JPH0898883A - Blood treatment and blood treating device using the same - Google Patents

Abstract

PURPOSE: To enhance the efficiency of removing materials such as amyloid protein and deteriorating materials by having a stage for dializing or filtering and dialyzing the blood with a selective sepn. membrane having an albumin removal rate of a prescribed value or above and a stage for replenishing the blood on the primary side of this selective sepn. membrane with albumin. CONSTITUTION: The blood is admitted from a blood introducing port 1 and is purified by a blood purifying device 3. The blood dialysis, blood filtration and dialysis or blood filtration is executed by the selective sepn. membrane 4 and the materials desired to be removed are introduced to the (b) side and the blood from which such materials desired to be removed are removed is introduced from the (a) side to a led-out blood flow rate sensor 22. The selective sepn. membrane 4 having the albumin removal rate of >=1.5% is used. The blood treating device is provided with a protein leaking rate sensor 25 and the albumin corresponding to the leaking rate is replenished by a protein replenishing pump 11 from a tank 12, by which the control of the protein amt. in the blood is executed.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a blood processing method using a selective separation membrane and a blood processing apparatus used therefor.

[0002]

2. Description of the Related Art Conventionally, regarding artificial dialysis or artificial filtration dialysis, albumin, which is a useful protein in blood, is used as an index for membrane performance, and so-called uremic substances having a molecular weight of less than that which albumin does not permeate can be used. It has been intended to be removed. In the conventional artificial dialysis system, too much effort is made to prevent the leakage of albumin, so that a medium-molecular weight protein having a molecular weight of 1 to 30,000 which can be penetrated by the living kidney tends to be accumulated in the body, resulting in various dialysis complications.

Furthermore, in recent years, it has been suggested that there is a substance which is difficult to be metabolized even in the living kidney of a healthy person or whose metabolism is insufficient due to the influence of certain diseases and aging, and the molecular weight range of the substance to be blood purified is It is spreading.

[0004]

In view of these facts, therefore, we have taken into account such a fact, substances such as amyloid protein that cannot be removed by the current dialysis technology, and senescent substances and saccharified substances that are not sufficiently removed even in the living kidney. It is an object of the present invention to provide a blood treatment method which is excellent in the removal efficiency of proteins and cross-linked products thereof, and a blood treatment apparatus used therefor.

[0005]

In order to achieve the above object, the present invention has the following constitution.

[(1) a step of hemodialysis or hemodiafiltration with a selective separation membrane having an albumin removal rate of 1.5% or more;
A step of supplying albumin to blood on the primary side of the selective separation membrane.

(2) A blood processing apparatus having a selective separation membrane having an albumin removal rate of 1.5% or more and an albumin replenishing section. In the present invention, by using a selective separation membrane having an albumin removal rate of 1.5% or more, a substance that could not be removed by a conventional artificial dialysis membrane, and a substance that is not metabolized even in the living kidney of a healthy person, or is metabolized It becomes possible to effectively remove substances that are difficult to do. Here, in the present invention, the albumin removal rate means {1- (selective separation after filtration when the selective separation membrane is filtered using a 1% albumin phosphate buffer aqueous solution as a liquid to be treated. It means the albumin concentration in the liquid to be treated remaining on the primary side of the membrane) / (the concentration of albumin in the liquid to be treated before filtration)} value. Furthermore, it is preferable that the blood coagulation factor VIII removal rate including von Willebrand factor is less than 70% because the blood coagulation property does not deteriorate too much. In the present invention, hemodialysis or hemofiltration dialysis is performed using the permselective membrane having the albumin removal rate of 1.5% or more, and the albumin removal rate of 1.5% or more and the blood coagulation factor VIII removal rate are obtained. By hemofiltration with less than 70% of the selective separation membrane, all or part of the desired protein can be removed, and the function of the living kidney can be brought close to the function as much as possible. It is also possible to remove substances in insufficient amounts. In the present invention, it is more effective when the selective separation membrane having the albumin removal rate of 3% or more, further 5% or more is used.

As a material for the selective separation membrane of the present invention, a high molecular polymer generally used for hemodialysis and hemofiltration is used. Specific examples thereof include polymethyl methacrylate, polyacrylonitrile, cellulose, cellulose acetate, polysulfone, polyvinyl alcohol, and vinyl alcohol copolymers such as copolymers of polyvinyl alcohol and ethylene, but are not particularly limited thereto. . Polysulfone, polymethylmethacrylate and cellulose acetate are preferred, and polysulfone and polymethylmethacrylate are more preferred. The form of the membrane module is not particularly limited, but for example, a hollow fiber type or a flat membrane laminated type is used.

To obtain the selective separation membrane of the present invention, for example,
In the case of a hollow fiber type, when the above polymer is dissolved in a solvent for the polymer and a permeable hollow fiber is produced by spinning from an annular spinner into a water-based coagulation bath, the concentration of the polymer solution and the coagulation / solidification A film structure is formed by adjusting the cooling conditions, the phase transition conditions of the stock solution system, the desolvation rate, and the like. In particular, it is preferable to make the stock solution non-uniform. For example, when a hollow fiber membrane is manufactured using a polymethylmethacrylate polymer as a membrane material, the polymer concentration is 20% by weight to 2%.
It is dissolved in a solvent such as dimethyl sulfoxide so as to be 5% by weight. When this solution is discharged from an annular spinneret to form hollow fibers, dry nitrogen gas is introduced from the inside and cooling gas is blown from the outside to form the hollow fibers. At this time, it is preferable that the cooling gas has a dry-bulb temperature of 5 to 17 ° C and a dew point of 5 to 15 ° C, which is a measure of water content. Then, it is introduced into a coagulation bath mainly composed of water to solidify,
Remove the solvent. The coagulation bath temperature at this time is 5 ° C to 30 ° C
It is preferable that When a hollow fiber membrane is produced by using a polysulfone polymer as a membrane material, it is dissolved in a polar solvent such as dimethylacetamide or N-methylpyrrolidone so that the polymer concentration becomes 15% by weight to 25% by weight, Further, 8 wt% to 15 wt% of polyvinylpyrrolidone as a swelling agent and 0.2 wt% to 3 wt% of water are added to prepare a high temperature phase separation type stock solution. When this solution is discharged from the tubular spinneret and hollow fibers are formed, an injection liquid such as a mixed solution of a polar solvent such as dimethylacetamide or dimethylsulfoxide and water is introduced inside to form hollow fibers. Then, it is introduced into a coagulation bath mainly composed of water, solidified and desolvated.

In the present invention, hemodialysis, hemodiafiltration or hemofiltration is carried out using such a selective separation membrane. When these treatments are applied, the desired substance desired to be removed in the present invention is desired, Of course, excessive leakage of the useful protein albumin occurs. Therefore, in the present invention, it is necessary to supplement albumin to the blood on the primary side of the selective separation membrane before or after performing hemodialysis, hemofiltration dialysis or hemofiltration with the selective separation membrane. Further, in the present invention, it is preferable to measure the amount of protein reduced by hemodialysis, hemodiafiltration or hemofiltration on the primary side of such selective separation membrane, or the amount of protein leakage to the secondary side. As a method for measuring the albumin content, an existing measuring device used for an ultraviolet absorbance monitor, a relative refractometer, a protein leak meter or the like can be used. It is also possible to measure the amount of protein offline. As a device for replenishing albumin, a commonly used one, for example, a liquid feed pump or the like is used, and it is also possible to add it by drip to a liquid feed line. The content of albumin is usually the initial value of 9
It is desirable to maintain the content at 0% or more, but it is preferable to appropriately set the lower limit of the normal value of blood albumin amount in a healthy person to 3.5 mg / dl. Moreover, it may be possible to exceed the initial value by supplementing. It is also preferable to monitor and control the balance between the amount of liquid removed and the amount of liquid replacement.

Here, in the present invention, the primary side of the selective separation membrane means the side of introducing blood into the header of the selective separation membrane (FIG. 1, a side of the selective separation membrane 4), and the selective separation membrane. The secondary side of is the permeate side of the blood treated with the selective separation membrane (FIG. 1, b side of the selective separation membrane 4).

In the present invention, it is preferable to directly treat whole blood because of its simplicity, but it is also possible to subject the plasma after the plasma components have been separated by a conventional plasma separation membrane in advance to the treatment of the present invention, In the treatment with the selective separation membrane of the present invention, there is no hemolysis, which is preferable. Furthermore, by preliminarily separating plasma components, it is possible to design the selective separation membrane of the present invention so as to actively have an adsorption function, such as lipoprotein (a) which is a cause of arteriosclerosis. Removal of large molecules is also possible. As a method of imparting such an adsorption function, conventional techniques such as fixing a ligand to a specific unwanted protein of hollow fibers and modifying the material of hollow fibers are used.

In the present invention, it is possible to add other chemicals when supplementing the protein. Also,
By carrying out on-line detection of protein concentration, it can be safely used for preventive use in healthy people.

A schematic diagram of the device of the present invention is shown in FIG. Blood is introduced from the blood inlet of 1 and purified by the blood purifier of 3. At this time, hemodialysis, hemofiltration dialysis or hemofiltration is performed by the selective separation membrane 4, the desired substance to be removed is on the b side, and the blood from which the desired substance is to be removed is removed from the a side by a blood flow rate of 22. Guided to the sensor. At this time, various sensors 21 to 24 (21 is an introduced blood flow rate sensor, 22 is a derived blood flow rate sensor, 23 is an introduced dialysate flow rate sensor, and 24 is a derived dialysate flow rate sensor), as in a normal dialysis system. 5, 6, 9 and 11 pumps (5 is a blood pump, 6 is a dialysate pump, 9 is a retention pump, 11
Indicates a protein replenishment pump), 7, 8, 10 and 12 tanks (7 indicates a dialysate tank before use, 8 indicates a dialysate tank after use, 10 indicates a retention tank, and 12 indicates a protein collection tank). Set up. With 25 protein leak sensors,
According to the output value, the amount of protein in blood is controlled by 11 protein supplement pumps. The mounting position of the sensor of 25 may be on the primary side or the secondary side. Further, the device of the present invention has a control unit and calculates outputs from various sensors. FIG. 2 shows a schematic diagram of the control unit, and 31 indicates a key panel. In the present invention, as a method for measuring the protein content, the amount of protein in blood (amount of albumin) and the amount of leakage are determined from the flow rate of outputs from various blood flow rate sensors and the output of protein concentration from 25 protein leakage sensors. A method of calculating is used. The protein content measuring unit refers to a combination of the above-mentioned various sensors.
Further, a schematic diagram in the case of separating plasma in advance is shown in FIG.
13 is a plasma separation membrane, 26 is a plasma flow rate sensor, 27 is an introduced blood pressure sensor, and 28 is a pressure sensor. Figure 4
The control part when separating plasma is shown.

[0015]

【Example】

Example 1 19 parts by weight of polysulfone (Udel P-3500; hereinafter abbreviated as PSF), 8 parts by weight of polyvinylpyrrolidone (K-30; hereinafter abbreviated as PVP), 1.2 parts by weight of water, dimethylaceamide (hereinafter abbreviated as DMAC). ) 71.8 parts by weight, and heated and dissolved. This stock solution for film formation has a pore size of 1.0 to 0.7.
Using a φ base, the base temperature was set to 45 ° C., and a mixed liquid of water and DMAC (weight ratio 40/60) was used as an injection liquid.
A hollow fiber membrane was obtained by using 60 ° C. water in the coagulation bath. This film had an albumin removal rate of 8.9%. A blood purification experiment was carried out on fresh bovine blood using this membrane and the apparatus described in FIG. All conditions for blood purification were performed according to the usual hemodialysis method. Bovine blood was circulated through the membrane at a rate of 200 ml / min using a total volume of 10 liters. Dialysate is 500 ml
Used at / min. Twenty-five protein leakage sensors were installed on the secondary side and used an ultraviolet absorption monitor. The absorbance of the dialysate at the wavelength of 280 nm was monitored as 0, and the signal was calculated by the control unit using the output value from the dialysate flow sensor of 24, and the amount of leaked protein was calculated. It was replenished from the 121 tank to the bovine blood side by using the 11 pump (the protein amount at the absorbance of 1 was 00.1 mg / ml). The total amount of protein leaked out after purification for 4 hours is 2
It became 4.8 g, and a replenishing solution of albumin equivalent to 24.8 g was continuously performed during the operation. The total amount of protein in bovine blood before and after blood purification was measured separately from 6.7 ml to 6.5 mg / m
The total amount of protein changed little, and blood purification was possible. FIG. 5 shows the spectrum when the protein purified at this time and discharged to the dialysate side was separated by a gel filtration column. The wavy line indicates that the conventional albumin removal rate is 1.
It is the gel filtration column separation spectrum of the protein that has flowed out to the dialysis side when it is carried out using a 1% membrane, and it can be seen that the purification of the high molecular weight protein was significantly performed in comparison with this.

[0016]

EFFECTS OF THE INVENTION According to the present invention, larger molecules than the existing dialysis membranes can be removed, so that glycated proteins and their cross-linked proteins whose production is considered to be accelerated by aging and diabetes are slow in metabolic decomposition in the liver and kidneys. Proteins (eg,
It is also possible to remove proteins that were previously unremovable, such as galactose-deficient glycoprotein in which the N-linked sugar chain of glycoprotein has undergone partial hydrolysis. Further, by using the present invention, it is possible to suppress the deterioration of the complexion of the artificial dialysis patient.

[Brief description of drawings]

FIG. 1 shows a schematic view of a blood processing apparatus of the present invention.

FIG. 2 shows a schematic diagram of a control unit of the present invention.

FIG. 3 shows a schematic view of the blood processing apparatus of the present invention.

FIG. 4 shows a schematic diagram of a control unit of the present invention.

FIG. 5 shows a gel filtration column separation spectrum of purified protein in Example 1 of the present invention.

[Explanation of symbols]

 1: Blood inlet 2: Blood outlet 3: Blood purifier 4: Selective separation membrane 9: Replacement fluid pump 10: Replacement fluid tank 11: Protein supplement pump 12: Protein supplement tank 25: Protein leakage amount sensor

Claims (13)

[Claims] 1. A method comprising: a step of hemodialyzing or hemodialyzing with a selective separation membrane having an albumin removal rate of 1.5% or more; and a step of supplying albumin to blood on the primary side of the selective separation membrane. Blood treatment method. 2. The blood processing method according to claim 1, wherein the albumin removal rate is 3% or more. 3. The blood processing method according to claim 1, wherein the albumin removal rate is 5% or more. 4. Measuring the protein content in the blood on the primary side or secondary side of the selective separation membrane after hemodialysis or hemodiafiltration with the selective separation membrane and before or at the same time as supplementing albumin. The blood processing method according to claim 1 or 2, wherein 5. The blood processing method according to claim 1, wherein a removal rate of blood coagulation factor VIII of the selective separation membrane is less than 70%. 6. The blood processing method according to claim 1, wherein separated plasma is used as the blood. 7. An albumin removal rate of 3% or more, blood coagulation VIII.
Selective separation membrane with factor removal rate less than 70%, hemodialysis,
At least one selected from hemodiafiltration and hemofiltration
A blood treatment method comprising: a step of treating seeds; and a step of supplying albumin to blood on the primary side of the selective separation membrane. 8. A blood processing apparatus comprising a selective separation membrane having an albumin removal rate of 1.5% or more and an albumin replenishing section. 9. The blood processing apparatus according to claim 8, wherein the albumin removal rate is 3% or more. 10. The blood processing apparatus according to claim 8, wherein the albumin removal rate is 5% or more. 11. The blood processing apparatus according to claim 8, further comprising a protein content measuring unit on the primary side or the secondary side of the selective separation membrane. 12. The selective separation membrane has a blood coagulation factor VIII removal rate of less than 70%.
The blood processing apparatus according to claim 1. 13. The blood processing apparatus according to claim 8, wherein a plasma separation membrane is used.