proposed scope of work for kdigo clinical ... - kidney disease€¦ · management of diabetes and...
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ProposedScopeofWorkforKDIGOClinicalPracticeGuidelineonthe
ManagementofDiabetesandChronicKidneyDisease
Introduction
KidneyDisease:ImprovingGlobalOutcomes(KDIGO)isanot-for-profitorganizationestablishedtodevelopandimplementglobalclinicalpracticeguidelinesforpatientswithkidneydisease.Sinceitsinceptionin2003,KDIGOhaspublishedtenguidelines,beginningwiththeKDIGOClinicalPracticeGuidelineforthePrevention,Diagnosis,Evaluation,andTreatmentofHepatitisCinChronicKidneyDisease(CKD).ThisproposedScopeofWorkisdesignedtobrieflydescribetherationalefordevelopmentofaguidelineonthemanagementofpatientswithdiabetesandCKDandtooutlinethetopicsthatthisguidelineintendstoaddress.WearenowseekingpubliccommentsontheproposedScopeofWorkpresentedheretoensurethatfeedbackfromallrelevantstakeholdersofthisglobalguidelineisdulyconsideredbeforeaformalsystematicreviewoftheliteratureisundertaken.
Background
Theprevalenceofdiabetesaroundtheworldhasreachedepidemicproportions.Whilediabetesisalreadyestimatedtoaffectmorethan8%oftheglobalpopulation−morethan425millionpeople−thisisprojectedtogrowtoover629millionpeopleby2045.1Ithasalsobeenestimatedthat40%ormoreofpeoplewithdiabeteswilldevelopCKD,includingasignificantnumberwhowilldevelopend-stagekidneydisease(ESKD)requiringdialysisandtransplantation.2PreventionofCKDindiabetesisthereforeahighpriority.DiabetesisalreadytheleadingcauseofESKDinmostdevelopedcountries,andthegrowthinthenumberofpeoplewithESKDaroundtheworldoverrecentdecadeshasbeendrivenprimarilybygrowthinthenumberofpeoplewithdiabetesastheunderlyingcause.3,4Inpeoplewithdiabetes,increasingalbuminuriaanddecliningGFR
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canbeduetoclassicdiabeticglomerulopathy.However,reducedGFRwithoutalbuminuriaisanincreasinglyrecognizedphenotypethatmayhavedifferentunderlyingmechanisms,andpeoplewithdiabetescandevelopkidneydiseaseforreasonsotherthandiabetesitself.Assuchtheneedfordiagnosticandprognostickidneybiopsiesinpeoplewithdiabetesremainsamatterofdiscussion.Thepresenceofkidneydiseaseisassociatedwithamarkedlyincreasedriskofcardiovasculardiseaseanddeathinpeoplewithdiabetes.5,6ThereforeaggressiveinterventionagainstcardiovascularriskfactorsisveryimportantinpeoplewithdiabetesandCKD.7Recentdatademonstratedeclineinincidenceofcardiovascularandothercomplicationsinsomepopulationsprobablyduetobetterscreeningforandtreatmentofriskfactors,butdespitethis,adeclineinESKDismuchlessapparent.8
AsprovisionofdialysistopeoplewithESKDconsumesapproximately6%ofallhealthcarecostsintheUSandmoreinsomeothercountries,4thereisastrongeconomicimperativetoimproveoutcomesforpeoplewithdiabetesandkidneydiseaseinadditiontothestrongpersonalandsocietalhealthrationale.Whiletheidentificationofrenin-angiotensinblockadeasaneffectivestrategyforthepreventionofESKDintype1andtype2diabetesmellitusalmost2decadesagowasamajorstepforward,9-11subsequentresearchhashadlimitedsuccessatmostinbuildinguponthesegains.Anumberofpromisingtreatmentshavebeenfoundtobeineffectiveorharmful,manyofwhichhavenowbeenabandonedinthispopulation.Ontheotherhand,anumberofnewagentsarecurrentlybeingtested,whichmayhopefullyimproveoutcomesforpeoplewithdiabetesandkidneydisease.TreatinghyperglycemiainpeoplewithdiabetesandCKDischallengingduetotheriskofhypoglycemiaandtheneedtoadjustselectionanddosingofmedicationsaccordingtolevelofGFR.Furthermore,assessingmeanbloodglucoseiscomplicatedinadvancedCKDbecauseoflimitationsofhemoglobinA1c(HbA1c).
Importantlysomeofthenewdrugclassesnowavailableforreducingbloodglucoseintype2diabetessuchassodium-glucosecotransportertype2(SGLT2)inhibitorsandglucagon-like-peptide-1(GLP-1)receptoragonistshaveturnedouttohavebeneficialeffectsoncardiovascularoutcomeinpeoplewithpreviouscardiovasculardisease,includingpatientswithmoderateCKD.12,13Inaddition,someoftheseagentsexertedbeneficialeffectsonrenaloutcomeparametersmeasuredassecondaryendpoints.14,15Thisincludedreductioninprogressionofalbuminuria,asurrogateforapotentialrenalbenefit,butforSGLT2inhibitorsareductioninlossofGFRwasalsodemonstrated.16,17
GiventhehighprevalenceofdiabetesandCKD,thelargehealthimpactofESKD,andthestrongrelationshipsofCKDwithcardiovascularmorbidityanddeath,KDIGOhas
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determinedthatthedevelopmentofaclinicalpracticeguidelineforthispatientpopulationistimelyandappropriateinviewofrecentdevelopmentinvariousmanagementandtreatmentoptions.
Topic1:PrimarypreventionofCKDamongpeoplewithdiabetesCKD,asrepresentedbyalbuminuriaorreducedGFR,isacommoncomplicationoftype1andtype2diabetes.Durationofdiabetes,glycemiccontrol,andotherCKDriskfactorsareknowntobeassociatedwiththeprevalenceandincidenceofCKD.Randomizedcontrolledtrialshaveshownthatintensiveglycemiccontrolandspecificglucose-loweringagentsreducetheriskofdevelopingCKDornew-onsetalbuminuria,18whileresultsoftrialsoflifestyleinterventionsandRASblockadeforprimaryCKDpreventionarelessclear.Relevantkeyquestions:HowcanwepreventonsetofCKDinpatientswithdiabetes?Whatistheevidenceforglycemiccontrolandarethereothereffectivestrategies?IsRASblockadeindicatedinpatientswithalbuminuriaA1category(<30mg/gor<3mg/mmol)forCKDprevention,regardlessofbloodpressure?Whatisthedefinitionofdiabetickidneydisease(DKD)?HowisDKDdiagnosedandwhatistheroleofkidneybiopsyindiagnosis?IsthereutilityinthestagingofDKD?Topic2:SecondarypreventionofCKDprogressionamongpeoplewithdiabetesPatientswithdiabetesandeitheralbuminuriaorreducedGFRareatriskofprogressingtoESKD.Infact,diabetesisthemostcommoncauseofESKDinmanycountries.Inaddition,riskofCKDcomplications(includingcardiovasculardisease)increaseswithseverityofCKD.Therefore,interventionstohaltorslowprogressionofCKDareimportanttoimprovetheoutcomesofpeoplewithdiabetesandCKD.Currenttherapeutictargetsincluderenin-angiotensinsystemandbloodpressurecontrol,aswellasglycemiccontrol.Othertherapeuticagentsunderdevelopmentnowtargettheroleofendothelialfunction,oxidativestress,andfibrosis.
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Relevantkeyquestions:ForwhichpatientswithdiabetesandprevalentCKDisthereastrongindicationforRASinhibition?DoestreatmentofglycemiapreventprogressionofestablishedCKDtoESKD?WhatistheoptimalapproachtoimplementRAASblockadeindiabetesandCKD?IstherearemainingrolefordualRASblockadeamongpatientswithdiabetesandCKD?WhatistheroleofmineralocorticoidreceptorantagonistsinthetreatmentofdiabetesandCKD?ArethereadditionaltreatmentsthatshouldbeconsideredforpreventingprogressionofCKDindiabetes(e.g.,SGLT2inhibitors,dipeptidylpeptidase-4inhibitors,endothelinantagonists,bardoxolone,pentoxifyline,anti-inflammatoryagents,etc.)?Topic3:MeasurementofglycemiainCKDHbA1cistheacceptedtherapeutictargetfortitratingglucosecontrolamongpeoplewithdiabetes.InadvancedCKD,changestohemoglobinkineticscomplicateinterpretationofHbA1c.Alternativebiomarkersofmeanglycemiahavenowbeendevelopedandevaluatedinobservationalstudies.However,itisunclearwhetherusingthesealternativebiomarkersimprovesglycemiamanagement.Withtheadvanceofcontinuousglucosemonitoringtechnology,measuringglucoseitselfhasbeenshowntoimproveglycemiccontrolamongpeoplewithdiabetes(withoutCKD).Oftheseoptionsformeasuringglycemia,theoptimalapproachamongpeoplewithdiabetesandCKDisnotclear.Relevantkeyquestions:DoesCKDmodifytheaccuracyandprecisionofHbA1cinascertainingglycemiaamongpeoplewithdiabetes?InCKDandthoseondialysistherapy,doalternativebiomarkerssuchasglycatedalbuminorfructosaminecorrelatemorepreciselywithglycemiathanHbA1c?
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InCKDandthoseondialysistherapy,doalternativebiomarkerssuchasglycatedalbuminorfructosaminecorrelatemorepreciselywithclinicaldiabetescomplicationsorbetterguideglucose-loweringtreatmentintensitycomparedwithHbA1c?IsselfmonitoredbloodglucoseorcontinuousglucosemonitoringofaddedvalueinpatientswithdiabetesandCKD?Topic4:GlycemiamanagementinCKDIngeneral,intensiveglycemiccontrolreducestheriskofdiabetescomplications(e.g.,CKD,retinopathy,neuropathy,andcardiovasculardisease)attheexpenseincreasedriskofhypoglycemia.Inaddition,individualglucose-loweringmedicationshavespecificbenefitsandrisks.Forexample,someSGLT2inhibitorsandGLP-1receptoragonistsreducetheriskofCKDorcardiovasculareventswithotherbeneficialeffects(e.g.,bloodpressureandweightreduction),thoughadverseeffects(e.g.,hypoglycemia,bonedisease)couldalsovary.InCKD,benefitsandrisksofintensiveglycemiccontrolingeneralandspecificglucose-loweringdrugsmayvary,andsomedrugsrequiredosereductionsorarecontraindicated.TheimpactofCKDonglycemiamanagementalsodiffersacrossthespectrumofCKDseverity,beinglargestamongpatientsondialysistherapy.Therefore,amongpeoplewithdiabetesandCKD,optimalglycemiatargetsandthepreferredagentsusedtoachievethemarenotclear.Relevantkeyquestions:WhatistheoptimaltargetrangeforHbA1c(oralternativeglycemiamarkers)inCKD?DotargetsvaryinaccordancetoseverityofCKD(e.g.,GFRcategories)?Aretherepreferredclasses/agentsfortreatinghyperglycemiainpatientswithdiabetesandCKD?HowdoestheselectionofagentsdifferbyseverityofCKD?Aretherepreferredclasses/agentsinpatientswithdiabetesandCKDtopreventrenal,cardiovascularandothermicrovascularcomplications?WhatistheimpactofhypoglycemiainpatientswithdiabetesandCKD?TowhatextentshouldinsulindosesbemodifiedinadvancedCKD?ShouldtreatmentbechangedwhenpatientswithCKDG5transition/startdialysis?
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Topic5:LifestyleandnutritionamongpeoplewithdiabetesandCKDExercise,weightloss,smokingcessation,andmodificationofdietaryprotein,sodium,andpotassiumareoftenadvisedtopreventCKDprogressionandcardiovascularcomplications.However,effectivenessoftheseinterventionsremainsunclear.Relevantkeyquestions:Isthereevidenceforabenefitoflifestyleintervention(e.g.,weightloss,exercise,physicalactivity)ondeclineinGFRorcardiovascularriskamongpatientswithdiabetesandCKD?Isthereanoptimaldietaryprotein,sodiumandpotassiumintakeinpatientswithdiabetesandCKD?WhatistheroleofpotassiumbindersinpatientswithdiabetesandCKD?Topic6:CardiovascularriskreductionamongpeoplewithdiabetesandCKDPatientswithdiabetesandCKDareathighriskofcardiovascularevents,includingcoronaryheartdisease,stroke,peripheralvasculardisease,heartfailure,andarrhythmia.Inadditiontoglycemiccontrolandlifestyleinterventions,bloodpressurelowering,lipidlowering,andantiplateletmedicationsarecommonlyusedtoreducecardiovascularrisk.BloodpressureloweringalsoaffectsCKDprogression.Itisnotclearwhetherdiabetesaltersoptimalbloodpressuretargets.RASinhibitorsarerecommendedforbloodpressureloweringamongpatientswithalbuminuria,butit’snotclearforexactlywhichpatientsRASinhibitorsshouldberecommendedoverotherantihypertensivemedications.QuestionssurroundingbloodpressuremanagementinCKDpatientswithdiabeteswillbeaddressedbytheupcomingKDIGOBloodPressureguidelineupdatingWorkGroup.Recentclinicaltrialshavealsodemonstratedcardiovascularbenefittointensifyinglipid-loweringtherapybeyondtypicalstatintherapy,targetinglowLDLcholesterolconcentrationsoraddingadditionalagentstostatintherapy.TheextenttowhichthisapproachmaybeusefulforpatientswithDKDisnotclear.
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Relevantkeyquestions:WhatistheoptimaltreatmentforCVDriskreductioninCKDG3a-G5Dpatientswithdiabetes?WhatistheoptimallipidinterventionstrategyinCKDG3a-5Dpatientswithdiabetes?Whatisknownabouttherisk-benefitratioofanti-plateletagentsandanticoagulantsinpatientswithCKDanddiabetes?Aretherenewagentsindevelopment(e.g.,CETPinhibitors,PCSK9inhibitors,mineralocorticoid-receptorantagonists)thatmightbeparticularlypromisingforpeoplewithdiabetesandCKD?
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