Jpn J Extra-Corporeal Technology 47（1）：8 − 14, 2020

Neutrophil gelatinase-associated lipocalin as an early indicatorof acute kidney injury following pediatric cardiac surgery
Yoshihito Wakamatsu 1），Keisuke Nakanishi 2），Satoshi Matsushita 2），Go Sato 1），
Hideaki Yasumoto 1），Shiori Kawasaki 2），Atsushi Amano 2）
Abstract
Early intervention can significantly improve patient outcomes in acute kidney injury (AKI ). In children with
underdeveloped kidneys, it takes longer than 24 hours for serum creatinine (sCr) to peak after AKI onset. Furthermore, even very subtle increases in sCr are associated with poor outcomes, making it more difficult to diagnose early AKI in pediatric cases.
The urinary neutrophil gelatinase-associated lipocalin ( NGAL) levels of 64 patients undergoing pediatriccardiac surgery using cardiopulmonary bypass from June 2018 to February 2019 were measured to evaluate
NGAL as an accurate indicator of postoperative AKI.
Sixteen patients (25%) developed AKI. The AKI group showed significantly higher Risk Adjustment in Congenital Heart Surgery ( RACHS-1) scores (p＝0.028) and a significantly longer operative time (p＝0.048), cardiopulmonary bypass time (p＝0.048), and ventilator use time (p＜0.001) than the non-AKI group. After surgery, urinary
NGAL was significantly higher in the AKI group with a median of 37.1ng/mL (11.1-148.3) against 5.6ng/mL (1.035.8) of the non-AKI group (p＝0.021). Using a cut-off value of 11.9ng/mL, the area under the curve of urinary
NGAL for predicting AKI was 0.69, the sensitivity was 75%, and the specificity was 44%.
Higher RACHS-1 scores are associated with postoperative AKI. Urinary NGAL shows a moderate correlation with AKI diagnosis, and may be useful for predicting AKI early in the perioperative period.
Key words：‌neutrophil gelatinase-associated lipocalin（NGAL），acute kidney injury（AKI），pediatric cardiac
surgery，cardiopulmonary bypass，The Risk Adjustment in Congenital Heart Surgery（RACHS-1）
systemⅠ．Introduction

CPB is reported to be as high as 20-30% 2). AKI sever-Risk factors for postoperative acute kidney in-

ity has a linear relationship with mortality 3), but itjury (AKI ) in patients undergoing cardiac surgery

has been shown that even a 0.3mg/dL increase ininclude ischemic-reperfusion injury associated withserum creatinine (sCr) can affect prognosis and treat-

microcirculatory dysfunction due to non-physiologicalment course 4). This highlights the importance of early

hemodynamics from cardiopulmonary bypass (CPB)

AKI diagnosis for improving patient outcomes

and inflammatory reaction due to the exposure ofthrough early initiation of therapeutic interventions.

blood to the CPB circuit . The incidence of AKI after

In 2011, to facilitate early detection of AKI, Kid-1)1）Department of Clinical Engineering, Juntendo University, School of Medicine, Tokyo. Japan2）Department of Cardiovascular Surgery, Juntendo University, School of Medicine, Tokyo. Japan
Corresponding author：‌Keisuke Nakanishi, MD, PhDAssociate Professor, Department of Cardiovascular Surgery, Juntendo University
2-1-1, Hongo, Bunkyo-ku, Tokyo, 113 - 8421, Japan［Received October 21, 2019：Accepted December 17, 2019］8

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Jpn J Extra-Corporeal Technology 47（1），2020

ney Disease：Improving Global Outcomes ( KDIGO)

2．Urinary NGAL evaluation

defined the diagnostic criteria for AKI as the pres-Written informed consent was obtained fromence of oliguria for 6 hours and an increase in sCr

the parents of each patient, and the study was ap-

within 48 hours . Although the use of the KDIGO

proved by the Institutional Review Board of Juntendo

criteria has been validated in pediatric cases 6), theUniversity Hospital (approval number 17-304). Urine

reference values of sCr for pediatric patients are high-collection was performed a total of nine times - before

ly variable. In newborns, as a result of the maternaland 0, 1, 2, 4, 8, 12, 24, and 72 hours after admission

transfer of creatinine, sCr levels can vary day byto the intensive care unit. Each sample was centri-

day , and in early childhood, sCr increases withfuged at a relative centrifugal force of 500G for 5 min-age . Furthermore, in children, sCr can take longer

utes and then stored at -80oC. Urinary NGAL wasthan 24 hours to peak after AKI onset , and even ameasured by a chemiluminescence immunoassay

small rise in sCr is shown to be associated with poor

using an ARCHITECT i200SR ® immunoassay ana-

clinical outcomes 10). Since the rise in sCr is too small

lyzer (Abbott Japan Co., Ltd,Tokyo,Japan). Absoluteto make a determination, in patients under the age ofurinary NGAL values, not creatinine-adjusted NGAL

18, AKI can be diagnosed using estimated glomerularconcentrations, were used to evaluate the role of uri-filtration rate (eGFR) . However, AKI diagnosis usingnary NGAL in the early diagnosis of AKI.

eGFR may not be suitable in neonates whose renal

3．CPB

5)

7)

8)

9)

5)

function is not yet mature . Furthermore, a common

For CPB, the priming volume was calculated ac-

eGFR equation may not be accurate due to differences

cording to institutional protocol with the target flow

in body composition between Caucasian and Japanese

rate based on a perfusion index ( PI ) of 2.6L/min/m 2 .

children 11). Given these limitations, a more sensitive

Body temperature was maintained at mild to moder-marker of early AKI in pediatric cases is thus re-ate hypothermic levels. Blood transfusion was used toquired.

correct low hematocrit values (lower limit of 18%)

6)

Neutrophil gelatinase-associated lipocalin (NGAL)

whenever feasible. In all cases, modified ultrafiltration

is rapidly expressed by renal epithelial cells following

was performed immediately after CPB discontinua-

AKI and accumulates in the urine due to reducedtion.

reabsorption in the proximal tubule

4．Perioperative management

12, 13). Recent stud-

Perioperative management was performed byies have reported the usefulness of NGAL in the early. Indeed, in the 2016 Japanese

an anesthesiologist and by a cardiovascular surgeon

Clinical Practice Guideline for Acute Kidney Injury,

after surgery. Hemodynamic management involved

NGAL was given the highest class of recommenda-

the administration of dopamine, dobutamine, nor-tion and level of evidence among urinary biomark-adrenaline, and nitroglycerin as appropriate. Ventila-

ers 19).

tion management was mainly performed via pressure

diagnosis of AKI

14-18)

This aim of this study was to evaluate the ef-

control ventilation, and nitric oxide ( NO) therapy was

fectiveness of urinary NGAL as an early indicator of

used in cases of poor oxygenation or high pulmonary

AKI in patients undergoing pediatric cardiac surgery

arterial pressure.

using CPB.

5．Data collection
Demographic and clinical data collected includ-

Ⅱ．Methoded patient background, operative time, CPB time, aor-

1．Population

tic cross-clamp time, postoperative ventilation use

This study included 67 consecutive patients whotime, pre- and post-operative PaO 2/FiO 2 ( P/F) ratio,

underwent pediatric cardiac surgery with CPB fromand NO therapy use. Intraoperatively, mean arterial

June 2018 to February 2019 in our institution. Patientsblood pressure (mBP), PI, cerebral regional oxygen

were stratified into AKI and non-AKI groups using

saturation (rSO 2), and abdominal rSO 2 . were recorded

the KDIGO criteria , as recommended by the 2016

every 10 minutes. Hemoglobin ( Hgb) and hematocrit

Japanese Clinical Practice Guideline for Acute Kidney( Hct) were measured every 20 minutes and used to

Injury 19).

calculate oxygen supply ( DO 2), carbon dioxide emis-

5)

sions ( VCO 2), and DO 2/VCO 2 ratio. In addition, pre体外循環技術

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and postoperative serum lactic acid levels and platelet

the KDIGO criteria. Of these 16 patients, 10 (16%) had

levels were compared. sCr was evaluated before andstage 1, 4 (2%) had stage 2, and 2 (3%) had stage 3
AKI ( Table 1). There were no cases of congenital kid-

12 and 36 hours after the operation.
The Risk Adjustment in Congenital Heart Sur-ney disease, blood purification therapy such as perito-

gery ( RACHS-1) system devised by Jenkins et al 20).

neal dialysis, or postoperative death in the AKI or

was used to classify the cases according to surgical

non-AKI group.
The median RACHS-1 score of the AKI groupoutcome.
6．Statistical analysis

was higher than that of the non-AKI group (3.0 vsNonparametric tests and logistic regression

2.0；p＝0.028). The median operative time (232 vs 184

analysis were performed using JMP 13.2 (SAS Insti-

minutes；p＝0.048) and median CPB time (97.5 vs 66.5

tute Inc., Cary, NC, USA). A p-value ＜0.05 was con-minutes；p＝0.048) of the AKI group were longer

sidered statistically significant. The diagnostic value

than those of the non-AKI group.

®

of NGAL was determined using receiver operatingWith regards to intraoperative CPB parameters,

characteristic ( ROC) curve analysis. The optimal cut-

the AKI group exhibited a lower median abdominal

off value for AKI diagnosis was defined as the pointrSO 2 (72% vs 75%) and a higher rSO 2 reduction rateon the ROC curve which maximized the Youden(7.4% vs 2.1%) then the non-AKI group. Both differ-index (sensitivity＋specificity－1).

ences were statistically significant (p＜0.001).
Median serum lactic acid levels after CPB were

Ⅲ．Results

higher in the AKI group (1.4 vs 1.1；p＝0.044). The

A total of 67 cases were included in this study.

AKI group also exhibited significantly higher sCr val-Three cases were excluded due to missing data. Of

ues 12 hours after surgery (median：0.57 vs 0.36；

the 64 patients, 16 (25%) developed AKI according top＜0.001). Notably, two patients in the AKI group ex-

Table 1‌Classification of the acute kidney injury diagnosis
group according to disease stage using KDIGO
guidelines
n＝64（AKI groups n＝16；25％）

hibited a maintained increase in sCr even after 36
hours.
Longer ventilation use was observed in the AKI
group (48 vs 2 hours；p＝0.037 ). There was one tra-AKI Stage1

n＝10；16％cheostomy case in the AKI group (6.3%) and five in

AKI Stage2

n＝4；6％

the non-AKI group (10.4%). NO therapy was used in

AKI Stage3

n＝2；3％

five cases in the AKI group (31.3%) and ten cases in
the non-AKI group (20.8%) ( Table 2.3.4).

AKI：acute kidney injury.

Table 2Age（months）
Weight（kg）
2
BSA（m ）RACHS-1 score
OP time（min）
CPB time（min）
Cardiac arrest time（min）
Post OP intubation time（min）
Pre OP P/F ratio（mmHg）
Post OP P/F ratio（mmHg）
Inhaled nitric oxide therapy（n（%））
Pre OP serum lactate（mmol/L）
Post OP serum lactate（mmol/L）
Pre OP sCr（mg/dL）
Post OP 12 h sCr（mg/dL）
Post OP 36 h sCr（mg/dL）

Patient characteristics and clinical outcomes
non-AKI group（n＝48）

AKI group（n＝16）

p-value32.5（10.0-67.8）
11.6（6.8-17.9）
0.52（0.40-0.72）
2.0（2.0-3.0）
184.0（150.5-238.8）
66.5（51.8-107.5）
38.0（19.8-107.5）
2.0（0.0-41.3）
301.9（155.0-474.4）
462.0（314.3-528.5）
10（20.8％）
0.8（0.7-1.1）
1.1（0.9-1.4）
0.32（0.24-0.38）
0.36（0.28-0.48）
0.30（0.22-0.38）

11.0（6.8-22.5）
7.7（6.0-11）
0.41（0.29-0.52）
3.0（2.0-3.0）
232.0（163.0-307.5）
97.5（67.3-138.8）
39.0（21.0-99.5）
48.0（16.5-80.5）
217.0（99.6-342.3）
432.0（185.3-468.5）
5（31.3％）1.0（0.8-1.1）
1.4（1.2-1.9）
0.26（0.21-0.34）
0.57（0.43-0.62）
0.31（0.27-0.35）

0.066（NS）
0.546（NS）
0.297（NS）
＊
0.028
0.048
0.048
0.376（NS）＜0.0010.145（NS）
0.104（NS）
0.330（NS）
0.844（NS）
0.044
0.43（NS）＜0.0010.25（NS）

Data are presented as median（interquartile range）.
AKI：acute kidney injury，BSA：body surface area，RACHS-1：risk adjustment in congenital heart surgery system，
OP：operative，CPB：cardiopulmonary bypass，P/F：PaO2/FiO2，sCr：serum creatinine，h：hours.
＊
p＜0.05 in the legend10

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Table 3

Surgical procedures categorized by RACHS-1 score
non-AKI group（n＝48）

AKI group（n＝16）

10

2

16
2
1
1

3
0
1
0

6
4
0
3
1
0
1
1
1
0
0
1

1
2
1
1
0
1
0
0
0
1
1
0

0
0

1
1

Category 1
ASD closure
Category 2
VSD closure
Coarctation repair
Tetralogy of Fallot repair
Bidirectional Glenn shunt
Category 3
DORV repair
Fontan procedure
Fontan＋ Fenestrated
Arterial switch operation
Coarctation repair＋PA banding
Complete AVSD repair
Glenn＋PA banding
Central shunt
VSD closure＋tricuspid valvuloplasty
Tricuspid valvuloplasty
Pulmon aryatresia＋VSD closure
Cor triatriatum repair
Category 4
Rastelli procedure
TAPVC repair

AKI：acute kidney injury，ASD：atrial septal defect，VSD：ventricular septal defect，DORV：double outlet rightventricle，PA：pulmonary artery，AVAD：atrioventricular septal defect，TAPVC：total anomalous pulmonary venous
connection
No patients underwent category 5 or 6 procedures.

Table 4

Cardiopulmonary bypass clinical outcomesmBP（mmHg）
2
PI（L/min/m ）HGB（g/dL）
HCT（％）
Cerebral rSO2（％）
Cerebral rSO2 deterioration rate（％）
Abdominal rSO2（％）
Abdominal rSO2 deterioration rate（％）
2
DO2（mL/min/m ）VCO2（mL/min）
DO2/VCO2 ratio

non-AKI group（n＝48）

AKI group（n＝16）

p-value38.0（32.0-45.0）
2.4（2.2-2.7）
8.6（7.8-9.9）
26.0（23.1-29.8）
69.0（61.0-76.0）
15.2（9.7-23.7）
75.0（47.8-83.0）
2.1（0.0-6.2）
280.1（231.9-324.6）
78.9（62.4-97.4）
3.7（2.9-4.4）

36.0（31.0-40.0）
2.4（2.2-2.6）
8.9（7.7-10.7）
27.0（23.0-31.0）
71.0（63.0-78.0）
11.0（3.2-22.7）
72.0（62.0-81.0）
7.4（4.0-17.8）
306.4（256.3-361.2）
77.5（65.2-89.6）
4.0（3.1-4.7）

0.134（NS）
0.478（NS）
0.067（NS）
0.090（NS）
0.074（NS）
0.43 （NS）＜0.0010.03
0.117（NS）
0.844（NS）
0.70 （NS）

Data are presented as median（interquartile range）.
AKI：acute kidney injury，mBP：mean blood pressure，PI：perfusion index，HGB：hemoglobin，HCT：hematocrit，rSO2：regional oxygen saturation，DO2：oxygen delivery，VCO2：volume of exhaled carbon dioxide

After surgery, the AKI group showed increased

7.8ng/mL, the AUC was 0.69, the sensitivity was 75%,

urinary NGAL levels (0 hour：37.1ng/mL vs 5.6ng/

and the specificity was 42%. Two hours after the op-mL；p＝0.021). This trend continued throughout theeration, using a cut-off value of 8.1ng/mL, the AUC

first 2 hours after surgery, but no significant differ-

was 0.68, the sensitivity was 56%, and the specificity

ences were found between the two groups from 4

was 35% (Fig.2；Table 6).

hours onwards (Fig.1；Table 5).

Ⅳ．Discussion

The diagnostic value of urinary NGAL wasevaluated. After the operation, using a cut-off value ofStudies have shown a correlation between low

11.9ng/mL, the area under the curve (AUC) was 0.69,

intraoperative perirenal rSO 2 values and the develop-

the sensitivity was 75%, and the specificity was 44%.

ment of postoperative AKI following pediatric cardiac

One hour after the operation, using a cut-off value ofsurgery 21, 22). In this study, although the derived val-

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（ng/mL）
350
＊

300

urinary NGAL

250

＊

＊

AKI group200（n＝16）

non-AKI group（n＝48）

150
100
50
0

pre

Fig.1

0

1

2
4
8
Hours post operation

12

24

72

Analysis of urinary neutrophil gelatinase-associated lipocalin

Data are presented as mean±SEM.
＊
p＜0.05 AKI groups vs. non-AKI groups．AKI：acute kidney injury diagnosis.

Table 5Pre- and postoperative urinary neutrophil gelatinase-associated lipocalin levels＊

Time after
OP（h）

non-AKI group（n＝48）（ng/mL）

pre
0
1
2
4
8
12
24
72

5.8（1.9-12.3）
5.6（1.0-35.8）
3.7（0.5-16.6）
2.1（0.6-6.6）
2.7（1.4-9.0）
3.8（1.8-8.5）
4.2（1.4-10.1）
4.9（1.4-10.1）
6.3（2.4-10.7）＊

AKI group（n＝16）（ng/mL）＊＊

Data are presented as median（interquartile range）；
AKI：acute kidney injury，OP：operative，h：hours

p-value8.1±1.2
39.4±11.7
30.0±9.8
25.6±10.934.3±20.5
9.4±2.438.9±27.9
17.8±7.0
15.1±3.813.8±3.9
132.2±50.9
125.1±60.9170.0±111.5
119.4±83.1
25.3±11.2
15.4±3.824.1±6.6
12.1±3.2

0.084（NS）
0.021
0.030
0.045
0.210（NS）
0.070（NS）
0.586（NS）
0.634（NS）
0.659（NS）

Data are presented as mean ± SEM

1.00

Table 60.80

Time after
AUC
operation（h）

0.40

0.00
0.00

Fig.2

12

After operative 0 hours
After operative 1 hours
After operative 2 hours
0.20

0.40

0.60

1-speciﬁcity

0.80‌Performance of urinary neutrophil gelatinase-associatedlipocalin in acute kidney injury diagnosis

pre
0
1
2
4
8
12
24
72

0.60

0.20

＊＊

AKI group（n＝16）（ng/mL）

6.9（4.6-16.3）
37.1（11.1-148.3）
19.9（6.7-78.6）
11.4（2.3-62.9）
6.6（2.7-24.6）
11.1（4.8-20.9）
8.8（7.2-17.8）
17.7（4.9-28.7）
6.4（2.9-16.8）＊

Sensitivity＊＊

non-AKI group（n＝48）（ng/mL）

0.61
0.69
0.69
0.68
0.67
0.73
0.32
0.72
0.47

Sensitivity

1-specificity

4.2
11.9
7.8
8.1
6.1
9.0
54.4
20.3
0.0

0.81
0.75
0.75
0.56
0.60
0.67
1.00
0.50
0.20

0.25
0.42
0.42
0.35
0.33
0.43
0.63
0.40
0.09

h：hours，AUC：area under the curve

1.00‌Receiver operating characteristic curves of urinary
neutrophil gelatinase-associated lipocalin in acutekidney injury diagnosis

体外循環技術Cut-off value

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Table 7Comparison of studies for early diagnosis of acute kidney injury（AKI）
Bennett M

RACHS-1 scoreurinary NGAL（ng/mL）

This study

1.6±0.5 vs 2.9±0.6＊
53.0±20.7 vs 646.3±69.8

2.2±0.1 vs 2.6±0.2＊＊
39.4±11.7 vs 132.2±50.9

Data are presented as mean±SEM for non-AKI vs. AKI.
＊＊＊First time interval that showed significant results； 2 hours post-cardiopulmonary bypass
0 hours post-operative.

ues are nonspecific, the decreasing rSO 2 and increased

use and NO therapy in this population, which sug-lactic acid levels point towards hypoperfusion andgests pulmonary dysfunction from the remote effects

metabolic issues in the abdominal region.

of AKI.

Twelve hours after the operation, the maximum

The importance of early diagnosis and thera-

and minimum values of sCr in the AKI group were

peutic intervention for AKI was advocated in the

1.29mg/dL and 0.3mg/dL, respectively, compared toJapanese Clinical Practice Guideline for AKI 2016 19).

the reference values of 0.38mg/dL and 0.16mg/dL.

Monitoring changes in urinary NGAL can be usefulThis correlates with other studies that have reported

in the early diagnosis of AKI, and can help to reducethat in pediatric cases where the baseline values ofand prevent postoperative complications. However,sCr are very low, even a small rise in sCr can predict

when compared to other urinary biomarkers, NGAL

8)

AKI .

appears to be less sensitive and specific because

Several studies in both adult and pediatric cases

NGAL levels are affected by systemic inflammatory

have shown that urinary NGAL increases significant-reactions such as those caused by pneumonia and uri-

ly in AKI and may be an early biomarker of AKI.

nary tract infection 26). Indeed, in this study, there

In a similar study conducted by Bennett et al 14), thewas a substantial variation in the NGAL values ob-

AKI group had significantly higher RACHS-1 scores

tained. This suggests that AKI diagnosis requires a(2.9±0.6 vs 1.6±0.5) and higher urinary NGAL values

comprehensive clinical evaluation of creatinine levels

2 hours after CPB (646.3±69.8ng/mL vs 53.0±20.7ng/

against urinary biomarkers as well as the use of mul-mL) than the non-AKI group. The present study also

tiple biomarkers and testing methods.

14-18)

found that the AKI group exhibited significantly

This suggests that AKI diagnosis may require

higher RACHS-1 scores (2.6±0.2 vs 2.2±0.1) and uri-

the use of multiple biomarkers and testing methods.

nary NGAL levels after surgery (132.2±50.9ng/mL

Ⅴ．Conclusion

vs 39.4±11.7ng/mL)（Table 7）. Although the urinary
NGAL values obtained were lower in the present

In this study, urinary NGAL was evaluated as

study, results were very similar, particularly the earli-an early indicator of AKI after pediatric cardiac sur-

est time-point at which urinary NGAL levels became

gery using CPB.

significantly elevated. These results support the idea

The group of patients who developed AKI

that urinary NGAL may be an early biomarker ofshowed higher RACHS-1 scores and longer operative

renal failure.

and CPB times. While urinary NGAL in this AKI

Clinical investigations suggest that AKI is notgroup was found to moderately predict AKI, exhibit-

only an indicator of renal failure, but is also associateding AUC values of 0.7 or higher during the early post-with multiorgan dysfunction. One such extrarenal ef-

operative period, there was substantial variation infect of AKI is pulmonary dysfunction, which is medi-

the NGAL values obtained.

ated via different mechanisms including increased

Urinary NGAL has a moderate correlation withlung vascular permeability and neutrophil infiltra-

AKI occurrence, and may be useful for predictingtion

AKI early in the perioperative period after pediatric23, 24). A previous study reported an association

between high RACHS-1 scores and longer ventilator
use

25)

. In the present study, although there was no

significant difference in P/F ratio among the more
complicated cardiac surgical cases in the AKI group,
there was a tendency towards prolonged ventilator
体外循環技術cardiac surgery cases using CPB.
［Disclosures］This research was conducted in collaboration
with Abbott Japan Co., Ltd. Abbott Japan Co., Ltd paid for thecollection, reagent fee, and measurement costs of the urinary
samples.

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体外循環技術Vol.47No.1

2020