e r u il a f y e n id k - aakpcarmen a. peralta, md, mas associate professor of medicine university...

KIDNEY FAILURE

1 March2017

AUTHORS

LEADAUTHOR

EkeminiA.U.Riley,PhD

CONTRIBUTINGAUTHORS

LaTeseBriggs,PhDMauraDonlan,MIASonyaDumanis,PhDYooRiKim,MS

ErikLontok,PhDEbonyMosleyDanielleSalkaMelissaStevens,MBA

KIDNEYDISEASESCIENTIFICADVISORYGROUP

WegraciouslythankthemembersofandliaisonstotheKidneyDiseaseScientificAdvisoryGroupfortheirparticipationandcontributiontotheKidneyFailureProjectandGivingSmarterGuide.Theinformativediscussionsbefore,during,andaftertheCalltoActionRetreatwerecriticaltoidentifyingthekeyunmetneedsandidealphilanthropicopportunitiestobenefitpatientsandadvancekidneydiseaseresearch.

MatthewBreyer,MDChiefScientificOfficer—LeadGenerationBioTechnologyDiscoveryResearchEliLillyandCompany

PaulConwayPresident,AmericanAssociationofKidneyPatientsBoardMember,KidneyHealthInitiative

JosefCoresh,MDG.W.ComstockProfessorofEpidemiology,Biostatistics&MedicineCKDPrognosisConsortiumFoundingLeaderJohnsHopkinsUniversity

LauraDember,MDProfessorofMedicineandEpidemiologyRenal,ElectrolyteandHypertensionDivisionUniversityofPennsylvania

JenniferEricksonAssistantDirector,InnovationforGrowthExecutiveOfficeofthePresidentOfficeofScienceandTechnologyPolicyTheWhiteHouse

WilliamFissell,MDAssociateProfessorNephrologyandHypertensionVanderbiltUniversity

JonathanHimmelfarb,MDProfessorofMedicineDirector,KidneyResearchInstituteUniversityofWashington

ThomasKleyman,MDChief,Renal-ElectrolyteDivisionSheldonAdlerProfessorofMedicineProfessorofCellBiology,PharmacologyandChemicalBiologyUniversityofPittsburghSchoolofMedicine

MatthiasKretzler,MDWarner-Lambert/Parke-DavisProfessorofMedicineNephrology/InternalMedicineandComputationalMedicineandBioinformaticsUniversityofMichigan

JeffreyLawson,MD,PhDChiefMedicalOfficerHumacyte

KristaLentine,MD,PhDMedicalDirectorofLivingDonationProfessorofMedicineSaintLouisUniversity

AndrewLevey,MDChief,DivisionofNephrologyDr.GeraldJ.andDorothyR.FriedmanProfessorTuftsUniversitySchoolofMedicine

2 March2017

PeterLinde,MDVicePresident,MedicalResearchAcceleronPharma

KennethNewell,MD,PhDViceChairforAcademicAffairsProfessorofSurgeryDepartmentofSurgeryEmoryUniversity

CarmenA.Peralta,MD,MASAssociateProfessorofMedicineUniversityofCaliforniaSanFranciscoandSanFranciscoVAMedicalCenterCo-FounderandExecutiveDirectorKidneyHealthResearchCollaborative

VladoPerkovic,MBBS,PhDExecutiveDirectorTheGeorgeInstituteAustraliaProfessorofMedicineUniversityofSydney

MartinPollak,MDProfessorofMedicine,HarvardMedicalSchoolChief,DivisionofNephrologyBethIsraelDeaconessMedicalCenter

NeilPowe,MD,MPH,MBAChiefofMedicine,ZuckerbergSanFranciscoGeneralHospitalConstanceB.WofsyDistinguishedProfessorandVice-ChairofMedicineUniversityofCaliforniaSanFrancisco

DorrySegev,MD,PhDMarjoryK.andThomasPozefskyProfessorofSurgeryandEpidemiologyAssociateViceChair,DepartmentofSurgeryDirector,EpidemiologyResearchGroupinOrganTransplantationTheJohnsHopkinsUniversity

RoySoberman,MDAssociateProfessorofMedicineHarvardMedicalSchoolNephrologyDivisionMassachusettsGeneralHospital

RobertStanton,MDAssociateProfessorofMedicineHarvardMedicalSchoolChief,Kidney&HypertensionSectionJoslinDiabetesCenter

KatalinSusztak,MD,PhDAssociateProfessorofMedicinePerelmanSchoolofMedicineUniversityofPennsylvania

RaviThadhani,MD,MPHProfessorofMedicineHarvardMedicalSchoolChief,DivisionofNephrologyMassachusettsGeneralHospital

AlizaThompson,MDMedicalOfficerDivisionofCardiovascularandRenalProductsCenterforDrugEvaluationandResearch(CDER)FoodandDrugAdministration

RobertaWeiss,MDSeniorDirectorClinicalDevelopment,RIAMedImmune

MelissaWestProjectDirector,KidneyHealthInitiativeAmericanSocietyofNephrology

KerryWillis,PhDChiefScienceOfficerNationalKidneyFoundation

MylesWolf,MD,MMScProfessorofMedicineChief,DukeNephrologyDukeUniversitySchoolofMedicine

3 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

4 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..........................................................................................................................................31

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

5 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

6 March2017

PHILANTHROPISTS’FOREWORD

FromthedeskofRobertandCynthiaCitrone

WhenRob’sfatherwasfirstdiagnosedwithendstagerenaldisease(ESRD)weweredevastated.Howhorrificisadiseasethatisnamed“endstage?”Whereisthehope?IwatchedindespairasRobsprungtoactiontohelpandcomforthisfather.

Howcouldwenotbedonors?Howdothebestdoctorsintheworldnothaveaplan?Robhasbuilthissuccessonactionandidentifyingopportunities,yetthisprocesswasanexerciseinfutilityinthisnewESRDterrain.ItwasthenthatwefoundTheMilkenInstituteanditsCenterforStrategicPhilanthropy(CSP).Mike,Melissa,andtheentireCSPteamworkedwithustoinvestigatetheproblem,mobilizeourresources,anddevelopacalltoaction.ThankstotheInstitute,weareenthusedandinvigoratedtodedicateourtimeandresourcestomakeanimpactintheESRDfield.Withitsleadership,wearepoisedtogivehopebacktoourfatherandsomanyothers.

FromthedeskofRobertL.Citrone

Chronic kidney disease, end stage renal failure, hemodialysis, peritoneal dialysis, major life changes, endlessmedicationsandtests,possible transplant; this is the lifeofapatientwith renaldisease.Likesomanydiseases,renaldiseaseisnotdiscriminating;ithappenstoallpeoplefromallwalksoflife,youngandoldalike.

When Iwas told that Iwouldendupondialysiswithin6 to12months, I feltas though Ihad justbeengivenadeathsentence.Life,as Iknewit,wouldneverbethesameagain,formeormyfamily.Asdialysisoptionswerediscussed, Imade the decision to do hemodialysis. However, once home, I began to domy own research and,contrarytosomemembersofmymedicalteam,discoveredthathemodialysiswasnottherightoptionformeormylifestyle.

As a new peritoneal dialysis patient, with end stage renal failure, the focus then turned to the possibility of akidney transplant. Forme, thiswas oneof themost heartbreaking and frustrating experiences ofmy life. EventhoughIamonawaitinglist,Ihavebasicallybeenprecludedbythegovernment’sguidelines.Ihavelearnedthat,forthemajorityoftransplantpatients,findingadonorfallsdirectlyontotheshouldersofthepatientandhisorherfamily.Throughtheprocessofseekingatransplant,Ihavediscoveredthatthereisareallackofknowledge,amongthegeneralpopulationandeventhemedicalworld.Severalyearsago,Iidentifiedafewpotentialkidneydonors.However,thedonorsthemselvesweredissuadedfromdonating.Withbetterknowledge,theremayhavebeenadifferentoutcome.

Weallliketothinkweareunique―thatourstoriesareoursalone.Butthatjustisn’ttrue.ThelongerIlivethelifeofarenalpatient,themoremylifeandstorybecomesintertwinedwithotherrenalpatientswhoIhavecometoknow,whoarefightingforalongerandbetterlife.IoftenthinkoftheU.S.veteran,whoisseekingakidneydonorbypostinghispleaonthewindowsofhiscar.Thegrandmotherwhorefusestogothroughtherigorsofdialysisand dies much too young. The 41-year-old man who dies of cardiac arrest in his sleep. The young transplantwomanwhoisgivenasecondchanceandgivesbirthtoahealthybaby.Theyoungathletewhoreceivedthegiftoflife11yearsagofromhissister.The12-year-olddaughterwholostherbelovedfather.Orthehusbandwhojustlosthiswifetokidneyfailure,butcontinueshisownbattlewiththedisease,evenifitmeanslosingvariouslimbs.

Ihavesomanyquestions…Whyshouldsomanypeoplehavetodiesoyoungfromsuchadisease?Whymustitbetheresponsibilityof individuals to findtheirowndonors?Whydoesn’t thegeneralpopulationandmedical fieldhaveabetterawarenessofkidneydisease?Whyisn’ttherebetterdonorawareness?Whatwillhappenwhen,orif,thetransplantedkidneysfail?Whyaretherenospecificdrugsforrenaldisease?Whataboutartificialkidneys?Isitpossibletohaveabettertypeofdialysis?Andthelistgoesonandon.Thisisnotabattletofightalone.

Andnow,wovenintoourstoryistheMilkenInstitute’sCenterforStrategicPhilanthropy.Inthenewchapterofourstory, CSP has brought together the preeminent doctors and researchers in the renal disease field to discuss,

7 March2017

strategize, prioritize needs, and set goals. Meeting with this team of doctors and researchers, I once againdiscovered that I amnotalone.Theyhave the samequestionsandconcerns.Andhowwonderful that, throughtheirwork,theyareseekingtoanswerthosequestions.

AsyoureviewtheGivingSmarterGuide,youwillfindthatitisapowerfultooltoguideusaswegoforthtodefeatkidneydisease.Iinviteyoutojoinourstory.Astorywherehopeisbeginningtobeintertwinedintothepages.Astoryofhopethatwillcontinueforgenerationstocome.Astoryofhopethatwillbringalongerandbetterlifeforrenaldiseasepatients.

RobertL.Citrone,March2017

8 March2017

EXECUTIVESUMMARY

ThisGivingSmarterGuideistheculminationofayear-longefforttoidentifystrategicphilanthropicopportunitiesthatcanmovetheneedleonunmetneedsspecifictokidneyfailureresearchandtreatment.Kidneyfailureisanirreversiblediseaseinwhichthekidneyscannolongersupportlifeontheirown.Tolive,patientssufferingfromkidneyfailuremustinitiatetreatmenttoreplacekidneyfunctionthroughdialysisorkidneytransplantation.AccordingtotheCentersforDiseaseControlandPrevention(CDC),morethan300peoplebegintreatmentforkidneyfailureevery24hoursintheUnitedStates.Thequalityoflife(QOL)forthesepatientsisseverelyimpactedbecausetheirlivesareforeverchanged.

Approximately17percentofU.S.adultslivewithchronickidneydisease(CKD),themostcommonformofkidneydiseasecharacterizedbyagraduallossinkidneyfunction.Nearly600,000CKDpatientshaveprogressedtoastateofkidneyfailure,thefinalstageofCKD.ApersonlivingwithCKDmaynotbeawareofthediseaseuntilithasprogressedtothepointofkidneyfailure.Thislackofawarenessisamajorbarrierwithseriousramificationsforpatienthealth,researchsupport,andcost.

Thehealthcarecostsarestaggering.Inaggregate,Medicarespendsabout$30billionperyearforkidneyfailurepatientcare—accountingforgreaterthan7percentofMedicarefee-for-servicespending.Asidefromtheeconomicburden,thisdiseasetakesanemotionaltollonpatientsandfamilies,astheynavigatetheirnewrealitiesofademandingdialysistreatmentschedule,extremeresultantfatigue,aswellaslostwagesandhighout-of-pocketcosts.

Althoughthefederalgovernmentprovidesnearly$600millioninCKD/kidneyfailureresearchfunding,itislessthan2percentofcarecostsandwoefullydisproportionatetodiseaseprevalence.Thepharmaceuticalindustryhasfacedseveraldrugdevelopmentchallenges,andtherehasneverbeenadrugdevelopedprimarilyforthepreventionofkidneyfailure.SeveralbarriersthatplaguetheCKD/kidneyfailurefieldcanbeclassifiedinthefollowingcategories:

• Lackofdiseaseawarenessandworkforcechallenges;• Lackofinnovationintransplantationanddialysisdelivery;and,• Limiteddiseaseunderstandingatthemolecularlevel.

AtthebehestoftheCitronefamily,theMilkenInstituteCenterforStrategicPhilanthropyconvenedworld-renownedkidneyexpertsandstakeholderstoidentifytransformativeresearchandsystemsopportunitieswherephilanthropycouldaccelerateprogressintheCKD/kidneyfailurespace.Theprimaryopportunitiesareasfollows:

• Channelingprivateinvestmenttospearheadpublicawarenesscampaignswouldbethefirststeptoraisethenationalprofileofthediseasestate,encouragepolicyreform,andattractfundingdollarsforresearchandimprovedtherapies—similartotheexperienceforotherhigh-profilediseases.

• Privategivingcanalsotransformthekidneydiseaseandtransplantationworkforcebyendowingannualsummitsandcreatingaglobalnetworkoffacultytonurturethefuturegenerationofresearchersandphysician-scientists.

• Philanthropicgivingcanmovetheneedleonorganscarcitybyfundinginnovativeeffortstoexpandaccesstotransplantation,increaselivingkidneydonationrates,andstrategicallyinvestinartificialkidneydevelopment.

• Thecatalyticpotentialofphilanthropycanfosteracultureshiftregardingkidneydisease,wherebypatientsarebetterinformedandencouragedtoparticipateinclinicaltrials.

9 March2017

ThisGuidewasdevelopedwiththeexpresspurposeofempoweringpatients,supporters,andstakeholderstomakestrategic,informeddecisionswhendirectingtheirenergyandphilanthropicinvestmentsintoresearchanddevelopmenteffortsalignedwiththeirinterests.

OVERVIEW

Chronickidneydisease(CKD)isaconditioncharacterizedbyagraduallossinkidneyfunction.ThelaststageofCKD,knownaskidneyfailure(orendstagerenaldisease[ESRD]),isanirreversiblediseaseinwhichthekidneysarenolongercapableofsupportingdailylife.About20millionAmericanadultsarelivingwithCKD,andmorethan600,000haveprogressedtokidneyfailure,thefifthandfinalstageofCKD.Althoughthereareseveralpossiblecausesofkidneyfailure,highbloodsugar(diabetes)andhighbloodpressure(hypertension)aretheleadingcauses.Infact,approximatelyoneinthreeadultswithdiabetesandoneinfiveadultswithhypertensioncurrentlyhaveCKD.EarlystagesofCKDareasymptomatic,andthereforeCKDpatientscanbeunawareoftheirstatus—leadingtoalargeproportionofpatientslearningoftheirkidneyfailureduringemergencysituations.Astartlingstatisticisthatgreaterthan50percentofalldialysispatientsendupreceivingdialysistreatmentduringanemergencyroomvisit,underscoringtheneedfordiseaseawarenessandearlydetection.Severalcomplicationsresultfromkidneyfailure,namelycardiovasculardisease(CVD)andcongestiveheartfailure(CHF),lowredbloodcellcount(anemia),andboneandmineraldisease.Treatmentofthesecomplicationstakesaseveretollonqualityandlengthoflife.Treatmentoptionsforkidneyfailurepatientsarequitelimited.Thereisadireneedforinnovationindialysisdeliveryandcare,aswellasincreasedaccesstokidneysfortransplantation.DialysisiswidelyaccessibleintheUnitedStatesbecauseitisaMedicare-coveredcondition,butdialysistreatmenthasnotimprovedsinceitsdevelopmentmorethan50yearsago,andmortalityratesremainabysmallyhigh.Kidneytransplantationisbyfarthebestoptionforkidneyfailurepatients,butdonororgansareinshortsupply.Consequently,preventingprogressionofCKDtokidneyfailureisofparamountimportance,underscoringtheneedtodevelopnoveltreatmentoptionsforCKD.

SOCIETALIMPACTOFKIDNEYFAILURE

POPULATIONBURDEN

KidneydiseasesaretheninthleadingcauseofdeathintheUnitedStates.AccordingtotheCDC,morethan1in10AmericansarecurrentlylivingwithCKD.Ofthose,morethan600,000peoplearelivingwithkidneyfailure.CKD/kidneyfailureismorecommoninpatientsaged60orolder,andthisat-riskpopulationisgrowingrapidly.Since2011,“BabyBoomers”(peoplebornbetween1946and1964),whocomprisemorethan20percentofthetotalU.S.population,begantoturnage65.TheU.S.CensusBureaureportsthatalloftheyoungestBabyBoomerswillbeoverage65by2029.Whentheprevalenceofdiabetesandhighbloodpressureisconsidered,theoutlookbecomesevenbleaker.Basedon2012statistics,nearly10percentoftheU.S.populationisdiabeticandnearly30percentishypertensiveandthereforeatriskofdevelopingCKD/kidneyfailure.Furthermore,CKDandkidneyfailuredisproportionatelyaffecttheU.S.populationintermsofrace,ethnicity,andsocioeconomicstatus(SES).BlackAmericansarethreetimesaslikelytodevelopkidneyfailureasWhite

10 March2017

Americans,andHispanicsare40percentmorelikelytodevelopkidneyfailurecomparedtonon-Hispanics.Similarly,lowSESisassociatedwithCKDincidence,progressiontokidneyfailure,andpoorhealthoutcomesandreducedaccesstoqualityhealthcare.Expertsstatethatlapsesincarequalityarestronglyassociatedwiththesedisproportionaterates.AlthoughthisGuidewillfocusonU.S.incidenceofkidneyfailure,kidneydiseaseisaglobalhealthcrisis.Accordingtothe2010GlobalBurdenofDiseasestudy,CKDranked18thinleadingcausesofdeathworldwide—upfrom27thinthe1990rankings.OnlyHIV/AIDShadalargerrankingchange.Accordingtoa2015reportinLancet,theestimated2.6millionpeoplewhoreceivekidneyreplacementtherapygloballyisprojectedtodoubleby2030.Alarmingly,onlyhalfofkidneyfailurepatientsaroundtheworldreceivelife-savingkidneyreplacementtherapy,effectivelymakingkidneyfailureadeathsentenceinmanycountries.Indeed,thereisworktobedonetostemthetideofkidneydiseaseincidence.

ECONOMICBURDEN

Since1972,anyonewithkidneyfailure(regardlessofageorincome)wasgrantedMedicareeligibilitytocoverthecostofdialysisorkidneytransplantationservices.Kidneyfailurewas,andstillis,theonlymedicalconditiontoreceiveuniversalcoverageunderthisgovernmentprogram.Atthattime,onlyabout10,000U.S.patientswerereceiving;however,thisnumberswelledtomorethan450,000patientsin2013,accordingtodatacollectedbytheU.S.RenalDataSystem(USRDS[seepage32]).Thisincreaseissignificantbecausetreatmentforkidneyfailureiscostly.OneyearofdialysistreatmentcostsMedicare$69,000to$85,000,and1yearoftransplant-associatedtreatmentcostsapproximately$30,000(Figure1).Inaggregate,Medicarespendsabout$30billionperyearforkidneyfailurepatientcare.Eventhoughkidneyfailurepatientscompriselessthan1percentofthetotalMedicarepopulation,theyaccountforgreaterthan7percentofMedicarefee-for-servicespending.

Patientsandtheircaregiverssufferdirectfinancialstrain.Kidneyfailureoftenrenderspatientsunabletoworkbecauseoftheextremefatiguethatoftenaccompaniesdialysistreatment,whichtranslatesintolostwages,lossoflifetimeearningpotential,andlossofretirementsavingsandsecurity.Inaddition,kidneydiseasepatientsincurthemostout-of-pocketexpensesofanyMedicarebeneficiary.

Individualsthatdonateafunctionalkidneytoakidneyfailurepatientarenotexemptfromfinancialstrain.Althoughpublicorprivateinsurancemaycovertheirsurgery,kidneydonorswillincurtransportationandchildcarecosts,aswellaslostincomeduetosurgeryandrecovery.Currently,livingdonorsdonothavejobprotectionundertheFamilyandMedicalLeaveAct(FMLA)duringthelongrecoveryprocess.Thesefinancialrisksdisincentivizekidneydonation,despitealtruisticintention,whichpartiallydrivestheshortageofkidneysdonors.Inturn,manypatientshavenoalternativetodialysis,whichisnotonlythreetimesmoreexpensivethankidneytransplantation,butalsolimitsQOLandlifeexpectancy.Apolicychangethatprovidesbettersupportforlivingdonationwouldsave

Figure1.Medicarecostsforkidneyfailurepatients.Perpersonperyearcostsofprevalentkidneyfailurepatients.Yearlycoststotreatapatientondialysisarenearlytriplethecoststotreatatransplantpatient.

11 March2017

thegovernmentanaverageof$60,000ayearforeverypatientthatreceivedakidneytransplantratherthandialysistreatment,accordingtothe2013EconomicReporttothePresident.

Astheprevalenceofat-riskindividualscontinuestorise,sotoowilltheimpendingcosts.NowisthetimetoaddressthesedifficultissuesbyidentifyingkeyunmetneedsthatimpederesearchprogressandtherapeuticinnovationinCKD/kidneyfailure.

POLICYANDREGULATORYINITIATIVES

ThissectionwillprofileaseriesoflegislativeandregulatorymatterssignificanttotheCKD/kidneyfailurecommunitypertainingtoaccesstocare,qualityofcare,andmedicalresearch.

LIVINGDONORPROTECTIONACTOF2016(H.R.4616,S.2584)

RepresentativeNadler(D-NY),RepresentativeBurgess(R-TX),SenatorKirk(R-IL),andSenatorGillibrand(D-NY)introducedtheLivingDonorProtectionAct,whichseekstoprohibitinsurancecompaniesfromdenyingorlimitinglife,disability,andlong-termcareinsurancetolivingdonorsandfromcharginghigherpremiumsafterdonations.ThebillalsoclarifiesthatlivingorgandonorsmayusetimegrantedthroughtheFamilyandMedicalLeaveAct(FMLA)torecoverfromdonation.

THECKDIMPROVEMENTINRESEARCHANDTREATMENTACTOF2015(H.R.1130,S.598)

RepresentativesTomMarino(R-PA),JohnLewis(D-GA)andPeterRoskam(R-IL)andSenatorsBenCardin(D-MD),MikeCrapo(R-ID),andBillNelson(D-FL)introducedtheChronicKidneyDiseaseImprovementinResearchandTreatmentActof2015inFebruary2015.Thebillseekstoimproveaccesstoqualitycareforpatients,promoteeducationandawareness,andincreaseefficiencyinbiomedicalresearchinCKD.

Specifically,thebillaugmentsaccesstocarebyallowingindividualsunderage65withkidneyfailuretoenrollinMedicareAdvantageplans.Furthermore,itproposesanexpansionofpatientaccesstokidneydiseaseeducationprogramsandhomedialysistreatmentoptions.Thebillalsoproposesaplantomoreeffectivelymanageandcoordinatebiomedicalresearchinkidneydisease.

ThebillmandatedanassessmentofcurrentfederalfundinglevelsrelativetoCKDcareexpenditures,thefindingsofwhichwererecentlypublishedbytheU.S.GovernmentAccountabilityOffice(GAO-17-121).Thelegislationalso

https://www.whitehouse.gov/administration/eop/cea/economic-report-of-the-President/2013

https://www.congress.gov/bill/114th-congress/house-bill/4616




http://www.gao.gov/products/GAO-17-121

12 March2017

mandatesafederalstudytobetterunderstandtheprogressionofkidneydiseaseandtreatmentofkidneyfailureinminoritypopulations.

QUALITYINCENTIVEPROGRAM

TheMedicareImprovementsforPatientsandProvidersActof2008createdaQualityIncentiveProgram(QIP)forMedicare’sESRDprogram.TheQIP,whichtookeffectin2012,aimstopromotehigh-qualityservicesinoutpatientdialysiscare.TheQIPlinksaportionoffacilities’MedicarereimbursementdirectlytoQIPperformancestandardsandthequalityofcarethatpatientsreceive.Forthosefacilitiesthatdonotmeetorexceedcertainstandards,theQIPreducespayments.

https://www.cms.gov/Medicare/Quality-Initiatives-Patient-Assessment-Instruments/ESRDQIP/index.html

https://www.cms.gov/Medicare/Quality-Initiatives-Patient-Assessment-Instruments/ESRDQIP/index.html

13 March2017

Figure2.Theurinarysystem.Illustrationofthemale(left)andfemale(right)urinarysystem.Source:NationalInstituteforDiabetesandDigestiveandKidneyDiseases(NIDDK).

THEBASICS:THEKIDNEYSANDHOWTHEYWORK

Kidneysarevitaltoeverydaylifebecausetheyarethecentralfiltrationsystemofthebody.Belowthebasicsofkidneyanatomyandfunctionareaddressedthroughaseriesofquestions:

WHEREARETHEKIDNEYSLOCATED?

Thekidneysaretwobean-shapedorganslocateddirectlyoppositeeachotherontheleftandrightsideoftheupperabdominalareapressedagainstthebackmuscles.

Thekidneysareakeypartoftheurinarysystem.Figure2illustratestheurinarysystemcomponents:

• Kidneys—Theseorgansfilterbloodandproduceurine.• Ureters—Thesetubescarryurinefromthekidneysto

thebladder.• Bladder—Thisholloworganstoresurinepriorto

excretion.• Urethra—Thistubeexpelsurine.

HOWDOTHEKIDNEYSWORK?

Thekidney’sprimaryfunctionistofilterwasteproductsoutoftheblood.Wasteisgeneratedfromthechemicalreactionsthatareperformedincellsalloverthebody.Thekidneyiscomposedofabout1millionfilteringunits,callednephrons.Thenephronconsistsoftwoparts:

• Glomerulus—Thisisthefiltercomponentofthenephron.Asbloodpassesthroughthisfilter,wasteproductsfromthebloodaretrappedandexcretedthroughtheurethrawhilebloodcellsandotherlargemolecules(suchasproteins)areretained.

• Tubule—Thistubeallowsforthereabsorptionofnecessarymineralsbackintothebloodandsendsexcessfluidandwastetotheureters.

Figure3.Pathofbloodthroughthekidney.Illustrationofakidneyshowingthevesselsthatcarrybloodintoandoutofthekidney,aswellasurinetothebladder.Zoom-in:anillustrationofanephron,thekidney’sfilteringunit.Source:NIDDK.

https://www.niddk.nih.gov/health-information/urologic-diseases/urinary-retention

https://www.niddk.nih.gov/health-information/kidney-disease/kidneys-how-they-work

14 March2017

Thekidneyperformsotheressentialfunctionstomaintainthefollowing:

• Bloodpressureandvolumebalance• Bonehealthandmineralbalance• Redbloodcellproduction

BLOODPRESSUREANDVOLUMEBALANCE

Healthykidneysmaintainfluidbalancebyremovingexcesswaterandsodiumfromtheblood.Whenthekidneysaredamaged,thebodyretainsfluidandswells,whichresultsinhighbloodpressure.

Conversely,whenapersonexperiencesasuddendropinbloodpressureordecreasedbloodflowthroughthekidney,suchasduringperiodsofdehydrationorhemorrhage,therenin-angiotensin-aldosteronesystem(RAAS)isactivated.TheRAASisdiscussedingreaterdetailintheMolecularBiologyofDiseasesectiononpage26.

BONEHEALTHANDMINERALBALANCE

Phosphorus,calcium,andvitaminDarenecessaryforproperbonehealth.ThekidneysplayanactiveroleinprocessingbothphosphorusandvitaminDtomaintainbonehealthandoverallmineralbalance.Thekidneysremoveexcessphosphorusintheblood,whichcaninducecalciumleakagefromthebones,leavingthemweakandbrittle.

VitaminDhelpstomaintainproperlevelsofcalciumandphosphorusintheblood.ThekidneyplaysaroleinconvertingvitaminDintoitsactiveform(alsoknownasvitaminDmetabolism),whichhelpstocontroltheamountofcalciumandphosphorusthatthebodycanabsorbfromingestedfood.Whenitsfunctioningiscompromised,thekidneylosesitsabilitytoactivatevitaminD,thusresultinginmineralimbalance.

REDBLOODCELLPRODUCTION

Redbloodcellsareproducedinthebonemarrowandareresponsibleforcarryingoxygentoalltissuesinthebody.Healthykidneysproducethehormoneerythropoietin(EPO),whichinducesredbloodcellproduction.Ahormoneisachemicalproducedbythebodyandreleasedintothebloodtotriggerorregulateparticularbodyfunctions.KidneydamageleadstoalackofEPOproduction,resultinginanemia(aconditioncharacterizedbylowlevelsofredbloodcells).Anemiahaspervasiveeffectsthroughoutthebody,becauseeachorganreceiveslessthantheamountofoxygenneededtoperformatoptimalcapacity.

15 March2017

CAUSALFACTORS,RISKFACTORS,ANDPREVENTION

Severaldiseasesandconditionscanleadtokidneyfailure(Figure4);however,thetoptwocausesarediabetesandhypertension.

Inaddition,thereareseveralriskfactorsassociatedwithdevelopingCKD/kidneyfailure.Bothgeneralandgeneticriskfactorsareoutlinedindetailbelow.

GENERALRISKFACTORS

Generalriskfactorsincludebutarenotlimitedto:

• Medicalconditions—Peoplelivingwithdiabetes,hypertension,otherkidneydiseases,andcardiovasculardiseaseareatincreasedriskofdevelopingCKD/kidneyfailure.

• Familyhistory—ThosewithafamilyhistoryofCKD/kidneyfailurearemorelikelytodevelopkidneyfailure.

• Age—Theincidenceandprevalenceofkidneyfailureincreaseswithage.CKDismostprevalentinpatientsage60orolder.

• Sex—Menaremorelikelytodevelopkidneyfailurethanwomen.

• Race—Blacks,Asians/PacificIslanders,andNativeAmericansaremorelikelytodevelopkidneyfailurethanWhites,atratiosof3:1,1.2:1,and1.2:1,respectively.

• Ethnicity—Hispanicsare40percentmorelikelythannon-Hispanicstodevelopkidneyfailure.

GENETICRISKFACTORS

RecentdiscoveriesindicatethatpatientswhoexpressbothpossiblegeneticvariantsoftheapolipoproteinL1(APOL1)gene—G1andG2—areatincreasedriskofdevelopingkidneyfailureduetohypertensionandotherconditions.

PREVENTION

PreventingkidneyfailureissynonymouswithpreventingeitheronsetorprogressionofCKDbycontrollingthediseasesorotherfactorsthatleadtoCKD:

• Eatabalanceddiettocontrolbloodsugarandcholesterollevels,therebypreventingorcontrollingtheonsetofdiabetes,hypertension,andCVD.

• Exercisetopreventorcontroltheonsetofdiabetes,hypertension,andCVD.

• Stopsmokingtoavoiddevelopmentofatherosclerosis,whichcandecreasebloodflowtothekidneysleadingtosustained,increasedbloodpressure.

Figure4.Primarycausesofkidneyfailure.Kidneyfailureisthefinaloutcomeofseveralpossibleincitingconditions.

16 March2017

• Controlbloodsugartopreventcomplicationsfromdiabetes.

• Maintainbloodpressurebelow130/80.

Asignificantbarriertoeffectivepreventionisalackofearlydetection.Severalfactorscontributetothissituation,suchasagenerallackofawarenessbythepublicaboutCKDoritsdiagnosis,absenceofsymptomsthatpatientsassociatewithkidneydisease,andlimitedtestingstrategiestopredictanddetectdecliningkidneyfunction.TheBarrierstoResearchProgressandKeyPhilanthropicOpportunitiessectiononpage33highlightswaysthatstrategicphilanthropycouldhelpmovetheneedleonthispressingissue.

SIGNSANDSYMPTOMSOFKIDNEYFAILURE

ApersonlivingwithCKDmaynotbeawareofthepresenceofdiseaseuntilithasprogressedtothepointofkidneyfailure.Thisisbecauseapersoncanloseupto90percentofkidneyfunctionbeforefeelinganyspecificsymptoms.Table1liststhekidneys’functionsandthesymptomsthatresultwhenthekidneysfailtoperformthesefunctions.

Table1.KidneyFunctionandSymptomsofKidneyFailureKidneyFunction SymptomsWhenKidneyFunctionFailsFilterwasteproductsoutoftheblood(Thisistheprimaryfunctionofthekidneys)

Wasteproducts(toxins)accumulateintheblood,possiblyleadingtothefollowingsymptoms:

• Problemsurinating• Itchy,paleskin• Nauseaandvomiting

Ifleftuntreated,toxinbuild-upcouldbefatal.Regulatebloodpressureandvolumebalance Failingkidneyslacktheabilitytoremoveextrafluid

fromtheblood,possiblyleadingtothefollowingsymptoms:

• Cardiovasculardiseases• Swelling• Shortnessofbreath

Maintainbonehealthandmineralbalance Failingkidneyslacktheabilitytoregulatepropermineralconcentrations,possiblyleadingtobonepain.

Promoteredbloodcellproduction Failingkidneyslosetheirabilitytoproduceahormonenecessarytomakeredbloodcells.Thispossiblyleadstothefollowingsymptoms:

• Anemia• Fatigue

17 March2017

DIAGNOSIS

Kidneyfailureiscurrentlydiagnosedbasedontheclinicalpresentationofproteinintheurine(knownasproteinuria)andthediminishedfiltrationcapacityofthekidneys,knownastheestimatedglomerularfiltrationrate(eGFR).Therefore,bothproteinuriaandeGFRarekidneydiseasebiomarkers.Abiomarkerisacharacteristicthatisobjectivelymeasuredandevaluatedasanindicatorofdiseasestateortreatmentefficacy.Abiomarkercanbedetectedinbiofluids(e.g.,blood,urine)andtissues(e.g.,kidney,skin).Anephrologist(physicianwhospecializesinkidneydiseases)typicallydiagnoseskidneyfailureusingthefollowinglaboratorytests:

• Urinealbuminorprotein—Thistestanalyzestheurineforthepresenceofprotein.Whenthekidneysarefailing,theyareunabletoreabsorbproteinbackintocirculation,resultinginproteinspillingintotheurine.Albuminisaspecifictypeofprotein,andtheteststomeasureitsabundancearemoresensitivefordetectingkidneydisease.

• Serumcreatininemeasurement—Thistestisusedtodetectevidenceofincreasedcreatinineintheblood.Creatinineisawasteby-productofmusclemetabolism.Healthykidneysfilteroutcreatininefromthebloodintotheurine.Elevatedcreatininelevelssignalkidneydamage.

o eGFRcalculation—eGFRiscalculatedusingserumcreatininelevelsandcertainformulasthatfactorinotherriskfactorssuchasage,gender,andrace.TheeGFRcalculationisusedtodeterminethestageofCKDasillustratedinFigure5.ItisimportanttouseeGFR,ratherthantheserumcreatininemeasurementinisolation,toenableearlydetectionofkidneydisease.

o CystatinCmeasurement—ThistestisusedtodetectevidenceofincreasedcystatinCintheblood.CystatinCisaninhibitorofaclassofproteinsthatbreakdownotherproteins(knownasproteases).Healthykidneysfilteroutcystatincfromthebloodintotheurine.Elevatedcystatinclevelssignalkidneydamageaswell.Incertaincircumstances,thecombinedmeasurementof

creatinineandcystatinCcanimprovetheaccuracyofeGFRestimation.

Figure5.eGFRmeterandstagesofCKD.Meter(left)andcorrespondingtable(right)illustratingeGFRnumbersthatdenotenormal,diseased,andfailedkidneyconditions.ModifiedandadaptedfromNIDDK.

Anephrologistmayalsoorderthefollowingsupportinglaboratorytests:

• Bloodureanitrogen(BUN)measurement—Thistestisanindicatorofkidneyandliverhealth.Ureanitrogenformsafterproteinhasbeenbrokendown.Healthykidneysfilteroutureanitrogenthathas

https://www.niddk.nih.gov/health-information/health-communication-programs/nkdep/learn/causes-kidney-disease/testing/understand-gfr/Pages/understand-gfr.aspx

18 March2017

traveledfromtheliver,intothebloodstreamandthroughthekidney.Higherthannormalcirculatingureanitrogenlevelsmayindicatekidneydamage.

• Bloodpressure—Elevatedbloodpressure,togetherwiththeotherkidneydamageindicatorslistedabove,supportthediagnosisofkidneyfailure.

• Mineralpanel—Failingkidneyscanleadtohigherthannormalcirculatinglevelsofcalcium,phosphorus,andpotassium;therefore,abloodtesttodetectthesemineralscanhelptoassesskidneyhealth.

• Hematocrit—Hematocritistheratioofredbloodcellstothetotalvolumeofblood.Alowhematocritscoreindicatesdecreasedredbloodcellcontent—asignofanemia.

• Hemoglobin—Thisistheoxygen-carryingproteinfoundinredbloodcells.Ifanemiaispresent,hemoglobincontentwillbelowerthannormal.

• Kidneybiopsy—Insomecases,abiopsy(pieceoftissue)istakenforfurthermicroscopicexaminationtodeterminetheextentofkidneytissuedamageaswellasCKDstage.AtarecentNationalInstitutesofHealth(NIH)workshop,thelackofkidneybiopsiesperformedwashighlightedasakeyunmetneedinthefield.Investigatorsunderscoredtheneedforincreased,standardizedkidneybiopsypracticestofuelresearchanddevelopmenteffortsinthequestfortherapeuticinnovation.

19 March2017

TREATMENT

Theonlytwotreatmentoptionsavailabletokidneyfailurepatientsaredialysisorkidneytransplantation.Althoughtheuseofmedicationtocontrolbloodpressureand/orbloodsugarcanslowtheprogressionthroughCKDstages1-4,thedamagetothekidneysispermanent.Nevertheless,thepatient’skidneyscanstillperformtheirkeyfunctionstosupportliving.Ifthepatientprogressestokidneyfailure(CKDstage5),thekidneyscannolongersupportlifeontheirown.

Althoughlifesaving,dialysisandtransplantationarefraughtwithchallenges.Regardingtheformer,thelackofinnovationindialysiscareisalargeunmetneedforthekidneydiseasefield.Regardingthelatter,accesstodonorkidneysisextremelylimited,whichhasmotivatedtheWhiteHousetochampioneffortstoaddressthedonororganshortage.Bothtreatmentoptionsaredescribedbelow.

DIALYSIS

Dialysistreatmentinvolvestheuseofspecializedmachinerytofilterthebloodwhenthekidneyscannolongerdoso.Therearetwotypesofdialysis:hemodialysisandperitonealdialysis.

HEMODIALYSIS

Hemodialysistreatmentusesadialysismachinetocleanthetotalvolumeofthepatient’sblood(Figure6).Thepatient’sbloodentersthedialysismachine,passesthroughthedialyzer(filterservingastheartificialkidney)toremovewasteandexcessfluid,andthenre-enterscirculationthroughavein.Arteriesandveinsaretwomajorbloodvesselsinthebody.Arteriestakebloodawayfromtheheart,andveinstakebloodbacktotheheart.About1pint(0.125gallons)ofbloodflowsthroughthedialysismachineperminute.

Inpractice,therearetwomethodsofhemodialysisdelivery:

• In-centerdialysis—Thismethodtypicallyinvolvesreceivingdialysistreatmentinadialysiscenter.Treatmentisadministeredthreetimesperweekforsessionslasting3to4

hourseach.• Homedialysis—Thismethodinvolvesthepatientand/or

caregiveradministeringdialysistreatmentathome,followingthoroughtrainingsessions.Thisprocesscaninvolvesmaller,moreportablemachines.

Hemodialysisisthemostcommonkidneyfailuretreatment.In2013,about88percentofnewlydiagnosedpatientsweretreatedusingthismodality.Thesuccessofhemodialysisdependsonthesurgicallyplacedvascularaccesspointfromwhichthebloodleavesandreturnstothebody.

Figure6.Depictionofhemodialysisprocess.Source:NIDDK.

https://www.niddk.nih.gov/health-information/health-topics/kidney-disease/treatment-methods-for-kidney-failure-in-children/Pages/facts.aspx

20 March2017

VASCULARACCESS

Accessingthepatient’svascularsystemiscriticaltodialysisbecausethevascularsystemisresponsibleforcirculatingblood.Fordialysistooccur,themachine’stubesmustbeconnectedtothepatient’svasculature,whichiscalledvascularaccess.Figure7illustratesthethreevascularaccesspossibilitiesdiscussedbelow:

• Arteriovenous(AV)fistula—Thissurgicalprocedurecreatesadirectconnectionbetweenanarteryandveinintheforearm.Thisproceduremustbeperformed2to3monthsinadvanceofusebecausetheAVfistulaneedstimetodevelop.TheAVfistulaisdesignedforlong-termuse,typicallylastingseveralyears.Thisisthegoldstandardforvascularaccess;howeveronly17percentofpatientsinitiatedialysiswithanAVfistuladuetovariouscontributingfactors(e.g.,age,vascularhealth).

• Arteriovenous(AV)graft―Thistubeissurgicallyinsertedundertheskinandconnectsanarterytoaveinintheforearm.Thisproceduremustalsobeperformedinadvance,about2to3weeks,ofuse.Duringdialysis,thistubingispuncturedtoconnectthemachinerytothevascularsystem.TheAVgraftisalsodesignedforlong-termuse,typicallylastingabout2to3years.ThismethodisusedwhenapatientisnotagoodcandidateforanAVfistulaorwhenanAVfistulafails.

• Venouscatheter―Thisflexibletubeissurgicallyinsertedintoaveinintheneck,chest,orlegnearthegroin.Thevenouscatheterisavailableforuseuponinsertion;however,itisonlyintendedforshort-termuse(2weeks

toamonth).Avenouscatheteristypicallyusedinemergencysituationsorwhenkidneydiseasehasprogressedmorerapidlythanexpected.

Figure7.Vascularaccessoptions.Depictionsofvascularaccessoptions,showingcommonplacementlocationsonthebody.AdaptedfromNIDDK.

https://www.niddk.nih.gov/health-information/health-topics/kidney-disease/vascular-access-for-hemodialysis/Pages/index.aspx10

21 March2017

PERITONEALDIALYSIS

Peritonealdialysisusestheliningofthepatient’sabdomen(theperitoneum)asthefilterforthepatient’sblood.ThisprocessisillustratedinFigure8:

• Thepatient’sabdominalcavityisfilledwithasalineandglucosesolution,orthedialysate.

• Wasteproductsandexcessfluidareabsorbedfromthebloodintothedialysateafterabout4to6hours,whichisthedwelltime.

• Theuseddialysateisdrainedandthestomachisre-filledwithfreshdialysate;thisexchangetypicallytakes30-40minutestocomplete.

Mostpatientstypicallycompletefourtosixexchangesdaily.Withcontinuousambulatoryperitonealdialysis(CAPD),theexchangeisperformedmanually.Withperitonealdialysisprocess,amachine(cycler)automaticallyperformsthreetofiveexchangeswhilethepatientsleeps.Thisisknownasautomatedperitonealdialysis(APD).Peritonealdialysisisnotascommonashemodialysis.In2013,amere9percentofnewlydiagnosedkidneyfailurepatientsweretreatedwiththismodality.PatientsreportthatCAPDandAPDallowforgreaterflexibilityandindependence.

COMPLICATIONSASSOCIATEDWITHDIALYSISTREATMENT

Dialysisisalifesavingtherapy,inthatkidneyfailurewouldbefatalwithoutthisintervention.Nevertheless,itisaverylimitedmaintenancetherapy.Theyearlymortalityrateisunacceptablyhighat15-20percent.Thesurvivalratefordialysispatientsisshockinglylow―approximately55percentofhemodialysispatientsand66percentofperitonealdialysispatientsarestilllivingafter3yearsoftreatment.Thedialysistreatmentparadigmhasimprovedonlymodestlyover30years,andthereforeinnovationisdesperatelyneededtobenefitpatients.

Severalcomplicationscanarisewithdialysis—allofwhichsignificantlyimpactQOL.AVgraftsandcathetersarepronetodevelopingbloodclotsandinfection,leadingtohospitalizationevents.Othercomplicationsincludenarrowingofbloodvessels,increasedbloodpressure,andlossofpropercirculationtothearmsandlegs(extremecasescanresultinamputation).AVfistulasarelesspronetobutnotexemptfromthesecomplications.

Asstatedabove,severalsecondaryhealthconditionsaccompanykidneyfailure,namelyanemia,boneandmineraldisease,andCVD.Consequently,patientsmustundergotreatmentforthosediseasesinadditiontotheirdialysistreatment.Dialysispatientsusuallytakemanydifferentmedicationstoovercomethesesecondaryconditions:erythropoietin-stimulatingagents(ESA)thatboostredbloodcellproduction,intravenous(IV)irontosupportoxygenbindingtoredbloodcells,activatedformsofvitaminD,bloodpressurepills,anddrugsthatbindphosphorusinfoodtoreducetoxicmineralbuildupinthebody.Somepatientssufferingfromanemiaalsoundergobloodtransfusions;howeverthistreatmentcanposechallengesforfuturetransplanteligibilitybecauseofpotentialover-sensitization(seeBarriersAssociatedwithKidneyTransplantationsectionbelowonpage23).

Figure8.Peritonealdialysis.Source:NIDDK.

https://www.niddk.nih.gov/health-information/health-topics/kidney-disease/treatment-methods-for-kidney-failure-peritoneal-dialysis/Pages/facts.aspx

22 March2017

Figure9.UNOSregions.TheU.S.isdividedinto11geographicregions.Source:HRSA.

BARRIERSASSOCIATEDWITHDIALYSISTREATMENT

Kidneyfailuretreatmentexistsatthenexusofmedicine,clinicalresearch,policy,andeconomicswheretherearecompetinginterestsandincentivestocatalyzechangeandrealizemuchneededprogress.Forexample,challengesexistwiththedeliveryandfrequencyofhemodialysistreatment.Scientificevidenceindicatesthatpatientsfarebetterwhentheyundergomorethanthreedialysissessionsperweek(whichisthecurrentin-centerregimen).Patientsmayreceivemorefrequentdialysis,buttheymustpayforextrasessionsoutofpocketbecauseMedicarewillonlyreimburseforthecurrentregimen.Becausethesepatientsalreadyincurthehighestamountofout-of-pocketcostsofallMedicarebeneficiaries,extrasessionsarelikelycostprohibitivefortheclearmajorityofthem.

KIDNEYTRANSPLANTATION

Asmentionedpreviously,thebesttreatmentoptionforeligiblepatientswithkidneyfailureiskidneytransplantation.Kidneytransplantationresultsinincreasedlifeexpectancy,QOL,andcostsavingsforbothpatientsandtaxpayers.However,becauseofthescarcityofavailabledonorkidneys,lessthan30percentofkidneyfailurepatientsreceiveatransplant.

Twotypesofdonorsprovidekidneysfortransplantation:

• Alivingkidneydonordonatesonefunctionalkidneywhilestillalive.Humanscanlivewithonefunctionalkidney.

• Adeceasedkidneydonorhaselectedtohavehisorherorgan(s)donatedupondeath.

Uponsuccessfulkidneytransplantation,thepatientmustremainonimmunosuppressivedrugsaslongasthetransplantisworkingtoensurethattheimmunesystemdoesnotattackthekidneyasforeigntissue.

ORGANTRANSPLANTWAITLIST

KidneysarethemosttransplantedorganintheUnitedStates.Theorgantransplantwaitlist,managedbytheUnitedNetworkforOrganSharing(UNOS),isdividedinto11geographicregionsandisusedtodetermineorganallocationthroughoutthecountry.Eligiblekidneyfailurepatientscanelecttobeplacedonthiswaitlistandbenotifiedonceakidneybecomesavailableforwhichtheyareeligible.Justover15percentofallkidneyfailurepatients(nearly87,000asof2013)arelistedforakidneytransplant.

TheKidneyAllocationSystem(KAS)guidesorganallocationthroughtheUnitedStates.Severalfactors(medicalandnon-medical)weighintotheallocationofeverydonatedorgan,suchasbloodtype,donor/recipientimmunesystemcompatibility,priorlivingdonorstatus,lengthoftimeonwaitlist,distancefromdonorhospital,survivalbenefit,andpediatricstatus.

TwocentralchangesemergedfromsignificantmodificationoftheKASin2015:

• Kidneydonorsandrecipientsarenowprofiledusingadifferentscoringsystem,and• Theconceptoflongevitymatchingofkidneystotransplantrecipientswasintroduced.

https://www.unos.org/

https://www.unos.org/

https://optn.transplant.hrsa.gov/members/regions/

23 March2017

DeceaseddonorsareassignedascorecalledtheKidneyDonorProfileIndex(KDPI).Thisnumericalmeasurecombines10donorfactorsintoasinglenumber―asopposedtofourfactorsusingtheprevioussystem—therebymakingitabetterpredictorofdonorquality.EveryadultpatientonthekidneywaitlistisassignedascorecalledtheEstimatedPostTransplantSurvival(EPTS).KDPIsummarizesintoasinglenumberthequalityofdeceaseddonorkidneysrelativetootherrecoveredkidneys.KDPIisnowusedfortheimplementationofthe“longevitymatching,”inwhichcandidateswithlongerestimatedpost-transplantlongevity(EPTSscoreof20percentorless)willreceivepriorityforkidneysfromdonorswithKDPIof20percent.

COMPLICATIONSASSOCIATEDWITHKIDNEYTRANSPLANTATION

Kidneytransplantationis,byfar,thebestavailableoptiontokidneyfailurepatients.In2012,theprobabilityofsurvivalwithin1yearpost-transplantwas95and98percentfordeceasedandlivingdonorkidneytransplantrecipients,respectively.Furthermore,theremaininglifeexpectancyofkidneytransplantrecipientsages65-69isnearlytriplethatofdialysispatientsasillustratedinFigure10.However,twomajorcomplicationsstillexistwithtransplantation:thepossibilityoforganrejectionandinfection.Fortheperiod2005-2008,survivalofthetransplantedkidney(calledagraft)at10years(about34-48percent)wasmuchlowerthansurvivalat1year(89-91percent),whichincreasesthelikelihoodofre-transplantationordialysis.Infact,greaterthan20percentoftransplantrecipientsreturntodialysisafter10years.Theimmunosuppressivedrugsthattransplantrecipientsmusttakefortheirremaininglifetimecanleavethepatientsusceptibletoinfectionsandcertainkindsofcancer.Philanthropycouldplayaroleineffortstoimprovetransplanttherapeutics.

BARRIERSASSOCIATEDWITHKIDNEYTRANSPLANTATION

Arecord17,878kidneysweretransplantedin2015;however,thisnumberpalesincomparisontothenumberofpatientsawaitingatransplant.Eachday,144peopleareaddedtotheorganwaitlistand22peoplediewhilewaitingforalifesavingtransplant.Forkidneyfailurepatients,mortalityonthetransplantlistisdirectlyrelatedtotimeondialysis.Severalchallengesplaguethekidneytransplantationfield,suchasthefollowing:

• Lackoflivingdonors—Althoughlivingdonationiswidelyacceptedbythepublic,andseveralsurveyssuggestthat50-90percentofpeoplearewillingtodonatetheirkidneytoafamilymemberorstranger,thisdoesnotnecessarilytranslateintoorgansdonated.In2013,about5,000peopledonatedtheirkidney,whichwaslessthanone-thirdofallkidneystransplanted.Giventhattransplantrecipientsfarebetterwithlivingdonorkidneys,measurestofacilitatelivingdonationareneeded.

• Patientsensitization—About30percentoftransplantpatientsaresensitized,whichaffectsaccesstotransplantation.Sensitizationmeansthatthepatienthasdevelopedproteinsthatwillattackforeigntissue,likeatransplantedorgan.Theseproteinscandevelopthroughpreviousexposuretoforeigntissuetypes,suchasthroughbloodtransfusions,pregnancy,orpreviousorgantransplants.AccordingtoJohns

Figure10.Expectedremaininglifetimeofkidneyfailurepatientsvs.generalU.S.population,bytreatment.Thisgraphillustratestheremaininglifetime,inyears,ofkidneyfailurepatientsages65-69bytreatmentmodalityofprevalentdialysispatients,prevalenttransplantpatients,andthegeneralU.S.population(2012),basedonUSRDSdataandtheNationalVitalStatisticsReport(2013).

24 March2017

HopkinsMedicine,sensitizedpatientsmaywaitthreetofourtimeslongerthanunsensitizedpatientsforacompatibledonorkidney.

• Lackofaccessduetoracial,ethnic,SES,andgeographicdisparities—Asmentionedabove,CKDdisproportionatelyaffectsracialandethnicminoritiesaswellasindividualswithlowSES.Likewise,theseindividualshavelessaccesstotransplantationoverall,arelesslikelytobeaddedtothewaitlist,andexperienceincreasedriskoftransplantedorganfailure.Inaddition,whereoneliveshasaprofoundeffectontransplantaccess.

• Limitedpreservationcapacity—Currently,akidneycanbepreservedforamaximumof24-48hours.Innovativesolutionstoincreasetheorganpreservationtimewouldexpandaccesstoavailableorgans.

• Lackofalternativetissueoptions—Kidneytransplantationiscurrentlylimitedtoorgansprovidedbypeople;however,bioengineeredcellsandtissuewouldgreatlyexpandgraftoptions.

• Highdiscardrates—Someofthe2,700kidneysdiscardedin2015organscouldhaveprovidedbenefitstodialysispatients.Overall,thediscardrateremainsatabout20percent.

Asthenumberofpatientsinneedofakidneytransplantcontinuestorisedisproportionatelytothenumberofdonorkidneysavailable,breakthroughsinresearchanddevelopmentaresorelyneeded.Thisisanareawherestrategicphilanthropicinvestmentcouldhavesignificantimpact—tosupportinnovationintransplanttherapeutics,organpreservation,aswellasbioengineeringofartificialcellsandtissues,whichmayonedaybeablereplacedamagedkidneytissue.

Organtransplantationisanationalpriority.ThemonthofAprilwasdeclaredNationalDonateLifemonthbypresidentialorderin2015.OnJune13,2016,theMilkenInstituteCenterforStrategicPhilanthropyattendedtheWhiteHouseOrganSummit,whichfocusednationalattentiononthecurrentplightoforgandonationandtransplantationintheUnitedStates,aswellasfacilitatednewinitiatives,collaborations,andpartnershipstoaggressivelyreducetheorganwaitlist.Thereistremendousopportunityforphilanthropytoleveragethisnationalattentionandmomentumtocatalyzechangebysupportinginnovativesolutionsthatreducethewaitlistandresearcheffortsthatexploreinnovativealternativestoconventionalkidneytransplants.

https://obamawhitehouse.archives.gov/blog/2016/06/13/saving-lives-and-giving-hope-reducing-organ-waiting-list

25 March2017

MOLECULARBIOLOGYOFDISEASE

Surprisinglylittleisknownaboutwhatcauseskidneyfailureatamolecularlevel.Assuch,targetedtherapiesarecurrentlynonexistent.ThereisaclearneedtoidentifyandaddressthechallengestoresearchprogressinCKDandkidneyfailure.Despitetheapparentdearthofknowledge,oneofthebiggestbreakthroughsinkidneydiseasebiologyexistsatthelevelofgenetics.

APOL1—AKEYGENETICRISKDETERMINANTINKIDNEYFAILURE

Therearetwocopiesofeachgeneinthebody(exceptforthegenesthatdeterminesex)—referredtoasalleles.Genescodeforproteins,whichinturncarryoutcellularfunctions.TheAPOL1genecodesfortheproteinapolipoproteinL1,acomponentofhighdensitylipoprotein(HDL,the“good”cholesterol).ApolipoproteinL1isalsofoundinkidneycells.ThetwogeneticvariantsofAPOL1,G1andG2,areassociatedwithrisktokidneyhealth.Recentscientificevidenceindicatesthatapersonwhoexpressesonecopyofeithervariantalleleisatanincreasedriskofdevelopingoneofseveralkidneydiseases,includingkidneyfailure.Furthermore,apersonwhoexpressestwocopiesofeithervariantalleleisatanevenhigherrisk,nearlyseventoeightfold,ofprogressingrapidlytokidneyfailure(non-diabetic,hypertension-associatedtype).Figure11conceptualizestheAPOL1riskvariantsandtherelativeriskassociatedwiththeirexpression.

SeveralexpertshavepostulatedthatthesegeneticriskvariantspartiallyexplaintheracialdisparitybetweenBlacksandWhitesbecausetheG1andG2variantsaremostcommoninpopulationsofrecentAfricanancestryandoccurveryrarelyinotherpopulations.Thefieldisworkingtounderstandthisphenomenonatamechanisticleveltounderstandexactlyhowthesevariantscontributetokidneydisease.InarecentarticlepublishedintheProceedingsoftheNationalAcademyofSciences,OlabisiandcolleaguesdescribeapotentialmechanismforhowAPOL1genevariantscausetoxicitywithinthecell,eventuallyleadingtocelldeath.TheydemonstratethatAPOL1riskvariantsoveractivatecertainproteinsthatareknowntomediatekidneyinjury.Thisandotherfuturediscoveriesmayprovidethefieldwithpotentialtherapeutictargetsforfutureresearchanddevelopmentefforts.

Thescienceunderlyingkidneyfailureisunfolding;however,controversyandunansweredquestionsremaindespitethisintensestudy.Ina2013articleintheJournalofClinicalInvestigation,FriedmanandPollakhighlightthat,althoughtherelativeriskofdevelopingkidneyfailureissignificantlyhigherinAPOL1riskvariantcarriers,theirpresenceisnotsufficienttocausedisease.ItishighlylikelythatothergeneticandenvironmentalcontributorsmodifytheexpressionoftheAPOL1riskvariantprofile.Kidneyfailureisacomplexdiseasecausedbyamyriadofconditionsthataffecttotalbodymetabolism.Therefore,itislikelythatothermolecularandenvironmentalfactorscontributetothisdisease.Itisextremelydifficulttoisolatecausalmolecularinteractionswithsomanycomorbidities.However,identificationofAPOL1riskvariantsrepresentsthegreatestmoleculardiscoveryinthefieldtodate.

Figure11.APOL1riskvariantsandpatternofexpression.

26 March2017

THERENIN-ANGIOTENSIN-ALDOSTERONESYSTEM(RAAS)—ATHERAPEUTICTARGET

TheRAASisahormonesystemthatregulatesbloodpressure,fluidvolume,andsodiumcontentinthebodyasillustratedinFigure12.Thekidneysproducereninandangiotensin-convertingenzyme(ACE),proteinsthatcatalyzecomplexbiologicalreactions(enzymes).ReninandACEdrivethecreationofangiotensinI,II,andaldosteroneinthebody.Together,angiotensinIIandaldosteroneworktoraisebloodvolume,bloodpressure,andsodiumlevelsinthebloodtorestorethebalanceofsodium,potassium,andfluids.However,chronicoveractivationoftheRAAScanleadtohypertension.BlockadeoftheRAASslowstheprogressionofproteinuria-associatedkidneydisease.TheseimportantmoleculesintheRAASrepresenttherapeutictargetsofcurrentlyuseddrugs(suchasACEinhibitorsandangiotensinIIreceptorblockers[ARBs])andexperimentaldrugsinclinicaltrials.

Figure12.Therenin-angiotensin-aldosteronesystem(RAAS).Reninandangiotensin-convertingenzyme(ACE)aretwokeyproteinsthataresecretedfromthekidneytodrivealdosteronesecretion.Aberrant,chronicoveractivationofthissystemcanleadtohighbloodpressureandotherdeleteriouseffects.Drugscommonlyusedtotargetthissystem,suchasACEinhibitorsandARBs,areoftenusedtotreatCKD.ImagemodifiedfromWikimediaCommons.

https://commons.wikimedia.org/wiki/File:Renin-angiotensin-aldosterone_system.png

27 March2017

Figure13.Phasesofclinicaltrials.DuringPhaseI,researcherstestanewdrugortreatmentforthefirsttimeinasmallgroupofpeopletoevaluateitssafety,determineasafedoserange,andidentifypotentialsideeffects.DuringPhaseII,proof-of-conceptstudiesareperformedasthedrugortreatmentisgiventoalargergroupofpeopletodeterminetheeffectiveandoptimaldose.DuringPhaseIII,thedrugortreatmentisgiventolargegroupsofpeopletoconfirmitseffectiveness,monitorsideeffects,andassessitsimpactcomparedtothecurrentstandardofcare.SomeclinicaltrialsinvolvemultiplephasestofacilitateseamlesstransitionfromonetoanotherandarewrittenasPhaseI/IIorPhaseII/III.Thesedesignationsarealsousedinadaptivetrials,whereinstudyparametersaremodifiedwithrespecttoongoingtrialresults.ImagecourtesyofDr.JasonLuke,UniversityofChicagoSchoolofMedicine.

CLINICALTRIALSANDINVESTIGATIONALTHERAPIES

CLINICALTRIALS—OVERVIEW

Clinicalresearch(alsoreferredtoasclinicaldevelopment)isabranchofbiomedicalresearchinvolvinghumansubjects.Thegoalofclinicalresearchistoevaluatethesafetyandefficacyofdrugs,medicaldevices,ordiagnosticsintendedforuseinhumanpatients.

Clinicaltrialsareanimportantcomponentofclinicalresearchbecausetheyareusedtoevaluatethesafetyandefficacyofanexperimentaldrugortherapyinhumansubjects.ClinicaltrialsaredividedintophasesasdescribedinFigure13.Theycanalsobeusedtocollectspecimensfromhumansubjectsforfurtherresearch.Importantly,informationonpotentialsideeffectsaregatheredduringtheclinicaltrialperiodandweighedagainstthepotentialtherapeuticbenefitofthetreatmentunderinvestigation.

Theresearchanddevelopment(R&D)process—theprocessbywhichalaboratorydiscoveryisdevelopedintoacommercialtherapeutic,diagnosticordevice—isverycostlyandtime-intensive.Itisestimatedthat95percentofnewdrugstestedinclinicaltrialsfailtomakeitintotheclinic.Thisisahighfailurerateforaprocessthatcostsabout$1billioninoverallresearchcostsandupto15yearsoftimeinvested.

28 March2017

Figure14.Interventionalclinicaltrialsforkidneyfailure.Ofthe90active,interventionalclinicaltrials,25(28%)areinPhase3.Dataobtainedfromwww.clinicaltrials.gov.

KIDNEYFAILURECLINICALTRIALS

AsofJuly2016,thereare90activeinterventionalclinicaltrialsforkidneyfailure.Figure14illustratesthedistributionofthesetrialsbyphase.

Kidneyfailureclinicaltrialsareexpensiveandinherentlyriskyforseveralreasons:

• Timeneededtocompleteastudy—Largepatientpopulations,oftennumberinginthethousands,needtobefollowedforlongperiodsoftimetocapturespecificeffectsaboveconventionaltherapy.

• Lackofreliablebiomarkerstopredictadversesafetyevents—Investmentsinclinicaltrialscouldbemoreappropriatelyallocatediftherewasareliablewaytopredictsafety.Accordingtoexperts,toomanylargetrialshavefailedbecauseofaninabilitytopredictdrugsafety.

• Heterogeneousnatureofthedisease—Severaldiseasepathsleadtokidneyfailure,whichinturnleadstoremarkableheterogeneityinthepresentationofCKDpatients.However,theprobabilityofsuccesswouldincreaseiftherewereareliablewaytoidentifyandselectivelyenrollCKDpatientswhoarelikelytoprogresstokidneyfailure(i.e.,“strongprogressors”).Patientheterogeneitycanhavenegativeeffectsonstudyresults.Testingauniformgroupofpatientswouldpreventdilutionoftreatmenteffectandenablefastrecognitionofeffectivetreatments.Thisissuehighlightstheneedforbetterpatientstratificationtoensurethatinvestigationaltreatmentsareappliedtotherightpatients.

Despitethemyriadofchallenges,therearenumerousopportunitiesforimprovementinthekidneydiseasefield.Philanthropyisuniquelypoisedtode-riskkidneydiseaseresearcheffortsandtherebyattractindustryinvestmenttospuradvances.Furthermore,strategicinvestmentincriticalresourcesandinfrastructurewillallowforaccelerationofpromisingsciencefrombasicresearch,throughthecriticaltranslationalresearchphase,andintoclinicaldevelopment.

INVESTIGATIONALTHERAPIES

Theclinicaldevelopmentlandscapeisincrediblybarrenbecauseofthepaucityofclinicallyrelevantmoleculestotargettherapeutically.Mostdrugsweredevelopedtotreatotherconditions,suchashypertensionanddiabetes,andadoptedtotreatkidneydisease.Furthermore,thevastmajorityofkidneyfailureclinicaltrialstesttreatmentsofthecomplicationsassociatedwithkidneyfailureandoptimizationofdialysisandtransplanttherapeutics.

Thedevelopmentofnewdrugsforkidneyfailurepresentssomeinterestingeconomicchallengesaswell.Medicarereimbursesthecostofdrugsasabundledpayment,definedasareimbursementtohealthcareproviders“onthebasisofexpectedcostsforclinically-definedepisodesofcare.”Therefore,thereisincentiveforapharmaceuticalcompanytohaveitsdrugcoveredwithinthebundledpaymentsystemtorealizeanyappreciableprofits.However,thestakestogetanewdrugcoveredinthebundledpaymentarehigh—thedrugmusthavedemonstratedefficacythatfarexceedsthosefordrugsalreadycovered.Therefore,thishighbarrierofentrymaydisincentivizecompaniesfrominnovatingandcreatingnewtherapeutics.

http://www.clinicaltrials.gov

29 March2017

ThevaluepropositionneedstobemodifiedtoaligninterestsinsearchofbettertherapeuticstoimproveQOLforpatients.Strategicphilanthropicinvestmentisuniquelypoisedtoaddressthesechallengesbecauseitisnimbleenoughtorespondtodynamicchangeswithinthekidneydiseasespace.

Giventhelackofinnovationinpharmaceuticalclinicaldevelopment,thesectionsbelowprovidetheconceptualframeworkforafewnewmedicaldevicesindevelopmentaswellashighlightkeyinitiativespresentedattheWhiteHouseOrganSummitthathavepotentialforhighimpact.

MEDICALDEVICEDEVELOPMENT

Belowareprofilesofdevicesthataimtoimprovedialysisoptionsbyaddingdesiredfeatures(e.g.,portability)orresolvingvascularaccesscomplications(e.g.,decreasingclotformation).

WEARABLEARTIFICIALKIDNEYPROTOTYPEINDEVELOPMENT

Standarddialysisgenerallyinvolvesattachingpatientstoanimmovabledialysismachine(eitherathomeorinaclinic)forsessionsthatrangefrom3to4hours.Standardpracticerecommendsdialysisthreetimesperweek.NewresearchsuggeststhatdailydialysisresultsinaconsiderableimprovementinQOL,resultingin:

• Substantialreductionincomplicationssuchasanemia,hypertension,electrolyteabnormalities,andacidbuildupinthebody

• Attenuationoftheneedforadditionalmedicationtotreattheaforementionedcomplications

• Fewerhospitalizations

• Fewerdietandfluidrestrictions

• IncreasedappetiteAwearableartificialkidney(WAK)device,whichwouldallowfordailydialysis,iscurrentlyindevelopmentandhaspassedanU.S.FoodandDrugAdministration(FDA)-approvedproof-of-conceptclinicaltrialinvolvingsevenpatients.TheFDAselectedtheWAKforafast-trackapprovalprogramin2012.Thepresentprototype(Figure)

isa10-pounddevice,poweredby9Vbatteriesandwornaroundthewaist.TheWAKprototypeisbeingredesignedtodecreasethesizeandimproveefficiencyandwillundergoadditionalsafetytesting.

TransitiontoadailydialysismodelusingaWAKdevicecouldleadtoimprovedpatientmobilityandpsychologicalwell-beinginadditiontothebenefitslistedabove.TheWAKwouldprovideapromisingtreatmentoption,inthefaceoflowavailabilityofkidneysfortransplantation,usheringinafundamentalshiftincaredelivery.Apartfromtheclearmedicalbenefits,thispromisingtechnologystandstosubstantiallydecreasetheeconomicburdenofdialysistreatmentbyreducingthenumberofhospitalizationevents.

Figure14.Wearableartificialkidney(WAK).Left:Illustration(Source).Right:Personwearingtheprototype(Source).

http://www.reuters.com/article/us-kidney-artificial-idUSL1243564120071214

http://www.techtimes.com/articles/163664/20160608/wearable-artificial-kidney-could-free-patients-from-dialysis-machines.htm

30 March2017

Figure15.Implantablebioartificialkidney.Source:UCSF.

Figure16.HemoaccessValveSystem®.Source.

IMPLANTABLEBIOARTIFICIALKIDNEY—THEKIDNEYPROJECTPROTOTYPEINDEVELOPMENT

Currently,thebesttreatmentoptionforkidneyfailureiskidneytransplantation;however,becauseofthelimitedavailabilityofkidneydonors,lessthan30percentofkidneyfailurepatientsreceiveatransplant.Asthenumberofpatientsinneedofakidneytransplantcontinuestorisedisproportionatelytothenumberofdonorkidneysavailable,thereisatremendousneedforanalternativemedicalsolution.

Theimplantablebioartificialkidneyrepresentsapromisingalternativetoconventionalkidneytransplantsthat:

• Addressestheorganscarcityissue

• Eliminatestheneedforconventionaldialysis

• Couldattenuatetheneedforlifelongimmunosuppressiontherapythatisrequiredforconventionaltransplantstoensurethatthebodydoesnotrejectthekidney

Thisprototypedeviceisdesignedtoconnectdirectlytothepatient’sbloodsupplyandbladder(theotherkeycomponentsofthebody’swasteremovalsystem),nearthenaturalkidneys,whichwillnotberemoved(seedepictioninFigure15).Usingnovelsiliconnanofiltersandlivingkidneycells,thedeviceisdesignedtooperatebasedonthepatient’sbloodpressurealone,withouttheneedforapumporanelectricalpowersource.GovernmentandprivatesourceshavefundedtheKidneyProjectsinceitsinception.Recently,theNationalInstitutesofHealth(NIH)awardedtheprojectwitha4-year,$6milliongrant.TheFDAalsoselectedtheKidneyProjectforafast-trackapprovalprogramin2012.Ifsuccessfulthisdevicecoulddramaticallychangeandsavethelivesofmillionsofpatientsandcouldbecomeanintegralpartofthekidneycaresetting—similartothepacemakerinthecardiologycaresetting.

HEMOACCESSVALVESYSTEM®(HVS)PROTOTYPEINDEVELOPMENT

Asdiscussedabove,accesstothepatient’svascularsystemiscriticaltodialysisbecausethevascularsystemisresponsibleforpumpingblood.Fordialysistooccur,themachine’stubesmustbeconnectedtothepatient’svasculature.

AVgraftsarefraughtwithcomplicationsinadditiontoinfectionandbloodclotting,suchasnarrowingofbloodvessels,increasedbloodpressure,andlossofpropercirculationtothearmsandlegs(extremecasescanresultinamputation).Thesecomplicationsaredueinlargeparttocontinuousbloodflowthroughthegraft.However,bloodflowthroughagraftisonlyneededfordialysispurposes,whichis,atmost,12hoursperweek,asopposedto24hoursaday.

LimitingbloodflowthroughanAVgrafttoonlythetimeswhenneededfordialysistreatmentcanbenefitthepatientbyextendingthelifeofthebloodvesselsnearthegraftsiteandpreventingveincollapseatthepatient’sprimaryaccesspointfordialysis.TheHVSindevelopment(Figure16)allowsforselectivebloodflowcontrolthroughanAVgraftonlywhenneededfordialysisandthenturnsoffthebloodflowtothegraftbetweendialysissessions.TheHVSwasalsoselectedbytheFDAforafast-trackapprovalprogramin2012andiscurrentlyinclinicaltrials.

http://pharm.ucsf.edu/kidney

https://es.slideshare.net/trimedmedia/the-fda-early-feasibility-study-pilot-and-the-innovation-pathway

31 March2017

Figure17.HumaGraft™.Source:Humacyte.

TISSUE-ENGINEEREDVASCULARGRAFT—HUMAGRAFT™PROTOTYPEINDEVELOPMENT

TherepetitivecomplicationsassociatedwithAVgraftsresultinincreasedhospitalizationeventsanddecreasedoverallQOL.ThesyntheticmaterialsusedtomakeAVgrafts,suchasTeflon®orpolytetrafluoroethylene(PTFE),areoftenblamedfortherepetitiveinfectionsassociatedwithtraditionalAV

grafts.Useofahumantissueplatformcouldeliminatetheadversereactiontosyntheticmaterialsbutcouldintroduceissueswithtissuematching.HumaGraft™isahumanbioengineeredbloodvesselthatcoulddeliveratissue-basedgraftthatdoesnotrequiretissuematching,resultinginthefollowing:

• Longergraftlife

• Lowriskofinfectionandbloodclots

• Lowriskofadverseimmuneresponses

TheHumaGraft™prototypeisabioengineeredveincomposedofhumansmoothmusclecells(Figure17),whicharedecellularizedtoreduceimmunogenicityandeliminatetheneedfortissuematching.Thesebioengineeredveinsdemonstratedexcellentbloodflowandresistancetobloodclotsinearlylabtesting,andtheycouldberefrigeratedforupto12months—makingthemviableforlong-termstorageathospitals.TheHumaGraft™wasselectedforfast-trackapprovalstatusbytheFDAin2014andiscurrentlyinPhaseIIIclinicaltrials.

PUBLICHEALTHMEASURES

PUBLICHEALTHINITIATIVES

InresponsetothesubstantialimpactofCKDandkidneyfailureonhealth,QOL,andhealthcarecosts,avarietyofpublichealthinitiativesareinplacetohelpreducetheprevalenceofCKDandkidneyfailureintheU.S.populationandpromoteaccesstoqualitycare.

ESRDNETWORKS

TheESRDNetworksoftheCentersforMedicare&MedicaidServices(CMS)werecreatedbystatutorymandatein1978toimprovecost-effectiveness,ensurequalityofcare,encouragekidneytransplantationandhomedialysis,provideassistancetoESRDbeneficiariesandproviders,andincreaseESRDNetworkProgramaccountability.

In2015,theCMSawarded$110millioninESRDNetworkfundingto7ofthe18ESRDNetworks.These7entitieswillworkovera5-yearcontractperiodtocontinueeffortstoimprovequalityofcareandaccesstocareforindividualswithirreversiblekidneydiseasewhorequiredialysisortransplantationtosustainlife.

HEALTHYPEOPLE2020

HealthyPeopleisanationalprogramtoprovidescience-based,10-yearnationalobjectivesforimprovingthehealthofallAmericans.Thisprogramhasbeeninplacefor30years,withthemostrecentlaunchin2010.

https://www.cms.gov/Medicare/End-Stage-Renal-Disease/ESRDNetworkOrganizations/index.html

https://www.healthypeople.gov/

http://www.humacyte.com/

32 March2017

CKDclaims14objectivesinthisambitiousprogram,oneofwhichisspecificallydedicatedtoreducingdeathsinpersonswithESRD(objectiveCKD-14).Theinitiativeseekstoaccomplishthisobjectivebyreducingthe:

• Totalnumberofdeathsforpersonsondialysis• Numberofdeathsindialysispatientswithinthefirst3monthsofinitiationofrenalreplacementtherapy• Numberofcardiovasculardeathsforpersonsondialysis• Totalnumberofdeathsforpersonswithafunctionalkidneytransplant• Numberofcardiovasculardeathsinpersonswithafunctionalkidneytransplant

CKDSURVEILLANCESYSTEM

IncollaborationwiththeUniversityofCaliforniaatSanFranciscoandtheUniversityofMichigan,theCDCimplementedthenationalCKDSurveillanceSystem.Thesystemtracksnationaltrendsinthenumberofcases,riskfactors,andcarepracticesthataffectCKDpreventionandcontrol,evaluatequalityimprovementefforts,andmonitorkidneydiseaseobjectivesforHealthyPeople2020(describedabove).Systematicmonitoringwouldinformeffortstoprevent,detect,andmanageCKDanditscomplications.Thesedataalsoinformevaluationsoftheefficacyandimpactofvariousgovernmentqualityimprovementprograms.

OrganizationsinvolvedinthiseffortincludeUniversityofCaliforniaatSanFrancisco,theUniversityofMichigan,AmericanAssociationofKidneyPatients(AAKP),AmericanAssociationofPediatricNephrology(AAPN),NationalKidneyDiseaseEducationProgram(NKDEP),NationalKidneyFund(NKF),Veteran’sHealthAssociation(VHA)NationalProgram,MedicalEducationInstitute,andtheAmericanSocietyofNephrology(ASN).

CKDHEALTHEVALUATIONANDRISKINFORMATIONSHARING(CHERISH)

IncollaborationwithNKF,theCDCestablishedCHERISHtoidentifyindividualsathighriskforCKD,assesstheparticipant’saccesstofollow-upcare,andexaminediseaseprogressioninthosewithCKD.

UsingnationaldatasetssuchastheUnitedStatesRenalDataSystem(describedbelow),theCDCstudiestheepidemiologyofCKDintheU.S.population.Underthisprogram,theCDCalsocollaborateswiththeVHAtostudyhealthoutcomesandthenationalhistoryofCKDamongvarioussubsetsofthepopulation.

UNITEDSTATESRENALDATASYSTEM(USRDS)

TheUSRDSisanationaldatasystemthatcollects,analyzes,anddistributesinformationaboutESRDintheUnitedStates.TheUSRDSisfundeddirectlybytheNIDDK.USRDSstaffcollaboratewithmembersofCMS,UNOS,andtheESRDnetworksbysharingdatasetsandactivelyworkingtoimprovetheaccuracyofESRDpatientinformation.

https://nccd.cdc.gov/ckd/

https://www.usrds.org/adr.aspx

33 March2017

BARRIERSTORESEARCHPROGRESSANDKEYPHILANTHROPICOPPORTUNITIES

InOctober2016,theMilkenInstituteCenterforStrategicPhilanthropyconvenedworld-renownedkidneyexpertstodiscussthestateofsciencerelevanttoCKDandkidneyfailure,aswellasthechallengescurrentlyimpedingprogresstowardimprovedtherapeuticsandcare.Theultimategoaloftheretreatwastoidentifyhigh-impactresearchandsystemsopportunitieswherephilanthropicinvestmentscouldaccelerateprogressintheCKD/kidneyfailurespace.Keychallengeareasincludethefollowing:DISEASEAWARENESSANDWORKFORCECHALLENGES

TRANSPLANTATIONANDDIALYSISINNOVATIONNEEDS

LIMITEDDISEASEUNDERSTANDING

Lackofdiseaseawarenessandeducationbyphysicians,systems,andpatients

Scarcityofdonororgans Lackofmoleculardiseasebiomarkers

Kidneydiseaseresearchworkforceshortfall

Inadequatelong-termtransplantoutcomes

Operationalchallengestoconductingsuccessfulclinicaltrials

Lackofinnovationinkidneyreplacementtherapy

Thesectionsbelowdiscusseachofthekeychallengesalongwithpotentialsolutionsandcorrespondingphilanthropicopportunitiestoaddressthesechallengesandaccelerateresearchprogress.Pleasenotethattheseopportunitiesarehigh-levelrepresentationsandshouldbeconsideredcarefullywithrespecttoyourphilanthropicgoalsanddiscussedindetailwithaphilanthropicadvisor.

DISEASEAWARENESSANDWORKFORCECHALLENGES

LACKOFDISEASEAWARENESSANDEDUCATION

THEPROBLEM

MostpatientsarenotdiagnosedwithCKDuntilthediseasereachesadvancedstages(kidneyfailure),eventhoughrelativelysimpleteststodetectearlierstagesofkidneydiseaseexist(e.g.,measuringcreatininelevelsinthebloodtoestimateGFRand/oralbuminlevelsintheurine).ThisproblempartiallyresultsfromagenerallackofawarenessoftheimportanceofmonitoringkidneyhealthbecauseoftheasymptomaticnatureofCKD.ManypatientswithCKDriskfactorsmaynotbescreenedatearlystagesofCKDwhenprogressionmaybeslowedorprevented,orreferredinatimelymannertospecialtycare.Insomecases,patientsmayhavehadkidneytestsperformed(seetheDiagnosissectiononpage17);however,thephysicianorpatientmaybeunaware.Thelackofawarenessandinequitiesineducationdisempowerpatientsaswellasproviders,resultinginalackofengagementandsuboptimalQOL.

PROPOSEDSOLUTIONSTOADDRESSTHECHALLENGE

FacilitatingeffortstoeducatethepubliconCKDriskfactors,diseasecourse,earlydiagnosis,andavailabletreatmentoptionswouldencourageashiftfrombeingreactivetoproactiveaboutCKDdiagnosisandtreatment.Likewise,providingprimarycarephysicians(PCPs)withthetoolstoproactivelymonitorkidneyhealthandeducatepatientswillfurtherencourageashift,therebyempoweringbothpatientsandproviders.

34 March2017

CORRESPONDINGPHILANTHROPICOPPORTUNITIES

• Fundtargetedpublicawarenesscampaigns—RaisingawarenessofCKD/kidneyfailureisthefirststeptowardraisingthenationalprofileofthediseasestate,whichfuelspolicyreformandattractsfundingdollarsforresearchandtherapeuticdevelopment.Variousdiseasecommunities(e.g.,heartdisease,HIV/AIDS,diabetes,cancer)havesuccessfullyimplementedthislessonandofferseveralexamplesandlessonslearnedfromwhichthekidneydiseasecommunitycanbenefit.Withevolvingsocialmediaandgamingtechnologies,thesecampaignscouldutilizenovelapproachestopromoteawareness.

• Engagepatientstoadvocateforimproved,patient-centeredservicesatallstagesofCKD—analogoustootherhigh-profilediseases(e.g.,HIV/AIDS,breastcancer,diabetes,ALS)—Increasingpatientengagementandadvocacyisthesecondsteptowardraisingthenationalprofileofthediseasestate.Again,therearekeylessonstobelearnedfromdiseasecommunitiesthathaverobustadvocacyprograms.Intentionallyengagingdisproportionatelyaffectedminoritygroups,asothersuccessfulcommunitieshavedone,isanecessarystepforward.Inaddition,successfullyengagingpatientsmayrequireuseofmoreaccessibleterms(e.g.,useof“kidney”ratherthan“renal”)aswellastermsthatcarrylessstigma(e.g.,useof“kidneyfailure”ratherthan“endstagerenaldisease”).

• Supportbioinformaticsinfrastructurethatwillenableinnovativeuseofelectronicmedicalrecords(EMRs)—EMRscontainvaluable,extractableinformationthatcanbeutilizedtocreatetoolsforearlydetectionofkidneydiseaseandidentifypatientsatincreasedriskforkidneyfailure.Leveragingofthiswealthofdatawouldprovideaninvaluabletoolforproviders.However,lackofEMRdatabaseinteroperabilityacrosshospitalsandthelackofbioinformaticstoolstoeasilyandeffectivelymineEMRdataposechallengestosuccessfuldataaggregation,harmonization,andstandardization.Fundinganinfrastructureplatformtoaddressthesechallengeswouldfacilitatecreation,evaluation,anddisseminationofnewCKDdecisionaidsforproviders,eveninlow-resourcesettings.

• Supportaresourcedevelopmentconsortium—Toavoidduplicativeeffortsandtobetterutilizeexistingresources,thisconsortiumwouldbechargedwithstandardizinganddisseminatingexistingeducationaltoolsfortrainees,providers,insurers,andpatients.Thisprocessofresourcedevelopmentwouldclarifytreatmentoptionsandclinicaltrialapplicabilitybasedonpatientneeds.Likewise,itwouldencourageearlierdiscoursebetweenpatientsandproviders,allowingformoreinformeddecision-making.

KIDNEYDISEASERESEARCHWORKFORCESHORTFALL

THEPROBLEM

ThegrowthofthenephrologyworkforcehasnotkeptpacewiththeglobalincidenceofCKD/ESRD.Aconfluenceoffactorsdisincentivizephysiciansandscientistsfrompursuinganephrologyspecialty,includingbutnotlimitedtoitsperceiveddifficulty,lackofinnovationintreatmentparadigms,polarizingpayerandpolicydynamics(thatareperceivedtostiflecreativity),andalackofinterestfromthepharmaceuticalandbiotechindustries.Despitethecomplexnatureofthediseaseandecosystemdynamics,anewinfluxofideaswouldcreatetheinnovativeculturenecessarytomovethefieldforward.

35 March2017


Investmentinhumancapitalthatwillfosteracultureofinnovation,facilitatenewideasandknowledgesharing,collaborateinresearchactivity,andimprovecarepracticesisdesperatelyneededtopropelthefieldforward.Togethertheseoutcomescanlaythegroundworkforthedevelopmentofnewtreatments.Thiscultureshiftwouldalsoencourageotherstakeholderstoinvestinthefieldasinnovativesolutionsbegintobearfruit.


• EndowanannualKidneyDiseaseSummit—Establishinganannualsummitofleadingmultidisciplinaryexpertstocreateavisionforfuturerenaltherapieswouldfacilitatemorecross-talkwithinthevariousnephrologycommunities(e.g.,dialysis,transplantation,basicandtranslationalscience,R&D),outlinecriticalpathsforthefield,andgalvanizethecommunitytodevelopinnovativesolutions.

• Endowanetworkofprofessorshipsinkidneydiseaseandtransplantinnovation—Thisglobalnetworkoffacultywouldusetheseendowedprofessorshipstofocusonmentorshipandnovelkidneydiseaseortransplantresearch.Abuilt-inmentorshipcomponentwouldfostercommunity-buildingandcareerdevelopmentforjuniorfaculty,thuspreparingthemtoserveasfutureleadersandmentors.

• Fundtrainingfellowshipsinkidneydiseasetoattractphysician-scientists—Grantstosupportfellowshipstipendsorprovidebridgefundingforyounginvestigatorswouldencouragethemtoenterandcontinueworkinginthenephrologyspace.

TRANSPLANTATIONANDDIALYSISINNOVATIONNEEDS

SCARCITYOFDONORORGANS

THEPROBLEM

Kidneytransplantationis,byfar,thebestavailabletreatmentforkidneyfailure.NotonlydoestransplantationcorrelatewithbettersurvivalratesandimprovedQOLcomparedtodialysis,butalsoitreducescostsforinsuranceproviders.Despitetheseobviousbenefits,severallimitationshinderinnovationinkidneytransplantation(listedindetailintheBarriersAssociatedwithKidneyTransplantationsectiononpage23).Keybarriersinclude:

• Accesstotransplant—Multifactorialandsystemicissuescontributetodisparitiesintransplantaccess,suchaslowSES,race,ethnicity,andgeographiclocation.

• Barrierstolivingdonation—Thereareapproximately100,000ESRDpatientsonthetransplantwaitlist,butonlyabout6,000livedonortransplantsperyear.Livingdonorscouldhelpfilltheorganshortagegap.Barrierstodonationincludebiologicalincompatibilitiesofdonorswiththeirintendedrecipient,financialburdensofdonation,andconcernfordonorhealthrisks.

• Variablehigh-riskprotocolsacrossclinics—Greatstrideshavebeenmadeindesensitizationprotocols,whichallowforsuccessfultransplantsofpreviouslyincompatiblekidneydonor-recipientmatches,therebyexpandingtransplantoptions.However,theseproceduresvaryfromclinictoclinic,whichleadstovariablesuccessrates.

36 March2017


Fundinginnovative,nontraditionaleffortstoexpandaccesstotransplantation,increaselivingkidneydonation,andinvestinartificialkidneydevelopmentcouldaddresstheorganscarcityissue.Thepotentialforshort-andlong-termgainsexistbecausearangeofmechanismsareavailabletoaddressthischallenge.Inaddition,improvedtransplantoutcomescanbeachievedbystandardizingthedesensitizationprotocols.Thisstandardizationcanleadtomoreefficientoutcomestrackingandsupportiterativeprotocolimprovement,therebyreducingthedisparitiesinsuccessratesacrosscentersnationwide.

CORRESPONDINGPHILANTHROPICOPPORTUNTIIES

• Fundstart-upcostsforacentralizednationalkidneyexchangeprogram—Kidneypaireddonationprogramsfacilitateexchangesbetweenincompatibledonor-recipientpairs.Theseeffortsarecurrentlydecentralized,whichcanleadtodifferentkidney-exchangechainscompetingforpotentialdonors,therebydecreasingthedonorpool.Centralizingthekidneyexchangeplatformwouldhelpmaximizethenumberofswapsthatcouldbemadewithinagivenchain.

• Fundstart-upcostsforalivingdonorregistry—Thecreationofadata-rich,technologicallyadvancedlivedonorregistrywouldinformunderstandingofthelong-termrisksandoutcomesassociatedwithkidneydonationandwouldfacilitateearlyrecognitionandinterventionswhenadonorisatincreasedriskforkidneyfailure.Currenttrackingsystemslacktherobustnesstofacilitatethedesiredlevelofdetection,analysis,andengagement.

• Fundapilotprogramthatcoverslostwagesandotheruncompensatedexpensesforlivingdonors—Althoughtravel,lodging,anddiningexpensesmaybecoveredforprospectivelivedonorsunderthegovernment-fundedprogramcalledNationalLivingDonorsAssistanceCenter(NLDAC),thisprogramislimitedtopatientswhoqualifybasedonincomecriteriaforboththedonorcandidateandtheintendedrecipient.Financialburdens,includinglostwages,remainanimportantdisincentivetoexpandinglivekidneydonation.Pilotstudiestestingthishypothesiswouldprovidethecost-benefitanalysistosubstantiateincreasedfundingfortheNLDACprogramorestablishsimilarprogramsthroughnonprofitfoundations.

• Fundwidedisseminationofnoveldonorengagementprograms—Socialmediaappshaveemergedasacreativetooltoengagepotentialkidneydonors;however,theseappsareoftendecentralizedandusuallyconfinedtoonetransplantcenter.Supportforwidespreaddisseminationandadoptioncouldhaveasubstantialimpactbyfacilitatingdonorengagement,sharingeducation,andemphasizingtheneedforlivingdonation.

• Supportthedevelopmentofamasterdesensitizationprotocoltoimprovedonorcompatibility—Thedevelopmentofamasterprotocolwouldacceleratedisseminationofproceduresamongtransplantcenters,promotehighersuccessratesnationwide,andprovideaplatformtofosterdevelopmentoffutureimprovedprotocols.

• Investinresearchanddevelopmentofbioartificialkidneys—Thereisgreatpromiseinafuturewhenbioengineeredkidneytissueand/ororgansareaviablereality,becausetheywouldlessentherelianceondonatedkidneys,attenuatetheneedforlifelongimmunosuppressiontherapy,andeliminatetheneedforconventionaldialysis.Thisworkremainsintheearlystagesofdevelopment,sophilanthropiccapitalwouldacceleratethetimelineandspurinnovationinthisspace.

37 March2017

INADEQUATELONG-TERMTRANSPLANTOUTCOMES

THEPROBLEM

Althoughthe1-yeartransplantsuccessrateisabout90percent,the10-yearsuccessrateismuchlowerat34-48percent.Severalfactorscontributetothisdisparity,includingthechallengeofappropriatetailoringofimmunosuppressiontomaintainefficacyandreducemorbidity,andthefinancialburdensfortransplantrecipientspost-procedure.Overall,immunosuppressionislargelyadministeredina“one-sizefitsallapproach,”suchthatsomepatientsfaceriskofrejectionandimmunologicalgraftloss,whileotherssuffercomplicationsofover-immunosuppression(e.g.,infection,cancer).Novelapproachesareneededtoidentifymarkersfortransplantsthatare“atrisk,”tobetterpersonalizeimmunosuppressiontoavoidirreversibleinjuryandexcessimmunosuppression.Furthermore,formanypatients,Medicarepaysforimmunosuppressionmedicationsforonlythefirst3years,afterwhichpatientsmustpayforthemedicationsoutofpocket.Thisfinancialburdencancausepatientstodiscontinuetheirmedicationsortakethemconsistently,whichdramaticallycompromiseslong-termsuccessratesfortransplantpatients.Overall,measurestoaddresstheseandsimilarfactorsmaybolsterlong-termsuccessrates.


Betterlong-termtransplantoutcomeswouldleadtoimprovedQOLfortransplantrecipientsandoverallsavingstothehealthcaresystem—potentiallymorethantheestimated$50,000costsavingsoftransplantoverdialysis.Pilotinglong-termimmunosuppressionsupportprogramsthatarehypothesizedtoincreaselong-termsuccessrateswouldprovidetheneededevidencetoattractCongressionalsupport.


• Supportapilotstudyassessingthecost-benefitanalysisforextendedtolerancemedicationscoverage—Payerscurrentlycovertolerancemedicationsforonly3yearspost-transplant.Thisstudywouldinvestigatewhetherlong-termcoveragedoesinfactincreaselong-termgraftsurvivalandreducetheoverallcostofcare(asareturntodialysistreatmentisacostlyprocedure).Suchevidencewouldinformpayersandprovidesupportforexpandedcoverageoptions.

• Supportexplorationofnewmarkersof“at-risk”organtransplantsbeforeirreversibleinjury—Serumcreatinineiscrudemarkeroftransplantedorganfunction;however,itisnotsensitivetosubtleorganinjury,whichcanleadtochronicrejection.Supportingthedevelopmentofnewbiomarkersforearlyrejectionmayfacilitatebetterimmunosuppressionpersonalizationtomaintainefficacyandreducemorbidity.

LACKOFINNOVATIONINKIDNEYREPLACEMENTTHERAPY

THEPROBLEM

Dialysistreatmentisindireneedofinnovationasthetechnologyhasnotimprovedsignificantlyoverthepastthirtyyears.Althoughdialysisisalife-savingoptionintheshort-term,ithasnegativelong-termimpactwithanannualmortalityrateof15-20percent.Treatmentdeliveryandvenousaccessaretwomainchallengeareastobeaddressed.

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• Treatmentdelivery–Standardhemodialysisgenerallyinvolvespatientsbeingattachedtoanimmovabledialysismachine(eitherinaclinicorathome)forsessionsthatrangebetween3-4hours,threetimesperweek.Thispracticeoftenleavespatientstootiredtolivefullyproductive,independentlives.Researchsuggeststhatmorefrequentdialysismaybebeneficialtopatients,howeverthisisimpracticalwithinthecurrentparadigm.

• Venousaccess–Achievinglong-termvascularaccess(e.g.fistulaorgraft)iscentraltohemodialysis,howevertheprimaryfailureratesleaveseveralpatientsusingshort-termalternatives(e.g.centralvenouscatheters[CVCs]).Prolongeduseofshort-termvenousaccessoptionsleadtocomplications,suchasinfectionandhospitalization,whichcompromisesuccessfuldialysistreatment.

POTENTIALSOLUTIONSTOADDRESSTHECHALLENGE

Deviceinnovationtosupportmorefrequentambulatorydialysisandlong-termvenousaccesspatencywoulddrasticallyimprovedialysistreatment.Further,fosteringacommunityforinnovationwouldprovidethemomentumnecessarytobringnovel,boldideastofruition.


• EndowanannualKidneyReplacementSummit—Effortstoradicallyre-imagineandre-inventdialysismachineryandconceiveofcompletelynovelalternativeswillrequirecollaborationacrossdisparatedisciplines(e.g.,nephrology,bioengineering,cellbiology).Anannualsummitspecificallydedicatedtothispurposewillprovidethespacetocreateavisionandencouragecreativityforrevolutionizingrenalreplacementtherapy.

• Funddevicedevelopment—Supportingeffortsto(1)buildatechnologically-advancedwearableorimplantabledialysisunit(seePrizeChallengeopportunityco-developedbytheAmericanSocietyofNephrologyandXPrize)or(2)developnovelvenousaccesstechnologieswouldexpandoptionsforpatients.Inadditiontoaddingportability,theseadvancementscouldallowfordailybloodfilteringandpossiblylowertheyearlymortalityrate.Lastly,supportingeffortsto(3)developremotemedicalmonitoringdevicesdesignedtoallowreal-timedialysismonitoring,targetedadjustmentstotreatments,andreal-timeupdatestoEMRs.Thisadvancementwouldempowerpatientstobemoreinformedabouttheircareandfacilitatediscussionswithcareproviders.

LIMITEDDISEASEUNDERSTANDING

LACKOFMOLECULARDISEASEBIOMARKERS

THEPROBLEM

Currentlythekidneydiseasefieldlackstissue-basedmolecularbiomarkerstodiagnosedisease,predictdiseaseprogressiontokidneyfailure,ortracktreatmentefficacy.Thisapparentlackseverelyhamperseffortstodevelopnewdrugs.Thefieldlacksthemeasurestotestwhetherthedrugisengagingitsintendedtargetorhavingthedesiredeffect,whichultimatelycontributestothehighcostandfailureofclinicaltrials.Thisbiomarkerchallengeis,inpart,duetoinsufficientmechanisticunderstandingofCKDprogressiontokidneyfailure.Tofurthercomplicatethislandscape,thefieldlacksthetoolstostudykidneydiseaseinvivo,makingitdifficulttodevelopimagingbiomarkersorvisualizeputativebiomarkerlocalization.

https://www.asn-online.org/news/2016/0613-XPRIZE_Fact_Sheet.pdf

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Promotingteamsciencewillbeacentralcomponenttosupportingnovelbiomarkerdiscoveryeffortsastheskillsnecessarytoaddressthisheterogeneousdiseaserequiresamulti-disciplinaryandmulti-stakeholderefforttoincreaseefficiencyandavoidduplication.


• Fundacentralizeddataexchangeplatform—Thiswouldbeago-toresourceplatform,whichhousesEMRdata,patient-reporteddata,aswellasbiofluidsandtissuesconducivetolarge-scaleanalysis.Ideally,thisplatformwouldlinktoanationalpatientregistry(describedinthenextsection).Suchaplatformwouldfacilitateefficientdatasharingaswellasenrichbasic,translationalandclinicalresearchwithitswealthofbiologicalandclinicalpatientdata.

• Fundconsortiachargedwithdevelopingaregulatorypathtowardsbiomarkerregistration—Onceabiomarkerhasbeenproposedwithinthekidneycommunity,aregulatorypathneedstobeoutlinedtoassessthevalidityandutilityofthesebiomarkersforclinicalpractice.Provingaroadmapthatoutlinestheprocesswouldhelpdisseminatetheincorporationofnewbiomarkersasbest-practicesthroughoutthecommunity.

OPERATIONALCHALLENGESTOCONDUCTINGSUCCESSFULCLINICALTRIALS

THEPROBLEM

Therehasneverbeenadrugdevelopedprimarilyforthepreventionofkidneyfailure.Weneedtherapiestostoppeoplewithkidneydiseasefromworseningandbeingrequiredtostartdialysis.PharmaceuticalcompaniesexpendmorethantheentireNIHbudgetindrugdevelopmentbuthavelargelyignoredkidneydisease.MajorcompanieswhichhavetentativelyventuredintodevelopingCKDtreatmentsoftenquicklyexitduetobothscientificandoperationalchallenges.Thesechallengesinclude,identifyingpatientswhoareunawarethattheyhavethediseaseandencouragingparticipationfromcaregiverswhomayhaveafatalisticviewthatthediseasewillinevitablyprogresstodialysis.RecruitmentratesforCKDarelessthan20-40percentofthoseforothermajordiseaseslikediabetes,heartdiseaseandAlzheimer’s.Thisresultsinlengthy,overlycostlytrialsyieldingunderpoweredresultsduetothesmallertargetenrollmentsizes.Inconcertwithawarenesseffortsoutlinedinthefirstsectionofthisdocument,theCKDpatientcommunitycanbemobilizedtomoreactivelyseekouttrialstestingnewtherapies.Opportunitiestosurmountthesebarrierswouldsignificantlyde-riskindustryinvestmenttodevelopnewtherapeuticoptionsandhelpleveragetheirsubstantialresourcesforbringingtherapeuticstothemarket.

POTENTIALSOLUTIONSTOADDRESSTHECHALLENGE

Fosteringacultureofpatientandproviderengagementcoulddramaticallyimproveclinicaltrialparticipation.Successfulexamplestobeemulatedcanbeseeninvariousdiseasecommunitiessuchascancer,HIV/AIDS,andmusculardystrophy.Intandem,creatingaglobalclinicaltrialsnetworkwouldexpandthepatientpoolavailableforrecruitmentandbuildcapacityformoreefficientclinicaltrialpractices.


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• Fundthecreationofanationaland/orinternationalCKDpatientregistry—Patientregistriesinformnaturalhistorystudies,assistinclinicaltrialrecruitment,facilitatesafetymonitoring,encouragepatientparticipationinresearchandcanserveasasiteforpatienteducationresources.Linkingeachpatient’sanonymizedhealthrecordtotheregistrywouldprovideacriticalnewcapabilityfordoctorstobetterunderstandthespectrumofkidneydiseaseprogress.Sucharegistrycouldenablereal-timefeedbacktosupportevidence-basedguidelinesforqualitycareandhousetrialreadycohortsandhealthsystems.EstablishingaCKDregistrycouldalsobetterconnecttheCKDpatientcommunitywithcaregiversandpolicymakerstohaveavoiceinkidneyresearchandcare.

• Supportadministrativecoststofacilitateaglobalclinicaltrialsnetwork—Aslowclinicaltrialenrollmentrateshaveresultedinterminatedorinconclusivetrials,leveragingtheglobalcommunityforpatientenrollmentcouldspeeduptheenrollmentprocessandreducecostsforaclinicaltrial.Inthisnetwork,enrolledacademicandnon-academicclinicalcenterswouldbeabletoconductdifferenttrialsatthesametime.Supportingacentralcoordinatingcenterforpatientrecruitmentthatwouldallowmultipleinternationalcenterstointeractwouldbekeytofacilitatingthisprocess.

• Fundapatient-reportedoutcomes(PRO)consortia—SupportingtheconsortiabyfacilitatingpatientandprofessionalmeetingstospurdevelopmentandvalidationofPROsfordialysisandtransplantationwouldencouragePROinclusioninregulatoryassessmentsforfuturetherapeuticoptions.

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KEYSTAKEHOLDERSINTHEKIDNEYDISEASECOMMUNITY

GOVERNMENT

Federalagenciesandfederally-mandatedinstitutesarethelargestfundersofCKD/kidneyfailure-relatedresearch,totalingmorethan$580Minaggregate(FY2015).Table2displaysfederalagencieswhoseresearchexpensesmeetorexceed$500KandFigureXprovidesavisualoverviewoffederalactivitysurroundingCKD/kidneyfailure.

Table2.FederalFundingforKidneyDiseaseResearchforFY2015AgencyorInstitute Research

ExpensesTotalBudget

NationalInstitutesofHealth(NIH) $564M $30BDepartmentofVeteransAffairs $20.9M $163.9BPatient-CenteredOutcomesResearchInstitute(PCORI)

$14M $462.8M

DepartmentofDefense(DOD) $7.1M $495.6BCentersforDiseaseControlandPrevention(CDC)

$2M $11.1B

AgencyforHealthcareResearchandQuality(AHRQ)

$1.3M $440M

FoodandDrugAdministration(FDA) $500K $4.7B

DOMESTICRESEARCHGRANT-MAKINGORGANIZATIONS

Thereareseveralnonprofitorganizationsspecificallyfocusedoncharitablegivingtosupportkidneyfailureandotherkidneydiseases.ThissectionprovidesabriefoverviewofthenonprofitorganizationsinvolvedinCKD/kidneyfailure-relatedresearch.ThissectiononlyincludesU.S.-basedkidneydiseaseorganizationsthatincludekidneyfailure(commonlyreferredtoasESRD)asaspecificresearchfocus.Organizationsthataresolelyinvolvedinpatientsupport,advocacy,awarenessorwhosemissionistofundonespecificresearchcenterareexcluded.Table3displaysthetopnonprofitfundersofCKD/kidneyfailure-relatedresearchwhoseresearchexpensesmeetorexceed$500K.Additionalinformationregardingtheirmission,keyresearchfundingmechanismsandclinicaltrialssupportactivitiesisalsoprovidedbelow.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

Figure18.FederalCKDActivitiesSource.

https://www.niddk.nih.gov/about-niddk/advisory-coordinating-committees/kidney-urologic-hematologic-diseases-interagency-coordinating-committee/federal-response-to-ckd/Pages/federal-response-to-ckd.aspx

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AMERICANSOCIETYFORNEPHROLOGY(ASN)

MISSION:

ASNleadsthefighttoprevent,treat,andcurekidneydiseasesthroughouttheworldbyeducatinghealthprofessionalsandscientists,advancingresearchandinnovation,communicatingnewknowledge,andadvocatingforthehighestqualitycareforpatients.

RESEARCHFUNDINGMECHANISMS:

ASNprovidessupportacrosstheentireresearchpipeline.Theirgrant-makingisdividedroughlyintothreecategories:careerdevelopmentfornewinvestigators,researchfellowships,andtravelgrantsforfellows,residentsandstudentstoattendKidneyWeek,theorganization’sannualconference.SinceASNbeganfundinggrantsin1996,thesocietyandthefoundationhaveawardedmorethan$35milliontosupportresearchandtravelawards.InFY2014,ASNdedicated$3Mtoresearch-relatedexpenses.

Formoreinformationaboutavailableawards,pleasevisitASN’swebsite.

AMERICANUROLOGICALASSOCIATION(AUA)

MISSION:

AUA’smissionistopromotethehigheststandardsofurologicalclinicalcarethrougheducation,researchandtheformulationofhealthcarepolicy.


AUAprovidessupporttobasic,translational,andclinicalresearch.TheAUAiscommittedtosupportingurologicresearchthroughfunding,advocacyandscholarlyexchange.TheAUAisaleaderinhelpingtoidentifygapsinknowledgeandcommunicatingurologyresearchneedstokeyconstituentsatthefederallevel.TheAUA'sResearchScholarsProgramhasprovidedsupporttoyoungurologyresearchersformorethan35years.AUAalsoadministersadatagrantsprogramtosupportpopulation-based,data-driven,specialtygeneralizablestudiesusingelectronichealthrecords,datamaintainedbytheAUAorotherdatasourcesalreadyavailabletoinvestigators.InFY2014,AUAdedicated$3Mtosupportingurologyresearch.

Formoreinformationaboutavailableawards,pleasevisitAUA’swebsite.

NATIONALKIDNEYFOUNDATION(NKF)

MISSION:

TheNationalKidneyFoundationistheleadingorganizationintheU.S.dedicatedtotheawareness,preventionandtreatmentofkidneydiseaseforhundredsofthousandsofhealthcareprofessionals,millionsofpatientsandtheirfamilies,andtensofmillionsofAmericansatrisk.

https://www.asn-online.org/

https://www.auanet.org/

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NKFsupportstranslational,earlyclinicalresearchaswellaslarge-scaleepidemiologicresearchregardingCKDriskfactors,progressionandprognosis.Since1968,theNationalKidneyFoundationhasprovidedmorethan$100millioninresearchgrantstothefield.InFY2014,NKFallocatedabout$1Mtotheirresearchprogram,whichsupportedfouryounginvestigatorsandoneclinicalinvestigator.Theorganizationalsopublishespeer-reviewedmedicaljournals,includingAmericanJournalofKidneyDiseases,AdvancesinChronicKidneyDisease,JournalofRenalNutrition,andJournalofNephrologySocialWork.

Formoreinformationaboutavailableawards,pleasevisitNKF’swebsite.

AMERICANSOCIETYOFTRANSPLANTATION(AST)

MISSION:

TheAmericanSocietyofTransplantationisanorganizationofprofessionalsdedicatedtoadvancingthefieldoftransplantationandimprovingpatientcarebypromotingresearch,education,advocacy,andorgandonation.


TheASTTransplantationandImmunologyResearchNetwork(TIRN)researchgrantsprogramseekstosupportfellows,juniorfaculty,andalliedhealthprofessionalsbyfundinginnovativeresearchinbasic,clinical,andtranslationalscience.InFY2014,ASTdedicatedabout$900ktosupportingresearch.

Formoreinformationaboutavailableawards,pleasevisitAST’swebsite.

COLLABORATIVEINITIATIVES

GOVERNMENTSPONSOREDPROGRAMS

ADVANCEDTISSUEBIOFABRICATIONMANUFACTURINGINNOVATIONINSTITUTE(ATB-MII)

TheATB-MIIwasannouncedinJune2016andwillreceive$80Minfederalfunding.Itwillbringtogetherfor-profitandnonprofitorganizations,institutionsofhighereducation,andfederalandstateagenciestoaccelerateinnovationbyinvestinginindustriallyrelevantmanufacturingtechnologieswithapplicationsintheTissueBiofabricationEcosystem.Thiseffortwillprovidesupporttohelpbridgethegapbetweenbasic/earlyresearchandproductdevelopmentbyadvancingandscalingcriticaltechnologiesinthemanufacturingreadinesslevel4to7range.TheATBMIIwillprovidesharedassetstohelpentities—particularlysmallmanufacturers—accesscutting-edgecapabilitiesandequipment,creatinganunparalleledenvironmenttoeducateandtrainstudentsandworkersinAdvancedTissueBiofabricationskills.

https://www.kidney.org/

https://www.myast.org/

https://www.dodmantech.com/Institutes/ATB-MII

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KIDNEYHEALTHINITIATIVE(KHI)

Recognizingboththelackofclinicaltrialsandthehugeunmetclinicalneedinkidneydisease,theAmericanSocietyofNephrology(ASN)andtheU.S.FoodandDrugAdministration(FDA)establishedtheKidneyHealthInitiative(KHI)inSeptember2012.KHI’smissionistoadvancescientificunderstandingofthekidneyhealthandpatientsafetyimplicationsofnewandexistingmedicalproductsandtofosterdevelopmentoftherapiesfordiseasesthataffectthekidneybycreatingacollaborativeenvironmentinwhichFDAandthegreaternephrologycommunitycaninteracttooptimizeevaluationofdrugs,devices,biologics,andfoodproducts.

Memberorganizationsincludepatientadvocacyorganizations,professionalorganizations,regulatedindustry(includingbothpharmaceuticalanddevicecompanies),dialysisproviders,academicresearchorganizations,contractresearchorganizations,researchinstitutes,andothergovernmentagencies.TomorefullyincorporatepatientstakeholderconcernsacrossallKHIclinicalandpolicydiscussions,KHIformedthePatientandFamilyPartnershipCouncil(PFPC).

KIDNEYINTERAGENCYCOORDINATINGCOMMITTEE(KICC)

TheKidneyInteragencyCoordinatingCommittee(KICC)isaprogramundertheNIDDK.ThecommitteeconsistsoffederalrepresentativesinvolvedinCKDprogramsandactivities.KICC'spurposeistoencouragecommunicationandcollaborationtoshapeamorecoordinatedfederalresponsetoCKD.Figure18outlinesKICCmemberagencies.

VETERANSADMINISTRATIONNATIONALKIDNEYPROGRAM

VApartneredwiththeMedicalEducationInstitutein2012todevelopaninteractiveweb-basedlearningsystem,knownastheVAeKidneyClinic,tohelpguideVeteransthroughtheprocessofmanagingCKDandmakingtreatmentrelateddecisions.TheeKidneyClinicisavailabletothepublicinadditiontoVApatientsandprovidersviatheVANationalKidneyProgram.

TheVAhasbeenactivelycollaboratingwithNIDDKandtheCentersforDiseaseControlinthereviewofpatienteducationmaterialspertainingtochronickidneydisease(CKD).ThesematerialsareavailabletoVAprovidersforpatientdisseminationwithintheclinicandaredirectlyavailabletopatientsviaVA'seKidneyClinic,aswellasthroughtheDepartmentofDefense'sclinicalpracticeguideline.

https://www.asn-online.org/khi/

https://www.asn-online.org/khi/

https://www.niddk.nih.gov/about-niddk/advisory-coordinating-committees/kidney-urologic-hematologic-diseases-interagency-coordinating-committee/federal-response-to-ckd/Pages/federal-response-to-ckd.aspx

http://ckd.vacloud.us/

https://www.va.gov/health/services/renal/

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CONSORTIA

Consortiaaretemporaryassociationsofstakeholdersfromvarioussectors—academia,industry,government,nonprofits,etc.—thatshareresourcesinordertoachieveacommongoal.AccordingtoFasterCures’Consortia-pediaCatalogue(adatabaseofbiomedicalresearchconsortia)thereareseveralconsortiafocusedonkidneydiseases.Describedbelowareselectconsortiathatareunderwayforkidneyfailure-relatedresearchandtherapeuticdevelopment.Forafulllist,pleasevisitConsortia-pediaCatalogue.

BIOLOGICALSUPPORTFORKIDNEYPATIENTS(BIOKID)

BiologicalSupportforKidneyPatients(BioKid),isabioreactorofkidneycellstoremovetoxinsthatremainafterhemodialysis.BioKidisanoutstandingaidinimprovingthequalityofhemodialysistreatmentsandinreducingtheriskofcomplications,suchascardiovascularproblems,resultingfromtheaccumulationoftoxicwasteproducts.TheBioKidprojectwasactivefrom2009-2014andisnowcurrentlycontinuedwithintheEuropeanUnionMarieCurieInnovativeTrainingNetwork(ITN)projectcalledBioArt.InApril2015,researchersreportedthecreationofalivingkidneymembrane—ahighlysoughtaftergoalwithinthekidneydiseasefield.

CHRONICKIDNEYDISEASEPROGNOSISCONSORTIUM(CKD-PC)

ChronicKidneyDiseasePrognosisConsortium(CKD-PC)isaresearchgroupcomposedofinvestigatorsrepresentingcohortsfromaroundtheworld.Investigatorssharedataforthepurposeofcollaborativemeta-analysestostudyprognosisinCKD.

CKD-PCwasestablishedin2009byKidneyDisease:ImprovingGlobalOutcomes(KDIGO)(sponsoredbytheU.S.NationalKidneyFoundation).Originallytaskedwithcompilingandmeta-analyzingthebestavailabledataonkidneymeasuresandclinicaloutcomes,theCKD-PCcurrentlyconsistsofover70cohorts,whicharisefromgeneral,high-risk,orCKDpopulations.Todate,theCKD-PChaspublishedover15highimpactpaperswithimportantimplicationsforthedefinition,staging,andmanagementofCKD.

CKDBIOMARKERSCONSORTIUM(BIOCON)

TheNationalInstituteofDiabetesandDigestiveandKidneyDiseases(NIDDK)establishedtheCKDBiomarkersConsortium(BioCon)topromotethediscoveryandvalidationofbiomarkerstoadvancethefieldofchronickidneydisease(CKD)research.TheNIDDKCKDBiomarkersConsortiumbringstogetherinvestigatorswhoseexpertiseincludesclinicalnephrology,epidemiology,molecularbiology,genomics,proteomics,metabolomics,systemsbiology,laboratorymedicine,biostatistics,andlaboratorytestverificationandqualification.BioConisacollaborativeeffortinvolvingnumerousinvestigatorsfrommultipleinstitutionsworkingtogethertopursuethedevelopmentandvalidationofnovelbiomarkersforCKDbyassayingbiologicalspecimensandutilizingdatafromthenation’slargestepidemiologicalstudiesofkidneydisease.

(RE)BUILDINGAKIDNEYCONSORTIUM

(Re)BuildingaKidneyisanNIDDK-fundedconsortiumofresearchprojectsworkingtooptimizeapproachesfortheisolation,expansion,anddifferentiationofappropriatekidneycelltypesandtheirintegrationintocomplexstructuresthatreplicatehumankidneyfunction.

http://consortiapedia.fastercures.org/consortia/

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Theultimategoalofthisconsortiumistocoordinateandintegrateresearchtosupportthedevelopmentandimplementationofstrategiessuchasdenovorepairofnephrons,there-generationofnephrons,andtheinvitroengineeringofabiologicalkidneytoenhancerenalrepairandpromotethegenerationofnewnephronsinthepostnatalorgan.

SYSTEMSBIOLOGYTOWARDSNOVELCHRONICKIDNEYDISEASEDIAGNOSISANDTREATMENT(SYSKID)

TheSystemsBiologytowardsnovelchronickidneydiseasediagnosisandtreatment(SysKid)consortiumisfocusedonexpandingthebasicscienceofchronickidneydisease.Theprojectpavesthewayforprogressinprevention,newdiagnosticstrategies,andtreatmentoptionsfordecliningkidneyfunction,whichaffectsmillionsofpatientssufferingfromdiabetesandhypertension.SysKidwaslaunchedbytheEuropeanCommissionSeventhFrameworkProgrammein2010.

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GLOSSARY

ALLELES TwocopiesofeachgeneinthebodyANEMIA LowredbloodcellcountAPOL1GENE ThegenethatencodesfortheproteinapolipoproteinL1APOLIPOPROTEINL1 AcomponentofhighdensitylipoproteinARTERIOVENOUS(AV)FISTULA Asurgicalprocedurethatcreatesadirectconnectionbetweenan

arteryandveinintheforearm

ARTERIOVENOUS(AV)GRAFT Atubesurgicallyinsertedundertheskinthatconnectsanarterytoaveinintheforearm

ATHEROSCLEROSIS Hardeningofthearteries,whichcandecreasebloodflowtothekidneys

BIOMARKER Acharacteristicthatcanbeobjectivelymeasuredandevaluatedasanindicatorofdiseasestateortreatmentefficacy

BIOPSY TissueremovedfromalivingbodyBLADDER Holloworganthatstoresurinepriortoexcretion

BLOODUREANITROGEN Indicatorofkidneyandliverhealth.Ureanitrogenformsafterproteinhasbeenbrokendown.

CLINICALRESEARCH Branchofbiomedicalresearchinvolvinghumansubjects

CREATININE WastebyproductofmusclemetabolismDIALYSISTREATMENT Involvestheuseofspecializedmachinerytofilterthebloodwhen

thekidneyscannolongerdosoEGRFCALCULATION Calculationusingserumcreatininelevelsandcertainformulasthat

factorinotherriskfactorssuchasage,gender,andrace

ENZYME Aproteinthatcatalyzescomplexbiologicalreactions

ERYTHROPOIETIN-STIMULATINGAGENTS(ESA)

Medicationthatboostsredbloodcellproduction

ESTIMATEDGLOMERULARFILTRATIONRATE(EGFR)

Theestimatedfiltrationratecapacityofthekidneys

GLOMERULUS ThefiltercomponentofthenephronGRAFT AtransplantedorganHEMATOCRIT Theratioofredbloodcellstothetotalvolumeofblood

HEMODIALYSIS Treatmentthatadialysismachinetocleanthetotalvolumeofthepatient’sblood

HEMOGLOBIN Theoxygen-carryingproteinfoundinredbloodcells

HUMAGRAFT™ Ahumanbioengineeredbloodvesselthatproposestodeliveratissue-basedgraftlackingtheneedfortissuematching

HYPERTENSION Highbloodpressure

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KIDNEYS OrgansthatfilterbloodandproduceurineNEPHROLOGIST Physicianwhospecializesinkidneydiseases

NEPHRON Thekidney’sfilteringunitPERITONEALDIALYSIS Treatmentthatinvolvesusingtheliningofthepatient’sstomach

(theperitoneum)asthefilterforthepatient’sblood

PROTEINURIA Clinicalpresentationofproteinintheurine

RAAS Ahormonesystemthatregulatesbloodpressure,fluidvolume,andsodiumcontentinthebody

RESEARCHANDDEVELOPMENT(R&D)

Theprocessbywhichalaboratorydiscoveryisdevelopedintoacommercialtherapeuticdiagnosticordevice

SENSITIZATION Astateinwhichthepatienthasdevelopedproteinsthatwillattackforeigntissue,likeatransplantedorgan

SERUMCREATININEMEASUREMENT

Testusedtodetectevidenceofincreasedcreatinineintheblood

TUBULE Tubeallowsforthereabsorptionofnecessarymineralsbackintothebloodandsendsexcessfluidandwastetotheureters

URETERS Tubesthatcarryurinefromthekidneystothebladder

URETHRA TubethatexpelsurineURINEANALYSIS Analyzestheurineforthepresenceofprotein

VENOUSCATHETER Asurgicallyinsertedflexibletubeinsertedintoaveinintheneck,chest,orlegnearthegroin

WEARABLEARTIFICIALKIDNEY(WAK)

Adevicecurrentlyindevelopment,whichwouldallowfordailydialysis

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e r u il a f y e n id k - aakpcarmen a. peralta, md, mas associate professor of medicine university...

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