BR112019011224B1 - SORBENT FOR A DIALYSIS DEVICE AND A DIALYSIS SYSTEM - Google Patents

Abstract

The invention relates to a sorbent for removing metabolic waste products from a dialysis fluid, the sorbent comprising a soluble source of sodium ions. The sorbent comprises an ion exchange system that converts urea to ammonium ions and that is configured to exchange ammonium ions for predominantly hydrogen ions and exchange Ca, Mg and K for predominantly sodium ions. The soluble source of sodium ions overcomes an initial drop in sodium concentration in the regenerated dialysate. When used in conjunction with an infusion system configured to use exchange of Ca, Mg and K for sodium during dialysate regeneration, a desired sodium ion concentration can be maintained.

Description

Field of Invention

[001] The present invention relates to a sorbent for dialysis as well as a sorbent system for regenerative dialysis which may be, but is not limited to, hemodialysis, peritoneal dialysis, liver dialysis, pulmonary dialysis, water purification and regeneration of biological fluids.

Fundamentals

[002] The listing or discussion of an apparently previously published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the prior art or is common general knowledge.

[003] Dialysis is the separation of particles in a fluid based on differences in their ability to pass through a membrane. In medicine, the term refers to the clinical purification of blood as a substitute for normal kidney function. In particular, dialysis is used to replace renal function for patients suffering from renal dysfunction or failure. The term can also refer to the purification of other biological fluids, including ascites, urine, and hemofiltrate. Purification is typically accomplished by contacting a biological fluid, such as blood, with a purification fluid, such as dialysate, through a semipermeable membrane. This process removes excess water, electrolytes, and waste toxins from the body, thereby ensuring that their concentrations are within physiological ranges. Most commonly, the purification fluid (typically dialysate) is used only once, and is simply discarded as “spent dialysis fluid” after it has contacted the biological fluid (typically blood) once. This is called “single-pass” dialysis. Sorbent-based regenerative dialysis, on the other hand, is a process that recycles a dialysis fluid after it has been used to purify a biological fluid. The process removes unwanted substances from the used dialysis fluid (regeneration) and replaces the desired substances (reconstitution) to produce a “fresh dialysis fluid,” which is then recontacted with the biological fluid to continue the dialysis process.

[004] The predominant form of dialysis used for patients with end-stage renal disease is single-pass hemodialysis in a facility. Hemodialysis involves the use of an extracorporeal system to remove toxins directly from the patient's blood, passing it through a filtration unit or dialyzer. In conventional single-pass hemodialysis procedures, patients are immobilized during dialysis, which can take many hours. The therapy requires the supply of large volumes of purified (ultrapure) water for the preparation of the dialysate, which is used once and immediately discarded.

[005] The other form of dialysis is peritoneal dialysis, which is commonly applied in Continuous Ambulatory Peritoneal Dialysis (CAPD) and Automated Peritoneal Dialysis (APD). In CAPD, fresh dialysate is infused into the patient's abdominal (peritoneal) cavity, where, through diffusion, metabolic waste products and electrolytes in the blood are exchanged with the dialysate across the peritoneal membrane. To allow sufficient diffusion of the electrolytes and metabolic waste products, the dialysate is typically retained in the peritoneal cavity for a few hours before removal and replacement of the used dialysate with fresh dialysate. The main disadvantages of CAPD include a low level of toxin clearance and the need to continually replace the used dialysate, which can be detrimental to the patient's daily activities. APD works similarly to CAPD, except that it allows dialysis to be performed at night or while the patient is at rest, and it allows the dialysate to be exchanged and replaced automatically.

[006] Similar to single-pass hemodialysis, CAPD and APD require comparatively large volumes of dialysate, which limits patient freedom and mobility. Devices are available that regenerate used dialysate from hemodialysis and/or peritoneal dialysis, rather than discarding it, to reduce the amount of fluid used. Dialysate can be regenerated by passing it through a sorbent that removes uremic toxins and excess electrolytes from the solution. For example, the original REDY (REcirculating DYalysis) Sorbent System includes a sorbent cartridge that has five layers through which dialysis solution containing waste uremic metabolites flows in order to be regenerated.

[007] Several sorbent dialysis systems, such as the REDY, Allient, or AWAK sorbent systems, employ a urease to convert urea, which (unlike other metabolic waste products such as creatinine and uric acid) is not readily adsorbed by activated carbon, into ammonium ions and bicarbonate ions. In the REDY system, a first layer consisting of activated carbon and hydrated zirconium oxide acts as a scrubbing layer, and prevents inactivation of the urease by trace metal contaminants. The second layer contains urease adsorbed on alumina particles. The third layer consists of buffered zirconium phosphate, which acts as a cation exchanger. As discussed in Drukker W. and van Doorn A. W. J. (1989) Dialysate Regeneration. In: Maher J. F. (eds) Replacement of Renal Function by Dialysis. Springer, Dordrecht, zirconium phosphate is loaded with hydrogen ions and sodium ions in a ratio of 1:8. Ammonium ions, together with calcium, magnesium and potassium ions, are exchanged for hydrogen and sodium ions. The released hydrogen ions are partially buffered by bicarbonate, but there is a fall in pH due to the release of hydrogen ions, a fall in carbonate concentration as a result of buffering but, after an initial fall, a gradual increase in the concentration of sodium ions in the dialysate due to the exchange of ammonium, calcium, magnesium and potassium ions for sodium ions. The fourth layer consists of hydrated zirconium oxide, which acts as an anion exchange resin and replaces the phosphate in the dialysate with acetate. Finally, a layer of activated carbon absorbs creatinine, uric acid and other metabolites.

[008] US Patent Publication 2010/0078387 describes a sorbent cartridge comprising a combination of acidic zirconium phosphate and alkaline hydrated zirconium oxide capable of restoring the balance of Na+ and HCO3- in the used dialysate to the levels found in fresh dialysate. In a preferred aspect, the system is based on reducing the pH and Na+ in the regenerated dialysate to a low level, and reducing HCO3- to zero. A NaHCO3 reinfusion system then brings the pH, Na+ and HCO3- to the desired levels.

[009] PCT Patent Publication No. WO 02/43859 describes a sorbent cartridge comprising layers of sodium zirconium carbonate and zirconium phosphate. The sodium zirconium carbonate layer adsorbs phosphate, while the zirconium phosphate adsorbs ammonia, Ca+2, Mg+2, K+ and toxic heavy metals present in used dialysate fluids. The exchange profile of the sorbent is influenced by the introduction of a novel compound, sodium zirconium carbonate, which acts to correct the pH and release bicarbonate.

[0010] US Patent No. 6,818,196 describes a method for preparing zirconium phosphate which involves treating sodium zirconium carbonate with caustic soda (sodium hydroxide) to form an alkaline hydrated zirconium oxide. This is subsequently heated and mixed with phosphoric acid to produce an acidic zirconium phosphate, which is further titrated with caustic soda to obtain the desired zirconium phosphate. The objective is to produce better quality zirconium phosphate for use in REDY sorbent cartridges.

[0011] US Patent No. 7,241,272 relates to the use of a resin bed in a cartridge for the removal of metabolic waste materials. It comprises at least four layers - a urease layer, a zirconium phosphate layer, a zirconium oxide layer and a carbon layer. The zirconium phosphate layer, which contains two counterions Na+ and H+, can absorb NH4+, Ca+2, Mg+2 and Na+. The release of the counterions is determined by the pH of the dialysate and the current state of charge (pH) of the resin. Na+ ions are also released in exchange for NH4+, Ca+2, Mg+2 and K+. Substantial fluctuations in pH, and in the levels of Na+ and bicarbonate are apparent in most of the figures.

[0012] U.S. Patent No. 8,580,112 describes a dialysis system that uses a sorbent cartridge comprising sodium zirconium carbonate, zirconium phosphate or other ammonia adsorbents, alumina, zirconium oxide, alumina-supported urease, and granular activated carbon to remove waste materials. The dialysis system has a feedback control system that relies on conductivity sensing to measure sodium levels and controls the concentration of sodium ions in the regenerated dialysate by adding water as a diluent when necessary.

[0013] PCT Publication No. WO 2009/157877 describes a sorbent for removing metabolic waste products from a dialysis fluid. The sorbent comprises a layer of immobilized uremic toxin treatment enzyme particles mixed with cation exchange particles. However, there are still substantial fluctuations in pH, Na+ and bicarbonate, and the effect of calcium, magnesium and potassium ions is not discussed.

[0014] PCT Publication No. WO 2005/123230 relates to a system containing two sorbent-type cartridges in which one is for breaking down urea and releasing Na+, while the other is for binding Na+. The sorbent that breaks down urea and releases sodium comprises one or more layers of activated carbon, urease, zirconium phosphate and/or zirconium oxide. The sorbent that binds Na+ may be a mixed-bed ion exchange resin comprising a cation exchange resin and an anion exchange resin that are mixed and contained in the same housing. Dialysate sodium control is optionally achieved by including or bypassing the second sorbent. The system relies on feedback control by conductivity sensing to accurately control sodium.

[0015] PCT Publication No. WO 2007/103411 describes a dialysis system having a replaceable cartridge that uses cation rejection membranes to reject Na, Ca, Mg, and K while the remaining waste components diffuse through the membrane to contact a purification layer that removes heavy metals, oxidants, and other uremic waste metabolites; a urea removal layer that eliminates urea from solution but rejects cations; and an ion exchange layer that removes phosphate and sulfate. This is supposed to make the purification system independent of the concentration of Ca, Mg, and K and presumably also prevents the release of Na in the exchange of NH4. Thus, the Na profile is expected to be independent of the urea concentration.

[0016] US Patent Publication No. 2013/0213890 describes a modular hemodialysis system with a sorbent cartridge containing at least one activated carbon material to absorb urea residue and creatinine and one zirconium oxide material to absorb phosphates from the dialysate. By allowing removal of urea, the cation exchange process releases sodium and hydrogen into the dialysate in a stoichiometric manner. In order to maintain a stable dialysate composition, the sodium ion concentration must be reduced by absorption of sodium ions or by dilution. In addition, the generation of carbon dioxide and hydrogen ions leads to instability of the dialysate pH which may require infusion of bicarbonate or other means to adjust the pH.

[0017] US Patent Publication No. 2013/0199998 relates to a hemodialysis system having a compliance controlled dialysis circuit with a pump to control fluid flow between the dialysis circuit and the extracorporeal circuit through a dialysis membrane. The Na+ concentration is monitored by measuring the conductivity of the dialysate and control is achieved by dilution.

[0018] There are problems associated with currently known methods. The Na+ concentration in the dialysate initially decreases, but then gradually increases over the duration of dialysis due to exchange processes during dialysate regeneration. The gradual change in concentration is then typically centered around a target concentration that is physiologically acceptable. For example, the dialysate regenerated in the REDY system is typically characterized by sodium concentrations that increase from about 100 mEq/L to about 160 mEq/L over the period of dialysis with an average of about 140 mEq/L. Therefore, while the Na+ concentration may reach the target concentration of 140 mEq/L when this approach is adopted, for the majority of the dialysis the Na+ concentration is either above or below the optimum.

[0019] Most commonly known sorbents, e.g. REDY sorbent, are selected to provide an approximately neutral total sodium equilibrium and neutral pH conditions. This is done by preconditioning the sorbent materials so that ammonium, as well as Ca, Mg and K are partially exchanged for protons, and partially exchanged for sodium (e.g. Drukker in REDY sorbent: H/Na charge ratio: 1:8). There is an initial phase of low dialysate sodium concentration, followed by a gradual increase in dialysate sodium concentration and ending with a final high dialysate sodium concentration. Throughout the entire therapy, the sodium concentration averages approximately at the desired target physiological sodium concentration. The sorbent and its exchange behavior are designed to produce pH conditions that are as neutral as possible, while avoiding extremely low and extremely high sodium concentrations. In order to produce this exchange behavior, the sorbent material is preconditioned and “preloaded” with sodium during synthesis. This is then often combined with a custom dialysate starting bath. Preloading can be applied to both cation and anion exchangers. In addition, some sorbents use chemical modifications of one of the ion exchange materials, such as, for example, using sodium zirconium carbonate as an anion exchanger instead of hydrated zirconium oxide. All these modifications have in common that they are not aimed at differentiating the exchange behaviors between ammonium and other dialysate cations. They are merely aimed at compensating for pH fluctuations while avoiding extreme sodium concentrations, without considering specific exchange selectivities.

[0020] Other known sorbents are selected to provide exchange properties that are more extreme, having a very low sodium load and providing approximately quantitative exchange of ammonium, Ca, Mg and K for protons, or having a very high sodium load and providing approximately quantitative exchange of these cations for sodium. These systems require feedback-controlled infusion systems to correct for the resulting extremely low or extremely high sodium concentrations in the regenerated dialysate. This can be done by feedback-controlled mixing of the two types of regenerated dialysates (low Na and high Na), or by feedback-controlled infusion of NaHCO3 (low Na regenerated dialysate) or dilution with water (high Na regenerated dialysate).

[0021] None of these sorbents are selected for differential exchange behavior for ammonium, and for Ca, Mg, and K, respectively. All of these cations are generally evaluated together, with the assumption of a similar H/Na exchange ratio for all of these cations, which is jointly determined by the Na preloading of the sorbent during synthesis. Indeed, the possibility of such differential exchange behavior and its exploitation to produce a desired sodium exchange profile has not been previously recognized.

[0022] Instead, ion exchange systems are pre-loaded with sodium in a manner that produces the intended exchange profile (either balanced at a physiological equilibrium concentration, or driven to extremes of complete exchange for proton, or sodium).

[0023] Other systems attempt to counteract this gradual change with feedback systems, measuring the sodium concentration and then administering a concentrate solution or water to increase or decrease the final sodium concentration. Such feedback systems are complicated, expensive, and prone to malfunction. They typically rely on conductivity measurements that are known to be problematic and have limited accuracy. In addition, they contribute to an increase in the physical size of the systems, and an increase in the number of disposable components.

[0024] Existing sorbent systems are characterized by a substantial degree of sodium release in exchange for ammonium, potassium, calcium and magnesium. This leads to a steady addition of sodium to the regenerated dialysate, which in turn results in a steady increase in the sodium concentration in the dialysate. Concomitantly with sodium, other component concentrations, such as bicarbonate and chloride concentrations, are also poorly controlled. This can result in undesirable and potentially harmful conditions for the patient, such as, for example, hyperchloremic acidosis. This is particularly relevant when chloride salts of Ca, Mg and K are used for the reconstitution of spent dialysate. Some previous sorbent systems, such as, for example, the REDY system, used Ca/Mg/K acetate saline solutions to nullify or ameliorate such undesirable effects. However, these acetate salt solutions are known to be problematic for thermal sterilization processes. Existing sorbent systems are therefore limited to using non-sterile solutions of these salts. Other weak acid salts, such as bicarbonate or lactate salts, have insufficient solubility to be of practical use in dialysate reconstitution.

[0025] The main problem with the above systems is that the selectivity of the exchange behavior between ammonium, and the other dialysate cations, Ca, Mg and K, has not been recognized and therefore the potential of exploiting such selectivity in sorbent-based dialysate regeneration has not been recognized. The prior art has struggled greatly to find a balance between low pH in the regenerated dialysate and high sodium release. This is done by pre-loading the sorbents with Na during synthesis, providing poorly acceptable pH profiles at the cost of significant sodium release. Patients are thus exposed to imperfect or potentially even harmful dialysate compositions for the majority of dialysis.

Summary

[0026] The present invention provides a sorbent for removing metabolic waste products from a dialysis fluid, the sorbent comprising a soluble source of sodium ions.

[0027] The soluble source of sodium ions may be present as a homogeneous mixture with at least one of: (a) uremic toxin treating enzyme particles comprising a uremic toxin treating enzyme immobilized on a solid support; (b) cation exchange particles configured to exchange ammonium ions for predominantly hydrogen ions and to exchange essential cations for predominantly sodium ions; and (c) anion exchange particles.

[0028] Accordingly, the present invention provides a sorbent for removing metabolic waste products from a dialysis fluid, the sorbent comprising a homogeneous mixture of: (a) uremic toxin treating enzyme particles comprising a uremic toxin treating enzyme immobilized on a solid support; (b) cation exchange particles configured to exchange ammonium ions for predominantly hydrogen ions and to exchange essential cations for predominantly sodium ions; and (c) anion exchange particles, and further comprising a soluble source of sodium ions.

[0029] Also provided is a process for preparing a sorbent comprising mixing a soluble source of sodium ions and at least one of: (a) uremic toxin treating enzyme particles comprising a uremic toxin treating enzyme immobilized on a solid support; b) cation exchange particles configured to exchange ammonium ions for predominantly hydrogen ions and to exchange essential cations for sodium ions; (c) anion exchange particles; and (d) organic compound absorbent particles, and containing the mixture.

[0030] In another aspect, a sorbent is provided that hydrolyzes urea to ammonium and bicarbonate, and binds predominantly to ammonium in exchange for protons. The protons exchanged for ammonium combine with bicarbonate, and the resulting carbonic acid is released as CO2. The sorbent thus removes urea by conversion to CO2. This produces repeatable chemical conditions in the regenerated dialysate that are independent of the urea concentration of the dialysate used.

[0031] In another aspect, a sorbent is provided that predominantly binds essential cations in exchange for sodium ions.

[0032] In a further aspect, a sorbent is provided that (a) hydrolyzes urea to ammonium and bicarbonate, and (b) binds predominantly to ammonium in exchange for protons and binds predominantly to essential cations in exchange for sodium ions.

[0033] In a further aspect, there is provided a sorbent cartridge comprising a sorbent as described herein housed in a cartridge.

[0034] In a further aspect, a dialysis system is provided for treating and recycling dialysate, the system comprising a sorbent cartridge as described herein that releases a predicted amount of sodium after ion exchange into the sorbent, a conduit for transporting spent dialysate from a source of spent dialysate to the sorbent cartridge, a conduit for transporting regenerated dialysate from the sorbent cartridge to the source of spent dialysate, and an infusion system for dosing an infusion solution comprising essential cations to the regenerated dialysate such that the solution combines with the predicted release of sodium ions from the sorbent cartridge to generate a predetermined dialysate sodium concentration.

[0035] The sorbent cartridge comprises a sorbent as described herein, which predominantly binds Ca, Mg and K in (stoichiometric) exchange for Na. The concentration of Ca, Mg and K in the used dialysate prior to sorbent regeneration is subject to only minor (absolute) fluctuations, and is largely controlled by the predetermined concentration generated by the addition of infusion solution during the previous regeneration and reconstitution process. The essential cations are generally introduced into an infusion solution. The concentration of the essential cations in the infusion solution is selected to correspond to the increase in Na released from the previous exchange of Ca, Mg and K from the used dialysate into the sorbent. The combination of regenerated dialysate with this corresponding infusion solution results in the generation of a desired (predetermined) sodium concentration. Depending on the choice of infusion composition and infusion rate, the system can be adapted to produce specific sodium profiles, or maintain a constant sodium concentration in the regenerated dialysate, without the need for a feedback control system.

[0036] Accordingly, in another aspect, there is provided a process for regenerating dialysate in a dialysis process, comprising repeating the steps of: (a) transporting spent dialysate from a source of spent dialysate to a sorbent that (a) hydrolyzes urea to ammonium and bicarbonate, and (b) binds predominantly to ammonium in exchange for protons and binds to essential cations predominantly in exchange for sodium ions, to produce regenerated dialysate; (b) introducing essential cations into the regenerated dialysate to reconstitute the dialysate; and (c) transporting reconstituted dialysate from the sorbent to the source of spent dialysate; characterized in that a predetermined concentration of sodium ions is generated after ion exchange in the sorbent.

[0037] In yet another aspect there is provided a kit comprising a sorbent as described herein and an infusion agent comprising salts of essential cations.

Designs

[0038] In order that the description may be readily understood and put into practice, reference will now be made to the embodiments as illustrated with reference to the accompanying figures and examples. The figures together with the description serve to further illustrate embodiments of the invention and explain various principles and advantages.

[0039] Figure 1 is a schematic diagram showing one possible interpretation of the ion exchange characteristics of a cation exchanger in accordance with the present invention.

[0040] Figure 2 is a schematic diagram illustrating a single-cycle dialysis system for testing sorbents.

[0041] Figure 3 is a schematic diagram illustrating a dual-cycle dialysis system for testing sorbents.

[0042] Figure 4 is (a) a graph showing the effect of patient urea level on sodium ion concentration and (b) is a graph showing the effect of dialysate urea and Ca/Mg/K on sodium ion concentration.

[0043] Figure 5 is a graph showing the sodium concentration of simulated patient biological fluid before and after purification in a dual-loop dialysis system (“Upstream Blood” and “Downstream Blood”), as well as the sodium concentration in regenerated and reconstituted dialysate (“Upstream Blood”) in accordance with the present invention.

[0044] Figure 6 is a diagram showing (a) the initial sodium drop and subsequent gradual increase in sodium concentration in conventional sorbent-based dialysis systems, (b) the effect of a sorbent modification to overcome the initial sodium drop without altering the gradual increase in sodium concentration, (c) the effect of system modification to address the initial sodium drop and subsequent gradual increase in sodium concentration to provide a stable sodium concentration throughout dialysis, and (d) the effect of system modification to the sodium drop and subsequent gradual increase in sodium concentration to provide a gradual reduction in sodium concentration during dialysis.

[0045] Figure 7 is a graph showing the effect of a patient's urea level on carbonate concentration.

[0046] Figure 8 is a graph showing the effect of a patient's urea level on chloride concentration.

[0047] Figure 9 is a graph showing the effect of a patient's urea level on pH.

[0048] Figure 10 is a graph showing the effect of dialysate urea and Ca/Mg/K on bicarbonate concentration.

[0049] Figure 11 is a graph showing the effect of dialysate urea and Ca/Mg/K on chloride concentration.

[0050] Figure 12 is a graph showing the effect of urea in dialysate and Ca/Mg/K on pH.

[0051] Figure 13 is a graph showing the effect of sodium bicarbonate in the sorbent on sodium ion concentration.

[0052] Figure 14 is a graph showing the effect of sodium bicarbonate in the sorbent on bicarbonate concentration.

[0053] Figure 15 is a graph showing the effect of sodium bicarbonate in the sorbent on chloride concentration.

[0054] Figure 16 is a diagram illustrating a dialysis process in accordance with the present invention.

Description

[0055] The present invention relates to a sorbent for removing metabolic waste products from a dialysis fluid. In particular, the invention relates to a sorbent for removing metabolic waste products from a dialysis fluid, the sorbent comprising a soluble source of sodium ions. As described herein, previous efforts to reduce the initial sodium drop in sorbent-based dialysis have been by modifying the sorbent during synthesis, or by infusing saline into the regenerated dialysate. The sorbent comprises an ion exchange system that converts urea to ammonium ions, and which is configured to exchange ammonium ions for predominantly hydrogen ions and to exchange essential cations for predominantly sodium ions. This may comprise uremic toxin treatment enzyme particles, which may be mixed with cation exchange particles as well as anion exchange particles.

[0056] A combination of cation exchange material and anion exchange material is selected for properties that favor the exchange of ammonium for proton, while the cation essential for sodium exchange is not affected. Accordingly, the sodium concentration in the regenerated dialysate is independent of the concentration of ammonium (i.e., urea) in the spent dialysate. On the contrary, the absolute amount of sodium in the regenerated dialysate is dependent on the sodium released in the cation exchange such as calcium, magnesium and potassium in the spent dialysate, which are known to be subject to comparatively small (absolute) concentration fluctuations. In fact, the concentration of Ca, Mg and K is approximately equal to the concentration predetermined by the process of regeneration and reconstitution of the dialysate in the dialysis system. The present invention also relates to the use of a sorbent as described above, in conjunction with an infusion (reconstitution) system configured to compensate for the (approximately constant) sodium release caused by the exchange of Ca, Mg and K during dialysate regeneration. The sorbent preferably comprises a sufficient amount of soluble sodium salt to avoid an initial “sodium drop” in the regenerated dialysate. Reconstitution, i.e. the infusion of Ca, Mg and K ions, is then done with a solution that is adjusted to a concentration that coincides with the concentration of released sodium, thus resulting in a desired target sodium concentration after reconstitution. In practice, the infusion solution is supplied at a total cation concentration that is approximately equal to the target sodium concentration.

[0057] Thus, the present invention allows a process for regenerating dialysate in which a predetermined amount of cations, such as Ca+2, Mg+2 and K+, are added to replenish the dialysate from which the metabolic waste products have been removed through contact with the sorbent as just described. The regenerated and reconstituted dialysate is reinfused into a patient in need of such treatment. After dialysis, the used dialysate will contain a known amount of the cations and will therefore release a corresponding amount of sodium ions from the sorbent; therefore, the sodium ion concentration is determined by the concentration of cations previously added to reconstitute the regenerated dialysate. The result is unprecedented precise control over the sodium concentration in the regenerated and reconstituted dialysate, without the need for additional (feedback-controlled) reinfusion systems.

[0058] The previously described ion exchange behavior would not have been considered desirable, as it requires a comparatively low “pre-loading” of ion exchange material with sodium ions. Without the herein described addition of a soluble sodium salt within the sorbent system, this would lead to a pronounced “sodium drop” in the initial phase of the sorbent dialysis treatment, with potentially harmful exposure of the patient to low sodium concentrations, low pH and consequently low bicarbonate concentrations. Furthermore, without the addition of a soluble sodium salt, this exchange system would likely result in a strongly negative total sodium balance, whereby excessive amounts of sodium would be removed from the patient in the initial phase of a treatment, without being replenished later in the treatment.

[0059] To overcome these complications, the sorbent is combined with a soluble source of sodium ions, such as a soluble sodium salt, which may be mixed with at least one component of the sorbent material. In contrast to the previously described sorbents, this combination provides the unique advantages of differential exchange behavior while allowing the maintenance of physiological conditions necessary for safe and effective dialysis treatment. The inclusion of a soluble sodium salt mixed with sorbent materials also provides unique advantages over alternative approaches, such as, for example, the use of a strongly basic anion exchange material mixed with an acidic cation exchange material, or the use of sodium-releasing anion exchange materials, such as sodium zirconium carbonate, as these materials are characterized by partial exchange of ammonium for sodium and thus increased sodium release, and dependence on the urea concentration in dialysate used, both contrasting with the sorbent properties described here of selective exchange behavior for ammonium and Ca/Mg and K.

[0060] Furthermore, it would previously have been considered undesirable to provide a sorbent as described herein, which is characterized by a regeneration process that continuously releases sodium while entirely avoiding an initial “sodium crash” phase. In a conventional sorbent system, this situation would be expected to lead to an excessive increase in the sodium concentration in the dialysate, resulting in excessive sodium release to the patient and thus a potentially harmful situation for the patient. This is effectively prevented and controlled by using a sorbent that exclusively releases sodium in exchange for Ca, Mg and K, by preventing a “sodium crash” by adding a soluble sodium source, and by configuring the reconstitution to use an infusion agent having a concentration that matches the target dialysate sodium concentration.

[0061] The term “sorbent,” as used herein, refers generically to a class of materials characterized by their ability to absorb the desired matter of interest.

[0062] The term “metabolic waste products” in the context of this specification means any constituents, typically toxic constituents, within a dialysate that are produced by metabolism and that are desirable to be removed in a dialysate detoxification process. Typical metabolic waste products include, but are not limited to, phosphates, urea, creatinine, and uric acid.

[0063] The term “essential cations” as used herein refers to cations other than sodium ions that are present in dialysis solutions and are essential for their safe and effective use. These ions are usually calcium and magnesium ions, but potassium ions may also be present. Calcium, magnesium, and potassium are removed by the sorbent and must be reintroduced into the regenerated dialysate to reconstitute the dialysate.

[0064] The term “cation equivalents” or “total cation equivalents” refers to the sum of all equivalents of positive charge other than protons in a solution. It is measured in mEq/L.

[0065] The term “sodium” or the symbol “Na” may be used in the specification to refer to sodium ions rather than the element itself, as would be well understood by one skilled in the art. Thus, the terms “sodium,” “Na,” “sodium ions,” and “Na+” are used interchangeably. Likewise, the terms “calcium,” “magnesium,” and “potassium” or the symbols “Ca,” “Mg,” and “K” may be used in the specification to refer to calcium ions, magnesium ions, and potassium ions, respectively.

[0066] The term a “source of spent dialysate” as used herein is a reference to a source of dialysate, however it is produced. The source may be any source of spent fluid where regeneration of biological fluids occurs by exchange across a membrane. If, for example, the dialysis process is hemodialysis, the source of spent dialysate would be a dialyser in a hemodialysis apparatus. In such apparatus, streams of a patient's blood and dialysate are in countercurrent flow, and exchange occurs across a membrane that separates the streams. Alternatively, it may be a patient, as in peritoneal dialysis, where dialysate is introduced into the patient's peritoneal cavity for exchange to occur.

[0067] The term “cation exchange particles,” as used herein, refers to particles capable of capturing or immobilizing cationic or positively charged species when in contact with such species, typically by passing a solution of the positively charged species over the surface of the particles.

[0068] The term “anion exchange particles,” as used herein, refers to particles capable of capturing or immobilizing anionic or negatively charged species when in contact with such species, typically by passing a solution of the negatively charged species over the surface of the particles.

[0069] The term “uremic toxin-treating enzyme,” as used herein, refers to an enzyme capable of reacting with a uremic toxin as a substrate. For example, the uremic toxin-treating enzyme may be an enzyme capable of reacting with urea as a substrate, uric acid as a substrate, or creatinine as a substrate. Uremic enzymes can be determined to have this function in vitro, for example, by allowing the enzyme to react with a uremic toxin in solution and measuring a decrease in the concentration of the uremic toxin. Examples of uremic toxin-treating enzymes include, but are not limited to, ureases (which react with urea), uricases (which react with uric acid), or creatininases (which react with creatinine).

[0070] The term “uremic toxin,” as used herein, refers to one or more compounds comprising waste products, e.g., from the breakdown of proteins, nucleic acids, or the like, as would be well understood by one of skill in the art. Non-limiting examples of uremic toxins include urea, uric acid, creatinine, and beta-2 microglobulin (β2). In healthy individuals, uremic toxins are generally excreted from the body via urine. However, in certain individuals, uremic toxins are not removed from the body at a sufficiently rapid rate, leading to uremic toxicity, that is, a disease or condition characterized by elevated levels of at least one uremic toxin relative to physiologically normal levels of the uremic toxin. Non-limiting examples of disorders associated with uremic toxins include kidney disease or dysfunction, gout, and uremic toxicity in individuals receiving chemotherapy.

[0071] The term “uremic toxin treating enzyme particles” as used herein refers to a uremic toxin treating enzyme in particulate form. The enzymes may be immobilized by means of covalent or physical attachment to a biocompatible solid support, or by cross-linking, or encapsulation, or any other means.

[0072] The term “soluble source” as used herein refers to a compound distinct from other sorbent components that may be added to and mixed with the other components, or be present as a separate layer or in a separate compartment from other sorbent components. It will typically be added to the sorbent in the form of solid particles that mix with other solid particles in the sorbent.

[0073] The term “biocompatible,” as used herein, refers to the property of a material that does not cause adverse biological reactions in the human or animal body.

[0074] The term “homogeneous,” as used herein, refers to a substantially homogeneous mixture, meaning that a mixture has the same proportions of the various components throughout a given sample, creating a consistent mixture. The composition of the mixture is substantially the same overall, although it is appreciated that in the mixture of solid particles there may be regions in a sample where the mixing is not complete.

[0075] The term “particle size” refers to the diameter or equivalent diameter of the particle. The term “mean particle size” means that a major proportion of the particles will be close to the specified particle size, although there will be some particles above and some particles below the specified size. The peak in the particle distribution will be at a specified size. Thus, for example, if the mean particle size is 50 microns, there will be some particles that are larger and some particles that are smaller than 50 microns.

[0076] The terms “regenerate” or “regenerated,” as used herein, refer to the action of detoxifying dialysate by destruction and/or absorption of uremic toxins by a sorbent.

[0077] The term “regenerated dialysate,” as used herein, refers to dialysate that has been detoxified by destruction and/or absorption of uremic toxins by a sorbent.

[0078] The term “reconstitute” or “reconstituted” as used herein refers to the action of converting the regenerated dialysate into essentially the same state and chemical composition as the fresh dialysate prior to dialysis.

[0079] The term “reconstituted dialysate” as used herein refers to dialysate that has been converted to essentially the same state and chemical composition as fresh dialysate prior to dialysis.

[0080] The term “predominantly,” as used herein, is intended to represent a situation or state that occurs for the most part or primarily, while not excluding the possibility that some amount of another situation or state also occurs to a minimal extent. For example, it may be >80% or >90% or >95% or greater than 99%. For the avoidance of doubt, the possibility that only that situation or state occurs, to the exclusion of all others, is covered by the term.

[0081] The word “substantially” does not exclude “completely”, for example, a composition that is “substantially free” of Y may be completely free of Y. Where necessary, the word “substantially” may be omitted from the definition of the invention.

[0082] Unless otherwise indicated, the terms “comprising” and “comprise,” and grammatical variants thereof, are intended to represent “open” or “inclusive” language so that they include the elements indicated but also allow for the inclusion of additional, unrecited elements. The terms may also be given an exclusive meaning equivalent to the term “consist of,” where the context so requires.

[0083] As used herein, the term “about” in the context of concentrations of components of formulations typically means ±5% of the stated value, more typically +/- 4% of the stated value, more typically ±3% of the stated value, more typically +/- 2% of the stated value, even more typically ±1% of the stated value, and even more typically +/- 0.5% of the stated value.

[0084] Throughout this description, certain embodiments may be described in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the ranges described. Thus, the description of a range should be considered to have specifically described all possible subranges as well as individual numerical values within that range. For example, the description of a range from 1 to 6 should be considered to have specifically described subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc. as well as individual numbers within that range, e.g., 1, 2, 3, 4, 5, and 6. This applies regardless of the width of the range.

[0085] The uremic toxin treating enzyme may be immobilized on any known support material that can provide immobilization for the uremic toxin treating enzyme particles. Immobilization may be by physical means, such as by adsorption onto alumina. In one embodiment, non-immobilized enzyme is used. Alternatively, other methods are used to convert urea to ammonia.

[0086] In one embodiment, the support material is a biocompatible substrate to which the enzyme is covalently attached. The biocompatible material may be a carbohydrate-based polymer, an organic polymer, a polyamide, a polyester, or an inorganic polymeric material. The biocompatible substrate may be a homogeneous substrate consisting of one material or a composite substrate consisting of at least two materials. The biocompatible substrate may be at least one of cellulose, Eupergit, silicon dioxide (e.g., silica gel), zirconium phosphate, zirconium oxide, nylon, polycaprolactone, and chitosan.

[0087] In one embodiment, immobilization of the uremic toxin treating enzyme onto the biocompatible substrate is accomplished by immobilization techniques selected from the group consisting of glutaric aldehyde activation, activation with epoxy groups, epichlorohydrin activation, bromoacetic acid activation, cyanogen bromide activation, thiol activation, and N-hydroxysuccinimide and diimide amide coupling. The immobilization techniques used may also involve the use of silane-based ligands, such as, (3-aminopropyl)triethoxysilane, (3-glycidyloxypropyl)trimethoxysilane, or (3-mercaptopropyl)trimethoxysilane. The surface of the biocompatible substrate may be further functionalized with a reactive and/or stabilizing layer, such as dextran or polyethylene glycol, and with suitable linker and stabilizing molecules, such as ethylenediamine, 1,6-diaminohexane, thioglycerol, mercaptoethanol, and trehalose. The uremic toxin treatment enzyme may be used in purified form, or in crude extract form, such as Jack Bean urease extract or other suitable urease sources.

[0088] The uremic toxin treating enzyme particles may be capable of converting urea to ammonium carbonate. In one embodiment, the uremic toxin treating enzyme is at least one of urease, uricase, and creatininase. In a preferred embodiment, the uremic toxin treating enzyme is urease.

[0089] In one embodiment, the uremic toxin treating enzyme particles are urease particles.

[0090] In one embodiment, the uremic toxin treating enzyme particles have an average particle size in the range of about 10 microns to about 1000 microns, about 100 microns to 900 microns, about 200 microns to 900 microns, about 300 microns to about 800 microns, about 400 microns to about 700, 500 microns to about 600 microns, about 25 microns to about 250 microns, about 25 microns to about 100 microns, about 250 microns to about 500 microns, about 250 microns to about 1000 microns microns, about 125 microns to about 20 microns, about 150 microns to about 200 microns, about 100 microns to about 175 microns, and about 100 microns to about 150 microns.

[0091] In one embodiment, 1000 to 10000 urease units are immobilized on said biocompatible substrate. The total weight of the immobilized urease and the substrate ranges from about 0.5 g to about 30 g.

[0092] In one embodiment, the cation exchange particles comprise a water-insoluble amorphous metal phosphate in protonated form. In one embodiment, the metal is selected from the group consisting of titanium, zirconium, hafnium, and combinations thereof. In one embodiment, the metal whose phosphate is poorly soluble in water is zirconium. Sparingly soluble phosphates are to be understood herein as phosphates having a solubility of no greater than 10 mg/L in water. Preferably, the cation exchange particles are zirconium phosphate particles that are configured to exchange ammonium ions for predominantly hydrogen ions and to exchange essential cations for sodium ions.

[0093] In one embodiment, the cation exchange particles are configured to exchange ammonium ions for predominantly hydrogen ions and to exchange essential cations for sodium ions, adjusting them to low pH during synthesis. To optimize this property, the cation exchange particles are typically adjusted to low pH and low sodium loading during synthesis. In one embodiment, the cation exchanger is synthesized in the presence of an acid. The pH is adjusted by adjustment to a desired level, such as by titration with a base such as sodium hydroxide to raise the pH to a level that provides the desired differential exchange behavior. The titration also serves to provide the cation exchange particles with a sufficient sodium loading to allow the desired exchange of sodium for calcium, magnesium, and potassium. In one embodiment, the cation exchange material is zirconium phosphate. This can be synthesized in conventional processes, such as from basic zirconium sulfate (BZS) or from zirconium carbonate by reaction with phosphoric acid. If other acids are used, a source of the phosphate group must be provided. Typically, the pH is adjusted to be in the range 3.5 to 5.0, advantageously about 4.5, by titration of the reaction product with a base.

[0094] The zirconium phosphate particles may have an average particle size in the range of from about 10 microns to about 1000 microns, from about 100 microns to about 900 microns, from about 200 microns to about 900 microns, from about 300 microns to about 800 microns, from about 400 microns to about 700, from about 500 microns to about 600 microns, from about 25 microns to about 200 microns, or from about 25 microns to about 150 microns, or from about 25 microns to about 80 microns, or from about 25 microns to about 50 microns, or from about 50 microns to about 100 microns, or from about 125 microns to about 200 microns, or from about 150 microns to about 200 microns, or from about 100 microns to about 175 microns, or from about 100 microns to about 150 microns, or from about 150 microns to about 500 microns, or from about 250 microns to about 1000 microns. The zirconium phosphate particles can be immobilized on any known support material, which can provide immobilization for the zirconium phosphate particles. In one embodiment, the support material is a biocompatible substrate. In one embodiment, the immobilization of the zirconium phosphate particles is a physical compaction of the particles into a predetermined volume. In one embodiment, the immobilization of the zirconium phosphate particles is achieved by sintering zirconium phosphate, or a mixture of zirconium phosphate and a suitable ceramic material. The biocompatible substrate may be a homogeneous substrate comprised of one material or a composite substrate comprised of at least two materials.

[0095] Suitable cation exchange materials are materials that are configured to exchange ammonium ions for predominantly hydrogen ions and to exchange essential cations for sodium ions. This property can be determined by measuring the ion exchange capabilities of the material. Measuring the change in sodium ion concentration over time in the presence of calcium, magnesium, and/or potassium ions should result in an increase in sodium ion concentration, but there will be no change in the absence of calcium, magnesium, and/or potassium ions if ammonium ions generated by the breakdown of urea are present.

[0096] The anion exchange particles may comprise a water-insoluble, amorphous, partially hydrated metal oxide in its hydroxide, carbonate, acetate and/or lactate ion form, wherein the metal may be selected from the group consisting of titanium, zirconium, hafnium and combinations thereof. In one embodiment, the metal is zirconium. The anion exchange particles may be zirconium oxide particles. Preferably, the anion exchange particles are hydrated zirconium oxide particles.

[0097] In one embodiment, the anion exchange particles are adjusted to an alkaline pH. In one embodiment, they are adjusted to a pH in the range of 7 to 14. In one embodiment, they are adjusted to a pH of 12 to 13. One way to achieve this is to saturate the anion exchange particles with a base. In one embodiment, the base is selected from the group consisting of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, magnesium hydroxide; calcium hydroxide, calcium carbonate, magnesium carbonate, potassium carbonate, potassium bicarbonate, ammonium carbonate, and ammonium hydroxide. Preferably, the base is selected from the group consisting of sodium hydroxide, sodium carbonate, and sodium bicarbonate. Alkaline anion exchange particles are preferred to produce the desired selective sorbent exchange properties for ammonium and Ca/Mg/K, respectively, particularly when combined with acidic cation exchange particles as described above. It will be understood that metal oxides used as cation exchange materials are typically synthesized by conversion of a precursor, such as a carbonate, to the oxide by reaction with hydroxide, followed by an optional titration, and that not washing the product will retain excess hydroxide within the products. If a sodium salt is used, then the base can act as the source of sodium ions, so sodium hydroxide is preferred if unwashed anion exchange particles are used.

[0098] The zirconium oxide particles may have an average particle size in the range of from about 10 microns to about 1000 microns, from about 100 microns to about 900 microns, from about 200 microns to about 900 microns, from about 300 microns to about 800 microns, from about 400 microns to about 700, from about 500 microns to about 600 microns, from about 10 microns to about 200 microns, or from about 10 microns to about 100 microns, or from about 10 microns to about 30 microns, or from about 10 microns to about 20 microns, or from about 20 microns to about 50 microns or from about 25 microns to about 50 microns or from about 30 microns to about 50 microns or from about 40 microns to about 150 microns or from about 80 microns to about 120 microns or from about 160 microns to about 180 or about 25 microns to about 250 or from about 250 microns to about 500 or from about 250 microns to about 1000. The zirconium oxide particles may be immobilized on any known support material that can provide immobilization for the zirconium oxide particles. In one embodiment, the immobilization of the zirconium phosphate particles is a physical compaction of the particles into a predetermined volume. In one embodiment, the immobilization of the zirconium oxide particles is achieved by sintering zirconium oxide, or a mixture of zirconium oxide and a suitable ceramic material. In one embodiment, the support material is a biocompatible substrate. The biocompatible material may be a carbohydrate-based polymer, an organic polymer, a polyamide, a polyester, a polyacrylate, a polyether, a polyolefin, or an inorganic polymeric or ceramic material. The biocompatible substrate may be at least one of cellulose, Eupergit, silicon dioxide, nylon, polycaprolactone, and chitosan.

[0099] In one embodiment, the zirconium oxide particles may be replaced by any particles that are capable of absorbing phosphate ions and other anions. Preferably, the particles are capable of absorbing anions selected from the group consisting of phosphate, fluoride, nitrate and sulfate ions. The zirconium oxide particles may also release ions such as acetate, lactate, bicarbonate and hydroxide in exchange for the absorbed anions. In one embodiment, the zirconium oxide particles are also good binders for iron, aluminum and heavy metals selected from the group consisting of arsenic, bismuth, cadmium, cobalt, copper, lead, mercury, nickel, palladium and silver.

[00100] In one embodiment, the ratio of cation exchange particle to anion exchange particle is in the range of 1:1 to 5:1. In one embodiment, the ratio of cation exchange particle to anion exchange particle is in the range of 2:1 to 3:1. In one embodiment, the ratio of cation exchange particle to anion exchange particle is about 2.4:1. The anion exchanger acts as a pH buffer for the low pH cation exchanger, however, at this ratio, the buffering capacity of the anion exchanger particles alone is insufficient to compensate for the acidification and drop in sodium concentration by the cation exchanger.

[00101] The sorbent comprises a soluble source of sodium. The provision of sodium overcomes the initial drop in sodium concentration. Accordingly, a sorbent material according to the present invention will exhibit a smaller drop in sodium ion concentration compared to conventional materials at an early stage of a dialysis process. Ideally, there will be no initial drop in sodium ion concentration.

[00102] In one embodiment, the soluble source of sodium ions may be particles of a soluble salt. In one embodiment, the soluble salt is a basic salt. In one embodiment, the soluble salt is selected from one or more of the group consisting of sodium carbonate, sodium bicarbonate, and sodium hydroxide. It may also be a neutral salt, such as sodium chloride, or a salt of a weak acid, such as, for example, sodium lactate or sodium acetate.

[00103] Producing the desired exchange selectivity requires a comparatively low Na loading of the sorbent materials during synthesis. Therefore, it is necessary to add a separate source of sodium ions to overcome the initial Na drop caused by the sorbent material.

[00104] The sorbent comprises bicarbonate which is generated in the breakdown of urea and transported from the patient in the dialysate. There is an initial drop in bicarbonate concentration due to neutralisation with hydrogen ions released from the cation exchanger, which results in the formation of carbon dioxide. Carbonate and/or bicarbonate may be introduced by adding a salt directly to the sorbent to compensate. This may be done by introducing, for example, sodium carbonate, sodium bicarbonate, or by introducing salts of weak acids such as sodium acetate or sodium lactate, which result in an increased bicarbonate in the dialysate. The sodium salt is preferred as it can also act as a source of sodium. There must also be a pH balance achieved, as the amount of anion exchanger is insufficient to compensate for the low pH cation exchanger. Equilibrium can be achieved by the introduction of a basic material such as, for example, sodium hydroxide, sodium carbonate or sodium bicarbonate. Although these compounds can be added separately to treat each of the deficiencies, it will be appreciated that the introduction of sodium carbonate or sodium bicarbonate resolves all deficiencies; therefore, sodium carbonate and sodium bicarbonate are the preferred source of sodium ions.

[00105] Although not wishing to be bound by theory, it is believed that the sorbent predominantly converts urea to CO2, allowing the chemistry of sorbent-based dialysate regeneration to be largely independent of the urea concentration in the spent dialysate. In a first step, the urea contained in the spent dialysate is converted to ammonium and bicarbonate. In a second step, the ion exchanger exchanges ammonium predominantly with protons. The protons then recombine with bicarbonate to form CO2, which is released from the system. Cations such as calcium, magnesium and potassium are exchanged predominantly for sodium. Advantageously, the sorbent is a homogeneous mixture containing a calculated amount of sodium carbonate and/or sodium bicarbonate. The addition of sodium carbonate/sodium bicarbonate influences the sodium concentration in the regenerated dialysate without altering the exchange characteristics of the sorbent.

[00106] The sorbent may optionally contain carbonic anhydrase to facilitate the release of CO2. Carbonic anhydrase catalyzes a reaction in which carbon dioxide and water are converted to carbonic acid, protons and bicarbonate ions. By way of example, carbonic anhydrase from human or bovine erythrocytes and recombinant human carbonic anhydrase may be used. The carbonic anhydrase may be immobilized on any known support material, such as described above for the uremic toxin treatment enzyme particles. The carbonic anhydrase may be immobilized separately on the uremic toxin treatment enzyme particles or on the same particles.

[00107] In one embodiment, the sorbent further comprises an organic compound absorbent. The organic compound absorbent may be mixed with uremic toxin treatment enzyme particles and cation exchange particles and/or anion exchange particles, or may form a separate layer. The organic compound absorbent may be selected from the group consisting of, but not limited to, activated carbons, molecular sieves, zeolites, and diatomaceous earth. The organic compound absorbent particles may be activated carbon particles. In one embodiment, the organic compound absorbent in the layer is an activated carbon filter block. In another embodiment, the organic compound absorbent comprises activated carbon particles.

[00108] The activated carbon particles may have an average particle size in the range of from about 10 microns to about 1000 microns, from about 10 microns to about 250 microns, from about 20 microns to about 200 microns, from about 25 microns to about 150 microns, from about 50 microns to about 100 microns, from about 25 microns to about 250 microns, or from about 100 microns to about 200 microns, or from about 100 microns to about 150 microns, or from about 150 microns to about 300 microns, or from about 200 microns to about 300 microns, or from about from 400 microns to about 900 microns or from about 500 microns to about 800 microns or from about 600 microns to about 700 microns or from about 250 microns to about 500 microns or from about 250 microns to about 1000 microns.

[00109] In one embodiment, the activated carbon particles may be replaced by any particles that are capable of absorbing organic compounds. Preferably, the particles are capable of absorbing organic compounds and/or organic metabolites selected from the group comprising creatinine, uric acid and other small and medium organic molecules without releasing anything in exchange. The activated carbon particles may also be physically compacted into a predetermined volume for space-saving purposes. In one embodiment, the activated carbon particles are physically compacted into an activated carbon filter block.

[00110] The invention also provides a process for preparing a sorbent comprising mixing immobilized uremic toxin treatment enzyme particles that convert urea to ammonium ions with cation exchange particles configured to exchange ammonium ions for predominantly hydrogen ions and to exchange essential cations for sodium ions, and further comprising providing a source of sodium and optionally mixing anion exchange particles and/or organic compound absorbent particles.

[00111] In one embodiment, the sorbent is housed in at least one cartridge. The sorbent cartridges may be configured so that they are readily removable from the dialysis device. The sorbent cartridge may also be compact and made of a material that is resistant to wear and tear. The cartridge may be made of resilient, chemically and biologically inert materials. The cartridge may also withstand the pressure within the flow system of the dialysis device without leakage. The cartridge may be made of a material that can withstand sterilization conditions such as heat sterilization, ethylene oxide sterilization, and ionizing radiation sterilization. In one embodiment, the sorbent cartridges are made of acrylonitrile butadiene styrene. The sorbent cartridges may also be made of polycarbonate, polypropylene, or polyethylene. In one embodiment, filter blocks and filter papers may also be located at the inlet and outlet of the sorbent cartridges and/or between the individual layers within the sorbent, to filter any particles arising from the sorbent layers.

[00112] The invention also relates to a process for regenerating dialysate in which a predetermined amount of cations, such as Ca+2, Mg+2 and K+ are added to replenish dialysate from which metabolic waste products have been removed by contact with the sorbent of the present invention. After dialysis, the used dialysate will contain a known amount of the cations and will therefore release a corresponding amount of sodium ions from the sorbent; thus, the sodium ion concentration in the regenerated dialysate is determined by the amount of cations previously added to reconstitute the dialysate. The system uses a sorbent, which predominantly converts urea to CO2, and predominantly exchanges cations, such as calcium, magnesium and potassium to sodium. The concentration of the infusion agent is chosen so that the amount of sodium exchanged for the constituents of the infusion agent (Ca, Mg, K) results in a desired target sodium concentration when recombined with the infusion volume used for reconstitution with Ca, Mg and K. Thus, the system for dialysate regeneration and reconstitution comprises an intrinsically regulated infusion system. The system can produce specific sodium profiles, or maintain a constant sodium concentration in the regenerated dialysate, without the need for a feedback control system.

[00113] An advantage of this invention is the ability to maintain sodium levels in the dialysis solution within a desired range. This may help to reduce discomfort experienced by the patient as a result of increased or decreased sodium levels in the patient's blood.

[00114] The system of this invention is capable of controlling the sodium concentration in the dialysate with significantly smaller variations than conventional dialysis apparatus. For example, accuracies of ±5% of a target concentration are achievable. For example, the system can maintain dialysate sodium concentrations within a range of 132 to 145 mEq/L. Furthermore, specific concentration profiles are accessible, for example for “sodium shaping”, and can also be achieved with accuracies of ±5%. Bicarbonate and chloride concentrations are significantly better controlled than in the prior art.

[00115] The sorbent system of this invention allows the use of chloride salts for electrolyte reinfusion, whereas previous systems had to use weak acid salts such as acetate salts to maintain the dialysate buffer system (buffer concentration and CI concentration) within the physiological range. Acetate salts are more expensive, and more difficult to provide in a sterile and stable form (composition changes during sterilization and storage) than chloride salts. However, although the present invention allows the possibility of providing infusate solutions based on chloride salts of Ca, Mg and K, the system is not limited to these salts. Chloride salts can be partially replaced by lactate salts, without changing the total salt concentration or the infusion rate. Since there would be only a partial replacement of chloride by lactate, the resulting infusion solution would not be limited by solubility problems. Advantageously, such mixed salt solutions can be used to increase the buffering capacity of a regenerated dialysate, counteracting patient acidosis. Most advantageously, such solutions can be similar to commercially available solutions for parenteral infusion, and may be suitable for steam sterilization.

[00116] The resulting system is simple, robust, small, cost-effective and has a smaller number of components compared to the prior art. Although not wishing to be bound by theory, it is believed that this is due to the characteristic of the sorbent to exchange ammonium predominantly for protons, while the divalent cations and potassium are predominantly exchanged for sodium. This is a result of the design of the ion exchange sorbent (zirconium phosphate), which is deliberately tuned to lower the pH and decrease the sodium loading during the synthesis of the sorbent. Surprisingly, it was found that the cation exchange properties for calcium, magnesium and potassium are independent of the pH of the sorbent, while the ammonium exchange property is strongly pH dependent. This allows to produce an ion exchange material with a pH that favors the exchange of ammonium for protons, while for calcium, magnesium and potassium the sodium exchange is not affected. The sorbent of the present invention combines such optimized zirconium phosphate with hydrated zirconium oxide with alkaline pH, so as to maintain the pH of the regenerated dialysate within a desired target range, e.g., 6.0 to 8.0, without interfering with the ion exchange selectivity. This system is subjected to a sharp Na drop at a dialysate Na concentration of approx. 100 mEq/L in the initial phase of dialysis. To counteract this Na drop, a calculated amount of sodium bicarbonate, sodium carbonate, sodium chloride or sodium hydroxide is added to the homogeneous sorbent mixture.

[00117] Consequently, the sodium concentration in the regenerated dialysate is independent of the ammonium (i.e. urea) concentration in the used dialysate. On the contrary, the absolute amount of sodium exchange depends on the concentrations of calcium, magnesium and potassium in the used dialysate, which are known and subject to only small fluctuations. These concentrations are in fact determined by the process of regeneration and reconstitution of the dialysate in the dialysis system. For example, typical concentrations of K, Ca and Mg are 2, 3 and 1 mEq/L. In other words, the actual amount of sodium released during the regeneration process is known, and depends directly on the concentrations of K, Ca and Mg determined by the system during the regeneration process. This makes it possible to calculate the concentration of the solution used to administer K, Ca and Mg, so that the increase in volume through the infusion of this concentrate coincides precisely with the increase in sodium caused by the ion exchange of K, Ca and Mg. For example, the concentration of the K, Ca and Mg solution can be adjusted so that the sodium equivalents released in exchange for the combined K, Ca and Mg equivalents are met by the required volume of solution to produce a desired target Na concentration of, for example, 138 mEq/L. For example, regeneration of 1 L of used dialysate containing 3 mEq/L of K, 3 mEq/L of Ca and 1 mEq/L of Mg can result in a total release of 5 to 7 mEq, for example, 7 mEq of sodium. The system of the present invention advantageously delivers a concentrate solution to reconstitute K, Ca and Mg, which has a total volume of 51 mL to reconstitute said 1 L of used dialysate. 7 mEq of sodium increase is therefore achieved with 51 mL of volume increase, which formally results in a sodium concentration of 7/0.051 mEq/L = 138 mEq/L in the added liquid components. Crucially, this concentration is the same as the target concentration and therefore does not affect the sodium concentration in the total regenerated volume of 1.051 L. Based on this model, the preferred mixing ratio of regenerated dialysate and K, Ca, and Mg concentrate is 1000:51. It should be noted that this mixing ratio is based on an idealized calculation, which can be adjusted by empirical optimization. In practice, the concentration of sodium ions and the essential ions is prescribed by a physician. Various settings can be provided, which may differ by the composition of the infusion solution, or by the dose volume of the infusion solution. A steady state with respect to sodium concentration can be maintained. Alternatively, other mixing ratios may produce an intentional deviation from a target concentration, for example as in sodium modeling. Alternatively, different target concentrations of Ca, Mg, K, and Na may be achieved using different concentration solutions and different infusion volume ratios.

[00118] In one embodiment, the concentrated infusion solutions may further comprise osmotic agents, such as glucose, to ensure the correct osmotic pressure of the dialysate after infusion.

[00119] In one embodiment, the infusion agent concentrate solutions may further comprise additional salts, such as sodium chloride, which may function as a variable component, or “substituent” replacing other chloride salts for different target concentrations of Ca, Mg and K. Advantageously, this allows for the provision of a variety of infusion concentrates that can be administered using the same infusion volume ratio, thereby facilitating device design. For example, such concentrate solutions may also contain an intentionally low sodium chloride concentration, thereby allowing for the creation of a negative sodium gradient in the dialysate following infusion.

[00120] Non-limiting examples embodying certain aspects of the invention will now be described.

Detailed Description of Drawings

[00121] Two experimental setups of different scales were used. The differences were as shown in Table 1. Table 1 Components of the infusion solution/toxin: • Cation infusion agent: Ca+2 - 1.5 mmol/L, Mg+2 - 0.5 mmol/L, K+ - 3.0 mmol/L; and • Toxin: urea - 8.9 mmol/L, creatinine - 370 μmol/L and phosphate - 1.3 mmol/L.

[00122] In conventional sorbent dialysis arrangements, 6 L of dialysate and up to 1 L of infusion are used. In one embodiment of the present invention, 2 L of dialysate and 4 to 5 L of infusion are used. Consequently, the total volume of fluid required to complete dialysis therapy is relatively unchanged in the present invention compared to conventional sorbent dialysis. Conventional sorbent dialysis uses a large volume of dialysate reservoir (as large as 6 L for a REDY system) to buffer changes in sodium, bicarbonate and pH; while infusion agent was kept to a smaller volume (1 L). In the present invention, although a larger infusion volume is used to achieve the required infusion, the dialysate reservoir is no longer required to act as a buffer volume and can be reduced to 2 L.

[00123] The miniature configuration 10 is as shown in Figure 2. The process first involves withdrawing a sample stream from a spent dialysate reservoir 15 equipped with an agitator 20, in which the dialysate stream is heated to 37°C by a heat exchanger 25. The flow rate is controlled by a pump 30 coupled to a pressure dampener and sensor 35. Initially, a solution containing urea is introduced into the spent dialysate reservoir. This mimics spent dialysate from a first dialysis cycle once heated by passing through the heat exchanger 25. The spent dialysate then passes through a sorbent cartridge 40 to produce a regenerated dialysate. The ammonium level may be monitored by an ammonia sensor 45. A suitable ammonia sensor is described in WO2017/034481, the contents of which are incorporated herein by reference. An infusion/toxin solution 50 is fed into the regenerated dialysate in this experimental system. The purpose is to maintain the salt concentration as described herein as closely mimicking the conditions under which patients are treated. The experimental system adds toxins along with the infusion agent, but it will be appreciated that the infusion agent would normally be introduced into the regenerated dialysate before the dialysate is reused for dialysis. In peritoneal dialysis, the reconstituted dialysate would be introduced into the peritoneal cavity of the patient so that diffusion of the toxins would occur, whereas in hemodialysis toxins diffused through a membrane, the reconstituted dialysate flows through a dialyser in the opposite direction to the patient's blood. In the experimental system, the reconstituted dialysate contains toxins and so is treated as used dialysate for a second cycle. The used dialysate is returned to the used dialysate reservoir 15. The used dialysate is withdrawn from the used dialysate reservoir for treatment into the sorbent in a second cycle. A gas burette 55 measures the volume of carbon dioxide gas that is produced in each cycle. A sample of the used dialysate and regenerated dialysate was collected through sample ports 60 (used dialysate) and 65 (regenerated dialysate), respectively, in each cycle for analysis. The miniature setup 10 was used in investigating the effect of how different dialysate components affect Na+ release over time.

[00124] The sorbent in the sorbent cartridge 40 varies depending on the experiment. In each case, it includes immobilized uremic toxin treatment enzyme particles that convert urea to ammonium ions, mixed with cation exchange particles. The cation exchange particles are configured to exchange ammonium ions for predominantly hydrogen ions and to exchange calcium, magnesium, and potassium ions for sodium ions in the present invention. The cation exchange material operates at a pH that favors ammonium-to-proton exchange, while divalent cation-to-sodium exchange is unaffected (Figure 1). Accordingly, the sodium concentration in the regenerated dialysate is independent of the ammonium (i.e., urea) concentration in the used dialysate.

[00125] The infusion/toxin solution 50 consisted of an aqueous solution of Ca, Mg, K salts as well as urea, creatinine, and a phosphate source. Ca, Mg, and K were typically introduced as chloride salts. In this experimental system, phosphate was introduced to mimic waste generation. Typically, phosphate was introduced as H3PO4 or KH2PO4. Where KH2PO4 was used as a phosphate source, the mass of KCl was correspondingly reduced in a 1:1 molar ratio to achieve the same target K concentration.

[00126] The full-scale configuration 110 is shown in Figure 3. The dual-loop process resembles that of the miniature configuration, but further includes a second circuit for the blood of a simulated patient. An aqueous dialysate solution is used to simulate the patient's blood. The process involves first pumping a sample stream from a dialysate reservoir 115 via a pump 145, through a heat exchanger 125 at 37°C to dialyzer 130, where exchange with simulated blood occurs. The simulated blood was pumped out of a reservoir 170 via a pump 180, through a heat exchanger 180 at 37°C. The heated simulated blood then passed through dialyzer 130 before returning to the patient reservoir 170. The simulated blood and dialysate flow to either side of a membrane (not shown) through which they exchange. The used dialysate is then pumped out of the dialyser 130 via a pump 135 and into a pressure buffer gauge 140, before being passed through a sorbent cartridge 145 to regenerate the dialysate. An infusion solution 150, controlled by an infusion pump 155, is fed to the regenerated dialysate to reconstitute the dialysate. Excess fluid is optionally removed by a drain pump 160 to a drain reservoir 165, while the remaining regenerated dialysate is fed into the dialysate reservoir 115.

[00127] Non-limiting examples embodying certain aspects of the invention will now be described.

Examples Example 1 - Preparation of Zirconium Phosphate

[00128] Zirconium phosphate is synthesized by conventional methods, for example, by reacting an aqueous mixture of Basic Zirconium Sulfate and phosphoric acid, as described in U.S. Patent No. 3,850,835. Alternatively, it is synthesized from an aqueous mixture of Sodium Zirconium Carbonate and phosphoric acid, as described in U.S. Patent No. 4,256,718.

[00129] The product was titrated to a solution pH of 4.5. A 5M sodium hydroxide solution was added in stages to an aqueous suspension of the zirconium phosphate until a pH of 4.5 was reached. After titration, the zirconium phosphate was washed until the filtrate was within acceptable leachable limits, and air dried.

Example 2 - Preparation of Hydrated Zirconium Oxide

[00130] Hydrated zirconium oxide is synthesized by conventional methods, for example, by reacting an aqueous mixture of sodium zirconium carbonate and sodium hydroxide as described in U.S. Patent No. 4,256,718. After synthesis of hydrated zirconium oxide, the product was titrated to a pH of 12 to 13. This was done by preparing an aqueous suspension of the hydrated zirconium oxide and titrating it with 5M sodium hydroxide until the suspension was at a pH of 12 to 13. In some cases, the hydrated zirconium oxide was then washed until the leachables concentration in the filtrate was within acceptable levels and air-dried. Alternatively, the HZO was recovered directly from the suspension and not washed before being air-dried. HZO subjected to a washing procedure is referred to as “washed HZO.” HZO recovered directly from the titration suspension is referred to as “unwashed HZO”.

Example 3 - Preparation of sorbent mixture for miniature cartridges

[00131] For each experiment, the sorbent cartridge consisted of the materials listed below. Zirconium phosphate (ZP) was prepared according to Example 1. Hydrated zirconium oxide (HZO) was prepared as described in Example 2, and both were washed with a foulant that was used as directed. Immobilized urease (IU) was prepared as described in Examples 1 and 2 of WO 2011/102807, the contents of which are incorporated herein by reference. Activated carbon (AC) has a particle size of 50 to 200 microns. In general, one experimental condition was changed at a time to distinguish the effect of this modification on the sodium concentration in the regenerated dialysate. The sodium and pH set point of the sorbent was adjusted in two ways in these experiments: 1) Use of soluble additive (Na2CO3, NaHCO3) and/or 2) HZO modification - use of unwashed and washed HZO

[00132] In each experiment, a flexible glass column with inlet and outlet was used as the receptacle for the sorbent. The sorbent materials, immobilized urease, and additive were weighed individually, then mixed and dried in the flexible column. The sorbent bed was held in place with a cotton plug, at which point it was ready for installation in the dialysate circuit. Experiments with miniature cartridges Table 2

Example 4 - Effect of urea concentration on dialysate chemistry

[00133] Three identical sorbent cartridges were constructed using a composition as given in Table 2 and tested in the recirculating miniature dialysis setup 10 described above. The three cartridges were challenged with low, medium, or high urea concentrations in the recirculating miniature dialysis setup 10 described above with reference to Figure 2, representing a range of incoming patient urea levels. Briefly, dialysate solutions containing low, medium, and high urea concentrations (2.2 mM, 4.5 mM, and 8.9 mM) were prepared for use as the initial dialysate solution. The toxin/infusion agent solution 50 was prepared so as to contain sufficient urea to maintain the low, medium, or high urea level, as well as the required concentrations of Ca+2, Mg+2, K+, creatinine, and phosphate. In each of the three experiments, toxin-containing dialysate was pumped through the sorbent cartridge, where Ca+2, Mg+2, K+, urea, creatinine, and phosphate were removed. The dialysate was then reconstituted by adding the toxin/infusion agent solution to maintain the challenge concentration of urea, creatinine, and phosphate and adding Ca+2, Mg+2, and K+. Aliquots of the dialysate were obtained through sampling port 60.

[00134] The following was observed: a) Sodium: The Na+ concentration over time for all three urea concentrations showed a similar trend, indicating that urea concentration had no effect on the release of Na+ from the sorbent cartridge (Figure 4a). b) Bicarbonate: The HCO3- profile shows only a weak dependence on the urea concentration in the dialysate. There is an initial loss of HCO3- in agreement with the bicarbonate drop described. Subsequently, the apparent lack of a significant increase in bicarbonate indicates that approximately all of the NH4+ formed from urea is exchanged for H+, where it combines with HCO3- formed from urea and released as CO2 (Figure 7). c) Chloride: The Cl- slope is independent of the urea concentration in the dialysate. There is a steady increase in Cl- upon addition of infusion agent (Figure 8). d) pH: The pH profile shows only a weak dependence on the area of urea dialysate concentration (Figure 9). Acidification occurs through a formal loss of HCO3- and an increase in Cl- is seen upon addition of infusion agent. Example 5 - Effect of Ca2+, Mg2+ and K+ infusion on dialysate chemistry. For the purpose of distinguishing the effects of urea (ammonia) removed dialysate vs Ca/Ma/K containing either urea or Ca Mg and K in the miniature recirculating dialysis setup 10 described above with reference to Figure 2. As in Example 4, in each experiment, dialysate was pumped through the sorbent cartridge followed by the addition of an infusion agent to replenish and maintain the respective dialysate concentration of Ca2+, Mg2+, K+, urea, creatinine and phosphate (where relevant). Aliquots of the dialysates were obtained via sampling port 60. The following were observed: a) Sodium: In the absence of urea, the Na+ profile over time resembled the typical profile shown with an initial decrease with a subsequent increase in Na+ concentration over time (Figure 4b). However, in the absence of Ca2+, Mg2+, and K+, the Na+ concentration showed a large initial decrease and remained relatively constant thereafter (at approximately 110 mmol/L) (Figure 4b). This shows that the increase in Na+ concentration is caused by Ca2+, Mg2+, and K+, presumably by cation exchange to displace and release Na+ from the sorbent cartridge. b) Bicarbonate, pH, Cl: The HCO3- profile shows only a weak dependence on the presence of infusing agent or urea. Neither urea nor Ca/Mg binding has a significant effect on HCO3- (Figure 10). It was observed that Cl- increased in the presence of infusing agent, with an increase approximately equal to the increase in Na+. There was no increase in Cl- in the presence of urea without infusing agent, but there was a steady increase in Cl upon addition of infusing agent (Figure 11). Therefore, addition of infusing agent formally increases the NaCl concentration. Additionally, a very low pH in the presence of Ca/Mg and absence of urea was observed (Figure 12). Acidification through formal loss of HCO3- and increase in Cl- upon addition of infusing agent was evident. Example 6 - Improvement of the Na+ profile after modification The effects of dialysate addition of soluble sodium salts to the sorbent were investigated by testing two sorbent compositions (see Table 2, Example 6) with identical dialysate and infusing agent solutions in the miniature recirculating dialysis setup 10 described above with reference to Figure 2. Regardless of the increase in sodium bicarbonate, the sorbents were identical in composition. a) Sodium: An initial Na+ drop is prevented, or at least reduced, by increasing the amount of Na+ (basic) salt in the sorbent mixture. The drop in Na+ rise during the steady phase is unaffected (Figure 13). Therefore, the addition of Na+ (basic) salt enhances or prevents the initial Na+ drop apparent in conventional systems without affecting the ion exchange behavior of the sorbent. b) Bicarbonate: The usual initial drop in HCO3- is significantly enhanced by increasing the amount of Na+ (basic) salt in the sorbent mixture. The increase in HCO3- during the stable phase is unaffected, and remains at approximately zero (Figure 13). Thus, the addition of a Na+ (basic) salt reduces the initial drop in HCO3- without affecting the ion exchange behavior of the sorbent. c) Chloride: The Cl- profile is essentially independent of the amount of Na-salt in the sorbent mixture (Figure 15). Thus, the addition of a Na+ (basic) salt does not significantly affect the Cl- concentration. Example 7 - Modification to the sorbent and infusion agent composition to allow control of the Na+ profile. In order to advantageously utilize the concepts disclosed in Examples 4, 5, and 6 to construct an intrinsically regulated sorbent dialysis system, a series of experiments were conducted with modified sorbents and infusion agent compositions. Three sorbent cartridges were run with modified sorbents and infusion agent compositions. Three sorbent cartridges were tested in the miniature recirculating dialysis setup 10 described above with reference to Figure 2 (see Table 23, Example 7). In the first experiment, an unmodified sorbent was used in the simulated dialysis session with unmodified infusion agent solution (Figure 6a), giving the characteristic drop in sodium followed by a steady rise. In the second experiment, the sorbent was modified to include additional Na2CO3 as the soluble sodium salt. This corrected the drop in sodium, but the subsequent sodium gradient remained (Figure 6b). In the third experiment, the same modified sorbent was included in the dialysis circuit with a modified infusion agent, whereby the infusion agent composition was changed to counteract the sodium dialysate gradient (Figure 6c). The infusion agent composition was amended by increasing the infusion agent volume. With further modifications, it is possible to achieve a negative sodium gradient similar to the gradients typically applied in sodium modeling (Figure 6d). For example, using an initial pre-dialysis bath of 142 mM Na and performing dialysis in combination with a suitably modified infusion agent composition and infusion rate can produce such a result with the sorbent disclosed here. Example 8 - Comparative effect of HZO modification, soluble sodium salt, and infusion conditions on cation exchange efficiency. Table 3

[00135] The use of unwashed HZO (with high Na loading) in Example 8F - 8G (Table 3) appeared to result in less favorable ammonium to H+ exchange properties (only 88% of ammonium exchanged for H+) compared to the use of washed HZO with lower Na loading (at least 94% ammonium to H+ exchange) in Example 8A - 8E (Table 3). This suggests that the traditional approach to sorbent modification in terms of pre-loading ZP or HZO with Na produces results that are inferior to the use of an additive as in the present invention.

Example 9 Formulas for calculating infusion agent composition and infusion rate for reconstitution process Solution to keep Na concentration stable:

[00136] • The regenerated dialysate exiting the sorbent cartridge must be reconstituted with a Ca+2/Mg+2/K+ solution containing approximately 138 mEq/L of combined Ca+2/Mg+2/K+.

[00137] • In this way, the additional Na+ exchanged for Ca+2/Mg+2/K+ will be achieved with an infusion volume, which will reconstitute the additional Na+ to a concentration of 138 mEq/L.

[00138] • In an idealized analysis, the salt concentration in the infusion agent should fulfill the following condition: where cICaMgK: concentration of combined Ca+2/Mg+2/K+ infusion agent cDNa: concentration of Na+ in target dialysate cINa: concentration of Na in infusion solution (if present)

More detailed analysis:

[00139] • In a more detailed analysis, the salt concentration in the infusion must fulfill the following condition where cICaMgK: concentration of combined Ca+2/Mg+2/K+ infusion agent cINa: concentration of Na+ infusion agent (optionally added; e.g. NaCl) cDNa: concentration of Na+ in the target dialysate cDurea: concentration of urea in the dialysate before regeneration ηCaMgK: exchange efficiency of Ca+2/Mg+2/K+ to Na+ (approx. 0.85 - 1) ηurea: exchange efficiency of urea to Na+ (<0.1)

[00140] • The optimal cICaMgK concentration and the best infusion ratio can further be determined for the targeted dialysate composition by empirical iterative optimization (fine-tuning)

Calculation of infusion ratio:

[00141] • In an idealized analysis, the perfusion ratio (ratio of the infusion agent addition rate to the regenerated dialysate rate) is calculated as where r: infusion ratio vI: infusion agent addition rate vD: regenerated dialysate rate cDCaMgK = Ca+2/Mg+2/K+ concentration in the target dialysate cDCa + cDMg + cDK cICaMgK = Ca+2/Mg+2/K+ concentration in the infusion agent Idealized example: An example of the dialysis reconstitution process is illustrated in Figure 16. In the illustrated example, the infusion solution is 51 mL in volume and includes 3 mEq/L Ca, 1 mEq/L Mg, 3 mEq/L K.

Additional examples with and without added NaCl:

[00142] A target dialysate composition can be achieved by infusing the following solution at an infusion ratio of 1:20

[00143] The same infusion rate can be used to produce a dialysate containing if an infusion agent of the following composition is used

Example 10: Full-scale in vitro experiment

[00144] A full-scale experiment according to the dialysis circuit 110 shown in Figure 3 was conducted on a simulated patient of 40 L of simulated body fluid. The sorbent composition consisted of the following materials: ZP (1141 g), washed HZO (472 g), AC (160 g), IU (27 g), and sodium carbonate (50 g). The sorbent was dry-packed in a vessel consisting of a cylindrical compartment with inlet and outlet, with filter papers installed before and after the sorbent layer. A volume of 4 L of infusion agent was infused over 4 h, containing sufficient salts to reconstitute 72 L of regenerated dialysate during dialysis. The dialysis session was conducted according to the parameters in Table 1. The infusion flow rate was 16.7 mL/min and the dialysate flow rate was 300 mL/min. A blood circuit flow rate of 300 mL/min and a simulated blood toxin concentration approximately 1.5 times (assuming approximately 60% total toxin transfer from the simulated patient's body fluid to the dialysate) the value stated in the description were used to provide the required toxin challenge for the cartridge in the dialysate circuit. The simulated patient solution contained 964.5 mmol urea, 40.4 mmol creatinine, and 137.4 mmol phosphate in 40 L of simulated body fluid. Blood upstream of the dialysator was sampled at “blood inlet,” blood downstream at “blood outlet,” and also into the dialysate circuit. As a result of intrinsic regulation through modified sorbent and infusion agent compositions, a stable sodium concentration was observed in both the blood and dialysate circuits throughout the dialysis session (Figure 5).

Claims of Invention

[00145] 1. A sorbent for removing metabolic waste products from a dialysis fluid, the sorbent comprising a soluble source of sodium ions.

[00146] 2. A sorbent as described in claim 1, wherein the soluble source of sodium ions is a soluble salt.

[00147] 3. A sorbent as described in claim 2, wherein the soluble salt is a basic salt.

[00148] 4. A sorbent as described in claim 3, wherein the soluble salt is selected from one or more of the group consisting of sodium carbonate, sodium bicarbonate, and sodium hydroxide.

[00149] 5. A sorbent as described in statement 4, wherein the soluble salt is sodium bicarbonate.

[00150] 6. A sorbent as described in statement 2, wherein the soluble salt is a neutral salt.

[00151] 7. A sorbent as described in claim 6, wherein the sodium salt is sodium chloride.

[00152] 8. A sorbent as described in statement 2, wherein the soluble salt is a salt of a weak acid.

[00153] 9. A sorbent as described in claim 8, wherein the soluble salt is sodium lactate or sodium acetate.

[00154] 10. A sorbent as described in any one of claims 1 to 9, the sorbent comprising a soluble source of sodium ions in homogeneous admixture with at least one of: (a) uremic toxin treating enzyme particles comprising a uremic toxin treating enzyme immobilized on a solid support; (b) cation exchange particles configured to exchange ammonium ions for predominantly hydrogen ions and to exchange essential cations for predominantly sodium ions; and (c) anion exchange particles.

[00155] 11. A sorbent as described in claim 10, wherein said cation exchange particles are adjusted to a pH in the range of 3.5 to 5.0.

[00156] 12. A sorbent as described in claim 11, wherein said cation exchange particles are adjusted to a pH of about 4.5.

[00157] 13. A sorbent as described in any one of claims 10 to 12, wherein said cation exchange particles have a particle size in the range of 10 to 1000 microns, preferably 25 to 150 microns, more preferably 50 to 100 microns.

[00158] 14. A sorbent as described in any one of claims 10 to 13, wherein said cation exchange particles comprise an amorphous, water-insoluble metal phosphate in partially protonated form.

[00159] 15. A sorbent as described in claim 14, wherein the metal is selected from the group consisting of titanium, zirconium, hafnium, and combinations thereof.

[00160] 16. A sorbent as described in claim 15, wherein the metal is zirconium.

[00161] 17. A sorbent as described in any one of claims 10 to 16 wherein said anion exchange particles are adjusted to a pH in the range of 7 to 14, preferably 12 to 13.

[00162] 18. A sorbent as described in any one of claims 10 to 17 wherein said anion exchange particles are saturated with a base.

[00163] 19. A sorbent as described in claim 18, wherein the base is selected from the group consisting of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, magnesium hydroxide; calcium hydroxide, ammonium carbonate, and ammonium hydroxide.

[00164] 20. A sorbent as described in claim 19, wherein the base is sodium hydroxide.

[00165] 21. A sorbent as described in any one of claims 10 to 20, wherein said anion exchange particles comprise a water-insoluble, amorphous, partially hydrated metal oxide in its hydroxide, carbonate, acetate, and/or lactate counterion form, wherein the metal may be selected from the group consisting of titanium, zirconium, hafnium, and combinations thereof.

[00166] 22. A sorbent as described in claim 21, wherein the anion exchange particles are zirconium oxide particles.

[00167] 23. A sorbent as described in claim 22, wherein the anion exchange particles are hydrated zirconium oxide particles.

[00168] 24. A sorbent as described in any one of claims 10 to 23, wherein said anion exchange particles have a particle size in the range of 10 to 1000 microns, preferably 25 to 150 microns, more preferably 50 to 100 microns.

[00169] 25. A sorbent as described in any one of claims 10 to 24 wherein the ratio of cation exchange particle to anion exchange particle is in the range of 1:1 to 5:1.

[00170] 26. A sorbent as described in claim 25, wherein the ratio of cation exchange particle to anion exchange particle is in the range of 2:1 to 3:1.

[00171] 27. A sorbent as described in claim 26, wherein the ratio of cation exchange particle to anion exchange particle is about 2.4:1.

[00172] 28. A sorbent as described in any one of claims 10 to 26, wherein said uremic toxin treating enzyme particles comprise a urease.

[00173] 29. A sorbent as described in any one of claims 10 to 28, wherein said uremic toxin treating enzyme particles have an average particle size in the range of 10 microns to 1000 microns.

[00174] 30. A sorbent as described in any one of claims 10 to 29 further comprises absorbent particles of organic compounds.

[00175] 31. A sorbent as described in claim 30, wherein said organic compound absorbent particles are activated carbon particles.

[00176] 32. A sorbent as described in claim 31, wherein said activated carbon particles have an average particle size in the range of 10 microns to 1000 microns.

[00177] 33. A sorbent as described in any one of claims 10 to 32, further comprising a carbonic anhydrase.

[00178] 34. A sorbent for removing metabolic waste products from a dialysis fluid, the sorbent comprising a homogeneous mixture of: (a) uremic toxin treating enzyme particles comprising a uremic toxin treating enzyme immobilized on a solid support; (b) cation exchange particles configured to exchange ammonium ions for predominantly hydrogen ions and to exchange essential cations for predominantly sodium ions; and (c) anion exchange particles, and further comprising a soluble source of sodium ions.

[00179] 35. A sorbent as described in claim 34, wherein the soluble source of sodium ions is a soluble salt.

[00180] 36. A sorbent as described in claim 35, wherein the soluble salt is a basic salt.

[00181] 37. A sorbent as described in claim 36, wherein the soluble salt is selected from one or more of the group consisting of sodium carbonate, sodium bicarbonate, and sodium hydroxide.

[00182] 38. A sorbent as described in claim 37, wherein the soluble salt is sodium bicarbonate.

[00183] 39. A sorbent as described in claim 38, wherein the soluble salt is a neutral salt.

[00184] 40. A sorbent as described in claim 39, wherein the sodium salt is sodium chloride.

[00185] 41. A sorbent as described in claim 40, wherein the soluble salt is a salt of a weak acid.

[00186] 42. A sorbent as described in claim 41, wherein the soluble salt is sodium lactate or sodium acetate.

[00187] 43. A sorbent as described in any one of claims 34 to 42, wherein said cation exchange particles are adjusted to a pH in the range of 3.5 to 5.0.

[00188] 44. A sorbent as described in claim 43, wherein said cation exchange particles are adjusted to a pH of about 4.5.

[00189] 45. A sorbent as described in any one of claims 34 to 44 wherein said cation exchange particles have a particle size in the range of 10 to 1000 microns, preferably 25 to 150 microns, more preferably 50 to 100 microns.

[00190] 46. A sorbent as described in any one of claims 34 to 45, wherein said cation exchange particles comprise an amorphous, water-insoluble metal phosphate in partially protonated form.

[00191] 47. A sorbent as described in claim 46, wherein the metal is selected from the group consisting of titanium, zirconium, hafnium, and combinations thereof.

[00192] 48. A sorbent as described in claim 47, wherein the metal is zirconium.

[00193] 49. A sorbent as described in any one of claims 34 to 48, wherein said anion exchange particles are adjusted to a pH in the range of 7 to 14, preferably 12 to 13.

[00194] 50. A sorbent as described in any one of claims 34 to 49, wherein said anion exchange particles are saturated with a base.

[00195] 51. A sorbent as described in claim 50, wherein the base is selected from the group consisting of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, magnesium hydroxide; calcium hydroxide, ammonium carbonate, and ammonium hydroxide.

[00196] 52. A sorbent as described in claim 51 wherein the base is sodium hydroxide.

[00197] 53. A sorbent as described in any one of claims 34 to 52, wherein said anion exchange particles comprise a water-insoluble, amorphous, partially hydrated metal oxide in its hydroxide, carbonate, acetate, and/or lactate counterion form, wherein the metal may be selected from the group consisting of titanium, zirconium, hafnium, and combinations thereof.

[00198] 54. A sorbent as described in claim 53, wherein the anion exchange particles are zirconium oxide particles.

[00199] 55. A sorbent as described in claim 54, wherein the anion exchange particles are hydrated zirconium oxide particles.

[00200] 56. A sorbent as described in any one of claims 34 to 55 wherein said anion exchange particles have a particle size in the range of 10 to 1000 microns, preferably 25 to 150 microns, more preferably 50 to 100 microns.

[00201] 57. A sorbent as described in any one of claims 34 to 56, wherein the ratio of cation exchange particle to anion exchange particle is in the range of 1:1 to 5:1.

[00202] 58. A sorbent as described in claim 57, wherein the ratio of cation exchange particle to anion exchange particle is in the range of 2:1 to 3:1.

[00203] 59. A sorbent as described in claim 58, wherein the ratio of cation exchange particle to anion exchange particle is about 2.4:1.

[00204] 60. A sorbent as described in any one of claims 34 to 59, wherein said uremic toxin treating enzyme particles comprise a urease.

[00205] 61. A sorbent as described in any one of claims 34 to 60, wherein said uremic toxin treating enzyme particles have an average particle size in the range of 10 microns to 1000 microns.

[00206] 62. A sorbent as described in any one of claims 34 to 60 further comprises absorbent particles of organic compounds.

[00207] 63. A sorbent as described in claim 62, wherein said organic compound absorbent particles are activated carbon particles.

[00208] 64. A sorbent as described in claim 63, wherein said activated carbon particles have an average particle size in the range of 10 microns to 1000 microns.

[00209] 65. A sorbent as described in any one of claims 34 to 64, further comprising a carbonic anhydrase.

[00210] 66. A process for preparing a sorbent comprising mixing a soluble source of sodium ions and at least one of: (a) uremic toxin treating enzyme particles comprising a uremic toxin treating enzyme immobilized on a solid support; b) cation exchange particles configured to exchange ammonium ions for predominantly hydrogen ions and to exchange essential cations for sodium ions; (c) anion exchange particles; and (d) particles absorbing organic compounds and containing the mixture.

[00211] 67. A sorbent that hydrolyzes urea to ammonium and bicarbonate, and binds predominantly to ammonium in exchange for protons.

[00212] 68. A sorbent that binds predominantly essential cations in exchange for sodium ions.

[00213] 69. A sorbent that (a) hydrolyzes urea to ammonium and bicarbonate, and (b) binds predominantly ammonium in exchange for protons and binds predominantly essential cations in exchange for sodium ions.

[00214] 70. A sorbent cartridge comprising a sorbent as described in any one of claims 1 to 69 contained within a cartridge.

[00215] 71. A dialysis system for treating and recycling dialysate, the system comprising a sorbent cartridge as described in any one of claims 1 to 69 that releases a predicted amount of sodium after ion exchange in the sorbent, a conduit for transporting spent dialysate from a source of spent dialysate to the sorbent cartridge, a conduit for transporting regenerated dialysate from the sorbent cartridge to the source of spent dialysate, and an infusion system for dosing an infusion solution comprising essential cations to the regenerated dialysate such that the solution combines with the predicted release of sodium ions from the sorbent cartridge to generate a predetermined dialysate sodium concentration.

[00216] 72. A dialysis system as described in claim 71, wherein the essential cations are divalent cations and/or potassium ions.

[00217] 73. A dialysis system as described in claim 72, wherein the divalent cations are calcium and/or magnesium ions.

[00218] 74. A dialysis system as described in any one of statements 71 to 73, adapted to maintain a constant sodium ion concentration in the dialysate.

[00219] 75. A dialysis system as described in claim 74 has been adapted to produce a sodium ion concentration of 132 mEq/L to 145 mEq/L.

[00220] 76. A dialysis system as described in any one of claims 71 to 73, adapted to reduce the sodium ion content in regenerated dialysate.

[00221] 77. A dialysis system as described in any one of claims 71 to 76, further comprising a source of an osmotic agent for addition to the regenerated dialysate.

[00222] 78. A dialysis system as described in any one of claims 71 to 77, further comprising a source of salts other than calcium, magnesium and potassium salts for addition to the regenerated dialysate.

[00223] 79. A dialysis system as described in claims 78, wherein the salt other than a calcium, magnesium and potassium salt is sodium chloride.

[00224] 80. A dialysis system as described in any one of claims 71 to 79, wherein the pH of the regenerated dialysate is maintained within a range of 6 to 8.

[00225] 81. A process for regenerating dialysate in a dialysis process, comprising repeating the steps of: (a) transporting spent dialysate from a source of spent dialysate to a sorbent that (a) hydrolyzes urea to ammonium and bicarbonate, and (b) binds predominantly to ammonium in exchange for protons and binds predominantly to essential cations in exchange for sodium ions, to produce regenerated dialysate; (b) introducing essential cations into the regenerated dialysate to reconstitute the dialysate; and (c) transporting reconstituted dialysate from the sorbent to the source of spent dialysate; characterized in that a predetermined concentration of sodium ions is generated after ion exchange in the sorbent.

[00226] 82. A process as described in claim 81 wherein the sorbent is a sorbent as described in any one of claims 1 to 65 or 69.

[00227] 83. A sorbent that (a) hydrolyzes urea to ammonium and bicarbonate, and (b) binds predominantly ammonium in exchange for protons and binds predominantly cations in exchange for sodium ions to produce regenerated dialysate for use in dialysate regeneration in the dialysis process.

[00228] 84. A kit comprising a sorbent as described in any one of claims 1 to 33, 34 or 38 and an infusion agent comprising salts of essential ions.

[00229] 85. A sorbent as described in either of claims 4 or 37, wherein the soluble salt is sodium carbonate.

[00230] 86. A sorbent as described in any one of claims 1 to 9, wherein the soluble sodium salt comprises a separate layer or compartment in the sorbent.

[00231] 87. A sorbent described in either of claims 33 or 65, wherein the carbonic anhydrase is immobilized by chemical or physical binding to a solid support, or immobilized by cross-linking or encapsulation.

[00232] 88. A dialysis system as described in claim 74 has been adapted to produce a sodium ion concentration of 120 mEq/L to 150 mEq/L.

[00233] 89. A dialysis system as described in claim 71 wherein the concentration of cation equivalents in the infusion solution is approximately equal to a predetermined dialysate sodium ion concentration such that ion exchange in the sorbent, followed by addition of the infusion solution, provides a target dialysate sodium concentration.

[00234] 90. A process as described in claim 81 wherein the essential cations are introduced as an infusion solution and the concentration of cation equivalents in the infusion solution is approximately equal to a predetermined dialysate sodium ion concentration such that ion exchange in the sorbent followed by addition of the infusion solution provides a target dialysate sodium concentration.

[00235] 91. The kit of claim 84, wherein the infusion agent is in the form of an infusion solution, wherein the concentration of essential cations is approximately equal to a target sodium ion concentration, or the kit includes instructions for preparing an infusion solution, wherein the concentration of essential cations is approximately equal to a target sodium ion concentration.

Claims (28)

1. A sorbent for removing metabolic waste products from a dialysis fluid, the sorbent comprising a homogeneous mixture of: (a) uremic toxin treating enzyme particles comprising a uremic toxin treating enzyme immobilized on a solid support; (b) cation exchange particles configured to exchange ammonium ions for predominantly hydrogen ions and to exchange essential cations for predominantly sodium ions; and (c) anion exchange particles, and further comprising a soluble source of sodium ions, wherein the cation exchange particles are adjusted to a pH range of 3.5 to 5.0. 2. Sorbent according to claim 1, characterized in that the soluble source of sodium ions is a soluble salt. 3. Sorbent according to claim 2, characterized in that the soluble salt is a basic salt. 4. Sorbent according to claim 3, characterized in that the soluble salt is selected from one or more of the group consisting of sodium carbonate, sodium bicarbonate and sodium hydroxide. 5. Sorbent according to claim 4, characterized in that the soluble salt is sodium bicarbonate. 6. Sorbent according to claim 2, characterized in that the soluble salt is a neutral salt or a salt of a weak acid. 7. Sorbent according to any one of claims 1 to 6, characterized in that it comprises particles of the soluble source of sodium ions. 8. Sorbent according to any one of claims 1 to 7, characterized in that said cation exchange particles are adjusted to a pH in the range of 4.5. 9. Sorbent according to any one of claims 1 to 8, characterized in that said cation exchange particles comprise a water-insoluble amorphous metal phosphate in protonated form. 10. Sorbent according to claim 9, characterized in that the metal is selected from the group consisting of titanium, zirconium, hafnium and combinations thereof. 11. Sorbent according to claim 10, characterized in that the metal is zirconium. 12. Sorbent according to any one of claims 1 to 11, characterized in that said anion exchange particles are adjusted to a pH in the range of 7 to 14, preferably 12 to 13. 13. Sorbent according to any one of claims 1 to 12, characterized in that said anion exchange particles comprise a water-insoluble, amorphous and partially hydrated metal oxide in its hydroxide, carbonate, acetate and/or lactate counterion form, wherein the metal may be selected from the group consisting of titanium, zirconium, hafnium and combinations thereof. 14. Sorbent according to claim 13, characterized in that the anion exchange particles are hydrated zirconium oxide particles. 15. Sorbent according to any one of claims 1 to 14, characterized in that the ratio of cation exchange particle to anion exchange particle is in the range of 1:1 to 5:1, preferably in the range of 2:1 to 3:1, more preferably about 2.4:1. 16. The sorbent of any one of claims 1 to 15, wherein said uremic toxin treating enzyme particles comprise a urease. 17. Sorbent according to any one of claims 1 to 16, characterized in that it additionally comprises absorbent particles of organic compounds. 18. Sorbent according to any one of claims 1 to 17, characterized in that it additionally comprises a carbonic anhydrase. 19. A process for preparing the sorbent as defined in claim 1, the process comprising mixing particles of a soluble source of sodium ions and at least one of: (a) uremic toxin treating enzyme particles comprising a uremic toxin treating enzyme immobilized on a solid support; (b) cation exchange particles configured to exchange ammonium ions for predominantly hydrogen ions and to exchange essential cations for predominantly sodium ions; (c) anion exchange particles; wherein the cation exchange particles are adjusted to a pH range of 3.5 to 5.0, such as said cation exchange particles. 20. Absorbent cartridge, characterized by the fact that it comprises a sorbent as defined in any one of claims 1 to 18, contained inside a cartridge. 21. A dialysis system for treating and recycling dialysate, the system comprising a sorbent cartridge as described in claim 20 that releases a predicted amount of sodium after ion exchange in the sorbent, a conduit for transporting spent dialysate from a source of spent dialysate to the sorbent cartridge, a conduit for transporting regenerated dialysate from the sorbent cartridge to the source of spent dialysate, and an infusion system for dosing an infusion solution comprising essential cations to the regenerated dialysate such that the solution combines with the predicted release of sodium ions from the sorbent cartridge to generate a predetermined dialysate sodium concentration. 22. The dialysis system of claim 21, wherein: (a) the volume of infusion solution to the volume of dialysate has a volume:volume ratio of from 1:10 to 1:30, such as from 1:15 to 1:25, such as from 1:18 to 1:20; or (b) the volume of infusion solution to the volume of dialysate has a volume:volume ratio of approximately 1:20 or approximately 51:1000. 23. The dialysis system of claim 21, further comprising a source of salts other than calcium, magnesium and potassium salts for addition to the regenerated dialysate, typically sodium chloride. 24. Dialysis system according to either of claims 21 or 23, characterized in that the pH of the regenerated dialysate is maintained within a range of 6 to 8. 25. The dialysis system of claim 21, wherein the concentration of cation equivalents in the infusion solution is approximately equal to a predetermined concentration of sodium ions in the dialysate, such that ion exchange in the sorbent followed by addition of the infusion solution provides a concentration of sodium in the dialysate. 26. A process for regenerating dialysate in a dialysis process, comprising repeating the steps of: (a) transporting used dialysate from a source of used dialysate to a sorbent as described in any one of claims 1 to 18, to produce regenerated dialysate; (b) introducing essential cations into the regenerated dialysate to reconstitute the dialysate using an infusion solution to provide a target sodium concentration of dialysate, wherein the concentration of cation equivalents in the infusion solution is approximately equal to a target sodium ion concentration, wherein the cation equivalents comprise one or more of calcium, magnesium, sodium and potassium; and (c) transporting reconstituted dialysate from the sorbent to the source of used dialysate; characterized in that a predetermined concentration of sodium ions is generated after ion exchange in the sorbent. 27. A kit comprising a sorbent as defined in any one of claims 1 to 18 or a sorbent cartridge as defined in claim 20 and an infusion agent comprising salts of essential ions. 28. The kit of claim 27, wherein the infusion agent is in the form of an infusion solution in which the concentration of essential cations is approximately equal to a sodium ion concentration or the kit includes instructions for preparing an infusion solution in which the concentration of essential cations is approximately equal to a target sodium ion concentration.