Pharmaceutical composition for treating chronic kidney disease with pre-treatment urinary albumin concentration in a particular range

Abstract

The present invention relates to a pharmaceutical composition, which is a pharmaceutical composition for the treatment of chronic kidney disease containing citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof, for the treatment of chronic kidney disease, for the treatment of chronic kidney disease patients whose urinary albumin concentration before the treatment is in a certain range.

Description

Technical Field

[0001] This invention relates to a pharmaceutical composition comprising citric acid, a pharmaceutically permissible salt of citric acid, or hydrates thereof or mixtures thereof, for the treatment of chronic kidney disease (CKD) in CKD patients with CKD whose pretreatment urinary albumin concentration is within a specific range.

[0002] This application claims priority based on Japanese Patent Application No. 2024-056972, filed in Japan on March 29, 2024, the contents of which are incorporated herein by reference. Background Technology

[0003] The number of patients with end-stage kidney disease (ESKD) requiring dialysis or transplantation is increasing worldwide. This trend is also increasing in Japan, where the number of dialysis patients was approximately 350,000 at the end of 2022.

[0004] CKD is recognized as a potential predisposition to ESKD. CKD is a concept encompassing chronically progressive kidney disease, regardless of the underlying cause. It includes all pathological conditions that are chronically persistent (lasting more than 3 months) and indicate kidney damage, such as decreased glomerular filtration rate (GFR). Because CKD not only carries the risk of progressing to ESKD but also the risk of serious complications such as cardiovascular disease (CVD), early detection and appropriate treatment are crucial. To date, although many CKD treatments have been established, they remain insufficient, necessitating further development of nephroprotective agents.

[0005] Bicarbonate ions (HCO3-) in the blood of patients with advanced CKD - The concentration of albumin in urine decreases, leading to metabolic acidosis. Therefore, alkalizing agents such as sodium bicarbonate (baking soda) or citrate preparations are administered. Furthermore, it has been reported that the progression of CKD was inhibited by administering baking soda as an alkalizing agent (Non-Patent Literature 1). Additionally, oral administration of baking soda to an animal model of nephrotic syndrome caused by protein overload has been reported to inhibit renal tubular cell damage induced by acidic urine (Non-Patent Literature 2). Further reports indicate that administration of citrate preparations to CKD patients in stages G2–G3b resulted in decreased urinary albumin concentration, increased urinary pH (Patent Literature 1), and decreased MCP-1 gene expression in the kidneys in a diabetic animal model (Patent Literature 2). However, these parameters vary considerably due to individual differences, and it is believed that large-scale trials using a large number of cases are necessary to demonstrate the effectiveness of citrate preparations.

[0006] Existing technical documents

[0007] Patent documents

[0008] Patent Document 1: International Publication No. 2020 / 080499

[0009] Patent Document 2: International Publication No. 2020 / 080451

[0010] Non-patent literature

[0011] Non-patent literature 1: Brito-Ashurst, ID, et al.: Bicarbonate supplementations lower progression of CKD and improve nutritional status. J. Am. Soc. Nephrol., 20: 2075-2084, 2009.

[0012] Non-patent document 2: Souma T., et al.: Luminal alkalinization attenuates proteinuria-induced oxidative damage in proximal tubular cells. J. Am. Soc. Nephrol., 22: 635-648, 2011. Summary of the Invention

[0013] One objective of this invention is to screen CKD patients for treatment using nephroprotective pharmaceutical compositions comprising citric acid, pharmaceutically permissible salts of citric acid, or hydrates thereof, or mixtures thereof (hereinafter sometimes simply referred to as "citric acid, etc."). Another objective of this invention is to provide a nephroprotective pharmaceutical composition comprising citric acid, etc., for treating the screened CKD patients.

[0014] In order to solve the above-mentioned problems, the inventors conducted in-depth research and found that screening CKD patients based on the pre-treatment urinary albumin concentration is useful for treating CKD with a drug composition containing citric acid, etc., and thus completed the present invention.

[0015] Therefore, the present invention relates to the following solutions:

[0016] [1] A pharmaceutical composition comprising citric acid, a pharmaceutically permissible salt of citric acid, or hydrates thereof or mixtures thereof, for the treatment of chronic kidney disease in patients with chronic kidney disease whose urinary albumin concentration is within a specific range prior to the above treatment.

[0017] [2] The pharmaceutical composition according to item [1], wherein the urinary albumin concentration of the patient with chronic kidney disease prior to the above treatment is in a specific range of 10 to 1000 mg / gCr.

[0018] [3] The pharmaceutical composition according to item [1], wherein the urinary albumin concentration of the patient with chronic kidney disease prior to the above treatment is in a specific range of 25 to 600 mg / gCr.

[0019] [4] The pharmaceutical composition according to item [1], wherein the urinary albumin concentration of the patient with chronic kidney disease prior to the above treatment is in a specific range of 150 to 600 mg / gCr.

[0020] [5] The pharmaceutical composition according to any one of items [1] to [4], wherein the urine of the patient with chronic kidney disease before the above treatment is morning urine.

[0021] [6] The pharmaceutical composition according to any one of items [1] to [5], wherein the urinary albumin concentration of the patient with chronic kidney disease before the above treatment is within 2 weeks before the start of treatment.

[0022] [7] The pharmaceutical composition according to any one of items [1] to [6], wherein the above-mentioned renal protection is the inhibition of proteinuria, the maintenance or improvement of glomerular function and renal tubular function, the inhibition of inflammation, or the alkalization of urine.

[0023] [8] The pharmaceutical composition according to item [7], wherein the above-mentioned urinary protein is albumin, transferrin, IgG or α1-microglobulin.

[0024] [9] The pharmaceutical composition according to item [7], wherein the inhibition of the above-mentioned inflammation is an inhibition of the concentration of MCP-1 in urine.

[0025]

[10] The pharmaceutical composition according to any one of items [1] to [9], wherein the above-mentioned citric acid, pharmaceutically permissible salts of citric acid, or hydrates thereof or mixtures thereof are a mixture of sodium citrate or its hydrate and potassium citrate or its hydrate.

[0026]

[11] The pharmaceutical composition according to item

[10] further comprises anhydrous citric acid.

[0027]

[12] The pharmaceutical composition according to any one of items [1] to

[11] , wherein the above-mentioned citric acid, pharmaceutically permissible salts of citric acid, or hydrates thereof or mixtures thereof are administered at 1 to 3 g / day.

[0028]

[13] The pharmaceutical composition according to any one of items [1] to

[12] , wherein the above-mentioned chronic kidney disease is stage G2 to stage G3b.

[0029]

[14] The pharmaceutical composition according to any one of items [1] to

[13] , wherein the above-mentioned citric acid, a pharmaceutically permissible salt of citric acid, or their hydrates or mixtures thereof are administered for more than 6 weeks.

[0030] By screening patients based on their pre-treatment urinary albumin concentration using the pharmaceutical composition provided by the present invention (hereinafter referred to as "the pharmaceutical composition"), CKD patients suitable for treatment with the pharmaceutical composition containing citric acid, etc., provided by the present invention can be identified. Using the pharmaceutical composition containing citric acid, etc., provided by the present invention, CKD patients with pre-treatment urinary albumin concentrations within a specific range (e.g., 10–1000 mg / gCr) can be effectively treated. Attached Figure Description

[0031] Figure 1 This is a graph showing the logarithmic concentration of urinary albumin before and after 6 months of treatment with citric acid preparations. (A) is the control group, and (B) is the citric acid preparation treatment group.

[0032] Figure 2 This graph shows the urinary albumin concentration in CKD patients before and after 6 months of treatment, where the pre-treatment urinary albumin concentration was above 150 mg / gCr and below 600 mg / gCr. (A) is the control group, (B) is the sodium bicarbonate treatment group, and (C) is the citric acid treatment group.

[0033] Figure 3 This graph shows the urinary transferrin concentration in CKD patients with a pre-treatment urinary albumin concentration of ≥150 mg / gCr and <600 mg / gCr 6 months before and after treatment. (A) is the control group, (B) is the sodium bicarbonate treatment group, and (C) is the citric acid treatment group.

[0034] Figure 4 This graph shows the urinary IgG concentrations of CKD patients with a pre-treatment urinary albumin concentration of ≥150 mg / gCr and <600 mg / gCr 6 months before and after treatment. (A) is the control group, (B) is the sodium bicarbonate treatment group, and (C) is the citric acid treatment group.

[0035] Figure 5 This graph shows the concentration of α1-microglobulin in the urine of CKD patients before and after 6 months of treatment, whose pre-treatment urinary albumin concentration was above 150 mg / gCr and below 600 mg / gCr. (A) is the control group, (B) is the sodium bicarbonate treatment group, and (C) is the citric acid treatment group.

[0036] Figure 6 This graph shows the concentration of MCP-1 in the urine of CKD patients before and after 6 months of treatment, whose pre-treatment urinary albumin concentration was above 150 mg / gCr and below 600 mg / gCr. (A) is the control group, (B) is the sodium bicarbonate treatment group, and (C) is the citric acid treatment group.

[0037] Figure 7 This graph shows the urinary pH of CKD patients before and after 6 months of treatment, where the pre-treatment urinary albumin concentration was above 150 mg / gCr and below 600 mg / gCr. (A) is the control group, (B) is the sodium bicarbonate treatment group, and (C) is the citric acid treatment group. Detailed Implementation

[0038] The present invention will now be described in detail with reference to specific embodiments. However, the present invention is not limited to the following embodiments and can be implemented in any manner without departing from the spirit of the present invention.

[0039] It should be noted that all patent gazettes, patent application publications, and non-patent documents cited in this specification are incorporated herein by reference in their entirety for all purposes.

[0040] In this specification, the "~" used when referring to numerical values ​​means a range of values ​​that falls between the specified reference value and the specified reference value.

[0041] In this specification, "inhibition" encompasses stopping or slowing the worsening or progression of symptoms, states, or diseases, and means for this purpose, including improving such symptoms, states, or diseases, or means for this purpose. Here, "improvement" encompasses means for bringing "pathological" or "abnormal" symptoms, states, or diseases closer to a "healthy" or "normal" state, and means for this purpose, as well as means for achieving a "healthy" or "normal" state, or means for this purpose. Therefore, in one embodiment, "improvement" includes a value that is an indicator of "pathological" or "abnormal" symptoms or states decreasing or increasing according to the aforementioned "improvement," approaching a normal value, or becoming a normal value. The aforementioned "worsening or progression of symptoms, states, or diseases" includes the worsening or progression of "pathological" or "abnormal" symptoms, states, or diseases, and the worsening or progression from a "healthy" or "normal" state to a "pathological" or "abnormal" state. In one embodiment, "inhibition" refers to stopping or slowing the worsening or progression of symptoms, states, or diseases, or means for this purpose. In another implementation, "inhibition" means stopping or slowing the worsening or progression of symptoms, conditions, or diseases.

[0042] In this specification, "healthy" means a state free from acute or chronic disease or disorder, and "normal" means a healthy object is in its usual state.

[0043] Here, the above-mentioned symptoms, conditions, or diseases are compared before and after administration of this pharmaceutical composition, or when administration of this pharmaceutical composition is compared with administration of a control or placebo.

[0044] In this specification, "treatment" includes the disappearance, cure, healing, or relief of "pathological" or "abnormal" symptoms, states, or diseases, and the means for this purpose; it includes "suppressing" the worsening of "pathological" or "abnormal" symptoms, states, or diseases, and the means for this purpose; and it includes the concept of "improvement." Here, "suppression" and "improvement" have the above meanings. In one embodiment, "treatment" refers to the disappearance, cure, healing, or relief of "pathological" or "abnormal" symptoms, states, or diseases, and the means for this purpose. In another embodiment, "treatment" refers to the disappearance, cure, healing, or relief of "pathological" or "abnormal" symptoms, states, or diseases.

[0045] In this specification, "prevention" is a concept that includes the prior prevention of the occurrence of "pathological" or "abnormal" symptoms, conditions or diseases, as well as the means for this purpose.

[0046] In this specification, "chronic kidney disease (CKD)" is a concept encompassing all chronically progressive kidney diseases, regardless of the underlying disease. It includes all pathological conditions that are chronically persistent (lasting more than 3 months) and indicate kidney damage, as expressed by decreased glomerular filtration rate (GFR). Examples of underlying diseases for CKD include diabetic nephropathy, nephrosclerosis (caused by hypertension or aging), chronic glomerulonephritis (including IgA nephropathy and membranous nephropathy), and polycystic kidney disease.

[0047] According to the 2012 CKD diagnosis and treatment guidelines (Journal of the Japanese Society of Nephrology 2012), the severity of CKD is evaluated by renal function (GFR:G) and the classification of albuminuria / proteinuria.

[0048] The distinctions between GFRs are as follows:

[0049] G1: GFR is normal or high (≥90 mL / min / 1.73 m). 2 )

[0050] G2: GFR is normal or slightly decreased (60–89 mL / min / 1.73 mcg). 2 )

[0051] G3a: GFR slightly to moderately decreased (45–59 mL / min / 1.73 m) 2 )

[0052] G3b: GFR moderate to highly reduced (30-44 mL / min / 1.73 m) 2 )

[0053] G4: GFR height decreased (15-29 mL / min / 1.73 m) 2 )

[0054] G5: End-stage renal failure (ESKD) (<15 mL / min / 1.73 m) 2 )

[0055] The distinction based on the concentration of albumin in urine (albuminuria) is classified using the urine albumin / creatinine (Cr) ratio as follows.

[0056] A1: Normal (less than 30 mg / gCr)

[0057] A2: Microalbuminuria (30–299 mg / gCr)

[0058] A3: Overt albuminuria (above 300 mg / gCr)

[0059] In addition, based on the concentration of protein in urine (proteinuria), the urine protein / creatinine (Cr) ratio is classified as follows.

[0060] A1: Normal (less than 0.15 g / gCr)

[0061] A2: Mild proteinuria (0.15~0.49g / gCr) (based on test strip method, it is (-)~(2+))

[0062] A3: High proteinuria (above 0.50g / gCr) (based on test strip method, it is (1+) to (3+))

[0063] According to the 2012 CKD Diagnosis and Treatment Guidelines (Journal of the Japanese Society of Nephrology 2012), the severity of CKD is classified using the primary disease, the above-mentioned categories G and A, for example, expressed as diabetes G2A3, chronic nephritis G3bA1, etc.

[0064] However, considering that the severity of CKD has previously been described only by the stages distinguished by GFR, the severity of CKD can also be described by stages such as G1, G2, G3a, G3b, G4 and G5, as in the past.

[0065] In this instruction manual, "morning urine" refers to the first urine after waking up, and "random urine" refers to urine other than the aforementioned "morning urine".

[0066] 1. Pharmaceutical Composition

[0067] This pharmaceutical composition may contain citric acid, pharmaceutically permissible salts of citric acid, or hydrates thereof or mixtures thereof as active ingredients.

[0068] Examples of pharmaceutically permissible salts of citric acid include alkali metal salts of citrate. Examples of alkali metal salts of citrate include potassium citrate and sodium citrate, or their respective stable hydrates such as potassium citrate monohydrate (C6H5K3O7·H2O) and sodium citrate dihydrate (C6H5Na3O7·2H2O).

[0069] Examples of preferred active ingredients contained in this pharmaceutical composition include sodium citrate, potassium citrate, or their hydrates or mixtures thereof. For example, it may be a mixture of potassium citrate monohydrate (C6H5K3O7·H2O) and sodium citrate dihydrate (C6H5Na3O7·2H2O). The mixing ratio of potassium citrate monohydrate (C6H5K3O7·H2O) and sodium citrate dihydrate (C6H5Na3O7·2H2O) can be appropriately set by those skilled in the art. For example, the molar ratio of potassium citrate monohydrate to sodium citrate dihydrate may be set such that the sodium citrate dihydrate is 0.01 to 100 relative to 1 part potassium citrate monohydrate. The molar ratio of potassium citrate (e.g., potassium citrate monohydrate) to sodium citrate (e.g., sodium citrate dihydrate) can be appropriately set by those skilled in the art, for example, it can be 0.85:1.15~1.15:0.85, 0.90:1.10~1.10:0.90, 0.95:1.05~1.05:0.95, or 0.99:1.01~1.01:0.99, preferably 1:1.

[0070] Other examples of active ingredients contained in this pharmaceutical composition include sodium citrate or its hydrate, for example, sodium citrate dihydrate (C6H5Na3O7·2H2O).

[0071] Other examples of active ingredients contained in this pharmaceutical composition include potassium citrate or its hydrate, for example, potassium citrate monohydrate (C6H5K3O7·H2O).

[0072] In one embodiment, the active ingredient contained in the pharmaceutical composition of the present invention may comprise a mixture of sodium citrate or its hydrate and potassium citrate or its hydrate.

[0073] In one embodiment, the active ingredient contained in the pharmaceutical composition of the present invention may be a mixture of potassium citrate, sodium citrate, and citric acid (e.g., anhydrous citric acid). In this case, the mixing ratio of citric acid (e.g., anhydrous citric acid), potassium citrate, and sodium citrate may be appropriately set by those skilled in the art, for example, it may be 1:1.7–2.3:1.7–2.3, 1:1.9–2.1:1.9–2.1, or 1:1.95–2.05:1.95–2.05, preferably 1:2:2.

[0074] In one embodiment, the active ingredient contained in the pharmaceutical composition of the present invention may be a mixture of potassium citrate monohydrate (C6H5K3O7·H2O), sodium citrate dihydrate (C6H5Na3O7·2H2O), and anhydrous citric acid. In this case, the mixing ratio of anhydrous citric acid, potassium citrate monohydrate (C6H5K3O7·H2O), and sodium citrate dihydrate (C6H5Na3O7·2H2O) can be appropriately set by those skilled in the art, for example, it may be 1:1.7–2.3:1.7–2.3, 1:1.9–2.1:1.9–2.1, or 1:1.95–2.05:1.95–2.05, preferably 1:2:2.

[0075] In one embodiment, the active ingredient contained in the pharmaceutical composition of the present invention may consist solely of a mixture of sodium citrate or its hydrate and potassium citrate or its hydrate.

[0076] In this specification, when referring to the weight of citric acid, pharmaceutically permissible salts of citric acid, or their hydrates or mixtures thereof (e.g., potassium citrate monohydrate (C6H5K3O7·H2O) and sodium citrate dihydrate (C6H5Na3O7·2H2O)), the weight may be the dry weight.

[0077] This pharmaceutical composition can be used for renal protection in CKD. Renal protection includes the protection of renal tissue and the protection of renal function.

[0078] For example, this pharmaceutical composition may be a pharmaceutical composition for protecting kidney tissue in CKD, a pharmaceutical composition for inhibiting kidney tissue damage accompanying the progression of CKD, a pharmaceutical composition for maintaining or improving kidney function in CKD, or a pharmaceutical composition for inhibiting the decline in kidney function accompanying the progression of CKD.

[0079] Examples of kidney tissue protected by this pharmaceutical composition include nephrons, or the renal tubules (e.g., proximal tubules) or glomeruli that make up the nephrons.

[0080] Examples of renal function maintained or improved by this pharmaceutical composition include the functions of the nephrons that produce urine from the blood, namely, filtration based on the glomerulus or reabsorption based on the renal tubules (e.g., proximal tubular function), inhibition of urine acidification, and urine pH regulation that alkalinizes the urine. Additionally, examples of renal function maintained or improved by this pharmaceutical composition include the functions of the nephrons, the glomeruli, and the renal tubules (e.g., proximal tubular function), including filtration, reabsorption, or urine pH regulation (urine alkalinization).

[0081] Therefore, this pharmaceutical composition can be a pharmaceutical composition for maintaining or improving nephron function in CKD, a pharmaceutical composition for inhibiting the decline in glomerular function and renal tubular function accompanying the progression of CKD, a pharmaceutical composition for maintaining or improving filtration function, reabsorption function, and urine pH regulation function in CKD, or a pharmaceutical composition for inhibiting the decline in filtration function, reabsorption function, and urine pH regulation function accompanying the progression of CKD.

[0082] The efficacy of this pharmaceutical composition can be confirmed by administering it to a chronic kidney disease (CKD) patient whose urinary albumin concentration was within a specific range prior to treatment with this pharmaceutical composition, and evaluating the CKD patient's renal function. Specifically, when this pharmaceutical composition is administered to a CKD patient whose urinary albumin concentration was within a specific range prior to treatment, the renal function of the treated CKD patient is improved compared to the pre-treatment renal function, or the renal function after treatment with this pharmaceutical composition is higher than that of a control group of CKD patients who did not receive this pharmaceutical composition. To investigate renal function, it can be evaluated by methods known in the art, such as measuring glomerular filtration rate (GFR), urinary protein, various mediators in urine (inflammation, fibrosis, blood pressure), or urinary pH. Examples of proteinuria include albumin, transferrin, α1-glycoprotein, hemoglobin, myoglobin, immunoglobulins (IgG, IgM, IgA, etc.), Bence Jones protein, β2-microglobulin, α1-microglobulin, retinol-binding protein, lysozyme, and protein-like substances (proteins, acetyl ethers, mucin, etc.). Among these, albumin, transferrin, α1-glycoprotein, and immunoglobulins (IgG, IgM, or IgA, etc.) are mainly associated with glomerular lesions (glomerular function), while β2-microglobulin, α1-microglobulin, retinol-binding protein, and lysozyme are mainly associated with tubular lesions (tubular function). Examples of mediators of inflammation include inflammatory cytokines (MCP-1, IL-1β, IL-6, or TNF-α, etc.). Examples of mediators of fibrosis include TGF-β. Examples of mediators of blood pressure include angiotensinogen or angiotensin I and II. These urinary proteins or various mediators can be measured using methods such as dye assays, enzyme antibody assays (ELISA), chemiluminescent enzyme immunoassay (CLEIA), immunoturbidimetry, immunoturbidimetric assays, dual immunodiffusion assays (DID), latex agglutination assays, or test strips. Alternatively, they can be measured by well-known testing institutions such as SRL Corporation. Furthermore, the levels of urinary proteins or various mediators can be corrected by dividing by the urinary creatinine concentration.

[0083] For example, by administering this pharmaceutical composition to CKD patients whose urinary albumin concentration was within a specific range before treatment with this pharmaceutical composition, and comparing the CKD patients before or under control with a higher GFR, it can be evaluated that the pharmaceutical composition has protected the renal tissue. That is, one aspect of the invention is a pharmaceutical composition comprising citric acid, a pharmaceutically permissible salt of citric acid, or hydrates thereof, or mixtures thereof, for treating CKD patients whose urinary albumin concentration was within a specific range before treatment. The improvement in GFR compared to the GFR of CKD patients before or under control can be a reduction, maintenance, or increase. It should be noted that the urinary albumin concentration can be measured, for example, by immunoturbidimetry, and can be corrected using creatinine.

[0084] For example, by administering this pharmaceutical composition to CKD patients whose urinary albumin concentration was within a specific range before treatment with this pharmaceutical composition, and comparing the CKD patients before administration or as a control group, if the CKD patients had lower levels of urinary proteins (albumin, transferrin, α1-glycoprotein, hemoglobin, myoglobin, IgG, IgM, IgA, Bence Jones protein, β2-microglobulin, α1-microglobulin, retinol-binding protein, lysozyme, or similar proteins, etc.), it can be evaluated that the pharmaceutical composition has protected the kidney tissue. That is, one aspect of the present invention is a pharmaceutical composition comprising citric acid, a pharmaceutically permissible salt of citric acid, or hydrates thereof, or mixtures thereof, for treating chronic kidney disease patients whose urinary albumin concentration was within a specific range before the aforementioned treatment. Urinary proteins can include albumin, transferrin, α1-glycoprotein, hemoglobin, myoglobin, IgG, IgM, IgA, Bence Jones protein, β2-microglobulin, α1-microglobulin, retinol-binding protein, lysozyme, or similar proteins. Compared to CKD patients before or in control groups, improvement in urinary protein can be seen as an increase, suppression, maintenance, or decrease. It should be noted that urinary albumin concentration can be measured, for example, by immunoturbidimetry and can be corrected using creatinine.

[0085] For example, by administering this pharmaceutical composition to CKD patients whose urinary albumin concentration was within a specific range before treatment with this pharmaceutical composition, compared with CKD patients before administration or as a control, if the CKD patients have lower levels of inflammatory mediators (MCP-1, IL-1β, IL-6, or TNF-α, etc.), fibrotic mediators (TGF-β, etc.), or blood pressure mediators (angiotensinogen, or angiotensin I, II, etc.) in their urine, it can be evaluated that the pharmaceutical composition protects the kidney tissue. That is, one aspect of the invention is a pharmaceutical composition comprising citric acid, pharmaceutically permissible salts of citric acid, or hydrates thereof, or mixtures thereof, for treating CKD patients whose urinary albumin concentration was within a specific range before treatment with this pharmaceutical composition. Compared with CKD patients before administration or as a control, the improvement in the aforementioned mediators can be an increase in inhibition, maintenance, or reduction. It should be noted that the urinary albumin concentration can be measured, for example, by immunoturbidimetry and can be corrected using creatinine.

[0086] For example, by administering this pharmaceutical composition to CKD patients whose urinary albumin concentration was within a specific range before treatment with this pharmaceutical composition, and if the CKD patient's urinary pH was higher compared to the pre-treatment or control CKD patients, it can be evaluated that the pharmaceutical composition protected the renal tissue. That is, one aspect of the invention is a pharmaceutical composition comprising citric acid, a pharmaceutically permissible salt of citric acid, or hydrates thereof, or mixtures thereof, for treating CKD patients whose urinary albumin concentration was within a specific range before the aforementioned treatment. The alkalization of urinary pH compared to the pre-treatment or control CKD patients can be a reduction, inhibition, maintenance, or increase. It should be noted that the urinary albumin concentration can be measured, for example, by immunoturbidimetry, and can be corrected using creatinine.

[0087] The target patients for treatment with this pharmaceutical composition are CKD patients whose urinary albumin concentration is within a specific range before treatment with this pharmaceutical composition. This urinary albumin concentration is, for example, within a specific range of 10–1000 mg / gCr, 25–1000 mg / gCr, 150–1000 mg / gCr, 10–800 mg / gCr, 25–800 mg / gCr, 150–800 mg / gCr, 10–600 mg / gCr, 25–600 mg / gCr, or 150 mg / gCr. Specific ranges of ~600 mg / gCr, more specifically, for example, 10–1000 mg / gCr, 25–1000 mg / gCr, 100–1000 mg / gCr, 150–1000 mg / gCr, 10–800 mg / gCr, 25–800 mg / gCr, 100–800 mg / gCr, 150–800 mg / gCr, 10–600 mg / gCr, 25–600 mg / gCr, 100–600 mg / gCr, or 150–600 mg / gCr. It should be noted that the concentration of albumin in urine can be determined, for example, by immunoturbidimetry and can be corrected using creatinine.

[0088] One aspect of the present invention is a pharmaceutical composition comprising citric acid, a pharmaceutically permissible salt of citric acid, or hydrates thereof, or mixtures thereof, for the treatment of CKD patients with CKD whose pre-treatment urinary albumin concentration is within a specific range of 10–1000 mg / gCr, 25–1000 mg / gCr, 150–1000 mg / gCr, 10–800 mg / gCr, 25–800 mg / gCr, 150–800 mg / gCr, 10–600 mg / gCr, 25–600 mg / gCr, or 150–600 mg / gCr. It should be noted that the urinary albumin concentration can be measured, for example, by immunoturbidimetry and can be corrected using creatinine.

[0089] One aspect of the present invention is a pharmaceutical composition comprising citric acid, a pharmaceutically permissible salt of citric acid, or hydrates thereof, or mixtures thereof, for the treatment of CKD patients with pre-treatment urinary albumin concentrations of 10–1000 mg / gCr, 25–1000 mg / gCr, 100–1000 mg / gCr, 150–1000 mg / gCr, 10–800 mg / gCr, 25–800 mg / gCr, 100–800 mg / gCr, 150–800 mg / gCr, 10–600 mg / gCr, 25–600 mg / gCr, 100–600 mg / gCr, or 150–600 mg / gCr. It should be noted that the urinary albumin concentration can be measured, for example, by immunoturbidimetry and can be corrected using creatinine.

[0090] One aspect of the present invention is a pharmaceutical composition comprising citric acid, a pharmaceutically permissible salt of citric acid, or hydrates thereof, or mixtures thereof, for the treatment of CKD patients with a pretreatment urinary albumin concentration of 10 or more but less than 1000 mg / gCr, 25 or more but less than 1000 mg / gCr, 100 or more but less than 1000 mg / gCr, 150 or more but less than 1000 mg / gCr, 10 or more but less than 800 mg / gCr, 25 or more but less than 800 mg / gCr, 100 or more but less than 800 mg / gCr, 150 or more but less than 800 mg / gCr, 10 or more but less than 600 mg / gCr, 25 or more but less than 600 mg / gCr, 100 or more but less than 600 mg / gCr, or 150 or more but less than 600 mg / gCr. Alternatively, one aspect of the invention can be a pharmaceutical composition comprising citric acid, a pharmaceutically permissible salt of citric acid, or hydrates thereof, or mixtures thereof, for the treatment of CKD patients exhibiting microalbuminuria and / or overt albuminuria. It should be noted that the concentration of albumin in the urine can be determined, for example, by immunoturbidimetry and can be corrected using creatinine.

[0091] In healthy individuals, the physiological urinary protein excretion is less than 0.1 g / gCr. The presence of urinary protein excretion exceeding 0.15 g / gCr is termed proteinuria. Specifically, the range of 0.15 g / gCr to 0.49 g / gCr is defined as mild proteinuria (- to 2+ according to test strips), above 0.50 g / gCr as severe proteinuria (1+ to 3+ according to test strips), and above 3.5 g / gCr as nephrotic syndrome (3+ to 4+ according to test strips). The concentration of urinary protein can be determined using methods known in the art, such as dye methods (e.g., pyrogallol red method) or test strip methods (e.g., Myuriace manufactured by Terumo Corporation, a registered trademark). This pharmaceutical composition can be used to treat CKD patients whose pre-treatment symptoms are mild proteinuria (- to 2+ according to test strips) or severe proteinuria (1+ to 3+ according to test strips). In addition, this pharmaceutical composition can be used for CKD patients whose symptoms are mild proteinuria ((-) to (2+) according to the test strip method) before treatment with this pharmaceutical composition.

[0092] To screen CKD patients for treatment with this pharmaceutical composition, urine samples need to be collected. The urine can be morning urine or random urine. One aspect of the invention is a pharmaceutical composition comprising citric acid, a pharmaceutically permissible salt of citric acid, or hydrates thereof, or mixtures thereof, for treating CKD patients with a pre-treatment morning urine albumin concentration within a specific range. Another aspect of the invention is a pharmaceutical composition comprising citric acid, a pharmaceutically permissible salt of citric acid, or hydrates thereof, or mixtures thereof, for treating CKD patients with a pre-treatment random urine albumin concentration within a specific range.

[0093] The pharmaceutical composition of the present invention is used to treat CKD patients whose urinary albumin concentration is within a specific range before treatment with the pharmaceutical composition. The urinary albumin concentration can be measured by immunoturbidimetry or similar methods before the start of treatment, for example, within 1 month, 3 weeks, 2 weeks, 10 days, 1 week, 5 days, 3 days, 2 days, or on the day treatment begins. Another aspect of the present invention is a pharmaceutical composition comprising citric acid, a pharmaceutically permissible salt of citric acid, or hydrates thereof, or mixtures thereof, for the treatment of CKD patients whose urinary albumin concentration is within a specific range before the start of treatment (within 1 month, 3 weeks, 2 weeks, 10 days, 1 week, 5 days, 3 days, 2 days, or on the day treatment begins).

[0094] This pharmaceutical composition may be administered orally or non-orally to humans or other mammals. Examples of non-oral administration include intravenous, subcutaneous, intramuscular, intra-articular, mucosal, transdermal, nasal, rectal, intramedullary, intraperitoneal, or local administration.

[0095] This pharmaceutical composition may be prepared by mixing citric acid, a pharmaceutically permissible salt of citric acid, or their hydrates or mixtures thereof as the active ingredient, directly or with a pharmaceutically permissible carrier, such as excipients (e.g., lactose, D-mannitol, crystalline cellulose, or glucose), binders (e.g., hydroxypropyl cellulose (HPC), gelatin, or polyvinylpyrrolidone (PVP)), lubricants (e.g., magnesium stearate or talc), disintegrants (e.g., starch or calcium carboxymethyl cellulose (CMC-Ca)), diluents (e.g., water for injection or physiological saline), or other additives (e.g., pH adjusters, surfactants, solubilizers, preservatives, emulsifiers, isotonic agents, or stabilizers) as necessary, and may be a formulation such as tablets, capsules, suspensions, injections, or suppositories. For example, in order to form tablets, citric acid, a pharmaceutically permissible salt of citric acid, or their hydrates or mixtures thereof, as the active ingredient, can be mixed with excipients (such as lactose, D-mannitol, crystalline cellulose, or glucose), disintegrants (such as starch or calcium carboxymethyl cellulose (CMC-Ca)), binders (such as hydroxypropyl cellulose (HPC), gelatin, or polyvinylpyrrolidone (PVP)) or lubricants (such as magnesium stearate or talc) to form the tablets.

[0096] In one embodiment of the invention, the pharmaceutical composition is a tablet. The tablets provided by the present invention may contain, in addition to citric acid, pharmaceutically permissible salts of citric acid, or hydrates or mixtures thereof (e.g., potassium citrate or its hydrate; sodium citrate or its hydrate; a mixture of potassium citrate monohydrate and sodium citrate dihydrate; or sodium bicarbonate) as active ingredients, pharmaceutically permissible additives commonly used in the pharmaceutical industry. Examples of such additives include excipients, binders, disintegrants, fluidizing agents, flavoring agents, lubricants, pH adjusters, surfactants, stabilizers, and flavorings.

[0097] The content of citric acid, pharmaceutically permissible salts of citric acid, or hydrates thereof or mixtures thereof as active ingredients in the tablets provided by the present invention may be 10 to 95% by weight relative to the tablet, preferably 30 to 90% by weight, and more preferably 60 to 85% by weight.

[0098] This pharmaceutical composition can be manufactured by methods known in the pharmaceutical field.

[0099] In one embodiment, the hardness of the resulting tablet can be 10 to 200 N, preferably 30 to 150 N.

[0100] The amount of citric acid, pharmaceutically permissible salts of citric acid, or their hydrates or mixtures thereof as active ingredients in this pharmaceutical composition may be appropriately set.

[0101] In one embodiment, the amount of citric acid, a pharmaceutically permissible salt of citric acid, or their hydrates or mixtures thereof as the active ingredient in the pharmaceutical composition may be set to the amount or less that improves acidic urine in gout or hyperuricemia by administering to a person the amount of citric acid, a pharmaceutically permissible salt of citric acid, or their hydrates or mixtures thereof as the active ingredient. For example, it may be set to 1-50% or 10-20% of the daily dose approved in Japan for improving acidic urine in gout or hyperuricemia (e.g., a tablet containing 231.5 mg of potassium citrate (C6H5K3O7·H2O) and 195.0 mg of sodium citrate hydrate (C6H5Na3O7·2H2O) per tablet, administered orally at a dose of 2 tablets three times a day, or 3-5 g orally per day when the alkalizing agent is sodium bicarbonate).

[0102] In one embodiment of the present invention, the pharmaceutical composition is a tablet, and one tablet may contain 10 mg to 1 g, preferably 100 mg to 500 mg, more preferably 400 mg to 500 mg of potassium citrate monohydrate or sodium citrate dihydrate.

[0103] In one embodiment, the pharmaceutical composition is a tablet, wherein one tablet may contain 10 mg to 300 mg of potassium citrate monohydrate and sodium citrate dihydrate, totaling 20 mg to 600 mg, preferably 150 to 250 mg of potassium citrate monohydrate and totaling 400 to 500 mg, and more preferably 190 to 240 mg of potassium citrate monohydrate and totaling 400 to 450 mg.

[0104] As one aspect of the present invention, the pharmaceutical composition is a tablet containing 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate. As additives, it may contain anhydrous citric acid, crystalline cellulose, partially α-starch, hydroxypropyl cellulose, magnesium stearate, hydroxypropyl methylcellulose, polyethylene glycol 6000, titanium dioxide, and carnauba wax.

[0105] As one aspect of the present invention, a tablet containing 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate can be used as one administration unit.

[0106] In this specification, "dosage unit" refers to a unit of the formulation, and "one dosage unit" refers to the smallest unit of the formulation. Therefore, for example, if it is a tablet, the dosage unit is the dosage, and one dosage unit represents one tablet. If it is an injection, the dosage unit is the injection placed in a sealed container such as an ampoule or vial, and one dosage unit represents the injection placed in one sealed container such as an ampoule or vial.

[0107] When this pharmaceutical composition is administered to humans or other mammals, one or more of the above-described administering units may be administered at one time, or the above-described administering unit may be divided and administered.

[0108] The dosage of citric acid, pharmaceutically permissible salts of citric acid, or their hydrates or mixtures thereof as active ingredients may be appropriately determined based on the method of administration, the age, weight, sex, symptoms, or sensitivity to the drug of the recipient, and may also be adjusted based on the improvement of symptoms.

[0109] As one aspect of the present invention, when administering the mixture of potassium citrate monohydrate and sodium citrate dihydrate orally to a human, half of the daily dose approved in Japan for improving acidic urine in gout and hyperuricemia (for example, in the case of citric acid preparations, a tablet containing 231.5 mg of potassium citrate (C6H5K3O7·H2O) and 195.0 mg of sodium citrate hydrate (C6H5Na3O7·2H2O) is administered orally at a dose of 2 tablets three times a day) can be used as the daily dose.

[0110] As one aspect of the present invention, when administering the mixture of potassium citrate monohydrate and sodium citrate dihydrate orally to a human, the daily dosage approved in Japan for improving acidic urine in gout and hyperuricemia (for example, in the case of citric acid preparations, a tablet containing 231.5 mg of potassium citrate (C6H5K3O7·H2O) and 195.0 mg of sodium citrate hydrate (C6H5Na3O7·2H2O) is administered orally at a dose of 2 tablets three times a day) can be used as the daily dosage.

[0111] As one aspect of the present invention, when administering the mixture of potassium citrate monohydrate and sodium citrate dihydrate orally to a human, half of the daily dose approved in Japan for improving acidic urine in gout and hyperuricemia (for example, in the case of citric acid preparations, a tablet containing 231.5 mg of potassium citrate (C6H5K3O7·H2O) and 195.0 mg of sodium citrate hydrate (C6H5Na3O7·2H2O) is administered orally at a dose of 2 tablets three times a day) can be started as the daily dose, and then the dose can be increased to the daily dose approved in Japan for improving acidic urine in gout and hyperuricemia.

[0112] As one aspect of the present invention, when administering the mixture of potassium citrate monohydrate and sodium citrate dihydrate, which are the active ingredients, orally to humans, the potassium citrate monohydrate and sodium citrate dihydrate can be administered at doses of 0.1–5 g / day and a total of 0.2–10 g / day, 0.1–3 g / day and a total of 0.2–6 g / day, 0.5–3 g / day and a total of 1–6 g / day, preferably 0.5–1.5 g / day and a total of 1–3 g / day, 1–1.5 g / day and a total of 2–3 g / day, or 0.5–1 g / day and a total of 1–2 g / day, or divided into 1–5 times per day, preferably 3 times per day.

[0113] As one aspect of the present invention, when potassium citrate monohydrate or sodium citrate dihydrate, which are the active ingredients, are administered orally to humans, the dosage can be 1-10 g / day, 1-6 g / day, 2-5.5 g / day, 1-3 g / day, 2-3 g / day, or 1-1.5 g / day, or it can be divided into 1-5 times a day, preferably 3 times a day.

[0114] As one aspect of the present invention, citric acid, pharmaceutically permissible salts of citric acid, or their hydrates or mixtures thereof, as the active ingredient, can be administered for extended periods, for example, at intervals of 1 week, 2 weeks, 3 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 24 weeks, 40 weeks, 60 weeks, 80 weeks, 100 weeks, 120 weeks, more than 1 week, more than 2 weeks, more than 3 weeks, more than 6 weeks, more than 8 weeks, more than 10 weeks, more than 12 weeks, and more than 24 weeks. The following conditions will be given: 1 week or more, 40 weeks or more, 60 weeks or more, 80 weeks or more, 100 weeks or more, 120 weeks or more, 6 weeks to 24 weeks, 12 weeks to 24 weeks, 6 weeks to 30 weeks, 12 weeks to 30 weeks, 6 weeks to 40 weeks, 12 weeks to 40 weeks, 6 weeks to 60 weeks, 12 weeks to 60 weeks, 6 weeks to 80 weeks, 12 weeks to 80 weeks, 6 weeks to 100 weeks, 12 weeks to 100 weeks, 6 weeks to 120 weeks, or 12 weeks to 120 weeks.

[0115] As one aspect of the present invention, beneficial effects (e.g., renal protective effects) on CKD patients can be detected by administering the pharmaceutical composition continuously for 6 weeks, 12 weeks, and / or 24 weeks.

[0116] As one aspect of the present invention, the pharmaceutical composition is administered to patients with early-stage CKD of low severity.

[0117] As one aspect of the present invention, the pharmaceutical composition is administered to CKD patients whose urinary albumin concentration before treatment with the pharmaceutical composition is within a specific range and is below G3b stage, preferably G2 stage or below.

[0118] As one aspect of the invention, the pharmaceutical composition is administered to CKD patients whose urinary albumin concentration before treatment with the pharmaceutical composition is within a specific range and who are in stage G2 to G3b (e.g., stage G2 and G3a; or stage G2, G3a, and G3b). It should be noted that the urinary albumin concentration can be measured, for example, by immunoturbidimetry and can be corrected using creatinine.

[0119] In one embodiment of the present invention, the pharmaceutical composition is given to a patient with progressive CKD whose urinary albumin concentration was within a specific range before treatment with the pharmaceutical composition. In one embodiment of the present invention, the pharmaceutical composition is given to a patient with CKD and hypertension whose urinary albumin concentration was within a specific range before treatment with the pharmaceutical composition. In one embodiment of the present invention, the pharmaceutical composition is given to a patient with diabetic nephropathy whose urinary albumin concentration was within a specific range before treatment with the pharmaceutical composition. In one embodiment of the present invention, the pharmaceutical composition is given to a patient with nephrosclerosis (caused by hypertension or aging, etc.) whose urinary albumin concentration was within a specific range before treatment with the pharmaceutical composition. In one embodiment of the present invention, the pharmaceutical composition is given to a patient with chronic glomerulonephritis (including IgA nephropathy, membranous nephropathy, etc.) whose urinary albumin concentration was within a specific range before treatment with the pharmaceutical composition. In one embodiment of the present invention, the pharmaceutical composition is given to a patient with polycystic kidney disease whose urinary albumin concentration was within a specific range before treatment with the pharmaceutical composition. It should be noted that the urinary albumin concentration can be measured, for example, by immunoturbidimetry and can be corrected using creatinine.

[0120] In one embodiment of the invention, the pharmaceutical composition is administered to a patient treated according to CKD guidelines. For example, it is administered to a patient receiving CKD treatment according to guidelines for blood pressure management (administering ARBs, ACE inhibitors, or other RA inhibitors, diuretics, or calcium antagonists, etc.), proteinuria management (administering RA inhibitors, etc.), blood glucose management (administering α-glucosidase inhibitors, etc.), lipid management (administering statins or fibrates, etc.), anemia management (administering erythropoietin, etc.), and / or bone and mineral management (administering bisphosphonates, etc.).

[0121] In one embodiment of the invention, the pharmaceutical composition is used in combination with an antihypertensive drug (e.g., an ARB, an ACE inhibitor, a diuretic, or a calcium antagonist).

[0122] In one embodiment, the pharmaceutical composition is used in combination with spherical adsorbed carbon (sold in Japan as Kremezin (registered trademark)) obtained by oxidizing and reducing spherical microparticle porous carbon derived from petroleum hydrocarbons at high temperature.

[0123] 2. Food Compositions

[0124] In one aspect of the invention, the food composition provided by the invention comprises citric acid, a pharmaceutically permissible salt of citric acid, or hydrates thereof or mixtures thereof, which, when ingested by a person whose urinary albumin concentration is within a specific range before ingestion of the food composition, exert a protective or health-maintaining effect on the kidneys.

[0125] In one aspect of the present invention, the food composition provided by the present invention exerts the effects of inhibiting urinary protein in the kidneys, maintaining or improving the function of the glomeruli and renal tubules, inhibiting inflammation, or alkalizing the urine.

[0126] Regarding the active ingredient, the active ingredient described in "1. Pharmaceutical Composition" above can be used. For example, the food composition provided by this invention can be a food composition containing alkali metal citrate salts, or their hydrates or mixtures thereof, preferably a mixture containing potassium citrate monohydrate (C6H5K3O7·H2O) and sodium citrate dihydrate (C6H5Na3O7·2H2O). It should be noted that the concentration of albumin in urine can be determined, for example, by immunoturbidimetry and can be corrected using creatinine.

[0127] The content of citric acid, pharmaceutically permissible salts of citric acid, or their hydrates or mixtures thereof in the food compositions provided by this invention can be appropriately determined according to the type of food. Examples of food compositions include specific health foods, functionally labeled foods, hospital patient foods, or supplements. There are no particular limitations on the form of these food compositions, as long as they contain an effective amount of citric acid, pharmaceutically permissible salts of citric acid, or their hydrates or mixtures thereof to achieve the above-mentioned effects and are orally ingestible. They can be in the form of ordinary food or beverages, or as formulations suitable for oral administration, such as tablets, capsules, or suspensions, applicable to the formulations of the aforementioned pharmaceutical compositions. Regarding the composition and manufacturing methods of these formulations, in addition to directly applying the methods for the composition and manufacturing of pharmaceutical preparations described in "1. Pharmaceutical Compositions" above in this specification, well-known formulation techniques can also be applied.

[0128] For example, in the case of foods for specific health purposes, functionally labeled foods, foods for hospital patients, or supplements, each serving may contain a total of 1 to 3 g of 1 / 3 of potassium citrate monohydrate and sodium citrate dihydrate as active ingredients, or 1 to 6 g of 1 / 3 of sodium bicarbonate as an active ingredient. When foods for specific health purposes, functionally labeled foods, foods for hospital patients, or supplements are provided in tablet form, for example, each 300 mg to 600 mg tablet may contain 70 to 80% by weight of citric acid, pharmaceutically permissible salts of citric acid, or hydrates thereof, or mixtures thereof.

[0129] When the food composition provided by the present invention is not formulated but provided in the form of a general food, it can be appropriately manufactured by those skilled in the art according to the type of food. For example, it can be manufactured by incorporating citric acid, a pharmaceutically permissible salt of citric acid, or hydrates thereof or mixtures thereof into the food raw materials.

[0130] Examples of the aforementioned food and beverage forms include liquid, milky, or paste-like foods such as beverages, soy sauce, milk, yogurt, or miso; semi-solid foods such as jelly or gummies; solid foods such as candy, chewing gum, tofu, or supplements; or powdered foods.

[0131] Examples of beverages include fruit juices, coffee drinks, oolong tea drinks, green tea drinks, black tea drinks, barley tea drinks, vegetable drinks, carbonated drinks as soft drinks, drinks with fruit extracts, fruit juices with vegetable extracts, water-based drinks, sports drinks, or weight-loss drinks.

[0132] In beverages, additives such as antioxidants, flavorings, various esters, organic acids, organic acid salts, inorganic acids, inorganic acid salts, inorganic salts, pigments, emulsifiers, preservatives, flavorings, sweeteners, acidulants, fruit juice extracts, vegetable extracts, nectar extracts, pH adjusters, or quality stabilizers can be added alone or in combination.

[0133] The term "giving" described in "1. Pharmaceutical Composition" above can also be applied to the situation of ingesting the "food composition" of the present invention. That is, regarding the "food composition" of the present invention, the term "giving" can be replaced with "ingestion". Therefore, for example, the terms "giving", "being given", etc. can be replaced with "causing ingestion", "ingestion", "being ingested", etc., depending on the context.

[0134] The present invention also has the following aspects.

[0135] <1a> A method for treating chronic kidney disease with renal protection, comprising: administering a therapeutically effective amount of citric acid, a pharmaceutically permissible salt of citric acid, or a hydrate thereof or a mixture thereof to a patient with chronic kidney disease whose pre-treatment urinary albumin concentration is within a specific range and who requires the treatment (e.g., a mammal including humans).

[0136] <2a> The method according to <1a>, wherein the urinary albumin concentration of the chronic kidney disease patient before the above treatment is in a specific range of 10 to 1000 mg / gCr;

[0137] <3a> The method according to <1a>, wherein the urinary albumin concentration of the chronic kidney disease patient before the above treatment is in a specific range of 25 to 600 mg / gCr;

[0138] <4a> The method according to <1a>, wherein the urinary albumin concentration of the chronic kidney disease patient before the above treatment is in a specific range of 150 to 600 mg / gCr;

[0139] <5a> The method according to any one of <1a> to <4a>, wherein the urine of the chronic kidney disease patient before the above treatment is morning urine;

[0140] <6a> The method according to any one of <1a> to <5a>, wherein the urinary albumin concentration of the chronic kidney disease patient before the above treatment is the concentration within 2 weeks before the start of treatment;

[0141] <7a> The method according to any one of <1a> to <6a>, wherein the above-mentioned renal protection is the inhibition of proteinuria, the maintenance or improvement of glomerular function and renal tubular function, the inhibition of inflammation, or the alkalization of urine;

[0142] <8a> The method described in <7a>, wherein the aforementioned urinary protein is albumin, transferrin, IgG, or α1-microglobulin;

[0143] <9a> According to the method described in <7a>, wherein the inhibition of the above-mentioned inflammation is an inhibition of the concentration of MCP-1 in the urine;

[0144] <10a> The method according to any one of <1a> to <9a>, wherein the above-mentioned citric acid, pharmaceutically permissible salts of citric acid, or hydrates thereof or mixtures thereof are a mixture of sodium citrate or its hydrate and potassium citrate or its hydrate;

[0145] <11a> The method according to <10a>, wherein it further comprises anhydrous citric acid;

[0146] <12a> The method according to any one of <1a> to <11a>, wherein the above-mentioned citric acid, pharmaceutically permissible salts of citric acid, or hydrates thereof or mixtures thereof are administered at 1 to 3 g / day;

[0147] <13a> The method according to any one of <1a> to <12a>, wherein the above-mentioned chronic kidney disease is stage G2 to G3b;

[0148] <14a> The method according to any one of <1a> to <13a>, wherein the above-mentioned citric acid, a pharmaceutically permissible salt of citric acid, or their hydrates or mixtures thereof are administered for more than 6 weeks;

[0149] <1b> A pharmaceutical composition for treating chronic kidney disease and for renal protection, comprising citric acid, a pharmaceutically permissible salt of citric acid, or hydrates thereof or mixtures thereof, for treating chronic kidney disease patients whose urinary albumin concentration is within a specific range prior to the above treatment.

[0150] <2b> The pharmaceutical composition for use according to <1b>, wherein the urinary albumin concentration of the patient with chronic kidney disease prior to the above treatment is in a specific range of 10 to 1000 mg / gCr;

[0151] <3b> The pharmaceutical composition for use according to <1b>, wherein the urinary albumin concentration of the patient with chronic kidney disease prior to the above treatment is in a specific range of 25 to 600 mg / gCr;

[0152] <4b> The pharmaceutical composition for use according to <1b>, wherein the urinary albumin concentration of the patient with chronic kidney disease prior to the above treatment is in a specific range of 150 to 600 mg / gCr;

[0153] <5b> The pharmaceutical composition for use according to any one of <1b> to <4b>, wherein the urine of the patient with chronic kidney disease prior to the above treatment is morning urine;

[0154] <6b> A pharmaceutical composition for use according to any one of <1b> to <5b>, wherein the urinary albumin concentration of the patient with chronic kidney disease prior to the above treatment is within 2 weeks prior to the start of treatment;

[0155] <7b> The pharmaceutical composition for use according to any one of <1b> to <6b>, wherein the above-mentioned renal protection is the inhibition of proteinuria, the maintenance or improvement of glomerular function and renal tubular function, the inhibition of inflammation, or the alkalization of urine;

[0156] <8b> The pharmaceutical composition for use according to <7b>, wherein the urinary protein is albumin, transferrin, IgG or α1-microglobulin;

[0157] <9b> The pharmaceutical composition for use according to <7b>, wherein the inhibition of the above-mentioned inflammation is an inhibition of the concentration of MCP-1 in the urine;

[0158] <10b> The pharmaceutical composition for use according to any one of <1b> to <9b>, wherein the above-mentioned citric acid, pharmaceutically permissible salts of citric acid, or hydrates thereof or mixtures thereof are a mixture of sodium citrate or its hydrate and potassium citrate or its hydrate;

[0159] <11b> The pharmaceutical composition for use according to <10b> further comprises anhydrous citric acid;

[0160] <12b> The pharmaceutical composition for use according to any one of <1b> to <11b>, wherein the above-mentioned citric acid, a pharmaceutically permissible salt of citric acid, or their hydrates or mixtures thereof are administered at 1 to 3 g / day;

[0161] <13b> A pharmaceutical composition for use according to any one of <1b> to <12b>, wherein the aforementioned chronic kidney disease is stage G2 to G3b;

[0162] <14b> The pharmaceutical composition for use according to any one of <1b> to <13b>, wherein the above-mentioned citric acid, a pharmaceutically permissible salt of citric acid, or their hydrates or mixtures thereof are administered for more than 6 weeks;

[0163] <1c> An application is the use of citric acid, a pharmaceutically permissible salt of citric acid, or hydrates thereof or mixtures thereof in the manufacture of a nephroprotective pharmaceutical composition for the treatment of chronic kidney disease, wherein the pharmaceutical composition is used to treat patients with chronic kidney disease whose urinary albumin concentration is within a specific range prior to the treatment thereof.

[0164] <2c> According to the application described in <1c>, wherein the urinary albumin concentration of the chronic kidney disease patient prior to the above treatment is within a specific range of 10 to 1000 mg / gCr;

[0165] <3c> According to the application described in <1c>, the urinary albumin concentration of the chronic kidney disease patient before the above treatment is in a specific range of 25 to 600 mg / gCr;

[0166] <4c> According to the application described in <1c>, the urinary albumin concentration of the chronic kidney disease patient before the above treatment is in a specific range of 150 to 600 mg / gCr;

[0167] <5c> Application according to any one of <1c> to <4c>, wherein the urine of the chronic kidney disease patient before the above treatment is morning urine;

[0168] <6c> Application according to any one of <1c> to <5c>, wherein the urinary albumin concentration of the chronic kidney disease patient before the above treatment is the concentration within 2 weeks before the start of treatment;

[0169] <7c> The application according to any one of <1c> to <6c>, wherein the above-mentioned renal protection is the inhibition of proteinuria, the maintenance or improvement of glomerular function and renal tubular function, the inhibition of inflammation, or the alkalization of urine;

[0170] <8c> According to the application described in <7c>, wherein the above-mentioned urinary protein is albumin, transferrin, IgG or α1-microglobulin;

[0171] <9c> According to the application described in <7c>, the inhibition of the above-mentioned inflammation is the inhibition of the concentration of MCP-1 in the urine;

[0172] <10c> Application according to any one of <1c> to <9c>, wherein the above-mentioned citric acid, pharmaceutically permissible salts of citric acid, or hydrates thereof or mixtures thereof are a mixture of sodium citrate or its hydrate and potassium citrate or its hydrate;

[0173] <11c> The application according to <10c> further comprises anhydrous citric acid;

[0174] <12c> Application according to any one of <1c> to <11c>, wherein the above-mentioned citric acid, pharmaceutically permissible salts of citric acid, or hydrates thereof or mixtures thereof are administered at 1 to 3 g / day;

[0175] <13c> Application according to any one of <1c> to <12c>, wherein the aforementioned chronic kidney disease is stage G2 to G3b; or

[0176] <14c> Application according to any one of <1c> to <13c>, wherein the above-mentioned citric acid, pharmaceutically permissible salts of citric acid, or hydrates thereof or mixtures thereof are administered for more than 6 weeks.

[0177] The present invention will be further illustrated below by way of examples, but the present invention is not limited thereto.

[0178] Example

[0179] To investigate the effects of oral administration of potassium citrate-sodium citrate hydrate compound preparation (hereinafter referred to as "citric acid preparation") and sodium bicarbonate preparation as oral alkalizing agents, a human clinical trial was conducted (Patent Document 1).

[0180] 1. Methods

[0181] Patients with chronic kidney disease (CKD) in stages G2–G3b (eGFR: 30–89 ml / min / 1.73 m³ / min) 2 Patients were randomly assigned to three groups: a citric acid preparation group, a sodium bicarbonate preparation group, and a control group. Within each group, patients were assigned in a manner that avoided bias based on age, sex, presence or absence of diabetes, and eGFR. Each group received treatment based on the "CKD Treatment Guidelines – Treatment Summary" (hereinafter referred to as standard treatment).

[0182] The control group did not receive alkalizing agents. The citric acid preparation group received three tablets daily, three times a day (morning, noon, and evening), orally for 6 months (24 weeks) containing 231.5 mg of potassium citrate (C6H5K3O7·H2O) and 195.0 mg of sodium citrate hydrate (C6H5Na3O7·2H2O). It should be noted that morning urine pH management should be implemented regularly. For cases with a morning urine pH less than 6.5, the dosage may be increased to six tablets daily, three times a day (morning, noon, and evening), as determined by a physician. The sodium bicarbonate preparation group received three tablets daily, three times a day (morning, noon, and evening), orally for 6 months (24 weeks) containing 500 mg of sodium bicarbonate. It should be noted that morning urine pH management should be implemented regularly. For cases with a morning urine pH less than 6.5, the dosage may be increased to six tablets daily, three times a day (morning, noon, and evening), as determined by a physician.

[0183] First morning urine samples were collected before (on the day of treatment initiation) and 24 weeks after treatment initiation. Creatinine concentration (manufactured by Canon Medical Diagnostics, Determiner L CRE), albumin (manufactured by Fujifilm and Hikari Pure Chemicals, Auto Wako Microalbumin), transferrin (manufactured by Nittobo Medical, N-AssayLA Micro Tf Nittobo), immunoglobulin IgG (manufactured by Takara Bio, MK136), α1-microglobulin (manufactured by Eiken Chemical Co., LZ Test (registered trademark) 'Eiken' α1-M), and MCP-1 (manufactured by R&D SYSTEMS, Quantikine (registered trademark) Human MCP-1 Immunoassay) were measured by SRL. Each measurement was corrected by dividing by the creatinine concentration. Changes in each parameter associated with treatment were calculated by subtracting pre-treatment measurements from post-treatment measurements.

[0184] 2. Stratification of subjects based on albumin concentration in morning urine

[0185] Figure 1 The changes in urinary albumin concentration in the morning urine of each subject are presented logarithmically before and after treatment. In the control group, urinary albumin concentration increased before and after treatment (119±318→153±333 mg / gCr (n=31); change before and after treatment: 34±148 mg / gCr), while it decreased with treatment with citrate (103±198→89±203 mg / gCr (n=29); change before and after treatment: -14±59 mg / gCr).

[0186] A detailed analysis of the progress of each subject revealed that subjects with low pre-treatment urinary albumin concentrations showed minimal changes in urinary albumin concentration before and after treatment, compared to both the control group and the citrate preparation group. For example, the results for subjects with pre-treatment urinary albumin concentrations below 10 mg / gCr are shown in Table 1.

[0187] On the other hand, in subjects with moderately high pre-treatment urinary albumin concentrations, the urinary albumin concentration increased during treatment in the control group, while the inhibitory effect was significant in the citrate group. For example, the results for subjects with pre-treatment urinary albumin concentrations of 25–600 mg / gCr or 150–600 mg / gCr are shown in Table 1, and the results for subjects with pre-treatment urinary albumin concentrations of 150–600 mg / gCr are shown in Table 2. Figure 2 .

[0188] It should be noted that when sodium bicarbonate was administered instead of citric acid, even with stratification of subjects, no reduction in urinary albumin levels before and after treatment was confirmed (overall: 50 ± 132 mg / gCr (n=31); subjects with pre-treatment morning urine albumin concentrations of 25–600 mg / gCr: 109 ± 179 mg / gCr (n=14); subjects with pre-treatment morning urine albumin concentrations of 150–600 mg / gCr: 337 ± 161 mg / gCr (n=3)). Individual measurements for subjects with pre-treatment morning urine albumin concentrations of 150–600 mg / gCr are presented below. Figure 2 In the control group and the sodium bicarbonate preparation group, the concentration of albumin in urine increased after treatment, while it decreased in the citric acid preparation group.

[0189] Based on the above information, when morning urinary albumin is used as an indicator, citrate preparations show significant effects on subjects with moderately high pre-treatment urinary albumin concentrations (e.g., 25–600 mg / gCr or 150–600 mg / gCr).

[0190] [Table 1]

[0191]

[0192] 3. Effects on other parameters

[0193] 3-1) Transferrin

[0194] Table 2 shows the changes in urinary transferrin levels when subjects were stratified by albumin concentration in their morning urine. Additionally, individual measurements for subjects with pre-treatment morning urine albumin concentrations of 150–600 mg / gCr are presented. Figure 3 In the control group and the sodium bicarbonate preparation group, the concentration of transferrin in urine increased after treatment, while it decreased in the citrate preparation group, thus maintaining and improving glomerular filtration function.

[0195] [Table 2]

[0196]

[0197] 3-2) Immunoglobulins (IgG)

[0198] Table 3 shows the changes in urinary IgG levels when subjects were stratified by albumin concentration in their morning urine. Additionally, individual measurements of subjects with pre-treatment morning urine albumin concentrations of 150–600 mg / gCr are presented. Figure 4In the control group and the sodium bicarbonate preparation group, the concentration of IgG in urine increased after treatment, while it decreased in the citric acid preparation group, thus maintaining and improving glomerular filtration function.

[0199] [Table 3]

[0200]

[0201] 3-3) α1-microglobulin

[0202] Table 4 shows the changes in α1-microglobulin in urine when subjects were stratified by morning urine albumin concentration. Individual measurements of subjects with pre-treatment morning urine albumin concentrations of 150–600 mg / gCr are also presented. Figure 5 In the control group, the concentration of α1-microglobulin in urine increased after treatment, while it decreased slightly in the sodium bicarbonate preparation group and the citric acid preparation group, thus maintaining and improving the reabsorption function of the renal tubules.

[0203] [Table 4]

[0204]

[0205] 3-4) MCP-1

[0206] Table 5 shows the changes in urinary MCP-1 when subjects were stratified by albumin concentration in their morning urine. Additionally, individual measurements of subjects with pre-treatment morning urine albumin concentrations of 150–600 mg / gCr are presented. Figure 6 In the control group and the sodium bicarbonate preparation group, the concentration of MCP-1 in urine increased by treatment, while it decreased in the citric acid preparation group, thus inhibiting inflammation in the kidneys.

[0207] [Table 5]

[0208]

[0209] 3-5) pH

[0210] Table 6 shows the changes in urine pH when subjects were stratified by albumin concentration in their morning urine. Additionally, individual measurements of subjects with pre-treatment morning urine albumin concentrations of 150–600 mg / gCr are presented. Figure 7 In the control group, urine pH remained almost unchanged after treatment, but alkalization occurred in the sodium bicarbonate preparation group and the citric acid preparation group.

[0211] [Table 6]

[0212]

[0213] Based on the above information, when morning urinary albumin is used as an indicator, the nephroprotective effect of citrate preparations in chronic kidney disease (inhibition of urinary protein, maintenance or improvement of glomerular and tubular function, inhibition of inflammation, or alkalization of urine, etc.) shows significant effects on subjects with moderately high pre-treatment urinary albumin concentrations (e.g., 25–600 mg / gCr or 150–600 mg / gCr).

[0214] Industrial availability

[0215] Through the treatment provided by this invention, the kidneys are protected, and the function of the glomeruli and renal tubules is maintained or improved.

Claims

1. A pharmaceutical composition comprising citric acid, a pharmaceutically permissible salt of citric acid, or hydrates thereof or mixtures thereof, for treating chronic kidney disease patients whose urinary albumin concentration is within a specific range prior to said treatment.

2. The pharmaceutical composition according to claim 1, wherein, The urinary albumin concentration of the patients with chronic kidney disease before treatment was within a specific range of 10 to 1000 mg / gCr.

3. The pharmaceutical composition according to claim 1, wherein, The urinary albumin concentration of the patients with chronic kidney disease before treatment was within a specific range of 25–600 mg / gCr.

4. The pharmaceutical composition according to claim 1, wherein, The urinary albumin concentration of the patients with chronic kidney disease before treatment was within a specific range of 150–600 mg / gCr.

5. The pharmaceutical composition according to claim 1 or 2, wherein, The urine of the patients with chronic kidney disease before treatment was morning urine.

6. The pharmaceutical composition according to claim 1 or 2, wherein, The urinary albumin concentration of the chronic kidney disease patients before treatment refers to the concentration within 2 weeks before the start of treatment.

7. The pharmaceutical composition according to claim 1, wherein, The kidney protection mentioned refers to the inhibition of proteinuria, the maintenance or improvement of glomerular and tubular function, the suppression of inflammation, or the alkalization of urine.

8. The pharmaceutical composition according to claim 7, wherein, The urinary proteins are albumin, transferrin, IgG, or α1-microglobulin.

9. The pharmaceutical composition according to claim 7, wherein, The inflammation was suppressed by inhibiting the concentration of MCP-1 in the urine.

10. The pharmaceutical composition according to claim 1 or 2, wherein, The citric acid, pharmaceutically permissible salts of citric acid, or hydrates thereof, or mixtures thereof, is a mixture of sodium citrate or its hydrate with potassium citrate or its hydrate.

11. The pharmaceutical composition according to claim 10, wherein, It further contains anhydrous citric acid.

12. The pharmaceutical composition according to claim 1 or 2, wherein, The citric acid, pharmaceutically permissible salts of citric acid, or their hydrates or mixtures thereof, shall be administered at a dose of 1–3 g / day.

13. The pharmaceutical composition according to claim 1 or 2, wherein, The chronic kidney disease described is stage G2 to stage G3b.

14. The pharmaceutical composition according to claim 1 or 2, wherein, The citric acid, pharmaceutically permissible salts of citric acid, or their hydrates or mixtures thereof, shall be administered for more than 6 weeks.

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