Patent Document

FIELD OF THE INVENTION 
     The present invention relates to hemodiafiltration devices and methods and, more particularly, to a new hemodiafiltration cartridge and its method of use. 
     BACKGROUND OF INVENTION 
     Current treatment for End Stage Renal Disease (ESRD)essentially consists of hemodialysis process, wherein blood to be cleaned flows on one side of a semipermeable membrane and a physiologic solution, a dialysate, flows on the other side of the membrane, whereby toxins in the blood are transferred from one side to the other. The primary driving force in this treatment is diffusion. This process is generally effective in removing small Molecular Weight (MW) toxins such as urea and creatinine. However, this process is much less effective in removing middle range MW substances, e.g., substances having a molecular weight higher than about 1 kDa, because of a low diffusion coefficient of such substances. 
     To a much lesser extent hemodiafiltration is used as a treatment modality. In hemodiafiltration, diffusion is combined with filtration to remove toxins from the blood. Sterile non-pyrogenic replacement fluid is added to the blood either prior to or after it enters a hemodiafiltration cartridge. The replacement fluid replaces plasma water which is filtered across the semi-permeable membrane during the hemodiafiltration process. The advantage of hemodiafiltration over hemodialysis is the use of filtration in conjunction with diffusion to remove toxins. As a result of this combination, hemodiafiltration is more efficient at removing small molecules, e.g., creatinine and urea, as well as removing much greater quantities of middle range MW substances, by filtration. 
     State of the art designs for hemodiafiltration filters are substantially equivalent to those of high flux dialyzers. Such filters consist of bundles of hollow fibers in a cylindrical housing. During operation of the hemodiafiltration system, replacement fluid is injected into the blood either upstream (pre-dilution) or downstream (post-dilution) of the filter cartridge. 
     Diafiltration devices using pre-dilution or post-dilution schemes have inherent efficiency limitations. Pre-dilution schemes allow for relatively unlimited filtration, however, because the blood is diluted prior to reaching the filter, the overall mass transfer of solutes is decreased. Post-dilution schemes have the advantage of keeping blood concentrations high, resulting in more efficient diffusion and convection of solutes, however, the increased concentration of blood cells and the resultant higher blood viscosity during filtration, poses a limit on the amount of water that can be filtered. 
     SUMMARY OF INVENTION 
     It is an object of some aspects of the present invention to provide a hemodiafiltration cartridge that enables a higher toxin removal rate and higher toxin removal efficiency than that of prior art hemodiafiltration devices. The present invention reduces and/or eliminates the above mentioned drawbacks of prior art hemodiafiltration devices by providing a scheme in which blood is diluted after it is partially, but not fully, diafiltered. The scheme of the present invention combines the benefits of predilution schemes, e.g., high filtration rate, with the benefits of post dilution schemes, e.g., high diffusive and convective efficiencies. The device of the present invention may be adapted to operate in conjunction with a dual-stage hemodiafiltration machine, or a standard dialysis machine using dual-stage hemodiafiltration, such as the machines described in PCT patent application No. PCT/US99/17468 and in PCT patent application No. PCT/US99/25804, assigned to the assignee of the present application, the disclosures of both of which are incorporated herein by reference in their entirety. Alternatively, by making appropriate alterations in a dual-stage device according to the present invention, e.g., by allowing direct flow of dialysate fluid between the two stages of the dual-stage device, the present invention may be adapted for use in conjunction with a standard dialysis machine using single stage diafiltration. 
     A hemodiafiltration cartridge in accordance with the present invention has blood and dialysate inlet and outlet ports. The cartridge of the present invention includes two housings, for example, two cylindrical housings, corresponding to two hemodiafiltration stages, wherein the first stage has a blood inlet and a dialysate outlet, and the second stage has a blood outlet and dialysate inlet. 
     In an embodiment of the present invention, the blood inlet and outlet ports and the dialysate inlet and outlet ports are located on one side, e.g., at the top, of the cartridge. Each of the two hemodiafiltration stages of the present invention may contain longitudinal bundles of high flux, semi-permeable, hollow fibers, which may be sealed off from the dialysate compartments at each end by a potting compound such as polyurethane. The blood inlet may include a header member that may be attached to a casing of the cartridge, at the fiber ends. 
     In one embodiment, the two stages are produced separately and then assembled together. Alternatively, the two stages may be manufactured as a single unit. The method of production does not affect the resultant dual-stage cartridge. 
     In an embodiment of the present invention, the cartridge includes two additional ports, preferably at the second end, e.g., the bottom end, of the cartridge. One of these additional ports may be a substitution fluid inlet where sterile replacement fluid is mixed with the blood. This mixing may take place in a common header space, between the first and second stages, where the blood exits the hollow fibers of the first stage and enters the fibers of the second stage. 
     The other additional port may be an inter-dialysate port, for example, a dual aperture port, which directs dialysate fluid exiting the second stage of the cartridge to cycle through the controlling machine, where the flow rate of the dialysate may be metered, and returns the dialysate to the first stage. While the total level of filtration of the cartridge is generally controlled by the dialysate inlet and outlet rates, the inter-dialysate port enables control of the individual filtration rates of the two cartridge stages. This port may also enable modification of the dialysate flow rate or dialysate composition between the two stages. In an alternative embodiment of the invention, the dialysate fluid exiting the second stage may be directed to flow directly into the first stage, e.g., by providing an aperture-connecting cap to the dual-aperture port. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     FIG. 1A is a schematic, cross-sectional, front view, illustration of a dual stage hemodliafiltration cartridge in accordance with one preferred embodiment of the present invention; 
     FIG. 1B is a schematic, cross-sectional, top view, illustration of the dual stage hemodiafiltration cartridge of FIG. 1A, taken along section lines  1 B— 1 B; 
     FIG. 2A is a schematic, cross-sectional, front view, illustration of a dual stage hemodiafiltration cartridge in accordance with another preferred embodiment of the present invention; 
     FIG. 2B is a schematic, cross-sectional, top view, illustration of the dual stage hemodiafiltration cartridge of FIG. 2A, taken along section lines  2 B— 2 B; 
     FIG. 2C is a schematic, cross-sectional, side view, illustration of the dual stage hemodiafiltration cartridge of FIG. 2A; 
     FIG. 3A is a schematic, cross-sectional, top view, illustration of the dual stage hemodiafiltration cartridge of FIG. 1A, taken along section lines  1 B— 1 B, showing connection of an inter-dialysate port of the cartridge to a hemodiafiltration machine; 
     FIG. 3B is a schematic, cross-sectional, top view, illustration of the dual stage hemodiafiltration cartridge of FIG. 1A, taken along section lines  1 B— 1 B, showing connection of a inter-dialysate port of the cartridge to an aperture-connecting cap. 
    
    
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS 
     Reference is made to FIGS. 1A and 1B which schematically illustrate a cross-sectional front view and a cross-sectional top view, respectively, of a dual stage hemodiafiltration cartridge  10  in accordance with one preferred embodiment of the present invention. Cartridge  10  includes a first stage  52  and a second stage  53 . Stages  52  and  53  preferably include generally cylindrical housings,  62  and  63 , respectively, of a rigid plastic material. Housings  62  and  63  contain longitudinal bundles of semipermeable hollow fibers  54 , as are known in the art. The semipermeable fibers serve as a means for transferring the toxins which are being filtered from the blood. 
     In an embodiment of the present invention, cartridge  10  is adapted to operate in conjunction with a dual stage-hemodiafiltration machine, or a standard dialysis machine using dual-stage hemodiafiltration, such as the machines described in PCT patent application No. PCT/US99/17468 and/or in PCT patent application No. PCT/US99/25804, the disclosures of both of which are incorporated herein by reference in their entirety. 
     During operation, blood transferred from the patient, via a blood pump of a dual stage hemodiafiltration machine, enters first stage  52  of cartridge  10  through an inlet port  55  which is preferably formed in a header cap  56  mounted on an inlet end of housing  62 . Cap  56  defines an inner header space  57  which may be separated from the rest of the cartridge by a potting compound  58 , which forms a seal around the outside surfaces of hollow fibers  54 . Header cap  56  may be removable and, in such case, header space  57  is preferably sealed from the external environment by a sealing member, such as an O-ring  59 . 
     As blood traverses down the insides of fibers  54 , along a main filtration space  60  of first stage  52 , the outsides of fibers  54  are immersed in dialysate. This results in first stage hemodiafiltration of toxins, i.e., both filtration and diffusion, which takes place along the entire length of fibers  54  within filtration space  60 . In an embodiment of the present invention, a significant portion, e.g., approximately 40%-60%, of the plasma water is filtered as the blood flows through first stage  52 . The partly hemodiafiltered blood exiting first stage  52  enters an inter-stage header space  11  associated with another end of housing  62 . The blood entering inter-stage header space  11  is in a hemoconcentrated state, i.e., the level of hematocrit in the blood is increased. In accordance with an embodiment of the invention, filtration space  60  of first stage  52  and a filtration space  61  of second stage  53  are separated from header  11 , for example, by a potting compound  68 , in analogy to the separation described above with reference to header space  57  and potting compound  58 . 
     Inter-stage header space  11 , which acts as a transition stage for blood exiting first stage  52  and entering second stage  53 , is defined by a stage connector  12  which is preferably made from rigid plastic material and is attached to both the outlet end of first stage  52  and the inlet end of second stage  53 , for example, by bonding or welding. Stage connector  12  encloses and defines header space  11  as well as two separate dialysate spaces,  19  and  69 . A removable inter-stage header cap  13  having an inlet port  15  is attached to stage connector  12 . Header space  11  may be sealed from the external environment by a sealing member, for example, an O-ring  14 . 
     The blood residing in header space  11  prior to entering second stage  53 , is diluted with a physiological sterile solution that enters cartridge  10  via header inlet port  15 . The sterile solution may be produced continuously, in an “on-line” manner, or provided from reservoirs, e.g., saline bags, as are known in the art. The blood in inter-stage space  11  is hemodiluted, i.e., the blood hematocrit level is decreased. The hemodiluted blood is then carried by fibers  64  disposed in second stage  53 , in a manner similar to that described above with reference to first stage  52 . At second stage  53  the blood undergoes further hemodiafiltration. The outlet end of second stage  53  is capped with a header cap  66 , defining a header space  67  therein, having a blood outlet port  16 , in analogy with the above description of header cap  56 . 
     In an embodiment of the present invention, the blood is diafiltered by cartridge  10  at such a rates so that upon exiting second stage  53 , via a blood outlet port  16 , the blood hematocrit level is substantially the same as that of the blood entering first stage  52 . As in standard hemodialysis processes, small changes in the blood hematocrit level may be required in order to control the net ultrafiltration, as may be necessary to maintain patient fluid balance. 
     As in standard dialysis processes, the dialysate in the present invention is perfused through cartridge  10  in a “counter-current” direction relative to the flow of blood. The dialysate enters second stage  53  via a dialysate inlet  17 . A flow disperser  18  ensures that the dialysate will better perfuse the fiber bundle in second stage  53 . An inter-dialysate port  20  is preferably associated with dialysate exit region  19  of second stage  53  and with dialysate inlet region  69  of fist stage  52 . Inter-dialysate port  20  (shown more clearly in FIG. 1B) is preferably a dual-aperture port including a second stage outlet  21  and a first stage inlet  22 . 
     Reference is now made also to FIG. 3A which schematically illustrates a cross-sectional side view of cartridge  10 , showing connection of inter-dialysate port  20  to a hemodiafiltration machine  71 , and to FIG. 3B which schematically illustrates a cross-sectional side view of cartridge  10 , showing connection of inter-dialysate port  20  to an aperture-connecting cap  73 . Machine  71  is preferably a dual-stage hemodiafiltration machine as described. As shown in FIG. 3A, inter-dialysate port  20  may be connected to machine  71  using a dual-aperture connector  24  which is adapted to fit connections  72  on hemodiafiltration machine  71 . 
     In an embodiment of the present invention, hemodiafiltration machine  71  is adapted to monitor the slow and/or dialysate pressures between the first and second stages of cartridge  10 . For example, the hemodiafiltration machine may include an inter-dialysate pump (not shown), which may be used to monitor the flow between the first and second stages of cartridge  10  and/or the relative dialysate pressures of the two stages. It should be appreciated, however, that machine  71  may include any other suitable mechanisms, as are know in the art, for controlling dialysate pressure and/or flow. The monitoring of inter-stage flow and/or pressure, enables control of the level of filtration in each of the first and second stages to optimize process efficiency. 
     Hemodiafiltration machine  71  may also be adapted to monitor and/or control other parameters of the dialysate fluid, between the first and second stages, as described in PCT application No. PCT/US99/17468 and in PCT application No. PCT/US99/25804. For example, the composition and/or salt concentration of the dialysate may be modified between the two stages as described in PCT/US99/25804. 
     After passing through both hemodiafiltration stages, either directly or via machine  71 , as described above, the used dialysate exits cartridge  10  via a dialysate outlet  23  of first stage  52 . 
     Blood inlet and outlet ports  55  and  16 , respectively, may be associated with locking connectors, as are known in the art, designed to mate with standard bloodlines. Dialysate inlet port  17  and dialysate outlet port  23  may be associated with standard Hansen connectors, as are know in the art. Substitution fluid inlet port  15  may be associated with a standard luer, e.g., a 6% tapered connector as specified in the ISO 594, adapted to accommodate an IV set, as is known in the art. 
     To accommodate a dialyzer reuse machines having blood inlet and outlet ports, as are know in the art, substitution fluid inlet port  15  may be capped during reuse. The use of removable header caps  56 ,  66  and  13 , as described above, enables tubesheet cleaning during reuse. Additionally, inter-dialysate port  20  may be fitted with the aperture-connecting cap  73  (FIG. 3B) which allows direct dialysate flow from second stage  53  to first stage  52 . Cap  73  seals inter-dialysate port  20  from the external environment while allowing flow of dialysate between dialysate outlet  21  of stage  53  and dialysate inlet  22  of stage  52 . Such sealing may be useful during reuse, whereby a dialyzer reuse machine may communicate with cartridge  10  as if it were a standard dialyzer. By allowing direct dialysate flow between the first and second stages, as described above, cartridge  10  may be used in conjunction with a standard dialysis machine, i.e., a dialysis machine designed to operate with a single-stage dialyzer. 
     A thread or any other suitable locking mechanism, as is known in the art, may be provided on the exterior surface of outlet port  24  to enable tight sealing of port  24  with either the dialysis machine connector  72  or aperture-connecting cap  73 . 
     In the embodiment of FIGS. 1A and 1B, the first and second stages may be manufactured separately and assembled together prior to packaging. Each of housings  62  and  63  is stuffed with a fiber bundle as described above, and may be centrifugally potted as is known in the art. A potting compound, for example, polyurethane resin, may be introduced into first stage  52  via dialysate outlet port  23 . At the other end of first stage  52 , the potting compound may be introduced via a dedicated potting port  25  which is analogous to the opening of a second dialysate port in conventional dialyzers. The assembly procedure for second stage  53  is analogous to that of first stage  52 . Thus, standard potting techniques and equipment may be used in the assembly of the cartridge of the present invention. 
     To complete the assembly process, the potted ends of the fibers are trimmed to form a smooth tubesheet of open fibers, and the two stages are assembled into a single unit. The final assembly may be preformed as follows. The two stages are locked together, for example, using a “tongue in groove” type bond or weld  26 , including a male portion  27  on housing  62  and a female portions  28  on housing  53 , or vice versa. This arrangement keeps the housings from being twisted out of alignment. Stage connector  12  may be bonded or welded to the two housings, as mentioned above. 
     Stage connector  12  may includes inter-dialysate port  20  as well as a mating portion  29  for connecting inter-stage header cap  15 . Connector  12  may be circumferentially welded or bonded to housings  62  and  63  at several locations. 
     A first bond may be formed along the flat ends of the outer rims  30  of housings  62  and  63 , where the tubesheet may be encased. This bond seals the blood sides of both stages  52  and  53  from the external environment, but allows free flow through the inter-stage header space  11  between stages  52  and  53 . The bond is preferably formed along the entire rim of each housing, including a common central mating portion  31 . 
     A second weld or bond may be formed along external flanges  32  of housings  62  and  63 . This bond seals the dialysate potting ports from the external environment and forces all the inter-dialysate flow to go through the inter-dialysate port. Here too there is a common central bond  33  that effectively separates the dialysate compartments of the two stages. 
     Stage connector  12  is preferably designed such that dialysate may flow out of potting port  25  into an external space  34  around the outside of the stage housings, as well as to the central area where inter-dialysate port  20  is located. 
     Reference is now made to FIGS. 2A-2C which schematically illustrate a cross-sectional front, a cross-sectional top view and a cross-sectional side-view, respectively, of a dual stage hemodiafiltration cartridge  110  in accordance with another preferred embodiment of the present invention. Most of the elements of cartridge  110 , as shown in the embodiment of FIGS. 2A-2C, as well as the features and functions of such elements, are substantially the same as described above with reference to the embodiment of FIGS. 1A and 1B. Cartridge  110  is mounted to a hemodiafiltration machine in the manner described above with reference to the embodiment of FIGS. 1A and 1B. 
     The difference between the two embodiments is primarily in the structure and assembly of the inter-stage section. In the embodiment of FIGS. 2A-2C, instead of bonding two separately formed cylindrical housings, a dual-housing structure  35  is molded as a single unit, including a first stage housing  162  and a second stage housing  163 , for a first hemodiafiltration stage  152  and a second hemodiafiltration stage  153 , respectively. This obviates the need for an inter-stage connector and interlocking web, as described above with reference to the embodiment of FIGS. 1A and 1B. These elements of the preceding embodiments are replaced by a common inter-stage molded encasement  37  and a molded web  36 , respectively. 
     Molded structure  35  is preferably formed with an integral, generally circular, end portion  38  which accommodates a removable inter-stage header cap  39 . In this arrangement, the entire cross-section of encasement  37  is filled with a potting compound  40 , thereby to seal the blood side of the fibers bundled in cartridge  110  from the dialysate side of the fibers. A dual-aperture inter-dialysate port  120 , shown particularly in FIG. 2B, is used in this embodiment substantially in the manner described above with reference to port  20  of FIG.  1 B. However, in this embodiment, the dialysate of first stage  152  is separated from the dialysate of second stage  153  by a rib member  41  across the entire diameter of inter-stage encasement  37 . Rib  41  may be molded to one end  42  of web  36  and sealed to the potting compound at the other end  43 . 
     It will be appreciated by persons skilled in the art that the present invention is not limited to the embodiments described thus far with reference to the accompanying drawing. Rather the present invention is limited only by the following claims.

Technology Category: 1