Blood purification through alkalifying agent

Abstract

To provide a pharmaceutical composition that is useful for maintaining kidney functions in mammals, particularly the human.SOLUTION: A pharmaceutical composition comprises an alkalinizing agent, particularly a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof, as an active ingredient.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This invention relates to blood purification using an alkalizing agent. This application claims priority based on Japanese Patent Application No. 2017-82423 filed in Japan on April 18, 2017, Japanese Patent Application No. 2017-85741 filed in Japan on April 24, 2017, Japanese Patent Application No. 2017-103935 filed in Japan on May 25, 2017, and PCT / JP2017 / 032931 filed internationally on September 12, 2017, the contents of which are incorporated herein by reference. [Background technology]

[0002] The number of patients with end-stage kidney disease (ESKD), requiring dialysis or transplantation, is increasing worldwide. This trend is also on the rise in Japan, with 320,000 dialysis patients at the end of 2014. Chronic kidney disease (CKD) is recognized as a precursor to ESKD. CKD is a comprehensive concept encompassing chronic kidney disease, regardless of the underlying disease, and includes all conditions in which there is a decline in renal function, expressed as glomerular filtration rate (GFR), or findings suggestive of kidney damage that 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 cardiovascular disease (CVD), etc. Therefore, early detection and appropriate treatment of CKD are extremely important. While many CKD treatments have been established, they are still insufficient, and further development of renal protective agents is needed.

[0003] In chronic kidney disease (CKD), various uremic substances accumulate in the body due to decreased renal clearance. In particular, indoxyl sulfate, a terminal metabolite of tryptophan, increases in blood concentration as CKD progresses, and high concentrations (100 μM to 1 mM) of indoxyl sulfate accumulate in the blood. Indoxyl sulfate is known to be deeply involved in the progression of renal damage due to renal fibrosis and in complications of CKD such as cardiovascular disease (CVD) due to vascular calcification, and there are reports that serum indoxyl sulfate concentration correlates with mortality and cardiovascular event incidence in dialysis patients (Non-Patent Literature 1). It is thought that lowering the blood concentration of indoxyl sulfate in CKD patients can suppress progression to advanced ketoglycemia (ESKD) and reduce the development of CVD associated with renal failure. In fact, a spherical activated carbon preparation (Kremezin®) that adsorbs indole, a precursor of indoxyl sulfate, in the intestinal tract and lowers blood indoxyl sulfate concentration delays the initiation of dialysis in CKD patients and improves arteriosclerosis (Non-Patent Literature 2).

[0004] On the other hand, in patients with advanced CKD, the blood contains bicarbonate ions (HCO3) - As the concentration of CKD decreases, metabolic acidosis develops, and alkalizing agents such as sodium bicarbonate and citrate preparations are administered. It has been reported that the administration of sodium bicarbonate, an alkalizing agent, suppresses the progression of CKD (Non-Patent Literature 3). In addition, in an animal model of nephrotic syndrome induced by protein overload, it has been reported that oral administration of sodium bicarbonate suppresses tubular cell damage caused by acidic urine (Non-Patent Literature 4). However, there have been no reports of administering alkalizing agents to early-stage CKD patients suppressing the progression of renal impairment, nor have there been any reports of a decrease in blood concentrations of uremic toxins. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Barreto, FC, et al.: Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients. Clin. J. Am. Soc. Nephrol., 4: 1551-1558, 2009. [Non-Patent Document 2] Nakamura T., et al.: Oral ADSORBENT AST-120 decreases carotid intima-media thickness and arterial stiffness in patients with chronic renal failure. Kidney Blood Press Res, 27: 121-6, 2004. [Non-Patent Document 3] 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 4] Souma T., et al.: Luminal alkalinization attenuates proteinuria-induced oxidative damage in proximal tubular cells. J. Am. Soc. Nephrol., 22: 635-648, 2011. [Overview of the project] [Problems that the invention aims to solve]

[0006] One of the objectives of the present invention is to provide a pharmaceutical agent useful for blood purification in patients with kidney disease. Another objective of the present invention is to provide a pharmaceutical agent useful for suppressing the progression of chronic kidney disease (worsening of chronic kidney disease), treating and preventing uremic symptoms, and delaying the initiation of dialysis. Another objective of the present invention is to provide a pharmaceutical agent useful for suppressing the progression from acute kidney disease to chronic kidney disease. Another objective of the present invention is to provide a food product for promoting the excretion of uremic substances from the body. Another objective of the present invention is to provide a food product for maintaining renal function (e.g., for suppressing tubular damage, protecting tubular cells, or maintaining tubular function). Another objective of the present invention is to provide a method for determining the suppression of the progression of chronic kidney disease, a decrease in the concentration of uremic substances in the blood, and / or promotion of the excretion of uremic substances in the urine. [Means for solving the problem]

[0007] The inventors of this invention conducted diligent research to achieve the above objectives and discovered that an agent that alkalizes body fluids is useful in promoting the excretion of uremic substances from the bodies of patients with kidney disease (for example, promoting the excretion of uremic substances into the urine), thus completing the present invention.

[0008] In one aspect, the present invention provides a pharmaceutical composition for promoting the excretion of uremic substances from the body, comprising an alkalizing agent.

[0009] In one aspect, the present invention provides a pharmaceutical composition for reducing the blood concentration of uremic substances, comprising an alkalizing agent.

[0010] In one aspect, the present invention provides a pharmaceutical composition for promoting urinary excretion in chronic kidney disease, comprising an alkalizing agent.

[0011] In one aspect, the present invention provides a pharmaceutical composition comprising an alkalizing agent for improving uremic symptoms in chronic kidney disease.

[0012] In one aspect, the present invention provides a pharmaceutical composition comprising an alkalizing agent for delaying the initiation of dialysis in chronic kidney disease.

[0013] In one aspect, the present invention provides a pharmaceutical composition for treating or preventing cardiovascular diseases associated with chronic kidney disease, which contains an alkalizing agent.

[0014] In one aspect, the present invention provides a pharmaceutical composition for suppressing the progression from acute kidney disease to chronic kidney disease, which contains an alkalizing agent.

[0015] In one aspect, the present invention provides a food composition for promoting the excretion of uremic substances outside the body, which contains an alkalizing agent.

[0016] In one aspect, the present invention provides a method for determining the suppression of the progression of chronic kidney disease.

[0017] In one aspect, the present invention provides a method for determining the decrease in the concentration of uremic toxins in human blood and / or the promotion of the excretion of uremic toxins into urine.

[0018] That is, the present invention has the following aspects. (1) A pharmaceutical composition for decreasing the blood concentration of uremic substances, which contains an alkalizing agent. (2) A pharmaceutical composition for promoting the urinary excretion of uremic substances, which contains an alkalizing agent. (3) A pharmaceutical composition for promoting the excretion of uremic substances outside the body, which contains an alkalizing agent. (4) The pharmaceutical composition according to (2) or (3), wherein the urinary excretion or excretion outside the body depends on the blood concentration of uremic substances. (5) The pharmaceutical composition according to any one of (1) to (4), which is administered to a patient with chronic kidney disease or acute kidney disease. (6) The pharmaceutical composition according to any one of (1) to (5), wherein the uremic substance is at least one selected from the group consisting of indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid, and argininosuccinic acid. (7) The pharmaceutical composition according to any one of (1) to (6), wherein the uremic substances are indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid, and argininosuccinic acid. The pharmaceutical composition according to any one of (1) to (6), wherein the uremic substances are indoxyl sulfate, p-cresyl sulfate and phenylacetyl-L-glutamine. The pharmaceutical composition according to any one of (1) to (6), wherein the uremic substances are indoxyl sulfate and phenylacetyl-L-glutamine. The pharmaceutical composition according to any one of (1) to (6), wherein the uremic substances are indoxyl sulfate and hippuric acid. The pharmaceutical composition according to any one of (1) to (6), wherein the uremic substances are phenylacetyl-L-glutamine and p-cresyl sulfate. The pharmaceutical composition according to any one of (1) to (6), wherein the uremic substance is indoxyl sulfate. A pharmaceutical composition for improving uremic symptoms in chronic kidney disease, comprising an alkalizing agent. A pharmaceutical composition for delaying the initiation of dialysis in chronic kidney disease, comprising an alkalizing agent. A pharmaceutical composition for treating or preventing cardiovascular diseases associated with chronic kidney disease, comprising an alkalizing agent. The pharmaceutical composition according to (15), which improves arteriosclerosis. A pharmaceutical composition for suppressing the progression of chronic kidney disease, comprising an alkalizing agent. A pharmaceutical composition for treating or preventing tubulointerstitial damage, comprising an alkalizing agent. The pharmaceutical composition according to any one of (1) to (18), which is administered to patients with early-stage chronic kidney disease. The pharmaceutical composition according to any one of (1) to (18), which is administered to patients with chronic kidney disease at stage G3b or lower. The pharmaceutical composition according to any one of (1) to (18), which is administered to patients with chronic kidney disease at stage G2 or higher and G3b or lower. The pharmaceutical composition according to any one of (1) to (18), which is administered to patients with chronic kidney disease at stages G2 and G3a. The pharmaceutical composition according to any one of (1) to (18), which is administered to patients with chronic kidney disease at stage G2. (24) A pharmaceutical composition according to any one of (1) to (18), which is administered to a patient whose urinary β2-microglobulin concentration is 290 μg / L or less. (25) A pharmaceutical composition according to any one of (1) to (18), which is administered to patients whose urinary β2-microglobulin concentration is 50 to 150 μg / L or less. (26) A pharmaceutical composition according to any one of (1) to (18), which is administered to patients whose blood cystatin C concentration is 0.5 to 2.2 mg / L or less. (27) A pharmaceutical composition according to any one of (1) to (18), which is administered to patients whose blood cystatin C concentration is 1.0 to 1.3 mg / L or less. (28) A pharmaceutical composition containing an alkalizing agent for inhibiting the progression from acute kidney disease to chronic kidney disease. (29) The pharmaceutical composition according to any one of (1) to (28), wherein the alkalizing agent is a pharmaceutically acceptable salt of citric acid, a hydrate thereof, or a mixture thereof. (30) The pharmaceutical composition according to any one of (1) to (29), wherein the alkalizing agent is sodium citrate, potassium citrate, or a hydrate thereof, or a mixture thereof. (31) The pharmaceutical composition according to any one of (1) to (30), wherein the alkalizing agent comprises a mixture of sodium citrate or its hydrate and potassium citrate or its hydrate. (32) The pharmaceutical composition according to any one of (1) to (31), wherein the alkalizing agent is sodium citrate or its hydrate. (33) A pharmaceutical composition according to any one of (1) to (32), wherein the pharmaceutical composition is a tablet. (34) A pharmaceutical composition according to any one of (1) to (33), wherein a decrease in the blood concentration of uremic substances compared to before the start of administration of the alkalizing agent is detected 12 weeks after administration of the alkalizing agent. (35) A pharmaceutical composition according to any one of (1) to (34), wherein an increase in the urinary concentration of uremic substances compared to before the start of administration of the alkalizing agent is detected 12 weeks after administration of the alkalizing agent. (36) A pharmaceutical composition according to any one of (1) to (35), wherein an increase in the excretion of uremic substances compared to before the start of administration of the alkalizing agent is detected 12 weeks after administration of the alkalizing agent. (37) The pharmaceutical composition according to any one of (1) to (36), wherein the increase in the concentration of β2-microglobulin in the urine is suppressed by the administration of an alkalizing agent. (38) The pharmaceutical composition according to any one of (1) to (37), wherein the increase in urinary β2-microglobulin concentration is suppressed 12 weeks after administration by the administration of an alkalizing agent. (39) A pharmaceutical composition according to any one of (1) to (38), wherein the administration of an alkalizing agent does not substantially reduce the β2-microglobulin concentration in the urine compared to before the start of administration. (40) A pharmaceutical composition according to any one of (1) to (39), wherein, after administration of an alkalizing agent, the urinary β2-microglobulin concentration is not substantially reduced compared to before administration at 12 weeks after administration. (41) A pharmaceutical composition according to any one of (1) to (40), wherein administration of an alkalizing agent does not substantially increase the amount of cystatin C in the blood compared to before administration. (42) A pharmaceutical composition according to any one of (1) to (41), wherein, upon administration of an alkalizing agent, blood cystatin C does not substantially increase 12 weeks after administration compared to before the start of administration. (43) A pharmaceutical composition according to any one of (1) to (42), wherein, upon administration of an alkalizing agent, no improvement in proximal tubular dysfunction and / or glomerular dysfunction is observed compared to before administration, but a decrease in blood concentration of uremic substances, promotion of urinary excretion of uremic substances and / or promotion of extracorporeal excretion of uremic substances are observed compared to before administration. (44) A pharmaceutical composition according to any one of (1) to (43), wherein, 12 weeks after administration of the alkalizing agent, no improvement in proximal tubular dysfunction and / or glomerular dysfunction is observed compared to before administration, but a decrease in blood concentration of uremic substances, promotion of urinary excretion of uremic substances and / or promotion of extracorporeal excretion of uremic substances are observed compared to before administration. (45) A pharmaceutical composition according to any one of (1) to (44), wherein an alkalizing agent is administered at a dose of 1 to 3 g / day. (46) A pharmaceutical composition according to any one of (1) to (45), wherein an alkalizing agent is administered at a dose of 1 to 1.5 g / day. (47) A pharmaceutical composition according to any one of (1) to (46), wherein an alkalizing agent is administered so that the pH of the early morning urine is pH 5.2 to pH 6.8. (48) A pharmaceutical composition according to any one of (1) to (47), wherein an alkalizing agent is administered so that the pH of the early morning urine is pH 6.0 or higher and less than pH 6.2. (49) A pharmaceutical composition according to any one of (1) to (48), wherein an alkalizing agent is administered for 12 weeks or more. (50) A pharmaceutical composition according to any one of (1) to (49), wherein an alkalizing agent is administered for 12 weeks. (50-1) A pharmaceutical composition according to any one of (1) to (50), wherein the amount of uremic substances in the urine increases upon administration of an alkalizing agent. (50-2) A pharmaceutical composition according to any one of (1) to (50) and (50-1), wherein the concentration of uremic substances in the urine increases upon administration of an alkalizing agent. (50-3) A pharmaceutical composition according to any one of (1) to (50), (50-1), and (50-2), wherein administration of an alkalizing agent exhibits an effect of reducing the blood concentration of uremic substances, promoting urinary excretion, and / or promoting excretion from the body, and the effects are observed compared to placebo administration. (50-4) A pharmaceutical composition according to any one of (1) to (50) and (50-1) to (50-3), wherein administration of an alkalizing agent exhibits an effect of reducing the blood concentration of uremic substances, promoting urinary excretion, and / or promoting excretion from the body, and the effects are observed compared to before administration of the alkalizing agent. (50-5) A pharmaceutical composition according to any one of (1) to (50) and (50-1) to (50-4), wherein the pharmaceutical composition is a tablet. (50-6) A pharmaceutical composition according to any one of (1) to (50) and (50-1) to (50-5), wherein the urine is early morning urine. (51) A food composition containing an alkalizing agent for reducing the blood concentration of uremic substances, promoting urinary excretion, and / or promoting excretion from the body. (52) The food composition according to (51), wherein the alkalizing agent is an alkali metal salt of citrate or its hydrate or a mixture thereof. (52-1) A food composition according to (51) or (52) that maintains renal function (suppresses tubular damage, protects tubular cells, or maintains tubular function). (52-2) A food composition according to any one of (51), (52), and (52-1), wherein the alkalizing agent is ingested at a rate of 1 to 3 g / day. (52-3) A food composition according to any one of (51), (52), (52-1), and (52-2), wherein the alkalizing agent is ingested at a rate of 1 to 1.5 g / day. (52-4) A food composition according to any one of (51), (52), and (52-1) to (52-3), wherein the blood concentration of uremic substances decreases compared to before ingestion of the alkalizing agent or compared to placebo ingestion. (52-5) A food composition according to any one of (51), (52), and (52-1) to (52-4), wherein the urinary concentration of uremic substances increases compared to before ingestion of the alkalizing agent or compared to placebo ingestion. (52-6) A food composition according to any one of (51), (52), and (52-1) to (52-5), wherein the amount of uremic substances in the urine increases compared to before ingestion of the alkalizing agent or compared to placebo ingestion. (52-7) A food composition according to any one of (51), (52), and (52-1) to (52-6), wherein the excretion of uremic substances from the body increases compared to before the start of alkalizing agent intake or compared to placebo intake. (52-8) The food composition according to any one of (51), (52), and (52-1) to (52-7), wherein the increase in β2-microglobulin concentration in the urine is suppressed by the intake of an alkalizing agent. (52-9) A food composition according to any one of (51), (52), and (52-1) to (52-8), wherein the intake of an alkalizing agent does not substantially reduce the urinary β2-microglobulin concentration compared to before intake or with placebo intake. (52-10) A food composition according to any one of (51), (52), and (52-1) to (52-9), wherein the intake of an alkalizing agent does not substantially increase cystatin C in the blood. (52-11) A food composition according to any one of (51), (52), and (52-1) to (52-10), wherein the alkalizing agent is ingested for 12 weeks or more. (52-12) A food composition according to any one of (51), (52), and (52-1) to (52-11), wherein an alkalizing agent is ingested for 12 weeks. (53) A method for determining the suppression of the progression of chronic kidney disease, comprising measuring the pH of urine. (54) A method for determining a decrease in the concentration of uremic substances in the blood of a patient with chronic kidney disease, comprising measuring the pH of the urine. (55) A method for determining the promotion of excretion of uremic substances into the urine of a patient with chronic kidney disease, comprising measuring the pH of the urine.

[0019] Furthermore, the present invention has the following aspects. (56) A pharmaceutical composition for reducing the blood concentration of uremic substances, comprising an alkalizing agent, the pharmaceutical composition being in the form of a tablet. (57) A pharmaceutical composition for promoting the urinary excretion of uremic substances, comprising an alkalizing agent, the pharmaceutical composition being in the form of a tablet. (58) The pharmaceutical composition according to (56) or (57), which is administered to patients with chronic kidney disease or acute kidney disease. (59) The pharmaceutical composition according to any one of (56) to (58), wherein the uremic substance is selected from the group consisting of indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and argininosuccinic acid, at least one of these. (60) A pharmaceutical composition according to any one of (56) to (59), wherein the uremic substance is indoxyl sulfate. (61) A pharmaceutical composition for inhibiting the progression of chronic kidney disease, comprising an alkalizing agent, the pharmaceutical composition being in the form of a tablet. (62) A pharmaceutical composition for the treatment or prevention of renal tubular disorders, comprising an alkalizing agent, the pharmaceutical composition being in the form of a tablet. (63) The pharmaceutical composition according to any one of (56) to (62), wherein the alkalizing agent is a pharmaceutically acceptable salt of citric acid, a hydrate thereof, or a mixture thereof. (64) The pharmaceutical composition according to any one of (56) to (63), wherein the alkalizing agent comprises a mixture of sodium citrate or its hydrate and potassium citrate or its hydrate.

[0020] Furthermore, the present invention has the following aspects. (65) A food composition containing an alkalizing agent for maintaining kidney function. (66) The food composition according to (65), wherein maintenance of renal function is suppression of tubular damage, protection of tubular cells, or maintenance of tubular function. (67) The food composition according to (66), wherein the renal tubule is the proximal tubule. (68) The food composition according to any one of (65) to (67), wherein the alkalizing agent is a food-acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof. (69) The food composition according to any one of (65) to (68), wherein the alkalizing agent comprises a mixture of sodium citrate or its hydrate and potassium citrate or its hydrate. (70) The food composition according to any one of (65) to (69), wherein the alkalizing agent is sodium citrate or its hydrate. (71) The food composition according to any one of (65) to (70), wherein the food composition is a tablet. (72) A food composition according to any one of (65) to (71), wherein the packaging, container, or instructions for the food composition indicate the effect of maintaining kidney function. (73) A food composition according to any one of (65) to (71), wherein the packaging, container, or instructions for the food composition indicate the effect of inhibiting tubular damage, protecting tubular cells, or maintaining tubular function. (74) A food composition described in any one of (65) to (72) for consumption by healthy individuals concerned about kidney health. (75) A food composition described in any one of (65) to (71) and (73) for consumption by healthy individuals concerned about the health of their renal tubules. (76) A food composition according to any one of (65) to (75) that is ingested by a subject whose urinary β2-microglobulin concentration is 290 μg / L or less. (77) A food composition according to any one of (65) to (76) that is ingested by a subject whose urinary β2-microglobulin concentration is 50 to 150 μg / L. (78) A food composition according to any one of (65) to (77) for ingestion to a subject whose blood cystatin C concentration is 0.5 to 2.2 mg / L. (79) A food composition according to any one of (65) to (78) for ingestion to a target whose blood cystatin C concentration is 1.0 to 1.3 mg / L. (80) A food composition according to any one of (65) to (79), wherein the intake of the food composition suppresses the increase in β2-microglobulin concentration in the urine. (81) The food composition according to any one of (65) to (80), wherein the increase in β2-microglobulin concentration in urine is suppressed after 12 weeks of ingestion. (82) A food composition according to any one of (65) to (81), wherein the intake of the food composition does not substantially reduce the β2-microglobulin concentration in the urine compared to before intake or with a placebo. (83) A food composition according to any one of (65) to (82), wherein, after ingestion of the food composition, the urinary β2-microglobulin concentration does not substantially decrease compared to before ingestion or placebo 12 weeks after ingestion. (84) A food composition according to any one of (65) to (83), wherein the intake of the food composition does not substantially increase the amount of cystatin C in the blood compared to before intake. (85) A food composition according to any one of (65) to (84), wherein ingestion of the food composition does not substantially increase blood cystatin C compared to placebo. (86) A food composition according to any one of (65) to (85) that, upon ingestion, suppresses the increase in the amount of β2-microglobulin in the early morning urine associated with the progression of chronic kidney disease. (87) A food composition according to any one of (65) to (86), which, upon ingestion, does not affect glomerular function in patients with chronic kidney disease, while suppressing proximal tubular cell damage associated with the progression of chronic kidney disease and protecting proximal tubular cells. [Effects of the Invention]

[0021] The pharmaceutical compositions and the like provided by the present invention allow for the excretion of uremic substances from the body in mammals. The methods provided by the present invention allow for a preliminary determination of whether or not uremic substances are excreted from the body and / or whether or not the progression of chronic kidney disease is suppressed. The food compositions and the like provided by the present invention enable the maintenance of renal function in mammals, more specifically, the suppression of tubular damage, the protection of tubular cells, or the maintenance of tubular function. [Brief explanation of the drawing]

[0022] [Figure 1] This figure shows the correlation between urinary indoxyl sulfate concentration and plasma indoxyl sulfate concentration in control group patients at 6, 12, and 24 weeks after the start of the trial. [Figure 2] This figure shows the correlation between urinary indoxyl sulfate concentration and plasma indoxyl sulfate concentration in patients treated with the potassium citrate / sodium citrate hydrate formulation at 6, 12, and 24 weeks after the start of the trial. [Figure 3] This figure shows the correlation between urinary indoxyl sulfate concentration and plasma indoxyl sulfate concentration in patients treated with sodium bicarbonate at 6, 12, and 24 weeks after the start of the trial. [Figure 4] This figure shows the correlation between urinary indoxyl sulfate concentration and plasma indoxyl sulfate concentration in all patients at 6, 12, and 24 weeks after the start of the study. [Figure 5]This figure shows the correlation between urinary p-cresyl sulfate concentration and plasma p-cresyl sulfate concentration in control group patients at 6, 12, and 24 weeks after the start of the study. [Figure 6] This figure shows the correlation between urinary p-cresyl sulfate concentration and plasma p-cresyl sulfate concentration in patients treated with the potassium citrate / sodium citrate hydrate formulation at 6, 12, and 24 weeks after the start of the trial. [Figure 7] This figure shows the correlation between urinary p-cresyl sulfate concentration and plasma p-cresyl sulfate concentration in patients treated with sodium bicarbonate at 6, 12, and 24 weeks after the start of the trial. [Figure 8] This figure shows the correlation between urinary p-cresyl sulfate concentration and plasma p-cresyl sulfate concentration in all patients at 6, 12, and 24 weeks after the start of the study. [Figure 9] This figure shows the correlation between urinary hippuric acid concentration and plasma hippuric acid concentration in control group patients at 6, 12, and 24 weeks after the start of the trial. [Figure 10] This figure shows the correlation between urinary hippuric acid concentration and plasma hippuric acid concentration in patients treated with the potassium citrate / sodium citrate hydrate formulation at 6, 12, and 24 weeks after the start of the trial. [Figure 11] This figure shows the correlation between urinary hippuric acid concentration and plasma hippuric acid concentration in patients treated with sodium bicarbonate at 6, 12, and 24 weeks after the start of the trial. [Figure 12] This figure shows the correlation between urinary hippuric acid concentration and plasma hippuric acid concentration in all patients at 6, 12, and 24 weeks after the start of the study. [Figure 13] This figure shows the correlation between urinary argininosuccinate concentration and plasma argininosuccinate concentration in control group patients at 6, 12, and 24 weeks after the start of the trial. [Figure 14] This figure shows the correlation between urinary argininosuccinate concentration and plasma argininosuccinate concentration in patients treated with the potassium citrate / sodium citrate hydrate formulation at 6, 12, and 24 weeks after the start of the trial. [Figure 15] This figure shows the correlation between urinary argininosuccinate concentration and plasma argininosuccinate concentration in patients treated with sodium bicarbonate at 6, 12, and 24 weeks after the start of the trial. [Figure 16] This figure shows the correlation between urinary argininosuccinate concentration and plasma argininosuccinate concentration in all patients at 6, 12, and 24 weeks after the start of the study. [Figure 17] This figure shows the correlation between urinary phenylacetyl-L-glutamine concentration and plasma phenylacetyl-L-glutamine concentration in control group patients at 6, 12, and 24 weeks after the start of the study. [Figure 18] This figure shows the correlation between urinary phenylacetyl-L-glutamine concentration and plasma phenylacetyl-L-glutamine concentration in patients treated with the potassium citrate / sodium citrate hydrate combination formulation at 6, 12, and 24 weeks after the start of the trial. [Figure 19] This figure shows the correlation between urinary phenylacetyl-L-glutamine concentration and plasma phenylacetyl-L-glutamine concentration in patients treated with sodium bicarbonate at 6, 12, and 24 weeks after the start of the trial. [Figure 20] This figure shows the correlation between urinary phenylacetyl-L-glutamine concentration and plasma phenylacetyl-L-glutamine concentration in all patients at 6, 12, and 24 weeks after the start of the study. [Modes for carrying out the invention]

[0023] 1. Pharmaceutical composition The pharmaceutical composition provided by the present invention may contain an alkalizing agent as an active ingredient. Alkalinizing agents are the HCO3 found in the bodily fluids of mammals (especially humans), such as blood or urine. - These are chemicals that have the ability to increase concentration or pH. Examples of alkalizing agents include pharmaceutically acceptable salts of citric acid, their hydrates, or mixtures thereof, and sodium bicarbonate (baking soda). Examples of pharmaceutically acceptable salts of citric acid include alkali metal citrate salts. Examples of alkali metal citrate salts include potassium citrate and sodium citrate, which may be stable monohydrates of potassium citrate (C6H5K3O7·H2O) and dihydrates of sodium citrate (C6H5Na3O7·2H2O), respectively. Examples of preferred alkalizing agents include sodium citrate, potassium citrate, their hydrates, or mixtures thereof. For example, a mixture of potassium citrate monohydrate (C6H5K3O7·H2O) and sodium citrate dihydrate (C6H5Na3O7·2H2O) may be used. The mixing ratio of potassium citrate monohydrate (C6H5K3O7·H2O) and sodium citrate dihydrate (C6H5Na3O7·2H2O) can be appropriately set by those skilled in the art. For example, the molar ratio of potassium citrate monohydrate to sodium citrate dihydrate can be 1 part potassium citrate monohydrate to 0.01 to 100 parts sodium citrate dihydrate. The mixing ratio may also be approximately 1:1 in molar ratio. Other examples of preferred alkalizing agents include sodium citrate or its hydrate, for example, sodium citrate dihydrate (C6H5Na3O7·2H2O). Other examples of preferred alkalizing agents include potassium citrate or its hydrate, which may be, for example, potassium citrate monohydrate (C6H5K3O7·H2O). In one embodiment, the alkalizing agent contained in the pharmaceutical composition of the present invention may include a mixture of sodium citrate or its hydrate and potassium citrate or its hydrate. In another embodiment, the alkalizing agent contained in the pharmaceutical composition of the present invention may consist only of a mixture of sodium citrate or its hydrate and potassium citrate or its hydrate. In this specification, when referring to the weight of an alkalizing agent (for example, potassium citrate monohydrate (C6H5K3O7·H2O) and sodium citrate dihydrate (C6H5Na3O7·2H2O)), the weight may be the dry weight.

[0024] In this specification, uremic substances refer to substances (waste products, toxins, etc.) that are normally excreted by a healthy kidney, but which increase (accumulate) in the blood and cause symptoms or diseases of uremia when the excretory function is impaired due to some cause such as impaired renal function. Examples of uremic substances include indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and argininosuccinate. Of these, indoxyl sulfate is produced when indole, which is generated from tryptophan derived from dietary protein by intestinal bacteria, is oxidized and sulfated in the liver. In the blood, most indoxyl sulfate exists bound to albumin and is not metabolized. In healthy individuals, it is excreted in the urine by the kidneys, but in patients with kidney disease, it remains accumulated in the blood at high concentrations due to impaired kidney function. Indoxyl sulfate, a uremic substance, not only causes uremia in patients with kidney disease but also leads to the need for dialysis in patients with chronic kidney disease. Therefore, by lowering the concentration of indoxyl sulfate in the blood, uremic symptoms in patients with kidney disease can be improved, making it possible to treat and / or prevent uremia. Furthermore, by lowering the concentration of indoxyl sulfate in the blood, it is possible to delay the initiation of dialysis in patients with chronic kidney disease. In one embodiment, the patient has progressive chronic kidney disease. In this specification, the expression "[A, B and / or C]" means "at least one selected from the group consisting of A, B and C." Therefore, for example, "indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid and / or argininosuccinic acid" means "at least one selected from the group consisting of indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid and argininosuccinic acid."

[0025] Furthermore, indoxyl sulfate, a uremic substance, induces myocardial fibrosis, arteriosclerosis, proliferation of vascular smooth muscle cells, vascular endothelial cell damage, thickening of arterial walls, and calcification of the aorta, leading to the development of cardiovascular diseases (e.g., heart failure, myocardial infarction) and / or cerebrovascular diseases such as stroke, which are complications of chronic kidney disease. Therefore, by lowering the concentration of indoxyl sulfate in the blood, it is possible to suppress myocardial fibrosis, arteriosclerosis, proliferation of vascular smooth muscle cells, vascular endothelial cell damage, arterial wall thickening, and aortic calcification, thereby enabling the treatment and / or prevention of cardiovascular and / or cerebrovascular diseases, which are among the complications of chronic kidney disease.

[0026] In one respect, the pharmaceutical compositions provided by the present invention can reduce the concentration of uremic substances in the blood (e.g., indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, argininosuccinic acid, and combinations thereof). Examples of indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, argininosuccinic acid, and combinations thereof include: indoxyl sulfate, p-cresyl sulfate, hippuric acid, and phenylacetyl-L-glutamine; indoxyl sulfate, p-cresyl sulfate, and phenylacetyl-L-glutamine; indoxyl sulfate, hippuric acid, and phenylacetyl-L-glutamine; indoxyl sulfate and p-cresyl sulfate; indoxyl sulfate and hippuric acid; indoxyl sulfate and phenylacetyl-L-glutamine; p-cresyl sulfate and phenylacetyl-L-glutamine; hippuric acid and phenylacetyl-L-glutamine; indoxyl sulfate; p-cresyl sulfate; hippuric acid; and phenylacetyl-L-glutamine. In this specification, "decrease in the concentration of uremic substances in the blood" means that the concentration of uremic substances in the blood after administration is lower compared to the concentration of uremic substances in the blood before administration of the pharmaceutical composition provided by the present invention, or that the concentration of uremic substances in the blood is lower compared to placebo administration by administration of the pharmaceutical composition provided by the present invention. In one embodiment, administration of the pharmaceutical composition provided by the present invention reduces the amount of uremic substances in the blood (e.g., indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, argininosuccinic acid, and combinations thereof) compared to before administration. The concentrations of phenylacetyl-L-glutamine (p-cresyl sulfate and phenylacetyl-L-glutamine), hippuric acid and phenylacetyl-L-glutamine, indoxyl sulfate, p-cresyl sulfate, hippuric acid, or phenylacetyl-L-glutamine)) decrease, but the amount of decrease is 1-5%, 3-5%, 1-10%, 3-10%, 5-10%, 1-15%, 3-15%, 5-15%, 1-30%, 1-40%, 3-40%, 5-40%, 1-50%, 3-50%, 5-50%, 30-50%, 1-60%, 5% or more, 10% or more, or 30% or more of the blood concentration of uremic substances before administration. In one embodiment, the decrease in the blood concentration of uremic substances is calculated using the following formula (1). Reduction in blood concentration of uremic substances (%) = [(Blood concentration of uremic substances before administration of the pharmaceutical composition (ng / mL) - Blood concentration of uremic substances after administration of the pharmaceutical composition (ng / mL)) / Blood concentration of uremic substances before administration of the pharmaceutical composition (ng / mL)] × 100 (1) In one embodiment, continuous administration of the pharmaceutical composition provided by the present invention for 6, 12, or 24 weeks reduces the amount of uremic substances in the blood compared to before administration (e.g., indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, argininosuccinic acid and combinations thereof (e.g., indoxyl sulfate, p-cresyl sulfate, hippuric acid and phenylacetyl-L-glutamine; indoxyl sulfate, p-cresyl sulfate and phenylacetyl-L-glutamine; indoxyl sulfate, hippuric acid and phenylacetyl-L-glutamine; indoxyl sulfate and p-cresyl sulfate; indoxyl sulfate and hippuric acid; indoxyl sulfate and hippuric acid; indoxyl sulfate and hippuric acid); The concentrations of indoxyl sulfate and phenylacetyl-L-glutamine; p-cresyl sulfate and phenylacetyl-L-glutamine; hippuric acid and phenylacetyl-L-glutamine; indoxyl sulfate; p-cresyl sulfate; hippuric acid; or phenylacetyl-L-glutamine) decrease, with the amount of decrease being 1-5%, 3-5%, 1-10%, 3-10%, 5-10%, 1-15%, 3-15%, 5-15%, 1-30%, 1-40%, 3-40%, 5-40%, 1-50%, 3-50%, 5-50%, 30-50%, 1-60%, 5% or more, 10% or more, or 30% or more of the blood concentration of uremic substances before administration. In one aspect, the pharmaceutical compositions provided by the present invention can promote the excretion of uremic substances (e.g., indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid, argininosuccinic acid, and combinations thereof) into the urine. Examples of indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid, argininosuccinic acid, and combinations thereof include: indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid and argininosuccinic acid; indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine and argininosuccinic acid; indoxyl sulfate, p-cresyl sulfate, hippuric acid and phenylacetyl L-glutamine; indoxyl sulfate, p-cresyl sulfate and phenylacetyl L-glutamine; indoxyl sulfate, phenylacetyl L-glutamine and argininosuccinic acid; indoxyl sulfate, horse Examples include uric acid and phenylacetyl-L-glutamine; indoxyl sulfate and hippuric acid; indoxyl sulfate and phenylacetyl-L-glutamine; hippuric acid and phenylacetyl-L-glutamine; indoxyl sulfate and p-cresyl sulfate; p-cresyl sulfate and phenylacetyl-L-glutamine; p-cresyl sulfate and hippuric acid; indoxyl sulfate and argininosuccinic acid; p-cresyl sulfate and argininosuccinic acid; hippuric acid and argininosuccinic acid; phenylacetyl-L-glutamine and argininosuccinic acid; indoxyl sulfate; p-cresyl sulfate; hippuric acid; argininosuccinic acid; and phenylacetyl-L-glutamine. In this specification, "promotion of excretion of uremic substances in urine" means that the concentration of uremic substances in the urine after administration increases compared to the concentration of uremic substances in the urine before administration of the pharmaceutical composition provided by the present invention; that the concentration of uremic substances in the urine increases compared to placebo administration by administration of the pharmaceutical composition provided by the present invention; that the amount of uremic substances in the urine after administration increases compared to the amount of uremic substances in the urine before administration of the pharmaceutical composition provided by the present invention; or that the amount of uremic substances in the urine increases compared to placebo administration by administration of the pharmaceutical composition provided by the present invention. In this specification, "urine" means, for example, "early morning urine." In one embodiment, administration of the pharmaceutical composition provided by the present invention reduces uremic substances in the urine compared to before administration (e.g., indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid, argininosuccinic acid and combinations thereof (e.g., indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid and argininosuccinic acid; indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine and argininosuccinic acid; indoxyl sulfate, p-cresyl sulfate, hippuric acid and phenylacetyl L-glutamine; indoxyl sulfate, p-cresyl sulfate and phenylacetyl L-glutamine; indoxyl sulfate, phenylacetyl L-glutamine and argininosuccinic acid; indoxyl sulfate, hippuric acid and phenylacetyl L-glutamine; indoxyl sulfate and horse Uric acid; indoxyl sulfate and phenylacetyl-L-glutamine; hippuric acid and phenylacetyl-L-glutamine; indoxyl sulfate and p-cresyl sulfate; p-cresyl sulfate and phenylacetyl-L-glutamine; p-cresyl sulfate and hippuric acid; indoxyl sulfate and argininosuccinic acid; p-cresyl sulfate and argininosuccinic acid; hippuric acid and argininosuccinic acid; phenylacetyl-L-glutamine and The concentration of arginosuccinic acid; indoxyl sulfate; p-cresyl sulfate; hippuric acid; argininosuccinic acid; or phenylacetyl-L-glutamine) increases by 1-100%, 1-50%, 3-50%, 5-50%, 10-50%, 15-50%, 1-40%, 5-40%, 10-40%, 1-30%, 5-30%, 10-30%, 15-30%, 10% or more, 20% or more, 30% or more, or 40% or more. In one embodiment, the increase in the concentration of uremic substances in the urine is calculated using the following formula (2). Increase in urinary concentration of uremic substances (%) = [(Urinary concentration of uremic substances after administration of the pharmaceutical composition (ng / mL) - Urinary concentration of uremic substances before administration of the pharmaceutical composition (ng / mL)) / Urinary concentration of uremic substances before administration of the pharmaceutical composition (ng / mL)] × 100 (2) In one embodiment, continuous administration of the pharmaceutical composition provided by the present invention for 6, 12, or 24 weeks reduces the amount of uremic substances in the urine compared to before administration (e.g., indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, argininosuccinic acid and combinations thereof (e.g., indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid and argininosuccinic acid; indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine and argininosuccinic acid; indoxyl sulfate, p-cresyl sulfate, hippuric acid and phenylacetyl-L-glutamine; indoxyl sulfate, p-cresyl sulfate and phenylacetyl-L-glutamine; indoxyl sulfate, phenylacetyl-L-glutamine and argininosuccinic acid; indoxyl sulfate, hippuric acid and phenylacetyl-L-glutamine; indoxyl sulfate Indoxyl sulfate and hippuric acid; indoxyl sulfate and phenylacetyl L-glutamine; hippuric acid and phenylacetyl L-glutamine; indoxyl sulfate and p-cresyl sulfate; p-cresyl sulfate and phenylacetyl L-glutamine; p-cresyl sulfate and hippuric acid; indoxyl sulfate and argininosuccinic acid; p-cresyl sulfate and argininosuccinic acid; hippuric acid and argininosuccinic acid; phenylacetyl L-glutamine The concentrations of (and argininosuccinic acid; indoxyl sulfate; p-cresyl sulfate; hippuric acid; argininosuccinic acid; or phenylacetyl-L-glutamine) increase by 1-100%, 1-50%, 3-50%, 5-50%, 10-50%, 15-50%, 1-40%, 5-40%, 10-40%, 1-30%, 5-30%, 10-30%, 15-30%, 10% or more, 20% or more, 30% or more, or 40% or more. In one aspect, the pharmaceutical compositions provided by the present invention can promote the excretion of uremic substances (e.g., indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid, argininosuccinic acid, and combinations thereof) from the blood into the urine and promote their excretion from the body. Examples of indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid, argininosuccinic acid, and combinations thereof include: indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid and argininosuccinic acid; indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine and argininosuccinic acid; indoxyl sulfate, p-cresyl sulfate, hippuric acid and phenylacetyl L-glutamine; indoxyl sulfate, p-cresyl sulfate and phenylacetyl L-glutamine; indoxyl sulfate, phenylacetyl L-glutamine and argininosuccinic acid; indoxyl sulfate, horse Examples include uric acid and phenylacetyl-L-glutamine; indoxyl sulfate and hippuric acid; indoxyl sulfate and phenylacetyl-L-glutamine; hippuric acid and phenylacetyl-L-glutamine; indoxyl sulfate and p-cresyl sulfate; p-cresyl sulfate and phenylacetyl-L-glutamine; p-cresyl sulfate and hippuric acid; indoxyl sulfate and argininosuccinic acid; p-cresyl sulfate and argininosuccinic acid; hippuric acid and argininosuccinic acid; phenylacetyl-L-glutamine and argininosuccinic acid; indoxyl sulfate; p-cresyl sulfate; hippuric acid; argininosuccinic acid; and phenylacetyl-L-glutamine. In one embodiment, administration of the pharmaceutical composition provided by the present invention increases the ratio of the concentration of uremic substances in urine to the concentration of uremic substances in blood after administration, compared to the ratio of the concentration of uremic substances in urine to the concentration of uremic substances in blood before administration of the pharmaceutical composition provided by the present invention. In one embodiment, administration of the pharmaceutical composition provided by the present invention increases the ratio of the concentration of uremic substances in urine to the concentration of uremic substances in blood compared to placebo administration. In one embodiment, administration of the pharmaceutical composition provided by the present invention reduces the concentration of uremic substances in the urine relative to the blood concentration (e.g., indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid, argininosuccinic acid and combinations thereof) compared to before administration. Sulfuric acid and phenylacetyl-L-glutamine; hippuric acid and phenylacetyl-L-glutamine; indoxyl sulfate and p-cresyl sulfate; p-cresyl sulfate and phenylacetyl-L-glutamine; p-cresyl sulfate and hippuric acid; indoxyl sulfate and argininosuccinic acid; p-cresyl sulfate and argininosuccinic acid; hippuric acid and argininosuccinic acid; phenylacetyl-L-glutamine and argininosuccinic acid; indoxyl sulfate; The ratio of the concentrations of p-cresyl sulfate (hippuric acid; argininosuccinate; or phenylacetyl-L-glutamine) (urinary concentration (ng / mL) / blood concentration (ng / mL)) increases by 1-100%, 1-50%, 3-50%, 5-50%, 10-50%, 15-50%, 1-40%, 5-40%, 10-40%, 1-30%, 5-30%, 10-30%, 15-30%, 10% or more, 20% or more, 30% or more, or 40% or more. In one embodiment, the increase in the ratio of the urinary concentration to the blood concentration of uremic substances (urinary concentration (ng / mL) / blood concentration (ng / mL)) is calculated using the following formula (3). Increase in the ratio of urinary concentration to blood concentration of uremic substances (%) = [(ratio of urinary concentration to blood concentration of uremic substances after administration of the pharmaceutical composition - ratio of urinary concentration to blood concentration of uremic substances before administration of the pharmaceutical composition) / ratio of urinary concentration to blood concentration of uremic substances before administration of the pharmaceutical composition] × 100 (3) In one embodiment, continuous administration of the pharmaceutical composition provided by the present invention for 6, 12, or 24 weeks reduces the blood concentration of uremic substances in urine (e.g., indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, argininosuccinic acid, and combinations thereof) compared to before administration. Indoxyl sulfate and phenylacetyl-L-glutamine; hippuric acid and phenylacetyl-L-glutamine; indoxyl sulfate and p-cresyl sulfate; p-cresyl sulfate and phenylacetyl-L-glutamine; p-cresyl sulfate and hippuric acid; indoxyl sulfate and argininosuccinate; p-cresyl sulfate and argininosuccinate; hippuric acid and argininosuccinate; phenylacetyl-L-glutamine and argininosuccinate; indoxyl The ratio of concentrations of sulfuric acid (p-cresyl sulfate; hippuric acid; argininosuccinate; or phenylacetyl-L-glutamine) (urinary concentration (ng / mL) / blood concentration (ng / mL)) increases by 1-100%, 1-50%, 3-50%, 5-50%, 10-50%, 15-50%, 1-40%, 5-40%, 10-40%, 1-30%, 5-30%, 10-30%, 15-30%, 10% or more, 20% or more, 30% or more, or 40% or more. In one embodiment, administration of the pharmaceutical composition provided by the present invention promotes the excretion of uremic substances from the body in a manner dependent on the blood concentration of uremic substances. In one embodiment, administration of the pharmaceutical composition provided by the present invention promotes the urinary excretion of uremic substances (e.g., indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, argininosuccinic acid, and combinations thereof) in a manner dependent on the blood concentration of the uremic substance. For example, when the blood concentration of a uremic substance is high, the amount of urinary excretion of the uremic substance increases accordingly. When the blood concentration of a uremic substance is low, the amount of urinary excretion of the uremic substance decreases. This blood concentration-dependent urinary excretion of uremic substances suggests that the pharmaceutical composition provided by the present invention has a low risk of side effects and excellent safety. Examples of indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, argininosuccinic acid, and combinations thereof include: indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and argininosuccinic acid; indoxyl sulfate, p-cresyl sulfate, and phenylacetyl-L-glutamine; indoxyl sulfate and phenylacetyl-L-glutamine; indoxyl sulfate and p-cresyl sulfate; p-cresyl sulfate and phenylacetyl-L-glutamine; indoxyl sulfate; p-cresyl sulfate; and phenylacetyl-L-glutamine. In one embodiment, administration of a pharmaceutical composition provided by the present invention promotes the excretion of uremic substances (e.g., indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, argininosuccinic acid, and combinations thereof) into the urine in a manner dependent on the blood concentration of the uremic substances, thereby lowering the blood concentration of the uremic substances. Examples of indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, argininosuccinic acid, and combinations thereof include: indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and argininosuccinic acid; indoxyl sulfate, p-cresyl sulfate, and phenylacetyl-L-glutamine; indoxyl sulfate and phenylacetyl-L-glutamine; indoxyl sulfate and p-cresyl sulfate; p-cresyl sulfate and phenylacetyl-L-glutamine; indoxyl sulfate; p-cresyl sulfate; and phenylacetyl-L-glutamine. In one embodiment, administration of the pharmaceutical composition provided by the present invention results in the excretion of indoxyl sulfate in the urine in a manner dependent on the blood concentration of indoxyl sulfate. As a result, the ratio of the urinary concentration to the blood concentration of indoxyl sulfate (urinary concentration / blood concentration) can be 1 to 1000, preferably 1 to 200, more preferably 1 to 100, and even more preferably 10 to 100. In this embodiment, the pharmaceutical composition provided by the present invention may be administered to a person (e.g., a patient with chronic kidney disease) with a blood concentration of indoxyl sulfate of 0.01 to 100 μg / mL (e.g., 0.1 to 30 μg / mL). Alternatively, as a result of administration, the blood concentration of indoxyl sulfate may become 0.01 to 10 μg / mL (e.g., 0.03 to 10 μg / mL). In one embodiment, upon administration of the pharmaceutical composition provided by the present invention, p-cresyl sulfate is excreted in the urine in a manner dependent on the blood concentration of p-cresyl sulfate. As a result, the ratio of the urinary concentration to the blood concentration of p-cresyl sulfate (urinary concentration / blood concentration) can be 0.1 to 1000, preferably 1 to 300, more preferably 1 to 150, and even more preferably 1 to 100. In this embodiment, the pharmaceutical composition provided by the present invention may be administered to a person (e.g., a patient with chronic kidney disease) with a blood concentration of p-cresyl sulfate of 0.003 to 300 μg / mL (e.g., 0.01 to 30 μg / mL). Furthermore, as a result of administration, the blood concentration of p-cresyl sulfate may become 0.001 to 100 μg / mL (e.g., 0.001 to 30 μg / mL). In one embodiment, administration of the pharmaceutical composition provided by the present invention results in the excretion of phenylacetyl-L-glutamine in the urine in a manner dependent on the blood concentration of phenylacetyl-L-glutamine. As a result, the ratio of the urinary concentration to the blood concentration of phenylacetyl-L-glutamine (urinary concentration / blood concentration) can be 1 to 1500, preferably 1 to 1000, more preferably 10 to 800, and even more preferably 10 to 600. In this embodiment, the pharmaceutical composition provided by the present invention may be administered to a person (e.g., a patient with chronic kidney disease) with a blood concentration of phenylacetyl-L-glutamine of 0.03 to 30 μg / mL (e.g., 0.1 to 10 μg / mL). Alternatively, as a result of administration, the blood concentration of phenylacetyl-L-glutamine may become 0.01 to 10 μg / mL (e.g., 0.03 to 10 μg / mL). In one embodiment, when the pharmaceutical composition provided by the present invention is administered to multiple individuals (e.g., patients with chronic kidney disease), the ratio of the urinary concentration to the blood concentration of indoxyl sulfate (urinary concentration / blood concentration) in each individual shows a high correlation. In this embodiment, the high correlation may be indicated by a Pearson test r value of 0.4 to 1, 0.5 to 1, 0.6 to 1, or 0.7 to 1 (preferably 0.7 to 1). Furthermore, the pharmaceutical composition provided by the present invention may be administered to individuals (e.g., patients with chronic kidney disease) with a blood concentration of indoxyl sulfate of 0.01 to 10 μg / mL (e.g., 0.1 to 10 μg / mL), and as a result of administration, the blood concentration of indoxyl sulfate may become 0.01 to 10 μg / mL (e.g., 0.1 to 10 μg / mL). In one embodiment, when the pharmaceutical composition provided by the present invention is administered to multiple individuals (e.g., patients with chronic kidney disease), the ratio of the urinary concentration of p-cresyl sulfate to the blood concentration (urinary concentration / blood concentration) in each individual shows a high correlation. In this embodiment, the high correlation may be indicated by a Pearson test r value of 0.4 to 1, 0.5 to 1, 0.6 to 1, or 0.7 to 1 (preferably 0.7 to 1). Furthermore, the pharmaceutical composition provided by the present invention may be administered to individuals (e.g., patients with chronic kidney disease) with a blood concentration of p-cresyl sulfate of 0.001 to 100 μg / mL (e.g., 0.01 to 50 μg / mL), and as a result of administration, the blood concentration of p-cresyl sulfate may become 0.001 to 100 μg / mL (e.g., 0.01 to 50 μg / mL). In one embodiment, when the pharmaceutical composition provided by the present invention is administered to multiple individuals (e.g., patients with chronic kidney disease), the ratio of the urinary concentration of phenylacetyl-L-glutamine to the blood concentration (urinary concentration / blood concentration) in each individual shows a high correlation. In this embodiment, the high correlation may be indicated by a Pearson test r value of 0.4 to 1, 0.5 to 1, 0.6 to 1, or 0.7 to 1 (preferably 0.7 to 1). Furthermore, the pharmaceutical composition provided by the present invention may be administered to individuals (e.g., patients with chronic kidney disease) with a blood concentration of phenylacetyl-L-glutamine of 0.01 to 10 μg / mL (e.g., 0.05 to 10 μg / mL), and as a result of administration, the blood concentration of phenylacetyl-L-glutamine may become 0.01 to 10 μg / mL (e.g., 0.05 to 10 μg / mL). Due to the characteristics of the pharmaceutical composition provided by the present invention, the pharmaceutical composition provided by the present invention can be used not only, in one aspect, as a pharmaceutical composition for lowering the blood concentration of uremic substances and / or as a pharmaceutical composition for promoting the urinary excretion of uremic substances, but also as any of the following: a pharmaceutical composition for improving uremic symptoms in patients with kidney disease, a pharmaceutical composition for treating and / or preventing uremia in patients with kidney disease, a pharmaceutical composition for inhibiting the progression of chronic kidney disease, and a pharmaceutical composition for delaying the initiation of dialysis in patients with chronic kidney disease. In this specification, “improvement” is a concept that includes bringing a “pathological” or “abnormal” symptom, condition, or disease closer to a “healthy” or “normal” state, or the act of doing so, and bringing it to a “healthy” or “normal” state, or the act of doing so. Accordingly, in one embodiment, “improvement” includes the fact that a numerical indicator of a “pathological” or “abnormal” symptom or condition becomes smaller or larger in accordance with the “improvement” to approach or become a normal value. In another embodiment, “improvement” includes the fact that the concentration of uremic substances in the blood decreases and the concentration of uremic substances in the urine increases in accordance with the “improvement,” and the concentration of uremic substances in the urine may further decrease when the concentration of uremic substances in the blood becomes sufficiently small. In this specification, "healthy" means a state free from acute or chronic disease or disability, and "normal" means a state in which a healthy subject is in its usual condition. In this specification, “treatment” means the disappearance, cure, remission or remission of a “pathological” or “abnormal” symptom, condition, or disease, and the actions taken therefor, and the suppression or suppression of the worsening of a “pathological” or “abnormal” symptom, condition, or disease, and the concept of “improvement.” Here, suppression has the meaning set forth below. In one embodiment, “treatment” means the disappearance, cure, remission or remission of a “pathological” or “abnormal” symptom, condition, or disease, and the actions taken therefor. In another embodiment, “treatment” means the disappearance, cure, remission or remission of a “pathological” or “abnormal” symptom, condition, or disease. In this specification, “prevention” is a concept that includes preventing the onset of “pathological” or “abnormal” symptoms, conditions, or diseases, and the actions taken for that purpose. In this specification, "delay" is a concept that includes extending the time until the event in question occurs, and the actions taken for that purpose, as well as extending the time so that the event in question does not occur. In this specification, “suppression” is a concept that includes stopping or slowing down the worsening or progression of a symptom, condition or disease, and also includes improving the symptom, condition or disease, where “improvement” has the meaning set forth above. 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” condition to a “pathological” or “abnormal” symptom, condition or disease. In one embodiment, “suppression” means stopping or slowing down the worsening or progression of a symptom, condition or disease, or the act thereof. In another embodiment, “suppression” means stopping or slowing down the worsening or progression of a symptom, condition or disease. Here, the symptoms, conditions, or diseases are compared before and after administration of the pharmaceutical composition provided by the present invention. Furthermore, due to the characteristics of the pharmaceutical composition provided by the present invention as described above, the pharmaceutical composition provided by the present invention can, in one aspect, be used as any of the following: a pharmaceutical composition for inhibiting myocardial fibrosis in patients with kidney disease; a pharmaceutical composition for inhibiting arteriosclerosis in patients with kidney disease; a pharmaceutical composition for inhibiting the proliferation of vascular smooth muscle cells in patients with kidney disease; a pharmaceutical composition for inhibiting vascular endothelial cell damage in patients with kidney disease; a pharmaceutical composition for inhibiting arterial wall thickening in patients with kidney disease; a pharmaceutical composition for inhibiting aortic calcification in patients with kidney disease; and a pharmaceutical composition for the treatment and / or prevention of cardiovascular diseases associated with chronic kidney disease.

[0027] Furthermore, it has been reported that when a drug that lowers the blood concentration of indoxyl sulfate was administered to patients with non-diabetic chronic kidney disease, pulse wave velocity and carotid intima-media thickness, which are indicators of arteriosclerosis, significantly improved compared to before administration (Nakamura T., et al.: Oral ADSORBENT AST-120 decreases carotid intima-media thickness and arterial stiffness in patients with chronic renal failure. Kidney Blood Press Res, 27: 121-6, 2004). Therefore, the pharmaceutical composition provided by the present invention that lowers the blood concentration of indoxyl sulfate can, in one aspect, be used as a pharmaceutical composition for improving arteriosclerosis or for improving thickening of arterial (e.g., carotid artery) walls in patients with kidney disease (preferably patients with chronic kidney disease, more preferably patients with non-diabetic chronic kidney disease).

[0028] Furthermore, it has been reported that drugs that lower the blood concentration of indoxyl sulfate suppress cisplatin-induced acute kidney injury (Morisaki T., et. Al.,: Regulation of renal organic ion transporters in cisplatin-induced acute kidney injury and uremia in rats. Pharm. Res., 25(11): 2526-33, 2008). Therefore, the pharmaceutical composition provided by the present invention, which lowers the blood concentration of indoxyl sulfate, can be used in one aspect as a pharmaceutical composition for the treatment of acute kidney disease, or as a pharmaceutical composition for suppressing the progression from acute kidney disease to chronic kidney disease.

[0029] Furthermore, p-cresyl sulfate, a uremic substance, has been reported to be a causative agent of vascular endothelial damage (Meijers BK, et. Al.,: The uremic retention solute p-cresyl sulfate and markers of endothelial damage., Am. J. Kidney Dis., 54: 891-901, 2009). The pharmaceutical composition provided by the present invention, which promotes the urinary excretion of p-cresyl sulfate, can in one aspect be used as a pharmaceutical composition for suppressing vascular endothelial damage in patients with kidney disease (preferably patients with chronic kidney disease). Furthermore, phenylacetyl-L-glutamine, a uremic substance, has been reported to increase the risk of developing cardiovascular disease in patients with chronic kidney disease. The pharmaceutical composition provided by the present invention, which promotes the urinary excretion of phenylacetyl-L-glutamine, can in one aspect be used as a pharmaceutical composition for the treatment and / or prevention of cardiovascular disease in patients with chronic kidney disease. In one embodiment, the pharmaceutical composition provided by the present invention promotes the urinary excretion of uremic substances such as indoxyl sulfate, p-cresyl sulfate, hippuric acid, argininosuccinic acid, and phenylacetyl-L-glutamine. Therefore, the pharmaceutical composition provided by the present invention can be used as a pharmaceutical composition for promoting the urinary excretion of indoxyl sulfate, p-cresyl sulfate, hippuric acid, argininosuccinic acid, and / or phenylacetyl-L-glutamine in patients with kidney disease (preferably patients with chronic kidney disease). In one embodiment, a pharmaceutically acceptable salt of citrate, or a hydrate thereof, or a mixture thereof (for example, a mixture of potassium citrate monohydrate and sodium citrate dihydrate) is administered to a patient with kidney disease (preferably a patient with chronic kidney disease) in order to lower the blood concentration of indoxyl sulfate, p-cresyl sulfate, hippuric acid, and / or phenylacetyl-L-glutamine. In one embodiment, a pharmaceutically acceptable salt of citrate, or a hydrate thereof, or a mixture thereof (for example, a mixture of potassium citrate monohydrate and sodium citrate dihydrate) is administered to a patient with kidney disease (preferably a patient with chronic kidney disease) in order to increase the concentration of indoxyl sulfate, p-cresyl sulfate, hippuric acid, arginosuccinate, and / or phenylacetyl-L-glutamine in the urine (preferably to increase the concentration of indoxyl sulfate, p-cresyl sulfate, and phenylacetyl-L-glutamine in the urine). In one embodiment, sodium bicarbonate is administered to patients with kidney disease (preferably patients with chronic kidney disease) to lower the blood concentration of p-cresyl sulfate and / or phenylacetyl-L-glutamine. In one embodiment, sodium bicarbonate is administered to patients with kidney disease (preferably patients with chronic kidney disease) to increase the concentration of arginosuccinate in the urine.

[0030] The pharmaceutical compositions provided by the present invention can be used, in one aspect, as a pharmaceutical composition for the treatment of renal tubular disorders, a pharmaceutical composition for the prevention of renal tubular disorders, or a pharmaceutical composition for the suppression of renal tubular disorders. The renal tubule may be, for example, the proximal tubule. The pharmaceutical composition provided by the present invention can, in another respect, be used as a pharmaceutical composition for maintaining renal function. As one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for inhibiting tubular cell damage, a pharmaceutical composition for protecting tubular cells, or a pharmaceutical composition for maintaining tubular cell function (for example, reabsorption of water, sodium ions, potassium ions, calcium ions, phosphate ions, bicarbonate ions, chloride ions, glucose, amino acids, vitamins, etc.). As one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for inhibiting proximal tubular cell damage, a pharmaceutical composition for protecting proximal tubular cells, or a pharmaceutical composition for maintaining proximal tubular cell function (e.g., reabsorption of glucose, amino acids, vitamins, etc.). As one embodiment, the pharmaceutical composition provided by the present invention suppresses the increase in the amount (concentration) of β2-microglobulin in the urine (e.g., early morning urine) associated with the progression of chronic kidney disease. In one embodiment, the pharmaceutical composition provided by the present invention does not affect glomerular function in patients with chronic kidney disease, while suppressing proximal tubular cell damage associated with the progression of chronic kidney disease and protecting proximal tubular cells. In this specification, “maintaining renal function” means, for example, suppression of tubular damage, protection of tubular cells, or maintenance of tubular function. The tubule may be, for example, the proximal tubule, and one aspect of maintaining tubular function or maintaining proximal tubular function is maintaining the function of tubular cells or maintaining the function of proximal tubular cells. In this specification, "cell protection" means maintaining or preserving the state of cells, or suppressing cell damage. Here, suppression has the meaning described above. In this specification, "maintenance of cellular function" means preservation of cellular function or suppression of deterioration of cellular function. Here, suppression has the meaning described above. Here, the state or function of the cells is compared before and after administration of the pharmaceutical composition provided by the present invention. In this specification, "early morning urine" refers to the first urine produced after waking up. In one embodiment, the pharmaceutical composition provided by the present invention suppresses the increase in the amount (concentration) of β2-microglobulin in the urine (e.g., early morning urine) 6 weeks, 12 weeks, and / or 24 weeks after administration compared to before administration. In one embodiment, the pharmaceutical composition provided by the present invention suppresses the increase in the amount (concentration) of β2-microglobulin in the urine (e.g., early morning urine) associated with the progression of chronic kidney disease, but does not substantially reduce the amount (concentration) of β2-microglobulin in the urine (e.g., early morning urine) compared to before administration of the pharmaceutical composition provided by the present invention. In this embodiment, for example, if the amount (concentration) of β2-microglobulin in the urine before administration of the pharmaceutical composition provided by the present invention (e.g., early morning urine) is set to 1, then the amount (concentration) of β2-microglobulin in the urine after administration (e.g., early morning urine) may be 0.7 to 1.0 or 1.0 or more, 0.8 to 1.0 or 1.0 or more, 0.85 to 1.0 or 1.0 or more, 0.9 to 1.0 or 1.0 or more, 0.7 to 2.0, 0.8 to 2.0, 0.85 to 2.0, 0.9 to 2.0, 0.7 to 1.6, 0.8 to 1.6, 0.85 to 1.6, or 0.9 to 1.6. In one embodiment, the pharmaceutical composition provided by the present invention suppresses the increase in the amount (concentration) of β2-microglobulin in the urine (e.g., early morning urine) associated with the progression of chronic kidney disease, but does not substantially reduce the amount (concentration) of β2-microglobulin in the urine (e.g., early morning urine) 6 weeks after administration, 12 weeks after administration, and / or 24 weeks after administration, compared to before administration of the pharmaceutical composition provided by the present invention. In this embodiment, for example, if the amount (concentration) of β2-microglobulin in the urine (e.g., early morning urine) before administration of the pharmaceutical composition provided by the present invention is set to 1, then the amount (concentration) of β2-microglobulin in the urine (e.g., early morning urine) 6 weeks after administration, 12 weeks after administration, or 24 weeks after administration may be 0.7 to 1.0 or 1.0 or more, 0.8 to 1.0 or 1.0 or more, 0.85 to 1.0 or 1.0 or more, 0.9 to 1.0 or 1.0 or more, 0.7 to 2.0, 0.8 to 2.0, 0.85 to 2.0, 0.9 to 2.0, 0.7 to 1.6, 0.8 to 1.6, 0.85 to 1.6, or 0.9 to 1.6. In one embodiment, the pharmaceutical composition provided by the present invention does not substantially increase the amount (concentration) of cystatin C in the blood (e.g., in plasma) compared to before administration. In this embodiment, for example, if the amount (concentration) of cystatin C in the blood (e.g., in plasma) before administration of the pharmaceutical composition provided by the present invention is set to 1, then the amount (concentration) of cystatin C in the blood (e.g., in plasma) after administration may be 1.0 or less or 1.0 to 1.2, 1.0 or less or 1.0 to 1.15, 1.0 or less or 1.0 to 1.1, 1.0 or less or 1.0 to 1.05, 0.9 to 1.2, 0.9 to 1.15, 0.9 to 1.1, 0.9 to 1.05, 0.95 to 1.2, 0.95 to 1.15, 0.95 to 1.1, or 0.95 to 1.05. In one embodiment, the pharmaceutical composition provided by the present invention does not substantially increase the amount (concentration) of cystatin C in the blood (e.g., in plasma) at 6 weeks, 12 weeks, and / or 24 weeks after administration compared to before administration. In this embodiment, for example, if the amount (concentration) of cystatin C in the blood (e.g., plasma) before administration of the pharmaceutical composition provided by the present invention is set to 1, then after 6 weeks, 12 weeks, or 24 weeks of administration, the amount (concentration) of cystatin C in the blood (e.g., plasma) may be 1.0 or less or 1.0 to 1.2, 1.0 or less or 1.0 to 1.15, 1.0 or less or 1.0 to 1.1, 1.0 or less or 1.0 to 1.05, 0.9 to 1.2, 0.9 to 1.15, 0.9 to 1.1, 0.9 to 1.05, 0.95 to 1.2, 0.95 to 1.15, 0.95 to 1.1, or 0.95 to 1.05. In one embodiment, administration of the pharmaceutical composition provided by the present invention results in no improvement in proximal tubular dysfunction and / or glomerular dysfunction at 6 weeks, 12 weeks, and / or 24 weeks after administration compared to before administration, but a decrease in blood concentration of uremic substances, promotion of urinary excretion of uremic substances and / or promotion of extracorporeal excretion of uremic substances are observed at 6 weeks, 12 weeks, and / or 24 weeks after administration compared to before administration. In one embodiment, administration of the pharmaceutical composition provided by the present invention results in no improvement in proximal tubular dysfunction and / or glomerular dysfunction at 6 weeks, 12 weeks, and / or 24 weeks after administration compared to before administration, but a decrease in blood concentration of uremic substances, promotion of urinary excretion of uremic substances and / or promotion of extracorporeal excretion of uremic substances are observed at 6 weeks, 12 weeks, and / or 24 weeks after administration compared to before administration.

[0031] The pharmaceutical compositions provided by the present invention are administered orally or parenterally to humans or other mammals. Examples of parenteral administration include intravenous, subcutaneous, intramuscular, intra-articular, transmucosal, transdermal, transnasal, rectal, intrathecal, intraperitoneal, and local administration. The pharmaceutical compositions provided by the present invention may be prepared by mixing an alkalizing agent as is, or with pharmaceutically acceptable carriers, such as excipients (e.g., lactose, D-mannitol, crystalline cellulose, glucose), binders (e.g., hydroxypropylcellulose (HPC), gelatin, polyvinylpyrrolidone (PVP)), lubricants (e.g., magnesium stearate, talc), disintegrants (e.g., starch, carboxymethylcellulose calcium (CMC-Ca)), diluents (e.g., water for injection, physiological saline), and, if necessary, other additives (e.g., pH adjusters, surfactants, solubilizers, preservatives, emulsifiers, isotonic agents, stabilizers), and may be in the form of tablets, capsules, suspensions, injections, suppositories, and other formulations. For example, to form tablets, the alkalizing agent 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 formulation. The tablets according to the present invention will be described in more detail below.

[0032] In one embodiment, the pharmaceutical composition provided by the present invention is a tablet. The tablet provided by the present invention may contain an alkalizing agent (e.g., potassium citrate or its hydrate; sodium citrate or its hydrate; a mixture of potassium citrate monohydrate and sodium citrate dihydrate; or sodium bicarbonate) as well as pharmaceutically acceptable additives commonly used in the pharmaceutical field. Examples of such additives include excipients, binders, disintegrants, fluidizers, flavoring agents, lubricants, pH adjusters, surfactants, stabilizers, and fragrances. The content of the alkalizing agent in the tablets provided by the present invention may be 10 to 95% by weight, preferably 30 to 90% by weight, and more preferably 60 to 85% by weight, relative to the tablet.

[0033] Examples of excipients that can be used in the tablets provided by the present invention include sugars such as lactose (e.g., lactose monohydrate, anhydrous lactose), glucose, sucrose, fructose, and maltose; sugar alcohols such as erythritol, sorbitol, maltitol, xylitol, and D-mannitol; starch (e.g., corn starch, potato starch, rice starch, wheat starch); crystalline cellulose; magnesium aluminometasilicate; anhydrous calcium phosphate; precipitated calcium carbonate; calcium silicate; calcium lactate; and ethylcellulose, with crystalline cellulose being particularly preferred. The excipient content in the tablets provided by the present invention may be 1 to 95% by weight, preferably 1 to 80% by weight, more preferably 3 to 80% by weight, and even more preferably 3 to 20% by weight, relative to the tablet.

[0034] Examples of binders that can be used in tablets provided by the present invention include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, dextrin, methylcellulose, polyvinyl alcohol, sodium alginate, aminoalkyl methacrylate copolymer, polyethylene glycol, pregelatinized starch (e.g., partially pregelatinized starch), agar, and gelatin, with hydroxypropylcellulose being particularly preferred. The binder content in the tablets provided by the present invention may be 0.1 to 30% by weight, preferably 0.1 to 10% by weight, and more preferably 0.3 to 3% by weight, relative to the tablet.

[0035] Examples of disintegrants that may be used in tablets provided by the present invention include croscarmellose sodium, carmellose calcium, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospovidone, starch (e.g., wheat starch, corn starch, partially pregelatinized starch), and carmellose, with partially pregelatinized starch being particularly preferred. The content of the disintegrant in the tablets provided by the present invention may be 0.3 to 20% by weight, preferably 1 to 10% by weight, and more preferably 3 to 10% by weight, relative to the tablet.

[0036] Examples of fluidizing agents that can be used in the tablets provided by the present invention include light anhydrous silicic acid, talc, and magnesium aluminometasilicate. The content of the fluidizing agent in the tablets provided by the present invention may be 0.03 to 3% by weight, preferably 0.1 to 3% by weight, and more preferably 0.3 to 3% by weight, relative to the tablet.

[0037] Examples of flavoring agents that can be used in tablets provided by the present invention include acidulants such as citric acid (e.g., anhydrous citric acid), malic acid, acetic acid, tartaric acid, fumaric acid, and ascorbic acid (however, the flavoring agents do not include the alkalizing agent according to the present invention), and sweeteners such as sodium saccharin, dipotassium glycyrrhizinate, aspartame®, stevia, thaumatin, and sucralose. The content of the flavoring agent in the tablets provided by the present invention may be 0.03 to 3% by weight, preferably 0.1 to 3% by weight, and more preferably 0.3 to 3% by weight, relative to the tablet.

[0038] Examples of lubricants that can be used in the tablets provided by the present invention include magnesium stearate, calcium stearate, talc, light anhydrous silicic acid, sucrose fatty acid ester, carnauba wax, macrogol, and sodium stearyl fumarate, with magnesium stearate being particularly preferred. The lubricant content in the tablets provided by the present invention may be 0.1 to 30% by weight, preferably 0.3 to 10% by weight, and more preferably 1 to 3% by weight, relative to the tablet.

[0039] Examples of pH adjusters that may be used in tablets provided by the present invention include citric acid, phosphates (e.g., sodium dihydrogen phosphate, potassium dihydrogen phosphate), carbonates (e.g., magnesium carbonate, sodium carbonate), tartrates, fumarates, acetates, and amino acid salts (provided that the pH adjusters do not include the alkalizing agents according to the present invention). The pH adjusting agent content in the tablets provided by the present invention may be 0.1 to 30% by weight, preferably 0.3 to 10% by weight, and more preferably 1 to 5% by weight, relative to the tablet.

[0040] Examples of surfactants that can be used in the tablets provided by the present invention include sodium lauryl sulfate, polysorbate, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyl stearate, macrogol, and poloxamer. The surfactant content in the tablets provided by the present invention may be 0.01 to 3% by weight, preferably 0.03 to 1% by weight, and more preferably 0.03 to 0.5% by weight, relative to the tablet. Examples of stabilizers that can be used in tablets provided by the present invention include citric acid (e.g., anhydrous citric acid), malic acid, acetic acid, tartaric acid, maleic acid, ascorbic acid, sodium edetate, and tocopherol (provided that the stabilizers do not include the alkalizing agent according to the present invention), with anhydrous citric acid being particularly preferred. The content of the stabilizer in the tablets provided by the present invention may be 0.01 to 30% by weight, preferably 0.1 to 30% by weight, and more preferably 1 to 20% by weight, relative to the tablet.

[0041] Examples of flavorings that can be used in the tablets provided by the present invention include citrus flavorings such as lemon, orange, and grapefruit, peppermint, spearmint, and menthol, which can be contained in appropriate amounts in the tablets (for example, 0.01 to 1% by weight, more preferably 0.01 to 0.1% by weight relative to the tablet). The total content of alkalizing agents and pharmaceutically acceptable additives in the tablets provided by the present invention does not exceed 100% by weight of the tablet.

[0042] The tablets provided by the present invention may contain the above-mentioned components and may be uncoated tablets without a coating layer, or film-coated tablets with a coating layer. The content of the coating layer can be appropriately determined by those skilled in the art, but for example, it may be 0.1 to 10% by weight relative to the uncoated tablet. In addition to the coating base, the coating layer may appropriately contain plasticizers, colorants, glossing agents, etc. Examples of coating bases that can be used in the tablets provided by the present invention include hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethylcellulose, cellulose acetate phthalate, methacrylic acid copolymer, and polyvinylpyrrolidone, with hydroxypropyl methylcellulose being particularly preferred. The content of the coating base in the tablets provided by the present invention may be 0.01 to 10% by weight, preferably 0.3 to 3% by weight, relative to the tablet. Examples of coating plasticizers that can be used in the tablets provided by the present invention include triethyl citrate, medium-chain triglyceride, triacetin, glycerin, propylene glycol, and polyethylene glycol (e.g., macrogol 6000), with macrogol 6000 being particularly preferred. The content of the coating plasticizer in the tablets provided by the present invention may be 0.01 to 1% by weight, preferably 0.03 to 3% by weight, relative to the tablet. Examples of coating colorants that can be used in the tablets provided by the present invention include titanium dioxide, yellow ferric oxide, ferric oxide, black iron oxide, Food Blue No. 2, and Food Blue No. 2 aluminum lake. The content of the coating colorant in the tablets provided by the present invention may be 0.01 to 1% by weight, preferably 0.03 to 3% by weight, relative to the tablet. An example of a coating glossing agent that can be used in the tablets provided by the present invention is carnauba wax. The content of the coating glossing agent in the tablets provided by the present invention may be 0.0001 to 0.1% by weight, preferably 0.001 to 0.01% by weight, relative to the tablet.

[0043] The pharmaceutical compositions provided by the present invention can be manufactured by methods known in the pharmaceutical field. For example, in the case of tablets, the manufacturing method may include a mixing step of mixing an alkalizing agent (e.g., potassium citrate or its hydrate; sodium citrate or its hydrate; a mixture of potassium citrate monohydrate and sodium citrate dihydrate; or sodium bicarbonate) with additives, a granulation step, a tableting step, and / or a coating step. The mixing step may include mixing an alkalizing agent with additives such as excipients, stabilizers, disintegrants, and / or binders. Furthermore, prior to the tableting step, the mixture containing the alkalizing agent and additives may be further mixed with a lubricant, flavoring agent, and / or fragrance. Mixing can be carried out using a V-type mixer, W-type mixer, container mixer, tumbler mixer, agitator mixer, or the like. The granulation process can be carried out using granulation methods known in the pharmaceutical field. Examples of granulation methods include dry granulation, wet granulation, and fluidized bed granulation. In one embodiment, the mixture obtained in the mixing step or the granules obtained in the granulation step can be appropriately ground and / or sieved to obtain a mixture or granules having a desired particle size. Grinding can be performed using grinders known in the pharmaceutical field, such as ball mills, jet mills, and hammer mills. Sieving can be performed using sieves ranging from 16-mesh (mesh opening 1000 μm) to 32-mesh (mesh opening 500 μm), etc. The tableting process can be carried out using tableting methods known in the pharmaceutical field. Examples of tableting methods include direct tableting, dry tableting, wet tableting, and external lubrication tableting. For example, the mixture or granules obtained in the above process can be tableted using tablet presses known in the pharmaceutical field, such as single-pull tablet presses or rotary tablet presses. When using single-pull tablet presses, rotary tablet presses, etc., a tableting pressure of 1kN to 30kN can be used. The coating process can be carried out by methods known in the pharmaceutical field. For example, it can be carried out by spray coating the outside of the uncoated tablet with a coating solution containing a coating base and appropriate amounts of plasticizer, colorant, glossing agent, etc. In one embodiment, the tablets provided by the present invention can be manufactured by mixing an alkalizing agent, an excipient (e.g., lactose, D-mannitol, crystalline cellulose and / or glucose), a binder (e.g., hydroxypropyl cellulose (HPC), gelatin and / or polyvinylpyrrolidone (PVP)), a stabilizer (e.g., anhydrous citric acid), a disintegrant (e.g., starch (e.g., partially pregelatinized starch) and / or carboxymethylcellulose calcium (CMC-Ca)) and a lubricant (e.g., magnesium stearate), and compressing them to obtain a tablet; and then forming a coating layer on the outside of the tablet containing a coating base (e.g., hydroxypropyl cellulose, hydroxypropyl methylcellulose and / or PVP), a plasticizer (e.g., triethyl citrate and / or macrogol 6000), a coloring agent (e.g., ferric oxide and / or titanium dioxide), and a brightening agent (e.g., carnauba wax). In one embodiment, the hardness of the resulting tablets may be 10 to 200 N, preferably 30 to 150 N.

[0044] The amount of alkalizing agent in the pharmaceutical composition provided by the present invention can be set as appropriate. In one embodiment, the amount of alkalizing agent in the pharmaceutical composition provided by the present invention may be set to an amount that, when administered to a human, improves acidic urine in gout or hyperuricemia, or a smaller amount. For example, it may be set to 1-50% or 10-20% of the daily dose approved in Japan for improving acidic urine in gout or hyperuricemia (for example, if the alkalizing agent is a citrate preparation: two tablets containing 231.5 mg of potassium citrate (C6H5K3O7·H2O) and 195.0 mg of sodium citrate hydrate (C6H5Na3O7·2H2O) per tablet are administered orally three times a day; if the alkalizing agent is sodium bicarbonate: 3-5 g is administered orally per day). 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 as an alkalizing agent. In one embodiment, the pharmaceutical composition provided by the present invention is a tablet, and each tablet may contain 10 mg to 300 mg each of potassium citrate monohydrate and sodium citrate dihydrate, for a total of 20 mg to 600 mg, preferably 150 to 250 mg each for a total of 400 to 500 mg, and more preferably 190 to 240 mg each for a total of 400 to 450 mg. 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, of sodium bicarbonate as an alkalizing agent. In one embodiment, the pharmaceutical composition provided by the present invention is a tablet containing 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate as alkalizing agents, and may also contain anhydrous citric acid, crystalline cellulose, partially pregelatinized starch, hydroxypropyl cellulose, magnesium stearate, hypromellose, macrogol 6000, titanium dioxide, and carnauba wax as additives. In one embodiment, one dose unit may be a tablet containing 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate. In this specification, "dosage unit" refers to a unit of the preparation, and "1 dose unit" refers to the smallest unit of the preparation. Therefore, for example, in the case of tablets, the dose unit is each tablet, and 1 dose unit represents one tablet. In the case of injectable preparations, the dose unit is the injectable preparation contained in a sealed container such as an ampoule or vial, and 1 dose unit represents the injectable preparation contained in a sealed container such as an ampoule or vial. When the pharmaceutical composition provided by the present invention is administered to a human or other mammal, one or more of the aforementioned administration units may be administered at a time, or one of the aforementioned administration units may be divided and administered in parts.

[0045] The dosage of the alkalizing agent should be determined appropriately according to the type of alkalizing agent, the method of administration, the age, weight, sex, symptoms, and sensitivity to the drug of the recipient, but the dosage may be adjusted according to the improvement of symptoms. In one embodiment, when administering a mixture of potassium citrate monohydrate and sodium citrate dihydrate or sodium bicarbonate orally to humans as an alkalizing agent, the daily dose may be half of the daily dose approved in Japan for the improvement of acidic urine in gout and hyperuricemia (for example, if the alkalizing agent is a citrate preparation: two tablets containing 231.5 mg of potassium citrate (C6H5K3O7·H2O) and 195.0 mg of sodium citrate hydrate (C6H5Na3O7·2H2O) per tablet are administered orally three times a day; if the alkalizing agent is sodium bicarbonate: 3 to 5 g is administered orally per day). In one embodiment, when administering a mixture of potassium citrate monohydrate and sodium citrate dihydrate or sodium bicarbonate orally to humans as an alkalizing agent, the daily dose may be the same as the daily dose approved in Japan for the improvement of acidic urine in gout and hyperuricemia (for example, if the alkalizing agent is a citrate preparation: two tablets containing 231.5 mg of potassium citrate (C6H5K3O7·H2O) and 195.0 mg of sodium citrate hydrate (C6H5Na3O7·2H2O) per tablet, administered orally three times a day; if the alkalizing agent is sodium bicarbonate: 3 to 5 g administered orally per day). In one embodiment, when administering a mixture of potassium citrate monohydrate and sodium citrate dihydrate or sodium bicarbonate orally to humans as an alkalizing agent, administration may be started at half the daily dose approved in Japan for the improvement of acidic urine in gout and hyperuricemia (for example, if the alkalizing agent is a citrate preparation: two tablets containing 231.5 mg of potassium citrate (C6H5K3O7·H2O) and 195.0 mg of sodium citrate hydrate (C6H5Na3O7·2H2O) per tablet, administered orally three times a day; if the alkalizing agent is sodium bicarbonate: 3-5 g administered orally per day), and the dose may then be increased to the daily dose approved in Japan for the improvement of acidic urine in gout and hyperuricemia. In one embodiment, the dosage of the alkalizing agent may be such that, upon oral administration of the alkalizing agent, the pH of human urine (e.g., early morning urine) becomes pH 5.2-6.8, pH 5.5-6.8, pH 5.8-6.8, pH 5.8-6.5, pH 5.8-6.2, pH 5.8 or higher but less than pH 6.2, pH 6.0-6.5, pH 6.0-6.4, pH 6.0-6.3, pH 6.0-6.2, pH 6.0 or higher but less than pH 6.2, pH 6.1-6.3, pH 6.2-6.8, pH 6.2-6.5, or pH 6.5-6.8. In one embodiment, the dosage of the alkalizing agent may be such that, upon oral administration of the alkalizing agent, the pH of human urine (e.g., early morning urine) after 6, 12, or 24 weeks of administration is pH 5.2-pH 6.8, pH 5.5-pH 6.8, pH 5.8-pH 6.8, pH 5.8-pH 6.5, pH 5.8-pH 6.2, pH 5.8 or higher but less than pH 6.2, pH 6.0-pH 6.5, pH 6.0-pH 6.4, pH 6.0-pH 6.3, pH 6.0-pH 6.2, pH 6.0 or higher but less than pH 6.2, pH 6.1-pH 6.3, pH 6.2-6.8, pH 6.2-pH 6.5, or pH 6.5-6.8. In one embodiment, when a mixture of potassium citrate monohydrate and sodium citrate dihydrate is orally administered to a human as an alkalizing agent, potassium citrate monohydrate and sodium citrate dihydrate may be administered in doses of 0.1 to 5 g / day each, totaling 0.2 to 10 g / day; 0.1 to 3 g / day each, totaling 0.2 to 6 g / day; 0.5 to 3 g / day each, totaling 1 to 6 g / day; preferably, 0.5 to 1.5 g / day each, totaling 1 to 3 g / day; 1 to 1.5 g / day each, totaling 2 to 3 g / day; or 0.5 to 1 g / day each, totaling 1 to 2 g / day, and may be administered 1 to 5 times a day, preferably divided into 3 doses per day. In one embodiment, when potassium citrate monohydrate or sodium citrate dihydrate is administered orally to humans as an alkalizing agent, the dosage may be 1-10 g / day, 1-6 g / day, 2-5.5 g / day, 1-3 g / day, 2-3 g / day, or 1-1.5 g / day, and it may be administered 1-5 times a day, preferably divided into 3 doses per day. In one embodiment, when sodium bicarbonate is orally administered to humans as an alkalizing agent, 1 to 6 g / day, preferably 1 to 3 g / day, or 3 to 5 g / day may be administered, and it may be administered 1 to 5 times a day, preferably in 3 divided doses per day.

[0046] One possible explanation is that the alkalizing agent may be administered over a long period, for example, 1 week, 2 weeks, 3 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 24 weeks, 40 weeks, 60 weeks, 80 weeks, 100 weeks, 120 weeks, 1 week or more, 2 weeks or more, 3 weeks or more, 6 weeks or more, 8 weeks or more, 10 weeks or more, 12 weeks or more, 24 weeks or more, 40 weeks or more, 60 weeks or more, 80 weeks or more, 100 weeks or more, 120 weeks or more. It is administered for 6 weeks to 24 weeks, 12 weeks to 24 weeks, 6 weeks to 30 weeks, 12 weeks to 30 weeks, 6 weeks to 40 weeks, 12 weeks to 40 weeks, 6 weeks to 60 weeks, 12 weeks to 60 weeks, 6 weeks to 80 weeks, 12 weeks to 80 weeks, 6 weeks to 100 weeks, 12 weeks to 100 weeks, 6 weeks to 120 weeks, or 12 weeks to 120 weeks. In one embodiment, the pharmaceutical composition provided by the present invention may exhibit beneficial effects in patients with kidney disease (e.g., chronic kidney disease) after 6 weeks of continuous administration, 12 weeks of continuous administration, and / or 24 weeks of continuous administration (e.g., effects of reducing blood concentrations of uremic substances (e.g., indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and / or argininosuccinate), effects of increasing urinary concentrations of uremic substances (e.g., indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and / or argininosuccinate) (effect of promoting excretion into urine), and / or effects of suppressing the increase in urinary β2-microglobulin concentration).

[0047] In one embodiment, the pharmaceutical composition provided by the present invention is administered to a person suffering from kidney disease. Unless otherwise specified, kidney disease includes acute kidney disease and chronic kidney disease. Examples of acute kidney disease include acute kidney disease caused by medications (e.g., nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, aminoglycoside antibiotics, fluoroquinolone antibacterial agents, iodine contrast agents, platinum-based drugs such as cisplatin), and acute kidney disease caused by renal ischemia. Chronic kidney disease (CKD) is a comprehensive concept encompassing all kidney diseases that progress chronically, regardless of the underlying disease. It includes all conditions in which there is a decline in renal function, expressed as glomerular filtration rate (GFR), or where findings suggestive of kidney damage persist chronically (for three months or more).

[0048] According to the CKD Treatment Guidelines 2012 (Japanese Journal of Nephrology 2012), the severity of chronic kidney disease is evaluated by classification based on the cause (C), renal function (GFR: G), and proteinuria (albuminuria: A). The GFR classifications are as follows: G1: GFR is normal or elevated (≧90 mL / min / 1.73 m) 2 ) G2: GFR is normal or slightly decreased (60-89 mL / min / 1.73 m²) 2 ) G3a: Mild to moderate decrease in GFR (45-59 mL / min / 1.73 m²) 2 ) G3b: Moderate to severe decrease in GFR (30-44 mL / min / 1.73 m) 2 ) G4: Severely decreased GFR (15-29 mL / min / 1.73 m) 2 ) G5: End-stage renal disease (ESKD) (<15 mL / min / 1.73 m 2 ) When the underlying disease is diabetes, the classification of proteinuria (albuminuria: A) is determined using the urinary albumin / creatinine (Cr) ratio as follows: A1: Normal (less than 30 mg / gCr) A2: Microalbuminuria (30-299 mg / gCr) A3: Overt albuminuria (≥300 mg / gCr) Furthermore, when the underlying disease is hypertension other than diabetes, nephritis, polycystic kidney disease, transplanted kidney, or other conditions, the classification based on proteinuria (albuminuria: A) is made 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) According to the 2012 CKD Treatment Guidelines (2012 Journal of the Japanese Society of Nephrology), 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, considering that the severity of chronic kidney disease has traditionally been expressed only in terms of stages classified by GFR, it is also possible to express the severity of chronic kidney disease in the traditional way, using stages G1, G2, G3a, G3b, G4, and G5.

[0049] In one embodiment, the pharmaceutical composition provided by the present invention is administered to patients with early-stage chronic kidney disease with low severity. In one embodiment, the pharmaceutical composition provided by the present invention is administered to patients with chronic kidney disease of stage G3b or lower, preferably stage G2 or lower. In one embodiment, the pharmaceutical composition provided by the present invention is administered to patients with chronic kidney disease who are in stage G2 or higher and stage G3b or lower (for example, stage G2 and stage G3a; or stage G2, stage G3a and G3b). In one embodiment, the pharmaceutical composition provided by the present invention is administered to patients with chronic kidney disease who are at stage G3b or lower and have microalbuminuria, preferably patients with chronic kidney disease who are at stage G2 and have microalbuminuria. In one embodiment, the pharmaceutical composition provided by the present invention is administered to patients with chronic kidney disease who are in stage G2 or higher and stage G3b or lower (for example, stage G2 and stage G3a; or stage G2, stage G3a and G3b) and have microalbuminuria. In one embodiment, the pharmaceutical composition provided by the present invention is administered to patients with chronic kidney disease in stage G3b or lower, with a urinary protein excretion of less than 3.5 g / gCr, preferably in stage G2, with a urinary protein excretion of less than 3.5 g / gCr. In one embodiment, the pharmaceutical composition provided by the present invention is administered to patients with chronic kidney disease who are in stage G2 or higher and stage G3b or lower (for example, stage G2 and stage G3a; or stage G2, stage G3a and stage G3b) 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 patient with progressive chronic kidney disease. In one embodiment, the pharmaceutical composition provided by the present invention is administered to patients with chronic kidney disease whose urinary (e.g., early morning urine) concentration of β2-microglobulin is 2000 μg / L or less, 1000 μg / L or less, 800 μg / L or less, 290 μg / L or less, 200 μg / L or less, 1 to 2000 μg / L, 1 to 1000 μg / L, 1 to 800 μg / L, 1 to 290 μg / L, 1 to 200 μg / L, 10 to 2000 μg / L, 10 to 1000 μg / L, 10 to 800 μg / L, 10 to 290 μg / L, 10 to 200 μg / L, or 80 to 200 μg / L. In one embodiment, the pharmaceutical composition provided by the present invention is administered to patients with chronic kidney disease whose blood (e.g., plasma or serum) concentration of cystatin C is 0.1-3.0 mg / L, 0.1-2.0 mg / L, 0.1-1.6 mg / L, 0.1-1.3 mg / L, 0.5-3.0 mg / L, 0.5-2.0 mg / L, 0.5-1.6 mg / L, 0.5-1.3 mg / L, or 0.9-1.3 mg / mL. In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with chronic kidney disease whose blood concentration of indoxyl sulfate is 0.001 to 100 μg / mL (for example, 0.1 to 30 μg / mL). In one embodiment, the pharmaceutical composition provided by the present invention is administered to patients with chronic kidney disease whose blood concentration of p-cresyl sulfate is 0.003 to 300 μg / mL (for example, 0.01 to 30 μg / mL). In one embodiment, the pharmaceutical composition provided by the present invention is administered to patients with chronic kidney disease whose blood hippuric acid concentration is 0.01 to 100 μg / mL (for example, 0.01 to 10 μg / mL). In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with chronic kidney disease whose blood concentration of arginosuccinic acid is 0.01 to 100 μg / mL (for example, 0.1 to 10 μg / mL). In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with chronic kidney disease whose blood concentration of phenylacetyl-L-glutamine is 0.03 to 30 μg / mL (for example, 0.1 to 10 μg / mL).

[0050] In one embodiment, the pharmaceutical composition provided by the present invention is administered to patients receiving treatment in accordance with the CKD treatment guidelines. For example, it is administered to patients receiving blood pressure management (administration of RA system inhibitors such as ARBs and ACE inhibitors, diuretics, calcium channel blockers, etc.), proteinuria management (administration of RA system inhibitors, etc.), blood glucose management (administration of α-glucosidase inhibitors, etc.), lipid management (administration of statins, fibrates, etc.), anemia management (administration of erythropoietin, etc.), and / or bone and mineral management (administration of bisphosphonates, etc.) in accordance with the CKD treatment guidelines. In one embodiment, the pharmaceutical composition provided by the present invention is used in combination with antihypertensive drugs (e.g., ARBs, ACE inhibitors, diuretics, calcium channel blockers). In one embodiment, the pharmaceutical composition provided by the present invention is used in combination with spherical adsorbent carbon (sold in Japan as Kremezin®), which is obtained by oxidizing and reducing spherical fine porous carbon derived from petroleum hydrocarbons at high temperatures.

[0051] In one embodiment, the pharmaceutical composition provided by the present invention is administered to patients with mild, early-stage chronic kidney disease (e.g., stage G3b or lower, preferably stage G2 to stage G3b, more preferably stage G2 and stage G3a, and even more preferably stage G2 chronic kidney disease) to reduce the concentration of uremic substances (e.g., indoxyl sulfate, hippuric acid and / or phenylacetyl-L-glutamine) in the patient's blood and to promote the excretion of uremic substances (e.g., indoxyl sulfate, p-cresyl sulfate, hippuric acid, argininosuccinate and / or phenylacetyl-L-glutamine) from the body (e.g., into the urine). In this embodiment, the pharmaceutical composition provided by the present invention may be a pharmaceutical composition for improving uremic symptoms, a pharmaceutical composition for treating or preventing uremia, a pharmaceutical composition for inhibiting the progression of chronic kidney disease, a pharmaceutical composition for delaying the initiation of dialysis, a pharmaceutical composition for inhibiting myocardial fibrosis, a pharmaceutical composition for inhibiting arteriosclerosis, a pharmaceutical composition for improving arteriosclerosis, a pharmaceutical composition for inhibiting the proliferation of vascular smooth muscle cells, a pharmaceutical composition for inhibiting vascular endothelial cell damage, a pharmaceutical composition for inhibiting arterial wall thickening, a pharmaceutical composition for improving arterial wall thickening, a pharmaceutical composition for inhibiting aortic calcification, or a pharmaceutical composition for treating or preventing cardiovascular diseases that are complications (e.g., heart failure, myocardial infarction, stroke, etc.). In one embodiment, the pharmaceutical composition provided by the present invention is administered to patients with mild, early-stage chronic kidney disease (e.g., stage G3b or lower, preferably stage G2 to stage G3b, more preferably stage G2 and stage G3a, and even more preferably stage G2 chronic kidney disease) to suppress the increase of β2-microglobulin in the urine of such patients. In this embodiment, the pharmaceutical composition provided by the present invention may be a composition for suppressing tubular (e.g., proximal tubule) damage, a composition for suppressing tubular (e.g., proximal tubule) cell damage, a composition for protecting tubular (e.g., proximal tubule) cells, or a pharmaceutical composition for maintaining tubular (e.g., proximal tubule) cell function (e.g., reabsorption of glucose, amino acids, etc.). In one embodiment, the pharmaceutical composition provided by the present invention is administered to patients with moderate to severe chronic kidney disease (e.g., patients with chronic kidney disease of stage G3b or higher) to reduce the concentration of uremic substances (e.g., indoxyl sulfate, hippuric acid, and / or phenylacetyl-L-glutamine) in the patient's blood and to promote the excretion of uremic substances (e.g., indoxyl sulfate, p-cresyl sulfate, hippuric acid, argininosuccinate, and / or phenylacetyl-L-glutamine) from the body (e.g., into the urine). In this embodiment, the pharmaceutical composition provided by the present invention may be a pharmaceutical composition for improving uremic symptoms, a pharmaceutical composition for treating or preventing uremia, a pharmaceutical composition for inhibiting the progression of chronic kidney disease, a pharmaceutical composition for delaying the initiation of dialysis, a pharmaceutical composition for inhibiting myocardial fibrosis, a pharmaceutical composition for inhibiting arteriosclerosis, a pharmaceutical composition for improving arteriosclerosis, a pharmaceutical composition for inhibiting the proliferation of vascular smooth muscle cells, a pharmaceutical composition for inhibiting vascular endothelial cell damage, a pharmaceutical composition for inhibiting arterial wall thickening, a pharmaceutical composition for improving arterial wall thickening, a pharmaceutical composition for inhibiting aortic calcification, a pharmaceutical composition for inhibiting the decrease in energy production in muscle cells, a pharmaceutical composition for inhibiting the decrease in muscle mass and / or muscle strength, or a pharmaceutical composition for treating or preventing cardiovascular diseases (e.g., heart failure, myocardial infarction, stroke, etc.) as complications. In one embodiment, the pharmaceutical composition provided by the present invention is administered to patients with moderate to severe chronic kidney disease (e.g., patients with chronic kidney disease of stage G3b or higher) to suppress the increase of β2-microglobulin in the urine of those patients. In this embodiment, the pharmaceutical composition provided by the present invention may be a composition for suppressing tubular (e.g., proximal tubular) damage, a composition for suppressing tubular (e.g., proximal tubular) cell damage, a composition for protecting tubular (e.g., proximal tubular) cells, or a pharmaceutical composition for maintaining tubular (e.g., proximal tubular) cell function (e.g., reabsorption of glucose, amino acids, etc.).

[0052] Other examples of embodiments of the present invention include the following. a) A method for reducing the blood concentration of uremic substances in a mammalian subject (e.g., a human), comprising administering an effective amount of an alkalizing agent to a subject in which it is necessary to reduce the blood concentration of uremic substances; b) A method for promoting the excretion of uremic substances into the urine in a mammalian subject (e.g., a human), comprising administering an effective amount of an alkalizing agent to a subject for which it is necessary to promote the excretion of uremic substances into the urine; c) A method for improving uremic symptoms in a mammal (e.g., a human), comprising administering an effective amount of an alkalizing agent to a subject in need of improvement of uremic symptoms, wherein the subject is suffering from kidney disease; d) A method for treating or preventing uremia in a mammal (e.g., a human), comprising administering an effective amount of an alkalizing agent to a subject in need of treatment or prevention of uremia, wherein the subject is suffering from kidney disease; e) A method for inhibiting the progression of chronic kidney disease in a mammal (e.g., human), comprising administering an effective amount of an alkalizing agent to a subject in which the progression of chronic kidney disease needs to be inhibited; f) A method for delaying the initiation of dialysis in a mammalian subject (e.g., human), comprising administering an effective amount of an alkalizing agent to a subject in need of delaying the initiation of dialysis, wherein the subject is suffering from chronic kidney disease; g) A method for inhibiting myocardial fibrosis in a mammalian subject (e.g., human), comprising administering an effective amount of an alkalizing agent to a subject in which inhibition of myocardial fibrosis is necessary, wherein the subject is suffering from kidney disease; h) A method for inhibiting arteriosclerosis in a mammal (e.g., a human), comprising administering an effective amount of an alkalizing agent to a subject in which inhibiting arteriosclerosis is necessary, wherein the subject is suffering from kidney disease; i) A method for inhibiting the proliferation of vascular smooth muscle cells in a mammalian subject (e.g., human), comprising administering an effective amount of an alkalizing agent to a subject in which the proliferation of vascular smooth muscle cells needs to be inhibited, wherein the subject is suffering from kidney disease; j) A method for suppressing vascular endothelial cell damage in a mammalian subject (e.g., human), comprising administering an effective amount of an alkalizing agent to a subject in which suppression of vascular endothelial cell damage is necessary, wherein the subject is suffering from kidney disease; k) A method for suppressing arterial wall thickening in a mammalian subject (e.g., human), comprising administering an effective amount of an alkalizing agent to a subject in which suppression of arterial wall thickening is necessary, wherein the subject is suffering from kidney disease; l) A method for inhibiting aortic calcification in a mammalian subject (e.g., human), comprising administering an effective amount of an alkalizing agent to a subject in which inhibiting aortic calcification is necessary, wherein the subject is suffering from kidney disease; m) A method for treating or preventing cardiovascular disease in a mammalian subject (e.g., human), comprising administering an effective amount of an alkalizing agent to a subject in need of treatment or prevention of cardiovascular disease, wherein the subject is suffering from kidney disease; n) A method for improving arteriosclerosis in a mammal (e.g., a human), comprising administering an effective amount of an alkalizing agent to a subject in need of improvement of arteriosclerosis, wherein the subject is suffering from kidney disease; o) A method for improving arterial wall thickening in a mammalian subject (e.g., human), comprising administering an effective amount of an alkalizing agent to a subject that needs improvement of arterial wall thickening, wherein the subject is suffering from kidney disease; p) A method for treating acute kidney disease in a mammal (e.g., human), comprising administering an effective amount of an alkalizing agent to a subject in need of treatment for acute kidney disease; q) A method for inhibiting the progression from acute kidney disease to chronic kidney disease in a mammal (e.g., human), comprising administering an effective amount of an alkalizing agent to a subject in whom the progression from acute kidney disease to chronic kidney disease needs to be inhibited; r) A method for treating or preventing tubular dysfunction in a mammalian subject (e.g., human), comprising administering an effective amount of an alkalizing agent to a subject in need of treatment or prevention of tubular dysfunction; s) A method for suppressing tubular damage in a mammalian subject (e.g., human), comprising administering an effective amount of an alkalizing agent to a subject in need of suppressing tubular damage; t) A method for suppressing proximal tubular cell damage in a mammalian subject (e.g., human), comprising administering an effective amount of an alkalizing agent to a subject in which suppression of proximal tubular cell damage is necessary; u) A method for protecting proximal tubular cells in a mammalian subject (e.g., human), comprising administering an effective amount of an alkalizing agent to a subject in need of protection of proximal tubular cells; v) A method for maintaining proximal tubular cell function in a mammalian subject (e.g., human), comprising administering an effective amount of an alkalizing agent to a subject in which maintenance of proximal tubular cell function is necessary; w) A method for promoting the excretion of uremic substances from the body in a mammalian subject (e.g., a human), comprising administering an effective amount of an alkalizing agent to a subject in need of promoting the excretion of uremic substances from the body; x) A method for excreting uremic substances into the urine in a mammalian subject (e.g., human) in a manner dependent on the blood concentration of the uremic substances, comprising administering an effective amount of an alkalizing agent to a subject that needs to excrete uremic substances into the urine;

[0053] aa) Alkalinizing agents used to lower the blood concentration of uremic substances; bb) Alkalinizing agents used to promote the excretion of uremic substances into the urine; cc) An alkalizing agent for use in improving uremic symptoms in patients with kidney disease; dd) An alkalizing agent for use in the treatment or prevention of uremia in patients with kidney disease; ee) An alkalizing agent used to slow the progression of chronic kidney disease; ff) An alkalizing agent for use in delaying the initiation of dialysis in patients with chronic kidney disease; gg) An alkalizing agent for use in inhibiting myocardial fibrosis in patients with kidney disease; hh) An alkalizing agent used to suppress arteriosclerosis in patients with kidney disease; ii) An alkalizing agent for use in inhibiting the proliferation of vascular smooth muscle cells in patients with kidney disease; jj) An alkalizing agent for use in suppressing vascular endothelial cell damage in patients with kidney disease; kk) An alkalizing agent for use in suppressing arterial wall thickening in patients with kidney disease; ll) An alkalizing agent for use in inhibiting aortic calcification in patients with kidney disease; mm) An alkalizing agent for use in the treatment or prevention of cardiovascular disease in patients with kidney disease; nn) An alkalizing agent for use in improving arteriosclerosis in patients with kidney disease; oo) An alkalizing agent for use in improving arterial wall thickening in patients with kidney disease; pp) Alkalinizing agent for use in the treatment of acute kidney disease; qq) An alkalizing agent used to suppress the progression from acute kidney disease to chronic kidney disease; rr) An alkalizing agent used for the treatment or prevention of renal tubular disorders; ss) An alkalizing agent used to suppress tubular damage; tt) An alkalizing agent used to suppress proximal tubular cell damage; uu) An alkalizing agent for use in protecting proximal tubular cells; vv) An alkalizing agent used to maintain proximal tubular cell function; (ww) An alkalizing agent used to promote the excretion of uremic toxins from the body; xx) Alkalinizing agents for use in the urinary excretion of uremic substances in a manner dependent on their blood concentration;

[0054] aaa) A pharmaceutical composition containing an alkalizing agent for use in reducing the blood concentration of uremic substances; bbb) Pharmaceutical compositions containing an alkalizing agent for use in promoting the excretion of uremic substances into the urine; (ccc) Pharmaceutical composition containing an alkalizing agent for use in improving uremic symptoms in patients with kidney disease; ddd) A pharmaceutical composition containing an alkalizing agent for use in the treatment or prevention of uremia in patients with kidney disease; eee) A pharmaceutical composition containing an alkalizing agent for use in inhibiting the progression of chronic kidney disease; fff) A pharmaceutical composition containing an alkalizing agent for use in delaying the initiation of dialysis in patients with chronic kidney disease; (ggg) A pharmaceutical composition containing an alkalizing agent for use in inhibiting myocardial fibrosis in patients with kidney disease; hhh) Pharmaceutical composition containing an alkalizing agent for use in inhibiting arteriosclerosis in patients with kidney disease; iii) A pharmaceutical composition containing an alkalizing agent for use in inhibiting the proliferation of vascular smooth muscle cells in patients with kidney disease; jjj) A pharmaceutical composition containing an alkalizing agent for use in suppressing vascular endothelial cell damage in patients with kidney disease; (KKK) A pharmaceutical composition containing an alkalizing agent for use in suppressing arterial wall thickening in patients with kidney disease; iii) A pharmaceutical composition containing an alkalizing agent for use in inhibiting aortic calcification in patients with kidney disease; A pharmaceutical composition containing an alkalizing agent for use in the treatment or prevention of cardiovascular disease in patients with renal disease (mmm); (nn) A pharmaceutical composition containing an alkalizing agent for use in improving arteriosclerosis in patients with kidney disease; ooo) A pharmaceutical composition containing an alkalizing agent for use in improving arterial wall thickening in patients with kidney disease; (ppp) Pharmaceutical compositions containing an alkalizing agent for use in the treatment of acute kidney disease; qqq) A pharmaceutical composition containing an alkalizing agent for use in inhibiting the progression from acute kidney disease to chronic kidney disease; rrr) A pharmaceutical composition containing an alkalizing agent for use in the treatment or prevention of renal tubular disorders; sss) A pharmaceutical composition containing an alkalizing agent for use in suppressing tubular damage; A pharmaceutical composition containing an alkalizing agent for use in suppressing proximal tubular cell damage; uuu) A pharmaceutical composition containing an alkalizing agent for use in protecting proximal tubular cells; vvv) A pharmaceutical composition containing an alkalizing agent for use in maintaining proximal tubular cell function; (www) Pharmaceutical compositions containing alkalizing agents for use in promoting the excretion of uremic substances from the body; xxx) A pharmaceutical composition containing an alkalizing agent for use in the urinary excretion of uremic substances in a manner dependent on their blood concentration;

[0055] aaaa) Use of alkalizing agents for manufacturing pharmaceutical compositions for reducing blood concentrations of uremic substances; bbbb) Use of an alkalizing agent for manufacturing a pharmaceutical composition for promoting the excretion of uremic substances in urine; cccc) Use of alkalizing agents for manufacturing pharmaceutical compositions for improving uremic symptoms in patients with kidney disease; dddd) Use of alkalizing agents for the manufacture of pharmaceutical compositions for the treatment or prevention of uremia in patients with kidney disease; eeee) Use of an alkalizing agent for manufacturing a pharmaceutical composition for inhibiting the progression of chronic kidney disease; ffff) Use of an alkalizing agent for manufacturing a pharmaceutical composition for delaying the initiation of dialysis in patients with chronic kidney disease; gggg) Use of an alkalizing agent for manufacturing a pharmaceutical composition for inhibiting myocardial fibrosis in patients with kidney disease; hhhh) Use of alkalizing agents for manufacturing pharmaceutical compositions for inhibiting arteriosclerosis in patients with kidney disease; iiii) Use of alkalizing agents for the manufacture of pharmaceutical compositions for inhibiting the proliferation of vascular smooth muscle cells in patients with kidney disease; jjjj) Use of an alkalizing agent for manufacturing a pharmaceutical composition for inhibiting vascular endothelial cell damage in patients with kidney disease; kkkk) Use of an alkalizing agent for manufacturing a pharmaceutical composition for inhibiting arterial wall thickening in patients with kidney disease; ll) Use of an alkalizing agent for manufacturing a pharmaceutical composition for inhibiting aortic calcification in patients with kidney disease; Use of an alkalizing agent for manufacturing pharmaceutical compositions for the treatment or prevention of cardiovascular disease in patients with renal disease; nnnn) Use of alkalizing agents for manufacturing pharmaceutical compositions for improving arteriosclerosis in patients with kidney disease; oooo) Use of an alkalizing agent for manufacturing a pharmaceutical composition for improving arterial wall thickening in patients with kidney disease; pppp) Use of alkalizing agents for manufacturing pharmaceutical compositions for the treatment of acute kidney disease; qqqq) Use of an alkalizing agent for manufacturing a pharmaceutical composition for inhibiting the progression from acute kidney disease to chronic kidney disease; rrrr) Use of alkalizing agents for the manufacture of pharmaceutical compositions for the treatment or prevention of renal tubular disorders; ssss) Use of an alkalizing agent for manufacturing a pharmaceutical composition for suppressing tubular damage; Use of an alkalizing agent for manufacturing a pharmaceutical composition for inhibiting proximal tubular cell damage; uuuu) Use of an alkalizing agent for manufacturing a pharmaceutical composition for protecting proximal tubular cells; vvvv) Use of an alkalizing agent for manufacturing a pharmaceutical composition for maintaining proximal tubular cell function; wwww) Use of alkalizing agents for manufacturing pharmaceutical compositions for promoting the excretion of uremic substances from the body; and xxxx) Use of an alkalizing agent for producing a pharmaceutical composition for the excretion of uremic substances in urine in a manner dependent on the blood concentration.

[0056] 2. Food composition In one embodiment, the food composition provided by the present invention contains an alkalizing agent and exhibits an effect of promoting the excretion of uremic substances (for example, indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid and / or argininosuccinic acid, preferably indoxyl sulfate, p-cresyl sulfate and phenylacetyl-L-glutamine, more preferably indoxyl sulfate and phenylacetyl-L-glutamine, and even more preferably indoxyl sulfate). In one embodiment, the food composition provided by the present invention contains an alkalizing agent and exhibits an effect of lowering the blood concentration of uremic substances. In one embodiment, the food composition provided by the present invention contains an alkalizing agent and exhibits an effect of promoting the urinary excretion of uremic substances. In one embodiment, the food composition provided by the present invention contains an alkalizing agent and exhibits a kidney function maintenance effect. In one embodiment, the food composition provided by the present invention contains an alkalizing agent and exhibits an effect of suppressing renal tubular damage. Here, the renal tubule can be, for example, the proximal tubule. In one embodiment, the food composition provided by the present invention contains an alkalizing agent and exhibits an inhibitory effect on proximal tubular cell damage. In one embodiment, the food composition provided by the present invention contains an alkalizing agent and exhibits a proximal tubular cell protective effect. In one embodiment, the food composition provided by the present invention contains an alkalizing agent and exhibits an effect of maintaining renal tubular function (for example, reabsorption of water, sodium ions, potassium ions, calcium ions, phosphate ions, bicarbonate ions, chloride ions, glucose, amino acids, vitamins, etc.). Here, the renal tubule is, for example, the proximal tubule, and the proximal tubular function is, for example, the reabsorption of glucose, amino acids, vitamins, etc. In the above embodiment, the food composition provided by the present invention has the effect of suppressing the increase in the amount (concentration) of β2-microglobulin in the urine (e.g., early morning urine) that occurs with the progression of chronic kidney disease. In the above embodiment, the food composition provided by the present invention does not affect glomerular function in patients with chronic kidney disease, while suppressing proximal tubular cell damage associated with the progression of chronic kidney disease and protecting proximal tubular cells. Regarding alkalizing agents, those described in "1. Pharmaceutical Compositions" above can be used. Examples of alkalizing agents include pharmaceutically acceptable salts of citric acid (e.g., alkali metal citrate salts or their hydrates or mixtures thereof) as food-acceptable salts of citric acid, and sodium bicarbonate. Preferably, a mixture of potassium citrate monohydrate (C6H5K3O7·H2O) and sodium citrate dihydrate (C6H5Na3O7·2H2O), or sodium citrate dihydrate. The uremic substances are as described in "1. Pharmaceutical Compositions" above. Examples of uremic substances include indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and argininosuccinic acid. The content of the alkalizing agent 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, nutritional supplements, 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 alkalizing agent to produce the above-mentioned effects and are in a form that can be taken orally. They may be in the form of ordinary food and beverages, or they may be provided as formulations suitable for oral administration from among the formulations that can be applied to the pharmaceutical composition, such as tablets, capsules, suspensions, etc. Regarding the composition and manufacturing method of these formulations, the composition and manufacturing method of pharmaceutical formulations described in "1. Pharmaceutical Compositions" above can be applied as is, and pharmaceutical formulation technologies that are known in the field of pharmaceutical formulation technology can also be applied. For example, in the case of Foods for Specified Health Uses, nutritional supplements, functional foods, or foods for hospital patients, each serving of food may contain 1 / 3 of a total of 1 to 3 g of potassium citrate monohydrate and sodium citrate dihydrate as alkalizing agents, or 1 / 3 of a total of 1 to 6 g of sodium bicarbonate as an alkalizing agent. When Foods for Specified Health Uses, nutritional supplements, functional foods, foods for hospital patients, or supplements are provided in tablet form, for example, each tablet containing 300 mg to 600 mg may contain 70 to 80% by weight of an alkalizing agent. If the food composition provided by the present invention is not formulated but provided in the form of ordinary food or beverage, it can be manufactured appropriately by a person skilled in the art depending on the type of food, for example, by incorporating an alkalizing agent (e.g., potassium citrate and / or sodium citrate) into the food material. Examples of the aforementioned food and beverage forms 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; or powdered foods. Examples of beverages include fruit juices, coffee drinks, oolong tea drinks, green tea drinks, black tea drinks, barley tea drinks, vegetable drinks, soft drinks such as carbonated beverages, fruit extract drinks, vegetable extract juices, near-water, sports drinks, and diet drinks. Beverages 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 individually or in combination. The food composition provided by the present invention can be used in the same manner as the pharmaceutical composition described in "1. Pharmaceutical Composition" above, and can also be used in a range that is not intended for the treatment or prevention of disease. That is, when the amount of alkalizing agent contained in the food composition according to the present invention is taken as a reference, the amount of alkalizing agent used in the food composition can be applied to the target of the pharmaceutical composition in the same amount as the alkalizing agent contained in the pharmaceutical composition. Furthermore, in one embodiment, the "food composition" according to the present invention can be applied to a subject (e.g., human or other mammal) that does not have "pathological" or "abnormal" symptoms, conditions, or diseases, i.e., a subject (e.g., human or other mammal) that is in a "healthy" or "normal" state, in order to maintain or improve that "healthy" or "normal" state. Moreover, it can be applied to a "healthy person concerned about kidney health" or a "healthy person concerned about renal tubular health" in order to maintain or improve that "healthy" or "normal" state. In this case, whether the alkalizing agent is a component of a pharmaceutical composition or a component of a food composition, the pharmacological effect of the alkalizing agent itself is basically the same. Therefore, the amount and method of application of the food composition can be appropriately adjusted based on the alkalizing agent, according to the desired effect. Food compositions applied to subjects (e.g., humans or other mammals) that do not have "pathological" or "abnormal" symptoms, conditions, or diseases, that is, subjects (e.g., humans or other mammals) that are in a "healthy" or "normal" state, in order to maintain or enhance that "healthy" or "normal" state, may be specifically referred to as "functional foods." The term "administration" as described in "1. Pharmaceutical Compositions" above can also be applied to the "food composition" according to the present invention, and furthermore, in the case of the "food composition" according to the present invention, the term "administration" can be read as "ingestion". Therefore, for example, terms such as "administer," "be administered," etc. can be changed in form and read as "cause to ingestion," "ingestion," "be ingestion," etc., depending on the context. Therefore, the following are examples of embodiments of the food composition according to the present invention. <1> Food composition containing an alkalizing agent for reducing blood concentrations of uremic substances; <2> Food composition containing an alkalizing agent for promoting the urinary excretion of uremic substances; <3> Food composition for maintaining kidney function, containing an alkalizing agent; <4> Food composition containing an alkalizing agent for inhibiting tubular damage; <5> A food composition containing an alkalizing agent for inhibiting tubular cell damage, preferably for inhibiting proximal tubular cell damage; <6> Food composition containing an alkalizing agent for the protection of renal tubular cells, preferably proximal tubular cells; <7> A food composition containing an alkalizing agent for maintaining renal tubular function (e.g., reabsorption of water, sodium ions, potassium ions, calcium ions, phosphate ions, bicarbonate ions, chloride ions, glucose, amino acids, vitamins, etc.), preferably for maintaining proximal tubular function (e.g., reabsorption of glucose, amino acids, vitamins, etc.); <11> A method for lowering the blood concentration of uremic substances, comprising administering a food composition containing an effective amount of an alkalizing agent to a subject who requires a reduction in the blood concentration of uremic substances; <22> A method for promoting the urinary excretion of uremic substances, comprising administering a food composition containing an effective amount of an alkalizing agent to a subject in need of promoting the urinary excretion of uremic substances; <33> A method for maintaining kidney function, comprising administering a food composition containing an effective amount of an alkalizing agent to a subject requiring maintenance of kidney function; <44> A method for suppressing renal tubular damage, comprising administering a food composition containing an effective amount of an alkalizing agent to a subject requiring suppression of renal tubular damage; <55> A method for suppressing damage to renal tubular cells, preferably proximal tubular cells, comprising administering a food composition containing an effective amount of an alkalizing agent to a subject in need of suppression of damage to renal tubular cells, preferably proximal tubular cells; <66> A method for protecting renal tubular cells, preferably proximal tubular cells, comprising administering a food composition containing an effective amount of an alkalizing agent to a subject in need of protection of renal tubular cells, preferably proximal tubular cells; <77> A method for maintaining renal tubular function (e.g., reabsorption of water, sodium ions, potassium ions, calcium ions, phosphate ions, bicarbonate ions, chloride ions, glucose, amino acids, vitamins, etc.), preferably proximal tubular function (e.g., reabsorption of glucose, amino acids, vitamins, etc.), comprising administering a food composition containing an effective amount of an alkalizing agent to a subject who requires maintenance of renal tubular function, preferably proximal tubular function; <111> Food composition containing an alkalizing agent for reducing the blood concentration of uremic substances; <222> Food composition containing an alkalizing agent for promoting the urinary excretion of uremic substances; <333> Food composition containing an alkalizing agent for maintaining kidney function; <444> Food composition containing an alkalizing agent for suppressing tubular damage; <555> Food compositions containing an alkalizing agent for inhibiting damage to renal tubular cells, preferably proximal tubular cells; <666> Food compositions comprising an alkalizing agent for the protection of renal tubular cells, preferably proximal tubular cells; <777> A food composition containing an alkalizing agent for maintaining renal tubular function (e.g., reabsorption of water, sodium ions, potassium ions, calcium ions, phosphate ions, bicarbonate ions, chloride ions, glucose, amino acids, vitamins, etc.), preferably proximal tubular function (e.g., reabsorption of glucose, amino acids, vitamins, etc.); <1111> Use of alkalizing agents for producing food compositions for reducing blood concentrations of uremic substances; <2222> Use of alkalizing agents for producing food compositions that promote the urinary excretion of uremic substances; <3333> Use of alkalizing agents for manufacturing food compositions for maintaining kidney function; <4444> Use of alkalizing agents for manufacturing food compositions for inhibiting renal tubular damage; <5555> Use of an alkalizing agent for producing a food composition for inhibiting damage to renal tubular cells, preferably proximal tubular cells; <6666> Use of alkalizing agents for producing food compositions for protecting tubular cells, preferably proximal tubular cells; and <7777> Use of an alkalizing agent for producing a food composition for maintaining renal tubular function (e.g., reabsorption of water, sodium ions, potassium ions, calcium ions, phosphate ions, bicarbonate ions, chloride ions, glucose, amino acids, vitamins, etc.), preferably proximal tubular function (e.g., reabsorption of glucose, amino acids, vitamins, etc.). It is preferable that the packaging, container, or instructions for the food composition according to the present invention indicate the effects of reducing the blood concentration of uremic substances, promoting the urinary excretion of uremic substances, maintaining renal function, suppressing tubular damage, suppressing tubular cell damage, suppressing proximal tubular cell damage, protecting tubular cells, protecting proximal tubular cells, maintaining tubular function (e.g., reabsorption of water, sodium ions, potassium ions, calcium ions, phosphate ions, bicarbonate ions, chloride ions, glucose, amino acids, vitamins, etc.), or maintaining proximal tubular function (e.g., reabsorption of glucose, amino acids, vitamins, etc.). In one embodiment, the "food composition" according to the present invention is ingested by a subject (e.g., a human or other mammal) whose urinary β2-microglobulin concentration is 290 μg / L or less, preferably 50 to 150 μg / L. In one embodiment, the "food composition" according to the present invention is ingested by a subject (e.g., a human or other mammal) whose blood cystatin C concentration is 0.5 to 2.2 mg / L, preferably 1.0 to 1.3 mg / L. In one embodiment, the intake of the "food composition" according to the present invention suppresses the increase in β2-microglobulin concentration in urine. In one embodiment, the intake of the "food composition" according to the present invention suppresses the increase in urinary β2-microglobulin concentration 12 weeks after administration. In one embodiment, the intake of the "food composition" according to the present invention does not substantially decrease the β2-microglobulin concentration in the urine compared to before administration. In one embodiment, after 12 weeks of administration, the β2-microglobulin concentration in the urine did not substantially decrease compared to before administration. In one embodiment, ingestion of the "food composition" according to the present invention does not substantially increase blood cystatin C compared to before administration. In one embodiment, ingestion of the "food composition" according to the present invention does not substantially increase blood cystatin C compared to before administration. In one embodiment, the intake of the "food composition" according to the present invention suppresses the increase in the amount of β2-microglobulin in early morning urine that occurs with the progression of chronic kidney disease. In one embodiment, the intake of the "food composition" according to the present invention does not affect glomerular function in patients with chronic kidney disease, while suppressing proximal tubular cell damage associated with the progression of chronic kidney disease and protecting proximal tubular cells.

[0057] 3. Methods for determining a decrease in the concentration of uremic substances in the blood, etc. In one embodiment, the present invention provides a method for determining a decrease in the concentration of uremic substances (e.g., indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid and / or argininosuccinate, preferably indoxyl sulfate, hippuric acid and / or phenylacetyl-L-glutamine, more preferably indoxyl sulfate and phenylacetyl-L-glutamine, and even more preferably indoxyl sulfate) in the blood of a patient with chronic kidney disease, the method comprising measuring the pH of the urine. In one embodiment, the present invention provides a method for determining the promotion of excretion of uremic substances (indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid and / or argininosuccinate, preferably indoxyl sulfate, p-cresyl sulfate, hippuric acid and / or phenylacetyl-L-glutamine, more preferably indoxyl sulfate and phenylacetyl-L-glutamine, and even more preferably indoxyl sulfate) into the urine of patients with chronic kidney disease, the method comprising measuring the pH of the urine. The content of uremic substances (e.g., indoxyl sulfate) in body fluids can be measured by HPLC or enzymatic methods. However, these methods require specialized and expensive reagents. As described herein, administering an alkalizing agent lowers uremic substances in the blood (e.g., indoxyl sulfate concentration, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and / or argininosuccinate) and promotes their excretion in the urine. Therefore, patients with chronic kidney disease can easily and inexpensively determine the decrease in uremic substances in the blood (e.g., indoxyl sulfate concentration, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and / or argininosuccinate) and / or the promotion of their excretion in the urine (e.g., indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and / or argininosuccinate) by measuring the pH of their urine. pH can be measured using well-known techniques, such as pH test strips, pH test solutions, or simple pH meters. In one embodiment, a patient with chronic kidney disease measures the pH of their early morning urine (first urine after waking) over time from the start of taking an alkalizing agent (e.g., a mixture of potassium citrate monohydrate and sodium citrate dihydrate, or sodium citrate dihydrate). If the pH of the urine rises, uremic substances in the blood (e.g., indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid and / or argininosuccinate, preferably indoxyl sulfate, hippuric acid and / or phenylacetyl-L-glutamine, more preferably indoxyl sulfate) are detected. It is possible to easily determine that a decrease in the concentration of syl sulfate and phenylacetyl L-glutamine (more preferably indoxyl sulfate) and / or promotion of the excretion of uremic substances (e.g., indoxyl sulfate, p-cresyl sulfate, phenylacetyl L-glutamine, hippuric acid and / or argininosuccinic acid, preferably indoxyl sulfate, p-cresyl sulfate, hippuric acid and / or phenylacetyl L-glutamine, more preferably indoxyl sulfate and phenylacetyl L-glutamine, and even more preferably indoxyl sulfate) into the urine has been achieved. In one embodiment, a patient with chronic kidney disease takes an alkalizing agent (e.g., a mixture of potassium citrate monohydrate and sodium citrate dihydrate, or sodium citrate dihydrate) and measures the pH of their first morning urine (the first urine after waking up). If the urine pH is in the range of 5.2 to 6.8 (e.g., pH 5.5 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), then uremic substances in the blood (e.g., indocyl) are measured. It is possible to easily determine that a reduction in the concentration of uremic substances (e.g., indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid and / or argininosuccinic acid, preferably indoxyl sulfate, hippuric acid and / or phenylacetyl-L-glutamine, more preferably indoxyl sulfate and phenylacetyl-L-glutamine, even more preferably indoxyl sulfate) and / or promotion of the excretion of uremic substances (e.g., indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid and / or argininosuccinic acid, preferably indoxyl sulfate, p-cresyl sulfate, hippuric acid and / or phenylacetyl-L-glutamine, more preferably indoxyl sulfate and phenylacetyl-L-glutamine, even more preferably indoxyl sulfate) into the urine has been achieved. Determining whether a reduction in the concentration of uremic substances in the blood (e.g., indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and / or argininosuccinate) and / or promotion of the excretion of uremic substances in the urine (e.g., indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and / or argininosuccinate) has been achieved in this manner can be helpful in diagnosing whether the progression of chronic kidney disease has been suppressed. Therefore, in one embodiment, the present invention provides a method for determining the suppression of the progression of chronic kidney disease, comprising measuring the pH of the urine (e.g., early morning urine) of a patient who has been administered an alkalizing agent (e.g., a mixture of potassium citrate monohydrate and sodium citrate dihydrate, or sodium citrate dihydrate). If an increase in urine pH over time, or if the urine pH is in the range of 5.8 to 6.8 (e.g., the urine pH is in the range of 6.0 to 6.2), is observed, it may be helpful in diagnosing that the progression of chronic kidney disease is being suppressed.

[0058] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in reducing the blood concentration of uremic substances, wherein potassium citrate monohydrate and sodium citrate dihydrate are administered orally as alkalizing agents at a total dose of 1 to 3 g / day, with each dose being 0.5 to 1.5 g / day, divided into 1 to 5 doses per day, preferably 3 doses per day. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in reducing the blood concentration of uremic substances, wherein one dose unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and is administered orally in doses of 3 to 6 dose units per day, divided into 3 doses per day.

[0059] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in promoting the excretion of uremic substances in urine, wherein potassium citrate monohydrate and sodium citrate dihydrate are administered orally as alkalizing agents at a total dose of 1 to 3 g / day, with each dose being 0.5 to 1.5 g / day, divided into 1 to 5 doses per day, preferably 3 doses per day. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in promoting the excretion of uremic substances in urine, wherein one dose unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and is administered orally in doses of 3 to 6 dose units per day, divided into 3 doses per day.

[0060] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in improving uremic symptoms in patients with kidney disease, comprising potassium citrate monohydrate and sodium citrate dihydrate as the alkalizing agents, administered orally in doses of 0.5 to 1.5 g / day each, totaling 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in improving uremic symptoms in patients with kidney disease, wherein one dose unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and is administered orally in doses of 3 to 6 dose units per day, divided into 3 doses per day.

[0061] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in the treatment or prevention of uremia in patients with kidney disease, wherein potassium citrate monohydrate and sodium citrate dihydrate are administered orally as alkalizing agents at a total dose of 1 to 3 g / day, with each dose being 0.5 to 1.5 g / day, divided into 1 to 5 doses per day, preferably 3 doses per day. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in the treatment or prevention of uremia in patients with kidney disease, wherein one dose unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and is administered orally in doses of 3 to 6 dose units per day, divided into 3 doses per day.

[0062] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in inhibiting the progression of chronic kidney disease, wherein potassium citrate monohydrate and sodium citrate dihydrate are administered orally as alkalizing agents at a total dose of 1 to 3 g / day, with each dose being 0.5 to 1.5 g / day, divided into 1 to 5 doses per day, preferably 3 doses per day. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in inhibiting the progression of chronic kidney disease, wherein one dose unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and is administered orally in doses of 3 to 6 dose units per day, divided into 3 doses per day.

[0063] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in delaying the initiation of dialysis in patients with chronic kidney disease, wherein potassium citrate monohydrate and sodium citrate dihydrate are administered orally as alkalizing agents at a total dose of 1 to 3 g / day, with each dose being 0.5 to 1.5 g / day, divided into 1 to 5 doses per day, preferably 3 doses per day. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in delaying the initiation of dialysis in patients with chronic kidney disease, wherein one dose unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and is administered orally in doses of 3 to 6 dose units per day, divided into three doses per day.

[0064] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in suppressing myocardial fibrosis in patients with kidney disease, wherein potassium citrate monohydrate and sodium citrate dihydrate are administered orally as alkalizing agents at a total dose of 1 to 3 g / day, with each dose being 0.5 to 1.5 g / day, divided into 1 to 5 doses per day, preferably 3 doses per day. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in suppressing myocardial fibrosis in patients with kidney disease, wherein one dose unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and is administered orally in doses of 3 to 6 dose units per day, divided into 3 doses per day.

[0065] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in suppressing arteriosclerosis in patients with kidney disease, wherein potassium citrate monohydrate and sodium citrate dihydrate are administered orally as alkalizing agents at a total dose of 1 to 3 g / day, with each dose being 0.5 to 1.5 g / day, divided into 1 to 5 doses per day, preferably 3 doses per day. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in suppressing arteriosclerosis in patients with kidney disease, wherein one dose unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and is administered orally in doses of 3 to 6 dose units per day, divided into 3 doses per day.

[0066] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in inhibiting the proliferation of vascular smooth muscle cells in patients with kidney disease, wherein potassium citrate monohydrate and sodium citrate dihydrate are administered orally as alkalizing agents at a total dose of 1 to 3 g / day, with each dose being 0.5 to 1.5 g / day, divided into 1 to 5 doses per day, preferably 3 doses per day. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in inhibiting the proliferation of vascular smooth muscle cells in patients with kidney disease, wherein one dose unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and is administered orally in doses of 3 to 6 dose units per day, divided into 3 doses per day.

[0067] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in suppressing vascular endothelial cell damage in patients with kidney disease, wherein potassium citrate monohydrate and sodium citrate dihydrate are administered orally as alkalizing agents at a total dose of 1 to 3 g / day, with each dose being 0.5 to 1.5 g / day, divided into 1 to 5 doses per day, preferably 3 doses per day. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in suppressing vascular endothelial cell damage in patients with kidney disease, wherein one dose unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and is administered orally in doses of 3 to 6 dose units per day, divided into three doses per day.

[0068] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in suppressing arterial wall thickening in patients with kidney disease, wherein potassium citrate monohydrate and sodium citrate dihydrate are administered orally as alkalizing agents at a total dose of 1 to 3 g / day, with each dose being 0.5 to 1.5 g / day, divided into 1 to 5 doses per day, preferably 3 doses per day. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in suppressing arterial wall thickening in patients with kidney disease, wherein one dose unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and is administered orally in doses of 3 to 6 dose units per day, divided into 3 doses per day.

[0069] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in inhibiting aortic calcification in patients with kidney disease, wherein potassium citrate monohydrate and sodium citrate dihydrate are administered orally as alkalizing agents at a total dose of 1 to 3 g / day, with each dose being 0.5 to 1.5 g / day, divided into 1 to 5 doses per day, preferably 3 doses per day. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in inhibiting aortic calcification in patients with kidney disease, wherein one dose unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and three to six dose units are administered orally in three divided doses per day.

[0070] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in the treatment or prevention of cardiovascular disease in patients with kidney disease, wherein potassium citrate monohydrate and sodium citrate dihydrate are administered orally as alkalizing agents at a total dose of 1 to 3 g / day, with each dose being 0.5 to 1.5 g / day, divided into 1 to 5 doses per day, preferably 3 doses per day. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in the treatment or prevention of cardiovascular disease in patients with kidney disease, wherein one dose unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and is administered orally in doses of 3 to 6 dose units per day, divided into three doses per day.

[0071] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in improving arteriosclerosis in patients with kidney disease, comprising potassium citrate monohydrate and sodium citrate dihydrate as alkalizing agents, administered orally in doses of 0.5 to 1.5 g / day each, totaling 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in improving arteriosclerosis in patients with kidney disease, wherein one dose unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and is administered orally in doses of 3 to 6 dose units per day, divided into 3 doses per day.

[0072] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in improving arterial wall thickening in patients with kidney disease, wherein potassium citrate monohydrate and sodium citrate dihydrate are administered orally as alkalizing agents at a total dose of 1 to 3 g / day, with each dose being 0.5 to 1.5 g / day, divided into 1 to 5 doses per day, preferably 3 doses per day. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in improving arterial wall thickening in patients with kidney disease, wherein one dose unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and three to six dose units are administered orally in three divided doses per day.

[0073] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in the treatment of acute kidney disease, wherein potassium citrate monohydrate and sodium citrate dihydrate are administered orally as alkalizing agents at a total dose of 1 to 3 g / day, with each dose being 0.5 to 1.5 g / day, divided into 1 to 5 doses per day, preferably 3 doses per day. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in the treatment of acute kidney disease, wherein one dose unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and is administered orally in doses of 3 to 6 dose units per day, divided into 3 doses per day.

[0074] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in suppressing the progression from acute kidney disease to chronic kidney disease, wherein potassium citrate monohydrate and sodium citrate dihydrate are administered orally as alkalizing agents at a total dose of 1 to 3 g / day, with each dose being 0.5 to 1.5 g / day, divided into 1 to 5 doses per day, preferably 3 doses per day. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in suppressing the progression from acute kidney disease to chronic kidney disease, wherein one dose unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and 3 to 6 dose units are administered orally in three divided doses per day.

[0075] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in the treatment or prevention of renal tubular disorders, wherein potassium citrate monohydrate and sodium citrate dihydrate are administered orally as alkalizing agents at a total dose of 1 to 3 g / day, with each dose being 0.5 to 1.5 g / day, divided into 1 to 5 doses per day, preferably 3 doses per day. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in the treatment or prevention of renal tubular disorders, wherein one dose unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and three to six dose units are administered orally in three divided doses per day.

[0076] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in suppressing tubular damage, wherein potassium citrate monohydrate and sodium citrate dihydrate are administered orally as alkalizing agents at a total dose of 1 to 3 g / day, with each dose being 0.5 to 1.5 g / day, 1 to 5 times a day, preferably in 3 divided doses. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in suppressing tubular damage, wherein one dose unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and is administered orally in doses of 3 to 6 dose units per day, divided into 3 doses per day.

[0077] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in suppressing proximal tubular cell damage, wherein potassium citrate monohydrate and sodium citrate dihydrate are administered orally as alkalizing agents at a total dose of 1 to 3 g / day, with each dose being 0.5 to 1.5 g / day, divided into 1 to 5 doses per day, preferably 3 doses per day. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in suppressing proximal tubular cell damage, wherein one dose unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and is administered orally in doses of 3 to 6 dose units per day, divided into 3 doses per day.

[0078] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in protecting proximal tubular cells, wherein potassium citrate monohydrate and sodium citrate dihydrate are administered orally as alkalizing agents at a total dose of 1 to 3 g / day, with each dose being 0.5 to 1.5 g / day, divided into 1 to 5 doses per day, preferably 3 doses per day. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in protecting proximal tubular cells, wherein one dose unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and is administered orally in doses of 3 to 6 dose units per day, divided into 3 doses per day.

[0079] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in maintaining proximal tubular cell function, wherein potassium citrate monohydrate and sodium citrate dihydrate are administered orally as alkalizing agents at a total dose of 1 to 3 g / day, with each dose being 0.5 to 1.5 g / day, divided into 1 to 5 doses per day, preferably 3 doses per day. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in maintaining proximal tubular cell function, wherein one dose unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and 3 to 6 dose units are administered orally in three divided doses per day.

[0080] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in promoting the excretion of uremic substances from the body, wherein potassium citrate monohydrate and sodium citrate dihydrate are administered orally as alkalizing agents at a total dose of 1 to 3 g / day, with each dose being 0.5 to 1.5 g / day, divided into 1 to 5 doses per day, preferably 3 doses per day. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in promoting the excretion of uremic substances from the body, wherein one dose unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and three to six dose units are administered orally in three divided doses per day.

[0081] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in the excretion of uremic substances in the urine in a blood concentration-dependent manner, wherein potassium citrate monohydrate and sodium citrate dihydrate are administered orally as alkalizing agents at a total dose of 1 to 3 g / day, with each dose being 0.5 to 1.5 g / day, divided into 1 to 5 doses per day, preferably 3 doses per day. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in the excretion of uremic substances in the urine in a blood concentration-dependent manner, wherein one dose unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and three to six dose units are administered orally in three divided doses per day.

[0082] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in reducing the blood concentration of uremic substances, wherein sodium bicarbonate is administered orally at a dose of 1 to 3 g / day, 1 to 5 times a day, preferably in 3 divided doses. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in reducing the blood concentration of uremic substances, wherein one dose unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dose units are administered orally in three divided doses per day.

[0083] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in promoting the excretion of uremic substances in urine, wherein sodium bicarbonate is administered orally at a dose of 1 to 3 g / day, 1 to 5 times a day, preferably in 3 divided doses. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in promoting the excretion of uremic substances in urine, wherein one dose unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dose units are administered orally in three divided doses per day.

[0084] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in improving uremic symptoms in patients with kidney disease, wherein sodium bicarbonate is administered orally at a dose of 1 to 3 g / day, 1 to 5 times a day, preferably in 3 divided doses. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in improving uremic symptoms in patients with kidney disease, wherein one dose unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dose units are administered orally in three divided doses per day.

[0085] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in the treatment or prevention of uremia in patients with kidney disease, wherein sodium bicarbonate is administered orally at a dose of 1 to 3 g / day, 1 to 5 times a day, preferably in 3 divided doses. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in the treatment or prevention of uremia in patients with kidney disease, wherein one dose unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dose units are administered orally in three divided doses per day.

[0086] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in inhibiting the progression of chronic kidney disease, wherein sodium bicarbonate is administered orally at a dose of 1 to 3 g / day, 1 to 5 times a day, preferably in 3 divided doses. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in inhibiting the progression of chronic kidney disease, wherein one dose unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dose units are administered orally in three divided doses per day.

[0087] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in delaying the initiation of dialysis in patients with chronic kidney disease, wherein sodium bicarbonate is administered orally at a dose of 1 to 3 g / day, 1 to 5 times a day, preferably in 3 divided doses. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in delaying the initiation of dialysis in patients with chronic kidney disease, wherein one dose unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dose units are administered orally in three divided doses per day.

[0088] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in inhibiting myocardial fibrosis in patients with kidney disease, wherein sodium bicarbonate is administered orally at a dose of 1 to 3 g / day, 1 to 5 times a day, preferably in 3 divided doses. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in suppressing myocardial fibrosis in patients with kidney disease, wherein one dose unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dose units are administered orally in three divided doses per day.

[0089] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in suppressing arteriosclerosis in patients with kidney disease, wherein sodium bicarbonate is administered orally at a dose of 1 to 3 g / day, 1 to 5 times a day, preferably in 3 divided doses. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in suppressing arteriosclerosis in patients with kidney disease, wherein one dose unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dose units are administered orally in three divided doses per day.

[0090] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in inhibiting the proliferation of vascular smooth muscle cells in patients with kidney disease, wherein sodium bicarbonate is administered orally at a dose of 1 to 3 g / day, 1 to 5 times a day, preferably in 3 divided doses. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in inhibiting the proliferation of vascular smooth muscle cells in patients with kidney disease, wherein one dose unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dose units are administered orally in three divided doses per day.

[0091] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in suppressing vascular endothelial cell damage in patients with kidney disease, wherein sodium bicarbonate is administered orally at a dose of 1 to 3 g / day, 1 to 5 times a day, preferably in 3 divided doses. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in suppressing vascular endothelial cell damage in patients with kidney disease, wherein one dose unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dose units are administered orally in three divided doses per day.

[0092] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in suppressing arterial wall thickening in patients with kidney disease, wherein sodium bicarbonate is administered orally at a dose of 1 to 3 g / day, 1 to 5 times a day, preferably in 3 divided doses. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in suppressing arterial wall thickening in patients with kidney disease, wherein one dose unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dose units are administered orally in three divided doses per day.

[0093] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in inhibiting aortic calcification in patients with kidney disease, wherein sodium bicarbonate is administered orally at a dose of 1 to 3 g / day, 1 to 5 times a day, preferably in 3 divided doses. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in inhibiting aortic calcification in patients with kidney disease, wherein one dose unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dose units are administered orally in three divided doses per day.

[0094] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in the treatment or prevention of cardiovascular disease in patients with kidney disease, wherein sodium bicarbonate is administered orally at a dose of 1 to 3 g / day, 1 to 5 times a day, preferably in 3 divided doses. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition comprising an alkalizing agent for use in the treatment or prevention of cardiovascular disease in patients with kidney disease, wherein one dose unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dose units are administered orally in three divided doses per day.

[0095] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in improving arteriosclerosis in patients with kidney disease, wherein sodium bicarbonate is administered orally at a dose of 1 to 3 g / day, 1 to 5 times a day, preferably in 3 divided doses. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in improving arteriosclerosis in patients with kidney disease, wherein one dose unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dose units are administered orally in three divided doses per day.

[0096] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in improving arterial wall thickening in patients with kidney disease, wherein sodium bicarbonate is administered orally at a dose of 1 to 3 g / day, 1 to 5 times a day, preferably in 3 divided doses. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in improving arterial wall thickening in patients with kidney disease, wherein one dose unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dose units are administered orally in three divided doses per day.

[0097] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for use in the treatment of acute kidney disease, wherein sodium bicarbonate is administered orally at a dose of 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in the treatment of acute kidney disease, wherein one dose unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dose units are administered orally in three divided doses per day.

[0098] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in suppressing the progression from acute kidney disease to chronic kidney disease, wherein sodium bicarbonate is administered orally at a dose of 1 to 3 g / day, 1 to 5 times a day, preferably in 3 divided doses. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in suppressing the progression from acute kidney disease to chronic kidney disease, wherein one dose unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dose units are administered orally in three divided doses per day.

[0099] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in the treatment or prevention of renal tubular disorders, wherein sodium bicarbonate is administered orally at a dose of 1 to 3 g / day, 1 to 5 times a day, preferably in 3 divided doses. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in the treatment or prevention of renal tubular disorders, wherein one dose unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dose units are administered orally in three divided doses per day.

[0100] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in suppressing tubular damage, wherein sodium bicarbonate is administered orally at a dose of 1 to 3 g / day, 1 to 5 times a day, preferably in 3 divided doses. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in suppressing tubular damage, wherein one dose unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dose units are administered orally in three divided doses per day.

[0101] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in suppressing proximal tubular cell damage, wherein sodium bicarbonate is administered orally at a dose of 1 to 3 g / day, 1 to 5 times a day, preferably in 3 divided doses. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in suppressing proximal tubular cell damage, wherein one dose unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dose units are administered orally in three divided doses per day.

[0102] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in protecting proximal tubular cells, wherein sodium bicarbonate is administered orally at a dose of 1 to 3 g / day, 1 to 5 times a day, preferably in 3 divided doses. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in protecting proximal tubular cells, wherein one dose unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dose units are administered orally in three divided doses per day.

[0103] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in maintaining proximal tubular cell function, wherein sodium bicarbonate is administered orally at a dose of 1 to 3 g / day, 1 to 5 times a day, preferably in 3 divided doses. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in maintaining proximal tubular cell function, wherein one dose unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dose units are administered orally in three divided doses per day.

[0104] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in promoting the excretion of uremic substances from the body, wherein sodium bicarbonate is administered orally at a dose of 1 to 3 g / day, 1 to 5 times a day, preferably in 3 divided doses. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in promoting the excretion of uremic substances from the body, wherein one dose unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dose units are administered orally in three divided doses per day.

[0105] In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in the excretion of uremic substances in the urine in a blood concentration-dependent manner, wherein sodium bicarbonate is administered orally at a dose of 1 to 3 g / day, 1 to 5 times a day, preferably in 3 divided doses. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition containing an alkalizing agent for use in the excretion of uremic substances in the urine in a blood concentration-dependent manner, wherein one dose unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dose units are administered orally in three divided doses per day.

[0106] Hereinafter, the present invention will be further described by way of examples, but the present invention is not limited thereto.

Example

[0107] A human clinical trial was conducted to examine whether oral administration of a formulation containing potassium citrate - sodium citrate hydrate, an oral alkalizing agent, and a sodium bicarbonate formulation promotes the urinary excretion of uremic substances.

[0108] 1. Method Forty-seven patients with chronic kidney disease at stages G2 - G3b (eGFR: 30 - 89 ml / min / 1.73m 2 ) were randomly divided into a group administered a formulation containing potassium citrate - sodium citrate hydrate (Group A: 16 patients), a group administered a sodium bicarbonate formulation (Group B: 16 patients), and a control group (Group C: 15 patients). Patients were assigned to each group so that age, gender, presence or absence of diabetes, and eGFR were not biased. Each group received treatment based on the "CKD Treatment Guide - Summary of Treatments" (hereinafter referred to as standard treatment). The control group was not administered an alkalizing agent. Group A was orally administered 3 tablets per day, 3 times a day (morning, noon, evening) for 24 weeks with tablets containing 231.5 mg of potassium citrate (C6H5K3O7·H2O) and 195.0 mg of sodium citrate hydrate (C6H5Na3O7·2H2O). In addition, the pH of early morning urine was managed over time, and in cases where the early morning urine had a pH of less than 6.5, the dosage could be increased up to 6 tablets per day, 3 times a day (morning, noon, evening) at the discretion of the physician. Group B was orally administered 3 tablets per day, 3 times a day (morning, noon, evening) for 24 weeks with tablets containing 500 mg of sodium bicarbonate. In addition, the pH of early morning urine was managed over time, and in cases where the early morning urine had a pH of less than 6.5, the dosage could be increased up to 6 tablets per day, 3 times a day (morning, noon, evening) at the discretion of the physician. Urine and blood samples were collected before administration, and at 6, 12, and 24 weeks after administration, and each sample was stored at -80°C. Indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and argininosuccinate in urine and plasma were quantitatively analyzed using the following liquid chromatography-quadrupole mass spectrometer (LC-MS / MS), referring to methods used in this field (e.g., Sato, E., et. al., Metabolic alteration by indoxyl sulfate in skeletal muscle induce uremic sarcopenia in chronic kidney disease., Sci Rep. 2016 Nov 10;6:36618. doi: 10.1038 / srep36618.). For LC, a NANOSPACE SI-2 (manufactured by Shiseido) was used, and a CAPCELLPAK MGIII was selected as the analytical column. MS was performed using a TSQ Quantiva (Thermo Fisher Scientific) to ionize five compounds in negative in-mode and detect them using the Selected Reaction Monitoring method. Quantitative values ​​were calculated using calibration curves created with standard solutions of each compound. Furthermore, the amount of β2-microglobulin in urine was measured using latex agglutination immunoassay with LZ test 'Eiken' β2-M and LZ-β2-M standard U 'Eiken' (Eiken Chemical, Tokyo, Japan). In addition, the amount of cystatin C in serum was measured using gold colloid agglutination immunoassay with Nescoat GC cystatin C (Nm) (Alfresa Pharma, Osaka, Japan). For statistical analysis, the Mann-Whitney test was used for group comparisons, and the Wilcoxon test was used for comparing changes over time. Pearson's test was used for correlation analysis.

[0109] 2.Results Based on the measurement results using LC-MS / MS, the following was calculated for each patient in Group A (potassium citrate / sodium citrate hydrate preparation), Group B (sodium bicarbonate preparation preparation), and Group C (control group): (i) Concentration of each uremic substance in plasma before the start of administration (ii) Concentration of each uremic substance in early morning urine before the start of administration (iii) Ratio of the concentration of uremic substance in early morning urine to the concentration of uremic substance in plasma before the start of administration (amount of uremic substance in urine / amount of uremic substance in plasma) (iv) Concentration of each uremic substance in plasma at 6 weeks, 12 weeks, and 24 weeks after the start of administration (v) Concentration of each uremic substance in early morning urine at 6 weeks, 12 weeks, and 24 weeks after the start of administration (vi) Ratio of the concentration of uremic substance in early morning urine to the concentration of uremic substance in plasma at 6 weeks, 12 weeks, and 24 weeks after the start of administration (amount of uremic substance in urine / amount of uremic substance in plasma) (vii) Amount of change in the concentration of each uremic substance in plasma from before the start of administration at 6 weeks, 12 weeks, and 24 weeks after the start of administration (viii) Amount of change in the concentration of each uremic substance in early morning urine from before the start of administration at 6 weeks, 12 weeks, and 24 weeks after the start of administration (ix) Amount of change in the ratio of the concentration of uremic substance in early morning urine to the concentration of uremic substance in plasma (amount of uremic substance in urine / amount of uremic substance in plasma) from before the start of administration at 6 weeks, 12 weeks, and 24 weeks after the start of administration And for the above (i) to (ix), the mean value and SD of each group were calculated. For each of the above (iv) to (ix), the mean value and SD of each group were calculated for all the data at 6 weeks, 12 weeks, and 24 weeks after the start of administration in each group. The results are shown in the following table. In the table and the figures, Group A: Potassium Citrate - Sodium Citrate Hydrate Formulation Administration Group is denoted as "Citrate", and Group B: Sodium Bicarbonate Formulation Administration Group is denoted as "Bicarbonate". Also, the numerical values in parentheses in the table indicate the number of cases. Table 1 - 1 - 1: Amount of indoxyl sulfate in plasma (ng / mL), Table 1 - 1 - 2: Amount of change in indoxyl sulfate in plasma from before the start of administration (ng / mL), Table 1 - 2 - 1: Amount of indoxyl sulfate in early morning urine (ng / mL), Table 1 - 2 - 2: Amount of change in indoxyl sulfate in early morning urine from before the start of administration (ng / mL), Table 1-3-1: Ratio of the amount of indoxyl sulfate in urine to the amount of indoxyl sulfate in plasma Table 1-3-2: Change in the ratio of the amount of indoxyl sulfate in urine to the amount of indoxyl sulfate in plasma from before the start of administration Table 2-1-1: Amount of p-cresyl sulfate in plasma (ng / mL) Table 2-1-2: Change in the amount of p-cresyl sulfate in plasma from before the start of administration (ng / mL) Table 2-2-1: Amount of p-cresyl sulfate in early morning urine (ng / mL) Table 2-2-2: Change in the amount of p-cresyl sulfate in early morning urine from before the start of administration (ng / mL) Table 2-3-1: Ratio of the amount of p-cresyl sulfate in urine to the amount of p-cresyl sulfate in plasma Table 2-3-2: Change in the ratio of the amount of p-cresyl sulfate in urine to the amount of p-cresyl sulfate in plasma from before the start of administration Table 3-1-1: Amount of hippuric acid in plasma (ng / mL) Table 3-1-2: Change in the amount of hippuric acid in plasma from before the start of administration (ng / mL) Table 3-2-1: Amount of hippuric acid in early morning urine (ng / mL) Table 3-2-2: Change in the amount of hippuric acid in early morning urine from before the start of administration (ng / mL) Table 3-3-1: Ratio of the amount of hippuric acid in urine to the amount of hippuric acid in plasma Table 3-3-2: Change in the ratio of the amount of hippuric acid in urine to the amount of hippuric acid in plasma from before the start of administration Table 4-1-1: Amount of argininosuccinic acid in plasma (ng / mL) Table 4-1-2: Change in the amount of argininosuccinic acid in plasma from before the start of administration (ng / mL) Table 4-2-1: Amount of argininosuccinic acid in early morning urine (ng / mL) Table 4-2-2: Change in the amount of argininosuccinic acid in early morning urine from before the start of administration (ng / mL) Table 4-3-1: Ratio of the amount of argininosuccinic acid in urine to the amount of argininosuccinic acid in plasma Table 4-3-2: Change in the ratio of the amount of argininosuccinic acid in urine to the amount of argininosuccinic acid in plasma from before the start of administration Table 5-1-1: Plasma phenylacetyl-L-glutamine (PAG) levels (ng / mL), Table 5-1-2: Change in plasma phenylacetyl-L-glutamine (PAG) levels from baseline (ng / mL), Table 5-2-1: Phenylates-L-glutamine (PAG) levels in early morning urine (ng / mL) Table 5-2-2: Change in phenylacetyl-L-glutamine (PAG) levels in early morning urine from baseline (ng / mL), Table 5-3-1: Ratio of phenylacetyl-L-glutamine (PAG) levels in urine to phenylacetyl-L-glutamine (PAG) levels in plasma. Table 5-3-2: Change in the ratio of phenylacetyl-L-glutamine (PAG) levels in urine to phenylacetyl-L-glutamine (PAG) levels in plasma from baseline.

[0110] In Group A (Citrate: potassium citrate / sodium citrate hydrate preparation), plasma indoxyl sulfate concentrations at 6, 12, and 24 weeks after administration were lower compared to Group B (Bicarbonate: sodium bicarbonate preparation preparation) and Group C (Control) (see Table 1-1-1). In addition, indoxyl sulfate (IS) concentrations in early morning urine at 12 and 24 weeks after administration were higher in Group A compared to Group C (see Table 1-2-1). Plasma indoxyl sulfate concentrations from 6 to 24 weeks were significantly lower in Group A compared to Groups B and C (see Table 1-1-1), and the increase in indoxyl sulfate concentration in early morning urine from 6 to 24 weeks was significantly greater in Group A compared to Groups B and C (see Table 1-2-2). Furthermore, administration of a potassium citrate / sodium citrate hydrate formulation to patients with chronic kidney disease resulted in an increase in the urinary concentration of indoxyl sulfate, a uremic substance, compared to before administration, and a decrease in the blood concentration of indoxyl sulfate compared to before administration. This effect was not observed with sodium bicarbonate formulations, even though both are alkalizing agents. Compared to sodium bicarbonate formulations, the potassium citrate / sodium citrate hydrate formulation exhibited a greater effect in reducing blood indoxyl sulfate concentration and increasing urinary indoxyl sulfate concentration. The effects of the potassium citrate / sodium citrate hydrate formulation on reducing blood indoxyl sulfate concentration and increasing urinary indoxyl sulfate concentration were observed from 12 weeks after administration. The ratio of indoxyl sulfate concentration in urine to indoxyl sulfate concentration in plasma indicated that administration of a potassium citrate / sodium citrate hydrate formulation promoted the excretion of indoxyl sulfate from the blood into the urine, thereby facilitating its removal from the body. This effect on the excretion of indoxyl sulfate from the blood into the urine was observed with the potassium citrate / sodium citrate hydrate formulation, but not with the sodium bicarbonate formulation (see Tables 1-3-1 and 1-3-2).

[0111] [Table 1-1-1]

[0112] [Table 1-1-2]

[0113] [Table 1-2-1]

[0114] [Table 1-2-2]

[0115] [Table 1-3-1]

[0116]

Table 1-3-2

[0117] Regarding p-cresyl sulfate (PCS), in Group A (Citrate: potassium citrate - sodium citrate hydrate formulation administration group), compared with Group C (Control: control group), the early morning urine p-cresyl sulfate concentrations at 12 and 24 weeks after administration were high. Also, compared with Group B (Bicarbonate: sodium bicarbonate formulation administration group), in Group A (potassium citrate - sodium citrate hydrate formulation administration group), the early morning urine p-cresyl sulfate concentrations at 6, 12, and 24 weeks after administration were high (see Table 2-2-1). The increase in early morning urine p-cresyl sulfate concentration from 6 to 24 weeks was only observed in Group A (see Table 2-2-2). Furthermore, by administering the potassium citrate - sodium citrate hydrate formulation to patients with chronic kidney disease, the urinary concentration of p-cresyl sulfate, an uremic substance, increased compared with that before administration (see Tables 2-2-1 and 2-2-2). Even with the same alkalinizing agent, such an effect was not observed with the sodium bicarbonate formulation. Compared with the sodium bicarbonate formulation, the potassium citrate - sodium citrate hydrate formulation exerted a stronger effect of increasing urinary p-cresyl sulfate concentration. The effect of increasing urinary p-cresyl sulfate concentration by the potassium citrate - sodium citrate hydrate formulation was observed from 12 weeks after administration. On the other hand, by administering the sodium bicarbonate formulation, the plasma concentration of p-cresyl sulfate, an uremic substance, decreased compared with that before administration (see Table 2-1-2). Such an effect of decreasing the plasma concentration of p-cresyl sulfate was strongly observed in Group B compared with Groups A and C (see Table 2-1-2). The ratio of p-cresyl sulfate concentration in urine to p-cresyl sulfate concentration in plasma suggests that administration of a potassium citrate / sodium citrate hydrate formulation promotes the excretion of p-cresyl sulfate from the blood into the urine, thereby facilitating its removal from the body. Furthermore, the effect of administering the potassium citrate / sodium citrate hydrate formulation on the excretion of p-cresyl sulfate from the blood into the urine was shown to be stronger than that of administering a sodium bicarbonate formulation (see Tables 2-3-1 and 2-3-2).

[0118] [Table 2-1-1]

[0119] [Table 2-1-2]

[0120] [Table 2-2-1]

[0121] [Table 2-2-2]

[0122] [Table 2-3-1]

[0123] [Table 2-3-2]

[0124] Regarding hippuric acid (HA), Group A (Citrate: potassium citrate / sodium citrate hydrate combination preparation administration group) had lower plasma hippuric acid concentrations 24 weeks after administration compared with Group B (Bicarbonate: sodium bicarbonate preparation administration group) and Group C (Control: control group) (see Table 3-1-1). This effect was not observed with the administration of sodium bicarbonate preparations. Furthermore, Group A had higher hippuric acid concentrations in early morning urine at 12 and 24 weeks after administration compared with Group C (see Table 3-2-1). Furthermore, administration of a potassium citrate / sodium citrate hydrate formulation to patients with chronic kidney disease resulted in a decrease in plasma hippuric acid concentration (a uremic substance) 24 weeks after administration compared to before administration (see Tables 3-1-1 and 3-2-2), and an increase in urinary hippuric acid concentration compared to before administration (see Tables 3-2-1 and 3-2-2). An increase in early morning urine hippuric acid concentration from weeks 6 to 24 was observed only in Group A (see Table 2-2-2). Even among alkalizing agents, the potassium citrate / sodium citrate hydrate formulation exhibited a greater effect in increasing urinary hippuric acid concentration compared to sodium bicarbonate formulations. The effect of the potassium citrate / sodium citrate hydrate formulation on increasing urinary hippuric acid concentration was observed from 6 weeks after administration. The ratio of hippuric acid concentration in urine to that in plasma suggests that administration of a potassium citrate / sodium citrate hydrate formulation promotes the excretion of hippuric acid from the blood into the urine, thereby facilitating its removal from the body. Furthermore, the effect of administering the potassium citrate / sodium citrate hydrate formulation on the excretion of hippuric acid from the blood into the urine during weeks 6 to 24 was shown to be stronger than that of administering a sodium bicarbonate formulation (see Tables 3-3-1 and 3-3-2).

[0125] [Table 3-1-1]

[0126] [Table 3-1-2]

[0127] [Table 3-2-1]

[0128] [Table 3-2-2]

[0129] [Table 3-3-1]

[0130] [Table 3-3-2]

[0131] Regarding argininosuccinate (ASA), group A (Citrate: group administered a potassium citrate / sodium citrate hydrate preparation) had higher concentrations of argininosuccinate in early morning urine compared to group C (Control: control group), while group B (Bicarbonate: group administered a sodium bicarbonate preparation) had lower concentrations (see Table 4-2-1). Furthermore, administration of a potassium citrate / sodium citrate hydrate formulation to patients with chronic kidney disease increased the urinary concentration of argininosuccinate, a uremic substance, compared to before administration (see Tables 4-2-1 and 4-2-2). The effect of the potassium citrate / sodium citrate hydrate formulation on increasing urinary argininosuccinate concentration was observed from 12 weeks after administration. The increase in argininosuccinate concentration in early morning urine from weeks 6 to 24 was greater in group B compared to group A (see Table 4-2-2). The ratio of argininosuccinate concentration in urine to argininosuccinate concentration in plasma suggests that administration of a potassium citrate / sodium citrate hydrate combination preparation promotes the excretion of argininosuccinate from the blood into the urine, thereby facilitating its removal from the body. Furthermore, the effect of sodium bicarbonate preparations on the excretion of argininosuccinate from the blood into the urine during weeks 6 to 24 was shown to be stronger than that of the potassium citrate / sodium citrate hydrate combination preparation (see Tables 4-3-1 and 4-3-2).

[0132] [Table 4-1-1]

[0133] [Table 4-1-2]

[0134] [Table 4-2-1]

[0135] [Table 4-2-2]

[0136] [Table 4-3-1]

[0137] [Table 4-3-2]

[0138] Regarding phenylacetyl-L-glutamine (PAG), Group A (Citrate: group administered a potassium citrate / sodium citrate hydrate combination preparation) had lower plasma phenylacetyl-L-glutamine concentrations compared to Group C (Control: control group) (see Table 5-1-1). In Group A, phenylacetyl-L-glutamine concentrations were higher in early morning urine at 12 and 24 weeks after administration compared to Group C (see Table 5-2-1). Furthermore, administration of a potassium citrate / sodium citrate hydrate combination preparation to patients with chronic kidney disease resulted in an increase in the urinary concentration of phenylacetyl-L-glutamine, a uremic substance, at 12 and 24 weeks after administration compared to before administration (see Tables 5-2-1 and 5-2-2). This effect was not observed with sodium bicarbonate preparations, even though both are alkalizing agents. The effect of potassium citrate / sodium citrate hydrate combination preparations on increasing urinary phenylacetyl-L-glutamine concentration was observed from 12 weeks after administration. Administration of a potassium citrate / sodium citrate hydrate combination preparation to patients with chronic kidney disease resulted in a decrease in the plasma concentration of phenylacetyl-L-glutamine, a uremic substance, compared to before administration (see Tables 5-1-1 and 5-2-2). The effect of reducing phenylacetyl-L-glutamine plasma concentration was more pronounced with sodium bicarbonate preparations compared to potassium citrate / sodium citrate hydrate combination preparations (see Table 5-1-2). The ratio of phenylacetyl-L-glutamine concentration in urine to phenylacetyl-L-glutamine concentration in plasma indicated that administration of a potassium citrate / sodium citrate hydrate formulation promoted the excretion of phenylacetyl-L-glutamine from the blood into the urine, thereby facilitating its removal from the body. Furthermore, the effect of administering the potassium citrate / sodium citrate hydrate formulation on the excretion of phenylacetyl-L-glutamine from the blood into the urine was shown to be stronger than that of administering a sodium bicarbonate formulation (see Tables 5-3-1 and 5-3-2).

[0139] [Table 5-1-1]

[0140] Table 5-1-2

[0141] Table 5-2-1

[0142] Table 5-2-2

[0143] Table 5-3-1

[0144] Table 5-3-2

[0145] The effects of potassium citrate / sodium citrate hydrate (Citrate) and sodium bicarbonate preparations on plasma concentrations, early morning urine concentrations, and the ratio of early morning urine concentrations to plasma concentrations for each uremic substance are summarized in the table below. In the table below, the control drug is sodium bicarbonate preparation in the case of potassium citrate / sodium citrate hydrate (Citrate), and sodium bicarbonate preparation in the case of sodium bicarbonate preparation (Bicarbonate). ○ is indicated when the effect is significantly superior to the control group or the control drug group, × is indicated when the effect is significantly inferior to the control group or the control drug group, and - is indicated when there is no significant difference. Note that the effect of the sodium bicarbonate preparation group on indoxyl sulfate concentration in early morning urine compared to the control group is indicated with (○) in the table below. This is because, while the group administered with sodium bicarbonate showed a significantly increased concentration of indoxyl sulfate in early morning urine compared to the control group, the concentration of indoxyl sulfate in early morning urine after administration of sodium bicarbonate decreased compared to before administration. Therefore, it is not possible to determine whether or not the sodium bicarbonate administration has a promoting effect on the urinary excretion of indoxyl sulfate. As shown in the table below, the effect of alkalizing agents on reducing the concentration of uremic substances in the blood (plasma) was clearly observed with indoxyl sulfate (IS) and phenylacetyl-L-glutamine (PAG). Of these, administration of a potassium citrate / sodium citrate hydrate combination preparation (Citrate) showed a significantly greater reduction than administration of a sodium bicarbonate preparation (Bicarbonate). Furthermore, the effect of alkalizing agents on increasing the concentration of uremic substances in urine (effect on the excretion of uremic toxins into the urine) was clearly observed with indoxyl sulfate (IS), p-cresyl sulfate (PCS), hippuric acid (HA), argininosuccinate (ASA), and phenylacetyl-L-glutamine (PAG). Of these, administration of a potassium citrate / sodium citrate hydrate preparation (Citrate) significantly increased the concentration of uremic substances in urine (excretion into the urine) compared to administration of a sodium bicarbonate preparation (Bicarbonate) for indoxyl sulfate (IS), p-cresyl sulfate (PCS), and phenylacetyl-L-glutamine (PAG). The effect of alkalizing agents on the excretion of uremic substances from the blood into the urine (extracorporeal excretion effect) was clearly observed with indoxyl sulfate (IS), p-cresyl sulfate (PCS), and phenylacetyl-L-glutamine (PAG). Of these, administration of indoxyl sulfate (IS) with a potassium citrate / sodium citrate hydrate combination preparation (Citrate) significantly increased the excretion of uremic substances from the blood into the urine (extracorporeal excretion) compared with administration of a sodium bicarbonate preparation (Bicarbonate).

[0146] [Table 6]

[0147] From the table above, it can be seen that, in general, preparations containing potassium citrate and sodium citrate hydrate exhibit a higher excretion effect of uremic substances from the body compared to preparations containing sodium bicarbonate. Furthermore, it was suggested that administering alkalizing agents to patients with chronic kidney disease not only in stage G3b but also in stage G2 can suppress the progression of chronic kidney disease, and that preparations containing potassium citrate and sodium citrate hydrate suppress the progression of chronic kidney disease more effectively than those containing sodium bicarbonate.

[0148] Furthermore, the results of measuring the amount of β2-microglobulin in urine and the amount of cystatin C in serum are shown below.

[0149] [Table 7-1]

[0150] [Table 7-2]

[0151] [Table 8]

[0152] There were no differences in plasma cystatin C concentrations among Group A (Citrate: potassium citrate / sodium citrate hydrate combined preparation), Group B (Bicarbonate: sodium bicarbonate preparation administered), and Group C (Control: control group), and no effect on glomerular function was observed with administration of potassium citrate / sodium citrate hydrate combined preparation or sodium bicarbonate preparation (Table 8). On the other hand, regarding urinary β2-microglobulin concentration, Group A (Citrate: group administered a potassium citrate / sodium citrate hydrate preparation) had lower urinary β2-microglobulin concentrations compared to Group C (Control), and Group A also had lower urinary β2-microglobulin concentrations compared to Group B (Bicarbonate: group administered a sodium bicarbonate preparation). Group B (Bicarbonate: group administered a sodium bicarbonate preparation) had higher urinary β2-microglobulin concentrations compared to Group C (Control). Administration of the potassium citrate / sodium citrate hydrate preparation suppressed the increase in urinary β2-microglobulin concentration associated with disease progression, and it was observed that there was no change in urinary β2-microglobulin concentration compared to before administration. These results indicate that administration of a potassium citrate / sodium citrate hydrate combination preparation suppresses tubular damage (proximal tubular damage) associated with disease progression. Conversely, administration of a sodium bicarbonate preparation did not suppress tubular damage (proximal tubular damage) associated with disease progression, but rather exacerbated it. These effects were observed starting 6 weeks after administration. Furthermore, the effects of administering potassium citrate / sodium citrate hydrate formulations on increasing uremic substance concentrations in urine and decreasing uremic substance concentrations in blood did not correlate with the effect of administering potassium citrate / sodium citrate hydrate formulations on suppressing the increase in urinary β2-microglobulin concentration. This suggests that the effect of administering potassium citrate / sodium citrate hydrate formulations on promoting urinary excretion of uremic substances is not solely due to the suppression of glomerular and proximal tubular damage.

[0153] The correlation between indoxyl sulfate (IS) concentrations in early morning urine and plasma indoxyl sulfate (IS) concentrations at 6, 12, and 24 weeks after the start of the study (6W, 12W, and 24W) was analyzed using Pearson's test for each group: Group C (Control), Group A (Citrate: potassium citrate / sodium citrate hydrate combination preparation), Group B (Bicarbonate: sodium bicarbonate preparation preparation), and all patients (all patients in Groups A, B, and C). The results are shown in Figures 1 to 4. Regarding indoxyl sulfate, the group administered a potassium citrate / sodium citrate hydrate formulation showed a higher correlation between plasma and urinary concentrations compared to the control group, and a higher correlation was also observed compared to the group administered a sodium bicarbonate formulation (see r values ​​in Figures 1-3). Figures 1-4 suggest that administration of the potassium citrate / sodium citrate hydrate formulation leads to the excretion of indoxyl sulfate into the urine in a manner dependent on the blood indoxyl sulfate concentration. This blood-intensive urinary excretion of indoxyl sulfate suggests that the increase in blood indoxyl sulfate concentration is suppressed, and the ratio of blood indoxyl sulfate concentration to urinary indoxyl sulfate concentration remains within a certain range.

[0154] The correlation between p-cresyl sulfate (PCS) concentration in early morning urine and plasma p-cresyl sulfate (PCS) concentration at 6, 12, and 24 weeks after the start of the study (6W, 12W, and 24W) was analyzed using Pearson's test for each group: Group C (Control), Group A (Citrate: potassium citrate / sodium citrate hydrate combination preparation), Group B (Bicarbonate: sodium bicarbonate preparation preparation), and all patients (all patients in Groups A, B, and C). The results are shown in Figures 5 to 8. Regarding p-cresyl sulfate, a correlation was observed between plasma and urinary concentrations in the control group, the potassium citrate / sodium citrate hydrate combination preparation group, and the sodium bicarbonate preparation group. A higher correlation was observed in the sodium bicarbonate preparation group compared to the potassium citrate / sodium citrate hydrate combination preparation group (see r values ​​in Figures 5-7). Figures 5-8 suggest that administration of sodium bicarbonate preparations or potassium citrate / sodium citrate hydrate combination preparations leads to the excretion of p-cresyl sulfate into the urine in a manner dependent on the blood p-cresyl sulfate concentration. This blood-dependent excretion of p-cresyl sulfate into the urine suggests that the increase in blood p-cresyl sulfate concentration is suppressed, and the ratio of blood p-cresyl sulfate concentration to urinary p-cresyl sulfate concentration remains within a certain range.

[0155] The correlation between hippuric acid (HA) concentration in early morning urine and plasma hippuric acid (HA) concentration at 6, 12, and 24 weeks after the start of the study (6W, 12W, and 24W) was analyzed using Pearson's test for each group: Group C (Control), Group A (Citrate: administered potassium citrate / sodium citrate hydrate), Group B (Bicarbonate: administered sodium bicarbonate), and all patients (all patients in Groups A, B, and C). The results are shown in Figures 9 to 12. Regarding hippuric acid, no high correlation was observed between plasma and urinary concentrations in the control group, the group administered a potassium citrate / sodium citrate hydrate preparation, and the group administered a sodium bicarbonate preparation.

[0156] The correlation between argininosuccinate (ASA) concentrations in early morning urine at 6, 12, and 24 weeks after the start of the study (6W, 12W, and 24W) and plasma argininosuccinate (ASA) concentrations was analyzed using Pearson's test for each group: Group C (Control), Group A (Citrate: potassium citrate / sodium citrate hydrate combination preparation), Group B (Bicarbonate: sodium bicarbonate preparation preparation), and all patients (all patients in Groups A, B, and C). The results are shown in Figures 13 to 16. Regarding argininosuccinate, no high correlation was observed between plasma and urinary concentrations in the control group, the group administered a potassium citrate / sodium citrate hydrate preparation, and the group administered a sodium bicarbonate preparation.

[0157] The correlation between phenylacetyl-L-glutamine (PAG) concentrations in early morning urine at 6, 12, and 24 weeks after the start of the study (6W, 12W, and 24W) and plasma phenylacetyl-L-glutamine (PAG) concentrations was analyzed using Pearson's test for each group: Group C (Control), Group A (Citrate: administered potassium citrate / sodium citrate hydrate), Group B (Bicarbonate: administered sodium bicarbonate), and all patients (all patients in Groups A, B, and C). The results are shown in Figures 17 to 20. Regarding phenylacetyl-L-glutamine, a correlation was observed between plasma and urinary concentrations in the control group, the potassium citrate / sodium citrate hydrate combination preparation group, and the sodium bicarbonate preparation group. A higher correlation was observed in the sodium bicarbonate preparation group compared to the potassium citrate / sodium citrate hydrate combination preparation group (see r values ​​in Figures 17-19). Figures 17-20 suggest that administration of sodium bicarbonate preparations or potassium citrate / sodium citrate hydrate combination preparations leads to phenylacetyl-L-glutamine excretion into the urine in a manner dependent on the blood phenylacetyl-L-glutamine concentration. This blood phenylacetyl-L-glutamine concentration-dependent urinary excretion suggests that the increase in blood phenylacetyl-L-glutamine concentration is suppressed, and the ratio of blood phenylacetyl-L-glutamine concentration to urinary phenylacetyl-L-glutamine concentration remains within a certain range.

[0158] The correlation between the early morning urine concentrations of indoxyl sulfate (IS), p-cresyl sulfate (PCS), hippuric acid (HA), argininosuccinate (ASA), and phenylacetyl-L-glutamine (PAG) at 6, 12, and 24 weeks after the start of the study (6W, 12W, and 24W) was analyzed using Pearson's test for each of the three groups: Group C (Control), Group A (Citrate: potassium citrate / sodium citrate hydrate combination therapy group), and Group B (Bicarbonate: sodium bicarbonate combination therapy group). The results are shown in Table 9. In the table, "Contro" refers to the control group, "Citrate" refers to the potassium citrate / sodium citrate hydrate combination therapy group, and "Bicarbonate" refers to the sodium bicarbonate combination therapy group. As a result, in the group administered with the potassium citrate / sodium citrate hydrate formulation, high correlations were observed between indoxyl sulfate and phenylacetyl-L-glutamine, p-cresyl sulfate and phenylacetyl-L-glutamine, and argininosuccinate and phenylacetyl-L-glutamine. In the group administered with the sodium bicarbonate formulation, high correlations were observed between indoxyl sulfate and argininosuccinate, indoxyl sulfate and phenylacetyl-L-glutamine, p-cresyl sulfate and argininosuccinate, p-cresyl sulfate and phenylacetyl-L-glutamine, and argininosuccinate and phenylacetyl-L-glutamine. The potassium citrate / sodium citrate hydrate formulation was suggested to increase the urinary concentrations of indoxyl sulfate, phenylacetyl-L-glutamine, p-cresyl sulfate, and argininosuccinate through a similar mechanism. Furthermore, it was suggested that sodium bicarbonate preparations may increase the urinary concentrations of indoxyl sulfate, phenylacetyl-L-glutamine, p-cresyl sulfate, and argininosuccinate through a similar mechanism.

[0159] [Table 9]

[0160] The correlation between plasma concentrations of indoxyl sulfate (IS), p-cresyl sulfate (PCS), hippuric acid (HA), argininosuccinate (ASA), and phenylacetyl-L-glutamine (PAG) at 6, 12, and 24 weeks after the start of the study (6W, 12W, and 24W) was analyzed using Pearson's test for each of the three groups: Group C (Control), Group A (Citrate: potassium citrate / sodium citrate hydrate combination therapy group), and Group B (Bicarbonate: sodium bicarbonate combination therapy group). The results are shown in Table 10. In the table, "Contro" refers to the control group, "Citrate" refers to the potassium citrate / sodium citrate hydrate combination therapy group, and "Bicarbonate" refers to the sodium bicarbonate combination therapy group. As a result, high correlations were observed between indoxyl sulfate and p-cresyl sulfate, indoxyl sulfate and phenylacetyl-L-glutamine, and p-cresyl sulfate and phenylacetyl-L-glutamine in the group administered the potassium citrate / sodium citrate hydrate formulation. High correlations were also observed between indoxyl sulfate and p-cresyl sulfate in the group administered the sodium bicarbonate formulation. The potassium citrate / sodium citrate hydrate formulation was suggested to lower the blood concentrations of indoxyl sulfate, phenylacetyl-L-glutamine, and p-cresyl sulfate through a similar mechanism. Furthermore, the sodium bicarbonate formulation was suggested to lower the blood concentrations of p-cresyl sulfate and phenylacetyl-L-glutamine through a similar mechanism. The mechanisms by which the potassium citrate / sodium citrate hydrate formulation and the sodium bicarbonate formulation lower the blood concentrations of uremic substances were suggested to be different.

[0161] [Table 10]

[0162] The specific gravity of early morning urine samples was analyzed before the start of the study (0W) and at 6, 12, and 24 weeks after the start of the study (6W, 12W, and 24W) for each of the three groups: Group C (Control), Group A (Citrate: potassium citrate / sodium citrate hydrate preparation), and Group B (Bicarbonate: sodium bicarbonate preparation). The results are shown in Table 11-0-1. Furthermore, the changes in urine specific gravity from before the start of the study to 6, 12, and 24 weeks after the start of the study are shown in Tables 11-0-2 and 11-0-3 below, as percentage relative values ​​to the urine specific gravity before the start of the study and as differences from the urine specific gravity before the start of the study, respectively. Urine specific gravity was measured using a urine hydrometer (PAL-09S, Atago Co., Ltd., Tokyo, Japan).

[0163] [Table 11-0-1]

[0164] [Table 11-0-2]

[0165] [Table 11-0-3]

[0166] As a result of the above study, compared to Group C (Control), Group A (Citrate: potassium citrate / sodium citrate hydrate preparation administration group) and Group B (Bicarbonate: sodium bicarbonate preparation administration group) showed a tendency for urine specific gravity to be maintained or to increase at 6, 12, and 24 weeks after the start of the study. Furthermore, compared to Group B (Bicarbonate: sodium bicarbonate preparation administration group), Group A (Citrate: potassium citrate / sodium citrate hydrate preparation administration group) showed a greater tendency for urine specific gravity to be maintained or to increase. Maintaining or increasing urine specific gravity can be understood as being based on maintaining or improving renal function. Therefore, from the above, it is suggested that administering alkalizing agents to patients with chronic kidney disease not only in stage G3b but also in stage G2 can suppress the progression of chronic kidney disease, and that potassium citrate / sodium citrate hydrate formulations suppress the progression of chronic kidney disease more effectively than sodium bicarbonate formulations.

[0167] The concentrations of uremic substances in early morning urine, namely indoxyl sulfate (IS), p-cresyl sulfate (PCS), phenylacetyl-L-glutamine (PAG), hippuric acid (HA), and argininosuccinate (ASA), before the start of the study (0W) and at 6, 12, and 24 weeks after the start of the study (6W, 12W, and 24W), were corrected using the following formula based on the specific gravity of the early morning urine before the start of the study (0W) and at 6, 12, and 24 weeks after the start of the study (6W, 12W, and 24W). These values ​​were then analyzed for each of the three groups: Group C (Control), Group A (Citrate: potassium citrate / sodium citrate hydrate preparation administration group), and Group B (Bicarbonate: sodium bicarbonate preparation administration group). See Tetsuo Aoki et al., Medical Laboratory Science, 1995, Vol. 44, No. 1, pp. 79-83. The urine specific gravity of 1.022 was converted to the reference value. Specific gravity correction value (unit / 1.022·UG) = Measured value × (1.022 - 1.000) / (Specific gravity value - 1.000) The results are shown in Tables 11-1-1, 11-2-1, 11-3-1, 11-4-1, and 11-5-1. Furthermore, the changes in the concentration of the aforementioned uremic substances in early morning urine, corrected for urine specific gravity, from before the start of the study to 6, 12, and 24 weeks after the start of the study, are shown in Tables 11-1-2, 11-1-3, 11-2-2, 11-2-3, 11-3-2, 11-3-3, 11-4-2, 11-4-3, 11-5-2, and 11-5-3, respectively, as the percentage relative value to the corrected value before the start of the study and the difference from the corrected value before the start of the study.

[0168] [Table 11-1-1]

[0169] [Table 11-1-2]

[0170] [Table 11-1-3]

[0171] Table 11-2-1

[0172] Table 11-2-2

[0173]

Table 11-2-3

[0174] Table 11-3-1

[0175] Table 11-3-2

[0176]

Table 11-3-3

[0177] Table 11-4-1

[0178]

Table 11-4-2

[0179]

Table 11-4-3

[0180]

Table 11-5-1

[0181] [Table 11-5-2]

[0182] [Table 11-5-3]

[0183] As a result of the above study, the groups administered with a potassium citrate / sodium citrate hydrate combination preparation (Citrate) showed a significantly increased concentration of uremic substances in urine (excretion into the urine) compared to the control group and the group administered with a sodium bicarbonate preparation (Bicarbonate) for indoxyl sulfate (IS), p-cresyl sulfate (PCS), and phenylacetyl-L-glutamine (PAG). Similarly, for hippuric acid (HA) and argininosuccinate (ASA), the groups administered with a potassium citrate / sodium citrate hydrate combination preparation (Citrate) showed a significantly increased concentration of uremic substances in urine (excretion into the urine) compared to the control group and the group administered with a sodium bicarbonate preparation (Bicarbonate). Furthermore, administration of a potassium citrate / sodium citrate hydrate formulation (Citrate) increased the concentrations (urinary excretion) of indoxyl sulfate (IS), p-cresyl sulfate (PCS), and phenylacetyl-L-glutamine (PAG) in urine compared to before the start of the study (0W).

[0184] The osmolality of early morning urine was analyzed before the start of the study (0W) and at 6, 12, and 24 weeks after the start of the study (6W, 12W, and 24W) for each of the three groups: Group C (Control), Group A (Citrate: potassium citrate / sodium citrate hydrate preparation), and Group B (Bicarbonate: sodium bicarbonate preparation). The results are shown in Table 12-0-1. Furthermore, the changes in osmolality of early morning urine from before the start of the study to 6, 12, and 24 weeks after the start of the study are shown in Tables 12-0-2 and 12-0-3 below, as percentage relative values ​​to the osmolality of early morning urine before the start of the study and as the difference from the osmolality of early morning urine before the start of the study, respectively. Osmolality was measured using the freezing point depression method.

[0185] [Table 12-0-1]

[0186] [Table 12-0-2]

[0187] [Table 12-0-3]

[0188] As a result of the above study, compared to Group C (Control), Group A (Citrate: potassium citrate / sodium citrate hydrate preparation administration group) and Group B (Bicarbonate: sodium bicarbonate preparation administration group) showed a tendency for the osmolality of early morning urine to be maintained or increase at 6, 12, and 24 weeks after the start of the study. Furthermore, compared to Group B (Bicarbonate: sodium bicarbonate preparation administration group), Group A (Citrate: potassium citrate / sodium citrate hydrate preparation administration group) showed a greater tendency for the osmolality of early morning urine to be maintained or increase. Maintaining or increasing the osmolality of early morning urine can be understood as being based on the maintenance or improvement of renal function. Therefore, from the above, it is suggested that administering alkalizing agents to patients with chronic kidney disease not only in stage G3b but also in stage G2 can suppress the progression of chronic kidney disease, and that potassium citrate / sodium citrate hydrate formulations suppress the progression of chronic kidney disease more effectively than sodium bicarbonate formulations.

[0189] The concentrations of uremic substances in early morning urine, namely indoxyl sulfate (IS), p-cresyl sulfate (PCS), phenylacetyl-L-glutamine (PAG), hippuric acid (HA), and argininosuccinate (ASA), before the start of the study (0W) and at 6, 12, and 24 weeks after the start of the study (6W, 12W, and 24W), were corrected using the following formula based on the osmolality of early morning urine before the start of the study (0W) and at 6, 12, and 24 weeks after the start of the study (6W, 12W, and 24W). These values ​​were then analyzed for each of the three groups: Group C (Control), Group A (Citrate: potassium citrate / sodium citrate hydrate preparation administration group), and Group B (Bicarbonate: sodium bicarbonate preparation administration group). See Tetsuo Aoki et al., Medical Laboratory Science, 1995, Vol. 44, No. 1, pp. 79-83. The urine osmolality of 770 mOsm / kg was converted to the reference value. Osmotic pressure correction value (unit / 500 mOsm·P) = Measured value × 500 / Osmotic pressure value The results are shown in Tables 12-1-1, 12-2-1, 12-3-1, 12-4-1, and 12-5-1. Furthermore, the changes in the concentration of the uremic substances in early morning urine, corrected for the osmotic pressure of early morning urine, from before the start of the study to 6, 12, and 24 weeks after the start of the study, are shown in Tables 12-1-2, 12-1-3, 12-2-2, 12-2-3, 12-3-2, 12-3-3, 12-4-2, 12-4-3, 12-5-2, and 12-5-3, respectively, as the percentage relative value to the corrected value before the start of the study and the difference from the corrected value before the start of the study.

[0190] [Table 12-1-1]

[0191] [Table 12-1-2]

[0192] [Table 12-1-3]

[0193] Table 12-2-1

[0194] Table 12-2-2

[0195]

Table 12-2-3

[0196]

Table 12-3-1

[0197] Table 12-3-2

[0198] Table 12-3-3

[0199] Table 12-4-1

[0200] Table 12-4-2

[0201]

Table 12-4-3

[0202]

Table 12-5-1

[0203] [Table 12-5-2]

[0204] [Table 12-5-3]

[0205] As a result of the above study, the group administered with a potassium citrate / sodium citrate hydrate combination preparation (Citrate) showed a significantly increased concentration of uremic substances in urine (excretion into the urine) compared to the control group and the group administered with a sodium bicarbonate preparation (Bicarbonate) for p-cresyl sulfate (PCS) and phenylacetyl-L-glutamine (PAG). Similarly, for indoxyl sulfate (IS), hippuric acid (HA), and argininosuccinate (ASA), the group administered with a potassium citrate / sodium citrate hydrate combination preparation (Citrate) showed a significantly increased concentration of uremic substances in urine (excretion into the urine) compared to the control group and the group administered with a sodium bicarbonate preparation (Bicarbonate). Furthermore, administration of a potassium citrate / sodium citrate hydrate formulation (Citrate) increased the concentrations (urinary excretion) of indoxyl sulfate (IS), p-cresyl sulfate (PCS), and phenylacetyl-L-glutamine (PAG) in urine compared to before the start of the study (0W). [Industrial applicability]

[0206] The pharmaceutical compositions provided by the present invention allow for the excretion of uremic substances from the body of mammals. The methods provided by the present invention allow for a preliminary determination of whether or not uremic substances are excreted from the body, and / or whether or not the progression of chronic kidney disease is suppressed.

Claims

1. A pharmaceutical composition for promoting the excretion of uremic substances from the body, comprising an alkalizing agent, wherein the alkalizing agent is a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof.

2. A pharmaceutical composition for reducing the blood concentration of a uremic substance, comprising an alkalizing agent, wherein the alkalizing agent is a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof.

3. A pharmaceutical composition for promoting urinary excretion of uremic substances, comprising an alkalizing agent, wherein the alkalizing agent is a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof.

4. A pharmaceutical composition for improving uremic symptoms in chronic kidney disease, comprising an alkalizing agent, wherein the alkalizing agent is a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof.

5. A pharmaceutical composition for delaying the initiation of dialysis in chronic kidney disease, comprising an alkalinizing agent for reducing the concentration of uremic substances in the blood by administering the alkalinizing agent compared to before administration, wherein the alkalinizing agent is a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof.

6. A pharmaceutical composition for inhibiting renal tubular cell damage in patients with kidney disease, comprising an alkalizing agent for reducing the concentration of uremic substances in the blood by administering the alkalizing agent compared to before administration, wherein the alkalizing agent is a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof.

7. A pharmaceutical composition for maintaining renal tubular cell function in patients with kidney disease, comprising an alkalizing agent for reducing the concentration of uremic substances in the blood by administering the alkalizing agent compared to before administration, wherein the alkalizing agent is a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof.

8. A pharmaceutical composition for treating or preventing cardiovascular disease associated with chronic kidney disease and for reducing the concentration of uremic substances in the blood, comprising an alkalizing agent, wherein the alkalizing agent is a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof.

9. A pharmaceutical composition for inhibiting the progression of chronic kidney disease and for reducing the concentration of uremic substances in the blood, comprising an alkalizing agent, wherein the alkalizing agent is a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof.

10. A pharmaceutical composition for inhibiting the progression of acute kidney disease to chronic kidney disease and for reducing the concentration of uremic substances in the blood, comprising an alkalizing agent, wherein the alkalizing agent is a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof.

11. A pharmaceutical composition described in any one of claims 4 to 10, wherein the alkalinizing agent is a mixture of potassium citrate monohydrate and sodium citrate dihydrate.

12. A pharmaceutical composition described in any one of claims 5 to 10, wherein the uremic substance is selected from the group consisting of indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid and argininosuccinic acid.

13. The pharmaceutical composition according to any one of claims 5 to 10, wherein the uremic substance is indoxyl sulfate and phenylacetyl-L-glutamine.

14. A pharmaceutical composition described in any one of claims 5 to 10, wherein the uremic substance is indoxyl sulfate.

15. A pharmaceutical composition described in any one of claims 4 to 10, which is administered for 6 weeks or more.

16. A pharmaceutical composition described in any one of claims 4 to 10, administered to patients with chronic kidney disease at stage G2 or higher and G3b or lower.

17. A pharmaceutical composition described in any one of claims 4 to 10, which is a tablet.

18. A food composition for promoting the excretion of uremic substances from the body, comprising an alkalizing agent, wherein the alkalizing agent is a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof.

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