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Renal Physiology Part 2

DrBernadetteBellette NationalCentreforAdultStemCellResearch GriffithUniversity Nathan Ext54418 b.bellette@griffith.edu.au

RenalPhysiology
UtilisingChapters25&26ofyourprescribedtextyoushouldaddresseachofthefollowing learningobjectives:. Describethestructureandfunctionofallcomponentsoftheurinarysystem. Describethegrossanatomyofthekidney. Outlinethefunctionsofthekidney. Describetheanatomyofanephron. Describethefunctionsofparticularregionsofthenephron. Explainthephysiologicalmechanismsinvolvedinurineproduction. Describethenormalpropertiesofurineaswellastheabnormalcomponents. Describethetwofluidcompartmentsofthebodyandtheircomponentparts. Describefactorsthatdeterminefluidshiftsinthebody. Describethemechanismsinvolvedinwaterbalance Explainthephysiologicalimportanceofthevariouselectrolytes. Describethemechanismsinvolvedinelectrolytebalance. Describethechemicalbuffersystems. Explaintheroleofboththerespiratory&urinarysystemsonacidbasebalance. Today

Revision

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Regulationofbodyfluidosmolarity&volume Regulationofwater Regulationofelectrolytes Acidbaseregulation. Endocrine Excretionofmetabolicproducts&foreign substances Gluconeogenesis Regulationofbonegrowththroughregulation ofcalciumandphosphateexcretion

FunctionsofKidney

Nephron
Functionalunit nephron:
Corpuscle
Bowmanscapsule Glomeruluscapillaries

Proximalconvolutedtubule (PCT) LoopofHenley Distalconvolutedtubule (DCT) Collectingduct

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Nephron
Productionoffiltrate Reabsorptionoforganic nutrients Reabsorptionofwater andions Secretionofwaste productsintotubular fluid

CorticalandJuxtamedullaryNephrons

BloodSupplytotheKidneys

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Filtration

GlomerularFiltration

Glomerular filtrateisproduced frombloodplasma Mustpassthrough: 1. Poresbetweenendothelialcells oftheglomerular capillary Basementmembrane acellular gelatinousmembranemadeof collagenandglycoprotein Filtrationslitsformedby podocytes Filtrateissimilartoplasmain termsofconcentrationsofsalts andoforganicmolecules(e.g., glucose,aminoacids)exceptitis essentiallyproteinfree
Fig.25.5

2.

3.

4.

Figure 26.10a, b

GlomerularFiltration
Principlesoffluiddynamicsthataccountfortissuefluidinthe capillarybedsapplytotheglomerulus aswell FiltrationisdrivenbyStarlingforcesacrosstheglomerular capillaries Starlingshypothesis statesthatthefluidmovementdueto filtrationacrossthewallofacapillaryisdependentonthebalance betweenthehydrostaticpressuregradient(pressurethatisexerted byaliquidwhenitisatrest) andtheoncotic pressuregradient (capillarybarrierisreadilypermeabletoions,theosmoticpressure withinthecapillaryisprincipallydeterminedbyplasmaproteins thatarerelativelyimpermeable)acrossthecapillary. changesintheseforcesandinrenalplasmaflowalterthe glomerular filtrationrate(GFR)

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Glomerular Filtration
Theglomerulus ismoreefficientthanothercapillarybeds because:
Itsfiltrationmembraneissignificantlymorepermeable Glomerular bloodpressureishigher Ithasahighernetfiltrationpressure

Plasmaproteinsarenotfilteredandareusedtomaintain oncotic (colloidosmotic)pressureoftheblood

ForcesInvolvedinGlomerularFiltration
NetFiltrationPressure(NFP) pressureresponsiblefor filtrateformation NFPequalstheglomerular hydrostaticpressure(HPg) minustheoncotic pressure ofglomerular blood(OPg) pluscapsularhydrostatic pressure(HPc) NFP = HPg (OPg + HPc) NFP = 55 (30 + 15) = 10

GlomerularFiltrationRate(GFR)
Thetotalamountoffiltrateformedperminuteby thekidneys Filtrationratefactors:
Totalsurfaceareaavailableforfiltrationandmembrane permeability(filtrationcoefficient=Kf) Netfiltrationpressure(NFP) GFR=Kf xNFP

GFRisdirectlyproportionaltotheNFP ChangesinGFRnormallyresultfromchangesin glomerular capillarybloodpressure

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RegulationofGlomerularFiltration
IftheGFRistoohigh,neededsubstancescannotbe reabsorbedquicklyenoughandarelostintheurine IftheGFRistoolow everythingisreabsorbed,including wastesthatarenormallydisposedof ControlofGFRnormallyresultfromadjustingglomerular capillarybloodpressure ThreemechanismscontroltheGFR
Renalautoregulation (intrinsicsystem) Neuralcontrols Hormonalmechanism(thereninangiotensin system)

Controlofrenalbloodsupply:Intrinsic Kidneycontrolled
Myogenic contractionorrelaxationof smoothmusclesurroundingrenalarterioles.
Contractionpreventsoverdistention ofvessels,increases resistanceandpreventsexcessiveincreaseinrenalblood flow(increasespressureresultsinconstriction) Decreasedpressureresultsinvasodilation andrelaxation

Tubuloglomerular maculadensa cells monitorbloodflowandbloodconcentration andchangediameterofvessels.

Controlofrenalbloodsupply:Extrinsic Outsidethekidney
Sympatheticnervoussystem(SNS) shuttingdown renalbloodsupply(adrenalineinduced vasoconstriction)

Endocrine reninangiotensin mechanism.

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http://en.wikipedia.org/wiki/File:Reninangiotensinaldosterone_system.png

ExtrinsicControls
Whenthesympatheticnervoussystemisatrest:
Renalbloodvesselsaremaximallydilated Autoregulation mechanismsprevail

Understress:
Norepinephrine isreleasedbythesympatheticnervoussystem Epinephrineisreleasedbytheadrenalmedulla Afferentarteriolesconstrictandfiltrationisinhibited

Thesympatheticnervoussystemalsostimulatestherenin angiotensin mechanism AdropinfiltrationpressurestimulatestheJuxtaglomerular apparatus(JGA)toreleaserenin anderythropoietin

OtherFactorsAffectingGlomerularFiltration
Prostaglandins(PGE2 andPGI2)
Vasodilatorsproducedinresponsetosympatheticstimulation andangiotensin II Arethoughttopreventrenaldamagewhenperipheral resistanceisincreased

Nitricoxide vasodilatorproducedbythevascular endothelium Adenosine vasoconstrictorofrenalvasculature Endothelin apowerfulvasoconstrictorsecretedby tubulecells

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ResponsetoaReductioninGFR

WhatHappensinPCT?
Reabsorption (intobody)
Na+viaactivetransport,whichsets upelectrochemicalgradientfor passivediffusionofothersolutes Virtuallyallnutrients(i.e.glucose, vitamins),activecotransportwith Na+ Cations,drivenbyelectrochemical gradient Anions,passivediffusionandcoactive transport Water,osmosis Ureaandfatsolublesolutes,diffusion drivenbywatermovement Smallproteins

Secretion(intourine) H+andammoniumsalts Bilesalts,drugs(eg penicillin) Prostaglandins,uricacid

Cellsare:cuboid withmicrovilli bigsurfacearea,andlotsof mitochondria needtheenergy! Activeenzymeproductionandexcretionintolumen

WhathappensintheLoopofHenle?
Reabsorption (intobody)
AfterthePCTcollectionofions thefiltrateinthedescending loopofHenle haslowosmotic pressuresowaterissuckedinto tissueandthenintoblood Littlesolutemomentin descendingloop Inascendinglooplotsof Na/K/Cl reasborption viaactive transport,cotransportand diffusion

Secretion(intourine) Verylittle

DescendingCellsare:simplesquamous epithelium freelypermeabletowater AscendingcellsarelikePCT somoreactive absorption

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Whathappensinthedistalconvoluted tubule(DCT)?
Secretion(intourine) Reabsorption (intobody) Na+,primaryactive H+andK+(acids) transporttriggeredby Drugs,toxins aldosterone Ca2+ Cl,diffusionand cotransport withNa+ Water,osmosisincreasedby ADHenhancing permeability
Cellsare:Cuboid epithelialcells.Thinner&fewer microvilli.Cluesforsecretion(notreabs.)

WhathappensintheCollectingDuct
Reabsorption (intobody) Secretion(intourine) Na+,H+,K+,HCO3,Cl, Na+,K+,H+and aldosterone mediated bicarbonateHCO3 activetransportofNa+, passivediffusionofHCO3 andCL andcotransportof H+,K+,HCO3 andCl Water,osmosisenhanced byADH Urea,facultativediffusionin responsetomedullary concenration gradient
Cellsare:More heterogeneouscells.Intercalatedcells;alpha cuboid abundantmicrovilli.Principalcells;beta lackmicrovilli

GOOD SUMMARY: Copstead& Banasik,2005 Figure267

Eachsegment ofthenephron isspecialized forcertain functions, whichis reflectedinthe typeof epithelialcells thatmakeup thetubules.

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GOOD SUMMARY: Copstead& Banasik,2005 Figure2616

Note: increasesin some solutes! SECRETION

Some solutesare mostly balanced

Summaryofnutrientandelectrolytecompositionofthefiltrateineach segmentofthenephron.Twothirdsofthefiltrateisreabsorbedintheproximal tubule.

ReninAngiotensinMechanism
Renin releaseistriggeredby:
ReducedstretchofthegranularJGcells StimulationoftheJGcellsbyactivatedmaculadensa cells DirectstimulationoftheJGcellsvia1adrenergicreceptorsbyrenalnerves

Renin actsonangiotensinogen toreleaseangiotensin Iwhichis convertedtoangiotensin II Angiotensin II:

Causesmeanarterialpressuretorise(VIAVASOCONSTRICTIONOF ARTERIOLES) Stimulatestheadrenalcortextoreleasealdosterone

Asaresult,bothsystemicandglomerular hydrostaticpressurerise

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Fig.25.10

AntiDiruetic HormonePathway(ADH)
Oneofthemostimportantrolesisin thebodysretentionofwater Releasedwhenbodyisdehydrated andcausesbodytoconservewater therebyconcentratingurineand reducingurinevolume waterpermeabilityofDTandCD, occursviainsertionofwaterchannels (aquaporins)intomembraneofDCT andCD Releaseistriggeredbyincreased osmolarity ofplasmaandtoalesser degreedecreasedvolumeof extracellularfluid

http://www.google.com.au/imgres?q=Antidiuretic+hormone+pathway&hl =en&client=firefoxa&sa=X&rls=org.mozilla:en GB:official&biw=1304&bih=780&tbm=isch&tbnid=hp5S6o_8URALmM:&i mgrefurl=http://medical dictionary.thefreedictionary.com/arginine%252Bvasopressin&docid=jEha Mb8xnm_2JM&w=300&h=176&ei=s9MwTsjGNuLmiAKJ8uCTBg&zoom=1 &iact=hc&vpx=843&vpy=511&dur=1159&hovh=140&hovw=240&tx=120 &ty=33&page=5&tbnh=111&tbnw=190&start=99&ndsp=24&ved=1t:429, r:10,s:99

Urine
Freshurineistransparent&yellowish (dueto urochrome) Colourmaychange Cloudyurine oftenindicativeofUTI Littleodour Sweetsmellingurine indicativeofdiabetesmellitus pH~6 shouldnotcontain;protein,blood/bloodcells,glucose, unmodifiedbilepigments,bacteria,viralparticles, ketone bodies

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Ureters +Bladder
Carryurineintobladder Internalepitheliumsurroundedbytransverse,circular& transversesmoothmuscle(peristalticurinetransport) PNS&SNSinput Verylittlechangetourinecontent(secretion/reabsorption) Bladderisretroperitonealsmoothstretchymuscularsacsitting onpelvicfloor Innerepithelium,centraldetrusor muscle(LCL),outerfibrous adventitia superiorlycoveredbyperitoneum

Fig.25.18

Epitheliumchangesnearopeningtostratifiedsquamous epithelium Internalbladderurethraljunctionguardedbyinternalurethral sphincter(invol) Externalurethralsphincter(sphincterurethrae)guardspassage thruurogenital diaphragm sk.Muscle(vol) EUSaidedbylevator ani muscleofpelvicfloor(pudendal motor fibres) Females tightlyboundtoanteriorvaginalwallemptyingat externalurethralorifice(meatus)betweenclitorisandvagina
Notebladderproximitytourethral&soanalopening

urethra

Males prostatic(~2.5cm),membranous(~2cm),spongyorpenile (~15cm)emptyingatexternalurethralorifice

Doublefunction carryingsemen&urine

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Controlofmicturition
Voiding/urination Stimulatedbyactivation ofstretchreceptorsin bladderwallsfrom ~200mls Reflexcontrolledby dorsolateral pons brain regioncanbeoverridden (andthusignored) initially Reflexreactivatedonsign. increasingstretch

Significanceofmedullarytransit
Changeinosmotic gradientinkidney medulla DescribedinmOmols (milliosmoles thousandthsofan Osmol) Bodyfluids ~300mOsmol
Fig.25.13

CountercurrentMechanisms
Occurswhenfluidflowsinoppositedirections intwoadjacentsegmentsofthesametube
FiltrateflowintheloopofHenle (countercurrent multiplier) Bloodflowinthevasa recta(countercurrent exchanger)

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CountercurrentMechanisms
Roleofcountercurrentmechanisms
Establishandmaintainanosmoticgradient (300 mOsm to1200 mOsm)fromrenalcortex throughthemedulla Allowthekidneystovaryurineconcentration

TheascendinglimboftheloopofHenle transportssolutes(NaCl)outofthetubule =highconcentrationofsolutesinECF Therearenowmoresolutesoutsidethe tubulethaninitsowatermovesoutof thetubuleinthedescendinglimbtotry andbringthingstoequilibrium(thisis whatwewant!Wewanttoabsorb water!) Buttocontinuallyabsorbwaterwemust drawthewaterawayfromtheinterstitial fluidsothattheosmoticgradientis maintained.Thisisachievedbythevasa rectapullingwaterintotheblood Theosmolarity oftheinterstitium is thereforemaintainedandthecyclecan keepgoing

CounterCurrentSystem

Enablesustovarytheconcentrationofoururinetomatch ourbodysrequirements. Whatifwearedehydrated?

Thecountercurrent systempermitsformingaconcentrated urine InthepresenceofADH,whichincreaseswaterpermeability, waterwillmoveintotissuesintheDTandCD. Somuchwateriswithheldthattheconcentrationoftheurineis increased(lesssolvent!)

CounterCurrentSystem

Whatifourbloodvolumeistoohigh?
hyposmotic fluidthatenterstheDTfromtheloopofHenle, continuestobedilutedbytransportofNaCl viaNaCl cotransporters andchannels. Waterreabsorption islimitedsothatthetubulefluidbecomes moreandmorediluteuntilitisexcretedasalargevolumeof hyposmotic urine

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TodaysLecture

FluidCompartmentsintheHumanBody
Extracellularfluid
Interstitial,surroundsthecellsofagiventissue
excessivefluidaccumulatesintheinterstitialspace,edemadevelops allowsformovementofions,proteinsandnutrientsacrossthecell barrier

Intravascular
complexfluidwithelementsofasuspension(bloodcells),colloid (globulins)andsolvent(glucoseandions). approximately3.5liters

OtherECF:lymph,CSF,humorsoftheeye,synovialfluid,serous fluid,andgastrointestinalsecretions

Intracellularfluid
Fluidinsidecells 6065%ofbodywater 28liters offluid,remainsinosmoticequilibriumwiththeECF

Total body water Volume = 40 L 60% body weight

Extracellular fluid (ECF)

Volume = 15 L 20% body weight

Intracellular fluid (ICF) Volume = 25 L 40% body weight

Interstitial fluid (IF)

Volume = 12 L 80% of ECF

Figure 26.1

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CompositionofBodyFluids
Water:theuniversalsolvent Solutes:nonelectrolytes andelectrolytes
Nonelectrolytes:mostareorganic
Donotdissociateinwater:e.g.,glucose,lipids, creatinine,andurea

Electrolytes
Dissociateintoionsinwater;e.g.,inorganicsalts,allacids andbases,andsomeproteins Themostabundant(mostnumerous)solutes Havegreaterosmoticpowerthannonelectrolytes,somay contributetofluidshifts Determinethechemicalandphysicalreactionsoffluids

IntracellularandExtracellularFluid
Eachfluidcompartmenthasadistinctive patternofelectrolytes ECF
Allsimilar,excepthigherproteincontentof plasma
Majorcation:Na+ Majoranion:Cl

IntracellularandExtracellularFluid
ICF:
LowNa+ andCl Majorcation:K+ MajoranionHPO42

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Blood plasma Interstitial fluid Intracellular fluid Na+ K+ Ca2+ Mg2+ Sodium Potassium Calcium Magnesium

HCO3 Bicarbonate Cl Chloride

HPO42 Hydrogen phosphate SO42 Sulfate

Figure 26.2

BodyWaterContent
Infants:73%ormorewater(lowbodyfat,low bonemass) Adultmales:~60%water Adultfemales:~50%water(higherfat content,lessskeletalmusclemass) Watercontentdeclinesto~45%inoldage

FactorsthatInfluenceFluidShift
Osmoticandhydrostaticpressures(pullor push) Osmolarity ofECFandICF(concentrationof solutes) Plasmaservesasthecommunicatingmedium betweenexternalandinternalenvironments

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ExternalInfluences
Externaltemperature whenitishot,wesweatmore andlosewater,therebymakingthebloodplasmamore concentrated. Amountofexercise ifweexercise,wegethotand increaseoursweating,sowelosemorewaterandthe bloodplasmabecomesmoreconcentrated. Fluidintake themorewedrink,themorewedilute thebloodplasma.Thekidneysrespondbyproducing morediluteurinetogetridoftheexcesswater. Saltintake saltmakestheplasmamoreconcentrated. Thismakesusthirsty,andwedrinkmorewateruntil theexcesssalthasbeenexcretedbythekidneys.

Lungs

Gastrointestinal tract

Kidneys

Blood plasma

O2

CO2

Nutrients H2O, Ions

H2O, Nitrogenous Ions wastes

Interstitial fluid

O2

CO2

Nutrients H2O

Ions Nitrogenous wastes

Intracellular fluid in tissue cells

Figure 26.3

WaterBalanceandECFOsmolality
Waterintake=wateroutput=2500ml/day Waterintake:beverages,food,andmetabolic water Wateroutput:urine,insensiblewaterloss (skinandlungs),perspiration,andfeces

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100 ml Metabolism 10% Foods 30% 250 ml 750 ml 2500 ml 1500 ml 200 ml 700 ml

Feces 4% Sweat 8% Insensible losses via skin and lungs 28%

Beverages 60%

1500 ml

Urine 60%

Average intake per day

Average output per day

Figure 26.4

RegulationofWaterIntake
Thirstmechanismisthedrivingforceforwaterintake Thehypothalamicthirstcenterosmoreceptors are stimulatedby
Plasmaosmolality of23% Angiotensin IIorbaroreceptor input Drymouth Substantialdecreaseinbloodvolumeorpressure

RegulationofWaterIntake
Drinkingwatercreatesinhibitionofthethirst center

Inhibitoryfeedbacksignalsinclude
Reliefofdrymouth Activationofstomachandintestinalstretchreceptors

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Plasma osmolality

Plasma volume* Blood pressure

Saliva

Osmoreceptors in hypothalamus

Granular cells in kidney Renin-angiotensin mechanism Angiotensin II

Dry mouth

Hypothalamic thirst center

Sensation of thirst; person takes a drink Water moistens mouth, throat; stretches stomach, intestine Water absorbed from GI tract

Initial stimulus Physiological response Result Increases, stimulates Reduces, inhibits

Plasma osmolality

(*Minor stimulus)

Figure 26.5

RegulationofWaterOutput
Obligatorywaterlosses
Insensiblewaterloss:fromlungsandskin Feces Minimumdailysensiblewaterlossof500mlin urinetoexcretewastes

BodywaterandNa+ contentareregulatedin tandembymechanismsthatmaintain cardiovascularfunctionandbloodpressure

RegulationofWaterOutput
Waterreabsorption incollectingductsis proportionaltoADHrelease ADH diluteurineand volumeofbody fluids ADH concentratedurine

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RegulationofWaterOutput:Influence ofADH
Hypothalamicosmoreceptors triggerorinhibit ADHrelease OtherfactorsmaytriggerADHreleasevia largechangesinbloodvolumeorpressure, e.g.,fever,sweating,vomiting,ordiarrhea; bloodloss;andtraumaticburns

Osmolality Na+ concentration in plasma Stimulates Plasma volume BP (1015%)

Osmoreceptors in hypothalamus Negative feedback inhibits Stimulates

Inhibits

Baroreceptors in atrium and large vessels Stimulates

Posterior pituitary Releases Antidiuretic hormone (ADH) Targets Collecting ducts of kidneys Effects Water reabsorption Results in ADH

Osmolality Plasma volume

Scant urine

Figure 26.6

DisordersofWaterBalance: Dehydration
Negativefluidbalance ECFwaterlossdueto:hemorrhage,severeburns, prolongedvomitingordiarrhea,profusesweating, waterdeprivation,diureticabuse Signsandsymptoms:thirst,dryflushedskin,oliguria Mayleadtoweightloss,fever,mentalconfusion, hypovolemic shock,andlossofelectrolytes

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1 Excessive loss of H2O from ECF

2 ECF osmotic pressure rises

3 Cells lose H2O to ECF by osmosis; cells shrink

(a) Mechanism of dehydration

Figure 26.7a

PatientCaseHistory1
Two23yroldsbringPatientA,a21yrold universitystudent,toemergencypresentingwith gastrointestinalupset,confusion,extreme lethargyandfatigue.Therearenoobvioussigns oftrauma. Whatsignsoftraumawouldyouobserve? Youaskthetwofriendsifyourfriendhas attendedaparty Sheattendedapartythenightbeforeandtheir weredrugs,includingEcstasy,attheparty

History
Observation Heart rate (beats/minute) Blood pressure (mmHg) Temperature (C) Glucose (mg/dl) Sodium (mM/L) Potassium (mM/L) Chloride (mM/L) Oxygen (mmHg) Carbon Dioxide (mM/L) Normal 60-100 90/50-140/0 37 60-109 135-146 3.5-5.5 95-109 80-100 22-32 Patient A 90 135/87 42 72 115 2.9 88 93 24

WhatdoyouthinkthetestresultssuggestiswrongwithPatientA Highbloodpressureorrapidheartrate? Hypoglycemia Hyperthermia Hypothermia Excessivewaterretention Dehydration

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More..
Younoticethatherelectrolytevaluesarelowandqueryas towhethershehaddrunktoomuchlastnight Whydoyouaskthetwofriendsthisquestion? Thetwofriendssaidsheonlyhadonebeerhowevershe wokeupincrediblythirstyanddrankmultipleglassesof water Whatdoesthissuggest? Normallyifapatientdrinksexcesswateritisexcretedby thekidneybymakingalargevolumeofdiluteurine.From yourmedicaltrainingyouknowthatEcstacy isananti diuretic.ThismeansitforcesPatientAskidneystomake averyconcentratedurine.Doesthisexplainherresults?

Diagnosis
PatientAwasdiagnosedwithhyponatremia
Hyponatremia isanelectrolytedisturbanceinwhichthesodiumconcentrationinthe serumislowerthannormal.Sodiumisthedominantextracellularcation andcannot freelycrossthecellmembrane.Itshomeostasisisvitaltothenormalphysiologic functionofcells.Normalserumsodiumlevelsarebetween135145mEq/L. Hyponatremia isdefinedasaserumleveloflessthan135mEq/Landisconsidered severewhentheserumlevelisbelow125mEq/L. Hyponatremia ismostoftenacomplicationofothermedicalillnessesinwhicheither fluidsrichinsodiumarelost(forexamplebecauseofdiarrhoeaorvomiting)orexcess wateraccumulatesinthebodyatahigherratethancanbeexcreted(forexamplein congestiveheartfailure,syndromeofinappropriateantidiuretic hormone,SIADH,or polydipsia). Hyponatremia canalsoaffectathleteswhoconsumetoomuchfluidduringendurance events,peoplewhofastonjuiceorwaterforextendedperiodsandpeoplewhose dietarysodiumintakeischronicallyinsufficient.

PatientAwastreatedbygivingIVfluidswithnormalorslightlyhighersodium concentrationstocorrectthesaltimbalanceinhertissues Aproblemassociatedwithacuteorsuddenhyponatremia,orwaterintoxication,is swellingoftissuetodueosmoticuptakeofwaterbycells FortunatelyPatientAreceivedtreatmentintimetoreversetheswellinginher brainbeforeherbrainstemwasdamaged

DisordersofWaterBalance:Hypotonic Hydration
Cellularoverhydration,orwaterintoxication Occurswithrenalinsufficiencyorrapidexcess wateringestion ECFisdiluted hyponatremia net osmosisintotissuecells swellingofcells severemetabolicdisturbances(nausea, vomiting,muscularcramping,cerebraledema) possibledeath

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PatientCaseHistory2
Mrs.TBisa36yearoldlawyerwhopresentswith ankleoedema. Eightyearhistoryofsystemiclupus erythematosis. Originallydiagnosedbecauseofjointrelated symptoms. Overthepastseveralweekshasdevelopeda prominentmalar rash. Hasankleedema. Recentserumcreatinine was3.2mg/dL (normal<1). B/P118/78 T=37.33

VisualUrineAnalysis

Dipstick

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Whatsgoingwrong?
Mrs.TBhasrenalfailureandisexhibitingthenephrotic syndrome. Whataffectwilllosingproteinintheperipheryhave? Edema.
Themostcommonsignisexcessfluidinthebodyduetotheserum hypoalbuminemia.Lowerserumoncotic pressurecausesfluidtoaccumulatein theinterstitialtissues.Sodiumandwaterretentionaggravatetheedema

Lotsofproteinloss. Hypoalbuminemia Broadcasts areprobablycomposedof congealedproteinlostthroughthe glomerular basementmembrane. Epithelialcellcastsindicatesometoxicitytotubularcells.

Thiscanhappenwithoverwhelmingproteinloss.

Thereisnobloodseen. Urineisrelativelydilute. Hercreatinine isprettybad. Asitturnsout,hercreatinine clearanceisonly12ml/min. Allindicationspointtosevereglomerular damage.

DisordersofWaterBalance:Oedema
AtypicalaccumulationofIFfluid tissueswelling Duetoanythingthatincreasesflowoffluidoutof thebloodorhindersitsreturn
Bloodpressure Capillarypermeability(usuallyduetoinflammatory chemicals) Incompetentvenousvalves,localizedbloodvessel blockage Congestiveheartfailure,hypertension, blood volume

Oedema
Hinderedfluidreturnoccurswithanimbalance incolloidosmoticpressures,e.g., hypoproteinemia ( plasmaproteins)
Fluidsfailtoreturnatthevenousendsofcapillary beds Resultsfromproteinmalnutrition,liverdisease,or glomerulonephritis

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Whataretheimportantelectrolytesinourbody?
theprimaryionsofelectrolytesareNa+,K+,Ca2+,Mg2+,Cl,HPO42,and HCO3. Gradientsaffectandregulatethehydrationofthebodyaswellasblood pH,andarecriticalfornerveandmusclefunction. Variousmechanismsexistinlivingspeciesthatkeeptheconcentrations ofdifferentelectrolytesundertightcontrol. musclecontractionisdependentuponthepresenceofCa2+,Na+,andK+. Withoutsufficientlevelsofthesekeyelectrolytes,muscleweaknessor severemusclecontractionsmayoccur electrolytehomeostasisisregulatedbyhormonessuchasantidiuretic hormone,aldosterone andparathyroidhormone. Seriouselectrolytedisturbances,suchasdehydrationandoverhydration, mayleadtocardiacandneurologicalcomplicationsand,unlesstheyare rapidlyresolved,willresultinamedicalemergency

Salts
Importanceofsalts
Controllingfluidmovements Excitability Secretory activity Membranepermeability

CentralRoleofSodium
Mostabundantcation intheECF SodiumsaltsintheECFcontribute280mOsm ofthetotal300mOsm ECFsolute concentration Na+ leaksintocellsandispumpedoutagainst itselectrochemicalgradient Na+ contentmaychangebutECFNa+ concentrationremainsstableduetoosmosis

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CentralRoleofSodium
Changesinplasmasodiumlevelsaffect
Plasmavolume,bloodpressure ICFandIFvolumes

Renalacidbasecontrolmechanismsare coupledtosodiumiontransport

RegulationofSodiumBalance
NoreceptorsareknownthatmonitorNa+ levelsinbodyfluids Na+waterbalanceislinkedtobloodpressure andbloodvolumecontrolmechanisms

RegulationofSodiumBalance: Aldosterone
Na+ reabsorption
65%isreabsorbedintheproximaltubules 25%isreclaimedintheloopsofHenle

Aldosterone activereabsorption of remainingNa+ WaterfollowsNa+ ifADHispresent

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K+ (or Na+) concentration in blood plasma*

Renin-angiotensin mechanism Stimulates

Adrenal cortex Negative feedback inhibits Releases Aldosterone Targets Kidney tubules Effects

Na+ reabsorption

K+ secretion Restores

Homeostatic plasma levels of Na+ and K+

Figure 26.8

RegulationofSodiumBalance: Atrial natriuretic peptide

Releasedbyatrial cellsinresponsetostretch ( bloodpressure) Effects Decreasesbloodpressureandbloodvolume:
ADH,renin andaldosterone production ExcretionofNa+ andwater Promotesvasodilation directlyandalsoby decreasingproductionofangiotensin II

Stretch of atria of heart due to BP Releases Negative feedback Atrial natriuretic peptide (ANP) Targets

JG apparatus of the kidney Effects Renin release*

Hypothalamus and posterior pituitary

Adrenal cortex

Effects

ADH release Angiotensin II Inhibits Collecting ducts of kidneys Vasodilation Effects

Aldosterone release Inhibits

Na+ and H2O reabsorption Results in Blood volume Results in Blood pressure

Figure 26.9

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InfluenceofOtherHormones
Estrogens: NaCl reabsorption (like aldosterone)
H2Oretentionduringmenstrualcyclesand pregnancy PUFFYeww gross:S

Progesterone: Na+ reabsorption (blocks aldosterone)

PromotesNa+ andH2Oloss

Glucocorticoids: Na+ reabsorption and promoteedema

CardiovascularSystemBaroreceptors
Baroreceptors alertthebrainofincreasesin bloodvolumeandpressure
Sympatheticnervoussystemimpulsestothe kidneysdecline Afferentarteriolesdilate GFRincreases Na+ andwateroutputincrease

Systemic blood pressure/volume

Stretch in afferent arterioles (+)

Filtrate NaCl concentration in ascending limb of loop of Henle (+) (+)

Inhibits baroreceptors in blood vessels (+) Sympathetic nervous system (+) Systemic arterioles

Granular cells of kidneys Release Renin

Catalyzes conversion Angiotensinogen (from liver) Angiotensin I

Causes Vasoconstriction Results in

Converting enzyme (in lungs) Peripheral resistance Angiotensin II (+) (+) Systemic arterioles Causes Vasoconstriction Results in Peripheral resistance (+) Adrenal cortex Secretes

(+) Posterior pituitary Releases ADH (antidiuretic hormone) (+)

Aldosterone Targets Distal kidney tubules Causes Na+ (and H2O) reabsorption Results in Blood volume

Collecting ducts of kidneys Causes H2O reabsorption

(+) stimulates Blood pressure

Renin-angiotensin system Neural regulation (sympathetic nervous system effects) ADH release and effects

Figure 26.10

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RegulationofPotassiumBalance
Importanceofpotassium:
AffectsRMPinneuronsandmusclecells (especiallycardiacmuscle)
ECF[K+] RMP depolarization reduced excitability ECF[K+] hyperpolarization andnonresponsiveness

H+ shiftinandoutofcells
LeadstocorrespondingshiftsinK+ intheopposite directiontomaintaincation balance Interfereswithactivityofexcitablecells

RegulationofPotassiumBalance
K+ balanceiscontrolledinthecortical collectingductsbychangingtheamountof potassiumsecretedintofiltrate HighK+ contentofECFfavorsprincipalcell secretionofK+ WhenK+ levelsarelow,typeAintercalated cellsreabsorbsomeK+ leftinthefiltrate

RegulationofPotassiumBalance
Influenceofaldosterone
StimulatesK+ secretion(andNa+ reabsorption)by principalcells IncreasedK+ intheadrenalcortexcauses
Releaseofaldosterone Potassiumsecretion

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RegulationofCalcium
Ca2+ inECFisimportantfor
Neuromuscularexcitability Bloodclotting Cellmembranepermeability Secretory activities

BodypH
pHaffectsallfunctionalproteinsand biochemicalreactions NormalpHofbodyfluids
Arterialblood:pH7.4 VenousbloodandIFfluid:pH7.35 ICF:pH7.0

Alkalosisoralkalemia:arterialbloodpH>7.45 Acidosisoracidemia:arterialpH<7.35

BodypH
MostH+ isproducedbymetabolism
Phosphoricacidfrombreakdownofphosphorus containingproteinsinECF Lacticacidfromanaerobicrespirationofglucose Fattyacidsandketone bodiesfromfatmetabolism H+ liberatedwhendissolvedCO2 isconvertedto HCO3 inblood

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AcidBaseBalance
Concentrationofhydrogenionsisregulated sequentiallyby
Chemicalbuffersystems:rapid;firstlineof defense Brainstemrespiratorycenters:actwithin13min Renalmechanisms:mostpotent,butrequire hourstodaystoeffectpHchanges

AcidBaseBalance
Strongacidsdissociatecompletelyinwater; candramaticallyaffectpH Weakacidsdissociatepartiallyinwater;are efficientatpreventingpHchanges Strongbasesdissociateeasilyinwater;quickly tieupH+ WeakbasesacceptH+ moreslowly

HCI

H2CO3

(a) A strong acid such as HCI dissociates completely into its ions.

(b) A weak acid such as H2CO3 does not dissociate completely.

Figure 26.11

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ChemicalBufferSystem
Chemicalbuffer:systemofoneormore compoundsthatacttoresistpHchanges whenstrongacidorbaseisadded
1. Bicarbonatebuffersystem 2. Phosphatebuffersystem 3. Proteinbuffersystem

BicarbonateBufferSystem
MixtureofH2CO3 (weakacid)andsaltsofHCO3 H2CO3 HCO3 +H+ HCO3 istheconjugatebaseofH2CO3.Itisthe bitleftoverwhenHcomesoff Althoughtechnicallyaweakbaseinpracticeit iswhatiscallled amphoteric.Itcanactasan acidorabase BuffersICFandECF TheonlyimportantECFbuffer

BicarbonateBufferSystem
Ifstrongacidisadded:
HCO3 tiesupH+ thatcomesfromtheacidand formsH2CO3
HCl +HCO3 H2CO3 +Cl

pHdecreasesonlyslightly,unlessallavailable HCO3 (alkalinereserve)isusedup HCO3 concentrationiscloselyregulatedbythe kidneys

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BicarbonateBufferSystem
Ifstrongbaseisadded
ItcausesH2CO3 todissociateanddonateH+ H+ tiesupthebase(e.g.OH) HCO3 +OH CO32 +H2O pHrisesonlyslightly H2CO3 supplyisalmostlimitless(fromCO2 releasedbyrespiration)andissubjectto respiratorycontrols

PhysiologicalBufferSystems
Respiratoryandrenalsystems
Actmoreslowlythanchemicalbuffersystems Havemorecapacitythanchemicalbuffersystems

RespiratoryRegulationofH+
RespiratorysystemeliminatesCO2 Areversibleequilibriumexistsintheblood:
CO2 +H2O H2CO3 H+ +HCO3

DuringCO2 unloadingthereactionshiftsto theleft(andH+ isincorporatedintoH2O) DuringCO2 loadingthereactionshiftstothe right(andH+ isbufferedbyproteins)

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RespiratoryRegulationofH+
Hypercapnia (toomuchCO2blood)activates medullary chemoreceptors RisingplasmaH+ activatesperipheral chemoreceptors
MoreCO2 isremovedfromtheblood H+ concentrationisreduced

RespiratoryRegulationofH+
Alkalosisdepressestherespiratorycenter
Respiratoryrateanddepthdecrease H+ concentrationincreases

Respiratorysystemimpairmentcausesacid baseimbalances
Hypoventilation respiratoryacidosis Hyperventilation respiratoryalkalosis

AcidBaseBalance
Chemicalbufferscannoteliminateexcess acidsorbasesfromthebody
Lungseliminatevolatilecarbonicacidby eliminatingCO2 Kidneyseliminateotherfixedmetabolicacids (phosphoric,uric,andlacticacidsandketones) andpreventmetabolicacidosis

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RenalMechanismsofAcidBaseBalance
Mostimportantrenalmechanisms
Conserving(reabsorbing)orgeneratingnewHCO3 ExcretingHCO3

GeneratingorreabsorbingoneHCO3 isthe sameaslosingoneH+ ExcretingoneHCO3 isthesameasgaining oneH+

RenalMechanismsofAcidBase Balance
Renalregulationofacidbasebalancedepends onsecretionofH+ H+ secretionoccursinthePCTandin collectingducttypeAintercalatedcells:
TheH+ comesfromH2CO3 producedinreactions catalyzedbycarbonicanhydrase insidethecells SeeSteps1and2ofthefollowingfigure

1 CO2 combines with water within the tubule cell, forming H2CO3. 2 H2CO3 is quickly split, forming H+ and bicarbonate ion (HCO3). 3a H+ is secreted into the filtrate.
Filtrate in tubule lumen Nucleus PCT cell
2K+ 3Na+ HCO3 + Na+ Cl

3b For each H+ secreted, a HCO3 enters the peritubular capillary blood either via symport with Na+ or via antiport with CI. 4 Secreted H+ combines with HCO3 in the filtrate, forming carbonic acid (H2CO3). HCO3 disappears from the filtrate at the same rate that HCO3 (formed within the tubule cell) enters the peritubular capillary blood. 5 The H2CO3 formed in the filtrate dissociates to release CO2 and H2O. 6 CO2 diffuses into the tubule cell, where it triggers further H+ secretion.

Peritubular capillary
2K+

ATPase
3Na+ Cl

HCO3

H+

3a

H+

4
H2CO3

2
H2CO3

HCO3

3b

HCO3 HCO3

ATPase 5
*

Na+

Na+ Primary active transport Secondary active transport Simple diffusion Transport protein Carbonic anhydrase

1 6
CO2 + H 2O

CA

H 2O

CO2

CO2

Tight junction

Figure 26.12

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Reabsorption ofBicarbonate
Tubulecellluminalmembranesareimpermeableto HCO3
CO2 combineswithwaterinPCTcells,formingH2CO3 H2CO3 dissociates H+ issecreted,andHCO3 isreabsorbedintocapillaryblood SecretedH+ uniteswithHCO3 toformH2CO3 infiltrate, whichgeneratesCO2 andH2O

HCO3 disappearsfromfiltrateatthesameratethatit enterstheperitubular capillaryblood

1 CO2 combines with water within the tubule cell, forming H2CO3. 2 H2CO3 is quickly split, forming H+ and bicarbonate ion (HCO3). 3a H+ is secreted into the filtrate.
Filtrate in tubule lumen Nucleus PCT cell
2K+ 3Na+ HCO3 + Na+ Cl

3b For each H+ secreted, a HCO3 enters the peritubular capillary blood either via symport with Na+ or via antiport with CI. 4 Secreted H+ combines with HCO3 in the filtrate, forming carbonic acid (H2CO3). HCO3 disappears from the filtrate at the same rate that HCO3 (formed within the tubule cell) enters the peritubular capillary blood. 5 The H2CO3 formed in the filtrate dissociates to release CO2 and H2O. 6 CO2 diffuses into the tubule cell, where it triggers further H+ secretion.

Peritubular capillary
2K+

ATPase
3Na+ Cl

HCO3

H+

3a

H+

4
H2CO3

2
H2CO3

HCO3

3b

HCO3 HCO3

ATPase 5
*

Na+

Na+ Primary active transport Secondary active transport Simple diffusion Transport protein Carbonic anhydrase

1 6
CO2 + H 2O

CA

H 2O

CO2

CO2

Tight junction

Figure 26.12

GeneratingNewBicarbonateIons
TwomechanismsinPCTandtypeA intercalatedcells
GeneratenewHCO3 tobeaddedtothealkaline reserve

Bothinvolverenalexcretionofacid(via secretionandexcretionofH+ orNH4+

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ExcretionofBufferedH+
DietaryH+ mustbebalancedbygenerating newHCO3 MostfilteredHCO3 isusedupbeforefiltrate reachesthecollectingduct

ExcretionofBufferedH+
IntercalatedcellsactivelysecreteH+ into urine,whichisbufferedbyphosphatesand excreted GeneratednewHCO3 movesintothe interstitialspaceviaacotransport systemand thenmovespassivelyintoperitubular capillary blood

RespiratoryandRenalCompensations
Ifacidbaseimbalanceisduetomalfunction ofaphysiologicalbuffersystem,theotherone compensates
Respiratorysystemattemptstocorrectmetabolic acidbaseimbalances Kidneysattempttocorrectrespiratoryacidbase imbalances

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RespiratoryCompensation
Inmetabolicacidosis
HighH+ levelsstimulatetherespiratorycenters Rateanddepthofbreathingareelevated BloodpHisbelow7.35andHCO3 levelislow AsCO2 iseliminatedbytherespiratorysystem, PCO2 fallsbelownormal

RespiratoryCompensation
Respiratorycompensationformetabolic alkalosisisrevealedby:
Slow,shallowbreathing,allowingCO2 accumulationintheblood HighpH(over7.45)andelevatedHCO3 levels

RenalCompensation
HypoventilationcauseselevatedPCO2 (respiratoryacidosis)
RenalcompensationisindicatedbyhighHCO3 levels

RespiratoryalkalosisexhibitslowPCO2 andhigh pH
Renalcompensationisindicatedbydecreasing HCO3 levels

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ImportantPoints
Describethefactorsthatdeterminefluidshifts inthebody Listtheroutesbywhichwaterentersand leavesthebody Whatisdehydration,hypotonichydrationand oedema Whatistheimportanceofsodium,calcium andpotassiumandhowaretheirlevels regulated

ImportantPoints
Whatisanacid? Whatisabase? Namethe3buffersystemsinthebodyand describehowtheyacttoresistchangeinpH Howisthebicarbonatebuffersystem amphoteric? Whatistherespiratoryandrenalcontrolofacid basebalance Whatisacidosisandalkalosis?

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