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

Title of Invention PHARMACEUTICAL COMPOSITION FOR TREATMENT OF CHRONIC KIDNEY DISEASE, WHEREIN URINE ALBUMIN CONCENTRATION BEFORE TREATMENT IS WITHIN SPECIFIC RANGE Technical Field

[0001] The present invention relates to a pharmaceutical composition for renal protection in chronic kidney disease (CKD), including citric acid, a pharmaceutically acceptable salt of citric acid, hydrates thereof, or a mixture thereof, the pharmaceutical composition being for treatment of CKD in a CKD patient whose urine albumin concentration before the treatment is in a specific range. The present application claims priority based on Japanese Patent Application No. 2024-056972 filed in Japan on March 29, 2024, and the contents of the application are incorporated herein by reference. Background Art

[0002] The number of patients with end-stage kidney disease (ESKD) requiring dialysis or transplantation is increasing worldwide. The number is also on an increasing trend in Japan, and the number of dialysis patients at the end of 2022 is about 350,000. CKD is recognized as a pre-ESKD condition. CKD is a concept that encompasses kidney diseases that chronically progress regardless of the primary disease, and is a concept that encompasses all pathological conditions in which there is a decrease in renal function represented by glomerular filtration rate (GFR) or findings suggestive of kidney damage chronically persist (three months or longer). Because CKD is not only a risk for progression to ESKD but also a strong risk for onset of cardiovascular disease (CVD) and the like, early detection of CKD and provision of appropriate treatment are very important. Many CKD treatment methods have been established to date, but treatment remains insufficient, and development of additional renoprotective agents is desired.

[0003] In patients with advanced CKD, the blood bicarbonate ion (HCO3“) concentration decreases and metabolic acidosis develops; therefore, alkalinizing agents such as sodium hydrogen carbonate (sodium bicarbonate) and citric acid preparations are administered. Administration of sodium bicarbonate, which is an alkalinizing agent, has been reported to suppress progression of CKD (Non Patent Literature 1) . In addition, in a nephrotic animal model induced by protein overload, oral administration of sodium bicarbonate has been reported to suppress tubular cell injury caused by acidic urine (Non Patent Literature 2). Furthermore, administration of a citric acid preparation to CKD patients at stages G2 to G3b has been reported to decrease urinary albumin concentration and increase urine pH (Patent Literature 1), and to decrease gene expression of MCP-1 in the kidney in a diabetic animal model (Patent Literature 2). However, because the parameters exhibit large variation due to individual differences, testing using a large number of cases was considered necessary to demonstrate the effect of citric acid preparations. Citation List Patent Literature

[0004] Patent Literature 1: WO 2020 / 080499 Patent Literature 2: WO 2020 / 080451 Non Patent Literature

[0005] Non Patent Literature 1: Brito-Ashurst, I.D., et al.: Bicarbonate supplementation slows progression of CKD and improves nutritional status. J. Am. Soc. Nephrol., 20: 2075-2084, 2009. Non Patent Literature 2: Souma T., et al.: Luminal alkalinization attenuates proteinuria-induced oxidative damage in proximal tubular cells. J. Am. Soc. Nephrol.r 22: 635-648, 2011. Summary of Invention Technical Problem

[0006] One object of the present invention is to select CKD patients for whom treatment with a pharmaceutical composition for renal protection including citric acid, a pharmaceutically acceptable salt of citric acid, hydrates thereof, or a mixture thereof (hereinafter also referred to as "citric acid or the like") is effective. Another object of the present invention is to provide a pharmaceutical composition for renal protection including citric acid or the like for treating the selected CKD patients. Solution to Problem

[0007] The present inventors conducted intensive studies to achieve the above objectives, found that selecting CKD patients based on urine albumin concentration before the treatment is useful for treatment of CKD with a pharmaceutical composition including citric acid or the like, and completed the present invention.

[0008] Accordinglyr the present invention relates to the following : [1] A pharmaceutical composition for renal protection for treatment of chronic kidney disease, including citric acid, a pharmaceutically acceptable salt of citric acid, hydrates thereof, or a mixture thereof, wherein the pharmaceutical composition is for treatment of a chronic kidney disease patient whose urine albumin concentration before the treatment is in a specific range. [2] The pharmaceutical composition according to item [1], wherein the urine albumin concentration of the chronic kidney disease patient before the treatment is in a specific range included in 10 to 1000 mg / gCr. [3] The pharmaceutical composition according to item [1], wherein the urine albumin concentration of the chronic kidney disease patient before the treatment is in a specific range included in 25 to 600 mg / gCr. [4] The pharmaceutical composition according to item [1], wherein the urine albumin concentration of the chronic kidney disease patient before the treatment is in a specific range included in 150 to 600 mg / gCr. [5] The pharmaceutical composition according to any one of items [1] to [4], wherein urine of the chronic kidney disease patient before the treatment is first morning urine . [6] The pharmaceutical composition according to any one of items [1] to [5]r wherein the urine albumin concentration of the chronic kidney disease patient before the treatment is a concentration within two weeks before initiation of the treatment. [7] The pharmaceutical composition according to any one of items [1] to [6]r wherein the renal protection is suppression of urinary protein, maintenance or improvement of glomerular function / 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 al-microglobulin. [9] The pharmaceutical composition according to item [7], wherein the suppression of inflammation is suppression of MCP-1 concentration in urine.

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

[11] The pharmaceutical composition according to item

[10] , further including anhydrous citric acid.

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

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

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

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

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

[13] , wherein the citric acid, the pharmaceutically acceptable salt of citric acid, the hydrate thereof, or the mixture thereof is administered for six weeks or longer. Advantageous Effects of Invention

[0009] By selecting patients based on the urine albumin concentration before treatment with the pharmaceutical composition provided by the present invention (hereinafter referred to as "the present pharmaceutical composition"), CKD patients suitable for treatment with the pharmaceutical composition including citric acid or the like provided by the present invention can be selected. With the pharmaceutical composition including citric acid or the like provided by the present invention, CKD patients whose urine albumin concentration before the treatment is in a specific range (for example, 10 to 1000 mg / gCr) can be effectively treated. Brief Description of Drawings

[0010] [Fig. 1] Fig. 1 is a diagram showing the logarithmically displayed urine albumin concentration before and after six months of treatment with a citric acid preparation. (A) Control group and (B) Citric acid preparation treatment group. [Fig. 2] Fig. 2 is a diagram showing the urinary albumin concentration before and after six months of treatment in CKD patients whose urine albumin concentration before the treatment is 150 mg / gCr or more and less than 600 mg / gCr. (A) Control group, (B) Sodium bicarbonate preparation treatment group, and (C) Citric acid preparation treatment group. [Fig. 3] Fig. 3 is a diagram showing the urinary transferrin concentration before and after six months of treatment in CKD patients whose urine albumin concentration before the treatment is 150 mg / gCr or more and less than 600 mg / gCr. (A) Control group, (B) Sodium bicarbonate preparation treatment group, and (C) Citric acid preparation treatment group. [Fig. 4] Fig. 4 is a diagram showing the urinary IgG concentration before and after six months of treatment in CKD patients whose urine albumin concentration before the treatment is 150 mg / gCr or more and less than 600 mg / gCr. (A) Control group, (B) Sodium bicarbonate preparation treatment group, and (C) Citric acid preparation treatment group . [Fig. 5] Fig. 5 is a diagram showing the urinary al-microglobulin concentration before and after six months of treatment in CKD patients whose urine albumin concentration before the treatment is 150 mg / gCr or more and less than 600 mg / gCr. (A) Control group, (B) Sodium bicarbonate preparation treatment group, and (C) Citric acid preparation treatment group. [Fig. 6] Fig. 6 is a diagram showing the urinary MCP-1 concentration before and after six months of treatment in CKD patients whose urine albumin concentration before the treatment is 150 mg / gCr or more and less than 600 mg / gCr. (A) Control group, (B) Sodium bicarbonate preparation treatment group, and (C) Citric acid preparation treatment group. [Fig. 7] Fig. 7 is a diagram showing urine pH before and after six months of treatment in CKD patients whose urine albumin concentration before the treatment is 150 mg / gCr or more and less than 600 mg / gCr. (A) Control group, (B) Sodium bicarbonate preparation treatment group, and (C) Citric acid preparation treatment group. Description of Embodiments

[0011] Hereinafter, the present invention will be described in detail with reference to specific embodiments. However, the present invention is not limited to the following embodiments and can be carried out in any form without departing from the gist of the present invention.

[0012] Patent gazettes, published patent applications. Non Patent Literatures, and the like cited in the present specification are each incorporated by reference into the present disclosure in the entirety of each cited document for all purposes.

[0013] As used herein, the term " to " as applied to numerical values refers to a range of values falling within a range equal to or greater than specified reference values and equal to or less than specified reference values.

[0014] As used herein, "suppression" is a concept including stopping or slowing worsening or progression of a symptom, condition, or disease, or an act for such stopping or slowing, and also including ameliorating the symptom, condition, or disease, or an act for such amelioration. Here, "amelioration" is a concept including bringing a "pathological" or "abnormal" symptom, condition, or disease closer to a "healthy" or "normal" state, or an act for such bringing, and causing the "pathological" or "abnormal" symptom, condition, or disease to become a "healthy" or "normal" state, or an act for such causing. Therefore, in one embodiment, "amelioration" includes a numerical value serving as an indicator of a "pathological" or "abnormal" symptom or condition becoming smaller or becoming larger in accordance with the "amelioration" to approach a normal value or become a normal value. The "worsening or progression of a symptom, condition, or disease" includes worsening or progression of a "pathological" or "abnormal" symptom, condition, or disease, and worsening or progression from a "healthy" or "normal" state to a "pathological" or "abnormal" symptom, condition, or disease. In one embodiment, "suppression" is stopping or slowing worsening or progression of a symptom, condition, or disease, or an act for such stopping or slowing. In another embodiment, "suppression" is stopping or slowing worsening or progression of a symptom, condition, or disease .

[0015] As used herein, "healthy" represents a state without an acute or chronic disease or disorder, and "normal" represents that a healthy subject is in a normally expressed state. Here, the symptom, condition, or disease is compared before administration of the present pharmaceutical composition and after administration of the present pharmaceutical composition, or comparison is made between administration of the present pharmaceutical composition and administration of a control or placebo.

[0016] As used herein, "treatment" is a concept including eliminating, completely curing, healing, or remitting a "pathological" or "abnormal" symptom, condition, or disease, or an act therefor, including "suppressing" worsening of a "pathological" or "abnormal" symptom, condition, or disease, or an act therefor, and also including "amelioration". Here, "suppression" and "amelioration" have the meanings described above. In one embodiment, "treatment" is eliminating, completely curing, healing, or remitting a "pathological" or "abnormal" symptom, condition, or disease, or an act therefor. In another embodiment, "treatment" is eliminating, completely curing, healing, or remitting a "pathological" or "abnormal" symptom, condition, or disease. As used herein, "prevention" is a concept including preventing onset of a "pathological" or "abnormal" symptom, condition, or disease in advance, or an act therefor.

[0018] As used herein, "chronic kidney disease (CKD)" is a concept that encompasses kidney diseases that chronically progress regardless of the primary disease, and is a concept that encompasses all pathological conditions in which there is a decrease in renal function represented by glomerular filtration rate (GFR) or findings suggestive of kidney damage chronically persist (three months or longer). Examples of primary diseases of CKD include diabetic nephropathy, nephrosclerosis (due to hypertension, aging, or the like), chronic glomerulonephritis (including IgA nephropathy, membranous nephropathy, and the like), polycystic kidney disease, and the like.

[0019] According to the CKD Clinical Practice Guide 2012 (Japanese Journal of Nephrology 2012), the severity of CKD is evaluated by classification based on renal function (GFR: G) and albuminuria / proteinuria. The GFR categories are as follows. G1: GFR is normal or high (^90 mL / min / 1.73 m2) G2: GFR is normal or mildly decreased (60 to 89 G3a: GFR is mildly to moderately decreased (45 to 59 mL / min / 1.73 m2) G3b: GFR is moderately to severely decreased (30 to 44 mL / min / 1.73 m2) G4: GFR is severely decreased (15 to 29 mL / min / 1.73 m2) G5: end-stage kidney disease (ESKD) (<15 mL / min / 1.73 m2)

[0020] The categories based on albumin concentration in urine (albuminuria) are classified as follows using the urine albumin / creatinine (Cr) ratio. Al: normal (less than 30 mg / gCr) A2: microalbuminuria (30 to 299 mg / gCr) A3: overt albuminuria (300 mg / gCr or more) Similarly, the categories based on protein concentration in urine (proteinuria) are classified as follows using the urine protein / creatinine (Cr) ratio. Al: normal (less than 0.15 g / gCr) A2: mild proteinuria (0.15 to 0.49 g / gCr) ((-) to (2+) according to the test strip method) A3: severe proteinuria (0.50 g / gCr or more) ((1+) to (3+) according to the test strip method)

[0021] According to the CKD Clinical Practice Guide 2012 (Japanese Journal of Nephrology 2012)r the severity classification of CKD is expressed using the primary disease and the classifications G and A, for example, as diabetes G2A3, chronic nephritis G3bAl, or the like. However, taking into consideration that the severity of CKD has conventionally been expressed only by stages categorized by GER, the severity of CKD can also be expressed in stages Gl, G2, G3a, G3b, G4, and G5 as in the conventional manner.

[0022] As used herein, "first morning urine" represents the first urine after waking, and "spot urine" represents urine other than the "first morning urine".

[0023] 1. Pharmaceutical composition The present pharmaceutical composition can include, as an active ingredient, citric acid, a pharmaceutically acceptable salt of citric acid, hydrates thereof, or a mixture thereof. Examples of the pharmaceutically acceptable salt of citric acid include alkali metal citrates. Examples of the alkali metal citrates include potassium citrate and sodium citrate, and the alkali metal citrates may each be a hydrate such as stable potassium citrate monohydrate (C6H5K3O7 • H2O) and sodium citrate dihydrate (CeHsNasO? • 2H2O) .

[0024] Examples of preferred active ingredients included in the present pharmaceutical composition include sodium citrate, potassium citrate, hydrates thereof, or a mixture thereof; for example, the active ingredient may be a mixture of potassium citrate monohydrate (C6H5K3O7 • H2O) and sodium citrate dihydrate (CeHsNasCh • 2H2O) . The mixing ratio of potassium citrate monohydrate (C6H5K3O7•H2O) and sodium citrate dihydrate (CeHsNasCh • 2H2O) can be appropriately set by a person skilled in the art; for example, the molar ratio of potassium citrate monohydrate to sodium citrate dihydrate can be 0.01 to 100 of sodium citrate dihydrate relative to 1 of potassium citrate monohydrate. The molar ratio of potassium citrate (for example, potassium citrate monohydrate) to sodium citrate (for example, sodium citrate dihydrate) can be appropriately set by a person skilled in the art; for example, the molar ratio may be 0.85 : 1.15 to 1.15 : 0.85, 0.90 : 1.10 to 1.10 : 0.90, 0.95 : 1.05 to 1.05 : 0.95, or 0.99 : 1.01 to 1.01 : 0.99, and 1 : 1 is preferred. Other examples of the active ingredient included in the present pharmaceutical composition include sodium citrate or a hydrate thereof, and the active ingredient may be, for example, sodium citrate dihydrate (C6HsNa3O7 • 2H2O) . Other examples of the active ingredient included in the present pharmaceutical composition include potassium citrate or a hydrate thereof, and the active ingredient may be, for example, potassium citrate monohydrate (C6H5K3O7-H2O) . In one embodiment, the active ingredient included in the pharmaceutical composition of the present invention may include a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof. In one embodiment, the active ingredient included in the pharmaceutical composition of the present invention may be a mixture of potassium citrate, sodium citrate, and citric acid (for example, anhydrous citric acid). In such a case, the mixing ratio of citric acid (for example, anhydrous citric acid), potassium citrate, and sodium citrate can be appropriately set by a person skilled in the art; for example, the mixing ratio may be 1 : 1.7 to 2.3 : 1.7 to 2.3, 1 : 1.9 to 2.1 : 1.9 to 2.1, or 1 : 1.95 to 2.05 : 1.95 to 2.05, and 1 : 2 : 2 is preferred. In one embodiment, the active ingredient included in the pharmaceutical composition of the present invention may be a mixture of potassium citrate monohydrate (C6H5K3O7 • H2O) , sodium citrate dihydrate (CeHsNasCh • 2H2O) , and anhydrous citric acid. In such a case, the mixing ratio of anhydrous citric acid, potassium citrate monohydrate (C6H5K3O7 • H2O) r and sodium citrate dihydrate (CeHsNasCh • 2H2O) can be appropriately set by a person skilled in the art; for example, the mixing ratio may be 1 : 1.7 to 2.3 : 1.7 to 2.3, 1 : 1.9 to 2.1 : 1.9 to 2.1, or 1 : 1.95 to 2.05 : 1.95 to 2.05, and 1 : 2 : 2 is preferred. In one embodiment, the active ingredient included in the pharmaceutical composition of the present invention may consist only of a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof. As used herein, when mention is made of the weight of citric acid, a pharmaceutically acceptable salt of citric acid, hydrates thereof, or a mixture thereof (for example, potassium citrate monohydrate (C6H5K3O7•H2O) and sodium citrate dihydrate (CeHsNasCh • 2H2O) ) , the weight can be a dry weight.

[0026] The present pharmaceutical composition can be used for renal protection in CKD. Renal protection includes protection of renal tissue and protection of renal function . For example, the present pharmaceutical composition can be a pharmaceutical composition for protection of renal tissue in CKD, a pharmaceutical composition for suppression of renal tissue injury accompanying progression of CKD, a pharmaceutical composition for maintenance or improvement of renal function in CKD, or a pharmaceutical composition for suppression of deterioration of renal function accompanying progression of CKD. Examples of renal tissue protected by the present pharmaceutical composition include a nephron, or a renal tubule (for example, a proximal tubule) or a glomerulus constituting a nephron. Examples of renal function maintained or improved by the present pharmaceutical composition include the function of a nephron that produces urine from blood, namely, filtration function by a glomerulus, reabsorption function by a renal tubule (for example, proximal tubular function), and urine pH-regulating function that suppresses acidification of urine and alkalinizes urine. Examples of renal function maintained or improved by the present pharmaceutical composition also include nephron function, glomerular function, and tubular function (for example, proximal tubular function), and include filtration function, reabsorption function, and urine pH-regulating function (alkalinization of urine). Thus, the present pharmaceutical composition can be a pharmaceutical composition for maintenance or improvement of nephron function in CKD, a pharmaceutical composition for suppression of deterioration of glomerular function and tubular function accompanying progression of CKD, a pharmaceutical composition for maintenance or improvement of filtration function, reabsorption function, and urine pH-regulating function in CKD, or a pharmaceutical composition for suppression of deterioration of filtration function, reabsorption function, and urine pH-regulating function accompanying progression of CKD.

[0027] Such effects of the present pharmaceutical composition can be confirmed by administering the present pharmaceutical composition to chronic kidney patients whose albumin concentration in urine before treatment with the present pharmaceutical composition is within a specific range and evaluating the renal function of the CKD patients. That is, when chronic kidney patients whose albumin concentration in urine before treatment with the present pharmaceutical composition is within a specific range are treated by administering the present pharmaceutical composition, the renal function of the chronic kidney patients after treatment is improved compared with the renal function before treatment, or the renal function after treatment by administering the present pharmaceutical composition is higher than the renal function of control chronic kidney patients to whom the present pharmaceutical composition has not been administered. To examine renal function, evaluation can be performed by measuring, for example, glomerular filtration rate (GFR)r urinary protein, various mediators in urine (inflammation, fibrosis, blood pressure), or urine pH by a method known in the art. Examples of urinary protein include albumin, transferrin, al-glycoprotein, hemoglobin, myoglobin, immunoglobulins (IgG, IgM, IgA, and the like), Bence Jones protein, |32-microglobulin, al-microglobulin, retinol-binding protein, lysozyme, and protein-like substances (albumose, acetic acid bodies, mucin, and the like); among the urinary proteins, albumin, transferrin, al-glycoprotein, immunoglobulins (IgG, IgM, IgA, and the like), and the like are mainly associated with glomerular lesions (glomerular function) , and |32-microglobulin, al-microglobulin, retinol-binding protein, and lysozyme are mainly associated with tubular lesions (tubular function). Examples of inflammation mediators include inflammatory cytokines (MCP-1, IL-1|3, IL-6, TNF-a, and the like), and the like. Examples of fibrosis mediators include TGF-p. Examples of blood pressure mediators include angiotensinogen, and angiotensin I and II. The urinary proteins and various mediators in urine can be measured using, for example, a dye method, enzyme immunoassays such as an ELISA method, a chemiluminescent enzyme immunoassay (CLEIA), immunoturbidimetry, immunonephelometry, a double immunodiffusion method (DID method), a latex agglutination method, test strips, or the like, and measurement can also be commissioned to a known testing institution such as SRL, Inc. Furthermore, urinary proteins and various mediators in urine can be corrected by dividing by the urinary creatinine concentration.

[0028] For example, when the GFR of a CKD patient is high as compared with before administration or with a control CKD patient by administering the present pharmaceutical composition to a CKD patient whose albumin concentration in urine before treatment with the present pharmaceutical composition is within a specific range, renal tissue may be evaluated as having been protected by the present pharmaceutical composition. That is, one aspect of the present invention is a pharmaceutical composition for renal protection for treatment for improving GFR in chronic kidney disease, including citric acid, a pharmaceutically acceptable salt of citric acid, hydrates thereof, or a mixture thereof, wherein the pharmaceutical composition is for treatment of a chronic kidney disease patient whose urine albumin concentration before the treatment is in a specific range. Improvement of GFR may be suppression of decrease, maintenance, or increase as compared with the GFR of a CKD patient before administration or a control CKD patient. The albumin concentration in urine can be measured, for example, by immunoturbidimetry and can be corrected with creatinine.

[0029] For example, when urinary protein (albumin, transferrin, al-glycoprotein, hemoglobin, myoglobin, IgG, IgM, IgA, Bence Jones protein, |32-microglobulin, al-microglobulin, retinol-binding protein, lysozyme, proteinlike substances, or the like) of a CKD patient is low as compared with before administration or with a control CKD patient by administering the present pharmaceutical composition to a CKD patient whose albumin concentration in urine before treatment with the present pharmaceutical composition is within a specific range, renal tissue may be evaluated as having been protected by the present pharmaceutical composition. That is, one aspect of the present invention is a pharmaceutical composition for renal protection for treatment for improving urinary protein in chronic kidney disease, including citric acid, a pharmaceutically acceptable salt of citric acid, hydrates thereof, or a mixture thereof, wherein the pharmaceutical composition is for treatment of a chronic kidney disease patient whose urine albumin concentration before the treatment is in a specific range. The urinary protein may be albumin, transferrin, al-glycoprotein, hemoglobin, myoglobin, IgG, IgM, IgA, Bence Jones protein, |32- microglobulin, al-microglobulin, retinol-binding protein, lysozyme, or a protein-like substance. Improvement of urinary protein may be suppression of increase, maintenance, or decrease as compared with the urinary protein of a CKD patient before administration or a control CKD patient. The albumin concentration in urine can be measured, for example, by immunoturbidimetry and can be corrected with creatinine.

[0030] For example, when an inflammation mediator (MCP-1, IL-113, IL-6, TNF-a, or the like) , a fibrosis mediator (TGF-|3 or the like) , or a blood pressure mediator (angiotensinogen, angiotensin I or II, or the like) in urine of a CKD patient is low as compared with before administration or with a control CKD patient by administering the present pharmaceutical composition to a CKD patient whose albumin concentration in urine before treatment with the present pharmaceutical composition is within a specific range, renal tissue may be evaluated as having been protected by the present pharmaceutical composition. That is, one aspect of the present invention is a pharmaceutical composition for renal protection for treatment for improving the mediators in chronic kidney disease, including citric acid, a pharmaceutically acceptable salt of citric acid, hydrates thereof, or a mixture thereof, wherein the pharmaceutical composition is for treatment of a chronic kidney disease patient whose urine albumin concentration before the treatment is in a specific range. Improvement of the mediators may be suppression of increase, maintenance, or decrease as compared with the urinary protein of a CKD patient before administration or a control CKD patient. The albumin concentration in urine can be measured, for example, by immunoturbidimetry and can be corrected with creatinine.

[0031] For example, when the urine pH of a CKD patient is high as compared with before administration or with a control CKD patient by administering the present pharmaceutical composition to a CKD patient whose albumin concentration in urine before treatment with the present pharmaceutical composition is within a specific range, renal tissue may be evaluated as having been protected by the present pharmaceutical composition. That is, one aspect of the present invention is a pharmaceutical composition for renal protection for treatment for alkalinizing urine pH in chronic kidney disease, including citric acid, a pharmaceutically acceptable salt of citric acid, hydrates thereof, or a mixture thereof, wherein the pharmaceutical composition is for treatment of a chronic kidney disease patient whose urine albumin concentration before the treatment is in a specific range. Alkalinization of urine pH may be suppression of decrease, maintenance, or increase as compared with the urine pH of a CKD patient before administration or a control CKD patient. The albumin concentration in urine can be measured, for example, by immunoturbidimetry and can be corrected with creatinine .

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

[0033] One aspect of the present invention is a pharmaceutical composition for renal protection for treatment of CKD, including citric acid, a pharmaceutically acceptable salt of citric acid, hydrates thereof, or a mixture thereof, wherein the pharmaceutical composition is for treatment of a CKD patient whose urine albumin concentration before the treatment is in 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. The albumin concentration in urine can be measured, for example, by immunoturbidimetry and can be corrected with creatinine.

[0034] One aspect of the present invention is a pharmaceutical composition for renal protection for treatment of CKD, including citric acid, a pharmaceutically acceptable salt of citric acid, hydrates thereof, or a mixture thereof, wherein the pharmaceutical composition is for treatment of a CKD patient whose urine albumin concentration before the treatment is 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, 10 to 600 mg / gCr, 25 to 600 mg / gCr, 100 to 600 mg / gCr, or 150 to 600 mg / gCr. The albumin concentration in urine can be measured, for example, by immunoturbidimetry and can be corrected with creatinine.

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

[0036] Physiological urinary protein excretion in healthy individuals is less than 0.1 g / gCr, and urinary excretion of 0.15 g / gCr or more is called proteinuria; among proteinuria, a range of 0.15 mg / gCr or more and 0.49 mg / gCr or less is called mild proteinuria ((-) to (2+) according to the test strip method), 0.50 or more is called severe proteinuria ((1+) to (3+) according to the test strip method), and 3.5 or more is called nephrosis ((3+) to (4+) according to the test strip method). The urine protein concentration can be determined by measurement using a method known in the art, such as a dye method (pyrogallol red method or the like) or a test strip method (for example, MyUliace (registered trademark) manufactured by Terumo Corporation or the like can be applied). The present pharmaceutical composition can be used for CKD patients whose symptom before treatment with the pharmaceutical composition is mild proteinuria ((-) to (2+) according to the test strip method) or severe proteinuria ((1+) to (3+) according to the test strip method). The present pharmaceutical composition can also be used for CKD patients whose symptom before treatment with the pharmaceutical composition is mild proteinuria ((-) to (2+) according to the test strip method).

[0037] To select CKD patients to be treated with the present pharmaceutical composition, urine of the patients is collected. The urine may be first morning urine or spot urine. One aspect of the present invention is a pharmaceutical composition for renal protection for treatment of CKD, including citric acid, a pharmaceutically acceptable salt of citric acid, hydrates thereof, or a mixture thereof, wherein the pharmaceutical composition is for treatment of a CKD patient whose first morning urine albumin concentration before the treatment is in a specific range, and another aspect of the present invention is a pharmaceutical composition for renal protection for treatment of CKD, including citric acid, a pharmaceutically acceptable salt of citric acid, hydrates thereof, or a mixture thereof, wherein the pharmaceutical composition is for treatment of a CKD patient whose spot urine albumin concentration before the treatment is in a specific range.

[0038] The pharmaceutical composition of the present invention is used for treatment of a CKD patient whose urine albumin concentration before treatment with the pharmaceutical composition is in a specific range. The urine albumin concentration only needs to be measured by immunoturbidimetry or the like before initiation of the treatment, and may be, for example, the urine albumin concentration within 1 month, within 3 weeks, within 2 weeks, within 10 days, within 1 week, within 5 days, within 3 days, within 2 days before initiation of the treatment, or on the day of initiation of the treatment. Another aspect of the present invention is a pharmaceutical composition for renal protection for treatment of CKD, including citric acid, a pharmaceutically acceptable salt of citric acid, hydrates thereof, or a mixture thereof, wherein the pharmaceutical composition is for treatment of a CKD patient whose urine albumin concentration within 1 month, within 3 weeks, within 2 weeks, within 10 days, within 1 week, within 5 days, within 3 days, within 2 days before initiation of the treatment, or on the day of initiation of the treatment is in a specific range.

[0039] The present pharmaceutical composition is administered orally or parenterally to humans or other mammals, and examples of parenteral administration include intravenous administration, subcutaneous administration, intramuscular administration, intraarticular administration, transmucosal administration, transdermal administration, intranasal administration, rectal administration, intrathecal administration, intraperitoneal administration, and topical administration.

[0040] The present pharmaceutical composition may be prepared by mixing citric acid, a pharmaceutically acceptable salt of citric acid, hydrates thereof, or a mixture thereof, which is an active ingredient, as is, or with a pharmaceutically acceptable carrier, for example, an excipient (for example, lactose, D-mannitol, crystalline cellulose, or glucose), a binder (for example, hydroxypropylcellulose (HPC), gelatin, or polyvinylpyrrolidone (PVP)), a lubricant (for example, magnesium stearate or talc), a disintegrant (for example, starch or calcium carboxymethylcellulose (CMC-Ca)), a diluent (for example, water for injection or physiological saline), or, when necessary, other additives (for example, a pH adjuster, a surfactant, a solubilizer, a preservative, an emulsifier, an isotonic agent, or a stabilizer), and can be a preparation such as a tablet, capsule, suspension, injection, or suppository. To form tablets, for example, citric acid, a pharmaceutically acceptable salt of citric acid, hydrates thereof, or a mixture thereof, which is an active ingredient, may be mixed with an excipient (for example, lactose, D-mannitol, crystalline cellulose, or glucose), a disintegrant (for example, starch or calcium carboxymethylcellulose (CMC-Ca)), a binder (for example, hydroxypropylcellulose (HPC), gelatin, or polyvinylpyrrolidone (PVP)), a lubricant (for example, magnesium stearate or talc), or the like, and formulated.

[0041] In one aspect of the present invention, the present pharmaceutical composition is a tablet. The tablet provided by the present invention may include, in addition to citric acid, a pharmaceutically acceptable salt of citric acid, hydrates thereof, or a mixture thereof (for example, 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), which is an active ingredient, a pharmaceutically acceptable additive that is conventional in the pharmaceutical field. Examples of such additives include excipients, binders, disintegrants, glidants, flavoring agents, lubricants, pH adjusters, surfactants, stabilizers, and fragrances. The content of citric acid, a pharmaceutically acceptable salt of citric acid, hydrates thereof, or a mixture thereof, which is an active ingredient 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 relative to the tablet.

[0042] The present pharmaceutical composition can be produced by a method known in the pharmaceutical field. In one embodiment, the hardness of the obtained tablet can be 10 to 200 N, preferably 30 to 150 N.

[0043] The amount of citric acid, a pharmaceutically acceptable salt of citric acid, hydrates thereof, or a mixture thereof, which is an active ingredient in the present pharmaceutical composition, can be appropriately set. In one embodiment, the amount of citric acid, a pharmaceutically acceptable salt of citric acid, hydrates thereof, or a mixture thereof, which is an active ingredient in the present pharmaceutical composition, may be set so that the dose of citric acid, a pharmaceutically acceptable salt of citric acid, hydrates thereof, or a mixture thereof, which is an active ingredient, is an amount by which acidic urine in gout or hyperuricemia is improved by administration to humans, or an amount smaller than that; for example, the amount may be set to be 1 to 50%, or 10 to 20%, of the daily dose approved in Japan for improvement of acidic urine in gout or hyperuricemia (for example, one tablet including 231.5 mg of potassium citrate (C6H5K3O7 •H2O) and 195.0 mg of sodium citrate hydrate (CeHsNasCh • 2H2O) per tablet is orally administered at two tablets per dose, three times daily; when the alkalinizing agent is sodium bicarbonate: 3 to 5 g is orally administered daily).

[0044] In one aspect of the present invention, the present pharmaceutical composition is a tablet and may include 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 one tablet. In one embodiment, the present pharmaceutical composition is a tablet and may include potassium citrate monohydrate and sodium citrate dihydrate each at 10 mg to 300 mg in one tablet, in a total amount of 20 mg to 600 mg, preferably each at 150 mg to 250 mg, in a total amount of 400 mg to 500 mg, and more preferably each at 190 mg to 240 mg, in a total amount of 400 mg to 450 mg.

[0045] In one aspect of the present invention, the present pharmaceutical composition is a tablet and may include 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and may include, as additives, anhydrous citric acid, crystalline cellulose, partially pregelatinized starch, hydroxypropylcellulose, magnesium stearate, hypromellose, macrogol 6000, titanium oxide, and carnauba wax.

[0046] In one aspect of the present invention, a tablet including 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate may be one dosage unit. As used herein, "dosage unit" represents a unit of a preparation, and "one dosage unit" represents the minimum unit of a preparation. Accordingly, for example, for a tablet, the dosage unit is each tablet, and one dosage unit represents one tablet. For an injection, the dosage unit is an injection contained in a sealed container such as an ampule or vial, and one dosage unit represents an injection contained in one sealed container such as an ampule or vial. When the present pharmaceutical composition is administered to humans or other mammals, one or two or more of the dosage units may be administered per dose, and the one dosage unit may be divided and administered.

[0047] The dose of citric acid, a pharmaceutically acceptable salt of citric acid, hydrates thereof, or a mixture thereof, which is an active ingredient, is appropriately determined according to administration method, age, body weight, sex, symptoms, sensitivity to a drug, or the like of an administration subject, and the dose may be adjusted according to the state of improvement of symptoms . In one aspect of the present invention, when a mixture of potassium citrate monohydrate and sodium citrate dihydrate is orally administered to a human, half the daily dose approved in Japan for improvement of acidic urine in gout and hyperuricemia (for example, in the case of a citric acid preparation: one tablet including 231.5 mg of potassium citrate (C6H5K3O7 • H2O) and 195.0 mg of sodium citrate hydrate (CeHsNasCh • 2H2O) per tablet is orally administered at two tablets per dose, three times daily) may be used as the daily dose.

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

[0049] In one aspect of the present invention, when a mixture of potassium citrate monohydrate and sodium citrate dihydrate is orally administered to a human, administration may be started with half the daily dose approved in Japan for improvement of acidic urine in gout and hyperuricemia (for example, in the case of a citric acid preparation: one tablet including 231.5 mg of potassium citrate (C6H5K3O7 •H2O) and 195.0 mg of sodium citrate hydrate (CeHsNasCh • 2H2O) per tablet is orally administered at two tablets per dose, three times daily) as the daily dose, and then the dose may be increased up to the daily dose approved in Japan for improvement of acidic urine in gout and hyperuricemia.

[0050] In one aspect 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 each be administered at 0.1 to 5 g / day, in a total amount of 0.2 to 10 g / day, each at 0.1 to 3 g / day, in a total amount of 0.2 to 6 g / day, each at 0.5 to 3 g / day, in a total amount of 1 to 6 g / day, preferably each at 0.5 to 1.5 g / day, in a total amount of 1 to 3 g / day, each at 1 to 1.5 g / day, in a total amount of 2 to 3 g / day, or each at 0.5 to 1 g / day, in a total amount of 1 to 2 g / day, and may be administered in one to five doses daily, preferably three doses daily.

[0051] In one aspect of the present invention, when potassium citrate monohydrate or sodium citrate dihydrate is orally administered to a human as an active ingredient, 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 may be administered, and may be administered in one to five doses daily, preferably three doses daily.

[0052] In one aspect of the present invention, citric acid, a pharmaceutically acceptable salt of citric acid, hydrates thereof, or a mixture thereof, which is an active ingredient, may be administered for a long term; for example, the active ingredient is administered for 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 longer, 2 weeks or longer, 3 weeks or longer, 6 weeks or longer, 8 weeks or longer, 10 weeks or longer, 12 weeks or longer, 24 weeks or longer, 40 weeks or longer, 60 weeks or longer, 80 weeks or longer, 100 weeks or longer, 120 weeks or longer, 6 weeks or longer and 24 weeks or shorter, 12 weeks or longer and 24 weeks or shorter, 6 weeks or longer and 30 weeks or shorter, 12 weeks or longer and 30 weeks or shorter, 6 weeks or longer and 40 weeks or shorter, 12 weeks or longer and 40 weeks or shorter, 6 weeks or longer and 60 weeks or shorter, 12 weeks or longer and 60 weeks or shorter, 6 weeks or longer and 80 weeks or shorter, 12 weeks or longer and 80 weeks or shorter, 6 weeks or longer and 100 weeks or shorter, 12 weeks or longer and 100 weeks or shorter, 6 weeks or longer and 120 weeks or shorter, or 12 weeks or longer and 120 weeks or shorter .

[0053] In one aspect of the present invention, with the present pharmaceutical composition, a beneficial effect (for example, a renal protective effect) for a CKD patient can be detected by continuous administration for 6 weeks, continuous administration for 12 weeks, and / or continuous administration for 24 weeks. In one aspect of the present invention, the present pharmaceutical composition is administered to early CKD patients with low severity. In one aspect of the present invention, the present pharmaceutical composition is administered to CKD patients whose urine albumin concentration before treatment with the pharmaceutical composition is in a specific range and who are at stage G3b or lowerr preferably stage G2 or lower. In one aspect of the present invention, the present pharmaceutical composition is administered to CKD patients whose urine albumin concentration before treatment with the pharmaceutical composition is in a specific range and who are at stage G2 or higher and stage G3b or lower (for example, stages G2 and G3a; or stages G2, G3a, and G3b). The albumin concentration in urine can be measured, for example, by immunoturbidimetry and can be corrected with creatinine .

[0055] In one aspect of the present invention, the present pharmaceutical composition is administered to progressive CKD patients whose urine albumin concentration before treatment with the pharmaceutical composition is in a specific range. In one aspect of the present invention, the present pharmaceutical composition is administered to CKD patients with hypertension whose urine albumin concentration before treatment with the pharmaceutical composition is in a specific range. In one aspect of the present invention, the present pharmaceutical composition is administered to patients with diabetic nephropathy whose urine albumin concentration before treatment with the pharmaceutical composition is in a specific range. In one aspect of the present invention, the present pharmaceutical composition is administered to patients with nephrosclerosis (due to hypertension, aging, or the like) whose urine albumin concentration before treatment with the pharmaceutical composition is in a specific range. In one aspect of the present invention, the present pharmaceutical composition is administered to patients with chronic glomerulonephritis (including IgA nephropathy, membranous nephropathy, and the like) whose urine albumin concentration before treatment with the pharmaceutical composition is in a specific range. In one aspect of the present invention, the present pharmaceutical composition is administered to patients with polycystic kidney disease whose urine albumin concentration before treatment with the pharmaceutical composition is in a specific range. The albumin concentration in urine can be measured, for example, by immunoturbidimetry and can be corrected with creatinine . In one aspect of the present invention, the present pharmaceutical composition is administered to patients receiving treatment according to the CKD Clinical Practice Guide. For example, the present pharmaceutical composition is administered to patients receiving blood pressure management (administration of RA system inhibitors such as ARBs and ACE inhibitors, diuretics, calcium channel blockers, or the like), proteinuria countermeasures (administration of RA system inhibitors or the like), blood glucose level management (administration of a-glucosidase inhibitors or the like), lipid management (administration of statins, fibrates, or the like), anemia management (administration of erythropoietin or the like), and / or bone / mineral countermeasures (administration of bisphosphonates or the like) according to the CKD Clinical Practice Guide. In one aspect of the present invention, the present pharmaceutical composition is used in combination with an antihypertensive drug (for example, an ARB, an ACE inhibitor, a diuretic, or a calcium channel blocker). In one embodiment, the present pharmaceutical composition is used in combination with spherical adsorptive carbon obtained by subjecting spherical fine porous carbon derived from petroleum-based hydrocarbons to oxidation and reduction treatment at high temperature (sold in Japan as Kremezin (registered trademark)).

[0057] 2 . Food composition In one aspect of the present invention, a food composition provided by the present invention includes citric acid, a pharmaceutically acceptable salt of citric acid, hydrates thereof, or a mixture thereof, is ingested by a human whose urine albumin concentration before ingestion of the food composition is in a specific range, and exerts an effect of protecting the kidney or maintaining health. In one aspect of the present invention, the food composition provided by the present invention exerts an effect of suppressing urinary protein in the kidney, maintaining or improving glomerular function / tubular function, suppressing inflammation, or alkalinizing urine. Regarding the active ingredient, the active ingredient described in "1. Pharmaceutical composition" above can be applied. For example, the food composition provided by the present invention can be a food composition including an alkali metal citrate, a hydrate thereof, or a mixture thereof, preferably a mixture of potassium citrate monohydrate (C6H5K3O7 • H2O) and sodium citrate dihydrate (CeHsNasO? • 2H2O) . The albumin concentration in urine can be measured, for example, by immunoturbidimetry and can be corrected with creatinine.

[0058] The content of citric acid, a pharmaceutically acceptable salt of citric acid, hydrates 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 the food composition include foods for specified health uses, foods with function claims, foods for hospital patients, and supplements. Forms of the food composition are not particularly limited as long as the forms include an effective amount of citric acid, a pharmaceutically acceptable salt of citric acid, hydrates thereof, or a mixture thereof for exerting the effects and are orally ingestible forms, and the forms may be ordinary food and drink forms, or may be provided as preparations suitable for oral administration among preparations applicable to the pharmaceutical composition, for example, preparations such as tablets, capsules, or suspensions. With respect to the configuration and production method of the preparations, the configuration and production method of the pharmaceutical preparations described in "1. Pharmaceutical composition" above can be applied as is herein, and formulation techniques known per se in the field of pharmaceutical formulation techniques can also be applied.

[0059] For example, in the case of foods for specified health uses, foods with function claims, foods for hospital patients, or supplements, one serving of food may include, as active ingredients, one-third of a total of 1 to 3 g of potassium citrate monohydrate and sodium citrate dihydrate, or may include, as an active ingredient, one-third of 1 to 6 g of sodium bicarbonate. When a food for specified health uses, a food with function claims, a food for hospital patients, or a supplement is provided as tablets, for example, a 300 mg to 600 mg tablet per tablet may include 70 to 80% by weight of citric acid, a pharmaceutically acceptable salt of citric acid, hydrates thereof, or a mixture thereof.

[0060] When the food composition provided by the present invention is not formulated and is provided as an ordinary food or drink form, the food composition can be appropriately produced by a person skilled in the art depending on the type of the food, and can be produced, for example, by blending citric acid, a pharmaceutically acceptable salt of citric acid, hydrates thereof, or a mixture thereof into a food material. Examples of the food and drink forms include liquid, milky, or paste-like foods such as beverages, soy sauce, milk, yogurt, and miso; semisolid foods such as jelly and gummies; solid foods such as candy, gum, tofu, and supplements; powdery foods; and the like. Examples of beverages include fruit juice / fruit beverages, coffee beverages, oolong tea beverages, green tea beverages, black tea beverages, barley tea beverages, vegetable beverages, carbonated beverages that are soft drinks, fruit-extract-containing beverages, vegetableextract-containing juices, near water, sports beverages, diet beverages, and the like.

[0061] Additives such as antioxidants, fragrances, 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, floral nectar extracts, pH adjusters, and quality stabilizers can be blended into beverages alone or in combination .

[0062] The term "administration" described in "1. Pharmaceutical composition" above can also be applied to a case in which the "food composition" according to the present invention is ingested, that is, regarding the "food composition" according to the present invention, the term "administration" can be read as "ingestion". Therefore, for example, terms such as "administer" and "is administered" can be read with inflection according to context as "cause to ingest", "ingest", "is ingested", and the like.

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

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

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

[0066] Hereinafter, the present invention will be further described by Examples, but the present invention is not limited to the Examples. Examples

[0067] To investigate effects of oral administration of a potassium citrate / sodium citrate hydrate combination preparation (hereinafter referred to as "citric acid preparation"), which is an oral alkalinizing agent, and a sodium bicarbonate preparation, a human clinical trial was conducted (Patent Literature 1).

[0068] 1. Method Patients with stage G2 to G3b chronic kidney disease (CKD) (eGFR: 30 to 89 mL / min / 1.73 m2) were randomly divided into a citric acid preparation group, a sodium bicarbonate preparation group, and a control group. Patients were assigned to each group so that age, sex, presence or absence of diabetes, and eGFR were not biased. Each group received treatment based on "CKD Clinical Practice Guide -Summary of Treatment" (hereinafter referred to as standard treatment).

[0069] No alkalinizing agent was administered to the control group. To the citric acid preparation group, tablets containing 231.5 mg of potassium citrate (C6H5K3O7 •H2O) and 195.0 mg of sodium citrate hydrate (CeHsNaaO? •2H2O) were orally administered at three tablets daily, in three doses daily (morning, noon, and evening), for six months (24 weeks). In addition, pH management of first morning urine was performed over time, and in cases in which first morning urine was less than pH 6.5, the dose could be increased as appropriate up to six tablets daily, in three doses daily (morning, noon, and evening), at the physician’s discretion. To the sodium bicarbonate preparation group, tablets containing 500 mg of sodium bicarbonate were orally administered at three tablets daily, in three doses daily (morning, noon, and evening), for six months (24 weeks). In addition, pH management of first morning urine was performed over time, and in cases in which first morning urine was less than pH 6.5, the dose could be increased as appropriate up to six tablets daily, in three doses daily (morning, noon, and evening), at the physician’s discretion.

[0070] First morning urine was collected before initiation of administration (on the day of initiation of administration) and 24 weeks after initiation of administration. Creatinine concentration (Determiner L CRE, manufactured by Canon Medical Diagnostics Inc.), albumin (Auto Wako Microalbumin, manufactured by FUJIFILM Wako Pure Chemical Corporation), transferrin (N-Assay LA Micro Tf Nittobo, manufactured by Nittobo Medical Co., Ltd.), immunoglobulin IgG (MK136, manufactured by Takara Bio Inc.), al-microglobulin (LZ Test (registered trademark) 'Eiken' al-M, manufactured by Eiken Chemical Co., Ltd.), and MCP-1 (Quantikine (registered trademark) Human MCP-1 Immunoassay, manufactured by R&D SYSTEMS, Inc.) were measured at SRL, Inc. Each measured value was corrected by dividing by the creatinine concentration. Changes in each parameter associated with treatment were calculated by subtracting measured values before the treatment from measured values after the treatment.

[0071] 2. Stratification of subjects based on albumin concentration in first morning urine Fig. 1 shows changes in the albumin concentration in first morning urine of each subject before and after treatment in logarithmic display. In the control group, the urine albumin concentration increased before and after treatment (119+318^153+333 mg / gCr (n=31); change before and after treatment was 341148 mg / gCr), whereas the urine albumin concentration decreased with treatment using the citric acid preparation (1031198^891203 mg / gCr (n=29); change before and after treatment was -14159 mg / gCr).

[0072] Upon detailed analysis of the changes in each subject, subjects with a low urine albumin concentration before the treatment had little change in the urine albumin concentration before and after the treatment period in both the control group and the citric acid preparation group. For example, Table 1 shows results for subjects whose urine albumin concentration before the treatment was 10 mg / gCr or less . By contrast, in subjects whose urine albumin concentration before the treatment was relatively moderately high, the urine albumin concentration increased during the treatment period in the control group, whereas the suppressive effect was evident in the citric acid preparation group. For example, results for subjects whose urine albumin concentration before the treatment was 25 to 600 mg / gCr or 150 to 600 mg / gCr are shown in Table 1, and results for subjects whose urine albumin concentration before the treatment was 150 to 600 mg / gCr are shown in Fig . 2. When the sodium bicarbonate preparation was administered instead of the citric acid preparation, no decrease in the change in urine albumin before and after the treatment period was observed even when the subjects were stratified (overall: 501132 mg / gCr (n=31); subjects whose first morning urine albumin concentration before the treatment was 25 to 600 mg / gCr: 1091179 mg / gCr (n=14); subjects whose first morning urine albumin concentration before the treatment was 150 to 600 mg / gCr: 3371161 mg / gCr (n=3)). Individual measurement results for subjects whose first morning urine albumin concentration before the treatment was 150 to 600 mg / gCr are shown in Fig. 2; in the control group and the sodium bicarbonate preparation group, the albumin concentration in urine increased with treatment, whereas the albumin concentration decreased in the citric acid preparation group. From the above, when first morning urine albumin was used as an indicator, the effect of the citric acid preparation was found to show a clear effect on subjects whose urine albumin concentration before the treatment was moderately high (for example, 25 to 600 mg / gCr or 150 to 600 mg / gCr).

[0073] [Table 1] Subject stratum Change in first morning urine albumin (mg / gCr) Significant difference# (p value) Control group (n) Citric acid preparation group (n) Overall 34 ± 148 (31) -14 ± 59 (29) 0.10 up to 10 1.0 ± 4.3 (16) 1.6 ± 8.0(15) 0.62 25 to 600 124 ± 200 (11) -56 ± 77* (9) 0.02 150 to 600 380 ± 54(4) -116 ± 64** (4) 0.00 *: Student’s t-test or Welch’s t-test (two-sided) (* : p < 0.05; ** : p < 0.01).

[0074] 3. Effect on other parameters 3-1) Transferrin Table 2 shows changes in urinary transferrin when the subjects were stratified by albumin concentration in first morning urine. Individual measurement results for subjects whose first morning urine albumin concentration before the treatment was 150 to 600 mg / gCr are shown in Fig. 3; in the control group and the sodium bicarbonate preparation group, the transferrin concentration in urine increased with treatment, whereas the transferrin concentration decreased in the citric acid preparation group, and glomerular filtration function in the kidney was maintained or improved.

[0075] [Table 2] Subject stratum Change in first morning urine transferrin (mg / gCr) Significant difference# (p value) Control group (n) Citric acid preparation group (n) Overall 1.77 ± 9.43(31) -0.94 ± 3.24(29) 0.14 up to 10 0.07 ± 0.41(16) 0.12 ± 0.55 (14) 0.78 25 to 600 6.82 ± 12.9(11) -2.99 ± 4.29* (9) 0.04 150 to 600 23.0 ± 3.00 (4) -6.04 ± 3.44**(4) 0.00 *: Student’s t-test or Welch’s t-test (two-sided) (* : p < 0.05; ** : p < 0.01).

[0076] 3-2) Immunoglobulin (IgG) Table 3 shows changes in urinary IgG when the subjects were stratified by albumin concentration in first morning urine. Individual measurement results for subjects whose first morning urine albumin concentration before the treatment was 150 to 600 mg / gCr are shown in Fig. 4; in the control group and the sodium bicarbonate preparation group, the IgG concentration in urine increased with treatment, whereas the IgG concentration decreased in the citric acid preparation group, and glomerular filtration function in the kidney was maintained or improved.

[0077] [Table 3] Subject stratum Change in first morning urine IgG (ug / gCr) Significant difference# (p value) Control group (n) Citric acid preparation group (n) Overall -91.6 ± 1926 (29) 327 ± 2369 (28) 0.47 up to 10 69.3 1 501 (16) 660 ± 2578 (14) 0.43 25 to 600 -99.6 ± 3063 (10) -266 ± 2308 (9) 0.90 150 to 600 3171 ± 1704 (3) -963 ± 2009 (4) 0.06 *: Student’s t-test or Welch’s t-test (two-sided).

[0078] 3-3) al-Microglobulin Table 4 shows changes in urinary al-microglobulin when the subjects were stratified by albumin concentration in first morning urine. Individual measurement results for subjects whose first morning urine albumin concentration before the treatment was 150 to 600 mg / gCr are shown in Fig. 5; in the control group, the al-microglobulin concentration in urine increased with treatment, whereas the al-microglobulin concentration slightly decreased in the sodium bicarbonate preparation group and the citric acid preparation group, and reabsorption function in renal tubules was maintained or improved.

[0079] [Table 4] Subject stratum Change in first morning urine al-microglobulin (mg / gCr) Significant difference# (p value) Control group (n) Citric acid preparation group (n) Overall -0.07 ± 4.76 (31) 0.04 ± 2.29 (29) 0.91 up to 10 0.17 ± 1.69(16) -0.05 ± 1.47(14) 0.72 25 to 600 -0.53 ± 7.57 (11) -0.11 ± 3.14(9) 0.88 150 to 600 2.74 ± 1.00(3) -0.13 ± 2.84(4) 0.14 *: Student’s t-test or Welch’s t-test (two-sided).

[0080] 3-4) MCP-1 Table 5 shows changes in urinary MCP-1 when the subjects were stratified by albumin concentration in first morning urine. Individual measurement results for subjects whose first morning urine albumin concentration before the treatment was 150 to 600 mg / gCr are shown in Fig. 6; in the control group and the sodium bicarbonate preparation group, the MCP-1 concentration in urine increased with treatment, whereas the MCP-1 concentration decreased in the citric acid preparation group, and inflammation in the kidney was suppressed.

[0081] [Table 5] Subject stratum Change in first morning urine MCP-1 (ng / gCr) Significant difference# (p value) Control group (n) Citric acid preparation group (n) Overall -57.6 ± 337 (31) -2.53 ± 98.1(29) 0.40 up to 10 -6.53 ± 62.0 (16) 19.5 ± 75.5 (14) 0.33 25 to 600 -165 ± 543 (11) -33.0 ±89.3(9) 0.47 150 to 600 69.3 ± 56.4(4) -31.1 ±89.8 (4) 0.08 *: Student’s t-test or Welch’s t-test (two-sided) (* : p < 0.05;      : p < 0.01).

[0082] 3-5) pH Table 6 shows changes in urine pH when the subjects were stratified by albumin concentration in first morning urine. Individual measurement results for subjects whose first morning urine albumin concentration before the treatment was 150 to 600 mg / gCr are shown in Fig. 7; in the control group, urine pH hardly changed with treatment, whereas urine pH was alkalinized in the sodium bicarbonate preparation group and the citric acid preparation group.

[0083] [Table 6] Subject Change in first morning urine pH Significant stratum Control group (n) Citric acid preparation group (n) difference# (p value) Overall 0.06 ± 0.60 (31) 0.37 ± 0.75 (29) 0.09 up to 10 -0.06 ± 0.67 (16) 0.14 ± 0.76(14) 0.45 25 to 600 -0.03 ± 0.30 (11) 0.74 ± 0.65* (9) 0.01 150 to 600 0.07 ± 0.20 (4) 0.54 ± 0.48 (4) 0.16 *: Student’s t-test or Welch’s t-test (two-sided) (*: p < 0.05) .

[0084] From the above, when first morning urine albumin was used as an indicator, the renal protective effect of the citric acid preparation in chronic kidney disease (suppression of urinary protein, maintenance or improvement of glomerular function / tubular function, suppression of inflammation, alkalinization of urine, and the like) was found to show a clear effect on subjects whose urine albumin concentration before the treatment was moderately high (for example, 25 to 600 mg / gCr or 150 to 600 mg / gCr). Industrial Applicability

[0085] With the treatment provided by the present invention, the kidney is protected, and glomerular function, tubular function, and the like are maintained or improved.

Claims

CLAIMS

1. A pharmaceutical composition for renal protection for treatment of chronic kidney disease, comprising citric acid, a pharmaceutically acceptable salt of citric acid, hydrates thereof, or a mixture thereof, wherein the pharmaceutical composition is for treatment of a chronic kidney disease patient whose urine albumin concentration before the treatment is in a specific range.

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

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

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

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

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

7. The pharmaceutical composition according to claim 1, wherein the renal protection is suppression of urinary protein, maintenance or improvement of glomerular function / 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 al-microglobulin.

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

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

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

12. The pharmaceutical composition according to claim 1 or 2, wherein the citric acid, the pharmaceutically acceptable salt of citric acid, the hydrate thereof, or the 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 stage G2 or higher and G3b or lower.

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

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