WO2011090943A1 - Retrait d'albumine pathologique du plasma d'un sujet - Google Patents

Retrait d'albumine pathologique du plasma d'un sujet Download PDF

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Publication number
WO2011090943A1
WO2011090943A1 PCT/US2011/021550 US2011021550W WO2011090943A1 WO 2011090943 A1 WO2011090943 A1 WO 2011090943A1 US 2011021550 W US2011021550 W US 2011021550W WO 2011090943 A1 WO2011090943 A1 WO 2011090943A1
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WIPO (PCT)
Prior art keywords
plasma
albumin
subject
pathological
solution
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PCT/US2011/021550
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English (en)
Inventor
Yukihiko Nose
Wadi N. Suki
Kazuhide Ohta
Junji Takaba
Hiroshi Miyamoto
Original Assignee
Baylor College Of Medicine
Otsuka Pharmaceutical Co., Ltd.
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Application filed by Baylor College Of Medicine, Otsuka Pharmaceutical Co., Ltd. filed Critical Baylor College Of Medicine
Priority to TW100102288A priority Critical patent/TW201138924A/zh
Publication of WO2011090943A1 publication Critical patent/WO2011090943A1/fr

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
    • B01D61/24—Dialysis ; Membrane extraction
    • B01D61/243—Dialysis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
    • A61M1/3472—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
    • A61M1/3486—Biological, chemical treatment, e.g. chemical precipitation; treatment by absorbents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3621—Extra-corporeal blood circuits
    • A61M1/3627—Degassing devices; Buffer reservoirs; Drip chambers; Blood filters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3672—Means preventing coagulation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3621—Extra-corporeal blood circuits
    • A61M1/3627—Degassing devices; Buffer reservoirs; Drip chambers; Blood filters
    • A61M1/3633—Blood component filters, e.g. leukocyte filters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3693—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits using separation based on different densities of components, e.g. centrifuging
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/04—Liquids
    • A61M2202/0413—Blood
    • A61M2202/0415—Plasma
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/36—General characteristics of the apparatus related to heating or cooling
    • A61M2205/3606—General characteristics of the apparatus related to heating or cooling cooled

Definitions

  • the present invention provides methods of removing pathological albumin (e.g., glycated albumin) from a subject's plasma.
  • Such methods generally comprise: (1) the addition of an anti-coagulating agent (e.g., heparin) to the subject's plasma, where the anti- coagulating agent associates with the pathological albumin to form a cryo-reactive albumin; (2) separating the subject's plasma from the subject's blood to form a plasma solution; (3) cooling the plasma solution to a temperature sufficient to form cryoaggregates and cryogels that comprise cryo-reactive albumins (e.g., temperatures lower than about 10 °C); and (4) filtering the cooled down plasma solution through a plasma fractionation filter membrane (e.g., a plasma fractionation filter membrane with a pore size of about 0.05 ⁇ to about 0.2 ⁇ and a surface area larger than about 0.8 m 2 ).
  • a plasma fractionation filter membrane e.g., a plasma fractionation filter membrane with
  • the methods of the present invention can also comprise a step for warming the plasma solution (desirably to a temperature higher than about 35 °C) before re-infusion to subjects.
  • the cooled plasma should be warmed prior to returning to the patient (desirably to temperatures higher than 35°C).
  • warming up can be essential to safe procedures.
  • such warming occurs after the filtering step (i.e., step 4).
  • the methods of the present invention have various additional embodiments.
  • the adding of the anti-coagulating agent i.e., step 1) occurs by intravenous administration of the anti-coagulating agent to the subject prior to the plasma separating step (i.e., step 2).
  • the plasma separating step involves at least one of (1) filtering the subject's blood through a plasma separation filter membrane; and/or (2) the utilization of a centrifugal method in order to separate the plasma from whole blood.
  • the cooling of the plasma solution i.e., step 3) comprises passing the plasma solution through a cooling chamber (e.g., a cooling chamber connected to a heat exchanger).
  • the warming step i.e., a warming step after step 4) comprises passing the plasma solution through a warming chamber (step 4).
  • the methods of the present invention may occur on-line or off-line.
  • cryo-reactive albumin removal apheresis CRARA
  • such systems comprise (1) a plasma separator (either membrane and/or centrifugal) for separating plasma from whole blood; (2) a cooler for cooling the plasma to a temperature sufficient to form cryogels and cryoaggregates; (3) a filter for separating the cryogels and cryoaggregates from the plasma; and (4) a warmer for warming the plasma.
  • the methods and systems of the present invention provide numerous improvements in treating various conditions and diseases in various subjects.
  • the methods and systems of the present invention may be used to treat human beings suffering from diabetes.
  • the methods and systems of the present invention can provide various improved therapies for various other diseases, including, without limitation, autoimmune diseases, renal failure, atherosclerosis, cardiomyopathy, and chronic respiratory failure.
  • FIGURE 1 Provides a schematic illustration of an exemplary cryo-reactive albumin removal apheresis (CRARA) system that can be used in conjunction with the methods of the present invention to remove pathological albumin from a subject's plasma.
  • CRARA cryo-reactive albumin removal apheresis
  • FIGURE 2 illustrates various aspects of cryogels and croyaggregates.
  • FIG. 2A illustrates the effect of reduced temperatures on plasma turbidity (i.e., temperatures at or below 30°C).
  • FIG. 2B illustrates various components associated with a cryogel that is formed when a plasma solution is cooled down (e.g., to temperatures lower than 4°C).
  • FIG. 2C illustrates particle size distribution in cooled down plasma. As indicated, particle sizes increase with lower temperatures.
  • FIGURE 3 illustrates various additional pathological albumin removal systems that can be utilized in accordance with various embodiments of the present invention.
  • FIGURE 4 shows experimental results pertaining to the in vitro removal of glycated albumin from the plasma of diabetic renal failure patients.
  • the plasma samples were cooled down to temperatures near 0°C and filtered through a 0.2 ⁇ filter membrane.
  • FIGURE 5 shows the percentage decrease of various macromolecules that were removed from the plasma of non-ischemic cardiomyopathic patients by cryoaggregate filtration.
  • the results show approximately 40% reduction in IgG3, IgM, and fibrinogen levels.
  • the results also show approximately 37% reduction in T-cholesterol levels and approximately 20% reduction in albumin levels (Alb).
  • FIGURE 6 illustrates a comparison of the cryoaggregation of albumin and globulin at different temperatures.
  • the chart illustrates that the cryoaggregation of albumin is more effective at lower temperatures (i.e., temperatures between about 0°C to about 10°C).
  • the cryoaggregation of globulin is more effective at higher temperatures (i.e., temperatures between about 10°C to about 30°C).
  • Modified forms of albumins are associated with many types of diseases (herein referred to as pathological albumins). For instance, one of the causes of diabetic complications in the kidneys, eyes, legs and circulatory systems are considered to be the increased level of glycated albumin (GA) in patients' plasma. In general, the patients develop diabetic complications when more than about 20% of patients' plasma albumin levels are converted to GA.
  • G glycated albumin
  • GA is recognized as a reliable marker for monitoring glycemic control, particularly in patients with end stage renal disease. For instance, it was demonstrated that diabetic patients with end stage renal disease that had high GA levels (> 29%) did not survive more than seven years. In contrast, 20% of patients with low GA levels ( ⁇ 29 %) survived longer than 10 years. See Fuk oka et al, "Glycated albumin levels predict long-term survival in diabetic patients undergoing haemodialysis.” Nephrology. 2008 (13):278-283.
  • kidney failure As an example, one of the most expensive complications for diabetic patients is kidney failure. At this time, approximately 1.5 million patients are on dialysis worldwide. More than half of these patients (particularly in Japan) have diabetes-induced kidney failures. To maintain these diabetic patients alive only on dialysis may cost at least $40 billion. In addition, many patients on dialysis develop eye and leg circulation failures that may eventually result in loss of eyesight and/or limbs.
  • Various embodiments of the present invention provide methods of treating diseases that are associated with pathological albumin (e.g., diabetes). Such methods generally involve the removal of pathological albumin (e.g., glycated albumin) from a subject's plasma.
  • pathological albumin e.g., glycated albumin
  • such methods generally comprise: (1) the addition of an anti-coagulating agent (e.g., heparin) to the subject's plasma, where the anti-coagulating agent associates with the pathological albumin to form a cryo-reactive albumin; (2) separating the subject's plasma from the subject's blood to form a plasma solution; (3) cooling the plasma solution to a temperature sufficient to form cryoaggregates and cryogels that contain the cryo-reactive albumin (e.g., lower than about 10 °C); and (4) filtering the cooled down plasma solution through a plasma fractionation filter membrane (e.g., a plasma fractionation filter membrane with a pore size of about 0.05 ⁇ to about 0.2 ⁇ and a surface area larger than about 0.8 m ).
  • the methods of the present invention can also comprise warming the plasma solution, desirably to a temperature higher than about 35 °C, prior to re-infusion into a patient.
  • the methods of the present invention also comprise a hemodialysis of the subject's plasma.
  • the hemodialysis occurs after the aforementioned steps 1-4.
  • the methods of the present invention may occur on-line (i.e., while a system is connected to a patient) or off-line (i.e., in-vitro or while the system is disconnected from a patient).
  • CRARA system 10 A specific example of a CRARA system in accordance with some embodiments of the present invention is shown as CRARA system 10 in FIG. 1
  • This system generally comprises a plasma separator 14 with a filter 15; a cooler 18; a filter 24 with a pore size of about 0.05-0.2 ⁇ and a surface area of larger than 0.8 m ; a warmer 28; and an optional hemodialysis system 32.
  • Cooler 18 and warmer 28 are optionally associated with heat exchangers 20 and 29, respectively.
  • the various components of the system are in fluid communication with each other and with patient 11 via a tubing network (i.e., tubings 12, 16, 22, 26 and 30-31).
  • CRARA system 10 may also be associated with various pumps, valves and other mechanical devices to facilitate fluid flow between the different components and tubing networks.
  • heparin is first intravenously administered to patient 11, desirably at dose levels of about 200 units per kg of body weight of the patient. Without being bound by theory, it is envisioned that heparin associates with the pathological albumin in the patient's blood to form a cryo-reactive albumin.
  • CRARA system 10 After the completion of heparin administration, the patient is connected to CRARA system 10 via tubings 12 and 31. The CRARA system is then actuated, thereby resulting in the extra-corporeal pumping out of the patient's whole blood to plasma separator 14 via tubing 12.
  • plasma separator 14 utilizes filter 15 to separate the whole blood into a plasma solution containing the cryo-reactive albumin, and a non-plasma solution containing other blood components (e.g., red blood cells, platelets, and leukocytes).
  • a plasma solution containing the cryo-reactive albumin e.g., red blood cells, platelets, and leukocytes.
  • the non-plasma solution flows back into patient 11 via tubing 31.
  • the plasma solution containing the cryo- reactive albumin flows into cooler 18 via tubing 16.
  • cooler 18 utilizes heat exchanger 20 to cool the plasma solution to a temperature lower than about 10 °C. This results in the formation of cryoaggregates and cryogels that contain cryo-reactive albumin (typically, cryoreactive albumins form cryoaggregates at 4-10°C and cryogels at 0-4°C). Thereafter, the cooled down plasma solution flows to filter 24.
  • the plasma fractionation filter membrane in filter 24 retains the cryogels and the cryoaggregates containing the cryo-reactive albumin. In addition, the plasma fractionation filter membrane releases the remaining plasma solution to warmer 28 through tubing 26.
  • warmer 28 utilizes heat exchanger 29 to warm the plasma solution to about 35°C -40 °C.
  • the warmed plasma solution then flows back into patient 11 through tubings 30 and 31.
  • the warmed plasma solution may also flow into hemodialysis system 32 for additional treatment before flowing back into patient 11.
  • the aforementioned treatment may occur within the framework of five sessions for three hours in ten days. Other treatments regimens can also be envisioned by persons of ordinary skill in the art.
  • plasma separator 14 in FIG. 1 is a filtration unit with filter 15.
  • plasma separator 14 may be a centrifuge -based plasma separator.
  • pathological albumins refer to modified forms of albumin that are associated with one or more diseases.
  • the pathological albumin is a glycated albumin (GA).
  • GA is associated with various types of diabetes.
  • GA is a very reactive albumin. Together with heparin, it forms a conjugated glycated albumin when the blood is cooled down below 30°C.
  • Other forms of pathological albumins can also be envisioned by persons of ordinary skill in the art.
  • a person of ordinary skill in the art will also recognize that various methods exist for the removal of pathological albumins from the subject's plasma. Such methods generally involve the association of the pathological albumin with one or more anti-coagulating agents. Without being bound by theory, it is envisioned that many pathological albumins become more cryo- reactive when they become associated with anti-coagulating agents. As described in more detail below, the formed cryo-reactive albumins can then be removed from the plasma by cooling the plasma.
  • the anti-coagulating agent is heparin.
  • the anti-coagulating agent may be a heparin-like molecule, such as a heparin derivative (e.g., low molecular weight heparin).
  • the anti-coagulating agent may be Coumadin, acenocoumarol, phenprocoumon, and/or phenindione.
  • association occurs by intravenously administering an effective amount of an anti-coagulating agent, such a heparin, to a subject's whole blood.
  • an anti-coagulating agent such as a heparin
  • effective amounts of anti-coagulant administration can include about 100 units to about 200 units per kg of the subject's body weight.
  • the anti-coagulant may be associated with the pathological albumin after a subject's whole blood is extracted from the subject. In other embodiments, the association may occur after the plasma is separated from the whole blood.
  • plasma separation refers to one or more methods of separating a subject's plasma from other components in the subject's whole blood (e.g., red blood cells, leukocytes and platelets). Various methods may be used to accomplish this task, as known by persons of ordinary skill in the art. For instance, in some embodiments, plasma separation occurs by centrifugation of the whole blood, in accordance with methods well known in the art.
  • plasma separation occurs by the filtration of the whole blood.
  • various filtration membranes can be used for the plasma separation step.
  • filters of the present invention may be any type common in the art.
  • the filters are comprised of a microfiber medium.
  • the materials include polyester, polypropylene, polyamide, polyethylene and the like. In some embodiments, the materials are preferably hydrophobic polypropylene and polyesters (e.g., polyethylene terephthalate).
  • the filters used to separate plasma from whole blood can also have various pore sizes. For instance, in some embodiments, the plasma separation filter membranes may have a pore size that ranges from about 0.1 ⁇ to about 0.5 ⁇ . Other suitable filter pore sizes can also be envisioned by persons of ordinary skill in the art.
  • plasma separation step can occur in various structures and devices. For instance, as shown in FIG. 1 and described above, plasma separation in some embodiments can occur in a plasma separator 14 that comprises a filter 15 for separating the plasma solution from the whole blood and transporting it to a cooler.
  • cryoaggregates and cryogels are well-known to persons of ordinary skill in the art. The terms are also discussed in more detail in U.S. Pat. No. 12/864,290.
  • cryoaggregates when a plasma solution is cooled below about 30°C, the plasma forms cryoaggregates. As illustrated in FIG. 2A, such cryoaggregates are generally characterized by turning a clear yellowish colored plasma to a white and milky solution. Furthermore, when the plasma is cooled below about 4°C, the plasma forms cryogels. Exemplary components of cryogels are illustrated in FIG. 2B. As shown in FIG. 2C, the molecular sizes of the aggregated molecules in the plasma become larger as the temperature decreases during cryoaggregation and cryogel formation.
  • cryogels and cryoaggregates can vary depending on environmental conditions, such as pressure. Generally, such temperatures are less than about 10 °C. In more specific embodiments, such temperatures may range from about 10 °C to about 0 °C. In more specific embodiments, the temperature is about 4 °C.
  • the cooling down of the plasma to a temperature lower than about 10°C in the presence of the formed cryo-reactive albumins results in their association with the formed cryoaggregates and cryogels. Accordingly, the removal of both the cryoaggregates and the cryogels at such temperatures can effectively eliminate substantial amounts of cryoreactive albumins from a subject's plasma.
  • the cooling may occur by passing the plasma solution through a cooling chamber, such as cooler 18 shown in FIG. 1.
  • the cooling chamber may be associated with a heat exchanger, such as heat exchanger 20 shown in FIG. 1.
  • the heat exchanger may be an electrical device that associates the cooling chamber with a cooling fluid, such as liquid nitrogen, water, or other fluids.
  • the cooling chamber may be associated with ice, dry ice, liquid nitrogen, water, or other cooling fluids in the presence or absence of a heat exchanger.
  • the plasma filtration methods of the present invention aim to separate the cooled plasma from the formed cryoaggregates and cryogels in the plasma solution. This in turn removes the pathological albumins that are associated with the cryogels and the cryoaggregates from the plasma solution.
  • a person of ordinary skill in the art will also recognize that various plasma filtration methods exist.
  • the plasma filtration methods of the present invention utilize plasma fractionation filter membranes that have pore sizes sufficient to retain cryogels and cryoaggregates that were derived from cooled down plasma solutions.
  • Suitable plasma fractionation filter membranes have been described above.
  • the plasma fractionation filter membrane has a pore size that ranges from about 0.01 ⁇ to about 0.5 ⁇ .
  • the plasma fractionation filter membrane has a pore size that ranges from about 0.05 ⁇ to about 0.2 ⁇ .
  • the membrane has a pore size of about 0.2 ⁇ .
  • Other suitable plasma fractionation filter membrane pore sizes can also be envisioned by persons of ordinary skill in the art.
  • the filters can have various surfaces areas.
  • the filter has a surface area larger than about 0.8 m .
  • the filter has a surface area larger than about 0.8 m and a pore size of about 0.2 ⁇ .
  • the filtered plasma solution can be returned to a subject directly after warming or after further treatment (e.g., hemodialysis).
  • temperatures are more than about 30 °C. In more preferred embodiments, such temperatures may range from about 35 °C to about 40 °C.
  • the warming may occur by passing the plasma solution through a warming chamber, such as warmer 28 shown in FIG. 1.
  • the warming chamber may be associated with a heat exchanger, such as heat exchanger 29 shown in FIG. 1.
  • the heat exchanger may be an electrical device that associates the warming chamber with a warming fluid, such as water or other fluids.
  • the warming chamber may be associated with water or other warming fluids without association with a heat exchanger.
  • the plasma temperature may be warmed to a suitable temperature by simple incubation at room temperature for a desired amount of time.
  • hemodialysis methods generally refer to dialysis methods for removing waste products from a patient's circulatory system, as known by persons of ordinary skill in the art.
  • Various embodiments of the present invention may utilize hemodialysis methods. Accordingly, many systems of the present invention may be coupled to a hemodialysis system, such as in cases where a patient is already suffering from kidney failure.
  • Suitable hemodialysis systems that can be used with the methods and systems of the present invention, include, without limitation, hemodialysis systems manufactured by Braun (e.g., Braun Dialog+® Hemodialysis System); and hemodialysis systems manufactured by Renal Solutions, Inc. (e.g., The Allient® Sorbent Hemodialysis System). Other suitable hemodialysis systems can also be envisioned by persons of ordinary skill in the art.
  • Braun e.g., Braun Dialog+® Hemodialysis System
  • Renal Solutions, Inc. e.g., The Allient® Sorbent Hemodialysis System
  • Other suitable hemodialysis systems can also be envisioned by persons of ordinary skill in the art.
  • the hemodialysis may occur before, during or after the removal of pathological albumin from a plasma solution.
  • the hemodialysis occurs after the cooled down plasma solution is filtered and warmed, as described previously.
  • the hemodialysis may occur after the cooled down plasma solution is filtered, but before it is warmed.
  • hemodialysis procedures necessitate providing heparin and also exteriorizing blood outside of the body, which might cool the blood down below 35°C. Under such conditions, cryoaggregation of the plasma would be able to occur accidentally (along with the heparinized cryoreactive albumins). Furthermore, occlusion of the small diameter arteriole in the patient should be able to cause loss of eye sight or legs of these dialysis patients. Thus, under such circumstances, it may be desirable to remove the cryo-reactive albumin in accordance with the methods of the present invention before initiating the hemodialysis.
  • CRARA therapy should be able to avoid many diabetic complications and provide therapeutic effects for patients.
  • CRARA therapy should occur before the end stage of kidney failure that would necessitate hemodialysis.
  • Such systems may also be off-line automatic plasma purifier for exchange transfusion (Off-LAPPET) systems.
  • the systems of the present invention in various embodiments generally comprise: (1) a plasma separator for separating plasma from whole blood; (2) a cooler for cooling the plasma to a temperature sufficient to form cryogels and cryoaggregates; (3) a filter for separating the cryogels and cryoaggregates from the plasma; and a (4) warmer for warming the plasma.
  • the systems of the present invention may further comprise a (5) hemodialysis system.
  • the systems of the present invention may also be associated with various components for controlling fluid flow, pressure, and temperature. For instance, in some embodiments, it may be essential to utilize pressure controllers to maintain the transmembrane pressure of the plasma separator systems near 0 mmHg or below about 50 mmHg. Such low pressure ranges may be required to maintain effective plasma separation in some embodiments. On the other hand, the transmembrane pressures of the plasma fractionator maintains the transmembrane pressure below 300 mmHg.
  • blood pumps may be used to properly control the extracorporeal blood flow.
  • extracorporeal blood flow rates are maintained at less than about 100 ml/min.
  • other extracorporeal blood flow rates can also be achieved in other embodiments.
  • Equipment available for use in various embodiments of the present invention can be widely varied. Specific examples mentioned herein are not to be construed as limiting, as would be understood by one of ordinary skill in the art.
  • any blood pump can be used. Examples of blood pumps include roller pump, systolic pumps, a reciprocating pump, double-action pump, suction pump, piston pump, kinetic pump, and/or the like.
  • blood may be removed from a patient at a rate of up to 100 ml/min.
  • any rate acceptable in the art field can be used with various embodiments of the present invention.
  • FIG. 1 A suitable CRARA system for removing pathological albumins is shown in FIG. 1.
  • the components of this CRARA system were previously described in detail.
  • Other suitable pathological albumin removal systems can also be envisioned by persons of ordinary skill in the art.
  • pathological albumin removal system 150 comprises a patient 100 (not shown) or other source of fluid containing plasma, a heparin infusion pump 110, a first blood pump 120, a plasma filter 130, a second blood pump (for separated plasma) 140, a third blood pump 155, a harvested plasma bag 145 or storage container, and a purified plasma bag 160 or storage container.
  • the aforementioned components are connected via tubing or pipes, such as tube 103, tube 195, tube 190, and tube 180. Multiple pressure and/or temperature readings are capable of being taken at various locations along the tubes.
  • a first blood pump 120 withdraws blood from patient 100 (not shown) through tube 103.
  • Pressure instrument 122 may be coupled to first blood pump 120 such that the rate of first blood pump 120 can be controlled by the pressure in tube 103 and/or pressure in tube 195. If needed, heparin can be infused to the withdrawn blood from heparin pump 110. The withdrawn blood is then conveyed along tube 195 across pressure instrument 124 and into plasma separator 130 where plasma is filtered from the other components of the subject's blood.
  • the pressure entering plasma filter 130 is such that it will not clog the filter.
  • P2 and P3 pressure instruments are utilized in some embodiments to maintain the transmembrane pressure of the filter membrane.
  • the transmembrane pressure of the plasma fractionation filter membrane should not exceed 300 mmHg.
  • the separated plasma solution is then conveyed along tube 190 to a harvested plasma bag 145.
  • a second blood pump 140 can also be used to pump the plasma solution into a harvested plasma bag 145, if needed or desired.
  • Harvested plasma bag 145 is then taken off-line for further processing, such as for plasma cooling to form cryogels and cryoaggregates followed by filtration, as previously described.
  • the harvested plasma bag 145 from FIG. 3A is removed from system 150 and connected to system 200 shown in FIG. 3B as plasma bag 220.
  • Cryoaggregate pump 260 pumps the plasma solution across a cooling unit 250 where the temperature of the plasma solution is reduced to below 10°C to commence the formation of cryoaggregates and cryogels.
  • the cooled plasma solution is then fed to at least one filter 240 wherein the cryoaggregates and cryogels are separated.
  • the tubing network then conveys the purified plasma solution from filter 240 to the purified plasma bag 210.
  • the processed plasma may then be re-connected into system 150 shown in FIG. 3A as purified plasma bag 160 and re-infused to patient 100.
  • the purified plasma stream is pumped from purified plasma bag 160 by the third blood pump 155 back to patient 100, where it can be re-infused.
  • FIG. 3 illustrates an off line CRARA method and system.
  • the patient's plasma containing cryo-reactive albumin
  • the purified plasma is then re-infused into the patient.
  • the CRARA system in FIG. 3 can be established as an on-line system by combining the systems shown in FIGS. 3A and 3B.
  • Another on-line CRARA system was previously shown in FIG. 1 and described in detail.
  • such on-line systems provide a simpler system for removal of pathological albumin from a patient's plasma. Nonetheless, since many apheresis centers utilize centrifugation to separate plasma, off-line CRARA systems are also applicable systems.
  • the methods and systems of the present invention provide numerous improvements in treating various conditions and diseases in various subjects.
  • the methods and systems of the present invention may be used to treat human beings suffering from various types of diabetes (e.g., Type 1 diabetes, Type 2 diabetes, diabetes mellitus, juvenile diabetes, and gestational diabetes).
  • types of diabetes e.g., Type 1 diabetes, Type 2 diabetes, diabetes mellitus, juvenile diabetes, and gestational diabetes.
  • the methods and systems of the present invention can provide various improved therapies for various other diseases that may be associated with complication from diabetes.
  • diseases include, without limitation, autoimmune diseases, renal failure, atherosclerosis, cardiomyopathy, and chronic respiratory failure.
  • Such complications may include diabetic nephropathy.
  • the complications may also include diabetic retinopathy and neuropathy that lead to circulatory failure in patients.
  • CRARA therapy of less than 5 sessions should be able to keep the diabetic patient complication free for longer than four years when blood sugar is controlled properly.
  • Example 1 In vitro GA removal from the plasma of diabetic renal failure patients.
  • Example 2 Cryoaggregate filtration of the plasma of non-ischemic cardiomyopathic patients
  • the aim of this trial was to remove pathological macromolecules from cardiomyopathic patients by cryoaggregate filtration. This method aimed primarily to remove pathological globulin, not albumin. Plasma samples from four patients with non-ischemic cardiomyopathy were collected and cooled down to about 10-15 °C. The collected plasma was then filtered in vitro through a 0.02-0.03 ⁇ filter. The levels of various macromolecules were then analyzed. The results are shown in FIG. 5.
  • the results show approximately 40% reduction in IgG3, IgM, and fibrinogen levels.
  • the results also show approximately 37% reduction in T-cholesterol levels.
  • the results only show approximately 20% reduction in albumin levels (Alb).
  • albumin levels albumin levels (Alb).
  • pathological albumins i.e., glycated albumins
  • non-pathological albumins at least in some embodiments.
  • thermofiltration and other methods of removing pathological molecules were introduced.
  • pathological molecules including cryoaggregate filtration
  • thermofiltration was effectively used for hyperlipedmia patients.
  • cryoaggregate filtration was used for cardiomyopathic patients (both non-ischemic and ischemic).
  • cardiomyopathic patients both non-ischemic and ischemic.
  • pathological albumins particularly in diabetic patients.
  • cryoaggregates become larger when the cooled down temperatures are lowered. See FIG. 2C. Since the size of albumin is smaller compared with that of globulin, the lower temperatures (5+5 °C) for the removal of cryoreactive albumins are necessary compared with the removal of cryoreactive globulins (20+10 °C). See FIG. 6. Thus, the conditions utilized in the prior systems would not have been able to remove pathological albumins that become cryo-reactive. Table 1 below provides a comparison of the old procedures with the new procedures described above.
  • the methods and systems of the present invention remove not only cryoaggregates formed at lower temperatures, but also cryogels. Furthermore, the above-described systems and methods of the present invention aim to remove pathological albumin molecules that are cryo-reactive and exist in a patient's plasma. In some embodiments, the systems of the present invention remove such pathological albumins from the plasma of diabetic patients.

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Abstract

Dans certains modes de réalisation, la présente invention porte sur des procédés de retrait d'albumine pathologique du plasma d'un sujet. Ces procédés comprennent de manière générale : (1) l'ajout d'un agent anticoagulant au plasma du sujet, l'agent anticoagulant étant associé à l'albumine pathologique pour former une albumine cryo-réactive, (2) la séparation du plasma du sujet du sang du sujet afin de former une solution de plasma, (3) le refroidissement de la solution de plasma à une température suffisante pour former des cryo-agrégats et des cryo-gels comprenant des albumines cryo-réactives, et (4) la filtration de la solution de plasma refroidie à travers une membrane de filtre de fractionnement de plasma. Dans différents modes de réalisation, les procédés de la présente invention comprennent également une étape consistant à (5) réchauffer la solution de plasma à une température supérieure à environ 35°C, le réchauffement ayant lieu avant la ré-infusion. Dans différents modes de réalisation, les procédés de la présente invention comprennent également une étape d'hémodialyse. Différents autres modes de réalisation de la présente invention portent sur des systèmes destinés au retrait d'albumine pathologique du plasma d'un sujet, conformément aux procédés de la présente invention.
PCT/US2011/021550 2010-01-22 2011-01-18 Retrait d'albumine pathologique du plasma d'un sujet WO2011090943A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4350156A (en) * 1980-05-29 1982-09-21 Japan Foundation For Artificial Organs Method and apparatus for on-line filtration removal of macromolecules from a physiological fluid
US20010034359A1 (en) * 1996-02-20 2001-10-25 Cohen Margo P. Albumin-binding compounds that prevent nonenzymatic glycation and that may be used for treatment of glycation-related pathologies
WO2009094666A2 (fr) * 2008-01-25 2009-07-30 Baylor College Of Medicine Filtration par cryo-agrégation utilisée pour le traitement des cardiomyopathies et d'autres maladies auto-immunes

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4350156A (en) * 1980-05-29 1982-09-21 Japan Foundation For Artificial Organs Method and apparatus for on-line filtration removal of macromolecules from a physiological fluid
US20010034359A1 (en) * 1996-02-20 2001-10-25 Cohen Margo P. Albumin-binding compounds that prevent nonenzymatic glycation and that may be used for treatment of glycation-related pathologies
WO2009094666A2 (fr) * 2008-01-25 2009-07-30 Baylor College Of Medicine Filtration par cryo-agrégation utilisée pour le traitement des cardiomyopathies et d'autres maladies auto-immunes

Non-Patent Citations (4)

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Title
LUDVIGSSON ET AL.: "Plasmapheresis in the initial treatment of insulin-dependent diabetes mellitus in children.", BRIT. MED. J. (CLIN. RES. ED.), vol. 286, no. 636, 15 January 1983 (1983-01-15), pages 176 - 178 *
MALCHESKY ET AL.: "On-line separation of macromolecules by membrane filtration with cryogelation.", THER. APHER., vol. 4, no. 1, February 2000 (2000-02-01), pages 34 - 37 *
NOSE ET AL.: "Therapeutic Cryogel Removal in Autoimmune Disease: What is Cryogel?", THER. APHER., vol. 4, no. 1, February 2000 (2000-02-01), pages 38 - 43 *
NOSE ET AL.: "Therapeutic Membrane Plasmapheresis.", THER. APHER., vol. 4, no. 1, February 2000 (2000-02-01), pages 3 - 9 *

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