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LUR DNEYFAI KI AUTHORS LEADAUTHOR EkeminiA.U.Riley,PhD CONTRIBUTINGAUTHORS LaTeseBriggs,PhD MauraDonlan,MIA SonyaDumanis,PhD YooRiKim,MS ErikLontok,PhD EbonyMosley DanielleSalka MelissaStevens,MBA KIDNEYDISEASESCIENTIFICADVISORYGROUP WegraciouslythankthemembersofandliaisonstotheKidneyDiseaseScientificAdvisoryGroupfortheir participationandcontributiontotheKidneyFailureProjectandGivingSmarterGuide.Theinformativediscussions before,during,andaftertheCalltoActionRetreatwerecriticaltoidentifyingthekeyunmetneedsandideal philanthropicopportunitiestobenefitpatientsandadvancekidneydiseaseresearch. MatthewBreyer,MD ChiefScientificOfficer—LeadGeneration BioTechnologyDiscoveryResearch EliLillyandCompany JonathanHimmelfarb,MD ProfessorofMedicine Director,KidneyResearchInstitute UniversityofWashington PaulConway President,AmericanAssociationofKidneyPatients BoardMember,KidneyHealthInitiative ThomasKleyman,MD Chief,Renal-ElectrolyteDivision SheldonAdlerProfessorofMedicine ProfessorofCellBiology,Pharmacologyand ChemicalBiology UniversityofPittsburghSchoolofMedicine JosefCoresh,MD G.W.ComstockProfessorofEpidemiology, Biostatistics&Medicine CKDPrognosisConsortiumFoundingLeader JohnsHopkinsUniversity LauraDember,MD ProfessorofMedicineandEpidemiology Renal,ElectrolyteandHypertensionDivision UniversityofPennsylvania JenniferErickson AssistantDirector,InnovationforGrowth ExecutiveOfficeofthePresident OfficeofScienceandTechnologyPolicy TheWhiteHouse WilliamFissell,MD AssociateProfessor NephrologyandHypertension VanderbiltUniversity 1 March2017 MatthiasKretzler,MD Warner-Lambert/Parke-DavisProfessorofMedicine Nephrology/InternalMedicineand ComputationalMedicineandBioinformatics UniversityofMichigan JeffreyLawson,MD,PhD ChiefMedicalOfficer Humacyte KristaLentine,MD,PhD MedicalDirectorofLivingDonation ProfessorofMedicine SaintLouisUniversity AndrewLevey,MD Chief,DivisionofNephrology Dr.GeraldJ.andDorothyR.FriedmanProfessor TuftsUniversitySchoolofMedicine PeterLinde,MD VicePresident,MedicalResearch AcceleronPharma RoySoberman,MD AssociateProfessorofMedicine HarvardMedicalSchool NephrologyDivision MassachusettsGeneralHospital KennethNewell,MD,PhD ViceChairforAcademicAffairs ProfessorofSurgery DepartmentofSurgery EmoryUniversity CarmenA.Peralta,MD,MAS AssociateProfessorofMedicine UniversityofCaliforniaSanFranciscoandSan FranciscoVAMedicalCenter Co-FounderandExecutiveDirector KidneyHealthResearchCollaborative RobertStanton,MD AssociateProfessorofMedicine HarvardMedicalSchool Chief,Kidney&HypertensionSection JoslinDiabetesCenter KatalinSusztak,MD,PhD AssociateProfessorofMedicine PerelmanSchoolofMedicine UniversityofPennsylvania VladoPerkovic,MBBS,PhD ExecutiveDirector TheGeorgeInstituteAustralia ProfessorofMedicine UniversityofSydney RaviThadhani,MD,MPH ProfessorofMedicine HarvardMedicalSchool Chief,DivisionofNephrology MassachusettsGeneralHospital MartinPollak,MD ProfessorofMedicine,HarvardMedicalSchool Chief,DivisionofNephrology BethIsraelDeaconessMedicalCenter AlizaThompson,MD MedicalOfficer DivisionofCardiovascularandRenalProducts CenterforDrugEvaluationandResearch(CDER) FoodandDrugAdministration NeilPowe,MD,MPH,MBA ChiefofMedicine,ZuckerbergSanFranciscoGeneral Hospital ConstanceB.WofsyDistinguishedProfessorand Vice-ChairofMedicine UniversityofCaliforniaSanFrancisco DorrySegev,MD,PhD MarjoryK.andThomasPozefskyProfessorofSurgery andEpidemiology AssociateViceChair,DepartmentofSurgery Director,EpidemiologyResearchGroupinOrgan Transplantation TheJohnsHopkinsUniversity RobertaWeiss,MD SeniorDirector ClinicalDevelopment,RIA MedImmune MelissaWest ProjectDirector,KidneyHealthInitiative AmericanSocietyofNephrology KerryWillis,PhD ChiefScienceOfficer NationalKidneyFoundation MylesWolf,MD,MMSc ProfessorofMedicine Chief,DukeNephrology DukeUniversitySchoolofMedicine 2 March2017 TABLEOFCONTENTS Authors................................................................................................................................................1 KidneyDiseaseScientificAdvisoryGroup.............................................................................................1 Philanthropists’Foreword....................................................................................................................6 ExecutiveSummary..............................................................................................................................8 Overview.............................................................................................................................................9 SocietalImpactofKidneyFailure.....................................................................................................................9 PolicyandRegulatoryInitiatives....................................................................................................................11 LivingDonorProtectionActof2016(H.R.4616,S.2584).................................................................................11 TheCKDImprovementinResearchandTreatmentActof2015(H.R.1130,S.598)........................................11 QualityIncentiveProgram.................................................................................................................................12 TheBasics:TheKidneysandHowTheyWork.....................................................................................13 WherearetheKidneysLocated?....................................................................................................................13 HowdotheKidneysWork?............................................................................................................................13 CausalFactors,RiskFactors,andPrevention......................................................................................15 GeneralRiskFactors..........................................................................................................................................15 GeneticRiskFactors...........................................................................................................................................15 Prevention.........................................................................................................................................................15 SignsandSymptomsofKidneyFailure...............................................................................................16 Diagnosis...........................................................................................................................................17 Treatment..........................................................................................................................................19 Dialysis..........................................................................................................................................................19 Hemodialysis......................................................................................................................................................19 PeritonealDialysis..............................................................................................................................................21 ComplicationsAssociatedwithDialysisTreatment...........................................................................................21 BarriersAssociatedwithDialysisTreatment.....................................................................................................22 3 March2017 KidneyTransplantation..................................................................................................................................22 ComplicationsAssociatedwithKidneyTransplantation....................................................................................23 BarriersAssociatedwithKidneyTransplantation..............................................................................................23 MolecularBiologyofDisease.............................................................................................................25 APOL1—AKeyGeneticRiskDeterminantinKidneyFailure............................................................................25 TheRenin-Angiotensin-AldosteroneSystem(RAAS)—ATherapeuticTarget...................................................26 ClinicalTrialsandInvestigationalTherapies.......................................................................................27 ClinicalTrials—Overview...............................................................................................................................27 KidneyFailureClinicalTrials...........................................................................................................................28 InvestigationalTherapies...............................................................................................................................28 MedicalDeviceDevelopment............................................................................................................................29 PublicHealthMeasures......................................................................................................................31 PublicHealthInitiatives.................................................................................................................................31 ESRDNetworks..................................................................................................................................................31 HealthyPeople2020..........................................................................................................................................32 CKDSurveillanceSystem....................................................................................................................................32 CKDHealthEvaluationandRiskInformationSharing(CHERISH)......................................................................32 UnitedStatesRenalDataSystem(USRDS)........................................................................................................32 BarrierstoResearchProgressandKeyPhilanthropicOpportunities...................................................33 DiseaseAwarenessandWorkforceChallenges...................................................................................33 LackofDiseaseAwarenessandEducation.....................................................................................................33 KidneyDiseaseResearchWorkforceShortfall................................................................................................34 TransplantationandDialysisInnovationNeeds..................................................................................35 ScarcityofDonorOrgans...............................................................................................................................35 InadequateLong-termTransplantOutcomes.................................................................................................37 LackofInnovationinKidneyReplacementTherapy.......................................................................................37 LimitedDiseaseUnderstanding..........................................................................................................38 4 March2017 LackofMolecularDiseaseBiomarkers...........................................................................................................38 OperationalChallengestoConductingSuccessfulClinicalTrials.....................................................................39 KeyStakeholdersintheKidneyDiseaseCommunity...........................................................................41 Government..................................................................................................................................................41 DomesticResearchGrant-MakingOrganizations............................................................................................41 AmericanSocietyforNephrology(ASN)............................................................................................................42 AmericanUrologicalAssociation(AUA).............................................................................................................42 NationalKidneyFoundation(NKF)....................................................................................................................42 AmericanSocietyofTransplantation(AST).......................................................................................................43 CollaborativeInitiatives.....................................................................................................................43 GovernmentSponsoredPrograms.................................................................................................................43 AdvancedTissueBiofabricationManufacturingInnovationInstitute(ATB-MII)...............................................43 KidneyHealthInitiative(KHI).............................................................................................................................44 KidneyInteragencyCoordinatingCommittee(KICC).........................................................................................44 VeteransAdministrationNationalKidneyProgram...........................................................................................44 Consortia.......................................................................................................................................................45 BiologicalSupportforKidneyPatients(BioKid).................................................................................................45 ChronicKidneyDiseasePrognosisConsortium(CKD-PC)..................................................................................45 CKDBiomarkersConsortium(BioCon)...............................................................................................................45 (Re)BuildingaKidneyConsortium.....................................................................................................................45 SystemsBiologyTowardsNovelChronicKidneyDiseaseDiagnosisandTreatment(SysKid)...........................46 Glossary.............................................................................................................................................47 References.........................................................................................................................................49 5 March2017 PHILANTHROPISTS’FOREWORD FromthedeskofRobertandCynthiaCitrone WhenRob’sfatherwasfirstdiagnosedwithendstagerenaldisease(ESRD)weweredevastated.Howhorrificisa diseasethatisnamed“endstage?”Whereisthehope?IwatchedindespairasRobsprungtoactiontohelpand comforthisfather. Howcouldwenotbedonors?Howdothebestdoctorsintheworldnothaveaplan?Robhasbuilthissuccesson actionandidentifyingopportunities,yetthisprocesswasanexerciseinfutilityinthisnewESRDterrain.Itwasthen thatwefoundTheMilkenInstituteanditsCenterforStrategicPhilanthropy(CSP).Mike,Melissa,andtheentire CSPteamworkedwithustoinvestigatetheproblem,mobilizeourresources,anddevelopacalltoaction.Thanks totheInstitute,weareenthusedandinvigoratedtodedicateourtimeandresourcestomakeanimpactinthe ESRDfield.Withitsleadership,wearepoisedtogivehopebacktoourfatherandsomanyothers. FromthedeskofRobertL.Citrone Chronic kidney disease, end stage renal failure, hemodialysis, peritoneal dialysis, major life changes, endless medications and tests, possible transplant; this is the life of a patient with renal disease. Like so many diseases, renaldiseaseisnotdiscriminating;ithappenstoallpeoplefromallwalksoflife,youngandoldalike. When I was told that I would end up on dialysis within 6 to 12 months, I felt as though I had just been given a deathsentence.Life,asIknewit,wouldneverbethesameagain,formeormyfamily.Asdialysisoptionswere discussed, I made the decision to do hemodialysis. However, once home, I began to do my own research and, contrarytosomemembersofmymedicalteam,discoveredthathemodialysiswasnottherightoptionformeor mylifestyle. As a new peritoneal dialysis patient, with end stage renal failure, the focus then turned to the possibility of a kidney transplant. For me, this was one of the most heartbreaking and frustrating experiences of my life. Even thoughIamonawaitinglist,Ihavebasicallybeenprecludedbythegovernment’sguidelines.Ihavelearnedthat, forthemajorityoftransplantpatients,findingadonorfallsdirectlyontotheshouldersofthepatientandhisorher family.Throughtheprocessofseekingatransplant,Ihavediscoveredthatthereisareallackofknowledge,among thegeneralpopulationandeventhemedicalworld.Severalyearsago,Iidentifiedafewpotentialkidneydonors. However,thedonorsthemselvesweredissuadedfromdonating.Withbetterknowledge,theremayhavebeena differentoutcome. Weallliketothinkweareunique―thatourstoriesareoursalone.Butthatjustisn’ttrue.ThelongerIlivethelife ofarenalpatient,themoremylifeandstorybecomesintertwinedwithotherrenalpatientswhoIhavecometo know,whoarefightingforalongerandbetterlife.IoftenthinkoftheU.S.veteran,whoisseekingakidneydonor bypostinghispleaonthewindowsofhiscar.Thegrandmotherwhorefusestogothroughtherigorsofdialysis and dies much too young. The 41-year-old man who dies of cardiac arrest in his sleep. The young transplant womanwhoisgivenasecondchanceandgivesbirthtoahealthybaby.Theyoungathletewhoreceivedthegiftof life11yearsagofromhissister.The12-year-olddaughterwholostherbelovedfather.Orthehusbandwhojust losthiswifetokidneyfailure,butcontinueshisownbattlewiththedisease,evenifitmeanslosingvariouslimbs. Ihavesomanyquestions…Whyshouldsomanypeoplehavetodiesoyoungfromsuchadisease?Whymustitbe theresponsibilityofindividualstofindtheirowndonors?Whydoesn’tthegeneralpopulationandmedicalfield haveabetterawarenessofkidneydisease?Whyisn’ttherebetterdonorawareness?Whatwillhappenwhen,or if,thetransplantedkidneysfail?Whyaretherenospecificdrugsforrenaldisease?Whataboutartificialkidneys?Is itpossibletohaveabettertypeofdialysis?Andthelistgoesonandon.Thisisnotabattletofightalone. Andnow,wovenintoourstoryistheMilkenInstitute’sCenterforStrategicPhilanthropy.Inthenewchapterofour story, CSP has brought together the preeminent doctors and researchers in the renal disease field to discuss, 6 March2017 strategize, prioritize needs, and set goals. Meeting with this team of doctors and researchers, I once again discovered that I am not alone. They have the same questions and concerns. And how wonderful that, through theirwork,theyareseekingtoanswerthosequestions. AsyoureviewtheGivingSmarterGuide,youwillfindthatitisapowerfultooltoguideusaswegoforthtodefeat kidneydisease.Iinviteyoutojoinourstory.Astorywherehopeisbeginningtobeintertwinedintothepages.A storyofhopethatwillcontinueforgenerationstocome.Astoryofhopethatwillbringalongerandbetterlifefor renaldiseasepatients. RobertL.Citrone,March2017 7 March2017 EXECUTIVESUMMARY ThisGivingSmarterGuideistheculminationofayear-longefforttoidentifystrategicphilanthropicopportunities thatcanmovetheneedleonunmetneedsspecifictokidneyfailureresearchandtreatment.Kidneyfailureisan irreversiblediseaseinwhichthekidneyscannolongersupportlifeontheirown.Tolive,patientssufferingfrom kidneyfailuremustinitiatetreatmenttoreplacekidneyfunctionthroughdialysisorkidneytransplantation. AccordingtotheCentersforDiseaseControlandPrevention(CDC),morethan300peoplebegintreatmentfor kidneyfailureevery24hoursintheUnitedStates.Thequalityoflife(QOL)forthesepatientsisseverelyimpacted becausetheirlivesareforeverchanged. Approximately17percentofU.S.adultslivewithchronickidneydisease(CKD),themostcommonformofkidney diseasecharacterizedbyagraduallossinkidneyfunction.Nearly600,000CKDpatientshaveprogressedtoastate ofkidneyfailure,thefinalstageofCKD.ApersonlivingwithCKDmaynotbeawareofthediseaseuntilithas progressedtothepointofkidneyfailure.Thislackofawarenessisamajorbarrierwithseriousramificationsfor patienthealth,researchsupport,andcost. Thehealthcarecostsarestaggering.Inaggregate,Medicarespendsabout$30billionperyearforkidneyfailure patientcare—accountingforgreaterthan7percentofMedicarefee-for-servicespending.Asidefromthe economicburden,thisdiseasetakesanemotionaltollonpatientsandfamilies,astheynavigatetheirnewrealities ofademandingdialysistreatmentschedule,extremeresultantfatigue,aswellaslostwagesandhighout-ofpocketcosts. Althoughthefederalgovernmentprovidesnearly$600millioninCKD/kidneyfailureresearchfunding,itisless than2percentofcarecostsandwoefullydisproportionatetodiseaseprevalence.Thepharmaceuticalindustryhas facedseveraldrugdevelopmentchallenges,andtherehasneverbeenadrugdevelopedprimarilyforthe preventionofkidneyfailure.SeveralbarriersthatplaguetheCKD/kidneyfailurefieldcanbeclassifiedinthe followingcategories: • Lackofdiseaseawarenessandworkforcechallenges; • Lackofinnovationintransplantationanddialysisdelivery;and, • Limiteddiseaseunderstandingatthemolecularlevel. AtthebehestoftheCitronefamily,theMilkenInstituteCenterforStrategicPhilanthropyconvenedworldrenownedkidneyexpertsandstakeholderstoidentifytransformativeresearchandsystemsopportunitieswhere philanthropycouldaccelerateprogressintheCKD/kidneyfailurespace.Theprimaryopportunitiesareasfollows: • Channelingprivateinvestmenttospearheadpublicawarenesscampaignswouldbethefirststeptoraise thenationalprofileofthediseasestate,encouragepolicyreform,andattractfundingdollarsforresearch andimprovedtherapies—similartotheexperienceforotherhigh-profilediseases. • Privategivingcanalsotransformthekidneydiseaseandtransplantationworkforcebyendowingannual summitsandcreatingaglobalnetworkoffacultytonurturethefuturegenerationofresearchersand physician-scientists. • Philanthropicgivingcanmovetheneedleonorganscarcitybyfundinginnovativeeffortstoexpandaccess totransplantation,increaselivingkidneydonationrates,andstrategicallyinvestinartificialkidney development. • Thecatalyticpotentialofphilanthropycanfosteracultureshiftregardingkidneydisease,whereby patientsarebetterinformedandencouragedtoparticipateinclinicaltrials. 8 March2017 ThisGuidewasdevelopedwiththeexpresspurposeofempoweringpatients,supporters,andstakeholdersto makestrategic,informeddecisionswhendirectingtheirenergyandphilanthropicinvestmentsintoresearchand developmenteffortsalignedwiththeirinterests. OVERVIEW Chronickidneydisease(CKD)isaconditioncharacterizedbyagraduallossinkidneyfunction.Thelaststageof CKD,knownaskidneyfailure(orendstagerenaldisease[ESRD]),isanirreversiblediseaseinwhichthekidneysare nolongercapableofsupportingdailylife.About20millionAmericanadultsarelivingwithCKD,andmorethan 600,000haveprogressedtokidneyfailure,thefifthandfinalstageofCKD.Althoughthereareseveralpossible causesofkidneyfailure,highbloodsugar(diabetes)andhighbloodpressure(hypertension)aretheleading causes.Infact,approximatelyoneinthreeadultswithdiabetesandoneinfiveadultswithhypertensioncurrently haveCKD.EarlystagesofCKDareasymptomatic,andthereforeCKDpatientscanbeunawareoftheirstatus— leadingtoalargeproportionofpatientslearningoftheirkidneyfailureduringemergencysituations.Astartling statisticisthatgreaterthan50percentofalldialysispatientsendupreceivingdialysistreatmentduringan emergencyroomvisit,underscoringtheneedfordiseaseawarenessandearlydetection. Severalcomplicationsresultfromkidneyfailure,namelycardiovasculardisease(CVD)andcongestiveheartfailure (CHF),lowredbloodcellcount(anemia),andboneandmineraldisease.Treatmentofthesecomplicationstakesa severetollonqualityandlengthoflife. Treatmentoptionsforkidneyfailurepatientsarequitelimited.Thereisadireneedforinnovationindialysis deliveryandcare,aswellasincreasedaccesstokidneysfortransplantation.Dialysisiswidelyaccessibleinthe UnitedStatesbecauseitisaMedicare-coveredcondition,butdialysistreatmenthasnotimprovedsinceits developmentmorethan50yearsago,andmortalityratesremainabysmallyhigh.Kidneytransplantationisbyfar thebestoptionforkidneyfailurepatients,butdonororgansareinshortsupply.Consequently,preventing progressionofCKDtokidneyfailureisofparamountimportance,underscoringtheneedtodevelopnovel treatmentoptionsforCKD. SOCIETALIMPACTOFKIDNEYFAILURE POPULATIONBURDEN KidneydiseasesaretheninthleadingcauseofdeathintheUnitedStates.AccordingtotheCDC,morethan1in10 AmericansarecurrentlylivingwithCKD.Ofthose,morethan600,000peoplearelivingwithkidneyfailure. CKD/kidneyfailureismorecommoninpatientsaged60orolder,andthisat-riskpopulationisgrowingrapidly. Since2011,“BabyBoomers”(peoplebornbetween1946and1964),whocomprisemorethan20percentofthe totalU.S.population,begantoturnage65.TheU.S.CensusBureaureportsthatalloftheyoungestBabyBoomers willbeoverage65by2029.Whentheprevalenceofdiabetesandhighbloodpressureisconsidered,theoutlook becomesevenbleaker.Basedon2012statistics,nearly10percentoftheU.S.populationisdiabeticandnearly30 percentishypertensiveandthereforeatriskofdevelopingCKD/kidneyfailure. Furthermore,CKDandkidneyfailuredisproportionatelyaffecttheU.S.populationintermsofrace,ethnicity,and socioeconomicstatus(SES).BlackAmericansarethreetimesaslikelytodevelopkidneyfailureasWhite 9 March2017 Americans,andHispanicsare40percentmorelikelytodevelopkidneyfailurecomparedtonon-Hispanics. Similarly,lowSESisassociatedwithCKDincidence,progressiontokidneyfailure,andpoorhealthoutcomesand reducedaccesstoqualityhealthcare.Expertsstatethatlapsesincarequalityarestronglyassociatedwiththese disproportionaterates. AlthoughthisGuidewillfocusonU.S.incidenceofkidneyfailure,kidneydiseaseisaglobalhealthcrisis.According tothe2010GlobalBurdenofDiseasestudy,CKDranked18thinleadingcausesofdeathworldwide—upfrom27th inthe1990rankings.OnlyHIV/AIDShadalargerrankingchange.Accordingtoa2015reportinLancet,the estimated2.6millionpeoplewhoreceivekidneyreplacementtherapygloballyisprojectedtodoubleby2030. Alarmingly,onlyhalfofkidneyfailurepatientsaroundtheworldreceivelife-savingkidneyreplacementtherapy, effectivelymakingkidneyfailureadeathsentenceinmanycountries.Indeed,thereisworktobedonetostemthe tideofkidneydiseaseincidence. ECONOMICBURDEN Since1972,anyonewithkidneyfailure(regardless ofageorincome)wasgrantedMedicareeligibility tocoverthecostofdialysisorkidney transplantationservices.Kidneyfailurewas,and stillis,theonlymedicalconditiontoreceive universalcoverageunderthisgovernment program.Atthattime,onlyabout10,000U.S. patientswerereceiving;however,thisnumber swelledtomorethan450,000patientsin2013, accordingtodatacollectedbytheU.S.RenalData System(USRDS[seepage32]).Thisincreaseis Figure1.Medicarecostsforkidneyfailurepatients. significantbecausetreatmentforkidneyfailureis Perpersonperyearcostsofprevalentkidneyfailurepatients. costly.Oneyearofdialysistreatmentcosts Yearlycoststotreatapatientondialysisarenearlytriplethecosts totreatatransplantpatient. Medicare$69,000to$85,000,and1yearof transplant-associatedtreatmentcosts approximately$30,000(Figure1).Inaggregate,Medicarespendsabout$30billionperyearforkidneyfailure patientcare.Eventhoughkidneyfailurepatientscompriselessthan1percentofthetotalMedicarepopulation, theyaccountforgreaterthan7percentofMedicarefee-for-servicespending. Patientsandtheircaregiverssufferdirectfinancialstrain.Kidneyfailureoftenrenderspatientsunabletowork becauseoftheextremefatiguethatoftenaccompaniesdialysistreatment,whichtranslatesintolostwages,lossof lifetimeearningpotential,andlossofretirementsavingsandsecurity.Inaddition,kidneydiseasepatientsincur themostout-of-pocketexpensesofanyMedicarebeneficiary. Individualsthatdonateafunctionalkidneytoakidneyfailurepatientarenotexemptfromfinancialstrain. Althoughpublicorprivateinsurancemaycovertheirsurgery,kidneydonorswillincurtransportationandchildcare costs,aswellaslostincomeduetosurgeryandrecovery.Currently,livingdonorsdonothavejobprotectionunder theFamilyandMedicalLeaveAct(FMLA)duringthelongrecoveryprocess.Thesefinancialrisksdisincentivize kidneydonation,despitealtruisticintention,whichpartiallydrivestheshortageofkidneysdonors.Inturn,many patientshavenoalternativetodialysis,whichisnotonlythreetimesmoreexpensivethankidneytransplantation, butalsolimitsQOLandlifeexpectancy.Apolicychangethatprovidesbettersupportforlivingdonationwouldsave 10 March2017 thegovernmentanaverageof$60,000ayearforeverypatientthatreceivedakidneytransplantratherthan dialysistreatment,accordingtothe2013EconomicReporttothePresident. Astheprevalenceofat-riskindividualscontinuestorise,sotoowilltheimpendingcosts.Nowisthetimeto addressthesedifficultissuesbyidentifyingkeyunmetneedsthatimpederesearchprogressandtherapeutic innovationinCKD/kidneyfailure. POLICYANDREGULATORYINITIATIVES ThissectionwillprofileaseriesoflegislativeandregulatorymatterssignificanttotheCKD/kidneyfailure communitypertainingtoaccesstocare,qualityofcare,andmedicalresearch. LIVINGDONORPROTECTIONACTOF2016(H.R.4616,S.2584) RepresentativeNadler(D-NY), RepresentativeBurgess(R-TX),SenatorKirk (R-IL),andSenatorGillibrand(D-NY) introducedtheLivingDonorProtectionAct, whichseekstoprohibitinsurance companiesfromdenyingorlimitinglife, disability,andlong-termcareinsuranceto livingdonorsandfromcharginghigher premiumsafterdonations.ThebillalsoclarifiesthatlivingorgandonorsmayusetimegrantedthroughtheFamily andMedicalLeaveAct(FMLA)torecoverfromdonation. THECKDIMPROVEMENTINRESEARCHANDTREATMENTACTOF2015(H.R.1130,S.598) RepresentativesTomMarino(R-PA),John Lewis(D-GA)andPeterRoskam(R-IL)and SenatorsBenCardin(D-MD),MikeCrapo (R-ID),andBillNelson(D-FL)introduced theChronicKidneyDiseaseImprovement inResearchandTreatmentActof2015in February2015.Thebillseekstoimprove accesstoqualitycareforpatients, promoteeducationandawareness,and increaseefficiencyinbiomedicalresearch inCKD. Specifically,thebillaugmentsaccesstocarebyallowingindividualsunderage65withkidneyfailuretoenrollin MedicareAdvantageplans.Furthermore,itproposesanexpansionofpatientaccesstokidneydiseaseeducation programsandhomedialysistreatmentoptions.Thebillalsoproposesaplantomoreeffectivelymanageand coordinatebiomedicalresearchinkidneydisease. ThebillmandatedanassessmentofcurrentfederalfundinglevelsrelativetoCKDcareexpenditures,thefindings ofwhichwererecentlypublishedbytheU.S.GovernmentAccountabilityOffice(GAO-17-121).Thelegislationalso 11 March2017 mandatesafederalstudytobetterunderstandtheprogressionofkidneydiseaseandtreatmentofkidneyfailurein minoritypopulations. QUALITYINCENTIVEPROGRAM TheMedicareImprovementsforPatients andProvidersActof2008createdaQuality IncentiveProgram(QIP)forMedicare’s ESRDprogram.TheQIP,whichtookeffect in2012,aimstopromotehigh-quality servicesinoutpatientdialysiscare.TheQIP linksaportionoffacilities’MedicarereimbursementdirectlytoQIPperformancestandardsandthequalityofcare thatpatientsreceive.Forthosefacilitiesthatdonotmeetorexceedcertainstandards,theQIPreducespayments. 12 March2017 THEBASICS:THEKIDNEYSANDHOWTHEYWORK Kidneysarevitaltoeverydaylifebecausetheyarethecentralfiltrationsystemofthebody.Belowthebasicsof kidneyanatomyandfunctionareaddressedthroughaseriesofquestions: WHEREARETHEKIDNEYSLOCATED? Thekidneysaretwobean-shapedorganslocateddirectlyopposite eachotherontheleftandrightsideoftheupperabdominalarea pressedagainstthebackmuscles. Thekidneysareakeypartoftheurinarysystem.Figure2illustrates theurinarysystemcomponents: • Kidneys—Theseorgansfilterbloodandproduceurine. • Ureters—Thesetubescarryurinefromthekidneysto thebladder. Bladder—Thisholloworganstoresurinepriorto excretion. Urethra—Thistubeexpelsurine. • • Figure2.Theurinarysystem. Illustrationofthemale(left)andfemale(right) urinarysystem.Source:NationalInstitutefor DiabetesandDigestiveandKidneyDiseases (NIDDK). HOWDOTHEKIDNEYSWORK? Thekidney’sprimaryfunctionistofilterwasteproductsoutoftheblood. Wasteisgeneratedfromthechemicalreactionsthatareperformedincells alloverthebody.Thekidneyiscomposedofabout1millionfilteringunits, callednephrons.Thenephronconsistsoftwoparts: • Glomerulus—Thisisthefiltercomponentofthenephron.As bloodpassesthroughthisfilter,wasteproductsfromtheblood aretrappedandexcretedthroughtheurethrawhilebloodcells andotherlargemolecules(suchasproteins)areretained. • Tubule—Thistubeallowsforthereabsorptionofnecessary mineralsbackintothebloodandsendsexcessfluidandwasteto theureters. Figure3.Pathofbloodthroughthe kidney. Illustrationofakidneyshowingthevessels thatcarrybloodintoandoutofthekidney, aswellasurinetothebladder.Zoom-in:an illustrationofanephron,thekidney’s filteringunit.Source:NIDDK. 13 March2017 Thekidneyperformsotheressentialfunctionstomaintainthefollowing: • • • Bloodpressureandvolumebalance Bonehealthandmineralbalance Redbloodcellproduction BLOODPRESSUREANDVOLUMEBALANCE Healthykidneysmaintainfluidbalancebyremovingexcesswaterandsodiumfromtheblood.Whenthekidneys aredamaged,thebodyretainsfluidandswells,whichresultsinhighbloodpressure. Conversely,whenapersonexperiencesasuddendropinbloodpressureordecreasedbloodflowthroughthe kidney,suchasduringperiodsofdehydrationorhemorrhage,therenin-angiotensin-aldosteronesystem(RAAS)is activated.TheRAASisdiscussedingreaterdetailintheMolecularBiologyofDiseasesectiononpage26. BONEHEALTHANDMINERALBALANCE Phosphorus,calcium,andvitaminDarenecessaryforproperbonehealth.Thekidneysplayanactiverolein processingbothphosphorusandvitaminDtomaintainbonehealthandoverallmineralbalance.Thekidneys removeexcessphosphorusintheblood,whichcaninducecalciumleakagefromthebones,leavingthemweakand brittle. VitaminDhelpstomaintainproperlevelsofcalciumandphosphorusintheblood.Thekidneyplaysarolein convertingvitaminDintoitsactiveform(alsoknownasvitaminDmetabolism),whichhelpstocontroltheamount ofcalciumandphosphorusthatthebodycanabsorbfromingestedfood.Whenitsfunctioningiscompromised, thekidneylosesitsabilitytoactivatevitaminD,thusresultinginmineralimbalance. REDBLOODCELLPRODUCTION Redbloodcellsareproducedinthebonemarrowandareresponsibleforcarryingoxygentoalltissuesinthebody. Healthykidneysproducethehormoneerythropoietin(EPO),whichinducesredbloodcellproduction.Ahormone isachemicalproducedbythebodyandreleasedintothebloodtotriggerorregulateparticularbodyfunctions. KidneydamageleadstoalackofEPOproduction,resultinginanemia(aconditioncharacterizedbylowlevelsof redbloodcells).Anemiahaspervasiveeffectsthroughoutthebody,becauseeachorganreceiveslessthanthe amountofoxygenneededtoperformatoptimalcapacity. 14 March2017 CAUSALFACTORS,RISKFACTORS,ANDPREVENTION Severaldiseasesandconditionscanleadtokidneyfailure (Figure4);however,thetoptwocausesarediabetesand hypertension. Inaddition,thereareseveralriskfactorsassociatedwith developingCKD/kidneyfailure.Bothgeneralandgenetic riskfactorsareoutlinedindetailbelow. GENERALRISKFACTORS Generalriskfactorsincludebutarenotlimitedto: Figure4.Primarycausesofkidneyfailure. • Medicalconditions—Peoplelivingwithdiabetes, hypertension,otherkidneydiseases,and cardiovasculardiseaseareatincreasedriskof developingCKD/kidneyfailure. • Familyhistory—ThosewithafamilyhistoryofCKD/kidneyfailurearemorelikelytodevelopkidney failure. • Age—Theincidenceandprevalenceofkidneyfailureincreaseswithage.CKDismostprevalentinpatients age60orolder. • Sex—Menaremorelikelytodevelopkidneyfailurethanwomen. • Race—Blacks,Asians/PacificIslanders,andNativeAmericansaremorelikelytodevelopkidneyfailure thanWhites,atratiosof3:1,1.2:1,and1.2:1,respectively. • Ethnicity—Hispanicsare40percentmorelikelythannon-Hispanicstodevelopkidneyfailure. Kidneyfailureisthefinaloutcomeofseveralpossible incitingconditions. Source:MilkenInstituteCenterforStrategicPhilanthropy GENETICRISKFACTORS RecentdiscoveriesindicatethatpatientswhoexpressbothpossiblegeneticvariantsoftheapolipoproteinL1 (APOL1)gene—G1andG2—areatincreasedriskofdevelopingkidneyfailureduetohypertensionandother conditions. PREVENTION PreventingkidneyfailureissynonymouswithpreventingeitheronsetorprogressionofCKDbycontrollingthe diseasesorotherfactorsthatleadtoCKD: • Eatabalanceddiettocontrolbloodsugarandcholesterollevels,therebypreventingorcontrollingthe onsetofdiabetes,hypertension,andCVD. • Exercisetopreventorcontroltheonsetofdiabetes,hypertension,andCVD. • Stopsmokingtoavoiddevelopmentofatherosclerosis,whichcandecreasebloodflowtothekidneys leadingtosustained,increasedbloodpressure. 15 March2017 • Controlbloodsugartopreventcomplicationsfromdiabetes. • Maintainbloodpressurebelow130/80. Asignificantbarriertoeffectivepreventionisalackofearlydetection.Severalfactorscontributetothissituation, suchasagenerallackofawarenessbythepublicaboutCKDoritsdiagnosis,absenceofsymptomsthatpatients associatewithkidneydisease,andlimitedtestingstrategiestopredictanddetectdecliningkidneyfunction.The BarrierstoResearchProgressandKeyPhilanthropicOpportunitiessectiononpage33highlightswaysthat strategicphilanthropycouldhelpmovetheneedleonthispressingissue. SIGNSANDSYMPTOMSOFKIDNEYFAILURE ApersonlivingwithCKDmaynotbeawareofthepresenceofdiseaseuntilithasprogressedtothepointofkidney failure.Thisisbecauseapersoncanloseupto90percentofkidneyfunctionbeforefeelinganyspecificsymptoms. Table1liststhekidneys’functionsandthesymptomsthatresultwhenthekidneysfailtoperformthesefunctions. Table1.KidneyFunctionandSymptomsofKidneyFailure KidneyFunction SymptomsWhenKidneyFunctionFails Filterwasteproductsoutoftheblood Wasteproducts(toxins)accumulateintheblood, (Thisistheprimaryfunctionofthekidneys) possiblyleadingtothefollowingsymptoms: • Problemsurinating • Itchy,paleskin • Nauseaandvomiting Ifleftuntreated,toxinbuild-upcouldbefatal. Regulatebloodpressureandvolumebalance Failingkidneyslacktheabilitytoremoveextrafluid fromtheblood,possiblyleadingtothefollowing symptoms: • Cardiovasculardiseases • Swelling • Shortnessofbreath Maintainbonehealthandmineralbalance Failingkidneyslacktheabilitytoregulateproper mineralconcentrations,possiblyleadingtobonepain. Promoteredbloodcellproduction Failingkidneyslosetheirabilitytoproduceahormone necessarytomakeredbloodcells.Thispossiblyleads tothefollowingsymptoms: • Anemia • Fatigue 16 March2017 DIAGNOSIS Kidneyfailureiscurrentlydiagnosedbasedontheclinicalpresentationofproteinintheurine(knownas proteinuria)andthediminishedfiltrationcapacityofthekidneys,knownastheestimatedglomerularfiltrationrate (eGFR).Therefore,bothproteinuriaandeGFRarekidneydiseasebiomarkers.Abiomarkerisacharacteristicthatis objectivelymeasuredandevaluatedasanindicatorofdiseasestateortreatmentefficacy.Abiomarkercanbe detectedinbiofluids(e.g.,blood,urine)andtissues(e.g.,kidney,skin).Anephrologist(physicianwhospecializesin kidneydiseases)typicallydiagnoseskidneyfailureusingthefollowinglaboratorytests: • Urinealbuminorprotein—Thistestanalyzestheurineforthepresenceofprotein.Whenthekidneysare failing,theyareunabletoreabsorbproteinbackintocirculation,resultinginproteinspillingintothe urine.Albuminisaspecifictypeofprotein,andtheteststomeasureitsabundancearemoresensitivefor detectingkidneydisease. • Serumcreatininemeasurement—Thistestisusedtodetectevidenceofincreasedcreatinineintheblood. Creatinineisawasteby-productofmusclemetabolism.Healthykidneysfilteroutcreatininefromthe bloodintotheurine.Elevatedcreatininelevelssignalkidneydamage. o eGFRcalculation—eGFRiscalculatedusingserumcreatininelevelsandcertainformulasthat factorinotherriskfactorssuchasage,gender,andrace.TheeGFRcalculationisusedto determinethestageofCKDasillustratedinFigure5.ItisimportanttouseeGFR,ratherthanthe serumcreatininemeasurementinisolation,toenableearlydetectionofkidneydisease. o CystatinCmeasurement—ThistestisusedtodetectevidenceofincreasedcystatinCinthe blood.CystatinCisaninhibitorofaclassofproteinsthatbreakdownotherproteins(knownas proteases).Healthykidneysfilteroutcystatincfromthebloodintotheurine.Elevatedcystatinc levelssignalkidneydamageaswell.Incertaincircumstances,thecombinedmeasurementof creatinineandcystatinCcanimprovetheaccuracyofeGFRestimation. Figure5.eGFRmeterandstagesofCKD. Meter(left)andcorrespondingtable(right)illustratingeGFRnumbersthatdenotenormal,diseased,andfailedkidney conditions.ModifiedandadaptedfromNIDDK. Anephrologistmayalsoorderthefollowingsupportinglaboratorytests: • Bloodureanitrogen(BUN)measurement—Thistestisanindicatorofkidneyandliverhealth.Urea nitrogenformsafterproteinhasbeenbrokendown.Healthykidneysfilteroutureanitrogenthathas 17 March2017 traveledfromtheliver,intothebloodstreamandthroughthekidney.Higherthannormalcirculatingurea nitrogenlevelsmayindicatekidneydamage. • Bloodpressure—Elevatedbloodpressure,togetherwiththeotherkidneydamageindicatorslistedabove, supportthediagnosisofkidneyfailure. • Mineralpanel—Failingkidneyscanleadtohigherthannormalcirculatinglevelsofcalcium,phosphorus, andpotassium;therefore,abloodtesttodetectthesemineralscanhelptoassesskidneyhealth. • Hematocrit—Hematocritistheratioofredbloodcellstothetotalvolumeofblood.Alowhematocrit scoreindicatesdecreasedredbloodcellcontent—asignofanemia. • Hemoglobin—Thisistheoxygen-carryingproteinfoundinredbloodcells.Ifanemiaispresent, hemoglobincontentwillbelowerthannormal. • Kidneybiopsy—Insomecases,abiopsy(pieceoftissue)istakenforfurthermicroscopicexaminationto determinetheextentofkidneytissuedamageaswellasCKDstage.AtarecentNationalInstitutesof Health(NIH)workshop,thelackofkidneybiopsiesperformedwashighlightedasakeyunmetneedinthe field.Investigatorsunderscoredtheneedforincreased,standardizedkidneybiopsypracticestofuel researchanddevelopmenteffortsinthequestfortherapeuticinnovation. 18 March2017 TREATMENT Theonlytwotreatmentoptionsavailabletokidneyfailurepatientsaredialysisorkidneytransplantation.Although theuseofmedicationtocontrolbloodpressureand/orbloodsugarcanslowtheprogressionthroughCKDstages 1-4,thedamagetothekidneysispermanent.Nevertheless,thepatient’skidneyscanstillperformtheirkey functionstosupportliving.Ifthepatientprogressestokidneyfailure(CKDstage5),thekidneyscannolonger supportlifeontheirown. Althoughlifesaving,dialysisandtransplantationarefraughtwithchallenges.Regardingtheformer,thelackof innovationindialysiscareisalargeunmetneedforthekidneydiseasefield.Regardingthelatter,accesstodonor kidneysisextremelylimited,whichhasmotivatedtheWhiteHousetochampioneffortstoaddressthedonor organshortage.Bothtreatmentoptionsaredescribedbelow. DIALYSIS Dialysistreatmentinvolvestheuseofspecializedmachinerytofilterthebloodwhenthekidneyscannolongerdo so.Therearetwotypesofdialysis:hemodialysisandperitonealdialysis. HEMODIALYSIS Hemodialysistreatmentusesadialysismachinetocleanthetotal volumeofthepatient’sblood(Figure6).Thepatient’sbloodenters thedialysismachine,passesthroughthedialyzer(filterservingasthe artificialkidney)toremovewasteandexcessfluid,andthenre-enters circulationthroughavein.Arteriesandveinsaretwomajorblood vesselsinthebody.Arteriestakebloodawayfromtheheart,and veinstakebloodbacktotheheart.About1pint(0.125gallons)of bloodflowsthroughthedialysismachineperminute. Inpractice,therearetwomethodsofhemodialysisdelivery: • • In-centerdialysis—Thismethodtypicallyinvolvesreceiving dialysistreatmentinadialysiscenter.Treatmentis administeredthreetimesperweekforsessionslasting3to4 hourseach. Figure6.Depictionofhemodialysisprocess. Homedialysis—Thismethodinvolvesthepatientand/or Source:NIDDK. caregiveradministeringdialysistreatmentathome, followingthoroughtrainingsessions.Thisprocesscaninvolvesmaller,moreportablemachines. Hemodialysisisthemostcommonkidneyfailuretreatment.In2013,about88percentofnewlydiagnosedpatients weretreatedusingthismodality.Thesuccessofhemodialysisdependsonthesurgicallyplacedvascularaccess pointfromwhichthebloodleavesandreturnstothebody. 19 March2017 VASCULARACCESS Accessingthepatient’svascularsystemiscriticaltodialysisbecausethevascularsystemisresponsiblefor circulatingblood.Fordialysistooccur,themachine’stubesmustbeconnectedtothepatient’svasculature,which iscalledvascularaccess.Figure7illustratesthethreevascular accesspossibilitiesdiscussedbelow: • Arteriovenous(AV)fistula—Thissurgicalprocedure createsadirectconnectionbetweenanarteryandveinin theforearm.Thisproceduremustbeperformed2to3 monthsinadvanceofusebecausetheAVfistulaneeds timetodevelop.TheAVfistulaisdesignedforlong-term use,typicallylastingseveralyears.Thisisthegold standardforvascularaccess;howeveronly17percentof patientsinitiatedialysiswithanAVfistuladuetovarious contributingfactors(e.g.,age,vascularhealth). • Arteriovenous(AV)graft―Thistubeissurgicallyinserted undertheskinandconnectsanarterytoaveininthe forearm.Thisproceduremustalsobeperformedin advance,about2to3weeks,ofuse.Duringdialysis,this tubingispuncturedtoconnectthemachinerytothe vascularsystem.TheAVgraftisalsodesignedforlongtermuse,typicallylastingabout2to3years.Thismethod isusedwhenapatientisnotagoodcandidateforanAV fistulaorwhenanAVfistulafails. • Venouscatheter―Thisflexibletubeissurgicallyinserted intoaveinintheneck,chest,orlegnearthegroin.The venouscatheterisavailableforuseuponinsertion; however,itisonlyintendedforshort-termuse(2weeks toamonth).Avenouscatheter istypicallyusedinemergency situationsorwhenkidney diseasehasprogressedmore rapidlythanexpected. 20 March2017 Figure7.Vascularaccessoptions. Depictionsofvascularaccessoptions,showingcommonplacementlocationson thebody.AdaptedfromNIDDK. PERITONEALDIALYSIS Peritonealdialysisusestheliningofthepatient’sabdomen(theperitoneum)asthefilterforthepatient’sblood. ThisprocessisillustratedinFigure8: • Thepatient’sabdominalcavityisfilledwithasalineandglucose solution,orthedialysate. • Wasteproductsandexcessfluidareabsorbedfromtheblood intothedialysateafterabout4to6hours,whichisthedwell time. • Theuseddialysateisdrainedandthestomachisre-filledwith freshdialysate;thisexchangetypicallytakes30-40minutesto complete. Figure8.Peritonealdialysis. Mostpatientstypicallycompletefourtosixexchangesdaily.With Source:NIDDK. continuousambulatoryperitonealdialysis(CAPD),theexchangeis performedmanually.Withperitonealdialysisprocess,amachine(cycler)automaticallyperformsthreetofive exchangeswhilethepatientsleeps.Thisisknownasautomatedperitonealdialysis(APD).Peritonealdialysisisnot ascommonashemodialysis.In2013,amere9percentofnewlydiagnosedkidneyfailurepatientsweretreated withthismodality.PatientsreportthatCAPDandAPDallowforgreaterflexibilityandindependence. COMPLICATIONSASSOCIATEDWITHDIALYSISTREATMENT Dialysisisalifesavingtherapy,inthatkidneyfailurewouldbefatalwithoutthisintervention.Nevertheless,itisa verylimitedmaintenancetherapy.Theyearlymortalityrateisunacceptablyhighat15-20percent.Thesurvival ratefordialysispatientsisshockinglylow―approximately55percentofhemodialysispatientsand66percentof peritonealdialysispatientsarestilllivingafter3yearsoftreatment.Thedialysistreatmentparadigmhasimproved onlymodestlyover30years,andthereforeinnovationisdesperatelyneededtobenefitpatients. Severalcomplicationscanarisewithdialysis—allofwhichsignificantlyimpactQOL.AVgraftsandcathetersare pronetodevelopingbloodclotsandinfection,leadingtohospitalizationevents.Othercomplicationsinclude narrowingofbloodvessels,increasedbloodpressure,andlossofpropercirculationtothearmsandlegs(extreme casescanresultinamputation).AVfistulasarelesspronetobutnotexemptfromthesecomplications. Asstatedabove,severalsecondaryhealthconditionsaccompanykidneyfailure,namelyanemia,boneandmineral disease,andCVD.Consequently,patientsmustundergotreatmentforthosediseasesinadditiontotheirdialysis treatment.Dialysispatientsusuallytakemanydifferentmedicationstoovercomethesesecondaryconditions: erythropoietin-stimulatingagents(ESA)thatboostredbloodcellproduction,intravenous(IV)irontosupport oxygenbindingtoredbloodcells,activatedformsofvitaminD,bloodpressurepills,anddrugsthatbind phosphorusinfoodtoreducetoxicmineralbuildupinthebody.Somepatientssufferingfromanemiaalsoundergo bloodtransfusions;howeverthistreatmentcanposechallengesforfuturetransplanteligibilitybecauseof potentialover-sensitization(seeBarriersAssociatedwithKidneyTransplantationsectionbelowonpage23). 21 March2017 BARRIERSASSOCIATEDWITHDIALYSISTREATMENT Kidneyfailuretreatmentexistsatthenexusofmedicine,clinicalresearch,policy,andeconomicswherethereare competinginterestsandincentivestocatalyzechangeandrealizemuchneededprogress.Forexample,challenges existwiththedeliveryandfrequencyofhemodialysistreatment.Scientificevidenceindicatesthatpatientsfare betterwhentheyundergomorethanthreedialysissessionsperweek(whichisthecurrentin-centerregimen). Patientsmayreceivemorefrequentdialysis,buttheymustpayforextrasessionsoutofpocketbecauseMedicare willonlyreimburseforthecurrentregimen.Becausethesepatientsalreadyincurthehighestamountofout-ofpocketcostsofallMedicarebeneficiaries,extrasessionsarelikelycostprohibitivefortheclearmajorityofthem. KIDNEYTRANSPLANTATION Asmentionedpreviously,thebesttreatmentoptionforeligiblepatientswithkidneyfailureiskidney transplantation.Kidneytransplantationresultsinincreasedlifeexpectancy,QOL,andcostsavingsforbothpatients andtaxpayers.However,becauseofthescarcityofavailabledonorkidneys,lessthan30percentofkidneyfailure patientsreceiveatransplant. Twotypesofdonorsprovidekidneysfortransplantation: • Alivingkidneydonordonatesonefunctionalkidneywhilestillalive.Humanscanlivewithonefunctional kidney. • Adeceasedkidneydonorhaselectedtohavehisorherorgan(s)donatedupondeath. Uponsuccessfulkidneytransplantation,thepatientmustremainonimmunosuppressivedrugsaslongasthe transplantisworkingtoensurethattheimmunesystemdoesnotattackthekidneyasforeigntissue. ORGANTRANSPLANTWAITLIST KidneysarethemosttransplantedorganintheUnitedStates. Theorgantransplantwaitlist,managedbytheUnitedNetwork forOrganSharing(UNOS),isdividedinto11geographicregions andisusedtodetermineorganallocationthroughoutthe country.Eligiblekidneyfailurepatientscanelecttobeplaced onthiswaitlistandbenotifiedonceakidneybecomesavailable forwhichtheyareeligible.Justover15percentofallkidney failurepatients(nearly87,000asof2013)arelistedforakidney Figure9.UNOSregions. transplant. TheU.S.isdividedinto11geographicregions.Source: HRSA. TheKidneyAllocationSystem(KAS)guidesorganallocation throughtheUnitedStates.Severalfactors(medicalandnon-medical)weighintotheallocationofeverydonated organ,suchasbloodtype,donor/recipientimmunesystemcompatibility,priorlivingdonorstatus,lengthoftime onwaitlist,distancefromdonorhospital,survivalbenefit,andpediatricstatus. TwocentralchangesemergedfromsignificantmodificationoftheKASin2015: • • Kidneydonorsandrecipientsarenowprofiledusingadifferentscoringsystem,and Theconceptoflongevitymatchingofkidneystotransplantrecipientswasintroduced. 22 March2017 DeceaseddonorsareassignedascorecalledtheKidneyDonorProfileIndex(KDPI).Thisnumericalmeasure combines10donorfactorsintoasinglenumber―asopposedtofourfactorsusingtheprevioussystem—thereby makingitabetterpredictorofdonorquality.Everyadultpatientonthekidneywaitlistisassignedascorecalled theEstimatedPostTransplantSurvival(EPTS).KDPIsummarizesintoasinglenumberthequalityofdeceased donorkidneysrelativetootherrecoveredkidneys.KDPIisnowusedfortheimplementationofthe“longevity matching,”inwhichcandidateswithlongerestimatedpost-transplantlongevity(EPTSscoreof20percentorless) willreceivepriorityforkidneysfromdonorswithKDPIof20percent. COMPLICATIONSASSOCIATEDWITHKIDNEYTRANSPLANTATION Kidneytransplantationis,byfar,thebestavailable optiontokidneyfailurepatients.In2012,theprobability ofsurvivalwithin1yearpost-transplantwas95and98 percentfordeceasedandlivingdonorkidneytransplant recipients,respectively.Furthermore,theremaininglife expectancyofkidneytransplantrecipientsages65-69is nearlytriplethatofdialysispatientsasillustratedin Figure10.However,twomajorcomplicationsstillexist withtransplantation:thepossibilityoforganrejection andinfection.Fortheperiod2005-2008,survivalofthe transplantedkidney(calledagraft)at10years(about Figure10.Expectedremaininglifetimeofkidneyfailure 34-48percent)wasmuchlowerthansurvivalat1year patientsvs.generalU.S.population,bytreatment. Thisgraphillustratestheremaininglifetime,inyears,ofkidney (89-91percent),whichincreasesthelikelihoodofrefailurepatientsages65-69bytreatmentmodalityofprevalent transplantationordialysis.Infact,greaterthan20 dialysispatients,prevalenttransplantpatients,andthegeneral percentoftransplantrecipientsreturntodialysisafter U.S.population(2012),basedonUSRDSdataandtheNational 10years.Theimmunosuppressivedrugsthattransplant VitalStatisticsReport(2013). recipientsmusttakefortheirremaininglifetimecanleavethepatientsusceptibletoinfectionsandcertainkindsof cancer.Philanthropycouldplayaroleineffortstoimprovetransplanttherapeutics. BARRIERSASSOCIATEDWITHKIDNEYTRANSPLANTATION Arecord17,878kidneysweretransplantedin2015;however,thisnumberpalesincomparisontothenumberof patientsawaitingatransplant.Eachday,144peopleareaddedtotheorganwaitlistand22peoplediewhile waitingforalifesavingtransplant.Forkidneyfailurepatients,mortalityonthetransplantlistisdirectlyrelatedto timeondialysis.Severalchallengesplaguethekidneytransplantationfield,suchasthefollowing: • Lackoflivingdonors—Althoughlivingdonationiswidelyacceptedbythepublic,andseveralsurveys suggestthat50-90percentofpeoplearewillingtodonatetheirkidneytoafamilymemberorstranger, thisdoesnotnecessarilytranslateintoorgansdonated.In2013,about5,000peopledonatedtheirkidney, whichwaslessthanone-thirdofallkidneystransplanted.Giventhattransplantrecipientsfarebetterwith livingdonorkidneys,measurestofacilitatelivingdonationareneeded. • Patientsensitization—About30percentoftransplantpatientsaresensitized,whichaffectsaccessto transplantation.Sensitizationmeansthatthepatienthasdevelopedproteinsthatwillattackforeign tissue,likeatransplantedorgan.Theseproteinscandevelopthroughpreviousexposuretoforeigntissue types,suchasthroughbloodtransfusions,pregnancy,orpreviousorgantransplants.AccordingtoJohns 23 March2017 HopkinsMedicine,sensitizedpatientsmaywaitthreetofourtimeslongerthanunsensitizedpatientsfora compatibledonorkidney. • Lackofaccessduetoracial,ethnic,SES,andgeographicdisparities—Asmentionedabove,CKD disproportionatelyaffectsracialandethnicminoritiesaswellasindividualswithlowSES.Likewise,these individualshavelessaccesstotransplantationoverall,arelesslikelytobeaddedtothewaitlist,and experienceincreasedriskoftransplantedorganfailure.Inaddition,whereoneliveshasaprofoundeffect ontransplantaccess. • Limitedpreservationcapacity—Currently,akidneycanbepreservedforamaximumof24-48hours. Innovativesolutionstoincreasetheorganpreservationtimewouldexpandaccesstoavailableorgans. • Lackofalternativetissueoptions—Kidneytransplantationiscurrentlylimitedtoorgansprovidedby people;however,bioengineeredcellsandtissuewouldgreatlyexpandgraftoptions. • Highdiscardrates—Someofthe2,700kidneysdiscardedin2015organscouldhaveprovidedbenefitsto dialysispatients.Overall,thediscardrateremainsatabout20percent. Asthenumberofpatientsinneedofakidneytransplantcontinuestorisedisproportionatelytothenumberof donorkidneysavailable,breakthroughsinresearchanddevelopmentaresorelyneeded.Thisisanareawhere strategicphilanthropicinvestmentcouldhavesignificantimpact—tosupportinnovationintransplanttherapeutics, organpreservation,aswellasbioengineeringofartificialcellsandtissues,whichmayonedaybeablereplace damagedkidneytissue. Organtransplantationisanationalpriority.ThemonthofAprilwasdeclaredNationalDonateLifemonthby presidentialorderin2015.OnJune13,2016,theMilkenInstituteCenterforStrategicPhilanthropyattendedthe WhiteHouseOrganSummit,whichfocusednationalattentiononthecurrentplightoforgandonationand transplantationintheUnitedStates,aswellasfacilitatednewinitiatives,collaborations,andpartnershipsto aggressivelyreducetheorganwaitlist.Thereistremendousopportunityforphilanthropytoleveragethisnational attentionandmomentumtocatalyzechangebysupportinginnovativesolutionsthatreducethewaitlistand researcheffortsthatexploreinnovativealternativestoconventionalkidneytransplants. 24 March2017 MOLECULARBIOLOGYOFDISEASE Surprisinglylittleisknownaboutwhatcauseskidneyfailureatamolecularlevel.Assuch,targetedtherapiesare currentlynonexistent.ThereisaclearneedtoidentifyandaddressthechallengestoresearchprogressinCKDand kidneyfailure.Despitetheapparentdearthofknowledge,oneofthebiggestbreakthroughsinkidneydisease biologyexistsatthelevelofgenetics. APOL1—AKEYGENETICRISKDETERMINANTINKIDNEYFAILURE Therearetwocopiesofeachgeneinthe body(exceptforthegenesthat determinesex)—referredtoasalleles. Genescodeforproteins,whichinturn carryoutcellularfunctions.TheAPOL1 genecodesfortheproteinapolipoprotein L1,acomponentofhighdensity lipoprotein(HDL,the“good”cholesterol). ApolipoproteinL1isalsofoundinkidney Figure11.APOL1riskvariantsandpatternofexpression. cells.ThetwogeneticvariantsofAPOL1,G1 Source:MilkenInstituteCenterforStrategicPhilanthropy andG2,areassociatedwithrisktokidney health.Recentscientificevidenceindicatesthatapersonwhoexpressesonecopyofeithervariantalleleisatan increasedriskofdevelopingoneofseveralkidneydiseases,includingkidneyfailure.Furthermore,apersonwho expressestwocopiesofeithervariantalleleisatanevenhigherrisk,nearlyseventoeightfold,ofprogressing rapidlytokidneyfailure(non-diabetic,hypertension-associatedtype).Figure11conceptualizestheAPOL1risk variantsandtherelativeriskassociatedwiththeirexpression. SeveralexpertshavepostulatedthatthesegeneticriskvariantspartiallyexplaintheracialdisparitybetweenBlacks andWhitesbecausetheG1andG2variantsaremostcommoninpopulationsofrecentAfricanancestryandoccur veryrarelyinotherpopulations.Thefieldisworkingtounderstandthisphenomenonatamechanisticlevelto understandexactlyhowthesevariantscontributetokidneydisease.Inarecentarticlepublishedinthe ProceedingsoftheNationalAcademyofSciences,Olabisiandcolleaguesdescribeapotentialmechanismforhow APOL1genevariantscausetoxicitywithinthecell,eventuallyleadingtocelldeath.TheydemonstratethatAPOL1 riskvariantsoveractivatecertainproteinsthatareknowntomediatekidneyinjury.Thisandotherfuture discoveriesmayprovidethefieldwithpotentialtherapeutictargetsforfutureresearchanddevelopmentefforts. Thescienceunderlyingkidneyfailureisunfolding;however,controversyandunansweredquestionsremain despitethisintensestudy.Ina2013articleintheJournalofClinicalInvestigation,FriedmanandPollakhighlight that,althoughtherelativeriskofdevelopingkidneyfailureissignificantlyhigherinAPOL1riskvariantcarriers, theirpresenceisnotsufficienttocausedisease.Itishighlylikelythatothergeneticandenvironmental contributorsmodifytheexpressionoftheAPOL1riskvariantprofile.Kidneyfailureisacomplexdiseasecausedby amyriadofconditionsthataffecttotalbodymetabolism.Therefore,itislikelythatothermolecularand environmentalfactorscontributetothisdisease.Itisextremelydifficulttoisolatecausalmolecularinteractions withsomanycomorbidities.However,identificationofAPOL1riskvariantsrepresentsthegreatestmolecular discoveryinthefieldtodate. 25 March2017 THERENIN-ANGIOTENSIN-ALDOSTERONESYSTEM(RAAS)—ATHERAPEUTICTARGET TheRAASisahormonesystemthatregulatesbloodpressure,fluidvolume,andsodiumcontentinthebodyas illustratedinFigure12.Thekidneysproducereninandangiotensin-convertingenzyme(ACE),proteinsthat catalyzecomplexbiologicalreactions(enzymes).ReninandACEdrivethecreationofangiotensinI,II,and aldosteroneinthebody.Together,angiotensinIIandaldosteroneworktoraisebloodvolume,bloodpressure,and sodiumlevelsinthebloodtorestorethebalanceofsodium,potassium,andfluids.However,chronic overactivationoftheRAAScanleadtohypertension.BlockadeoftheRAASslowstheprogressionofproteinuriaassociatedkidneydisease.TheseimportantmoleculesintheRAASrepresenttherapeutictargetsofcurrentlyused drugs(suchasACEinhibitorsandangiotensinIIreceptorblockers[ARBs])andexperimentaldrugsinclinicaltrials. Figure12.Therenin-angiotensin-aldosteronesystem(RAAS). Reninandangiotensin-convertingenzyme(ACE)aretwokeyproteinsthataresecretedfromthekidneytodrivealdosterone secretion.Aberrant,chronicoveractivationofthissystemcanleadtohighbloodpressureandotherdeleteriouseffects.Drugs commonlyusedtotargetthissystem,suchasACEinhibitorsandARBs,areoftenusedtotreatCKD.Imagemodifiedfrom WikimediaCommons. 26 March2017 CLINICALTRIALSANDINVESTIGATIONALTHERAPIES CLINICALTRIALS—OVERVIEW Clinicalresearch(alsoreferredtoasclinicaldevelopment)isabranchofbiomedicalresearchinvolvinghuman subjects.Thegoalofclinicalresearchistoevaluatethesafetyandefficacyofdrugs,medicaldevices,ordiagnostics intendedforuseinhumanpatients. Clinicaltrialsareanimportantcomponentofclinicalresearchbecausetheyareusedtoevaluatethesafetyand efficacyofanexperimentaldrugortherapyinhumansubjects.Clinicaltrialsaredividedintophasesasdescribedin Figure13.Theycanalsobeusedtocollectspecimensfromhumansubjectsforfurtherresearch.Importantly, informationonpotentialsideeffectsaregatheredduringtheclinicaltrialperiodandweighedagainstthepotential therapeuticbenefitofthetreatmentunderinvestigation. Theresearchanddevelopment(R&D)process—theprocessbywhichalaboratorydiscoveryisdevelopedintoa commercialtherapeutic,diagnosticordevice—isverycostlyandtime-intensive.Itisestimatedthat95percentof newdrugstestedinclinicaltrialsfailtomakeitintotheclinic.Thisisahighfailurerateforaprocessthatcosts about$1billioninoverallresearchcostsandupto15yearsoftimeinvested. Figure13.Phasesofclinicaltrials. DuringPhaseI,researcherstestanewdrugortreatmentforthefirsttimeinasmallgroupofpeopletoevaluateits safety,determineasafedoserange,andidentifypotentialsideeffects.DuringPhaseII,proof-of-conceptstudiesare performedasthedrugortreatmentisgiventoalargergroupofpeopletodeterminetheeffectiveandoptimaldose. DuringPhaseIII,thedrugortreatmentisgiventolargegroupsofpeopletoconfirmitseffectiveness,monitorside effects,andassessitsimpactcomparedtothecurrentstandardofcare.Someclinicaltrialsinvolvemultiplephasesto facilitateseamlesstransitionfromonetoanotherandarewrittenasPhaseI/IIorPhaseII/III.Thesedesignationsarealso usedinadaptivetrials,whereinstudyparametersaremodifiedwithrespecttoongoingtrialresults.Imagecourtesyof Dr.JasonLuke,UniversityofChicagoSchoolofMedicine. 27 March2017 KIDNEYFAILURECLINICALTRIALS AsofJuly2016,thereare90activeinterventionalclinicaltrialsforkidneyfailure.Figure14illustratesthe distributionofthesetrialsbyphase. Kidneyfailureclinicaltrialsareexpensiveandinherently riskyforseveralreasons: • Timeneededtocompleteastudy—Large patientpopulations,oftennumberinginthe thousands,needtobefollowedforlongperiods oftimetocapturespecificeffectsabove conventionaltherapy. • Lackofreliablebiomarkerstopredictadverse safetyevents—Investmentsinclinicaltrials couldbemoreappropriatelyallocatedifthere wasareliablewaytopredictsafety.According toexperts,toomanylargetrialshavefailed becauseofaninabilitytopredictdrugsafety. • Figure14.Interventionalclinicaltrialsforkidney failure. Ofthe90active,interventionalclinicaltrials,25(28%)arein Phase3.Dataobtainedfromwww.clinicaltrials.gov.Source: MilkenInstituteCenterforStrategicPhilanthropy Heterogeneousnatureofthedisease—Severaldiseasepathsleadtokidneyfailure,whichinturnleadsto remarkableheterogeneityinthepresentationofCKDpatients.However,theprobabilityofsuccesswould increaseiftherewereareliablewaytoidentifyandselectivelyenrollCKDpatientswhoarelikelyto progresstokidneyfailure(i.e.,“strongprogressors”).Patientheterogeneitycanhavenegativeeffectson studyresults.Testingauniformgroupofpatientswouldpreventdilutionoftreatmenteffectandenable fastrecognitionofeffectivetreatments.Thisissuehighlightstheneedforbetterpatientstratificationto ensurethatinvestigationaltreatmentsareappliedtotherightpatients. Despitethemyriadofchallenges,therearenumerousopportunitiesforimprovementinthekidneydiseasefield. Philanthropyisuniquelypoisedtode-riskkidneydiseaseresearcheffortsandtherebyattractindustryinvestment tospuradvances.Furthermore,strategicinvestmentincriticalresourcesandinfrastructurewillallowfor accelerationofpromisingsciencefrombasicresearch,throughthecriticaltranslationalresearchphase,andinto clinicaldevelopment. INVESTIGATIONALTHERAPIES Theclinicaldevelopmentlandscapeisincrediblybarrenbecauseofthepaucityofclinicallyrelevantmoleculesto targettherapeutically.Mostdrugsweredevelopedtotreatotherconditions,suchashypertensionanddiabetes, andadoptedtotreatkidneydisease.Furthermore,thevastmajorityofkidneyfailureclinicaltrialstesttreatments ofthecomplicationsassociatedwithkidneyfailureandoptimizationofdialysisandtransplanttherapeutics. Thedevelopmentofnewdrugsforkidneyfailurepresentssomeinterestingeconomicchallengesaswell.Medicare reimbursesthecostofdrugsasabundledpayment,definedasareimbursementtohealthcareproviders“onthe basisofexpectedcostsforclinically-definedepisodesofcare.”Therefore,thereisincentiveforapharmaceutical companytohaveitsdrugcoveredwithinthebundledpaymentsystemtorealizeanyappreciableprofits.However, thestakestogetanewdrugcoveredinthebundledpaymentarehigh—thedrugmusthavedemonstratedefficacy 28 March2017 thatfarexceedsthosefordrugsalreadycovered.Therefore,thishighbarrierofentrymaydisincentivize companiesfrominnovatingandcreatingnewtherapeutics. ThevaluepropositionneedstobemodifiedtoaligninterestsinsearchofbettertherapeuticstoimproveQOLfor patients.Strategicphilanthropicinvestmentisuniquelypoisedtoaddressthesechallengesbecauseitisnimble enoughtorespondtodynamicchangeswithinthekidneydiseasespace. Giventhelackofinnovationinpharmaceuticalclinicaldevelopment,thesectionsbelowprovidetheconceptual frameworkforafewnewmedicaldevicesindevelopmentaswellashighlightkeyinitiativespresentedatthe WhiteHouseOrganSummitthathavepotentialforhighimpact. MEDICALDEVICEDEVELOPMENT Belowareprofilesofdevicesthataimtoimprovedialysisoptionsbyaddingdesiredfeatures(e.g.,portability)or resolvingvascularaccesscomplications(e.g.,decreasingclotformation). WEARABLEARTIFICIALKIDNEY PROTOTYPEINDEVELOPMENT Standarddialysisgenerallyinvolvesattachingpatientstoanimmovabledialysismachine(eitherathomeorina clinic)forsessionsthatrangefrom3to4hours.Standardpracticerecommendsdialysisthreetimesperweek.New researchsuggeststhatdailydialysisresultsinaconsiderableimprovementinQOL,resultingin: • Substantialreductionincomplicationssuchasanemia,hypertension,electrolyteabnormalities,andacid buildupinthebody • Attenuationoftheneedforadditionalmedication totreattheaforementionedcomplications • Fewerhospitalizations • Fewerdietandfluidrestrictions • Increasedappetite Awearableartificialkidney(WAK)device,whichwould allowfordailydialysis,iscurrentlyindevelopmentandhas passedanU.S.FoodandDrugAdministration(FDA)approvedproof-of-conceptclinicaltrialinvolvingseven patients.TheFDAselectedtheWAKforafast-track approvalprogramin2012.Thepresentprototype(Figure) isa10-pounddevice,poweredby9Vbatteriesandworn aroundthewaist.TheWAKprototypeisbeingredesigned todecreasethesizeandimproveefficiencyandwill undergoadditionalsafetytesting. Figure14.Wearableartificialkidney(WAK). Left:Illustration(Source).Right:Personwearingthe prototype(Source). TransitiontoadailydialysismodelusingaWAKdevicecouldleadtoimprovedpatientmobilityandpsychological well-beinginadditiontothebenefitslistedabove.TheWAKwouldprovideapromisingtreatmentoption,inthe faceoflowavailabilityofkidneysfortransplantation,usheringinafundamentalshiftincaredelivery.Apartfrom theclearmedicalbenefits,thispromisingtechnologystandstosubstantiallydecreasetheeconomicburdenof dialysistreatmentbyreducingthenumberofhospitalizationevents. 29 March2017 IMPLANTABLEBIOARTIFICIALKIDNEY—THEKIDNEYPROJECT PROTOTYPEINDEVELOPMENT Currently,thebesttreatmentoptionforkidneyfailureiskidney transplantation;however,becauseofthelimitedavailabilityofkidney donors,lessthan30percentofkidneyfailurepatientsreceiveatransplant. Asthenumberofpatientsinneedofakidneytransplantcontinuestorise disproportionatelytothenumberofdonorkidneysavailable,thereisa tremendousneedforanalternativemedicalsolution. Theimplantablebioartificialkidneyrepresentsapromisingalternativeto conventionalkidneytransplantsthat: Figure15.Implantablebioartificial kidney. Source:UCSF. • Addressestheorganscarcityissue • Eliminatestheneedforconventionaldialysis • Couldattenuatetheneedforlifelongimmunosuppressiontherapy thatisrequiredforconventionaltransplantstoensurethatthebodydoesnotrejectthekidney Thisprototypedeviceisdesignedtoconnectdirectlytothepatient’sbloodsupplyandbladder(theotherkey componentsofthebody’swasteremovalsystem),nearthenaturalkidneys,whichwillnotberemoved(see depictioninFigure15).Usingnovelsiliconnanofiltersandlivingkidneycells,thedeviceisdesignedtooperate basedonthepatient’sbloodpressurealone,withouttheneedforapumporanelectricalpowersource. GovernmentandprivatesourceshavefundedtheKidneyProjectsinceitsinception.Recently,theNational InstitutesofHealth(NIH)awardedtheprojectwitha4-year,$6milliongrant.TheFDAalsoselectedtheKidney Projectforafast-trackapprovalprogramin2012.Ifsuccessfulthisdevicecoulddramaticallychangeandsavethe livesofmillionsofpatientsandcouldbecomeanintegralpartofthekidneycaresetting—similartothepacemaker inthecardiologycaresetting. HEMOACCESSVALVESYSTEM®(HVS) PROTOTYPEINDEVELOPMENT Asdiscussedabove,accesstothepatient’svascularsystemiscriticaltodialysis becausethevascularsystemisresponsibleforpumpingblood.Fordialysistooccur, themachine’stubesmustbeconnectedtothepatient’svasculature. AVgraftsarefraughtwithcomplicationsinadditiontoinfectionandbloodclotting, suchasnarrowingofbloodvessels,increasedbloodpressure,andlossofproper circulationtothearmsandlegs(extremecasescanresultinamputation).These complicationsaredueinlargeparttocontinuousbloodflowthroughthegraft. However,bloodflowthroughagraftisonlyneededfordialysispurposes,whichis,at most,12hoursperweek,asopposedto24hoursaday. LimitingbloodflowthroughanAVgrafttoonlythetimeswhenneededfordialysis Figure16.Hemoaccess ValveSystem®. treatmentcanbenefitthepatientbyextendingthelifeofthebloodvesselsnearthe Source. graftsiteandpreventingveincollapseatthepatient’sprimaryaccesspointfor dialysis.TheHVSindevelopment(Figure16)allowsforselectivebloodflowcontrol throughanAVgraftonlywhenneededfordialysisandthenturnsoffthebloodflowtothegraftbetweendialysis 30 March2017 sessions.TheHVSwasalsoselectedbytheFDAforafast-trackapprovalprogramin2012andiscurrentlyinclinical trials. TISSUE-ENGINEEREDVASCULARGRAFT—HUMAGRAFT™ PROTOTYPEINDEVELOPMENT TherepetitivecomplicationsassociatedwithAVgraftsresult inincreasedhospitalizationeventsanddecreasedoverall QOL.ThesyntheticmaterialsusedtomakeAVgrafts,suchas Teflon®orpolytetrafluoroethylene(PTFE),areoftenblamed fortherepetitiveinfectionsassociatedwithtraditionalAV grafts.Useofahumantissueplatformcouldeliminatethe Figure17.HumaGraft™. adversereactiontosyntheticmaterialsbutcouldintroduce Source:Humacyte. issueswithtissuematching.HumaGraft™isahuman bioengineeredbloodvesselthatcoulddeliveratissue-basedgraftthatdoesnotrequiretissuematching,resulting inthefollowing: • Longergraftlife • Lowriskofinfectionandbloodclots • Lowriskofadverseimmuneresponses TheHumaGraft™prototypeisabioengineeredveincomposedofhumansmoothmusclecells(Figure17),which aredecellularizedtoreduceimmunogenicityandeliminatetheneedfortissuematching.Thesebioengineered veinsdemonstratedexcellentbloodflowandresistancetobloodclotsinearlylabtesting,andtheycouldbe refrigeratedforupto12months—makingthemviableforlong-termstorageathospitals.TheHumaGraft™was selectedforfast-trackapprovalstatusbytheFDAin2014andiscurrentlyinPhaseIIIclinicaltrials. PUBLICHEALTHMEASURES PUBLICHEALTHINITIATIVES InresponsetothesubstantialimpactofCKDandkidneyfailureonhealth,QOL,andhealthcarecosts,avarietyof publichealthinitiativesareinplacetohelpreducetheprevalenceofCKDandkidneyfailureintheU.S.population andpromoteaccesstoqualitycare. ESRDNETWORKS TheESRDNetworksoftheCentersforMedicare&MedicaidServices(CMS)werecreatedbystatutorymandatein 1978toimprovecost-effectiveness,ensurequalityofcare,encouragekidneytransplantationandhomedialysis, provideassistancetoESRDbeneficiariesandproviders,andincreaseESRDNetworkProgramaccountability. In2015,theCMSawarded$110millioninESRDNetworkfundingto7ofthe18ESRDNetworks.These7entities willworkovera5-yearcontractperiodtocontinueeffortstoimprovequalityofcareandaccesstocarefor individualswithirreversiblekidneydiseasewhorequiredialysisortransplantationtosustainlife. 31 March2017 HEALTHYPEOPLE2020 HealthyPeopleisanationalprogramtoprovidescience-based,10-yearnationalobjectivesforimprovingthe healthofallAmericans.Thisprogramhasbeeninplacefor30years,withthemostrecentlaunchin2010. CKDclaims14objectivesinthisambitiousprogram,oneofwhichisspecificallydedicatedtoreducingdeathsin personswithESRD(objectiveCKD-14).Theinitiativeseekstoaccomplishthisobjectivebyreducingthe: • • • • • Totalnumberofdeathsforpersonsondialysis Numberofdeathsindialysispatientswithinthefirst3monthsofinitiationofrenalreplacementtherapy Numberofcardiovasculardeathsforpersonsondialysis Totalnumberofdeathsforpersonswithafunctionalkidneytransplant Numberofcardiovasculardeathsinpersonswithafunctionalkidneytransplant CKDSURVEILLANCESYSTEM IncollaborationwiththeUniversityofCaliforniaatSanFranciscoandtheUniversityofMichigan,theCDC implementedthenationalCKDSurveillanceSystem.Thesystemtracksnationaltrendsinthenumberofcases,risk factors,andcarepracticesthataffectCKDpreventionandcontrol,evaluatequalityimprovementefforts,and monitorkidneydiseaseobjectivesforHealthyPeople2020(describedabove).Systematicmonitoringwouldinform effortstoprevent,detect,andmanageCKDanditscomplications.Thesedataalsoinformevaluationsofthe efficacyandimpactofvariousgovernmentqualityimprovementprograms. OrganizationsinvolvedinthiseffortincludeUniversityofCaliforniaatSanFrancisco,theUniversityofMichigan, AmericanAssociationofKidneyPatients(AAKP),AmericanAssociationofPediatricNephrology(AAPN),National KidneyDiseaseEducationProgram(NKDEP),NationalKidneyFund(NKF),Veteran’sHealthAssociation(VHA) NationalProgram,MedicalEducationInstitute,andtheAmericanSocietyofNephrology(ASN). CKDHEALTHEVALUATIONANDRISKINFORMATIONSHARING(CHERISH) IncollaborationwithNKF,theCDCestablishedCHERISHtoidentifyindividualsathighriskforCKD,assessthe participant’saccesstofollow-upcare,andexaminediseaseprogressioninthosewithCKD. UsingnationaldatasetssuchastheUnitedStatesRenalDataSystem(describedbelow),theCDCstudiesthe epidemiologyofCKDintheU.S.population.Underthisprogram,theCDCalsocollaborateswiththeVHAtostudy healthoutcomesandthenationalhistoryofCKDamongvarioussubsetsofthepopulation. UNITEDSTATESRENALDATASYSTEM(USRDS) TheUSRDSisanationaldatasystemthatcollects,analyzes,anddistributesinformationaboutESRDintheUnited States.TheUSRDSisfundeddirectlybytheNIDDK.USRDSstaffcollaboratewithmembersofCMS,UNOS,andthe ESRDnetworksbysharingdatasetsandactivelyworkingtoimprovetheaccuracyofESRDpatientinformation. 32 March2017 BARRIERSTORESEARCHPROGRESSANDKEYPHILANTHROPICOPPORTUNITIES InOctober2016,theMilkenInstituteCenterforStrategicPhilanthropyconvenedworld-renownedkidneyexperts todiscussthestateofsciencerelevanttoCKDandkidneyfailure,aswellasthechallengescurrentlyimpeding progresstowardimprovedtherapeuticsandcare.Theultimategoaloftheretreatwastoidentifyhigh-impact researchandsystemsopportunitieswherephilanthropicinvestmentscouldaccelerateprogressintheCKD/kidney failurespace. Keychallengeareasincludethefollowing: DISEASEAWARENESSAND TRANSPLANTATIONANDDIALYSIS LIMITEDDISEASEUNDERSTANDING WORKFORCECHALLENGES INNOVATIONNEEDS Lackofdiseaseawarenessand Scarcityofdonororgans Lackofmoleculardiseasebiomarkers educationbyphysicians,systems, andpatients Kidneydiseaseresearchworkforce Inadequatelong-termtransplant Operationalchallengestoconducting shortfall outcomes successfulclinicaltrials Lackofinnovationinkidney replacementtherapy Thesectionsbelowdiscusseachofthekeychallengesalongwithpotentialsolutionsandcorresponding philanthropicopportunitiestoaddressthesechallengesandaccelerateresearchprogress.Pleasenotethatthese opportunitiesarehigh-levelrepresentationsandshouldbeconsideredcarefullywithrespecttoyourphilanthropic goalsanddiscussedindetailwithaphilanthropicadvisor. DISEASEAWARENESSANDWORKFORCECHALLENGES LACKOFDISEASEAWARENESSANDEDUCATION THEPROBLEM MostpatientsarenotdiagnosedwithCKDuntilthediseasereachesadvancedstages(kidneyfailure),even thoughrelativelysimpleteststodetectearlierstagesofkidneydiseaseexist(e.g.,measuringcreatininelevelsin thebloodtoestimateGFRand/oralbuminlevelsintheurine).Thisproblempartiallyresultsfromagenerallackof awarenessoftheimportanceofmonitoringkidneyhealthbecauseoftheasymptomaticnatureofCKD.Many patientswithCKDriskfactorsmaynotbescreenedatearlystagesofCKDwhenprogressionmaybeslowedor prevented,orreferredinatimelymannertospecialtycare.Insomecases,patientsmayhavehadkidneytests performed(seetheDiagnosissectiononpage17);however,thephysicianorpatientmaybeunaware.Thelackof awarenessandinequitiesineducationdisempowerpatientsaswellasproviders,resultinginalackofengagement andsuboptimalQOL. PROPOSEDSOLUTIONSTOADDRESSTHECHALLENGE FacilitatingeffortstoeducatethepubliconCKDriskfactors,diseasecourse,earlydiagnosis,andavailable treatmentoptionswouldencourageashiftfrombeingreactivetoproactiveaboutCKDdiagnosisandtreatment. Likewise,providingprimarycarephysicians(PCPs)withthetoolstoproactivelymonitorkidneyhealthandeducate patientswillfurtherencourageashift,therebyempoweringbothpatientsandproviders. 33 March2017 CORRESPONDINGPHILANTHROPICOPPORTUNITIES • Fundtargetedpublicawarenesscampaigns—RaisingawarenessofCKD/kidneyfailureisthefirststep towardraisingthenationalprofileofthediseasestate,whichfuelspolicyreformandattractsfunding dollarsforresearchandtherapeuticdevelopment.Variousdiseasecommunities(e.g.,heartdisease, HIV/AIDS,diabetes,cancer)havesuccessfullyimplementedthislessonandofferseveralexamplesand lessonslearnedfromwhichthekidneydiseasecommunitycanbenefit.Withevolvingsocialmediaand gamingtechnologies,thesecampaignscouldutilizenovelapproachestopromoteawareness. • Engagepatientstoadvocateforimproved,patient-centeredservicesatallstagesofCKD—analogousto otherhigh-profilediseases(e.g.,HIV/AIDS,breastcancer,diabetes,ALS)—Increasingpatient engagementandadvocacyisthesecondsteptowardraisingthenationalprofileofthediseasestate. Again,therearekeylessonstobelearnedfromdiseasecommunitiesthathaverobustadvocacy programs.Intentionallyengagingdisproportionatelyaffectedminoritygroups,asothersuccessful communitieshavedone,isanecessarystepforward.Inaddition,successfullyengagingpatientsmay requireuseofmoreaccessibleterms(e.g.,useof“kidney”ratherthan“renal”)aswellastermsthatcarry lessstigma(e.g.,useof“kidneyfailure”ratherthan“endstagerenaldisease”). • Supportbioinformaticsinfrastructurethatwillenableinnovativeuseofelectronicmedicalrecords (EMRs)—EMRscontainvaluable,extractableinformationthatcanbeutilizedtocreatetoolsforearly detectionofkidneydiseaseandidentifypatientsatincreasedriskforkidneyfailure.Leveragingofthis wealthofdatawouldprovideaninvaluabletoolforproviders.However,lackofEMRdatabase interoperabilityacrosshospitalsandthelackofbioinformaticstoolstoeasilyandeffectivelymineEMR dataposechallengestosuccessfuldataaggregation,harmonization,andstandardization.Fundingan infrastructureplatformtoaddressthesechallengeswouldfacilitatecreation,evaluation,and disseminationofnewCKDdecisionaidsforproviders,eveninlow-resourcesettings. • Supportaresourcedevelopmentconsortium—Toavoidduplicativeeffortsandtobetterutilizeexisting resources,thisconsortiumwouldbechargedwithstandardizinganddisseminatingexistingeducational toolsfortrainees,providers,insurers,andpatients.Thisprocessofresourcedevelopmentwouldclarify treatmentoptionsandclinicaltrialapplicabilitybasedonpatientneeds.Likewise,itwouldencourage earlierdiscoursebetweenpatientsandproviders,allowingformoreinformeddecision-making. KIDNEYDISEASERESEARCHWORKFORCESHORTFALL THEPROBLEM ThegrowthofthenephrologyworkforcehasnotkeptpacewiththeglobalincidenceofCKD/ESRD.Aconfluence offactorsdisincentivizephysiciansandscientistsfrompursuinganephrologyspecialty,includingbutnotlimitedto itsperceiveddifficulty,lackofinnovationintreatmentparadigms,polarizingpayerandpolicydynamics(thatare perceivedtostiflecreativity),andalackofinterestfromthepharmaceuticalandbiotechindustries.Despitethe complexnatureofthediseaseandecosystemdynamics,anewinfluxofideaswouldcreatetheinnovativeculture necessarytomovethefieldforward. 34 March2017 PROPOSEDSOLUTIONSTOADDRESSTHECHALLENGE Investmentinhumancapitalthatwillfosteracultureofinnovation,facilitatenewideasandknowledgesharing, collaborateinresearchactivity,andimprovecarepracticesisdesperatelyneededtopropelthefieldforward. Togethertheseoutcomescanlaythegroundworkforthedevelopmentofnewtreatments.Thiscultureshiftwould alsoencourageotherstakeholderstoinvestinthefieldasinnovativesolutionsbegintobearfruit. CORRESPONDINGPHILANTHROPICOPPORTUNITIES • EndowanannualKidneyDiseaseSummit—Establishinganannualsummitofleadingmultidisciplinary expertstocreateavisionforfuturerenaltherapieswouldfacilitatemorecross-talkwithinthevarious nephrologycommunities(e.g.,dialysis,transplantation,basicandtranslationalscience,R&D),outline criticalpathsforthefield,andgalvanizethecommunitytodevelopinnovativesolutions. • Endowanetworkofprofessorshipsinkidneydiseaseandtransplantinnovation—Thisglobalnetworkof facultywouldusetheseendowedprofessorshipstofocusonmentorshipandnovelkidneydiseaseor transplantresearch.Abuilt-inmentorshipcomponentwouldfostercommunity-buildingandcareer developmentforjuniorfaculty,thuspreparingthemtoserveasfutureleadersandmentors. • Fundtrainingfellowshipsinkidneydiseasetoattractphysician-scientists—Grantstosupportfellowship stipendsorprovidebridgefundingforyounginvestigatorswouldencouragethemtoenterandcontinue workinginthenephrologyspace. TRANSPLANTATIONANDDIALYSISINNOVATIONNEEDS SCARCITYOFDONORORGANS THEPROBLEM Kidneytransplantationis,byfar,thebestavailabletreatmentforkidneyfailure.Notonlydoestransplantation correlatewithbettersurvivalratesandimprovedQOLcomparedtodialysis,butalsoitreducescostsforinsurance providers.Despitetheseobviousbenefits,severallimitationshinderinnovationinkidneytransplantation(listedin detailintheBarriersAssociatedwithKidneyTransplantationsectiononpage23).Keybarriersinclude: • Accesstotransplant—Multifactorialandsystemicissuescontributetodisparitiesintransplantaccess, suchaslowSES,race,ethnicity,andgeographiclocation. • Barrierstolivingdonation—Thereareapproximately100,000ESRDpatientsonthetransplantwaitlist, butonlyabout6,000livedonortransplantsperyear.Livingdonorscouldhelpfilltheorganshortagegap. Barrierstodonationincludebiologicalincompatibilitiesofdonorswiththeirintendedrecipient,financial burdensofdonation,andconcernfordonorhealthrisks. • Variablehigh-riskprotocolsacrossclinics—Greatstrideshavebeenmadeindesensitizationprotocols, whichallowforsuccessfultransplantsofpreviouslyincompatiblekidneydonor-recipientmatches, therebyexpandingtransplantoptions.However,theseproceduresvaryfromclinictoclinic,whichleadsto variablesuccessrates. 35 March2017 PROPOSEDSOLUTIONSTOADDRESSTHECHALLENGE Fundinginnovative,nontraditionaleffortstoexpandaccesstotransplantation,increaselivingkidneydonation,and investinartificialkidneydevelopmentcouldaddresstheorganscarcityissue.Thepotentialforshort-andlongtermgainsexistbecausearangeofmechanismsareavailabletoaddressthischallenge.Inaddition,improved transplantoutcomescanbeachievedbystandardizingthedesensitizationprotocols.Thisstandardizationcanlead tomoreefficientoutcomestrackingandsupportiterativeprotocolimprovement,therebyreducingthedisparities insuccessratesacrosscentersnationwide. CORRESPONDINGPHILANTHROPICOPPORTUNTIIES • Fundstart-upcostsforacentralizednationalkidneyexchangeprogram—Kidneypaireddonation programsfacilitateexchangesbetweenincompatibledonor-recipientpairs.Theseeffortsarecurrently decentralized,whichcanleadtodifferentkidney-exchangechainscompetingforpotentialdonors, therebydecreasingthedonorpool.Centralizingthekidneyexchangeplatformwouldhelpmaximizethe numberofswapsthatcouldbemadewithinagivenchain. • Fundstart-upcostsforalivingdonorregistry—Thecreationofadata-rich,technologicallyadvancedlive donorregistrywouldinformunderstandingofthelong-termrisksandoutcomesassociatedwithkidney donationandwouldfacilitateearlyrecognitionandinterventionswhenadonorisatincreasedriskfor kidneyfailure.Currenttrackingsystemslacktherobustnesstofacilitatethedesiredlevelofdetection, analysis,andengagement. • Fundapilotprogramthatcoverslostwagesandotheruncompensatedexpensesforlivingdonors— Althoughtravel,lodging,anddiningexpensesmaybecoveredforprospectivelivedonorsunderthe government-fundedprogramcalledNationalLivingDonorsAssistanceCenter(NLDAC),thisprogramis limitedtopatientswhoqualifybasedonincomecriteriaforboththedonorcandidateandtheintended recipient.Financialburdens,includinglostwages,remainanimportantdisincentivetoexpandinglive kidneydonation.Pilotstudiestestingthishypothesiswouldprovidethecost-benefitanalysisto substantiateincreasedfundingfortheNLDACprogramorestablishsimilarprogramsthroughnonprofit foundations. • Fundwidedisseminationofnoveldonorengagementprograms—Socialmediaappshaveemergedasa creativetooltoengagepotentialkidneydonors;however,theseappsareoftendecentralizedandusually confinedtoonetransplantcenter.Supportforwidespreaddisseminationandadoptioncouldhavea substantialimpactbyfacilitatingdonorengagement,sharingeducation,andemphasizingtheneedfor livingdonation. • Supportthedevelopmentofamasterdesensitizationprotocoltoimprovedonorcompatibility—The developmentofamasterprotocolwouldacceleratedisseminationofproceduresamongtransplant centers,promotehighersuccessratesnationwide,andprovideaplatformtofosterdevelopmentof futureimprovedprotocols. • Investinresearchanddevelopmentofbioartificialkidneys—Thereisgreatpromiseinafuturewhen bioengineeredkidneytissueand/ororgansareaviablereality,becausetheywouldlessentherelianceon donatedkidneys,attenuatetheneedforlifelongimmunosuppressiontherapy,andeliminatetheneedfor conventionaldialysis.Thisworkremainsintheearlystagesofdevelopment,sophilanthropiccapital wouldacceleratethetimelineandspurinnovationinthisspace. 36 March2017 INADEQUATELONG-TERMTRANSPLANTOUTCOMES THEPROBLEM Althoughthe1-yeartransplantsuccessrateisabout90percent,the10-yearsuccessrateismuchlowerat34-48 percent.Severalfactorscontributetothisdisparity,includingthechallengeofappropriatetailoringof immunosuppressiontomaintainefficacyandreducemorbidity,andthefinancialburdensfortransplantrecipients post-procedure.Overall,immunosuppressionislargelyadministeredina“one-sizefitsallapproach,”suchthat somepatientsfaceriskofrejectionandimmunologicalgraftloss,whileotherssuffercomplicationsofoverimmunosuppression(e.g.,infection,cancer).Novelapproachesareneededtoidentifymarkersfortransplantsthat are“atrisk,”tobetterpersonalizeimmunosuppressiontoavoidirreversibleinjuryandexcessimmunosuppression. Furthermore,formanypatients,Medicarepaysforimmunosuppressionmedicationsforonlythefirst3years,after whichpatientsmustpayforthemedicationsoutofpocket.Thisfinancialburdencancausepatientstodiscontinue theirmedicationsortakethemconsistently,whichdramaticallycompromiseslong-termsuccessratesfor transplantpatients.Overall,measurestoaddresstheseandsimilarfactorsmaybolsterlong-termsuccessrates. PROPOSEDSOLUTIONSTOADDRESSTHECHALLENGE Betterlong-termtransplantoutcomeswouldleadtoimprovedQOLfortransplantrecipientsandoverallsavingsto thehealthcaresystem—potentiallymorethantheestimated$50,000costsavingsoftransplantoverdialysis. Pilotinglong-termimmunosuppressionsupportprogramsthatarehypothesizedtoincreaselong-termsuccess rateswouldprovidetheneededevidencetoattractCongressionalsupport. CORRESPONDINGPHILANTHROPICOPPORTUNITIES • Supportapilotstudyassessingthecost-benefitanalysisforextendedtolerancemedicationscoverage— Payerscurrentlycovertolerancemedicationsforonly3yearspost-transplant.Thisstudywould investigatewhetherlong-termcoveragedoesinfactincreaselong-termgraftsurvivalandreducethe overallcostofcare(asareturntodialysistreatmentisacostlyprocedure).Suchevidencewouldinform payersandprovidesupportforexpandedcoverageoptions. • Supportexplorationofnewmarkersof“at-risk”organtransplantsbeforeirreversibleinjury—Serum creatinineiscrudemarkeroftransplantedorganfunction;however,itisnotsensitivetosubtleorgan injury,whichcanleadtochronicrejection.Supportingthedevelopmentofnewbiomarkersforearly rejectionmayfacilitatebetterimmunosuppressionpersonalizationtomaintainefficacyandreduce morbidity. LACKOFINNOVATIONINKIDNEYREPLACEMENTTHERAPY THEPROBLEM Dialysistreatmentisindireneedofinnovationasthetechnologyhasnotimprovedsignificantlyoverthepast thirtyyears.Althoughdialysisisalife-savingoptionintheshort-term,ithasnegativelong-termimpactwithan annualmortalityrateof15-20percent.Treatmentdeliveryandvenousaccessaretwomainchallengeareastobe addressed. 37 March2017 • Treatmentdelivery–Standardhemodialysisgenerallyinvolvespatientsbeingattachedtoanimmovable dialysismachine(eitherinaclinicorathome)forsessionsthatrangebetween3-4hours,threetimesper week.Thispracticeoftenleavespatientstootiredtolivefullyproductive,independentlives.Research suggeststhatmorefrequentdialysismaybebeneficialtopatients,howeverthisisimpracticalwithinthe currentparadigm. • Venousaccess–Achievinglong-termvascularaccess(e.g.fistulaorgraft)iscentraltohemodialysis, howevertheprimaryfailureratesleaveseveralpatientsusingshort-termalternatives(e.g.centralvenous catheters[CVCs]).Prolongeduseofshort-termvenousaccessoptionsleadtocomplications,suchas infectionandhospitalization,whichcompromisesuccessfuldialysistreatment. POTENTIALSOLUTIONSTOADDRESSTHECHALLENGE Deviceinnovationtosupportmorefrequentambulatorydialysisandlong-termvenousaccesspatencywould drasticallyimprovedialysistreatment.Further,fosteringacommunityforinnovationwouldprovidethe momentumnecessarytobringnovel,boldideastofruition. CORRESPONDINGPHILANTHROPICOPPORTUNITIES • EndowanannualKidneyReplacementSummit—Effortstoradicallyre-imagineandre-inventdialysis machineryandconceiveofcompletelynovelalternativeswillrequirecollaborationacrossdisparate disciplines(e.g.,nephrology,bioengineering,cellbiology).Anannualsummitspecificallydedicatedtothis purposewillprovidethespacetocreateavisionandencouragecreativityforrevolutionizingrenal replacementtherapy. • Funddevicedevelopment—Supportingeffortsto(1)buildatechnologically-advancedwearableor implantabledialysisunit(seePrizeChallengeopportunityco-developedbytheAmericanSocietyof NephrologyandXPrize)or(2)developnovelvenousaccesstechnologieswouldexpandoptionsfor patients.Inadditiontoaddingportability,theseadvancementscouldallowfordailybloodfilteringand possiblylowertheyearlymortalityrate.Lastly,supportingeffortsto(3)developremotemedical monitoringdevicesdesignedtoallowreal-timedialysismonitoring,targetedadjustmentstotreatments, andreal-timeupdatestoEMRs.Thisadvancementwouldempowerpatientstobemoreinformedabout theircareandfacilitatediscussionswithcareproviders. LIMITEDDISEASEUNDERSTANDING LACKOFMOLECULARDISEASEBIOMARKERS THEPROBLEM Currentlythekidneydiseasefieldlackstissue-basedmolecularbiomarkerstodiagnosedisease,predictdisease progressiontokidneyfailure,ortracktreatmentefficacy.Thisapparentlackseverelyhamperseffortstodevelop newdrugs.Thefieldlacksthemeasurestotestwhetherthedrugisengagingitsintendedtargetorhavingthe desiredeffect,whichultimatelycontributestothehighcostandfailureofclinicaltrials.Thisbiomarkerchallenge is,inpart,duetoinsufficientmechanisticunderstandingofCKDprogressiontokidneyfailure.Tofurther complicatethislandscape,thefieldlacksthetoolstostudykidneydiseaseinvivo,makingitdifficulttodevelop imagingbiomarkersorvisualizeputativebiomarkerlocalization. 38 March2017 PROPOSEDSOLUTIONSTOADDRESSTHECHALLENGE Promotingteamsciencewillbeacentralcomponenttosupportingnovelbiomarkerdiscoveryeffortsastheskills necessarytoaddressthisheterogeneousdiseaserequiresamulti-disciplinaryandmulti-stakeholdereffortto increaseefficiencyandavoidduplication. CORRESPONDINGPHILANTHROPICOPPORTUNITIES • Fundacentralizeddataexchangeplatform—Thiswouldbeago-toresourceplatform,whichhousesEMR data,patient-reporteddata,aswellasbiofluidsandtissuesconducivetolarge-scaleanalysis.Ideally,this platformwouldlinktoanationalpatientregistry(describedinthenextsection).Suchaplatformwould facilitateefficientdatasharingaswellasenrichbasic,translationalandclinicalresearchwithitswealthof biologicalandclinicalpatientdata. • Fundconsortiachargedwithdevelopingaregulatorypathtowardsbiomarkerregistration—Oncea biomarkerhasbeenproposedwithinthekidneycommunity,aregulatorypathneedstobeoutlinedto assessthevalidityandutilityofthesebiomarkersforclinicalpractice.Provingaroadmapthatoutlinesthe processwouldhelpdisseminatetheincorporationofnewbiomarkersasbest-practicesthroughoutthe community. OPERATIONALCHALLENGESTOCONDUCTINGSUCCESSFULCLINICALTRIALS THEPROBLEM Therehasneverbeenadrugdevelopedprimarilyforthepreventionofkidneyfailure.Weneedtherapiestostop peoplewithkidneydiseasefromworseningandbeingrequiredtostartdialysis.Pharmaceuticalcompanies expendmorethantheentireNIHbudgetindrugdevelopmentbuthavelargelyignoredkidneydisease.Major companieswhichhavetentativelyventuredintodevelopingCKDtreatmentsoftenquicklyexitduetoboth scientificandoperationalchallenges.Thesechallengesinclude,identifyingpatientswhoareunawarethatthey havethediseaseandencouragingparticipationfromcaregiverswhomayhaveafatalisticviewthatthediseasewill inevitablyprogresstodialysis.RecruitmentratesforCKDarelessthan20-40percentofthoseforothermajor diseaseslikediabetes,heartdiseaseandAlzheimer’s.Thisresultsinlengthy,overlycostlytrialsyielding underpoweredresultsduetothesmallertargetenrollmentsizes.Inconcertwithawarenesseffortsoutlinedinthe firstsectionofthisdocument,theCKDpatientcommunitycanbemobilizedtomoreactivelyseekouttrialstesting newtherapies.Opportunitiestosurmountthesebarrierswouldsignificantlyde-riskindustryinvestmentto developnewtherapeuticoptionsandhelpleveragetheirsubstantialresourcesforbringingtherapeuticstothe market. POTENTIALSOLUTIONSTOADDRESSTHECHALLENGE Fosteringacultureofpatientandproviderengagementcoulddramaticallyimproveclinicaltrialparticipation. Successfulexamplestobeemulatedcanbeseeninvariousdiseasecommunitiessuchascancer,HIV/AIDS,and musculardystrophy.Intandem,creatingaglobalclinicaltrialsnetworkwouldexpandthepatientpoolavailablefor recruitmentandbuildcapacityformoreefficientclinicaltrialpractices. CORRESPONDINGPHILANTHROPICOPPORTUNITIES 39 March2017 • Fundthecreationofanationaland/orinternationalCKDpatientregistry—Patientregistriesinform naturalhistorystudies,assistinclinicaltrialrecruitment,facilitatesafetymonitoring,encouragepatient participationinresearchandcanserveasasiteforpatienteducationresources.Linkingeachpatient’s anonymizedhealthrecordtotheregistrywouldprovideacriticalnewcapabilityfordoctorstobetter understandthespectrumofkidneydiseaseprogress.Sucharegistrycouldenablereal-timefeedbackto supportevidence-basedguidelinesforqualitycareandhousetrialreadycohortsandhealthsystems. EstablishingaCKDregistrycouldalsobetterconnecttheCKDpatientcommunitywithcaregiversand policymakerstohaveavoiceinkidneyresearchandcare. • Supportadministrativecoststofacilitateaglobalclinicaltrialsnetwork—Aslowclinicaltrialenrollment rateshaveresultedinterminatedorinconclusivetrials,leveragingtheglobalcommunityforpatient enrollmentcouldspeeduptheenrollmentprocessandreducecostsforaclinicaltrial.Inthisnetwork, enrolledacademicandnon-academicclinicalcenterswouldbeabletoconductdifferenttrialsatthesame time.Supportingacentralcoordinatingcenterforpatientrecruitmentthatwouldallowmultiple internationalcenterstointeractwouldbekeytofacilitatingthisprocess. • Fundapatient-reportedoutcomes(PRO)consortia—Supportingtheconsortiabyfacilitatingpatientand professionalmeetingstospurdevelopmentandvalidationofPROsfordialysisandtransplantationwould encouragePROinclusioninregulatoryassessmentsforfuturetherapeuticoptions. 40 March2017 KEYSTAKEHOLDERSINTHEKIDNEYDISEASECOMMUNITY GOVERNMENT Federalagenciesandfederally-mandatedinstitutesarethelargestfundersofCKD/kidneyfailure-relatedresearch, totalingmorethan$580Minaggregate(FY2015).Table2displaysfederalagencieswhoseresearchexpensesmeet orexceed$500KandFigureXprovidesavisualoverviewoffederalactivitysurroundingCKD/kidneyfailure. Table2.FederalFundingforKidneyDiseaseResearchforFY2015 AgencyorInstitute Research Total Expenses Budget NationalInstitutesofHealth(NIH) DepartmentofVeteransAffairs $564M $20.9M $30B $163.9B Patient-CenteredOutcomesResearchInstitute (PCORI) DepartmentofDefense(DOD) CentersforDiseaseControlandPrevention (CDC) AgencyforHealthcareResearchandQuality (AHRQ) FoodandDrugAdministration(FDA) $14M $462.8M $7.1M $2M $495.6B $11.1B $1.3M $440M $500K $4.7B Figure18.FederalCKDActivities Source. DOMESTICRESEARCHGRANT-MAKINGORGANIZATIONS Thereareseveralnonprofitorganizationsspecificallyfocusedoncharitablegivingtosupportkidneyfailureand otherkidneydiseases.ThissectionprovidesabriefoverviewofthenonprofitorganizationsinvolvedinCKD/kidney failure-relatedresearch.ThissectiononlyincludesU.S.-basedkidneydiseaseorganizationsthatincludekidney failure(commonlyreferredtoasESRD)asaspecificresearchfocus.Organizationsthataresolelyinvolvedin patientsupport,advocacy,awarenessorwhosemissionistofundonespecificresearchcenterareexcluded.Table 3displaysthetopnonprofitfundersofCKD/kidneyfailure-relatedresearchwhoseresearchexpensesmeetor exceed$500K.Additionalinformationregardingtheirmission,keyresearchfundingmechanismsandclinicaltrials supportactivitiesisalsoprovidedbelow. Table3.TopNonprofitOrganizationsFundingCKD/ESRDResearchforFY2014 Organization FoundingYear ResearchExpenses TotalExpenses AmericanSocietyforNephrology(ASN) 2012 $3M $3M AmericanUrologicalAssociation(AUA) 2005 $3M $3.4M NationalKidneyFoundation(NKF) 1950 $1M $34.5M AmericanSocietyofTransplantation(AST) 1982 $900K $4M 41 March2017 AMERICANSOCIETYFORNEPHROLOGY(ASN) MISSION: ASNleadsthefighttoprevent,treat,andcurekidneydiseasesthroughouttheworldbyeducatinghealth professionalsandscientists,advancingresearchandinnovation,communicatingnewknowledge,andadvocating forthehighestqualitycareforpatients. RESEARCHFUNDINGMECHANISMS: ASNprovidessupportacrosstheentireresearchpipeline.Theirgrant-makingisdividedroughlyintothree categories:careerdevelopmentfornewinvestigators,researchfellowships,andtravelgrantsforfellows,residents andstudentstoattendKidneyWeek,theorganization’sannualconference.SinceASNbeganfundinggrantsin 1996,thesocietyandthefoundationhaveawardedmorethan$35milliontosupportresearchandtravelawards. InFY2014,ASNdedicated$3Mtoresearch-relatedexpenses. Formoreinformationaboutavailableawards,pleasevisitASN’swebsite. AMERICANUROLOGICALASSOCIATION(AUA) MISSION: AUA’smissionistopromotethehigheststandardsofurologicalclinicalcarethrougheducation,researchandthe formulationofhealthcarepolicy. RESEARCHFUNDINGMECHANISMS: AUAprovidessupporttobasic,translational,andclinicalresearch.TheAUAiscommittedtosupportingurologic researchthroughfunding,advocacyandscholarlyexchange.TheAUAisaleaderinhelpingtoidentifygapsin knowledgeandcommunicatingurologyresearchneedstokeyconstituentsatthefederallevel.TheAUA's ResearchScholarsProgramhasprovidedsupporttoyoungurologyresearchersformorethan35years.AUAalso administersadatagrantsprogramtosupportpopulation-based,data-driven,specialtygeneralizablestudiesusing electronichealthrecords,datamaintainedbytheAUAorotherdatasourcesalreadyavailabletoinvestigators.In FY2014,AUAdedicated$3Mtosupportingurologyresearch. Formoreinformationaboutavailableawards,pleasevisitAUA’swebsite. NATIONALKIDNEYFOUNDATION(NKF) MISSION: TheNationalKidneyFoundationistheleadingorganizationintheU.S.dedicatedtotheawareness,preventionand treatmentofkidneydiseaseforhundredsofthousandsofhealthcareprofessionals,millionsofpatientsandtheir families,andtensofmillionsofAmericansatrisk. 42 March2017 RESEARCHFUNDINGMECHANISMS: NKFsupportstranslational,earlyclinicalresearchaswellaslarge-scaleepidemiologicresearchregardingCKDrisk factors,progressionandprognosis.Since1968,theNationalKidneyFoundationhasprovidedmorethan$100 millioninresearchgrantstothefield.InFY2014,NKFallocatedabout$1Mtotheirresearchprogram,which supportedfouryounginvestigatorsandoneclinicalinvestigator.Theorganizationalsopublishespeer-reviewed medicaljournals,includingAmericanJournalofKidneyDiseases,AdvancesinChronicKidneyDisease,Journalof RenalNutrition,andJournalofNephrologySocialWork. Formoreinformationaboutavailableawards,pleasevisitNKF’swebsite. AMERICANSOCIETYOFTRANSPLANTATION(AST) MISSION: TheAmericanSocietyofTransplantationisanorganizationofprofessionalsdedicatedtoadvancingthefieldof transplantationandimprovingpatientcarebypromotingresearch,education,advocacy,andorgandonation. RESEARCHFUNDINGMECHANISMS: TheASTTransplantationandImmunologyResearchNetwork(TIRN)researchgrantsprogramseekstosupport fellows,juniorfaculty,andalliedhealthprofessionalsbyfundinginnovativeresearchinbasic,clinical,and translationalscience.InFY2014,ASTdedicatedabout$900ktosupportingresearch. Formoreinformationaboutavailableawards,pleasevisitAST’swebsite. COLLABORATIVEINITIATIVES GOVERNMENTSPONSOREDPROGRAMS ADVANCEDTISSUEBIOFABRICATIONMANUFACTURINGINNOVATIONINSTITUTE(ATB-MII) TheATB-MIIwasannouncedinJune2016andwillreceive$80Minfederalfunding.Itwillbringtogetherfor-profit andnonprofitorganizations,institutionsofhighereducation,andfederalandstateagenciestoaccelerate innovationbyinvestinginindustriallyrelevantmanufacturingtechnologieswithapplicationsintheTissue BiofabricationEcosystem.Thiseffortwillprovidesupporttohelpbridgethegapbetweenbasic/earlyresearchand productdevelopmentbyadvancingandscalingcriticaltechnologiesinthemanufacturingreadinesslevel4to7 range.TheATBMIIwillprovidesharedassetstohelpentities—particularlysmallmanufacturers—accesscuttingedgecapabilitiesandequipment,creatinganunparalleledenvironmenttoeducateandtrainstudentsandworkers inAdvancedTissueBiofabricationskills. 43 March2017 KIDNEYHEALTHINITIATIVE(KHI) Recognizingboththelackofclinicaltrialsandthehugeunmetclinicalneedinkidneydisease,theAmericanSociety ofNephrology(ASN)andtheU.S.FoodandDrugAdministration(FDA)establishedtheKidneyHealthInitiative (KHI)inSeptember2012.KHI’smissionistoadvancescientificunderstandingofthekidneyhealthandpatient safetyimplicationsofnewandexistingmedicalproductsandtofosterdevelopmentoftherapiesfordiseasesthat affectthekidneybycreatingacollaborativeenvironmentinwhichFDAandthegreaternephrologycommunitycan interacttooptimizeevaluationofdrugs,devices,biologics,andfoodproducts. Memberorganizationsincludepatientadvocacyorganizations,professionalorganizations,regulatedindustry (includingbothpharmaceuticalanddevicecompanies),dialysisproviders,academicresearchorganizations, contractresearchorganizations,researchinstitutes,andothergovernmentagencies.Tomorefullyincorporate patientstakeholderconcernsacrossallKHIclinicalandpolicydiscussions,KHIformedthePatientandFamily PartnershipCouncil(PFPC). KIDNEYINTERAGENCYCOORDINATINGCOMMITTEE(KICC) TheKidneyInteragencyCoordinatingCommittee(KICC)isaprogramundertheNIDDK.Thecommitteeconsistsof federalrepresentativesinvolvedinCKDprogramsandactivities.KICC'spurposeistoencouragecommunication andcollaborationtoshapeamorecoordinatedfederalresponsetoCKD.Figure18outlinesKICCmemberagencies. VETERANSADMINISTRATIONNATIONALKIDNEYPROGRAM VApartneredwiththeMedicalEducationInstitutein2012todevelopaninteractiveweb-basedlearningsystem, knownastheVAeKidneyClinic,tohelpguideVeteransthroughtheprocessofmanagingCKDandmaking treatmentrelateddecisions.TheeKidneyClinicisavailabletothepublicinadditiontoVApatientsandproviders viatheVANationalKidneyProgram. TheVAhasbeenactivelycollaboratingwithNIDDKandtheCentersforDiseaseControlinthereviewofpatient educationmaterialspertainingtochronickidneydisease(CKD).ThesematerialsareavailabletoVAprovidersfor patientdisseminationwithintheclinicandaredirectlyavailabletopatientsviaVA'seKidneyClinic,aswellas throughtheDepartmentofDefense'sclinicalpracticeguideline. 44 March2017 CONSORTIA Consortiaaretemporaryassociationsofstakeholdersfromvarioussectors—academia,industry,government, nonprofits,etc.—thatshareresourcesinordertoachieveacommongoal.AccordingtoFasterCures’ConsortiapediaCatalogue(adatabaseofbiomedicalresearchconsortia)thereareseveralconsortiafocusedonkidney diseases.Describedbelowareselectconsortiathatareunderwayforkidneyfailure-relatedresearchand therapeuticdevelopment.Forafulllist,pleasevisitConsortia-pediaCatalogue. BIOLOGICALSUPPORTFORKIDNEYPATIENTS(BIOKID) BiologicalSupportforKidneyPatients(BioKid),isabioreactorofkidneycellstoremovetoxinsthatremainafter hemodialysis.BioKidisanoutstandingaidinimprovingthequalityofhemodialysistreatmentsandinreducingthe riskofcomplications,suchascardiovascularproblems,resultingfromtheaccumulationoftoxicwasteproducts. TheBioKidprojectwasactivefrom2009-2014andisnowcurrentlycontinuedwithintheEuropeanUnionMarie CurieInnovativeTrainingNetwork(ITN)projectcalledBioArt.InApril2015,researchersreportedthecreationofa livingkidneymembrane—ahighlysoughtaftergoalwithinthekidneydiseasefield. CHRONICKIDNEYDISEASEPROGNOSISCONSORTIUM(CKD-PC) ChronicKidneyDiseasePrognosisConsortium(CKD-PC)isaresearchgroupcomposedofinvestigatorsrepresenting cohortsfromaroundtheworld.Investigatorssharedataforthepurposeofcollaborativemeta-analysestostudy prognosisinCKD. CKD-PCwasestablishedin2009byKidneyDisease:ImprovingGlobalOutcomes(KDIGO)(sponsoredbytheU.S. NationalKidneyFoundation).Originallytaskedwithcompilingandmeta-analyzingthebestavailabledataon kidneymeasuresandclinicaloutcomes,theCKD-PCcurrentlyconsistsofover70cohorts,whicharisefromgeneral, high-risk,orCKDpopulations.Todate,theCKD-PChaspublishedover15highimpactpaperswithimportant implicationsforthedefinition,staging,andmanagementofCKD. CKDBIOMARKERSCONSORTIUM(BIOCON) TheNationalInstituteofDiabetesandDigestiveandKidneyDiseases(NIDDK)establishedtheCKDBiomarkers Consortium(BioCon)topromotethediscoveryandvalidationofbiomarkerstoadvancethefieldofchronickidney disease(CKD)research.TheNIDDKCKDBiomarkersConsortiumbringstogetherinvestigatorswhoseexpertise includesclinicalnephrology,epidemiology,molecularbiology,genomics,proteomics,metabolomics,systems biology,laboratorymedicine,biostatistics,andlaboratorytestverificationandqualification.BioConisa collaborativeeffortinvolvingnumerousinvestigatorsfrommultipleinstitutionsworkingtogethertopursuethe developmentandvalidationofnovelbiomarkersforCKDbyassayingbiologicalspecimensandutilizingdatafrom thenation’slargestepidemiologicalstudiesofkidneydisease. (RE)BUILDINGAKIDNEYCONSORTIUM (Re)BuildingaKidneyisanNIDDK-fundedconsortiumofresearchprojectsworkingtooptimizeapproachesforthe isolation,expansion,anddifferentiationofappropriatekidneycelltypesandtheirintegrationintocomplex structuresthatreplicatehumankidneyfunction. 45 March2017 Theultimategoalofthisconsortiumistocoordinateandintegrateresearchtosupportthedevelopmentand implementationofstrategiessuchasdenovorepairofnephrons,there-generationofnephrons,andtheinvitro engineeringofabiologicalkidneytoenhancerenalrepairandpromotethegenerationofnewnephronsinthe postnatalorgan. SYSTEMSBIOLOGYTOWARDSNOVELCHRONICKIDNEYDISEASEDIAGNOSISANDTREATMENT (SYSKID) TheSystemsBiologytowardsnovelchronickidneydiseasediagnosisandtreatment(SysKid)consortiumisfocused onexpandingthebasicscienceofchronickidneydisease.Theprojectpavesthewayforprogressinprevention, newdiagnosticstrategies,andtreatmentoptionsfordecliningkidneyfunction,whichaffectsmillionsofpatients sufferingfromdiabetesandhypertension.SysKidwaslaunchedbytheEuropeanCommissionSeventhFramework Programmein2010. 46 March2017 GLOSSARY ALLELES ANEMIA APOL1GENE APOLIPOPROTEINL1 ARTERIOVENOUS(AV)FISTULA Twocopiesofeachgeneinthebody Lowredbloodcellcount ThegenethatencodesfortheproteinapolipoproteinL1 Acomponentofhighdensitylipoprotein Asurgicalprocedurethatcreatesadirectconnectionbetweenan arteryandveinintheforearm ARTERIOVENOUS(AV)GRAFT Atubesurgicallyinsertedundertheskinthatconnectsanarteryto aveinintheforearm ATHEROSCLEROSIS Hardeningofthearteries,whichcandecreasebloodflowtothe kidneys Acharacteristicthatcanbeobjectivelymeasuredandevaluatedas anindicatorofdiseasestateortreatmentefficacy Tissueremovedfromalivingbody Holloworganthatstoresurinepriortoexcretion BIOMARKER BIOPSY BLADDER BLOODUREANITROGEN CLINICALRESEARCH Indicatorofkidneyandliverhealth.Ureanitrogenformsafter proteinhasbeenbrokendown. Branchofbiomedicalresearchinvolvinghumansubjects CREATININE DIALYSISTREATMENT Wastebyproductofmusclemetabolism Involvestheuseofspecializedmachinerytofilterthebloodwhen thekidneyscannolongerdoso EGRFCALCULATION Calculationusingserumcreatininelevelsandcertainformulasthat factorinotherriskfactorssuchasage,gender,andrace ENZYME Aproteinthatcatalyzescomplexbiologicalreactions ERYTHROPOIETIN-STIMULATING AGENTS(ESA) ESTIMATEDGLOMERULAR FILTRATIONRATE(EGFR) GLOMERULUS GRAFT HEMATOCRIT Medicationthatboostsredbloodcellproduction HEMODIALYSIS Treatmentthatadialysismachinetocleanthetotalvolumeofthe patient’sblood Theoxygen-carryingproteinfoundinredbloodcells HEMOGLOBIN Theestimatedfiltrationratecapacityofthekidneys Thefiltercomponentofthenephron Atransplantedorgan Theratioofredbloodcellstothetotalvolumeofblood HUMAGRAFT™ Ahumanbioengineeredbloodvesselthatproposestodelivera tissue-basedgraftlackingtheneedfortissuematching HYPERTENSION Highbloodpressure 47 March2017 KIDNEYS NEPHROLOGIST Organsthatfilterbloodandproduceurine Physicianwhospecializesinkidneydiseases NEPHRON PERITONEALDIALYSIS Thekidney’sfilteringunit Treatmentthatinvolvesusingtheliningofthepatient’sstomach (theperitoneum)asthefilterforthepatient’sblood PROTEINURIA Clinicalpresentationofproteinintheurine RAAS Ahormonesystemthatregulatesbloodpressure,fluidvolume,and sodiumcontentinthebody RESEARCHANDDEVELOPMENT (R&D) Theprocessbywhichalaboratorydiscoveryisdevelopedintoa commercialtherapeuticdiagnosticordevice SENSITIZATION Astateinwhichthepatienthasdevelopedproteinsthatwillattack foreigntissue,likeatransplantedorgan SERUMCREATININE MEASUREMENT TUBULE Testusedtodetectevidenceofincreasedcreatinineintheblood URETERS Tubesthatcarryurinefromthekidneystothebladder URETHRA URINEANALYSIS Tubethatexpelsurine Analyzestheurineforthepresenceofprotein VENOUSCATHETER Asurgicallyinsertedflexibletubeinsertedintoaveinintheneck, chest,orlegnearthegroin WEARABLEARTIFICIALKIDNEY (WAK) Adevicecurrentlyindevelopment,whichwouldallowfordaily dialysis 48 March2017 Tubeallowsforthereabsorptionofnecessarymineralsbackinto thebloodandsendsexcessfluidandwastetotheureters REFERENCES 1. 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