WO2011136228A1 - 腎臓病診断用マーカー及びその利用 - Google Patents
腎臓病診断用マーカー及びその利用 Download PDFInfo
- Publication number
- WO2011136228A1 WO2011136228A1 PCT/JP2011/060178 JP2011060178W WO2011136228A1 WO 2011136228 A1 WO2011136228 A1 WO 2011136228A1 JP 2011060178 W JP2011060178 W JP 2011060178W WO 2011136228 A1 WO2011136228 A1 WO 2011136228A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- concentration
- kidney disease
- urine
- value
- marker
- Prior art date
Links
Images
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/62—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating the ionisation of gases, e.g. aerosols; by investigating electric discharges, e.g. emission of cathode
-
- 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
- G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
- G01N33/6806—Determination of free amino acids
-
- 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
- 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
Definitions
- the present invention relates to a kidney disease diagnosis marker and a computer program for diagnosis of kidney disease using the marker.
- Kidney disease is a disease caused by a lesion in each tissue of the kidney.
- kidney disease progresses and falls into renal failure, it is difficult to recover and maintain renal function even if treatment is started, so dialysis treatment is necessary.
- dialysis treatment is necessary.
- the number of patients requiring dialysis treatment has increased, and the accompanying increase in medical costs has become a problem. Therefore, it is important to find patients with kidney disease early by accurate diagnosis.
- GFR glomerular filtration rate
- urinary microalbumin, type IV collagen, transferrin, IgG, laminin, fibronectin, ⁇ -1 microglobulin, ⁇ -2 microglobulin, cystatin C, N-acetyl- ⁇ -D-glucosaminidase (NAG), L-type fatty acid binding protein (L-FABP), glycocymidine and derivatives thereof are also used (see Patent Documents 1 and 2).
- An object of the present invention is to provide a novel marker for renal disease diagnosis. Another object of the present invention is to provide a computer program for diagnosing kidney disease using the kidney disease diagnostic marker.
- Glycolic acid N 5 -[(dimethylamino) iminomethyl] -ornithine; 5-oxo-2-tetrahydrofurancarboxylic acid; From trimethylglycine and any one selected from glycolic acid, N 5 -[(dimethylamino) iminomethyl] -ornithine, guanidinoacetic acid, 4-guanidinobutyric acid, N 6 -acetyllysine, N 1 -acetylhistidine and histidine
- a computer An acquisition step of acquiring a concentration of the diagnostic marker described above contained in urine and / or plasma collected from a subject suspected of having kidney disease; A determination step for determining whether or not the subject has kidney disease based on the obtained concentration; and an output step for outputting the determination result; A computer program for executing the above is provided.
- the diagnostic marker of a kidney disease useful for a highly accurate diagnosis can be provided.
- the diagnostic marker for kidney disease of the present invention can be used not only to diagnose whether or not the subject has kidney disease, but when the subject is being treated for kidney disease, the degree of improvement or treatment of the symptoms It is also possible to evaluate the effectiveness of. Furthermore, according to the present invention, it is possible to provide a computer program for diagnosing kidney disease using the above-mentioned kidney disease diagnostic marker.
- N 5 in healthy subjects and each patient group - [(dimethylamino) iminomethyl] - ornithine (hereinafter, also referred to as "ADMA") is a diagram showing the quantitative value of, (a) shows the quantitative value of the urine, (b) Represents the quantitative value in plasma, and (c) represents the ratio between the quantitative value in urine and the quantitative value in plasma. It is a figure which shows the ratio of trimethylglycine in urine (henceforth "TMG”) and guanidinoacetic acid in urine in a healthy subject and each patient group. It is a figure which shows the ratio of TMG in urine and glycolic acid in urine in a healthy subject and each patient group.
- TMG trimethylglycine in urine
- TMG guanidinoacetic acid
- N 6 of TMG and urine in the urine in healthy subjects and each patient group - is a diagram showing the ratio of the acetyl-lysine.
- Healthy subjects and N 1 of TMG and urine in the urine of each patient group - is a diagram showing the ratio of the acetyl histidine.
- FIG. 6 is a flowchart executed by a CPU when the computer-implemented kidney disease diagnosis method of the first embodiment is realized. 6 is a flowchart executed by a CPU when the computer-implemented method for diagnosing kidney disease according to the second embodiment is implemented. 10 is a flowchart executed by a CPU when the computer-implemented method for diagnosing kidney disease according to the third embodiment is implemented.
- the names of substances used as diagnostic markers for kidney disease and their structural formulas according to the present invention are shown in the following chemical formulas 1 to 5.
- the diagnostic marker for kidney disease of the present invention includes one substance shown in Chemical Formulas 1 to 5 or a combination of two substances.
- the diagnostic marker for kidney disease comprising a combination of two substances
- the following combinations of substances 1 to 4 can be mentioned. These combinations 1 to 4 are shown more specifically in Tables 1 to 4, respectively. That is, the diagnostic marker for kidney disease comprising the combination of the two substances of the present invention is selected from the combinations of substance A and substance B shown in each table.
- TMG Trimethylglycine
- ADMA guanidinoacetic acid
- 4-guanidinobutyric acid N 6 -acetyl lysine
- N 1 -acetyl histidine A combination with substance B which is any one selected from histidine.
- Combination 2 A combination of substance A which is glycolic acid and substance B which is any one selected from ADMA, cytidine, valine, kynurenine, 2-oxoglutaric acid, glycocymidine and choline.
- Combination 3 A combination of substance A which is cystine and substance B which is any one selected from N 1 -acetylhistidine, histidine, glycine, tryptophan and methionine.
- kidney disease is not particularly limited as long as it is a disease caused by a lesion in each tissue of the kidney.
- the kidney disease include diabetic nephropathy, glomerulonephritis, tubule / interstitial nephritis, and the like.
- the renal disease diagnostic marker of the present invention can be suitably used as a diagnostic marker for diabetic nephropathy that develops with diabetes among the above-mentioned renal diseases.
- kidney disease It is possible to diagnose kidney disease by using the diagnostic marker for kidney disease of the present invention.
- a diagnostic method is not particularly limited as long as it is performed by measuring the above-described diagnostic marker for kidney disease contained in urine and / or plasma collected from a subject suspected of having kidney disease.
- the concentration of the above-mentioned diagnostic marker for kidney disease in urine and / or plasma collected from a subject suspected of having kidney disease can be measured, and kidney disease can be diagnosed based on the obtained measurement result .
- Diagnosis of kidney disease includes definitive diagnosis of kidney disease, screening test for kidney disease, evaluation of therapeutic effect on kidney disease, and the like, and screening test for kidney disease is particularly preferable.
- the urine collected from the subject is not particularly limited depending on the physical condition of the subject, the presence or absence of medication and medication, the time of collection, etc., but is preferably early morning urine (first urine).
- the plasma collected from the subject is not particularly limited by the physical condition of the subject, the presence or absence of a meal and medication, the collection time, and the like, and may be any plasma obtained from blood collected from the subject.
- Embodiment 1 and Embodiment 2 are methods for diagnosing kidney disease when a diagnostic marker for kidney disease comprising one substance is used.
- Embodiment 1 (1) measuring the concentration of a marker contained in urine or plasma collected from a subject suspected of having kidney disease; (2) comparing the measured marker concentration value with a threshold; (3) Based on the comparison result, it is determined whether or not the subject has kidney disease.
- (Embodiment 2) (1) measuring the concentration of a marker contained in urine and plasma collected from a subject suspected of having kidney disease; (2) obtaining a value relating to the ratio between the measured concentration of the marker in urine and the concentration in plasma; (3) comparing a threshold value with a value relating to a ratio between the concentration of the marker obtained in urine and the concentration in plasma; (4) Based on the comparison result, it is determined whether or not the subject has kidney disease.
- the values relating to the ratio between the urinary concentration and the plasma concentration of the marker include the values of “plasma concentration / urine concentration” and “urine concentration / plasma concentration”. Can be mentioned.
- any of glycolic acid, ADMA, and 5-oxo-2-tetrahydrofurancarboxylic acid is suitable.
- Embodiment 3 is a method for diagnosing kidney disease when a diagnostic marker for kidney disease comprising a combination of two substances is used.
- Embodiment 3 (1) Measure the concentrations of two substances contained in urine and / or plasma collected from a subject suspected of having kidney disease; (2) obtaining a value relating to the ratio of the measured concentrations of the two substances; (3) comparing the acquired value relating to the concentration ratio of the two substances with a threshold; (4) Based on the comparison result, it is determined whether or not the subject has kidney disease.
- the value relating to the ratio of the concentrations of two substances when the two substances constituting the marker are substance A and substance B, respectively, “A (in plasma) / B (in plasma)”, “ A (in plasma) / B (in urine), “A (in urine) / B (in plasma)”, “A (in urine) / B (in urine)”, “B (in plasma) / A ( “Plasma)”, “B (Plasma) / A (Urine)”, “B (Urine) / A (Plasma)” and “B (Urine) / A (Urine)” It is done. “A (in plasma)” and “A (in urine)” indicate the concentrations of substance A in plasma and urine, respectively. “B (in plasma)” and “B (in urine)” The concentrations of substance B in plasma and urine are shown, respectively.
- a marker selected from the above combinations 1 to 4 is preferable.
- the above threshold can be set as follows, for example. First, urine and / or plasma is collected from a person who has previously been confirmed not to have kidney disease (ie, a healthy person) by conventional techniques. Next, for these, the concentration of the diagnostic marker for kidney disease of the present invention is measured, and further, the concentration value and the value relating to the concentration ratio are obtained. Then, the obtained result is set as a predetermined threshold value.
- the threshold value set in this way makes it possible to determine whether a subject diagnosed using the kidney disease diagnostic marker of the present invention is healthy or has kidney disease.
- the threshold value can be set using urine and / or plasma from a patient in the first or second stage of diabetic nephropathy instead of urine and / or plasma collected from a healthy person.
- whether the subject diagnosed using the diagnostic marker for kidney disease of the present invention is the first or second stage of diabetic nephropathy or a more severe kidney disease is determined based on the threshold value.
- the threshold it is preferable that the number of healthy persons and / or diabetic nephropathy patients in the first or second stage from which a sample is collected is plural.
- the method for measuring the concentration of the above-mentioned marker for diagnosis of kidney disease in urine and plasma is not particularly limited, and can be appropriately selected according to the physical or chemical properties of each marker.
- a sample to be measured is prepared from urine or plasma collected from a subject suspected of having kidney disease.
- the marker contained in the sample is separated by high performance liquid chromatography (HPLC), gas chromatography (GC), capillary electrophoresis (CE), or the like.
- HPLC high performance liquid chromatography
- GC gas chromatography
- CE capillary electrophoresis
- the concentration of the marker in urine or plasma can be measured by subjecting the separated marker to a measurement system such as a UV detection method, a fluorescence detection method, or a mass spectrometry (MS).
- a measurement system using a redox electrode method, a colorimetric method, or the like by contacting a marker contained in urine or plasma collected from the subject with an enzyme using the marker as a substrate and causing an enzyme reaction. By attaching to the marker, the concentration of the marker in urine or plasma can be measured.
- FIG. 1 illustrates the variation pattern of the concentration or concentration ratio of the diagnostic marker for kidney disease of the present invention in each disease state of kidney disease.
- “healthy” means a healthy person
- “diabetes” means a patient in the first stage of diabetic nephropathy (early nephropathy)
- “early” means the second stage of diabetic nephropathy.
- the patient of (early nephropathy stage) is shown, and “explicit” shows the patient of diabetic nephropathy 3rd and 4th stage (apparent nephropathy stage).
- FIG. 1a shows a variation pattern in which the marker concentration or concentration ratio tends to increase as the stage of kidney disease progresses from “healthy” to “apparent”.
- FIG. 1b shows a variation pattern in which the marker concentration or the ratio of the concentrations increases from “healthy” to “early”, but is almost constant from “early” to “apparent”.
- FIG. 1c) is a variation pattern in which the marker concentration or concentration ratio tends to decrease as the stage of kidney disease progresses from “healthy” to “apparent”.
- FIG. 1 d) shows a variation pattern in which the marker concentration or the ratio of the concentrations tends to decrease from “healthy” to “early”, but is almost constant from “early” to “obvious”.
- the concentration or the ratio of the concentration of the diagnostic marker for kidney disease of the present invention shows a variation pattern that increases or decreases from “healthy” to “early”. Therefore, kidney disease can be diagnosed by setting the concentration of a marker for diagnosing kidney disease or a ratio of the concentrations that can determine “early” as a threshold.
- “Embodiment 1” using the concentration in urine is preferred as the diagnostic method.
- the concentration of glycolic acid in urine shows a variation pattern that decreases from “healthy” to “early” as shown in FIG. 1c). Therefore, when the value of the concentration of glycolic acid contained in urine collected from a subject is lower than a predetermined threshold, it can be diagnosed that the subject has kidney disease.
- “Embodiment 1” using the concentration in urine is preferred as the diagnostic method.
- the concentration of 5-oxo-2-tetrahydrofurancarboxylic acid in urine shows a fluctuation pattern that decreases from “healthy” to “early” as shown in FIG. 1c). Therefore, when the concentration of 5-oxo-2-tetrahydrofurancarboxylic acid contained in urine collected from a subject is lower than a predetermined threshold, it can be diagnosed that the subject has kidney disease.
- Embodiment 1 When diagnosis is performed using N 5 -[(dimethylamino) iminomethyl] -ornithine (ADMA) as a diagnostic marker for kidney disease, “Embodiment 1” using concentrations in urine as diagnostic methods and urine and plasma “Embodiment 2” using medium concentrations is preferred.
- the concentration of ADMA in urine shows a variation pattern that decreases from “healthy” to “early” as shown in FIG. 1c). Therefore, when the value of the concentration of ADMA contained in urine collected from the subject is lower than the predetermined threshold, it can be determined that the subject has kidney disease.
- the value of the concentration of ADMA in plasma / the concentration in urine shows a variation pattern that increases from “healthy” to “early” as shown in FIG. 1a). Therefore, when the value of ADMA plasma concentration / urine concentration is higher than a predetermined threshold, it can be determined that the subject has kidney disease.
- the ratio of the concentrations of the two substances is preferably the concentration of trimethylglycine in urine and urine It is a ratio with the density
- the value relating to the ratio of the concentrations of the two substances is preferably the concentration of glycolic acid in urine and It is the value of the ratio to the concentration of substance B described in Table 2 in plasma or urine.
- the value for the ratio of the two substance concentrations is more preferably the concentration of glycolic acid in urine and the concentration of substance B in plasma And the ratio value.
- the value relating to the ratio of the concentrations of the two markers is more preferably the ratio between the concentration of glycolic acid in urine and the concentration of substance B in urine Is the value of
- the value relating to the ratio of the concentrations of the two substances is preferably the concentration of cystine in urine, It is the value of the ratio with the concentration of substance B described in Table 3 in urine.
- the value relating to the ratio of the concentrations of the two substances is preferably the concentration of tryptophan in plasma, It is the value of the ratio with the concentration of ornithine in plasma.
- the computer program of the present invention is a computer program for causing a computer to realize the above-described diagnostic method using the renal disease diagnostic marker of the present invention, preferably the above-described renal disease diagnostic method of Embodiments 1 to 3.
- the computer program of the present invention acquires a concentration of a diagnostic marker for kidney disease of the present invention contained in urine and / or plasma collected from a subject suspected of having kidney disease (hereinafter also referred to as “acquisition step”). ); Determining whether or not the subject has kidney disease based on the acquired concentration (hereinafter, also referred to as “determination step”); and outputting a determination result; Can be executed by a computer.
- the computer program further causes the computer to execute a step of comparing the value of the marker concentration obtained by the obtaining step with a threshold value.
- the obtaining step comprises glycolic acid, N 5 -[(dimethylamino) iminomethyl] -ornithine and 5-oxo-2-tetrahydrofurancarboxyl contained in urine or plasma collected from a subject suspected of having kidney disease.
- the step of obtaining the concentration value of at least one marker selected from acids is the step of determining whether or not the subject has kidney disease based on the comparison result obtained by the comparison step. .
- the computer program of this invention can make a computer implement
- the computer program causes the computer to calculate the urine concentration and the plasma concentration of the marker from the values of the urine and plasma marker concentrations obtained by the obtaining step.
- the obtaining step comprises glycolic acid, N 5 -[(dimethylamino) iminomethyl] -ornithine and 5-oxo-2-tetrahydrofurancarboxyl contained in urine and plasma collected from a subject suspected of having kidney disease.
- the computer program of this invention can make a computer implement
- the computer program causes the computer to store the concentration of one substance of a diagnostic marker for kidney disease consisting of a combination of two substances in urine and / or plasma obtained by the obtaining step. And a calculation step of calculating a value related to the ratio of the concentration of the two substances from the concentration of the other substance; and a comparison step of comparing the calculated value related to the ratio of the concentration of the two substances with a threshold value .
- the obtaining step includes at least one marker substance selected from a diagnostic marker for kidney disease consisting of a combination of two substances contained in urine and plasma collected from a subject suspected of having kidney disease.
- the concentration value is acquired, and the determination step is a step of determining whether or not the subject has kidney disease based on the comparison result obtained in the comparison step.
- the computer program of this invention can make a computer implement
- the combination of two substances in urine and / or plasma is a combination of trimethylglycine and N 5 -[(dimethylamino) iminomethyl] -ornithine or guanidinoacetic acid. .
- the scope of the present invention includes a computer-readable storage medium storing the above computer program.
- FIG. 28 shows an example of a computer system in which such a computer program of the present invention operates.
- the computer 100 mainly includes a main body 110, a display unit 120, and an input device 130.
- the CPU 110a, the ROM 110b, the RAM 110c, the hard disk 110d, the reading device 110e, the input / output interface 110f, and the image output interface 110g are connected to each other via a bus 110h so that data communication is possible.
- the CPU 110a can execute computer programs stored in the ROM 110b and computer programs loaded in the RAM 110c.
- the ROM 110b is configured by a mask ROM, PROM, EPROM, EEPROM, or the like, and stores a computer program executed by the CPU 110a and data used therefor.
- the RAM 110c is configured by SRAM, DRAM, or the like.
- the RAM 110c is used to read out computer programs recorded in the ROM 110b and the hard disk 110d.
- the RAM 110c is used as a work area when the CPU 110a executes these computer programs.
- the hard disk 110d is installed with various computer programs to be executed by the CPU 110a, such as an operating system and application system program, and data used for executing the computer program.
- a computer program 140a for causing the computer 100 to implement the kidney disease diagnosis method of the first to third embodiments described later and the threshold used in the first to third embodiments are also installed in the hard disk 110d.
- the reading device 110e is configured by a flexible disk drive, a CD-ROM drive, a DVD-ROM drive, or the like, and can read a computer program or data recorded on the portable storage medium 140.
- the portable storage medium 140 is a storage medium known per se in the art, such as a flexible disk, CD-ROM, or DVD-ROM.
- a computer program 140a related to the determination by the computer as to whether or not the subject has kidney disease is recorded so as to be readable by the computer.
- the CPU 110a can also read the computer program 140a from the portable storage medium 140 and install it on the hard disk 110d.
- the input / output interface 110f includes, for example, a serial interface such as USB, IEEE 1394, and RS-232C, a parallel interface such as SCSI, IDE, and IEEE 1284, and an analog interface including a D / A converter and an A / D converter.
- the An input device 130 including a keyboard and a mouse is connected to the input / output interface 110f. Therefore, by using the input device 130 by the user, it is possible to input data on the concentration of a diagnostic marker for kidney disease contained in urine and plasma collected from the subject into the computer main body 110.
- the input / output interface 110f can be connected to a measuring device 200 that can measure the concentration of a diagnostic marker for kidney disease contained in urine and plasma collected from a subject. In this case, concentration data of a diagnostic marker for kidney disease can be input from the measuring apparatus 200 to the computer main body 110.
- the image output interface 110h is connected to the display unit 120 configured by an LCD or a CRT, and outputs a video signal to the display unit 120 in accordance with image data given from the CPU 110a.
- the display unit 120 outputs image data according to the input video signal. Further, the display unit 120 outputs a determination result given from a CPU 110a described later.
- FIG. 29 is a diagram illustrating a flowchart executed by the CPU 110a when the computer 100 realizes the kidney disease diagnosis method of the first embodiment.
- the CPU 110a stores the concentration value of glycolic acid via the input / output interface 110f in the RAM 110c and the hard disk. 110d is stored (step S11).
- the CPU 110a determines that the subject has kidney disease if the concentration value of glycolic acid is lower than the threshold value (step S13). Further, if the concentration value of glycolic acid is equal to or greater than the threshold value, the CPU 110a determines that the subject has no kidney disease (step S14).
- the CPU 110a stores the determination result in the hard disk 110d and outputs it to the display unit 120 via the image output interface 110g (step S15).
- glycolic acid was used as a diagnostic marker for kidney disease, but the present invention is not limited thereto.
- 5-oxo-2-tetrahydrofurancarboxylic acid and / or ADMA can also be used as a diagnostic marker for kidney disease.
- FIG. 30 is a diagram illustrating a flowchart executed by the CPU 110a when the computer 100 realizes the kidney disease diagnosis method of the second embodiment.
- the CPU 110a stores the value of ADMA concentration in the RAM 110c and the hard disk 110d (step S21). ).
- the CPU 110a reads the value of the concentration of ADMA contained in the urine and plasma stored in the RAM 110c, calculates the value of “the concentration in plasma / the concentration in urine” of ADMA (step S22), and stores it in the RAM 110c.
- the CPU 110a determines that the subject has kidney disease if the value of ADMA “concentration in plasma / concentration in urine” is higher than a threshold value (step S24). CPU 110a determines that the subject is not suffering from kidney disease if the value of ADMA “concentration in plasma / concentration in urine” is equal to or less than a threshold value (step S25).
- the CPU 110a stores the above determination result in the hard disk 110d and outputs it to the display unit 120 via the image output interface 110g (step S26).
- FIG. 31 is a diagram illustrating a flowchart executed by the CPU 110a when the computer 100 realizes the kidney disease diagnosis method of the third embodiment.
- the CPU 110a receives these concentrations via the input / output interface 110f. Is stored in the RAM 110c and the hard disk 110d (step S31).
- the CPU 110a calculates the value of “the concentration of TMG in urine / the concentration of glycolic acid in urine” from the value of the concentration of TMG in urine and the value of concentration of glycolic acid (step S32).
- the CPU 110a determines that the subject has kidney disease if the value of “concentration of TMG in urine / concentration of glycolic acid in urine” is higher than a threshold value (step S34). CPU 110a determines that the subject is not suffering from kidney disease if the value of “concentration of TMG in urine / concentration of glycolic acid in urine” is equal to or less than a threshold value (step S35).
- the CPU 110a stores the determination result in the hard disk 110d and outputs it to the display unit 120 via the image output interface 110g (step S36).
- a combination of TMG and glycolic acid is used as a diagnostic marker for kidney disease, but this is not a limitation. That is, as a diagnostic marker for kidney disease, the diagnostic markers for kidney disease of combinations 1 to 4 shown in Tables 1 to 4 can be used.
- the urinary ratio between TMG and glycolic acid (the value of “the concentration of TMG in urine / the concentration of glycolic acid in urine”) is used as the value relating to the concentration ratio, it is not limited to this.
- the value relating to the concentration ratio can be appropriately set depending on the combination of substances used as a diagnostic marker for kidney disease. More specifically, the values relating to the ratio of concentrations shown in Tables 7 to 10 of Example 2 described later can be set according to the diagnostic marker for kidney disease to be used.
- concentration of the marker was input via the input device 130 by the user, it is not limited to this.
- the marker concentration may be input from the measurement apparatus 200 connected via the input / output interface 110f.
- the marker concentration measured by the measuring device 200 may be stored in the portable storage medium 140, and the reading device 110e may read the marker concentration from the portable storage medium 140.
- Example 1 Metabolome analysis was performed as follows. (1) Sample Plasma and early morning urine collected from the same day from 60 healthy subjects and 40 patients from the following 40 patient groups were used as samples.
- the patient group consists of 19 diabetic patients, 12 diabetic nephropathy stage 2 (early nephropathy stage) patients, 7 diabetic nephropathy stage 3 and 4 (explicit nephropathy stage) patients, and chronic kidney There were 2 patients with disease (CKD).
- a chronic kidney disease patient is a patient with non-diabetic nephropathy. That is, by using the data obtained from a patient with chronic kidney disease as a positive control, it is shown that the results obtained in this example are not due to diabetes.
- Plasma sample Add 50 ⁇ L of plasma to 450 ⁇ L of methanol solution containing both L-methionine sulfone and D-camphor-10-sulfonic acid as internal standard substances at a final concentration of 10 ⁇ M and stir. did. To this, 500 ⁇ L of chloroform and 200 ⁇ L of distilled water were added and stirred, followed by centrifugation (2,300 ⁇ g, 4 ° C., 5 minutes).
- the aqueous phase was transferred to an ultrafiltration tube (Ultra Free MCPBCC centrifugal filter unit 5 kDa: manufactured by MILLIPORE) (200 ⁇ L ⁇ 2) and subjected to ultrafiltration (9,100 ⁇ g, 4 ° C., 120 minutes).
- the filtrate was dried and dissolved in 25 ⁇ L of distilled water to obtain a plasma sample.
- the sample diluted 2 times was used for the measurement mentioned later.
- Each substance was identified by the following procedure. Substance groups were separated by CE according to ionic strength (see FIG. 2), and MS was measured continuously (see FIG. 3). Each substance has CE migration time (min) (hereinafter may be abbreviated as MT) and mass-to-charge ratio (m / z) (value up to the fourth decimal place; hereinafter abbreviated as m / z) Information). And the exact mass was calculated
- min CE migration time
- m z mass-to-charge ratio
- MS / MS measurement of a standard substance was performed (see FIG. 4). Then, MT, m / z, and MS / MS data of the substance to be identified and the standard substance were collated. When the respective data matched, it was determined that the substance to be identified was the same as the standard substance. Table 5 shows the MT value and m / z value of each identified substance.
- the measured values of glycolic acid or 5-oxo-2-tetrahydrofurancarboxylic acid in urine show a variation pattern that decreases from “healthy” to “early” as shown in FIG. 1c). Therefore, it was shown that whether or not the subject has kidney disease can be determined using the value of the concentration of glycolic acid or 5-oxo-2-tetrahydrofurancarboxylic acid contained in urine collected from the subject.
- the ratio of ADMA between urine and plasma tends to increase from “healthy” to “early” as shown in FIG. 1a). Therefore, it was shown that the urine and plasma collected from a subject can be used to determine whether or not the subject has kidney disease using the value of the concentration in plasma / the concentration in urine.
- Example 2 About the substance identified in Example 1, the substance which can become a marker was selected by the combination.
- the combination of urine and plasma concentrations of each substance in healthy subjects and patients with kidney disease in each case was examined.
- the ratio obtained by dividing the value of the concentration of one substance by the value of the concentration of the other substance represents the fluctuation pattern of the ratio of the concentration of each disease state of kidney disease as shown in FIG.
- the combinations shown were marker candidate combinations.
- Tables 7 to 10 show the relationship between the value related to the ratio of the concentration of the marker composed of the combination of the two substances and the variation pattern of the value related to the concentration ratio in each disease state of kidney disease.
- the value obtained by dividing the concentration value of substance B in plasma or urine by the value of the concentration of glycolic acid (substance A) in urine tend to increase from “healthy” to “early” as shown in FIG. 1a) or b). Therefore, in the urine and plasma collected from the subject, the values of B (plasma) / A (in urine) or B (in urine) / A (in urine) of the two substances shown in Table 8 are used. It has been shown that it can be determined whether or not the subject has kidney disease.
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Physics & Mathematics (AREA)
- Biomedical Technology (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- General Health & Medical Sciences (AREA)
- Analytical Chemistry (AREA)
- Pathology (AREA)
- General Physics & Mathematics (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- Medicinal Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Food Science & Technology (AREA)
- Cell Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Electrochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Bioinformatics & Computational Biology (AREA)
- Biophysics (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
Description
したがって、正確な診断により腎臓病の患者を早期に発見することが重要である。
また、腎臓病の診断マーカーとして、尿中微量アルブミン、IV型コラーゲン、トランスフェリン、IgG、ラミニン、フィブロネクチン、α-1ミクログロブリン、β-2ミクログロブリン、シスタチンC、N-アセチル-β-D-グルコサミニダーゼ(NAG)、L型脂肪酸結合タンパク(L-FABP)、グリコシアミジン及びその誘導体なども用いられている(特許文献1及び2参照)。
グリコール酸;
N5-[(ジメチルアミノ)イミノメチル]-オルニチン;
5-オキソ-2-テトラヒドロフランカルボン酸;
トリメチルグリシンと、グリコール酸、N5-[(ジメチルアミノ)イミノメチル]-オルニチン、グアニジノ酢酸、4-グアニジノ酪酸、N6-アセチルリシン、N1-アセチルヒスチジン及びヒスチジンから選択されるいずれか1つとからなる組合せ;
グリコール酸と、N5-[(ジメチルアミノ)イミノメチル]-オルニチン、シチジン、バリン、キヌレニン、2-オキソグルタル酸、グリコシアミジン及びコリンから選択されるいずれか1つとからなる組合せ;
シスチンと、N1-アセチルヒスチジン、ヒスチジン、グリシン、トリプトファン及びメチオニンから選択されるいずれか1つとからなる組合せ;及び
トリプトファンとオルニチンとからなる組合せ;
の少なくとも1つから選択される、腎臓病の診断用マーカーが提供される。
腎臓病が疑われる被験者から採取された尿及び/又は血漿に含まれる、上記の診断用マーカーの濃度を取得する取得ステップ;
取得された濃度に基づいて、被験者が腎臓病であるか否かを判定する判定ステップ;及び
判定結果を出力する出力ステップ;
を実行させるためのコンピュータプログラムが提供される。
さらに、本発明によれば、上記の腎臓病診断用マーカーを用いる腎臓病の診断のためのコンピュータプログラムを提供できる。
トリメチルグリシン(TMG)である物質Aと、グリコール酸、N5-[(ジメチルアミノ)イミノメチル]-オルニチン(ADMA)、グアニジノ酢酸、4-グアニジノ酪酸、N6-アセチルリシン、N1-アセチルヒスチジン及びヒスチジンから選択されるいずれか1つである物質Bとの組合せ。
グリコール酸である物質Aと、ADMA、シチジン、バリン、キヌレニン、2-オキソグルタル酸、グリコシアミジン及びコリンから選択されるいずれか1つである物質Bとの組合せ。
シスチンである物質Aと、N1-アセチルヒスチジン、ヒスチジン、グリシン、トリプトファン及びメチオニンから選択されるいずれか1つである物質Bとの組合せ。
トリプトファンである物質Aとオルニチンである物質Bとの組合せ。
本発明の腎臓病の診断用マーカーは、上記の腎臓病の中でも、糖尿病に伴って発症する糖尿病性腎症の診断用マーカーとして好適に用いることができる。
(実施形態1)
(1)腎臓病が疑われる被験者から採取された尿又は血漿に含まれるマーカーの濃度を測定する;
(2)測定されたマーカーの濃度の値と、閾値とを比較する;
(3)比較結果に基づいて、該被験者が腎臓病であるか否かを判定する。
(1)腎臓病が疑われる被験者から採取された尿及び血漿に含まれるマーカーの濃度を測定する;
(2)測定された該マーカーの尿中の濃度と血漿中の濃度との比に関する値を取得する;
(3)取得した該マーカーの尿中の濃度と血漿中の濃度との比に関する値と、閾値とを比較する;
(4)比較結果に基づいて、該被験者が腎臓病であるか否かを判定する。
(実施形態3)
(1)腎臓病が疑われる被験者から採取された尿及び/又は血漿に含まれる2つの物質の各濃度を測定する;
(2)測定された該2つの物質の濃度の比に関する値を取得する;
(3)取得した該2つの物質の濃度の比に関する値と、閾値とを比較する;
(4)比較結果に基づいて、該被験者が腎臓病であるか否かを判定する。
なお、「A(血漿中)」及び「A(尿中)」は、それぞれ血漿中及び尿中の物質Aの濃度を示し、「B(血漿中)」及び「B(尿中)」は、それぞれ血漿中及び尿中の物質Bの濃度を示す。
また、上記の閾値は、健常者から採取した尿及び/又は血漿に代えて、糖尿病性腎症第1又は第2期の患者からの尿及び/又は血漿を用いて設定することもできる。この場合、その閾値により、本発明の腎臓病の診断用マーカーを用いて診断される被験者が、糖尿病性腎症第1又は第2期であるか、或いはより重症の腎臓病であるかの判定を可能にする。
なお、閾値の設定において、検体を採取される健常者及び/又は糖尿病性腎症第1又は第2期の患者の人数は、複数であることが好ましい。
例えば、腎臓病が疑われる被験者から採取された尿又は血漿から測定されるべきサンプルを調製する。次に、該サンプルに含まれるマーカーを高速液体クロマトグラフィー(HPLC)、ガスクロマトグラフィー(GC)、キャピラリー電気泳動(CE)などで分離する。そして、分離したマーカーを、UV検出法、蛍光検出法、質量分析法(MS)などによる測定系に付すことによって、尿中又は血漿中のマーカーの濃度を測定できる。
或いは、該被験者から採取された尿又は血漿に含まれるマーカーと、該マーカーを基質とする酵素とを接触させて、酵素反応により生じた物質を、酸化還元電極法、比色法などによる測定系に付すことによって、尿中又は血漿中のマーカーの濃度を測定できる。
図1b)は、「健常」から「早期」までマーカーの濃度又は濃度の比が増加傾向を示すが、「早期」から「顕性」まではほぼ一定である変動パターンである。
図1c)は、「健常」から「顕性」まで腎臓病の段階が進行するにしたがって、マーカーの濃度又は濃度の比が減少する傾向にある変動パターンである。
図1d)は、「健常」から「早期」までマーカーの濃度又は濃度の比が減少傾向を示すが、「早期」から「顕性」まではほぼ一定である変動パターンである。
このように、本発明の腎臓病の診断用マーカーの濃度又は濃度の比は、「健常」から「早期」にかけて、増加又は減少する変動パターンを示す。そのため、閾値として、「早期」を判別できる、腎臓病の診断用マーカーの濃度又は濃度の比を設定することで、腎臓病の診断を行うことができる。
したがって、被験者から採取された尿に含まれるグリコール酸の濃度の値が、所定の閾値より低い場合、該被験者が腎臓病であると診断できる。
したがって、被験者から採取された尿に含まれる5-オキソ-2-テトラヒドロフランカルボン酸の濃度の値が、所定の閾値より低い場合、該被験者が腎臓病であると診断できる。
実施形態1の場合、尿中のADMAの濃度は、図1c)のように「健常」から「早期」にかけて減少する変動パターンを示す。
したがって、被験者から採取された尿に含まれるADMAの濃度の値が、所定の閾値より低い場合に、該被験者が腎臓病であると判定することができる。
また、実施形態2の場合、ADMAの血漿中の濃度/尿中の濃度の値は、図1a)のように「健常」から「早期」にかけて増加する変動パターンを示す。
したがって、ADMAの血漿中の濃度/尿中の濃度の値が、所定の閾値より高い場合に、該被験者が腎臓病であると判定することができる。
特に、物質BがADMA、キヌレニン、2-オキソグルタル酸又はコリンである場合、2つの物質の濃度の比に関する値は、より好ましくは尿中のグリコール酸の濃度と、血漿中の該物質Bの濃度との比の値である。また、物質Bがバリン、シチジン又はグリコシアミジンである場合、2つのマーカーの濃度の比に関する値は、より好ましくは尿中のグリコール酸の濃度と、尿中の該物質Bの濃度との比の値である。
本発明のコンピュータプログラムは、腎臓病が疑われる被験者から採取された尿及び/又は血漿に含まれる、本発明の腎臓病の診断用マーカーの濃度を取得するステップ(以下、「取得ステップ」ともいう);
取得された濃度に基づいて、該被験者が腎臓病であるか否かを判定するステップ(以下、「判定ステップ」ともいう);及び
判定結果を出力するステップ;
をコンピュータに実行させることができる。
なお、より好ましい実施形態においては、上記の尿中及び/又は血漿中の2つの物質の組合せは、トリメチルグリシンと、N5-[(ジメチルアミノ)イミノメチル]-オルニチン又はグアニジノ酢酸との組合せである。
RAM110cは、SRAM又はDRAMなどによって構成される。RAM110cは、ROM110b及びハードディスク110dに記録されているコンピュータプログラムの読み出しに用いられる。また、RAM110cは、CPU110aがこれらのコンピュータプログラムを実行するときの作業領域として利用される。
可搬型記憶媒体140は、フレキシブルディスク、CD-ROM又はDVD-ROMなどの当該技術においてそれ自体公知の記憶媒体である。可搬型記憶媒体140には、被験者が腎臓病であるか否かのコンピュータによる判定に係るコンピュータプログラム140aが、コンピュータに読み取り可能に記録されている。CPU110aは、可搬型記憶媒体140からコンピュータプログラム140aを読み出し、これをハードディスク110dにインストールすることも可能である。
以下の説明において、腎臓病の判定に係るコンピュータプログラム140aは、該オペレーティングシステム上で動作するものとする。
図29は、上記の実施形態1の腎臓病の診断方法をコンピュータ100に実現させる場合に、CPU110aによって実行されるフローチャートを示す図である。
以下のようにしてメタボローム解析を行った。
(1)サンプル
健常者20名と以下の患者群40名の計60名から同一日に採取した血漿及び早朝尿を検体として用いた。
患者群は、糖尿病患者19名、糖尿病性腎症第2期(早期腎症期)患者12名、糖尿病性腎症第3及び第4期(顕性腎症期)患者7名、並びに慢性腎臓病(CKD)患者2名であった。
なお、慢性腎臓病患者とは、非糖尿病性腎症の患者である。すなわち、慢性腎臓病患者から得られたデータを陽性対照とすることにより、本実施例で得られた結果が糖尿病に起因するものではないことが示される。
(2-1)血漿サンプル
内部標準物質としてL-メチオニンスルホン及びD-カンフル-10-スルホン酸の両方を終濃度10μMで含むメタノール溶液450μLに、血漿50μLを添加して撹拌した。これにクロロホルム500μLと蒸留水200μLを加えて攪拌し、遠心分離(2,300×g、4℃、5分)を行った。そして、水相を限外ろ過チューブ(ウルトラフリーMCPBCC遠心式フィルターユニット5kDa:MILLIPORE社製)に移し(200μL×2本分)、限外ろ過処理(9,100×g、4℃、120分)した。ろ液を乾固させ、これを蒸留水25μLに溶解して、血漿サンプルを得た。なお、後述する測定には2倍希釈したサンプルを用いた。
尿20μLに、上記の内部標準物質を終濃度250μMで含む蒸留水80μLを加えて撹拌した後、これを限外ろ過チューブ(ウルトラフリーMCPBCC遠心式フィルターユニット5kDa:MILLIPORE社製)に移し取った。これを限外ろ過処理(9,100×g、4℃、60分)した。ろ液を乾固させ、これを蒸留水25μLに溶解して、尿サンプルを得た。なお、後述するカチオン測定及びアニオン測定には、それぞれ10倍希釈及び5倍希釈したサンプルを用いた。
装置として、Agilent CE-TOF/MS system(Agilent Technologies社)を用い、キャピラリーとして、Fused silica capillary i.d.50μm×80 cmを用いた。
また、測定条件は、以下のとおりである。
CE voltage:カチオン;27 kV、アニオン;30 kV
MS ionization:ESI Positive or Negative
MS capillary voltage:カチオン;4,000 V、アニオン;3,500 V
MS scan range:m/z 50~1,000
Sample injection:カチオン;50 mbar、10秒、アニオン;50 mbar、25秒
各物質の同定は、以下の手順で行った。
CEにより物質群をイオン強度に伴って分離し(図2参照)、連続してMS測定した(図3参照)。各物質はCEの移動時間(分)(以下、MTと略称する場合がある)及び質量電荷比(m/z)(小数点以下第4位までの値;以下、m/zと略称する場合がある)の情報を取得した。そして、同定対象の物質の質量電荷比から、精密質量を求めた。また、同定対象の物質の精密質量に基づいて、推定の化学構造をもつ物質(標準物質)を探索し、標準物質のCE-MS測定を行った。
さらに、部分構造情報(プロダクトイオン)を得るために、標準物質のMS/MS測定を行った(図4参照)。そして、同定対象の物質と標準物質とのMT、m/z及びMS/MSデータを照合した。それぞれのデータが一致した場合に、同定対象の物質が、標準物質と同一であると判定した。同定された各物質のMT値及びm/z値を、表5に示す。
上記の(3)のCE-MSによる測定で得られたMSピークの数は、血漿サンプルでは700ピーク、尿サンプルでは902ピークであった。これらについて、血漿サンプルでは内部標準物質により補正し、尿サンプルでは内部標準物質及び尿クレアチニンにより補正した相対ピーク面積値を用いて、マーカー候補物質の選出を行った。結果を図5~7に示す。また、単独でマーカーとなり得る物質を表6に示す。
したがって、被験者から採取された尿に含まれるグリコール酸又は5-オキソ-2-テトラヒドロフランカルボン酸の濃度の値を用いて、被験者が腎臓病であるか否かを判定できることが示された。
また、尿中と血漿中とのADMAの比率は、図1a)に示されるような「健常」から「早期」にかけて増加する傾向を示す。
したがって、被験者から採取された尿及び血漿において血漿中の濃度/尿中の濃度の値を用いて、該被験者が腎臓病であるか否かをと判定できることが示された。
実施例1で同定された物質について、組み合わせによりマーカーとなり得る物質の選出を行った。健常者及び各症例の腎臓病患者における各物質の尿中及び血漿中の濃度の組み合わせについて検討した。
2つの物質の組合せにおいて、一方の物質の濃度の値を他方の物質の濃度の値で除して得た比率が、図1に示すような腎臓病の各病態の濃度の比の変動パターンを示す組合せをマーカー候補の組合せとした。
得られた結果を図8~27に示す。また、2つの物質の組合せからなるマーカーの濃度の比に関する値と、腎臓病の各病態における濃度の比に関する値の変動パターンとの関係を、表7~10に示す。
したがって、被験者から採取された尿において、表7に示される2つの物質のA(尿中)/B(尿中)の値を用いて、該被験者が腎臓病であるか否かを判定できることが示された。
したがって、被験者から採取された尿及び血漿において、表8に示される2つの物質のB(血漿中)/A(尿中)又はB(尿中)/A(尿中)の値を用いて、該被験者が腎臓病であるか否かを判定できることが示された。
したがって、被験者から採取された尿において、表9に示される2つの物質のA(尿中)/B(尿中)の値を用いて、該被験者が腎臓病であるか否かを判定できることが示された。
したがって、被験者から採取された尿において、表10に示される2つの物質のB(血漿中)/A(血漿中)の値を用いて、該被験者が腎臓病であるか否かを判定できることが示された。
110 本体
110a CPU
110b ROM
110c RAM
110d ハードディスク
110e 読出装置
110f 入出力インターフェース
110g 画像出力インターフェース
110h バス
120 表示部
130 入出力デバイス
140 可搬型記憶媒体
140a コンピュータプログラム
200 測定装置
Claims (7)
- グリコール酸;
N5-[(ジメチルアミノ)イミノメチル]-オルニチン;
5-オキソ-2-テトラヒドロフランカルボン酸;
トリメチルグリシンと、グリコール酸、N5-[(ジメチルアミノ)イミノメチル]-オルニチン、グアニジノ酢酸、4-グアニジノ酪酸、N6-アセチルリシン、N1-アセチルヒスチジン及びヒスチジンから選択されるいずれか1つとからなる組合せ;
グリコール酸と、N5-[(ジメチルアミノ)イミノメチル]-オルニチン、シチジン、バリン、キヌレニン、2-オキソグルタル酸、グリコシアミジン及びコリンから選択されるいずれか1つとからなる組合せ;
シスチンと、N1-アセチルヒスチジン、ヒスチジン、グリシン、トリプトファン及びメチオニンから選択されるいずれか1つとからなる組合せ;及び
トリプトファンとオルニチンとからなる組合せ;
の少なくとも1つから選択される腎臓病の診断用マーカー。 - 腎臓病が、糖尿病性腎症である、請求項1に記載の診断用マーカー。
- コンピュータに、
腎臓病が疑われる被験者から採取された尿及び/又は血漿に含まれる、請求項1に記載の腎臓病の診断用マーカーの濃度を取得するステップ;
取得された濃度に基づいて、前記被験者が腎臓病であるか否かを判定するステップ;及び
判定結果を出力するステップ;
を実行させるためのコンピュータプログラム。 - コンピュータに、取得ステップにより取得されたマーカーの濃度の値と、閾値とを比較するステップをさらに実行させ、
取得ステップが、腎臓病が疑われる被験者から採取された尿又は血漿に含まれる、グリコール酸、N5-[(ジメチルアミノ)イミノメチル]-オルニチン及び5-オキソ-2-テトラヒドロフランカルボン酸から選択される少なくとも1つのマーカーの濃度の値を取得するステップであり、
判定ステップが、比較ステップにより得られた比較結果に基づいて、被験者が腎臓病であるか否かを判定するステップである、
請求項3に記載のコンピュータプログラム。 - コンピュータに、
取得ステップにより取得された尿中及び血漿中のマーカーの濃度の値から、前記マーカーの尿中の濃度と血漿中の濃度との比に関する値を算出するステップ;及び
算出された前記マーカーの尿中の濃度と血漿中の濃度の比に関する値と、閾値とを比較するステップ;
をさらに実行させ、
取得ステップが、腎臓病が疑われる被験者から採取された尿及び血漿に含まれる、グリコール酸、N5-[(ジメチルアミノ)イミノメチル]-オルニチン及び5-オキソ-2-テトラヒドロフランカルボン酸から選択される少なくとも1つ物質の濃度の値を取得するステップであり、
判定ステップが、比較ステップにより得られた比較結果に基づいて、被験者が腎臓病であるか否かを判定するステップである、
請求項3に記載のコンピュータプログラム。 - コンピュータに、
取得ステップにより取得された尿中及び/又は血漿中の2つの物質の組合せからなる腎臓病の診断用マーカーの一方の物質の濃度と他方の物質の濃度とから、2つの物質の濃度の比に関する値を算出する算出ステップ;及び
算出された2つの物質の濃度の比に関する値と、閾値とを比較する比較ステップ;
をさらに実行させ、
取得ステップが、腎臓病が疑われる被験者から採取された尿及び血漿に含まれる、2つの物質の組合せからなる腎臓病の診断用マーカーから選択される少なくとも1つのマーカーの物質の濃度の値を取得するステップであり、
判定ステップが、比較ステップにより得られた比較結果に基づいて、被験者が腎臓病であるか否かを判定するステップである、
請求項3に記載のコンピュータプログラム。 - 腎臓病の診断用マーカーが、トリメチルグリシンと、N5-[(ジメチルアミノ)イミノメチル]-オルニチン又はグアニジノ酢酸との組合せである、請求項6に記載のコンピュータプログラム。
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP11775009.1A EP2565646B1 (en) | 2010-04-27 | 2011-04-26 | Diagnostic marker for kidney diseases and use thereof |
CN2011800207529A CN102859357A (zh) | 2010-04-27 | 2011-04-26 | 肾脏病诊断用标志物及其利用 |
JP2012512860A JP5832425B2 (ja) | 2010-04-27 | 2011-04-26 | 腎臓病診断用マーカー及びその利用 |
US13/660,440 US8927221B2 (en) | 2010-04-27 | 2012-10-25 | Diagnostic marker for kidney diseases and use thereof |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2010-102374 | 2010-04-27 | ||
JP2010102374 | 2010-04-27 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/660,440 Continuation US8927221B2 (en) | 2010-04-27 | 2012-10-25 | Diagnostic marker for kidney diseases and use thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2011136228A1 true WO2011136228A1 (ja) | 2011-11-03 |
Family
ID=44861526
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2011/060178 WO2011136228A1 (ja) | 2010-04-27 | 2011-04-26 | 腎臓病診断用マーカー及びその利用 |
Country Status (5)
Country | Link |
---|---|
US (1) | US8927221B2 (ja) |
EP (1) | EP2565646B1 (ja) |
JP (1) | JP5832425B2 (ja) |
CN (1) | CN102859357A (ja) |
WO (1) | WO2011136228A1 (ja) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013115283A1 (ja) * | 2012-01-31 | 2013-08-08 | 味の素株式会社 | 早期腎症の評価方法、早期腎症評価装置、早期腎症評価方法、早期腎症評価プログラム、早期腎症評価システムおよび情報通信端末装置 |
JP2017223694A (ja) * | 2012-08-13 | 2017-12-21 | ランドックス ラボラトリーズ リミテッド | 腎疾患バイオマーカー |
WO2019124267A1 (ja) * | 2017-12-18 | 2019-06-27 | 国立研究開発法人国立成育医療研究センター | ニーマンピック病c型の診断のための検査方法 |
WO2019244140A1 (ja) * | 2018-06-21 | 2019-12-26 | マルハニチロ株式会社 | 腎機能維持及び保護剤、並びに、その効果評価方法 |
JP2020002125A (ja) * | 2018-06-21 | 2020-01-09 | マルハニチロ株式会社 | 腎機能維持及び保護剤、並びに、その効果評価方法 |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20130276513A1 (en) * | 2010-10-14 | 2013-10-24 | The Regents Of The University Of California | Methods for diagnosing and assessing kidney disease |
KR101361038B1 (ko) * | 2013-02-21 | 2014-02-12 | 경북대학교 산학협력단 | 신장 이식 후 환자의 뇨 시료로부터 사구체여과율을 예측하는 방법 |
JP2018048962A (ja) * | 2016-09-23 | 2018-03-29 | シスメックス株式会社 | 糖尿病性腎症の進行リスクの診断を補助する方法及び装置 |
TWI839361B (zh) * | 2018-06-21 | 2024-04-21 | 中國醫藥大學 | 腎病變小分子生物標記及其應用 |
CN109161591A (zh) * | 2018-08-01 | 2019-01-08 | 上海交通大学医学院附属瑞金医院 | 单基因遗传性肾脏病基因联合筛查方法、试剂盒及其制备方法 |
US20230137741A1 (en) | 2021-11-01 | 2023-05-04 | Matterworks Inc | Methods and compositions for analyte quantification |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH02288867A (ja) * | 1989-02-01 | 1990-11-28 | Nippon Zoki Pharmaceut Co Ltd | グリコシアミジン誘導体 |
JP2001174459A (ja) * | 1999-12-17 | 2001-06-29 | Nippon Zoki Pharmaceut Co Ltd | 腎機能検査法 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6087800A (ja) * | 1983-10-18 | 1985-05-17 | Kikkoman Corp | グアニジノ化合物の定量方法及びその定量用試薬 |
US5013750A (en) | 1989-02-01 | 1991-05-07 | Nippon Zoki Pharmaceutical Co., Ltd. | Glycocyamidine derivatives |
WO2009052186A1 (en) * | 2007-10-15 | 2009-04-23 | Georgia Tech Research Corporation | Metabolomics-based identification of disease-causing agents |
-
2011
- 2011-04-26 CN CN2011800207529A patent/CN102859357A/zh active Pending
- 2011-04-26 WO PCT/JP2011/060178 patent/WO2011136228A1/ja active Application Filing
- 2011-04-26 JP JP2012512860A patent/JP5832425B2/ja not_active Expired - Fee Related
- 2011-04-26 EP EP11775009.1A patent/EP2565646B1/en not_active Not-in-force
-
2012
- 2012-10-25 US US13/660,440 patent/US8927221B2/en not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH02288867A (ja) * | 1989-02-01 | 1990-11-28 | Nippon Zoki Pharmaceut Co Ltd | グリコシアミジン誘導体 |
JP2001174459A (ja) * | 1999-12-17 | 2001-06-29 | Nippon Zoki Pharmaceut Co Ltd | 腎機能検査法 |
Non-Patent Citations (8)
Title |
---|
ARATA ICHIYAMA: "Idenshibyo Manual Yukisan Taisha Ijosho Genpatsusei Ko Shusan Nyosho", MOL MED, vol. 32, 1995, pages 100 - 101, XP008167278 * |
BARBAS C ET AL.: "Urinary analysis of nephrolithiasis markers", J CHROMATOGR B, vol. 781, no. 1/2, 2002, pages 433 - 455, XP004394168 * |
HIDEHIRO TABATA ET AL.: "Sentensei Jin Shikkan to Jin Fuzen VIII Taishasei Shikkan -Ko Shusan Kessho ni Shoten o Atete", THE JAPANESE JOURNAL OF CLINICAL DIALYSIS, vol. 25, no. 4, 2009, pages 483 - 488, XP008168910 * |
HITOSHI KITAGAWA ET AL.: "Gas Chromatography Shitsuryo Bunseki ni yoru Kuroge Washugyu no Nyo Oyobi Ketsueki no Taisha Sanbutsu Kaiseki", JAPANESE SOCIETY OF VETERIANY SCIENCE GAKUJUTSU SHUKAI KOEN YOSHISHU, vol. 133, 2002, pages 148, XP008169118 * |
NAKADA SHINJI ET AL.: "Transgenic mice overexpressing a mutant of CaM kinase II (Thr286Asp) in pancreatic beta cells as a model for diabetic nephropathy", JOURNAL OF JAPANESE BIOCHEMICAL SOCIETY, 2006, pages 12032, XP008167276 * |
PORTER W H ET AL.: "Ethylene Glycol Toxicity: The Role of Serum Glycolic Acid in Hemodialysis", J TOXICOL CLIN TOXICOL, vol. 39, no. 6, 2001, pages 607 - 615, XP009172667 * |
See also references of EP2565646A4 * |
SHERWOOD R A ET AL.: "Measurement of plasma and urine amino acids by high-performance liquid chromatography with electrochemical detection using phenylisothiocyanate derivatization", J CHROMATOGR, vol. 528, no. 2, 1990, pages 293 - 303, XP055069858 * |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013115283A1 (ja) * | 2012-01-31 | 2013-08-08 | 味の素株式会社 | 早期腎症の評価方法、早期腎症評価装置、早期腎症評価方法、早期腎症評価プログラム、早期腎症評価システムおよび情報通信端末装置 |
JP2017223694A (ja) * | 2012-08-13 | 2017-12-21 | ランドックス ラボラトリーズ リミテッド | 腎疾患バイオマーカー |
WO2019124267A1 (ja) * | 2017-12-18 | 2019-06-27 | 国立研究開発法人国立成育医療研究センター | ニーマンピック病c型の診断のための検査方法 |
WO2019244140A1 (ja) * | 2018-06-21 | 2019-12-26 | マルハニチロ株式会社 | 腎機能維持及び保護剤、並びに、その効果評価方法 |
JP2020002125A (ja) * | 2018-06-21 | 2020-01-09 | マルハニチロ株式会社 | 腎機能維持及び保護剤、並びに、その効果評価方法 |
GB2590868A (en) * | 2018-06-21 | 2021-07-07 | Maruha Nichiro Corp | Kidney function maintenance and protection agent, and method for evaluating effect thereof |
JP7013416B2 (ja) | 2018-06-21 | 2022-01-31 | マルハニチロ株式会社 | 腎機能維持及び保護剤、並びに、その効果評価方法 |
Also Published As
Publication number | Publication date |
---|---|
CN102859357A (zh) | 2013-01-02 |
JP5832425B2 (ja) | 2015-12-16 |
EP2565646A1 (en) | 2013-03-06 |
EP2565646B1 (en) | 2017-10-18 |
US20130157252A1 (en) | 2013-06-20 |
JPWO2011136228A1 (ja) | 2013-07-22 |
US8927221B2 (en) | 2015-01-06 |
EP2565646A4 (en) | 2013-10-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5832425B2 (ja) | 腎臓病診断用マーカー及びその利用 | |
JP6595984B2 (ja) | 腎機能に関連付けられるバイオマーカーおよびそれを使用する方法 | |
JP6927212B2 (ja) | 軽度認知障害又はアルツハイマー型認知症の評価方法 | |
JP6870679B2 (ja) | アルツハイマー型認知症の将来の発症リスクの評価方法 | |
JP2018013492A (ja) | 切断型Her2 SRM/MRMアッセイ | |
JP6762529B2 (ja) | 腎臓病の病態バイオマーカー | |
JP6081912B2 (ja) | c−Src選択反応モニタリングアッセイ | |
JP2019191192A (ja) | 糖尿病を判定するための血液試料の分析方法及びシステム | |
JP6128631B2 (ja) | 糖尿病性腎症鑑別用マーカー及びその用途 | |
JP5850374B2 (ja) | アルツハイマー病の診断補助方法、及び診断システム | |
JP6727660B2 (ja) | 糖尿病性腎症の判定マーカー | |
CN111065922A (zh) | 肾上腺髓质素原作为危重病患者的肾脏替代治疗的指标 | |
WO2023079706A1 (ja) | 糖尿病性腎症の判定方法 | |
JP7434678B2 (ja) | 認知症又はそのリスクの検査方法 | |
JP6046145B2 (ja) | 死受容体5タンパク質に対するmrm/srmアッセイ | |
Şambel et al. | Serum Mindin, Nephrin and Podocalyxin Levels in Patients with Type 1 Diabetes: Are These New Markers to Detect the Development of Nephropathy? | |
Jayasinghe et al. | SAT-195 Diagnostic utility of whole-exome sequencing in a chronic kidney disease cohort | |
Magalhães et al. | Unravelling molecular basis of normal and abnormal renal tract: a proteomic approach | |
Vera et al. | SAT-194 Plasma peptidomics based multivariable model for the classification of hypertensive from normotensive subjects in CKD | |
EP3699596A1 (en) | Method for the diagnosis of macce in patients who underwent gastrointestinal surgery | |
Dawood | Comparison between Certain Parameters for Diagnosis of Acute Myocardial Infarction |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 201180020752.9 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 11775009 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2012512860 Country of ref document: JP |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 3301/KOLNP/2012 Country of ref document: IN |
|
REEP | Request for entry into the european phase |
Ref document number: 2011775009 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2011775009 Country of ref document: EP |