©2013 mfmer | slide-1 biomarkers of aki: kidney troponin kianoush kashani, md assistant professor...

©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)[email protected]

mailto:[email protected]


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

Hypervolemia

Euvolemia

Hypovolemia


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


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


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


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


Cystatin C and mortality

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


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


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


NGAL and Cystatin C after CPB

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


NGAL predictive value

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


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


Angiopoietin 2:A prognostic marker?


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


Rena-Stick Human Rena-Stick

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


Multi-bead assay

Vaidya et al, 2008 Clin. Trans Sci.


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


Discovery Cohort in Search forNew Kidney Troponins


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

Val

idat

ion

Dis

cove

ry

Best 2 markers

Pilotstudies


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


Sapphire Trial


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

Val

idat

ion

Dis

cove

ry

Best 2 markers

SapphireTrial


0

5

10

15

20

Urine KIM-1Sapphire Study

Con

cent

ratio

n (n

g/m

L)

ICU admission

Cardiova

scular

Cerebro

vasc

ular

Sepsis

Respira

tory

Surgery

Diabetes

CHFCAD

CKDCOPD

Emphysema

Chronic

bronch

itis

Respira

tory other

No RIF

LE

RIFLE R

RIFLE I

RIFLE F

Subjects without AKI AKI subjects stratified by RIFLE


0

400

800

1,200

Urine NGALSapphire Study

Con

cent

ratio

n (n

g/m

L)

ICU admission

Cardiova

scular

Cerebro

vasc

ular

Sepsis

Respira

tory

Surgery

Diabetes

CHFCAD

CKDCOPD

Emphysema

Chronic

bronch

itis

Respira

tory other

No RIF

LE

RIFLE R

RIFLE I

RIFLE F



0

5

10

15

20

25

30

Sapphire Study

ICU admission

Cardiova

scular

Cerebro

vasc

ular

Sepsis

Respira

tory

Surgery

Diabetes

CHFCAD

CKDCOPD

Emphysema

Chronic

bronch

itis

Respira

tory other

No RIF

LE

RIFLE R

RIFLE I

RIFLE F


[TIM

P2]

[IG

FB

P7]


Sapphire Study

Tertile 1 Tertile 2 Tertile 30

2

4

6

8

10

P=0.00008

P<0.00003

Re

lativ

e r

isk

of R

IFL

E-I

/F


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


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


�شكر ًا

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


Questions & Discussion

©2013 mfmer | slide-1 biomarkers of aki: kidney troponin kianoush kashani, md assistant professor...

Documents

mgdlkoyner et

aki definition2013 mfmer

aki cystatin c

cpb haase et

mishra j et

wagener et al426adult50

serum cystatin c

bennett et al196paediatric50