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Kidney Stress Testing Lakhmir S. Chawla, MD Professor of Medicine Veterans Affairs Medical Center Washington DC

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Page 1: Kidney Stress Testing - Food and Drug Administration · Kidney Stress Testing LakhmirS. Chawla, MD ... Stress Test -Furosemide is not ... • FST is a novel functional assessment

KidneyStressTesting

Lakhmir S.Chawla,MDProfessorofMedicine

VeteransAffairsMedicalCenterWashingtonDC

Page 2: Kidney Stress Testing - Food and Drug Administration · Kidney Stress Testing LakhmirS. Chawla, MD ... Stress Test -Furosemide is not ... • FST is a novel functional assessment

Disclosures

• Nxstage Medical,AstuteMedical,andBaxterMedical.

• LaJollaPharmaceutical– Employer(Sabbatical)

Page 3: Kidney Stress Testing - Food and Drug Administration · Kidney Stress Testing LakhmirS. Chawla, MD ... Stress Test -Furosemide is not ... • FST is a novel functional assessment

StressTesting

• Foracutecoronarysyndrome(ACS)–• Severityofdiseaseifoftenconfirmedwithstresstesting– Doesthepatienthaveacriticallesion?– Treadmill?Dobutamine?

• MostcommonformsofAKIinvolvetubularinjury

Page 4: Kidney Stress Testing - Food and Drug Administration · Kidney Stress Testing LakhmirS. Chawla, MD ... Stress Test -Furosemide is not ... • FST is a novel functional assessment

GFRversusTime

GFR

24hourday7am 12p 7p

Page 5: Kidney Stress Testing - Food and Drug Administration · Kidney Stress Testing LakhmirS. Chawla, MD ... Stress Test -Furosemide is not ... • FST is a novel functional assessment

Fig.1

Normal Conditions Physiological StressPathological Stress

DrugsPregnancyExercise

HighaltitudeStressecho

DrugsPregnancy

Highprotein dietAgingHighCO

HypertensionSepsisAnemia

HemorrhageIschemia

DiabetesCKDAKI

C-RSyndromeHyperfiltration

Functional reserve utilization

Page 6: Kidney Stress Testing - Food and Drug Administration · Kidney Stress Testing LakhmirS. Chawla, MD ... Stress Test -Furosemide is not ... • FST is a novel functional assessment
Page 7: Kidney Stress Testing - Food and Drug Administration · Kidney Stress Testing LakhmirS. Chawla, MD ... Stress Test -Furosemide is not ... • FST is a novel functional assessment

GFR

ProteinConsumption(gms/kg)

0.250.5.751.01.251.52.0

BaselineGFR

MaximumGFRBoschLimit

RenalFunctionalReserve

Page 8: Kidney Stress Testing - Food and Drug Administration · Kidney Stress Testing LakhmirS. Chawla, MD ... Stress Test -Furosemide is not ... • FST is a novel functional assessment

Functioning Nephron mass (%)

180

120

0

G F

R (m

l/min

)

100 50 0

RFR-G

Baseline GFR

Stress GFR 7

6

5

4

3

2

1

0

sC

reat

inin

e (m

g/dl

)sCrea

Page 9: Kidney Stress Testing - Food and Drug Administration · Kidney Stress Testing LakhmirS. Chawla, MD ... Stress Test -Furosemide is not ... • FST is a novel functional assessment

TubularReserve?

Page 10: Kidney Stress Testing - Food and Drug Administration · Kidney Stress Testing LakhmirS. Chawla, MD ... Stress Test -Furosemide is not ... • FST is a novel functional assessment
Page 11: Kidney Stress Testing - Food and Drug Administration · Kidney Stress Testing LakhmirS. Chawla, MD ... Stress Test -Furosemide is not ... • FST is a novel functional assessment
Page 12: Kidney Stress Testing - Food and Drug Administration · Kidney Stress Testing LakhmirS. Chawla, MD ... Stress Test -Furosemide is not ... • FST is a novel functional assessment
Page 13: Kidney Stress Testing - Food and Drug Administration · Kidney Stress Testing LakhmirS. Chawla, MD ... Stress Test -Furosemide is not ... • FST is a novel functional assessment
Page 14: Kidney Stress Testing - Food and Drug Administration · Kidney Stress Testing LakhmirS. Chawla, MD ... Stress Test -Furosemide is not ... • FST is a novel functional assessment

KidneyReserveTesting

• GlomerularReserve– Canbetestedwithproteinloadingori.v. aminoacids

• TubularReserve• Canbetestedwithproteinloadingori.v. creatinine

• Doeslossofreservematter?– Revealsvulnerability– OpportunitytoIntervene– Examples:pre-diabetesanddiminishedFEV1

Page 15: Kidney Stress Testing - Food and Drug Administration · Kidney Stress Testing LakhmirS. Chawla, MD ... Stress Test -Furosemide is not ... • FST is a novel functional assessment

FurosemideInducedStressTest

-Furosemideisnotfiltered-Tightlyproteinbound-MustbeactivelysecretedbyHOAT-SecretedinS1-S3segmentsofPCT

ForAKI,aimtotesttubularintegrity

-specificallyPCT-S1,S2,andS3-TAL

StressTestinginAKI?

Page 16: Kidney Stress Testing - Food and Drug Administration · Kidney Stress Testing LakhmirS. Chawla, MD ... Stress Test -Furosemide is not ... • FST is a novel functional assessment

Hypothesis

• Renaltubularintegritycanbetestedwithafunctionaltest

• Theresponseorlackofresponsetofurosemideasmeasuredbyurineoutputmayindicateseverityoftubularinjurybeforeserumcreatinine andurineoutput

Page 17: Kidney Stress Testing - Food and Drug Administration · Kidney Stress Testing LakhmirS. Chawla, MD ... Stress Test -Furosemide is not ... • FST is a novel functional assessment

• TheprimaryoutcomewastheprogressiontoAKINstageIIIwithin14daysofFST

• ThesecondaryoutcomewasthecompositeofachievingstageAKINIIIordeathwithin14daysoftheFST.

Page 18: Kidney Stress Testing - Food and Drug Administration · Kidney Stress Testing LakhmirS. Chawla, MD ... Stress Test -Furosemide is not ... • FST is a novel functional assessment
Page 19: Kidney Stress Testing - Food and Drug Administration · Kidney Stress Testing LakhmirS. Chawla, MD ... Stress Test -Furosemide is not ... • FST is a novel functional assessment

UrineOutput ROCAUC(s.e.)OneHour 0.82(0.05)

TwoHours 0.87(0.05)

ThreeHours 0.86(0.05)

FourHours 0.86(0.05)

FiveHours 0.85(0.05)

SixHours 0.85(0.05)

FurosemideStressTestReceiverOperationCharacteristicsforProgressionto AKINStageIII

Page 20: Kidney Stress Testing - Food and Drug Administration · Kidney Stress Testing LakhmirS. Chawla, MD ... Stress Test -Furosemide is not ... • FST is a novel functional assessment

TotalUrineOutputover2hours

Sensitivity Specificity

<100ml 90.2% 60.0%

<200ml 87.1% 84.1%

<300ml 85.3% 88.0%

<400ml 66.7% 88.0%

<500ml 50.5% 88.0%

SensitivityandSpecificityofTwoHourUrineThresholdsforProgressiontoAKINStageIII

Page 21: Kidney Stress Testing - Food and Drug Administration · Kidney Stress Testing LakhmirS. Chawla, MD ... Stress Test -Furosemide is not ... • FST is a novel functional assessment
Page 22: Kidney Stress Testing - Food and Drug Administration · Kidney Stress Testing LakhmirS. Chawla, MD ... Stress Test -Furosemide is not ... • FST is a novel functional assessment
Page 23: Kidney Stress Testing - Food and Drug Administration · Kidney Stress Testing LakhmirS. Chawla, MD ... Stress Test -Furosemide is not ... • FST is a novel functional assessment

KeyPoints• Thefurosemidestresstest(FST)isfeasibleandwelltoleratedin

criticallyillpatientswithearlyAKI.• TheperformanceoftheFSTtopredicttheprimaryoutcomewas

robustandconsistentinbothcohorts,witharangeinROCAUCof0.82- 0.87.

• Patientsshouldbeeuvolemic beforeundertakinganytypeoffurosemidechallenge,andthatvolumereplacementismandatoryinpatientswhoarenotobviouslyvolumeoverloaded.

• FSTshouldbeconductedinanappropriateclinicalsettingwhereUO,heartrate,andbloodpressurecanbemonitoredfrequently.

• FSTisanovelfunctionalassessmentoftubularfunctionthatappearstohavegoodpredictivecapacitytoidentifythosepatientsthatwillprogresstoadvancedstageAKI.FurthervalidationstudiesoftheFSTarewarranted.

Page 24: Kidney Stress Testing - Food and Drug Administration · Kidney Stress Testing LakhmirS. Chawla, MD ... Stress Test -Furosemide is not ... • FST is a novel functional assessment

AKIDiagnostics

• Pre-testProbabilitySchemeswillimprovetheperformanceofAKIbiomarkers– RenalAngina– RiskBiomarker

• AKIStressTestingProvidesaFrameworkforConfirmatoryTesting

Page 25: Kidney Stress Testing - Food and Drug Administration · Kidney Stress Testing LakhmirS. Chawla, MD ... Stress Test -Furosemide is not ... • FST is a novel functional assessment

FSTandCKD?

Page 26: Kidney Stress Testing - Food and Drug Administration · Kidney Stress Testing LakhmirS. Chawla, MD ... Stress Test -Furosemide is not ... • FST is a novel functional assessment

FibrosisandandTubularFunction

• DegreeofFibrosisisonethebestpredictorsoflong-termkidneysurvival

Page 27: Kidney Stress Testing - Food and Drug Administration · Kidney Stress Testing LakhmirS. Chawla, MD ... Stress Test -Furosemide is not ... • FST is a novel functional assessment
Page 28: Kidney Stress Testing - Food and Drug Administration · Kidney Stress Testing LakhmirS. Chawla, MD ... Stress Test -Furosemide is not ... • FST is a novel functional assessment

Bechtel, Nature Medicine 16, 544–550 (2010) 5 azacytidine

Page 29: Kidney Stress Testing - Food and Drug Administration · Kidney Stress Testing LakhmirS. Chawla, MD ... Stress Test -Furosemide is not ... • FST is a novel functional assessment

Atubular Glomeruli in CKD

Behzad Najafian et al. JASN 2003;14:908-917

©2003 by American Society of Nephrology

Page 30: Kidney Stress Testing - Food and Drug Administration · Kidney Stress Testing LakhmirS. Chawla, MD ... Stress Test -Furosemide is not ... • FST is a novel functional assessment

FibrosisandandTubularFunction

• Hypothesis– FurosemidesecretioninpatientswithCKDisasurrogatefortubularfunctionalreserve

– TubularFunctionalReserveisrepresentativeofthedegreefibrosis

Page 31: Kidney Stress Testing - Food and Drug Administration · Kidney Stress Testing LakhmirS. Chawla, MD ... Stress Test -Furosemide is not ... • FST is a novel functional assessment

NextSteps

• ValidationofFSTinAKI• PilotStudiesofFSTinpatientsundergoingkidneybiopsy

• PilotstudiesofuseofAKIinthepredictionofDGFinkidneyallografttransplantation

• FSTinpatientswithadvancedCKD– attempttopredicttimeRRTinitiation

Page 32: Kidney Stress Testing - Food and Drug Administration · Kidney Stress Testing LakhmirS. Chawla, MD ... Stress Test -Furosemide is not ... • FST is a novel functional assessment

KidneyStressTesting

• KSTmayrevealastateof‘pre-CKD’• Renalreservetestinginconjunctionwithbiomarkerssuchasalbuminuriaandothersmayallowearlyintervention

• TubularstresstestingmaybeonbenefitinbothAKIandCKDforpredictingoutcomesandinformingcliniciansaboutoptimalintervention


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