Abstract:
The present invention describes a process and a device for saving diafiltrate by partial regeneration using adsorbers. An object of the invention is to decrease the requirement of dialysate and/or substitute in the depletion of a substance of class X by means of special microstructured adsorption/filtration devices. An object of the invention is also to enable control of the concentration of a substance group X by hemodialysis and/or hemofiltration, such that by partial recirculation of the diafiltrate in the regeneration circuit, the net throughput of diafiltrate can be kept lower. The process serves for saving dialysate and/or substitute solution in control of the concentration of a substance group X in a complex biological liquid compartment, wherein the net throughput of dialysate and/or substitute is minimized by some of the diafiltrate being regenerated by an internal regeneration cycle (RKL) which is able to deplete substrates or products (substance group Y) of the substance group X in the biological liquid compartment.

Description:
FIELD OF THE INVENTION 
     The present invention describes a method and a device for limiting Diafiltrate waste by partial regeneration using adsorbents. 
     BACKGROUND OF THE INVENTION 
     The use of sterile packed hemofiltration substitute solutions represents the largest single cost factor in continuous diafiltration treatment processes. While recent data suggests an improved outcome with higher diafiltrate flow, this might increase process costs. 
     Specific terms used in the description of the present invention are defined below: 
     Complex biological fluid compartment (A) is comprised of one or more communicating fluid compartments. Concentrations of chemicals or biochemicals are influenced by formation, distribution, transformation and elimination. Those processes can vary between a biochemical X or Y. 
     An example of a complex biological fluid compartment are bioreactors with active components, for example liver cells that transform or metabolize toxins. In this case, the reactor medium fluid chamber would be one compartment and the interior of the liver cells a second compartment, both communicating via the cell membrane. Enzymatic processes inside the cell, and transport processes of substances through the cell membrane will affect concentrations of the substances in the reactor medium fluid chamber. Another example of a complex biological fluid compartment (A) is mammal, such as human, blood. 
     Membrane dialysis/filtration: a combined procedure for monitoring the concentration of substances in a complex biological fluid compartment (A). It is conducted by conducting fluid (A), which is filled with undesired substances along a flow path including a porous membrane which separates (A) from a rinsing side (B) which contains a rinsing fluid and does NOT contain the undesired substances. In the case of dialysis, if the molecular size of the undesired substances are small enough to pass through the pores of the porous membrane then the undesired substances will follow the concentration gradient from (A) to (B), thereby passing to the rinsing side. This process can be supported by a convective transport. In this case, a liquid flow (crossflow) from A to B is applied by a pressure gradient. The substances are then also transported by convection through the membrane, wherein the fluid leaving compartment (A) by filtration (i.e., the filtrate) can be replaced completely or in part by a substitution solution, i.e., substitution fluid (substitute). A combination of dialysis and filtration can occur but in extreme cases can also be applied as only filtration or only dialysis. 
     Rinsing compartment (B): the compartment that is separated from the complex biological fluid compartment (A) by a separating device, which can be a membrane. rinsing compartment (B) is filled with dialysate, filtrate, or both. 
     Dialysate is the fluid described above in the definition of “membrane dialysis/filtration”, present in in the rinsing compartment (B) and can take up the undesired substances by concentration gradient. 
     Substitute fluid is the fluid described above in the definition of “membrane dialysis/filtration” which is supplied to compartment (A) as replacement fluid in a filtration process. 
     Diafiltrate is the fluid described above in the definition of “membrane dialysis/filtration” that is present in the rinsing compartment (B) that has absorbed undesired molecules by diffusion and or convection in the process of cleaning the fluid on the (A) side and is thus enriched with undesired molecules. 
     Net throughput of dialysate/substitute fluid: the diafiltrate that is removed from the process after a single passage along the membrane filter, thereby not entering the cleaning regeneration cycle (RGC) that is re-supplied to the diafiltrate. 
     The regeneration cycle (RGC): The regeneration cycle is a device that removes the hereinafter described substance Y out of the diafiltrate, but not the hereinafter described substance X, by means of filtration, adsorption, or biological treatment processes. 
     Substance group X: one or a plurality of disease-causing substances (undesired molecules), which cannot be eliminated directly by the regeneration cycle (RGC) because known technologies do not provide retention or adsorption capacity for a substance from substance group X. A substance from substance group X can pass the separating device/membrane from (A) to (B) by dialysis or filtration due to pore size and molecular weight range. 
     Substance X: one or a plurality of substances from substance group X. 
     Substance group Y: one or a plurality of substances that can be depleted by the regeneration cycle (RGC), because it has retention/adsorption capacity for Y. 
     Substance Y: one or a plurality of substances from substance group Y. 
     The cleaning procedure of complex biological fluid compartments systems such as bioreactor fluids or blood by membrane dialysis/filtration today often involves unnecessarily high consumption of dialysate or substitute fluid, as their flow rate needs to be adjusted/increased to the point that the concentration of fast generated undesired toxins can be controlled. 
     In complex biological fluid compartments, such as in bioreactors for the cultivation of liver cells, this may for example be urea, formed by the Krebs cycle. Urea could be removed from the reactor medium by diafiltration. Also urea accumulates in the bloodstream of patients with kidney damage. 
     Particularly in the critical care applications of diafiltration, this leads to an often unnecessary consumption of cost intensive sterile prepackaged dialysate and substitute solutions. 
     Treatment time is adjusted according to the removal of the undesired substance under a given dialysate/filtrate flow. If the removal rate is low due to low flow rates, treatment time must be extended. This may result in prolonged anticoagulation (eg, heparin or citrate), which can have side effects) (e.g., bleeding or alkalosis and hypernatremia). 
     Extracorporeal blood purification by diafiltration is based on the diffusive (dialysis) and/or convective (diafiltration) transport of permeable molecules from the blood or plasma through a porous membrane into a rinsing solution compartment. 
     In the case of dialysis and filtration, the rinsing solution should be free of unwanted and undesired substances or toxins. The rinsing solution would be used as a substitute fluid during filtration or as a dialysate in case of dialysis. On the other hand, valuable substances should not be transferred from the biological fluid to the dialysate or filtrate. For example, in the case of blood, glucose is a valuable component that should not be transferred, which can be achieved by maintaining the valuable components at the same concentration in the rinsing solution. In this widely used approach, dialysis fluids are usually mixed from concentrates and reverse osmosis water lines. It needs a complex technology (water treatment systems, dialysis machines). Because of the high technological complexity, trained technicians and dialysis nurses knowledgeable in the logistics of water flow are needed. 
     Alternative known prior art includes systems with a closed dialysate circuit without continuous flow of dialysate and/or substitute fluid. 
     In the BioLogic DT system a small closed dialysate reservoir is recycled. The reservoir is regenerated by a suspension of ion exchange resins and a relatively fine-pored charcoal. It is used with no steady dialysate flow which makes for the depletion of dialyzable, but non-absorbed substances. Although the system saves the dialysate, it has not been particularly useful for monitoring the urea and ammonia levels. 
     In the REDY system, a small closed set dialysate reservoir is regenerated in a recirculation system. The reservoir is regenerated through a complex process that includes charcoal but also requires the decomposition of urea in toxic ammonia by an enzyme (urease) which is secondarily adsorbed chemically by zirconium phosphate. 
     Because the system saves dialysate due to production of ammonia by the urease it makes an effective removal of ammonia from the patient&#39;s blood impossible. 
     Also, no continuous dialysate flow is used, which would allow the depletion of non adsorbed unwanted substances from blood. It should be noted that many of the undesirable substances in complex biological fluids are not yet known. 
     In the REDY system, where there is a 100 percent recovery of dialysate or substitute, there is a risk of accumulation of unwanted non-adsorbed substances in the regeneration cycle which compromises the effective cleaning process by dialysis. 
     In the Genius System, a large volume dialysate reservoir is used. Detoxification utilizes an extremely high volume of dialysate (up to 80 liters). No adsorbents are used. If the concentration is increased in the dialysate to the blood level the system stops working and must be changed. 
     Combined dialysis and adsorption (e.g. by Renaltech are presented in series and in direct contact with blood, and therefore are less biocompatible and the two mechanisms are not independently adjustable. These adsorbents in direct contact with blood are used to remove non dialyzable substances by adsorption from the blood. 
     Methods in which adsorbents are used in conjunction with a plasmapheresis filter (plasmapheresis, Prometheus) allow, usually no high trans membrane flows and include risk of loss of important proteins or other valuable materials to the adsorbents. 
     The MARS procedure (EP 0615780 B1) combines the removal of water-soluble and protein-bound substances. Its uniqueness is that the biological compartment (A), mostly blood, passes through a protein impermeable (blood) side of an asymmetric dialysis membrane, which is coated with proteins that have a bond with toxins with high protein, affinity. On the opposite side of the Dialyzer there is dialysis fluid that contains a dissolved protein with binding capacity for protein bound toxins. Those proteins enter the dialysis membrane fiber which has larger pores on the outside, allowing those proteins entering and diffusing close to the inner side where smaller pores prevent them from entering the blood. This enables passage of albumin bound and small water soluble molecules. 
     Since these proteins are expensive, the protein-containing dialysate is regenerated by sequential dialysis, followed by serial adsorption by two sorbents. The effect is that albumin bound toxins are finally bound by the sorbents. A differentiated regeneration of the dialysate in the interest of saving the dialysate does not occur. On the contrary, dialysis efficacy is reduced by applying a secondary dialyzer circuit to remove diffusible substances. In published clinical trials (Heemann et al. Hepatology 2002) supporting clinical efficacy, dialysate flow rates of 500 ml/min had been applied in the secondary dialysate circuit. 
     SUMMARY OF THE INVENTION 
     An object of the invention is to reduce the net flow (volume/time) of dialysate/substitute rinsing fluids in the depletion of substance X by a regeneration cycle that removes substance Y that are either precursors or metabolites of substance X in the complex biological fluid compartment (A). This is achieved by recycling part of the Diafiltrate via Adsorption-/Filtration (in an RGC). By doing this the net flow rate of the dialysate or filtrate that is flowing into waste bags or drains is minimized, while the concentration of selected markers of substance X in the complex biological fluid compartment does not exceed the targeted values. 
     The object of the invention is also to possibly control the concentration of substance X by hemodialysis and/or hemofiltration more effectively and aiming at lower concentrations of substance X in the biological system without having to increase the diafiltrate flow. Again, this is done by partial recirculation of used diafiltrate and reduction of substance Y in the regeneration cycle (RGC), so that the net throughput of Diafiltrate remains economically and logistically reasonable. 
     The present invention describes a method and a device for limiting Diafiltrate waste by partial regeneration using adsorbents. 
     According to the invention, the object is achieved by the fact that the regeneration cycle (RGC) is based on adsorption and/or filtration properties that remove substance Y from used diafiltrate, reduce the concentration of substance X in complex biological fluid compartments (A) indirectly due to reduced formation or increased metabolism of substance X, even if substance X is not directly removed by the regeneration cycle. This is possible because molecules of substance Y represent either a source/inducer or a metabolite in the degradation of substance X in the framework of metabolic processes in complex biological fluid compartments (A), hence resulting in their reduction in (A). 
     It was surprisingly observed that urea can be controlled and reduced in such complex biological fluids by partial regeneration of the dialysate through adsorption and/or filtration units to remove metabolites and precursors of urea, but not urea itself. 
     The advantages of the invention is a better control of concentrations of substance X in complex biological fluid compartments at the lowest possible net loss of sterile dialysate. 
     The process disclosed herein not only significantly reduces the costs of treatment, but also the logistics of transporting dialysate (typically 4.5 l delivered in heavy bags) will be reduced. 
     One of the biggest advantages of the invention, however, is the sustainability of intermittent diafiltration treatments. By eliminating substance Y, the reproduction of substance X is delayed or the degradation of substance X is enhanced. 
    
    
     
       BRIEF DESCRIPTION OF FIGURES 
       The invention will be explained in more detail through reference to following figures. 
         FIG. 1 a    depicts urea kinetics with and without employing the regeneration cycle shown in the process depicted in  FIG. 3 ;  FIG. 1 b    depicts glutamine clearance at normal CVVHD with and without the regeneration cycle shown in the process depicted in  FIG. 3 ; 
         FIG. 2  shows the course of ammonia, in μmol/l, over time (i.e., concentration of ammonia over time, in plasma as a complex biological fluid compartment during standard dialysis with and without the regeneration cycle depicted in  FIG. 3 ; 
         FIG. 3  shows a process diagram of a dialysis process having a regeneration cycle (RGC), 
         FIGS. 4 a  and 4 b    show a circuit diagram for a filtration process where part of the filtrate is recycled in a regeneration cycle (RGC). The substitute flow can either be in the form of “postdilution” i.e. behind the filter ( FIG. 4 a   ) or as “predilution” i.e. before the filter ( FIG. 4 b   ). 
         FIG. 5  shows a circuit diagram for a combined dialysis and filtration (diafiltration) with substitution, with both parts of the dialysate as well as the substitute flow comprising filtrate regenerated by regeneration cycle. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     EXAMPLE 1 
     Urea as Substance X; Glutamine and/or Ammonia as Substance Y 
       FIG. 3  depicts a flow diagram for a process for carrying out the present invention. The process employs an activated carbon adsorber not having adsorption capacity for urea. A portion of the sterile bicarbonate dialysis fluid (flow 150 ml/min) is recycled during a CVVHD treatment mode with slow blood flow (150 ml/min)), and moderate net diafiltrate flow (50 ml/min)) and thus lower urea clearance (50 ml/min) based on dialyzer blood and dialysis flow. Despite the short treatment time (&lt;8 h) in patients with acute renal failure with a weight of 60 kg, which stands for a Kt/V ratio (clearance times time, divided by body volume) of only 0.48 (which should normally have been maintained above 1) over a treatment period of 3 days, there was an effective reduction of urea with later onset, but continuing after the end of treatment. However, when the same parameters for dialysate flow, blood flow, same dialyzer and treatment time where used in CVVHD not having a regeneration cycle in patients of the same weight and comparable renal dysfunction, a significant increase of the urea concentration was observed ( FIG. 1 a   ). 
     Potential co-variates of urea kinetic, such as endogenous formation by catabolism or renal urea clearance as the cause for this surprising observation were also comparable and could be ruled out. 
     In a more detailed investigation of the phenomenon it was found that the internal recycling of the sterile bicarbonate dialysis solution did not lead to direct removal of urea as a target substance, as the activated carbon used in the process has no urea binding capacity. However, it was found that in the partial recycling mode, the glutamine clearance over the dialyzer was significantly higher, indicating glutamine adsorption ( FIG. 1 b   ) for the process employing the regeneration circuit as opposed to conventional CVVHD, although in both cases the net flow rate of bicarbonate-based diafiltrate was identical. 
     In more extensive studies it was shown that good binding capacity for glutamine was enhanced by a microstructure design that targets control of perfusion channels of a charcoal stationary bed adsorbent between 10 nanometers to 100 micrometers. This resulted in complete removal (100%) of glutamine in a single passage which maximized the concentration gradient for glutamine over the membrane despite low net flow of dialysate. In contrast to such stationary bed adsorbent concepts, in the BioLogic DT System adsorbent is arranged as “fluid bed” adsorbents in the dialysate, leading to a significant increase in the diffusion distances between the individual adsorbent particles. Therefore, in BioLogic DT the glutamine clearance is significantly limited due to a higher concentration gradient for glutamine across the membrane. In the present invention though, a partial recycling of diafiltrate using a regeneration circuit based on charcoal with 10 nm to 100 micrometers leads to an effective removal of nitrogen sources which will result in an additional reduction of urea formation. 
     A special adsorbent can be used either in addition to or in combination with a charcoal filter to remove ammonia, which is a source of nitrogen and thus facilitates control of the urea concentration in complex biological systems. 
     EXAMPLE 2 
     Ammonia as Substance X; Glutamine as Substance Y 
     According to the state of the art, ammonia is effectively removed from complex biological compartments by dialysis when it is set at minimum flow of about 200 ml/min and a dialysate flow of over 500 ml/min at a membrane surface area of 1.3 m (Cordoba et al. 1996). 
     It has been shown that by using an internal regeneration cycle (RCG) based on activated carbon, an effective decrease of the ammonia occurs, even at considerably lower net flow rate of the dialysate, below 500 ml/min from complex biological systems, which is based on a selective elimination of glutamine related to glutamate concentrations. This again can increase the glutamate/glutamine ratio which is a therapeutic goal. 
     This was carried out in an in vitro set up completing the following experiments: 
     Following the model described by Cordoba for building complex biological fluid compartments, a patient model was established by treating each with one liter of plasma in experiments A, B and C and one liter of 5% human albumin solution in experiment D with an initial level of 53 mg of ammonia. The redistribution from the tissue was simulated, by continuous infusion of a solution with 1350 mg/l of ammonia into the patient model. Ammonia concentration in the blood was measured at a rate of 90 ml/min. Experiment D was performed with albumin as a patient model in order to demonstrate that the absence of enzymes in albumin that are present in plasma in trace amounts (eg gamma-glutamyl transferasis-GGT) could provide different kinetics for processing ammonia in the patient undergoing treatment. 
     In experiment B the patient model was dialyzed with a 1.7 sq. ft. standard dialyzer (patient side flow rate 250 ml/min, net dialysis flow 50 ml min). In experiment C, under otherwise identical conditions, a regeneration cycle having a charcoal filter at 250 ml/min was incorporated. Experiment A was conducted without active detoxification (primary dialysate not activated) in order to document the natural accumulation of toxins in the patient&#39;s medium, if no detoxification were to occur. The concentration profile of ammonia in the patient model in A, B, C and D was determined at the beginning and after 10, 20, 30, 45, 60, 90 and 120 minutes. In addition, over the same period, ammonia samples were taken before and after the dialyzer in order to detect ammonia clearance according to the formula:
 
Clearance=(Patient)blood flow×((Inlet concentration minus outlet concentration)/inlet concentration).
 
     Concentration changes of ammonia in the patients accounted for the metabolizing of glutamine, ammonia, and ammonia clearance. In addition, ammonia was measured in experiment C before and after the charcoal filter. Patient concentrations of ammonia over time are shown in  FIG. 2  for experiments A through D. Compared to a normal dialysis process (represented by B) the presence of a charcoal filter as a RGC can significantly stop ammonia increase (p=0.036, paired Wilcoxon test), as shown in experiment C. However, by detecting the clearance data over the dialyzer it becomes evident that this was not related to dialyzer ammonia clearance, since even though the clearance was not higher, the ammonia reduction was even better (lower increase profile). In addition the ammonia increase in the dialysis model of albumin solutions D was moderate compared to B. 
     The ammonia tests of experiments B, C and D are shown in  FIG. 2 . The ammonia increase in control experiment A is only shown over 30 minutes due to axis limit. 
     The tests demonstrate that plasma as a complex biological fluid is influenced by active biochemistry induced by ammonia (substance X) generation e.g. due to gamma glutamyl transferase activity and that can be prevented by substrate reduction (Glutamine, a substance Y in this case). 
     EXAMPLE 3 
     Substance X: Nitric Oxide: Substance Y: Arginine 
     Nitric oxide is a short-lived radical which is not considered to be removable by extracorporeal therapies. 
     Including a regeneration circuit (RCG) according to the invention in a CVVHD device which allows improved depletion of arginine by microstructured adsorbents enables control of plasmatic NO levels in plasma. 
     A CVVHD therapy device with an effective blood flow of 120 ml/min and a dialysate flow of 40 ml/min was equipped according to the invention with a regeneration circuit (RGC) of 100 ml/min with a microstructured charcoal adsorbent (perfusion channel with at maximum 100 μm). For control, a comparable CVVHD was done without RGC. 
     With RGC included, the nitrate/nitrite level as an indicator for NO in plasma was decreased from 112 to 26 μmol/l within 24 hours, and from 108 to 24 μmol/l in 16 h. With standard CVVH, the NO level increased from 24 to 125 μmol/l within 48 hours. While the dialysis of NO itself is not measurable, Arginine clearance in the regeneration circuit is 72+25 ml/min while standard CVVHD delivers 36+3 ml/min (p&lt;0.05). 
     EXAMPLE 4 
     Substance X TNF alpha; Substance Y: IL1 
     During CVVHF the course of TNF alpha and IL 1 beta was compared between a device that provided a RGC and an otherwise identical device that did not. Blood flow was 150 ml/min, and substitute/filtrate flow during CVVHF was 2.5 l/hour. A highly permeable F50 (Fresenius) filter was used. The regenerated flow in the RGC device was 150 ml/min. All other parameters were identical. IL1 beta and TNF alpha in blood were measured before and after. In addition, the filtration of TNF alpha into the filtrate is measured. 
     The device having a recirculation mode reached a reduction of TNF alpha in the blood from 150+90 to 100+40 pg/ml (p&lt;0.05 in a paired t-test), whereas standard CVVHF did not result into a significant reduction. Also, the recirculation mode reached a significant reduction of IL1 beta from 9+7 to 6+6 pg/ml (p&lt;0.05 in the paired t-test). The device representing a standard CVVHF process failed to attain a reduction of statistical significance. 
       FIGS. 3 to 5  depict flow diagrams for alternative processes employed in the present invention, specifically, a dialysis process ( FIG. 3 ), a filtration process ( FIGS. 4 a  and 4 b   ), and a diafiltration process ( FIG. 5 ).  FIG. 3  presents a scheme for dialysis having a regeneration circuit. Complex biological fluid compartment A (e.g. blood) is connected via tubes on to an entrance provided on a first side of a separation apparatus provided with a membrane filter. The filter preferably has a pore size in the range between 5,000 Dalton and 500,000 Dalton. Dialysate fluid circulates in the apparatus on a second side of the filter, relative to the first filter side on which the blood flows. Depending on the balancing features of the device, a balanced ultrafiltration is possible (convective by a net stream through the membrane into the dialysate). The diafiltrate splits in two streams after exiting the filter. One stream, the net diafiltrate stream, is discarded as waste and the other stream enters a regeneration circuit (RGC) provided with a substance Y removing component, forming a regenerate stream. With this arrangement, substance Y is retained by the substance Y removing component, but not substance X, and the regenerate stream is replenished with fresh, i.e., net dialysate, which enters the separation apparatus on the second side. The net-diafiltrate stream including substance X is discarded. 
       FIGS. 4 a  and 4 b    depict filtration arrangements in which fluid substitution occurs after dilution of the biological fluid, which occurs in the course of filtration ( FIG. 4 a   ), or fluid substitution occurs before dilution ( FIG. 4 b   ). A complex biological fluid compartment A (i.e., blood) is connected by tubes to a the first side of a separation apparatus provided with a membrane filter having a pore size in the range set forth above in the description of  FIG. 3 . Depending on the balancing features of the machine used, a filtrate comprising substance X, substance Y, and a fluid, all of which pass through the membrane from the blood, is generated in the filtrate compartment on a second side of the membrane filter. Depending on the balance desired, replacement fluid (i.e., substitute fluid) is added to biological compartment A either after dilution (i.e., after filtration  FIG. 4 a   ) or before dilution (i.e., before filtration  FIG. 4 b   ). The filtrate splits in two streams after exiting the filter. One stream, that is the net diafiltrate stream, is discarded and the other stream enters a regeneration circuit (RGC) provided with a substance Y removing component, forming the regenerate stream. With this arrangement, substance Y is retained in the regeneration circuit, but not substance X. Further, the regenerate stream is replenished with net substitute fluid. The net-diafiltrate stream including substance X is discarded. 
       FIG. 5  depicts a dialysis and filtration (i.e., diafiltration) arrangement employing dialysis fluid and a substitute fluid in which a portion of the regenerated fluid is combined with fresh dialysate fluid and a portion of the regenerated fluid is combined with substitute fluid. A complex biological fluid compartment A (i.e., blood) is connected by tubes to a an apparatus having a membrane filter provided with a pore size in the range set forth above in the description of  FIG. 3 . The complex biological fluid compartment A flows in the apparatus on one side of the membrane filter. Dialysate fluid circulates on a second side of the membrane filter. Depending on the balancing features of the device, an additional filtration is also possible, with convective stream through the membrane into the diafiltrate compartment. Fluid loss in the biological fluid compartment A is partially or totally replaced with substitute fluid. The diafiltrate is split into two streams after exiting the apparatus. One stream, a/k/a the net diafilatrate steam, is discarded as waste and the other stream enters a regeneration circuit (RGC), forming the regenerate stream. In this arrangement, substance Y is retained in the regeneration circuit by a substance Y removing component present in the regeneration circuit, but not substance X. A portion of the regenerate stream exiting the regeneration circuit is combined with net dialysate, that is, fresh dialysate fluid, which enters the second side of the separation apparatus, and a portion of the regenerate stream is combined with the net substitute fluid, which in turn is combined with the filtered blood at a predetermined location, which could be pre-filtration, post-filtration, or on the blood flow side of the separation apparatus. The net-diafiltrate stream transports substance X as waste. Also, combinations of  FIGS. 3 and 4  are possible. 
     The regeneration circuit includes filters made, but not exclusively, of polysulfone, polyamide, polymethylmethacrylate, polyacrylnitrile. In a procedure to reduce waste of dialysate and or substitution fluids by differenciated control of disease related concentration deviations of metabolites belonging to a group X and Y in a complex biological fluid compartment by membrane dialysis/filtration against or into a cleaning/rinsing solution compartment, in some embodiments the net flow for dialysate and or substitute is less than 500 ml/min. In other embodiments the net flow for dialysate and or substitute is less than 300 ml/min. In other embodiments the net flow for dialysate and/or substitute is less than 100 ml/min. In some embodiments the flow of the internal regeneration circuit is greater than 5 ml/min. In other embodiments, the flow of the internal regeneration circuit is greater than 50 ml/min. In other embodiments, the flow of the internal regeneration circuit is greater than 100 ml/min.