Novel pharmaceutical composition

Abstract

To provide a pharmaceutical composition for renal protection.SOLUTION: The present invention relates to a pharmaceutical composition for renal protection in chronic kidney disease. The pharmaceutical composition is in the form of a tablet and contains citric acid, a pharmaceutically acceptable salt of citric acid, or their hydrate, or their mixture.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical composition for renal protection and a pharmaceutical composition for diagnosing renal function, which comprises citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof. The present invention also relates to a pharmaceutical composition comprising citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate or a mixture thereof, for inhibiting activation of the intrarenal renin-angiotensin system and for inhibiting acidosis or improving acidic urine in patients with chronic kidney disease. This application claims priority based on Japanese Patent Application No. 2018-195568 filed in Japan on October 17, 2018, Japanese Patent Application No. 2018-195810 filed in Japan on October 17, 2018, Japanese Patent Application No. 2019-32126 filed in Japan on February 25, 2019, Japanese Patent Application No. 2019-86945 filed in Japan on April 28, 2019, and Japanese Patent Application No. 2019-119297 filed in Japan on June 27, 2019, the contents of which are incorporated herein by reference. [Background technology]

[0002] The number of patients with end-stage kidney disease (ESKD) who require dialysis or transplants is increasing worldwide. The number of dialysis patients in Japan is also on the rise, reaching 320,000 at the end of 2014. Chronic kidney disease (CKD) is recognized as a precursor to ESKD. CKD is a concept that encompasses all chronic kidney diseases, regardless of the underlying disease, and includes all pathological conditions in which there is a decrease in renal function represented by glomerular filtration rate (GFR) or findings suggesting kidney damage persist chronically (for more than 3 months). CKD is not only a risk factor for progression to ESKD, but also a strong risk factor for developing cardiovascular disease (CVD), etc., so it is very important to detect CKD early and provide appropriate treatment. Many CKD treatments have been established so far, but they are still insufficient, and further development of renal protective agents is required.

[0003] In advanced CKD patients, the blood bicarbonate ion (HCO3 - ) concentration decreases, leading to the onset of metabolic acidosis, and therefore alkalizing agents such as sodium bicarbonate and citric acid preparations are administered. It has been reported that administration of sodium bicarbonate, an alkalizing agent, inhibits the progression of CKD (Non-Patent Document 1). It has also been reported that oral administration of sodium bicarbonate inhibits renal tubule cell damage caused by acidic urine in an animal model of nephrosis induced by protein overload (Non-Patent Document 2). It is also known that administration of alkalizing agents to early-stage CKD patients inhibits the progression of renal damage and reduces the blood concentration of uremic substances (Patent Documents 1 and 2). However, it is not known that renal function can be evaluated using alkalizing agents such as citric acid preparations.

[0004] Meanwhile, in recent years, many renal injury markers for CKD and acute kidney injury (AKI) have been reported.

[0005] It is known that activation of the renin-angiotensin system (RAS) in the kidney is deeply involved not only in hypertension but also in the progression of renal damage. Angiotensinogen in the kidney is involved in the onset and progression of hypertension and renal damage. It has also been reported that angiotensinogen excreted in urine shows a positive correlation with angiotensinogen expressed in the kidney (Non-Patent Document 3).

[0006] 8-hydroxy-2'-deoxyguanosine (8-OHdG) is one of the most widely used oxidative stress markers currently in use, and it is known that 8-OHdG production increases with renal injury.

[0007] However, it is not known that administration of an alkalizing agent to patients with CKD or AKI can suppress urinary angiotensinogen concentrations or oxidative stress. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Publication No. 2018 / 193648 [Patent Document 2] International Publication No. 2018 / 193752 [Non-patent literature]

[0009] [Non-Patent Document 1] Brito-Ashurst, ID, et al.: Bicarbonate supplementation slows progression of CKD and improves nutritional status. J. Am. Soc. Nephrol., 20: 2075-2084, 2009. [Non-Patent Document 2] Souma T., et al.: Luminal alkalinization attenuates proteinuria-induced oxidative damage in proximal tubular cells. J. Am. Soc. Nephrol., 22: 635-648, 2011. [Non-Patent Document 3] J. Am. Soc. Nephrol, 18: pp.1558-1565, 2007 Summary of the Invention [Problem to be solved by the invention]

[0010] An object of the present invention is to provide a pharmaceutical composition for renal protection, comprising citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof. Another object of the present invention is to provide a pharmaceutical composition for renal function diagnosis, comprising citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof. Another object of the present invention is to provide a medicine that inhibits intrarenal RAS activation and is useful for treating or preventing acidosis in patients with chronic kidney disease, or inhibits intrarenal RAS activation and is useful for improving urine flow in patients with chronic kidney disease. Another object of the present invention is to provide a medicine that is useful for inhibiting oxidative stress in the kidney. Another object of the present invention is to provide a food for renal protection or for inhibiting oxidative stress. [Means for solving the problem]

[0011] Means for Solving the Problems The present inventors have conducted intensive research to achieve the above-mentioned object and have found that a composition containing citric acid, a pharma- ceutical acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, is useful for renal protection and evaluation of renal function, thereby completing the present invention. Furthermore, the present inventors have found that a composition containing citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, is useful for suppressing an increase in urinary angiotensinogen concentration or suppressing urinary 8-OHdG concentration compared to sodium bicarbonate, and have found that the agent is useful for suppressing intrarenal RAS activation and simultaneously suppressing acidosis in patients with chronic kidney disease, for suppressing intrarenal RAS activation and simultaneously improving acidic urine in patients with chronic kidney disease, or for suppressing oxidative stress in the kidney, thereby completing the present invention.

[0012] In one aspect, the present invention provides a pharmaceutical composition for renal protection in chronic kidney disease, comprising citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof. In one aspect, the present invention provides a pharmaceutical composition for diagnosing renal function, which comprises citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof. In one aspect, the present invention provides a method for determining renal function, comprising administering to a subject a pharmaceutical composition containing citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, and measuring the pH of the subject's spot urine after administration. In one aspect, the present invention provides a method for assessing renal function, comprising administering to a subject a pharmaceutical composition containing citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, and measuring the pH of the subject's early morning urine before administration and the pH of the subject's casual urine after administration. In one embodiment, the present invention provides a pharmaceutical composition for suppressing acidosis or improving acidic urine in a patient with chronic kidney disease accompanied by hypertension, comprising citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof. In one aspect, the present invention provides a pharmaceutical composition for suppressing oxidative stress in the kidney, comprising citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof. In one aspect, the present invention provides a pharmaceutical composition for suppressing an increase in urinary 8-OHdG concentration, an increase in urinary β2-microglobulin concentration, an increase in urinary albumin concentration, or an increase in protein concentration in spot urine that accompanies the progression of chronic kidney disease, the pharmaceutical composition comprising citric acid, a pharma- ceutical acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof. In one aspect, the present invention provides a pharmaceutical composition useful for maintaining or improving renal tubular function in chronic kidney disease, or suppressing the decline in renal tubular function in chronic kidney disease, the pharmaceutical composition comprising citric acid, a pharma- ceutical acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof. In one aspect, the present invention provides a food useful for renal protection or suppressing oxidative stress in the kidney, which contains citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof. Effect of the Invention

[0013] The pharmaceutical composition or food composition provided by the present invention protects the kidneys in patients with chronic kidney disease. The pharmaceutical composition provided by the present invention enables evaluation of renal function. The pharmaceutical composition or food composition provided by the present invention makes it possible to suppress activation of the intrarenal renin-angiotensin system and simultaneously suppress acidosis in patients with chronic kidney disease, and to suppress activation of the intrarenal renin-angiotensin system and simultaneously improve acidic urine in patients with chronic kidney disease. [Brief description of the drawings]

[0014] [Figure 1] FIG. 1 shows the correlation between random urine pH and eGFR in the control group. [Diagram 2] FIG. 1 shows the correlation between spot urine pH and eGFR in the potassium citrate-sodium citrate hydrate formulation administration group. [Diagram 3] FIG. 1 shows the correlation between random urine pH and eGFR in a sodium bicarbonate preparation administration group. [Figure 4] FIG. 1 shows the correlation between the pH difference between random urine and early morning urine in a control group and eGFR. [Diagram 5] FIG. 1 shows the correlation between the difference in pH between random urine and early morning urine and eGFR in the group administered a potassium citrate-sodium citrate hydrate formulation. [Figure 6] FIG. 1 shows the correlation between the pH difference between random urine and early morning urine and eGFR in a group administered a sodium bicarbonate preparation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] 1. Pharmaceutical Compositions The pharmaceutical compositions provided by the present invention may contain, as an active ingredient, citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof. Examples of pharma- ceutically acceptable salts of citric acid include alkali metal citrates, such as potassium citrate and sodium citrate, which may be hydrated, such as the stable monohydrate of potassium citrate (C6H5K3O7·H2O) and the dihydrate of sodium citrate (C6H5Na3O7·2H2O), respectively.

[0016] Examples of preferred active ingredients contained in the pharmaceutical composition provided by the present invention include sodium citrate, potassium citrate, or a hydrate thereof, or a mixture thereof, and may be, for example, a mixture of potassium citrate monohydrate (C6H5K3O7·H2O) and sodium citrate dihydrate (C6H5Na3O7·2H2O). The mixing ratio of potassium citrate monohydrate (C6H5K3O7·H2O) and sodium citrate dihydrate (C6H5Na3O7·2H2O) can be appropriately set by those skilled in the art, and for example, the molar ratio of potassium citrate monohydrate to sodium citrate dihydrate can be 1:0.01 to 100:00. The molar ratio of potassium citrate (e.g., potassium citrate monohydrate) and sodium citrate (e.g., sodium citrate dihydrate) can be appropriately set by a person 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. . Other examples of active ingredients contained in the pharmaceutical composition provided by the present invention include sodium citrate or a hydrate thereof, such as sodium citrate dihydrate (C6H5Na3O7·2H2O).

[0017] Another example of an active ingredient contained in the pharmaceutical composition provided by the present invention is potassium citrate or a hydrate thereof, for example 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 set by those 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, and is preferably 1:2:2. In one embodiment, the active ingredient contained in the pharmaceutical composition of the present invention may be a mixture of potassium citrate monohydrate (C6H5K3O7·H2O), sodium citrate dihydrate (C6H5Na3O7·2H2O) and anhydrous citric acid. In this case, the mixing ratio of anhydrous citric acid, potassium citrate monohydrate (C6H5K3O7·H2O) and sodium citrate dihydrate (C6H5Na3O7·2H2O) can be appropriately set by those skilled in the art, 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, and is preferably 1:2:2. 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. As used herein, when referring to the weight of citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate or mixture thereof (e.g., potassium citrate monohydrate (C6H5K3O7·H2O) and sodium citrate dihydrate (C6H5Na3O7·2H2O)), the weight may be the dry weight.

[0018] The pharmaceutical composition provided by the present invention can be used for diagnosing renal function. The pharmaceutical composition for diagnosing renal function provided by the present invention can contain, as an active ingredient, citric acid, a pharma- ceutical acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof (e.g., a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof (e.g., a mixture of potassium citrate monohydrate (C6H5K3O7·H2O) and sodium citrate dihydrate (C6H5Na3O7·2H2O))). Thus, in one embodiment, the present invention provides a pharmaceutical composition for diagnosing renal function, comprising citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof. In addition, in one embodiment, the present invention provides a method for determining renal function of a subject, comprising administering to the subject a pharmaceutical composition for diagnosing renal function comprising citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, and measuring the pH of the subject's urine after administration. The amount of active ingredient in the pharmaceutical composition for diagnosing renal function provided by the present invention is not particularly limited. For example, when the pharmaceutical composition for diagnosing renal function is in the form of a tablet, one tablet may contain 231.5 mg of potassium citrate (C6H5K3O7·H2O) and 195.0 mg of sodium citrate hydrate (C6H5Na3O7·2H2O). The pharmaceutical composition for diagnosing renal function provided by the present invention can be used for diagnosing glomerular filtration function and can serve as an index of improvement or deterioration of eGFR or of eGFR. The pharmaceutical composition for diagnosing renal function provided by the present invention can be administered to subjects who require evaluation of renal function, for example, patients with chronic kidney disease or patients with acute kidney disease. In one embodiment, a kit is provided which contains the pharmaceutical composition for diagnosing renal function provided by the present invention together with an instrument for measuring urinary pH, a reagent (eg, pH test paper), and the like. The pharmaceutical composition for diagnosing renal function provided by the present invention is administered to a subject (e.g., human) whose renal function needs to be evaluated, and the renal function can be evaluated by measuring the pH of the urine of the subject after administration. The administration may be any time of the day, morning, or night, and there is no particular limit to the number of times of administration, but a single administration is preferable. The timing of measuring the pH of the urine after administration may be appropriately set, for example, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or 6 hours after administration. The pH of the urine can be measured by a measurement method known in the art, for example, using a pH test paper. Preferably, the renal function of the subject can be determined by measuring the initial urine pH after administration of the pharmaceutical composition for diagnosing renal function provided by the present invention. In one embodiment, the pharmaceutical composition for diagnosing renal function provided by the present invention can be used to determine the renal function of a patient who has been treated or prevented with chronic kidney disease or acute kidney disease (e.g., a patient who has been administered a medicine for treating or preventing chronic kidney disease or acute kidney disease (e.g., a urinary alkalinizer)) or to determine the effect of the above treatment or prevention. For example, before administering the above treatment or prevention (e.g., administering a medicine for treatment or prevention), the pharmaceutical composition for diagnosing renal function provided by the present invention is administered, and the pH of urine (e.g., the first urine sample taken at random after administration) is measured after administration (this pH value is taken as value A); after administering the above treatment or prevention (e.g., administering a medicine for treatment or prevention), the pharmaceutical composition for diagnosing renal function provided by the present invention is administered, and the pH of urine (e.g., the first urine sample taken at random after administration) is measured after administration (this pH value is taken as value B); if value B is higher than value A, it can be determined that renal function has been improved by the above treatment or prevention (e.g., administering a medicine for treatment or prevention). Conversely, for example, before administering the above-mentioned treatment or prevention (e.g., administering a therapeutic or preventive medicament), the pharmaceutical composition for diagnosing renal function provided by the present invention is administered, and after administering the above-mentioned treatment or prevention (e.g., administering a therapeutic or preventive medicament), the pH of urine (e.g., the first random urine after administration) is measured (this pH value is designated as value A), and after administering the above-mentioned treatment or prevention (e.g., administering a therapeutic or preventive medicament), the pharmaceutical composition for diagnosing renal function provided by the present invention is administered, and after administering the above-mentioned treatment or prevention (e.g., administering a therapeutic or preventive medicament), the pH of urine (e.g., the first random urine after administration) is measured (this pH value is designated as value B), and if value B is lower than value A, it can be determined that renal function has deteriorated due to the above-mentioned treatment or prevention (e.g., administration of a therapeutic or preventive medicament). In this embodiment, the above-mentioned therapeutic or preventive medicament (e.g., a urinary alkalizing agent) may be administered continuously (e.g., for 6, 12, 24, 48, or 72 weeks), and the pharmaceutical composition for diagnosing renal function provided by the present invention may be administered before and after the continuous administration, and the pH of urine (e.g., the first random urine after administration) may be measured after administration to determine improvement or deterioration of renal function. Furthermore, in this embodiment, when the administered pharmaceutical for treating or preventing chronic kidney disease or acute kidney disease and the pharmaceutical composition for diagnosing renal function provided by the present invention are the same drug, the drug administered immediately before measuring the pH of the urine may be the pharmaceutical composition for diagnosing renal function provided by the present invention.

[0019] In one embodiment, renal function can be evaluated by measuring the pH of early morning urine of a subject (e.g., a human) whose renal function needs to be evaluated, regardless of administration of the pharmaceutical composition for diagnosing renal function provided by the present invention. In this embodiment, the subject whose renal function is evaluated may be a patient who has been treated or prevented for chronic kidney disease or acute kidney disease (e.g., a patient who has been administered a medicine for treating or preventing chronic kidney disease or acute kidney disease (e.g., a urinary alkalizing agent)). The medicine for treating or preventing chronic kidney disease or acute kidney disease (e.g., a urinary alkalizing agent) may be administered once or continuously, and the early morning urine for measuring the pH may be the morning urine on the day before and / or the day after administration of the medicine for treating or preventing chronic kidney disease or acute kidney disease (e.g., a urinary alkalizing agent). In one embodiment, in order to assess the renal function of a patient who has been treated or prevented for chronic kidney disease or acute kidney disease (e.g., a patient who has been administered a therapeutic or preventive medicine for chronic kidney disease or acute kidney disease (e.g., a urinary alkalinizer)) or to assess the effect of the above treatment or prevention, the pH of early morning urine (e.g., the last early morning urine before the above treatment or prevention is administered) before the above treatment or prevention is administered (e.g., administration of the therapeutic or preventive medicine) is measured (this pH value is taken as value A), and the pH of early morning urine (e.g., the first early morning urine after the above treatment or prevention is administered) after the above treatment or prevention is administered (e.g., administration of the therapeutic or preventive medicine) is measured (this pH value is taken as value B), and if value B is higher than value A, it can be judged that renal function has been improved by the above treatment or prevention (e.g., administration of the therapeutic or preventive medicine). Conversely, for example, before administering the above treatment or prevention (e.g., administering a therapeutic or preventive medicament), the pH of early morning urine (e.g., the last early morning urine before administering the above treatment or prevention) is measured (this pH value is taken as value A), and after administering the above treatment or prevention (e.g., administering a therapeutic or preventive medicament), the pH of early morning urine (e.g., the first early morning urine after administering the above treatment or prevention) is measured (this pH value is taken as value B), and if value B is lower than value A, it can be determined that renal function has deteriorated due to the above treatment or prevention (e.g., administration of a therapeutic or preventive medicament). In this embodiment, the above therapeutic or preventive medicament (e.g., a urinary alkalinizer) may be administered continuously (e.g., may be administered continuously for 6 weeks, 12 weeks, 24 weeks, 48 ​​weeks, or 72 weeks), and the pH of early morning urine may be measured before and after the continuous administration to determine improvement or deterioration of renal function.

[0020] In one embodiment, the pharmaceutical composition for diagnosing renal function provided by the present invention is administered to a subject (e.g., human) whose renal function needs to be evaluated, and renal function can be evaluated by measuring the pH of the subject's early morning urine (e.g., the last early morning urine before administration) before administration and the pH of the subject's urine (e.g., the first random urine after administration). Administration may be any time of day, morning, or night, but is preferably in the morning, and there is no particular limit to the number of times of administration, but is preferably a single administration. The timing of measuring the pH of urine after administration of the pharmaceutical composition for diagnosing renal function provided by the present invention can also be appropriately set, and may be, for example, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or 6 hours after administration, and the pH of the first urine (random urine) after administration of the pharmaceutical composition for diagnosing renal function provided by the present invention may be measured. The early morning urine may be the last early morning urine before administration of the pharmaceutical composition for diagnosing renal function provided by the present invention. For example, early morning urine may be early morning urine collected up to 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or 6 hours before administration of the pharmaceutical composition for diagnosing renal function provided by the present invention. In addition, for example, the first urine after administration of the pharmaceutical composition for diagnosing renal function provided by the present invention, in which pH is measured (random urine), and the last early morning urine before administration of the pharmaceutical composition for diagnosing renal function provided by the present invention may be urine collected on the same day. In one embodiment, when the difference (A value - B value) between the pH value of the subject's urine (e.g., the first random urine after administration) after administration of the pharmaceutical composition for diagnosing renal function provided by the present invention (this pH value is designated as A value) and the pH value of the subject's early morning urine (e.g., the last early morning urine before administration) before administration (this pH value is designated as B value) is -1 or less, the subject's eGFR value can be determined to be less than 50. In addition, in one embodiment, when the difference (A value - B value) between the pH value of the subject's urine (e.g., the first random urine after administration) after administration of the pharmaceutical composition for diagnosing renal function provided by the present invention (this pH value is designated as A value) and the pH value of the subject's early morning urine (e.g., the last early morning urine before administration) before administration (this pH value is designated as B value) is 1 or more, the subject's eGFR value can be determined to be 50 or more. In one embodiment, the pharmaceutical composition for diagnosing renal function provided by the present invention can also be used to assess the renal function of a patient receiving treatment or prevention of chronic kidney disease or acute kidney disease (e.g., a patient receiving a medicine for the treatment or prevention of chronic kidney disease or acute kidney disease (e.g., a urinary alkalinizer)) or to assess the effect of the above treatment or prevention. For example, before performing the above-mentioned treatment or prevention (e.g., administering a therapeutic or preventive medicament), a pharmaceutical composition for diagnosing renal function provided by the present invention is administered, and the difference (A value - B value) between the pH value of the subject's urine after administration (e.g., the first random urine after administration) (this pH value is designated as value A) and the pH value of the subject's early morning urine (e.g., the last early morning urine before administration) before administration (this pH value is designated as value B) is determined; after performing the above-mentioned treatment or prevention (e.g., administering a therapeutic or preventive medicament), a pharmaceutical composition for diagnosing renal function provided by the present invention is administered, and the difference (C value - D value) between the pH value of the subject's urine after administration (e.g., the first random urine after administration) (this pH value is designated as value C) and the pH value of the subject's early morning urine (e.g., the last early morning urine before administration) before administration (this pH value is designated as value D) is determined; and if (C value - D value) is higher than (A value - B value), it can be determined that renal function has been improved by the above-mentioned treatment or prevention (e.g., administration of a therapeutic or preventive medicament). Conversely, for example, before performing the above-mentioned treatment or prevention (e.g., administering a therapeutic or preventive medicament), a pharmaceutical composition for diagnosing renal function provided by the present invention is administered, and the difference (A value - B value) between the pH value of the subject's urine after administration (e.g., the first random urine after administration) (this pH value is taken as value A) and the pH value of the subject's early morning urine (e.g., the last early morning urine before administration) before administration (this pH value is taken as value B) is determined; after performing the above-mentioned treatment or prevention (e.g., administering a therapeutic or preventive medicament), a pharmaceutical composition for diagnosing renal function provided by the present invention is administered, and the difference (C value - D value) between the pH value of the subject's urine after administration (e.g., the first random urine after administration) (this pH value is taken as value C) and the pH value of the subject's early morning urine (e.g., the last early morning urine before administration) before administration (this pH value is taken as value D) is determined; and if (C value - D value) is lower than (A value - B value), it can be determined that renal function has deteriorated due to the above-mentioned treatment or prevention (e.g., administration of a therapeutic or preventive medicament).In this embodiment, the therapeutic or preventive medicament (e.g., urinary alkalinizing agent) may be administered continuously (e.g., for 6, 12, 24, 48, or 72 weeks), and the pharmaceutical composition for diagnosing renal function provided by the present invention may be administered before and after the continuous administration, and the pH of early morning urine (e.g., the last early morning urine before administration) before administration of the pharmaceutical composition for diagnosing renal function provided by the present invention and the pH of urine (e.g., the first random urine after administration) after administration of the pharmaceutical composition for diagnosing renal function provided by the present invention may be measured to determine improvement or deterioration of renal function. In this embodiment, the early morning urine before administration of the pharmaceutical composition for diagnosing renal function provided by the present invention and the random urine after administration of the pharmaceutical composition for diagnosing renal function provided by the present invention, whose pH is measured, may be urine on the same day. In this embodiment, when the administered therapeutic or preventive medicament for chronic kidney disease or acute kidney disease and the pharmaceutical composition for diagnosing renal function provided by the present invention are the same drug, the drug administered immediately before the measurement of urine pH may be the pharmaceutical composition for diagnosing renal function provided by the present invention.

[0021] The pharmaceutical composition provided by the present invention can also be used for renal protection in chronic kidney disease. Renal protection includes protection of renal tissue and protection of renal function. For example, the pharmaceutical composition provided by the present invention may be a pharmaceutical composition for protecting renal tissue in chronic kidney disease, a pharmaceutical composition for suppressing renal tissue damage associated with the progression of chronic kidney disease, a pharmaceutical composition for maintaining or improving renal function in chronic kidney disease, or a pharmaceutical composition for suppressing decline in renal function associated with the progression of chronic kidney disease. Examples of renal tissues that may be protected by the pharmaceutical compositions provided by the present invention include renal tubules (eg, proximal tubules). Furthermore, examples of renal functions that are maintained or improved by the pharmaceutical compositions provided by the present invention include tubular functions (eg, proximal tubular functions), and examples of tubular functions include urinary concentrating ability. Therefore, the pharmaceutical composition provided by the present invention can be a pharmaceutical composition for maintaining or improving renal tubular function in chronic kidney disease, a pharmaceutical composition for suppressing the decline in renal tubular function associated with the progression of chronic kidney disease, a pharmaceutical composition for maintaining or improving urinary concentrating ability in chronic kidney disease, or a pharmaceutical composition for suppressing the decline in urinary concentrating ability associated with the progression of chronic kidney disease. The effect of the pharmaceutical composition provided by the present invention can be evaluated by measuring the early morning urine 8-OHdG concentration, early morning urine β2-microglobulin concentration, early morning urine albumin concentration, random urine albumin concentration, random urine protein concentration and / or early morning urine osmolality in patients with chronic kidney disease to which the pharmaceutical composition provided by the present invention has been administered, using methods known in the art. For example, if administration of the pharmaceutical composition provided by the present invention to a patient with chronic kidney disease reduces the 8-OHdG concentration in the patient's early morning urine compared to before administration, it can be evaluated that the pharmaceutical composition provided by the present invention has protected renal tissue. For example, when a patient with chronic kidney disease administered the pharmaceutical composition provided by the present invention has a lower 8-OHdG concentration in early morning urine compared to a patient with chronic kidney disease not administered the pharmaceutical composition provided by the present invention, it can be evaluated that the pharmaceutical composition provided by the present invention has suppressed renal tissue damage associated with the progression of chronic kidney disease. For example, if administration of the pharmaceutical composition provided by the present invention to a patient with chronic kidney disease reduces the concentration of β2-microglobulin in the patient's early morning urine compared to before administration, it can be evaluated that the pharmaceutical composition provided by the present invention has protected the renal tubular tissue. For example, when a patient with chronic kidney disease administered the pharmaceutical composition provided by the present invention has a lower concentration of β2-microglobulin in early morning urine compared to a patient with chronic kidney disease not administered the pharmaceutical composition provided by the present invention, it can be evaluated that the pharmaceutical composition provided by the present invention has suppressed tubular tissue damage associated with the progression of chronic kidney disease. For example, when administration of the pharmaceutical composition provided by the present invention to a patient with chronic kidney disease does not result in an increase in the early morning urinary albumin concentration, the random urine albumin concentration, and / or the random urine protein concentration of the patient, compared to before administration, it may be evaluated that renal function has been maintained or improved by the pharmaceutical composition provided by the present invention. For example, when a patient with chronic kidney disease administered the pharmaceutical composition provided by the present invention has lower early morning urine albumin concentration, random urine albumin concentration, and / or random urine protein concentration compared to a patient with chronic kidney disease not administered the pharmaceutical composition provided by the present invention, it may be evaluated that the pharmaceutical composition provided by the present invention has suppressed the decline in renal function associated with the progression of chronic kidney disease. For example, if administration of the pharmaceutical composition provided by the present invention to a patient with chronic kidney disease does not result in a decrease in the osmotic pressure of the patient's early morning urine compared to before administration, it may be evaluated that the pharmaceutical composition provided by the present invention has maintained or improved renal tubular function, or that the pharmaceutical composition provided by the present invention has maintained or improved urine concentrating ability. For example, when a patient with chronic kidney disease to which the pharmaceutical composition provided by the present invention has been administered has a higher osmolality in early morning urine compared to a patient with chronic kidney disease to which the pharmaceutical composition provided by the present invention has not been administered, it may be evaluated that the pharmaceutical composition provided by the present invention has suppressed the decline in renal tubular function accompanying the progression of chronic kidney disease, or that the pharmaceutical composition provided by the present invention has suppressed the decline in urinary concentrating ability accompanying the progression of chronic kidney disease.

[0022] In one embodiment, the pharmaceutical composition provided by the present invention reduces the urinary concentration of 8-OHdG, which is an index of oxidative stress in the kidney, and therefore can be a pharmaceutical composition for suppressing oxidative stress in the kidney of a patient with chronic kidney disease. The reduction in the urinary concentration of 8-OHdG can be evaluated by comparing the results before and after administration of the pharmaceutical composition provided by the present invention, or comparing the results after administration of the pharmaceutical composition provided by the present invention and without administration.

[0023] In addition, in one embodiment, administration of the pharmaceutical composition provided by the present invention can suppress activation of the intrarenal renin-angiotensin system, thereby treating or preventing acidosis in patients with chronic kidney disease and improving acidic urine, and therefore the pharmaceutical composition provided by the present invention can be a pharmaceutical composition for treating or preventing acidosis in patients with chronic kidney disease accompanied by hypertension or a pharmaceutical composition for improving acidic urine in patients with chronic kidney disease accompanied by hypertension. "Suppression of activation of the intrarenal renin-angiotensin system" can be evaluated by suppression of an increase in urinary angiotensinogen concentration after administration of a pharmaceutical composition provided by the present invention compared to the urinary angiotensinogen concentration before administration, or by suppression of an increase in urinary angiotensinogen concentration by administration of a pharmaceutical composition provided by the present invention compared to placebo administration or a control. In one embodiment, administration of the pharmaceutical composition provided by the present invention suppresses an increase in urinary (e.g., early morning urine) 8-OHdG concentration, an increase in urinary (e.g., early morning urine) angiotensinogen concentration, an increase in urinary (e.g., early morning urine) β2-microglobulin concentration, an increase in urinary (e.g., early morning urine) albumin concentration, an increase in urinary (e.g., random urine) albumin concentration, an increase in urinary (e.g., random urine) protein concentration, or a decrease in urinary (e.g., early morning urine) osmolality. The pharmaceutical composition provided by the invention may be a pharmaceutical composition for suppressing an increase in urinary (e.g., early morning urine) 8-OHdG concentration, an increase in urinary (e.g., early morning urine) angiotensinogen concentration, an increase in urinary (e.g., early morning urine) β2-microglobulin concentration, an increase in urinary (e.g., early morning urine) albumin concentration, an increase in urinary (e.g., random urine) albumin concentration, an increase in urinary (e.g., random urine) protein concentration, or a decrease in urinary (e.g., early morning urine) osmolality. These effects can also be evaluated by comparing before and after administration of the pharmaceutical composition provided by the present invention, and comparing a group administered the pharmaceutical composition provided by the present invention with a placebo or control group.

[0024] In the present specification, "suppression" refers to a concept including stopping or slowing down the worsening or progression of a symptom, condition, or disease, and also including improving the symptom, condition, or disease. Here, "improvement" refers to a concept including bringing a "pathological" or "abnormal" symptom, condition, or disease closer to a "healthy" or "normal" state, and bringing the symptom, condition, or disease into a "healthy" or "normal" state. Thus, in one embodiment, "improvement" refers to a numerical value that is an index of a "pathological" or "abnormal" symptom or condition becoming smaller or larger according to the "improvement" and approaching a normal value or becoming a normal value. The "worsening or progression of a symptom, condition, or disease" includes 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 down the worsening or progression of a symptom, condition, or disease, or includes a concept including bringing a "pathological" or "abnormal" symptom, condition, or disease closer to a "healthy" or "normal" state and bringing the symptom, condition, or disease into a "pathological" or "abnormal" state. In another embodiment, "inhibiting" refers to stopping or slowing the worsening or progression of a symptom, condition or disease.

[0025] As used herein, "healthy" refers to a state free of acute or chronic disease or disorder, and "normal" refers to a state that is normally manifested in a healthy subject. Here, the symptoms, condition or disease are compared before and after administration of a pharmaceutical composition provided by the present invention, or when a pharmaceutical composition provided by the present invention is administered compared to when a control or placebo is administered.

[0026] As used herein, "treatment" refers to the elimination, complete cure, cure or remission of "pathological" or "abnormal" symptoms, conditions or diseases, and includes the "suppression" of the worsening of "pathological" or "abnormal" symptoms, conditions or diseases, and includes the "improvement". Here, "suppression" and "improvement" have the above-mentioned meanings. In one embodiment, "treatment" refers to the elimination, complete cure, cure or remission of "pathological" or "abnormal" symptoms, conditions or diseases, and includes the "improvement". In another embodiment, "treatment" refers to the elimination, complete cure, cure or remission of "pathological" or "abnormal" symptoms, conditions or diseases.

[0027] 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.

[0028] In this specification, "early morning urine" refers to the first urine after waking up, and "random urine" refers to urine other than the above-mentioned "early morning urine".

[0029] The pharmaceutical compositions provided by the present invention may be administered to humans or other mammals orally or parenterally. 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.

[0030] The pharmaceutical composition provided by the present invention may be prepared by mixing the active ingredient, citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, as it is, or with a pharma- ceutically acceptable carrier, for example, an excipient (e.g., lactose, D-mannitol, crystalline cellulose, glucose), a binder (e.g., hydroxypropylcellulose (HPC), gelatin, polyvinylpyrrolidone (PVP)), a lubricant (e.g., magnesium stearate, talc), a disintegrant (e.g., starch, carboxymethylcellulose calcium (CMC-Ca)), a diluent (e.g., water for injection, physiological saline), and, if necessary, other additives (e.g., pH adjuster, surfactant, solubilizer, preservative, emulsifier, isotonicity agent, stabilizer), and may be in the form of a tablet, capsule, suspension, injection, suppository, or other formulation. For example, to prepare tablets, the active ingredient, citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof, may be mixed with excipients (e.g., lactose, D-mannitol, crystalline cellulose, glucose), disintegrants (e.g., starch, carboxymethylcellulose calcium (CMC-Ca)), binders (e.g., hydroxypropylcellulose (HPC), gelatin, polyvinylpyrrolidone (PVP)), lubricants (e.g., magnesium stearate, talc), etc., to form a tablet.

[0031] In one embodiment, the pharmaceutical composition provided by the present invention is a tablet.The tablet provided by the present invention may contain citric acid, a pharma- ceutically 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) as an active ingredient, as well as pharma- cetically acceptable additives commonly 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 citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate 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 weight of the tablet.

[0032] The pharmaceutical compositions provided by the present invention can be prepared by methods known in the pharmaceutical art. In one embodiment, the hardness of the resulting tablet may be 10 to 200N, preferably 30 to 150N.

[0033] The amount of citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, which is an active ingredient in the pharmaceutical composition provided by the present invention, can be appropriately set. In one embodiment, the amount of citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, which is an active ingredient in the pharmaceutical composition provided by the present invention, may be set so that the dose of the active ingredient, citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, which is an active ingredient, is an amount that improves acidic urine in gout or hyperuricemia when administered to a human, or an amount less than that, and may be set so as to be, for example, 1 to 50%, or 10 to 20%, of the daily dose approved in Japan for improving acidic urine in gout or hyperuricemia (for example, 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, when the alkalinizing agent is sodium bicarbonate: orally administered 3 to 5 g per day).

[0034] In one embodiment, the pharmaceutical composition provided by the present invention 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 one embodiment, the pharmaceutical composition provided by the present invention is a tablet, and one 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 and 400 to 500 mg of total, and more preferably 190 to 240 mg of each and 400 to 450 mg of total.

[0035] In one embodiment, the pharmaceutical composition provided by the present invention is a tablet, which 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.

[0036] In one embodiment, a tablet containing 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate may be a single dosage unit. In this specification, "dosage unit" refers to a unit of a formulation, and "one dosage unit" refers to the smallest unit of a formulation. Thus, for example, in the case of a tablet, the dosage unit is each tablet, and one dosage unit refers to one tablet. In the case of an injection, the dosage unit is an injection placed in a sealed container such as an ampoule or vial, and one dosage unit refers to an injection placed in a sealed container such as an ampoule or vial. When the pharmaceutical composition provided by the present invention is administered to humans or other mammals, one or more of the dosage units may be administered per time, or one dosage unit may be divided and administered.

[0037] The dosage of the active ingredient, citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, is appropriately determined depending on the method of administration, and the age, weight, sex, symptoms, sensitivity to drugs, etc. of the subject, and the dosage may be adjusted depending on the degree of improvement of symptoms. In one embodiment, 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 gout and acidic urine in 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) each are orally administered three times a day).

[0038] In one embodiment, when a mixture of potassium citrate monohydrate and sodium citrate dihydrate is orally administered to a human, the daily dosage may be the daily dosage approved in Japan for the improvement of gout and acidic urine in 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) per tablet, orally administered three times a day).

[0039] In one embodiment, when a mixture of potassium citrate monohydrate and sodium citrate dihydrate is orally administered to a human, the daily dosage is initially half the daily dosage approved in Japan for the improvement of gout and acidic urine in 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), and the dosage may then be increased to the daily dosage approved in Japan for the improvement of gout and acidic urine in hyperuricemia.

[0040] In one embodiment, the dosage of the active ingredient, citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, may be such that oral administration of the active ingredient, citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, results in a human urine (e.g., early morning urine) having a pH of 5.2 to 6.8, pH 5.5 to 6.8, pH 5.8 to 6.8, pH 5.8 to 6.5, pH 5.8 to 6.2, pH 5.8 or higher and lower than pH 6.2, pH 6.0 to pH 6.5, pH 6.0 to pH 6.4, pH 6.0 to pH 6.3, pH 6.0 to pH 6.2, pH 6.0 or higher and lower than pH 6.2, pH 6.1 to pH 6.3, pH 6.2 to 6.8, pH 6.2 to pH 6.5, or pH 6.5 to 6.8.

[0041] In one embodiment, the dosage of the active ingredient, citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, may be such that oral administration of the active ingredient, citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, results in a human urine (e.g., early morning urine) of pH 5.2 to pH 6.8, pH 5.5 to pH 6.8, pH 5.8 to pH 6.8, pH 5.8 to pH 6.5, pH 5.8 to pH 6.2, pH 5.8 or higher but less than pH 6.2, pH 6.0 to pH 6.5, pH 6.0 to pH 6.4, pH 6.0 to pH 6.3, pH 6.0 to pH 6.2, pH 6.0 or higher but less than pH 6.2, pH 6.1 to pH 6.3, pH 6.2 to 6.8, pH 6.2 to pH 6.5, or pH 6.5 to 6.8 at 6 weeks, 12 weeks, or 24 weeks after administration.

[0042] In one embodiment, 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.

[0043] In one embodiment, 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 1 to 5 times a day, preferably 3 times a day.

[0044] In one embodiment, the active ingredient, citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof, may be administered chronically, for example, 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 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, 8 weeks or more, The treatment is administered for 0 weeks or more, 100 weeks or more, 120 weeks or more, 6 weeks or more and 24 weeks or less, 12 weeks or more and 24 weeks or more, 6 weeks or more and 30 weeks or more, 12 weeks or more and 30 weeks or more, 6 weeks or more and 40 weeks or more, 12 weeks or more and 40 weeks or more, 6 weeks or more and 60 weeks or more, 12 weeks or more and 60 weeks or more, 6 weeks or more and 80 weeks or more, 12 weeks or more and 80 weeks or more, 6 weeks or more and 100 weeks or more, 12 weeks or more and 100 weeks or more, 6 weeks or more and 120 weeks or more, 12 weeks or more and 120 weeks or more.

[0045] In one embodiment, the pharmaceutical composition provided by the present invention can be detected to have a beneficial effect (e.g., a renal protective effect) in a patient with chronic kidney disease by continuous administration for 6 weeks, 12 weeks, and / or 24 weeks.

[0046] Chronic kidney disease (CKD) is a concept that encompasses all chronic kidney diseases, regardless of the underlying disease, and includes all pathological conditions in which there is a decline in renal function, as measured by glomerular filtration rate (GFR), or signs suggesting kidney damage persist chronically (for three months or more).

[0047] According to the CKD Clinical Practice Guide 2012 (Journal of the Japanese Society of Nephrology 2012), the severity of chronic kidney disease is evaluated by classification based on cause (Cause: C), renal function (GFR: G), and proteinuria (albuminuria: A). The GFR classification is as follows: G1: Normal or high GFR (≥ 90 mL / min / 1.73 m 2 ) G2: Normal or mildly decreased GFR (60-89 mL / min / 1.73 m 2 ) G3a: Mild to moderate decrease in GFR (45 to 59 mL / min / 1.73 m 2 ) G3b: Moderate to severe decline in GFR (30 to 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 )

[0048] When the primary disease is diabetes, proteinuria (albuminuria: A) 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) In addition, classification of proteinuria (albuminuria: A) when the primary disease is hypertension, nephritis, polycystic kidney disease, kidney transplant, or other diseases other than diabetes, is performed using the urinary protein / creatinine (Cr) ratio as follows: A1: Normal (less than 0.15 g / gCr) A2: Mild proteinuria (0.15~0.49 g / gCr) A3: Severe proteinuria (0.50 g / gCr or more)

[0049] According to the CKD Treatment Guide 2012 (Journal of the Japanese Society of Nephrology 2012), the severity classification of chronic kidney disease (CKD) is expressed using the above C, G, and A, for example, diabetes G2A3, chronic nephritis G3bA1, etc. However, taking into consideration that the severity of chronic kidney disease has traditionally been expressed only in stages classified by GFR, it is now possible to continue to express the severity of chronic kidney disease in stages, G1, G2, G3a, G3b, G4, and G5, as in the past.

[0050] In one embodiment, the pharmaceutical compositions provided herein are administered to patients with less severe, early stage chronic kidney disease. In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with chronic kidney disease at stage G3b or below, preferably at stage G2 or below. In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with chronic kidney disease at stage G2 or higher and up to stage G3b (eg, stage G2 and stage G3a; or stage G2, stage G3a and stage G3b).

[0051] In one embodiment, the pharmaceutical composition provided by the present invention is administered to a chronic kidney disease patient with stage G3b or lower and microalbuminuria, preferably to a chronic kidney disease patient with stage G2 and microalbuminuria. In one embodiment, the pharmaceutical composition provided by the present invention is administered to a chronic kidney disease patient with stage G2 or greater and stage G3b or less (e.g., stage G2 and stage G3a; or stage G2, stage G3a and stage G3b) who has microalbuminuria.

[0052] In one embodiment, the pharmaceutical composition provided by the present invention is administered to a chronic kidney disease patient whose stage is G3b or lower and whose urinary protein excretion is less than 3.5 g / gCr, preferably to a chronic kidney disease patient whose stage is G2 and whose urinary protein excretion is less than 3.5 g / gCr. In one embodiment, the pharmaceutical composition provided by the present invention is administered to a chronic kidney disease patient with stage G2 or higher and stage G3b or lower (e.g., stage G2 and stage G3a; or stage G2, stage G3a and stage G3b) and with urinary protein excretion of less than 3.5 g / gCr. In one embodiment, the pharmaceutical compositions provided herein are administered to a patient with progressing chronic kidney disease. In one embodiment, the pharmaceutical compositions provided herein are administered to a patient with chronic kidney disease accompanied by hypertension.

[0053] In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient undergoing treatment in accordance with the CKD Medical Care Guide, for example, to a patient undergoing blood pressure control (administration of RA system suppressants such as ARBs and ACE inhibitors, diuretics, Ca antagonists, etc.), proteinuria control (administration of RA system suppressants, etc.), blood glucose control (administration of α-glucosidase inhibitors, etc.), lipid control (administration of statins, fibrates, etc.), anemia control (administration of erythropoietin, etc.), and / or bone and mineral control (administration of bisphosphonates, etc.) in accordance with the CKD Medical Care Guide. In one embodiment, the pharmaceutical composition provided by the present invention is used in combination with an antihypertensive agent (eg, an ARB, an ACE inhibitor, a diuretic, a Ca antagonist). In one embodiment, the pharmaceutical composition provided by the present invention is used in combination with spherical adsorbent carbon (sold in Japan as Kremezin (registered trademark)) obtained by subjecting spherical, microporous carbon derived from petroleum hydrocarbons to high temperature oxidation and reduction treatment.

[0054] Examples of other embodiments of the present invention include the following. 1-1) A method for renal protection in a mammalian subject (e.g., a human) suffering from chronic kidney disease, comprising administering to a subject in need of renal protection an effective amount of citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof; 1-2) A method for suppressing acidosis associated with chronic kidney disease or improving acidic urine in a mammalian subject (e.g., human), comprising administering to a subject in need of suppression of acidosis associated with chronic kidney disease an effective amount of citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, thereby suppressing RAS activation in the kidney of the subject; 1-3) A method for suppressing oxidative stress in the kidney of a mammalian subject (e.g., a human) suffering from chronic kidney disease, comprising administering to a subject in need of suppression of oxidative stress an effective amount of citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof; 1-4) A method for assessing glomerular filtration function in a mammalian subject (e.g., a human), comprising administering to a subject in need of assessment of the glomerular filtration function an effective amount of a pharmaceutical composition comprising citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, measuring the urinary pH before and after the administration, and calculating the difference between the urinary pH after the administration and the urinary pH before the administration (e.g., when the difference is -1 or less, the eGFR is assessed to be less than 50, and when the difference is 1 or more, the eGFR is assessed to be 50 or more);

[0055] 2-1) A pharmaceutical composition comprising citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, for use in renal protection in a mammalian subject (e.g., a human) suffering from chronic kidney disease; 2-2) A pharmaceutical composition comprising citric acid, a pharma- ceutical acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, for use in suppressing intrarenal RAS activation and suppressing acidosis or improving acidic urine associated with chronic kidney disease; 2-3) A pharmaceutical composition comprising citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, for use in suppressing oxidative stress in the kidney of a mammalian subject (e.g., a human) suffering from chronic kidney disease; 2-4) A pharmaceutical composition comprising citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, for use in assessing glomerular filtration function;

[0056] 3-1) Use of citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, for the manufacture of a pharmaceutical composition for renal protection in a mammalian subject (e.g., a human) suffering from chronic kidney disease; 3-2) Use of citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, for producing a pharmaceutical composition for suppressing intrarenal RAS activation, thereby suppressing acidosis associated with chronic kidney disease, or improving acidic urine; 3-3) Use of citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof for the manufacture of a pharmaceutical composition for suppressing oxidative stress in the kidney of a mammalian subject (e.g., a human) suffering from chronic kidney disease; and 3-4) Use of citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, for producing a pharmaceutical composition for assessing glomerular filtration function.

[0057] 2. Food Composition In one embodiment, the food composition provided by the present invention comprises citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof, and exerts a renal protective or health-promoting effect. In one embodiment, the food composition provided by the present invention has the effect of suppressing oxidative stress in the kidney. Regarding the active ingredient, the active ingredients described in "1. Pharmaceutical Composition" above can be applied. For example, the food composition provided by the present invention can be a food composition containing an alkali metal citrate salt or its hydrate or a mixture thereof, preferably a mixture of potassium citrate monohydrate (C6H5K3O7·H2O) and sodium citrate dihydrate (C6H5Na3O7·2H2O).

[0058] The content of citric acid, a pharma- ceutically acceptable salt of citric acid, or 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 pharma-ceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof for achieving the above-mentioned effect, and are in a form that can be taken orally. They may be in the form of ordinary food and drink, or may be provided as a formulation suitable for oral administration, such as a tablet, capsule, or suspension, among the formulations that can be applied to the pharmaceutical composition. Regarding the composition and manufacturing method of these formulations, the composition and manufacturing method of the pharmaceutical formulation described in the above "1. Pharmaceutical composition" can be applied as is, and in the field of pharmaceutical formulation technology, formulation technology known per se 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 potassium citrate monohydrate and sodium citrate dihydrate as active ingredients in a total amount of 1 to 3 g (1 / 3), or sodium bicarbonate as an active ingredient in a total amount of 1 to 6 g (1 / 3).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 of 300 mg to 600 mg may contain 70 to 80% by weight of citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof.

[0060] When the food composition provided by the present invention is not formulated but is provided in the form of a normal food or beverage, it can be prepared appropriately by a person skilled in the art depending on the type of food, for example, by blending citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, with a food ingredient. Examples of the form of the food and drink include liquid, milky, or paste-like foods such as beverages, soy sauce, milk, yogurt, and miso; semi-solid foods such as jelly and gummies; solid foods such as candy, gum, tofu, and supplements; and powdered foods. Examples of beverages include fruit juices, coffee beverages, oolong tea beverages, green tea beverages, black tea beverages, barley tea beverages, vegetable beverages, carbonated soft drinks, beverages containing fruit extracts, juices containing vegetable extracts, near water, 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, and quality stabilizers, either alone or in combination.

[0062] The term "administration" described in "1. Pharmaceutical composition" above can also be applied to the "food composition" of the present invention, and further, for 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," "ingested," "ingested," etc., depending on the context. Therefore, embodiments of the food composition according to the present invention include the following.

[0063] <1> A food composition for maintaining kidney health comprising citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof; <11> A method for maintaining kidney health, comprising administering to a subject in need thereof a food composition comprising an effective amount of citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof; <111> Use of citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, for the manufacture of a food composition for maintaining kidney health. The food composition according to the present invention preferably has effects such as maintaining kidney health indicated on its packaging, container, or instructions.

[0064] Other examples of embodiments of the present invention include the following: (1) A pharmaceutical composition for renal protection in chronic kidney disease, comprising citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof; (2) The pharmaceutical composition according to (1), which protects renal tissue; (3) The pharmaceutical composition according to (1) or (2), which maintains or improves renal function; (4) The pharmaceutical composition according to any one of (1) to (3), which protects renal tubular tissue; (5) The pharmaceutical composition according to any one of (1) to (4), which maintains or improves renal tubule function; (6) The pharmaceutical composition according to any one of (1) to (5), which maintains or improves urine concentrating ability; (7) The pharmaceutical composition according to any one of (1) to (6), which suppresses oxidative stress in the kidney; (8) A pharmaceutical composition for treating or preventing acidosis or ameliorating acidic urine in chronic kidney disease accompanied by hypertension, comprising citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof; (9) The pharmaceutical composition according to any one of (1) to (8), wherein the citric acid, a pharma- ceutically 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; (10) The pharmaceutical composition according to any one of (1) to (9), further comprising anhydrous citric acid; (11) The pharmaceutical composition according to any one of (1) to (10), wherein citric acid, a pharma- ceutical acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof is administered at 1 to 3 g / day; (12) The pharmaceutical composition according to any one of (1) to (11), wherein citric acid, a pharma- ceutical acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof is administered at 1 to 1.5 g / day; (13) The pharmaceutical composition according to any one of (1) to (12), which is administered to a patient with chronic kidney disease at stage G2 or higher and G3b or lower; (14) The pharmaceutical composition according to any one of (1) to (13), wherein citric acid, a pharma- ceutical acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof is administered for 6 weeks or more; (15) A pharmaceutical composition for diagnosing renal function comprising citric acid, a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof; (16) The pharmaceutical composition according to (15), wherein the renal function is a glomerular filtration function; (17) The pharmaceutical composition according to (15) or (16), which is administered to a patient with chronic kidney disease and is a pharmaceutical composition for diagnosing renal function in the patient with chronic kidney disease; (18) The pharmaceutical composition according to any one of (15) to (17), wherein the citric acid, a pharma- ceutically 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; (19) The pharmaceutical composition according to any one of (15) to (18), further comprising anhydrous citric acid; (20) The pharmaceutical composition according to any one of (15) to (19), wherein citric acid, a pharma- ceutical acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof is administered at 1 to 3 g / day; (twenty one) The pharmaceutical composition according to any one of (15) to (20), wherein citric acid, a pharma- ceutical acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof is administered at 1 to 1.5 g / day; (twenty two) The pharmaceutical composition according to any one of (15) to (21), which is administered to a patient with chronic kidney disease at stage G2 or higher and G3b or lower; (twenty three) A pharmaceutical kit for diagnosing renal function, comprising the pharmaceutical composition according to any one of (15) to (22) and a test paper for measuring the pH of human urine; (twenty four) A method for assessing renal function, comprising administering to a subject the pharmaceutical composition according to any one of (15) to (22) above, and measuring the pH of the subject's urine after the administration; (twenty five) The method according to (24), wherein the post-administration urine of the subject is the first post-administration urine of the subject; (26) The method according to (24) or (25), wherein the subject's urine after administration is the subject's urine 2 to 5 hours after administration; (27) The method according to any one of (24) to (26), wherein the subject is a chronic kidney disease patient to whom a pharmaceutical composition containing an alkalizing agent is continuously administered; (28) The method according to any one of (24) to (27), wherein the subject is a chronic kidney disease patient to whom a pharmaceutical composition containing an alkalizing agent has been continuously administered, and the renal function of the subject is determined to be improved when the pH value of the urine of the subject, which has been collected after administration of the pharmaceutical composition according to any one of (15) to (22) following the continuous administration of the alkalizing agent, is higher than the pH value of the urine of the subject, which has been collected after administration of the pharmaceutical composition according to any one of (15) to (22) following the continuous administration of the alkalizing agent; (29) A method for assessing renal function, comprising administering to a subject the pharmaceutical composition according to any one of (15) to (22) above, and measuring the pH of the subject's early morning urine before the administration and the pH of the subject's urine after the administration; (30) The method according to (29), wherein the subject's early morning urine before administration is the subject's last early morning urine before administration; (31) The method according to (29) or (30), wherein the subject's urine before administration is the subject's early morning urine up to 3 hours before administration; (32) The method according to any one of (29) to (31), wherein the urine of the subject after administration is the first urine of the subject after administration; (33) The method according to any one of (29) to (32), wherein the urine of the subject after administration is urine of the subject 2 to 5 hours after administration; (34) The method according to any one of (29) to (33), wherein the subject is a chronic kidney disease patient to whom a pharmaceutical composition containing an alkalizing agent is continuously administered; (35) The method according to any one of (29) to (34), wherein the subject is a chronic kidney disease patient to whom a pharmaceutical composition containing an alkalizing agent has been continuously administered, and the renal function of the subject is determined to be improved when a difference between a urinary pH of the subject after administration of the pharmaceutical composition according to any one of (15) to (22) minus a morning urine pH of the subject before administration of the pharmaceutical composition according to any one of (15) to (22) is large, comparing a pH after the continuous administration with a pH before the continuous administration; (36) The method according to any one of (29) to (35), wherein the eGFR is determined to be less than 50 when the difference between the pH of the urine of the subject after administration of the pharmaceutical composition according to any one of (15) to (22) and the pH of the first-morning urine of the subject before administration of the pharmaceutical composition according to any one of (15) to (22) is −1 or less; and (37) The method according to any one of (29) to (36), wherein the eGFR is determined to be 50 or more when the difference between the pH of the urine of the subject after administration of the pharmaceutical composition according to any one of (15) to (22) and the pH of the first-morning urine of the subject before administration of the pharmaceutical composition according to any one of (15) to (22) is 1 or more. Examples include:

[0065] The present invention will be further described below with reference to examples, but the present invention is not limited to these. EXAMPLES

[0066] A human clinical trial was conducted to investigate the effects of oral administration of potassium citrate / sodium citrate hydrate and sodium bicarbonate preparations, which are oral alkalizing agents.

[0067] 1. Method Patients with chronic kidney disease in stages G2 to G3b (eGFR: 30 to 89 ml / min / 1.73 m 2 47 patients were randomly divided into a potassium citrate / sodium citrate hydrate compound group (Group A: 16 patients), a baking soda (sodium bicarbonate) compound group (Group B: 16 patients), and a control group (Group C: 15 patients). Patients were assigned to each group so that they were balanced in terms of age, sex, presence or absence of diabetes, and eGFR. Each group received treatment based on the "CKD Medical Care Guide - Summary of Treatment" (hereafter referred to as standard treatment).

[0068] The control group was not administered any alkalinizing agent. Group A was orally administered three tablets containing potassium citrate (C6H5K3O7·H2O) 231.5 mg and sodium citrate hydrate (C6H5Na3O7·2H2O) 195.0 mg per day for 24 weeks. The pH of early morning urine was controlled over time, and in cases where the pH of early morning urine was less than 6.5, the dosage could be increased to six tablets per day, three times a day (morning, midday, and evening) at the discretion of the physician. Group B was orally administered three tablets containing sodium bicarbonate 500 mg per day for 24 weeks. The pH of early morning urine was controlled over time, and in cases where the pH of early morning urine was less than 6.5, the dosage could be increased to six tablets per day, three times a day (morning, midday, and evening) at the discretion of the physician.

[0069] Early morning urine, random urine and blood were collected before the start of treatment, and 6, 12 and 24 weeks after the start of treatment, and each sample was stored at -80°C. Urinary 8-OHdG and angiotensinogen concentrations were measured by ELISA. Serum iron concentrations were measured by the nitroso-PSAP method, and ferritin concentrations by the CLEIA (chemiluminescence enzyme immunoassay) method. Urinary β2-microglobulin levels were measured by latex agglutination immunoassay using LZ test 'Eiken' β2-M and LZ-β2-M standard U 'Eiken' (Eiken Chemical, Tokyo, Japan). Urine osmolality was measured using the freezing point depression method. Urinary albumin and protein concentrations were measured using immunoturbidimetric and colorimetric methods. Urinary creatinine concentration was measured by an enzymatic method. Statistical analysis was performed using the Mann-Whitney test for between-group comparisons, the Wilcoxon test for time-course comparisons, and the Pearson test for correlations.

[0070] 2.Results From the measurement results, the following was calculated for each patient in Group A (group administered a potassium citrate-sodium citrate hydrate compound preparation), Group B (group administered a sodium bicarbonate preparation), and Group C (control group): (i) The concentration of 8-OHdG and angiotensinogen in early morning urine before the start of treatment divided by the urinary creatinine concentration (ii) The concentrations of 8-OHdG and angiotensinogen in early morning urine at 6, 12, and 24 weeks after the start of administration were divided by the urinary creatinine concentration. (iii) The ratio of the concentration of 8-OHdG in early morning urine at 6, 12, and 24 weeks after the start of administration divided by the urinary creatinine concentration to the concentration of 8-OHdG in early morning urine before the start of administration divided by the urinary creatinine concentration (the ratio of the concentration of 8-OHdG in early morning urine at 6, 12, and 24 weeks after the start of administration divided by the urinary creatinine concentration / the ratio of the concentration of 8-OHdG in early morning urine before the start of administration divided by the urinary creatinine concentration)

[0071] (iv) The concentration of β2-microglobulin and albumin in the early morning urine before the start of administration divided by the urinary creatinine concentration (v) The concentrations of β2-microglobulin and albumin in early morning urine divided by the urinary creatinine concentration at 6, 12, and 24 weeks after the start of administration (vi) The difference between the values ​​obtained by dividing the concentrations of β2-microglobulin and albumin in early morning urine by the urinary creatinine concentration at 6, 12, and 24 weeks after the start of administration and the values ​​obtained by dividing the concentrations of β2-microglobulin and albumin in early morning urine by the urinary creatinine concentration before the start of administration (the values ​​obtained by dividing the concentrations of β2-microglobulin and albumin in early morning urine by the urinary creatinine concentration at 6, 12, and 24 weeks after the start of administration - the values ​​obtained by subtracting the concentrations of β2-microglobulin and albumin in early morning urine by the urinary creatinine concentration before the start of administration) (vii) The albumin and protein concentrations in random urine samples before the start of administration divided by the urinary creatinine concentration (viii) The albumin and protein concentrations in early morning urine divided by the urinary creatinine concentration at 6, 12, and 24 weeks after the start of administration. (ix) The difference between the values ​​obtained by dividing the concentrations of albumin and protein in early morning urine by the urinary creatinine concentration at 6, 12, and 24 weeks after the start of administration and the values ​​obtained by dividing the concentrations of albumin and protein in early morning urine by the urinary creatinine concentration before the start of administration (the values ​​obtained by dividing the concentrations of albumin and protein in early morning urine by the urinary creatinine concentration at 6, 12, and 24 weeks after the start of administration - the values ​​obtained by subtracting the concentrations of albumin and protein in early morning urine by the urinary creatinine concentration before the start of administration) (x) Osmolality of early morning urine before starting treatment (xi) Osmolality values ​​of early morning urine at 6, 12, and 24 weeks after the start of administration

[0072] Then, the average value and SD of each group were calculated for (i) to (xii) above. The results are shown in the table below. In the tables and figures, Group A, which received the potassium citrate-sodium citrate hydrate formulation, is referred to as "Citrate," and Group B, which received the sodium bicarbonate formulation, is referred to as "Bicarbonate."

[0073] Table 1 shows the ratio (%) of the 8-OHdG concentration in early morning urine divided by the urinary creatinine concentration 6, 12, and 24 weeks after the start of administration to the 8-OHdG concentration in early morning urine divided by the urinary creatinine concentration before the start of administration.

[0074] [Table 1]

[0075] In group A (administered citrate: potassium citrate and sodium citrate hydrate preparation), the concentration of 8-OHdG in early morning urine was lower at 6, 12 and 24 weeks after administration compared to group B (administered bicarbonate: sodium bicarbonate preparation) and group C (control: control group) (see Table 1). In group A, the concentration of 8-OHdG in early morning urine at 6 to 24 weeks after administration was significantly lower than in groups B and C (see Table 1). The concentration of 8-OHdG in urine reflects the accumulation of 8-OHdG in the kidney, which is an indicator of tissue damage. The above results show that administration of potassium citrate and sodium citrate hydrate preparation is useful for suppressing oxidative stress in the kidney of patients with chronic kidney disease, and that administration of potassium citrate and sodium citrate hydrate preparation exerts a protective effect on kidney tissue.

[0076] Table 2 shows the values ​​(μg / gCr) obtained by dividing the amount of angiotensinogen in early morning urine by the urinary creatinine concentration before the start of administration, and at 6, 12, and 24 weeks and 6 to 24 weeks after administration.

[0077] [Table 2]

[0078] In group B (bicarbonate: sodium bicarbonate preparation administered group), the concentration of angiotensinogen in early morning urine was significantly higher from 6 to 24 weeks of administration compared to group A (citrate: potassium citrate-sodium citrate hydrate preparation administered group) (see Table 2). It was shown that administration of sodium bicarbonate acts to enhance the intrarenal renin-angiotensin system, whereas administration of potassium citrate-sodium citrate hydrate preparation did not have such an effect.

[0079] Table 3 shows the difference (μg / gCr) obtained by subtracting the value obtained by dividing the β2-microglobulin concentration in early morning urine by the urinary creatinine concentration before the start of treatment from the value obtained by dividing the β2-microglobulin concentration in early morning urine by the urinary creatinine concentration 6, 12, and 24 weeks after the start of treatment.

[0080] [Table 3]

[0081] In Group A (Citrate: group administered a potassium citrate / sodium citrate hydrate compound preparation), there was a tendency for the concentration of β2 microglobulin in early morning urine to be lower from 6 to 24 weeks of administration compared to Group C (Control: control group) (see Table 3). This tendency was not observed in Group B (Bicarbonate: group administered a sodium bicarbonate compound preparation) (see Table 3). It was suggested that administration of a potassium citrate / sodium citrate hydrate compound preparation exerts a protective effect on renal tubular tissue compared to the control group.

[0082] Table 4 shows the difference (mg / gCr) obtained by subtracting the value obtained by dividing the early morning urine albumin concentration by the urinary creatinine concentration at 6, 12, and 24 weeks after the start of treatment from the value obtained by dividing the early morning urine albumin concentration by the urinary creatinine concentration before the start of treatment.

[0083] [Table 4]

[0084] In Group A (Citrate: group administered a potassium citrate-sodium citrate hydrate compound), the albumin concentration in early morning urine tended to be lower after administration compared to before the start of administration. This tendency was not observed in Group B (Bicarbonate: group administered a sodium bicarbonate compound) or Group C (Control: control group) (see Table 4). Furthermore, in Group A (Citrate: potassium citrate / sodium citrate hydrate compound administered group), the albumin concentration in early morning urine from 6 to 24 weeks of administration was significantly lower than in Group B (Bicarbonate: sodium bicarbonate administered group) and Group C (Control: control group) (see Table 4). It was demonstrated that administration of potassium citrate / sodium citrate hydrate compound protected renal function.

[0085] Table 5 shows the difference (mg / gCr) obtained by subtracting the value obtained by dividing the random urinary albumin concentration by the urinary creatinine concentration before the start of administration from the value obtained by dividing the random urinary albumin concentration by the urinary creatinine concentration 6, 12, and 24 weeks after the start of administration.

[0086] [Table 5]

[0087] In group A (administered citrate: potassium citrate-sodium citrate hydrate compound preparation group), albumin concentration in random urine after administration tended to be lower than before administration. This tendency was not observed in group B (administered bicarbonate: sodium bicarbonate preparation group) and group C (control group) (see Table 5). Additionally, in Group A (Citrate: potassium citrate / sodium citrate hydrate compound administered group), the albumin concentration in early morning urine from 6 to 24 weeks of administration was lower than in Group B (Bicarbonate: sodium bicarbonate administered group) and Group C (Control: control group) (see Table 5). It was demonstrated that administration of potassium citrate / sodium citrate hydrate compound protected renal function. Administration of the potassium citrate-sodium citrate hydrate combination formulation reduced urinary albumin concentrations compared to Group C (control group) in both early morning urine (see Table 4) and random urine (see Table 5), demonstrating that the potassium citrate-sodium citrate hydrate combination formulation exerts a renal function protective effect throughout the day.

[0088] Table 6 shows the difference (mg / gCr) obtained by subtracting the value obtained by dividing the protein concentration in random urine by the urinary creatinine concentration before the start of administration from the value obtained by dividing the protein concentration in random urine by the urinary creatinine concentration 6, 12, and 24 weeks after the start of administration.

[0089] [Table 6]

[0090] In group A (administered citrate: potassium citrate-sodium citrate hydrate compound preparation group), there was a tendency for random urine protein concentrations to be lower after administration compared to before the start of administration. This tendency was not observed in group B (administered bicarbonate: sodium bicarbonate preparation group) and group C (control group) (see Table 6). Furthermore, in group A (administered a citrate: potassium citrate-sodium citrate hydrate formulation), the protein concentration in early morning urine from 6 to 24 weeks of administration was lower than in group B (administered a bicarbonate: sodium bicarbonate formulation) and group C (control), indicating that renal function was protected.

[0091] Table 7 shows the osmolality values ​​(mOsm / kg H2O) of early morning urine at 6, 12, and 24 weeks after the start of administration.

[0092] [Table 7]

[0093] In Group A (Citrate: potassium citrate-sodium citrate hydrate compound administered group), early morning urine osmolality tended to be maintained or to increase after administration compared to before administration. In Group B (Bicarbonate: sodium bicarbonate administered group), early morning urine osmolality also tended to be maintained after administration compared to before administration, but in Group C (Control: control group), early morning urine osmolality tended to decrease after administration compared to before administration (see Table 7). It was suggested that administration of a combination of potassium citrate and sodium citrate hydrate maintained or improved urinary concentrating ability as a renal tubular function.

[0094] In addition, for Group A (Citrate: group administered with potassium citrate and sodium citrate hydrate), Group B (Bicarbonate: group administered with sodium bicarbonate), and Group C (Control: group administered with control), the pH of urine collected 2 to 5 hours after taking the morning medication (random urine: Spot in Figures 1 to 3) was measured, and the relationship with eGFR was plotted (Figures 1 to 3). In addition, the pH of urine collected 2 to 5 hours after taking the morning medication (random urine) and the pH of early morning urine were measured, and the relationship between the difference (pH of random urine - pH of early morning urine: Spot-Morning in Figures 4 to 6) and eGFR was plotted (Figures 4 to 6). As a result, only in Group A (Citrate: group administered with potassium citrate and sodium citrate hydrate), a significant correlation was observed between the value of "random urine pH" and eGFR (Figure 2), and a significant correlation was observed between the value of "random urine pH - early morning urine pH" and eGFR (Figure 5). [Industrial Applicability]

[0095] The pharmaceutical composition provided by the present invention protects the kidney and maintains or improves renal tubular function, and also allows evaluation of renal function.

Claims

[Claim 1] A pharmaceutical composition for renal protection in chronic kidney disease, comprising citric acid, a pharma- ceutical acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, the pharmaceutical composition being in the form of a tablet.

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