Composition for improving kidney function

Abstract

The present invention provides a new use of 1,5-anhydrofructose and 1,5-anhydroglucitol that is a metabolic product of 1,5-anhydrofructose. The present invention pertains to a composition for improving renal function, said composition comprising 1,5-anhydrofructose and / or 1,5-anhydroglucitol as an active ingredient.

Description

[Technical Field]

[0001] The present invention relates to a composition for improving renal function. [Background technology]

[0002] The kidneys are vital organs essential for maintaining life, with a wide range of functions, including excretion of waste products from the body, maintaining the body's water balance, maintaining electrolyte homeostasis and thereby maintaining the body's acid-base balance, producing and secreting the red blood cell-forming hormone erythropoietin and the blood pressure-regulating hormone renin, and expressing and regulating the function of vitamin D, which regulates calcium and phosphorus metabolism.

[0003] The body has two kidneys, one on each side. Each kidney has approximately one million nephrons (each consisting of a pair of glomerulus and tubule), the smallest functional unit, performing its functions, resulting in a large reserve capacity. However, nephrons lack the ability to regenerate, and as a result, renal function gradually declines with age (age-related renal decline). This decline is accelerated by the presence of chronic kidney disease (CKD) due to metabolic syndrome (hypertension, diabetes, hyperlipidemia, etc.), hyperuricemia, and medication (e.g., anticancer drugs), ultimately leading to renal failure and ultimately to a condition known as uremia, which makes life difficult to sustain. In recent years, artificial dialysis has been used to treat this condition. However, artificial dialysis places a significant mental, physical, and medical financial burden on patients and their families. According to 2018 statistics from the Japanese Society for Dialysis Therapy, there are approximately 340,000 dialysis patients in Japan, with approximately 40,000 new patients with end-stage renal failure beginning dialysis treatment each year. As a result, the cost of dialysis treatment amounts to 1.6 trillion yen per year, accounting for 4% of total medical expenses and placing a strain on Japan's medical economy. Furthermore, dialysis is a symptomatic treatment, and once initiated, it must be continued for life.

[0004] For these reasons, maintaining kidney function and preventing its deterioration are major challenges, and the development of measures to prevent and control metabolic syndrome and to treat the deterioration of kidney function associated with aging has become an urgent issue. This gradual increase in dialysis patients is not limited to Japan, but is a global trend due to metabolic syndrome and the aging of the global population. However, at present, there is no effective "direct treatment" for kidney dysfunction, and the current situation is that only "indirect treatments" such as dietary therapy (restricting the intake of protein, salt, potassium, etc.) to control the underlying metabolic syndrome can avoid or delay the initiation of dialysis. The creation of a "direct treatment" that acts on the kidney itself to halt the progression of dysfunction and even improve it is becoming a major social issue, not just a medical one.

[0005] On the other hand, 1,5-anhydrofructose (hereinafter sometimes referred to as "1,5-AF") is a monosaccharide that is thought to be produced in vivo in the liver by the action of lyase on starch. In vitro, it can be produced by the action of α-1,4-glucan lyase, an enzyme derived from certain ascomycetes and red algae, on starch or its hydrolysates.

[0006] Various uses of 1,5-AF have been known. For example, Patent Document 1 discloses an antitumor agent containing 1,5-AF and / or its dehydration product, ascopyrone. Patent Document 2 discloses a functional inhibitor of apoptosis-associated speck-like card protein (ASC) and a therapeutic agent for diseases or symptoms associated with ASC, each containing 1,5-AF as an active ingredient, as well as an inflammasome pathway inhibitor and a therapeutic agent for diseases or symptoms associated with the inflammasome pathway, each containing 1,5-AF as an active ingredient. Patent Document 3 discloses a cell aging inhibitor containing 1,5-AF as an active ingredient.

[0007] Furthermore, Patent Document 4 discloses that 1,5-anhydroglucitol (hereinafter sometimes referred to as "1,5-AG"), a metabolite of 1,5-AF, activates nitric oxide synthase and increases nitric oxide production, thereby protecting blood vessels and being effective in the treatment and prevention of ischemic diseases.

[0008] Although there are few reports on the physiological functions of 1,5-AG, it has been reported that it has an effect of secreting insulin from the β cells of the pancreatic islets of Langerhans (Non-Patent Document 1).

[0009] However, the relationship between 1,5-AF and 1,5-AG and renal function has not been reported. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] International Publication No. 2005 / 040147 [Patent Document 2] International Publication No. 2015 / 016178 [Patent Document 3] Japanese Patent Application Laid-Open No. 2017-128550 [Patent Document 4] Japanese Patent Application Publication No. 2020-100601 [Non-patent literature]

[0011] [Non-Patent Document 1] Biochimica et Biophysica Acta 1623 (2003) 82-87 Summary of the Invention [Problem to be solved by the invention]

[0012] An object of the present invention is to provide new uses for 1,5-AF and its metabolite, 1,5-AG. [Means for solving the problem]

[0013] As a result of intensive research to solve the above problems, the inventors of the present invention discovered that 1,5-AF and its metabolite, 1,5-AG, act directly on the kidneys to prevent and improve renal dysfunction, leading to the completion of the present invention.

[0014] That is, the gist of the present invention is as follows. (1) A composition for improving renal function, comprising 1,5-anhydrofructose and / or 1,5-anhydroglucitol as an active ingredient. (2) A composition for improving renal function according to (1) above, which is used for the prevention or treatment of renal failure. (3) A composition for improving renal function according to (1) or (2) above, which is a pharmaceutical composition or a food composition. [Effects of the Invention]

[0015] According to the present invention, renal function can be improved and various renal dysfunctions can be treated or prevented. [Brief explanation of the drawings]

[0016] [Figure 1] FIG. 1 shows the state of the kidneys of a control group (left) and an adenine-administered group (right) when rats exhibiting renal failure were created by oral administration of adenine. [Figure 2] FIG. 2 shows the results of measuring serum creatinine levels in renal failure model rats. [Figure 3] FIG. 3 shows the results of measuring serum urea nitrogen (BUN) in renal failure model rats. [Figure 4] FIG. 4 shows the results of measuring serum phosphorus in renal failure model rats. [Figure 5] FIG. 5 shows the results of measuring serum uric acid in renal failure model rats. [Figure 6] FIG. 6 shows the results of measuring serum calcium in renal failure model rats. [Figure 7] FIG. 7 shows pathological images of the kidneys in renal failure model rats. [Figure 8] FIG. 8 shows the results of measuring blood 1,5-AG concentrations in renal failure model rats. DETAILED DESCRIPTION OF THE INVENTION

[0017] The present invention will be described in detail below. The composition for improving renal function of the present invention can improve renal function and treat or prevent various renal dysfunctions.

[0018] In the present invention, renal dysfunction refers to a state caused by acute or chronic nephritis, or diabetes, gout, side effects of medication, etc., and characterized by symptoms such as decreased renal filtration function and abnormalities in internal circulation. Specific examples include glomerulonephritis (acute glomerulonephritis, rapidly progressive glomerulonephritis, chronic glomerulonephritis, membranoproliferative glomerulonephritis), chronic nephritis, secondary nephritis, nephrotic syndrome, uremia, renal failure (acute renal failure, chronic renal failure), diabetic nephropathy, hypertensive nephropathy (nephrosclerosis), pyelonephritis, gouty kidney, interstitial nephritis, nephrosclerosis, polycystic kidney disease, kidney stones (urinary tract stones, kidney stones), renal tumors (renal cell carcinoma, renal pelvic carcinoma), nephritis (lupus nephritis) associated with autoimmune diseases (such as systemic lupus erythematosus), and kidney damage associated with drug administration such as anticancer drugs.

[0019] 1,5-AF, the active ingredient in the composition for improving renal function of the present invention, can be prepared in accordance with known methods, such as the method described in JP-A-9-505988 ("Use of α-1,4-glucan lyase for preparing 1,5-D-anhydrofructose").

[0020] 1,5-AG can be prepared according to known methods such as the method described in Japanese Patent No. 5075376 ("Method for producing 1,5-D-anhydroglucitol").

[0021] The composition for improving renal function of the present invention is stable and does not undergo further changes, so in addition to the active ingredients 1,5-AF and / or 1,5-AG, it is possible to add other preparations or products, such as pharmaceutical carriers, excipients, solubilizers, stabilizers, etc.

[0022] Furthermore, the renal function improving composition of the present invention can be used as a pharmaceutical product, a quasi-drug, a health food, a food for specified health uses, or a food with functional claims, or can be incorporated into foods, beverages, etc.

[0023] The composition for improving renal function of the present invention can be administered by various known methods depending on its dosage form, and the dosage, administration site, administration interval, administration period, etc. can be appropriately determined taking into consideration the age and weight of the patient, the condition of the disease, or the use in combination with other drugs or treatments, etc. The administration method is not particularly limited, and examples thereof include oral administration, injection or intravenous drip infusion, or topical administration in the form of a spray, ointment, etc.

[0024] The dosage of the composition for improving renal function of the present invention varies depending on its dosage form, administration method, or symptoms to be treated. For example, the dosage can be 1 to 500 mg, preferably 10 to 100 mg, of the active ingredient (1,5-AF and / or 1,5-AG) per kg of patient body weight. The composition can be administered at an appropriate frequency, such as once or several times a day, by continuous infusion, or even once every few days.

[0025] Dosage forms of the composition for improving renal function of the present invention include, but are not limited to, powders, granules, fine granules, capsules (e.g., capsules containing powder), tablets, liquids, injections, drip infusions, sprays, ointments, etc.

[0026] This specification includes the contents disclosed in the specification and drawings of Japanese Patent Application No. 2020-155273, which is the basis of priority for this application. [Example]

[0027] The present invention will be described in more detail below using examples, but the technical scope of the present invention is not limited to these examples.

[0028] (Example 1) Verification of the renal function improving effect of 1,5-AF / 1,5-AG in animal experiments As described below, the present inventors have discovered that 1,5-AF, produced by treating sweet potato starch with a lyase derived from seaweed (Gracilaria verrucosa), and 1,5-AG produced in vivo by oral ingestion of this 1,5-AF, prevent or alleviate the pathology of renal failure induced by adenine administration in an experimental renal failure model (hereinafter referred to as "adenine nephropathy"). The following experiments demonstrate that 1,5-AF, or 1,5-AG metabolically converted from 1,5-AF in vivo, acts directly on the kidney and is effective in preventing or alleviating the decline in renal function in renal failure. This demonstrates that 1,5-AF and 1,5-AG may slow or inhibit the progression of renal failure in humans, potentially providing a valuable strategy for preventing or delaying the need for dialysis.

[0029] 1. Adenine Nephropathy Model Adenine is one of the five bases that make up nucleic acids and a purine compound that is widely distributed in the body. Because adenine is poorly soluble in water, oral administration of a certain amount or more results in crystallization and accumulation in the kidney, ultimately leading to renal failure, commonly known as uremia. Therefore, adenine is widely used as a representative experimental renal failure model. The present inventors have also used this model to achieve results regarding the pathology of renal dysfunction (Oyama Y., et al., Lab Invest, (2010) 90(6): 853-66). This model is considered to be similar to the human clinical model of hyperuricemia-induced nephropathy and renal failure.

[0030] Using this nephropathy model, the present inventors have now verified that the monosaccharides 1,5-AF and 1,5-AG ameliorate the pathological condition of renal failure in this nephropathy model rat.

[0031] 2. Pathological condition of adenine nephropathy model and the ameliorative effect of 1,5-AF Rats exhibiting typical signs of renal failure were created by oral administration of adenine according to the method described in Oyama Y., et al., Lab Invest, (2010) 90(6): 853-66 (Figure 1).

[0032] Compared to the control group (left), the kidneys of the adenine-treated group (right) were enlarged and showed a whitish discoloration. The kidney weight of the adenine-treated group was approximately twice that of the control group (control group average: 650g, adenine group average: 1360g).

[0033] Therefore, the effect of 1,5-AF (provided by Sanas Co., Ltd.) was examined in this nephropathy model rat.

[0034] The rats were divided into two groups: an adenine-only group and an adenine + 1,5-AF group. The adenine-only group received 10g / day of powdered feed containing 0.75% adenine, while the adenine + 1,5-AF group received 10g / day of powdered feed containing 0.75% adenine, plus 200mg / day of 1,5-AF. On the 14th day, blood samples were taken and kidneys were removed for biochemical and pathological analysis.

[0035] As a result, we were able to significantly correct the metabolic abnormalities and electrolyte metabolism typical of renal failure, such as increases in serum creatinine (Figure 2), serum urea nitrogen (BUN) (Figure 3), serum phosphorus (Figure 4), and serum uric acid (Figure 5), and decreases in serum calcium (Figure 6).

[0036] Furthermore, pathological findings of the kidneys showed that the 1,5-AF-administered group showed reduced infiltration of inflammatory cells and fibrosis compared to the adenine-only-administered group (Figure 7).

[0037] The group administered adenine alone showed significant renal enlargement and changes in color (a-1), whereas the group administered 1,5-AF in combination with adenine showed relatively good retention of thickness, including the cortex, and white color (Fig. 7, a-2).

[0038] The adenine-only administration group (b-1) showed stronger infiltration of inflammatory cells (purple) than the 1,5-AF administration group (b-2).

[0039] In the adenine-only administration group, the presence of dilated tubules (*) (c-1) and interstitial fibrosis (arrow) (lower left of c-1) were prominent, but these were alleviated in the 1,5-AF administration group (c-2) (HE staining).

[0040] Furthermore, when the blood 1,5-AG concentration of rats administered 1,5-AF was measured, a significant increase was observed in the 1,5-AF administration group compared to the adenine alone administration group (Figure 8).

[0041] These data clearly demonstrate that 1,5-AF, as well as its metabolite 1,5-AG, have an effect on improving the function and pathological morphology of the pathological condition of "adenine nephropathy." From the above, we have obtained evidence that 1,5-AF and 1,5-AG alleviate the pathological conditions of renal failure and uremia.

[0042] 3. Discussion Renal failure, also known as uremia, is the final stage of kidney disease in which toxins that should be excreted by the kidneys, such as metabolic products and waste products like urea nitrogen and uric acid, accumulate in the body, causing serious complications such as electrolyte imbalance, encephalopathy, osteoporosis, and arteriosclerosis, and ultimately death.

[0043] Currently, this condition is treated with an artificial kidney, or dialysis. However, the time and social constraints that dialysis places on patients, as well as the financial burden, are becoming serious problems. Furthermore, with the advent of an aging society and the rise of metabolic syndrome, the number of patients who progress from kidney failure to dialysis is steadily increasing, and new solutions are being sought.

[0044] In the course of a series of studies on the in vivo monosaccharide 1,5-AF and its metabolite, 1,5-AG, the inventors discovered that 1,5-AF not only halts the progression of renal damage but can also alleviate and improve the pathology of renal failure itself. 1,5-AF is a monosaccharide produced in the body from starch, and is rapidly converted to 1,5-AG, excreted by the kidney, and has no side effects. Therefore, it may be a promising drug for improving the progression of nephritis, treating renal failure, and avoiding dialysis.

[0045] 4. Conclusion 1,5-AF is a rare sugar in the body, and the present inventors have confirmed its safety. However, this monosaccharide and its metabolite, 1,5-AG, have been shown to be effective in improving the pathology of renal failure and alleviating symptoms, and are believed to present an effective therapeutic strategy for renal disorders. Furthermore, no drugs or treatments that can alleviate nephritis and nephropathy pathology and directly control the progression to renal failure have been known to date, and 1,5-AF and 1,5-AG are the first, and are expected to have a major impact on the therapeutics of kidney disease.

[0046] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.

Claims

1. A composition for improving renal function, which contains 1,5-anhydrofructose and / or 1,5-anhydroglucitol as active ingredients, and is used to prevent or treat renal failure.

2. The composition for improving renal function according to claim 1, which is a pharmaceutical composition or a food composition.

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