Pediatr Nephrol (2005) 20:1552–1556
DOI 10.1007/s00467-005-2022-6
ORIGINAL ARTICLE
Vincenzo Zanardo · Stefania Vedovato · Paola Lago ·
Daniele Trevisanuto · Flaviano Favaro ·
Diego Faggian · Mario Plebani
Urinary ET-1, AVP and sodium in premature infants treated
with indomethacin and ibuprofen for patent ductus arteriosus
Received: 18 February 2005 / Revised: 1 June 2005 / Accepted: 1 June 2005 / Published online: 17 August 2005

IPNA 2005
Abstract The relative potency and interrelationship be-
tween vasoactive and natriuretic mediators are thought to
be important in the transition from fetal to neonatal life.
The relationship between urinary vasoactive factors and
sodium excretion has not been adequately addressed in
premature infants receiving indomethacin and ibuprofen
for therapy of patent ductus arteriosus. Excretion rates of
AVP, ET-1 and sodium were measured in premature in-
fants with RDS receiving indomethacin or ibuprofen.
Forty-four RDS premature infants (<34-week gestation)
with PDA received either ibuprofen (n=22) in an initial
dose of 10 mg/kg followed by two doses of 5 mg/kg each
after 24 and 48 h or 3 doses at 12-h intervals of indo-
methacin (n=24), 0.2 mg/kg, infused continuously over a
period of 15 min. Urinary ET-1, AVP and sodium ex-
cretion were measured before and after treatment. Indo-
methacin treatment caused a significant decrease in uri-
nary ET-1 and AVP excretion (UET-1/Ucr 0.14€0.01 vs.
0.10€0.05 fenton/mmol; P<0.05; 24.42€6.18 vs. 12.63€
3.06 pg/mmol; P<0.05, respectively), along with a sig-
nificant reduction in urinary sodium (92.1€36.1 vs. 64.8€
35.6 mmol/l; P<0.01), fractional excretion of sodium
(6.8€37.1 vs. 4.5€37.1%; P<0.01) and urinary osmolality
(276.2€103.9 vs. 226.4€60.3 mOsmol/kg; P<0.05). Ibu-
profen treatment caused a significant decrease in urinary
AVP (UAVP/Ucr 24.5€3.4 vs. 16.3€2.04 pg/mmol; P<
0.01), along with a significant decrease in urinary sodium
(78.0€8.4 vs. 57.0€8.0 mmol/l; P<0.05) and in fractional
excretion of sodium (7.5€1.3 vs. 3.9€3.0%; P<0.05),
while it did not modify urinary ET-1 excretion. The as-
sociation of renal ET-1 and AVP activity with sodium
V. Zanardo ()) · S. Vedovato · P. Lago · D. Trevisanuto
Department of Pediatrics,
Padua University School of Medicine,
Via Giustiniani 3, 35128 Padua, Italy
e-mail: zanardo@pediatria.unipd.it
Tel.: +39-49-8213505
F. Favaro · D. Faggian · M. Plebani
Institute of Laboratory Medicine,
Padua University School of Medicine,
Padua, Italy
excretion in premature infants treated with indomethacin
and ibuprofen supports the hypothesis that these factors
may play a role in the physiologic changes in sodium
excretion.
Keywords Sodium · Renal endothelin-1 (ET-1) ·
Arginine vasopressin (AVP) · Indomethacin · Ibuprofen ·
Patent ductus arteriosus
Introduction
The contribution of local vasoactive factors to renal so-
dium regulation is increasingly recognized as an impor-
tant component of volume regulation and excretory
functions in the neonatal period. In addition to their role
in the circulatory adaptation to extrauterine life [1], en-
dothelin-1 (ET-1) and arginine vasopressin (AVP) are
involved in the tubular transport processes, and the uri-
nary excretion of ET-1 and AVP has been positively
correlated to sodium excretion. However, the state of high
ET-1 and AVP activity at birth and the unclear mecha-
nism of both indomethacin and ibuprofen renal effects in
the premature kidney limit the pathophysiological inter-
pretation of the observed fall of sodium excretion reported
after indomethacin and ibuprofen treatment.
Renal effects of indomethacin and ibuprofen are based
on their primary pharmacological mechanism of action,
the inhibition of prostaglandin synthesis through the in-
hibition of cyclooxygenase (COX). Increased sodium re-
absorption is thought to be caused primarily by the inhi-
bition of prostaglandin E2 (PGE2) synthesis [2, 3]. Nev-
ertheless, the AVP pathway parallels ET-1 action in the
renal tubular system and may be a downstream effector of
ET-1 [4, 5]. AVP, the antidiuretic hormone of humans, is
involved in the mechanisms of control of renal sodium
excretion by direct intrarenal actions, by neural-hormonal
interactions and via the secondary effects of fluid volume
retention [6]. ET-1 has been shown to participate in the
control of several cardiovascular, renal and endocrine
functions [7, 8]. In the kidney, its production is not con-

fined to the vascular endothelium; it is also released by
epithelial cells derived from different nephron segments
[9, 10]. The locally produced ET-1 acts as an autocrine/
paracrine factor to modulate renal tubular transport pro-
cesses, including the reabsorption of sodium and water
[11, 12]. Convincing evidence exists that ET-1 is regu-
lated by a variety of stimuli including angiotensin II,
AVP, epinephrine, fluid-mechanical shear stress, acute
physical stress, vaginal delivery [13, 14], respiratory
distress syndrome (RDS) and asphyxia.
Despite the functional convergence of these pathways,
few studies have evaluated urinary ET-1 and AVP ex-
cretion in humans with respect to sodium excretion. In
addition, given that indomethacin- and ibuprophen-treat-
ed premature infants with patent ductus arteriosus (PDA)
are more prone to an electrolyte imbalance, the natriuretic
mechanism with respect to the ET-1 and AVP pathways
may be potentially different in these treatment groups.
Therefore, the current study was conducted to assess re-
lationships between renal excretion of ET-1, AVP and
sodium in premature infants treated with indomethacin
and ibuprofen for patent ductus arteriosus (PDA) phar-
macological closure.
Patients and methods
During a randomized study to evaluate the efficacy of ibuprofen
and indomethacin for the pharmacological closure of PDA [15], we
examined the urinary ET-1, AVP and sodium excretion in 50
consecutive preterm infants (<34-week gestational age) admitted to
the Neonatal Intensive Care Units of the University of Padua, Italy,
between September 2000 and June 2002. The criteria for enroll-
ment were echocardiographic diagnosis of PDA from the 2nd day
of life and respiratory distress syndrome, which necessitated me-
chanical ventilation. We excluded premature infants with major
congenital malformations, renal or gastrointestinal abnormalities,
persistent pulmonary hypertension, urinary outputs below 1 ml per
kg of body weight per h during the preceding 12 h, recent bleeding
(less than 48 h), a platelet count of less than 50,000/mm3 and
incomplete blood and urinary data. Informed written consent was
obtained from one or both parents, and the study was approved by
the Ethics Committee of the Pediatric Department of Padua Uni-
versity.
The preterm infants were randomly assigned to a treatment
group. Each infant received 3 doses of either indomethacin (Ly-
ometacen, Chiesi Farmaceutici, Parma, Italy) 0.2 mg/kg at 12-h
intervals or ibuprofen (Arfen, Lisapharma, Erba, Como, Italy) in an
initial dose of 10 mg/kg followed by 2 doses of 5 mg/kg each after
24 and 48 h. The medications were infused continuously over a
period of 15 min. The doses and intervals for ibuprofen were in
accordance with recommendations for its use in infants and neo-
nates based on preliminary pharmacodynamic data [16].
When the ductus was still patent after the randomly assigned
treatment in a patient of either group who was receiving mechanical
ventilation, another three doses of the same medication were given
as a non-randomized rescue treatment. If this therapy also failed to
promote ductal closure or further pharmacological treatment was
contraindicated, or if the premature infant continued to receive
mechanical ventilation or had a hemodynamically significant duc-
tus, surgical ligation of the ductus was performed.
A complete echocardiographic and Doppler evaluation (HDI
3000 CV, ATL, USA or Vingmed Sound, System5, Norway, with a
7.5-MHz transducer) was performed in all infants eligible for the
study by physicians unaware of the infant’s treatment group. The
purpose was to evaluate the patency of the ductus arteriosus and
1553
shunting at the baseline and after each dose of the drug. The di-
agnosis of PDA was based on the typical flow pattern obtained by
color Doppler echocardiography [17]. All premature infants un-
derwent echocardiographic and Doppler evaluation after the last
dose of treatment and after a second non-randomized rescue
treatment when necessary or whenever there was clinical suspicion
that the ductus had reopened after closure. Fluid intake was guided
by body weight, serum sodium concentration and serum osmolality.
For the treatment of RDS, infants received respiratory support
(conventional or high-frequency oscillatory ventilation), oxygen
supplementation and early rescue therapy with natural surfactant
(Curosurf, Chiesi Farmaceutici, Parma, Italy) in one or more doses
of 100 mg/kg. Prophylactic antibiotics, ampicillin and gentamicin,
were administered upon admission to the neonatal intensive care
unit and stopped after a mean of 3 days if bacterial cultures re-
mained negative.
We recorded the following clinical data: gestational age, birth
weight, sex, cesarean section, Apgar score at 1 and 5 min, need for
positive pressure ventilation in delivery room, surfactant adminis-
tration, the beginning day of therapy, type of ventilation during
PDA treatment, radiological grade of RDS, fractional inspired
oxygenation (FiO2%) and the efficacy of the treatment. The pro-
tocol included a 24-h pretreatment study period and a subsequent
24-h period following three doses of indomethacin or ibuprofen
administration to evaluate kidney function parameters and urine
AVP and ET-1 excretion. Each urine collection period started and
ended by empting the bladder according to Crede’s method. Blood
samples for creatinine, electrolytes and osmolality were obtained
by a standard capillary technique at the midpoint of each urine
collection period, by Technicon SMAC analyzer (Technicon, Ter-
rytown, USA). After collection, urine was analyzed for fractional
excretion of sodium using a standard formula as follows:
UNa
Pcr
FENað%Þ ¼
100 ð1Þ
Ucr
PNa
where UNa indicates urinary sodium concentration (mmol/l); Pcr,
plasma creatinine (mmol/l); Ucr, urinary creatinine (mmol/l); PNa,
plasma sodium (mmol/l).
In the urine, the ET-1 concentration was measured using an
enzyme immunoassay (Biomedica Gruppe, A-121D Wien, Diois-
chgassi) and was expressed as fenton per mmol creatinine, while
the AVP concentration was measured out using radio immunoassay
(Diagnostic Systems Laboratories, Wesblur, Texas) and was ex-
pressed as picogram per mmol creatinine.
We also studied the respiratory outcome (bronchopulmonary
dysplasia, BPD), the presence of intraventricular hemorrhage
(IVH), of retinopathy of prematurity (ROP) and of pneumothorax
(PNX).
Data were evaluated by Wilcoxon nonparametric test and by
binomial distribution analysis. Results were expressed as mean €
SD or mean € SEM. The statistically significant difference was set
at P<0.05.
Results
We studied 50 consecutive RDS preterm infants with a
hemodynamically significant PDA. Four were subse-
quently excluded because of incomplete urine and blood
data or absent parental consent. Forty-six were included
in the statistical analysis: 22 of them received ibuprofen
and 24 received indomethacin. The clinical and anthro-
pometrical characteristics of the two groups of preterm
infants, as well as their baseline biochemical values, re-
spectively, before treatment with ibuprofen or indometh-
acin, are comparable (Table 1).
After treatment, the rate of closure of the PDA was
similar in the ibuprofen (16/22, 72%) and indomethacin
1554
Table 1 Anthropometric and clinical characteristics of the infants Pre- and post-treatment fluid intakes with ibuprofen
with PDA (V vaginal; C cesarean section; HFO high frequency and indomethacin were comparable (135.3€8.7 vs. 147.6€
oscillator)
8.1 ml/kg/day and 130.5€8.6 vs. 134.9€8.9 ml/kg/day),
Ibuprofen Indomethacin P value along with a comparable urine output (90.6€8.0 vs.
(n=22) (n=24) 97.1€7.0 ml/kg/day and 91.5€8.3 vs. 96.9€11.5 ml/kg/
Delivery: V/C 9/13 4/20 n.s. day) and a similar significant physiologic body weight
Gestational age (weeks) 27€2.9 28€3.03 n.s. decrease (853€383 vs. 823€389 g; P<0.05 and 1,001€406
<26 weeks 12 7 vs. 975€415 g; P<0.05), respectively.
27–28 weeks 5 8
29–30 weeks 2 4
In addition, in the group treated with ibuprofen there
31–32 weeks 2 2 were 8 cases of bronchopulmonary dysplasia (BPD), 9 of
33–34 weeks 1 3 first and second grade retinopathy of prematurity (ROP),
Birth weight (g) 853€383 1,001€406 n.s. 5 of first and second grade intraventricular hemorrhage
Apgar index (IVH) and no cases of pneumothorax (PNX). In premature
1 min 4.1€2.3 4.8€2.2 n.s.
5 min 6.8€1.8 7.4€1.3 n.s. infants treated with indomethacin, there were 8 cases of
Resuscitation at birth 16 18 n.s. BPD, 8 of first and second grade ROP, 5 of first and
Assisted ventilation second grade IVH and 1 of PNX.
Conventional/HFO 21/1 21/3 n.s.
Surfactant treatment
1 dose 10 11 n.s
>2 doses 5 8 n.s Discussion
Age of treatment (day) 4.7€4.2 3.6€2.9 n.s
All values are expressed as mean € SD. n.s.=P>0.05 The association of renal ET-1 and AVP activity with
sodium excretion found in premature infants treated with
indomethacin and ibuprofen for patent ductus arteriosus
(21/24, 87.5%) groups. Nine neonates who did not re- supports the hypothesis that these factors play a role in the
spond to the pharmacological treatment underwent ductal physiologic changes in sodium excretion. However, the
legation. state of high ET-1 and AVP activity at birth and the lack
The preterm infants treated with indomethacin had a of control data of untreated neonates and of the urinary
significant decrease in urinary ET-1 excretion (UET-1/ PGE2 limit the pathophysiological interpretation of the
Ucr 0.14€0.01 vs. 0.10€0.01 fenton/mmol; P<0.05) com- observed fall of vasoactive factors ET-1, AVP and sodium
pared to pretreatment values. Changes in ET-1 urinary excretion after indomethacin and ibuprophen treatment.
excretion paralleled urine AVP excretion (UAVP/Ucr Furthermore, our data cannot distinguish among the var-
24.4€6.8 vs. 12.6€3.0 pg/mmol; P<0.01). On the con- ious mechanisms responsible for sodium retention.
trary, ibuprofen treatment caused a significant decrease in However, the observation in the indomethacin series that
urinary AVP (UAVP/Ucr 24.5€3.4 vs. 16.3€2.0 pg/mmol; the decrease in urine sodium and osmolality was signifi-
P<0.05), while not modifying urinary ET-1 excretion cantly associated with a reduced excretion of ET-1 and
(Table 2). AVP speaks in favor of an important role of ET-1 and
In addition, indomethacin treatment caused a signifi- AVP.
cant reduction in urinary sodium concentration (92.1€7.7 Eicosanoid products of the cytocrome P-450 (CYP450)
vs. 64.8€7.6 mmol/l; P<0.01), fractional excretion of so- monooxygenase system are important paracrine hormones
dium (7.0€0.7 vs. 4.6€3.7%; P<0.01) and urinary osmo- in the kidney that make important contributions to the
lality (276.2€22.1 vs. 226.2€22.1 mOsmol/kg; P<0.05). regulation of the vasomotor tone as well as to the regu-
Also ibuprofen treatment caused a significant decrease lation of salt and water excretion [18]. In fact, in previous
in urinary sodium concentration (78.0€8.6 vs. 57.0€ reports [19], it was demonstrated that nonsteroidal anti-
8.0 mmol/l; P<0.05) and in the fractional excretion of inflammatory drugs (NSAIDs) reduce the synthesis of
sodium (7.5€1.3 vs. 3.9€0.6%; P<0.05), while not modi- prostaglandins (PGs), with several effects. First of all,
fying urinary osmolality (Table 2). they produce an increase of renal vascular resistance, and

Table 2 Excretion rates for sodium and vasoactive factors before and after indomethacin and ibuprofen treatment in premature infants
with PDA (patent ductus arteriosus)
Fractional sodium Urinary sodium Urine osmolality UET-1/Ucr ratio UAVP/Ucr ratio
excretion (%) (mmol/l) (mOsmol/kg) (fenton/mmol) (pg/mmol)
Indomethacin
Pre-treatment 7.0+0.7 92.1€36.1 276.2€103.9 0.14€0.01 24.42€6.18
Post-treatment 4.6+0.7** 64.8€35.6** 226.4€60.3* 0.10€0.05* 12.63€3.06*
Ibuprofen
Pre-treatment 7.5+1.3 78.0€8.4 235.2€19 0.16€0.01 24.55€3.47
Post-treatment 3.9+0.6* 57.0€8.0* 241.5€31 0.13€0.01 16.39€2.04*
Values are expressed as mean € SEM. *P<0.05; **P<0.001

a consequent drop in urine flow [20, 21]. Secondly, they
reduce the natriuretic effect of the PGs, which decrease
sodium reabsorption at the thick ascending limb of the
loop of Henle [21]. Thirdly, endogenous PGs play a
central role in the control of AVP secretion [22].
Moreover, evidence has accumulated over the years
confirming that AVP, in addition to its principal action
promoting water reabsorption in the collecting system of
the nephron, can induce natriuresis [23]. The mechanism
of AVP natriuresis is unclear. Early and more recent
studies suggest that the natriuretic effect is mediated by
PGs [24]. In support of this interpretation, Guignard et al.
found that renal hemodynamic responses of neonatal and
young adult rabbits to acute i.v. doses of NSAIDs are
mainly due to non-specific inhibition of the renal COX
[20]. In particular, ibuprofen caused a dose dependency, a
significant reduction in the urine volume, glomerular
filtration rate, renal blood flow with a reduction of the
filtration fraction in the animals receiving the highest
dose of ibuprofen, accompanied by a urinary sodium
excretion decrease, and a very steep rise in renal vascular
resistance, no less than that previously seen with indo-
methacin.
On the other hand, studies investigating the activity of
ET-1 on sodium reabsorption have given conflicting or
unconvincing results [25]. Urinary ET-1 excretion has
been documented to reflect renal synthesis of the peptide;
therefore, it may be used as an estimate of renal ET-1
production [13]. ET-1 is an extremely potent and long-
lasting vasoconstrictor peptide. Its gene expression has
different patterns in a wide variety of cell types [26], and
it is regulated by a variety of stimuli, including angio-
tensin II, AVP, epinephrine, fluid-mechanical shear
stress, acute physical stress [13, 14, vaginal delivery [14],
RDS [27] or birth asphyxia [1, 14]. Moreover, in dogs and
in newborn piglets, ET-1, infused intrarenally, had a va-
soconstrictor effect and, in parallel, stimulated the syn-
thesis of PGI2 and PGE2, which act to downregulate the
contractile response seen with elevated ET-1. Pretreat-
ment with indomethacin significantly augmented the ET-
1 vasoconstrictor effect because it blocked the negative
feedback signal [4, 28]. In contrast, in rats, in the presence
of ibuprofen, the renal hemodynamic was preserved with
ET-1 [28, 29]. The kidney is both a target organ and a
major source of ET-1 production. The role of ET-1 in
renal control of sodium and water homeostasis during the
neonatal period has not been completely understood.
Rascher et al. found that renal ET-1 secretion contributes
to the maintenance of the sodium balance. In premature
infants, ET-1 enhanced renal tubular sodium reabsorption
during a sodium-depleted state, probably through renin-
angiotensin-aldosterone system mediation, and a correc-
tion of the sodium and water balance normalized plasma
ET-1 levels [30]. In septic neonatal piglets, Radhakrish-
nan found that incremental doses of endotoxin induce
greater release of ET-1 with an early proportionate in-
crease in FeNa [31].
In conclusion, the relationship between ET-1, AVP
and decreased urinary sodium appeared similar in RDS
1555
premature infants treated with indomethacin and ibupro-
fen. This suggests that the ET/AVP natriuretic axis plays
a role in the physiologic changes in sodium excretion in
premature infants treated for PDA pharmacological clo-
sure. In this case, considering the efficacy and adverse
effect, indomethacin and ibuprofen should be used with
the same caution in RDS preterm infants with patent
ductus arteriosus.
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