The importance of bisphenol A, an uraemic toxin from exogenous sources, in haemodialysis patients

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RevistadelaSociedadEspañoladeNefrología www . r e v i s t a n e f r o l o g i a . c o m

Editorial

The importance of bisphenol A, an uraemic toxin from exogenous sources, in haemodialysis patients ^夽

Importancia del bisfenol A, una toxina urémica de origen exógeno, en el paciente en hemodiálisis

Sebastián Mas

^∗

, Jesús Egido, Emilio González-Parra, en representación del Grupo de Análisis del Papel del Bisfenol A en el Paciente en Hemodiálisis

^♦

ServiciodeNefrologíaeHipertensiónII-S,FundaciónJiménezDíaz,UniversidadAutónoma,Madrid,Spain

In recent years in the scientific community, the harmful effectofaphenolictypeofenvironmentaltoxicant,knownas bisphenolA(BPA),hasachievedgreatrelevance(Fig.1).The interestin thiscompound isincreasingowingtoits possi- bleadverseeffectsonseveralorgans,whichhasledseveral organisationstorecommendtheprohibitionoratleastuse reduction,withwiderepercussionsinthemedia.BPAhasalso arousedinterest inthenephrological community, asit has beenlinkedtokidneyandendocrinedisorders.SinceBPAis clearedbythekidneys,plasmaand tissuelevelsofBPAare markedlyincreasedinpatientswithimpairedrenalfunction.

ButwhatisbisphenolAandwhydoesitarousesuchinter- est?ThesignificanceofBPAstemsfromitsubiquity,because itisacompoundthatisfoundinthemostcommonlyused plasticcontainers(polycarbonates)andepoxyresinsinpack- aging. BPAis releasedfrom these plasticcontainers and it is absorbed by humans that consume food or liquid that isbeingstoredinthesecontainers.BPAwassynthesisedin the1930sasasyntheticoestrogen,¹ and wassubsequently replacedbydiethylstilbestrol.²Itisconvertedintoamonomer

夽Pleasecitethisarticleas:MasS,EgidoJ,González-ParraE.ImportanciadelbisfenolA,unatoxinaurémicadeorigenexógeno,enel pacienteenhemodiálisis.Nefrologia.2017;37:229–234.

∗ Correspondingauthor.

E-mailaddress:[email protected](S.Mas).

♦ AlistofthemembersofthisgroupcanbefoundinAppendixA.

duringthemanufactureofvariouscommonlyusedproducts, suchasplasticbottles,babybottlesor contactlenses. BPA- containingepoxyresinsare usedasacoatingincansused forfood,althoughthereisnowatendencytobesubstituted bypolyesters.³GiventhewidespreaduseofBPA,itspotential risktohumanhealthasasyntheticoestrogenfordailycon- sumptionhasbeenatopicofdebateinregulatoryagenciesfor manyyears.

BPAgenerallypassesintothebloodstreamthroughtheoral route, usuallyaccompanyingtheproductscontainedinthe plasticcontainers.Itisimmediatelyabsorbed(5–20min)and hasabioavailabilitygreaterthan70%.^4,5Aswithphenolspro- ducedbygutbacteria,BPAisconjugatedintheintestineand liverwithglucuronicacidandiseliminatedalmostexclusively intheurine.⁶Exposureinwaysotherthantheoralroutemay alsooccur, andso it isconsidered anenvironmentaltoxic, e.g.byinhalation(thismay causecough,asthmaticattacks andbronchospasms);eyeexposure(causingswellingaround theeyes,facialpruritusandconjunctivitis)orskinexposure (rednessandroughness).

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CH

₃

CH

₃

C O C O

O

n

Fig.1–ChemicalstructureofthebisphenolAmonomer.

Molecularmass:284Da.

However,morecontroversialisitsroleasanendocrineago- nistafterprolongedconstantexposureformanyyears.BPA iscommonlyreferredtoasanendocrine“disruptor”.Despite theevidencepublished,⁷theEuropeanandAmericanauthor- itiesconsiderthat,becauseitiseliminatedrapidly,BPAmay beconsideredasarelativelysafecompound.Dailyoraland cutaneousexposuretobisphenolhasrecentlybeenestimated tobe0.2–0.3mgBPA␮g/kgofweight.⁸

In the absence of conclusive scientific evidence, it is recommended to reduce exposure as much as possible,⁹ withmaximumsafetylevelsof5mg/kg/dayinadults.How- ever, following a precautionary principle, baby bottles and rubber nipples were banned throughout the EU from June 2011onwards,sincemuchgreaterpotentialharmhasbeen observedinnewborns.

Thereasons why amore widespreadban has notbeen imposedarebasedonthefollowing:

• Higheconomiccostofcompletelyeliminatingthecontain- erscurrentlyused.

• Thestrongest evidence has been seen in animals, with limitedinformationoftoxicityinhumans.

• Differencesinthemetabolismbetweenlaboratoryanimals andhumans.

• Completerenaleliminationimmediatelyafteringestion.

However, other authors support the elimination of its industrialuseduetotheincreasingamountofevidenceon theassociationofBPAexposurewiththedevelopmentofdis- eases,bothinlaboratoryanimalsandbasedonobservational studiesinhumans.

Evidence in animal testing

TherearedirectdataonBPA’stoxicityinlaboratoryanimals.

Theyincludethefollowing:

a) Effectsonthereproductivesystem:Inratsgivenhighdoses ofBPA thereisanincreaseinimmaturespermatozoa.¹⁰ TheeffectsofBPAexposureinneonatalmicewasdiffer- ent depending on the amount of BPA administered. At 2mg/kg,theweightofanadultprostateincreases¹¹ and at10mg/kg,prostatedevelopmentstops.¹² Inadultmale rats,adoseof10mg/kgincreasesthesusceptibilityofthe prostateglandtodevelophormonalcarcinogenesis¹⁰and spermcountsandtestosteronelevelsarereduced,witha significantimpactonfertility.¹³

b) Neurologicaleffects:Astudyofdevelopingzebrafishembryos showedthatBPAmayinfluencebraindevelopment,includ- ingthehypothalamus,telencephalonandpreopticarea.¹⁴

Studiesinrodentsshowedthatperinataloruterine-related BPAexposurecancausepermanentchangesinbehaviour, includingincreasedlevelsofaggressionandanxiety,and changes in learning, memory, searching and emotional responsiveness.¹⁵ Several studies with mice concluded that exposure to low doses of maternal BPA has long- term consequencesonneurobehaviouraldevelopment.¹⁶ Also, neonatal BPA exposure may affect brain mor- phology, with sexual dimorphism and adult neuronal phenotypes.¹⁷

c) Effectsonweight:ContinuedBPAexposurehaslastingeffects onbodyweightandadiposity.¹⁸ Onestudyperformedon rats showed that perinatal exposure to drinking water with1mg/LofBPA increasedadipogenesis infemalesat weaning.¹⁹

Evidence in humans

Manyofthefindingsobservedinlaboratoryanimalshavebeen confirmedinclinicalstudies.

a) Reproductive system and endocrine disorders. It has been observed that even very low concentrations of BPA are capable ofproducing changes in spermatogenesis²⁰ andoestrogenproduction,²¹pancreaticdamage,²²thyroid problems²³orliverdamage.²⁴

b) Tumourigenesis.BPAexposurehasbeenassociatedwiththe appearanceofneuroblastomasandbreasttumours.²⁵ c) Neurologicaleffects.Inasubgroupofyoungchildren,pre-

natalBPAexposuremaybeassociatedwithanincreasein hyperactivityandaggressiveness.²⁶

d) Obesity and diabetes. BPA exposure has been associated with the onset of obesity,²⁷ insulin resistance and diabetes,^14,28,29 and BPA inhibits the release of adiponectin.³⁰

e) Cardiovasculardisease. Inrecentyears,numerous studies haverelatedthiscompoundwithvariousabnormalitiesin thecardiovascularsystem,suchasarrhythmias,bybinding tocalciumchannels,³¹ andanincreaseincardiovascular risk.For every increase of4.5mg/L ofBPA in urine, the increaseintheincidenceofcoronarydiseasegoesupby 13%overa10years’time.³²Butitcannotberuledoutthat thisincreasemaybeduetoothercausesincethattheneg- ativeeffectofBPAwaslostafteradjustingfortraditional cardiovascularriskfactors.itislikelythatbloodpressure isinfluencedbyBPA.InhealthyadultsintheUnitedStates, urinaryBPAlevelsgreaterthan4g/Lhavebeenassociated witha50%increaseintheprevalenceofhypertensionas comparedwithurinaryBPAlevels<1.5mg/L.³³Recently,the relationshipbetweenBPAandvasculardamagehasbeen reviewedbyBoschetal.³⁴Table1summarisessomeofthe mostrelevantarticles.

Role of BPA in kidney disease

TherelationshipofBPAtokidneydiseasemeritsaseparate chapter, giventhat,inthiscase,notonlyisit acompound that plays a direct role in kidney damage, but it is also

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Table1–CardiovasculareffectsofBPA.

Metabolicsyndrome Vasiliu,Epidemiology,2006²⁷ Obesityandinsulin

resistance

Wang,JClinEndocrinolMetab, 2012⁵⁰

Atherosclerosis Lindetal.,Atherosclerosis, 2011

Coronaryheartdisease Melzeretal.,Circulation, 2012²⁹

Hypertension Shankaretal.,JEnvironPublic Health,2012³⁰

clearedmainly in urine; therefore it accumulates inthese patients.

Thegreaterthedecreaseinglomerularfiltration,thelower the rate of elimination of BPA in urine. Thus, patients on haemodialysis are not able to clear BPA,³⁵ and there is a strongcorrelationbetweenBPA accumulationandimpaired renalfunction.³⁶However,the2003–2006NationalHealthand Nutrition ExaminationSurvey (NHANESIII), witha sample of2573patients,alsofoundadecreaseintheeliminationof BPAinrelationtothelevelofimpairmentinrenalfunction, althoughitwasonlysignificantinwomen.³⁷Onlyfewstud- ieshavemeasuredtheplasmaconcentrationofBPAinrenal patients;Krieteretal.³⁸observedacorrelationbetweenthe impairmentinrenalfunctionandplasmaconcentrationsof BPA,regardlessofgender.InCKDstages1–2,the levelsare similartohealthycontrolsandbelowthelevelsofdetection used (<0.2ng/mL), and in stages 3–4 patients the levels of BPArisesharply,to0.7±1.0ng/mL.InstageG5thevaluesare upto1.6±1.8ng/mL(p<0.05),whileinG5Dthevalueswere 10.0±6.6ng/mL. Although it is known that chronic kidney disease decreases urinary excretion, thepharmacokinetics, bioavailability and tissueaccumulation inhumans are not known.

Among the evidence that points to a possible causal role in kidney disease is the fact that in healthy adults, urinary BPA levels >1.4mg/L are associated with a 23%

higherrisk ofmicroalbuminuria than in adultswithlevels

<0.5mg/L³⁷andinchildren.³⁹Ithasalsobeenassociatedwith low-grade albuminuria in Chinese adults.⁴⁰ The suggested possiblemechanismsofBPA-mediatednephrotoxicityinclude increased oxidative stress, inflammation and induction of hypertension.^41,42

IthasalsorecentlybeenreportedthatserumBPAmaybea predictorofkidneydiseaseprogressioninpatientswithType 2Diabetes,⁴³suchthatpatientswithelevatedplasmalevels ofBPAexperiencegreaterkidneydiseaseprogression.Table2 liststheprincipalpublicationsthatrelateBPAexposureand kidneydamage.

However, it is the accumulation of this substance in patientswithdecreasedglomerularfiltrationthathasmoti- vated theanalysis ofthe compoundas apossibleuraemic toxin.⁴⁴ One of the arguments put forward by the various OfficialAgenciesforconsideringtheuseofBPAinordinary consumptiontobesafeisitsalmostcompleteeliminationin urineasaconjugatedcompound.⁴⁵ Therefore,patientswith kidneydamage,inwhomeliminationisimpaired,shouldbe consideredapopulationespeciallysusceptibleofthepotential adverseeffectsofBPAexposure.

BPA in patients on dialysis

Patientsonhaemodialysisareparticularlysusceptibletothe risk of toxicity due to BPA, as renal elimination is com- pletelyimpaired.Thisisfurtherexacerbatedinpatientson haemodialysis,sinceBPA,beingaubiquitouscomponent,is partofthecompositionoftheplasticmaterialofsomedial- ysersand commonlyuseddialysis systems, intheformof polycarbonateinthecasingsandinmultipledialysismem- branes,such aspolysulfone(PS) or polyester-polymeralloy (PEPA).

Inthesedialysers,thepolymerisinconstantcontactwith thebloodanditmaybereleasedintothecirculatorysystem,so thattheincreaseofBPAinhaemodialysispatientsmaybedue notonlytoenvironmentalexposure,butpossiblyalsotothe methoditself.⁴⁶Severalstudieshavereportedthateffluents fromdialysersmadeofthesematerialshavehigherconcentra- tionsofBPA,^36,44,45withincreasedBPAmigrationwhenblood isusedinsteadofsaline.⁴⁶Therefore,inthesepatientsitis verydifficulttodeterminewhethertheplasmaconcentrations exceedrecommendedlevels.

Despiteallthisinformation,therearepracticallynolong- term prospective studies that relate haemodialysis to the presenceofBPAanditspossibleeffects.In2013,Krieteretal.³⁸ studied the effect ofhaemodialysis on BPA over a 4-week period and concluded that the differences between mem- branes withbisphenol(polysulfone) and withoutbisphenol (polynephron)werenotsignificant.However,thefactthatthe casingsofallthedialysersusedcontainedBPAandtheshort durationofthestudymightexplainthatthevaluesofBPAwere notdifferent.

To evaluatethis discrepancy betweenin vitro studies or studies in a single session and Krieter’s results, we have recently published (Bosch-panadero et al.⁴⁷) a longer-term study (3 months); this is a crossover study of69 patients, comparing dialysers with BPA (polysulfone) and without BPA (polynephron), we found that serum and intracellu- lar levels of BPA increased with the use of polysulfone (48.8±6.8 to 69.1±10.1ng/mL), and decreased with dialy- siswithpolynephron(70.6±8.4to47.1±7.5ng/mL;p<0.05).

TheincreaseinBPAwereassociatedwithelevatedlevelsof intracellularfreeradicalsandcirculatinginflammatorymark- ers(IL-6,TNF-␣,C-reactiveprotein).Itwasalsoobservedin invitroexperimentsusingcirculatingcellsthatBPApolysul- fonemembranesreleasedbisphenolintotheculturemedium andresultedintheincreasedproductionofcytokinesinlym- phocytesinculture.⁴⁷

Regardinghaemodiafiltration,therearecurrentlynowell- designedstudiestodeterminetheeffectofthistechniqueon the eliminationofBPA.Althoughit wouldbeexpectedbet- tereliminationwithhaemodiafiltration,thereinfusionoffluid usedcirculatesbyBPAmembranes,whichmayincreasedthe infusionofBPA.

Lastly,inthecaseofperitonealdialysis,thereisonlyone studythatlooksattheimpactofBPA,whichfoundthatitscon- centrationindialysisfluidiswellbelowthepermittedvalue.

Althoughonly4patientswerestudied,levelsonlyseemedto increaseinoneofthem,sotheauthorsconcludethatBPAdoes notappeartobereducedorincreasedbyperitonealdialysis.⁴⁸

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Table2–SignificanceofbisphenolAinnephrology.MainpublicationsrelatingtheeffectsofBPAonthekidneys, impairedeliminationoritsrelationtodialysis.

BPAinurineandmicroalbuminuria UrinaryBPA>1.4mg/L:A23%increasein albuminuria

Lietal.,KidneyInt,2014⁴⁰

BPAinurineandmicroalbuminuriain children

Increaseof0.28mg/gandMAperunitofurinary BPA

Transandeetal.,KidneyInt,2013³⁹

BPApodocytopathyinlaboratoryanimals BPAip50mg/kginducesproteinuria,glomerular hyperfiltrationandpodocytopenia

Olea-Herreraetal.,CellPhysiol, 2014⁴¹

BPAandhypertension TheNHANESstudyfoundacorrelationbetween BPAandHTN

Shankaretal.,JEnvironPublic Health,2012³³

BPAandprogressionoftype2DM SerumBPAcorrelatesnegativelywithGF(OR:

6.65)

Huetal.,ActaDiabetológica, 2015⁴³

BPAandrenalfunction SerumBPA:inversecorrelationwithGF Krieteretal.,ArtifOrgans,2013³⁸ SerumBPAincreasesinHD 15patientsonHDsawelevatedBPAwithPS Murakamietal.,BloodPurif,2007³⁶ SerumBPAisaffectedbythetypeofdialyser In69patientsonHD(crossoverstudy),BPA

increasedwithPSanddecreasedwithPN

Bosch,JAmSocNephrol,2015⁴⁷

SerumBPAwasassociatedwith inflammationandoxidationinHD

BPAanddialyserfibreswithBPAincreased inflammationandoxidationinmononuclear cells

Bosch,JAmSocNephrol,2015⁴⁷

GF:glomerularfiltration;HD:haemodialysis;MA:microalbuminuria;PN:polynephron;PS:polysulfone;UrinaryBPA:bisphenolinurine.

Some considerations regarding bisphenol in nephrology

CanBPAbeconsideredanuraemictoxin?Doserumandtis- suelevelsincreaseinchronickidneydisease?Weknowthat patientswithkidney diseasehave elevatedserum levelsof BPA andthat someoftheeffects ofBPA inlaboratoryani- malsalsoappearinuraemicpatientsonhaemodialysis,but itisnotknownwhetherthereisadirectrelationship.Itisnot yetknownwhetherremovingBPAfromthematerialandthe solutionswillsolvesigns andsymptomsassociatedtoBPA.

Our study⁴⁷ showed how the use of membraneswith BPA increasesserumandintracellularlevelsofBPAinhaemodial- ysispatients.Therewasnocorrelationwithtimeondialysis, andtherewasalsohighvariabilityamongthedifferentindi- viduals, which may suggest that there the metabolisation processisnotuniforminallpatients.BPAmayberesponsible, atleastinpart,fortheincreaseintheinflammatorymarkers andoxidationobservedinthesepatients.However,itseems appropriate,asrecommendedbyFDAinothersituations,to attempttoreduceBPA exposureasmuchaspossible,asit seemslikelythatitmay beconsideredtobeanexogenous uraemictoxinwithpossibleclinicalimplications.

Recent evidence has led the Scientific Committee on Emerging andNewlyIdentified Health Riskscommissioned bythe EuropeanUniontoissueinearly2015areportenti- tled“Finalopinionon thesafety oftheuse ofbisphenolA in medical devices”, in which they conclude that there is ariskofadverse effectsfrom BPAwhen itis “availablefor systemicexposureafternon-oralexposureroutes,especially forneonatesinintensivecareunits,infantsundergoingpro- longedmedicalproceduresandfordialysispatients”,⁴⁹and theythereforerecommendlimitingitsuse wheneverpossi- bleandemphasisethatthebeneficialeffectsofthematerial used(rigidity,durability,etc.)donotexceedthepotentialrisk ofBPA.

ThedecreaseintheurinaryeliminationofBPAinpatients with chronic kidney disease,in the stages before dialysis,

shouldleadtospecificstudiestodeterminewhetherthispop- ulationshouldbeconsidered,togetherwithnewborns,asan at-riskpopulationintermsofenvironmentalexposuretothis compound.

Conflicts of interest

Thestudypublishedbyourgroupmentionedinthetextwas fundedbyaresearchgrantfromNiproCorporation(Boschetal.

JASN206).Thesponsorshadnoinfluenceinthedesign,the interpretationoftheresultsorthedraftingofthemanuscript.

Acknowledgements

The Kidney Disease and DiabetesResearch Group (IIS-FJD) is fundedbythe followingagencies:Health ResearchFund (PI14/00386;PIE13/00051andPI16/01298),theSpanishSociety ofNephrology(SENEFRO)andFundaciónRenalÍ ˜nigoÁlvarez deToledo(FRIAT).

Appendix A. Members of the group analysing the role of bisphenol A in haemodialysis patients

Enrique Bosch, Alberto Ruiz-Piego, Esther Civantos and SebastiánMas,oftheKidneyDisease,VascularDiseaseand DiabetesLaboratory,FundaciónJiménezDíaz,Madrid.

Didier Sanchez-Ospina, of the Dialysis Unit, Fundación JiménezDíazandFundaciónRenalI ˜nigoÁlvarezdeToledo, Madrid.

VanesaCamarero,IsabelSaez-CaleroandPedroAbaigar,of theNephrologyDepartment,ComplejoHospitalariodeBurgos, Burgos.

Vanesa Pérez-Gómez, Alberto Ortiz, Jesús Egido and Emilio González-Parra, of the II-S Nephrology and Hyper- tension Department, Fundación Jiménez Díaz, Universidad Autónoma,Madrid.

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