A Rigorous DiscoveryValidation Path Was Taken 2 Discovery Study 340 proteins analyzed including KIM1 urine NGAL plasma NGAL Cystatin C IL18 piGST and LFABP Validation Study Primary Endpoint moderate to severe AKI KDIGO stage 23 within 12 hours of ID: 459393
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©2013 Astute Medical, Inc. PN 0138 Rev B 2013/03/19Slide2
A Rigorous Discovery-Validation Path Was Taken
2
Discovery Study
340 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)
Kashani
et al. Critical Care 2013, 17:R25Slide3
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 rankedTop performing biomarkers identifiedTissue Inhibitor of Metalloproteinases-2 (TIMP-2)
Insulin-like Growth Factor Binding-Protein 7 (IGFBP7)3Kashani et al. Critical Care 2013, 17:R25Slide4
TIMP-2 and IGFBP7 Outperform Existing Biomarkers
AUC for [TIMP-2]•[IGFBP7] was significantly greater than any existing biomarkers
4
Kashani
et al. Critical Care 2013, 17:R25Slide5
5
TIMP-2 and IGFBP7 Work Well In Important Subgroups
Sepsis
Surgery
Kashani
et al. Critical Care 2013, 17:R25Slide6
[TIMP-2]•[IGFBP7] Has a Compelling Specificity Profile
6
Urine NGAL (
ng
/mL)
[TIMP-2]•[IGFBP7] ((
ng
/mL)
2 / 1000)Kashani et al. Critical Care 2013, 17:R25Slide7
[TIMP-2]•[IGFBP7] Has a Compelling Specificity Profile
7
Urine KIM-1 (
ng
/mL)
[TIMP-2]•[IGFBP7] ((
ng/mL)2
/ 1000)
Kashani et al. Critical Care 2013, 17:R25Slide8
MAKE30 Analysis Shows TIMP-2 and IGFBP7 Are Clinically Meaningful Biomarkers
8
KDIGO 2-3 in 12h
MAKE30
MAKE30 (30 days)
Death
RRTPersistently elevated sCr (2x over baseline)
Kashani et al. Critical Care 2013, 17:R25Slide9
TIMP-2 and IGFBP7 Have Compelling Mechanistic Origins in Early Cellular Injury
9
Proposed mechanism
IGFBP7 & 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 damagedIGFBP7 & 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:R25Slide10
TIMP-2 and IGFBP7 Remain Highly Significant In Clinical Models With Risk Factors
10
Variable
P-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]. Slide11
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 > 2.011
Kashani et al. Critical Care 2013, 17:R25Slide12
12
“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.”Slide13
13
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 clinical
judgment
…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