EP1244480A1

EP1244480A1 - Haemofiltration system

Info

Publication number: EP1244480A1
Application number: EP00989978A
Authority: EP
Inventors: Ulrich Baurmeister
Original assignee: Membrana GmbH
Current assignee: Membrana GmbH
Priority date: 1999-12-23
Filing date: 2000-12-14
Publication date: 2002-10-02
Also published as: JP2003527167A; US6776912B2; US20020190000A1; WO2001047580A1

Abstract

The invention relates to a haemofiltration system for treating the blood, comprising a membrane module (1), in whose housing (2) hollow-fibre membranes (3) are arranged longitudinally. The ends of said fibres are embedded in filling compounds (4, 5) which form a fluid-tight seal with the inner wall of the housing. The membrane module has a dialysate chamber (12), a fluid-tight substitution fluid chamber (11) which is separated from the dialysate chamber (12) by a continuous partition (10), means for supplying (18, 19) a dialysate to and evacuating said dialysate from the dialysate chamber (12), in addition to means for supplying (21) a substitution fluid to the substitution chamber (11). The same hollow-fibre membranes (3) are used to treat the blood, to filter the substitution fluid and to supply the substitution fluid to the blood. An external chamber surrounds the hollow-fibre membranes (3). Said chamber is delimited by the inner wall of the housing (2) and the sealing compounds (4, 5) and is subdivided, at a point along the length of the housing (2), into the substitution fluid chamber (11) and the dialysate chamber (12). The partition (10) surrounds each individual hollow-fibre membrane (3).

Description

hemodiafiltration

Description:

The invention relates to a hemodiafiltration system for the treatment of blood, comprising a membrane module which has a cylindrical housing with a longitudinal extension, in which hollow-fiber membranes with a semipermeable wall embedded in the first and second potting compound, which can flow through on the lumen side and at their ends are embedded in a fluid-tight manner with the inner wall of the housing Are arranged in the direction of the longitudinal extent, and which has a dialysate space into which an inlet device for dialysate and an outlet device for dialysate open, and a substituate space into which an inlet device for substituate opens, means for supplying a dialysate with a defined volume flow via the inlet device for dialysate into the dialysate chamber, means for discharging the dialysate via the outlet device for dialysate from the dialysate room, means for feeding a substituate with a defined volume flow via the inlet device for sub stituat in the substituatraum, wherein the membrane module is designed as a uniform component for blood treatment, for filtering the substituate and for mixing the substituate with the blood, and the substituatraum and the dialysatraum are separated from each other in a fluid-tight manner by means of a continuous partition. The invention also relates to a membrane module for hemodiafiltration. Hemodiafiltration or the hemodiafiltration process is a membrane-based combination process for blood purification, in which hemodialysis and hemofiltration are carried out simultaneously. This procedure combines the advantages of convective mass transfer in hemofiltration with those of diffusion in hemodialysis. In hemofiltration, blood is directed past one side of the membrane of a hemofilter, with part of the liquid in the blood being drawn off through the membrane by ultrafiltration. This partial flow is replaced by a sterile and pyrogen-free substitution liquid or a substitute which is supplied to the extracorporeal blood flow either upstream of the hemofilter in the form of a pre-dilution (predilution) or downstream of the hemofilter in the form of a post-dilution (post-dilution). In addition, the usual hemodialysis is also carried out in hemodiafiltration, in which dialysate is passed past the other side of the membrane of the hemodialyzer, so that substances that require urine can be removed across the membrane.

By combining diffusive mass transport with convective mass transport in hemodiafiltration, it is not only advantageous to remove substances with a low molecular weight from the blood, which are also responsible for urine. The slowly diffusing middle molecules with molecular weights in the range of approx. 1 to 55 kD benefit from the convective mass transfer, and the larger the molecules and the larger the filtrate flow through the membrane, the more this will be the case. At approximately 60 kD, the membranes are said to be approximately tight, so that the patient does not release more than 4 g of proteins from the blood into the dialysate during approximately four hours of treatment.

In the conventional hemodialysis method, only the amount of liquid that is removed as ultrafiltrate via the dialysis membrane, which the patient has taken between dialysis treatments. The amount of fluid removed corresponds to approximately 6 to 8% of the blood volume flow. So-called volume-controlled dialysis machines are generally used to carry out hemodialysis processes. These control the amount of liquid removed. speaking of the preset net filtration by balancing the dialysate stream which is fed to the dialyzer with the dialysate stream which is withdrawn from the dialyzer.

In contrast, in hemodiafiltration, the amount of ultrafiltrate is significantly increased to approximately 20 to 30% of the blood volume flow due to the liquid fraction which is required to increase the convective transport across the membrane. The net amount of fluid ultimately withdrawn from the patient corresponds to that in conventional hemodialysis. The amount of liquid going beyond that to increase the convective transport is, as stated, replaced by a substituate.

To carry out hemodiafiltration processes, modified dialysis machines are generally used, which allow control of the ultrafiltration rates and carry out a balancing of the ultrafiltration volume flow and the substituate volume flow.

Different requirements are generally placed on the dialysate and the substitution liquid with regard to their purity. The dialysate can be produced on-line from fresh water and an electrolyte concentrate, the fresh water usually being sterile and the electrolyte concentrate being self-sterile. The substitution liquid in turn can be prepared online from the dialysate. However, there is no general guarantee that the dialysate produced on-line is absolutely sterile and free of endotoxins and pyrogens or CIS.

Cell fragments of dead bacteria are referred to as endotoxins. The endotoxin concentration is usually determined using the so-called LAL test, a biological assay such as that produced by BioWhittaker Inc. Pyrogens are temperature-increasing substances. For example, they increase the body temperature when infused into rabbits. Pyrogens can include endotoxins or exotoxins. The latter are produced by living bacteria. In human blood, these substances stimulate monocytes, which in turn produce cytokines and thus trigger a cascade of further cell stimulation. Endotoxins, exotoxins, pyrogens and other blood-stimulating substances from the dialysate are therefore now combined under the abbreviation CIS (Cytokine Inducing Substances). One of the relevant cytokines produced by stimulation of stimulated monocytes is interleukin 6 (IL 6). The determination of CIS by the detection of IL 6 is, for example, by BL Jaber et al., Blood Purif. 1998, Vol. 16, pages 210-219.

Therefore, the dialysate for the preparation of the substitution liquid should e.g. be converted into the sterile and ideally CIS-free state using a filter. Of course, the substitution liquid produced in this way can also be used as a dialysate. Modern dialysis machines generally contain a device with which the dialysate is filtered on-line in such a way that it has a concentration of endodoxins of less than 0.5 EU per ml of dialysate. This means that even with so-called high-flux dialysis, there are almost no more pyrogenic reactions in the patient, which are frequently observed in dialysate contaminated by endotoxins. However, with an endotoxin concentration of <0.03 EU / ml, the detection limit of the common LAL tests, there may still be CIS in the dialysate. The demand for CIS-free dialysate is therefore stricter than for LAL-negative dialysate.

EP-A 692 269 describes a hemodiafiltration device which has two blood filters connected in series. The blood filters each contain membranes over which the blood to be cleaned flows on one side and dialysate on the other side. The dialysate fed to the hemodiafiltration device is previously passed through a sterile filter. In the device described in EP-A 692 269, in one of the two blood filters, due to the positive transmembrane pressure set there in the direction of the blood path through the membrane of this blood filter, dialysate as a substitution liquid is transferred directly into the blood. A negative transmembrane pressure is detected in the second blood filter testifies, and there is a separation of part of the blood fluid and removal of urinary substances in the dialysate via diafiltration.

Such hemodiafiltration devices with blood filters connected in series prove to be complex in operation and, due to the design and the associated special and complex control, cannot generally be used on the dialysis machines customary on the market.

EP-A 451 429 also discloses a hemodiafiltration device which contains two membrane modules connected in series. Here, the first membrane module is a hemofilter, in which a partial flow of liquid is extracted from the blood to be purified, which primarily contains the medium-molecular substances to be removed from the blood. The ultrafiltrate is regenerated in a special filter and returned to the blood stream before it is introduced into the second membrane module. This blood flow is then in the second membrane module. undergo hemodialysis.

In addition to the aforementioned disadvantages of series-connected and separate blood filters, the hemodiafiltration devices described in EP-A 451 429 have the further disadvantage that a special regenerator is required by means of which the ultrafiltrate must be cleaned.

DE-A 196 07 162 describes a hemodiafiltration system with a controlled feed for a substituate and a controlled feed for a dialysate in a dialyzer, the dialyzer as a single component for blood treatment, the substituate filtration and the mixing of the substituate with the treating blood is trained. In its elongated housing, the dialyzer contains two membrane modules arranged next to one another, each with a bundle of hollow fiber membranes, the membrane modules being separated from one another by a partition wall which is essentially parallel to the hollow fiber membranes. The first membrane module is used for hemodiafiltration and the second membrane branch module for sterile filtration of the substituate. The dialyzer further comprises a chamber in which the purified substituate is combined with the blood to be treated.

It is true that the hemodiafiltration system described in DE-A 196 07 162 is simpler and more clearly structured in comparison to the systems with several blood filters connected in series. However, the manufacture of the dialyzers comprising two modules disclosed in DE-A 196 07 162 proves to be difficult, in particular because of the handling of two different hollow fiber membrane bundles. In addition, the membrane modules in the dialyzer are not arranged rotationally symmetrically, so that there is a risk of a non-uniform flow, in particular of the outer space around the hollow fiber membranes of the first membrane module, which is used for hemodiafiltration.

It is therefore an object of the present invention to provide a hemodiafiltration system which has a simple structure, allows a predeterminable and reproducible supply of substituate and of dialysate and which can be used in volume-controlled dialysis machines without major changes. It is a further object of the present invention to provide a membrane module for hemodiafiltration which can be used in a hemodiafiltration system and by means of which sterile filtration of the substituate is simultaneously possible.

The object is achieved on the one hand by a hemodiafiltration system according to the preamble of claim 1, which is characterized in that the hollow fiber membranes are combined into a single bundle and the same hollow fiber membranes are used for blood treatment, for filtering the substituate and for supplying the substituate to the blood, that the hollow fiber membranes are formed around an outer space which is delimited by the inner wall of the housing and the first and second potting compound and which along the longitudinal extent of the housing through the partition into the substituate space and the dialysate space is divided, with the partition enclosing each hollow fiber membrane.

In a preferred embodiment of the hemodiafiltration system according to the invention, the housing of the membrane module used according to the invention is circular-cylindrical around its longitudinal axis oriented in the direction of the longitudinal extent, and the hollow fiber membranes are arranged in a bundle which is essentially rotationally symmetrical about the longitudinal axis.

In the membrane module of the hemodiafiltration system according to the invention, the hollow fiber membranes are embedded at their ends in a fluid-tight manner in casting compounds, which at the same time distribute the outer space formed around the hollow fibers opposite a distribution space, in which the blood to be treated and introduced via a blood inlet device into the distribution space is distributed to the lumens of the hollow fiber membranes is closed, or opposite a collecting space in which the blood flowing out of the lumens is collected and discharged from the module via a blood outlet device. The hollow fiber membranes extend with their ends open at the ends through the respective potting compound and are connected to the distributor space or the collection space on the lumen side, so that the blood to be treated can flow through them.

Due to the fact that in the membrane module used in the hemodiafiltration system according to the invention the same hollow fiber membranes are used for blood treatment, for filtering the substituate and for supplying the substituate to the blood, and the dialysate space and the substituate space are separated from one another by means of a partition, it follows that the hollow fiber membranes extend in the direction of extension seen dialysate space and substituate space are arranged side by side at different positions along the hollow fiber membranes, wherein the partition fills the inner cross section of the housing. The partition wall in the membrane module used in the hemodiafiltration system according to the invention is preferably arranged essentially transversely to the hollow fiber membranes. In the application of the hemodiafiltration system according to the invention, the blood removed from the patient and to be purified is introduced into the membrane module via the blood inlet device and passed through the lumen of the hollow fiber membranes. Via the means for supplying dialysate, which comprise suitable conveying means, for example in the form of a pump or a metering unit for conveying dialysate with a defined volume flow, and a dialysate line connected to the inlet device for the dialysate, fresh dialysate with a defined volume flow is supplied to the membrane module and via the Inlet device for the dialysate introduced into the dialysate room. There, the dialysate is directed past the hollow fiber membranes, at the same time taking up the ultrafiltrate drawn from the blood through ultrafiltration through the walls of the hollow fiber membranes. Hemodiafiltration of the blood takes place in the area of the dialysate room, in which the urinary substances are extracted from the blood via diffusive and convective transport mechanisms. The dialysate mixed with the ultrafiltrate is drawn off from the dialysate space by means of a dialysate flow pump via the outlet device for the dialysate, and the dialysate drain is drained off.

The substituate is introduced via its own means for supplying substituate with a defined volume flow via the inlet device for substituate under excess pressure into the substituate space and there via the walls of the sections of the hollow fiber membranes located in the substituate space to the blood flowing through the lumens of the hollow fiber membranes with a defined volume flow. The amount of substituate to be supplied per unit of time, ie the volume flow of substituate, results from the difference between the liquid flow drawn from the blood in the area of the dialysate space via ultrafiltration and the net filtration controlled and permanently preset by the dialysis machine. The volume flow of substituate is generally smaller than the flow of dialysate introduced into the dialysate chamber. Depending on the flow direction of the blood through the hollow fiber membranes, the substituate can be added to the blood before it is subjected to hemodiafiltration (pre-dilution) or after it has been subjected to hemodiafiltration (post-dilution). Via a balancing unit connected to the dialysate circuit a control of the dialysate cycle including the administration of substituate. The net filtration, ie the net amount of liquid to be withdrawn from the blood in the area of the dialysate chamber, is set by means of an ultrafiltrate pump which is coupled to the balancing unit in terms of control technology.

In one embodiment of the hemodiafiltration system according to the invention, the means for supplying the substituate are physically completely separate from the means for supplying the dialysate and comprise suitable subsidies for conveying substituate with a defined volume flow, e.g. in the form of a pump or a metering unit, and a substituate line which is separate from the dialysate line and is in fluid communication with the inlet device for the substituate. In this case, the funding for dialysate and the funding for substituate must be controlled separately by means of control loops coupled together.

In a preferred embodiment of the hemodiafiltration system according to the invention, the means for supplying substituate and the means for supplying dialysate are coupled to one another. The coupling is particularly preferably realized in that these means comprise a common multiple pump, to which a dialysate feed line connected to the inlet device for dialysate and a substituate feed line connected to the inlet device for substituate are connected. This multiple pump comprises a common pump drive to which two separate pump heads are coupled. The ratio of the substituate volume flow to the dialysate volume flow can be set via the delivery rate of the pump heads.

In a further particularly preferred embodiment, the means for supplying dialysate comprise a conveying device for dialysate and a dialysate feed line, and the means for feeding substituate include a substituate feed line, and the substituate feed line branches off from the dialysate feed line via a branch. In this case, the substituate is removed via this branch from the dialysate feed line as a partial stream from the dialysate flowing through the dialysate feed line and via the substituate feed line and the inlet device for substituate into the substituate chamber, from where it is supplied to the blood flowing through the hollow fiber membranes via the walls of the hollow fiber membranes.

To set a defined substituate flow, it is particularly preferred if a pump is installed in the substituate feed line, through which a defined delivery of the substituate takes place, i.e. Via which the substituate volume flow is set, the pump being advantageously controllable. The setting of the volume flows of dialysate and substituate or the ratio of these volume flows to each other can also be done via throttles. Therefore, in a likewise particularly preferred embodiment, a throttle is installed in the dialysate feed line in the area between the branching and the inlet device for dialysate or in the substituate feed line and the dialysate feed line in the area between the branching and the inlet device for dialysate for adjusting the ratio of the substituate volume flow to the dialysate volume flow.

A throttle is understood to mean a defined narrowing of a flow cross-section for the targeted generation of a defined pressure loss in the flow of a fluid through this constriction, ie the throttle has a flow cross-section that is reduced in the flow direction compared to the flow cross-section in front of and behind the throttle. The flow cross section of the throttle has a defined fixed value that is independent of the medium flowing through or can be set to a defined value that is independent of the medium flowing through. With such throttles, the pressure loss occurring during the flow can be predetermined. The throttles with a fixed flow cross-section include, for example, orifices in the form of perforated shutters or slit diaphragms, the flow cross-section of which can preferably be adjusted to the fixed cross-section, or capillary tubes with defined diameters, and the throttles with an adjustable cross-section, e.g. valves or throttle valves, in the pipelines are installed. The chokes used according to the invention are preferably adjustable and particularly preferably controllable. The dialysate flow introduced into the dialysate space and the substituate flow, and thus also the ratio of these two flows to one another, can be set to a defined value in a simple manner via the throttles arranged in the dialysate feed line or in the substituate feed line.

The hemodiafiltration system according to the invention is due to the membrane module used according to the invention, in which the dilution of the blood with substituate required in hemodiafiltration and the hemodiafiltration are integrated in a single membrane module in a simple, controllable and reproducible manner and, like conventional hemodialyzers, is a bundle of only Contains hollow fiber membranes, significantly simplified compared to the systems of the prior art. At the same time, the concept according to the invention of the separate supply of dialysate and substituate via respective means in the dialysate space and the substituate space, which are separated from one another in a fluid-tight manner, enables the dialysate and substituate volume flows required to be adjusted in a manner adapted to the hemodiafiltration application. In addition, with the hemodiafiltration system according to the invention, hemodiafiltration can be carried out in dialysis machines on the market with volume flow-controlled ultrafiltration.

DE-A 28 51 929 discloses a module construction based on hollow fiber membranes, in which the dialysate space is divided into two partial spaces by a dense partition. In one embodiment, dialysate is passed through the one sub-space, which is provided with an inlet device and with an outlet device, in order to remove substances that require urine from the blood flowing through the hollow fiber membranes by diffusion. A negative pressure is applied to the second partial space, which is provided with an outlet device, in order to draw off a filtrate from the blood flowing through the hollow fiber membranes via the walls of the hollow fiber membranes. However, DE-A 28 51 929 does not disclose the use of such a membrane module in a hemodiafiltration system or the use of such a membrane module in a hemodiafiltration process. The invention therefore also relates to the use of a membrane module which has a cylindrical housing with a longitudinal extension in which, in the direction of the longitudinal extension, a bundle of hollow fiber membranes through which the lumen can flow and which is embedded at its ends in a first and second potting compound which is fluid-tightly connected to the inner wall of the housing is arranged with a semi-permeable wall, and in which around the hollow fiber membranes is formed an outer space delimited by the inner wall of the housing and the first and second potting compound, which along the longitudinal extent of the housing by means of a continuous partition wall enclosing each individual hollow fiber membrane into a dialysate space and a substituate chamber, which is separated from the dialysate chamber in a fluid-tight manner, for carrying out a hemodiafiltration process in which, in addition to the actual blood treatment, the filtration also uses the bundle of hollow fiber membranes of the substituate and the delivery of the substituate to the blood.

In the membrane module of the hemodiafiltration system according to the invention, the substituate can be supplied to the blood before or after the blood has been subjected to hemodiafiltration in the region of the dialysate chamber. In individual cases, it is also possible to divide the substituate space and thus the supply of the substituate to the blood along the extension of the hollow fiber membranes and to supply part of the substituate to the blood before and part after hemodiafiltration. In this case, for example, in the membrane module according to the invention, two substituate subspaces are arranged along the extension of the hollow fiber membranes adjacent to the embeddings of the hollow fiber membrane ends, each of which is separated from an intermediate dialysate space in a fluid-tight manner by a partition. Accordingly, it is also possible to divide the dialysate space and thus the hemodiafiltration and to arrange, for example, two dialysate subspaces in the membrane module along the extension of the hollow fiber membranes adjacent to the embeddings of the hollow fiber membrane ends, each of which is separated from an intermediate substituate space by a partition. For applications in which the blood is subsequently diluted with a substituate, the blood flows into the hollow fiber membranes at the end of the membrane module facing the dialysate space and flows through them in the direction of the end facing the substituate space. The blood is then first withdrawn from the blood in the area of the dialysate space by means of ultrafiltration and then the substituate is added to the area of the substituate area. It is advantageous if the dialysate inlet device is arranged adjacent to the dividing wall and the dialysate outlet device is arranged adjacent to the casting compound which delimits the dialysate space and surrounds the hollow fiber membrane ends. The dialysate then flows through the dialysate chamber in the opposite direction to the blood flow.

For applications in which the blood is prediluted with a substituate, the blood flows into the hollow fiber membranes at the end of the membrane module facing the substituate space and flows through them in the direction of the end facing the dialysate space. Here, the blood is first supplied with substituate in the area of the substituate area and then the necessary liquid is removed in the area of the dialysate area by means of ultrafiltration. In this case, it is advantageous if the dialysate inlet device is arranged adjacent to the potting compound delimiting the dialysate chamber and enclosing the hollow fiber membrane ends, and the dialysate outlet device is arranged adjacent to the partition, so that the dialysate flows through the dialysate chamber in the opposite direction to the flow of blood.

When hemodiafiltration is carried out, an external sterile filter is often connected upstream of the actual membrane module, by means of which sterile filtration of the dialysate or at least of the liquid supplied as a substituate is carried out. As a rule, however, sterile filtration of the entire dialysate is not necessary, since the part of the dialysate ultimately passed as a dialysate over the hollow fiber membranes does not have to meet the high purity requirements as is the case for the substituate. In an advantageous embodiment, the sterile filtration of the substituate In the form of the hemodiafiltration system according to the invention, a sterile filter is arranged within the membrane module in the region of the substituate around the hollow fiber bundle, which surrounds the hollow fiber membrane bundle.

Furthermore, the invention also relates to a membrane module, comprising a cylindrical housing with a longitudinal extension, in which a bundle of hollow fiber membranes with a semipermeable wall through which the lumen can flow and oriented in the direction of the longitudinal extension of the housing is arranged, the ends of which are in a first and in a second with the Potting compound connected to the interior of the housing in a fluid-tight manner is embedded in such a fluid-tight manner that an outer space is formed around the hollow fiber membranes and is delimited by the first and the second potting compound and the interior wall of the housing and along the longitudinal extent of the housing by a partition wall enclosing each hollow fiber membrane and essentially transverse to the hollow fiber membranes is divided into a dialysate space and a substituate space, the dialysate space having an inlet device and an outlet device for introducing or discharging a dialysate, and the substituate space having at least one opening, e.g. Ur introduction of a substituate, characterized in that a sterile filter is arranged in the area of the substituate between the inlet device for the substituate and the hollow fiber membranes located in the substituate space, which divides the substituate space into an outer substituate part space and an inner substituate part space spatially separated from the outer substituate part space by the sterile filter , wherein the outer substituate compartment is in fluid communication with the inlet device for substituate and the hollow fiber membranes are arranged in the inner substituate compartment.

Spatial separation is understood here to mean that a fluid introduced into the outer substituate subspace via the inlet device for substituate can only get into the inner substituate subspace via the sterile filter itself, ie the sterile filter acts as a so-called dead-end filter. In a preferred embodiment of the membrane module according to the invention, the sterile filter is arranged around the hollow fiber bundle and encloses the hollow fiber membrane bundle. In this preferred embodiment, the sterile filter divides the substituate space perpendicular to the hollow fiber membranes into the outer substituate subspace, in which the substituate can be uniformly distributed over the sterile filter, and into the inner substituate subspace containing the bundle of the hollow fiber membranes. An optionally pleated flat membrane can advantageously be used as a sterile filter. The use of a continuous microporous flat membrane is advantageous. The sterile filter is preferably tight to the passage of endotoxins, ie endotoxin-tight, and particularly preferably ClS-impermeable, so as to ensure the supply of a sterile endotoxin- and pyrogen-free and preferably CIS-free substituent to the hollow fiber membranes in use. Here, a sterile filter which is impervious to the passage of endotoxins is understood to be a filter which, when filtered, contains a dialysate contaminated with an endotoxin concentration of up to 30 EU / ml _. tration rate of 150 ml / min over a period of 4 hours through the sterile filter, the filtrate has an endotoxin concentration below the detection limit of conventional tests, ie below about 0.03 EU / ml. The endotoxin concentration is then determined by means of conventional LAL tests as (Multi-test Limulus amebocyte lysates Pyrogent ^®) are marketed and described, for example, by the company. BioWhitteker Inc..

In individual cases, in the membrane module used in the hemodiafiltration system according to the invention or in the membrane module according to the invention to increase the substituate flow to be supplied to the blood, it is also possible to embed additional semipermeable membrane elements into the potting compound adjacent to the substituate space, in which the hollow fiber membrane ends are embedded. end mode and through which the substituate space and the. the other side of the potting compound, which, depending on the design of the membrane module according to the invention, is the distributor or collection space for the blood, is in fluid communication. These membrane elements allow the blood, which is then located in the adjacent collection or distribution space, part of the substituate can also be supplied. These semipermeable membrane elements can be present, for example, in the form of capillary membranes which are closed at one end, preferably continuously microporous, which are embedded in the sealing compound and which protrude with their closed end into the substituate space. Like the previously mentioned sterile filter, these membrane elements are preferably impervious to the passage of endotoxins and particularly preferably CIS-impermeable. With regard to the definition of the endotoxin tightness or the CIS tightness and with regard to the respective measurement methods, reference is made to the statements made above.

For the application, it is advantageous if the partition of the membrane module used in the hemodiafiltration system according to the invention or of the membrane module according to the invention consists of an essentially dimensionally stable material, i.e. from a material which essentially maintains its dimension in use under the then prevailing conditions and in particular through the liquids used, i.e. especially through the dialysate, is not swollen. Not least for reasons of ease of manufacture, the dividing wall preferably consists of a hardened casting compound in which the hollow fiber membranes are embedded in such a way that they enclose each hollow fiber membrane. The partition, the first and the second casting compound are particularly preferably made of the same material. The materials that are usually used as potting compounds for embedding hollow fiber membranes can be used here, such as cured polyurethane resins, epoxy resins and the like.

When using the hemodiafiltration system according to the invention or the membrane module according to the invention, the most uniform possible distribution of substituate and dialysate over the bundle cross section is required in the membrane module. An even distribution can be achieved by a suitable design of the housing. The housing of the membrane module is preferably designed such that it bundles the hollow fiber membranes in the major part of the dialysis Satraums tightly encloses with its inside and has an expansion of the cross-section in the area of the casting compounds as well as the partition and the substituate area. As a result, in an advantageous embodiment, annular spaces are formed in these areas around the bundle of hollow fiber membranes for distributing the dialysate onto the hollow fiber membrane bundle, for collecting the dialysate from the membrane bundle and / or for distributing the substituate over the bundle.

The bundle preferably has, at least in the major part of the dialysate space, a packing density of the hollow fiber membranes of between 40 and 65%, which is based on the bundle cross section and is essentially uniform due to the extent of the bundle in this area. It has been shown that for the membrane module used according to the invention or according to the invention with such packing densities, a good removal of the urinary substances from the blood is made possible.

In a likewise advantageous embodiment, the housing of the membrane module is shaped in such a way that it closely encloses the inside of the bundle of hollow fiber membranes in the area of the dialysate chamber and has an expansion of the housing cross section in the area of the casting compounds and the partition wall and the substituate chamber, and is the hollow fiber membrane bundle so arranged in the housing that the cross section of the hollow fiber membrane bundle widens in the area of the partition and the substituate space and thus the packing density of the hollow fiber membranes in this area is lower than in the majority of the dialysate space. In the area of the enlarged cross section, the packing density of the hollow fiber membrane bundle is particularly preferably essentially homogeneous over the cross section. As a result, the hollow fiber membranes in the interior of the bundle can also be easily reached from the dialysate or the substituate, and the substituate flows uniformly into all hollow fiber membranes of the bundle. At the same time, the manufacture of the membrane module is also simplified, since in the case of a dividing wall which consists of a casting compound, when the hollow-fiber membranes are embedded, the casting can enclose the individual hollow fiber membranes better. In its expanded area, the bundle preferably has a packing density of between 20 and 55%, based on the respective bundle cross section.

In order to carry out an efficient hemodiafiltration, it is necessary that a sufficiently large exchange area is available for the diafiltration in order to be able to remove the urinary substances efficiently from the blood. On the other hand, a sufficient membrane area must also be available to enable the required amount of substituate to be safely supplied to the blood. It was found that for the membrane module according to the present invention, in the direction of the extension of the hollow fiber membranes, the ratio L _d / L _{s of} the extension of the dialysate space L _d to the extension of the substituate space L _{s should} preferably be greater than 3. L _d / L _s is therefore preferably in the range between 3 and 20 and particularly preferably between 5 and 15.

In order to have the largest possible membrane area available for the supply of substituents to the blood and for hemodiafiltration, the thickness of the partition wall of the membrane module should be as small as possible. On the other hand, a certain minimum thickness is required to ensure sufficient stability of the partition. It is therefore advantageous if the partition wall has a thickness between 1 and 15 mm, and is particularly advantageous if it has a thickness between 5 and 10 mm.

For efficient hemodiafiltration, it is necessary to generate a sufficiently high convective transport to remove in particular the slowly diffusing urinary substances with a medium molecular weight. On the other hand, it is advantageous if only a relatively small section of the hollow fiber membrane bundle is required for the supply of substituate to the blood. This means that it must be possible to achieve a sufficiently high filtrate flow across the membrane wall. Therefore, the hollow fiber membranes used in the invention or in the membrane module according to the invention preferably have an ultrafiltration rate for Water between 20 and 1500 ml / (hm ² mmHg), the ultrafiltration rate being determined by the method described in DE-A 195 18 624, the disclosure of which is expressly referred to here.

For safe operation of the hemodiafiltration system according to the invention, it is important that, in particular when the substituate is supplied to the blood, there is no undesirable contamination of the blood flowing through the hollow fiber membranes with bacteria, endotoxins or pyrogens. According to the above statements, the dialysate and / or at least the substituate can be subjected to sterile filtration in a separate or in a sterile filter integrated in the membrane module of the hemodiafiltration system according to the invention. Alternatively or additionally, this sterile filtration can also take place in the hollow fiber membranes of the membrane module of the hemodiafiltration system according to the invention itself. In a preferred embodiment, the hollow fiber membranes are therefore impervious to endotoxins and particularly preferably impervious to cytokine-inducing substances. In this case, the impermeability can be achieved by an appropriately set pore size of the separation-active layer of the membranes and / or by adsorptive properties of the hollow fiber membranes. With regard to the definition of the endotoxin tightness or the CIS tightness and with regard to the respective measurement methods, reference is made to the statements made above.

The hollow fiber membranes used according to the invention preferably have an inside diameter between 140 and 260 μm, the wall thickness is preferably between 5 and 100 μm and particularly preferably between 20 and 60 μm. Preferred membrane materials are those which have good blood tolerance. These include polymers from the group of cellulosic polymers, such as cellulose or regenerated cellulose, modified cellulose, such as cellulose esters, cellulose ethers, amine-modified celluloses, and mixtures of cellulosic polymers, from the group of synthetic polymers such as polyacrylonitrile and corresponding copolymers, polyarylsulfones and Polyarylether- sulfones, such as polysulfone or polyether sulfone, polyamides, polyether block amides, polycarbonates or polyesters, and modifications, blends, mixtures or copolymers of these polymers obtained therefrom. Further polymers such as polyethylene oxide, polyhydroxy ether, polyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol or polycaprolactone can be added to these polymers or polymer mixtures as additives. In individual cases, the membrane may also have been subjected to surface modification, for example, in order to adjust certain properties of the membrane surface, for example in the form of certain functional groups, or to achieve hydrophilization of an otherwise hydrophobic membrane on its surfaces, as is described, for example, in JP-A 10118472 ,

The arrangement of the bundle of hollow fiber membranes arranged in the membrane module of the hemodiafiltration system according to the invention, ie the arrangement of the hollow fiber membranes to form a bundle, can be as desired, with a good flow around the individual hollow fiber membranes being ensured. In an advantageous design, the hollow fiber membranes are essentially parallel to one another and to the longitudinal axis of the bundle and are kept at a distance from one another by means of textile threads. This can be achieved, for example, by weaving the hollow fiber membranes into a mat or a ribbon of parallel hollow fiber membranes by means of the textile threads and then configuring them into a bundle before they are formed into a bundle. The bundle of hollow fiber membranes contained in the membrane module according to the invention can also be composed of partial bundles as long as each of the hollow fiber membranes of the bundle is used in the treatment of blood, for filtering the substituate and for supplying the substituate to the blood. Such a construction from partial bundles, in which the partial bundles are wound with winding threads to improve the flow around the hollow fiber membranes and the hollow fiber membranes are kept at a distance within the partial bundles via supporting threads, is described for example in EP-A 732 141. In addition, the hollow fiber membranes can also have an undulation. The invention is explained in more detail below with reference to the figures. In a simplified schematic representation:

1 shows a detail of a hemodiafiltration system according to the invention with a membrane module inserted therein in a longitudinal sectional view, a procedure with a redilution of the blood being shown,

2 shows a detail of a hemodiafiltration system according to the invention with a membrane module inserted therein in a longitudinal sectional view, a procedure with a predilution of the blood being shown,

3: segment of a longitudinal section through a membrane module used in the hemodiafiltration system according to the invention or a membrane module according to the invention with a sterile filter integrated in the housing of the module,

4: Scheme of a hemodiafiltration system according to the invention, in which a procedure with a redilution of the blood is shown,

5: Scheme of a hemodiafiltration system according to the invention, in which a procedure with a predilution of the blood is shown.

Figure 1 shows schematically a section of a hemodiafiltration system according to the invention with a membrane module 1 inserted therein in a longitudinal sectional view. The membrane module 1 has a cylindrical housing 2, in which a bundle of hollow fiber membranes 3 oriented in the direction of the longitudinal extent of the housing is arranged. The ends of the hollow fiber membranes are embedded in a fluid-tight manner in casting compounds 4, 5, which in turn are fluid-tightly connected to the inner wall of the housing 2. The hollow fiber membranes are embedded in the casting compounds 4.5 in such a way that their ends pass through the casting compounds 4.5. pass through and their lumens open into a distribution space 6 or a collection space 7. The distribution space 6 has a blood inlet device 8 and the collecting space 7 has a blood outlet device 9.

An outer space is formed around the hollow fiber membranes 3 between the casting compounds 4, 5 and the inner wall of the housing 2, which is along the extension of the hollow fiber membranes 3 by a partition wall 10, which runs transversely to the hollow fiber membranes 3, e.g. is divided from a hardened epoxy or polyurethane casting compound into a substituate chamber 11 and a dialysate chamber 12. The partition wall 10 surrounds the individual hollow fiber membranes 3 and is connected to the housing inner wall in a fluid-tight manner, so that the substituate space 11 and the dialysate space 12 are separated from one another in a fluid-tight manner.

The dialysate room has an inlet device 13 and an outlet device 14 for dialysate, the substituate room has an inlet device 15 for substituate. In order to be able to achieve a good distribution of dialysate or of substituate in the dialysate space 12 or in the substituate space 11 in use, the cross section of the housing 2 of the membrane module shown in FIG. 1 is widened in the region of the dividing wall 10 and in the region of the substituate space 11 , In the area of the outlet device 14, the cross section of the housing 2 is also widened in order to be able to pull the dialysate evenly out of the module.

A method of hemodiafiltration is indicated schematically in FIG. 1, in which the blood is subsequently diluted with a substituate, that is, when the blood flows through the membrane module, the ultrafiltrate is first withdrawn and then the substituate is added. In use, the blood, which is indicated by the arrows 16, flows through the blood inlet device 8 into the distribution chamber 6, flows through the lumens of the hollow fiber membranes 3, then flows out of the hollow fiber membranes 3 into the collecting chamber 7 and is removed from the membrane module via the blood outlet device 9 ie derived from the hemodia filter. The dialysate, represented by the arrows 17, is introduced into the dialysate chamber 12 by means of a pump 18 serving as a conveying device via the dialysate feed line 19 connected to the inlet device 13 and flows through the dialysate chamber 12 in the opposite direction to the flow of blood. Here, the dialysate 17 absorbs the ultrafiltrate flowing out over the walls of the hollow fiber membranes 3 together with the urinary substances removed from the blood. The dialysate 17 mixed with the ultrafiltrate is withdrawn from the dialysate chamber 12 via the outlet device 14.

In the embodiment shown in FIG. 1, the substituate represented by the arrow 20 is removed as a partial stream via a substituate feed line 21 branching off the dialysate feed line 19 from the dialysate flowing through the dialysate feed line 19 and introduced into the substituate space 11 via the inlet device 15, from where it flows flows through hollow fiber membranes 3 passing through and mixes with the blood flowing through the hollow fiber membranes 3. A throttle 22 is installed in the dialysate feed line 19 in the area between the branch and the inlet device 13 for dialysate for the defined setting of the ratio of the dialysate volume flow to the substituate volume flow.

The membrane module shown schematically in longitudinal section in FIG. 2 corresponds in its essential features to the membrane module shown in FIG. 1, so that the same parts are provided with the same reference numerals and a detailed description is omitted again. In FIG. 2, however, a section of a hemodiafiltration system is shown, in which, when used in hemodiafiltration, the blood is prediluted, that is, when the membrane module flows through it, the substituate is first supplied and then the ultrafiltrate is removed.

In hemodiafiltration, the blood 16 is conducted into the hollow fiber membranes 3 via the blood inlet device 8 and the distribution space 6 and flows through them. Here, the blood in the area of the substituate space 11 is first supplied with and the blood is diluted with substituate before it continues on its way through the hollow fiber membranes 3 through the area of the dialysate chamber 12, in which the required amount of liquid is withdrawn from it through ultrafiltration through the walls of the hollow fiber membranes and the urinary substances are removed in the process. The cleaned blood, adjusted to the required liquid content, leaves the membrane module according to the invention via the blood outlet device 9.

The dialysing liquid 17 is introduced into the dialysate chamber via the inlet device 13, which in the present case is located at the end of the dialysate chamber facing away from the partition 10, and flows through the dialysate chamber in the opposite direction to the flow of blood in the direction of the partition 10. In this case, it takes the ultrafiltrate with the urinary substances removed from the blood and is then withdrawn from the dialysate chamber 12 via the outlet device 14 located near the partition 10. As also shown in FIG. 1, the substituate is taken as a partial stream via a substituate feed line 21 branching off the dialysate feed line 19 from the dialysate flowing through the dialysate feed line 19, introduced into the substituate space 11 via the inlet device 15 and supplied to the blood from there via hollow fiber membranes 3 , In the embodiment shown in FIG. 2, however, a pressure booster pump 23 built into the substituate feed line 21 is used to set the ratio of the dialysate volume flow to the substituate volume flow.

FIG. 3 shows, in an enlarged representation compared to FIGS. 1 and 2, a segment comprising the substituate space and the partition 10 of a membrane module 1 used in the hemodiafiltration system according to the invention or of a membrane module 1 according to the invention. The membrane module shown in detail in FIG Membrane module, so that the same parts are provided with the same reference numerals and a detailed description is omitted again. The membrane module embodiment shown in FIG. 3 has a sterile filter 24 integrated in the housing 2 for sterile filtration of the substituate 20. The sterile filter 24, preferably in the form of a bacteria- and endotoxin-tight flat membrane, encloses the hollow fiber membrane bundle in the region of the substituate space and divides the substituate space into an outer substituate part space 25 and an inner substituate part space 26, which are separated in a fluid-tight manner from the dialysate space 12 via the partition 10. The sterile filter can be embedded in a simple manner together with the hollow fiber membranes 3 in the sealing compound 5 and the partition 10. In the embodiment of the membrane module according to the invention shown in FIG. 3, the substituate 20 introduced into the housing via the inlet device 15 is uniformly distributed over the entire circumference in the outer substituate subspace 25 and flows completely through the sterile filter 24, whereby it is subjected to sterile filtration. After flowing through the sterile filter 24, the substituate 20 is distributed over the inner substituate subspace 26 and flows from there through the walls of the hollow fiber membranes 3 into the blood flowing through them.

FIG. 4 schematically shows the basic structure of a hemodiafiltration system according to the invention, which comprises a membrane module 1 with a partition 10, as shown in FIG. 1. The hemodiafiltration system according to FIG. 4 is suitable for hemodiafiltration processes in which the blood is rediluted with a substituate. The blood withdrawn from the patient is fed in the arrow direction a via a blood supply line 27 and the blood inlet device 8 of the membrane module 1 serving as a hemodia filter to the membrane module 1 and passed through the lumen of the hollow fiber membranes arranged in the membrane module. The cleaned blood is discharged from the membrane module 1 via the blood outlet device 9 and is returned to the patient in the direction of arrow a via the blood discharge line 28 and a drip chamber 29.

Via the dialysate feed line 19 and the inlet device 13 for the dialysate, dialysate is conveyed in the direction of arrow b into the dialysate chamber of the hemodia filter 1. It flows through the dialysate chamber in the opposite direction to the blood flow in Direction towards the outlet device 14 for dialysate, wherein it receives the ultrafiltrate extracted from the blood via the hollow fiber membranes and containing the urinary substances. The dialysate enriched with the ultrafiltrate leaves the membrane module via the outlet device 14 and is drawn off via the dialysate discharge line 30 in the direction of arrow c by means of the dialysate flow pump 31 and the ultrafiltrate pump 33.

In the embodiment of the hemodiafiltration system according to the invention shown in FIG. 4, the substituate to be supplied to the blood is introduced into the substituate space of the membrane module 1 through the substituate line 21 branching off from the dialysate line 19 and via the inlet device 15, and from there via the walls of the hollow fiber membranes to be supplied with blood flowing in the hollow fiber membranes. In the present case, there is a preferably controllable pump 23 in the substituate feed line 21, by means of which the substituate volume flow and thus the ratio of dialysate volume flow to substituate volume flow is set.

The dialysate circuit is checked via the balancing unit 32 and the net filtrate flow withdrawn from the blood in the region of the dialysate chamber is adjusted via the ultrafiltrate pump 33. The balancing unit 32 works in such a way that the volume flow conveyed by the pump 31 is replaced by an equally large volume flow of fresh dialysate.

A further embodiment of the hemodiafiltration system according to the invention is shown schematically in FIG. With regard to the essential elements, the hemodiafiltration system according to FIG. 5 corresponds to the hemodiafiltration system shown in FIG. 4, so that the same elements are provided with the same reference symbols. In contrast to the hemodiafiltration system of FIG. 4, however, the hemodiafiltration system according to FIG. 5 is suitable for hemodiafiltration processes in which the blood is prediluted with a substituate. The dialysate, which serves as a hemodia filter via the dialysate feed line 19. the membrane module 1 is supplied, flows through the dialysate inlet device 13 into the dialysate chamber of the hemodia filter, the dialysate inlet device 13 being in the present case at the end of the hemodia filter facing the blood outlet device 9. In the dialysate chamber, the dialysate flows counter to the flow direction of the blood in the direction of the dialysate outlet device 14, which is arranged adjacent to the partition wall 10, which is only indicated here. The dialysate mixed with the ultrafiltrate taken up in the dialysate chamber leaves the dialysate chamber via the dialysate outlet device 14 and is drawn off via the dialysate discharge line 30 in the direction of arrow c by means of the dialysate flow pump 31 and the ultrafiltrate pump 33.

In the embodiment of the hemodiafiltration system according to the invention shown in FIG. 5, the substituate to be supplied to the blood is likewise branched off from the dialysate stream by a substituate line 21 branching off from the dialysate line 19 and introduced into the substituate space of the membrane module 1 via the inlet device for the substituate 15, from where it is introduced via the Walls of the hollow fiber membranes to be supplied to the blood flowing in the hollow fiber membranes. In the embodiment of the hemodiafiltration system according to the invention shown in FIG. 5, a throttle 22 is located in the dialysate feed line 19 between the branch of the substituate feed line 21 and the inlet device for dialysate 13, preferably in the form of an adjustable valve, by means of which the ratio of dialysate volume flow to substituate volume flow is set ,

Claims

claims:

1. Hemodiafiltration system for the treatment of blood, comprising a membrane module (1), which has a cylindrical housing (2) with a longitudinal extension, in which the lumen side can flow through and at its ends into a first and second fluid-tightly connected to the inner wall of the housing (2) Potting compound (4, 5) embedded hollow fiber membranes (3) are arranged with a semipermeable wall in the direction of the longitudinal extent, and which has a dialysate space (12) into which an inlet device (13) for dialysate and an outlet device (14) for dialysate open , and a substituate chamber (11) into which an inlet device (15) for substituate opens, means for feeding a dialysate with a defined volume flow via the inlet device (13) for dialysate into the dialysate chamber (12), means for discharging the dialysate via the outlet device (14) for dialysate from the dialysate chamber (12), means for supplying a substituate with a defined volume umenstrom over the inlet device (15) for substituate in the substituate chamber (11), wherein the membrane module (1) is designed as a unitary component for blood treatment, for filtering the substituate and for mixing the substituate with the blood and the substituate chamber (11) and Dialysate chamber (12) are separated from one another in a fluid-tight manner by means of a continuous partition wall (10), characterized in that the hollow fiber membranes (3) form a single one Bundles are combined and the same hollow fiber membranes (3) are used for blood treatment, for filtering the substituate and for supplying the substituate to the blood, that an outer space is formed around the hollow fiber membranes (3), which is formed by the inner wall of the housing (2) and the first and second potting compound (4, 5) is limited and which is divided along the longitudinal extent of the housing (2) by the partition (10) into the substituate space (11) and the dialysate space (12), the partition (10) each individual hollow fiber membrane (3) encloses.

2. Hemodiafiltration system according to claim 1, characterized in that the partition (10) is arranged substantially transversely to the hollow fiber membranes (3).

3. Hemodiafiltration system according to one or more of claims 1 or 2, characterized in that the means for supplying substituate and the means for supplying dialysate are coupled to one another.

4. Hemodiafiltration system according to claim 3, characterized in that the means for supplying substituate and the means for supplying dialysate comprise a common multiple pump to which a dialysate supply line (19) connected to the inlet device (13) for dialysate and one with the inlet device (15) for substituate-connected substituate feed line (21) are connected.

5. Hemodiafiltration system according to claim 3, characterized in that the means for supplying dialysate comprise a conveying device (18) for dialysate and a dialysate supply line (19) and the means for supplying substituate a substituate supply line (21) and that the substituate supply line (21) branches off from the dialysate feed line (19) via a branch.

6. Hemodiafiltration system according to claim 5, characterized in that a substituate pump (23) for conveying the substituate is installed in the substituate feed line (21).

7. Hemodiafiltration system according to claim 5, characterized in that in the dialysate feed line (19) in the area between the branching and the inlet device (13) for dialysate or in the substituate feed line (21) and the dialysate feed line (19) in the area between the branching and Inlet device (13) for dialysate, a throttle (22) for adjusting the ratio of substituate volume flow to dialysate volume flow is installed.

8. Hemodiafiltration system according to one or more of claims 1 to 7, characterized in that the membrane module (1) in the region of the substituate (11) around the bundle of hollow fiber membranes (3) around a bundle enclosing sterile filter (24).

9. hemodiafiltration system according to claim 8, characterized in that the sterile filter (24) is a microporous flat membrane.

10. Hemodiafiltration system according to one or more of claims 1 to 9, characterized in that the membrane module (1) seen in the direction of the longitudinal extension of the housing (2) has a ratio L _d / L _{s of} the extension L _{d of} the dialysate chamber (12) for extension L _{s of} the substituate space (11) in the range between 3 and 20.

11. Hemodiafiltration system according to claim 10, characterized in that the ratio is between 5 and 15.

12. Hemodiafiltration system according to one or more of claims 1 to 11, characterized in that the partition (10) of the membrane module (1) consists of a hardened casting compound.

13. Hemodiafiltration system according to claim 12, characterized in that the partition (10), the first and the second potting compound (4,5) consist of the same material.

14. Hemodiafiltration system according to one or more of claims 1 to 13, characterized in that the partition (10) of the membrane module (1) has a thickness between 1 and 15 mm.

15. Hemodiafiltration system according to one or more of claims 1 to 14, characterized in that the housing (2) of the membrane module (1) in the area of the dialysate space (12) tightly encloses the bundle of hollow fiber membranes (3) with its inside and in the area the casting compounds (4, 5) as well as the partition (10) and the substituate space (11) have an expansion of the cross section.

16. Hemodiafiltration system according to one or more of claims 1 to 15, characterized in that the hollow fiber membranes (3) of the membrane module (1) have an ultrafiltration rate for water between 20 and 1500 ml / (hm ² -mmHg).

17. Hemodiafiltration system according to one or more of claims 1 to 16, characterized in that the hollow fiber membranes (3) of the membrane module (1) are endotoxin-tight.

18. Use of a membrane module (1), which has a cylindrical housing (2) with a longitudinal extension, in which in the direction of the longitudinal extension a bundle of flowable on the lumen side and at its ends in a fluid-tightly connected first and with the inner wall of the housing (2) second potting compound (4, 5) embedded hollow fiber membranes (3) is arranged with a semi-permeable wall, and in which around the hollow fiber membranes (3) around an outer space bounded by the inner wall of the housing (2) and the first and second potting compound (4,5) is formed, which along the longitudinal extent of the housing (2) by means of a continuous partition wall surrounding each individual hollow fiber membrane (3) (10) is divided into a dialysate chamber (12) and a substituate chamber (11) which is separated from the dialysate chamber (12) in a fluid-tight manner, for carrying out a hemodiafiltration process in which, in addition to the actual blood treatment, the bundle of hollow fiber membranes also filters the substituate and supplies the Substituted to the blood.

19. membrane module comprising a cylindrical housing (2) with a longitudinal extension, in which one in the direction of the longitudinal extension of the housing

(2) oriented bundle of hollow fiber membranes through which the lumen can flow

(3) is arranged with a semi-permeable wall, the ends of which are embedded in a first and in a second potting compound (4, 5) which is connected in a fluid-tight manner to the housing inner wall in such a manner that around the hollow fiber membranes one of the first and the second potting compound (4, 5) and the inner wall of the housing (2) is designed as an outer space which, along the longitudinal extent of the housing (2), through a dividing wall (10) which surrounds each hollow fiber membrane (3) and is essentially transverse to the hollow fiber membranes (3) into a dialysate space (12) and a substituate space (11), the dialysate space (12) having an inlet device (13) and an outlet device (14) for introducing or discharging a dialysate and the substituate room (11) at least one inlet device (15) for introduction have a substituate, characterized in that in the area of the substituate space (11) between the inlet device (15) for the substituate and the in the Subst ituatraum (11) located hollow fiber membranes (3) a sterile filter (24) is arranged, which divides the substituate space into an outer substituate subspace (25) and an inner substituate subspace (26) spatially separated from the outer substituate subspace (25) by the sterile filter (24), the outer substituate subspace (25) with the inlet device (15) stands for substituate in fluid connection and the hollow fiber membranes (3) are arranged in the inner substituate subspace (26).

20. Membrane module according to claim 19, characterized in that the sterile filter (24) is arranged around the bundle of hollow fiber membranes (3) and encloses the bundle of hollow fiber membranes (3).

21. Membrane module according to one or more of claims 19 or 20, characterized in that the sterile filter (24) is a microporous flat membrane.

22. Membrane module according to one or more of claims 19 to 21, characterized in that the sterile filter (24) is sealed against the passage of endotoxins.