Biomarker for prognosis prediction and / or monitoring of renal functions

Abstract

To provide a method of predicting prognosis of chronic kidney disease patients using a novel chronic kidney disease marker.SOLUTION: A method of predicting prognosis of a chronic kidney disease patient is provided, the method comprising detecting the level of proline betaine in a biological sample collected from a subject suffering from chronic kidney disease.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to biomarkers for the prognosis and / or monitoring of kidney function. [Background technology]

[0002] To date, few predictors of renal function prognosis are known. Albumin is well known as a prognostic factor for diabetic nephropathy (DKD) (Non-Patent Document 1), but few other predictors of prognosis for chronic kidney disease are known.

[0003] There is a need for methods of more accurately prognosing and / or monitoring renal function in a subject, as well as for agents for preventing and / or treating renal dysfunction in a subject. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] F. Persson et al., Kidney Int Suppl (2011). 2018 Jan;8(1):2-7. doi: 10.1016 / j.kisu.2017.10.003. Summary of the Invention [Problem to be solved by the invention]

[0005] The present invention addresses the above needs by identifying and providing uses of biomarkers to prognose and / or monitor renal function in a subject. [Means for solving the problem]

[0006] The present invention encompasses the embodiments described below. Section 1. 1. A method for prognosing and / or monitoring renal function in a subject, comprising: A method comprising the step of measuring the amount of proline betaine in a biological sample taken from a subject. Section 2. Item 1. The method according to item 1, further comprising the following step (I) or (II): (I) comparing the measured amount of proline betaine with a reference value of the amount of proline betaine that indicates a poor prognosis of renal dysfunction; wherein the measured amount of proline betaine is lower than the reference value, which indicates that the subject has renal dysfunction or a poor prognosis for renal function; (II) comparing the value obtained by dividing the measured amount of proline betaine by the amount of creatinine in the biological sample collected from the subject with a reference value obtained by dividing the amount of proline betaine by the amount of creatinine, which indicates a poor prognosis of renal dysfunction; Here, if the value obtained by dividing the measured amount of proline betaine by the amount of creatinine in the biological sample collected from the subject is lower than the reference value, this is an indicator that the subject has a poor prognosis for renal function. Section 3. Item 1. The method according to item 1, further comprising the following step (I) or (II): (I) comparing the measured amount of proline betaine with a reference value of the amount of proline betaine that indicates a good prognosis of renal dysfunction; wherein a higher amount of proline betaine measured compared to the reference value is an indication that the subject has a good prognosis for renal dysfunction; (II) comparing the value obtained by dividing the measured amount of proline betaine by the amount of creatinine in the biological sample collected from the subject with a reference value obtained by dividing the amount of proline betaine by the amount of creatinine, which indicates a good prognosis for renal dysfunction; Here, if the value obtained by dividing the measured amount of proline betaine by the amount of creatinine in the biological sample collected from the subject is higher than the reference value, this is an indicator that the subject has a good prognosis for renal dysfunction. Section 4. Item 10. The method according to Item 1, wherein the subject is a patient with chronic kidney disease. Section 5. Item 10. The method according to Item 1, wherein the subject is a patient with non-diabetic chronic kidney disease. Section 6. Item 6. The method according to any one of Items 1 to 5, wherein the biological sample is whole blood, serum, plasma, or urine. Section 7. A preventive or therapeutic agent for renal dysfunction, comprising proline betaine as an active ingredient. Section 8. Use of proline betaine for the manufacture of an agent for the prevention or treatment of renal dysfunction. Section 9. A method for screening a candidate compound to be used as a drug for preventing or treating renal dysfunction, comprising: providing a candidate compound; and selecting the candidate compound when the amount of proline betaine in a biological sample collected from the subject after administering the candidate compound to the subject is increased compared to the amount of proline betaine in a biological sample collected from the subject before administering the candidate compound to the subject, or when the value obtained by dividing the amount of proline betaine in a biological sample collected from the subject after administering the candidate compound to the subject by the amount of creatinine in a biological sample collected from the subject after administering the candidate compound to the subject is increased compared to the value obtained by dividing the amount of proline betaine in a biological sample collected from the subject before administering the candidate compound to the subject by the amount of creatinine in a biological sample collected from the subject before administering the candidate compound to the subject. [Brief explanation of the drawings]

[0007] [Figure 1] Volcano plot of metabolomic analysis of plasma metabolites in two groups: Group 0 with a decline in eGFR of less than 15% and Group 1 with a decline in eGFR of 15% or more. [Figure 2] Graph of the amount of proline betaine in plasma of Group 0 and Group 1. Student's test. The unit of the vertical axis is μM. [Figure 3] Volcano plot of metabolomic analysis of urinary metabolites from Group 0 and Group 1. [Figure 4]Graph of the amount of proline betaine in urine from Group 0 and Group 1. Student's test. The unit of the vertical axis is μmol / gCre. [Figure 5] Volcano plot of metabolome analysis of plasma metabolites in two groups of non-diabetic patients with chronic kidney disease and hypertension: one with a decline in eGFR of less than 15% and one with a decline in eGFR of 15% or more. [Figure 6] Volcano plot of metabolome analysis of plasma metabolites in two groups of diabetic patients with chronic kidney disease and hypertension: one with a decline in eGFR of less than 15% and one with a decline in eGFR of 15% or more. [Figure 7] Volcano plot of metabolome analysis of urinary metabolites in two groups of non-diabetic patients with chronic kidney disease and hypertension: one with a decline in eGFR of less than 15% and one with a decline in eGFR of 15% or more. [Figure 8] Volcano plot of metabolome analysis of urinary metabolites in two groups of patients with chronic kidney disease and hypertension who also suffer from diabetes: one with a decline in eGFR of less than 15% and one with a decline in eGFR of 15% or more. [Figure 9] Volcano plot of metabolome analysis of plasma metabolites in two groups of chronic kidney disease and hypertension patients with positive urinary protein: one with a decline in eGFR of less than 15% and one with a decline in eGFR of 15% or more. [Figure 10] Volcano plot of metabolome analysis of plasma metabolites in two groups of chronic kidney disease and hypertension patients with negative urinary protein: one with a decline in eGFR of less than 15% and one with a decline in eGFR of 15% or more. [Figure 11] Volcano plot of metabolome analysis of urinary metabolites in two groups of chronic kidney disease and hypertension patients with positive urinary protein: one with a decline in eGFR of less than 15% and one with a decline in eGFR of 15% or more. [Figure 12] Volcano plot of metabolome analysis of urinary metabolites in two groups of chronic kidney disease and hypertension patients with negative urinary protein: one with a decline in eGFR of less than 15% and one with a decline in eGFR of 15% or more. [Figure 13]ROC curve for predicting progression of renal failure using plasma proline betaine levels. [Figure 14] ROC curve for predicting progression of renal failure using urinary proline betaine levels. DETAILED DESCRIPTION OF THE INVENTION

[0008] As used herein, the singular forms "a," "an," and "the" are intended to include both the singular and the plural unless otherwise expressly stated herein or otherwise clearly contradicted by context.

[0009] In this specification, the term "comprise" is a concept that encompasses "consist essentially only of" and "consist only of."

[0010] As used herein, mammals include humans, cows, horses, pigs, monkeys, dogs, cats, mice, rats, rabbits, goats, and sheep.

[0011] As used herein, the "amount" of proline betaine can be used interchangeably with the "concentration" of proline betaine or the "level" of proline betaine.

[0012] As used herein, the term "chronic kidney disease / hypertension patient" refers to a patient suffering from either or both of chronic kidney disease and hypertension.

[0013] The present inventors have found that the amount of proline betaine in clinical samples from patients is an index for evaluating renal function. In particular, proline betaine showed a significant correlation with estimated glomerular filtration rate (eGFR), a clinical parameter related to renal function. Proline betaine is a compound represented by the following formula and has CAS Registry Number 471-87-4.

[0014] [ka]

[0015] According to one aspect of the present invention, there is provided a method for prognosing and / or monitoring renal function in a subject, the method comprising measuring the amount of proline betaine in a biological sample obtained from the subject.

[0016] The subject is a mammal, including a human, and preferably a human. The subject includes a patient with renal dysfunction and a patient suspected of having renal dysfunction. A "patient suspected of having renal dysfunction" may be a subject who the subject himself / herself subjectively suspects, or a subject who has been determined or diagnosed with renal dysfunction based on some objective evidence (for example, a subject who has been diagnosed by a doctor as being suspected of having renal dysfunction based on abnormalities in urine findings, etc.).

[0017] Renal dysfunction includes, but is not limited to, chronic kidney disease and acute kidney injury. Chronic kidney disease includes, but is not limited to, chronic glomerulonephritis, diabetic nephropathy, nephrosclerosis, and autosomal dominant polycystic kidney disease. In one embodiment, the renal dysfunction is chronic kidney disease. In one embodiment, the renal dysfunction is in a patient with non-diabetic chronic kidney disease. In one embodiment, the renal dysfunction is in a patient with protein-negative urinary chronic kidney disease.

[0018] The method for prognosing and / or monitoring renal function in a subject can be performed in vitro based on the measurement of the amount of proline betaine in a biological sample collected from the subject, without the need for a doctor's judgment. Therefore, the method excludes diagnostic methods for humans. The method for prognosing and / or monitoring renal function in a subject may also be a method for providing data for prognosing and / or monitoring renal function in the subject.

[0019] The above methods of prognosing and / or monitoring renal function in a subject can be performed at two or more sequential time points to allow for monitoring of renal function in the subject.

[0020] In one embodiment, the method for prognosing and / or monitoring renal function in a subject further comprises the following step (I) or (II): (I) comparing the measured amount of proline betaine with a reference value of the amount of proline betaine that indicates a poor prognosis of renal dysfunction; wherein the measured amount of proline betaine is lower than the reference value, indicating that the subject has a poor prognosis for renal function; (II) comparing the value obtained by dividing the measured amount of proline betaine by the amount of creatinine in the biological sample collected from the subject (amount of proline betaine / amount of creatinine) with a reference value which is a value obtained by dividing the amount of proline betaine by the amount of creatinine, and which indicates a poor prognosis of renal dysfunction; Here, if the value obtained by dividing the measured amount of proline betaine by the amount of creatinine in the biological sample collected from the subject is lower than the reference value, this is an indicator that the subject has a poor prognosis for renal function.

[0021] The amount of proline betaine in a subject's biological sample may increase or decrease without any change in apparent symptoms. In such cases, the change in the proline betaine marker precedes the change in apparent symptoms and serves as a highly sensitive measure. The above-mentioned method for prognosticating and / or monitoring renal function in a subject allows for earlier prediction of a poor prognosis for renal dysfunction and aids in the diagnosis of renal dysfunction or poor prognosis for renal dysfunction in a subject. For patients predicted to have a poor prognosis for renal dysfunction, therapeutic intervention can be initiated earlier, which may be more effective than waiting for symptoms to worsen.

[0022] The reference value of the proline betaine amount indicating a poor prognosis of renal dysfunction can be the amount of proline betaine measured in one or more samples from one or more subjects with a poor prognosis of renal dysfunction. When the reference value is the amount of proline betaine measured in multiple samples from multiple subjects, the reference value can be the average or median proline betaine amount of the multiple subjects with a poor prognosis of renal dysfunction, or a cut-off value of the proline betaine amount that distinguishes between a patient group with a poor prognosis of renal dysfunction and a patient group with a good prognosis of renal dysfunction. When comparing the amount of proline betaine in a subject with a reference value, the amount of proline betaine in the same biological sample is compared (for example, when the amount of proline betaine in a subject is the amount of proline betaine in plasma, the reference value is also the amount of proline betaine in plasma).

[0023] The reference value of the amount of proline betaine / the amount of creatinine indicating a poor prognosis of renal dysfunction can be the amount of proline betaine measured in one or more samples from one or more subjects with a poor prognosis of renal dysfunction divided by the amount of creatinine in the same subjects. When the reference value is the amount of proline betaine / the amount of creatinine measured in multiple samples from multiple subjects, the reference value can be the average or median value of the amounts of proline betaine / creatinine measured in multiple subjects with a poor prognosis of renal dysfunction, or a cut-off value of the amount of proline betaine / creatinine that distinguishes between a patient group with a poor prognosis of renal dysfunction and a patient group with a good prognosis of renal dysfunction. When comparing the amount of proline betaine / the amount of creatinine in a subject with a reference value, the amount of proline betaine / the amount of creatinine in the same biological sample is compared (e.g., if the amount of proline betaine / the amount of creatinine in a subject is the amount of proline betaine / the amount of creatinine in urine, the reference value is also the amount of proline betaine / the amount of creatinine in urine).

[0024] In one embodiment, the method for prognosticating and / or monitoring renal function in a subject further comprises the following step (I) or (II): (I) comparing the measured amount of proline betaine with a reference value of the amount of proline betaine that indicates a good prognosis of renal dysfunction; wherein a higher amount of proline betaine measured compared to the reference value is an indication that the subject has a good prognosis for renal dysfunction; (II) comparing the value obtained by dividing the measured amount of proline betaine by the amount of creatinine in the biological sample collected from the subject (amount of proline betaine / amount of creatinine) with a reference value obtained by dividing the amount of proline betaine by the amount of creatinine, which indicates a good prognosis of renal dysfunction; Here, if the value obtained by dividing the measured amount of proline betaine by the amount of creatinine in the biological sample collected from the subject is higher than the reference value, this is an indicator that the subject has a good prognosis for renal dysfunction.

[0025] The method for predicting and / or monitoring renal function in a subject allows for early prediction of a favorable prognosis for renal dysfunction, thereby assisting in the diagnosis of recovery from renal dysfunction in a subject.

[0026] The reference value of the amount of proline betaine indicating a good prognosis of renal dysfunction can be the amount of proline betaine measured in one or more samples from one or more subjects with a good prognosis of renal dysfunction. When the reference value is the amount of proline betaine measured in multiple samples from multiple subjects, the reference value can be the average or median of the amounts of proline betaine measured in multiple subjects with a good prognosis of renal dysfunction. When the amount of proline betaine in a subject is compared with the reference value, the amount of proline betaine in the same biological sample is compared (for example, when the amount of proline betaine in a subject is the amount of proline betaine in plasma, the reference value is also the amount of proline betaine in plasma).

[0027] The reference value of the amount of proline betaine / creatinine indicating a good prognosis of renal dysfunction can be the amount of proline betaine / creatinine from one or more subjects with a good prognosis of renal dysfunction. When the reference value is the amount of proline betaine / creatinine measured in multiple samples from multiple subjects, the reference value can be the average or median value of the amount of proline betaine / creatinine from multiple subjects with a good prognosis of renal dysfunction. When the amount of proline betaine / creatinine in a subject is compared with the reference value, the amount of proline betaine / creatinine in the same biological sample is compared (for example, when the amount of proline betaine / creatinine in a subject is the amount of proline betaine / creatinine in urine, the reference value is also the amount of proline betaine / creatinine in urine).

[0028] As used herein, the term "biological sample" includes any biological specimen obtained from a subject. The biological sample is not particularly limited and may be a body fluid, tissue, or cell. Examples of body fluids include blood, plasma, serum, saliva, urine, tears, and sweat, which can be easily collected from a living body, and cerebrospinal fluid, bone marrow fluid, pleural effusion, ascites, synovial fluid, aqueous humor, vitreous humor, and lymphatic fluid, which are relatively easy to collect. In one embodiment, the biological sample is whole blood, serum, plasma, or urine. These biological samples are preferred because they are minimally invasive to the subject and relatively easy to obtain.

[0029] The amount of proline betaine in a biological sample can be measured by, for example, capillary electrophoresis, mass spectrometry, or a combination thereof. The amount of creatinine in a biological sample can be measured by a measurement method well known to those skilled in the art, including, but not limited to, an immunological method using an anti-creatinine antibody.

[0030] According to another aspect of the present invention, there is provided an agent for preventing or treating renal dysfunction, which comprises proline betaine as an active ingredient.

[0031] Proline betaine can be produced by known methods or is commercially available.

[0032] The above-mentioned agent for preventing or treating renal dysfunction can be used for mammalian subjects including human subjects, and is preferably used for humans.

[0033] The dosage form of the preventive or therapeutic agent for renal dysfunction may be, for example, an oral agent, an injection, a suppository, etc., with an oral agent or an injection being preferred. These dosage forms can be prepared by formulation methods known and commonly used by those skilled in the art. The dosage form can be selected depending on the drug.

[0034] The amount of proline betaine to be incorporated into each dosage unit varies depending on the symptoms of the subject to which it is to be administered or on the dosage form, but is generally about 1 to 5,000 mg per dosage unit. The daily dose of proline betaine in the dosage form varies depending on the symptoms, body weight, age, sex, etc. of the subject and cannot be determined in general, but is usually about 10 mg to 5,000 mg per day for an adult (body weight 50 kg), and this is preferably administered once a day or in divided doses.

[0035] The agent for preventing or treating renal dysfunction may be provided as a pharmaceutical composition for preventing or treating renal dysfunction containing an effective amount of proline betaine, optionally mixed with a pharmaceutical carrier.

[0036] Pharmaceutical carriers are various organic or inorganic carrier substances commonly used as formulation materials, and are formulated as excipients, binders, disintegrants, lubricants, colorants in solid formulations, and solvents, solubilizers, suspending agents, isotonicity agents, buffers, soothing agents, etc. in liquid formulations. Furthermore, formulation additives such as preservatives, antioxidants, colorants, sweeteners, stabilizers, etc. can also be used as needed.

[0037] The dosage form of the pharmaceutical composition may be, for example, an oral agent, an injection agent, a suppository, etc., with an oral agent or an injection agent being preferred. These dosage forms can be prepared by conventional formulation methods known to those skilled in the art. The pharmaceutical composition can be used in mammals, including humans, and is preferably used in humans.

[0038] According to another aspect of the present invention, there is provided a method for preventing and / or treating tumors, comprising the step of administering to a patient an amount of proline betaine effective for treating and / or preventing renal dysfunction. The subjects, administration route, dosage form, and dosage of proline betaine are as described above for the agent for preventing or treating renal dysfunction.

[0039] According to another aspect of the present invention, there is provided use of proline betaine for the manufacture of an agent for the prophylaxis or treatment of renal dysfunction. The administration target, administration route, dosage form, and dosage of proline betaine are as described above for the agent for the prophylaxis or treatment of renal dysfunction.

[0040] According to another aspect of the present invention, there is provided a method for screening a candidate compound to be used as a drug for preventing or treating renal dysfunction, comprising the steps of: providing a candidate compound; comparing the amount of proline betaine in a biological sample collected from a subject after administering the candidate compound to the subject with the amount of proline betaine in a biological sample collected from the subject before administering the candidate compound to the subject; or dividing the amount of proline betaine in the biological sample collected from the subject after administering the candidate compound by the amount of creatinine in the biological sample collected from the subject after administering the candidate compound to the subject; and selecting the candidate compound when the amount of proline betaine in a biological sample collected from a subject after administering the candidate compound to the subject is increased compared to the amount of proline betaine in a biological sample collected from the subject before administering the candidate compound to the subject, or when the value obtained by dividing the amount of proline betaine in a biological sample collected from a subject after administering the candidate compound by the amount of creatinine in a biological sample collected from the subject after administering the candidate compound is increased compared to the value obtained by dividing the amount of proline betaine in a biological sample collected from the subject before administering the candidate compound to the subject by the amount of creatinine in a biological sample collected from the subject before administering the candidate compound to the subject.

[0041] The subject to which the candidate compound is administered may be a human or a non-human mammal. The non-human mammal may be an animal model for renal dysfunction. By administering the candidate compound to a non-human mammal in vivo, screening that is more suitable for application to humans can be performed compared to in vitro screening.

[0042] For example, measure the amount of proline betaine in biological sample at a first time point before administering candidate compound.Then, administer candidate compound to the subject.Then, measure the amount of proline betaine and optionally the amount of creatinine in biological sample at a second time point after administering candidate compound.

[0043] If the amount of proline betaine in the biological sample measured at the second time point is elevated compared to the amount of proline betaine in the biological sample measured at the first time point, or if the ratio of the amount of proline betaine / the amount of creatinine in the biological sample measured at the second time point is elevated compared to the ratio of the amount of proline betaine / the amount of creatinine in the biological sample measured at the first time point, such a candidate compound can be considered a candidate drug effective in preventing or treating renal dysfunction.

[0044] According to another aspect of the present invention, there is provided a method for screening a candidate compound to be used as a drug for preventing or treating renal dysfunction, comprising the steps of: providing a candidate compound; comparing the amount of proline betaine in a tissue or cell after administering the candidate compound to the tissue or cell with the amount of proline betaine in the tissue or cell before administering the candidate compound; or dividing the amount of proline betaine in the tissue or cell after administering the candidate compound by the amount of creatinine in the tissue or cell after administering the candidate compound by the amount of proline betaine in the tissue or cell before administering the candidate compound; and selecting the candidate compound when the amount of proline betaine in the tissue or cell after administration of the candidate compound to the tissue or cell is increased compared to the amount of proline betaine in the tissue or cell before administration of the candidate compound, or when the value obtained by dividing the amount of proline betaine in the tissue or cell after administration of the candidate compound to the tissue or cell by the amount of creatinine in the tissue or cell after administration of the candidate compound is increased compared to the value obtained by dividing the amount of proline betaine in the tissue or cell before administration of the candidate compound by the amount of creatinine in the tissue or cell before administration of the candidate compound.

[0045] The tissue or cells may be tissue or cells derived from a mammal with renal dysfunction. The tissue or cells may be established cultured renal cells. By administering a candidate compound to the tissue or cells in vitro, more rapid and efficient screening can be performed.

[0046] The disclosures of all patent applications and publications cited herein are hereby incorporated by reference in their entirety.

[0047] The following examples are intended for illustrative purposes only and are not intended to limit the scope of the present invention in any way. Unless otherwise specified, reagents are commercially available or are obtained or prepared according to conventional techniques or literature procedures in the art. [Example]

[0048] Proline betaine as a predictive marker for renal function prognosis 1. Method <Usage data> We used cohort data from 100 outpatients with kidney and hypertension (diagnosed with either or both of chronic kidney disease and hypertension) at Tohoku University Hospital. In addition to the patients' clinical information, this cohort data included comprehensive metabolite analysis of blood, urine, and stool samples at the time of enrollment, as well as the results of subsequent general blood and urine tests collected through regular hospital visits.

[0049] Of these patients, the eGFR at enrollment was 30 ml / min / 1.73m 2 Eighteen patients were excluded: those with a blood glucose level below 18.8, those who had not been enrolled for three years, and those whose eGFR was not measured at enrollment or three years later. Eighty-two patients were included in the study. eGFR was calculated using the GFR estimation formula based on serum creatinine (Cr): GFR (male) = 194*Cr -1.094 *age -0.287 ,GFR(female)= 194*Cr -1.094 *age -0.287 *0.739).

[0050] The percentage change in eGFR from the time of enrollment to 3 years later was calculated (mean eGFR 63.1 mL / min / 1.73 m 2Standard deviation 21.5, diabetes n = 38 (46.3%), overt albuminuria and heavy proteinuria n = 16 (19.5%). Among these, 68 plasma samples and 71 urine samples for which comprehensive metabolite analysis of plasma and urine could be performed at the time of registration were targeted. The group with a less than 15% decrease in eGFR, that is, the group with relatively less deterioration of renal function, was defined as Group0 (plasma: n = 36, urine: n = 38), and the group with a 15% or more decrease in eGFR, that is, the group with deteriorated renal function, was defined as Group1 (plasma: n = 32, urine: n = 33). Metabolites between the two groups were compared.

[0051] <Comprehensive metabolite analysis> Capillary electrophoresis-time of flight mass spectrometry (CE-TOFMS) method was used to perform comprehensive analysis of each metabolite in plasma and urine.

[0052] <Statistical analysis> Student’s t-test and Fold Change (FC) were used. As exploratory analysis, the significance level of the P value was set to 0.1, and the threshold of FC was set to -0.5 or less or 2 or more. Group0 and Group1 were compared, and metabolites that met both the criteria of Student’s t-test and FC were extracted. In addition, in order to reduce the influence of individual differences on metabolites in urine, the metabolite concentration in urine was the value obtained by dividing the metabolite concentration by the creatinine concentration.

[0053] <ROC analysis> ROC analysis was performed to evaluate the diagnostic ability. The ROC graph was calculated according to the algorithm described in https: / / doi.org / 10.1016 / j.patrec.2005.10.010 using commercially available software (R version 4.2.1). AUC was calculated from the ROC curve. The cut-off value for diagnosis was the measured value of the point with the minimum distance from the upper left vertex.

[0054] <Subgroup analysis> Patients were divided into two groups according to the presence or absence of diabetes and the presence or absence of proteinuria, and subgroup analysis was similarly performed regarding the decrease in eGFR.

[0055] 2.Results See Table 1 for patient characteristics. Comprehensive metabolite analysis detected 132 metabolites in plasma and 226 metabolites in urine. Of these, one metabolite in plasma and five metabolites in urine were significantly different between the two groups (Table 2, Figures 1-2, Table 3, Figures 3-4). The only metabolite that showed a significant difference in both plasma and urine was proline betaine. Proline betaine concentrations were significantly lower in the eGFR-decreased group (Group 1) (plasma: Group 0, 7.69±10.58 μM vs. Group 1, 3.33±3.36 μM, FC=2.31, p=0.03; urine: Group 0, 172.51±220.24 μmol / g Cre vs. Group 1, 80.0±108.96 μmol / g Cre, FC=2.16, p=0.03).

[0056] In subgroup analysis (Figures 5-12), it was found to be useful as a marker in the plasma and urine of the group without diabetes (Tables 4 and 5, Figures 5 and 7), in the plasma of the group without proteinuria (Table 6, Figure 11), and in the urine of the group with proteinuria (Table 7, Figure 11).

[0057] 13 and 14 show ROC curves for predicting the progression of renal failure using the amounts of proline betaine in plasma and urine, respectively.

[0058] A blood concentration of 6.3 μM or less predicts the progression of renal failure with a sensitivity of 87.5% and a specificity of 38.9% (Figure 13). A urinary concentration of 99.3 μmol / gCre or less predicts the progression of renal failure with a sensitivity of 84.8% and a specificity of 47.4% (Figure 14).

[0059] From the above, proline betaine is considered to be useful as a marker for predicting renal prognosis in patients with chronic kidney disease (CKD), and furthermore, as a marker for predicting renal prognosis in non-diabetic and non-proteinuric CKD patients, for whom there are currently no effective predictive indicators.

[0060] [Table 1]

[0061]

Table 2

[0062]

Table 3

[0063]

Table 4

[0064]

Table 5

[0065]

Table 6

[0066]

Table 7

Claims

1. 1. A method for prognosing and / or monitoring renal function in a subject, comprising: A method comprising the step of measuring the amount of proline betaine in a biological sample taken from a subject.

2. The method according to claim 1, further comprising the following step (I) or (II): (I) comparing the measured amount of proline betaine with a reference value of the amount of proline betaine that indicates a poor prognosis of renal dysfunction; wherein the measured amount of proline betaine is lower than the reference value, which is an indication that the subject has impaired renal function or that the subject has a poor prognosis for renal function; (II) comparing the value obtained by dividing the measured amount of proline betaine by the amount of creatinine in the biological sample collected from the subject with a reference value obtained by dividing the amount of proline betaine by the amount of creatinine, which indicates a poor prognosis of renal dysfunction; Here, if the value obtained by dividing the measured amount of proline betaine by the amount of creatinine in the biological sample collected from the subject is lower than the reference value, this is an indicator that the subject has a poor prognosis for renal function.

3. The method according to claim 1, further comprising the following step (I) or (II): (I) comparing the measured amount of proline betaine with a reference value of the amount of proline betaine that indicates a good prognosis of renal dysfunction; wherein a higher amount of proline betaine measured compared to the reference value is an indication that the subject has a good prognosis for renal dysfunction; (II) comparing the value obtained by dividing the measured amount of proline betaine by the amount of creatinine in the biological sample collected from the subject with a reference value obtained by dividing the amount of proline betaine by the amount of creatinine, which indicates a good prognosis of renal dysfunction; Here, if the value obtained by dividing the measured amount of proline betaine by the amount of creatinine in the biological sample collected from the subject is higher than the reference value, this is an indicator that the subject has a good prognosis for renal dysfunction.

4. The method of claim 1, wherein the subject is a patient with chronic kidney disease.

5. The method of claim 1, wherein the subject is a patient with non-diabetic chronic kidney disease.

6. The method according to any one of claims 1 to 5, wherein the biological sample is whole blood, serum, plasma, or urine.

7. A preventive or therapeutic agent for renal dysfunction, comprising proline betaine as an active ingredient.

8. Use of proline betaine for the manufacture of an agent for the prevention or treatment of renal dysfunction.

9. A method for screening a candidate compound to be used as a drug for preventing or treating renal dysfunction, comprising: providing a candidate compound; and selecting the candidate compound when the amount of proline betaine in a biological sample collected from the subject after administering the candidate compound to the subject is increased compared to the amount of proline betaine in a biological sample collected from the subject before administering the candidate compound to the subject, or when the value obtained by dividing the amount of proline betaine in a biological sample collected from the subject after administering the candidate compound to the subject by the amount of creatinine in a biological sample collected from the subject after administering the candidate compound to the subject is increased compared to the value obtained by dividing the amount of proline betaine in a biological sample collected from the subject before administering the candidate compound to the subject by the amount of creatinine in a biological sample collected from the subject before administering the candidate compound to the subject.

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