www.jped.com.br
ORIGINAL
ARTICLE
Evaluation
of
clinical
and
laboratory
variables
associated
with
anemia
in
pediatric
patients
on
hemodialysis
夽
,
夽夽
Johnathan
S.
de
Freitas
∗,
Paulo
Sucasas
Costa,
Luciane
Rezende
Costa,
Alessandra
V.
Naghettini
UniversidadeFederaldeGoiás(UFG),Goiânia,GO,Brazil
Received22January2014;accepted28May2014 Availableonline19September2014
KEYWORDS
Anemia; Adolescent; Child;
Kidneydialysis; Renalfailure
Abstract
Objective: Toidentifytheoccurrenceofanemiainpediatricpatientsonhemodialysisandthe
associationbetweenhemoglobinlevelsandanemiainCKD-relatedvariables.
Methods: This wasa retrospectivestudy.Patients aged upto 18 yearswith chronickidney
diseaseundergoinghemodialysisatthisservicebetweenJanuaryof2009andDecemberof2010
were selected.Clinical andlaboratory datawereobtained frommedicalrecords.Statistical
analysiswasperformedwithchi-squaredtest,Student’st-testandgeneralestimatingequations
(GEE)usingSPSS20.0,assumingasignificancelevelof5%.
Results: Atotalof357medicalrecordsdepictingthemonthlyevolutionof29patientswere
analyzed.Themostcommonetiologyforchronickidneydiseasewasmalformationsofthe
geni-tourinarytract(28%).Hemoglobinshowedamean(standarddeviation)valueof9.20(1.8)g/dL,
withtheoccurrenceofanemiain65.3%ofcases.Anemiawasassociatedwithhospitalization;
antibioticuse;transfusion;useofintravenousironhydroxide;lowvaluesofcreatinine,
hema-tocrit, andalbumin; andhighvaluesofferritin, aluminum,andequilibratedKt/V (p<0.05).
Theoddsratioforanemiawiththeuseofintravenousironhydroxidewas0.36(95%CI:0.25to
0.89),i.e.,a2.78-foldhigherchanceofdevelopinganemiawithouttheuseofthismedication.
Conclusions: Anemiapredominatedinchildrenandadolescentswithchronickidneydisease;
intravenousironhydroxideusewasaprotectivefactor.
©2014SociedadeBrasileiradePediatria.PublishedbyElsevierEditoraLtda.Allrightsreserved.
夽 Pleasecitethisarticleas:deFreitasJS,CostaPS,CostaLR,NaghettiniAV.Evaluationofclinicalandlaboratoryvariablesassociated withanemiainpediatricpatientsonhemodialysis.JPediatr(RioJ).2015;91:87---92.
夽夽
StudyconductedatPost-GraduationprograminHealthSciences,UniversidadeFederaldeGoiás(UFG),Goiânia,GO,Brazil.
∗Correspondingauthor.
E-mail:[email protected](J.S.deFreitas).
http://dx.doi.org/10.1016/j.jped.2014.05.009
PALAVRAS-CHAVE
Anemia; Adolescente; Crianc¸a; Diáliserenal; Insuficiênciarenal
Avaliac¸ãodevariáveisclínicaselaboratoriaisassociadasàanemiaempacientes pediátricosemhemodiálise
Resumo
Objetivo: Identificaraocorrênciadeanemiaentrepacientespediátricosemhemodiáliseea
associac¸ãoentreosvaloresdehemoglobinaevariáveisrelacionadasàanemianaDRC.
Métodos: Estudoretrospectivo.Selecionadospacientesaté18anosdeidadecomdoenc¸arenal
crônicaem hemodiáliseno servic¸o entrejaneiro de 2009adezembro de2010. Verificados
prontuáriosparacoletadedadosclínicoselaboratoriais.Análiseestatísticacomtestesde
qui-quadrado,tdeStudenteGeneralEstimatingEquations(GEE)emprogramaStatisticalPackage
fortheSocialSciences20.0,assumindo-seníveldesignificânciade5%.
Resultados: Analisadas357fichasdeevoluc¸ãomédicamensalde29pacientes.Aetiologiamais
frequenteparaadoenc¸arenalcrônicaforamasmalformac¸õesdotratogenito-urinário(28%).
Hemoglobinaapresentouvalormédio(desviopadrão)de9,20(1,8)g/dL,comocorrênciade
anemiaem65,3%dasconsultas.Anemiaassociou-seainternac¸ão,usodeantibiótico,transfusão,
usodehidróxidodeferroendovenoso,valoresbaixosdecreatinina,hematócritoealbuminae
valoresaltosdeferritina,alumínioeKt/Vequilibrado(p<0,05).Aoddsratioparaanemiacom
usodehidróxidodeferroendovenosofoi0,36(95%IC0,25-0,89),ouseja,umachance2,78
vezesmaiordedesenvolveranemiasemousodessamedicac¸ão.
Conclusões: Aanemiapredominouemcrianc¸aseadolescentescomdoenc¸arenalcrônica,tendo
comofatorprotetorousodehidróxidodeferroendovenoso.
©2014SociedadeBrasileiradePediatria.PublicadoporElsevierEditoraLtda.Todososdireitos
reservados.
Introduction
The prevalence of renal replacement therapy in children aged0-19 yearsinBrazilis of23:1,000,000 inthe related agerange.The survivalofthesechildrenis approximately 30-foldlower than that of their healthy peers.The main causeof mortalityin thisgroup is cardiovasculardisease, accountingfor40%ofdeaths,andanemiaisidentifiedasa factorrelatedtohigherratesofmortality.1,2
The prevalenceof anemiainBrazilianchildren without a diagnosis of any disease ranges from25.6% to 63.7%,3,4
whileinchildrenwithchronickidneydisease(CKD),chronic hyporegenerative anemiais common.If untreated,it can leadto growthand development impairment,left ventri-cularhypertrophy,andtachycardia.Whenonhemodialysis, bloodlossinthedialysiscircuitandbloodcollectionsdueto frequentexaminationscontributetofurtherexacerbationof anemia.5
Anemia is a limiting survival factor of children on hemodialysis.Thus,thisstudyaimedtoidentifythe occur-renceofanemiainpediatric patientsonhemodialysisand the association between hemoglobin levels and anemia-relatedvariablesinCKD.
Methods
Studydesignandsetting
ThiswasaretrospectivecohortstudyapprovedbytheEthics CommitteeinHumanandAnimalMedicalResearch,of Hospi-taldasClínicasdaUniversidadeFederaldeGoiás(HC/UFG).
Data were collected at the Renal Replacement Therapy Service,HemodialysisSector,HC/UFG.
Studyparticipants
Thestudyparticipantsweresubjectsundergoing hemodial-ysis in HC/UFG between January of 2009 and December of 2010whomettheinclusioncriteria: age<18yearsand diagnosis of CKD. Cases whose medical records were not availablewereexcluded.
Datacollectionandvariables
An expert researcher (a pediatric nephrologist) collected thedataonthevariablesofinterestfrompatients’records, specifically the recordsof monthlymedical progress, and recordedthemindigitalform.Recordsurveywasconducted at the Hemodialysis Sector and the Division of Medical RecordsandHealthInformationofHC/UFG.
Thedependentvariablewastheoccurrenceofanemia, measuredbyhemoglobinlevels(mg/dL).
albumin,andaluminum.6EquilibratedKt/V(EKT/V)was
cal-culatedasproposedbyFischbachetal.7
StatisticalAnalysis
Data were tabulated and analyzed using descriptive and inferential statistics using IBM SPSS Statistics software, release20(IBMCorporation,NY,USA).
After exploratory data analysis, continuous variables were categorized based on clinical parameters to better interprettheresults,consideringthelimitednumberof sub-jectsincludedinthestudy.
Serumhemoglobinvalueswereclassifiedasadequateor inadequate(anemia)asrecommendedbytheNational Insti-tute for Health and Clinical Excellence (NICE) criteriaof 2011,8whichconsidersbothagegroups(0-2yearsandover2
years).Student’st-testandthechi-squaredtestwerethen usedtotest associations betweenthe described variables andtheoccurrenceofanemia.
This longitudinalobservationalstudy includedrepeated measurementsforthesamevariableinthesamesubject.As thedependentvariablewascategorical(havingornot ane-mia),theanalysisofvarianceforrepeatedmeasurescould notbeused.Moreover,multiplelinearregressionwouldbe contraindicated because the assumption of independence ofrandomvariablescouldnotbemet,asthedatahadan interdependentassociation(repeatedmeasures).Thus,the statisticalanalysisthatwouldbetterdeterminepredictive variablesforanemiawerethegeneralizedestimating equa-tions(GEEs).9
TheGEEapproach,whichisanextensionofgeneralized linear models, was developed to produce more efficient and less biased regression estimates for use with cor-related data, as repeated longitudinal measures.10 Thus,
GEEanalyzesdata dependingonexposure over successive periodsoftime.Fortheanalysisofthisstudy,amodelfor thedependentvariable‘‘anemia’’wascreated.The inde-pendent variables were ‘‘hospitalization’’, ‘‘infection of double-lumencatheter(DLC)’’,‘‘antibioticuse,’’‘‘useof
intravenousironhydroxide.’’Missingdataweretreatedby theGEEmechanismthatusesallavailabledatatoinclude evasiondata.Theoddsratio(OR)andconfidenceintervals (95%CI)werecalculatedtoreflectthepossibleassociations betweenpredictivefactorsanddependentvariable.
Allstatisticaltestsweretwo-tailed,withasignificance levelof0.05.
Results
Atotalof31patientswereincluded,buttwowereexcluded duetoinaccessible files. The finalsample consistedof 29 patients,correspondingto357filesofmonthlyclinical evo-lutionthroughout24months.Eachpatientwasfollowed-up for oneto 23 consultations. The mean age of patients at baseline was 10 years and 3 months (standard deviation [SD]34.6 months). Of the 29 patients included, 21 were males(72.4%).The etiologiesofCKDwiththeirrespective percentagesareshowninFig.1.
All patients but one had anemia at some point during their follow-up, which corresponded to 65.3% of consul-tations (n=233). The mean hemoglobin (g/dL) for the categorized groups were: anemic - 8.2g/dL (SD 1.2); non-anemic - 11.2g / dL (SD 1.0) (p<0.001). The mean hemoglobinvalueforthetotalsamplewas9.2(SD1.8).
Thebivariateanalysisshowedthatanemiawasassociated withseveralclinicalsituations(Table1):needfor hospital-ization,antibioticuse,transfusion,andlessfrequentuseof intravenousironhydroxide(p<0.05).Asforthelaboratory findings,anemiawasrelatedtolowerlevelsofcreatinine, hematocrit,andalbumin,aswellastohighervaluesof fer-ritinandaluminum,andEKt/V(Table1).
Based on the results of the chi-squared and Student’s
t-test,theauthorssoughttodeterminethepredictive clini-calfactorsforanemiainthisgroupofpatients,considering theclinical variables thatreached p<0.2 in thebivariate analysis.Amongthese,thevariable‘‘needfortransfusion’’ was excluded, as it is not logical to evaluate this vari-ableasa predictor ofanemia. Thus,through GEE, it was
28% 10%
14% 10% 7% 7% 7%
17%
0% 5% 10% 15% 20% 25% 30%
Exclusively GUT malformations Exclusively neurogenic bladder Association of GUT malformation + neurogenic bladder FSGS ARPKD Sequelae of acute injury (HUS/sepsis) Urinary metabolic disorder (nephrocalcinosis/hyperoxalosis) Undetermined
Figure1 Etiologyofchronickidneydisease.
HUS,hemolyticuremicsyndrome;ARPKD,autosomalrecessivepolycystickidneydisease;FSGS,focalandsegmental
glomeruloscle-rosis;GUT,genitourinarytract.
Table1 Associationbetweenclinicalandlaboratoryvariablesandtheoccurrenceofanemiainchildrenwithchronickidney
diseaseonhemodialysis(357filesof29patients).
Independentvariables n Totalsample Anemia p
Yes(n=233) No(n=124)
Medicalhistory,n(%)
Needforhospitalization 316 52(14.6%) 43(20.7%) 9(8.3%) 0.005a
Antibioticuse 316 60(16.8%) 48(23.1%) 12(11.1%) 0.010a
Needfortransfusion 316 11(3.1%) 56(26.9%) 3(2.8%) <0.001a
Double-lumencatheterinfection 316 59(16.5%) 10(4.8%) 1(0.9%) 0.105a
Mainmedicationsusedinthetreatmentofanemia,n(%)
Folicacid 339 333(93.3%) 222(98.7%) 111(97.4%) 0.392a
VitaminBcomplex 339 332(93.0%) 221(98.2%) 111(97.4%) 0.601a
VitaminC 339 327(91.6%) 219(97.3%) 108(94.7%) 0.222a
Erythropoietin 321 303(84.9%) 201(94.4%) 102(94.4%) 0.977a
Intravenousironhydroxide 318 160(44.8%) 89(42.4%) 71(65.7%) <0.001a
Laboratoryexams,mean(standarddeviation)
Pre-hemodialysissessionurea(mg/dL) 353 140.5(42.3) 143.2(42.9) 135.5(40.8) 0.104b
Creatinine(mg/dL) 352 6.2(2.1) 5.9(2.1) 6.6(2.1) 0.002b
Hematocrit(%) 356 28.3(5.7) 25.1(4.0) 34.3(3.0) <0.001b
Powerofhydrogen(pH)(AV) 119 7.4(0.6) 7.4(0.1) 7.4(0.1) 0.177b
Bicarbonate(mmol/L) 120 20.2(3.8) 19.8(3.4) 20.7(4.1) 0.197b
Ferritin(ng/L) 351 709.3(460.0) 754.0(479.1) 625.1(413.1) 0.012b
Transferrinsaturationindex(TSI)(%) 357 35.5(19.4) 36.0(20.2) 34.5(17.9) 0.474b
Iron(uG/dL) 340 75.7(93.5) 74.7(95.9) 78.0(89.8) 0.754b
Parathormone(PTH)(pg/mL) 347 520.3(495.1) 526.2(519.4) 513.2(450.7) 0.815b
Albumin(g/dL) 343 3.9(0.5) 3.8(0.6) 4.1(0.2) <0.001b
Aluminum(ug/dL) 167 24.1(28.6) 28.0(30.8) 16.0(21.6) 0.011b
EquilibratedKt/V(eKt/V)(AV) 294 1.9(0.4) 2.0(0.4) 1.8(0.4) 0.004b
Valuesinboldshowstatisticallysignificantassociations(p<0.05). AV,absolutevalue.
aPearson’schi-squaredtest. b Student’st-test.
Table2 Clinicalfactorspredictiveofanemiainchildrenandadolescentsonhemodialysis.
Independentvariables Oddsratio 95%Confidenceinterval pvalue
Minimum Maximum
Needforhospitalization 1.00 0.52 1.93 0.988
Antibioticuse 1.97 0.89 4.35 0.095
Double-lumencatheterinfection 4.13 0.49 34.60 0.191
Useofintravenousironhydroxide 0.36 0.25 0.89 <0.001
demonstrated that the use of intravenous iron hydroxide wasaprotectivefactorforanemia(Table2):theoddsthe children on hemodialysisto have anemia when using this medicationwas0.36 timesthe oddsofthosewhodidnot useit.Calculatingtheinverseof0.36,itisobservedthatthe chanceofchildrenwhodidnotuseintravenousiron hydrox-idetohaveanemiawas2.78timesthechanceofthosewho usedit. The other variables didnot showsuch significant predictorsintheGEE.
Discussion
This article emphasizes the high prevalence of ane-mia in children undergoing hemodialysis, in spite of the
administrationof recombinanthuman erythropoietin, and reaffirms the importance of intravenous iron supplemen-tationinthispopulation.
It is worth mentioning the use of medications for the treatment of CKD-associatedanemia:94.4% used erythro-poietin; 50.5% used intravenous iron hydroxide in the present study. In the Brazilian dialysis census of 2011, prescriptionsof thesemedicationswere 80.0%and 53.1%, respectively.14
The target-hemoglobin valuesfor children and adoles-cents with CKD in the literature are divergent and have been revised over the past years.12,15,16 It is known that,
in children and adolescents, age and gender should be taken into account in order to define target hemoglobin (Hgb) values.17 The recommendation of the last NICE
criteria8 to define Hgb in patients asadequate or
inade-quate wasadopted; therefore, the present study showed thatHgb valuesbelowthe expected(anemia)werefound in most monthly records of patients (65.3%), albeit still above those found in the last Brazilian dialysis census (39.3%).14
The authors believe that this difference is due to the study methodology, in which the same patient with ane-miawasreviewedduringsuccessivemonths,overestimating thefrequencyofanemia.Inother studies,thehemoglobin valueisusuallyconsideredinasingleannualmeasurement (onlyonemonthoftheyear);theauthorsbelievethatthis, conversely,mayunderestimatethe prevalenceof anemia. The mean Hgb observed was 9.2 (SD 1.8) g/dL. Compar-atively, Americandatashow a meanHgb of 11.5(SD 1.6) g/dL,with68%ofpatientsshowingthetargetHgbvalues.2
DatafromtheUnited Kingdomshowedthat mostchildren onrenalreplacementtherapy areanemic(47%ofchildren onhemodialysis).18APolishstudyevidencedameanHgbof
10.91(SD1.2)g/dL.19
ItisknownthatserumHgbvariesoverthemonths,and withdrawal of erythropoietinin the last 60 daysand hos-pitalization are related to Hgb<11g/dL. The longer the hospital length of stay, the greater the chance of more significant decreasesinHgb values.20 A14.6%rateof
hos-pitalizationwasobserved inthepresent study,which may alsohave contributedtotheanemiain thepresent popu-lation.Appropriatevaluesofserumalbuminarerelatedto adequateHgbvalues.21 Adequatemeanserumalbumin
lev-elswereobservedinthepresentstudy,inagreementwith otherauthors.15,19
Good markers of ferritin and transferrin saturation index(TSI) wereidentified,asthe ironstores are replen-ished intravenously,asrecommended inthe literaturefor over a decade for hemodialysis patients receiving human erythropoietin.22,23
In91.6%ofthefiles,patientswerereceivingvitaminC, which is importantfor releaseof ironstored in thebody, ensuringitsavailabilityforerythropoiesis.24,25
WhentheGEEwasperformed,intravenousironhydroxide receivedduringthatmonthshowedtobeprotectiveagainst anemia.The variable‘‘transfused’’wasremovedfromthe GEEanalysis,asitultimatelyreflectstheeventthroughout themonth. Abloodsample wascollectedforthe monthly testsonthefirstThursdayofeachmonth.Thosewhometthe criteriafor receivingpackedredbloodcells(includingthe lowHgvalues)receivedthebloodproductinsubsequent ses-sions.Thus,theanswer‘‘yes’’tothevariable‘‘transfused’’ meantthat,duringthatmonth,hemoglobinlevelswerevery lowandthepatientrequiredbloodtransfusion.Therefore,
thetransfusionevent couldbeerroneously indicated asa riskfactorforanemiaintheGEE.
The main limitation of thisstudy was itsretrospective design,withanalysisofdatafoundinmedicalrecords.The lackofcontrolindatacollectionandinformationloss consti-tutebiasesofretrospectivestudies.Thesewereobservedin thepresentstudy,compromisingthesampleanddecreasing thepowerofdatarepresentation.Thelongitudinalrepeated measuresweretreatedbyGEE.
Inconclusion,thestudypopulationconsistedofchildren andadolescentswithend-stagerenaldiseaseon hemodial-ysis.Anemiawasprevalentandtheuseofintravenousiron hydroxidewasaprotectivefactor.
Conflicts
of
interest
Theauthorsdeclaretohavenoconflictsofinterest.
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