A system for producing dialysate and a system for quantifying glucose in used dialysate.

Abstract

In fluorometer diagnostic mode, the system moves water and fluorescent probe material from the mixing chamber to the fluorometer. In filter diagnostic mode, the system moves water and fluorescent probe material from the mixing chamber to the inlet so that (i) a first portion of water and fluorescent probe material exits through the bypass outlet, moves into the mixing chamber, and returns, and (ii) a second portion of water passes through the filter to the fluorometer. In dialysate dispensing mode, the system moves dialysate and fluorescent probe material from the mixing chamber to the inlet so that (i) a first portion of dialysate and fluorescent probe material exits through the bypass outlet, moves into the mixing chamber, and returns, and (ii) a second portion of dialysate passes through the filter to the fluorometer.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the priority of U.S. Provisional Patent Application No. 63 / 498,685, filed on April 27, 2023, the entire content of which is incorporated herein by reference.

[0002] This application incorporates by reference in its entirety the content of International Application PCT / US22 / 82269, filed on December 22, 2022.

Background Art

[0003] There are two main dialysis methods used to assist patients who need renal replacement therapy: hemodialysis and peritoneal dialysis. Peritoneal dialysis utilizes the patient's own peritoneum as a semi - permeable membrane. The peritoneum is the membranous inner layer of the body cavity that surrounds all the organs between the diaphragm and the pelvis and can act as a natural semi - permeable membrane due to the numerous blood vessels and capillaries embedded within it.

[0004] In peritoneal dialysis, a sterile dialysis solution is injected into the peritoneal cavity through an indwelling catheter. This can be achieved manually by gravity or using a machine known as a cycler. By including an osmotic agent in the peritoneal dialysis solution, an osmotic gradient is created. The osmotic agent most commonly used in the majority of peritoneal dialysis solutions is glucose. The dialysis solution may be left in the peritoneal cavity for a sufficient time (e.g., 4 hours) to effect a net removal of toxins and water, after which the dialysis solution is drained and replaced with fresh dialysis solution.

[0005] Peritoneal dialysis (PD) primarily comes in two forms: continuous ambulatory peritoneal dialysis (CAPD) and continuous periodic peritoneal dialysis (CCPD). In CCPD, fluid exchange can be performed while the patient is asleep, with the inflow and outflow of dialysate controlled by a cycler. This is designed to protect the patient from the arduous task of fluid exchange while they are awake. Typically, the cycler leaves a final fill volume in the patient just before they wake up, which remains in the peritoneum until noon when the patient drains. The patient then has the option of remaining "dry" until the night, which has the advantage of allowing the peritoneum to recover from the constant onslaught of low pH / high osmotic solution, or, if more toxins and water removal is needed, the patient can manually inject another fill volume for the rest of the day.

[0006] One drawback of CCPD is the burden of storing, connecting, cutting, and disposing of supplies used during the process, such as sterile bags of solution, tube sets and connectors, as well as auxiliary supplies required to perform sterile connection / cutting.

[0007] Some devices are designed to produce injectable quality dialysate to deliver renal replacement therapy online during a treatment session. Some of these methods, which use cryofiltration sterilization, use at least two redundant depyrogenation filters (e.g., ultrafilters) in series to ensure that only sterile, pyrogen-free dialysate reaches the patient, even if there is a membrane leak in one of the filters during dialysis treatment.

[0008] Dual ultrafiltration designs require both filters to be tested for membrane integrity before each dialysis treatment (i.e., T0 test). Some designs have achieved this by filling the filters with air, pressurizing them, and then tracking the rate of pressure decay with a pressure sensor to determine if the decay rate is within a safe range that correlates with an intact membrane. Following this, the filters are reprimed by replacing the air with fluid, which can be difficult to achieve without human intervention, as microbubbles tend to adhere to the membrane surface and require mechanical agitation to facilitate their release. The effective surface area of ​​the membrane is reduced to the extent that bubbles remain. [Overview of the Initiative] [Means for solving the problem]

[0009] The first example is a system for generating dialysate, the system comprising a mixing chamber, a pump, a filter cartridge including a filter, an inlet, a bypass outlet, and a filtration outlet, a fluorometer, one or more valves, and one or more tubing lines, the system being configured to operate in a fluorometer diagnostic mode, a filter diagnostic mode, and a dialysate dispensing mode, in which the fluorometer diagnostic mode, one or more valves and one or more tubing lines are configured to allow the pump to move water and fluorescent probe material from the mixing chamber to the inlet, out through the bypass outlet, and to the fluorometer, and in which the filter diagnostic mode, one or more valves and one or more tubing lines are configured, ( The system includes a pump configured to move water and fluorescent probe material from the mixing chamber to the inlet, such that (i) a first portion of water and fluorescent probe material exits through a bypass outlet and returns to the mixing chamber, and (ii) a second portion of water passes through a filter and exits through a filtration outlet to move to a fluorometer, and in dialysate dispensing mode, one or more valves and one or more tubular lines are configured to allow the pump to move dialysate and fluorescent probe material from the mixing chamber to the inlet, such that (i) a first portion of dialysate and fluorescent probe material exits through a bypass outlet and returns to the mixing chamber, and (ii) a second portion of dialysate passes through a filter and exits through a filtration outlet to move to a fluorometer.

[0010] A second example is a method for operating the system of the first example, the method comprising: moving a first portion of water and a first portion of fluorescent probe material from the mixing chamber to the inlet and out the bypass outlet to a fluorometer; detecting the first portion of fluorescent probe material in the first portion of water using the fluorometer; moving a second portion of water and a second portion of fluorescent probe material from the mixing chamber to the inlet in response to the detection, so that the second portion of water passes through the filter and out the filtration outlet to the fluorometer; and using the fluorometer, detecting when the amount of the second portion of fluorescent probe material is less than a first threshold amount together with the second portion of water. The method includes determining that the material has passed through the filter; in response to this determination, filling the mixing chamber with dialysate and moving a third portion of the dialysate and fluorescent probe material from the mixing chamber to the inlet so that the dialysate passes through the filter and exits the filtration outlet to move to a fluorometer; dispensing dialysate via a patient line in response to the determination that less than a second threshold amount of the third portion of the fluorescent probe material has passed through the filter with the dialysate; or dispensing dialysate via a drain line in response to the determination that an amount exceeding a second threshold amount of the third portion of the fluorescent probe material has passed through the filter with the dialysate.

[0011] A third example is a non-temporary computer-readable medium that, when executed by a computing device, stores instructions that cause the computing device to perform the method of the second example.

[0012] Where the terms “substantially” or “about” are used herein, it means that the listed characteristics, parameters, or values ​​do not need to be achieved exactly, but deviations or variations, including, for example, tolerances, measurement errors, measurement accuracy limits, and other factors known to those skilled in the art, may occur in an amount that does not negate the effect that the characteristic was intended to provide. In some examples disclosed herein, “substantially” or “about” means within + / - 0 to 5% of the listed values.

[0013] These, as well as other embodiments, advantages, and alternative forms, will become apparent to those skilled in the art by reading the following detailed description with due reference to the accompanying drawings. Furthermore, it should be understood that this summary and other descriptions and figures provided herein are intended to illustrate the invention only as examples, and therefore numerous modifications are possible. [Brief explanation of the drawing]

[0014] [Figure 1] This is a block diagram of a system including computing devices, as an example. [Figure 2] This is a schematic diagram of a system, as an example. [Figure 3] This is a schematic diagram of a system configured to operate in fluorometer diagnostic mode, as an example. [Figure 4] This is a schematic diagram of a system configured to operate in filter diagnostic mode, as an example. [Figure 5] This is a schematic diagram of a system configured to operate in dialysate generation mode, as an example. [Figure 6] This is a schematic diagram of a system configured to operate in dialysate dispensing mode, as an example. [Figure 7] This is a schematic diagram of a system configured to operate in a glucose quantification mode, as an example. [Figure 8] This is a block diagram of an example method. [Figure 9] This is a block diagram of an example method. [Figure 10] This is a schematic diagram of a system, as an example. [Figure 11] This is a schematic diagram of a system, as an example. [Figure 12] This is a data plot illustrating the relationship between the fluorescence of used dialysate and its glucose concentration, as an example. [Modes for carrying out the invention]

[0015] A significant improvement over conventional methods for establishing the patency of depyrogenation filters is the ability to continuously monitor for fiber leakage throughout the entire dialysis treatment, thereby eliminating the need for a second filter and the need to perform pneumatic decay tests. This disclosure relates to a method for supporting the membrane integrity of a depyrogenation filter used in the preparation of injectable quality dialysate, not only immediately before the start of dialysis treatment but continuously throughout the treatment. This method can reduce the need for redundant filters and can reduce the need to perform pneumatic decay tests or other tests as verification of membrane integrity and subsequent repriming.

[0016] A second aspect of this disclosure relates to a method for quantifying the amount of glucose in the dialysate excreted from a patient undergoing peritoneal dialysis. Glucose (dextrose) is included in the peritoneal dialysate as an osmotic agent that plays a role in drawing water from the patient's blood to compensate for the inability to remove excess water through urination. During the retention period of the peritoneal dialysis procedure, water moves from the blood to the dialysate, and at the same time, glucose moves from the dialysate to the blood, resulting in a lower concentration of glucose excreted from the patient after the retention period than during intravenous infusion. This is a clear drawback of the peritoneal dialysis method. Absorbed glucose tends to reduce the patient's appetite for protein, and while weight gain from the continuous absorption of calories from sugar can lead to protein malnutrition. As a result, many people become obese. Absorbed glucose also complicates diabetes management, which is a significant concern given that more than 50% of the new dialysis population in the United States has diabetes.

[0017] Knowing the amount of glucose absorbed by a patient during a given treatment would be highly desirable to help clinicians prescribe the optimal dextrose concentration for use in the dialysate, as well as the amount and timing of insulin injections. This data can also be directly provided by continuous glucose monitoring devices used by many patients. Therefore, any peritoneal dialysis machine capable of providing quantitative data on absorbed glucose can have a differential competitive advantage.

[0018] FIG. 1 is a block diagram of a peritoneal dialysis system 200. The system 200 includes a computing device 100A. In some examples, the computing device 100A directly controls the system 200, while in other examples, the computing device 100B can control the system 200 by sending instructions to the computing device 100A via a wired or wireless connection. For example, the computing device 100B can take the form of a tablet computer, a laptop computer, a smartphone, etc. The features and components of the computing device 100 described below can refer to the computing device 100A and / or the computing device 100B in various examples. Further features of the system 200 are detailed in subsequent figures.

[0019] The computing device 100 includes one or more processors 102, a non - transient computer - readable medium 104, a communication interface 106, and a user interface 108. The components of the computing device 100 are linked to each other by a system bus, a network, or other connection mechanism 112.

[0020] The one or more processors 102 can be any type of one or more processors such as a microprocessor, a field - programmable gate array, a digital signal processor, a multi - core processor, etc., coupled to the non - transient computer - readable medium 104.

[0021] The non-temporary computer-readable medium 104 can be any type of memory, such as volatile memory like random access memory (RAM), dynamic random access memory (DRAM), or static random access memory (SRAM), or non-volatile memory like read-only memory (ROM), flash memory, magnetic or optical disk, or compact disk read-only memory (CD-ROM), among other devices used to store data or programs temporarily or permanently.

[0022] Furthermore, the non-temporary computer-readable medium 104 can store instructions 111. Instructions 111 are executable by one or more processors 102 to cause the computing device 100 to perform any of the functions or methods described herein.

[0023] The communication interface 106 may include hardware that enables communication within the computing device 100 and / or between the computing device 100 and one or more other devices. The hardware may include, for example, any type of input and / or output interface, a Universal Serial Bus (USB), PCI Express, a transmitter, a receiver, and an antenna. The communication interface 106 may be configured to facilitate communication with one or more other devices according to one or more wired or wireless communication protocols. For example, the communication interface 106 may be configured to facilitate wireless data communication for the computing device 100 according to one or more wireless communication standards such as the IEEE 801.11 standard, ZigBee standard, or Bluetooth standard. As another example, the communication interface 106 may be configured to facilitate wired data communication with one or more other devices. The communication interface 106 may also include an analog-to-digital converter (ADC) or a digital-to-analog converter (DAC) that the computing device 100 can use to control various components of the computing device 100 or external devices.

[0024] The user interface 108 may include any type of display component configured to display data. For example, the user interface 108 may include a touchscreen display. Another example is that the user interface 108 may include a flat panel display such as a liquid crystal display (LCD) or a light-emitting diode (LED) display. The user interface 108 may include one or more pieces of hardware used to provide data and control signals to the computing device 100. For example, the user interface 108 may include a mouse or pointing device, a keyboard or keypad, a microphone, a touchpad, or a touchscreen, among other possible types of user input devices. In general, the user interface 108 may allow an operator to interact with a graphical user interface (GUI) provided by the computing device 100 (e.g., displayed by the user interface 108).

[0025] Figure 2 is a schematic diagram of system 200. In addition to the components shown in Figure 1, system 200 includes a mixing chamber MC, pumps CPU1-6, and a filter cartridge 202. Filter cartridge 202 includes a pyrogen filter, an inlet 204, a bypass outlet 206, and a filtration outlet 208. System 200 also includes a fluorometer, valves CV1-16, and tubular lines providing fluid connections for valves CV1-16 and other components of system 200. System 200 also includes a water reservoir, temperature sensors CT1-4, conductivity sensors CC1-4, pressure sensors CP1-5, a heater, a container for bicarbonate, a container for electrolytes and citrates and / or acetates, a container for simple sugars such as glucose or dextrose, a container for osmotic agents such as icodextrin, a container for fluorescent probe materials such as fluorescein isothiocyanate (FITC), and a container in the form of a Con A filter. In some cases, the fluorescent probe material can take the form of rhodamine (TRITC), coumarin, or cyanine derivatives. Other fluorescent probe materials are also possible.

[0026] The mixing chamber MC is inflatable and collapsible so that its volume can be increased or decreased to accommodate different volumes of dialysate or other liquids. This inflatable property of the mixing chamber MC eliminates the need to remove air from the mixing chamber when filling it with liquid.

[0027] A Con A filter has one or more surfaces (e.g., stacked plates or fibers) to which lectins such as concanavalin A are bound. The lectins can also take the form of lentils, peas, and / or Vicia ervilia. The Con A filter also contains a fluorescent probe material such as FITC and a polysaccharide (e.g., dextran) that binds to each other and to the lectins. The lectins have a binding affinity to glucose that is greater than their binding affinity to the polysaccharides.

[0028] System 200 includes a closed fluid loop comprising a mixing chamber MC, a pump CPU 5, an inlet 204, a bypass outlet 206, and a valve CV12. Temperature sensors CT3 / CT4 are configured to detect the temperature of the fluid flowing through the closed fluid loop.

[0029] System 200 includes a valve CV10, a fluorometer line 212, and a drain line 210 connected to a pyrogen filter via a valve CV16. System 200 also includes a patient line 214. The fluorometer line 212 connects its filtration outlet 208 to the patient line 214 via a valve CV14.

[0030] System 200 includes an expandable dissolution chamber 214A, an expandable dissolution chamber 214B, a water reservoir, a container B containing a simple sugar such as dextrose, a container C containing an osmotic agent such as icodextrin, a container A containing an electrolyte and citrate and / or acetate, and a container D containing FITC.

[0031] System 200 is configured to operate in fluorometer diagnostic mode, filter diagnostic mode, dialysate generation mode, dialysate dispensing mode, and glucose quantification mode.

[0032] Figure 2 shows a system 200 that performs a process in which water and dissolved FITC are moved into a mixing chamber MC and circulated by pump CPU 5. That is, pump CPU 5 and / or pump CPU 1 move water from the water reservoir through container D so that water and dissolved FITC enter through inlet 204 through pump CPU 5, exit through bypass outlet 206, enter the mixing chamber MC through valve CV12, and fill and expand the mixing chamber MC with water and dissolved FITC.

[0033] Figure 3 shows system 200 operating in fluorometer diagnostic mode. Pump CPU 5 moves a first portion of water and a first portion of fluorescent probe material (e.g., FTIC) from the mixing chamber MC into inlet 204, out through bypass outlet 206, through valve CV11, through the fluorometer, through valve CV16, and into the drain line 210. Valve CV10 is closed and valve CV11 is opened, thereby allowing the fluorescent probe material, formed from particles too large to pass through the working filter, to freely reach the fluorometer. System 200 uses the fluorometer to detect the first portion of fluorescent probe material dissolved in the first portion of water as a diagnostic check to determine that the fluorometer is functioning. System 200 then operates in filter diagnostic mode in response to system 200 passing through fluorometer diagnostic mode by detecting FITC, which was known to flow through the fluorometer.

[0034] Figure 4 shows system 200 operating in filter diagnostic mode in response to passing through fluorometer diagnostic mode. Pump CPU 5 moves the second portion of water and the second portion of fluorescent probe material from the mixing chamber MC to the inlet 204 so that the second portion of water passes through the filter, exits from the filter outlet 208, proceeds to the fluorometer, passes through valve CV16, and moves to the drain line 210. As shown in the figure, valve CV10 is open and valve CV11 is closed so that most of the water entering inlet 204 passes through the filter instead of exiting through the bypass outlet 206. However, a small amount of water and the second portion of fluorescent probe material entering inlet 204 can escape back to the mixing chamber MC through the bypass outlet 206 and a slightly open valve CV12. If the filter is functioning properly, the fluorescent probe material particles are too large to pass through the filter. Next, system 200 uses the fluorometer to determine that less than a first threshold amount of the second portion of fluorescent probe material has passed through the filter along with the second portion of water. This means that the filter is functioning properly. As a result, system 200 is ready to safely generate and dispense dialysate to the patient. System 200 operates in dialysate dispensing mode in response to the determination that less than a first threshold amount of the second portion of the fluorescent probe material has passed through the filter together with the second portion of water.

[0035] Figure 5 shows system 200 operating in dialysate generation mode. First, the water pump CPU1 moves water from the water reservoir through containers A, B, and C to fill dissolution chamber 214A with water, electrolytes, and citrate and / or acetate solutions, and dissolution chamber 214B with a solution of water and simple sugars, such as dextrose, which is a standard retention osmotic agent (unlike icodextrin, which is a long retention osmotic agent). Next, the water pump CPU1 moves water from the water reservoir through valve CV5 to mix with the contents of dissolution chamber 214A and dissolution chamber 214B to form dialysate in mixing chamber MC.

[0036] Figure 6 shows the system 200 operating in dialysate dispensing mode. As described above with reference to Figure 5, after the mixing chamber MC is filled with dialysate, the pump CPU 5 moves a third portion of dialysate and fluorescent probe material from the mixing chamber MC to the inlet 204 so that the dialysate passes through the filter, exits from the filtration outlet 208, and moves through the fluorometer.

[0037] If the fluorescent meter detects an amount of the third portion of the fluorescent probe material below the threshold, the dialysate is dispensed via the patient line 214. However, if the fluorescent meter detects an amount of the third portion of the fluorescent probe material exceeding the threshold, the dialysate is dispensed via the drain line 210. The fluorescent probe material acts as a substitute for pyrogen due to their similar particle size. That is, as long as the fluorescent meter detects a negligible amount of fluorescent probe material, it can be assumed that the filter is functioning properly and that there is no significant amount of pyrogen in the filtered dialysate dispensed to the patient. However, if the fluorescent meter detects a non-negligible amount of fluorescent probe material, it can be assumed that the filter is not functioning properly and that there may be a considerable amount of pyrogen in the filtered dialysate dispensed to the patient, which is why the dialysate is discarded in this case.

[0038] Figure 7 shows system 200 operating in glucose quantification mode. The container, in the form of a Con A filter, has (i) one or more surfaces (e.g., stacked plates and / or fibers) to which lectins such as concanavalin A are bound, and (ii) fluorescent probe material and polysaccharides bound to each other and to the lectins. The Con A filter receives used dialysate via the patient line 214, thereby binding glucose present in the used dialysate to the lectins and moving the polysaccharides and fluorescent probe material away from the lectins. Pump CPU 6 moves the used dialysate, polysaccharides, and fluorescent probe material to a fluorometer. The fluorometer detects the amount of fluorescent probe material in the used dialysate. This detected amount of fluorescent probe material is proportional to the amount of glucose remaining in the used dialysate received from the patient.

[0039] Figures 8 and 9 are block diagrams of Method 300, which in some examples is performed by System 200 and / or manually. As shown in Figures 8-9, Method 300 includes one or more operations, functions, or actions, such as those indicated by blocks 302, 304, 306, 308, 310, 312, and / or 314. Although the blocks are shown in a sequential order, these blocks may also be performed in parallel and / or in an order different from the order described herein. Furthermore, the various blocks may be combined into fewer blocks, split into additional blocks, and / or removed, based on the desired implementation form.

[0040] In block 302, method 300 includes a system 200 that moves a first portion of water and a first portion of fluorescent probe material from the mixing chamber MC to the inlet 204 and out of the bypass outlet 206 to the fluorometer. The functions related to block 302 are described above with reference to Figure 3.

[0041] In block 304, method 300 includes a system 200 that uses a fluorophotometer to detect a first portion of a fluorescent probe material in a first portion of water. The functions related to block 304 are described above with reference to Figure 3.

[0042] In block 306, method 300 includes the system 200 moving the second portion of water and the second portion of the fluorescent probe material from the mixing chamber MC to the inlet 204 so that, in response to detection, the second portion of water passes through the filter and exits the filtration outlet 208 to the fluorometer. The functions related to block 306 are described above with reference to Figure 4.

[0043] In block 308, method 300 includes a system 200 that uses a fluorophotometer to determine that less than a first threshold amount of the second portion of the fluorescent probe material has passed through the filter together with the second portion of water. The functions related to block 308 are described above with reference to Figure 4.

[0044] In block 310, method 300 includes the system 200 filling the mixing chamber MC with dialysate and moving a third portion of dialysate and fluorescent probe material from the mixing chamber MC to the inlet 204, so that in response to a determination, the dialysate passes through the filter and exits the filtration outlet 208 to move to the fluorometer. The functions associated with block 310 are described above with reference to Figures 5 and 6.

[0045] In block 312, method 300 includes the system 200 dispensing dialysate through the patient line 214 in response to determining that less than a second threshold amount of the third portion of the fluorescent probe material has passed through the filter with the dialysate. The functions related to block 312 are described above with reference to Figure 6.

[0046] In block 314, method 300 includes the system dispensing dialysate through the drain line 210 in response to determining that an amount exceeding a second threshold amount of the third portion of the fluorescent probe material has passed through the filter with the dialysate. Functions related to block 314 are described above with reference to Figure 6, although they are not explicitly shown in Figure 6.

[0047] Further exemplary embodiments Figure 10 shows a system 200 that produces injectable quality peritoneal dialysate by metering purified water into a mixing chamber along with concentrates of magnesium, sodium, calcium, bicarbonate, and dextrose, and then ultra-purifying the homogenized solution through a depyrogenation filter. In this embodiment, a single depyrogenation filter is used instead of two. The recirculation circuit is constructed by forming a closed loop of tubing that exits the mixing chamber at its bottom, connects to a recirculation pump (PU5), then flows through a pyrogenation filter (PF1), a three-way valve V3, and then returns to the mixing chamber. This recirculation loop includes redundant conductivity and temperature sensors used to help ensure that the composition of the mixed dialysate is correct and that the mixed dialysate is at a predetermined temperature before being administered to the patient.

[0048] Valve V3 connects this recirculation loop to the drain line via valves V5, V6, and V9. A tubular segment between valves V5 and V6 houses an in-line flow-through fluorometer designed to detect fluorescent marker molecules, one example being fluorescein isothiocyanate (FITC). One advantage of FITC is its availability as a conjugate for dextran of various molecular weight sizes. Some of these conjugates have molecular sizes too large to pass through the intact membrane of the pyrogen filter (e.g., >70,000 Daltons).

[0049] A valve V10, which isolates the container of 70K Dalton FITC dextran from the loop, is included in the recirculation loop. The first step in preparing for dialysis treatment is to flush all fluid pathways with ultrapure water. At the end of that stage, all fluid pathways are filled with water, and pump PU5 continues to recirculate that water around the loop. At that point, a sufficient amount of FITC dextran can be introduced into the recirculation loop by opening valve V10 so that the resulting concentration can be reliably detected by an in-line fluorometer.

[0050] Next, a T0 test is performed to verify that the fluorometer is functioning correctly. This is achieved by allowing some of the water in the recirculation loop to exit through valve V3, pass through valve V5, and then pass through the fluorometer. If the fluorometer is functioning as expected, the fluorescence signal from FITC dextran is registered and the T0 test is passed.

[0051] Next, a T0 test is performed on the pyrogen filter to verify that the pyrogen filter membrane is intact. This is achieved by closing valve V3 and opening valve V5 to the pyrogen filter's generated water output port so that water in the recirculation loop is pushed through the pyrogen filter membrane (the volume of the suitable mixing chamber decreases as the fluid is removed from the recirculation loop). This generated water passes through valve V5, then through a fluorometer, then through valves V6 and V9, and then down the drain line.

[0052] In this case, it is expected that the FITC dextran in the recirculation loop will be too large to pass through the intact pyrogen filter membrane, and therefore no fluorescence will be detected by the fluorometer. If any FITC dextran were to penetrate the membrane and register a positive fluorescence reading by the fluorometer, it could only mean that there was fiber breakage or other perforation in the membrane, which would fail a test requiring replacement before another dialysis treatment could be permitted.

[0053] Once in the recirculation loop, FITC dextran remains throughout the treatment. Before the dialysate concentrate is metered into the mixing chamber to produce the predetermined final dialysate formulation, most, though not all, of the water previously present in the recirculation loop is drained through a pyrogen filter membrane while being monitored by a fluorometer. A small amount of water is retained in the loop so that FITC dextran can still be retained in the solution. The amount of water retained is known with the required precision because the volume of the recirculation loop is known when the mixing chamber is at its minimum volume (compliance is completely minimized). This volume of water is taken into consideration (in software) when instructing how much concentrate and additional water to introduce into the mixing chamber to obtain the exact final dialysate composition.

[0054] In this way, FITC dextran is generally always present in the recirculation loop, and as a result, the integrity of the pyrogen filter membrane is continuously supported before, during, and after dialysis treatment, thereby continuously supporting patient safety. By doing so, the requirement for a second redundant pyrogen filter can be eliminated, and there is no need to perform any other method to verify membrane integrity, such as pneumatic decay tests.

[0055] FITC dextran can also be used in conjunction with an inline fluorometer to create a method for quantifying the amount of glucose present in the effluent dialysate discharged from the patient during each draining stage. However, in this embodiment, the source of FITC dextran is not the same container connected to the recirculation loop. Rather, it is coupled to the surface of a container located at the extension of the drain line coming from the cycler, as shown in Figure 11 between valve V4 and the fluorometer.

[0056] FITC dextran can bind to lectins such as concanavalin A, and then to any surface through which the effluent dialysate can be perfused. This surface may be a pyrogen filter or a hollow fiber of a filtration device structurally similar to a hemodialyzer. This technique is based on a competitive binding assay. FITC dextran has a constant binding strength to Con A, which is lower than the binding strength of monomeric glucose. As a result, when glucose-containing effluent dialysate enters a hollow fiber (e.g.) to which FITC dextran is bound, the glucose competitively displaces the FITC dextran and is sent downstream, passing through an in-line fluorometer. The intensity of the fluorescence signal has been shown to be precisely proportional to the concentration of glucose in the perfused solution, as shown in Figure 12.

[0057] Using this type of fluorescence to convert to glucose concentration, it is possible to quantify the total amount of glucose excreted from the patient. Then, when the amount of glucose excreted is subtracted from the amount infused into the fresh dialysate from the previous filling cycle, the amount of glucose absorbed by the patient is obtained.

[0058] Exemplary Enumerated Embodiments (EEE) EEE1 is a system for generating dialysate, the system comprising a mixing chamber, a pump, a filter cartridge including a filter, an inlet, a bypass outlet, and a filtration outlet, a fluorometer, one or more valves, and one or more tubing lines, the system being configured to operate in fluorometer diagnostic mode, filter diagnostic mode, and dialysate dispensing mode, in fluorometer diagnostic mode, one or more valves and one or more tubing lines being configured to allow the pump to move water and fluorescent probe material from the mixing chamber to the inlet, out through the bypass outlet, and to the fluorometer, and in filter diagnostic mode, one or more valves and one or more tubing lines are configured, ( The system includes a pump configured to move water and fluorescent probe material from the mixing chamber to the inlet, such that (i) a first portion of water and fluorescent probe material exits through a bypass outlet and returns to the mixing chamber, and (ii) a second portion of water passes through a filter and exits through a filtration outlet to move to a fluorometer, and in dialysate dispensing mode, one or more valves and one or more tubular lines are configured to allow the pump to move dialysate and fluorescent probe material from the mixing chamber to the inlet, such that (i) a first portion of dialysate and fluorescent probe material exits through a bypass outlet and returns to the mixing chamber, and (ii) a second portion of dialysate passes through a filter and exits through a filtration outlet to move to a fluorometer.

[0059] EEE2 is the system described in EEE1 in which the mixing chamber is expandable.

[0060] EEE3 is the system according to any one of EEE1 to 2, further comprising a container having (i) a surface to which lectins are bound, and (ii) a fluorescent probe material and polysaccharides bound to each other and to the lectins, wherein the system is further configured to operate in a glucose quantification mode, wherein one or more valves and one or more tubular lines are configured to (i) allow the container to receive used dialysate containing glucose, thereby binding the glucose to the lectins and moving the polysaccharides and fluorescent probe material away from the lectins, and (ii) allow the used dialysate, polysaccharides and fluorescent probe material to be moved to a fluorometer.

[0061] EEE4 is the system described in EEE3, in which the lectin contains concanavalin A.

[0062] EEE5 is the system described in EEE3, wherein the lectin has a binding affinity for glucose that is greater than the binding affinity of the lectin for polysaccharides.

[0063] EEE6 is a system described in any one of EEE1-5, in which the filter includes a pyrogen filter.

[0064] EEE7 is a system described in any one of EEE1 to 6, wherein the fluorescent probe material contains fluorescein isothiocyanate.

[0065] EEE8 is a system described in any one of EEE1-7, wherein the system includes a closed fluid loop comprising a mixing chamber, a pump, an inlet, and a bypass outlet.

[0066] EEE9 is the system described in EEE8, further comprising one or more temperature sensors configured to detect the temperature of a fluid flowing through a closed fluid loop.

[0067] EEE10 is a system described in any one of EEE1 to 9, wherein one or more tubular lines include a drain line, and one or more valves and one or more tubular lines connect a filter to the drain line.

[0068] EEE11 is the system described in EEE10, wherein one or more tubular lines include a fluorometer line connecting a filter to a drain line via one or more valves, and the fluorometer line passes through a fluorometer.

[0069] EEE12 is the system described in EEE11, wherein one or more tubular lines include the patient line, and the fluorometer line connects the filter to the patient line via one or more valves.

[0070] EEE13 is a system according to any one of EEE1 to 12, further comprising a first expandable dissolution chamber, a water reservoir, a first container containing a simple sugar, and a second container containing an osmotic agent, wherein the system is configured to operate in a dialysate generation mode in which one or more valves and one or more tubular lines are configured to allow water to flow from the water reservoir through the first and second containers, thereby moving the water, simple sugar, and osmotic agent into the first expandable dissolution chamber.

[0071] EEE14 is the system according to EEE13, further comprising a second expandable dissolution chamber and a third container containing an electrolyte and citrate and / or acetate, wherein in dialysate generation mode the system is further configured to allow water to flow from a water reservoir through the third container to move water, electrolyte and citrate and / or acetate into the second expandable dissolution chamber.

[0072] EEE15 is the system described in EEE14, wherein in dialysate generation mode, the system is further configured to allow (i) water, electrolytes, and citrate and / or acetate to be moved from a second expandable dissolution chamber to a mixing chamber, and (ii) water, osmotic agents, and simple sugars to be moved from a first expandable dissolution chamber to a mixing chamber.

[0073] EEE16 is a method for operating the system described in any one of EEE1 to 15 for dispensing dialysate, the method comprising: moving a first portion of water and a first portion of fluorescent probe material from the mixing chamber to the inlet and out of the bypass outlet to a fluorometer; detecting the first portion of fluorescent probe material in the first portion of water using the fluorometer; moving a second portion of water and a second portion of fluorescent probe material from the mixing chamber to the inlet in response to the detection, so that a second portion of water moves through the filter out of the filtration outlet to a fluorometer; and using the fluorometer, detecting a first threshold amount of the second portion of fluorescent probe material. The method includes determining that a full amount has passed through the filter with the second portion of water; in response to this determination, filling the mixing chamber with dialysate and moving the third portion of dialysate and fluorescent probe material from the mixing chamber to the inlet so that the dialysate passes through the filter and exits the filtration outlet to move to the fluorometer; in response to the determination that an amount less than a second threshold of the third portion of fluorescent probe material has passed through the filter with the dialysate, dispensing dialysate via the patient line; or in response to the determination that an amount exceeding a second threshold of the third portion of fluorescent probe material has passed through the filter with the dialysate, dispensing dialysate via the drain line.

[0074] EEE17 is the method of EEE16, further comprising filling a mixing chamber with water and fluorescent probe material before moving the first portion of water and the first portion of fluorescent probe material.

[0075] EEE18 is a method according to any one of EEE16-17, further comprising: a container for receiving spent dialysate, thereby binding glucose to lectin and moving polysaccharides and fluorescent probe material away from the lectin; moving the spent dialysate, polysaccharides and fluorescent probe material to a fluorometer; and using the fluorometer to detect the amount of fluorescent probe material in the spent dialysate.

[0076] EEE19 is a method according to any one of EEE16-18, wherein the filter includes a pyrogen filter.

[0077] EEE20 is a method according to any one of EEE16-19, wherein the fluorescent probe material contains fluorescein isothiocyanate.

[0078] EEE21 is a method according to any one of EEE16-20, further comprising flowing water from a water reservoir through a first and second containers to transfer water, a simple sugar, and an osmotic agent into a first expandable dissolution chamber.

[0079] EEE22 is a method according to EEE22, further comprising flowing water from a water reservoir through a third vessel to transfer water, electrolytes, and citrate and / or acetate into a second expandable dissolution chamber.

[0080] EEE23 is the method according to EEE22, further comprising (i) moving water, an electrolyte, and citrate and / or acetate from a second expandable dissolution chamber to a mixing chamber, and (ii) moving water, an osmotic agent, and a simple sugar from a first expandable dissolution chamber to a mixing chamber.

[0081] EEE24 is a non-temporary computer-readable medium that, when executed by a computing device, stores instructions that cause the computing device to perform any one of the methods described in EEE16-23.

[0082] While various exemplary embodiments and models are disclosed herein, other embodiments and models will be apparent to those skilled in the art. The various exemplary embodiments and models disclosed herein are for illustrative purposes only and are not intended to limit, and the true scope and spirit are indicated by the following claims.

[0083]

Claims

1. A system for generating dialysate, wherein the system Mixing chamber and Pump and A filter cartridge including a filter, inlet, bypass outlet, and filtration outlet, A fluorescein photometer and, One or more valves, The system comprises one or more tubular lines and is configured to operate in a fluorescence spectrometer diagnostic mode, a filter diagnostic mode, and a dialysate dispensing mode. In the fluorometer diagnostic mode, the one or more valves and the one or more tubular lines are configured to allow the pump to move water and fluorescent probe material from the mixing chamber to the inlet, out of the bypass outlet, and to the fluorometer. In the filter diagnostic mode, the one or more valves and the one or more tubular lines are configured to allow the pump to move the water and the fluorescent probe material from the mixing chamber to the inlet such that (i) a first portion of the water and the fluorescent probe material exits the bypass outlet and returns to the mixing chamber, and (ii) a second portion of the water passes through the filter and exits the filtration outlet to the fluorometer. In the dialysate dispensing mode, the system is configured such that the one or more valves and the one or more tubular lines allow the pump to move the dialysate and the fluorescent probe material from the mixing chamber to the inlet, such that (i) a first portion of the dialysate and the fluorescent probe material exits the bypass outlet and returns to the mixing chamber, and (ii) a second portion of the dialysate passes through the filter and exits the filtration outlet to the fluorometer.

2. The system according to claim 1, wherein the mixing chamber is expandable.

3. The system according to any one of claims 1 to 2, further comprising a container having (i) a surface to which lectin is bound, and (ii) a fluorescent probe material and a polysaccharide bound to each other and to the lectin, wherein the system is further configured to operate in a glucose quantification mode, wherein the one or more valves and the one or more tubular lines are configured to allow (i) the container to receive used dialysate containing glucose, thereby binding the glucose to the lectin and moving the polysaccharide and the fluorescent probe material away from the lectin, and (ii) the used dialysate, the polysaccharide and the fluorescent probe material to move to the fluorometer.

4. The system according to claim 3, wherein the lectin comprises concanavalin A.

5. The system according to claim 3, wherein the lectin has a binding affinity for glucose that is greater than the binding affinity of the lectin for the polysaccharide.

6. The system according to any one of claims 1 to 5, wherein the filter includes a pyrogen filter.

7. The system according to any one of claims 1 to 6, wherein the fluorescent probe material comprises fluorescein isothiocyanate.

8. The system according to any one of claims 1 to 7, wherein the system includes a closed fluid loop comprising the mixing chamber, the pump, the inlet, and the bypass outlet.

9. The system according to claim 8, further comprising one or more temperature sensors configured to detect the temperature of a fluid flowing through the closed fluid loop.

10. The system according to any one of claims 1 to 9, wherein the one or more tubular lines include a drain line, and the one or more valves and the one or more tubular lines connect the filter to the drain line.

11. The system according to claim 10, wherein the one or more tubular lines include a fluorometer line connecting the filter to the drain line via the one or more valves, and the fluorometer line passes through the fluorometer.

12. The system according to claim 11, wherein the one or more tubular lines include a patient line, and the fluorometer line connects the filter to the patient line via the one or more valves.

13. The system according to any one of claims 1 to 12, further comprising a first expandable dissolution chamber, a water reservoir, a first container containing a simple sugar, and a second container containing an osmotic agent, wherein the system is configured to operate in a dialysate generation mode configured such that the one or more valves and the one or more tubular lines allow water to flow from the water reservoir through the first container and the second container to move the water, the simple sugar, and the osmotic agent into the first expandable dissolution chamber.

14. The system according to claim 13, further comprising a second expandable dissolution chamber and a third container containing an electrolyte and a citrate and / or acetate, wherein in the dialysate generation mode, the system is further configured to allow the water to flow from the water reservoir through the third container to move the water, the electrolyte, and the citrate and / or acetate into the second expandable dissolution chamber.

15. The system according to claim 14, wherein in the dialysate generation mode, the system is further configured to allow (i) the water, the electrolyte, and the citrate and / or the acetate to be moved from the second expandable dissolution chamber to the mixing chamber, and (ii) the water, the osmotic agent, and the simple sugar to be moved from the first expandable dissolution chamber to the mixing chamber.

16. A method for operating the system according to any one of claims 1 to 15 for dispensing dialysate, The first portion of the water and the first portion of the fluorescent probe material are moved from the mixing chamber to the inlet and out of the bypass outlet to the fluorometer. Using the fluorometer, the first portion of the fluorescent probe material in the first portion of the water is detected. In response to the detection, the second portion of the water and the second portion of the fluorescent probe material are moved from the mixing chamber to the inlet so that the second portion of the water passes through the filter and exits the filtration outlet to the fluorometer. Using the fluorometer, it is determined that an amount less than the first threshold of the second portion of the fluorescent probe material has passed through the filter together with the second portion of the water. In response to the determination, the mixing chamber is filled with dialysate, and the third portion of the dialysate and the fluorescent probe material is moved from the mixing chamber to the inlet so that the dialysate passes through the filter and exits the filtration outlet to move to the fluorometer. In response to the determination that less than a second threshold amount of the third portion of the fluorescent probe material has passed through the filter together with the dialysate, the dialysate is dispensed via the patient line, or In response to the determination that an amount exceeding the second threshold amount of the third portion of the fluorescent probe material has passed through the filter together with the dialysate, the dialysate is dispensed via the drain line. Methods that include...

17. The method according to claim 16, further comprising filling the mixing chamber with the water and the fluorescent probe material before moving the first portion of the water and the first portion of the fluorescent probe material.

18. A container for receiving the used dialysate, thereby binding the glucose to the lectin, and transferring the polysaccharide and the fluorescent probe material from the lectin, Transferring the used dialysis fluid, the polysaccharide, and the fluorescent probe material to the fluorometer, The amount of the fluorescent probe material in the used dialysis fluid is detected using the aforementioned fluorescence spectrometer. The method according to any one of claims 16 to 17, further comprising:

19. The method according to any one of claims 16 to 18, wherein the filter includes a pyrogen filter.

20. The method according to any one of claims 16 to 19, wherein the fluorescent probe material comprises fluorescein isothiocyanate.

21. The method according to any one of claims 16 to 20, further comprising flowing water from the water reservoir through the first container and the second container to move the water, the simple sugar and the osmotic agent into the first expandable dissolution chamber.

22. The method according to claim 22, further comprising flowing water from the water reservoir through the third container to move the water, the electrolyte, and the citrate and / or acetate into the second expandable dissolution chamber.

23. The method according to claim 22, further comprising (i) moving the water, the electrolyte, and the citrate and / or acetate from the second expandable dissolution chamber to the mixing chamber, and (ii) moving the water, the osmotic agent, and the simple sugar from the first expandable dissolution chamber to the mixing chamber.

24. A non-temporary computer-readable medium that, when executed by a computing device, stores instructions causing the computing device to perform the method according to any one of claims 16 to 23.

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