Detecting zirconium concentrations

Abstract

Methods and systems are provided. A method comprises determining a zirconium concentration of a fluid exiting a sorbent cartridge of a dialysis system and controlling a dialysis treatment to a patient, such that, when the zirconium concentration of the fluid is greater than a threshold, the dialysis treatment is discontinued. Related methods and related systems are also provided.

Description

Attorney Docket No. 218079-021701 / PCT Mozarc Ref. No. A0009118 PCT DETECTING ZIRCONIUM CONCENTRATIONS CROSS-REFERENCE TO RELATED APPLICATIONS[OOOIJThis application claims priority to U.S. Provisional Patent Application No.63 / 748,662, filed January 23, 2025, and titled “DETECTING ZIRCONIUM CONCENTRATIONS”, which is herein incorporated by reference it is entirety.FIELD

[0002] The present disclosure relates to detecting zirconium concentration of a fluid, and related systems and related methods.BACKGROUND

[0003] Sorbent-based recirculating dialysis systems may include zirconium-based sorbent components such as zirconium phosphate and hydrous zirconium oxide. These zirconium-based components may sometimes leach zirconium into the dialysate, depending on the solution conditions in the sorbent cartridge. High levels of zirconium may be harmful to a patient and exposure to such high levels in a dialysate should be minimized. Hence, there is a need for systems and methods for detecting levels of zirconium in a dialysate in order to cease dialysis therapy as needed, if the expected zirconium levels exceed safe levels for the patient.SUMMARY

[0004] Some embodiments relate to a method. In some embodiments, the method comprises adding a bicarbonate from a bicarbonate source to a fluid exiting a sorbent cartridge of a dialysis system. In some embodiments, the method comprises determining a zirconium concentration of the fluid at a location downstream of the sorbent cartridge and upstream of the bicarbonate source. In some embodiments, the method comprises controlling a dialysis treatment to a patient, such that, when the zirconium concentration of the fluid is greater than a threshold, the dialysis treatment is discontinued.1ACTIVE 717707681 v1Attorney Docket No. 218079-021701 / PCT Mozarc Ref. No. A0009118 PCT

[0005] In some embodiments, the sorbent cartridge comprises at least one sorbent comprising at least one of a zirconium phosphate, a zirconium oxide, or any combination thereof.

[0006] In some embodiments, the step of determining the zirconium concentration of the fluid comprises determining the zirconium concentration of the fluid based on a flow rate of the bicarbonate added to the fluid from the bicarbonate source.

[0007] In some embodiments, the step of determining the zirconium concentration of the fluid comprises determining the zirconium concentration of the fluid based on a bicarbonate prescription concentration and a concentration of the bicarbonate added to the fluid.

[0008] In some embodiments, the step of determining the zirconium concentration of the fluid comprises measuring a first conductivity of the fluid before the bicarbonate is added to the fluid; measuring a second conductivity of the fluid after the bicarbonate is added to the fluid; and determining the zirconium concentration of the fluid based on a difference between the second conductivity and the first conductivity.

[0009] In some embodiments, when the zirconium concentration of the fluid is less than the threshold, the dialysis treatment is continued.

[0010] In some embodiments, the threshold is a percentage of a zirconium toxicity limit, wherein the zirconium toxicity limit is a mass of zirconium per mass of patient per day.

[0011] Some embodiments relate to a method. In some embodiments, the method comprises determining a zirconium concentration of a fluid exiting a sorbent cartridge of a dialysis system. In some embodiments, the method comprises controlling a dialysis treatment to a patient, such that, when the zirconium concentration of the fluid is greater than a threshold, the dialysis treatment is discontinued.

[0012] In some embodiments, the sorbent cartridge comprises at least one sorbent comprising at least one of a zirconium phosphate, a zirconium oxide, or any combination thereof.2ACTIVE 717707681 v1Attorney Docket No. 218079-021701 / PCT Mozarc Ref. No. A0009118 PCT

[0013] In some embodiments, the step of determining the zirconium concentration of the fluid comprises determining the zirconium concentration of the fluid based on a bicarbonate concentration of the fluid.

[0014] In some embodiments, the step of determining the zirconium concentration of the fluid comprises determining the zirconium concentration of the fluid based on a pH of the fluid.

[0015] In some embodiments, the method further comprises adding a water, from a water source, to the fluid at a location upstream of the sorbent cartridge. In some embodiments, the step of determining the zirconium concentration of the fluid comprises determining the zirconium concentration of the fluid based on an amount of the water added to the fluid from the water source and a change in conductivity across the sorbent cartridge.

[0016] In some embodiments, when the zirconium concentration of the fluid is less than the threshold, the dialysis treatment is continued.

[0017] In some embodiments, the threshold is a percentage of a zirconium toxicity limit, wherein the zirconium toxicity limit is a mass of zirconium per mass of patient per day.

[0018] Some embodiments relate to a system. In some embodiments, the system comprises a dialyzer. In some embodiments, the system comprises a sorbent cartridge. In some embodiments, the system comprises a bicarbonate source. In some embodiments, the dialyzer, the sorbent cartridge, and the bicarbonate source are connectable by a fluid flow path. In some embodiments, the bicarbonate source is configured to contain a bicarbonate for addition to a fluid exiting the sorbent cartridge. In some embodiments, the system comprises a controller. In some embodiments, the controller is configured to determine a zirconium concentration of the fluid downstream of the sorbent cartridge and upstream of the bicarbonate source. In some embodiments, the controller is configured to control a dialysis treatment to a patient, such that, when the zirconium concentration of the fluid is greater than a threshold, the dialysis treatment to the patient is discontinued.3ACTIVE 717707681 v1Attorney Docket No. 218079-021701 / PCT Mozarc Ref. No. A0009118 PCT

[0019] In some embodiments, the controller is configured to determine the zirconium concentration of the fluid based on a bicarbonate concentration of the fluid.

[0020] In some embodiments, the controller is configured to determine the zirconium concentration of the fluid based on a bicarbonate prescription concentration and a concentration of the bicarbonate added to the fluid from the bicarbonate source.

[0021] In some embodiments, the controller is configured to determine the zirconium concentration of the fluid based on a flow rate of the bicarbonate added to the fluid from the bicarbonate source.

[0022] In some embodiments, the system further comprises a first sensor for measuring a first conductivity. In some embodiments, the first sensor is upstream of the bicarbonate source. In some embodiments, the system further comprises a second sensor for measuring a second conductivity. In some embodiments, the second sensor is downstream of the bicarbonate source. In some embodiments, the controller is configured to determine the zirconium concentration of the fluid based on a difference between the second conductivity and the first conductivity.

[0023] In some embodiments, the system further comprises a water source. In some embodiments, the water source is connectable to the fluid flow path. In some embodiments, the water source is configured to contain a water for addition to the fluid entering the sorbent cartridge. In some embodiments, the controller is configured to determine the zirconium concentration of the fluid based at least on an amount of the water added to the fluid from the water source and a change in conductivity across the sorbent cartridge.BRIEF DESCRIPTION OF THE DRAWINGS

[0024] FIG. 1 is a flowchart of a method for determining a zirconium concentration of a fluid, according to some embodiments.

[0025] FIG. 2 is a flowchart of a method for determining a zirconium concentration of a fluid, according to some embodiments.4ACTIVE 717707681 v1Attorney Docket No. 218079-021701 / PCT Mozarc Ref. No. A0009118 PCT

[0026] FIG. 3 is a schematic diagram of a system for determining a zirconium concentration of a fluid, according to some embodiments.

[0027] FIG. 4 is a graph showing cumulative zirconium mass exiting the sorbent cartridge vs. the sorbent cartridge effluent pH for a simulated dialysis session, according to some embodiments.

[0028] FIG. 5 is a graph showing the cumulative mass of zirconium exiting the sorbent cartridge vs. the bicarbonate level exiting the cartridge for a simulated dialysis session, according to some embodiments.

[0029] FIG. 6 is a graph showing the sorbent effluent pH profile for several runs vs. the total CO2 exposure to the cartridge for a simulated dialysis session, according to some embodiments.

[0030] FIG. 7 is a graph showing cumulative zirconium mass in a dialysate vs. treatment volume cartridge for a simulated dialysis session, according to some embodiments.

[0031] FIG. 8 is a graph showing cumulative zirconium mass in the dialysate vs. bicarbonate pump rate for a simulated dialysis session, according to some embodiments.

[0032] FIG. 9 is a graph showing cumulative zirconium mass in the dialysate vs. bicarbonate pump rate divided by dialysate flow rate for a simulated dialysis session, according to some embodiments.

[0033] FIG. 10 is a graph showing cumulative zirconium mass in the dialysate vs. the bicarbonate added after the sorbent cartridge by the bicarbonate pump for a simulated dialysis session, according to some embodiments.

[0034] FIG. 11 is a graph showing cumulative zirconium mass in the dialysate vs. sorbent cartridge outlet bicarbonate concentration for a simulated dialysis session, according to some embodiments.

[0035] FIG. 12 is a graph showing cumulative zirconium mass in the dialysate vs. the conductivity delta between the sorbent outlet and after the bicarbonate pump for a simulated dialysis session, according to some embodiments.5ACTIVE 717707681 v1Attorney Docket No. 218079-021701 / PCT Mozarc Ref. No. A0009118 PCT

[0036] FIG. 13 is a graph showing cumulative zirconium mass in the dialysate vs. a trigger value for a simulated dialysis session, according to some embodiments.

[0037] FIG. 14 is a graph showing zirconium concentration in the dialysate vs. a trigger value for a simulated dialysis session, according to some embodiments.

[0038] FIG. 15 is a graph showing cumulative zirconium mass in the dialysate vs. zirconium concentration in the dialysate (Zr Instant) along with a polynomial regression for a simulated dialysis session, according to some embodiments.

[0039] FIG. 16 is a graph showing sorbent effluent zirconium concentration and sorbent effluent conductivity vs. volume of sorbent effluent, according to some embodiments.

[0040] FIG. 17 is a graph showing sorbent effluent zirconium concentration vs. sorbent effluent conductivity, according to some embodiments.DETAILED DESCRIPTION

[0041] Unless defined otherwise, all technical and scientific terms used have the same meaning as commonly understood by one of ordinary skill in the art.

[0042] The articles “a” and “an” are used to refer to one to over one (i.e. , to at least one) of the grammatical object of the article. For example, “an element” means one element or over one element.

[0043] The term “adding,” to “add,” or “addition” refers to pumping additional fluid into an existing fluid or into a component or system.

[0044] The term “bicarbonate” refers to HCO3- ions, as well as any species existing in equilibrium with bicarbonate ions, including carbonate ions and carbon dioxide.

[0045] The term “bicarbonate concentration” refers to an amount of bicarbonate dissolved in a solvent per a given amount of solvent.

[0046] A “bicarbonate prescription” is an intended bicarbonate concentration in the dialysate or blood.6ACTIVE 717707681 v1Attorney Docket No. 218079-021701 / PCT Mozarc Ref. No. A0009118 PCT

[0047] The term “bicarbonate source” can refer to a source of bicarbonate ions or bicarbonate predecessors. The bicarbonate source may include, for example, sodium carbonate. The bicarbonate can be in acid or basic form and can include substances that react to form bicarbonate when used in a dialysis system.

[0048] The term “comprising” includes, but is not limited to, whatever follows the word “comprising.” Use of the term indicates the listed elements are required or mandatory but that other elements are optional and may be present.

[0049] The term “conductivity” refers to the inverse of the electrical resistance of a fluid.

[0050] The term “conductivity increase” refers to a positive change in conductivity of a fluid as the fluid moves through a system.

[0051] The term “conductivity sensor” refers to any component capable of measuring the electrical conductance or the electrical resistance of a fluid.

[0052] The term “consisting of” includes and is limited to whatever follows the phrase “consisting of.” The phrase indicates the limited elements are required or mandatory and that no other elements may be present.

[0053] The term “consisting essentially of” includes whatever follows the term “consisting essentially of” and additional elements, structures, acts, or features that do not affect the basic operation of the apparatus, structure or method described.

[0054] The terms “control,” “controlling,” or “controls” can refer to the ability of one component to direct the actions of a second component.

[0055] A “controller” is a device which monitors and affects the operational conditions of a given system. The operational conditions are typically referred to as output variables of the system wherein the output variables can be affected by adjusting certain input variables.

[0056] A “degasser” refers to any device, component, or system that can be used to remove one or more gases from a fluid.

[0057] The term “detect” refers to ascertaining a state of a system or component.7ACTIVE 717707681 v1Attorney Docket No. 218079-021701 / PCT Mozarc Ref. No. A0009118 PCT

[0058] The terms “determining,” “determines,” and the like, generally refer to, in the broadest reasonable interpretation, any process or method for obtaining or coming to a decision, value, number, or finding, for any one or more value, output, parameter, or variable, by any means applicable to the relevant parameter being determined.

[0059] The term “dialysate” refers to any mixture that provides for passing solutes of any type through a membrane of any type. Typically, a dialysate contains a concentration of solutes to exchange solutes across a gradient to and from the dialysate during dialysis therapy.

[0060] The term “dialysate flow path” refers to a pathway through which dialysate travels during dialysis therapy.

[0061] The term “dialysate flow rate” refers to a volume of dialysate moving through a system per unit of time.

[0062] The term “dialysate inlet” refers to an opening or conduit through which dialysate can enter a component.

[0063] The term “dialysate outlet” refers to an opening or conduit through which dialysate can exit a component.

[0064] The term “dialyzer” can refer to a cartridge or container with two flow paths separated by semi-permeable membranes. One flow path can be for blood and one flow path can be for dialysate. The membranes can be in hollow fibers, flat sheets, or spiral wound or other conventional forms known to those of skill in the art. Membranes can be selected from any one or combination of materials: polysulfone, polyethersulfone, poly (methyl methacrylate), modified cellulose, or other materials known to those skilled in the art.

[0065] The term “dilute” means to lower a concentration of one or more solutes in solution.

[0066] The term “downstream” refers to a position of a first component in a flow path relative to a second component wherein fluid, gas, or combinations thereof, will pass by the second component prior to the first component during normal8ACTIVE 717707681 v1Attorney Docket No. 218079-021701 / PCT Mozarc Ref. No. A0009118 PCT operation. The first component can be said to be “downstream” of the second component, while the second component is “upstream” of the first component.

[0067] The term “estimate” can refer to an approximation of a value for a particular parameter.

[0068] The terms “exit” or “exiting” refer to a fluid leaving a container or component.

[0069] The term “fluidly connectable” refers to the ability to provide passage of fluid, gas, or combinations thereof, from one point to another point. The ability to provide such passage can be any mechanical connection, fastening, or forming between two points to permit the flow of fluid, gas, or combinations thereof. The two points can be within or between any one or more of compartments, modules, systems, components, and rechargers, all of any type. Notably, the components that are fluidly connectable, need not be a part of a structure. For example, an outlet “fluidly connectable” to a pump does not require the pump, but merely that the outlet has the features necessary for fluid connection to the pump.

[0070] The term “fluidly connected” refers to a particular state or configuration of one or more components such that fluid, gas, or combination thereof, can flow from one point to another point. The connection state can also include an optional unconnected state or configuration, such that the two points are disconnected from each other to discontinue flow. It will be further understood that the two “fluidly connectable” points, as defined above, can form a “fluidly connected” state. The two points can be within or between any one or more of compartments, modules, systems, components, all of any type.

[0071] The term “infusate source” refers to one or more sources of cations, such as potassium, calcium, or magnesium cations, for addition to a dialysate.

[0072] The term “low pH” refers to a pH low enough that will result in substantially all bicarbonate being converted to carbon dioxide.

[0073] The term “measuring” or “to measure” can refer to determining any parameter or variable. The parameter or variable can relate to any state or value of a system, component, fluid, gas, or mixtures of one or more gases or fluids.9ACTIVE 717707681 v1Attorney Docket No. 218079-021701 / PCT Mozarc Ref. No. A0009118 PCT

[0074] The term “patient bicarbonate level” refers to the bicarbonate concentration in the blood of a patient.

[0075] The term “pH” refers to a value equal to the negative log of the H+ ion concentration in a fluid.

[0076] The term “pH sensor” refers to any sensor or set of sensors that can be used to determine the pH of a fluid.

[0077] The term “preset” refers to a value of a parameter or state of a component or system that is determined in advance of a dialysis session.

[0078] The term “programmed,” when referring to a processor, can mean a series of instructions that cause a processor to perform certain steps.

[0079] The term “sodium” refers to Na+ ions in solution.

[0080] The term “sodium concentration” refers to an amount of sodium ions dissolved in a given amount of solvent.

[0081] A “sodium prescription” is an intended sodium concentration in a dialysate or blood.

[0082] The terms “sorbent cartridge” and “sorbent container” can refer to a cartridge containing one or more sorbent materials for removing specific solutes from solution, such as urea. The term “sorbent cartridge” does not require the contents in the cartridge be sorbent based, and the contents of the sorbent cartridge can be any contents that can remove waste products from a dialysate. The sorbent cartridge may include any suitable amount of one or more sorbent materials. In certain instances, the term “sorbent cartridge” can refer to a cartridge which includes one or more sorbent materials in addition to one or more other materials capable of removing waste products from dialysate. “Sorbent cartridge” can include configurations where at least some materials in the cartridge do not act by mechanisms of adsorption or absorption. In any embodiment, a system may include a number of separate cartridges which can be physically separated or interconnected wherein such cartridges can be optionally detached and reattached as desired.10ACTIVE 717707681 v1Attorney Docket No. 218079-021701 / PCT Mozarc Ref. No. A0009118 PCT

[0083] The term “upstream” refers to a position of a first component in a flow path relative to a second component wherein fluid, gas, or combinations thereof, will pass by the first component prior to the second component during normal operation. The first component can be said to be “upstream” of the second component, while the second component is “downstream” of the first component.

[0084] A “water source” can be any fluid source from which water can be obtained. The source can be any type of reservoir, fluid line, or receptacle. The water from the water source can be water with or without any dissolved solutes, including one or more buffer or ions.

[0085] The term “zirconium concentration” refers to the amount of zirconium within a defined amount of fluid. For example, the amount of zirconium may be a mass of zirconium per unit volume.

[0086] “Zirconium oxide” or “hydrous zirconia” is a sorbent material that removes anions from a fluid.

[0087] “Zirconium phosphate” is a sorbent material that removes cations from a fluid, exchanging the removed cations for different cations.

[0088] ZIRCONIUM DETECTION

[0089] The present disclosure relates to systems and methods for detecting when an unsafe level of zirconium may be present in dialysate during a hemodialysis therapy. In some cases, sorbent components in a dialysis system may include zirconium phosphate and hydrous zirconium oxide, which can leach zirconium into the dialysate, depending on the solution conditions in the sorbent cartridge. High levels of zirconium may be harmful to a patient such that exposure to these high levels in a dialysate should be minimized. In general, as the bicarbonate level in the sorbent cartridge increases, the level of zirconium leaving the cartridge increases. The present disclosure provides systems and methods for determining when levels of bicarbonate increase in the sorbent cartridge in order to stop therapy as needed if the expected zirconium levels exceed safe levels for the patient in therapy.11ACTIVE 717707681 v1Attorney Docket No. 218079-021701 / PCT Mozarc Ref. No. A0009118 PCT

[0090] FIG. 1 depicts a simplified diagram of a sorbent-based dialysis system 100 according to embodiments of the present disclosure. As depicted in FIG. 1, in some embodiments, a dialyzer 102 may be fluidly connected to an extracorporeal flow path (not shown) and fluidly connectable to a dialysate flow path 101. Blood from a patient may enter the dialyzer 102 through blood inlet 103 and exit the dialyzer 102 through a blood outlet 104. At the same time, dialysate can enter the dialyzer 102 through a dialysate inlet 106 and exit through a dialysate outlet 107. The dialysate and blood may be separated in the dialyzer 102 by a semi-permeable membrane 105. Solutes and fluid may pass between the blood and the dialysate through the semi-permeable membrane 105.

[0091] After exiting the dialyzer 102, the dialysate may be pumped through the dialysate flow path 101. In some embodiments, one or more pumps (not shown) may provide the driving force necessary to control the movement of dialysate through the dialysate flow path 101. A portion of the dialysate may be drawn off as ultrafiltrate by an ultrafiltration system 108. If necessary to control sodium concentration water may be added to the dialysate from a water source 110 that is connected to the dialysate flow path 101. The used dialysate may be pumped through a sorbent cartridge 112 to regenerate the dialysate.

[0092] In some embodiments, the sorbent cartridge 112 may include one or more sorbent materials to remove solutes from the dialysate, allowing the dialysate to be reused. In some embodiments, the sorbent cartridge 112 may include activated carbon to remove at least one of creatinine, glucose, uric acid, [32-microglobulin or other nonionic toxins, except urea, from the dialysate. In some embodiments, the sorbent cartridge may also include urease, which converts urea to ammonium ions and carbon dioxide. The zirconium oxide in the sorbent cartridge 112 may remove at least one of phosphate, fluoride, or other anions from the dialysate. Zirconium phosphate in the sorbent cartridge 112 may remove the ammonium ions generated from the breakdown of urea by the urease. The zirconium phosphate in the sorbent cartridge 112 may also remove at least one of potassium, calcium, or magnesium cations. The cations removed by the zirconium phosphate may be exchanged for sodium and hydrogen ions.12ACTIVE 717707681 v1Attorney Docket No. 218079-021701 / PCT Mozarc Ref. No. A0009118 PCT

[0093] Carbon dioxide present in the dialysate exiting the sorbent cartridge 112 (i.e., sorbent cartridge effluent) may be removed by a degasser 113 located downstream of the sorbent cartridge 112. Bicarbonate may be added to the dialysate from a bicarbonate source 115 and cations, such as potassium, magnesium, and calcium, may be added back into the dialysate from a cation infusate source 117. In some embodiments, the dialyzer 102, the sorbent cartridge 112, and the bicarbonate source 115 are connectable by a fluid flow path. In some embodiments, a bypass line 120 and a bypass valve 119 may be included to bypass either the dialyzer 102 or the sorbent cartridge 112.

[0094] In some embodiments, the system 100 may include a first conductivity sensor 114 for measuring a first conductivity of the fluid. The first sensor 114 may be positioned on the dialysate flow path 101 upstream of the bicarbonate source 115, as depicted in FIG. 1. The system 100 may also include a second sensor 116 for measuring a second conductivity of the fluid. The second sensor 114 may be positioned on the dialysate flow path 101 downstream of the bicarbonate source 115.

[0095] One of skill in the art will understand that the system illustrated in FIG. 1 is a simplified system for illustrative purposes only. Additional components may be included. For example, in some embodiments, additional pumps and valves can be included for operation of the degassing system, as well as control over ultrafiltration and addition of water, bicarbonate, and cation infusate. In some embodiments, the pumps and valves may be operated by a controller (not shown). In some embodiments, the controller may be programmed to receive data from sensors at various positions in the dialysate flow path 101, to determine any parameters or system state based on the received data, and to control the components of the dialysis system. For example, in addition to first conductivity sensor 114 and second conductivity sensor 116, a conductivity sensor 109 may be included to determine the conductivity of the dialysate exiting the dialyzer 102. In some embodiments, a conductivity sensor 111 may be included to determine the conductivity of dialysate after addition of water and prior to reaching the sorbent cartridge 112. In some embodiments, a conductivity sensor 118 may be included 13ACTIVE 717707681 v1Attorney Docket No. 218079-021701 / PCT Mozarc Ref. No. A0009118 PCT to measure the conductivity after the addition of the cation infusate to ensure the final dialysate has a proper composition prior to reaching the dialyzer 102. Additional sensors (not shown), such as temperature sensors, pressure sensors, pH sensors, or any other sensors may be included.

[0096] The controller may be configured to determine a zirconium concentration based on various parameters, as described in further detail below. For example, the controller may be configured to determine a zirconium concentration of the fluid downstream of the sorbent cartridge 112 and upstream of the bicarbonate source. The controller may be configured to control a dialysis treatment to a patient, such that when the zirconium concentration of the fluid is greater than a threshold, the dialysis treatment to the patient is discontinued. As described in further detail below, the controller may be configured to determine the zirconium concentration of the fluid based on at least one of: a bicarbonate concentration of the fluid, a bicarbonate prescription concentration and a concentration of the bicarbonate added to the fluid from the bicarbonate source, a flow rate of the bicarbonate added to the fluid from the bicarbonate source, an amount of the water added to the fluid from the water source, a change in conductivity across (e.g., the conductivity delta) the sorbent cartridge 112, or any combination thereof.

[0097] FIG. 2 is a flowchart of a method 200 for determining a zirconium concentration of a fluid (e.g., a dialysate) according to some embodiments. At 210, once a dialysis session has begun, a bicarbonate is added from the bicarbonate source 115 to a fluid exiting a sorbent cartridge 112 of the dialysis system 100. In some embodiments, the bicarbonate may be added from the bicarbonate source 115 to the fluid exiting the sorbent cartridge 112 to accurately control bicarbonate concentration within the dialysate. The amount of bicarbonate that is added from the bicarbonate source 115 may be determined based on a bicarbonate prescription and other various factors such as, but not limited to, an effluent bicarbonate concentration, a pH of the effluent or a conductivity of the effluent, as will be described in greater detail below.

[0098] At 220, a zirconium concentration of the fluid at a location downstream of the sorbent cartridge and upstream of the bicarbonate source is determined. As will be14ACTIVE 717707681 v1Attorney Docket No. 218079-021701 / PCT Mozarc Ref. No. A0009118 PCT discussed in further detail below, the zirconium concentration of the fluid at a location downstream of the sorbent cartridge and upstream of the bicarbonate source may be determined using various different methods, according to embodiments of the present disclosure.

[0099] During recirculating dialysis with the system 100, the sorbent cartridge effluent begins in a low pH phase and increases in pH during treatment. As the pH of the sorbent effluent increases, so does the level of bicarbonate due to the shifting equilibrium of total CO2 from carbonic acid to the bicarbonate form. As the bicarbonate level increases, so does the level of zirconium leaving the sorbent cartridge, possibly due to increased solubility of the zirconium-based sorbents contained in the sorbent cartridge. The pH of the cartridge will rise depending on the total exposure to CO2 sources during therapy. The CO2 sources include the conversion of urea to ammonium carbonate via the urease enzyme and bicarbonate maintained in the recirculating dialysate and transferring across the dialyzer due to the patient bicarbonate levels. Given the influence of patient urea and bicarbonate levels on the exposure of total CO2 to the sorbent cartridge, it has been difficult for known dialysis systems to predict when a pH rise in the sorbent cartridge may begin and when zirconium levels may become unsafe in the dialysate. In some embodiments, the current method provides various methods for determining the zirconium concentration in the dialysate.

[0100] In some embodiments, the zirconium concentration of the fluid is determined based on a flow rate of the bicarbonate added to the fluid from the bicarbonate source. A zirconium concentration of the fluid is strongly correlated to the amount of bicarbonate pumped out of the bicarbonate source 115. Restated, the flow rate of bicarbonate out of the bicarbonate source 115 is a strong indicator of the zirconium concentration in the sorbent cartridge effluent. At the beginning of a dialysis session, the sorbent cartridge 112 may be a low-pH sorbent cartridge. The pH of the sorbent cartridge 112 may be controlled by controlling the initial hydrogen to sodium ratio of the zirconium phosphate. A higher proportion of hydrogen ions will result in a lower pH of fluid exiting the sorbent cartridge 112. When the sorbent cartridge effluent pH is below a preset pH, substantially all bicarbonate in the 15ACTIVE 717707681 v1Attorney Docket No. 218079-021701 / PCT Mozarc Ref. No. A0009118 PCT dialysate will be converted to carbon dioxide and subsequently removed by the degasser, effectively reducing the total CO2 or bicarbonate in the sorbent cartridge effluent downstream of the degasser to a concentration approaching 0-mM. Accordingly, to meet the bicarbonate prescription of the dialysis therapy session, the bicarbonate source 115 will pump the entire prescription amount of bicarbonate to the sorbent cartridge effluent. As the dialysis session continues, however, the pH rises above a threshold level and bicarbonate remains in the sorbent cartridge effluent. Because the bicarbonate concentration in the sorbent cartridge effluent downstream of the degasser is above 0-mM, less bicarbonate will be pumped out of the bicarbonate source 115 to the sorbent cartridge effluent to meet the bicarbonate prescription. Thus, the flow rate of bicarbonate out of the bicarbonate source 115 when the pH has crossed above the threshold pH value will be less than the flow rate of bicarbonate out of the bicarbonate source 115 at the beginning of the dialysis session. Because zirconium concentration in the sorbent cartridge effluent increases as bicarbonate in the sorbent cartridge effluent increases, one may determine that when the flow rate of bicarbonate out of the bicarbonate source 115 decreases, the zirconium concentration within the sorbent cartridge effluent is increasing.

[0101] For example, if the dialysate prescription is 40-mM bicarbonate, then the bicarbonate source 115 will be pumping 40-mM sodium bicarbonate into the sorbent cartridge effluent during the low pH phase of therapy when the bicarbonate exiting the sorbent cartridge 112 is approximately 0-mM. As the pH rises above the threshold level, the system 100 will detect this rise and begin metering sodium bicarbonate to reach a desired conductivity set point corresponding to the prescribed bicarbonate level. An output, or flow rate, out of the bicarbonate source 115 will decrease as the pH rises due to increased bicarbonate exiting the sorbent cartridge 112. For example, if the bicarbonate source 115 decreases to an addition rate corresponding to a bicarbonate add of 25-mM to achieve 40-mM bicarbonate in the dialysate, the addition rate would indicate that the bicarbonate level exiting the sorbent cartridge is 15-mM. Given the strong correlation between bicarbonate level and zirconium level exiting the sorbent cartridge 112, the dialysate zirconium16ACTIVE 717707681 v1Attorney Docket No. 218079-021701 / PCT Mozarc Ref. No. A0009118 PCT concentration can also be estimated and the therapy ended if the concentration is becoming unsafe. The dialysate zirconium concentration may be estimated based properties of the zirconium phosphate and zirconium oxide within the sorbent. For example, in some embodiments, the zirconium concentration may be determined as a function of the specifications of the specific sorbent. As the properties of sorbents vary, the properties may be determined prior to use to be able to determine zirconium concentration during use.

[0102] In some embodiments, the threshold pH is 4.2 to 5.0, or the threshold pH is 4.2 to 4.8, or the threshold pH is 4.2 to 4.4, or the threshold pH is 4.4 to 5.0, or the threshold pH is 4.6 to 5.0, or the threshold pH is 4.8 to 5.0, or the threshold pH is 4.3 to 4.5, or the threshold pH is 4.5 to 4.7, or the threshold pH is 4.4 to 4.6.

[0103] In some embodiments, the zirconium concentration of the fluid is determined based on a bicarbonate prescription concentration and a concentration of the bicarbonate added to the fluid. A zirconium concentration of the fluid is strongly correlated to the bicarbonate level exiting the sorbent cartridge. As discussed above, when the sorbent cartridge effluent pH is below a preset pH, substantially all bicarbonate in the sorbent cartridge effluent will be converted to carbon dioxide and subsequently removed by the degasser 113, effectively reducing the bicarbonate in the sorbent cartridge effluent downstream of the degasser to a concentration approaching 0-mM. Accordingly, to meet the bicarbonate prescription of the dialysis session, the bicarbonate source 115 will add the entire prescription amount of bicarbonate to the sorbent cartridge effluent. As the dialysis session continues, because the bicarbonate concentration in the sorbent cartridge effluent downstream of the degasser is above 0-mM, less bicarbonate will be added to the sorbent cartridge effluent to meet the bicarbonate prescription.

[0104] Using the example provided above, if the dialysate prescription is 40-mM bicarbonate, then the bicarbonate pump will be delivering 40-mM sodium bicarbonate during the low pH phase of therapy when the bicarbonate concentration of the sorbent cartridge effluent downstream of the degasser is approximately zero. As the pH rises above the threshold level, the output of the17ACTIVE 717707681 v1Attorney Docket No. 218079-021701 / PCT Mozarc Ref. No. A0009118 PCT bicarbonate source 115 will decrease as the pH rises due to an increased concentration of bicarbonate in the sorbent cartridge effluent. For example, if the bicarbonate pump decreases to an addition rate corresponding to a bicarbonate add of 25-mM to achieve the prescription concentration of 40-mM bicarbonate in the dialysate, the addition amount would indicate that the bicarbonate concentration exiting the sorbent cartridge is 15-mM. Because the concentration of bicarbonate added to the sorbent cartridge effluent has decreased from the bicarbonate prescription concentration, one can deduce that the bicarbonate concentration in the sorbent cartridge effluent has increased. Given the strong correlation between bicarbonate concentration in the sorbent cartridge effluent and zirconium level in the sorbent cartridge effluent, the dialysate zirconium concentration can also be estimated.

[0105] In some embodiments, the zirconium concentration of the fluid is determined based on a change in the conductivity of the fluid. The system may control the addition of bicarbonate to achieve a post-bicarbonate conductivity setpoint, measured after bicarbonate is added by the bicarbonate source 115 to the sorbent cartridge effluent, as measured by conductivity sensor 116. The post-bicarbonate conductivity setpoint can be a fixed value for each individual patient based on the sodium and bicarbonate prescription. Alternatively, the post-bicarbonate conductivity setpoint can be based on achieving a target conductivity delta between the conductivity sensor 114 and the post-bicarbonate conductivity sensor 116. As the pH of the sorbent cartridge increases, the bicarbonate concentration, and corresponding sodium concentration, increases, resulting in a smaller conductivity change between the conductivity sensor 114 and the post-bicarbonate conductivity sensor 116. Thus, a change in conductivity of the sorbent cartridge effluent may be determined by measuring a first conductivity of the sorbent cartridge effluent before the bicarbonate is added thereto, measuring a second conductivity of the sorbent cartridge effluent after the bicarbonate is added thereto, and determining a difference between the second conductivity and the first conductivity. Based on the difference between the second conductivity and the first conductivity, the zirconium concentration of the sorbent cartridge effluent may18ACTIVE 717707681 v1Attorney Docket No. 218079-021701 / PCT Mozarc Ref. No. A0009118 PCT be determined. Specifically, if the delta between the pre-bicarbonate conductivity and the post-bicarbonate conductivity decreases below a threshold value, it may be determined that the pH of the sorbent cartridge has increased above the pH threshold value, and thus, the bicarbonate concentration and, therefore, the zirconium concentration in the sorbent cartridge effluent has increased.

[0106] Alternatively, the detection of sorbent outlet pH can be determined based on the conductivity change across the sorbent cartridge normalized to the water dilution rate needed to achieve the target post-sorbent conductivity set point by using equation (1):(SCS - PCS) / (1-Q-H2O / QDout),where SCS is the conductivity measured by conductivity sensor 114, PCS is the conductivity measured by conductivity sensor 111, Q-H2O is the water addition rate from water source 110, and QDout is the dialysate flow rate at the dialyzer outlet 107. In addition, the SCS and PCS values used in equation (1) can be offset in time due to the volume of the sorbent cartridge and the time it takes fluid to flow from the inlet of the cartridge to the outlet. For example, a sorbent cartridge with a void volume of 4 liters will require 8 minutes for fluid to flow from the inlet to outlet at a flow rate of 500-mL / min. Therefore, the SCS value at 8 minutes should be compared to the PCS value at 0 minutes. The conductivity delta across the sorbent cartridge, SCS-PCS, is mainly influenced by the concentration of sodium bicarbonate entering the sorbent cartridge 112, which is determined by the bicarbonate prescription and patient parameters. In the low pH phase, all of the sodium bicarbonate entering the sorbent cartridge 112 is removed resulting in a conductivity decrease. Because the SCS-PCS, or conductivity delta across the sorbent cartridge 112, can vary in the low pH phase due to difference in prescription or patient parameters, a plateau value can be calculated and subsequent conductivity deltas across the sorbent cartridge 112 can be compared to the plateau value to determine when the pH has increased to the threshold pH value. The plateau value can be determined by averaging the SCS-PCS values over a certain time, or dialysate volume, and starting at a particular dialysate volume.19ACTIVE 717707681 v1Attorney Docket No. 218079-021701 / PCT Mozarc Ref. No. A0009118 PCT

[0107] For example, after 40-I iters of dialysate volume the SCS-PCS values, or the values calculated in Eq (1), can be averaged from 40 to 50-liters. Then the conductivity delta across the sorbent cartridge (SCS-PCS) can be compared to the average plateau value to determine when the pH value has exceeded the threshold pH value. For example, an increase in SCS-PCS of 0.44-mS / cm relative to the plateau value can indicate the pH has risen to a value exceeding a threshold value of, for example, 4.8. Again, as the pH rises, the bicarbonate concentration in the sorbent cartridge effluent will start to rise, indicating that the zirconium concentration in the sorbent cartridge effluent is rising.

[0108] At 230, the controller compares the zirconium concentration within the fluid dialysate to a zirconium concentration threshold value. The zirconium concentration threshold value may be determined based on a toxic limit for a patient with a safety margin as needed. The toxic limit for a patient may be based on previously determined / measured toxicity limits and animal toxicity studies. If the zirconium concentration of the fluid is greater than the zirconium concentration threshold value, at 240 the dialysis treatment is discontinued. If the zirconium concentration of the fluid is less than the zirconium concentration threshold value, at 250 the dialysis treatment is continued. As described herein, the zirconium toxicity limit is a mass of zirconium per mass of patient per day. Thus, the zirconium toxicity limit will vary between patients, depending on the mass of the patient.

[0109] FIG. 3 is a flowchart of a method 300 for determining a zirconium concentration of a fluid, according to some embodiments. At 310, a zirconium concentration of a fluid exiting a sorbent cartridge of a dialysis system is determined. As will be discussed in further detail below, the zirconium concentration of a fluid exiting a sorbent cartridge of a dialysis system may be determined using various different methods, according to embodiments of the present disclosure.

[0110] In some embodiments, the zirconium concentration of the fluid is determined based on a bicarbonate concentration of the fluid. As described above with regard to method 200, during recirculating dialysis with the system 100, the sorbent cartridge effluent begins in a low pH phase and increases in pH during treatment.20ACTIVE 717707681 v1Attorney Docket No. 218079-021701 / PCT Mozarc Ref. No. A0009118 PCT As the pH of the sorbent effluent increases, so does the bicarbonate concentration due to the shifting equilibrium of total CO2 from carbonic acid to the bicarbonate form. As the bicarbonate concentration increases, so does the level of zirconium leaving the sorbent cartridge, possibly due to increased solubility of the zirconium- based sorbents contained in the sorbent cartridge 112.

[0111] In some embodiments, the zirconium concentration of the fluid is determined based on a pH of the fluid. As described above, during dialysis therapy, sodium and bicarbonate is added to the sorbent cartridge effluent at the prescription concentration while the sorbent effluent pH is low enough to convert substantially all the bicarbonate to carbon dioxide. The controller can monitor the sorbent cartridge effluent pH and determine whether the sorbent cartridge effluent pH is below the threshold pH level. If the sorbent cartridge effluent pH is below the threshold pH, the system 100 continues to add bicarbonate and sodium at the prescription concentration. However, if the pH exceeds the threshold pH, the controller determines that some concentration of bicarbonate, and thus, a concentration of zirconium, remains in the dialysate after passing through the sorbent cartridge 112 and degasser 113.

[0112] The system 100 may use a pH sensor at the outlet of the sorbent cartridge to measure the effluent pH. Alternatively, the system can monitor the degasser output to determine changes in the sorbent effluent pH. As the pH rises, there will be less CO2 to degas, and the degasser output will decrease. In certain embodiments, the system can detect the sorbent cartridge effluent pH state based on conductivity changes across the sorbent cartridge. As the pH of the sorbent cartridge increases, the bicarbonate concentration, and corresponding sodium concentration, increases, resulting in a smaller conductivity change across the sorbent cartridge. A zirconium concentration in the sorbent cartridge effluent is closely correlated with the rise in the pH of the sorbent cartridge effluent such that the zirconium concentration may be determined based on the increase of the pH above the threshold value.

[0113] In some embodiments, the zirconium concentration of the fluid is determined based on an amount of the water added to the fluid from the water source 110 upstream of the sorbent cartridge 112. The system 100 may also detect the sorbent21ACTIVE 717707681 v1Attorney Docket No. 218079-021701 / PCT Mozarc Ref. No. A0009118 PCT cartridge effluent pH state based on changes in the water addition rate needed to maintain the sorbent outlet conductivity target. As the pH rises and the sodium bicarbonate concentration increases, the sorbent outlet conductivity will increase and require an increase in water dilution to maintain the post-sorbent conductivity setpoint.

[0114] For example, if a dialysate sodium of 140-mM and bicarbonate of 40-mM are desired, the sodium chloride level needed at sorbent outlet would be 100-mM and the conductivity set-point would correspond to the conductivity of a 100-mM sodium chloride solution. The remaining 40 mM of sodium will be added by addition of sodium bicarbonate after the dialysate passes through the degasser 113. Water from water source 110 can be added to the dialysate to dilute the dialysate if necessary to reach the post-sorbent conductivity setpoint. However, the amount of water added to the dialysate will increase to maintain the post-sorbent conductivity setpoint as the pH rises in the sorbent cartridge effluent, and the sodium bicarbonate concentration increases. Although illustrated in FIG.1 as upstream of the sorbent cartridge 112, the water source 110 can alternatively be positioned downstream of the sorbent cartridge 112.

[0115] At 320, the controller compares the zirconium concentration within the fluid dialysate to a zirconium concentration threshold value. The zirconium concentration threshold value may be determined based on a toxic limit for a patient with a safety margin as needed. The toxic limit for a patient may be based on previously determ ined / measured toxicity limits and animal toxicity studies. If the zirconium concentration of the fluid is greater than the zirconium concentration threshold value, at 330 the dialysis treatment is discontinued. If the zirconium concentration of the fluid is less than the zirconium concentration threshold value, at 340 the dialysis treatment is continued. In some embodiments, the threshold is a percentage of a zirconium toxicity limit, where the zirconium toxicity limit is a mass of zirconium per mass of patient per day. Thus, the zirconium toxicity limit will vary between patients, depending on the mass of the patient. In some embodiments, the percentage of the zirconium toxicity limit may be 10% to 100%, or 20% to 100%, or 30% to 100%, or 40% to 100%, or 50% to 100%, or 60% to 100%, or 70% to 100%, or 80% to 100%, or 90% to 100%, or 10% to 90%, or 10% to 80%, or 10% to 70%, or 10% to 60%, or 10% to 50%, or 10% to 40%, or 10% to 30%, or 10% to 20%,22ACTIVE 717707681 v1Attorney Docket No. 218079-021701 / PCT Mozarc Ref. No. A0009118 PCT or 40% to 50%, or 20% to 30%, or 20% to 50%, or 40% to 70%, or 70% to 90%, or 30% to 60%.

[0116] EXAMPLES

[0117] An example of the control approach utilized a prototype hemodialysis test system configured similar to the system of FIG. 1 for 5 runs. The graphs depicted in FIG.4- FIG. 6 below illustrate correlations between cumulative zirconium mass in the dialysate and various parameters on the console that are controlled, monitored, or calculated during a simulated treatment. As an example, one can consider a zirconium toxicity exposure limit of 0.22 mg / kg / day. For a 30 kg patient receiving 5 therapies perweekthe per therapy exposure limit would be 9.24 mg of zirconium. Assuming an addional safety limit of 20%, based on uncertainies, the alarm limit could be 1.8 mg. A 110 kg patient receiving 5 therapies per week the per therapy exposure limit would be 33.88 mg of zirconium. Assuming an addional safety limit of 20%, based on uncertainies, the alarm limit could be 6.8 mg. FIG. 4 depicts a cumulative zirconium mass exiting the sorbent cartridge versus the sorbent cartridge effluent pH during a simulated therapy. The X represents the average mass of 15 experiments. FIG. 5 depicts the cumulative mass of zirconium exiting the sorbent cartridge vs. the bicarbonate level exiting the cartridge for 15 experiments. FIG. 6 is a graph depicts the sorbent effluent pH profile vs. the total CO2 exposure to the cartridge.

[0118] An example of the control approach utilized a prototype hemodialysis test system configured the same as FIG. 1 for 7 runs. The graphs below illustrate correlations between cumulative zirconium mass in the dialysate and various parameters on the console that are controlled, monitored, or calculated during a simulated treatment. As an example, one can consider a zirconium toxicity exposure limit of 0.22 mg / kg / day. For a 30 kg patient receiving 7 therapies per week the per therapy exposure limit would be 6.6 mg of zirconium. Assuming an addional safety limit of 20%, based on uncertainies, the alarm limit could be 1.3 mg. A 90 kg patient would have an alarm limit 3 times higher than a 30 kg patient, so for this example the 90 kg patient alarm limit could be 3.9 mg.23ACTIVE 717707681 v1Attorney Docket No. 218079-021701 / PCT Mozarc Ref. No. A0009118 PCT

[0119] FIG. 7 is a graph depicting cumulative zirconium mass in the dialysate versus treatment volume. All of the runs except one exceed the example exposure limit of 1.3 mg before reaching the end of therapy, illustrating the need for protective system to prevent over zirconium exposure.

[0120] FIG. 8 is a graph depicting cumulative zirconium mass in the dialysate versus bicarbonate pump rate (Q-Bicarb). Zirconium mass increases as the bicarbonate pump rate decreases. As the bicarbonate level exiting the sorbent cartridge increases, the bicarbonate pump rate decreases and the zirconium level increases.

[0121] FIG. 9 is a graph depicting cumulative zirconium mass in the dialysate versus bicarbonate pump rate (QBicarb) divided by dialysate flow rate (QD). FIG. 9 is similar to the graph in FIG. 8, but the bicarbonate flow rate is normalized to the dialysate flow rate.

[0122] FIG. 10 is a graph depicting cumulative zirconium mass in the dialysate versus the bicarbonate added after the sorbent cartridge by the bicarbonte pump. The bicarbonate added is calculated based on the bicarbonate pump flow rate, dialysate flow rate and the concentration of the bicarbonate solution added, in this case 1300 mM.

[0123] FIG. 11 is a graph depicting cumulative zirconium mass in the dialysate versus sorbent cartridge outlet bicarbonate concentration. The sorbent outlet bicarbonate concentration is calculated based on the bicarbonate add (depicted in the graph of FIG.10) and the dialysate bicarbonate target. For example, if the calculated bicarbonate add is 20 mM and the dialysate bicarbonate target is 40 mM, then the sorbent outlet bicaronate level is 20 mM.

[0124] FIG. 12 is a graph depicting cumulative zirconium mass in the dialysate versus the conductivity delta between the sorbent outlet (SCS) and after the bicarbonate pump (BCS). The conductivity delta decreases as less bicarbonate is added by the bicarbonate pump, indicating increasing levels of bicarbonate exiting the sorbent cartridge and therefore increased zirconium mass. For a 1.3 mg Zr limit, the system could alarm and stop therapy when the BCS minus SCS conductivity delta equals 1.2 mS / cm or less. Also, shown is a polynomial regression fit, which 24ACTIVE 717707681 v1Attorney Docket No. 218079-021701 / PCT Mozarc Ref. No. A0009118 PCT could be used to estimate alarm limits for larger patients. For a 90 kg patient with an alarm limit of 3.9 mg the therapy could stop if the BCS minus SCS conductivity reaches 0.8 mS / cm.

[0125] FIG. 13 is a graph depicting cumulative zirconium mass in the dialysate versus a trigger value, where the trigger value is calculated as the difference between the pre-sorbent conductivity (PSC) and the post-sorbent conductivity (SCS) normalized to the fraction of water added (QW) to dilute the dialysate (QD) with the following equation:Trigger = (PCS - SCS) / (1 - (QW / QD)) - Plateau Valuewhere the Plateau value is the 10-liter average (PCS - SCS) / (1 - (QW / QD)) value calculated from 40 to 50 liters during therapy. The test runs show that a 1.3 mg zirconium limit would equal a trigger value of 2.0 mS / cm, whereas a 3.9 mg zirconium limit would equal a trigger value of approximately 2.5 mS / cm, based on the exponential regression shown.

[0126] FIG. 14 is a graph depcting zirconium concentration in the dialysate versus a trigger value. In addition to stopping the therpay based on reaching a zirconium mass limit, a concentration limit could also stop the therapy. In some cases, a high zirconium concentration could be hazardous to the patient, or be used as a surrogate for zirconium mass. As an example, if the zirconium concentration limit was set to 200 mg / L = 200 ppm, the therapy could stop when the trigger value reaches 2.2 mS / cm. All the examples shown above could also be based on zirconium concentration instead of zirconium mass.

[0127] FIG. 15 is a graph depicting cumulative zirconium mass in the dialysate versus zirconium concentration in the dialysate (Zr Instant) along with a polynomial regression. The instantaneous zirconium concentration can be used to stop the therapy based on correlation with the zirconium mass or based on a concentration safety limit, using the parameter correlations shown above.

[0128] FIG. 16 is a graph depicting sorbent effluent zirconium concentration and sorbent effluent conductivity vs. volume of sorbent effluent. As shown in the figure, as the conductivity of the sorbent effluent increases, zirconium concentration increases,25ACTIVE 717707681 v1Attorney Docket No. 218079-021701 / PCT Mozarc Ref. No. A0009118 PCT which would require an increased water dilution rate in order to maintain a fixed conductivity value.

[0129] FIG. 17 is a graph depicting effluent zirconium concentration vs. sorbent effluent conductivity. As shown in the figure, as the conductivity of the sorbent effluent increases, zirconium concentration increases, which would require an increased water dilution rate in order to maintain a fixed conductivity value.

[0130] One of skill in the art will understand the data used in FIGS. 3-15 are from a simulated patient and provided for illustrative purposes only. The same methods can be used with any patient to accurately control the sodium and bicarbonate content of the dialysate.

[0131] One skilled in the art will understand that various combinations and / or modifications and variations can be made in the described systems and methods depending upon the specific needs for operation. Various aspects disclosed herein may be combined in different combinations than the combinations specifically presented in the description and accompanying drawings. Moreover, features illustrated or described as being part of an aspect of the disclosure may be used in the aspect of the disclosure, either alone or in combination, or follow a preferred arrangement of one or more of the described elements. Depending on the example, certain acts or events of any of the processes or methods described herein may be performed in a different sequence, may be added, merged, or left out altogether (e g., certain described acts or events may not be necessary to carry out the techniques). In addition, while certain aspects of this disclosure are described as performed by a single module or unit for purposes of clarity, the techniques of this disclosure may be performed by a combination of units or modules associated with, for example, a medical device.

[0132] ASPECTS

[0133] Various Aspects are described below. It is to be understood that any one or more of the features recited in the following Aspect(s) can be combined with any one or more other Aspect(s).Aspect 1. A method comprising:26ACTIVE 717707681 v1Attorney Docket No. 218079-021701 / PCT Mozarc Ref. No. A0009118 PCT adding a bicarbonate, from a bicarbonate source, to a fluid exiting a sorbent cartridge of a dialysis system;determining a zirconium concentration of the fluid at a location downstream of the sorbent cartridge and upstream of the bicarbonate source; andcontrolling a dialysis treatment to a patient, such that:when the zirconium concentration of the fluid is greater than a threshold, the dialysis treatment is discontinued.Aspect 2. The method according to Aspect 1 , wherein the sorbent cartridge comprises at least one sorbent comprising at least one of a zirconium phosphate, a zirconium oxide, or any combination thereof.Aspect s. The method according to any one of Aspects 1-2, wherein the step of determining the zirconium concentration of the fluid comprises:determining the zirconium concentration of the fluid based on a flow rate of the bicarbonate added to the fluid from the bicarbonate source.Aspect 4. The method according to any one of Aspects 1-3, wherein the step of determining the zirconium concentration of the fluid comprises:determining the zirconium concentration of the fluid based on a bicarbonate prescription concentration and a concentration of the bicarbonate added to the fluid.Aspect s. The method according to any one of Aspects 1-4, wherein the step of determining the zirconium concentration of the fluid comprises:measuring a first conductivity of the fluid before the bicarbonate is added to the fluid;measuring a second conductivity of the fluid after the bicarbonate is added to the fluid; anddetermining the zirconium concentration of the fluid based on a difference between the second conductivity and the first conductivity.27ACTIVE 717707681 v1Attorney Docket No. 218079-021701 / PCT Mozarc Ref. No. A0009118 PCT Aspect 6. The method according to any one of Aspects 1-5, wherein, when the zirconium concentration of the fluid is less than the threshold, the dialysis treatment is continued.Aspect 7. The method according to any one of Aspects 1-6, wherein the threshold is a percentage of a zirconium toxicity limit, wherein the zirconium toxicity limit is a mass of zirconium per mass of patient per day.Aspect 8. A method comprising:determining a zirconium concentration of a fluid exiting a sorbent cartridge of a dialysis system; andcontrolling a dialysis treatment to a patient, such that:when the zirconium concentration of the fluid is greater than a threshold, the dialysis treatment is discontinued.Aspect 9. The method according to Aspect 8, wherein the sorbent cartridge comprises at least one sorbent comprising at least one of a zirconium phosphate, a zirconium oxide, or any combination thereof.Aspect 10. The method according to any one of Aspects 8-9, wherein the step of determining the zirconium concentration of the fluid comprises:determining the zirconium concentration of the fluid based on a bicarbonate concentration of the fluid.Aspect 11. The method according to any one of Aspects 8-10, wherein the step of determining the zirconium concentration of the fluid comprises:determining the zirconium concentration of the fluid based on a pH of the fluid. Aspect 12. The method according to any one of Aspects 8-11 , further comprising: adding a water, from a water source, to the fluid at a location upstream of the sorbent cartridge;wherein the step of determining the zirconium concentration of the fluid comprises:28ACTIVE 717707681 v1Attorney Docket No. 218079-021701 / PCT Mozarc Ref. No. A0009118 PCT determining the zirconium concentration of the fluid based on at least an amount of the water added to the fluid from the water source a change in conductivity across the sorbent cartridge.Aspect 13. The method according to any one of Aspects 8-12, wherein, when the zirconium concentration of the fluid is less than the threshold, the dialysis treatment is continued.Aspect 14. The method according to any one of Aspects 8-13, wherein the threshold is a percentage of a zirconium toxicity limit, wherein the zirconium toxicity limit is a mass of zirconium per mass of patient per day.Aspect 15. A system comprising:a dialyzer;a sorbent cartridge;a bicarbonate source;wherein the dialyzer, the sorbent cartridge, and the bicarbonate source are connectable by a fluid flow path;wherein the bicarbonate source is configured to contain a bicarbonate for addition to a fluid exiting the sorbent cartridge; anda controller;wherein the controller is configured to:determine a zirconium concentration of the fluid downstream of the sorbent cartridge and upstream of the bicarbonate source; and control a dialysis treatment to a patient, such that:when the zirconium concentration of the fluid is greater than a threshold, the dialysis treatment to the patient is discontinued. Aspect 16. The system according to Aspect 15, wherein the controller is configured to determine the zirconium concentration of the fluid based on a bicarbonate concentration of the fluid.29ACTIVE 717707681 v1Attorney Docket No. 218079-021701 / PCT Mozarc Ref. No. A0009118 PCT Aspect 17. The system according to any one of Aspects 15-16, wherein the controller is configured to determine the zirconium concentration of the fluid based on a bicarbonate prescription concentration and a concentration of the bicarbonate added to the fluid from the bicarbonate source.Aspect 18. The system according to any one of Aspects 15-17, wherein the controller is configured to determine the zirconium concentration of the fluid based on a flow rate of the bicarbonate added to the fluid from the bicarbonate source.Aspect 19. The system according to any one of Aspects 15-18, further comprising: a first sensor for measuring a first conductivity,wherein the first sensor is upstream of the bicarbonate source; and a second sensor for measuring a second conductivity,wherein the second sensor is downstream of the bicarbonate source; wherein the controller is configured to determine the zirconium concentration of the fluid based on a difference between the second conductivity and the first conductivity.Aspect 20. The system according to any one of Aspects 15-19, further comprising: a water source,wherein the water source is connectable to the fluid flow path; wherein the water source is configured to contain a water for addition to the fluid entering the sorbent cartridge;wherein the controller is configured to determine the zirconium concentration of the fluid based on an amount of the water added to the fluid from the water source and a change in conductivity across the sorbent cartridge.30ACTIVE 717707681 v1

Claims

Attorney Docket No. 218079-021701 / PCT Mozarc Ref. No. A0009118 PCT CLAIMS WHAT IS CLAIMED IS:

1. A system comprising:a dialyzer;a sorbent cartridge;a bicarbonate source;wherein the dialyzer, the sorbent cartridge, and the bicarbonate source are connectable by a fluid flow path;wherein the bicarbonate source is configured to contain a bicarbonate for addition to a fluid exiting the sorbent cartridge; anda controller;wherein the controller is configured to:determine a zirconium concentration of the fluid downstream of the sorbent cartridge and upstream of the bicarbonate source; and control a dialysis treatment to a patient, such that:when the zirconium concentration of the fluid is greater than a threshold, the dialysis treatment to the patient is discontinued.

2. The system of claim 1, wherein the controller is configured to determine the zirconium concentration of the fluid based on a bicarbonate concentration of the fluid.

3. The system of claim 1, wherein the controller is configured to determine the zirconium concentration of the fluid based on a bicarbonate prescription concentration and a concentration of the bicarbonate added to the fluid from the bicarbonate source.

4. The system of claim 1, wherein the controller is configured to determine the zirconium concentration of the fluid based on a flow rate of the bicarbonate added to the fluid from the bicarbonate source.

5. The system of claim 1, further comprising:a first sensor for measuring a first conductivity,31ACTIVE 717707681 v1Attorney Docket No. 218079-021701 / PCT Mozarc Ref. No. A0009118 PCT wherein the first sensor is upstream of the bicarbonate source; and a second sensor for measuring a second conductivity,wherein the second sensor is downstream of the bicarbonate source; wherein the controller is configured to determine the zirconium concentration of the fluid based on a difference between the second conductivity and the first conductivity.

6. The system of claim 1 , further comprising:a water source,wherein the water source is connectable to the fluid flow path; wherein the water source is configured to contain a water for addition to the fluid entering the sorbent cartridge;wherein the controller is configured to determine the zirconium concentration of the fluid based on an amount of the water added to the fluid from the water source and a change in conductivity across the sorbent cartridge.

7. A method comprising:adding a bicarbonate, from a bicarbonate source, to a fluid exiting a sorbent cartridge of a dialysis system;determining a zirconium concentration of the fluid at a location downstream of the sorbent cartridge and upstream of the bicarbonate source; andcontrolling a dialysis treatment to a patient, such that:when the zirconium concentration of the fluid is greater than a threshold, the dialysis treatment is discontinued.

8. The method of claim 7, wherein the sorbent cartridge comprises at least one sorbent comprising at least one of a zirconium phosphate, a zirconium oxide, or any combination thereof.32ACTIVE 717707681 v1Attorney Docket No. 218079-021701 / PCT Mozarc Ref. No. A0009118 PCT 9. The method of claim 7, wherein the step of determining the zirconium concentration of the fluid comprises:determining the zirconium concentration of the fluid based on a flow rate of the bicarbonate added to the fluid from the bicarbonate source.

10. The method of claim 7, wherein the step of determining the zirconium concentration of the fluid comprises:determining the zirconium concentration of the fluid based on a bicarbonate prescription concentration and a concentration of the bicarbonate added to the fluid.

11. The method of claim 7, wherein the step of determining the zirconium concentration of the fluid comprises:measuring a first conductivity of the fluid before the bicarbonate is added to the fluid;measuring a second conductivity of the fluid after the bicarbonate is added to the fluid; anddetermining the zirconium concentration of the fluid based on a difference between the second conductivity and the first conductivity.

12. The method of claim 7, wherein, when the zirconium concentration of the fluid is less than the threshold, the dialysis treatment is continued.

13. The method of claim 7, wherein the threshold is a percentage of a zirconium toxicity limit, wherein the zirconium toxicity limit is a mass of zirconium per mass of patient per day.

14. The method of claim 7, wherein the step of determining the zirconium concentration of the fluid comprises:determining the zirconium concentration of the fluid based on a pH of the fluid.

15. The method of claim 7, further comprising:33ACTIVE 717707681 v1Attorney Docket No. 218079-021701 / PCT Mozarc Ref. No. A0009118 PCT adding a water, from a water source, to the fluid at a location upstream of the sorbent cartridge;wherein the step of determining the zirconium concentration of the fluid comprises:determining the zirconium concentration of the fluid based on an amount of the water added to the fluid from the water source and a change in conductivity across the sorbent cartridge.34ACTIVE 717707681 v1

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