the edema syndromes - budapest nephrology...

THE EDEMA SYNDROMESTHE EDEMA SYNDROMES

SOME COMMON EDEMA STATESSOME COMMON EDEMA STATES

Primary renalPrimary renalNa retentionNa retention

acute GNacute GN

Arterial Arterial UnderfillingUnderfilling

systolic failuresystolic failure

pericardial constrictionpericardial constriction

late cirrhosislate cirrhosis

IVC and/or lymphatic occlusionIVC and/or lymphatic occlusion

third space disordersthird space disorders

ControversialControversial

early cirrhosisearly cirrhosis

early early nephrosisnephrosis

NaNa++ BALANCEBALANCEQUANTITATIVE DILEMMASQUANTITATIVE DILEMMAS

VariableVariable FeNaFeNaNaNa++

(mEq)(mEq) (%)(%)

~ 3000~ 3000Total body NaTotal body Na++

~ 2200~ 2200extracellularextracellular

(140 mEq/L) (180 L/24 hrs)(140 mEq/L) (180 L/24 hrs)

Filtered Na load/24 hoursFiltered Na load/24 hours(P(PNaNa) X (GFR)) X (GFR) ~ 25000 ~ 25000

~ 1%~ 1%NaNa++ intake/24 hrsintake/24 hrs(~ 5(~ 5--6 gm)6 gm)

240240

THE EDEMA ODYSSEYTHE EDEMA ODYSSEYI. SOME EARLY LANDMARKSI. SOME EARLY LANDMARKS

1. 1. ““In heart failure . . . in consequence of low arterialIn heart failure . . . in consequence of low arterialpressure, the loss of fluids by the kidney ispressure, the loss of fluids by the kidney isdiminished. The ultimate result is diminished. The ultimate result is hydremichydremic plethora.plethora.””

Starling, 1896Starling, 1896


1. Starling (1896): 1. Starling (1896): ““hydremichydremic plethoraplethora””

2. 2. TigerstedtTigerstedt and Bergmann (1898): a saline extractand Bergmann (1898): a saline extractfrom kidneys, termed from kidneys, termed reninrenin,, raised raised b.pb.p..


1. Starling (1896): 1. Starling (1896): ““hydremichydremic plethoraplethora””

2. 2. TigerstedtTigerstedt and Bergmann (1898): and Bergmann (1898): reninrenin

3. 3. ““The kidneys react to changes in the volume ofThe kidneys react to changes in the volume ofthe circulating bloodthe circulating blood””((arterial receptors were implicit in Petersarterial receptors were implicit in Peters’’ argument)argument)

Peters (1935)Peters (1935)

THE EDEMA ODYSSEYTHE EDEMA ODYSSEYTHE CARDIAC EDEMA DEBATE: 1935THE CARDIAC EDEMA DEBATE: 1935--1945 1945

4. Harrison (1935) : backward failure4. Harrison (1935) : backward failure

““DyspneaDyspnea and edema . . . can both be accountedand edema . . . can both be accountedfor by the backfor by the back--pressure theory and are notpressure theory and are notexplicable on any other basisexplicable on any other basis””

Harrison (1935)Harrison (1935)

HARRISONHARRISON’’S S ““BACKWARD FAILUREBACKWARD FAILURE””DIASTOLIC DYSFUNCTIONDIASTOLIC DYSFUNCTION

DiastolicDiastolicdysfunctiondysfunction

Left

Ven

tric

ular

Pre

ssur

eLe

ft V

entr

icul

ar P

ress

ure

Left Ventricular VolumeLeft Ventricular Volume

EDEMAEDEMATHE CARDIAC EDEMA DEBATE: 1935THE CARDIAC EDEMA DEBATE: 1935--1945 1945

5. 5. ““The signs of a marked decrease in cardiacThe signs of a marked decrease in cardiacoutput . . . may be similar to that of shockoutput . . . may be similar to that of shock””

Stead and Ebert (1942)Stead and Ebert (1942)

6. Warren and Stead (1944)6. Warren and Stead (1944)

observation: CHF patients gain weightobservation: CHF patients gain weightbefore venous pressure risesbefore venous pressure rises

conclusion: conclusion: ““In congestive failure the cardiacIn congestive failure the cardiacoutput is inadequate . . . and theoutput is inadequate . . . and thekidneys are no longer able tokidneys are no longer able toexcrete saltexcrete salt””

WARREN AND STEADWARREN AND STEAD’’S S ““FORWARD FAILUREFORWARD FAILURE””PUMP FAILUREPUMP FAILURE

CHFCHFnormalnormal

Left

Ven

tric

ular

Pre

ssur

eLe

ft V

entr

icul

ar P

ress

ure

Left Ventricular VolumeLeft Ventricular Volume

THE EDEMA ODYSSEYTHE EDEMA ODYSSEYHORMONES AND EDEMA: 1945HORMONES AND EDEMA: 1945--1950 1950

7. 7. ““ReninRenin increases with a low cardiac outputincreases with a low cardiac outputdue to a decrease in blood available to thedue to a decrease in blood available to thekidney.kidney.””

A. J. Merrill (1946)A. J. Merrill (1946)

8. 8. LeutscherLeutscher (1950): (1950): ““The preliminary observations . . .The preliminary observations . . .indicate sodiumindicate sodium--retaining factors in the urine ofretaining factors in the urine ofsome cardiac or some cardiac or nephrosisnephrosis patientspatients””

THE EDEMA ODYSSEYTHE EDEMA ODYSSEYVOLUME RECEPTORS VOLUME RECEPTORS

9. The 9. The GauerGauer--Henry reflex (1947Henry reflex (1947--51):51):positive pressure breathing: positive pressure breathing: antidiuresisantidiuresisnegative pressure breathing: water negative pressure breathing: water diuresisdiuresis

conclusion: nonconclusion: non--osmotic ADH release driven byosmotic ADH release driven byleft left atrialatrial stretch receptor releasestretch receptor release

10. 10. HyponatremiaHyponatremia following following mitralmitral commisurotomycommisurotomy

THE EDEMA ODYSSEYTHE EDEMA ODYSSEYVOLUME RECEPTORS VOLUME RECEPTORS

11. Epstein (1953): 11. Epstein (1953): ““Circulating states in which kidneysCirculating states in which kidneystend to retain sodium are characterized by inadtend to retain sodium are characterized by inadequateequatefilling of the arterial tree.filling of the arterial tree.””

12. Homer Smith (1957): 12. Homer Smith (1957): ““Volume receptors are involvedVolume receptors are involvedin sodium conservation . . . Where these receptoin sodium conservation . . . Where these receptors arers arelocated is moot (the Cheshire cat hypothesis).located is moot (the Cheshire cat hypothesis).””

BARORECEPTORS: HOMER SMITHBARORECEPTORS: HOMER SMITH’’S S CHESHIRE CATCHESHIRE CAT

High SensitivityHigh Sensitivity Lower SensitivityLower Sensitivity IntrarenalIntrarenal HepaticHepatic

Portal veinPortal veinsinusoidalsinusoidal

? significance? significance

low pressure areaslow pressure areas

left atriumleft atriumthoracic veinsthoracic veins

high pressure areashigh pressure areas

carotid sinuscarotid sinusaortic archaortic arch

JGA JGA

HemodynamicHemodynamic changeschangesNa avidityNa avidity

DEPLETIONDEPLETIONTHE VOLUME REPLETION CASCADETHE VOLUME REPLETION CASCADE

AngiotensinAngiotensin IIII CatecholaminesCatecholamines

CNSCNS AldosteroneAldosterone

ThirstThirst Na retentionNa retentionHypoperfusionHypoperfusion

ADHADH

WaterWaterretentionretention

REPLETIONREPLETION

AtriopeptinAtriopeptin PGEPGE22NitricNitricOxideOxide

EndothelinsEndothelins

KEY FACTORS IN EDEMA STATESKEY FACTORS IN EDEMA STATES

PRECIPITATING FACTORSPRECIPITATING FACTORS MANDATORY REQUIREMENTMANDATORY REQUIREMENT

Deranged Starling ForcesDeranged Starling Forces


Altered Volume/Capacitance RatioAltered Volume/Capacitance Ratio

Primary Renal NaPrimary Renal Na++ AvidityAvidity

steadysteady--statestate

positive Napositive Na++ balancebalance

DERANGED STARLING FORCESDERANGED STARLING FORCESTHE STARLING EQUATIONTHE STARLING EQUATION

J = J = KKff ((∆∆ P P -- σσ ∆∆ ππ) ) vvThe equationThe equation

The termsThe terms JJvv = flow= flow

σσ = solute reflection coefficient= solute reflection coefficient((σσ = 0 : wholly permeable solute)= 0 : wholly permeable solute)((σσ = 1 : wholly impermeable solute)= 1 : wholly impermeable solute)

KKff = capillary permeability= capillary permeability∆∆ P = hydrostatic pressureP = hydrostatic pressure∆∆ ππ = = oncoticoncotic pressurepressure

DERANGED STARLING FORCESDERANGED STARLING FORCESσσ DISORDERSDISORDERS

SyndromeSyndrome

ARDSARDS

RhabdomyolysisRhabdomyolysis

BurnsBurns

Cyclical edemaCyclical edemasyndromesyndrome

AbnormalityAbnormality

leaky pulmonaryleaky pulmonarycapillariescapillaries

leaky muscleleaky musclecapillariescapillaries

leaky capillariesleaky capillariesloss of loss of cutaneouscutaneous

barrierbarrier

generalized capillarygeneralized capillaryleakleak

Net NaNet Na+ + BalanceBalance

++

varies c magnitude ofvaries c magnitude offluid sequestrationfluid sequestration

massive Namassive Na++ losseslosses

++

KEY FACTORS IN EDEMA STATESKEY FACTORS IN EDEMA STATES








SOME COMMON EDEMA STATESSOME COMMON EDEMA STATESPrimary renalPrimary renalNa retentionNa retention

acute GNacute GN










STARLING DERANGEMENTS (STARLING DERANGEMENTS (∆∆ P) WITH P) WITH ARTERIAL UNDERFILLINGARTERIAL UNDERFILLING

THE HEART FAILURE SYNDROMESTHE HEART FAILURE SYNDROMESFeaturesFeatures↓↓ contractility and EFcontractility and EF↑↑ endend--diastolic volumediastolic volume

demand > performancedemand > performance↓↓ volume/capacitance ratiovolume/capacitance ratio

↓↓ compliance and fillingcompliance and fillingnormal EFnormal EF““flashflash”” pulmonary edemapulmonary edema

LowLow--output Failureoutput Failure

HighHigh--output Failureoutput Failure

Diastolic failureDiastolic failure

LOW AND HIGH OUTPUT HEART FAILUREREDUCED ECV, BUT FOR DIFFERENT REASONS

ARTERIESVEINS

Normal

Lowoutputfailure

highoutputfailure

PATHOPHYSIOLOGY OF ARTERIAL PATHOPHYSIOLOGY OF ARTERIAL UNDERFILLINGUNDERFILLING

PATHOLOGIC SEQUENCEPATHOLOGIC SEQUENCE RESULT RESULT

HemodynamicHemodynamic response (minutes)response (minutes)

↑↑ Heart rateHeart rate↓↓ Capacitance (venous)Capacitance (venous)↑↑ Systemic resistanceSystemic resistance

(arterial)(arterial)

Renal Response (days)Renal Response (days)

NaNa++ avidityavidity

Local or systemic venousLocal or systemic venouspressure increasespressure increases

Reduced venousReduced venousarterial blood transferarterial blood transfer

Reduced effective Reduced effective circulating volumecirculating volume

HEART FAILURE: A SUICIDAL SYNDROMEHEART FAILURE: A SUICIDAL SYNDROME

““ ↓↓ filling . . . arterial treefilling . . . arterial tree””

NaNa++ avidityavidity

↑↑ preloadpreload

hemodynamichemodynamic changeschanges

↑↑ afterloadafterload

↑↑ end end -- diastolic volumediastolic volume

further further ↓↓ E. F. E. F.

PRINCIPAL SODIUMPRINCIPAL SODIUM--AVID SEGMENTSAVID SEGMENTSIN UNDERFILLINGIN UNDERFILLING

Normal Normal % Na Absorbed% Na Absorbed

60%60%

10%10%

5%5%

FactorsFactors↑↑ Na absorptionNa absorption

FFFFAA--IIIIcatecholscatechols

ADHADHaldoaldoANP resistance (?)ANP resistance (?)

ANP resistanceANP resistance

↑↑ TGFTGF

SegmentSegment

proximalproximal

late DCT; CCDlate DCT; CCD

IMCDIMCD

↓↓ ECV ECV

REDUCED ECV: GLOMERULAR AND HEMODYNAMIC REDUCED ECV: GLOMERULAR AND HEMODYNAMIC RESPONSERESPONSE

catecholaminescatecholamines AIIAII ADHADH endothelinendothelin II

↓↓↓↓ RBF, RBF, ↓↓ GFR GFR →→ ↑↑ FFFF

↑↑ net proximal absorptionnet proximal absorption

↓↓ distal Nadistal Na++ deliverydelivery

activation of JGA activation of JGA baroceptorsbaroceptors

reninrenin -- AIIAII

HH

HH++

ClCl

NaNa

NaNa

sugarssugarsamino acidsamino acidsPPii

2K2K

3Na3Na

[(Na) (3HCO[(Na) (3HCO33 )])]==

C. A.C. A.

GENERAL MODEL FOR PROXIMAL GENERAL MODEL FOR PROXIMAL TRANSPORTTRANSPORT

(HCO(HCO22 •• F)F)--

STARLING DERANGEMENTS (STARLING DERANGEMENTS (∆∆ P) WITH P) WITH ARTERIAL UNDERFILLINGARTERIAL UNDERFILLING

ACTIVATION OF TGFACTIVATION OF TGFNormalNormal

FiltrationFiltration

Proximal absorptionProximal absorption

Thick limb absorptionThick limb absorption

Macula Macula densadensa deliverydelivery

ReninRenin

↑↑ ATPATP↑↑ adenosineadenosine

increasesincreases

AA--IIII AA--IIII

reducesreduces



60%60%

10%10%

5%5%


AA--IIIIcatecholscatechols

ADHADHaldoaldo


↑↑ TGFTGF

SegmentSegment

proximalproximal


IMCDIMCD

THE CD PRINCIPAL CELLTHE CD PRINCIPAL CELL

ATPaseATPaseNaNa2K2K

KK

ClCl

ClCl

KK

3Na3Na

HH22OO

amilorideamiloride

•• ADH, via ADH, via cAMPcAMP↑↑ ENaCENaC↑↑ AQPAQP22

•• Aldo, via nuclearAldo, via nuclearreceptorsreceptors↑↑ ENaCENaC

-- 20 mV20 mV -- 80 mV80 mV 0 mV0 mV

ENaCEpithelial Na Channel • Each α subunit :

amiloride-sensitiveNa channel

• β and γ subunits:↑surface delivery of ENaC

• Liddle's syndrome:β subunit mutation

• pseudohypoaldo I:α or β subunit mutation

• ARDS :α subunit mutation

News in Physiol. Sci.12:55, 1997

AQUAPORIN 2: AGRE'S HOURGLASS MODELAQUAPORIN 2: AGRE'S HOURGLASS MODEL

AgreAgre, , et al.et al.JBC JBC 269:14648, 1994269:14648, 1994



60%60%

10%10%

5%5%


AA--IIIIcatecholscatechols

ADHADHaldoaldo


↑↑ TGFTGF

SegmentSegment

proximalproximal


IMCDIMCD

THE IMCDTHE IMCD

ATPaseATPase3Na3Na

2K2K

-- 5 mV5 mV

ClCl

NaNa

CHARACTERISTICSCHARACTERISTICS

•• Classical Classical UssingUssingepitheliumepithelium

•• AldosteroneAldosterone-- sensitivesensitive•• Major locus forMajor locus for

ANPANP-- natriuresisnatriuresis•• ANPANP--resistance inresistance in

cirrhosis, CHF,cirrhosis, CHF,nephroticnephrotic syndromesyndrome

cGMPcGMPPDIEPDIE

GMPGMP

ANPANP NONO

MAJOR ACTIONS OF ANPMAJOR ACTIONS OF ANP

•• ↓↓ Afferent arteriolar resistanceAfferent arteriolar resistance

•• ↓↓ Aldo effect in CCDAldo effect in CCD

•• ↓↓ IMCD NaIMCD Na++ absorptionabsorption

ANP RESISTANCEANP RESISTANCE

DisorderDisorder

Experimental CHFExperimental CHF

Experimental cirrhosisExperimental cirrhosis

Experimental Experimental nephrosisnephrosis

MechanismMechanism

↓↓ ANPANPAA densitydensity((AJP AJP 265:F119, 1993)265:F119, 1993)

↑↑ cGMPcGMP -- PDIEPDIE((AJPAJP 271:F3, 1996)271:F3, 1996)

↑↑ cGMPcGMP -- PDIEPDIE((AJPAJP 271:F3, 1996)271:F3, 1996)



acute GNacute GN










EDEMATOUS STATES: CIRRHOSISEDEMATOUS STATES: CIRRHOSIS








Classical Classical UnderfillingUnderfilling TheoryTheorySinusoidal Portal HypertensionSinusoidal Portal Hypertension

Lymph Formation > Lymph RemovalLymph Formation > Lymph Removal

AscitesAscites FormationFormation

Reduction of Plasma VolumeReduction of Plasma Volume

Activation of Activation of ReninRenin -- AngiotensinAngiotensin, , Sympathetic Nervous System and AVPSympathetic Nervous System and AVP

SecretionSecretion

SODIUM ANDSODIUM ANDWATER RETENTIONWATER RETENTION

OVERFLOW THEORYOVERFLOW THEORYSinusoidal Portal HypertensionSinusoidal Portal Hypertension

Hepatic PressureHepatic PressureReceptorsReceptors

PRIMARY SODIUM ANDPRIMARY SODIUM ANDWATER RETENTIONWATER RETENTION

Plasma Volume ExpansionPlasma Volume Expansion

AscitesAscites FormationFormation

CIRRHOSISCIRRHOSISUNDERFILLING VS. OVERFILLINGUNDERFILLING VS. OVERFILLING

MassryMassry and and GlassockGlassockTextbook of NephrologyTextbook of NephrologyEd. 3; Fig. 34Ed. 3; Fig. 34--44

CIRRHOSISCIRRHOSISOVERFILLINGOVERFILLING ARGUMENTS IN EARLY DISEASEARGUMENTS IN EARLY DISEASE

1.1. In In somesome experimental cirrhosis:experimental cirrhosis:NaNa+ + retention precedes retention precedes ascitesascites

2.2. In preIn pre--asciticascitic cirrhosis:cirrhosis:↑↑ cardiac outputcardiac output↑↑ blood volumeblood volume↑↑ splanchnicsplanchnic poolingpooling

3.3. In preIn pre--asciticascitic cirrhosis:cirrhosis:nlnl reninreninnlnl aldoaldo

CIRRHOSISCIRRHOSISKEY STRUCTURAL DERANGEMENTSKEY STRUCTURAL DERANGEMENTS

NormalNormal CirrhoticCirrhotic

Symmetrically placedSymmetrically placedhepatic lobuleshepatic lobules

Portal triad Portal triad →→ sinusoidsinusoid→→ central veincentral vein

Asymmetrically distributedAsymmetrically distributedregenerating nodulesregenerating nodules

Regenerating nodulesRegenerating nodulesno central veinno central veinsinusoidal compressionsinusoidal compression

CIRRHOSISCIRRHOSISCONSEQUENCES OF ABNORMAL REGENERATIVE CONSEQUENCES OF ABNORMAL REGENERATIVE

NODULESNODULES

high inflow resistancehigh inflow resistance

↓↓ portal / arterial flowportal / arterial flow

portal hypertensionportal hypertension

splanchnicsplanchnic poolingpooling

compression of adjacent sinusoidscompression of adjacent sinusoids

↑↑ intrasinusoidalintrasinusoidal pressurepressure

ascitesascites(a weeping liver)(a weeping liver)

SOME COMMON EDEMA STATESSOME COMMON EDEMA STATESPrimary renalPrimary renalNa retentionNa retention

acute GNacute GN










NEPHRITIC AND NEPHROTIC SYNDROMESNEPHRITIC AND NEPHROTIC SYNDROMESGENERAL FEATURESGENERAL FEATURES

Acute NephritisAcute Nephritis NephroticNephrotic SyndromeSyndrome

HematuriaHematuriaProteinuriaProteinuriaHypoalbuminemiaHypoalbuminemia↓↓ GFRGFRHypertensionHypertensionDilutionalDilutional anemiaanemia

++++++++++++

++++++++++++++++++++

++--

++--++++++++++++++++

++--++--++--

THE NEPHROTIC SYNDROMETHE NEPHROTIC SYNDROMETHE EDEMA CONTROVERSYTHE EDEMA CONTROVERSY

““UnderfillingUnderfilling””ProteinuriaProteinuria and and hypoalbuminemiahypoalbuminemia

Reduced effective volumeReduced effective volume

Activation of: Activation of: ReninRenin--angiotensinangiotensin systemsystem

Sympathetic nervous systemSympathetic nervous systemAVP secretionAVP secretion

Sodium and water retentionSodium and water retention

EDEMA FORMATIONEDEMA FORMATION

““OVERFILLINGOVERFILLING””Primary renal sodium retentionPrimary renal sodium retention

Increased plasma volumeIncreased plasma volumeand arterial pressureand arterial pressure

HypoalbuminemiaHypoalbuminemia

EDEMA FORMATIONEDEMA FORMATION

Adapted fromAdapted fromMassryMassry and and GlassockGlassockTextbook of NephrologyTextbook of NephrologyEd. 3; Fig. 34Ed. 3; Fig. 34--44

NEPHROTIC SYNDROMENEPHROTIC SYNDROMEARGUMENTS FAVORING PRIMARY RENAL Na AVIDITYARGUMENTS FAVORING PRIMARY RENAL Na AVIDITY

1.1. Congenital Congenital hypoalbuminemiahypoalbuminemia: generally edema: generally edema--freefree

2.2. NephroticNephrotic edema can resolve edema can resolve ⎯⎯cc hypoalbuminemiahypoalbuminemia

3.3. ↑↑ cGMPcGMP--PDIE levels; PDIE levels; ↓↓ ANP levels with edemaANP levels with edema

IMCD: putative locusIMCD: putative locusfor primary Na avidityfor primary Na avidity

THE NEPHROTIC SYNDROMETHE NEPHROTIC SYNDROMEA CLINICAL SPECTRUMA CLINICAL SPECTRUM

1. 1. NephroticNephrotic syndrome is a clinical and syndrome is a clinical and hemodynamichemodynamicspectrum:spectrum:

↑↑ blood volumeblood volume ↓↓ or normal volumeor normal volumeolder patients younger older patients younger patientspatients

glomerularglomerular inflammationinflammation little inflammationlittle inflammation↓↓ GFR normal GFRGFR normal GFR↑↑ b. p. normal b. p.b. p. normal b. p.

↓↓ reninrenin/AII /AII nlnl or or ↑↑ aldoaldo..

2. Most 2. Most nephroticsnephrotics without without glomerularglomerular inflammationinflammationact act underfilledunderfilled..

THE NEPHROTIC SYNDROMETHE NEPHROTIC SYNDROMESOME GENERAL CONCLUSIONSSOME GENERAL CONCLUSIONS

1. Primary renal Na1. Primary renal Na++ retention occurs:retention occurs:ANP resistanceANP resistance? other factors? other factors

2. 2. ↓↓ albumin contributes to vascular/interstitialalbumin contributes to vascular/interstitialdistribution of accumulated fluiddistribution of accumulated fluid

3. 3. ↓↓ GFR: GFR: resemble nephritic syndrome resemble nephritic syndrome NL GFR: NL GFR: resemble resemble ““purepure”” nephrosisnephrosis

EDEMATOUS STATESEDEMATOUS STATES





Primary Renal NaPrimary Renal Na+ + AvidityAvidity



THE NEPHRITIC SYNDROMETHE NEPHRITIC SYNDROMEACUTE GN ACUTE GN →→ PRIMARY NaPRIMARY Na++ RETENTIONRETENTION

1. 1. GlomerularGlomerular InflammationInflammation↓↓ KKffNormal RPFNormal RPF

2. 2. ↓↓ GFR GFR ↓↓ axial delivery axial delivery ↑↑ proximal Naproximal Na++ absorptionabsorption

3. Continued Na3. Continued Na++ intake:intake:Plasma expansion Plasma expansion dilutionaldilutional edemaedemaHypertension edema; pulmonary cHypertension edema; pulmonary congestionongestion↑↑ ANPANP↓↓ reninrenin / / aldosteronealdosterone

↓↓ FFFF



acute GNacute GN










KEY FACTORS IN EDEMA FORMATIONKEY FACTORS IN EDEMA FORMATION








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