THEUNIVERSITYOFCONNECTICUTHEALTHCENTER

SchoolsofMedicineandDentalMedicine
MechanismsofDiseaseCommittee
DiseasesAffectingHomeostasis
DiseasesoftheBlood,Pulmonary,RenalandCardiovascularSystems
(SecondYear)
20162017

RelationshipbetweenHeartFailure,KidneyFunction,andAnemia

Objectives
1) ToknowthemechanismsresponsiblefordecreasedNaexcretioninCHF.
2) ToknowthereasonsfordecreasedresponsetodiureticsinCHF.
3) Toknowtherationalforcombiningloopdiuretics,thiazides,andaldosteroneantagonistsinCHF
4)ToknowthepotentialreasonsforadeclineinrenalfunctioninpatientswithCHF.
5)ToknowthepotentialreasonsforhyperkalemiainpatientsonACEinhibitors.
6)Toknowthemechanism(s)ofanemiainCHFandkidneydisease

References
Harrison18thedition.AcuteKidneyInjuryChapter279.
HeartFailureChapter234.

StudyQuestions
A60yearoldmanwithcongestiveheartfailuresecondarytoischemiaisadmittedinheartfailure.Hehada
myocardialinfarction2yearsagoandcurrentlyhasanejectionfractionof35%.HewasdoingwellonASA81mg,
lisinopril20mg,carvedilol3.1252XD,atorvastatin80mg,andfurosemide40mg.Threeweeksagohedeveloped
shoulderpainandstartedtakingNSAIDs.Hesubsequentlynoticedaweightgainof10lbs.,paroxysmalnocturnal
dyspnea,orthopnea,andincreaseddyspnea.HecalledhisdoctorwhotoldhimtostoptheNSAIDsandtodoublethe
furosemideto40mg2XD.Hedidntrespondoverthenext3daysandwasadmitted.

PhysicalExam:BP120/80mmHg,P80/min,R20/min;Neck:jugularvenousdistention10cm;Lungs:crackles1/2
wayup;Heart:S3gallopand2/6mitralregurgitationmurmur;Extremities:2+edema;creatinine1.6mg/dL(baseline
1.0mg/dL);BUN40mg/dL(baseline16mg/dL).Otherlabswerenormal.

1) WhatarethepossiblereasonsNSAIDscausedhimtobeinafluidoverloadstateandcauseddecreased
renalfunction?

Hewasdiuresedandonday4hewassignificantlybetter.JVD<5(normal<5)lungsclear,noedema.Creatinine
thoughhadincreasedto2.0mg/dLandBUN60mg/dL.

2) Whatis(are)themostlikelyreason(s)fortheincreaseinCrandwhywasthereagreaterriseinurea
comparedtocreatinine?

3)Atthetimeofdischarge,whatmedicationshouldpossiblybeaddedtohisregimen?

Lecture
Inpatientswithmyocardialfailurethedecreasedcardiacoutputandthecompensatoryhormonalresponsesincluding
increasedAII,SNS,endothelinandAVPaffectsrenalfunctionandhomeostasisofmanysubstancesincludingsodium,
potassiumandwater.

I. RenalResponsetoCardiacFailure

A. Compensationfordecreasedrenalplasmaflowsecondarytodecreasedcardiacoutputseeninheartfailure
withreducedEFandpreservedEF.

1)ProstaglandinsandNOdilatetheafferentarteryopposingthevasoconstrictorsincludingAII,SNS,AVP,
andendothelin.ThatiswhyNSAIDs(notlowdoseASA)arepotentiallydeleteriousinprerenalstates.
Theywillworsenaprerenalstatesinceyounowhaveunopposedconstrictionoftheafferentartery.

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 2)AIIandSNSconstricttheefferentarterycausinganincreaseinglomerularpressure(PGC).
AsaresultofincreasedPGC,filtrationfractionincreases(GFR/RenalPlasmaFlow).Thishelpstopreserve
renalfunctioninsettingofdecreasedrenalplasmaflow.Itisimportantthatthiscompensationwillnotreturn
GFRtonormal.

AnexampleisanormalpatienthasaGFR120cc/minwithrenalplasmaflow600cc/mini.e.
FiltrationFraction=120cc/min/600cc/min=20%.IfhedevelopedCHFandrenalplasmaflowdecreased
to400cc/min,theGFRwouldbe80cc/miniftherewasnocompensation.Duetoconstrictionoftheefferent
arterywhichincreasesfiltrationfractionbyincreasingPGCtheGFRmayonlyfallto100cc/mini.e.,FF%=
100cc/minx100/400cc/min=25%.

B. DecreasedSodiumExcretion

PositiveNabalanceleadstocongestivesymptoms(dyspnea,orthopnea,PND)andsigns(edema,crackles,
andincreasedJVP).Reasonsfordecreasedsodiumexcretioninclude:

1)DecreasedfiltrationofNaduetodecreasedGFR.

2) IncreasedproximalreabsorptionduetodirecteffectsofAIIandSNSandindirecteffectofincreasing
filtrationfraction(figure1below).Iffiltrationfractionincreases(forexample)from20%to25%thenat
theendoftheglomerulus;whateverproteinsarepresentwillbeconcentratedin75ccinsteadof80cci.e.
increasedoncoticpressure.Thisincreasedoncoticpressurethengoestotheperitubularcapillariesand
increasesreabsorptionofNaandH2O.

3) IncreasedAIIincreasingdistaltubulesodiumreabsorptionandaldosteroneincreasingreabsorptionCDa

Normal CHF

Glomerular Efferent Peritubular Glomerular Efferent Peritubular

capillary artery capillary capillary artery capillary

Figure1

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II. Diuretics

A. NaHomeostasis

DiureticsarefrequentlyutilizedinCHFtocountertheincreasedsodiumreabsorptionresultingindecreased
sodiumexcretion.Loopdiureticsarefilteredandsecretedbytheproximaltubule.InCHFwithoutrenal
failurethereisnormalintraluminalconcentration.InpatientswithsevereCHF,thereisoftenconcomitant
renalinsufficiency.Inthatsituationorganicanionscompetewiththecarriersystemtransportingdiuretics
intothetubularfluidsothatmuchhigherdosageswillbeneededtohaveanormalintraluminalconcentration.
Evenwithnormalintraluminalconcentration,theincrementinsodiumexcretionafterloopactingdiureticsis
lessinpatientswithCHFthaninpatientswithoutCHFasshownbelowinFigure2.Thereasonsinclude:

1) IncreasedproximalreabsorptioncausingdecreaseddistaldeliveryofNatoascendinglimbofHenle

2) AbilityofdistalsegmentstoincreaseNaabsorptioninpartduetoincreasedAIIandaldosterone
levelsbutalsohypertrophyhasbeenshowninanimalsinthedistaltubulepromotingincreasedNa
absorption.

Normal
3.0 CHF

2.5
Sodium excretion (mEq/min)

2.0

1.5

1.0

0.5

0
1 4 10 40 100400

Furosemide excretion ug/min

Figure2

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Inheartfailuretheremaybearesponsetoagivendosebutafterthediureticeffectdiminishes,therewillbepositiveNa
balancetherestoftheday,i.e.frequentdosagesareoftenneeded.Evenwithfrequentdosesadditionalagentsthat
blockNareabsorptionareused.ThiazidesareoftenusedwithfurosemidetoblockNaabsorptionatthedistaltubule
andincreasenatriuresis.Metolazone,athiazidelikediuretic,worksinrenalfailurewhileotherthiazidesdont.In
patientsonACEinhibitorstheexpecteddecreaseinaldosteronedoesnotpersistsoaldosteroneantagonistslike
spironolactonecanbeusedbutconcernaboutcausinghyperkalemia.Sincealdosteroneplaysaroleinremodelingand
fibrosis,aldosteroneantagonistshavebeenshowntodecreasemortality.Ifyouuseallthreediuretics(loop,thiazide,
andaldosteroneantagonist)thenyouwillblockmostNathatisdeliveredtotheloopofHenle.

B. RenalFunction

Asaresultoftheincreaseinsodiumexcretion,oneofthecomplicationsofdiureticsisoverdiuresis,whichresultsin
decreasedpreloadleadingtoadecreaseincardiacoutput.Oneofthefirstmanifestationsofthedecreaseincardiac
outputisanincreaseintheBUN/creatinineratio.Ascardiacoutputdecreases,thisresultsinfurtherincreasesinAII
andSNStomaintainbloodpressure.Theincreaseinthesehormonesincreasesefferentarteryconstrictionand
increasesfiltrationfraction.TheincreasedAll,SNS,andincreasedfiltrationfraction(increasesperitubularoncotic
pressureintheproximaltubule)allcauseincreasedproximalreabsorptionofNaandH20.Theincreasedsodiumand
H20reabsorptionwillresultinincreasedureareabsorption.Amountureaexcreted=(PureaxGFR)reabsorption.In
ordertomaintainureabalancethebodyincreasesPurea.Byincreasingthefilteredloadofureathiswillallownormal
ureaexcretionevenwithincreasedreabsorption.Asaresultoftheureaclearance(amountureaexcreted/Purea)being
reducedmorethancreatinineclearance,theBUNincreasesmorethancreatinineBUN/Crratio.SincePlasma
urea=amountexcreted/clearanceurea,increasedureaexcretion(GIbleed,catabolicstate,prednisonetherapy,and
highproteindietwillalsoincreasetheBUN/creatininelevel.

III.ACEInhibitors

A.RenalFunction

OnewouldanticipatethatgivingACEinhibitorswoulddecreaserenalfunctionasaresultofdecreasingAll
constrictionoftheefferentartery,leadingtoadecreasedfiltrationfraction,thuscausingadecreasedGFR.Fortunately
ACEinhibitorsinpatientswithheartfailurewithreducedEFcardiacoutputusuallyimproves(intheshorttermdueto
decreasedafterloadandlongtermdecreasedremodeling).InmostpatientswithCHFwhoarestartedonanACEIthere
isnochangeinrenalfunction.AnexamplewouldbeapatientwithCHFhasarenalplasmaflow400cc/minandGFR
100cc/minwithFF%=100cc/minx100/400cc/min=25%.AfterbeinggivenACEinhibitorthefiltrationfraction
decreasesto20%,butifrenalplasmaflowincreasedto500cc/min,theGFRwouldbeunchangedat100cc/minFF=
100cc/minx100/500cc/min=20%.Insomepatientsthereisaslightdecreaseinrenalfunction.Intheprevious
example,ifafterbeingstartedonACEI,renalplasmaflowonlyincreasedfrom400cc/minto450cc/min,thenwitha
filtrationfractionof20%GFRwouldbe90cc/min(slightdecreasefrom100cc/minbeforebeinggivenanACE
inhibitor).Ingeneral,ifthecreatinineincreases<0.4mg/dL,afterbeingstartedonanACEI,youshouldcontinuethe
ACEinhibitor.

Apotentialreasonforadeclineinrenalfunctionisifthepatienthasbeenoverdiuresed(seeabove).Thisresultsina
fallinfillingpressuresandafurtherdecreaseincardiacoutput.ThesystemicvasodilationafterbeinggivenanACE
inhibitormaynotimprovecardiacoutput,butmayleadtoasignificantdropinarterialpressure.Thisfallinmean
arterialpressurecombinedwiththedropinglomerularpressureduetovasodilationoftheefferentarterycausesrenal
functiontodeteriorate.
AnotherconsiderationwhenpatientsrenalfunctiondecreaseswhileonACEinhibitorsisrenalarterystenosis.
PatientswithRASneedtoconstricttheefferentarteryinsettingofalowflowstateandlowafferentpressuresecondary
tothestenosis.IfonanACEinhibitorthentheywouldbeunabletoconstricttheefferentarterycausingadecreasein
renalfunction.

B. Hyperkalemia

HyperkalemiaisapotentialsideeffectofACEinhibitorsinpatients(especiallydiabetics)withcongestiveheartfailure.
Followingarepotentialreasons:
DecreasedfilteredloadofKifchronickidneydisease

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 DecreaseddeliveryofNatocollectingductduetoincreasedproximalNareabsorption
Possiblyunderlyinghyporeninhypoaldosteronism(typeIVRTA,especiallyindiabetics)
ACEIdecreasealdosteronelevels

Potentialtherapiesifitdevelopsinclude:
IffluidoverloadedgiveloopdiuretictoblockNaKClsymporter,whichdeliversmoreKandNato
collectingduct
IfmetabolicacidosisadministerNaHCO3andloopdiuretictoincreaseNadelivery
DecreaseoralintakeofK
LowerdoseofACEI

InsomepatientswithhyperkalemiayouneedtodiscontinueACEIifthereisreducedejectionfractionandgivenitrates
plushydralazine.

TwodrugsthatexchangeKwithcalcium(zircomium)andhydrogenandsodium(patiromer)maybeusefulonce
approved.Thereisalsoanewdrugthatdirectlybindspotassium

IV.AVPreceptorantagonists

TheV2receptorblockerTolvaptanhasbeenshowninstudiestoimproveserumsodiumbutduetopotentialliver
toxicity,theFDAhasonlyapprovedthemfor1monthduration

V. CardiorenalSyndrome

Cardiorenalsyndromesareaseriesofdisordersoftheheartandkidneys,wherebyacuteorchronicdysfunctionin
oneorganmayinduceacuteorchronicdysfunctionoftheother.Atypicalhistoryofcardiorenalsyndromeisa
patientwhohasadeclineinrenalfunctionwhileattemptingtodiurese,buthasdefiniteevidenceofbeingfluid
overloaded(tachyphea,crackles,edema,andelevatedjugularvenouspressure).Classicteachinghasbeenthat
patientswithCHFneedhigherfillingpressuresanddiuresisdecreasescardiacoutput,whichthenworsensrenal
function.Infact,patientsstrokevolumeismaximalatnearnormallevelsofleftventricularfillingpressuresfor
mostpatientswithchronicdilatedheartfailure.Thehigherfillingpressurescancauseincreasedwallstressand
causefunctionalmitralregurgitation(duetoadilatedmitralannulussecondarytoleftventriculardilation),which
worsensforwardstrokevolume.Alsoasshownbelowthepressuremaybesohighthatthepatientisonthe
descendinglimboftheStarlingCurve.AtthispointACEinhibitorswouldnothelpincreasestrokevolumebut
preventthekidneyfromtryingtocompensateforlowflowstate.Whenrenalfunctiondeclinesandthepatientis
stillclinicallyvolumeoverloadedcontinueddiuresismayresultinrenalfunctiondecliningandrequiringdialysis.
Arecentstudy(Dec,2012)showedcontinueddiuresisissuperiortoremovingfluidbyamachine(called
ultrafiltration).AfterdiuresisandrenalfunctionimprovesrestartACEIsincemaybebeneficial

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VI.Anemia

InpatientswithCHF(bothHFREFandHFPEF)thepresenceofanemia(25%ofpatients)isassociatedwith
reducedexercisecapacity(decreasedpeakoxygenconsumptionVO2),greaterhospitalreadmissionrates,higher
BNPlevels&increasedmortality(notsureifcauseandeffectorassociation).ThemechanismofanemiainCHF
isduetoacombinationofpotentialfactors:

Heartfailurecancauseanemiaofchronicinflammation
Irondeficiency(storesabsentorfunctionaldeficiency)hasrecentlybeendescribedasbeing
presentinupto20%ofpatientswithheartfailureduetoREFrelatedtoacombinationof
decreasednutrition,increasedhepcidinblockingduodenalironabsorption,anddecreased
expressionofferroproteinwhichpreventsthereleaseofironfromtotalbodystores(iron
restrictederythropoiesis).AlsotheremaybebloodlossfromASAanduremicgastritis.Some
patientsareirondeficientwithoutanemia.
Dilutionalaffectduetoincreasedplasmavolumecanbesignificantwhenfluidoverloaded
DecreasedEPOifconcomitantrenaldiseaseandACEIalsodecreaseEPOlevels

IfanemiaissevereitmayalsoprecipitateheartfailureduetotheneedtoincreaseCO.Ingeneralinpatientswith
mildanemia>30theycancompensatebyincreasingtissueextractionieloweringmixedvenousO2Unclearif
treatmentwithEPOwilldecreasemortalitybutitdoesincreaseexercisecapacity

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