Neonatal Acute Kidney Injury

David T. Selewski, MD, MSa, Jennifer R. Charlton, MD, MSb, Jennifer G. Jetton, MDc, Ronnie Guillet, MD, PhDd,
Maroun J. Mhanna, MD, MPHe, David J. Askenazi, MD, MPHf, Alison L. Kent, BMBS, FRACP, MDg

In recent years, there have been signicant advancements in our abstract

understanding of acute kidney injury (AKI) and its impact on outcomes across
medicine. Research based on single-center cohorts suggests that neonatal AKI
is very common and associated with poor outcomes. In this state-of-the-art
review on neonatal AKI, we highlight the unique aspects of neonatal renal
physiology, denition, risk factors, epidemiology, outcomes, evaluation, and
management of AKI in neonates. The changes in renal function with
a
gestational and chronologic age are described. We put forth and describe the Division of Nephrology, Department of Pediatrics and
Communicable Diseases, C.S. Mott Childrens Hospital,
neonatal modied Kidney Diseases: Improving Global Outcomes AKI criteria University of Michigan, Ann Arbor, Michigan; bDivision of
and provide the rationale for its use as the standardized denition of neonatal Nephrology, Department of Pediatrics, University of
Virginia, Charlottesville, Virginia; cDivision of Nephrology,
AKI. We discuss risk factors for neonatal AKI and suggest which patient Dialysis and Transplantation, Stead Family Department of
populations may warrant closer surveillance, including neonates ,1500 g, Pediatrics, University of Iowa Childrens Hospital, Iowa City,
Iowa; dDivision of Neonatology, Department of Pediatrics,
infants who experience perinatal asphyxia, near term/ term infants with low University of Rochester Medical Center, Rochester, New
Apgar scores, those treated with extracorporeal membrane oxygenation, and York; eDivision of Neonatology, Department of Pediatrics,
Case Western Reserve University at MetroHealth Medical
those requiring cardiac surgery. We provide recommendations for the Center, Cleveland, Ohio; fDivision of Nephrology, Department
evaluation and treatment of these patients, including medications and renal of Pediatrics, University of Alabama at Birmingham,
replacement therapies. We discuss the need for long-term follow-up of Birmingham, Alabama; and gDepartment of Neonatology,
Centenary Hospital for Women and Children, Canberra
neonates with AKI to identify those children who will go on to develop chronic Hospital, Australian Capital Territory, Australia
kidney disease. This review highlights the decits in our understanding of Dr Selewski conceptualized and designed the outline
neonatal AKI that require further investigation. In an effort to begin to address of the manuscript, and reviewed and revised the
these needs, the Neonatal Kidney Collaborative was formed in 2014 with the manuscript; Drs Charlton, Jetton, and Kent provided
substantial acquisition and assimilation of the data,
goal of better understanding neonatal AKI, beginning to answer critical
drafted sections of the manuscript, and critically
questions, and improving outcomes in these vulnerable populations. revised the manuscript; Drs Guillet, Mhanna, and
Askenazi critically revised the manuscript; and all
authors approved the nal manuscript as
Over the past 15 years, there have been a tremendous amount of work is submitted.
signicant advancements in the study needed to optimize our ability to detect www.pediatrics.org/cgi/doi/10.1542/peds.2014-3819
of acute kidney injury (AKI) regarding and intervene in newborns with AKI. DOI: 10.1542/peds.2014-3819
the diagnosis, recognition, intervention, To advance the eld, the National
Accepted for publication Mar 16, 2015
and impact of AKI on morbidity and Institute of Diabetes and Digestive
Address correspondence to Jennifer R. Charlton MD,
mortality in critically ill children.14 It and Kidney Diseases (NIDDK)
MS, Department of Pediatrics, University of Virginia,
has become apparent that children who sponsored a workshop dedicated to Box 800386, Charlottesville, VA 22908. E-mail: jrc6n@
survive an episode of AKI are at neonatal AKI in April 2013. An hscmail.mcc.virginia.edu
increased risk for chronic kidney important result of this meeting was PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online,
disease (CKD) and warrant long-term the recognition that collaboration 1098-4275).
follow-up.5,6 Neonatal AKI studies have between neonatologists and
Copyright 2015 by the American Academy of
nephrologists is imperative to Pediatrics
begun to show similar conclusions: AKI
advance the study of neonatal AKI and
is common and is associated with FINANCIAL DISCLOSURE: Dr Askenazi is a speaker for
to improve outcomes in these the AKI Foundation; the other authors have indicated
poor outcomes.712 These studies remain
vulnerable patients. In this state-of- they have no nancial relationships relevant to this
limited to small single-center cohorts the-art review, we examine aspects of article to disclose.
using varying denitions of AKI, neonatal AKI, including neonatal renal FUNDING: No external funding.
making generalization difcult. physiology, denitions, risk factors,
POTENTIAL CONFLICT OF INTEREST: The authors have
Although progress has been made in epidemiology and outcomes, and indicated they have no potential conicts of interest
our understanding of neonatal AKI, evaluation and management of AKI. to disclose.

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PEDIATRICS Volume 136, number 2D,oAw REVIEW ARTICL E
NEONATAL RENAL PHYSIOLOGY
Although a detailed discussion of
renal development is outside the
scope of this review, there are
a number of features of neonatal
renal physiology that are pertinent to
AKI in neonates, including the
duration of nephrogenesis, renal
blood ow, glomerular ltration rate
(GFR), and tubular immaturity.
Nephrogenesis begins at the fth
week of gestation and continues until
34 to 36 weeks,13 yielding the adult
complement of 200 000 to 2.7 million
nephrons.14,15 The impact of
prematurity, intrauterine growth
restriction, and AKI on nephrogenesis
has not been fully delineated, but
small studies suggest that the
extrauterine environment and AKI are
detrimental to optimal
nephrogenesis.1619
There are signicant changes in
neonatal renal blood ow after birth
that are relevant to the study of AKI
in neonates. In comparison with the
20% to 25% of cardiac output
received by the adult kidney, at birth
the kidneys receive 2.5% to 4.0% of
the cardiac output. Over time, this
increases to 6% at 24 hours of life,
10% at 1 week, and 15% to 18% at
6 weeks of age.2023 The changes in
renal blood ow after birth result
from increased renal perfusion
pressure, increased systemic
arteriolar resistance, and decreased
renal vascular resistance due to
neurohumoral changes with
angiotensin II and prostaglandins
playing major roles.24
In the fetal and neonatal period, the
renin-angiotensin system is critical to
normal renal development and blood
ow. Angiotensin II, the effector
molecule of the renin-angiotensin
system, causes vasoconstriction at the
afferent and efferent arterioles with
the greatest impact at the efferent
arteriole.25,26 Prostaglandins
represent the most important
counter-regulatory molecules in the
neonatal period and lead to afferent
arteriole dilatation.27 The importance
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of each of these systems is seen in the
exacerbated response that critically ill
neonates have to inhibition of these
systems by medications when
oliguria and/or AKI develops after
exposure.
GFR represents the most recognized
measure of kidney function. In term
infants, the GFR improves from 10 to
20 mL/min/1.73 m2 during the rst
days of life to 30 to 40 mL/min/1.73 m2
by 2 weeks of life. In premature
infants, the GFR at birth is even lower
and increases slower than in term
infants. The GFR improves steadily
over the rst few months of life,
reaching the adult GFR by 2 years of
age.2830 The dynamic nature of the
neonatal GFR has implications for the
care of neonates particularly with
regard to drug exposures, dosing, and
susceptibility to the development of
AKI.
The term neonate has more mature
renal tubular function, which can
appropriately respond to homeostatic
needs. The tubular function is
immature in premature infants, with
a decreased ability to reabsorb
electrolytes and protein and to
concentrate urine. This has important
implications for the management and
diagnosis of AKI in premature infants,
who rely on the clinician to
appropriately prescribe uids and
replace electrolyte losses. The
immaturity of these mechanisms in
the neonatal kidneys explains some of
the subtleties of urinary ndings
(fractional excretion of sodium) in
neonatal AKI that differ from that in
older children.
DEFINITION OF NEONATAL AKI
AKI is classically dened as a sudden
decline in kidney function resulting in
derangements in uid balance,
electrolytes, and waste products.31
Currently, the diagnosis of AKI is
dependent on a rise in serum
creatinine (SCr) or decrease in urine
output. Unfortunately, SCr is
a suboptimal biomarker as it is
a marker of kidney function, not
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damage. As a result, there is
a signicant delay in the rise of SCr
after an insult (4872 hours) and
a signicant amount of function has
to be lost before SCr will rise (.50%
of the GFR). SCr also has unique
challenges in the neonatal population,
including the presence of maternal
creatinine, varying degrees of
creatinine reabsorption in the
proximal tubules, overall lower GFRs,
and maturational differences.3235 As
a result, there has been a signicant
amount of research to identify novel
biomarkers of damage to allow for
the earlier identication of neonates
with AKI (up to 48 hours before SCr
rise). These novel biomarkers include
urine neutrophil gelatinase-
associated lipocalin, cystatin-c, kidney
injury molecule-1, and others.3642 By
detecting earlier stages of kidney
injury, these biomarkers may allow
for prevention of or early
intervention in AKI in neonates.
Although these biomarkers continue
to show promise, currently SCr is the
standard used for the diagnosis of
AKI in all populations.
In 2005, an empirical denition for
AKI was introduced into the adult and
pediatric literature that recognized
stages of severity based on a decrease
in GFR and/or urine output. This
denition was developed based on
evidence that even small changes in
SCr were associated with increased
morbidity and mortality. Current
denitions have demonstrated that
even small degrees of AKI are
associated with increased morbidity
and mortality in children and
adults.1,3,43 This empirical denition
has evolved based on observational
data from millions of patients and
hundreds of studies into the Kidney
Diseases: Improving Global Outcomes
(KDIGO) AKI denition published in
2013, maintaining a 3-tiered
categorical staging model depicting
mild, moderate, and severe stages of
AKI.44 The use of standardized
denitions of AKI has allowed
comparison between studies and was
a fundamental rst step that has been
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integral to the study of AKI in
medicine.
Before 2008, most neonatal AKI
studies used arbitrary denitions of
AKI frequently dened by an absolute
SCr $1.5 mg/dL. In response to the
trends in the diagnosis of AKI,
a number of neonatal studies were
performed by using the Risk, Injury,
Failure, Loss of kidney function, and
End-stage kidney disease (RIFLE) and
Acute Kidney Injury Network (AKIN)
denitions of AKI.8,45 One such
standardized denition of AKI
described in detail by Jetton and
Askenazi is based on a modication of
the KDIGO denition termed the
neonatal modied KDIGO criteria
(Table 1). This denition stages AKI
based on an absolute rise in SCr from
a previous trough and should be used
in children ,120 days of age. In
April 2013, neonatologists and
pediatric nephrologists participating
in the NIDDK workshop carefully
scrutinized this denition. They
concluded that, at this time, this
denition offers a reasonable starting
point and would allow for consistency
throughout studies. As this denition
is empirical, large multicenter studies
are greatly needed to validate this
denition and address all aspects of
the denitions, including the degree
of SCr rise, age of utilization, and how
to deal with a rise in SCr from 0.2 to
0.3 mg/dL, which technically
represents a 1.5-fold increase and
would qualify as AKI. Some have
suggested that the SCr should rise to
an absolute value of .0.5 mg/dL and
meet the previous criteria to qualify
as AKI.1,12
TABLE 1 Neonatal AKI KDIGO Classication
Stage SCr
0 No change in SCr or rise ,0.3 mg/dL
1 SCr rise $ 0.3 mg/dL within 48 h or SCr rise
$1.51.9 3 reference SCra within 7 d
2 SCr rise $2.02.9 3 reference SCra
3 SCr rise $3 3 reference SCra or SCr $2.5 mg/dLb or
Receipt of dialysis
Differences between the proposed neonatal AKI denition and KDIGO include the following:
a Reference SCr will be dened as the lowest previous SCr value.
b SCr value of 2.5 mg/dL represents ,10 mL/min/1.73m2 .
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RISK FACTOR FOR NEONATAL AKI
The change in renal function that
denes AKI should be thought of as
the result of a combination of
susceptibility factors and
exposures.44 Although neonates are
subject to the same risk factors
present in critically ill children of all
ages, special consideration must be
made to risk factors inherent to
neonatal renal development and
physiology. Therefore, we will review
perinatal and postnatal risk factors
associated with AKI, including
perinatal events/exposures, sepsis,
and nephrotoxic medication
exposure that may identify neonates
who require enhanced vigilance
(Table 2).
Perinatal Exposures and Events
As a result of the unique neonatal
renal physiology, a number of
maternal exposures and perinatal
events can lead to neonatal AKI. For
example, maternal exposure to
nonsteroidal anti-inammatory drugs
predisposes neonates to oliguria and
AKI.47 The multiple roles of the renin-
angiotensin system in renal
development prenatally, as well as the
maintenance of renal blood ow
postnatally, can lead to a broad range
of outcomes in the newborns exposed
to angiotensin-converting enzyme
inhibitors ranging from renal
agenesis to AKI, depending on the
timing and duration of exposure.
Perinatal risk factors associated with
the development of AKI are outlined
in Table 2 and include low Apgar
scores, intubation, low cord pH, and
asystole.810,12,45,4750
Urine Output
$ 0.5 mL/kg/h
,0.5 mL/kg/h for 6 to 12 h
,0.5 mL/kg/h for $ 12 h
,0.3 mL/kg/h for $24 h or anuria
for $12 h
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Sepsis
Sepsis is a cause of signicant
morbidity and mortality in neonates.
Sepsis has been consistently shown to
be a risk factor for the development
of AKI across neonatal populations,
contributing to up to 78% of the
cases of AKI.5154 Mathur et al55
described 200 term neonates with
sepsis of whom 52 developed AKI.
Those who developed AKI had
a lower birth weight and were more
likely to have meningitis,
disseminated intravascular
coagulation, and septic shock.
Neonates who develop sepsis are
classically thought to be predisposed
to AKI secondary to the hypotension
associated with systemic
inammation, but there also appears
to be a direct impact on the
kidneys.56 Furthermore, AKI may
develop despite the maintenance of
systemic blood pressures and
renal blood ow, suggesting that
sepsis may directly damage the
kidney by effects on
microvasculature.5659
Nephrotoxic Medications
Nephrotoxic medications are known
to be a cause of AKI across the
spectrum of critically ill and
hospitalized children.60,61 Exposure
to nephrotoxic medications is also
associated with AKI in neonates and
may represent a modiable risk
factor.47,48,62 Table 3 provides
a description of common nephrotoxic
medications used in the NICU. In
2013, Rhone et al62 evaluated the
epidemiology and impact of
nephrotoxic medication exposure in
107 very low birth weight (VLBW)
infants. In this study, 87% of neonates
were exposed to at least 1
nephrotoxic medication and on
average these neonates were exposed
to 14 days of nephrotoxic medications
during their NICU stay. Although this
study represents an important step,
the epidemiology of exposure to
nephrotoxic medications in
general NICU populations remains
unstudied.
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TABLE 2 Risk Factors for AKI in Neonates
Study Population Study Size Risk Factors Associated With AKI
Cataldi et al 200548 Premature infants 172 Low Apgar scores, exposure to ampicillin, ceftazidime,
ibuprofen
Cuzzolin et al 200647 Premature infants 246 Maternal nonsteroidal anti-inammatory drugs during
pregnancy, intubation at birth, low Apgar scores, ibuprofen
administration to infant
Koralkar et al 201110 VLBW 229 Lower birth weight, lower gestational age, lower Apgar scores,
UAC, mechanical ventilation, inotrope support
Viswanathan et al 201265 ELBW 472 High mean airway pressures, lower mean arterial pressures,
higher exposure to cefotaxime
Mathur et al 200655 Neonates with sepsis 200 Lower birth weight, meningitis, DIC, and shock
Selewski et al 201312 Asphyxiated neonates undergoing therapeutic 96 Asystole at the time of birth, clinical seizures before cooling,
hypothermia persistent pulmonary hypertension, elevated gentamicin or
vancomycin levels, pressor support, transfusions
Bruel et al 2013103 Premature infants (,33 wk) 1461 Serum sodium variation, PDA, catecholamine treatment,
nosocomial infections, BPD, cerebral lesions, neonatal
surgery
Gadepalli et al 20118 Congenital diaphragmatic hernia 68 Lower 5-min Apgar score, AKI correlated with left-sided CDH
Bolat et al 201354 General NICU 1992 Pregnancy-induced hypertension, PPROM, antenatal
corticosteroids, SGA, birth weight ,1500 g, endotracheal
intubation, UVC, ibuprofen therapy for PDA closure, sepsis
Askenazi et al 201363 Birth weight .2000 g, gestational age .34 wk, 58 Lower birth weight, male, lower Apgar scores at 5 min, lower
5-min Apgar ,7 cord pH, mechanical ventilation
BPD, bronchopulmonary dysplasia; CDH-congenital diaphragmatic hernia; DIC, disseminated intravascular coagulation; PPROM, preterm premature rupture of membranes; UAC, umbilical
artery catheter; UVC, umbilical venous catheter.

EPIDEMIOLOGY AND OUTCOMES OF
NEONATAL AKI
There have been a number of single-
center studies that have evaluated the
impact of AKI in VLBW neonates,
extremely low birth weight (ELBW)
neonates, sick near-term/term
neonates, neonates on extracorporeal
membrane oxygenation (ECMO), and
asphyxiated newborns showing that
AKI is common and associated with
TABLE 3 Common Nephrotoxic Medications in NICU
Mechanism Acyclovir
Urinary precipitation, especially with low ow and
Angiotensin-converting enzyme
inhibitors
Aminoglycosides
Amphotericin B
Nonsteroidal antiinammatory drugs
Radiocontrast agents
Vancomycin
poor outcomes (Table 4).812,45,6264 until 36 weeks postmenstrual age.
Here we review AKI studies in some The incidence of AKI, by using the
exemplar patient populations. neonatal modied KDIGO criteria,
was 18%. The mortality in infants
VLBW and ELBW Neonates with AKI was signicantly higher than
There have been 3 large single- those without AKI (42% vs 5%,
center studies to date that have P , .001). After adjusting for potential
evaluated AKI in VLBW neonates confounders, those with AKI had
(5001500 g).10,65,66 In 2011, Koralkar a signicantly higher chance of death
et al10 reported on 229 VLBW infants (hazard ratio 2.4, 95% condence
followed prospectively from birth interval [CI] 0.956.0; P , .06).
Viswanathan et al65 reported similar
ndings in a retrospective single-
center study, where 12.5% (59/472)
Drug of all ELBW infants developed AKI
and mortality among those with AKI
was signicantly higher than controls
hypovolemia, with renal tubular obstruction and damage (70% vs 22%, respectively). In a large
and decreased GFR. May cause direct tubular toxicity retrospective study of VLBW infants,
(metabolites).
Decreased angiotensin II production inhibiting compensatory
constriction of the efferent arteriole to maintain GFR. Carmody et al66 examined 455 VLBW
Toxic to the proximal tubules (transport in the tubule, infants and found an AKI incidence of
accumulate in lysosome, intracellular rise in reactive 39.8%. In this study, AKI was
oxygen species and phospholipidosis, cell death); intrarenal independently associated with
vasoconstriction and local glomerular/mesangial cell
increased mortality (odds ratio 4.0,
contraction.
Distal tubular toxicity, vasoconstriction, and decreased GFR. 95% CI 1.411.5) and length of stay
Decreased afferent arteriole dilatation as a result of inhibiting (11.7 hospital days, 95% CI 5.118.4).
prostaglandin production resulting in reduced GFR.
Renal tubular toxicity secondary to increase in reactive oxygen Perinatal Asphyxia
species; intrarenal vasoconstriction may play a role.
Mechanism of AKI unclear, possible mechanism includes Infants with perinatal asphyxia have
proximal tubular injury with generation of reactive oxygen been recognized as a group that is at
species. high risk of AKI. Recently there have

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TABLE 4 Neonatal AKI Studies
Study Population
Askenazi et al 200945 VLBW infants (n = 195)
Gadepalli et al 20118 Congenital diaphragmatic hernia
on ECMO (n = 68)
Kaur et al 20119 Perinatal asphyxia (n = 36)
Koralkar et al 201110 VLBW infants (n = 229)
Askenazi et al 201363 Sick near-term neonates (n = 58) Neonatal Modied KDIGO
Alabbas et al 201364 Cardiac surgery ,28 d (n = 122) AKIN criteria
Selewski et al 201311,12 Perinatal asphyxia (n = 96)
Zwiers et al 201369 ECMO ,28 d (n = 242)
Rhone et al 201362 VLBW infants (n = 107)
Carmody et al 201466 VLBW infants (n = 455)
been 2 single-center studies that have
looked at the incidence of AKI by
using modern AKI denitions. Kaur
et al9 reported an incidence of AKI of
41.7%. Selewski et al12 evaluated
newborns undergoing therapeutic
hypothermia for perinatal asphyxia
and found that 36 (38%) of 96 had
AKI. Even after controlling for
important potential confounders,
children with AKI on average were
ventilated 4 days longer (P , .001)
and hospitalized 3.4 days longer
(P = .023). In addition, these
investigators also showed that AKI
during therapeutic hypothermia was
associated with abnormal brain MRI
ndings at 7 to 10 days of life,
implicating AKI as a potential marker
for neurologic outcomes.11
ECMO
Neonates supported with ECMO
represent a unique patient population
that is particularly prone to AKI
based on the severity of their illness
and the inammatory response that
accompanies exposure to the
extracorporeal circuit.67,68 Zwiers
et al69 evaluated AKI in 242 neonates
on ECMO over a 14-year period
showing an AKI incidence of 64% and
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Denition Incidence of AKI, %
AKIN criteria Matched case-control AKI is associated with increased mortality
study
RIFLE criteria
AKIN criteria
Neonatal Modied KDIGO
criteria
criteria
Neonatal Modied KDIGO
criteria
RIFLE criteria
Neonatal Modied KDIGO
criteria
Neonatal Modied KDIGO
criteria
a mortality of 65% when AKI
progressed to the highest stage. These
mirror the ndings of Gadepalli et al8
in neonates with congenital
diaphragmatic hernia on ECMO where
AKI occurred in 71% of neonates, and
those with the highest stage of AKI
had a mortality of 73%.
Neonatal Cardiac Surgery
The association of AKI with cardiac
surgery in older children has been
well studied and the association of
AKI with increased mortality is clear.
Alabbas et al64 published
a retrospective study of 122 neonates
(,28 days) showing that AKI
occurred in 62% of the neonates. The
highest stage of AKI was associated
with increased mortality and
increased ICU length of stay. These
ndings are similar to the ndings
reported by Blinder et al7 in 430
infants (,90 days) undergoing
cardiac surgery.
EVALUATION AND MANAGEMENT OF
NEONATAL AKI
The evaluation of a neonate who
develops AKI requires a systematic
approach, which frequently involves
http://pediatrics.aappublications.org/by
Findings
after adjustment for confounders
71.0 Increased risk of mortality at highest level
of AKI (Failure)
41.7 Modern staging systems (AKIN) capture AKI
previously missed by previous standard
of SCr .1.5 mg/dL
18.0 Adjusting for severity of illness, AKI was
associated with increased mortality
15.6 AKI associated with increased mortality and
positive uid balance
62.0 Severe AKI (Stage III) was associated with
increased mortality and length of stay after
adjusting for severity of illness.
38.0 AKI predicted prolonged mechanical ventilation,
length of stay, and abnormal brain MRI
ndings at 710 d of life
64.0 Increased risk of mortality at highest level of
AKI (Failure)
26.2 AKI is associated with nephrotoxic medication
exposure
39.8 AKI associated with increased mortality and
length of stay adjusted for severity of illness
evaluating prerenal, intrinsic, and
postrenal causes. We highlight
important aspects of the evaluation. A
detailed clinical history should
include assessment of gestational age,
antenatal (ultrasounds), maternal
(nephrotoxic medication), birth (fetal
heart rate monitoring and
resuscitation), and postnatal
(nephrotoxic medications,
hypotension) events. The physical
examination should focus on volume
status and vital signs. A thorough
evaluation of volume status also
requires assessment of serum
electrolytes, uid balance, and,
importantly, body weight. Utilization
of these 3 measurements can assist in
determining both hypovolemia from
insensible losses, as well as
hypervolemia from uid overload.
Assessment of fractional excretion of
sodium can help to differentiate the
prerenal (hypovolemia) from intrinsic
(acute tubular necrosis) causes of
AKI, although in premature infants
this metric may not be as helpful.
Finally, to evaluate potential
postrenal (obstruction) causes of AKI,
an ultrasound should be obtained.
After the diagnosis of AKI, it becomes
important to prevent the
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development of sequelae. Daily
evaluation of medications and the
participation of a pharmacist are
paramount in the management of the
critically ill neonate to monitor drug
levels and avoid nephrotoxic
exposures when clinically feasible.
Strict documentation of all uid input
and output, serum electrolytes, and
weight is essential to optimize uid
status. Tracking cumulative uid
overload provides a global
assessment of uid status.
Hypervolemia may dictate
intervention and nephrology
consultation.
There are sparse data documenting
interventions that can prevent AKI in
at-risk patients or ameliorate AKI
once it is established. In neonates
with perinatal asphyxia, adenosine
receptor antagonists (theophylline)
may prevent AKI by inhibiting the
adenosine-induced vasoconstriction.
Several independent randomized
studies in asphyxiated infants have
shown that prophylactic theophylline,
given early after birth, was associated
with better kidney function.7073 As
a result, the KDIGO guidelines
recommend a single dose of
theophylline for asphyxiated infants
at risk for AKI.44 Caution must be
taken, as theophylline has some
potentially harmful neurologic
effects.74 Other drugs that have been
studied to prevent the development
of AKI and improve renal blood ow
include dopaminergic agonists
(dopamine and fenoldopam).7577
Although each of these agents has
shown promise in the
prevention of AKI, the clinical
studies have been mixed, and
rm recommendations on their
use cannot be made.
Diuretics are frequently used in
patients with AKI in attempts to
maintain urine output. Studies in
critically ill patient populations have
not demonstrated a benecial effect
of diuretics on outcomes and have
occasionally demonstrated worse
outcomes in patients with AKI treated
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with diuretics. For example, in
a retrospective case-control study,
bumetanide was shown to improve
the urine output of ELBW infants
with AKI at the expense of increasing
their SCr.78 In another study,
bumetanide was also shown to
increase signicantly the urine
output, in premature infants with
oliguric AKI, but at the expense of
a transient increase in SCr.79 Despite
the lack of evidence in neonates,
a trial of diuretics in oliguric neonates
with AKI is warranted given the
complexity of renal replacement
therapy. Large-scale multicenter trials
of these medications in neonates are
greatly needed.
Because of the lack of successful
strategies to prevent or ameliorate
AKI, the primary therapy for severe
cases of AKI is renal replacement
therapy. Indications for renal
replacement therapy in neonates
include refractory acidosis, uremia,
electrolyte abnormalities, inability to
provide adequate nutrition, and uid
overload. The association between
uid overload and mortality in
critically ill patients is one of the
hottest topics in acute care
nephrology and warrants special
mention. Pediatricians have been at
the forefront of identifying uid
overload as a risk factor for mortality
in critically ill patients.80 This is
highlighted by the ndings of the
prospective pediatric continuous
renal replacement therapy (CRRT)
registry. Sutherland et al81 showed in
a prospective registry of 227 children
who were on CRRT that those with
a percentage uid overload ,20% at
initiation of renal replacement
therapy had improved rates of
survival compared with those with
a cumulative uid balance .20%
(46% vs 68%, P , .01). These
ndings have since been veried in
a number of different pediatric
patient populations highlighting
the importance of uid overload
and the timing of renal
replacement therapy in critically ill
children.8285
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onOctober
Recent data extend these ndings to
critically ill children and adults
independent of renal replacement
therapy.8688 The impact of uid
overload is highlighted in the practice
guidelines proposed by the American
College of Critical Care Medicine for
pediatric and neonatal septic shock,
which recommend that interventions
to address uid balance are
warranted when critically ill children
amass 10% volume overload.89
Limited data are available on uid
overload in neonates. Askenazi et al63
showed that sick late preterm
neonates with AKI had a higher
median uid overload at day of life 3
than those without AKI (+8.2% vs
4%, P , .001). As uid overload is
a potentially modiable risk factor for
mortality, research into its impact on
neonatal outcomes is critical to
provide information to clinicians
about uid provision and the timing
of renal replacement therapy.
Throughout adult and pediatric
intensive care medicine, renal
replacement therapy has transitioned
from being a last-ditch effort to an
early therapy directed at supporting
the critically ill patient by maintaining
electrolyte homeostasis, allowing for
provision of adequate nutrition, and
preventing/reducing hypervolemia.
This mindset of early intervention has
not fully reached the neonatal
population, possibly because of the
added risk of dialysis machines,
ethical considerations, and a lack of
studies that illustrate the role of uid
overload on poor outcomes in these
patients. Renal replacement therapy
poses particular challenges in the
neonate, as most equipment was
designed for older children. Currently,
peritoneal dialysis (PD) is the
modality of choice in infants. PD is
technically easier, as there is no need
for vascular access or an
extracorporeal blood circuit.90 If
peritoneal dialysis is felt to be
a short-term requirement,
a temporary catheter can be placed.
Several studies describe successful
peritoneal dialysis by several
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 et al5 reported that 10% of
different techniques in critically ill GFR ,60 mL/min/1.73 m2, 1 to
children who developed AKI in the
neonates as small as 830 g.9195 3 years later. Perhaps even more
PICU had
When PD is technically difcult alarming was the nding that nearly
because of abdominal wall defects, 50% of this cohort was found to be
skin infections, communication to the at risk for CKD.
pleural space, or high ultraltration The role that AKI plays in the
needs, CRRT can be performed. development of CKD in the neonatal
CRRT is performed with a population is unknown. Several case
hemodialysis catheter placed in a reports document that CKD occurs in
central location and either regional or infants who had AKI; however, these
systemic anticoagulation. The volume studies are small, single-center
of the extracorporeal circuit is retrospective reports. Recognizing the
particularly critical in the neonatal long-term implications of AKI, the most
population and often these neonates recent KDIGO practice guidelines
will require that the CRRT machine recommend that all patients who
be primed with blood if the circuit experience AKI be evaluated after 3
volume exceeds months for new onset or worsening of
10% to 15% of the total blood CKD.44 They caution that even if CKD
volume.96 In the United States, is not present at that time, those with
current CRRT machines are approved AKI are considered to have increased
only for those weighing .20 kg, but risk for CKD long-term. Although these
these machines have been used off- recommendations are likely pertinent
label in children ,5 kg.97 There are to infants, currently there is not
a number of considerations when enough rm evidence to make formal
evaluating CRRT in a neonate, follow-up recommendations after
including center expertise, prescription, episodes of neonatal AKI. General
and error rates of current machines, pediatricians should consider neonates
which has been recognized and led to who have suffered AKI at increased
the development of neonatal CRRT risk and monitor blood pressure with
machines.98 CRRT systems, such as consideration of
CARPEDIEM99 (Bellco, Mirandola, further testing on a case-by-case basis.
Italy) and Nidus,100 are being used in Large longitudinal multicenter studies
countries outside the United States in designed to follow neonates after
neonates. These machines show critical illness are greatly needed to
promise, as they have smaller dene the most appropriate
extracorporeal volumes and are surveillance protocols, as well as
highly accurate. Despite these recent identify those most at risk.
advances, the evidence on the
practice of renal replacement therapy
in neonates is limited to single-center CONCLUSIONS
case series with a complete lack of Neonatal AKI represents a rapidly
multicenter data. evolving area in clinical research, but a
signicant amount of work remains to
improve the outcomes in these
CONSEQUENCES AND FOLLOW-UP OF patients. An important rst step
NEONATAL AKI moving forward is the development of
Previously, it was assumed that those a standardized denition of AKI.
who survived an episode of AKI Initially, the neonatal modied KDIGO
would recover kidney function AKI denition will be used as common
without long-term effects. Recent nomenclature to unify and compare
data from animals,101 critically ill research in neonatal AKI. Although
children,5,6 and adults102 with AKI this denition represents the best
suggest that survivors are at risk for available, it remains limited in that it
the development of CKD. Mammen has not been systematically

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studied in a multicenter manner
evaluating the association of AKI with
outcomes. Further work in neonatal
AKI needs to focus on dening risk
factors, the implications of uid
balance, renal replacement therapy,
and the long-term outcomes,
including the development of CKD in
this susceptible population.
After the NIDDK-sponsored workshop
on neonatal AKI, an international,
multi-institutional, multidisciplinary
group, the Neonatal Kidney
Collaborative, was formed. This
group aims to answer some of the
questions surrounding neonatal AKI
with the goal of improving outcome
and optimizing care for these
vulnerable patients.

ABBREVIATIONS
AKI: acute kidney injury
CRRT: continuous renal
replacement therapy
CKD: chronic kidney disease
ECMO: extracorporeal membrane
oxygenation
ELBW: extremely low birth weight
GFR: glomerular ltration rate
KDIGO: Kidney Diseases:
Improving Global
Outcomes
NIDDK: National Institute of
Diabetes and Digestive
and Kidney Diseases
PD: peritoneal dialysis
SCr: serum creatinine
VLBW: very low birth weight
infants

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 Neonatal Acute Kidney Injury
David T. Selewski, Jennifer R. Charlton, Jennifer G. Jetton, Ronnie Guillet, Maroun J.
Mhanna, David J. Askenazi and Alison L. Kent
Pediatrics 2015;136;e463
DOI: 10.1542/peds.2014-3819 originally published online July 13, 2015;

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Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since . Pediatrics is owned, published, and trademarked by the
American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,
60007. Copyright 2015 by the American Academy of Pediatrics. All rights reserved. Print
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 Neonatal Acute Kidney Injury
David T. Selewski, Jennifer R. Charlton, Jennifer G. Jetton, Ronnie Guillet, Maroun J.
Mhanna, David J. Askenazi and Alison L. Kent
Pediatrics 2015;136;e463
DOI: 10.1542/peds.2014-3819 originally published online July 13, 2015;

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/136/2/e463

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since . Pediatrics is owned, published, and trademarked by the
American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,
60007. Copyright 2015 by the American Academy of Pediatrics. All rights reserved. Print
ISSN: .

Downloaded from http://pediatrics.aappublications.org/

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