Abstract:
The invention is directed towards a method for preventing the loss of functionality of a fistula due to the formation of calcium phosphate and other precipitates within the fistula. The method comprises profiling the amount of calcium in the dialysis fluid or blood in relation to the amount of phosphorous in the blood plasma. This invention also comprises a system for profiling calcium during a dialysis procedure.

Description:
FIELD OF THE INVENTION  
         [0001]    The present invention relates generally to a dialysis procedure, in particular to a procedure for profiling the concentration of calcium in a fluid over time.  
         BACKGROUND OF THE INVENTION  
         [0002]    In a dialysis treatment, it is necessary to lead a portion of the patient&#39;s blood through an extracorporeal circuit, i.e. outside the body of the patient. For this, access to the patient&#39;s bloodstream is needed. The best and most widely used vascular access for chronic hemodialysis treatment is the creation of an arterio-venous fistula (known hereafter as an A-V fistula). An A-V fistula is a joint that is typically surgically created to be a direct connection between a vein and an artery of a patient. The patient&#39;s blood flows through the fistula from the artery to the vein. The fistula provides a blood access site to create a blood loop wherein an arterial or inlet line flows from the patient to a dialysis apparatus and a venous or outlet line flows from the dialysis apparatus, back to the patient. The inlet line draws blood to be treated from the patient through a first cannula inserted into the fistula, while the outlet line returns treated blood (i.e., after dialysis), to the patient through a second cannula inserted into the fistula between the first cannula and the vein. Alternatively, the fistula may be a synthetic or animal organ graft connecting any artery to any vein. As used herein, the term “fistula” refers to both of these and any other surgically created or implanted joint between one of the patient&#39;s veins and one of the patient&#39;s arteries, however created. More generally, the terms “shunt” or “access” also may refer to any similar joint, either in a hemodialysis patient, or in another area.  
           [0003]    One side effect of dialysis treatment is that the patient&#39;s fistula often gradually loses its ability to efficiently transport blood from artery to vein. Fat and other deposits such as calcium phosphate build up within the fistula over time, and consequently blood flow within the fistula is gradually reduced. Eventually, blood flow may be reduced to such an extent that the fistula must be replaced. Often, multiple replacements may be needed and such repetitious replacements can account for half or more of the long term costs of dialysis treatment.  
           [0004]    A well-functioning vascular access is essential for dialysis patients to receive an adequate dose of dialysis. Consequently, sustaining viability of the access remains an important challenge in the management of dialysis patients.  
           [0005]    In the United States alone, complications associated with vascular access are a major cause of morbidity in hemodialysis patients, representing over 20% of all hospitalizations. It has been reported that this morbidity accounts for as much as 25% of total end-stage renal disease costs (Butterly, D.; Schwab, S. J.;  Reducing the Risk of Hemodialysis Access,  Am. J. Kidney Dis. 34:362-363, (1999)), and in 1996 Feldman and co-workers reported the annual costs of access-related morbidity in the United States to amount to $1 billion Feldman, H. I.; Kobrin, S.; Wasserstein, A.;  Hemodialysis Vascular Access Morbidity , J. Am. Soc. Nephrol. 7:523-535 (1996)).  
           [0006]    One major cause of access dysfunction is the development of vascular stenosis. Vascular stenosis is the abnormal narrowing or constriction of blood vessels. Stenosis causes impairment in the quality of the dialysis procedure and increases the risk of blood clots. Several clinical strategies are commonly used to detect stenosis, such as monitoring venous dialysis pressure, intra-access pressure monitoring and measurement of access recirculation and/or access flow. Correction of the stenotic vessel using percutaneous angioplasty or surgical revision reduces the rate of thrombosis and prolongs survival of the access. However, considering both the suffering of the patients and the associated costs for society it seems equally important to try to identify the underlying pathogenic mechanisms of access stenosis so that preventative strategies can be developed and implemented.  
           [0007]    Similarly, access stenosis is the abnormal narrowing or constriction of the access site or fistula. As noted above, access stenosis may also be caused by deposits in the access site or fistula. One such pathogenic mechanism leading to access stenosis may be caused by the breakdown products formed in the blood during cellular metabolism. Such breakdown products are acidic, and consequently cause the blood to become acidic. In people with normal kidney function, the physiological buffer bicarbonate is released from the kidneys in response to a low blood pH, to increase the blood pH to a more neutral level. In patients on dialysis however, this buffering capacity is no longer available from their kidneys, and must be provided by the dialysis procedure. One consequence of the loss of kidney function is that phosphate ions are no longer excreted by the kidneys and thus accumulate in the blood plasma. Low blood acidity may trigger the precipitation of soluble ions such as phosphorous out of the patient&#39;s blood. Such precipitation may cause crystals to form in a patient&#39;s veins and in the access site or fistula. Calcification of the access site may also occur. Calcification is the hardening of tissue resulting from the deposition of calcium salts and other minerals within the tissue. Calcification may consist of deposition of crystals of calcium phosphate such as brushite, which precipitates out of blood in an acidic environment. Brushite is formed most probably via the reaction of Ca+HPO 4 →CaHPO 4 . Furthermore, the shape of the brushite crystals may cause activation and damage to both the circulating blood cells as well as to the cells of the vascular wall. In support of this hypothesis, it has been shown that aggregating platelets and fibrin may be found around depositions of brushite in a stenotic vein.  
           [0008]    It is believed as noted above that the deposition of calcium phosphate and subsequent deposition of brushite might be involved in the development of stenotic lesions in AV-fistulas of patients in chronic renal failure. Brushite may form in the A-V fistula because the combined concentrations of calcium and phoshate in both the blood and in the dialysis fluid are too high. The deposition of brushite in a fistula may occur because the fistula is a location where blood to be dialysed containing both a high phosphorous ion concentration and a low pH comes in contact with blood which has been dialysed and contains both a lower concentration of ions as well as a higher pH.  
           [0009]    In a dialysis procedure both calcium and phosphate ions are transferred from the blood side of the dialyzer to the dialysate side. However, the blood calcium level must be kept above a certain level (about 1.0 mM to prevent life-threatening physiologic failures. To prevent such life-threatening physiologic failures, a hemodialysis procedure must therefore involve the addition of calcium ions to the dialysate to compensate for the blood calcium lost through the dialysis procedure. It is to this difficult balance of calcium regulation in the dialysis fluid and the prevention of brushite formation in an A-V fistula that the present invention is directed.  
         SUMMARY OF THE INVENTION  
         [0010]    The invention comprises a method for reducing the loss of functionality of a fistula in a patient undergoing dialysis treatment wherein blood is removed from the patient&#39;s body at the fistula, circulated through a blood side of a dialyzer and returned to the patient&#39;s body at the fistula, and wherein a solution is administered to the patient which comprises administering the solution to the patient at a first calcium concentration for a first period of time; and administering the solution to the patient at a second calcium concentration, greater than the first calcium concentration, for a second period of time following the first period of time. A solution, comprising calcium is commonly known as a calcium solution. “Administrating” or “administered” means administering or delivering to a patient. A method is also provided for varying the concentration of calcium over time.  
           [0011]    The invention further comprises a method for reducing the loss of functionality of a fistula in a patient undergoing dialysis treatment wherein blood is removed from the patient&#39;s body at the fistula, circulated through a blood side of a dialyzer and returned to the patient&#39;s body at the fistula, and wherein calcium is administered to the patient which comprises administering calcium at a first rate, and increasing the rate of calcium administered to the patient over time. A method is also provided for varying the flow rate of the calcium solution over time. The invention also comprises a system for dialysis comprising a first flow circuit for a dialysate solution, a second flow circuit for blood, a filtration unit which includes a semi permeable membrane which divides the filtration unit into a first chamber connected to the first flow circuit and a second chamber connected to the second flow circuit, in which the system is characterized by a supply of calcium concentrate to provide a calcium concentrate fluid flow, and a calcium concentrate fluid flow regulating device for controlling the flow of calcium concentrate fluid. Reference to delivery and administration is found in the “Handbook of Dialysis” 1988, J. T. Daugirdas and T. S. Ing, Little, Brown &amp; Co., Boston/Toronto. 
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0012]    [0012]FIG. 1 shows an arterio-venous fistula created in the arm of a dialysis patient.  
         [0013]    [0013]FIG. 2 is a graph of the X-ray spectral patterns of the ions deposited on the interior wall of a stenotic fistula.  
         [0014]    [0014]FIG. 3 is a graph of the X-ray spectral patterns of the ions deposited on the interior wall of a non-stenotic fistula.  
         [0015]    [0015]FIG. 4 depicts a representative profile of calcium to phosphorous ions in the dialysate fluid during a dialysis procedure.  
         [0016]    [0016]FIG. 5 is a schematic representation of a dialysis circuit that may be used to vary the amount of calcium during the dialysis procedure.  
         [0017]    [0017]FIG. 6 is a schematic representation of another embodiment of a dialysis circuit that may be used to vary the amount of calcium during the dialysis procedure. 
     
    
     DETAILED DESCRIPTION  
       [0018]    As introduced above, a fistula is generally used in a dialysis procedure to access a patient&#39;s blood stream. The general term dialysis as used here includes hemodialysis, hemofiltration, hemodiafiltration and therapeutic plasma exchange (TPE), among other similar treatment procedures. In dialysis generally, blood is taken out of a patient&#39;s body and exposed to a treatment device to separate substances therefrom and/or to add substances thereto, and is then returned to the body. Although the dialysis procedure used in the present invention will be described by way of example with respect to hemodialysis, it is understood that the invention is not so limited in scope.  
         [0019]    [0019]FIG. 1 shows an arterio-venous fistula  60  created, for example, in the arm  18  of a dialysis patient. The surgically created connection  60  between an artery  86  and a vein  9  serves as the location of vascular access to the patient&#39;s blood. Blood needing to be dialyzed is withdrawn from the fistula and cleaned blood that has been dialyzed is returned to the patient through the fistula. A fistula is usually located in the arm of a patient, but may be located anywhere a fistula may be placed.  
         [0020]    [0020]FIG. 2 shows a graph of the X-ray spectral patterns of the ions found deposited on the interior walls of a human stenotic fistula. As shown in the graph, the concentration of phosphorus ions to calcium ions are found in a 1:1 ratio. This corresponds to descriptions of brushite formation in the literature, which describe a 1:1 ratio of phosphorus to calcium. (Elliot, J. C.;  Structure and Chemistry of the Apatites and Other Calcium Orthophosphates,  Stud. In Inorganic Chem., 18, 23-30 (1994)). In brushite formation, phosphorus exists as monohydrogen phosphate, and deposition of brushite occurs through the direct reaction between the monohydrogen phosphate ion and the calcium ion.  
         [0021]    In comparison, FIG. 3 shows a graph of the X-ray spectral patterns of the ions deposited on the interior wall of a non-stenotic fistula. As shown in the graph of FIG. 3, the concentration of phosphorus to calcium ions in a non-stenotic fistula is not found in a 1:1 ratio. This finding corresponds to the lack of brushite crystals found in a non-stenotic fistula.  
         [0022]    In order to prevent the formation of brushite in a fistula due to the 1:1 concentration of calcium ions to phosphorous ions such as that shown in FIG. 2, the concentration of calcium administered to a patient during the dialysis procedure may be varied over time. As shown in FIG. 4, the amount of calcium present in the dialysate may be varied over the time of the procedure, as well as varied in accordance with any decrease in concentration of phosphorous in the plasma. Alternatively, calcium may be varied over time in a step-wise fashion (not shown). A sensor may also be used which detects the concentration of phosphorous in the blood plasma of the individual patient and adjusts the calcium concentration accordingly. In another alternative, a calcium profile could be set up which presumes that the phosphorous concentration in blood plasma decreases at a standard rate regardless of the patient, and so utilizes a standard profile.  
         [0023]    Calcium profiling is premised on the fact that the blood level of monohydrogen phosphate decreases during the dialysis session. Therefore, at some time period after the start of the dialysis procedure, when monohydrogen phosphate level is low enough that it is unlikely brushite formation will occur, the addition of calcium to the blood or to the dialysate fluid may be initiated.  
         [0024]    To further clarify, the calcium ion concentration in the fistula depends to some extent on the concentration of calcium contained in the dialysate fluid, whereas the phosphorous ion concentration comes solely from plasma phosphate. If the concentration of phosphate in blood plasma may be decreased by dialysate having a low concentration of calcium, then when the dialysis session has been going on for some period of time, for example between 15 to 30 minutes as shown in the exemplary profile of FIG. 4, the concentration of plasma calcium may then be increased by addition of calcium to the dialysate fluid. Such calcium profiling may help decrease the likelihood of brushite formation. This concept assumes that the concentration of phosphorous ions in the blood is highest at the beginning of a dialysis procedure and subsequently decreases over time as the procedure continues. Furthermore, by keeping the pH of the dialysate high, calcium and phosphate ions will more easily remain in solution, and possible brushite formation in a fistula may be potentially avoided.  
         [0025]    [0025]FIG. 4 shows one proposed profile of the ratio of calcium ions in the dialysate to phosphorus ions in the blood of a dialysis patient during a dialysis procedure in accordance with the instant invention. The concentration of calcium ions in the dialysate is graphed against the concentration of phosphorus ions in blood plasma over time. As shown in FIG. 4, at the beginning of the dialysis procedure, at a first period of time, the concentration of phosphorus in the blood plasma is high. Accordingly, the concentration of calcium administered to the patient in either the dialysate fluid or directly into the patient&#39;s blood is kept low. As the dialysis procedure progresses, at a second period of time, the amount of phosphorous in the blood decreases due to filtration by the dialyzer. Accordingly, the concentration of calcium in the dialysate solution is increased. By varying the concentration of calcium in response to the concentration of phosphorus in the blood in accordance with the instant invention, the formation of brushite crystals in the fistula may be avoided, thereby decreasing the probability of calcification of the fistula and subsequent stenosis due to brushite formation.  
         [0026]    In another embodiment, (not shown) the amount of calcium administered to the patient either in the dialysis fluid or directly into the patient&#39;s blood may be increased by increasing the flow rate of the solution containing calcium over time.  
         [0027]    The profile shown in FIG. 4 is merely exemplary, and is not meant to be limiting. It is understood that other profiles could be developed by those skilled in the art utilizing the principles described herein. The use of different profiles will be described in greater detail below.  
         [0028]    Here below follows descriptions of embodiments which are currently believed to be solutions to avoid the formation of brushite in fistulas of dialysis patients.  
         [0029]    Referring to the figures, in which like reference numerals refer to like portions thereof, FIG. 5 shows by way of a schematic diagram one embodiment of an extracorporeal blood treatment system capable of performing a calcium profiling procedure according to the present invention.  
         [0030]    A first flow circuit  40  for a dialysis procedure comprises a main or primary conduit  1  which originates from a suitable source of water, such as a liquid reservoir or heating vessel  2 . The liquid reservoir  2  may include an inlet  15  for introduction of pure water thereinto, for example, from a reverse osmosis unit (not shown). The main conduit  1  may include a throttling mechanism  3 , a pressure gauge  4 , a pump  5  and a deaerating device  6  which may be provided with an air outlet (not shown). The main conduit may also contain one or more conductivity meters  14  and  26  respectively.  
         [0031]    Water may enter the first flow circuit  40  from the liquid reservoir  2  via the main or primary conduit  1  or alternatively may enter the circuit through a first concentrate circuit  8 . Concentrate circuit  8  may contain a powder concentrate column  10 , which may contain sodium bicarbonate powder. The first concentrate circuit  8  communicates with the main conduit  1  at a mixing point  7 . A conductivity meter  14  or other measuring device may also be provided in the main conduit  1 . The conductivity meter  14  or other measuring device is adapted to control a flow regulating device or pump  13  provided in the concentrate conduit  8  downstream of the powder concentrate column  10 . If, as described below, the flow regulating device  13  is a throttle, the main line throttle device  3  should be located upstream of the mixing point  7  as shown. According to another embodiment, the flow regulating device may be a metering dosage pump, a variable displacement pump, or a proportional valve (not shown).  
         [0032]    As mentioned, the flow regulating device  13  may be a simple adjustable throttling device. This is advantageous in that a single pump  5  may be employed for withdrawing water from the reservoir  2  for both the main dialysate flow through line  1  and for production of the concentrate fluid in fluid conduit  8 . If the throttling device  3  is located in the main line  1  between the source of water  2  and mixing point  7 , and if the deaerating device  6  is located in the main duct downstream of pump  5 , the same pump  5  may also be used to deaerate both the main line  1  and the prepared dialysate fluid. For the preparation of dialysate fluids, the pump  5  is preferably operative to handle flow rates up to at least 500 ml/min, and more preferably, up to approximately 1,000 ml/min in the main line  1 . The flow regulating means  13  on the other hand should be preferably operative to handle flow rates up to approximately 40 ml/min or at least 30 ml/min at flow rates of approximately 1,000 ml/min in the main line  1 .  
         [0033]    A second mixing point  23  is provided downstream of conductivity meter  14 . At mixing point  23 , a second concentrate fluid preferably containing sodium chloride, magnesium chloride, potassium chloride, small amounts of acetic acid and glucose may be introduced into the main line  1  via a second concentrate conduit or duct  24 . This second concentrate may be in a solid or a liquid form, however, in the preferred embodiment, the concentrate is in a liquid form. The second concentrate  25  corresponds substantially to the conventional “A” concentrate known in the art. In a preferred embodiment, the second concentrate does not contain calcium. The flow of second concentrate fluid through the second concentrate duct  24  may be regulated with the aid of a conductivity meter  26  or other measuring device which may be located downstream of mixing point  23  in the main conduit  1 . Conductivity meter  26  controls a flow regulating device  27 , located in the second concentrate duct  24 .  
         [0034]    In the embodiment shown in FIG. 5, a third mixing point  53  may be provided downstream of conductivity meter  26 . At mixing point  53 , a fluid containing concentrated calcium may be introduced into the primary conduit  1  via a third concentrate conduit or duct  54 . Duct  54  communicates with a source of concentrate  55 , which in this instance, is a container containing calcium concentrate. The concentrated calcium may be in a solid or a liquid form such as a calcium solution without departing from the spirit and scope of the invention. According to one embodiment, the calcium concentration in a dialysate solution may be a solution containing calcium chloride. The calcium solution may have a variable amount of calcium of between 1 mM to 1.75 mM (Kracler, M., Scharfetter, H., Wimsberger, G. H.,  Clinical Nephrology,  2000, 54:35-44, and Argiles i Ciscart, A,  Nephrol Dial. Transplant.  1995, 10:451-454).  
         [0035]    The amount of calcium concentrate released through the third concentrate duct  54  may be regulated with the aid of a conductivity meter  56  or other measuring device located in the main conduit  1 . Conductivity meter  56  may control a flow regulating device  57  located in concentrate duct  54 . Flow regulating device  57  may be a variable output pump or may be a proportional valve.  
         [0036]    Thus, as shown in FIG. 5, it will be appreciated that if three concentrates  10 ,  25  and  55  respectively are to be conducted to the main duct  1  at three separate mixing points  7 ,  23  and  53  it is important that conductivity meters  14 ,  26  and  56  or other similar measuring devices for accurate monitoring of the composition of the prepared solution be used. In this fashion, the dialysate solution composition may be accurately monitored both upstream as well as downstream of the second and third mixing points  23  and  53 .  
         [0037]    For ultimate monitoring of the pH of the prepared dialysate solution, an optional pH meter  28  maybe located in the main conduit  1  downstream of the third mixing point  53 , but upstream of a bypass valve  29  and a main valve  30  through which the system may be connected to a dialyzer  100 . If the measurements obtained in the main conduit  1  from any one or all of conductivity meters  14 ,  26  or  56  and/or pH meter  28  are not in accord with the desired values, the main valve  30  may be closed and bypass valve  29  opened. For this purpose, conductivity meters  14 ,  26  and  56  and pH meter  28  are all shown as providing input for controlling valves  29  and  30 . Although the various meters for measuring the properties of the fluid being conducted through main conduit  1  preferably control the valves  29  and  30 , it will also be appreciated that it is possible instead to control one or more of the pumps  5 ,  13 ,  27  and  57  to stop or otherwise alter the flow of fluid into and through the various conduits.  
         [0038]    As shown in FIG. 5, control unit  110  is preferably connected to the variable output pump  57  for controlling the concentration of calcium in the dialysate as a function of time. For this purpose the control unit  110  receives a signal from conductivity meter  56  and sends a control signal to pump  57 . Thus the variable output pump  57  is controlled by a closed loop feedback system. A number of profiles of a desired calcium concentration versus time may be stored in the control unit  110 . One example of such a profile is shown in FIG. 4 described above. Because patients react very differently to low calcium concentrations, one embodiment may comprise the personal calcium concentration profiles of individual patients stored in control unit  110 . Another embodiment may be to store specific profiles for certain patient types or patient groups. The control unit  110  may also comprise a user interface  115  for manual or automatic adjustment and selection of a specific calcium profile. According to another embodiment the control unit  110  communicates with other control elements (not shown) of the dialysis system for exchange of data in order to perform an automatic selection and adjustment of a calcium profile.  
         [0039]    In the embodiment of FIG. 5, downstream of valve  30  a flow meter  46  may be located in the primary conduit  1 . The primary conduit  1  extends to the filtration or processing unit  100 . In dialysis, filtration unit  100  may be a dialyzer, which may also be referred to as a filter. The dialyzer or filtration unit  100  may be a hemodialfiltration unit, a hemofiltration unit, an ultrafiltration unit, or other types of filtration devices known in the art. Filtration unit  100  is shown schematically divided into a primary chamber  101  separated from a secondary chamber  102  by a semi-permeable membrane  103  (not shown in detail). In this extracorporeal system, primary chamber  101  of the dialyzer  100  accepts fluid from the dialysate or first flow circuit  40  and secondary chamber  102  accepts blood from the blood or second flow circuit  12 . A conduit  68  extends from flow meter  47  to pump  63 , which transports the dialysate to an outlet  64 . Another conduit  69  connects the outlet of valve  29  to conduit  68 .  
         [0040]    As introduced above, the system generally includes a second flow circuit  12 , which is an extracorporeal blood flow circuit, having first and second conduits  71  and  72  which are both connected to the vascular system of a patient (see element  60  of FIG. 1). Blood access and return devices  76  and  77  respectively, remove and return blood to the patient. The access and return devices  76  and  77  may be cannulas, catheters, winged needles or the like as understood in the art. Conduits  71  and  72  are also connected to the filtration or processing unit  100 . A peristaltic pump  80  is disposed in operative association with the first conduit  71 . In FIG. 5, the extracorporeal blood flow circuit  12  preferably includes a conventional anticoagulant pump  85  for mixing anticoagulant such as heparin into the flow of blood at a mixing point  74 . The anticoagulant pump  85  may be a syringe filled with heparin concentrate and may contain an actuator  87  that may be controlled from a control unit (not shown). As understood in the art, an air bubble trapping drip chamber  66  for deaerating the blood is shown in the second conduit  72 . A bubble detector  67  is often included on or adjacent to bubble trap  66 . Numerous other component devices may be used in the extracorporeal blood flow circuit  12  without departing from the spirit and scope of the invention. Pressure sensors  88 ,  89  and  90  may be included in the extracorporeal circuit as well as tubing clamps  61  and  62 .  
         [0041]    As shown in FIG. 6, and as previously described above with reference to the embodiment described in FIG. 5, the first flow circuit for a dialysis solution comprises a main or primary conduit  1  in which various concentrates may be mixed. Except as described in further detail below, the embodiment of FIG. 6 is similar to the embodiment described in FIG. 5, wherein like numbers represent corresponding like elements. Repeat description of these elements will not be further repeated here. In FIG. 6, the calcium concentrate sub-system (see mixing point  53 , tubing  54 , container  55  and pump  57  of FIG. 5) is not included for connection into primary line  1 .  
         [0042]    In FIG. 6 a calcium pump  95  similar in construction to conventional anticoagulant pump  85  may be used to deliver calcium to the blood flow side of extracorporeal circuit  12 . The pump  95  delivers calcium to the circuit  12  at a calcium mixing point  75  located in conduit  71  downstream of the anticoagulant mixing point  74 . Some calcium added to blood circuit  12  from pump  95  may migrate across membrane  103  of the filter  100  and may enter the dialysis circuit  40 . Once calcium enters the dialysis circuit  40 , some calcium may be lost via the dialysate outlet  64 . Because of this, calcium must be added to the system in a higher concentration or amount than necessary for the patient, with the understanding that some amount of calcium will be lost to the dialysis circuit side  40 .  
         [0043]    An alternative embodiment (not shown) to prevent the loss of calcium across the membrane  103  is to connect a calcium pump similar to pump  95  shown in FIG. 6 to the blood circuit side  12  at location  42  of tubing segment  72 . Such a connection may prevent calcium from entering the dialysis circuit. The calcium would flow directly into the patient via blood return device  76 .  
         [0044]    The calcium pump  95  may be a syringe containing calcium concentrate infusion fluid and may also be connected to an actuator mechanism  97 , which may in turn be connected to control unit  110 .  
         [0045]    According to another embodiment (not shown) the calcium pump for delivering the calcium concentrate may be a peristaltic pump. For accurate dosing of a patient, the calcium concentrate may also be supplied from a bag that is suspended from a balance. A signal from the balance may be used by the control unit  110  to drive the pump. The addition of calcium into the extracorporeal circuit may also be added at other locations within the circuit without departing from the spirit and scope of the present invention. Calcium addition can be by other well known methods and means including but not limited to a stepper motor.  
         [0046]    It has been further hypothesized that the pH of blood may play a role in the formation of brushite crystals in a fistula. At a pH less than 7.3, calcium phosphate may precipitate out of the blood in such a way as to form brushite crystals. At a blood pH greater than 7.5 however, calcium phosphate may precipitate out of the blood as hydroxyapatite crystals, which do not contribute to the formation of stenosis in a fistula. Another way to avoid brushite formation is to keep the pH of plasma sufficiently high in some way, either with or without the calcium profiling described above. This might be achieved by acetate free bio-filtration (not shown) or by infusing bicarbonate directly into the blood stream (not shown).  
         [0047]    It should be understood that various changes and modifications to the described embodiments will be apparent to those skilled in the art. These examples are not meant to be limiting, but rather are exemplary of the modifications that can be made without departing from the spirit and scope of the present invention and without diminishing its attendant advantages.