Systems and methods for using nitric oxide in dialysis

Abstract

A hemodiafiltration (HDF) system for performing a hemodiafiltration (HDF) treatment is provided. The HDF system includes a mixing system for mixing nitric oxide (NO) and other chemicals to produce a dialysis fluid. The HDF system further includes an extracorporeal blood circulation circuit including a filter capable of separating the dialysis fluid into a dialysate and a NO-containing replacement fluid. The extracorporeal blood circulation circuit further comprises a dialyzer capable of receiving the dialysate from the filter and a blood line connected to the dialyzer, the blood line comprising an access point connected to the filter for administering the NO-containing replacement fluid to a patient during HDF therapy.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This patent application claims priority to U.S. Provisional Patent Application No. 63 / 433,357, filed on December 16, 2022, which is incorporated herein by reference in its entirety. Background Art

[0003] Various extracorporeal blood treatment methods are used to remove toxic substances and excess water from patients with chronic kidney disease. Healthy patients excrete many of these toxins through urine. In hemodialysis, the patient's blood is purified outside the body by passing it through a dialyzer. The dialyzer consists of a blood chamber and a dialysis fluid chamber separated by a semipermeable membrane. During treatment, the patient's blood flows through the blood chamber. To effectively remove substances normally excreted in urine, fresh dialysis fluid continuously flows through the dialysis fluid chamber, removing water and toxins through diffusion and convection.

[0004] In hemodialysis (HD), the transport of low-molecular-weight substances across the dialyzer membrane is primarily determined by the concentration difference between the dialysis fluid and the blood (diffusion). In contrast, in hemofiltration (HF), dissolved substances, particularly high-molecular-weight substances, are effectively removed from the aqueous plasma fraction of the blood by the high fluid flow across the dialyzer membrane (convection). In HF, the dialyzer acts as a filter. Hemodiafiltration (HDF) is a combination of these two processes.

[0005] In HDF, part of the plasma water drawn through the dialyzer membrane must be replaced with a sterile replacement fluid, which is usually delivered to the extracorporeal blood circulation circuit upstream (pre-dilution) or downstream (post-dilution) of the dialyzer. In known HDF mechanisms, the dialysis fluid is prepared online from sterile water and a dialysis fluid concentrate, and this replacement fluid is prepared online from the dialysis fluid.

[0006] However, the convection associated with HDF causes more endothelial stress when removing high molecular weight substances compared to HD. HDF is also more expensive, requires more training for clinical staff, and results in a greater loss of beneficial blood proteins such as albumin. Therefore, HDF is sometimes limited to acute care (short-term) settings. In addition, some patients (such as those with hypertension or other comorbidities) have difficulty tolerating HDF because it places more burden and stress on the patient's body than HD. Therefore, there remains a need for technologies that reduce endothelial and / or other types of stress on the patient's body during HDF treatment. There is also a need to develop methods to expand the accessibility of HDF treatment to patients with specific comorbidities such as hypertension. Summary of the Invention

[0007] This summary is intended to introduce some exemplary embodiments that are further described below. This summary is not intended to identify key features or essential features of the present disclosure.

[0008] In some cases, a hemodiafiltration (HDF) system for performing HDF treatment is provided. The HDF system includes a mixing system, an extracorporeal blood circulation circuit, and a controller. The mixing system includes: a nitric oxide dispenser configured to provide nitric oxide (NO) to a mixing chamber; a chemical dispenser configured to provide chemicals to the mixing chamber; and a mixing chamber configured to mix NO and chemicals to produce a dialysis fluid. The extracorporeal blood circulation circuit includes: a filter configured to separate the dialysis fluid into a dialysate and a replacement fluid containing NO; a dialyzer configured to receive the dialysate from the filter; and a blood line connected to the dialyzer and including one or more entry points, wherein the one or more entry points are connected to the filter to deliver the replacement fluid containing NO during HDF treatment using the one or more entry points. The controller is configured to: provide instructions to the mixing system to produce a dialysis fluid containing NO; and provide instructions to the extracorporeal blood circulation circuit to perform HDF treatment using the dialysate and the replacement fluid containing NO.

[0009] In some examples, the blood circuit includes an arterial blood circuit and a venous blood circuit, wherein the arterial blood circuit supplies blood from the patient to a blood chamber of the dialyzer and the venous blood circuit returns the patient's blood from the blood chamber to the patient, and wherein the one or more access points are arterial access points located on the arterial blood circuit and configured to provide a replacement fluid containing NO before the blood chamber for pre-dilution HDF treatment.

[0010] In some variations, the blood circuit includes an arterial blood circuit and a venous blood circuit, wherein the arterial blood circuit supplies blood from the patient to a blood chamber of the dialyzer and the venous blood circuit returns the patient's blood from the blood chamber to the patient, and wherein the one or more access points are venous access points located on the venous blood circuit and configured to provide a replacement fluid containing NO after the blood chamber for post-dilution HDF therapy.

[0011] In some cases, the filter includes a membrane, a first chamber, and a second chamber, and wherein the filter is configured to separate the dialysis fluid by allowing a first portion of the dialysis fluid to remain in the first chamber without passing through the membrane, and a second portion of the dialysis fluid to pass through the membrane into the second chamber, wherein the first portion of the dialysis fluid is a dialysate and the second portion of the dialysis fluid is a replacement fluid containing NO.

[0012] In some examples, the extracorporeal blood circulation circuit further includes: a dialysate line connecting the first chamber of the filter to the dialyzer; and a replacement fluid line connecting the second chamber of the filter to one or more access points.

[0013] In some variations, the nitric oxide dispenser includes a nitric oxide source, and wherein the nitric oxide source provides the nitric oxide in liquid form.

[0014] In some cases, the nitric oxide dispenser includes a nitric oxide source, and wherein the nitric oxide source provides the nitric oxide in gaseous form.

[0015] In some examples, providing instructions to the mixing system to produce the dialysis fluid includes providing instructions to the nitric oxide dispenser to dispense a set amount of NO to the mixing chamber.

[0016] In some variations, the extracorporeal blood circulation circuit further comprises a pump configured to pump a replacement fluid containing NO into the one or more access points, and wherein providing instructions to the extracorporeal blood circulation circuit to perform HDF therapy comprises controlling a rate at which the pump supplies the replacement fluid containing NO to the one or more access points.

[0017] In some examples, a hemodiafiltration (HDF) system for performing HDF treatment is provided. The HDF system includes a controller configured to: provide instructions to generate a dialysis fluid containing nitric oxide (NO); and provide instructions to perform HDF treatment using the dialysis fluid containing NO. The HDF system also includes an extracorporeal blood circulation circuit comprising: a filter configured to separate the dialysis fluid into a dialysate and a replacement fluid containing NO; a dialyzer configured to receive the dialysate from the filter; and a blood line connected to the dialyzer and including one or more access points for administering the replacement fluid containing NO during HDF treatment.

[0018] In some cases, the blood line includes an arterial blood line and a venous blood line, and wherein the one or more access points are arterial access points located on the arterial blood line and configured to enable administration of a NO-containing replacement fluid prior to the dialyzer for pre-dilution HDF therapy.

[0019] In some variations, the blood line comprises an arterial blood line and a venous blood line, and wherein the one or more access points are venous access points located on the venous blood line and configured to enable administration of a NO-containing replacement fluid after the dialyzer for post-dilution HDF therapy.

[0020] In some examples, the filter includes a membrane, a first chamber, and a second chamber, wherein the filter is configured to separate the dialysis fluid by allowing a first portion of the dialysis fluid to remain in the first chamber without passing through the membrane and a second portion of the dialysis fluid to pass through the membrane into the second chamber, wherein the first portion of the dialysis fluid is a dialysate and the second portion of the dialysis fluid is a replacement fluid containing NO.

[0021] In some cases, the extracorporeal blood circulation circuit further comprises: a dialysate line connecting the first chamber of the filter to the dialyzer; and a replacement fluid line connecting the second chamber of the filter to one or more access points.

[0022] In some variations, providing instructions to generate a dialysis fluid comprising NO includes providing instructions to a nitric oxide dispenser to dispense a set amount of NO to the mixing chamber.

[0023] In some variations, a method for performing hemodiafiltration (HDF) treatment is provided. The method includes generating a dialysis fluid containing nitric oxide (NO) for use in performing HDF treatment on a patient; and performing HDF treatment on the patient using an HDF system, wherein the HDF system includes an extracorporeal circulation circuit comprising: a filter for separating the dialysis fluid into a dialysate and a replacement fluid containing NO; a dialyzer for receiving the dialysate from the filter; and a blood line connected to the dialyzer and including one or more access points for administering the replacement fluid containing NO during HDF treatment.

[0024] In some cases, the blood line includes an arterial blood line and a venous blood line, wherein the arterial blood line supplies blood from the patient to a blood chamber of the dialyzer and the venous blood line returns the patient's blood from the blood chamber to the patient, wherein the one or more access points are arterial access points located on the arterial blood line, and wherein performing HDF treatment on the patient includes: performing pre-dilution HDF treatment based on providing a replacement fluid containing NO before the blood chamber using the arterial access point.

[0025] In some examples, the blood line includes an arterial blood line and a venous blood line, wherein the arterial blood line supplies blood from the patient to a blood chamber of the dialyzer and the venous blood line returns the patient's blood from the blood chamber to the patient, wherein the one or more access points are venous access points located on the venous blood line, and wherein performing HDF treatment on the patient includes performing post-dilution HDF treatment based on providing a replacement fluid containing NO after the blood chamber using the venous access point.

[0026] In some variations, the filter comprises a membrane, a first chamber, and a second chamber, and wherein the filter is configured to separate the dialysis fluid by allowing a first portion of the dialysis fluid to remain in the first chamber without passing through the membrane, and a second portion of the dialysis fluid to pass through the membrane into the second chamber, wherein the first portion of the dialysis fluid is a dialysate and the second portion of the dialysis fluid is a replacement fluid containing NO.

[0027] In some cases, generating a dialysis fluid comprising NO for HDF treatment of a patient includes providing instructions to a nitric oxide dispenser to dispense a set amount of NO to a mixing chamber.

[0028] Further features and aspects will be described in more detail below with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 An exemplary extracorporeal blood treatment apparatus for a hemodiafiltration system according to one or more examples of the present disclosure is shown;

[0030] Figure 2 A block diagram illustrating an exemplary hybrid system according to one or more examples of the present disclosure is shown;

[0031] Figure 3A Another exemplary extracorporeal blood treatment apparatus for a hemodiafiltration system according to one or more examples of the present disclosure is shown;

[0032] Figure 3B Another exemplary extracorporeal blood treatment apparatus for a hemodiafiltration system according to one or more examples of the present disclosure is shown;

[0033] Figure 4 A block diagram illustrating an exemplary hemodiafiltration system according to one or more examples of the present disclosure; and

[0034] Figure 5 A flow chart illustrating an exemplary process for using a hemodiafiltration system according to one or more examples of the present disclosure is shown. DETAILED DESCRIPTION

[0035] An exemplary embodiment of the present application provides a hemodiafiltration (HDF) system using nitric oxide (NO). For example, as described above, compared to a hemodialysis (HD) system, an HDF system may cause more stress (e.g., endothelial stress) on the patient's body and make some patients (e.g., hypertensive patients) unable to use HDF treatment. In addition, the HDF system causes more fluid loss in the blood, so a replacement fluid (pre-dilution or post-dilution) may be used before it is returned to the patient. Therefore, an embodiment of the present application uses nitric oxide (NO) to freely enter the bloodstream during HDF treatment. By introducing NO into the extracorporeal blood circulation circuit, this can reduce the patient's endothelial stress associated with HDF treatment and can further lower the patient's blood pressure. In addition, NO can also reduce inflammation during and after HDF treatment and reduce platelet aggregation in the dialyzer. In some cases, a NO source (e.g., a NO donor) that is and / or includes S-nitrosoglutathione and S-nitrosocysteine can be used. Both S-nitrosoglutathione and S-nitrosocysteine can be used because they break down into nitric oxide and glutathione or cysteine, all of which are naturally present in the human body. In other cases, the NO source can be NO gas dissolved in a liquid for HDF treatment.

[0036] In some cases, embodiments of the present application include systems configured to dissolve gaseous NO in water for replacement fluid and infuse / mix the replacement fluid containing NO into the blood through extracorporeal blood circulation (ECC). In other cases, embodiments of the present application include systems configured to directly infuse gaseous NO into the blood through extracorporeal circulation (ECC) during HDF treatment. Additionally and / or alternatively, the system can administer NO during pre-dilution and / or post-dilution. By using pre-dilution, NO is exposed to the membrane (e.g., the semipermeable membrane of a dialyzer), which reduces platelet aggregation at the membrane. This will be further explained below.

[0037] In some examples, embodiments of the present application utilize a controlled administration of NO dosage over time, which can avoid significant side effects, including a sudden drop in a patient's blood pressure caused by the administration of large doses of NO. For example, because HDF systems use both convection and diffusion, NO dosage can be better controlled in HDF than in HD systems. For example, the diffusion process alone makes it difficult for HD systems to control the amount of NO introduced into a patient through the dialysis fluid. In contrast, HDF systems are able to precisely control the dose of NO provided to a patient over a period of time by directly controlling the amount of NO entering the patient through the NO-containing replacement fluid. The effect of NO is controlled by simultaneously measuring methemoglobin in the patient's body using CO-oximetry to ensure the correct dosage.

[0038] In some variations, embodiments of the present application can distinguish NO added to the bloodstream during HDF treatment from nitrate / nitrite / nitric oxide already present in the bloodstream. In some cases, embodiments of the present application enable the system to accurately and precisely measure nitric oxide administered during HDF treatment, reduce platelet aggregation using a NO donor, and measure the performance of the NO donor in a continuous blood circuit (including a dialyzer and a pump), as well as the effect of this addition over time. In some examples, the NO donor is added directly to the blood. For example, the system can administer a replacement fluid containing NO during HDF treatment at pre-dilution or post-dilution. Post-dilution infusion of NO can provide greater benefits to the patient's endothelial tissue (e.g., by reducing endothelial stress). Pre-dilution infusion of NO can administer NO directly to the membrane. In other examples, the NO donor is added to the dialysis fluid and allowed to transfer into the bloodstream by convection.

[0039] Figure 1 An exemplary extracorporeal blood treatment apparatus for a hemodiafiltration system according to one or more examples of the present disclosure is shown. For example, Figure 1 An embodiment of a portion 100 of a HDF system using NO is shown in schematic form. Figure 1 are exemplary only, and the HDF system may include additional and / or alternative components for performing HDF therapy using NO. Figure 1 Some components shown in may not be present in all HDF systems described in this article.

[0040] The part 100 of the HDF system comprises a dialyzer 1 which is divided by a semipermeable membrane 2 into a first chamber 3 (through which blood flows, hereinafter referred to as the blood chamber) and a second chamber 4 (through which a dialysis fluid, such as a dialysate, flows, hereinafter referred to as the dialysis fluid chamber). The first chamber 3 is incorporated into the extracorporeal blood circulation circuit ( Figure 1 ), while the second chamber 4 is incorporated into the dialysis fluid system of the HDF system ( Figure 1 The flow rate between the membranes 2 (e.g., membrane flow rate) is shown by Qm.

[0041] The extracorporeal blood circulation circuit comprises an arterial blood line 6 leading to the inlet 3a of the blood chamber 3 and a venous blood line 7 extending away from the outlet 3b of the blood chamber 3 of the dialyzer 1. The patient's blood is transported through the blood chamber 3 of the dialyzer 1 by an arterial blood pump 8 (e.g., a roller pump) provided on the arterial blood line 6. The blood pump 8 supplies blood to the blood chamber 3 of the dialyzer at a specific blood flow rate Qb. The blood lines 6, 7 and the dialyzer 1 can form a disposable consumable that is inserted into the HDF system during HDF treatment. In some variations, an air separator (e.g., a drip chamber) can be incorporated into the arterial and venous blood lines to eliminate air bubbles.

[0042] Fresh dialysis fluid is provided in a dialysis fluid source 9, which is Figure 2 The dialysis fluid system may include a dialysis fluid source 9 and other lines, such as a dialysis fluid supply line 10 and a dialysis fluid drain line 11. For example, the dialysis fluid supply line 10 leads from the dialysis fluid source 9 to the inlet 4a of the dialysis fluid chamber 4 of the dialyzer 1. The dialysis fluid drain line 11 leads from the outlet 4b of the dialysis fluid chamber 4 to a drain 12. A first dialysis fluid pump 13 is incorporated into the dialysis fluid supply line 10, and a second dialysis fluid pump 14 is incorporated into the dialysis fluid drain line 11. The first dialysis fluid pump 13 delivers dialysis fluid from the dialysis fluid source to the inlet 4a of the dialysis fluid chamber 4 at a specific dialysis fluid supply rate Qdi, while the second dialysis fluid pump 14 delivers dialysis fluid from the outlet 4b of the dialysis fluid chamber 4 to the drain 12 at a specific dialysis fluid flow rate Qdo.

[0043] During HDF treatment, dialysis fluid can be supplied as replacement fluid from the dialysis fluid system to the extracorporeal blood circulation circuit via a replacement fluid line 15, which branches off from the dialysis fluid supply line 10 upstream of the first dialysis fluid pump 13. For example, during HDF treatment, a portion of the dialysis fluid can be separated (e.g., by a filter). The first portion of the dialysis fluid can become the replacement fluid supplied to the replacement fluid line 15, and the second portion can be supplied to the dialyzer 1.

[0044] The replacement fluid line 15 comprises two line sections 15a and 15b: one line section 15a leads to the arterial blood line 6 and the other line section 15b leads to the venous blood line 7.

[0045] The replacement fluid is delivered using a pump 16 (e.g., a roller pump), into which the replacement fluid line 15 is inserted. The pump has a replacement rate Qs. Upstream of the pump 16 (e.g., a replacement pump), integrated into the replacement fluid line 15, is a sterile filter 17 divided into two chambers 17a and 17b. The pump 16, along with the corresponding lines and sterile filter, forms the replacement device of the HDF system. Closure elements, such as hose clamps or valves, can be provided to clamp the two line sections 15a and 15b of the replacement fluid line 15, but are not shown for clarity. Although only one sterile filter 17 is shown, the HDF system can include multiple filters (e.g., two). For example, the first filter can be located on the fluid supply line 10, before the branch between the supply line 10 and the replacement fluid line 15. The second filter can be located at the same location as the sterile filter 17. Alternatively and / or additionally, the first filter can be located before the branch between the fluid supply line 10 and the replacement fluid line 15, and the second filter can be located at the branch between the supply line 10 and the replacement fluid line 15.

[0046] The blood pump 8, the first and second dialysis fluid pumps 13 and 14 and the pump 16 are connected to a controller (eg Figure 4 ), which controls the pump according to preset treatment parameters.

[0047] The blood pump 8 and the first and second dialysis fluid pumps 13 and 14 are operated to operate the HDF system as a hemodialysis device, with dialysis fluid flowing through the dialysis fluid chamber 4 of the dialyzer 1. The pump 16 is operated to operate the HDF system as a hemodiafiltration device, so that sterile dialysis fluid is delivered as replacement fluid through a sterile filter 17, optionally to an arterial access point 19 downstream of the pump 8 and upstream of the blood chamber 3 (pre-dilution) or to a venous access point 20 downstream of the blood chamber (post-dilution). However, it is also possible to operate the HDF system only as a hemofiltration device (for example, if the first dialysis fluid pump 13 is not operated, thereby interrupting the flow of dialysis fluid into the dialysis fluid chamber of the dialyzer).

[0048] In addition, the HDF system provides NO in the replacement fluid, either pre-dilution (e.g., via arterial access point 19) or post-dilution (e.g., via venous access point 20). For example, the dialysis fluid source 9 can provide NO so that NO can be introduced into the patient's bloodstream during HDF treatment. As shown, the HDF system can provide pre-dilution or post-dilution NO. By providing pre-dilution NO, the replacement fluid will enter the blood side of the membrane. This can reduce coagulation in the membrane and enhance endothelial health. For example, during pre-dilution HDF treatment, a replacement fluid containing NO is introduced into the extracorporeal circulation before the dialyzer 1 and can provide anti-thrombotic properties and reduce coagulation on or in the dialyzer membrane 2. By providing post-dilution NO, NO may not be exposed to the membrane. Furthermore, during post-dilution HDF treatment, the replacement fluid can be introduced into the blood after the blood has been concentrated by ultrafiltration (while passing through the dialyzer 1). After the blood passes through the dialyzer 1, the replacement fluid containing NO can be added to the blood, reconstituting the blood and simultaneously administering a precise dose of NO to the patient. By using this treatment, NO is intended to improve the patient's endothelial and cardiovascular health. Additionally and / or alternatively, the HDF system may provide NO directly to the blood chamber 3 .

[0049] The measuring devices 21A-21C can be used as measuring devices or sensors connected to the controller. For example, the measuring device 21A can be used to measure the density of the blood, the hematocrit (HCT) level, the pressure such as the venous pressure and / or other measurements. Furthermore, the measuring device 21A may include a transmitter 21A' and a receiver 21A". The measuring device 21C may be used to measure blood density, HCT levels, pressures such as arterial pressure in the arterial line 6. The measuring device 21B may be used to measure blood density and / or other measurements downstream of the blood chamber 3 and upstream of the venous access point 20. Additionally and / or alternatively, the HDF system may include other measuring devices that measure characteristics of the patient's blood during HCT treatment. For example, the HDF system may include a carbon monoxide (CO) oximeter to measure the concentration of methemoglobin, which increases in concentration in the bloodstream as NO is added. By measuring methemoglobin, the HDF system may measure the patient's NO level in real time by maintaining the methemoglobin below a certain threshold, such as a threshold of 5%, which is safe for the patient. Furthermore, the real-time measurement may protect the patient from excessively high NO doses during HDF treatment.

[0050] In some cases, the controller controls pump 16 to control the delivery rate during HDF treatment. For example, the controller can control pump 16 to provide a certain amount of NO to the patient over a period of time (e.g., at a rate at which NO is provided to the patient). The controller can also control whether NO is provided pre-dilution or post-dilution. The operation of the controller will be described in more detail below.

[0051] Figure 1 The blood treatment device is merely exemplary, and the HDF system using NO may include additional and / or alternative embodiments (e.g., additional and / or alternative components) of a blood treatment device, such as a blood circuit, for providing NO during HDF treatment of a patient. For example, the blood treatment device may be, for example, a blood treatment device as disclosed in U.S. Patent No. 8,216,478 to Noack et al., a hemodiafiltration delivery module as disclosed in U.S. Patent No. 10,821,216 to Collins et al., and / or an extracorporeal circulation and dialysis fluid circulation having a hemodialyzer and a hemofilter as disclosed in U.S. Patent No. 10,172,994 to Tschulena et al., which are incorporated herein by reference in their entireties.

[0052] Figure 2 A block diagram of an exemplary mixing system according to one or more examples of the present disclosure is shown. For example, mixing system 200 includes a water source 202, a chemical dispenser 206, a nitric oxide dispenser 208, and a mixing chamber 204. Water source 202 provides water to mixing chamber 204.

[0053] The chemical dispenser 206 can include a chemical source that provides chemical concentrates. The chemical concentrates are used as components of dialysis fluids (e.g., dialysate mixtures and replacement fluid mixtures). The chemical concentrates can be liquid concentrates of varying viscosities, or solid concentrates in tablet, pill, or powder form. The chemical source is a container that holds these chemical concentrates. Thus, the chemical dispenser 206 can hold concentrates of potassium chloride (KCl), calcium chloride (CaCl2), magnesium chloride (MgCl2), citric acid, dextrose, sodium chloride (NaCl), sodium bicarbonate (NaHCO3), acetic acid, glucose, and the like. Not all available chemical concentrates need to be used in every dialysate formulation or replacement fluid formulation.

[0054] The chemical dispenser 206 may also include an actuator that facilitates dispensing a specific amount of chemical concentrate into the mixing chamber 204 to mix a batch of dialysis fluid (e.g., dialysate for the dialyzer 1 and / or replacement fluid for pre-dilution and / or post-dilution). The actuator may control the amount of chemical concentrate provided to the mixing chamber 204 and may also control the amount of water used to mix the batch of dialysis fluid from the water source 202. The water source 202 may be a water interface for receiving filtered water or water suitable for use in dialysis treatments.

[0055] Chemical dispenser 206 and / or water source 202 provide chemical concentrate and water to mixing chamber 204. The contents of mixing chamber 204 are stirred for an appropriate time until the chemical concentrate is fully distributed throughout the chamber. In some cases, mixing chamber 204 is heated to help dissolve and / or distribute the chemical concentrate, creating a uniform solution. Once a uniform solution is achieved, mixing chamber 204 can be adjusted to an appropriate temperature for HDF treatment.

[0056] The mixing chamber 204 of the mixing system 200 provides mixed dialysis fluid to the dialyzer, e.g. Figure 1 The dialyzer 1 and / or sterile filter shown in, for example Figure 1 , which then forwards it to an access point for pre-dilution or post-dilution (e.g., arterial access point 19 and / or venous access point 20). In some examples, mixing chamber 204 is multi-chambered, wherein a first chamber is used to mix the dialysis fluid and a second chamber is used to store and deliver the dialysis fluid.

[0057] In some variations, the mixing chamber 204 may include sensors for sensing the dialysis fluid levels in the first and / or second chambers. The mixing chamber 204 may also include means (e.g., sensors) for alerting the controller when a batch of dialysis fluid has been mixed and provided forward.

[0058] The mixing system 200 also includes a NO distributor 208 that provides NO to the mixing chamber 204. For example, the NO distributor 208 can include a NO source that provides NO. In some cases, the NO distributor 208 can use liquid NO (e.g., S-nitrosoglutathione and S-nitrosocysteine), which is provided to the mixing chamber 204. For example, the NO distributor 208 can include a NO source and one or more actuators configured to provide NO to the mixing chamber 204.

[0059] Additionally and / or alternatively, the NO dispenser 208 may utilize an NO source that provides NO in gaseous form. For example, the NO dispenser 208 may include a NO gas supply source that provides NO, a flow meter connected to the NO gas supply source, and a NO gas supply path having a pressure gauge and a medical gas filter to ensure gas sterility. The NO dispenser 208 may also include a component that dissolves the NO gas in a liquid before providing it to the mixing chamber 204.

[0060] In some examples, NO dispenser 208 can provide NO to water source 202. For example, instead of NO dispenser 208 providing NO to mixing chamber 204, NO dispenser 208 can provide NO to water source 202, which provides purer NO because it can pass through more filters. Thus, this example can provide another step to purify NO before it reaches the dialyzer or patient.

[0061] The hybrid system 200 is merely exemplary, and a HDF system using NO may include additional and / or alternative embodiments (eg, additional and / or alternative components) of a hybrid system for providing NO during HDF treatment of a patient.

[0062] Figure 3A FIG. 3 shows another exemplary extracorporeal blood treatment apparatus for a hemodiafiltration system according to one or more examples of the present disclosure. For example, the extracorporeal blood treatment apparatus 300 may include Figure 1 For example, as shown in the figure, it includes a blood line 302, which is similar to Figure 1 The arterial blood line 6 and the venous blood line 7 are connected. The pump 304 is used to transport blood through the blood line 302. For example, the pump 304 can be an arterial blood pump, such as Figure 1 The arterial blood pump 8 is shown in FIG. The pump 304 moves the patient's blood through the dialyzer 306, which may be similar to Figure 1The dialyzer 1 of FIG. 302 may include two blood chambers and a semipermeable membrane. Dialysis fluid may be provided to one of the two blood chambers of the dialyzer 306. The arrows in the dialyzer 306 illustrate the direction of blood flow in one chamber, the direction of dialysis fluid flow in the other chamber, and the transport of substances in the blood through the semipermeable membrane. Afterwards, in the blood line 302 is a venous drip chamber 308 (e.g., a venous bubble trap, which may include one or more air detectors). The venous drip chamber 308 is a protective system for returning blood to the patient.

[0063] Also included is a dialysis fluid balancing chamber 310 that provides precise volume control of dialysis fluid and substitution circuit flow. Filters 312 and 314 are sterile filters that may be similar to Figure 1 Filter 17 shown in . Filters 312 and 314, such as DIASAFE filters, may include two chambers for filtering the dialysis fluid. In some cases, filters 312 and 314 may be other types of filters (e.g., non-DIASAFE type filters). The first filter 312 performs a first filtration on the dialysis fluid. The second filter 314 also filters and separates the dialysis fluid. For example, the second filter 314 is connected to a dialysate line 316, which provides a first portion of the dialysis fluid to the dialyzer 306. A valve 318 is provided in the dialysate line 316. The second filter 314 is also connected to a replacement fluid line 320, which provides a second portion of the dialysis fluid (e.g., replacement fluid) for HDF treatment. The replacement fluid line 320 is connected to the blood line 302 at entry points 322 and 324. For example, the entry point 322 may be an arterial entry point, such as Figure 1 The arterial access point 19 is upstream of the dialyzer 306 for pre-dilution. The access point 324 may be a venous access point, such as Figure 1 The venous access point 20 is provided downstream of the dialyzer 306 for post-dilution. NO can be provided to either access point 322 or 324 for pre-dilution or post-dilution.

[0064] In some cases, first filter 312 acts as a dead-end filter, with all liquid forced through the membrane. In some examples, second filter 314 is a tangential filter, in which pressure is used to pull liquid through the membrane from the main stream of liquid that would otherwise pass directly through the line (e.g., not filtered by second filter 314). Thus, the retentate (e.g., dialysate or the first portion of the dialysis fluid) moves through dialysate line 316. In contrast, the permeate (e.g., the replacement fluid or the second portion of the dialysis fluid) is pulled from the dialysate circuit through second filter 314 and is simultaneously filtered a second time as it is pulled through the membrane of second filter 314. The permeate from second filter 314 meets the requirements of ISO 23500 and ISO 11663 for infusion fluids of the International Organization for Standardization. The permeate then enters replacement fluid line 320. Therefore, the distinction between dialysate and replacement fluid can include unique sterility and pyrogenicity requirements for liquids designated for infusion.

[0065] The dialyzer 306 is also connected to a drain line 326, which may be similar to Figure 1 326 can be connected to the fluid discharge line 11. Therefore, the discharge line 326 can lead to the discharge end. A valve 328 is included in the discharge line 326. In addition, the component 330 can be a connector, such as a replacement fluid port, which splits the replacement fluid line 320. For example, the connector 330 can connect the replacement fluid line 320 to the replacement fluid discharge line 332. The replacement fluid discharge line 332 can include a connector 336 (e.g., a rinse / filtrate port) and two valves 334 and 338. Another discharge line 340 is connected to the first filter 312, which allows discharge from the first filter 312. The discharge line 340 includes a valve 342 (e.g., a retentate valve).

[0066] In addition, there are two pumps 344 and 346. The first pump 344 is a flow pump and the second pump 346 is an ultrafiltration pump. The pump 344 in the outflow dialysate circuit drives the flow of dialysate from the dialyzer 306, and the pump 346 generates sufficient pressure in the dialysate fluid chamber of the dialyzer 306 to force fluid and solutes from the blood across the membrane into the dialysate circuit.

[0067] In some examples, one or more additional filters may be used to filter the dialysis fluid. For example, another filter may be included in the replacement fluid circuit 320 to further filter the replacement fluid before providing it to the patient.

[0068] Figure 3A The extracorporeal blood treatment apparatus 300 shown in FIG. 3 including the rates is exemplary only and may include additional / alternative components and / or rates.

[0069] Figure 3BFIG. 3 shows another exemplary extracorporeal blood treatment apparatus for a hemodiafiltration system according to one or more examples of the present disclosure. For example, the extracorporeal blood treatment apparatus 350 may include Figure 3A Extracorporeal blood treatment apparatus 350 may include similar and / or additional components. Furthermore, extracorporeal blood treatment apparatus 350 may include other components and / or devices. For example, apparatus 350 includes an arterial bubble trap 352, which may function similarly to venous bubble trap 308, but on the arterial blood line. Furthermore, two additional valves 354 and 356 are shown. Valve 354 is a fill valve, and valve 356 is a drain valve.

[0070] Apparatus 350 also includes a vent valve and hydrophobic filter 360, a pressure sensor 358, a condition and temperature monitoring device 362, a filter / test valve 364, and a pressure sensor 366. Pressure sensors 358 and 366 detect pressure measurements and provide them to a controller, such as controller 402. Vent valve and hydrophobic filter 360 can be used during calibration of pressure sensors, such as sensor 366. Sensor assembly 362 monitors the conductivity and temperature of the effluent stream from filter 312. Filter / test valve 364 is used during internal pressure testing.

[0071] Furthermore, in the replacement circuit 320, a pump 368 is included. The pump 368 may be similar to Figure 1 Pump 16. In addition, a Y-connector 370 is also included in the replacement line 320, which separates the replacement fluid for pre-dilution and post-dilution through administration points 322 and 324.

[0072] Figure 4 A block diagram of an exemplary hemodiafiltration system according to one or more examples of the present disclosure is shown. For example, a hemodiafiltration (HDF) system 400 includes one or more controllers 402, a mixing system 404, and an extracorporeal blood circulation circuit 406. The mixing system 404 may be Figure 2 The extracorporeal blood circulation circuit 406 may be and / or include Figure 1 and 3 , and is used to perform HDF treatment. The dashed line shows the connection between the mixing system 400 and the extracorporeal blood circulation circuit 406 , which may include the dialysis fluid flowing to the extracorporeal blood circulation circuit 406 .

[0073] The controller 402 can be any type of hardware and / or software logic, such as a central processing unit (CPU), a field programmable gate array (FPGA), an application specific integrated circuit (ASIC), a processor with a non-transitory computer readable medium, and / or logic that executes computer executable instructions for performing the functions, processes, and / or methods described herein. For example, the controller 402 can control components of the mixing system 404, such as actuators, and / or components of the extracorporeal blood circulation circuit 406, such as pumps, valves, sensors, and / or Figure 1 and other components described in FIG. 3 . For example, controller 402 may provide instructions for mixing the dialysis fluid, including providing NO from NO dispenser 208 . Furthermore, controller 402 may provide instructions for releasing the mixed dialysis fluid into extracorporeal blood circulation circuit 406 . Furthermore, controller 402 may provide instructions to pumps, valves, etc. to perform HDF treatment on the patient. In some cases, controller 402 may obtain user input from a monitor or user device. User input may indicate flow rates for controlling HDF treatment, including the amount of NO provided during HDF treatment. For example, based on user input, controller 402 may indicate the amount and / or rate of NO to be mixed in the mixing chamber and / or the amount and / or rate of NO provided during HDF treatment. For example, controller 402 may control pump 16 of FIG. 1 to control the rate at which replacement fluid is provided to the patient. In some cases, controller 402 may control the amount of NO provided to the patient based on individual patient characteristics, such as a patient-specific formulation. For example, controller 402 may control the amount of NO provided by NO dispenser 208 and / or the pumping rate of the replacement fluid based on the patient's personalized formulation.

[0074] Figure 5 A flow chart illustrating an exemplary process for using a hemodiafiltration system according to one or more examples of the present disclosure is shown. Figure 5 A flow chart illustrating a process 500 that a controller, such as controller 402 , may use to perform HDF therapy.

[0075] At block 502, the controller 402 initiates HDF therapy on the patient. For example, the controller 402 may receive user input indicating the start of HDF therapy.

[0076] At block 504, controller 402 mixes the dialysis fluid for HDF treatment. Mixing includes providing nitric oxide to a mixing chamber of the HDF system. For example, controller 402 controls chemical dispenser 206 and / or NO dispenser 208, such as an actuator of the dispenser, to dispense a certain amount of chemical to mixing chamber 204. In some cases, controller 402 may control the amount of NO provided by NO dispenser 208. Controller 402 may then control a valve to provide the dialysis fluid to extracorporeal blood circulation circuit 406.

[0077] At block 506, the controller 402 performs HDF therapy, including providing replacement fluid to the patient. For example, the controller 402 may use Figure 1 The filters 314 and / or 17 of or 3 separate the dialysis fluid into a first part, eg, dialysate, provided to the dialyzer, and a second part, eg, replacement fluid, and provide the replacement fluid to the patient at the entry point for pre-dilution and / or post-dilution.

[0078] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[0079] The terms "a", "an", "said" and "at least one" and similar references used in describing the present invention, especially in the context of the following claims, should be interpreted as covering the singular and plural, unless otherwise indicated herein or clearly contradicted by the context. The use of the term "at least one" followed by a list of one or more items, such as "at least one A and B", should be interpreted as referring to one item A or B selected from the listed items or any combination A and B of two or more listed items, unless otherwise indicated herein or clearly contradicted by the context. The terms "including", "having" and "comprising" should be interpreted as open-ended terms, i.e., meaning "including but not limited to", unless otherwise indicated. References to numerical ranges herein are intended only as a shorthand method of individually citing each individual value falling within the range, unless otherwise indicated herein, and each individual value is incorporated into the specification as if it were individually cited herein. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by the context. Any and all examples or exemplary language used herein, such as "such as", are intended only to better illustrate the present invention and do not limit the scope of the present invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0080] The preferred embodiments of the present invention are described herein, including the best mode known to the inventor for carrying out the present invention. After reading the above description, variations of these preferred embodiments may become apparent to those of ordinary skill in the art. The inventor expects that the skilled person will appropriately adopt these variations, and the inventor intends that the present invention be implemented in a manner different from that specifically described herein. Therefore, the present invention includes all modifications and equivalents of the subject matter cited in the appended claims, as permitted by applicable law. In addition, any combination of the above elements is encompassed by the present invention in all possible variations, unless otherwise indicated herein or clearly contradicted by the context.

[0081] Reference to numerical ranges herein is intended only as a shorthand method of individually quoting each individual value falling within the range, unless otherwise indicated herein, and each individual value is incorporated into the specification as if it were individually quoted herein. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by the context. Any and all examples or exemplary language used herein, such as "such as", are intended only to better illustrate the present invention and do not limit the scope of the present invention unless otherwise claimed. Any language in the specification should not be construed as indicating any unclaimed element as an element essential to the implementation of the present invention.

Claims

1. A hemodiafiltration (HDF) system for performing HDF treatment, comprising: Hybrid system, including: a nitric oxide dispenser configured to provide nitric oxide (NO) to the mixing chamber; a chemical dispenser configured to provide chemicals to the mixing chamber; and a mixing chamber configured to mix the NO and the chemical to produce a dialysis fluid; Extracorporeal blood circulation circuit, including: a filter configured to separate the dialysis fluid into a dialysate and a replacement fluid containing NO; a dialyzer configured to receive the dialysate from the filter; and a blood line connected to the dialyzer and comprising one or more access points, wherein the one or more access points are connected to the filter and the NO-containing replacement fluid is administered through the one or more access points during HDF treatment; A controller configured to: providing instructions to the mixing system to produce a dialysis fluid comprising the NO; and Instructions are provided to the extracorporeal blood circulation circuit to perform HDF treatment using the dialysate and the NO-containing replacement fluid.

2. The HDF system according to claim 1, wherein: The blood line includes an arterial blood line that supplies blood from the patient to the blood chamber of the dialyzer and a venous blood line that returns the patient's blood from the blood chamber to the patient, and The one or more access points are arterial access points located on the arterial blood line and are configured to provide the NO-containing replacement fluid before the blood chamber for pre-dilution HDF therapy.

3. The HDF system according to claim 1, wherein: The blood line includes an arterial blood line that supplies blood from the patient to the blood chamber of the dialyzer and a venous blood line that returns the patient's blood from the blood chamber to the patient, and The one or more access points are venous access points located on the venous blood line and are configured to provide the NO-containing replacement fluid after the blood chamber for post-dilution HDF therapy.

4. The HDF system according to claim 1, wherein: The filter includes a membrane, a first chamber, and a second chamber, and is configured to separate the dialysis fluid by allowing a first portion of the dialysis fluid to remain in the first chamber without passing through the membrane, and allowing a second portion of the dialysis fluid to pass through the membrane and enter the second chamber, wherein the first portion of the dialysis fluid is a dialysate and the second portion of the dialysis fluid is a replacement fluid containing NO.

5. The HDF system according to claim 4, wherein: The extracorporeal blood circulation circuit further comprises: a dialysate line connecting the first chamber of the filter to the dialyzer; and A replacement fluid line connects the second chamber of the filter to the one or more access points.

6. The HDF system according to claim 1, wherein: The nitric oxide dispenser includes a nitric oxide source that provides nitric oxide in liquid form.

7. The HDF system according to claim 1, wherein: The nitric oxide dispenser includes a nitric oxide source that provides nitric oxide in gaseous form.

8. The HDF system according to claim 1, wherein: Providing instructions to the mixing system to produce the dialysis fluid includes: Instructions are provided to the nitric oxide dispenser to dispense a set amount of NO into the mixing chamber.

9. The HDF system according to claim 1, wherein: The extracorporeal blood circulation circuit further comprises: A pump is configured to pump the NO-containing replacement fluid into the one or more access points, and providing instructions to the extracorporeal blood circulation circuit to perform HDF treatment includes controlling the rate at which the pump supplies the NO-containing replacement fluid to the one or more access points.

10. A hemodiafiltration (HDF) system for performing HDF treatment, comprising: A controller configured to: providing instructions to generate a dialysis fluid comprising nitric oxide (NO); as well as providing instructions to perform HDF treatment using a dialysis fluid comprising said NO; and an extracorporeal blood circulation circuit, including: a filter configured to separate the dialysis fluid into a dialysate and a replacement fluid containing NO; a dialyzer configured to receive the dialysate from the filter; and A blood line is connected to the dialyzer and includes one or more access points for administering the NO-containing replacement fluid during HDF treatment.

11. The HDF system according to claim 10, wherein: The blood line includes an arterial blood line and a venous blood line, and The one or more access points are arterial access points located on the arterial blood line and are configured to enable administration of the NO-containing replacement fluid before the dialyzer for pre-dilution HDF treatment.

12. The HDF system according to claim 10, wherein: The blood line includes an arterial blood line and a venous blood line, and The one or more access points are venous access points located on the venous blood line and are configured to enable administration of the NO-containing replacement fluid after the dialyzer for post-dilution HDF therapy.

13. The HDF system according to claim 10, wherein: The filter includes a membrane, a first chamber, and a second chamber, and is configured to separate the dialysis fluid by allowing a first portion of the dialysis fluid to remain in the first chamber without passing through the membrane, and allowing a second portion of the dialysis fluid to pass through the membrane and enter the second chamber, wherein the first portion of the dialysis fluid is a dialysate and the second portion of the dialysis fluid is a replacement fluid containing NO.

14. The HDF system according to claim 13, wherein: The extracorporeal blood circulation circuit further comprises: a dialysate line connecting the first chamber of the filter to the dialyzer; and A replacement fluid line connects the second chamber of the filter to the one or more access points.

15. The HDF system according to claim 10, wherein: Providing instructions to generate the dialysis fluid comprising NO comprises: Instructions are provided to the nitric oxide dispenser to dispense a set amount of NO into the mixing chamber.

16. A method for performing hemodiafiltration (HDF) treatment, comprising: Producing dialysis fluid containing nitric oxide (NO) for use in HDF treatment of a patient; as well as HDF treatment is performed on the patient using an HDF system, wherein the HDF system includes an extracorporeal circulation circuit, the extracorporeal circulation circuit comprising: a filter for separating the dialysis fluid into a dialysate and a replacement fluid containing NO; a dialyzer for receiving the dialysate from the filter; and a blood line connected to the dialyzer and including one or more access points for administering the replacement fluid containing NO during HDF treatment.

17. The method according to claim 16, wherein The blood line includes an arterial blood line that supplies blood from the patient to the blood chamber of the dialyzer and a venous blood line that returns the patient's blood from the blood chamber to the patient, the one or more access points being arterial access points on the arterial blood line, and Wherein, performing HDF treatment on the patient includes: Pre-dilution HDF therapy is performed based on providing the NO-containing replacement fluid prior to the blood chamber using the arterial access point.

18. The method according to claim 16, wherein The blood circuit includes an arterial blood circuit that supplies blood from the patient to the blood chamber of the dialyzer and a venous blood circuit that returns the patient's blood from the blood chamber to the patient, the one or more access points being venous access points on the venous blood circuit, and Wherein, performing HDF treatment on the patient includes: Post-dilution HDF therapy is performed based on providing the NO-containing replacement fluid after the blood chamber using the venous access point.

19. The method according to claim 16, wherein The filter includes a membrane, a first chamber, and a second chamber, and is configured to separate the dialysis fluid by allowing a first portion of the dialysis fluid to remain in the first chamber without passing through the membrane, and allowing a second portion of the dialysis fluid to pass through the membrane and enter the second chamber, wherein the first portion of the dialysis fluid is a dialysate and the second portion of the dialysis fluid is a replacement fluid containing NO.

20. The method according to claim 16, wherein Generating the dialysis fluid containing NO for HDF treatment of the patient comprises: Instructions are provided to the nitric oxide dispenser to dispense a set amount of NO into the mixing chamber.

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