Biomarkers of fast progression of chronic kidney disease

Abstract

The present invention relates to methods for the prediction of the progression of chronic kidney disease in a patient. More particularly, the invention relates to the early prediction of the fast progression of chronic kidney disease using specific biomarker signatures in urine sample of patients.

1 . An in vitro method for the prediction of fast progression of chronic kidney disease in a subject, comprising the steps of evaluating the expression of one or more biomarkers in a biological sample obtained from said subject, wherein said one or more biomarkers are selected from the group consisting of transforming growth factor alpha (TGF-α), epidermal growth factor (EGF), and monocyte chemoattractant protein 1 (MCP1). 
     
     
         2 . The method of  claim 1 , comprising evaluating at least the expressions of EGF, MCP1, and TGF-α, and, optionally, Neutrophil Gelatinase-associated Lipocalin (NGAL). 
     
     
         3 . The method of  claim 1 , wherein the evaluating step include (a) quantifying the expression of one or more of the selected biomarkers in a biological sample obtained from said subject to obtain an expression value for each quantified biomarker, and (b) comparing said expression value obtained at step (a) to a corresponding control value, wherein an expression value of TGF-α above a control value, and/or an expression value of EGF below a control value and/or an expression value of MCP1 above a control value and/or an expression value of NGAL above a control value, indicates that the subject is at increased risk of fast progression. 
     
     
         4 . The method of  claim 1 , wherein the expression of one or more biomarkers selected from the group consisting of: Growth and Differentiation Factor 15 (GDF15), Neutrophil Gelatinase-associated Lipocalin (NGAL), Cystatin C, Fatty Acid Binding Protein (FABP), Fibronectin, Kidney Injury Molecule 1 (KIM1), Osteopontin, Tissue Inhibitor of Metalloprotease 1 (TIMP1), Uromodulin, Interleukin-6 (IL6), Leukemia Inhibitory Factor (LIF), Matrix Metallopeptidase 9 (MMP9) and Vascular Endothelial Growth Factor A (VEGFA) is further evaluated. 
     
     
         5 . The method of  claim 1 , wherein said biological sample is urine or serum sample. 
     
     
         6 . The method of  claim 1 , wherein said expression is protein expression, for example as quantified in an immunoassay. 
     
     
         7 . The method of  claim 1 , wherein a subject predicted of fast progression is a subject who is at risk of losing more than 10% of the baseline measured glomerular filtration rate (mGFR) per year. 
     
     
         8 . The method of  claim 1 , wherein said subject predicted of fast progression is then selected for treatment with a therapeutic agent for treating chronic kidney disease. 
     
     
         9 . An in vitro method for monitoring the efficacy of a therapeutic agent for treating chronic kidney disease in a subject, comprising evaluating the expressions of biomarkers in a biological sample of said subject, wherein said biomarkers are TGF-α, EGF, and, MCP1, and, optionally, evaluating the expression of NGAL. 
     
     
         10 . The method of  claim 9 , comprising a first evaluating step prior to treating chronic kidney disease and repeating said evaluating step during or after said treatment step, wherein a change in the expressions of said biomarkers is indicative of a response to said treatment. 
     
     
         11 . A kit for carrying out any one of the methods of  claims 1 - 10 , said kit comprising means for quantifying protein expression of at least the following biomarker: TGF-α, EGF, and MCP1, and, optionally, means for quantifying protein expression of NGAL. 
     
     
         12 . The kit of  claim 11 , wherein said means for quantifying protein expression include unlabelled antibodies specific of each biomarker and, optionally, second labeled antibodies for detecting said biomarker/unlabelled antibodies in an immunoassay. 
     
     
         13 . The kit of  claim 12 , for use in an immunoassay, comprising:
 antibodies specific of TGF-α,   antibodies specific of EGF; and,   antibodies specific of MCP1;   optionally antibodies specific of NGAL.   
     
     
         14 . The kit of  claim 13 , wherein said antibodies are immobilized on a support. 
     
     
         15 . The kit of  claim 12 , wherein said antibodies are conjugated to reporter molecule.