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©2013 Astute Medical, Inc. PN 0138 Rev B 2013/03/19
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A Rigorous Discovery-Validation Path Was Taken
Discovery Study340 proteins analyzed
(including KIM-1, urine NGAL, plasma NGAL, Cystatin-C, IL-18,
pi-GST, and L-FABP)
Validation StudyPrimary Endpoint: moderate to
severe AKI (KDIGO stage 2-3) within 12 hours of sample collection
(based on serum creatinine and hourly urine output)
Sapphire Study35 sites
(20 North America, 15 Europe)Age > 21, Critically Ill3, no AKI (Stage 2 or 3)4
N = 744
Vienna CohortAge > 18,
in ICU + SepsisN = 134
Duke CohortAge > 18,
At least 1 risk factor1
N = 123
Mayo CohortAge > 18,
At least 1 risk factor2
N = 265
N = 7285
No AKIN = 416
AKI Stage 1N = 211
AKI Stage 2N = 83
AKI Stage 3N = 18
16 patients excluded (2 withdrew consent, 7
lost to follow-up, 7 with invalid or missing test
results)
Best Two Markers
Dis
cove
ryV
alid
atio
n
Within12 hrs
Kashani et al. Critical Care 2013, 17:R25
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Revolutionary Biomarkers Were Identified
• Biomarkers identified through hypotheses based on AKI pathophysiology
• 340 candidate biomarkers identified
• Biomarkers ranked by ability to predict development of AKI RIFLE I or F within 12 to 36 hours
• All possible combinations of two-four biomarkers (novel or previously described) were ranked
• Top performing biomarkers identified– Tissue Inhibitor of Metalloproteinases-2 (TIMP-2)– Insulin-like Growth Factor Binding-Protein 7 (IGFBP7)
Kashani et al. Critical Care 2013, 17:R25
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TIMP-2 and IGFBP7 Outperform Existing Biomarkers
AUC for [TIMP-2]•[IGFBP7] was significantly greater than any existing biomarkers
Kashani et al. Critical Care 2013, 17:R25
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TIMP-2 and IGFBP7 Work Well In Important Subgroups
Sepsis Surgery
Kashani et al. Critical Care 2013, 17:R25
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[TIMP-2]•[IGFBP7] Has a Compelling Specificity Profile
Urine NGAL (ng/mL) [TIMP-2]•[IGFBP7] ((ng/mL)2 / 1000)
Kashani et al. Critical Care 2013, 17:R25
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[TIMP-2]•[IGFBP7] Has a Compelling Specificity Profile
Urine KIM-1 (ng/mL) [TIMP-2]•[IGFBP7] ((ng/mL)2 / 1000)
Kashani et al. Critical Care 2013, 17:R25
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MAKE30 Analysis Shows TIMP-2 and IGFBP7 Are Clinically Meaningful Biomarkers
0
0.1
0.2
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0.4
0.5
0.6
0.7
0.8
0.9
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Risk
for A
KI (K
DIGO
Sta
ge 2
-3)
A
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
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0.01 0.1 1 10 100
Risk
for M
AKE3
0
[TIMP-2]•[IGFBP7] ((ng/mL)²/1000)
B
KDIGO 2-3 in 12h
MAKE30MAKE30 (30 days)DeathRRTPersistently elevated sCr (2x over baseline)
Kashani et al. Critical Care 2013, 17:R25
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TIMP-2 and IGFBP7 Have Compelling Mechanistic Origins in Early Cellular Injury
Proposed mechanismIGFBP7 & TIMP-2 are markers of G1 cell cycle arrest during early cell injury
Renal tubular cells enter a short period of G1 cell-cycle arrest following injury
G1 cell-cycle arrest presumably prevents the cells from dividing when the DNA may be damaged
IGFBP7 & TIMP-2 may also signal in autocrine and paracrine fashions, spreading ‘alarm’ from the site of injury
These processes and marker signals occur early enough in injury to take action
Kashani et al. Critical Care 2013, 17:R25
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TIMP-2 and IGFBP7 Remain Highly Significant In Clinical Models With Risk Factors
VariableP-value
(Cox PH Model)P-value
(GEE Model)[TIMP-2]•[IGFBP7] <0.0001 <0.0001
Age 0.35 0.32
APACHE III Score 0.35 0.067
Hypertension 0.004 0.013
Nephrotoxic drugs 0.12 0.013
Liver Disease 0.069 0.057
Sepsis 0.32 0.64
Diabetes 0.29 0.35
Chronic Kidney Disease 0.27 0.64
Serum Creatinine <0.0001 <0.0001
C-stat (AUC) 0.87 0.87
Endpoint was KDIGO 2-3 (RIFLE I/F) within 12 hours. All clinical risk factors with univariate p-value ≤ 0.1 for predicting the endpoint were included in the models. Net reclassification and integrated discrimination improvement analyses were also performed and showed significant enhancement of the models by [TIMP-2][IGFBP7].
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Key Messages• Both IGFBP7 and TIMP-2 are inducers of G1 cell cycle arrest, a key
mechanism implicated in AKI
• IGFBP7 and TIMP-2 are new biomarkers for AKI and perform better than existing biomarkers for predicting the development of moderate or severe AKI (KDIGO stage 2 or 3) within 12 hours of sample collection
• [TIMP-2]•[IGFBP7] significantly improved risk stratification when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement
• Risk for major adverse kidney events within 30 days (MAKE30) elevated sharply above [TIMP-2]•[IGFBP7] values > 0.3 and doubled when [TIMP-2]•[IGFBP7] values were > 2.0
Kashani et al. Critical Care 2013, 17:R25
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“An intriguing implication of this study is that, because both of these new markers can be upregulated in response to a wide range of noxious stimuli, they have the potential to be a nonspecific alarm raised by the renal tubules in response to stress.
Detecting this alarm will permit several things to happen, including appropriatetriage of patients, more intensive monitoring, and perhaps early involvement from specialists in nephrology and critical care who can promptly evaluate these patients while they are still in the golden hours of this disease prior to irreversible damage to the kidneys.”
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KDIGO Consensus Guideline for AKI
KDIGO: Kidney Disease Improving Global Outcomes; Kidney International Supplements (2012) 2, 1; doi: 0.1038/kisup.2012.1; MacLeod A. NCEPOD report on acute kidney injury- must do better. Lancet 2009; 374: 1405-1406
Actions recommended to start when patients are at high risk…
…But NO available method to reliably identify high risk to aid clinicaljudgment …often resulting in
failure to initiate kidney-sparing management strategies
….Why Risk Assessment Is Needed and What To Do For a Positive Test Result
KDIGO Management Options