Download Neonatal Acute Kidney Injury

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 significant advancements in our
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, definition, risk factors, epidemiology, outcomes, evaluation, and
management of AKI in neonates. The changes in renal function with
gestational and chronologic age are described. We put forth and describe the
neonatal modified Kidney Diseases: Improving Global Outcomes AKI criteria
and provide the rationale for its use as the standardized definition of neonatal
AKI. We discuss risk factors for neonatal AKI and suggest which patient
populations may warrant closer surveillance, including neonates ,1500 g,
infants who experience perinatal asphyxia, near term/ term infants with low
Apgar scores, those treated with extracorporeal membrane oxygenation, and
those requiring cardiac surgery. We provide recommendations for the
evaluation and treatment of these patients, including medications and renal
replacement therapies. We discuss the need for long-term follow-up of
neonates with AKI to identify those children who will go on to develop chronic
kidney disease. This review highlights the deficits in our understanding of
neonatal AKI that require further investigation. In an effort to begin to address
these needs, the Neonatal Kidney Collaborative was formed in 2014 with the
goal of better understanding neonatal AKI, beginning to answer critical
questions, and improving outcomes in these vulnerable populations.
Over the past 15 years, there have been
significant advancements in the study
of acute kidney injury (AKI) regarding
the diagnosis, recognition, intervention,
and impact of AKI on morbidity and
mortality in critically ill children.1–4 It
has become apparent that children who
survive an episode of AKI are at
increased risk for chronic kidney
disease (CKD) and warrant long-term
follow-up.5,6 Neonatal AKI studies have
begun to show similar conclusions: AKI
is common and is associated with
poor outcomes.7–12 These studies remain
limited to small single-center cohorts
using varying definitions of AKI,
making generalization difficult.
Although progress has been made in
our understanding of neonatal AKI,
PEDIATRICS Volume 136, number 2, August 2015
a tremendous amount of work is
needed to optimize our ability to detect
and intervene in newborns with AKI.
To advance the field, the National
Institute of Diabetes and Digestive
and Kidney Diseases (NIDDK)
sponsored a workshop dedicated to
neonatal AKI in April 2013. An
important result of this meeting was
the recognition that collaboration
between neonatologists and
nephrologists is imperative to
advance the study of neonatal AKI and
to improve outcomes in these
vulnerable patients. In this state-ofthe-art review, we examine aspects of
neonatal AKI, including neonatal renal
physiology, definitions, risk factors,
epidemiology and outcomes, and
evaluation and management of AKI.
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abstract
a
Division of Nephrology, Department of Pediatrics and
Communicable Diseases, C.S. Mott Children’s Hospital,
University of Michigan, Ann Arbor, Michigan; bDivision of
Nephrology, Department of Pediatrics, University of
Virginia, Charlottesville, Virginia; cDivision of Nephrology,
Dialysis and Transplantation, Stead Family Department of
Pediatrics, University of Iowa Children’s Hospital, Iowa City,
Iowa; dDivision of Neonatology, Department of Pediatrics,
University of Rochester Medical Center, Rochester, New
York; eDivision of Neonatology, Department of Pediatrics,
Case Western Reserve University at MetroHealth Medical
Center, Cleveland, Ohio; fDivision of Nephrology, Department
of Pediatrics, University of Alabama at Birmingham,
Birmingham, Alabama; and gDepartment of Neonatology,
Centenary Hospital for Women and Children, Canberra
Hospital, Australian Capital Territory, Australia
Dr Selewski conceptualized and designed the outline
of the manuscript, and reviewed and revised the
manuscript; Drs Charlton, Jetton, and Kent provided
substantial acquisition and assimilation of the data,
drafted sections of the manuscript, and critically
revised the manuscript; Drs Guillet, Mhanna, and
Askenazi critically revised the manuscript; and all
authors approved the final manuscript as
submitted.
www.pediatrics.org/cgi/doi/10.1542/peds.2014-3819
DOI: 10.1542/peds.2014-3819
Accepted for publication Mar 16, 2015
Address correspondence to Jennifer R. Charlton MD,
MS, Department of Pediatrics, University of Virginia,
Box 800386, Charlottesville, VA 22908. E-mail: jrc6n@
hscmail.mcc.virginia.edu
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online,
1098-4275).
Copyright © 2015 by the American Academy of
Pediatrics
FINANCIAL DISCLOSURE: Dr Askenazi is a speaker for
the AKI Foundation; the other authors have indicated
they have no financial relationships relevant to this
article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have
indicated they have no potential conflicts of interest
to disclose.
STATE-OF-THE-ART REVIEW ARTICLE
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 flow, glomerular filtration rate
(GFR), and tubular immaturity.
Nephrogenesis begins at the fifth
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.16–19
There are significant changes in
neonatal renal blood flow 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.20–23 The changes in
renal blood flow 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
flow. 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 first
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 first few months of life,
reaching the adult GFR by 2 years of
age.28–30 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 fluids and
replace electrolyte losses. The
immaturity of these mechanisms in
the neonatal kidneys explains some of
the subtleties of urinary findings
(fractional excretion of sodium) in
neonatal AKI that differ from that in
older children.
DEFINITION OF NEONATAL AKI
AKI is classically defined as a sudden
decline in kidney function resulting in
derangements in fluid 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 significant delay in the rise of SCr
after an insult (48–72 hours) and
a significant 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.32–35 As
a result, there has been a significant
amount of research to identify novel
biomarkers of damage to allow for
the earlier identification of neonates
with AKI (up to 48 hours before SCr
rise). These novel biomarkers include
urine neutrophil gelatinaseassociated lipocalin, cystatin-c, kidney
injury molecule-1, and others.36–42 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 definition 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
definition was developed based on
evidence that even small changes in
SCr were associated with increased
morbidity and mortality. Current
definitions have demonstrated that
even small degrees of AKI are
associated with increased morbidity
and mortality in children and
adults.1,3,43 This empirical definition
has evolved based on observational
data from millions of patients and
hundreds of studies into the Kidney
Diseases: Improving Global Outcomes
(KDIGO) AKI definition published in
2013, maintaining a 3-tiered
categorical staging model depicting
mild, moderate, and severe stages of
AKI.44 The use of standardized
definitions of AKI has allowed
comparison between studies and was
a fundamental first step that has been
SELEWSKI et al
integral to the study of AKI in
medicine.
Before 2008, most neonatal AKI
studies used arbitrary definitions of
AKI frequently defined 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)
definitions of AKI.8,45 One such
standardized definition of AKI
described in detail by Jetton and
Askenazi is based on a modification of
the KDIGO definition termed the
neonatal modified KDIGO criteria
(Table 1). This definition 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 definition. They
concluded that, at this time, this
definition offers a reasonable starting
point and would allow for consistency
throughout studies. As this definition
is empirical, large multicenter studies
are greatly needed to validate this
definition and address all aspects of
the definitions, 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
RISK FACTOR FOR NEONATAL AKI
Sepsis
The change in renal function that
defines 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).
Sepsis is a cause of significant
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.51–54 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
inflammation, 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 flow, suggesting that
sepsis may directly damage the
kidney by effects on
microvasculature.56–59
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-inflammatory drugs
predisposes neonates to oliguria and
AKI.47 The multiple roles of the reninangiotensin system in renal
development prenatally, as well as the
maintenance of renal blood flow
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.8–10,12,45,47–50
TABLE 1 Neonatal AKI KDIGO Classification
Stage
SCr
0
1
No change in SCr or rise ,0.3 mg/dL
SCr rise $ 0.3 mg/dL within 48 h or SCr rise
$1.5–1.9 3 reference SCra within 7 d
SCr rise $2.0–2.9 3 reference SCra
SCr rise $3 3 reference SCra or SCr $2.5 mg/dLb or
Receipt of dialysis
2
3
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
Differences between the proposed neonatal AKI definition and KDIGO include the following:
a Reference SCr will be defined as the lowest previous SCr value.
b SCr value of 2.5 mg/dL represents ,10 mL/min/1.73m2 .
PEDIATRICS Volume 136, number 2, August 2015
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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 modifiable 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.
e465
TABLE 2 Risk Factors for AKI in Neonates
Study Size
Risk Factors Associated With AKI
Cataldi et al 200548
Study
Premature infants
Population
172
Cuzzolin et al 200647
Premature infants
246
Koralkar et al 201110
VLBW
229
Viswanathan et al 201265
ELBW
472
Mathur et al 200655
Selewski et al 201312
Neonates with sepsis
Asphyxiated neonates undergoing therapeutic
hypothermia
200
96
Bruel et al 2013103
Premature infants (,33 wk)
1461
Gadepalli et al 20118
Bolat et al 201354
Congenital diaphragmatic hernia
General NICU
68
1992
Askenazi et al 201363
Birth weight .2000 g, gestational age .34 wk,
5-min Apgar ,7
Low Apgar scores, exposure to ampicillin, ceftazidime,
ibuprofen
Maternal nonsteroidal anti-inflammatory drugs during
pregnancy, intubation at birth, low Apgar scores, ibuprofen
administration to infant
Lower birth weight, lower gestational age, lower Apgar scores,
UAC, mechanical ventilation, inotrope support
High mean airway pressures, lower mean arterial pressures,
higher exposure to cefotaxime
Lower birth weight, meningitis, DIC, and shock
Asystole at the time of birth, clinical seizures before cooling,
persistent pulmonary hypertension, elevated gentamicin or
vancomycin levels, pressor support, transfusions
Serum sodium variation, PDA, catecholamine treatment,
nosocomial infections, BPD, cerebral lesions, neonatal
surgery
Lower 5-min Apgar score, AKI correlated with left-sided CDH
Pregnancy-induced hypertension, PPROM, antenatal
corticosteroids, SGA, birth weight ,1500 g, endotracheal
intubation, UVC, ibuprofen therapy for PDA closure, sepsis
Lower birth weight, male, lower Apgar scores at 5 min, lower
cord pH, mechanical ventilation
58
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.
poor outcomes (Table 4).8–12,45,62–64
Here we review AKI studies in some
exemplar patient populations.
EPIDEMIOLOGY AND OUTCOMES OF
NEONATAL AKI
There have been a number of singlecenter 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
VLBW and ELBW Neonates
There have been 3 large singlecenter studies to date that have
evaluated AKI in VLBW neonates
(500–1500 g).10,65,66 In 2011, Koralkar
et al10 reported on 229 VLBW infants
followed prospectively from birth
TABLE 3 Common Nephrotoxic Medications in NICU
Drug
Acyclovir
Angiotensin-converting enzyme
inhibitors
Aminoglycosides
Amphotericin B
Nonsteroidal antiinflammatory drugs
Radiocontrast agents
Vancomycin
e466
Mechanism
Urinary precipitation, especially with low flow and
hypovolemia, with renal tubular obstruction and damage
and decreased GFR. May cause direct tubular toxicity
(metabolites).
Decreased angiotensin II production inhibiting compensatory
constriction of the efferent arteriole to maintain GFR.
Toxic to the proximal tubules (transport in the tubule,
accumulate in lysosome, intracellular rise in reactive
oxygen species and phospholipidosis, cell death); intrarenal
vasoconstriction and local glomerular/mesangial cell
contraction.
Distal tubular toxicity, vasoconstriction, and decreased GFR.
Decreased afferent arteriole dilatation as a result of inhibiting
prostaglandin production resulting in reduced GFR.
Renal tubular toxicity secondary to increase in reactive oxygen
species; intrarenal vasoconstriction may play a role.
Mechanism of AKI unclear, possible mechanism includes
proximal tubular injury with generation of reactive oxygen
species.
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until 36 weeks postmenstrual age.
The incidence of AKI, by using the
neonatal modified KDIGO criteria,
was 18%. The mortality in infants
with AKI was significantly higher than
those without AKI (42% vs 5%,
P , .001). After adjusting for potential
confounders, those with AKI had
a significantly higher chance of death
(hazard ratio 2.4, 95% confidence
interval [CI] 0.95–6.0; P , .06).
Viswanathan et al65 reported similar
findings in a retrospective singlecenter study, where 12.5% (59/472)
of all ELBW infants developed AKI
and mortality among those with AKI
was significantly higher than controls
(70% vs 22%, respectively). In a large
retrospective study of VLBW infants,
Carmody et al66 examined 455 VLBW
infants and found an AKI incidence of
39.8%. In this study, AKI was
independently associated with
increased mortality (odds ratio 4.0,
95% CI 1.4–11.5) and length of stay
(11.7 hospital days, 95% CI 5.1–18.4).
Perinatal Asphyxia
Infants with perinatal asphyxia have
been recognized as a group that is at
high risk of AKI. Recently there have
SELEWSKI et al
TABLE 4 Neonatal AKI Studies
Study
Population
Definition
Askenazi et al 200945
VLBW infants (n = 195)
AKIN criteria
Gadepalli et al 20118
RIFLE criteria
Kaur et al 20119
Congenital diaphragmatic hernia
on ECMO (n = 68)
Perinatal asphyxia (n = 36)
Koralkar et al 201110
VLBW infants (n = 229)
Askenazi et al 201363
Alabbas et al 201364
AKIN criteria
Neonatal Modified KDIGO
criteria
Sick near-term neonates (n = 58) Neonatal Modified KDIGO
criteria
Cardiac surgery ,28 d (n = 122) AKIN criteria
Selewski et al 201311,12 Perinatal asphyxia (n = 96)
Neonatal Modified KDIGO
criteria
Zwiers et al 201369
ECMO ,28 d (n = 242)
RIFLE criteria
Rhone et al 201362
VLBW infants (n = 107)
Carmody et al 201466
VLBW infants (n = 455)
Neonatal Modified KDIGO
criteria
Neonatal Modified KDIGO
criteria
been 2 single-center studies that have
looked at the incidence of AKI by
using modern AKI definitions. 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
findings 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 inflammatory 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
PEDIATRICS Volume 136, number 2, August 2015
Incidence of AKI, %
Findings
Matched case-control AKI is associated with increased mortality
study
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 fluid 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
findings at 7–10 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
a mortality of 65% when AKI
progressed to the highest stage. These
mirror the findings 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
findings are similar to the findings
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
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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, fluid balance, and,
importantly, body weight. Utilization
of these 3 measurements can assist in
determining both hypovolemia from
insensible losses, as well as
hypervolemia from fluid 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
e467
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 fluid input
and output, serum electrolytes, and
weight is essential to optimize fluid
status. Tracking cumulative fluid
overload provides a global
assessment of fluid 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.70–73 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 flow
include dopaminergic agonists
(dopamine and fenoldopam).75–77
Although each of these agents has
shown promise in the
prevention of AKI, the clinical
studies have been mixed, and
firm 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 beneficial effect
of diuretics on outcomes and have
occasionally demonstrated worse
outcomes in patients with AKI treated
e468
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 significantly 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 fluid
overload. The association between
fluid 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 fluid
overload as a risk factor for mortality
in critically ill patients.80 This is
highlighted by the findings 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 fluid overload ,20% at
initiation of renal replacement
therapy had improved rates of
survival compared with those with
a cumulative fluid balance .20%
(46% vs 68%, P , .01). These
findings have since been verified in
a number of different pediatric
patient populations highlighting
the importance of fluid overload
and the timing of renal
replacement therapy in critically ill
children.82–85
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Recent data extend these findings to
critically ill children and adults
independent of renal replacement
therapy.86–88 The impact of fluid
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 fluid balance are
warranted when critically ill children
amass 10% volume overload.89
Limited data are available on fluid
overload in neonates. Askenazi et al63
showed that sick late preterm
neonates with AKI had a higher
median fluid overload at day of life 3
than those without AKI (+8.2% vs
–4%, P , .001). As fluid overload is
a potentially modifiable risk factor for
mortality, research into its impact on
neonatal outcomes is critical to
provide information to clinicians
about fluid 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 fluid
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
SELEWSKI et al
different techniques in critically ill
neonates as small as 830 g.91–95
When PD is technically difficult
because of abdominal wall defects,
skin infections, communication to the
pleural space, or high ultrafiltration
needs, CRRT can be performed. CRRT
is performed with a hemodialysis
catheter placed in a central location
and either regional or systemic
anticoagulation. The volume of the
extracorporeal circuit is particularly
critical in the neonatal population and
often these neonates will require that
the CRRT machine be primed with
blood if the circuit volume exceeds
10% to 15% of the total blood
volume.96 In the United States,
current CRRT machines are approved
only for those weighing .20 kg, but
these machines have been used offlabel in children ,5 kg.97 There are
a number of considerations when
evaluating CRRT in a neonate,
including center expertise, prescription,
and error rates of current machines,
which has been recognized and led to
the development of neonatal CRRT
machines.98 CRRT systems, such as
CARPEDIEM99 (Bellco, Mirandola,
Italy) and Nidus,100 are being used in
countries outside the United States in
neonates. These machines show
promise, as they have smaller
extracorporeal volumes and are
highly accurate. Despite these recent
advances, the evidence on the
practice of renal replacement therapy
in neonates is limited to single-center
case series with a complete lack of
multicenter data.
CONSEQUENCES AND FOLLOW-UP OF
NEONATAL AKI
Previously, it was assumed that those
who survived an episode of AKI
would recover kidney function
without long-term effects. Recent
data from animals,101 critically ill
children,5,6 and adults102 with AKI
suggest that survivors are at risk for
the development of CKD. Mammen
et al5 reported that 10% of children
who developed AKI in the PICU had
PEDIATRICS Volume 136, number 2, August 2015
GFR ,60 mL/min/1.73 m2, 1 to
3 years later. Perhaps even more
alarming was the finding that nearly
50% of this cohort was found to be
“at risk” for CKD.
The role that AKI plays in the
development of CKD in the neonatal
population is unknown. Several case
reports document that CKD occurs in
infants who had AKI; however, these
studies are small, single-center
retrospective reports. Recognizing the
long-term implications of AKI, the
most recent KDIGO practice
guidelines recommend that all
patients who experience AKI be
evaluated after 3 months for new
onset or worsening of CKD.44 They
caution that even if CKD is not
present at that time, those with AKI
are considered to have increased risk
for CKD long-term. Although these
recommendations are likely pertinent
to infants, currently there is not
enough firm evidence to make formal
follow-up recommendations after
episodes of neonatal AKI. General
pediatricians should consider
neonates who have suffered AKI at
increased risk and monitor blood
pressure with consideration of
further testing on a case-by-case
basis. Large longitudinal multicenter
studies designed to follow neonates
after critical illness are greatly
needed to define the most
appropriate surveillance protocols, as
well as identify those most at risk.
CONCLUSIONS
Neonatal AKI represents a rapidly
evolving area in clinical research, but
a significant amount of work remains
to improve the outcomes in these
patients. An important first step
moving forward is the development
of a standardized definition of AKI.
Initially, the neonatal modified KDIGO
AKI definition will be used as
common nomenclature to unify and
compare research in neonatal AKI.
Although this definition represents
the best available, it remains limited
in that it 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 defining risk
factors, the implications of fluid
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 filtration 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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e473
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; originally published online July 13, 2015;
DOI: 10.1542/peds.2014-3819
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. 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: 0031-4005. Online ISSN: 1098-4275.
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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; originally published online July 13, 2015;
DOI: 10.1542/peds.2014-3819
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
/content/136/2/e463.full.html
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. 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: 0031-4005. Online ISSN: 1098-4275.
Downloaded from by guest on August 11, 2017