APPARATUS FOR PROVIDING AUTOMATED PERITONEAL DIALYSIS

Abstract

An apparatus peritoneal dialysis (1) comprising an automated peritoneal dialysis cycler (3) programmed to run a treatment session including a plurality of cycles, each cycle including a fill phase, a dwell phase and a drain phase of a peritoneal cavity of a patient (P), the treatment session lasting at most 720 min; the cycler (3) has a patient line (54) in communication with the patient (P), a source (S) of treatment fluid which includes an osmotic agent, a pump (5) to circulate the treatment fluid and a control system (74) configured to drive the cycler (3) to deliver the treatment session. The control system (74) is programmed to run a fill phase of a first cycle delivering a first treatment fluid to the patient, the first treatment fluid having a first concentration of the osmotic agent; subsequently to the first cycle, to run a fill phase of a second cycle delivering a second treatment fluid to the patient, the second treatment fluid having a second concentration of the osmotic agent different from the concentration of the first treatment fluid; subsequently to the second cycle, to run a fill phase of a third cycle delivering a third treatment fluid to the patient, the third treatment fluid having a third concentration of the osmotic agent different from the concentration of the second treatment fluid. The second concentration of the osmotic agent is lower than the first concentration of the osmotic agent and the third concentration of osmotic agent is higher than the second concentration of osmotic agent.

Claims

1-25. (canceled)

26. An apparatus for peritoneal dialysis comprising: an automated peritoneal dialysis cycler programmed to run a treatment session including a plurality of cycles, each cycle including a fill phase, a dwell phase, and a drain phase of a peritoneal cavity of a patient, the treatment session lasting at most 720 min, the cycler having: a patient line configured to be placed in communication with the peritoneal cavity of the patient; at least a source of treatment fluid which includes an osmotic agent; and at least one pump to circulate the treatment fluid to be delivered to the patient through said patient line; and a control system configured to drive said cycler to deliver the treatment session, wherein, during the same treatment session, the control system configured to: run a fill phase of a first cycle delivering a first treatment fluid to the patient, the first treatment fluid having a first concentration of the osmotic agent; subsequently to the first cycle, run a fill phase of a second cycle delivering a second treatment fluid to the patient, the second treatment fluid having a second concentration of the osmotic agent different from the concentration of the first treatment fluid; and subsequently to the second cycle, run a fill phase of a third cycle delivering a third treatment fluid to the patient, the third treatment fluid having a third concentration of the osmotic agent different from the concentration of the second treatment fluid, wherein the second concentration of the osmotic agent is lower than the first concentration of the osmotic agent and the third concentration of osmotic agent is higher than the second concentration of osmotic agent, or wherein the second concentration of the osmotic agent is higher than the first concentration of the osmotic agent and the third concentration of osmotic agent is lower than the second concentration of osmotic agent.

27. The apparatus according to claim 26, wherein the osmotic agent is, or includes, glucose, L-carnitine, glycerol, or combinations thereof, in particular the osmotic agent being or including glucose.

28. The apparatus according to claim 26, wherein the control system is programmed to run the first cycle followed by one or more additional cycles before running the second cycle and/or wherein the control system is programmed to run the second cycle followed by one or more additional cycles before running the third cycle.

29. The apparatus according to claim 26, wherein the control system is programmed to run the first cycle immediately followed by the second cycle and/or wherein the control system is programmed to run the second cycle immediately followed by the third cycle.

30. The apparatus according to claim 26, wherein, during the same treatment session, the control system delivers a plurality of cycles using a treatment fluid with high concentration of osmotic agent, alternating with a plurality of cycles using a treatment fluid with low or no concentration of osmotic agent, said high concentration of osmotic agent being higher than said low concentration of osmotic agent.

31. The apparatus according to the claim 30, wherein the treatment fluid with high concentration of osmotic agent includes a concentration of osmotic agent equal to or higher than 3% by weight, optionally equal to or higher than 4% by weight, and in more detail equal to or higher than 5% by weight, said osmotic agent being in particular glucose.

32. The apparatus according to claim 30, wherein the treatment fluid with low concentration of osmotic agent includes a concentration of osmotic agent equal to or lower than 2% by weight, optionally equal to or lower than 1.5% by weight, and in more detail equal to or lower than 0.5% by weight, said osmotic agent being in particular glucose.

33. The apparatus according to claim 30, wherein during said plurality of cycles using a treatment fluid with high concentration of osmotic agent alternating with said plurality of cycles using a treatment fluid with low or no concentration of osmotic agent, the cycle using a treatment fluid with high concentration of osmotic agent is followed by one or more subsequent cycles before the cycle using a treatment fluid with low or no concentration of osmotic agent.

34. The apparatus according to claim 30, wherein during said plurality of cycles using a treatment fluid with high concentration of osmotic agent alternating with said plurality of cycles using a treatment fluid with low or no concentration of osmotic agent, the cycle using a treatment fluid with low or no concentration of osmotic agent is followed by one or more subsequent cycles before the cycle using a treatment fluid with high concentration of osmotic agent.

35. The apparatus according to claim 30, wherein during said plurality of cycles using a treatment fluid with high concentration of osmotic agent alternating with said plurality of cycles using a treatment fluid with low or no concentration of osmotic agent, the cycle using a treatment fluid with high concentration of osmotic agent is immediately followed by the cycle using a treatment fluid with low or no concentration of osmotic agent.

36. The apparatus according to claim 30, wherein during said plurality of cycles using a treatment fluid with high concentration of osmotic agent alternating with said plurality of cycles using a treatment fluid with low or no concentration of osmotic agent, the cycle using a treatment fluid with low or no concentration of osmotic agent cycle is immediately followed by the cycle using a treatment fluid with high concentration of osmotic agent.

37. The apparatus according to claim 26, wherein the control system is configured to leave the treatment fluid in the peritoneal cavity for a dwell time, the dwell time of a treatment fluid with higher osmotic agent concentration being different from, and in particular lower than, a dwell time of a treatment fluid with lower or no osmotic agent concentration.

38. The apparatus according to claim 26, wherein the cycler includes at least two sources of treatment fluid, each source being configured for feeding a treatment fluid that differs from a treatment fluid of another source, the treatment fluids differing at least by the concentration of the osmotic agent, in particular each source being a respective treatment fluid bag.

39. The apparatus according to claim 26, wherein the cycler includes a disposable unit including said patient line configured to be connected to the patient and a peritoneal dialysis unit including said pump and a compartment configured to receive the disposable unit, the pump being arranged so that when the disposable unit is disposed within the compartment, the pump cooperates with the disposable unit to deliver the treatment fluid to and drain the treatment fluid from the peritoneal cavity of the patient via the patient line of the disposable unit.

40. The apparatus according to claim 39, wherein the disposable unit includes at least one inlet port connected to a source of treatment fluid and at least one container configured for receiving the treatment fluid from the source, in particular the cycler being configured to heat the treatment fluid in the container for receiving the treatment fluid before delivering the treatment fluid to the patient via the patient line.

41. The apparatus according to claim 39, wherein the disposable unit includes at least two inlet ports, said inlet ports being respectively connected to sources of treatment fluid having different concentrations of osmotic agent, in particular a different concentration of glucose.

42. The apparatus according to claim 41, wherein the cycler includes a valve device to selectively put into communication one of the sources of treatment fluid with the container for receiving the treatment fluid, the control system receiving a target concentration of osmotic agent in the treatment fluid and driving the valve device and the pump to withdraw a prefixed amount of treatment fluid from one of the sources and a prefixed amount of treatment fluid from at least another of the sources to obtain a treatment fluid in the container for receiving the treatment fluid with a concentration of osmotic agent substantially matching the target concentration.

43. The apparatus according to claim 26, comprising a sensor for sensing a parameter of the treatment fluid to be delivered to the patient via the patient line, the control system being further configured to receive a signal from said sensor and for determining the concentration of osmotic agent in the treatment fluid to be delivered to the patient.

44. The apparatus according to claim 39, comprising at least one source of a first concentrate, wherein the disposable unit includes: a water port; at least a first inlet port in fluid connection with said source of a first concentrate; and at least a container configured for receiving a treatment fluid prepared by mixing at least water and a first concentrate.

45. The apparatus according to claim 44, including: a water purifier for preparing purified water and feeding purified water to said water port, a water line for feeding purified water to the water port of the disposable unit, said water line being fluidly connected to the water purifier to receive purified water; a drain line connected to a drain port of the disposable unit to drain fluids at least from the disposable unit; and a sensor for detecting a property of a fluid flowing in the drain line, wherein the control system is further configured to: send the treatment fluid to be checked contained in the container configured for receiving a treatment fluid into the drain line; and push the treatment fluid to be checked to the sensor, and wherein the control system is further configured to push the treatment fluid by sending purified water along the water line and directing said purified water from the water line into the drain line, said purified water in the drain line pushing the treatment fluid to be checked so as to reach the sensor.

46. The apparatus according to claim 26, wherein the control system includes a memory storing a prediction algorithm, the control system, based on said prediction algorithm, being configured to determine at least the first concentration of osmotic agent in the first treatment fluid, the second concentration of osmotic agent in the second treatment fluid, and the third concentration of osmotic agent in the third treatment fluid.

47. The apparatus according to claim 46, wherein the control system, based on said prediction algorithm, is configured to determine at least a first dwell time for the first treatment fluid, a second dwell time for the second treatment fluid, and a third dwell time for the third treatment fluid.

48. The apparatus according to claim 46, wherein the control system receives as input a desired total ultrafiltration (UF) volume to be removed at the end of the treatment session and/or a desired total small solute removal target to be removed at the end of said treatment session and provides said first, second, and third concentrations for the osmotic agent as an output.

49. The apparatus according to claim 46, wherein the control system receives as input a total number (N) of cycles of the treatment session and provides as an output, based on said prediction algorithm, a corresponding concentration of osmotic agent and a corresponding dwell time for each of the N cycles to achieve a desired total ultrafiltration (UF) volume and desired total small solute removal target at the end of the treatment session.

50. The apparatus according to claim 46, wherein the prediction algorithm includes a modified three pore model based on the equation: $\frac{{\mathrm{dV}}_d}{\mathrm{dt}}=J_{v,C}+J_{v,S}+J_{v,L}-L+J_{\mathrm{fill}}-J_{\mathrm{drain}.Math.}$ wherein: J.sub.v,C is a net flow of water (in mL/min) across aquaporins; J.sub.v,S is a net flow of water (in mL/min) across highly selective pathways; J.sub.v,L is a net flow of water (in mL/min) across weakly selective pathways; L is a net lymphatic clearance (in mL/min) from the peritoneal cavity to the circulation; J.sub.fill is a flow of volume (in mL/min) to the source of treatment fluid; and J.sub.drain is a flow of volume (in mL/min) from the source of treatment fluid.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0147] The description will now follow, with reference to the appended figures, provided by way of non-limiting example, in which:

[0148] FIG. 1 schematically represents an apparatus for peritoneal dialysis made according to an illustrating embodiment;

[0149] FIG. 1a shows a disposable unit including a cassette to be used with the apparatus of FIG. 1 or 2;

[0150] FIG. 1b schematically shows a hydraulic circuit in the disposable cassette of the automated peritoneal dialysis cycler;

[0151] FIG. 2 schematically represents an apparatus for peritoneal dialysis made according to an alternative illustrating embodiment;

[0152] FIG. 3 schematically represents an apparatus for peritoneal dialysis made according to another illustrating embodiment;

[0153] FIG. 4 is a perspective view of a peritoneal blood vessel showing the different sizes of pores used in a three pore model for predicting peritoneal dialysis therapy results;

[0154] FIG. 5 shows simulated urea clearances as a function of DFR for the different techniques (IPD, TPD75/50/25), different transport types: Fast (lines labeled A), Average (lines labeled C), Slow (lines labeled B) and three different glucose concentrations: 1.5% (dotted line), 2.27% (solid line) and 3.86% (dashed line);

[0155] FIG. 6 shows osmotic water transport (UF) per session hour as a function of DFR for the different techniques (IPD, TPD75/50/25), different transport types: Fast (lines labeled A), Average (lines labeled C), Slow (lines labeled B) and three different glucose concentrations: 1.5% (dotted line), 2.27% (solid line) and 3.86% (dashed line);

[0156] FIG. 7 shows osmotic water transport (UF) in mL per gram glucose absorbed (or UF efficiency) plotted as a function of DFR for the different techniques (IPD, TPD75/50/25), different transport types: Fast (lines labeled A), Average (lines labeled C), Slow (lines labeled B) and three different glucose concentrations: 1.5% (dotted line), 2.27% (solid line) and 3.86% (dashed line);

[0157] FIG. 8 shows the small solute transport efficiency (in mmol urea removed per g glucose absorbed) as a function of DFR for the different techniques (IPD, TPD75/50/25), different transport types: Fast (lines labeled A), Average (lines labeled C), Slow (lines labeled B) and three different glucose concentrations: 1.5% (dotted line), 2.27% (solid line) and 3.86% (dashed line);

[0158] FIG. 9 shows the clearance of .sub.2-microglobulin as a function of DFR for the different techniques (IPD, TPD75/50/25), different transport types: Fast (lines labeled A), Average (lines labeled C), Slow (lines labeled B) and three different glucose concentrations: 1.5% (dotted line), 2.27% (solid line) and 3.86% (dashed line);

[0159] FIG. 10 shows osmotic water transport (UF) in mL per liter dialysis fluid consumed as a function of DFR for the different techniques, transport types and different glucose concentrations: Fast (lines labeled A), Average (lines labeled C), Slow (lines labeled B) and three different glucose concentrations: 1.5% (dotted line), 2.27% (solid line) and 3.86% (dashed line);

[0160] FIG. 11 shows simulated scenarios where each dwell is optimized for either UF (using 3.86% glucose) or small-solute transport (using 0% glucose) keeping the glucose absorption low (the corresponding transport parameters are shown in Table 3);

[0161] FIG. 12 shows other simulated scenarios where each dwell is optimized for either UF (using 6% or 3.86% glucose) or small-solute transport (using 0% or 0.55% glucose) keeping the glucose absorption low.

DETAILED DESCRIPTION

[0162] FIG. 1 illustrates an apparatus 1 for peritoneal dialysis treatment in an embodiment of the invention.

[0163] The apparatus 1 is generally intended for the on-site treatment of a patient P with proper treatment fluid/s.

[0164] More in detail the system is designed for treating patients suffering of renal insufficiency, particularly with an automated peritoneal dialysis (APD) cycler 3.

[0165] The APD cycler 3 comprises a peritoneal dialysis (PD) unit 3a and a corresponding disposable unit 3b. The PD unit 3a includes a control system 74 and all the sensors and actuators to properly move the fluids inside the hydraulic circuit of the disposable unit 3a, as well as a user interface to e.g. input/output of data.

[0166] The disposable unit 3b (represented in FIG. 1a) is connectable on the PD unit 3a and includes a patient line 54 to be connected to a catheter implanted in the patient P to allow fill and drain operations of the peritoneal cavity of the patient him/herself.

[0167] The apparatus for peritoneal dialysis 1 includes two or more sources S of treatment fluid connected by means of respective feeding lines to corresponding treatment ports 7, 8, 9 of the disposable unit 3a.

[0168] FIG. 1 shows three sources S of treatment fluid in the form of collapsible bags 6 filled with respective dialysate solutions. The content of each of the bag 6 is intended to be delivered to the peritoneal cavity of the patient, eventually after being heated.

[0169] In particular at least two (and eventually each) of said sources S include treatment fluids differing one from the other at least in respect to the concentration of an osmotic agent contained therein.

[0170] It is noted that the osmotic concentration of the treatment fluid relative to the blood determines to what extent fluids are exchanged between the PD solution and the blood. A high osmotic concentration in the treatment fluid creates a high gradient.

[0171] In any of the described embodiments, the osmotic agent may be, or include, glucose (or polyglucose), L-carnitine, glycerol, icodextrin, or any other suitable agents. Alternative osmotic agents may be fructose, sorbitol, mannitol and xylitol.

[0172] Glucose at concentration of 1.36%, 2.27% and 3.86% weigh/volume are commonly used. Alternatively glucose at concentrations of 0.5%, 1.5%, 2.5%, and 4.25% (296, 347, 397, and 485 mOsm/L respectively) are used. Glucose is continuously absorbed during dialysis which reduces the osmotic gradient and leads to a decline in ultrafiltration over time of the dwell.

[0173] Another osmotic agent used is polyglucose 7.5% (isoosmolar). Polyglucose is absorbed at a slower rate than glucose, which makes it suitable for long dwells.

[0174] As to peritoneal dialysis treatment solutions for the bag 6, Dianeal solution, Nutrineal solution, Extraneal solution or Physioneal solution, currently marketed by Baxter may be used.

[0175] Dianeal solution has different glucose content, namely 0.5%, 1.5%, 2.5% and 4.5% (weight/volume) glucose.

[0176] Nutrineal solution is glucose free, while Extraneal solution uses icodextrin instead of glucose as a primary osmotic agent.

[0177] Physioneal solution has different glucose content, namely 1.36%, 2.27% and 3.86% (weight/volume) glucose.

[0178] Though not limiting, in general treatment fluids for peritoneal dialysis have a composition including:

[0179] Na between 130 and 140 mmol/L;

[0180] Mg between 0.25 and 0.5 mmol/L;

[0181] Ca between 1.25 and 1.75 mmol/L;

[0182] Lactate between 30 and 40 mmol/L; alternatively lactate and bicarbonate with a total buffer concentration between 30 and 40 mmol/L (e.g. 15 lactate and 25 bicarbonate);

[0183] Glucose between 1.36% and 4% weight/volume as osmotic agent; or Glucose between 0.5% and 4% weight/volume as osmotic agent.

[0184] It is noted that glucose is also sometimes named as dextrose in the PD field. The term glucose is herewith intended to comprise dextrose, too.

[0185] As mentioned, some solution may be osmotic agent free or include icodextrin instead of glucose as osmotic agent, particularly for treatment solution destined for long dwell.

[0186] Moving back to FIG. 1, the bags 6 contains treatment fluids with different osmotic agent concentration, e.g. one bag with no glucose and the other with 2.27% and 3.86% glucose (anhydrous). Of course more than three bags 6 may be connected to different inlet ports of the disposable unit 3b. Also more than one bag with identical composition may be connected to the same inlet port, for example connecting the respective tubes with an Y connector.

[0187] In a first working example, the content of one of the connected bags 6 is delivered via a pump 5 to a container 41 for receiving a treatment fluid where the treatment fluid is properly heated and thereafter delivered to the patient P via patient line 54 for a fill, dwell and drain cycle. The subsequent cycle, depending on the treatment session prescription (as will be detailed in the following part of the description), may use the same treatment fluid, or a treatment fluid from a different bag 6 (i.e. with different osmotic agent concentration). The plurality of cycles of a treatment session are automatically executed by the control system delivering the prescribed treatment fluid with specific osmotic agent content for each cycle.

[0188] In a different working example, it is possible to properly mix the content of different bags 6 to generate a treatment fluid with a concentration of osmotic agent different from the concentration of any of the prepackaged bags 6 so that the concentration of osmotic agent (e.g. glucose) may be varied before treating the patient. As discussed, one of the therapy parameters is percent osmotic agent (e.g. glucose) of the solution, which affects the amount of UF removed and the amount of calories absorbed by the patient. More glucose results in more UF removed, which is generally desirable. More glucose, however, results in more caloric intake and weight gain by the patient, which is not desirable.

[0189] Glucose profiling is therefore an important factor in selecting the patient's possible therapies. For example, if using Dianeal fluid, the different solutions are provided in different glucose percentages, such as 1.36%, 2.27% and 3.86% glucose. The APD machine described in connection with the present apparatus has the ability to connect to multiple solution bags having different glucose percentages and pull solution from the different bags to form a mixed or blended solution, e.g., in the container 41 or in the patient's peritoneum if inline heating is used, having a desired glucose percentage different from the rated percentages, e.g., 2.0%, 2.88%, 3.38% and 3.81% glucose.

[0190] Alternatively, sensor 15 may be positioned on a drain line 44 to sense proper mixing of the mixed solution with a specific testing procedure described in respect to the apparatus of FIG. 2.

[0191] FIG. 2 illustrates an alternative embodiment of the apparatus of FIG. 1.

[0192] The apparatus 1 depicted in FIG. 2 is generally intended for the on-site preparation of treatment fluids and for the treatment of the patient with the prepared fluids.

[0193] In other terms, the apparatus 1 is generally configured for preparing a peritoneal dialysis treatment fluid by mixing purified water (e.g. on site prepared) and concentrates and for treating a patient in a peritoneal dialysis treatment.

[0194] Therefore, the apparatus according to FIG. 2 mainly differs from the previously described APD cycler because no use is made of different bags (or sources S) containing respective treatment fluids ready to be infused into the patient peritoneal cavity.

[0195] In the apparatus of FIG. 2, the treatment fluid has to be prepared properly mixing concentrates and water; therefore, the source S of treatment fluid is container 41 where the treatment fluid is obtained.

[0196] The apparatus 1 includes a water preparation module 2 and the APD cycler 3. As per the case depicted in FIG. 1, the cycler 3 is made of a peritoneal dialysis (PD) unit 3a and of a disposable unit 3b particularly in the form of a cassette 40 to which a plurality of lines and a container 41 configured for receiving a treatment fluid are connected.

[0197] According to FIG. 2, the water preparation module 2 receives water from a water source 4, particularly a continuous water source such as the water pipelines of the water main.

[0198] In general, the water preparation module 2 is installed in a room having access to the water source 4 to provide purified water to the APD cycler 3 as apparent from below description.

[0199] Water enters a water purifier 10 via a water intake 11. The water purifier 10 may be a reverse osmosis unit (WRO unit) of known type not herein detailed.

[0200] The purified water leaves the WRO unit through the purified water outlet and goes to the APD cycler via a (purified) water line 42.

[0201] A pressure regulator 57 may be positioned at the purified water outlet upstream the water line 42 along the water flow for regulating fluid pressure in the water line.

[0202] The water line 42 feeds purified water to a water port 43 of the cassette 40 of the disposable unit 3b. The water line 42 is a flexible tube having one first end 42a connected to an exit of the purifying circuit 12 of the water purifier 10 and a second end 42b connected to the water port 43 of the cassette 40.

[0203] The apparatus 1 also include a drain line 44 to bring fluid to a drain, for example the drain 30 of the water purifier 10.

[0204] Also the drain line 44 is a tube having one first end connected to the proportioning device 3 and a second end preferably connected to the purifying circuit 12 of the water purifier 10.

[0205] The water line 42 and the drain line 44 may (or may not) run parallel in the form of a dual lumen tubing, for example. In this respect, also the drain line 44 includes a flexible tube and is connected to a drain port 19 of the cassette 40.

[0206] In an advantageous embodiment, the water line 42 includes a first tract 42a and a second tract 42b connected to the first tract with a connector 46; the second tract 42b is connected to said water port 43 and may present a first and a second sterile filter. The two filters may be disposable filters as well. In particular the second tract 42b may be fixedly (but also removable when needed) connected to the cassette 40 and be a disposable part.

[0207] Notably, the water line 42 and the drain line 44 comprise a terminal connector (e.g. connector 46) configured for connecting a free end of the respective line to an intake 58 of the purifying circuit of the water purifier 10 for disinfection of the water and drain lines.

[0208] As exemplified in FIG. 1B showing a portion of the hydraulic circuit of the disposable unit 3b according to both FIG. 1 and FIG. 2 examples, respective ends of the water and of the drain line 42, 44 enters into the water port 43 and drain port 19, respectively; a fluid line exits the port 43 to direct fluid into the cassette 40 (or the disposable unit 3b) and a fluid line enters the drain port 19 to direct fluid out of the cassette 40 (or the disposable unit 3b).

[0209] The apparatus 1 further includes at least a sensor 15 for detecting a property of a fluid flowing in the disposable unit 3b (e.g. the patient line), water line 42 and/or in the drain line 44. The sensor 15 may be a sensor for detecting a property of the treatment fluid allowing the control system 74 to determine the osmotic agent concentration in the treatment fluid to be delivered to the patient P. As an example the sensor may be a concentration sensor for the osmotic agent, e.g. a glucose concentration sensor. Alternatively, the sensor 15 may be a conductivity sensor and may be placed in the drain line 44. Possibly, but not necessarily, the sensor 15 is included in the hydraulic circuit of the water purifier 10. Since osmotic agent (e.g. glucose) content is linked in a known manner with treatment fluid conductivity, the control system 74 receiving the signal form conductivity sensor 15 may determine the concentration of osmotic agent in the sensed treatment fluid.

[0210] Moving to the proportioning of the fluids (back to FIG. 2), the apparatus 1 further comprises at least one source 50 of a first concentrate in fluid connection with the first inlet port 59 of the proportioning device 3. In particular, the source 50 of the first concentrate is a first container 51; the container 51 may be used for several PD fluid preparation cycles and it is substituted only once all the concentrate contained therein has been completely used.

[0211] The first concentrate contains an appropriate osmotic agent, such as glucose. In a non-limiting example, the first concentrate includes 50% glucose at pH between 2 and 3. Preferred volumes may be comprised between 1 and 4 liters.

[0212] The apparatus 1 further comprises at least one source 52 of a second concentrate in fluid connection with the second inlet port 60 of the proportioning device 3. In particular, the source 52 of the second concentrate is a second container 53; the container 53 may be used for several PD fluid preparation cycles and it is substituted only once all the concentrate contained therein has been completely used.

[0213] The second concentrate contains electrolytes and a buffer agent, for example lactate. In a non-limiting example, the second concentrate includes sodium chloride, calcium chloride, magnesium chloride and sodium lactate at pH higher than 6. Preferred volumes may be comprised between 0.5 and 4 liters.

[0214] In general two concentrates containers 51, 53 will be used, however it is not excluded the possibility to use three or more concentrates.

[0215] For example, a source of a third concentrate in fluid connection with a third inlet port 61 of the disposable unit 3b may be provided. In particular, the source 62 of the third concentrate is a third container; the container may be used for several PD fluid preparation cycles and it is substituted only once all the concentrate contained therein has been completely used.

[0216] In case three concentrates are used, the second concentrate may, as an example, include sodium chloride, sodium lactate and sodium bicarbonate and the third concentrate may, as an example, contain other electrolytes, such as calcium and magnesium chloride.

[0217] Of course different content for the concentrates may be adopted depending on the patient need and on the circumstances.

[0218] As mentioned, the proportioning device 3 is made up of two main parts: the APD cycler 3a and the disposable unit 3b in the form of a disposable set which is generally replaced after each treatment session (see FIG. 1a). The disposable unit 3a of FIGS. 1 and 2 is substantially identical and shown in FIG. 1a.

[0219] The disposable unit 3b includes a disposable cassette 40, as well as a set of tubes. As shown in FIG. 1a, the tubing set includes a container line 64 emerging from a container port 65 of the cassette and terminating in a container 41 configured for receiving a treatment fluid. The container 41 is in the form of a collapsible bag to be positioned e.g. in a dedicated tray on the cycler 3a (see FIG. 1).

[0220] The tubing set also includes a portion of the water line 42 and a portion of the drain line 44 both emerging from the respective water port 43 and drain port 19 and three (or more) line portions emerging from first, second and third concentrate ports 59, 60 and configured for connection to respective concentrate bags. FIG. 1a shows three line portions for connection to concentrates; FIG. 1 illustrates (on the right side) the water port 43, the drain port 19 and three additional ports in the cassette, two of them for connection to concentrates.

[0221] The patient line 54 emerges from a respective patient port 66; one end of the patient line 54 is configured for connection to a patient P. An additional line 67 emerging from an additional port 68 in the cassette 40 may be present, as currently shown. This additional line 67 may be used as an additional drain or (as shown) may have one end connected to the patient line 54 to create a loop.

[0222] It should be appreciated however that other lines associated with the cassette 40 may be provided.

[0223] The cassette 40 is also provided with a first and (possibly) a second pump chamber 69, 70 (see for example FIG. 1b). Each of the pump chambers is selectively in fluid communication with the described ports 43, 59, 60, 61, 19, 65, 66 and 68.

[0224] In particular the water port 43 (and therefore the water line 42 and the drain line 44), and the first, second and third port 59, 60, 61 (and therefore the concentrates) and the drain port 19 are fluidly connected to a first common line 72, this latter is fluidly connected to one side of the pump chambers 69, 70. Also the patient port 66 (shown e.g. on the opposite side of the cassette 40) is connected to the first common line 72.

[0225] The container port 65 (and therefore the container 41) and the additional port 68 are fluidly connected to a second common line 73, this latter is fluidly connected to the opposite side of the pump chambers 69, 70.

[0226] First common line 72 and second common line 73 communicate one with the other by means of the pump chambers 69, 70. In case the patient line 54 and the additional line 67 are connected to each other, there is a further communication path between common lines 72, 73.

[0227] In correspondence of each of the mentioned ports and also in correspondence of the respectively opposite fluid connections to the pump chambers (on line 72 and 73), at least one valve 71 is provided. See again FIG. 1b.

[0228] Acting on the valves 71 (e.g. opening and closing the passages) allows to selectively change fluid flow path inside the disposable unit 3b.

[0229] The cycler 3a receives the cassette 40 and the set of tubing. The cycler 3a is provided with a control system 74 driving respective valve actuators to opening or closing the each one of the valves and therefore creating the different flow paths inside the hydraulic circuit.

[0230] The cycler 3a also has a respective actuator for each of the pump chamber 69, 70, active to push and release the membrane of the pump chamber thereby creating a fluid pressure inside the chamber and a corresponding fluid flow inside the fluid path of the disposable unit 3b.

[0231] Pump chambers and actuators define a first pump, in particular a membrane pump, for moving fluid towards and from the container 41 for receiving the treatment fluid (and moving fluids towards/from the requested ports) and a second pump, in particular a membrane pump, for moving fluid towards and from the container 41 for receiving the treatment fluid (and moving fluids towards/from the requested ports).

[0232] Once fluid connections have been made, the preparation of the treatment fluid for the patient treatment with the apparatus of FIG. 2 may start.

[0233] The water purifier 10 feeds purified water to the water line 42, the water port 43 is opened, purified water enters into the cassette 40 and wet the latter; water is directed into the container 41.

[0234] Then, the first concentrate (if not known) may be checked. Water port 43 is closed and first inlet port 59 is opened. The control system 74 acts on pumps and valves of the proportioning device to withdraw some concentrate from the source 50 of the first concentrate and send said concentrate into the cassette 40, particularly filling (at least partly) one of the pump chamber 69, 70.

[0235] First inlet port 69 is closed and drain port 19 is opened. The pump of the chamber containing the first concentrate is activated so that the first concentrate is forced through the drain port 19 towards and in the drain line 44. Some first concentrate reaches the first drain tract 49a.

[0236] In subsequent step, the control system 74 drives the APD cycler 3 to withdraw purified water form container 41; purified water from the container 41 is used to pushing forward the first concentrate in the drain line. First concentrate is forced through the drain line 44 towards the sensor 15.

[0237] In more detail, the control system 74 is configured to send the first concentrate into a first tract 49a of the drain line 44; said first tract is positioned (immediately) downstream the drain port 19. The control system pushes the first concentrate in the drain line 44 by means of purified water from the container 41 so that the first concentrate reaches the sensor 15 and simultaneously flush the pump chamber 70. The property of the first concentrate may then be measured and the first concentrate (i.e. the concentrate connected to the first inlet port 59) properly identified/checked.

[0238] A similar procedure is adopted for the second concentrate. Second concentrate is checked by sensor 54 and identified.

[0239] It is apparent that the identification steps are optional since the container identification may be left to the user and/or achieved through use of dedicated mechanical connectors which may not allow connecting a concentrate container different from the right container to the respective inlet port.

[0240] The apparatus is now ready for mixing the concentrates and water to produce PD treatment fluid with the desired osmotic agent concentration.

[0241] Firstly purified water is pumped to the container 41 from the water purifier thought the water port 43 and pump chambers 69, 70 via container line 64. First concentrate is then pumped into the container 41 via the first inlet port 59 and properly mixed.

[0242] Subsequently, additional purified water is supplied via the water line 42 to the container 41 so that pump chambers are rinsed with water and first mixed fluid still in the pump chamber moved to container 41. Second concentrate is added to container 41 via second inlet port 60, the pump chambers 69, 70 and the container line 64.

[0243] Once the required and metered quantity of the two concentrates has been supplied to the container 41, a main dilution phase starts. Purified water is added to the container configured form the RO water purifier 10, to reach about 90-95% of final fluid volume in the container 41.

[0244] The diluted second mixed fluid is then checked to verify that the fluids have been properly mixed and particularly that the osmotic agent concentration is the desired one. To check this, a sensor may be placed on the container 41 to check concentration of a specific substance (e.g. the osmotic agent) or to check conductivity of the prepared treatment fluid. Alternatively sensor 15 on the drain line 44 is used. One of the pumps 69 or 70, or both withdraws some diluted second mixed fluid from container and directs it into the first drain tract 49a via drain port 43.

[0245] In order not to waste treatment fluid, as soon as diluted second mixed fluid reaches the drain line 44, purified water is pushed by the water purifier 10 in the water line towards the drain line 44 thereby forcing the diluted second mixed fluid to the sensor 15 for fluid property check.

[0246] An auxiliary dilution step to fine tune the treatment fluid composition may be run if necessary. In particular, additional purified water is added to the container to further dilute. The amount of added purified water is calculated as a function of the measured property (e.g. conductivity) of the diluted second mixed fluid. In more detail the amount of added purified water is calculated as a function of the measured property also in relation to the previously filled amount of fluid (water and concentrates).

[0247] Conductivity of the additionally diluted second mixed fluid may then be checked to confirm correct preparation of the treatment fluid.

[0248] Some additionally diluted second mixed fluid is withdrawn from container 41 and fed to the drain line 44 and then purified water from water line 42 pushes the additionally diluted second mixed fluid to the sensor 15 for final check.

[0249] The apparatus is now ready for treating a patient according to the treating sessions/required cycles following a procedure according to the invention as explained in the final part of the present description. In general, the patient is connected, spent dialysate (if present) is removed from the peritoneal cavity and sent to drain 30 via drain line 44; fresh dialyzing fluid, on-site prepared and having the desired concentration of osmotic agent, is directed from container 41 (which is therefore the source S of treatment fluid) to the patient P. Once all the consecutive cycles (e.g. 1 or more cycles) with this specific treatment fluid are concluded, a second treatment fluid with a second concentration of osmotic agent is prepared according to the previously described preparation phases. The patient undergoes all the consecutive cycles required by the treatment prescription with the treatment fluid having the second concentration of osmotic agent. The treatment session proceeds with the preparation of the third treatment fluid having a third concentration of osmotic agent (different from the second concentration) and the respective cycle/cycles are administered to the patient.

[0250] It is noted that the disposable unit 3b may include additional bags (e.g. connected to the mentioned inlet ports of the cassette 40) which might be filled with treatment solution having a certain osmotic agent concentration previously prepared by the apparatus and to be used subsequently to another treatment fluid with different osmotic agent content.

[0251] In this respect, in case a treatment session requires two treatment fluids, only, with high and low (or no) osmotic agent (e.g. glucose) concentration to be alternated, once the first treatment fluid is prepared and used, the residual amount contained in the container 41 is directed and stored in a receiving additional bag connected to one port of the cassette 40. A second treatment fluid is prepared in the container 41, used and thereafter stored in a different additional bag connected to the cassette 40. Therefore, the first treatment fluid may be withdrawn from the receiving bag where it was stored, directed to the container 41 and used for further cycles while the residual second treatment fluid remains provisionally stored in another receiving bag for the subsequent use. Operating as above described allows to prepare each of the two fluids only once, but to administer treatment cycles to the patient P alternating the two treatment fluids.

[0252] At the end of the treatment session, the patient P is disconnected and the disposable unit 3b (e.g. the cassette 40 and connected tubing set) is disposed.

[0253] A third embodiment of a PD apparatus is very schematically shown in FIG. 3.

[0254] The PD cycler 3 receives a dialysis fluid from a feeding line 12; dialysis solution may be contained in a treatment solution container 13 or may be on-line prepared from water and concentrates as known in the art.

[0255] An osmotic agent concentrate container 14 is also provided connected to the cycler 3. A metering pump 16 feeds the osmotic agent (e.g. glucose) concentrate towards a mixing point 17 on a main line 18 circulating the dialysis solution. The dialysis solution and the osmotic agent concentrate mix properly to generate a PD treatment fluid with the desired concentration of osmotic agent. In this respect the source S of treatment fluid is the line downstream the mixing point 17.

[0256] A main pump 5 is used to direct the treatment fluid to the patient P via the patient line 54. A sensor 15 on the patient line measures a property of the treatment fluid allowing the control system 74 of the cycler to determine that the treatment fluid has the correct and desired concentration of osmotic agent. A feedback control loop on the metering 16 pump may be created to adjust osmotic agent concentration in case of deviations from the desired value.

[0257] The same main pump 5 may operate in reverse mode to drain fluid from the patient P directing PD treatment fluid along a drain line towards a drain 30. In this respect, the control system 74 controls metering and main pump 5 and 16, as well as valves 20 to properly mixing and directing fluids. The control system 74 also receives signal from the sensor 15 and inputs/outputs from a user interface 21.

[0258] The apparatus of FIG. 3 allows to prepare any treatment fluid with a specifically desired concentration of osmotic agent.

[0259] The Extended Three Pore Model

[0260] In order to determine an optimized APD treatment session with regard to maximizing UF and small solute transport and, at the same time, minimizing the metabolic cost in terms of glucose absorption, an extended three pore model has been developed and used.

[0261] Referring now to FIG. 4, a cross-section from a peritoneal blood vessel illustrates the three-pores of the vessel.

[0262] The three-pores each have their own solute and UF clearance, leading to one kinetic model called the three-pore model. The three-pore model is a mathematical model that describes, correlates and predicts relationships among the time-course of solution removal, fluid transfer, treatment variables and physiological properties. The three-pore model is a predictive model that can be used for different types of treatment fluid, such as Dianeal, Physioneal, Nutrineal, and Extraneal dialysates marketed by Baxter.

[0263] The classical three-pore model (3PM) of peritoneal dialysis is more than 25 years old. Given what is known about the actual structure of the peritoneal barrier, the use of pores is phenomenological. However, the theory of hindered solute transport is most completely developed for the case of spherical solute molecules in a long cylindrical (or slit-shaped) pore while transport in other media is less completely understood. Hence, the 3PM represents an idealized equivalent barrier which is used to describe the function of the peritoneal transport barrier rather than its structural or anatomical features. Separating the peritoneal membrane into, basically, three parallel porous membranes with different size-selective properties makes it possible to understand phenomena such as sodium sieving, middle-molecule transport and the osmotic behavior of polydisperse osmotic agents such as icodextrin. Since its first development, the 3PM has been modified numerous times. However, the classic 3PM does not simulate the inflow and/or outflow phase of the dwell. Notably, at higher dialysate flows, a significant part of the exchange time is spent either filling or draining the peritoneal cavity. Therefore, an extended 3PM having an additional compartment has been developed, allowing simulation also of the drain and fill phases of the dwell. The extended model may be then used to optimize the treatment with APD with regard to osmotic water transport (UF), small/middle-molecule clearance and glucose absorption. The results demonstrate that the metabolic cost in terms of glucose absorption can be significantly reduced by using higher DFRs and a bimodal regime where short dwells containing a high glucose concentration are combined with longer dwells containing no or a low glucose concentration. In addition, it is demonstrated that these regimes make it possible to shorten the total treatment time while achieving the same or better small-solute transport and UF.

[0264] The Modified 3-Pore Model Differential Equations

[0265] During peritoneal dialysis, the net volume flow across the peritoneal membrane, at any time t from the start of the filling phase, is assumed to be the sum of six different volume flows:

[00002]$\begin{array}{cc}\frac{{\mathrm{dV}}_D}{\mathrm{dt}}=J_{v,C}+J_{v,S}+J_{v,L}-L+J_{\mathrm{fill}}-J_{\mathrm{drain}}& \left(1\right)\end{array}$

[0266] In this equation, J.sub.v,C, J.sub.v,S, and J.sub.v,L represent the net flow of water (in mL/min) across the aquaporines, the highly selective pathways (small pores) and the weakly selective pathways (large pores), respectively.

[0267] In other terms, V.sub.D is the peritoneal fluid volume, J.sub.v,C is the flow of fluid through transcellular pores or aquaporines shown in FIG. 5, J.sub.v,S is the flow of fluid through small pores shown in FIG. 5 and J.sub.v,L is the flow of fluid through large pores shown in FIG. 5.

[0268] In the 3-pore model, the flows in equation 1 are assumed to vary only as a function of time and are directed into the peritoneal cavity when positive. The net lymphatic clearance from the peritoneal cavity to the circulation is denoted L (in mL/min) and is typically on the order of 0.2-0.3 mL/min when measured as a clearance to the circulation.

[0269] The model has been extended to include also the fill and drain phases of the dwell. Thus, J.sub.drain and J.sub.fill represent the flows of volume (in mL/min) to and from the source of treatment fluid, respectively. The change in the intra-peritoneal concentration of a solute i (denoted dC.sub.D,i/dt in mmol/mL/min) at any time t is dependent on three separate terms:

[00003]$\begin{array}{cc}\frac{{\mathrm{dC}}_{D,i}}{\mathrm{dt}}=\frac{J_{s,S,i}+J_{s,L,i}}{V_D}-C_{D,i}.Math.\frac{J_{v,C}+J_{v,S}+J_{v,L}+J_{\mathrm{fill}}}{V_D}+\frac{C_{B,i}.Math.J_{\mathrm{fill}}}{V_{D.Math.}}& \left(2\right)\end{array}$

[0270] The first term

[00004]$\left(\frac{J_{s,S,i}+J_{s,L,i}}{V_D}\right)$

is the change in intra-peritoneal concentration caused by the flow of solutes (through small and large pores, J.sub.s,S,i and J.sub.s,L,i in mmol/min) in and out of the peritoneal cavity. As can be seen, a positive solute flow is directed into the peritoneal cavity, increasing the concentration in the dialysate. The second term

[00005]$\left(C_{D,i}.Math.\frac{J_{v,C}+J_{v,S}+J_{v,L}+J_{\mathrm{fill}}}{V_D}\right)$

represents the dilution/concentration due to volume flux in and out of the peritoneum. Only water flows that affect the dialysate concentration are included in this term (i.e. L and J.sub.drain are not included). The last term

[00006]$\left(\frac{C_{B,i}.Math.J_{\mathrm{fill}}}{V_D}\right)$

is the change in concentration due to the inflow of fresh dialysate J.sub.fill having a concentration C.sub.B,i (in mmol/mL). The change in concentration in the drain reservoir of solute i (dC.sub.B,i(t)/dt in mmol/mL/min) is given by:

[00007]$\begin{array}{cc}\frac{{\mathrm{dC}}_{B,i}}{\mathrm{dt}}=\frac{J_{\mathrm{drain}}.Math.C_{D,i}-J_{\mathrm{fill}}.Math.C_{B,i}}{V_B}-\frac{C_{B,i}}{V_B}.Math.\frac{{\mathrm{dV}}_B}{\mathrm{dt}}& \left(3\right)\end{array}$

[0271] The change in reservoir bag volume V.sub.B is simply

[00008]$\begin{array}{cc}\frac{{\mathrm{dV}}_B}{\mathrm{dt}}=-J_{\mathrm{fill}}+J_{\mathrm{drain}}& \left(4\right)\end{array}$

[0272] Thus, the concentration in the reservoir does not change during the fill phase (dC.sub.B,i/dt=0). This equation implies that the drain compartment is identical to the compartment with fresh dialysis fluid which is not the case in actual practice. However, since drain fluid and fresh dialysis fluid are never mixed, there is no need for more than one reservoir compartment in the model. Hence, the compartment V.sub.B acts as a source during the fill phase and as a collector of drain fluid during the drain phase. The initial conditions for the simulations are:

V.sub.D(0)=V.sub.r(5)

C.sub.D,i(0)=C.sub.p,i(6)

C.sub.B,i(0)=C.sub.I,i(7)

V.sub.B(0)=V.sub.I(8)

[0273] where V.sub.r is the residual volume, V.sub.I the fill/instilled volume (at the start of the fill phase) or 0 at the start of the drain phase), C.sub.I,i is the dialysis fluid concentration of solute i, C.sub.p,i is the plasma concentration of solute i which is assumed to be constant during the dwell. The ordinary differential equations (ODE) 1-4 above, along with the initial conditions, represent the initial value problem (IVP) to be solved in order to obtain the unknown functions V.sub.D(t), C.sub.D,i(t), V.sub.B(i) and C.sub.B,i(t).

[0274] Volume and Solute Flow in the Three-Pore Model

[0275] The solute flow (in mmol/min) over each pathway is calculated according to the Patlak equation:

[00009]$\begin{array}{cc}{J}_{s,S,i}=J_{v,S}\left(1-{}_{s,i}\right).Math.\frac{C_{P,i}-C_{D,i}.Math.e^{-{\mathrm{Pe}}_{S,i}}}{1-e^{-{\mathrm{Pe}}_{S,i}}}& \left(9\right)\\ J_{s,I,i}=J_{v,L}\left(1-{}_{L,i}\right).Math.\frac{C_{P,i}-C_{D,i}.Math.e^{-{\mathrm{Pe}}_{L,i}}}{1-e^{-{\mathrm{Pe}}_{L,i}}}& \left(10\right)\end{array}$

[0276] where Pe.sub.S,i=J.sub.vS(1.sub.S,i)/PS.sub.S,i and Pe.sub.L,i=J.sub.vL(1.sub.L,i)/PS.sub.L, i are the Pclet numbers (the ratio between the maximum convective and diffusive clearance for solute i) for the small and large pore pathway, respectively. The mass transfer area coefficients, PS.sub.S,i and PS.sub.L,i (in mL/min), are either set according to following Table 1 or calculated according to pore theory PS=D.Math.A.sub.0/x.Math.A/A.sub.0 where A/A.sub.0 is the diffusive restriction factor and D is the free diffusion coefficient. The reflection coefficients are calculated according to theory. The volume flow (mL/min) is calculated using Starling equilibria over each parallel pathway

J.sub.vC=.sub.cL.sub.pS(PRT.sub.i=1.sup.N.sub.i(C.sub.p,iC.sub.D,i))(11)

J.sub.vS=.sub.SL.sub.pS(PRT.sub.i=1.sup.N.sub.i.sub.S,i(C.sub.p,iC.sub.D,i))(12)

J.sub.vL=.sub.LL.sub.pS(PRT.sub.i=1.sup.N.sub.i.sub.L,i(C.sub.p,iC.sub.D,i))(13)

[0277] where .sub.C, .sub.S and .sub.L are the fractional hydraulic conductances for the different pathways (see next Table 1), .sub.i is the osmotic coefficient for solute i, R is the gas constant and T is the body temperature (310 K). Thus, the osmotic reflection coefficients are assumed to be the same for osmosis and solute transport. To account for the recruitment/loss of peritoneal surface area due to a high/low IPV, an area factor was multiplied to all PS-values and L.sub.pS according to Keshavia et al (Keshaviah P, Emerson P F, Vonesh E F, and Brandes J C. Relationship between body size, fill volume, and mass transfer area coefficient in peritoneal dialysis. J Am Soc Nephrol 4: 1820-1826, 1994.).

af=16.18(1e.sup.0.00077.Math.V.sup.D.sup.(t)/13.3187(14)

[0278] Thus, the mass transfer area coefficients and the filtration coefficient were inflated for volumes >2250 mL and vice versa.

[0279] Pressure Dynamics in the 3-Pore Model

[0280] The average capillary hydrostatic pressure was calculated according to a pre-to-post-capillary resistance ratio (PTP=R.sub.a/R.sub.v) of 8:1. Thus, given the mean arterial pressure (MAP) and the large-vein pressure (P.sub.v) of the patient, the capillary pressure is calculated according to the equation:

P.sub.c=fR.sub.v.Math.MAP+fR.sub.a.Math.P.sub.v(15)

[0281] where fR.sub.a=1fR.sub.v and fR.sub.a=PTP/(PTP+1) are the fractional pre-capillary and post-capillary resistances, respectively. The net hydrostatic pressure gradient is simply

P=P.sub.cIPP(16)

[0282] where the intra-peritoneal pressure (IPP) was assumed to be dependent only on the intraperitoneal volume (IPV). A modified equation by Twardowski et al for the supine position is used (Twardowski Z J, Prowant B F, Nolph K D, Martinez A J, and Lampton L M. High volume, low frequency continuous ambulatory peritoneal dialysis. Kidney Int 23: 64-70, 1983):

[00010]$\begin{array}{cc}\mathrm{IPP}=4.7+\frac{\mathrm{VD}\left(t\right)}{690}& \left(17\right)\end{array}$

[0283] The intercept used is higher than that obtained in the study by Twardowski et al since the IPP for a total IPV of 2250 mL is here assumed to be 8 mmHg in the supine position. However, in a patient nave to peritoneal dialysis, a lower (negative) intercept can be expected. Furthermore, IPP might not be a completely linear function of IPV especially in the lower and higher ranges. In the current article, a MAP of 90 mmHg was used and, further, it is assumed that the large-vein pressure is equal to the intra-peritoneal pressure (P.sub.v=IPP).

[0284] Temporal Discretization and Numerical Solution of the 3-Pore IVP

[0285] To solve above equations (1-4) numerically, a fourth order Runge-Kutta scheme was implemented. If N represents the total number of solutes included in the simulation, the system of equations (1-4) can be re-written:

[00011]$\begin{array}{cc}\frac{{\mathrm{dV}}_D}{\mathrm{dt}}=\left(t,C_{D,1},C_{D,2},\mathrm{.Math.}.Math.,C_{D,N}\right)& \left(18\right)\\ \frac{{\mathrm{dC}}_{D,i}}{\mathrm{dt}}=.Math.\left(t,C_{D,i},C_{B,i},V_D\right)& \left(19\right)\\ \frac{{\mathrm{dC}}_{B,i}}{\mathrm{dt}}=\left(t,C_{D,i},C_{B,i},V_B\right)& \left(20\right)\end{array}$

[0286] where , and are functionals (functions of functions) corresponding to the right-hand side of equations 1-3 and i=0.1, . . . , N. All functions of interest (V.sub.D(t), C.sub.D,i(t), V.sub.B(i) and C.sub.B,i(t)) are defined on Q+1 equally spaced grid points over the total simulation time [0,] with a time-step t=/Q. The grid points are labeled k=0, 1, 2, . . . , Q with k=0 representing the initial values. The functions are then calculated on the grid points C.sub.D,i,k=C.sub.D,i(kt), C.sub.B,i,k=C.sub.B,i(kt) and V.sub.D,i,k=V.sub.D,i(kt). Starting with the initial value (k=0) the next grid point (k+1) is calculated according to:

[00012]$\begin{array}{cc}.Math.K_1=.Math..Math.t.Math.\left(k.Math..Math..Math..Math.t,C_{D,1,k},C_{D,2,k},\mathrm{.Math.}.Math.,C_{D,N,k}\right)& \left(21\right)\\ .Math.L_{1,i}=.Math..Math.t.Math..Math.\left(k.Math..Math..Math..Math.t,C_{D,i,k},C_{B,i,k},V_{D,k}\right)& \left(22\right)\\ .Math.M_{1,i}=.Math..Math.t.Math.\left(k.Math..Math..Math..Math.t,C_{D,i,k},C_{B,i,k},V_{D,k}\right)& \left(23\right)\\ K_2=.Math..Math.t.Math.\left(k.Math..Math..Math..Math.t+\frac{.Math..Math.t}{2},C_{D,1,k}+\frac{L_{1,1}}{2},C_{D,2,k}+\frac{L_{1,2}}{2},\mathrm{.Math.}.Math.,C_{D,N,k}+\frac{L_{1,N}}{2}\right)& \left(24\right)\\ L_{2,i}=.Math..Math.t.Math..Math.\left(k.Math..Math..Math..Math.t+\frac{.Math..Math.t}{2},C_{D,i,k}+\frac{L_{1,i}}{2},C_{B,i,k}+\frac{M_{1,i}}{2},V_{D,k}+\frac{K_1}{2}\right)& \left(25\right)\\ M_{2,i}=.Math..Math.t.Math.\left(k.Math..Math..Math..Math.t+\frac{.Math..Math.t}{2},C_{D,i,k}+\frac{L_{1,i}}{2},C_{B,i,k}+\frac{M_{1,i}}{2},V_{D,k}+\frac{K_1}{2}\right)& \left(26\right)\\ K_3=.Math..Math.t.Math.\left(k.Math..Math..Math..Math.t+\frac{.Math..Math.t}{2},C_{D,1,k}+\frac{L_{2,1}}{2},C_{D,2,k}+\frac{L_{2,2}}{2},\mathrm{.Math.}.Math.,C_{D,N,k}+\frac{L_{2,N}}{2}\right)& \left(27\right)\\ L_{3,i}=.Math..Math.t.Math..Math.\left(k.Math..Math..Math..Math.t+\frac{.Math..Math.t}{2},C_{D,i,k}+\frac{L_{2,i}}{2},C_{B,i,k}+\frac{M_{2,i}}{2},V_{D,k}+\frac{K_2}{2}\right)& \left(28\right)\\ M_{3,i}=.Math..Math.t.Math.\left(k.Math..Math..Math..Math.t+\frac{.Math..Math.t}{2},C_{D,i,k}+\frac{L_{2,i}}{2},C_{B,i,k}+\frac{M_{2,i}}{2},V_{D,k}+\frac{K_2}{2}\right)& \left(29\right)\\ K_4=.Math..Math.t.Math.\left(k.Math..Math..Math..Math.t+.Math..Math.t,C_{D,1,k}+L_{3,1},C_{D,2,k}+L_{3,2},\mathrm{.Math.}.Math.,C_{D,N,k}+L_{3,N}\right)& \left(30\right)\\ .Math.L_{4,i}=.Math..Math.t.Math..Math.\left(k.Math..Math..Math..Math.t+.Math..Math.t,C_{D,i,k}+L_{3,i},C_{B,i,k}+M_{3,i},V_{D,k}+K_3\right)& \left(31\right)\\ .Math.M_{4,i}=.Math..Math.t.Math.\left(k.Math..Math..Math..Math.t+.Math..Math.t,C_{D,i,k}+L_{3,i},C_{B,i,k}+M_{3,i},V_{D,k}+K_3\right)& \left(32\right)\\ .Math.V_{D,k+1}=V_{D,k}+\frac{K_1+2.Math.K_2+2.Math.K_3+K_4}{6}& \left(33\right)\\ .Math.C_{D,i,k+1}=C_{D,i,k}+\frac{L_{1,i}+2.Math.L_{2,i}+2.Math.L_{3,i}+L_{4,i}}{6}& \left(34\right)\\ .Math.C_{B,i,k+1}=C_{B,i,k}+\frac{M_{1,i}+2.Math.M_{2,i}+2.Math.M_{3,i}+M_{4,i}}{6}& \left(35\right)\\ .Math.V_{B,i,k+1}=V_{B,i,k}+.Math..Math.t\left(J_{\mathrm{drain}}-J_{\mathrm{fill}}\right)& \left(36\right)\end{array}$

[0287] The total simulation time () was chosen so that a total of 25 subsequent dwells was simulated with a time step of 0.001 min. This short time step was chosen so that the error in fill/drained volume would be less than 0.1 mL per dwell.

[0288] Regulation of Fill/Drain Cycles

[0289] In the simulations, a fill flow rate of 200 mL/min was used. For the drain phase, drain flow rates of 350 mL/min (fast-phase) and 36 mL/min (slow-phase) were implemented with a transition point (break point) at an intraperitoneal volume of 381 mL. Each cycle starts with a fill phase followed by a dwell phase which lasts for a pre-determined dwell time (DT) after which the drain phase starts. The whole duration of the cycle, consisting of the fill-, dwell- and drain-time is referred to as the exchange time (ET). For IPD, the drain phase ends when the calculated intra-peritoneal volume for the next grid point is less than the residual volume (V.sub.D,k+1<Vr) after which either a new cycle starts or the simulation ends. Depending on the time-step chosen, this leads to a small error since the actual volume left in the peritoneal cavity after a cycle will always be larger than (or equal to) V.sub.r. For TPD without overfill or overdrain, the drain phase terminates when the calculated volume for the next grid point is less than the sum of the residual volume and the tidal reserve volume (V.sub.D,k+1<V.sub.r+TRV).

[0290] Moreover, IPD was simulated for fill and drain volumes of 2 L, while TPD was simulated using a tidal volumes of 0.5 L, 1 L, or 1.5 L with full drains and subsequent fills (2 L) occurring after every fifth dwell. A total of 25 cycles for a large number of different DFRs were simulated using 3 different glucose concentrations (1.5%, 2.27% and 3.86%) and 3 different peritoneal transport types: low (PET D/P.sub.crea<0.6), high (PET D/P.sub.crea>0.8) and average.

TABLE-US-00001 TABLE 1 Parameters used for computer simulations of intraperitoneal volume vs. time V(t) curves according to a three- pore model of membrane selectivity Small pore radius (r.sub.s) () 43 Large pore radius (r.sub.L) () 250 Fractional small pore UF-coeff. (.sub.s) 0.900 Fractional transcellular UF-coeff. (.sub.c) 0.020 Fractional large pore UF-coeff. (.sub.L) 0.080 Ultrafiltration coefficient (L.sub.pS) 0.074 (mL/min/mmHg) Osmotic conductance to glucose 3.6 (L.sub.pS .sub.g) (L/min/mmHg) Unrestricted pore area over unit 25,000* diffusion distance for small pores (A.sub.0/X).sub.s (cm) PS (MTAC) for glucose (mL/min) 15.4 PS (MTAC) for urea (mL/min) 26.0 PS (MTAC) for Na and anion 4.5 (mL/min) PS (MTAC) for phosphate (mL/min) 10.2 Peritoneal lymph flow (L)(mL/min) 0.3 Transperitoneal oncotic pressure 22 gradient (.sub.prot) (mmHg) Peritoneal residual volume (V.sub.r) (mL) 250 Serum urea concentration (mmol/L) 20 Serum creatinine concentration (mol/l) 660 Dialysis fluid sodium concentration 132 (mmol/L) Serum sodium (and sodium associated 140 anion concentration) (mmol/L) Serum glucose concentration (mmol/L) 6.5 Dissociation factor for Na.sup.+ and 0.93 anions *25,000 cm was used for an average peritoneal transport type, 40,000 cm for high transporters and 15,000 cm for low transporters.

[0291] Results from Simulations

[0292] Urea Clearance

[0293] In FIG. 5, the simulated urea clearance as a function of DFR is plotted for the different techniques (IPD, TPD75/50/25) and different transport types: Fast (lines labeled A), Average (lines labeled C), Slow (lines labeled B) for three different glucose concentrations: 1.5% (dotted line), 2.27% (solid line) and 3.86% (dashed line). At low to moderate dialysate flow rates (<2-3 L/h) the intermittent technique provides slightly higher clearances than the tidal technique. For slow transporters, higher volume flows become ineffective (reach a plateau) at lower DFRs compared to average and fast transport types. Thus, for small solute transport, there is little benefit in exceeding 2 L/h for a slow transporter. For the lower tidal volumes (TPD50 and TPD25), the urea clearance is lower in the leftmost part of the curve compared to the other modalities, demonstrating a relative inefficiency of low tidal volumes at lower DFRs. The right-most value for each curve represents the maximal flow rate possible at the chosen fill and drain flow rates (i.e. all time is spent either filling or draining the peritoneal cavity) and is, expectedly, higher for the tidal technique. The results for the other small solutes, creatinine, sodium and phosphate are very similar to the urea results (data not shown) although the transport of sodium more closely follow the UF curve.

[0294] Osmotic Water Transport (UF)

[0295] In FIG. 6, the osmotic water transport, or UF, per session hour is shown as a function of DFR. Expectedly, in absolute terms, the UF is higher for the slow transporters due to the slower dissipation of glucose, improving the average osmotic pressure gradient. The peak values occur at similar DFRs compared to the urea clearance vs. DFR curves in FIG. 6. At first glance, this might seem a bit surprising, since it is at these DFRs that the glucose absorption is at its greatest. However, the increased glucose dissipation at these high DFRs will be more than well compensated by the influx of fresh dialysis fluid. Thus the glucose gradient will be maintained despite increasing absorption. Thus, it is the addition of fresh dialysis fluid that will increase both UF and clearance of small solutes at higher DFRs. The inefficiency at higher flows is due to the fact that, in relative terms, more time is spent filling and draining the peritoneal cavity, leading to a decrease in both UF and small solute clearance.

[0296] Osmotic Water Transport (UF) Efficiency

[0297] The osmotic transport of water (in mL) occurs at a metabolic cost, in terms of glucose absorption. In FIG. 7 the UF in mL per gram glucose absorbed (or UF efficiency) is plotted as a function of DFR. The UF efficiency is markedly improved by increasing the DFR up to about 2 L/h after which a plateau is reached and small or no further improvements are attained. The higher glucose concentrations are far more efficient in achieving UF. Thus, at a DFR of 2 L/h, the patient will absorb more than twice the amount of glucose for the same amount of UF using the 1.5% solution compared to the 3.86% solution.

[0298] Small-Solute Transport Efficiency (Mmol UreaR Per g Glucose Absorbed)

[0299] In FIG. 8, the small solute transport efficiency (in mmol urea removed per g glucose absorbed) as a function of DFR is plotted. Similar to the osmotic efficiency, the removal reaches an early plateau at DFRs higher than 2 L/h. However, here the situation is the opposite compared to UF efficiency. The higher glucose concentrations are much less efficient in achieving urea transport. Similarly, the patient will absorb almost twice the amount of glucose per mmol of urea removed using a 3.86% solution instead of a 1.5% solution.

[0300] Middle Molecule Transport Vs. DFR

[0301] In FIG. 9, the clearance of .sub.2-microglobulin as a function of DFR is shown. In comparison to the results for the small-solute transport, no peak or decrease in clearance was observed at higher DFRs for the tidal techniques. Furthermore, smaller tidal volumes are clearly beneficial for middle-molecule transport.

[0302] Comparison with Clinical Studies

[0303] In Table 2, the extended 3PM is compared with the study by Aasard and colleagues. There is good agreement between the model and the clinical measurements, although there seems to be a tendency for the model to underestimate the clearances at higher DFRs.

TABLE-US-00002 TABLE 2 DFR IPD Cl.sub.urea TPD 50% Cl.sub.urea 1.1 L/h 14.3* mL/min (14.9) 13.3 mL/min (13.9) 1.6 L/h 16.9 mL/min (17.0) 15.9 mL/min (16.2) 2.7 L/h 20.9 mL/min (18.8) 19.9 mL/min (19.1)

[0304] Osmotic Efficiency

[0305] The osmotic efficiency expressed in terms of UF per liter dialysis fluid consumed as a function of DFR is shown in FIG. 11 for the different techniques, transport types and different glucose concentrations. Generally, the osmotic efficiency is markedly improved by increasing the DFR up to about 2 L/h after which a plateau is reached and small or no further improvements can be observed.

[0306] Optimization Procedure

[0307] According to the above discussed results, if the osmotic agent (e.g. glucose) strength is varied and low or no osmotic agent strengths (preferably <0.5% glucose) during some of the cycles, while the osmotic agent strengths are kept high in other cycles (preferably >3.86% glucose), it is possible to separate volume removal from the small solute removal and thereby maximize them both and at the same time minimize the osmotic agent (e.g. glucose) taken up by the patient.

[0308] In more general terms, the treatment procedure executed by the control system 74 comprises a sequence of cycles alternating in a proper arrangement high glucose strength treatment fluid with low or no glucose strength treatment fluids. In the present description alternating high osmotic agent strength treatment fluid with low or no osmotic agent strength treatment fluid, does not imply that a cycle with high osmotic agent strength treatment fluid is immediately followed by a cycle with low or no osmotic agent strength treatment fluid and vice versa; indeed, intermediate additional cycles may be included between the mentioned high and low/no osmotic agent cycles.

[0309] The control system 74 of the PD apparatus is programmed to run a fill phase of a first cycle delivering a first treatment fluid to the patient, in which the first treatment fluid has a first concentration of the osmotic agent; subsequently to the first cycle, the control system 74 runs a fill phase of a second cycle delivering a second treatment fluid to the patient, in which the second treatment fluid has a second concentration of the osmotic agent different from the concentration of the first treatment fluid; subsequently to the second cycle, the control system 74 runs a fill phase of a third cycle delivering a third treatment fluid to the patient, in which the third treatment fluid has a third concentration of the osmotic agent different from the concentration of the second treatment fluid.

[0310] In the sequence, the second concentration of the osmotic agent is higher than the first concentration of the osmotic agent and the third concentration of osmotic agent is lower than the second concentration of osmotic agent (the first and the third concentration of osmotic agent may be or may be not identical).

[0311] Alternatively, in the mentioned sequence, the second concentration of the osmotic agent is lower than the first concentration of the osmotic agent and the third concentration of osmotic agent is higher than the second concentration of osmotic agent (the first and the third concentration of osmotic agent may be or may be not identical).

[0312] It is noted that first, second and third cycles do not imply that they are executed one immediately after the other. In other terms, the first cycle may be followed by one or more additional cycles before running the second cycle and/or the second cycle may be followed by one or more additional cycles before running the third cycle. In other terms, first, second and third cycle only imply that there is a temporal sequence and thereby the first cycle is executed before the second cycle, which, in turn, is executed before the third cycle during a treatment session. In the example of FIG. 12, upper treatment session, the first cycle with 6% glucose concentration is immediately followed by the second cycle with 0% glucose concentration; then an additional cycle with 0% glucose concentration is performed before the third cycle, again with 6% glucose concentration is run.

[0313] Generalizing the above concept, the control system 74 delivers a plurality of cycles using a treatment fluid with high concentration of osmotic agent, alternating with a plurality of cycles using a treatment fluid with low or no concentration of osmotic agent. Again and as previously explained, there may be a certain number of cycles with high glucose concentration followed by a certain number of cycles with low/no glucose concentration before a new cycle with high glucose concentration.

[0314] The treatment fluid with low concentration of osmotic agent includes a concentration of osmotic agent equal or lower than 2.5% in weight, optionally equal or lower than 2% in weight, optionally equal or lower than 1.5% in weight, and in more detail equal or lower than 0.5% in weight. The treatment fluid with low osmotic agent/glucose concentration also includes a treatment fluid with no osmotic agent/glucose.

[0315] The treatment fluid with high concentration of osmotic agent includes a concentration of osmotic agent equal or higher than 2.5% in weight, optionally equal or higher than 3% in weight, and in more detail equal or higher than 3.86% in weight. In certain treatment sessions also an osmotic agent with a concentration higher than 5% strength may be used.

[0316] Additionally, it is relevant to mention that the procedure includes leaving the treatment fluid in the peritoneal cavity for a dwell time, wherein the dwell time of a treatment fluid with high osmotic agent concentration is different from, and in particular lower than, a dwell time of a treatment fluid with low or no osmotic agent concentration.

[0317] In other terms, the dwell time of the treatment fluid having high glucose strength is much shorter that the dwell time of the treatment fluid with low/no glucose strength.

[0318] As can be immediately inferred, in case an apparatus according to FIG. 1 is used, at least two sources S (or bags 6) of treatment fluid have a different content of osmotic agent (one will have a high glucose strength and the other will have a low/no glucose strength). The two sources are properly alternated in the cycles as above described up to the end of the treatment session.

[0319] As also explained, starting from a discrete number of bags with different osmotic agent concentration, it is possible to generate blended solution with an intermediate glucose concentration to better fit with the patient needs.

[0320] Using, vice versa, the apparatus of FIG. 2, the concentrates may be properly mixed to obtain the treatment fluid with the correct osmotic agent concentration to be used for the specific cycle/cycles; then a different treatment fluid with different osmotic agent concentration is generated to administer the other cycle/cycles in the correct alternating treatment session.

[0321] A similar procedure is adopted with the apparatus of FIG. 3, properly mixing the osmotic agent concentrate solution with the dialysis solution.

[0322] The control system 74 may receive the prescription for the treatment session (e.g. night session) in terms of number of cycles for the treatment session, as well as in terms of concentration of osmotic agent and dwell time for each cycle of the treatment session.

[0323] Alternatively, the control system 74 includes a memory storing a prediction algorithm; the control system 74 receives as input the desired total UF volume to be removed at the end of the treatment session and a desired total small solute volume, e.g. urea volume, to be removed at the end of said treatment session and, based on said prediction algorithm, is configured to determine at least the first concentration of osmotic agent in the first treatment fluid, the second concentration of osmotic agent in the second treatment fluid and the third concentration of osmotic agent in the third treatment fluid. In general, based on the prediction algorithm, the control system may determine the concentration of osmotic agent and the dwell time of each of the cycles of the treatment session; eventually the prediction algorithm may also indicate the optimum number of cycles in the treatment session. The prediction algorithm may be based on the modified three pore model equation (1).

Optimization Examples

[0324] In FIGS. 11 and 12, some possible optimization examples are shown.

[0325] FIG. 11, upper graphic shows a standard prescription for peritoneal dialysis of 62 L 1.36% glucose with a duration of 9 hours (540 min). The treatment session consists of 6 identical cycles and is a night session.

[0326] Each of the fill phases F (with a treatment fluid having 1.36% strength in glucose) fills the patient peritoneal cavity up to a bit more than 2 liters of treatment fluid.

[0327] During each dwell phase DW the fluid volume in the peritoneal cavity increases since fluids moves from the patient body to the peritoneal cavity.

[0328] The drain phase DR is then shown having two slopes DR.sub.1, DR.sub.2 corresponding to the initial fast drain step and to the final slow drain step.

[0329] Six identical cycles in the same treatment session are shown having substantially the same shape (same effects).

[0330] The corresponding transport parameters in terms of urea removal, UF, glucose absorption are shown in Table 3, first line.

[0331] The upper curve is compared with scenarios were each dwell is optimized for either UF (using 3.86% glucose) and/or small-solute transport (using 0% glucose) keeping the glucose absorption low. The treatment time for the two latter scenarios was chosen to fit the UF and urea transport of the standard prescription, i.e. same UF and same urea removal targets.

[0332] The intermediate curve includes 8 cycles of two different alternating treatment fluids.

[0333] The first cycle is performed with a high glucose concentration treatment fluid (3.86% strength) and has a short dwell time T.sub.1.

[0334] Each cycle has a fill phase F, a dwell phase DW and a drain phase DR with first fast drain DR.sub.1 and second slow drain DR.sub.2.

[0335] In the first cycle, during the dwell phase, the volume inside the peritoneal cavity increases due to net fluid transfer towards the peritoneal cavity.

[0336] The second cycle is performed with a low/no glucose concentration treatment fluid (0% strength) and has a longer dwell time T.sub.2.

[0337] In the second cycle, during the dwell phase, the volume inside the peritoneal cavity decreases due to net fluid transfer from the peritoneal cavity towards the patient body.

[0338] The third and the fifth cycles are identical to the first cycle, while the fourth and the sixth cycles are identical to the second cycle.

[0339] As apparent from below table 3, the urea removal and the UF of the upper and intermediate treatment sessions are essentially the same.

[0340] Vice versa, the glucose absorption is reduced by about 19% and the total treatment time for achieving the mentioned target removals is reduced to 510 min.

[0341] The lower treatment session again optimize UF, urea removal, treatment time and glucose absorption.

[0342] The treatment session is made of 10 cycles; the first cycle is performed with a high glucose concentration treatment fluid (3.86% strength) and has a short dwell time T.sub.1 (shorter than in the previously described first cycle of the intermediate session).

[0343] In the first cycle, during the dwell phase, the volume inside the peritoneal cavity increases due to net fluid transfer towards the peritoneal cavity.

[0344] The second cycle is performed with a low/no glucose concentration treatment fluid (0% strength) and has a dwell time T.sub.2 longer then the dwell time T.sub.1.

[0345] In the second cycle, during the dwell phase, the volume inside the peritoneal cavity decreases due to net fluid transfer from the peritoneal cavity towards the patient body.

[0346] The third, the fifth and the seventh cycles are identical to the first cycle, while the fourth, the sixth and the eighth cycles are identical to the second cycle.

[0347] As apparent from below table 3, the urea removal and the UF of the upper and lower treatment sessions are essentially the same.

[0348] Vice versa, the glucose absorption is reduced by about 22% and the total treatment time for achieving the mentioned target removals is reduced to 475 min.

[0349] This clearly reflects in a benefit for the patient.

TABLE-US-00003 TABLE 3 Glucose Regime UreaR UF abs. Decrease Total time 6 2 L 1.36% 158 mmol 458 mL 41.5 g 0% 540 min 4 2 L 3.86% + 158 mmol 456 mL 33.8 g 19% 510 min 4 2 L 0% 5 2 L 3.86% + 157 mmol 457 mL 32.3 g 22% 475 min 5 2 L 0%

[0350] FIG. 12 shows other possible optimization embodiments.

[0351] The upper treatment session includes 10 cycles. The first cycle uses a treatment fluid with high glucose concentration (6% strength) for a short time T.sub.1.

[0352] The second and third cycles use a treatment fluid with no glucose content. Dwell time T.sub.2 is longer and net fluid is transferred to the patient.

[0353] The treatment session then provides a fourth and a sixth cycle with high glucose content and a fifth, seventh, eighth, ninth and tenth cycle with no glucose.

[0354] Again total treatment time is reduced to 463 min and targets in UF and urea removal are unaltered with respect to table 3.

[0355] Intermediate graph in FIG. 12 illustrates a treatment session of 12 cycles, the first, fourth and sixth make use of a treatment fluid having a glucose concentration of 6%. All the other nine cycles have no glucose in the treatment fluid.

[0356] Total treatment time is reduced to 450 min and targets in UF and urea removal are unaltered with respect to table 3.

[0357] A final example is presented in the lower portion of FIG. 12. Ten cycles are performed by the cycler. First, third and fifth cycles have a treatment fluid with high glucose content (3.86%), the other seven cycles are performed with a treatment fluid having a low glucose content of 0.55%.

[0358] Total treatment time is reduced to 460 min and targets in UF and urea removal are unaltered with respect to table 3.

[0359] Notwithstanding the fact that all the examples make use of two different treatment fluids only, it is possible to use three of more treatment fluids differing each other due to the osmotic agent concentration, e.g. a first cycle with 6% glucose concentration, a second cycle with no glucose, a third cycle with 3.86% glucose concentration, a fourth cycle with 0.55% glucose concentration, etc.