Alkalizing blood purification

Abstract

The present invention relates to a food composition containing an alkalinizing agent, particularly an alkali metal citrate, whose ingestion maintains kidney function.

Description

[Technical Field]

[0001] The present invention relates to blood purification with alkalinizing agents. 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 international application PCT / JP2017 / 032931 filed 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) who require dialysis or transplants is increasing worldwide. This trend is also evident in Japan, where the number of dialysis patients reached 320,000 at the end of 2014. Chronic kidney disease (CKD) is recognized as a precursor to ESKD. CKD is a comprehensive concept encompassing all chronic kidney diseases, regardless of the underlying cause, including all pathological conditions in which there is a decline in renal function, as measured by glomerular filtration rate (GFR), or signs suggesting kidney damage persist chronically (for 3 months or longer). CKD not only poses a risk for progression to ESKD, but also a strong risk for the development of cardiovascular disease (CVD), making early detection of CKD and appropriate treatment extremely important. While many CKD treatments have been established to date, they are still insufficient, and further development of renal protective agents is needed.

[0003] In CKD, various uremic substances accumulate in the body due to decreased renal clearance. In particular, the blood concentration of indoxyl sulfate, a terminal metabolite of tryptophan, increases with the progression of CKD, resulting in high concentrations (100 μM to 1 mM) of indoxyl sulfate. Indoxyl sulfate is known to be deeply involved in CKD complications, such as the progression of renal fibrosis-related kidney damage and vascular calcification-related CVD. It has been reported that serum indoxyl sulfate concentrations correlate with the mortality rate and incidence of cardiovascular events in dialysis patients (Non-Patent Document 1). It is believed that reducing blood indoxyl sulfate concentrations in CKD patients can slow the progression to ESKD and the onset of CVD associated with renal failure. In fact, a spherical adsorbent charcoal preparation (Kremezin®), which adsorbs indole, a precursor of indoxyl sulfate, in the intestinal tract and reduces blood indoxyl sulfate concentrations, delays the initiation of dialysis and improves arteriosclerosis in CKD patients (Non-Patent Document 2).

[0004] On the other hand, in patients with advanced CKD, the blood bicarbonate ion (HCO3 - Because the CKD concentration decreases and metabolic acidosis develops, alkaline agents such as sodium bicarbonate and citric acid preparations are administered. It has been reported that the administration of sodium bicarbonate, an alkaline agent, inhibits the progression of CKD (Non-Patent Document 3). It has also been reported that oral administration of sodium bicarbonate inhibits renal tubular cell damage caused by acidic urine in an animal model of nephrosis induced by protein overload (Non-Patent Document 4). However, there have been no reports on the suppression of the progression of kidney damage by administering alkalinizing agents to early stage CKD patients, nor on the reduction of blood concentrations of uremic substances. [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. Summary of the Invention [Problem to be solved by the invention]

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

[0007] The present inventors have conducted extensive research to achieve the above-mentioned object and have found that drugs that alkalize body fluids are useful for 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), thereby 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, which comprises an alkalinizing agent.

[0009] In one aspect, the present invention provides a pharmaceutical composition for reducing the blood concentration of a uremic substance, which comprises an alkalinizing agent.

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

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

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

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

[0014] In one aspect, the present invention provides a pharmaceutical composition for inhibiting progression from acute kidney disease to chronic kidney disease, comprising an alkalinizing agent.

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

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

[0017] In one aspect, the present invention provides a method for determining whether a uremic toxin concentration in human blood is reduced and / or whether excretion of a uremic toxin into urine is promoted.

[0018] That is, the present invention has the following aspects. (1) A pharmaceutical composition for reducing the blood concentration of a uremic substance, comprising an alkalizing agent. (2) A pharmaceutical composition for promoting urinary excretion of uremic substances, comprising an alkalizing agent. (3) A pharmaceutical composition for promoting the excretion of uremic substances from the body, comprising an alkalizing agent. (4) The pharmaceutical composition according to (2) or (3), wherein the urinary or extracorporeal excretion depends on the blood concentration of the uremic substance. (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 substance is indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, or argininosuccinic acid. (8) The pharmaceutical composition according to any one of (1) to (6), wherein the uremic substance is indoxyl sulfate, p-cresyl sulfate, or phenylacetyl-L-glutamine. (9) The pharmaceutical composition according to any one of (1) to (6), wherein the uremic substance is indoxyl sulfate and phenylacetyl-L-glutamine. (10) The pharmaceutical composition according to any one of (1) to (6), wherein the uremic substance is indoxyl sulfate and hippuric acid. (11) The pharmaceutical composition according to any one of (1) to (6), wherein the uremic substance is phenylacetyl-L-glutamine and p-cresyl sulfate. (12) The pharmaceutical composition according to any one of (1) to (6), wherein the uremic substance is indoxyl sulfate. (13) A pharmaceutical composition for improving uremic symptoms in chronic kidney disease, comprising an alkalizing agent. (14) A pharmaceutical composition for delaying the initiation of dialysis in chronic kidney disease, comprising an alkalinizing agent. (15) A pharmaceutical composition for treating or preventing cardiovascular diseases associated with chronic kidney disease, comprising an alkalizing agent. (16) The pharmaceutical composition according to (15), which improves arteriosclerosis. (17) A pharmaceutical composition for inhibiting the progression of chronic kidney disease, comprising an alkalizing agent. (18) A pharmaceutical composition for treating or preventing renal tubular disorders, comprising an alkalizing agent. (19) The pharmaceutical composition according to any one of (1) to (18), which is administered to a patient with early stage chronic kidney disease. (20) The pharmaceutical composition according to any one of (1) to (18), which is administered to a patient with chronic kidney disease at stage G3b or lower. (21) The pharmaceutical composition according to any one of (1) to (18), which is administered to a patient with chronic kidney disease at stage G2 or higher and G3b or lower. (22) 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. (23) The pharmaceutical composition according to any one of (1) to (18), which is administered to a patient with stage G2 chronic kidney disease. (24) The 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) The pharmaceutical composition according to any one of (1) to (18), which is administered to a patient having a urinary β2-microglobulin concentration of 50 to 150 μg / L or less. (26) The pharmaceutical composition according to any one of (1) to (18), which is administered to a patient having a blood cystatin C concentration of 0.5 to 2.2 mg / L or less. (27) The pharmaceutical composition according to any one of (1) to (18), which is administered to a patient having a blood cystatin C concentration of 1.0 to 1.3 mg / L or less. (28) A pharmaceutical composition for inhibiting the progression of acute kidney disease to chronic kidney disease, comprising an alkalizing agent. (29) The pharmaceutical composition according to any one of (1) to (28), wherein the alkalinizing 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 alkalinizing agent is sodium citrate, potassium citrate, a hydrate thereof, or a mixture thereof. (31) The pharmaceutical composition according to any one of (1) to (30), wherein the alkalinizing agent comprises a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof. (32) The pharmaceutical composition according to any one of (1) to (31), wherein the alkalinizing agent is sodium citrate or a hydrate thereof. (33) The pharmaceutical composition according to any one of (1) to (32), which is in the form of a tablet. (34) The pharmaceutical composition according to any one of (1) to (33), wherein a decrease in the blood concentration of the uremic substance compared to before the start of administration of the alkalinizing agent is detected 12 weeks after administration of the alkalinizing agent. (35) The pharmaceutical composition according to any one of (1) to (34), wherein an increase in the urinary concentration of a uremic substance compared to before the start of administration of the alkalinizing agent is detected 12 weeks after administration of the alkalinizing agent. (36) The pharmaceutical composition according to any one of (1) to (35), wherein an increase in excretion of uremic substances from the body compared to before the start of administration of the alkalinizing agent is detected 12 weeks after administration of the alkalinizing agent. (37) The pharmaceutical composition according to any one of (1) to (36), wherein an increase in urinary β2-microglobulin concentration is suppressed by administration of an alkalinizing agent. (38) The pharmaceutical composition according to any one of (1) to (37), wherein the administration of the alkalinizing agent suppresses an increase in urinary β2-microglobulin concentration 12 weeks after the administration. (39) The pharmaceutical composition according to any one of (1) to (38), wherein administration of the alkalinizing agent does not substantially decrease the concentration of β2-microglobulin in the urine compared to before the start of administration. (40) The pharmaceutical composition according to any one of (1) to (39), wherein the administration of the alkalinizing agent does not substantially decrease the β2-microglobulin concentration in the urine 12 weeks after the administration compared to the concentration before the start of the administration. (41) The pharmaceutical composition according to any one of (1) to (40), wherein administration of the alkalinizing agent does not substantially increase blood cystatin C compared to before the start of administration. (42) The pharmaceutical composition according to any one of (1) to (41), wherein administration of the alkalinizing agent does not substantially increase blood cystatin C 12 weeks after administration compared to before the start of administration. (43) The pharmaceutical composition according to any one of (1) to (42), wherein administration of an alkalinizing agent does not result in improvement of proximal tubular damage and / or improvement of glomerular damage compared to before the start of administration, but results in a decrease in the blood concentration of uremic substances, promotion of urinary excretion of uremic substances and / or promotion of excretion of uremic substances from the body compared to before the start of administration. (44) The pharmaceutical composition according to any one of (1) to (43), wherein 12 weeks after administration of the alkalinizing agent, no improvement in proximal tubular damage and / or glomerular damage is observed compared to before the start of administration, and a decrease in blood concentration of uremic substances, promotion of urinary excretion of uremic substances and / or promotion of excretion of uremic substances from the body is observed compared to before the start of administration. (45) The pharmaceutical composition according to any one of (1) to (44), wherein the alkalinizing agent is administered at 1 to 3 g / day. (46) The pharmaceutical composition according to any one of (1) to (45), wherein the alkalinizing agent is administered at 1 to 1.5 g / day. (47) The pharmaceutical composition according to any one of (1) to (46), wherein the alkalinizing agent is administered so that the pH of early morning urine is pH 5.2 to pH 6.8. (48) The pharmaceutical composition according to any one of (1) to (47), wherein the alkalinizing agent is administered so that the pH of early morning urine is equal to or higher than pH 6.0 and lower than pH 6.2. (49) The pharmaceutical composition according to any one of (1) to (48), wherein the alkalinizing agent is administered for 12 weeks or more. (50) The pharmaceutical composition according to any one of (1) to (49), wherein the alkalinizing agent is administered for 12 weeks. (50-1) The pharmaceutical composition according to any one of (1) to (50), wherein the amount of uremic substances in urine increases upon administration of an alkalizing agent. (50-2) The pharmaceutical composition according to any one of (1) to (50) and (50-1), wherein the concentration of a uremic substance in urine increases upon administration of an alkalinizing agent. (50-3) The pharmaceutical composition according to any one of (1) to (50), (50-1) and (50-2), wherein administration of an alkalinizing agent exerts the effect of lowering the blood concentration of uremic substances, the effect of promoting urinary excretion, and / or the effect of promoting excretion from the body, and these effects are observed compared to administration of a placebo. (50-4) The pharmaceutical composition according to any one of (1) to (50) and (50-1) to (50-3), wherein administration of an alkalizing agent exerts the effect of lowering the blood concentration of uremic substances, the effect of promoting urinary excretion, and / or the effect of promoting excretion from the body, and the effect is observed compared to before administration of the alkalizing agent. (50-5) The 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) The 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 for reducing blood concentrations of uremic substances, promoting urinary excretion, and / or promoting excretion from the body, comprising an alkalizing agent. (52) The food composition according to (51), wherein the alkalizing agent is an alkali metal citrate, a hydrate thereof, or a mixture thereof. (52-1) A food composition according to (51) or (52), which maintains renal function (suppresses tubular damage, protects tubular cells, or maintains tubular function). (52-2) The food composition according to any one of (51), (52), and (52-1), wherein the alkalinizing agent is ingested at 1 to 3 g / day. (52-3) The food composition according to any one of (51), (52), (52-1), and (52-2), wherein the alkalinizing agent is ingested at 1 to 1.5 g / day. (52-4) The food composition according to any one of (51), (52), and (52-1) to (52-3), in which the blood concentration of uremic substances is reduced compared to before the ingestion of the alkalinizing agent or compared to the ingestion of a placebo. (52-5) The food composition according to any one of (51), (52), and (52-1) to (52-4), which increases the urinary concentration of uremic substances compared to before the ingestion of the alkalinizing agent or compared to the ingestion of a placebo. (52-6) The food composition according to any one of (51), (52), and (52-1) to (52-5), in which the amount of uremic substances in urine increases compared to before the ingestion of the alkalinizing agent or compared to the ingestion of a placebo. (52-7) The food composition according to any one of (51), (52), and (52-1) to (52-6), which increases excretion of uremic substances from the body compared to before ingestion of the alkalinizing agent or compared to ingestion of a placebo. (52-8) The food composition according to any one of (51), (52), and (52-1) to (52-7), wherein an increase in urinary β2-microglobulin concentration is suppressed by ingestion of an alkalizing agent. (52-9) The food composition according to any one of (51), (52), and (52-1) to (52-8), wherein the intake of the alkalinizing agent does not substantially decrease the urinary β2-microglobulin concentration compared to before intake or after intake of a placebo. (52-10) The food composition according to any one of (51), (52), and (52-1) to (52-9), wherein blood cystatin C does not substantially increase upon ingestion of the alkalinizing agent. (52-11) The food composition according to any one of (51), (52), and (52-1) to (52-10), wherein the alkalinizing agent is ingested for 12 weeks or more. (52-12) The food composition according to any one of (51), (52), and (52-1) to (52-11), wherein the alkalinizing agent is ingested for 12 weeks. (53) A method for determining whether progression of chronic kidney disease has been inhibited, the method comprising measuring urinary pH. (54) A method for determining a decrease in the concentration of uremic substances in the blood of a patient with chronic kidney disease, the method comprising measuring the pH of urine. (55) A method for determining the promotion of excretion of uremic substances into the urine of a patient with chronic kidney disease, the method 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 a uremic substance, comprising an alkalizing agent, said pharmaceutical composition being in the form of a tablet. (57) A pharmaceutical composition for promoting urinary excretion of uremic substances, comprising an alkalizing agent, said pharmaceutical composition being in the form of a tablet. (58) The pharmaceutical composition according to (56) or (57), which is administered to a patient 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 at least one selected from the group consisting of indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and argininosuccinic acid. (60) The 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 treating or preventing renal tubular damage, 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 alkalinizing 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 alkalinizing agent comprises a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof.

[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 the maintenance of renal function is suppression of renal tubular damage, protection of renal tubular cells, or maintenance of renal tubular function. (67) The food composition according to (66), wherein the renal tubule is a proximal renal tubule. (68) The food composition according to any one of (65) to (67), wherein the alkalinizing 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 alkalinizing agent comprises a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof. (70) The food composition according to any one of (65) to (69), wherein the alkalizing agent is sodium citrate or a hydrate thereof. (71) The food composition according to any one of (65) to (70), which is in the form of a tablet. (72) The food composition according to any one of (65) to (71), wherein the effect of maintaining renal function is indicated on the packaging, container, or instruction manual of the food composition. (73) A food composition according to any one of (65) to (71), wherein the effects of inhibiting renal tubular damage, protecting renal tubular cells, or maintaining renal tubular function are indicated on the packaging, container, or instructions of the food composition. (74) The food composition according to any one of (65) to (72), which is taken by a healthy person who is concerned about kidney health. (75) The food composition according to any one of (65) to (71) and (73), which is taken by a healthy person who is concerned about the health of the renal tubules. (76) The food composition according to any one of (65) to (75), which is to be ingested by a subject having a urinary β2-microglobulin concentration of 290 μg / L or less. (77) The food composition according to any one of (65) to (76), which is ingested by a subject having a urinary β2-microglobulin concentration of 50 to 150 μg / L. (78) The food composition according to any one of (65) to (77), which is ingested by a subject with a blood cystatin C concentration of 0.5 to 2.2 mg / L. (79) The food composition according to any one of (65) to (78), which is ingested by a subject with a blood cystatin C concentration of 1.0 to 1.3 mg / L. (80) The food composition according to any one of (65) to (79), wherein ingestion of the food composition suppresses an increase in urinary β2-microglobulin concentration. (81) The food composition according to any one of (65) to (80), wherein ingestion of the food composition inhibits an increase in urinary β2-microglobulin concentration 12 weeks after ingestion. (82) The food composition according to any one of (65) to (81), wherein ingestion of the food composition does not substantially decrease the concentration of β2-microglobulin in urine compared to before ingestion or compared to a placebo. (83) The food composition according to any one of (65) to (82), wherein 12 weeks after ingestion of the food composition, the concentration of β2-microglobulin in urine does not substantially decrease compared to before ingestion or a placebo. (84) The food composition according to any one of (65) to (83), wherein ingestion of the food composition does not substantially increase blood cystatin C levels compared to levels before ingestion. (85) The 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 a placebo. (86) The food composition according to any one of (65) to (85), wherein ingestion of the food composition suppresses an increase in the amount of β2-microglobulin in early morning urine that accompanies the progression of the stage of chronic kidney disease. (87) A food composition according to any one of (65) to (86), wherein ingestion of the food composition 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 enable uremic substances to be excreted from the body in mammals. The methods provided by the present invention enable preliminary determination of whether uremic substances are being excreted from the body and / or whether the progression of chronic kidney disease has been inhibited. The food compositions and the like provided by the present invention enable maintenance of renal function in mammals, more specifically, inhibition of tubular damage, protection of tubular cells, or maintenance of tubular function. [Brief explanation of the drawings]

[0022] [Figure 1] FIG. 1 shows the correlation between urinary indoxyl sulfate concentrations and plasma indoxyl sulfate concentrations in patients in the control group 6, 12, and 24 weeks after the start of the study. [Figure 2] FIG. 1 shows the correlation between urinary indoxyl sulfate concentrations and plasma indoxyl sulfate concentrations in patients administered a potassium citrate / sodium citrate hydrate formulation 6, 12, and 24 weeks after the start of the study. [Figure 3] FIG. 1 shows the correlation between urinary indoxyl sulfate concentrations and plasma indoxyl sulfate concentrations in patients in the sodium bicarbonate preparation administration group at 6, 12, and 24 weeks after the start of the study. [Figure 4] FIG. 1 shows the correlation between urinary indoxyl sulfate concentrations and plasma indoxyl sulfate concentrations in all patients 6, 12, and 24 weeks after the start of the study. [Figure 5]FIG. 1 shows the correlation between urinary p-cresyl sulfate concentrations and plasma p-cresyl sulfate concentrations in patients in the control group 6, 12, and 24 weeks after the start of the study. [Figure 6] FIG. 1 shows the correlation between urinary p-cresyl sulfate concentrations and plasma p-cresyl sulfate concentrations in patients administered a potassium citrate / sodium citrate hydrate formulation 6, 12, and 24 weeks after the start of the study. [Figure 7] FIG. 1 shows the correlation between urinary p-cresyl sulfate concentrations and plasma p-cresyl sulfate concentrations in patients in the sodium bicarbonate preparation administration group at 6, 12, and 24 weeks after the start of the study. [Figure 8] FIG. 1 shows the correlation between urinary p-cresyl sulfate concentrations and plasma p-cresyl sulfate concentrations in all patients 6, 12, and 24 weeks after the start of the study. [Figure 9] FIG. 1 shows the correlation between urinary hippuric acid concentration and plasma hippuric acid concentration in patients in the control group 6, 12 and 24 weeks after the start of the study. [Figure 10] FIG. 1 shows the correlation between urinary hippuric acid concentration and plasma hippuric acid concentration in patients in the potassium citrate / sodium citrate hydrate combination preparation administration group at 6, 12, and 24 weeks after the start of the study. [Figure 11] FIG. 1 shows the correlation between urinary hippuric acid concentration and plasma hippuric acid concentration in patients in the sodium bicarbonate preparation administration group at 6, 12 and 24 weeks after the start of the study. [Figure 12] FIG. 1 shows the correlation between urinary hippuric acid concentration and plasma hippuric acid concentration in all patients 6, 12 and 24 weeks after the start of the study. [Figure 13] FIG. 1 shows the correlation between urinary argininosuccinic acid concentrations and plasma argininosuccinic acid concentrations in patients in the control group 6, 12, and 24 weeks after the start of the study. [Figure 14] FIG. 1 shows the correlation between urinary argininosuccinic acid concentrations and plasma argininosuccinic acid concentrations in patients in the potassium citrate / sodium citrate hydrate combination preparation administration group at 6, 12, and 24 weeks after the start of the study. [Figure 15] FIG. 1 shows the correlation between urinary argininosuccinic acid concentration and plasma argininosuccinic acid concentration in patients in the sodium bicarbonate preparation administration group at 6, 12, and 24 weeks after the start of the study. [Figure 16] FIG. 1 shows the correlation between urinary argininosuccinic acid concentrations and plasma argininosuccinic acid concentrations in all patients 6, 12, and 24 weeks after the start of the study. [Figure 17] FIG. 1 shows the correlation between urinary phenylacetyl-L-glutamine concentrations and plasma phenylacetyl-L-glutamine concentrations in patients in the control group 6, 12, and 24 weeks after the start of the study. [Figure 18] FIG. 1 shows the correlation between urinary phenylacetyl-L-glutamine concentrations and plasma phenylacetyl-L-glutamine concentrations in patients administered a potassium citrate-sodium citrate hydrate formulation 6, 12, and 24 weeks after the start of the study. [Figure 19] FIG. 1 shows the correlation between urinary phenylacetyl-L-glutamine concentrations and plasma phenylacetyl-L-glutamine concentrations in patients in the sodium bicarbonate formulation administration group at 6, 12, and 24 weeks after the start of the study. [Figure 20] FIG. 1 shows the correlation between urinary phenylacetyl-L-glutamine concentrations and plasma phenylacetyl-L-glutamine concentrations in all patients 6, 12, and 24 weeks after the start of the study. DETAILED DESCRIPTION OF THE INVENTION

[0023] 1. Pharmaceutical Composition The pharmaceutical compositions provided by the present invention may contain an alkalizing agent as an active ingredient. Alkalizing agents are used to reduce the HCO3 content of mammalian (especially human) body fluids, such as blood or urine. - Alkalizing agents are agents capable of increasing concentration or pH. Examples of alkalinizing 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 citrates. Examples of alkali metal citrates include potassium citrate and sodium citrate, which may be hydrated, such as stable potassium citrate monohydrate (C6H5K3O7·H2O) and sodium citrate dihydrate (C6H5Na3O7·2H2O), respectively. Examples of preferred alkalinizing agents include sodium citrate, potassium citrate, or hydrates thereof, 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 determined by those skilled in the art. For example, the molar ratio of potassium citrate monohydrate to sodium citrate dihydrate can be 1 part potassium citrate monohydrate to 0.01 to 100 parts sodium citrate dihydrate. The mixing ratio may be approximately 1:1. Another example of a preferred alkalizing agent is sodium citrate or a hydrate thereof, such as sodium citrate dihydrate (C6H5Na3O7·2H2O). Another example of a preferred alkalizing agent is potassium citrate or a hydrate thereof, such as potassium citrate monohydrate (C6H5K3O7·H2O). In one embodiment, the alkalinizing agent included in the pharmaceutical composition of the present invention may comprise a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof. In another embodiment, the alkalinizing agent contained in the pharmaceutical composition of the present invention may consist solely of a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof. When referring to the weight of an alkalizing agent (e.g., potassium citrate monohydrate (C6H5K3O7·H2O) and sodium citrate dihydrate (C6H5Na3O7·2H2O)) herein, the weight may be the dry weight.

[0024] As used herein, "uremic substances" refer to substances (such as waste products and toxins) excreted by normal kidneys that increase (accumulate) in the blood and cause the symptoms or disease of uremic disease when excretory function declines 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 argininosuccinic acid. Of these, indoxyl sulfate is produced in the liver by oxidation and sulfate conjugation of indole produced by intestinal bacteria from tryptophan derived from dietary protein. Most indoxyl sulfate exists in the blood bound to albumin, is not metabolized, and is excreted in the urine by the kidneys in healthy people, but in patients with kidney disease, high concentrations of indoxyl sulfate remain in the blood due to impaired kidney function. Indoxyl sulfate, a uremic substance, not only induces uremia in patients with kidney disease but also leads patients with chronic kidney disease to undergo dialysis. Therefore, by reducing the blood indoxyl sulfate concentration, uremic symptoms in kidney disease patients are improved, and uremia can be treated and / or prevented. Furthermore, by reducing the blood indoxyl sulfate concentration, it is possible to delay the initiation of dialysis in chronic kidney disease patients. In one embodiment, the chronic kidney disease patient has progressive chronic kidney disease. As used herein, the expression [A, B, and / or C] means "at least one selected from the group consisting of A, B, and C." Thus, 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] In addition, indoxyl sulfate, a uremic substance, induces myocardial fibrosis, arteriosclerosis, proliferation of vascular smooth muscle cells, vascular endothelial cell damage, thickening of arterial walls, calcification of the aorta, and the like, leading to the development of cardiovascular diseases (e.g., heart failure, myocardial infarction), which are complications of chronic kidney disease, and / or cerebrovascular diseases such as stroke. Therefore, by lowering the blood concentration of indoxyl sulfate, myocardial fibrosis, arteriosclerosis, proliferation of vascular smooth muscle cells, vascular endothelial cell damage, thickening of arterial walls, calcification of the aorta, etc. can be suppressed, making it possible to treat and / or prevent cardiovascular disease and / or cerebrovascular disease, which are complications of chronic kidney disease patients.

[0026] In one aspect, the pharmaceutical composition provided by the present invention is capable of reducing 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. As used herein, the term "reduction in the concentration of uremic substances in the blood" means that the concentration of uremic substances in the blood after administration of the pharmaceutical composition provided by the present invention is reduced compared to the concentration of uremic substances in the blood before administration, or that the administration of the pharmaceutical composition provided by the present invention reduces the concentration of uremic substances in the blood compared to administration of a placebo. In one embodiment, administration of the pharmaceutical composition provided by the present invention increases the level of uremic substances in the blood (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) compared to before administration. 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) is reduced, and the amount of reduction is 1 to 5%, 3 to 5%, 1 to 10%, 3 to 10%, 5 to 10%, 1 to 15%, 3 to 15%, 5 to 15%, 1 to 30%, 1 to 40%, 3 to 40%, 5 to 40%, 1 to 50%, 3 to 50%, 5 to 50%, 30 to 50%, 1 to 60%, 5% or more, 10% or more, or 30% or more of the blood concentration of the uremic substance before administration. In one embodiment, the reduction in blood concentration of a uremic substance is calculated by the following formula (1). Reduction in blood concentration of uremic substance (%) = [(blood concentration of uremic substance before administration of pharmaceutical composition (ng / mL) - blood concentration of uremic substance after administration of pharmaceutical composition (ng / mL)) / blood concentration of uremic substance before administration of 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 results in a decrease in the level of uremic substances in the blood (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 Indoxyl sulfate; p-cresyl sulfate and phenylacetyl-L-glutamine; hippuric acid and phenylacetyl-L-glutamine; indoxyl sulfate; p-cresyl sulfate; hippuric acid; or phenylacetyl-L-glutamine) is reduced by 1 to 5%, 3 to 5%, 1 to 10%, 3 to 10%, 5 to 10%, 1 to 15%, 3 to 15%, 5 to 15%, 1 to 30%, 1 to 40%, 3 to 40%, 5 to 40%, 1 to 50%, 3 to 50%, 5 to 50%, 30 to 50%, 1 to 60%, 5% or more, 10% or more, or 30% or more of the blood concentration of the uremic substance before administration. In one aspect, the pharmaceutical composition provided by the present invention is capable of promoting the excretion of uremic substances (e.g., indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, argininosuccinic acid, and combinations thereof) into 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, 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. As used herein, "promoting excretion of uremic substances into urine" means that the concentration of uremic substances in urine after administration of the pharmaceutical composition provided by the present invention is increased compared to the concentration of uremic substances in urine before administration; that the administration of the pharmaceutical composition provided by the present invention is increased compared to the administration of a placebo; that the amount of uremic substances in urine after administration of the pharmaceutical composition provided by the present invention is increased compared to the amount of uremic substances in urine before administration; or that the administration of the pharmaceutical composition provided by the present invention is increased compared to the administration of a placebo. In this specification, "in urine" means, for example, "in early morning urine." In one embodiment, administration of the pharmaceutical composition provided by the present invention reduces the levels of uremic substances in urine (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, hippuric acid, and phenylacetyl L glutamine; indoxyl sulfate, and 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 (argininosuccinic acid; indoxyl sulfate; p-cresyl sulfate; hippuric acid; argininosuccinic acid; or phenylacetyl-L-glutamine) is increased 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 urinary concentration of a uremic substance is calculated by the following formula (2). Increase in urinary concentration of uremic toxins (%) = [(urinary concentration of uremic toxins after administration of the pharmaceutical composition (ng / mL) - urinary concentration of uremic toxins before administration of the pharmaceutical composition (ng / mL)) / urinary concentration of uremic toxins 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 results in a decrease in the levels of uremic substances in urine (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, hippuric acid, and phenylacetyl L glutamine; indoxyl sulfate, p-cresyl sulfate, 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 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 concentration of (amino acids and argininosuccinic acid; indoxyl sulfate; p-cresyl sulfate; hippuric acid; argininosuccinic acid; or phenylacetyl-L-glutamine) is increased by 1 to 100%, 1 to 50%, 3 to 50%, 5 to 50%, 10 to 50%, 15 to 50%, 1 to 40%, 5 to 40%, 10 to 40%, 1 to 30%, 5 to 30%, 10 to 30%, 15 to 30%, 10% or more, 20% or more, 30% or more, or 40% or more. In one aspect, the pharmaceutical composition 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 urine, thereby promoting 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, hippuric acid, and phenylacetyl-L-glutamine; indoxyl sulfate, p-cresyl sulfate, and phenylacetyl-L-glutamine; indoxyl sulfate, p-cresyl sulfate, and phenylacetyl-L-glutamine; indoxyl sulfate, phenylacetyl-L-glutamine, and argininosuccinic acid; indoxyl sulfate, p-cresyl sulfate, and phenylacetyl-L-glutamine; indoxyl sulfate, phenylacetyl-L-glutamine, and argininosuccinic acid; indoxyl sulfate, 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 a pharmaceutical composition provided by the present invention increases the ratio of uremic to urinary uremic to blood uremic concentrations after administration compared to the ratio of uremic to urinary uremic to blood uremic concentrations before administration of the pharmaceutical composition provided by the present invention. In one embodiment, administration of a pharmaceutical composition provided by the present invention increases the ratio of uremic to urinary uremic to blood uremic concentrations compared to administration of a placebo. In one embodiment, administration of the pharmaceutical composition provided by the present invention reduces the blood concentration of uremic substances (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, hippuric acid, and phenylacetyl L glutamine; indoxyl sulfate, p-cresyl sulfate, 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, hippuric acid, and phenylacetyl L glutamine; indoxyl sulfate, hippuric acid, and 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; The ratio of the concentrations of (p-cresyl sulfate; hippuric acid; argininosuccinic acid; or phenylacetyl-L-glutamine) (urinary concentration (ng / mL) / blood concentration (ng / mL)) increases by 1 to 100%, 1 to 50%, 3 to 50%, 5 to 50%, 10 to 50%, 15 to 50%, 1 to 40%, 5 to 40%, 10 to 40%, 1 to 30%, 5 to 30%, 10 to 30%, 15 to 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 of a uremic substance to the blood concentration (urinary concentration (ng / mL) / blood concentration (ng / mL)) is calculated by the following formula (3). Increase in the ratio of uremic substance concentration in urine to blood (%) = [(ratio of uremic substance concentration in urine to blood after administration of the pharmaceutical composition - ratio of uremic substance concentration in urine to blood before administration of the pharmaceutical composition) / ratio of uremic substance concentration in urine to blood before administration of the pharmaceutical composition] × 100 (3) In one embodiment, continuous administration of a pharmaceutical composition provided by the present invention for 6, 12, or 24 weeks results in a decrease in 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 (e.g., indoxyl sulfate, p-cresyl sulfate, phenylacetyl L glutamine, hippuric acid, 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, 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, hippuric acid, and phenylacetyl L glutamine; indoxyl sulfate, 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 The ratio of the concentrations of (sulfuric acid; p-cresyl sulfate; hippuric acid; argininosuccinic acid; or phenylacetyl-L-glutamine) (urinary concentration (ng / mL) / blood concentration (ng / mL)) increases by 1 to 100%, 1 to 50%, 3 to 50%, 5 to 50%, 10 to 50%, 15 to 50%, 1 to 40%, 5 to 40%, 10 to 40%, 1 to 30%, 5 to 30%, 10 to 30%, 15 to 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 excretion of uremic substances from the body depending on the blood concentration of the uremic substances. In one embodiment, administration of the pharmaceutical composition provided by the present invention promotes urinary excretion of a uremic substance (e.g., indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, argininosuccinic acid, and combinations thereof) depending on the blood concentration of the uremic substance. For example, when the blood concentration of the uremic substance is high, the amount of the uremic substance excreted in urine increases accordingly. When the blood concentration of the uremic substance is low, the amount of the uremic substance excreted in urine decreases accordingly. Such 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 is highly safe. 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 promotes urinary excretion of uremic substances (e.g., indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, argininosuccinic acid, and combinations thereof) depending on the blood concentration of the uremic substance, thereby reducing the blood concentration of the uremic substance. 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 excretion of indoxyl sulfate into urine depending on the blood concentration of indoxyl sulfate, resulting in a ratio of the urinary concentration of indoxyl sulfate to the blood concentration of indoxyl sulfate (urinary concentration / blood concentration) of 1 to 1,000, 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 human (e.g., a patient with chronic kidney disease) whose blood concentration of indoxyl sulfate is 0.01 to 100 μg / mL (e.g., 0.1 to 30 μg / mL). Alternatively, administration may result in a blood concentration of indoxyl sulfate of 0.01 to 10 μg / mL (e.g., 0.03 to 10 μg / mL). In one embodiment, administration of the pharmaceutical composition provided by the present invention results in excretion of p-cresyl sulfate into urine depending on the blood concentration of p-cresyl sulfate, and as a result, the ratio of the urinary concentration of p-cresyl sulfate 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 human (e.g., a patient with chronic kidney disease) whose blood concentration of p-cresyl sulfate is 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 be 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 urinary excretion of phenylacetyl-L-glutamine depending on its blood concentration, resulting in a ratio of urinary to blood phenylacetyl-L-glutamine concentration (urinary concentration / blood concentration) of 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 human (e.g., a patient with chronic kidney disease) whose blood phenylacetyl-L-glutamine concentration is 0.03 to 30 μg / mL (e.g., 0.1 to 10 μg / mL). Furthermore, administration may result in a blood phenylacetyl-L-glutamine concentration of 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 humans (e.g., patients with chronic kidney disease), the ratio of the urinary concentration of indoxyl sulfate to the blood concentration of indoxyl sulfate (urinary concentration / blood concentration) for each individual shows a high correlation. In this embodiment, the high correlation may be indicated by an r value obtained by Pearson's test 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 a human (e.g., patient with chronic kidney disease) whose blood indoxyl sulfate concentration is 0.01 to 10 μg / mL (e.g., 0.1 to 10 μg / mL), and the administration may result in a blood indoxyl sulfate concentration of 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 humans (e.g., patients with chronic kidney disease), the ratios of the urinary concentration of p-cresyl sulfate to the blood concentration of p-cresyl sulfate (urinary concentration / blood concentration) for each individual show a high correlation. In this embodiment, the high correlation may be indicated by an 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 a human (e.g., patient with chronic kidney disease) whose blood p-cresyl sulfate concentration is 0.001 to 100 μg / mL (e.g., 0.01 to 50 μg / mL), and the administration may result in a blood p-cresyl sulfate concentration of 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 humans (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) for each individual shows a high correlation. In this embodiment, a high correlation may be indicated by an r value obtained by Pearson's test 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 humans (e.g., patients with chronic kidney disease) whose blood phenylacetyl-L-glutamine concentration is 0.01 to 10 μg / mL (e.g., 0.05 to 10 μg / mL), and the resulting blood phenylacetyl-L-glutamine concentration may be 0.01 to 10 μg / mL (e.g., 0.05 to 10 μg / mL). Due to these characteristics of the pharmaceutical composition provided by the present invention, in one aspect the pharmaceutical composition provided by the present invention can be used not only as a pharmaceutical composition for reducing the blood concentration of uremic substances and / or a pharmaceutical composition for promoting urinary excretion of uremic substances, but also as 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. As used herein, "improvement" is a concept that includes bringing a "pathological" or "abnormal" symptom, condition, or disease closer to a "healthy" or "normal" state, or actions aimed at that, and bringing the condition to a "healthy" or "normal" state. Accordingly, in one embodiment, "improvement" includes a numerical value that is an indicator of a "pathological" or "abnormal" symptom or condition decreasing or increasing in accordance with the "improvement," approaching a normal value or becoming a normal value. In another embodiment, "improvement" includes a decrease in the concentration of a uremic substance in blood, an increase in the concentration of a uremic substance in urine, and further, the concentration of a uremic substance in urine may begin to decrease when the concentration of a uremic substance in blood becomes sufficiently small. As used herein, "healthy" refers to a state free from acute or chronic disease or disorder, and "normal" refers to a state that a healthy subject normally experiences. As used herein, "treatment" includes eliminating, curing, curing, or remission of "pathological" or "abnormal" symptoms, conditions, or diseases, and includes inhibiting the worsening of "pathological" or "abnormal" symptoms, conditions, or diseases, and also includes the "improvement" described above. Here, inhibit has the meaning described below. In one embodiment, "treatment" refers to eliminating, curing, curing, or remission of "pathological" or "abnormal" symptoms, conditions, or diseases, and also includes the "improvement" described above. In another embodiment, "treatment" refers to eliminating, curing, curing, or remission of "pathological" or "abnormal" symptoms, conditions, or diseases. As used herein, the term "prevention" refers to a concept that includes preventing the onset of "pathological" or "abnormal" symptoms, conditions, or diseases, and actions therefor. As used herein, the term "delay" refers to a concept that includes extending the time until a target event occurs, and also includes extending the time so that the target event does not occur. As used herein, "suppression" refers to stopping or slowing the worsening or progression of a symptom, condition, or disease, and also refers to improving the symptom, condition, or disease. Here, "improvement" has the same meaning as above. The "worsening or progression of a symptom, condition, or disease" refers to the worsening or progression of a "pathological" or "abnormal" symptom, condition, or disease, and the worsening or progression from a "healthy" or "normal" state to a "pathological" or "abnormal" symptom, condition, or disease. In one embodiment, "suppression" refers to stopping or slowing the worsening or progression of a symptom, condition, or disease, or refers to the worsening or progression of a symptom, condition, or disease. In another embodiment, "suppression" refers to stopping or slowing the worsening or progression of a symptom, condition, or disease. wherein the symptoms, conditions or diseases are compared before and after administration of the pharmaceutical compositions provided by the present invention. Furthermore, due to the characteristics of the pharmaceutical composition provided by the present invention as described above, in one aspect the pharmaceutical composition provided by the present invention can be used as any of 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 treating and / or preventing cardiovascular diseases associated with chronic kidney disease.

[0027] Furthermore, it has been reported that when a drug that reduces 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, in one aspect, the pharmaceutical composition provided by the present invention that reduces the blood concentration of indoxyl sulfate can be used as a pharmaceutical composition for improving arteriosclerosis or improving thickening of the arterial wall (e.g., carotid artery) 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 reduce the blood concentration of indoxyl sulfate suppress acute kidney injury induced by cisplatin (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, in one aspect, the pharmaceutical composition provided by the present invention that reduces the blood concentration of indoxyl sulfate can be used as a pharmaceutical composition for treating acute kidney disease or a pharmaceutical composition for suppressing the progression of acute kidney disease to chronic kidney disease.

[0029] In addition, 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). In one aspect, the pharmaceutical composition of the present invention that promotes urinary excretion of p-cresyl sulfate can be used as a pharmaceutical composition for suppressing vascular endothelial damage in patients with kidney disease (preferably patients with chronic kidney disease). In addition, it has been reported that the uremic substance phenylacetyl-L-glutamine increases the risk of developing cardiovascular disease in patients with chronic kidney disease. In one aspect, the pharmaceutical composition of the present invention that promotes urinary excretion of phenylacetyl-L-glutamine can be used as a pharmaceutical composition for treating and / or preventing cardiovascular diseases in patients with chronic kidney disease. In one embodiment, the pharmaceutical composition provided by the present invention promotes urinary excretion of uremic substances such as indoxyl sulfate, p-cresyl sulfate, hippuric acid, argininosuccinic acid, and phenylacetyl-L-glutamine, and therefore can be used as a pharmaceutical composition for promoting 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 citric acid, or a hydrate thereof, or a mixture thereof (e.g., 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) to reduce blood indoxyl sulfate levels, blood p-cresyl sulfate levels, blood hippuric acid levels, and / or blood phenylacetyl-L-glutamine levels. In one embodiment, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof (e.g., 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) to increase urinary indoxyl sulfate concentration, urinary p-cresyl sulfate concentration, urinary hippuric acid concentration, urinary argininosuccinic acid concentration, and / or urinary phenylacetyl-L-glutamine concentration (preferably, to increase urinary indoxyl sulfate concentration, urinary p-cresyl sulfate concentration, and urinary phenylacetyl-L-glutamine concentration). In one embodiment, sodium bicarbonate is administered to a patient with kidney disease (preferably a patient with chronic kidney disease) to reduce blood p-cresyl sulfate and / or blood phenylacetyl-L-glutamine concentrations. In one embodiment, sodium bicarbonate is administered to a kidney patient (preferably a chronic kidney patient) to increase urinary argininosuccinic acid levels.

[0030] In one aspect, the pharmaceutical composition provided by the present invention can be used as a pharmaceutical composition for treating, preventing, or suppressing renal tubular damage. The renal tubule may be, for example, a proximal tubule. In another aspect, the pharmaceutical composition provided by the present invention can be used as a pharmaceutical composition for maintaining renal function. In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for inhibiting renal tubular cell damage, a pharmaceutical composition for protecting renal tubular cells, or a pharmaceutical composition for maintaining renal tubular cell function (e.g., reabsorption of water, sodium ions, potassium ions, calcium ions, phosphate ions, bicarbonate ions, chloride ions, glucose, amino acids, vitamins, etc.). In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for inhibiting damage to proximal tubule cells, a pharmaceutical composition for protecting proximal tubule cells, or a pharmaceutical composition for maintaining proximal tubule cell function (e.g., reabsorption of glucose, amino acids, vitamins, etc.). In one embodiment, the pharmaceutical composition provided by the present invention suppresses the increase in the amount (concentration) of β2-microglobulin in urine (for example, early morning urine) that accompanies the progression of the stage 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 tubule cell injury associated with the progression of chronic kidney disease and protecting proximal tubule cells. As used herein, "maintenance of renal function" refers to, for example, suppression of renal tubule damage, protection of renal tubule cells, or maintenance of renal tubule function. The renal tubule may be, for example, a proximal renal tubule, and one aspect of maintaining renal tubule function or maintaining proximal renal tubule function is maintaining the function of renal tubule cells or maintaining the function of proximal renal tubule cells. As used herein, "protection of cells" means maintaining or preserving the state of cells or suppressing cell damage, where suppression has the meaning described above. As used herein, "maintaining cell function" means preserving cell function or suppressing deterioration of cell function. Here, suppression has the above-mentioned meaning. Here, the state or function of the cells is compared before and after administration of the pharmaceutical composition provided by the present invention. As used herein, "early morning urine" refers to the first urine after waking up. In one embodiment, the pharmaceutical composition provided by the present invention suppresses an increase in the amount (concentration) of β2-microglobulin in urine (e.g., early morning urine) 6, 12, and / or 24 weeks after administration compared to before the start of administration. In one embodiment, the pharmaceutical composition provided by the present invention suppresses the increase in the amount (concentration) of β2-microglobulin in urine (e.g., early morning urine) that accompanies the progression of the stage of chronic kidney disease, but does not substantially reduce the amount (concentration) of β2-microglobulin in urine (e.g., early morning urine) compared to before the start of administration of the pharmaceutical composition provided by the present invention. In this embodiment, for example, if the amount (concentration) of β2-microglobulin in urine (e.g., early morning urine) before the start of administration of a pharmaceutical composition provided by the present invention is taken as 1, the amount (concentration) of β2-microglobulin in urine (e.g., early morning urine) after administration can 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 urine (e.g., early morning urine) that accompanies the progression of the stage of chronic kidney disease, but does not substantially reduce the amount (concentration) of β2-microglobulin in urine (e.g., early morning urine) 6 weeks, 12 weeks, and / or 24 weeks after administration of the pharmaceutical composition provided by the present invention compared to before the start of administration. In this embodiment, for example, if the amount (concentration) of β2-microglobulin in urine (e.g., early morning urine) before the start of administration of a pharmaceutical composition provided by the present invention is taken as 1, the amount (concentration) of β2-microglobulin in 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., plasma) compared to before the start of administration. In this embodiment, for example, when the amount (concentration) of cystatin C in the blood (e.g., plasma) before the start of administration of the pharmaceutical composition provided by the present invention is taken as 1, the amount (concentration) of cystatin C in the blood (e.g., plasma) after administration can 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., plasma) 6 weeks, 12 weeks, and / or 24 weeks after administration compared to before the start of administration. In this embodiment, for example, if the amount (concentration) of cystatin C in the blood (e.g., plasma) before the start of administration of the pharmaceutical composition provided by the present invention is taken as 1, the amount (concentration) of cystatin C in the blood (e.g., plasma) 6 weeks after administration, 12 weeks after administration, or 24 weeks 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, administration of the pharmaceutical composition provided by the present invention does not result in improvement of proximal tubular damage and / or improvement of glomerular damage 6 weeks, 12 weeks, and / or 24 weeks after administration compared to before the start of administration, but does result in a decrease in blood concentrations of uremic substances, enhanced urinary excretion of uremic substances, and / or enhanced excretion of uremic substances from the body 6 weeks, 12 weeks, and / or 24 weeks after administration compared to before the start of administration. In one embodiment, administration of the pharmaceutical composition provided by the present invention does not result in improvement of proximal tubular damage and / or improvement of glomerular damage 6 weeks, 12 weeks, and / or 24 weeks after administration compared to before the start of administration, but does result in a decrease in blood concentrations of uremic substances, enhanced urinary excretion of uremic substances, and / or enhanced excretion of uremic substances from the body 6 weeks, 12 weeks, and / or 24 weeks after administration compared to before the start of administration.

[0031] The pharmaceutical compositions provided by the present invention are administered to humans or other mammals orally or parenterally. Examples of parenteral administration include intravenous administration, subcutaneous administration, intramuscular administration, intraarticular administration, transmucosal administration, transdermal administration, nasal administration, rectal administration, intrathecal administration, intraperitoneal administration, and topical administration. The pharmaceutical compositions provided by the present invention may be prepared by mixing the alkalinizing agent directly or with pharmaceutically acceptable carriers, such as excipients (e.g., lactose, D-mannitol, crystalline cellulose, glucose), binders (e.g., hydroxypropyl cellulose (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, isotonicity agents, stabilizers), and may be in the form of tablets, capsules, suspensions, injections, suppositories, and the like. For example, to prepare tablets, the alkalinizing 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., hydroxypropyl cellulose (HPC), gelatin, polyvinylpyrrolidone (PVP)), lubricants (e.g., magnesium stearate, talc), etc. The tablets according to the present invention are described in more detail below.

[0032] In one embodiment, the pharmaceutical composition of the present invention is a tablet. The tablet of the present invention may contain an alkalizing agent (e.g., potassium citrate or a hydrate thereof; sodium citrate or a hydrate thereof; a mixture of potassium citrate monohydrate and sodium citrate dihydrate; or sodium bicarbonate) as well as pharmaceutically acceptable additives commonly used in the pharmaceutical field. Examples of such additives include excipients, binders, disintegrants, flow agents, flavoring agents, lubricants, pH adjusters, surfactants, stabilizers, and flavoring agents. The content of the alkalizing agent in the tablet provided by the present invention may be 10 to 95% by weight, preferably 30 to 90% by weight, more preferably 60 to 85% by weight, based on the weight of 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 hydrate, anhydrous lactose), glucose, sucrose, fructose, maltose, etc.; sugar alcohols such as erythritol, sorbitol, maltitol, xylitol, D-mannitol, etc.; 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 ethyl cellulose, with crystalline cellulose being particularly preferred. The content of excipients 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, based on the weight of the tablet.

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

[0035] Examples of disintegrants that can be used in the tablets provided by the present invention include croscarmellose sodium, carmellose calcium, sodium carboxymethyl starch, 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 tablet provided by the present invention may be 0.3 to 20% by weight, preferably 1 to 10% by weight, more preferably 3 to 10% by weight, based on the tablet.

[0036] Examples of glidants 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 fluidizer in the tablet provided by the present invention may be 0.03 to 3% by weight, preferably 0.1 to 3% by weight, more preferably 0.3 to 3% by weight, based on the tablet.

[0037] Examples of flavoring agents that can be used in the 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 (provided that the flavoring agents do not include the alkalizing agent according to the present invention), and sweeteners such as sodium saccharin, dipotassium glycyrrhizinate, aspartame (registered trademark), stevia, thaumatin, and sucralose. The content of the flavoring agent in the tablet provided by the present invention may be 0.03 to 3% by weight, preferably 0.1 to 3% by weight, more preferably 0.3 to 3% by weight, based on 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 esters, carnauba wax, macrogol, and sodium stearyl fumarate, with magnesium stearate being particularly preferred. The content of the lubricant in the tablet provided by the present invention may be 0.1 to 30% by weight, preferably 0.3 to 10% by weight, more preferably 1 to 3% by weight, based on the tablet.

[0039] Examples of pH adjusters that can be used in the 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 (however, the pH adjusters do not include the alkalinizing agents of the present invention). The content of the pH adjuster in the tablet provided by the present invention may be 0.1 to 30% by weight, preferably 0.3 to 10% by weight, more preferably 1 to 5% by weight, based on 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 content of the surfactant in the tablet provided by the present invention may be 0.01 to 3 wt %, preferably 0.03 to 1 wt %, more preferably 0.03 to 0.5 wt %, based on the tablet. Examples of stabilizers that can be used in the 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 (however, the stabilizers do not include the alkalinizing agent according to the present invention), with anhydrous citric acid being particularly preferred. The content of the stabilizer in the tablet provided by the present invention may be 0.01 to 30% by weight, preferably 0.1 to 30% by weight, more preferably 1 to 20% by weight, based on the tablet.

[0041] Examples of flavors that can be used in the tablets provided by the present invention include citrus flavors such as lemon, orange, and grapefruit, as well as peppermint, spearmint, and menthol, and can be contained in the tablets in an appropriate amount (for example, 0.01 to 1% by weight, more preferably 0.01 to 0.1% by weight, based on the tablet). In the tablet provided by the present invention, the total content of the alkalinizing agent and the pharmaceutically acceptable additives does not exceed 100% by weight of the tablet.

[0042] The tablet provided by the present invention contains the above-mentioned ingredients and can be a plain tablet without a coating layer, or a film-coated tablet with a coating layer. The content of the coating layer can be appropriately determined by those skilled in the art, but may be, for example, 0.1 to 10 wt% of the plain tablet. In addition to the coating base, the coating layer can also contain, as appropriate, a plasticizer, a colorant, a glossing agent, etc. Examples of coating bases that can be used in the tablets provided by the present invention include hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, 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, of the tablet. Examples of coating plasticizers that can be used in the tablets provided by the present invention include triethyl citrate, medium-chain fatty acid triglycerides, 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, based on the tablet. Examples of coating colorants that can be used in the tablets provided by the present invention include titanium oxide, yellow ferric oxide, ferric oxide, black ferric oxide, Food Blue No. 2, and aluminum lake Food Blue No. 2. 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, based on the weight of the tablet. An example of a coating polishing agent that can be used in the tablet provided by the present invention is carnauba wax. The content of the coating polishing agent in the tablet provided by the present invention may be 0.0001 to 0.1% by weight, preferably 0.001 to 0.01% by weight, based on the tablet.

[0043] The pharmaceutical composition of the present invention can be prepared by a method known in the pharmaceutical field. For example, when it is prepared as a tablet, the preparation method may include a mixing step of mixing an alkalizing agent (e.g., potassium citrate or a hydrate thereof; sodium citrate or a hydrate thereof; a mixture of potassium citrate monohydrate and sodium citrate dihydrate; or sodium bicarbonate) with an additive, a granulation step, a tableting step, and / or a coating step. The mixing step may include a step of mixing an alkalizing agent with additives such as excipients, stabilizers, disintegrants, and / or binders. Furthermore, the method may further include a step of mixing the mixture containing the alkalizing agent and additives with a lubricant, flavoring agent, and / or fragrance prior to the tableting step. Mixing can be performed using a V-type mixer, W-type mixer, container mixer, tumbler mixer, stirrer mixer, or the like. The granulation step can be carried out by a granulation method known in the pharmaceutical field, examples of which include dry granulation, wet granulation, and fluidized bed granulation. In one embodiment, the mixture obtained in the mixing step and the granules obtained in the granulation step can be appropriately pulverized and / or sieved to obtain a mixture or granules having a desired particle size. Pulverization can be performed using a pulverizer known in the pharmaceutical field, such as a ball mill, jet mill, or hammer mill. Sieving can be performed using a 16 mesh sieve (opening 1000 μm) to 32 mesh sieve (opening 500 μm), etc. The tableting step can be carried out by a tableting method 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 step can be tableted using a tableting machine known in the pharmaceutical field, such as a single-punch tableting machine or a rotary tableting machine. When a single-punch tableting machine, a rotary tableting machine, or the like is used, a tableting pressure of 1 kN to 30 kN can be used. The coating step can be carried out by a method known in the pharmaceutical field, for example, by spray coating the outside of the uncoated tablet with a coating liquid containing a coating base and appropriate additives such as a plasticizer, a colorant, and a glossing agent. In one embodiment, the tablet provided by the present invention can be produced by mixing an alkalinizing 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 the mixture to obtain a core tablet; and then forming a coating layer on the outer surface of the core tablet, the coating layer containing a coating base (e.g., hydroxypropyl cellulose, hydroxypropylmethylcellulose, and / or PVP), a plasticizer (e.g., triethyl citrate and / or macrogol 6000), a colorant (e.g., red iron oxide and / or titanium oxide), and a glazing agent (e.g., carnauba wax). In one embodiment, the hardness of the resulting tablet may be 10 to 200N, preferably 30 to 150N.

[0044] The amount of alkalizing agent in the pharmaceutical composition provided by the present invention can be appropriately determined. In one embodiment, the amount of the alkalinizing agent in the pharmaceutical composition provided by the present invention may be set so that the dose of the alkalinizing agent administered to a human is an amount that improves acidic urine associated with gout or hyperuricemia, or an amount less than that, and may be set so that it is, for example, 1 to 50%, or 10 to 20%, of the daily dose approved in Japan for improving acidic urine associated with gout or hyperuricemia (e.g., when the alkalinizing agent is a citric acid preparation: two tablets containing 231.5 mg of potassium citrate (C6H5K3O7·H2O) and 195.0 mg of sodium citrate hydrate (C6H5Na3O7·2H2O) are orally administered three times a day; when the alkalinizing agent is sodium bicarbonate: 3 to 5 g are orally administered daily). In one embodiment, the pharmaceutical composition provided by the present invention is a tablet, and one 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 one tablet may contain 10 mg to 300 mg of potassium citrate monohydrate and 20 mg to 600 mg in total, preferably 150 to 250 mg of each and 400 to 500 mg in total, and more preferably 190 to 240 mg of each and 400 to 450 mg in total, of potassium citrate monohydrate and sodium citrate dihydrate. In one embodiment, the pharmaceutical composition provided by the present invention is in the form of a tablet, and one 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 contain anhydrous citric acid, microcrystalline cellulose, partially pregelatinized starch, hydroxypropyl cellulose, magnesium stearate, hypromellose, macrogol 6000, titanium oxide, and carnauba wax as excipients. In one embodiment, a single dosage 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 a formulation, and "one dosage unit" refers to the smallest unit of a formulation. Thus, for example, in the case of tablets, the dosage unit is each tablet, and one dosage unit represents one tablet. In the case of injections, the dosage unit is an injection placed in a sealed container such as an ampoule or a vial, and one dosage unit represents an injection placed in a sealed container such as an ampoule or a vial. When the pharmaceutical composition provided by the present invention is administered to humans or other mammals, one or more of the dosage units may be administered at a time, or one dosage unit may be divided and administered.

[0045] The dosage of the alkalizing agent is determined appropriately depending on the type of alkalizing agent, the method of administration, the age, weight, sex, symptoms, sensitivity to the drug, etc. of the subject, but the dosage may be adjusted depending on the degree of improvement in symptoms. In one embodiment, when a mixture of potassium citrate monohydrate and sodium citrate dihydrate or sodium bicarbonate is orally administered to a human as an alkalinizing agent, the daily dosage may be half of the daily dosage approved in Japan for the improvement of acidic urine in gout and hyperuricemia (e.g., when the alkalinizing agent is a citric acid preparation: two tablets containing 231.5 mg of potassium citrate (C6H5K3O7·H2O) and 195.0 mg of sodium citrate hydrate (C6H5Na3O7·2H2O) are orally administered three times a day; when the alkalinizing agent is sodium bicarbonate: 3 to 5 g are orally administered daily). In one embodiment, when a mixture of potassium citrate monohydrate and sodium citrate dihydrate or sodium bicarbonate is orally administered to a human as an alkalinizing agent, the daily dosage may be the same as the daily dosage approved in Japan for the improvement of acidic urine in gout and hyperuricemia (e.g., when the alkalinizing agent is a citric acid preparation: two tablets containing 231.5 mg of potassium citrate (C6H5K3O7·H2O) and 195.0 mg of sodium citrate hydrate (C6H5Na3O7·2H2O) are orally administered three times a day; when the alkalinizing agent is sodium bicarbonate: 3 to 5 g are orally administered daily). In one embodiment, when a mixture of potassium citrate monohydrate and sodium citrate dihydrate or sodium bicarbonate is orally administered to a human as an alkalinizing agent, administration may be initiated at a daily dose that is half the daily dose approved in Japan for the improvement of gout and acidic urine associated with hyperuricemia (e.g., when the alkalinizing agent is a citric acid preparation: two tablets containing 231.5 mg of potassium citrate (C6H5K3O7·H2O) and 195.0 mg of sodium citrate hydrate (C6H5Na3O7·2H2O) are orally administered three times a day; when the alkalinizing agent is sodium bicarbonate: 3 to 5 g are orally administered daily), and the dose may then be increased to the daily dose approved in Japan for the improvement of gout and acidic urine associated with hyperuricemia. In one embodiment, the dosage of the alkalinizing agent may be such that oral administration of the alkalinizing agent will result in a pH of human urine (e.g., early morning urine) of 5.2 to 6.8, 5.5 to 6.8, 5.8 to 6.8, 5.8 to 6.5, 5.8 to 6.2, 5.8 or more and less than 6.2, 6.0 to 6.5, 6.0 to 6.4, 6.0 to 6.3, 6.0 to 6.2, 6.0 or more and less than 6.2, 6.1 to 6.3, 6.2 to 6.8, 6.2 to 6.5, or 6.5 to 6.8. In one embodiment, the dosage of the alkalinizing agent may be such that oral administration of the alkalinizing agent results in a pH of human urine (e.g., early morning urine) of 5.2 to 6.8, 5.5 to 6.8, 5.8 to 6.8, 5.8 to 6.5, 5.8 to 6.2, 5.8 or more but less than 6.2, 6.0 to 6.5, 6.0 to 6.4, 6.0 to 6.3, 6.0 to 6.2, 6.0 or more but less than 6.2, 6.1 to 6.3, 6.2 to 6.8, 6.2 to 6.5, or 6.5 to 6.8 at 6 weeks, 12 weeks, or 24 weeks after administration. In one embodiment, when a mixture of potassium citrate monohydrate and sodium citrate dihydrate is orally administered to a human as an alkalinizing agent, potassium citrate monohydrate and sodium citrate dihydrate may be administered at 0.1 to 5 g / day each for a total of 0.2 to 10 g / day, 0.1 to 3 g / day each for a total of 0.2 to 6 g / day, 0.5 to 3 g / day each for a total of 1 to 6 g / day, preferably 0.5 to 1.5 g / day each for a total of 1 to 3 g / day, 1 to 1.5 g / day each for a total of 2 to 3 g / day, or 0.5 to 1 g / day each for a total of 1 to 2 g / day, and may be administered 1 to 5 times a day, preferably 3 times a day. In one embodiment, when potassium citrate monohydrate or sodium citrate dihydrate is orally administered to a human as an alkalinizing agent, the dose may be 1 to 10 g / day, 1 to 6 g / day, 2 to 5.5 g / day, 1 to 3 g / day, 2 to 3 g / day, or 1 to 1.5 g / day, and may be administered 1 to 5 times a day, preferably 3 times a day. In one embodiment, when sodium bicarbonate is orally administered to a human as an alkalinizing agent, the dosage may be 1 to 6 g / day, preferably 1 to 3 g / day or 3 to 5 g / day, and may be administered in divided doses 1 to 5 times a day, preferably 3 times a day.

[0046] In one embodiment, the alkalinizing agent may be administered chronically, for example, for 1 week, 2 weeks, 3 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 24 weeks, 40 weeks, 60 weeks, 80 weeks, 100 weeks, 120 weeks, 1 week or more, 2 weeks or more, 3 weeks or more, 6 weeks or more, 8 weeks or more, 10 weeks or more, 12 weeks or more, 24 weeks or more, 40 weeks or more, 60 weeks or more, 80 weeks or more, 100 weeks or more, 120 weeks or more , 6 weeks or more but not more than 24 weeks, 12 weeks or more but not more than 24 weeks, 6 weeks or more but not more than 30 weeks, 12 weeks or more but not more than 30 weeks, 6 weeks or more but not more than 40 weeks, 12 weeks or more but not more than 40 weeks, 6 weeks or more but not more than 60 weeks, 12 weeks or more but not more than 60 weeks, 6 weeks or more but not more than 80 weeks, 12 weeks or more but not more than 80 weeks, 6 weeks or more but not more than 100 weeks, 12 weeks or more but not more than 100 weeks, 6 weeks or more but not more than 120 weeks, or 12 weeks or more but not more than 120 weeks. In one embodiment, the pharmaceutical composition provided by the present invention can be continuously administered for 6 weeks, 12 weeks, and / or 24 weeks to detect beneficial effects in patients with kidney disease (e.g., chronic kidney disease) (e.g., an effect of reducing the blood concentration of uremic substances (e.g., indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and / or argininosuccinic acid), an effect of increasing the urinary concentration of uremic substances (e.g., indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and / or argininosuccinic acid) (an effect of promoting urinary excretion), and / or an effect of suppressing increases in urinary β2-microglobulin concentration).

[0047] In one embodiment, the pharmaceutical compositions provided herein are administered to a human suffering from kidney disease, which includes acute kidney disease and chronic kidney disease unless otherwise specified. Examples of acute kidney disease include acute kidney disease caused by drugs (e.g., nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, aminoglycoside antibiotics, fluoroquinolone antibacterial agents, iodinated contrast agents, and platinum preparations such as cisplatin) and acute kidney disease caused by renal ischemia. Chronic kidney disease (CKD) is a concept that encompasses all chronic kidney diseases, regardless of the underlying disease, and includes all pathological conditions in which there is a decline in renal function, as measured by glomerular filtration rate (GFR), or findings suggesting kidney damage persist chronically (for more than three months).

[0048] According to the CKD Clinical Practice Guide 2012 (Journal of the Japanese Society of Nephrology 2012), the severity of chronic kidney disease is assessed by classification based on the cause (Cause: C), renal function (GFR: G), and proteinuria (albuminuria: A). The GFR classification is as follows: G1: Normal or high GFR (≥ 90 mL / min / 1.73 m 2 ) G2: Normal or mildly reduced GFR (60–89 mL / min / 1.73 m 2 ) G3a: Mild to moderate decrease in GFR (45 to 59 mL / min / 1.73 m 2 ) G3b: Moderate to severely decreased GFR (30 to 44 mL / min / 1.73 m 2 ) G4: Severely decreased GFR (15-29 mL / min / 1.73 m 2 ) G5: End-stage renal disease (ESKD) (<15 mL / min / 1.73 m 2 ) When the primary disease is diabetes, proteinuria (albuminuria: A) is classified as follows using the urinary albumin / creatinine (Cr) ratio: A1: Normal (less than 30 mg / gCr) A2: Microalbuminuria (30-299 mg / gCr) A3: Overt albuminuria (300 mg / gCr or more) In addition, classification based on proteinuria (albuminuria: A) is performed using the urinary protein / creatinine (Cr) ratio as follows when the primary disease is hypertension, nephritis, polycystic kidney disease, transplanted kidney, or other conditions other than diabetes. 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 CKD Treatment Guide 2012 (Journal of the Japanese Society of Nephrology 2012), the severity classification of chronic kidney disease (CKD) is expressed using the above C, G, and A, for example, diabetes G2A3, chronic nephritis G3bA1, etc. However, taking into consideration that the severity of chronic kidney disease has traditionally been expressed only in stages classified by GFR, it is now possible to express the severity of chronic kidney disease in stages, G1, G2, G3a, G3b, G4, and G5, as in the past.

[0049] In one embodiment, the pharmaceutical compositions provided herein are administered to patients with less severe, early stage chronic kidney disease. In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with chronic kidney disease at stage G3b or below, preferably at stage G2 or below. In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with chronic kidney disease at stage G2 or higher and stage G3b or lower (e.g., stage G2 and stage G3a; or stage G2, stage G3a and stage G3b). In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with chronic kidney disease at stage G3b or below and with microalbuminuria, preferably to a patient with chronic kidney disease at stage G2 and with microalbuminuria. In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with chronic kidney disease at stage G2 or higher and stage G3b or lower (e.g., stage G2 and stage G3a; or stage G2, stage G3a and stage G3b) who has microalbuminuria. In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with chronic kidney disease at stage G3b or below and with urinary protein excretion of less than 3.5 g / gCr, preferably to a patient with chronic kidney disease at stage G2 and with urinary protein excretion of less than 3.5 g / gCr. In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with chronic kidney disease at stage G2 or higher and stage G3b or lower (e.g., 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 compositions provided herein are administered to patients with advanced chronic kidney disease. In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with chronic kidney disease having a urinary (e.g., early morning urine) concentration of β2-microglobulin of 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 a patient with chronic kidney disease whose blood (e.g., plasma or serum) concentration of cystatin C is 0.1 to 3.0 mg / L, 0.1 to 2.0 mg / L, 0.1 to 1.6 mg / L, 0.1 to 1.3 mg / L, 0.5 to 3.0 mg / L, 0.5 to 2.0 mg / L, 0.5 to 1.6 mg / L, 0.5 to 1.3 mg / L, or 0.9 to 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 (eg, 0.1 to 30 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 p-cresyl sulfate is 0.003 to 300 μg / mL (eg, 0.01 to 30 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 hippuric acid 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 argininosuccinic acid is 0.01 to 100 μg / mL (eg, 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 (eg, 0.1 to 10 μg / mL).

[0050] In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient undergoing treatment in accordance with the CKD Medical Care Guide, for example, to a patient undergoing blood pressure control (administration of RA system inhibitors such as ARBs and ACE inhibitors, diuretics, and calcium channel blockers, etc.), proteinuria control (administration of RA system inhibitors, etc.), blood glucose control (administration of α-glucosidase inhibitors, etc.), lipid control (administration of statins and fibrates, etc.), anemia control (administration of erythropoietin, etc.), and / or bone and mineral control (administration of bisphosphonates, etc.) in accordance with the CKD Medical Care Guide. In one embodiment, the pharmaceutical composition provided by the present invention is used in combination with an antihypertensive agent (eg, an ARB, an ACE inhibitor, a diuretic, or a calcium channel blocker). In one embodiment, the pharmaceutical composition provided by the present invention is used in combination with spherical adsorbent carbon (sold in Japan as Kremezin (registered trademark)) obtained by subjecting spherical, microporous carbon derived from petroleum hydrocarbons to high-temperature oxidation and reduction treatment.

[0051] In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with less severe, early stage chronic kidney disease (e.g., a patient with chronic kidney disease at stage G3b or below, preferably at stage G2 or above and stage G3b or below, more preferably at stage G2 and stage G3a, and even more preferably at stage G2) to reduce the concentration of uremic substances (e.g., indoxyl sulfate, p-cresyl sulfate, hippuric acid, and / or phenylacetyl-L-glutamine) in the patient's blood and promote the excretion of uremic substances (e.g., indoxyl sulfate, p-cresyl sulfate, hippuric acid, argininosuccinic acid, 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 a complication of cardiovascular disease (e.g., heart failure, myocardial infarction, stroke, etc.). In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with less severe, early stage chronic kidney disease (e.g., a patient with chronic kidney disease at stage G3b or below, preferably at stage G2 or above but not exceeding stage G3b, more preferably at stage G2 and stage G3a, and even more preferably at stage G2) to suppress an increase in urinary β2-microglobulin in the patient. In this embodiment, the pharmaceutical composition provided by the present invention may be a composition for suppressing renal tubule (e.g., proximal tubule) damage, a composition for suppressing renal tubule (e.g., proximal tubule) cell damage, a composition for protecting renal tubule (e.g., proximal tubule) cells, or a pharmaceutical composition for maintaining renal tubule (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 a patient with chronic kidney disease of moderate or greater severity (e.g., a patient with chronic kidney disease at stage G3b or greater) to reduce the concentration of uremic substances (e.g., indoxyl sulfate, hippuric acid, and / or phenylacetyl-L-glutamine) in the patient's blood and promote the excretion of uremic substances (e.g., indoxyl sulfate, p-cresyl sulfate, hippuric acid, argininosuccinic acid, 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 a decrease in energy production in muscle cells, a pharmaceutical composition for inhibiting a decrease in muscle mass and / or muscle strength, or a pharmaceutical composition for treating or preventing a complication of cardiovascular disease (e.g., heart failure, myocardial infarction, stroke, etc.). In one embodiment, the pharmaceutical composition provided by the present invention is administered to a patient with chronic kidney disease of moderate or greater severity (e.g., a patient with chronic kidney disease at stage G3b or greater) to suppress an increase in urinary β2-microglobulin in the patient. In this embodiment, the pharmaceutical composition provided by the present invention may be a composition for suppressing renal tubule (e.g., proximal tubule) damage, a composition for suppressing renal tubule (e.g., proximal tubule) cell damage, a composition for protecting renal tubule (e.g., proximal tubule) cells, or a pharmaceutical composition for maintaining renal tubule (e.g., proximal tubule) cell function (e.g., reabsorption of glucose, amino acids, etc.).

[0052] Examples of other embodiments of the present invention include the following. a) a method for reducing the blood concentration of a uremic substance in a mammalian subject (e.g., a human), the method comprising administering to a subject in need thereof an effective amount of an alkalinizing agent; b) a method for enhancing urinary excretion of uremic substances in a mammalian subject (e.g., a human), comprising administering to a subject in need thereof an effective amount of an alkalinizing agent; c) a method for ameliorating uremic symptoms in a mammalian subject (e.g., a human), comprising administering to a subject in need thereof an effective amount of an alkalinizing agent, wherein the subject is suffering from kidney disease; d) a method for treating or preventing uremia in a mammalian subject (e.g., a human), comprising administering to a subject in need thereof an effective amount of an alkalinizing agent, wherein the subject is suffering from kidney disease; e) a method for inhibiting the progression of chronic kidney disease in a mammalian subject (e.g., a human), comprising administering to a subject in need thereof an effective amount of an alkalinizing agent; f) a method for delaying the onset of dialysis in a mammalian subject (e.g., a human), comprising administering to a subject in need of delayed onset of dialysis an effective amount of an alkalinizing agent, wherein the subject is suffering from chronic kidney disease; g) a method for inhibiting myocardial fibrosis in a mammalian subject (e.g., a human), the method comprising administering to a subject in need thereof an effective amount of an alkalinizing agent, the subject suffering from kidney disease; h) a method for inhibiting arteriosclerosis in a mammalian subject (e.g., a human), comprising administering to a subject in need thereof an effective amount of an alkalinizing agent, wherein the subject is suffering from kidney disease; i) a method for inhibiting vascular smooth muscle cell proliferation in a mammalian subject (e.g., a human), comprising administering to a subject in need thereof an effective amount of an alkalinizing agent, wherein the subject is suffering from kidney disease; j) A method for inhibiting vascular endothelial cell damage in a mammalian subject (e.g., human), comprising administering an effective amount of an alkalinizing agent to a subject in need of inhibiting vascular endothelial cell damage, wherein the subject is suffering from kidney disease; k) a method for inhibiting arterial wall thickening in a mammalian subject (e.g., a human), the method comprising administering to a subject in need thereof an effective amount of an alkalinizing agent, the subject suffering from kidney disease; l) a method for inhibiting aortic calcification in a mammalian subject (e.g., a human), comprising administering to a subject in need thereof an effective amount of an alkalinizing agent, wherein the subject is suffering from kidney disease; m) a method for treating or preventing cardiovascular disease in a mammalian subject (e.g., a human), comprising administering to a subject in need thereof an effective amount of an alkalinizing agent, wherein the subject is suffering from kidney disease; n) a method for ameliorating arteriosclerosis in a mammalian subject (e.g., a human), the method comprising administering to a subject in need thereof an effective amount of an alkalinizing agent, the subject suffering from kidney disease; o) a method for improving arterial wall thickening in a mammalian subject (e.g., a human), comprising administering an effective amount of an alkalinizing agent to a subject in need of improving arterial wall thickening, wherein the subject is suffering from kidney disease; p) a method for treating acute kidney disease in a mammalian subject (e.g., a human), the method comprising administering to a subject in need of treatment for acute kidney disease an effective amount of an alkalinizing agent; q) a method for inhibiting the progression of acute kidney disease to chronic kidney disease in a mammalian subject (e.g., a human), the method comprising administering to a subject in need thereof an effective amount of an alkalinizing agent; r) a method for treating or preventing renal tubular damage in a mammalian subject (e.g., a human), comprising administering to a subject in need thereof an effective amount of an alkalinizing agent; s) a method for inhibiting renal tubular damage in a mammalian subject (e.g., a human), comprising administering to a subject in need thereof an effective amount of an alkalinizing agent; t) A method for inhibiting proximal tubule cell injury in a mammalian subject (e.g., a human), comprising administering to a subject in need thereof an effective amount of an alkalinizing agent; u) a method for protecting renal proximal tubule cells in a mammalian subject (e.g., a human), the method comprising administering to a subject in need thereof an effective amount of an alkalinizing agent; v) a method for maintaining proximal tubule cell function in a mammalian subject (e.g., a human), comprising administering to a subject in need thereof an effective amount of an alkalinizing agent; w) a method for enhancing the excretion of uremic substances from the body in a mammalian subject (e.g., a human), comprising administering to a subject in need thereof an effective amount of an alkalinizing agent; x) a method for excreting a uremic substance into urine depending on the blood concentration of the uremic substance in a mammalian subject (e.g., a human), the method comprising administering an effective amount of an alkalinizing agent to a subject in need of excreting the uremic substance into urine;

[0053] aa) alkalinizing agents for use in reducing blood levels of uremic substances; bb) alkalinizing agents for use in promoting the excretion of uremic substances in the urine; cc) alkalinizing agents for use in improving uremic symptoms in patients with kidney disease; dd) an alkalinizing agent for use in the treatment or prevention of uremia in patients with kidney disease; ee) alkalinizing agents for use in slowing the progression of chronic kidney disease; ff) alkalinizing agents for use in delaying the initiation of dialysis in patients with chronic kidney disease; gg) an alkalinizing agent for use in inhibiting myocardial fibrosis in patients with kidney disease; hh) alkalinizing agents for use in inhibiting arteriosclerosis in patients with kidney disease; ii) an alkalinizing agent for use in inhibiting vascular smooth muscle cell proliferation in patients with kidney disease; jj) an alkalinizing agent for use in inhibiting vascular endothelial cell damage in patients with kidney disease; kk) an alkalizing agent for use in inhibiting arterial wall thickening in patients with kidney disease; ll) an alkalinizing agent for use in inhibiting aortic calcification in patients with kidney disease; mm) alkalinizing agents 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) an alkalinizing agent for use in the treatment of acute kidney disease; qq) Alkalizing agents for use in preventing the progression of acute kidney disease to chronic kidney disease; rr) an alkalinizing agent for use in the treatment or prevention of renal tubular disorders; ss)Alkalizing agents for use in inhibiting renal tubular damage; tt) an alkalinizing agent for use in inhibiting proximal tubule cell injury; uu) Alkalizing agents for use in proximal tubule cell protection; vv) alkalinizing agents for use in maintaining proximal tubule cell function; ww) alkalinizing agents for use in promoting the excretion of uremic substances from the body; xx) Alkalizing agents for use in urinary excretion of uremic substances depending on their blood concentration;

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

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

[0056] 2. Food Composition In one embodiment, the food composition provided by the present invention contains an alkalizing agent and has the effect of promoting 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 and phenylacetyl-L-glutamine, more preferably indoxyl sulfate and phenylacetyl-L-glutamine, even more preferably indoxyl sulfate) from the body. In one embodiment, the food composition provided by the present invention contains an alkalizing agent and has the effect of lowering the blood concentration of uremic substances. In one embodiment, the food composition provided by the present invention contains an alkalizing agent, which has the effect of promoting the excretion of uremic substances into the urine. In one embodiment, the food composition provided by the present invention contains an alkalizing agent and has the effect of maintaining kidney function. In one embodiment, the food composition provided by the present invention contains an alkalizing agent and exhibits the effect of suppressing renal tubule damage, where the renal tubule includes, for example, the proximal tubule. In one embodiment, the food composition provided by the present invention contains an alkalizing agent and exhibits the effect of inhibiting proximal tubule cell damage. In one embodiment, the food composition provided by the present invention comprises an alkalinizing agent, which exerts a protective effect on proximal tubule cells. In one embodiment, the food composition provided by the present invention contains an alkalinizing agent and has the effect of 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.). Here, examples of renal tubules include proximal tubules, and examples of proximal tubular function include reabsorption of glucose, amino acids, vitamins, etc. In the above-mentioned embodiment, the food composition provided by the present invention has the effect of suppressing an increase in the amount (concentration) of β2-microglobulin in urine (for example, early morning urine) that accompanies the progression of the stage of chronic kidney disease. In the above-mentioned embodiment, the food composition provided by the present invention does not affect the glomerular function of patients with chronic kidney disease, while suppressing proximal tubular cell damage that accompanies the progression of chronic kidney disease and protecting proximal tubular cells. The alkalinizing agent may be any of those described in "1. Pharmaceutical Compositions" above. Examples of alkalinizing agents include pharmaceutically acceptable salts of citric acid (e.g., alkali metal citrates or their hydrates, or mixtures thereof) that are acceptable as foodstuffs, and sodium bicarbonate. Preferably, the alkalinizing agent is a mixture of potassium citrate monohydrate (C6H5K3O7·H2O) and sodium citrate dihydrate (C6H5Na3O7·2H2O), or sodium citrate dihydrate. The uremic substances are also as described above in "1. Pharmaceutical Compositions." 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 determined appropriately 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 achieve the above-mentioned effect and are in a form that can be taken orally. They may be in the form of ordinary food or beverages, or they may be provided as formulations suitable for oral administration, such as tablets, capsules, suspensions, etc., that can be used in the pharmaceutical compositions. The composition and production methods of these formulations can be directly applied to the pharmaceutical formulations described in "1. Pharmaceutical Compositions" above, or formulation techniques known per se in the field of pharmaceutical formulation technology can be applied. For example, in the case of a food for specified health uses, a dietary supplement, a functional food, or a food for hospital patients, a single serving of food may contain a total of 1 to 3 g (1 / 3) of potassium citrate monohydrate and sodium citrate dihydrate as an alkalizing agent, or a single serving of food may contain 1 to 6 g (1 / 3) of sodium bicarbonate as an alkalizing agent. When a food for specified health uses, a dietary supplement, a functional food, a food for hospital patients, or a supplement is provided as a tablet, for example, a single tablet of 300 mg to 600 mg may contain 70 to 80 wt% of an alkalizing agent. When the food composition provided by the present invention is not formulated but is provided in the form of a normal food or beverage, it can be prepared appropriately by a person skilled in the art depending on the type of food, for example, by blending an alkalizing agent (e.g., potassium citrate and / or sodium citrate) with the food material. Examples of the form of the food and drink include liquid, milky, or paste-like foods such as beverages, soy sauce, milk, yogurt, and miso; semi-solid foods such as jelly and gummies; solid foods such as candy, gum, tofu, and supplements; and powdered foods. Examples of beverages include fruit juices, coffee drinks, oolong tea drinks, green tea drinks, black tea drinks, barley tea drinks, vegetable drinks, carbonated soft drinks, drinks containing fruit extracts, juices containing vegetable extracts, near-water, sports drinks, and diet drinks. The beverage may contain additives such as antioxidants, flavorings, various esters, organic acids, organic acid salts, inorganic acids, inorganic acid salts, inorganic salts, colorants, emulsifiers, preservatives, seasonings, sweeteners, acidulants, fruit juice extracts, vegetable extracts, nectar extracts, pH adjusters, and quality stabilizers, either alone or in combination. The food compositions provided by the present invention can be used in the same manner as pharmaceutical compositions described above under "1. Pharmaceutical Compositions." They can also be used for purposes other than the treatment or prevention of disease. That is, the food compositions can be applied to subjects to which the pharmaceutical composition is applied so that the amount of alkalinizing agent used in the food composition is the same as the amount of alkalinizing agent contained in the pharmaceutical composition. In one embodiment, the "food compositions" of the present invention can be applied to subjects (e.g., humans or other mammals) who do not have any "pathological" or "abnormal" symptoms, conditions, or diseases, i.e., subjects in a "healthy" or "normal" state (e.g., humans or other mammals), to maintain or promote a "healthy" or "normal" state. Furthermore, they can be applied to "healthy individuals concerned about kidney health" or "healthy individuals concerned about renal tubular health" to maintain or promote a "healthy" or "normal" state. In this case, whether the alkalinizing agent is a component of a pharmaceutical composition or a food composition, the pharmacological effect of the alkalinizing agent itself is basically the same, so the amount and method of application of the food composition can be adjusted appropriately based on the alkalinizing agent depending on the expected effect. Food compositions that are applied to subjects (e.g., humans or other mammals) that do not have any "pathological" or "abnormal" symptoms, conditions, or diseases, i.e., subjects (e.g., humans or other mammals) that are in a "healthy" or "normal" state, in order to maintain or promote the "healthy" or "normal" state, may be specifically referred to as "functional foods." The term "administration" described in "1. Pharmaceutical composition" above can also be applied to the "food composition" of the present invention, and furthermore, with regard to the "food composition" of the present invention, the term "administration" can be read as "ingestion." Therefore, for example, the terms "administer" and "administered" can be read as "ingested," "taken," "ingested," etc., depending on the context. Therefore, the food composition according to the present invention may be embodied as follows: <1> A food composition for reducing blood levels of uremic substances, comprising an alkalizing agent; <2> a food composition for promoting urinary excretion of uremic substances, comprising an alkalizing agent; <3> A food composition for maintaining kidney function, comprising an alkalizing agent; <4> A food composition for inhibiting renal tubular damage, comprising an alkalizing agent; <5> a food composition for inhibiting renal tubular cell damage, preferably for inhibiting proximal renal tubular cell damage, comprising an alkalizing agent; <6> a food composition for protecting renal tubular cells, preferably for protecting proximal renal tubular cells, comprising an alkalizing agent; <7> a food composition for maintaining renal tubule 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 renal tubule function (e.g., reabsorption of glucose, amino acids, vitamins, etc.), comprising an alkalinizing agent; <11> A method for reducing blood levels of uremic substances, comprising having a subject in need of a reduction in blood levels of uremic substances ingest a food composition containing an effective amount of an alkalizing agent; <22> A method for promoting urinary excretion of uremic substances, comprising having a subject in need of promotion of urinary excretion of uremic substances ingest a food composition containing an effective amount of an alkalizing agent; <33> A method for maintaining renal function, comprising having a subject in need of maintaining renal function ingest a food composition containing an effective amount of an alkalizing agent; <44> A method for suppressing renal tubular damage, comprising having a subject in need of suppression of renal tubular damage ingest a food composition containing an effective amount of an alkalizing agent; <55> A method for suppressing damage to renal tubular cells, preferably proximal tubular cells, comprising having a subject in need of suppression of damage to renal tubular cells, preferably proximal tubular cells, ingest a food composition containing an effective amount of an alkalizing agent; <66> A method for protecting renal tubular cells, preferably proximal tubular cells, comprising administering to a subject in need of protection of renal tubular cells, preferably proximal tubular cells, a food composition comprising an effective amount of an alkalizing agent; <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 having a subject in need of maintaining renal tubular function, preferably proximal tubular function, ingest a food composition containing an effective amount of an alkalinizing agent; <111> A food composition containing an alkalizing agent for reducing blood levels of uremic substances; <222> A food composition containing an alkalizing agent for promoting urinary excretion of uremic substances; <333> A food composition containing an alkalizing agent for maintaining kidney function; <444> A food composition containing an alkalizing agent for inhibiting renal tubular damage; <555> A food composition containing an alkalizing agent for inhibiting damage to renal tubular cells, preferably proximal tubular cells; <666> a food composition comprising an alkalizing agent for protecting renal tubular cells, preferably proximal tubular cells; <777> A food composition comprising an alkalinizing 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 renal tubular function (e.g., reabsorption of glucose, amino acids, vitamins, etc.); <1111> Use of an alkalizing agent for producing a food composition for reducing blood levels of uremic substances; <2222> Use of an alkalizing agent for producing a food composition for promoting urinary excretion of uremic substances; <3333> Use of an alkalizing agent for producing a food composition for maintaining kidney function; <4444> Use of an alkalizing agent for producing a food composition 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 an alkalizing agent for producing a food composition for protecting renal tubular cells, preferably proximal renal 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 renal tubular function (e.g., reabsorption of glucose, amino acids, vitamins, etc.). It is preferable that the packaging, container, or instructions for the food composition of the present invention display effects such as reducing blood concentrations of uremic substances, promoting urinary excretion of uremic substances, maintaining renal function, inhibiting tubular damage, inhibiting tubular cell damage, inhibiting 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" of the present invention is ingested by a subject (e.g., a human or other mammal) with a urinary β2-microglobulin concentration of 290 μg / L or less, preferably 50 to 150 μg / L. In one embodiment, the "food composition" of the present invention is taken by a subject (eg, a human or other mammal) with a blood cystatin C concentration of 0.5 to 2.2 mg / L, preferably 1.0 to 1.3 mg / L. In one embodiment, ingestion of the "food composition" according to the present invention suppresses an increase in urinary β2-microglobulin concentration. In one embodiment, ingestion of the "food composition" according to the present invention suppresses an increase in urinary β2-microglobulin concentration 12 weeks after administration. In one embodiment, ingestion of the "food composition" according to the present invention does not substantially reduce the concentration of β2-microglobulin in urine compared to before the start of administration. In one embodiment, intake of the "food composition" according to the present invention does not substantially reduce the concentration of β2-microglobulin in urine 12 weeks after administration compared to before the start of administration. In one embodiment, ingestion of the "food composition" according to the present invention does not substantially increase blood cystatin C levels compared to levels before the start of administration. In one embodiment, ingestion of the "food composition" according to the present invention does not substantially increase blood cystatin C levels compared to levels before the start of administration. In one embodiment, ingestion of the "food composition" according to the present invention suppresses the increase in the amount of β2-microglobulin in early morning urine that accompanies the progression of the stage of chronic kidney disease. In one embodiment, ingestion of the "food composition" of the present invention does not affect glomerular function in patients with chronic kidney disease, while suppressing proximal tubule cell damage that accompanies the progression of chronic kidney disease and protecting proximal tubule cells.

[0057] 3. Methods for determining the decrease in the concentration of uremic substances in the blood In one embodiment, the present invention provides a method for determining a decrease in the concentration of a uremic substance (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) in the blood of a chronic kidney disease patient, 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 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 of a patient 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, but these methods require specialized and expensive reagents. As described herein, administration of an alkalinizing agent reduces blood uremic substances (e.g., indoxyl sulfate concentration, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and / or argininosuccinic acid) and promotes urinary excretion of these uremic substances. Therefore, by measuring the pH of their urine, patients with chronic kidney disease can easily and inexpensively determine whether they have reduced blood uremic substances (e.g., indoxyl sulfate concentration, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and / or argininosuccinic acid) and / or promoted urinary excretion of uremic substances (e.g., indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and / or argininosuccinic acid). pH can be measured using well-known techniques, such as pH test paper, a pH test solution, or a simple pH meter. In one embodiment, a chronic kidney disease patient measures the pH of early morning urine (the first urine after waking up) over time from the start of administration of an alkalinizing agent (e.g., a mixture of potassium citrate monohydrate and sodium citrate dihydrate, or sodium citrate dihydrate), and if the urine pH increases, it is considered that the patient has a high level of uremic toxins in the blood (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, p-cresyl sulfate, ... It can be easily determined whether a decrease 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, p-cresyl 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 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. In one embodiment, a chronic kidney disease patient measures the pH of early morning urine (the first urine after waking up) after taking an alkalinizing agent (e.g., a mixture of potassium citrate monohydrate and sodium citrate dihydrate, or sodium citrate dihydrate), and if the urine pH is in the range of 5.2 to 6.8 (e.g., pH 5.5 to 6.8, pH 5.8 to 6.8, pH 5.8 to 6.5, pH 5.8 to 6.2, pH 5.8 or higher but lower than pH 6.2, pH 6.0 to 6.5, pH 6.0 to 6.4, pH 6.0 to 6.3, pH 6.0 to 6.2, pH 6.0 or higher but lower than pH 6.2, pH 6.1 to 6.3, pH 6.2 to 6.8, pH 6.2 to 6.5, or pH 6.5 to 6.8), the patient is diagnosed with a high level of uremic toxins (e.g., indoxaliplatin) in the blood. It can be easily determined whether a decrease 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 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. The determination of whether or not a reduction in the concentration of uremic substances (e.g., indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and / or argininosuccinic acid) in the blood and / or promotion of excretion of uremic substances (e.g., indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and / or argininosuccinic acid) into the urine has been achieved can aid in diagnosing whether or not the progression of chronic kidney disease has been suppressed. Thus, in one embodiment, the present invention provides a method for determining whether progression of chronic kidney disease has been inhibited, the method comprising measuring the pH of urine (e.g., early morning urine) from a patient to whom an alkalinizing agent (e.g., a mixture of potassium citrate monohydrate and sodium citrate dihydrate, or sodium citrate dihydrate) has been administered. Observing an increase in urine pH over time or a urine pH in the range of 5.8 to 6.8 (e.g., a urine pH in the range of 6.0 to 6.2) can aid in the diagnosis of inhibition of progression of chronic kidney disease.

[0058] In one embodiment, the pharmaceutical composition provided by the present invention comprises an alkalinizing agent for use in reducing blood concentrations of uremic substances, and the alkalinizing agents are potassium citrate monohydrate and sodium citrate dihydrate, each administered orally at 0.5 to 1.5 g / day, for a total 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 comprising an alkalinizing agent for use in reducing blood concentrations of uremic substances, wherein one dosage unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and is orally administered at a dose of 3 to 6 dosage units per day, three times a day.

[0059] In one embodiment, the pharmaceutical composition provided by the present invention comprises an alkalinizing agent for use in promoting the excretion of uremic substances into urine, and the alkalinizing agents are potassium citrate monohydrate and sodium citrate dihydrate, each of which is orally administered at 0.5 to 1.5 g / day, for a total 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 comprises an alkalinizing agent for use in promoting the excretion of uremic substances into urine, wherein one dosage unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and 3 to 6 dosage units are orally administered three times a day.

[0060] In one embodiment, the pharmaceutical composition provided by the present invention comprises an alkalinizing agent for use in improving uremic symptoms in patients with kidney disease, and the alkalinizing agents are potassium citrate monohydrate and sodium citrate dihydrate, each administered orally at 0.5 to 1.5 g / day, for a total 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 comprising an alkalinizing agent for use in improving uremic symptoms in patients with kidney disease, wherein one dosage unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and 3 to 6 dosage units are orally administered three times a day.

[0061] In one embodiment, the pharmaceutical composition provided by the present invention comprises an alkalinizing agent for use in the treatment or prevention of uremia in patients with kidney disease, and the alkalinizing agents are potassium citrate monohydrate and sodium citrate dihydrate, each administered orally at 0.5 to 1.5 g / day, for a total 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 comprising an alkalinizing agent for use in the treatment or prevention of uremia in patients with kidney disease, wherein one dosage unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and 3 to 6 dosage units are orally administered three times a day.

[0062] In one embodiment, the pharmaceutical composition provided by the present invention comprises an alkalinizing agent for use in suppressing the progression of chronic kidney disease, and the alkalinizing agents are potassium citrate monohydrate and sodium citrate dihydrate, each administered orally at 0.5 to 1.5 g / day, for a total 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 comprising an alkalinizing agent for use in suppressing the progression of chronic kidney disease, wherein one dosage unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and is orally administered at a dose of 3 to 6 dosage units per day, three times a day.

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

[0064] In one embodiment, the pharmaceutical composition provided by the present invention comprises an alkalinizing agent for use in suppressing myocardial fibrosis in patients with kidney disease, and the alkalinizing agents are potassium citrate monohydrate and sodium citrate dihydrate, each administered orally at 0.5 to 1.5 g / day, for a total 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 comprising an alkalinizing agent for use in inhibiting myocardial fibrosis in patients with kidney disease, wherein one dosage unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and 3 to 6 dosage units are orally administered three times a day.

[0065] In one embodiment, the pharmaceutical composition provided by the present invention comprises an alkalinizing agent for use in inhibiting arteriosclerosis in patients with kidney disease, and the alkalinizing agents are potassium citrate monohydrate and sodium citrate dihydrate, each administered orally at 0.5 to 1.5 g / day, for a total 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 comprising an alkalinizing agent for use in inhibiting arteriosclerosis in patients with kidney disease, wherein one dosage unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and 3 to 6 dosage units are orally administered three times a day.

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

[0067] In one embodiment, the pharmaceutical composition provided by the present invention comprises an alkalinizing agent for use in inhibiting vascular endothelial cell damage in patients with kidney disease, and the alkalinizing agents are potassium citrate monohydrate and sodium citrate dihydrate, each administered orally at 0.5 to 1.5 g / day, for a total 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 comprising an alkalinizing agent for use in inhibiting vascular endothelial cell damage in patients with kidney disease, wherein one dosage unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and 3 to 6 dosage units are orally administered three times a day.

[0068] In one embodiment, the pharmaceutical composition provided by the present invention comprises an alkalinizing agent for use in inhibiting arterial wall thickening in patients with kidney disease, and the alkalinizing agents are potassium citrate monohydrate and sodium citrate dihydrate, each administered orally at 0.5 to 1.5 g / day, for a total 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 comprising an alkalinizing agent for use in inhibiting arterial wall thickening in patients with kidney disease, wherein one dosage unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and 3 to 6 dosage units are orally administered three times a day.

[0069] In one embodiment, the pharmaceutical composition provided by the present invention comprises an alkalinizing agent for use in inhibiting aortic calcification in patients with kidney disease, and the alkalinizing agents are potassium citrate monohydrate and sodium citrate dihydrate, each administered orally at 0.5 to 1.5 g / day, for a total 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 comprising an alkalinizing agent for use in inhibiting aortic calcification in patients with kidney disease, wherein one dosage unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and 3 to 6 dosage units are orally administered three times a day.

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

[0071] In one embodiment, the pharmaceutical composition provided by the present invention comprises an alkalinizing agent for use in improving arteriosclerosis in patients with kidney disease, and the alkalinizing agents are potassium citrate monohydrate and sodium citrate dihydrate, each administered orally at 0.5 to 1.5 g / day, for a total 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 comprising an alkalinizing agent for use in improving arteriosclerosis in patients with kidney disease, wherein one dosage unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and 3 to 6 dosage units are orally administered three times a day.

[0072] In one embodiment, the pharmaceutical composition provided by the present invention comprises an alkalinizing agent for use in improving arterial wall thickening in patients with kidney disease, and the alkalinizing agents are potassium citrate monohydrate and sodium citrate dihydrate, each administered orally at 0.5 to 1.5 g / day, for a total 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 comprising an alkalinizing agent for use in improving arterial wall thickening in patients with kidney disease, wherein one dosage unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and 3 to 6 dosage units are orally administered three times a day.

[0073] In one embodiment, the pharmaceutical composition provided by the present invention comprises an alkalinizing agent for use in the treatment of acute kidney disease, and the alkalinizing agents are potassium citrate monohydrate and sodium citrate dihydrate, each administered orally at 0.5 to 1.5 g / day, for a total of 1 to 3 g / day, 1 to 5 times a day, preferably 3 times a day. In one embodiment, the present invention provides a pharmaceutical composition comprising an alkalinizing agent for use in the treatment of acute kidney disease, wherein one dosage unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and 3 to 6 dosage units are orally administered three times a day.

[0074] In one embodiment, the pharmaceutical composition provided by the present invention comprises an alkalinizing agent for use in suppressing progression from acute kidney disease to chronic kidney disease, and the alkalinizing agents are potassium citrate monohydrate and sodium citrate dihydrate, each administered orally at 0.5 to 1.5 g / day, for a total 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 comprising an alkalinizing agent for use in inhibiting progression from acute kidney disease to chronic kidney disease, wherein one dosage unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and 3 to 6 dosage units are orally administered three times a day.

[0075] In one embodiment, the pharmaceutical composition provided by the present invention comprises an alkalinizing agent for use in the treatment or prevention of renal tubular damage, and the alkalinizing agents are potassium citrate monohydrate and sodium citrate dihydrate, each of which is orally administered at 0.5 to 1.5 g / day, for a total 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 comprising an alkalinizing agent for use in the treatment or prevention of renal tubular damage, wherein one dosage unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and is orally administered at a dose of 3 to 6 dosage units per day, three times a day.

[0076] In one embodiment, the pharmaceutical composition provided by the present invention comprises an alkalinizing agent for use in suppressing renal tubular damage, and the alkalinizing agents are potassium citrate monohydrate and sodium citrate dihydrate, each of which is orally administered at 0.5 to 1.5 g / day, for a total 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 comprising an alkalinizing agent for use in suppressing renal tubular damage, wherein one dosage unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and is orally administered at a dose of 3 to 6 dosage units per day, three times a day.

[0077] In one embodiment, the pharmaceutical composition provided by the present invention comprises an alkalinizing agent for use in suppressing proximal tubule cell damage, and the alkalinizing agents are potassium citrate monohydrate and sodium citrate dihydrate, each administered orally at 0.5 to 1.5 g / day, for a total 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 comprising an alkalinizing agent for use in suppressing proximal tubule cell damage, wherein one dosage unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and 3 to 6 dosage units are orally administered three times a day.

[0078] In one embodiment, the pharmaceutical composition provided by the present invention comprises an alkalinizing agent for use in protecting proximal tubule cells, and the alkalinizing agents are potassium citrate monohydrate and sodium citrate dihydrate, each administered orally at 0.5 to 1.5 g / day, for a total 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 comprising an alkalinizing agent for use in proximal tubule cell protection, wherein one dosage unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and is orally administered at a dose of 3 to 6 dosage units per day, three times a day.

[0079] In one embodiment, the pharmaceutical composition provided by the present invention comprises an alkalinizing agent for use in maintaining proximal tubule cell function, and the alkalinizing agents are potassium citrate monohydrate and sodium citrate dihydrate, each administered orally at 0.5 to 1.5 g / day, for a total 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 comprising an alkalinizing agent for use in maintaining proximal tubule cell function, wherein one dosage unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and is orally administered at a dose of 3 to 6 dosage units per day, three times a day.

[0080] In one embodiment, the pharmaceutical composition provided by the present invention comprises an alkalinizing agent for use in promoting the excretion of uremic substances from the body, and the alkalinizing agents are potassium citrate monohydrate and sodium citrate dihydrate, each administered orally at 0.5 to 1.5 g / day, for a total 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 alkalinizing agent for use in promoting the excretion of uremic substances from the body, wherein one dosage unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and 3 to 6 dosage units are orally administered three times a day.

[0081] In one embodiment, the pharmaceutical composition provided by the present invention comprises an alkalinizing agent for use in excreting uremic substances into urine depending on their blood concentration, and the alkalinizing agents are potassium citrate monohydrate and sodium citrate dihydrate, each administered orally at 0.5 to 1.5 g / day, for a total 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 comprises an alkalinizing agent for use in excreting uremic substances into urine depending on their blood concentration, and one dosage unit (preferably one tablet) contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and is orally administered at a dose of 3 to 6 dosage units per day, three times a day.

[0082] In one embodiment, the pharmaceutical composition provided by the present invention comprises an alkalinizing agent for use in reducing blood concentrations of uremic substances, and the alkalinizing agent is sodium bicarbonate, which is orally administered 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 comprising an alkalinizing agent for use in reducing blood levels of uremic substances, wherein one dosage unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dosage units are orally administered three times a day.

[0083] In one embodiment, the pharmaceutical composition provided by the present invention comprises an alkalinizing agent for use in promoting urinary excretion of uremic substances, and the alkalinizing agent is sodium bicarbonate, which is orally administered 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 comprises an alkalinizing agent for use in promoting the excretion of uremic substances into urine, wherein one dosage unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dosage units are orally administered three times a day.

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

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

[0086] In one embodiment, the pharmaceutical composition provided by the present invention comprises an alkalinizing agent for use in suppressing the progression of chronic kidney disease, and the alkalinizing agent is sodium bicarbonate, which is orally administered 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 comprising an alkalinizing agent for use in inhibiting the progression of chronic kidney disease, wherein one dosage unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dosage units are orally administered three times a day.

[0087] In one embodiment, the pharmaceutical composition provided by the present invention comprises an alkalinizing agent for use in delaying the initiation of dialysis in patients with chronic kidney disease, wherein the alkalinizing agent is sodium bicarbonate, which is orally administered 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 comprising an alkalinizing agent for use in delaying the initiation of dialysis in patients with chronic kidney disease, wherein one dosage unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dosage units are orally administered three times a day.

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

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

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

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

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

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

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

[0095] In one embodiment, the pharmaceutical composition provided by the present invention comprises an alkalinizing agent for use in improving arteriosclerosis in patients with kidney disease, and the alkalinizing agent is sodium bicarbonate, which is orally administered 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 comprising an alkalinizing agent for use in improving arteriosclerosis in patients with kidney disease, wherein one dosage unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dosage units are orally administered three times a day.

[0096] In one embodiment, the pharmaceutical composition provided by the present invention comprises an alkalinizing agent for use in improving arterial wall thickening in patients with kidney disease, and the alkalinizing agent is sodium bicarbonate, which is orally administered 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 comprising an alkalinizing agent for use in improving arterial wall thickening in patients with kidney disease, wherein one dosage unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dosage units are orally administered three times a day.

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

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

[0099] In one embodiment, the pharmaceutical composition provided by the present invention comprises an alkalinizing agent for use in the treatment or prevention of renal tubular damage, and the alkalinizing agent is sodium bicarbonate, which is orally administered 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 comprising an alkalinizing agent for use in the treatment or prevention of renal tubular damage, wherein one dosage unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dosage units are orally administered three times a day.

[0100] In one embodiment, the pharmaceutical composition provided by the present invention comprises an alkalinizing agent for use in suppressing renal tubular damage, and the alkalinizing agent is sodium bicarbonate, which is orally administered 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 comprising an alkalinizing agent for use in suppressing renal tubular damage, wherein one dosage unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dosage units are orally administered three times a day.

[0101] In one embodiment, the pharmaceutical composition provided by the present invention comprises an alkalinizing agent for use in suppressing proximal tubule cell injury, and the alkalinizing agent is sodium bicarbonate, which is orally administered 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 comprising an alkalinizing agent for use in inhibiting proximal tubule cell injury, wherein one dosage unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dosage units are orally administered three times a day.

[0102] In one embodiment, the pharmaceutical composition provided by the present invention comprises an alkalinizing agent for use in protecting proximal tubule cells, and the alkalinizing agent is sodium bicarbonate, which is orally administered 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 comprising an alkalinizing agent for use in proximal tubule cell protection, wherein one dosage unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dosage units are orally administered three times a day.

[0103] In one embodiment, the pharmaceutical composition provided by the present invention comprises an alkalinizing agent for use in maintaining proximal tubule cell function, and the alkalinizing agent is sodium bicarbonate, which is orally administered 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 comprising an alkalinizing agent for use in maintaining proximal tubule cell function, wherein one dosage unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dosage units are orally administered three times a day.

[0104] In one embodiment, the pharmaceutical composition provided by the present invention comprises an alkalinizing agent for use in promoting the excretion of uremic substances from the body, and the alkalinizing agent is sodium bicarbonate, which is orally administered 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 alkalinizing agent for use in promoting the excretion of uremic substances from the body, wherein one dosage unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and 3 to 6 dosage units are orally administered three times a day.

[0105] In one embodiment, the pharmaceutical composition provided by the present invention comprises an alkalinizing agent for use in excreting uremic substances into urine depending on their blood concentration, and the alkalinizing agent is sodium bicarbonate, which is orally administered 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 comprises an alkalinizing agent for use in excreting uremic substances into urine depending on their blood concentration, and one dosage unit (preferably one tablet) contains 500 mg of sodium bicarbonate, and three to six dosage units are orally administered three times a day.

[0106] The present invention will be further explained below with reference to examples, but the present invention is not limited to these examples. [Example]

[0107] A human clinical trial was conducted to investigate whether oral administration of potassium citrate-sodium citrate hydrate compound preparations and sodium bicarbonate preparations, which are oral alkalinizing agents, promotes urinary excretion of uremic substances.

[0108] 1. Method Patients with stage G2-G3b chronic kidney disease (eGFR: 30-89 ml / min / 1.73m 2 Forty-seven patients were randomly divided into a potassium citrate and sodium citrate hydrate compound group (Group A: 16 patients), a baking soda (sodium bicarbonate) compound group (Group B: 16 patients), and a control group (Group C: 15 patients). Patients were assigned to each group so that they were balanced in terms of age, gender, presence or absence of diabetes, and eGFR. Each group received treatment based on the "CKD Clinical Practice Guide - Treatment Summary" (hereinafter referred to as standard treatment). The control group received no alkalinizing agents. Group A received three tablets containing 231.5 mg of potassium citrate (C6H5K3O7·H2O) and 195.0 mg of sodium citrate hydrate (C6H5Na3O7·2H2O) orally three times daily (morning, noon, and evening) for 24 weeks. The pH of early morning urine was monitored over time, and if the pH of the early morning urine was below 6.5, the physician's discretion allowed the dosage to be increased to six tablets three times daily (morning, noon, and evening). Group B received three tablets containing 500 mg of sodium bicarbonate orally three times daily (morning, noon, and evening) for 24 weeks. The pH of early morning urine was monitored over time, and if the pH of the early morning urine was below 6.5, the physician's discretion allowed the dosage to be increased to six tablets three times daily (morning, noon, and evening). Early morning urine and blood samples were collected before the start of treatment and at 6, 12, and 24 weeks after the start of treatment, and each sample was stored at -80°C. Urine and plasma indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid, and argininosuccinic acid were quantitatively analyzed using a liquid chromatography triple quadrupole mass spectrometer (LC-MS / MS) according to methods used in the 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). LC was performed using NANOSPACE SI-2 (Shiseido) and CAPCELLPAK MGIII was selected as the analytical column. MS was performed using a TSQ Quantiva (Thermo Fisher Scientific) with five compounds ionized in negative in-mode and detected using selected reaction monitoring. Quantitative values ​​were calculated using a calibration curve prepared using standard solutions of each compound. Urinary β2-microglobulin levels were measured by latex agglutination immunoassay using LZ Test 'Eiken' β2-M and LZ-β2-M Standard U 'Eiken' (Eiken Chemical, Tokyo, Japan). Serum cystatin C levels were measured by gold colloid agglutination assay using Nescort GC Cystatin C (Nm) (Alfresa Pharma, Osaka, Japan). Statistical analysis was performed using the Mann-Whitney test for between-group comparisons, the Wilcoxon test for comparisons of time-course changes, and the Pearson test for correlations.

[0109] 2.Results From the results of measurements using LC-MS / MS, the following was calculated for each patient in Group A (potassium citrate-sodium citrate hydrate compounded preparation group), Group B (sodium bicarbonate preparation group), and Group C (control group): (i) Plasma concentration of each uremic substance before administration (ii) Concentration of each uremic substance in early morning urine before the start of administration (iii) The ratio of the concentration of uremic toxins in early morning urine to the concentration of uremic toxins in plasma before the start of administration (amount of uremic toxins in urine / amount of uremic toxins in plasma) (iv) Plasma concentrations of each uremic toxin at 6, 12, and 24 weeks after the start of administration (v) Concentrations of each uremic substance in early morning urine at 6, 12, and 24 weeks after the start of administration (vi) The ratio of uremic toxin concentration in early morning urine to plasma (amount of uremic toxin in urine / amount of uremic toxin in plasma) at 6, 12, and 24 weeks after the start of administration. (vii) Changes in plasma concentrations of each uremic substance from pre-treatment levels 6, 12, and 24 weeks after the start of administration (viii) Changes in the concentration of each uremic substance in early morning urine from pre-treatment levels at 6, 12, and 24 weeks after the start of treatment (ix) Changes in the ratio of uremic toxin concentrations in early morning urine to plasma (amount of uremic toxins in urine / amount of uremic toxins in plasma) from before the start of administration at 6, 12, and 24 weeks after the start of administration The mean and SD of each group were calculated for (i) to (ix) above. For each of (iv) to (ix) above, the mean and SD of each group were calculated for all data from 6, 12, and 24 weeks after the start of administration in each group. The results are shown in the table below. In the tables and figures, Group A (the group administered the potassium citrate and sodium citrate hydrate formulation) is referred to as "Citrate," and Group B (the group administered the sodium bicarbonate formulation) is referred to as "Bicarbonate." The numbers in parentheses in the tables indicate the number of cases. Table 1-1-1: Plasma indoxyl sulfate (ng / mL) Table 1-1-2: Changes in plasma indoxyl sulfate from before administration (ng / mL) Table 1-2-1: Amount of indoxyl sulfate in early morning urine (ng / mL) Table 1-2-2: Changes in early morning urine indoxyl sulfate from before administration (ng / mL) Table 1-3-1: Ratio of indoxyl sulfate in urine to indoxyl sulfate in plasma Table 1-3-2: Changes in the ratio of indoxyl sulfate in urine to indoxyl sulfate in plasma from before the start of administration. Table 2-1-1: Plasma p-cresyl sulfate (ng / mL) Table 2-1-2: Changes in plasma p-cresyl sulfate from before administration (ng / mL) Table 2-2-1: Amount of p-cresyl sulfate in early morning urine (ng / mL) Table 2-2-2: Changes in p-cresyl sulfate in early morning urine from before administration (ng / mL) Table 2-3-1: Ratio of p-cresyl sulfate in urine to p-cresyl sulfate in plasma Table 2-3-2: Changes in the ratio of p-cresyl sulfate in urine to p-cresyl sulfate in plasma from before the start of administration. Table 3-1-1: Hippuric acid content in plasma (ng / mL) Table 3-1-2: Change in plasma hippuric acid from before administration (ng / mL) Table 3-2-1: Hippuric acid content in early morning urine (ng / mL) Table 3-2-2: Change in hippuric acid in early morning urine from before the start of administration (ng / mL) Table 3-3-1: Ratio of hippuric acid in urine to hippuric acid in plasma Table 3-3-2: Changes in the ratio of hippuric acid in urine to hippuric acid in plasma from before the start of administration Table 4-1-1: Plasma argininosuccinic acid content (ng / mL) Table 4-1-2: Changes in plasma argininosuccinic acid from before administration (ng / mL) Table 4-2-1: Amount of argininosuccinic acid in early morning urine (ng / mL) Table 4-2-2: Change in argininosuccinic acid in early morning urine from before administration (ng / mL) Table 4-3-1: Ratio of argininosuccinic acid in urine to that in plasma Table 4-3-2: Changes in the ratio of argininosuccinic acid in urine to 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: Changes in plasma phenylacetyl-L-glutamine (PAG) levels from before administration (ng / mL) Table 5-2-1: Phenylethysmidine-L-glutamine (PAG) levels in early morning urine (ng / mL) Table 5-2-2: Changes in phenylacetyl-L-glutamine (PAG) in early morning urine from before the start of administration (ng / mL) Table 5-3-1: Ratio of phenylacetyl-L-glutamine (PAG) amount in urine to that in plasma Table 5-3-2: Change in the ratio of phenylacetyl-L-glutamine (PAG) levels in urine to those in plasma from before the start of administration.

[0110] Group A (treated with a citrate (potassium citrate and sodium citrate hydrate) formulation) had lower plasma indoxyl sulfate concentrations at 6, 12, and 24 weeks of administration compared with Group B (treated with a bicarbonate (sodium bicarbonate) formulation) and Group C (control) (see Table 1-1-1). Furthermore, Group A had higher indoxyl sulfate (IS) concentrations in early morning urine at 12 and 24 weeks of administration compared with Group C (see Table 1-2-1). Plasma indoxyl sulfate concentrations from 6 to 24 weeks were significantly lower in Group A compared with Groups B and C (see Table 1-1-1), and the increase in indoxyl sulfate concentrations in early morning urine from 6 to 24 weeks was significantly greater in Group A compared with Groups B and C (see Table 1-2-2). Furthermore, when a potassium citrate-sodium citrate hydrate formulation was administered to patients with chronic kidney disease, the urinary concentration of the uremic toxin indoxyl sulfate increased compared to before administration, and the blood concentration of indoxyl sulfate decreased compared to before administration. Although sodium bicarbonate is also an alkalizing agent, this effect was not observed. Compared to sodium bicarbonate, the potassium citrate-sodium citrate hydrate formulation exhibited a greater effect in lowering blood indoxyl sulfate concentrations and increasing urinary indoxyl sulfate concentrations. The effects of the potassium citrate-sodium citrate hydrate formulation in lowering blood indoxyl sulfate concentrations and increasing urinary indoxyl sulfate concentrations were observed from 12 weeks after administration. The ratio of indoxyl sulfate concentration in urine to that in plasma showed that administration of potassium citrate and sodium citrate hydrate preparations promoted the excretion of indoxyl sulfate from the blood into urine, thereby promoting its excretion from the body. The excretion effect of indoxyl sulfate from the blood into urine was observed with the administration of potassium citrate and sodium citrate hydrate preparations, but not with the administration of sodium bicarbonate preparations (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), Group A (administered a citrate: potassium citrate and sodium citrate hydrate formulation) had higher p-cresyl sulfate concentrations in early morning urine after 12 and 24 weeks of administration compared to Group C (control group), and Group A (administered a potassium citrate and sodium citrate hydrate formulation) had higher p-cresyl sulfate concentrations in early morning urine after 6, 12, and 24 weeks of administration compared to Group B (administered a bicarbonate: sodium bicarbonate formulation) (see Table 2-2-1). An increase in p-cresyl sulfate concentrations in early morning urine from 6 to 24 weeks was only observed in Group A (see Table 2-2-2). Furthermore, when a potassium citrate-sodium citrate hydrate compound was administered to patients with chronic kidney disease, the urinary concentration of p-cresyl sulfate, a uremic substance, increased compared to before administration (see Tables 2-2-1 and 2-2-2). Although both are alkalinizing agents, sodium bicarbonate preparations did not show this effect, and the potassium citrate-sodium citrate hydrate compound had a stronger effect of increasing urinary p-cresyl sulfate concentrations than sodium bicarbonate preparations. The effect of the potassium citrate-sodium citrate hydrate compound on increasing urinary p-cresyl sulfate concentrations was observed from 12 weeks after administration. On the other hand, administration of the sodium bicarbonate preparation reduced the plasma concentration of p-cresyl sulfate, a uremic toxin, compared to before administration (see Table 2-1-2). This effect of lowering the plasma concentration of p-cresyl sulfate was more pronounced in Group B than in Groups A and C (see Table 2-1-2). The ratio of p-cresyl sulfate concentrations in urine to those in plasma suggests that administration of a potassium citrate-sodium citrate hydrate formulation promotes the excretion of p-cresyl sulfate from the blood into urine, thereby promoting its excretion from the body. Furthermore, it was shown that the excretion effect of p-cresyl sulfate from the blood into urine was stronger with administration of a potassium citrate-sodium citrate hydrate formulation than with administration of 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 (administered a citrate: potassium citrate and sodium citrate hydrate formulation) had lower plasma hippuric acid concentrations after 24 weeks of administration compared to Group B (administered a bicarbonate: sodium bicarbonate formulation) and Group C (control group) (see Table 3-1-1). Such an effect was not seen with the administration of a sodium bicarbonate formulation. Furthermore, Group A had higher hippuric acid concentrations in early morning urine after 12 and 24 weeks of administration compared to Group C (see Table 3-2-1). Furthermore, when a potassium citrate-sodium citrate hydrate compound was administered to patients with chronic kidney disease, the plasma concentration of hippuric acid, a uremic substance, decreased after 24 weeks of administration compared to pre-administration (see Tables 3-1-1 and 3-2-2), and the urinary concentration of hippuric acid increased compared to pre-administration (see Tables 3-2-1 and 3-2-2). An increase in early morning urine hippuric acid concentration from 6 to 24 weeks was observed only in Group A (see Table 2-2-2). Even though both alkalinizing agents were used, the potassium citrate-sodium citrate hydrate compound exhibited a greater effect in increasing urinary hippuric acid concentrations than sodium bicarbonate. The effect of the potassium citrate-sodium citrate hydrate compound on increasing urinary hippuric acid concentrations was observed from 6 weeks of administration. The ratio of hippuric acid concentration in urine to that in plasma suggests that administration of potassium citrate-sodium citrate hydrate preparations promotes the excretion of hippuric acid from the blood into urine, thereby promoting its excretion from the body.Furthermore, it was shown that the effect of excreting hippuric acid from the blood into urine from 6 to 24 weeks was stronger with administration of potassium citrate-sodium citrate hydrate preparations than with administration of sodium bicarbonate preparations (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 argininosuccinic acid (ASA), the argininosuccinic acid concentration in early morning urine was higher in Group A (Citrate: potassium citrate and sodium citrate hydrate preparation administered group) compared to Group C (Control: control group), but was lower than in Group B (Bicarbonate: sodium bicarbonate preparation administered group) (see Table 4-2-1). Furthermore, when a potassium citrate-sodium citrate hydrate compound was administered to patients with chronic kidney disease, the urinary concentration of argininosuccinic acid, a uremic substance, increased compared to before administration (see Tables 4-2-1 and 4-2-2). The effect of the potassium citrate-sodium citrate hydrate compound on increasing urinary argininosuccinic acid concentrations was observed from 12 weeks after administration. The increase in argininosuccinic acid concentrations in early morning urine from 6 to 24 weeks was greater in Group B than in Group A (see Table 4-2-2). The ratio of argininosuccinic acid concentration in urine to that in plasma suggests that administration of a potassium citrate-sodium citrate hydrate formulation promotes the excretion of argininosuccinic acid from the blood into urine, thereby promoting its excretion from the body.Furthermore, it was shown that the effect of sodium bicarbonate administration on the excretion of argininosuccinic acid from the blood into urine over the period from 6 to 24 weeks was stronger when compared to administration of a potassium citrate-sodium citrate hydrate formulation (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), plasma phenylacetyl-L-glutamine concentrations were lower in Group A (the group administered a citrate: potassium citrate and sodium citrate hydrate formulation) compared to Group C (control group) (see Table 5-1-1). Phenyacetyl-L-glutamine concentrations in early morning urine were higher in Group A compared to Group C at 12 and 24 weeks of administration (see Table 5-2-1). Furthermore, administration of a potassium citrate-sodium citrate hydrate formulation to patients with chronic kidney disease increased urinary concentrations of the uremic toxin phenylacetyl-L-glutamine at 12 and 24 weeks after administration compared to baseline (see Tables 5-2-1 and 5-2-2). Although sodium bicarbonate is also an alkalinizing agent, this effect was not observed with the potassium citrate-sodium citrate hydrate formulation. The effect of increasing urinary phenylacetyl-L-glutamine concentrations with the potassium citrate-sodium citrate hydrate formulation was observed from 12 weeks after administration. Administration of a potassium citrate-sodium citrate hydrate formulation to patients with chronic kidney disease reduced plasma concentrations of the uremic toxin phenylacetyl-L-glutamine compared to baseline (see Tables 5-1-1 and 5-2-2). The sodium bicarbonate formulation significantly reduced plasma phenylacetyl-L-glutamine concentrations compared to the potassium citrate-sodium citrate hydrate formulation (see Table 5-1-2). The ratio of phenylacetyl-L-glutamine concentration in urine to that in plasma showed that administration of potassium citrate-sodium citrate hydrate preparation promoted the excretion of phenylacetyl-L-glutamine from the blood into urine, thereby promoting its excretion from the body.Furthermore, it was shown that the excretion effect of phenylacetyl-L-glutamine from the blood into urine was stronger with administration of potassium citrate-sodium citrate hydrate preparation compared to administration of sodium bicarbonate preparation (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 (Bicarbonate) on plasma concentrations, early morning urine concentrations, and ratios of early morning urine concentrations to plasma concentrations of each uremic substance are summarized in the table below. In the table below, the comparator is the sodium bicarbonate (Citrate) in the case of potassium citrate-sodium citrate hydrate (Citrate), and the potassium citrate-sodium citrate hydrate (Citrate) in the case of sodium bicarbonate (Bicarbonate). A circle indicates a significantly superior effect compared to the control group or comparator group; an × indicates a significantly inferior effect compared to the control group or comparator group; and a - indicates no significant difference. The effect of the sodium bicarbonate (Bicarbonate) group on early morning urine indoxyl sulfate concentrations compared to the control group is indicated by a circle in the table below. This is because the sodium bicarbonate (Bicarbonate) administration group significantly increased the indoxyl sulfate concentration in early morning urine compared to the control group, but the indoxyl sulfate concentration in early morning urine after administration of the sodium bicarbonate (Bicarbonate) preparation decreased compared to before the start of administration, so it is not possible to determine whether there is an effect of promoting the excretion of indoxyl sulfate into the urine. As can be seen from the table below, the effect of alkalinizing agents in lowering uremic substance concentrations in blood (plasma) was clearly observed with indoxyl sulfate (IS) and phenylacetyl-L-glutamine (PAG). Of these, administration of potassium citrate and sodium citrate hydrate preparation (Citrate) for indoxyl sulfate (IS) resulted in a more significant reduction than administration of sodium bicarbonate preparation (Bicarbonate). Furthermore, the effect of alkalinizing agents in increasing urinary uremic toxin concentrations (urinary excretion of uremic toxins) was clearly observed with indoxyl sulfate (IS), p-cresyl sulfate (PCS), hippuric acid (HA), argininosuccinic acid (ASA), and phenylacetyl-L-glutamine (PAG).Of these, administration of potassium citrate-sodium citrate hydrate preparations (Citrate) significantly increased urinary uremic toxin concentrations (urinary excretion) compared with administration of sodium bicarbonate preparations (Bicarbonate). The effect of alkalinizing agents on the excretion of uremic substances from the blood into the urine (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) in potassium citrate-sodium citrate hydrate preparation (Citrate) significantly increased the excretion of uremic substances from the blood into the urine (excretion effect) compared with administration of sodium bicarbonate preparation (Bicarbonate).

[0146] [Table 6]

[0147] From the table above, it can be seen that potassium citrate-sodium citrate hydrate preparations generally have a higher excretion effect on uremic substances than sodium bicarbonate preparations. It also suggests that administering alkalinizing agents to patients with chronic kidney disease in stage G2 as well as stage G3b can slow the progression of chronic kidney disease, and that potassium citrate-sodium citrate hydrate preparations slow the progression of chronic kidney disease more than sodium bicarbonate preparations.

[0148] The amounts of β2-microglobulin in urine and cystatin C in serum were measured, and the results are shown below.

[0149] [Table 7-1]

[0150] [Table 7-2]

[0151] [Table 8]

[0152] There was no difference in plasma cystatin C concentration among Group A (Citrate: potassium citrate-sodium citrate hydrate compound group), Group B (Bicarbonate: sodium bicarbonate compound group), and Group C (Control: control group), and no effect of potassium citrate-sodium citrate hydrate compound or sodium bicarbonate compound administration on glomerular function was observed (Table 8). On the other hand, urinary β2-microglobulin concentrations were lower in Group A (Citrate: potassium citrate and sodium citrate hydrate group) compared to Group C (Control group), and were also lower in Group A (Potassium citrate and sodium citrate hydrate group) compared to Group B (Bicarbonate: sodium bicarbonate group). Urinary β2-microglobulin concentrations were higher in Group B (Bicarbonate: sodium bicarbonate group) compared to Group C (Control group). Administration of the potassium citrate and sodium citrate hydrate group inhibited the increase in urinary β2-microglobulin concentrations associated with disease progression, and no change in urinary β2-microglobulin concentrations was observed compared to before administration. These results showed that administration of a potassium citrate-sodium citrate hydrate combination preparation suppressed renal tubular damage (proximal tubular damage) associated with disease progression. Furthermore, administration of a sodium bicarbonate preparation did not suppress renal tubular damage (proximal tubular damage) associated with disease progression, but rather exacerbated it. These effects were observed from 6 weeks after administration. Furthermore, there was no correlation between the effect of potassium citrate-sodium citrate hydrate combination preparations on increasing urinary uremic toxin concentrations or decreasing urinary uremic toxin concentrations, and the effect of potassium citrate-sodium citrate hydrate combination preparations on inhibiting increases in urinary β2-microglobulin concentrations. This suggests that the effect of potassium citrate-sodium citrate hydrate combination preparations in promoting urinary excretion of uremic toxins is not solely due to inhibition of glomerular and proximal tubule damage.

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

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

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

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

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

[0159] [Table 9]

[0160] The correlations between plasma concentrations of indoxyl sulfate (IS), p-cresyl sulfate (PCS), hippuric acid (HA), argininosuccinic acid (ASA), and phenylacetyl-L-glutamine (PAG) at 6, 12, and 24 weeks (6W, 12W, and 24W) were analyzed using Pearson's test for Group C (Control), Group A (Citrate: potassium citrate-sodium citrate hydrate combination group), and Group B (Bicarbonate: sodium bicarbonate combination group). The results are shown in Table 10. In the table, "Control" refers to the control group, "Citrate" refers to the potassium citrate-sodium citrate hydrate combination group, and "Bicarb" refers to the sodium bicarbonate combination group. As a result, in the potassium citrate-sodium citrate hydrate combination group, 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 sodium bicarbonate combination group, high correlations were observed between indoxyl sulfate and p-cresyl sulfate. It was suggested that the potassium citrate-sodium citrate hydrate combination may decrease the blood concentrations of indoxyl sulfate, phenylacetyl-L-glutamine, and p-cresyl sulfate through a similar mechanism. It was also suggested that the sodium bicarbonate combination may decrease the blood concentrations of p-cresyl sulfate and phenylacetyl-L-glutamine through a similar mechanism. These results suggest that the mechanisms by which the potassium citrate-sodium citrate hydrate combination and sodium bicarbonate combination decrease the blood concentrations of uremic substances differ.

[0161] [Table 10]

[0162] The specific gravity of early morning urine was analyzed for Group C (control), Group A (Citrate: potassium citrate-sodium citrate hydrate formulation group), and Group B (Bicarbonate: sodium bicarbonate formulation group) before the start of the study (0W) and 6, 12, and 24 weeks after the start of the study (6W, 12W, and 24W). The results are shown in Table 11-0-1. The changes in each 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, respectively, as a percentage of the urine specific gravity before the start of the study and as a difference from the urine specific gravity before the start of the study. Urine specific gravity was measured using a urinary 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, compared with Group C (Control group), Group A (Citrate: potassium citrate and sodium citrate hydrate compounded formulation group) and Group B (Bicarbonate: sodium bicarbonate compounded formulation 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 with Group B (Bicarbonate: sodium bicarbonate compounded formulation group), Group A (Citrate: potassium citrate and sodium citrate hydrate compounded formulation group) showed a tendency for urine specific gravity to be maintained or to increase more. The maintenance or increase of urine specific gravity can be understood as being due to the maintenance or improvement of renal function. Therefore, the above results suggest that administering alkalinizing agents to patients with chronic kidney disease in stage G2 as well as stage G3b can slow the progression of chronic kidney disease, and that potassium citrate-sodium citrate hydrate preparations are more effective at slowing the progression of chronic kidney disease than sodium bicarbonate preparations.

[0167] The concentrations of uremic substances, namely indoxyl sulfate (IS), p-cresyl sulfate (PCS), phenylacetyl-L-glutamine (PAG), hippuric acid (HA), and argininosuccinic acid (ASA), in early morning urine samples at baseline (0W) and 6, 12, and 24 weeks (6W, 12W, and 24W) were corrected using the following formula using the specific gravity of early morning urine at baseline (0W) and 6, 12, and 24 weeks (6W, 12W, and 24W). The values ​​were analyzed for Group C (control group), Group A (treated with a potassium citrate-sodium citrate hydrate formulation), and Group B (treated with a sodium bicarbonate formulation). (Reference: Aoki et al., Medical Testing, 1995, Vol. 44, No. 1, pp. 79-83.) The urine specific gravity of 1.022 was converted into the standard value. Specific gravity correction value (unit / 1.022 UG) = actual measurement value x (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. The changes in the concentrations of the 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.

[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, for indoxyl sulfate (IS), p-cresyl sulfate (PCS), and phenylacetyl-L-glutamine (PAG), the group administered potassium citrate and sodium citrate hydrate (Citrate) showed significantly higher urinary uremic concentrations (urinary excretion) than the control group and the groups administered sodium bicarbonate.For hippuric acid (HA) and argininosuccinic acid (ASA), the group administered potassium citrate and sodium citrate hydrate (Citrate) showed significantly higher urinary uremic concentrations (urinary excretion) than the control group and the groups administered sodium bicarbonate. Furthermore, administration of potassium citrate and sodium citrate hydrate (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 for Group C (Control), Group A (Citrate: potassium citrate and sodium citrate hydrate formulation group), and Group B (Bicarbonate: sodium bicarbonate formulation group) before the start of the study (0W) and 6, 12, and 24 weeks after the start of the study (6W, 12W, and 24W). The results are shown in Table 12-0-1. The change in early morning urine osmolality from before the start of the study to 6, 12, and 24 weeks after the start of the study is shown in Tables 12-0-2 and 12-0-3 below, respectively, as a percentage relative 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. 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] The results showed that compared with Group C (Control), Group A (Citrate: potassium citrate and sodium citrate hydrate formulation group) and Group B (Bicarbonate: sodium bicarbonate formulation group) tended to maintain or increase the osmolality of early morning urine at 6, 12, and 24 weeks after the start of the study. Furthermore, compared with Group B (Bicarbonate: sodium bicarbonate formulation group), Group A (Citrate: potassium citrate and sodium citrate hydrate formulation group) tended to maintain or increase the osmolality of early morning urine to a greater extent. The maintenance or increase in osmolality of early morning urine can be understood as due to the maintenance or improvement of renal function. Therefore, the above results suggest that administering alkalinizing agents to patients with chronic kidney disease in stage G2 as well as stage G3b can slow the progression of chronic kidney disease, and that potassium citrate-sodium citrate hydrate preparations are more effective at slowing the progression of chronic kidney disease than sodium bicarbonate preparations.

[0189] The concentrations of uremic substances, namely indoxyl sulfate (IS), p-cresyl sulfate (PCS), phenylacetyl-L-glutamine (PAG), hippuric acid (HA), and argininosuccinic acid (ASA), in early morning urine samples at baseline (0W) and 6, 12, and 24 weeks (6W, 12W, and 24W) were corrected using the following formula using the osmolality of early morning urine at baseline (0W) and 6, 12, and 24 weeks (6W, 12W, and 24W). The values ​​were analyzed for Group C (control group), Group A (Citrate: potassium citrate-sodium citrate hydrate combination group), and Group B (Bicarbonate: sodium bicarbonate combination group). (Reference: Aoki et al., Medical Testing, 1995, Vol. 44, No. 1, pp. 79-83.) A urine osmolality of 770 mOsm / kg was converted into the reference value. Osmolality correction value (unit / 500 mOsm·P) = actual measurement value × 500 / osmolality value The results are shown in Tables 12-1-1, 12-2-1, 12-3-1, 12-4-1, and 12-5-1. The changes in the concentrations of the uremic substances in early morning urine, corrected for the 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 12-1-2, 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 below, respectively, as % relative values ​​to the corrected values ​​before the start of the study and as differences from the corrected values ​​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, for p-cresyl sulfate (PCS) and phenylacetyl-L-glutamine (PAG), the group administered potassium citrate and sodium citrate hydrate (Citrate) showed significantly higher urinary uremic concentrations (urinary excretion) than the control group and the groups administered sodium bicarbonate.For indoxyl sulfate (IS), hippuric acid (HA), and argininosuccinic acid (ASA), the group administered potassium citrate and sodium citrate hydrate (Citrate) showed significantly higher urinary uremic concentrations (urinary excretion) than the control group and the groups administered sodium bicarbonate. Furthermore, administration of potassium citrate and sodium citrate hydrate (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 composition etc. provided by the present invention allows uremic substances to be excreted from the body in mammals. The method provided by the present invention allows a preliminary determination of whether uremic substances are being excreted from the body and / or whether the progression of chronic kidney disease has been inhibited.

Claims

1. A pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, 1) For the treatment or prevention of renal tubular damage associated with the progression of chronic kidney disease, and 2) A pharmaceutical composition for promoting the excretion of uremic substances from the body or reducing their blood concentration.

2. Contains a mixture of potassium citrate monohydrate and sodium citrate dihydrate, 1) For the treatment or prevention of renal tubular damage associated with the progression of chronic kidney disease, and 2) A pharmaceutical composition for promoting the excretion of uremic substances from the body or reducing their blood concentration.

3. 3. The pharmaceutical composition according to claim 1, wherein the uremic substance is selected from the group consisting of indoxyl sulfate, p-cresyl sulfate, phenylacetyl-L-glutamine, hippuric acid and argininosuccinic acid.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the uremic substances are indoxyl sulfate and phenylacetyl-L-glutamine.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the uremic substance is indoxyl sulfate.

6. The pharmaceutical composition according to any one of claims 1 to 5, which is administered for 6 weeks or longer.

7. The pharmaceutical composition according to any one of claims 1 to 6, which is administered to a patient with chronic kidney disease at stage G2 or higher and G3b or lower.

8. The pharmaceutical composition according to any one of claims 1 to 7, which is in the form of a tablet.

Images