Pharmaceutical composition for treating chronic kidney disease with pretreatment urinary albumin concentration within specific range

Abstract

The present invention relates to a pharmaceutical composition for renal protection for treating chronic kidney diseases, the composition containing: citric acid or a pharmaceutically acceptable citric acid salt; a hydrate of the same; or a mixture thereof. The pharmaceutical composition is for treating a patient having a chronic kidney disease for which the pretreatment urinary albumin concentration is within a specific range.

Description

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

[0001] The present invention relates to a pharmaceutical composition for renal protection in chronic kidney disease (CKD), comprising citric acid, a pharmaceutically acceptable salt of citric acid, a hydrate thereof, or a mixture thereof, for treating CKD in patients with CKD whose urinary albumin concentration before treatment is within a specific range. This application claims priority to Japanese Patent Application No. 2024-056972, filed on March 29, 2024, the contents of which are incorporated herein by reference.

[0002] The number of patients with end-stage kidney disease (ESKD), requiring dialysis or transplantation, is increasing worldwide. This trend is also evident in Japan, where the number of dialysis patients is expected to reach approximately 350,000 by the end of 2022. CKD is recognized as a potential risk factor for ESKD. CKD encompasses all chronic kidney diseases, regardless of underlying cause, and encompasses all pathologies characterized by a decline in renal function, as measured by glomerular filtration rate (GFR), or by chronic (more than three months) persistent signs of renal impairment. CKD not only poses a risk for progression to ESKD but also a significant risk factor for cardiovascular disease (CVD). Therefore, early detection and appropriate treatment of CKD are crucial. While numerous CKD treatments have been established, they are still insufficient, and further development of renal protective agents is needed.

[0003] In patients with advanced CKD, blood bicarbonate ions (HCO3 -Because the urinary tract saccharin (CKD) concentration decreases and metabolic acidosis develops, alkaline agents such as sodium bicarbonate (sodium bicarbonate) and citric acid preparations are administered. It has been reported that the administration of sodium bicarbonate, an alkaline agent, inhibits the progression of CKD (Non-Patent Document 1). It has also been reported that oral administration of sodium bicarbonate inhibits renal tubular cell damage caused by acidic urine in an animal model of nephrosis induced by protein overload (Non-Patent Document 2). Furthermore, it has been reported that administration of citric acid preparations to patients with CKD stages G2 to G3b decreases urinary albumin concentration and increases urinary pH (Patent Document 1), and reduces MCP-1 gene expression in the kidney in an animal model of diabetes (Patent Document 2). However, these parameters vary significantly among individuals, and it was considered necessary to conduct tests using a large number of cases to demonstrate the effectiveness of citric acid preparations.

[0004] International Publication No. 2020 / 080499 International Publication No. 2020 / 080451

[0005] Brito-Ashurst, ID, et al.: Bicarbonate supplementation slows progression of CKD and improves nutritional status. J. Am. Soc. Nephrol., 20: 2075-2084, 2009. Souma T., et al.: Luminal alkalinization attenuates proteinuria-induced oxidative damage in proximal tubular cells. J. Am. Soc. Nephrol., 22: 635-648, 2011.

[0006] One objective of the present invention is to select CKD patients for whom treatment with a pharmaceutical composition for renal protection containing citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof (hereinafter sometimes referred to as "citric acid, etc.") Another objective of the present invention is to provide a pharmaceutical composition for renal protection containing citric acid, etc., for treating the selected CKD patients.

[0007] The present inventors have conducted extensive research to achieve the above object and have found that selecting CKD patients based on their pre-treatment urinary albumin concentration is useful for treating CKD with a pharmaceutical composition containing citric acid and the like, thereby completing the present invention.

[0008] Therefore, the present invention relates to the following: [1] A pharmaceutical composition for nephroprotection for treating chronic kidney disease, comprising citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, wherein the patient with chronic kidney disease has a urinary albumin concentration within a specific range before treatment. [2] The pharmaceutical composition according to item [1], wherein the patient with chronic kidney disease has a urinary albumin concentration within a specific range of 10 to 1000 mg / gCr before treatment. [3] The pharmaceutical composition according to item [1], wherein the patient with chronic kidney disease has a urinary albumin concentration within a specific range of 25 to 600 mg / gCr before treatment. [4] The pharmaceutical composition according to item [1], wherein the patient with chronic kidney disease has a urinary albumin concentration within a specific range of 150 to 600 mg / gCr before treatment. [5] The pharmaceutical composition according to any one of items [1] to [4], wherein the patient with chronic kidney disease has a urinary albumin concentration within a specific range of 150 to 600 mg / gCr before treatment. [6] The pharmaceutical composition according to any one of items [1] to [5], wherein the urinary albumin concentration of the chronic kidney disease patient before treatment is the concentration within two weeks before the start of treatment. [7] The pharmaceutical composition according to any one of items [1] to [6], wherein the renal protection is suppression of urinary protein, maintenance or improvement of glomerular function and tubular function, suppression of inflammation, or alkalinization of urine. [8] The pharmaceutical composition according to item [7], wherein the urinary protein is albumin, transferrin, IgG, or α1-microglobulin. [9] The pharmaceutical composition according to item [7], wherein the suppression of inflammation is suppression of urinary MCP-1 concentration.

[0010] The pharmaceutical composition according to any one of items [1] to [9], wherein the citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof is a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof.

[0011] The pharmaceutical composition according to item

[0010] , further comprising anhydrous citric acid.

[0012] The pharmaceutical composition according to any one of items [1] to

[0011] , wherein the citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof is administered at 1 to 3 g / day.

[0013] The pharmaceutical composition according to any one of items [1] to

[0012] , wherein the chronic kidney disease is at stage G2 or higher and G3b or lower.

[0014] A pharmaceutical composition described in any one of items [1] to

[0013] , wherein the citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof is administered for 6 weeks or more.

[0009] By selecting patients based on their urinary albumin concentration before treatment with the pharmaceutical composition provided by the present invention (hereinafter referred to as "the pharmaceutical composition"), it is possible to select CKD patients suitable for treatment with the pharmaceutical composition provided by the present invention containing citric acid, etc. The pharmaceutical composition provided by the present invention containing citric acid, etc. can effectively treat CKD patients whose urinary albumin concentration before treatment is within a specific range (e.g., 10 to 1000 mg / gCr).

[0010] Figure 1 shows logarithmic urinary albumin concentrations before and after six months of treatment with citric acid preparations. (A) Control group; (B) Citric acid preparation treatment group. Figure 2 shows urinary albumin concentrations before and after six months of treatment in CKD patients with urinary albumin concentrations of 150 mg / gCr or greater and less than 600 mg / gCr before treatment. (A) Control group; (B) Sodium bicarbonate preparation treatment group; (C) Citric acid preparation treatment group. Figure 3 shows urinary transferrin concentrations before and after six months of treatment in CKD patients with urinary albumin concentrations of 150 mg / gCr or greater and less than 600 mg / gCr before treatment. (A) Control group; (B) Sodium bicarbonate preparation treatment group; (C) Citric acid preparation treatment group. Figure 4 shows urinary IgG concentrations before and after six months of treatment in CKD patients with urinary albumin concentrations of 150 mg / gCr or greater and less than 600 mg / gCr before treatment. (A) Control group; (B) Sodium bicarbonate preparation treatment group; (C) Citric acid preparation treatment group. Figures showing urinary α1-microglobulin concentrations before and after six months of treatment in CKD patients with urinary albumin concentrations of 150 mg / gCr or greater and less than 600 mg / gCr before treatment. (A) Control group, (B) Sodium bicarbonate treatment group, (C) Citric acid treatment group. Figures showing urinary MCP-1 concentrations before and after six months of treatment in CKD patients with urinary albumin concentrations of 150 mg / gCr or greater and less than 600 mg / gCr before treatment. (A) Control group, (B) Sodium bicarbonate treatment group, (C) Citric acid treatment group. Figures showing urinary pH before and after six months of treatment in CKD patients with urinary albumin concentrations of 150 mg / gCr or greater and less than 600 mg / gCr before treatment. (A) Control group, (B) Sodium bicarbonate treatment group, (C) Citric acid treatment group.

[0011] The present invention will be described in detail below with reference to specific embodiments, but the present invention is not limited to the following embodiments and can be embodied in any form without departing from the spirit of the present invention.

[0012] All patent publications, published patent applications, non-patent publications, and the like cited in this specification are hereby incorporated by reference in their entirety into this disclosure for all purposes.

[0013] In this specification, when applied to a numerical value, the term "to" refers to a range of values ​​that is equal to or greater than the specified reference value and is equal to or less than the specified reference value.

[0014] As used herein, "suppression" refers to stopping or slowing the worsening or progression of a symptom, condition, or disease, and also refers to improving the symptom, condition, or disease. Here, "improvement" refers to bringing a "pathological" or "abnormal" symptom, condition, or disease closer to a "healthy" or "normal" state, or referring to such a state, and to bringing the symptom, condition, or disease to a "healthy" or "normal" state. Accordingly, in one embodiment, "improvement" refers to a numerical value indicating a "pathological" or "abnormal" symptom or condition decreasing or increasing in accordance with the "improvement," approaching a normal value, or returning to a normal value. The "worsening or progression of a symptom, condition, or disease" refers to the worsening or progression of a "pathological" or "abnormal" symptom, condition, or disease, and the worsening or progression from a "healthy" or "normal" state to a "pathological" or "abnormal" symptom, condition, or disease. In one embodiment, "suppression" refers to stopping or slowing the worsening or progression of a symptom, condition, or disease, or referring to such a state. In another embodiment, "inhibiting" refers to stopping or slowing the worsening or progression of a symptom, condition, or disease.

[0015] As used herein, "healthy" refers to a state in which there is no acute or chronic disease or disorder, and "normal" refers to a state that a healthy subject normally experiences. Here, the symptoms, conditions, or diseases are compared before and after administration of the pharmaceutical composition, or when the pharmaceutical composition is administered with a control or placebo.

[0016] As used herein, "treatment" includes eliminating, curing, curing, or remission of "pathological" or "abnormal" symptoms, conditions, or diseases, and includes "suppressing" the worsening of "pathological" or "abnormal" symptoms, conditions, or diseases, and also includes "improvement." Here, "suppression" and "improvement" have the same meanings as above. In one embodiment, "treatment" refers to eliminating, curing, curing, or remission of "pathological" or "abnormal" symptoms, conditions, or diseases, and also includes "improvement." In another embodiment, "treatment" refers to eliminating, curing, curing, or remission of "pathological" or "abnormal" symptoms, conditions, or diseases.

[0017] As used herein, the term "prevention" refers to a concept that includes preventing the onset of "pathological" or "abnormal" symptoms, conditions, or diseases, and actions therefor.

[0018] As used herein, "chronic kidney disease (CKD)" is a comprehensive concept that encompasses chronic kidney diseases, regardless of the underlying disease, and encompasses all pathological conditions in which there is a decline in renal function, as measured by glomerular filtration rate (GFR), or findings suggesting kidney damage persist chronically (for three months or more). Primary diseases of CKD include diabetic nephropathy, nephrosclerosis (due to hypertension, aging, etc.), chronic glomerulonephritis (including IgA nephropathy and membranous nephropathy), polycystic kidney disease, etc.

[0019] According to the CKD Clinical Practice Guide 2012 (Journal of the Japanese Society of Nephrology 2012), the severity of CKD is evaluated by classification based on renal function (GFR: G) and albuminuria / proteinuria. GFR classification is as follows: G1: GFR is normal or high (≥ 90 mL / min / 1.73 m 2 G2: GFR is normal or slightly decreased (60-89 mL / min / 1.73 m 2 G3a: Mild to moderate decrease in GFR (45-59 mL / min / 1.73 m 2 G3b: Moderate to severe decrease in GFR (30-44 mL / min / 1.73 m 2 G4: Severely decreased GFR (15-29 mL / min / 1.73 m 2) G5: End-stage renal disease (ESKD) (<15 mL / min / 1.73 m 2 )

[0020] Urinary albumin concentration (albuminuria) is classified as follows using the urinary albumin / creatinine (Cr) ratio: A1: Normal (less than 30 mg / gCr) A2: Microalbuminuria (30-299 mg / gCr) A3: Macroalbuminuria (300 mg / gCr or more) Similarly, urinary protein concentration (proteinuria) is classified as follows using the urinary protein / creatinine (Cr) ratio: A1: Normal (less than 0.15 g / gCr) A2: Mild proteinuria (0.15-0.49 g / gCr) ((-) to (2+) by test strip method) A3: Severe proteinuria (0.50 g / gCr or more) ((1+) to (3+) by test strip method)

[0021] According to the CKD Treatment Guide 2012 (Journal of the Japanese Society of Nephrology 2012), the severity of CKD is classified using the primary disease and the aforementioned classifications G and A, for example, diabetes G2A3, chronic nephritis G3bA1, etc. However, taking into consideration that the severity of CKD has traditionally been expressed only by stages classified by GFR, it is now possible to express the severity of CKD in the conventional stages of G1, G2, G3a, G3b, G4, and G5.

[0022] In this specification, "early morning urine" refers to the first urine after waking up, and "random urine" refers to urine other than the aforementioned "early morning urine."

[0023] 1. Pharmaceutical Composition The pharmaceutical composition may contain, as an active ingredient, citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof. Examples of pharmaceutically acceptable salts of citric acid include alkali metal citrates. Examples of alkali metal citrates include potassium citrate and sodium citrate, which may be in the form of stable hydrates such as potassium citrate monohydrate (C6H5K3O7·H2O) and sodium citrate dihydrate (C6H5Na3O7·2H2O), respectively.

[0024] Examples of preferred active ingredients contained in the pharmaceutical composition include sodium citrate, potassium citrate, or hydrates thereof, or mixtures thereof, such as a mixture of potassium citrate monohydrate (C6H5K3O7·H2O) and sodium citrate dihydrate (C6H5Na3O7·2H2O). The mixing ratio of potassium citrate monohydrate (C6H5K3O7·H2O) to sodium citrate dihydrate (C6H5Na3O7·2H2O) can be appropriately determined by those skilled in the art. For example, the molar ratio of potassium citrate monohydrate to sodium citrate dihydrate can be 1 part potassium citrate monohydrate to 0.01 to 100 parts sodium citrate dihydrate. The molar ratio of potassium citrate (e.g., potassium citrate monohydrate) to sodium citrate (e.g., sodium citrate dihydrate) can be appropriately determined by one skilled in the art and may be, for example, 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, with 1:1 being preferred. Another example of an active ingredient contained in the pharmaceutical composition is sodium citrate or a hydrate thereof, such as sodium citrate dihydrate (C6H5Na3O7.2H2O).

[0025] Another example of the active ingredient contained in the pharmaceutical composition includes potassium citrate or a hydrate thereof, such as potassium citrate monohydrate (C6H5K3O7·H2O). In one embodiment, the active ingredient contained in the pharmaceutical composition of the present invention may comprise a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof. 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 can be appropriately determined by one skilled in the art and may be, for example, 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, with 1:2:2 being preferred. 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 determined by one skilled in the art, and may be, for example, 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, with 1:2:2 being preferred. 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 a hydrate thereof and potassium citrate or a hydrate thereof. When referring herein to the weight of citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof (e.g., potassium citrate monohydrate (C6H5K3O7·H2O) and sodium citrate dihydrate (C6H5Na3O7·2H2O)), the weight may be the dry weight.

[0026] The pharmaceutical composition can be used for renal protection in CKD. Renal protection includes the protection of renal tissue and renal function. For example, the pharmaceutical composition can be a pharmaceutical composition for protecting renal tissue in CKD, a pharmaceutical composition for suppressing renal tissue damage associated with the progression of CKD, a pharmaceutical composition for maintaining or improving renal function in CKD, or a pharmaceutical composition for suppressing decline in renal function associated with the progression of CKD. Examples of renal tissue protected by the pharmaceutical composition include nephrons, or tubules (e.g., proximal tubules) that constitute nephrons, or glomeruli. Examples of renal function maintained or improved by the pharmaceutical composition include the function of nephrons that produce urine from blood, i.e., the filtration function by glomeruli and the reabsorption function by renal tubules (e.g., proximal tubule function), and the urinary pH regulation function that suppresses urinary acidification and alkalinizes urine. Furthermore, examples of renal function maintained or improved by the pharmaceutical composition include nephron function, glomerular function, and tubular function (e.g., proximal tubule function), including filtration function, reabsorption function, and urinary pH regulation function (urine alkalinization). Thus, the pharmaceutical composition may be a pharmaceutical composition for maintaining or improving nephron function in CKD, a pharmaceutical composition for suppressing decline in glomerular function or tubular function associated with the progression of CKD, a pharmaceutical composition for maintaining or improving filtration function, reabsorption function, or urinary pH regulation function in CKD, or a pharmaceutical composition for suppressing decline in filtration function, reabsorption function, or urinary pH regulation function associated with the progression of CKD.

[0027] The efficacy of the pharmaceutical composition can be confirmed by administering the pharmaceutical composition to a chronic kidney disease patient whose urinary albumin concentration falls within a specific range before treatment with the pharmaceutical composition and evaluating the renal function of the patient. That is, when the pharmaceutical composition is administered to a chronic kidney disease patient whose urinary albumin concentration falls within a specific range before treatment with the pharmaceutical composition, the renal function of the treated chronic kidney disease patient is improved compared to the renal function before treatment, or the renal function after treatment with the pharmaceutical composition is higher than the renal function of a control chronic kidney disease patient who is not administered the pharmaceutical composition. Renal function can be assessed, for example, by measuring glomerular filtration rate (GFR), urinary protein, various urinary mediators (inflammation, fibrosis, blood pressure), or urinary pH using methods known in the art. Urinary proteins include albumin, transferrin, α1-glycoprotein, hemoglobin, myoglobin, immunoglobulins (e.g., IgG, IgM, IgA), Bence Jones protein, β2-microglobulin, α1-microglobulin, retinol-binding protein, lysozyme, and proteinoids (e.g., albumin, acetate, mucin). Of these, albumin, transferrin, α1-glycoprotein, and immunoglobulins (e.g., IgG, IgM, or IgA) are primarily associated with glomerular pathology (glomerular function), while β2-microglobulin, α1-microglobulin, retinol-binding protein, and lysozyme are primarily associated with tubular pathology (tubular function). Inflammatory mediators include inflammatory cytokines (e.g., MCP-1, IL-1β, IL-6, or TNF-α). Fibrotic mediators include TGF-β. Examples of blood pressure mediators include angiotensinogen, angiotensin I, and angiotensin II. These urinary proteins and various urinary mediators can be measured using, for example, dye methods, enzyme-linked immunosorbent assays such as ELISA, chemiluminescent enzyme immunoassay (CLEIA), immunoturbidimetry, immunonephelometry, double immunodiffusion (DID), latex agglutination, or test strips, or can be requested from a known testing institution such as SRL. Furthermore, urinary proteins and various urinary mediators can be corrected by dividing by the urinary creatinine concentration.

[0028] For example, by administering the pharmaceutical composition to a CKD patient whose urinary albumin concentration before treatment is within a specific range, if the CKD patient's GFR is higher compared to that before administration or in a control CKD patient, it can be evaluated that the pharmaceutical composition has protected renal tissue. That is, one aspect of the present invention is a pharmaceutical composition for renal protection used in the treatment of chronic kidney disease to improve GFR, comprising citric acid, a pharmaceutically acceptable salt of citric acid, a hydrate thereof, or a mixture thereof, wherein the pharmaceutical composition is for treating patients with chronic kidney disease whose urinary albumin concentration before treatment is within a specific range. The improvement in GFR may be suppression of decline, maintenance, or increase compared to the GFR before administration or in a control CKD patient. The urinary albumin concentration can be measured, for example, by immunoturbidimetry and corrected for creatinine.

[0029] For example, by administering the pharmaceutical composition to a CKD patient whose urinary albumin concentration before treatment with the pharmaceutical composition is within a specific range, it can be evaluated that the pharmaceutical composition has protected renal tissue if the CKD patient's urinary protein levels (albumin, transferrin, α1-glycoprotein, hemoglobin, myoglobin, IgG, IgM, IgA, Bence Jones protein, β2-microglobulin, α1-microglobulin, retinol-binding protein, lysozyme, or proteinoids, etc.) are lower than those before administration or in control CKD patients. That is, one aspect of the present invention is a pharmaceutical composition for renal protection used in the treatment of chronic kidney disease to improve urinary protein, comprising citric acid, a pharmaceutically acceptable salt of citric acid, a hydrate thereof, or a mixture thereof, wherein the pharmaceutical composition is for treating patients with chronic kidney disease whose urinary albumin concentration before treatment is within a specific range. The urinary protein may be albumin, transferrin, α1-glycoprotein, hemoglobin, myoglobin, IgG, IgM, IgA, Bence Jones protein, β2-microglobulin, α1-microglobulin, retinol-binding protein, lysozyme, or proteinoids. The improvement in urinary protein may be suppression of increase, maintenance, or reduction compared to the urinary protein level before administration or in control CKD patients. The urinary albumin concentration can be measured, for example, by immunoturbidimetry and corrected for creatinine.

[0030] For example, by administering the pharmaceutical composition to a CKD patient whose urinary albumin concentration is within a specific range before treatment with the pharmaceutical composition, the CKD patient's urinary levels of inflammatory mediators (e.g., MCP-1, IL-1β, IL-6, or TNF-α), fibrotic mediators (e.g., TGF-β), or blood pressure mediators (e.g., angiotensinogen or angiotensin I or II) can be evaluated as having protected renal tissue if they are lower than those of the CKD patient before treatment or control CKD patients. That is, one aspect of the present invention is a pharmaceutical composition for renal protection that improves mediators of chronic kidney disease, comprising citric acid, a pharmaceutically acceptable salt of citric acid, a hydrate thereof, or a mixture thereof, for treating patients with chronic kidney disease whose urinary albumin concentration is within a specific range before treatment. The improvement in mediators may be suppression of increase, maintenance, or reduction of urinary protein levels compared to those of the CKD patient before treatment or control CKD patients. The albumin concentration in urine can be measured, for example, by immunoturbidimetry and can be corrected for with creatinine.

[0031] For example, by administering the pharmaceutical composition to a CKD patient whose urinary albumin concentration before treatment is within a specific range, if the CKD patient's urinary pH is higher compared to that before administration or in a control CKD patient, it can be evaluated that the pharmaceutical composition has protected renal tissue. That is, one aspect of the present invention is a pharmaceutical composition for renal protection used in the treatment of chronic kidney disease patients by alkalinizing the urinary pH, comprising citric acid, a pharmaceutically acceptable salt of citric acid, a hydrate thereof, or a mixture thereof, wherein the pharmaceutical composition is for treating patients with chronic kidney disease whose urinary albumin concentration before treatment is within a specific range. The alkalinization of the urinary pH may be inhibited, maintained, or increased compared to the urinary pH before administration or in a control CKD patient. The urinary albumin concentration can be measured, for example, by immunoturbidimetry and corrected for creatinine.

[0032] CKD patients who are candidates for treatment with this pharmaceutical composition are chronic kidney patients whose urinary albumin concentration before treatment with this pharmaceutical composition is within a specific range. The concentration of albumin in the urine is, for example, a specific range included in 10 to 1000 mg / gCr, a specific range included in 25 to 1000 mg / gCr, a specific range included in 150 to 1000 mg / gCr, a specific range included in 10 to 800 mg / gCr, a specific range included in 25 to 800 mg / gCr, a specific range included in 150 to 800 mg / gCr, a specific range included in 10 to 600 mg / gCr, a specific range included in 25 to 600 mg / gCr, or a specific range included in 150 to 600 mg / gCr, more specifically, for example, 10 to 1000 mg / gCr, 25 to 1000 mg / gCr, 100 to 1000 mg / gCr, 150 to 1000 mg / gCr, 10 to 800 mg / gCr, 25 to 800 mg / gCr, 100 to 800 mg / gCr, 150 to 800 mg / gCr, The albumin concentration in urine can be measured, for example, by immunoturbidimetry and can be corrected for by creatinine.

[0033] One aspect of the present invention is a pharmaceutical composition for renal protection for treating CKD, comprising citric acid, a pharmaceutically acceptable salt of citric acid, a hydrate thereof, or a mixture thereof, wherein the pharmaceutical composition is for treating a CKD patient whose urinary albumin concentration before treatment is within a specific range of 10 to 1,000 mg / gCr, 25 to 1,000 mg / gCr, 150 to 1,000 mg / gCr, 10 to 800 mg / gCr, 25 to 800 mg / gCr, 150 to 800 mg / gCr, 10 to 600 mg / gCr, 25 to 600 mg / gCr, or 150 to 600 mg / gCr. The urinary albumin concentration can be measured, for example, by immunoturbidimetry and corrected for creatinine.

[0034] One aspect of the present invention is a pharmaceutical composition for renal protection for treating CKD, comprising citric acid, a pharmaceutically acceptable salt of citric acid, a hydrate thereof, or a mixture thereof, wherein the pharmaceutical composition is for treating a CKD patient whose urinary albumin concentration before treatment is 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. The urinary albumin concentration can be measured, for example, by immunoturbidimetry and corrected for creatinine.

[0035] One aspect of the present invention is a pharmaceutical composition for renal protection for the treatment of CKD, comprising citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, wherein the pharmaceutical composition is for treating a CKD patient whose urinary albumin concentration before treatment is 10 to less than 1000 mg / gCr, 25 to less than 1000 mg / gCr, 100 to less than 1000 mg / gCr, 150 to less than 1000 mg / gCr, 10 to less than 800 mg / gCr, 25 to less than 800 mg / gCr, 100 to less than 800 mg / gCr, 150 to less than 800 mg / gCr, 10 to less than 600 mg / gCr, 25 to less than 600 mg / gCr, 100 to less than 600 mg / gCr, or 150 to less than 600 mg / gCr. Another aspect of the present invention is a pharmaceutical composition for renal protection for treating CKD, comprising citric acid, a pharmaceutically acceptable salt of citric acid, a hydrate thereof, or a mixture thereof, and may be a pharmaceutical composition for treating CKD patients exhibiting microalbuminuria and / or macroalbuminuria. The albumin concentration in urine can be measured, for example, by immunoturbidimetry and can be corrected for creatinine.

[0036] In healthy individuals, the physiological urinary protein excretion level is less than 0.1 g / gCr, and urinary excretion of 0.15 g / gCr or more is called proteinuria. Of this range, a range of 0.15 mg / gCr to 0.49 mg / gCr is called mild proteinuria ((-) to (2+) by the test strip method), 0.50 or more is called severe proteinuria ((1+) to (3+) by the test strip method), and 3.5 or more is called nephrotic ((3+) to (4+) by the test strip method). Urinary protein concentration can be measured by methods known in the art, such as the dye method (e.g., pyrogallol red method) or the test strip method (e.g., MyUrease (registered trademark) manufactured by Terumo Corporation). This pharmaceutical composition can be used for CKD patients whose symptoms before treatment with the pharmaceutical composition are mild proteinuria ((-) to (2+) by test strip method) or severe proteinuria ((1+) to (3+) by test strip method).In addition, this pharmaceutical composition can be used for CKD patients whose symptoms before treatment with the pharmaceutical composition are mild proteinuria ((-) to (2+) by test strip method).

[0037] To select CKD patients who are candidates for treatment with the pharmaceutical composition, urine is collected from the patients. The urine may be early morning urine or random urine. One aspect of the present invention is a pharmaceutical composition for nephroprotection for the treatment of CKD, comprising citric acid, a pharmaceutically acceptable salt of citric acid, a hydrate thereof, or a mixture thereof, the pharmaceutical composition being for treating CKD patients whose early morning urine albumin concentration before treatment is within a specific range. Another aspect of the present invention is a pharmaceutical composition for nephroprotection for the treatment of CKD, comprising citric acid, a pharmaceutically acceptable salt of citric acid, a hydrate thereof, or a mixture thereof, the pharmaceutical composition being for treating CKD patients whose random urine albumin concentration before treatment is within a specific range.

[0038] 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 may be measured by immunoturbidimetry or the like before the start of treatment. For example, the urinary albumin concentration may be measured within one month, three weeks, two weeks, ten days, one week, five days, three days, or two days before the start of treatment, or on the day of treatment initiation. Another aspect of the present invention is a pharmaceutical composition for renal protection for the treatment of CKD, comprising citric acid, a pharmaceutically acceptable salt of citric acid, a hydrate thereof, or a mixture thereof, and the pharmaceutical composition is for treating CKD patients whose urinary albumin concentration is within a specific range within one month, three weeks, two weeks, ten days, one week, five days, three days, or two days before the start of treatment, or on the day of treatment initiation.

[0039] The pharmaceutical compositions are administered to humans or other mammals orally or parenterally, examples of parenteral administration include intravenous, subcutaneous, intramuscular, intraarticular, transmucosal, transdermal, nasal, rectal, intrathecal, intraperitoneal, or topical administration.

[0040] The pharmaceutical composition may be prepared by mixing the active ingredient, citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, as is, or with a pharmaceutically acceptable carrier, for example, an excipient (e.g., lactose, D-mannitol, crystalline cellulose, or glucose), a binder (e.g., hydroxypropyl cellulose (HPC), gelatin, or polyvinylpyrrolidone (PVP)), a lubricant (e.g., magnesium stearate or talc), a disintegrant (e.g., starch or carboxymethylcellulose calcium (CMC-Ca)), a diluent (e.g., water for injection or physiological saline), or, if necessary, other additives (e.g., pH adjusters, surfactants, solubilizers, preservatives, emulsifiers, isotonicity agents, or stabilizers), and may be in the form of tablets, capsules, suspensions, injections, suppositories, or other formulations. For example, to prepare a tablet, the active ingredient, citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, may be mixed with an excipient (e.g., lactose, D-mannitol, crystalline cellulose, or glucose), a disintegrant (e.g., starch or carboxymethylcellulose calcium (CMC-Ca)), a binder (e.g., hydroxypropyl cellulose (HPC), gelatin, or polyvinylpyrrolidone (PVP)), or a lubricant (e.g., magnesium stearate or talc), and the like, to form a formulation.

[0041] In one embodiment of the present invention, the pharmaceutical composition is a tablet. The tablet provided by the present invention may contain, in addition to the active ingredient, citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof (e.g., potassium citrate or a hydrate thereof; sodium citrate or a hydrate thereof; a mixture of potassium citrate monohydrate and sodium citrate dihydrate; or sodium bicarbonate), pharmaceutically acceptable additives conventionally used in the pharmaceutical field. Examples of such additives include excipients, binders, disintegrants, flow agents, flavoring agents, lubricants, pH adjusters, surfactants, stabilizers, and flavoring agents. The content of the active ingredient, citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, in the tablet provided by the present invention may be 10 to 95% by weight, preferably 30 to 90% by weight, and more preferably 60 to 85% by weight, of the tablet.

[0042] The pharmaceutical composition can be prepared by a method known in the pharmaceutical art. In one embodiment, the hardness of the resulting tablet can be 10-200N, preferably 30-150N.

[0043] The amount of citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, which is an active ingredient in the pharmaceutical composition, can be appropriately determined. In one embodiment, the amount of citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, which is an active ingredient in the pharmaceutical composition, may be set so that the dose of the active ingredient, citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, which is an active ingredient, when administered to a human, improves acidic urine in gout or hyperuricemia, or an amount less than that amount. For example, the amount may be set so that the daily dose approved in Japan for improving acidic urine in gout or hyperuricemia is 1 to 50%, or 10 to 20%, of the daily dose approved (e.g., two tablets containing 231.5 mg of potassium citrate (C6H5K3O7.H2O) and 195.0 mg of sodium citrate hydrate (C6H5Na3O7.2H2O) per tablet, administered orally three times a day; when the alkalinizing agent is sodium bicarbonate, administered orally 3 to 5 g a day).

[0044] In one aspect of the present invention, the pharmaceutical composition is a tablet, and each tablet may contain 10 mg to 1 g, preferably 100 mg to 500 mg, and more preferably 400 mg to 500 mg, of potassium citrate monohydrate or sodium citrate dihydrate. In another embodiment, the pharmaceutical composition is a tablet, and each tablet may contain 10 mg to 300 mg of potassium citrate monohydrate and sodium citrate dihydrate, for a total of 20 mg to 600 mg, preferably 150 to 250 mg of each, for a total of 400 to 500 mg, and more preferably 190 to 240 mg of each, for a total of 400 to 450 mg.

[0045] In one embodiment of the present invention, the pharmaceutical composition is a tablet and contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and may contain anhydrous citric acid, microcrystalline cellulose, partially pregelatinized starch, hydroxypropyl cellulose, magnesium stearate, hypromellose, macrogol 6000, titanium oxide, and carnauba wax as excipients.

[0046] In one embodiment of the present invention, one dosage unit may be a tablet containing 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate. As used herein, "dosage unit" refers to a unit of a formulation, and "one dosage unit" refers to the smallest unit of a formulation. For example, in the case of tablets, a dosage unit is each tablet, and one dosage unit represents one tablet. In the case of an injection, a dosage unit is an injection contained in a sealed container such as an ampoule or vial, and one dosage unit represents an injection contained in a sealed container such as an ampoule or vial. When the pharmaceutical composition is administered to humans or other mammals, one or more of the dosage units may be administered at a time, or one dosage unit may be divided and administered.

[0047] The dosage of the active ingredient, citric acid, a pharmaceutically acceptable salt of citric acid, a hydrate thereof, or a mixture thereof, is determined appropriately depending on the administration method, the age, weight, sex, symptoms, or drug sensitivity of the recipient, and may be adjusted depending on the degree of symptom improvement. In one embodiment of the present invention, when a mixture of potassium citrate monohydrate and sodium citrate dihydrate is orally administered to a human, the daily dosage may be half the daily dosage approved in Japan for the improvement of acidic urine in gout and hyperuricemia (e.g., in the case of a citric acid preparation, two tablets containing 231.5 mg of potassium citrate (C6H5K3O7.H2O) and 195.0 mg of sodium citrate hydrate (C6H5Na3O7.2H2O) are orally administered three times a day).

[0048] In one embodiment of the present invention, when a mixture of potassium citrate monohydrate and sodium citrate dihydrate is orally administered to a human, the daily dosage may be the same as the daily dosage approved in Japan for the improvement of acidic urine in gout and hyperuricemia (for example, in the case of a citric acid preparation: two tablets containing 231.5 mg of potassium citrate (C6H5K3O7.H2O) and 195.0 mg of sodium citrate hydrate (C6H5Na3O7.2H2O) per tablet, orally administered three times a day).

[0049] In one embodiment of the present invention, when a mixture of potassium citrate monohydrate and sodium citrate dihydrate is orally administered to a human, the daily dosage may be initially half the daily dosage approved in Japan for the improvement of gout and acidic urine associated with hyperuricemia (for example, in the case of a citric acid preparation: two tablets containing 231.5 mg of potassium citrate (C6H5K3O7.H2O) and 195.0 mg of sodium citrate hydrate (C6H5Na3O7.2H2O) are orally administered three times a day), and the dosage may then be increased to the daily dosage approved in Japan for the improvement of gout and acidic urine associated with hyperuricemia.

[0050] In one embodiment of the present invention, when a mixture of potassium citrate monohydrate and sodium citrate dihydrate is orally administered to a human as an active ingredient, potassium citrate monohydrate and sodium citrate dihydrate may be administered at 0.1 to 5 g / day each for a total of 0.2 to 10 g / day, 0.1 to 3 g / day each for a total of 0.2 to 6 g / day, 0.5 to 3 g / day each for a total of 1 to 6 g / day, preferably 0.5 to 1.5 g / day each for a total of 1 to 3 g / day, 1 to 1.5 g / day each for a total of 2 to 3 g / day, or 0.5 to 1 g / day each for a total of 1 to 2 g / day, and may be administered 1 to 5 times a day, preferably 3 times a day.

[0051] In one embodiment of the present invention, when potassium citrate monohydrate or sodium citrate dihydrate is orally administered to a human as an active ingredient, the dose may be 1 to 10 g / day, 1 to 6 g / day, 2 to 5.5 g / day, 1 to 3 g / day, 2 to 3 g / day, or 1 to 1.5 g / day, and may be administered 1 to 5 times a day, preferably 3 times a day.

[0052] In one embodiment of the present invention, the active ingredient, citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, may be administered for a long period of time, for example, 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, 1 week or more, 2 weeks or more, 3 weeks or more, 6 weeks or more, 8 weeks or more, 10 weeks or more, 12 weeks or more, 24 weeks or more, 40 weeks or more, 60 weeks or more, 80 weeks or more The administration is for at least 100 weeks, at least 120 weeks, at least 6 weeks and no more than 24 weeks, at least 12 weeks and no more than 24 weeks, at least 6 weeks and no more than 30 weeks, at least 12 weeks and no more than 30 weeks, at least 6 weeks and no more than 40 weeks, at least 12 weeks and no more than 40 weeks, at least 6 weeks and no more than 60 weeks, at least 12 weeks and no more than 60 weeks, at least 6 weeks and no more than 80 weeks, at least 12 weeks and no more than 80 weeks, at least 6 weeks and no more than 100 weeks, at least 12 weeks and no more than 100 weeks, at least 6 weeks and no more than 120 weeks, or at least 12 weeks and no more than 120 weeks.

[0053] In one embodiment of the present invention, the pharmaceutical composition can be administered continuously for 6 weeks, 12 weeks, and / or 24 weeks to detect beneficial effects (e.g., renal protective effects) in CKD patients.

[0054] In one embodiment of the present invention, the pharmaceutical composition is administered to patients with less severe, early-stage CKD. In another embodiment 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 who are at stage G3b or below, preferably stage G2 or below. In another embodiment 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 who are at stage G2 or above and stage G3b or below (e.g., stage G2 and stage G3a; or stage G2, stage G3a and stage G3b). The urinary albumin concentration can be measured, for example, by immunoturbidimetry and can be corrected for creatinine.

[0055] In one embodiment of the present invention, the pharmaceutical composition is administered to a patient with advanced CKD who has a urinary albumin concentration within a specific range before treatment with the pharmaceutical composition. In one embodiment of the present invention, the pharmaceutical composition is administered to a patient with CKD and hypertension who has a urinary albumin concentration within a specific range before treatment with the pharmaceutical composition. In one embodiment of the present invention, the pharmaceutical composition is administered to a patient with diabetic nephropathy who has a urinary albumin concentration within a specific range before treatment with the pharmaceutical composition. In one embodiment of the present invention, the pharmaceutical composition is administered to a patient with nephrosclerosis (due to hypertension, aging, etc.) who has a urinary albumin concentration within a specific range before treatment with the pharmaceutical composition. In one embodiment of the present invention, the pharmaceutical composition is administered to a patient with chronic glomerulonephritis (including IgA nephropathy and membranous nephropathy, etc.) who has a urinary albumin concentration within a specific range before treatment with the pharmaceutical composition. In one embodiment of the present invention, the pharmaceutical composition is administered to a patient with polycystic kidney disease who has a urinary albumin concentration within a specific range before treatment with the pharmaceutical composition. The urinary albumin concentration can be measured, for example, by immunoturbidimetry and corrected for creatinine.

[0056] In one aspect of the present invention, the pharmaceutical composition is administered to patients undergoing treatment in accordance with the CKD Clinical Practice Guide. For example, the pharmaceutical composition is administered to patients undergoing blood pressure control (e.g., administration of RA system inhibitors such as ARBs and ACE inhibitors, diuretics, or calcium channel blockers), proteinuria control (e.g., administration of RA system inhibitors), blood glucose control (e.g., administration of α-glucosidase inhibitors), lipid control (e.g., administration of statins or fibrates), anemia control (e.g., administration of erythropoietin), and / or bone and mineral control (e.g., administration of bisphosphonates) in accordance with the CKD Clinical Practice Guide. In one aspect of the present invention, the pharmaceutical composition is used in combination with an antihypertensive drug (e.g., an ARB, ACE inhibitor, diuretic, or calcium channel blocker). In one embodiment, the pharmaceutical composition is used in combination with spherical adsorbent carbon (sold in Japan under the trademark Kremezin®) obtained by high-temperature oxidation and reduction of spherical, microporous carbon derived from petroleum hydrocarbons.

[0057] 2. Food Compositions In one aspect of the present invention, the food composition provided by the present invention contains citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof. When ingested by a human whose urinary albumin concentration before ingestion is within a specific range, the food composition provides kidney protection or health maintenance effects. In another aspect of the present invention, the food composition provides the effects of suppressing urinary protein in the kidney, maintaining or improving glomerular and tubular function, suppressing inflammation, or alkalinizing urine. The active ingredients may be those described above under "1. Pharmaceutical Compositions." For example, the food composition provided by the present invention may contain an alkali metal citrate salt, a hydrate thereof, or a mixture thereof, preferably a mixture of potassium citrate monohydrate (C6H5K3O7·H2O) and sodium citrate dihydrate (C6H5Na3O7·2H2O). Urinary albumin concentration can be measured, for example, by immunoturbidimetry and corrected for creatinine.

[0058] The content of citric acid, a pharmaceutically acceptable salt of citric acid, a hydrate thereof, or a mixture thereof in the food composition provided by the present invention can be appropriately determined depending on the type of food. Examples of food compositions include foods for specified health uses, functional foods, foods for hospital patients, and supplements. The form of these food compositions is not particularly limited as long as they contain an effective amount of citric acid, a pharmaceutically acceptable salt of citric acid, a hydrate thereof, or a mixture thereof to achieve the above-mentioned effect and are orally ingestible. They may be in the form of ordinary food or beverages, or may be provided as a formulation suitable for oral administration, such as a tablet, capsule, or suspension, among formulations applicable to the pharmaceutical composition. The composition and manufacturing method of these formulations can be directly applied to the pharmaceutical formulations described in "1. Pharmaceutical Compositions" above, or any formulation technology known per se in the field of pharmaceutical formulation technology can be applied.

[0059] For example, in the case of a food for specified health uses, a food with functional claims, a food for hospital patients, or a supplement, one serving of food may contain a total of 1 to 3 g (⅓ of a total) of potassium citrate monohydrate and sodium citrate dihydrate as active ingredients, or 1 to 6 g (⅓ of a total) of sodium bicarbonate as an active ingredient. When a food for specified health uses, a food with functional claims, a food for hospital patients, or a supplement is provided as a tablet, for example, each tablet may contain 70 to 80 wt% of citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, per 300 mg to 600 mg tablet.

[0060] When the food composition of the present invention is not formulated but is provided in the form of a conventional food or beverage, it can be prepared by those skilled in the art as appropriate depending on the type of food. For example, it can be prepared by blending citric acid, a pharmaceutically acceptable salt of citric acid, a hydrate thereof, or a mixture thereof with a food ingredient. Examples of the food or beverage form include liquid, milky, or paste-like foods such as beverages, soy sauce, milk, yogurt, or miso; semi-solid foods such as jellies or gummies; solid foods such as candy, gum, tofu, or supplements; or powdered foods. Examples of beverages include fruit juice drinks, coffee drinks, oolong tea drinks, green tea drinks, black tea drinks, barley tea drinks, vegetable drinks, carbonated soft drinks, fruit extract drinks, vegetable extract juices, near-water drinks, sports drinks, and diet drinks.

[0061] The beverage may contain additives such as antioxidants, flavorings, various esters, organic acids, organic acid salts, inorganic acids, inorganic acid salts, inorganic salts, colorants, emulsifiers, preservatives, seasonings, sweeteners, acidulants, fruit juice extracts, vegetable extracts, nectar extracts, pH adjusters, or quality stabilizers, either alone or in combination.

[0062] The term "administration" described in "1. Pharmaceutical Composition" above can also be applied to the ingestion of the "food composition" of the present invention; that is, with respect to the "food composition" of the present invention, the term "administration" can be read as "ingestion." Therefore, for example, the terms "administer," "administered," etc. can be read as "ingested," "taken," "ingested," etc., depending on the context.

[0063] The present invention also has the following aspects: <1a> A method for nephroprotection for the treatment of chronic kidney disease, the method comprising administering a therapeutically effective amount of citric acid, a pharmaceutically acceptable salt of citric acid, a hydrate of these, or a mixture of these to a patient with chronic kidney disease whose urinary albumin concentration before treatment is within a specific range and who is in need of the treatment (e.g., a mammal including a human); <2a> The method according to <1a>, wherein the urinary albumin concentration of the patient with chronic kidney disease before treatment is within a specific range of 10 to 1000 mg / gCr; <3a> The method according to <1a>, wherein the urinary albumin concentration of the patient with chronic kidney disease before treatment is within a specific range of 25 to 600 mg / gCr; <4a> The method according to <1a>, wherein the urinary albumin concentration of the patient with chronic kidney disease before treatment is within a specific range of 150 to 600 mg / gCr; <5a> The method according to any one of <1a> to <4a>, wherein the urine of the patient with chronic kidney disease before treatment is early morning urine; <6a> The method according to any one of <1a> to <5a>, wherein the urinary albumin concentration of the chronic kidney disease patient before treatment is the concentration within two weeks before the start of treatment; <7a> The method according to any one of <1a> to <6a>, wherein the renal protection is suppression of urinary protein, maintenance or improvement of glomerular function / renal tubular function, suppression of inflammation, or alkalinization of urine; <8a> The method according to <7a>, wherein the urinary protein is albumin, transferrin, IgG, or α1-microglobulin; <9a> The method according to <7a>, wherein the suppression of inflammation is suppression of urinary MCP-1 concentration; <10a> The method according to any one of <1a> to <9a>, wherein the citric acid, a pharmaceutically acceptable salt of citric acid, a hydrate thereof, or a mixture thereof is a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof; <11a> The method according to <10a>, further comprising anhydrous citric acid; <12a> The method according to any one of <1a> to <11a>, wherein the citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof is administered at 1 to 3 g / day; <13a> The method according to any one of <1a> to <12a>, wherein the chronic kidney disease is at stage G2 or higher and G3b or lower;<14a> The method according to any one of <1a> to <13a>, wherein the citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof is administered for 6 weeks or more;

[0064] <1b> A pharmaceutical composition comprising citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, for use in nephroprotection in the treatment of chronic kidney disease, wherein the pharmaceutical composition is used to treat a patient with chronic kidney disease whose urinary albumin concentration before treatment is in a specific range; <2b> The pharmaceutical composition for use according to <1b>, wherein the urinary albumin concentration of the patient with chronic kidney disease before treatment is in a specific range of 10 to 1000 mg / gCr; <3b> The pharmaceutical composition for use according to <1b>, wherein the urinary albumin concentration of the patient with chronic kidney disease before treatment is in a specific range of 25 to 600 mg / gCr; <4b> The pharmaceutical composition for use according to <1b>, wherein the urinary albumin concentration of the patient with chronic kidney disease before treatment is in a specific range of 150 to 600 mg / gCr; <5b> The pharmaceutical composition for use according to any one of <1b> to <4b>, wherein the urine of the patient with chronic kidney disease before treatment is early morning urine; <6b> The pharmaceutical composition for use according to any one of <1b> to <5b>, wherein the urinary albumin concentration of the chronic kidney disease patient before treatment is the concentration within two weeks before the start of treatment; <7b> The pharmaceutical composition for use according to any one of <1b> to <6b>, wherein the renal protection is suppression of urinary protein, maintenance or improvement of glomerular function / renal tubular function, suppression of inflammation, or alkalinization of urine; <8b> The pharmaceutical composition for use according to <7b>, wherein the urinary protein is albumin, transferrin, IgG, or α1-microglobulin; <9b> The pharmaceutical composition for use according to <7b>, wherein the suppression of inflammation is suppression of urinary MCP-1 concentration; <10b> The pharmaceutical composition for use according to any one of <1b> to <9b>, wherein the citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof is a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof; <11b> The pharmaceutical composition for use according to <10b>, further comprising anhydrous citric acid; <12b> The pharmaceutical composition for use according to any one of <1b> to <11b>, wherein the citric acid, a pharmaceutically acceptable salt of citric acid, a hydrate thereof, or a mixture thereof is administered at 1 to 3 g / day;<13b> The pharmaceutical composition for use according to any one of <1b> to <12b>, wherein the chronic kidney disease is at stage G2 or higher and at most G3b; <14b> The pharmaceutical composition for use according to any one of <1b> to <13b>, wherein the citric acid, a pharmaceutically acceptable salt of citric acid, a hydrate thereof, or a mixture thereof is administered for 6 weeks or longer;

[0065] <1c> Use of citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, for producing a pharmaceutical composition for nephroprotection for treating chronic kidney disease, wherein the pharmaceutical composition is for treating a patient with chronic kidney disease whose urinary albumin concentration before treatment is within a specific range; <2c> The use according to <1c>, wherein the urinary albumin concentration of the patient with chronic kidney disease before treatment is within a specific range of 10 to 1000 mg / gCr; <3c> The use according to <1c>, wherein the urinary albumin concentration of the patient with chronic kidney disease before treatment is within a specific range of 25 to 600 mg / gCr; <4c> The use according to <1c>, wherein the urinary albumin concentration of the patient with chronic kidney disease before treatment is within a specific range of 150 to 600 mg / gCr; <5c> The use according to any one of <1c> to <4c>, wherein the urine of the patient with chronic kidney disease before treatment is early morning urine; <6c> The use according to any one of <1c> to <5c>, wherein the urinary albumin concentration of the chronic kidney disease patient before treatment is the concentration within two weeks before the start of treatment; <7c> The use according to any one of <1c> to <6c>, wherein the renal protection is suppression of urinary protein, maintenance or improvement of glomerular function / renal tubular function, suppression of inflammation, or alkalinization of urine; <8c> The use according to <7c>, wherein the urinary protein is albumin, transferrin, IgG, or α1-microglobulin; <9c> The use according to <7c>, wherein the suppression of inflammation is suppression of urinary MCP-1 concentration; <10c> The use according to any one of <1c> to <9c>, wherein the citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof is a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof; <11c> The use according to <10c>, further comprising anhydrous citric acid; <12c> The use according to any one of <1c> to <11c>, wherein the citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof is administered at 1 to 3 g / day; <13c> The use according to any one of <1c> to <12c>, wherein the chronic kidney disease is at stage G2 or higher and G3b or lower;<14c> The use according to any one of <1c> to <13c>, wherein the citric acid, a pharmaceutically acceptable salt of citric acid, a hydrate thereof, or a mixture thereof is administered for 6 weeks or more.

[0066] The present invention will be further explained below with reference to examples, but the present invention is not limited to these examples.

[0067] A human clinical trial was conducted to investigate the effects of oral administration of a potassium citrate / sodium citrate hydrate compound preparation (hereinafter referred to as "citric acid preparation") and a sodium bicarbonate preparation, which are oral alkalizing agents (Patent Document 1).

[0068] 1. Methods Patients with stage G2-G3b chronic kidney disease (CKD) (eGFR: 30-89 ml / min / 1.73m) 2 The patients were randomly divided into a citric acid group, a sodium bicarbonate group, and a control group. Patients were assigned to each group so that age, gender, presence or absence of diabetes, and eGFR were balanced. Each group received treatment based on the "CKD Clinical Practice Guide - Treatment Summary" (hereinafter referred to as standard treatment).

[0069] The control group received no alkalinizing agents. The citric acid group received three tablets containing 231.5 mg of potassium citrate (C6H5K3O7·H2O) and 195.0 mg of sodium citrate hydrate (C6H5Na3O7·2H2O) orally three times daily (morning, noon, and evening) for six months (24 weeks). Early morning urine pH was monitored over time, and in cases where the early morning urine pH was below 6.5, the physician's discretion allowed for an increase to six tablets three times daily (morning, noon, and evening). The sodium bicarbonate group received three tablets containing 500 mg of sodium bicarbonate orally three times daily (morning, noon, and evening) for six months (24 weeks). In addition, the pH of early morning urine was managed over time, and in cases where the pH of early morning urine was below 6.5, the dosage could be increased to 6 tablets per day, 3 times a day (morning, noon, and evening) as appropriate, at the doctor's discretion.

[0070] Early morning urine samples were collected before and 24 weeks after the start of treatment. Creatinine concentrations (Canon Medical Diagnostics, Determiner L CRE), albumin (Fujifilm Wako Pure Chemical Industries, Autowako Microalbumin), transferrin (Nittobo Medical, N-Assay LA Micro Tf Nittobo), immunoglobulin IgG (Takara Bio, MK136), α1-microglobulin (Eiken Chemical, LZ Test® 'Eiken' α1-M), and MCP-1 (R&D Systems, Quantikine® Human MCP-1 Immunoassay) were measured by SRL. Each measurement was corrected by dividing by the creatinine concentration. The change in each parameter associated with treatment was calculated by subtracting the pretreatment measurement from the posttreatment measurement.

[0071] 2. Stratification of subjects based on albumin concentration in early morning urine Figure 1 shows the logarithmic change in early morning urine albumin concentration before and after treatment for each subject. In the control group, urinary albumin concentration increased before and after treatment (119±318→153±333mg / gCr (n=31); change before and after treatment was 34±148 mg / gCr), whereas it decreased after treatment with citric acid (103±198→89±203mg / gCr (n=29); change before and after treatment was -14±59 mg / gCr).

[0072] Detailed analysis of the time course for each subject revealed that subjects with low pretreatment urinary albumin concentrations showed little change in urinary albumin concentration before and after treatment in both the control and citric acid preparation groups. For example, the results for subjects with pretreatment urinary albumin concentrations of 10 mg / gCr or less are shown in Table 1. On the other hand, for subjects with relatively high pretreatment urinary albumin concentrations, the control group showed an increase in urinary albumin concentration during the treatment period, while the citric acid preparation group showed a clear inhibitory effect. For example, the results for subjects with pretreatment urinary albumin concentrations of 25-600 mg / gCr or 150-600 mg / gCr are shown in Table 1, and the results for subjects with pretreatment urinary albumin concentrations of 150-600 mg / gCr are shown in Figure 2. When sodium bicarbonate preparations were administered instead of citric acid preparations, no decrease in urinary albumin change was observed before and after the treatment period, even when subjects were stratified (overall: 50±132 mg / gCr (n=31); subjects with early morning urine albumin concentration of 25-600 mg / gCr before treatment: 109±179 mg / gCr (n=14); subjects with early morning urine albumin concentration of 150-600 mg / gCr before treatment: 337±161 mg / gCr (n=3)). Figure 2 shows the individual measurement results for subjects with early morning urine albumin concentration of 150-600 mg / gCr before treatment. Urinary albumin concentration increased after treatment in the control group and sodium bicarbonate preparation group, but decreased in the citric acid preparation group. From the above, when early morning urine albumin is used as an indicator, it was found that the effect of citric acid preparations is clearly seen in subjects with moderately high pre-treatment urinary albumin concentrations (e.g., 25-600 mg / gCr or 150-600 mg / gCr).

[0073] *: Student's t-test or Welch's t-test (two-tailed) (*: p<0.05; **: p<0.01).

[0074] 3. Effects on other parameters 3-1) Transferrin Table 2 shows the change in urinary transferrin levels when subjects were stratified by early morning urine albumin concentration. Figure 3 shows the individual measurement results for subjects with early morning urine albumin concentrations of 150-600 mg / gCr before treatment. In the control group and the sodium bicarbonate group, urinary transferrin concentration increased with treatment, whereas it decreased in the citric acid group, maintaining and improving filtration function in the renal glomeruli.

[0075] *: Student's t-test or Welch's t-test (two-tailed) (*: p<0.05; **: p<0.01).

[0076] 3-2) Immunoglobulin (IgG) Table 3 shows the change in urinary IgG when subjects were stratified by early morning urine albumin concentration. Figure 4 shows the individual measurement results for subjects with early morning urine albumin concentrations of 150-600 mg / gCr before treatment. In the control group and the sodium bicarbonate group, urinary IgG concentration increased with treatment, whereas it decreased in the citric acid group, maintaining and improving the filtration function of the renal glomerulus.

[0077] *: Student's t-test or Welch's t-test (two-tailed).

[0078] 3-3) α1-microglobulin Table 4 shows the change in urinary α1-microglobulin when subjects were stratified by early morning urine albumin concentration. Figure 5 shows the individual measurement results for subjects with early morning urine albumin concentrations of 150-600 mg / gCr before treatment. While urinary α1-microglobulin concentrations increased with treatment in the control group, they decreased slightly in the sodium bicarbonate and citric acid groups, maintaining and improving reabsorption function in the renal tubules.

[0079] *: Student's t-test or Welch's t-test (two-tailed).

[0080] 3-4) MCP-1 Table 5 shows the change in urinary MCP-1 when subjects were stratified by early morning urine albumin concentration. Figure 6 shows the individual measurement results for subjects with early morning urine albumin concentrations of 150-600 mg / gCr before treatment. In the control group and the sodium bicarbonate group, urinary MCP-1 concentration increased after treatment, whereas it decreased in the citric acid group, indicating that kidney inflammation was suppressed.

[0081] *: Student's t-test or Welch's t-test (two-tailed) (*: p<0.05; **: p<0.01).

[0082] 3-5) pH Table 6 shows the change in urinary pH when subjects were stratified by early morning urine albumin concentration. Figure 7 shows the individual measurement results for subjects with early morning urine albumin concentrations of 150-600 mg / gCr before treatment. In the control group, there was almost no change in urinary pH due to treatment, but it became alkaline in the sodium bicarbonate formulation group and the citric acid formulation group.

[0083] *: Student's t-test or Welch's t-test (two-tailed) (*: p<0.05).

[0084] From the above, when early morning urine albumin is used as an indicator, it was found that the renal protective effects of citric acid preparations in chronic kidney disease (suppression of urinary protein, maintenance or improvement of glomerular function and tubular function, suppression of inflammation, or alkalinization of urine) are clearly effective in subjects with moderately high pre-treatment urinary albumin concentrations (e.g., 25-600 mg / gCr or 150-600 mg / gCr).

[0085] The treatment provided by the present invention protects the kidney and maintains or improves glomerular function, renal tubular function, and the like.

Claims

1. A pharmaceutical composition for renal protection for treating chronic kidney disease, comprising citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, wherein the urinary albumin concentration of the patient with chronic kidney disease before treatment is within a specific range.

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

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

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

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

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

7. The pharmaceutical composition according to claim 1, wherein the renal protection is suppression of urinary protein, maintenance or improvement of glomerular function or tubular function, suppression of inflammation, or alkalinization of urine.

8. The pharmaceutical composition according to claim 7, wherein the urinary protein is albumin, transferrin, IgG, or α1-microglobulin.

9. The pharmaceutical composition according to claim 7, wherein the suppression of inflammation is suppression of urinary MCP-1 concentration.

10. The pharmaceutical composition according to claim 1 or 2, wherein the citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof is a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof.

11. The pharmaceutical composition of claim 10, further comprising anhydrous citric acid.

12. The pharmaceutical composition according to claim 1 or 2, wherein the citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof is administered at 1 to 3 g / day.

13. The pharmaceutical composition according to claim 1 or 2, wherein the chronic kidney disease is at stage G2 or higher and G3b or lower.

14. The pharmaceutical composition of claim 1 or 2, wherein the citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, is administered for six weeks or more.

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