Download - Renal 2-3 2017 - Honors Human Physiologyhonorshumanphysiology.com/LectureNotes/Renal 2-3.pdf · Renal 2-3 October 23 & 25 ... Clearance of a substance = urine excretion rate of the

Renal2-3 October23&25,2017

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NROSCI/BIOSCI1070

RenalPhysiology2-3(2017)

Points:

•Largeamountsarefiltered•Formanysubstances,alargeamountisabsorbed,solittleisexcreted[slide1]

Itisusefultoconsidertwogeneralcategoriesofreabsorption:bulk(non-regulated)reabsorptionversusregulatedreabsorption.Formanysubstances,nephronshaveahighcapacitysystemthatreabsorbsmostofthesubstance,andthenaseparateregulatedsystemthatfinetunesreabsorptiontomeethomeostaticneeds.Typically,bulkreabsorptionoccursintheproximaltubule,whereasregulatedprocessestakeplacedistaltotheloopofHenle.


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Withsubstancesgettingreabsorbed(orsecreted)theymustpassthrough2celllayers:theepithelialcellsliningthetubuleandthecapillaryendothelialcells[slide2].Thismeansthattheyneedtocross4membranes:theluminal(alsocalledapical)membraneofthetubuleepithelialcell,thebasolateralmembraneofthetubuleepithelialcell,andthetwosurfacesoftheperitubulecapillaryendothelialcell.Alternatively,moleculescanpassthroughthetightjunctionsjoiningadjacenttubulecells.Wewon’ttalkmuchaboutthis"paracellularpathway",butforsomesubstancesitisimportant;forexample,Mg++movesthroughchannelsintheproteinmatrixofthetightjunctionsmadefromtheproteinparacellulin1.

Commentontheluminalsurface,orbrushborder;numerousmicrovilliprotrudingintothelumen(slide3)


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Onceasubstanceisintheinterstitialfluidoftherenalcortex,havingpassedfromthetubulethroughtheepithelialcell,itenterstheperitubulecapillaryby"bulkflow"[slide4],aswasdiscussedinthecirculationlectures.Rememberthattherewasahighhydrostaticpressureintheglomerularcapillaries.Butnow,havingpassedthroughtheefferentarteriole,thehydrostaticpressureintheperitubularcapillariesisonly~15mmHgandthisisopposedbyahydrostaticpressureintherenalinterstitialfluidthatissignificantlygreaterthanzero(~6mmHg),sothenethydrostaticpressureisonly~7mmHg.Thisisincontrasttothe~17mmHgosmoticpressure,sothereisa~10mmHgpressuredrivingflowfrominterstitialfluidintoperitubularcapillaries.(Note,theproteinosmoticpressureoftheperitubularcapillaryfluid,~32mmHg,ishigherthanwhatyouweretoldwhenyouwerediscussingcapillarydynamicsinothersystemictissues.Why?)Whatarethemechanismsinvolvedinthetransportofsubstancesfromthetubularfluidtotheinterstitialfluid?Theanswerisalltypes.Allmechanismsofmolecularmovementareimportantinkidneyprocesses:diffusion,osmosis,facilitateddiffusion,primaryactivetransport,secondaryactivetransport.Letusnowconsidersomeofthesespecificprocesses.[slides5,6]


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[slide7]


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Forsubstancesthatareactivelyreabsorbed,therearelimitstothecapacityofthisprocess:transportmaximum.Themaximalrateatwhichamembranecantransportasubstanceisduetothenumberoftransportersandtheinherenttransporttimeofthetransporter.So,forsubstancesfilteredandenteringtheproximaltubule(tubularload),thereisafinitecapacityforreabsorption.[slides8and9]

Inadditiontobeingsaturable,transportersalsoshow"specificity"and"competition".Secretionisalwaysanactiveprocess,sinceitmust(bydefinition)betransportupaconcentrationgradient.K+andH+secretionarebyprimaryactivetransport,whereasthesecretionofeverythingelseisbysecondaryactivetransport.Movementofwaterispassivediffusion(i.e.,osmosis)throughaquapores.ThemovementofwaterfollowsmainlythetransportofNa+.Differentportionsofthetubulesystemarespecializedfordifferentprocesses:theylookdifferent,andtheirmorphologyreflectstheirfunction.

Proximaltubule[slide10]:morethanhalfofthefilteredloadofNaandwaterarereabsorbedhere,asismostoftheloadofglucose,aminoacids,etc.[slide11]Thesecellsareverymetabolicallyactive(i.e.,lotsofactivetransport),andhavelotsofmitochondria.Thetubularborderisveryconvoluted(andthereforehasagreatsurfaceareareferredtoasa"brushborder".


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LoopofHenle[slide12]:Thereare3distinctregionsoftheloopofHenle,thedescendingthinlimb,theascendingthinlimb,andtheascendingthicklimb.We'llputoffourdiscussionoftheseuntilnexttime,butthedifferentportionshavedifferentpermeabilitiesfordifferentsubstances.Inparticular,thethickascendinglimbactivelytransportsavarietyofions,butisimpermeabletowater.Thethinlimbslackactiveprocesses.Distaltubule[slide13]:theearlydistaltubuleissimilartothethickascendinglimboftheloopofHenle(andsoitisnotclearjustwheretheborderis);solutesareactivelyreabsorbedbutthetubuleisrelativelyimpermeabletowaterandsothetubulefluidbecomesincreasinglydilute.Latedistaltubuleandcorticalcollectingduct:theprimaryfeaturehereistheNa+/K+transporteronthebasolateralmembrane;itisinvolvedintheregulatedreabsorptionofNaandsecretionofK.Also,H+transport(involvedinacid/basebalance).Also,regulatedpermeabilitytowater(whichwinbethefocusofnextclass).[slide14]


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Generalprinciplesofregulationofreabsorption:Thereare3majorfactorsthatareinvolvedintheregulationofreabsorption.Ofthese,hormonalregulationisarguablythemostprominent.Regulationbyhormones[slide15]:

Regulationbyphysicalforces:Iftheforcesdrivingflowfrominterstitialfluidtoperitubularcapillarieschange,thiswillchangereabsorption.Thus,ifperitubulehydrostaticpressurefalls,thiswillfavorreabsorption.[Whatmightinfluenceperitubulehydrostaticpressure?]Regulationbyneuralinfluences:Thesympatheticinnervationofthekidneycanpromotesodium(andwater)retentionby3mechanisms:stimulationofreninsecretion(andtherebyangiotensinproduction)whichactstostimulateNatransport(seeabove),directstimulationofsodiumtransportintheproximaltubule,andbyreducingbloodflowandtherebyGFR.


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Theconceptofclearance:[slide16]Clearanceisanabstract(butveryuseful)conceptthatdescribeshowmanymlofplasmawouldhaveasolutetotallyremovedbythekidneyperunittime.Clearanceofasubstance=urineexcretionrateofthesubstanceIplasmaconc.ofit(mg/mindividedbymg/mlgivesavalueinml/min,whicharetheunitsofclearance)Cs=UsXV/PsLet'srunthroughsuchacalculationforinulin:assumeaplasmainulinconcentrationof1mg/mlandaurineexcretionof125mg/minandsotheclearanceis(plugitintoaboveformula)125ml/min.Notsurprisingly,theclearanceofasubstancethatisneitherreabsorbednorsecretedisequaltoGFR.WhileinulincanbeusedintheclinictopreciselydetermineGFR,creatinineclearanceismoretypicallyusedtoestimateGFRsinceitisnormallypresentinplasmaandit’sclearancerateisclosetoGFR).Thus,ifGFRdecreases,plasmacreatininelevelsincreaseinproportion(slide17).ComparingtheclearanceofasubstancetoGFR(i.e.,clearanceofinulin,~clearanceofcreatinine)itisreadilyapparentifasubstanceisreabsorbed(clearancelessthanGFR)orsecreted(clearancegreaterthanGFR).[slide18]Forasubstancethatisfilteredplustotallysecreted[slide19],clearance=renalplasmaflow.Paraaminohippuricacid(PAH)issuchasubstance(almost);clearanceis~650ml/min.IfwetaketheGFRanddivideitbyrenalplasmaflow(i.e.,inulinclearancedividedbyPAHclearance),wegetthefractionofplasmathatpassesthroughthekidneythatgetsfiltered:thefiltrationfraction.

Slide20isanicereviewoftherelevantterms


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Aswehavestressedpreviously,regulationofbodyfluidvolumeandcompositionisofextremeimportance.Wehavebeendiscussingthemechanismsbywhichthekidneysfilterbloodplasmaandthenprocessthatfiltrate.Nowwewillbegintofocusonsomeoftheregulatoryaspectsofthatprocess.

Considerthatanorganismneedstobalancewaterlossandwaterintake,andalsoalterwaterlossandintakewiththelossandintakeofsolutes,soastomaintainanormalfluidvolumeandcomposition.Thefigurebelow[slide21]showssomenormalvaluesforwaterbalance.However,thesevaluescanvarymarkedlyfromdaytoday.Inordertoregulatewaterloss,andtobalanceitwithintakeandioniccomposition,itisnecessarytobeabletoindependentlyalterwaterandsoluteexcretion.Ifweconsumeadditionalwater,weneedtobeabletoexcreteitwithoutalsoloosingadditionalsolute.Conversely,ifwearedeniedaccesstowaterweneedtobeabletoexcretelesswater,whilestillexcretingappropriateamountsofvarioussolutes.Butifwateronlymovesbydiffusion(i.e.,followingtheconcentrationofsolute),howcanthisbeaccomplished?[slide22]


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Let'sfirstconsidertheconditionofneedingtoexcreteanexcessofwater[slide23].Gettingridofexcesswateriseasytopicture:justmakeasegmentofthetubuleimpermeabletowaterbutcontinuetoreabsorbsolutes[slide24].So,ifwemakethetubulesystemfromtheascendinglimboftheloopofHenlethroughthecollectingductimpermeabletowater,whilestillreabsorbingNa+(andothersolutes)wecouldgenerateahypotonicurine.Indeed,thebodyiscapableofproducinglargequantitiesofhypotonicurine(~20Lof50mOSm/Lperday)inthismanner.(Notethateveninthisextremecase,wearestillreabsorbingmostofthat180L/daythatgotfiltered!)[slide25]

TheascendinglimboftheloopofHenleinparticularhasahighcapacityforreabsorbingsolutes,butitisimpermeabletowater.IthasahighcapacityforreabsorbingNa,K,andClviaco-transport,drivenbytheNagradientcreatedbytheNa,K-ATPaselocatedonthebasolateralmembrane(slide26).Despitethetransportofsolute,waterdoesnotfollowbyosmosisbecausethissegmentisimpermeabletowater-itlacksaquapores.Thus,thefluidpassingfromtheascendinglimboftheloopofHenleisalwayshypotonic(~100mOsm/L).

Howcouldwemakeitmoreconcentratedthanthat?Simplyaddwaterchannels(aquaporin)inaregulatedmanner(slides27,28,29).Thatisexactlywhatantidiuretichormone(ADH,alsocalledvasopressin)doesatthelevelofthecollectingducts.(Diuresis=urineflow)ADHactsontheepithelialcellsofthecollectingductstocausethecellstoinsertmoreaquaporesintotheapicalmembrane.Theseregulatedaquaporesaremadeoftheproteinaquaporin2,andtheyarestoredinvesicularmembranesinsidethecells.InthepresenceofADH,moreofthesevesiclesbecomeinsertedintotheluminalmembrane.Conversely,intheabsenceofADHtheyremovefromthesegmentsofmembranepinchbackofftoformintracellularvesicles(i.e.,anendocytoticmechanism).ADHactsonaG-proteincoupledreceptor(theV2typeofADHreceptor)andthroughawell-characterizedintracellularsignalingpathwayinvolvingcAMPandPKApromotestheinsertionofAQP2intotheapicalmembrane.


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Slides30and31showthelocalizationofV2receptorsandAQ2onthecellsofthecollectingduct.(Alsonotethereisanothertypeofcell,theintercalatedcells,thatdon’thaveeithertheV2receptorsorAQ2;thesecellsareinvolvedinacid-basebalance.)

Let'spausefromdiscussingthekidneystospendalittletimetalkingaboutantidiuretichormone.Asyoualreadycovered,ADHisreleasedfromtheposteriorpituitary[slide32].Theposteriorpituitarycanbeviewedasthenerveterminalsofthemagnocellularneuronsofthesupraopticandparaventricularnucleiofthehypothalamus.Theseneuronssynthesizeoneofthetwoposteriorpituitaryhormones-ADHoroxytocin.Bothofthesehormonesaresmallpeptides;theyaremadeinthesomaoftheneuronandthentransportedtotheterminalintheposteriorpituitary.Attheleveloftheposteriorpituitarytheyaresecretedintothebloodinresponsetoactionpotentialsdepolarizingthenerveterminal.


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TherearetwoprimarystimuliforADHsecretion:hyperosmolalityandhypovolemia.[slide33]

Hyperosmolalityissensedby"centralosmoreceptors"(slide34),thatarelocatedinthehypothalamus.Howmightanosmosensorwork?Asthetonicityoftheinterstitialfluidchanges,waterwilldiffuseintooroutofcells.Inthecaseoftoomuchwater,hypoosmolality,waterwilldiffuseintocells,causingthemtoswell;thisinfluencesstretchsensitiveionchannelsinthemembrane,therebyhyperpolarizingtheneuronandresultingindecreasedADHsecretionintoblood.Conversely,asECFosmolalityincreases,ADHreleaseincreases.(Note,thatmanycellsareultimatelysensitivetolargechangesinECFosmolality;whatmakesthe"centralosmoreceptors"uniqueistheirexquisitesensitivity.Thus,changesinpOsmofonlyafewmilliosmolesinfluencesADHsecretion.[Thesecentralosmoreceptorsmaynotbetheonlyosmoreceptors(orNa+sensors)criticalfortheregulationofADHsecretion.Thereisevidencethattheingestionofosmolesandtheirabsorptioninthegastrointestinalsystemmayalsobeimportant.Indeed,recentdatasuggeststhatsignalsderivedfromthehepaticcirculationmaybequiteimportant.]

Hypovolemiaissensedlargelybyatrialstretchreceptors.AlthoughADHreleaseisnotverysensitivetohypovolemia,thisisaverypowerfulstimulusforADH,andADHlevelsaremarkedlyelevatedduringhypovolemia.HypotensionalsoappearstobeanindependentstimulusforADHsecretion,andchangesinbloodvolumeandbloodpressuremayactsynergistically.AngiotensinmayalsoplayaroleinstimulatingADHsecretionduringdecreasedbloodpressureand/orvolume.

ADHhastwoprimaryactions:[slides35,36]

Antidiuretic:duetoverylowlevelsofADH(1-15pM)actingonV2receptorsinthekidneytocausetheinsertionofaquaporin2intotheepithelialcellmembraneinthecollectingducts.

Vasopressor:athigherlevelsthanneededforantidiuresisandisduetoanactionatVIreceptorsonarterioles.ThoughADHappearstobeaverypotentvasoconstrictor,itisnotaverypotentvasopressor.ThisdiscrepancybetweenthevasoconstrictorandvasopressorpotenciesappearstorelatetoanactionofADHonthebaroreceptorreflex.


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So,gettingbacktothekidney,intheabsenceofADHtherewouldbeexcretionoflargevolumesofhypotonicurine.Theclinicalconditionofunregulatedexcretionoflargevolumesofhypotonicurineisknownasdiabetesinsipidus[slide36].DiabetesinsipiduscouldresultfromeithertheabsenceofADH(centraldiabetesinsipidus)orfailureofthekidneytorespondtoADH(nephrogenicdiabetesinsipidus).

Whataboutretainingwater?Asweinsertwaterchannelsintothecollectingduct,itiseasytopicturehowwecouldreabsorbwater,andgetanisotonicurine-osmoticmovementofwater.Buthowcouldwemakeahypertonicurine(evenupto1200mOsm)?[slide33]ThiscouldhappenifwerunthecollectingductthroughaveryhypertonicECF.(Ofcoursethisassumesthatthecollectingductispermeabletowater-i.e.,ADHispresent.)[slide38]

ButhowdowegetahypertonicECF?ThatiswhattheloopsofHenleofthejuxtamedullarynephronsdo.Considerthefollowingscenario.[slide39]TheascendinglimboftheloopofHenlepumpssoluteintotheinterstitialfluidbutdoesn'tletwaterfollow.[slide40]

However,thedescendinglimbrightadjacenttotheascendinglimbispermeabletowaterbutdoesnottransportNa.Waterwilldiffuseoutofthedescendinglimb,leavingbehindanowsomewhathypertonicfluid.Furthermore,itisthisfluidthatthenpassestotheascendinglimb:


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TheloopofHenlefunctionsasacountercurrentmultipliersystem,Inthismanner,thedeepestportionsofthemedullahaveanECFosmolarityof~1200mOsm,whereasthefluidreachingthedistaltubuleisquitedilute(~100mOsm)[slide41],Thus,asthetubularfluidpassesalongthecollectingduct,theosmolarityofthefluidcanincreasetoupto~1200mOsmdependinguponhowpermeablethecollectingductistowater,whichdependsonhowmuchADHispresent.[slide42]

NoticethatthebloodsupplyforthemedullamustfollowtheloopofHenleorthisgradientwouldgetwashedawaybythebloodstream;thesespecialperitubularbloodvesselsassociatedwiththeloopofHenlearecalledthevasarecta.[slide44]


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However,thegradientisn'tallNa,K,andCl;ureacontributessignificantlytothisaswell.Thethickascendinglimb,distaltubule,andcorticalcollectingductareimpermeabletourea,butthemedullarycollectingductisverypermeabletourea,andsoitmovesdownitsconcentrationgradient.[slides44-46]

Becauseureamovespassivelydownitsconcentrationgradient,theextenttowhichureacontributestothegradientdependsinpartastohowmuchwaterisbeingreabsorbedorexcreted.


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Solet’stakealookaswhathappenstovolumeandosmolalityalongthelengthofthenephron[slide47]

Obligatewaterloss[slide48]:undernormalconditions,weneedtoexcreteabout600milliosmolesofsoluteperday,representingmetabolicwaste.Sincewecanonlyconcentrateurineupto1200mOsm/Lthereisanecessarylossof0.5L/day.

Ifweapplytheconceptofclearancetowater,wecantalkabout"freewaterclearance".Thisisthedifferencebetweenwaterexcretion(i.e.,urineflowrate)andtotalsoluteclearance;so=V-Uosm/Posm.Thus,ifweareproducingmoreurinethanweareclearingsolutefrommillilitersofplasma(i.e.,ahypotonicurine),wearelosingwaterfreeofsolute.

Negativefeedbackcontrolofplasmaosmolarity,whichisaverytightlycontrolledparameter[slide49&50]


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Slide51:

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