Annals of Tropical Paediatrics

International Child Health

ISSN: 0272-4936 (Print) 1465-3281 (Online) Journal homepage: http://www.tandfonline.com/loi/ypch19

Evaluation of glomerular and tubular renal

function in neonates with birth asphyxia

S Kaur, S Jain, A Saha, D Chawla, V R Parmar, S Basu & J Kaur

To cite this article: S Kaur, S Jain, A Saha, D Chawla, V R Parmar, S Basu & J Kaur (2011)
Evaluation of glomerular and tubular renal function in neonates with birth asphyxia, Annals of
Tropical Paediatrics, 31:2, 129-134, DOI: 10.1179/146532811X12925735813922

To link to this article: https://doi.org/10.1179/146532811X12925735813922

Published online: 22 Nov 2013.

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Annals of Tropical Paediatrics (2011) 31, 129–134

Evaluation of glomerular and tubular renal function in

neonates with birth asphyxia

S. KAUR, S. JAIN, A. SAHA, D. CHAWLA, V. R. PARMAR, S. BASU & J. KAUR*

Departments of Pediatrics and *Biochemistry, Government Medical College and Hospital, Chandigarh, India

(Accepted December 2010)

Abstract
Background: Acute kidney injury (AKI) is one of the commonest manifestations of end-organ damage associated
with birth asphyxia.
Objective: To evaluate glomerular and tubular dysfunction in neonates with moderate to severe birth asphyxia.
Design: Prospective cohort study.
Setting: Neonatal unit of a teaching hospital.
Methods: Subjects were inborn neonates of >34 completed weeks of gestation with an APGAR score ,7 at 1 min
after birth. Renal function tests including serum electrolytes were measured daily until 96 hrs of life along with
urinary output. Fractional excretion of sodium (FeNa), renal failure index (RFI), urinary myoglobin and creatinine
clearance (CrCl) were calculated using timed urine collection. Staging of AKI was undertaken using Acute Kidney
Injury Network criteria (AKIN).
Primary outcome measurement: Recovery of glomerular function.
Results: A total of 2196 neonates were born during the study period (September 2006 to April 2007), 44 of whom
met the inclusion criteria. Data from 36 neonates were available for final analysis. AKI developed in 9.1% (1/11)
infants with moderate asphyxia and 56.0% (12/25) infants with severe asphyxia, making a total incidence of 41.7%.
AKI persisted in 16.6% neonates at 96 hours of life. Ten neonates (27.7%) had serum creatinine levels .1.5 mg/
dl. In neonates with AKI, tubular function (Fe Na, RFI, urinary myoglobin) was significantly deranged until 72–
96 hrs of life. One infant died and one who was critically ill was discharged against medical advice; both had AKI.
Conclusion: It is feasible to use AKIN staging for evaluating AKI in neonates with birth asphyxia.

Introduction various studies its incidence has been

Perinatal asphyxia is one of the most common
causes of neonatal morbidity and mortality in
developing countries and accounts for 20%
of perinatal deaths (50% if stillbirths are
included).1 In 2002–2003, the incidence of
perinatal asphyxia in institutional deliveries
was reported by the National Neonatal
Perinatal Database of India to be 8.4%.2
In asphyxiated infants, the kidney is one
of the most frequently injured organs and in
Corresponding Author: Dr Abhijeet Saha, Division
of Pediatric Nephrology, PGIMER & Associated
Dr Ram Manohar Lohia Hospital, New Delhi. Email:
drabhijeetsaha@yahoo.com
# W. S. Maney & Son Ltd 2011
DOI: 10.1179/146532811X12925735813922
reported to be between 50 and 72%.3–7 In
most studies, kidney injury in neonates has
been defined as serum creatinine .1.5 mg/dl;
however, there is no universally accepted
definition.3–7 In asphyxiated infants, early
recognition of renal injury is important for
maintenance of fluid and electrolyte home-
ostasis and decreasing the resultant mor-
tality and morbidity.8 In 2007, the Acute
Kidney Injury Network (AKIN), a collabora-
tive group of investigators from all major
critical care and nephrology societies, pro-
posed the term ‘acute kidney injury’ (AKI).9
A classification system comprising stages 1
(mild), 2 (moderate) and 3 (severe) AKI was
proposed.9 The same year, Akcan-Arikan
130 S. Kaur et al.
et al. proposed a similar classification system
for children—‘pediatric RIFLE’.10
The objective of this study was to evaluate
glomerular function using the AKIN classi-
fication system for AKI and tubular function
in inborn infants with moderate-to-severe
asphyxia.
Methods
This prospective study was conducted in 36
consecutive inborn neonates suffering from
moderate-to-severe birth asphyxia and
admitted to the neonatal intensive care unit
(NICU) for further special care over a period
of 9 months (September 2006 to April 2007).
All neonates born at >34 weeks gestation
with Apgar scores of ,7 at 1 minute were
enrolled. Infants already diagnosed with
structural renal disease, and those receiving
indomethacin, ibuprofen, furosemide and
vancomycin were excluded. Written infor-
med consent was obtained from either of the
parents after explaining the purpose of the
study, and ethical clearance was obtained
from the institution’s ethics committee.
Maternal and neonatal data and delivery
details were recorded in a pre-tested pro-
forma for all enrolled subjects. Gestational
age was determined by dates and the Ballard
scoring method. Birth asphyxia was defined
according to the National Neonatology
Forum of India, i.e. an Apgar score of ,7
at 1 minute, moderate birth asphyxia with
an Apgar score between 4 and 6 at 1 minute
and severe birth asphyxia ,3 at 1 minute.2
Infants were weighed twice daily. Urine
output was measured and recorded daily
until day 4 of life. Urine output was
measured by application of minicom. Base-
line serum electrolyte levels (serum sodium
and potassium) with renal function tests
(blood urea and creatinine) were done
within 6 hours of birth. These tests were
repeated once daily until day 4 of life. A 6-hr
midway urine collection was undertaken
during two periods at 24–36 hrs and 72–
96 hrs of postnatal age. These were used to
calculate creatinine clearance (CrCl), frac-
tional excretion of sodium (FeNa) and renal
failure index (RFI). However, shorter timed
collections (e.g. ,1 hr) have also been
found to be accurate and urinary volume
variation does not seem to affect the
estimation of CrCl.8 Serum creatinine esti-
mation was undertaken by Jaffe’s method.11
Urinary myoglobin was measured in 6-hr
urine collections at 24–36 and 72–96 hrs of
life. Urinary myoglobin estimation was done
by Latex-Enhanced Immuno-turbidimetric
Assay.12 AKI was staged using AKIN
criteria (Table 1).9 FeNa of .3% and RFI
.3 were considered abnormal.13 Renal
function tests were calculated as follows:
Creatinine clearance14 (Cr Cl)~
Urine creatinine (mg=dl)|Urine flow rate (ml=min)
Serum creatinine (mg=dl)
(1)
ð1Þ
Fractional excretion of sodium14 (Fe Na)~
Urinary sodium|Serum creatinine
(2) ð2Þ
Urinary creatinine|Serum sodium
Renal failure index14 (RFI)~
Urinary sodium|Serum creatinine ð3Þ
(3)
Urinary creatinine
Statistical analysis
Statistical analysis was carried out using
STATA 9.0 (College Station, TX, USA).
Data are presented as numbers (percentages)
TABLE 1. Acute Kidney Injury Network (AKIN)
staging of acute kidney injury.
Stage Serum creatinine Urine output
I q .0.3 mg/dl or ,0.5 ml/kg/hr66 hrs
q .150–200%
from baseline
II q .200–300% ,0.5 ml/kg/hr .12 hrs
from baseline
III q .300% from ,0.3 ml/kg/hr .24 hrs
baseline or . or Anuria for .12 hrs
4.0 mg/dl with
an acute rise of
at least 0.5 mg/dl
 Birth asphyxia & renal function 131

FIG. 1. Flow chart showing details of patient enrollment.

or mean (SD), as appropriate. Charac-
teristics were compared using Fischer’s
Exact test for dichotomous variables and
the Wilcoxon rank-sum test for continuous
variables. A two-tailed p-value of ,0.05 was
considered statistically significant.
Results
A total of 2196 neonates were born during
the study period. A total of 44 infants fulfilled
the inclusion criteria and were enrolled. Final
analysis was undertaken in 36 neonates
TABLE 2. Incidence of AKI with staging.
Postnatal age, n (%)
AKI Stage 24–36 hrs 72–96 hrs
(Fig. 1). Moderate birth asphyxia was pre-
sent in 11 (30.6%) and severe birth asphyxia
in 25 (69.4%). AKI developed in one of 11
infants (9.1%) with moderate asphyxia and
in 12 of 25 (56%) with severe asphyxia,
making a total incidence of 41.7% (Table 2).
AKI persisted in 16.6% infants at 96 hours of
life. Ten infants (27.7%) had serum creati-
nine levels >1.5 mg/dl. Those whose creati-
nine was .1.5 mg/dl within 6 hours of life
took longer to achieve a normal level than
those in whom it rose after 6 hours of life
(Fig. 2). In infants with AKI, tubular func-
tion (Fe Na, RFI, urinary myoglobin) was
significantly deranged until 72–96 hrs of life
(Table 3). One infant died and one who was
critically ill was discharged against medical
advice; both had AKI.

I 7 (19.4) 3 (8.3) Discussion

II 7 (19.4) 2 (5.5)
III 1 (2.7) 1 (2.7)
Total 15 (41.7) 6 (16.7)
The incidence of AKI in asphyxiated infants
using AKIN staging was 41.7%. Most
132 S. Kaur et al.

FIG. 2. Trends in serum creatinine in infants with AKI (–X– creatinine .1.5 mg/dl within 6 hrs of life; –&–
creatinine .1.5 mg/dl at 24 hrs of life; –m– creatinine .1.5 mg/dl at 48 hrs of life).

previous investigators have defined AKI in functional changes in serum creatinine

neonates as serum creatinine .1.5 mg/dl.5,8
Only ten of our infants had serum creatinine
.1.5 mg/dl. Liu et al. recently reported
similar findings.15 Of their 30 infants with
severe asphyxia, AKI using AKIN criteria
was present in 56.7%, while serum creatinine
was .1.5 mg in only 20% of infants. It seems
that a significant number of neonates with
AKI could be missed if the new classification
systems are not used.
Despite the new classification system, the
diagnosis of AKI in neonates remains
problematic. Serum creatinine in the 1st
few days of life is influenced by the maternal
creatinine level. The current diagnosis of
AKI relies on two functional abnormalities:
(marker of GFR) and oliguria. Both of these
are late consequences of injury and not
markers of injury itself. A marker which is
up-regulated shortly after injury and is
independent of GFR level would be ideal.16
The AKI classification system using early
injury biomarkers (in addition to functional
marker such as GFR and urine output)
which can ultimately predict morbidity or
mortality is of paramount importance. Cur-
rently, the most promising early non-inva-
sive biomarkers of AKI are serum and
urinary neutrophil gelatinase-associated
lipocalin (NGAL), urinary interleukin-18
(IL-18), kidney injury molecule-1 (KIM-
1), serum cystatin c and osteopontin.17

TABLE 3. Glomerular and tubular function in neonates with and without AKI.

24–36 hrs 72–96 hrs

AKI indices AKI (n515) No AKI (n521) p-value AKI (n56) No AKI (n530) p-value

Glomerular function
Serum creatinine (mg/dl) 1.49 (0.46) 0.8 (0.11) ,0.0001 1.65 (0.53) 0.81 (0.09) ,0.0001
CrCl (ml/m/1.73 m2 10.52 (11.92) 19.07 (13.81) 0.06 12.31 (7.41) 27.23 (16.71) 0.03
Tubular function
Fractional excretion 5.59 (5.6) 2.00 (1.18) 0.007 9.42 (15.56) 1.26 (0.90) 0.004
of sodium (%)
Renal failure index 7.49 (7.47) 2.73 (1.63) 0.007 2.21 (19.69) 2.21 (3.20) 0.01
Urine myoglobin (mg/L) 1052 (1321) 9.98 (17.99) 0.02 1246 (1496) 223 (624) 0.03

All values are mean (SD).


Fe Na, RFI and urinary myoglobin were
found to be significantly higher in infants
with AKI at both 24–36 and 72–96 hours of
age compared with infants without AKI.
Tubule segments in the outer medulla,
especially the S3 segment of the proximal
tubule, are most susceptible to injury.18 In
the setting of decreased oxygen tension, the
S3 segment of the proximal tubule has
limited capacity to undergo anaerobic meta-
bolism. With short periods of ischaemia-
reperfusion, tubule cells lose polarity and
on sustained or severe ischaemia the epithe-
lial cell is irreversibly damaged, leading to
impaired re-absorption at tubular level
which results in increased excretion of
sodium in tubular fluid with implications
for electrolyte balance.19 Mathew et al.
observed that FeNa of .2.5% and RFI of
.2.5% are indicators of ischaemic renal
damage in neonates.20 Myoglobin causes
renal damage in a variety of ways, including
direct nephrotoxicity, tubular obstruction
and alteration of renal perfusion and vas-
cular resistance. There is a strong associa-
tion between myoglobinuria, birth asphyxia
and the development of acute kidney
injury.21 Haftel et al. reported that myoglo-
bin pigment is itself toxic to kidneys, causing
a spectrum of diseases from minimal tubular
damage to fulminant severe acute tubular
necrosis.22
In a significant proportion of infants with
AKI, glomerular function improves by 72–
96 hours of life, i.e. normalization of serum
creatinine and normal creatinine clearance.
A reduction in the number of functional
nephrons caused by asphyxia leading to AKI
evokes compensatory hypertrophy of the
residual nephrons, thus leading to improved
glomerular function. Chevalier et al. found
that birth-asphyxiated neonates with AKI
demonstrated remarkable recovery of GFR,
as evidenced by follow-up serum creatinine.23
However, it has also been reported that, on
follow-up, up to 40% of survivors of neonatal
AKI may have decreased creatinine clear-
ance, renal tubular acidosis or concentrating
defect.24 Therefore neonates with AKI
Birth asphyxia & renal function 133
following birth asphyxia need long-term
follow-up of both glomerular and tubular
function.
AKIN staging is useful in evaluating AKI in
neonates with birth asphyxia. Larger studies
with long-term follow-up are required to
evaluate the residual glomerular and tubular
dysfunction.
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