J. Pediatr. (Rio J.) vol.92 número6

www.jped.com.br

ORIGINAL

ARTICLE

Acute

kidney

injury

in

HIV-infected

children:

comparison

of

patients

according

to

the

use

of

highly

active

antiretroviral

therapy

夽

Douglas

de

Sousa

Soares

_,

_Malena

_Gadelha

_Cavalcante

_,

Samille

Maria

Vasconcelos

Ribeiro

_,

_Rayana

_Café

_Leitão

_,

Ana

Patrícia

Freitas

Vieira

_,

_Roberto

_da

_Justa

_Pires

_Neto

_,

Geraldo

Bezerra

da

Silva

Junior

_,

_Elizabeth

_de

_Francesco

_Daher

a_{UniversidadeFederaldoCeará(UFC),FaculdadedeMedicina,DepartamentodeMedicinaInterna,Fortaleza,CE,Brazil} b_{UniversidadedeFortaleza(UNIFOR),FaculdadedeMedicina,CentrodeCiênciasdaSaúde,Fortaleza,CE,Brazil}

Received5July2015;accepted2March2016 Availableonline16August2016

KEYWORDS Acutekidneyinjury; HIV;

Children; HAART

Abstract

Objective: Toassessclinicalandlaboratorydata,andacutekidneyinjury(AKI)inHIV-infected

childrenusingandnotusinghighlyactiveantiretroviraltherapy(HAART)priortoadmission.

Methods: AretrospectivestudywasconductedwithHIV-infectedpediatricpatients(<16years).

ChildrenwhowereusingandnotusingHAARTpriortoadmissionwerecompared.

Results: Sixty-three patients were included. Mean age was 5.3± 4.27 years; 55.6% were

females. AKI was observed in33 (52.3%) children.Patients onHAART presentedlower

lev-els of potassium (3.9±0.8 vs. 4.5±0.7mEq/L, p=0.019) and bicarbonate (19.1±4.9 vs.

23.5± 2.2mEq/L,p=0.013)andhadahigherestimatedglomerularfiltrationrate(102.2± 36.7

vs.77.0±32.8mL/min/1.73m2_{,p=0.011)thanthosenotonHAART.Inthemultivariate}

analy-sis,theuseofHAARTpriortotheadmissionwasaprotectivefactorforAKI(p=0.036;OR=0.30;

95%CI=0.097---0.926).

Conclusion: AKIisacommoncomplicationofpediatricHIVinfection.UseofHAARTpriortothe

admissionpreservedglomerularfiltrationandwas aprotectivefactorfor AKI,butincreased

medicationsideeffects,suchashypokalemiaandrenalmetabolicacidosis.

©2016SociedadeBrasileiradePediatria.PublishedbyElsevierEditoraLtda.Thisisanopen

accessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/

4.0/).

夽

Pleasecitethisarticleas:SoaresDS,CavalcanteMG,RibeiroSM,LeitãoRC,VieiraAP,PiresNetoRJ,etal.Acutekidneyinjuryin HIV-infectedchildren:comparisonofpatientsaccordingtotheuseofhighlyactiveantiretroviraltherapy.JPediatr(RioJ).2016;92:631---7.

∗_{Correspondingauthor.}

E-mail:[email protected](E.F.Daher).

http://dx.doi.org/10.1016/j.jped.2016.03.009

PALAVRAS-CHAVE Insuficiênciarenal aguda;

HIV; Crianc¸as; TARV

Lesãorenalagudaemcrianc¸ascomHIV:estudocomparativoentrepacientescome semterapiaantirretroviralaltamenteativa

Resumo

Objetivo: Avaliardadosclínicos elaboratoriais, bemcomo ocorrência delesão renalaguda

(LRA)emcrianc¸asHIVpositivascomesemusodeterapiaantirretroviralaltamenteativa(TARV)

antesdaadmissão.

Método: FoirealizadoestudoretrospectivoempacientespediátricosHIVpositivos(<16anos).

Foramcomparadasascrianc¸as queestavam emuso comaquelassemusodeTARV préviaà

internac¸ão.

Resultados: Foramincluídos63pacientes,commédiadeidadede5,3± 4,27anos,sendo55,6%

dosexofeminino.LRAfoiencontrada em33 casos(52,3%).OspacientesusandoTARV

apre-sentarammenoresníveisdepotássio(3,9± 0,8vs.4,5± 0,7mEq/L,p=0,019)ebicarbonato

(19,1±4,9 vs. 23,5±2,2 mEq/L, p=0,013), bemcomo maior taxa de filtrac¸ão glomerular

estimada(102,2± 36,7vs.77,0± 32,8mL/min/1,73m2_{,p=0,011)que opacientessemTARV}

prévia.NaanálisemultivariadaousodeTARVpréviaàinternac¸ãofoifatorprotetorcontraLRA

(p=0,036;RC=0,30;ICde95%=0,097-0,926).

Conclusão: ALRAéumacomplicac¸ãocomumdainfecc¸ãopediátricapeloHIV.OusodeTARV

antesdainternac¸ãofoiassociadoamelhortaxadefiltrac¸ãoglomerularefoifatordeprotec¸ão

contraLRA,porémdesencadeouefeitoscolateraiscomohipocalemiaeacidosemetabólica.

©2016SociedadeBrasileiradePediatria.PublicadoporElsevierEditoraLtda.Este ´eumartigo

OpenAccesssobumalicenc¸aCCBY-NC-ND(http://creativecommons.org/licenses/by-nc-nd/4.

0/).

Introduction

According to the United Nations Program on HIV/AIDS (UNAIDS), it wasestimated that approximately35 million peopleworldwidewerelivingwithHIVoracquiredimmune deficiencysyndrome(AIDS)in2012.Furthermore,the2012 annualnumberofnewHIVinfectionswascalculatedtobe nearly2.5million.Over12%ofthem(330,000cases world-wide) occurred in the pediatric population younger than 15 years.In 2011, 230,000 children died due toHIV/AIDS worldwide.1

TheprevalenceofrenaldiseasesinHIV-infectedpediatric patients varies substantially among regions and periods. In the pre-Highly Active Antiretroviral Therapy (HAART) era, most of the infected children in the United States diedofnon-renalAIDScomplications,suchasopportunistic infections(OIs).Thisphenomenonis stillcommoninsome developing countries, where this therapy is not available toallpatients.However,aftertheestablishmentofHAART in developed countries, the number of HIV-infected chil-drenwhorequirerenalreplacementtherapyhasincreased considerably.2_{KidneydiseasecomplicatingHIVinfectionis} nowamongthe10mostcommonnon-infectiousconditions occurring in perinatally HIV-infectedchildren and adoles-centsintheHAARTera,withan incidencerateof2.6per 100patients.3

HIV patients are at high risk of developing both acute kidney injury (AKI) and chronic kidney disease (CKD) due to several factors.4 _{In this context, the spectrum of} kidney diseases in HIV-infected pediatric population is different from adults, including chronic glomerular dis-orders, such as HIV-associated nephropathy; HIV immune complexkidneydisease;sometypesofthrombotic microan-giopathies, such as atypical forms of hemolytic uremic

syndromeandthrombocytopenicpurpura;tubulardisorders; andAKI.5

Theaim ofthis studywastoevaluateclinical and lab-oratory data, aswell asthe occurrence of AKI, using the modified pediatric RIFLE (pRIFLE) criteria in HIV-infected children,bycomparinggroupsaccordingtotheuseofHAART priortohospitaladmission.

Patients

and

methods

Settingandpatientselection

ThiswasaretrospectivestudyperformedwithHIV-infected childrenconsecutivelyadmittedtoSãoJoséInfectious Dis-eases Hospital, Northeast Brazil, from January 2007 to December 2012. All children younger than 16 years with confirmedserologyforHIVinfectionwereincluded.This is the sameage rangefor which the Schwartz equationwas validated.6_{Patientswithhistoryofpreviousrenaldiseases,} arterialhypertension,diabetesmellitus,nephrolithiasis,use of nephrotoxic drugs (except for HAART), and other co-morbiditiesthatcouldaffectrenalfunctionwereexcluded.

Studiedparameters

Laboratory data included assessments of serum cre-atinine (Cr), urea (Ur), sodium (Na), potassium (K), albumin (Alb), alanine aminotransferase (ALT), aspar-tateaminotransferase(AST),lactatedehydrogenase(LDH), hemoglobin (Hb), hematocrit (Ht), platelets, leukocytes, lymphocytes,serumpH(pH), CO2 partialpressure(pCO2), bicarbonate (HCO3), urine pH, and urine density. Mean viral load (VL) and CD4 count were also evaluated. VL=100,000copies/mm3 _{and CD4 count=200/mm}3 _were established as cut off points in order tocompare HAART andnon-HAARTpatients,sincethesevalueswerepreviously associatedwithdevelopmentofAKIandpooroutcomes.7

Definitions

Acute Kidney Injury was defined according to pediatric RIFLE (pRIFLE) criteria, using Schwartz equation to esti-mateglomerularfiltrationrate (eGFR).6_{pRIFLEcategories} include:8,9

- Risk:eGFRreductionby25%orurineoutput<0.5mL/kg/h for8h.

- Injury: eGFR reduction by 50% or urine out-put<0.5mL/kg/hfor16h.

- Failure: eGFR reduction by 75% or eGFR<35mL/ min/1.73m2 _{or urine output<0.3mL/kg/h for 24h or}

anuricfor12h.

- Loss:persistentfailure>fourweeks.

- End-stagerenaldisease:persistentfailure>threemonths.

A baseline eGFR of 120mL/min/m2 _{was assigned to}

all children as previously reported, since none of them had available serum creatinine levels measured within threemonthsbeforeadmission.8,9_{eGFRwascalculatedby} usingserumcreatinineonhospitaladmission.The percent-age of eGFR reduction [100×(baseline eGFR−admission eGFR)/baseline eGFR] was assessed to determine pRIFLE category. Patients were classified according pRIFLE cate-goryonadmission. Duetothe absenceof anthropometric datain charts, meanheightfor each age andgender was obtained from World Health Organization (WHO) Growth data,inordertocalculateeGFR.10,11

Oliguria was defined as urine output <1mL/kg/h in infants(0---12months)and<0.5mL/kg/hinchildrenwhohad been effectivelyhydrated. Dialysis wasindicated in those patientsthatremainedoliguricaftereffectivehydration,in thosecaseswhereuremiawasassociatedwithhemorrhagic orsevererespiratoryfailure,andthosewithhyperkalemiaor metabolicacidosisrefractorytoclinicaltreatment.Dialysis wasindicatedinthosepatientswhoremainedoliguricafter effectivehydration,inrapidelevationofbloodurea nitro-gen(hypercatabolicstate),inthosecaseswhereuremiawas associatedtohemorrhagicorsevererespiratoryfailure,and thosewithhyperkalemiaormetabolicacidosisrefractoryto clinicaltreatment.

Childrenweredividedintotwogroups:thosewhowere inuseofHAARTpriortotheadmissionandthosewhowere not.Demographical,clinical,andlaboratorydataofthetwo groupswerecompared.

Treatment

The HAART drugs used in the treatment were: zidovu-dine(AZT), didanosine (ddI),lamivudine (3TC),stavudine (D4T),abacavir(ABC),tenofovirdisoproxilfumarate(TDF), lopinavir(LPV),nelfinavir(NFV),saquinavir(SQV),ritonavir (RTV),amprenavir (APV), efavirenz (EFZ), and nevirapine (NPV),according totheprotocolsoftheBrazilian Ministry ofHealth.

Statisticalanalysis

The SPSS software for Windows, release 20.0 (IBM Corp. Released2011.IBMSPSSStatisticsforWindows,version20.0, USA)wasusedforstatisticalanalysis.Chi-squaredtestwas used to analyze frequencies in the patients’ groups. All independentvariables weretestedfor normaldistribution using the Kolmogorov---Smirnov test. Differences between twoindependentvariableswereevaluatedusingStudent’s

t-test or Mann---Whitney test as appropriate. Data were expressedasmeans±SD,andap≤0.05wasconsidered sta-tisticallysignificant.

Amultivariatelogisticregressionwasperformedto ana-lyzethepossibleriskfactorsassociatedwithAKI.Initially, aunivariateanalysiswasdonewithalldichotomous varia-blesavailable,includinggender,presenceofeachsymptom andcomorbidity,HAARTuse,viralload>100,000copies,and CD4 count <200/mm3_{. These parameters were evaluated} forsignificantdifferencebetweenAKIandnon-AKIgroups, usingthechi-squaredtest andcrosstabs.Secondly, param-etersincluded in the multivariate model were thosethat presented a significance level (p≤0.05) in the univariate analysis. Only one of them (HAART use) was significantly different,soit wasevaluated asa risk factor for AKI, by calculatingtheadjustedoddsratio(OR)and95%confidence interval(95%CI).

Ethics

The study protocol wasreviewed and approved by Ethics Committees from WalterCantídio University Hospital and SãoJoséInfectiousDiseasesHospital.

Results

Table1 Demographicdata,clinicalmanifestations,infectionstatus,andoutcomesofchildrenwithhumanimmunodeficiency

virus(HIV)accordingtotheuseofhighlyactiveantiretroviraltherapy(HAART).

HAART(n=43) Non-HAART(n=20) p

Age(years) 6.3±4.1 3.1±3.8 0.002

Gender

Males 20(46.6%) 12(60%) 0.786

Females 23(53.4%) 8(40%) 0.786

Hospitalstay(days) 35.4±66.2 31.4±33.2 0.088

Signsandsymptoms(%)

Fever 35(81.3%) 17(85%) 1.000

Cough 30(69.7%) 13(65%) 0.775

Dyspnea 16(37.2%) 6(30%) 0.777

Diarrhea 16(37.2%) 7(35%) 1.000

Vomiting 15(34.8%) 3(15%) 0.139

Weightloss 3(6.9%) 3(15%) 0.372

Associatedinfections(%)

Pneumonia 20(46.6%) 8(40%) 0.786

Tuberculosis 3(6.9%) 3(15%) 0.372

Varicella 3(6.9%) 1(5%) 1.000

Infectionstatus(%)

Meanviralload>100,000copies/mm3 _{9(20.9%) 9(45%) 0.124}

CD4lymphocytes<200/mm3 _{6(13.9%) 6(30%) 0.162}

Outcomes(%)

Dialysis 1(2.3%) 0 1.000

Death 1(2.3%) 0 1.000

Ageandhospitalstayarepresentedasmean±SD.Therestofthedataarepresentedasnumber(percentage).Student’st-testandthe chi-squaredtestwereused.p-values≤0.05wereconsideredstatisticallysignificant.

in Table 1. Among all patients, the most frequent opportunisticinfections(OIs)werepneumonia(44.4%), pul-monarytuberculosis(9.5%),andvaricellazoster/chickenpox (6.3%).

Comparing groups, it was noticed that those patients on HAART presented significantly lower levels of serum bicarbonate(19.1±4.9vs.23.6±2.2mEq/L,p=0.013)and serumpotassium (3.9±0.8 vs. 4.5±0.7mEq/L,p=0.019) thanthosenotonHAART,respectively.Also,thosepatients not on HAART presented significantly higher levels of AST (123.1±189.9U/L vs. 39.8±26.7, p=0.008) and ALT (77.9±102.8U/L vs. 25.3±21.5, p=0.001) than those on HAART, respectively. Moreover, eGFR was remarkably higher in patients on HAART than in those not onHAART (102.2±36.7 vs. 77.0±32.8mL/min/1.73m2_{, p=0.011).}

Therewasnosignificantdifferencebetweenthetwogroups when comparing percentage of patients who presented CD4<200/mm3 _{and VL>100,000copies/mm}3_{. A}

compari-son of laboratory data between groups is presented in Table2.

AKIwasobservedin33(52.3%)children.Nineteenwere classified as Risk (57.5%), 13 as injury (39.4%), and one asfailure(3.1%).Prevalenceof AKI waslowerin thoseon HAARTthanthosenotonHAART(41.86%vs.75%,p=0.037). Inthemultivariateanalysis,useofHAARTpriortoadmission wasa protective factor for AKI (p=0.036; OR=0.30; 95% CI=0.097---0.926). Comparison of AKI prevalence between groupsisshowninTable3.

Discussion

This was the firststudy toevaluate demographical, clini-cal,andlaboratorydataofHIV-infectedchildrenadmittedto aninfectiousdiseaseshospitalinFortaleza,stateofCeará, Brazil,focusingonrenalfunctionand thedevelopmentof AKI.ItwasobservedthatHAARTappearstobeaprotective factoragainstAKIinchildrenwithHIV.

Inthepresentstudy,meanageof thechildrenwas5.3 years,withapredominanceoffemales,whichissimilarto past studies that evaluated renal disease in HIV-infected children.12---14_{Furthermore,themostprevalentsymptomsin} thepresentstudywerefeverandcough,whichreflectmain associatedinfections,theleadingcauseofhospitalization. In tworecent pediatric studies, themain symptoms were identicaltothoseofthepresentcohort.15,16_{Regardingviral} andimmunologicstatus,mostpatientspresentedhigh lev-elsofmeanviralloadandlowCD4count,buttherewasnot significantdifferencebetweengroups.

Table2 Comparisonoflaboratorydatabetweenchildrenwithhumanimmunodeficiencyvirus(HIV)accordingtouseofhighly

activeantiretroviraltherapy(HAART).

HAART(n=43) Non-HAART(n=20) p

Meanviralload(103_copies/mm3_{) 82.18±143.93 209.01±223.14 0.157}

CD4count(/mm3_{) 695.7± 615.6 875.5± 928.6 0.472}

pH 7.3±0.2 7.4±0.1 0.548

PCO2(mmHg) 33.2± 13.0 36.3± 3.2 0.486

HCO3(mEq/L) 19.1±4.9 23.6±2.2 0.013

Na(mEq/L) 135.5± 4.4 136.5± 2.5 0.374

K(mEq/L) 3.9±0.8 4.5±0.7 0.019

Hb(g/dL) 9.8± 1.7 9.2± 1.2 0.141

Ht(%) 29.9± 4.5 28.7± 3.7 0.295

Leukocytes(/mm3_{) 9175.2±6234.3 9448.6±6120.1 0.872}

Lymphocytes(/mm3_{) 2402.1± 1542.7 3519.4± 2977.4 0.128}

Platelets(103_/mm3_{) 279.19±132.60 211.75±127.41 0.063}

LDH(U/L) 710.3± 583.8 1134.5± 1562.3 0.364

Ur(mg/dL) 22.5±11.3 28.2±15.1 0.107

Cr(mg/dL) 0.5± 0.19 0.52± 0.2 0.781

Albumin(g/dL) 3.6±0.6 3.7±0.5 0.594

AST(U/L) 39.8±26.7 123.1±189.9 0.008

ALT(U/L) 25.3± 21.5 77.9± 102.8 0.001

eGFR(mL/min/1.73m2_{) 102.2±36.7 77.0±32.8 0.011}

Dataarepresentedasmean±SD.

pH,serum hydrogenionicpotential;PCO2,carbon dioxidepartialpressure;HCO3, serum bicarbonate;Na, serum sodium;K, serum

potassium;Hb,serumhemoglobin;Ht,hematocrit;LDH,lactatedehydrogenase;Ur,serumurea;Cr,serumcreatinine;Albumin,serum albumin;AST,aspartateaminotransferase;ALT,alanineaminotransferase;eGFR,estimatedglomerularfiltrationrate.Student’st-test andMann---Whitneytestswereused.p-values≤0.05wereconsideredstatisticallysignificant.

Table3 Comparison of acutekidney injury (AKI)

preva-lenceaccordingtouseofhighlyactiveantiretroviraltherapy

(HAART).

HAART

(n=43)

Non-HAART

(n=20)

p

AKI 18(41.86%) 15(75%) 0.037

Non-AKI 25(58.14%) 5(25%)

Datawerepresentedasnumber(percentage).Thechi-squared testwasused.

p-values≤0.05wereconsideredstatisticallysignificant.

abnormalities induced by this drug.19 _{In addition, lower} body weight and high-doseof the drug were significantly associatedwithTDF-inducednephrotoxicityinHIV-infected childrenfromtheUnitedKingdom.20

Inadditiontohypokalemia,lacticacidosishasalsobeen reportedasaconsequenceofHAARTtoxicity,specificallyby thenucleosidereversetranscriptaseinhibitors(NRTIs).This isan importantcauseof acidosisin HIV-infectedpatients, both children and adults.21,22 _{In the present study, lower} meanlevelsofserumbicarbonatewereobservedinpatients onHAARTthaninthosenotonHAART,whichindicateshigher incidenceofmetabolicacidosisinthefirstgroup. Further-more,mitochondrialtoxicityinproximaltubulecellsisthe responsibleforanotherwell-describedcauseofacidosisin HIV patients using HAART: Fanconi syndrome.23,24 _Hence, HAARTtoxicityismostlikelythemajorcauseofmetabolic acidosis in the present cohort instead of eGFR decrease,

sinceserumbicarbonate waslower in patientson HAART, whopresentedhigherlevelsofeGFR.

Otherinterestingfindingsinthepresentstudywerethe highermeanlevelsofASTandALTinpatientsnotonHAART when compared to those on HAART, which may indicate liverinjury. Accordingto a recent review of liverdisease in HIV-infected adult patients, there are several factors relatedtoliverinjuryandHIV,includinghepatitisBandC virusesco-infection;steatosisandnon-alcoholic steatohep-atitis(NASH);metabolicchangessuchasinsulinresistance; livertoxicityofthemedications,especiallyHAART;andalso adirecteffectoftheHIVontheliver.25_{Someofthesefactors} probablycontributedtoASTandALTelevationinthepresent cohort.Sincehigherlevelsofliverenzymeswerepresented bythepatientswhowerenotonHAART,liverimpairmentis mostlikelyduetocausesotherthandrugtoxicity.

SincetheintroductionofHAART,chronicconditionssuch asrenal disease have been rising as important causes of morbidityandmortalityofpatientswithHIV.Inthepresent study,itwasobservedthatthosenotonHAARTpresentedan importantrenalfunctionimpairmentandhigherincidence ofAKI when comparedto patients onHAART. In addition, AKI is acommon complicationin ambulatory HIV-infected adultpatientstreatedwithHAART,havingbeenassociated with previous renal impairment, lower CD4 levels, AIDS, hepatitisCvirusco-infectionandliverdisease.26,27_Usually, thedevelopmentofAKIinthesepatientsismultifactorial, includingsepsis,nephrotoxicdrugs,volumedepletion,and useofradiocontrast.28

explainedbythe benefits of HAARTin reducingviral load andthendecreasingrenaleffectsofHIV.Thereisevidence toprovetheefficacyofHAARTinpreventingHIV-associated nephropathy and delaying progression to end-stage renal diseaseinHIV-infectedadultpatients.29,30

In conclusion, renal disease is rising as an important long-termcomplicationofHIV infectioninchildren world-wide.Thecomparisonbetweenthetwogroupsshowedthat children using HAART prior to the admission had higher eGFR,butlowerlevelsofpotassiumandbicarbonate.HAART use was shown to be a protective factor for AKI. These findings may indicatethat the use of HAART prior tothe admissionpreservedglomerularfiltrationandreduced inci-denceofAKI,butincreasedmedicationsideeffects,suchas hypokalemiaandrenalmetabolicacidosis,whicharemainly associatedwithsomeantiretorvirals,suchasTDF.

Study

limitations

Study limitations include some data missing due to the retrospectivenatureoftheresearch,andthesample selec-tion,which wasbased only on hospitalized patients. The authors did not have access to data on children’s urine output,asthiswasaretrospective study.Ingeneral, non-criticalcare units donot accurately record urine output, especiallyinthepediatricpopulation.Someanthropometric data,suchasheightandweight,werealsonotavailablein children’scharts,soitwasnecessarytoobtainsomeofthem fromWHO GrowthDatainordertoestimateGFRby using Schwartzformula.DurationofHAARTwasalsonotavailable inpatient’srecords.Serumcreatininewithinthreemonths before admission was also not available, thus a baseline eGFRof120mL/min/1.73m2_{wasassumedforallchildren,} sincetheydidnotpresentanyidentifiedfactorsforprevious chronickidneydiseaseanditwasnotpossibletoestimate therealGFR.UsingAKIastheoutcomeofinterestmayhave reduced the accuracy of logistic regression results, since thenumberof AKI patientswaslimited(only 33),butdid notunderminetheimportanceofthemultivariateanalysis findings.

Funding

Conselho Nacional de Desenvolvimento Científico e Tec-nológico,CNPq(BrazilianResearchCouncil).EdsonQueiroz Foundation/UniversityofFortaleza.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgements

The authors would like to thank the team of physicians, residents,medicalstudents,andnursesfromtheSãoJosé InfectionDisease Hospital for providing technical support todevelopthisresearchandfortheexceptionalassistance providedtothe patients. This research wassupported by theConselhoNacionaldeDesenvolvimentoCientíficoe Tec-nológico(CNPq;BrazilianResearchCouncil).

References

1.UNAIDSreportontheglobalAIDSepidemic2013;2014. Avail-able from: www.unaids.org/en/media/unaids/contentassets/ documents/epidemiology/2013/gr2013/unaidsglobalreport 2013 en.pdf[03.09.14].

2.ShahinianV,RajaramanS,BoruckiM,GradyJ,HollanderWM, AhujaTS.PrevalenceofHIV-associatednephropathyin autop-siesofHIV-infectedpatients.AmJKidneyDis.2000;35:884---8. 3.PurswaniMU,ChrnoffMC,MitchellCD,SeageGRIII,Zilleruelo G,AbitbolC,etal.Chronickidneydiseaseassociatedwith peri-natalHIVinfectioninchildrenandadolescents.PediatrNephrol. 2012;27:981---9.

4.BalowJE.NephropathyinthecontextofHIVinfection.Kidney Int.2005;67:1632---3.

5.RamsuranD, BhimmaR, RamdialPK, Naicker E,Adhikari M, DeonarainJ,etal.ThespectrumofHIV-relatednephropathy inchildren.PediatrNephrol.2012;27:821---7.

6.SchwartzGJ,Mu˜nozA,SchneiderMF,MakRH,KaskelF,Warady BA,etal.NewequationstoestimateGFRinchildrenwithCKD. JAmSocNephrol.2009;20:629---37.

7.LiY,ShlipakMG,GrunfeldC,ChoiAI.Incidenceandrisk fac-torsfor acutekidney injury inHIV infection. AmJNephrol. 2012;35:327---34.

8.Akcan-ArikanA,ZappitelliM,LoftisLL,WashburnKK,Jefferon LS,GoldsteinSL.ModifiedRIFLEcriteriaincriticallyillchildren withacutekidneyinjury.KidneyInt.2007;71:1028---35. 9.PalmieriT,LavrentievaA,GreenhalghD.Anassessmentofacute

kidneyinjurywithmodifiedRIFLEcriteriainpediatricpatients withsevereburns.IntensiveCareMed.2009;35:2125---9. 10.WHO. Child Growth Standards; 2006. Available from:

http://www.who.int/childgrowth/en/[19.04.14].

11.WHO.Growthreferencedatafor 5---19years;2007.Available from:http://www.who.int/growthref/en/[19.04.14]. 12.ShahI,ShradhaG,ShahDM,DhabeH,LalaM.Renal

manifesta-tionsofHIVinfectedhighlyactiveantiretroviraltherapynaïve childreninIndia.WorldJPediatr.2012;80:252---5.

13.IduoriyekemwenNJ,SadohWE,SadohAE.Prevalenceofrenal diseasein Nigerian childreninfectedwiththehuman immu-nodeficiencyvirusandonhighlyactiveanti-retroviraltherapy. SaudiJKidneyDisTranspl.2013;24:172---7.

14.DickoF,Desmonde S,Koumakpai S, Dior-MbodjH, KouétaF, BaetaN,etal.ReasonforhospitalizationinHIV-infected chil-dreninWestAfrica.JIntAIDSSoc.2014;17:18818.

15.ShahrinL, LeungDT,MatinN, KawserCA,Pervez MM, Chisti MJ. Clinical profile of hospitalized HIV-infected children in Bangladesh,a lowHIV-prevalencecountry.PeadiatrIntChild Health.2014;34:133---7.

16.ObiagwuPN,Hassan-HangaF,IbrahimM.PediatricHIVinKano, Nigeria.NigerJClinPract.2013;16:521---5.

17.Shepp DH,Curtis S, Rooney JF.Causes and consequencesof hypokalemiainpatientsontenofovirdisoproxilfumarate.AIDS. 2007;21:1479---90.

18.CirinoCM,KanVL. HypokalemiainHIVpatientsontenofovir. AIDS.2006;20:1669---77.

19.KohlerJJ,HosseiniSH,Hoying-BrandtA,GreenE,JohnsonDM, RussR,etal.Tenofovirrenaltoxicitytargetsmitochondriaof renalproximaltubules.LabInvest.2009;89:513---9.

20.LimY,LyallH,FosterC.Tenofovir-associatednephrotoxicityin childrenwithperinatally-acquiredHIVinfection:asingle-centre cohortstudy.ClinDrugInvestig.2015;35:327---33.

21.MargolisAM,HeverlingR,PhamPA,StolbachA.Areviewofthe toxicityofHIVmedications.JMedToxicol.2014;10:26---39. 22.Barlow-Mosha L, Eckard AR, McComsey GA, Musoke PM.

23.KapadiaJ,SamidhS,ChetnaD,MiraD,ShivaniP,AshaNS,etal. TenofovirinducedFanconi syndrome:a possible pharmacoki-neticinteraction.IndianJPharmacol.2013;45:191---2. 24.NelsonM,AzwaA,SokwalaA,Shah-HaraniaR,StebbingJ.

Fan-coni syndrome lactic acidosis associatedwith stavudine and lamivudinetherapy.AIDS.2008;22:1369---76.

25.RockstrohJK,MohrR,BehrensG,SpenglerU.Liverfibrosisin HIV:whichroledoesHIVitself,long-termdrugtoxicitiesand metabolicchangesplay?CurrOpinHIVAIDS.2014;9:365---70. 26.FranceschiniN,NapravnikS,EronJJJr,SzczechLA,FinnWF.

Incidenceandetiologyofacuterenalfailureamongambulatory HIV-infectedpatients.KidneyInt.2005;67:1526---31.

27.IbrahimF,NaftalinC,CheseremE,RoeJ,CampbellLJ,BansiL, etal.Immunodeficiencyandrenalimpairmentareriskfactors forHIV-associatedacuterenalfailure.AIDS.2010;24:2239---44. 28.LopesJA,MeloMJ,ViegasA,RaimundoM,CâmaraI,AntunesF, etal.AcutekidneyinjuryinhospitalizedHIV-infectedpatients: acohortanalysis.NephrolDialTransplant.2011;26:3888---94. 29.RosenbergAZ,NalckerS,WinklerCA,KoppJB.HIV-associated

nephropathies: epidemiology, pathology, mechanisms and treatment.NatRevNephrol.2015;11:150---60.