Keywords
acute kidney injury - accuracy - cystatin C - perinatal asphyxia - neonates
Introduction
The kidneys of neonates are particularly susceptible to hypoperfusion because of the
physiologic characteristics of neonatal kidneys, including high renal vascular resistance,
high plasma renin activity, low glomerular filtration rate (GFR), decreased intracortical
perfusion rate, and decreased reabsorption of sodium in proximal convoluted tubules
in the first day of neonatal life.[1] Acute kidney injury (AKI) is defined as kidneys' inability to excrete nitrogenous
waste products and maintain fluid and electrolyte homeostasis. It is fairly common
in newborn population and is a major contributing factor of neonatal mortality and
morbidity.[2]
[3]
Perinatal asphyxia (PA) is a serious event that can have significant consequences
during the neonatal period. It is a common issue in neonatal care and a major cause
of morbidity and mortality among term and preterm neonates.[4] The incidence of PA is estimated to be between 5 and 10 per 1,000 live births and
is influenced by factors such as birth weight, gestational age, and access to medical
resources in the local area.[5] PA can result in multiorgan dysfunction through redirection of cardiac output to
maintain cerebral, cardiac, and adrenal perfusion while potentially compromising perfusion
to nonvital organs including skin perfusion, gastrointestinal tract, and kidneys,
causing AKI.[6]
[7]
[8] The incidence of AKI after PA in term neonates ranged from 30 to 56%. During PA,
the neonate's body tries to compensate for the lack of oxygen by redirecting blood
flow to vital organs, such as brain and heart, at the expense of other organs, such
as kidneys. This can lead to reduced blood flow to the kidneys, which can damage the
kidney tissue and lead to AKI.[9]
Human cystatin C (CystC) is a small protein produced by all nucleated cells and filtered
through the glomerular basement membrane in the kidneys. It is a reliable marker of
GFR as it is freely filtered and almost completely reabsorbed in the proximal tubules,
without being secreted or metabolized in the kidneys. Due to its characteristics,
CystC is considered a more accurate marker of renal function than creatinine, especially
in neonates with impaired renal function.[10] Early detection of AKI is crucial for timely interventions to prevent further kidney
damage and improve patient outcomes. Currently, serum creatinine is the most commonly
used marker for diagnosing AKI, but it has limitations, particularly in neonates.
Creatinine production is influenced by muscle mass, which is variable in neonates,
and it does not increase until after a significant reduction in GFR has occurred.[11]
[12] Several studies have shown that CystC is a useful biomarker for the early detection
of AKI in neonates. In a study conducted in a neonatal intensive care unit (NICU),
CystC was found to be a better predictor of AKI than creatinine.[13]
[14]
[15] Another study found that CystC was significantly elevated in neonates with AKI compared
with those without AKI, and that CystC levels were detectable before serum creatinine
levels increased.[16]
The current study aimed to investigate the role of serum CystC as an early predictor
for both diagnosis and short-term outcome evaluation of AKI in full-term neonates
with PA admitted to NICU.
Patients and Methods
Study Setting and Design
A prospective cohort study was performed at the NICU of Assiut University Children
Hospital, Assiut, Egypt from January 2019 to January 2021. Approval of the local ethics
committee broad was obtained (approval # 17200233, 06/08/2018), and the study was
conducted according to Declaration of Helsinki. The inclusion criteria were full-term
neonates (37–42 weeks of gestation), admitted with PA, which was confirmed by the
presence of at least two of the following criteria: fetal distress (heart rate <100
beats/minute, late decelerations, or an absence of heart rate variability), thick
meconium-stained amniotic fluid and respiratory depression, hypotonia, or bradycardia,
low Apgar score (less than 5 at 1 minute or 7 or less at 5 minutes), need for advanced
resuscitation (with positive pressure ventilation and oxygen immediately after birth)
for more than 1 minute, and blood pH value of less than 7.20 or a base deficit of
at least 12 mmol/L within the first hour after birth.[17] The study excluded neonates who met any of the following criteria: gestational age
<37 or > 42 weeks, AKI due to causes other than asphyxia, (e.g., septicemia, respiratory
distress syndrome, necrotizing enterocolitis, and major congenital anomalies of skeletal,
kidney, and urinary tract) or newborns who were born to mothers with renal insufficiency,
or who were given nephrotoxic drugs such as aminoglycosides. AKI was defined as an
increase in serum creatinine of 0.3 mg/dL or more (≥26.5 µmol/L) or 50% or more from
the previous lowest value, or a urinary output of < 1 mL/kg/h on postnatal days 2
to 7, according to the Kidney Disease: Improving Global Outcomes workgroup modified
AKI definition for neonates.[18]
[19] All neonates showing signs of hypoxic-ischemic encephalopathy (HIE) were classified
according to the Sarnat and Sarnat scoring system[20] into three stages, according to the conscious level, neurological, and autonomic
parameters.
Sample Size Calculation
Total coverage sample technique was applied where all full-term neonates who were
admitted to NICU with documented PA during the study period were eligible for the
study. A total of 70 full-term neonates (37–42 weeks of gestation) with PA were enrolled
in the study.
Methods
Before enrolling their neonates in the study, the parents were asked to provide written
consent after being informed of the study's details. On admission, all neonates were
subjected to the following: full history evaluation including maternal condition during
pregnancy (hypertension, premature rupture of membrane, or diabetes mellitus). Natal
history included mode and duration of delivery and antepartum or postpartum hemorrhage.
Postnatal history including first cry, cyanosis, Apgar score at 1, 5, and 10 minutes,
need for resuscitation, medications, anesthesia, respiratory distress, and convulsions.
On admission, thorough clinical evaluation was done in form of vital signs (heart
rate, respiratory rate, and temperature), general examination, systemic examination,
and anthropometric measurements (daily follow-up of body weight and weekly follow-up
of head circumference). On admission, blood glucose, arterial blood gases, and blood
grouping were done. Other routine laboratory investigations as complete blood count,
coagulation profile, serum electrolytes (sodium, potassium, and calcium), urine analysis,
urinary sodium and potassium, and liver function tests were done on the second day
of life except in case of antepartum hemorrhage, complete blood count was done on
admission. Follow-up of these routine investigations was individualized according
to each case progression. Daily follow-up of serum creatinine was done for all neonates
with PA in the first 3 days of life and continued for the seventh day for those in
neonates with rising level. Radiological evaluation was done on the day of admission
by abdominal ultrasound to exclude the possibility of any congenital structural anomalies
in kidneys or urinary tract.
Serum CystC was estimated during the first day of life by utilized Human Cystatin
C (Cys-C) ELISA kit (SinoGeneClon BiotechCo., Ltd, Hangzhou, China).
Statistical Analysis
Analyzes was made by IBM SPSS Statistics for Windows, version 23 (IBM SPSS, IBM Corp.,
Armonk, New York, United States). Shapiro–Wilk's test was used to evaluate normal
data distribution. The variables were expressed as mean ± standard deviation for parametric
parameters and as frequency (%) for categorized parameters. Unpaired Student “t” test was performed to compare difference between parametric between two groups,
while Pearson's chi-square analysis was used to compare categorized variables. Predictors
of AKI in the current study were determined by logistic regression analysis. Cutoff
point of serum CystC and area under the curve (AUC) for prediction AKI in full-term
neonates with PA was determined by receiver operating characteristics (ROC) curve.
Level of confidence was kept at 95%, and hence, p-value was significant if p < 0.05.
Results
Risk Factors for Development of AKI and PA
Out of 70 neonates with PA included in the study, 21 (30%) neonates developed AKI,
while the other 49 (70%) neonates did not develop AKI. There were insignificant differences
between neonates with and without AKI except for significantly lower birth weight
among AKI group (2.83 ± 0.65 vs. 3.19 ± 0.56 kg, p < 0.001). The number of neonates with low birth weight (LBW) were significantly higher
in those with AKI versus those without AKI (57.1 vs. 28.6%, p = 0.020). Frequency of antepartum hemorrhage was significantly higher among AKI group
versus those without AKI (28.6 vs. 6.1%; p = 0.010). Other risk factors as obstructed labor, meconium aspiration syndrome, cord
prolapses, and rupture uterus showed insignificant differences between both groups
([Table 1]).
Table 1
Risk factors for development of AKI and perinatal asphyxia in full-term neonates
|
Risk factors
|
Neonates with AKI
(n = 21)
|
Neonates without AKI
(n = 49)
|
p-Value
|
|
Neonatal risk factors for AKI
|
|
Gender
|
|
Male
|
12 (57.1%)
|
30 (61.2%)
|
0.120
|
|
Female
|
9 (42.9%)
|
19 (38.8%)
|
|
Gestational age (wk)
|
38.99 ± 2.02
|
39.93 ± 1.01
|
0.550
|
|
Birth weight (kg)
|
2.83 ± 0.65
|
3.19 ± 0.56
|
< 0.001
|
|
Low birth weight
|
12 (57.1%)
|
14 (28.6%)
|
0.020
|
|
Length (cm)
|
44.44 ± 0.53
|
45.86 ± 0.97
|
0.060
|
|
Maternal risk factors for AKI
|
|
Maternal age (y)
|
24.76 ± 6.39
|
25.22 ± 5.99
|
0.770
|
|
Gravidity
|
2 (0–4)
|
1 (0–5)
|
0.180
|
|
Multiple gestation
|
3 (14.3%)
|
5 (10.2%)
|
0.450
|
|
Mode of delivery
|
|
Vaginal delivery
|
13 (61.9%)
|
26 (53.1%)
|
0.190
|
|
Cesarean section
|
8 (38.1%)
|
23 (46.9%)
|
|
Comorbidities
|
|
Hypertension
|
2 (9.5%)
|
3 (6.1%)
|
0.470
|
|
Urinary tract infection
|
3 (14.3%)
|
6 (12.2%)
|
0.540
|
|
Diabetes mellitus
|
1 (4.8%)
|
2 (4.1%)
|
0.660
|
|
Preeclampsia
|
2 (9.5%)
|
3 (6.1%)
|
0.470
|
|
Premature rupture of membrane
|
1 (4.8%)
|
3 (6.1%)
|
0.650
|
|
Drug usage
|
|
Antibiotics
|
2 (9.5%)
|
6 (12.2%)
|
0.340
|
|
Nonsteroidal anti-inflammatory drugs
|
3 (14.3%)
|
7 (14.3%)
|
0.650
|
|
Steroids therapy
|
1 (4.8%)
|
3 (6.1%)
|
0.650
|
|
Hypoglycemic agents
|
1 (4.8%)
|
2 (4.1%)
|
0.660
|
|
Magnesium sulfate (MgSO4)
|
2 (9.5%)
|
3 (6.1%)
|
0.470
|
|
Risk factors for perinatal asphyxia
|
|
Antepartum hemorrhage
|
6 (28.6%)
|
3 (6.1%)
|
0.010
|
|
Obstructed labor
|
13 (61.9%)
|
27 (55.1%)
|
0.390
|
|
Meconium aspiration syndrome
|
6 (28.6%)
|
18 (36.7%)
|
0.350
|
|
Cord prolapses
|
8 (38.1%)
|
12 (24.5%)
|
0.190
|
|
Rupture uterus
|
2 (9.5%)
|
5 (10.2%)
|
0.650
|
Abbreviation: AKI, acute kidney injury.
Statistical significant p-Values are shown in bold.
Clinical Data and Management of Neonates with and without AKI
There was significant increase among neonates with AKI versus those without AKI in
hypotension (38.1 vs. 12.2%, p = 0.010), frequency of mechanical ventilation (MV) (61.9 vs. 18.4%, p < 0.001), use of vasopressor (28.6 vs. 6.1%; p = 0.040), duration of MV (5.22 ± 1.55 vs. 2.56 ± 1.23 days, p = 0.040), and usage of vasopressor (3.40 ± 1.98 vs. 1.50 ± 0.50 days, p = 0.030). Normal urine output in neonates with AKI was significantly lower than those
without AKI (61.9 vs. 100.0%, p < 0.001). It was found that majority (61.2%) of neonates without AKI group had stage-I
HIE, while majority (61.9%) of those with AKI had stage-III with significant differences
between both groups (p < 0.001). Length of hospital stay was significantly longer among those with versus
those without AKI (8.28 ± 2.14 vs. 5.41 ± 1.32 days, p < 0.001). Majority of neonates without AKI were discharged (95.9%) and only two neonates
(4.1%) were died. Meanwhile, in patients with AKI, only 11 cases (52.4%) were discharged
and 10 (47.6%) neonates were deteriorated and died with significant differences between
both groups (p < 0.001) ([Table 2]).
Table 2
Clinical data and management of full-term neonates with perinatal asphyxia based on
development of AKI
|
Data
|
Neonates with AKI
(n = 21)
|
Neonates without AKI
(n = 49)
|
p-Value
|
|
Heart rate
|
|
Normal (120–160 beat/min)
|
13 (61.9%)
|
25 (51%)
|
0.650
|
|
Tachycardia
|
5 (23.8%)
|
17 (34.7%)
|
|
Bradycardia
|
3 (14.3%)
|
7 (14.3%)
|
|
Respiratory rate
|
|
Normal (40–60 cycle/min)
|
10 (47.6%)
|
26 (53.1%)
|
0.840
|
|
Tachypnea
|
7 (33.3%)
|
13 (26.5%)
|
|
Bradypnea
|
4 (19%)
|
10 (20.4%)
|
|
Apgar score
|
|
At 1 min
|
4.52 ± 0.51
|
4.88 ± 0.88
|
0.090
|
|
At 5 min
|
6.14 ± 0.47
|
6.39 ± 0.78
|
0.190
|
|
Blood pressure (table based)
|
|
Normotensive
|
13 (61.9%)
|
43 (87.8%)
|
0.010
|
|
Hypotensive
|
8 (38.1%)
|
6 (12.2%)
|
|
Edema
|
2 (9.5%)
|
9 (18.4%)
|
0.290
|
|
Convulsion
|
3 (14.3%)
|
11 (22.4%)
|
0.330
|
|
Urine output
|
|
Oliguric
|
8 (38.1%)
|
–
|
< 0.001
|
|
Normal urinary output
|
13 (61.9%)
|
49 (100%)
|
|
Stage of hypoxic-ischemic encephalopathy
|
|
I
|
3 (14.3%)
|
30 (61.2%)
|
< 0.001
|
|
II
|
5 (23.8%)
|
16 (32.7%)
|
|
III
|
13 (61.9%)
|
3 (6.1%)
|
|
Chest compression
|
11 (52.4%)
|
26 (53.1%)
|
0.580
|
|
Positive pressure ventilation
|
13 (61.9%)
|
32 (65.3%)
|
0.170
|
|
Mechanical ventilation
|
13 (61.9%)
|
9 (18.4%)
|
< 0.001
|
|
Duration (days)
|
5.22 ± 1.55
|
2.56 ± 1.23
|
0.040
|
|
Central catheterization
|
2 (9.5%)
|
5 (10.2%)
|
0.650
|
|
Blood transfusion
|
7 (33.3%)
|
5 (10.2%)
|
0.060
|
|
Use of vasopressor
|
6 (28.6%)
|
3 (6.1%)
|
0.030
|
|
Duration (days)
|
3.40 ± 1.98
|
1.50 ± 0.50
|
0.030
|
|
Total parenteral nutrition duration (days)
|
5.14 ± 0.50
|
5.39 ± 0.78
|
0.190
|
|
Length of hospital stay (days)
|
8.28 ± 2.14
|
5.41 ± 1.32
|
< 0.001
|
|
Outcome
|
|
Discharged
|
11 (52.4%)
|
47 (95.9%)
|
< 0.001
|
|
Died
|
10 (47.6%)
|
2 (4.1%)
|
Abbreviation: AKI, acute kidney injury.
Statistical significant p-Values are shown in bold.
Laboratory Investigations in Neonates with and without AKI
In neonates with AKI versus neonates without AKI, there were significant increase
in 48-hour creatinine (103.22 ± 10.11 vs. 99.48 ± 5.35; p < 0.001), 72-hour creatinine (295.19 ± 44.56 vs. 91.33 ± 6.65; p < 0.001), and serum CystC (1.50 ± 0.12 vs. 0.90 ± 0.14; p < 0.001) ([Table 3]).
Table 3
Laboratory data of full-term neonates with perinatal asphyxia based on development
of AKI
|
Data
|
Neonates with AKI
(n = 21)
|
Neonates without AKI
(n = 49)
|
p-Value
|
|
Leucocytes (103/µL)
|
7.09 ± 1.58
|
7.40 ± 1.35
|
0.400
|
|
Hemoglobin (g/dL)
|
9.91 ± 0.98
|
9.92 ± 0.83
|
0.960
|
|
Platelets (103/µL)
|
260.14 ± 83.18
|
283.78 ± 106.85
|
0.370
|
|
Albumin (g/L)
|
32.22 ± 2.57
|
34.94 ± 2.57
|
0.980
|
|
Bilirubin (mmol/L)
|
8.71 ± 2.49
|
8.35 ± 3.97
|
0.720
|
|
Aspartate transaminase (µ/L)
|
25.46 ± 6.23
|
24.40 ± 6.87
|
0.540
|
|
Alanine transaminase (µ/L)
|
20.52 ± 5.97
|
23.16 ± 6.63
|
0.100
|
|
Serum calcium (g/dL)
|
8.10 ± 0.75
|
9.71 ± 2.34
|
0.450
|
|
Serum sodium (mmol/L)
|
134.05 ± 3.58
|
133.22 ± 3.85
|
0.400
|
|
Serum potassium (mmol/L)
|
4.50 ± 0.59
|
4.26 ± 0.73
|
0.170
|
|
Urea (mmol/L)
|
13.16 ± 4.44
|
12.51 ± 5.84
|
0.800
|
|
Baseline creatinine (mmol/L)
|
70 ± 15.99
|
75.48 ± 14.26
|
0.150
|
|
48 h-creatinine (mmol/L)
|
103.22 ± 10.11
|
99.48 ± 5.35
|
< 0.001
|
|
72 h-creatinine (mmol/L)
|
295.19 ± 44.56
|
91.33 ± 6.65
|
< 0.001
|
|
eGFR (mL/min)
|
99.71 ± 4.09
|
101.38 ± 2.22
|
0.840
|
|
INR
|
1.04 ± 0.08
|
1.02 ± 0.06
|
0.300
|
|
C-reactive protein (mg/dL)
|
8.86 ± 3.78
|
7.39 ± 2.61
|
0.060
|
|
Random blood sugar (mg/dL)
|
96.76 ± 7.13
|
93.89 ± 6.13
|
0.090
|
|
Serum CystC (ng/mL)
|
1.50 ± 0.12
|
0.90 ± 0.14
|
< 0.001
|
|
Urinary sodium (mEq/day)
|
79.33 ± 2.10
|
81.48 ± 3.85
|
0.950
|
|
Urinary potassium (mEq/day)
|
30.35 ± 5.18
|
30.88 ± 4.60
|
0.160
|
Abbreviations: AKI, acute kidney injury; CystC, cystatin C; eGFR, estimated glomerular
filtration rate; INR, international randomized ratio.
Statistical significant p-Values are shown in bold.
Predictors for Acute Kidney Injury among the Studied Neonates
Based on the current study, the predictors for AKI among neonates with PA were LBW
(odds ratio [OR] = 1.45, 95% confidence interval [CI]: 1.22–3.98, p = 0.010), hypotension (OR = 2.22, 95% CI: 1.87–4.67, p = 0.010), stage-III HIE (OR = 2.87, 95% CI: 2.01–5.89, p < 0.001), serum CystC (OR = 3.11, 95% CI: 2.22–6.01, p < 0.001) ([Table 4]).
Table 4
Predictors for acute kidney injury among the studied full-term neonates
|
Predictors
|
OR
|
95% CI
|
p-Value
|
|
Low birth weight
|
1.45
|
1.22–3.98
|
0.010
|
|
Antepartum hemorrhage
|
1.01
|
0.98–2.34
|
0.220
|
|
Hypotension
|
2.22
|
1.87–4.67
|
0.010
|
|
Stage-III HIE
|
2.87
|
2.01–5.89
|
< 0.001
|
|
Serum CystC
|
3.11
|
2.22–6.01
|
< 0.001
|
|
Mechanical ventilation
|
2.01
|
0.89–5.01
|
0.190
|
|
Usage of vasopressor
|
1.76
|
0.33–2.98
|
0.980
|
Abbreviations: CI, confidence interval; CystC, cystatin C; HIE, hypoxic-ischemic encephalopathy;
OR, odds ratio.
Note: The p-value was significant if < 0.05.
Statistical significant p-Values are shown in bold.
With ROC curve, it was found that serum CystC has the best diagnostic accuracy (94.3%,
AUC = 0.939, p < 0.001) for prediction of AKI ([Fig. 1]) followed by stage-III HIE (84.4%, AUC = 0.779, p < 0.001), hypotension (68.6%, AUC = 0.643, p = 0.043), and least was LBW (66.8%, AUC = 0.517, p = 0.824) ([Table 5]).
Table 5
Accuracy of hypotension, LBW, stage III HIE, and CystC in prediction of acute kidney
injury
|
Items
|
Hypotension
|
LBW
|
Stage-III HIE
|
CystC
|
|
Sensitivity
|
9.5%
|
57%
|
62%
|
95%
|
|
Specificity
|
94%
|
71%
|
94%
|
94%
|
|
Positive predictive value
|
40%
|
46%
|
81.3%
|
86.4%
|
|
Negative predictive value
|
71%
|
79.5%
|
85.2%
|
97.9%
|
|
Accuracy
|
68.6%
|
66.8%
|
84.4%
|
94.3%
|
|
Cutoff point
|
–
|
–
|
–
|
> 1.43 ng/mL
|
|
AUC
|
0.517
|
0.643
|
0.779
|
0.939
|
|
p-Value
|
0.824
|
0.043
|
< 0.001
|
< 0.001
|
Abbreviations: AUC, area under the curve; CystC, cystatin C; HIE, hypoxic-ischemic
encephalopathy; LBW, low birth weight.
Fig. 1 Accuracy of serum cystatin C and other predictors in prediction of acute kidney injury.
CystC, cystatin C; HIE, hypoxic-ischemic encephalopathy.
Discussion
PA is a condition where there is a lack of oxygen (hypoxia) and/or blood flow (ischemia)
that is severe and prolonged enough to cause functional and/or biochemical changes
in different organs of the body. Since the kidneys are particularly vulnerable to
oxygen deprivation, they may experience renal insufficiency within 24 hours of a hypoxic-ischemic
episode. If the oxygen deprivation continues, it may even cause irreversible cortical
necrosis. Renal injury in PA can occur due to the body's adaptive mechanisms. AKI,
acute tubular necrosis, and renal vein thrombosis are all recognized complications
of this condition. Among these, AKI is the most common and has a poor prognosis. It
may even cause permanent renal damage in up to 40% of the survivors.[21] Traditionally, AKI described as the increase of serum creatinine above 1.5 mg/dL
(132 µmol/L). AKI is often observed in neonates, and ∼8 to 24% were observed among
those in NICU.[22]
The current study enrolled 70 full-term neonates admitted to NICU with documented
PA. This study aimed to assess efficacy of CystC in early prediction of AKI in neonates
with PA. Out of 70 neonates included in this study, 21 (30%) neonates developed AKI,
while the other 49 (70%) neonates did not develop AKI. The exact prevalence of AKI
among neonates with PA is unknown and incidence varies from 6 to 24% in NICUs worldwide.[7]
[23]
[24] In agreement with results of this study, AKI incidence was 30% in a worldwide study
that included data from different four countries (Australia, Canada, India, United
States).[25] A low frequency of AKI (13.3%) among neonates with PA was reported by Memon et al
at NICU at tertiary care hospital.[26] Alaro et al's study from Kenya revealed 11.7% AKI in cases of birth asphyxia.[27] This variation in the frequency of AKI among neonates with PA may be attributed
to different study designs, method and timing of diagnosis of AKI, different sample
size.
In the current investigation, PA was found in males more often than females (60.0
vs. 40.0%). Many earlier researches reported predominance of PA in males than females.
In a study performed in Hyderabad by Memon et al,[26] 56.7% of PA neonates were males, and 43.3% were females. In a study carried in Kenya,
Alaro et al[27] reported that 60% of PA participants were males. In a study done in Sudan by Medani
et al,[28] 59% PA neonates were males. Chishty et al[29] reported that 2.6 times as many males as females neonates had PA. Malik et al[30] and Afzal et al[31] reported that 78 and 60% of the PA participants were males.
In the current study, neonates with and without AKI had insignificant difference as
regard baseline data apart from significantly lower birth weight among AKI group.
Also, AKI group had significantly high frequency of LBW neonates whose birth weight < 2,500 g
compared with neonates without AKI (57.1 vs. 28.6%). Previous study noticed that most
newborns in AKI group had a birth weight < 2,500 g.[32] Meanwhile, other studies found insignificant difference in neonatal birth weight
in neonates with and without AKI.[15]
[22]
Also, results of this study revealed significant increase in frequency of antepartum
hemorrhage among AKI group versus neonates without AKI (28.6 vs. 6.1%). While other
PA risk factors as cord prolapse and meconium aspiration syndrome were comparable
in both groups. In agreement with this study, previous study reported significant
higher frequency of antepartum hemorrhage among AKI group versus neonates without
AKI (1.86 vs. 0.00%).[33]
Another finding in the current study was that frequency of hypotension, MV, and usage
of vasopressor were significantly higher among those with AKI compared with those
without AKI with significantly longer duration of MV and usage of vasopressor.
In agreement with this study, Viswanathan et al studied 472 extreme LBW neonates and
reported that 59 (12.5%) of them developed AKI. The authors also found that neonates
with AKI had significantly lower mean systolic blood pressure than those without AKI
(25.9 ± 9.9 vs. 35.5 ± 13.7 mm Hg, p < 0.001).[34]
On the contrary, El-Gammacy et al stated that frequency of MV was insignificantly
higher among AKI group (61.5 vs. 45.9%; p = 0.33) and yet, they agreed with results of this study as regard vasopressor support
that was higher among neonates with AKI (30.8 vs. 8.1%; p = 0.04).[15] Cataldi et al conducted a study and found that there was a significant risk of AKI
among infants with a VLBW, with 79% of cases occurring in infants weighing < 1,500 g.[35]
In this study, AKI neonates mostly (61.9%) had nonoliguric AKI. Only 8 (38.1%) neonates
had oliguric AKI. This agreed with the study of El-Gammacy et al who reported that
30.8% of AKI group had oliguric AKI.[36]
The results of this study revealed that majority (61.2%) of non-AKI group had stage-I
HIE, while majority (61.9%) of those with AKI had stage-III with significant differences
between both groups. Also, Gohiya et al stated stage of HIE was more advanced among
neonates with AKI.[33]
The main finding in the current study was that there was significantly higher serum
CystC among AKI group than those without AKI. In line with this study, a previous
study reported similar findings with significant higher serum cystatin c among asphyxiated
neonates with AKI (2.35 ± 2.77 vs. 0.96 ± 0.37 (mg/L); p = 0.03).[22]
This study revealed that majority (95.9%) of non-AKI group was discharged and only
two patients (4.1%) died. Meanwhile, 10 (47.6%) patients with AKI were deteriorated
and died. Also, length of hospital stay was significantly longer among those with
AKI versus those without AKI (8.28 ± 2.14 vs. 5.41 ± 1.32 days). Many previous studies
agreed with these findings and reported that neonates with AKI had significant longer
hospital stay with significant poor prognosis.[36]
[37]
Another study stated that although both groups of neonates had insignificant differences
as regard hospital stay but hospital mortality was significantly higher among AKI
group versus those without AKI (16.8 vs. 0.99%).[33]
Based on the current study, the predictors for AKI among neonates with PA were LBW
(OR = 1.45, 95% CI = 1.22–3.98, p < 0.010), hypotension (OR = 2.22, 95% CI = 1.87–4.67, p < 0.010), stage-III HIE (OR = 2.87, 95% CI = 2.01–5.8, p < 0.010), and high serum cystC (OR = 3.11, 95% CI = 2.22–6.01, p < 0.010). With ROC curve, it was found that serum CystC at cutoff point of 1.43 ng/mL
has 94.3%, overall accuracy for prediction of AKI with AUC was 0.939, then stage-III
HIE (AUC = 0.779, p < 0.001) and LBW (AUC = 0.643, p = 0.043). Hidayati et al studied serum CystC as a predictor of AKI; they found that
at cutoff value for CystC 1.605 mg/L, sensitivity was 84.8%; specificity was 67.4%;
and accuracy was 67.4%. The AUC for CystC was 84.9%.[32] Previous studies about normal CystC level in neonates are lacking. However, a study
showed that CystC levels were 1.54 mg/L ( ± 0.28) at birth, 1.38 mg/L ( ± 0.36)
within 48 to 72 hours of life, and 1.50 mg/L ( ± 0.31) after 7 days.[38] In agreement with these findings, previous study stated that ROC curve analysis
showed AUC for CystC was 0.692 (sensitivity of 82.0%, specificity of 94%). These values
may discriminate in case of reduced GFR after perinatal hypoxia/asphyxia in newborns,
but the sample size was not sufficient to validate this cutoff.[39] This indicates that CystC could detect renal dysfunction 1 to 2 days before serum
creatinine. This comes in agreement with Ahmed et al who reported that there was increase
of CystC before the increase in serum creatinine. These findings suggest that CystC
is a more sensitive marker in early detection of AKI preceding serum creatinine increase
by a few days.[40]
Limitations of the current study included relatively small sample size, being conducted
in single tertiary center, absent of control group to assess serum CystC in healthy
neonates, and finally, lack of long-term follow-up to determine effect of CystC on
survival analysis of those neonates with PA and AKI.
Conclusion
High frequency of AKI (30.0%) was noted in neonates with PA. LBW, stage-III HIE, and
elevated serum CystC within first day of life were significantly associated with AKI.
Serum CystC is a promising marker for early detection of AKI in full-term neonates
with PA. Multiple future studies are required to confirm such results and serial analysis
of levels of serum CystC in PA neonates is recommended.
