©2013 MFMER | slide-1

Biomarkers of AKI:Kidney Troponin

Kianoush Kashani, MDAssistant Professor in Internal Medicine Consultant Division of Nephrology and HypertensionConsultant Division of Pulmonary and Critical CareProgram Director – Critical Care FellowshipMayo Clinic Multidisciplinary Simulation Center (MCMSC)kashani.kianoush@mayo.edu

©2013 MFMER | slide-2

Therapeutic Window

Himmelfarb et al: Clin J Am Soc Nephrol 3:962, 2008

High Risk

Volume ResponsiveAKI

Volume UnresponsiveAKI

Therapeutic Window

Kidney FunctionMortality

BiomarkersSensitive Traditional

HypervolemiaEuvolemia

Hypovolemia

©2013 MFMER | slide-3

Kidney Troponin

Period ACS AKI

1960s LDH Serum creatinine

1970s CPK, myoglobin Serum creatinine

1980s CK-MB Serum creatinine

1990s Troponin T Serum creatinine

2000s Troponin I Serum creatinine

• Developed multiple therapies

• mortality

• Supportive therapy

• High mortality

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Serum and urinary cystatin C

• 13KDa protein • Synthesized and released into plasma by all

nucleated cells• Still dependent on lean body mass

• (MacDonald, AJKD, 48(5) 712-719, 2006)

• Serum cystatin C freely filtered (small and non-ionic)• More sensitive than Scr as marker of GFR

• Cystatin C catabolized in PT• Tubular damage appearance in urine

Won K et al, Curr Opin Crit Care, 10:476-482, 2004

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Cystatin C

Cystatin C

Obesity and Waste circumference

HyperthyroidGlucocorticoid use

Smoker

Non-HispanicWhite

Male

IncreasedCRP

Madero, et al; CO Neph HTN. 18:258–263. 2009

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Cystatin C and mortality• N = 845 ICU patients

• Based on RIFLE criteria

• 271 AKI; 562 non-AKI

• Cystatin C and mortality related in both cohorts• Stronger in patients without AKI

Bell et al. Nephrol Dial Transplant (2009) 1 of 7

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Cystatin C and mortality

Bell et al. Nephrol Dial Transplant (2009) 1 of 7

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Neutrophil Gelatinase-Associated Lipocalin (NGAL)

Won K: Curr Opin Crit Care 10:476, 2004Mishra J et al: JASN 14:534, 2003

• Lipocalin superfamily• Markedly up-regulated in early post-ischemic

kidney in proliferating PT cells• NGAL in plasma and urine

•Marker of AKI•Appears in urine within 3 hours of ischemic injury and cisplatin exposure

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NGAL 2-3 Hours After CPB as the Predictor of AKI

Haase-Fielitz et al: NDT, May 27, 2009

Timing of NGAL AUC-ROC toPatients Creatinine Timing of postop measurement predict AKI

Reference (no.) Setting increase creatinine increase (after end of CPB) (plasma/urine)

Mishra et al 71 Paediatric >50% Within 5 days At 2 h 0.91/0.99

Dent et al 120 Paediatric >50% Within 5 days At 2 h 0.96/–

Bennett et al 196 Paediatric >50% Within 5 days At 2 h –/0.95

Wagener et al 81 Adult >50% Within 5 days At 3 h –/0.74

Wagener et al 426 Adult >50% or Within 2 days At 3 h –/0.60>0.3 mg/dL

Koyner et al 72 Adult >25% or need Within 3 days At ~2 h* 0.53/0.70for RRT

Haase-Fielitz et al 100 Adult >50% Within 5 days At ~2 h* 0.80/–

AKI definition

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NGAL and Cystatin C after CPB

Haase et al; Ann Thorac Surg 2009;88:124 –30. 2009

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NGAL predictive value

Nickolas et al; Ann Intern Med. 2008;148:810-819

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Angiopoietin 2:A prognostic marker?

• Angiopoietin-2 (Ang-2)• Circulating antagonistic ligand of the endothelial-specific Tie2

receptor• Increases capillary leak• Is not removed during dialysis

• n= 117 AKI at the time of initiation of RRT • Circulating Ang-2 correlated with:

• Impaired oxygenation• low mean arterial pressure• vasopressor dose • SOFA score

• Ang-2 significantly higher in non-survivors at day 0 and day 14 after initiation of RRT

Kumpers et al. Intensive Care Med (2010) 36:462–470

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Angiopoietin 2:A prognostic marker?

©2013 MFMER | slide-14

Kidney injury molecule-1 (KIM-1)

• Transmembrane protein • Not detectable in normal kidney tissue • Very high in dedifferentiated PT cells after

ischemic or toxic injury • Protein and mRNA up-regulated in 48-hr post

ischemic

Won et al, KI, 62: 237-244, 2002

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Rena-Stick Human Rena-Stick

Vaidya et al, Kidney International (2009) 76, 108–114

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Multi-bead assay

Vaidya et al, 2008 Clin. Trans Sci.

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Urinary and Serum Biomarkers for the Diagnosis Of AKI: An In-depth Review of the Literature

Vanmassenhove et al. Nephrol Dial Transplant (2012) 0: 1–20

©2013 MFMER | slide-18

Discovery Cohort in Search forNew Kidney Troponins

©2013 MFMER | slide-19

Vienna CohortAge 18

ICU + sepsisn=134

Duke CohortAge 18

At least 1 risk factorn=123

Mayo CohortAge 18

At least 1 risk factorn=265

Sapphire Study35 sites

(20 North American, 15 Europe)Age >21, critically ill3,no AKI (stage 2 or 3)4

n=744

No stage 1n=211

No stage 2n=83

AKI stage 3n=18

No AKIn=416

n=7285

16 patients excluded(2 withdrew consent,7 lost to follow-up,

7 with invalid or missing test results)

Within12 hr

Valid

atio

nD

isco

very

Best 2 markers

Pilotstudies

©2013 MFMER | slide-20

ROC-AUC – Comparison of Novel Markers

[TIMP-2] [IGFBP7]

Urine TIMP-2

Urine IGFBP7

Urine NGAL

Serum creatinine

Plasma NGAL

Plasma cystatin C

AUC (with 95% CI)

0.4 0.90.80.70.60.5

©2013 MFMER | slide-21

Sapphire Trial

©2013 MFMER | slide-22

Vienna CohortAge 18

ICU + sepsisn=134

Duke CohortAge 18

At least 1 risk factor1

n=123

Mayo CohortAge 18

At least 1 risk factor2

n=265

Sapphire Study35 sites

(20 North American, 15 Europe)Age >21, critically ill,no AKI (stage 2 or 3)

n=744

AKI stage 1n=211

AKI stage 2n=83

AKI stage 3n=18

No AKIn=416

n=728

16 patients excluded(2 withdrew consent,7 lost to follow-up,

7 with invalid or missing test results)

Within12 hr

Valid

atio

nD

isco

very

Best 2 markers

SapphireTrial

©2013 MFMER | slide-23

0

5

10

15

20

Urine KIM-1Sapphire Study

Con

cent

ratio

n (n

g/m

L)

ICU admission

Cardiovasc

ular

Cerebrovasc

ular

Sepsis

Respira

tory

Surgery

Diabetes

CHFCAD

CKDCOPD

Emphysema

Chronic bronch

itis

Respira

tory other

No RIFLE

RIFLE R

RIFLE I

RIFLE F

Subjects without AKI AKI subjects stratified by RIFLE

©2013 MFMER | slide-24

0

400

800

1,200

Urine NGALSapphire Study

Con

cent

ratio

n (n

g/m

L)

ICU admission

Cardiovasc

ular

Cerebrovasc

ular

Sepsis

Respira

tory

Surgery

Diabetes

CHFCAD

CKDCOPD

Emphysema

Chronic bronch

itis

Respira

tory other

No RIFLE

RIFLE R

RIFLE I

RIFLE F

Subjects without AKI AKI subjects stratified by RIFLE

©2013 MFMER | slide-25

0

5

10

15

20

25

30

Sapphire Study

ICU admission

Cardiovasc

ular

Cerebrovasc

ular

Sepsis

Respira

tory

Surgery

Diabetes

CHFCAD

CKDCOPD

Emphysema

Chronic bronch

itis

Respira

tory other

No RIFLE

RIFLE R

RIFLE I

RIFLE F

Subjects without AKI AKI subjects stratified by RIFLE

[TIM

P2][

IGFB

P7]

©2013 MFMER | slide-26

Sapphire Study

Tertile 1 Tertile 2 Tertile 30

2

4

6

8

10

P=0.00008

P<0.00003

Rel

ativ

e ris

k of

RIF

LE-I/

F

©2013 MFMER | slide-27

MAKE30

• Composite score

• Major adverse kidney events truncated in 30 days

1. Death

2. Need for RRT

3. Double Scr at 30 day or d/c

0.01 0.1 1 10 1000.0

0.2

0.4

0.6

0.8

1.0

[TIMP2][IGFBP7] ((ng/mL)2/1000)

Ris

k of

MA

KE

30

Ris

k fo

r AK

I (K

DIG

O s

tage

2-3

)

0.01 0.1 1 10 1000.0

0.2

0.4

0.6

0.8

1.0

Sensitivitythreshold

0.3

Specificitythreshold

2

©2013 MFMER | slide-28

Kidney Troponin:where are we?

Period ACS AKI

1960s LDH Serum creatinine

1970s CPK, myoglobin Serum creatinine

1980s CK-MB Serum creatinine

1990s Troponin T Serum creatinine

2000s Troponin I Serum creatinine

©2013 MFMER | slide-29

شكر ا

“The best interest of the patient is the only interest to be considered”

©2013 MFMER | slide-30

Questions & Discussion