CROSS-REFERENCE TO RELATED APPLICATION  
       [0001]     This patent application is a continuation-in-part of U.S. patent application Ser. No. 10/181,138, filed Jul. 9, 2002, which claims the priority to PCT Application No. PCT/US01/01023, filed on Jan. 11, 2001, which claims the benefit of U.S. provisional patent application No. 60/175,578, filed in the U.S. Patent and Trademark Office on Jan. 11, 2000, all of which are incorporated herein by reference in their entireties. 
     
    
     TECHNICAL FIELD  
       [0002]     This invention relates to dialysis and hemodiafiltration in general and, more particularly, to improved hemodiafiltration methods and devices for removal of blood toxins.  
       BACKGROUND  
       [0003]     Hemodialysis and Hemodiafiltration are well known methods for removing toxic substances from a patient&#39;s blood, thereby reducing the level of toxins in the patient&#39;s blood as part of an extracorporeal blood cleansing system. Both these methods are based on flowing blood through a cartridge containing a semi-permeable membrane which separates the cartridge into two compartments. In general, hemodialysis is a process whereby blood flows through a blood-side compartment of the cartridge, while a cleansing solution, i.e., a dialysate solution, flows through a dialysate-side compartment of the cartridge. Toxins are removed from the blood by diffusion across the semi-permeable membrane from the blood-side compartment to the dialysate-side compartment. The rate of diffusion is determined by the concentration gradient established between a higher concentration of toxins in the blood relative to the dialysate fluid. Hemodiafiltration is process whereby the normal removal of toxins by diffusion is augmented by a convective flow of plasma water across the semi-permeable membrane which assists in carrying toxins by bulk flow of fluid from the bloodside of the membrane to the dialysate side of the membrane. The transportation of plasma water across the semi-permeable membrane is achieved by establishing a pressure gradient, generally referred to as Transmembrane Pressure (TMP), across the membrane. In hemodiafiltration, an equivalent amount of a substitution fluid, or replacement fluid, must be added to the blood to replace the plasma water that is filtered across the membrane. This substitution fluid is generally added either before the blood enters the cartridge (pre-dilution mode) or after the blood exits the cartridge (post-dilution mode).  
         [0004]     Hemodiafiltration systems using two cartridges connected in series are also known in the art. In such systems, a first cartridge is used as a conventional diafiltration cartridge providing simultaneous diffusion and filtration of plasma water across the semi-permeable membrane. In a second cartridge, toxins are diffused from the blood to the dialysate fluid, and a reverse pressure gradient is used to reverse-filter dialysate fluid from the dialysate-side compartment, across the membrane, and into the blood-side compartment. The reverse-filtered dialysate fluid serves as a substitution fluid to replace the amount of plasma water that is filtered from the blood-side compartment to the dialysate-side compartment in the first cartridge. Such a method is described in J. H. Miller et al., “Technical Aspects of High-Flux Hemodiafiltration for Adequate Short (Under 2 Hours) Treatment,” Transactions of American Society of Artificial Internal Organs (1984), pp. 377-380.  
       SUMMARY  
       [0005]     Certain hemodialysis/diafiltration applications use two cartridges connected in series. The dialysate fluid in the first cartridge is made hypertonic or hypotonic (by adjusting the electrolyte levels of the dialysate stream) to improve toxin removal efficiency. This method is disclosed in PCT Application No. PCT/US99/25804 entitled “Non-Isosmotic Diafiltration System” filed in the name of Collins et al., the entirety of which is hereby incorporated by reference.  
         [0006]     One embodiment of the present invention includes a method whereby hydrogen ion concentration (or pH) of the dialysate fluid entering a first filtration cartridge is decreased by introducing a secondary strong base or a salt of a weak acid. The second filtration cartridge then serves to correct for blood pH shifts occurring in the first filtration cartridge. One advantage of this method is that it allows one to carry out the diffusion and/or diafiltration process in the first cartridge outside the normal limit of blood pH. This method improves the removal of certain substances, such as protein-bound substances that disassociate more readily from proteins at high pH. This method also allows for enhanced removal of other substances that may be affected by changes in the number of charged polar groups (acidic or basic) and/or structural changes of blood proteins (i.e., those proteins circulating in the blood stream or those protein that accumulate and/or adsorb near the semi-permeable membrane) due to changes in pH.  
         [0007]     It is a further object of the invention to provide hemodialysis or hemodiafiltration method using two cartridges (or two stages), preferably in series, that improves clearance of certain substances by introducing a basic solution into the dialysate fluid stream of the first cartridge. The process is such that blood in the first cartridge is dialyzed or diafiltered against a high pH dialysate solution, while blood in the second cartridge is dialyzed or diafiltered against a standard dialysate (i.e., within a pH range from 7.0 to 7.8). The second cartridge then may serve three main functions which are 1) to correct for blood pH shifts caused by the high pH dialysate in the first cartridge, 2) to continue to remove blood toxins by diffusion or diafiltration against standard dialysate, and 3) to correct for electrolyte imbalances in the blood. In a hemodialysis application, correction of blood pH and electrolyte imbalance is accomplished by diffusion of substances across the semi-permeable membrane separating the blood and dialysate compartments of the second cartridge. For example, neutralizing substances present in the dialysate (such as citric acid) may diffuse into the blood compartment while various electrolytes (such as hydroxyl or bicarbonate ions) diffuse out of the blood and into the dialysate compartment. In a hemodiafiltration application, these corrections are accomplished by introducing a substitution fluid containing neutralizing substances (such as citric acid) and electrolytes into the blood stream in addition to diffusion of these substances across the semi-permeable membrane of the second cartridge.  
         [0008]     The present invention may be embodied in an improved dialysis machine that allows for the addition of a secondary basic solution into the dialysate fluid path. The machine may include other basic components used in current dialysis machines, such as a water preparation module to degas and heat water necessary for preparing dialysate, an ultrafiltration control system which may include a flow balancing system and an ultrafiltration (UF) pump, a dialysate proportioning system which may introduce dialysate concentrates into the water stream, and extracorporeal monitoring and control components which may include a blood pump for circulating blood through the extracorporeal circuit.  
         [0009]     When performing hemodiafiltration, a system of the present invention may include a substitution fluid system (including pump and substitution fluid filters when preparing a substitution fluid on-line using dialysate fluid), and an interdialysate flow control system (which may include an interdialysate pump) to regulate the relative ultrafiltration rates of the two dialyzer cartridges.  
         [0010]     In a preferred embodiment, blood to be cleansed flows into a first dialyzer or hemodiafilter cartridge. The cartridge contains a semi-permeable membrane that separates the cartridge into two compartments, a first compartment containing the blood to be cleansed, and a second compartment containing a dialysate fluid. The pH of the dialysate fluid in this compartment is increased above that of standard dialysate (i.e., pH&gt;7.8) by addition of a stream of a strong base or a solution formed from a salt of a weak acid before the dialysate is delivered to this first dialyzer cartridge. The effect of this is to increase the pH of the blood in order to enhance removal of certain substances. These substances might include protein-bound substances that may dissociate at higher pH conditions or other substances that may be affected by changes in the number of charged polar groups (acidic or basic) of proteins in the blood stream.  
         [0011]     As blood flows through the blood compartment of the first dialyzer cartridge, in addition to the pH of the blood being increased, toxins are removed by diffusion resulting from a concentration gradient between the blood and the dialysate fluid. Also, electrolytes may be imbalanced depending on the amount of dilution or concentration that may or may not occur as a result of adding the basic stream to the dialysate fluid. In performing hemodiafiltration, an additional removal of toxins may occur by convection as a portion of plasma water from the blood compartment is filtered across the semi-permeable membrane and into the dialysate compartment.  
         [0012]     Upon exiting the first dialyzer cartridge, the partially dialyzed/hemodiafiltered blood may be mixed with a substitution fluid. The substitution fluid helps correct the pH shift and electrolyte imbalance resulting from the first cartridge process since the substitution fluid contains proper electrolyte levels that restore the buffering capacity of the blood. In addition, the substitution fluid may contain neutralizing agents, such as a citric acid, to reduce the blood pH.  
         [0013]     The blood then enters a second dialyzer cartridge. In this second cartridge, the blood is dialyzed (or hemodiafiltered) against a standard dialysate containing electrolytes within their normal ranges. Blood toxins continue to move across the semi-permeable membrane into the dialysate fluid by diffusion (and perhaps by convection), while electrolytes and neutralizing agents from the dialysate may move across the semi-permeable membrane and into the blood. Upon exiting the second cartridge, the blood pH and composition of electrolytes are within normal ranges.  
         [0014]     Dialysate fluid is prepared by proportioning dialysate concentrates with a treated water as is known in the art. The dialysate may include citric acid as an ingredient. Flow of the dialysate fluid into and out of the dialyzer cartridges is controlled precisely using a flow balance system that is known in the art. In treating a patient according to the present invention, the device typically must remove a portion of plasma water in order to maintain the patient&#39;s dry weight. This can be done using an ultrafiltration pump as is known in the art. When performing hemodiafiltration, substitution fluid may be generated on line using a portion of the fresh dialysate fluid by filtering it through at least one sterilizing filter or substitution fluid filter.  
         [0015]     Fresh dialysate enters into the dialysate inlet of the second cartridge, where it may flow countercurrent to the blood flow. As the dialysate fluid traverses the cartridge, toxins and ultrafiltered plasma water from the blood begin to accumulate in the dialysate fluid. Some electrolytes may be gained in dialysate as they move from a higher concentration in the blood to the lower concentration in the dialysate. Some electrolytes and neutralizing agents from the dialysate may be depleted from the dialysate fluid as they move from the higher concentration in the dialysate to the lower concentration in the blood.  
         [0016]     The partially spent dialysate fluid exiting the dialysate outlet of the second cartridge is mixed in a mixing chamber with a metered portion of a basic solution (preferably a strong base solution or a solution of a salt of a weak acid) to raise the dialysate pH to above 7.8. In one embodiment, the basic solution source is a solution obtained by flowing a portion of treated water through a closed container containing a concentrated solution of a strong base or the powdered form of a dry salt of a weak acid. In a second embodiment, the basic solution is introduced from an externally supplied container using a pump. The mixed dialysate stream then flows toward the dialysate inlet of the first cartridge. A regulator which controls the relative amounts of plasma water filtered off in the two cartridges may be used. For example, a servo-controlled interdialysate pump that changes speed based on an algorithm calculated using measured pressure differentials (TMP&#39;s) across the semi-permeable membrane may be used.  
         [0017]     The partially spent basic dialysate fluid then enters the dialysate inlet of the first cartridge. As it flows through the cartridge, blood toxins and filtered plasma water may accumulate in this fluid. The high pH of this dialysate fluid results in an imbalance of hydrogen ions across the membrane such that the pH of the blood may increase above its normal range. The spent dialysate fluid exits the first cartridge and flows back toward the flow balance system where it eventually flows out to the drain.  
         [0018]     It should be apparent to those skilled in the art that this method can be performed with at least two dialyzer cartridges operating in a typical dialysis mode or it can be performed with two high flux dialyzer or hemodiafiltration cartridges in a hemodiafiltration mode. The limiting factor being the ability of the second cartridge to recover from the perturbation caused by the first cartridge. A preferred method includes the hemodiafiltration mode whereby the substitution fluid is introduced into the blood stream between the two cartridges, so as to help restore the blood back to its normal ranges prior to infusion to a patient. 
     
    
     BRIEF DESCRIPTION OF THE PREFERRED EMBODIMENTS  
       [0019]     Further aspects of the instant invention will be more readily appreciated upon review of the detailed description of the preferred embodiments included below when taken in conjunction with the accompanying drawings, of which:  
         [0020]      FIG. 1  is a schematic diagram illustrating a first embodiment of a multistage hemodiafiltration device using an internally supplied basic stream; and  
         [0021]      FIG. 2  is a schematic diagram illustrating a first embodiment of a multistage hemodiafiltration device using an externally supplied basic stream. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0022]     Referring now to  FIGS. 1-2 , wherein similar components of the instant invention are referenced in like manner, a preferred apparatus for ionic enhanced dialysis/hemodiafiltration, and accompanying methods for using the same, are disclosed.  
         [0023]     Turning now to  FIG. 1 , depicted therein is a first embodiment of a hemodialysis/hemodiafiltration device which uses an internally supplied basic solution stream.  
         [0024]     A water source  102  supplies water or other base fluids, such as saline, to system  100  in order to create dialysate, substitution fluids and the like. The water, or other fluid is then provided to a water preparation device  104  which pre-treats the incoming fluid by heating, degassing and/or any other suitable method known to one of ordinary skill in the art.  
         [0025]     The pre-treated fluid is next transported via appropriate tubing or the like to a flow balance system  106  which has an inlet controller  106   a  and outlet controller  106   b , which in turn may continuously monitor and adjust flow rates of fluids entering or exiting the internal components of system  100 . Flow balance system  106  may contain one or more microprocessor controls and the like which are programmed to automatically accomplish this functionality within predefined parameters.  
         [0026]     The pre-treated fluid is transported first to internal components of system  100  through inlet controller  106   a . A portion of the pre-treated fluid equivalent to the net amount of fluid to be removed from the patient may be siphoned through an ultrafiltration pump  108  to a drain  134 . A remaining portion of pre-treatment fluid is next transported via appropriate tubing or the like to an auxiliary pump  110 .  
         [0027]     Pump  110  transports a pre-determined portion of the pre-treated fluid to a closed vessel  112  which may contain a concentrated base (e.g., a strong base, such as sodium hydroxide or the like) or a salt of a weak acid, such as sodium acetate, sodium citrate, or sodium bicarbonate, to form a secondary basic solution for provision to dialyzer cartridge  122 , as described below. Pump  110  may be controlled by, for example, a microprocessor controller which is programmed to accept a predetermined portion of pre-treated fluid for creating the secondary basic solution. Alternatively, the flow through pump  110  may be manually monitored and adjusted as needed.  
         [0028]     The secondary basic solution flows from vessel  112  to a base inlet valve  114 . The base inlet valve may likewise be automatically or manually controlled to allow a predetermined rate of secondary basic solution to flow therethrough. The secondary basic solution then flows to a mixing chamber  116 . The mixing chamber  116  has a second inlet which receives dialysate solution from outlet port  148  of second dialyzer cartridge  138 , described further below. Mixing chamber  116  may be automatically or manually monitored and adjusted to allow a predetermined amount of secondary basic solution to flow to inlet port  120  of first dialyzer cartridge  122  via interdialysate pump  118 .  
         [0029]     A remaining portion of the pre-treated fluid which is not accepted through pump  110  is transported to inlet port  146  of second dialyzer cartridge  138 . The system  100  may be provided with monitoring means for determining the appropriate pH that is required to return blood treated in first dialyzer cartridge  122  to a normal level. Once that level has been determined, the acid pump  154  and/or a bicarbonate pump  156  may be employed to pull additional acid concentrate  150  or bicarbonate concentrate  152  to adjust the pH of the remaining pre-treated fluid prior to providing the fluid to inlet  146 .  
         [0030]     Blood to be cleaned is received from a patient and enters the first dialyzer cartridge  122 . The blood is carried by suitable tubing, as is known in the art, for example, bloodline tubing made from flexible polyvinylchloride (PVC). The flow rate of incoming blood is generally in the range of 100 to 600 ml/min, preferably 200 to 500 ml/min. First dialyzer cartridge  122  contains a semi-permeable membrane  124  that divides the dialyzer cartridge  122  into a bloodside compartment  126  and a dialysate compartment  128 . As blood passes through blood compartment  126 , plasma water containing blood substances is filtered across semi-permeable membrane  124 . At the same time, basic dialysate received from dialysate port  120  flows through dialysate compartment  128  in a direction counter to the blood flow. Hydroxyl ions (or a corresponding conjugate base resulting from dissolving the salt of the weak acid in water) are transferred from the dialysate compartment into the blood, thereby increasing the pH of the blood as it passes through the blood compartment. Blood substances and toxins are transferred across semi-permeable membrane  124  by diffusion due to a difference in concentration between the blood in blood compartment  126  and the basic dialysate in dialysate compartment  128 . The higher blood pH helps to dissociate protein-bound toxins from various blood proteins (such as albumin). Upon dissociation from the protein, these free toxins are more readily able to move across the semi-permeable membrane and into the dialysate compartment. The basic dialysate containing blood substances and toxins removed from the blood are transported to drain  134  via dialysate pump  132  and outlet controller  106   b.    
         [0031]     The partially dialyzed blood then exits first dialyzer cartridge  122  through conduit  136 . The blood then flows through conduit  136  and enters bloodside compartment  142  of second dialyzer cartridge  138 . The second dialyzer cartridge preferably contains a semi-permeable membrane  140  which divides the second dialyzer cartridge  138  into a bloodside compartment  142  and a dialysate compartment  144 . As the blood passes through bloodside compartment  142 , blood toxins are further removed from the blood as they diffuse across the semi-permeable membrane into the dialyste compartment which contains a lower concentration of toxins. In addition, the pH of the blood passing through the bloodside compartment is returned to a normal pH level due to the differences in concentration between the high pH blood in bloodside compartment  142  and the lower pH dialysate in dialysate compartment  144  as received through inlet port  146 . Transfer by diffusion across the semi-permeable membrane of various electrolytes and neutralizing agents may occur in both directions as different concentrations can exist in the bloodside compartment relative to the dialysate side compartment. For example, hydroxyl ions or ions of the conjugate base that are present in the higher pH blood will diffuse across the semi-permeable membrane into the lower pH dialysate, while neutralizing agents present in the dialysate compartment, such as citric acid used in the manufacture of Citrasate by Advanced Renal Technologies, Bellevue, Wash., may diffuse from the dialysate compartment into the bloodside compartment. Cleansed blood then exits the second dialyzer cartridge  138  and is recycled to the patient (not shown) through suitable tubing, for example, bloodline PVC tubing, as is known in the art. The dialysate exits the dialysate compartment  144  of second dialyzer cartridge  138  through outlet port  148  and is provided to mixing chamber  116 , described above.  
         [0032]     The dialyzer cartridges  122 ,  138  may be of any type suitable for hemodialysis, hemodiafiltration, hemofiltration, or hemoconcentration, for example, the Fresenius F60, available from Fresenius Medical Care, Lexington, Mass., the Baxter Conn. 110, available from Baxter Health Care, Deerfield, Ill., the Minntech Hemocor HPH 400, available from Minntech Corporation, Minneapolis, Minn., or the Hospal Filtral 16, available from Hospal A. G., Switzerland. Membranes  124 ,  140  are preferably medium or high flux membranes, for example, the polysulfone, cellulose triacetate or acrylonitrile membranes available from Fresenius Medical Care, Lexington, Mass., Minntech Corporation, Minneapolis, Minn., Baxter Health Care, Deerfield, Ill., or Hospal A. G., Switzerland.  
         [0033]     In an embodiment of the present invention in which hemodiafiltration is desired, the blood may be mixed with sterile substitution fluid between the first and second dialyzer cartridges at inlet  180  of conduit  136  to form a blood/substitution fluid mixture. One way to accomplish this is disclosed in PCT Application No. PCT/US99/17468 entitled “Method for Efficient Hemodiafiltration” filed in the name of Collins et al., the entirety of which is hereby incorporated by reference. Collins et al. uses two cartridges connected in series to perform forward filtration of plasma water from the blood compartment to the dialysate compartment in both cartridges simultaneously. Substitution fluid is added directly into the blood after it exits the first cartridge and before it enters the second cartridge.  
         [0034]     In the present invention, preparation of a sterile substitution fluid may be performed by filtration of a portion of pre-treated dialysate which is received from the inlet controller  106   a  through substitution filter pump  158 . The pre-treated dialysate flows across at least two filter membranes  166 ,  174  with a preferred molecular weight cut-off of not more than 40,000 Daltons. To accomplish this, a portion of the fresh dialysate solution may be split off the dialysate fluid stream at some point prior to entering dialysate compartment  144  of the second dialyzer cartridge  138 . The split-off portion of the dialysate solution may flow through a conduit or the like which leads to a substitution pump  158 . Substitution fluid pump  158  generates the needed pressure to force the fluid down a conduit into inlet ports  162  of first substitution fluid filter cartridge  160 .  
         [0035]     First substitution filter cartridge  160  contains a semi-permeable membrane  166  that separates the filter cartridge  160  into an upstream compartment  164  and a downstream compartment  166 . First upstream compartment  164  has inlet ports  162 . First downstream compartment  168  has one or more outlet ports connected to conduits  170 . The substitution fluid from first downstream compartment  168  then flows into second substitution fluid cartridge  171  containing a semi-permeable membrane  174  which separates the second cartridge  171  into a second upstream compartment  172  and a second downstream compartment  176 . The sterile substitution fluid exits second substitution fluid cartridge  171  through second outlet ports  178  and is mixed with blood exiting first cartridge  122  to form the blood/substitution fluid mixture described above. It should be understood that introduction of the sterile substitution fluid into the high pH blood exiting the first cartridge  122  has the effect of reducing the pH of the blood prior to entering the blood compartment of the second cartridge  142 . This partially due to a simple dilution of the hydroxyl ion or conjugate base concentrations that result by adding substitution fluid containing a lower concentration of these substance. In addition, the sterile substitution fluid may contain neutralizing agents that result in a lowering of pH if for example the substitution fluid is derived from a portion of the dialysate fluid that contains citric acid.  
         [0036]     The pre-treated dialysate not used as substitution fluid enters the second dialyzer cartridge  138  through inlet port  146  of dialysate compartment  144 , and flows counter-parallel to the blood flow as it traverses through bloodside compartment  142 . During diafiltration, excess plasma water filters across semi-permeable membrane  140  and mixes with the dialysate fluid, so as to maintain a patient&#39;s dry weight as the treated blood is infused. The dialysate fluid together with the filtered plasma water exits the second dialyzer cartridge  138  at outlet port  148 , through a tube or conduit which directs the fluid to the mixing chamber  116 , described previously above.  
         [0037]     Referring now to  FIG. 2 , therein is depicted second embodiment of a hemodialysis/hemodiafiltration system  200  which uses an externally supplied basic solution stream. The system  200  functions in a similar manner to system  100  except that basic solution  112   a  may be provided pre-mixed from an external source, and drawn into the mixing chamber  116  by a base pump  113 , rather than being mixed within the machine as in system  100 .  
         [0038]     The hemodialysis/hemodiafiltration methods and devices of present invention described above may be used as an add-on type system in conjunction with an existing ultrafiltration-controlled dialysis machine. However, it should be appreciated that the hemodialysis/hemodiafiltration methods and devices of the present invention can also be embodied in a unitary, stand-alone hemodialysis/hemodiafiltration machine.  
         [0039]     In one embodiment of the present invention, the hemodialysis/hemodiafiltration device includes first and second dialyzer cartridges  122 ,  138 . Alternatively, a single cartridge having at first and second separate dialyzer sections may be used.  
         [0040]     The device may also include at least one sterility filter  160 ,  171 , which may contain semi-permeable membranes. The sterility filter(s)  160 ,  171  are operative to remove bacteria, endotoxins, and other particulate from the dialysate, thereby generating a suitable substitution fluid stream on-line. A sterile/non-pyrogenic substitution fluid for use in conjunction with the present invention may be prepared by drawing a portion of fresh dialysate solution from a dialysate inlet line and pumping it through one or more sterile filter cartridge  160 ,  171 . In a preferred embodiment of the present invention, the sterile filter cartridges  160 ,  171  perform at least a double filtration of the dialysate solution before the solution is introduced into the blood as a substitution fluid. This double filtration can be performed by two separate ultrafiltration filter cartridges or a single cartridge that has multiple sections to perform multiple filtration of the substitution fluid. The use of multiple filtration to generate the on-line substitution fluid makes the system of the present invention safer, should one of the filters fail during treatment.  
         [0041]     During operation of one embodiment of the present invention, blood enters a blood side compartment  126  of a first dialyzer cartridge  122 , whereby a portion of plasma water is filtered across the semi-permeable membrane  124  into the adjacent dialysate compartment  128 . As the blood leaves the first dialyzer cartridge  122 , substitution fluid may be added to the blood at a rate higher than the rate at which blood is filtered out of the first dialyzer cartridge. The diluted blood may then enter the bloodside compartment  142  of the second dialyzer cartridge  138 , whereby additional plasma water (equal to the excess amount of substitution fluid) is filtered across the semi-permeable membrane  140  and into the adjacent dialysate compartment  144 . In this manner, the substitution fluid acts as a post-dilution fluid relative to the first dialyzer cartridge as well as a pre-dilution fluid relative to the second dialyzer cartridge.  
         [0042]     The dialysate fluid may be generated by a dialysis machine, or by any other method known to one of ordinary skill in the art. In an embodiment of the present invention, the dialysate fluid enters the second dialyzer cartridge  138  and runs counter-parallel to the blood flow direction. The dialysate fluid acts to provide a concentration gradient against the bloodside fluid thereby facilitating the diffusion of solutes across the semi-permeable membrane  140 . As the dialysate traverses through the dialysate compartment, the dialysate flow rate increases due to plasma water filtering across into the dialysate compartment  144 , as mentioned above. Upon exiting the second dialyzer cartridge  138 , the dialysate fluid may be pumped into the mixing chamber  116 . Upon exiting the dialyzer cartridges  122 ,  138 , the used dialysate may be transported back either to the dialysis machine or to the drain  134 .  
         [0043]     The dialysis machine used in conjunction with the present invention may perform all of its normal functions, such as preparing dialysate, metering dialysate flow rate, monitoring pressures, controlling net ultrafiltration, monitoring used dialysate for blood presence, etc. The hemodiafiltration add-on system operates in conjunction with the dialysis machine, whereby the dialysate fluid from the dialysis machine is re-distributed by the hemodiafiltration add-on system to its respective dialyzer and sterile filter cartridges. The fluid handling components of the hemodiafiltration add-on system may be integrated with a microprocessor unit for controlling and executing the hemodiafiltration aspect of the treatment.  
         [0044]     The systems disclosed in the foregoing may contain further pumps, monitoring devices, valves, electronic components, controllers, connector fittings, tubing, etc., as required in order to coordinate the operation of the system components.  
         [0045]     Although the invention has been described in detail in the foregoing embodiments, it is to be understood that they have been provided for purposes of illustration only and that other variations both in form and detail can be made thereupon by those skilled in the art without departing from the spirit and scope of the invention, which is defined solely by the appended claims.
A dual-stage system and methods for using the same include first and second filtration cartridges is provided and is particularly suited for hemodiafiltration and/or hemodialysis. As fluid enters the first filtration cartridge, the hydroxyl ion concentration and hence pH is increased by exposing it to either a strong base or a salt of a weak acid across a filter membrane. This stage allows for improved removal of certain toxins in the fluid, such as protein-bound substances that disassociate more readily from proteins at higher pH. As the filtered fluid enters the second filtration cartridge, the pH of the fluid is restored to normal levels prior to infusion to a patient.