Nephrol Dial Transplant (2007) 22: 96–103
doi:10.1093/ndt/gfl550
Advance Access publication 23 September 2006
Original Article
The effect of intrauterine growth retardation on renal
function in the first two months of life
Vasileios Giapros1, Photeini Papadimitriou1, Anna Challa2 and Styliani Andronikou1
1
Neonatal Intensive Care Unit, Child Health Department and 2Research Laboratory of the Child Health Department,
University of Ioannina, Greece
Abstract
Background. Children born with growth retardation
(GR) have a smaller nephron number and are at
increased risk for the development of renal disease and
hypertension in adult life. Data on the immediate postnatal development of renal function in neonates born
with GR are limited and data on the effects of
aminoglycosides (AGs) on renal function in these
infants are lacking.
Methods. This was a prospective study of 81 preterm
neonates with a mean gestational age of 32.5 weeks,
40 born with GR (small for gestational age, SGA)
and 41 without GR (appropriate for gestational age,
AGA). The infants were classified into 4 groups.
Groups A (n ¼ 21) and B (n ¼ 20) consisted of AGA
and SGA neonates, respectively, who received
AGs, and groups C (n ¼ 20) and D (n ¼ 20) of AGA
and SGA neonates, respectively, who did not receive
AG treatment. Indices of renal function were: serum
creatinine (SeCr), the fractional excretion of sodium
(FENa), potassium (FEK), phosphorus (FEP), magnesium and uric acid (FEUA), the urinary calcium/
creatinine ratio and the transtubular potassium
gradient (TTKG).
Results. No differences were observed in the parameters examined between SGA and AGA neonates
who did not receive AGs. Conversely, SGA infants
who received AGs after birth (group B) exhibited
higher values of SeCr 2 months later. Specifically, their
mean SD value of SeCr (mmol/l) was 42 05
compared with 33 08 in group D, 35 04 in
group A and 33 04 in group C (P < 0.01). These
infants also had significantly higher values of TTKG
than SGA infants without AG treatment (22 9
vs 13 3 in group D) and FEUA (60 23 vs 35 14
in group D). Their FENa and FEP were also
inappropriately high despite having lower serum
levels of Na and P.
Correspondence and offprint requests to: V. Giapros, University
of Ioannina, Medical School, Child Health Department,
PO Box 1186, Ioannina, 45 110, Greece. Email: [email protected]
Conclusion. Preterm SGA infants who had no need
of AG treatment after birth have similar renal
functional maturation than AGA preterm infants at
2 months of life, but preterm SGA infants who
received AGs had indications of impaired glomerular
and tubular function at this age.
Keywords: aminoglycosides; FENa; renal function;
small for gestational age; transtubular potassium
gradient (TTKG); tubular function
Introduction
Small for gestational age (SGA) neonates are a
group of infants reported to have increased perinatal
and long-term morbidity [1–3]. Epidemiological
studies show that adults who were born SGA are at
increased risk for the development of renal disease and
hypertension [2,3]. Recent studies have shown that
low birth weight (LBW) may be associated with a
lower number of nephrons at birth [4,5]. Brenner
and Chertow proposed that the link between LBW,
adult hypertension and renal functional decline may
be impaired nephrogenesis [6,7]. They suggested that
the reduced number of glomeruli leads to hyperfiltration, which in turn leads to systemic hypertension,
glomerular sclerosis and progressive deterioration of
renal function [6,7].
Renal tubular function and glomerular function
are immature at birth [8]. Preterm infants born
before 34–36 weeks of gestational age (GA) have not
completed formation of the structural units of the
kidney, the nephrons; a process that continues after
birth, up to the 36th week of corrected chronological
age (CA) (CA ¼ GA þ post-natal age) [8]. Preterm
kidneys must adapt post-natally in order to cope
with the increased metabolic demands of the rapid
growth in this period. This is achieved by functional
and structural renal maturation [8]. In addition,
SGA neonates have a numerically smaller nephron
endowment [4,5]. Aminoglycosides (AGs), which are
ß The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
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Intrauterine growth retardation and renal function
by far the most commonly administered nephrotoxic
drugs during the neonatal period, may further
compromise renal function in SGA infants.
There are only limited data on renal functional
maturation in SGA infants immediately after birth [9],
and none on the effects of AGs on renal tubular
and glomerular function in SGA infants. As renal
function is involved in long-term arterial blood
pressure regulation, the question remains as to whether
restricted intrauterine growth may affect renal
function during the neonatal period.
This study was designed to investigate the development of the glomerular and tubular function in
SGA and appropriate for gestational age (AGA)
preterm neonates in the first 2 months of life, and
to study the effects on their renal function of AGs
administered shortly after birth.
Patients and methods
The study population consisted of 81 preterm neonates
with a GA of 28–34 weeks, born at the University Hospital
of Ioannina and admitted immediately to the Neonatal
Intensive Care Unit (NICU) of the same Hospital. This is
a regional hospital covering the majority of deliveries
(>85%) in the area of Northwest Greece. The GA at
birth was assessed according to the mothers’ menstrual
history and ultrasound (US) examination at 12–18 weeks
of GA and confirmed by assessment of the babies’
maturity within 2 h of birth by neonatologists. Forty-one
of the infants were categorized as AGA (BW 10th–90th
percentile for GA) and 40 as SGA (BW < 10th percentile for
GA) using the Gairdner and Pearson growth charts [10].
The AGA infants were classified into two subgroups;
group A (n ¼ 21) comprised those who received AG
treatment and group C (n ¼ 20) those who did not need
AGs. The SGA infants also were classified into two groups;
group B (n ¼ 20) comprised those who received AG
treatment and group D (n ¼ 20) those who did not need
AGs. The Scientific Committee of the University Hospital
of Ioannina approved the study protocol and informed
parental consent for participation of the infants was
obtained.
Inclusion criteria
All preterm SGA neonates born between 28 and 34 weeks
GA at this hospital during a period of 2 years were
considered eligible for the study. AGA infants were selected
to match with the SGA infants with respect to GA,
gender, mode of delivery, parity and prenatal maternal
steroid treatment. All infants included in the study were
respiratory and metabolically stable: pH 7.25–7.40, PaO2
50–70 mmHg (6.6–9.2 kPa), PaCO2 < 55 mmHg (<7.31 kPa)
and SBE < 10 mmol/l, and their diuresis was normal (1–4 ml/
kg/h) during the study period. Infants with perinatal
asphyxia, severe (grades III and IV) respiratory distress
syndrome (RDS), hypotension, severe hyperbilirubinaemia
or urinary infection were excluded, because these conditions
can affect renal function [11]. All infants had a renal US
study and those with abnormal findings were excluded.
97
None of the infants received treatment with diuretics,
corticosteroids, xanthines, dopamine–dobutamine, talazoline or indomethacin.
On the first day of life, the infants received either total
parenteral nutrition (TPN) or a special formula for preterm
neonates, depending on their clinical condition. TPN was
substituted gradually the following days by oral feeding.
Blood and 3 h urine samples were obtained in all groups
at five study periods ranging from the third day of life to
the 40th week of CA. Specifically, in the two groups of
infants (A and B) who received AGs, blood and 3 h
urine samples were obtained immediately before the
infusion of the AG, on the third and the seventh day of
treatment (first and second study periods, respectively) and
7 days following discontinuation of therapy (third study
period). Two further samples were obtained at the CA of
36 and 40 weeks (fourth and fifth study periods). Serum
and renal parameters in the untreated groups of AGA and
SGA infants (C and D) were evaluated at the same post-natal
ages. Blood and urine samples were all collected during
routine procedures. In all infants, the daily and weekly intake
of fluid, calories, protein, calcium (Ca), phosphorus (P),
sodium (Na), potassium (K) and magnesium (Mg) were
monitored throughout the study period. Urinalysis was
performed for all neonates regularly.
AGs were administered to the infants in groups A and B
along with cefotaxime for sepsis or suspected infection
according to the Rodwell criteria [a haematological scoring
system taking into consideration the following: total
leucocyte count, total neutrophil count (PMN), immature
PMN count, ratio of immature to total and immature to
mature PMN, degenerative change in netrophils and platelet
count] [12]. The AGs were administered intravenously over
a 30 min period in a total volume of 5 ml distilled water.
For infants aged 0–7 days the doses were 10 mg/kg
of amikacin, and 3 mg/kg of gentamicin and netilmicin,
every 24 h, while for infants aged >7 days the doses were
7.5 mg/kg of amikacin, and 2.5 mg/kg of gentamicin and
netilmicin, every 12 h [13]. Trough and peak serum AG
concentrations were obtained immediately before and 30 min
after the drug administration, and doses were adjusted if
necessary to maintain serum drug levels within the
therapeutic range.
Renal tubular function was assessed by examining the
fractional excretion (FE) of Na (FENa), K (FEK), P (FEP),
Mg (FEMg) and uric acid (FEUA). The urinary Ca excretion
as the Ca/creatinine (UCa/UCr) ratio and the transtubular
potassium gradient (TTKG) were also determined. The
fractional excretion of the various substances (x) was
calculated using the formula: FE(x) ¼ Ux SeCr/Sex UCr,
where Ux, Sex are the concentrations of any substance in the
urine and serum, respectively, and UCr and SeCr are the
concentrations of creatinine (Cr) in urine and plasma. The
TTKG was calculated using the formula TTKG ¼ [K] urine/
(urine/plasma) osmolality [K] venous blood [14]
Serial determinations of SeCr were performed throughout
the study to assess the maturational changes in glomerular
function. Measurements of Na, K, Ca, P, Mg, uric acid (UA)
and Cr in serum and urine specimens were performed using
the automatic analyser RA-100 (Technicon). The osmolality
of urine and serum was calculated with a cryoscopic
osmometer (Osmomat, Gonotec). Serum concentrations
of the AGs were determined using the polarized
98
immunofluorescence assay (System TDX, Abbott
Laboratories). The inter- and intra-assay coefficients of
variation were 1.02 and 2.5% for amikacin, 1.5 and 2.4%
for gentamicin and 1.4 and 2% for netilmicin, respectively.
Statistical analysis
A sample size of 81 infants was calculated to be adequate
for detecting a difference of one SD in blood and urine
parameters between the AGA and SGA groups with a
power of 88% at a significance level of 5% [15]. Differences
were considered significant at a level of P < 0.05. The data
were analysed using two-way repeated measurements
analysis of variance (ANOVA). Testing the differences
of BW-percentile classified groups (SGA, AGA) vs treatment
or time groups yielded a statistically significant P-value
(<0.05) and one-way ANOVA was subsequently performed.
A logarithmic transformation was made in order to normalize the distribution of the values of the urinary variables.
Values are expressed as means SD.
Results
Of the 54 preterm SGA neonates eligible to
participate in the study during the 2-year period, the
parents of 51 agreed for them to participate. Eleven of
these were excluded during the course of the study
because they did not meet the inclusion criteria and
40 finished the study. Forty-one preterm infants
born AGA (matched controls) participated in the
study. The clinical characteristics of the four groups
of SGA and AGA neonates of the study are depicted
in Table 1.
Calories, protein, mineral and electrolyte intake
was similar during the study period among the
four groups (P ¼ NS). Only in the first study period
(third day), was the protein and mineral intake lower
in group A than group C. During the following
periods the mean intake of calories and protein
varied as follows: calories (kcal/kg/day) from
131 31 to 157 7, protein (g/kg/day) from 3.7 0.8
to 4.7 0.6 (P ¼ NS). The respective intake of
minerals (mmol/kg/day) ranged as follows: Na, from
2.1 0.9 to 2.8 0.3; K, 2.8 0.9 to 3.7 0.2; Ca,
4.1 1 to 4.8 0.9; P, 2.5 0.5 to 3.04 0.5 and Mg,
0.57 0.24 to 0.73 0.16 (P ¼ NS). Weight gain,
urine output and blood pressure did not differ among
the four groups throughout the study. AG treatment
for suspected infection or sepsis was introduced
during the first 48 h in all cases in groups A and B
(Table 1). Three and four infants, respectively, of
groups A and B needed a second course with
another AG (Table 1). Serum levels of AGs were
maintained within the therapeutic range and did not
differ between the two groups A and B during the
period of the treatment. The mean AGs serum levels
(trough and peak, respectively) (mg/ml) in two groups
ranged, for amikacin from 5.8 4 to 6.4 2 (trough)
and 23 4 to 26þ6 (peak), for netilmicin from 1 0.6
to 1.2 0.6 (trough) and 7.1 1.8 to 7.6 2.4 (peak),
V. Giapros et al.
Table 1. Clinical characteristics of the study groups of preterm
neonates
Characteristics
Birth weight (kg)
Gestational
age (weeks)
RDS* grade
I or II
PPV# > 3
Days
TPN** after
first week
Breast milk
feeding
AG treatment
(days)
Netilmicin
(courses)
Gentamicin
(courses)
Amikacin
(courses)
Sepsis
Groups
A (n ¼ 21)
B (n ¼ 20)
C (n ¼ 20)
D (n ¼ 20)
1.92 0.3
32.5 0.8
1.64 0.3
32.6 0.8
1.94 0.3
32.6 0.7
1.51 0.2
32.6 0.6
9
5
5
5
2
1
1
1
2
2
1
2
3
3
4
4
8.1 3.2
7.3 2.2
–
–
16
16
–
–
5
4
–
–
3
4
–
–
2
1
–
–
Group A: appropriate for gestational age (AGA) receiving
aminoglycosides (AGs); Group B: small for gestational age (SGA)
receiving AGs; Group C: AGA not receiving AGs; Group D: SGA
not receiving AG.
*RDS, respiratory distress syndrome; #PPV, positive pressure
ventilation; **TPN, total parenteral nutrition.
and for gentamicin from 1.2 0.4 to 1.3 0.4 (trough)
and 6.1 2.4 to 7.2 1.8 (peak).
Serum and renal parameters
Serum creatinine. The most remarkable differences
in SeCr were observed in group B (SGA infants
who received AGs) in comparison with all the other
groups. In this group, SeCr was lower than in group D
of SGA infants during the first period of the study
(Table 2). At the fourth study period (36 weeks of CA),
in the SGA infants, SeCr was higher in group B
than in group D (P < 0.05) (Table 2). This difference
became more significant at 40 weeks of CA (fifth study
period) (P < 0.001).
Serum electrolytes and uric acid. Significant differences in SeK and SeP levels were observed between
the various groups, as depicted in Table 2. No
differences were observed between the various groups
in SeCa, SeNa and SeMg throughout the study
and their mean values (mmol/l) varied: SeCa from
2.2 0.15 to 2.5 0.1; SeNa from 137 3 to 143 3
and SeMg from 0.66 0.08 to 0.78 0.08. Only at
40 weeks was SeNa higher in group D compared
to group B (140 1 vs 138 2, P < 0.05). SeUA
(mmol/l) was high in all groups at the first study
period, varying between 226 59 and 250 101, and
declined thereafter to between 89 18 and 107 47. At
40 weeks SeUA was higher in group D SGA infants
compared to group B (124 47 vs 89 12, P < 0.01).
Para-meter
Group
Study period
First (3rd day)
Second (7th day)
Third (14th day)
Fourth (36 weeks CA)
Fifth (40 weeks þCA)
4.6 0.5
4.7 0.7
5.3 0.4***
5.3 0.7***
A vs C (P < 0.001),
B vs D (P < 0.001)
2.17 0.3
2.17 0.4
2.33 0.2*
2.30 0.2
A vs C (P < 0.05)
55 08
61 09
59 09
59 09
B vs A (P ¼ 0.08)
4.8 0.56
4.7 0.6
5.2 0.5*
5.3 0.6**
A vs C (P < 0.05),
B vs D (P < 0.01)
2.24 0.8
2.17 0.4*
2.30 0.5
2.40 0.7
B vs D (P < 0.05)
53 12
55 09*
52 09
51 09
B vs D (P < 0.05)
5.4 0.5
4.9 0.7
5.2 0.5
5.3 0.3*
B vs D (P < 0.05)
B vs A (P ¼ 0.06)
2.21 0.2
1.98 0.3***
2.24 0.2
2.33 0.2
B vs D,A,C, (P < 0.001)
35 04
42 05***
33 04
33 08
B vs C, D (P < 0.001),
B vs A (P < 0.01)
SeK mmol/l
A
B
C
D
P-value
4.3 0.4
4.2 0.5
4.6 0.6
4.7 0.8*
B vs D (P < 0.05)
4.5 0.6
4.5 0.7
4.7 0.5
4.9 0.6*
B vs D (P < 0.05)
SeP mmol/l
A
B
C
D
P-value
A
B
C
D
P-value
1.80 0.2
1.76 0.3
2.10 0.3*
1.86 0.5
A vs C (P < 0.05)
90 13
89 08
96 017
101 16*
B vs D (P < 0.05)
1.98 0.4
2.14 0.4
2.27 0.3**
2.24 0.2
A vs C (P < 0.01)
68 10
74 14
70 11
78 21
NS
SeCr mmol/l
Intrauterine growth retardation and renal function
Table 2. Serum values of potassium (SeK), phosphate (SeP) and creatinine (SeCr) in the study groups of preterm neonates
Group A: appropriate for gestational age (AGA) receiving aminoglycosides (AGs) (n ¼ 21); Group B: small for gestational age (SGA) receiving AGs (n ¼ 20); Group C: AGA not receiving AGs
(n ¼ 20); Group D: SGA not receiving AGs (n ¼ 20).
CA, corrected age ¼ Gestational age þ Age after birth.
*P < 0.05, **P < 0.01, ***P < 0.001.
99
13 9
22 9**
12 3
13 3
B vs D, C, A (P < 0.01)
40 13
60 23***
36 12
35 14
B vs D, C, A (P < 0.001)
10 6
14 8
12 7
14 7
NS
54 23
64 30*
50 21
54 16
B vs C (P < 0.05)
7.6 5.8
5.0 0.3
7.3 5.7
6.2 3.3
NS
56 22
64 27
57 25
60 24
NS
FEUA
A
B
C
D
P-value
A
B
C
D
P-value
TTKG
Group A: AGA receiving aminoglycosides (AGs) (n ¼ 21); Group B: SGA receiving AGs (n ¼ 20); Group C: AGA not receiving AGs (n ¼ 20); Group D: SGA not receiving AGs (n ¼ 20).
CA, Corrected age ¼ Gestational age þ Age after birth.
*P < 0.05, **P < 0.01, ***P < 0.001.
24 11
31 10
24 11
23 09
B vs D (P ¼ 0.07)
21 14
24 9
23 8
23 9
NS
A
B
C
D
P-value
FEK
21 12*
11 4
21 9
31 12***
A vs B (P < 0.05),
B vs D (P < 0.001)
6.3 3.9
3.4 2.4*
6.2 3.0
6.2 2.6
B vs D, C, A (P < 0.05)
55 20
73 24
63 33
62 42
NS
12 8
12 3
14 7
19 11***
A, B vs D (P < 0.001)
15 9
15 9
25 9***
21 8*
A vs C (P < 0.001),
B vs D (P < 0.05)
7.7 5.0
9.5 5.0
9.9 4.0
9.6 4.0
NS
53 24
58 21
49 17
48 13
B vs D (P ¼ 0.08)
Fifth (40 week CA)
First (3rd day)
Group
Study period
Second (7th day)
Third (14th day)
Fourth (36 week CA)
V. Giapros et al.
Parameter
Table 3. Fractional potassium excretion (FEK), transtubular potassium gradient (TTKG) and fractional excretion of uric acid (FEUA) in the study groups of neonates
100
Urinary parameters. The main finding in the
urinary parameters was an increase in TTKG
and FEUA at 40 weeks CA in group B infants
compared to the other three groups (Table 3), in
spite of lower SeK (Table 2) and SeUA levels.
Inappropriately high FEP and FENa (Table 4), despite
their significant lower serum levels (P < 0.001 and
0.05, respectively, Table 2) were also observed in this
group at the same study period. At this period urine
osmolality (UOsm) was lower in group B than in
groups A and C (P < 0.05), although fluid intake did
not differ among the four groups. The mean values
of UOsm (mosmol/kg) for the groups A,B,C and D,
respectively, were 145 90, 101 50, 154 53 and
139 42.
Tables 5 and 6 (See online supplementary data)
depict the respective intakes and serum levels of all
examined parameters and Table 7 (See online supplementary data) depict serum AGs levels.
Discussion
It has been postulated that serial determinations
of SeCr in the neonatal period are a reliable indicator
of renal function as they represent the glomerular
filtration rate (GFR) [16]. The results of the present
study indicate that the SeCr values in preterm SGA
infants with a mean GA of 32.6 weeks who did not
receive AGs post-natally were similar to those of AGA
infants during the whole study period. The SeCr levels
showed a normal decline after birth in this SGA group,
following a similar pattern to that of the AGA groups,
and the SeCr values in these groups were close to those
reported recently by Gallini et al. [17] in preterm
infants. These findings imply that either glomerular
function is not impaired in this group of SGA infants
up to the second month of life or that a compensatory process of hypertrophy or accelerated renal
growth may take place [18]. It was recently reported
that most preterm SGA neonates of a GA similar
to the babies of this study exhibit accelerated renal
growth as estimated by US during the first months
of life [19].
Scarce clinical data are available regarding maturation of renal function in preterm SGA infants. In the
single published study no difference was found in SeCr
between two groups of AGA and SGA preterm infants
during the first 2 weeks of life, and GFR estimation,
based on 6 h urine collections, was lower in SGA
infants in the same period [9]. Experimental studies
in rats showed that intrauterine growth retardation
(GR) was accompanied by a nephron deficit that may
not be fully compensated for within the first weeks
after birth, despite compensatory hypertrophy, and
that overall renal function was impaired [20]. Other
authors studying piglets have shown impaired secretory capacity in SGA compared to AGA animals in the
immediate post-natal period [21].
The results of the present study showed that the
SGA preterm neonates who received AGs during the
Intrauterine growth retardation and renal function
101
Table 4. Fractional excretion of sodium (FENa), phosphate (FEP) and magnesium (FEMg), and urinary calcium to creatinine ratio
(UCa/UCr) in the study groups of preterm neonates
Parameter
Group
FENa
A
B
C
D
P-value
FEP
A
B
C
D
P-value
A
B
C
D
P-value
A
B
C
D
P-value
FEMg
UCa/Cr
(mmol/mmol)
Study period
First (3rd day)
Second (7th day)
Third (14th day)
Fourth (36 week CA)
Fifth (40 week CA)
1.9 1.1***
2.8 1.3*
1.1 0.6
1.7 0.8
A vs C (P < 0.001),
B vs D (P < 0.05)
22 15
19 14
21 10
26 17
0.9 0.5
1.3 1.1**
0.7 0.3
0.9 0.5
B vs C,D (P < 0.05)
0.61 0.3
0.73 0.5
0.61 0.2
0.54 0.2
0.64 0.3
0.64 0.3
0.57 0.2
0.53 0.2
0.77 0.5
0.88 0.5
0.52 0.3
0.54 0.2
B vs D (P ¼ 0.06)
12 06
16 12
24 13
16 09
14 08
16 06
24 13**
16 09
A vs C (P < 0.01)
3.6 2.0
2.2 1.5
5.5 2.8**
3.6 2.2
B vs C (P < 0.01)
0.90 0.45
0.59 0.37
1.04 0.54
0.82 0.63
15 09
20 13
23 14
22 12
15 07
18 10
18 11
17 08
3.8 2.8
2.5 1.4
4.7 2.6*
4.1 3.3
B vs C (P < 0.05)
1.19 0.62
0.74 0.54
1.05 0.54
1.21 0.96
4.7 2.9
4.6 2.3
6.3 3.1
5.2 2.6
2.8 1.4*
3.8 1.5**
1.2 0.6
3.0 2.4
A,B vs C (P < 0.01)
0.62 0.45*
0.76 0.45*
0.28 0.20
0.54 0.39
A vs C (P < 0.05)
B vs D (P < 0.05)
2.7 1.8
2.3 1.2
2.0 1.2
2.5 1.2
0.99 0.59**
0.54 0.28
0.39 0.22
0.45 0.34
A vs C (P < 0.01)
1.27 0.85
1.13 0.65
1.19 0.65
1.13 0.62
Group A: AGA receiving aminoglycosides (AGs) (n ¼ 21); Group B: SGA receiving AGs (n ¼ 20); Group C: AGA not receiving AGs (n ¼ 20);
Group D: SGA not receiving AGs (n ¼ 20).
CA, Corrected age ¼ Gestational age þ Age after birth.
*P < 0.05, **P < 0.01, ***P < 0.001.
first days after birth had considerably higher SeCr
levels about 2 months later, at a CA of 40 weeks. This
group of infants had 21% higher SeCr levels, in
comparison not only with the SGA infants who did not
receive AGs, but also with AGA infants who did not
receive AG treatment. In the immediate post-natal
period GFR is based on the function of the medullar
nephrons, which are mature and receive a major
fraction of the renal blood flow [8,22]. The more
recently formed nephrons in the superficial cortex have
little contribution [8,22]. It has been shown in studies
on puppies that AG administration early in life affects
mainly the medullary nephron function [23]. Any
damage at this site during the first days of life could
be offset by the subsequent development of more
superficial nephrons [23]. It is tempting to speculate
that preterm SGAs, having possibly a lower number of
superficial nephrons, are unable to offset the compromised renal function caused by AG administration
early in life. In addition, a direct adverse effect of AGs
on the nephrogenesis process cannot be excluded in
this group [24]. These factors render them unable
to exhibit the normal decline in SeCr observed in the
other groups.
FEK and TTKG are both useful indices of K
handling by the kidney [25]. FEK is considered as an
index that estimates renal K transport along the whole
nephron. TTKG reflects K handling in the collecting
duct, where free water is reabsorbed and K is excreted
under aldosterone stimulation. TTKG might be a
better indicator of renal K excretion during the
neonatal period [14,25]. SGA neonates who received
AGs exhibited an altered pattern of TTKG, showing
very low TTKG during AG treatment, in accordance
with the observed lower serum K levels in this group at
this period, and a gradual increase thereafter. A late
increase in TTKG with a concomitant decrease in
UOsm was observed in this group of SGA infants at
40 weeks CA. At this age, SGA infants who had
received AGs had a mean TTKG value almost double
that of the other groups of SGA and AGA infants.
This increase in TTKG was observed in spite of
significantly lower SeK values in this group, and might
be attributed to a tubular functional or structural
lesion caused by AGs.
Urinary UA also increased gradually in SGA infants
receiving AGs and at 40 weeks CA was almost double
that of the SGA infants not receiving AG. FENa
also remained higher in AG-treated SGA neonates
throughout the study period. Urinary P excretion at
36 and 40 CA weeks, although similar among the four
groups, seems to be inappropriately high in the SGA
infants who received AGs, taking into consideration
their significantly lower SeP levels at that period.
The urinary levels of Ca and Mg were similar in
SGA and AGA infants and were unaffected by AG
administration, except in the first week of life. During
the first period of the study (third day of AG
treatment) the excretion of these ions were higher in
the AG-treated groups, a finding consistent with the
findings of previous reports on AG administration in
preterm infants [26,27].
102
In the SGA infants receiving AGs, the coexistence of
increased TTKG with high urinary UA and P and Na,
despite their significant lower serum values compared
to the other study groups, implies a state of ‘tubulopathy’ in these neonates, possibly attributable to the
combined effects of being SGA and having early AG
exposure.
The study design and its inclusion criteria minimized
the possibility that other perinatal factors may have
affected renal function. The group of SGA infants who
received AGs was comparable to the three other
groups of SGA and AGA infants in all respects. This
study did not include neonates with GA <28 weeks
because this age group often has a complicated
perinatal period and therefore it is difficult to attribute
any disturbance of renal function solely to administered drugs.
Subtle tubular disturbances have been reported in
children and adults born SGA, but there are no studies
on the long-term effect of AGs on tubular function in
this group [28–30]. Monge et al. [29] observed elevated
calciuria and NAG excretion in children born with
LBW between 4 and 12 years of age. Young male
adults born with BW <2500 g were found to have
higher FENa, partially attributable to a concomitant
increase in blood pressure [28]. A recent study in
children born preterm, but not SGA, has shown a
correlation between AG administration during the
neonatal period and increased Ca excretion during
childhood, implying long-term tubular derangements
[31]. Further studies are needed to delineate the course
of the derangements in tubular function observed in
the neonates of this study later in life.
AGs are possibly the commonest antibiotics to be
administered during the neonatal period. The findings
of the present study imply that renal functional
maturation in SGA infants born preterm may be
compromised by early administration of AGs.
Glomerular and tubular function may both be
affected, despite maintenance of drug levels within
the normal therapeutic range. Long-term follow-up of
renal function in this subgroup of SGA neonates is
needed.
Conflict of interest statement. None declared.
References
1. Kramer M, Olivier M, McLean F, Willis D, Usher R. Impact of
intrauterine growth retardation and body proportionality on fetal
and neonatal outcome. Pediatrics 1990; 86: 707–713
2. Barker DJP, Osmond C, Golding J, Kuh D, Wadsworth MEJ.
Growth in utero, blood pressure in childhood and adult life,
and mortality from cardiovascular disease. Br Med J 1989; 298:
564–567
3. Yiu V, Burka S, Zurakowski D, McCormick M, Brenner B,
Jabs K. Relationship between birth weight and blood pressure in
childhood. Am J Kidney Dis 1999; 33: 253–260
4. Manalich R, Reyes L, Herrera M, Melendi C, Fundora I.
Relationship between weight at birth and the number and size of
renal glomeruli in humans: a histomorphometric study. Kidney Int
2000; 58: 770–773
V. Giapros et al.
5. Bassan H, Trejo LL, Bassan NKM, Berger E, Gozes AFI,
Harel S. Experimental intrauterine growth retardation alters
renal development. Pediatr Nephrol 2000; 15: 192–195
6. Rostand SG. Oligonephronia, primary hypertension and renal
disease: ‘is the child father to the man?’ Nephrol Dial Transplant
2003; 18: 1434–1438
7. Brenner BM, Chertow GM. Congenital oligonephronia and the
etiology of adult hypertension and progressive renal disease.
Am J Kidney Dis 1994; 23: 171–175
8. Yared A, Ichikawa I. Postnatal development of
Glomerular filtration. In: Polin R, Fox W, eds. Fetal and
Neonatal Physiology, WB Saunders, Philadelphia: 1992;
1200–1204
9. Narang A, Bhakoo ON, Majumdar S, Kumar CH. Renal
function in SFD and AFD preterm babies. Indian Pediatr 1993;
30: 201–215
10. Gairdner D, Pearson J. A growth chart for premature and other
infants. Arch Dis Child 1971; 46: 783–787
11. Gouyon JB, Guignard JP. Management of acute renal failure in
newborn. Pediatr Nephrol 2000; 14: 1037–1044
12. Rodwell RL, Leslie AL, Tudehope DI. Early diagnosis of
neonatal sepsis using a hematologic scoring system. J Pediatr
1988; 112: 761–767
13. Nechyba C, Gunn V. eds. The Harriet Lane Handbook, 16th edn,
The Johns Hopkins Hospital Part IV, Formulary. Philadelphia,
US, MOSBY: 2002; 571–951
14. Nako Y, Ohki Y, Harigaya A, Tomomasa T, Morikawa A.
Transtubular potassium concentration gradient in preterm
neonates. Pediatr Nephrol 1999; 13: 880–885
15. Altman D. Sample size. Practical Statistics for Medical
RESEARCH, Chapman and Hull, London: 1994; 456–460
16. Arant B. Estimating glomerular filtration rate in infants.
J Pediatr 1984; 104: 890–893
17. Gallini F, Maggio L, Romagnoli C, Marrocco G, Tortorolo G.
Progression of renal function in preterm neonates
with gestational age 32 weeks. Pediatr Nephrol 2000; 15:
119–124
18. Chevalier R. The response to nephron loss in early development.
In: Polin R, Fox W, eds. Fetal and Neonatal Physiology,
WB Saunders, Philadelphia, US: 1992; 1264–1268
19. Hotoura E, Argyropoulou M, Papadopoulou F et al. Kidney
development in the first year of life in small-for-gestational-age
preterm infants. Pediatr Radiol 2005; 35: 991–994
20. Merlet-Bénichou C, Gilbert T, Muffat-Joly M, LelièvrePégorier M, Leroy B. Intrauterine growth retardation leads to
a permanent nephron deficit in the rat. Pediatr Nephrol 1994; 8:
175–180
21. Bauer R, Walter B, Ihring W, Kluge H, Lampe V, Zwiener U.
Altered renal function in growth-restricted newborn piglets.
Pediatr Nephrol 2000; 14: 735–739
22. Seikaly MG, Arant BS. Development of renal hemodynamics:
glomerular filtration and renal blood flow. Clinics Perinatol
1992; 19: 1–13
23. Cowan RH, Jukkola AF, Arant BS. Pathophysiologic evidence
of gentamicin nephrotoxicity in neonatal puppies. Pediatr Res
1980; 14: 1204–1211
24. Lelievre-Pegorier M, Gilbert T, Sakly R, Meulemans A,
Merlet-Benichou C. Effect of fetal exposure to gentamicin on
kidneys of young guinea pigs. Antimicrob Agents Chemother
1987; 31: 88–92
25. Rodriguez-Soriano J, Ubetagoyena M, Valo A. Transtubular
potassium concentration gradient: a useful test to estimate
aldosterone bioactivity in infants and children. Pediatr Nephrol
1990; 4: 105–110
26. Giapros VI, Andronikou S, Cholevas VI, Papadopoulou ZL.
Renal function in premature infants during aminoglycoside
therapy. Pediatr Nephrol 1995; 9: 163–166
27. Giapros V, Cholevas V, Andronikou S. Acute effects of
gentamicin on urinary electrolyte excretion in neonates.
Pediatr Nephrol 2004; 19: 322–325
Intrauterine growth retardation and renal function
28. Vásárhelyi B, Dobos M, Reusz GS, Szabó A, Tulassay T.
Normal kidney function and elevated natriuresis in young men
born with low birth weight. Pediatr Nephrol 2000; 15: 96–100
29. Monge M, Garcia-Nieto VM, Domenech E, Barac-Nieto M,
Muros M, Perez-Gonzalez E. Study of renal metabolic
disturbances related to renal lithiasis at school age in very-lowbirth-weight children. Nephron 1998; 79: 269–273
103
30. Hoy WE, Rees M, Kile E, Mathews J, Wang Z. A new
dimension to the Barker hypothesis: low birthweight
and susceptibility to renal disease. Kidney Int 1999; 56:
1072–1077
31. Jones C, Bowden L, Watling R, Ryan S, Judd B. Hypercalciuria
in ex-preterm children, aged 7–8 years. Pediatr Nephrol 2001; 16:
665–671
Received for publication: 17.5.06
Accepted in revised form: 16.8.06