Macrophage inhibitory cytokine-1 (mic-1) as a prognostic marker in chronic kidney disease

Abstract

The present invention relates to methods of prognosing the survival of a diseased subject, particularly a subject with chronic kidney disease (CKD), as well as selecting an end-stage renal disease subject for a kidney transplant. The methods involve detecting an elevated amount of macrophage inhibitory cytokine-1 (MIC-1) in a test body sample from the diseased subject. A method of preventing or reducing the risk of death in a CKD subject which involves removing or inactivating MIC-1 present in the blood, plasma or serum of the subject, is also disclosed.

1 - 22 . (canceled) 
     
     
         23 . A method of prognosing the likelihood of death of a chronic kidney disease (CKD) test subject from all cause mortality, the method comprising detecting an elevated amount of MIC-1 in a test body sample from said subject, wherein the elevated amount of MIC-1 is associated with an increased likelihood of death of the subject. 
     
     
         24 . The method of  claim 23 , wherein the elevated amount of MIC-1 in the test body sample is detected by using serial measurement by:
 (i) determining the amount of MIC-1 present in the said test body sample; and   (ii) comparing said amount of MIC-1 against an amount or a range of amounts of MIC-1 present in comparative body sample(s) taken from the same subject at an earlier time point;   wherein the amount of MIC-1 present in step (i) is elevated compared to the amount or range of amounts of MIC-1 present in said comparative body sample(s).   
     
     
         25 . The method of  claim 23 , wherein the elevated amount of MIC-1 in the test body sample is detected by comparison with a normal subject by:
 (i) determining the amount of MIC-1 present in the said test body sample; and   (ii) comparing said amount of MIC-1 against an amount or a range of amounts of MIC-1 present in comparative body sample(s) taken from normal subject(s);   wherein the amount of MIC-1 present in step (i) is elevated compared to the amount or range of amounts of MIC-1 present in said comparative body sample(s).   
     
     
         26 . The method of  claim 23 , wherein the elevated amount of MIC-1 in the test body sample is detected by comparison with an end-stage renal disease subject by:
 (i) determining the amount of MIC-1 present in the said test body sample; and   (ii) comparing said amount of MIC-1 against an amount or a range of amounts of MIC-1 present in comparative body sample(s) taken from at least one other subject that has been diagnosed with end-stage renal disease;   such that when the amount of MIC-1 present in step (i) is increased compared to the amount or range of amounts of MIC-1 present in said comparative body sample(s), the test subject has an increased likelihood of death compared to the at least one other subject.   
     
     
         27 . A method of prognosing the likelihood of death of a chronic kidney disease (CKD) test subject from all cause mortality, the method comprising the following steps:
 (i) determining the amount of MIC-1 in a test body sample from said subject; and   (ii) comparing the amount of MIC-1 determined in step (i) with a reference amount of MIC-1 that is an elevated amount of MIC-1 associated with an increased likelihood of death of the subject;   such that when the amount of MIC-1 determined in step (i) is greater than or substantially equivalent to the reference amount, the subject has an increased likelihood of death, and when the amount of MIC-1 determined in step (i) is less than the reference amount, the subject has a decreased likelihood of death.   
     
     
         28 . A method of selecting an end-stage renal disease test subject for a kidney transplant, the method comprising detecting an elevated amount of MIC-1 in a test body sample from said subject, wherein the elevated amount of MIC-1 is associated with an increased likelihood of death of the subject in the absence of a kidney transplant. 
     
     
         29 . The method of  claim 28 , wherein the method comprises the following steps:
 (i) determining the amount of MIC-1 in a test body sample from said subject; and   (ii) comparing the amount of MIC-1 determined in step (i) with a reference amount of MIC-1 that is associated with an increased likelihood of death of the subject in the absence of a kidney transplant;   such that when the amount of MIC-1 determined in step (i) is greater than or substantially equivalent to the reference amount, the subject has an increased likelihood of death in the absence of a kidney transplant, and when the amount of MIC-1 determined in step (i) is less than the reference amount, the subject has a decreased likelihood of death in the absence of a kidney transplant.   
     
     
         30 . The method of  claim 28 , wherein the elevated amount of MIC-1 in the test body sample is detected by using serial measurement by:
 (i) determining the amount of MIC-1 present in the said test body sample; and   (ii) comparing said amount of MIC-1 against an amount or a range of amounts of MIC-1 present in comparative body sample(s) taken from the same subject at an earlier time point;   wherein the amount of MIC-1 present in step (i) is elevated compared to the amount or range of amounts of MIC-1 present in said comparative body sample(s).   
     
     
         31 . The method of  claim 28 , wherein the elevated amount of MIC-1 in the test body sample is detected by comparison with a normal subject by:
 (i) determining the amount of MIC-1 present in the said test body sample; and   (ii) comparing said amount of MIC-1 against an amount or a range of amounts of MIC-1 present in comparative body sample(s) taken from normal subject(s);   wherein the amount of MIC-1 present in step (i) is elevated compared to the amount or range of amounts of MIC-1 present in said comparative body sample(s).   
     
     
         32 . The method of  claim 28 , wherein the elevated amount of MIC-1 in the test body sample is detected by comparison with an end-stage renal disease subject by:
 (i) determining the amount of MIC-1 present in the said test body sample; and   (ii) comparing said amount of MIC-1 against an amount or a range of amounts of MIC-1 present in comparative body sample(s) taken from at least one other subject that has been diagnosed with end-stage renal disease;   such that when the amount of MIC-1 present in step (i) is increased compared to the amount or range of amounts of MIC-1 present in said comparative body sample(s), the test subject has an increased likelihood of death compared to the at least one other subject.   
     
     
         33 . A method of assessing an end-stage renal disease test subject undergoing dialysis for tolerance of said dialysis, the method comprising detecting an elevated amount of MIC-1 in a test body sample from said subject, wherein the elevated amount of MIC-1 is associated with poor tolerance to dialysis. 
     
     
         34 . The method of  claim 33 , wherein the method comprises the following steps:
 (i) determining the amount of MIC-1 present in a test body sample from said subject; and   (ii) comparing said amount of MIC-1 determined in step (i) against an amount or a range of amounts of MIC-1 present in comparative body sample(s) taken from said test subject at an earlier time point(s) before or after commencement of said dialysis, or end-stage renal disease control subject(s) with long term tolerance to dialysis,   such that when the amount of MIC-1 determined in step (i) is an elevated amount compared to the amount or range of amounts of MIC-1 present in said comparative body sample(s), the subject is likely to have a poor tolerance to dialysis, and when the amount of MIC-1 determined in step (i) is less than or substantially equivalent to the amount or range of amounts of MIC-1 present in said comparative body sample(s), the subject is likely to tolerate dialysis; or   (iii) comparing said amount of MIC-1 determined in step (i) with a reference amount of MIC-1 that is associated with long term tolerance to dialysis,   such than when the amount of MIC-1 determined in step (i) is an elevated amount compared to the reference amount of MIC-1, the subject is likely to have poor tolerance to dialysis, and when the amount of MIC-1 determined in step (i) is less than or substantially equivalent to the reference amount of MIC-1, the subject is likely to tolerate dialysis.   
     
     
         35 . The method of  claim 23 , wherein the method further comprises detecting at least one predictor of mortality selected from the group consisting of decreased body mass index (BMI), decreased fat component of body mass index (FBMI), decreased nutritional subjective global assessment (SGA) score, increased weight loss, increased serum C-reactive protein (CRP) level, increased fibrinogen level, and increased 8-hydroxydeoxyguanosine (8-OHdG) level; wherein the predictor(s) of mortality is at or beyond a pre-determined cut off point. 
     
     
         36 . The method of  claim 23 , wherein the test body sample is selected from the group consisting of blood, plasma, serum and urine. 
     
     
         37 . The method of  claim 36 , wherein the elevated amount of MIC-1 is or corresponds to a serum MIC-1 level of more than about 6000 pg/ml. 
     
     
         38 . The method of  claim 36 , wherein the elevated amount of MIC-1 is or corresponds to a serum MIC-1 level of more than about 7000 pg/ml. 
     
     
         39 . The method of  claim 36 , wherein the elevated amount of MIC-1 is or corresponds to a serum MIC-1 level of more than about 14000 pg/ml. 
     
     
         40 . A method of preventing death or reducing the risk of death in a chronic kidney disease (CKD) subject, comprising treating blood, plasma or serum of said subject so as to remove or inactivate MIC-1 present in said blood, plasma or serum. 
     
     
         41 . The method of  claim 40 , wherein the subject is suffering from end-stage renal disease. 
     
     
         42 . The method of  claim 40 , wherein the subject has been receiving renal replacement therapy for between 1 month and 30 years. 
     
     
         43 . The method of  claim 40 , wherein the subject has been receiving renal replacement therapy for about 3 years. 
     
     
         44 . The method of  claim 23 , wherein the MIC-1 is mature human MIC-1 protein, D6 mature human MIC-1 variant protein and/or heterodimers thereof.