Peritoneal dialysis fluid, peritoneal dialysis fluid kit, components for use in peritoneal dialysis, and peritoneal dialysis methods.

Abstract

DEPCT64 This invention provides a method for optimally controlling the balance between water and sodium. Peritoneal dialysate therapy avoids adverse effects of other treatments. The remaining renal function, without causing hyponatremia, involves the passage of dialisate fluid through the mucous membrane. This abdominal cavity contains 1.5 to 1.8 weight / volume% of glucose and 120 to 130 milliequivalence units / liter of... Sodium and dialiset were administered alone, once or twice a day, through the peritoneal membrane. It was used in combination with other peritoneal dialisate fluids containing 1.35 to 2.5 weight / volume%. The glucose and 132 to 135 milliequivalents / liter of sodium pass through the peritoneal membrane where... The following procedure was performed three to five times a day: injecting 1.5 to 2.0 liters of dialysate fluid. Peritoneal dialysis (DIAL) is the collection of dialysis fluid through the peritoneal membrane into the patient's abdominal cavity; And the release of dialysate fluid through the peritoneum. -----------------------------------------------------------

Description

Peritoneal dialysis solution, peritoneal dialysis solution set, composition used in peritoneal dialysis, and method for performing peritoneal dialysis

[0001] The present invention relates to peritoneal dialysis solutions, peritoneal dialysis sets, compositions for use in peritoneal dialysis, and methods for performing peritoneal dialysis.

[0002] Peritoneal dialysis is a dialysis method that uses the peritoneal membrane as a dialysis membrane. It is a therapy that corrects fluid abnormalities by transferring and removing metabolic products from the blood via the peritoneal membrane into the peritoneal dialysis fluid in the peritoneal cavity through concentration differences (diffusion) and by transferring and removing excess fluid via osmotic pressure differences (ultrafiltration or dehydration). Currently, CAPD (Continuous Ambulatory Peritoneal Dialysis) therapy is the mainstream. In CAPD therapy, peritoneal dialysis fluid is injected into the peritoneal cavity through a catheter, retained for a certain period of time, and then drained. This procedure is repeated 3 to 5 times per day.

[0003] In existing peritoneal dialysis solutions, the sodium concentration is set constant regardless of the glucose concentration, with the glucose concentration being 1.35 to 4.00 w / v% and the sodium concentration being 132 to 135 mEq / L. With such existing peritoneal dialysis solutions, the amount of water removed increases as the glucose concentration increases, but the amount of sodium removed tends to be insufficient. Therefore, if sodium remains in the body, the patient becomes thirsty and drinks more water, which can result in insufficient water removal even when water is removed by dialysis. If this occurs repeatedly, there is a risk of fluid overload.

[0004] Therefore, peritoneal dialysis solutions with a lower sodium concentration than serum have been proposed (Patent Documents 1 to 3). In Patent Documents 1 to 3, an osmotic pressure regulator such as an amino acid, polypeptide, or polyglucose is added to the peritoneal dialysis solution to improve water removal performance, thereby increasing the amount of sodium removed from the circulatory system into the peritoneal cavity.

[0005] It has also been reported that if a peritoneal dialysis fluid with a low sodium concentration is used, sodium movement (diffusion) can be caused by the difference in sodium concentration without increasing the osmotic pressure (Non-Patent Documents 1 and 2).Non-Patent Documents 1 and 2 investigated the relationship between the water removal and sodium removal effects and sodium concentration changes over a range of 100 to 132 mEq / L, with the glucose concentration fixed at 1.36 w / v% or 2.27 w / v%.

[0006] According to Non-Patent Documents 1 and 2, when the sodium concentration of the peritoneal dialysis fluid is reduced at a glucose concentration of 2.27 w / v%, the amount of water removed decreases, and therefore the amount of sodium removed also decreases. However, the ratio of sodium removed to water removed increases, resulting in an increase in net sodium removal. When using peritoneal dialysis fluid within the above sodium concentration range, no significant change in serum sodium concentration during dialysis is observed. For this reason, it has been reported that peritoneal dialysis fluid with a low sodium concentration is preferable for patients with sodium overload, and a glucose concentration of 2.27 w / v% and a sodium concentration of 120 mEq / L are preferred. Furthermore, Non-Patent Documents 1 and 2 state that a glucose concentration of 1.36 w / v% is not appropriate because the amount of water removed is too low.

[0007] As mentioned above, generally, reducing the sodium concentration of a peritoneal dialysis solution can be expected to increase the amount of sodium removed by diffusion, but the reduced sodium concentration also reduces osmotic pressure, which may result in a decrease in the amount of water removed. A decrease in the amount of water removed means an insufficient amount of dialysis, which may be problematic in treatment. Furthermore, if the amount of sodium removed is inappropriate relative to the amount of water removed, there is a risk of fluid overload due to insufficient sodium removal, or conversely, hyponatremia due to excessive sodium removal. Therefore, Patent Document 4 proposes a peritoneal dialysis solution that does not reduce water removal performance, can remove sodium in a balanced manner relative to the amount of water removed, and in particular, does not leave any residual sodium.

[0008] According to Non-Patent Document 3, when 2.0 L of peritoneal dialysis fluid with glucose and sodium concentrations of 0.9 w / v% and 133 mEq / L, 1.6 w / v% and 126 mEq / L, and 2.5 w / v% and 118 mEq / L, respectively, was retained for 4 hours, the sodium gap (amount of residual sodium) was nearly zero. However, when these peritoneal dialysis fluids were administered in combination for one day, the sodium gap per day was shown to be negative, ranging from -32 to -48 mEq. Although such sodium-free peritoneal dialysis fluids perform as expected when the retention time per session is limited to four hours, the retention time in actual clinical use varies from 2 to 11 hours. The risk of hyponatremia due to excessive sodium removal when administered daily or continuously, as well as the impact on residual renal function, have not been clarified, and no solution to this problem has been disclosed.

[0009] US Patent No. 5,589,197 US Patent No. 5,629,025 US Patent No. 5,631,025 Japanese Patent Application Laid-Open No. 2002-253667

[0010] M. Nakayama et al., Clinical Nephrology, 1994, Vol. 41, No. 6, p. 357-363M. Nakayama et al., Clinical Nephrology, 1996, Vol. 45, No. 1, p. 66-68M. Nakayama et al., Peritoneal Dialysis International, 2009, Vol. 29, No. 5, p. 528-535

[0011] Therefore, an object of the present invention is to provide a means for appropriately managing the balance of water and sodium during peritoneal dialysis treatment without causing hyponatremia and while avoiding adverse effects on residual renal function.

[0012] The present inventors have conducted extensive research to solve the above problems, and as a result, according to a first aspect of the present invention, there is provided a peritoneal dialysis solution containing 1.5 to 1.8 w / v % glucose and 120 to 130 mEq / L sodium, which is used alone once to twice a day, and which is used in combination with another peritoneal dialysis solution containing 1.35 to 2.5 w / v % glucose and 132 to 135 mEq / L sodium for peritoneal dialysis, which involves injecting, storing, and draining 1.5 to 2.0 L of dialysis into a subject's peritoneal cavity three to five times a day.

[0013] According to a second aspect of the present invention, there is provided a peritoneal dialysis set comprising: a first peritoneal dialysis solution containing 1.5 to 1.8 w / v % glucose and 120 to 130 mEq / L of sodium; and a second peritoneal dialysis solution containing 1.35 to 2.5 w / v % glucose and 132 to 135 mEq / L of sodium, wherein the first peritoneal dialysis solution and the second peritoneal dialysis solution are used for peritoneal dialysis, in which a volume of 1.5 to 2.0 L is each independently injected into, retained in, and drained from the peritoneal cavity of a subject, a total of 3 to 5 times per day; and wherein the first peritoneal dialysis solution set is used 1 to 2 times per day.

[0014] According to a third aspect of the present invention, there is provided a composition for use in peritoneal dialysis, the composition comprising 1.5 to 1.8 w / v % glucose and 120 to 130 mEq / L sodium, the composition being used in combination with another composition for use in peritoneal dialysis comprising 1.35 to 2.5 w / v % glucose and 132 to 135 mEq / L sodium, the composition and the other composition being each independently infused into the peritoneal cavity of a subject in an amount of 1.5 to 2.0 L, allowed to stagnate, and then drained, a total of 3 to 5 times per day, and the composition being used 1 to 2 times per day.

[0015] According to a fourth aspect of the present invention, there is provided a method for performing peritoneal dialysis, comprising infusing, dwelling, and draining a first peritoneal dialysis solution and a second peritoneal dialysis solution into a subject's peritoneal cavity, each independently in an amount of 1.5 to 2.0 L, three to five times per day in total, wherein the first peritoneal dialysis solution contains 1.5 to 1.8 w / v % glucose and 120 to 130 mEq / L sodium and is used once to twice per day, and the second peritoneal dialysis solution contains 1.35 to 2.5 w / v % glucose and 132 to 135 mEq / L sodium.

[0016] Figure 1 shows the total amount of water removed per day in Test Example 1. Figure 2 shows the total amount of salt removed per day in Test Example 1. Figure 3 shows the value obtained by subtracting the recommended salt intake in the peritoneal dialysis guidelines from the total amount of salt removed per day in Test Example 1. Figure 4 shows the expected amount of water removed and the expected amount of salt removed per day in Test Example 2. Figure 5 shows the results of a simulation of the degree to which the sodium concentration in the extracellular fluid is diluted when the injected peritoneal dialysis fluid is completely absorbed by the body.

[0017] An embodiment of the present invention will be described below, but the present invention is not limited to the following embodiment.

[0018] In this specification, the range "x to y" means "x or more and y or less." Unless otherwise specified, operations and measurements of physical properties are performed under conditions of room temperature (1 to 30°C) and a relative humidity of 40 to 50% RH.

[0019] <First Aspect: Peritoneal Dialysis Solution> The first aspect of the present invention is a peritoneal dialysis solution containing 1.5 to 1.8 w / v % glucose and 120 to 130 mEq / L sodium, used alone once or twice per day, and used in combination with another peritoneal dialysis solution containing 1.35 to 2.5 w / v % glucose and 132 to 135 mEq / L sodium for peritoneal dialysis, which involves injecting, storing, and draining 1.5 to 2.0 L into a subject's peritoneal cavity three to five times per day. This configuration enables appropriate management of water and sodium balance during peritoneal dialysis treatment without causing hyponatremia and avoiding adverse effects on residual renal function.

[0020] The peritoneal dialysis solution according to the first aspect of the present invention (also referred to in this specification as the "first peritoneal dialysis solution") contains 1.5 to 1.8 w / v % glucose and 120 to 130 mEq / L of sodium. The first peritoneal dialysis solution preferably contains 123 to 128 mEq / L of sodium, and more preferably 125 to 128 mEq / L of sodium.

[0021] The first peritoneal dialysis solution may further contain components contained in ordinary peritoneal dialysis solutions. Such components include calcium, magnesium, chlorine, an alkalizing agent, etc. The first peritoneal dialysis solution preferably contains 2.0 to 4.0 mEq / L of calcium, 0.5 to 1.5 mEq / L of magnesium, 86.0 to 98.0 mEq / L of chlorine, and 35 to 40 mEq / L of an alkalizing agent.

[0022] Examples of alkalizing agents include lactate ions, bicarbonate ions, etc. The concentration of the alkalizing agent is the sum of the lactate ions, bicarbonate ions, etc. used, and for example, a combination of lactate ions and bicarbonate ions can provide an alkalizing agent of 35 to 40 mEq / L. The alkalizing agent is preferably lactate ions.

[0023] The first peritoneal dialysis solution is used in combination with another peritoneal dialysis solution (also referred to herein as the "second peritoneal dialysis solution") containing 1.35 to 2.5 w / v% glucose and 132 to 135 mEq / L sodium.

[0024] The second peritoneal dialysis solution can further contain components contained in normal peritoneal dialysis solutions. Such components include calcium, magnesium, chlorine, an alkalizing agent, etc. The second peritoneal dialysis solution preferably contains 2.3 to 4.0 mEq / L of calcium, 0.5 to 1.5 mEq / L of magnesium, 95.0 to 105.5 mEq / L of chlorine, and 35 to 40 mEq / L of an alkalizing agent.

[0025] The alkaline agent contained in the second peritoneal dialysis solution can be the same as the alkaline agent contained in the first peritoneal dialysis solution described above.

[0026] The first and second peritoneal dialysates may further contain other components as needed, as long as the object of the present invention is not impaired. For example, the first and second peritoneal dialysates may contain an organic acid or the like depending on the difference in concentration between total cations and chloride ions in order to maintain the electrical neutrality of the peritoneal dialysates. Examples of such organic acids include propionic acid, malic acid, fumaric acid, succinic acid, oxalacetic acid, N-acetylglycine, N-acetyl-L-cysteine, glutaric acid, glucuronic acid, ascorbic acid, citric acid, isocitric acid, gluconic acid, N-acetyl-L-aspartic acid, N-acetyl-L-glutamic acid, N-acetyl-L-methionine, N-acetyl-L-proline, N-acetyl-L-valine, N-acetyl-L-glutamine, N-acetyl-L-arginine, N-acetyl-L-histidine, N-acetyl-L-leucine, N-acetyl-L-tryptophan, and salts thereof.

[0027] The pH of the first peritoneal dialysis fluid and the second peritoneal dialysis fluid is usually about pH 5.0 to 7.5, preferably about pH 6.5 to 7.5.

[0028] The osmotic pressure of the first peritoneal dialysate and the second peritoneal dialysate is usually about 300 to 500 mOsm / kg, preferably about 330 to 450 mOsm / kg.

[0029] In peritoneal dialysis, typically, 1.5 to 2.0 L of peritoneal dialysis fluid is injected into the subject's peritoneal cavity, allowed to saturate for 4 to 8 hours, and then drained after the expected effect is achieved. The above procedure counts as one session, and continuous procedures are performed 3 to 5 times per day. The first peritoneal dialysis fluid is used in combination with the second peritoneal dialysis fluid. That is, the first peritoneal dialysis fluid and the second peritoneal dialysis fluid are each used alone for peritoneal dialysis a total of 3 to 5 times per day. The first peritoneal dialysis fluid is used alone 1 to 2 of the 3 to 5 sessions per day. In this way, by appropriately combining the first peritoneal dialysis fluid with the second peritoneal dialysis fluid, water and sodium balance can be appropriately managed during peritoneal dialysis treatment without causing hyponatremia and avoiding adverse effects on residual renal function.

[0030] The subject for peritoneal dialysis is, for example, a mammal, preferably a human.

[0031] The injection volume, retention time, and number of operations are adjusted appropriately depending on symptoms, blood biochemical values, imbalance of body fluids, age, body weight, etc. The injection rate and drainage rate are usually 300 mL / min or less.

[0032] The method for preparing the first peritoneal dialysis solution and the second peritoneal dialysis solution is not particularly limited, and a general method for preparing a peritoneal dialysis solution can be used. For example, a method can be used in which glucose; a cation and chlorine ion source such as sodium chloride, calcium chloride, magnesium chloride, sodium lactate, a calcium salt, a magnesium salt, or sodium bicarbonate; an acid component, and the like are dissolved in water (e.g., water for injection) so that the glucose concentration, sodium concentration, and, if necessary, the concentrations of calcium, magnesium, chlorine, an alkalizing agent, and the like fall within the above-mentioned ranges.

[0033] The prepared peritoneal dialysis solution is preferably sealed in a soft plastic bag or a glass container, and then subjected to high-pressure steam sterilization or hot water sterilization. Examples of soft plastic materials include polyvinyl chloride, polypropylene, polyethylene, polyester, polyamide, ethylene-vinyl alcohol copolymer, polyethylene terephthalate, polyvinylidene chloride, and ethylene-vinyl acetate copolymer, and a combination of these materials may also be used by laminating them.

[0034] <Second Aspect: Peritoneal Dialysis Solution Set> A second aspect of the present invention is a peritoneal dialysis solution set comprising: a first peritoneal dialysis solution containing 1.5-1.8 w / v % glucose and 120-130 mEq / L of sodium; and a second peritoneal dialysis solution containing 1.35-2.5 w / v % glucose and 132-135 mEq / L of sodium, wherein the first peritoneal dialysis solution and the second peritoneal dialysis solution are used for peritoneal dialysis, in which 1.5-2.0 L of each peritoneal dialysis solution is individually injected into, retained in, and drained from the peritoneal cavity of a subject three to five times a day in total, and the first peritoneal dialysis solution is used once or twice a day. This configuration enables appropriate management of water and sodium balance during peritoneal dialysis treatment without causing hyponatremia and avoiding adverse effects on residual renal function.

[0035] In the second embodiment, the "first peritoneal dialysis fluid," the "second peritoneal dialysis fluid," and the "peritoneal dialysis" are the same as those in the first embodiment, and therefore description thereof will be omitted.

[0036] <Third Aspect: Composition for Use in Peritoneal Dialysis> The third aspect of the present invention is a composition for use in peritoneal dialysis, the composition comprising 1.5-1.8 w / v% glucose and 120-130 mEq / L sodium, the composition being used in combination with another composition for use in peritoneal dialysis comprising 1.35-2.5 w / v% glucose and 132-135 mEq / L sodium, the composition and the other composition being each independently infused into the peritoneal cavity of a subject in a volume of 1.5-2.0 L, retained, and drained, a total of 3-5 times per day, and the composition being used 1-2 times per day. This configuration enables appropriate management of water and sodium balance during peritoneal dialysis treatment without causing hyponatremia and avoiding adverse effects on residual renal function.

[0037] In the third embodiment, the "composition used for peritoneal dialysis" corresponds to the "first peritoneal dialysis solution" in the first embodiment, the "other composition used for peritoneal dialysis" corresponds to the "second peritoneal dialysis solution" in the first embodiment, and the "peritoneal dialysis" is the same as in the first embodiment, and therefore will not be described here.

[0038] <Fourth Aspect: Method for Performing Peritoneal Dialysis> A fourth aspect of the present invention is a method for performing peritoneal dialysis, comprising injecting, retaining, and draining a first peritoneal dialysis solution and a second peritoneal dialysis solution into a subject's peritoneal cavity, each individually at a volume of 1.5 to 2.0 L, a total of 3 to 5 times per day, wherein the first peritoneal dialysis solution contains 1.5 to 1.8 w / v% glucose and 120 to 130 mEq / L sodium and is used 1 to 2 times per day, and the second peritoneal dialysis solution contains 1.35 to 2.5 w / v% glucose and 132 to 135 mEq / L sodium. This configuration allows for appropriate management of water and sodium balance during peritoneal dialysis treatment without causing hyponatremia and avoiding adverse effects on residual renal function.

[0039] In the fourth embodiment, the "first peritoneal dialysis fluid," the "second peritoneal dialysis fluid," and the "peritoneal dialysis" are the same as those in the first embodiment, and therefore description thereof will be omitted.

[0040] The effects of the present invention will be explained using the following examples and comparative examples. However, the technical scope of the present invention is not limited to the following examples. In the following examples, the terms "parts" and "%" may be used, but unless otherwise specified, they represent "parts by weight" or "% by weight." Furthermore, unless otherwise specified, each operation is carried out at room temperature (1 to 30°C).

[0041] <Preparation of peritoneal dialysis solution> The required amounts of anhydrous glucose, sodium chloride, calcium chloride dihydrate, magnesium chloride hexahydrate, and sodium L-lactate solution were used to obtain the glucose, sodium, calcium, magnesium, chlorine, and lactate ion concentrations shown in Table 1, and the solution was prepared according to the method for preparing injections in the General Provisions of Preparations of the Japanese Pharmacopoeia, and then filtered through a membrane filter. The filtered dialysis solution was dispensed into polypropylene resin two-compartment containers for peritoneal dialysis that conform to the test method and sealed. The dialysis solution was then sealed in a packaging bag made of multilayer laminate film and sterilized by high-pressure steam.

[0042]

[0043] <Test Example 1> The following clinical trial was carried out on patients with chronic renal failure undergoing peritoneal dialysis therapy.

[0044] (Inclusion criteria) Patients who met the following criteria and were able to give consent were eligible for the study. (1) Patients who had been undergoing peritoneal dialysis therapy for at least six months prior to the start of the study. (2) Patients who had been undergoing peritoneal dialysis therapy using peritoneal dialysis solution A or B for at least one month prior to the start of the study. (3) Age and gender: 20 years of age or older (at the time of obtaining written consent), regardless of gender. (4) Inpatient or outpatient status: regardless of gender.

[0045] (Exclusion criteria) (1) Patients using peritoneal dialysis fluid with a glucose concentration of 4.0% (2) Patients with hypotension (systolic blood pressure less than 100 mmHg) (3) Patients with low serum sodium concentration (less than 130 mEq / L) or symptomatic hyponatremia (4) Patients who have developed peritonitis within two months prior to the start of the study (5) Patients who have had a parathyroidectomy less than three months ago (6) Patients with serious complications of the liver, heart, lungs, etc. or serious abnormalities in the blood (7) Patients who have developed renal failure due to a serious disease such as cancer (8) Patients who are pregnant, breastfeeding, or may be pregnant (9) Women of childbearing potential who cannot use appropriate contraception during the clinical trial (10) Patients who have participated in other clinical trials within six months prior to the start of this study (11) Other patients who are deemed inappropriate by the principal investigator or co-investigator.

[0046] (Criteria for discontinuing the trial) The principal investigator (sub-investigator) discontinued the trial if any of the following criteria were met: (1) If the subject or their legal representative requested discontinuation of the trial (2) If it was discovered that the subject was not eligible after the trial had begun (3) If symptoms worsened, making it difficult to continue the trial (4) If an adverse event occurred, making it difficult to continue the trial (5) If the principal investigator or sub-investigator recognized the need to discontinue the trial for any other reason.

[0047] (Group Composition) Thirty peritoneal dialysis patients were divided into groups according to the number of bottles of second peritoneal dialysis solution B used: Group 1 (12 patients), Group 2 (6 patients), Group 3 (8 patients), and Group 4 (4 patients).

[0048] Group 1: Subjects who used 0 bottles of the second peritoneal dialysis fluid B. Group 2: Subjects who used 1 bottle of the second peritoneal dialysis fluid B. Group 3: Subjects who used 2 bottles of the second peritoneal dialysis fluid B. Group 4: Subjects who used 3 or more bottles of the second peritoneal dialysis fluid B.

[0049] (Administration Schedule) A one-day evaluation was performed on a subject who was continuing peritoneal dialysis therapy using a single or combined prescription of the second peritoneal dialysis solution A or the second peritoneal dialysis solution B. After a period of 2 to 5 weeks, the same patient underwent peritoneal dialysis with the same prescription but with the second peritoneal dialysis solution A replaced with the first peritoneal dialysis solution X and the second peritoneal dialysis solution B replaced with the peritoneal dialysis solution Y, and the evaluation was performed on a one-day basis. Table 2 shows the prescription breakdown and the number of cases, and Table 3 shows the total number of times each peritoneal dialysis solution was used.

[0050]

[0051]

[0052] (Dosage and Administration) The above-prepared peritoneal dialysis solution was injected into the abdominal cavity in a volume of 1.5 to 2.0 L per injection, allowed to dwell for 4 to 8 hours, and then removed after the expected effect was achieved. The above procedure was counted as one injection, and the second peritoneal dialysis solution A and the second peritoneal dialysis solution B were used in appropriate combination or alone, and the operation was continued, usually 3 to 5 times per day. For the first peritoneal dialysis solution X and the peritoneal dialysis solution Y, the second peritoneal dialysis solution A was replaced with the first peritoneal dialysis solution X, and the second peritoneal dialysis solution B was replaced with the peritoneal dialysis solution Y, and the same operation was continued.

[0053] The infusion volume, retention time, and number of operations were adjusted appropriately depending on symptoms, blood biochemistry values, imbalance of retention, age, body weight, etc. The infusion and drainage rates were usually set to 300 mL / min or less.

[0054] (Drugs and therapies prohibited for concomitant use) During the evaluation period, the second peritoneal dialysis solution A and the second peritoneal dialysis solution B were to be used except when the first peritoneal dialysis solution X and the first peritoneal dialysis solution Y were used, and the use of other peritoneal dialysis solutions was prohibited. In addition, dialysis therapies other than peritoneal dialysis therapy were prohibited.

[0055] <Evaluation> Using the effluent collected from the patients and the collected urine, the amount of water removed (mL / dialysis) and amount of salt removed (g / dialysis) per session for each peritoneal dialysis solution, as well as the amount of water removed per day (mL / day), urine volume (mL / day), amount of salt removed by peritoneal dialysis (g / day), amount of urinary salt excretion (g / day), and the recommended salt intake (g / day) in the peritoneal dialysis guidelines (2009 edition of the Japanese Society for Dialysis Therapy (Journal of Dialysis Society 42: 285-315, 2009)) were calculated using the following methods.

[0056] (Amount of fluid removed per peritoneal dialysis session (mL / session)) Amount of fluid removed (mL / session) = amount of fluid drained (mL / session) - amount of fluid injected (mL / session).

[0057] (Amount of salt removed per peritoneal dialysis session (g / session)) Amount of salt removed (g / session) = (Na concentration in effluent (mEq / L) × amount of effluent (L / session) - Na concentration in dialysis solution (mEq / L) × amount of dialysis solution injected (L / session)) × 0.0585.

[0058] (Amount of water removed per day (mL / day)) Amount of water removed (mL / day) = Total amount of water removed per peritoneal dialysis session (mL / session) per day.

[0059] (Daily urine volume (mL / day)) Urine volume (mL / day) = accumulated urine (mL) for one day.

[0060] (Daily Amount of Salt Removed by Peritoneal Dialysis (g / day)) Amount of salt removed (g / day) = total amount of salt removed per peritoneal dialysis fluid (g / time) for one day.

[0061] (Daily urinary salt excretion (g / day)) Urinary salt excretion (g / day) = urinary sodium concentration (mEq / L) × urine volume (L / day) × 0.0585.

[0062] (Recommended salt intake (g / day) in peritoneal dialysis guidelines) Salt intake (g / day) = amount of fluid removed (L / day) x 7.5 g + 0.5 g per 100 mL of urine volume.

[0063] <Results> Table 4 shows the daily volume of water removed (mL / day), daily urine volume (mL / day), daily volume of salt removed by peritoneal dialysis (g / day), daily urinary salt excretion (g / day), and the recommended salt intake (g / day) according to the peritoneal dialysis guidelines. These average values ​​were used to calculate the total volume of water removed and total salt removed per day. Figure 1 shows the total volume of water removed per day, and Figure 2 shows the total volume of salt removed per day for each group. Figure 3 shows the value obtained by subtracting the recommended salt intake according to the peritoneal dialysis guidelines from the total volume of salt removed per day (the sum of the daily volume of salt removed by peritoneal dialysis and the daily urinary salt excretion) for each group. Negative values ​​indicate insufficient salt removal, while positive values ​​indicate excessive salt removal. Table 5 also shows the amount of water removed (mL / session) and the amount of salt removed (g / session) per peritoneal dialysis session for the second peritoneal dialysis solution A, the second peritoneal dialysis solution B, and the first peritoneal dialysis solution X for each group.

[0064]

[0065]

[0066] <Discussion> This study revealed for the first time the interrelationship between residual renal function (urine volume), peritoneal dialysis, and salt removal. Details are provided below.

[0067] 1) It can be seen that the decline in residual renal function can be predicted from the number of bottles of second peritoneal dialysis solution B used. As the proportion of bottles of peritoneal dialysis solution with a high glucose concentration used increases, as shown in Figure 1, there are more cases where the amount of water removed becomes excessive, which disrupts the fluid balance and may worsen residual renal function.

[0068] 2) It can be seen that there is a risk of hyponatremia when only a peritoneal dialysate with a low sodium concentration (first peritoneal dialysate X or a combination of first peritoneal dialysate X and peritoneal dialysate Y) is used. As shown in Figure 3, when a peritoneal dialysate with a low sodium concentration was used, excessive salt removal was observed, particularly in Groups 2 to 4, which used peritoneal dialysate Y. Since this is the result of one-day administration, there is a risk of hyponatremia when only the combination of first peritoneal dialysate X and peritoneal dialysate Y is administered daily.

[0069] 3) From Figures 1 and 2, it can be seen that in Groups 1 and 2, in which the urine volume was sufficient (500 mL or more), even when the amount of salt removal using a peritoneal dialysate with a low sodium concentration (first peritoneal dialysate X or a combination of first peritoneal dialysate X and peritoneal dialysate Y) was increased compared to the amount of salt removal using an existing peritoneal dialysate (second peritoneal dialysate A or a combination of second peritoneal dialysate A and second peritoneal dialysate B), although urinary salt excretion tended to decrease (Figure 2), there was almost no effect on the urine volume (Figure 1).

[0070] 4) Figures 1 and 2 show that in Group 3 with oliguria (defined as a daily urine volume of 400 mL or less), increasing salt removal by peritoneal dialysis may have a negative effect on residual renal function, whereas in Group 4 with anuria (defined as a daily urine volume of 100 mL or less), no effect was observed.

[0071] 5) Judging from the data of Group 1, Figures 1 and 3 show that the first peritoneal dialysis solution X alone appears to be suitable for adjusting water balance and sodium balance. However, an adverse event (abnormal fluctuation in blood sodium concentration: normal value → abnormal value) was observed in one patient who used the first peritoneal dialysis solution X five times a day. Therefore, it is clear that the number of times peritoneal dialysis solution X is used must be limited.

[0072] 6) As can be seen from Figure 3, in Groups 1, 2, and 3, in order to balance the salt intake amount recommended in the peritoneal dialysis guidelines, it is sufficient to increase the amount of salt removed by peritoneal dialysis by about 1 to 2 g per day compared to the amount of salt removed by existing peritoneal dialysate (second peritoneal dialysate A or a combination of second peritoneal dialysate A and peritoneal dialysate B).

[0073] 7) Table 5 shows that the amount of salt removed per peritoneal dialysis session with the first peritoneal dialysis solution X is approximately 1 g greater than that with the second peritoneal dialysis solution A in all three groups: Group 1, Group 2, and Group 3.

[0074] From the above 1) to 7), it has been found that although the peritoneal dialysates disclosed in Patent Document 4 and Non-Patent Document 3 have almost zero residual sodium, when these peritoneal dialysates are used clinically alone or in combination, there is a risk of hyponatremia due to excessive salt removal, and further there is concern about adverse effects on residual renal function.

[0075] Test Example 2 To address the above problem, an investigation was conducted based on the data obtained in Test Example 1, and the expected daily volume of water removal (mL / day) and the expected daily volume of salt removal (g / day) were calculated when using a combination of the first peritoneal dialysate X with the second peritoneal dialysate A and / or the second peritoneal dialysate B. The results are shown in Figure 4. As shown in Figure 4, by using up to one or two bottles of the first peritoneal dialysate X per day and using the remainder in combination with the second peritoneal dialysate A and / or the second peritoneal dialysate B, more treatment options for water removal and salt removal are available than before, and it can be seen that the balance of water and sodium can be appropriately managed while avoiding adverse effects on residual renal function.

[0076] Furthermore, by using this method, even if drainage problems occur twice consecutively while using the first peritoneal dialysis solution X, it is possible to avoid the risk of hyponatremia, as shown in Figure 5.

[0077] FIG. 5 shows the results of a simulation of the extent to which the sodium concentration in the extracellular fluid is diluted when the injected peritoneal dialysate is completely absorbed by the body.

[0078] Specifically, the calculation was performed as follows: If, based on the water distribution of body fluids, the extracellular fluid volume is 20% of body weight, then the extracellular fluid volume for a patient weighing 60 kg would be 12 L. Assuming that 2 L of the first peritoneal dialysis fluid X (Na concentration 126 mEq / L) is completely absorbed into the body due to drainage problems, the extracellular fluid with a Na concentration of 135 mEq / L would be diluted to 133.7 mEq / L, as shown in the following formula.

[0079]

[0080] Similarly, in the second run, the extracellular fluid with a Na concentration of 133.7 mEq / L is diluted to 132.6 mEq / L as shown in the following formula.

[0081]

[0082] This is performed four times to obtain the results for a body weight of 60 kg. The same calculation is performed for a body weight of 30 kg.

[0083] To make the conditions more stringent, the body weight was fixed and the extracellular fluid volume was calculated as 20% of the body weight. The results are shown in Figure 5A.

[0084] Next, when the third and fourth peritoneal dialysis fluids were replaced with the existing standard sodium concentration (135 mEq / L), the extracellular sodium concentration was corrected toward 135 mEq / L. The results are shown in Figure 5B.

[0085] Generally, the lower the body weight, the greater the impact, but even if the patient weighs 30 kg, if drainage trouble occurs no more than twice, the extracellular fluid sodium concentration is unlikely to fall below 130 mEq / L. It is known that clinical symptoms do not usually appear up to 130 mEq / L.

[0086] As described above, as shown in Figures 4 and 5, by using up to one or two bottles of the first peritoneal dialysis solution X per day and using the remainder in combination with the second peritoneal dialysis solution A and / or the second peritoneal dialysis solution B, it is possible to appropriately manage the balance of water and sodium during peritoneal dialysis treatment without causing hyponatremia and while avoiding adverse effects on residual renal function.

[0087] This application is based on Japanese Patent Application No. 2018-036394 filed on March 1, 2018, the disclosure of which is incorporated herein by reference in its entirety.

Claims

DEPCT641. Peritoneal dialysate containing 1.5 to 1.8 w / v% glucose and 120 to 130 m³ / L sodium is administered independently once or twice daily. This dialysate is used in combination with another peritoneal dialysate containing 1.35 to 2.5 w / v% glucose and 132 to 135 m³ / L sodium. The peritoneal dialysate involves the injection of 1.5 to 2.0 liters per dose into the patient's peritoneal cavity, followed by collection and drainage. Three to five times per day.

2. Dialiset through the peritoneal membrane under claim 1, which includes 123 to 128 milliequivalents / liter of sodium.

3. Dialiset through the peritoneal membrane under claim 1 or 2, which further includes 2.0 to 4.0 milliequivalents / liter of calcium; 0.5 to 1.5 milliequivalents / liter of magnesium; 86.0 to 98.0 milliequivalents / liter of chlorine; and 35 to 40 milliequivalents / liter of alkaline agent.

4. Dialiset through the peritoneal membrane under any one of claims 1 to 3, where other dialisets through the peritoneal membrane also include 2.3 to 4.0 milliequivalence / liter of calcium; 0.5 to 1.5 milliequivalence / liter of magnesium; 95.0 to 105.5 milliequivalence / liter of chlorine; and 35 to 40 milliequivalence / liter of alkaline agent.

5. Peritoneal dialysate set consisting of: primary peritoneal dialysate containing 1.5 to 1.8 weight / volume% of glucose and 120 to 130 milliequivalence / liter of sodium; and secondary peritoneal dialysate containing 1.35 to 2.5 weight / volume% of glucose and 132 to 135 milliequivalence / liter of sodium, where the primary peritoneal dialysate and secondary peritoneal dialysate were administered. A second, independently administered peritoneal dialysis was used three to five times daily in peritoneal dialysis, involving the injection of 1.5 to 2.0 liters into the patient's peritoneal cavity, collection, and drainage, where the first peritoneal dialysis was administered once or twice daily. The composition for use in peritoneal dialysis included 1.5 to 1.8 weight / volume% of glucose and 120 to 130 milliequivalents / liter of sodium, which was used in combination with other components containing 1.35 to 2.

5. The method for intraperitoneal dialysis consists of: independently injecting 1.5 to 2.0 liters of each dialiset into the patient's peritoneal cavity, collected and drained three to five times daily, where the dialiset contains 1.5 to 1.8 weight / volume% glucose and 120 to 130 milliequivalents / liter of sodium and is used once or twice daily; and collecting and draining the dialiset three to five times daily.