US20120107420A1 - Methods of prognosis in chronic kidney disease - Google Patents

Methods of prognosis in chronic kidney disease Download PDF

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US20120107420A1
US20120107420A1 US12/998,484 US99848409A US2012107420A1 US 20120107420 A1 US20120107420 A1 US 20120107420A1 US 99848409 A US99848409 A US 99848409A US 2012107420 A1 US2012107420 A1 US 2012107420A1
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mic
amount
subject
body sample
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Samuel Norbert Breit
David Alexander Brown
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St Vincents Hospital Sydney Ltd
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6863—Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3621—Extra-corporeal blood circuits
    • A61M1/3624—Level detectors; Level control
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/52—Assays involving cytokines
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/34—Genitourinary disorders
    • G01N2800/347—Renal failures; Glomerular diseases; Tubulointerstitial diseases, e.g. nephritic syndrome, glomerulonephritis; Renovascular diseases, e.g. renal artery occlusion, nephropathy
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present invention relates to a method of prognosing the survival of a diseased subject.
  • the invention relates to a method of prognosing the survival of a subject with chronic kidney disease.
  • Macrophage inhibitory cytokine (MIC)-1 is a transforming growth factor- ⁇ (TGF- ⁇ ) superfamily protein.
  • TGF- ⁇ transforming growth factor- ⁇
  • MIC-1 was originally cloned as macrophage inhibitory cytokine-1 and later identified as placental transforming growth factor- ⁇ (PTGF- ⁇ ), placental bone morphogenetic protein (PLAB), non-steroidal anti-inflammatory drug-activated gene 1 (NAG-1), prostate-derived factor (PDF) and growth development factor-15 (GDF-15) (Bootcov et al., 1997; Hromas et al., 1997; Lawton et al., 1997; Yokoyama-Kobayashi et al., 1997; Paralkar et al., 1998).
  • MIC-1 is synthesised as an inactive precursor protein, which undergoes disulphide-linked homodimerisation. Upon proteolytic cleavage of the N-terminal pro-peptide, mature MIC-1 is secreted as an approximately 24.5 kDa dimeric protein (Bauskin et al., 2000). Amino acid sequences for MIC-1 are disclosed in WO 99/06445, WO 00/70051, WO 01/81928, WO 2005/113585, Bottner et al. (1999b); Bootcov et al., 1997; Baek et al., 2001; Hromas et al.
  • FIG. 1 The amino acid sequence for the common or “wild type” mature MIC-1 polypeptide is shown at FIG. 1 :
  • MIC-1 is expressed in several tissues (Moore et al., 2000; Bottner et al., 1999a; Fairlie et al., 1999; Bauskin et al., 2006). For example, Northern blots of human tissues indicate the presence of small amounts of MIC-1 mRNA in the kidney, pancreas and prostate, and large amounts in the placenta (Moore et al., 2000; Fairlie et al., 1999). Further, serum MIC-1 levels have been shown to increase with age in normal, apparently healthy subjects.
  • MIC-1 overexpression has been associated with cancer, particularly prostate cancer (Welsh et al., 2003), and high serum concentrations of MIC-1 are associated with the presence of metastatic disease (Welsh et al., 2003; Brown et al., 2006).
  • Serum MIC-1 is also elevated in chronic inflammatory diseases and predicts atherosclerotic events independently of traditional risk factors. Serum MIC-1 levels are also increased in chronic kidney disease (CKD; Johen et al., 2007).
  • CKD also known as chronic renal disease
  • chronic renal disease is characterised by a progressive loss of renal function over a period of months or years through five stages.
  • CKD is initially characterised by mildly diminished renal function with few overt symptoms, which can eventually progress through to the final stage, known as chronic kidney failure (CKF), chronic renal failure (CRF), or end-stage renal disease, that is characterised by a severe illness and usually requires some form of “renal replacement therapy” (eg dialysis or renal transplant).
  • CKF chronic kidney failure
  • CRF chronic renal failure
  • end-stage renal disease that is characterised by a severe illness and usually requires some form of “renal replacement therapy” (eg dialysis or renal transplant).
  • renal replacement therapy eg dialysis or renal transplant.
  • More than 15.5 million adults in the United States of America have moderately severe impairment of renal function, and more than 480,000 are receiving active treatment for end-stage renal disease with more than 100,000 new patients starting treatment annually. Of the patients receiving treatment in 2005, more than 80,000 died.
  • CKD patients tend to suffer from accelerated atherosclerosis (a chronic inflammatory disease affecting arterial blood vessels), and are more likely to develop cardiovascular disease than the general population.
  • Increased levels of inflammatory markers such as C-reactive protein (CRP) are considered to be a risk factor for acute cardiovascular events for both end-stage renal disease patients and normal populations (Apple et al., 2004).
  • End-stage renal disease is associated with anorexia, weight loss and cachexia. There is thought to be a link between malnutrition and inflammation in renal failure patients with the two conditions often coexisting.
  • Some patients with end-stage renal disease can survive indefinitely on dialysis; however, many patients are likely to die in the absence of a kidney transplant. Weight loss, a lowered body mass index (BMI) and elevated serum inflammatory markers are considered to be predictors of mortality. However, the contribution of malnutrition and inflammation to disease outcome and the nature of the link between them is ill-defined. There are currently no reliable prospective methods for determining which patients are likely to die in the absence of a kidney transplant, and it is accordingly difficult to determine patients for whom a kidney transplant may be life saving.
  • BMI body mass index
  • MIC-1 levels can advantageously provide a means for selecting an end-stage renal disease subject for a kidney transplant.
  • the present invention provides 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.
  • CKD chronic kidney disease
  • the present invention provides a method of prognosing the likelihood of death of a CKD test subject from all cause mortality, the method comprising the following steps:
  • the present invention provides 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.
  • the method of the third aspect preferably comprises the following steps:
  • the present invention provides 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.
  • the method of the fourth aspect preferably comprises the following steps:
  • the present invention provides a method of preventing death or reducing the risk of death in a CKD subject, particularly a CKD subject suffering from end-stage renal disease, comprising treating blood, plasma or serum of said subject so as to remove or inactivate MIC-1 present in said blood, plasma or serum.
  • FIG. 1 provides (A) the amino acid sequence for the common or “wild type” mature human MIC-1 polypeptide; and (B) the amino acid sequence of a D6 mature human MIC-1 variant;
  • MIC-1 is a predictor of mortality in chronic kidney disease (CKD).
  • the present invention provides 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.
  • CKD chronic kidney disease
  • MIC-1 encompasses monomers, homodimers and/or heterodimers of a MIC-1 polypeptide, as well as variants, subunits and fragments (eg degradation products or digestion products of the MIC-1) thereof.
  • MIC-1 variants encompassed by the term include mature human MIC-1 proteins which comprise a polypeptide comprising an amino acid sequence differing from that shown at FIG. 1A by 1 to 3 amino acids due to an amino acid substitution, deletion and/or addition, and which preferably show substantially equivalent biological activity to the polypeptide comprising the amino acid sequence shown at FIG.
  • MIC-1 subunits and fragments encompassed by the term include subunits and fragments of the polypeptide comprising the amino acid sequence shown at FIG. 1A or FIG. 1B and which show substantially equivalent immunological and/or biological activity to those polypeptides.
  • the MIC-1 detected in the method of the first aspect is mature human MIC-1 protein, D6 mature human MIC-1 variant protein and/or heterodimers thereof.
  • chronic kidney disease and the abbreviation “CKD” are to be understood as referring to a condition characterised by the progressive and permanent loss of renal function over a period of months or years.
  • Subjects with CKD frequently have other medical conditions such as cardiovascular disease (including atherosclerosis and ischaemic heart disease), hypertension, malnutrition, inflammatory disease and diabetes or combinations thereof.
  • CKD is recognised to progress through five stages as described in Table 1. The stages can, in part, be characterised by measuring the “glomerular filtration rate” (GFR), which can be described as the flow rate of filtered fluid through the kidney.
  • GFR glomerular filtration rate
  • Stages of chronic kidney disease Stage 1 Slightly diminished function; normal or increased GFR* (>90 mL/min/ 1.73 m 2 ); kidney damage is defined as pathologic abnormalities or markers of damage, including abnormalities in blood or urine test or imaging studies Stage 2 Mild reduction in GFR (60-89 mL/min/1.73 m 2 ); kidney damage is defined as pathologic abnormalities or markers of damage, including abnormalities in blood or urine test or imaging studies Stage 3 Moderate reduction in GFR (30-59 mL/min/1.73 m 2 ) Stage 4 Severe reduction in GFR (15-29 mL/min/1.73 m 2 ) Stage 5 Established kidney failure (GFR ⁇ 15 mL/min/1.73 m 2 ), (end-stage or receiving permanent renal renal disease) replacement therapy
  • the CKD test subject suffers from stage 1 CKD, preferably stage 2 CKD, more preferably stage 3 CKD, still more preferably stage 4 CKD, and most preferably, stage 5
  • renal replacement therapy is to be understood as referring to some type of intervention that is capable of at least partially Compensating for reduced renal function, for example, dialysis (including haemodialysis, peritoneal dialysis or haemofiltration), a kidney transplant, etc.
  • dialysis including haemodialysis, peritoneal dialysis or haemofiltration
  • a kidney transplant etc.
  • type of renal replacement therapies are not to be limited to the above examples, as other therapies may suffice as renal replacement therapies.
  • the timing and intensity of renal replacement therapy may vary from subject to subject, depending on the disease progression and other medical factors associated with an individual subject, as well as standard operating procedures at various institutions (eg dialysis units).
  • some subjects may temporarily undergo dialysis prior to progressing to end-stage renal disease.
  • the intensity of dialysis may vary from subject from subject (for example, some subjects may undergo dialysis twice a week, whilst some subjects may undergo dialysis daily). In most CKD subjects, indefinite renal replacement therapy will eventually be required to survive.
  • indefinite renal replacement therapy is to be understood as referring to the situation where the renal replacement therapy is normally expected to be required for the remainder of the subject's life. At this point, the subject can usually be considered to be suffering from end-stage renal disease.
  • end-stage renal disease is to be understood as referring to a condition characterised in Table 1, wherein the subject has permanently lost substantial renal function, for example, having a glomerular filtration rate below 15 ml/min/1.73 m 2 , or the subject is receiving indefinite renal replacement therapy (eg dialysis such as haemodialysis or peritoneal dialysis).
  • indefinite renal replacement therapy eg dialysis such as haemodialysis or peritoneal dialysis.
  • the term “likelihood of death” is to be understood as referring to the probability of premature death of the CKD subject as compared to the normal expectancy of survival of a healthy subject or other CKD subjects (ie CKD subjects with normal or reduced amounts of MIC-1).
  • the elevated amount of MIC-1 predicts an increased likelihood of death of the subject within a period of 10 years from the taking of the test body sample.
  • the elevated amount of MIC-1 predicts an increased likelihood of death of the subject within a period of 3 years from the taking of the test body sample.
  • the elevated amount of MIC-1 predicts an increased likelihood of death of the subject within a period of 1 year from the taking of the test body sample.
  • all cause mortality relates to the cause of death of the subject due to any medical cause; that is, the cause of death may be any cause other than accident or misadventure.
  • the subject may die from, for example, renal failure, cardiovascular disease (including atherosclerosis and ischaemic heart disease), hypertension, malnutrition, inflammatory disease, diabetes, or complications thereof or a combination thereof.
  • death is due to a cause selected from the group consisting of renal failure, cardiovascular disease and inflammatory disease.
  • Prognosing the likelihood of death in a subject with CKD is advantageous as it may allow for life saving intervention. For example, prognosing mortality may facilitate the selection or prioritisation of subjects for whom a kidney transplant would be life saving. Additionally, or alternatively, it may indicate that a particular subject would benefit from an alteration in therapy in order to attempt to prolong his/her life.
  • the subject may benefit from additional renal replacement therapy (eg more frequent dialysis); or alteration of other therapies, for example, alteration of therapies that are intended to replicate kidney endocrine function (such as the replacement of erythropoietin and vitamin D3, and the administration of calcium, phosphate binders, etc), or alteration of therapies to control other associated diseases (such as hypertension, cardiovascular disease, diabetes, inflammatory disease, etc).
  • additional renal replacement therapy eg more frequent dialysis
  • other therapies for example, alteration of therapies that are intended to replicate kidney endocrine function (such as the replacement of erythropoietin and vitamin D3, and the administration of calcium, phosphate binders, etc), or alteration of therapies to control other associated diseases (such as hypertension, cardiovascular disease, diabetes, inflammatory disease, etc).
  • test body sample refers to a sample of a body fluid, separated cells (ie cells taken from the body and at least partially separated from other body components), a tissue or an organ.
  • Samples of body fluids can be obtained by well known techniques, and tissue or organ samples may be obtained from any tissue or organ by, for example, biopsy.
  • Separated cells may be obtained from a body fluid; tissue or organ by separating techniques such as centrifugation or cell sorting.
  • cell, tissue or organ samples are obtained from those cells, tissues or organs which express or produce MIC-1.
  • test body sample for use in the method of the first aspect may, therefore, be preferably selected from whole blood, blood plasma, serum, buffy coat, urine, cerebrospinal fluid, seminal fluid, synovial fluid, a tissue biopsy and/or an organ biopsy. More preferably, the test body sample is selected from the group consisting of whole blood, blood plasma, serum and urine. Most preferably, the test body sample is serum.
  • the test body sample may be taken from the subject at various time points during the course of CKD.
  • a sample may be taken from the subject prior to the subject commencing a renal replacement therapy (eg dialysis) or before commencing an indefinite renal replacement therapy, and then again at one or more time points while the subject is receiving renal replacement therapy or indefinite renal replacement therapy.
  • a renal replacement therapy eg dialysis
  • indefinite renal replacement therapy e.g dialysis
  • amount encompasses the absolute amount of MIC-1, the relative amount or concentration of MIC-1 as well as any value or parameter which correlates or corresponds thereto, or can be derived therefrom, such as, for example, values or parameters comprising intensity signal values from all specific physical or chemical properties obtained from MIC-1 by direct measurements (eg intensity values in mass spectra or NMR spectra) or indirect measurements (eg response levels determined from biological read out systems in response to MIC-1 or intensity signals obtained from specifically bound ligands). It is to be understood that values correlating to the above-mentioned amounts or parameters can also be obtained by standard mathematical operations well known to persons skilled in the art.
  • the amount of MIC-1 that may be regarded as an “elevated amount” of MIC-1 for the purposes of the present invention may vary according to any of a number of factors, for example, the particular body sample type used, the sex of the subject (nb. males subjects show a mean serum MIC-1 level higher than that of female subjects), the age of the subject, the body mass index (BMI) of the subject, the smoking status of the subject (nb. former smokers tend to show increased levels of serum MIC-1 compared to those who have never smoked, while current smokers tend to show even greater levels of serum MIC-1), any use of non-steroidal anti-inflammatory drugs (NSAIDs)(nb.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • NSAID use can be associated with increased serum MIC-1 levels, particularly in male subjects), the waist-to-hip ratio in female subjects (nb. elevated waist-to-hip ratio in women is associated with increased serum MIC-1 levels), the stage of CKD the subject is suffering from, when the test body sample is taken, and the predicted period of time in which the death is likely to occur in, whether the patient is already receiving renal replacement therapy, and the method used to detect the elevated amount of MIC-1.
  • the greater the elevated amount of MIC-1 detected in a subject the greater the likelihood of death.
  • a subject receiving indefinite renal replacement therapy may have a lower serum MIC-1 level than a subject with CKD that is not receiving indefinite renal replacement therapy as, for example, dialysis may decrease the MIC-1 level in whole blood, blood plasma and serum samples.
  • An elevated amount of MIC-1 for the purposes of the present invention may be represented by an amount greater than a specific pre-determined amount such as, for example, a serum MIC-1 level greater than about 6000 pg/ml (or, in the case of a whole blood or blood plasma sample, a level that corresponds to a serum MIC-1 level greater than about 6000 pg/ml); for example, since serum comprises about 50-55% of whole blood, a whole blood MIC-1 level of about 3000 pg/ml approximately corresponds to a serum MIC-1 level of about 6000 pg/ml) or, preferably, a serum MIC-1 level greater than about 7000 pg/ml (or, in the case of a whole blood or blood plasma sample, a level that corresponds to a serum MIC-1 level greater than about 7000 pg/ml), more preferably, a serum MIC-1 level greater than 10000 pg/ml (or, in the case of a whole blood or blood plasma sample, a level
  • the MIC-1 level is (or corresponds to) a serum level of greater than about 6300 pg/ml, preferably greater than about 7400 pg/ml, more preferably greater than about 14200 pg/ml.
  • the term “about” is to be understood as referring to an amount that is ⁇ 25% of the stated amount, preferably ⁇ 20%, more preferably ⁇ 10%, more preferably ⁇ 5%, and most preferably ⁇ 2% of the stated amount.
  • an elevated amount of MIC-1 for the purposes of the present invention may also be represented by an increase in the amount of MIC-1 within a subject that is detectable by serial measurements. Accordingly, the amount of MIC-1 in a test body sample may be determined at different time points in the same subject. For example, the amount of MIC-1 in a test body sample may be detected at certain time intervals. The time intervals may be determined on a case-by-case basis according to the needs of the subject and may be, for example, three months, one year, three years, five years or ten years, but it is to be understood that the time intervals may be adjusted according to any relevant health and medical factors of the subject.
  • An elevated amount of MIC-1 in a test body sample within a subject may, accordingly, be detected by comparing the amount of MIC-1 in a test body sample at a given time point with the amount of MIC-1 in the same test body sample at an earlier time point. In this manner, an elevated amount of MIC-1 can be detected by determining the increase in the amount of MIC-1 present in the test body sample within any given subject over time.
  • the elevated amount of MIC-1 in the test body sample may be detected by using serial measurement by:
  • the elevated amount of MIC-1 in the test body sample may be detected by comparison with a normal subject, for example, by
  • the term “normal subject” refers to a subject who does not die from any cause other than accident or misadventure within 10 years of the taking of the comparative body sample(s).
  • the normal subject(s) are age-matched, wherein the normal subject(s) are within 10 years of the age of the subject from which the relevant test body sample has been taken. More preferably, the normal subject(s) are within 5 years of the age of the subject from which the relevant test body sample has been taken.
  • the elevated amount of MIC-1 in the test body sample may be detected by comparison with an end-stage renal disease subject, for example, by
  • the amount of MIC-1 in the test body sample may also be compared to a data set comprising information in relation to the level of MIC-1 in any of the foregoing subjects or a population comprising same.
  • An elevated amount of MIC-1 for the purposes of the present invention may also be detected by comparison with a reference amount of MIC-1 that is known to be associated with an increased likelihood of death of a CKD subject (eg an end-stage renal disease subject), wherein the reference amount is an increased amount compared to the amount or a range of amounts of MIC-1 present in comparative body sample(s) taken from normal subject(s).
  • a reference amount of MIC-1 that is known to be associated with an increased likelihood of death of a CKD subject (eg an end-stage renal disease subject)
  • the reference amount is an increased amount compared to the amount or a range of amounts of MIC-1 present in comparative body sample(s) taken from normal subject(s).
  • the present invention provides a method of prognosing the likelihood of death of a CKD test subject from all cause mortality, the method comprising the following steps:
  • the method of the second aspect may further comprise the step of:
  • the MIC-1 detected in the method of the second aspect is mature human MIC-1 protein, D6 mature human MIC-1 variant protein and/or heterodimers thereof.
  • the elevated amount of MIC-1 may be as described above in respect of the first aspect.
  • the test body sample may also be as described above in respect of the first aspect, however preferably, the test body sample is selected from the group consisting of whole blood, blood plasma, serum and urine.
  • the method of the second aspect enables the reference amount of MIC-1 to be used as a prognostic marker, wherein the amount of MIC-1 in the test body sample may be simply compared to that reference amount.
  • the sensitivity and specificity of such a method may depend on more than just the analytical “quality” of the method; it may also depend on the definition of what constitutes an abnormal result. That is, typically, for any particular marker, the distribution of marker levels for subjects with and without a disease overlaps such that a diagnostic/prognostic test based on that marker will not absolutely distinguish a normal subject from a diseased subject with complete accuracy.
  • the method may further comprise calculating receiver operating characteristic (ROC) curves by, for example, plotting the value of the MIC-1 amount versus the relative frequency of that value in “normal” and “disease” populations.
  • ROC receiver operating characteristic
  • the present invention provides a method for prognosing the likelihood of death of an end-stage renal disease subject.
  • the prognosis achieved by the method may predict that the subject is unlikely to survive without a kidney transplant.
  • the present invention provides 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.
  • the elevated amount of MIC-1 in the test body sample is detected by using serial measurement by:
  • the elevated amount of MIC-1 in the test body sample is detected by comparison with a normal subject by:
  • the method of the third aspect may further comprise the step of
  • the MIC-1 detected in the method of the third aspect is mature human MIC-1 protein, D6 mature human MIC-1 variant protein and/or heterodimers thereof.
  • the elevated amount of MIC-1 may be as described above in respect of the first aspect, and may be, therefore, compared to a reference amount (as described above) in order to select an end-stage renal disease test subject for a kidney transplant, wherein the reference amount is known to be associated with an increased risk of death in the absence of a kidney transplant (ie such that when the determined amount of MIC-1 in the test body sample is greater than or substantially equivalent to the reference amount, the subject is selected for a kidney transplant, and when the determined amount of MIC-1 in the test body sample is less than the reference amount, the subject may not be selected for a kidney transplant).
  • the test body sample may be as described above in respect of the first aspect, however preferably, the test body sample is selected from the group consisting of whole blood, blood plasma, serum and urine.
  • MIC-1 levels tend to be lower in CKD subjects that can tolerate long term dialysis.
  • the present invention provides 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.
  • the method of the fourth aspect preferably comprises the following steps:
  • the MIC-1 detected in the method of the fourth aspect is mature human MIC-1 protein, D6 mature human MIC-1 variant protein and/or heterodimers thereof.
  • the test body sample may be as described above in respect of the first aspect, however preferably, the test body sample is selected from the group consisting of whole blood, blood plasma, serum and urine.
  • the amount of MIC-1 in a test body sample may be used to assess an end-stage renal disease subject undergoing dialysis for tolerance of said dialysis, wherein the determination of: an elevated amount of MIC-1 (in the test body sample) relative to, for example, one or more preferably age-matched, end-stage renal disease subject(s) with long term tolerance to dialysis, is associated with poor tolerance of the dialysis; a substantially equivalent or reduced amount of MIC-1 relative to, for example, one or more preferably age-matched, end-stage renal disease subject(s) with long term tolerance to dialysis, is associated with acceptable or good tolerance of the dialysis; and a substantially unchanged (ie stable) or reduced amount of MIC-1 relative to a MIC-1 amount determined at an earlier time point(s) before or after commencement of dialysis, is associated with acceptable or good tolerance of the dialysis.
  • the methods of the present invention may be conducted in vitro or ex vivo. However, preferably, the methods are conducted in vitro.
  • the amount of MIC-1 present in a test body sample may be readily determined by any suitable method including, for example, immunoassays such as enzyme-linked immunosorbant assay (ELISA), radioimmunoassay (RIA) or immunohistochemistry (eg with sectionalised samples of a tissue biopsy) using anti-MIC-1 antibodies or fragments thereof.
  • immunoassays such as enzyme-linked immunosorbant assay (ELISA), radioimmunoassay (RIA) or immunohistochemistry (eg with sectionalised samples of a tissue biopsy) using anti-MIC-1 antibodies or fragments thereof.
  • ELISA enzyme-linked immunosorbant assay
  • RIA radioimmunoassay
  • immunohistochemistry eg with sectionalised samples of a tissue biopsy
  • MIC-1 levels of MIC-1
  • other methods well known to persons skilled in the art such as, for example, methods involving the detection of binding of MIC-1 to a MIC-1 receptor (eg as disclosed in WO 2009/21293), or any other ligands that may bind MIC-1 (eg fetuin as disclosed in WO 2005/99746).
  • Particularly suitable methods for determining the amount of MIC-1 present in a test body sample are immunoassays utilising labelled molecules in various sandwich, competition, or other assay formats. Such immunoassays will develop a signal which is indicative for the presence or absence of MIC-1.
  • the strength of the signal generated by such immunoassays may be correlated directly or indirectly (for example, reversely proportional) to the amount of MIC-1 present in a sample.
  • Other particularly suitable methods for determining the amount of MIC-1 present in a test body sample are methods comprising the measurement of a physical or chemical property specific for MIC-1 such as a precise molecular mass or nuclear magnetic resonance (NMR) spectrum. Such methods may, therefore, be conducted using biosensors, optical devices coupled to immunoassays, biochips, analytical devices such as mass-spectrometers, NMR-analysers, or chromatography devices.
  • micro-plate ELISA-based methods include micro-plate ELISA-based methods, fully-automated or robotic immunoassays (available, for example, on Elecsys® analysers (Roche Diagnostics Corporation, Indianapolis, Ind., United States of America), enzymatic Cobalt Binding Assay (CBA) (available, for example, on Roche-Hitachi analysers (Roche Diagnostics Corporation), and latex agglutination assays (available, for example, on Roche-Hitachi analysers).
  • CBA enzymatic Cobalt Binding Assay
  • Roche-Hitachi analysers Roche-Hitachi analysers
  • latex agglutination assays available, for example, on Roche-Hitachi analysers.
  • Still further examples of particularly suitable methods for determining the amount of MIC-1 present in a test body sample include methods involving precipitation (eg immunoprecipitation), electrochemiluminescence (ie electro-generated chemiluminescence), electrochemiluminescence sandwich immunoassays (ECLIA), dissociation-enhanced lanthanide fluoro immunoassay (DELFIA), scintillation proximity assay (SPA), turbidimetry, nephelometry, and latex-enhanced turbidimetry and nephelometry.
  • precipitation eg immunoprecipitation
  • electrochemiluminescence ie electro-generated chemiluminescence
  • EELFIA electrochemiluminescence sandwich immunoassays
  • DELFIA dissociation-enhanced lanthanide fluoro immunoassay
  • SPA scintillation proximity assay
  • turbidimetry turbidimetry
  • the determination of the amount of MIC-1 in the test body sample may comprise the steps of (i) contacting MIC-1 with a specific ligand, (ii) optionally removing non-bound ligand, and (iii) measuring the amount of bound ligand.
  • the bound ligand (which may be bound by covalent and/or non-covalent binding) will generate an intensity signal.
  • the ligand may be selected from anti-MIC-1 antibodies or fragments thereof but might otherwise be any other ligands that may bind MIC-1 such as, for example, any compound (including peptides, polypeptides, nucleic acids, aptamers (for example nucleic acid or peptide aptamers), glycoproteins such as fetuin, and small molecules) that binds to MIC-1.
  • any compound including peptides, polypeptides, nucleic acids, aptamers (for example nucleic acid or peptide aptamers), glycoproteins such as fetuin, and small molecules) that binds to MIC-1.
  • the ligand is selected from anti-MIC-1 antibodies or fragments thereof (including polyclonal and monoclonal antibodies, as well as fragments thereof, such as Fv, Fab and F(ab) 2 fragments that are capable of binding MIC-1, and recombinant antibodies such as single chain antibodies (eg scFV antibodies)) and a MIC-1 receptor (eg as disclosed in WO 2009/21293) or fragment thereof comprising at least one binding domain that binds to MIC-1.
  • anti-MIC-1 antibodies or fragments thereof including polyclonal and monoclonal antibodies, as well as fragments thereof, such as Fv, Fab and F(ab) 2 fragments that are capable of binding MIC-1, and recombinant antibodies such as single chain antibodies (eg scFV antibodies)) and a MIC-1 receptor (eg as disclosed in WO 2009/21293) or fragment thereof comprising at least one binding domain that binds to MIC-1.
  • Methods of preparing such ligands are well known to
  • the ligand binds specifically to MIC-1.
  • the term “specific binding” and grammatical equivalents means that the ligand should not bind substantially to (that is, substantially “cross-react” with) another peptide, polypeptide or substance present in the test body sample.
  • the specifically bound MIC-1 will be bound with at least 3 times higher, more preferably at least 10 times higher, and most preferably at least 50 times higher affinity than any other relevant peptide, polypeptide or substance.
  • Non-specific binding may be tolerable, if it can still be distinguished and measured unequivocally, for example, according to its size on a Western Blot, or by the relatively higher abundance of MIC-1 in the sample, or if it can be controlled for using a negative control sample or a normal subject control sample.
  • the ligand may be coupled covalently or non-covalently to a label allowing detection and measurement of the ligand.
  • Suitable labelling may be performed by any of the direct or indirect methods well known to persons skilled in the art.
  • direct labeling involves the coupling of the label directly (covalently or non-covalently) to the ligand
  • indirect labeling involves the binding (covalently or non-covalently) of a secondary ligand to the ligand (ie “first ligand”) wherein the secondary ligand should specifically bind to the first ligand and may be coupled with a suitable label and/or be the target (receptor) of tertiary ligand binding to the secondary ligand.
  • Suitable secondary and higher order ligands may include antibodies, secondary antibodies, and the well-known streptavidin-biotin system (Vector Laboratories, Inc, Burlingame, Calif., United States of America).
  • the ligand may also be “tagged” with one or more tags well known to persons skilled in the art, which tags may then be targets for higher order ligands.
  • Suitable tags include biotin, digoxygenin, His-Tag, glutathione-S-transferase, FLAG, Green Fluorescent Protein (GFP), myc-tag, Influenza A virus haemagglutinin (HA), maltose binding protein and the like.
  • the tag is preferably located at the N-terminus and/or C-terminus.
  • Suitable labels include any labels that are detectable by an appropriate detection method such as, for example, gold particles, latex beads, acridan ester, luminol, ruthenium, enzymatically-active labels, radioactive labels, magnetic labels (for example, “magnetic beads”, including paramagnetic and superparamagnetic labels), and fluorescent labels.
  • Suitable enzymatically-active labels include, for example, horseradish peroxidase, alkaline phosphatase, ⁇ -galactosidase, luciferase and derivatives thereof.
  • Suitable substrates for enzymatically-active labels to enable detection include di-amino-benzidine (DAB), 3,3′-5,5′-tetramethylbenzidine, 4-nitro blue tetrazolium chloride and 5-bromo-4-chloro-3-indolyl-phosphate (NBT-BCIP), available as a ready-made stock solution from Roche Diagnostics Corporation), CDP-StarTM (Amersham Biosciences Inc, Fairfield, Conn., United States of America), and ECFTM (Amersham Biosciences Inc).
  • Suitable radioactive labels include 35 S, 125 I, 32 P, 33 P and the like.
  • Radioactive labels can be detected by any of the methods well known to persons skilled in the art including, for example, a light-sensitive film or a phosphor imager.
  • Suitable fluorescent labels include fluorescent proteins (such as GFP and its derivatives, Cy3, Cy5, Texas Red, Fluorescein, and the Alexa dyes (for example, Alexa 568)).
  • fluorescent proteins such as GFP and its derivatives, Cy3, Cy5, Texas Red, Fluorescein, and the Alexa dyes (for example, Alexa 568)).
  • Alexa dyes for example, Alexa 568)
  • the amount of MIC-1 in a test body sample may be determined as follows: (i) contacting a solid support comprising a ligand for MIC-1 as described above with said test body sample comprising MIC-1 and thereafter (ii) measuring the amount of MIC-1 which has become bound to the support.
  • the ligand is selected from the group of ligands consisting of nucleic acids, peptides, polypeptides, antibodies and aptamers, and, preferably, is provided on the solid support in an immobilised form.
  • the solid support may be composed of any of the typical materials well known to persons skilled in the art including, inter alia, commercially available column materials, polystyrene beads, latex beads, magnetic beads, colloid metal particles, glass and/or silicon chips and surfaces, nitrocellulose strips, membranes, sheets, duracytes, wells and walls of suitable reaction trays such as 96-well plates and other plates, plastic tubes etc.
  • the ligand used in such embodiments may also be bound to a suitable carrier such as glass, polystyrene, polyvinyl chloride (PVC), polypropylene, polyethylene, polycarbonate, dextran, nylon, amyloses, natural and modified celluloses, polyacrylamides, agaroses and magnetite.
  • the nature of the carrier can be either soluble or insoluble. Suitable methods for immobilising the ligand to the solid support are well known to persons skilled in the art and include, for example, ionic, hydrophobic, covalent interactions and the like. It is also contemplated to use “suspension arrays” (Nolan and Sklae, 2002), wherein a carrier such as a microbead or microsphere is present in suspension, and the array consists of different microbeads or microspheres, possibly labeled, carrying different ligands. Methods of producing such arrays, for example based on solid-phase chemistry and photo-labile protective groups, are well known to persons skilled in the art (see, for example, U.S. Pat. No. 5,744,305).
  • the test subject will be in need of renal replacement therapy. It is to be understood that the renal replacement therapy may be temporary or indefinite as described above.
  • the MIC-1 level can be used as an independent predictor of mortality.
  • predictor of mortality is to be understood as referring to a medical factor that can be measured or considered in a subject to determine the likelihood of death.
  • independent predictor of mortality is to be understood as indicating that the factor (ie MICA level) is able to predict the likelihood of death without considering any other factor (which may or may not be concurrently measured). Accordingly, in some embodiments of the methods of the first and second aspects, the elevated amount of MIC-1 is used as an independent predictor of mortality. However, such methods according to the present invention may alternatively be used in conjunction with other predictors of mortality.
  • the methods may be used in combination with BMI, interleukin-6 (IL-6) levels, C-reactive protein (CRP) levels and/or short telomere length (De Meyer et al., 2008) as predictors for mortality. Therefore, determining an amount of MIC-1 along with BMI and/or CRP and MIC-1 at or beyond predetermined levels, may be used to prognose the likelihood of death of a CKD subject.
  • IL-6 interleukin-6
  • CRP C-reactive protein
  • the present applicant has additionally realised that serum MIC-1 levels in incident CKD subjects has an independent relationship with the subjective global nutritional assessment (SGA) score. Further, the role of MIC-1 in weight regulation (Johen et al., 2007), and the prominent involvement of MIC-1 in inflammatory processes (Brown et al., 2002b; Brown et al., 2007) indicate that other factors may be associated with serum MIC-1 concentrations.
  • SGA subjective global nutritional assessment
  • MIC-1 levels in CKD subjects is independently related to the fat component of BMI (FBMI), as well as fibrinogen levels and 8-hydroxydeoxyguanosine (8-OHdG) levels, indicating that serum MIC-1 is an important, and previously unrecognised, link between inflammation, oxidative stress, and reduced nutrition in renal failure, which are all considered determinants of mortality in end-stage renal disease.
  • FBMI fat component of BMI
  • 8-OHdG 8-hydroxydeoxyguanosine
  • the methods of the present invention may be used in conjunction with at least one other predictor of mortality selected from the group consisting of weight loss, a decreased BMI, a decreased FBMI, decreased SGA, history of diabetes, history of cardiovascular disease, and increased serum inflammatory marker levels (such as C-reactive protein (CRP) level and fibrinogen level) and oxidation marker levels (such as 8-hydroxydeoxyguanosine (8-OHdG)); wherein the at least one other predictor of mortality is at or beyond a pre-determined cut off point. Suitable pre-determined cut-off points for each of the above predictors of mortality to predict mortality will be well understood by persons skilled in the art.
  • the likelihood of death may be predicted using a hazard analysis.
  • the likelihood of death may be predicted using a parametric proportional hazard model, a semi-parametric proportional hazard model, a regression model, or a Poisson regression model.
  • Such models which are well known to persons skilled in the art, include the Cox proportional hazard model, the Weibull proportional hazard model, and the Cox regression model.
  • the present invention provides a method of preventing (ie delaying) death or reducing the risk of death in a CKD subject, particularly a CKD subject suffering from end-stage renal disease, comprising treating blood (eg whole blood), plasma or serum of said subject (in vivo or ex vivo) so as to remove or inactivate MIC-1 present in said blood, plasma or serum.
  • blood eg whole blood
  • plasma or serum of said subject in vivo or ex vivo
  • a suitable in vivo treatment of blood may comprise administering an effective amount of a MIC-1 inhibitory agent such as those described in WO 2005/099746; the entire content of which is herein incorporated by reference.
  • a MIC-1 inhibitory agent such as those described in WO 2005/099746; the entire content of which is herein incorporated by reference.
  • a suitable ex vivo treatment of blood may consist in a method comprising the steps of:
  • the test subject is suffering from end-stage renal disease.
  • the test subject is in need of renal replacement therapy.
  • the test subject has been receiving renal replacement therapy for between 1 month and 30 years.
  • the test subject has been receiving renal replacement therapy for between about 1 month to about 10 years, more preferably from about 1 month to about 5 years. Even more preferably, the test subject has been receiving renal replacement therapy for about 3 years.
  • the glomerular filtration rate as estimated by the mean of creatinine and urea clearance, was calculated from 24-h urinary samples (ie urine samples collected over the course of one day) using routine methods. Other biochemical analyses were performed using routine methods including measuring serum 8-hydroxydeoxyguanosine (8-OHdG; as a measure of oxidative stress), serum creatinine and albumin.
  • Nutritional status was assessed by subjective global assessment (SGA) (Qureshi et al., 1998) using a questionnaire that included six different components: three subjective assessments performed by the patient concerning the patient's history of weight loss, incidence of anorexia, and incidence of vomiting; and three objective assessments performed by the evaluators that are based on the presence of muscle atrophy (MA), oedema and the loss of subcutaneous fat.
  • SGA subjective global assessment
  • the grading of MA was assessed by a specially trained nurse examining the temporalis muscle, the prominence of the clavicles, the contour of the shoulders (rounded indicates well-nourished; squared indicates malnutrition), visibility of the scapula, the visibility of the ribs, and interosseous muscle mass between the thumb and forefinger, and the quadriceps muscle mass.
  • the signs of MA were scored as follows: 1, no signs of MA; 2, mild signs of MA; 3, moderate signs of MA; 4, severe signs of MA. This assessment was completed either at the time of, or within 1 week of, blood sample collection.
  • Body mass index (BMI) was calculated as weight (kg)/height (m) 2 .
  • the lean component of BMI was estimated by dual energy X-ray absorptiometry (DXA) using the DPX-L device (Lunar Corporation, Madison, Wis., United States of America) as previously described (Kyle et al., 2003).
  • the fat component of BMI ie FBMI
  • Handgrip strength was evaluated in both the dominant and non-dominant arms using the Harpenden Handgrip Dynamo-meter (Yamar, Jackson, Mich., United States of America). Handgrip strength was repeated three times and the highest value was recorded.
  • RRs relative risks
  • 95% confidence intervals were estimated by use of Cox proportional hazard models. Adjusted RRs were estimated after first fitting models with variables identified in previous analyses as independent risk factors. Survival curves were computed by the Kaplan-Meier method and compared among risk stratification groups using the log-rank statistic. Analyses were done with StatView 5.0 software (SAS Inc, Cary, N.C., United States of America).
  • MIC-1 serum levels were determined as described in Brown et al. (2002) using a MIC-1 sandwich ELISA. Briefly, the sandwich ELISA was established using the mouse monoclonal antibody (MAb) 26G6H6 (Brown et al., 2002a; Moore et al., 2000) for antigen capture and a sheep polyclonal antibody (PAb) 233B3-P for detection (Brown et al., 2002a). The optimum concentration of both antibodies was determined and then used for all subsequent studies.
  • MAb mouse monoclonal antibody
  • PAb sheep polyclonal antibody
  • the plates were washed three times, followed by addition of 100 ⁇ L/well of the sheep PAb 233B3-P diluted 1:5000 in antibody diluent (PBS containing 1% (wt/vol) BSA and 0.05% (vol/vol) Tween-20) and incubated for 1 h at 37° C.
  • ELISA plates were then washed three times, and 100 ⁇ L/well of biotinylated donkey anti-sheep IgG diluted to 1:5000 Ab dil was added and incubated for 1 h at 37° C.
  • the concentration of rhMIC-1 in the standard curve was determined on the basis of a comparison of this standard to a master standard of highly purified recombinant MIC-1.
  • the master standard protein concentration was determined by an average of eight estimations of total amino acid composition. All samples were assayed in triplicate on at least two occasions. Results are presented as the mean+/ ⁇ SD.
  • the mean patient age was 61 years, which was significantly older than the Swedish population (p ⁇ 0.0001, unpaired t-test), and 58% were male. Diabetes and a history of coronary artery disease (CAD) were found in 46% and 30% of patients, respectively.
  • the median number of years on dialysis was 2.0 years (range: 0.1-22 years).
  • Mean patient follow-up was 1.6 years (range: 41 days to 3 years), with a total of 108 deaths occurring during 615 patient-years of follow-up.
  • Serum MIC-1 is Related to Subjective Global Nutritional Assessment (SGA) in the Swedish Cohort
  • Patients with serum MIC-1 above the median (7430 pg/ml) were significantly more likely to have an abnormal SGA (p 0.0001, chi-square).
  • Serum MIC-1 level above the median was independently associated with SGA in multivariate logistic regression (Table 3).
  • Serum MIC-1 Level is Related to Nutrition and Markers of Inflammation and Oxidative Damage in the Swedish Cohort
  • serum MIC-1 level was compared to the levels of circulating markers of inflammation (CRP, fibrinogen), oxidation (8-OHdG) and age in the Swedish population, as these factors may be indicators of mortality in end-stage renal disease.
  • MIC-1 is independently related to FBMI, as well as fibrinogen and 8-OHdG, indicating that serum MIC-1 is an important, previously unrecognised link between inflammation, oxidative stress, and reduced nutrition in renal failure, which are all considered determinants of mortality in end-stage renal disease.
  • Serum MIC-1 Predicts Mortality in Incident Haemodialysis Patients in the Swedish Cohort
  • the present applicant sought to determine whether serum MIC-1 level was predictive of mortality in haemodialysis patients.
  • CKD patients with CKD often have protein energy wasting associated with significant inflammation as determined by elevated circulating inflammatory markers and markers of oxidative stress. Oxidative damage is thought to enable chronic inflammatory states seen in advanced CKD.
  • serum MIC-1 is also related to BMI as well as the nutritional measure SGA, independently of BMI and CRP. Only a component of BMI, FBMI, fibrinogen and 8-OHDG, an in vivo measure of oxidative stress, are independently related to serum MIC-1 levels indicating that MIC-1 is a an important, previously unrecognised, link between oxidative stress, inflammation, reduced BMI and mortality in CKD. These results show that serum MIC-1 levels are significantly related to the circulating markers of inflammation and oxidative stress.
  • Serum MIC-1 Level Predicts Mortality in the First Three Years of Dialysis
  • the present applicant investigated whether MIC-1 can predict mortality in prevalent dialysis patients.
  • Serum MIC-1 is a Predictor of Early Mortality in End-Stage Renal Disease in the US Cohort
  • serum MIC-1 level is an additional predictor of mortality, appears to have a predictive power equal or superior to CRP and is independent of traditional markers.
  • the predictive power of serum MIC-1 level was maintained in the first three years of dialysis in both cohorts.
  • the test Swedish population was sampled prior to the institution of renal replacement therapy, had a lower number of diabetics and was younger, while the prevalent validation US cohort was sampled after institution of dialysis. These population differences are likely to have significantly affected the power of serum MIC-1 level to predict mortality in the US cohort, as indicated by the finding that dialysis institution was associated with lower serum MIC-1 levels.
  • MIC-1 was validated as an independent marker of mortality in a prevalent dialysis population undergoing three or less years of dialysis. Accordingly, reduction in MIC-1 levels by dialysis institution should not significantly impact the effect of MIC-1 upon processes leading to mortality. Additionally, patients with serum MIC-1 levels in the top decile had significantly increased mortality regardless of time on dialysis.
  • MIC-1 may be a mediator of inflammation, oxidative stress and cachexia in CKD.
  • the incidence of CKD is steadily climbing and the demand for renal transplantation continues to exceed organ availability leading to significant morbidity and mortality in dialysis patients waiting for transplantation.
  • the ability to discriminate between those patients who will not tolerate dialysis for long periods offers a way to rationalise the allocation of organs.

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US20140205684A1 (en) 2014-07-24
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CA2740632A1 (en) 2010-05-06
US10705096B2 (en) 2020-07-07

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