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J ݌ '  Ќ     Sif    Theetiologyofvasculardiseaseinthedialysispatientis_multifactorial_.Thefocusofthisreview i  isonabnormalitiesoflipidmetabolisminthesepatients,butclearly,attentionmustbepaidto U otherknownandputativecardiacriskfactorssuchasci_garette_Ԁsmoking,hypertension, A _hypervolemia_,and_hyperhomocysteinemia_.  ݌ -} Ќ     Sl   Thepastdecadehasseenthepublicationofmanystudiesinthe_nonuremic_Ԁpopulation,showing  statisticallysignificantreductionsincardiovascularmortalitywithvariouslipidlowering  therapies.However,becauseofthelackoflongtermcontrolledstud_ies_,itremainsunclear  whetherthesetreatmentsareapplicabletopatientswithESRD.Ontheonehand,becausethereis  suchahighprevalenceofcardiovascularmorbidityandmortalityindialysispatients,onemight o expectthatthesetherapieswould_hav_Ԁeanevenmoredramaticeffectonthis  highevent [ populationcomparedtothegeneralpopulation.Ontheotherhand,theetiologyofthese G abnormalitiesmaybeevenmorecomplexintherenalfailurepatient,anditispossiblethatthe 3 treatmentsgiventothe_nonuremic_Ԁpopulationmayhavesurprisinglylittlebenefitinthose  o patientsondialysis. ݌  ![ Ќ     S"J"   Thepurposeofthisdocumentistoaddresstheissueoflipidloweringtherapyinpatientswith " ESRD,particularlypatientsonperitonealdialysis(_PD_).Thefirstsectionwilladdresswhatis # knownaboutthepathogenesisoflipidabnormalitiesinpatientswithchronicrenalfailure.The u$ secondsectionwillexaminetheevidenceforabnormalitiesinlipidmetabolismasariskfor a%  vasculardiseaseinpatientson_PD_.Thethirdsectionwillbrieflyreviewthelipidloweringstudies M&! thathavebeenperformedonthe_nonuremic_Ԁpopulation.Inthefourthsection,wewilldiscuss 9'"  whatisknownaboutthesafetyandefficacyofthecommonlyusedlipidloweringdrugsinthe %(u#! renalfailurepopulation.Inthefinalsection,wewillgivetherecommendations,asof1998,asto )a$" whatwecanhopeforusinglipidloweringtherapyinourpatientson_PD_. ?݌ )M%# Ќ     S+&<+& `  LipidDisordersinPeritonealDialysisPatients:DescriptionandPathogenesis `݌ +&$ Ќ     S!-q(,( V  Whilewatersolublesubstancessuchasglucoseandaminoacidsaretransportedinaqueous !-q(% solutionintheblood,transportofthewaterinsolublelipidsinvolvestheparticipationofarange  ofcomplexmolecules.Lipidsmaybeeither  simple(cholesteroland_nonesterified_Ԁfattyacids)  or  complex(cholesterolestersandglycerolesters).Becauseoftheirinsolubilityinplasma,  alllipidsaretransportedassociatedwith  _apoproteins_,forminglipoproteincomplexes.These t complexescontainvarying_propor_Ԁ_tions_Ԁoftriglycerides,_phospholipids_,andcholesterolandits ` esters.Partialexceptionsarethe_nonesterified_Ԁfattyacids,ofwhich99%aretransportedboundto L  albumin. V݌ 8  Ќ     S w  !  _Apoproteins_:_Apoproteins_Ԁhavefunctionsotherthanenablingtransportoflipids.Someserveto   definethetypeofreceptorwithwhichthelipoproteincanbind,whileothersservetoactivate   lipoproteinspecificenzymes,ormaythemselvesbeenzymes. !!݌    Ќ     S4 1  #  Fivegroupsof_apoproteins_Ԁhavebeenidentified(_ApoA_Ԁto_ApoE_).The_ApoA_ԄӀand_ApoB_Ԅ 4  containing_lipoproteins_Ԁarethetwomajorclasses.Insomecases,thereismorethanonegenefor  p  eachgroup,inwhichcasetheyarespecifiedbypostscriptssuchas  _ApoA_ԄӀIand  _ApoC_Ԅ  \  II.Furthermore,_polymorphisms_Ԁofthesegeneloci,whichmayconferincreasedsusceptibility H  tocertaindiseases,existwithinthegeneralpopulation.Forexample,threedifferentalleles(E2, 4 E3,andE4)atthe_ApoE_Ԁgenelocuscodefor_thre_Ԁedifferentprotein_isoforms_,ApoE2,E3,and   E4,respectively,resultinginsixdifferentphenotypes._Apoproteins_Ԁforwhichadefiniterolehas   beenidentifiedarelistedinTable1. ##݌  Ќ     S:7 )  _Lipoproteins_:Separationof_lipoproteins_Ԁbydensityyieldsfivemajorfractions.Theseare,in : orderofdecreasingdensity,highdensity_lipoproteins_Ԁ(HDL),lowdensity_lipoproteins_Ԁ(LDL), &v intermediatedensity_lipoproteins_Ԁ(IDL),verylowdestiny_lipoprot_Ԁ_eins_Ԁ(_VLDL_),and b _chylomicrons_.HDL,LDL,IDL,and_VLDL_Ԁareallderivedfromendogenouslipidcomponents, N whereas_chylomicrons_ԀaremanufacturedintheGolgiapparatusofintestinal_mucosal_Ԁcells,from : dietaryfat.All_lipoproteins_Ԁcarryalltypesoflipid,butindifferentproportions,sothatthedensity & isdirectlyproportionaltotheproteincontentandinverselyproportionaltothelipidcontent  (Table2). )*݌  Ќ     S@= T/  TABLE1 @ FunctionalRolesofSomeSpecific_Apolipoproteins_Ԁ T//݌ , | Ќ  S*FG ddd Xdd Xdd X(#(#,l`,{ll+  8DD'k!k!  8   S!k! S 1  _Apoprotein_ 11݌ ?DDD,!!DD ?Ќ     S!k! 2  Identifiedrole 22݌ UDDD,!  DDD  UЌ     S #Y" 3  _ApoA_Ԅ1 33݌ ?DDD,! #YDD ?Ќ     S #Y" 4  Activateslecithincholesterol_acyltransferase_Ԁ(_LCAT_) 44݌ UDDD, #Y   DDD  UЌ     ST$$Q  6  _ApoB_Ԅ100  6;6݌ ?DDD,!T$!DD ?Ќ     ST$$Q 7  FacilitatesbindingofLDLparticlestoLDLreceptors 7E7݌ UDDD,T$"  DDD  UЌ     S% L%  28  _ApoB_Ԅ48 28b8݌ ?DDD,!% #DD ?Ќ     S% L%  ;9  Facilitatesbindingof_chylomicron_Ԁremnantstoliverreceptors ;9k9݌ UDDD,% $  DDD  UЌ     S&:"&! :  _ApoC_ԄII ::݌ ?DDD,!&:"%DD ?Ќ     S&:"&! ;  Activateslipoprotein_lipase_ ;;݌ UDDD,&:"&  DDD  UЌ     S5(#'2# <  _ApoD_ <<݌ ?DDD,!5(#'DD ?Ќ     S5(#'2# =  TransferscholesterolestersfromHDL3 ==݌ UDDD,5(#(  DDD  UЌ     S)$-)}$ >  _ApoE_ >>݌ ?DDD,!)$)DD ?Ќ     S)$-)}$ ?  Facilitatesbindingof_chylomicron_Ԁremnantstoliverreceptors ??݌<20)$*   DDD <Ќ     S+n&*& @  A_subpopulation_ԀofLDLhasbeenidentifiedinwhichanadditionalproteinisattachedto_ApoB_Ԅ +n&* 100.Thisaccessoryproteinhasbeencalled_apolipoprotein_(a),andtheparticlescarryingit,  ,Z'+ lipoprotein(a),or_Lp_(a).This_apolipoprotein_Ԁisverysimilarinst_ructure_Ԁto_plasminogen_Ԁandmay ,F(, shareitsabilitytobindtofibrininbloodclots,therebybringingLDLintoareaswheretissue -2)- repairisrequired,andprovidingcholesterolformanufactureofnewplasmamembranes.  Whetherthisisitsroleornotremainstobeseen,butparadoxicallyitscirculatingconcentration  hasbeenshowntostronglypositivelycorrelatewiththeoccurrenceofatheromatousvascular  disease(1). @A݌ t Ќ     S V E  _Lipoproteins_ԀandRenalDisease:Inrecentyears,muchattentionhasbeenfocusedonthe  V relationshipofplasma_lipoproteins_Ԁtovasculardisease""theleadingcauseofdeathinthe  B Westernworld.Manystudiesthroughouttheworldhavedemonstratedacorrel_ation_Ԁbetween  . elevatedplasmalipidlevels(especiallycholesterol)andatheromatousvascularmorbidityand   mortality. EE݌   Ќ     SH E  H  Inpatientswithrenaldisease,lipoproteinmetabolismisaltered.Thisismorecloselyreflectedin H  the_apolipoprotein_Ԁprofilethanthelipidprofile,andmaythereforenotalwaysresultin 4  _hyperlipidemia_Ԁ(2).Itfollowsthatsimplemeasurementsofplasmacholesterolandtriglyceride  p  concentrationsprobablyunderestimatetheextentof  _uremic_Ԁ_dyslipoproteinemia_.  \  Nevertheless,chronicrenalfailureisusuallyassociatedwithanincreasedprevalenceof H  _hypertriglyceridemia_Ԁandlipoproteinabnormalities,_i_Ԁ_ncluding_Ԁincreased_VLDL_ԀandLDL,with 4 decreasedHDL(3,4). HH݌   Ќ     Sb_ M  Ingeneral,alterationsoflipoproteinconcentrationsresultfromanimbalancebetweenlipoprotein b synthesisanddegradation.Inrenaldisease,_lipolytic_Ԁenzymeactivityisknowntobereduced N ""inparticularlipoprotein_lipase_Ԁ(_LPL_),hepatictriglyceride_lipase_Ԁ(_HTGL_),andlecithin : cholesterol_acyltransferase_Ԁ(_LCAT_)(2).Theunderlyingmechanismsforreduced_LPL_Ԁactivityare &v unclear,butmayincludefunctionalinsulindeficiencyorresistance(possiblymediatedby b vitaminDdeficiency/_hyperparathyroidism_Ԁ),andthepresenceofa_nondialyzable_Ԁinhibitorof N _LPL_Ԁintheplasmaof_uremic_Ԁpatients.Thereducedactivityisdetectableataglomerularfiltration : rateof50_mL_/min,whichmaygosomewaytoexplainingtheongoinglipidabnormalitiesfound & inmanytr_ansplant_Ԁpatients. M>M݌  Ќ     STQ PS  Reduced_LPL_Ԁactivityresultsindelayedhydrolysisof_ApoB_Ԅcontaining_lipoproteins_Ԁand T preferentialenrichmentofpartially_delipidized_,triglyceriderich_particulates_Ԁwith_ApoC_ @ _polypeptides_.Individualvariationsinlipoproteinproductionrates,_LPL_Ԁand_HTGL_Ԁactivities,and , | thecompositionof_lipoproteins_Ԁwilldetermineplasmalipidandlipoproteinlevels;butingeneral, !h theendresultisadecreaseinlevelsof_nonartherogenic_Ԁ_ApoA_Ԅcontaining_lipoproteins_,andan "T increaseinlevelsof_proatherogenic_ԀAp_oC_ԄIIIenriched_ApoB_Ԅcontaining_lipoproteins_Ԁofvery "@ lowandlowdensityproperties.(SeeRef.2foranindepthreviewoftheseabnormalities.) PSS݌ #, Ќ     Sn% %k  Y  TABLE2 n%  CharacteristicsoftheFiveMajorLipoproteinGroups YY݌ Z&!! Ќ  S*pHI ddl`{ll{FG(#(#p,}q,}q,}q,}}+  8DD''""'"  8   S'<#'" S [  Density [\݌ =DD,!'<##DD =Ќ     S'<#'" \  Diameter \\݌ =DD,!'<#$DD =Ќ     S'<#'" ]  Cholesterol ]]݌ ?DDD,!'<#%DD ?Ќ     S'<#'" a^  Triglycerid '<#& e a^^݌<20(($'  DDD <Ќ  S*JL dd}q}q}q}}HI(#(#,}q,}q,}q,}q,}}+  8DD'#*s%'#*s%  8   S*%/*% S `  Lipoprotein ` a݌ =DD,!*%(DD =Ќ     S*%/*% a  (g/_mL_) aa݌ =DD,!*%)DD =Ќ     S*%/*% b  (_nm_) bb݌ =DD,!*%*DD =Ќ     S*%/*% c  (%) cc݌ ?DDDD,!*%+DD ?Ќ     S*%/*% vd  (%) vdd݌ UDDD,*%,  DDDD  UЌ     S+'z+& ae  HDL aee݌ =DD,!+'-DD =Ќ     S+'z+& 4f  1.063!!1.210 4fdf݌ =DD,!+'.DD =Ќ     S+'z+& &g  8 &gVg݌ =DD,!+'/DD =Ќ     S+'z+& g  ~20 g'h݌ ?DDD,!+'0DD ?Ќ     S+'z+& h  ~6 hh݌ UDDD,+'1  DDD  UЌ     S-h(,( i  LDL ii݌ =DD,!-h(2DD =Ќ     S-h(,( j  1.019!!1.063 jj݌ =DD,!-h(3DD =Ќ     S-h(,( {k  22 {kk݌ =DD,!-h(4DD =Ќ     S-h(,( Ml  55!!65 Ml}l݌ ?DDD,!-h(5DD ?Ќ     S-h(,( ;m  ~10 ;mkm݌ UDDD,-h(6  DDD  UЌ     SS &n  IDL &nVn݌ =DD,!SDD =Ќ     SS n  1.006!!1.019 n)o݌ =DD,!SDD =Ќ     SS o  27 op݌ =DD,!SDD =Ќ     SS p  ~38 pp݌ ?DDD,!SDD ?Ќ     SS q  ~23 qq݌ UDDD,S  DDD  UЌ     SNK }r  _VLDL_ }rr݌ =DD,!NDD =Ќ     SNK qs  <1.006 qss݌ =DD,!NDD =Ќ     SNK Gt  43 Gtwt݌ =DD,!NDD =Ќ     SNK u  15!!20 uIu݌ ?DDD,!N DD ?Ќ     SNK v  ~60 v7v݌ UDDD,N   DDD  UЌ     SF v  _Chylomicron_ v"w݌ =DD,! DD =Ќ     SF w  <0.950 wx݌ =DD,! DD =Ќ     SF x  500 xx݌ =DD,! DD =Ќ     SF y  ~5 yy݌ ?DDD,!DD ?Ќ     SF jz  ~85 jzz݌<20   DDD <Ќ     S7 4 <{   HDL=highdensity_lipoproteins_;LDL=lowdensity_lipoproteins_;IDL=intermediatedensity # s _lipoproteins_;_VLDL_Ԁ=verylowdestiny_lipoproteins_. <{|{݌  _ Ќ     S N  F}  Lipoprotein(a)levelsaretwotothreetimeshigherin_uremic_Ԁpatientsthanincontrols(5,6).   _Hyperparathyroidism_Ԁhasbeenshowntoinfluencelipidmetabolisminexperimentalchronic   renalfailure,butitsimportanceintheclinicalsettingisunknown(7). F}v}݌ y  Ќ     S [   Y  _Lipoproteins_ԀandPeritonealDialysis:Thecharacteristiclipoproteinabnormalitiesdescribedin  [  _PD_ԀpatientshaverecentlybeenthoroughlyreviewedbyWheeler(8).Dialysisdoesnotcorrect G  _uremic_Ԁ_dyslipoproteinemia_,butmayalteritspattern(9).Severalstudieshaveshownthat,once 3  dialysiscommences,continuousambulatoryperitonealdialysis(CAPD)patientsdevelopa  somewhatdifferentandprobablymore_atherogenic_Ԁlipoproteinprofilethandohemodialysis(HD)   patients(10!!15). Y݌  Ќ     S96   Notallreportsagreeontheexactdifferencesbetweenthetwotreatmentmodalities,butthismay 9 notbesurprisingwhenoneconsidersthatthestudiescomefromethnicallyandgeographically %u distinctpopulationssuchasnorthernEurope,southernEurope,andtheU.S.A.Furthermore,bias a inpatientandmodalityselectionwillvaryfromonecentertothenext.However,comparedwith M _uremic_ԀpatientsorthoseonHD,CAPDpatientsappeartohavehigherLDLandtotalcholesterol 9 concentrationswithsimilarorl_ower_ԀHDLlevels(10!!12)._Llopart_Ԁreportsamoremarked %  elevationintriglyceridelevelsinSpanishpatients,reflectingatwofoldincreaseinIDLmassand ! greatertriglycerideenrichmentof_VLDL_,IDL,andLDL(15). 2݌ " Ќ     S?<   Inanattempttoovercomethedifficultiesofcrosssectionalstudies,_Avram_Ԁetal.prospectively ?# measuredserumtotalcholesterol,HDL,_ApoA_Ԅ1,and_ApoB_Ԁovera3yearperiodin273CAPD +{$ andHDpatients(10).Usingmultipleregressionanalysisitwas_foun_Ԁdthatserumalbumin,race,  g% gender,anddiabetes,butnot_PTH_,independentlyinfluencedlipoproteinprofilesinbothgroups !S& ofpatients.Adjustingforserumalbuminandotherfactorsand_covariates_,triglycerideandHDL !?' levelsweresimilar,butCAPD_patie_Ԁ_nts_Ԁhadsignificantlyhighertotalcholesterol,total "+( cholesteroltoHDLratios,and_ApoB_Ԁlevels.Furthermore,CAPDpatientsalsodemonstrateda #) lower_ApoA_Ԅ1to_ApoB_Ԁratio.PatientswithdiabetestendedtohavealowerHDLlevelbut $ * otherwisehadlipidpr_ofiles_Ԁsimilartootherpatients. Ӈ݌ % + Ќ     S1'"&."    Interestingly,in_Avram_sstudy_hyperlipidemia_Ԁwasassociatedwithimprovedvisceralprotein 1'", status.However,theassociatedlipidriskwasfaroutweighedbytheincreasedoverallmortality (m#- ofpatientswith_hypolipidemia_,suggestingthatmalnutritionisofgreaterprognosticimportance  )Y$. thanis_uremic_Ԁ_dyslipidemia_.Therewasasmallbutsignificantdeclinein_ApoB_Ԁlevelsinthis )E%/ study(16).Otherstudieshavedemonstratednochangeinlipidandlipoproteinlevelsovertime *1&0 (11,17).Othershorter_longitudin_Ԁalstudies,involvingfewerpatients,havereportedaworsening +'1 oflipoproteinabnormalitieswithtimeonCAPD(18,19).  =݌ , (2 Ќ     SS   AnumberoffactorsmaybeimportantinproducingadifferentlipoproteinprofileinCAPD S patientscomparedtoHDpatients.GlucoseabsorptionfromtheperitonealcavityofCAPD ? patientsvariesbetween100!!200g/day,andresultsinincreasedinsulinlev_els_Ԁwhichare + thoughttoenhancesynthesisoftriglycerideintheliver(11).Inaddition,proteinlossintothe  dialysateoccursatarateof5!!15g/day,alongwith_lipoproteins_Ԁofalltypegroups.Sieving  resultsinpreferentiallossofthesmallermo_lecules_ԀsuchasHDL,whichislostatarate   equivalentto34%ofitsdailysyntheticrate(19).Thisstatehasbeencomparedtothe_nephrotic_   syndrome,wherein_hypoalbuminemia_Ԁisthoughttostimulatehepaticlipoproteinsynthesis, w  althoughasignificantdifferenceisthatthekidneyisnotcontributingtoalbumincatabolismin c  CAPDpatients.Ithasbeensuggestedthatperitonealproteinlosses_upregulate_Ԁhepatic_VLDL_ O   production,butthemajorityofstudieshavenotdemonstratedacorrelationbetweentrig_lyceride_ ;  or_VLDL_ԀlevelsandproteinlossesoralbuminlevelsinCAPDpatients(8,19). ̒݌ 'w  Ќ     S f  Ù  Severalstudieshavespecificallyconcentratedonlevelsof_Lp_(a)(6,14,20,21)becauseofits   knownstrongassociationwithatheromatousdiseaseinthegeneralpopulation.Allthestudies   found_Lp_(a)levelstobetwotothreetimeshigherinCAPDpatientsthaninhealthycontrols.   _Siamopoulos_Ԁetal.(14)compared_Lp_(a)levelsinCAPDandHDpatientsandfoundthelevelsto } beslightlyhigherinCAPDpatients,butthedifferencewasnotsignificant(0.28vs0.20g/L,p= i 0.056).Inthestudyof_Shoji_Ԁetal.,median_Lp_(a)levelswerealmosttwiceashighinCAPD U patientscomparedtothoseonHD.Furthermore,therewasanassociationbetween_Lp_(a)levels A andapositivehistoryofischemicheartdisease(20).Thisfindingwasnotconfirmedby_Anwar_Ԁet -} al.(6),whonotedthatlevelsashighasthosefoundinhisseriesoccurinfewerthan5%ofthe i generalpopulation.Themechanismsthatleadtoelevated_Lp_(a)concentrationsinCAPDare U unclear,anditisnotknownwhethertheincreaseisaresultofimpairedrenalfunctionorof A CAPDitself.Onepossibilityisthatincreasedlossof_lipoproteins_Ԁandotherplasmaproteinsinto - thedialysatemaystimulate_Lp_(a)synthesisintheliver(6,20). Ù݌  Ќ     S[X r  Insummary,itwouldappearthatCAPDisassociatedwithamore_atherogenic_Ԁlipoproteinprofile [ thanisHD;asummaryofthelikelyabnormalitiestobefoundinwellnourishedCAPDpatients G isshowninTable3.Factorscontributingtothisdifferencemayincludeglucoseuptakefrom 3 dialysisfluid,proteinandlipoproteinlossintothedialysisfluidstimulatinghepatic_VLDL_  o synthesis,andpreferentialsievingofsmaller  protectiveHDLmolecules.However,detailed  ![ mechanismsremaintobeelucidated,anditwouldappearthatgeographicallydistinctCAPD !G populationsmayexhibitsubtlydifferentabnormalities.Thisisnotsurprisingbecausegeneticand "3 environmentalfactorswillvary. r݌ #  Ќ     Sa% %^  إ  TABLE3 a% ! TypicalLipoproteinProfileofCAPDPatientsComparedtoApproximateMeansofaHealthy M&!" Population إ݌ 9'"# Ќ  S*MP dd}q}q}q}q}}JL(#(#, }q,"}q, }}+  8DD'x(#$x(#  8   S($x(# S w  Lipoprotein w݌ =DD,!($%DD =Ќ     S($x(# h  HealthfulMean h݌ ?DDD,!($&DD ?Ќ     S($x(# H  EffectofCRF/CAPD Hx݌ UDDD,($'  DDD  UЌ     S*f%)% B  Totaltriglycerides Br݌ =DD,!*f%(DD =Ќ     S*f%)% %  1.25(_mmol_/L) %U݌ ?DDD,!*f%)DD ?Ќ     S*f%)% $  Increased''2!!''3 $T݌ UDDD,*f%*  DDD  UЌ     Sa+&+^& P  Totalcholesterol P݌ =DD,!a+&+DD =Ќ     Sa+&+^& 1  5.90(_mmol_/L) 1a݌ ?DDD,!a+&,DD ?Ќ     Sa+&+^& 0  Increasedby1!!2_mmol_/L 0`݌ UDDD,a+&-  DDD  UЌ     S,'Y,' f  _VLDL_Ԁcholesterol f݌ =DD,!,'.DD =Ќ     S,'Y,' f  0.45(_mmol_/L) f݌ ?DDD,!,'/DD ?     S,'Y,' o  Increased''2!!''3 o݌ UDDD,,'0  DDD  UЌ     SS   LDLcholesterol ˴݌ =DD,!SDD =     SS   4.00(_mmol_/L) ݌ ?DDD,!SDD ?Ќ     SS   Increasedby0.5_mmol_/L ݌ UDDD,S  DDD  UЌ     SNK   HDLcholesterol ҷ݌ =DD,!NDD =Ќ     SNK   1.30(_mmol_/L) ݌ ?DDD,!NDD ?Ќ     SNK   Decreasedby0.2!!0.4_mmol_/L ݌ UDDD,N  DDD  UЌ     SF   Lipoprotein(a) ݌ =DD,!DD =Ќ     SF   10.0mg/_dL_ Ȼ݌ ?DDD,!DD ?Ќ     SF   Increased''2!!''4 ļ݌ UDDD,   DDD  UЌ     S4   _Apolipoprotein_ԀB ݌ =DD,!4 DD =Ќ     S4   80mg/_dL_ ݌ ?DDD,!4 DD ?Ќ     S4   Increasedby50%!!100% ݌ UDDD,4   DDD  UЌ     S/  ,   _Apolipoprotein_ԀA1 ݌ =DD,!/  DD =Ќ     S/  ,   100!!200mg/_dL_ ݌ ?DDD,!/ DD ?Ќ     S/  ,   Reducedby10%!!50% ݌<20/    DDD <Ќ     S z     CAPD=continuousambulatoryperitonealdialysis;CRF=chronicrenalfailure;_VLDL_Ԁ=very   lowdestinylipoprotein;LDL=lowdensitylipoprotein;HDL=highdensitylipoprotein. ݌   Ќ     S7 4    Inviewofthefindingsof_Avram_Ԁetal.,a  normallipoproteinprofilemayreflectmalnutrition 7  andincreasedriskofdeath(16).AnyCAPDpatientwhoisfoundtohavea  favorable #s  lipoproteinprofile,asdistinctfromthatshowninTable3,shouldbec_arefully_Ԁassessedforsigns _  ofmalnutrition. ݌ K  Ќ     S: 7  LipidsasaRiskFactorforVascularDiseaseinPatientsonPeritonealDialysis 7g݌  Ќ     So /  Insubjectswithoutrenaldisease,elevatedcholesterolisariskfactorforischemicheartdisease, o andlipidloweringtreatmentlowersthisrisk.Thisassociationhasnotbeendemonstratedin  [ subjectswithESRD.Cardiovasculardiseaseisthemostcommoncauseofdeathin_PD_Ԁpatients. G Manypatientsstartingdialysishavepreexistingcardiovasculardisease,whichisassociatedwith 3 alowersurvivalondialysis(22!!25).The_CANUSA_ԀtrialandtheItalianCooperativePeritoneal  DialysisStudyGroupboth_foun_Ԁdthatcardiovascularmortalityrelatestodiseasepresentatthe   startofdialysis,andnottosomefactorassociatedwithdialysis(23,24).However,_Khanna_Ԁetal.  foundanincidenceofdenovoischemicheartdiseaseof8.8%at1yearand15%at2years(22),  whichishigherthanthatseenintheFraminghamcohort. /_݌  Ќ     Sa k  Thestudiesofwhethercholesterolisariskfactorforischemicheartdiseasearemixed.Some a  investigatorshavestressedriskfactorsotherthanlipids,suchasleftventricularhypertrophy, M! hypertension,andabnormalcalciummetabolism,toaccountforthehighcardiovascularmortality 9" (26,27).InHDpatients,theriskassociatedwithcholesterolisaJcurve(28,29)._Lowrie_Ԁetal.  %# foundthatthegreatestriskwasassociatedwithalowcholesterol(<150mg/_dL_).Theriskthen !$ progressivelydecreasedforhigherlevelsofcholesteroluntilthecholesterolwasover300mg/_dL_, "% atwhichleveltheriskincreased(29).Thisstudydidnotseeanypatternofriskassociatedwith #& cholesterolin_PD_Ԁpatients.Alowcholesterolwithalowalbuminhasbeenassociatedwithhigher $' mortalityin_PD_Ԁpatientsinsomestudies(16,30). k݌ q% ( Ќ     S'S"&"   Thisdemonstratestheimportanceofpoornutritionasariskfactorformortality.Thestrengthof 'S") theriskassociatedwithlowcholesterol(andmalnutrition)mayobscuretheriskofvascular '?#* diseaseassociatedwithhigherlevelsofcholesterol(16). ݌ (+$+ Ќ     Sm*%*j% i  Otherinvestigatorshaveseenanassociationbetweenelevatedlipoproteinlevelsandischemic m*%, heartdisease(31!!33).Gambaetal.,inaretrospectivestudy,foundahighermortalitywitha Y+&- lowalbuminandalow_creatinine_Ԁ(indicatingpoornutrition),butalsowithahighcholesterol E,'. level(33).Pollocketal.foundthatpatientswhosurvivedhadahigheraveragealbuminanda 1-(/ loweraveragetriglyceridelevel(2.95_mmol_/Lvs3.84_mmol_/L),althoughthisstudyexamined  eachvariableindividuallyanddidnotuse_multivariate_Ԁanalysistocontrolforother_covariates_  (31)._Gault_Ԁetal.foundthatelevated_ApoB_Ԁlevelsandanelevatedcholesterol/HDLratio  correlatedwiththeseverityofischemicheartdisease.Anelevatedtriglyceridelevelwasalso t associatedw_ith_Ԁanincreasedrisk,buttherelationshipwaslessstrong(32).Furthermore,this ` studydidnotexaminepatientsfromthestartofdialysis,butfromthestartofthestudyperiod. L  Theexclusionofpatientswhodiedpriortothestartofthestudymayhaveinfluencedtheresults. 8   i݌̌     S c     TreatmentofLipidsinNormalSubjects  :݌   Ќ     SH E    Insubjectswithoutrenalfailure,highLDLcholesterolandlowHDLcholesterolareriskfactors H  forcardiovascularmortality(34,35).Whetheranincreasedtriglyceridelevelisanindependent 4  riskfactorforcardiovasculardisease(_CVD_),onceadjustedforother_covariates_,iscontroversial.  p  ThetriglyceridelevelisgenerallyinverselyrelatedtotheHDLlevel.TheFraminghamstudy  \  foundthatthetriglyceridelevelwasapredictoralone(especiallyinwomen),butonceother H  factorsweretakeninto_accoun_Ԁt,itwasnolongerasignificantindependentpredictorof_CVD_ 4 (35).Arecentmetaanalysisfoundthatthetriglyceridelevelisanindependentriskfactor,even   whenadjustedforHDL(36).However,inthismetaanalysis,notallofthestudiesusedhadc   _omplete_Ԁdataonother_covariates_.  ݌  Ќ     S:7 #  Lipidloweringbymultipleinterventionshasbeenshowntodecreasetheincidenceof : cardiovascularevents,forbothprimarypreventiontrials(37!!41)andsecondaryprevention &v trials(42!!44).TheLipidResearchClinicstrialrandomizedasymptomatic_subjec_Ԁ_ts_Ԁto b _cholestyramine_Ԁorplacebo.TheLDLwasloweredby20%,whichledtoa19%decreasein N nonfatalmyocardialinfarction(MI),a24%decreasein_CVD_Ԁdeath,anda21%decreaseinthe : needforbypasssurgery(38).Asignificantdecreaseinoverall_mortali_Ԁ_ty_Ԁwasnotseen(observed & 7%loweroverallmortality)becauseofanincreaseinviolentandaccidentaldeath. #S݌  Ќ     STQ   AsimilarfindingofalowerincidenceofMIand_CVD_Ԁmortalitywithanincreaseinnon_CVD_ T mortalityhasbeenseenwith_fibric_Ԁacidresins(37).Whetherthisisafunctionofchanceor @ relatedtoaneffectofthetreatmentisunclear.Morerecenttrialsusing_HMG_Ԅ_CoA_Ԁ_reductase_ , | inhibitorshaveproducedgreaterdecreasesinLDLcholesterol,andhaveshownalower !h incidenceofcardiovasculareventsandaloweroverallmortality(40,41,44).Inthe_Pravastatin_ "T MultinationalStudy,subjectsassignedto_pravasta_Ԁtinhada26%lowerLDL,whichledtoa31% "@ decreaseinnonfatalMI,a28%decreasein_CVD_Ԁdeath,a32%decreaseinoverallmortality,and #, a37%decreaseintheneedfor_revascularization_Ԁ(40).The4Strialwasalargesecondary $  preventiontrialusing_sim_Ԁ_vastatin_Ԁinsubjectswithahistoryofcoronaryarterydisease(44).In %!! thesubjectson_simvastatin_,theLDLwasreducedby35%andtherewasa42%lowerincidence &!" of_CVD_Ԁdeath,a32%lowerincidenceofnonfatalcardiovascularevents,anda37%decrease_i_Ԁn '"# theneedfor_revascularization_.Therewasnodifferencein_noncardiovascular_Ԁdeaths(44). ݌ x(#$ Ќ     S *Z%)%   Acommonlipidabnormalityin_PD_Ԁpatientsis_hypertriglyceridemia_ԀwithlowHDLlevels(see  *Z%% secondsection).Evidencethattreatingtheseabnormalitiesintheabsenceofabnormalitiesin *F&& LDLcholesterolisbeneficial,isnotclearcut.Onetrialof_clofibr_Ԁateandnicotinicacidstudied +2'' subjectswithahistoryofMI,butdidnotselectsubjectsbasedonthetypeof_hyperlipidemia_Ԁ(43). ,(( _Inthistrial,hypertriglyceridemiawasthemostcommonlipidabnormalityseen.Treatmentwas - )) associatedwitha36%lowerCVDmortalityanda26%lowerincidenceinoverallmortality.The  mortalitybenefitwasseenonlyinsubjectswithtriglyceridelevelsabove1.5mmol/L,andthe  benefitappearedtoberelatedtothedegreeoftriglyceridelowering.However,thisstudydidnot  controlforchangesinHDLcholesterolandwasanonblinded,althoughrandomized,trial. ݌ t Ќ     S V   IntheHelsinkiHeartStudy,therewasnoconsistentrelationshipbetweenthechangeinserum  V triglyceridesandthelowerincidenceofcardiovasculareventsseen,althoughtheeffectwas  B greatestinsubjectswithelevatedbaselinetriglyceridelevels(45).Itshouldbenotedhowever,  . thatinpatientswithelevatedtriglycerides,loweringofLDLcholesterolcanhaveabeneficial   impact,eveninthepresenceofothermetabolicallyunfavorablefactorssuchaslowHDL   cholesterolorraisedtriglycerides.ThePostCABGtrialrevealedthataggressivelyreducingLDL    cholesterolattenuatestheriskassociatedwithunfavorableHDLcholesterolandtriglyceride   profiles(46). 3݌ z  Ќ     S \     TreatmentofHyperlipidemiainPeritonealDialysisPatients  ݌  \  Ќ     S K    WhilealipidloweringdietcanbemoderatelyeffectiveinHDpatients(47,48),nodataare   availableconcerningdietarymanipulationofplasmalipidsinpatientsonPD(49).Atthis  juncturehowever,itisimportanttonotethateffectinggoodglycemiccontrolindiabeticpatients v onPDmaybeimportantinimprovinglipidabnormalities,particularlyhypertriglyceridemia. ݌ b Ќ     SD *  Thereareseveralstudiesthatexaminetheeffectofpharmacologictherapyonlipidabnormalities D inpatientsonPD.ItisclearthattheHMGCoAreductaseinhibitorsreducebothtotalandLDL 0 cholesterolinthesepatients.Arecentretrospectiveanalysisoflipidloweringtherapyinpatients  withdifferenttypesofrenaldiseasesurveyed18interventionalstudiesinpatientsonCAPD.The  analysisdemonstratedthattheHMGCoAreductaseinhibitorsreducedtotalandLDLcholesterol  levels,andsignificantlyincreasedHDLlevels.Furthermore,thefibricacidanalogsledtoa  significantreductioninplasmatriglycerides(49).However,aswasnotedpreviouslyinthis | paper,thetreatmentbenefitsfromreducingplasmatriglyceridesalonewithregardtocardio h vasculardiseaseremainuncertain.Theextentofnormalizationofserumlipidswassimilar T amongthedifferentrenaldiseasegroupsexamined,includingCAPDpatients,thoseonHD, @ patientswithchronicrenalinsufficiency,patientswithafunctioningrenaltransplant,and , | patientswithnephroticsyndrome.Ifanything,patientsonCAPDorwithnephroticsyndromehad !h agreaterreductionintriglyceridesandanincreaseinHDLcholesterolwithHMGCoAreductase "T inhibitors,comparedtothoseintheotherrenaldiseasecategories.Thesimilarityofresponsein "@ CAPDandnephroticpatientsmaybetheresultofasimilarityofpathogenesisoflipid #, abnormalitiesinthesetwogroups,thatis,lossofproteinintothedialysiseffluent(PD)orthe $  urine(nephroticsyndrome)(49). *Z݌ %!! Ќ     SF'"&C" `  Thefibricacidsshouldbedosereducedtoavoidmyopathy.Lowdosesoftheseagentshowever F'"" donotappeartoleadtorhabdomyolysis(49).Intheretrospectiveanalysisdescribed,in18 2(## studiesoffibricacidanalogs,therewerenodocumentedepisodesofrhabdomyolysisin282 )n$$ patientswithdecreasedrenalfunction,treatedforatotalof109patientyears(49).Although  *Z%% experiencewiththeseagentsinPDpatientsisrecent,itappearsthattheHMGCoAreductase *F&& inhibitorsdonothavetobedosereducedforrenalfailure.However,evenintheabsenceof +2'' overtclinicalsideeffects,creatininephosphokinase(CPK)levelsmayincrease.Inonestudyof ,(( CAPDpatients,just10mgofsimvastatinledtoasmuchasatenfoldincreaseinCPKlevels - )) (50).Similarsideeffectshavebeenreportedwithotheragentssuchaspravastatin(51). `݌  Ќ     SB?    FishoilsupplementationlowerstriglyceridesinPDpatientsbyapproximately30%(52!!55). B Theeffectonotherlipoproteinfractionshasbeenvariable.Somestudieshaveshownadecrease .~ (54),anincrease(52),ornochange(53)inHDL.MoststudiesshowednochangeinLDL j (52,53,55),althoughonestudydidshowanincreaseinLDLcholesterolwithfishoil  V supplementation(54).  P݌  B Ќ     S 1     Carnitinehasbeenadvocatedtoimprovelipidsinrenalfailurepatients.Carnitineisinvolvedin   mitochondrialtransportoffattyacids(56).InpatientsonHD,plasmaandmusclecarnitinelevels p  decrease(57).Thismayleadtoneuromuscularsymptomsandincreasedtriglycerides,although \  thistheoryiscontroversial.TheeffectsofsupplementationontriglyceridelevelsinHDpatients H  havebeenmixed.Somestudieshaveshownanimprovedlipoproteinprofile(lowertriglycerides 4  andhighHDL)(58!!60),whileotherstudieshaveshownnochange(61,62)orworsened  p  triglyceridelevels(63!!65).InPDpatients,totalplasmaormusclecarnitinelevelsdonotappear  \  todecreasewithtime(57).TherearefewerstudiesofcarnitinesupplementationdoneinPD H  patients.Waradyetal.didnotseeaneffectonlipidswithcarnitinesupplementationinpediatric 4 PDpatients(66).Wanneretal.foundthatcarnitinesupplementationledtoanincreasein   triglyceridelevels(65).   ݌   Ќ     SNK   RecommendationsfortheTreatmentofLipidDisordersinPatientsonPeritonealDialysis N݌ N Ќ     S0   Ascanbenotedfromtheforegoingsections,thefollowingprinciplesareestablished: N݌ 0 Ќ   K(03S""  X<( ` hp x X<  Sro 2.3  Ԁ  Lipoproteinabnormalitiesareprevalentinpatientsonperitonealdialysis.V݌ r Ќ X XX   ?+ ` hp x X?""  X<( ` hp x X<  ST 2.3  Ԁ  Cardiovasculardiseaseisthemostimportantsinglecauseofdeathinpatientsonperitoneal T dialysis.e݌ @ Ќ X XX   ?+ ` hp x X?""  X<( ` hp x X<  S/ 2.3  Ԁ  Treatmentoflipoproteinabnormalities,particularlyLDLcholesterol,isassociatedwith  reductionincardiovascularmorbidityandmortalityinthenondialysispopulation.݌ n Ќ X XX   ?+ ` hp x X?""  X<( ` hp x X<  S P n2.3  Ԁ  BothHMGCoAreductaseinhibitorsandfibricacidderivativeseffectsignificantreduction  P inelevatedlipidlevelsinperitonealdialysispatients.n&݌  < Ќ X XX   ?+ ` hp x X?""  X<( ` hp x X<  S~"+"{ 2.3  Ԁ  Thereisnoevidencethatimprovementinlipidlevelsleadstoareductionincardiovascular ~" eventsinpatientsonperitonealdialysis.݌ j# Ќ X XX   ?+ ` hp x X?   S$L $ I  Broadlycategorized,treatmentstrategiesforhyperlipidemiacanbeeitherprimaryorsecondary $L  treatmentprograms.Inprimaryprevention,apatientistreatedbecausehehasameasured %8! abnormalityinhislipoproteinprofile,butnoknowncoexistingcardiovasculardisease.The &$" WOSCOPStudyisanexampleofaprimarypreventionintervention(41).Secondaryprevention '# treatmentstrategiestreatpatientswithalaboratoryabnormalityinlipoproteinprofileonlyifthe (#  individualisknowntohavepreexistingCVD.Secondarypreventionstudiesincludethe4Sand )$! CAREtrials(44,67). Iy݌ *%" Ќ     S,f'+' !  Inpatientswithrenalfailure,onemustconsiderwhethertheincidenceofCVDissohighthatthe ,f'# coexistenceofuremiadefinesallofourrenalfailurepatientsasbeingatsufficientriskfor -R($ vasculardiseasethattreatmentshouldbeconsideredwithinthecontextofsecondaryprevention. ->)% SuchastrategypresupposesthatallpatientswithuremiawillhavesomesignificantCVD,albeit  inmanycasesasymptomatic.Treatmentrecommendationsaredifferent,dependingonwhether  onechoosestoapproachpatientswithaprimaryorasecondarypreventionstrategy.Inuremia,  thisremainsanunsettledquestionandtheindividualnephrologistmustcometosomedecisionin t thisregardinapproachingtherapiesforpatientsinarationalfashion. !!݌ ` Ќ     S B  %  Thereisnostudythatadequatelyaddresseswhetherornottreatmentoflipidabnormalitieswill  B alterthecourseofCVDinuremicpatients. %&݌  . Ќ     Sp  m )'  Untilsuchevidenceisclearlyavailable,thefollowingtreatmentstrategiesareproposedbasedon p  current(asof1998)recommendationsfromtheNationalCholesterolExpertPanel,whichhas \  recentlyreducedtargetlevelsforLDLcholesteroltolevelslowerthaneverbefore(68)(see H  Table4). )'Y'݌ 4  Ќ     S s  4)  SecondaryPrevention(Patientswithknownpreexistingcoronaryarterydiseaseandperhapsall   patientswithuremia):LDLcholesterolistobereducedtolessthan2.56mmol/L(100mg/dL).   HMGCoAreductaseinhibitorsshouldbeusedasthefirstlinetherapytoreachtheseobjectives.   LiverfunctionandCPKlevelsshouldbemonitoredaspartoftheroutinebloodworkforthefirst  year.Thisrecommendationisnotevidencebased,butbasedontheextrapolationofdatafroma v nonuremicpopulation.Inotherwords,itisassumedthattheriskreductionwiththisclassof b drugsisatleastasgreatinthedialysispopulationasitisinthenondialysispopulation.Should N HMGCoAreductaseinhibitorsnotbetoleratedbythepatient,theuseofbileacidsequestrants : canbetried.Itshouldbenotedthatthesedrugsarealsooftenpoorlytolerated,andmayimpair &v gastrointestinalabsorptionofothermedications. 4)d)݌ b Ќ     SQ i.  TABLE4  NationalCholesterolExpertPanelGuidelinesforLDLCholesterollevels i..݌  Ќ  S*QR d d }q "}q" }} MP(#(#, }q,}}+  8DD'  8   S"r S 0  Primaryprevention 00݌ ?DDD,!"rDD ?Ќ     S"r 1  <3.33mmol/L(130mg/dL) 11݌ UDDD,"r  DDD  UЌ     Smj 2  Secondaryprevention 22݌ ?DDD,!mDD ?Ќ     Smj 3  <2.56mmol/L(100mg/dL) 33݌<20m   DDD <Ќ     S [ q4  PrimaryPrevention1(Noknowncoexistingatheroscleroticcoronaryarterydiseaseand  [ discountinguremiaasaconditionimplicatingcoexistentcoronaryarterydisease):Inpatients  G withknownadditionalriskfactorsforatherosclerosis,andafastingserumLDLcholesterolof !3 greaterthan4.5mmol/L,ifdietaryrestrictionisineffective,thetargetlevelforLDLcholesterol " islessthan3.3mmol/L.Asinsecondarypreventiontreatmentgroups,HMGCoAreductase #  inhibitorsremainthefirstlineoftherapytoachievethesetargets. q44݌ $  Ќ     S9&!%6! 7  PrimaryPrevention2(Inuremicpatientswithnoknowncoronaryarterydisease;noadditional 9&!! riskfactor,includingtheabsenceofapositivefamilyhistoryforcoronaryarterydisease;anda %'u"" fastingLDLcholesterolbetween2.3and4.5mmol/L):Inthisgroup,ifoneconsidersuremia (a## itselftoconfersufficientrisktoconsiderallpatientstobeapproachedasasecondaryprevention (M$$ group,thentargetLDLcholesterolwouldbelessthan2.56mmol/L.Ifoneconsidersuremianot )9%% tobeasufficientriskfactortoassumethatallpatientshavecoronaryarterydisease,thenno *%&& treatmentwouldbeindicatedandregularsurveillanceforsignificantchangesintheirclinical +'' statusand/ortheirlipidprofileshouldbemonitoredona6monthlybasis.Shouldthepatients ,'( thenfallintocategories  secondaryor  primary1,thetreatmentwouldbeinitiated -() accordingly. 77݌  Ќ     SB? <  Noneofthesedrugsarerecommendedforuseduringpregnancy,andcautionshouldbetakenfor B fertilewomen.Breastfeedingisnotrecommendedwhileusinglipidloweringdrugs. .~ Contraindicationsforuseofthestatinsandthefibratesareknownsideeffectstothedrug,active j liverdisease,orincreasedliverenzymesofunknownorigin.Overallcautionshouldbetakenin  V abusersofalcoholanddrugsduetotheriskforuncontrolledinteractions.Patientswithhepatitis  B Cshouldbecloselymonitoredwhileonthesemedications.Inpatientswithsevererenal  . impairmentthereisalsoacontraindicationfortheuseofclofibrate,niceritrol,andnicotinicacid   statedbythemanufacturers. <=݌   Ќ     SH E  @  Additionalcautionisgivenforpatientswithinflammatoryboweldiseasewhenconsidering H  cholestyramineandcolestipol.Patientswithdiabetesmellitusmayhaveanimpairmentoftheir 4  glucosemetabolismbynicotinicaciddrugs,clofibrate,andbezafibrate. @A݌  p  Ќ     S _  B  Erythropoietinhasbeenreportedtoreduceserumlipids,butthisshouldbeconsideredabonus,   andnotanindicationforuseofthisexpensivemedication(69). BB݌   Ќ     S0- D  TherearenopublishedstudiesontheroleofdietarymodificationinPDpatientsanditseffecton 0 lipidlevels.Inprinciple,however,dietshouldavoidhighlevelsofcholesterolandsaturatedfat. l Thisshouldnotbeattheexpenseofproteinorenergyintake,becauseproteincalorie X malnutritionisaseriouscomplicationandportendsapoorprognosis. D1D݌ D Ќ     S3 KF  Insofarastheevidencelinkingelevatedserumtriglycerideconcentrationtoatherogenicriskis  tenuousinthenonuremicpopulation,itisdifficulttoknowwhatapproachshouldbetakenwith r thehypertriglyceridemicpatient.Itshouldbenotedhowever,inpatientsinwhomtheserum ^ triglycerideexceeds2.6mmol/L,thetotalserumcholesterolandLDLcholesterolwillbe J inaccurateandpotentiallymisleading,withrespecttothenatureofthelipidabnormality.Insuch 6 cases,ameasurementofApoBgivesabetterindexastowhetherornotthereistrulyanelevation "r inthenumberofLDLparticles,andthuswhethertreatmentisindicatedonthebasisofanLDL ^ abnormality.Forthepatientwithmildlyelevatedserumtriglycerides,dietaryinterventionmayb J ehelpful,asmentionedabove(70).Attentionshouldbepaidtoglycemiccontrolindiabetics,and 6 hypertonicdialysateshouldbeavoided,ifpossible.Formoreserioushypertriglyceridemia,fibric  " acidanalogsarehelpful,sincetheydiminishproductionofVLDLandstimulatelipoprotein ! lipase(71). KF{F݌ " Ќ     S<$#9 K  References K+L݌ <$ Ќ  / /""  X<( ` hp x X<  S%!{%  L2.3  Ԁ  DahlenG,GuytonJR,ArrarM,FarmerJA,KautzJA,andGottoAM.Associationoflevels %! oflipoprotein(a),plasmalipids,andotherlipoproteinswithcoronaryarterydisease & "  documentedbyangiography.Circulation1986;74:758!!65.LM݌ '"! Ќ X XX   ?+ ` hp x X?""  X<( ` hp x X<  S8)$(5$ O2.3  Ԁ  AttmanP,SamuelssonO,andAlaupovicP.Lipoproteinmetabolismandrenalfailure.AmJ 8)$" KidneyDis1993;21:573!!92.O|P݌ $*t%# Ќ X XX   ?+ ` hp x X?""  X<( ` hp x X<  S+'c+& &R2.3  Ԁ  NorbeckHE,CarlsonLA.Theuremicdyslipoproteinemia:itscharacteristicsandrelations +'$  toclinicalfactors.ActaMedScand1981;209:489!!503.&RR݌ ,'% Ќ X XX   ?+ ` hp x X?""  X<( ` hp x X<  SS T2.3  Ԁ  BergesioF,MonzaniG,CiutiR,SerrutoA,BenucciA,FrizziV,etal.Lipidsand S  apolipoproteinschangeduringtheprogressionofchronicrenalfailure.ClinNephrol ? 1992;38:264!!70.TfU݌ + Ќ X XX   ?+ ` hp x X?""  X<( ` hp x X<  Smj rW2.3  Ԁ  GruberKK,HoffnerSM,TuttleKR.IncreasedLp(a)concentrationsinchronicrenalfailure. m JAmSocNephrol1992;3:333.rW*X݌ Y  Ќ X XX   ?+ ` hp x X?""  X<( ` hp x X<  S ;  Y2.3  Ԁ  AnwarN,BhatnagarD,ShortCD,MacknessMI,DurringtonPN,PraisH,etal.Serum  ; lipoprotein(a)concentrationsinpatientsundergoingcontinuousambulatoryperitoneal  ' dialysis.NephrolDialTransplant1993;8:71!!4.YzZ݌   Ќ X XX   ?+ ` hp x X?""  X<( ` hp x X<  SU R  \2.3  Ԁ  AkmalM,KasimSE,SolimanAR,MassrySG.Excessparathyroidhormoneadversely U  affectslipidmetabolisminchronicrenalfailure.KidneyInt1990;37:854!!8.\T]݌ A  Ќ X XX   ?+ ` hp x X?""  X<( ` hp x X<  S#   '_2.3  Ԁ  WheelerDC.AbnormalitiesoflipoproteinmetabolisminCAPDpatients.KidneyInt1996; #  50(Suppl56):S41!!6.'__݌   Ќ X XX   ?+ ` hp x X?""  X<( ` hp x X<  SQN a2.3  Ԁ  LacourB,RoulletJ,BeyneP,KreisH,TheveninM,DruekeT.Comparisonsofseveral Q  atherogenicityindicesbytheanalysisofserumlipoproteincompositioninpatientswith =  chronicrenalfailurewithorwithouthemodialysis,andinrenaltransplantpatients.JClin )y ChemClinBiochem1985;23:805!!10.a9b݌ e Ќ X XX   ?+ ` hp x X?" "  X<( ` hp x X<  ST d2.3  Ԁ  AvramMM,FeinPA,AntignaniA,MittmanN,MushnickRA,LustigAR,etal.  Cholesterolandlipiddisturbancesinrenaldisease:thenaturalhistoryofuremic  dyslipidemiaandtheimpactofhemodialysisandCAPD.AmJMed1989;87:55N!!60N.  d}e݌̌ X XX   ?+ ` hp x X?" "  X<( ` hp x X<  SM g2.3  Ԁ  LindholmBandNorbeckHE.Serumlipidsandlipoproteinsduringcontinuousambulatory M peritonealdialysis.ActaMedScand1986;220:143!!51.gmh݌ 9 Ќ X XX   ?+ ` hp x X?" "  X<( ` hp x X<  S{(x /j2.3  Ԁ  HorkkoS,HuttuneneK,LaaraE,KerinenK,andKesaniemiYA.Effectsofthreetreatment { modesonplasmalipidsandlipoproteinsinuremicpatients.AnnMed1994;26:271!!82./jj݌ g Ќ X XX   ?+ ` hp x X?" "  X<( ` hp x X<  S I  l2.3  Ԁ  WebbAT,ReaveleyDA,ODonnellM,OConnorB,SeedM,BrownEA.Lipidsand  I lipoprotein(a)asriskfactorsforvasculardiseaseinpatientsonrenalreplacementtherapy. !5 NephrolDialTransplant1995;10:354!!7.lm݌ "! Ќ X XX   ?+ ` hp x X?" "  X<( ` hp x X<  Sc$$` o2.3  Ԁ  SiamopoulosKC,ElisafMS,BairaktariHT,PappasMB,SferopoulosGD,NikolakakisNG. c$ Lipidparametersincludinglipoprotein(a)inpatientsundergoingCAPDand O%  hemodialysis.PeritDialInt1995;15:342!!7.op݌ ;&! Ќ X XX   ?+ ` hp x X?""  X<( ` hp x X<  S'#z'" r2.3  Ԁ  LlopartR,DonateT,OliviaJA,RodaM,RousaudF,Gonzalez!!SasatreF,etal. '# TriglyceriderichlipoproteinabnormalitiesinCAPDtreatedpatients.NephrolDial ( $ Transplant1995;10:537!!40.rRs݌ )$  Ќ X XX   ?+ ` hp x X?""  X<( ` hp x X<  S7+&*4& u2.3  Ԁ  AvramMM,GoldwasserP,BurrellDE,AntignaniA,FeinPA,MittmanN.Theuremic 7+&! dyslipidemia:acrosssectionalandlongitudinalstudy.AmJKidneyDis1992; #,s'" 20:324!!35.uHv݌ -_(# Ќ X XX   ?+ ` hp x X?""  X<( ` hp x X<  SS Kx2.3  Ԁ  KawaguchiY,KuboH,YamamotoH,NakayamaM,YokoyamaK,ShigematsuT,etal.Is S atherosclerosisacceleratedbyCAPD?PeritDialInt1996;16(Suppl1):S223!!30.Kxy݌ ? Ќ X XX   ?+ ` hp x X?""  X<( ` hp x X<  S.~ z2.3  Ԁ  RamosJM,HeatonA,McGurkJG,WardMK,andKerrDNS.Sequentialchangesinserum  lipidsandtheirsubfractionsinpatientsreceivingCAPD.Nephron1983;35:20!!3.z{݌ m Ќ X XX   ?+ ` hp x X?""  X<( ` hp x X<  S O  j}2.3  Ԁ  KaganA,BarKhayimY,SchaferZ,andFainaruM.Kineticsofperitonealproteinloss  O duringCAPD:lipoproteinleakageanditsimpactonplasmalipidlevels.KidneyInt1990;  ; 37:980!!90.j}"~݌  ' Ќ X XX   ?+ ` hp x X?""  X<( ` hp x X<  Si  f 52.3  Ԁ  ShojiT,NishizawaY,NishitaniH,YamakawaM,andMoriiH.Highserumlipoprotein(a) i  concentrationsinuremicpatientstreatedwithcontinuousambulatoryperitonealdialysis. U  ClinNephrol1992;38:271!!6.5݌ A  Ќ X XX   ?+ ` hp x X?""  X<( ` hp x X<  S#   2.3  Ԁ  MurphyBG,McNameeP,DulyE,HenryW,ArchboldP,andTrinickT.Increasedserum #  apolipoprotein(a)inpatientswithchronicrenalfailuretreatedwithcontinuous   ambulatoryperitonealdialysis.Atherosclerosis1992;93:53!!7.݌   Ќ X XX   ?+ ` hp x X?""  X<( ` hp x X<  S=: 2.3  Ԁ  KhannaR,WuG,VasS,OreopoulosDG.Mortalityandmorbidityoncontinuous =  ambulatoryperitonealdialysis.ASAIOJ1983;6:197!!204.݌ )y Ќ X XX   ?+ ` hp x X?""  X<( ` hp x X<  S h [2.3  Ԁ  LupoA,TarchiniR,CancariniG,CatizoneL,CocchiR,DeVecchiA,etal.Longterm   outcomeincontinuousambulatoryperitonealdialysis:a10yearsurveybytheItalian  CooperativePeritonealDialysisStudyGroup.AmJKidneyDis1994;24:826!!37.[݌  Ќ X XX   ?+ ` hp x X?""  X<( ` hp x X<  S%u" g2.3  Ԁ  CanadaUSA(CANUSA)PeritonealDialysisStudyGroup.Adequacyofdialysisand %u nutritionincontinuousperitonealdialysis:associationwithclinicaloutcomes.JAmSoc a Nephrol1996;7:198!!207.g݌ M Ќ X XX   ?+ ` hp x X?""  X<( ` hp x X<  S< :2.3  Ԁ  NichollsAJ,CattoGRD,EdwardN,EngesetJ,MacleodM.Acceleratedatherosclerosisin  longtermdialysisandrenaltransplantpatients:factorfiction?Lancet1980;1:276!!8.:݌ { Ќ X XX   ?+ ` hp x X?""  X<( ` hp x X<  S ]  2.3  Ԁ  PrichardS,SnidermanA,CianfloneK,MarpoleD.Cardiovasculardiseaseinperitoneal  ] dialysis.PeritDialInt1996;16(Suppl1):S19!!22.݌  I Ќ X XX   ?+ ` hp x X?""  X<( ` hp x X<  S"8" _2.3  Ԁ  RostandSG,BrunzellJD,CannonIIIRO,VictorRG.Cardiovascularcomplicationsinrenal " failure.JAmSocNephrol1991;2:1053!!62._݌ w# Ќ X XX   ?+ ` hp x X?""  X<( ` hp x X<  S %Y $  ѕ2.3  Ԁ  TschopeW,KochM,ThomasB,RitzE,andtheGermanStudyGroupDiabetesand  %Y  Uremia.Serumlipidspredictcardiacdeathindiabeticpatientsonmaintenance %E! hemodialysis.Nephron1993;64:354!!8.ѕ݌ &1" Ќ X XX   ?+ ` hp x X?""  X<( ` hp x X<  Ss(# (p# 2.3  Ԁ  LowrieEG,HuangWH,LewNL.Deathriskpredictorsamongperitonealdialysisand s(# hemodialysispatients:apreliminarycomparison.AmJKidneyDis1995;26:220!!8.M݌ _)$ Ќ X XX   ?+ ` hp x X?""  X<( ` hp x X<  S*A&*% %2.3  Ԁ  PiccoliGB,QuarelloF,SalomoneM,IadarolaGM,FunaroL,MarcielloA,etal.Areserum *A&  albuminandcholesterolreliableoutcomemarkersinelderlydialysispatients?Nephrol +-'! DialTransplant1995;10(Suppl6):72!!7.%ݛ݌ ,(" Ќ X XX   ?+ ` hp x X?""  X<( ` hp x X<  SS 2.3  Ԁ  PollockCA,IbelsLS,CatersonRJ,MahoneyJF,WaughDA,CocksedgeB.Continuous S ambulatoryperitonealdialysis:eightyearsofexperienceatasinglecenter.Medicine ? 1989;68:293!!308.݌ + Ќ X XX   ?+ ` hp x X?""  X<( ` hp x X<  Smj 2.3  Ԁ  GaultMH,LongerichL,PrabhakaranV,PurchaseL.Ischemicheartdisease,serum m cholesterolandapolipoproteinsinCAPD.ASAIOTrans1991;37:M513!!14.s݌ Y  Ќ X XX   ?+ ` hp x X?" "  X<( ` hp x X<  S ;  @2.3  Ԁ  GambaG,MejiaJL,SaldivarS,PenaJC,Correa!!RotterR.DeathriskinCAPDpatients:  ; thepredictivevalueoftheinitialclinicalandlaboratoryvalues.Nephron1993;65:23!!7.  ' @݌̌ X XX   ?+ ` hp x X?"!"  X<( ` hp x X<  SU R  2.3  Ԁ  CastelliWP,GarrisonRJ,WilsonPWF,AbbottRD,KalousdianS,KannelWB.Incidence U  ofcoronaryheartdiseaseandlipoproteincholesterollevels:TheFraminghamStudy. A  JAMA1986;256:2835!!8.݌ -}  Ќ X XX   ?+ ` hp x X?"""  X<( ` hp x X<  S l  2.3  Ԁ  GordonT,CastelliWP,HjortlandMC,KannelWB,DawberTR.Highdensitylipoprotein   asaprotectivefactoragainstcoronaryheartdisease:TheFraminghamStudy.AmJMed   1997;62:707!!14.o݌   Ќ X XX   ?+ ` hp x X?"#"  X<( ` hp x X<  S)y& t2.3  Ԁ  HokansonJE,AustinMA.Plasmatriglyceridelevelisariskfactorforcardiovascular )y diseaseindependentofhighdensitylipoproteincholesterollevels:ametaanalysisof e populationbasedprospectivestudies.JCardiovascRisk1996;3:213!!19.t,݌ Q Ќ X XX   ?+ ` hp x X?"$"  X<( ` hp x X<  S@ {2.3  Ԁ  CommitteeofPrincipalInvestigators.WHOCooperativeTrialonprimarypreventionof  ischemicheartdiseasewithclofibratetolowerserumcholesterol:finalmortalityfollow  up.Lancet1984;2:600!!4.{3݌ k Ќ X XX   ?+ ` hp x X?"%"  X<( ` hp x X<  SM F2.3  Ԁ  LipidResearchClinicsProgram.TheLipidsResearchClinicscoronaryprimaryprevention M trialresults:reductioninincidenceofcoronaryheartdisease.JAMA1984;251:351!!63.F݌ 9 Ќ X XX   ?+ ` hp x X?"&"  X<( ` hp x X<  S{(x 2.3  Ԁ  FrickMH,EloO,HaapaK,HeinonenOP,HeinsalmiP,HeloP,etal.HelsinkiHeartStudy: { primarypreventiontrialwithgemfibrizolinmiddleagedmenwithdyslipidemia.NEngl g JMed1987;317:1237!!45.݌ S  Ќ X XX   ?+ ` hp x X?"'"  X<( ` hp x X<  S!5! 2.3  Ԁ  ThePravastatinMultinationalStudyGroupforCardiacRiskPatients.Effectsofpravastatin !5 inpatientswithserumtotalcholesterollevelsfrom5.2to7.8mmol/L(200to300mg/dL) "! plustwoadditionalatheroscleroticriskfactors.AmJCardiol1993;72:1031!!7.w݌ #  Ќ X XX   ?+ ` hp x X?"("  X<( ` hp x X<  SO% $L  ǹ2.3  Ԁ  ShepherdJ,CobbeSM,FordI,IslesCG,LorimerAR,McFarlanePW,etal.Preventionof O%  coronaryheartdiseasewithpravastatininmenwithhypercholesterolemia.Westof ;&! ScotlandCoronaryPreventionStudy.NEnglJMed1995;333:1301!!7.ǹ݌ ''w" Ќ X XX   ?+ ` hp x X?")"  X<( ` hp x X<  S( $f(# 2.3  Ԁ  TheCoronaryDrugProjectResearchGroup.Clofibrateandniacinincoronaryheartdisease. ( $ JAMA1975;231:360!!81.m݌ )$  Ќ X XX   ?+ ` hp x X?"*"  X<( ` hp x X<  S7+&*4& 2.3  Ԁ  CarlsonLA,RosenhamerG.ReductionofmortalityintheStockholmIschemicHeart 7+&! DiseaseSecondaryPreventionStudybycombinedtreatmentwithclofibrateandnicotinic #,s'" acid.ActaMedScand1988;223:405!!18.Ϳ݌ -_(# Ќ X XX   ?+ ` hp x X?"+"  X<( ` hp x X<  SS 2.3  Ԁ  ScandinavianSimvastatinSurvivalStudyGroup.Randomizedtrialofcholesterollowering S in4444patientswithcoronaryheartdisease:theScandinaviansimvastatinsurvivalstudy ? (4S).Lancet1994;344:1383!!9.݌ + Ќ X XX   ?+ ` hp x X?","  X<( ` hp x X<  Smj 2.3  Ԁ  ManninenV,HuttunenJK,HeinonenOP,TenkanenL,FrickMH.Relationbetween m baselinelipidandlipoproteinvaluesandtheincidenceofcoronaryheartdiseaseinthe Y  HelsinkiHeartStudy.AmJCardiol1989;63:42H!!47H.r݌ E  Ќ X XX   ?+ ` hp x X?"-"  X<( ` hp x X<  S '  2.3  Ԁ  ThePostCoronaryArteryBypassGraftTrialInvestigators.Theeffectofaggressive  ' loweringoflowdensitylipoproteincholesterollevelsandlowdoseanticoagulationon   obstructivechangesinsaphenousveincoronaryarterybypassgra