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Our novel biomarker identification led to a tool that measures biomarkers of acute kidney injury.

Novel Biomarker Identification. Rapid Risk Assessment.

The innovative end result of Astute Medical’s novel biomarker identification, the NephroCheck® Test provides risk assessment of critically ill patients who may develop acute kidney injury. A single-use cartridge designed to detect biomarkers of acute kidney injury (AKI), the NephroCheck® Test is available for use with the Astute140® Meter. By producing results in approximately 20 minutes, the test aids clinicians in making more rapid responses for critically ill patients.

Certain physicians use the Astute140 Meter, an in vitro diagnostic device, to test for novel biomarkers of acute medical conditions such as AKI.
Introducing the
NephroCheck® Test.

Revolutionary cell cycle arrest biomarkers in human acute kidney injury: TIMP-2 and IGFBP-7

The diagnosis of AKI is still made on the basis of a change in serum creatinine or urine output, both of which are derived from an altered glomerular filtration which identifies dysfunction not damage. Dysfunction only becomes evident when more than 50% of the renal mass is compromised and implies that it may be a later phenomenon in the time course of an AKI. Unlike these surrogates, the NephroCheck® Test identifies actual renal stress, before damage or dysfunction has occurred.

The test consists of two novel biomarkers, TIMP-2 and IGFBP-7, which alert the clinician of ongoing kidney cellular stress before kidney dysfunction becomes apparent. TIMP-2 and IGFBP-7 both are involved in G1 cell cycle arrest during the very early phases of cellular stress and are robust measures of risk for AKI manifesting within the next 12-24 hours.

TIMP-2 (Tissue Inhibitor of MetalloProteinases-2)
  • Inhibitor of the matrix metalloproteinases (MMPs)1
  • Directly suppresses the proliferation of endothelial cells2-5
  • Implicated in epithelial cell-cycle arrest6-9
IGFBP-7 (Insulin-like Growth Factor Binding Protein-7)
  • Regulation of tissue availability of insulin and IGFs10-14
  • Stimulates cell adhesion15-17
  • Implicated in epithelial cell-cycle arrest18

TIMP-2 and IGFBP-7 used in the NephroCheck Test® have been found to provide superior clinical utility which equip the medical community with an unprecedented and valuable tool for early risk assessment of AKI in critically ill patients.

Novel Biomarker Detection Process

After the user inserts the NephroCheck® Test cartridge, the Astute140® Meter converts the fluorescent signals for the individual immunoassays—the specific novel biomarkers—into concentrations, combining them into a single numerical test result. The NephroCheck® Test and Astute140™ Meter employ a sandwich immunoassay technique along with fluorescence detection technology to quantitatively measure biomarkers of acute kidney injury in human urine samples. Multiple levels of controls (internal, external and electronic) ensure reliable and accurate test results.

Intended Use

The NephroCheck Test® result is intended as an aid in the risk assessment of acute kidney injury in the critically ill. The NephroCheck® Test results should be evaluated in the context of all clinical and laboratory data available.

The NephroCheck® Test and the Astute140® Meter are CE marked.

1. UniProt Knowledgebase, Comprehensive Protein Database. Universal Protein Resource (UniProt); 2002—2013. http://www.uniprot.org/uniprot/P16035. Entry modified November 28, 2012. Accessed January 10, 2013.
2. Seo DW, Li H, Guedez L, et al. TIMP-2 mediated inhibition of angiogenesis: an MMP-independent mechanism. Cell. 2003;114(2):171-180.
3. Seo DW, Kim SH, Eom SH, et al. TIMP-2 disrupts FGF-2-induced downstream signaling pathways. Microvasc Res. 2008;76(3):145-151. doi: 10.1016/j.mvr.2008.07.003.
4. Seo DW, Saxinger WC, Guedez L, Cantelmo AR, Albini A, Stetler-Stevenson WG. An integrin-binding N-terminal peptide region of TIMP-2 retains potent angio-inhibitory and anti-tumorigenic activity in vivo. Peptides. 2011;32(9):1840-1848. doi: 10.1016/j.peptides.2011.08.010.
5. Bourboulia D, Jensen-Taubman S, Rittler MR, et al. Endogenous angiogenesis inhibitor blocks tumor growth via direct and indirect effects on tumor microenvironment. Am J Pathol. 2011;179(5):2589-2600. doi: 10.1016/j.ajpath.2011.07.035.
6. Seo DW, Li H, Qu CK, et al. Shp-1 mediates the antiproliferative activity of tissue inhibitor of metalloproteinase-2 in humanmicrovascular endothelial cells. J Biol Chem. 2006;281(6):3711-3721.
7. Stetler-Stevenson. Tissue Inhibitors of Metalloproteinases: Regulation of Cell Growth and Differentiation. National Cancer Institute Web site. http://ccr.cancer.gov/staff/staff.asp?profileid=5853. Updated May 17, 2011. Accessed January 10, 2013.
8. Stetler-Stevenson WG. Tissue inhibitors of metalloproteinases in cell signaling: metalloproteinase-independent biological activities. Sci Signal. 2008;1(27):re6. doi: 10.1126/scisignal.127re6.
9. Pérez-Martínez L, Jaworski DM. Tissue inhibitor of metalloproteinase-2 promotes neuronal differentiation by acting as an anti-mitogenic signal. J Neurosci. 2005;25(20):4917-4929.
10. Burger AM, Leyland-Jones B, Banerjee K, Spyropoulos DD, Seth AK. Essential roles of IGFBP-3 and IGFBP-rP1 in breast cancer. Eur J Cancer. 2005;41(11):1515-1527.
11. Benatar T, Yang W, Amemiya Y, et al. IGFBP7 reduces breast tumor growth by induction of senescence and apoptosis pathways. Breast Cancer Res Treat. 2012; 133(2):563-573. doi: 10.1007/s10549-011-1816-4.
12. Hwa V, Oh Y, Rosenfeld RG. The insulin-like growth factor-binding protein (IGFBP) superfamily. Endocr Rev. 1999;20(6):761:787.
13. Oh Y, Nagalla SR, Yamanaka Y, Kim HS, Wilson E, Rosenfeld RG. Synthesis and characterization of insulin-like growth factor-binding protein (IGFBP)-7. Recombinanthuman mac25 protein specifically binds IGF-I and -II. J Biol Chem. 1996;271(48):30322-30325.
14. Yamanaka Y, Wilson EM, Rosenfeld RG, Oh Y. Inhibition of insulin receptor activation by insulin-like growth factor binding proteins. J Biol Chem. 1997;272(49):30729-30734.
15. Nagakubo D, Murai T, Tanaka T, et al. AA high endothelial venule secretory protein, mac25/angiomodulin, interacts with multiple high endothelial venule-associated molecules including chemokines. J Immunol. 2003;171(2):553-561.
16. Sato J, Hasegawa S, Akaogi K, et al. Identification of cell-binding site of angiomodulin (AGM/TAF/Mac25) that interacts with heparan sulfates on cell surface. J Cell Biochem. 1999;75(2):187-195.
17. Sato Y, Chen Z, Miyazaki K. Strong suppression of tumor growth by insulin-like growth factor-binding protein-related protein1/tumor-derived cell adhesion factor/mac25. Cancer Sci. 2007;98(7):1055-1063.
18. Sprenger CC, Vail ME, Evans K, Simurdak J, Plymate SR. Over-expression of insulin-like growth factor binding protein-related protein-1(IGFBP-rP1/mac25) in the M12 prostate cancer cell line alters tumor growth by a delay in G1 and cyclin A associated apoptosis. Oncogene. 2002;21(1):140-147.


Novel Biomarker Identification. Rapid Risk Assessment.

The innovative end result of Astute Medical's novel biomarker identification, the NephroCheck® Test provides risk assessment of critically ill patients who may develop acute kidney injury. A single-use cartridge designed to detect biomarkers of acute kidney injury (AKI), the NephroCheck® Test is available for use with the Astute140® Meter. By producing results in approximately 20 minutes, the test aids clinicians in making more rapid responses for critically ill patients.

Introducing the
NephroCheck® Test.


Revolutionary cell cycle arrest biomarkers in human acute kidney injury: TIMP-2 and IGFBP-7

The diagnosis of AKI is still made on the basis of a change in serum creatinine or urine output, both of which are derived from an altered glomerular filtration which identifies dysfunction not damage. Dysfunction only becomes evident when more than 50% of the renal mass is compromised and implies that it may be a later phenomenon in the time course of an AKI. Unlike these surrogates, the NephroCheck® Test identifies actual renal stress, before damage or dysfunction has occurred.
 

The test consists of two novel biomarkers, TIMP-2 and IGFBP-7, which alert the clinician of ongoing kidney cellular stress before kidney dysfunction becomes apparent. TIMP-2 and IGFBP-7 both are involved in G1 cell cycle arrest during the very early phases of cellular stress and are robust measures of risk for AKI manifesting within the next 12-24 hours.

TIMP-2 (Tissue Inhibitor of MetalloProteinases-2)
  • Inhibitor of the matrix metalloproteinases (MMPs)1
  • Directly suppresses the proliferation of endothelial cells2-5
  • Implicated in epithelial cell-cycle arrest6-9
IGFBP-7 (Insulin-like Growth Factor Binding Protein-7)
  • Regulation of tissue availability of insulin and IGFs10-14
  • Stimulates cell adhesion15-17
  • Implicated in epithelial cell-cycle arrest18

TIMP-2 and IGFBP-7 used in the NephroCheck Test® have been found toprovide superior clinical utility which equip the medical community with an unprecedented and valuable tool for early risk assessment of AKI in critically ill patients.


Novel Biomarker Detection Process

After the user inserts the NephroCheck® Test cartridge, theAstute140® Meter converts the fluorescent signals for the individual immunoassays—the specific novel biomarkers—into concentrations, combining them into a single numerical test result. The NephroCheck® Test and Astute140™ Meter employ a sandwich immunoassay technique along with fluorescence detection technology to quantitatively measure biomarkers of acute kidney injury in human urine samples. Multiple levels of controls (internal, external and electronic) ensure reliable and accurate test results.

Intended Use

The NephroCheck Test® result is intended as an aid in the risk assessment of acute kidney injury in the critically ill. The NephroCheck®Test results should be evaluated in the context of all clinical and laboratory data available.

The NephroCheck® Test and the Astute140® Meter are CE marked.


1. UniProt Knowledgebase, Comprehensive Protein Database. Universal Protein Resource (UniProt); 2002—2013. http://www.uniprot.org/uniprot/P16035. Entry modified November 28, 2012. Accessed January 10, 2013.
2. Seo DW, Li H, Guedez L, et al. TIMP-2 mediated inhibition of angiogenesis: an MMP-independent mechanism. Cell. 2003;114(2):171-180.
3. Seo DW, Kim SH, Eom SH, et al. TIMP-2 disrupts FGF-2-induced downstream signaling pathways. Microvasc Res. 2008;76(3):145-151. doi: 10.1016/j.mvr.2008.07.003.
4. Seo DW, Saxinger WC, Guedez L, Cantelmo AR, Albini A, Stetler-Stevenson WG. An integrin-binding N-terminal peptide region of TIMP-2 retains potent angio-inhibitory and anti-tumorigenic activity in vivo. Peptides. 2011;32(9):1840-1848. doi: 10.1016/j.peptides.2011.08.010.
5. Bourboulia D, Jensen-Taubman S, Rittler MR, et al. Endogenous angiogenesis inhibitor blocks tumor growth via direct and indirect effects on tumor microenvironment. Am J Pathol. 2011;179(5):2589-2600. doi: 10.1016/j.ajpath.2011.07.035.
6. Seo DW, Li H, Qu CK, et al. Shp-1 mediates the antiproliferative activity of tissue inhibitor of metalloproteinase-2 in humanmicrovascular endothelial cells. J Biol Chem. 2006;281(6):3711-3721.
7. Stetler-Stevenson. Tissue Inhibitors of Metalloproteinases: Regulation of Cell Growth and Differentiation. National Cancer Institute Web site.http://ccr.cancer.gov/staff/staff.asp?profileid=5853. Updated May 17, 2011. Accessed January 10, 2013.
8. Stetler-Stevenson WG. Tissue inhibitors of metalloproteinases in cell signaling: metalloproteinase-independent biological activities. Sci Signal. 2008;1(27):re6. doi: 10.1126/scisignal.127re6.
9. Pérez-Martínez L, Jaworski DM. Tissue inhibitor of metalloproteinase-2 promotes neuronal differentiation by acting as an anti-mitogenic signal. J Neurosci. 2005;25(20):4917-4929.
10. Burger AM, Leyland-Jones B, Banerjee K, Spyropoulos DD, Seth AK. Essential roles of IGFBP-3 and IGFBP-rP1 in breast cancer. Eur J Cancer. 2005;41(11):1515-1527.
11. Benatar T, Yang W, Amemiya Y, et al. IGFBP7 reduces breast tumor growth by induction of senescence and apoptosis pathways. Breast Cancer Res Treat. 2012; 133(2):563-573. doi: 10.1007/s10549-011-1816-4.
12. Hwa V, Oh Y, Rosenfeld RG. The insulin-like growth factor-binding protein (IGFBP) superfamily. Endocr Rev. 1999;20(6):761:787.
13. Oh Y, Nagalla SR, Yamanaka Y, Kim HS, Wilson E, Rosenfeld RG. Synthesis and characterization of insulin-like growth factor-binding protein (IGFBP)-7. Recombinanthuman mac25 protein specifically binds IGF-I and -II. J Biol Chem. 1996;271(48):30322-30325.
14. Yamanaka Y, Wilson EM, Rosenfeld RG, Oh Y. Inhibition of insulin receptor activation by insulin-like growth factor binding proteins. J Biol Chem. 1997;272(49):30729-30734.
15. Nagakubo D, Murai T, Tanaka T, et al. AA high endothelial venule secretory protein, mac25/angiomodulin, interacts with multiple high endothelial venule-associated molecules including chemokines. J Immunol. 2003;171(2):553-561.
16. Sato J, Hasegawa S, Akaogi K, et al. Identification of cell-binding site of angiomodulin (AGM/TAF/Mac25) that interacts with heparan sulfates on cell surface. J Cell Biochem. 1999;75(2):187-195.
17. Sato Y, Chen Z, Miyazaki K. Strong suppression of tumor growth by insulin-like growth factor-binding protein-related protein1/tumor-derived cell adhesion factor/mac25.Cancer Sci. 2007;98(7):1055-1063.
18. Sprenger CC, Vail ME, Evans K, Simurdak J, Plymate SR. Over-expression of insulin-like growth factor binding protein-related protein-1(IGFBP-rP1/mac25) in the M12 prostate cancer cell line alters tumor growth by a delay in G1 and cyclin A associated apoptosis. Oncogene. 2002;21(1):140-147.
©2017 Astute Medical, Inc. Astute Medical®, the AM logo, Astute140®NephroCheck®, the NephroCheck® logo, and AKIRisk® are registered trademarks of Astute Medical, Inc. in the United States. For information regarding trademarks and other intellectual property applicable to this product, including international trademarks, please see AstuteMedical.com/about/intellectualproperty. PN 0098 Rev D 2015/07/28