Techniques for increasing red blood cell count

Abstract

The described technology can include methods of treating a population of red blood cells (RBCs) in an individual, particularly a chronic kidney disease (CKD) patient with renal anemia, by reducing the amount of a Piezo1 chemical agonist in the patient's blood. In one embodiment, a method of treating a patient with renal anemia can include increasing RBC lifespan of a population of RBCs in the patient by reducing Piezo1 channel activation duration of at least a portion of the population of RBCs by reducing the amount of a target uremic compound in the patient's blood, the target uremic compound having a form that prolongs Piezo1 channel activation duration, wherein the amount of the target uremic compound can be reduced by selectively removing at least a portion of the target uremic compound from the patient's blood. Other embodiments are also described.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 113,403, filed November 13, 2020, entitled “Methods and Apparatuses for Increasing Red Blood CellLifespan,” the contents of which are incorporated herein by reference in their entirety. Invention Field

[0003] This disclosure generally relates to methods for increasing the lifespan of red blood cells in the human circulatory system, and more specifically, to techniques for increasing and / or maintaining a healthy red blood cell count by influencing the activation of red blood cell ion channels to increase red blood cell lifespan. Background of the Invention

[0005] In healthy individuals, red blood cells (RBCs) have a lifespan of approximately 100 to 120 days in circulation. In patients with kidney disease (such as those with chronic kidney disease (CKD) requiring dialysis), RBC lifespan is typically shortened, exacerbating renal anemia, a complication associated with decreased quality of life and increased morbidity and mortality.

[0006] Standard treatment for anemia may include pharmacological regimens that increase the RBC population or count and / or increase RBC lifespan. Example pharmacological regimens may include administration of erythropoietin (EPO), EPO stimulants (ESAs), and / or iron supplements. The exact biological mechanisms determining normal RBC lifespan in healthy individuals and the shortened RBC lifespan in anemic patients are not fully understood. Identifying and addressing these mechanisms underlying the shortened RBC lifespan in dialysis patients would benefit both anemic patients and healthcare providers. For example, increasing a patient's RBC lifespan could improve their quality of life, reduce health problems and morbidity, and decrease healthcare costs and dependence on it (e.g., if EPO administration could be reduced or even eliminated).

[0007] Taking these and other factors into account, the current improvements may be useful. Invention Overview

[0009] This overview is provided to introduce some concepts in a simplified form, which will be further described in the detailed description below. This overview is not necessarily intended to identify key or essential features of the claimed subject matter, nor is it intended to help determine the scope of the claimed subject matter.

[0010] In one embodiment, a method of treating a patient with renal anemia may include increasing the RBC lifespan of a patient's RBC population by reducing the amount of a target uremic compound in the patient's blood to decrease the duration of Piezol channel activation in at least a portion of the red blood cell (RBC) population, said target uremic compound having a form that prolongs the duration of Piezol channel activation, wherein said amount of the target uremic compound is reduced by selectively removing at least a portion of said target uremic compound from the patient's blood.

[0011] In some embodiments of the method, the target uremic compound may be 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF). In various embodiments of the method, the method may include using a mathematical model of erythropoiesis to monitor mean RBC lifespan. In some embodiments of the method, the patient may receive a dose (e.g., the maximum dose) of at least one erythropoietin-stimulating agent (ESA) to treat renal anemia. In various embodiments, the patient may receive a dose of a hypoxia-inducible factor (HIF) prolyl hydroxylase (PH or PHD) enzyme inhibitor, such as roxadustat, to treat renal anemia. In various embodiments of the method, the method may include reducing the ESA (and / or HIF-PHD) dose based on an increase in the patient's RBC lifespan.

[0012] In exemplary embodiments of the method, selective removal of the target uremic compound includes an adsorption process on the patient's blood. In some embodiments of the method, the adsorption process includes component plasma separation adsorption (FPSA). In various embodiments of the method, the adsorption process uses a ligand to adsorb CMPF, the ligand having a binding affinity for CMPF of approximately K. l =10 6 Up to 10 8 Scope. In some embodiments of the method, the method may include single-agent retrieval to selectively remove a target uremic compound. In various embodiments of the method, the method may include single-agent retrieval with a displacer that targets the RBC binding site of at least one uremic compound. In exemplary embodiments of the method, the displacer may include dithymoquinone (DTQ) or a chemical analogue thereof.

[0013] In one embodiment, the device for treating a patient with renal anemia may include a target compound reduction system configured to connect to the patient's blood to reduce the amount of the target compound in the patient's blood by selectively removing at least a portion of the target compound from the patient's blood, wherein reducing the amount of the target compound in the patient's blood increases the RBC lifespan of the red blood cell (RBC) population in the patient's blood by reducing the Piezol channel activation duration of at least a portion of the RBC population, the target compound having a form that prolongs the Piezol channel activation duration.

[0014] In some embodiments of the device, the target compound may be a uremic compound. In various embodiments of the device, the target compound may be 3-carboxy-4-methyl-5-propyl-2-furanopropionic acid (CMPF). In exemplary embodiments of the device, the target compound reduction system is operable to perform an adsorption process on a patient's blood. In various embodiments of the device, the adsorption process includes component plasma separation adsorption (FPSA). In some embodiments of the device, the adsorption process uses a ligand to adsorb CMPF, the ligand having a binding affinity for CMPF of approximately K. l =10 6 Up to 10 8 The scope of the target compound reduction system is defined in various embodiments of the device. In various embodiments of the device, the target compound reduction system is operable to perform single-absorption to selectively remove the target compound. In exemplary embodiments of the device, single-absorption can be performed using a displacement agent that targets the RBC binding site of the at least one target compound. In various embodiments of the device, the displacement agent may include dithyroquinone (DTQ) or a chemical analogue thereof. Brief description of the attached diagram

[0016] As an example, a specific implementation scheme will now be described with reference to the accompanying drawings, in which:

[0017] Figure 1 Exemplary ion channel activation in red blood cells (RBCs) according to this disclosure is illustrated;

[0018] Figure 2 Exemplary information relating to Piezo1 activation and RBC lifetime is shown in accordance with this disclosure;

[0019] Figure 3A An exemplary Piezo1 agonist according to this disclosure is shown;

[0020] Figure 3B Exemplary Piezo1 agonist activation sites in an RBC according to this disclosure are shown;

[0021] Figure 4Carboxy-4-methyl-5-propyl-2-furanopropionic acid (CMPF) according to this disclosure is shown;

[0022] Figure 5A Exemplary pathways leading to a reduction in the RBC population according to this disclosure are shown;

[0023] Figure 5B An exemplary approach to achieving a healthy RBC population coverage using treatment methods according to this disclosure is shown;

[0024] Figure 6 A first exemplary Piezo1 agonist removal system according to this disclosure is shown;

[0025] Figure 7A A second exemplary Piezo1 agonist removal system according to this disclosure is shown; and

[0026] Figure 7B A second exemplary Piezo1 agonist removal system according to this disclosure is shown.

[0027] Detailed description

[0028] Embodiments will now be described more fully below with reference to the accompanying drawings, in which several exemplary embodiments are illustrated. However, the subject matter of this disclosure may be embodied in many different forms and should not be construed as limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will convey the scope of the subject matter to those skilled in the art. In the accompanying drawings, the same numerals refer to the same elements throughout.

[0029] The embodiments described in this disclosure are generally applicable to therapeutic procedures, methods, systems, and / or devices for increasing an individual's red blood cell (RBC) count. In one instance, the therapeutic procedure described in this disclosure can be used to treat an individual with a low RBC count, particularly including patients with anemia. A low RBC count may be due to one or both of reduced RBC production (e.g., due to a deficiency of erythropoietin, iron, vitamins, trace elements, etc.) and / or shortened RBC lifespan (e.g., due to blood loss, erythrocyte death, hemolysis, etc.). Therefore, a therapeutic procedure according to some embodiments can be performed to increase the RBC count by influencing erythrocyte production (RBC generation) and / or erythrocyte death (RBC death).

[0030] Various implementation schemes may be beneficial in increasing RBC counts in patients with chronic kidney disease (CKD), particularly those exhibiting shortened RBC lifespan, including those with renal anemia. Globally, approximately 700 million people suffer from chronic kidney disease (CKD). Most patients with advanced CKD develop renal anemia at some point, a complication associated with decreased quality of life and increased morbidity and mortality. Erythropoietin (EPO) is the primary erythropoietic stimulating hormone, mainly produced by the kidneys. EPO deficiency is common in CKD and is a well-documented cause of renal anemia. Other factors include absolute and / or functional iron deficiency, inflammation with elevated hepcidin levels, and shortened RBC lifespan. Enhancing erythropoiesis is a widely used treatment strategy, and renal anemia is often managed with erythropoietic stimulants (ESAs; with effects similar to endogenous EPO), iron supplements, and more recently, hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHD; e.g., roxadustat), medications that increase EPO production, improve iron availability, and decrease hepcidin levels.

[0031] In healthy individuals, the lifespan of red blood cells (RBCs) is approximately 100 to 120 days. In most patients with advanced chronic kidney disease (CKD), RBC lifespan is shortened, leading to the development of renal anemia. For example, in CKD patients undergoing hemodialysis, the average RBC lifespan is shortened to approximately 50 to 70 days. Since the steady-state number of circulating RBCs depends on the balance between RBC formation and RBC death, shortened RBC lifespan is considered a major cause of renal anemia. This suggests that interventions that systematically increase RBC lifespan in CKD patients may alleviate anemia, leading to a larger steady-state RBC pool and thus increasing hemoglobin concentration. Furthermore, such interventions could reduce the total amount of exogenous saline-alcohol (ESA) required to maintain adequate hemoglobin levels.

[0032] In some implementations, the treatment process may target the activation of ion channels embedded in the RBC membrane. In some implementations, the ion channels may be those that regulate calcium (Ca, Ca++, Ca) levels. 2+Intracellular Ca (iCa++) and / or analogues) are ion channels that function in RBCs. For example, Ca++ influx has been shown to be a key event in erythrocyte death (e.g., when an imbalance of Ca++ influx and efflux occurs) (see, for example, Dias et al., “The Role of Eryptosis in the Pathogenesis of Renal Anemia: Insights from Basic Research and Mathematical Modeling,” Frontiers in Cell and Developmental Biology, December 9, 2020, which is incorporated herein by reference as if fully expounded herein).

[0033] In various implementations, the ion channel may be a Piezo channel, which opens in response to a mechanical force applied to the RBC to allow Ca++ and / or other ions to enter the RBC (see, for example, [link to relevant documentation]). Figure 1 Non-limiting examples of ion channels could be the Piezo1 channel, which regulates RBC cell volume, etc.

[0034] In exemplary embodiments, a treatment procedure can be operated to reduce Piezo1 channel activation in RBCs. In some embodiments, the treatment procedure may be directed to remove, inactivate, or otherwise affect a Piezo1 channel agonist to reduce agonist-induced Piezo1 channel activation. Reducing Piezo1 channel activation may include reducing the number of activations and / or reducing the duration of channel activation. More specifically, some embodiments may include methods for reducing or even eliminating non-mechanically based Piezo1 channel activation (number of activations and / or duration of activation) caused by chemical activation, such as by a Piezo1 channel agonist. A non-limiting example of a Piezo1 channel agonist may include uremic compounds. Another non-limiting example of a Piezo1 channel agonist may include 3-carboxy-4-methyl-5-propyl-2-furanopropionic acid (CMPF). In some embodiments, systems, devices, and / or apparatuses may be operated to perform the treatment procedure described in this disclosure for increasing RBC lifespan.

[0035] Typically, Piezo1 channel activation in red blood cells (RBCs) can affect RBC lifespan (i.e., the greater the Piezo1 channel activation, the lower the RBC lifespan). Piezo1 channel activation can occur due to mechanoactivation when RBCs flow through portions of vessels, splenic slits, or other structures smaller than the RBC in diameter (i.e., allowing the RBC to become more flexible to accommodate smaller diameter portions). However, Piezo1 channel activation can be prolonged by certain compounds. Reducing chemical stimulation can decrease overall Piezo1 channel activation in RBCs, thereby increasing RBC lifespan.

[0036] The lifespan of red blood cells (RBCs) in mammals is asymmetrically proportional to body weight; therefore, lower-weight mammals generally have shorter RBC lifespans compared to higher-weight mammals. Across the four body weight classes, although RBC lifespans differ significantly, the number of cycles during the RBC lifespan is remarkably constant (150,000 to 250,000 cycles). One biological reason for this phenomenon is likely, or may include, a cumulative RBC "erosion," where, for example, an RBC (approximately 7 μm in diameter) needs to pass through a much smaller capillary (2–5 μm) in each cycle. Consequently, the RBC undergoes geometric changes and shrinks in diameter through stretching, exhibiting a remarkable deformability. This process can last approximately 700 msec through capillaries.

[0037] Treatment procedures according to certain implementation schemes can offer several technological advantages over existing systems and methods. In one non-limiting technological advantage, treatment procedures according to certain implementation schemes can treat anemia (e.g., achieve healthy RBC counts) without the use of medication or with reduced medication dosage for the patient, thus reducing costs and impact on patient health. In another non-limiting technological advantage, treatment procedures according to certain implementation schemes can treat abnormal RBC counts by removing the Piezo1 agonist, which is not possible with conventional treatments. In yet another non-limiting technological advantage, treatment procedures according to certain implementation schemes can provide an intervention to reduce CMPF levels to systematically increase RBC lifespan in CKD patients, alleviate renal anemia, and reduce ESA requirements.

[0038] Figure 1 Exemplary ion channel activation in red blood cells (RBCs) according to this disclosure is illustrated. An example of the RBC deformation mechanism can be found in Danielczok et al., “Red Blood Cell Passage of Small Capillaries Is Associated with Transient Ca2+”. 2+"-mediated Adaptations," Frontiers in Physiology, December 5, 2017, is incorporated by reference as if fully elaborated in this article.

[0039] Figure 101 illustrates transient Piezo1 activation in normal or healthy individuals. Figure 1 As shown, RBC 120 can pass through blood vessels, splenic sutures, or other parts of the human anatomy 110. RBC 120 can have a larger volume, diameter, circumference, or other characteristics than the narrow portion 111 of the blood vessel 110. Therefore, RBC 120 cannot pass through the narrow portion 111 without altering its shape.

[0040] RBC 120 deformation is mediated via Piezo1 mechanosensitive ion channel 121. Mechanical stimulation (e.g., the external lateral pressure of RBC 120 against the inner wall of vessel 110, particularly near and / or within the stenotic segment 111) promotes Ca2+ ionization. 2+ It flows in via Piezo1 channel 121. Upon activation, Piezo1 121 opens Ca. 2+ Channel, Ca 2+ It flows into RBC 120 along an electrochemical gradient, where it activates a series of intracellular processes, resulting in increased RBC flexibility. For example, Ca... 2+ It also chelates with calmodulin and then co-binds to RBC-NOS. When RBC-NOS is activated, NO is produced, which binds to α- and β-spectrin, leading to increased flexibility and improved deformability of RBC 120 cells. Furthermore, RBCs undergo water and Cl- loss... - and K + This results in a reduction in the volume of RBC 120. Therefore, RBC 120 can move through the narrow section 111.

[0041] Activation of Gardos channel 122 is for continuous Ca 2+ Inflow response. Gardos channel 122 is opened to facilitate K. + Outflow leads to the loss of intracellular fluid. Simultaneously, Ca... 2+ Through the plasma membrane Ca 2+ -ATPase (PMCA) transports RBC120 out. RBC120 undergoes cell shrinkage and also experiences a temporary loss of deformability. During this phase, RBC120 has passed through the narrow portion 111 and the Piezo1 channel 121 and Gardos channel 122 have closed.

[0042] Although Ca 2+Inflow to RBC 120 is crucial for its transcapillary passage, but divalent cations need to flow out of RBC 120 rapidly due to prolonged intracellular Ca2+. 2+ Elevated levels stimulate processes that promote RBC 120 destruction. Similarly, it is important that Piezo1 121 is activated only briefly, during the passage of RBC 120 through the narrowing segment 111 (e.g., capillaries in a larger vascular system). However, as shown in Figure 102, CKD patients, particularly those with renal anemia, may experience prolonged Piezo1 121 activation. In particular, Piezo1 121 may remain open in Figure 102 after RBC 120 has already passed through the narrowing segment 111.

[0043] Persistent activation of Piezo1 leads to shortened RBC lifespan, as evidenced by several mutations (e.g., R2456H, T2127M, and E2496ELE) that exhibit gain-of-function (GOF) and / or loss-of-function (LOF) phenotypes. Figure 2 Exemplary information relating to Piezo1 activation and RBC lifetime is shown according to this disclosure. More specifically, Figure 2 Figure 210 depicts the reduced RBC lifespan due to Piezo1-GOF, and Figure 220 depicts the increased RBC lifespan due to Piezo1LOF. Therefore, the Piezo1 GOF mutation shortens RBC lifespan, while the Piezo1LOF mutation increases it. Examples of Piezo1 GOF and LOF mutations and their effects on RBC lifespan can be found in Rotordam et al., “A novel gain-of-function mutation of Piezo1 is functionally affirmed in red blood cells by high-throughput patch clamp,” Haematologica, 104(5):e179–e183 (2019) and Ma et al., “Correlation between Inflammatory Biomarkers and Red Blood Cell Life Span in Chronic Hemodialysis Patients,” Blood Purification 2017; 43(1-3):200-5, both of which are incorporated herein by reference as if fully described herein.

[0044] Therefore, prolonged Piezo1 activation appears to negatively impact RBC lifetime and thus RBC count. Typically, the mechanoreceptors Piezo1 located on the RBC surface stimulate Ca2+. 2+ Inflow. This facilitates the passage of RBCs through capillaries, splenic sutures, and other narrowing vascular structures. However, elevated calcium... 2+ It is a key trigger for erythrocyte death. Prolonged Piezo1 activation leads to Ca2+ death. 2+ Prolonged inflow and excessive erythrocyte death. Furthermore, Piezo1 activation slows erythrocyte production and promotes cardiac hypertrophy.

[0045] Figure 3A An exemplary Piezo1 agonist according to this disclosure is shown. More specifically, Figure 3A The Piezo1 agonists Jedi1 301, Jedi2 302, and Yoda1 303 are described. The small molecules 301-303 have been shown to stimulate Piezo1 (see, for example, Wang et al., “A lever-like transduction pathway for long-distance chemical-and mechano-gating of the mechanosensitive Piezo1 channel,” Nature Communications, 9(1), Article Number 1300 (2018), the contents of which are incorporated herein by reference as if fully expounded herein). Figure 3B An exemplary Piezo1 agonist activation of the RBC according to this disclosure is illustrated. Figure 3B As shown, Piezo1 channel 330 can be embedded in membrane 361 of RBC 310. Piezo1 channel 330 can have activation sites targeting Jedi1 331, Jedi2332 and Yoda1333.

[0046] Figure 4 Carboxy-4-methyl-5-propyl-2-furanopropionic acid (CMPF)401 is shown according to this disclosure. CMPF is a 240 Da metabolite of furan fatty acids, a protein-bound uremic retained solute that is normally cleared by healthy kidneys. In CKD patients, CMPF levels are increased 5 to 15 times compared to healthy subjects.

[0047] Return to reference Figure 3AGroup 311 of Jedi1 301 and group 312 of Jedi 302 are the portions or "active centers" that activate Piezo1 in these small molecules. Group 411 of CMPF 401 has structural similarity to group 311 of Jedi1 301 and group 312 of Jedi2 302. Therefore, it appears that CMPF 401, for example through portion 411 as the "active center," can activate Piezo1 in the same or similar manner as portions 311 and 312 of Jedi1 301 and / or Jedi2 302, respectively. Therefore, since CKD patients have elevated CMPF levels, they may have elevated Piezo1 activation through CMPF activation of Piezo1 as a Piezo1 agonist.

[0048] Figure 5A Exemplary pathways leading to a reduction in the RBC population according to this disclosure are shown. Figure 5A As shown, renal failure in CKD patients 502 can lead to erythropoietin deficiency 520, which plays a pre-existing role in the pathogenesis of renal anemia, resulting in a reduced RBC population 530. Furthermore, renal failure 502 may also lead to increased CMPF levels and CMPF accumulation 504. CMPF can activate Piezo1. Therefore, increased CMPF levels can lead to prolonged activation of Piezo1 in RBCs 506, and thus increased calcium influx into RBCs 508. CMPF accumulation in CKD patients can lead to shortened RBC lifespan 510 and increased erythrocyte mortality 512, ultimately resulting in a reduced RBC population 530 and renal anemia.

[0049] Therefore, some implementation schemes may include a treatment process targeting CMPF levels because: (a) CMPF prolongs Piezo1 activation and calcium influx, thereby triggering the erythrocyte death pathway; (b) elevated CMPF levels in CKD shorten RBC lifespan, leading to renal anemia; and (c) reducing CMPF levels in CKD patients will improve anemia by reducing the chemical activation of Piezo1.

[0050] Figure 5B Exemplary approaches to achieving a healthy or healthier RBC population range using treatment procedures according to this disclosure are shown. Figure 5B As shown, renal failure in CKD patients can lead to erythropoietin deficiency and CMPF accumulation, both of which may result in a reduced RBC population (see e.g., see [link to relevant documentation]). Figure 5A ESA treatment regimen 522 can result in an increased RBC population range 580 (e.g., compared to no treatment).

[0051] In some implementations, the treatment process may include a Piezo1 agonist treatment regimen 556. For example, the treatment process may include the removal or inactivation of one or more Piezo1 agonists, such as CMPF, which is increased in CKD patients. Removal of one or more Piezo1 agonists may result in a reduction of Piezo1 activation in RBCs 558, and thus a reduction in calcium influx into RBCs 560 (e.g., compared to no treatment). In this way, the treatment process may result in an increase in RBC lifespan 562 and a decrease in erythrocyte mortality 564, which may result in an increase in RBC population size (e.g., compared to no treatment).

[0052] Although CMPF is used as an example in this disclosure, the implementation is not limited thereto. For example, there are many compounds (including uremic retention solutes) that can also interact with Piezo1 and thus affect RBC lifespan, which can be treated with treatment procedures (including but not limited to Piezo1-agonist treatment regimens).

[0053] CMPF is a major endogenous ligand found in the serum of patients with renal failure. CMPF can exist in free and / or bound forms. For example, CMPF can bind to human serum albumin (HSA). In some embodiments, the treatment process may include adsorption-based removal of CMPF (and / or other Piezo1 agonists). For example, in the adsorption removal of one or more agonists, identification of the location of the agonist binding site / pocket to HSA can be used to design, develop, select, or otherwise determine adsorbent materials that specifically remove CMPF and / or other agonists of interest. Furthermore, knowing normal and elevated serum levels provides information about the quality of toxins to be depleted or removed. Therefore, in some embodiments, the treatment process may be based on agonist binding site / pocket information and / or normal and elevated serum levels (toxin quality) to remove the target compound.

[0054] For example, regarding the CMPF and HSA methods, CMPF is a typical representative of urofuranoid acids, exhibiting significant lipophilic properties and a high affinity for HSA molecules (e.g., at or around 10). 8 M -1 Association constant. CMPF has an atrophy at the bilirubin-binding center (also known as binding site 1) on the albumin molecule. The mean normal concentration of CMPF can be approximately 4.6 ± 1.8 mg / L (±SD), ranging from approximately 3.6 to 7.7 mg / L. The mean concentration (CU) in patients with uremia is approximately 25.9 ± 10.2 mg / L (range approximately 3.7 to 94 mg / L).

[0055] Therefore, the relative increase (CU / CN) may be more than 5 times higher than the average normal concentration. Chemically, CMPF is a weak organic base with a mass of 240 Da and exhibits strong lipophilic characteristics. Up to 99.5% of CMPF can be found bound to HSA in serum. Therefore, due to the low renal clearance rate in uremic patients, for example, at a rate of about 0.05 mL / min, compared to 0.40 mL / min in healthy patients, this high association with HSA can prevent sufficient secretion. Due to the strong binding affinity of CMPF to HSA, removal of CMPF by routine hemodialysis is often difficult, or even practically ineffective.

[0056] Therefore, treatment procedures according to some embodiments may use or include an adsorption device configured to have an effective depletion capacity leading to normal physiological ranges. In some embodiments, the effective depletion per treatment can be up to 500 mg / L. Some embodiments may include various methods leading to a reduction (or even elimination) of CMPF from the patient's serum. In various embodiments, the treatment procedure may be configured to remove CMPF using component plasma separation adsorption (FPSA) alone or in combination with dialysis. In other embodiments, the treatment procedure may be configured to remove CMPF using a therapeutic apheresis method with an exogenous binding competitive agent (“displacement agent”). In various embodiments, the displacement agent may be configured to be a compound that targets CMPF, such as targeting HSA (e.g., HSA binding site 1) with high affinity, or a combination thereof. Embodiments are not limited thereto, as other methods may be used.

[0057] Figure 6 A first exemplary Piezo1 agonist removal system according to this disclosure is shown. Figure 6 As shown, patient 650 can be fluidly coupled to Piezo1 agonist removal system 605. In some embodiments, Piezo1 agonist removal system 605 may include a dialysis circuit or system 610 fluidly coupled to an adsorption circuit or system 611. In various embodiments, adsorption circuit 611 may be or may include an FPSA circuit. In various embodiments, adsorption circuit 611 may be used for single-harvest during adsorption. Non-limiting examples of FPSA circuits may be or may include those with FPSA circuits provided by Fresenius Medical Care of Bad Homburg, Germany. Machine. In some embodiments, dialysis circuit 610 may be or may include a hemodialysis (HD) system. Non-limiting examples of dialysis circuit 610 may include Fresenius systems provided by Fresenius Medical Care. High-throughput dialysis machine.

[0058] In various embodiments, to achieve specific adsorption of CMPF within the adsorption loop 611, a ligand with affinity for CMPF can be used. The ligand can be within a range competing with HAS (e.g., approximately K). l =10 6 Up to 10 8 Scope; see, for example, Sakai et al., “Characterization of binding site of uremic toxins on humanserum albumin,” Biol Pharm Bull 18(12):1755-61 (1995) and Hendersen et al., “Interaction of 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid, an inhibitor of plasma protein binding in uraemia, with human albumin,” Biochem Pharmacol 40(11):2543-48 (1990), both of which are incorporated herein by reference as if fully described herein). Furthermore, in exemplary embodiments, the CMPF-specific adsorbent-ligand may have lower binding affinity for other HSA binding site 1-binding agents (such as bilirubin).

[0059] Structural information regarding the HSA binding pocket indicates that the primary interaction with CMPF occurs between residues Tyr-150, Lys-99, Arg-222, and Arg-257, with bond lengths of 2.9 Å, 3.0 Å, 3.0 Å, and 3.2 Å, respectively (see, for example, Faiza 2017). The molecular imprinting transfer / preservation of this binding pocket obtained from the CMPF interaction can be used to design / develop binding site mimics with appropriate pocket size and physicochemical force densities primarily targeting CMPF.

[0060] Therefore, the adsorption circuit 611 can be configured to remove CMPF from patient serum via a component plasma separation adsorption (FPSA) process combined with conventional hemodialysis (HD). Various adsorbent materials for CMPF can be used. In some embodiments, the adsorbent material can be any material having an affinity for CMPF sufficient to remove it from the serum as it passes through the adsorption circuit 611. In one example, the CMPF-ligand can exhibit binding affinity for CMPF in the same molar range as albumin.

[0061] In the first step, an albumin-rich plasma fraction can be separated and contacted with an adsorbent material carrying CMPF-specific ligands to remove free and albumin-bound CMPF as the patient's blood passes through adsorption circuit 611. The purified plasma can then be recombined with the blood flow, which is then advanced to the conventional HD procedure via dialysis circuit 610.

[0062] In some embodiments, a displacer compound having a higher binding affinity for albumin (e.g., binding site 1) can be presented to albumin-rich plasma, rather than relying on a specific ligand to deplete CMPF from the plasma stream or using albumin. A non-limiting compound (or displacer) may be or may include dithymoquinone (DTQ) or a chemical analogue thereof. DTQ exhibits a higher binding affinity for HSA binding site 1 than for CMPF, which can release CMPF, allowing it to be adsorbed by an adsorbent material (see, for example, Faiza et al., “Dithymoquinone as a novel inhibitor for 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) to prevent renal failure,” Quantitative Methods, July 23, 2017, which is incorporated by reference as fully set forth in this disclosure (“Faiza 2017”). Although DTQ or chemical analogues are used in the examples, the embodiments are not limited thereto, as this disclosure relates to any type of displacer (e.g., ibuprofen) capable of operating according to some embodiments.

[0063] Figure 7A A second exemplary Piezo1 agonist removal system according to this disclosure is shown. More specifically, Figure 7A Examples of dialysis removal of CMPF using a displacement agent according to some embodiments of this disclosure are described. For example... Figure 7A As shown, the dialysis machine 705 can be operated to cause dialysate inflow 704 and dialysate outflow along with unwanted substance 706. Patient blood 702 may include target material in the form of CMPF 710' bound to albumin 720 and free or unbound CMPF 710. Unbound CMPF 710 can pass through the dialysis membrane 750 and be removed as unwanted substance 706 along with the dialysate outflow. Bound CMPF 710' cannot pass through the dialysis membrane 750 and therefore cannot be removed as unwanted substance 706 along with the dialysate outflow.

[0064] In some embodiments, the dialysis machine 705 may include a replacement agent container 740 or be in fluid communication with the replacement agent container 740, the replacement agent container 740 being operable to facilitate the infusion of replacement agent 730 via the patient's blood into the patient's blood 702. For example... Figure 7A As shown, the replacement agent 730 can compete for binding sites on HSA 720, resulting in a reduction (or even elimination) of bound CMPF 710 and an increase in free CMPF 710. The increase in free CMPF 710 can facilitate the removal of CMPF 710 from patient blood 702 or the removal of a greater amount of CMPF 710 compared to what can be achieved without the replacement agent 730.

[0065] Figure 7B A third exemplary Piezo1 agonist removal system according to this disclosure is shown. Figure 7B In the system, blood effluent 703 with increased free CMPF due to the displacement process can flow into an adsorption circuit 711 configured according to some embodiments. The displacement agent 730, such as DTQ, exhibits a higher binding affinity for HSA binding site 1 than for CMPF, which can release CMPF, allowing it to be adsorbed by the adsorbent material within the adsorption circuit 711. In some embodiments, the adsorption circuit 711 can be fluidly coupled to the dialysis system (not shown; see, for example, see...). Figure 6 ).

[0066] In some implementations, blood inflow 701 may originate from the apheresis process (e.g., blood inflow 701 is actually "plasma inflow" and blood outflow 703 is actually "plasma outflow"). In such implementations, "plasma outflow" 703 may allow plasma to recombine with red blood cells after the replacement circuit.

[0067] Therefore, refer to Figure 7A and 7B Displacement-based treatment processes can provide various pathways for removing CMPF from the blood: (1) via a displacement process followed by dialysis; (2) via a displacement process followed by an adsorption circuit; (3) via a displacement process within an adsorption circuit; and / or (4) via a displacement process, through an adsorption circuit, followed by dialysis. Reference Figure 6 Path (3) may include the use of a displacement agent within the adsorption loop 611, for example, within the adsorption filter module. The implementation is not limited to this context.

[0068] Although the displacement agent process is shown to be used in combination with HD and / or adsorption processes, the implementation is not limited thereto. For example, the displacement agent method can be used without an adsorption process. In various implementations, for example, the displacement agent method can be used in combination with HD, blood filtration, or hemodialysis filtration without an adsorption process.

[0069] In some implementations, various models can be used to determine the RBC characteristics of a patient's RBC population. For example, the average RBC lifespan of a patient can be determined by using a mathematical model of erythrocyte production. RBC characteristics can be determined before, during, and / or after treatment according to certain implementations to increase RBC lifespan, thereby increasing the patient's RBC population. In this way, healthcare professionals can use RBC characteristics to determine the configuration of a treatment procedure and / or to determine progress (e.g., an increase in RBC lifespan due to a treatment procedure according to certain implementations).

[0070] Non-limiting examples of biological models of RBC that can be used to identify RBC characteristics include Fuertinger et al., “A model of erythropoiesis in adults with sufficient iron availability,” J Math Biol. 2013 May; 66(6):1209-40 and Fuertinger et al., and “Prediction of hemoglobin levels in individual hemodialysis patients by means of amathematical model of erythropoiesis,” PLOS ONE, April 18, 2018, both of which are incorporated herein by reference as if fully elaborated herein.

[0071] This document sets forth numerous specific details to provide a comprehensive understanding of the implementation scheme. However, those skilled in the art will understand that the implementation scheme can be practiced without these specific details. In other instances, well-known operations, components, and loops have not been described in detail to avoid obscuring the implementation scheme. It is understood that the specific structural and functional details disclosed herein may be representative and do not necessarily limit the scope of the implementation scheme.

[0072] Some implementations may be described using the terms “coupled” and “connected” and their derivatives. These terms are not intended to be synonyms with each other. For example, the terms “connected” and / or “coupled” may be used to describe some implementations to indicate that two or more elements are in direct physical or electrical contact with each other. However, the term “coupled” may also mean that two or more elements are not in direct contact with each other, but still cooperate or interact with each other.

[0073] Unless otherwise expressly stated, terms such as “processing,” “computation,” “operation,” and “determine” refer to actions and / or processes of a computer or computing system or similar electronic computing device that manipulate and / or convert data representing physical quantities (e.g., electronic) in the registers and / or memory of the computing system into other data representing physical quantities similarly in the memory, registers, or other such information storage, transmission, or display devices of the computing system. Implementations are not limited thereto.

[0074] It should be noted that the methods described herein need not be performed in the stated order or any particular order. Furthermore, the various activities described with respect to the methods herein can be performed serially or in parallel.

[0075] Although specific embodiments have been illustrated and described herein, it should be understood that any arrangement calculated to achieve the same purpose can be substituted for the specific embodiments shown. This disclosure is intended to cover any and all adaptations or variations of the various embodiments. It should be understood that the above description is in an illustrative rather than restrictive manner. Combinations of the above embodiments and other embodiments not specifically described herein will be apparent to those skilled in the art upon review of the above description. Therefore, the scope of the various embodiments includes any other applications using the above compositions, structures, and methods.

[0076] Although the subject matter has been described in language specific to structural features and / or methodological behavior, it should be understood that the subject matter defined in the appended claims is not necessarily limited to the specific features or actions described above. Rather, the specific features and actions described above are disclosed as exemplary forms for implementing the claims.

[0077] As used herein, elements or operations quoted in the singular and beginning with the word "a" or "an" should be understood to not exclude plural elements or operations unless such exclusion is explicitly enumerated. Furthermore, references to "one embodiment" of this disclosure are not intended to exclude the existence of additional embodiments that also include the described features.

[0078] The scope of this disclosure is not limited to the specific embodiments described herein. In fact, based on the foregoing description and drawings, various other embodiments and modifications of this disclosure will be apparent to those skilled in the art in addition to those described herein. Therefore, such other embodiments and modifications fall within the scope of this disclosure. Furthermore, although this disclosure is described herein in the context of a specific implementation in a specific environment for a particular purpose, those skilled in the art will recognize that its usefulness is not limited thereto, and that this disclosure can be advantageously implemented in any number of environments for any number of purposes. Therefore, the following claims should be interpreted in accordance with the full breadth and spirit of this disclosure as set forth herein.

Claims

1. Use of a displacement agent compound in the preparation of a medicament for treating patients with renal anemia, wherein the medicament is configured to: The RBC lifespan of the patient's RBC population is increased by reducing the amount of the target uremic compound in the patient's blood to decrease the duration of Piezol channel activation in at least a portion of the red blood cell (RBC) population, wherein the target uremic compound has a form that prolongs the duration of Piezol channel activation. The amount of the target uremic compound is reduced by selectively removing at least a portion of the target uremic compound from the patient's blood.

2. The use according to claim 1, wherein the target uremic compound is 3-carboxy-4-methyl-5-propyl-2-furanopropionic acid (CMPF).

3. The use according to claim 1, wherein the drug is configured to be administered to a patient receiving at most maximal doses of at least one erythropoietin stimulant (ESA) for the treatment of renal anemia.

4. The use according to claim 1, wherein the drug is configured to be administered to a patient undergoing an adsorption process on the patient's blood.

5. The use according to claim 4, wherein the adsorption process includes component plasma separation adsorption (FPSA).

6. The use according to claim 4, wherein the adsorption process uses a ligand to adsorb CMPF, the binding affinity of the ligand to CMPF being in the range of K. l = 10 6 Up to 10 8 The range.

7. The use according to claim 1, wherein the drug is configured to be administered to a patient undergoing a single-absorption process to selectively remove the target uremic compound.

8. The use according to claim 6, wherein the medicament is configured to target the RBC binding site of the at least one target uremic compound.

9. The use according to claim 7, wherein the displacement agent comprises dithyroquinone (DTQ) or a chemical analog thereof.

10. A device for treating patients with renal anemia, the device comprising: A targeted uremic compound reduction system is configured to interface with the patient's blood to reduce the amount of the targeted uremic compound in the patient's blood by selectively removing at least a portion of the targeted uremic compound from the patient's blood. Specifically, the target uremic compound increases the RBC lifespan of the patient's blood RBC population by reducing the Piezol channel activation duration of at least a portion of the red blood cell (RBC) population, wherein the target uremic compound has a form that prolongs the Piezol channel activation duration.

11. The apparatus of claim 10, wherein the target uremic compound is 3-carboxy-4-methyl-5-propyl-2-furanopropionic acid (CMPF).

12. The apparatus of claim 10, wherein the targeted uremic compound reduction system is operable to perform an adsorption process on the patient's blood.

13. The apparatus of claim 12, wherein the adsorption process comprises component plasma separation adsorption (FPSA).

14. The apparatus of claim 13, wherein the adsorption process uses a ligand to adsorb CMPF, the ligand having a binding affinity for CMPF at K... l = 10 6 Up to 10 8 The range.

15. The apparatus of claim 10, wherein the targeted uremic compound reduction system is operable to perform single-sampling to selectively remove the targeted uremic compound.

16. The apparatus of claim 15, wherein single retrieval is performed with a displacement agent that targets the RBC binding site of the at least one target uremic compound.

17. The apparatus of claim 16, wherein the displacement agent comprises dithyroquinone (DTQ) or a chemical analog thereof.

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