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©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
Hypervolemia
Euvolemia
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
©2013 MFMER | slide-4
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
©2013 MFMER | slide-5
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
©2013 MFMER | slide-6
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
©2013 MFMER | slide-7
Cystatin C and mortality
Bell et al. Nephrol Dial Transplant (2009) 1 of 7
©2013 MFMER | slide-8
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
©2013 MFMER | slide-9
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
©2013 MFMER | slide-10
NGAL and Cystatin C after CPB
Haase et al; Ann Thorac Surg 2009;88:124 –30. 2009
©2013 MFMER | slide-11
NGAL predictive value
Nickolas et al; Ann Intern Med. 2008;148:810-819
©2013 MFMER | slide-12
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
©2013 MFMER | slide-13
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
©2013 MFMER | slide-15
Rena-Stick Human Rena-Stick
Vaidya et al, Kidney International (2009) 76, 108–114
©2013 MFMER | slide-16
Multi-bead assay
Vaidya et al, 2008 Clin. Trans Sci.
©2013 MFMER | slide-17
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
Val
idat
ion
Dis
cove
ry
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
Val
idat
ion
Dis
cove
ry
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
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
©2013 MFMER | slide-24
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
Subjects without AKI AKI subjects stratified by RIFLE
©2013 MFMER | slide-25
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
Subjects without AKI AKI subjects stratified by RIFLE
[TIM
P2]
[IG
FB
P7]
©2013 MFMER | slide-26
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
©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
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