Improvement in renal hypofunction

Abstract

The present invention addresses the problem of providing a novel means for suppressing renal hypofunction, the means being capable of fundamentally improving diseases associated with renal hypofunction including chronic kidney disease (CKD).　The inventors of the present invention have solved the above problem by providing a novel means for suppressing renal hypofunction, the means suppressing and improving renal hypofunction in vivo using lactitol or a derivative thereof. More specifically, the present invention has solved the above problem by providing an agent for suppressing renal hypofunction that contains lactitol or a derivative thereof.

Description

Improvement of decreased kidney function

[0001] The present invention relates to providing a new means for suppressing renal function decline and improving renal function in vivo using lactitol, more specifically, to providing a new means for suppressing renal function decline using lactitol.

[0002] Chronic kidney disease (CKD), a serious condition associated with impaired kidney function, is thought to affect 13.3 million people in Japan (one in eight adults aged 20 and over), with the number increasing every year. It is also the eighth leading cause of death in Japan, and is said to be a new national disease due to its significant impact on the health of the nation. CKD is often overlooked due to the lack of noticeable symptoms, but if it worsens and requires dialysis, the burden of medical expenses increases and the patient's quality of life declines significantly.

[0003] Although the importance of CKD prevention is gradually becoming more widely recognized internationally, only symptomatic treatments are available and no fundamental cures exist. Strengthening measures to prevent the onset and progression of kidney disease by developing preventive and therapeutic methods for CKD is an urgent issue.

[0004] https: / / www.mhlw.go.jp / bunya / kenkou / pdf / jinshikkan01_0001.pdf

[0005] An objective of the present invention is to provide a new means for suppressing renal dysfunction, which can fundamentally improve diseases accompanied by renal dysfunction, including chronic kidney disease (CKD).

[0006] The inventors of the present invention have solved the above-mentioned problems by providing a new means for suppressing renal function decline in vivo, that is, by using lactitol or a derivative thereof to suppress or improve renal function decline. More specifically, the present invention has solved the above-mentioned problems by providing an agent for suppressing renal function decline, which comprises lactitol or a derivative thereof.

[0007] More specifically, in order to solve the above-mentioned problems, the present application provides the following aspects: [1]: A suppressant for renal function decline, comprising lactitol or a derivative thereof; [2]: The suppressant for renal function decline according to claim 1, wherein the renal function decline is selected from renal function decline in the early nephropathy stage (stage 2), renal function decline in the overt nephropathy stage (stage 3A), and renal failure stage (stage 4); [3]: A suppressant for renal function decline in patients in whom the renal function decline is in the GFR classification of G2, G3a, G3b, or G4 (GFR value of 15 mL / min / 1.73 m 2 or more, 90 mL / min / 1.73 m 2 [4]: A pharmaceutical composition for treating a disease accompanied by renal function decline, comprising lactitol or a derivative thereof; [5]: The pharmaceutical composition according to claim 4, wherein the disease accompanied by renal function decline is selected from diseases accompanied by renal function decline in the early nephropathy stage (stage 2), diseases accompanied by renal function decline in the overt nephropathy stage (stage 3A), and diseases accompanied by renal function decline in the renal failure stage (stage 4); [6]: A pharmaceutical composition according to claim 4, wherein the disease accompanied by renal function decline is selected from diseases accompanied by renal function decline in the early nephropathy stage (stage 2), diseases accompanied by renal function decline in the overt nephropathy stage (stage 3A), and diseases accompanied by renal function decline in the renal failure stage (stage 4); [7]: A pharmaceutical composition according to claim 4, wherein the disease accompanied by renal function decline is selected from diseases accompanied by renal function decline in the GFR classification of G2, G3a, G3b, or G4 (GFR value of 15 mL / min / 1.73 m 2 or more, 90 mL / min / 1.73 m 2 The pharmaceutical composition according to claim 4 or 5, wherein the pharmaceutical composition is in a state of less than 100 mg / kg.

[0008] The present invention provides a novel means for suppressing renal function decline in vivo and improving renal function by providing an agent for suppressing renal function decline containing lactitol or a derivative thereof.

[0009] Figure 1 is a graph showing the change in serum creatinine levels in a subject (male, 47 years old) before and after one month of lactitol intake. Figure 2 is a graph showing the change in eGFR (calculated based on the serum creatinine levels shown in Figure 1) in a subject (male, 47 years old) before and after one month of lactitol intake. Figure 3 is a graph showing serum creatinine (CRE) levels after 21 days of lactitol intake in a renal failure model induced by feeding adenine to test mice (male, 60 weeks old). Figure 4 is a graph showing blood urea nitrogen (BUN) levels after 21 days of lactitol intake in a renal failure model induced by feeding adenine to test mice (male, 60 weeks old). Figure 5 is a graph showing blood lactate dehydrogenase (LDH) levels after 21 days of lactitol intake in a renal failure model induced by feeding adenine to test mice (male, 60 weeks old). Figure 6 is a graph showing blood creatine kinase (CK) levels after 21 days of lactitol intake in a renal failure model induced by feeding test mice (male, 60 weeks old) adenine. Figure 7 is a graph showing blood albumin (ALB) levels after 21 days of lactitol intake in a renal failure model induced by feeding test mice (male, 60 weeks old) adenine.

[0010] The inventors of the present invention have conducted extensive research and development and hypothesized that by having individuals with impaired renal function ingest lactitol, a type of sugar alcohol, the decline in renal function may be suppressed or improved. They therefore decided to conduct human trials in subjects with high blood creatinine levels to verify the effect of lactitol on markers of renal failure.

[0011] As a result, the inventors of the present invention have found that lactitol can suppress and improve renal function decline in vivo, and have demonstrated that lactitol or its derivatives can provide a new means for suppressing renal function decline. More specifically, the present invention provides an agent for suppressing renal function decline, comprising lactitol or its derivatives.

[0012] In the present invention, when lactitol or its derivatives are orally administered, they can effectively reduce blood creatinine levels, which is a marker of renal dysfunction. Therefore, in the present invention, lactitol or its derivatives can suppress or improve renal dysfunction in vivo, more specifically, improve chronic kidney disease (CKD).

[0013] In the present invention, lactitol is used as an active ingredient, but its derivatives can also be used as active ingredients. Here, lactitol derivatives refer to compounds obtained by changing a small part of the molecular structure of lactitol, and refer to compounds that maintain the basic structure and properties of lactitol while undergoing modifications such as the introduction of functional groups, oxidation, reduction, and atom replacement in part of the structure.

[0014] In the present invention, in addition to lactitol or its derivatives as an active ingredient, other substances that have been shown to have an inhibitory effect on the decline of renal function can be used in combination.

[0015] The intake amount of lactitol or its derivatives in the present invention can be a commonly used intake amount. The intake amount of lactitol or its derivatives can be 5 to 40 g per day. For example, when used as a pharmaceutical, it can be 18 to 40 g, and when used as a food, it can be 5 to 20 g. The intake schedule of lactitol or its derivatives can be any, for example, once a day, three times a day, or even less frequently, such as once a week or once a month.

[0016] The agent for suppressing renal function decline of the present invention may contain various additives commonly used in foods or medicines in addition to lactitol or a derivative thereof as the active ingredient.

[0017] In the present invention, the suppression of decline in renal function can include bringing the values ​​of renal function markers in plasma closer to the normal range, and the like. Such plasma kidney function markers include: glomerular damage markers, such as albumin, type IV collagen, ceruloplasmin, creatinine, and serum cystatin C; tubular damage markers, such as NGAL, α1-MG, KIM-1, L-FABP, angiotensinogen, NAG, and β2-microglobulin; inflammatory markers, such as inflammatory cytokines (IL-6, IL-8, IL-18, IP-10, TNF-α, and TNF-α receptors), growth factors (TGF-β and CTGF), adhesion molecules (ICAM-1 and VCAM-1), fetuin-A, soluble CD40 ligand, and human α1-acid glycoprotein; oxidative stress markers, such as 8-OHdG, pentosidine, and blood AGE; and CKD markers, such as glomerular filtration rate (GFR), cystatin C, uric acid, and creatinine. By measuring these and comparing the values ​​with those within the normal range, it is possible to determine whether kidney function is declining or being prevented from declining.

[0018] As an example of a marker of declining kidney function, the standard values ​​for serum creatinine levels are set as shown in Table 1 below.

[0019]

[0020] The agent for suppressing renal function decline of the present invention is preferably administered to an individual whose serum creatinine level is mildly abnormal, requires reexamination and lifestyle improvement, or requires detailed examination and treatment, based on the reference values ​​for serum creatinine levels shown in Table 1. Suppression of renal function decline when the agent for suppressing renal function decline of the present invention is administered to such an individual includes any case in which the serum creatinine level decreases, for example, when the serum creatinine level decreases to a level within the "normal" range after a certain period of administration to an individual whose eGFR value falls within the "mildly abnormal" range, or when the serum creatinine level decreases from the initial level but remains within the "mildly abnormal" range after administration to an individual whose eGFR value falls within the "mildly abnormal" range.

[0021] The agent for suppressing renal function decline of the present invention can be applied to any disease in which renal function declines, such as glomerulonephritis, chronic kidney disease (CKD), etc. In particular, the agent for suppressing renal function decline of the present invention is particularly effective against CKD, and is even more effective against renal function decline selected from early nephropathy stage (stage 2), overt nephropathy stage (stage 3A), and renal failure stage (stage 4) of CKD.

[0022] CKD, which is the target of the renal function decline inhibitor of the present invention, has various pathological conditions, ranging from a state in which there is only abnormal urinary findings and no decline in renal function at all, to end-stage renal failure requiring renal replacement therapy (dialysis or kidney transplantation). Therefore, CKD in humans is characterized by the estimated glomerular filtration rate (eGFR) (ml / min / 1.73m), which is estimated from age, sex, serum creatinine level or cystatin C level to estimate renal function. 2 Whether estimated from serum creatinine or cystatin C, if the eGFR is 60 or less, there is a suspicion of decreased renal function and further examination is considered necessary.

[0023] The formula for calculating eGFR in humans is as follows: Formula for calculating eGFR value based on serum creatinine value (Cr (mg / dl)): Men: eGFR (ml / min / 1.73 m 2 ) = 194 × Cr (mg / dl) -1.094 × Age (years) -0.287 Women: eGFR (ml / min / 1.73 m 2 ) = 194 × Cr (mg / dl) -1.094 × Age (years) -0.287 × 0.739 Formula for calculating eGFR based on serum cystatin C (Cys-C (mg / L)): Men: eGFR (ml / min / 1.73 m 2 ) = (104 × Cys-C (mg / L) -1.019 ×0.996 年齢（歳） )-8 Women: eGFR (ml / min / 1.73 m 2 ) = (104 × Cys-C (mg / L) -1.019 ×0.996年齢（歳） ×0.929)-8

[0024] Based on the eGFR thus estimated, renal function can be divided into six stages: G1, G2, G3a, G3b, G4, and G5. The characteristics of these stages are summarized in Table 2.

[0025]

[0026] The agent for suppressing renal function decline of the present invention is effective in suppressing renal function decline in patients with G2, G3a, G3b, or G4 renal function decline based on the GFR classification shown in Table 2 (i.e., a GFR value of 15 mL / min / 1.73 m 2 or more, 90 mL / min / 1.73 m 2 The suppression of renal function decline when the agent for suppressing renal function decline of the present invention is administered to such an individual includes any case in which the eGFR value increases, for example, when the agent is administered for a certain period to an individual whose eGFR value falls within the "G3a" category, and the eGFR value increases to a value within the "G2" category, or when the agent is administered to an individual whose eGFR value falls within the "G2" category, and the eGFR value increases within the range of the "G2" category.

[0027] The present invention can treat or prevent diseases accompanied by renal function decline by administering the aforementioned agent for suppressing renal function decline to an individual with renal decline. Therefore, in a second aspect, the present invention can provide a composition having an effect of suppressing renal function decline, which comprises lactitol or a derivative thereof.

[0028] The composition in this embodiment may be a food composition (a composition for a general food or a composition for a food having a bioregulatory function (e.g., a food for specified health uses, a food with nutrient function claims, or a food with functional claims)) or a pharmaceutical composition. In one preferred embodiment, the present invention can provide a pharmaceutical composition for treating a disease accompanied by decreased kidney function, comprising lactitol or a derivative thereof.

[0029] The composition of the present invention may contain, in addition to lactitol or its derivatives, other ingredients and various additives commonly used in foods or medicines, and any of these other ingredients and various additives is acceptable.

[0030] As described above, lactitol or its derivatives that can be used in the composition of the present invention can efficiently reduce serum creatinine levels and improve (increase) eGFR, which is an index of kidney function.

[0031] The content of the active ingredient in the composition of the present invention can be an amount generally used for lactitol or its derivatives.

[0032] The composition of the present invention can be applied to any disease in which kidney function declines, such as glomerulonephritis, chronic kidney disease (CKD), etc. In particular, the agent for suppressing kidney function decline of the present invention is particularly effective against CKD, and is even more effective against kidney function decline in the early nephropathy stage (stage 2), overt nephropathy stage (stage 3A), and renal failure stage (stage 4) of CKD.

[0033] The composition of the present invention is effective in patients with reduced renal function who are classified as G2, G3a, G3b, or G4 in terms of GFR (GFR value of 15 mL / min / 1.73 m 2 or more, 90 mL / min / 1.73 m 2 It is preferred to administer to individuals who are in a state where:

[0034] The present invention will be specifically illustrated by the following examples, which are not intended to limit the present invention in any way.

[0035] Example 1: Examination of effects on kidney function markers (1) In this example, lactitol was administered to humans to confirm the effects of lactitol on kidney function.

[0036] A subject (male, 47 years old, creatinine level = 1.05 mg / dL) whose serum creatinine level exceeded the reference value as a result of a blood test was given 5 g of lactitol orally per day for one month. After one month, serum creatinine levels were measured using blood samples taken from the subject, and the estimated glomerular filtration rate (eGFR) was also calculated based on age, sex, and serum creatinine levels.

[0037] (1-1) Measurement of serum creatinine (Cr) levels. Serum creatinine (Cr), a marker of kidney function, was measured using serum separated from blood collected from a male subject who had been orally taking lactitol (Bussan Food Science Co., Ltd.) for one month. Serum creatinine was measured using a colorimetric method. As a negative control, serum creatinine levels were measured using a blood sample from the same male subject before the lactitol intake.

[0038] The results are shown in Figure 1. When blood creatinine levels were measured, it was confirmed that the value, which was 1.25 mg / dL before ingestion, had decreased to 0.90 mg / dL, within the normal range, after one month of lactitol ingestion.

[0039] (1-2) Calculation of estimated glomerular filtration rate (eGFR) Based on the serum creatinine level of the subject measured in (1-1), the following formula was used: Men: eGFR (ml / min / 1.73 m 2 ) = 194 × Cr (mg / dl) -1.094 × Age (years) -0.287 eGFR was estimated based on this.

[0040] The results are shown in Figure 2. The estimated eGFR based on a serum creatinine level of 1.25 mg / dL before intake was 50.3 (ml / min / 1.73 m 2After one month of intake, the estimated eGFR based on a serum creatinine level of 0.90 mg / dL rose to 72.1. As mentioned above, an eGFR of 60 or less is considered to indicate a decline in kidney function, and the value improved from 50.3 to 72.1, within the normal range (60 or above), demonstrating that lactitol intake has an effect on improving the treatment of CKD.

[0041] Example 2: Examination of effects on kidney function markers (2) In this example, lactitol was administered to animals to confirm the effects of lactitol on kidney function.

[0042] In this study, 60-week-old C57BL / 6J male mice (30 mice total, hereafter referred to as "subject mice") were used. The mice were individually housed in plastic cages (170 W × 240 D × 120 H mm, CLEA Japan, Inc.) with bedding made of paper chips and Peperclean (Japan SLC, Inc.) autoclaved (121°C, sterilization for 40 minutes, drying for 30 minutes). The temperature and humidity were kept at 20–26°C, 30–70%, and with a 12-hour photoperiod (lights on at 7:00 AM, lights off at 7:00 PM) for 12 hours per day. Temperature and humidity were recorded daily and stored as raw data.

[0043] Adenine-induced renal failure model was created using these test mice and used in the experiment. Specifically, the control group (referred to as the "Con group") was fed AIN-93M (Research Diets), a diet for mice and rats. The adenine-fed group (referred to as the "Adenine group") and the adenine-lactitol-fed group (referred to as the "Adenine+L group") were fed AIN-93M supplemented with 0.1% adenine ad libitum. Water was provided ad libitum in 100 mL polycarbonate bottles. The Con and Adenine groups received home-pumped water supplemented with 0.025% sodium hypochlorite (Tsurukuron, Tsurumi Soda Co., Ltd.), while the Adenine+L group received water supplemented with 5% lactitol (Butsusan Food Science Co., Ltd.). The experimental group composition is summarized in Table 3 below.

[0044]

[0045] The Adenine+L group, which was an adenine-induced renal failure model (same formulation as the Adenine group), was given 5 g of lactitol orally per day for 21 days (3 weeks).

[0046] After 21 days (3 weeks), blood samples were collected from the abdominal vena cava of each group of mice under isoflurane inhalation anesthesia using a heparinized syringe. The collected blood was stored on ice, then centrifuged (3000 rpm / 10 min), and the obtained plasma was stored at -80°C.

[0047] Plasma samples collected from test mice in each group were used to measure blood creatinine, urea nitrogen, albumin, lactate dehydrogenase, and creatinine kinase by Oriental Yeast Co., Ltd. Statistical analysis was performed using Dunnett's multiple comparison test, and in the figures below for each measurement value, significant differences of p<0.05 are indicated between different signs.

[0048] (2-1) Measurement of serum creatinine (CRE) levels The serum creatinine measurement results for samples from test mice in each group are shown in Figure 3. When blood creatinine levels (mg / dL) were measured, they were significantly lower in the Adenine+L group, which had been given lactitol for 21 days, compared to the Adenine group, which had not been given lactitol.

[0049] (2-2) Measurement of urea nitrogen (UN) High blood urea nitrogen (BUN) levels may indicate poor kidney function, and it is known that when kidney function declines, urea cannot be excreted in urine, causing the blood urea nitrogen level to rise. Figure 4 shows the blood urea nitrogen (BUN) measurement results for samples from test mice in each group. The blood urea nitrogen level (mg / dL) was significantly lower in the Adenine+L group, which had taken lactitol, compared to the Adenine group, which had not taken lactitol.

[0050] (2-3) Measurement of lactate dehydrogenase (LDH) It is known that LDH levels in the blood rise when organs such as the kidneys are destroyed. Figure 5 shows the results of measuring blood LDH levels in samples from test mice in each group. Blood LDH levels (IU / L) were significantly lower in the Adenine+L group, which had taken lactitol, compared to the Adenine group, which had not taken lactitol.

[0051] (2-4) Creatine Kinase (CK) Measurement It is known that CK levels rise due to immune abnormalities caused by renal failure. Figure 6 shows the results of measuring blood CK levels in samples from test mice in each group. Blood CK levels (IU / L) in the Adenine+L group, which ingested lactitol, decreased to a level that was not significantly different from the Con group.

[0052] (2-5) Measurement of Albumin (ALB) It is known that when kidney damage occurs, albumin leaks into the urine, leading to a decrease in blood albumin concentration. Figure 6 shows the results of measuring blood albumin levels in samples from test mice in each group. The decrease in blood albumin levels (g / dL) was significantly suppressed in the Adenine+L group, which had taken lactitol, compared to the Adenine group, which had not taken lactitol.

[0053] The results shown in (2-1) to (2-5) revealed that continuous oral administration of lactitol for 21 days in adenine-induced renal failure model mice improved all of the values ​​associated with chronic kidney disease (CKD), including creatinine, blood urea nitrogen, albumin, lactate dehydrogenase, and creatine kinase.

[0054] The present invention provides an agent for suppressing renal function decline containing lactitol or a derivative thereof, thereby providing a new means for suppressing renal function decline in the body and improving renal function using lactitol or a derivative thereof.

Claims

1. A renal function decline inhibitor containing lactitol or its derivatives.

2. The agent for suppressing renal function decline described in claim 1, wherein the renal function decline is selected from renal function decline in the early nephropathy stage (stage 2), renal function decline in the overt nephropathy stage (stage 3A), and renal failure stage (stage 4).

3. Renal function decline is classified as G2, G3a, G3b, or G4 (GFR value is 15 mL / min / 1.73 m 2 or more, 90 mL / min / 1.73 m 2 3. The agent for suppressing renal function decline according to claim 1 or 2, wherein the amount of renal function decline is less than 100%.

4. A pharmaceutical composition for treating a disease accompanied by decreased renal function, comprising lactitol or a derivative thereof.

5. The pharmaceutical composition according to claim 4, wherein the disease accompanied by decreased renal function is selected from diseases accompanied by decreased renal function in the early nephropathy stage (stage 2), diseases accompanied by decreased renal function in the overt nephropathy stage (stage 3A), and diseases accompanied by decreased renal function in the renal failure stage (stage 4).

6. Renal function decline is classified as G2, G3a, G3b, or G4 (GFR value is 15 mL / min / 1.73 m 2 or more, 90 mL / min / 1.73 m 2 The pharmaceutical composition according to claim 4 or 5, wherein the pharmaceutical composition is in a state of less than 100 mg / kg.

Images