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CHRONICRENAL DISEASE

SECONDEDITION

Editedby PAUL L.KIMMEL

MARK E.ROSENBERG

AcademicPressisanimprintofElsevier

125LondonWall,LondonEC2Y5AS,UnitedKingdom 525BStreet,Suite1650,SanDiego,CA92101,UnitedStates 50HampshireStreet,5thFloor,Cambridge,MA02139,UnitedStates TheBoulevard,LangfordLane,Kidlington,OxfordOX51GB,UnitedKingdom

Exceptiontotheabove:Chapters28,48,and52:2020PublishedbyElsevierInc.

Nopartofthispublicationmaybereproducedortransmittedinanyformorbyanymeans,electronicormechanical,including photocopying,recording,oranyinformationstorageandretrievalsystem,withoutpermissioninwritingfromthepublisher. Detailsonhowtoseekpermission,furtherinformationaboutthePublisher’spermissionspoliciesandourarrangementswith organizationssuchastheCopyrightClearanceCenterandtheCopyrightLicensingAgency,canbefoundatourwebsite: www.elsevier.com/permissions .

ThisbookandtheindividualcontributionscontainedinitareprotectedundercopyrightbythePublisher(otherthanasmaybenoted herein).

Notices

Knowledgeandbestpracticeinthis ﬁeldareconstantlychanging.Asnewresearchandexperiencebroadenourunderstanding, changesinresearchmethods,professionalpractices,ormedicaltreatmentmaybecomenecessary.

Practitionersandresearchersmustalwaysrelyontheirownexperienceandknowledgeinevaluatingandusinganyinformation, methods,compounds,orexperimentsdescribedherein.Inusingsuchinformationormethodstheyshouldbemindfuloftheirown safetyandthesafetyofothers,includingpartiesforwhomtheyhaveaprofessionalresponsibility.

Tothefullestextentofthelaw,neitherthePublishernortheauthors,contributors,oreditors,assumeanyliabilityforanyinjury and/ordamagetopersonsorpropertyasamatterofproductsliability,negligenceorotherwise,orfromanyuseoroperationofany methods,products,instructions,orideascontainedinthematerialherein.

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TypesetbyTNQTechnologies

Dedication

Ifacethedualchallengesoflookingforwardandback astheSecondEditionof ChronicRenalDisease emerges intoprint.IamdelightedwiththereceptiontheFirst Editionreceivedandtookitasasummonstocreatean evenbettersecondeffort.Wehavesoughttoputnew informationintoperspective,vitalforthecareofpatients,andtorecruitthebestauthorstoupdatethetext andpresentcomplexnewconceptsinameaningfulway.

ThisSecondEditionisdedicatedtomyteachers,who showedmethebeautyofphysiology,pathophysiology, andtreatment,aswellastheinterconnectionsbetween ourselvesasteachersandphysicians,andourpatients andtheirfamilies.Thegreatestteachersfosteredcritical thinkingandinspiredmetoaskandtrytoanswermany differentquestionsaboutrenaldisease.Eachonehada distinctivepersona.Iambothimpressedbyand amusedbythemultiplicityofviewpointsinourdiscipline.Countlesscolleaguesworkedwithmeonprojects, helpingmetoseeﬁndingsindifferentways,enhancing myapproachestounderstandingdata.Inaddition,I recognizetheroleofmyparentsandsisterinthiseffort. Theywouldhavetrulylovedtohaveseenthisbook.

ThisSecondEditionhasnewauthorsandnew chapters,makingitmorecomprehensive,useful,and focusedonourpatientsworldwide.Thechapter authors allrecognizedexpertsintheirﬁelds have donearemarkablejobofconceptualizingtheirsubjects inclearlanguageandpictures,aswellasrespondingto manyanddiverseeditorialquibblesandcavils.The interactionbetweenauthorsandeditorshasbeenboth scholarlyandveryproductive.Ithankthereturning authorsaswellasthenewonesheartily.Mycoeditor hasbeenajoytoworkwith,complementingmydeﬁciencieswiththoughtfulness,equanimity,goodsense, andgoodhumor.IthankthestaffatElsevierfortheir

guidanceandperseverance.Theyallunderstoodand immediatelysharedthegoalofcreatingascientiﬁc, well-written,useful,andbeautifulbook.Ihopewehave achievedthosegoals.

Thisbookisalsomeanttoimprovethecareandlives ofourpatients.Thelastﬁveyearshavewitnessedasea changeinclinicalresearchinnephrology,including patientsaspartnersandcollaboratorsinallaspectsof theresearchenterprise.Thisbookisforthemaswell. Finallyandperhapsforemost,thisbookisforourstudents,whocontinuetoteachaswellaschallengeus,in additiontohopefullylearningfromus.Ihopetheywill ﬁndthisbookhelpfulinthinkingaboutthekidneyand renaldisease,andincaringfortheirpatients.Andhow couldInotthankmywife?Thisbookcouldcertainly havebeenwrittenwithouther,butitwouldnothave beenasmuchfun.Ideeplyappreciateherwisdomand consideration.

PaulL.Kimmel

Thisbookisdedicatedtothemanystudents,residents, andfellowswhocontinuetoinspiremetoteachand learn,tomymentorswhohaveshownmethepathways tofollowinmedicineandlife,andtothepatientsIhave caredforwhohavetaughtmeabouttheperseverance andcourageneededtolivewithachronicillness. Heartfeltthankstothemanyauthorswhohave contributedtothisbookandtotheeditorialteamat Elsevierfortheiroutstandingwork.Mostofall,I dedicatethisbooktomywifeMonicaandmychildren Joel,Madeline,andJack thanksforyourunending love,support,andmotivation,andforteachingmehow tohavefun!

MarkE.Rosenberg

ListofContributors

BlaiseAbramovitz Renal-ElectrolyteDivision,Department ofMedicine,UniversityofPittsburghSchoolofMedicine, Pittsburgh,PA,UnitedStates

DwomoaAdu HonorarySeniorResearchFellowand ConsultantNephrologist,SchoolofMedicineandDentistry, UniversityofGhana,Accra,Ghana

FarsadAfshinnia DivisionofNephrology,Departmentof InternalMedicine,UniversityofMichigan,AnnArbor,MI, UnitedStates

AnupamAgarwal DivisionofNephrology,Universityof AlabamaatBirmingham,BirminghamVeterans AdministrationMedicalCenter,Birmingham,AL,United States

SarahC.Andrews DivisionofKidneyDiseasesand Hypertension,DepartmentofMedicine,George WashingtonUniversity,Washington,DC,UnitedStates

GeraldAppel DivisionofNephrology,ColumbiaUniversity MedicalCenter,NewYork,NY,UnitedStates

JamesL.Bailey RenalDivision,EmoryUniversity,Atlanta, GA,UnitedStates

GeorgeL.Bakris ComprehensiveHypertensionCenter, DepartmentofMedicine,TheUniversityofChicago Medicine,Chicago,IL,UnitedStates

CarolynA.Bauer DivisionofNephrology,Bronx,NY, UnitedStates

PravirV.Baxi DivisionofNephrology,RushUniversity MedicalCenter,Chicago,IL,UnitedStates

JeffreyS.Berns Renal-ElectrolyteandHypertension Division,DepartmentofMedicine,PerelmanSchoolof MedicineoftheUniversityofPennsylvaniaSchoolof Medicine,Philadelphia,PA,UnitedStates

PeterBirks BritishColumbiaRenalAgency,Vancouver,BC, Canada

AndrewBomback DivisionofNephrology,Departmentof Medicine,ColumbiaUniversityIrvingMedicalCenter,New York,NY,UnitedStates

AnirbanBose DivisionofNephrology,Departmentof Medicine,UniversityofRochesterSchoolofMedicineand Dentistry,Rochester,NY,UnitedStates

FrankC.Brosius,3rd DivisionofNephrology,Department ofInternalMedicine,UniversityofMichigan,AnnArbor, MI,UnitedStates;DivisionofNephrology,Universityof ArizonaCollegeofMedicine,Tucson,AZ,UnitedStates

LeeK.Brown DepartmentofInternalMedicine,University ofNewMexicoSchoolofMedicine,Albuquerque,NM, UnitedStates;UniversityofNewMexicoHealthSciences Center,Albuquerque,NM,UnitedStates;UniversityofNew MexicoSchoolofEngineering,Albuquerque,NM,United States;UniversityofNewMexicoHealthSystemSleep DisordersCenters,Albuquerque,NM,UnitedStates

DavidA.Bushinsky DivisionofNephrology,Departmentof Medicine,UniversityofRochesterSchoolofMedicineand Dentistry,Rochester,NY,UnitedStates

LaurenceW.Busse EmoryUniversity,Divisionof Pulmonary,Allergy,CriticalCareandSleepMedicine, DepartmentofMedicine,EmoryJohnsCreekHospital, JohnsCreek,GA,UnitedStates

RuthC.Campbell MedicalUniversityofSouthCarolina, DivisionofNephrology,Charleston,SC,UnitedStates

MarkCanney UBCDivisionofNephrologyandBritish ColumbiaRenalAgency,Vancouver,BC,Canada

HelenCathro DepartmentofPathologyandLaboratory Medicine,UniversityofVirginiaMedicalCenter, Charlottesville,VA,UnitedStates

JonathanCha ´ vez-In ˜ iguez DivisionofNephrology,Hospital CivildeGuadalajara,UniversityofGuadalajaraHealth ScienceCenter,Guadalajara,Jalisco,Me ´ xico

LakhmirS.Chawla DepartmentofAnesthesiologyand CriticalCareMedicine,GeorgeWashingtonUniversity MedicalCenter,Washington,DC,UnitedStates;Divisionof KidneyDiseasesandHypertension,Departmentof Medicine,GeorgeWashingtonUniversity,Washington,DC, UnitedStates;UniversityCaliforniaofSanDiego,San Diego,CA,UnitedStates

SheldonChen MDAndersonCancerCenter,Houston,TX, UnitedStates

GlennM.Chertow StanfordUniversitySchoolofMedicine, DivisionofNephrology,PaloAlto,CA,UnitedStates

EmilyY.Chew DivisionofEpidemiologyandClinical Applications,NationalEyeInstitute,NationalInstitutesof Health,Bethesda,MD,UnitedStates

MichelChonchol DivisionofRenalDiseasesand Hypertension,UniversityofColoradoDenverAnschutz MedicalCampus,Aurora,CO,UnitedStates

DeborahJ.Clegg UniversityofCaliforniaatLosAngeles, MedicalCenter,LosAngeles,CA,UnitedStates

DavidM.Clive UniversityofMassachusettsMedical School,DepartmentofMedicine,DivisionofRenal Medicine,Worcester,MA,UnitedStates

PiaH.Clive UMassMemorialMedicalCenter,Worcester, MA,UnitedStates

ScottD.Cohen DivisionofKidneyDiseasesand Hypertension,DepartmentofMedicine,George WashingtonUniversity,Washington,DC,UnitedStates

Ashte’K.Collins DivisionofKidneyDiseasesand Hypertension,DepartmentofMedicine,George WashingtonUniversity,Washington,DC,UnitedStates

JamesE.Cooper DivisionofNephrology,Universityof ColoradoAnschutzMedicalCampus,Aurora,CO,United States

RicardoCorrea-Rotter DepartmentofNephrologyand MineralMetabolism,InstitutoNacionaldeCiencias Me ´ dicasyNutricio ´ nSalvadorZubira ´ n,Me ´ xicoCity,Me ´ xico

DanielCukor BehavioralHealth,TheRogosinInstitute, NewYork,NY,UnitedStates

MonicaDalal MedicalFacultyAssociates,George WashingtonUniversity,Washington,DC,UnitedStates

AndrewDavenport UCLCentreforNephrology,University CollegeLondon,RoyalFreeHospital,London,United Kingdom

ScottDavis DivisionofNephrology,UniversityofColorado AnschutzMedicalCampus,Aurora,CO,UnitedStates

SaraN.Davison DepartmentofMedicine,Universityof Alberta,Edmonton,AB,Canada

PierreDelanaye DepartmentofNephrology-DialysisTransplantation,UniversityofLie ` ge,Lie ` ge,Belgium

DickdeZeeuw DepartmentofClinicalPharmacology, UniversityofGroningen,UniversityMedicalCenter Groningen,Groningen,TheNetherlands

MirelaA.Dobre CaseWesternReserveUniversity,Schoolof Medicine,UniversityHospitalCaseMedicalCenter, Cleveland,OH,UnitedStates

PaulDrawz DivisionofRenalDiseasesandHypertension, UniversityofMinnesotaMedicalSchool,Minneapolis,MN, UnitedStates

NatalieEbert Charite ´ UniversityHospital,InstituteofPublic Health,Berlin,Germany

PaulEggers NationalInstituteofDiabetesandDigestiveand KidneyDiseases,NationalInstitutesofHealth,Bethesda, MD,UnitedStates

SilviaFerre ` CharlesandJanePakCenterforMineral MetabolismandClinicalResearch,UniversityofTexas SouthwesternMedicalCenter,Dallas,TX,UnitedStates; DepartmentofInternalMedicine,UniversityofTexas SouthwesternMedicalCenter,Dallas,TX,UnitedStates

BarryI.Freedman DepartmentofInternalMedicine; SectiononNephrology,WakeForestSchoolofMedicine, MedicalCenterBoulevard,Winston Salem,NC, UnitedStates

SusanL.Furth TheChildren’sHospitalofPhiladelphia, Philadelphia,PA,UnitedStates

BixiaGao RenalDivision,DepartmentofMedicine,Peking UniversityFirstHospital;PekingUniversityInstituteof Nephrology,Beijing,China

GuillermoGarcı´a-Garcı ´ a DivisionofNephrology,Hospital CivildeGuadalajara,UniversityofGuadalajaraHealth ScienceCenter,Guadalajara,Jalisco,Me ´ xico

CaseyN.Gashti DivisionofNephrology,RushUniversity MedicalCenter,Chicago,IL,UnitedStates

GregoryG.Germino NationalInstituteofDiabetesand DigestiveandKidneyDisease,NationalInstitutesof Health,Bethesda,MD,UnitedStates

DavidGoldsmith Guy’sandStThomas’Hospital,London, UnitedKingdom

LadanGolestaneh AlbertEinsteinCollegeofMedicine, RenalDivision,MonteﬁoreMedicalCenter,Bronx,NY, UnitedStates

MichaelS.Goligorsky DepartmentsofMedicine, PharmacologyandPhysiology,RenalResearchInstitute, NewYorkMedicalCollege,Valhalla,NY,UnitedStates

ArthurGreenberg DivisionofNephrology,Departmentof Medicine,DukeUniversityMedicalCenter,Durham,NC, UnitedStates

L.ParkerGregg UniversityofTexasSouthwesternand VeteransAffairsNorthTexasHealthCareSystem,Dallas, TX,UnitedStates

LisaM.Guay-Woodford TheGeorgeWashington University,CenterforTranslationalScience,Clinical andTranslationalInstituteatChildren’sNational, Children’sNationalHealthSystem,Washington,DC, UnitedStates

LeeHamm TulaneUniversity,NewOrleans,LA,UnitedStates

AllysonHart DivisionofNephrology,HennepinHealthcare, UniversityofMinnesotaMedicalSchool,Minneapolis,MN, UnitedStates

DanielleHaselby DivisionofNephrology,Hennepin Healthcare,UniversityofMinnesotaMedicalSchool, Minneapolis,MN,UnitedStates

S.SusanHedayati UniversityofTexasSouthwestern,Dallas, TX,UnitedStates

HiddoJ.L.Heerspink DepartmentofClinicalPharmacology, UniversityofGroningen,UniversityMedicalCenter Groningen,Groningen,TheNetherlands

CharlesA.Herzog DivisionofCardiology,Departmentof Medicine,HennepinCountyMedicalCenterandUniversity ofMinnesota,Minneapolis,MN,UnitedStates

ThomasH.Hostetter DepartmentofMedicine,Universityof NorthCarolina,ChapelHill,NC,UnitedStates

AndrewA.House DivisionofNephrology,Departmentof Medicine,WesternUniversityandLondonHealthSciences Centre,London,ON,Canada

KeithA.Hruska DivisionofPediatricNephrology, DepartmentofPediatrics,WashingtonUniversity,St.Louis, MO,UnitedStates;DepartmentsofMedicineandCell Biology,WashingtonUniversity,St.Louis,MO,UnitedStates

AreefIshani MinneapolisVAHealthCareSystem, UniversityofMinnesota,Minneapolis,MN,UnitedStates

RobertT.Isom StanfordUniversitySchoolofMedicine, DivisionofNephrology,PaloAlto,CA,UnitedStates

MatthewT.James DepartmentofMedicine,Cumming SchoolofMedicine,UniversityofCalgary,Calgary,AB, Canada

KenarD.Jhaveri DivisionofKidneyDiseasesand Hypertension,NorthShoreUniversityHospitalandLong IslandJewishMedicalCenter,ZuckerSchoolofMedicineat Hofstra/Northwell,GreatNeck,NY,UnitedStates

KirstenJohansen DivisionofNephrology,Hennepin CountyMedicalCenter,Minneapolis,MN,UnitedStates

RichardJ.Johnson DivisionofRenalDiseasesand Hypertension,UniversityofColoradoAnschutzMedical Campus,Aurora,CO,UnitedStates

Duk-HeeKang DivisionofNephrology,Departmentof InternalMedicine,EwhaWomen’sUniversitySchoolof Medicine,Seoul,SouthKorea

HirokoKanno TokyoWomen’sMedicalUniversity,Tokyo, Japan

YoshihikoKanno TokyoMedicalUniversity,Tokyo,Japan

AmritaD.Karambelkar DepartmentofInternalMedicine, EmoryUniversitySchoolofMedicine,GMEOfﬁceof GraduateMedicalEducation,Atlanta,GA,UnitedStates

FionaE.KaretFrankl DepartmentofMedicalGeneticsand DivisionofRenalMedicine,UniversityofCambridge, Cambridge,UnitedKingdom

CharbelC.Khoury WashingtonUniversityinSt.Louis,St. Louis,MO,UnitedStates

PaulL.Kimmel DivisionofKidneyDiseasesand Hypertension,DepartmentofMedicine,George WashingtonUniversity,Washington,DC,UnitedStates

JeffreyB.Kopp NationalInstituteofDiabetes,Digestiveand KidneyDiseases,NationalInstitutesofHealth,Bethesda, MD,UnitedStates

StephenM.Korbet DivisionofNephrology,Rush UniversityMedicalCenter,Chicago,IL,UnitedStates

EttyKruzel-Davila DepartmentofNephrology,Rambam HealthCareCampus,RappaportFacultyofMedicineand ResearchInstitute,Technion IsraelInstituteofTechnology, Haifa,Israel

AndrewKummer HealthPartnersNephrology,St.Paul,MN, UnitedStates

LauraLaFave DivisionofEndocrinology,Hennepin Healthcare,UniversityofMinnesotaMedicalSchool, Minneapolis,MN,UnitedStates

JayI.Lakkis UniversityofHawaiiJohnA.BurnsSchoolof Medicine,Wailuku,HI,UnitedStates

LilachO.Lerman DivisionofNephrologyand Hypertension,MayoClinic,Rochester,MN,UnitedStates

AdeeraLevin UBCDivisionofNephrologyandBritish ColumbiaRenalAgency,Vancouver,BC,Canada

SusieQ.Lew DivisionofKidneyDiseasesand Hypertension,DepartmentofMedicine,George WashingtonUniversity,Washington,DC,UnitedStates

ValerieA.Luyckx InstituteofBiomedicalEthicsandthe HistoryofMedicine,UniversityofZurich,Zurich, Switzerland;RenalDivision,BrighamandWomen’s Hospital,HarvardMedicalSchool,Boston,MA,United States

TejK.Mattoo Children’sHospitalofMichigan,WayneState UniversitySchoolofMedicine,Detroit,MI,UnitedStates

SharonE.Maynard UniversityofSouthFloridaMorsani CollegeofMedicine,LehighValleyHealthNetwork, Allentown,PA,UnitedStates

PeterA.McCullough BaylorUniversityMedicalCenter, Dallas,TX,UnitedStates;BaylorHeartandVascular Institute,Dallas,TX,UnitedStates;BaylorJackandJane HamiltonHeartandVascularHospital,Dallas,TX,United States

RajnishMehrotra UniversityofWashington,Seattle,WA, UnitedStates

TimothyW.Meyer StanfordUniversity,SchoolofMedicine, VeteransAffairsHealthCareSystem,PaloAlto,CA,United States

WilliamE.Mitch NephrologyDivision,BaylorCollegeof Medicine,Houston,TX,UnitedStates

OrsonW.Moe CharlesandJanePakCenterforMineral MetabolismandClinicalResearch,DepartmentofInternal Medicine,DepartmentofPhysiology,UniversityofTexas SouthwesternMedicalCenter,Dallas,TX,UnitedStates

SamerMohandes DivisionofNephrology,Departmentof InternalMedicine,OhioStateUniversityWexnerMedical Center,Columbus,OH,UnitedStates

AlvinH.Moss CenterforHealthEthicsandLaw,RobertC. ByrdHealthSciencesCenter,WestVirginiaUniversity, Morgantown,WV,UnitedStates

MarvaMoxey-Mims Children’sNationalHealthSystem, TheGeorgeWashingtonUniversitySchoolofMedicine, Washington,DC,UnitedStates

SangeethaMurugapandian DivisionofNephrology, UniversityofArizonaCollegeofMedicine,Tucson,AZ, UnitedStates;BannerUniversityMedicalCenterTucson andSouth,Tucson,AZ,UnitedStates

KarlA.Nath DivisionofNephrologyandHypertension, MayoClinic,Rochester,MN,UnitedStates

JoelNeugarten AlbertEinsteinCollegeofMedicine,Renal Division,MonteﬁoreMedicalCenter,Bronx,NY,United States

JavierA.Neyra CharlesandJanePakCenterforMineral MetabolismandClinicalResearch,UniversityofTexas SouthwesternMedicalCenter,Dallas,TX,UnitedStates; DepartmentofInternalMedicine,DivisionofNephrology, BoneandMineralMetabolism,UniversityofKentucky, Lexington,KY,UnitedStates

AllenR.Nissenson DepartmentofMedicine,DavidGeffen SchoolofMedicine,UniversityofCalifornia,LosAngeles, CA,UnitedStates;DaVita,Inc.,Denver,CO,UnitedStates

EhsanNobakht DivisionofKidneyDiseasesand Hypertension,DepartmentofMedicine,George WashingtonUniversity,Washington,DC,UnitedStates

ThomasD.Nolin CenterforClinicalPharmaceutical Sciences,DepartmentofPharmacyandTherapeuticsand DepartmentofMedicineRenalElectrolyteDivision, UniversityofPittsburghSchoolsofPharmacyand Medicine,Pittsburgh,PA,UnitedStates

KeithC.Norris DepartmentofMedicine,DavidGeffen SchoolofMedicine,UniversityofCalifornia,LosAngeles, CA,UnitedStates

JennaM.Norton NationalInstituteofDiabetesand DigestiveandKidneyDiseases,NationalInstitutesof Health,Bethesda,MD,UnitedStates

KristenL.Nowak DivisionofRenalDiseasesand Hypertension,UniversityofColoradoDenverAnschutz MedicalCampus,Aurora,CO,UnitedStates

AkinloluO.Ojo AssociateVicePresidentforClinical ResearchandGlobalHealthInitiatives,Universityof ArizonaHealthSciences,Tucson,AZ,UnitedStates

MadeleineV.Pahl DivisionofNephrologyand Hypertension,UCIMedicalCenter,Orange,CA,United States

MarkS.Paller UniversityofMinnesota,Minneapolis,MN, UnitedStates

BiffF.Palmer DepartmentofInternalMedicine,University ofTexasSouthwesternMedicalCenter,Dallas,TX,United States

NicholetteD.Palmer DepartmentofBiochemistry,Wake ForestSchoolofMedicine,MedicalCenterBoulevard, Winston Salem,NC,UnitedStates

SamirS.Patel RenalSection,VeteransAffairsMedical Center,Washington,DCandGeorgeWashingtonUniversity MedicalCenter,Washington,DC,UnitedStates

RobertoPecoits-Filho SchoolofMedicine,Pontiﬁcia UniversidadeCatolicadoParana,Curitiba,Brazil

StevenJ.Peitzman DrexelUniversityCollegeofMedicine, Philadelphia,PA,UnitedStates

AldoJ.Peixoto SectionofNephrology,YaleSchoolof Medicine,andHypertensionProgramattheYaleNew HavenHospitalHeartandVascularCenter,NewHaven, CT,UnitedStates

Phuong-ThuT.Pham DepartmentofMedicine,Nephrology Division,DavidGeffenSchoolofMedicineatUCLA, KidneyTransplantProgram,LosAngeles,CA,United States

Phuong-ChiT.Pham DepartmentofMedicine,Nephrology andHypertensionDivision,DavidGeffenSchoolof MedicineatUCLA,UCLA-OliveViewMedicalCenter, Sylmar,CA,UnitedStates

BethPiraino UniversityofPittsburgh,Pittsburgh,PA, UnitedStates

RobertoPisoni MedicalUniversityofSouthCarolina, DivisionofNephrology,Charleston,SC,UnitedStates

TonRabelink DepartmentofNephrology,LeidenUniversity MedicalCenter,Leiden,Netherlands

JaiRadhakrishnan DivisionofNephrology,Departmentof Medicine,ColumbiaUniversityIrvingMedicalCenter,New York,NY,UnitedStates

MahboobRahman UniversityHospitalsClevelandMedical Center,CaseWesternReserveUniversity,LouisStokes ClevelandVAMedicalCenter,Cleveland,OH,United States

DominicS.Raj DivisionofKidneyDiseasesand Hypertension,DepartmentofMedicine,George WashingtonUniversity,Washington,DC,UnitedStates

JuanC.Ramı´rez-Sandoval DepartmentofNephrologyand MineralMetabolism,InstitutoNacionaldeCiencias Me ´ dicasyNutricio ´ nSalvadorZubira ´ n,Me ´ xicoCity,Me ´ xico

JananiRangaswami EinsteinMedicalCenter,Philadelphia, PA,UnitedStates;SidneyKimmelCollegeofThomas JeffersonUniversity,Philadelphia,PA,UnitedStates

JaneF.Reckelhoff Women’sHealthResearchCenter, UniversityofMississippiMedicalCenter,Jackson,MS, UnitedStates

RenuRegunathan-Shenk DivisionofKidneyDiseasesand Hypertension,DepartmentofMedicine,George WashingtonUniversity,Washington,DC,UnitedStates

ScottReule MinneapolisVAHealthCareSystem,University ofMinnesota,Minneapolis,MN,UnitedStates

ClaudioRonco Universita ` degliStudidiPadova,Padova, Italy;DepartmentofNephrology,Dialysisand Transplantation,SanBortoloHospital,Vicenza,Italy

MarkE.Rosenberg DivisionofRenalDiseasesand Hypertension,UniversityofMinnesotaMedicalSchool, Minneapolis,MN,UnitedStates

MitchellH.Rosner DivisonofNephrology,Universityof Virginia,Charlottesville,VA,UnitedStates

BradRovin DivisionofNephrology,DepartmentofInternal Medicine,OhioStateUniversityWexnerMedicalCenter, Columbus,OH,UnitedStates

PrabirRoy-Chaudhury TheUniversityofNorthCarolina KidneyCenter,ChapelHill,NC,UnitedStates

RebeccaRuebner JohnsHopkinsUniversitySchoolof Medicine,Baltimore,MD,UnitedStates

AndrewD.Rule DivisionofNephrologyandHypertension andDivisionofEpidemiology,MayoClinic,Rochester,MN, UnitedStates

JeffM.Sands RenalDivision,EmoryUniversity,Atlanta, GA,UnitedStates

LynnE.Schlanger RenalDivision,EmoryUniversity, Atlanta,GA,UnitedStates

SarahJ.Schrauben Renal-ElectrolyteandHypertension Division,DepartmentofMedicine,PerelmanSchoolof MedicineoftheUniversityofPennsylvaniaSchoolof Medicine,Philadelphia,PA,UnitedStates

StephenSeliger DepartmentofMedicine,Divisionof Nephrology,UniversityofMarylandSchoolofMedicine, Baltimore,MD,UnitedStates

MaulinShah NephrologyDivision,BaylorCollegeof Medicine,Houston,TX,UnitedStates;NephrologySection, MichaelE.DeBakeyVeteransAffairsMedicalCenter, Houston,TX,UnitedStates

RichardH.Sterns UniversityofRochesterSchoolof MedicineandDentistryandRochesterGeneralHospital, Rochester,NY,UnitedStates

ErikStites DivisionofNephrology,UniversityofColorado AnschutzMedicalCampus,Aurora,CO,UnitedStates

ToshifumiSugatani DivisionofPediatricNephrology, DepartmentofPediatrics,WashingtonUniversity,St.Louis, MO,UnitedStates

StephenC.Textor DivisionofNephrologyand Hypertension,MayoClinic,Rochester,MN,UnitedStates

RaviThadhani Cedars-SinaiMedicalCenter,LosAngeles, CA,UnitedStates;HarvardMedicalSchool,Boston,MA, UnitedStates

BijinThajudeen DivisionofNephrology,Universityof ArizonaCollegeofMedicine,Tucson,AZ,UnitedStates; BannerUniversityMedicalCenterTucsonandSouth, Tucson,AZ,UnitedStates

SurabhiThakar UniversityofMinnesota,Minneapolis,MN, UnitedStates

GeorgeThomas ClevelandClinicFoundation,Cleveland, OH,UnitedStates

RaymondR.Townsend DepartmentofMedicine,Perelman SchoolofMedicine,UniversityofPennsylvania, Philadelphia,PA,UnitedStates

JeffreyTurner YaleUniversity,NewHaven,CT,United States

MarkL.Unruh DepartmentofInternalMedicine,University ofNewMexicoSchoolofMedicine,Albuquerque,NM, UnitedStates;NephrologySection,NewMexicoVeterans Hospital,Albuquerque,NM,UnitedStates

BradleyL.Urquhart DepartmentofPhysiologyand PharmacologyandDivisionofNephrology,Departmentof

Medicine,SchulichSchoolofMedicineandDentistry, WesternUniversity,London,ON,Canada

JosephA.Vassalotti DivisionofNephrology,Departmentof Medicine,IcahnSchoolofMedicineatMountSinai,and NationalKidneyFoundation,Inc.,NewYork,NY,United States

NosratolaD.Vaziri DivisionofNephrologyand Hypertension,UCIMedicalCenter,Orange,CA,United States

ManuelT.Velasquez DivisionofKidneyDiseasesand Hypertension,DepartmentofMedicine,George WashingtonUniversity,Washington,DC,UnitedStates

NishaVerHalen CenterforIntegrativeHealthand Wellbeing,WeilCornellMedicine,NewYork,NY,United States

SalinaP.Waddy AtlantaVeteransAdministration, DepartmentofNeurology,Decatur,GA,UnitedStates

JinweiWang RenalDivision,DepartmentofMedicine, PekingUniversityFirstHospital;PekingUniversity InstituteofNephrology,Beijing,China

MarcWeber KidneySpecialistsofMinnesota,Minneapolis, MN,UnitedStates

MatthewR.Weir DivisionofNephrology,Universityof MarylandSchoolofMedicine,Baltimore,MD,UnitedStates

ChristineA.White DivisionofNephrology,Queen’s University,Kingston,ON,Canada

WilliamL.Whittier DivisionofNephrology,Rush UniversityMedicalCenter,Chicago,IL,UnitedStates

MatthewJ.Williams DivisionofPediatricNephrology, DepartmentofPediatrics,WashingtonUniversity,St.Louis, MO,UnitedStates

AlexanderC.Wiseman DivisionofNephrology,University ofColoradoAnschutzMedicalCampus,Aurora,CO, UnitedStates

DavidC.Wymer UniversityofFlorida,MalcomRandall VAMC,Gainesville,FL,UnitedStates

DavidT.G.Wymer MountSinaiMedicalCenter,Miami Beach,FL,UnitedStates

JerryYee HenryFordHospital,DivisionofNephrologyand Hypertension,Detroit,MI,UnitedStates

LuxiaZhang RenalDivision,DepartmentofMedicine, PekingUniversityFirstHospital;PekingUniversity InstituteofNephrology,Beijing,China

ShougangZhuang DepartmentofNephrology,Shanghai EastHospital,TongjiUniversitySchoolofMedicine, Shanghai,China

FuadN.Ziyadeh FacultyofMedicine,AmericanUniversity ofBeirut,Beirut,Lebanon

AbouttheEditors

PaulL.Kimmel,MD,MACP,FRCP,FASN, was educatedatYaleCollegeandtheNewYorkUniversity SchoolofMedicine.Hecompletedhisinternalmedicine residencyatBellevueHospitalinNewYorkCityand NephrologyfellowshipattheHospitaloftheUniversity ofPennsylvania.Hewasamemberofthefacultyatthe UniversityofPennsylvaniaandtheGeorgeWashington University,whereheattainedtherankofprofessor. From2001to2006,Dr.KimmelservedasDirectorofthe DivisionofRenalDiseasesandHypertensionatGeorge WashingtonUniversity.From2006to2008,hewasthe DirectorofEducationoftheAmericanSocietyof Nephrology.Dr.KimmelcurrentlyisClinicalProfessor ofMedicineatGeorgeWashingtonUniversityin Washington,DC.Hisinterestsincludepsychosocial adaptationtochronicrenaldisease,sleepdisordersin patientswithkidneydisease,zincmetabolisminrenal diseases,HIV-associatedkidneydiseases,theclinical geneticsofcommonkidneydisease,andtheinterrelationshipsbetweenacutekidneyinjuryand chronickidneydisease.

MarkE.Rosenberg,MD,FASN, attendedmedical schoolattheUniversityofManitobainWinnipeg, Canada,anddidhisinternalmedicineresidencyand nephrologyfellowshipattheUniversityofMinnesota. HeservedasDirectoroftheDivisionofRenalDiseases andHypertensionattheuniversityfrom2000to2009. From2009to2012,hewastheChiefofMedicineand DirectorofthePrimaryandSpecialtyMedicineService LineattheMinneapolisVAHealthCareSystem. Dr.RosenbergcurrentlyservesasViceDeanforEducationandAcademicAffairs,andProfessorofMedicine attheUniversityofMinnesotaMedicalSchoolinMinneapolis,Minnesota.Inthisposition,heisresponsible forthecontinuumofmedicaleducation.Heservedas ChairofthePostgraduateEducationCommitteeand EducationDirectorforKidneyWeekfor6yearsbefore beingelectedin2013totheCounciloftheAmerican SocietyofNephrology.Dr.RosenbergservedasPresidentoftheAmericanSocietyofNephrologyin2019.His interestsincludepathophysiologyandprogressionof chronickidneydisease,kidneyregenerationfollowing acuteinjury,modelsofcaredeliveryincludingtelehealth,andworkforceissuesinnephrology.

Abbreviations

ACEI Angiotensin-convertingenzymeinhibitor

ACR Albumin:creatinineratio

ADPKD Autosomaldominantpolycystickidneydisease

AIDS Acquiredimmunodeﬁciencysyndrome

AKI Acutekidneyinjury

ARB Angiotensinreceptorblocker

BMI Bodymassindex

bpm Beatsperminute

CCB Calciumchannelblocker

CHF Congestiveheartfailure

CKD Chronickidneydisease

CPAP Continuouspositiveairwaypressure

CRS Cardiorenalsyndrome

CrCl Creatinineclearance

CRP C-reactiveprotein

CT Computedtomography

CVD Cardiovasculardisease

DM Diabetesmellitus

DN Diabeticnephropathy

DR Diabeticretinopathy

EPO Erythropoietin

ESA Erythropoiesis-stimulatingagent

ESRD End-stagerenaldisease

FDA FoodandDrugAdministration

FGF-23 Fibroblastgrowthfactor23

GFR Glomerularﬁltrationrate

eGFR Estimatedglomerularﬁltrationrate

mGFR Measuredglomerularﬁltrationrate

HBV HepatitisBvirus

HCV HepatitisCvirus

HD Hemodialysis

HIV Humanimmunodeﬁciencyvirus

HIVAN Humanimmunodeﬁciencyvirus associated nephropathy

HTN Hypertension

HUS Hemolyticuremicsyndrome

IL Interleukin

LN Lupusnephritis

MN Membranousnephropathy

MCD Minimalchangedisease

MGUS Monoclonalgammopathyofunknownsigniﬁcance

MRI Magneticresonanceimaging

NAD Nicotinamideadeninedinucleotide

NIH NationalInstitutesofHealth

NIDDK NationalInstituteofDiabetesandDigestiveandKidney Diseases

NSAID Nonsteroidalantiinﬂammatorydrug

OSA Obstructivesleepapnea

PCR Protein:creatinineratio

PD Peritonealdialysis

RAAS Renin angiotensin aldosteronesystem

RBC Redbloodcells

RVD Renalvasculardisease

RCT Randomizedcontrolledtrials

RRT Renalreplacementtherapy

RT Renaltransplantation

SC Subcutaneous

SCD Sicklecelldisease

SCN Sicklecellnephropathy

SLE Systemiclupuserythematosus

S[Alb] Serumalbuminconcentration

S[Ca] Serumcalciumconcentration

S[Cr] Serumcreatinineconcentration

S[K] Serumpotassiumconcentration

S[Mg] Serummagnesiumconcentration

S[P] Serumphosphateconcentration

S[UA] Serumuricacidconcentration

S[X] SerumXconcentration

T1DM Diabetesmellitus,type1

T2DM Diabetesmellitus,type2

TGF Transforminggrowthfactor

TNF Tumornecrosisfactor

TTP Thromboticthrombocytopenicpurpura

UNA Urinarynitrogenappearance

UAlbV Urinaryalbuminexcretion

UACR Urinealbumin:creatinineratio

UProV Urinaryproteinexcretion

UPCR Urineprotein:creatinineratio

USRDS UnitedStatesRenalDataSystem

VEGF Vascularendothelialgrowthfactor

25(OH)D3 25hydroxyvitaminD 1,25(OH)2D3 1,25dihydroxycholecalciferol,calcitriol

1 Introduction ChronicRenalDisease

PaulL.Kimmela,MarkE.Rosenbergb

aDivisionofKidneyDiseasesandHypertension,DepartmentofMedicine,GeorgeWashingtonUniversity,Washington, DC,UnitedStates; bDivisionofRenalDiseasesandHypertension,UniversityofMinnesotaMedicalSchool,Minneapolis, MN,UnitedStates

INTRODUCTIONTOTHE FIRSTEDITION

Inourdiscussionsasweplannedthiswork,wewere struckthatnomajortextbookhadconsideredtherelativelynewfieldofchronickidneydisease CKD asa coherentwhole.Itmustbeacknowledgedthatthe CKDrevolutionhastransformedtheclinicalandscientificlandscapesofnephrology,bysystematizingtheclassificationoftheproteanaspectsofthediscipline,and settingboundariesthathaveallowedclinicalepidemiologyandclinicalresearchtoadvance,perhapsexponentially.CKDclassificationshaveledtonew nomenclatureforacuterenaldiseaseaswell,which hasproveduseful.Inaddition,theapproachhasledto advancesinconsideringacutekidneyinjury(AKI)and CKDasinterrelatedsyndromes.Nevertheless,theclassificationapproachmustnotnarrowtherichnessofclinicalobservationanddiagnosticetiologicclaritythat hascharacterizedourfieldoverthelastcenturyorso. Thisbookcoversbroadly,butcomprehensively,thehistory,pathophysiology,andpracticalapproachestodiagnosis,patientcare,andtreatmentissuesinCKD.The scopeofthisbookislimitedtoCKD uptotheinitiation ofend-stagerenaldisease(ESRD)care.Thisdelineated population,however,entailsthevastmajorityofCKD patients.

Wehavespeciﬁcallysolicitedpreeminentauthors whoareexpertsinthescientiﬁcunderpinningsand theclinicalimplicationsoftheirchosentopicsto contributetothebook.Basicbiologicknowledgeof courseisthefoundationofpathophysiologicapproaches andclinicaltherapeutics.Overthepastdecade,

enormousadvanceshavebeenmadeinourunderstandingofthegeneticsofkidneydisease.Ourappreciationof animportantcauseofCKDasacommondisorderthat hasMendelianaspectsaswellhasmadeusreassessapproachestoscreeningandtreatmentandmayrevolutionizepatientcare,bringingpersonalizedmedicineto theCKDclinic.WeunderstandCKDasadiseasethat variesacrosstheglobe,asaresultofcomplexinteractionsofgeneticsandtheenvironment,including poverty.Greatstrideshavebeenmadeinourunderstandingofthebreadthandnaturalhistoryofpediatric CKD,inpartbecauseoftheestablishmentofwelldesignedobservationalstudiesmorethanadecade ago.Theroleofcommoncomorbiditiessuchasdiabetes mellitusandhypertensionhasbeenstudied,butaswith nutritionanditsimprovementinthispopulation,much workremainstobedone.Overthepasttwodecades,the roleofinflammationinCKDhasbeenincreasingly determined,buttreatmentsusingthisknowledgehave beenelusive.Treatmentsoforgansystemcomplications ofdiminutioninglomerularfiltrationrate(GFR)and uremiaareatwidelyvaryingstagesofdevelopment andmaturity,andourevidencebaseinafewofthesedomainsandinspecificpatientsubpopulationsiswoefully inadequate.Althoughseveralpathwaysculminatingin kidneydiseasehavebeenidentified,withdiversetreatmentopportunitiesandimplications,wehavelearnedto ourchagrinthatmoretreatmentisnotnecessarilybetter treatment.Wemustdevelopandtestnoveltherapies andinterventionstopreventtheinitiationandamelioratetheprogressionofCKD.Ifandwhenthetime comes,wemusthelpourpatientsprepareforESRD care.Advancesintheclinicaltrialsandbasicsciences

associatedwithCKDmayhelpusachieveourgoals improvingthequantityandqualityoflifeofourpatients withCKD.

Thisbook,wehope,willbeareferenceforallwho wanttoknowaboutorincreasetheirknowledge regardinganyorallaspectsofCKD.Asbefitsa21stcenturypublication,itisavailableinpaperandelectronic versions.Therearespecificchaptersregardingconsiderationsofcertainpatientscenariosorsyndromes.Each chapterisgroundedintheexperienceofaspecific patient whomwehaveseen,andthatyouhaveseen orwillencounteroveryourcareer.Perusingthe TableofContents,afewchaptersmayatfirstblush seemduplicative,buttheyinfactapproachproblems fromverydifferentangles,withdifferentexpertise. TheproblemsinCKDarenecessarilyinterdigitated andoverlapping.Wedidnotwanttheauthorstobeartificiallylimitedbychaptertitles.Itishopedthateach chapteriscomprehensiveandcanstandonitsownas areference.Weoweagreatdebttotheindividualauthorsandthankthemsincerelyfortheirexemplary work.Thisbookisafteralljustpaperandbyteswithout them.

Wesetahighbarforthistext.Weintendedthebook tobepatient-oriented,todealwithcommonclinical problems,butatthesametimetobesynopticinscope, broadlyinclusive,scientiﬁc,andusefulasareference fortherapy.Webelievethattheauthorshaveachieved thisgoal!

Thisbookisknowinglyandspecificallytitled Chronic RenalDisease tohighlightitsembeddinginthescientific literature.“Kidney”istheMiddleEnglishtermforthe organwelove.“Renal”and“nephrology”(fromthe FrenchandGreek,respectively)arescientifictermsfor usebyprofessionals.Aswegrappledwith“hypertension”comparedwith“highbloodpressure”inour educationalyouth,wehadtolearnanomenclatureas wedevelopedmedicalexpertise.As“hypertension” and“highbloodpressure”meanthesamething,“kidney”and“renal”arethesame,whileatthesametime

havingdifferent,importantconnotations.Theintellectualmansionbuiltbyourpredecessors,Bright,Addis, Peters,Richards,andSmith,tonameafew,hasmany rooms.Inkeepingwiththescientificfocusof Chronic RenalDisease,allthebookchaptersaregroundedinbasic andclinicalscientificprinciples,sotheclinicalcharacteristicsandtherapyoftheindividualtopicunderconsiderationineachchaptercanbeappreciatedasalogical developmentfrompreviousknowledge.Controversial issuesarehighlightedanddealtwithclearly,directly, andemphatically.Whentherearegapsordeficiencies intheliterature,orinourtherapeuticknowledge and thereare theseareclearlyacknowledged.Thisisa bookforcliniciansandscientists,notnecessarilythe laypublic.

WehopethisbookwillservepeopleinterestedinclinicalCKD rangingfrommedicalstudents,toresidents, internists,andpediatricians,torenalfellows, nephrologyfaculty,andpractitioners.Educationalprincipleshaveadvancedaswelloverthelastdecades.We knowthatdifferentreaders,includingthosewhotackle asubjectfromvaryinglevelsandperspectives,learnin differentways.Eachchapterisaccompaniedbymultiple choicequestions.Weconceivedthequestionsasanintegralpartofthebook complementingthechapters,and functioningasbothself-studytoolsandthepointofdeparturefordiscussioninclinicalconferences.Theelectronicversionofthetextandquestionswillhelp mobileuserskeepcurrentonthego.Inkeepingwith currentnotionsofCKD,asetofabbreviationshasbeen usedconsistentlythroughoutthetext.

Weareinterestedinyourfeedbackandconstructive andothercriticisms.Pleaseletusknowwhatyouthink ofthebook includingoverallperceptionsand commentsregardingindividualchapters.Youare encouragedtocontactus withyourkudosand concerns bycontactingourpublisher.Wehopeyou enjoythebookandﬁnditusefulsimultaneously.

PaulL.Kimmel

MarkE.Rosenberg

INTRODUCTIONTOTHE SECONDEDITION

Thereceptionoftheﬁrsteditionof ChronicRenalDisease hasbeenverygratifying.Thepublicationofthesecondeditionallowsonetoconsiderthechangesthathave occurredinunderstandingandtreatingkidneydisease overthelasthalfdecade,aswellasfactorsthathave notchangedappreciablyovertime.Inmanyways,progresshasbeenincremental,ratherthanradical.

TheclinicalutilityofapolipoproteinL1(APOL1)variantsstillremainstobedetermined,asdotheunderlyingmechanismsofinjury.Westilldonotknowhowto useknowledgeregardingAPOL1variantstoassistpatientsinmakingchoicesorhowtocraftpreventiveor therapeuticapproaches,althoughprospectivestudies toevaluatethecourseofkidneytransplantpatients mayholdpromise.

WeawaittheidentiﬁcationandvalidationofbiomarkersthatwillenhancethevalueofmeasuringGFR andproteinuria,andtheirlongitudinalassessments,in patientswithCKDandatriskfordevelopingCKD,to providebetterprognosticationofcourseandresponse totherapies,withhopebuthealthyskepticism.Theclinicalutilityofthesesimplemetricsdevelopedintheearly 20thcenturymustbeacknowledgedassimplyremarkable,whileadmittingthattheirrobustvaluehighlights thelackofprogresswehavebeenabletoachievein thisﬁeld.Innephrology,wetrulystandontheshoulders ofgiants.

TheinterrelationshipbetweenAKIandCKDappears tohavebeenstrengthenedbyevidencegarneredover thelastseveralyears,buthowtotreatpatientsafter thedevelopmentofAKI,intheclinicafterhospital discharge,topreventthedevelopmentofCKD,orto ameliorateitsprogressionisunknown,andstandsasa majorgapinclinicalpractice.

ThemediatorsofprogressionofCKDappeartobe unchangedfromthoseoutlinedinthefirstedition:pathogenicfibrosisasaresultofattemptstorepairinjury, viciouscyclessetupbycomponentsofthe renin angiotensin aldosteronesystem,andthedeleteriouseffectsofinflammationandhypertension.Single nephronGFR(SNGFR),animportantparameterfor ourunderstandingofcommonmechanismsofprogressivekidneydiseaseinanimalmodels,cannowbeestimatedinhumans.Suchstudieshaveprovided confirmatoryevidencethathyperfiltrationmaytruly beanimportantpathogenicfactorindiseaseinourpatients.Perhapsadvancesinimagingtechniqueswill allowthemeasurementofSNGFRinhumansinthe nearfuture.

Advancesinaddressingﬁbrosisremainstubbornly resistanttotranslationintoclinicalpractice.Effortsto usekidneytissuetoelucidatepathwaysofrepair,injury, andprogressivedysfunctionareneededandinfact, beginning,buttherapeuticsinthisﬁeldareintheir infancy.

TheSPRINTtrialhasledtoadvancesinunderstandingapproachestotreatinghypertensioninpatients withCKD,buttheprecisesweetspotforthegoalblood pressure,andoptimizingthebalancebetweentherapeuticresponsesandadverseeffectsremaintobe determined.

Wedonotyetknowhowtobetteraddresstheravages ofinﬂammationinourpatients,witheitherrelatively prevalentcausesofCKDorwiththerarerbutdevastatingmultisystemautoimmunedisorders,toachieve betteroutcomes.Advancesinunderstandingthegeneticsofpediatricrenaldiseasehavenotculminatedin thedevelopmentoftherapeuticagentsforchildren.

Thiseditionof ChronicRenalDisease highlightsthe importanceofconsiderationofpaininourpatients,as wellasthepotentiallydevastatingeffectsofopioidprescriptionsinthispopulation.Moreresearchremainsto bedonetoimprovethequalityoflifeofpatientswith CKD.

Meanwhile,povertyandracismremainkeysocialdeterminantsofoutcomesforCKDpatientsacrossthe globe.TheroleofmaternaldeprivationincausingincipientCKDinoffspringisincreasinglyappreciated.Improvementsinthesearenas,however,willtakemore thanthecombinedworkofphysiciansandpatientsto achievesalutarychangeandwillrequiretheeffortsof policymakersacrosstheglobe,aswellastheassentof thepopulationsandpoliticians.

Wehaveendeavoredtohighlightpatient-centeredissuesinCKD,althoughweacknowledgethatthisisin largepartanasymptomaticillness,untilverylatestages areencountered.Nonetheless,patients,physicians,and healthsystemsmustcooperateintheidentiﬁcationof CKDpatients,andintheprovisionofthebesttreatments toall,intheUSaswellasacrosstheglobe.

Progresshasbeenmadeinourunderstandingofthe roleofcomplementbiologyinthepathogenesisofC3 glomerulopathiesandcomplement-mediatedthromboticmicroangiopathies,aswellaspossiblyinotherkidneydiseases.Monitoringlevelsofcirculating phospholipaseA2 receptorduringtherapyformembranousnephropathyhasbeenagreatadvanceinthetreatmentofglomerulardiseases trulyalandmark biomarker,dependingonarigoroussetofpreceding basicandclinicalstudies.Asprecisionmedicaltechniquesevolve,wehaveimprovedourtherapeutic

approachestopatientswithlupusnephritis,through well-designedclinicaltrials.Evidencepointstothe importanceoftubulointerstitialdiseaseasakeyprognosticfactorinthisdisorder.

Developmentofothernoveltherapeuticshashoweverlagged.CKDisindeedatoughnuttocrack.

Advancesinresearch,inadditiontotheworkdonein basicandpreclinicallaboratories,includeenhancement oftheroleofparticipantsinresearch.Aspatientsassist indesigningtheresearch,sitonSteeringCommittees andDataSafetyMonitoringBoards,andhelpdisseminatethetriumphsandfailuresofourwork,ourjoint abilitytotranslateresearchintocureswillbenecessarily enhanced,bybetterresearchstrategiesandcommunicationofresults.

Allthesechallengesremainasopportunitiesfor futureresearch,aswellasforup-and-comingresearchers,hopefullywithpatientsasparticipantsand partnersintheenterprise.

Wehaveinvitedauthorswhowrotewell-received chapterstocontributetothesecondedition.Wealso haveinvitednewauthorstotackleproblemsandhave triedtoincludenewexpertstoweighinonissues.

WehaveaddedchaptersonCKDasaglobalchallengeandenhancedconsiderationofthesocialdeterminantsofCKDtoatextwhichalreadycoveredtheﬁeld comprehensively.Inaddition,thisbookhasbeen expandedbychaptersconsideringCKDinaglobal context,focusingonparticularregionsaroundthe world.Thescopeofthesecondeditionremainsunchangedfromtheﬁrst:thehistory,pathophysiology, andpracticalapproachestodiagnosis,patientcare, andtreatmentissuesinCKD uptotheinitiationof ESRDcare.

Wehavebeenpleasedbythefeedbackregardingthe beautyofthisbook,itsscholarlyexcellence,timeliness, usefulness,andscope,fromaspectrumofreaders, rangingfrommedicalstudentstoProfessorsofMedicine.Wethankourpublishers,andMaraConner,for guidingusthroughourﬁrstefforts,andTariBroderick andTracyTufagaformakingthesecondeditionareality. Thiseditionhastheclinicalmultiplechoicequestions includedinthetext,whichwehopewilladvanceitsuse asateachingtool,onmanylevels.Thisbookisagain availableinpaperandelectronicversionstoenhance itsaccessibilityandaccommodatedifferentlearning stylesandneeds.

Mostimportantly,wethanktheexceptionalauthors ofthefirstandsecondeditionsforproducinganimportant,scholarly,andusefultext.Onceagain,wenotethat thisbookisjustpaperandbyteswithouttheinputofthe authors.Asinthefirstedition,wesoughttocombine basicscientificunderpinningswithbestapproachesto practice,toensureatextthatwouldbesatisfyingtoa broadrangeofreaders.Wehopethissecondedition of ChronicRenalDisease willbeusefulforstudents,teachers,practitioners,and,perhapsmostimportantly,forour patients.

Wehaveelectedtocontinuewithanold-fashionedtitle.Newtherapiesbuildonthecollectedexperienceof manyyearsofpatientcare,whenchronicrenaldisease asterminologywas aucourant.Wehopetheconjoint perspectiveonthepastandthefutureisoneofthe distinctive,uniqueaspectsofthisbook.Onceagain, pleaseletushearfromyouaboutwhatyouliked,and whatyoudidnot,aboutthissecondedition.Wehope, again,youenjoythebookandﬁnditusefulaswell.

PaulL.Kimmel MarkE.Rosenberg

FromBright’sDiseasetoChronicKidneyDisease

StevenJ.Peitzman

DrexelUniversityCollegeofMedicine,Philadelphia,PA,UnitedStates

Abstract

Inthe1820sand1830s,RichardBrightofGuy’sHospitalin Londonshowedthatdropsy(edema)whenassociatedwith heat-coagulableurine(albuminuria)predictedoneor anotherformofpathologicallyalteredkidneysatautopsy. Hisfirstcaseswereofhospitalizedpatients,buthelater recognizedanddescribedindolentcases,whatwewouldcall chronicdisease.Subsequentpathologistscreatedclassificationschemesforchronicrenaldisease.Inthelate19thcentury,amovementcalled“functionaldiagnosis”turned attentiontothekidney’s“power”inhealthanddisease, usingtestsofexcretionandconcentration.Herearoseterms suchas“chronicrenalfailure,”whichpersistedintothe 1990s.Thenotionofrenal“work”ledtoattemptsto“rest” thepresumablyoverworkingnephronsofimpairedkidneys withthelow-proteindiet.KeyfigureswereThomasAddisin the1920 1940sandBarryBrennerinthelaterdecadesofthe 20thcentury.Meanwhile,cliniciansidentifiedvariouscauses ofchronickidneydisease,onlyinrecentdecadesincluding diabetes.TreatmentfromBright’stimeonwardaimedat reducingsymptoms,suchasedema,untilconceptsof hyperfiltrationandtheinjuriouseffectsofproteinuria promptedtherapies(beyonddiet)aimedatslowingprogression.Withasensethatthecourseofchronicrenaldisease ifidentifiedearlymightbefavorablyinfluenced(particularly byinhibitionoftherenal angiotensin aldosteroneaxis), nephrologistsintheUSandelsewherethroughtheir organizationseffectedchangesinnomenclature(e.g., “kidney”not“renal”)andothermeasurestodemystifyand raiseawarenessofkidneydisease.Thehopewasthatearlier detectionmightallowinterventionstoslowprogressionand thusavoidordelaytheneedforrenalreplacementtherapy.

BRIGHT’SDISEASE

In1840,RichardBright(1789 1858)(Figure2.1),the ﬁrstauthorityonproteinurickidneydisease,whounintentionallyprovidedthedisorder’searliestname, describedwhatwewouldcallachroniccase.The patient,presumablyfromBright’sprivatepractice,was a“man,agedabout25,paleandscrofulousinappearance,anddeeplypittedwiththesmallpox,”who,in

earlyMarchof1835,“cametome,laboringunder anasarca,andhavingalbuminousurine.”Hisillness beganwithaboutofdiarrhea.Asherecovered,the youngmanwasabletospendamonthinthecountry, butthere“hislegsbegantoswell,andanasarcaproceededuphisthighsandabdomen.”Brightfoundthe urine“exceedinglycoagulable”and“frothyonagitation.”Thepatienttendedtopasslarge,notsmall,quantitiesofurine.“Iorderedhimtoadoptmoststrictlya milkdiet,andtoputonwarmclothing,withﬂannel nexttotheskin.”Becausethestomach“sympathized” withtheskinandkidneys,itsirritabilityhadtobequietedwithaneasydietandgentlemedicinessuchas bicarbonateofsoda.

Thepatientimprovedbrieﬂy,withlesscoagulability oftheurine,butinAprilhedevelopedsomecough, andhis“skininclinedtobedry.”Brightprescribedagain someipecac,asadiaphoreticand“expectorant.”By June,thepatienthadimprovedgreatly,hisswelling wasalmostgone,thoughtheurinestill“frothsmuch.” Then,apainful“periostealenlargement”appearedon hisleftshin,whichthepatientfearedwasthereappearanceof“somevenerealsymptoms,”presumablysyphilis.Brightprescribedaconcoctionforthis.ByJuly9, thepatientwasagain“greatlyimproved,”andthe readernowlearnsthathewasabletoreturntohis workasabookbinder.Brightdesiredhim“topersistin allhiscaresandprecautions[therestricteddietandﬂannelontheskin],toabstainfromallspirits,andcarefully avoidatmosphericexposures.”

InFebruaryof1836,Bright“sawhimcasually”and foundthathestillworkedandhad“nocomplaintto make.”Butthebookbinderadmittedtoaslightheadachenowandthen.Inaddition,thepatienthimself(a craftsmanwhoworkedwithhishands)testedhisankles fromtimetotimeandfoundthatsometimespressureof theﬁngermadeapit.Hesleptwellearlyinthenightbut became“restless”laterandhadtogetuponcetopass urine.Theurinewas“naturalinquantity,”butboth

FIGURE2.1 RichardBright(1789 1858)asaphysiciantoGuy’s HospitalinLondonshowedinthelate1820sthatdropsy(generalized edema),whenassociatedwithalbumenintheurine,predicted diseasedkidneysifapatientwiththeseﬁndingscametoautopsy. Later,Brightrecognizedandtreatedpersonswithmoreindolent,or chronic,formsofnephropathy. CourtesyoftheNationalLibraryof Medicine.

heatandnitricaciddetectedthatitwasstill“verydecidedlycoagulable.”Thus,thediseasepersisted,though thepatientfeltgenerallywell.Importantly(inBright’s assessment),theskinwas“freelyperspirable”andhad beenforsolongnow“thatheforgetsiteverwasotherwise.”Buttheyoungmanhadceasedtakinghismedicationsregularly.Thepox-markedbookbinderchoseto definehimselfasamongtheworking,nonsick.However,ifhefeltsomeflankpain,ornotedsomeotherhintof hiscomplaintsreturning,forafewweekshetookthe powdersBrighthadprescribed,with“hefancies.the besteffect.”Andhewasalwaysverycarefulto“guard hisbodywithflannelnexttotheskin.”

Then,inOctober1839,thegentlemanconsulted Brightaftera4-yearabsence(“losttofollow-up”as wewouldsay).Hehadcontinuedinseeminggood healthwithnormalurineoutputuntil3or4months ago.Lately,hesuffered“frequentcallstopassitafter goingtobed,”andhecomplainedofheadache,nausea, andvomiting.Afewdayslater,Brightwasabletotest theurine:itcoagulatedslightlytoheat,butreadilywith nitricacid.Hepassednow“alargequantityofurineat night,butlittleintheday;hisankleshadswollen slightlyoflate.”Brightcommentedthat“itisdifﬁcult tosay”towhatextentthemedicines,ortheprecautionarymeasuresofdietandclothing,hadearliercontributed“tothereliefofhisdisease.”Thereisevenahint inBright’slanguage(thepa tient“fancies”thepowders didhimgood)thattheprescriberhimselffeltsome

skepticismabouttheactualpowerofthepowders. Here,Brightconcludeshispatient’sstory,onethatis, inmanyofitsessentials,representativeofchronic andslowlyprogressiveproteinuricrenaldiseaseat anytime.Ofcourse,thestoryofRichardBright’sbookbinderoffersarcanemedicationsandstrangetherapeuticideas,andapeculiarsortofpathophysiology involving“sympathy”betweentheskin,stomach, andkidney,bywhichadisturbanceinonecouldeffect injuryanddysfunctioninanother.Inthesurprising mannerbywhicholdconceptssometimesreturn withnewreﬁnements,whenIﬁrstwrotethischapter numerousarticlesinthemedicalliteraturerefertothe “crosstalk”betweenorgans.Weshallseesomeother furloughedideasenjoyarevivalwithinnephrology laterinthischapter.

Froma21stcenturyperspective,thepatientdescribed abovehad“CKD” chronickidneydisease andlikely nephroticsyndrome.InBright’sday,mostphysicians cametocallthatmaladycomprisingedema,albuminous urine,andavarietyofsymptomsBright’sdisease(morbusBrightii, maladiedeBright),likelytheﬁrstwidelyused medicaleponymintheEnglishlanguage,andaterm thatenduredroughlythroughthe1940s(withone revival,aswillbeseen).RichardBright,workingat Guy’sHospitalinLondonduringtheeraofclinical pathologicalcorrelation,hadshownthattheurineof somepatientswithdropsy(edemaoranasarca)was coagulablebyheat(albuminuric)andthatwhensuch patientsbecameavailableforautopsy,thekidneys showedoneofseveralformsofalteration,particularly a“granulardegeneration.”

Brightpublishedhisdiscoveryofproteinuricrenal disease(andmuchelse)in1827inthefirstvolumeof hismagisterial ReportsofMedicalCasesSelectedwitha ViewofIllustratingtheSymptomsandCureofDiseasebya ReferencetoMorbidAnatomy.Thisworkincludedmagnificentcoloredengravingsandisalandmarkin nephrology,pathology,andmedicalpublishing.Richard BrightandBright’sdiseaserepresentthebeginningofa modernunderstandingofdiffuse,chronicrenaldisease. Hisfundamentalfindingslinkingedema,albuminuria,a setofsymptoms,andstructurallyabnormalkidneys weresoonconfirmedbyotherworkerssuchasRobert Christison(1797 1882)inBritainandPierreRayer (1793 1867)inFrance.Brightalsocametorecognize anddescribevirtuallyallelementsofuremiaincluding pallor,“lassitude,”“hardpulse,”vomiting,seizures, pericarditis,andcardiachypertrophy.

Since,bypurpose,the ReportsofMedicalCases sought tocorrelateclinicalﬁndingsinhospitalizedpatients withﬁndingsatnecropsy,therenalcasesaremostlyof shortduration,theoutcomesnecessarilyfatal.The termBright’sdiseaselongtaggedtheprocessof becomingillthroughthekidneys.Perhapsowingtoits

earlyassociationwiththehospitalandthedissectiontable,thediseasemaintainedanominousreputationinthe popularmindassomethingclosetoadeathsentence,a diagnosisthatwouldextinguishallhope.(“CKD”is likelymoreobscuretopatientsthanwas“Bright’sdisease,”thoughatleastnotasuniformlyfrightening.) Bright,however,cametorecognizethemoreindolent, orchronic,picture,asseeninthedropsicalbookbinder. Inanarticlepublishedin1840,aftermuchexperience withrenaldisease,heofferedthesoundadvicethat “whateverremedyisgiventoovercomeadiseaseso chronicandconfirmed,mustbeadministeredwith exemplarypatienceandperseverance.”1 ThatadiagnosisofBright’sdiseasecouldbecompatiblewithdecadesoflivingwaswellunderstoodbysomelater19th centurynephrologicalauthors.BritishphysicianLionel S.Bealeinhispopulartreatiseonrenaldiseaseassured hisreadersin1870that“withjudiciousmanagement,a patientmaylivetwentyortwenty-fiveyearsalthough afflictedwithincurablerenaldisease.”2

Myaimisnotadetailedexpositionofscientiﬁc accomplishment,butratheraninvestigationofseveral themes.Attimes,nonetheless,thenarrativewillseem likealinear,almostinevitable,marchtowardthe present atypeofstorymostdistastefultomodernhistoriansofscience,whocallitsproduction presentism.A shortaccountsuchasthisrecallsthoseindividuals whoseideassurvived,asitignoresthecountlesserrors, fancies,andfailedhypotheses aswellaspossiblyvalid andusefulpracticeswhichnonethelesssunkintothe medicalshadowland.Thehistoryoftreatmentofirreversiblerenalfailurebydialysisortransplantationis notcoveredinthischapterinkeepingwiththeoverall intentofthevolume.Oncethepatienthasreached “end-stagerenaldisease,”thefailedkidneysthemselves arenolongermuchunderconsideration,andarenotbeingtreated.Avarietyofhistoricalaccountsofdialysis andtransplant,however,exist.3 7

Forconvenience,Iwillsometimesusetheterms “nephrology”and“nephrologist”anachronistically thatis,beforetherewasadeﬁnedspecialtyandbefore thesewordswereevenknown.

PATHOLOGIES

In1761,theItalianphysicianGiovanniBattistaMorgagni(1682 1771)publishedhismassive DeSedibus,et causismorborumperanatomenindagatislibriquinque,or, OntheSeatandCauseofDiseasesShownbyAnatomy. Intothelater18thandearly19thcenturies,particularly inpost-revolutionParis,butalsoinothercitiesof Europe,physiciansferventlyembracedclinical pathologicalcorrelationasanobjectivemethodtostudy diseases.Theobjectwastocorrelatepatternsofﬁndings

intheillpersonwithlocalizedstructuralabnormalities deepwithintheautopsiedbody.Classiﬁcationsderived frommorbidanatomywouldreplacenosographies basedonlyonpatients’symptoms.

RichardBright,amajorfigureinthismovement, addedanearlylaboratorymanifestation,albuminuria, tothecomplex.Hisinitial1827publication,the Reports ofMedicalCases, basedon24cases,suggestedthree formsofderangedkidneystructure,accompanying albuminuricdropsy.Thefirstwasakindofsoftening withyellowmottling.Thesecondformwasonein which“thewholecorticalpartisconvertedintoagranulatedtexture ”Thethird“iswherethekidneyisquite roughandscabroustothetouchexternally,andisseen toriseinnumerousprojectionsnotmuchexceedinga largepin’shead [andthereisa]contractionofevery partoftheorgan. ”8 Thesethreedescriptionsholdlittle meaningforthenephrologistofthe21stcentury,who rarelyseesortouchesafreshdiseasedkidney.Bright allowedthatthethreeformsmightbeonlystagesof oneprocess,thoughheseemedtofavorthreecategories. Sofromthefirstpublicationonthedisorder,Bright’sdiseasewasnotheldtobeonespecificentity,notevenby Bright.

AlthoughnotallsubsequentphysiciansandpathologistswouldagreethatBright’sdiseasewasinflammatoryinnature(asdidBright),theterm“nephritis” entereduseby1840forpathologicalclassification, thoughthebroadcategoryofillnessremainedBright’s disease.Thestoryofthesupersedingandcompeting classificationsisfartoocomplextoexploreexceptin thebroadestofstrokes.Themicroscopecametosupplantgrossobservationandthetouchingoftherenal surface.ThegreatpathologistandtheoristRudoph Virchow(1821 1902)in1858suggested“parenchymatousnephritis,”“interstitialnephritis,”and“amyloid degeneration.”BritonGeorgeJohnsonin1873proposed theseparationofanacuteform(“acutenephritis”),and threechronicvarieties:“redgranularkidney,”“large whitekidney”and“lardaceouskidney”(whichisthe sameasamyloidkidney).WilliamOsler(1849 1919) inhispopulartext ThePrinciplesandPracticeofMedicine favored“acuteBright’sdisease,”“chronicparenchymatousnephritis,”and“chronicinterstitialnephritis.”Amyloidwasdispatchedtoitsownpathologicalcategory. Intothe20thcentury,theextremelyinfluentialmonographbyFranzVolhard(1872 1950)andTheodor Fahr(1877 1945)publishedin1914, DieBrightscheNierenkrankheit,providedafresh butstilltrinitarian organization:degenerativediseases,the“nephroses”; inflammatorydiseases,the“nephritides”;andarterioscleroticdiseases,the“nephroscleroses.”9 12 Thomas AddisofStanfordUniversityinthe1920soffereda modificationofthislastframeworkwhichgained somepopularity:“hemorrhagicBright’sdisease,”

“degenerativeBright’sdisease,”and“arteriosclerotic Bright’sdisease.”13 Itislikelysignificantthatanarterioscleroticcategoryappearedintheearly20thcentury, probablyanearlyreflectionofourmodernmannerof becomingchronicallyill(seebelow,“Causes”).Today, wefindutilityinthinkingintermsofglomerulardisease,tubulointerstitialdisease,orvasculardisease,but whenappropriateseekaspecific,causaldiagnosisusing biopsyordetectionofmarkermoleculesinbloodor urine.Ofinteresthere, chronic asappliedtorenaldisease foralongtimereferredtothepathologicalappearance morethantoadefinedclinicalcourse.Chronicingood partmeantsclerosisorfibrosis.Now,adiagnosisof CKDemphasizesauniformclinicalpictureandimplies adisinterestinunderlyingstructure.“CKD”repudiates pathology.

PHYSIOLOGIES

Intothe1830and1840s,RichardBrightassembleda teamofcolleaguesandpupilsatGuy’sHospitalandits medicalschooltostudyalbuminouskidneydisease. Forpartof1842,theyweregiventwowardstouse fortheirinvestigations,connectedbywhatwewould callaconferenceroomandasmalllaboratory“fitted upanddecoratedentirelytoourpurpose.”This arrangement,somewhatprefiguringthemetabolic ward,waslikelyafirstinWesternmedicine.Several ofBright’schemicallyadeptcolleagueswereableto crudelymeasureurearetainedinthebloodofpatients withdiseasedkidneys.14,15 Physiciansofthisperiod ofcourseunderstoodthekidneysasexcretoryorgans, thebody’s“filters”or“greatdepurators.”Oneimportantwastedischargedwasurea,anitrogenousproduct ofingestionofmeatsandother“proteid”foods.How thekidneysdidthiswasunknown.Inthesameyear thatfoundRichardBrightandhiscolleaguescollecting renalpatientsintwoassignedwardsofGuy’sHospital, ayoungWilliamBowman(1816 1892)publishedhis paper“OntheStructureandUseoftheMalpighian BodiesoftheKidney”inwhichhededucedfromthe nephron’sstructurethattheglomeruluscreatesfiltrate (hedidnotusethatword)whichisthenmodifiedby thetubules. 16 Muchdebateforthenext80years centeredonthevalidityoffiltration reabsorption versusdominantsecretionasthekidney’sprimary wayofmakingurine.

Intothelater19thcentury,thecenterofgravityof medicineshiftedfromthedeadhousesofFranceand EnglandtothelaboratoriesofGermany,wherethe experimentalapproachexempliﬁedbyClaudeBernard (1813 1878)andVirchowbesttookhold.InGermany, beginninginthe1870s,severalphysiologicallyminded physicians,mostnotablyOttomarRosenbach

(1851 1907),apparentlyfatiguedwithahalfcentury ofpathologicalclassification,advancedaprogram knownas“functionaldiagnosis.”Theypursuedtwoobjectives.Onewastoreplacestaticclassificationsbased onstructurewithanewexplorationofwhatadiseased organcould,orcouldnot, do thisinformationheldto bemorehelpfulintheclinic.Thesecond,relatednotion, wastoidentifyillnessinapositedearlyfunctional phase,beforethedevelopmentofchangesinanorgan’s fabric.Particularly,thoughtRosenbach,“inchronicdiseasesitmustaboveallbetheobjecttorecognizethediseaseinitsveryearlystage,i.e.,theincipientfunctional disorder.”17 The21st-centuryphysicianlikelyfindsthis ideafanciful,evenmystical thatsomealterationinan organ’sfunctionprecedesanidentifiablechangeinits structure,especiallyifwereducestructuretothemolecularlevel.Butthebeliefpersistedthroughoutthe19th century.RichardBrightthoughtittrueofrenaldisease thata“functionalderangementoftheorganmaysometimesprecedethestructuralchangeforaperiodofmany weeksandmanymonths.”1

Theclinician-researcherswhocreatedfunctional diagnosisusedthelanguageof work.OneGerman authorwrotein1903that“oneseekstobecome acquaintedwiththeorganwhenitisatwork,andwhere one’schiefdesireistolearnwhetherthisworkissufficientforthesystemornot.”18,19 AnAmericanphysician’s1907manualonkidneydiseasesuggested “Nephritisclinicallyisaquestionofgoingbeyondthe limitofefficiencyofthekidneys.”20 Verylikely,thislanguageandapproachreflectedtheculturalenvironment oflate19thandearly20thcenturyEuropeandNorth America.Industrializationenlargedandspreadasnever before,andthemachine(especiallythesteamengine) ruled.Notunexpectedly,theoldideaofthebodyasmachinegainednewplausibility:oneshouldanalyzethe physiologicalapparatusofanorganasonewouldmeasurethemaximalworkoutputofamachine.“Efficiency,”appliedtoengines,andallelse,becamethe bywordoftheProgressiveEra,atleastintheUS.

RosenbachandotherGermanworkersinfunctional diagnosisreliedontheconceptandphrase“insufficiency”(insufficienz),thoughitwouldacquirevarying meanings.Themethodrequiredchallenginganorgan tomeasureits“reserve” acertainkindoftestmeal tothestomach,aperiodofbriefintenseexerciseto stressthecardiacmuscle,aurealoadtoassesstherenal excretorywork.“Relativeinsufficiency”existedifthe organcouldnotfullycallonitsreserve(or“compensation”)todealwithachallenge,whereas“absolute”or “completeinsufficiency”denotedfindingsofinadequatefunctionatbaseline,suchasnonprovokedretentionofureainthebloodinthecaseofthekidney.21 By 1934,thedistinguishedBritishauthorityonkidneydiseaseRobertPlatt(1900 1978)usedtheterms“renal

insufficiency”and“renalfailure”todescribethetwo phasesofimpairedfunction. 22 Eventually,“chronic renalfailure”(“CRF”)cametosomewhatlooselylabel anyirreversibleriseinbloodcreatinineconcentration (ordecreaseinglomerular filtrationrate(GFR)),even thoughpatientswithonlysmalldeviationsfrom normalusuallyfeltfineanddidnotconsiderthemselves,northeirkidneys,tobefailures,nordidtheir doctors,forthemostpart,thoughtheseniorsamong usrecallreadilyusingthephrase.CRFendureduntil forcefullystruckdownbythenephrologydiscipline in2000.Fewnephrologistsbythenrealizedthatthe newlyscornednomenclaturewentback100years,to theforgottenmovementcalledfunctionaldiagnosis.

Duringtheeraoffunctionaldiagnosis,relianceon creatininemeasurementandeventheconfirmedreality ofglomerularfiltrationwereinthefuture.Thekidney wasprobedasanexcretoryblackbox.TheEuropean workerssawits“work”astheexcretionofconcentrated solutes.TheHungarianphysicianSandor(Alexander) vonKoranyi(1866 1944)appliedcryoscopy(measurementofosmolalitybyfreezingpointdetermination) anddeemedakidney“hyposthenuric” literally“of lowurinepower” ifitdidnotadequatelyconcentrate. Othersassessedthekidney’sabilitytodischargeurea, salt,orwaterafteradefinedload.Avarietyofinvestigatorsdeviseddyemarkers,whoseexcretoryratemight aidinthefunctionaldiagnosisofrenaldisease.The mostsuccessfulofthesewasthephenolsulfonphthalein excretiontestofLeonardRowntreeandJohnT.Geraghtydescribedin1912,andmercifullyshortenedto “PSP”or“phthalein”onceinregularuse.Thedye wouldbeinjected,thenitsappearancedeterminedin timedurinecollections.Delayedexcretionindicated renalinsufficiency.ThePSPtestwassimpleand remainedinuseintothe1950s,laterinsomeareas.23

Intotheﬁrstdecadeofthe20thcentury,renalfunction wastested,asdescribedabove,throughsomemeasurementoftheurine.Urinewas,afterall,whatthekidney made,andusuallyadequateamountsstoodreadyfor use.Feasibletechniquesformeasuringurea,orother solutes,insmallsamplesofpatients’blooddidnotexist beforeabout1910.Infact,drawingbloodfromavein intoasyringerarelyoccurred.Thischangedquickly overthesubsequenttwodecadeswiththeinventionof colorimetrictechniquessuitableforsmallsamplesby theScandinavianIvarBang(1869 1918)and(more enduring)bySwedish-AmericanOttoFolin (1867 1934),andthecreationofgasometricassaysby theAmericanchemistDonaldD.VanSlyke (1883 1971).Theseingenioussystemsallowedfairly rapidmeasurementofurea,uricacid,creatinineconcentrations,andacid baseparameters,andclearlyaided theearlygrowthofnephrology.

Onceureacouldbereadilymeasuredinurineand blood,earlystudentsofrenalinsufﬁciencysuchasthe FrenchmanLeonAmbard(1876 1962)andtheScotsbornAmericanThomasAddis(1881 1949)learned thatneitherthesimplemeasurementofretainedurea intheblood,theureaconcentrationintheurine,nor evenaday’stotalureaexcretionseemedtoreliably correlatewithotherindicatorsofthekidney’slossof excretoryfunctionormass.Theythentriedtoestablish thatsomeexpressionofureaexcretioninrelationto bloodureaconcentrationmightpredictactualfunction. Aftermuchexperimentaltrial,Ambardin1910 1912 proposedacomplexrelationshipamongtheconcentrationsofureainblood(B)andurine(U)andtheurinary ﬂowrateorvolumeinaunitoftime(V):

Ambard’scoefficient

¼ B2 ðUVOVÞ

ThomasAddis(1881 1949)ofStanfordUniversity, oneofthemostcomprehensiveobserversofrenaldiseaseatthebedsideandinthelaboratory,alsointhe 1910ssethimselfthesametask tofindanexpression ofureaexcretionthatwouldanswerthequestion “howcantheextentofarenallesionbemeasuredina livingman?”24,25 Throughextensiveandmeticulous investigation,Addisandcoworkersshowedthatunder conditionsofhighurineflow,theratiooftherateof ureaexcretiontothebloodureaconcentration(D/Bas Addiscalleditinhis1928HarveyLecture,butmore familiarlyUV/B)correlateswithfunctioningrenal mass.DonaldD.VanSlykeandcoworkersattheRockefellerInstituteforMedicalResearchanditsHospital eventuallyarrivedataratioessentiallyidenticalto Addis’.Supposedly,theterm“clearance”arosein 1926,whenVanSlyke,onatraintoBaltimorewhere hewastolecture,hitonthe“worddefinition”:theratio ofureain1hurineovertheureain100mLofblood reallyequalsthevolumeofblood“cleared”ofureaby thekidneyinthatunitoftime.26

The1920ssawaninternationaloutpouringofnew findingsandideasinrenalphysiologyanddisease.In 1921,A.NewtonRichardsandcolleaguesinPhiladelphiasucceededinmicropuncturingthefrogglomerulus andobtainedresultsstronglysupportingthefiltration reabsorption(Ludwig-Cushny)modelofurineformation.27 In1926,theDanishphysiologistPoulBrandt Rehberg(1895 1985)publishedhisinvestigationsnominatingcreatinineasasuitable“marker”forglomerular filtration,suggestingavalueofbetween100and 200mL/minforman.28 ThomasAddisinthe1940s usedcreatinineclearanceinhisresearchandproposed asimplemethodforusingserumcreatinineconcentration(S[Cr])asanindicatorofrenalfunctioninclinical work.29 ProbablynottoomanycliniciansusedAddis’ fondmethod,whichdependedonpicricacidand

naked-eyecolormatching,butbythe1950screatinine (oritsclearance)wasbeginningtoreplaceureainrenal medicine.Andsoithasbeeneversince,withregression equationssupplantingurinebottles.Chronicrenal diseaseisdeﬁnedassustainedelevatedS[Cr].

Thedesiretounderstandtheactualdisordersofhomeostasiscausedbychronicrenaldiseaseinvitedmore complexanalysisthanthatseenwith“functionaldiagnosis.”RobertPlattandothersrecognizedandworked tounderstandtheremarkableadaptationswhichoccur inthechronicallydiseasedkidney(Figure2.2).Such adaptations,heexplained,untilthemostadvanced phaseofthedisease,maintainnormalbloodconcentrationsofpotassium,sodium,andphosphateandallow thedailyexcretionofthesesubstancesinamountsto matchintake.Accountingforthese“compensations” required,fortheelectrolytes,theconceptof glomerular tubularbalance thenowfamiliaridea thatinthefaceofdiminishedGFR,tubulesadaptto reabsorblesssodiumandphosphateandsecretemore potassium.PlattdescribedtheessentialsoftheseconceptsinhisLumleianLecturestotheRoyalCollegeof PhysiciansofLondonin1952.30 Earlyinhislecture, heclearlystatedthatthe“commonstructuralbasis” of“chronicrenalfailure”is“adiminutioninthe numberoffunctioningnephrons,”heraldingacentral andenduringprinciple.30 (Ofinterest,manyofthe authorsPlattcitedwereAmerican.Thepost-World WarIIerasawtheepicenterofmedicalresearchshift totheUS,owingingoodparttofundingfromthe NationalInstitutesofHealthandmajorfoundations, andpostwardisruptioninGermany.)

In1960,NealBrickerpublishedhis“expositionofthe ‘intactnephronhypothesis’,”furtheradvancingthe notionthatinchronicrenaldiseasesomenephronsare gonealtogether(thisisevidenthistologically),whereas remainingintactnephronsfunctionnormally,oradaptively.31,32 Brickerinthispapertriedtorevivetheterm “chronicBright’sdisease,”becauseit“tendstogroup togetheranumberofdiseasesofdiverseetiology, differingpathogenesisandwidelyvaryingpathologic characteristics.Asingulartermimpliestheexistenceof acommondenominatorinthesediseaseentitieswhich supersedestheirdifferences.”31,32 Itisnoanachronism toassertthatBricker’s“chronicBright’sdisease”isour “CKD.”Headdedthat“themoreadvancedthepathologicalprocessbecomes,thelessevidentarethedifferentiatingfeatures.”31,32 Thisreviewfrom1960of coursecitedPlatt,JohnMerrill,33 andotherexperimental workers,aswellasstudiesfromhislaboratoryatWashingtonUniversityinSt.Louis.

In1972,Brickerofferedanother“exposition,”this timeofthe“trade-offhypothesis,”basedonstudiesof phosphatehandlingandparathyroidglandactivityin “chronicprogressiverenaldisease”or“theuremic state”34 (“Bright’sdisease”wasreconsignedtothe past).Thekeynotion,ofcourse,wasthataninstrument ofcompensationfornephronloss heretheelevationof parathyroidhormoneleveltoeffectlessreabsorptionof phosphate maycomeatacost,inthiscasebonedisease.Subsequentdecadeswouldseethevariousadaptationschaseddowntotheiroppressivelycomplex molecularlevel channels,signalingmolecules,growth factors,andthegenesforallofthese.Buttheessential

Acute nephritis

Nephrosis

Pregnancy kidney

Renal tuberculosis, pyelonephritis, &c.

Subacute nephritis

Latent nephritis

Polycystic kidney

Chronic nephritis

Renal failure

Nephrosclerosis

Essential hypertension

Embolic nephritis

FIGURE2.2 RobertPlatt(1900 1978)wasaleading20th-centuryBritishauthorityonthekidney.Shownhereishisconceptoftheetiologyof chronicrenaldisease.Plattadvancedtheuseoftheterms“renalinsufficiency”and“renalfailure.”Plattalsowasamongthefirsttodefinethe tubularadaptationstonephronloss. From:Nephritisandallieddiseases:theirpathogenyandtreatment(1934),diagramfromp.37.Bypermissionof OxfordUniversityPress.

conceptofacommonsetofadaptivephysiologicalprocessesasthehallmarkoftheslowlyfailingkidney, regardlessofcause,seemedwellestablishedbytheearly 1970s.

Alterationsintubularfunctionallowedintactnephronstoadapttooveralllossoffunctioningrenalmass. Bothinthisregardandinthestudyofnormalphysiology,academicnephrologistsofthe1960and1970s mostlyattendedtothetubule.Ifyouwerenotmicropuncturingsomewhereinatubuletostudytransport, youweren’tanybody.Thetubulewasthecognitive partofthenephron.CarlLudwig,ArthurCushny,and A.N.Richardshandeddowntheconceptoftheglomerulusasapassiveultraﬁlter.Butin1982,nephrologist BarryBrenner,ofHarvardMedicalSchoolandthePeter BentBrighamHospitalinBoston,withhiscolleagues, publishedareviewsummarizingtheirmicropuncture workintheratglomerulus.Theirproposalwasthatin chronicrenaldisease“remnant”glomeruliadaptedby hyperﬁlteringtosustainGFR,butatthecostoffurther lossofnephronsfromasortofwearandtearinjury.35 Theimplicationsofthishypothesiswillbediscussedunder“Treatments.”

CAUSES

Evenifthepathophysiologyofchronicrenaldisease varieslittlewithunderlyingcausation,etiologycanmatter.Thecorrectdiagnosismaycriticallyguidetreatment inearlyphasesofsomerenaldisorders theapproach tolupusnephropathydiffersgreatlyfromthatforadult polycystickidneydisease,thoughbothcangoontothe chronicstage.Generalawarenessofcausesofkidney diseasecansuggestprevention:avoidingdiabetes wouldmeanfewerdestroyedkidneys.Finally,bothpatientsanddoctorswanttoknow“whydidthis happen?”.

Ithasalwaysbeenlegitimatetoaskifthecauseof choleraisthe vibrio microbeorabadwatersupply, andsimilarquestions.Themeaningofcausationhas neverbeenfreeofambiguityandhasgrownmore murkywithincreasedreferencetoriskfactors,genetic predisposition,andeven,perhaps,probabilisticor Bayesianthinking.Butfromanearlier(andsimpler?) time,amanualofkidneydiseasefrom1917included thecausesof“chronicnephritis”shownin Table2.1 (notallfromthatsourcearelisted).36

Readerswilltendtomentallyratethesefromthe familiar,throughtheodd,tothebizarre.Obviously, ideasaboutcausationchangeovertimewithshifts(or advances,ifyoulike)inmedicaltheoryandpractice. Causes necessarilycomeandgo:radiocontrastnephropathycouldnotoccurbeforetheinventionof

TABLE2.1 FromBright’sDiseasetoChronicKidneyDisease

Repeatedattacksofacutenephritis

Overindulgenceinmeatandcannedfoods

Intestinalindigestion

Overindulgenceinalcohol,especiallybeer

Prolongedhypertension

Pregnancy

Loosekidney

Syphilis

Gout

Arteriosclerosis

Chronicleadpoisoning

Longcontinueduseofmercurialandcertaindrugs

Repeatedexposuretoseverecold

Selectedcausesof“chronicnephritis”fromarepresentativemanualofkidney diseasefrom1917,OliverT. Osborne’sDisturbancesoftheKidney (Chicago: AmericanMedicalAssociation,1917),p.114.

radiocontrast.Butfactorsbeyondmedicinecandeterminepathogeniccauses,oratleasttheperceptionof causes.RichardBrightsawthecausationofgranular kidneythisway:“Anintemperatecourseoflife,or somesuchcause,haspredisposedthekidneytosuffer. Thepatienthas,inthisstate,beenexposedtovicissitudesoftemperature;theirritablekidneyhasimmediatelysympathizedwiththeskin,andmorbidaction hasbeeninducedinthatorgan ”37 Brightmeantthat excessalcoholingestionsetsthecircumstancesforrenal injury,bywayoftheskin,whenthemiscreantendures exposureto cold,especiallycoldandwet.Suchachill wouldsuppressthe“insensibleperspiration,”whose flowearlyphysiciansdeemedessentialforhealth. Suchsuppressionled, via “sympathy,”toinflammation orcongestion,orsomesortofperturbation,inanother organsuchasthekidney.HospitalsinBright’stime lookedaftermainlytheindigentandworkingpoor so Brightorhispupilsreadilyobtainedhistoriesofdrinking,andexposuretocoldanddamp(England,after all)onthewayhomefromtheginhouse,oratoutdoor labor.ArthurM.Fishberg(1898 1992)stilltookseriouslythenotionofcoldasacauseofrenaldiseasein hisbook HypertensionandNephritis of1930,evenreviewingexperimentalfindingsthatchillingtheskinmay indeedcauserenalvasoconstriction.Butsoonthispurportedconnectiondisappearedfrombooks,thoughit persistedinthepopularmind.38

ThePhiladelphiainternistandauthorJamesTyson (Figure2.3)in1881held“habitualexposuretocold”

FIGURE2.3 JamesTyson(1841 1919),aprofessorofmedicineat theUniversityofPennsylvaniainPhiladelphia,wasauthorof ATreatise onBright’sDiseaseandDiabetes,publishedin1881,withasecondedition in1904.Thiswoodengravingfromtheﬁrsteditionshowstestingfor proteinuriausingacidprecipitation.Tysonalsopublishedawidely usedmanualofurinalysis,apamphletondecapsulationastreatment ofchronicBright’sdisease,andanarticleon“cardiovascular-renal disease.” Author’scollection.

asacauseofchronicrenaldisease,butalso scarlatina. ThatdropsyandBright’sdiseasecouldfollowthis ailmentwasclearintheearly19thcentury.Thiswas, ofcourse,poststreptococcalglomerulonephritis.9 This causecouldonlyenterthetextbookswiththematurationofthegermtheory(microbialunderstandingofdisease)inthe1890sandbeyondwiththeworkofLouis Pasteur(1822 1895)andRobertKoch(1843 1910). Tysonalsocitedcontemporaryreportsthatmalaria mightcauserenaldiseaseandalsolistedgoutand leadtoxicity.

Theverylate19thandearly20thcenturiesbroughta noveletiologicpossibilitytochronicrenaldisease, whichby1900intheUSwasthesixthleadingcauseof death.39 WilliamOslerinhis PrinciplesandPracticeof Medicine of1892statedthatafactoraccountingforthe prevalenceofchronicBright’sdiseaseamongmenin theUSwas“theintenseworryandstrainofbusiness, combinedastheyoftenare,withhabitsofharriedand overeatingandalackofproperexercise.”40 Inalater edition(1909),hereferredtothesemiddle-agedmen asthe“victimsofthestrenuouslife.”Aphysicianin Rochester,NewYork,SeelyeW.Little(1867 1937)in

his1907bookonnephritisconfidentlyidentifiedthe likelyvictimthisway:“Theruddy,healthylooking manwithalittletoomuchabdominalfat,whoisa goodliver,whousesalcoholmoderatelybutregularly, andwhousestobacco,isthetypeofmanwhoinmiddle lifeorsoonaftersuffersfromcertainformsofkidney disease.”ThecauseofmostchronicBright’sdisease, Littlecontinued,“isgenerallyspeakingandmostoften, simplycivilization,especiallywithreferencetofoodand drink.”20 RichardBrightintheearly1800shadassociatedrenaldropsywiththelower-classworkingmanor woman,theEnglishcharitypatienttoomuchgivento thedrinkingofspirits,andsubjectintheirdailylabors tocoldandwet.BytheGildedAge1890s,chronicrenal diseasehadrisentobecomeacharacteristicdisorder oftheaffluentbankerorindustrialist,amishapof capitalismatitsotherpole.Aswithmanydiseases, nephropathy,oratleastideasaboutit,ariseswithina socialandeconomicframework.

Suchanotioncontinueswithdiabeticnephropathy andthe“epidemic”ofdiabetesandobesityofthelate 20thand21stcenturies,clearlyspreadingaroundthe developingworld.PaulKimmelstielandCliffordWilsondescribednodularglomerulosclerosisineightpersonswithwhatwouldnowbetype2diabetesina pathology,notclinical,journal,in1936.41 Butevenas lateasthe1960and1970s,textbooksgaveverylittle attentiontodiabeticrenaldisease fewerpagesthan “hypokalemicnephropathy”in DiseasesoftheKidney editedbyMauriceStraussandLouisG.Welt,oneof theﬁrstmultiauthornephrologytexts,publishedin 1963!42 Eventhethirdeditionfrom1972ofthepopular Britishtitle RenalDisease editedbyDouglasBlackcontainedonlyafewparagraphsonthesubject.43 With theincreasedavailabilityofmaintenancedialysis,at leastintheUS,bythe1970and1980s,itbecameclear thatdiabeteswasacommonsubstrateforrenalfailure, particularlywhencoexistentwithhypertensionin personsofAfricanbackground.Aswithtype2diabetes itself,diabeticrenaldiseaseseemedtobeeverywhere. Similarly,thenumberofjournalarticlesdealingwith diabeticnephropathyshowedasharpslopeupward beginninginthe1980s,from137in1979to722 by2000.44

Thegrievouslyhighprevalenceofrenaldisease amongsomepopulationsofAfricanbackgroundfound explanationintherevelatorydiscoveryofvariantsfor theapolipoproteinL1genethatsharplyraisesusceptibilitytonondiabeticnephropathies,especiallyfocal segmentalglomerulosclerosis.45 Anexampleofthe interactionofgeneticvulnerabilityandthesocialenvironment,butwiththerequirementofamicrobe,isof courseHIV-associatednephropathy.Inlargeregionsof Africawherepovertyandendemicwarfarehinder effortsatpublichealth,partlypreventableparasitic

diseasessuchasmalariaandschistosomiasisaccountfor muchoftheburdenofrenaldisease.

Thecauses,understoodbroadly,ofchronicrenaldisease,then,havecomeandgonewithchangingsocial andenvironmentalconditions,thedeclineofoldmicrobesbutappearanceofnewones,and,ofcourse, reﬁnementinmedicalthoughtandevolvingwaysof determiningwhatis“evidence.”

TREATMENTSANDPROGRESSION

Bydeﬁnition,chronicdiseasecannotbecured,so treatmentofchronicrenaldiseasehasaimedatalleviatingsymptomsandavoidingfurtherinjurytothekidneys.RichardBrightsawexposureoftheskintocold astheincitingeventforalbuminuricrenaldisease,and inthe1830srecommendedwarmclothingandtravel. Thereafter,seeminglysodideveryphysicianwhowrote aboutBright’sdiseaseforthenext80orsoyears.

“Onthesubjectofclothing,”wroteBrightin1836,“I havealreadysaidallthatisnecessary:letflannelbe wornconstantly,andeveryprecautionbehabitually adoptedwhichmayobviatetheeffectsofwhateveris calculatedtochillthesurfaceorchecktheperspiration.”1 LionelBeale’stextof1870insistedon“Shetland woolgarments,socks,&c,”andevenspecifiedashop wheresuchcouldbeobtainedyear-round.2 JamesTyson in1881demanded“woolengarmentsnexttotheskin”(his italics).9 OliverOsborneinhismanualof1917urgedthat “warmclothingbewornduringthecoldseason.”36 And althoughrecognizingthat“thediseasebeing,unfortunately,mostapttooccurinthoseleastabletosubmit totheabsencefrombusiness,”Brighthadadvisedin his1836articlethatremovalto“somedecidedly southernabode OneofthemorehealthyoftheWestIndiaislands,asSt.Vincent’s,wouldprobablybe beneficial.”1 Brightadmitted,however,thathesofar hadnotencounteredanypatientwhocouldactually manage thisrecommendation.Tyson,likeBright50years earlier,recommended“residenceinawarmequable climate.”9 Thisseemedafavoritephrase,aspresumably oneauthordutifullyread(andcopiedfrom)hispredecessors.Osleralsoliked“awarmequableclimate”in thechapteronchronicBright’sdiseaseinhis1909edition,specifyingSouthernCalifornia.11 Elwyn,aslateas 1926,mentioned“awarm,dry,equableclimate,”though withminimalconviction.21 Removaltoamoresalubriousplacelonghadbeenadvisedforchronicdiseases, particularlytuberculosis,buthowmanynephritictravelerseverfoundtheir“equableclimate”remainsunknown.Forthatmatter,historianscanknowlittle abouthowwellgeneraldoctorsfollowedtheexperts’ printedadvice,orhowdiligentlypatientsfollowedtheir doctors’prescriptions.

Nodoubtadheringtotheplanprovesmostdifﬁcult fordiet,whichhasbeenvaryinglydeemedanessential componentoftherapeuticssincethetimeofHippocrates.Virtually,alltheauthorsreferredtointhischapter,andmanyotherswhogavespecialattentiontorenal disease,recommendedsomerestrictionofmeat. Broadly,theysawthemainworkofthekidneytobe excretingnitrogenouswaste,andthoughtitwiseto resttheimpairedorgan.Manyrenalpatientsofthe 19thandearly20thcenturiesenduredperiodsoftime onamilkregimen.FrenchphysiologistFernandWidal (1862 1919)madecleartheassociationofsodiumwith edema,sodropsicalpatientsweretoldtolimitsaltand intakeofwater.

Intheearlydecadesofthe20thcentury,diethad becomepartofthetechnologyofhospitalmedicine hospitaldietmanualsofthe1930scouldlistasmany as50dietsforallmannerofdisordersandneeds.In thiscontext,ThomasAddisofStanford(Figure2.4), morethananyotherphysicianfocusingonkidneydisease,supportedthelow-proteindietwithexperimental work.Asoneexample,heandhislaboratory“group” (ashecalledhiscoworkers)showedthatproteinfeeding inducedhypertrophyintheratremnant-kidneymodel, whichheinterpretedasaresponsetoexcesswork. Addiscametobelievethattheneedtoexcreteurea againstanosmoticgradientconstitutedamajorpartof renalwork,andthatoverworkingremainingfunctioningnephronswouldeventuallydestroythem.He

FIGURE2.4 ThomasAddis(1881 1949)atStanfordUniversity SchoolofMedicineinthe1920 1940sstudiedchronicrenaldiseasein theclinicandlaboratory.Hewasamongtheﬁrsttorecognizethe progressivenatureofchronicrenaldiseaseregardlessofcause. Believingthatremainingnephronsmustsufferinjuryfromanobligatoryincreased“work”inexcretingurea,hedesignedandprescribeda low-proteindiet. CourtesyoftheStanfordMedicalHistoryCenter.

prescribedamountsofproteinprecisely,tothegram, andwithhiswife,adietician,didallthatwaspossible toensurecompliance.Amongthosewhosucceeded wasLinusPauling,whobecameAddis’patientand friendwhenhedevelopednephroticsyndrome.Pauling’sverycapablewife,AvaHelen,learnedquantitative dieteticsassheassumedtheresponsibilityforpreparing meals.Paulingrecoveredcompletely,whetherowingto his14yearsofproteinrestrictionortoaspontaneous remission.46 49

Thelow-proteindiettoslowthecourseofchronic renaldiseasedidnotfarewellafterAddis’deathin 1949.Butitwasnotdiscreditedbyanyclinicaltrial; thesedidnotexistatthetime.Rather,avarietyofincidentalfactorsplayedarole.47,48 Withthe1950scame penicillinandother“wonder”drugs,theintensive careunit,andothernewformsofmedicaltechnology. Dietarytherapycametoseemarchaic,andnotvery interesting.ThomasAddispublishedhisﬁndingsand philosophyinanidiosyncratic(butinsomeways delightful)bookcalled GlomerularNephritis, 25 atatime whenthenewandrelevantappearedinjournals.Addis, workinginrelativeisolationatStanfordUniversity CollegeofMedicine(theninSanFrancisco),preferred hisstable“group”oflabassociatesandvolunteers, includinghisChinese-Americandieners.Hedidnot raiseupdisciples.Ironically,theonemajorﬁgurein nephrologywhoattributedhisinterestinthekidneyto workingwithTomAddis(asaseniorstudent)wasBeldingScribner,whoseachievementwas,ofcourse,the creationofchronicdialysis.Withthespreadofmaintenancedialysis,interestamongpractitionerscentered on,andrewardderivedfromtreatingpatientswhen theyreachedthepointofuremia,notsomuchondelayingthisoutcome.Meanwhile,nephrologistsinAmericanacademiachosemainlytoexplorenormalrenal physiology,apreferencereadilycatalyzedbyfunding fromtheNationalInstitutesofMedicine.

BarryBrenner’sexperimentalworkshowinghyperfiltrationinremnantnephronsprovidedsupportfor dietaryinterventionsforpatientswithchronicrenal disease.Supposingsuchhyperfiltrationtocause furtherlossofnephrons,Brenner(whocitedThomas Addis)andcolleaguescoupledthisconceptwiththe establishedknowledgethatGFRinmammalsvaries, tosomeextent,withproteiningestion.Brenner’sgroup publishedtheirsynthesisintheprestigiousandwidely read NewEnglandJournalofMedicine in1982,andother researchersadvancedcompatiblefindings.35 Thelowproteindietreawakened.Butconfirmingitseffectivenessinslowingtheprogressionofchronicrenaldisease provedelusive.Thelargesttrial,theModificationof DietinRenalDiseaseStudy,producedequivocalresults ofsufficientcomplexitytosustainyearsofdebate followingtheinitial1994publication.50 Theavailability

ofangiotensin-convertingenzymeinhibitorsinthe 1990sstimulatedanewmodel,andthebeneﬁtof “RAASinhibition”toslowprogressionmoreeasily gainedacceptancefollowingfavorabletrials.Along theway,hyperﬁltrationasculpritgavewaytoproteinuria(oralbuminuria),asstudiesdeterminedthatproteinpassingthroughtheglomerularsieveitself inducesfurtherdamage.Proteinrestrictionnevervanishedaltogether,however,atleastasameansfor reducingsymptomsinthepatientwithuremia.

Theconceptof“progression”meritsfurtherdiscussion.PhysiciansgoingbacktoRichardBrightunderstoodthatpersonswithrenaldiseasecouldliveand feelwellforyearsorevende cades,thougheventually uremia(notatermusedinBright’sera)wouldensue. Thiswaswhatissometimestermed“tacit”knowledge: thinkingthatwasnotexplicitlythoughtabout,almosta given.Ofcourse,therewereexceptions,suchas ThomasAddis.Thischangedinthelate1970and 1980s,when“progression”becamereifiedassomethingtobediscussed,studied,writtenabout,indexed, andtaught.Brenner’s1982paper,thefulltitleofwhich was“DietaryProteinIntakeandtheProgressiveNature ofKidneyDisease,”nodoubtplayedarole.In1976, WilliamMitchandcolleaguespublisheddatawhich supportedtheideathataplotof1/[creatinine],the reciprocalofS[Cr]andineffectasurrogateforGFR, declinedlinearlyinanygivenpatientwithchronic renaldisease.51 Althoughtheirfindingswere challengedandtheplotof1/[creatinine]failedtowin lastinguse,“progression”hadgainedacredible scientificimageintheformofa slope .Journalarticles dealingwithchronicrenaldiseasecontainingthe word“progression”intheirtitlewentfrom1in1976 to15in1983,then30ormoreby1988.WilliamMitch editedavolumetitled TheProgressiveNatureofRenal Disease whichappearedin1986.52 Slowingprogression becamenotonlyafruitfulsubjectforresearchbutalsoa dominantobjectiveofoutpatientnephrology.Bythe mid-1980s,manynephrologistsviewedtheceaseless marchofpatientsintodialysisunitswithfrustration, ifnotdespair,andwarmlyembracedtheoptimistic notionthatendstagemightbedeferredoreven avoided.

Treatmenttoslowprogression,morefullydescribed inalaterchapter,ﬁtswellintoapracticeknownonly tomedicineofthelast50yearsorso theprescribing ofmanymedicinesforpersonswhofeelwell.Thisis, ofcourse,exempliﬁedbythetreatmentofhypertension, itselfusuallyacomponentofmanagementinchronic renaldisease.Othermedicationssuchasphosphate binders,vitaminDanalogues,andsodiumbicarbonate havebeenaddedovertheyearstorightabnormallaboratoryvaluesand(itishoped)avoidcomplications,and toprotectGFR.

Physicianscaringforpersonswithrenaldiseasehave hadtoseekwaystodealwithedema(dropsy),whether fromnephroticsyndromeoreventuallossofGFR.The mainstaysoftraditionalWesternmedicine,purgatives andemetics,probably did workforthisneed,ifforlittle else,astheireffectwouldbetoejectsaltandwater fromthebody.Thesamewouldhavebeentruefordrugs consideredsudorifics.Someoftheplantagentsused,or mercurialsaltssuchasthepopularpreparationcalomel (mercurouschloride),mighthaveactedassaluretics.In the19thcentury,somepractitionersusedacontrivance calledthehot-airbath,asimpledevicetoflowwarm airontotheedematouspatient.Clearlyeffectivemercurialdiuretics(mainlymercurhydrin)cameintouse, mainlyforheartfailure,inthe1920s,followinganaccidentaldiscoveryin1919byAlfredVogl(1895 1973), whileamedicalstudentinGermany.Hefoundthatthe injectableantisyphiliticNovasurol,amercurialdrug, inducedabriskdiuresis.Fromworkonsulfonamidecarbonicanhydraseinhibitorscamethefirstreliableoral diuretics,chlorothiazide,in1958,andhydrochlorothiazidein1959.Theseprovedfeeble,however,intheface ofseverelossofGFRorintenserenalsodiumavidity. Thefirstloopdiuretic,furosemide,appearedin1964, andsoonwonthemarket.Edemawasneverthe same.53,54

CHRONICKIDNEYDISEASE

Althoughcertaininterventionsseemedabletodelay theonsetofterminalrenalfailure,nephrologistsofthe 21stcenturystillregularlyconfrontedpersonspresentinginemergencydepartmentswithend-stagedisease, alreadyinneedofdialysis.Someneverknewthatthey hadkidneydisease.Moreawarenessandearlier detectionseemedimperative.Butthelayandprofessionalleadersconcernedwithkidneydiseaserealized thattheyﬁrsthadtoovercomeaproblemwith “branding” thatis,amongorgans,thekidneysuffered frompoornamerecognitionandinattention.People contemplatedtheirheartsandattendedtotheircolons, butnottheirkidneys.ApresidentoftheAmerican SocietyofNephrologyinhisannualaddressatthe 2002meetingsaid:

First,wehavetomarketkidneydiseasebetter.Thepeople whoareinterestedinstroke,cardiovasculardisease,andcancer havedoneafarmoreeffectivejobthanwehaveindeliveringa messagetothelaypopulationandtopracticingphysiciansthan wehaveaccomplished.55

Somethoughtthatoneobstacletoraisingawareness ofkidneydiseasewasfaultylanguage,particularly “chronicrenalfailure.”Presumably,fewpersonsknew

what“renal”meant,and(thisismyownspeculation) “failure”seemedanunattractivetermtotheleadership ofnephrologyintheUS.Americansdonotlike“failure.” Atthebeginningofthe“ExecutiveSummary”ofthe importantnewsetofguidelinesforthedetection andcareofkidneydiseasefrom2002,calledthe “K/DOQI”orKidney/DialysisOutcomesQuality Initiative,sponsoredbytheNationalKidneyFoundation,thereaderseesthisexplanation:

Why“kidney”? Theword“kidney”isofMiddleEnglish originandisimmediatelyunderstoodbypatients,their families,providers,healthcareprofessionals,andthelay publicofnativeEnglishspeakers.Ontheotherhand,“renal” and“nephrology,”derivedfromLatinandGreekroots,respectively,commonlyrequireinterpretationandexplanation.The WorkGroup[fortheseguidelines]andtheNKFarecommitted tocommunicatinginlanguagethatcanbewidely understood ”56

Thus,nationalleadersurgedthatthesimplephrase “chronickidneydisease”shortenedto“CKD”replaces “chronicrenalfailure”tolabellong-standingand usuallyprogressivelossofkidneyfilteringcapacity, regardlessofunderlyingcause.Tobringmoreorderto nomenclatureandtoaidthedevelopmentanduseof practiceguidelines,CKDwasstratifiedintofivestages basedonGFRestimationsfrombloodcreatinineconcentrationvalues.“Staging”longhadbeenusedforcancer andheartdisease.Thedemystificationoflanguageand thestagingschemerapidlywonapprovalfollowing the2002publicationsandpresentations.“See-kay-dee” wasinstantlyandeverywhereonthelipsofAmerican nephrologistsandparticularlytheirfellows.Onlycarelessold-timerswouldoccasionallyreferto“chronic renalfailure.”Understandingthemeritsofthenew systemandlanguage,I(anold-timer)wasstillamazed athowquicklythenewnamesandframework“took.” Perhaps,hierarchyandauthorityplayagreaterrolein theconductofmodernmedicineandsciencethanwe liketothink.

Levelsofcreatinineoncedeemedofnoconcerncould nowdenoteearly-stagechronicrenaldisease.By extrapolation,eightmillionormorepersonsintheUS intheearly2000swouldhavehada“disease”only recentlylookedonasrelativelyrare.In2004,theCouncil ofAmericanKidneySocietieslauncheda“Chronic KidneyDiseaseInitiative”inparttofurtherthe detectionofpersonswhowouldﬁtintoanearlystage basedonbloodcreatinineconcentration(albuminuria cametoplayalargerroleinlaterrevisionofthe stages).57 Eventually,theconceptspreadinternationally, includingthegenesisofa“WorldKidneyDay”in 2007.58,59

Despitethewidespreadacceptanceofthenew framework,atleastintheUS,theUnitedKingdom,