Neonatal Acute Kidney InjuryDavid 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

abstractIn recent years, there have been significant advancements in ourunderstanding of acute kidney injury (AKI) and its impact on outcomes acrossmedicine. Research based on single-center cohorts suggests that neonatal AKIis very common and associated with poor outcomes. In this state-of-the-artreview on neonatal AKI, we highlight the unique aspects of neonatal renalphysiology, definition, risk factors, epidemiology, outcomes, evaluation, andmanagement of AKI in neonates. The changes in renal function withgestational and chronologic age are described. We put forth and describe theneonatal modified Kidney Diseases: Improving Global Outcomes AKI criteriaand provide the rationale for its use as the standardized definition of neonatalAKI. We discuss risk factors for neonatal AKI and suggest which patientpopulations may warrant closer surveillance, including neonates ,1500 g,infants who experience perinatal asphyxia, near term/ term infants with lowApgar scores, those treated with extracorporeal membrane oxygenation, andthose requiring cardiac surgery. We provide recommendations for theevaluation and treatment of these patients, including medications and renalreplacement therapies. We discuss the need for long-term follow-up ofneonates with AKI to identify those children who will go on to develop chronickidney disease. This review highlights the deficits in our understanding ofneonatal AKI that require further investigation. In an effort to begin to addressthese needs, the Neonatal Kidney Collaborative was formed in 2014 with thegoal of better understanding neonatal AKI, beginning to answer criticalquestions, and improving outcomes in these vulnerable populations.

Over the past 15 years, there have beensignificant advancements in the studyof acute kidney injury (AKI) regardingthe diagnosis, recognition, intervention,and impact of AKI on morbidity andmortality in critically ill children.1–4 Ithas become apparent that children whosurvive an episode of AKI are atincreased risk for chronic kidneydisease (CKD) and warrant long-termfollow-up.5,6 Neonatal AKI studies havebegun to show similar conclusions: AKIis common and is associated withpoor outcomes.7–12 These studies remainlimited to small single-center cohortsusing varying definitions of AKI,making generalization difficult.

Although progress has been made inour understanding of neonatal AKI,

a tremendous amount of work isneeded to optimize our ability to detectand intervene in newborns with AKI.To advance the field, the NationalInstitute of Diabetes and Digestiveand Kidney Diseases (NIDDK)sponsored a workshop dedicated toneonatal AKI in April 2013. Animportant result of this meeting wasthe recognition that collaborationbetween neonatologists andnephrologists is imperative toadvance the study of neonatal AKI andto improve outcomes in thesevulnerable patients. In this state-of-the-art review, we examine aspects ofneonatal AKI, including neonatal renalphysiology, definitions, risk factors,epidemiology and outcomes, andevaluation and management of AKI.

aDivision of Nephrology, Department of Pediatrics andCommunicable Diseases, C.S. Mott Children’s Hospital,University of Michigan, Ann Arbor, Michigan; bDivision ofNephrology, Department of Pediatrics, University ofVirginia, Charlottesville, Virginia; cDivision of Nephrology,Dialysis and Transplantation, Stead Family Department ofPediatrics, University of Iowa Children’s Hospital, Iowa City,Iowa; dDivision of Neonatology, Department of Pediatrics,University of Rochester Medical Center, Rochester, NewYork; eDivision of Neonatology, Department of Pediatrics,Case Western Reserve University at MetroHealth MedicalCenter, Cleveland, Ohio; fDivision of Nephrology, Departmentof Pediatrics, University of Alabama at Birmingham,Birmingham, Alabama; and gDepartment of Neonatology,Centenary Hospital for Women and Children, CanberraHospital, Australian Capital Territory, Australia

Dr Selewski conceptualized and designed the outlineof the manuscript, and reviewed and revised themanuscript; Drs Charlton, Jetton, and Kent providedsubstantial acquisition and assimilation of the data,drafted sections of the manuscript, and criticallyrevised the manuscript; Drs Guillet, Mhanna, andAskenazi critically revised the manuscript; and allauthors approved the final manuscript assubmitted.

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 ofPediatrics

FINANCIAL DISCLOSURE: Dr Askenazi is a speaker forthe AKI Foundation; the other authors have indicatedthey have no financial relationships relevant to thisarticle to disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The authors haveindicated they have no potential conflicts of interestto disclose.

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NEONATAL RENAL PHYSIOLOGY

Although a detailed discussion ofrenal development is outside thescope of this review, there area number of features of neonatalrenal physiology that are pertinent toAKI in neonates, including theduration of nephrogenesis, renalblood flow, glomerular filtration rate(GFR), and tubular immaturity.Nephrogenesis begins at the fifthweek of gestation and continues until34 to 36 weeks,13 yielding the adultcomplement of 200 000 to 2.7 millionnephrons.14,15 The impact ofprematurity, intrauterine growthrestriction, and AKI on nephrogenesishas not been fully delineated, butsmall studies suggest that theextrauterine environment and AKI aredetrimental to optimalnephrogenesis.16–19

There are significant changes inneonatal renal blood flow after birththat are relevant to the study of AKIin neonates. In comparison with the20% to 25% of cardiac outputreceived by the adult kidney, at birththe kidneys receive 2.5% to 4.0% ofthe cardiac output. Over time, thisincreases to 6% at 24 hours of life,10% at 1 week, and 15% to 18% at6 weeks of age.20–23 The changes inrenal blood flow after birth resultfrom increased renal perfusionpressure, increased systemicarteriolar resistance, and decreasedrenal vascular resistance due toneurohumoral changes withangiotensin II and prostaglandinsplaying major roles.24

In the fetal and neonatal period, therenin-angiotensin system is critical tonormal renal development and bloodflow. Angiotensin II, the effectormolecule of the renin-angiotensinsystem, causes vasoconstriction at theafferent and efferent arterioles withthe greatest impact at the efferentarteriole.25,26 Prostaglandinsrepresent the most importantcounter-regulatory molecules in theneonatal period and lead to afferentarteriole dilatation.27 The importance

of each of these systems is seen in theexacerbated response that critically illneonates have to inhibition of thesesystems by medications whenoliguria and/or AKI develops afterexposure.

GFR represents the most recognizedmeasure of kidney function. In terminfants, the GFR improves from 10 to20 mL/min/1.73 m2 during the firstdays of life to 30 to 40 mL/min/1.73 m2

by 2 weeks of life. In prematureinfants, the GFR at birth is even lowerand increases slower than in terminfants. The GFR improves steadilyover the first few months of life,reaching the adult GFR by 2 years ofage.28–30 The dynamic nature of theneonatal GFR has implications for thecare of neonates particularly withregard to drug exposures, dosing, andsusceptibility to the development ofAKI.

The term neonate has more maturerenal tubular function, which canappropriately respond to homeostaticneeds. The tubular function isimmature in premature infants, witha decreased ability to reabsorbelectrolytes and protein and toconcentrate urine. This has importantimplications for the management anddiagnosis of AKI in premature infants,who rely on the clinician toappropriately prescribe fluids andreplace electrolyte losses. Theimmaturity of these mechanisms inthe neonatal kidneys explains some ofthe subtleties of urinary findings(fractional excretion of sodium) inneonatal AKI that differ from that inolder children.

DEFINITION OF NEONATAL AKI

AKI is classically defined as a suddendecline in kidney function resulting inderangements in fluid balance,electrolytes, and waste products.31

Currently, the diagnosis of AKI isdependent on a rise in serumcreatinine (SCr) or decrease in urineoutput. Unfortunately, SCr isa suboptimal biomarker as it isa marker of kidney function, not

damage. As a result, there isa significant delay in the rise of SCrafter an insult (48–72 hours) anda significant amount of function hasto be lost before SCr will rise (.50%of the GFR). SCr also has uniquechallenges in the neonatal population,including the presence of maternalcreatinine, varying degrees ofcreatinine reabsorption in theproximal tubules, overall lower GFRs,and maturational differences.32–35 Asa result, there has been a significantamount of research to identify novelbiomarkers of damage to allow forthe earlier identification of neonateswith AKI (up to 48 hours before SCrrise). These novel biomarkers includeurine neutrophil gelatinase-associated lipocalin, cystatin-c, kidneyinjury molecule-1, and others.36–42 Bydetecting earlier stages of kidneyinjury, these biomarkers may allowfor prevention of or earlyintervention in AKI in neonates.Although these biomarkers continueto show promise, currently SCr is thestandard used for the diagnosis ofAKI in all populations.

In 2005, an empirical definition forAKI was introduced into the adult andpediatric literature that recognizedstages of severity based on a decreasein GFR and/or urine output. Thisdefinition was developed based onevidence that even small changes inSCr were associated with increasedmorbidity and mortality. Currentdefinitions have demonstrated thateven small degrees of AKI areassociated with increased morbidityand mortality in children andadults.1,3,43 This empirical definitionhas evolved based on observationaldata from millions of patients andhundreds of studies into the KidneyDiseases: Improving Global Outcomes(KDIGO) AKI definition published in2013, maintaining a 3-tieredcategorical staging model depictingmild, moderate, and severe stages ofAKI.44 The use of standardizeddefinitions of AKI has allowedcomparison between studies and wasa fundamental first step that has been

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integral to the study of AKI inmedicine.

Before 2008, most neonatal AKIstudies used arbitrary definitions ofAKI frequently defined by an absoluteSCr $1.5 mg/dL. In response to thetrends in the diagnosis of AKI,a number of neonatal studies wereperformed by using the Risk, Injury,Failure, Loss of kidney function, andEnd-stage kidney disease (RIFLE) andAcute Kidney Injury Network (AKIN)definitions of AKI.8,45 One suchstandardized definition of AKIdescribed in detail by Jetton andAskenazi is based on a modification ofthe KDIGO definition termed theneonatal modified KDIGO criteria(Table 1). This definition stages AKIbased on an absolute rise in SCr froma previous trough and should be usedin children ,120 days of age. InApril 2013, neonatologists andpediatric nephrologists participatingin the NIDDK workshop carefullyscrutinized this definition. Theyconcluded that, at this time, thisdefinition offers a reasonable startingpoint and would allow for consistencythroughout studies. As this definitionis empirical, large multicenter studiesare greatly needed to validate thisdefinition and address all aspects ofthe definitions, including the degreeof SCr rise, age of utilization, and howto deal with a rise in SCr from 0.2 to0.3 mg/dL, which technicallyrepresents a 1.5-fold increase andwould qualify as AKI. Some havesuggested that the SCr should rise toan absolute value of .0.5 mg/dL andmeet the previous criteria to qualifyas AKI.1,12

RISK FACTOR FOR NEONATAL AKI

The change in renal function thatdefines AKI should be thought of asthe result of a combination ofsusceptibility factors andexposures.44 Although neonates aresubject to the same risk factorspresent in critically ill children of allages, special consideration must bemade to risk factors inherent toneonatal renal development andphysiology. Therefore, we will reviewperinatal and postnatal risk factorsassociated with AKI, includingperinatal events/exposures, sepsis,and nephrotoxic medicationexposure that may identify neonateswho require enhanced vigilance(Table 2).

Perinatal Exposures and Events

As a result of the unique neonatalrenal physiology, a number ofmaternal exposures and perinatalevents can lead to neonatal AKI. Forexample, maternal exposure tononsteroidal anti-inflammatory drugspredisposes neonates to oliguria andAKI.47 The multiple roles of the renin-angiotensin system in renaldevelopment prenatally, as well as themaintenance of renal blood flowpostnatally, can lead to a broad rangeof outcomes in the newborns exposedto angiotensin-converting enzymeinhibitors ranging from renalagenesis to AKI, depending on thetiming and duration of exposure.Perinatal risk factors associated withthe development of AKI are outlinedin Table 2 and include low Apgarscores, intubation, low cord pH, andasystole.8–10,12,45,47–50

Sepsis

Sepsis is a cause of significantmorbidity and mortality in neonates.Sepsis has been consistently shown tobe a risk factor for the developmentof AKI across neonatal populations,contributing to up to 78% of thecases of AKI.51–54 Mathur et al55

described 200 term neonates withsepsis of whom 52 developed AKI.Those who developed AKI hada lower birth weight and were morelikely to have meningitis,disseminated intravascularcoagulation, and septic shock.Neonates who develop sepsis areclassically thought to be predisposedto AKI secondary to the hypotensionassociated with systemicinflammation, but there also appearsto be a direct impact on thekidneys.56 Furthermore, AKI maydevelop despite the maintenance ofsystemic blood pressures andrenal blood flow, suggesting thatsepsis may directly damage thekidney by effects onmicrovasculature.56–59

Nephrotoxic Medications

Nephrotoxic medications are knownto be a cause of AKI across thespectrum of critically ill andhospitalized children.60,61 Exposureto nephrotoxic medications is alsoassociated with AKI in neonates andmay represent a modifiable riskfactor.47,48,62 Table 3 providesa description of common nephrotoxicmedications used in the NICU. In2013, Rhone et al62 evaluated theepidemiology and impact ofnephrotoxic medication exposure in107 very low birth weight (VLBW)infants. In this study, 87% of neonateswere exposed to at least 1nephrotoxic medication and onaverage these neonates were exposedto 14 days of nephrotoxic medicationsduring their NICU stay. Although thisstudy represents an important step,the epidemiology of exposure tonephrotoxic medications ingeneral NICU populations remainsunstudied.

TABLE 1 Neonatal AKI KDIGO Classification

Stage SCr Urine Output

0 No change in SCr or rise ,0.3 mg/dL $ 0.5 mL/kg/h1 SCr rise $ 0.3 mg/dL within 48 h or SCr rise

$1.5–1.9 3 reference SCra within 7 d,0.5 mL/kg/h for 6 to 12 h

2 SCr rise $2.0–2.9 3 reference SCra ,0.5 mL/kg/h for $ 12 h3 SCr rise $3 3 reference SCra or SCr $2.5 mg/dLb or

Receipt of dialysis,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.

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EPIDEMIOLOGY AND OUTCOMES OFNEONATAL AKI

There have been a number of single-center studies that have evaluated theimpact of AKI in VLBW neonates,extremely low birth weight (ELBW)neonates, sick near-term/termneonates, neonates on extracorporealmembrane oxygenation (ECMO), andasphyxiated newborns showing thatAKI is common and associated with

poor outcomes (Table 4).8–12,45,62–64

Here we review AKI studies in someexemplar patient populations.

VLBW and ELBW Neonates

There have been 3 large single-center studies to date that haveevaluated AKI in VLBW neonates(500–1500 g).10,65,66 In 2011, Koralkaret al10 reported on 229 VLBW infantsfollowed prospectively from birth

until 36 weeks postmenstrual age.The incidence of AKI, by using theneonatal modified KDIGO criteria,was 18%. The mortality in infantswith AKI was significantly higher thanthose without AKI (42% vs 5%,P , .001). After adjusting for potentialconfounders, those with AKI hada significantly higher chance of death(hazard ratio 2.4, 95% confidenceinterval [CI] 0.95–6.0; P , .06).Viswanathan et al65 reported similarfindings in a retrospective single-center study, where 12.5% (59/472)of all ELBW infants developed AKIand mortality among those with AKIwas significantly higher than controls(70% vs 22%, respectively). In a largeretrospective study of VLBW infants,Carmody et al66 examined 455 VLBWinfants and found an AKI incidence of39.8%. In this study, AKI wasindependently associated withincreased 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 havebeen recognized as a group that is athigh risk of AKI. Recently there have

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 duringpregnancy, intubation at birth, low Apgar scores, ibuprofenadministration 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 shockSelewski et al 201312 Asphyxiated neonates undergoing therapeutic

hypothermia96 Asystole at the time of birth, clinical seizures before cooling,

persistent pulmonary hypertension, elevated gentamicin orvancomycin levels, pressor support, transfusions

Bruel et al 2013103 Premature infants (,33 wk) 1461 Serum sodium variation, PDA, catecholamine treatment,nosocomial infections, BPD, cerebral lesions, neonatalsurgery

Gadepalli et al 20118 Congenital diaphragmatic hernia 68 Lower 5-min Apgar score, AKI correlated with left-sided CDHBolat et al 201354 General NICU 1992 Pregnancy-induced hypertension, PPROM, antenatal

corticosteroids, SGA, birth weight ,1500 g, endotrachealintubation, UVC, ibuprofen therapy for PDA closure, sepsis

Askenazi et al 201363 Birth weight .2000 g, gestational age .34 wk,5-min Apgar ,7

58 Lower birth weight, male, lower Apgar scores at 5 min, lowercord pH, mechanical ventilation

BPD, bronchopulmonary dysplasia; CDH-congenital diaphragmatic hernia; DIC, disseminated intravascular coagulation; PPROM, preterm premature rupture of membranes; UAC, umbilicalartery catheter; UVC, umbilical venous catheter.

TABLE 3 Common Nephrotoxic Medications in NICU

Drug Mechanism

Acyclovir Urinary precipitation, especially with low flow andhypovolemia, with renal tubular obstruction and damageand decreased GFR. May cause direct tubular toxicity(metabolites).

Angiotensin-converting enzymeinhibitors

Decreased angiotensin II production inhibiting compensatoryconstriction of the efferent arteriole to maintain GFR.

Aminoglycosides Toxic to the proximal tubules (transport in the tubule,accumulate in lysosome, intracellular rise in reactiveoxygen species and phospholipidosis, cell death); intrarenalvasoconstriction and local glomerular/mesangial cellcontraction.

Amphotericin B Distal tubular toxicity, vasoconstriction, and decreased GFR.Nonsteroidal antiinflammatory drugs Decreased afferent arteriole dilatation as a result of inhibiting

prostaglandin production resulting in reduced GFR.Radiocontrast agents Renal tubular toxicity secondary to increase in reactive oxygen

species; intrarenal vasoconstriction may play a role.Vancomycin Mechanism of AKI unclear, possible mechanism includes

proximal tubular injury with generation of reactive oxygenspecies.

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been 2 single-center studies that havelooked at the incidence of AKI byusing modern AKI definitions. Kauret al9 reported an incidence of AKI of41.7%. Selewski et al12 evaluatednewborns undergoing therapeutichypothermia for perinatal asphyxiaand found that 36 (38%) of 96 hadAKI. Even after controlling forimportant potential confounders,children with AKI on average wereventilated 4 days longer (P , .001)and hospitalized 3.4 days longer(P = .023). In addition, theseinvestigators also showed that AKIduring therapeutic hypothermia wasassociated with abnormal brain MRIfindings at 7 to 10 days of life,implicating AKI as a potential markerfor neurologic outcomes.11

ECMO

Neonates supported with ECMOrepresent a unique patient populationthat is particularly prone to AKIbased on the severity of their illnessand the inflammatory response thataccompanies exposure to theextracorporeal circuit.67,68 Zwierset al69 evaluated AKI in 242 neonateson ECMO over a 14-year periodshowing an AKI incidence of 64% and

a mortality of 65% when AKIprogressed to the highest stage. Thesemirror the findings of Gadepalli et al8

in neonates with congenitaldiaphragmatic hernia on ECMO whereAKI occurred in 71% of neonates, andthose with the highest stage of AKIhad a mortality of 73%.

Neonatal Cardiac Surgery

The association of AKI with cardiacsurgery in older children has beenwell studied and the association ofAKI with increased mortality is clear.Alabbas et al64 publisheda retrospective study of 122 neonates(,28 days) showing that AKIoccurred in 62% of the neonates. Thehighest stage of AKI was associatedwith increased mortality andincreased ICU length of stay. Thesefindings are similar to the findingsreported by Blinder et al7 in 430infants (,90 days) undergoingcardiac surgery.

EVALUATION AND MANAGEMENT OFNEONATAL AKI

The evaluation of a neonate whodevelops AKI requires a systematicapproach, which frequently involves

evaluating prerenal, intrinsic, andpostrenal causes. We highlightimportant aspects of the evaluation. Adetailed clinical history shouldinclude assessment of gestational age,antenatal (ultrasounds), maternal(nephrotoxic medication), birth (fetalheart rate monitoring andresuscitation), and postnatal(nephrotoxic medications,hypotension) events. The physicalexamination should focus on volumestatus and vital signs. A thoroughevaluation of volume status alsorequires assessment of serumelectrolytes, fluid balance, and,importantly, body weight. Utilizationof these 3 measurements can assist indetermining both hypovolemia frominsensible losses, as well ashypervolemia from fluid overload.Assessment of fractional excretion ofsodium can help to differentiate theprerenal (hypovolemia) from intrinsic(acute tubular necrosis) causes ofAKI, although in premature infantsthis metric may not be as helpful.Finally, to evaluate potentialpostrenal (obstruction) causes of AKI,an ultrasound should be obtained.

After the diagnosis of AKI, it becomesimportant to prevent the

TABLE 4 Neonatal AKI Studies

Study Population Definition Incidence of AKI, % Findings

Askenazi et al 200945 VLBW infants (n = 195) AKIN criteria Matched case-controlstudy

AKI is associated with increased mortalityafter adjustment for confounders

Gadepalli et al 20118 Congenital diaphragmatic herniaon ECMO (n = 68)

RIFLE criteria 71.0 Increased risk of mortality at highest levelof AKI (Failure)

Kaur et al 20119 Perinatal asphyxia (n = 36) AKIN criteria 41.7 Modern staging systems (AKIN) capture AKIpreviously missed by previous standardof SCr .1.5 mg/dL

Koralkar et al 201110 VLBW infants (n = 229) Neonatal Modified KDIGOcriteria

18.0 Adjusting for severity of illness, AKI wasassociated with increased mortality

Askenazi et al 201363 Sick near-term neonates (n = 58) Neonatal Modified KDIGOcriteria

15.6 AKI associated with increased mortality andpositive fluid balance

Alabbas et al 201364 Cardiac surgery ,28 d (n = 122) AKIN criteria 62.0 Severe AKI (Stage III) was associated withincreased mortality and length of stay afteradjusting for severity of illness.

Selewski et al 201311,12 Perinatal asphyxia (n = 96) Neonatal Modified KDIGOcriteria

38.0 AKI predicted prolonged mechanical ventilation,length of stay, and abnormal brain MRIfindings 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 ofAKI (Failure)

Rhone et al 201362 VLBW infants (n = 107) Neonatal Modified KDIGOcriteria

26.2 AKI is associated with nephrotoxic medicationexposure

Carmody et al 201466 VLBW infants (n = 455) Neonatal Modified KDIGOcriteria

39.8 AKI associated with increased mortality andlength of stay adjusted for severity of illness

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development of sequelae. Dailyevaluation of medications and theparticipation of a pharmacist areparamount in the management of thecritically ill neonate to monitor druglevels and avoid nephrotoxicexposures when clinically feasible.Strict documentation of all fluid inputand output, serum electrolytes, andweight is essential to optimize fluidstatus. Tracking cumulative fluidoverload provides a globalassessment of fluid status.Hypervolemia may dictateintervention and nephrologyconsultation.

There are sparse data documentinginterventions that can prevent AKI inat-risk patients or ameliorate AKIonce it is established. In neonateswith perinatal asphyxia, adenosinereceptor antagonists (theophylline)may prevent AKI by inhibiting theadenosine-induced vasoconstriction.Several independent randomizedstudies in asphyxiated infants haveshown that prophylactic theophylline,given early after birth, was associatedwith better kidney function.70–73 Asa result, the KDIGO guidelinesrecommend a single dose oftheophylline for asphyxiated infantsat risk for AKI.44 Caution must betaken, as theophylline has somepotentially harmful neurologiceffects.74 Other drugs that have beenstudied to prevent the developmentof AKI and improve renal blood flowinclude dopaminergic agonists(dopamine and fenoldopam).75–77

Although each of these agents hasshown promise in theprevention of AKI, the clinicalstudies have been mixed, andfirm recommendations on theiruse cannot be made.

Diuretics are frequently used inpatients with AKI in attempts tomaintain urine output. Studies incritically ill patient populations havenot demonstrated a beneficial effectof diuretics on outcomes and haveoccasionally demonstrated worseoutcomes in patients with AKI treated

with diuretics. For example, ina retrospective case-control study,bumetanide was shown to improvethe urine output of ELBW infantswith AKI at the expense of increasingtheir SCr.78 In another study,bumetanide was also shown toincrease significantly the urineoutput, in premature infants witholiguric AKI, but at the expense ofa transient increase in SCr.79 Despitethe lack of evidence in neonates,a trial of diuretics in oliguric neonateswith AKI is warranted given thecomplexity of renal replacementtherapy. Large-scale multicenter trialsof these medications in neonates aregreatly needed.

Because of the lack of successfulstrategies to prevent or ameliorateAKI, the primary therapy for severecases of AKI is renal replacementtherapy. Indications for renalreplacement therapy in neonatesinclude refractory acidosis, uremia,electrolyte abnormalities, inability toprovide adequate nutrition, and fluidoverload. The association betweenfluid overload and mortality incritically ill patients is one of thehottest topics in acute carenephrology and warrants specialmention. Pediatricians have been atthe forefront of identifying fluidoverload as a risk factor for mortalityin critically ill patients.80 This ishighlighted by the findings of theprospective pediatric continuousrenal replacement therapy (CRRT)registry. Sutherland et al81 showed ina prospective registry of 227 childrenwho were on CRRT that those witha percentage fluid overload ,20% atinitiation of renal replacementtherapy had improved rates ofsurvival compared with those witha cumulative fluid balance .20%(46% vs 68%, P , .01). Thesefindings have since been verified ina number of different pediatricpatient populations highlightingthe importance of fluid overloadand the timing of renalreplacement therapy in critically illchildren.82–85

Recent data extend these findings tocritically ill children and adultsindependent of renal replacementtherapy.86–88 The impact of fluidoverload is highlighted in the practiceguidelines proposed by the AmericanCollege of Critical Care Medicine forpediatric and neonatal septic shock,which recommend that interventionsto address fluid balance arewarranted when critically ill childrenamass 10% volume overload.89

Limited data are available on fluidoverload in neonates. Askenazi et al63

showed that sick late pretermneonates with AKI had a highermedian fluid overload at day of life 3than those without AKI (+8.2% vs–4%, P , .001). As fluid overload isa potentially modifiable risk factor formortality, research into its impact onneonatal outcomes is critical toprovide information to cliniciansabout fluid provision and the timingof renal replacement therapy.

Throughout adult and pediatricintensive care medicine, renalreplacement therapy has transitionedfrom being a “last-ditch effort” to anearly therapy directed at supportingthe critically ill patient by maintainingelectrolyte homeostasis, allowing forprovision of adequate nutrition, andpreventing/reducing hypervolemia.This mindset of early intervention hasnot fully reached the neonatalpopulation, possibly because of theadded risk of dialysis machines,ethical considerations, and a lack ofstudies that illustrate the role of fluidoverload on poor outcomes in thesepatients. Renal replacement therapyposes particular challenges in theneonate, as most equipment wasdesigned for older children. Currently,peritoneal dialysis (PD) is themodality of choice in infants. PD istechnically easier, as there is no needfor vascular access or anextracorporeal blood circuit.90 Ifperitoneal dialysis is felt to bea short-term requirement,a temporary catheter can be placed.Several studies describe successfulperitoneal dialysis by several

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different techniques in critically illneonates as small as 830 g.91–95

When PD is technically difficultbecause of abdominal wall defects,skin infections, communication to thepleural space, or high ultrafiltrationneeds, CRRT can be performed. CRRTis performed with a hemodialysiscatheter placed in a central locationand either regional or systemicanticoagulation. The volume of theextracorporeal circuit is particularlycritical in the neonatal population andoften these neonates will require thatthe CRRT machine be primed withblood if the circuit volume exceeds10% to 15% of the total bloodvolume.96 In the United States,current CRRT machines are approvedonly for those weighing .20 kg, butthese machines have been used off-label in children ,5 kg.97 There area number of considerations whenevaluating CRRT in a neonate,including center expertise, prescription,and error rates of current machines,which has been recognized and led tothe development of neonatal CRRTmachines.98 CRRT systems, such asCARPEDIEM99 (Bellco, Mirandola,Italy) and Nidus,100 are being used incountries outside the United States inneonates. These machines showpromise, as they have smallerextracorporeal volumes and arehighly accurate. Despite these recentadvances, the evidence on thepractice of renal replacement therapyin neonates is limited to single-centercase series with a complete lack ofmulticenter data.

CONSEQUENCES AND FOLLOW-UP OFNEONATAL AKI

Previously, it was assumed that thosewho survived an episode of AKIwould recover kidney functionwithout long-term effects. Recentdata from animals,101 critically illchildren,5,6 and adults102 with AKIsuggest that survivors are at risk forthe development of CKD. Mammenet al5 reported that 10% of childrenwho developed AKI in the PICU had

GFR ,60 mL/min/1.73 m2, 1 to3 years later. Perhaps even morealarming was the finding that nearly50% of this cohort was found to be“at risk” for CKD.

The role that AKI plays in thedevelopment of CKD in the neonatalpopulation is unknown. Several casereports document that CKD occurs ininfants who had AKI; however, thesestudies are small, single-centerretrospective reports. Recognizing thelong-term implications of AKI, themost recent KDIGO practiceguidelines recommend that allpatients who experience AKI beevaluated after 3 months for newonset or worsening of CKD.44 Theycaution that even if CKD is notpresent at that time, those with AKIare considered to have increased riskfor CKD long-term. Although theserecommendations are likely pertinentto infants, currently there is notenough firm evidence to make formalfollow-up recommendations afterepisodes of neonatal AKI. Generalpediatricians should considerneonates who have suffered AKI atincreased risk and monitor bloodpressure with consideration offurther testing on a case-by-casebasis. Large longitudinal multicenterstudies designed to follow neonatesafter critical illness are greatlyneeded to define the mostappropriate surveillance protocols, aswell as identify those most at risk.

CONCLUSIONS

Neonatal AKI represents a rapidlyevolving area in clinical research, buta significant amount of work remainsto improve the outcomes in thesepatients. An important first stepmoving forward is the developmentof a standardized definition of AKI.Initially, the neonatal modified KDIGOAKI definition will be used ascommon nomenclature to unify andcompare research in neonatal AKI.Although this definition representsthe best available, it remains limitedin that it has not been systematically

studied in a multicenter mannerevaluating the association of AKI withoutcomes. Further work in neonatalAKI needs to focus on defining riskfactors, the implications of fluidbalance, renal replacement therapy,and the long-term outcomes,including the development of CKD inthis susceptible population.

After the NIDDK-sponsoredworkshop on neonatal AKI, aninternational, multi-institutional,multidisciplinary group, the NeonatalKidney Collaborative, was formed.This group aims to answer some ofthe questions surrounding neonatalAKI with the goal of improvingoutcome and optimizing care forthese vulnerable patients.

ABBREVIATIONS

AKI: acute kidney injuryCRRT: continuous renal

replacement therapyCKD: chronic kidney diseaseECMO: extracorporeal membrane

oxygenationELBW: extremely low birth weightGFR: glomerular filtration rateKDIGO: Kidney Diseases:

Improving GlobalOutcomes

NIDDK: National Institute ofDiabetes and Digestiveand Kidney Diseases

PD: peritoneal dialysisSCr: serum creatinineVLBW: very low birth weight

infants

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DOI: 10.1542/peds.2014-3819 originally published online July 13, 2015; 2015;136;e463Pediatrics 

Mhanna, David J. Askenazi and Alison L. KentDavid T. Selewski, Jennifer R. Charlton, Jennifer G. Jetton, Ronnie Guillet, Maroun J.

Neonatal Acute Kidney Injury

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