eoaf019 (1) by Integrative Centers for Science and Medicine

Evolutionarymedicineof emunctoryfunctionsofthe kidney:anempiricalreview

NoelT.Boaz 1 , 2 , 3 , * and RobertL.Chevalier4

1 CenterforEvolutionaryMedicine,IntegrativeCentersforScienceandMedicine,Martinsville,VA,USA; 2 VirginiaMuseumof NaturalHistory,Martinsville,VA,USA; 3 DepartmentofBiology,NorfolkStateUniversity,Norfolk,VA,USA;and 4 Department ofPediatrics,UniversityofVirginia,Charlottesville,VA,USA

* Correspondingauthor.CenterforEvolutionaryMedicine,IntegrativeCentersforScienceandMedicine,12Starling,Avenue, Martinsville,VA24112,USA.E-mail: noeltboaz@integrativemedsci.org Received23November2024;revisedversionaccepted2July2025.

ABSTRACT

Primitiveemunctoryfunctionstoexpelharmfulsubstancesfromcellsandtheinterstitialspaceof multicellularorganismsevolvedoverthepastbillionandahalfyearsintothecomplexphysiologyofthe metanephrickidney.Integrativebiologyallowsempiricaltestingofhypothesesoftheoriginsofrenalstructures fromhomologoussingle-celledprecursors.Emunctorycellcomplexescallednephridiaevolvedinmetazoan (cnidarian)ancestors750millionyearsago(mya).Thepronephrickidneywasametamericstructurethat evolvedsome700myainearlybilaterianstoexcretewasteproductsthroughnephridialslitsinthebody wallfromheadtotail.Themesonephrickidneyevolved635myawhenpharyngealslitsdifferentiatedinto filter-feedinggillsandaheart-kidneyevolvedinlaterbilaterians.Themesonephricfilteringglomerulilost theirexternalexitsthroughthebodywallandnowdrainedthroughaninternalmesonephricductintothe coelom.Whenchordatesmovedintofreshwaterfromthesea588myathehigh-pressureglomerulusevolved inthemesonephros,increasingwaterexcretion.Tetrapodsmovedontolandlosingthebuoyancyofwater. Bloodpressureandglomerularfiltrationroseandthemetanephrickidneyevolvedinamniotes.Thehigh pressure-flowglomeruluspredisposespodocytestoinjuryanddetachmentleadingtosclerosis,whereasthe highmitochondrialactivityofthetubulecontributestosusceptibilitytoischemia,hypoxia,andoxidativeinjury. Thekidneyevolvedacounter-currentmechanismandureacycletooptimizewaterretention.Perturbations inthecomplexdevelopmentofthemetanephrickidney,whichparallelsitsphylogeny,explainmanyrenal pathologies,whicharetraceabletotheseadaptations.

KEYWORDS : kidney;renal-evolution;kidney-disease;evolutionary-medicine

©TheAuthor(s)2025.PublishedbyOxfordUniversityPressonbehalfoftheFoundationforEvolution,Medicine,andPublicHealth. ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(https://creativecommons.org/licenses/by/4.0/), whichpermitsunrestrictedreuse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.

REVIEW

INTRODUCTION

Chronickidneydiseasehasbecomeoneoftheleadingcauses ofglobalmorbidityandmortality,buteffectivetherapiesare limitedbythevulnerabilityofthekidneytobothhemodynamic andmetabolicinjury[1].Theultimatecausesofvulnerabilityof thisexcretoryorganlieinitslongevolutionaryhistoryandits adaptationtoachangingplanetaryenvironment[2, 3].Inthe courseofahumanlifespanthenumberofnephronsformedat birthisdependentonfetalenvironmentandreducedby50%by lateadulthood,theproductofsusceptibilityofthemetanephric kidneytoprogressiveglomerularandtubularinjury[4, 5].

Humankidneysbasicallyfunctiontomakeurine,butas evolutionaryphysiologistHomerSmithfamouslyintoned,‘in amoreconsideredviewonecansaythatthekidneysmake thestuffofphilosophyitself’[6].Admittedlygrandiose,Smith’s pointisthatthemetabolicallyexpensivekidneyshaveplayedan importantroleinmaintainingphysiologicalhomeostasisthrough evolutionaryhistory.Inthisreviewweconcentrateonthemost fundamentalofthekidney’sfunctions,excretingwasteproducts.

Delineatingtheevolutionarystepsthataccountforkidney anatomyandphysiology,andhowtheywereadaptiveintheir owntimeandplace,isessentialtoafullunderstandingof renalfunction.Darwindoesnotpromisethatthegradations mustbeteleologicallylinearorthattheirlogicmustcohere toourmodern-daysynchronicnotionsofefficientorpracticable perfection[7].Thehumankidneymustrecover99%ofthefiltrate, anenergeticallyexpensiveandinefficientprocess.Understanding themultifariousinteractionsofthekidneyinhealthanddisease hasbeenamajorbiomedicalchallenge.Ifweseektounderstand thekidneybiomedicallywemustunderstanditsevolutionary history.

Inthisreviewweconsiderthemorphophysiologicaladaptationsoftheurinarysystemthroughtime.Homologousgenes andcomparativebiologyofextantorganismsnowinformusof ancientprecursorsofthekidneythatextendbacktoProterozoic single-celledprecursors.Becausethisancestrytracesback beforetheeumetazoanevolutionoforgans perse,virtually everyotherorgansysteminthebodyhasbeenaffectedby theontophylogeneticformandfunctionofthekidney,and instructivecomparisonsmayinvolveunfamiliarorganisms.New discoveriesin‘omicsfieldshavepotentiatedreliabletestsof homology,allowingmorepreciseandwell-controlled‘‘time tree’’phylogeniestobereconstructed[8, 9].Newpaleontological discoverieshavefilledinmanygapsinthefossilrecord,replete withreliablepaleoenvironmentaldataandgeochronological control[10].ItisnowpossibleusingthemethodsofEvolutionary andDevelopmental(Evo-Devo)Biology[11, 12, 13, 14]to elucidatetheoriginsofrenalphysiologytoapplythemto clinicalconcernswithinthedevelopingdisciplineofEvolutionary Medicine[3, 15].Becausethenomenclatureofkidneyevolution

hasbeenvariouslymisinterpreted,weincludeaglossaryofterms asappliedinthisreview.

Evolutionarymedicineresearchestheultimateorevolutionary causesofpathologies[16, 17, 18, 19, 20, 21, 22, 23].Inthis approachhumanstructureandfunctionareunderstoodas productsofadaptationshonedbynaturalselectionthrough geologicaltime,atmanyevolutionarylevelsandthroughmany differentecologies.Thisapproachisnotnew(Explanatory Box1), butwearenowabletochartthroughtimethenetresultofgene cascadesanddevelopmentalbauplansnestedwithinoneanother bynaturalselectionovereons.Renalmalformationordisease resultwhenevolvedrenaladaptationsgoawry:anevolutionary medicalperspectivecanbenefitfutureresearchinmedicaland surgicalcareofthesedisorders[24].

THEPHYLOGENYOFRENALEMUNCTORY FUNCTIONS

Theprimaryandmostprimitivefunctionofthekidneyas anorganis‘emunctory’[25],expellinguselessorharmful substancesviaultrafiltrationandsecretion,withmuchthesame effectasvacuolizationandexpulsionofsubstancesacrossthe cellmembranebytheearliestcells.Expelledsubstanceswere nitrogenouswastessuchasammonia,urea,andurate,and xenobioticsubstancessuchasalkaloidsandtoxins.Atone stageofevolution(betweenchordatesandthefirstvertebrates, Table1),low-salinitywaterbecameapotentiallyfatalsubstance thathadtobeexcreted[6].Explanatory Box1 reviewsearlybut stillprescientbroadevolutionarynarrativesofkidneyevolution. Figure1 presentsanevolutionarytimetreeof Homosapiens derivedfromconsensusgenomicandpaleontologicaldata[27] withinawellconstrainedtaxonomicandtemporalframework thatallowsreconstructionofbroadpaleoenvironmentalcontexts. Methodologyforconstructingthephylogeneticdiagramused Timetree5software[9]tocreateanevolutionarytimeline for H.sapiens with30best-fitadjusteddivergencedates derivedfrommolecularandpaleontologicaldatabases.This perspectivegroundsourreviewofrenaladaptations.Genomics andintegrativebiologyhaveallowedamuchmoreprecise understandingofthephylogeneticrelationshipsofwholephyla ofspecies[11],especiallyintheearliestprevertebratephases ofhumanevolution.Theseearliestphasesofrenalevolution, thoughdimlyglimpsedinthelastcentury[6, 25],remainkey tounderstandingthekidney’sadaptationsinthesurrounding mediumofwaterthroughtime(seeExplanatory Box1).

EXCRETIONOFMETABOLICWASTEPRODUCTS ANDFOREIGNCHEMICALS

Oureukaryoticpremetazoan,single-celledancestorexpelled metabolicwasteproductsandforeignchemicalsby

Extant homologue

Clostridioides

Ecology

Physiology

Hydothermal- vent/ hot-spring, anoxic,marine/ ?Freshwater

Transcriptionandtranslation,exocytosis ofnitrogenouswastes,Wood-Ljungdahl Pathway,thermophile

Table1. Normaladaptationsbyevolutionarycladesin Homosapiens.

Anatomy

Divergence date(mya) Divergence geological stageage

Single-cellprokayote,bilaminarcell membrane,verysmallsize,ribosomes

Hadean/ Eoarchean

4250

Clade

Marine Paramecium

TCACycle,oxidativemetabolism, photosynthesis,ECMgenes

Pronephridia,cellnucleus,mitochondria, vacuoles,ribosomes,cytoskeleton, lysosomes,peroxisomes

Paleo/Meso- proterozoic

LUCA/Cellular Organisms

Eukaryota 1598

Monosiga (choano- flagellate)

Marine/freshwater

Adhesiongenes,predatoryonbacteria

Hydrostaticskeleton,apicalflagellae

Mesopro- terozoic

1275

Opisthokonta

Acropora (Basal Cnidarian;larval ‘planula’)

Thalia (Salp), Combjelly

Caeno-rhabditis elegans / Priapulus (Penis worm)/Planaria (flatworm) Sacco-glossus (Acornworm [Hemochor-date]) (continued)

Marine

Paxgenes,ETS,HOX,POU,T-box transcription

Nephridiaof3cells,radialsymmetry, diploblastic,coelenteron,mouth, tentacles,nervenet

Neoprotero- zoic

Marine

Glutamateneurotransmitter,ciliated locomotion

Triploblastic,mesodermalmuscle, neurons

Neoprotero- zoic

Marine

Peristalsis,excretoryorgans,nerve transmissiontocircularandlongitudinal muscle,ammoniaexcretion.

Gillswithfliteringandrespiratory functions,detritusfeeder,iodine utilization,transcriptionfactors eya, six1/2,pou3,sall,ihx1/5 and osr ,and structuralgenes nephrin,kirre,andzo1

AVPprecursor/ADH

Pronephroswithprotonephridia,open circulatorysystem,protostomal (acoelomate)digestivetract,headand tailinrostro-caudalaxis,specialsense organs; Coelom,pronephricglomeruliwith metanephridia,deuterostomaldigestive tract,heart-kidney,closedcirculatory system,cloacalexcretion,endostyle

Neoprotero- zoic

758

743

708 635

Metazoa

Eumetazoa

BilateriaEarly Late

Extant homologue

Ecology

Branchiosto-ma (lancelet)

Marine/estuarine

Physiology

Filterfeeder,integumentary respiration,closedcirculatorysystem

Ichthyo-myzon, Lampetra (lamprey)

Freshwater

Gillrespiration,Vit.D,AVPV1,V2, increasedlocomotorspeed

Freshwater Chimera (rabbit fish)

Anatomy

Divergence geological stageage

Divergence date(mya)

Table1. Continued. Clade

Mesonephricglomeruliwith metanephridia,pharyngealfiltering gillsreplacepronephricslits, cartilaginousskeleton,integument, largerbodysize,thyroidgland

Neoprotero- zoic

Mesonephroswithhigher-pressure glomerulus,2-chamberedheart, respiratorygills,limbs,post-analtail, ostracodermbonyskeleton,cranial nerves,parathyroidglands

Neoprotero- zoic

Ureaexcretion

Jaws,teeth,separateanalandgenital openings,pelvicfins,basipterygia copulatoryorgans

Freshwater

Chordata

Vertebrata

Gnathostomata

Ureaexcretion

Latimeria (coelacanth) Dipnotetrapodo- morpha

Xenopus (clawedfrog)

Freshwa- ter/episodically terrestrial

Mixedgillandairrespiration, aldosteronesecretion

Lung,suprarenalgland

Protopterus (lungfish) Tetrapoda

Terrestrialwith aquatic reproduction

Lungandintegumentalrespiration, increasedbasalmetabolicrate

Larvalmesonephros,3-chambered heart,pentadactyly,mesonephricduct connectstotestistobecomeductus deferens

Carbonifer- ous

Terrestrial Anolis (lizard) (continued)

Amnioticeggreproduction, renin-angiotensin-aldosteroneaxis, increasedbasalmetabolicrate

Metanephrickidney,urinarybladder, renalmedulla,renalvenousportal system

Carbonifer- ous

Sarcopterygii

Amniota

Table1. Continued.

Terrestrial Rattus (rat)

Livebirth,milkproduction,increased protectionofyoung,lactation,increased basalmetabolicrate

Nephronloop(ofHenle),highblood pressure,singlerenalartery,norenal portalsystem,homeothermy, heterodonty,hair,4-chamberedheart, descentoftestes,synepithelio-chorial placenta

Chlorocebus (greenmonkey)

Terrestrial/arbo- real

Quadrupedalclimbing, insectivor-ous/frugivorousrequiring VitaminC

Orbitalfrontality,prehensilehandsand feet,thinned(hemochorial)placenta

Pongo (orangutan)

Terrestrial/arbo- real (forest/wood- land)

Pan (chimpanzee)

Terrestrial (forest/wood- land/savanna)

Uricosuria,frugivory

Increasedbrainsize,increasedbodysize, truncalerectness,lossoftail,facultative bipedality;urateoxidasegeneloss

Uricosuria,brachiation/facul-tative bipedality/knuckle-walking,increased carnivorousdiet

Thermoregulatoryadaptationssuchas sweatglands,lossofhairovermostof body(humans),primarybipedality (humans),encephalization(humans)

Datesofevolutionarydivergencearegiveninmillionsofyearsbeforepresent.Anatomy,physiology,andecologyofancestralorganismsarelistedi ncolumns4through6.Extant/modelorganismsthatshowhomologoustraitsandsimilar adaptationstoancestorsarelistedintherightmostcolumn.LUCAartbyartistGayleneBarnes,bypermission.

BOX1. TWOINFLUENTIALNARRATIVESOFKIDNEYEVOLUTION.

TheevolutionofexcretionoutlinedbyurologistFrankHinmanoftheUniversityofCalifornia,SanFranciscoinhis1111-pageopusonthe Principlesand PracticeofUrology (1937)[25]isshownabove.Hinmanmarshalledcomparativeanatomicalanddevelopmentalevidencetopositstagesofinvertebrate andvertebrateexcretoryevolutionbeginninginthePre-Cambrian,butherefrainedfromconnectingthetwo.Stymiedbyadearthoffossilsofsoft-bodied ancestorshelistedan‘UnknownAncestor’(circledinred)leadingfrominvertebratestovertebrates.Presciently,however,hefiguredahypotheticaldashed line(circledingreen)fromhemichordatestothebaseofthevertebratelineage,arelationshipthathasnowbeenshowntobehomologousintheGenomic Age,asdiscussedinthisreview.

Aboveisdepictedanotherseminaltheoryofrenalevolution,thatofrenalphysiologistHomerSmithoftheUniversityofVirginiaandsubsequentlyNewYork University[26]Smith’stheoryfocusedontheoriginsofthevertebratekidney,forwhichhehypothesizeda‘protovertebrate’chordateancestorsimilartothe extantlancelet,despitealackoffossilevidence.Thathypothesishassincebeenwidelysupportedbygenomic,comparativeanatomical,andpaleontological evidence.Smith’sformulationwasalsoinnovativeinincludingecologicalcontextinhisconsiderationofrenaladaptations,mostnotablyinrespecttothe freshwateroriginsofthevertebratekidney.Hisideashavebeenveryinfluentialinrenalphysiologyandhavecontinuedtobedebatedtothepresentday,as discussedinthisreview.ThetableaboveupdatestermsusedbySmithtocurrentzoologicaltaxonomy,geologicalera,andbest-fitevolutionarydivergence timeasindicatedinTimetree.org(seetext.).

Figure1. ATimeTreephylogramfor Homosapiens backtothelastuniversalcommonancestor(LUCA)at4.25billionyearsago,constructedandreconfigured from Timetree.org.Divergencedatesof30lineagesareindicatedbydarkcirclesfornameddivergencesandopencirclesindicatingunnameddivergences. Taxonomiccategoriesarearrangedbydecreasingrankfromlefttorightatthetopofthefigure.Aphylogenyof10selectedlineageswithbest-fitdivergence datesinmillionsofyearsisshowninthemiddleofthefigure.Separateareasofthephylogenydepictmarinehabitat(‘‘Sea’’showninblue),freshwater habitat(showninblue-green),andterrestrialhabitat(‘‘Land’’showninyellow).Thegeologicaltimescaleinmillionsofyearsago(MYA)witheras (above)and eons(below)isshownatthebottomofthefigure.Abbreviationsare:A=2-chamberedheart,B=3-chamberedheart,C=4-chamberedheart,HDE=Hadean, Pr=Proterozoic,EA=Eoarchean,U=Paleoarchean,V=Mesoarchean,W=Neoarchean,X=Paleoproterozoic,Y=Mesoproterozoic,Z=Neoproterozoic.

nondiscriminatory‘emunctory’processesthatincludedions, water,acids,andbases.ThisLastUniversalCommonAncestor (LUCA, Table1)wasanearlyautotrophic(chemolithotropic) organismthatlivedintheHadeanEon,estimatedat4.25 billionyearsago[10, 27, 28].Emunctoryprocessesinearlycells, emergingsome1.6billionyearsagoinhumanphylogeny,were similartotheextant Paramecium (Fig.2).

Emunctoryfunctionentailsthetrans-membranediffusion ofammoniaortheintracellularengulfingandvacuolationof nitrogenouswastesandxenobioticsubstancesexpelledinto theenvironmentbyfusionwiththecellularmembrane.These processesareubiquitousinsingle-celledorganismsandremain withintherealmoffunctionsofindividualcellsnowembedded withinmulticellularorganisms,includingthehumankidney tubule.Evolutionwastoelaboratethemintothespecialized, multi-organphysiologicalprocessesofexcretion,secretion, digestion,respiration,andcirculation[25, 29].Activeexcretion acrossdigestivetissuesevolvedinpre-bilaterianMetazoa (theCnidariaandXenacoelomorphaofAndrikou[30])(Table1, Fig.1).

Thetransitionfromprimitiveemunctorytoexcretoryfunctions inthehumanevolutionarylineageoccurredsome700million

yearsagointhebasalbilateriananimals,organismssimilar totheextantnematodeworm, Caenorhabditiselegans (Table1) [31].Livinginsandynear-shoreseabeds,thesesmallmarine creaturesevolvedthree-cellproto-nephroncomplexesknown asprotonephridia(Fig.3a).Protonephridiausedciliaryaction toexpelinternalwastethroughthebodywalltotheexterior. Aterminal‘flame’cellultra-filteredinterstitialfluidthrough fenestrationsinitscellwallandacrossaspecializedextracellular membrane,retainingthelargerproteinmoleculesandletting thesmallerammoniaandureamoleculesflowoutwithwater intoachannelformedbythesecondcellintheseries,aduct cell.Theductcellhadspecializedcellwallsthatwereboth resorptive(engulfingandreclaimingsmallmolecules,including water,thatthecellstillneeded),andsecretory(removingmore smallxenobioticwastemoleculesfromtheinterstitialspaceand addingthemtothefiltrate).Thethirdinlineprotonephridialunit wasthenephroporecellwhichformedachannel,thewallsof whichalsoresorbedwaterandothersmallmolecules,andthen transportedexcretedwastefluidtotheexteriorthroughapertures inthebodywall.

Recentgenomicstudieshaveshownthatregulatorygenes expressedinthedevelopmentofultrafiltration-basedcellular

Figure2. Diagramofasingle-celledeukaryotic Paramecium showingingestion ofsolidfoodparticlesandwaterintoitscytoplasm,digestion,andfinally extrusionasexcreta,shownbyarrowstotheexterior.Internalcirculation ofwaterwithuptakeofwasteproductsintoacytosolicvacuole,shownby internalarrows,bindswiththecellmembraneandemptiesitscontentsto theexterior. Paramecium divergedfromthehumantimetreesome1.6billion yearsago[9].FigurefromHinman[25]. aggregatesinawidearrayofbilateriansareconserved evolutionarily[33].Transcriptionfactors eya, six1/2, pou3, sall, ihx1/5,and osr ,andstructuralgenes nephrin, kirre,and zo1 arehomologousthroughoutBilateria.Thisevidencesupports thehypothesisthatthelastcommonancestorofbilaterians, datingtoca.708Ma(Table1, Fig.1),possessedrenalprecursor cellsthatcouldselectivelyfilteroutbysizesomemolecules andretainothermoleculestomaintaininternalhomeostasis. Thisprotonephridialadaptationwashomologousandbroadly ancestraltolaterinvertebrateandvertebratemacroscopic excretoryorgans(Fig.3b).Theterminalcellevolvedintoa fenestratedcelltermedthepodocytewhichformsthefiltration slitofthemetanephricglomerulus[34].Thepodocytesformthe visceralwallsofglomerular(Bowman’s)capsules.Parietalwalls originateasembryonicvesiclesfromintermediatemesoderm

(35)orphylogeneticallyasdetachedsegmentsofthecoelomic membrane[31, 35].

Thepronephros

TheimportanceofanEvo-Devoapproachtokidneyevolutionis underscoredbythesequentialappearanceinthehumanembryo ofatransientnonfunctioningpronephros,followedbyatransient functioningmesonephros,followedbythemetanephrosthat beginstoexcreteurinebythe10th fetalweek.Inductionofthe mesonephrosisdependentontheformationofarudimentary pronephros,andinductionofthemetanephrosrequiresprior formationofthemesonephros.

Evidencenowsupportsthatpreviouslyscatteredprotonephridialcellsmassedtogetherinbilaterianstoforman elongatemodularorgan,theprimordialkidney,whichweterm here,basedongenomicandcomparativeanatomicalevidence, the‘pronephros.’Romer[36]termedthelargelyhypothetical primordialkidneyofvertebratesthe‘holonephros,’atermthat hasfallenintodisuse,butheidentifieditwiththepronephros, theembryonic‘fore-kidney.’Supportinganevenearlierrenal primordium,Gasiorowskietal.[33]statedthat‘[o]urresults showthatalltypesofultrafiltration-basedexcretoryorgans arepatternedbyaconservedsetofdevelopmentalgenes,an observationthatsupportstheirhomology.Weproposethatthe lastcommonancestorofprotostomesanddeuterostomes[i.e. Bilateria]alreadypossessedanultrafiltration-basedorganthat latergaverisetothevastdiversityofextantexcretoryorgans, includingbothproto-andmetanephridia.’

Thepronephrosthenwasanexcretorystructureextending fromheadtotail(Fig.1).Itisanancientstructureinhuman ancestry,appearingonlytransientlyinhumanembryological development[37],butretainingitsplesiomorphicanatomyin someextantprimitivebilaterianssuchaspriapulids(‘penis worms’)[31].Thesespeciesshowprotonephridialopeningson theexteriorsoftheirbodies.Inhumanembryologyonlythe cervicalportionofthepronephros(the‘fore-kidney’)isobserved asadiscretestructure,whereasthemiddleandcaudalportions ofthepronephros(termedbyRomer[35]the‘opisthonephros’) becomeincorporatedduringdevelopmentintothemesonephros (‘middlekidney’)andmetanephros(the‘greatkidney’).Because ofthispreemptionofthemiddleandcaudalsegmentsofthe pronephrosbysubsequentevolution,theembryologicalliterature hastendedtotreatthepronephrosasacervicalrudiment only.Comparativeanatomyandgenomicshavenowrectified thisperspective,andthepronephrosistreatedhereasa modularrenalstructureextendingthecranio-caudallengthof earlybilaterians.

Intheearlybilaterianstherewasnotyetacoelomsurrounding thenowunidirectionalgastrointestinalsystemfrommouthto anusandtherewasnoheartandcirculatorysystem(asseen

Figure3. Bilateriannephridia.Above:Cross-sectionindorsalviewofaplanarianflatworm[27],showingthebilaterianbodyplaninwhichthegutisnot surroundedbyabodycavity(acoelom).Theemunctoryrenalprecursor,theprotonephridia,drainsthelargeinterstitialspacedirectlytotheexteriorviathe nephridiopore.Below:(a)aprotonephridiumcomposedofthreecells------Terminal(flame)cell,ductcell,andnephroporecell,characteristicofearlybilaterians. Solidarrowsindicateflowoffluidfromtheintercellularspacethroughtheextracellularmembrane(ECM),thenreabsorptionandsecretionbytheductcell, andreaborptionbythenephroporecell.(b)themetanephridiumevolvesinlaterbilaterianswhenkidneyultrafiltratedrainsintothecoelom,andnotdirectly outofthebody.Thecoelomislinedbyamesothelium,termedherethe‘coelothel’.Figureadaptedfrom[31](below)and[32](above). intheextantplanarianflatwormsandpenisworms),sothe commondescriptionofthepronephricnephronas‘avascular glomerulusprotrudingintothecoelom’[38]isnolongeraccurate. Thepronephrosnephridialslitslosttheirconnectionstothe pronephricductinternally,connectinginsteadtothenearby cranialportionoftheguttube,thefuturepharynx[39].They retainedtheirprimitivenephridioporeoutletstotheexteriorof thebody.Theseopeningsbecamegills,afilter-feedingadaptation thattrappedplanktonanddetritusfromgulpedwaterthatwas thenpumpedoutthroughthefilteringmembraneofthepharynx bymusclecontraction,withtheretainedfoodparticlesthen swallowed.

Thepronephrospostdatedtheevolutionarydivergenceofall bilateriansandpredatedinhumanphylogenytheanatomical adaptationsnowrecognizedasfirstarisinginhemichordates, exemplifiedbytheextantacornworms[40](Fig.3, Table1). Filtrateflowedfromtheinterstitiumtoanephrostome(ciliated ductcell, Fig.3b),aciliatedtubulethatdrainsintotheproximal nephrictubule,distaltubule,andpronephricducttotheexterior ofthebody(i.e.notintoanonexistentcoelom).Thereare fourtubuledomainsinthedevelopingpronephrosoftheAfrican clawedfrog:proximal,intermediate,distal,andconnectingtubule segments,withclosehomologieswiththehumanmetanephric tubules[41].Theproximaltubuleexpressestransportersfor glucose,aminoacids,andpeptidesecretionoforganicacids andanions.Thedistaltubuleshareshomologieswiththe metanephricthickascendinglimbofHenle’sLoop(impermeable towaterandactivereabsorptionofsodium)anddistalconvoluted tubule(regulationofpHandammoniatransport)[40].Inthe larvalaxolotlthepronephricductepitheliumconsistsofonecell typewithbasolateralNa/KATPaseforsodiumreabsorptionand presumablyalsocontainsseparateapicalchannelsforpotassium secretionintothefiltrateandsodiumuptakefromthefiltrate[42], indicatinghomologywiththevertebratecollectingduct. Thereisnoevidenceofajuxataglomerularapparatusinthe earlybilaterianpronephros,whichevolvedlaterinassociation withthedevelopingcardiovascularsystem.

Themesonephros

About635millionyearsago,laterbilaterian(hemichordate, alsotermed‘deuterostome’)ancestorsofhumansevolvedthe mesonephric(‘middle’)kidney.Wedefinethemesonephros asthatpartoftheprimordialkidneyretainingaconnection toitslongitudinalductandlocatedcaudaltothepharynx. Incontrasttothe‘fore-kidney,’whichbecameincorporated intothealimentarysystem,thesemorecaudalportionsofthe primitivepronephrosremainedintheurinarysystem.They losttheirexternalconnectionsthroughthebodywallbut retainedtheirinternalconnectionstothelongitudinalductthat wasnowrenamedthemesonephricduct.Thisductpassed dorsaltothegutandenteredthetailendofthecoelomto exitthebodyatthecloaca,withtheevolvingcardiovascular systemdevelopeddorsaltothecoelom.Themembrane-lined bodycavity,thecoelom,surroundingthenowenlargedgut, becametheterminusofthemesonephricduct,exemplifiedby suchextanthemichordatetaxaasacornworms[32](Table1, Fig.4).

Ancestralhemichordateshadaprimitivehemolymphsystem drainingtheinterstitialfluidspaceofthebodythatparallelledthe developingarterio-venouscirculatorysystem.Afferentlymphatic vesselsmaintainedavascularconnectiontothelower-pressure venousdrainage,returningfluidtothecirculation.Thethoracic

andleftlymphaticductsemptyingintotheleftsubclavianartery inhumansexemplifythispattern.Efferentlymphaticchannels, however,disappearedundertheinfluenceofhigher-pressure mesonephricarteriescomingfromtheheart.Mesonephric nephronsclosedofftheirserialoutletstotheexteriorand drainedurineinsteadintotheremnantofthepronephricduct, nowrenamedthemesonephricduct.Themesonephroshada greaterglomerularfiltrationrate,morefilteringcapacity,and morerapidflowthroughlargerdiameterducts.Hemolymph fromtheinterstitiumbecameacomponentofplasmainthe bloodandwaspushedunderpressuretodispersedglomeruli,in whichultrafiltrationoccurred(Fig.4).

Theflowofurineinthepronephroswasdrivenbyciliary actionfromtheinterstitialfluidspacetotheexterior.Inthe mesonephros,interstitialfluidwaspulledintothevenousand lymphaticsystemsbyosmoticpressureandfilteredthrough theglomerulibyhydrostaticpressuregeneratedbytheheart. Dorsalportionsofthecoelomfragmentedintomanyisolated spacesasdoublemesothelial-linedpocketswerepinchedoff tobecomethefutureglomerular(Bowman’s)capsules,into whichtheglomerularcapillariesinvaginated.Thetail-end (‘opisthonephric’)mesonephrosoftheprimitivevertebrate,the lamprey,preservesasinglepartiallysegmented‘glomus’that mayrepresentanintermediatephaseofglomerularcapsule evolution[43](Table1).

Filtratefromtheglomerulusflowsintothecollectingducts andthenceintotheureterofthefuturemetanephros,which isaderivativeoftheuretericbud,acaudalmesonephricduct inturndevelopedfromthelowestpronephricduct.Thisduct developstotransmiturinefromkidneytobladderbecausethe middleandcranialportionsofthemesonephric(Wolffian)ducts werepreemptedbythereproductivesystemtoformtheductus deferenstotransmitsemen[44](seeExplanatory Box2).The urethraisatubethatrunsfromthebladdertoexcreteurine totheexteriorofthebody.Itisaderivativeoftheembryonic urogenitalsinus[36].

Theclinicalrelevanceofthisevolutionaryscenarioisthat peripheralpittingedema,aside-effectofdecreasedhydrostatic pressure,inchronickidneyfailureorheartfailure,orreduced plasmacolloidalosmoticpressure,resultsfromfluidfirstbacking upintothedependentpartsofthebody’sinterstitialspace,e.g. thefeet,ankles,andhands.Onlysecondarilydoesinterstitial fluidbreachthecoelomicmembraneandflowintoderivativesof thebodycavity,theperitonealcavity(resultinginascites)orthe lungs(resultinginpulmonaryedema).

Themetanephros

Priortotheevolutionofthemetanephrickidney,themesonephric kidney,coupledwitha2-chamberedheart,wasasuccessful

Figure4. Viewsoftheheart-kidneycomplexoflaterbilaterians(hemichordates),nowknowntobehomologouswithsuccessivechordatesandvertebrates. Protonephridialcoelomoductshavenowbecomegillslitsandcommunicatedirectlyfromtheexteriortothecoelomiccavity(pharyngealgut)forfilter-feeding. Morerostrally,protonephridialductslosetheirexternalopeningsanddrainfiltratefromtheinterstitiumtoanarterialanastomosis,theglomerulus,through whichfiltratepassesintoasinglelongmesonephricducttobevoided(notshown).Above:Sagittalviewofheart-kidneycomplexinthehemichordateacorn worm Saccoglossus.Below:Leftanteriorviewoftheasymmetricalarrangementoftheleftprobosciscoelomenclosingthesimpleglomerulus,homologouswith thechordateglomerularcapsule(ofBowman).Cranio-caudalfoldinginthehumanembryowillbringtheheartandsegmentingmesonephroscaudallyintothe trunk(see Fig.5).Figureadaptedfrom[39].

excretoryadaptationthatlastedforover150millionyears, fromearlychordatestoearlyfish,asexemplifiedbythe extantlamprey(Fig.1, Table1).However,themesonephric glomeruluswasalower-pressurefiltrationsystemthatwas supersededbythemetanephros,withmuchhigherglomerular filtrationpressure,anadaptationthatwasforeshadowedin

dipnotetrapodomorphlungfishintheDevonianPeriod(Fig.1, Table1).Theseremarkablevertebrateswithmesonephrickidneys couldadapttotheextremesoffreshwateraswellasaestivationin dryseasons.Urineflowratesandglomerularfiltrationrates(GFR) arehighbutionexcretionlowcomparedtofreshwaterteleosts [46].Theenvironmentalcontextinwhichthemetanephros

BOX2. ANEXPLANATIONOFTHEMALE‘WOLFFIAN’DUCTSANDTHEFEMALE‘MULLERIAN’DUCTS

TeasingaparttheEvo-Devodetailsoftheevolutionofthekidneyhasalsoelucidatedimportantaspectsoftheoriginsofthemaleandfemalereproductive systems,whichshareadevelopmentalsiteoforigininthenephrogenicridgeoftheintermediatemesoderm.ThemesonephricductintheXYhuman embryoiscooptedfromtheurinarysystembythereproductivesystemtobecometheadultductthatdeliversspermtotheejaculatoryductandontothe exteriorofthebody.Longknownasthe‘Wolffianduct’itwasdiscoveredbytheearlyGerman-RussianembryologistKasparWolffandshowntobethe primordiumoftheductus(vas)deferens.Initiallyitwasthoughtthatthe‘Wolffian’ductwasalsohomologoustothefemaleuterine(fallopian)tube,butthe GermanembryologistJohannesMüllerdemonstratedthatanentirelydifferentductoriginatingfromtheinfoldingcoelomicwallledfromtheprimitiveoviduct openingtotheregionoftheovary,formingtheuterinetube.Thisembryonicstructureisknownastheparamesonephric(‘Müllerian’)duct.Intheabove 3Dreconstructionusingimmunohistochemicalmarkersofa10-dayoldembryonicmalefrog(Xenopus)Omoteharaandcolleagues[45]showedtheleftrete testisconnectingtothemesonephric(Wolffian)duct.Craniadistotheright.Themesonephric(Wolffian)ductandmesonephrictubulesarerepresentedin redandothercolors,respectively.Cord-likestructuresingrayrepresentthePax2-positiverete(testicular)cells.Frogsdivergedfromthehumanlineagesome 350millionyearsago.Atthistimetheproximalmesonephricductdirectlyconnectedtotheretetestisandwascapturedbythemalereproductivesystemin thetetrapods.Theductus(vas)deferenswasformedfromtheremnantductasthemesonephrositselfwasdegeneratingandthemetanephroswasevolving Thisembryologicalhistoryexplainswhytheductus,amesonephricstructure,bypassestheureter,aseparatemetanephricstructureenteringthebladder,to entertheurethra,aderivativeofthealimentarysystemdistaltothebladder.Adultfemaleshaveamesonephricductrudiment(Gärtner’sduct)lateraltothe vaginalwallwhichoccasionallycanbethesiteofinflammation.Thisembryologicalhistoryalsoexplainstheparamesonephricopeningoftheuterinetubein thefemale,theonlysuchpiercingoftheperitonealcavityinthehumanbodyandanimportantpartoftheetiologyofintracoelomicectopicpregnancy. Males retainablindparamesonephricrudiment,theparadidymus.

evolvedincludedfreshwaterrivers,streams,andlakes:alarge anddiversespectrumofecologicalnichesthathadnotbeen occupiedbyvertebrates.

Themostrevolutionarychangeinthelongevolutionaryhistory ofthehumankidneyoccurredwhenthelimblessandstill wormlikeearlychordatesventuredfromtheancientseaof theirancestorsintonewandunchartedterritory------freshwater (Table1).Themediumwasthesame,butthiswaterheld anunknownandinvisibledanger.Anover-zealouslancelet, dependentonitspronephroswithoutthedevelopmentofa tubulardilutingsegment,dartingimpulsivelyintofreshwater afterpreycouldsuddenlyfinditselfovercomeandobtundedby waterintoxication,amassiveinfluxoffreshwaterintoitsmostly salinebodytissues.Withinminutesitwoulddieifitcouldnot swimbacktoitsbrinyhaven.‘Waterpoisoning’canstill(rarely) affecthumanswhodrinktoomuchwaterduringorafterlengthy andstrenuousexercise,suchasrunningamarathon.Deathcan evenresult,andfrombasicallythesamereasonthatourancient lanceletintheriversuccumbed.Exogenousfreshwaterpouring intothebodycantherebydilutethebloodandtheinterstitial fluidsuchthatsalt(sodiumchloride)reachingthecellsisnot sufficienttodrivethesodium-potassiumpumpsnecessaryfor life.Thelostlanceletandthewater-intoxicatedmarathonrunner bothsufferfromdilutionalhyponatremia.

Exaptationsexisted,however,thatwereselectedtoraisethe bloodpressure,reinforcetheglomerulitowithstandgreater filtrationpressures,andincreasethemetabolismtoswim inswiftlyrunningcurrents.Themetanephrickidney,withits highpressureglomerulusandcomplexdifferentiatedtubuleto modifythefiltratewasabletoexcretethemassiveinfluxesof waterthatoverwhelmedthemesonephrosoftheirancestors. Earlyvertebratesfirstpopulatedthelargerivers,butasspecies expandedtheirrangesintosmallerstreamsandlakes,another majorenvironmentalobstacleconfrontedthem.Unlikethesea andlargerrivers,whichwereconstant,smallerwaterbodies weresubjecttoperiodicdryingout.Themetanephrickidney respondedbyevolvingmechanismsinwhichmetabolismcould continueeveninair. Figure5 showstheearlydifferentiationof thelungbuds,bilateraloutpocketingsofthetracheoesophageal diverticulumthatformtheair-breathinglungs,anadaptation thatallowedaestivatinglungfishancestorstorespireeven astheylaydormantindesiccatedlakebedsawaitingthe returnoftherains.AnincreasinglycompleteDevonianfossil recordhasprovidedstrongsupportforthishypothesis[40, 41].Evidenceforafreshwatertransitionfrommarineto terrestrialenvironment(asproposedbyHomerSmith[6],and supportedhere)hasbeenrecentlycontested(SeeExplanatory Box3).

Figure5. Top:Lateralviewofageneralizedancestralhemichordatefrom[40]showingthecloseassociationthe1-chamberedheart,theexternalglomerulus ofasegmentoftheearlymesonephrickidney,surroundedbytheprobosciscoelom,apossiblehomologueoftheparietalwalloftheglomerularcapsule(of Bowman).Thecoelomoductexitsthroughthebodywall.Below:AviewfromthecaudalaspectofahumanembryoatCarnegieStage15(Week7)showingthe closespatialrelationshipofthemesonephroswiththedevelopingheart,areflectionoftheembryologicaldevelopmentfromthepre-chordateheart-kidney. Imagefrom[47].Greenboxeshighlightthejuxtapositionofheartandmesonephrosinancestralhemichordateandhumanembryo.

Theglomerulus,atuftofarterialcapillariesthatsuppliedblood tothesmallencapsulatedcoelomicspaceoftheglomerular (Bowman’s)capsules,solvedtheancientlancelet’sfreshwater dilemmabyvastlyincreasingitsfiltrationrate[56].Thevertebrate kidney’sprimaryfunction,afterwasteremoval,istoexcretewater andexcessionswhileretainingtheessentialsalts,nutrients, andbloodproteinsinthebody[6].Theevolvedvertebrate kidneydifferentiatedthespecificexcretory(versusthemore generalizedemunctory)removalofnitrogenouswastesandwater fromthebody.Theglomerulusfilterswaterandsolutefromthe extracellularareasbetweenorgansandotherstructuresinthe bodyoutsidethecellsthemselves,andthetubuleisresponsible

forfine-tuningofthefinalurinecompositionandvolumeby reabsorptiveandsecretoryprocesses,criticaltotheselective excretionofwater.Thedistributionoftotalbodywaterhas significantimplicationsforthemaintenanceofhomeostasis (SeeExplanatory Box4).

Heartandkidneyco-evolution

Theheartandthekidneysharedanintimateco-evolution (Figs1 and 5)[39].Thesingle-chambered‘heart-kidney’ wasapre-chordateadaptationthatelevatedtheultrafiltration pressureofthemesonephricglomeruli.Thedevelopingheart

BOX3. CONTROVERSYINTHEINTERPRETATIONOFTHECURRENTPHYLOGENETIC-PALEONTOLOGICALHISTORYOFTHE MAMMALIANKIDNEY.

HomerSmith’sconclusionthatthemetanephrickidneyowesitsoriginstoanancestorinafreshwaterenvironmenthasbeenrecentlychallengedby argumentsforamarineratherthanfreshwaterancestry.MeyerandHostetter[48]proposedthathighGFRinthehumankidneyisanadaptationtoexcrete smallmolecularweighttoxinspresentinamarineenvironmentandcorrelateswithincreasedmetabolicrateratherthananancestralneedtoexcretewater inahypotonicenvironment.Ouranalysisdemonstratesthatwhereasmarineinvertebratesevolvedultrafilteringnephridiahomologouswithmetanephric podocytesover750millionyearsago,evolutionofanopisthonephrickidneydidnotdevelopuntil200millionyearslater,reflectedinextantprimitive vertebrateswithatwo-chamberedheart(lamprey)(Fig.1 and Table1).Themetanephricnephrondidnotevolveuntil250millionyearslaterasamniotes adaptedtoaterrestrialenvironmentwitha3-chamberedheart,andanother180millionyearsbeforetheappearanceofhomeothermicmammalswitha 4-chamberedheart,higherbloodpressure,andincreasedmetabolismcoupledwithincreasingGFR.Morerecently,Evans[49]proposedamarineoriginfor theglomerulusin‘firstvertebrates,’butitisbasedonmisinterpretationofareportdescribingthedivergenceoffossiljawedfishesdated480to360million yearsago,largelyalreadyradiatingintomarinehabitats[50].HisclaimcontradictsthereportofDevonianfossillobefinfishfromGreenlandfreshwaterand floodplainsediments[51]andfreshwaterstreamsforTiktaalikfromDevoniansedimentsinNewfoundland[52].ExtantlobefinfishinhabitfreshwaterinAfrica, SouthAmerica,andAustraliaandfossillungfishburrowsrevealthatlungfishfreshwaterhabitatshavepersistedthroughtheMesozoicandCenozoic eras [53, 54].Moreover,earlytetrapodfossilsfromtheDevonianofthenortheasternUnitedStatesshowedcloseassociationofearlytetrapodfossilswithflooded freshwaterwoodlandenvironments[55].Therearemanypossibleenvironmentalfactorsthatmayhavecontributedselectionpressuretowardsevolution ofthemetanephrickidney.However,accumulatingevidenceoverthepast70yearshasnotdiminishedtheimportanceorlikelihoodofHomerSmith’s contributions.

BOX4. EVOLUTIONARYHISTORYCLARIFIESTHECOMPARTMENTALIZATIONOFHUMANBODYFLUIDS.

Theanatomicallydisaggregatedextracellularfluidvolume(ECFV),composedofinternalizedancientseawater(sodium-richintercellularfluidandplasma), isnowmodifiedandmaintainedindiversemembrane-boundcompartmentswhichnaturalselectionhasadaptedforspecificfunctionsinthevertebrate body.Blood,lymph,saliva,endolymph,perilymph,tears,sweat,milk,mucous,cerebrospinalfluid,andsemenareallexamplesofsodium-richderivativesof seawaterwhichmakeuproughlyonethirdofthebody’swater.TheintracellularfluidvolumeorICFVcomprisestwo-thirdsofthebody’swaterinsidethecells themselves,thehigh-potassiumintracellularfluid[29].Theextracellularfluidspacemaybesubdividedintotheinterstitialfluidvolume(ISFV)andtheplasma volume(PV).Thecolloquiallyusedterm‘thirdspace’referstothatportionoftheextracellularfluidthatcanaccumulateintheinterstitialspace (asopposed totheintracellularandintravascularspaces)followingsurgicalprocedures,inchronickidneydisease,andinheartfailure[57].

wasconnectedwithadiffusesetofcapillariessupplying nearbyglomeruli.Thecombinedrelationshipofthepericardial coelomsurroundingthedevelopingheart,theadjoining anteriorprobosciscoelom,andtheprimordiumofvascularized glomeruli,setthestagefortheevolutionofasinglehighpressureexcretoryorgan,themetanephrickidney(Table1, Fig.1).Selectionpressurescontributingtotheevolutionof themetanephrickidneyhavehadasimilardramaticimpact oninterdependentorgans.Thisincludestheappearanceofthe four-chamberedheartthatincreasesoxygendeliverytotissues withcomplexcapillarycirculation,suchasthekidney.Equally important,evolutionofendothermyfollowedtheinnovation ofnonshiveringthermogenesisinbrownadiposetissueand increasedexpressionofuncouplingprotein1(UCP1)[58].This wasa2-stepprocessbeginningwiththeappearanceofnonshiveringthermogenesisinectothermicteleostsover400mya, followedbythedevelopmentofthermogenicUCP1inplacental mammals180mya.Endothermyislinkedtoincreasingblood pressurethatenhanceddeliveryofoxygentohighlymetabolic organsincludingthebrain,liver,heart,andkidney.Resulting

increasedglomerularcapillarypressureinmammalianglomeruli ledtodevelopmentofstressfibersinextraglomerularmesangial cellswithcytoplasmicprocessesadheringtotheglomerular basementmembrane.Theseadaptationsmaintaintheintegrity ofthehighpressureglomerulus[59],butfailinthefaceof hypertensionorglomerularinjury.

Theevolutionarytransitionfromhemichordatetochordate descendantsisnotclearlyrecordedinthefossilrecord.Wemust thereforerelyonontogeneticcluestoreconstructthishistory, whichthemolecularclockindicatestookplaceapproximately588 millionyearsago(Table1).Chordatesevolvedaclosedcirculatorysystem,i.e.onewitharteriesleadingawayfromtheheart, passingthroughacapillary‘portalsystem’throughtheglomeruli, postglomerularcapillaries,thenconnectingthroughveins returningtotheheart.ThehumanembryofromCarnegieStages 10to15(weeks3to7)showsasimilarproximityofthedeveloping hearttotheintermediatemesodermofthemesodermalridge whichformstheembryonicmesonephrickidney(Fig.5).

Thisearlyspatial-functionalrelationshipoftheprimitive heartandrenalprimordiawastransfiguredbysubsequent

BOX5. PHYSIOLOGYOFTHEURINECONCENTRATINGMECHANISMSOFTHEMAMMALIANMETANEPHROS.

Duetodifferentialtransepithelialpropertiesofthetubulesegments,energy-dependentactivetransportofsodiumchloridefromfiltratetointerstitium aroundthethickascendinglimbpromotespassiveflowofsodiumandurea(butnotwater)outofthethinascendinglimb.Thisgeneratesacorticomedullary osmoticgradientintheinterstitium,concentrationoffiltrateinthecollectingduct,andexcretionofhyperosmolarurine.Thelengthoftheloopisamajor (butnottheonly)determinantofmaximalurineconcentratingcapacity,withavariablecombinationoflongandshortloopsinmammals.Superficialcortical glomeruliareconnectedtoshortloops,andjuxtamedullaryglomerulihavelongloops.Longerloopspredominateinmammalsadaptedtoaridenvironments (kangaroorats)whereasshorterloopsaremorenumerousinaquaticmammals(beavers).Incontrasttobirds,thatexcretenitrogenasuricacid,mammals haveboostedtheircapacityforwaterconservationbytheincorporationofthearginine---ureacycle(AUC)intubularmetabolism.TheAUCevolvedin unicellulareukaryotesinresponsetovariableavailablenitrogenintheirmarineenvironment(ananabolicprocess).TheAUCwaslateradaptedbymetazoans intheircatabolicmetabolismofnitrogenforitsexcretionasurea.Ahydrophilicmolecule,ureacandisruptaprotein’shydrogenbondsthatpreserveits 3-dimensionalfoldedconfigurationnecessaryforitsfunction.Thispresentsachallengeencounteredbycoelacanthsexcretingurea,andmammalsrelyingon ureaasasolutetoamplifyurinaryconcentratingcapacity.Evolvedproductionofmethylaminesenhanceproteinfoldingandligandbindingandcounteract perturbationbyurea[62].Interrestrialmammalswaterconservationisaccomplishedbybindingofargininevasopressin(AVP)toV2receptorsonthe innermedullarycollectingductthatsignalactivationofureatransporters.Bymaintainingtheosmoticgradientandincreasingureaandwaterpermeability thismaximizeswaterconservationbutalsoincreasessodiumreabsorptioninthethickascendinglimb,therebyreducingtubuloglomerularfeedback and increasingglomerularfiltrationrate(Fig.6).Thisisimportant,ashighglomerularfiltrationmustbematchedbyparallelenergy-consumingreabsorptionof sodium,glucose,andaminoacids.Inpatientswithsevereburns,pathologichyperfiltrationresultsfromhighlevelsofAVPrespondingtofluidloss.Thisis augmentedbygreaterrecyclingofureageneratedbyproteincatabolism.Theroleofthekidneyinadaptationtolong-termfastinghasfolloweddivergent pathwaysthroughevolution[55].Elephantsealpupsundergocompletefastingfor2---3monthsjustafterweaning.Duringaestivationindryseasons,lungfish cansurvive2---3yearsencasedinasubterraneancocoonwithasmallbreathinghole[63].Humansshareacommonancestorwiththeseal100mya,and withthelungfish400mya.ThelungfishmarkedlyreducemetabolicrateandGFR,withactivationofthevasotocin---aquaporinpathway,andgeneratewater fromproteincatabolism.Thesealsmaintaintheirhighmetabolicratebynotonlyactivatingvasopressin-aquaporinbutalsoactivatingthealdosterone-ENaC pathwaytoconservesalt,andgeneratingwaterbymetabolismofstoredlipids.Bycontrast,humanscanonlysurvivefor3---5dayswithoutfoodorwater.

developmentofthecardiovascularsystemandthemetanephros, butthehumanlymphaticsystemisaremnantofthisancient pre-chordateadaptation.Inhumansthelymphaticsystem remainsisolatedfromthehigh-pressureand‘closed’arteriovenouscirculatorysystem,butlymphiseventuallypushedintothe venoussystemthroughthethoracicductattheleftsubclavian veinbyintra-abdominalandintra-thoracicpressure.

Adaptationtoland

Transitiontolandpresentedamajorchallengetoanexcretory organthatwasadaptedtoafreshwaterenvironment:rather thandefendingtheorganismfromaninfluxofwater,itbecame necessarytoconservewaterandsodiumthatcouldbescarce. ThechallengebecamethematchingofhighGFRrelativeto theextracellularfluidvolume.Inaddition,theinterdigitated podocytessupportingthecriticalfiltrationbarrierwerevulnerable toincreasingsystemicbloodpressurethatthreatenedpodocyte detachmentandglomerularinjury.Thisrequiredfinelybalanced tubularadjustmentofbothextracellularfluidvolumeand sodiumconcentrationinsynchronywithautoregulationofrenal bloodflowthatreducedbarotraumabymaintainingintrarenal pressuresatanoptimallevel[60].Thetwoprimarymechanisms forrenalautoregulationofGFRaremyogenic(constriction ofafferentandefferentarteriolesmediatedbythereninangiotensin-aldosteroneaxis)andtubuloglomerularfeedback (throughsignalingatthemaculadensa,juxataglomerular

apparatus,andrenin-angiotensin-aldosterone).Appearingin theearlyreptilelineage,theseinnovationsmaintainedhigh GFRinthefaceoflimitedsodiumintake.However,with currenthighhumandietarysodiumcontent,dysfunctionof tubuloglomerularfeedbackorthejuxtaglomerularapparatusnow leadtohypertension[61].

Anotherkeyadaptationwastheintermediatesegmentbetween proximalanddistalsegmentsinthemesonephrickidneyoffish whichbecametheloopofHenleinbirdsandmammals.This gaverisetotheformationofacountercurrentmultipliersystem basedonthejuxtapositionofdescendingandascendingvasa rectaandlimbsoftheloopofHenle(Fig.6)(SeeExplanatory Box5).

Bichirs,Africaneel-likefreshwaterfishthathavefunctioning lungscansurviveonlandwheretheyambulatebyusing pectoralfinstopropelthemselves.Unlikemostray-finned fishthateitherremainedinfreshwaterortransitionedback toamarineenvironment,bichirsevolvedtraitspermitting survivalinterrestrialenvironments.Inaningeniousexperiment comparingterrestrial-andaquatic-rearedbichirs,theformer walkedfasterandmoreefficiently,withmorphologyofneck andshoulderbonesthatparallelledthoseoflobe-finnedfishes thatevolvedintoamphibians[68].Thisstudyrevealedthat environmentallyinducedphenotypescouldbeobservedin ‘terrestrialized’individuals,consistentwithphenotypicplasticity likelyofimportanceintheadaptationsofstemtetrapodslike

EVOLUTIONARYMEDICINEOFKIDNEYDISEASE

Evolutionarymedicinefocusesonunderstandingtheultimate etiologiesofdiseaseorpathologyandformulatingtherapiesthat arepopulational,preventive,andusuallylong-term,whereas biomedicineprimarilyfocusesonunderstandingproximate etiologiesandformulatingtherapiesthatareindividualized,

Figure6. Structureofthemammalianmetanephricnephron.Amajoranatomicalchangeinthemammalswasthelossoftherenalportalsystem(theafferent arteriolesdonotenteranarteriovenouscapillarybedfromwhichveinsemerge,butratheranastomosewithglomerulararterioles).Thisadaptation reduces vascularresistanceandallowsahigher-pressurebloodflowtotheglomerulus,accountingfor20%ofcardiacoutput.Asecondmajoradaptationofthe mammaliankidneyisthedifferentiationoffunctionalsegmentsofthealdosterone-sensitivedistalnephron,comprisingthedistalconvolutedtubuleand collectingduct[64 66].Thedistalconvolutedtubuletransportssodium,potassium,magnesiumandcalciumandfunctionsasadilutingsegmentanalogous toitsoriginsinorganismsadaptingtoafreshwaterenvironment.Dilutionoftubularfluidinthethickascendinglimbanddistalconvolutedtubuleisfollowed bypassivemovementofwateroutofthewater-permeablecorticalandmedullarycollectingductinthepresenceofvasopressin.Theconnectingtubule and corticalcollectingductcontainprincipalcellsthatregulatesodiumreabsorptionthroughENaCchannelsinresponsetoaldosterone,whereasintercalatedcells (lackingprimarycilia)mediateacid---baseandpotassiumtransportandsodiumreabsorptionthroughregulationofENaCchannels.Thethirdmajoradaptation includestheloopofHenle,alongwithactivesodiumreabsorptionfromthethickascendinglimbandurearecyclingfromcollectingducttovasarectamarkedly enhanceurineconcentrationthroughthecountercurrentsystem.From[67]andbypermissionfrom theLancet lungfish.Ultrastructureofmesonephricnephronsofbichirs alongwiththoseoflungfishandamphibiansisconsistent withconvergentadaptationtoaterrestrialenvironment[69]. ThesestudiessupporttherelevanceofanEvo-Devoapproach tounderstandingthefactorscontributingtotransitionfroma freshwatertoaterrestrialenvironment.

reactivetointernalorexternalenvironmentalstressors,and usuallyshort-term[22, 23].Nevertheless,bothapproaches arefullycompatible,andwhenusedtogether,provideamore completepictureofapatient’scondition.Criticaltoouranalysis wasreliablyascertainingthegeological(absolute)agesof adaptationsofthekidneyinhumanphylogeny.

Thiswasundertakenwiththerealizationthattraitsor structureswhentheyfirstappearinevolution,albeithomologous basedoncomparativeanatomyandgenomicsynapomorphies, aremoregeneralizedthantheirlater,morederivedand specializedforms.Forexample,thefiltrationapparatusofthe renalglomerulus,althoughquiteancient(Proterozoic)inits single-celloriginasaflamecell,becameamuchmoreselective andspecializedmulticellularstructureovertime.

Anothercaveatisthatthereisaninverserelationshipofthe ageofanadaptationandhowfundamentalitisinunderlying theetiologyofdisease.Forexample,ciliarepresentanancient adaptationthatoriginatedinsingle-celledchoanoflagellates some1.6billionyearsago.

Ciliopathiescanmanifestassuchurinary-system-specific maladiesascystickidneydiseaseaffectingthehumankidney, yetthisorgandidnotevolvetoitscurrentformuntilsome 180millionyearsago.Ancientadaptationscanmanifestas pathologiesinvolvingciliaryactionaffectingawidearrayof systemsinadditiontotheurinarysystem[70].

Theevolutionaryhistoryofthemammaliannephrontraced inthisreviewcanaccountformanyofthevulnerabilitiesof thekidneytostressorsthatcanoccurinearlyliferesultingin impairednephrogenesis,orenvironmentalstressorsthrough agingandsenescence[4, 5].Urineproductionbythefetal metanephrosbeginsatweek10,increasingexponentiallywith nephrogenesisthroughsecondandthirdtrimesters,contributing to50%ofamnioticfluidvolume.Becauselackofmetanephric development(bilateralrenalagenesis)leadstoimpairedfetal lungdevelopment,infantsbornwiththisconditionoftendie ofrespiratoryfailureshortlyafterbirth.Throughoutpostnatal life,thehighpressure-flowglomeruluspredisposespodocytes toinjuryanddetachmentleadingtosclerosis,whereasthehigh mitochondrialactivityofthetubulecontributestosusceptibility toischemia,hypoxia,andoxidativeinjury.Withongoingnephron lossthroughthelifecycle,overloadofremainingnephronshas beenproposedasafinalcommonpathwayforprogressivekidney disease[71].Hemodynamicoverloadisresponsibleforshear stressontheglomerularfiltrationbarrier,whereasmetabolic overloaddrivestubularinjury[72].Theprocessofprogressive nephronlossthroughthelifespanoccursthroughagingand contributestohemodynamicandtubulardamagethatleadto acutekidneyfrailty[68].Theseconsiderationsharkenbacktothe interdependenceofthecardiopulmonaryandrenalsystemsthat evolvedhundredsofmillionsofyearsago.

Wehavefocusedontheevolvingprimaryexcretoryfunctions ofthekidneyinanempiricallyfalsifiableontophylogenetic frameworkintimatelytyinganatomyandphysiologytotime andenvironment.AsDawkins[73]hasrecentlyobservedin supportingsuchanadaptationistparadigm,’’thewholebody throughandthrough,itsverywarpandwoof,everyorgan,every cellandbiochemicalprocess,everysmidgenofanyanimal, includingitsgenome,canbereadasdescribingancestral worlds.’’Anevolutionarymedicalcorollaryofthisapproachis thatcomplexetiologiesofrenalpathologiesinvolvingmanytimeconstrainedgenomic,cellular,tissue,organ,andinter-organ adaptations,withinthecontextsofpastenvironments,aretobe expected,andindeedrequired,indiagnosingultimatecauses.

Biomedicalphysiologists[29]haveoperationallydelineated sixdiscretefunctionsofthehumankidneyinadditiontothe primaryfunctionofexcretingmetabolicwastesandpoisonous substances:(i)glucosesynthesis;(ii)regulationofwaterand electrolytebalances;(iii)regulationofarterialpressure;(iv) regulationofacid---basebalance;(v)regulationoferythrocyte production;and(vi)regulationof1,25dihydroxyvitamin-D3.It remainsforongoingandfutureresearch,suchasgenomic‘multimillion-yearnaturalexperiments’[74]aimedatunderstandingthe sequence,timing,andcausalinteractionsoftheseevolutionary adaptations,tounravelmorefullythenaturalhistoryofkidney disease.Thiswillrequireapproachescomplementarytothe Zoonomiagenomicsproject,toincludeevolutionaryphysiology, developmentalplasticity,andepigenetics[75 77].Evolutionarily informedandmorepreciseclinicaldiagnoseswillultimately enhancethequalityofmedicalcare.

AUTHORCONTRIBUTIONS

NoelT.Boaz(Conceptualization[equal],Formalanalysis[equal], Investigation[equal],Methodology[equal],Writing------original draft[equal])andRobertL.Chevalier(Conceptualization[equal], Formalanalysis[equal],Methodology[equal],Writing------original draft[equal],Writing------review&editing[equal])

SUPPLEMENTARYDATA

Supplementarydata isavailableat EMPH online.

Conflictofinterest: Nonedeclared.

FUNDING

Nonedeclared.

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©TheAuthor(s)2025.PublishedbyOxfordUniversityPressonbehalfoftheFoundationforEvolution,Medicine,andPublicHealth.ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(https://creativecommons.org/licenses/by/4.0/),whichpermitsunrestricted reuse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited. Evolution,Medicine,andPublicHealth[2025]pp.229--247 https://doi.org/10.1093/emph/eoaf019 Review