Atypical hemolytic uremic syndrome biomarker proteins

Abstract

The disclosure provides biomarker proteins, a change in the concentration or activity level of which are associated with atypical hemolytic uremic syndrome (aHUS) or clinically meaningful treatment of aHUS with a complement inhibitor. Also provided are compositions and methods for interrogating the concentration and/or activity of one or more of the biomarker proteins in a biological fluid. The compositions and methods are useful for, among other things, evaluating risk for developing aHUS, diagnosing aHUS, determining whether a subject is experiencing the first acute presentation of aHUS, monitoring progression or abatement of aHUS, and/or monitoring response to treatment with a complement inhibitor or optimizing such treatment.

1 . A method for monitoring responsiveness of a subject to treatment with an inhibitor of complement, the method comprising: determining the concentration of at least two aHUS-associated biomarker proteins in a biological fluid obtained from the subject, wherein the aHUS-associated biomarker proteins are selected from the group consisting of: CXCL10, MCP-1, TNFR1, IFN-γ, IL-6, a proteolytic fragment of complement component factor B, soluble C5b9 (sC5b9), prothrombin fragment F1+2, D-dimer, thrombomodulin, VCAM-1, von Willebrand Factor (vWF), complement component C5a, β2 microglobulin (β2M), clusterin, cystatin C, NAG, TIMP-1, NGAL, fatty acid binding protein 1 (FABP-1), albumin, CXCL9, KIM-1, and CCL5,
 wherein the subject has, is suspected of having, or is at risk for developing aHUS, wherein the subject has been or is being treated with an inhibitor of complement, and wherein: (a) a reduced concentration, as compared to the concentration in a sample of biological fluid of the same type obtained from the subject prior to treatment with the inhibitor, of at least one of CXCL10, MCP-1, TNFR1, IFN-γ, IL-6, a proteolytic fragment of complement component factor B, soluble C5b9 (sC5b9), prothrombin fragment F1+2, D-dimer, thrombomodulin, VCAM-1, von Willebrand Factor (vWF), complement component C5a, β2 microglobulin (β2M), clusterin, cystatin C, NAG, TIMP-1, NGAL, fatty acid binding protein 1 (FABP-1), albumin, CXCL9, and KIM-1; or (b) an increased concentration, as compared to the concentration in a sample of biological fluid of the same type obtained from the subject prior to treatment with the inhibitor, of CCL5, indicates that the subject is responsive to treatment with the inhibitor. 
 
     
     
         2 - 129 . (canceled) 
     
     
         130 . A method for diagnosing a subject as having or being at risk for developing atypical hemolytic uremic syndrome (aHUS), the method comprising: determining the concentration of at least two aHUS-associated biomarker proteins in a biological fluid obtained from a subject, wherein the aHUS-associated biomarker proteins are selected from the group consisting of: a proteolytic fragment of complement component factor B, soluble C5b9 (sC5b9), thrombomodulin, VCAM-1, von Willebrand Factor (vWF), soluble CD40 ligand (sCD40L), prothrombin fragment F1+2, D-dimer, CXCL10, MCP-1, TNFR1, IFN-γ, ICAM-1, IL-1 beta, IL-12 p70, complement component C5a, β2 microglobulin (β2M), clusterin, cystatin C, NAG, TIMP-1, NGAL, fatty acid binding protein 1 (FABP-1), CXCL9, KIM-1, IL-18, vascular endothelial cell growth factor (VEGF), IL-6, albumin, IL-8, and CCL5,
 wherein an elevated concentration, as compared to the concentration in a normal control biological fluid of the same type, of at least one of a proteolytic fragment of complement component factor B, soluble C5b9 (sC5b9), thrombomodulin, VCAM-1, von Willebrand Factor (vWF), soluble CD40 ligand (sCD40L), prothrombin fragment F1+2, D-dimer, CXCL10, MCP-1, TNFR1, IFN-γ, ICAM-1, IL-1 beta, IL-12 p70, complement component C5a, β2 microglobulin (β2M), clusterin, cystatin C, NAG, TIMP-1, NGAL, fatty acid binding protein 1 (FABP-1), CXCL9, KIM-1, IL-18, vascular endothelial cell growth factor (VEGF), IL-6, albumin, IL-8, and CCL5, indicates that the subject has, or is at risk for developing, aHUS. 
 
     
     
         131 - 138 . (canceled) 
     
     
         139 . A method for determining whether a subject is experiencing a first acute atypical hemolytic uremic syndrome (aHUS) manifestation, the method comprising: determining one or both of the concentration of D-dimer and the concentration of fatty acid binding protein 1 (FABP-1) in a biological fluid from said subject, wherein i) an elevation in the D-dimer concentration, as compared to the concentration of D-dimer in a normal control biological fluid of the same type, ii) an elevation in the FABP-1 concentration, as compared to the concentration of FABP-1 in a normal control biological fluid of the same type, or iii) both i and ii indicates that the subject is experiencing a first acute aHUS manifestation. 
     
     
         140 - 151 . (canceled) 
     
     
         152 . A method for diagnosing a patient as having atypical hemolytic uremic syndrome (aHUS), the method comprising:
 (i) measuring in a biological sample obtained from a patient suspected of having aHUS or at risk of developing aHUS the concentration of each of at least two aHUS-associated biomarkers selected from the group consisting of: a proteolytic fragment of factor B, C5a, soluble C5b-9 (sC5b-9), soluble TNFR1 (sTNFR1), soluble VCAM-1 (sVCAM-1), thrombomodulin, prothrombin fragments 1 and 2 (F1+2), D-dimer, clusterin, TIMP-1, FABP-1, beta-2 microglobulin (b2m), and cystatin-C, and   (ii) diagnosing a patient as having aHUS if the concentrations of at least two of the aHUS-associated biomarkers are elevated as compared to normal control concentrations of the same at least two biomarkers.   
     
     
         153 . The method according to  claim 152 , wherein the at least two aHUS-associated biomarker proteins are measured using an immunoassay. 
     
     
         154 . The method of  claim 153 , wherein the immunoassay is an enzyme-linked immunosorbent assay (ELISA) or a radioimmunoassay (RIA). 
     
     
         155 . The method of  claim 152 , wherein the concentrations of at least three aHUS-associated biomarker proteins are determined. 
     
     
         156 . The method of  claim 152 , wherein the concentrations of at least five aHUS-associated biomarker proteins are determined. 
     
     
         157 . The method of  claim 152 , wherein the biological fluid is blood. 
     
     
         158 . The method of  claim 152 , wherein the biological fluid is a blood fraction. 
     
     
         159 . The method according to  claim 158 , wherein the blood fraction is plasma or serum. 
     
     
         160 . The method of  claim 152 , wherein the biological fluid is urine. 
     
     
         161 . The method of  claim 152 , wherein the concentration of at least one aHUS-associated biomarker is measured in two or more types of biological fluid. 
     
     
         162 . The method of  claim 152 , wherein the concentration of a first of the at least two aHUS biomarker proteins is measured in one type of biological fluid and the concentration of a second of the at least two aHUS biomarker proteins is measured in a second type of fluid. 
     
     
         163 - 292 . (canceled) 
     
     
         293 . The method of  claim 152 , wherein the concentrations of two or more of proteolytic fragment of factor B, C5a, and sC5b-9 are measured. 
     
     
         294 . The method of  claim 152 , wherein the concentrations of C5a and sC5b-9 are measured. 
     
     
         295 . The method of  claim 152 , wherein the concentrations of sVCAM-1 and thrombomodulin are measured. 
     
     
         296 . The method of  claim 152 , wherein the concentrations of F1+2 and D-dimer are measured. 
     
     
         297 . The method of  claim 152 , wherein the concentrations of two or more of clusterin, TIMP-1, β2m, FABP-1, and cystatin-C are measured. 
     
     
         298 . The method of  claim 152 , wherein the concentrations of at least ten biomarker proteins are determined.