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    • 专利摘要:
    method of hemodiafiltration the invention relates to a device for hemodiafiltration with an extracorporeal circulation (10) for receiving the blood to be purified and having a hemodialyzer and/or hemofilter (20), which is connected to the blood circulation (10), of such that the blood circulation (10) has at least one inlet line (12, 14) for the supply of a replacement fluid upstream and downstream of the hemodialyzer and/or hemofilter (20), characterized in that that the device also comprises measuring apparatus for recording transmembrane pressure and/or hematocrit (hkt) and/or blood density, such that the measuring apparatus are connected to a control unit (100) to control a or more of the transmembrane pressure and/or hematocrit (hkt) and/or blood density, the unit control (100) being constructed so that the control is performed with the help of at least one of the infusion rates (qspre , qspost) of the replacement fluid (1 3, 15), and the blood to be purified is exposed to a high-frequency electromagnetic field and/or a dc electric field (70) before and/or during contact with the hemodialyzer and/or hemofilter (20).
    公开号:BR112015014618B1
    申请号:R112015014618-0
    申请日:2013-12-19
    公开日:2021-06-01
    发明作者:Ulrich Tschulena；Joachim Jankowski；Anselm Fabig；Carsten Müller
    申请人:Fresenius Medical Care Deutschland Gmbh；
    IPC主号:
    专利说明:

    [001] The present invention relates to an apparatus for performing a hemodiafiltration treatment under the influence of an alternating electromagnetic field and/or a direct electric field.
    [002] The purpose of healthy kidneys is to eliminate the end products of metabolism (substances that must be eliminated in the urine) and toxins (uremic toxins) from the body through the formation of urine. The kidneys remove a wide spectrum of substances of different molecular weights. A review of uremic toxins was published by R. Vanholder et al. (R. Vanholder et al., Kidney International, 63 (2003) 1934-1943). Uremic toxins are divided into three classes and based on their molecular weight. Toxins with a molecular weight of less than 500 Daltons form the low molecular weight group. Medium sized molecules are of a medium range with a molecular weight between 500 D and 12000 D. Medium molecules include, for example, β2-microglobulin (11800 D). The third class of uremic toxins is made up of molecules with a molecular weight of more than 12000 D.
    [003] Furthermore, they are differentiated according to the water solubility of the uremic toxins. Examples of uremic toxins having good water solubility and a low molecular weight include urea, creatinine, oxalates, guanidines and uric acid.
    [004] Examples of uremic toxins having a low solubility in water include p-cresol, indoxyl sulfate, phenol, hippuric acid and homocysteine. These uremic toxins mainly bind to proteins when they are present in serum.
    [005] In a healthy individual, uremic toxins are eliminated with urine through the kidneys. In chronic renal failure, however, uremic toxins remain in the patient's blood and must be removed by hemodialysis or peritoneal dialysis.
    [006] Although it is possible to easily remove water-soluble toxins, eg urea and creatinine, by hemodialysis, it is extremely difficult to remove hydrophobic uremic toxins that have poor solubility by hemodialysis methods due to protein binding. It is generally assumed that there is a chemical balance between the free dissolved toxin and the protein-bound toxin, said balance being heavily shifted towards the protein-bound toxin. This means that most of these uremic toxins are bound to protein and only a small part is dissolved in blood plasma.
    [007] Since a large part of substances are components of low molecular weight, only a small part of which are present in free form, which, in principle, are dialyzable.
    [008] In addition, albumin is presumed to function as a binding partner for hydrophobic uremic toxins. Albumin is retained by dialysis membranes due to its molecular weight. Albumin is not removed by hemodialysis methods. Thus, only the dissolved portion free of uremic toxins can be removed from the patient's blood. The rate determination step is the establishment of a balance during dialysis. While it might be expected that after removing the dissolved toxins from the blood, a balance would be re-established between free toxins and protein-bound toxins and that a substantial portion of the toxins can be removed if the dialysis time is long enough, but this time is not available in hemodialysis treatment. There is therefore a demand for dialysis processes that also remove protein-bound uremic toxins from the patient's blood.
    [009] The present invention relates to a device for hemodiafiltration with an extracorporeal circulation to hold blood to be purified and with a hemodialyzer and/or a hemofilter, which is connected to the blood circulation in such a way that the blood circulation has at least an inlet line to supply a replacement fluid upstream or downstream of the hemodialyzer and/or hemofilter. In addition, the apparatus has means for generating an alternating high-frequency electromagnetic field and/or a unit for generating a DC electric field, such that the blood to be purified is exposed to the alternating high-frequency electromagnetic field and/ or to the DC electric field before and/or during its contact with the dialyzer. The present invention thus provides a method that shifts the position of the balance between free and protein-bound toxins and accelerates the establishment of balance during dialysis treatment.
    [0010] Those skilled in the art are familiar with the methods of hemodialysis and hemofiltration. A summary of the most important hemodialysis methods and machines can be found in the publications "Replacing kidney function with dialysis" (Drukker, Parsons and Maher; Kluwer Academic Publishers, 4th edition, 1996; and "Hemodialysis Machines and Monitors" by HD Polaschegg and NW Levin), the disclosure content of which is referenced in the attachment. In hemodialysis, a patient's blood is routed through an arterial blood line and into the blood chamber of a dialyzer. Blood is normally transported with the help of a peristaltic rotary pump arranged in the arterial blood line. After passing through the pump, blood is passed through the dialyzer blood chamber and finally returned to the patient via a venous drip chamber and a venous blood line connected to it. A venous pressure monitor is connected to the venous drip chamber as a protection system for direct determination of blood loss to the environment. If necessary, the two needles needed for the arterial and venous cannulae can be replaced with a single needle in so-called single-needle dialysis. In this type of dialysis, the extracorporeal circulation consists of a single-needle cannula with a connected Y-piece. From the dialyzer, the venous line leads back to the Y-piece. Arterial and venous lines are alternately sealed by clamps. One or more blood pumps are in operation to ensure alternating flow to and from the Y-piece.
    [0011] In hemodialysis, dissolved substances are removed from the blood by diffusion across the dialyzer membrane. Although a low transmembrane pressure is applied for ultrafiltration of excess water from a patient, this filtration hardly plays any role in purifying the blood to remove specific substances.
    [0012] Dissolved substances are removed in hemofiltration by convection and not by diffusion. At the same time, the ultrafiltrate is almost completely replaced by a replacement fluid with a composition similar to that of dialysate in hemodialysis. In this method, the resemblance to the natural kidney and the effective removal of larger molecules are emphasized. However, the removal of low molecular weight substances is reduced compared to hemodialysis, because a maximum of 45% of the blood can be ultrafiltered in so-called post-dilution hemofiltration. Hemofiltration is currently used in only a small number of patients due to the high cost of commercial replacement fluid and the high arterial blood transfer rate required to carry out the treatment in an appropriate period of time.
    [0013] Hemofiltration machines for maintenance therapy comprise the same extracorporeal pump and monitoring systems as hemodialysis machines. The dialysate circulation is replaced by a liquid balance and heating system. In the so-called pre-dilution mode, replacement fluid is added to the blood upstream of the dialyzer and the filtrate is created by the corresponding transmembrane pressure. To be clinically effective, a very large amount of replacement fluid is needed. Due to the high cost of the commercial replacement fluid, this method has not yet been successful. More common is the post-dilution mode because it requires less replacement fluid. In this mode, replacement fluid is added to the blood downstream of a dialyzer. Good purification coefficients are achieved in post-dilution mode. Typically about 20 to 24 liters of replacement fluid is added during a 4 hour treatment. However, the effectiveness of this method is limited due to a critical transmembrane pressure above which blood is damaged.
    [0014] Several systems have been proposed for fluid equilibrium. In the gravimetric balancing method, the ultrafiltrate can be withdrawn by the ultrafiltrate pump into a bag or container, which is standing or hanging from a balance platform. Replacement fluid from a bag or container on the same platform is pumped by an additional pump into the venous drip chamber. Nominal fluid withdrawal is achieved either by an additional ultrafiltration pump or by a programming unit that controls the replacement pump so that it delivers less fluid than that withdrawn by the filtration pump.
    [0015] Hemodiafiltration, which is a combination of hemodialysis and hemofiltration, can be performed by combining extracorporeal circulation from a hemofiltration machine with that of a hemodialysis machine. Hemodialysis machines with volumetrically controlled ultrafiltration can be easily adapted for hemodiafiltration which is less expensive. This is especially beneficial from a cost standpoint if replacement fluid is prepared from the dialysis fluid in-line.
    [0016] Treatment parameters such as dialysate content (sodium concentration), ultrafiltration rate and blood and dialysate transfer rate are varied during dialysis to increase or maintain efficiency and/or to reduce symptoms that occur during dialysis. The change follows either a kinetic model or more often a "clinical assessment". Symptoms that occur during dialysis, in particular low blood pressure, are closely associated with ultrafiltration. In dialysis machines with ultrafiltration pumps, which are independent of the dialysate pumps, a profile effect occurs due to the change in the ultrafiltration rate.
    [0017] In summary, it can be concluded that in hemodialysis the patient's blood is purified by the fact that the substances to be removed from the blood diffuse across the membrane due to a concentration gradient across the dialyzer membrane and these substances therefore , reach the dialysis fluid. The driving force in hemofiltration is essentially a pressure difference across the membrane that causes convective transport of substances across the membrane and, in so doing, purifies the blood especially of higher molecular substances. In hemofiltration and the combined hemodiafiltration method, fluid that must be replaced except for a small differential amount to control fluid exchange is removed from the patient's blood.
    [0018] Pre-dilution is preferably used for patients with a higher risk of blood clotting. This risk is reduced by diluting the blood before blood treatment.
    [0019] Low concentrations of hematocrit lead to large amounts of free, i.e. water not compliantly bound, which makes a characteristic convective transport of substances across the membrane possible. Therefore, the cleaning effect can be greater in case of moderate and high molecular substances in predilution mode than in post-dilution mode.
    [0020] Furthermore, pre-dilution of the blood to be purified results in the fact that more protein-bound uremic toxins can enter the plasma and be dialyzed. With the present invention, it is therefore advantageous if the ratio of infusion rates (Qspre, Qspost) of the replacement fluid is controlled such that Qspre is always greater than or equal to Qspost. The ratio of Qspre/Qspost infusion rates is preferably at least 1.2.
    [0021] To combine the advantages of pre- and post-dilution modes, it has also been proposed that the two modes can be used simultaneously with a fixed replacement fluid transfer ratio from pre- and post-dilution (L. Pedrini and V .De Cristofaro, Abstract at the EDTNERA Congress, Madrid, 1999).
    [0022] Publication WO 98/50091 refers to a method for controlling a blood purification apparatus, which includes at least one inlet line to the blood circulation for supplying replacement fluid upstream and downstream from the filter. A control unit is provided for monitoring a blood pump, an ultrafiltrate pump and replacement fluid pumps and monitoring means for weighing the corresponding amount of fluid. The control unit monitors the pumps at predetermined intervals to regulate the instantaneous flow rate of blood circulation, ultrafiltrate and substitute products.
    [0023] The publication WO 00/09182 relates to a fluid actuation device, which is suitable for removing certain blood elements and/or blood constituents by diffusion through a semi-permeable membrane. This device is equipped with a blood pump, a pump to deliver pre-dilution replacement fluid, a pump for the supply of post-dilution replacement fluid, and an ultrafiltration pump. Valves are arranged in such a way that liquid is passed through a container that can be brought into a liquid connection with each of the pumps in order to control the operation of the pumps and, consequently, the flow rates of the corresponding liquids.
    [0024] Another disadvantage of the post-dilution mode is the fact that a limiting membrane is created in the membrane of the hemodialyzer and/or hemofilter during blood purification. The thickness of this membrane increases with increasing duration of treatment, which reduces the permeability of the membrane. Therefore, the cleaning effect is aggravated - at constant transmembrane pressure. If a constant purification effect is to be achieved, an increase in transmembrane pressure would be necessary, but this could result in damage to the membrane.
    US Patent 5,578,223 discloses an artificial kidney which functions in the post-dilution mode and is suitable for use in a hemofiltration, hemodiafiltration and hemodialysis treatment. To maintain a desired bicarbonate concentration in a patient's blood, the device includes means for perfusing a bicarbonate-containing liquid into the extracorporeal circulation after passing through the exchange means and metering means for adjusting the blood bicarbonate concentration. of a patient to a desired level. An extraction pump that is connected to the exchanger outlet is controlled by a control unit to maintain a desired measure of weight loss over the duration of the treatment. The flow rate of the bicarbonate solution is controlled by the control unit as a function of the flow rate of the extraction pump, the desired bicarbonate concentration in a patient's blood, and the concentration of the bicarbonate solution before perfusion to the cardiopulmonary bypass. .
    [0026] The object of the present invention is to provide a device for blood purification by means of hemodialysis and/or hemofiltration with which the advantages of the pre-dilution mode and the post-dilution mode can be combined and in which the Purifying effect of hemodialyzer and/or hemofilter for protein-bound toxins is improved at the same time.
    [0027] In the context of an apparatus according to the preamble of claim 1, this object is achieved by the fact that the apparatus also comprises measuring apparatus for recording transmembrane pressure and/or hematocrit and/or blood density, in which the measuring devices are connected to a control unit (100) to control one or more of the transmembrane pressure and/or the hematocrit and/or the blood density, wherein the control unit is constructed so that control is carried out with the help of at least one of the replacement fluid infusion rates, and the blood to be purified is exposed to a high frequency electromagnetic field and/or a DC electric field before and/or during contact with the dialyzer.
    [0028] The apparatus according to the invention as defined in the preamble of claim 1 has additional means for generating a high-frequency electromagnetic field and/or a DC electric field. The invention is based on the discovery that the adjustment of the balance between protein-bound and free toxins can be accelerated with the help of a high-frequency electromagnetic field and/or a DC electric field. Those skilled in the art are familiar with such means. The apparatus according to the invention can have, for example, a high-frequency capacitor, a high-frequency coil and/or a high-frequency electrode for generating a high-frequency electromagnetic field. The high frequency electromagnetic field has a frequency from 100 kHz to 2 GHz, preferably from 1 MHz to 1 GHz.
    [0029] Furthermore, the apparatus according to the invention may have means for generating a DC electric field. Those skilled in the art are familiar with such means. The apparatus according to the invention can be constructed, for example, of a plate capacitor having two, four or more plates. The DC electric field has a field strength of up to 1500 V/m. In a preferred embodiment, the DC electric field has a field strength of from 10 V/m to 400 V/m, especially preferably from 100 V/m to 250 V/m. A rotating or traveling DC field can be generated through low frequency inversion of the polarity of the capacitor plates.
    [0030] The means for generating a high-frequency electromagnetic field and/or a DC electric field can be embodied and arranged within and/or on the blood circulation, such that the blood to be purified can be exposed to the electromagnetic field of high frequency, before, during or even before and during contact of the blood to be purified with the dialyzer and/or with the semipermeable membrane of the dialyzer.
    [0031] By adding replacement solutions for extracorporeal circulation upstream and downstream of the hemodialyzer and/or hemofilter, the advantages of post-dilution and pre-dilution can be combined on the one hand, that is, satisfactory results are obtained for purification of low molecular weight substances and for medium and high molecular weight substances. On the other hand, in accordance with the present invention, the infusion rates of one or both replacement fluids supplied upstream and downstream can be used to control operating parameters and/or blood parameters.
    [0032] For example, in the case of a high transmembrane pressure or a high blood hematocrit value, the infusion rate of the replacement solution added upstream of the dialyzer can thus be increased until it reaches the desired levels to be controlled or until the values fall below given threshold values. Therefore, in the case of a low transmembrane pressure or a low hematocrit, the infusion rate of the replacement fluid added downstream of the dialyzer can be increased, which leads to an improvement in the diffusional transport of substances, i.e., to an improved purification effect for low molecular weight substances due to the resulting higher concentration gradient across the membrane.
    [0033] The infusion rate of replacement solutions added upstream of the hemodialyzer and/or hemofilter is preferably increased compared to the infusion rate of replacement solutions added downstream of the hemodialyzer and/or hemofilter with an increase in transmembrane pressure and/or an increase in blood density and/or an increase in blood hematocrit. Transmembrane pressure and/or hematocrit and/or blood density can be detected continuously.
    [0034] It is especially advantageous if the infusion rates of the replacement solutions are chosen so that an essentially stationary limiting membrane is formed on the membrane side of the hemodialyzer and/or the hemofilter opposite the chamber through which the blood flows. This has the advantage that the efficacy and spectrum of the hemodialyzer and/or hemofilter screen coefficients remain constant during the treatment period.
    [0035] Furthermore, predilution of the blood to be purified results in more protein-bound uremic toxins entering the plasma and being dialyzed - in particular due to the influence of the electric field. It is therefore advantageous with the present invention if the ratio of infusion rates (Qspre, Qspost) of the replacement fluid is controlled such that Qspre is always greater than or equal to Qspost. The ratio of Qspre/Qspost infusion rates is preferably at least 1.2. The ratio between Qspre/Qspost infusion rates is especially preferably at least 1.5.
    [0036] The relationship between the infusion rates of Qspre/Qspost replacement solutions into the bloodstream can be changed after the end of treatment to dissolve the limiting membrane. In this way, most of the proteins that form the limiting membrane can be returned to the patient after the end of the blood treatment.
    [0037] The measuring devices may comprise pressure sensors each of which is arranged in the extracorporeal circulation and/or in the dialysis fluid circulation upstream and/or downstream of the hemodialyzer and/or hemofilter.
    [0038] In another embodiment of the present invention, the measuring devices comprise sensors in the extracorporeal circulation upstream and/or downstream of the hemodialyzer and/or hemofilter to detect the hematocrit.
    [0039] According to a preferred embodiment, agents for controlling at least one infusion rate (Qspre, Qspost) are pumps in the air inlet lines.
    [0040] In another embodiment, the means for controlling the at least one infusion rate (Qspre, Qspost) are valves in the air inlet lines.
    [0041] Additional details and advantages of the present invention are explained with reference to the following figures and embodiments. Are shown in the Figures:
    [0042] Figure 1 is a schematic diagram of a part of the extracorporeal circulation and dialysis fluid circulation with a hemodialyzer and a hemofilter as well as inlet lines for the replacement fluid.
    [0043] Figure 2 are experimental results concerning the influence of high frequency magnetic fields on the protein-bound portion of uremic toxins.
    [0044] Figure 3 are experimental results as proof of the lack of damage to the membrane by high frequency fields.
    [0045] Figure 4 are experimental results concerning the influences of an HF field in the frequency range of 1-170 MHz on the protein-bound portion of uremic toxins.
    [0046] Figure 5 are experimental results concerning the influences of an HF field in the 110-115 MHz frequency range on the protein-bound portion of uremic toxins.
    [0047] Figure 6 are experimental results concerning the influences of an H field in the frequency ranges 1 to 6 MHz and 9 to 13 MHz in the protein-bound portion of the uremic toxins.
    [0048] Figure 7 are experimental results concerning the influences of field strength on the protein-bound portion of uremic toxins.
    [0049] Figure 1 shows a part of the extracorporeal circulation 10 through which blood is circulated at the flow rate QB by means of a blood pump 11 in the direction of the arrow. A pressure sensor 40 and a detector 50 are placed upstream of the hemodialyzer or hemofilter 20 in the extracorporeal circulation 10 to detect arterial blood pressure Part and hematocrit HKTin prior to blood purification.
    Suitable measuring devices 40, 50 for detecting the corresponding Pven and HKTout values after blood purification are arranged downstream of the hemodialyzer and/or hemofilter 20.
    [0051] Dialysis fluid flows countercurrently with the blood stream in the direction of the arrow at QD flow rate through the hemodialyzer or hemofilter 20. The dialysis fluid line 30 has pressure sensors 40 upstream and downstream of the hemodialyzer or hemofilter for the respective pressure PDin and PDout of the dialysis fluid. The circulation of the dialysis fluid is controlled by pumping means and/or balancing means 31 and 32.
    [0052] The hemodialyzer and/or hemofilter is/are subdivided by means of a semipermeable membrane 21 into a blood chamber 22 and a dialysis fluid chamber 23.
    [0053] The hemodialyzer and/or hemofilter 20 is/are surrounded by means to generate a high-frequency electromagnetic field and/or a DC electric field 70.
    [0054] In another modality, in addition to the hemodialyzer and/or hemofilter 20, a part of the extracorporeal blood circulation 10 upstream therefrom is surrounded by means to generate a high-frequency electromagnetic field and/or a DC electric field 70 . Upstream and downstream of the hemodialyzer and/or hemofilter 20 there are inlet lines 12, 14 with liquid pumps 13 and/or 15 that are provided for the supply of replacement fluid for the blood flowing in extracorporeal circulation 10 during the treatment. The respective flow rates are labeled Qspre and Qspost.
    [0055] The two infusion rates Qspre and Qspost of the replacement fluid can be varied according to the invention with the help of the control unit 100. The control unit 100 is connected to all actuators and sensors presented here by connections ( not represented). Infusion rates are varied according to the measured values of the control values to be controlled. In the embodiment illustrated in Figure 1, the measured values of arterial and venous blood pressure Part, Pven as well as dialysis fluid pressures PDin and PDout before and after passage through the hemodialyzer and hemofilter 20 are shown. The resulting transmembrane pressure TMP is adjusted or maintained at the desired target level in accordance with the present invention by appropriately modifying the flow rates Qspre and Qspost to the desired target value. Instead of TMP transmembrane pressure, hematocrit values HKTin, HKTout can also be used as control values. TMP can also be approximated using less than the four pressure sensors shown here. With dialysis machines that are currently commonplace, pressure sensors are typically used for Pven and PDout.
    [0056] The effect achieved with the aid of the device claimed here is that the limiting membrane, which is built on the membrane side of the hemodialyzer or hemofilter in front of the chamber in which blood is present, can be maintained in a steady state, which results in a constant spectrum of purification and a constant degree of purification during treatment. At the same time, the transmembrane pressure can be kept constant during treatment because the pressure drop caused by the membrane and the limiting membrane also remain constant.
    [0057] Due to the limitation of the transmembrane pressure to a predetermined level, the risk of a large loss of albumin across the membrane due to high convection forces can be avoided. When using high-flux membranes, limiting the transmembrane pressure is especially important.
    [0058] Especially in patients with severe clotting problems, the combination of pre- and post-dilution contributes to a reduction in the consumption of heparin, which is normally infused into the blood to prevent blood clotting in the extracorporeal circulation. When blood is diluted upstream of the hemodialyzer and/or hemofilter, less anticoagulant fluid is needed to reduce the risk of blood clotting in the hemodialyzer and/or hemofilter because the latter is the most significant potential for blood clotting in the extracorporeal circulation.
    [0059] In addition to the aforementioned advantages of constant operating behavior, a good purification performance for protein-bound uremic toxins can be achieved through the combination of pre-dilution and post-dilution and through the action of a high electromagnetic field frequency and/or a DC electric field.
    [0060] The following experimental results serve as experimental proof of the effect of an electric field on the separation of protein-bound toxins during dialysis.
    [0061] The effect of an HF field in the frequency range between 1 and 20 MHz is described in mode 1. Mode 2 shows the effect of the HF field in the frequency range of 1-170 MHz in the separation of phenylacetic acid. The phenylacetic acid separation rate was able to be increased by at least 45.3% under the influence of the HF field. The effect was particularly pronounced at 54.6% in the 110-120 MHz sub-band. The 110-120 MHz sub-band is looked at more closely in mode 3. Mode 4 shows the influence of an H field in the 1-6 MHz bands and 9-15 MHz. Mode 5 shows the influence of the field strength of the separation of phenylacetic acid.
    [0062] The temperature was kept constant in all modes 1 to 5 so that the observed changes are based on the properties of the electric field and not on a heating. Mod 1
    [0063] The influence of high-frequency electromagnetic fields on the protein-bound portion of uremic toxins was examined in a series of in vitro experiments.
    [0064] A dialysis module was created for this purpose in which conventional hemofiltration capillaries were cast as loops using silicone to a neck receiving syringe. An aqueous solution of albumin was introduced into the respective module in the presence of phenylacetic acid, p-hydroxyhippuric acid and indoxyl sulfate of uremic toxins. This solution was filtered with the dialysis module using a syringe pump for 10 min. A high-frequency electromagnetic field was subsequently induced into the solution by means of a high-frequency electrode (HF electrode). The electromagnetic field is increased by means of a high frequency voltage source over a period of 10 minutes from 1 to 20 MHz in steps of 1 MHz. The concentration of phenylacetic acid, p-hydroxy-hippuric acid and sulfate of indoxyl from uremic toxins previously added to the artificial plasma was determined in the resulting filtrates. The effect of the HF field on the binding between proteins and uremic toxins was able to be evaluated by comparing the uremic toxin concentration in the resulting filtrates.
    [0065] Quantitative determination of uremic toxin concentration in the resulting filtrates showed that high frequency electromagnetic fields significantly increase the filtration rates of protein-bound uremic toxins (Figure 2). Protein concentration in the filtrate was determined using Bradford protein staining to see if high frequency electromagnetic fields damaged dialysis membranes. The results show that no significant change in protein concentration can be detected in dialysis modules without and with the influence of high frequency electromagnetic fields (Figure 3). Macroscopic damage to the membrane can be prevented based on these data. Modality 2
    [0066] Examination of the HF field effect in the frequency range 1-170 MHz.
    [0067] An aqueous solution of bovine serum albumin (BSA, 60 mg/ml) was introduced into the dialysis module of Example 1 in the presence of uremic toxin phenylacetic acid (1 mmol/l of 0.9% NaCl solution ). The HF field was varied into 10 MHz subbands in the 1-170 MHz frequency range and was compared to a control experiment without an HF field.
    Quantitative determination of phenylacetic acid was performed using HPLC.
    [0069] The results of the experiments are collected in Figure 4. The separation rate for phenylacetic acid was able to be increased by at least 45.3% under the influence of the HF field. The effect was particularly pronounced at 54.6% in the 110-120 MHz sub-band. Modality 3
    [0070] This modality arises from the examinations according to Modality 2 that showed that the effect was particularly pronounced in the 110120 MHz sub-band.
    [0071] In continuous examinations according to modality 3, the frequency range of about 110-115 MHz was, in particular, able to be identified as an effective frequency range for the release of protein-bound uremic toxins. Figure 5 shows the respective effect on the corresponding release and subsequent separation of phenylacetic acid.
    [0072] According to the current status, the frequency ranges named summarily in Table 1 are suitable for the separation of protein-bound uremic toxins. Table 1: suitable frequencies in the HF field

    [0073] The respective frequency bands are the bands in which the maximum separation effect has been determined. An increase in separation was determined in part in the unnamed frequency ranges compared to the control; however, it was lower than in the named frequency ranges. Modality 4
    [0074] An increased release and therefore separation of protein-bound uremic toxins, in addition, was also able to be determined in the H-field range.
    [0075] It can be seen from Figure 6, that the H-field range of 1-6 MHz and the range of 9-13 MHz are suitable for releasing protein-bound uremic toxins from protein binding and, consequently, separate them dialytically. The effect on phenylacetic acid is shown in Figure 6. Modality 5
    [0076] In addition to the frequency of the field used, its field strength is also relevant to the resulting release and separation. As the field strength increases, the respective uremic toxins are increasingly released from protein binding and are subsequently separated.
    [0077] Figure 7 shows the effect of an increase in field strength on the content of protein-bound uremic toxins in the retained material for the example of phenylacetic acid.
    权利要求:
    Claims (10)
    [0001]
    1. Apparatus for hemodiafiltration with an extracorporeal circulation (10) for receiving blood to be purified and having a hemodialyzer and/or hemofilter (20) which is connected to the bloodstream (10), such that the bloodstream (10) has at least one inlet line (12, 14) for the supply of a replacement fluid upstream and downstream of the hemodialyzer and/or hemofilter (20), characterized in that: the device also comprises measuring devices for recording the transmembrane pressure and/ or hematocrit (HKT) and/or blood density, such that the measuring devices are connected to a control unit (100) to control one or more of the transmembrane pressure and/or the hematocrit (HKT) and/or the density blood, such that the control unit (100) is constructed so that the control is implemented with the help of at least one of the infusion rates (Qspre, Qspost) of the replacement fluid (13, 15), and the blood to be purified is exposed to a camp. the high frequency electromagnetic and/or a DC electric field (70) before and/or during contact with the hemodialyzer and/or hemofilter (20).
    [0002]
    2. Apparatus according to claim 1, characterized in that the measuring devices comprise sensors (40) that are arranged in the extracorporeal circulation (10) and/or in the dialysis fluid circulation (30) upstream and/ or downstream of the hemodialyzer and/or hemofilter (20).
    [0003]
    3. Apparatus according to claim 1 or 2, characterized in that the control unit (100) controls the infusion rates (Qspre, Qspost) of the replacement fluid so that Qspre is greater than or equal to Qspost during treatment.
    [0004]
    4. Apparatus according to claim 3, characterized by the fact that the ratio of infusion rates Qspre/Qspost is at least 1.2.
    [0005]
    5. Apparatus according to claim 3 or 4, characterized by the fact that the ratio of infusion rates Qspre/Qspost is at least 1.5.
    [0006]
    6. Apparatus according to any one of claims 1 to 5, characterized by the fact that the high-frequency electromagnetic field is generated by a high-frequency coil, a high-frequency electrode and/or a high-frequency capacitor.
    [0007]
    7. Apparatus according to any one of claims 1 to 6, characterized by the fact that the DC electric field is generated by a capacitor that has at least two plates.
    [0008]
    8. Apparatus according to any one of claims 1 to 7, characterized by the fact that the high-frequency electromagnetic field has a frequency of 100 kHz to 2 GHz, preferably 1 MHz to 1 GHz.
    [0009]
    9. Apparatus according to any one of claims 1 to 8, characterized by the fact that the DC electric field has a field strength of up to 1500 V/m.
    [0010]
    10. Apparatus according to any one of claims 1 to 9, characterized by the fact that the DC electric field has a field strength of 10 to 400 V/m.
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    BR112015014618A2|2017-07-11|
    JP2016500319A|2016-01-12|
    US20150343134A1|2015-12-03|
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    EP2934620B1|2016-12-14|
    CA2895350A1|2014-06-26|
    EA029566B1|2018-04-30|
    US10172994B2|2019-01-08|
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    2021-06-01| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 19/12/2013, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
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    US201261740026P| true| 2012-12-20|2012-12-20|
    DE102012025052.5A|DE102012025052A1|2012-12-20|2012-12-20|Hämodiafiltrationsverfahren|
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