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Neonatal Acute Kidney Injury

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Neonatal Acute Kidney Injury

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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 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, definition, risk factors, epidemiology, outcomes, evaluation, and
management of AKI in neonates. The changes in renal function with
a
Division of Nephrology, Department of Pediatrics and
gestational and chronologic age are described. We put forth and describe the Communicable Diseases, C.S. Mott Children’s Hospital,
neonatal modified 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 definition 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 Children’s 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,
Birmingham, Alabama; and gDepartment of Neonatology,
replacement therapies. We discuss the need for long-term follow-up of 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 deficits 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 final manuscript as
Over the past 15 years, there have been a tremendous amount of work is submitted.
significant 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 field, 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.1–4 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.7–12 These studies remain
vulnerable patients. In this state-of- they have no financial relationships relevant to this
limited to small single-center cohorts
the-art review, we examine aspects of article to disclose.
using varying definitions of AKI,
neonatal AKI, including neonatal renal FUNDING: No external funding.
making generalization difficult. physiology, definitions, risk factors, POTENTIAL CONFLICT OF INTEREST: The authors have
Although progress has been made in epidemiology and outcomes, and indicated they have no potential conflicts of interest
our understanding of neonatal AKI, evaluation and management of AKI. to disclose.

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PEDIATRICS Volume 136, number 2, August 2015 STATE-OF-THE-ART REVIEW ARTICLE
NEONATAL RENAL PHYSIOLOGY of each of these systems is seen in the damage. As a result, there is
Although a detailed discussion of exacerbated response that critically ill a significant delay in the rise of SCr
renal development is outside the neonates have to inhibition of these after an insult (48–72 hours) and
scope of this review, there are systems by medications when a significant amount of function has
a number of features of neonatal oliguria and/or AKI develops after to be lost before SCr will rise (.50%
renal physiology that are pertinent to exposure. of the GFR). SCr also has unique
AKI in neonates, including the GFR represents the most recognized challenges in the neonatal population,
duration of nephrogenesis, renal measure of kidney function. In term including the presence of maternal
blood flow, glomerular filtration rate infants, the GFR improves from 10 to creatinine, varying degrees of
20 mL/min/1.73 m2 during the first creatinine reabsorption in the
(GFR), and tubular immaturity.
proximal tubules, overall lower GFRs,
Nephrogenesis begins at the fifth days of life to 30 to 40 mL/min/1.73 m2
by 2 weeks of life. In premature and maturational differences.32–35 As
week of gestation and continues until
a result, there has been a significant
34 to 36 weeks,13 yielding the adult infants, the GFR at birth is even lower
and increases slower than in term amount of research to identify novel
complement of 200 000 to 2.7 million
infants. The GFR improves steadily biomarkers of damage to allow for
nephrons.14,15 The impact of
over the first few months of life, the earlier identification of neonates
prematurity, intrauterine growth
reaching the adult GFR by 2 years of with AKI (up to 48 hours before SCr
restriction, and AKI on nephrogenesis
age.28–30 The dynamic nature of the rise). These novel biomarkers include
has not been fully delineated, but
neonatal GFR has implications for the urine neutrophil gelatinase-
small studies suggest that the
care of neonates particularly with associated lipocalin, cystatin-c, kidney
extrauterine environment and AKI are
regard to drug exposures, dosing, and injury molecule-1, and others.36–42 By
detrimental to optimal
susceptibility to the development of detecting earlier stages of kidney
nephrogenesis.16–19
AKI. injury, these biomarkers may allow
There are significant changes in for prevention of or early
neonatal renal blood flow after birth The term neonate has more mature intervention in AKI in neonates.
that are relevant to the study of AKI renal tubular function, which can Although these biomarkers continue
in neonates. In comparison with the appropriately respond to homeostatic to show promise, currently SCr is the
20% to 25% of cardiac output needs. The tubular function is standard used for the diagnosis of
received by the adult kidney, at birth immature in premature infants, with AKI in all populations.
the kidneys receive 2.5% to 4.0% of a decreased ability to reabsorb
electrolytes and protein and to In 2005, an empirical definition for
the cardiac output. Over time, this
concentrate urine. This has important AKI was introduced into the adult and
increases to 6% at 24 hours of life,
implications for the management and pediatric literature that recognized
10% at 1 week, and 15% to 18% at
diagnosis of AKI in premature infants, stages of severity based on a decrease
6 weeks of age.20–23 The changes in
in GFR and/or urine output. This
renal blood flow after birth result who rely on the clinician to
appropriately prescribe fluids and definition was developed based on
from increased renal perfusion
replace electrolyte losses. The evidence that even small changes in
pressure, increased systemic
immaturity of these mechanisms in SCr were associated with increased
arteriolar resistance, and decreased
the neonatal kidneys explains some of morbidity and mortality. Current
renal vascular resistance due to
the subtleties of urinary findings definitions have demonstrated that
neurohumoral changes with
(fractional excretion of sodium) in even small degrees of AKI are
angiotensin II and prostaglandins
neonatal AKI that differ from that in associated with increased morbidity
playing major roles.24
older children. and mortality in children and
In the fetal and neonatal period, the adults.1,3,43 This empirical definition
renin-angiotensin system is critical to has evolved based on observational
normal renal development and blood DEFINITION OF NEONATAL AKI data from millions of patients and
flow. Angiotensin II, the effector AKI is classically defined as a sudden hundreds of studies into the Kidney
molecule of the renin-angiotensin decline in kidney function resulting in Diseases: Improving Global Outcomes
system, causes vasoconstriction at the derangements in fluid balance, (KDIGO) AKI definition published in
afferent and efferent arterioles with electrolytes, and waste products.31 2013, maintaining a 3-tiered
the greatest impact at the efferent Currently, the diagnosis of AKI is categorical staging model depicting
arteriole.25,26 Prostaglandins dependent on a rise in serum mild, moderate, and severe stages of
represent the most important creatinine (SCr) or decrease in urine AKI.44 The use of standardized
counter-regulatory molecules in the output. Unfortunately, SCr is definitions of AKI has allowed
neonatal period and lead to afferent a suboptimal biomarker as it is comparison between studies and was
arteriole dilatation.27 The importance a marker of kidney function, not a fundamental first step that has been

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e464 SELEWSKI et al
integral to the study of AKI in RISK FACTOR FOR NEONATAL AKI Sepsis
medicine. The change in renal function that Sepsis is a cause of significant
Before 2008, most neonatal AKI defines AKI should be thought of as morbidity and mortality in neonates.
studies used arbitrary definitions of the result of a combination of Sepsis has been consistently shown to
AKI frequently defined by an absolute susceptibility factors and be a risk factor for the development
SCr $1.5 mg/dL. In response to the exposures.44 Although neonates are of AKI across neonatal populations,
trends in the diagnosis of AKI, subject to the same risk factors contributing to up to 78% of the
a number of neonatal studies were present in critically ill children of all cases of AKI.51–54 Mathur et al55
performed by using the Risk, Injury, ages, special consideration must be described 200 term neonates with
Failure, Loss of kidney function, and made to risk factors inherent to sepsis of whom 52 developed AKI.
End-stage kidney disease (RIFLE) and neonatal renal development and Those who developed AKI had
Acute Kidney Injury Network (AKIN) physiology. Therefore, we will review a lower birth weight and were more
definitions of AKI.8,45 One such perinatal and postnatal risk factors likely to have meningitis,
standardized definition of AKI associated with AKI, including disseminated intravascular
described in detail by Jetton and perinatal events/exposures, sepsis, coagulation, and septic shock.
Askenazi is based on a modification of and nephrotoxic medication Neonates who develop sepsis are
the KDIGO definition termed the exposure that may identify neonates classically thought to be predisposed
neonatal modified KDIGO criteria who require enhanced vigilance to AKI secondary to the hypotension
(Table 1). This definition stages AKI (Table 2). associated with systemic
based on an absolute rise in SCr from inflammation, but there also appears
a previous trough and should be used Perinatal Exposures and Events to be a direct impact on the
in children ,120 days of age. In As a result of the unique neonatal kidneys.56 Furthermore, AKI may
April 2013, neonatologists and renal physiology, a number of develop despite the maintenance of
pediatric nephrologists participating maternal exposures and perinatal systemic blood pressures and
in the NIDDK workshop carefully events can lead to neonatal AKI. For renal blood flow, suggesting that
scrutinized this definition. They example, maternal exposure to sepsis may directly damage the
concluded that, at this time, this nonsteroidal anti-inflammatory drugs kidney by effects on
definition offers a reasonable starting predisposes neonates to oliguria and microvasculature.56–59
point and would allow for consistency AKI.47 The multiple roles of the renin-
throughout studies. As this definition angiotensin system in renal Nephrotoxic Medications
is empirical, large multicenter studies development prenatally, as well as the Nephrotoxic medications are known
are greatly needed to validate this maintenance of renal blood flow to be a cause of AKI across the
definition and address all aspects of postnatally, can lead to a broad range spectrum of critically ill and
the definitions, including the degree of outcomes in the newborns exposed hospitalized children.60,61 Exposure
of SCr rise, age of utilization, and how to angiotensin-converting enzyme to nephrotoxic medications is also
to deal with a rise in SCr from 0.2 to inhibitors ranging from renal associated with AKI in neonates and
0.3 mg/dL, which technically agenesis to AKI, depending on the may represent a modifiable risk
represents a 1.5-fold increase and timing and duration of exposure. factor.47,48,62 Table 3 provides
would qualify as AKI. Some have Perinatal risk factors associated with a description of common nephrotoxic
suggested that the SCr should rise to the development of AKI are outlined medications used in the NICU. In
an absolute value of .0.5 mg/dL and in Table 2 and include low Apgar 2013, Rhone et al62 evaluated the
meet the previous criteria to qualify scores, intubation, low cord pH, and epidemiology and impact of
as AKI.1,12 asystole.8–10,12,45,47–50 nephrotoxic medication exposure in
107 very low birth weight (VLBW)
infants. In this study, 87% of neonates
TABLE 1 Neonatal AKI KDIGO Classification were exposed to at least 1
Stage SCr Urine Output nephrotoxic medication and on
0 No change in SCr or rise ,0.3 mg/dL $ 0.5 mL/kg/h average these neonates were exposed
1 SCr rise $ 0.3 mg/dL within 48 h or SCr rise ,0.5 mL/kg/h for 6 to 12 h to 14 days of nephrotoxic medications
$1.5–1.9 3 reference SCra within 7 d during their NICU stay. Although this
2 SCr rise $2.0–2.9 3 reference SCra ,0.5 mL/kg/h for $ 12 h study represents an important step,
3 SCr rise $3 3 reference SCra or SCr $2.5 mg/dLb or ,0.3 mL/kg/h for $24 h or anuria
the epidemiology of exposure to
Receipt of dialysis for $12 h
nephrotoxic medications in
Differences between the proposed neonatal AKI definition and KDIGO include the following:
a Reference SCr will be defined as the lowest previous SCr value. general NICU populations remains
b SCr value of 2.5 mg/dL represents ,10 mL/min/1.73m2 . unstudied.

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PEDIATRICS Volume 136, number 2, August 2015 e465
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-inflammatory 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 poor outcomes (Table 4).8–12,45,62–64 until 36 weeks postmenstrual age.
NEONATAL AKI Here we review AKI studies in some The incidence of AKI, by using the
There have been a number of single- exemplar patient populations. neonatal modified KDIGO criteria,
center studies that have evaluated the was 18%. The mortality in infants
impact of AKI in VLBW neonates, VLBW and ELBW Neonates with AKI was significantly higher than
extremely low birth weight (ELBW) There have been 3 large single- those without AKI (42% vs 5%,
neonates, sick near-term/term center studies to date that have P , .001). After adjusting for potential
neonates, neonates on extracorporeal evaluated AKI in VLBW neonates confounders, those with AKI had
membrane oxygenation (ECMO), and (500–1500 g).10,65,66 In 2011, Koralkar a significantly higher chance of death
asphyxiated newborns showing that et al10 reported on 229 VLBW infants (hazard ratio 2.4, 95% confidence
AKI is common and associated with followed prospectively from birth interval [CI] 0.95–6.0; P , .06).
Viswanathan et al65 reported similar
findings in a retrospective single-
TABLE 3 Common Nephrotoxic Medications in NICU center study, where 12.5% (59/472)
Drug Mechanism of all ELBW infants developed AKI
Acyclovir Urinary precipitation, especially with low flow and and mortality among those with AKI
hypovolemia, with renal tubular obstruction and damage was significantly higher than controls
and decreased GFR. May cause direct tubular toxicity (70% vs 22%, respectively). In a large
(metabolites).
Angiotensin-converting enzyme Decreased angiotensin II production inhibiting compensatory
retrospective study of VLBW infants,
inhibitors constriction of the efferent arteriole to maintain GFR. Carmody et al66 examined 455 VLBW
Aminoglycosides 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
contraction.
increased mortality (odds ratio 4.0,
Amphotericin B Distal tubular toxicity, vasoconstriction, and decreased GFR. 95% CI 1.4–11.5) and length of stay
Nonsteroidal antiinflammatory drugs Decreased afferent arteriole dilatation as a result of inhibiting (11.7 hospital days, 95% CI 5.1–18.4).
prostaglandin production resulting in reduced GFR.
Radiocontrast agents Renal tubular toxicity secondary to increase in reactive oxygen Perinatal Asphyxia
species; intrarenal vasoconstriction may play a role.
Vancomycin 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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e466 SELEWSKI et al
TABLE 4 Neonatal AKI Studies
Study Population Definition Incidence of AKI, % Findings
Askenazi et al 200945 VLBW infants (n = 195) AKIN criteria Matched case-control AKI is associated with increased mortality
study after adjustment for confounders
Gadepalli et al 20118 Congenital diaphragmatic hernia RIFLE criteria 71.0 Increased risk of mortality at highest level
on ECMO (n = 68) of AKI (Failure)
Kaur et al 20119 Perinatal asphyxia (n = 36) AKIN criteria 41.7 Modern staging systems (AKIN) capture AKI
previously missed by previous standard
of SCr .1.5 mg/dL
Koralkar et al 201110 VLBW infants (n = 229) Neonatal Modified KDIGO 18.0 Adjusting for severity of illness, AKI was
criteria associated with increased mortality
Askenazi et al 201363 Sick near-term neonates (n = 58) Neonatal Modified KDIGO 15.6 AKI associated with increased mortality and
criteria positive fluid balance
Alabbas et al 201364 Cardiac surgery ,28 d (n = 122) AKIN criteria 62.0 Severe AKI (Stage III) was associated with
increased mortality and length of stay after
adjusting for severity of illness.
Selewski et al 201311,12 Perinatal asphyxia (n = 96) Neonatal Modified KDIGO 38.0 AKI predicted prolonged mechanical ventilation,
criteria length of stay, and abnormal brain MRI
findings at 7–10 d of life
Zwiers et al 201369 ECMO ,28 d (n = 242) RIFLE criteria 64.0 Increased risk of mortality at highest level of
AKI (Failure)
Rhone et al 201362 VLBW infants (n = 107) Neonatal Modified KDIGO 26.2 AKI is associated with nephrotoxic medication
criteria exposure
Carmody et al 201466 VLBW infants (n = 455) Neonatal Modified KDIGO 39.8 AKI associated with increased mortality and
criteria length of stay adjusted for severity of illness

been 2 single-center studies that have a mortality of 65% when AKI evaluating prerenal, intrinsic, and
looked at the incidence of AKI by progressed to the highest stage. These postrenal causes. We highlight
using modern AKI definitions. Kaur mirror the findings of Gadepalli et al8 important aspects of the evaluation. A
et al9 reported an incidence of AKI of in neonates with congenital detailed clinical history should
41.7%. Selewski et al12 evaluated diaphragmatic hernia on ECMO where include assessment of gestational age,
newborns undergoing therapeutic AKI occurred in 71% of neonates, and antenatal (ultrasounds), maternal
hypothermia for perinatal asphyxia those with the highest stage of AKI (nephrotoxic medication), birth (fetal
and found that 36 (38%) of 96 had had a mortality of 73%. heart rate monitoring and
AKI. Even after controlling for resuscitation), and postnatal
important potential confounders, Neonatal Cardiac Surgery (nephrotoxic medications,
children with AKI on average were The association of AKI with cardiac hypotension) events. The physical
ventilated 4 days longer (P , .001) surgery in older children has been examination should focus on volume
and hospitalized 3.4 days longer well studied and the association of status and vital signs. A thorough
(P = .023). In addition, these AKI with increased mortality is clear. evaluation of volume status also
investigators also showed that AKI Alabbas et al64 published requires assessment of serum
during therapeutic hypothermia was a retrospective study of 122 neonates electrolytes, fluid balance, and,
associated with abnormal brain MRI (,28 days) showing that AKI importantly, body weight. Utilization
findings at 7 to 10 days of life, occurred in 62% of the neonates. The of these 3 measurements can assist in
implicating AKI as a potential marker highest stage of AKI was associated determining both hypovolemia from
for neurologic outcomes.11 with increased mortality and insensible losses, as well as
increased ICU length of stay. These hypervolemia from fluid overload.
ECMO findings are similar to the findings Assessment of fractional excretion of
Neonates supported with ECMO reported by Blinder et al7 in 430 sodium can help to differentiate the
represent a unique patient population infants (,90 days) undergoing prerenal (hypovolemia) from intrinsic
that is particularly prone to AKI cardiac surgery. (acute tubular necrosis) causes of
based on the severity of their illness AKI, although in premature infants
and the inflammatory response that this metric may not be as helpful.
accompanies exposure to the EVALUATION AND MANAGEMENT OF Finally, to evaluate potential
extracorporeal circuit.67,68 Zwiers NEONATAL AKI postrenal (obstruction) causes of AKI,
et al69 evaluated AKI in 242 neonates The evaluation of a neonate who an ultrasound should be obtained.
on ECMO over a 14-year period develops AKI requires a systematic After the diagnosis of AKI, it becomes
showing an AKI incidence of 64% and approach, which frequently involves important to prevent the

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PEDIATRICS Volume 136, number 2, August 2015 e467
development of sequelae. Daily with diuretics. For example, in Recent data extend these findings to
evaluation of medications and the a retrospective case-control study, critically ill children and adults
participation of a pharmacist are bumetanide was shown to improve independent of renal replacement
paramount in the management of the the urine output of ELBW infants therapy.86–88 The impact of fluid
critically ill neonate to monitor drug with AKI at the expense of increasing overload is highlighted in the practice
levels and avoid nephrotoxic their SCr.78 In another study, guidelines proposed by the American
exposures when clinically feasible. bumetanide was also shown to College of Critical Care Medicine for
Strict documentation of all fluid input increase significantly the urine pediatric and neonatal septic shock,
and output, serum electrolytes, and output, in premature infants with which recommend that interventions
weight is essential to optimize fluid oliguric AKI, but at the expense of to address fluid balance are
status. Tracking cumulative fluid a transient increase in SCr.79 Despite warranted when critically ill children
overload provides a global the lack of evidence in neonates, amass 10% volume overload.89
assessment of fluid status. a trial of diuretics in oliguric neonates Limited data are available on fluid
Hypervolemia may dictate with AKI is warranted given the overload in neonates. Askenazi et al63
intervention and nephrology complexity of renal replacement showed that sick late preterm
consultation. therapy. Large-scale multicenter trials neonates with AKI had a higher
of these medications in neonates are median fluid overload at day of life 3
There are sparse data documenting
greatly needed. than those without AKI (+8.2% vs
interventions that can prevent AKI in
Because of the lack of successful –4%, P , .001). As fluid overload is
at-risk patients or ameliorate AKI
strategies to prevent or ameliorate a potentially modifiable risk factor for
once it is established. In neonates
AKI, the primary therapy for severe mortality, research into its impact on
with perinatal asphyxia, adenosine neonatal outcomes is critical to
receptor antagonists (theophylline) cases of AKI is renal replacement
therapy. Indications for renal provide information to clinicians
may prevent AKI by inhibiting the about fluid provision and the timing
adenosine-induced vasoconstriction. replacement therapy in neonates
include refractory acidosis, uremia, of renal replacement therapy.
Several independent randomized
studies in asphyxiated infants have electrolyte abnormalities, inability to Throughout adult and pediatric
shown that prophylactic theophylline, provide adequate nutrition, and fluid intensive care medicine, renal
given early after birth, was associated overload. The association between replacement therapy has transitioned
with better kidney function.70–73 As fluid overload and mortality in from being a “last-ditch effort” to an
a result, the KDIGO guidelines critically ill patients is one of the early therapy directed at supporting
recommend a single dose of hottest topics in acute care the critically ill patient by maintaining
theophylline for asphyxiated infants nephrology and warrants special electrolyte homeostasis, allowing for
at risk for AKI.44 Caution must be mention. Pediatricians have been at provision of adequate nutrition, and
the forefront of identifying fluid preventing/reducing hypervolemia.
taken, as theophylline has some
overload as a risk factor for mortality This mindset of early intervention has
potentially harmful neurologic
in critically ill patients.80 This is not fully reached the neonatal
effects.74 Other drugs that have been
highlighted by the findings of the population, possibly because of the
studied to prevent the development
prospective pediatric continuous added risk of dialysis machines,
of AKI and improve renal blood flow
renal replacement therapy (CRRT) ethical considerations, and a lack of
include dopaminergic agonists
registry. Sutherland et al81 showed in studies that illustrate the role of fluid
(dopamine and fenoldopam).75–77
a prospective registry of 227 children overload on poor outcomes in these
Although each of these agents has
who were on CRRT that those with patients. Renal replacement therapy
shown promise in the
a percentage fluid overload ,20% at poses particular challenges in the
prevention of AKI, the clinical
initiation of renal replacement neonate, as most equipment was
studies have been mixed, and
therapy had improved rates of designed for older children. Currently,
firm recommendations on their
survival compared with those with peritoneal dialysis (PD) is the
use cannot be made.
a cumulative fluid balance .20% modality of choice in infants. PD is
Diuretics are frequently used in (46% vs 68%, P , .01). These technically easier, as there is no need
patients with AKI in attempts to findings have since been verified in for vascular access or an
maintain urine output. Studies in a number of different pediatric extracorporeal blood circuit.90 If
critically ill patient populations have patient populations highlighting peritoneal dialysis is felt to be
not demonstrated a beneficial effect the importance of fluid overload a short-term requirement,
of diuretics on outcomes and have and the timing of renal a temporary catheter can be placed.
occasionally demonstrated worse replacement therapy in critically ill Several studies describe successful
outcomes in patients with AKI treated children.82–85 peritoneal dialysis by several

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e468 SELEWSKI et al
different techniques in critically ill GFR ,60 mL/min/1.73 m2, 1 to studied in a multicenter manner
neonates as small as 830 g.91–95 3 years later. Perhaps even more evaluating the association of AKI with
When PD is technically difficult alarming was the finding that nearly outcomes. Further work in neonatal
because of abdominal wall defects, 50% of this cohort was found to be AKI needs to focus on defining risk
skin infections, communication to the “at risk” for CKD. factors, the implications of fluid
pleural space, or high ultrafiltration The role that AKI plays in the balance, renal replacement therapy,
needs, CRRT can be performed. CRRT development of CKD in the neonatal and the long-term outcomes,
is performed with a hemodialysis population is unknown. Several case including the development of CKD in
catheter placed in a central location reports document that CKD occurs in this susceptible population.
and either regional or systemic infants who had AKI; however, these After the NIDDK-sponsored
anticoagulation. The volume of the studies are small, single-center workshop on neonatal AKI, an
extracorporeal circuit is particularly retrospective reports. Recognizing the international, multi-institutional,
critical in the neonatal population and long-term implications of AKI, the multidisciplinary group, the Neonatal
often these neonates will require that most recent KDIGO practice Kidney Collaborative, was formed.
the CRRT machine be primed with guidelines recommend that all This group aims to answer some of
blood if the circuit volume exceeds patients who experience AKI be the questions surrounding neonatal
10% to 15% of the total blood evaluated after 3 months for new AKI with the goal of improving
volume.96 In the United States, onset or worsening of CKD.44 They outcome and optimizing care for
current CRRT machines are approved caution that even if CKD is not these vulnerable patients.
only for those weighing .20 kg, but present at that time, those with AKI
these machines have been used off- are considered to have increased risk
label in children ,5 kg.97 There are for CKD long-term. Although these ABBREVIATIONS
a number of considerations when recommendations are likely pertinent
AKI: acute kidney injury
evaluating CRRT in a neonate, to infants, currently there is not
CRRT: continuous renal
including center expertise, prescription, enough firm evidence to make formal
replacement therapy
and error rates of current machines, follow-up recommendations after
CKD: chronic kidney disease
which has been recognized and led to episodes of neonatal AKI. General
ECMO: extracorporeal membrane
the development of neonatal CRRT pediatricians should consider
oxygenation
machines.98 CRRT systems, such as neonates who have suffered AKI at
ELBW: extremely low birth weight
CARPEDIEM99 (Bellco, Mirandola, increased risk and monitor blood
GFR: glomerular filtration rate
Italy) and Nidus,100 are being used in pressure with consideration of
KDIGO: Kidney Diseases:
countries outside the United States in further testing on a case-by-case
Improving Global
neonates. These machines show basis. Large longitudinal multicenter
Outcomes
promise, as they have smaller studies designed to follow neonates
NIDDK: National Institute of
extracorporeal volumes and are after critical illness are greatly
Diabetes and Digestive
highly accurate. Despite these recent needed to define the most
and Kidney Diseases
advances, the evidence on the appropriate surveillance protocols, as
PD: peritoneal dialysis
practice of renal replacement therapy well as identify those most at risk.
SCr: serum creatinine
in neonates is limited to single-center
VLBW: very low birth weight
case series with a complete lack of
CONCLUSIONS infants
multicenter data.
Neonatal AKI represents a rapidly
evolving area in clinical research, but
CONSEQUENCES AND FOLLOW-UP OF a significant amount of work remains
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PEDIATRICS Volume 136, number 2, August 2015 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
DOI: 10.1542/peds.2014-3819 originally published online July 13, 2015;

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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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located on the World Wide Web at:
http://pediatrics.aappublications.org/content/136/2/e463

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