Biomarkers of AKI:
Kidney Troponin
Kianoush Kashani, MD
Assistant Professor in Internal Medicine
Consultant Division of Nephrology and Hypertension
Consultant Division of Pulmonary and Critical Care
Program Director – Critical Care Fellowship
Mayo Clinic Multidisciplinary Simulation Center (MCMSC)
kashani.kianoush@mayo.edu
©2013 MFMER | slide-1
Therapeutic Window
Volume Responsive
AKI
Volume Unresponsive
AKI
High Risk
Hypervolemia
Euvolemia
Hypovolemia
Therapeutic Window
Sensitive
Biomarkers
Traditional
Mortality
Kidney Function
Himmelfarb et al: Clin J Am Soc Nephrol 3:962, 2008
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Kidney Troponin
Period
ACS
AKI
1960s
LDH
Serum creatinine
1970s
1990s
multiple
CK-MB
therapies
•  mortality
Troponin T
Serum creatinine
• Supportive
therapy
Serum creatinine
• High mortality
Serum creatinine
2000s
Troponin I
Serum creatinine
1980s
myoglobin
• CPK,
Developed
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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
Male
Obesity and Waste
circumference
Non-Hispanic
White
Cystatin C
Smoker
Hyperthyroid
Increased
Glucocorticoid use
CRP
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)
• 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
Won K: Curr Opin Crit Care 10:476, 2004
Mishra J et al: JASN 14:534, 2003
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NGAL 2-3 Hours After CPB as the Predictor of AKI
AKI definition
Setting
Creatinine
increase
Timing of postop
creatinine increase
Timing of NGAL
measurement
(after end of CPB)
AUC-ROC to
predict AKI
(plasma/urine)
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
>0.3 mg/dL
Within 2 days
At 3 h
–/0.60
72
Adult
>25% or need
for RRT
Within 3 days
At ~2 h*
0.53/0.70
100
Adult
>50%
Within 5 days
At ~2 h*
0.80/–
Reference
Patients
(no.)
Mishra et al
Koyner et al
Haase-Fielitz et al
Haase-Fielitz et al: NDT, May 27, 2009
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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?
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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
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Discovery Cohort in Search for
New Kidney Troponins
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Discovery
Vienna Cohort
Age 18
ICU + sepsis
n=134
Duke Cohort
Age 18
At least 1 risk factor
n=123
Mayo Cohort
Age 18
At least 1 risk factor
n=265
Pilot
studies
Best 2 markers
Validation
Sapphire Study
35 sites
(20 North American, 15 Europe)
Age >21, critically ill3,
no AKI (stage 2 or 3)4
n=744
n=7285
No AKI
n=416
No stage 1
n=211
No stage 2
n=83
16 patients excluded
(2 withdrew consent,
7 lost to follow-up,
7 with invalid or
missing test results)
AKI stage 3
n=18
Within
12 hr
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ROC-AUC – Comparison of Novel Markers
[TIMP-2]  [IGFBP7]
Urine TIMP-2
Urine IGFBP7
Urine NGAL
Serum creatinine
Plasma NGAL
Plasma cystatin C
0.4
0.5
0.6
0.7
0.8
0.9
AUC (with 95% CI)
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Sapphire Trial
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Discovery
Vienna Cohort
Age 18
ICU + sepsis
n=134
Duke Cohort
Age 18
At least 1 risk factor1
n=123
Mayo Cohort
Age 18
At least 1 risk factor2
n=265
Best 2 markers
Validation
Sapphire Study
35 sites
(20 North American, 15 Europe)
Age >21, critically ill,
no AKI (stage 2 or 3)
n=744
n=728
No AKI
n=416
AKI stage 1
n=211
AKI stage 2
n=83
Sapphire
Trial
16 patients excluded
(2 withdrew consent,
7 lost to follow-up,
7 with invalid or
missing test results)
AKI stage 3
n=18
Within
12 hr
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Urine KIM-1
Sapphire Study
Concentration (ng/mL)
20
15
10
5
0
ICU admission
Subjects without AKI
AKI subjects stratified by RIFLE
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Urine NGAL
Sapphire Study
Concentration (ng/mL)
1,200
800
400
0
ICU admission
Subjects without AKI
AKI subjects stratified by RIFLE
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Sapphire Study
[TIMP2][IGFBP7]
30
25
20
15
10
5
0
ICU admission
Subjects without AKI
AKI subjects stratified by RIFLE
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Sapphire Study
Relative risk of RIFLE-I/F
10
P<0.00003
8
6
4
P=0.00008
2
0
Tertile 1
Tertile 2
Tertile 3
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MAKE30
• Composite score
Risk for AKI
(KDIGO stage 2-3)
1.0
3. Double Scr at
30 day or d/c
Risk of MAKE30
2. Need for RRT
0.6
Sensitivity
threshold
0.3
0.4
Specificity
threshold
2
0.2
0.0
0.01
1.0
• Major adverse kidney
events truncated in
30 days
1. Death
0.8
0.1
1
10
100
0.1
1
10
100
0.8
0.6
0.4
0.2
0.0
0.01
[TIMP2][IGFBP7] ((ng/mL)2/1000)
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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
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‫شكرا‬
“The best interest of the patient is the only interest to be considered”
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Questions & Discussion
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