FIELD OF THE INVENTION

The invention generally relates to an extracorporeal blood purification system based on hemofiltration and hemo-concentration. More specifically, the invention relates to removal, or clearance, of protein-bound molecules from blood through hemo-concentration in an hemofilter.

BACKGROUND TO THE INVENTION

Extracorporeal blood purification has been widely used, most commonly in continuous renal replacement therapies (CRRT) to treat patients suffering loss or impairment of natural kidney functions. More recently, extracorporeal blood filtration has been adapted for more general application in plasmapheresis, the purification of blood through removal of noxious components circulating in the blood plasma. Considerable interest has arisen in using plasmapheresis as a means for treating ICU patients suffering from inflammatory mediator- related diseases such as septic shock, systemic inflammatory response syndrome (SIRS), and multiple organ failure (MOF). These conditions can arise from excessive release of inflammatory mediators into the bloodstream by overstimulation of the immune system. Thus, plasmapheresis as well as other CRRT has been proposed as mechanisms for removing inflammatory mediators from the bloodstream to counteract an excessive inflammatory response. However, these technologies that exchange the full plasma or that use standard CRRT procedures never demonstrated any relevant efficacy for controlling the inflammatory answer or supporting sepsis recovery.

In a typical hemofiltration system blood is removed from a patient through an access site, usually by insertion of a venous catheter in a limb or central vein, and pumped through an extracorporeal circuit that includes an artificial kidney or hemofilter. The hemofilter includes a semi-permeable membrane, usually synthetic, with pore sizes selected to pass unwanted molecules. Hemofiltration processes are classified as either low-volume hemofiltration (LVH or LVHF) or high-volume hemofiltration (HVH or HVHF). In both processes, a hydrostatic pressure circulates blood along one surface of the filter membrane thereby creating an increase of protein concentration inside the hemofilter and pushing water and waste products across the filter membrane into a filtration fluid. As a result, bonded proteins and suspended solids and solutes of high molecular weight remain in the blood and hemo-concentration is increased. Downstream of the hemofilter, a sterile substitution fluid, usually containing bicarbonate, is then added to the blood flow to replace vital fluids and electrolytes that were lost through the transmembrane filtration. During this addition, with respect to a particular protein-bound mediator, a concentration difference is created between the blood and the substitution fluid because the blood contains a high concentration of a protein-bound mediator, while the substitution fluid is essentially mediator free. This condition promotes a break of liaison, or breakage of the bond, between mediators and protein, resulting in a higher concentration of free mediators once the two fluids (blood and substitution fluid) have combined. Generally, a second hemofilter is then used to filter out these free mediators, having a smaller molecular weight than protein-bound mediators, out of the blood through the filter membrane before they can be bound back to protein. The combined blood and substitution fluid is then returned to the patient through another venous access site.

In HVH therapy, the procedural principle is removal of plasma water from blood through a hemofilter, and replacement of the lost fluid by addition of substitution solution. An analysis of hemofiltration therapies revealed that HVH removes different quantities of certain molecules than LVH therapies and showed that HVH improves the clearance of unwanted molecules as compared to LVH. For example, Ronco showed that HVH can be effective at removing inflammatory mediators, whereas LVH has no effect on plasma levels of inflammatory mediators. C. Ronco, "Pulse High-Volume Hemofiltration in Sepsis", European Renal and Genito-U nary Disease, pp. 39-45, 2006. However, HVH has also several disadvantages. For example, in order to support high volume blood flow, multiple catheters or a very large catheter may need to be installed in the patient to reduce resistance. Also HVH requires larger, more expensive hemofilters with high flux membranes that can process large volumes of fluid exchange daily. Finally, HVH must be critically monitored to prevent complications, such as hypothermia.

Hemofiltration is thus a means to deplete the blood from unwanted molecules, however, a problem which arises during hemofiltration is that a number of unwanted molecules, such as inflammatory or apoptotic mediators are fixed and transported by proteins such as albumin. As such, these molecules cannot be sufficiently cleared from the blood, since these complexes do not pass through the hemofilter into the filtrate fluid. It was now surprisingly found that the addition of citrate to the blood flow, before it passes the hemofilter provides a solution to this problem, in that the addition of citrate results in a release of molecules bound to albumin. Therefore, these unwanted molecules become freely available in the blood flow and can be cleared by passages through the hemofilter. The addition of citrate is considered safe for the patient, because it is converted into bicarbonate in the Krebs cycle. Furthermore, since the addition of citrate will also result in the release of Ca ²⁺ from being bound to albumin, a calcium sensor can be used to follow-up and control this process, thereby allowing the (automatic) adjustment of the amount of citrate to be added to the system. Finally, the pH decrease due to the addition of citrate, was also found to result in an even further increase in hemoconcentration. SUMMARY OF THE INVENTION

In a first aspect, the present invention provides an extracorporeal blood filtration system for removing unwanted molecules from a flow of blood from a patient, comprising:

a hemofilter for raising hemoconcentration of the blood in a filtered blood flow;

- a first influx system to add citrate to the blood flow before the blood flow passes the hemofilter;

a second influx system to add a substitution fluid to the filtered blood flow for return to the patient; and

a control system to set the filtration ratio for hemoconcentration in the hemofilter to be higher than 33%; in particular higher than 33% and lower than 45%. Using these settings the blood haematocrit level outside the hemofilter can reach values over 50%.

Within the context of the present invention said filtration ratio (in the absence of citrate addition) is calculated by: 100% x (filtration flow rate / blood flow rate). If citrate is added to the blood flow, the filtration ratio is calculated by: 100% x [filtration flow rate / (blood flow rate + citrate flow rate)]. The filtration flow rate representing the flow rate of filtered fluid through the hemofilter. The blood flow rate representing the flow rate of blood (optionally in combination with the flow rate of citrate added to the blood flow) entering the filtration system. In a particular embodiment, the hemofilter of said extracorporeal blood filtration system includes a semi-permeable membrane having pore sizes selected to pass the free unwanted molecules. In a further embodiment, said unwanted molecules include one or more mediators. In an even further embodiment, these one or more mediators are inflammatory mediators. In another embodiment, the extracorporeal blood filtration system comprises a blood haematocrit sensor. Said haematocrit sensor can regulate the blood flow (with optionally the citrate flow rate) or the filtration flow rate in order to reach the determined filtration ratio (higher than 33% and lower than 45%).

In yet another embodiment, the extracorporeal blood filtration system comprises a continuous pH sensor that adjusts the blood flow or the filtration flow rate if a pH below 7.2 is measured in the blood after the blood flow has passed through the hemofilter.

In a further particular embodiment, the extracorporeal blood filtration system comprises a means for adjusting blood flow through the hemofilter. In a further embodiment, the extracorporeal blood filtration system comprises a controller for optimizing a removal rate of the unwanted molecules from the blood flow. In further embodiment, said controller adjusts one or more of blood flow in the hemofilter, transmembrane pressure in the hemofilter, flow of the substitution fluid, and pressure drop across the hemofilter. In a further aspect, the present invention comprises an extracorporeal blood filtration system as described herein above wherein the first influx system controls the addition of citrate to the blood flow before the blood flow passes the hemofilter such as to reach a final citrate concentration between 2 and 6 mmol per liter of blood, preferably between 3 and 4 mmol per liter of blood..

In yet another aspect, the present invention comprises a method for removing unwanted molecules from a flow of blood from a patient using an extracorporeal blood filtration system as described herein above. BRIEF DESCRIPTION OF THE DRAWINGS

With specific reference now to the figures, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of the different embodiments of the present invention only. They are presented in the cause of providing what is believed to be the most useful and readily description of the principles and conceptual aspects of the invention. In this regard no attempt is made to show structural details of the invention in more detail than is necessary for a fundamental understanding of the invention. The description taken with the drawings making apparent to those skilled in the art how the several forms of the invention may be embodied in practice.

Figure 1. Schematic representation of the pH variation in the blood circuit using an extracorporeal blood filtration system with a filtration ratio of 22% (blue) or 32% (red). pH was measured at three different locations in the blood circuit of the present invention, namely pre-filter, across the hemofilter and in the post-dilution volume. The increased filtration ratio in the hemofilter of the present invention results in a decreased pH in the blood across the hemofilter.

Figure 2. Schematic representation of the concentration of free proteins, albumin and CI ^" in an extracorporeal blood filtration system using a filtration ratio of 22% (A) or a filtration ratio of 32% (B). Concentration of free proteins, albumin and CI ^" was measured at 4 different locations in the blood circuit of the system, namely pre-filter, across the hemofilter, in the post-dilution volume and in the filtration fluid (ultrafiltrate; UF). DETAILED DESCRIPTION OF THE INVENTION

As indicated herein before, the present invention in particular aims at providing an extracorporeal blood filtration system for removing unwanted molecules from a flow of blood from a patient. Thereto, in a first aspect, the present invention provides an extracorporeal blood filtration system for removing unwanted molecules from a flow of blood from a patient comprising:

a hemofilter for raising hemoconcentration of the blood in a filtered blood flow;

a first influx system to add citrate to the blood flow before the blood flow passes the hemofilter;

- a second influx system to add a substitution fluid to the filtered blood flow for return to the patient; and

a control system to set the filtration ratio for hemoconcentration in the hemofilter to be higher than 33%; in particular higher than 33% and lower than 45%, such that the blood haematocrit level outside the hemofilter can reach values over 50%.

Said filtration ratio (in the absence of citrate addition) is calculated by: 100% x (filtration flow rate / blood flow rate). If citrate is added to the blood flow as anticoagulant, the filtration ratio is calculated by: 100% x [filtration flow rate / (blood flow rate + citrate flow rate)]. Typical for the present invention, and different from blood filtration systems available in the prior art, is that the filtration ratio in the hemofilter of the system is set higher than 33% and lower than 45%. In contrast to the presently available filtration systems, which are set to operate at a filtration ratio below 30%, the filtration ratio of the system of the present invention is largely increased, in particular higher than 33% and lower than 45%. Due to this increased filtration ratio, hemoconcentration of the blood at the hemofilter is increased. One could expect that this increased hemoconcentration will cause side effects such as increased clotting risk. Nevertheless, the increased filtration ratio in the hemofilter was found to result in a pH decrease in the blood. This reduced pH in the blood not only favours the filtration cascade, it also reduces the clotting risk, as discussed herein below. Furthermore, typical for the present invention is that the blood haematocrit level outside the hemofilter can reach values over 50%. Furthermore, due to the addition of citrate, unwanted molecules being bound to albumin, were found to be released from the albumin and hence more efficiently removed from the blood. In addition citrate is also an anti-coagulant and thus serves two purposes within the context of the invention. In a particular embodiment, said citrate is added to the blood in a concentration to reach a final citrate concentration between 2 and 6 mmol of citrate per liter of blood before the blood flow passes the hemofilter, more preferably between 3 and 4 mmol of citrate per liter of bloods. The extracorporeal blood filtration system according to the present invention comprises a hemofilter for raising the hemoconcentration of the blood in a filtered blood flow and a substitution fluid for supplementing the filtered blood flow for return to the patient. Typical for the present invention is that the filtration ratio for hemoconcentration in the hemofilter is set higher than 33% and lower than 45%. This high filtration ratio results in an increased hemoconcentration of the blood. Unexpectedly, this also results in a decrease of the pH of the blood across the hemofilter (Figure 1 ). The reduced pH leads to fragilizing the protein link between proteins and mediators in the blood. After all, the blood contains a number of inflammatory or apoptotic mediators that are fixed and transported by proteins such as albumin. The reduced pH catalyses a break of liaison, or breakage of the bonds, between mediators and their protein transporters thereby releasing the inflammatory mediators in the blood. These mediators are subsequently removed from the blood flow through the hemofilter in the filtrate fluid. Surprisingly, this fragilizing of the association between proteins and mediators in the blood results in a significant shift between pro- and anti-inflammatory mediators is created. Furthermore, the addition of citrate and its anticoagulation effect plays an additional beneficial effect in the albumin detoxification since also citrate reduces the pH of the blood before the blood is filter through the hemofilter. Therefore, despite the possibility of using a standard anticoagulation procedure without citrate, it can be recommended to use citrate as anticoagulation procedure in order to catalyse the albumin detoxification objectives.

Not only inflammatory or apoptotic mediators are linked to protein transporters in the blood. Approximately 50% of the calcium, an important clotting and co-enzyme factor in the clotting cascade, in the blood is effectively linked to albumin. By increasing the filtration ratio in the present extracorporeal blood filtration system, also part of the fixed calcium is released from albumin due to the pH change and becomes filtered through the hemofilter into the filtration fluid. The high filtration ratio therefore also reduces the clotting risk and increases the clotting time by reducing the calcium concentration in the blood.

As already outlined above, the reduced pH leads to fragilizing the protein link between transporter proteins and mediators in the blood. As a result, transporter proteins, such as albumin, are discharged from their bounded mediators such as inflammatory cytokines or standard molecules (for example calcium) and become present in an electronegative charge across the hemofilter. Since these negatively charged transporter proteins are unable to cross the semi-permeable membrane of the hemofilter due to their high molecular weight, other negatively charged molecules with a lower molecular weight, such as chloride ions (CI ^" ) will cross the semi-permeable membrane of the hemofilter, based on the Gibbs-Donnan effect. Said effect describes that the presence of a charged impermeant ion (for example albumin) on one side of a semi-permeable membrane will result in an asymmetric distribution of permeant charged ions (for example CI ^" ) over the membrane. The Gibbs-Donnan equation at equilibrium states: [anions _side i ] x [cations _side i ] = [a nions _s id _e 2] x [cations _S id _e 2]- As a result of this Gibbs- Donnan effect low molecular weight and negatively charged molecules that are easily transported by convection will pass across the hemofilter from the blood to the filtrate fluid (ultrafiltrate) to compensate the increase of negatively charged albumin. Consequently, the difference between the CI ^" concentration in the filtrate fluid (ultrafluid) and the CI ^" concentration across the filter (also represented as ACI ^" ) can be used as a marker for filtration efficiency in the extracorporeal blood filtration system according to the present invention. For example, and as evidenced in Figure 2, the use of a filtration ratio of 32% markedly decreases the CI ^" concentration across the hemofilter, as compared to the use of a filtration ratio of 22%. As a result, ACI ^" is increased when using a filtration ratio of 32% as compared to the use of a filtration ratio of 22%.

Due to its high filtration ratio and corresponding pH decrease in the blood and removal of inflammatory mediators and calcium from the blood, the extracorporeal blood filtration system according to the present invention is particularly useful for removing unwanted molecules from a flow of blood from a patient, for example intensive care unit (ICU) patients suffering from inflammatory mediator-related diseases such as septic shock, systemic inflammatory response syndrome (SIRS), and multiple organ failure (MOF). These conditions can arise from excessive release of inflammatory mediators into the bloodstream by overstimulation of the immune system. Sepsis, for example, is characterized by a complex systemic inflammatory response to a microbial pathogen. First, the presence of microorganisms in the bloodstream causes an innate immune response characterized by the stimulation of monocytes and release of proinflammatory cytokines and the activation of a medley of different immune pathways. Conventional therapy such as antibiotics and surgical procedures to remove the source of infection is crucial for treating sepsis, but these approaches cannot reverse the effects of the bacterial toxins already release into the blood or of the endogenous inflammatory mediators produced by the host in response to bacteria. Blood purification techniques including hemoperfusion, plasma exchange, and hemofiltration with hemoperfusion are associated with lower mortality in patients with sepsis. Devices to remove endotoxin or inflammatory cytokines have been designed as a strategy to reduce the morbidity and mortality associated with sepsis. Nevertheless, none of the current techniques have been proven as efficient because of the complexity of the pro- and anti-inflammatory immunomodulation during sepsis. The extracorporeal blood filtration system according to the present invention is therefore particularly useful for the treatment of patients suffering septic shock, thereby improving their survival.

In one embodiment of the present invention, the extracorporeal blood filtration comprises a hemofilter that includes a semi-permeable membrane having pore sizes to pass the free unwanted molecules. As described above, the high filtration ratio applied in the extracorporeal blood filtration system according to the present invention results in increased hemoconcentration leading to a pH decrease in the blood flow. As a result, unwanted molecules are liberated from their protein transporters. The semi-permeable membrane may be selected for a membrane pore size that passes unwanted inflammatory or apoptotic mediators and that also removes calcium ions that are liberated from albumin as well. As already specified above, in one embodiment of the present invention, the unwanted molecules include one or more mediators, in particular inflammatory mediators.

In another embodiment of the present invention, the extracorporeal blood filtration system comprises a haematocrit sensor for monitoring the blood haematocrit level in the blood flow outside the hemofilter. Said haematocrit sensor can regulate the blood flow (with optionally the citrate flow rate) if filtration flow rate is fixed, or said haematocrit sensor can regulate the filtration flow rate if the blood flow rate is fixed. This enables to reach a determined filtration ratio higher than 33% in the extracorporeal blood filtration system according to the present invention.

In yet another embodiment of the present invention, the extracorporeal blood filtration system comprises a continuous pH sensor for monitoring the pH in the blood flow. Said continuous pH sensor adjusts the blood flow or filtration rate if a pH below 7.2 is measured in the blood after the blood flow has passed through the hemofilter. In particular, the continuous pH sensor decreases the blood flow or increases the filtration flow rate if a pH below 7.2 is measured in the blood after the blood flow has passed through the hemofilter.

In yet another embodiment of the present invention, the extracorporeal blood filtration system comprises a Ca ²⁺ sensor. Since, Ca ²⁺ ions are captured by albumin, they are also released from the albumin under the influence of the addition of citrate. Therefore, measurement of Ca ²⁺ ions can assist in the monitoring of the hemofiltration efficiency and may thus be used to assist in (automatically) adjusting citrate influx by the device. In yet another embodiment of the present invention, the extracorporeal blood filtration system comprises one or more chloride sensors. In a particular embodiment of the present invention, the system comprises a chloride sensor for measuring chloride concentration in the blood flow. In another particular embodiment, the present invention comprises a second chloride sensor for measuring chloride concentration in the filtrate fluid. In yet another particular embodiment, the present invention comprises a chloride sensor for measuring chloride concentration in the blood flow, and another chloride sensor for measuring chloride concentration in the filtrate fluid. As explained above, the values measured by the two chloride sensors allow the calculation of ΔΟΓ that serves as a marker for therapy efficiency. The higher ACV is, the higher the filtration efficiency in the system. Thus in another embodiment, the extracorporeal blood filtration system comprises means to determine the ΔΟΓ over the hemofilter, such as for example by means of a chloride sensor for measuring chloride concentration in the blood flow, and another chloride sensor for measuring chloride concentration in the filtrate fluid. Analogous to the pH above, the ACI over the hemofilter can be used as a parameter to adjust the filtration ratio for hemoconcentration in the hemofilter.

Being an indirect marker of albumins binding capabilities, wherein an increase in ΔΟΓ over the hemofilter indicates break of liaison, or breakage of the bonds, between mediators and albumin, said ACI can be used as a marker for the detoxification of albumin across a semipermeable filter. It is thus an objective of the present invention to provide the use of ACI as a marker for the detoxification of albumin across a semi-permeable filter.

In another embodiment of the present invention, the extracorporeal blood filtration system comprises a means for adjusting blood flow through the hemofilter.

In one embodiment, the patient access site of the extracorporeal blood filtration system may represent one or more intravenous catheters, PICC lines or central venous catheters or equivalent means for penetrating a blood vessel of the patient to draw a flow of unfiltered blood in the circuit of the extracorporeal blood filtration system. A sensor, which may be a blood flow detector or blood pressure sensor, may be provided to measure the flow or pressure of blood leaving the patient at the patient access site. The sensor may be any commercial detector known in the art and commonly used for this purpose, such as a noninvasive infrared or ultrasonic Doppler type detector. In one embodiment, the sensor may be a pressure sensor for detecting a differential pressure between two points in the blood flow, for derivation of a signal representative of the blood flow. In this and other embodiments, additional sensors may be located at various points in the circuit. Hereinafter, the sensors will be disclosed as pressure sensors, although it should be appreciated that flow sensors may also be employed.

The present invention may also comprise a blood pump providing the mechanical force to sustain a continuous flow of blood. The blood pump may be any conventional pump known in the medical field and suitable for the purpose. It should be understood that the blood pump, as well as other pumps described herein or otherwise used in different embodiments of the invention, may be conventional diaphragm, centrifugal, or peristaltic pumps typically used in the medical field. ln another embodiment, the extracorporeal blood filtration system may also comprise a means for adjusting transmembrane pressure in the hemofilter.

A pre-filter sensor may be installed to measure pressure in blood flow upstream of the hemofilter. The hemofilter may be of conventional design and selected from commercial stock, and may include two flow paths separated from each other by a semi-permeable membrane. The semi-permeable membrane may be selected for its particular pore size, i.e. its ability to pass molecules up to a certain atomic weight. By osmotic or hydrostatic pressure, water and waste solutes in blood flow pass through the semi-permeable membrane and exit the hemofilter along one flow path as a filtrate flow. A filtrate pump may be installed to draw filtrate fluid from the hemofilter along one flow path as a filtrate flow. A sensor may be located in filtrate flow to measure the pressure in that line. The filtrate in flow may be collected in a filtrate collector, and may ultimately be disposed of as a waste product.

A blood leak detector may also be installed in the filtrate flow path to detect excessive presence of blood plasma.

The second flow path in the hemofilter is provided for filtered blood, which exits the hemofilter as blood flow on the downstream side. The extracorporeal blood filtration system according to the present invention also comprises a substitution fluid for supplementing the filtered blood flow for return to the patient. This substitution fluid (also called 'post-dilution volume') is provided to add to the blood flow to compensate for volume lost as filtrate flow. The substitution fluid may be any sterile intravenous fluid having a desired concentration of electrolytes, such as a dialysate solution commonly known in the art. Additionally, the substitution fluid may be formulated as a buffer to maintain a desired acid-base balance. For example, the substitution fluid may be an acetate-based, lactate-based, citrate-based or bicarbonate-based buffer.

A substitution fluid pump may be installed to force the substitution fluid to combine with the blood flow. A heater may be installed in the flow path of the substitution fluid to maintain proper temperature levels and prevent hypothermia. A temperature sensor may also be installed to sense and transmit an analogue or digital signal representing substitution fluid temperature to a controller to effect temperature control. Optionally, a pressure sensor may be located in the circuit at this point where the blood flow is combined with the substitution fluid. This pressure sensor is placed for pressure or flow measurements. In other embodiments, an air bubble trap, an air bubble detector, and/or an automatic clamp may be installed in the circuit as safety precautions at points upstream of a patient blood return site. The air bubble trap may be placed into the blood flow for removal of unwanted micro bubbles. The air bubble detector may be placed into the blood flow downstream of all pumps in the circuit, to detect the undesirable presence of air bubbles or air gaps in blood flow. Any air bubble detector known in the medical field, such as ones operating on ultrasonic or infrared sensing technology may be used for this purpose. The automatic clamp may be placed between the air bubble detector and a patient blood return site. In one embodiment, a solenoid valve may be employed as the automatic clamp. In another embodiment, the air bubble detector and the automatic clamp interface electronically with a controller. The return site may be provided using an appropriate and complimentary catherization method as used for the access site.

In yet another embodiment, the extracorporeal blood filtration system according to the present invention comprises a controller for optimizing a removal rate of the unwanted molecules from the blood flow. In a further embodiment, this controller adjusts one or more of blood flow in the hemofilter, transmembrane pressure in the hemofilter, flow of the substitution fluid, and pressure drop across the hemofilter.

In a further embodiment of the present invention, a central computer or controller may allow a user to manually or automatically control components within the hemofiltration circuit. The components may include the blood pump, the filtrate pump, substitution fluid pump, the substitution fluid heater and the automatic clamp. Control loops may be enabled by the controller that communicates with and/or receives sensoring input from various instrumentation within the hemofiltration circuit.

In yet another aspect, the present invention comprises a method for removing unwanted molecules from a flow of blood from a patient using an extracorporeal blood filtration system as described herein above. It is accordingly an objective of the present invention to provide a method of treating patients suffering from inflammatory mediator-related diseases such as septic shock, systemic inflammatory response syndrome (SIRS), and multiple organ failure (MOF), said method comprising:

- taking a flow of blood from the patient;

- adding citrate to the blood flow before it passes the hemofilter;

- exposing said blood flow to a hemofiltration step wherein the filtration ratio for hemoconcentration in the hemofilter is higher than 33%; in particular higher than 33% and lower than 45%;

- adding a substitution fluid (also called 'post-dilution volume') to the blood flow to compensate for volume lost as filtrate flow; and

- returning the thus filtered blood to the patient.

In a further embodiment of the aforementioned method of treatment said citrate is added in a concentration to reach a final citrate concentration between 2 and 6 mmol per liter of blood, preferably between 3 and 4 mmol per liter of blood, wherein the citrate is added to the blood flow before the blood flow passes the hemofilter.