EP3024510A1

EP3024510A1 - Blood purification systems and devices with internally generated replacement fluid

Info

Publication number: EP3024510A1
Application number: EP14753223.8A
Authority: EP
Inventors: Jacek RÓZGA; Piotr MALKOWSKI
Original assignee: Hemotx Spolka Z Ograniczona Odpowiedzialnoscia
Current assignee: Hemotx Spolka Z Ograniczona Odpowiedzialnoscia
Priority date: 2013-07-25
Filing date: 2014-07-25
Publication date: 2016-06-01
Also published as: WO2015011290A1; ITMI20131250A1

Abstract

A blood purification system has a primary purification device (32) and receives, at an input via a primary inlet line (31), a primary input fluid from a fluid source. The primary purification device (32) partitions the input fluid into two output streams. The first output stream (33) is enriched in larger components and the second output stream (34) is enriched in smaller components. The first output stream is returnable to the source via a primary outlet line (33). The secondary purification device (36) receives fluid from the primary purification device (32) and partitions the fluid into two further streams: a third output stream (37) enriched in larger components and a fourth output stream (39) enriched in smaller components including toxins and incidental beneficial molecules. The third output stream (37) is directed to flow to the sink (38). A tertiary purification device (40) receives the fourth output stream (39) and purifies the fourth stream from toxins. The purified fourth stream merges with either the primary inlet line (31) or the first output stream (33). As a result, a wide spectrum of blood borne toxins is removed from the source, including small molecular weight toxins, albumin saturated with toxins, defective forms of albumin, albumin bound and unbound toxins, middle size toxins, inflammatory mediators and mediators of unwanted biological responses, while, at the same time, the volume of wasted fluid and losses of incidental beneficial molecules are reduced.

Description

Blood purification systems and devices with internally generated replacement fluid

Technical Field

The present invention relates to systems and methods for removal of harmful components from the blood for therapeutic purposes. Specifically, the present invention relates to blood purification systems utilizing dialyzers and filters with increased permeability to albumin and system components to internally produce replacement fluids enriched with beneficial incidental molecules removed from the blood for treating illnesses associated with accumulation of hepatic failure toxins, uremic toxins, defective forms of albumin, albumin-bound and unbound toxins, inflammatory mediators and other target molecules in the blood, including but not limited to acute and chronic renal failure, acute liver failure, acute exacerbation of chronic liver disease commonly called acute- on-chronic liver failure, inflammatory mediator related diseases such as sepsis and septic shock, systemic inflammatory response syndrome ("SIRS"), multi-organ system dysfunction syndrome ("MODS"), multi-organ failure ("MOF"), acute respiratory distress syndrome, anti-inflammatory response syndrome ("CARS"), and other diseases. For purposes of this patent application, each and all of these conditions will be referred to as life-threatening illnesses („LTIs").

Background

Patients with diseases and other pathological conditions in which there is an accumulation of harmful components in the circulating blood may benefit from the removal of such substances via blood or plasma purification therapy. Examples of such treatments include: blood/plasma sorption therapy, hemodialysis, albumin dialysis, hemofiltration, hemodiafiltration, cascade hemofiltration, plasmafiltration, fractionated plasma therapy (which may include filtration, sorption, fluid exchange or a combination thereof), cell-based therapies, whole plasma exchange therapy, and selective blood or plasma filtration.

Blood purification techniques may have utility in the treatment of acute and chronic liver failure, hepato-renal syndrome, acute and chronic renal failure, trauma (the crush syndrome), congestive heart failure, rheumatoid arthritis, infection, sepsis, hyperlipidemia, ARDS, SIRS, MOF, CARS, and other LTIs. Blood/plasma toxins, mediators and other harmful or defective compounds which may contribute to these conditions may include: small water soluble toxins (e.g., urea, creatinine, ammonia), middle-size uremic toxins, albumin bound and unbound toxins (e.g., bile acids, bilirubin, short-chain fatty acids, phenols, merkaptans), cytokines (e.g., interleukins IL-6, IL-1, IL-18, tumor necrosis factor alpha - TNFa), chemokines (e.g., IL-8), leukotrienes, platelet activating factor (PAF), thromboxane A2, interferon gamma (INFy), bacterial toxins, lipid A, anaphylatoxins (C3a), reactive oxygen species, vasoactive mediators such as nitric oxide (NO), certain prostaglandins, defective forms of endogenous albumin, albumin molecules with no binding sites available for detoxification, and other biological components. In hemodialysis, hemofiltration, hemodiafiltration or plasmafiltration techniques (e.g., fractionated plasma filtration - "FPF"), a semipermeable membrane, often a hollow-fiber filter, may be used to remove components that, by virtue of their molecular weight, charge, hydrodynamic radius and other properties, can permeate the membrane. Since these membranes are generally permeable to water, these purification techniques (dialysis, filtration, diafiltration) will generally remove liquid from the blood. The removed liquid that in addition to harmful components (toxins) contains also beneficial molecules that can permeate the membrane (called herein "incidental beneficial molecules") is replaced with electrolyte solution, albumin, plasma or other fluid enriched with specific exogenous compounds, or a combination thereof. The fraction of blood, plasma or other body fluid that permeates the membrane is called the "ultrafiltrate". Examples of hemofiltration techniques designed to remove inflammatory mediators are described in U.S. Patents No. 6,287,516, 6,730,266; 6,736,972; 6,787,404; and U.S. Published Patent Application No. 20060129082, all of which are hereby incorporated by reference.

Hemodialysis is generally designed to remove small water-soluble molecules with a molecular weight ("MW") of up to 10,000 Daltons. In conventional hemodialysis, solute transfer occurs by diffusion down a concentration gradient between plasma water and dialysate. H D is commonly used to treat chronic and some forms of acute renal failure. I n hemofiltration, transfer of solute occurs by convection down a pressure gradient across the membrane. HF is also used to treat acute renal failure and, in some cases, chronic renal failure. Conventional dialyzers and hemofilters are generally designed to minimize or avoid sieving of albumin. The reason for this is that removal of albumin during renal replacement therapy is of no benefit. Further, it is considered as a deleterious side effect, because the oncotic pressure of plasma would be reduced and tissue edema promoted. Albumin could be replaced, but it would add cost and risk with no therapeutic benefits. For these reasons, conventional dialyzers and hemofilters have a nominal or effective MW cut-off of less than 67,000 Dalton - the MW of albumin. In standard HD, removal of uremic toxins such as urea and creatinine and other small water-soluble molecules is accomplished by diffusion across the membrane separating blood from the dialysate. In standard HF, removal of the similar spectrum of molecules is accomplished by convection, i.e., water-soluble toxins are removed and discarded in an ultrafiltrate while water and electrolytes are replaced using commercially available hemofiltration fluid. HD and HF using conventional filters is very useful to provide renal replacement therapy, but useless for removing the majority of hepatic failure toxins and inflammatory mediators. Therefore, the clinical utility of these therapeutic modalities is limited to the treatment of renal failure/injury and drug toxicity. In hemodiafiltration, diffusion and convection are combined deliberately by superimposing a controlled amount of convection on top of diffusion. An ultrafiltration rate in excess of that required to achieve dry weight is used, with the patient's volume being maintained by infusion of a sterile, pyrogen-free electrolyte solution either before (predilution) or after (postdilution) the filter. HDF requires use of a high-flux dialyzer and it is widely used with the aim of optimizing middle molecule clearance in Continuous Renal Replacement Therapy ("CRRT"). The goal of using high-flux membranes is to pass relatively large molecules such as beta-2-microglobulin (MW 11 ,600 Daltons) and other large uremic toxins, but to not pass albumin. Only minimal amounts of albumin and plasma constituents of similar MW can leak through the membrane and are discarded with this method. A typical high-flux membrane is the PUREMA® product from Membrana GmbH (Germany). It is manufactured according to the patent application US20080000828 Al ("High-flux membrane with an improved separation behavior" Friedbert Wechs, Arne Gehlen, Bodo von Harten, Richard Kruger, Oliver Schuster inventors; U.S. Classification: 210/496; 210/500; 264/5151, USPTO) and has an optimized middle molecule clearance with a minimized loss of albumin. An attempt to develop a membrane with improved clearance of middle-size molecules has also been made by Gambro. However, their high-flux HCO 1100 membrane is intended for removal of plasma constituents with a MW of up to 45 kDa, i.e., molecules smaller than albumin. Therefore, it is useless for removing many hepatic failure toxins and mediators of inflammation, including defective forms of albumin, albumin-bound toxins, certain inflammatory mediators and many noxious peptides, peptide multimers and small proteins. During FPF, a portion of the plasma is separated and is either discarded or undergoes further treatment before it is returned to the patient. For example, in the extracorporeal liver support system known as PROMETHEUS® (Fresenius MC, Germany), a large MW fraction of the separated plasma undergoes "regeneration" (purification) using two sorbent columns before it is returned to the patient via back filtration through the same FPF-filter. In addition, conventional HD is performed downstream of FPF to increase clearance of small water-soluble toxins. During therapy, the fractionated plasma filtrate is thought to be cleared off albumin-bound toxins. However, valuable proteins, including but not limited to blood coagulation factor VIII and antithrombin III, are also removed from the filtrate. Recently, blood coagulation problems were attributed to the use of the PROMETHEUS® system, as reported by A. Wilmcr (Detoxifying Capacity and Kinetics of Prometheus^® - A New Extracorporeal System for the Treatment of Liver Failure. Blood Purif ^'2005; 23:349-358).

The patents of Jacek Rozga (WO2004014315 A2, CA2495459) and James Matson (US 6,287,516 Bl, US6787040 B2, WO20040907) also disclose treatment modalities involving FPF, which are described as Selective Plasma Exchange Therapy ("SEPET®") and Plasma Colloid Exchange, respectively. The underlying common idea is to remove only certain selection of plasma components from plasma and to replace the removed plasma fraction with the replacement fluid composed of the electrolyte solution and a combination of albumin solution and fresh frozen plasma ("FFP"). These patent disclosures appear to not provide for an effective and sufficient clearance of uremic toxins at the proposed ultrafiltration rates and lengths of treatment; for example, during renal replacement therapy the blood clearance of urea and creatinine should be significantly higher than the proposed 10 ml/min. Both disclosures are therefore useless for a large group of patients in whom acute renal failure develops in conjunction with hepatic failure, sepsis, MODS, MOF, SIRS, ARDS, and other LTIs. In addition, hemofilters described by Rozga and Matson cannot be used for hemodiafiltration, because the filters lack certain engineering features (e.g., fiber spacers). There is growing scientific evidence that by increasing the membrane permeability to albumin and other middle molecules (peptides and small proteins with molecular weight in the range of 500-60,000 Da) beyond that seen in modern high-flux dialyzers may be of benefit to many patients with LTIs. However, use of protein-leaking membranes may result not only in improved clearance of albumin- bound toxins and middle molecules, but also in marked losses of essential albumin, which may cause tissue edema, fatigue, hypotension and other unwanted effects. Furthermore, many other useful beneficial plasma compounds may also be lost - particularly at high-volume treatments - and this can lead to deleterious depletion of substances such as total, essential and branched-chain amino acids, vitamins, hormones, growth factors, antithrombin III, fibrinogen, certain complement components, enzymes, enzyme inhibitors, transport proteins other than albumin, and medications used in a patient such as antibiotics, diuretics, cardiotropes, vasopressors, sedatives, and analgesics. In order to exercise full therapeutic potential of blood purification using protein-leaking membranes, replacement (substitution) fluids must be enriched with incidental molecules that are lost in the spent dialysate or ultrafiltrate. This, in turn, would result in a high cost of therapy due to consumption of albumin, fresh frozen plasma, exogenous incidental molecules and large amounts of sterile replacement (substitution) fluid. Several strategies and practical solutions (technologies) have been developed to lower the cost of commercially prepared replacement fluids, to reduce the amount of fluid discarded (and necessarily replaced) and to limit the net losses of incidental molecules during blood purification therapy. For example, on-line HDF has been designed to replace the use of expensive replacement fluid in bags with freshly prepared ultrapure dialysatc that is taken from the dialysate inlet line and processed with multiple filtration steps before being used as a replacement fluid (Jorstad, et al. Removal of uremic toxins and regeneration of hemofiltrate by a selective dual hemofiltration artificial kidney (SEDUFARK). Clin Nephrol 1980: 13:85-92; Civati, et al. Hemofiltration without substitution fluid: A physiological approach in renal replacement therapy. Dial Transplant 1987: 16:545-554; Selecta system from Bellco, Mirandola, Italy, as used by Martinez, et al. Hemodiafiltration with online regeneration of the ultrafiltrate. Kidney Int 2000; 58(suppl. 76): S-66-S-71 ). Another example is the use of cascade hemofiltration methods that may reduce the amount of fluid discarded. In cascade hemofiltration, a secondary hollow-fiber filtration cartridge removes fluid and low molecular weight components from the ultrafiltrate for return to the patient, thereby reducing the quantity of replacement fluid needed. Accordingly, the quantity of waste generated is reduced. To accomplish this, the molecular weight cutoff value for the secondary filter must be less than for primary filter. Examples of hemofiltration systems with coupled filters include those described in US Patent, 6,198,681, US Patent Application Publication No. 20040182787; Ho, et al. Gut 2002, 50, 869-876; and Bruni, et al., Transfusion Sci 1999, 21, 193-199, all of which are hereby incorporated herein by reference.

Paired hemodiafiltration with endogenous reinfusion represents an offspring of cascade filtration (de Francisco, et al. Hemodiafiltration with on-line endogenous reinfusion. Blood Purif 2000; 18:231-236). In this technique, a dual stage filter with high-flux membranes in both chambers is used. The main feature of HDF with endogenous reinfusion is the online regeneration of the ultrafiltrate by an adsorption device. The regenerated ultrafiltrate is then reinfused as an endogenous substitution fluid Despite the advantages of cascade hemofiltration and paired hemodiafiltration with endogenous reinfusion in conserving replacement fluid and incidental molecules, these techniques are of limited usefulness in the systems that employ large-pore protein-leaking membranes. Indeed, they are applicable to devices and systems that utilize low-flux membranes and high-flux membranes with limited permeability to albumin. For example, in the cascade configuration, use of the low-flux membrane in the secondary filter might help conserve substitution fluid, but it would not reduce losses of incidental molecules other than small MW solutes. In the context of this last remark, one of the key features of the present invention is the cascade sorbent based component designed to remove water soluble toxins, including uraemic toxins and small MW hepatotoxins and neurotoxins, form the primary ultrfiltrate so that a substantial portion of said primary ultrafiltrate containing incidental beneficial molecules is returned to the treated patient as an endogenous substitution fluid.

Summary of the Invention

In illustrative embodiments of the present invention, a blood purification apparatus includes a primary purification device that receives a primary input fluid at an input via a primary inlet line. The primary purification device is adapted to partition the input fluid into a first output stream that is enriched in larger components and a second output stream that is enriched in smaller components. The first output stream is returnable to the patient via a primary outlet line. A secondary purification device receives a second output stream at an input via a secondary inlet line. The secondary purification device partitions the inflowing second output stream into a third output stream that is enriched in larger components and a fourth output stream that is enriched in smaller components. The third output stream is discarded into the sink via a secondary outlet line. A tertiary purification device receives the fourth output stream from the secondary purification device at an input via a tertiary inlet line. The tertiary purification device is adapted to remove smaller components from the fourth output stream and, optionally, to remove chemical stabilizer from molecules of exogenous albumin which is infused into the fourth output stream. The purified fourth output stream enriched (optionally) with exogenous albumin freed (optionally) of chemical stabilizers is returnable to the patient via a tertiary outlet line that is coupled to the first output stream.

Optionally or in addition, the first and second purification devices may be a first hollow-fiber filter and a second hollow-fiber filter. The first filter may have a sieving distribution favoring larger components, thereby causing larger components to return to the source (e.g., a patient). The second filter may have a sieving distribution favoring smaller components of the second output stream, thereby discarding smaller components of the second output stream into the sink.

The nominal molecular weight cutoff of the first filter may be less than about 4,000,000 daltons and the nominal molecular weight cutoff of the second filter may be less than about 2,000,000 daltons. The molecular weight cutoffs of the primary and secondary purification devices may be selected to cause removal and disposition of a toxin binding protein. The toxin-binding protein may be albumin. The molecular weight cutoff of the primary purification device may be selected to direct immunoglobulins and molecules larger than immunoglobulins to the first output stream. The effective or nominal molecular weight cutoffs of the primary purification device may be between 50,000 and 2,000,000 daltons. The molecular weight of the secondary purification device may be selected to direct albumin and molecules larger than albumin to the third output stream. The effective or nominal molecular weight cutoffs of the secondary purification device may be between 1 ,000 and 1 ,000,000 daltons.

The apparatus may also include an optional tertiary purification device adapted to remove toxins that are normally removed by the kidney or liver and chemical substances used to stabilize commercial preparations of human albumin. For example, the tertiary purification device may be an adsorption device.

The fluid source may be a patient vasculature or an external fluid source or a combination thereof. Optionally or in addition, the apparatus may include a pumping system that is coupled to cause flow through the primary purification device, through the secondary purification device, and through the tertiary purification device. The pumping system may include at least one pump to cause flow of dialysate, hemofiltration fluid, substitution fluid, solution of exogenous albumin, or a combination thereof. The pumping system may include at least one centrifugal pump. The system may be configured so that the flow rates of the second and the fourth output streams may be approximately equal. Optionally or in addition, the system may be configured so that the flow rate of the second output stream is larger than the flow rate of the fourth output stream.

The pumping system may operate to induce a fluid flow through the primary purification device at the rate that is between 10 ml/min and 5000 ml/min. The pumping system may operate to induce a flow of the second output stream at the rate that is between 1 ml/min and 1500 ml/min. The pumping system may operate to induce a fluid flow through the second purification device at a rate that is between 10 ml/min and 1500 ml/min. The pumping system may operate to induce a flow of the fourth output stream having a rate that is between 1 ml/min and 1500 ml/min.

In accordance with another embodiment of the invention, a method for removing a component species from a source (e.g., blood, blood fraction or other bodily fluid such as cerebrospinal fluid, ascitic fluid, pleural fluid) includes receiving a primary input fluid via an inlet line. In the preferred embodiment of the invention, the primary input fluid contains components of the blood. The input fluid is partitioned into a first output stream that is enriched in larger components and a second output stream that is enriched in smaller components. The first output stream is returned to the blood source and the second output stream is partitioned into a third output stream that is enriched in larger components and a fourth output stream that is enriched in smaller components. The third output stream is discarded and the fourth output stream is pumped through an adsorptive column to remove smaller components and, optionally, chemical stabilizers from exogenous albumin molecules infused, optionally, into the fourth output stream. After purification, the fourth output stream enriched, optionally, with exogenous albumin freed of chemical stabilizers is directed to merge with a fluid of the first output stream.

Optionally or in addition, the flow rates in the respective streams are controlled so that no additional replacement fluid need be provided to the patient, except in an embodiment where a primary purification device is a hemofilter. The flow rate of the second stream and the fourth stream may be about equal so that the fluid returns to the patient at about the same rate as fluid that is removed from the patient.

Optionally or in addition, toxins and chemical stabilizers of exogenous albumin may be removed from the fourth outlet stream using tertiary purification device with a toxin-binding stationary phase. Optionally or in addition, an adsorption device may be used to remove low molecular weight toxins and, optionally in addition, also from the fourth output stream.

Optionally or in addition, the fluid source may be a patient and the input fluid drawn from the patient through the inlet line. The first output stream returns to the patient via an outlet line. The patient, inlet line, and outlet line form a circuit. Optionally or in addition, the partitioning of the input fluid includes causing albumin to enter the second output stream and the partitioning of the second output stream causes albumin and albumin-bound toxins to be discarded into the sink via the third output stream.

Optionally or in addition, fluid may be recovered from the sink (e.g., a spent dialysate, ultrafiltrate or hemo(dia)filtration fluid). At least one valuable biological component may be extracted from the ultrafiltrate, spent dialysate or spent diafiltration fluid and used for research or therapeutic uses including administering the component to a patient.

In accordance with another embodiment of the invention, a method for purifying a first fluid includes removing a quantity of the first fluid from a source, selectively extracting toxin-carrying molecules from the first fluid to generate an extract fluid enriched in the toxin-carrying molecules, recovering incidental beneficial molecules of a lower molecular weight than the extracted toxin- carrying molecules from the extract fluid; and returning the beneficial molecules of a lower molecular weight to the source.

Optionally or in addition, the toxin-carrying molecule is a protein. For example, the toxin- carrying molecule may be albumin.

Optionally or in addition, the removed molecule is a protein. For example, the removed molecule may be albumin.

Optionally or in addition, the removed molecule may be any molecule that can cross the semipermeable membrane of the primary purification device.

Brief Description of the Drawings

The foregoing features of the invention will be more readily understood by reference to the following detailed description, taken with reference to the accompanying drawings, in which:

Fig. 1 is a flow diagram showing a general method for purifying a fluid in accordance with an embodiment of the present invention;

Fig. 2 is a flow diagram of a specific embodiment in accordance with the method of Fig. 1 ;

Fig. 3 is a flow diagram of a further specific embodiment in accordance with the method of

Fig. 1 ;

Fig. 4a is a block diagram showing a blood purification system with return of at least a portion of the primary output stream carrying at least one incidental beneficial molecule and, optionally, exogenous albumin purified of chemical stabilizers to the patient, in accordance with the embodiment of Fig. 3;

Fig. 4b is a block diagram showing a blood purification system with internally generated replacement fluid containing at least one incidental beneficial molecule utilizing hemodialysis device as primary purification device, in accordance with an embodiment of Fig.4a; Fig. 4c is a block diagram showing a blood purification system with internally generated replacement fluid containing at least one incidental beneficial molecule utilizing hemofiltration device as primary purification device, in accordance with an embodiment of Fig.4a;

Fig. 4d is a block diagram showing a blood purification system with internally generated replacement fluid containing at least one incidental beneficial molecule utilizing hemodiafiltration device as primary purification device, in accordance with an embodiment of Fig.4a.

Detailed Description of Specific Embodiments

Definitions. As used in this description and the accompanying claims, the following terms shall have the meanings indicated, unless the context otherwise requires: "Toxins" means components, which due to their inherent detrimental biological activity and/or a detrimentally high concentration in the body, may be beneficially removed from a patient. Examples of toxins include any of a variety of such molecules, which due to a detrimentally high concentration in the body play a role in the pathophysiology of specific diseases or failure of one or more body organs. Such toxins include ammonia, urea, creatinine, free bile acids, bilirubin, phenols, inflammatory mediators ("IMs"; typically cytokines, interleukins and chemokines), albumin-bound toxins, defective forms of endogenous albumin, mediators of hemodynamic instability, and other molecules normally removed by the liver, lungs, gastrointestinal tract, kidneys, and other tissues and organs.

A "toxin-binding molecule" is a molecule, typically a macromolecule such as a protein that binds toxins. Albumin is used throughout as an exemplary toxin-binding molecule, but other proteins or non-protein macromolecules may be used as toxin-binding molecules as well.

An "incidental beneficial molecule" is a molecule, typically a normal blood component such as an ion, peptide, enzyme, protein, carbohydrate, hormone, vitamin, nutrient, regulatory agent, mediator, or drug used to treat a patient has no negative effects on a living organism or that participates is involved in normal metabolic and physiological processes.

"Components" means molecules, ions, macromolecular complexes, cells, aggregates, fragments or portions thereof, or other species that are dissolved or suspended in a fluid. A "purification device" means a device that partitions components in an input fluid into a plurality of output streams, each containing a distribution of components that is a proper subset of the input stream components. Examples of purification devices include hemofilters, hollow-fiber hemofilters, hollow-fiber hemodiafilters, dialysis cartridges, centrifuges, systems based on gradient centrifugation with or without use of substances such as ficoll, absorptive filters, adsorptive columns, affinity columns, columns loaded with particles with specific antibodies attached to them, and cell- based artificial organs (including artificial livers).

An "output stream enriched in smaller components", in the context of a purification device, means a fluid stream, resulting from passage of an input fluid through the purification device, having a distribution of components that is, by a statistical measure, of lower molecular weight or hydrodynamic radius than the distribution of components in the input fluid. Examples of such statistical measures include the mean, median, mode, and range.

An "output stream enriched in larger components", in the context of a purification device, means a fluid stream, resulting from passage of an input fluid through the purification device, having a distribution of components that is, by a statistical measure, of higher molecular weight or hydrodynamic radius than the distribution of components in the input fluid. Examples of such statistical measures include the mean, median, mode, and range.

A "nominal molecular weight cutoff means the mean pore size of a semipermeable membrane (e.g., as stated by the manufacturer). A "90% effective molecular weight cutoff of a purification device means the molecular weight of components of an input fluid at which the purification device will act to direct at least 90% of those components to the output stream enriched in larger components.

A "sieving coefficient" is a measure predictive of the fractional permeation of a given blood component placed on one side of a semipermeable membrane. A "sieving distribution" of a semipermeable membrane is the set of sieving coefficients corresponding to a plurality of components found in a fluid sample exposed to the membrane.

A "sieving distribution favoring larger components" in the context of a purification device, means that the purification device produces an output stream enriched in larger components. In illustrative embodiments of the present invention, a purification system removes toxins from a biological fluid without discarding a portion of the fluid. In specific embodiments of the present invention said non-discarded portion of the biological fluid is purified from toxins and administered to the patient. As a result, large amounts of replacement fluid need not be administered to the patient and non-discarded portion of the biological fluid that contains incidental beneficial molecules is included in the overall volume of the replacement fluid. Embodiments may be used to treat acute and chronic liver failure, hepato-renal syndrome, renal failure, trauma (the crush syndrome), congestive heart failure, rheumatoid arthritis, infection, sepsis, hyperlipidemia, ARDS, SIRS, MOF, MODS, burns, certain congenital disorders (e.g., the Guillain-Barre syndrome, Goddpasture's syndrome, anti-GMB nephritis, Waldenstrom's macroglobulinemia, systemic lupus erythematosus) and other diseases or conditions resulting in accumulation of toxins, including mediators of inflammation and other harmful components in the blood.

Embodiments remove albumin, defective forms of endogenous albumin, albumin-bound toxins, and other toxic components, including but not limited to inflammatory mediators, mediators of hemodynamic instability, active endotoxin components, and other middle molecules and small proteins from bodily fluids. Other embodiments may include the use of complementary purification elements to remove toxins that are normally excreted, metabolized, or otherwise processed by the liver or kidneys. Examples of complementary purification elements include absorptive filters, adsorptive columns, dialysis cartridges, affinity columns, columns loaded with particles with specific antibodies attached to them, and cell-based artificial organs (including artificial livers). For simplicity, certain illustrative embodiments described herein relate to the purification of blood, but could also be used to purify blood plasma, blood serum, other blood fractions, or non-blood complex body fluids such as ascitic fluid and cerebro-spinal fluid. Related embodiments of the present invention provide methods and apparatus for efficiently purifying blood using ultrafiltration with a minimum of wasted fluid and minimal or no loss of incidental beneficial molecules, including but not limited to electrolytes, hormones, vitamins, nutrients and administered medications (e.g., antibiotics, antivirals, diuretics, cardiotropes, vasopressors, steroids, sedatives and analgesics).

Fig. 1 shows a flow diagram of a method in accordance with an embodiment of the invention. A fluid, such as blood, blood plasma or other bodily-derived fluid, is withdrawn from a source, such as a human patient or an external container (step 100). Toxin-carrying molecules are selectively extracted from the fluid (step 110). The toxin-carrying molecules may be, for instance, albumin-bound toxins. The lower molecular weight incidental molecules are recovered from extract fluid (step 120) and returned to the source (step 130). This process (steps 100-130) may be repeated or performed continuously.

Fig. 2 shows a flow diagram of another a method in accordance with an embodiment of the present invention. A primary circuit is created (step 200). The primary circuit includes an in-line primary purification device. Fluid is caused to flow from the source and through the primary circuit (step 210). The fluid flow may be induced by pumping, force of gravity, centrifugation, or other suitable method. The action of the primary purification device results in the generation of two output streams that contain larger and lower molecular weight molecules, respectively (step 220). Larger molecular weight molecules of the first output stream are returned to the fluid source via an output line downstream of primary purification device (step 230). Blood cells, large proteins and lipids, antibodies, multimers of various molecules are specific examples of a larger molecular weight molecule of the first output stream that are to be retained in the fluid source. Lower molecular weight molecules of the second output stream are caused to flow from the primary circuit through the secondary purification device (step 240). Albumin is a specific example of a smaller molecular weight molecule of the first output stream that is removed via a second output streams and that also happens to be a toxin-binding protein molecule. The action of the secondary purification device results in the generation of a larger molecular weight output stream (the third output stream) and a smaller molecular weight output stream (the fourth output stream). A larger molecular weight stream is caused to flow into the sink (step 250). Albumin, albumin-bound toxins, and inflammatory mediators are examples of molecules contained in this third larger molecular weight stream and caused to flow into the sink. A fourth lower molecular weight output stream is caused to flow through the tertiary purification device (step 260). Urea, ammonia and creatinine are examples of a smaller molecular weight output fourth stream molecules that are caused to flow through the tertiary purification device and be removed from the stream by the tertiary purification device. Optionally, solution containing exogenous albumin is also caused to flow through the tertiary purification device so that chemical stabilizers can be removed by the tertiary purification device from the exogenous albumin molecules (step 280). The purified lower molecular weight output stream with incidental beneficial molecules and exogenous albumin purified of chemical stabilizers is returned to source (step 270). Hormones, vitamins and amino acids, drugs, small regulatory peptides, growth factors are examples of incidental beneficial molecules that are to be returned to the primary source.

Fig. 3 shows another flow diagram for yet another method in accordance with an embodiment of the invention. An input fluid is received (step 300). The input fluid is partitioned into two output streams (step 310). A first output stream is relatively enriched in larger components derived from the source fluid and a second output stream is relatively enriched in smaller components derived from the source fluid. The first stream (with the larger components) is returned to the blood source (step 320). The second stream is further partitioned into two output streams (step 330). A third output stream is relatively enriched in larger components derived from the second output stream and a fourth output stream is relatively enriched in smaller components. The third stream (with the larger components) is collected in sink (step 340). The fourth stream is enriched in toxins but also incidental beneficial molecules and, optionally, exogenous albumin molecules. Urea, creatinine and ammonia are examples of toxins, while vitamins, hormones and amino acids are examples of incidental beneficial molecules. The toxins and chemical stabilizers of exogenous albumin are removed from the fourth output stream and retained by the purification device (step 350). The fourth output stream enriched in the incidental beneficial molecules and exogenous albumin freed of chemical stabilizers is returned to the source (step 360); for example, by returning the stream to the source. Fig. 4a shows a block-diagram for a blood purification system in accordance with an embodiment of the present invention. Fluid (e.g., blood, plasma or non-blood bodily fluid) is transferred from a fluid source (e.g., a patient or a reservoir) via a primary inlet line 31 to an input of a primary purification device 32. The primary purification device 32 partitions the fluid into two streams: a first output stream 33 and a second output stream 34. Due to the action of the primary purification device, the first output stream 33 will contain larger components (as measured by hydrodynamic radius or mass) and the second output stream 34 will contain smaller components including toxins and other molecular components that are to be removed, as well as incidental beneficial components that are to be extracted and returned to the patient. The larger components (e.g., blood cells, antibodies and other large proteins, lipids, certain blood clotting factors, to name but a few) in the first output stream 33 flow back to the fluid source through a primary return outlet line 35. The inlet line 31, primary purification device 32, first output stream 33, primary return outlet line 35 and the fluid source define a primary circuit when connected with a fluid source. The second output stream 34 is caused to flow into a secondary purification device 36.

A secondary purification device 36 accepts the fluid loaded with toxins and incidental beneficial molecules from the primary purification device 32, and creates two further output streams from this fluid: a third output stream 37 containing relatively large molecules (e.g., albumin and albumin-bound toxins, other small proteins, inflammatory mediators, mediators of vascular and other unwanted pathophysiologic responses) for disposal into a sink 38, and a fourth output stream 39 containing smaller molecules (e.g., urea, creatinine and other toxins, but also beneficial incidental molecules like, for example, nutrients, vitamins, amino acids, electrolytes, hormones, medications) for perfusion through a tertiary purification device 40. In addition, a fourth output stream 39 solution accepts exogenous albumin 41 is at the inlet of a tertiary purification device 40. The tertiary purification device 40 removes from the fourth output stream 39 small molecular weight uraemic toxins, neurotoxins, toxins of hepatic failure and chemical stabilizers of exogenous albumin. The purified fourth output stream 39 containing fluid, electrolytes, purified exogenous albumin and other beneficial incidental molecules is returned to the patient via the primary return outlet line 35. By extracting the fourth output stream 39 containing small molecular weight incidental beneficial molecules from the second output stream 34 and by removing uraemic toxins, other small molecular weight toxins and chemical stabilizers from albumin solution 41 by the tertiary purification device 40, and by returning the purified fourth output stream enriched with beneficial incidental molecules and exogenous albumin freed of chemical stabilizers to the fluid source through a primary return outlet line 35 (e.g., patient's blood circulation), only the larger toxins may thereby be disposed in the sink 38 while a fraction of the second output stream that contains water, beneficial incidental molecules and exogenous albumin freed of chemical stabilizers is returned to the fluid source (e.g., patient's blood circulation). As a result of this processes, only minimal or no replacement of fluid is needed and only limited amounts, if any, of incidental molecules are disposed into a sink 38. The lines 31, 33, 34, 35, 37, 39 and other lines described herein may be implemented, as is well known in the art, as standard medical-grade tubing or other suitable conduit structure.

Thus, as compared to prior art systems and methods that involve discarding much or all of the second output stream (e.g., ultrafiltrate, dialysate, hemodiafiltrate), the volume of replacement fluid needed to balance the system is reduced or completely eliminated because the system of the present embodiment recycles significant amounts of water and lower molecular weight components. Furthermore, said lower molecular weight components include an array of incidental beneficial molecules, including but not limited to electrolytes, nutrients, hormones, vitamins, certain clotting factors, regulatory peptides, small proteins, anti-inflammatory mediators, and medications used to treat a patient. For added convenience, safety and therapeutic effectiveness, the recycled fluid being returned to the patient's blood circulation may be enriched with additional components, beneficial molecules, exogenous albumin freed of chemical stabilizers, nutrients, drugs, and other therapeutic substances. Fig. 4b. In a specific embodiment of the invention shown on Fig. 4b, the primary purification device 32 may be a hemofilter. By way of example, the primary purification device 32 may be a permselective hemofiltration cartridge with an effective molecular weight cutoff value (e.g., a 90% effective molecular cutoff) of between 5000 and 100,000 daltons and the secondary purification device 36 may be a permselective plasmafiltration cartridge with an effective molecular weight cutoff value of between 3000 and 5000 daltons. In a further example, if the primary purification device 32 has an effective cutoff value of 150,000 daltons and the secondary purification device 36 has an effective cutoff value of about 1000 daltons, then molecules with a molecular weight of between about 1000 and 150,000 daltons (including albumin, a 69,000 dalton protein) will be disposed in the sink 38, although these ranges may change depending on which components one wishes to remove from the blood and changes in the effective molecular weight cutoffs as a function of fluid flux. These changes may be a function of feed flow, ultrafiltration rate, composition and structure of the semipermeable membrane, fluid viscosity, fluid osmolality, membrane hydrophilicity, presence or lack of an anti-fouling membrane coating, membrane polarity, and other factors. Since defective forms of albumin, albumin-bound and unbound toxins and many inflammatory mediators fall within this 1000 - 150,000-dalton range, these unwanted blood/plasma components will be disposed in the sink 38.

Fig. 4c. In an alternate embodiment shown on Fig. 4c, the primary purification device 32 may be a dialysis cartridge. By way of example, the primary purification device 32 may be a permselective dialysis cartridge with an effective molecular weight cutoff value (e.g., a 90% effective molecular cutoff) of between 5000 and 500,000 daltons. As shown on Figure 4c, the primary purification device 32 receives dialysis solution through the inlet fluid line 42 and the spent dialysate 34 processed by the secondary purification device 36 is collected in the sink 38. According to the teaching of this embodiment, the spent dialysate 34 is processed by the secondary purification device 36 and the processed spent dialysate 37 is disposed in the sink 38.

Fig. 4d. In still another alternate embodiment shown on Fig. 4d, the primary purification device 32 may be a hemodiafilter. By way of example, the primary purification device 32 may be a permselective hemodiafiltration cartridge with an effective molecular weight cutoff value (e.g., a 90% effective molecular cutoff) of between 5000 and 500,000 daltons. As shown on Figure 4d, the primary purification device 32 receives a hemodiafiltration solution through the inlet fluid line 42. The stream of hemodiafiltrate 34 is comprised of the spent dialysate and ultrafiltrate; it is pumped through the secondary purification device 36 and the stream of the hemodiafiltrate 37 processed by the secondary purification device 36 is collected in the sink 38. According to the teaching of this embodiment, the spent hemodiafiltrate 34 is processed by the secondary and tertiary purification devices as above described (Fig. 4a). In addition, the volume of the recycled fluid 39 that is returned to the fluid source (e.g., patient's blood circulation) may be adjusted to be equal to the volume of the hemodiafiltrate 44.

The effective cutoff value and sieving coefficients for individual blood/plasma components and the nominal cutoff value (related to the average pore size before use) of a given permselective membrane may differ as a function of chemical and mechanical characteristics of the permselective membrane (e.g., type of polymer and porophores used, porosity wetting properties, charge, symmetry, resistance to fouling, surface exchange area, thickness), operational characteristics (feed flow rate, velocity, ultrafiltration rate, transmembrane pressure), and interactions between blood or plasma components and the filter membrane. For example, in selecting a membrane that has an effective molecular weight cutoff that allows permeation of albumin, a polysulfone membrane may require a nominal cutoff value of 400 kDa or greater, while a polyethersulfone or cellulose acetate membrane may require a nominal cutoff value of only 200 kDa or less. Additionally, the effective molecular weight cutoff of the primary purification device may be selected to be low enough to retain immunoglobulins and return them to the blood source, thereby retaining the beneficial effects of these molecules. Generally, the molecular weight cutoff will be selected to be below about 1,000,000 daltons for this purpose. In the embodiments shown in Figs. 4a, 4b, 4c and 4d, the recycled fourth output stream enriched with beneficial incidental molecules and, optionally, exogenous purified albumin freed of chemical stabilizers is returned to the primary fluidic circuit (e.g., a patients blood circulation) downstream of the primary purification device 32. This configuration is referred to as post-dilution configuration, since it dilutes the blood after it exits the primary purification device 32. In alternate embodiments, the recycled fourth output stream enriched with beneficial incidental molecules may be returned to the primary fluidic circuit (e.g., a patients blood circulation) upstream of the primary purification device 32. This configuration is referred to as pre-dilution configuration, since it dilutes the blood before it enters the primary purification device 32. Pre-dilution may prevent adverse effects, such as protein aggregation and blood coagulation in the primary purification device 32, that may occur due to concentration of the blood by the primary purification device. Post-dilution may enhance blood/plasma purification because in such an embodiment, the secondary output stream (e.g., ultrafiltrate) is not diluted. In still another embodiments, a portion of the recycled fourth output stream enriched with beneficial incidental molecules may be returned to the primary fluidic circuit (e.g., a patients blood circulation) upstream of the primary purification device 32 while the remainder of the recycled fourth output stream may be returned downstream of the primary purification device 32. This configuration is referred to as pre/post-dilution configuration. In alternate embodiments of the systems shown on Figures 4a, 4b and 4c, the tertiary purification component may be omitted or optionally by -passed when the treated subject does not have clinically relevant toxemia that includes small molecular weight uremic toxins, ammonia, or any other toxin in the blood that can be removed by any tertiary purification device. In these instances, the fourth lower molecular weight output stream is caused to flow directly into the primary return outlet line 35 and the fluid source (e.g., the patient's blood circulation).

In illustrative embodiments, the fluid flow through the primary purification device 30 may be about between 10 and 5000 ml/min. The flow rate of the second output stream may be about 1 to 500 or about 1 to 1500 ml/min.

Various control schemes may ensure the desired system performance. For example, flow- rate sensors may be employed along with a microcontroller to adjust the pumping rates so as to ensure a proper fluid flow rate. To further increase safety, efficacy, or convenience, additional sensors, such as blood-chemistry sensors, may also be incorporated into the system to monitor the rate at which specific toxins or beneficial incidental molecules are being removed from the patient's blood circulation and/or returned into the patient's blood circulation during therapy. Albumin, select inflammatory mediators, growth factors, specific regulatory peptides, blood clotting factors, nutrients, amino acids, and drugs are examples of such molecules.

Embodiments shown on Figures 3 and 4b through 4d combine dialysis, hemofiltration and hemodiafiltration with adsorption. The tertiary purification devices may operate to remove low molecular weight toxins with the result of clearing these toxins from the fourth output stream 39, thus mimicking the action of a healthy liver or kidney. Optionally, the tertiary purification devices may operate in embodiments shown on Figures 3 and 4b through 4d to remove chemical stabilizers from exogenous albumin molecules contained in albumin solution 41. Medical devices and systems based on these embodiments may replace or supplement the liver and/or kidney function of a patient with liver failure of any etiology and severity, with systemic inflammatory syndrome, with sepsis, with multiorgan dysfunction syndrome, or a combination thereof. In the embodiments that employ an adsorptive purification device 40, such device includes a casing defining one or more chambers, which hold adsorptive material (i.e., a toxin-binding stationary phase) to remove specific toxins. The adsorbent material may include activated charcoal, resins (e.g., uncharged, neutral, anion exchange or cation exchange resins), silica, albumin, immobilized antibodies, cancer cells, malignant liver cells, liver cell lines derived from benign or malignant liver tumours, immobilized receptors, immobilized specific antagonists, polymers, cellulose derivatives, and immobilized antibiotics, or combinations thereof. The adsorbent material may be organized in a number of ways, e.g., as beads, rods, porous granules, a sieve, a matrix with anchored molecules, etc. The adsorptive device receives the stream of secondary ultrafiltrate (the fourth output stream 39 and selectively or non-selectively removes components that cause or aggravate liver failure, renal failure or any other disease or pathological condition associated with accumulation in the blood circulation of toxic substances, including but not limited to ammonia, phenols, mercaptans, aromatic amino acids, urea, creatinine, oxygen reactive species, nitric oxide, chemical stabilizers of exogenous commercially available albumin, and vasoactive substances. Some commercially available or preclinical systems utilizing adsorptive device technology which may be used with the embodiments of Figs. 4a, 4b, 4c and 4d include: (1) Adsorba columns (Gambro, Hechingen, Germany) which contains activated charcoal as the sorbent, (2) BioLogic-DT System (HaemoCleanse, West Lafayette, IN), which contains a mixture of charcoal, silica and exchange resins as the sorbent, (3) HepAlbin device containing sorbents (Albutec GmbH, Rostock), (4) MARS (Molecular Adsorbent Recirculating System; Gambro GmbH, Hechingene, Germany), which uses charcoal and resin as the sorbent, and (4) Prometheus™ (Fresenius, Germany), which uses two types of ion exchange resins as sorbents.

In alternate embodiments of the present invention, any of the embodiments previously described may additionally include a cell-based device to provide specific biologic function (e.g., metabolism and/or synthesis of specific blood components, metabolism and/or removal of specific blood components including but not limited to inflammatory mediators, anti-inflammatory mediators, mediators of vasodilatory effects, and mediators and toxins of any other unwanted physiological response). For example, a HepatAssist-2 cartridge loaded with viable liver cells (Arbios Systems, Inc.) may be included in a fluidic line 39 to provide metabolic detoxification or an ELAD bioartificial liver (Vital Therapies, Inc.) loaded with C3a cells derived from HepG2 liver cells line derived from human hepatoblastoma, or a bioreactor loaded with cancer cells or immortalized liver cells derived from any benign or malignant liver tumour. Additionally, various combinations of dialysis, sorption, and cell-based purification may be used. In further related embodiments, any of the embodiments previously described may utilize a digital control system for regulating flow within parameters as described above and for maintaining acceptable operating conditions.

In a further embodiment, fluid may be recovered from the sink 38 and used for research (biomedical or otherwise) or for therapeutic purposes. The sink fluid will tend to be enriched in valuable biological components. These components may be recovered by various processing and purification procedures that are known in the art (fractionation, chromatography, microdialysis, etc.) and formulated and packaged for sale and use in research or for administration to patients as therapeutic agents. Examples of valuable components include cytokines, chemokines, immunomodulators, growth factors, regulatory peptides and proteins.

The described embodiments of the invention are intended to be merely exemplary and numerous variations and modifications will be apparent to those skilled in the art. All such variations and modifications are intended to be within the scope of the present invention as defined in the appended claims. For example, the purification devices described herein may be combined with instrumentation for gas exchange (including oxygenation), pathogen sterilization, temperature control, gamma irradiation, ultraviolet light treatment, etc. The purification devices are not limited to hollow fiber filters, but may operate on other principles, including centrifugation and gradient centrifugation.

Claims

1. A blood purification apparatus comprising:

a primary purification device to receive, at an input via a primary inlet line, a primary input fluid, the primary purification device adapted to partition the input fluid into a first output stream enriched in larger components and a second output stream enriched in smaller components, wherein the first output stream is returnable to the patient via a primary outlet line;

and a secondary purification device, in fluid communication with the primary purification device and the sink, to receive fluid from the primary purification device and to partition the fluid into a third output stream enriched in larger components and a fourth output stream enriched in smaller components, wherein the third output stream is directed to flow to a sink and the fourth output stream that is directed to flow to a tertiary purification device;

and a source of exogenous albumin solution, in fluid communication with the tertiary purification device through the fourth output stream;

and a tertiary purification device to receive at an input a fourth output stream from the secondary purification device and to purify the fourth output stream from uremic toxins and other small molecular weight toxins, and to remove chemical stabilizers from exogenous albumin molecules, wherein the purified fourth output stream is returnable to the patient via a primary outlet line.

2. An apparatus according to claim 1, characterized in, that it comprises at least one of the following features:

i) the first and second purification devices are a first hollow-fiber filter and a second hollow- fiber filter,

ii) the first purification devices is a dialysis device,

iii) the first purification devices is a dialysis device utilizing albumin- leaking membrane, iv) the first purification devices is a hemofilter,

v) the first purification devices is a hemofilter device utilizing albumin- leaking membrane, vi) the first purification devices is a hemodiafiltration device,

vii) the first purification devices is a hemodiafiltration device utilizing albumin-leaking membrane,

viii) the first filter has a sieving distribution favoring larger components and the second filter has a sieving distribution favoring smaller components, thereby returning larger components to the source and directing smaller components to the sink,

ix) the nominal molecular weight cutoff of the first filter is less than about 4,000,000 daltons and the nominal molecular weight cutoff of the second filter is less than about 2,000,000 daltons, x) it further includes a tertiary purification device adapted to remove toxins normally removed by the kidney or liver, and chemical substances used to stabilize commercial preparations of albumin,

xi) the tertiary purification device is one of an adsorption device or a cell based device, xii) it further includes a pumping system coupled to cause flow through the primary purification device, through the secondary purification device, and through the tertiary purification device,

xiii) the pumping system includes at least one centrifugal pump,

xiv) the flow rate of the fourth output stream is approximately equal to the ultrafiltration rate of the second output stream,

xv) the pumping system operates to induce a fluid flow through the primary purification device at the rate that is between 10 ml/min and 5000 ml/min,

xvi) the pumping system operates to induce a flow of the second output stream at the rate that is between 1 ml/min and 1500 ml/min,

xvii) the pumping system operates to induce a fluid flow through the second purification device at a rate that is between 10 ml/min and 1,500 ml/min,

xviii) the pumping system operates to induce a flow of the fourth output stream having a rate that is between 1 ml/min and 1 ,000 ml/min,

xix) the pumping system operates to induce a fluid flow through the tertiary purification device at a rate that is between 1 ml/min and 1 ,000 ml/min,

xx) molecular weight cutoffs of the primary and secondary purification devices are selected so as to cause the flow of a toxin binding protein into the sink,

xxi) the toxin binding protein is albumin,

xxii) the toxin is a defective form of endogenous albumin, albumin bound toxin, protein bound toxin, toxic middle molecule, inflammatory mediator or any other toxin or mediator of physiological or pathophysiological process,

xxiii) the molecular weight cutoff of the primary purification device is selected to direct immunoglobulins and molecules larger than immunoglobulins to the first output stream, xxiv) the molecular weight cutoff of the secondary purification device is selected to direct electrolytes, carbohydrates, amino acids, nutrients, drugs, growth factors, small regulatory peptides and proteins, small molecular weight mediators, vitamins, hormones, drugs and other beneficial incidental molecules to the fourth output stream,

xxv) the tertiary purification device removes urea, creatinine, ammonia, other small water-soluble toxins, molecules used to stabilize albumin molecules, inflammatory mediators, antiinflammatory mediators, mediators of other unwanted pathophysiological responses, and regulatory peptides from the fourth output stream,

xxvi) the tertiary purification device is a sorbent based device,

xxvii) the tertiary purification device is a cell-based based device,

xxviii) it further includes a source of exogenous albumin molecules,

xxix) it further includes a fluid source selected from one of a patient vasculature and a fluid source reservoir,

xxx) it further includes any of the patient extravascular space such as abdominal cavity, pleural cavity, subarachnoidal space.

3. A method for removing a component species from a fluid source, the method comprising: receiving via an inlet line a primary input fluid containing at least components of the source fluid; partitioning the input fluid into a first output stream enriched in larger components and a second output stream enriched in smaller components; returning the first output stream to the fluid source; partitioning the second output stream into a third output stream enriched in larger components and a fourth output stream enriched in smaller components; removing small water-soluble uremic toxins, ammonia, albumin chemical stabilizers and other small toxins (if present) from the fourth output stream from; directing the purified fourth output stream containing incidental beneficial molecules to merge with the first output stream to the fluid source;

4. A method according to claim 3, wherein the binding agent is an adsorbent or a cell obtained from human or animal tissue or benign or malignant tumor.

5. A method according to claim 3, further comprising controlling flow rates in the respective streams so that the volume of the replacement fluid is reduced.

6. A method according to claim 3, further comprising controlling retention of lower molecular weight beneficial incidental molecules so that only additional limited amounts of incidental beneficial molecules need be provided to the patient.

7. A method according to any of claims 3 to 6, wherein the volume of the ultrafiltration component of the second output stream and the fourth output stream are about equal so that no additional replacement fluid need be provided to the patient.

8. A method according to any of claims 3 to 6, wherein the fluid source is a blood source or a sink.

9. A method according to any of claims 3 to 6, wherein the fluid source is an external container.

10. A method according to claims 8 or 9, wherein the source contains a patient bodily fluid, possibly selected from the group consisting of blood, plasma, serum, cerebro-spinal fluid, or ascitic fluid.