Mcam as a biomarker for fluid homeostasis

Abstract

The application discloses MCAM as a new biomarker for fluid homeostatic imbalance; methods for predicting, diagnosing, prognosticating and/or monitoring fluid homeostatic imbalance based on measuring said biomarker; and kits and devices for measuring said biomarker and/or performing said methods.

What is claimed is: 
     
         1 . A method for diagnosing, predicting, prognosticating and/or monitoring an impaired fluid homeostasis in a subject, wherein the examination phase of the method comprises measuring the quantity of melanoma cell adhesion molecule (MCAM) in a sample from the subject. 
     
     
         2 . The method according to  claim 1 , comprising:
 (i) measuring the quantity of MCAM in the sample from the subject;   (ii) comparing the quantity of MCAM measured in (i) with a reference value of the quantity of MCAM, said reference value representing a known diagnosis, prediction and/or prognosis of impaired or normal fluid homeostasis;   (iii) finding a deviation or no deviation of the quantity of MCAM measured in (i) from said reference value;   (iv) attributing said finding of deviation or no deviation to a particular diagnosis, prediction and/or prognosis of impaired fluid homeostasis in said subject.   
     
     
         3 . The method according to  claim 1  for monitoring impaired fluid homeostasis, preferably in the course of a medical treatment of the subject, comprising:
 (i) measuring the quantity of MCAM in samples from the subject from two or more successive time points; 
 (ii) comparing the quantity of MCAM between the samples as measured in (i); 
 (iii) finding a deviation or no deviation of the quantity of MCAM between the samples as compared in (ii); 
 (iv) attributing said finding of deviation or no deviation to a change in fluid or water homeostasis in the subject between the two or more successive time points. 
 
     
     
         4 . A method for monitoring a change in the diagnosis, prediction and/or prognosis of impaired fluid homeostasis in a subject, preferably in the course of a medical treatment of the subject, comprising:
 (i) applying the method of  claim 1  to the subject at two or more successive time points, whereby the diagnosis, prediction and/or prognosis of impaired fluid homeostasis in the subject is determined at said successive time points;   (ii) comparing the diagnosis, prediction and/or prognosis of impaired fluid homeostasis in the subject at said successive time points as determined in (i); and   (iii) finding the presence or absence of a change between the diagnosis, prediction and/or prognosis of impaired fluid homeostasis in the subject at said successive time points as determined in (i).   
     
     
         5 . The method according to  claim 1 , wherein said impaired fluid homeostasis is characterized by any one or more or all of an increased or decreased vascular filling volume or pressure in said subject and/or a weight gain (such as characterised by oedema) or weight loss (such as characterised by dehydration) due to fluid build-up or fluid drainage, respectively in said subject. 
     
     
         6 . A method to determine whether a subject is or is not (such as, for example, still is, or is no longer) in need of a therapy to treat impaired fluid homeostasis, comprising:
 (i) measuring the quantity of MCAM in the sample from the subject;   (ii) comparing the quantity of MCAM measured in (i) with a reference value of the quantity of MCAM, said reference value representing a known diagnosis, prediction and/or prognosis of impaired or normal fluid homeostasis;   (iii) finding a deviation or no deviation of the quantity of MCAM measured in (i) from said reference value;   (iv) inferring from said finding the presence or absence of a need for a therapy to treat impaired fluid homeostasis.   
     
     
         7 . The method according to  claim 6 , wherein said therapy is:
 (i) a therapy to restore fluid homeostasis by decreasing the vascular filling volume or pressure or reversing weight gain due to fluid build-up, if the quantity of MCAM in said sample is higher than said reference value, wherein said reference value represents normal (euvolemic) fluid homeostasis and/or the reference value represents a threshold value above which value is indicative of the need for a therapy to decrease the vascular filling volume or to reverse weight gain due to fluid build-up, preferably wherein the therapy comprises administering exogeneous and/or endogeneous diuretic agents and/or ultrafiltration to remove salts and corresponding fluid from the circulation; or   (ii) a therapy to restore fluid homeostasis by increasing the vascular filling volume or reversing weight loss due to fluid drainage, if the quantity of MCAM in said sample is lower than said reference value, wherein said reference value represents a threshold value below which value is indicative of the need for a therapy to increase the vascular filling volume or to reverse weight loss due to fluid drainage, preferably wherein the therapy comprises administering exogeneous and/or endogeneous antidiuretic or vassopressive agents and/or fluid administration.   
     
     
         8 . The method according to  claim 6 , wherein the subject is receiving or has received an anti-diabetes treatment, preferably one or more insulin sensitizers, more preferably one or more agonists of peroxisome proliferator-activated receptor gamma (PPAR-gamma), even more preferably one or more thiazolidinediones (glitazones), such as rosiglitazone and/or pioglitazone. 
     
     
         9 . The method according to  claim 8 , whereby patients receiving or having received the anti-diabetes treatment are stratified to identify patients having or being at risk of having impaired fluid homeostasis or having a poor prognosis for impaired fluid homeostasis and likely to respond to a therapy to restore fluid homeostasis. 
     
     
         10 . The method according to  claim 1 , wherein said impaired fluid homeostasis is caused by systolic dysfunction. 
     
     
         11 . The method according to  claim 10 , wherein said systolic dysfunction is characterized by a decreased left ventricular ejection fraction (LVEF), preferably wherein said LVEF is less than 55% or less than 50% or less than 45%, and/or by increased cardiac filling pressure. 
     
     
         12 . A method for diagnosing, predicting, prognosticating and/or monitoring (i) dyspnea associated with or caused by volume overload in a subject or (ii) heart failure (HF) or acute heart failure (AHF) associated with or caused by volume overload in a subject, or (iii) HF or AHF associated with or caused by systolic dysfunction in a subject, wherein the examination phase of the method comprises measuring the quantity of MCAM in a sample from the subject. 
     
     
         13 . The method according to  claim 12 , comprising:
 (i) measuring the quantity of MCAM in the sample from the subject;   (ii) comparing the quantity of MCAM measured in (i) with a reference value of the quantity of MCAM, said reference value representing a known diagnosis, prediction and/or prognosis of the respective condition;   (iii) finding a deviation or no deviation of the quantity of MCAM measured in (i) from said reference value;   (iv) attributing said finding of deviation or no deviation to a particular diagnosis, prediction and/or prognosis of the respective condition in said subject.   
     
     
         14 . The method according to  claim 12  for monitoring the respective condition, preferably in the course of a medical treatment of the subject, comprising:
 (i) measuring the quantity of MCAM in samples from the subject from two or more successive time points; 
 (ii) comparing the quantity of MCAM between the samples as measured in (i); 
 (iii) finding a deviation or no deviation of the quantity of MCAM between the samples as compared in (ii); 
 (iv) attributing said finding of deviation or no deviation to a change in the respective condition in the subject between the two or more successive time points. 
 
     
     
         15 . A method for monitoring a change in the diagnosis, prediction and/or prognosis of a condition as defined in  claim 12  in a subject, comprising:
 (i) applying the method of  claim 12  to the subject at one or more successive time points, whereby the diagnosis, prediction and/or prognosis of the respective condition in the subject is determined at said successive time points; 
 (ii) comparing the diagnosis, prediction and/or prognosis of systolic dysfunction in the subject at said successive time points as determined in (i); and 
 (iii) finding the presence or absence of a change between the diagnosis, prediction and/or prognosis of the respective condition in the subject at said successive time points as determined in (i). 
 
     
     
         16 . The method according to  claim 1 , wherein the examination phase of the method further comprises measuring the presence or absence and/or quantity of one or more other biomarkers useful for diagnosing, predicting and/or prognosticating the respective condition in the sample from the subject. 
     
     
         17 . The method according to  claim 16  comprising:
 (i) measuring the quantity of MCAM and the presence or absence and/or quantity of said one or more other biomarkers in the sample from the subject; 
 (ii) using the measurements of (i) to establish a subject profile of the quantity of MCAM and the presence or absence and/or quantity of said one or more other biomarkers; 
 (iii) comparing said subject profile of (ii) to a reference profile of the quantity of MCAM and the presence or absence and/or quantity of said one or more other biomarkers, said reference profile representing a known diagnosis, prediction and/or prognosis of the respective condition; 
 (iv) finding a deviation or no deviation of the subject profile of (ii) from the reference profile; 
 (v) attributing said finding of deviation or no deviation to a particular diagnosis, prediction and/or prognosis of the respective condition in the subject. 
 
     
     
         18 . The method according to  claim 16 , wherein said other biomarker useful for diagnosing, predicting and/or prognosticating impaired fluid homeostasis or systolic dysfunction is selected from the group consisting of atrial natriuretic peptide (ANP), pro-ANP, mid-regional portion of pro-ANP (MR-proANP), B-type natriuretic peptide (BNP), pro-B-type natriuretic peptide (proBNP), amino terminal pro-B-type natriuretic peptide (NTproBNP), Cystatin C, NGAL, Albumin, γ-GT, NAG, A1M, B1M, creatinine, ureum, vasopression, copeptin, aldosteron, angiotensin, ACE and fragments or precursors of any one thereof. 
     
     
         19 . A method for establishing a MCAM base-line or reference value in a subject, comprising:
 (i) measuring the quantity of MCAM in the sample from the subject at different time points wherein the subject is not suffering from a condition as defined in  claim 1 , and   (ii) calculating the range or mean value of the subject, which is the MCAM base-line or reference value for said subject.   
     
     
         20 . The method according to  claim 1 , wherein the quantity of MCAM and/or the presence or absence and/or quantity of the one or more other biomarkers is measured using, respectively, a binding agent capable of specifically binding to MCAM and/or to fragments thereof, and a binding agent capable of specifically binding to said one or more other biomarkers. 
     
     
         21 . The method according to  claim 1 , wherein the quantity of MCAM and/or the presence or absence and/or quantity of the one or more other biomarkers is measured using an immunoassay technology, or using a mass spectrometry analysis method or using a chromatography method, or using a combination of said methods. 
     
     
         22 . The method according to  claim 1 , wherein said sample is plasma, and wherein the plasma circulating form of MCAM is detected. 
     
     
         23 . A kit for performing the method according to  claim 1 , the kit comprising (i) means for measuring the quantity of MCAM in a sample from the subject, and preferably further comprising (ii) a reference value of the quantity of MCAM or means for establishing said reference value, wherein said reference value represents a known diagnosis, prediction and/or prognosis of impaired fluid homeostasis in the subject. 
     
     
         24 . A testing device capable of measuring the quantity of MCAM in a sample from a subject comprising:
 (i) means for measuring the quantity of MCAM in said sample, and   (ii) means of storing the reference value in the device, and   (iii) means of comparing the obtained quantity with the stored reference value, and   (iv) means for visualising the quantity of MCAM measured in the sample.   
     
     
         25 . The method according to  claim 1 , wherein the subject is receiving or has received an anti-diabetes treatment, preferably one or more insulin sensitizers, more preferably one or more agonists of peroxisome proliferator-activated receptor gamma (PPAR-gamma), even more preferably one or more thiazolidinediones (glitazones), such as rosiglitazone and/or pioglitazone. 
     
     
         26 . The method according to  claim 25 , whereby patients receiving or having received the anti-diabetes treatment are stratified to identify patients having or being at risk of having impaired fluid homeostasis or having a poor prognosis for impaired fluid homeostasis and likely to respond to a therapy to restore fluid homeostasis.