Dialysis system incorporating a toxin removal loop

Abstract

The protected fluid circuit can utilize an osmotic membrane or other membrane type that is highly selective for urea transport. The membrane can achieve sufficient diffusion flux of urea in a forward osmosis structure. When combined with an oxidation unit, this protected structure can have a high selective flux of urea from the spent dialysate side to the urea removal side, balance of patient fluid (water) levels with forward osmosis flow by controlling the water evaporation rate through the vapor permeable membrane, protection of the patient dialysate / blood loop from oxidation by-products, and the ability to optimize oxidation system performance (pH, ionic strength, other electrolytes, etc.) that would be incompatible with blood contact.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 171,503, filed April 6, 2021, the entire contents of which are expressly incorporated by reference herein. [Background technology]

[0002] End-stage kidney disease (ESKD) forces approximately 4 million people worldwide to undergo dialysis to maintain their life, and this number is expected to continue to increase. Dialysis treatment is a physical and economic burden for patients, their families, and society. Moreover, traditional hemodialysis is considered suboptimal in terms of rehabilitation, quality of life, and mortality and morbidity rates.

[0003] Longer term, more frequent dialysis has shown potential improvements in health-related outcomes compared to traditional three times weekly institutional dialysis therapy. However, a significant challenge to home dialysis treatment is the continuous dialysate supply that allows portability. Currently, approximately 120 L (approximately 120 Kg) of fresh dialysate is used per session, which is impossible to carry in a portable system. Portability could potentially be achieved by having a dialysis system in which the spent dialysate is continuously regenerated. Modes of urea removal that have been attempted for dialysate regeneration include, but are not limited to, urease-based enzymes, sorbent-based, and oxidation-based elements.

[0004] Uremic toxins removed by dialysis include urea, Na+, K+, phenylacetic acid, creatinine, uric acid, phenylacetylglutamine, phosphorus, hippuric acid, oxalic acid, dimethylamine, p-cresyl sulfate, β2-microglobulin, phenylsulfate, indican, p-cresyl glucuronide, 3-hydroxyphenylacetic acid, trimethylamine-N-oxide, 4-hydroxyhippuric acid, indoxyl sulfate, 3-hydroxyhippuric acid, Ca 2+These include, but are not limited to, complement factor D, acrolein, guanidinosuccinic acid, indole-3-acetic acid, cystatin C, methylguanidine, symmetric dimethylarginine, and guanidinoacetic acid. Of these, urea is the single most abundant small molecule metabolic waste product that needs to be removed during dialysis, either in a single-pass system or with regenerated dialysate.

[0005] At a combined mass greater than 23.0 g, these uremic toxins interfere with the urea removal element of the dialysis circuit, regardless of the type of urea removal element selected.

[0006] Also, the large amount of nutrients that coexist with urea in the spent dialysate will hinder urea removal efficiency if there is not sufficient chemical selectivity in the membrane, sorbent, or conversion system. The inevitable loss of nutrients during conventional single-pass HD is a secondary effect of uremic toxin removal and is an important component of dialysis-related catabolism. Nutrient losses include, but are not limited to, albumin, amino acids, globulins, glucose, cholesterol, bilirubin, and transferrin. These lost solutes generally participate in antioxidant, anti-inflammatory, toxin removal, and vasodilatory functions at reduced concentrations, contributing to additional adverse effects on uremic treatment. If a dialysis regeneration system were developed that does not selectively remove the amino acid glucose and functional proteins, HD nutritional losses would be effectively eliminated.

[0007] Another important consideration is the purity of the dialysate water source. The large volume of traditional dialysate (approximately 120 L) poses significant hurdles to portability, especially with stringent requirements for water quality followed by electrolyte balance. This cost can be significantly reduced by switching to a dialysate regeneration system.

[0008] FIG. 1 shows a WAK dialysis circuit that includes a dialysate loop 104 separated from a patient's blood circuit 102 by a dialysis membrane 110. The blood circuit 102 recirculates the patient's blood. The dialysate loop 104 recirculates the dialysate fluid. Toxins from the patient's blood are transferred to the dialysate through the membrane 110. The dialysate then proceeds through a urea removal cartridge 114. After the dialysate flows through the bottom four layers of the cartridge to remove urea / ammonia / salts, the top layer of activated charcoal is generally sufficient to remove other uremic toxins before passing again through the membrane 110 for reuse. It is also important to note that the activated charcoal is largely inert to both urea and glucose, allowing the glucose to remain in the dialysate loop.

[0009] Despite significant innovations in the design of devices and modes of operation, urease, sorbents, and oxidation methods for regenerating dialysate remain challenges. Summary of the Invention

[0010] This Summary is provided to introduce a selection of concepts in a simplified form that are further described below in the Detailed Description. This Summary is not intended to identify key features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter.

[0011] In one embodiment, the liquid dialysis circuit includes a dialysate loop 204 separated from the patient's blood circuit 202 by a dialysis membrane 210 and a toxin removal loop 206 separated by a toxin-selective membrane 212 configured to selectively pass toxins from the dialysate loop 204 to the toxin removal loop 206.

[0012] In one embodiment, the toxin is a uremic toxin.

[0013] In one embodiment, the toxin-selective membrane 212 is a permeable membrane.

[0014] In one embodiment, the toxin-selective membrane 212 is configured to operate as a forward osmosis membrane.

[0015] In one embodiment, the toxin-selective membrane 212 is configured to operate as a reverse osmosis membrane.

[0016] In one embodiment, the toxin-selective membrane 212 operates based on the mechanisms of ion exchange (to pursue negatively charged toxins), affinity binding, ultrafiltration, reverse osmosis, or forward osmosis.

[0017] In one embodiment, the toxin removal loop 206 includes a non-biocompatible liquid.

[0018] In one embodiment, the dialysate loop 204 includes a liquid filter 214 configured to remove uremic toxins from the dialysate flowing through the dialysate loop 204 .

[0019] In one embodiment, the toxin removal loop 206 includes a liquid filter 216 configured to remove uremic toxins or oxidation products from the toxin removal liquid flowing through the toxin removal loop 206 .

[0020] In one embodiment, the toxin removal loop 206 comprises a toxin removal element 218 in fluid contact with the toxin removal fluid flowing through the toxin removal loop 206 .

[0021] In one embodiment, the toxin removal element 218 is selected from a photo-oxidation element, an electro-oxidation element, and combinations thereof.

[0022] In one embodiment, the toxin removal element 218 is selected from enzyme (urease) based, bacteria based (bioreactor), sorbent based, oxidation based, and combinations thereof.

[0023] In one embodiment, the toxin removal element 218 includes a photooxidation element.

[0024] In one embodiment, the liquid dialysis circuit is capable of filtering at least 0.625 g / hr of toxins from the dialysate loop.

[0025] In one embodiment, the liquid dialysis circuit is capable of removing between 0.5 L and 4.0 L of water from the dialysate loop 204 in a 24 hour period.

[0026] In one embodiment, the fluid dialysis circuit is configured to controllably remove water from the dialysate loop 204 via a photooxidation element 218 in the toxin removal loop 206 .

[0027] In one embodiment, the dialysate loop 204 contains dialysate that is configured to receive uremic blood toxins from the patient's blood across the dialysis membrane 210 .

[0028] In one embodiment, the dialysate loop 204 is configured to receive spent ascites fluid.

[0029] In one embodiment, the toxin-selective membrane comprises a hollow fiber membrane.

[0030] In one embodiment, the toxin-selective membrane is at least 2.4 mm 2 of surface area for mass transfer.

[0031] In one embodiment, the toxin removal loop flows inside the hollow fiber membrane and the dialysate loop flows on the outside of the hollow fiber membrane.

[0032] In one embodiment, the flow of the toxin removal loop is at least 36 mL / min.

[0033] In one embodiment, the flow of the dialysate loop is at least 3.7 times the flow of the toxin removal loop.

[0034] In one embodiment, a kidney dialysis system comprises a liquid dialysis circuit as described in any of the preceding embodiments.

[0035] In one embodiment, the kidney dialysis system is a hemodialysis system, a peritoneal dialysis system, a hemofiltration system, or a hemodiafiltration system.

[0036] In one embodiment, the kidney dialysis system has a form factor selected from the group consisting of portable, wearable, mobile, and stationary.

[0037] In one embodiment, the kidney dialysis system is configured for use in a home or dialysis center.

[0038] In one embodiment, the method of treating a patient having toxic blood comprises: a. flowing a toxic fluid from a patient through a fluid dialysis circuit according to any of the preceding embodiments, the toxic fluid flowing along the dialysis membrane and allowing uremic toxins to pass into the dialysate loop to produce a toxic dialysate; b. flowing the toxic dialysate along a toxin-selective membrane in the dialysate loop to produce a detoxified dialysate in the dialysate loop and a toxic fluid containing electrolytes in the toxin removal loop, the detoxified dialysate being returned toward the dialysis membrane; c. in the toxin removal loop, flowing the toxic fluid containing electrolytes through the toxin removal element to produce a detoxified fluid containing electrolytes, the detoxified fluid containing electrolytes being flowed back towards the toxin-selective membrane.

[0039] In one embodiment, the toxic fluid is blood or peritoneal dialysis fluid.

[0040] In one embodiment, the method further comprises the step of adding electrolyte to a fluid containing electrolyte.

[0041] In one embodiment, the method of regenerating dialysate comprises: a. flowing a toxic dialysate along a toxin-selective membrane to produce a detoxified dialysate in the dialysate loop and a toxic fluid containing electrolytes in the toxin removal loop; b. in the toxin removal loop, flowing the toxic fluid containing electrolytes through a toxin removal element to produce a detoxified fluid containing electrolytes, the detoxified fluid containing electrolytes being flowed back towards the toxin-selective membrane.

[0042] In one embodiment, the fluid dialysis circuit comprises: a dialysate loop; a toxin removal loop separated by a toxin selective membrane configured to selectively pass toxins from the dialysate loop to the toxin removal loop.

[0043] In one embodiment, the toxin-selective membrane comprises a hollow fiber membrane.

[0044] In one embodiment, the toxin-selective membrane is at least 2.4 mm 2 of surface area for mass transfer.

[0045] In one embodiment, the toxin removal loop flows inside the hollow fiber membrane and the dialysate loop flows on the outside of the hollow fiber membrane.

[0046] In one embodiment, the flow of the toxin removal loop is at least 36 mL / min.

[0047] In one embodiment, the flow of the dialysate loop is at least 3.7 times the flow of the toxin removal loop.

[0048] In one embodiment, the dialysate loop contains a uremic toxin.

[0049] In one aspect, a liquid dialysis circuit is provided that includes a dialysate loop separated from a patient's blood circuit by a dialysis membrane and a toxin removal loop separated by a toxin-selective membrane configured to selectively pass toxins from the dialysate loop to the toxin removal loop.

[0050] In another aspect, a renal dialysis system is provided that includes a liquid dialysis circuit as disclosed herein.

[0051] In yet another aspect, a method of treating a patient having toxic blood, comprising: a. flowing toxic fluid from a patient through a fluid dialysis circuit as disclosed herein, the toxic fluid flowing along a dialysis membrane and allowing uremic toxins to pass into the dialysate loop to produce toxic dialysate; b. flowing the toxic dialysate along a toxin-selective membrane in the dialysate loop to produce a detoxified dialysate in the dialysate loop and a toxic electrolyte in the toxin removal loop, the detoxified dialysate being returned toward the dialysis membrane; c. flowing the toxic electrolyte through a toxin removal element in a toxin removal loop to produce detoxified electrolyte, the detoxified electrolyte being returned towards a toxin-selective membrane.

[0052] Portable dialysis devices offer the possibility of long-term treatment and much smoother serum composition changes over time that mimic physiological conditions. The patient's quality of life is also dramatically improved compared to 3 times weekly 4-hour treatments. The challenge for portable dialysis devices is to regenerate the limited amount of dialysate so that it can be used continuously for further removal of blood toxins. Urea removal can be achieved with urease, which hydrolyzes urea to ammonium and bicarbonate, which need to be removed with additional ion exchange materials. Adsorbents with a binding capacity of tens of mg / g for urea can also be used to remove urea and simplify the electrolyte balance process. Oxidation-based urea removal has the ability to run continuously.

[0053] Despite all of their potential advantages in urea removal, the urease, adsorbent and oxidation guarantees cannot be fully optimized as long as urea and other serum molecules coexist in the same circuit. In particular, the presence of an excess of small and medium MW molecules reduces the efficiency of the enzymes and adsorbents through competition. Existing membrane technologies such as RO membranes can be utilized to achieve selective separation of urea into a urea-only capture loop. [Brief description of the drawings]

[0054] The foregoing aspects and many of the attendant advantages of this invention will become more readily appreciated as the same become better understood by reference to the following detailed description when taken in conjunction with the accompanying drawings, in which:

[0055] [Figure 1] FIG. 1 is a schematic illustration of a conventional wearable artificial kidney dialysis system. [Diagram 2] FIG. 1 is a schematic, illustrative diagram of a dialysis system including a toxin removal loop, according to one embodiment. [Diagram 3] FIG. 1 is a schematic illustration of a device including a hollow fiber membrane. [Figure 4A] FIG. 1 is a schematic illustration of a urease-based toxin removal element. [Figure 4B] FIG. 1 is a schematic illustration of a sorbent-based toxin removal element. [Figure 4C] FIG. 1 is a schematic illustration of a photooxidation-based toxin removal element. [Diagram 5] FIG. 1 shows the molecular weight cut-offs of different membrane classes with examples of species tolerated in each regime. [Figure 6A] FIG. 1 is a schematic illustration of urea photooxidation by the POUR (Photooxidation Urea Removal) device using 10 mM urea dissolved in either 0.15 M NaCl or spent dialysate collected from the clinic, as used in the examples. [Figure 6B] FIG. 1 is a schematic illustration of a combined FO-POUR (forward osmosis photooxidation urea removal) setup used in the examples. [Figure 7] 1 is a graphical representation of urea removal rate and corresponding mass transfer coefficient in 24 hours using a commercially available AQUAPORIN® FO cartridge at different inner fiber flow rates from the Examples, where the outer flow rate for 10 mM urea dialysate delivery is 3.7 times the inner fiber flow rate. [Figure 8A] 1 is a bar graph representation of cytotoxicity measured by MTT assay (untreated 3T3 cells and latex control samples with different dilution factors) from the Examples. [Figure 8B] 1 is a bar graph representation of cytotoxicity measured by MTT assay (t=0 time samples and POUR from untreated 3T3 cells and spent dialysate either neat or treated with activated charcoal) from the examples. [Figure 8C] 1 is a bar graph representation of cytotoxicity measured by MTT assay (untreated 3T3 cells, and t=24 hour samples collected from standalone spent dialysate separated from the FO-POUR device, and t=24 hour samples collected from spent dialysate, and POUR collected in the FO-POUR device) from the examples. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0056] Portable and wearable hemodialysis has the potential to improve health outcomes and quality of life for patients with renal failure at low cost. Removal of urea, necessary for dialysate regeneration, is a central function of any existing / potential portable dialysis device. Urea in the spent dialysate coexists with non-urea uremic toxins, nutrients, and electrolytes, all of which impede urea removal efficiency, whether the underlying urea removal mechanism is based on urease conversion, direct adsorption of urea, or oxidation. The present disclosure describes a toxin removal loop separated from the dialysate loop by a toxin-selective membrane. The toxin removal loop additionally includes at least one toxin removal element, the performance of which can be improved and advantageously enable dialysate regeneration.

[0057] Referring to FIG. 2, one embodiment of a liquid dialysis circuit is illustrated, which includes a dialysate loop 204 separated from a patient's blood circuit 202 by a dialysis membrane 210. The liquid dialysis circuit includes a toxin removal loop 206 separated by a toxin-selective membrane 212 configured to selectively pass toxins from the dialysate loop 204 to the toxin removal loop 206. The liquid dialysis circuit includes a toxin removal element 218. The dialysate in the loop 204 can be any commercially available or conventional dialysate currently in use. The fluid in the loop 206 can include, for example, saline, an aqueous solution mixed with non-NaCl electrolytes, an aqueous solution of acidic or basic pH value. The toxin removal loop 206 can protect the toxin removal element 218 by using a toxin-selective membrane 212 in contact with the dialysate. For example, the urea removal element described herein can benefit from a urea-selective membrane 212 separating the dialysate loop 204 and the toxin removal loop 206. In one embodiment, the toxins removed are uremic toxins. In one embodiment, the toxin removed is urea.

[0058] As used herein, a "loop" or "circuit" refers to one or more conduits that carry fluids through one or more devices. The blood flow in the blood circuit 202 may be single pass, meaning that fresh or new blood is continuously pumped into the blood circuit 202. The dialysate and fluid flow in the loops 204 and 206 is designed to be multi-pass, meaning that the fluids are regenerated and can be used for extended periods of time. The flow in the loops 204, 206 can be continuous or semi-continuous, such that the fluids are repeatedly circulated through the various devices in the conduits and loops. The flow can be created by a pump, such as a peristaltic pump. Chemical species and / or fluids can be transferred between the dialysate loop 204 and the blood circuit 202, and between the dialysate loop 204 and the toxin removal loop 206 through membranes 210 and 212, respectively. External fluids and / or nutrients may also be introduced into the loops 204, 206 and circuit 202, and fluids within the loops 204, 206 and circuit 202 may also be removed continuously or semi-continuously. In one embodiment, the loops may have a constant flow rate through the loops. In one embodiment, the flow in the loop may increase or decrease over time.

[0059] Using urea as an example, the toxin removal loop 206 is separated by a urea selective membrane 212 configured to selectively pass urea from the dialysate loop 206 to the toxin removal loop 206. In this case, the dialysate loop 204 of FIG. 2 includes a cartridge 214 that includes a similar amount of activated charcoal sorbent (bottom layer) to adsorb non-urea toxins and potentially add other selective sorbents (top layer) as needed or developed. Activated charcoal is a typical filter material, although any other compatible filter or method may be used.

[0060] In the liquid dialysis circuit shown in FIG. 2, urea from the dialysate loop 204 is removed across the urea-selective membrane 212 along with other unavoidable compounds. The urea is then removed from the urea loop 212 by any of the urea removal elements, where the urea removal element 219 can include a photo-oxidation urea removal element (POUR). When using a POUR as the urea removal element 218, it is also advantageous to include an additional activated carbon filter 216 in the toxin removal loop 206 to remove oxo-chloro species that may be by-products during urea oxidation. Although urea is used as a representative toxin, it is understood that other uremic toxins can be removed from the dialysate loop 204 to the toxin removal loop 206 by selecting the appropriate toxin-selective membrane 212. Furthermore, more than one toxin can be removed, including two or more toxin removal loops, each with a different toxin-selective membrane. Alternatively, two or more different toxin-selective membranes can be used at the interface between the dialysate loop 204 and the toxin removal loop 206. The toxin removal element 218 can be enzyme (urease) based, bacteria based (bioreactor), sorbent based, and oxidation based. Figure 2 shows one embodiment of a photooxidation urea removal element.

[0061] In the present disclosure, the dialysis system of Figure 2 may be compared to the conventional WAK system of Figure 1. However, the use of the toxin removal loop 206 and toxin-selective membrane 212 described with respect to Figure 2 may be applied to other dialysis systems, such as hemodialysis systems, peritoneal dialysis systems, hemofiltration systems, or hemodiafiltration systems. Additionally, the kidney dialysis system of the present disclosure may be configured to have a form factor selected from the group of portable, wearable, mobile, and fixed systems, and the kidney dialysis system may be configured for use in the home or in a dialysis center.

[0062] Urea removal element The present disclosure aims to improve upon the operation of currently available urea removal elements by including an additional toxin removal loop 206 separated from the dialysate loop 204 by a toxin-selective membrane 212. The toxin-selective membrane 212 can selectively allow urea to pass through the toxin removal loop 206 while blocking other compounds, thereby improving the operation of the toxin removal element 218.

[0063] In one embodiment, the toxin removal element 218 can be selected from a photo-oxidation element or an electro-oxidation element. In one embodiment, the toxin removal element 218 can be selected from enzyme (urease) based, bacteria based (bioreactor), sorbent based, oxidation based, and combinations thereof. In one embodiment, the toxin removal element 218 is a photo-oxidation element.

[0064] Urea has been removed by enzymes, adsorbents, anodic oxidation, bacterial degradation, polymer membrane capsules, electrodialysis, and reverse osmosis. Methods of urea removal that have been developed in the context of portable dialysis devices that regenerate dialysate can be divided into three categories: urease conversion followed by ion exchange (Figure 4A), direct adsorption (Figure 4B), and oxidation (Figure 4C).

[0065] Urease-based urea removal Dialysis treatments can be performed in dialysis machines that use the urease enzyme as a urea removal method, such as the conventional REDY® (regenerative dialysis) system. The process begins with urease, which catalyzes the hydrolysis of urea and converts it to ammonium and bicarbonate, which are easily adsorbed by some cartridge elements. The capture of ammonium is beneficial because ammonium is toxic at low concentrations of about 100 μM in the bloodstream. Urease can be immobilized on a support and retain its activity as a robust enzyme. Immobilized urea has been found to be less sensitive to pH changes and maintain its activity over longer periods of time. Urease immobilization has been performed on many different types of scaffolds. Chemical immobilization is generally preferred over physical adsorption due to the greater stability of the immobilization. However, as a result of the mild reaction conditions of urease immobilization, even chemical bonds such as amine epoxy cure, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC), N-cyclohexyl-N′-(b-[N-methylmorpholino]ethyl)carbodiimide p-toluenesulfonic acid (CMC), and glutaraldehyde (GA) are reversible and subject to attack from the amine groups.

[0066] 4A, the urease removal element for use as the toxin removal element 218 of FIG. 2 may be provided as a cartridge 400. Cartridge 400 may include a first layer 402 that functions as a "scavenger layer" that removes non-urea uremic toxins to some extent, but has the primary purpose of protecting the urease from species that may inactivate or desorb it. Following the scavenger or first layer 402, cartridge 400 includes a urease layer 404. Immediately following the urease layer 404, cartridge 400 contains its pre-loaded Na + and H + Using the urease layer 404, NH4 + , and K + , Ca 2+ , and Mg 2The cartridge 400 may include a zirconium phosphate layer 406 that exchanges with other cations, including ammonium, phosphate, and other anions ...

[0067] Adsorbent-based urea removal Referring to FIG. 4B, another embodiment of the toxin removal element 218 is a high capacity urea sorbent cartridge 420. The cartridge 420 can include a first layer of activated carbon 422 and a second layer of one or more sorbents 424. The sorbents remove urea based on reaction with electrophilic carbonyl groups such as aldehydes or molecular size selection using materials such as activated carbon, zeolites and MXene. A wide range of urea binding capacities are possible, including up to 0.35 g / g. However, when applied to media close to serum or spent dialysate, the urea binding capacity can drop to less than 1 mg / g. For example, activated carbon is effective in removing uremic toxins such as creatinine, uric acid, indicants, phenols, guanidines, and organic acids. The pores of charcoal-derived mesoporous carbon can be tailored to precisely match pores to inflammatory compounds. For urea, there is significant adsorption (>5 mg / g) outside physiological serum conditions. The adsorption capacity of activated carbon around physiological urea concentration (10 mM urea) is approximately 1 mg / g.

[0068] A decrease in urea binding capacity may occur with other sorbents when applied in spent dialysis fluid. ×MXene can adsorb urea at an equilibrium concentration of 25 mM with a capacity of about 16 mg / g at 37°C. In contrast, when exposed to dialysate from a patient, MXene lost more than 96% of its binding capacity, showing only a capacity of about 0.5 mg / g under similar conditions. Similarly, oxidized starch was found to adsorb urea at a capacity of up to 8 mg / g at 37°C under pH 7.4 via aldehyde groups that also adsorb other amine group-containing molecules. A polymeric adsorbent based on phenylglyoxyaldehyde (PGA) modification on surface polystyrene beads demonstrated a urea binding capacity of more than 36 mg / g at 37°C with 30 mM urea in phosphate buffered saline. The binding mechanism of PGA for urea is based on its interaction with amino groups. Another adsorbent can include zeolite, which has an impressive urea binding capacity of about 30 mg / g at 37°C in a solution with 8.6 mM starting urea and a pH of 5.4.

[0069] The sorbent-based urea removal cartridge 420 has a simpler structure compared to the enzyme system. Various high-capacity urea sorbents have been developed that work under simple physiological conditions, i.e., 37° C., ionic strength of about 0.15 M, and pH of about 7.4. However, the coexistence of other components in the dialysis fluid, such as molecules with amine and carboxylic acid groups, may outweigh urea in the binding event.

[0070] Oxidation-Based Urea Removal Referring to FIG. 4C, another embodiment of the toxin removal element 218 is an oxidation-based element. The oxidation-based urea removal element may include an oxidation cell 430 and an activated carbon cartridge 432. The advantage of urea oxidation is that the electrodes have a virtually infinite storage capacity and potentially thousands of hours of operational life depending on the type of electrode used. The disadvantage of the electrochemical approach may be the oxidation of very common (about 150 mM NaCl) chloride to highly toxic chlorine. If a urea-selective electrode is developed and the operating parameters are optimized, only small amounts of scavengers are needed to reduce free Cl2 and total chlorine concentrations to safe levels that comply with FDA regulations for water quality used for dialysis.

[0071] Under certain conditions, when using platinum and other dimensionally stable anodes, urea can be oxidized to CO2 and N2, largely eliminating the need for adsorbents and ion exchange materials to remove the partial oxidation product NH3. However, Cl2 and oxo-chloro species can be by-products during urea oxidation that can often be effectively removed by activated carbon. The applied bias, current density, and pH all affect the efficiency and selectivity for urea oxidation. Ca on the cathode 2+ and Mg 2+ The problem of induced deposits can be eliminated by periodically switching the polarity of the anode and cathode.

[0072] Nickel oxyhydroxide (NiOOH) is one of the most urea-selective electrodes. Nickel oxyhydroxide has urea-active surface sites similar to the Ni(II) sites of urease, and ClOOH is the most selective electrode for urea. - It gives higher chemical selectivity for urea than Ni. However, optimal efficiency is at a pH above 10, which is not compatible with contact of the dialysate with blood. There is also fast Ni corrosion at physiological pH, reducing performance and potentially being toxic. Ni can be doped with other metals and have nanostructured synthesis for higher performance in urea oxidation.

[0073] TiO2 is a photooxidation catalyst capable of oxidizing a wide range of organics, including uremic toxins. Photoelectrochemical cells with TiO2 anodes and Pt / C cathodes have shown complete oxidation to CO2, H2O, and N2, as well as high selectivity (>90%) for urea over chlorides, reducing the need for scrubbing with activated carbon. Photooxidation Urea Removal (POUR) elements for urea removal can use hydrothermally prepared, randomly oriented, single-crystalline TiO2 nanowire meshes coated on fluorinated tin oxide (FTO) conductive substrates.

[0074] Any organic solute that can be oxidized directly on the anode or by the generated Cl2 can produce a wide variety of by-products. Amino acids and proteins are the primary targets for oxidation due to their abundance and higher rate constants for the reaction. Chlorination of amino acids can produce a variety of organic monochloramines or dichloramines depending on the ratio of chlorine to amino acid. Organic chloramines can be further decomposed into aldehydes, nitriles, and N-chloraldimines (chlorination of amino acids). For example, tryptophan has phenols and amino acids as reactive functional groups. At Cl:AA=0.8, N-monochlorotyrosine was formed. At Cl:AA=2.8, chlorine substitution on the aromatic ring was observed by NMR, and a mixture of N-monochloro-3-chlorotyrosine and N,N-dichlorotyrosine was formed in a ratio slightly lower than 1:1. Therefore, for oxidation strategies, it is beneficial to reduce the amount of chemical species to be processed in order to reduce the amount of oxidation by-products.

[0075] When selecting the toxin removal element 218 of FIG. 2, consideration of the specific application and advantages of each must be taken into account. Enzyme systems have high selectivity, but + They have capture complexity and stability issues. Adsorption systems are simple to create and operate but may have poor binding capacity at physiological conditions and may be impractical based on size and weight requirements. Oxidation systems are durable and do not require repeated replacement, but low urea selectivity may result in oxidation of nutrients and production of oxidation by-products.

[0076] The advantage of urease-based dialysis devices is the specific targeting of urea. On the other hand, the requirement of ammonia removal using a zirconium-based sorbent imposes constraints on the overall system. A 100-500 g sorbent cartridge is estimated to last 12-24 hours. Due to the removal of non-sodium cations, extra electrolyte infusate is required to maintain electrolyte balance. Furthermore, extra zirconium phosphate must be used to guarantee a safety margin and blood ammonium concentrations must be carefully monitored to ensure adequate ammonium removal in the recycled dialysate.

[0077] Toxin-selective membranes The present disclosure aims to provide a toxin-selective membrane 212 that is highly permeable to urea but can block other compounds that may interfere with the toxin removal element 218 from passing from the dialysate loop 204 to the toxin removal loop 206.

[0078] In general, dialysis membranes focus on pore size to maximize the removal of low molecular weight proteins, while sharpening the molecular weight cut-off for high flux membranes. Each membrane has a specific region and profile that depends on other variables such as thickness, zeta potential, molecular weight retention onset (MWRO), molecular weight cut-off (MWCO), etc.

[0079] FIG. 5 shows the MWCO of four classes of dialysis membranes 210. FIG. 5 lists common toxins and nutrients. Low flux dialyzers have a MWCO of about 5 kDa, while high flux dialyzers are closer to about 20 kDa, targeting β2-macroglobulin. Nanofiltration membranes can nominally have a MWCO closer to 100 Da, although 200 Da is more common in practice. Reverse osmosis (RO) membranes are membranes with a MWCO of 23 Da for Na +A formal MWCO is not generally applied since RO membranes are a classification of membranes with sub-nanometer channels that are very effective at excluding charged species even at low MW, such as urea. Small neutral organics such as urea have a high permeability through RO membranes. This list shows that there is no MWCO that allows only uremic toxins to pass, but not nutrients such as glucose (180D) and amino acids (75-204D). Table 1 below lists 20 common small molecules (MW < 200 Da) that are cleared in three weekly hemodialysis sessions. [Table 1]

[0080] The total mass removal of expected species with molecular weights below 200 Da (achievable through commercial nanofiltration membranes) is over 64.3 g (or 67.6 g for the top 50 most removed small molecules). Of this total, approximately 23.6 g is the target urea, and the remaining 44.0 g is non-urea small molecules (a 186% increase in mass). For a non-selective, oxidation-based urea removal / degradation system, a proportionately larger system would be required. Complete oxidation of urea with a MW of 60 Da requires 6e - process. Taking into account the average body composition (C:H:N:O ratio) it is 8.1e- / 60Da, which further increases the current requirement by 35% compared to urea alone. Due to the excess mass and current requirement, the oxidation unit needs to increase in capacity by about 251% or nearly triple in size due to saturating the system with competing chemicals.

[0081] For example, by using a 100 DaMWCO membrane instead, such as NF90 (nominal 90 DaMWCO), the mass of the non-urea small molecules (from Table 1) is reduced from 44.0 g to 9.3 g (MW<120), dramatically reducing saturation due to competition. The mass of non-urea small molecules with MW<120 should be <1 g. The increase in current required for non-urea oxidation (approximately 8.1 e -), the units should be only 53% larger (or a <6% increase) when using a 100 Da MWCO membrane.

[0082] Thus, unless a toxin-selective membrane 212 and toxin removal loop 206 are used prior to the oxidation-based urea removal element 218, oxidation by-products may be numerous.

[0083] The toxin removal loop 206 and toxin-selective membrane 212 can also aid the urease-based urea removal / degradation system by blocking interfering species such as amino acids. Although urease is immobilized on the cartridge by either physical adsorption or click chemistry, there can be leaching of urease due to competition for binding with the scaffolding material from the amino acids. This urease release can generate toxic ammonia concentrations downstream from the ammonia adsorption system and contact the hemodialyzer. The toxin removal loop 206 can include an ammonia removal sorbent that allows any residual ammonia to circulate through the ammonia removal sorbent. The reduction of amino acids by the toxin removal loop 206 also increases enzyme activity by preventing interference with the enzyme active site.

[0084] Similarly, sorbent-based urea removal would also benefit from the toxin removal loop 206 and toxin-selective membrane 212 by limiting the amount of competing solutes. The sorbent binding mechanism typically relies on interactions with the amine groups of urea molecules. However, the combined concentration of amino acids in healthy individuals is already above 3 mM, except for polypeptide and protein molecules. This is a likely mechanism for the rapid decrease in urea binding capacity when a potential sorbent is switched from PBS buffer to actual spent dialysate solution.

[0085] The toxin removal loop 206 and toxin-selective membrane 212, e.g., a urea-selective membrane, can benefit the above-mentioned modes of urea removal, increasing safety and efficiency while reducing costs. The urea-selective membrane 212 would also benefit the portability of hemodiafiltration devices, where the same urea removal strategy would still be applied and non-urea uremic toxin removal could be enhanced compared to hemodialysis. For the oxidized urea removal approach, no special zirconium phosphate or zirconium oxide ion exchange materials would be required, only activated carbon, which is a very inexpensive consumable item, may be required.

[0086] The implementation of a toxin removal loop in wearable and portable kidney dialysis devices may impose new requirements on the membrane at the blood interface, where the sieving coefficient may be a useful parameter characterizing the likelihood of solutes (most importantly intermediate molecules) passing across the dialyzer membrane 210, especially under convective conditions that accompany patient fluid level management. At the interface between the dialysate loop 204 and the toxin removal loop 206, the membrane 212 should have high selectivity for urea over other small molecules to further enhance the function of the urea removal element 218.

[0087] In one embodiment, the urea selective membrane 212 may be based on size exclusion using a membrane that is controllably reduced from larger pores. In one embodiment, a cellulose acetate membrane may be used as the toxin removal membrane 212 to separate urea. In one embodiment, the toxin removal membrane 212 may be a commercially available polymer-based, polyamide-based, or other polymer-based membrane used in reverse osmosis (RO), low pressure RO, forward osmosis (FO), and nanofiltration (NF). Forward osmosis (FO) membranes allow the loop to operate without mechanical pressure and balance liquid levels. Transport operates by diffusion across the FO membrane. Reverse osmosis (RO) membranes require mechanical pressure, reject salts (Cl-), and toxin transport is a combination of diffusion and fluid flow and do not provide liquid balance.

[0088] For pressure-driven flow through RO and NF membranes, urea has a low rejection rate of 18% and 22%, respectively. In contrast, creatinine has a high rejection rate that drops only slightly by 96% to 89% when switching from RO to NF membranes. For RO, the urea / creatinine selectivity is 20:1 and for NF, it is 7:1. Higher selectivity can be expected for most of the common serum molecules, and this 20:1 selectivity factor is higher than that required to protect the oxidation unit from saturation. Easy flow of urea through commercial RO membranes is a long-standing problem in wastewater treatment, but in this application, it may be beneficial to have selectivity for urea transport.

[0089] In one embodiment, a commercially available hollow fiber FO membrane is used for the toxin-selective membrane 212 in the toxin removal loop 206. Figure 3 is a schematic, illustrative diagram of a device 300 including multiple hollow fiber membranes 312. The device 300 can be incorporated into the circuit 200 of Figure 2 for use as the toxin-selective membrane 212 to separate the dialysate loop 204 from the toxin removal loop 206.

[0090] Generally, the hollow fiber membrane device 300 includes a plurality of hollow fibers 312 formed with a permeable membrane separating the interior from the exterior of the hollow fibers. Thus, the device 300 is configured to separate a first fluid flowing within the hollow fibers 312 from a second fluid flowing across the exterior of the hollow fibers 312. For example, the hollow fibers 312 may be arranged such that each end of each of the hollow fibers 312 passes through and terminates at a septum, thereby sealing the interior channel of the hollow fibers 312 from the exterior of the hollow fibers. This allows the first fluid within the hollow fibers 312 to flow axially and the second fluid to flow across the exterior of the hollow fibers 312 to cause migration of chemical species across the hollow fibers 312. For example, the flow of the toxin removal loop 206 enters the nozzle 304 and exits through the nozzle 306, thereby passing through the interior of the hollow fibers 312. The flow of dialysate loop 204 can enter through either nozzle 308 or 310 and exit through the other. Toxins such as urea can migrate from dialysate loop 204 through the membranes that form the walls of hollow fibers 312 to toxin removal loop 206.

[0091] In one embodiment, the toxin removal loop 206 includes a photoelectrochemical urea oxidation system as the urea removal element 218. In one embodiment, the hollow fiber membrane 212 is operated in forward osmosis mode. In one embodiment, the hollow fiber membrane operating in forward osmosis mode can transport about 15 g / day to 30 g / day of urea with a concentration gradient of about 10 mM and an inner fiber flow rate of 50 mL / min. About 30 g / day is more than twice the daily urea production rate of the patient and corresponds to a mass transfer coefficient of 1.2 μm / sec. In one embodiment, the fluid transport rate across the hollow fiber membrane was sufficient to remove up to 4.5 L of water by evaporation in the oxidation system. Photoelectrochemical oxidation performance was increased by 3 times using a hollow fiber membrane as the toxin-selective membrane 212 in the toxin removal loop 206 and was shown to be safe by cytotoxicity studies.

[0092] In one embodiment, an activated carbon cartridge 214 is used in the dialysate loop 204 of Figure 2 to remove non-urea uremic toxins. In one embodiment, the liquid dialysis circuit can include a dialysate loop 204 and a toxin removal loop 206 separated by a toxin-selective membrane 212 configured to selectively pass toxins from the dialysate loop to the toxin removal loop. In one embodiment, the toxin-selective membrane 212 comprises a hollow fiber membrane. In one embodiment, the toxin-selective membrane is at least 2.4 mm thick. 2 In one embodiment, the toxin-selective membrane has a surface area for mass transfer of 1 to 5 m 2 In one embodiment, the toxin-selective membrane has a surface area for mass transfer of 2 to 4 m 2 In one embodiment, the toxin removal loop flows inside the hollow fiber membrane and the dialysate loop flows outside the hollow fiber membrane. In one embodiment, the flow of the toxin removal loop is at least 36 mL / min. In one embodiment, the flow of the toxin removal loop is 10-100 mL / min. In one embodiment, the flow of the toxin removal loop is 10-80 mL / min. In one embodiment, the flow of the toxin removal loop is 20-50 mL / min. In one embodiment, the flow of the dialysate loop is at least 3.7 times the flow of the toxin removal loop. In one embodiment, the flow of the dialysate loop is 1-5 times the flow of the toxin removal loop. In one embodiment, the flow of the dialysate loop is 2-4 times the flow of the toxin removal loop. In one embodiment, the dialysate loop contains uremic toxins.

[0093] In view of the above, exemplary embodiments may include, but are not limited to, the following.

[0094] 1. A liquid dialysis circuit comprising a dialysate loop 204 separated from a patient's blood circuit 202 by a dialysis membrane 210 and a toxin removal loop 206 separated by a toxin-selective membrane 212 configured to selectively pass toxins from the dialysate loop 204 to the toxin removal loop 206.

[0095] 2. The liquid dialysis circuit of embodiment 1, wherein the toxin is a uremic toxin.

[0096] Representative uremic toxins include urea, creatinine, indoxyl sulfate, uric acid, and phenylacetic acid.

[0097] 3. The liquid dialysis circuit of embodiment 1, wherein the toxin-selective membrane 212 is a permeable membrane.

[0098] 4. A liquid dialysis circuit as described in embodiment 1, wherein the toxin-selective membrane 212 is configured to operate as a forward osmosis membrane.

[0099] Forward osmosis (FO) membranes allow the circuit to operate without mechanical pressure and to balance the liquid levels. Transport operates by diffusion across the FO membrane.

[0100] 5. A liquid dialysis circuit as described in embodiment 1, wherein the toxin-selective membrane 212 is configured to operate as a reverse osmosis membrane.

[0101] Reverse osmosis (RO) membranes require mechanical pressure, reject salt (Cl-), and toxin transport is a combination of diffusion and fluid flow and does not provide fluid balance.

[0102] 6. A liquid dialysis circuit according to any of the preceding embodiments, wherein the toxin-selective membrane 212 operates based on the mechanisms of ion exchange (to pursue negatively charged toxins), affinity binding, ultrafiltration, reverse osmosis or forward osmosis.

[0103] 7. The fluid dialysis circuit of any of the preceding embodiments, wherein the toxin removal loop 206 comprises a non-biocompatible fluid.

[0104] Such an embodiment allows operation without NaCl solutions. Examples include NaHCO3 and NaOH. The loop can also operate at non-physiological pH. "Non-biocompatible" includes chemistry and pH, CO2 levels, ammonia, total chlorine (Cl gas, ions, and Cl-containing species - oxidative), and toxic metal ions.

[0105] 8. A liquid dialysis circuit as described in any of the preceding embodiments, wherein the dialysate loop 204 includes a liquid filter 214 configured to remove uremic toxins from the dialysate flowing through the dialysate loop 204.

[0106] Activated carbon is a typical filter material, but any other compatible filter or method may be used.

[0107] 9. A liquid dialysis circuit as described in any of the preceding embodiments, wherein the toxin removal loop 206 comprises a liquid filter 216 configured to remove uremic toxins or oxidation products from the toxin removal fluid flowing through the toxin removal loop 206.

[0108] 10. A liquid dialysis circuit as in any of the preceding embodiments, wherein the toxin removal loop 206 comprises a toxin removal element 218 in liquid contact with the toxin removal fluid flowing through the toxin removal loop 206.

[0109] The toxin removal components 218 include photo-oxidation, electro-oxidation, enzymes, adsorbents, and (bacterial) bioreactors.

[0110] 11. The liquid dialysis circuit of embodiment 10, wherein the toxin removal element 218 is selected from a photooxidation element, an electrooxidation element, and combinations thereof.

[0111] 12. The liquid dialysis circuit of embodiment 10 or 11, wherein the toxin removal element 218 is selected from enzyme (urease)-based, bacteria-based (bioreactor), sorbent-based, oxidation-based, and combinations thereof.

[0112] 13. A liquid dialysis circuit according to any of embodiments 10-12, wherein the toxin removal element 218 comprises a photooxidation element.

[0113] 14. The liquid dialysis circuit of embodiment 13, wherein the liquid dialysis circuit is capable of filtering at least 0.625 g / hr of toxins from the dialysate loop.

[0114] 15. A liquid dialysis circuit according to any of the preceding embodiments, wherein the liquid dialysis circuit is capable of removing between 0.5 L and 4.0 L of water from the dialysate loop 204 in 24 hours.

[0115] 16. A liquid dialysis circuit as described in any of the preceding embodiments, wherein the liquid dialysis circuit is configured to controllably remove water from the dialysate loop 204 via a photooxidation element 218 in the toxin removal loop 206.

[0116] In certain embodiments, photo-oxidation heats the water, which escapes through non-watertight components in the system (e.g., carbon cloth electrodes). This evaporation can be controlled and measured to determine fluid loss in the system.

[0117] 17. A liquid dialysis circuit as described in any of the preceding embodiments, wherein the dialysate loop 204 contains dialysate, the dialysate being configured to receive uremic blood toxins from the patient's blood across the dialysis membrane 210.

[0118] 18. The liquid dialysis circuit of any of the preceding embodiments, wherein the dialysate loop 204 is configured to receive spent ascites fluid.

[0119] 19. The liquid dialysis circuit of any of the preceding embodiments, wherein the toxin-selective membrane comprises a hollow fiber membrane.

[0120] 20. The toxin-selective membrane is at least 2.4 m 2 3. The liquid dialysis circuit of any preceding embodiment, having a surface area for mass transfer of

[0121] 21. The liquid dialysis circuit of embodiment 19, wherein the toxin removal loop flows inside the hollow fiber membrane and the dialysate loop flows outside the hollow fiber membrane.

[0122] 22. The fluid dialysis circuit of embodiment 21, wherein the flow of the toxin removal loop is at least 36 mL / min.

[0123] 23. The liquid dialysis circuit of embodiment 22, wherein the flow of the dialysate loop is at least 3.7 times the flow of the toxin removal loop.

[0124] 24. A kidney dialysis system comprising a liquid dialysis circuit according to any of the preceding embodiments.

[0125] 25. The renal dialysis system of embodiment 24, wherein the renal dialysis system is a hemodialysis system, a peritoneal dialysis system, a hemofiltration system, or a hemodiafiltration system.

[0126] 26. The kidney dialysis system of embodiment 24 or 25, wherein the kidney dialysis system has a form factor selected from the group consisting of portable, wearable, mobile, and fixed.

[0127] 27. A renal dialysis system as described in any of embodiments 24 to 26, wherein the renal dialysis system is configured for use in the home or in a dialysis center.

[0128] 28. A method of treating a patient having toxic blood, comprising: a. flowing toxic fluid from a patient through a fluid dialysis circuit according to any of the preceding embodiments, wherein the toxic fluid flows along the dialysis membrane and allows uremic toxins to pass into the dialysate loop to produce a toxic dialysate; b. flowing the toxic dialysate along a toxin-selective membrane in the dialysate loop to produce a detoxified dialysate in the dialysate loop and a toxic fluid containing electrolytes in the toxin removal loop, the detoxified dialysate being returned toward the dialysis membrane; c. flowing the toxic fluid containing electrolytes through a toxin removal element in a toxin removal loop to produce a detoxified fluid containing electrolytes, the detoxified fluid containing electrolytes being flowed back towards the toxin-selective membrane.

[0129] 29. The method of embodiment 28, wherein the toxic fluid is blood or peritoneal dialysis fluid.

[0130] 30. The method of embodiment 28 or 29, further comprising the step of adding an electrolyte to a fluid containing an electrolyte.

[0131] 31. A method for regenerating dialysis fluid, comprising: a. flowing a toxic dialysate along a toxin-selective membrane 212 to produce a detoxified dialysate in the dialysate loop 204 and a toxic fluid containing electrolytes in the toxin removal loop 206; b. A method comprising: flowing a toxic fluid containing electrolytes through a toxin removal element 218 in a toxin removal loop 206 to produce a detoxified fluid containing electrolytes, the detoxified fluid containing electrolytes being flowed back toward a toxin-selective membrane 212.

[0132] 32. A liquid dialysis circuit comprising: a dialysate loop 204; A liquid dialysis circuit comprising: a toxin removal loop separated by a toxin-selective membrane configured to selectively pass toxins from the dialysate loop to the toxin removal loop.

[0133] 33. The liquid dialysis circuit of embodiment 32, wherein the toxin-selective membrane 212 comprises a hollow fiber membrane 312.

[0134] 34. The toxin-selective membrane 212 is at least 2.4 m 2 34. The liquid dialysis circuit of embodiment 32 or 33, having a surface area for mass transfer of

[0135] 35. A liquid dialysis circuit as described in embodiment 34, in which the toxin removal loop 206 flows inside the hollow fiber membrane 312 and the dialysis loop 204 flows outside the hollow fiber membrane 312.

[0136] 36. The liquid dialysis circuit of embodiment 35, wherein the flow of the toxin removal loop 206 is at least 36 mL / min.

[0137] 37. A liquid dialysis circuit as described in embodiment 36, wherein the flow of the dialysate loop 204 is at least 3.7 times the flow of the toxin removal loop 206.

[0138] 38. The liquid dialysis circuit of embodiment 32, wherein the dialysate loop contains a uremic toxin. EXAMPLES

[0139] To demonstrate the influence of other molecular species on urea, a controlled study of urea removal in human spent dialysate and saline was performed. As shown in Figure 6A, a previously developed photo-oxidative urea removal (POUR) device was used to remove urea. For urea infusion, both the spent dialysate and saline had the same initial urea concentration (~10 mM) at the start of the experiment and were then expanded to ~2000 cm, a size acceptable for kidney dialysis systems. 2 Urea was continuously injected in an amount that would correspond to 15 g urea / day if scaled up to 100%. When the urea oxidation rate meets the target, the urea concentration remains constant emulating continuous operation, similar to the normal function of the kidney. These results are shown in Table 2 below. Table 2. POUR urea removal rates in 0.15 M NaCl medium versus human spent dialysate with initial urea loading and 15 g / day equivalent urea infusion. [Table 2]

[0140] Using simple saline with added urea, 0.29 mg / (cm 2 The urea removal rate was 0.31 mg / (cm ·h). 2 This target flux is close to the target velocity of 2000 cm 2 This corresponds to 15 g / day of a benchtop demonstration device of the present invention with a catalytic surface area of ​​0.09 mg / (cm). However, using human spent dialysis fluid, the urea removal rate was 0.09 mg / (cm 2hr), exceeding a three-fold decrease in performance (34%) close to that expected for competing oxidation. The glucose removal rate was 0.087 mg / (cm 2 The photocurrent otherwise utilized in urea removal was now diverted to the oxidation of glucose and other organic species that were present in the human spent dialysate. Although solute interference was demonstrated with this photooxidation-based urea removal device, this interference is expected to be common to other oxidation-based urea removal approaches.

[0141] Due to competition from other solutes, a urea-selective membrane was used with sufficient permeability for the target of 15 g urea / day. For wastewater treatment and desalination, reverse osmosis (RO) membranes have been very effective at removing most solutes based on the principles of size and charge exclusion. However, urea is an important exception, showing only about 20% rejection in the filtration product where other species typically approach 95-99% rejection. Although problematic for wastewater treatment, this indicates that RO membranes are highly selective for urea transport and may be used for dialysate regeneration by urea removal. To examine the selectivity of RO membranes for molecular species in spent dialysate, we compiled a list of 11 representative molecules including urea, glucose, amino acids, and uremic toxins, as shown in Table 3 below. Table 3. Common molecular species in human spent dialysate and uremic plasma concentrations used as feed solutions for RO and FO separations. Observed RO and FO retentate concentrations and calculated rejection, removal, and mass transfer coefficients. The flow rates used are 100 and 400 mL / min for the inner fiber and outer volume, respectively. [Table 3]

[0142] Urea is the most abundant uremic waste product (23.6 g), while glucose is the most common nutrient (19.4 g). Glycine and tryptophan were selected for their small molecular weight and characteristic functional groups, while ammonium is a potential by-product from urea photooxidation. Their respective concentrations have been reported previously. This list is largely representative of the molecular species that a urea-selective membrane must encounter in actual spent dialysate.

[0143] RO selectivity results are shown in Table 3. Rejection of urea is 20%, similar to that observed in wastewater treatment. Rejection of glucose, the most common competing solute, is 99%. Amino acid nutrients range from 96-100% rejection. The feed solution had a urea:non-urea mass ratio of 1:2.4, which was reduced to 1:0.1 in the RO filtrate product. This effectively removes competing solutes with only an expected decrease in urea removal efficiency of about 10%.

[0144] However, the RO mode of operation is designed to remove all solutes, including NaCl, which requires approximately 7.5 bar of water pressure to produce a urea-rich filtrate product, which adds significant power usage and complexity, especially considering that the retentate and permeate product streams are recombined after the urea removal step.

[0145] As shown in Figure 6B, the urea-selective membrane can operate in FO mode with negligible hydraulic pressure. Water still flows across the membrane due to the osmotic pressure difference in the dialysate loop and the urea removal loop. This can occur due to water evaporation at the air-permeable cathode of the POUR unit, thus concentrating salts in the urea removal loop and generating osmotic pressure. Urea flux is generated by a diffusion concentration gradient across the membrane. The diffusion flux should be sufficient to remove approximately 15 g of urea per day in a practically sized membrane for portable dialysis.

[0146] Table 3 shows the 2.3m 2It is shown that with a hollow fiber forward osmosis (HFFO) cartridge of 1000 μM and a concentration gradient of 20 mM, urea removal of 86.4 g / day is possible, far exceeding the daily requirement. The inner fiber flow channel was used as the "draw" solution for the urea removal loop (output is the FO filtrate product), while the outer fiber volume was used as the urea source for the dialysate loop (output is the FO retentate). The mass transport coefficient showed 0.91 μm / sec urea, with 90% less ammonium and 99.9% less glucose, making the FO membrane highly selective for urea and a protective barrier.

[0147] Figure 7 shows the urea removal rate and corresponding mass transfer coefficient in 24 hours using AQUAPORIN® FO cartridges at different inner fiber flow rates. The outer flow rate of 10 mM urea dialysate feed is 3.7 times the inner fiber flow rate. Figure 7 shows the inner flow rate dependence for urea removal and mass transfer coefficient with 10 mM urea feed solution. As expected, the higher the flow rate, the more urea is removed due to the larger amount of filtrate product at similar outlet concentration. In a diffusion-limited process, when the flow rate is fast enough not to be saturated, the total flux of urea is set by the concentration drop, not the flow rate. This is seen by the flow rate-independent mass transfer coefficient, which occurs at inner fiber flow rates faster than 100 ml / min with a value of 1.2 μm / s (Figure 7). For a 100 nm "skin" layer typical of FO membranes, this is 1.2×10 -9 cm 2 This corresponds to a diffusion coefficient of 2.3 m / s, about four orders of magnitude smaller than aqueous bulk diffusion. 2is sufficient for the target 15 g day using an area of ​​100 mm. Assuming a constant supply of 600 mg / L (10 mM) urea on the spent dialysate side and 0 urea on the draw side, approximately 30 g urea can be removed through the FO cartridge in 24 hours at a hollow fiber flow rate of 50 mL / min (total removal of urea by the POUR unit). FO experiments were performed with urea supply on the outside of the fiber and draw solution on the inside of the fiber, as opposed to a conventional outside "draw". This is because the outside volume is 5 times the inside fiber volume, so any urea flux is diluted 5 times, reducing the efficiency of the POUR unit. Urea mass transfer rates were measured by inverting the sides of the feed and draw solutions, and similar results for the mass transfer coefficient were obtained, indicating that the asymmetric FO membrane structure does not significantly change the urea diffusion coefficient. Water removal from the dialysate is necessary for clinical use (approximately 2.5 L / day) and can be achieved by higher osmolality / salt concentration on the urea removal loop. Using a 1 mM NaCl draw solution to DI water, we observed a water removal rate of approximately 1.25 L per 24 hours.

[0148] The setup shown in Figure 6B is used to demonstrate and quantify the urea and water removal capabilities of the FO-POUR device. The dialysate loop circulates 1 L of human spent dialysate collected during an outpatient hemodialysis session. The glucose concentration was measured to be 3 mM. Urea was added to bring the starting urea concentration to 10 mM and the POUR unit was run over 36 channels (approximately 20-40 cm). 2 A 0.5M urea solution was continuously infused (0.61 ml / hr) which, when scaled up to 10 mL / min, would give the equivalent of 15 g / day of continuous production of urea in an ESRD patient. In the POUR loop, a 0.7 L volume of 0.15 M NaCl was used as the starting solution (circulating at 10 mL / min). This is approximately the same as in saline, at 0.32 mg / (cm), without interference from other chemical species. 2 This corresponds to a urea removal rate of 100 μg / mL (100 μg / mL) per hour, supporting that the FO membrane is selective for both urea transport in the FO mode and diffusion through the membrane to be fast enough for clinically relevant urea removal rates.

[0149] Three separate tests of 24 hour continuous operation of the FO-POUR device were conducted and the results are summarized in Table 4 below. Table 4. 24-hour performance of the FO-POUR device. [Table 4]

[0150] 2000cm 2 Extrapolating to an active area of ​​100 µm, the FO-POUR unit can remove 15.4 g urea and 3.9 L water in 24 hours, meeting both clinical requirements. The extrapolated water removal in Figure 6B was approximately equally distributed from the spent dialysate loop (1.92 L) and the POUR loop (1.98 L), as expected for osmotic equilibrium with the FO membrane. The water removal rate can be determined by evaporation through the carbon paper air permeable cathode of the POUR device. This evaporation increases the osmotic pressure in the POUR circuit solution, which draws more water across the FO membrane. The net result is the removal of excess water from the spent dialysate.

[0151] Samples were collected from both the spent dialysate and the POUR loop in the FO-POUR study (Figure 6B), both collected prior to the 24-hour study. The resulting MTT cytotoxicity studies are summarized in Figures 8A, 8B, and 8C. Figure 8A shows the control group using latex controls diluted to different ratios. Figures 8B and 8C show the cytotoxicity of samples before and after 24 hours of FO-POUR, respectively. At t=24 hours, no significant difference was found between their cytotoxicity, with a viability of 79.8% (±9.3%) for the POUR output solution treated with activated charcoal (AC) and 82.9% (±15.8%) from the spent dialysate separated from the FO-POUR device but left at ambient conditions for 24 hours. These viability numbers are also statistically close to the 85.1% (±6.4%) viability of the spent dialysate collected from the spent dialysate circuit at the end of the 24-hour study. The activated carbon at the POUR outlet is sufficient to remove oxidative or radical species to produce a non-cytotoxic result. The FO membrane acts as an additional protective barrier to the patient dialysate loop and does not add any cytotoxicity to the system.

[0152] Dialysate regeneration allows for portable dialysis devices that allow for more frequent or nearly continuous treatment for better health-related outcomes in ESRD patients. However, human spent dialysate is a complex solution, with urea being only 40% of the target solute removal mass. This would equate to approximately 2 / 3 reduction in performance of the oxidized urea removal system due to competing reactions. This was confirmed experimentally by using urea-infused human spent dialysate through the POUR system, resulting in a 69% reduction in performance compared to urea-infused saline. Urea-selective membranes are necessary to limit the exposure of the oxidizing system to competing solutes while simultaneously minimizing oxidation by-products from entering the regenerated dialysate and ultimately the patient's body. In water purification applications, RO membranes have the property of high urea transport (20% rejection). This property allows these membranes to be used as urea-selective membranes to protect the urea oxidation system from other small molecules. Rejection rates of common uremic species have typically been measured to be greater than 95%, with the exception of creatinine and ammonium, which have near 80% rejection. A useful mode of operation is the FO configuration, where urea diffuses across the osmotic membrane without applied hydraulic pressure. Using commercially available hollow fiber, forward osmosis cartridges, urea can be removed with high selectivity from spent dialysate at rates of over 30 g per day, at inner fiber flow rates of 50 mL / min, and urea concentrations of 600 mg / L (10 mM) in the human spent dialysate feed stream. The diffusion rate of urea is 1 to 5 orders of magnitude higher than other representative molecular species removed during a dialysis session. The mass transport coefficient for urea is 1.2 × 10 -9 cm 2 In the combined FO-POUR setup, urea was 0.32 mg / (cm 2 hr) and a therapeutically useful velocity of 0.081 g / (cm 2 urea can be removed at a water removal rate of 0.01 mg / mL per hour. In addition, there appears to be no significant difference in cytotoxicity between untreated and treated spent dialysate. Thus, sufficient urea removal from spent dialysate can be achieved using the FO-POUR device without the urease enzyme and associated ion exchange materials, which may provide a useful portable dialysis device.

[0153] Experimental Section Reverse Osmosis: MEMBRANE SOLUTIONS® 75 GPD RO coiled flat sheet membrane was used with an AQUATEC® 6800 booster pump. Flow rate was controlled with a NXSTOP LZT™ M-15 0.05-0.5 GPM flow meter and calibrated using a graduated cylinder. The retentate flow rate was 190 mL / min versus a 90 mL / min product filtrate flow rate with a pressure differential of 150 psi.

[0154] Forward osmosis: AQUAPORIN INSIDE® hollow fiber forward osmosis (HFFO) membrane HFFO2-220 was used. A MASTERFLEX® L / S variable speed peristaltic pump with a 77800-60 pump head was used. The flow rates through the inner fiber and outer space were set between 20-160 and 80-640 mL / min, respectively. Before each sample collection, the cartridge was completely drained and then rinsed thoroughly with fresh solution of 10 times the volume of the FO cartridge. The inner fiber volume was 28 mL and the outer volume was 156 mL. The mass transfer coefficient (k) was

number

number

[0155] Chemical quantification: Urea, creatinine, glucose, lactose, and ammonium ions are quantified according to the AU system of Beckman Coulter using the corresponding kits with standard operating protocols. The calibration curve for urea concentration measurement was prepared using standard solutions with urea concentrations of 2, 4, 6, 8, and 10 mM urea with a quadratic fitting curve.

[0156] Indoxyl sulfate was quantified using liquid chromatography-tandem mass spectrometry according to the procedure described in the literature. Indoxyl sulfate was first extracted by solid phase extraction and then reconstituted in 80 μL of 5% acetonitrile / 0.2% formic acid in water. The sample solution was further filtered and a volume of 5 μL was injected onto a RESTEK® PFPP chromatography column (Restek PN:9419252) and developed using a gradient (SHIMADZU® NEXERA® XR20A). The eluate from the column was introduced into a triple quadrupole tandem mass spectrometer (SCIEX® 6500). Five replicates were used to obtain the average peak area.

[0157] Amino acids were quantified using standard clinical protocols. Samples were combined with an internal standard (S-(2-aminoethyl)-L-cysteine, SIGMA-ALDRICH® Catalog No. A2636) dissolved in SERAPREP™ (Pickering Laboratories, Catalog No. SP100), vortexed, and centrifuged to remove any precipitates. The supernatant was injected onto a BIOCHROM® 30+ Amino Acid Analyzer (Biochrom Ltd, Cambridge, England), an HPLC system that separates free amino acids with baseline resolution using a series of lithium citrate buffers. Each amino acid reacts with ninhydrin in a post-column reaction for detection by UV absorbance at 570 and 440 nm. The amount of each amino acid is calculated based on a two-point standard curve generated using stock standards of 250 and 500 μM, respectively. Data were analysed and quantified using OPENLAB® (EZ CHROM™, Biochrom Ltd, Cambridge, England).

[0158] Phenylacetic acid was quantified using a MOLECULAR DEVICES® SPECTRAMAX® i3x spectrometer based on the absorption peak intensity at 280 nm using a four-point calibration with two-fold dilutions at each step starting with 0.5 mg / L phenylacetic acid in aqueous solution.

[0159] Cytotoxicity: All reagent calibrations, elutions, and cell and assay incubations were performed at 37'C, 5% CO2. Growth medium was high glucose DMEM without phenol red with final concentrations of 10% calf serum and 2mM L-glutamine. Log phase 3T3 mouse fibroblasts were plated in multi-well plates to be sub-confluent at 24 hours. Concurrently, latex strips were eluted in growth medium (0.2g / ml) for 24 hours and used as a positive control for cytotoxicity. Liquid samples were diluted in a mixture of 2x and 1x growth medium to a final concentration of 1x growth medium. At 24 hours, eluted latex medium or diluted liquid samples were transferred to quadruplicate cell wells and incubated for 48 hours. Quadruplicate wells that received untreated growth medium were used as negative controls and baselines for calculations. Unseeded wells that received growth medium were used to calculate background.

[0160] At 48 hours, all wells were visually assessed and assigned an ISO10993-5 numerical score followed by the MTT cell proliferation assay (ABCAM™ 211091). Viable cells convert the water-soluble 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide compound to an insoluble formazan product that serves as a colorimetric marker of viability. Media was aspirated from cell wells and replaced with MTT reagent diluted in serum-free growth media. After 3 hours of incubation, well contents were aspirated and MTT solvent was added. Plates were wrapped in foil, shaken on an orbital shaker for 15 minutes, and read at absorbance 590 nm (BIOTEK® Synergy LX plate reader). Percent viability was per sample and was the average of: [sample-background) / (negative control-background)×100].

[0161] POUR device assembly and testing: TiO2-coated FTO / borosilicate substrates were hydrothermally prepared according to a previous procedure. 2Pt black coated carbon paper was purchased from FUEL CELL STORE™ (#1610009-1). Fluorinated tin oxide (FTO) on borosilicate glass slides (2.54 cm x 7.62 cm) was purchased from MTI Corporation (FTO257630TEC7gp25). The TiO2 coated FTO, Pt black coated carbon paper, and laser cut acrylic frame (1 / 8 inch thick clear acrylic frame 85635K451 purchased from MCMASTER-CARR®) were assembled using LOCTITE® EA M-21HP epoxy. The flow channel is 3 mm thick and 23 mm wide. Three slides were used in series to give a channel length of 24.6 cm. The adapters used are COLE PARMER® MASTERFLEX® fittings, female luer to 1 / 4" ID hose barb (EW-45502-20), and male luer x 1 / 4-28UNF (EW-45505-82). SAINT GOBAIN® TYGON® 3350 1 / 4*3 / 8 silicone tubing was used to connect between the adapters. LED light panels were assembled from realUV™ LED strip lights from WAVEFORM LIGHTING™ on aluminum sheets (McMaster 89015K38, cut to 5" x 10", 360 LEDs per panel). The LED strips on each panel were soldered in two parallel circuits. The exposed edges of the aluminum sheets were protected using KAPTON® polyimide film (3M® Tape 5413). A FILMGRADE™ DC power supply was used to power the LED panel. A METROHM® Autolab PGSTAT204 was used to apply the bias and record the photocurrent.

[0162] Pump: ISMATEC® peristaltic pump 78017-10 was used at a flow rate of 1.5 mL / min for the interference experiment shown in Figure 6A. COLE PARMER® MASTERFLEX® L / S model 77200-62 pump was used for RO / FO experiment to obtain the data in Table 3 at flow rates of 100 mL / min and 400 mL / min through the inside and outside of the hollow fiber, respectively. For the 24-hour experiment, the ISMATEC® pump was used at 1.5 mL / min for the POUR side circulation and the COLE PARMER® MASTERFLEX® pump was used at a flow rate of 10 mL / min for the circulation of the spent dialysate to confirm the urea removal efficiency in the spent dialysate.

[0163] While illustrative embodiments have been illustrated and described, it will be understood that various changes can be made therein without departing from the spirit and scope of the invention.

Claims

1. 1. A liquid dialysis circuit comprising: a dialysate loop separated from a patient's blood circuit by a dialysis membrane; and a toxin removal loop separated by a toxin-selective membrane configured to selectively pass toxins from the dialysate loop to the toxin removal loop.

2. The fluid dialysis circuit of claim 1 , wherein the toxin is a uremic toxin.

3. 2. The fluid dialysis circuit of claim 1, wherein the toxin-selective membrane is a permeable membrane.

4. The fluid dialysis circuit of claim 1 , wherein the toxin-selective membrane is configured to operate as a forward osmosis membrane.

5. The fluid dialysis circuit of claim 1 , wherein the toxin-selective membrane is configured to operate as a reverse osmosis membrane.

6. The liquid dialysis circuit of any one of claims 1 to 5, wherein the toxin-selective membrane operates based on the mechanisms of ion exchange, affinity binding, ultrafiltration, reverse osmosis or forward osmosis.

7. The fluid dialysis circuit of any one of claims 1 to 5, wherein the toxin removal loop comprises a non-biocompatible fluid.

8. The fluid dialysis circuit of any one of claims 1 to 5, wherein the dialysate loop comprises a fluid filter configured to remove uremic toxins from the dialysate flowing through the dialysate loop.

9. 6. The fluid dialysis circuit of claim 1, wherein the toxin removal loop comprises a fluid filter configured to remove uremic toxins or oxidation products from the toxin removal fluid flowing through the toxin removal loop.

10. The fluid dialysis circuit of any one of claims 1 to 5, wherein the toxin removal loop comprises a toxin removal element in fluid contact with a toxin removal fluid flowing through the toxin removal loop.

11. The fluid dialysis circuit of claim 10 , wherein the toxin removal element is selected from a photooxidation element, an electrooxidation element, and combinations thereof.

12. 11. The fluid dialysis circuit of claim 10, wherein the toxin removal element is selected from enzyme (urease) based, bacteria based (bioreactor), sorbent based, oxidation based, and combinations thereof.

13. The fluid dialysis circuit of claim 10 , wherein the toxin removal element comprises a photooxidation element.

14. 14. The liquid dialysis circuit of claim 13, wherein the liquid dialysis circuit is capable of filtering at least 0.625 g / hr of toxins from the dialysate loop.

15. The liquid dialysis circuit of any one of claims 1 to 5, wherein the liquid dialysis circuit is capable of removing 0.5 L to 4.0 L of water from the dialysate loop in 24 hours.

16. The liquid dialysis circuit of any one of claims 1 to 5, wherein the liquid dialysis circuit is configured to controllably remove water from the dialysate loop via a photooxidation element in the toxin removal loop.

17. 6. The liquid dialysis circuit of claim 1, wherein the dialysate loop contains dialysate, the dialysate being configured to receive uremic blood toxins from the patient's blood across the dialysis membrane.

18. The fluid dialysis circuit of any one of claims 1 to 5, wherein the dialysate loop is configured to receive spent ascites fluid.

19. The liquid dialysis circuit of any one of claims 1 to 5, wherein the toxin-selective membrane comprises a hollow fiber membrane.

20. The toxin-selective membrane is at least 2.4 mm ２ A liquid dialysis circuit according to any one of claims 1 to 5, having a surface area for mass transfer of

21. 20. The liquid dialysis circuit of claim 19, wherein the toxin removal loop flows inside the hollow fiber membranes and the dialysate loop flows outside the hollow fiber membranes.

22. 22. The fluid dialysis circuit of claim 21, wherein the flow of the toxin removal loop is at least 36 mL / min.

23. 23. The liquid dialysis circuit of claim 22, wherein the flow of the dialysate loop is at least 3.7 times the flow of the toxin removal loop.

24. A kidney dialysis system comprising a liquid dialysis circuit described in any one of claims 1 to 5.

25. 25. The renal dialysis system of claim 24, wherein the renal dialysis system is a hemodialysis system, a peritoneal dialysis system, a hemofiltration system, or a hemodiafiltration system.

26. 25. The renal dialysis system of claim 24, wherein the renal dialysis system has a form factor selected from the group consisting of portable, wearable, mobile, and stationary.

27. 25. The renal dialysis system of claim 24, wherein the renal dialysis system is configured for use in a home or a dialysis center.

28. A method of operating a renal dialysis system, comprising: a. flowing a toxic liquid through the liquid dialysis circuit of any one of claims 1 to 5, said toxic liquid flowing along a dialysis membrane and allowing uremic toxins to pass into the dialysate loop to produce a toxic dialysate; b. flowing the toxic dialysate along the toxin selective membrane in the dialysate loop to produce a detoxified dialysate in the dialysate loop and a toxic fluid containing electrolytes in the toxin removal loop, the detoxified dialysate being returned toward the dialysis membrane; c) passing the electrolyte-containing toxic fluid through a toxin removal element in the toxin removal loop to produce an electrolyte-containing detoxified fluid, the electrolyte-containing detoxified fluid being returned towards the toxin-selective membrane.

29. 29. The method of claim 28, wherein the toxic fluid is blood or peritoneal dialysis fluid.

30. 30. The method of claim 28, further comprising the step of adding electrolyte to the electrolyte-containing fluid.

31. 1. A method for regenerating dialysate, comprising: a. flowing a toxic dialysate along a toxin-selective membrane to produce a detoxified dialysate in the dialysate loop and a toxic fluid containing electrolytes in the toxin removal loop; b) passing the electrolyte-containing toxic fluid through a toxin removal element in a toxin removal loop to produce an electrolyte-containing detoxified fluid, the electrolyte-containing detoxified fluid being returned towards the toxin-selective membrane.

32. 1. A fluid dialysis circuit comprising: a dialysate loop; a toxin removal loop separated by a toxin-selective membrane configured to selectively pass toxins from the dialysate loop to the toxin removal loop.

33. 33. The fluid dialysis circuit of claim 32, wherein the toxin-selective membrane comprises a hollow fiber membrane.

34. The toxin-selective membrane is at least 2.4 mm ２ 34. The fluid dialysis circuit of claim 32 or 33, having a surface area for mass transfer of

35. 35. The liquid dialysis circuit of claim 34, wherein the toxin removal loop flows inside the hollow fiber membranes and the dialysate loop flows outside the hollow fiber membranes.

36. 36. The fluid dialysis circuit of claim 35, wherein the flow of the toxin removal loop is at least 36 mL / min.

37. 37. The fluid dialysis circuit of claim 36, wherein the flow of the dialysate loop is at least 3.7 times the flow of the toxin removal loop.

38. 33. The fluid dialysis circuit of claim 32, wherein the dialysate loop contains a uremic toxin.

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