CA1067830A - Dialysis apparatus with selective chemical activity - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

A dialysis apparatus with selective chemical activity, of the type having a semipermeable dialysis membrane as a partition between the liquid to be dialyzed and a dialysate.
According to the invention, the dialysis membrane permits the passage of substances wi?h molecular weights at least up to 2500, preferably up to 10,000 - 15,000, wherein at least one of the surfaces of the dialysis membrane facing towards the dialyzed liquid and, respectively, the dialysate is covered with at least one selectively chemically active substance of the type of enzyme, antibiotic or another active substance with similar chemical composition insolubilized on the surface by a known method. At least one selectivley acting adsorbent is provided in the circuit of the dialysate.

Description

~71330 The present invention relates to devices for dialysis, preferably such applied to hemodialysis, but can also be used for purification of liquids other than blood. According to the inven-tion, enzymes, antibiotics or substances with a similar chemical character are insolubilized on the dialysis membrane of the apparatus which thereby is rendered selectively chemically active which results in improved and faster dialysis. The apparatus according to the invention r furthermore, can be utilized for che-motherapy in such pathological conditions, which can be treated by selectively affecting the liquid phase of the ~l~od, and blood cells for example by enzymatic degradation. The apparatus according to the invention operates with recirculating dialysate, which is continuously purified by means of an adsorbent, preferably precon-ditioned zirconium phosphate and/or zirconium oxide, and is pro-vided with at leas~ one drop dosimeter for supplying to the dialy-sate the blood constituents desired, which constituent can pass through the pores of the dialysis membrane which preferably are of a size substantially greater than the pores of conventional dialysis membranes. A spectrometer with a filter adjusted to hemoglobin is connected into the circuit of t~e dialysate and alarms via an electronic circuit when blood or free hemoglobin appears in the dialysate. Those parts of the device which directly or indirectly come into contact with blood and the adsorbent are preferably intended to be disposable. A preferred embodiment of the invention consists of an artificial kidney with the possibility of chemotherapy, said artificial kidney having very small dimen-sions, city and being simple and cheap to manufacture and utilize and, therefore, also well suited for home dialysis. The artificial kidney is designed as a compact unit having a weight of 5-7 kg, - 1 - ~

~L~6783~ 2 nclusive of the dialysate, and need be connected only to a conventional source oF current supply.

In the following, dialysis d~vicss are described, both such which are previously known and the apparatus according to the invention, emphasis being laid on so-called artificial kidneys.
It should, however, be reminded that the apparatus according to ths invention, like several known dialysis apparatuses, also can be used for purification of liquids other than blood.

At first, the following should be mentioned about the known state of art.
.

It is known since a relatively long time ago to treat patients suffering from an acutely or chronically f'ailing kidney function with an arti~icial kidneyJ which during the healing period or while waiting for a suitab'le kidney transplantate performs the~
function of the natural kidney to eliminate urea and other un-desirable constituents in the blood. The patient's blood can flow from an artery through the artificial kidney and return to a vein by means of an extracorporeal shunt arranged for this purpose. The original design of ths artificial kidney, of which a plurality of improved variants still are predominantly in use at hemod'ialysis, is a dialysis apparatus with a semipermeable msmbrane, which separates a blood stream and a dialysate stream, in such a manner that undesirable as well as som~ desirable substances in the olood pass through the pores of ths dialy is ' membrane to the dialysate. This i5 a purely physical method without any kind of chemical activity. The original dsvices of 3 this type were very large and heavy units, which contain up to 1000 litres of dialysate and wers both expensive and labour-dsmandin~. Therefors, only a limited number of dialysis centers could be established in special clinics. Owing to succsssive improvsments of the original types of devices, implying e.g.
improved dialysis membrane, pre-fabricated sterils disposable membrane packs, compact~design, improvsd instrumentation etc.', dialysis apparatuses havs been devslopsd which to-day have much smaller dimensions and show better dialysis results and which, furthermore, involvs lower initial and operational costs. The apparatuses, notwithstanding, are relatively large and expsnsive and require for their operation specially trained personnel in : .
._ .............. . . ~ 7 .. ~ . , ~

~al67~33~:) hospitals in rooms e~uipped for this purpose.
In view of the fact that a further development of the purely physical dialysis device probably can result only in margi-nal improvements, development has recently turned in new directions.
By combining the dialysis with various kinds of chemical activity, one has succeeded in improving the dialysis result and at the same time diminishing the dimensions of the dialysis devices. Moreover, the medical application range of the dialysis apparatus was widened beyond the dialysis at kidney failure. Among known devices, the chemical activity is assigned mainly to the dialysate part or, in some cases, to an ultrafiltrate, which su~sequent to chemical treat-ment is returned to the patient's blood circulation.
~ y a continuous chemical puxification of the dialysate the amount of dialysate can be reduced to a few litres and thereby renders it possible to design dialysis devices with considerably smaller dimensions than previously. The purification of the dialy-sate takes place, in principle, as follows. Urea transferred from the blood to the dialysate is degraded selectively by the enzyme urease to ammonium carbonate whereafter ammonium ions and other ~0 undesirable constituents separated from the blood are caught by adsorbents. The adsorbents, usually are specific ones and have been pre-conditioned by known methods so as to catch the undesirable j constituents, while the constituents desirable for the dialysate, ~ ~ e.g. chloride ions, remain in the d;alysate. Known adsorbents are ; anionic and cationic exchange resins, zirconium phosphate, zirconium oxide and activated carbon.
The widened medical application range is related to such a form of enzyme therapy, the object of which is to selectively remove undesirable proteins from the blood for therapeutical purposes, for example to degrade asparagine by means of L-asparaginase, as this was found to have a therapeutical effect on certain forms of cancer.

Thereby, not only kidney failure is made accessible to treatment by a dialysis apparatus, but also, in principle, all pathological ~ _ 3 _ ~L~67830 conditions, at which a therapeutical effect can be ach-~eved by separating from the blood at least one undesirable cons-tituent by means of a dialysis mem~rane, whereafter this cons-tituent is selectively degraded on the dialysate side by an enzyme. Certain enzymes have a toxic effect and this is the - 3a -~671~3~

reason why enzymes are not used in contact with the blood in such apparatus.
As examples of known dialysis devices combined with che-mical activity the following U.S. patent specifications can be referred to. According to the patent specification USA 3,608,729, Haselden, it is known bo purify a non-circulating dialysate by means of adsorbents, which are packed into pockets formed by a profiled dialysis membrane. As adsorbent is used an ionic exchange resin, possibly in combination with activated carbon and possibly with an enzyme, for example urease to degrade urea. A vibrator is proposed to facilitate the transpor of the constituents to be separated from the dialysate to the adsorbent. The patent speci-fication USA 3,617,545, Dubois, shows an eIèctrodialyzer for the purification of dialysate and, alternatively an ultrafiltrate (blood plasma), which contains constituents having molecular weights up to about 70,000 in several steps, comprising deminerali-zation, degradation of urea by means of urease, cation exchanger for adsorption of ammonium ions, remineralization, adsorption of uric acid and creatinine with activated carbon and adsorption of sulphate and phosphate ions by means of an anion exchanger.
The patent specification USA 3,619,423, Galletti et al, shows a cascade dialysis apparatus for purification of blood, in which apparatus a dialysis section and an ultrafilter, utilize one and the same recirculating dialysate and each contains a dialysis membrane, the pores of which permit substances with molecular weights up to about 10,000 to pass. An undesirable constituent in the blood which can pass through the membrane of the dialysis section into the dialysate, and which for a therapeutical purpose is desired to be selectively separated, is degraded with the cor-responding enzyme, which is solved in the dialysate. The consti-tuents desirable for the blood are returned to the blood via the membrane of the ultrafilter which does not permit the passage of ~67~30 enzymes since these have molecular weights of about 100,000. The circulating dialysate is purified continuously by specific or non-specific adsorbents of a kind not stated in detail. The reduction of the asparagine content of the blood by means of L-asparaginase is mentioned as an example of chemotherapy at cancer. The patent specification USA 3,669,878, Marantz et al, finally shows a dialy-sate purification device for a conventional dialysis apparatus.
The purification device, which is designed as a column flown through by the dialysate, is connected in series to the circuit of the dialysate. The column is filled with an anorganic adsorbent, zirconium phosphate, on which urease is adsorbed. The urease degrades enzymatically urea to ammonium carbonate. The zirconium phosphate acts as ion exchanger and adsorbs the ammonium ions, whereby sodium ions, which were adsorbed on the zirconium phosphate are released according to a reaction formula shown. The sodium ions are not harmful since they normally exist in great amounts in the dialysate.
In spite of the additional improvements obtained by the introduction of chemical activity in combination with dialysis, dialysis apparatuses for hemo~ialysis still are relatively large, expensive and technically complicated and are neither suitablenor possible to use for home dialysis. A further disadvantage of known apparatuses is that the pore size of the dialysis membranes must be limited to the passage of substances having molecular weights of up to 2500 - 3000, in order not to lose in the dialy-sate too great amounts of constituents with a low molecular weight which are desirable for the blood. When, however, the aforedescribed method with ultrafilter is used, the pore size can be increased to examplified molecular weights of between 10,000 - 70,000. Alternatively, in a conventional dialysis apparatus with filters having larger pores, it is ~ossible to balance the increased loss of desirable constituents in the blood by adding an excess of these contituents to the dialysate. Both said alternatives result primarily in higher dialysis costs.

1~6~3~

When an ultrafilter is introduced, the apparatus increases in size and becomes more expensive and more complicated. To add the desirable constituents of which, for example, watersoluble proteins are expensive, to a relatively great amount of dialysate, is uneconomic. There is evidence of the fact that impurities are found in the blood which have an incompletely known composition and molecular weights of between 10,000-15,000. According to an ever widely spread opinion in the large kidney clinics, a better dialysis result would probably be achieved, if also these impurities could be removed. An increase in pore size, besides, would facili-tate the passage through the dialysis membrane and thereby shorten ;
the time necessary for dialysis. A further disadvantage of known devices for hemodialysis is, the utilization of enzymes in order to selectively separate undesirable constituents from the blood for therapeutical purposes, is restricted to the dialysate side. This restriction has its reason in the fact that several enzymes have an antigenic or other toxic effect on the blood, for which reason a direct contact between blood and enzyme has been avoided, because no safe method for insolubilizing the enzymes with maintained 20 chemical activity was known. Several of the constituents to be selectively separated have relatively high molecular weights and, therefore, pass through the pores of the dialysis membrane, so that the separation on the dialysate side takes more time than it would re~uire at a direct contact between blood and enzyme. It is, therefore, desirable at hemodialysis to be use enzyme~ in contact with the blood without risk.
A remarkable development work has resulted in a better, simpler and cheaper hemodialysis, but the known dialysis appara-tuses with associated peripheral equipment still require much space and are both expensive and complicated. Simultaneously there is a demand partly to improve the dialysis result and partly to widen the application range in chemotherapy. It is a matter of great interest, particularly with respect to dialysis at kidney failure, 6783t~

to develop a simple, cheap, easy-to-service dialysis apparatus with good dialysis properties, which apparatus would render it possible to increase the number of dialysis treatments in hospitals at maintained costs and also in suitable cases to perform the dialysis at home.
It is the object of the present invention to overcome the aforedescribed and other disadvantages involved with known dialysis apparatuses, specially so-called artificial kidneys.
Another object of the present invention is to produce a dialysis apparatus in the form of a compact, complete, easily operated and cheap unit, which in suitable cases also can be used for home dialysis.
Still another object of the present invention is to bring about an improvement in the dialysis result.
A further object of the present invention is to be able to perform a hemodialysis in a shorter time than is possible with known apparatus.
Another object o~ the present invention is to separate from the blood also only incompletely known impurities with a high molecular weight, up to 10,000 - 15,000, Still another object of the present invention is to com-bine dialysis through a semipermeable membrane with chemical activity on the dialysate side of the membrane in order to purify the dialysate.
A further object of the present invention is to combine dialysis through a semipermeable membrane with chemical activity on the blood side of the membrane in order selectively and without toxic side-effects to a~fect both the liquid phase of the blood and the blood cells for achieving a therapeutical effect at different pathalogical conditions.

A further object of the present invention is to design the dialysis apparatus so that it involves the smallest possible risk of spreading inoculation hepatitis.
~ - 7 ~06783V

Another object of thR presenk invention is to prevent the coagulation of ~lood in the dialysis apparatus.
In one aspect of this invention, there is provided a dialysis apparatus with selective chemical activity, of-the type of an artificial~kidney operating with a circulating dialysate, said apparatus being provided with a dialysis membrane; at least one surface of said dialysis membrane possessing a selective chemical activity caused by at least one selectively chemically active substance, said substance being insolubilized on said at least one surface of the dialysis membrane, by means of covalent bonds.
In another aspect of this invention there is provided in a dialysis apparatus with selective chemical activity, such as in an artificial kidney, comprising a semipermeable dialysis membrane as a partition between the liquid to be dialyzed and a circulating dialysate, the improvement comprising said dialysis membrane per mitting the passage of substances with molecular weights of up to about 10,000, at lea~t the surface of said dialysis membrane facing toward the li~uid to be dialyzed having at least one select-ively chemically active therapeutic substance insolubilized thereon with covalent bonds, circulating means for circulating said cart ridge containing the adsorbent and positioned in a return hose of the dialysate circuit.
In still another aspect of this invention there is pro-vided in a dialysis apparatus with selective chemical activity t such as an artificial kidney, comprising a semipermeable dialysis membrane as a partition between the liquid to be dialyzed and dialysate, the improvement comprising said dialysis membrane per-mitting the passage of substances with molecular weights up to 10,000 - 15,000 at least the surface of the dialysis membrane facing toward the liquid to be dialyzed carrying at least one selectively chemically active therapeutic substance sel~cted from ~ - 7a -~67~3~

the group consisting of L-asparaginase, urease and an antibiotic that is insolubilized on the surface with covalent bonds, and that at least one selectively acting adsorbent is provided in the cir-cuit of the dialysate, metering means for metering a therapeutic additive fluid into the dialysate, said dialysis membrane consis-ting of a material, the surface of which is so prepared by hydro-lysis that it shows an increased number of hydroxyl groups for rendering possible the insolubilization of said selective chemi-cally active substance in a great amount. In a further aspect of this invention there is provided a dialysis apparatus comprising a dialysate container, cover means for said dialysate container, a dialysis container mounted on said cover means, said dialysis container having an inlet means and an outlet means, spectrometer means mounted on said cover means, a first fluid circuit means connecting said dialysis container and said dialysate container through said spectrometer means, said first fluid circuit including purification means in said dialysate container, a dialysis membrane . for permitting passage of substances with molecular weights of up ~: to between 10,000 - 15,000 removably mounted in said dialysis container and having a selectively chemically active therapeutic substance insolubilized on at least the surface facing the liquid to be dialyzed, pump means mounted on said cover means for pumping dialysate from said dialysate container to said dialysis container, a second fluid circuit means connecting said pump means with said dialysate container and said dialysis container, and at least one dosimeter means on said dialysate container for metering fluid into said dialysate container~
In a still further aspect of this invention there is pro-vided a dialysis apparatus comprising a dialysate container, cover means for said dialysate container, a dialysis container mounted on said cover means, said dialysis container having an inlet means and an outlet means, spectrometer means mounted on said cover means, a ~ - 7b -first fluid circuit means connectiny said dialysis container and said dialysate container through said spectrometer means, ~aid first fluid circuit including purification means in said dialysate container, a dialysis membrane for permitting passage of substances' with molecular weights up to 10,000 - 15,000 removably mounted in said dialysis container and having a selectively chemically active therapeutic substance selected from the group consisting of L-asparaginase, urease and an antibiotic insolubilized on at least the surface facing the liquid to be dialyzed for purifying liquid passing through said apparatus, pump means mounted on said cover means for pumping dialysate from said dia~ysate container to said dialysis container, a second fluid circuit means connecting said pump means with said dialysate container and said dialysate con-tainer and at least one dosimeter means on said dialysate container for metering fluid into said dialysate container.
The advantages involved with the aforesaid objects and aspects have been achieved with a dialysis apparatus according to the present invention, partly by applying with a good combinational effect some methods, which were previously known individually or in other combinations in connection with dialysis and, respectively, biochemistry, ana partly by providing the apparatus according to the invention with a ne~ and improved design. The factors contri-buting to the said good combinational effect are as follows:

:., 1. The apparatus is provided with a dialysis membrane, the pore size of which permits the~passage of constituents with mole-cular weights up to between 10, oao and 15,000. Such membranes can be manufactured by known methods (Craig, L.C. and Konings-~ 7c ~

~783~
berg, W.J., Phys. Chem., 65, 166, 1~61) of, for example, cellu-lose base, partially saponified cellulose acetate, copolymers of ; vinyl acetate and vinyl alcoho, homo- or copolymers of polymethyl-, hydroxypropyl , glycerol- or glycidil metachrylate and of copoly-mers of acrylonitrile. Particularly suitable are those membrane materials, which are characterized by a certain hydropily and the surface o~ which by hydrolysIs or other known methods receives an increased amount of hydroxyl groups, which facilitates the method described below in item 2 for rendering the surface selectively chemically active. The increase of pore size at the dialysis of blood from molecular wights of 2500 -3000 as they are possible with known apparatuses, to 10000 - 15000 provides two advantages, viz.
the possibility of separating from the aforementioned impurities, which are incompletely known as to their composition and which have molecular weights from about 3,000 up to 10,000 - 15,000 and a shorter time re~uired for the dialysis due to said increased pore size. The simultaneously arising disadvantage that also several constituents being important and desirable for the blood and having molecular weights below 10,000 - 15,000 can pass through the pores, is eliminated by the factors described below in items 3 and ~.
As examples of constituents, which have molecular weights of up to about 3,000 and which are separated by known technique, can be mentioned ionizable or non-ionizable acids solved in water, salts, urea, creatinine and sugar types. For those cases, in which it is considered sufficient to separate these substances and to refrain from the separation of the aforesaid impurities with molecular weights from about 3,000 up to 10,000 - 15,000, the apparatus according to the invention can be provided with a dialy-sis membrane having the pore size applied in the known techni~uefor a maximum molecular weight of 3,000 and yet obtain substantial advantages over known dialysis apparatuses.

~)6~7~3~

2. The surface of the dialysis membrane has been made select-ively chemically active by insolubilizing at least one chemically active substance on that side where the chemical activity is of interest. The active substances are enzymes and/or antibiotics, which by covalent bonds are very well insolubilized at the surface of the dialysis membrane. The method results both in a substan-, tially longer active life of the substance in question and permitsthe use of active substances with antigen or other toxic effect, when such use is motivated for therapeutical reasons, in direct contact with blood, because nothing or only negligible amounts of the substa~ce pass out in free state into the blood. These pro-perties just mentioned have been confirmed by clinical tests carried out for more than 2 years, at which tests an extracorporeal device constructed by the inventor and intended for enzyme therapy was used which is described in Arzneimittel-Forschung (Drug -Research) 21, 1671-1675 (1971). At said tests it was found, that the enzyme L-asparaginase, which was insolubilized on a matrix in contact with blood in order to lower the asparagine content in the blood, has no appreciable antigen effect or other side effect on, for example, trombocytes or by developing allergic conditions.
Insolubilization of the selectively chemically active ; substance on the dialysis membrane surface facing toward the dia-lysate is of interest when impurities originating from the blood are to be removed from the dialysate in order to keep the compo-sition of the dialysate constant. ~ne can~, for example, by the enzyme urease, degrade urea to ammonium carbonate, which in its turn is adsorbed as explained below in item 3. According to the aforesaid, this reaction can also be placed on the blood side of the dialysis membrane, but since urea without difficulties passes through the pores of the dialysis membrane, there is no reason of unnecessarily placing the enzyme reaction on the blood side. When, however, it is desired to selectively separate from _ g _ /

1~6~33V
the blood a substance, for example a protein, with a molecular weight so high that it cannot at all ox only with difficulty pass through the pores of the dialysis membrane, then the enzyme must be insolubilized on the blood side. The intimate contact between the blood and the chemically active surface is favourable for the reaction. The degradation products have a low molecular weight and pass easily through the dialysis membrane to the dialysate where they are adsorbed as described below in item 3. The dialysis, therefore, proceeds rapidly.
A group of substances which are considered ~esponsible for some toxic symptoms at kidney failure, a.o. disturbances in the nervous system, are indole substances, indole, indican and other tryptophane derivatives. The selective chemical activity being placed on the blood side of the dialysis membrane, such and other constituents can be removed from the blood by enzymatic degradation.
Mycosis infections are a serious diesease condition, which heretofore were difficult to access for effective treatment. Anti-biotics are known which are highly effective against these fungus types. Unfortunately, they cannot be used in free form because they also are highly toxic. With a known method, however, an anti-biotic can be insolubilized on a dialysis membrane of the afore-said kind, at which the antibiotic with maintained chemical activity is insolubilized on the dialysis membrane by convalent bonds. The bonding to the dialysis membrane is very strong and, therefore, no antibiotic occurs in free form. By insolubilization of a suitable antibiotic on the blood side of the dialysis membrance, according to the invention an effective and riskless form of therapy at mycosis infections is obtained.
Enzymes, antibiotics and substances having a similar chemical nature can be insolubilized on a carrier consisting of anyone of the materials preferred in item 1 for the dialysis membrane by means of a well-known insolubilization method, for ~L~6783~

example the silanizing method or the cyanobromine met~od. The principle is described in detail a.o. in r~eetall, H.H. and ~eliky, N., Nature 204, ~96, 1964, Porath, J., Axen, R. and Ernback, S., Nature 215, 1491, 1967 and Mosbach, X,. Acta Chem. Scand., 24, 2084, 1970.

3. The dialysate is,purified continuously from the impurities passing through the dialysis membrane by means of adsorbents, which are known in other connections and have a physical and chemical adsorbing effect, and which where so is possible, have been made selective for the impurities in question by known methods. As ~; examples of adsorbents of the kind con~erned can be mentioned activated carbon and anorganic ion exchangers, zirconium phosphate and/or zirconium oxide specially preconditioned for this purpose.
In order to improve the effectiveness, small cellulose balls are preferably used as carriers for the adsorbents. The adsorbents are arranged in the circulation system of the dialysate in the manner described below. In order to maintain the dialysate and the adsor-bent moving relative to one another and thereby to facilitate the transport of those constituents in the dialysate which are to be adsorbed, the dialysis part of the apparatus is preferably provided in known manner with a vibrator, which may be small, simple and of optional type, but is preferably operated electrically. A suitable oscillation frequency is about 5~10 cyclos per second. The com-position of the dialysate can by means of the adsorbents practi-cally be kept constant during a dialysis treatment. The adsorbents and the apparatus details, in which they are disposed, are intended to be discarded and replaced by new ones after each treatment. It is, therefore, of advantage that only a relatively small amount of an expensive substance, such as a zirconium preparation, is required for a treatment. It is, moreover, possible to regenerate the zir-conium preparation according to known methods when such regeneration is economically profitable. The greatest advantage of being able 78~

to maintain the composition of the dialysate constant is, that it is possible, without deterioration of the dialysis result, to reduce the amount of necessary dialysate from 250 - 1,000 litres required at known techni~ue to a few litres, viz. accordiny to calculations and practical tests with an apparatus for hemodialysis to 3 - 5 litres. This has become possible partly thereby that the apparatus according to the invention could be given the desired small dimensions and the desired simple design, and partly thereby that the constituents which, as mentioned in item 1, are important for the blood and have a low molecular weight, and which are lost through the dialysis membrane, can be added to the dialysate at reasonable costs, so that said loss is balanced. It is, further, possible to add to the dialysate substances with molecular weights of about 8 - 9,000, for example a hormone, e.g. thyreoglobulin or growth hormone at children.

4. The apparatus is provided with means in the form of at least one small and simple drop dosimeter disposed on the dialy-sate supply container for continuously adding to the dialysate the substances being important for the blood as mentioned in items 1 and 3.
The combination effect reported above in items 1 - 4 has rendered it possible to design the apparatus according to the invention after lines which are entirely novel in several respects and provide essential advantages. The basic layout of the appa-ratus and the resulting advantages are briefly described in the following:
The desire of obtaining a dialyzer in the form of a small, compact and easy-to-service unit has been satisfied thereby that the container for the dialysate simultaneously serves as a stand for other components, which to the greatest possible extent are simplified and miniaturized and which are limited in number to what is absolutely necessary from an operation and safety point of view.

~10167~330 The unit thus designed is a lightweight, transportable apparatus which, inclusive of the dialysate, has a weight of only about 5-7 kg and for its operation must be connected only to a normal mains socket ox, alternatively, an electric battery mounted on the appa-ratus.
The principle which re~uires that, if possible, all medical equipment, which involves the risk of spreading inoculation hepa-tites to patients and medical staff members, should be disposable, is applied consistently. Only the dialysate container with the control and operation components attached thereon is intended for repeated use. The remaining components, which directly or indi-~rectly come into contact with the blood, as well as those carrying the absorbents are discarded after each treatment. A complete set of these latter components plus the necessary additives for the dialysate are, due to the small amounts and dimensions and the simple design, substantially cheaper than corresponding components at known dialyzers. The structural material in the apparatus according to the invention, if not specified otherwise, can be selected among the materials, which have been tested already in connection with dialyzers, heart--lung machines and similar appara-tuses. The disposable details preferably are made of some plastic material.
The feature that the dialysis membrane is given the form of a flat hose, which together with an intermediate distance and support member in the form of a flexible strip with open structure is helically wound and located in a cylindric container, provides several advantages. The blood and, respectively, dialysate can easily be led to and from the container by means of two connections per circuit which are located on the shell surface of the container 3Q and its cover and, respectively, bottom. The circuits preferably are connected in counter-flow for rendering maximum dialysis effect. It will become apparent from a following embodiment, that '783~

the components disposed in and on the cylindric container can be mounted in a simple manner with satisfactory sealing and without risk of leakage between the two circuits for the blooa and, res-pectively, dialysate. As a practical example of the small dimen-sions of the apparatus can be mentioned that, if the dialysis membrane is given a total active surface of 0,99 m2, the length is 2,08 m and the distance between two adjacent membrane layers is 0,35 mm, then the total volume is 0,35 litre, about half of it being blood. The small blood amount in the apparatus, about 175 -200 ml, is of advantage, because thereby no blood from a bloodbank must be used for priming the system before its use nor must a blood substitute, for example Rheo-macrodex solution, be supplied to the patient. Blood remaining in the apparatus after the dialy-sis can easily be returned to the patient by filling an adjusted amount of a liquid neutral to the blood through the blood supply hose. The blood loss arising at a dialysis treatment can hereby be held negligibly small. The blood and dialysate run in a laminar flow on both sides of the dialysis membrane, and the small distance, about 0,35 mm, between contiguous membranes implies a good contact between the liquids and the membrane, which facilitates the dia-lysis. A ~actor contributing thereto is also the vibrator men-tioned in item 3. With the dimensions indicated a~ove, the flow resistance of the blood will not exceed the difference in pressure which normally exists between an artery and a vein more than that the necessary amount of blood, about 200 ml/min, will flow through the apparatus. The need of a blood pump is thereby eleminated in most cases.
For circulating the small amount of dialysate here con-cerned, a small simple pump of optional type with associated electromotor is sufficient.
The adsorbents are provided both by being pressed into the open structure of the aforesaid distance and supporting member ~(3 6783~
and in a separate purifying cartridge in the return line of the dialysate. Both these components with adsorbents are discardes after completed dialysis. The adsorbents being provided in two places, the purifyin~ effect will be better and the safety greater.
The purifying cartridge in the return line can, if this exception-ally should be necessary, be e~changed whilst the dialysis is going on.
In order during the proceeding dialysis to supply to the dialysate adjusted amounts of the constituents being important for the blood and having a molecular weight passing through the dia-lysis membrane, the supply container for the dialysis is provided with at least one, preferably several threaded pipe sockets, their mouths being covered with exchangeable elastic membranes. A drop dosimeter known per se, which is formed as a bottle having an externally threaded neck and a canule-shaped outlet, is connected to the pipe socket. The canule is pierced through the elastic membrane, and the bottle is screwn into the pipe socket. The liquid additives can then be metered in a manner known per se.
The apparatus can also be provided with a safety device, which at the dialysis of blood emits an acoustic and/or optical signal when blood passes out into the dialysate or when the patient is subjected to hemolysis, in which both cases the dialysis must be interrupted. Said safety device comprises a small and simple spectrometer, which is disposed about or in the return line for the dialysate and the filter of which is so chosen as to indicate absorption typical of hemoglobin, and connected to said spectro-meter an electronic alarm circuit of a kind known per se which includes a buzzer and/or a warning lamp.
For preventing cooling of the blood, the apparatus accord-ing to the invention is provided with a thermostat-controlled heating device, which preferably is electric and disposed in the supply container for the dialysate. The heating device can be ~6783(~
completed with external insulation o~ the supply container by means of, for example, expanded polystyrene, glass wool or another suitable insulation material.
At the dialysis of blood, furthermore, all surfaces coming into contact with the blood consist of known non-trombogenous materials or are made non-trombogenous in known mann~r by heparin bonded at the surfaces.
As an example of th~ efficiency of the apparatus, the result of four tests with an urea solution are reported below, at which the urea concentration was set to the high values, which are observed in the blood at kidney insufficiency, 350 mg/100 ml.
At the tests an apparatus according to the invention was used, the dimensions of which were reduced to laboratory test scale and which had the data as follows:
The dialysis membrane was of cellulose base with an active surface of 0,3 m on the flat helically wound hose of 3,50 m lengthO The distance between contiguous membranes was 0,5 m.
Urease was insolubilized on the membrane surface facing toward the dialysate (= outer system) with an urease solution containing 100 IE/ml in a 10 M buffert solution, pH 7,3, according to a known method of Weetall and Weliky. The inner system contained 500 ml urea solution, 350 mg/100 ml 10 2 M buffert, pH 7,4, which circulated with 150 ml/min. The other system contained 1000 ml - 10 2 M buffert, pH 7,4 which circulated in a counter-flow with 380 ml/min. The apparatusl in order to obtain "pure" test values, did not contain adsorbents. The tests were carried out at room temperature. [NH4 ] was measured with a cation-electrode, Beckmann 39137 and with an ammonium probe E.J.L. 8002. The [NH4 ]-content was measured in the inner and outer solution during a dialysis time of 4 h. The urea amount corresponding to the [NH4 ]-concen-tration was calculated in both solutions and summed up whereafter the mean values for the four tests were calculated. The urea ~067~33~

concentration had ater 4 h decreased from 350 to 180 mg/100 ml.
The individual tests show a spread about the mean value of + 18 mg/
100 ml.
If at the aforesaid test series an adsorbent, precondi-tioned zirconium phosphate, would have been found in the outer system, which would have been the case at dialysis treatment of blood in vivo, the adsorbent would have taken up the ammonium s~tpplied at the dialysis. The dialysis thereby would have pro-ceeded still faster at the same time as ammonium was transported .~
from the inner to the outer system.

A preferred embodiment of the invention is described in greater detail in the following with reference to the accompanying drawings, in which:

Fig. 1 shows a basic layout of the invention, Fig. 2 is a perspective view of a dialysis apparatus according to the invention, Fig. 3 is a perspective view of a dialysis cylinder partially cut open, Fig. 4 is a perspective view of the dialysis cylinder according to Fig. 3, with connections for blood supply, one connec- `
tion being shown pulled apart, Fig. 5 is a perspective view of a section of a dialysis hose with associated distance member, Fig. 6 is a perspective view of a spread portion of the distance member according ~o Fig. 5, its carrying part being partially exposed, Fig. 7 is a perspective view of an alternative embodiment of a distance member, Fig. 8 is a horizontal view of a cross-section through mounted distance members according to Fig. 7, Figs. 9 and 10 are sectional and, respec~ively, perspective views of a spectrometer, ~7133(~

Fig. 11 is a perspective view of a purifying cartridge with adsorbents/ and Fig. 12 is a longitudinal section through a drop dosimeter. In all Figures, one and the same detail is designated by the same re~erence character.
The basic layout of the apparatus is apparent from Fig.
1. A dialysis membrane in the form of a flat hose, together with an intermediate distance member 2, is helically wound and disposed in a cylindric dialysis container 7 shown if Fig. 2. The interior of the hose-shaped dialysis membrane forms an active part of an inner circuit for the liquid to be dialysed. The space formed by the distance member 2 between the turns of the membrane 1 consti-tutes an active part of an outer circuit for the dialysate 8.
The two circuits are connected in counter-flow relationship. The inner circuit is provided with a supply hose 3 and an outlet hose 4, which at the dialysis of blood are connected to an artery and, respectively, a vein. A dialysate container 9 is comprised in the outer circuit for the dialysate 8 and provided with a pump 10/
which pumps the dialysate 8 through a supply hose 5 to the dialysis part of the outer circuit, ~rom which the dialysate is returned through a return hose 6, which is connected to a purification cartridge 11 immersed into the dialysate container 9. The return hose 6 extends through a hole provided in the beam path for a spectrometer 12 comprised in an electronic circuit of known kind (not shown) which includes an optic and/or acoustic alarm device providing alarm if blood or hemoglobin would appear in the dialy-sate 8. A thermostat-controlled heating device 14 is provided in the dialysate container 14 to maintain the dialysate at body temperature. An exchangeable drop dosimeter 13 of known kind is arranged on the dialysate container 9 and renders possible conti-nuous supply of additives to the dialysate. On the surface inclu-ded in the inner circuit of the dialysis membrane 1, enzyme, ~6~B3~

antibiotic or another actiYe substance with a similar chemical composition, depending on the chemical activity desired in the individual case, is insolubilized, which substance in Fig. 1 is designated by E. As it had become apparent from the general part of the disclosure, these substances can in applicable cases be insolubilized alternatively on the dialysis membrane surface facing toward the dialysate 8. The material and pore size of the dialysis membrane are described in the introduc-tory part of the disclosure. The distance member 2, which is des-cribed in the following, has an open structure, into which theadsorbent designated by A is impressed. Also the purification cartridge 11 contains adsorbent of the aforesaid kind.
A small electric vibrator 48 is mounted on the outside of the dialysate container 7, Fig. 2, in order to intensify the liquid flow about the dialysis membrane 1 and, respectively, adsorbent A and thereby to accelerate the dialysis as well as to prevent the blood from coagulating where the flow velocity is low.
Fig. 2 shows how the apparatus components shown if Fig. 1 can be arranged in a suitable manner. The Figure shows lowermost the dialysate container 9, above the cover 15 of which the dialysis container 7 is mounted on supports 16. The pump 10 is mounted directly on thecDver 15, and further is mounted there an instrument box 17, which includes the spectrometer 12 with associated alarm device, for example a buzzer 18 and necessary control means. The drop metering means 13 is screwn into one of the pipe sockets 19 provided for this purpose at the upper portion of the dialysate container 9.
In view of the difficulty in procuring a flat dialysis hose of sufficient width, the dialysis container 7, Figs. 2-4, 3 contains two helical units connected in parallel which consist of the dialysis membrane 1 and the distance member 2 of the kind described above in relation to Fig. 1. For the inner circuit, i.e. the mouths of the hose-shaped dialyses membranes 1, separate 783~
connections to the supply and return hoses 3 and 4, respectively, are provided. The supply takes places via a central distribution means, substantially concealed in Fig. 2, the outer part o~ which consists of a supply socket 20 provided on the upper surface of the dialysis container 7 and having two distribu~ion hoses 21 and one ; branch pipe 19, to which the supply hose 3 is connected. Said concealed part of the distribution means is in principle identical with a corresponding collecting means provided on the shell surface of the dialysis container 7. Said collecting means consists of two connections 22, Figs. 2 and 4, fastened on the shell surface of the dialysis container 7 and by means of hoses 23, 24 connected to a branch pipe 25, which in its turn is connected to the return hose 4. Each connection comprises a base 26, Fig. 4, a gasket 27, a washer 28, a hose base 29 clamped in the washer 28 for the hose-shaped dialysis membrane 1 and the return hose 23 and, respectively, 24.
Fig. 3 shows in the sectional portion how the two sets with the dialysis membrane 1 and distance member 2 are disposed ; upon one another. The distance member 2, Fig. 6, consists of a base portion 30, which is provided with fine through holes and serves as a carrier for an open structure in the form of ridees 31 fastened thereon and forming an oblique angle ( about 45) with the longitudinal direction of the distance member 2. The oblique-angled ridges 31, upon the helical winding of the distance member together with the dialysis membrane 1, form in adjacent turns angles with each other. The points of intersection between ridges 31 located against each other form thereby a chequered pattern of supporting points for the dialysis membrane l, Fig. 5. This arrangement provides both the desired distance between contiguous turns of the dialysis membrane 1, and in a simple manner unifcrmly distributed supporting points over the entire surface of the dialysis membrane. As mentioned before, the open structure in the ridges 31 is filled with the adsorbent or adsorbents used, ~0~7~33~

designated in Fig. 1 h~ A.
The distance member canl alternatively, be designed as aplastic-bonded, this, fle~ible I-shaped beam 32 moulded of a fibrous material, Figs. 7 and 8. When the distance member 32 is wound to helical shape, a channel 33 is formed between two conti-guous turns, which channel encloses the dialysis membrane 1. The open fibrous structure of the distance member 32 is filled with the adsorbent A.
The spectrometer 12, Figs. 1, 9 and 10, is a miniature spectrometer of simple design. It consists of a parallelepipedic - frame 34, which is provided with a through hole 35 for a lamp 36, a filter 37 and a photoelectric cell 38. A second hole per-pendicular to the hole 35 for the return hose 6 is so arranged that the return hose 6 of transparent material will intersect the beam path between the lamp 36 and the photoelectric cell 38. The filter 37 is so chosen that its absorption is typical of hemo-globin. When the absorption exceeds a certain pre-set value deter-mined for safety reasons, the electronic circuit known per se and comprising the spectrometer 12 is actuated. The buzzer 18 is there-by energized and emits a warning signal.
The purification cartridge 11, Figs. 1 and 11, is formed as a cylindric container, which contains the adsorbent A in a suitable, for example grainy, state. The cartridge 11 is suspended vertically immersed into the dialysate 8 in the return hose 6, which is connected to a hose base provided on the upper end wall 40 of the cylindric container. On the opposed end wall 42 forming the purification cartridge 11 a short discharge pipe 41 is provided.
In order to prevent the adsorbent from being flushed out~ the end wall 42 is covered on the inside with glass wool, fine-meshed cloth 49 or the like, Fig. 1. Impurities in the dialysate 8 which were not adsorbed by the adsorbent in the distance member 2, are adsorbed in the purification cartridge 11, whereby the compositicn ~ C)6~30 of the dialysate 8 is maintained constant as the dialysis proceeds.
The adsorbent in the purification cartridge ll can be recovered and regenerated, if this is deemed profitable.
The drop dosimeter 13, Figs. l, 2 and 12, is located on the upper portion of the dialysate container 9 and comprises at least one, but preferably three to four pipe sockets l9 with e~ternal threads. A membrane 43 of rubber or another elastic material covers the mouth of the pipe socket l9 and is retained by a nut 44. A bottle 45 containing the additive to be metered is provided with an outwardly threaded neck and a canule-shaped discharge pipe 46. This discharge pipe 46 is pierced through the membrane 43 whereafter the bottle 45 is screwn into the nut 44.
By adjusting a valve (concealed in Fig. 12) by means of a valve nut 47, an adjusted amount of air is passed into the bottle 45, and thereby the additive is metered out through the discharge pipe 46.
Several designs of devices operating after this principle for sterile metering of a liquid are known.
According to an alternative embodiment (not shown) of the invention, the dialysis part of the apparatus is formed as a parallelepipedic dialysis container, which includes dialysis mem-branes and distance members of the aforesaid kind as a battery ; of flat elements, i.e. in a way being usual among known dialyzers.

Claims (52)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A dialysis apparatus with selective chemical activity, operating with a circulating dialysate, said apparatus being provided with a dialysis membrane; at least one surface of said dialysis membrane possessing a selective chemical activity caused by at least one selectively chemically active substance, said substance being insolubilized on said at least one surface of the dialysis membrane, by means of covalent bonds.

2. Apparatus as claimed in Claim 1, wherein said selectively active substance is a therapeutic substance selected from the group consisting of enzymes, antibiotics, antigens, antibodies and synthetic adsorbents.

3. Apparatus as claimed in claim 1 or 2, wherein the dialysis membrane is permitting the passage of substances with molecular weights of up to 10,000.

4. Apparatus as claimed in Claim 2, wherein the dialysis membrane is made of a material having said at least one surface hydrolyzed to provide hydroxyl groups for facilitating increased insolubilization of selectively chemically active substances.

5. In a dialysis apparatus with selective chemical activity, comprising a semi-permeable dialysis membrane as a partition between the liquid to be dialyzed and a circulating dialysate, the improvement comprising said dialysis membrane permitting the passage of substances with molecular weights of up to 10,000, at least the surface of said dialysis membrane facing toward the liquid to be dialyzed having at least one selectively chemically active therapeutic substance insolubilized thereon with covalent bonds, circulating means for circulating said dialysate, at least one selectively acting adsorbent in the dialysate circuit, and metering means for metering a therapeutic additive fluid into the dialysate.

6. The dialysis apparatus of Claim 5 wherein said dialysis membrane is wound helically together with a distance member, the dialysis membrane is formed as a flat hose, and the distance member has an open structure carrying an adsorbent.

7. The dialysis apparatus of Claim 6 wherein said distance member has a flat shape.

8. The dialysis apparatus of Claim 5 wherein said dialysis membrane comprises a material having at least one surface which is hydrolyzed to provide hydroxyl groups for facilitating increased insolubilization of selectively chemically active therapeutic substances.

9. The dialysis apparatus of Claim 6 wherein said distance member comprises a base having fine passages there-through and a plurality of ridges thereon, said ridges forming an oblique angle with the longitudinal direction of the distance member.

10. The dialysis apparatus of Claim 6 wherein said distance member is formed as a plastic-bonded, thin and flexible beam with an I-shaped cross-section moulded of a fibrous material.

11. The dialysis apparatus of Claim 5 wherein the adsorbent is selected from the group consisting of pre-conditioned zirconium phosphate, zirconium oxide and a mixture thereof.

12. The dialysis apparatus of Claim 5 wherein the adsorbent is selected from the group consisting of pre-conditioned zirconium phosphate and/or zirconium oxide in combination with activated carbon.

13. The dialysis apparatus of Claim 5 including a cartridge containing the adsorbent and positioned in a return hose of the dialysate circuit.

14. The dialysis apparatus of Claim 5 which includes means for vibrating said apparatus.

15. The dialysis apparatus of Claim 5 in the form of a compact transportable unit weighing less than 7 kilograms including dialysate.

16. In a dialysis apparatus with selective chemical ac-tivity, comprising a semipermeable dialysis membrane as a partition between the liquid to be dialyzed and a circulating dialysate, the improvement comprising said dialysis membrane permitting the passage of substances with molecular weights up to 10,000 at least the surface of the dialysis membrane facing toward the liquid to be dialyzed carrying at least one selectively chemically active therapeutic substance selected from the group consisting of L-asparaginase, urease and an antibiotic that is insolubilized on the surface with covalent bonds, and that at least one selectively acting adsorbent is provided in the circuit of the dialysate, metering means for metering a therapeutic additive fluid into the dialysate, said dialysis membrane consisting of a material, the surface of which is hydrolyzed to provide hydroxyl groups for facilitating increased insolubilization of selectively chemically active therapeutic substances.

17. A dialysis apparatus with selective chemical activity with a circulating dialysate comprising a dialysate container, cover means for said dialysate container, a dialysis container mounted on said cover means, said dialysis container having an inlet means and an outlet means, spectrometer means mounted on said cover means, a first fluid circuit means connecting said dialysis container and said dialysate container through said spectrometer means, said first fluid circuit including purification means in said dialysate container, a dialysis membrane for permitting passage of substances with molecular weights of up to 10,000 removably mounted in said dialysis container and having a selectively chemically active therapeutic substance insolubilized with covalent bonds on at least the surface facing the liquid to be dialyzed, pump means mounted on said cover means for pumping the dialysate from said dialysate container to said dialysis container, a second fluid circuit means connecting said pump means with said dialysate container and said dialysis container, and at least one metering means on said dialysate container for metering fluid into said dialysate container.

18. The dialysis apparatus of Claim 17 including heating means in said dialysate container.

19. The dialysis apparatus of Claim 17 including signal means in combination with said spectrometer means.

20. The dialysis apparatus of Claim 17 wherein said membrane is in the form of a helically wound flat hose and said membrane is wound with a distance means.

21. The dialysis apparatus of Claim 17 including vibrator means mounted on said dialysate container for intensifying the liquid flow about said membrane.

22. The dialysis apparatus of Claim 17 wherein said purification means is an adsorption means.

23. The dialysis apparatus of Claim 17 including distribution means for distributing the liquid about said membrane.

24. The dialysis apparatus of Claim 5 wherein said chemically active therapeutic substance is selected from the group consisting of enzymes, antibiotics, antigens, antibodies and synthetic adsorbents.

25. The dialysis apparatus of Claim 17 wherein said chemically active therapeutic substance is selected from the group consisting of enzymes, antibiotics, antigens, antibodies and synthetic adsorbents.

26. The dialysis apparatus comprising a dialysate container, cover means for said dialysate container, a dialysis container mounted on said cover means, said dialysis container having an inlet means and an outlet means, spectrometer means mounted on said cover means, a first fluid circuit means connecting said dialysis container and said dialysate container through said spectrometer means, said first fluid circuit including purification means in said dialysate container, a dialysis membrane for permitting passage of substances with molecular weights up to 10,000 removably mounted in said dialysis container and having a selectively chemically active therapeutic substance selected from the group consisting of L-asparaginase, urease and an antibiotic insolulubilized on at least the surface facing the liquid to be dialyzed for purifying liquid passing through said apparatus, pump means mounted on said cover means for pumping dialysate from said dialysate container to said dialysis container, a second fluid circuit means connecting said pump means with said dialysate container and said dialysis container, and at least one metering means on said dialysate container for metering fluid into said dialysate container.

27. An artificial kidney apparatus with selective chemical activity, operating with a circulating dialysate, said apparatus being provided with a dialysis membrane; at least one surface of said dialysis membrane possessing a selective chemical activity caused by at least one selectively chemically active substance, said substance being insolubilized on said at least one surface of the dialysis membrane, by means of covalent bonds.

28. Apparatus as claimed in Claim 27, wherein said selectively active substance is a therapeutic substance selected from the group consisting of enzymes, antibiotics, antigens, antibodies and synthetic adsorbents.

29. Apparatus as claimed in Claim 27 or 28, wherein the dialysis membrane is permitting the passage of substances with molecular weights of up to 10,000.

30. Apparatus as claimed in Claim 28, wherein the dialysis membrane is made of a material having said at least one surface hydrolyzed to provide hydroxyl groups for facilitating increased insolubilization of selectively chemically active substances.

31. In an artificial kidney apparatus with selective chemical activity, comprising a semi-permeable dialysis membrane as a partition between the liquid to be dialyzed and a cir-culating dialysate, the improvement comprising said dialysis membrane permitting the passage of substances with molecular weights of up to 10,000, at least the surface of said dialysis membrane facing toward the liquid to be dialyzed having at least one selectively chemically active therapeutic substance insolubilized thereon with covalent bonds, circulating means for circulating said dialysate, at least one selectively acting adsorbent in the dialysate circuit, and metering means for metering a therapeutic additive fluid into the dialysate.

32. The apparatus of Claim 31, wherein said dialysis membrane is wound helically together with a distance member, the dialysis membrane is formed as a flat hose, and the distance member has an open structure carrying an adsorbent.

33. The apparatus of Claim 32 wherein said distance member has a flat shape.

34. The apparatus of Claim 31 wherein said dialysis membrane comprises a material having at least one surface which is hydrolyzed to provide hydroxyl groups for facilitating increased insolubilization of selectively chemically active therapeutic substances.

35. The apparatus of Claim 32 wherein said distance member comprises a base having fine passages therethrough and a plurality of ridges thereon, said ridges forming an oblique angle with the longitudinal direction of the distance member.

36. The apparatus of Claim 32, wherein said distance member is formed as a plastic-bonded, thin and flexible beam with an I-shaped cross-section moulded of a fibrous material.

37. The apparatus of Claim 31 wherein the adsorbent is selected from the group consisting of pre-conditioned zirconium phosphate, zirconium oxide and a mixture thereof.

38. The apparatus of Claim 31 wherein the adsorbent is selected from the group consisting of pre-conditioned zirconium phosphate and/or zirconium oxide in combination with activated carbon.

39. The apparatus of Claim 31 including a cartridge containing the adsorbent and positioned in a return hose of the dialysate circuit.

40. The apparatus of Claim 31 which includes means for vibrating said apparatus.

41. The apparatus of Claim 31 in the form of a compact transportable unit weighing less than 7 kilograms including dialysate.

42. In an artificial kidney apparatus with selective chemical activity, comprising a semi-permeable dialysis membrane as a partition between the liquid to be dialyzed and a cir-culating dialysate, the improvement comprising said dialysis membrane permitting the passage of substances with molecular weights up to 10,000 at least the surface of the dialysis membrane facing toward the liquid to be dialyzed carrying at least one selectively chemically active therapeutic substance selected from the group consisting of L-asparaginase, urease and an antibiotic that is insolubilized on the surface with covalent bonds, and that at least one selectively acting adsorbent is provided in the circuit of the dialysate, metering means for metering a therapeutic additive fluid into the dialysate, said dialysis membrane consisting of a material, the surface of which is hydrolyzed to provide hydroxyl groups for facilitating increased insolubilization of selectively chemically active therapeutic substances.

43. An artificial kidney apparatus with selective chemical activity with a circulating dialysate comprising a dialysate container, cover means for said dialysate container, a dialysis-container mounted on said cover means, said dialysis container having an inlet means and an outlet means, spectrometer means mounted on said cover means, a first fluid means connecting said dialysis container and said dialysate container through said spectrometer means, said first fluid circuit including purification means in said dialysate container, a dialysis membrane for permitting passage of substances with molecular weights of up to 10,000 removably mounted in said .

dialysis container and having a selectively chemically active therapeutic substance insolubilized with covalent bonds on at least the surface facing the liquid to be dialyzed, pump means mounted on said cover means for pumping the dialysate from said dialysate container to said dialysis container, a second fluid circuit means connecting said pump means with said dialysate container and said dialysis container, and at least one metering means on said dialysate container for metering fluid into said dialysate container.

44. The apparatus of Claim 43, including heating means in said dialysate container.

45. The apparatus of Claim 43 including signal means in combination with said spectrometer means.

46. The apparatus of Claim 43 wherein said membrane is in the form of a helically wound flat hose and said membrane is wound with a distance means.

47. The apparatus of Claim 43 including vibrator means mounted on said dialysate container for intensifying the liquid flow about said membrane.

48. The apparatus of Claim 43 wherein said purification means is an adsorption means.

49. The apparatus of Claim 43 including distribution means for distributing the liquid about said membrane.

50. The apparatus of Claim 31 wherein said chemically active therapeutic substance is selected from the group consisting of enzymes, antibiotics, antigens, antibodies and synthetic adsorbents.

51. The apparatus of Claim 43 wherein said chemically active therapeutic substance is selected from the group consisting of enzymes, antibiotics, antigens, antibodies and synthetic adsorbents.

52. An artificial kidney apparatus comprising a dialysate container, cover means for said dialysate container, a dialysis container mounted on said cover means, said dialysis container having an inlet means and an outlet means, spectro-meter means mounted on said cover means, a first fluid circuit means connecting said dialysis container and said dialysate container through said spectrometer means, said first fluid circuit including purification means in said dialysate container, a dialysis membrane for permitting passage of substances with molecular weights up to 10,000 removably mounted in said dialysis container and having a selectively chemically active therapeutic substance selected from the group consisting of L-asparaginase, urease and an antibiotic insolubilized on at least the surface facing the liquid to be dialyzed for purifying liquid passing through said apparatus, pump means mounted on said cover means for pumping dialysate from said dialysate container to said dialysis container, a second fluid circuit means connecting said pump means with said dialysate container and said dialysis container, and at least one metering means on said dialysate container for metering fluid into said dialysate container.