Evaluation of carotid intima-media thickness and factors associated with cardiovascular disease in

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ORIGINAL ARTICLE

Evaluation of carotid intima-media thickness and factors associated with cardiovascular disease in

children and adolescents with chronic kidney disease ^夽

Renata Lopes

^a^,∗

, Mauro Batista de Morais

^b

, Fernanda Luisa Ceragioli Oliveira

^c

, Ana Paula Brecheret

^a

, Ana Lucia Cardoso Santos Abreu

^a

, Maria Cristina de Andrade

^d

aUniversidadeFederaldeSãoPaulo(Unifesp),EscolaPaulistadeMedicina(EPM),SãoPaulo,SP,Brazil

bUniversidadeFederaldeSãoPaulo(Unifesp),EscolaPaulistadeMedicina(EPM),DepartamentodePediatria,Disciplinade GastroenterologiaPediátrica,SãoPaulo,SP,Brazil

cUniversidadeFederaldeSãoPaulo(Unifesp),EscolaPaulistadeMedicina(EPM),ProgramadePós-Graduac¸ãoemNutric¸ão, SãoPaulo,SP,Brazil

dUniversidadeFederaldeSãoPaulo(Unifesp),EscolaPaulistadeMedicina(EPM),DepartamentodePediatria,Setorde NefrologiaPediátrica,SãoPaulo,SP,Brazil

Received28February2018;accepted6June2018 Availableonline1August2018

KEYWORDS Chronickidney disease;

Cardiovascular diseases;

Carotidintima-media thickness;

Adolescents;

Children

Abstract

Objective: Toassessthecarotidintima-mediathicknessandfactorsassociatedwithcardiovas- culardiseaseinchildrenandadolescentswithchronickidneydisease.

Materialandmethods: Observational, cross-sectional study carried outat the Universidade FederaldeSãoPaulo(chronickidneydiseaseoutpatientclinics)with55patients(60%males) witha medianageof11.9years(I25---I75:9.2---14.8 years). Ofthe 55patients, 43 wereon conservativetreatmentand12wereondialysis.Serumlaboratoryparameters(creatinine,uric acid, C-reactiveprotein, total cholesterol andfractions, andtriglycerides), nutritionalstatus(z-scoreofbodymassindex,z-scoreofheight/age),bodyfat(fatpercentageandwaist circumference),andbloodpressurelevelswereevaluated.Thecarotidintima-mediathickness measurewasevaluatedbyasingleultrasonographerandcomparedwithpercentilesestablished accordingtogenderandheight.DatacollectionwasperformedbetweenMay2015andMarch 2016.

夽 Pleasecitethisarticleas:LopesR,MoraisMB,OliveiraFL,BrecheretAP,AbreuAL,AndradeMC.Evaluationofcarotidintima-media thicknessandfactorsassociatedwithcardiovasculardiseaseinchildrenandadolescentswithchronickidneydisease.JPediatr(RioJ).

2019;95:696---704.

∗Correspondingauthor.

E-mail:[email protected](R.Lopes).

https://doi.org/10.1016/j.jped.2018.06.010

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Results: Ofthechildrenandadolescentswithchronickidneydisease,74.5%(95%CI:61.0;85.3) showedanincrease(>P95)incarotidintima-mediathickness.InpatientswithstagesIandII hypertension, 90.9% had increasedcarotid intima-media thickness. Nutritional status,body fat andlaboratorytests werenotassociatedwithincreasedcarotidintima-mediathickness.

Aftermultivariateadjustment,onlypuberty(PR=1.30, p=0.037)andstagesIandIIarterial hypertension(PR=1.42,p=0.011)were independentlyassociated withcarotidintima-media thicknessalterations.

Conclusion: Theprevalenceofincreasedcarotidthicknesswashighinchildrenandadolescents withchronickidneydisease.Pubertyandarterialhypertensionwereindependentlyassociated withincreasedcarotidintima-mediathickness.

4.0/).

PALAVRAS-CHAVE Insuﬁciênciarenal crônica;

Doenc¸as

cardiovasculares;

Espessura intima-média carotídea;

Adolescentes;

Crianc¸as

Avaliaçãodaespessuramédio-intimaldacarótidaefatoresassociadosàdoença cardiovascularemcriançaseadolescentescomdoençarenalcrônica

Resumo

Objetivo: Avaliaraespessuramédio-intimaldacarótidaeosfatoresassociadosàdoençacar- diovascularemcriançaseadolescentescomdoençarenalcrônica.

Materialemétodos: Estudo observacional transversal feito na Universidade Federal de São Paulo(ambulatóriosdedoençarenalcrônica)com55pacientes(60%dosexomasculino)com medianade11,9anos(I25-I75:9,2---14,8).Dos55pacientes,43estavamemtratamentoconser- vadore12emterapiadialítica.Foramavaliadososparâmetroslaboratoriaisséricos(creatinina, ácido úrico,proteínaC-reativa,colesteroltotalefraçõesetriglicérides),estadonutricional (escorezde índicedemassa corpórea,escorez deestatura/idade),gorduracorporal(per- centual de gordurae circunferência abdominal)e pressão arterial. A medida daespessura médio-intimaldacarótidafoiavaliadaporumúnicoultrassonografistaecomparadacomper- centisestabelecidosdeacordocomosexoeaestatura.Acoletadedadosfoifeitaentremaio de2015emarçode2016.

Resultados: Dascriançaseadolescentescomdoençarenalcrônica,74,5%(IC95%:61,0;85,3) apresentaram aumento (> P95)da espessuramédio-intimalda carótida.Nos pacientescom hipertensãoarterialestágiosIeII,90,9%apresentaramaumentodaespessuramédio-intimalda carótida.Oestadonutricional,agorduracorporaleosexameslaboratoriaisnãoapresentaram associaçãocomoaumentodaespessuramédio-intimaldacarótida.Apósajustemultivariado, apenas a puberdade(RP=1,30; p=0,037)e ahipertensãoarterial estágiosIeII (RP=1,42;

p=0,011)mostraram-seindependentementeassociadosàalterac¸ãodaespessuramédio-intimal dacarótida.

Conclusão: A prevalência do aumento da espessura dacarótida foi elevada em crianc¸as e adolescentescomdoenc¸arenal crônica.Apuberdadeeahipertensãoarterialmostraram-se independentementeassociadasaoaumentodaespessuramédio-intimaldacarótida.

0/).

Introduction

Cardiovascularcomplicationsaretheleadingcauseofdeath inpatientswithchronickidneydisease(CKD).Riskfactors attributed to cardiovascular disease (CVD) are important notonly toidentifypotentialalterationsbut alsotoeval- uate the effect of treatments, aiming to reduce the risk ofdeath.¹ThepresenceoftraditionalriskfactorsforCVD such as hypertension, hyperlipidemia, diabetes, physical inactivity,smoking, andadvancedage isoften aggravated byseveralnontraditionalriskfactorsrelatedtopoorrenal function such as anemia, volume overload, altered lipid metabolism(dyslipidemia),calcium-phosphorusmetabolism

abnormalities (hyperparathyroidism), hyperhomocysteine- mia,microalbuminuria,hyperuricemia,andchronicinﬂam- mation.Allthosefactorsincreasetheriskofdeathdueto CVDinpatientswithCKD.^2,3ChildrenwithCKDconstitutea populationthatislessexposedtotraditionalcardiovascular riskfactors whencomparedtoadult patients,thus allow- inga sensitive evaluation of metabolic and hemodynamic abnormalitiesinthepathophysiologyofarteriopathicrenal disease.⁴

Somestudieshaveassessedthefrequencyoftraditional riskfactorsforthedevelopmentofCVDinchildrenwithCKD.

Silversteinetal.³evaluated45transplantedchildren,allin stages2---4 of CKDat the timeofthe study.They veriﬁed

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thattwo-thirdsofthepatientshadatleasttworiskfactors forCVD,whileone-thirdofthemhadatleastthreefactors.

Noninvasive vascular alteration and circulatory biomarker measurement methods are important for assessingthepresenceandseverityofcardiovasculardam- ageandhave been commonlyusedtostudy theevolution of CVD. Measurement of carotid intima-media thickness (CIMT)hasbecomeanadditionaltoolforearlydetectionof arterialinjury anditsalterationhas beenassociated with anincreasedriskofcoronaryeventsandmortalityinadult patientsondialysis.Inpediatrics,thisalterationhasbeen reportedinboth patients ondialysisand instages 2---4 of CKD.¹Mitsnefesetal.⁵observed thecarotidintima-media thickness of 31 children and adolescents after kidney transplantationandfoundearlyatherosclerosis,inaddition toanassociationbetweentheincreaseinCIMTandarterial hypertension. In a study carried out by Oh et al.⁶ with 39 adolescents on dialysis and post-renal transplant, the carotidthicknessmeasurementwasfoundtobesigniﬁcantly higherwhencomparedtothecontrolgroup.

The increasing number of studies onthe evaluation of CIMT in children and adolescents withCKD indicates this methodshouldbeintroducedasaroutinetoolintheeval- uation and monitoring of these patients. Thus, current evidenceindicatesthattheroutineassessmentofcardiovas- cularriskisimportantfortheearlydetectionandtreatment ofvascularalterations.Thepresentstudyaimedtoevaluate thecarotid intima-mediathicknessand factorsassociated withcardiovasculardiseaseinchildrenandadolescentswith CKD.

Methods

This cross-sectional, observational study included 55 patients with CKD in the dialysis and non-dialysis phases followed at the pediatric nephrology outpatient clinic of UniversidadeFederaldeSãoPaulo(UNIFESP).Theexclusion criteriaforthestudywere:age<6and≥18yearsandpre- viousdiagnosisofcardiovascular,neoplastic,infectious,or inﬂammatorydiseasesaswellassystemiclupuserythemato- sus.DatacollectionwasperformedbetweenMay2015and March2016.

ThestudywasapprovedbytheResearchEthicsCommit- teeofUNIFESPandthefreeandinformedconsentformas well as the term of assent were obtained from all study participantsandtheirparentsorguardians.

Pubertalstaging

Pubertalstagingwasevaluatedbythepediatriciansofthe service team using as criterion the development of sec- ondary sexual characteristics as proposed by Marshall &

Tanner.⁷

Bloodpressure

A digital device (Dixtal^®, SP, Brazil) was used for blood pressure measurement after the patient had rested for 3---5min,withacuffsuitableforarmcircumference(width andlength)usedatthemidpointbetweentheolecranonand

acromion. Bloodpressure wasconﬁrmed by the ausculta- torymethodandclassiﬁedaccordingtotheClinicalPractice GuidelineforScreeningandControlofHighBloodPressure inChildrenandAdolescents.⁸

Nutritionalstatusandbodycomposition

Patientswere weighedin theirunderwear, without shoes, onanelectronicscale(Filizola^®,SP,Brazil),andheightwas measuredusingastadiometerfixedtothewall.Weightand heightmeasureswereusedtocalculatethez-scoreofbody massindex(z-BMI)andz-scoreof height/age(z-H/A),fol- lowingthereferencestandardsandrecommendationsofthe WorldHealthOrganization (WHO,2007).⁹Bodymassindex (BMI)wascalculatedastheweightdividedbysquaredheight (kg/m²).Theabdominalcircumferencewasmeasuredusing aflexible,inextensibletape,withanaccuracyof0.1cmand classifiedaccordingtoFreedman.¹⁰Thebodyfatpercentage inboysandgirlswasestimated usingthetricipital, bicipital, subscapular,andsuprailiacskinfolds, accordingtothe Bray’sequation,¹¹andclassifiedaccordingtothepercentile tableproposedbyMcCarthy.¹² ALange^® adipometerwitha precisionof1mm(BetaTechnologyInc.,CA,USA)wasused tomeasuretheskinfolds.

% of Fat=8.71+0.19×SSF (subscapular skinfolds)+0.76×BSF (bicipital skinfolds)+0.18×SupraSF (suprailiacskinfolds)+0.33×TSF(tricipitalskinfolds).

Laboratorytests

The followinglaboratory parameterswereanalyzed inthe serum after a 12-hour fast in a Cobas^® C 501 equip- ment (RocheDiagnostics^®, IN,USA): creatinine,uric acid, C-reactiveprotein(CRP),totalcholesterol(TC),HDLcholes- terol (HDL-c), and triglycerides(TG). The LDL-cholesterol fraction was obtained using the equation of Friedewald etal.¹³LDL-c=(TC-HDL-c+TG/5).

TheIGuidelinefor AtherosclerosisPrevention inChild- hoodandAdolescencewasusedtoidentifydyslipidemias.¹⁴ Chronickidneydiseaseclassiﬁcation

Chronickidneydiseasewasclassifiedinfivestages,accord- ing to the classification proposed by the National Kidney Foundation(NKFKDOQI).¹⁵

The glomerular ﬁltration rate was estimated by the Schwartzequation¹⁶:

0.413×height (cm) serumcreatinine (mg/dL)

Ultrasonographyofthecarotidarteryintima-media complex

Measurement of the media-intima complex thicknesswas performedbyasinglesonographer,blindedtothepatient’s identity and to the study group, using an ultrasound devicewithalineartransducer of7MHzoffrequency and 0.1mmresolution(GeneralElectric^®,WI,USA).Thepatients

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remainedonastretcherinthesupineposition,withthehead turnedslightlytothecontralateralside,andhada10-min restbeforetheexaminationbegan.Themeasurementwas performedontheposteriorwalloftheleftcarotidarteryin thelongitudinalaxis,includingthefirstechogeniclineand the hypoechogenicline in the distal thirdof the common carotidartery,asitisamorereproduciblemeasure,dueto thefactthatitdoesnotsufferinterferencecausedbyultra- soundartifactsatthesite.Fortheclassificationofcarotid thickness,thetableofpercentilesproposedbyDoyon¹⁷was usedaccordingtogenderandheight.Carotidintima-media thicknessvalues>95thpercentilewereclassifiedasaltered.

Statisticalanalysis

Initially, the prevalence of children and adolescents with CIMTalterationamongthosewithCKDwasestimatedwith the respective 95% conﬁdence interval (95% CI). Qualita- tive variables were described as number and percentage (%),whereasthe quantitativevariablesweredescribed as median and interquartilerange (I25;I75). Aimingto esti- matetheassociationof CIMTalterationswithrisk factors, the prevalenceratio (PR) andits95% CIwere calculated, with CIMT alteration as the dependent variable and the severalexposurefactorsastheindependentvariables.The variablesselectedintheunivariateanalysisthatshoweda p-value<0.20wereselectedtoconstitutethemultivariate model.Wechosetocalculatetheprevalenceratioinstead of calculating the odds ratio, since the evaluated event (CIMTalteration)wasfrequent,i.e.withprevalence≥20%.

Theprevalence ratiosandtheirrespective95%conﬁdence intervalswereestimatedusingthegeneralizedlinearmodel (GLM) withbinomial distributionandloglinkfunction. All testsweretwo-sided,andap-value<5%(p<0.05)wascon- sideredstatisticallysigniﬁcant.Allanalyseswereperformed usingtheSTATAsoftware,version14.2forWindows(STATA, CollegeStation,TX,USA).

Results

Themedianagewas11.9years(I25---I75:9.2---14.8years).Of the55patients(60%males),43receivedconservativetreat- mentand 12wereondialysistherapy.Anincrease (above the 95thpercentile) in CIMT was found in 74.5% (95% CI:

61.0;85.3)ofthechildrenandadolescentswithCKD.The main clinical and demographic characteristics are shown in Table 1. As shown in Fig. 1, among the patients with stage I and II arterial hypertension, 90.9% had increased CIMT.Nutritional status andbody fat werenot associated withincreasedCIMT(Table1).Regardinglaboratory tests, C-reactiveproteinanduricacidwereelevatedin54.5%and 45.5%ofpatientswithCKD,respectively.Therewasnoasso- ciation of increasedC-reactive proteinand uricacid with increasedCIMT(Table1).

Table2showsthevariableschosentoconstitutethemul- tivariatemodel,thatis,theonesthatshowedresultswith ap-value<0.2.

Afterthemultivariateadjustment,asshowninTable3, only puberty(PR=1.30,95% CI:1.01; 0.66;p=0.037) and arterialhypertensionstagesIandII(PR=1.42,95%CI:1.08;

1.85; p=0.011) wereindependently associated withCIMT alteration.

Discussion

Thepresent studywithchildrenand adolescentsin stages 2---5of CKD showedthat the presenceof certain risk fac- torsforcardiovasculardiseasesuchasarterialhypertension (40%),increase in LDLcholesterol (51.9%),pubertal stage (58.2%),andinﬂammation (54.5%) is frequentlyobserved.

Increasedthicknessofthemedia-intimalayerwasevidenced in 90.9% of patients with arterial hypertension. It should benotedthatarterialhypertension andpubertywerethe variablesindependently associated withincreasedcarotid thicknessinpediatricpatientswithCKD.

Nutritionalstatusandbodycomposition

The importance of anthropometric markers is evidenced bytheirassociationwithmortalityandwidelydescribedin pediatricpatientswithCKD.

BMIisgenerallyusedasanindicatorofadiposityinchil- drenandadolescents.TheincreaseinBMIinchildhoodisa strongpredictorofprematuredeathduetoCVDinmiddle andlateadulthood.However,obesity-relatedcomorbidities aremoreassociatedwiththepatternofbodyfatdistribu- tionthanwithtotalfatmass.¹⁸Abdominalcircumferenceis amoresensitiveindicatorthanBMIforCVDriskassessment andisassociatedwithatherogenicityinchildrenandadoles- centswithoutCKD.¹⁹AlthoughthereisahigherriskofCVD inthesepatients,theresultsofthisstudyshowednoassoci- ationbetweenabdominaladiposityandbodyfatpercentage withcarotidalterationinthemultivariateanalysis.

Inourstudy,67.3%ofthepatientshadadequateheight for age.Contrary toour ﬁndings,Ku etal.²⁰ showedthat childrenandadolescentsondialysisorafterrenaltransplant withshortstaturehadanincreasedriskofmortality,mainly duetocardiacandinfectiouscauses.

AstudycarriedoutintheUnitedStatesbyWongetal.²¹ showedthat the mortalityrisk increased by 14% for each unitreductioninheightz-scores,regardlessofthetypeof treatment(dialysisortransplant).

The excess fat variables (anthropometricindex --- BMI, and body composition --- fat mass and central adiposity) andshortstature were notpart of the multivariate analysis. In this study, patients received dietary intervention witha nutritionist, which reﬂects on nutrition education andmonitoring,resultinginbetterqualityofeatingamong theassessedpopulation. Arecentstudy observedchanges innutritionalstatusandbodycompositioninadultpatients withCKDfollowedfor6monthsafternutritionalguidance.²²

Laboratorytests

Lipid alterations have been established as a risk factor for the development of atherosclerosis. The association betweendyslipidemiaand increasedcarotid intima-media thickness has been evidenced in studies with children.

Bradyetal. evaluatedpediatric patients instages 2---4 of CKD anddemonstrated this association.²³ In the study by

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Table1 Demographic,clinical,anthropometric,andlaboratorycharacteristicsofpediatricpatientswithchronickidneydis- ease,accordingtothepresenceofcarotidintimal-mediathicknessalteration.

Alteredcarotid/height(n=41)

Total N % PR 95%CI p

Demographiccharacteristics

Gender 0.803

Female 22 16 72.7 1.00

Male 33 25 75.8 1.04 0.76---1.43

Age(years) 0.615

Median(I25;I75) 11.9(9.2;14.8) 11.1(9.2;14.7) 0.99 0.94---1.03

Agerange 0.400

<12years 29 23 79.3 1.00

≥12years 26 18 69.2 0.87 0.64---1.20

Pubertalstage 0.063

Prepubertal 32 21 65.6 1.00

Pubertal 23 20 87.0 1.32 0.98---1.78

Clinicalcharacteristics EtiologyofCKD

Urinarytractmalformation 30 25 83.3 1.00

Glomerulopathy 7 6 85.7 1.03 0.73---1.45 0.872

Others 18 10 55.6 0.67 0.43---1.04 0.073

TimeofCKD(years) 0.520

Median(I25;I75) 5.5(2.1;9.0) 5.0(2.0;9.0) 0.99 0.95---1.03

DurationofCKD >0.999

<1year 5 4 80.0 1.00

1---2years 6 5 83.3 1.04 0.59---1.83 0.888

2---5years 15 11 73.3 0.92 0.54---1.56 0.749

≥5years 29 21 72.4 0.90 0.55---1.48 0.692

Treatment 0.738

Conservative 43 32 74.4 1.00

Peritonealdialysis 5 3 60.0 0.81 0.38---1.68

Hemodialysis 7 6 85.7 1.15 0.81---1.63

CKDstage 0.341

Stage2 10 5 50.0 1.00

Stage3A 7 5 71.4 1.43 0.66---3.11

Stage3B 12 9 75.0 1.50 0.74---3.02

Stage4 10 9 90.0 1.80 0.94---3.46

Stage5 16 13 81.2 1.62 0.84---3.15

Clinicalcharacteristics

Bloodpressureclassiﬁcation^a 0.124

Normal 28 18 64.3 1.00

Elevated 5 3 60.0 0.93 0.43;2.01 0.860

StageIarterialhypertension 17 15 88.2 1.37 0.99;1.90 0.057

StageIIarterialhypertension 5 5 100.0 ---

Bloodpressureclassiﬁcation^a 0.016

Normalorelevated 33 21 63.6 1.00

StageIorIIhypertension 22 20 90.9 1.43 1.07;1.91

Anthropometricindexes BMI^b/Agez

Median(I25;I75) −0.6(−1.5;+0.5) −1.0(−1.5;−0.1)

Nutritionalstatus^c 0.003

Thinness 7 5 71.4 0.82 0.51;1.34 0.440

Normalweight 37 32 86.5 1.00

Excessweight 11 4 36.4 0.42 0.93;1.19 0.032

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Table1(Continued)

Alteredcarotid/height(n=41)

Total N % PR 95%CI p

Height/agez 0.290

Median(I25;I75) −1.0(−2.6;−0.0) −1.2(−2.6;−0.2) 0.96 0.89---1.03

Adequate 35 26 74.3 1.00

Shortstature(<−2) 20 15 75.0 1.01 0.73---1.39

Adiposity

Abdominalcircumference(cm)^d

Median(I25;I75) 60.2(56.0;69.2) 59.0(56.0;67.0) ---

Adequate(<P90) 53 41 77.4 ---

Elevated(≥P90) 2 0 0.0 ---

Bodyfat(%) 0.044

Median(I25;I75) 18.9(17.4;24.1) 18.3(17.3;20.2) 0.97 0.94---1.00 Bodyfat^e

Lowdepositoffat 1 1 100.0 ---

Adequate 42 35 83.3 1.00

Excess 4 2 50.0 0.60 0.22;1.61 0.312

Obesity 8 3 37.5 0.45 0.18;1.11 0.084

Laboratorytests

Uricacid(mg/dL) 0.178

Median(I25;I75) 5.5(5.0;6.6) 5.2(4.9;6.3) 0.91 0.80;1.04

Uricacid 0.122

≤5.7 30 25 83.3 1.00

>5.7 25 16 64.0 0.77 0.55;1.07

CRP(mg/L) <0.001

Median(I25;I75) 1.1(0.6;2.2) 1.0(0.6;2.7) 1.01 1.00;1.01

CRP 0.392

≤1 25 20 80.0 1.00

>1 30 21 70.0 0.87 0.64;1.19

Totalcholesterol(mg/dL)

Median(I25;I75) 175.0(150.0;201.0) 177.0(151.0;208.0) ---

Totalcholesterol^f 0.442

Desirable 12 9 75.0 1.00

Borderline 13 8 61.5 0.82 0.48;1.41 0.473

Increased 30 24 80.0 1.07 0.73;1.55 0.734

LDL(mg/dL)^f

Median(I25;I75) 102.0(85.0;126.0) 108.5(86.5;131.5) ---

LDL(mg/dL)^a 0.394

Desirable 26 18 69.2 1.00

Borderline 17 12 70.6 1.02 0.68;1.52 0.924

Increased 11 10 90.9 1.31 0.96;1.80 0.092

HDL(mg/dL) 0.698

Median(I25;I75) 47.0(39.0;54.0) 47.0(39.0;54.0) 1.00 0.98;1.01

HDL(mg/dL)^f 0.826

≥45mg/dL 34 25 73.5 1.00

<45mg/dL 21 16 76.2 1.04 0.76;1.42

Triglycerides(mg/dL)

Median(I25;I75) 108.0(73.0;142.0) 108.0(76.0;138.0) ---

Triglycerides^f 0.234

Desirable 23 17 73.9 1.00

Borderline 13 12 92.3 1.25 0.93;1.67 0.132

Increased 19 12 63.2 0.85 0.56;1.30 0.464

Interquartile(I25---I75);PR,prevalenceratio;95%CI,95%conﬁdenceinterval.

a Flynnetal.,2017.⁸

b Bodymassindex(BMI).

c WHO,2006.⁹

d Freedmanetal.,1999.¹⁰

e McCarthyetal.,2006.¹²

f Giulianoetal.,2005.¹⁴

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0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Normal or elevated Stage I or Stage II 63.6%

90.9%

Normal Carotid/Height Altered Carotid/Height

p = 0.023

Figure1 Bloodpressureandcarotidintima-mediathicknessalterationinpediatricpatientswithchronickidneydisease.

Table2 Univariateanalysis offactorsassociated with increasedcarotidintima-media thicknessinpediatric patients with chronickidneydisease.

Univariate

bPR(95%CI) p

Pubertalstage---Pubertal×Prepubertal 1.32(0.98;1.78) 0.063

CKDetiology

Glomerulopathy×Malformation 1.03(0.73;1.45) 0.872

Others×Malformation 0.67(0.43;1.04) 0.073

CKDstage

Stage3Aor3B×Stage2 1.47(0.75;2.89) 0.261

Stage4×Stage2 1.80(0.94;3.46) 0.078

Stage5×Stage2 1.62(0.84;3.15) 0.151

%BodyFat 0.97(0.94;1.00) 0.044

BloodpressureStageIorIIHypertension×NormalorElevated 1.43(1.07;1.91) 0.016

CRP 1.01(1.00;1.01) <0.001

LDL

Borderline×Desirable 1.02(0.68;1.52) 0.924

Increased×Desirable 1.31(0.96;1.80) 0.092

bPR,crudeprevalenceratio(univariatemodel).

Table3 Multivariateanalysisoffactorsassociatedwithincreasedmeancarotidintima-mediathicknessinpediatricpatients withchronickidneydisease.

Multivariate

adjPR(95%CI) p

Pubertalstage---Pubertal×Prepubertal 1.30(1.01;0.66) 0.037

BloodpressureStageIorIIHypertension×NormalorElevated 1.42(1.08;1.85) 0.011 adjPR,adjustedprevalenceratio(multivariatemodel).

Khandelwal et al.,²⁴ the association of increased carotid media-intimathickness,triglycerides,totalcholesterol,and LDLcholesterolwasfoundinchildrenatdifferentstagesof CKD.

Inthisstudy,LDLcholesterolshowedanassociationwith alteredcarotidthicknessintheunivariateanalysis,butthe multivariateanalysisdidnotconﬁrmthisassociation.

Inflammation is one of the events responsible for CVD in CKD, and high levels of inflammatory markers are identified in children undergoing dialysis.²⁵ Our findings demonstratedthat althoughhigh levelsof CRPshowedan associationwithalteredcarotidthicknessintheunivariate analysis, no association was observed in the multivariate analysis.

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Hyperuricemiahasbeen widelystudiedinpatientswith CKD,asitisamodifiablecardiovascularriskfactorandplays a significantrole inendothelial dysfunction,inflammation and atherosclerosis.¹⁸ In our study,45.5% of the patients hadhyperuricemia,andthismarkerwasnotassociatedwith alteredcarotidthickness.

Arterialhypertensionandpuberty

Systemicarterialhypertension(SAH)isoneofthemostcriti- caldeterminantsofrenaldiseaseprogressioninchildrenand a major risk factor for cardiovascular complications. The literature ﬁndingsshow a correlation between high blood pressure and signs of arterio/atherosclerosis in children, beingoneofthemostimportantmodiﬁablefactorsamong theriskfactorsforCVD.²⁶

Our study showed that of the 40% of stages I and II hypertensive patients 90.4% had an increase in carotid thickness, whereas in the group withnormal or elevated blood pressuremore than50% (63.6%)of patients already had an increase in the carotid intima-media thickness.

When comparingthetwogroups, astatisticallysignificant differencewasobserved in the proportionsof the media- intimalayeralteration(p=0.023).Arterialhypertensionis a frequent findingin patients with CKD andseveral studies have demonstrated this risk factor for cardiovascular complications.Inthe studybyFlynn etal.²⁷ including586 children with CKD, it was observed that arterial hypertension was present in 54% of the patients. Despite the useof antihypertensivemedication,48% ofthesechildren showedinadequateblood pressurecontrol. AnotherNorth Americanstudy withpediatric transplantpatients showed that 48% of uncontrolled arterial hypertension at CKD onsetincreasedto50---75%inthefinal stageofCKD.After transplantation, the reported prevalence of hypertension was50---87%.²⁸

CarotidarteryalterationswerealsoconﬁrmedbyBrady et al.,²³ who assessed risk factors for CVD and found thatarterialhypertensionwassigniﬁcantlyassociatedwith increasedcarotidthicknessinchildrenaged2---18yearswith CKD.Poyrazogluetal.²⁹ assessedthecarotidmedia-intima thicknessof34childrenwithCKDandfoundanincreasein CIMTinthispopulation,aswellasanassociationbetween increasedCIMTandarterialhypertension.

As for pubertal staging, pubertal patients (G2/M2---G5/M5) showed a greater association with increasedcarotid thickness(PR=1.30; 95% CI:1.01; 0.66;

p=0.037).In astudy withhealthychildren carriedoutby Baroncini et al.³⁰ it was observed that carotid thickness alterations were associated with increased age, as seen inadults.Theseﬁndings couldberelatedtothefact that at puberty, hormonal changes may induce an increase in the percentage of total body fat and alterations in lipoproteins,especiallyLDL-c increase.³⁰ Anotherpossible explanation would be that CIMT increases in response to the physiological vessel reaction in ordertoadapt to the blood pressureincrease thatoccurswithadvancingage.¹⁷ Moreover,inastudywith24childrenwithCKDcarriedout byBilgineretal.,²⁸ anassociation wasfoundbetween the timeofCKDandtheincreaseinCIMT.

Amongthelimitationsofthisstudy,alargersamplesize couldprovidegreaterpowerandlowerconﬁdenceintervals.

Anotherlimitationisthefactthat,ifthestudyhadacon- trolgroup,theoccurrenceofCVDriskfactors non-speciﬁc to CKD could be compared in the group of studied patients.

We conclude that puberty and arterial hypertension are important determinants in CIMT increase. Moreover, the assessed risk factors play an important role in CVD- associated morbidity and mortality in children with CKD.

The implications ofthese ﬁndings requireinvestigation in furtherstudies.However,early androutineassessment of these factors, together with appropriate intervention, is crucialtopreventCVD progressionandmortality inthese patients.

Conﬂicts of interest

Theauthorsdeclarenoconﬂictsofinterest.

References

1.ShroffR,DégiA,KertiA,KisE,CseprekálO,ToryK,etal.Cardio- vascularriskassessmentinchildrenwithchronickidneydisease.

PediatrNephrol.2013;28:875---84.

2.Dégi A,KertiA, KisE,CseprekálO, Tory K,SzabóAJ,et al.

Cardiovascular risk assessment in children following kidney transplantation.PediatrTransplant.2012;16:564---76.

3.Silverstein DM, MitchellM, LeBlanc P,Boudreaux JP. Assess- mentofriskfactorsforcardiovasculardiseaseinpediatricrenal transplantpatients.PediatrTransplant.2007;11:721---9.

4.Litwin M, Wühl E,Jourdan C, NiemirskaA, Schenk JP, Jobs K, et al. Evolutionof large-vessel arteriopathyin paediatric patientswithchronickidneydisease.NephrolDialTransplant.

2008;23:2552---7.

5.Mitsnefes MM,Kimball TR,Witt SA,Glascock BJ,KhouryPR, DanielsSR.Abnormalcarotidarterystructureandfunctionin childrenandadolescentswithsuccessfulrenaltransplantation.

Circulation.2004;110:97---101.

6.Oh J, Wunsch R, Turzer M, Bahner M, Raggi P, Querfeld U, et al. Advanced coronary and carotid arteriopathy in young adultswithchildhood-onsetchronicrenalfailure.Circulation.

2002;106:100---5.

7.Marshall WA, Tanner JM. Variations in pattern of pubertal changesingirlsandboys.ArchDisChild.1969;44:291---303.

8.FlynnJT,KaelberDC,Baker-SmithCM,BloweyD,CarrollAE, DanielsSR,etal.Clinicalpracticeguidelineforscreeningand managementofhighbloodpressureinchildrenandadolescents.

Pediatrics.2017;140:e20171904.

9.World Health Organization. WHO Child Growth Standards:

length/height-for-age, weight-for-age, weight-for-length, weight-for-heightand bodymassindex-for-age.Methods and development.Geneva,Switzerland:WHO;2006.

10.FreedmanDS,SerdulaMK,SrinivasanSR,BerensonGS.Relation ofcircumferencesandskinfoldthicknessestolipidandinsulin concentrationsinchildrenandadolescents:theBogalusaHeart Study.AmJClinNutr.1999;69:308---17.

11.BrayGA,DeLanyJP,HarshaDW,VolaufovaJ,ChampagneCC.

Evaluation of bodyfat in fatter and leaner 10-y-old African Americanandwhitechildren:theBatonRougeChildren’sStudy.

AmJClinNutr.2001;73:687---702.

12.McCarthyHD,ColeTJ,FryT,JebbSA,PrenticeAM.Bodyfat referencecurvesforchildren.IntJObes.2006;30:598---602.

13.Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentrationoflow-densitylipoproteincholesterolinplasma,

(9)

without use of the preparative ultracentrifuge. Clin Chem.

1972;18:499---502.

14.GiulianoIC,CaramelliB,PellandaL,DuncanB,MattosS,Fon- secaFH.IDiretrizdeprevenc¸ãodaaterosclerosenainfânciae adolescência.ArqBrasCardiol.2005;85:S4---36.

15.K/DOQIclinicalpracticeguidelinesforchronickidneydisease:

evaluation, classiﬁcationand stratiﬁcation.Am JKidneyDis.

2002;39:S1---266.

16.SchwartzGJ,Mu˜nozA,SchneiderMF,MakRH,KaskelF,Warady BA,etal.NewequationstoestimateGFRinchildrenwithCKD.

JASN.2009;20:629---37.

17.Doyon A, Kracht D,Bayazit AK, Deveci M, Duzova A, Krmar RT, et al. 4C Studyconsortium.Carotid artery intima-media thicknessanddistensibilityinchildrenandadolescents:refe- rence values and role of body dimensions. Hypertension.

2013;62:550---6.

18.NavaneethanSD,BeddhuS.Associationsofserumuricacidwith cardiovasculareventsandmortalityinmoderatechronickidney disease.NephrolDialTransplant.2009;24:1260---6.

19.MaffeisC,BanzatoC,TalaminiG.Waist-to-heightratio,auseful indextoidentifyhighmetabolicriskinoverweightchildren.J Pediatr.2008;152:207---13.

20.KuE,FineRN,HsuCY,McCullochC,GliddenDV,GrimesB,etal.

Height atﬁrst RRT and mortalityin children.ClinJ AmSoc Nephrol.2016;11:832---9.

21.WongCS,GipsonDS, GillenDL,EmersonS,KoepsellT,Sher- rardDJ,etal.Anthropometricmeasuresandriskofdeathin childrenwithend-stagerenaldisease.AmJKidneyDis.2000;

36:811---9.

22.PérezTA,GonzálezGE,GarciaLH,DelPesoG,López-Sobaler AM,SelgasR.Improvementinnutritionalstatusinpatientswith chronickidneydisease-4byanutritioneducationprogramwith noimpactonrenalfunctionanddeterminedbymalesex.JRen Nutr.2017;27:303---10.

23.BradyTM, SchneiderMF, FlynnJT, CoxC,Samuels J, Saland J, et al. Carotid intima-media thickness in children with CKD: results from the CKiD study. Clin J Am Soc Nephrol.

2012;7:1930---7.

24.KhandelwalP, Murugan V, Hari S, Lakshmy R, Sinha A, Hari P, et al. Dyslipidemia, carotid intima-media thickness and endothelialdysfunctioninchildrenwithchronickidneydisease.

PediatrNephrol.2016;31:1313---20.

25.GoldsteinSL,CurrierH,WattersL,HempeJM,ShethRD,Silver- steinD.Acuteandchronicinﬂammationinpediatricpatients receivinghemodialysis.JPediatr.2003;143:653---7.

26.LitwinM,NiemirskaA.Intima---mediathicknessmeasurements inchildrenwithcardiovascular riskfactors.PediatrNephrol.

2009;24:707---19.

27.FlynnJT,MitsnefesM,PierceC,ColeSR,ParekhRS,FurthSL, etal.,Chronickidney diseaseinchildrenstudygroup.Blood pressureinchildrenwithchronickidneydisease:areportfrom the chronic kidney disease in children study. Hypertension.

2008;52:631---7.

28.BilginerY, OzaltinF,BasaranC,Aki TF, KarabulutE, Duzova A,etal.Carotidintima-mediathicknessinchildrenandyoung adultswithrenaltransplant:internalcarotidarteryvs.common carotidartery.PediatrTransplant.2007;11:888---94.

29.Poyrazo˘glu HM, Düs¸ünsel R, Yikilmaz A, Narin N, AnaratR, Gündüz Z, et al. Carotid artery thickness in children and young adultswithend stage renal disease. Pediatr Nephrol.

2007;22:109---16.

30.BaronciniLA, SylvestreLC,PecoitsFR.Assessmentofintima- mediathicknessinhealthychildrenaged1to15years.ArqBras Cardiol.2016;106:327---32.

Evaluation of carotid intima-media thickness and factors associated with cardiovascular disease in

ORIGINAL ARTICLE