Abstract:
A method of hemodiafiltration including the steps of supplying a blood inflow, diafiltering the blood inflow using a first non-isosmotic dialysate fluid to provide a partially diafiltered blood outflow, mixing the partially diafiltered blood outflow with a substitution fluid to provide a blood/substitution fluid mixture, and diafiltering the blood/substitution fluid mixture using a second non-isosmotic dialysate fluid.

Description:
This application claims the benefit of provisional application 60/106,322 filed Oct. 30, 1998. 
    
    
     FIELD OF THE INVENTION 
     The present invention relates to blood cleansing in general and, more particularly, to diafiltration systems. 
     BACKGROUND OF THE INVENTION 
     Hemodiafiltration combines standard dialysis and hemofiltration into one process, whereby a dialyzer cartridge containing a high flux membrane is used to remove substances from the blood both by diffusion and by convection. The removal of substances by diffusion is accomplished by establishing a concentration gradient across a semi-permeable membrane by flowing a dialysate solution on one side of the membrane while simultaneously flowing blood on the opposite side of the membrane. To enhance removal of substances using hemodiafiltration, a substitution fluid is continuously added to the blood either prior to the dialyzer cartridge (pre-dilution) or after the dialyzer cartridge (post-dilution). An amount equal to that of the substitution fluid is then ultrafiltered across the dialyzer cartridge membrane carrying with it additional solutes. 
     Substitution fluid is usually purchased as a sterile/non-pyrogenic fluid contained in large flexible bags or is produced by on-line filtration of a non-sterile dialysate through a suitable filter cartridge rendering it sterile and non-pyrogenic. Such on-line production of substitution fluid is described, inter alia, in D. Limido et al., “Clinical Evaluation of AK-100 ULTRA for Predilution HF with On-Line Prepared Bicarbonate Substitution Fluid. Comparison with HD and Acetate Postdilution HF”,  International Journal of Artificial Organs , Vol. 20, No.3 (1997), pp. 153-157. 
     In general, hemodiafiltration schemes use a single dialyzer cartridge containing a high flux semi-permeable membrane. Such a scheme is described, for example, in P. Ahrenholz et al., “On-Line Hemodiafiltration with Pre- and Postdilution: A comparison of Efficiency”,  International Journal of Artificial Organs , Vol. 20, No.2 (1997), pp 81-90 (“Ahrenholz et al.”). Substitution fluid is introduced into the blood stream either in a pre-dilution mode or in a post-dilution mode relative to the dialyzer cartridge. The preferred mode for maximal removal of both small and large substances from blood is the post-dilution mode, which achieves the highest concentration gradient between the blood and the dialysate fluid. In a typical pre-dilution mode with on-line generation of the substitution fluid, however, the bloodside concentration is lowered relative to the dialysate fluid. As a result, removal (or clearance) of substances can decrease, as described in Ahrenholz et al. This is particularly true for smaller molecules like urea, whereby mass transport is driven more by the diffusion process than by the convection process. 
     A hemodiafiltration scheme using first and second dialyzer cartridges 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. In this scheme, the substitution fluid is reverse-filtered through a membrane of the second dialyzer cartridge with simultaneous filtration of fluid across a membrane in the first dialyzer cartridge. Counter-current flow of dialysate occurs at both cartridges. 
     Certain trade-offs exist with respect to removal of different size molecules when comparing pre-dilution diafiltration and post-dilution diafiltration using a single dialyzer cartridge. For example, with on-line pre-dilution diafiltration, one can achieve higher convective filtration rates (compared to on-line post-dilution diafiltration) to enhance removal of large molecules, however, this comes at the expense of reducing the removal of small molecules like urea and creatinine. In on-line post-dilution diafiltration, however, only a limited amount of fluid can be filtered from the blood as it passes through the dialyzer cartridge. The filterable amount is dependent upon several factors, including blood flow rate, blood hematocrit and blood protein concentration. Typically, the filterable amount is 20% to 30% of the incoming blood flow, depending on blood flow rate. For example, at a blood flow rate of 300 ml/min, the filterable amount is limited to about 90 ml/min. Additionally, in on-line pre-dilution or post-dilution diafiltration, there is some loss in clearance due to the lower dialysate flow rate through the diafilter cartridge. For example, at a nominal dialysate flow of 500 ml/min, when 100 ml/min is used as an on-line source of substitution fluid, the resultant dialysate flow into the diafilter cartridge is 400 ml/min. 
     SUMMARY OF THE INVENTION 
     It is an object of the present invention to provide a hemodiafiltration method and a device which overcome the limitations associated with convection filtration in existing on-line post-dilution schemes. It is also an object of the present invention to reduce the loss of small molecule clearance associated with on-line pre-dilution diafiltration using a single dialyzer cartridge. In accordance with the present invention, clearance is improved by introducing a non-isosmotic fluid to the dialysate fluid stream and optionally to the substitution fluid stream. 
     The present invention may be embodied in an improved dialysis machine, e.g., a dialysis machine which is adapted to perform improved hemodiafiltration in accordance with the invention. Alternatively, the hemodiafiltration device of the present invention may be embodied in an “add-on” system which may be used in conjunction with a standard UF controlled dialysis machine to perform improved hemodiafiltration. 
     A hemodiafiltration device in accordance with an embodiment of the present invention includes at least one dialyzer (e.g., a dialyzer cartridge) for diafiltration, at least one sterility filter (e.g., a sterility filter cartridge) for generating a sterile substitution fluid, a non-isosmotic fluid supply, and a control unit which controls fluid inputs and outputs between the at least one dialyzer, the at least one sterility filter cartridge, the non-isosmotic fluid supply and the dialysis machine. 
     The dialyzer may contain a semi-permeable membrane which may be embedded within a jacket or housing of a dialyzer cartridge. The membrane separates the dialyzer into a blood compartment and a dialysate compartment. In an embodiment of the present invention, at least first and second dialyzers are used to carry out the diafiltration process. The first and second dialyzers may include first and second dialyzer cartridges or a single cartridge having first and second dialyzer sections. The at least one sterility filter may contain semi-permeable membranes and may be used to remove bacteria, endotoxins, and other particulate from the dialysate, thereby generating a suitable substitution fluid stream on-line. The control unit may contain various pumps, pressure monitoring devices, valves, electronic components, connector fittings, tubing, etc., as required in order to coordinate the operation of the other system components. 
     Blood enters the bloodside compartment of the first dialyzer, whereby some plasma water is filtered across the semi-permeable membrane into the adjacent dialysate compartment. As the blood leaves the first dialyzer, substitution fluid is added to the blood at a rate higher than the rate at which plasma water is filtered out of the first dialyzer. In accordance with an embodiment of the present invention, the substitution fluid may include a non-isosmotic substitution fluid. 
     The diluted blood then enters the bloodside compartment of the second dialyzer, whereby additional plasma water (equal to the excess amount of substitution fluid) is filtered across the semi-permeable membrane and into the adjacent dialysate compartment. In this manner, the substitution fluid acts as a post-dilution fluid relative to the first dialyzer as well as a pre-dilution fluid relative to the second dialyzer. 
     An advantage of this process is that a gain in clearance of small molecular weight substances in the first dialyzer overshadows a loss in clearance of small molecular weight substances due to the dilution of blood concentration entering the second dialyzer. Further, clearance of larger molecular weight substances is enhanced considerably, because the total filtration level of plasma water is practically doubled (e.g. 40% to 80% of the incoming blood flow rate may be filtered) compared to filtration using a single dialyzer operating in a post-dilution mode. 
     The dialysate fluid may be generated by the dialysis machine. Preparation of the dialysate solution may include mixing of water with dialysate concentrate. Using a water preparation module, a supply of water may be pre-treated, e.g., by heating and/or degassing or using any other pre-treatment method known in the art. A dialysate preparation module, as is known in the art, may be used to supply dialysate concentrate to obtain suitable proportioning of dialysate to water. 
     When two dialyzers are used, the dialysate fluid may enter the second dialyzer cartridge and run counter-parallel to the blood flow direction. In accordance with an embodiment of the present invention, the dialysate preparation module produces non-isosmotic or isosmotic dialysate fluid. The dialysate fluid acts to provide a concentration gradient against the bloodside fluid thereby facilitating the diffusion of solutes across the semi-permeable membrane. As the dialysate traverses through the dialysate compartment, the dialysate flow rate increases due to plasma water filtering across into the dialysate compartment as mentioned above. Upon exiting the second dialyzer cartridge, the dialysate fluid may be pumped into the first dialyzer cartridge, again running counter-parallel to the bloodside fluid. At this point, a non-isosmotic dialysate fluid may be added to the dialysate fluid, resulting in fluid which is either hypertonic or hypotonic relative to the blood. The addition of this fluid may have the following effects: (a) an increase in the overall dialysate flow results in a reduction of the dialysate side-mass transport resistance; (b) a reduction in the dialysate inlet solute concentration prior to entering the first dialyzer cartridge results in an increase of the concentration gradient across the semi-permeable membrane; (c) a fluid shift across the red blood cell membrane further enhances transport of solutes out of the red blood cells; and (d) larger molecules sieved by the red blood cell membrane are trapped in the plasma water space thus increasing their concentration gradient relative to the dialysate. In some embodiments of the invention, pre-treated water is used as the non-isosmotic fluid added to the dialysate fluid. This may have the added benefit of increasing dialysate flow without increasing costs associated with the amount of dialysate concentrate being used. 
     The dialysate flow rate increases as it traverses through the dialysate compartment again, due to filtration of plasma water across the semi-permeable membrane. Upon exiting the dialyzer cartridges, the used dialysate is transported back to the dialysis machine. A dialysate pump may be placed between the first and second dialyzers. The pump may be used to control the relative amount of plasma water filtered across the membranes of the two dialyzers. 
     Preparation of the sterile/non-pyrogenic substitution fluid may be performed by drawing a portion of fresh dialysate solution from a dialysate inlet line and pumping it through the sterile filter cartridge. Water from the water preparation module may be added to the dialysate, such that the substitution fluid becomes hypotonic before it is infused into the blood stream. The sterile filter cartridge may perform multiple filtration of the dialysate solution, e.g., using a plurality of filtration cartridges or a plurality of filtration sections in a single cartridge, before introducing the dialysate into the blood stream as substitution fluid. This enhances safety, e.g., should one of the filters fail during treatment. 
     To ensure that the blood does not become diluted or over-concentrated as it passes through the dialyzer cartridges, control of filtration may be accomplished by use of two independent fluid balancing systems and a separate UF pump. A main balance system may regulate the overall dialysate flows, while a secondary balance system may be used to balance dialysate flows that are offset by the addition of a second fluid stream to the dialysate circuit as part of the non-isosmotic flow streams. To ensure that the blood being cleaned returns substantially to its original osmotic state before going back to the patient, the primary dialysate fluid may be isotonic, slightly hypertonic, or slightly hypotonic, depending on the nature of the second dialysate fluid. Pressures may be monitored both on the bloodside and dialysate side of each dialyzer cartridge as a means to determine transmembrane pressure (TMP) across each of the dialyzers. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     The present invention will be understood and appreciated more fully from the following detailed description of embodiments of the present invention, taken in conjunction with the accompanying drawing in which: 
     FIG. 1A is a schematic illustration of a first section of a non-isosmotic hemodiafiltration device system in accordance with an embodiment; 
     FIG. 1B is a schematic illustration of a second section of a non-isosmotic hemodiafiltration system in accordance with an embodiment; and 
     FIG. 2 is a schematic illustration of a control unit for monitoring and controlling the operation of the hemodiafiltration system of FIG. 1 in accordance with an embodiment of the present invention. 
    
    
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS 
     The hemodiafiltration method and device of the present invention will be described below in the context of a stand-alone dialysis/hemodiafiltration machine. It should be appreciated, however, that the hemodiafiltration method and device of the present invention can also be embodied in an add-on type system used in conjunction with an existing UF controlled dialysis machine. 
     In an embodiment of the present invention, as described below with reference to the drawing, the hemodiafiltration device includes first and second dialyzer cartridges. Alternatively, a single cartridge having first and second, separate, dialyzer sections may be used. 
     The hemodiafiltration device further includes at least one sterility filter, which may contain semi-permeable membranes for removing bacteria, endotoxins, and other particulate from the dialysate, thereby to generate a suitable substitution fluid stream on-line. The device also includes a fluid module to coordinate between different elements of the system. The fluid module contains various pumps, pressure monitoring devices, valves, electronic components, connector fittings, tubing, etc., as required in order to coordinate the operation of the other system components. 
     In accordance with an embodiment of the present invention, preparation of dialysate solution includes mixing of water with dialysate concentrate. Using a water preparation module, a supply of water may be pre-treated, e.g., by heating and/or degassing or using any other pre-treatment method known in the art. A dialysate preparation module may be used to supply a predetermined amount of dialysate concentrate to obtain a suitable proportioning of dialysate to water. 
     When two dialyzers are used, the dialysate fluid may enter the second dialyzer cartridge and run counter-parallel to the blood flow direction. In accordance with an embodiment of the present invention, the dialysate preparation module produces non-isosmotic dialysate fluid. The dialysate fluid acts to provide a concentration gradient against the bloodside fluid thereby facilitating the diffusion of solutes across the semi-permeable membrane. As the dialysate traverses through the dialysate compartment, the dialysate flow rate increases due to plasma water filtering across into the dialysate compartment as mentioned above. Upon exiting the second dialyzer cartridge, the dialysate fluid may be pumped into the first dialyzer cartridge, again running counter-parallel to the bloodside fluid. At this point, a non-isosmotic dialysate fluid may be added to the dialysate fluid, resulting in fluid which is either hypertonic or hypotonic relative to the blood. The addition of non-isosmotic fluid to the dialysate fluid may have the following effects: (a) an increase in the overall dialysate flow results in a reduction of the dialysate side-mass transport resistance; (b) a reduction in the dialysate inlet solute concentration prior to entering the first dialyzer cartridge results in an increase of the concentration gradient across the semi-permeable membrane; (c) a fluid shift across the red blood cell membrane further enhances transport of solutes out of the red blood cells; and (d) larger molecules sieved by the red blood cell membrane are trapped in the plasma water space thus increasing their concentration gradient relative to the dialysate. In an embodiment of the invention, pretreated water is used as the non-isosmotic fluid added to the dialysate fluid. This may have the added benefit of increasing dialysate flow without increasing costs associated with the amount of dialysate concentrate being used. 
     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 a sterile filter cartridge. In an embodiment of the present invention, the sterile filter cartridge performs at least a double filtration of the dialysate solution before the solution is introduced into the blood stream 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. 
     The dialysis machine used in conjunction with the present invention may perform all of its normal functions, such as metering dialysate flow rate, monitoring pressures, controlling net ultrafiltration, monitoring used dialysate for blood presence, etc. The hemodiafiltration device of the present invention operates in conjunction with the dialysis machine, either as part of the dialysis machine or as an add-on system, e.g., to re-distribute dialysate fluid to its respective dialyzer and sterile filter cartridges. Preparation of non-isosmotic dialysate fluid, as described in detail below, may be performed by a preparation module included in the dialysis machine. The fluid handling components of the hemodiafiltration system may be integrated with a microprocessor unit for controlling and executing the diafiltration aspect of the treatment, or a control unit of the dialysis machine may be adapted to control the hemodiafiltration aspects of the treatment. 
     Reference is now made to the FIG. 1, which schematically illustrates a non-isosmotic hemodiafiltration device in accordance with an embodiment of the present invention. It should be appreciated that the system of FIG. 1 demonstrates only one preferred embodiment of the invention, and that other possible configurations of the system of the present invention may be equally or even more suitable, depending on specific requirements. For example, the use of a substantially hypotonic dialysate fluid in the first dialyzer stage and a substantially hypertonic dialysate fluid in the second dialyzer stage, as described below, may be reversed in some embodiments of the invention, i.e., a substantially hypertonic dialysate fluid may be used in the first dialyzer stage and a substantially hypotonic dialysate fluid may be used in the second dialyzer stage. 
     In the system of FIG. 1, blood to be cleaned  27  enters a first dialyzer cartridge  23  after passing through blood monitoring devices  137  and  26 . Blood monitoring devices  137  and  26  monitor the incoming blood pressure and/or the incoming blood flow rate and provide an input, responsive to the monitored rate, to a control unit  40 . 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  23  contains a semi-permeable membrane  24  that divides the dialyzer into a blood compartment  45  and a dialysate compartment  46 . As blood  27  passes through blood compartment  45 , plasma water containing blood substances is filtered across semi-permeable membrane  24 . Additional blood substances are also transferred across semi-permeable membrane  24  by diffusion due to a difference in concentration between blood compartment  45  and dialysate compartment  46 . 
     The dialyzer cartridge 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 CT 110, available from Baxter Health Care, Deerfield, Ill., the Minntech Hemocor HPH 1000, available from Minntech Corporation, Minneapolis, Minn., or the Hospal Filtral 16, available from Hospal A.G., Switzerland. Membrane  24  is preferably a medium to high flux membrane, 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. 
     Partially diafiltered blood (denoted  18 ) exiting dialyzer cartridge  23  is mixed with sterile substitution fluid  16  to form a blood/substitution fluid mixture  17 . This mixture enters a second dialyzer cartridge  22  containing a semi-permeable membrane  25  which divides the dialyzer cartridge  22  into a blood compartment  47  and a dialysate compartment  48 . As mixture  17  passes through blood compartment  47 , plasma water containing blood substances is filtered across the semi-permeable membrane. As in the first dialyzer cartridge, additional blood substances are transferred across semi-permeable membrane  25  by diffusion due to concentration gradients between the blood and dialysate compartments. Cleansed blood  28  exits second dialyzer cartridge  22  and is recycled to the patient (not shown) through suitable tubing, for example, bloodline PVC tubing, as is known in the art. The pressure of cleansed blood  28  may also be monitored by a pressure sensor  136 . 
     The second dialyzer cartridge 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 CT 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. Membrane  25  is preferably a medium or high flux membrane, for example, the polysulfone, cellulose triacetate or acrylonitrile membranes mentioned above with reference to membrane  24 . 
     In accordance with an embodiment of the present invention, the dialysate solution used for the present invention may be prepared as follows. A suitable quality of water, such as reverse osmosis water as is known in the art, is provided from a water source  150 . The water enters a water preparation module  151  that heats and degasses the water being used by the hemodiafiltration system. Any suitable heating and degassing module as is known in the art may be used in conjunction with the present invention. Examples of such modules are included in the following systems: the Baxter SPS1550, available from Baxter Health Care, Deerfield, Ill.; the Cobe Centry System 3, available from Cobe Labs, Lakewood, Colo.; the Fresenius A2008, available from Fresenius Medical Care, Lexington, Mass.; and the Althin System 1000, available from Althin Medical, Miami, Fla. The degassed, heated water feeds into two water supply lines, namely, water feed lines  152  and  153 . 
     Feed line  153  supplies water to prepare a non-isosmotic substitution fluid in accordance with the present invention, as described below, and/or to increase the flow of dialysate into first dialyzer cartridge  23 . Feed line  152  supplies water to a dialysate preparation module  154 . In dialysate preparation module  154 , water is mixed with suitable amounts of dialysate concentrates. Any suitable dialysate preparation module as is known in the art may be used in conjunction with the present invention. Examples of such modules are included in the following systems: the Baxter SPS1550, available from Baxter Health Care, Deerfield, Ill.; the Cobe Centry System 3, available from Cobe Labs, Lakewood, Colo.; the Fresenius A2008, available from Fresenius Medical Care, Lexington, Mass.; and the Althin System 1000, available from Althin Medical, Miami, Fla. The mixed dialysate fluid exiting dialysate preparation module  154  flows through a conduit  157  leading to a primary dialysate balancing module  158 , which may include a fluid balancing chamber as is known in the art. Primary balancing module  158  regulates flow in the sense that flow into balancing module  158  is equal to flow out of the balancing module. This provides initial filtration control which prevents the blood from becoming over-diluted or over-concentrated when exiting dialyzer cartridge  22 . Upon exiting primary balancing module  158 , the dialysate fluid flows via conduit  41  to a connector  39  which connects the fluid flow to a dialysate port  1  of compartment  48  of second dialyzer cartridge  22 . 
     In an embodiment of the present invention, preparation of a sterile substitution fluid is performed by filtration of a dialysate across at least two filter membranes with a molecular weight cut-off of not more than 40,000 Daltons. In some embodiments, the nominal molecular weight cut-off for the second filter or final filter (when more than two filters are used) is not more than 10,000 Daltons, preferably not more than 5,000 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  48  of second dialyzer cartridge  22 . The split-off portion of the dialysate solution may flow through a conduit  2  leading to a substitution pump  8 . Flow rate and pre-pump pressure in conduit  2  may be monitored by a flow meter  10  and a pressure transducer  9 . Substitution fluid pump  8  generates the needed pressure to force the fluid down a conduit  12 , across first and second sterile filter cartridges,  11  and  13 , respectively, and into blood stream  18 . En route to sterile filters  11  and  13 , post-pump pressure and temperature may be monitored by a pressure transducer  132  and a temperature sensor  133 . 
     To change the osmolality of the substitution fluid, water from a conduit  178  may be added to the substitution fluid at some point downstream of substitution fluid pump  8 . The resultant osmolality of the substitution fluid is a function of the relative flow rates of substitution fluid pump  8  and a pump  163  which may be provided along water conduit  178 . The mixed substitution fluid stream may be monitored for conductivity by a conductivity meter  187 . If the conductivity is determined to be outside a pre-determined range, a bypass valve  188  is opened to allow substitution fluid to flow via a conduit  189  which leads to a dialysate outlet port  52  of dialysate compartment  46  of dialyzer cartridge  23 . 
     First sterile filter cartridge  11  contains a semi-permeable membrane  14  that separates the filter cartridge into an upstream compartment  49  and a downstream compartment  5 . Upstream compartment  49  has an inlet port  56  and an outlet port  54 , the latter being connected to a conduit  19 . Air maybe vented from upstream compartment  49 , via outlet port  54  and conduit  19  upon opening of a valves  130  and a valve  29 . Closing of valve  130  forces the dialysate fluid to filter (or permeate) across semi-permeable membrane  14  and into downstream compartment  5 . 
     The filtrate from downstream compartment  5  then flows into second sterile filter cartridge  13  containing a semi-permeable membrane  15  which separates the filter cartridge into an upstream compartment  50  and a downstream compartment  51 . Upstream compartment  50  has an outlet port  55  for venting air from both compartment  5  of cartridge  11  and compartment  50  of cartridge  13 . Outlet port  55  is connected to a conduit  20  which is connected to the venting line between valves  130  and  29 . Closing of both valves  29  and  130  forces the dialysate to filter across semi-permeable membrane  15  and into downstream compartment  51 . The filtered dialysate flows out of compartment  51  and through a check valve  134 , which minimizes blood back-flow into sterile filter cartridge  13 . 
     The sterile dialysate (or substitution fluid)  16  exiting sterile filter cartridge  13  is mixed with blood exiting cartridge  23  to form the blood/substitution fluid mixture  17  described above. In some embodiments of the present invention (not shown in the drawings), a portion of substitution fluid may be added to the blood stream exiting second dialyzer cartridge  22 , provided that the blood does not become overly viscous in the second dialyzer cartridge due to hemoconcentration. 
     During priming or flushing of sterile filter cartridges  11  and  13 , valves  130  and  29  are opened to allow flow therethrough. The flow downstream of valve  29  is directed, via a suitable fluid conduit, to a junction near dialysate outlet port  52  of dialyzer cartridge  23 . An air detector  124  may be placed downstream of valve  29 , to ensure that air is purged from sterile filter cartridges  11  and  13  during priming. 
     The dialysate not used as substitution fluid enters the second dialyzer cartridge  22  through inlet port  1  of dialysate compartment  48 , and flows counter-parallel to the blood flow as it traverses through compartment  48 . During diafiltration, plasma water filters across semi-permeable membrane  25  and mixes with the dialysate fluid. The dialysate fluid together with the filtered plasma water exits the dialyzer cartridge, at outlet port  3 , through a tubing conduit  174  which directs the fluid to a first path, including a bypass valve  131 , and a second path including a pump  120 . Downstream of valve  131  and pump  120 , the two paths are rejoined and the combined fluid flow is connected to an inlet port  4  of dialysate compartment  46  of first dialyzer cartridge  23 . 
     In an embodiment of the present invention, to raise the dialysate flow rate into first dialyzer cartridge  22 , an additional flow of water  164  may be added to the dialysate flow stream downstream of pump  120 . The addition of water flow  164  into the dialysate flow stream raises the dialysate flow rate and increases the dialysate concentration gradient in dialyzer cartridge  23 . The non-isosmotic nature of the dialysate may cause a fluid shift across red cell membranes in the treated blood, thereby improving the removal of solutes from the blood. 
     Pressure transducers  123  and  122  monitor pre-pumping and post-pumping pressures, respectively, across pump  120 , and inputs responsive to these pressures are provided to control unit  40 . A flow switch  34  and a conductivity meter  185  may be placed on the line leading to dialysate inlet port  4 . Flow switch  34  may be used to ensure that a minimum dialysate flow is maintained to carry out the diafiltration operation. The output of conductivity meter  185  may be used to ensure that the conductivity of the dialysate is maintained within a predetermined, acceptable range, for example, a conductivity range which yields a final dialysate sodium concentration (i.e., concentration after dilution with water) of about 70 meq/L to about 135 meq/L. Based on the output of conductivity meter  185 , if the dialysate conductivity falls outside the acceptable range, opening of a bypass valve  186  directs the dialysate fluid to bypasses first dialyzer cartridge  23  via a bypass conduit  190 . 
     During normal operation of the system, valve  131  is closed whereby all flow is diverted to pump  120 . In this mode, the speed of the pump can be used to control the amount of ultrafiltration that occurs across the second dialyzer cartridge membrane  25 . For example, if the rate of fluid flow pumped by pump  120  matches the inlet dialysate flow rate into compartment  48 , then the net ultrafiltration of fluid across the membrane is zero. Increasing the speed of the pump to pump above the inlet dialysate flow rate results in an ultrafiltration rate equal to the difference between these two flow rates. Dialysate fluid entering first dialyzer cartridge  23  through inlet port  4  runs counter-parallel to the blood flow as it traverses through the dialysate compartment  46 . Plasma water filters across semi-permeable membrane  24  of cartridge  23  into compartment  46 , where the plasma water is combined with the dialysate fluid, and the combined fluid exits at dialysate outlet port  52 . 
     The used dialysate fluid may be returned to primary balancing module  158  via a dialysate outlet line connector  38 , connected to dialysate outlet port  52  of dialyzer cartridge  23 , and a conduit  42 . A conduit  165  carries the used dialysate from dialysate outlet connector  38  to an air trap  166 . In the air trap, air is removed via a conduit  196  which leads to a drain  176 . The resultant air-free, used, dialysate fluid flows through a conduit  167  where it branches to a main dialysate pump  169  and, via a conduit  168 , to a secondary dialysate pump  170 . Main dialysate pump  169  feeds used dialysate fluid, via a blood leak detector  173  and conduit  42 , back to main balancing module  158 . The used dialysate exits main balancing module  158  via a conduit  175  which leads to drain  176 . A heat exchanger (not shown in the drawing) may be used to partially heat the incoming water, thereby to assist the heating function of water preparation module  151 . 
     The used dialysate fluid not entering main balancing module  158  is pumped by secondary pump  170  via a conduit  168  to a secondary balancing module  160 , which may include a fluid balancing chamber as is known in the art. The purpose of second balancing module  160  is to ensure that any additional flow of water into the dialysate fluid circuit and/or into the substitution fluid circuit, i.e., into the non-isosmotic portions of system, is balanced by a substantially equivalent removal of used dialysate fluid from those non-isosmotic circuits. The used dialysate from secondary balancing module  160  exits via a conduit  172  which leads to drain. The flow of this exiting stream is matched by the entering flow of fresh water from the water preparation module  151  via conduit  153 , pump  159  and conduit  161 . Fresh water  162  exiting secondary balancing module  160  branches into two water streams, namely a stream  177  which feeds water to pump  163 , leading to the substitution fluid circuit, and a stream  164  which feeds water to the dialysate fluid circuit. 
     It will be appreciated by persons skilled in the art that the use of two dialyzer stages, as described above, enables increased dialysate flow into the first dialyzer and, thus, increased solute clearance in the first dialyzer, without increasing the cost normally associated with increased dialysate flow. This is achieved by using a substantially hypotonic dialysate in the first dialyzer stage and a substantially isotonic dialysate or slightly hypertonic in the second dialyzer stage. Isotonic or slightly hypertonic dialysate is introduced only in the second dialyzer stage to bring the substantially hypotonic blood exiting the first dialyzer stage to a desired range of isotonicity, thereby reducing the amount of isotonic dialysate used. The hypotonic dialysate used in the first stage is less expensive than the isotonic dialysate used in the second stage because the hypotonic dialysate is more diluted (i.e., contains less salts per unit volume) than isotonic dialysate. The diluted dialysate used in the first stage operates to remove salts from the blood, and these salts are replaced by salts from the more concentrated dialysate used in the second stage. 
     Reference is now made also to FIG. 2 which schematically illustrates an embodiment of control unit  40 . Control unit  40  may include a processor  220  which monitors and controls the operation the hemodiafiltration system. As shown more specifically in FIG. 1, control unit  40  receives inputs from various components of the hemodiafiltration device, e.g., from pressure transducers, flow meters, conductivity meters, flow switches, etc., as described above. These inputs may be processed by sensor signal processing circuits  200 , which may include analog-to-digital (D/A) converters and other circuits as are known in the art, providing an input which is readable by processor  220 . Using suitable control hardware and/or software, for example, device actuator circuits  230  as shown in FIG. 2, control unit  40  controls various system functions, such as setting values for pump speeds, opening/closing valves. Various system parameters, calculated based on the inputs may be displayed on a display  210  of control unit  40 . 
     While certain specific embodiments of the invention are disclosed as typical, the invention is not limited to these particular forms, but rather is applicable broadly to all such variations as fall within the scope of the appended claims. To those skilled in the art to which the invention pertains many modifications and adaptations will occur. Thus, the specific structures and methods discussed in detail above are merely illustrative of specific embodiments of the invention.