Blood purifier, blood purification device, and method of operating the blood purification device

Abstract

The present invention provides a blood purifier that enables large-volume post-HDF filtration with a replacement fluid volume of 20 L or more while minimizing albumin leakage and / or fluctuations in the intermembrane pressure difference. [Solution] A blood purifier in which bundles of hollow fiber membranes with an inner diameter greater than 200 μm and 250 μm or less are filled into a container at a filling rate of 55% to 70%, and when subjected to a predetermined circulation test using predetermined bovine blood, the total amount of protein leakage is 0.30 to 0.65 compared to the total amount of protein leakage of a blood purifier made of the same material and having the same configuration except that the inner diameter of the hollow fiber membrane is 200 μm, and the pressure loss value (ΔPB) at 10 minutes after the start of the circulation test is 0.30 to 0.65. 10 ) is a blood purifier with the same configuration as ΔPB, except that the inner diameter of the hollow fiber membrane is 200 μm. 10 A blood purifier with a value between 0.60 and 0.85.

Description

[Technical Field]

[0001] This disclosure relates to a blood purifier, a blood purifying device, and a method for operating a blood purifying device, which are suitable for performing post-dilution type hemodiafiltration by increasing the replacement fluid volume or total filtration volume. [Background technology]

[0002] Hemodiafiltration (HDF), a blood purification method, is being adopted by many medical institutions, partly due to the establishment of a new technical fee for online HDF in the 2012 revision of the medical fee regulations. Furthermore, research to investigate the clinical effects of HDF or online HDF is being conducted worldwide, and the results are being published.

[0003] For example, Non-Patent Document 1 presents data that investigates and analyzes mortality rates when the total filtration volume (convection volume) in online hemodialysis (HD) is varied, using hemodialysis (HD) as the baseline. Non-Patent Document 1 describes the process of performing post-dilution online HDF (hereinafter referred to as "post-online HDF"), where the total filtration volume per blood purification procedure is 23 L / 1.73 m³. 2 They have reported that increasing this value reduces both overall mortality and mortality due to cardiovascular disease. [Prior art documents] [Patent Documents]

[0004] [Non-Patent Document 1] Peter J. Blankestijn et al., Clinical evidence on haemodiafiltration, Nephrol Dial Transplant (2018) 33: iii53-iii58 [Overview of the project] [Problems that the invention aims to solve]

[0005] The total filtration volume (convection volume) per blood purification procedure is the sum of the replacement fluid volume and the amount of fluid removed in one procedure. The replacement fluid volume corresponds to the total amount of substances (solute + solvent) that pass through the hollow fiber membrane of the blood purifier from the blood side to the dialysate side during one blood purification procedure. The greater the total filtration volume or replacement fluid volume, the more albumin in the blood moves (leaks) into the dialysate side. Albumin is a useful protein for patients, and increased albumin leakage is thought to lead to a decline in the patient's nutritional status and affect their prognosis.

[0006] This disclosure aims to provide a blood purifier and blood purification device that enables high-volume post-HDF, which is considered to have a lower mortality risk, to be performed with reduced albumin leakage and / or reduced fluctuations in the transmembrane pressure difference (TMP). It also aims to provide a method for operating the blood purification device that enables such online HDF. [Means for solving the problem]

[0007] This disclosure provides, as one embodiment, a blood purifier in which hollow fiber membranes are packed in bundles into a cylindrical container, The inner diameter of the hollow fiber membrane is greater than 200 μm and less than or equal to 250 μm. The bundle of hollow fiber membranes is filled in the container with a filling rate of 55% to 70%. The aforementioned blood purifier uses bovine blood with a total protein concentration (TP) of 6.0 g / dL or more and 6.5 g / dL or less, and a hematocrit (Ht) of 32 ± 2%, and the blood flow rate Q B Dialysis fluid volume Q: 300 mL / min D Set to 0 mL / min, blood filtration rate Q F When subjected to a circulation test at a flow rate of 100 mL / min for 240 minutes, 1) A) The total amount of protein leakage is equal to the amount of protein lost per 1 m² of membrane area. 2 It is 1.0g or less per serving, and B) Intermembrane pressure difference (TMP) 10 minutes after the start of the circulation test 10 ) The intermembrane pressure difference (TMP) at 240 minutes after the start of the circulation test240 ) ratio (TMP 10 / TMP 240 ) is 0.77 or more, or 2) A) the total amount of total protein leakage is more than 1.0 g and 2.5 g or less per 1 m 2 of membrane area, and B) the ratio of the transmembrane pressure difference (TMP 10 ) at 240 minutes after the start of the circulation test to the transmembrane pressure difference (TMP 240 ) at 10 minutes after the start of the circulation test (TMP 10 / TMP 240 ) is 0.80 or more, A blood purifier is provided.

[0008] The present disclosure also provides, as another embodiment, a blood purification apparatus comprising a blood flow path including an arterial blood line and a venous blood line connected to a blood purifier, a dialysate flow path including a dialysate supply line and a dialysate discharge line connected to the blood purifier, a blood pump disposed on the blood flow path, a dialysate supply pump disposed on the dialysate flow path, a replacement fluid supply flow path connected to the blood flow path at the venous blood line, and a replacement fluid pump disposed on the replacement fluid flow path line, As the blood purifier, a large-diameter hollow fiber membrane blood purifier in which hollow fiber membranes having an inner diameter of more than 200 μm and 250 μm or less are packed in a container in a bundle at a packing ratio of 55% or more and 70% or less can be attached, When the large-diameter hollow fiber membrane blood purifier is attached, the filtration flow rate Q F is 80 mL / min or more and 130 mL / min or less, the blood flow rate is three times or more of Q F , and the dialysate flow rate Q D is 300 mL / min or more and 700 mL / min or less, the blood pump and the dialysate supply pump are controlled so that hemodiafiltration is performed, and the treatment time is controlled so that the replacement fluid volume in one blood purification treatment is 20 L or more. The blood purification apparatus is provided with a control means for performing the control.

[0009] This disclosure further describes a method for operating a blood purification device, which, in another embodiment, includes a blood flow path including an arterial blood line and a venous blood line connected to a blood purifier, a dialysate flow path including a dialysate supply line and a dialysate discharge line connected to the blood purifier, a blood pump provided on the blood flow path, a dialysate supply pump provided on the dialysate flow path, a replacement fluid supply flow path connected to the blood flow path by the venous blood line, and a replacement fluid pump provided on the replacement fluid flow path line. As the blood purifier, a blood purifier is used in which hollow fiber membranes with an inner diameter greater than 200 μm and 250 μm or less are bundled together and filled into a container with a filling rate of 55% to 70%, and The filtration flow rate is calculated from the discharge volume of the blood pump and the discharge volume of the dialysate supply pump, and the replacement fluid volume is determined from the calculated filtration flow rate and the operating time of the blood purification device. The present invention provides a method for operating a blood purification device, including the following: [Effects of the Invention]

[0010] The blood purifier of this disclosure is equipped with a hollow fiber membrane with an inner diameter greater than 200 μm and less than or equal to 250 μm, making it possible to suppress albumin leakage even when performing hemodialysis filtration with a blood filtration rate of approximately 100 mL / min and a replacement fluid volume of 20 L or more. Therefore, the blood purifier of this disclosure makes it possible to perform high-volume filtration, which is considered to have a low risk of death, with less impact on the patient's nutritional status. [Modes for carrying out the invention]

[0011] (Background leading to the embodiments of this disclosure) As mentioned above, although it has already been reported that high-volume post-HDF can reduce overall mortality, it has not yet been widely adopted in medical practice. One reason for this is the leakage of albumin due to the large volume of blood that is filtered.

[0012] The inventors investigated the configuration of a blood purifier (including those marketed as "dialyzers," "blood filters," or "hemodialysis machines") to enable safer mass filtration post-HDF. The inventors discovered that one of the factors affecting albumin leakage is the inner diameter of the hollow fiber membrane, and found that increasing this diameter beyond a certain value suppresses the increase in albumin leakage.

[0013] Furthermore, the inventors confirmed that TMP does not fluctuate significantly even when the inner diameter of the hollow fiber membrane is increased. One factor that affects albumin leakage is an increase in the intermembrane pressure difference (TMP). When performing post-dilution or post-replacement type online HDF (hereinafter referred to as "high-volume filtration post-HDF") with a large amount of replacement fluid per cycle in the blood purification device, the amount of blood components passing through the hollow fiber membrane is large, making it easy for TMP to increase due to fouling, etc. When TMP increases, the albumin sieving coefficient increases, and more albumin leaks out. The inventors confirmed that TMP does not increase significantly even when high-volume filtration is performed with a large inner diameter of the hollow fiber membrane, and found that a blood purification device with a large inner diameter of the hollow fiber membrane is practical for high-volume filtration post-HDF. Hereinafter, we will first describe a blood purifier, which is one embodiment of the present disclosure.

[0014] (Blood purifier) One embodiment of the blood purifier described herein has a structure in which hollow fiber membranes, formed by shaping a porous membrane into hollow fibers, are bundled together and filled into a container. One form of a blood purifier with such a structure is marketed as a hemodialyzer, hemofilter, or dialyzer. The structure of the hollow fiber membrane will be described below.

[0015] <Hollow fiber membrane> In this embodiment, the hollow fiber membrane has an inner diameter greater than 200 μm and less than or equal to 250 μm, particularly greater than 210 μm and less than or equal to 250 μm, and more particularly greater than or equal to 215 μm and less than or equal to 250 μm. The inner diameter of the hollow fiber membrane affects the rate of albumin leakage and the time-dependent changes in TMP during hemodialysis filtration, and by keeping the inner diameter within the above range, the time-dependent changes in albumin leakage and TMP are suppressed. If the inner diameter of the hollow fiber membrane is too small, the time-dependent changes in albumin leakage and TMP tend to be large. If the inner diameter of the hollow fiber membrane is too large, the strength of the hollow fiber membrane tends to be lower compared to a membrane with the same film thickness but a smaller inner diameter.

[0016] The inner diameter of a hollow fiber membrane can be determined from an SEM image of the cross-section of the hollow fiber membrane (in a direction perpendicular to the length of the hollow fiber membrane). The inner diameter of a hollow fiber membrane may vary depending on its manufacturing conditions. In this embodiment, 20 hollow fiber membranes are arbitrarily selected from those contained in a single blood purifier, and the average value of the inner diameters measured by observing their cross-sections is taken as the inner diameter of the hollow fiber membranes in the blood purifier.

[0017] The hollow fiber membrane may be formed by mixing a hydrophilic polymer with a hydrophobic polymer. Examples of hydrophilic polymers include polysulfone resins, polyethersulfone resins, polyamide resins, polyimide resins, polyphenyl ether resins, and polyphenylene sulfide resins.

[0018] Examples of hydrophilic polymers include polyethylene glycol, polyvinyl alcohol, carboxymethylcellulose, and polyvinylpyrrolidone. Polyvinylpyrrolidone is preferred due to its hydrophilic properties, safety, and industrial availability.

[0019] In this embodiment, the hollow fiber membrane may have a film thickness of, for example, 10 μm to 100 μm, particularly 10 μm to 50 μm, and more particularly 30 μm to 45 μm. If the film thickness is too small or too large, spinning the hollow fiber membrane may become difficult. Also, if the film thickness is too small, the strength of the hollow fiber membrane may decrease. If the film thickness is too large, the diffusion or filtration of urea, β2-MG, etc., in the blood through the hollow fiber membrane may be hindered, resulting in a decrease in their clearance performance. Also, if the film thickness is too large, the thickness of the hollow fiber membrane increases, making it difficult to insert the hollow fiber membrane into the housing when filling a container of a predetermined size to a predetermined membrane area, which may reduce the yield.

[0020] The dimensions of the fine pores formed in the hollow fiber membrane, i.e., the pore size, may be, for example, 40 Å to 80 Å, particularly 42 Å to 78 Å, and more particularly 48 Å to 73 Å. The pore size is selected according to the molecular weight of the substance to be removed by the blood purifier. In hemodiafiltration, for example, if the removal of high molecular weight substances such as α1-MG is emphasized, the pore size may be set to 55 Å to 75 Å, and if the removal of β2-MG is emphasized, it may be set to 45 Å to 75 Å. The pore size is a value measured by a method using a dextran solution, as described later.

[0021] The hollow fiber membrane may be crimped. The crimp may be applied, for example, by rotating two gears having meshing teeth, passing the hollow fiber membrane between the rotating gears, and, if necessary, heat-treating the membrane during or after passing to fix the crimp. Another method of applying the crimp is to wind the hollow fiber membrane onto a bobbin or cone, heat-treat it, and then unwind it from the bobbin or cone. The crimp may be applied by methods other than those described above. The shape of the crimp may be sinusoidal, with sharp or rounded bends, or a combination thereof. The pitch and amplitude of the crimp are not particularly limited; the pitch may be, for example, 1 mm to 20 mm, particularly 4 mm to 8 mm, and the amplitude may be 2 mm to 8 mm, particularly 4 mm to 6 mm. The pitch and amplitude of the crimp may vary within a single hollow fiber membrane. Furthermore, a single blood purifier may include two or more hollow fiber membranes having different forms of crimp, or it may include a hollow fiber membrane with crimp and a hollow fiber membrane without crimp.

[0022] <Blood Purifier> Next, a blood purifier constructed using the hollow fiber membrane described above will be explained. The blood purifier has a configuration in which a bundle of hollow fiber membranes is filled into a cylindrical container. The cylindrical container has a housing that has ends with ports for supplying and discharging dialysate, and a body containing most of the length of the hollow fiber membrane, similar to blood purifiers normally used in hemodialysis or hemodiafiltration, and headers attached to both ends of the housing. The ends of the housing usually have larger inner and outer diameters than the body. The ends may have a tapered shape in which the inner diameter decreases towards the body. The headers have ports for inlet and outlet of blood and are attached after the housing is filled with hollow fiber membranes and both ends are potted.

[0023] The potting of the hollow fiber membrane bundle is performed with the hollow fiber membrane filled into the housing. The potting agent used may be a resin composition containing polyurethane resin, epoxy resin, or silicone resin. The potting is performed so that the hollow fiber membrane is fixed over an area of ​​more than 0 mm and less than or equal to 8.0 mm from both ends of the hollow fiber membrane.

[0024] In the blood purifier of this embodiment, the hollow fiber membrane has a membrane area of ​​0.9 m². 2 Approximately 3.0m 2 The following, in particular, is about 1.4m 2 Approximately 2.8m 2 Below, approximately 1.9m 2 About 2.5m or more 2 The cylindrical container may be filled as follows. The membrane area is calculated from the effective length L (mm) and inner diameter D (μm) of the hollow fiber membrane, pi π, and the number of hollow fiber membranes n in the cylindrical container, according to the following formula. Membrane area (mm 2 ) = n × L × π × B × 10 -9 Here, the effective length of the hollow fiber membrane is measured as the distance between the inner ends of the potting in the hollow fiber membrane. Here, the inner end of the potting refers to the end of the potting material (e.g., resin) that secures the bundle of hollow fiber membranes, closest to the center of the body of the blood purifier.

[0025] A larger membrane surface area increases dialysis and filtration efficiency (e.g., clearance of urea, creatinine, etc.), enabling more stable and high-volume filtration. On the other hand, since the dimensions of the blood purifier container are generally fixed, increasing the membrane surface area increases the packing density, narrows the flow path of the dialysate, and can increase pressure loss on the dialysate side. Also, a larger membrane surface area tends to result in greater albumin leakage.

[0026] In the blood purifier of this embodiment, the ratio of the effective length L (mm) to the inner diameter D (mm) of the cylindrical container (L / D) may be, for example, 6.9 or more and 7.6 or less, and particularly 7.1 or more and 7.5 or less. As L / D increases, the amount of albumin leakage tends to increase, but even when L / D is within this range, the blood purifier of this embodiment can reduce the amount of albumin leakage associated with large-volume filtration relatively small.

[0027] The blood purifier of this embodiment may be provided in a sterilized state by irradiation with an electron beam or radiation (e.g., gamma rays). Sterilization by irradiation with an electron beam or radiation may be performed with the blood purifier sealed in an airtight packaging bag, or with the blood purifier sealed in the packaging bag placed in a case such as a cardboard box. However, the sterilization method is not limited to these.

[0028] The blood purifier of this embodiment has a configuration in which bundles of hollow fiber membranes are filled into a cylindrical container to a filling rate of 55% to 70%, and uses bovine blood with a total protein concentration (TP) of 6.0 g / dL to 6.5 g / dL and a hematocrit (Ht) of 32 ± 2%, with a blood flow rate Q B Dialysis fluid volume Q: 300 mL / min D Set to 0 mL / min, blood filtration rate Q F When subjected to a circulation test at a flow rate of 100 mL / min for 240 minutes, 1) A) The total amount of protein leakage is equal to the amount of protein lost per 1 m² of membrane area. 2 It is 1.0g or less per serving, and B) Intermembrane pressure difference (TMP) 10 minutes after the start of the circulation test 10 ) The intermembrane pressure difference (TMP) at 240 minutes after the start of the circulation test 240 ) ratio (TMP 10 / TMP 240 ) is 0.77 or higher, or 2)A) The total amount of protein leakage is when the membrane area is 1 m². 2 It is greater than 1.0g and less than or equal to 2.5g per serving, and B) Intermembrane pressure difference (TMP) 10 minutes after the start of hemodialysis filtration 10 ) The intermembrane pressure difference (TMP) at 240 minutes after the start of the circulation test240 ) ratio (TMP 10 / TMP 240 ) is 0.80 or higher. It is provided as a product.

[0029] The filling rate refers to the rate at the center of the cylindrical container's body, and corresponds to the ratio of the area of ​​the hollow fiber membrane to the area of ​​the container's cavity when observing the cross-section at the center of the body. The filling rate varies depending on the membrane area required by a single blood purifier, and in cases where the membrane area is small, the product may be designed so that the filling rate is less than 55%. Even in such cases, the blood purifier may be included in this embodiment as long as it exhibits the above characteristics regarding albumin leakage when the hollow fiber membrane is filled to a filling rate of 55% or more and 70% or less and subjected to the circulation test described above.

[0030] In this embodiment, the total protein leakage during a predetermined circulatory test and TP are used as indicators to evaluate the amount of albumin leakage when hemofiltration is performed under predetermined conditions. Since albumin accounts for a larger proportion of total protein in the blood (especially total serum protein) than other proteins, a larger total protein leakage will result in a larger albumin leakage (and vice versa).

[0031] The circulatory test, total protein leakage, and total protein concentration (TP) measurement will be described in detail in the examples. The conditions for the circulatory test used here, namely the blood filtration rate Q, will be explained here. F Setting the flow rate to 100 mL / min means that when a 4-hour circulation test is performed, the total volume of blood components passing through the hollow fiber membrane in the hemodialysis filter is 24 L. This condition is similar to that of high-volume post-online HDF and evaluates the performance of the blood purifier when a large volume of blood is filtered without dilution. It is a more stringent condition compared to online HDF performed with pre-dilution.

[0032] Under the above conditions, the dialysate volume Q DThe flow rate is set to 0 mL / min, and both the blood components that pass through the hollow fiber membrane without filtration and the blood components that pass through the hollow fiber membrane (filtrate) are returned to the blood supply and circulated. Therefore, the test is conducted without or with minimal change in the concentration of the test solution during the circulation test. By suppressing the concentration change of the test solution during the test, the concentration of components filtered from the blood components can be kept almost constant during the test, thus enabling accurate evaluation.

[0033] Furthermore, when evaluating the clearance of a hemodialysis filter, a single-pass evaluation method is sometimes employed, in which the blood purified by the blood purifier is discarded without being circulated back into the blood circuit. This evaluation method exists to prevent the destruction of solutes in the blood, considering that prolonged circulation tests can cause this. Conversely, single-pass evaluation can be said to be a method for evaluating hemodialysis filters that may not be able to withstand prolonged clinical use of hemodialysis. In the embodiments of this embodiment described later, evaluation was carried out using a circulation test, but no destruction of solutes in the blood occurred in any of the embodiments. This result is evidence that the blood purifier of this embodiment is highly safe and can withstand prolonged clinical use.

[0034] As described above, the blood purifier of this embodiment has a total protein leakage rate of 1 m² of membrane area. 2 When the amount is 1.0g or less per unit, the intermembrane pressure difference (TMP) at 10 minutes after the start of the circulation test. 10 ) The intermembrane pressure difference (TMP) at 240 minutes after the start of the circulation test 240 ) ratio (TMP 10 / TMP 240 The device is provided with a value of 0.77 or higher. Such blood purifiers tend to be obtained when using hollow fiber membranes with relatively small pore sizes, for example, hollow fiber membranes with a pore size of 65 Å or less.

[0035] The transmembrane pressure difference (TMP) correlates with blood filtration rate, and beyond a certain value, blood filtration rate does not increase. An increase in TMP can also be caused by membrane contamination or clogging, resulting in the undesirability that small pores are blocked, preventing the removal of moderately molecular weight substances, while larger molecules (especially albumin) pass through the hollow fiber membrane and are removed. The smaller the pore size of the hollow fiber membrane, the more pronounced the increase in TMP becomes. 10 / TMP 240 The amount tends to decrease. According to the blood purifier of this embodiment, the hollow fiber membrane is such that the total amount of total protein leakage decreases (for example, membrane area 1 m² 2 Even with a small pore size (less than 1.0 g per pore), the degree of increase in TMP during treatment can be suppressed. Therefore, according to this embodiment, even when the blood filtration rate is increased and blood purification treatment is performed, hemodiafiltration can be performed stably, and the preferential passage and leakage of large molecular weight molecules (especially albumin) through the hollow fiber membrane can be suppressed.

[0036] In this case, the total amount of protein leakage is calculated per 1 m² of membrane area. 2 It may be 0.5g or less per unit, especially 0.3g or less, and more especially 0.2g or less. Also, TMP 10 / TMP 240 It may be 0.80 or higher, especially 0.83 or higher.

[0037] Alternatively, the blood purifier of this embodiment has a total protein leakage rate of 1 m² of membrane area. 2 When the amount is greater than 1.0g but less than or equal to 2.5g, TMP 10 / TMP 240 It is provided that the value is 0.80 or higher. When the total amount of total protein leakage is within this range, the hollow fiber membrane has a relatively large pore size. In this case, TMP 10 / TMP 240 Because of its larger size, it becomes possible to perform more stable hemodialysis filtration while suppressing albumin leakage.

[0038] In this case, the total amount of protein leakage is calculated per 1 m² of membrane area.2 The amount may be greater than 1.0g and less than or equal to 2.0g, and in particular, it may be greater than 1.0g and less than or equal to 1.5g. Also, TMP 10 / TMP 240 It may be 0.83 or higher, and especially 0.85 or higher. Total protein leakage and TMP 10 / TMP 240 By maintaining the above-mentioned range, it is possible to provide a highly reliable blood purifier that enables appropriate treatment.

[0039] Here, considering that the membrane area of ​​blood purifiers may vary depending on the product, we use a membrane area of ​​1 m². 2 This indicates the total amount of protein leakage per unit. In medical settings, the total amount of protein leaked during a single procedure tends to be used as an indicator of albumin leakage. Therefore, it is preferable to design the blood purifier considering the pore size and membrane area of ​​the hollow fiber membrane so that the total amount of protein leaked during the above circulation test is 5.3g or less, particularly 3.5g or less, more preferably 2.0g or less, and even more preferably 1.0g or less per blood purifier.

[0040] The blood purifier of this embodiment has a transmembrane pressure difference (TMP) of 10 minutes after the start of the circulation test. 10 ) may be 70 mmHg or less. TMP 10 If it becomes too large, TMP 10 / TMP 240 Even if the above range is met, the absolute value of TMP may become high near the end of hemodialysis filtration, making it impossible to secure the predetermined blood filtration volume (i.e., replacement fluid volume). 10 The pressure may be 68 mmHg or less, and more particularly 65 mmHg. Alternatively, if the inner diameter of the hollow fiber membrane is large (e.g., 230 μm to 250 μm) and / or the pore size is small (e.g., 65 Å or less), TMP 10 It may be 85 mmHg or less, and especially 75 mmHg or less. TMP 10 If the TMP is too low, backfiltration or excessive filtration may occur due to the high permeability of the membrane. Therefore, TMP 10The lower limit may be, for example, 55 mmHg, and especially 60 mmHg. TMP 10 By keeping the parameters within the aforementioned range, it becomes possible to more reliably implement appropriate treatment and provide a more reliable blood purification device.

[0041] TMP is measured by taking the pressure at the blood inlet / outlet and filtrate sides at regular intervals during the predetermined circulation test described above, and then determining the colloid osmotic pressure under predetermined conditions described later, and calculating TMP from these values. Details will be explained in the examples.

[0042] Alternatively, the blood purifier of this embodiment is a blood purifier in which hollow fiber membranes are filled in a cylindrical container in a bundle, The hollow fiber membrane has an inner diameter greater than 200 μm and less than or equal to 250 μm. The bundle of hollow fiber membranes is filled in the container with a filling rate of 55% to 70%. The aforementioned blood purifier uses bovine blood with a total protein concentration (TP) of 6.0 g / dL or more and 6.5 g / dL or less, and a hematocrit (Ht) of 32 ± 2%, and the blood flow rate Q B Dialysis fluid volume Q: 300 mL / min D Set to 0 mL / min, blood filtration rate Q F When subjected to a circulation test at a flow rate of 100 mL / min for 240 minutes, The total amount of protein leakage was between 0.30 and 0.65 compared to the total amount of protein leakage of blood purifiers made of the same material and identical in composition except that the inner diameter of the hollow fiber membrane was 200 μm. The pressure loss value (ΔPB) after 10 minutes from the start of the circulation test. 10 ) is a blood purifier with the same configuration as ΔPB, except that the inner diameter of the hollow fiber membrane is 200 μm. 10 For comparison, the value is between 0.60 and 0.85. It may be provided as a product.

[0043] The circulation test under the specified conditions described above is, as stated above, quite demanding for a hemodialysis machine. If a blood purifier filled with hollow fiber membranes having an inner diameter of 200 μm is subjected to this circulation test, the total protein leakage will be large, potentially affecting the patient. By increasing the diameter of the hollow fiber membrane, the blood purifier of this embodiment can reduce such effects compared to a blood purifier with substantially the same configuration (hollow fiber membrane material, pore size, packing density, L / D ratio, etc.) except for the inner diameter of the hollow fiber membrane being 200 μm. This enables safer high-volume filtration, which can improve the patient's prognosis.

[0044] Here, the pressure loss value (ΔP B ΔP is the difference between the blood inlet pressure and the blood outlet pressure, and its measurement method is as described below. B In circulatory tests, ΔP increases as the blood filtration rate increases. B The larger ΔP becomes, the more likely it is that clogging of the hollow fiber membrane is occurring. According to this embodiment, even if the blood filtration rate is increased, ΔP B This suppresses the rise in the material, making it less likely for the hollow fiber membrane to become clogged.

[0045] The blood purifier of this embodiment is configured as described above, and the filtration flow rate Q F It can be used in online hemodiafiltration (post-online HDF) with a flow rate of 80 mL / min to 130 mL / min. Since the treatment time for one hemodiafiltration is usually about 4 to 6 hours, the blood purifier of this embodiment allows for hemodiafiltration with a replacement fluid volume of approximately 20 liters or more in a single treatment. Also, the filtration flow rate Q F is blood flow Q B It is preferable to set it to about one-third or less of the filtration flow rate Q. F Increasing this value only leads to an increase in pressure and does not tend to improve filtration performance. Therefore, in medical settings, the blood flow rate Q during hemodialysis filtration is considered important. B Considering that the upper limit is set at around 400 mL / min, the filtration flow rate Q F The upper limit is approximately 130 mL / min.

[0046] From the viewpoint of reducing the overall mortality rate and the mortality rate due to cardiovascular diseases, the substitution fluid volume is particularly preferably 24 liters or more. Such a substitution fluid volume can be achieved, for example, when the single treatment time is 4 hours, by setting the filtration flow rate Q F to about 100 mL / min or more. In post-online HDF, blood is filtered through the hollow fiber membrane without being diluted, so the filtration flow rate Q F is set to 80 mL / min or more, particularly about 100 mL / min or more, whereby the hollow fiber membrane performs filtration under more stringent conditions. The blood purifier of the present embodiment suppresses an increase in TMP even under such stringent conditions, and enables hemodiafiltration in which the amount of albumin leaking out during a single treatment is suppressed.

[0047] (Blood purification device) The blood purifier of the present embodiment is used by being incorporated into a blood purification device. Hereinafter, the blood purification device of the present embodiment will be described. The blood purification device of the present embodiment includes: a blood flow path including an arterial blood line and a venous blood line connected to the blood purifier; a dialysate flow path including a dialysate supply line and a dialysate discharge line connected to the blood purifier; a blood pump provided on the blood flow path; a dialysate supply pump provided on the dialysate flow path; a substitution fluid supply flow path connected to the blood flow path at the venous blood line; and a substitution fluid pump provided on the substitution fluid flow path line, the blood purification device being characterized in that The blood purifier of the present embodiment can be mounted as the blood purifier, When the blood purifier of the present embodiment is mounted, under the flow rate conditions where the filtration flow rate Q F is 80 mL / min or more and 130 mL / min or less, the blood flow rate is three times or more of Q F , and the dialysate flow rate Q D is 300 mL / min or more and 700 mL / min or less, means for controlling the blood pump and the dialysate supply pump so that hemodiafiltration is performed, and It is provided with a control means for controlling the treatment time so that the substitution fluid volume in a single blood purification treatment is 20 L or more.

[0048] The blood purification apparatus of the present embodiment has a configuration generally included in blood purification apparatuses for performing post-online HDF, and when the blood purifier of the present embodiment is used, it is controllable so that large-volume filtration with a replacement fluid volume of 20 L or more, particularly 24 L or more can be performed during a single treatment session. The duration of a single treatment session may be 240 minutes or more and 360 minutes or less.

[0049] As described above, in order to perform large-volume filtration within 240 minutes to 360 minutes, the filtration flow rate Q F needs to be 80 mL / min or more, particularly about 100 mL / min or more, and 130 mL / min or less. In order to achieve such a filtration flow rate, the blood flow rate Q B is preferably about three times the filtration flow rate Q F , and the dialysate flow rate Q D is preferably 300 mL / min or more and 700 mL / min or less.

[0050] In order to control the filtration flow rate Q F , the blood purification apparatus of the present embodiment may be provided with a clamp on the circulation circuit. By providing the circulation circuit with the clamp, a positive pressure is applied to the blood circuit side to adjust TMP, so that a desired filtration flow rate can be achieved in combination with appropriately setting the blood flow rate Q B .

[0051] In the hemodiafiltration apparatus, the dialysate performs dialysis according to the osmotic pressure difference with blood, and serves as a medium for discharging blood components that have passed through the hollow fiber membrane via blood filtration to the outside of the apparatus. Therefore, in the hemodiafiltration apparatus of the present embodiment, the dialysate flow rate Q D is appropriately selected from the above range so that the dialysate fulfills these roles. In the present embodiment, the dialysate flow rate Q D is the flow rate of the dialysate supplied into the blood purifier.

[0052] The blood purification device of this embodiment includes a replacement fluid supply channel connected to the blood flow path in the venous blood line, and a replacement fluid pump provided on the replacement fluid flow path, so that post-online HDF can be performed. The replacement fluid supply channel may be branched from the channel that supplies dialysate from the dialysate tank (dialysis fluid supply channel), or it may be connected to a tank dedicated to replacement fluid. The replacement fluid pump replenishes (replaces) the blood components lost by hemofiltration, with a filtration flow rate Q F The pump is controlled to replenish the replacement fluid at a flow rate corresponding to the filtration flow rate Q. F It is preferable that the flow rate of the replacement fluid be controlled by means that can control the flow rate in response to fluctuations in the hemodiafiltration.

[0053] The blood purification device of this embodiment includes means for monitoring the hematocrit value (percentage of red blood cells in the blood) in the blood, and may further include means for controlling either or both of the blood pump and the dialysate supply pump according to the monitoring results of the monitoring means. The hematocrit value in the blood is one indicator of the patient's condition during hemodiafiltration, and by controlling either or both of the blood pump and the dialysate supply pump based on fluctuations in this value, the blood flow rate Q B and / or dialysate flow rate Q D By adjusting the blood pump, hemodialysis filtration can be performed more safely according to the patient's condition. F It is also controlled accordingly, and the filtration flow rate Q F is blood flow Q B It also becomes possible to control it so that it does not exceed one-third of that amount.

[0054] The normal hematocrit value is considered to be around 40% to 50% for adult males and around 35% to 45% for adult females. In this embodiment, the status of hemodiafiltration can be understood by monitoring the hematocrit value of the blood diluted with replacement fluid after hemofiltration, or by monitoring the hematocrit value of the withdrawn blood. In post-online HDF, the blood in the blood purifier tends to become concentrated, especially in the filtration flow rate QF As the value increases, this tendency becomes more pronounced. As a result, hematocrit values ​​may fall outside the normal range, potentially having clinically undesirable effects on the patient. Monitoring this allows for a more accurate understanding of the patient's condition during treatment, enabling the implementation of high-volume post-online HDF under appropriate conditions.

[0055] (How to operate a hemodialysis filtration device) This disclosure also discloses, as one embodiment, a method for operating a hemodialysis apparatus to enable high-volume filtration in a hemodialysis filtration apparatus capable of performing post-HDF. Specifically, A method for operating a blood purification device, comprising: a blood flow path including an arterial blood line and a venous blood line connected to a blood purifier; a dialysate flow path including a dialysate supply line and a dialysate discharge line connected to the blood purifier; a blood pump provided on the blood flow path; a dialysate supply pump provided on the dialysate flow path; a replacement fluid supply flow path connected to the blood flow path by the venous blood line; and a replacement fluid pump provided on the replacement fluid flow path line, As the blood purifier, a blood purifier is used in which hollow fiber membranes with an inner diameter greater than 200 μm and 250 μm or less are bundled together and filled into a container with a filling rate of 55% to 70%, and The filtration flow rate is calculated from the discharge volume of the blood pump and the discharge volume of the dialysate supply pump, and the replacement fluid volume is determined from the calculated filtration flow rate and the operating time of the blood purification device. The present invention provides a method for operating a blood purification device, including the following: [Examples]

[0056] The blood purifier of this embodiment will be described below with reference to examples. (Example 1) A hollow fiber membrane was prepared with an inner diameter of 215 μm, a film thickness of 40 μm, and a pore size of 62 Å, and was given a zigzag crimp with a pitch of 5.0 mm and an amplitude of 0.15 mm. The hollow fiber membrane was manufactured by a method that involved spinning a spinning stock containing these resins together with the hollow internal liquid from a spinneret, and then solidifying it in a coagulation bath, with the membrane being based on a polyethersulfone resin and containing 3.4% by mass of polyvinylpyrrolidone resin. The crimp was given by a method that involved passing a bundle of hollow fiber membranes between two gears having meshing teeth, and then heating it.

[0057] These 10,726 hollow fiber membranes were placed in a cylindrical container with a housing having an inner diameter of 38.9 mm and a body length of 305 mm, with a filling rate of 61.7% and a membrane area of ​​2.1 m². 2 The bundle of hollow fiber membranes was filled in this manner, and after potting each end of the bundle over a length of approximately 7.5 mm, headers were attached to both ends of the housing. Subsequently, sterilization was performed by irradiating with gamma rays (15 kGy) to obtain the blood purifier.

[0058] (Example 2) A hollow fiber membrane was prepared with an inner diameter of 215 μm, a film thickness of 40 μm, a pore size of 69 Å, and zigzag crimps with a pitch of 5.0 mm and an amplitude of 0.15 mm. The materials constituting the hollow fiber membrane were the same as those in Example 1. A blood purifier was obtained in the same manner as in Example 1, except that a bundle of these hollow fiber membranes was packed into a cylindrical container to a packing rate of 61.7%.

[0059] (Example 3) A hollow fiber membrane was prepared with an inner diameter of 215 μm, a film thickness of 40 μm, a pore size of 73 Å, and zigzag crimps with a pitch of 5.0 mm and an amplitude of 0.15 mm. The materials constituting the hollow fiber membrane were the same as those in Example 1. A blood purifier was obtained in the same manner as in Example 1, except that a bundle of these hollow fiber membranes was packed into a cylindrical container to a packing rate of 61.7%.

[0060] (Example 4) A hollow fiber membrane was prepared with an inner diameter of 230 μm, a film thickness of 40 μm, and a pore size of 62 Å, and was given a zigzag crimp with a pitch of 5.0 mm and an amplitude of 0.15 mm. The hollow fiber membrane was manufactured by a method that involved spinning a spinning stock containing these resins together with the hollow fluid from a spinneret, and then solidifying it in a coagulation bath, with the membrane being based on a polyethersulfone resin and containing 3.4% by mass of polyvinylpyrrolidone resin. The crimp was given by a method that involved passing a bundle of hollow fiber membranes between two gears having meshing teeth, and then heating it.

[0061] These 10026 hollow fiber membranes were placed in a cylindrical container with a housing having an inner diameter of 38.9 mm and a body length of 305 mm, with a filling rate of 63.7% and a membrane area of ​​2.1 m². 2 The bundle of hollow fiber membranes was filled in this manner, and after potting each end of the bundle over a length of approximately 7.5 mm, headers were attached to both ends of the housing. Subsequently, sterilization was performed by irradiating with gamma rays (15 kGy) to obtain the blood purifier.

[0062] (Example 5) A hollow fiber membrane was prepared with an inner diameter of 230 μm, a film thickness of 40 μm, a pore size of 69 Å, and zigzag crimps with a pitch of 5.0 mm and an amplitude of 0.15 mm. The materials constituting the hollow fiber membrane were the same as those in Example 1. A blood purifier was obtained in the same manner as in Example 1, except that a bundle of these hollow fiber membranes was packed into a cylindrical container to a packing rate of 63.7%.

[0063] (Example 6) A hollow fiber membrane was prepared with an inner diameter of 250 μm, a film thickness of 40 μm, and a pore size of 62 Å, and was given a zigzag crimp with a pitch of 5.0 mm and an amplitude of 0.15 mm. The hollow fiber membrane was manufactured by a method that involved spinning a spinning stock containing these resins together with the hollow fluid from a spinneret, and then solidifying it in a coagulation bath, with the membrane being based on a polyethersulfone resin and containing 3.4% by mass of polyvinylpyrrolidone resin. The crimp was given by a method that involved passing a bundle of hollow fiber membranes between two gears having meshing teeth, and then heating it.

[0064] These 9224 hollow fiber membranes were placed in a cylindrical container with a housing having an inner diameter of 38.9 mm and a body length of 305 mm, with a filling rate of 66.4% and a membrane area of ​​2.1 m². 2 The bundle of hollow fiber membranes was filled in this manner, and after potting each end of the bundle over a length of approximately 7.5 mm, headers were attached to both ends of the housing. Subsequently, sterilization was performed by irradiating with gamma rays (15 kGy) to obtain the blood purifier.

[0065] (Example 7) A hollow fiber membrane was prepared with an inner diameter of 250 μm, a film thickness of 40 μm, a pore size of 69 Å, and zigzag crimps with a pitch of 5.0 mm and an amplitude of 0.15 mm. The materials constituting the hollow fiber membrane were the same as those in Example 1. A blood purifier was obtained in the same manner as in Example 1, except that a bundle of these hollow fiber membranes was filled into a cylindrical container to a filling rate of 66.4%.

[0066] (Comparative Example 1) A hollow fiber membrane was prepared with an inner diameter of 200 μm, a film thickness of 40 μm, a pore size of 62 Å, and zigzag crimps with a pitch of 5.0 mm and an amplitude of 0.15 mm. The materials constituting the hollow fiber membrane were the same as those in Example 1. A blood purifier was obtained in the same manner as in Example 1, except that a bundle of these hollow fiber membranes was filled into a cylindrical container to a filling rate of 59.6%.

[0067] (Comparative Example 2) A hollow fiber membrane was prepared with an inner diameter of 200 μm, a film thickness of 40 μm, a pore size of 69 Å, and zigzag crimps with a pitch of 5.0 mm and an amplitude of 0.15 mm. The materials constituting the hollow fiber membrane were the same as those in Example 1. A blood purifier was obtained in the same manner as in Example 1, except that a bundle of these hollow fiber membranes was packed into a cylindrical container to a packing rate of 59.6%.

[0068] (Comparative Example 3) A hollow fiber membrane was prepared with an inner diameter of 200 μm, a film thickness of 40 μm, a pore size of 73 Å, and zigzag crimps with a pitch of 5.0 mm and an amplitude of 0.15 mm. The materials constituting the hollow fiber membrane were the same as those in Example 1. A blood purifier was obtained in the same manner as in Example 1, except that a bundle of these hollow fiber membranes was packed into a cylindrical container to a packing rate of 59.6%.

[0069] The pore sizes of the hollow fiber membranes used in each example and comparative example were measured after assembling the blood purifier according to the following procedure.

[0070] <Measuring pore size> (Priming, preparation of test solution) • Approximately 1 liter of RO water was flowed at approximately 150 mL / min into the blood side of the sample (blood purifier). • Approximately 5 liters of RO water were flowed at approximately 500 mL / min on the dialysate side of the sample. 7.5g of dextran 40,000 (average molecular weight 32,000-45,000, manufactured by Wako Pure Chemical Industries, Ltd., code: 049-22331) and 7.5g of dextran 60,000 (manufactured by Wako Pure Chemical Industries, Ltd., code: 047-30522) were added to 3L of RO water and dissolved to obtain a 0.5% dextran solution.

[0071] (sampling) • 2.2 L of the test solution was placed in a constant temperature water bath and heated. After confirming that the temperature was 37 ± 10°C during circulation, the test solution was circulated at a flow rate of 250 mL / min through the Bin side (blood inlet side) of the sample. The first 100 mL discharged from the Bout side (blood outlet side) was discarded. Furthermore, the test solution was filtered at 65 mL / min, and the filtrate (F) was taken from the dialysate outlet side of the sample and returned to the test solution tank for circulation. The flow rate was measured and adjusted using a graduated cylinder and stopwatch. • After 60 minutes of circulation, samples were taken in the following order: F, Bout (test solution on the Bout side), and Bin (test solution on the Bin side). After measurement, an amount of test solution (100 mL) equivalent to the amount of test solution initially discarded was added to the test solution tank to prepare the sample to be used in the following measurements.

[0072] (Measurement of solute) The peak intensity of dextran was measured by high-performance liquid chromatography (HPLC) under the following conditions. • HPLC measurement conditions Power Ram: Shodex Asahipak GF-510HQ+GF710 Column temperature: 350℃ Mobile phase: 50 mM sodium chloride aqueous solution Flow rate: 0.8mL / min Injection volume: 50μL Detector: RI (Differential Refractometer)

[0073] (Calculation of pore size) • Baseline correction was performed by subtracting the peak intensity at 14 minutes for Bin and Bout, and at 17 minutes for F. The sieving coefficients for each elution time were calculated using the following formula based on the HPLC chromatogram data. Sieving coefficient = 2 × CF ÷ (Cin + Cout) Cin: Dextran strength at the inlet side Cout: Dextran strength at the outlet side CF: Dextran strength of the filtrate

[0074] We measured pullulan with a known molecular weight (P-82, manufactured by Showa Denko K.K.) and created a calibration curve for elution time and dextran molecular weight. • Using a calibration curve of elution time and dextran molecular weight, each elution time is converted to molecular weight, and then the following formula is used. * The molecular weight was then converted to solute diameter. Solute diameter (Å) = Stokes radius (cm) × 2 × 10 8 = 3.06 × 10 -9 ×Molecular weight 0.456 ×2×10 8 *Artificial Organs, Vol. 13, No. 6, pp. 1460-1467: 1984, "Mechanism of Solute Membrane Permeation in Dialyzers" Artificial Organs, Vol. 39, No. 1, pp. 46-47: 2010, "Development of Novel PMMA-Based Artificial Human Organs" (Toray) A molecular weight-sieving coefficient graph was created, with molecular weight on the X-axis and the sieving coefficient for each molecular weight on the Y-axis. Based on the dextran intensities of F, Bin, and Bout after 60 minutes of circulation, the sieving coefficient at each elution time was determined, and the solute diameter at which the sieving coefficient was approximately 0.5 was defined as the pore size.

[0075] Albumin leakage amount and TMP of the blood purifier in each example and comparative example. 10 and TMP 240 The clearances of TMP, ΔPB, and various substances were evaluated after a predetermined time elapsed, including the following: The evaluation method is as follows.

[0076] <Preparation of physiological saline solution> Sodium chloride (manufactured by Yamazen Pharmaceutical Co., Ltd.) was dissolved in RO water to prepare physiological saline solution (0.9% sodium chloride aqueous solution). <Priming of blood purification devices> (1) More than 450 mL of physiological saline solution was passed through the blood side channel of the blood purifier at a flow rate of approximately 150 mL / min. (2) The fluid discharged from the outlet of the blood-side channel was guided to the dialysate-side channel, and 1 liter or more was passed through at a flow rate of approximately 150 mL / min. (3) The dialysate side channel was plugged, and physiological saline solution was again passed through only the blood side channel at approximately 150 mL / min. (4) The fluid flow was terminated after confirming that no air was being discharged from the blood side channel of the blood purifier.

[0077] <Preparation of bovine blood for testing> (1) Bovine blood (Tokyo Shibaura Organ Co., Ltd.) was treated with heparin sodium (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) to prevent anticoagulation. The amount of heparin sodium added was approximately 10,000 units per liter of blood. (2) After filtering the bovine blood through four pieces of gauze, a portion was centrifuged at 3500 rpm for 5 minutes to collect bovine plasma. (3) The total protein concentration (TP) of bovine blood and bovine plasma was measured. Details of the measurement method are as follows in "(Solute Concentration Measurement)". The TP of bovine plasma was measured using plasma collected by centrifuging bovine blood at 3000 rpm for 10 minutes. (4) The hematocrit value (Ht) of bovine blood was measured. Ht was measured by i) placing bovine blood in a glass capillary tube and centrifuging it at approximately 10,000 rpm for 3 minutes, and ii) measuring the lengths of the blood cell components and plasma components after centrifugation and calculating Ht from their ratio. (5) Bovine blood was mixed with bovine plasma and physiological saline to prepare bovine blood for circulation testing (Ht=32±2%, TP=6.0±0.5g / dL). (6) Bovine blood was prepared by adding bovine plasma and physiological saline solution containing evaluation solutes (urea (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.), β2-MG (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.), and prolactin (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) to bovine blood to prepare bovine blood for clearance measurement (Ht=32±2%, TP=6.0~6.5g / dL, urea=125±25mg / dL, β2-MG=300±100μg / L, prolactin≧15μg / L).

[0078] <Circulation Test> (1) Approximately 2.2 L of the circulating test fluid was heated to 37°C in a constant temperature water bath. (2) Approximately 10 mL of bovine blood for circulating tests was collected for TP concentration measurement. (3) After priming, 250 mL or more of bovine blood for the circulation test was passed through the blood purifier to replace the priming fluid in the blood purifier with bovine blood for the circulation test. (4)Q B =300 mL / min, Q F = 100 mL / min, Q D Filtration circulation was started at 0 mL / min. The circulation flow rate was measured by collecting blood in a graduated cylinder while timing with a stopwatch, and the amount of blood collected per minute was used to determine the circulation flow rate. If the flow rate was not as specified, the pump flow rate was adjusted to achieve the desired flow rate. (5) Every 10 minutes from the start of circulation, the blood inlet pressure (PBin), blood outlet pressure (PBout), and filtrate pressure (PF) (all in mmHg) were measured, and approximately 3 mL of filtrate was collected. This procedure was carried out until 1 hour of circulation. (6) The blood purifier was removed from the circulatory circuit, and clearance was measured one hour after circulation. Then the blood purifier was reconnected to the circuit and circulation was started again. Details of the clearance measurement are as described in "Clearance Measurement" below. (7) Every 30 minutes from the start of recirculation, PBin, PBout, and PF were measured in the same manner as in operation (5), and filtrate samples were taken. This operation was continued until the total circulation time was 4 hours. (8) Remove the blood purifier from the circulatory circuit and measure the clearance after 4 hours of circulation, then reconnect it to the circuit and Q B Circulation was started at 300 mL / min. (9)Q F Four different Q values ​​for ≤30 mL / min F Measure the pressure with Q F and TMP O (TMP O = (PBin + PBout) ÷ 2 - P F From the relationship (vertical axis: QF, horizontal axis: TMP), the colloid osmotic pressure π was obtained from the linear approximation. p We calculated (Q F = 0 mL / min TMP O (This was defined as colloid osmotic pressure). Colloid osmotic pressure was measured only once per sample of bovine blood (procedures (8) and (9)). When circulatory tests were performed on different test days, colloid osmotic pressure was measured only once per sample of bovine blood on each test day using a blood purifier of the appropriate type.

[0079] (Clearance measurement) The blood purifier was set into a Nipro Corporation personal dialysis machine "NDF-21" one hour and four hours after the start of the circulation test, and the clearance was measured using the method described below. (1) Bovine blood for clearance measurement was heated to 37±1℃ in a constant temperature water bath. Kindaly dialysis agent AF2 (manufactured by Fuso Pharmaceutical Industries, Ltd.) was also set in the dialysis machine. (2) The blood flow rate and dialysate flow rate of the dialysis machine were adjusted to the flow rates for each condition. The fluid flow rate was Q B =300 mL / min, Q D The flow rate was 500 mL / min, and was measured and adjusted using a graduated cylinder and stopwatch. (3) The sample was placed in the dialysis machine and dialysis was started. Approximately 30 seconds after the start of dialysis, the flow rate at the blood outlet was measured using a graduated cylinder and stopwatch to confirm the amount of fluid removed. The amount of fluid removed was set to 100 mL / min. (4) After passing approximately 1 liter of bovine blood for clearance measurement through the dialysate outlet, approximately 10 mL each of dialysate and bovine blood for clearance measurement were collected from the dialysate outlet, the blood outlet, and the blood inlet in that order. The concentration of the target substance (solute) in the collected dialysate and bovine blood was measured, and the clearance was calculated.

[0080] (Solute concentration measurement) The methods for measuring each solute concentration are described below. Blood samples were collected by centrifugation at 3000 rpm for 10 minutes, and the solute concentrations were measured from the collected plasma. A) Measurement of TP concentration in bovine blood before preparation Measurement reagent: ESP-TP (manufactured by Fujifilm Wako Pure Chemical Corporation) (Biuret method) Standard solution: Anaceram ALB-TP standard solution (TP = 6.0 g / dL) (manufactured by Sekisui Medical Co., Ltd.) operation (1) 33.3 μL of the sample and standard solution were collected, and 2 mL of the measurement reagent was added. (2) The sample was heated in a 37°C constant temperature water bath for 10 minutes. (3) The absorbance at a wavelength of 550 nm was measured using a Hitachi U-3900H spectrophotometer. (4) A calibration curve was created from the results of the standard solution, and the TP concentration in bovine blood was calculated.

[0081] B) Measurement of total protein concentration (TP) in bovine blood for circulation testing and clearance measurement. Measurement reagent: ESP-TP (manufactured by Fujifilm Wako Pure Chemical Corporation) (Biuret method) Standard solution: Anaceram ALB-TP standard solution (TP = 6.0 g / dL) (manufactured by Sekisui Medical Co., Ltd.) Equipment: TBA-120FR Sora Edition Automated Analyzer (manufactured by Toshiba Medical Systems Corporation)

[0082] C) Measurement of trace total protein concentration (TP) Measurement reagent: Micro-TP-AR (manufactured by Fujifilm Wako Pure Chemical Corporation) (Pyrogallol Red method) Standard solution: Prepared by diluting Anaceram ALB-TP standard solution (TP=6.0g / dL) (manufactured by Sekisui Medical Co., Ltd.) with physiological saline (TP=200mg / dL). Equipment: TBA-120FR Sora Edition Automated Analyzer (manufactured by Toshiba Medical Systems Corporation)

[0083] D) Measurement of urea concentration (calculated from urea nitrogen concentration) Measurement reagent: ESP-UN Liquid (Urease-Leucine Dehydrogenase Method) Standard solution: Nipro Multi-Calibrator (urea nitrogen = 46.2 mg / dL) (manufactured by Nipro Corporation) Equipment: TBA-120FR Sora Edition Automated Analyzer (manufactured by Toshiba Medical Systems Corporation) Calculation formula: Urea concentration (mg / dL) = Urea nitrogen concentration (mg / dL) ÷ 28.0134 × 60.055

[0084] E) β2-MG concentration measurement Measurement reagent: LT Auto Wako β2m (manufactured by Fujifilm Wako Pure Chemical Corporation) (latex agglutination immunoassay) Standard solution: Prepared by diluting β2m calibrator set L for urine (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) (β2-MG = 3.00, 6.00, 8.00 mg / L) with physiological saline (β2-MG = 15, 40, 150, 300, 400 μg / L). Equipment: TBA-120FR Sora Edition Automated Analyzer (manufactured by Toshiba Medical Systems Corporation)

[0085] F) Measurement of prolactin concentration Measurement method: Electrochemiluminescence immunoassay (ECLIA method) Reagent: Elecsys Prolactin III reagent (manufactured by Roche Diagnostics, Inc.) Equipment: Modular Analytics (manufactured by Hitachi, Ltd.)

[0086] (Calculation of △PB and TMP) Using the pressures measured in procedures (5) and (7) of the circulation test, △PB and TMP were calculated for each circulation time. The calculation formula is as follows, and the result from procedure (9) of the circulation test was used for the colloid osmotic pressure when calculating TMP. • Calculation formulas for △PB and TMP △PB(mmHg) = PBin - PBout TMP(mmHg)=(PBin+PBout)÷2-PF-π p PBin: Blood inlet pressure (mmHg) PBout: Blood outlet pressure (mmHg) PF: Filtrate pressure (mmHg) π p : Colloid osmotic pressure (mmHg)

[0087] (Calculation of clearance) The clearance and mass balance error (MBE) of each solute (urea, β2-MG, prolactin) were calculated from the solute concentrations of the test solutions collected in the clearance measurement procedure (4). The calculation formulas are described below. • Clearance calculation formula Clearance (mL / min) = (QBin × CBin - QBout × CBout) ÷ CBin QBin: Blood side inlet flow rate (mL / min) QBout: Blood side outlet flow rate (mL / min) CBin: Solute concentration at the blood inlet. CBout: Solute concentration at the blood outlet. • MBE calculation formula MBE(%) = (MB - MD) ÷ MB × 100 MB: QBin×CBin-QBout×CBout MD: QDout × CDout QDout: Dialysate side outlet flow rate (mL / min) CDout: Solute concentration at the dialysate outlet If the MBE value exceeded 50%, the clearance obtained for that sample was not used as the average value when calculating the average of the values ​​measured for two or more samples.

[0088] (Calculation of total protein leakage) Using the TP concentration of the filtrate collected in procedures (5) and (7) of the circulation test, a graph of the natural logarithm of the filtrate's TP and circulation time (vertical axis: TP (mg / dL), horizontal axis: natural logarithm of circulation time (min)) was created, and the total protein leakage over 4 hours was calculated from the approximation line. The calculation formula is as follows, and considering linearity, the approximation line was divided into three time frames of 20 minutes and 60 minutes of circulation, and the total protein leakage was calculated using different calculation formulas for each. • Formula for calculating total protein leakage Total protein loss over 4 hours (g) = Total protein loss during 0-20 minutes of circulation + Total protein loss during 20-60 minutes of circulation + Total protein loss during 60-240 minutes of circulation Total protein leakage (g) during 0-20 minutes of circulation = Average TP (protein per minute) × QF (quantitative fatigue) during 0-20 minutes of circulation × 20 ÷ 100 ÷ 1000 Average TP (mg / dL) for 0-20 minutes of circulation = -slope a1 + intercept b1 + slope a1 × ln(20) Total protein leakage (g) during 20-60 minute circulation = Average TP (protein per minute) × QF (queen factor) × 40 ÷ 100 ÷ 1000 Average TP (mg / dL) for 20-60 minute cycles = {(-slope a² + intercept b² + slope a² × ln(60)) × 60 - (-slope a² + intercept b² + slope a² × ln(20)) × 20} ÷ 40 Total protein leakage (g) over 60-240 minutes of circulation = Average TP (protein per minute) × QF (queen factor) × 180 ÷ 100 ÷ 1000 Average TP (mg / dL) over 60-240 minutes of circulation = {(-slope a3 + intercept b3 + slope a3 × ln(240)) × 240 - (-slope a3 + intercept b3 + slope a3 × ln(60)) × 60} ÷ 180 Slope a1: Slope of the approximation line with a cyclical pattern of 0 to 20 minutes. Intercept b1: Intercept of the approximation line for cyclical time 0-20 minutes Slope a2: Slope of the approximate straight line with a cyclical time of 20 to 60 minutes. Intercept b2: Intercept of the approximation line for cyclical 20-60 minute intervals Slope a3: Slope of the approximate straight line for the 60-240 minute cycle. Intercept b3: Intercept of the approximation line for the 60-240 minute cycle.

[0089] Each measurement was performed on three or two samples for each example or comparative example, and the average value was used as the evaluation result for that example or comparative example.

[0090] The evaluation results for each example and each comparative example are shown in Tables 1-3.

[0091] [Table 1]

[0092] [Table 2]

[0093] [Table 3]

[0094] Examples 1, 2, and 3, Examples 4 and 5, and Examples 6 and 7 are groups in which the inner diameter of the hollow fiber membrane is the same, but the pore size is varied. By comparing the examples in these groups, it can be seen that the total protein leakage amount increases as the pore size increases.

[0095] Examples 1, 4, and 6, and Comparative Example 1 (group a), Examples 2, 5, and 7, and Comparative Example 2 (group b), and Examples 3 and Comparative Example 3 (group c) are groups in which the inner diameter of a hollow fiber membrane made of the same material and having approximately the same pore size is varied. The pore size of the hollow fiber membrane is smallest in group a and largest in group c.

[0096] In group a, Example 1 showed a film area of ​​1 m² compared to Comparative Example 1. 2 The total amount of protein leakage per unit is low, TMP 10 / TMP 240 High, ΔP B The value was low. Film area of ​​Examples 4 and 6: 1 m² 2Although the total amount of protein leakage per unit was slightly greater than that of Comparative Example 1, the TMP of Examples 4 and 6 was lower. 10 / TMP 240 The values ​​were larger than those in Comparative Example 1, and all were 0.77 or higher. Also, the ΔP of Examples 4 and 6 B This was smaller than that of Comparative Example 1. Therefore, Examples 1, 4, and 6 are all more suitable for large-scale filtration compared to Comparative Example 1.

[0097] In group b, Examples 2, 5, and 7 all showed a film area of ​​1 m² compared to Comparative Example 2. 2 The total amount of protein leakage per unit is low, TMP 10 / TMP 240 High, ΔP B The value was low. In group c, Example 3 had a film area of ​​1 m² compared to Comparative Example 3. 2 The total amount of protein leakage per unit is low, TMP 10 / TMP 240 High, ΔP B The value was low. Therefore, the examples in groups b and c are also more suitable for large-scale filtration compared to the comparative examples in each group. [Industrial applicability]

[0098] The blood purifier of this disclosure exhibits small fluctuations in TMP over time and can suppress total protein leakage (and consequently albumin leakage) even when used in post-displacement hemodiafiltration, making it suitable for use in large-volume post-HDF filtration where the replacement fluid volume is 20L or more.

Claims

1. A blood purifier in which hollow fiber membranes are packed in bundles into a cylindrical container, The inner diameter of the hollow fiber membrane is greater than 200 μm and less than or equal to 250 μm. The bundle of hollow fiber membranes is filled in the container with a filling rate of 55% to 70%. The aforementioned blood purifier uses bovine blood with a total protein concentration (TP) of 6.0 g / dL or more and 6.5 g / dL or less, and a hematocrit (Ht) of 32 ± 2%, and the blood flow rate Q Ｂ 300 mL / min, dialysate volume Q Ｄ If the flow rate is 0 mL / min, and the blood filtration rate is Q Ｆ When subjected to a circulation test at a flow rate of 100 mL / min for 240 minutes, The total amount of protein leakage was between 0.30 and 0.65 compared to the total amount of protein leakage of blood purifiers made of the same material and identical in composition except that the inner diameter of the hollow fiber membrane was 200 μm. The pressure loss value (ΔPB) after 10 minutes from the start of the circulation test. 10 ) is a blood purifier with the same configuration as ΔPB, except that the inner diameter of the hollow fiber membrane is 200 μm. 10 A blood purifier with a value between 0.60 and 0.

85.

2. The blood purifier according to claim 1, wherein the hollow fiber membrane comprises a polysulfone-based or polyethersulfone-based resin and a hydrophilic polymer.

3. Filtration flow rate Q Ｆ A blood purifier according to claim 1 or 2, used for online post-dilution hemodiafiltration, wherein the flow rate is 80 mL / min or more and 130 mL / min or less, and the amount of replacement fluid in a single blood purification procedure is 20 L or more.

4. The blood purifier according to any one of claims 1 to 3, wherein the ratio (L / D) of the effective length L (mm) of the hollow fiber membrane to the inner diameter D (mm) of the cylindrical container is 6.9 or more and 7.6 or less.

5. The blood purifier according to any one of claims 1 to 4, wherein the pore size of the hollow fiber membrane is 40 Å or more and 80 Å or less.

6. The hollow fiber membrane has a membrane area of ​​0.9 m². ２ Approximately 3.0m ２ A blood purifier according to any one of claims 1 to 5, wherein the cylindrical container is filled as follows:

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