J. Pediatr. (Rio J.) vol.93 número1

www.jped.com.br

ORIGINAL

ARTICLE

Predictive

factors

of

mortality

in

pediatric

patients

with

acute

renal

injury

associated

with

sepsis

夽

,

夽夽

Marcia

C.

Riyuzo

,

Liciana

V.

de

A.

Silveira

,

Célia

S.

Macedo

,

José

R.

Fioretto

a_{UniversidadeEstadualPaulista(UNESP),FaculdadedeMedicina,DepartamentodePediatria,Botucatu,SP,Brazil}

b_{UniversidadeEstadualPaulista(UNESP),InstitutodeBiociênciasdeBotucatu,DepartamentodeBioestatística,Botucatu,}

SP,Brazil

Received15October2015;accepted8April2016 Availableonline2July2016

KEYWORDS

Acutekidneyinjury; Sepsis;

Predictivefactors; Mortality

Abstract

Objective: Toevaluatetheprognosisfactorsofchildrenwithsepsisandacutekidneyinjury.

Methods: Thiswasaretrospectivestudyofchildrenwithsepsisandacutekidneyinjurythat

wereadmittedtothepediatricintensivecareunit(PICU)ofatertiaryhospital.Amultivariate analysiswasperformedtocompareriskfactorsformortality.

Results: Seventy-seven children (47 males) were retrospectively studied, median age of4

months.Meanlengthofhospitalstaywas7.33±0.16days,68.9%ofpatientsreceived mechan-ical ventilation, 25.9% had oligo-anuria, and peritoneal dialysis was performed in 42.8%. The pRIFLE criteria were: injury (5.2%) and failure(94.8%), and the staging system crite-ria were: stage 1 (14.3%), stage 2 (29.9%), and stage 3 (55.8%). The mortality rate was 33.7%. In themultivariate analysis, therisk factorsfor mortalitywere PICU length ofstay (OR=0.615, SE=0.1377, 95% CI=0.469---0.805, p=0.0004); invasive mechanical ventilation (OR=14.599,SE=1.1178,95%CI=1.673---133.7564,p=0.0155);needfor dialysis (OR=9.714, SE=0.8088,95%CI=1.990---47.410,p=0.0049),andhypoalbuminemia(OR=10.484,SE=1.1147, 95%CI=1.179---93.200,p=0.035).

Conclusions: Theriskfactorsformortalityinchildrenwithacutekidneyinjurywereassociated withsepsisseverity.

©2016PublishedbyElsevierEditoraLtda.onbehalfofSociedadeBrasileiradePediatria.Thisis anopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/

by-nc-nd/4.0/).

夽

Pleasecitethisarticleas:RiyuzoMC,SilveiraLV,MacedoCS,FiorettoJR.Predictivefactorsofmortalityinpediatricpatientswithacute renalinjuryassociatedwithsepsis.JPediatr(RioJ).2017;93:28---34.

夽夽

StudyconductedatUniversidadeEstadualPaulista(UNESP),Botucatu,SP,Brazil.

∗_{Correspondingauthor.}

E-mail:mriyuzo@fmb.unesp.br(M.C.Riyuzo).

http://dx.doi.org/10.1016/j.jped.2016.04.006

PALAVRAS-CHAVE

Lesãorenalaguda; Sepse;

Fatorespreditivos; Mortalidade

Fatorespreditivosdemortalidadeempacientespediátricoscomlesãorenalaguda associadacomsepse

Resumo

Objetivo: Avaliarosfatoresprognósticosdecrianc¸ascomsepseelesãorenalaguda.

Métodos: Estudo retrospectivo de crianc¸as internadas com sepse e lesão renal aguda em

unidade deterapia intensivapediátrica deservic¸oterciário.Usou-sea análisemultivariada nacomparac¸ãodosfatoresderiscoparamortalidade.

Resultados: Foram avaliados 77 pacientes (47 masculinos) com mediana de 4 meses de

idade. A média do tempo de internac¸ão foi de 7,33±0,16 dias, 68,9% necessitaram de ventilac¸ãomecânica,25,9%eramoligoanúricose42,8%necessitaramdediálise.Aclassificac¸ão da lesão renal aguda foi pRIFLE I em 5,2% e F em 94,8% e estágio 1 (14,3%), estágio 2 (29,9%) e estágio 3 (55,8%). A taxa de mortalidade foi de 33,7%. Na análise multivari-ada os fatores de risco foram tempo de internac¸ão (OR=0,615 erro padrão=0,1377, 95% CI=0,469-0,805, p=0,0004), ventilac¸ão mecânica (OR=14,599, erro padrão=1,1178, 95% CI=1,673-133,7564, p=0,0155), necessidade de diálise (OR=9,714, erro padrão=0,8088, 95%CI=1.990-47,410,p=0,0049)ehipoalbuminemia(OR=10,484,erropadrão=1,1147,95% CI=1,179-93,200,p=0,035).NomodelodeCoxasobrevidafoiinfluenciadapelanecessidade dediálise(HR=2,952,erropadrão=0,44862,95%CI=1,225-7,112,p=0,016)ehipoalbuminemia (HR=3,326,erropadrão=0,59474,95%CI=1,037-10,670,p=0,043).

Conclusões: Osfatoresderiscopara mortalidadenascrianc¸ascomlesão renalagudaforam

associadosàgravidadedasepse.

©2016PublicadoporElsevierEditoraLtda.emnomedeSociedadeBrasileiradePediatria.Este ´

eumartigoOpenAccesssobumalicenc¸aCCBY-NC-ND(http://creativecommons.org/licenses/

by-nc-nd/4.0/).

Introduction

Acute kidney injury (AKI) is a significant factor that con-tributes to the morbidity and mortality of children and newborns admitted to intensive care units.1 _The admis-sion of patients with AKI to the pediatric intensive care unit (PICU) ranges between 48% and 68%.1,2 _An associa-tionbetweensepsisandAKIwasobservedin71.03%ofthe patientsadmittedtothisPICU.

MultiplefactorsmaybeimplicatedintheetiologyofAKI inchildrenwithsepsis.1_{Thefrequencyofsepsis-associated} AKIhasincreased3---5_{;between10%andover30%ofcasesof} AKIwereduetosepsisandinfection.2,6---8_{Pediatricpatients} with sepsis and multiple systemic organ dysfunction had lowersurvivalratesthan thosewithischemia.4 _Sepsiswas associatedwithdeathin62%ofpatientswithAKIandwasa riskfactorformortality.8---10_{Childrenwithsepsishada} ten-foldhigherriskofdeath.8_{Thereisascarcityofpublications} abouttheriskfactorsformortalityinpediatricpatientswith AKIandsepsis.Moststudiesreporteddataonneonatesand childrenwithAKIafterheartsurgery.3,11,12

In pediatric patients admitted to the PICU with AKI associated withhemolytic uremicsyndrome or cancer, or post-heart surgery, the factors related to mortality were thrombocytopenia,age>12 years,and presenceof hypox-emia and/or hypotension and/or coagulopathy.5 _{In this} study,themortalityofpatientswithAKIwashigher(29.6%) whencomparedwiththatofpatientswithoutit(2.3%).5_The determinationofpredictivefactorsofmortalityinpediatric patients withsepsis-associated AKI maycontribute to the identificationofthesepatients,aswellasthe implementa-tionofearlytherapeuticmeasurestoreducemortality.

For years, the definition of AKI was heterogeneous. The proposal to standardize the definition of AKI using the pediatric RIFLE (pRIFLE) criteria13---17 _{and the staging} system14,16,18,19_{favorsthecomparisonofresultsbetween} dif-ferentstudies.Aprospectivestudyshowedthattheinjury andfailureclassificationofthepRIFLEwasapredictive fac-torofmortalityinchildrenadmittedtothePICU.17

This study assessed independent predictive factors of mortalityinapediatricpatientcohortwithsepsis-associated AKI.

Methods

Patients,definitions,andassessedparameters

Thiswasaretrospectiveobservationalstudyofapediatric patientcohortadmittedtothePICUofFaculdadede Medi-cina of Botucatu, UNESP-Universidade Estadual Paulista, which is a tertiary hospital. Data were obtained from a databaseofpatientsadmittedtothePICUfromJanuary1990 toDecember1994.Thestudyincludedchildrenaged1to132 monthsofage,ofbothgenders,admittedtothePICUwith adiagnosisofsepsisandAKI.

whentheserumcreatininevaluewashigherthanthenormal valueforageandheightaccordingtothereportsofGuignard andSantos.20_{Allpatientsincludedinthestudyhada} diag-nosisofsepsisdefinedbytheInternationalPediatricSepsis ConsensusConferencecriteria.21,22

The analyzed data were: (a) demographic data (age, gender), (b) days in the PICU; (c) clinical data (olig-uria or anuria, hypotension or hypertension, number of vasoactive drugs, use and duration of mechanical venti-lation, need for dialysis, AKI classification criteria, and evolution during PICU stay); (d) laboratory data: serum albumin (hypoalbuminemia if value <2.5g/dL), serum bicarbonate(metabolicacidosisifvalue<15mEq/L), elec-trolytes(hypocalcemiaifserumcalciumvalue<7.9mg/dL; hyperkalemia if potassium >5.5mEq/L, or hypokalemia if potassium <2.5mEq/L, hyponatremia if sodium value <125mEq/L), and serum glucose (hypoglycemia if value <50mg%andhyperglycemiaifvalue>150mg%);hematocrit, plateletcount,andproteinuria(dipstickmethod+1or+2on urinalysis).

Oliguria was defined as diuresis <500mL/24h in older childrenor<1mL/kg/hinsmallerchildrenandinfants.23,24 Anuria was defined as complete cessation of diuresis for a period of 24h.23,24 _{Hypotension was defined as a} sys-tolicbloodpressure lowerthanthefifth percentileofthe normal level for age.25 _{Hypertension was defined as} sys-tolicand/ordiastolicbloodpressureequaltoorabovethe 95thpercentileforage,gender,andheight.26 Thrombocyto-peniawasdefinedasplateletlevel<50,000/mm3_.Thislevel isconsideredasmoderatethrombocytopenia,andplatelet count>50,000/mcLdonotrequireroutinetreatment. The classificationcriterion wasappliedonthe firstday of AKI diagnosis.

The pRIFLE criteria defined AKI as: pRIFLE R, or Risk (25%decreaseintheestimatedcreatinineclearance[CrCl] or diuresis<0.5mL/kg/hfor 8h); pRIFLE I,or injury (50% decreaseinCrClordiuresis<0.5mL/kg/hfor16h);pRIFLEF, orfailure(75%decreaseinCrCl,orCrCl<35mL/min/1.73m, or diuresis <0.3mL/kg/h for 24h, or anuria for 12h); pRIFLEL,orloss(persistentfailure>fourweeks);and pRI-FLE E, or end-stage (end-stage kidney disease-persistent failure>three months).18,27 _{Only the R, I, and F} classi-fications for AKI were used in the present study. The Schwartz equation was used to calculate CrCl.18,27 _Basal CrCl was calculated through the Schwartz equation using theserumcreatininevalueuptothreemonthsbeforePICU admission.

ThestagingsystemdefinedAKIas:stage1---serum cre-atinineincrease>0.3mg/dL(>26.4mmoL/L)or≥150---200% increase (1.5- to two-fold) from baseline or urine out-put <0.5mL/kg/h for >6h); stage 2 --- serum creatinine increase >200---300% (two- to three-fold) frombaseline or urineoutput<0.5mL/kg/hfor>12h);stage3---serum cre-atinine increase >300% (> three-fold) >24h frombaseline or serum creatinine ≥4.0mg/dL [354␮moL/L] or with a sharpincreaseofatleast0.5mg/dL[44␮moL/L])ordiuresis <0.3mL/kg/horanuriafor12h).18

In this study, the use of the pRIFLE criterion was car-riedoutaccordingtoCrClalterationandthestagingsystem accordingtoalterationsinserumcreatininelevels,as74.1% ofthepatientshadnon-oliguricAKI.

ThestudywasapprovedbytheLocalEthicsCommittee.

Statisticalanalysis

TheresultswereanalyzedusingtheSASSystemforWindows (SAS InstituteInc.®_{, USA). Descriptive dataarepresented}

as percentage. Continuous variables (age, PICU length of stay, daysof mechanical ventilation, urinary volume,and laboratory test values) were expressed as mean±SD or median.Categoricalvariables(gender,presenceofoliguria, hypotensionorhypertension,vasoactivedrugs,mechanical ventilation,need fordialysis,hypocalcemia, hyperkalemia or hypokalemia,hyponatremia,thrombocytopenia,and/or presence of proteinuria) were expressed as frequency of occurrence. When comparing the survivor and deceased groups, Mann---Whitney’s U test was used to analyze the continuousvariablesandFisher’sexacttestforcategorical variables.Multiple logisticregressionanalysiswasusedto define therisk factorsand theevolution ofvariables that showedp<0.20at theunivariateanalysis;oddsratiowere adjustedandconfidenceintervalswerecalculated.

Kaplan---Meier survival curves were generated and the log-rank analysiswasused tocomparesurvival rates. Cox regressionanalysiswasperformedtoassesstheriskfactors formortalityduringPICUstay.p-Values<0.05were consid-eredsignificant.

Results

Thestudyincluded77childrenwithsepsisandAKI.Diarrhea and/orpneumoniawerethemostcommoncausesofsepsis (84%).

The mean age of patients was 12.79±23.45 months (median 4 months); 77% were ≤10 months; 61.03% were boys.ThemeannumberofdaysinthePICUwas7.33±0.16 days(range1---18days);66patients(85.7%)hadadiagnosis ofAKIonthefirstdayofPICUadmission;11patients(14.3%) werehospitalizedforamedianof2days(range1---43days) beforeAKIdiagnosis.Diuresisrangedfrom0to11mL/kg/h; 57 patients (74.1%) had non-oliguric AKI and ten (12.9%) were anuric. Three patients (0.04%) hadhypotension and eight(10.3%)hadhypertension;98.7%requiredvasopressor drugsand92.2%receivedmorethantwovasoactivedrugs. Fifty-fourpatients(70.1%)requiredmechanicalventilation and42.8%requiredacuterenalreplacementtherapy; perit-onealdialysiswascarriedoutinthesepatients.Indications fordialysisincludedoliguria,increaseinserumurea, hyper-kalemia(K>5.5mEq/L),pulmonaryedema,andinsufficient diuresis to allow administration of medications and/or nutrition.

ThepRIFLEclassificationofAKIpatientswas:pRIFLEIin four(5.2%)andpRIFLEFin73(94.8%).CrClrangedfrom4.19 to56.66mL/min/1.73m2_{.As for theclassification}

Table1 Clinicalfeaturesandevolutionofpatientswithsepsisandacutekidneyinjury.

Variable Survived(n=51) Deceased(n=26) pa

Age(months,median) 4 6 0.37b

Gender(male/female,n) 32/19 15/11 0.80c

PICUadmission(days,median) 8 4.5 0.001b

Diuresis(mL/kg/h,median) 2.0 1.4 0.19b

Oligoanuria(n) 9 11 0.039c

Hypotension(n)/hypertension(n) 1/6 2/2 0.50c

Vasoactivedrug(n)0/1/2ormore 1/4/46 0/1/25 0.77c

Mechanicalventilation(n) 30 24 0.0015c

Daysonventilation(median) 5 4 0.18b

Dialyzed(n) 14 19 0.0002c

Acutekidneyinjuryclassificationcriteria: pRIFLE

pRIFLEIn(%) 2(4) 2(7.6)

0.60c

pRIFLEFn(%) 49(96) 24(92.4)

Stagingsystem

Stage1n(%) 11(21.6) 0

0.021c

Stage2n(%) 13(25.5) 10(38.5)

Stage3n(%) 27(52.9) 16(61.5)

n,numberofpatients;PICU,pediatricintensivecareunit;pRIFLE,pediatricrisk,injury,failure,loss,endstagerenaldisease.

a _{Statisticalanalysis.} b _{Mann---Whitney’sUtest.} c _{Fisher’sexacttest.}

Patients’ laboratory data and evolution are shown in

Table 2. Hypoalbuminemia was observed in 28.3% and metabolicacidosisin90.7%(68/75)ofpatients.

The mortalityrate was 33.7% (26/77). Elevenpatients had disseminated intravascular coagulation, and ten died (onehadacuterespiratorysyndromeandonehadmultiple organfailure).

Attheunivariateanalysis,thefactorsPICUlengthofstay, oligo-anuria,invasivemechanicalventilation,needfor dial-ysis, AKI stage 2 and 3 criteria, hypoalbuminemia, serum bicarbonate, and thrombocytopenia were associated with mortality.

In the multiple logistic regression analysis, the inde-pendentrisk factors associated withmortality were PICU

Table2 Laboratoryfeaturesandevolutionofpatientswithsepsisandacutekidneyinjury.

Variable Survived(n=51) Deceased(n=26) pa

Creatinine(mg/dL,median) 1.39 1.69 0.27b

Urea(mg/dL,median) 111 89 0.40b

Albumin(g/dl,mean±SD) 3.13±0.93 2.30±0.70 0.006b

Bicarbonate(mEq/L,mean±SD) 7.39±5.29 11.11±6.58 0.01b

Calcium(mg/dL,median) 8.6 8.45 0.62b

Hypocalcemia(n) 19 7 0.99c

Potassium(mEq/L,median) 4 3.9 0.53b

Hyperkalemia(n) 6 3 1.00c

Hypokalemia(n) 14 9 0.70c

Sodium(mEq/L,median) 138 138 0.44b

Hyponatremia(n) 10 11 0.065c

Glucose(mg/dL,median) 121 110 0.53b

Hypoglycemia(n) 1 3 0.29c

Hyperglycemia(n) 11 8 0.98c

Hematocrit(%,mean±SD) 28.7±5.81 29.9±4.9 0.37b

Thrombocytopenia(n) 3 8 0.015c

Proteinuria(n) 29 10 1.00c

n,numberofpatients.

Days of PICU stay

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0

Kaplan-Meier survival curve estimated by hypoalbuminemia

100

75

50

25

0

Without hypoalbuminemia: With hypoalbuminemia:

% survival

Figure1 SurvivalcurveinAKIrelatedtohypoalbuminemia.

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 100

75

50

25

0

Without dialysis: With dialysis:

Days of PICU stay

Kaplan-Meier survival curve estimated by dialysis

% survival

Figure2 SurvivalcurveinAKIrelatedtodialysis.

lengthofstay(OR=0.615SE=0.1377,95%CI=0.469---0.805,

p=0.0004), invasive mechanical ventilation (OR=14.599, SE=1.1178,95% CI=1.673---133.7564, p=0.0155),need for dialysis (OR=9.714, SE=0.8088, 95% CI=1.990---47.410,

p=0.0049), hypoalbuminemia (OR=10.484 SE=1.1147, 95% CI=1.179---93.200, p=0.035), and serum bicarbonate (OR=1.231,SE=0.0735,95%CI=1.066---1.422,p=0.0046).

Othervariableswerenotassociatedwithmortality: olig-uria, anuria (OR=1.13, SE=0.1302 95% CI=0.881---1.467,

p=0.32), thrombocytopenia (OR=1.469, SE=1.0595, 95% CI=0.184---11.718, p=0.72), and AKI stage (OR=0.060, SE=2.2017,95%CI≤0.001---4.557,p=0.20).

The estimated probabilitiesof survivalduring thePICU staywere25%inhypoalbuminemicpatients,whencompared with75% inpatientswithnormalalbumin(logrank=5.88,

p=0.015)and24%inpatientsrequiringdialysiscomparedto 76%ofpatientswhodidnotneeddialysis(logrank=8.513,

p=0.0035;Figs.1and2).

InthesurvivalanalysisusingCoxmodel,theparameters thatinfluencedsurvivalwere:needfordialysis(HR=2.952, SE=0.44862, 95% CI=1.225---7.112, p=0.016), hypoalbu-minemia (HR=3.326, SE=0.59474, 95% CI=1.037---10.670,

p=0.043),andserumbicarbonate(HR=1.097,SE=0.04098, 95%CI=1.042---1.198,p=0.024).Needforinvasive mechan-ical ventilation did not influence survival (HR=2.424, SE=1.07710,95%CI=0.294---20.016,p=0.411).

The median of daystoAKI improvementwas fivedays (range2---21days)inpatientswithAKI stage1;sevendays (3---19daysvariation)inpatientswithstage2;andeightdays (3---21daysvariation)inpatientswithstage3.AKIrecovery inthefirstweek occurredin72.7%(8/11)ofpatientswith AKIstage1,61.5%(8/13)ofpatientswithstage2,and48.1% (13/27)ofpatientswithstage3.

Discussion

An association between sepsis and AKI was observed in 71.03%ofthepatientsadmittedtothisPICU;thesepatients hadahighmortalityrate(33.7%),similartothatdescribed inotherstudies.4,8,13,28---31

There is a high incidence of sepsis-associated AKI in critically-illpatients.31_{TheidentificationofsevereAKI} pre-dictivefactorshasthepotentialtooptimizetreatment.31,32 Among thefactors associatedwithmortality, the pres-ence of oliguria or anuria, need for dialysis, need for mechanical ventilation, and hypoalbuminemia should be emphasized.

did not remain as such in the multivariate analysis. The lowerproportion ofoligo-anuric patients must have influ-encedthestatisticalanalysis.Mostofthepresentpatients werenon-oliguric,differentfromwhatwasobservedinthe aforementionedstudies.Thepresenceofoliguriamakesthe disease more severe, hindering fluid administration, thus facilitatingthedevelopmentofhypervolemia,which com-plicatestheunderlyingdisease.31

The need for dialysis increased by 3.76 times the risk of mortality in children with AKI,29 _{especially in patients} undergoingdialysisforlongerperiods.9_{Thepresentdataare} consistentwiththeaforementionedstudies.9,29

Needformechanicalventilationwasassociatedwith mor-talityinpatientswithAKIunrelatedtoprimaryurinarytract disorder9,23 _{and in those with prerenal and non-prerenal} AKI11,29_{; the present findings are consistent with these} studies.9,11,23 _{Patientswithsepsis-associated AKI aremore} likelytorequiremechanical ventilationandhemodynamic supportwithvasoactivetherapy,andtoreceivelarge vol-umes of fluid for resuscitation.31 _{This fact contributes to} longerhospitalstayinthePICUandincreasedmortality.33

In the present study, patients with decreased serum bicarbonatelevelshadhighersurvival.Intheliterature,the presenceofacidosiswasnotanindependentfactorforthe mortalityofpatientswithAKI.24_{Thepresentstudywas} con-ductedinatertiaryinstitutionthatisareferencecenterfor medicalorsurgicalcritically-illpatients,whohadprobably beentreatedforacidosiswithbicarbonatesolutionsbefore arrivalatthisservice.

Hypoalbuminemiawasassociated withhighermortality inpediatric patients.12 _{In228pediatric patientswithAKI,} serumalbuminwashigheramongsurvivors(3.3±0.9g/dL) than in non-survivors (2.6±0.7g/dL).12 Hypoalbumine-mia may result from accelerated protein catabolism of metabolic alterations in AKI.30 _{Moreover, albumin} synthe-sisissuppressedinresponsetoinflammatoryconditions,34 and inflammatorymediators areinvolved in children with sepsis.21,31 _{Inchildren withseveredisease,} hypoalbumine-miawasassociatedwithhigh mortalityandlongertimeof mechanicalventilation.35

Theclassificationofrenalinjuryseverityhasbeen asso-ciatedwithincreasedhospitallengthofstayandincreased in-hospital relativemortalityrisk.31 _{According tothe} pRI-FLEcriteria, the patientsin thepresent study hadsevere AKI(mostwereclassifiedaspRIFLEF).Incontrast,the stag-ing criterion showed an evendistribution between stages 1,2,and3.This factmustbeassociatedwithdifferences in theuse of parameterstodefine AKI. The pRIFLE crite-ria used CrCl and the staging criteria used the increase in serum creatinine levels. Evidence suggests that small changesinserumcreatinineareassociatedwithincreased patientmortality.18_{Otherauthorshavefoundsignificant} dif-ferencesinAKIseveritydistributionwhenserumcreatinine increasewasusedinsteadofCrCltodefineAKI; thelatter showedgreatersensitivity.14,16,18

PatientswithpRIFLEIorFatadmissionshowedatwo-fold higherriskofmortality,whencomparedtopatientswith pRI-FLER.13,17_{Noassociationwasobservedbetweenthestrata} ofpRIFLEcriteriaandmortality,similartothedatareported byPlötzetal.15

WhentheAKIstagingcriterionwasappliedtothepresent patients,resultssimilartothosereportedbyOzc¸akaretal.19

were observed. The mortality rate was 33%, and it was higher in patients with AKI stage 2 and 3, similarto the presentresults.Insepsis-associatedAKI,theprobabilityof deathwashigherinpatientsclassifiedasstage3AKI,when comparedwiththoseclassifiedasstage1.31

Studieshaveshownanassociationbetweenthedegreeof kidneydiseaseseverityandimprovementinrenalfunction: 46%ofpatientsshowedrenalfunctionrecoverywithin48h, predominatingin62.5%patientswithpRIFLERatadmission, whencomparedtothosewithpRIFLEI(38.1%)orpRIFLEF (26.7%).13_{TherecoveryfromAKIinthefirstweek,according} tothe stagingcriterion, occurred in allpatients with AKI stage1, in half of thepatients with stage2, andin one-thirdof patients withstage3.19 _{The present resultswere} consistentwiththeaforementionedstudies.

Theassessedpredictive factorsofmortalityinchildren with sepsis-associated AKI comprised clinical, laboratory, andAKIclassificationparameters.Thereisnosingle consen-susonwhichparameter isidealforearlydiagnosis ofAKI, whichwouldimplyinearly-onsettherapyaimedatreducing mortality.

The constant monitoring of critically-ill patients, assessingthepresenceofoliguria,hypertensionor hypoten-sion,andhypoalbuminemia,aswellastheevolutiontothe needformechanicalventilationand/ordialysis,shouldraise theearlysuspicionofAKIdevelopment.Atthesametime, theAKIclassificationshouldberoutinely carriedoutsince thefirstdayofhospitalization,andonthethirddayforthe earlydetectionofAKI,accordingtoparameterevolution.31 Authors have validated the Renal Angina Index (RAI) usingtheproductof theriskfactors (admissiontoPICU ---score1,stemcelltransplantation---score3,ventilationand inotropics---score5)andtheinjuryfactors(deathrate evo-lutionassociatedwithfluidoverloadpercentage,decrease intheestimatedcreatinine clearance,percentageoffluid overload---scorerangingfrom1,2,4,and8),whoseRAIvalue rangesfrom1to40.32 _{TheRAIcutoffvalue≥8isindicative} ofhighriskforAKI.

Thepresent studyhaslimitations,suchasthe observa-tionalretrospectivedesignwithasmallnumberofpatients studied in a single center; however, this cohort included theevaluation of AKI inpediatric patients witha specific condition,i.e., sepsis.The smallnumberof patients with thepRIFLEIclassificationmayhaveinfluencedthepowerof statistics.

It can be concludedthat the mortality rate is high in patientswithsepsisandAKI;thepredictivefactorsrelated tomortalitywere easytoapply, aswell astheAKI classi-ficationbythestagingsystemor pRIFLEandreflectedthe evolutionofpatientswithsepsisandAKI.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

References

2.GokcayG,EmreS,TanmanF,SirinA,ElciogluN,DolunayG.An epidemiologicalapproachtoacuterenalfailureinchildren.J TropPediatr.1991;37:191---3.

3.Moghal NE, Brocklebank JT, Meadow SR. A review of acute renalfailureinchildren:incidence,etiologyandoutcome.Clin Nephrol.1998;49:91---5.

4.Hui-StickleS,BrewerED,GoldsteinSL.PediatricARF epidemi-ologyatatertiarycarecenterfrom1999to2001.AmJKidney Dis.2005;45:96---101.

5.BaileyD,PhanV,LitalienC,DucruetT,MérouaniA,LacroixJ, etal.Riskfactorsofacuterenalfailureincriticallyillchildren:a prospectivedescriptiveepidemiologicalstudy.PediatrCritCare Med.2007;8:29---35.

6.Anochie IC,EkeFU.Acuterenal failurein Nigerianchildren: PortHarcourtexperience.PediatrNephrol.2005;20:1610---4. 7.DuzovaA,BakkalogluA,KalyoncuM,PoyrazogluH,DelibasA,

OzkayaO,etal.Etiologyandoutcomeofacutekidneyinjuryin children.PediatrNephrol.2010;25:1453---61.

8.VachvanichsanongP,DissaneewateP,LimA,McNeilE.Childhood acuterenalfailure:22-yearexperienceinauniversityhospital insouthernThailand.Pediatrics.2006;118:e786---91.

9.OtukeshH,HoseiniR,HoomanN,ChalianM,ChalianH, Tabar-roki A. Prognosis of acute renal failure in children. Pediatr Nephrol.2006;21:1873---8.

10.Loza R,Estremadoyro L, Loza C,Cieza J.Factorsassociated withmortalityinacuterenalfailure(ARF)inchildren.Pediatr Nephrol.2006;21:106---9.

11.GallegoN,GallegoA,Pascual J,Lia˜noF,EstepaR,Ortu˜noJ. Prognosisofchildrenwithacuterenal failure:astudyof138 cases.Nephron.1993;64:399---404.

12.WilliamsDM,SreedharSS,MickellJJ,ChanJC.Acutekidney fail-ure:apediatricexperienceover20years.ArchPediatrAdolesc Med.2002;156:893---900.

13.Akcan-ArikanA,ZappitelliM,LoftisLL,WashburnKK,Jefferson LS,GoldsteinSL.ModifiedRIFLEcriteriaincriticallyillchildren withacutekidneyinjury.KidneyInt.2007;71:1028---35. 14.ZappitelliM,ParikhCR,Akcan-ArikanA,WashburnKK,Moffett

BS,GoldsteinSL.Ascertainmentandepidemiologyofacute kid-neyinjuryvarieswithdefinitioninterpretation.ClinJAmSoc Nephrol.2008;3:948---54.

15.Plötz FB, Bouma AB, van Wijk JA, Kneyber MC, Bökenkamp A. Pediatric acutekidney injury in theICU:an independent evaluation of pRIFLE criteria. Intensive Care Med. 2008;34: 1713---7.

16.KavazA,Ozc¸akarZB,KendirliT,OztürkBB,EkimM,Yalc¸inkaya F. Acute kidney injury in a paediatric intensive care unit: comparison of the pRIFLE and AKIN criteria. Acta Paediatr. 2012;101:e126---9.

17.SolerYA,Nieves-PlazaM,PrietoM,García-DeJesúsR, Suárez-RiveraM.Pediatricrisk,injury, failure,loss,end-stage renal diseasescoreidentifiesacutekidneyinjuryandpredicts mor-talityincriticallyillchildren:aprospectivestudy.PediatrCrit CareMed.2013;14:e189---95.

18.BaggaA,BakkalogluA,DevarajanP,MehtaRL,KellumJA,Shah SV,etal.Improvingoutcomesfromacutekidneyinjury:report ofaninitiative.PediatrNephrol.2007;22:1655---8.

19.Ozc¸akarZB,Yalc¸inkayaF,AltasB,ErgünH,KendirliT,Ates¸C, etal.ApplicationofthenewclassificationcriteriaoftheAcute

KidneyInjuryNetwork:apilotstudyinapediatricpopulation. PediatrNephrol.2009;24:1379---84.

20.GuignardJP,SantosF.Laboratoryinvestigations.In:AvnerED, HarmonWE,NiaudetP,editors.Pediatricnephrology.5thed. Baltimore:Lippincott,WilliamsandWilkins;2004.p.399---424. 21.FiorettoJR,BorinFC,BonattoRC,RicchettiSM,KurokawaCS, deMoraesM,etal. Procalcitonininchildrenwithsepsisand septicshock.JPediatr(RioJ).2007;83:323---8.

22.Goldstein B, Giroir B, Randolph A, International Consensus ConferenceonPediatricSepsis.Internationalpediatric sepsis consensusconference:definitionsforsepsisandorgan dysfunc-tioninpediatrics.PediatrCritCareMed.2005;6:2---8.

23.Gallego N, Pérez-Caballero C,Gallego A, Estepa R, Lia˜noF, Ortu˜noJ.Prognosisofpatientswithacuterenalfailurewithout cardiopathy.ArchDisChild.2001;84:258---60.

24.AroraP,KherV,RaiPK,SinghalMK,GulatiS,GuptaA. Prog-nosisofacuterenalfailureinchildren:amultivariateanalysis. PediatrNephrol.1997;11:153---5.

25.ECCCommittee,SubcommitteesandTaskForcesofthe Amer-ican Heart Association. 2005 American Heart Association Guidelinesfor CardiopulmonaryResuscitationandEmergency CardiovascularCare.Circulation.2005;112.IV1-203.

26.NationalHighBloodPressureEducationProgramWorkingGroup on High Blood Pressure in Children and Adolescents. The fourthreportonthediagnosis,evaluation, andtreatmentof high blood pressure in children and adolescents. Pediatrics. 2004;114:555---76.

27.Schwartz GJ, Brion LP, Spitzer A. The use of plasma creat-inine concentration for estimating glomerular filtration rate ininfants,children,and adolescents.Pediatr ClinNorthAm. 1987;34:571---90.

28.MedinaVillanuevaA, López-HerceCid J,López FernándezY, AntónGameroM,ConchaTorreA,ReyGalánC,et al.Acute renalfailure incritically-illchildren.Apreliminary study.An Pediatr(Barc).2004;61:509---14.

29.BresolinN,SilvaC,HalllalA,ToporovskiJ,FernandesV,Góes J,etal.Prognosisforchildrenwithacutekidneyinjuryinthe intensivecareunit.PediatrNephrol.2009;24:537---44. 30.DrumlW.Proteinmetabolisminacuterenalfailure.Miner

Elec-trolyteMetab.1998;24:47---54.

31.Alobaidi R, Basu RK, Goldstein SL, Bagshaw SM. Sepsis-associatedacutekidneyinjury.SeminNephrol.2015;35:2---11. 32.BasuRK, Zappitelli M,Brunner L,Wang Y, WongHR,Chawla

LS,etal.Derivationand validationoftherenalanginaindex toimprovethepredictionofacutekidneyinjuryincriticallyill children.KidneyInt.2014;85:659---67.

33.AlkandariO,EddingtonKA,HyderA,GauvinF,DucruetT, Gottes-manR,etal.Acutekidneyinjuryisanindependentriskfactor forpediatricintensivecareunitmortality,longerlengthofstay andprolongedmechanicalventilationincriticallyillchildren:a two-centerretrospectivecohortstudy.CritCare.2011;15:R146. 34.MoshageHJ,JanssenJA,FranssenJH,HafkenscheidJC,YapSH. Studyofthemolecularmechanismofdecreasedliversynthesis ofalbuminininflammation.JClinInvest.1987;79:1635---41. 35.LeiteHP,Rodrigues daSilvaAV,deOliveiraIglesiasSB,Koch