Download Urinary Interleukin-18 level as an Early Biomarker in Acute Kidney

Urinary Interleukin-18 level as an Early Biomarker in Acute Kidney Injury in
Critically Ill children.
Abd El-Hameed. A. Abd El-Hameed a , Shaheen. A. Dabour , Soha. A. Ibrahim a, Eman. R. Abd ElGwad b, Eman. R. A bd-Almonaema, Effat. H. Assara and Wesam. E. Afifi a..
a The Pediatric Department, Faculty of Medicine, Benha University, Egypt.
b Clinical Chemical Pathology Department, Faculty of Medicine, Benha University, Egypt.
Correspondence to Wesam. E. Afifi, email
Abstract
Background: Interleukin-18 is a protein which in humans which encoded by the IL18 gene .The protein
encoded by this gene is a pro inflammatory cytokine which is a mediator of renal ischemia–reperfusion
injury, causing acute tubular necrosis, and neutrophil and monocyte infiltration of the renal parenchyma, so
urinary IL-18 level has been shown a good biomarker in predicting AKI .
Aim The aim of this work is to study of urinary interleukin -18 as an earlier predictor of AKI in critically ill
children.
Methodology: Fifty critically ill patients were included in our study (22 males, 28 females), patients collected
from the Pediatrics ICU, Pediatric Department, Benha University Hospital. During the period from January
2015 to January 2016. The following investigations were done for all patients: CBC, CRP, urea, creatinine,
blood culture, Na, K, glucose, albumin, ABG, bleeding profile & urinary IL-18, urinary IL-18 were measured
on admission & after 48 hours.
Results: the incidence of AKI was 44%, 3 patients from them were received dialysis, the most common
admission diagnosis was infectious causes (44.8%), Urinary interleukin 18 has higher both sensitivity
(90.9%) & specificity (92.9%) & has both better positive predictive value & negative predictive value. Serum
creatinine has higher specificity (100%) & lower sensitivity (68.2%) & has good negative predictive value,
but low in positive predictive value. Urinary interleukin 18 is better in predication of AKI than serum
creatinine, as we can see from ROC curve that interleukin 18 has higher area under the curve (0.947) than
creatinine (0.908). The best cut values for urinary interleukin 18 & serum creatinine from ROC curve, for
creatinine the best cut value is 0.35 with sensitivity 95.5% & specificity 75% while for urinary interleukin
18 we can see that the best cut value was 80 with high both sensitivity (95.5%) & specificity (92.9%) which
con firms that interleukin 18 is a better in predication of AKI than serum creatinine.
Conclusion: urinary interleukin -18 as an earlier predictor of AKI in critically ill children prior
to rise serum creatinine.
Keywords: urinary Interleukin-18, Acute kidney injury, Systemic review, Predictive value.
Introduction:
Acute kidney injury (AKI) is characterized by a sudden and generally revertible renal function
impairment, involving inability to maintain the normal homeostasis, and may or not be
accompanied by reduced diuresis. Usually, AKI is categorized as pre-renal, related to reduced
renal blood flow for inappropriate cardiac output or intravascular volume; intrinsic renal disease,
from an insult to the renal parenchyma including ischemic , tubular, vascular or glomerular
disorders; and post renal , due to urinary tract obstruction either in single kidney or both kidneys(1).
During the childhood, the main AKI causes are sepsis, renal ischemia, and nephrotoxic
drugs in critically ill patients (1).
These patients, particularly those staying in intensive care units, are exposed to a number
of conditions which may lead to renal impairment, thus significantly increasing the morbity &
mortality rate. (2)
Acute kidney injury occurs in approximately 30% of patients admitted to the intensive care
unit and is commonly associated with multiple organ dysfunction syndromes. It is now known that
acute kidney injury has a negative impact on patient morbidity and mortality that is caused mainly
by non-renal organ failure (3).
Although regarded as the standard indicators of kidney function loss, serum creatinine
(sCr) level and urine output are recognized as having limitations. On the one hand, sCr cannot
accurately reflect the GFR in a patient with unsteady state, and urine output is easily affected by
water intake and the primary fluid state of the body (4). On the other hand, sCr and urine output
have limited sensitivity and specificity, and a delayed response to kidney impairment. All these
factors suggest that sCr and urine output are not appropriate markers in the early detection of AKI.
Thus, an accurate and timely biomarker to predict AKI onset or progression after renal insult is
urgently needed.
Interleukin-18 is an eighteen pro-inflammatory cytokine up-regulated during endogenous
inflammatory processes, and also it plays an important role in the pathophysiology of sepsis (5). it
is necessary to evaluate the utility of urinary interleukin-18 as an AKI biomarker to clarify the
relation between AKI, sepsis & mortality in critically ill patients with varying degree of underlying
infection (6).
The advances in new biomarkers that increases early clinical diagnosis capacity and the
implementation of possible early treatment have promoted the study of AKI in children. Despite
these advances and new technologies in renal replacement therapies, the mortality rate from AKI
is still elevated. (7)
Patient & methods:
This study was conducted on patients collected from the Pediatrics ICU, Pediatric Department,
Benha University Hospital. During the period from January, 2015 to January, 2016. Informed
consents were taken from parents of included patients. The study was approved by the ethical
committee of Benha University Then the cases were be further subdivided into two groups
according to pRIFLE .
Patient: 50 critically ill patients admitted to our ICU were divided into groups:
Group (I): PICU cases without acute kidney injury (28 cases). Group (II): PICU cases with acute kidney
injury (22 cases).The group (II) cases were classified into subgroups according to pediatric RIFLE maximum
(pRIFLE max) which refer to the worst GFR during PICU stay period. Into 3 subgroups (R: Risk , I:
Injury& F: Failure ) .The patient’s normal baseline GFR value of 100ml/1.73m2/24h was considered as a
reference(8). Our cases are selected according to the following inclusion and exclusion criteria:
Inclusion criteria: Both sex were included, Requirement for mechanical ventilation And / or More than
one system failure (e.g. shock, respiratory failure, coma, IEM, DIC).
Exclusion criteria: less than one month of age, more than 18 years of age, less than 24 hours
stay in PICU, brain death at admission and chronic kidney disease which defined as GFR is
less than 60ml/min1.73m2, for 3 months or more(9), end stage renal disease on regular
hemodialysis, patients need medication of nephrotoxic drugs.
Methodes:
All our subject were submitted to the following: Full history ( Age and sex, History of the presenting problem,
History of other systems affection (renal and non-renal), Administration of any medication), General
examination including (Blood Pressure , weight, height, respiratoy distress, conscious level, UOP), Systemic
examination (chest , heart , abdominal and neurological examination), and Laboratory investigations ( CBC,
CRP, urea, creatinine, blood culture, Na, K, glucose, ABG, liver profile, bleeding profile, urinary interleukin18) GFR Glomerular filtration rate (GFR) was estimated using the following equation The original Schwartz
formula is: crCl = k* height / serum creatinine (10).
Height is measured in cm. Serum creatinine is measured in mg/dl. (National Kidney Disease Education
Program recommendation).
Two Urine samples were taken for measurement of interleukin -18 (one on admission & second sample 24
hours after admission), with Normal range: 5ng/ L– 100ng /L.
Statistical methods:
Data management and statistical analysis were performed using the Statistical Package for Social
Sciences (SPSS) vs. 22.
Numerical data were summarized using means and standard deviations or median and ranges (if
non parametric). Categorical data were summarized as numbers and percentages. Comparisons between
the 2 groups with respect to normally distributed numeric variables were done using the independent t-test
or Mann Whitney’s U test (if non parametric). For categorical variables, differences were analyzed with 2
(chi square) test or Fisher’s exact test when appropriate.
Spearman Correlation between variables was done, “rs” (Spearman correlation coefficient) ranges
from +1 to -1, a value of 0 indicates that there is no association between the two variables; a value greater
than 0 indicates a positive association; a value less than 0 indicates a negative association.
Standard diagnostic indices including sensitivity, specificity, positive predictive value (PPV),
negative predictive value (NPV) were calculated for IL18 and Creatinine.
Receiver operator characteristics (ROC curve) was used to determine the best cut off point of IL18
and Creatinine for prediction of acute kidney injury.
All p-values are two-sided. P-values < 0.05 were considered significant.
RESULTS:
Our results will be demonstrated in the following tables & figures:
Table (1): Study profile regarding incidence of AKI & its class
Classification
N
%
Normal
28
56.0
Risk
3
6.0
Injury
9
18.0
Failure
10
20.0
Table (2): Statistical comparison between AKI and non AKI cases regarding to least UOP & renal
functions parameters:
Non AKI
cases(I)
AKI
Cases(II)
P value
Median
1.4
0.9
<0.001
Minimum
0.9
0.1
Maximum
2.5
1.9
Highest urea
Mean
30.6
131.8
(mg/dl)
±SD
3.9
61.5
Least UOP (ml/kg h)
Highest creatinine
(mg/dl)
Lowest GFR
(ml∕min∕1.73m2)
Minimum
25
35
Maximum
38
305
Median
0.4
1.2
Minimum
0.2
0.7
Maximum
0.6
6
Median
97.47
32.13
Minimum
75
10.4
Maximum
137.5
75.71
<0.001
<0.001
<0.001
Table (3): Statistical comparison between AKI and non AKI cases regarding urinary interleukin 18 on
admission & after 48 hours:
IL18 on admission
(ng/ L)
IL18 at 48h
(ng/L)
Non AKI
cases(I)
AKI
Cases(II)
P value
Median
40
190
<0.001
Minimum
14
40
Maximum
70
230
Median
50
310
Minimum
20
40
Maximum
80
440
<0.001
Table (4): Statistical comparison between AKI and non AKI cases regarding serum creatinine on
admission & after 48 hours:
Non AKI
Cases(I)
AKI
Cases(II)
P value
Creatinine on admission
(mg/dl)
Creatinine at 48h
(mg/dl)
Median
0.3
0.5
Minimum
0.2
0.3
Maximum
0.5
0.9
Median
0.3
0.9
Minimum
0.2
0.4
Maximum
0.6
1.3
<0.001
<0.001
Table (5): Standard diagnostic indices for urinary interleukin 18:
RIFLE
Positive (N=22)
Negative (n=28)
N
%
N
%
Positive
20
90.9
2
7.1
IL18
Negative
2
9.1
26
92.9
Sensitivity= 90.9 % , Specificity= 92.9 %, PPV= 90.9 %, NPV= 92.9 %
Table (6): Standard diagnostic indices for serum creatinine:
RIFLE
Positive (N=22)
Negative (28)
n
%
N
%
15
68.2
0
0.0
Creatinine Positive
Negative
7
31.8
28
100.0
Sensitivity= 68.2 %, Specificity= 100 % , PPV= 100 %, NPV= 80 %
Total
22
28
Total
15
35
Fig. (1): Receiver operating characteristic (ROC) curve to detect the sensitivity and specificity of
urinary interleukin-18 on admission versus serum creatinine in predicting acute kidney injury.
Table (7): comparison of the area under ROC curve (AUC) between urinary interleukin18 and serum
creatinine:
IL18
AUC
0.947
Std. Error
0.037
P value
< 0.001
95% C.I.
0.875 – 1
Creatinine
0.908
0.04
< 0.001
0.83 - 0.987
Table (8): best cut-off values for urinary Interleukin18 and serum creatinine:
IL18
Creatinine
Cutoff value
80
0.35
Sensitivity
95.5
95.5
Specificity
92.9
75.0
DICUSSION:
The critically ill patients, particularly those staying in intensive care units, are exposed to
a number of conditions which may lead to renal impairment, thus significantly increasing the
morbidity & mortality rate (2).
Infectious causes were most common causes of admission in our study (44.8%), followed
by heart failure (11.7%) & neurological causes (11.7%) denoting that infection was the most
significant causes of PICU admission.
Our study includes 50 critically patients 22 males (44%) and 28 females (56%) with median
value of age was 0.67 year in non AKI cases and 2.75 year in AKI cases which shows statistically
significant difference (p value 0.02).
The incidence of AKI in this study was (44%), representing (22) cases, out of (50) cases
admitted to the PICU admission. As regard to the incidence of AKI in various studies, the incidence
was variable as Hoste et al., 2006 (11) reported incidence of 67.2%. while Ostermann
&Chang,2007(2) reported AKI incidence of 35.8%. Bagshaw et al.,2008 (12) reported incidence of
36.1 %. Plotz et al.,2008 (13) reported incidence of 58 %. Keina et al.,2010 (14) reported that the
incidence of AKI was 82%. This variation can be explained by specific epidemiological
characteristics according to the area of study.
The group II was subdivided into 3 subgroups representing the classes of AKI (severity)
according to pRIFLE : Class (R) Risk, Class (I) injury & Class (F) failure In this study the
different AKI classes incidences at maximal RIFLE were as the followings : 3 cases R (13.65%),
9 cases I (40.9%) & 10 cases F (45.45%).
The AKI level incidence was different in other studies as keina et al.,2010 (14) reported that
the maximal RIFLE score found during the patients stay was 39.1% for class (R), 37.2% for class
( I ) and 21.8% for class (F) while Akcan et al.,2007 (8) found 48.8%, 26% and 25.2%,respectively.
Plotz et al .,2008 (13) reported incidences of 52%, 37% and11%, respectively .This variability of
incidences can be explained by keina et al., 2010 (14) who reported that the cause of this variability
was due to different populations studied, and the different ICU characteristics.
Dialysis was needed in 3 patients (13.6 %) who were classified as RIFLE III stage of AKI
(failure) having massively increased levels of serum creatinine of the 2nd samples in relation to the
1st samples and prolonged duration of oliguria. 2 of them were improved & one died, the patient
of AKI group received conservative management. Blood pressure significantly decreased in group
I (53.6 %) of cases compared to group II (36.4),while increased in group II (45.5%) of cases
compared to group I (3.6%) & normal blood pressure level is higher in group I (42.9%) compared
to group II (18.2%).
As regards to sepsis there significant difference between two groups as sepsis was (72.7%)
in group II compared to group I (42.9%). This agree with some studies which referred to sepsis as
a cause and a consequence of AKI (Zapitelli, 2011 (15) and Mehta et al., 2002 (16), another
American study referred to sepsis as a less important cause of AKI, being replaced by other causes
such as oncologic and hematological causes in addition to respiratory failure (Williams et al.,
2002(17).
In addition, our study showed that dehydration was significantly associated with
development of AKI as severe dehydration are common in group II (22.7%) than group I (3.6%),
bad perfusion is common in group II (68.3%) than group I (39.3%) and that was in agreement with
a Turkish study which showed that, according to the acute kidney injury network (AKIN)
definitions and classifications, dehydration is considered one of the important AKI risk factors
(Ozçakar et al.,2009 (18). It is also in agreement with Lameire et al.,2005 (19) who reported that
shock was one of the risk factors for AKI and had been implicated in the pathophysiology of AKI,
as during these periods (hypoperfusion), as a result of either cardiovascular shock or the
vasoconstrictive auto regulatory process, as the metabolically active tubular epithelium is placed
under hypoxic/ischemic stress.
In group I, urinary interleukin on admission ranged from (14-70 ng / L) the median value
is 40 ng/ L, urinary interleukin at 48 h ranged from (20- 80 ng / L) the median value is 50 ng/ L.
While in group II, urinary interleukin on admission ranged from (40-230 ng/ L) the median
value is 190 ng/ L, urinary interleukin at 48h ranged from(40-440 ng/ L) the median value is 310
ng/ L.
There is highly statistical significant differance in urinary interleukin -18 on admission &
at 48hours after admission between group II and group I with p value<0.001, it was higher in
group II on admission & after 48hours.
In group I, serum creatinine on admission ranged from (0.2- 0.5 mg/dl) the median value
is 0.3 mg/dl , serum creatinine at 48h ranged from(0.2 -0.6 mg/ dl) the median value is 0.3 mg/ dl.
While in group II, serum creatinine on admission ranged from (0.3- 0.9 mg/dl) the median value
is 0.5 mg/dl , serum creatinine at 48h ranged from(0.4 -1.3 mg/ dl) the median value is 0.9 mg/ dl.
There is highly statistical significant differance in serum creatinine on admission & at
48hours after admission between group II and group I with p value<0.001. it was higher in group
II 48h after admission. but this difference in serum creatinine on admission clinically insignificant
as the level is in normal range in both group.
Regarding patients' laboratory results, the 1st serum creatinine sample taken upon
enrollment showed no clinical significant difference between patients with AKI and those with no
AKI, while the 2nd sample that was taken 48 hours later was significantly higher in patients with
AKI. These results were in agreement with multiple studies that serum creatinine can be used as a
late marker for diagnosis of AKI (Honore et al.,2007 (20)and Melnikov and Molitoris,2008 (21).
While the 1st serum creatinine sample was not an indicator of evident AKI, the 1st urinary
interleukin-18 sample taken at the same time was significantly higher in patients with AKI and
subsequently, the 2nd urinary interleukin-18 sample that was taken 48 hours later, in addition to
the interleukin-18 rise in both samples which showed the same significant rise in patients with
AKI.
This was in accordance with many other studies which proved that interleukin-18
contributes to renal damage after ischemia-reperfusion injury and that ischemic kidney tissue
damage initiates production of interleukin-18 (Wu et al.,2008 (22) and also proved that interleukin18 is increased in the glomeruli of patients with autoimmune lupus nephritis (LN) (Calvani et
al.,2004(23).
All of the previous results confirm that rise of urinary interleukin-18 level preceded rise of
serum creatinine level by 48 hours in critically ill children who developed AKI which was in
agreement with many other studies that showed the same fact (Parikh et al,2006 (24) ,
Devarajan,2008 (25), and Washburn et al.,2008 (6). However, a single recent American study
showed that urinary interleukin-18 did not reliably predict AKI development, but did predict only
poor clinical outcomes, but we have to clarify that this study was different for being performed on
adults, not children (Siew et al., 2010(26).
Urinary interleukin 18 showed highly statistical significant positive correlation with
highest urea, highest creatinine & serum K, and show highly statistical significant negative
correlation between urinary interleukin 18 & lowest UOP, GFR, PH &bicarbonate with p
value<0.001
There was significant negative correlation between interleukin 18 & HB, platelet , CRP &
serum albumin with p value =0.002, and there were no significant correlation between interleukin
18 & other parameters.
Serum creatinine showed highly statistical significant positive correlation with highest
urea, highest creatinine & serum K, and show highly statistical significant negative correlation
between serum creatinine & lowest UOP, GFR, PH &bicarbonate with p value<0.001
There was significant negative correlation between serum creatinine & HB& platelet with
p value =0.02, and there are no significant correlation between interleukin 18 & other parameters.
Urinary interleukin 18 has higher both sensitivity (90.9%) & specificity (92.9%) & has
both better positive predictive value & negative predictive value.
Serum creatinine has higher specificity (100%) & lower sensitivity ( 68.2%) & has good
negative predictive value , but low in positive predictive value.
Urinary interleukin 18 is better in predication of AKI than serum creatinine, as we can see
from ROC curve that interleukin 18 has higher area under the curve (0.947) than creatinine (0.908).
The best cutoff values for urinary interleukin 18 & serum creatinine from ROC curve, for
creatinine the best cut value is 0.35mg/dl with sensitivity 95.5% & specificity 75% while for
urinary interleukin 18 we can see that the best cut value was 80 ng/L with high both sensitivity
(95.5%)& specificity(92.9%) which confirms that interleukin 18 is a better in predication of AKI
than serum creatinine.
Somewhat different cut off levels were reported by (Washburn et al,(8) who found that
interleukin-18 concentration in critically ill children at cut off level of 100 ng /l had the best
specificity (81%) to predict AKI development upon enrollment, while at cut off level 200 ng /l,
interleukin-18 had the highest specificity (93%) and to predict AKI after 48 hours after admission.
This might suggest that the test needs further standardization and layer scale study to be
used routinely for detecting AKI in different populations in the critical care setting.
Conclusion:
Our study showed that elevation of urinary interleukin-18 level preceded rise in serum creatinine
level in critically ill patients who developed AKI by 48 hours, making the urinary interleukin-18
is an early AKI biomarker in this category of children.
Recommendation:
Frequent monitoring and observation of critically ill children admitted to pediatric intensive care
unit which is extremely important to prevent AKI that represents a significant but under-recognized
problem in clinical medicine, with serious immediate and long-term consequences, Further
researches should continue to identify new risk factors that could be responsible for occurrence of
AKI in PICU, Further studies have to be done in order to confirm and properly utilize the urinary
interleukin-18 as an early acute kidney injury biomarker in critically ill children.
Conflict of interest:
None declared.
Acknowledgement:
We like to thank all the doctors who participated in the study, the parents of the patients and the nursing staff.
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