 g and collected their urine for first 2 week of life and concluded that urine
NGAL can be easily obtained in premature infants. Specifically in the neonatal
population, serum and urine NGAL were evaluated in patients after Cardiopul-
monary Bypass (CPB) surgery [20]. Plasma and serum NGAL collected 2 hours
after CPB were able to predict AKI with a sensitivity and specificity of nearly
90%. Another study evaluated urinary NGAL at day 1 in preterm infants and af-
ter full adjustment for other factors; it remained significantly associated with
AKI development [22]. A recent study on AKI in preterm infants concluded that
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urinary NGAL may be very useful to predict AKI development prior to changes
in serum creatinine in preterm infants [23]. The study found that NGAL level
was much higher in AKI group than in non-AKI group. In non-AKI group, the
level of NGAL in control group was 0.598 µg/ml whereas in AKI group it was
found to be as high as 4.24 µg/ml. This study was performed on preterm infants
below 32 weeks of gestation age. Oncel NY
et al.
[24] studied 41 cases of new-
born with a diagnosis of perinatal asphyxia and classified the cases into AKI and
non-AKI groups. The AKI group included 15 newborns and Non-AKI group in-
cluded 26 newborns. The biomarker NGAL was measured on day 1 and day 4.
The study concluded that urinary NGAL was higher in patients with AKI on day
as well as day 4 and it can be used as an important diagnostic biomarker in such
patients. Our results showed the same significance with the above.
KIM-1, under normal physiological conditions, did not increase or increase in
low amount but expression was significantly increased in ischemic or nephro-
toxic injury [25] [26]. The KIM-1 is stable in the urine for prolonged periods of
time and can be detected in the kidney and urine in a number of nephrotoxic
models in animals [27] [28] and in humans with AKI [29]. During proximal tu-
bular damage KIM-1 can be detected in urine, in the form of a soluble fragment,
stable nature [30] [31]. Han
et al.
demonstrated marked expression of KIM-1 in
kidney biopsy specimens from six patients with acute tubular necrosis, and
found elevated urinary levels of KIM-1 after an initial ischemic renal insult,
prior to the appearance of casts in the urine [12]. A longitudinal prospective
study conducted by van Timmeren
et al.
[32] reported that elevated urinary
KIM-1 serves as an independent predictor of long-term graft loss in renal trans-
plant recipients (n = 145 patients) independent of donor age, creatinine clear-
ance and proteinuria.
Sabbisetti VS
et al.
[33], conducted a study on ischemia reperfusion in mice
and found that there are significant expression of KIM-1 for 12 hours before Scr
increased. Sprenkle P
et al.
[34] found that, in the event of tissue ischemia, by
detecting Scr alone prediction of early AKI was missed. The KIM-1 has a value
of early diagnosis. Mihye Jeong
et al.
[35], studied drug-induced renal toxicity in
rats and found that KIM-1 has important significance in early detection of AKI
with high sensitivity. Song L
et al.
[36], studied on 69 patients after renal trans-
plantation and found that increasing the tubular cell damage and the extent of
renal injury and KIM-1 levels were positively correlated. Van Timmeren MM
et
al.
[37] studied in 109 cases with biopsy specimens, of which 102 cases have kid-
ney injury and seven cases of normal controls. Urinary KIM-1 was measured by
ELISA, the study found that KIM-1 was highly expressed in proximal tubules.
KIM-1 can be used as non-invasive biomarker of kidney injury. Tubular KIM-1
levels are virtually undetectable in healthy kidney tissues but are markedly in-
creased after injury to the kidney [12]. Lee HE
et al.
[38], demonstrated signi-
ficance expression of KIM-1 on cohort study of infants with febrile urinary tract
infection that suggest renal injujry.
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Zwiers AJ
et al.
[39] conducted a prospective observational cohort study of
100 term-born infants ages 1 day to 1 year on mechanical ventilation. Thirty-five
patients had evidence of AKI within the first 48 hours post-admission, of whom
24 (69%) already had AKI when they entered the PICU. KIM-1 concentrations
in AKI peaked between 6 to 12 hours and between 12 to 24 hours post-admission.
Gurkan Genc
et al.
[40] studied in 48 premature babies hospitalized in the neo-
natal intensive care unit were included in the study and divided into three
groups: group I, healthy premature infants; group II, preterm infants with RDS
without AKI; group III, preterm infants with RDS and AKI. Urinary KIM-1
along with Scr levels were measured with ELISA on days 1, 3, and 7 of life. On
day 1 babies with RDS and AKI, KIM-1 were higher than the other two groups.
Nephrotoxicity is a common side effect of therapeutic interventions, environ-
mental insults, and exposure to toxicants. Although biomarkers for nephrotoxic-
ity are available, they often lack sensitivity and are not specific as indicators of
epithelial cell injury [41] [42]. Urinary KIM-1 expression may be detected after
exposure to a variety of nephrotoxic agents, even when serum creatinine con-
centrations do not increase, and this has been accepted by regulatory authorities
as a sensitive biomarker of AKI [43]. We also found that urinary KIM-1is a very
sensitive biomarker in neonates with AKI.
Our study results indicated that both NGAL and KIM-1 are more sensitive
and easier to detect for the neonates with AKI than Scr.
5. Conclusion
AKI is vital for the neonates, especially preterm neonates. Early diagnosis is crit-
ical for the treatment and better prognosis. Our study showed that urinay NGAL
and KIM-1 are beneficial and easier biomarkers for the early diagnosis of AKI in
preterm neonates. However, further investigation that whether these biomarkers
can predict the clinical outcome is indicated. Larger samples of preterm neo-
nates with different courses of AKI are needed.
Conflicts of Interest
The authors declare no conflicts of interest regarding the publication of this
paper.
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