Renal Association Clinical Practice Guideline on Haemodialysis

This guideline is written primarily for doctors and nurses working in dialysis units and related areas of medicine in the UK, ... Skiptomaincontent Advertisement SearchallBMCarticles Search RenalAssociationClinicalPracticeGuidelineonHaemodialysis DownloadPDF DownloadPDF Guidelines OpenAccess Published:17October2019 RenalAssociationClinicalPracticeGuidelineonHaemodialysis DamienAshby1,NatalieBorman2,JamesBurton3,RichardCorbett1,AndrewDavenport4,KenFarrington5,KateyFlowers2,JamesFotheringham6,R.N.AndreaFox7,GailFranklin8,ClaireGardiner9,R.N.MartinGerrish10,SharleneGreenwood11,DaljitHothi12,AbdulKhares13,PelagiaKoufaki14,JeremyLevy1,ElizabethLindley15,JamieMacdonald16,BrunoMafrici17,AndrewMooney9,JamesTattersall9,KayTyerman9,EnricVillar5&…MartinWilkie6 Showauthors BMCNephrology volume 20,Article number: 379(2019) Citethisarticle 37kAccesses 75Citations 13Altmetric Metricsdetails AbstractThisguidelineiswrittenprimarilyfordoctorsandnursesworkingindialysisunitsandrelatedareasofmedicineintheUK,andisanupdateofapreviousversionwrittenin2009.Itaimstoprovideguidanceonhowtolookafterpatientsandhowtorundialysisunits,andprovidesstandardswhichunitsshouldingeneralaimtoachieve.Wewouldnotadvisepatientstointerprettheguidelineasarulebook,butperhapstoanswerthequestion:“whatdoesgoodqualityhaemodialysislooklike?”Theguidelineissplitintosections:eachbeginswithafewstatementswhicharegradedbystrength(1isafirmrecommendation,2ismorelikeasensiblesuggestion),andthetypeofresearchavailabletobackupthestatement,rangingfromA(goodqualitytrialssoweareprettysurethisisright)toD(moreliketheopinionofexpertsthanknownforsure).Afterthestatementsthereisashortsummaryexplainingwhywethinkthis,oftenincludingadiscussionofsomeofthemosthelpfulresearch.Thereisthenalistofthemostimportantmedicalarticlessothatyoucanreadfurtherifyouwantto–mostofthisisfreelyavailableonline,atleastinsummaryform.Afewnotesontheindividualsections: 1. Thissectionisabouthowmuchdialysisapatientshouldhave.Theeffectivenessofdialysisvariesbetweenpatientsbecauseofdifferencesinbodysizeandageetc.,sodifferentpeopleneeddifferentamounts,andthissectiongivesguidanceonwhatdefines“enough”dialysisandhowtomakesureeachpersonisgettingthat.Quiteabitofthissectionisverytechnical,forexample,theterm“eKt/V”isoftenused:thisisacalculationbasedonbloodtestsbeforeandafterdialysis,whichmeasurestheeffectivenessofasingledialysissessioninaparticularpatient. 2. Thissectiondealswith“non-standard”dialysis,whichbasicallymeansanythingotherthan3timesperweek.Forexample,afewpeopleneed4ormoresessionsperweektokeephealthy,andsomepeoplearefinewithonly2sessionsperweek–thisisusuallypeoplewhoareolder,orthosewhohaveonlyjuststarteddialysis.Specialconsiderationsforchildrenandpregnantpatientsarealsocoveredhere. 3. Thissectiondealswithmembranes(thetypeof“filter”usedinthedialysismachine)and“HDF”(haemodiafiltration)whichisamorecomplexkindofdialysiswhichsomedoctorsthinkisbetter.Studiesarestillbeingdone,butatthemomentwethinkit’sasgoodasbutnotbetterthanregulardialysis. 4. Thissectiondealswithfluidremovalduringdialysissessions:howtoremoveenoughfluidwithoutcausingcrampsandlowbloodpressure.Amongstotherrecommendationsweadviseclosecollaborationwithpatientsoverthis. 5. Thissectiondealswithdialysate,whichisthefluidusedto“pull”toxinsoutoftheblood(itissometimescalledthe“bath”).Thelevelofthingslikepotassiuminthedialysateisimportant,otherwisetoomuchortoolittlemayberemoved.Thereisasectionondialysatebuffer(bicarbonate)andalsoasectiononphosphate,whichoccasionallyneedstobeaddedintothedialysate. 6. Thissectionisaboutanticoagulation(bloodthinning)whichisneededtostopthecircuitfromclotting,butsometimescausessideeffects. 7. Thissectionisaboutcertainsafetyaspectsofdialysis,notseekingtoreplacewell-establishedlocalprotocols,butfocussingonjustafewwherewethoughtsomenational-levelguidancewouldbeuseful. 8. Thissectiondrawstogetherafewaspectsofdialysiswhichdon’teasilyfitelsewhere,andwhichimpactonhowdialysisfeelstopatients,ratherthanthemedicaloutcome,thoughofcoursethesearelinked.Thisiswherehomehaemodialysisandexercisearecovered. Thereisanappendixattheendwhichcoversafewaspectsinmoredetail,especiallythemathematicalideas.Severalaspectsofdialysisarenotincludedinthisguidelinesincetheyarecoveredelsewhere,oftenbecausetheyareaspectswhichaffectnon-dialysispatientstoo.Thisincludes:anaemia,calciumandbonehealth,highbloodpressure,nutrition,infectioncontrol,vascularaccess,transplantplanning,andwhendialysisshouldbestarted. IntroductionHaemodialysiscontinuestoexpandintheUKwithover25000patientsnowbeingtreated,representinga10%increasesincepublicationofthepreviousRenalAssociationguidelineforhaemodialysis.Inadditionthepatientgroupcontinuestodevelop:thetypicalpatientisnow67yearsoldwithamedianhistoryof3.2yearsonrenalreplacementtherapy.Theauthorsofthisguidelineaimedprincipallytoupdatethepreviousguidelineaccordingtothelatestresearchandexperience,butalsotoexpandthescopeintoareasnotpreviouslycoveredbutrelevanttohaemodialysispractice.Theguidelinewaswrittencollaboratively:leadandco-authorsforeachsectionconductedliteraturereviewsandwrotefirstdraftsofthestatementsandrationale.Feedbackanddiscussionwereprovidedbyallauthorsviaemailexchangesandmeetings,revisedversionswereproducedwitheditorialinputfromthechair,andtheseweresubsequentlyagreedbyallauthors.Twocurrenthaemodialysispatientsgaveadviceontoneandreadability.SystematicliteraturesearcheswereundertakenbyleadauthorstoidentifyallrelevantevidencepublishedupuntiltheendofJune2018.Compoundsearchtermswereusedwhichincludedadialysisidentifier(hemodialysis[tiab]ORhaemodialysis[tiab]ORdialysis[tiab])followedbytitle/abstract-filteredtopicterms(“dialysisdose”,Kt/V,augmented,intensive,conservative,incremental,pregnancy,membrane,hydration,“dryweight”,“fluidoverload”,dialysate,potassium,bicarbonate,buffer,phosphate,“dialyserreaction”,hypersensitivity,“bloodloss”,“needledislodgment”,exsanguination,“homehaemodialysis”,“nocturnalhaemodialysis”,exercise,“physicaltraining”)followedbynegativeterms(e.g.toexcludeanimalstudiesandacutekidneyinjury)finallywithdateandlanguagerestrictions(“1990/01/01”[dp]:“3000”[dp]ANDenglish[lang]).SearcheswereconductedinMEDLINE,PUBMED,Embase,andTheCochraneLibrary,andsupplementedwithpapershandpickedfromthereferencelistsofreviewpapers.ThestrengthsoftherecommendationsandthelevelofsupportingevidencearecodedaspreviouslyusingtheModifiedGRADEsystem.Thereareafewchangesinscope,forexampledialysiswatertreatmentisnowcoveredinanotherguideline,asaremanyaspectsofdialysis,including: Planning,initiation&withdrawalofRenalReplacementTherapy VascularAccessforHaemodialysis CardiovascularDisease BloodBorneViruses AssessmentofthePotentialKidneyTransplantRecipient Nutrition Anaemia CKD-MineralandBoneDisorder WaterTreatmentFacilities,DialysisWaterandDialysisFluidQuality Wehaveremovedthesectionontargetsforbloodtestingsincethesearebettercoveredinotherguidelines,andhavenotcoveredinfrastructureorworkforcesincethesewillbeaddressedseparatelybytheRenalAssociationinadifferentformat.However,inmostwaystheupdateisbroaderthanpreviousversions.Forexample,newsectionshavebeenwrittencoveringfluidmanagement(surelyanessentialtopicbutnotreallycoveredpreviouslyorelsewhere)anddialysate(oftenunderestimatedinimportance).Inotherareasthisupdateseemstomakenosubstantialchangetopreviousguidance(aswithdialysisdose,forexample,wheretheliteratureremainsdominatedbypreviouslargetrials),howeverwhilstkeyconceptsremainvalid,theirunderstandinghasdeveloped,andtheguidelineaimstoprovidegreatercontext,encouragingamoreholisticinterpretation.Discussionsaboutdialysisoftenbecomeoverlytechnical–theseconceptsareimportantbuthardtofitintoanarrativesowehavemovedafewaspectsintotheappendix,whereweaimtoprovidesimplifiedsummaries.Wehavetriedtomaintainahighstandardofreadabilitysinceconceptualunderstandingisthekeygoal,andastheguidelineisnotintendedtoreplacereviewarticlesororiginalpapers,itseemscorrecttofavourreadabilityoverdetail.SummaryofclinicalpracticeguidelinesDialysisdoseinthriceweeklydialysisschedulesWerecommendeKt/Vasthemostclinicallyvalidsmall-solutemeasureofdialysisdose,andrecommendmonitoringofdialysisdoseonamonthlybasisforthemajorityofcentre-baseddialysispatients.[1B]WerecommendtargetingdialysisdosetoachieveconsistentlyaminimumeKt/Vof1.2forthriceweeklypatients,intheabsenceofameasuredcontributionfromresidualfunction.[1B]Werecommendaminimumof12hoursperweekforthemajorityofthriceweeklypatientswithminimalresidualfunction.[1B]Non-standardschedules(Guidelines2.1–2.4)Guideline2.1-AugmentedschedulesWesuggestofferinganaugmentedscheduletopatientswhoareunabletoachieveadequacytargetsorfluidcontrolonastandardthriceweeklyschedule.[2B]Wesuggestthatrelativecontraindicationstoaugmentedschedulesshouldbeconsidered,suchassignificantresidualfunctionorproblematicfistulaaccess.[2C]Guideline2.2-IncrementalschedulesWesuggestthatlowerhaemodialysisdosetargetsmaybeoptimalinpatientswithsignificantresidualrenalfunction.[2D]Werecommendthatresidualrenalfunctionshouldbequantifiedintermittentlyinpatientsonincrementaldialysisschedules.[1D]Guideline2.3-ConservativeschedulesWesuggestthatlowerhaemodialysisdosetargetsmaybeoptimalwhenqualityoflifeistheprimarygoaloftreatment,ratherthanlongevity.[2D]Guideline2.4-PaediatricschedulesInchildrenandadolescentswerecommendanapproachtotheassessmentofdialysisadequacywhichgoesbeyondbiochemicaltargets,incorporatingclinicalgoalssuchasgrowth,bonehealth,cardiacfunctionandqualityoflife.[1C]WerecommendtargetingdialysisdosetoachieveaminimumeKt/Vof1.2forthriceweeklypatients,orastandardizedKt/Vof2.2forthoseonaugmentedschedules.[1C]Wesuggestanaugmentedscheduleforchildrenonpredominantlyliquidnutrition,andthosewithventricularsystolicdysfunction.[2D]Werecommendabloodflowrateof5-7ml/kg/minforthemajorityofpatients,usingconsumablesappropriatetobodysize,withextracorporealvolumelessthan10%ofthepatient’sbloodvolume.[1C]Guideline2.5-SchedulesduringpregnancyWerecommendcounsellingwomenofreproductiveagewhoarereceivingoranticipatingdialysis,sothattheyareawareoftheinteractionsbetweenrenalreplacementtherapiesandpregnancywhichmayimpactonfamilyplanningandmodalitydecisions.[1D]Fordialysispatientswishingtocontinuetheirpregnancy,werecommendchangingasearlyaspossibletoanindividualised,augmentedhaemodialysisschedule.Forthosewithminimalresidualfunctionthisshouldbeatleast20hoursperweek,deliveredoveratleast6sessions.[1B]Werecommendanindividualiseddialysateprescriptionappropriatetothedialysisscheduleandbiochemistryresults,anticipatingthefrequentneedforahighpotassium/lowbicarbonatedialysate,supplementedwithphosphate.[1C]Wesuggestanindividualisedfluidmanagementprotocol,withlowultrafiltrationratesandregularclinicalassessment,anticipatingthetypicalchangeinweightduringpregnancy.[2C]MembranefluxandhaemodiafiltrationWerecommendthatpatientswithminimalresidualfunctionshouldbetreatedwithhigh-fluxdialysers.[1B]Wesuggestthathaemodiafiltrationmaybeconsideredasatreatmentforintra-dialytichypotensionrefractorytoothermeasures,andfordialysispatientswithfavourableprognosiswhoareunableorunlikelytobetransplanted.[2B]Fluidinhaemodialysis(Guidelines4.1–4.2)Guideline4.1-FluidassessmentandmanagementinadultsWerecommendassessmentoffluidstatuswhenpromptedbyclinicalcircumstances,andonaquarterlybasisforstablepatients.[1C]Wesuggestamultidisciplinaryapproachtofluidassessment,withpatientinvolvementandtheadoptionofpatient-friendlyterminologysuchas“targetweight”,“fluidgain”and“over-hydration”.[2D]Werecommendclinicalassessmentoffluidstatusonamonthlybasisforthemajorityofpatients.[1C]Wesuggestsupplementingclinicalassessmentoffluidstatuswithavalidatedobjectivemeasurement,suchasbioimpedance,atregularintervals,whenclinicalassessmentisunclear,andfollowinganintercurrentillness.[2C]Werecommendadialysatetemperaturenotgreaterthan36'Cifstandardised.[1C]Werecommendavoidingexcessiveultrafiltrationratesbyaddressingfluidgains,acceptingstagedachievementoftargetweight,orusinganaugmentedschedule,asnecessary.[1B]Werecommendpromptnursinginterventiontorestorehaemodynamicstabilityinsymptomatic/severeintradialytichypotension,withsuchinterventionsleadingtoclinicalreview.[1C]Guideline4.2-PaediatricfluidconsiderationsIngrowingchildrenwerecommendclinicalassessmentoffluidstatusandtargetweight,anddieteticassessment,atleastmonthly.[1C]Wesuggestsupplementingclinicalassessmentwithavalidatedobjectivemeasureoffluidstatussuchasbioimpedance,onamonthlybasisormorefrequentlyduringperiodsofrapidgrowthorillness.[2C]Werecommendregularassessmentofultrafiltrationtolerance,usingextendedtimestoavoidexcessiveultrafiltrationrates.[1D]Dialysate(Guidelines5.1–5.4)Guideline5.1-SelectionofdialysatepotassiumWerecommendanoptimalpre-dialysisserumpotassiumintherange4.0–6.0mmol/L,rememberingtoconsidermeasurementerrors(e.g.duetohaemolysis)wheninterpretinglevels.[1B]Wesuggestchoosingdialysatepotassiumbetween1.0and3.0mmol/Lforthemajorityofpatients,usinganindividualisedapproach,ingeneralusingthehighestdialysatepotassiumthatissufficienttocontrolpre-dialysishyperkalaemia.[2C]Wesuggestacombinedapproachtomanaginghyperkalaemia,whichmayincludedecreasingdialysatepotassiumand/orothermeasures,includingdietaryadvice,medicationreviewandincreaseddialysisfrequency.[2D]Guideline5.2-SelectionofdialysatebufferWerecommendanoptimalpre-dialysisserumbicarbonateintherange18.0-26.0mmo/L,rememberingtoconsidermeasurementerrors(e.g.duetoexposuretoair)wheninterpretinglevels.[1C]Wesuggesttheterm‘dialysatebuffer’ratherthan‘dialysatebicarbonate’toavoidconfusionarisingfromdifferencesinmanufacturers’terminology.[2C]Wesuggestchoosingdialysatebufferbeloworequalto37.0mEq/Lforthemajorityofpatients,usingastandardisedorindividualisedapproach.[2C]Wesuggestacombinedapproachtoabnormalpre-dialysisserumbicarbonate,whichmayincludeincreasingdialysisdose,oralbicarbonate,nutritionalsupport,orindividualisingdialysatebuffer.[2D]Guideline5.3-SupplementationofdialysatewithphosphateWesuggestconsideringsupplementationofthedialysatewithphosphateinpatientsonaugmenteddialysisschedules.[2D]Guideline5.4-PaediatricdialysateconsiderationsWerecommendindividualisationofdialysateelectrolyteconcentrations,includingpotassium,bufferandcalcium.[1C]Wesuggestanindividualiseddialysatetemperature,betweencoretemperatureand0.5°Cbelow,withmonitoringofintradialyticcoretemperatureforneonatesandsmallerchildren.[2D]AnticoagulationWerecommendthatpatientswithoutincreasedbleedingriskshouldbegivenunfractionatedorlow-molecular-weightheparinduringdialysistoreduceclottingoftheextracorporealsystem.[1A]Werecommendthatsystemicanticoagulationshouldbeomittedorminimisedinpatientswithincreasedbleedingrisk.[1C]Werecommendthatpatientswithheparinallergiesshouldbeprescribedanon-heparinformofanticoagulation.[1A]Adverseeventsduringdialysis(Guidelines7.1–7.3)Guideline7.1-RoutinebloodlossWesuggestthatduringwashback,dialysislinesanddialyserareobservedtoensureresidualbloodlossiskepttoaminimum.[2C]Guideline7.2-DisconnectionhaemorrhageWerecommendmaintainingawarenessoftheriskofdisconnection,thelimitationsofpressurealarms,andimportanceofdirectobservation,throughaprogramofeducation,includingpatientsandcarers.[1D]Wesuggestregularassessmentofindividualrisk,sothathighriskpatientscanhaveenhancedmonitoring,whichcouldincludespecificdevices.[2B]Guideline7.3-ImmunereactionsduringdialysisWerecommendthatdialysisstaffshouldbeawareofthefeaturesandmanagementofdialysisreactions,andshouldhaveaccesstoarangeofdialysertypes.[1C]Patientexperienceofdialysis(Guidelines8.1–8.4)Guideline8.1-HomehaemodialysisWerecommendthathomehaemodialysisshouldbeavailableinallunitsaspartofacomprehensiverenalreplacementtherapyprogramme.[1A]Wesuggesttrainingpatientsand/orcarepartnerstoachieveadefinedsetofcompetencies,usinganindividualisedapproachtotrainingmethodandspeed.[2D]Wesuggestunitsformacontractwithpatientsoutliningresponsibilities,includinganagreementtodialyseasperprescriptionandtrainedtechnique,andincludingapolicyforre-imbursementofdirectlyarisingpatientcosts.[2D]Wesuggestsupportingpatientswithaspecificteamincludingnephrologists,technicians,andnurses,withrapidaccesstodialysisin-centrewhenrequired.[2C]Wesuggestanagreedindividualisedprescriptionforhomehaemodialysis,takingintoaccountlifestylegoals,withthesamedoseandtimetargetconsiderationsascentre-basedpatients.[2C]Werecommendenhancedsafetymeasuresforpatientswhodialysealoneorovernight,andanenhancedriskassessmentforpatientswithblood-borneviruses.[1C]Guideline8.2-SharedhaemodialysiscareWesuggestthatallcentre-basedhaemodialysispatientsshouldhaveopportunityandencouragementtolearnaspectsoftheirdialysistreatment,andtakeanactiveroleintheircare.[2D]Guideline8.3-IntradialyticexerciseWerecommendthatintradialyticexerciseshouldbeavailableinallunits,asatreatmentforenhancingphysicalfunctioning,inpatientswithoutcontraindications.[1B]Wesuggestthatintradialyticexercisebeconsideredasamethodofenhancingqualityoflife.[2C]Wesuggestthatexerciseregimesbedevisedbyappropriatelytrainedstaff.[2C]Guideline8.4-DialysisexperienceforchildrenandadolescentsWerecommendthathaemodialysisforchildrenandadolescentsshouldbedeliveredinadedicatedpaediatricdialysiscentreorathome,withtheinvolvementofapaediatricmultidisciplinaryteam.[1C]Werecommendthatadolescentsshouldcommenceanactivetransitionprogrammeby14years,oratthetimeofpresentationinthosealreadyover14.[1D]Summaryofauditmeasures AuditMeasure1:Amongstthrice-weeklypatientsondialysisformorethanayear,themedianeKt/V,andproportionachievingeKt/Vatleast1.2. AuditMeasure2:Amongstthrice-weeklypatientsondialysisformorethanayear,themediandialysistimeperweek,andproportionreceivingatleast12hours. AuditMeasure3:Theproportionofpatientsdialysing4ormoretimesperweek(eitherin-centreorathome). AuditMeasure4:Theproportionofpatientsdialysinglessthan3timesperweek,separatedinto:(a)patientsintheirfirstyearofdialysis,and(b)patientsondialysisformorethanayear. AuditMeasure5:Themedianultrafiltrationrate,andproportionofpatientswithresidualkidneyfunction(Kru>2ml/min,orurinevolume>500ml/d),separatedinto:(a)patientsintheirfirstyearofdialysis,and(b)patientsondialysisformorethanayear. AuditMeasure6:Theproportionofpatientsreceivinghaemodiafiltration,andthemedianconvectionvolumeinthisgroup. AuditMeasure7:Themostcommonlyuseddialysatesodiumlevel,andproportionofpatientsusingthisdialysatesodiumlevel. AuditMeasure8:Theavailabilityofanobjectivetoolforfluidstateassessment,thetypeoftoolusedmostcommonly,andtheproportionofpatientsassessedwithanobjectivetoolduringthelastyear. AuditMeasure9:Themedianpre-dialysisserumpotassium,andproportionofpatientsarrivingwithaveragepotassiumover6.0mmol/l,andproportionwithaverageunder4.0mmol/l. AuditMeasure10:Theproportionofpatientsusingadialysatepotassiumlevelinthefollowingcategories:lessthan2.0,2.0,andmorethan2.0mmol/l. AuditMeasure11:Thenumberofdisconnectionhaemorrhageeventseachyear. AuditMeasure12:Theproportionofhaemodialysispatientshavingallormostoftheirdialysisathome. AuditMeasure13:Theproportionofin-centrepatientsrecognisedasengagingin“SharedCare”. AuditMeasure14:Theavailabilityofaprogramforintra-dialyticexercise,theresourceavailable(equipment,physiotherapisttime),andtheproportionofin-centrepatientsengagingwithregularintra-dialyticexercise. RationaleforClinicalPracticeGuidelinesDialysisdoseinthriceweeklydialysisschedulesWerecommendeKt/Vasthemostclinicallyvalidsmall-solutemeasureofdialysisdose,andrecommendmonitoringofdialysisdoseonamonthlybasisforthemajorityofcentre-baseddialysispatients.[1B]WerecommendtargetingdialysisdosetoachieveconsistentlyaminimumeKt/Vover1.2forthriceweeklypatients,intheabsenceofameasuredcontributionfromresidualfunction.[1B]Werecommendaminimumof12hoursperweekforthemajorityofthriceweeklypatientswithminimalresidualfunction.ThismayleadtohigherthanminimumeKt/Vinsmalleradultpatientswhichisappropriate.[1B]RationaleDialysisadequacyencompassesconceptsincludingtheclinicalassessmentofgeneralwellbeing,fluidstatus,andcontroloflaboratoryparameters,alongwithquantificationofthedoseofdialysisprovided.Thepurposeofdialysisistoprovideenoughremovalofuraemicsolutesandfluidthataccumulateinkidneyfailuretomaintainhealthandqualityoflife:morespecificgoalsincludecontrolofuraemicsymptoms,maintenanceofsafeelectrolytelevels,preventionofnutritionaldecline,andoptimumlongtermmortality.Whilsttheearlieritemsinthislistarereadilyassessedoverashorttimescale,conceptsofdialysisdosearerequiredtodefinetheamountofdialysislikelytoachievelongertermgoalsoftreatment.Duetothesimplicityandlowcostofmeasurementofureainblood,measurementofdialysisadequacyhashistoricallyfocusedonclearanceofsmallsolutes,representedbyurea.Concentrationofarangeofuraemictoxinsoflargersize(e.g.β-2microglobulin)islikelytobeimportant,buttheirmeasurementisnotcommonlyperformed.Useofthriceweeklyhaemodialysisschedulesemergedfromtherealisationduringtheearlyeraofhaemodialysistreatmentthatonceortwice-weeklyhaemodialysisschedulesinpatientswithminimalresidualfunctionwasinsufficienttocontrolthesymptomsandcomplicationsofsevereuraemia.Mostresearchondialysisdoseisthereforebasedonureaclearance,inpatientsonathriceweeklyschedule.Ureaclearancemaybecalculatedbythreemethodsincommonuse:UreaReductionRatio,andthe‘singlepool’and‘equilibrated’formulasforKt/V.Kt/VislesscommonlycalculatedbyUreaKineticModelling-thesemethodsaresummarisedmathematicallyinAppendix1.Thediversityofmethodscanleadtoduplicationofeffort,confusionoverthemeaningoftargets,andimpedescomparisonbetweencentres,soasinglewidelyusedmethodwouldbedesirable.Asthemostadjustedmethod,andtheonewhichhasbeenmostcommonlyvalidatedinoutcomeliterature,eKt/Vappearstobeoptimum,andwehavethereforegivendosetargetsintermsofeKt/V.Equivalenttargetsusingothermethodsmaybederivedforindividualpatientsdependingontheirdialysisdurationandfluidremoval.Theliteratureonclinicaloutcomeatdifferentdosesofdialysisisdominatedbytworandomisedstudies.TheNationalCooperativeDialysisStudy(NCDS)wasthelandmarkstudywhichledtotheconceptofathresholddialysisdoseabovewhichtreatmentwasadequate,aswellastheestablishmentofKt/Vastheacceptedindexofdialysisdose.Reportingin1981,thestudyrandomised151patientsina2x2designtohighvslowtime-averagedurea,andshortvslongdialysisduration-thekeyfindingwasalowerrateoftreatmentfailure(deathorhospitaladmission)inthelowurea(highdialysisdose)group[1].WhenreanalysingthegroupwiththenewlyproposedKt/Vmeasure,aclearthresholdeffectappeared,withKt/Vdefiningthewatershedbetween‘adequate’andinadequatedialysis(Kt/Vovervsunder1.0)[2].Alargenumberofobservationalstudiessubsequentlyreportedanassociationbetweenhigherdialysisdoses(beyondmerelyachievingtheNCDSthreshold)andimprovedsurvival[3,4,5,6],andthiswastestedintheHEMOstudy.Reportingin2002theHEMOstudyrandomised1846patientsinanother2x2designtohighvsstandarddialysisdose(eKt/V1.45vs1.05)andhighvslowflux[7].Over2.8yearsfollow-upwithgroupswellseparatedintermsofachievedeKt/V(1.53vs1.16),higherdoseprovidednobenefitintermsofsurvivaloranumberofsecondaryendpoints.Thebasicconceptsofthesestudieshavenotbeensuperseded,hencetherecommendationfordialysisdose(eKt/V>1.2)isbasedlargelyontheeKt/VachievedinthestandarddosegroupoftheHEMOstudy.AlternativemeasuressuchasURRorspKt/Vmaybemorefamiliartosomecliniciansandequallyusefulforthemajorityofpatients.Equivalentthresholdsusingtheseparametersareapproximatesincetheyvarybetweenpatients,butthedifferencesaresmall:Appendix1summarisesthemathematicsbehindtheseconcepts.Whether‘adequate’dialysisisthesameforallpatientsorwhetherdoseshouldbeindividualisedisunclear,butthelatterviewissupportedbyseveralstudiessuggestingthatgenderandbodysizemayaffecttheoptimumdialysisdose[8,9,10].Observationalstudiessuggestthatdialysisdoseismorestronglyrelatedtosurvivalinwomenthanmen,andwhentheHEMOstudyanalysisisrestrictedtowomen,thehighdosegroupshowsignificantlyimprovedsurvival.ThereasonforthisinteractionbetweengenderandoptimumeKt/Visunknown,butmaybeduetothescalingparameter‘V’,whichislowerinwomenandinlessmuscularpatients,andisanindependentpredictorofsurvival.Alternativescalingfactorssuchasbodysurfacearea,havebeensuggested[11,12,13,14],butnoneisinwidespreaduse,andthecollinearitybetweendifferentbodysizeparametersmakesanalysesdifficulttointerpret,butitseemslikelythattheoptimumKt/Vmaybehigherthan1.2inwomenandsmallerpatients,withoutacleardefinitionof‘small’[15].DialysistimeTheoptimumtreatmentdurationforthriceweeklyhaemodialysisisslightlylessclear,sinceitisdifficulttoseparatetheeffectoftreatmenttimefromdialysisdose[16].Theevolutionofdialysistechnologyhasmadedialysisdosetargetsachievableovershortdialysissessions.However,thereareuraemicsolutesotherthanurea,suchasphosphateandβ2-microglobulin,whicharealsoimportantpredictorsofoutcome,andwhichareinefficientlyremovedbydialysis[17,18].Extendingdialysisdurationincreasestheremovalofthesehighlysequesteredandlargermolecules,independentofanychangeinsmallsoluteclearance[19,20].Intheotherpartofits2x2design,theNCDSstudyalsocomparedsessionduration(4.5-5.0vs2.5-3.0hours)andalthoughstandardsignificance‘level’wasnotachieved(p=0.06),showedreducedtreatmentfailureinthelongersessiongroup[1].Mostobservationalstudiesalsoreportimprovedoutcomeswithlongertreatmenttimes.LowmortalityrateswerereportedfromTassinwith8hourovernightdialysis,attributedtoimprovedbloodpressurecontrolandslowerultrafiltration[21,22],andlowermortalityisassociatedwithlongertreatmenttimesinnationalregistrystudies(overvsunder3.5hoursinUSpatients[23],andovervsunder4.5hoursinAustralia[24]).TheinternationalDOPPSstudyexaminedtheeffectoftreatmenttimewhilstcontrollingforconfoundersusingstandardregressionandinstrumentalvariableapproaches,concludingthatpatientswiththelongesttreatmenttime(atleast4hours)hadthelowestriskforall-causeandcardiovascularmortality[25].Otherclinicalmarkerssuchasbloodpressure,anaemiaandphosphatecontrolwerealsoimproved.Whilstrecognisingthelimitationsofobservationalstudies,aminimumdurationforoptimumdialysisclearlyexists,andismostlikelycloseto4hours,atleastforpatientswithminimalresidualkidneyfunction.AdurationthresholdmayleadtohigherthanminimumeKt/Vinsmalleradultpatients,whichisappropriatesinceoptimalKt/Vmaybehigherinthisgroup.SummaryOptimaloutcomesinpatientsonthriceweeklydialysisareachievedwithsessionsofatleast4hours,providingeKt/Vatleast1.2.Regularmonitoringisstronglyrecommended,andthisoccursmonthlyinthemajorityofunits.Underachievementmaybeaddressedbyattentiontovascularaccess[26],sessionduration[27],bloodordialysateflow[28,29,30],dialyserefficiency[31]oranticoagulation[32],andinsomepatientsunderachievementmaysuggesttheneedforanaugmentedschedule.Achievementofthesetargetsdoesnotguaranteeoptimaloutcome,witheKt/Vbeingunaffectedbymissedsessions,forexample.Thesedosetargetsapplytothriceweeklypatients,withminimalresidualfunction,forwhomsurvivaldurationisaprimarytreatmentgoal.Therearespecificclinicalscenariosanddifferentpatientvaluesforwhichitmaybeappropriatetoadjustordisregardnumerictargetsfordialysisdose.Non-standardschedules(Guidelines2.1–2.4)Guideline2.1-AugmentedschedulesWesuggestofferinganaugmentedscheduletopatientswhoareunabletoachieveadequacytargetsorfluidcontrolonastandardthriceweeklyschedule.[2B]Wesuggestthatrelativecontraindicationstoaugmentedschedulesshouldbeconsidered,suchassignificantresidualfunctionorproblematicfistulaaccess.[2C]RationaleDialysisdoseonathriceweeklyscheduleislimitedbypatienttoleranceandthenecessitytoutilise‘slots’efficiently,sothatsessionsover5hoursareveryuncommon.‘Augmented’inthisguidelinereferstoincreasedfrequency(4-6sessionsperweek)orthriceweeklydialysistotallingmorethan15hoursperweek.Thelatterisusuallydeliverednocturnallywhenin-centre,butbothareoftendeliveredinthecontextofhomehaemodialysiswheremuchoftheevidenceregardingaugmenteddialysisscheduleshasbeenobtained.Augmentedscheduleshavebeenassessedinfourrandomisedstudies[20,33,34,35],oneinterventionalstudywithmatchedcontrols[36],andahandfulofobservationalstudies.Evidenceofclinicalbenefitlimitedtointerventionalstudiesissummarisedbelow,withstudiesdividedintothreegroupsforeaseofdiscussion,accordingtothetypeofaugmentedschedule[20,33,34,35,36,37].Afourthgroupofaugmentedscheduleswhichmightbetermed‘modestlyfrequent’(4or5sessionsperweek,ofupto4hourseach)ispoorlyrepresentedinstudies. Group Frequentnocturnal Shortdaily Nocturnal Definition >6x/week >6hours >6x/week <4hours 3x/week >6hours Leadauthor/studytype (patientnumberininterventiongroup) Culleton/RCT(26) Rocco/RCT(45) Chertow/RCT(125) Ok/NRI(247) Ipema(metanalysis) Leftventricularmass Decreased(Culleton) Nochange(Rocco) Decreased   Bloodpressure Improved Improved Improved Hyperphosphatemia Improved Improved Improved Nutritionalstatus    Improved Compositehealthscore/qualityoflife Nochange Improved   Abbreviations:RCTrandomizedcontrolledtrial,NRInon-randomisedintervention Whereassessed,improvementsindepression,cognitionoranaemiaparametersweregenerallynotseeninthesestudies,althoughimprovementsintheseaspectshavebeenreportedinanumberofobservationalstudies.Qualityoflifeisanimportantoutcomesincetheinterventionclearlyinvolvesincreasedtreatmentburden.Observationalstudiessuggestthatqualityoflifeoflifeisimprovedindailydialysisbyapproximately6%,whereasnocturnalscheduleshavenotbeenshowtoimprovequalityoflife[38,39,40].Therandomisedstudieswerenotdesignedprimarilytoassessmortalitywithinthestudyperiod,buttwoofthesepublishedmortalityresultswithfollow-upextendedbyapproximately2.5years[41,42],andmortalityeffectshavealsobeenreportedinothertypesofstudy.Findingshavebeensurprisinglyinconsistent,however,andaresummarisedinthetablebelow[36,41,42,43,44,45]. Group Frequentnocturnal Shortdaily Nocturnal Definition >6x/week >6hours >6x/week <4hours 3x/week >6hours Leadauthor/studytype (patientnumberonaugmentedschedule) Rocco/RCT(45) Chertow/RCT(125) Marshall/OS(?) Suri/OS(318) Ok/NRI(247) Rivara/OS(1206) Hazardratioformortality (lessthan1.0favoursaugmentedschedule) 3.88 0.54 1.00/0.41(unit/home) 1.60 0.28 0.67 Abbreviations:RCTrandomizedcontrolledtrial,NRInon-randomisedintervention,OSobservationalstudy Authorsstressthatclinicaltrialsofmoreintensivedialysiswerenotdesignedtoevaluatemortality,andthatobservationalanalysesoftenemploystatisticaltechniqueswhichdonotadequatelyaddressthetime-varyingnatureoftheriskfactorsassociatedwithboththeinitiationofaugmenteddialysisandmortality.Thelargerrandomisedtrialsofaugmentedscheduleshavealsoidentifiedpotentialharms,forexamplereducingresidualfunction,animportantdeterminantofsurvivalonhaemodialysis.Inpatientswhohadsignificantresidualfunctionatenrolment,bothfrequentnocturnalandshortdailydialysisledtoamorerapiddeclineinfunctioncomparedtocontrolgroups[46].Interventionpatientshadashortertimetofirstvascularaccessintervention,andthereweresmallincreasesintheburdenoncarers,asperceivedbypatients,thoughtheauthorshighlightthatcarersthemselveswerenotassessed[47].Takentogetherthesestudiessuggestequivalentmortalityandmodestimprovementinsomedialysis-relatedconditions,offsetbyincreasedtreatmentburdenandpossibleharmstovascularaccessandresidualfunction.Whilstthereisnooveralladvantagefortheaveragepatientthesestudiesdosuggestspecificgroupswhowouldbeexpectedtobenefit.Forexample,adequacytargetscouldcertainlybeachievedinthosestillunableto,despiteareasonablylongthriceweeklyschedule.Similarly,patientsfailingtoachievefluidcontrolarelikelytobenefitfromanincreaseindialysisfrequency-thismightincludethosewithresistanthypertension,intra-dialytichypotension,andthosewithweekendadmissionstohospital.Thelattergrouparetheobviouscontributorstotheexcessmortalityofthetwo-daydialysisgap,andmayhavethemosttogainfromanincreaseindialysisfrequency.Theaugmentationofdialysisinthesesettingsshouldbeaimedatachievingaspecificpurpose,anditislikelythatafourthsessionperweekwouldbesufficientinmanycases.Inconclusion,augmentedschedulesoffernoclearadvantageforthemajorityofpatients,butshouldbeconsideredasatreatmentoptionforthosepatientswhoseadequacyorfluidcontroltargetsarenotmetwithastandardschedule.Amodestlyaugmentedschedulewouldbesufficientinthemajorityofthesepatients.Guideline2.2-IncrementalschedulesWesuggestthatlowerhaemodialysisdosetargetsmaybeoptimalinpatientswithsignificantresidualrenalfunction.[2D]Werecommendthatresidualrenalfunctionshouldbequantifiedintermittentlyinpatientsonincrementaldialysisschedules.[1D]RationaleIncrementalhaemodialysisisbasedonthecommonsenseconceptthattheamountofdialysisrequiredforoptimaloutcomediffersbetweenthosewithsignificantresidualfunctionandthosewithout.Thelattergrouphoweverislarger,andmakesupthemajorityinstudiesofdoseandoutcome,whichthereforemaynotbeapplicableintheformergroup.Optimaldialysisdoseisthereforenotfixedbutdependentonthelevelofresidualkidneyfunction,andtheprescribedschedulemaythereforebereducedinfrequencyordoseinthissetting.Thepracticeofincrementalhaemodialysisisconsistentwithaconceptofprogressivelyincreasingtherapyovertime,whichmayincludeaugmentedschedulesatalaterstage(Fig. 1). Fig.1Schematictoillustrateprincipleofincrementalhaemodialysis(numbersonlyasexamples)FullsizeimageLessfrequentandreduceddosedialysispracticesco-evolvedalongwithstandardthrice-weeklyschedules:referenceismadetotwiceweeklydialysisinobservationalstudiesfromthe1990sandinthe1997KDOQIguidelines[48].Forexample,inanobservationalstudyof15000Americanpatientspublishedin1999,Hansonreportedtwiceweeklyschedulesin6.1%ofpatientsduringtheirfirstyear,and2.7%ofpatientsthereafter[49].Outcomeswereatleastasgood,andinfactamortalityadvantagewasobservedwithtwiceweeklyschedules,mostlikelyduetodifferencesinbaselinefactors:nomortalitydifferencewasseenafteradjustmentforthelevelofresidualfunctionatdialysisinitiation.Thenon-inferiorityoftwiceweeklyschedulesinselectedpatientshasbeenfurthersupportedbymorerecentstudies.InaThaistudyof500twice-weeklypatientsPanaputreportedequivalentmortalityandhospitalisationoverthenextyear[50],andinapropensity-matchedKoreanstudyof300patientsfollowedforoneyear,Parkreportedequivalentmortalityandimprovedqualityoflifewithscheduleslessthanthrice-weekly[51].Non-inferiorityofclinicaloutcomewithreducedtreatmentburdenthereforeprovidesapowerfulargumentinfavourofincrementalschedules,butadditionalbenefitsmayexist:incrementalhaemodialysisscheduleshavealsobeenassociatedinsomeobservationalstudieswithreduceddeclineinresidualkidneyfunction[52,53].Preservationofresidualfunctionisofclinicalimportancesinceitprovidessignificantsoluteandfluidremoval,andisassociatedwithimprovedqualityoflifeandsurvival[54].Theliteratureonincrementalschedulesislimitedinparticularbyitsobservationalnature,withinherentproblemsofselectionandlead-timebias.Variationalsoexistsinthedefinitionofincrementaldialysis,whichisfrequentlydefinedastwice-weekly,withoutreferencetoresidualfunction.Clinicianbiasmayalsobeimportant:cliniciansworkinginthe1990swillremembertwice-weeklyschedulesprincipallyasaresource-sparingexercise,andeveninmodernseries,financiallyconstraintsplayapartintheiruse[55].Patientselectionisthereforecrucial:factorscurrentlyassociatedwithreducedscheduleuseinalargeChinesestudyincludeearlyvintage,femalesexandminimalcomorbidity[56].Andthelevelofresidualfunctionappearsperhapsunsurprisinglytobethemostimportantfactor:inalargeAmericanstudyinwhich350twice-weeklypatientswerematchedwithathrice-weeklygroup,twice-weeklyschedulesyieldedequivalentoneyearoutcomeinmany,butwereclearlyinferiorinthosewiththepoorestresidualfunction(clearancelessthan3ml/min/1.73m2)[57].Thosewithresidualclearanceof3ml/minorlessmaystillbesuitableforathrice-weeklyincrementalschedule(i.e.withdosetargetlessthanKt/V1.2and/orlessthan4hours).Theuseofincrementalhaemodialysisthereforerequiresregularmonitoringofresidualfunction,withfunctionreassessedaftermajorintercurrentillness[58].Suitablepatientsshouldbeawarethatdialysisdurationislikelytoincreaseovertime,andshouldbewillingtocooperatewithresidualfunctionmeasurements[59].IncrementaldialysisisentirelyconsistentwiththeconceptsofadequatedialysisdoseestablishedintheNCDSandHEMOstudiesasdiscussedinSection1,butincorporatesthecontributionofresidualfunction,sothatdialysisandresidualfunctionareseenasbothcontributingtooverallclearance.Thereareanumberofdifferentmethodsforquantifyingcombinedkidneyanddialysisureaclearance(summarisedinAppendix2)whichcanhelpwithscheduleanddoseselection.Theseshouldbeinterpretedinclinicalcontext,withdueobservationofindirectmeasuresofdialysisadequacysuchascontrolofsymptoms,bloodpressure,fluidgainsandelectrolytes,sothatdialysisdosecanbeappropriatelyescalatediftreatmentappearsclinicallyinadequate.Guideline2.3-ConservativeschedulesWesuggestthatlowerhaemodialysisdosetargetsmaybeoptimalwhenqualityoflifeistheprimarygoaloftreatment,ratherthanlongevity.[2D]RationaleWhilstconceptsofdialysisdosehavebeendevelopedoverthelasttwodecades,thedialysispopulationhasbeenchanging,withthemedianageoftheprevalentdialysispopulationincreasingbynearly20years,anddiabetesbecomingoneoftheleadingcausesofestablishedkidneyfailure.Formanypatients,dialysisisalong-termmaintenancetherapythatcontinuesuntildeathordialysiswithdrawal,withincreasingcomorbidityandfrailtydevelopingduringthistime[60].Thischangingdemographichasimportantimplicationsfortheclinicalapplicationofdialysisdose.Firstly,studieshavetypicallyfocusedonyoungerpatients(medianage49intheNCDSstudyincludingnodiabetics,andmeanage58intheHEMOstudy)sothatapplyingtheirconclusionsinamoreelderlygroupisanextrapolation.Secondly,studiesaregenerallymoreconcernedwithmortality,andmanystrategiesindialysisareaimedatpreventingfuturecomplications,whereascurrentsymptomsandqualityoflifeareoftenmorerelevanttothefrailerpatient.Andthirdly,theburdenofdialysisoftenincreaseswithincreasingfrailty,sothatthereisagreatertrade-offwhenconsideringtheburdenversusthebenefitoftreatment.Inthecontextofthischangingdemography,itisreasonabletoquestionwhetherconventionaldialysisdosingandtargetsremainappropriateforthispopulation[61].Frailtyasaclinicalsyndromecanbedefinedwhenanumberoffactorsarepresentincluding:unintentionalweightloss,self-reportedexhaustion,weaknessandlowphysicalactivity.Thepresenceoffrailtyisassociatedwithincreasingdisabilityandhospitalisation,andindialysispatients,withanadversequalityoflifeirrespectiveofdialysismodality.Theoptimumdialysisforfrailpatientshasonlybeenstudiedinsmallcohorts.Someoverlapexistsbetweenthefeaturesoffrailtyandthoseofunderdialysis,anditcouldbearguedbethatmoreintensivedialysismightbettercontrolsomeaspectssuchasfluidoverload,intradialytichypotensionorsarcopenia,orconverselythatnutritionaldeclinemightbeacceleratedbyreduceddialysis.Reductionsindialysisquantityshouldthereforenotbemisunderstoodasamethodofimprovingtheseaspectsoffrailty.However,whileincreasinghoursorfrequencyofdialysismaytheoreticallyovercomesomeoftheseproblems,patientsoftenperceivetheburdenofdialysisontheirqualityoflifemorethanthesymptomaticbenefit,anddialysisitselfmayconferspecificharmsinthisgroup:aretrospectivestudyidentifiedfrequentfunctionaldeteriorationamongdependentpatientsfollowingtheinitiationofdialysis[62].Inachallengingclinicalareawithapaucityofoutcomedata,itthereforeseemsentirelyappropriatetoreduceordisregardnumerictargetsfordialysisdose,insteadindividualisingdialysisaccordingtospecificpatientgoals.Goal-orientedcareisanestablishedapproachinpatientswithmultipleco-morbiditieswhichovercomestheproblemsinherentindisease-specificcareprocesses,withdiscussionsinsteadconcentratingonapatient’sindividualaimsoftreatment.Shareddiscussionsaboutdialysisschedule,drivenbypatient-centredgoalscanensurethatpatientsareneitherunderorover-treated,andinsomecasesmightbeaprecursortodialysiswithdrawal.Suchdiscussionsmayneedfrequentreviewfollowingchangesinthepatient’sclinicalorpersonalcircumstances.Guideline2.4-PaediatricschedulesInchildrenandadolescentswerecommendanapproachtotheassessmentofdialysisadequacywhichgoesbeyondbiochemicaltargets,incorporatingclinicalgoalssuchasgrowth,bonehealth,cardiacfunctionandqualityoflife.[1C]WerecommendtargetingdialysisdosetoachieveaminimumeKt/Vof1.2forthriceweeklypatients,orastandardizedKt/Vof2.2forthoseonaugmentedschedules.[1C]Wesuggestanaugmentedscheduleforchildrenonpredominantlyliquidnutrition,andthosewithventricularsystolicdysfunction.[2D]Werecommendabloodflowrateof5-7ml/kg/minforthemajorityofpatients,usingconsumablesappropriatetobodysize,withextracorporealvolumelessthan10%ofthepatient’sbloodvolume.[1C]RationaleThelowincidenceofdialysis-requiringkidneydiseaseinchildhood,meansthatmanytreatmentdecisionsareinformedbyobservationaldataandstudiescarriedoutinadults.Thesmall-solutedosetargetforadults(eKt/Vover1.2)thereforehassomerelevancetochildren,thoughcautiousinterpretationofatargetextrapolatedfromadifferentclinicalsettingwouldleadmanyclinicianstoaimforamoreconservative(i.e.higher)targetdose.Inaddition,uniquephysiologicalaspectsofchildhood,suchasgrowth,maybeimprovedbyincreaseddialysisdose,andtherearestrongargumentstosuggestthatoptimumKt/Vmaybesize-dependentinadults,sothatahigherminimumKt/Vmaybeappropriate[63].ThedesirablelowerlimitforeKt/Visthereforethoughttobebetween1.2and1.4.However,asisincreasinglyrecognizednowinadults,ithaslongbeenarguedthattheoptimalquantityofdialysisforchildrencannotbecharacterizedbyasinglenumericalmeasurement[64].Inadditiontothedesirableclinicaloutcomessharedwithadults,thetherapeuticgoalsforchildrenandadolescentsreceivingdialysisincludeachievementofnormalgrowth,bonematurationandsocialdevelopment,alongwithavoidanceofcardiaccompromiseanddisruptededucation.Theincreasingevidencethatdialysisdoseandscheduleisabletoimprovecardiacfunctionandoutcomesinmanyofthesedomainsarguesforabroaderconceptof“adequacy”whichmightbestbeassessedusingaconstellationofclinicaloutcomes,aswellasbiochemicaltargets.Augmenteddialysis,withincreasedfrequencyinparticular,isthereforeincreasinglyadvisedbyclinicians,anddespitetheobviousdrawbackoftreatmentburden,doesnotseemtoreducequalityoflife,eveninadolescents[65].Itispossiblethataugmentedschedulesareoptimalforallchildren,butsomegroupsseemparticularlylikelytobenefit,includingthosewithcardiacdysfunctionandthoseonaliquiddiet,inwhomitmightotherwisebedifficulttoachievesafefluidcontrol[66].Safelimitsappropriatetobodysizeareadvocatedformanyaspectsoftheextracorporealcircuit,suchasabloodflowrateof5-7ml/min/kg,whichisoftenadequatetoachievedialysisdosewithdoubleneedles,witharterialaspirationpressuresbelow200mmHg,tolimitendothelialtrauma.Forsingle-needledialysisthehighestbloodflowrateisobtainedusingadoublepumpsystem(venousflowhigherthanarterial)monitoredbypressure(timepressureregulation),withclamptechniquesusedtoachieveanacceptablecompromisebetweenrecirculationandbloodflow[67].Consumablesappropriatetobodysizeshouldbeselectedsothattotalextracorporealvolumeislessthan10%ofbloodvolume,toreducethevolumeloadwithwash-backattheendofthesession.Systemprimingwithalbuminorevenbloodmaysometimesberequiredforbabiesandsmallinfants.Guideline2.5-SchedulesduringpregnancyWerecommendcounsellingwomenofreproductiveagewhoarereceivingoranticipatingdialysis,sothattheyareawareoftheinteractionsbetweenrenalreplacementtherapiesandpregnancywhichmayimpactonfamilyplanningandmodalitydecisions.[1D]Fordialysispatientswishingtocontinuetheirpregnancy,werecommendchangingasearlyaspossibletoanindividualised,augmentedhaemodialysisschedule.Forthosewithminimalresidualfunctionthisshouldbeatleast20hoursperweek,deliveredoveratleast6sessions.[1B]Werecommendanindividualiseddialysateprescriptionappropriatetothedialysisscheduleandbiochemistryresults,anticipatingthefrequentneedforahighpotassium/lowbicarbonatedialysate,supplementedwithphosphate.[1C]Wesuggestanindividualisedfluidmanagementprotocol,withlowultrafiltrationratesandregularclinicalassessment,anticipatingthetypicalchangeinweightduringpregnancy.[2C]RationaleSuccessfulpregnanciesinwomenonhaemodialysisarebecomingmorecommon:priorto1995datafromtheUSAsuggestedonly40%infantsurvival,butoutcomesinthecurrenteraaresubstantiallybetter[68].However,pregnancycomplicationsinhaemodialysispatientsarestillmorecommonthaninpre-dialysisandtransplantpatients,andmayresultinHLAsensitisation,sodelayinguntilaftertransplantationmaybefavourableforsome.Conceptionmaybemorelikelywithaugmenteddialysisschedules[69],butthepossibilityofpregnancyorneedforcontraceptionshouldbeconsideredregardlessofdialysisschedule.Theliteraturelinkinghaemodialysisprescriptiontooutcomeinpregnantdialysispatientsislimitedtocaseseriesandsystematicreviews[70].Inarecentmeta-analysisof681pregnanciesin647patientsbetween2000and2014,authorsfoundthatlongerweeklydialysisdurationsignificantlyassociatedwithalowerincidenceofpretermdeliveryandbabiessmallfortheirgestationalage[71].Morefrequentdialysiswasalsoassociatedwithfewersmallbabies.Normalisationofbiochemistryandfluidstatusappearstogivethebestoutcome,andvirtuallyeverypublicationadvocatesintensifieddialysis.ThebestevidenceforthisapproachtodateisthecomparisonofdatafromtheTorontoandUSregistriesofpregnancyindialysispatients[72].Inwomenestablishedondialysisbeforebecomingpregnant,11of13pregnanciesweresuccessfulwithatleast36hoursperweek,comparedto22of46withupto20hours(p=0.02).Moreintensivedialysiswasalsoassociatedwithreducedpretermdeliveryandgreaterbirthweight.Residualkidneyfunctionfacilitatesnormalisationoffluidandelectrolytes,sotheacceleratedlossofresidualfunctionseenwithaugmentedschedulesraisesconcernsaboutthisapproachinwomenwithgoodurineoutput[73].IntheToronto/USregistrystudyallofthe17womenwhostarteddialysispartwaythroughthepregnancyhadasuccessfuloutcome.Since13ofthemwereintheshortertreatmentgroup,itappearsthatlongertreatmenttimeswouldhavebeenunnecessarilyburdensome,andpossiblydetrimental,topatientswithsignificantresidualfunction.InacomprehensivereviewHladunewichsuggestedtitratingthedialysisdosetoachieveurea10-15mmol/Lafterthelongestbreakbetweensessions[74].Theauthorsalsoprovideadviceonadjustingmedication,anaemiamanagementandfetalmonitoringwhichareoutsidethescopeofthisguideline.Withaugmentedschedulesdialysateshouldbeindividualised,withhighpotassium/lowbufferoftenrequired.Toensuretheneedsoffoetalskeletaldevelopmentaremet,lowserumcalciumandphosphateshouldbeavoided,whichmayinvolveadjustmentofdiet,medicationanddialysate:supplementationofthedialysatewithphosphateisoftennecessary.Magnesiumshouldpossiblybemonitoredinthethirdtrimester,sincelowlevelsmayinduceuterinecontraction.Augmentedschedulesallowpatientswithminimalresidualkidneyfunctiontoremainclosetotheirtargetweightandavoidhighultrafiltrationrates.Fluidstatusneedstobeassessedfrequentlyduringpregnancy,asthereisahighriskoffluiddepletion,especiallyinthesecondandthirdtrimester,andbioimpedanceandurinevolumemaybeusefulmeasurementsinthissetting.Typicalweightgainsduringahealthypregnancyrangefromaround150g/weekduringthefirsttrimester,toaround450g/weekduringthethirdtrimester.MembranefluxandhaemodiafiltrationWerecommendthatpatientswithminimalresidualfunctionshouldbetreatedwithhigh-fluxdialysers.[1B]Wesuggestthathaemodiafiltrationmaybeconsideredasatreatmentforintra-dialytichypotensionrefractorytoothermeasures,andfordialysispatientswithfavourableprognosiswhoareunableorunlikelytobetransplanted.[2B]Rationale Convectiveclearance Haemodialysisremovesuraemictoxinsbytwoverydifferentphysicalprocesses:diffusionandconvection. Diffusionisthemovementofsolutesindependentofsolventwhentheconcentrationdiffersbetweenthetwosidesofamembrane.Therateisdependentontheconcentrationdifference,thediffusioncoefficientofthemembrane,aswellasthebloodanddialysateflows,andthisprocessisextremelyefficientforsmallsolutes,suchasurea.Convectionisthemovementofthosesolutesnotexcludedbyporesize,alongwiththeirsolventasitcrossesthemembrane.Theratedependsonmolecularsizeandtheultrafiltrationrate,andthisprocessismostimportantformoleculestoolargeforefficientdiffusion,butstillsmallerthanthemembranepores,oftentermed‘middlemolecules’[18]. Convectiveclearanceisthereforeameasurablecomponentofdialysis,whichisqualitativelyandquantitativelydistinctfromureaclearanceandtreatmenttime.DiffusionofasoluteisusuallyquantifiedbyitsKt/V(Appendix1)whereasconvectionisbestquantifiedbyitssievingcoefficientandtheultrafiltrationrate(Appendix3). Ascendingquantitiesofconvectionarethereforeachievedwithlow-fluxdialysis,highfluxdialysis,andhaemodiafiltration.Historicallylow-fluxdialysiswasstandard,inpartbecauseitrequireslessaccurateultrafiltrationcontrolfromthedialysismachine-ultrafiltrationinstandardlow-fluxdialysisissimplyequaltothefluidremovedfromthepatient,usuallyaround2litres.Inhigh-fluxdialysisporesizeisincreased,increasingthesievingcoefficientformiddlemolecules,butalsothepermeabilitytowaterisimproved,sothatinternalfiltration(bidirectionalmovementofwaterwithinthedialyser)becomessignificant:netultrafiltrationofcourseremainsthesame,buttotalultrafiltration,allofwhichcontributestomiddlemoleculeclearance,isgreaterandmaybeasmuchas10litres[75].Inhaemodiafiltrationalargevolumeofreplacementfluidisgiven,toallownetultrafiltrationtobeincreasedtoaround20litres(Appendix3).Thereislittledifferenceinclearanceofsmallsolutesbetweenthesemethods[76]. Ofthe(over100)uraemictoxinsknown,manyaremiddlemolecules(withmolecularweightintherange0.6-60kDa)forwhichclearanceislargelydependentthereforeonconvection[18].Convectivequantitydoesnotimproveclearanceofallpoorly-diffusingmolecules,withphosphateclearanceforexample,largelyunaffected,butclearanceofmany,suchasβ-2-microglobulin,isprogressivelyincreasedbyhigh-fluxdialysisandhaemodiafiltration[77,78,79].Acontributionofconvectivedialysisquantitytofavourableoutcomeisstronglysuspected. Membraneflux Severalinterventionalstudiesgiveinsightintotheimpactofmembranefluxondialysisoutcomes,forexampleintheotherpartofits2x2design,theHEMOstudygroupcomparedhigh-fluxwithlow-fluxdialysis[80].Inthewholegroup(N=1846)high-fluxdialysisdidnotconferaclearsurvivaladvantage(RR0.92,95%CI0.81-1.04)althoughcardiacmortalitywasreduced(RR0.80,95%CI0.65-0.99).Intheroughlyone-third(N=577)ofpatientswithover3.7yearsdialysisvintagepriortorandomisation,high-fluxdialysisimprovedsurvivalsubstantially(RR0.68,95%CI0.53-0.86). TheMembranePermeabilityOutcomestudyrandomised738incidentpatientstohighvslow-fluxdialysis,stratifiedbyserumalbumin(normalvssubnormal)[81].Overameanobservationof3years,high-fluxdialysisreducedmortalityinthelowalbumingroup(N=493,HR0.63,95%CI0.45-0.90)withalessclearreductioninmortalityinthewholegroup.High-fluxwassimilarlyadvantageousinthesubgroupwithdiabetes. Ameta-analysisof33studiescomparinghigh-fluxwithlow-fluxdialysisin3820patients,foundreducedcardiovascularmortality(RR0.83,95%CI0.70-0.99)andalessclearreductioninall-causemortality(RR0.95,96%CI0.87-1.04)[82].Endotoxintendstobeabsorbedwithinhigh-fluxmembranes,ratherthanpassingthrough,andinitialconcernsthatdialysateendotoxinwouldbemoreproblematicwithhigh-fluxdialysisappeartohavebeenunfounded[83]. Whilstnostudyhasunequivocallydemonstratedthesuperiorityofhigh-fluxdialysisforsurvival,thereisclearevidenceofimprovedcardiovascularoutcomes,andall-causemortalityappearstobeimprovedinseveralsubgroups[84].Atthesametime,evidenceofharmislacking,allmodernmachineshaveaccurateultrafiltrationcontrol,andmembranecostsarenowequivalent.Furtherresearchonthisquestionthereforedoesnotseemtobeahighpriority. Haemodiafiltration Theeffectofhaemodiafiltrationhasbeeninformedbyfourrandomisedcontrolledstudies,summarisedinthetablebelow.Inthreeofthese,marginalbutnon-significantadvantageswereseeninthehaemodiafiltrationgroup,withsubgroupanalysissuggestingfavourableoutcomewiththehighestconvectionvolumes,thoughthelattertosomeextentmayreflectbodysizeortreatmenttolerance[85,86,87]. AclearadvantagewithhaemodiafiltrationwasseenintheESHOLstudy,whichspecifiedahigherconvectionvolumeof23litres,butconsequentlymaybeconfoundedbysubjects’abilitytosustainthesevolumes,whichisdependentonhighbloodflow,sothatcensoringmaybemostfrequentinthehighestriskpatients[88].ApartfromtheCONTRASTstudy[85]thesewereallanalysed‘astreated’,withright-censoringwhentreatmentwasdiscontinuedforanyreason,leadingtopotentialbiassinceendpointsaremorelikelytobehiddeninthehaemodiafiltrationarm.Anothercriticismconcernsthemechanismoftheclinicalbenefit,sincemiddlemoleculelevelswerenotdemonstrablyimprovedbyhaemodiafiltration:plasmalevelsofβ-2-microglobulinincreasedsignificantlyinbotharmsoftheESHOLstudy. Reducedmortalitywithhaemodiafiltrationwasobservedwithpooledanalysisofthefourstudies(HR0.86,95%CI0.75-0.99)dueinparticular,toareductionincardiovascularevents,withauthorsestimatingthepreventionofonecardiovasculardeathforevery75patient-yearsoftreatment[89].However,duetobiaseswithinstudydesigns,considerabledoubtoverthesuperiorityofhaemodiafiltrationremains[90]. Studyname(location) Yearofmainpublication NumberIntvsControl Meanage Interventions Meanobservation Mortality%IntvsControl HR(95%CI)ifsignificant CONTRAST(Europe/Canada) 2012 358vs356 64.1 HDFvslowflux 3years 36.6vs38.8 TurkishHDF(Turkey) 2013 391vs391 56.5 HDFvshighflux 1.9years 13.3vs16.6 ESHOL(Spain) 2013 456vs450 65.4 HDFvs92%highflux 1.9years 18.6vs22.8 0.70(0.53-0.92) FRENCHIE(France) 2017 190vs191 76.2 HDFvshighflux 2years 18.9vs22.5 HaemodiafiltrationwasalsoassessedinaDOPPSstudy,inwhichafteradjustment,noassociationbetweenconvectionvolumeandsurvivalwasobserved[91].Severalofthesestudiesalsofoundalowerfrequencyofintradialytichypotensionwithhaemodiafiltrationcomparedtothecontrolgroup,thoughtheauthorsacknowledgethedifficultyinexcludingconfoundingfactorssuchascoolingandpositivesodiumbalance[92]. Fluidinhaemodialysis(Guidelines4.1–4.2)Guideline4.1-FluidassessmentandmanagementinadultsWerecommendassessmentoffluidstatuswhenpromptedbyclinicalcircumstances,andonaquarterlybasisforstablepatients.[1C]Wesuggestamultidisciplinaryapproachtofluidassessment,withpatientinvolvementandtheadoptionofpatient-friendlyterminologysuchas“targetweight”,“fluidgain”and“over-hydration”.[2D]Wesuggestsupplementingclinicalassessmentoffluidstatuswithavalidatedobjectivemeasurement,suchasbioimpedance,atregularintervals,whenclinicalassessmentisunclear,andfollowinganintercurrentillness.[2C]Werecommendadialysatetemperaturenotgreaterthan36'Cifstandardised.[1C]Werecommendavoidingexcessiveultrafiltrationratesbyaddressingfluidgains,acceptingstagedachievementoftargetweight,orusinganaugmentedschedule,asnecessary.[1B]Werecommendpromptnursinginterventiontorestorehaemodynamicstabilityinsymptomatic/severeintradialytichypotension,withsuchinterventionsleadingtoclinicalreview.[1C]RationaleFluidcontrolisanessentialclinicalgoalofmaintenancehaemodialysis,butcorrectfluidmanagementrequiresclinicianstosteerbetweenthetwocompeting/overlappingproblemsoffluidoverloadandintra-dialytichypotension.Failuretocontrolfluidoverloadmayleadtoobviousshort-termeffectsincludinghypertensionandbreathlessness,andnephrologytraineesquicklybecomefamiliarwiththeemergencydialysisadmissionwithpulmonaryoedema.Inthelongertermalso,chronicfluidoverloadisoneofthemaindriversofhypertensionandisindependentlyassociatedwithpooroutcomes:forexample,inaUSstudyofover10000prevalenthaemodialysispatients,Flythereportedclinicaloutcomesover2years’follow-up,accordingtoachievementoftargetweightduringthebaselinemonth[93].Comparedtothoseachievingwithin2kgoftargetweightonatleast70%ofsessions,the15%ofpatientsfrequentlyremainingover-hydratedpostdialysishadincreasedmortality(HR1.28,95%CI1.15-1.43)asdidthe7%ofpatientswhowerefrequentlyunder-hydratedpostdialysis(HR1.22,95%CI1.05-1.40).Oftencompeting,thoughsometimesassociatedwithfluidcontrol,isintra-dialytichypotension,whichalsohasimmediateconsequencesfamiliarinthedialysisunit,includingdizzinessandcramps,aswellasmorelong-termadverseeffects.Forexample,Sandsstudiedtheoccurrenceofintra-dialytichypotension(definedasadropinsystolicbloodpressureofatleast30mmHg,tobelow90mmHg)in1137patientsin13dialysisfacilities,overanaverageperiodof3months[94].Withthisdefinition,hypotensioncomplicated17.2%ofsessions,affecting74.9%ofpatientsatleastonce,and16.2%ofpatientsonatleastonethirdoftheirsessions.Thosemostpronetointra-dialytichypotensionwereolder,morecomorbidandwithlowerpre-dialysisbloodpressure,withassociatedsessionalfactorsincludinghighultrafiltrationvolumeandnon-achievementoftargetweight.Outcomesassociatedwithintra-dialytichypotensionincludedshortenedsurvivalandincreasedhospitaladmission.Thetwomaintreatmentparametersbywhichcliniciansaimtooptimisefluidcontrol,aretargetweightandultrafiltrationrate.Sincetheearliestdaysofdialysis,settingultrafiltrationtoachieveasettargetweightpostdialysis,atwhichthepatientisattheircorrectvolume(or“dry”)hasbeentheacceptedmethodofmaintainingaconsistentvolumestate,butthemethodisdependentonaccurateestimationofthecorrecttargetweight.Thoughmostoftenassessedbyclinicalexamination,theinaccuracyofthismethodiswidelyappreciatedsothatbothoverestimationandunderestimationarecommon,withtheformercontributingtohypertensionandleftventricularhypertrophy,andthelatteracceleratingthelossofresidualkidneyfunctionandperhapsriskingmyocardialstunning.Toimproveonclinicalassessment,nephrologistsatonetimeadvocated“probing”targetweight:gradualreductionuntilpatientsreportsymptomssuggestinghypovolaemia,butthismayreducetreatmentcomplianceandamorecollaborativeapproachismorecommon:wherepossible,patientsshouldbeaskedtoparticipateinmonitoringtheirfluidstatus.Tothisendterminologyshouldbesimpleandintuitivelyunderstood:forexample,whendiscussingtargetweight,theterm“dryweight”cangivetheimpressionthattheaimistoremoveasmuchfluidaspossible,and“idealweight”canbeconfusingasitisalsousedtodescribethepreferredbodymassindex.Althoughlessaccurate,“hydration”isamorefamiliartermthan“volume”asadescriptionoffluidstatus.Stablepatientsshouldbeassessedfortargetweightchangesperhapsquarterly,butstaffandpatientsshouldbeparticularlyvigilantwhenchangesinfleshweightarelikely,suchasfollowinghospitaladmission,orwhenstartingnutritionalsupplementation.Fluidmanagementoftenrequiresinputfromamultidisciplinaryteam,soadocumentedpolicymayensurethattheapproachisconsistent.Improvementonclinicalassessmentusingobjectivemethodsforselectingtargetweighthasbeensoughtforalongtime,thoughnosinglemeasurementhassofargainedwidespreadacceptance.Methodshavefallenintooneofanumberofcategories:imaging(suchasinferiorvenacavadiameter),biochemistry(suchasbrainnatriureticpeptide),electrophysiology(suchasbioimpedance)anddynamicintradialyticmeasurement(suchasbloodvolumemonitoring).Manypublicationsaddressoneormoreofthesemethods,andseveraldetailedreviewsareavailable.Someofthesestudiessufferfromthelimitationsofself-referencingdesign(demonstratingthattheuseofmethodXtoguideselectionoftargetweight,reducesthefrequencyofover-hydrationasdefinedbymethodX)andimprovementinclinicaloutcomesareoftenhardertodemonstrate.Forexample,Leungstudiedintradialytichypotensionin32haemodialysispatientsduring8weeksofstandardcareand8weeksduringwhichultrafiltrationwasinformedbybloodvolumemonitoring,butnoadvantagewasseenintermsofhypotensionfrequencyorsymptoms[95].Noclearrecommendationcanbemaderegardingtheoptimalmethod,butwhenclinicalassessmentfeelsuncertain,itseemsveryreasonabletosupplementthiswithanobjectivemeasure,andbioimpedancehassomeofthemostpromisingdataonclinicallyrelevantendpoints.Inarandomisedstudyof156patients,Nurusedbioimpedancedatatoadjusttargetweightintheinterventiongroup,whilstcontrolpatientshadbioimpedancemeasuredbutnotavailabletotreatingphysicians[96].Overthe12monthstudy,bioimpedance-definedfluidoverloadwasreducedintheinterventiongroup,aswasbloodpressureandleftventricularmassindex(131±36to116±29g/m2,p<0.001).Regardlessofthefinalvolumeachieved,therateofultrafiltrationappearsseparatelytoinfluenceintra-dialytichypotensionandclinicaloutcome.InaDOPPSstudyof22000patientsin7countries,Saranobservedthatanultrafiltrationrateover10ml/h/kgwasassociatedwithbothintra-dialytichypotension(RR1.30,p=0.04)andmortality(RR1.09,p=0.02)[97].AndusingdatafromtheHEMOstudy(N=1846)Flythedividedpatientsaccordingtoultrafiltrationrateintothreegroups:lessthan10,10-13,andover13ml/h/kg,demonstratingincreasedmortalityinthehighestultrafiltrationrategroup(HR1.59,95%CI1.29-1.96)[98].Inthesamestudy,whentreatingultrafiltrationrateasacontinuousvariable(usingacubicsplinemethod)theauthorsidentified10ml/h/kgasthethresholdbeyondwhichmortalitybeginstoincrease,possiblyquitesharply.Thesestudiesarenon-interventional,thereforeassociationsarewithobserved(ratherthanprescribed)ultrafiltrationrate,andthereisalsoacloseinteractionwithsessionlength(sincerateisobviouslythevolumeoverthetime)butthesedataprovideaconvincingargumentforavoidanceofexcessiverates.Thisshouldnothoweverbeattheexpenseofnon-achievementoftargetweightandacceptanceofover-hydration(thoughstagedachievementoveranumberofsessionsisfrequentlyappropriate)butrathershouldfocuscliniciansonsessionlengthoraddressingfluidgainsbetweendialysissessions.Theultrafiltrationrequiredduringdialysisdependsonthedegreeofover-hydrationpresentatthestartofthesession,sorestrictingfluidintakereducesultrafiltrationrate,andispartofstandardadviceforthemajorityofpatients.Considerationmustbegiventothecauseofincreasedfluidintakesuchashabitualdrinkingorthirstassociatedwitheitherdietarysodiumintakeorraisedbloodglucose.Adviceonmanagingfluidintakeisthereforebestdeliveredonanindividualisedbasis,aspartofadietarymanagementplantosupportadherenceandpatientexperience.Thistopiciscoveredinguidelinesforthenutritionalmanagementofkidneydisease.Otherrelevantaspectsofthedialysisprescriptionincludedialysatesodiumandtemperature.Sodiumbalance,thirstandfluidcontrolarealsoinfluencedbydialysatesodium.ManyobservationalstudiesreportlowerfluidgainsandlowerbloodpressureinpatientstreatedwithlowdialysateNa(typically136-138mmol/l).Antihypertensivetreatmentisfrequentlyoverlookedinlargestudies,butreasonablesupportiveevidencecanalsobefoundininterventionalstudies.Forexample,Gumrukcuoglureduceddialysatesodiumfrom140to137mmol/lin41patientsover6months,reportingreducedfluidgains,andnobloodpressurechangebutareductioninantihypertensiveusefrom1.9to1.2agentsperpatient[99].Thispotentialbenefitwasnotwithoutdrawbackshowever:incommonwithothergroups,investigatorsalsofoundthatcrampsandintra-dialytichypotensionbecamemorefrequent.Loweringdialysatesodiumthereforedoesappeartoimprovefluidcontrolandbloodpressure,albeitwithsomesideeffects,howeveranothernoteofcautionarisesfromobservationsonmortalityindifferentdialysatesodiumgroups.Studyingalmost30000patientsfromDOPPSphases1-4,withdialysatesodiumvaryingbetween138and142mmol/lin90%ofpatients,Heckingfoundthathigherdialysatesodiumwas,asexpected,associatedwithmodestlyincreasedfluidgainandsystolicbloodpressure(increasingby0.17%bodyweightand0.66mmHgper2mmol/lincreaseindialysatesodium)[100].However,whenaddressingindicationbiasbystudyingonlythe56%offacilitiesusingastandardiseddialysatesodium,theyfoundthathigherdialysatesodiumwasunexpectedlyassociatedwithreducedmortality(HR0.88per2mmol/lincreaseindialysatesodium,95%CI0.83-0.94).Thereisinsufficientconsistencyintheliteratureforaclearrecommendationondialysatesodium,thoughifastandardiseddialysatesodiumisusedforallpatients,someclinicianswouldavoidachoicebelow140mmol/l.Dialysatetemperaturehasbeenconsistentlyassociatedwithintra-dialytichypotension.Eventhermoneutralhaemodialysis(temperature-matchedsothatthedialysiscircuitneitherheatsnorcoolsthepatient)leadstoanincreaseincoretemperature,thoughitisnotclearifthisisduetoreducedheatloss(forexampleduetocutaneousvasoconstriction)orincreasedthermogenesis(forexampleduetoincreasedcardiacoutput)[101].Reduceddialysatetemperaturehasthereforebeenthesubjectofanumberofinterventionalstudiesandtwometa-analyses[102,103].Inthemostrecentofthese,Mustafareportedon26studiestotalling484patients[103],observinganaverage70(95%CI49-89)percentreductioninhypotension,thoughwithanincreaseincold-relatedsymptoms.Twenty-fourofthesestudieshoweverwereeithersmall(lessthan20patients)orofshortduration(lessthan3sessions).Thetwolargeststudiesprovidefurtherinsight:inMaggiore'sstudyof95patientsover12sessions[104],isothermic(inwhichdialysatetemperatureissetsothatcoretemperatureisunchanged)ratherthanthermoneutraldialysisreducedhypotensionfrom50to25%ofsessions.InFine’sstudyof128patientsover10sessions[105],35'Cdialysateratherthan37'Csimilarlyreducedhypotension,butthebenefitwasseenonlyinthosewithsubnormaltemperaturebeforedialysis.Preventingtemperaturerisethereforeappearstobemoreimportantthancooling,whichmaybeachievedonanindividualbasisusingdialysate0.5-1.0degreelowerthancoretemperatureorinthewholeunitbyusingdialysatetemperature36'Corlower.Thelatterisprobablyadequateformostpatients,withindividualisationseemingareasonableoptionforthosewithpersistinghypotensionorcold-relatedsymptoms,anditisreasonablyclearthatifastandardiseddialysatetemperatureisbeingused,thenthechoiceshouldbeatorunder36'C.Regardlessofthequalityofdialysisprescription,intra-dialytichypotensionwillstilloccur,insomepatientsmorethanothers,forwhichpromptnursinginterventionisessential[106].Commonmeasuresincludelegraisedpositioning,ceasingultrafiltration,andfluidadministration(salinebeingasgoodasalbuminandfarcheaper[107]).Measuresfor“simple”intra-dialytichypotensionshouldbecoupledwithassessmentforunderlyingintercurrentillness(suchasinfectionorcardiacarrhythmia)orlesscommonlyaspecificdialysiscomplication(suchasairembolismordialyserreaction).Frequentinterventionshouldleadtore-assessmentoftargetweight/ultrafiltrationsettingandamedicationreview-insomecasespredialysishypertensionmaybepreferabletodialysisintolerance.Specificpharmacologicalmeasuresarerarelyusedbutthealfa-agonistMidodrinehasreasonablesupportiveevidence:inmeta-analysistheaverageimprovement(increase)insystolic/diastolicpost-dialysisbloodpressurewas12.4/7.7mmHg[108].Guideline4.2-PaediatricfluidconsiderationsIngrowingchildrenwerecommendclinicalassessmentoffluidstatusandtargetweight,anddieteticassessment,atleastmonthly.[1C]Wesuggestsupplementingclinicalassessmentwithavalidatedobjectivemeasureoffluidstatussuchasbioimpedance,onamonthlybasisormorefrequentlyduringperiodsofrapidgrowthorillness.[2C]Werecommendregularassessmentofultrafiltrationtolerance,usingextendedtimestoavoidexcessiveultrafiltrationrates.[1D]RationaleAssessmentoftargetweightinchildrenandadolescentsisparticularlychallengingasitneedsfrequentadjustmentinlinewithgrowthorperiodsofillness.Thisisparticularlytrueforinfantsandadolescentsduringrapidphasesofgrowth.Overestimationoftargetweightwillresultinchronicfluidoverloadleadingtohypertensionandleftventricularhypertrophy,whereaschronicunder-hydrationislikelytodetrimentallyaffectresidualkidneyfunctionandleadtoincreasedsymptomatichypotensionbothduringandimmediatelypost-dialysis.Hypotensivetendencyisalsomultifactorialandcannotalonebereliedontoascertainapatient’stargetweight.Itisthereforeessentialthattargetweightisadjustedatleastonamonthlybasisfollowingclinicalassessment,inconjunctionwithdieteticreview[109,110].Dialysate(Guidelines5.1–5.4)Whenthe2ndeditionoftheRAGuidelineswaspublishedin1997,theonlyrecommendationrelatingtothecompositionofthedialysatewasthatrenalunitsphaseouttheuseofacetateinfavourofbicarbonatebuffering,sincetheimprovedefficiencyofdialysiscouldoverwhelmthecapacitytometaboliseacetate.Theneedtokeepbicarbonateseparatefromdivalentcationstopreventprecipitationmeantthatdialysatehadtobeproducedusingtwodifferentconcentrates,leadingtothemodernproportioningsysteminwhichsodiumbicarbonateismixedwithanelectrolyteconcentrate(‘acidconcentrate’)atthepointofuse,allowingindependentcontrolofmostdialysateconstituents.Somedialysateconstituentshavediversifiedwhereasothershavegraduallybecomestandardized.Dialysatecalciumwasoftensupra-physiologicalinthe1990’s(around1.75mmol/L)topreventhypocalcaemia,butthisbecameunnecessarywithincreasinguseofvitaminDanaloguesandcalcium-containingphosphatebinders,sothatdialysatecalciumhasbecomereasonablystandardized,usuallyintherange1.25-1.50mmol/L.Non-standarddialysatecalciummaysometimesbehelpful,forexampleinthecontextofcalciphylaxis,butthisisusuallydrivenbybone-mineralconsiderationsandisoutsidethescopeofthisguideline.Inthe1990’s,dialysatewasusuallyglucose-freeduetocostandmicrobiologicalconcerns,andhypoglycaemiawasoftenaproblemfordiabeticpatients.Glucosecontainingdialysatewasinitiallyprescribedfordiabeticpatients,butextendedtoallascostsimproved,sothatadialysateglucoseof5.5mmol/LisnowstandardinalmostallUKdialysisunits.Theotherconstituentofdialysisthathasbecomestandardisedismagnesium,withlow(usually0.25or0.375mmol/L)orhigh(usually0.75mmol/L)magnesiumbeingreplacedbyadialysatemagnesiumof0.5mmol/L,closetothelowerendofthenormalrange.Opposingthesetrends,therehasbeensignificantdiversificationindialysatepotassium,andsimilarly,bufferconcentrationsandpracticesvarybetweenunitsandmanufacturers,andarediscussedbelow.Guideline5.1-SelectionofdialysatepotassiumWerecommendanoptimalpre-dialysisserumpotassiumintherange4.0–6.0mmol/L,rememberingtoconsidermeasurementerrors(e.g.duetohaemolysis)wheninterpretinglevels.[1B]Wesuggestchoosingdialysatepotassiumbetween1.0and3.0mmol/Lforthemajorityofpatients,usinganindividualisedapproach,ingeneralusingthehighestdialysatepotassiumthatissufficienttocontrolpre-dialysishyperkalaemia.[2C]Wesuggestacombinedapproachtomanaginghyperkalaemia,whichmayincludedecreasingdialysatepotassiumand/orothermeasures,includingdietaryadvice,medicationreviewandincreaseddialysisfrequency.[2D]RationaleHistorically,itwasoftendifficulttoremovethepotassiumaccumulatedbetweendialysissessions,sodialysatepotassiumbetweenzeroand2mmol/Lwascommon.Therequirementfordialysatewithpotassiumlevelsthatarecloseto,orwithin,thenormalrangereflectstheincreasedefficiencyofmoderndialysisandtheincreasedageofthemodernpatient.Inmostunitsdialysatepotassiumisdeterminedbythechoiceofacidconcentrate:zeropotassiumisnolongerused,andsuppliersofferconcentrateswithpotassiumbetween1and4mmol/L.Removalofaccumulatedpotassiumbyintermittenthaemodialysisinevitablyleadstoafluctuatingprofileofserumpotassiumwithariskofcardiacarrhythmiasatbothhighandlowconcentrations.Thisprobablycontributestotheclusteringofsuddencardiacdeatharoundtheperidialyticperiod,andattheendoftheweekendgap[111].Bothlowandhighpre-dialysispotassiumareassociatedwithincreasedmortality,sothatthemortalitycurveisU-shaped.Lowpotassiumoftenappearsmoreharmfulinunadjusteddata:forexample,inastudyof483Taiwanesepatientsfollowedfrom2004to2008,Hwangshowedthatthosewithpre-dialysispotassiumbelow3.5mmol/Lhadmorethantwicetheriskofmortalitythanthosewithhigherlevels[112].Butthislinkmaybeduetoconfoundingbycomorbiditymalnutrition:inamuchlargerstudyof74219patientsbetween2001and2004,aU-shapedriskcurvewasseen,withincreasedmortalitywithpre-dialysispotassiumoutsidetherange4.3–5.6mmol/L[113].Afteradjustmentforcasemixandmalnutritionparametershowever,theincreasedriskofmortalityremainedonlyforthehighpotassiumpatients(thoughthelessthan4.0mmol/Lcategorywasnotsubdivided).Theoptimumpre-dialysispotassiumthereforeappearstobeabove4.0withanupperlimitbetween5.6and6.0mmol/L,thoughthebroaderrangeseemsmoreappropriategiventheconsiderationsbelow.Therelationshipbetweenpost-dialysispotassiumandmortalityisunknown,asitisrarelymeasured,buttherisksofpost-dialysishypokalaemiacanbeinferredfromstudiesofdialysatepotassium[114,115].Forexample,Puncompared502patientswhoexperiencedsuddencardiacarrestindialysisunitsbetween2002and2004,with1632ageandvintagematchedcontrols,findingthatriskwasdoubledifthepatientlastdialysedwithalowdialysatepotassium(lessthan2.0mmol/L)[163].TheDOPPSreviewofmodifiablepracticesassociatedwithsuddendeathincluded36235patientsin12countriesofwhom6606weredialysedwithdialysatepotassiumatleast3.0mmol/L[116].Anincreasedriskofsuddendeathwasobservedwithdialysatepotassiumbelow3.0mmol/L(HR1.17,95%CI1.01–1.37),thoughitwasnotclearifthisriskextendedtothosewithpre-dialysisserumpotassiumover5.0mmol/L.Othershavesuggestedthatlowerdialysatepotassiummaypreventsuddendeathinthissubgroup[111,113],butthelatestDOPPSanalysisfoundnomeaningfuldifferenceinmortalityorarrhythmiaeventsbetweenpatientstreatedwithdialysatepotassiumof2.0or3.0mmol/L[117].Theunderstandablystrongimpulsetocontrolpre-dialysishyperkalaemiashouldthereforebetemperedbyconsiderationofthelessvisibleriskofpost-dialysishypokalaemia.Pragmaticallythereforeonecanconcludethefollowinggeneralprinciples:Firstly,pre-dialysishyperkalaemiashouldbecontrolled,thoughanoverlytightrangemaybecounterproductive,sothepreviouslyrecommendedtargetforpre-dialysispotassiumstillseemsoptimal(4.0–6.0mmol/L).Caveatstointerpretingthisrangeshouldbenoted:firstly,achievementofpre-dialysispotassiumwithinthisrangedoesnotnecessarilymeanthatdialysatepotassiumisoptimal,andsecondly,consistentadherencetotreatmentismostlikelyjustasimportantasspecificsofthepotassiumrangeordialysisprescription.Secondly,non-dialysateapproachestohyperkalaemiamaysometimesbemorefavourable[118,119].Dietaryreductionmaybepreferableifitcanbeachievedwithoutanadverseeffectonprotein-calorieintake,andotherdialysischangesmaybeappropriate,suchasincreasingbloodflow,durationorfrequency.Considerationcouldalsobegiventopotassiumbindingresins[120].Thirdly,lowerdialysatepotassiumdoesincreasetheremovalofpotassiumduringeachsession[121],andbasedontheriskofarrhythmiasduetohyperkalaemia,dialysatepotassiumshouldbereducedifothermeasuresarenotpossibleorsuccessful[122].However,dialysatepotassiumshouldbenolowerthanisnecessarytoachievethisgoal–individualizationdoesthereforeseemnecessary,sothateachpatientusesthehighestdialysatepotassiumwhichstillcontrolspre-dialysishyperkalaemia.Thispragmaticapproachhasprobablydriventhesteadyincreaseintheuseofhigherpotassiumdialysates,andreductionintheuseofconcentrationsbelow2.0mmol/L,overthe5DOPPSphasesbetween1996and2015[117].Finally,andparticularlyformeasurementstakenremotefromthelaboratory,therelativelyhighfrequencyofmeasurementerrors(forexampleduetoinvitrohaemolysis)shouldberememberedwheninterpretingpotassiumlevels.Guideline5.2-SelectionofdialysatebufferWerecommendanoptimalpre-dialysisserumbicarbonateintherange18.0-26.0mmo/L,rememberingtoconsidermeasurementerrors(e.g.duetoexposuretoair)wheninterpretinglevels.[1C]Wesuggesttheterm‘dialysatebuffer’ratherthan‘dialysatebicarbonate’toavoidconfusionarisingfromdifferencesinmanufacturers’terminology.[2C]Wesuggestchoosingdialysatebufferbeloworequalto37.0mEq/Lforthemajorityofpatients,usingastandardisedorindividualisedapproach.[2C]Wesuggestacombinedapproachtoabnormalpre-dialysisserumbicarbonate,whichmayincludeincreasingdialysisdose,oralbicarbonate,nutritionalsupport,orindividualisingdialysatebuffer.[2D]RationaleWesuggestacombinedapproachtoabnormalpre-dialysisserumbicarbonate,whichmayincludeincreasingdialysisdose,oralbicarbonate,nutritionalsupport,orindividualisingdialysatebuffer.[2D]Theliteratureondialysatebicarbonateisdifficulttointerpretduetouncleardefinitionswhenreportingthebicarbonateandadditionalalkalicomponents.Mostcommonlytheelectrolyteconcentratecontainsanon-bicarbonateacid,toreducethedepositionofcalciumandmagnesiumsalts–aceticacidisperhapsthemostcommon,butcitricacidandsodiumdiacetatemayalsobeused.Whenmixedtoformthedialysate,acetatereactswithsodiumbicarbonatetoformsodiumacetate,waterandcarbondioxide: $${\mathsf{H}\mathsf{C}}_{\mathsf{2}}{\mathsf{H}}_{\mathsf{3}}{\mathsf{O}}_{\mathsf{2}}+{\mathsf{NaHCO}}_{\mathsf{3}}\to{\mathsf{NaC}}_{\mathsf{2}}{\mathsf{H}}_{\mathsf{3}}{\mathsf{O}}_{\mathsf{2}}+{\mathsf{H}}_{\mathsf{2}}\mathsf{O}+{\mathsf{CO}}_{\mathsf{2}}$$Theadditionof3mmolofaceticacidtoalitresolutioncontaining35mmolofbicarbonatethereforereducesthebicarbonateconcentrationto32mmol/L.Inpublications,bicarbonateconcentrationinthisdialysatemayvariablybereferredtoashavingabicarbonateconcentrationof32or35mmol/L,withtheacetatecontentrarelyreported.Inaddition,thebicarbonate‘setting’onmachinesfromdifferentmanufacturers,refersvariablytothebicarbonateconcentrationeitherpriorto(eg.Braun)orafter(eg.Fresenius)mixingwiththeelectrolyteconcentrate.Theterms‘actual’bicarbonate(becausethatiswhatisactuallyaddedassodiumbicarbonate)and‘final’bicarbonate(becausethatisthebicarbonateinthedialysateatthepointofuse)aresometimesusedtoseparatetheirmeaning.However,thetotalbufferconcentrationremainsthesamebeforeandafterthismixing,sothistermhasaclearunambiguousmeaning(equivalenttothesumofbicarbonateandacetateconcentrationsinthefinaldialysate).InadiscussionoftheDOPPSstudyofdialysatebicarbonate,Tentoriobservedthatwhenaskedeitherforthebicarbonateortotalbufferconcentration,mostDOPPSunitsreturnedthesamefigure,suggestingthatcliniciansgenerallymean‘actual’ratherthan‘final’bicarbonate,whichisthesameastotaldialysatebuffer[123,124,125].Thefactorsaffectingpre-dialysisserumbicarbonatelevelsincludeproteinintake,residualkidneyfunction,interdialyticfluidgain,dialysatebufferconcentration,dialysisadequacy,oralsodiumbicarbonateandotheralkalinemedicationssuchascalciumcarbonate[126].Observationalstudiesofpre-dialysislevelsusuallyshowaJ-shapedmortalitycurve,withmostoftheexcessriskassociatedwithhighlevelsofbicarbonate[127,128],butthisappearstobeduetothecloselinkbetweenhighbicarbonateandmalnutrition.Forexample,inastudyof56385between2001and2003,Wuobservedaprogressiveincreaseinmortalityaspre-dialysisbicarbonateincreasedbeyond23mmol/L,butalsostrongassociationsbetweenhigherbicarbonateandworseningmarkersofnutritionincludingalbumin,phosphateandproteinintake[129].Whenadjustedforcomorbidityand12parametersassociatedwithmalnutrition,mostoftheincreasedmortalityappearswithlowbicarbonate,atlevelsbelow18–21mmol/L.Someguidelinegroupshavethereforeincreasedthelowerlimitforoptimalpre-dialysisbicarbonateto20or22mmol/L[130,131].Post-dialysisbicarbonateisrarelymeasured,butthreeconsiderationsargueforcautioninattemptingtoachieveaminimumpre-dialysisbicarbonate.Firstly,therisksassociatedwithabnormalbicarbonatearelessclearandofalowermagnitudethanthoseassociatedwithabnormalpotassium(mortalityhazardratioofapproximately1.2forthemostextremecategoryofbicarbonateversus1.5forpotassium).Secondly,althoughitisprincipallylowbicarbonatewhichcarriesrisk,highpre-dialysisbicarbonatealsoappearstobeharmful.Whilstmuchoftheriskobservedisattenuatedbyadjustment,pre-dialysisbicarbonateisstillassociatedwithincreasedmortalityatlevelsabove27mmol/L[129].Additionally,anincreasedriskofperi-dialyticcardiacarresthasbeenobservedwithhighpre-dialysisbicarbonate:aFreseniusMedicalCarememoin2011reportedaninternalcase-controlstudyof941patientsin667facilitieswhosufferedcardiacarrestin2010.Riskwas4.7timeshigherinpatientswithpre-dialysisbicarbonateover28mmol/L,and6.3timeshigheriftheyalsohadpre-dialysispotassiumbelow4mmol/L[132].Thirdly,highdialysatebufferisassociatedwithincreasedmortality.Forexample,inalargestudyofdialysatebufferusingDOPPSdata(collectedfrom17031dialysispatientsin11countriesbetween2002and2011)Tentoriobservedalowerriskofmortalityinpatientstreatedwithdialysatebufferlessthanorequalto32mmol/L,regardlessofpre-dialysisbicarbonate(HR0.90,95%CI0.80–1.01)andhigherriskwithdialysatebufferatorabove38mmol/L(HR1.07,95%CI0.97–1.19)[123].Pragmaticallythereforeonecanconcludethefollowinggeneralprinciples:Firstly,pre-dialysisacidaemiashouldbecontrolled,thoughanoverlytightrangemaybecounterproductive,sothepreviouslyrecommendedlowertargetforpre-dialysisbicarbonatestillseemsoptimal,thoughtheuppertargetcouldsafelybeincreased(18.0–26.0mmol/L).Aswithpotassium,achievementofthisrangedoesnotnecessarilyensureoptimaldialysisprescription.Secondly,dialysatebufferatorover38mmol/Lshouldgenerallybeavoided,andtheoptimaldialysatebufferforthemajorityofpatientsisprobablyintheregionof32–35mmol/L.Thirdly,manyotherfactorsaffectpre-dialysisbicarbonate,thedominantonesbeingnutritionalstateanddialysisdose,sothatabnormalitiesofpre-dialysisbicarbonateshouldnotleadcliniciansautomaticallytothinkofadjustingdialysatebuffer.Highbicarbonateinparticularshouldpromptanutritionalthoughtprocessinitially.Itisnotclearthatadjustmentofdialysatebufferisahelpfulstrategyforoptimisingpre-dialysisbicarbonate,orthatsuchanadjustmenthasmuchimpactonpre-dialysisbicarbonatelevels.Specificgroupshowever,suchaspatientswithabnormallevelsdespiteoptimaldietanddialysisstrategy,mayhavesomethingtogainfromdialysatebufferadjustment.Conversely,increaseddialysatebuffermaybemorehazardousincertaincircumstances,suchasincombinationwithlowpotassiumdialysate[122,133].Whilstitisaveryreasonablethingtodo,andmightprovetobebeneficialinfuturestudies,itisnotcurrentlyclearthatindividualizationofdialysatebufferissuperiortostandardization.Finally,andparticularlyformeasurementstakenremotefromthelaboratory,therelativelyhighfrequencyofmeasurementerrors(forexampleduetocarbondioxideescape)shouldberememberedwheninterpretingbicarbonatelevels[134,135].Guideline5.3-SupplementationofdialysatewithphosphateWesuggestconsideringsupplementationofthedialysatewithphosphateinpatientsonaugmenteddialysisschedules.[2D]RationaleTheconventionalhaemodialysispatientstrugglestoachievesufficientphosphateremoval,andhistoricallydialysatehasalwaysbeenphosphate-free.Guidelinesusuallyfocusmoreontheupperlimitthanthelowerlimitforoptimalpre-dialysisphosphateandrangesintheregionof1.1-1.7mmol/Lareoftensuggested,withmostoftheemphasisontreatmentstoreducephosphate-indeed,mostoftheRenalAssociation'sadviceonphosphatecanbefoundintheguidelineonmineral-bonemanagement.However,withdemographicandtreatmenttrendsofthelastdecade,lowphosphateisbecomingmorecommon,andsincethesymptomsofhypophosphataemiaarenon-specific[136],thisproblemmaybeeasilyoverlooked.Therelationshipbetweenpre-dialysisphosphateandmortalityisJ-shaped,withincreasedriskoccurringatbothhighandlowlevels.Butphosphateisstronglyassociatedwithageandnutritionalstate,sothatthemortalityriskassociatedwithlowphosphateissubstantially(althoughincompletely)attenuatedbyadjustmentforcomorbidityandmalnutrition[137].Inthecontextoflowpre-dialysisphosphatetherefore,themainclinicalfocusshouldbeonnutritionalassessmentandsupport.Whenpatientsareunabletoconsumesufficientphosphatetomatchintradialyticloss,supplementationofthedialysateisalogicalapproachtomanaginghypophosphataemia.Theargumentforsupplementationisgenerallyacceptedinthecontextofaugmenteddialysis,whenpost-dialysisphosphateisoftenmeasured,andmaybefoundtobeverylowinwell-nourishedpatients[138].Itiscommonpractice,forexample,tosupplementdialysatewithphosphateinpregnantpatientsreceivingdailydialysis.Supplementationcouldalsobeusedtopreventundesiredlossofphosphateinpatientsonconventionalregimeswithlowpre-dialysisphosphatethatisrefractorytoothermeasures[139].Whilethisdoesappeartobeclinicallyhelpfulincasereports,datatosupportthisapproachremainlimited.However,aspatientswithlowpre-dialysisphosphatecurrentlyreceiveaformofdialysiswhichinevitablyworsensthisabnormality,sotheinstinctto‘donoharm’maybeasufficientlypersuasiveargumentforsomeclinicians.Phosphateprecipitatesinsolutionscontainingcalciumormagnesium,solikebicarbonate,mustbeaddedtotheelectrolyteconcentrateatthepointofuse,butthereiscurrentlynocommerciallyavailablephosphateadditiveapprovedforuseinintermittenthaemodialysis[140,141].‘Inhouse’supplementationcanbeachievedbyaddingphosphatesaltstotheelectrolyteconcentrateatthestartofthesession,butsolutionsintendedforintravenoususetypicallycontainpotassiumandaretoodilute.Pharmaceuticalgradephosphatesaltsinpowderformcanbeused,butrequirequalityassuranceonstoring,weighing,addingandensuringcompletedissolution.Themostcommonmethodistherefore‘offlabel’useofsolutionsintendedasenemas:Cleen(formerlyFleet)Enemaforexample,isverysuitableforenrichingdialysate[142],althoughitcontainsantimicrobialpreservatives(benzalkoniumchlorideanddisodiumedetate)whicharewidelyusedinmedicalproductssuchaseyedrops,whichmighthaveadverseeffectsinthiscontext.TheuseofCleenEnemaindialysatehasagoodsafetyrecordhowever:Pierratosfirstreporteditsuseinnocturnaldialysisinthelate1990s[143],andfrequentdialysisprogrammesinmanycountrieshaveadoptedthismethod[144,145].PracticaladviceonaddingphosphatetodialysateisprovidedinAppendix4.Guideline5.4-PaediatricdialysateconsiderationsWerecommendindividualisationofdialysateelectrolyteconcentrations,includingpotassium,bufferandcalcium.[1C]Wesuggestanindividualiseddialysatetemperature,betweencoretemperatureand0.5°Cbelow,withmonitoringofintradialyticcoretemperatureforneonatesandsmallerchildren.[2D]RationaleAdultguidelinesfordialysatecomposition(sections5.1–5.3)aregenerallyapplicabletochildren,thoughthereareanumberofadditionalconsiderations.Inchildrenwithresidualkidneyfunction,tubulardysfunctionisnotuncommon,leadingtoelectrolytewastingandhypokalaemiaoracidosis.Calciumbalanceisalsomorecomplexinchildren:thenormalrangeforcalciumisage-dependentandgrowingchildrenrequireapositivecalciumbalance,sothathypocalcaemiamaybebothmorecommonandmoreharmful,andyetvascularcalcificationissometimesseeneveninchildrenandadolescents,inwhomcalcium-phosphateproductisanimportantriskfactor[146,147].Similarly,dietaryproteinintakeisoftenproportionatelygreaterthanthatofadults,andpre-dialysisacidosisthereforemorecommon.Thecomplexityandclinicalheterogeneityoftheseissuesthereforearguesstronglyforamoreindividualizedapproachtodialysatecompositioninchildren[148].Thermalexchangesduringdialysismayalsobemoresignificantparticularlyinneonatesandyoungerchildren,duetotheproportionatelygreaterbloodflow,andsometimesareducedcapacityforcompensationduetobodysize.Hypothermiashouldthereforebeavoidedbyindividualisingdialysatetemperature,withintradialyticmonitoringinthosemostatrisk.Controlofthermalexchangesisavailableonsomemoderndialysismachines.AnticoagulationWerecommendthatpatientswithoutincreasedbleedingriskshouldbegivenunfractionatedorlow-molecular-weightheparinduringdialysistoreduceclottingoftheextracorporealsystem.[1A]Werecommendthatsystemicanticoagulationshouldbeomittedorminimisedinpatientswithincreasedbleedingrisk.[1C]Werecommendthatpatientswithheparinallergiesshouldbeprescribedanon-heparinformofanticoagulation.[1A]RationalePlateletactivationintheextracorporealcircuitacceleratesthrombingenerationviatheintrinsiccoagulationpathway,sothatanticoagulationisusuallyrequiredtopreventthrombosis.Unfractionatedheparinisusedasthestandardanticoagulantworldwideinviewofitsprovenefficacy,easeofuseandlongsafetyrecordunlessthepatienthasrecentoractivebleeding,thrombocytopenia,heparinallergyorheparininducedthrombocytopenia.Withameanhalf-lifeof1.5hours,heparinisusuallyadministeredasaloadingdoseof1000-2000IUfollowedbyacontinuousinfusionof500-1500U/hthatisdiscontinuedapproximately30minutesbeforetheendofthedialysissession.Monitoringcanbeperformedbymeasuringtheactivatedpartialthromboplastintimeratio(aPTTr)orthewhole-bloodactivatedclottingtimeaimingforaround150%ofpre-dialysisorcentrenormalvalues[149,150].Butinpracticethebolusdose,infusionrateandstoppingtimesareadjustedempirically,accordingtoclotformationinthedialysiscircuit,andthetimeforneedlesitestostopbleeding.Heparindosemayneedtobeincreasedwithhigherhaematocrit,orreduced/withdrawninpatientsatriskofhaemorrhage,thosewiththrombocytopeniaoronlongtermanticoagulation[151].Alternatively,alowmolecularweightheparinmaybeused[152],havingalongerhalf-life,givenasasingle‘arteriallimb’bolusatthestartofdialysis[153].Althoughmonitoringcanbeperformedusinganti-Xaactivity,thesearenotalwaysavailableandlaboratorytestingcorrelateslessdirectlywithclinicaleffect,soaswithunfractionatedheparin,doseadjustmentisusuallyempirical,butlargerorrepeateddosesmaybeneededdependingonconvectiveclearanceandsessionlength,andreduceddosesforthoseatriskofhaemorrhage[154].Severalsystematicreviewscomparinglow-molecular-weightwithunfractionatedheparinhavefoundnodifferenceintheincidenceofbleedingcomplications,post-dialysisaccessbleeding,orthrombosisoftheextracorporealcircuit[155,156,157,158].Withitsconveniencefornursingstaff,theuseoflow-molecular-weightheparinisbecomingmorecommoninEurope.Forpatientsatincreasedriskofbleeding,severaloptionsareusedinclinicalpractice.Firstly,severaltechniquesrequirenoanticoagulationtobeadministeredduringdialysis,including:combiningahighbloodflowrateandregularpre-dialyzercircuitflushingevery15-30minutes[159,160];usingaheparincoateddialyzer[161,162];addingheparintotherinsingsolution[160];orusingadialysatecontainingcitrate[163,164,165].Secondly,aregionalanticoagulantcanbeusedsuchascitrate,prostacyclin(epoprostenol)ornafamostat(notcurrentlyavailableinUK).Regionalanticoagulationwithcitrate[166]andepoprostenolol[167]havebothbeenreportedtoreducetheriskofhaemorrhagecomparedtoheparin,thoughtherearedrawbacks:epoprostenolmayinducehypotensionandiscostly,whereascitrateadministrationrequiresre-infusionofcalciumbasedonelectrolytemonitoring,addingcomplexityandnursingstafftime[168].Finally,lowerdosesofunfractionatedorlow-molecular-weightheparinhavebeenusedwithcautioninpatientsatriskofbleeding[151,154].Heparininducedthrombocytopenia,usuallyoccurringshortlyafterregularexposuretoheparin,andsometimeswiththrombosis,mayoccurinheparin-treateddialysispatients[169,170].Theriskofheparininducedthrombocytopeniacanbeestimatedusingthe4Tscoringsystem[171],andisusuallyconfirmedbylaboratorytestinganddetailedguidelinesondiagnosisandtreatmentarepublishedbytheBritishSocietyofHaematology,butinsuspectedorconfirmedcases,allheparinsshouldbewithdrawn[172].Theriskofthrombosisincreaseswiththeseverityofthrombocytopaenia,andanticoagulationisusuallystartedwitheitherthedirectthrombininhibitorargatroban[173],oranatural(danaparoid)orsynthetic(fondaparinux)heparinoid[174,175].Argatrobanisreversible,givenbycontinuousinfusion,andrequirescarefullaboratorymonitoringwithaPTTr.Theheparinoidsarerenallyexcretedandhaveprolongedhalf-livesindialysispatients,suchthatmonitoringofthebolusgivenwithadialysissessioncanbebasedonanti-Xaactivitypriortothefollowingsession.Oncetheplateletcountreturnstonormal,patientsareusuallyanticoagulatedwithwarfarin,butinthemajorityofcasesantibodiesdisappearwithtime,andpatientshavebeensuccessfullyre-challengedwithunfractionatedandlow-molecular-weightheparinsoncelaboratorytestingbecomesnegative[176].Adverseeventsduringdialysis(Guidelines7.1–7.3)Guideline7.1-RoutinebloodlossWesuggestthatduringwashback,dialysislinesanddialyserareobservedtoensureresidualbloodlossiskepttoaminimum.[2C]RationaleAsmallamountofbloodlossoccursduringnormalhaemodialysis,forexampleduetobloodretainedinthedialyserandcircuitafterwashback,andbleedingintothedressingoverneedlingsites,butthereisnoclearconsensusastowhatconstitutesa‘normal’quantityofbloodlossduetodialysis.Theliteratureonminimisingbloodlossduringhaemodialysisissparse,andmuchoftheevidenceisoflimitedquality.Theweighedgauzemethodhasbeentoquantifybleedingafterremovalofneedles,with‘excessive’definedasblood-soakedgauzeweighingover4g[177].Andexcessivebleedinghasbeenassociatedwithpooroutcomes,forexampleinastudyof4152dialysissessionsin143patients,Linfoundthatexcessivebleedingfollowingdialysisneedleremovaloccurredregularly,andwasassociatedwithlowerhaemoglobinlevels[178,179].Kalantar-Zadehsuggestedpatientscanloseupto3gironperyear,withonegrambeinglostinthelinesanddialyser,andafurthergramlostinbloodsampling[180].Thoughitisunclearhowtheyarederived,theseestimatessuggestthatupto20mlpersessionmaybenormal.Inacomparisonofbuttonholeversusrope-laddercannulationin33patients,Verhallenfoundnodifferenceinbleedingtimesafterneedleremovalbetweenthetwotechniques[181].Varioussuggestionshavebeenmade,forexampleMcCannsuggestedneedlingatanangleof25degrees[182],andFruitssuggestedflushingthearterialdialysisneedlewithsaline,andreducingtheamountofblooddrawnfortesting,butnoneofthesemeasuresiswellsupportedbyclinicalevidence[183].Currentlythereisinsufficientevidencethereforetosupportanyrecommendationsregardingbloodpreservationandmanagementofvascularaccess.Clottingofthedialysiscircuitleadstomuchgreaterbloodlossthanisroutine.Adequatebutsafeanticoagulationisanimportantcomponentofprevention,andiscoveredelsewhereinthisguideline,butregularmonitoringduringdialysisandobservationofthecolourofthelinesanddialyserpost-dialysis,alsoplayarole.Thisconceptissupportedinliterature,forexampleKalocheritisnotedthecontributionofthistypeofbloodlosstoanaemia,andtherelevanceofhumanfactors[184].Reasonableconsensusthereforesupportstheimportanceofnursingobservation,particularlyduringwashback.Noevidencewasfoundregardingtheeffectsofexcessivebloodsamplingonbloodloss.DaugirdasandTattersallpointoutthaton-linemeasurementofadequacymayreducetheneedforbloodsampling,butdescribethebenefitsmainlyinrespectofcostandstafftime[185].However,ensuringthatbloodsamplesaretakenonlywhenrequiredforroutinemonitoringorforadditionaldiagnosticindications,isperhapsobviouscommonsense.Guideline7.2-DisconnectionhaemorrhageWerecommendmaintainingawarenessoftheriskofdisconnection,thelimitationsofpressurealarms,andimportanceofdirectobservation,throughaprogramofeducation,includingpatientsandcarers.[1D]Wesuggestregularassessmentofindividualrisk,sothathighriskpatientscanhaveenhancedmonitoring,whichcouldincludespecificdevices.[2B]RationaleDisconnectionleadingtohaemorrhagemayoccuratanypartofthedialysiscircuit,thoughvenousneedledislodgementmaybethemostfrequentandserious,withrapidbloodlossoccuringattherateofthebloodflowpump,untilitisdetected.Disconnectionincidentsarethoughttobeuncommon,butthetrueprevalenceisuncertainduetoinconsistentreporting.Oncedetected,managementbeginswithhaemostasisandfluidresuscitation,aswithanymajorhaemorrhage,andtheliteratureconcentratesinsteadonmethodstominimiseriskandenhancedetection,withpublicationsavailablefromtheEDTNA/ERCAandtheAmericanNephrologyNursesAssociation[186,187].Variabilityinhumanprocessesisrecognisedasanimportantfactor,andmostunitshaveestablishedprotocolstoensureconsistencyinaspectsofcaresuchastapingneedlesinpositiontominimisethechanceofdisconnection[188].Dialysismachineshaveseveraltypesofsafetymonitor[189]andifdisconnectiondoesoccur,thedropinpressureshouldbedetectedandcausethemachinetoalarm.However,ithasbeenrepeatedlydemonstratedthatthesealarmscannotbereliedontodetectallcases[190].Theuseofasymmetricwindows(suchas-30to+70mmHg)maybehelpfultomaximisethedetectionofdisconnection,whileminimisingalarmsfromincreasesinpressureatthevenousneedle[191,192].Becausemachinealarmscannotbereliedon,directobservationremainsimportant,involvingvigilanceonthepartofnursingstaff,andunitmanagement,sothatlinesofsightarenotobscured,patientsarenotdialysingaloneandtheirvascularaccesssitesarenotcovered.Becauseofthelowprevalenceofdisconnection,complacencymaydevelop:continuouseducationisthereforeadvocatedtoensureawarenessamongsthealthcarestaff,patientsandtheircarers[193].Riskofdisconnectionisgreaterinsomepatients,andenhancedmonitoringmaybeappropriatebasedonindividualriskassessment.Simplyplacingpatientsclosertothenursingdeskmaybesufficient,butreliablemonitoringcanalsobeachievedbyuseofbloodlossdetectiondevices,whichtypicallyaresecuredatthesiteofvascularaccessandalarmonthedetectionofblood[194,195].Devicemonitoringmaybeappropriateforpatientsathighrisk,suchasconfusedoragitatedpatients,andmayhaveagreaterroleinhomehaemodialysisprogrammes[196,197,198,199].Oneinterventionalstudyconsideredtheeffectofbloodlossdetectiondevicesonnursingstaff,showinganimprovementinself-reportedfeelingofsafetywhendeviceswereused[200].Guideline7.3-ImmunereactionsduringdialysisWerecommendthatdialysisstaffshouldbeawareofthefeaturesandmanagementofdialysisreactions,andshouldhaveaccesstoarangeofdialysertypes.[1C]RationaleFromtheearly1980sreportsappeareddescribingabruptclinicalreactionsoccurringsoonaftertheonsetofdialysis[201].Thesehavetraditionallybeenclassifiedintotwotypes.TypeAreactionsweresaidtoaffectlessthan1%ofpatientsperyear,oftenre-occurringinthesamepatient,withonsetwithinthefirstfewminutesofdialysis.Mainlyoccurringwithfirstuse,ratherthanre-useddialysersthefeatureswerequite‘anaphylactic’innature(itching,flushing,bronchospasm,hypotension,sometimeswithburningattheaccesssite)andoftensevere,withcardiacarrestoccasionallydescribed[202].Associatedwitheosinophilia,thesereactionswerecausedmainlybyresidualethylenedioxide(usedtosterilizemembranes)withantibodiesdetectableinmanycases[203].Similarreactionsweredescribedtopolyacrylonitrilemembranes,especiallyinACEinhibitortreatedpatients(byincreasingkininactivation)andinhydrogenperoxidetreatedre-usedmembranes[204].Immediatecessationofdialysiswasusuallynecessary,alongwithanaphylaxis-typetreatment.Extrarinsingorachangeofmembranesterilisationwouldoftenpreventreoccurrence.TypeBreactions,saidtobemorecommon,occurringlaterinthedialysissession,weretypicallylesssevere,improvingwithcontinueddialysis.Characterisedmainlybychestandbackpain(alsosometimeswithvomiting,breathlessnessandhypotension)theywerecausedbycomplementactivationandpulmonarycellsequestration,andassociatedwithtransientreductionsincirculatingwhitecells.Thesereactionswereclearlylinkedwiththe‘bio-incompatibility’ofcellulose-basedmembranes[205].Dialyserre-use,ethylenedioxidesterilisationandunmodifiedcellulosemembranesareallnowveryuncommon,andasdialysispracticeshaveevolved,theepidemiologyofthesereactionshaschanged,reflectedinthechangingliterature(Fig. 2).Inmodernpracticedialysisreactionsareuncommonbutdostilloccur,includingpolysulphoneallergy,heparinallergyandisolatedthrombocytopenia. Fig.2LiteraturetimelineshowingthechangingepidemiologyofdialysisreactionsFullsizeimageReactionswith‘typeA’(anaphylactic)featurescontinuetooccurwithpolysulphonemembranes,thoughmanyvariantsaredescribed,includingthosewithfeverasthepredominantsymptom[206].Eosinophiliaisanimportantclue,thoughnotinvariablypresent,andotherbloodtests(tryptase,totalIgE)maybeuseful[207].Thediagnostichallmarkisresolutionofthesyndromefollowingachangeofmembranetype,and(thoughlittleguidanceisavailablefromliterature)anaphylaxistreatmentsareoftengiven,withsteroidpre-treatmentsometimesusedbeforedialysissessions.StoppingACEinhibitorsmayalsoreducetheseverity.Reactionstointra-dialyticheparinaresometimesdescribed,ranginginseverityfromasymptomatictoaserotonin-likesyndromeofbreathlessnessandflushing,oftenwithhypertension.Theseareusuallybutnotalwaysassociatedwiththrombocytopenia(persistingbetweendialysissessions)andthromboticcomplicationsmayoccur.Transientasymptomaticthrombocytopeniahasalsobeendescribed,oftenrecoveringbetweendialysissessionssothatpre-dialysisplateletcountmaybenormal.Thisreactionhasbeenassociatedwithelectronbeammembranesterilization,butthemechanismisunknown[208].Severalcomplicationsotherthandialyserreactionsmaypresentwithsimilarperi-dialyticsymptoms.Morecommononesincludebacteraemiaandhypovolaemia,whilstdisequilibrium,airembolismandthechloramine/hardwatersyndromesarerarer.Waterpurificationcomplicationsmaybemorecommoninthehomehaemodialysissetting.Patientexperienceofdialysis(Guidelines8.1–8.4)Guideline8.1-HomehaemodialysisWerecommendthathomehaemodialysisshouldbeavailableinallunitsaspartofacomprehensiverenalreplacementtherapyprogramme.[1A]Wesuggesttrainingpatientsand/orcarepartnerstoachieveadefinedsetofcompetencies,usinganindividualisedapproachtotrainingmethodandspeed.[2D]Wesuggestunitsformacontractwithpatientsoutliningresponsibilities,includinganagreementtodialyseasperprescriptionandtrainedtechnique,andincludingapolicyforre-imbursementofdirectlyarisingpatientcosts.[2D]Wesuggestsupportingpatientswithaspecificteamincludingnephrologists,technicians,andnurses,withrapidaccesstodialysisin-centrewhenrequired.[2C]Wesuggestanagreedindividualisedprescriptionforhomehaemodialysis,takingintoaccountlifestylegoals,withthesamedoseandtimetargetconsiderationsascentre-basedpatients.[2C]Werecommendenhancedsafetymeasuresforpatientswhodialysealoneorovernight,andanenhancedriskassessmentforpatientswithblood-borneviruses.[1C]RationaleThereisincreasingevidenceofthebenefitsofaugmentedhaemodialysisschedules,intermsofbothoutcomeandhealth-relatedqualityoflife,butprovidingmorefrequentdialysisin-centreisachallengeintheUK,anditiswidelyrecognisedthataugmentedschedulesaremosteasilyaccommodatedinthehomesetting[33,35,209,210,211,212].Theliteratureonhomehaemodialysisandaugmentedschedulesthereforeoverlapssubstantially,buthomehaemodialysisadditionallyisincreasinglyacknowledgedtoprovidealevelofconvenienceandflexibilitynotachievablein-centre.DespitethesebenefitsthepenetrationofhomehaemodialysisintheUKremainslow,comprisingonly0.4%ofincidentand2%ofprevalentdialysispatients.ManyorganisationssuchasNICEandKDIGOpromoteuniversalavailabilityforclinicallysuitablepatients,acknowledgingthatcollaborativeworkingbetweencentresmayberequired[213,214].Butitisclearfromregistrydatathatvariabilityofaccessstillexists,withsomecentresnotofferingthismodality,andconsiderablevariationinuptakebetweencentres.Homehaemodialysispatientsmustbeabletomanagetheirdialysissafely,andmonitortheircondition.Modalitydecisionsshouldbesupportedbyafullassessmentofclinicalandsocialcircumstances,aswellasthehomeenvironment,includingadiscussionoftheimpactoftherapyonotherswithinthehousehold[215].Itisessentialthatpatientandcarerexpectationsandfearsareappropriatelyaddressedbeforecommencingtraining[217].Fewdataareavailabletoguidanceonclinicalsuitability,buttheabilitytocompletetrainingmaybemoreimportantthanclinicaldiagnosis:anumberofprogrammeshavereportedthatpatientswithcomplexcomorbiditiescanimprovewithmorefrequenttherapy,moretailoredtotheirneeds[222,223].Trainingona‘1to1’basiswithaspecifictrainingstaffiswidelyacceptedasoptimal,withthelearningstyleandtrainingdurationadaptedtotheindividual[221].Typeofvascularaccessshouldnotbealimitingfactor,butappropriatetraining,surveillanceandtechniqueassessmentformessentialpartsofthehomehaemodialysisprogramme[224,225].Thesuccessofahomehaemodialysisprogrammeisdependentuponaskilledandspecificmulti-disciplinaryteamfacilitatingeducation,trainingandpatientsupportinthecommunity,andoptimalindividualoutcomesaredependentonpatientunderstanding,andappropriatecooperativeliaisonwiththissupport[218].Thismaybefacilitatedwithanexplicitcontract,sothatthemannerinwhichthisclinicalresponsibilityissharedisclear.Thefinancialresponsibilityfortreatmentrestswiththeprovider,andre-imbursementofdirectlyarisingpatientcostsshouldbereadilyavailable[216].AhomehaemodialysisProgrammerequiresadequatemedical,nursingandtechnicalsupport,andshouldsupportatleast12to20patients,andtrainatleast10patientsperyearinordertomaintainappropriatestaffexpertiseandcosteffectiveness,sosmallerrenalunitsmayfinditmoreappropriatetoshareresourceswithothercentres.Minimumsafestafftopatientratiosarenotwelldefined,butrecommendationsforperitonealdialysis(suchasminimumof1nurseper20patients)mayberelevant[218,219,220].However,astrainingforhomehaemodialysisismorecomplex,additionalstaffingshouldbeconsideredtoensurethattrainingnewpatientsdoesnotdetractfromthesupportofestablishedpatients[217].Patientmixshouldalsobeconsidered,sothatprogrammeswithagreaternumberofcomplexpatientsarestaffedmorefavourably[224,226].Homehaemodialysispatientsshouldreceivethesamelevelofmedicalsupervision,andthesamemonitoringanddoseconsiderationsasin-centrepatients,andasforotherpatients,thescheduleshouldbeindividualiseddependingonpatientvaluesandtherapeuticgoals.Dialysisdoseshouldbequantifiedasforotheraugmentedschedules,butshouldbeinterpretedwiththeflexibilityofthepatient’sschedulealsoinmind.Toensurethatthehomedialysisteamcanprovidethebestpossiblesupportthatisresponsivetotheindividual,recordingofsessionaldetailsbythepatientorcarerisdesirable[229].Specificcircumstancesmayrequireadditionalriskassessmentsand/oradditionalmeasures:enhancedsafetymeasures,forexampletodetectdisconnection,shouldbeavailableforpatientsdialysingaloneorovernight,andprotectionofhouseholdcontactsofpatientswithblood-bornevirusesshouldbeconsidered,particularlyforthosedirectlyinvolvedintherapy[187,224,227,228].Guideline8.2-SharedhaemodialysiscareWesuggestthatallcentre-basedhaemodialysispatientsshouldhaveopportunityandencouragementtolearnaspectsoftheirdialysistreatment,andtakeanactiveroleintheircare.[2D]RationaleThereislittleresearchthathasbeendirectlyconductedintosharedhaemodialysiscare,howeverthereisconsiderableevidenceofthebenefitsofsupportedself-careinotherlongtermconditions[230].Lowhealthliteracyamongstdialysispatientsisassociatedwithworsesurvival[231]whereasself-motivationandeducationcanresultinbettercare,forexample,inphosphatecontrolandfluidbalance[232,233].AswiththebroaderNHS,dialysisservicesareexperiencingconsiderablepressuretodeliverhighqualityinthefaceoffiscalchallenge,andanimportantmechanismtoensurethatqualityofcareismaintained,istoengageserviceusersastruepartnersintheirowntreatment:self-managementisanambitionin‘KidneyHealth:DeliveringExcellence’[234].Toachievethis,healthcareprofessionalsneedtoenhancetheirroles,becomingeducatorsandfacilitators,supportingpatientstotakeagreaterroleintheirowncare,andincreasingtheiropportunitiesfordialysingathome.Sharedhaemodialysiscareimpactsonalldomainsofhealth.Centralamongtheseare:theenhancedpatientsafetythatcomesfromeducationoninfectioncontrol(seetheWHOcampaign‘Savelives:cleanyourhands’[235]);theenhancedequityconsequentonofferingallpatientstrainingintheirtreatmentratherthanonlythoseplanninghaemodialysisathome;andtheenhancedexperiencewhenpatientscanputthemselvesontodialysis,ormanagetheirownalarms,withoutwaitingforanurse[236].Theprocessofhaemodialysiscanbebrokendownintoapproximately14tasks(Appendix5).Theexactarrangementsmayvarybetweenunitsbuttheconceptisessentiallythesame:thatcentre-basedpatientsaregiventheopportunitytotraintoperformoneormoreofthesetasks.Itiskeythatpatientinvolvementisvoluntary,andthatlearningisindividualisedtothestyleandspeedoftheindividual.Sharedhaemodialysiscareisassociatedwitharangeofbarriersandenablersthatarebestexploredthroughqualityimprovementwork,inordertodesignfavourableconditionsforsuccessfulimplementation.Guideline8.3-IntradialyticexerciseWerecommendthatintradialyticexerciseshouldbeavailableinallunits,asatreatmentforenhancingphysicalfunctioning,inpatientswithoutcontraindications.[1B]Wesuggestthatintradialyticexercisebeconsideredasamethodofenhancingqualityoflife.[2C]Wesuggestthatexerciseregimesbedevisedbyappropriatelytrainedstaff.[2C]RationaleWhilstcardiovasculardiseaseremainstheprincipalcausesofdeathindialysispatients[237],thereisasignificantinteractionwithbodycomposition,withmusclewastinginparticularexacerbatingmortality[238].Musclewastingandpoorphysicalfitnessalsoreducefunctionalabilitiesincludingactivitiesofdailyliving,thusreducingqualityoflifeinhaemodialysispatients[254].However,musclewastingismodifiablebyexercise,andepidemiologicalstudiessuggestthatregularexercisecanevenreducemortality[239],butunfortunatelydailyphysicalactivityistypicallylowinhaemodialysispatients,perhapsduetothetimeburdenandsymptomsassociatedwithtreatment[240].Basedonevidencefromeightsystematicreviewsandmeta-analyses[241,242,243,244,245,246,247,248],analysingdatafrom1000adultparticipantsondialysis,theclinicaleffectivenessofexerciseonphysicalfunctionandhealthrelatedqualityoflifecanbesummarisedasfollows: 1) Despitethehigh-riskstatusofdialysispatients,noseriousexercise-relatedadverseeventshavebeenreportedfromover30000patient-hoursofexerciseobserved[244,246].Adverseeventsreportedincludepost-exercisehypotension,fatigue,myalgias,painfulfeet,andaggravationoffootulcers,thoughnotwithincreasedincidenceinexercisegroups.Compliancewithexerciseprogrammesrangedfrom43to100%,anddropoutratesfrom15to50%. 2) Shortterm(2-6months)prescribedexerciseofanytype,frequencyandintensity,resultedinsignificantandclinicallymoderate/largeimprovementincardiorespiratoryfitness,withameanincreaseinpeakVO2of5ml/kg/min[243,246]. 3) Anyprescribedexercisedeliveredduringhemodialysissessionsproducedsignificantandclinicallymoderateimprovementinmusclestrength[245],withameanincreaseof9.9kg[243]. 4) Anytypeofprescribedexerciseconsistentlyproducedsignificantandclinicallylargeimprovementsinsomeindicesoffunctionalcapacity,suchas‘sittostand’transfers[247],whereasotherindices,suchaswalkingperformance,wereimprovedaccordingtosomereviews[247]butnotothers[243,245]. 5) Self-reportedphysicalfunctionwassignificantlyimprovedinexercisingpatients[247].Thisoftencontributestoqualityoflifescores,andmaythereforeexplainwhysomestudiesconcludethatexerciseimprovedqualityoflife. Takentogetherthereisthereforegoodevidencethattheuptakeofregularexerciseimprovesphysicalfunctionandqualityoflifeinhaemodialysispatients,withoutcausingsignificantharm,andthatdeliveryofexercisewithinhaemodialysissessionscanachievethis.Exerciseduringthedialysisprocessmayalsoassistwithsoluteclearance.EnhancedureaclearanceispredictedbymodellingbutanimpactonKt/Visfoundinsomestudies(nineofeighteenstudiesreviewed)butnotothers[249],whereasimprovementsinphosphateclearanceandserumlevelsareconsistentlyobserved[249,250,251,252,253].Someevidencesuggeststhetypeofexercisemostlikelytobebeneficial:largerimprovementswereobservedwithinterventionsdeliveringaprogressivelyincreasingexercisevolume,atleastthreetimesperweek,foratleast30minutes,lastingforatleastfourmonths,andincludinganadditionalresistance-trainingcomponent[244,246,247,248].Comparativeevidenceforspecificexerciseprogrammesiscurrentlyunavailable,butsomeguidanceonpracticalimplementationofintradialyticexerciseisofferedinAppendix6.Guideline8.4-DialysisexperienceforchildrenandadolescentsWerecommendthathaemodialysisforchildrenandadolescentsshouldbedeliveredinadedicatedpaediatricdialysiscentreorathome,withtheinvolvementofapaediatricmultidisciplinaryteam.[1C]Werecommendthatadolescentsshouldcommenceanactivetransitionprogrammeby14years,oratthetimeofpresentationinthosealreadyover14.[1D]RationaleHaemodialysissessionsareassociatedwithphysicalsymptoms,socialrestriction,andlossofcontrol,whichforchildrenandadolescentsmaybeparticularlydepersonalisingandunpleasant.Theseeffectsmaybemitigatedbyanappropriateenvironmentandtrainedsupportstaff,andin-centredialysisisthereforebestdeliveredinadedicatedunit,withpaediatricnephrologistsworkingalongsidethefullmultidisciplinaryteam,includingnurses,dietitians,psychologists,playtherapists,teachersandsocialworkers[148,255,256].Inthiswaychildrencanbesupportedtoreachtheirfullpotentialdespitetheburdensoftreatment.Thefirstdialysissessionisofparticularimportanceinestablishingtherapeutictrustandparentalconfidence-psychologicalpreparationforthiseventcanalleviateanxiety,reducesymptomsandimprovethetolerabilityofdialysis.Childrenandadolescentscanbesupportedtotakeonaspectsoftheirowncare,oftenalongwithparentsorguardians,andarelikelytogainasmuchbenefitasadultsfrominvolvementinasharedcareprogram[257].Andhomehaemodialysishasmanyadvantagesforchildren,allowinganaugmentedschedulewithoutinstitutionalisation,andprovidingaflexibilitywhichcanreducetheimpactofdialysisonsocialdevelopment.Transitiondescribestheprocessofpreparingadolescents,alongwiththeirfamilies,forthemovefrompaediatrictoadultcare.Itshouldbeindividualised,takingintoconsiderationthephysicalandpsychologicaldevelopmentoftheadolescent,andrequiresavariableamountoftime[258].Adolescentswillsuffertheleastdisruptionifmovedtoadultcarefollowingengagementwithatransitionprogramme,andshouldbeintroducedtotheconceptoftransitioninearlyadolescence(12-14years).Forthoseover14whenpresentingtopaediatricservices,transitionplanningshouldcommenceimmediatelyalongsideotheraspectsofcare. 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Methodusedtoarriveatarecommendation Therecommendationsforthefirstdraftofthisguidelineresultedfromacollectivedecisionreachedbyinformaldiscussionbytheauthorsand,whenevernecessary,withinputfromtheChairoftheClinicalPracticeGuidelinesCommittee.Ifnoagreementhadbeenreachedontheappropriategradingofarecommendation,avotewouldhavebeenheldandthemajorityopinioncarried.Howeverthiswasnotnecessaryforthisguideline. FundingNotapplicableAuthorinformationAuthorsandAffiliationsHammersmithHospital,ImperialCollegeHealthcareNHSTrust,London,EnglandDamienAshby, RichardCorbett & JeremyLevyWessexKidneyCentre,PortsmouthNHSTrust,Portsmouth,EnglandNatalieBorman & KateyFlowersUniversityHospitalsofLeicesterNHSTrust,Leicester,EnglandJamesBurtonRoyalFreeLondonNHSFoundationTrust,London,UKAndrewDavenportListerHospital,East&NorthHertfordshireNHSTrust,Stevenage,EnglandKenFarrington & EnricVillarSheffieldTeachingHospitalsNHSFoundationTrust,Sheffield,EnglandJamesFotheringham & MartinWilkieSchoolofNursingandMidwifery,UniversityofSheffield,Sheffield,EnglandR.N.AndreaFoxEast&NorthHertfordshireNHSTrust,Stevenage,EnglandGailFranklinLeedsTeachingHospitalsNHSTrust,Leeds,UKClaireGardiner, AndrewMooney, JamesTattersall & KayTyermanUnitedLincolnshireHospitalsNHSTrust,Lincoln,UKR.N.MartinGerrishRenalandExerciseRehabilitation,King’sCollegeHospital,London,EnglandSharleneGreenwoodGreatOrmondStreetHospital,London,EnglandDaljitHothiHaemodialysisPatient,c/oTheRenalAssociation,Bristol,UKAbdulKharesSchoolofHealthSciences,QueenMargaretUniversity,Edinburgh,ScotlandPelagiaKoufakiDepartmentofRenalMedicine,LeedsTeachingHospitalsNHSTrust,Leeds,EnglandElizabethLindleySchoolofSport,HealthandExerciseSciences,BangorUniversity,Bangor,UKJamieMacdonaldNottinghamUniversityHospitalsNHSTrust,Nottingham,UKBrunoMafriciAuthorsDamienAshbyViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarNatalieBormanViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarJamesBurtonViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarRichardCorbettViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarAndrewDavenportViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarKenFarringtonViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarKateyFlowersViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarJamesFotheringhamViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarR.N.AndreaFoxViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarGailFranklinViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarClaireGardinerViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarR.N.MartinGerrishViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarSharleneGreenwoodViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarDaljitHothiViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarAbdulKharesViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarPelagiaKoufakiViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarJeremyLevyViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarElizabethLindleyViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarJamieMacdonaldViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarBrunoMafriciViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarAndrewMooneyViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarJamesTattersallViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarKayTyermanViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarEnricVillarViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarMartinWilkieViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarContributionsAllauthorsreadandapprovedthefinalmanuscript.CorrespondingauthorCorrespondenceto DamienAshby.Ethicsdeclarations Ethicsapprovalandconsenttoparticipate Notapplicable Consentforpublication Granted Competinginterests AllauthorsmadedeclarationsofinterestinlinewiththepolicyintheRenalAssociationClinicalPracticeGuidelinesDevelopmentManual.FurtherdetailscanbeobtainedonrequestfromtheRenalAssociation. AdditionalinformationPublisher’sNoteSpringerNatureremainsneutralwithregardtojurisdictionalclaimsinpublishedmapsandinstitutionalaffiliations.RAGuidelinesCommitteeManager:MelanieDillon,‘[email protected]’canbecontactedforanycorrespondencerelatedtothisarticle.AppendicesAppendix1Simplifiedmathematicsofureaclearance UreaKineticModellingandKt/V InthedesignoftheNCDSstudy,‘dose’ofdialysiswasdefinedasatargetfortime-averagedurea(lowurea=highdosegroup).However,urealevelindialysedpatientsdependsasmuchonproteinintakeastheamountofdialysis:lossofappetitemayleadtolowurea,sothiscannotbereliedontoindicatesufficientdialysis.TheconceptofKt/Vemergedfromthisstudy,whereKisdialyserclearance(ofurea),tistreatmenttimeandVisvolumeofdistribution(ofurea).Despiteitsappearance,Kt/VisnotintendedassomethingtocalculatefromitsconstituentsK,tandV,sinceonlytisaccuratelyknown,butbyconsiderationofthefollowingrelationship:therateofremovalofureaisproportionaltoitsconcentration.Followingthisbasicrule,theconcentrationofureaafteradialysissessionofdurationt,isthereforeapproximatedby: $${\mathsf{U}}_{\mathsf{post}}={\mathsf{U}}_{\mathsf{pre}}\\mathsf{x}\\mathsf{e}\hat{\mkern6mu}\left(-\mathsf{Kt}/\mathsf{V}\right)$$where $${\mathsf{U}}_{\mathsf{post}}=\mathsf{urea}\\mathsf{post}\\mathsf{dialysis}$$ $${\mathsf{U}}_{\mathsf{pre}}=\mathsf{urea}\\mathsf{pre}\\mathsf{dialysis}$$Kt/Visthereforethenegativeexponentinanumericalmodeldescribingthefallinureaduringasingledialysissession.DifferentformsofKt/Vreflectmodelswithdifferinglevelsofcomplexity,whichinadditiontotheconceptabove,mayalsotakeaccountofotheraspectssuchas:urearemovalbyconvection,ureageneration,andseparate“pools”withinwhichureaisdistributed.ThegoldstandardKt/Visderivedfrom‘UreaKineticModelling’:iterativecomputationtogivethebestfittingcoefficientsforureaclearanceandgeneration,basedonthreeureameasurements(spanninganinterdialyticintervalandadialysissession).Thisapproachisbroadlyaccepted,butalthoughonlineprogramsareavailable(e.g.SoluteSolver,www.ureakinetics.org)thenon-formulamethodhinderswidespreaduse,andanumberofsimplifiedapproachesaremorecommon-threearecommonlyusedandsummarisedhere. Log-RatioandUreaReductionRatio Ifthebasicmodelaboveisused,ignoringotherfactors,withureaassumedtobedistributedevenlyinbodywater,thenKt/Visgivenbythelogratio: $$\mathsf{Kt}/\mathsf{V}=-{\mathsf{\log}}_{\mathsf{e}}\\left[\{\mathsf{U}}_{\mathsf{post}}/{\mathsf{U}}_{\mathsf{pre}}\\right]$$ThissimpleformofKt/V,sometimescalledthe“Log-Ratio”,ismathematicallyrelatedtotheUreaReductionRatio(URR),thereductioninureaasaratioofthepre-dialysislevel,oftenexpressedasapercentage: $$\mathsf{URR}\\mathsf{100}\\mathsf{x}\\left({\mathsf{U}}_{\mathsf{pre}}-{\mathsf{U}}_{\mathsf{post}}\right)/{\mathsf{U}}_{\mathsf{pre}}$$ $$\mathsf{Kt}/\mathsf{V}={\mathsf{\log}}_{\mathsf{e}}\\left[\\mathsf{100}/\left(\mathsf{100}-\mathsf{URR}\right)\\right]$$AthresholdforURRisthereforepreciselythesameasathresholdforKt/VcalculatedbytheLog-Ratio.URRisthesimplestmeasureofdialysisdose,andisthecurrentauditmeasurecollectedbytheRenalRegistry.URRhasthedisadvantagethatitdoesnotaccountforclearanceduetoultrafiltration,ureagenerationorurearebound.Ittendstoover-estimatedialysisdoseinshortertreatments,andunder-estimatedoseintreatmentslongerthan4hours.However,itislongestablishedandthereisnoargumentoveritscalculation. Single-poolKt/V(spKt/V) Althoughtheaboveistechnicallyalsoasingle-poolmethod,theterm‘singlepoolKt/V’usuallyreferstothemethodproposedbyDaugirdas,whichcalculatesKt/Vbyaformulatakingaccountoftheeffectofultrafiltration: $$\mathsf{spKt}/\mathsf{V}=-{\mathsf{\log}}_{\mathsf{e}}\\left[\\left({\mathsf{U}}_{\mathsf{post}}/{\mathsf{U}}_{\mathsf{pre}}\right)-\left(\mathsf{t}/\mathsf{7500}\right)\\right]+\left[\\left(\mathsf{UF}/\mathsf{TW}\right)\ast\right(\mathsf{4}-\left(\mathsf{3.5}\ast\left({\mathsf{U}}_{\mathsf{post}}/{\mathsf{U}}_{\mathsf{pre}}\right)\right)\\Big]$$where $$\mathsf{t}=\mathsf{dialysis}\\mathsf{t}\mathsf{ime}\\left(\mathsf{\min}\right)$$ $$\mathsf{UF}=\mathsf{ultrafiltration}\\left(\mathsf{litres}\right)$$ $$\mathsf{TW}=\mathsf{target}\\mathsf{weight}\\left(\mathsf{kg}\right)$$Thismethodtakesaccountofmorefactorsbutconsistentlyover-estimatesKt/V.TargetshavethereforeoftenbeenexpressedwithanadjustmentfactorifusingspKt/V(eg.“eKt/V=1.2,orspKt/V=1.4”). EquilibratedKt/V(eKt/V) Thedynamicinteractionbetweenureaconcentrationsinintra-andextra-cellularpools,resultsinreducedeffectivenessoftreatmentbecausedialysisremovesureaonlyfromtheextracellularpool,whichisthenrefilledfromtheintracellularpoolduringandafterdialysis.Thisresultsinagradualreboundinureaconcentrationforapproximatelyonehourafterdialysis,sothatifpost-dialysisureaismeasuredimmediately,thenthetreatmenteffectisover-estimated.EquilibratedKt/Vattemptstocorrectforthisbyusingapost-reboundureameasurement: $$\mathsf{eKt}/\mathsf{V}=-{\mathsf{\log}}_{\mathsf{e}}\\left[\{\mathsf{U}}_{\mathsf{post}-\mathsf{rebound}}/{\mathsf{U}}_{\mathsf{pre}}\\right]$$Duetotheinconvenienceofmeasuringureapost-rebound(anhourafterdialysishasfinished)aformulaisusedtoadjustforthisreasonablypredictableeffectusingureameasuredimmediately.Morethanoneequationhasbeenpublishedbutthereisverylittledifferencebetweenthem.ThisoneisknownastheTattersallversion: $$\mathsf{eKt}/\mathsf{V}=\left(\mathsf{spKt}/\mathsf{V}\ast\mathsf{t}\right)/\left(\mathsf{t}+\mathsf{35}\right)$$Apparentureareboundisdependentonvascularaccess,so35isreplacedby22inpatientsdialysingviaacatheter.Thismethodisnon-biasedandhasmostoftenbeenusedinstudiesofdialysisdose,suchastheHEMOstudy.TargetsgivenintermsofothermeasuresofdialysisdosesuchasURRmaybeusefulincomparingunits,butarenotaccurateforindividualpatients.AllformsofKt/V(includingeKt/V)implicitlyuseVtonormaliseforbodysize,whereasbodysurfaceareaisconventionallyusedtonormaliserenalfunction.TherearetheoreticalreasonstobelievethatnormalisationofKt/Vtootherbodysizeparameterssuchasbodysurfaceareawouldbemoreuseful,buttheseconceptshavenotgainedwidespreadacceptance.TheLog-RatioisareasonableapproximationofeKt/Vsincetheunderestimation(fromignoringultrafiltrationandureageneration)isoffsetbyoverestimation(fromignoringurearebound).Infact,fora4hoursession,withUF/TW=0.02,inafistulapatient,theLog-RatioisalmostidenticaltoeKt/V,withURR=70beingequivalenttoeKt/V=1.2.However,inmostothersettings,Log-Ratiowillunderestimateoroverestimatedose,sothatthetargetURRrequiredtoachieveeKt/V=1.2needstobevaried,asinthistable: UreaReductionRatioequivalenttoeKt/V=1.2 Time(h)byaccesstype UF/TW Fistula Catheter 0.02 0.03 0.04 3.5   71.0 70.2 69.4 4.0   70.0 69.2 68.4 4.5 3.5 69.1 68.3 67.5 5.0 4.0 68.2 67.4 66.6   4.5 67.4 66.6 65.8   5.0 66.8 66.0 65.2 Appendix2AdjustingdialysisforresidualfunctionSinceresidualrenalclearance(Kru)iscontinuous,anddialysisclearanceisintermittent(withKt/Vreferringtoclearanceduringasingledialysissession),thequantitiesofbothcannotsimplybeadded.Whenitisplannedtoreducedialysisdosebyincorporatingthecontributionofresidualfunction,itisnecessarytosomehowaddtheseclearancessothatthedialysiscomponentisappropriate.Threemethodsofcombiningtheseclearanceshavebeenproposed. ConvertingKrutoanequivalenteKt/V(CombinedeKt/V) Inthismethod,residualkidneyfunctionisconvertedtoanequivalentper-sessioneKt/V,bymultiplyingbyafactorF,whichempiricallyinflatesthetimeoverwhichresidualclearanceismeasured,toaccountforitsgreaterefficiencycomparedtothatofdialysis,withthevalueofFdependingondialysisfrequency.A“CombinedKt/V”iscalculated: $$\mathsf{Combined}\\mathsf{eKt}/\mathsf{V}=\mathsf{eKt}/{\mathsf{V}}_{\mathsf{Dialysis}}+\mathsf{eKt}/{\mathsf{V}}_{\mathsf{Kidney}}$$ $$\mathsf{eKt}/{\mathsf{V}}_{\mathsf{Kidney}}=\mathsf{Kru}\ast\mathsf{F}/\mathsf{Vu}$$where: $$\mathsf{eKt}/{\mathsf{V}}_{\mathsf{Dialysis}}\\mathsf{is}\\mathsf{calculated}\\mathsf{as}\\mathsf{above}$$ $$\mathsf{Vu}=\mathsf{volume}\\mathsf{of}\\mathsf{distribution}\\mathsf{of}\\mathsf{urea}\\left(\mathsf{ml}\right),\mathsf{approximated}\\mathsf{by}\\mathsf{580}\ast\mathsf{TW}\\left(\mathsf{kg}\right)$$ $$\mathsf{F}=\mathsf{5500}\\left(\mathsf{for}\\mathsf{thrice}\\mathsf{weekly}\\mathsf{schedules}\right)$$Withthemethodabove,aCombinedeKt/VcanbecalculatedandthedialysiscomponentadjustedtoachieveatargetCombinedeKt/Vof1.2. ConvertingKt/Vtoanequivalentrenalclearance(EKRc) Analternativemethodistoconvertper-sessionKt/VintoanequivalentcontinuousrenalclearanceandthenaddittoKru.CasinoandLopezcomputedkineticestimatesofcombineddialysisandkidneyureaclearance(normalizedtovolume)whichtheytermed“equivalentrenalureaclearance”(EKRc).Intheabsenceofresidualfunction,aneKt/Vtargetof1.2equatestoEKRc13ml/min.ForathriceweeklyscheduleEKRcisgivenbytheformula: $$\mathsf{EKRc}\\left(\mathsf{ml}/\mathsf{\min}\right)=\mathsf{1}+\left(\\mathsf{10}\ast\mathsf{eKt}/\mathsf{V}\\right)$$WiththismethodKruisaddedtoEKRcandthedialysiscomponentadjustedtoachieveatotalof13ml/min. ConvertingbotheKt/VandKrutoaweeklydialysisdose(stdKt/V) Dialysisscheduleanddosecanbeconvertedtoanequivalentweeklyclearance,“StandardKt/V”(stdKt/V)proposedbyGotch,basedonkineticmodelswhichrelateureagenerationtoaverageweeklypre-dialysisurea.Thisallowscomparisonbetweenschedules:afrequentschedulewithstdKt/V=2.1isequivalent(intermsofsmallsoluteclearance)toathrice-weeklyschedulewitheKt/V=1.2.ResidualfunctioncanbeincorporatedintostdKt/V(sometimestermed“TotalStandardKt/V”)byformulasavailable[259].Appendix3QuantifyingconvectionConvectiveclearanceofatoxindependsfirstlyonthesievingcoefficient.Seivingcoefficient(SC)isameasureoftheeasewithwhichasolutepassesthroughthemembranerelativetosolvent,sothisdependslargelyontherelativesizeofthesolutemoleculeandthemembraneporecross-section.Itcanbemeasuredduringpureultrafiltrationastheratioofsoluteconcentrationbeforeandafterpassingthroughthemembrane.SCtakesvaluesbetween0(themoleculeisunabletopassthroughthemembrane)and1(themoleculepassesjustaseasilyaswater).Secondly,convectiveclearancedependsontheultrafiltrationrate.Inpurehaemofiltration,clearanceisachievedentirelybyultrafiltration.Thelossoffluidbyultrafiltrationisreplacedbyinfusionintotheblooddownstreamofthefilter(“post-dilution”).Inthiscase,clearance(K)foranysoluteisequaltoconvectiveclearance(Kc)andcanbecalculatedfrom: $$\mathsf{K}=\mathsf{Kc}=\mathsf{Quf}\ast\mathsf{SC}$$where: $$\mathsf{Quf}=\mathsf{ultrafiltrate}\\mathsf{flow}\\mathsf{rate}$$Inhaemodiafiltration(HDF),thereisamixtureofdiffusionandconvection.Diffusionreducestheconcentrationsintheultrafiltrate,reducingKc.Clearanceinhaemodiafiltrationcanbepredictedbythefollowingequation: $$\mathsf{Kc}=\mathsf{Quf}\ast\mathsf{SC}\ast\left(\\left(\mathsf{Qp}-\mathsf{Kd}\right)/\mathsf{Qp}\\right)$$ $$\mathsf{K}=\mathsf{Kc}+\mathsf{Kd}$$where: $$\mathsf{Qp}=\mathsf{plasma}\\mathsf{flow}\\mathsf{rate}$$ $$\mathsf{Kd}=\mathsf{diffusive}\\mathsf{clearance}$$Theeffectofthisistodiminishtheconvectivecomponent.Inpost-dilutionHDF,convectionwillalwaysincreasetotalclearance,butthisincreaseisnegligibleforsmallsoluteswhichdiffuseeasily(suchasurea).Forlargermolecules(suchasbeta-2-microglobulin)convectioncansignificantlyandusefullyincreaseclearance.Pre-dilutionHDF,inwhichreplacementfluidisgivenupstreamofthedialyser,islesscommonlypracticed,andmorecomplexmathematically.Convectionissimilarlyreducedbydiffusionasabove,butinadditionbothconvectionanddiffusionaresubstantiallyreducedbythedilutionaleffectofthereplacementfluid.Theultrafiltraterateandvolumeareusuallyadjustedtoaccountforthis.InpublicationstheconvectivecomponentofHDFisquantifiedasthefiltrationvolume.Thismeansthetotalsessionalfiltrationvolumeinpost-dilutionHDF,ortheequivalentadjustedvolumeinpre-dilutionHDF.Appendix4AddingphosphatetodialysateCleenReady-To-Useenemacomesina133mlpackcosting68p(March2017).Thepackisdesignedtodelivera118mldosecontaining21.4gofsodiumacidphosphate(sodiumdihydrogenphosphatedihydrateNaH2PO4.2H2O)and9.4gsodiumphosphate(disodiumphosphatedodecahydrateNa2HPO4.12H2O).Thisgivesaconcentrationof1.38mmol/mlphosphate.Theacidconcentrate,togetherwiththeaddedenema,willbedilutedaccordingtotheproportioningratioofthedialysismachine.Thevolumeofenema(VE)thatneedstobeaddedtothecanisterisgivenby: $${\mathsf{V}}_{\mathsf{E}}\\left(\mathsf{ml}\right)={\mathsf{C}}_{\mathsf{PO4}}\ast{\mathsf{V}}_{\mathsf{AC}}\ast\mathsf{DF}/\mathsf{1.38}$$where: $${\mathsf{C}}_{\mathsf{PO4}}=\mathsf{target}\\mathsf{dialysate}\\mathsf{phosphate}\\left(\mathsf{0}.\mathsf{4mmol}/\mathsf{l}\\mathsf{is}\\mathsf{commonly}\\mathsf{used}\right)$$ $${\mathsf{V}}_{\mathsf{AC}}=\mathsf{volume}\\mathsf{of}\\mathsf{the}\\mathsf{acid}\\mathsf{concentrate}\\left(\mathsf{e}.\mathsf{g}.\mathsf{6L}\right)$$ $$\mathsf{DF}=\mathsf{dilution}\\mathsf{factor}\\mathsf{for}\\mathsf{the}\\mathsf{dialysate}\\left(\mathsf{eg}.\mathsf{35}\\mathsf{for}\\mathsf{machine}\\mathsf{proportioning}\\mathsf{at}\\mathsf{1}:\mathsf{34}\right)$$Usingthesenumbers,forexample,givesanenemavolumeof61mltobeaddedtotheconcentrate.NotethatthisformuladependsontheformulationoftheenemaandisspecifictoCleen.Thissimpleformulaignoresthesmallchangeinconcentratevolume,astheeffectisbelowthe5%toleranceallowedforelectrolyteconcentrationsforhaemodialysisandrelatedtherapies(ISO23500Part4).AlbalateusedtheaboveformulatopreparedialysateswithCPO4between0.48to1.12mmol/l,reportinggoodagreementbetweenmeasuredandtargetCPO4usingGambroandFreseniusmachinesandarangeofacidconcentrates[260].Sodiumcontentinthephosphate-enrichedacidconcentratewillbereduced(sincetheenemasodiumis37g/l,comparedtoaround83g/lforanacidconcentratethatproportionsat1:34,and107g/lforonethatproportionsat1:44).Thiswillleadtoalowerdialysatesodium(by0.7to0.9mmol/l)withvolumetricproportioning,andahigherconcentratepumpratewithconductivityfeedback.Itispossiblethatthiseffectcouldtriggermachinealarms,requiringmachinere-programming.Appendix5HaemodialysistasksforsharedcareListofdialysis-relatedtasksthatanindividualmaychoosetolearntoperform,aspartofsharedcare: 1. Washingyourhandspriortoallproceduresandarm(asappropriate)iffistulaorgraftisused. 2. Recordingyourweight 3. Recordingyourbloodpressureandpulse 4. Recordingyourtemperature 5. Settingupyourdialysismachine 6. Preparingyourdressingpack 7. Programmingyourprescriptiononthedialysismachine 8. Puttingyourneedlesinorpreparingyouraccessline 9. Connectingyourlinesandcommencingdialysis 10. Respondingtoalertsfromyourdialysismachine 11. Disconnectinglinesandcompletingyourdialysis 12. Applyingpressuretoneedlesitesafterdialysisor 13. Lockingyourownaccessline 14. Administeringanyofyourinjections. Appendix6ImplementingintradialyticexerciseWesuggestthefollowingguidanceforimplementationofintradialyticexercise: a. Exerciseshouldbesupervisedforgreatestcomplianceandefficacybyanappropriatelytrainedindividual(e.g.physiotherapist,sportscientist,cardiacrehabilitationspecialistoranassistantphysiotherapist/dietitian/nursewithadditionaltrainingfromoneoftheformergroups). b. Exerciseshouldbecompletedbetween30minandtwohoursofthedialysisprocedure. c. Exerciseshouldbecompletedduringalldialysissessions(unlesscontraindicated). d. Exerciseshouldincludebothaerobic(e.g.intradialyticcycling)andresistance(e.g.TheraBandsand/orliftingofankleweights)componentsoflowerorupperbody,dependentonaccesssite. e. Exerciseshouldbeprecededbywarmupactivities(e.g.exercisingforaminimumoffiveminutes,graduallyincreasingintensityuntilonehalfofprescribedtrainingintensityisobtained). f. Exerciseshouldbecompletedforatleast30minutesperhemodialysissession. g. Exerciseshouldbecompletedatmoderatetovigorousintensity,rangingfrom40-75%ofVO2reserveorheartratereserve(ifagradedexercisetestiscompleted).Whenagradedexercisetestcannotbecompleted,andformuscleconditioningexercises,aratingofperceivedexertionontheBorgCR100scaleof“moderate”(20)to“strongheavy(50)”orontheBorgRPEscaleof12to15canbeusedwithcautionasamethodtoprescribeexerciseintensity. h. Volumeofexerciseshouldbeprogressedgraduallybyadjustingduration,frequency,and/orintensityuntilthedesiredexercisegoal(maintenance)isattained. i. Exerciseshouldbefollowedbycooldownactivities(e.g.exercisingforaminimumoffiveminutes,startingatonehalfofprescribedtrainingintensityandgraduallydecreasingintensityuntilexerciseisstopped). j. Oncepatientsareestablishedexercisingduringdialysis,theyshouldbeencouragedtocompleteadditionalexerciseonnon-dialysisdays. k. Toenhanceadoptionandadherenceinnoviceexercisers,moderate-intensityactivityshouldbeprescribed. l. Tomaintainexercisebehaviour,behaviouralstrategiessuchassocialsupport,goalsettingandmotivationalinterviewingshouldbeimplemented. Wesuggestthefollowingpatientexclusioncriteria/contraindicationstoexerciseduringhaemodialysis: a. Lessthanthreemonthsafterinitiationofhaemodialysis. b. Anyuncontrolledmedicalconditionincluding(butnotlimitedto)infectionorfever;recent(within8weeks)myocardialinfarctionorundiagnosedchestpain. c. PatientinclassD(unstablecondition)asperAmericanHeartAssociation/AmericanCollegeofSportsMedicineJointPositionStatement:1)unstableischemia;2)heartfailurethatisnotcompenstated;3)uncontrolledarrhythmias;4)severeandsymptomaticaorticstenosis;5)hypertrophiccardiomyopathyorcardiomyopathyfromrecentmyocarditis;6)severepulmonaryhypertension;or7)otherconditionsthatcouldbeaggravatedbyexercise(forexample,restingsystolicbloodpressure>200mmHgorrestingdiastolicbloodpressure>110mmHg;activeorsuspectedmyocarditisorpericarditis;suspectedorknowndissectinganeurysm;thrombophlebitisandrecentsystemicorpulmonaryembolus). d. Symptomatichyper-orhypotension. e. Signsandsymptomsofdeepveinthrombosis. f. Excessiveinter-dialyticweightgainthatseverelyimpactsuponindicesoffluidretention,e.g.bloodpressuregreaterthan160/100;heartrateabove100bpm;breathlessnessatrest;orsignsofsubstantialperipheraloedema. g. Ifdiabetic,bloodglucoseabove16.7mmol/L(300mg/dL)ANDpatientisinketosis(fruitybreath,rapidbreathingorshortnessofbreath,excessivethirst,frequenturination,stomachpain,nausea,vomiting,fatigueorconfusion),isdehydrated,orisfeelingunwell. h. Inindividualstakinginsulinand/orinsulinsecretagogues,ifhypoglycaemiabelow5.5mmol/L(100mg/dL)isobserved,andglucosecontainingdialysatefailstoelevatebloodglucosesufficiently,advisepatienttoeatordrinkapproximately15gcarbohydrateandre-assessbloodglucoseconcentrationafter20min.Repeatuntilbloodglucoseexceeds5.5mmol/L. Wesuggestthefollowingsafetymonitoring: a. Priortoexercise,askpatienthowtheyfeel,recordrestingbloodpressureandheartrate,andifdiabetic,recordbloodglucoseconcentration. b. Duringexercise,monitorsignsandaskpatienttoreportsymptomsofpain,excessivefatigue,alteredconsciousness,overheating,cyanosis,anxiety,severebreathlessness,chestpain,dizziness/light-headedness. c. Ifhypertensive,regularlycheckbloodpressureduringexercise.Ifvaluesexceed220/105mmHg,reduceexerciseintensityorceaseexercisinguntilbloodpressurereduces. d. Usearatingofperceivedexertionscale(BorgCR100orBorgRPEscales)andensureexerciseintensitydoesnotprovokeresponsesgreaterthan50/strongheavyontheBorgCR100or15/hard(heavy)ontheBorgRPEscale e. Postexercise,monitorbloodpressureandheartrateuntilrestingvaluesareapproximatelyobtained,observepatientforatleast20min,andbeawareofpossibilityofhypotensionduringremainderofthedialysissession. 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BMCNephrol20,379(2019).https://doi.org/10.1186/s12882-019-1527-3DownloadcitationReceived:21August2019Accepted:21August2019Published:17October2019DOI:https://doi.org/10.1186/s12882-019-1527-3SharethisarticleAnyoneyousharethefollowinglinkwithwillbeabletoreadthiscontent:GetshareablelinkSorry,ashareablelinkisnotcurrentlyavailableforthisarticle.Copytoclipboard ProvidedbytheSpringerNatureSharedItcontent-sharinginitiative DownloadPDF AssociatedContent Collection RenalAssociationClinicalPracticeGuidelines Advertisement BMCNephrology ISSN:1471-2369 Contactus Submissionenquiries:[email protected] Generalenquiries:[email protected]