WO2011000086A1

WO2011000086A1 - Method and apparatus for reducing serum phosphate in hemodialysis patients

Info

Publication number: WO2011000086A1
Application number: PCT/CA2010/000981
Authority: WO
Inventors: Marcello Tonelli; Braden Manns
Original assignee: The Governors Of The University Of Alberta
Priority date: 2009-07-03
Filing date: 2010-06-30
Publication date: 2011-01-06

Abstract

The present invention relates to an improved method and apparatus for reducing serum phosphate levels and calcium phosphate product in patients by hemodialysis. The method and apparatus is particularly useful for treating patients in which conventional hemodialysis treatment alone is usually insufficient to control serum phosphate levels and therefore must be combined with administration of calcium-based phosphate binders. The apparatus includes a dialyser having a hemodialysis membrane with a total surface area of at least 3.0 m². A dialyser having a membrane surface area of at least 3.0 m² controls serum phosphate levels to the extent that the patient's predialysis blood phosphate levels are consistently lower between dialysis sessions compared to conventional hemodialysis treatment.

Description

METHOD AND APPARATUS FOR REDUCING SERUM PHOSPHATE

IN HEMODIALYSIS PATIENTS

Cross-Reference to Related Applications

This application claims the benefit of and priority from United States provisional patent application no. 61/222,974 filed July 3, 2009, which is incorporated herein by reference in its entirety.

Field of the Invention

The present invention relates to a method and apparatus for reducing serum phosphate levels and calcium phosphate product in patients by hemodialysis. Background of the Invention

Higher levels of serum phosphate are independently associated with an increased risk of death in hemodialysis patients (1 , 2). Although it is unknown whether better control of hyperphosphatemia would improve clinical outcomes, current practice guidelines recommend tight control of serum phosphate (3), given an expectation that such management will lead to improved clinical outcomes and survival in hemodialysis patients.

Calcium-based phosphate binders have traditionally been the cornerstone of treatment for hyperphosphatemia. However recent data support an association between vascular calcification and accelerated cardiovascular disease in end-stage renal disease (ESRD) (4-15), and observational data suggesting that higher doses of calcium-based phosphate binders may contribute to vascular calcification (16). Furthermore, these medications are not only associated with high costs and increase the number of pills that a patient need to take, but they appear to only modestly reduce serum phosphate levels and calcium phosphate product. Therefore, there has been considerable interest in controlling serum phosphate while minimizing oral calcium load. While most attention has focused on the use of non-calcium containing phosphate binders such as sevelamer and lanthanum (17), modifying the dialysis regimen to improve phosphate clearance is an alternative approach that has received little attention to date.

Multiple recent publications and practice guidelines promote the need to achieve better control of serum phosphate, and calcium phosphate product, in hemodialysis patients (3-5, 10-15). Although it remains to be confirmed that achieving tighter control of either the serum phosphate or calcium phosphate product will improve patient outcomes, it is clear that considerable time and money are currently spent in pursuit of this goal Contemporary approaches to lowering serum phosphate center on the choice and dose of oral phosphate binders— and minimizing intake of calcium-based agents has become an important secondary objective for clinicians While it appears that quotidian hemodialysis allows markedly better control of serum phosphate (26-28), this modality is not an option for the majority of hemodialysis patients and few data address the potential benefits of modifying conventional hemodialysis to achieve this objective

The relative lack of interest in enhancing phosphate clearance during conventional hemodialysis is probably because most phosphate is intracellular, and thus perceived to be unavailable for removal by hemodialysis Although many nephrologists assume that intradialytic concentrations of serum phosphate parallel those of urea, it appears that phosphate kinetics are considerably more complex (29) Serum phosphate declines sharply during the first 60-120 minutes of dialysis and remains relatively constant thereafter, apparently independent of dialyser blood flow, and type of dialyser membrane (30-32) Mathematical modeling suggests that the constant blood levels during the latter part of dialysis are most consistent with mobilization of phosphate from an extracellular compartment that does not equilibrate freely with serum (29) Factors governing the release of phosphate from this third compartment are unknown, but it may be triggered by reduction of serum phosphate to below 1 1 - 1 2 mmol/l (33) A fourth compartment may also exist, serving to defend against critically low intracellular phosphate concentrations by releasing phosphate into the intracellular space from an unknown reservoir (33) This putative compartment may reduce the amount of phosphate available for removal by hemodialysis by altering the ratio of intracellular to extracellular phosphate, although this remains speculative Taken together, these theoretical considerations suggest that 1 ) the rate limiting step for intradialytic phosphate removal is equilibration between the intracellular and extracellular space, 2) factors which enhance dialytic clearance of urea will not necessarily lead to greater phosphate clearance, and 3) factors which predispose to low intradialytic phosphate levels (such as very rapid dialyser blood flow rates, low body size or low predialysis serum phosphate levels) may reduce capacity for net phosphate removal

Surprisingly, the present inventors have found that a dialyser having a hemodialysis membrane total surface area of at least 3 0 m² significantly reduces serum phosphate levels and calcium phosphate product in patients compared to conventional hemodialysis Moreover, the use of a dialyser having a membrane surface area of at least 3 0 m² controls serum phosphate levels to the extent that the patient's predialysis blood phosphate levels are consistently lower between dialysis sessions compared to conventional hemodialysis treatment

Accordingly, the present invention provides a method and apparatus for reducing serum phosphate levels and calcium phosphate product in hemodialysis patients Summary of the Invention

In one aspect, the invention provides a method and apparatus for treating hemodialysis patients with concomitant hyperphosphatemia

In one aspect, the invention provides a method and apparatus that is useful for treating patients in which conventional hemodialysis treatment alone is usually insufficient to control serum phosphate levels and therefore must be combined with administration of calcium-based phosphate binders

In another aspect, a dialyser having a membrane surface area of at least 3 0 m² controls serum phosphate levels to the extent that the patient's predialysis blood phosphate levels are consistently lower between dialysis sessions compared to conventional hemodialysis treatment

The method is performed using a dialyser in which a blood compartment is separated from a dialysate compartment by a semi-permeable membrane having a total surface area of at least 3 0 m² Preferably, the semi-permeable membrane has a total surface area of at least 3 3 m², more preferably, the semi-permeable membrane has a total surface area of at least 3 6 m² In one embodiment, the invention may be practiced using a single dialyser having a total surface area of at least 3 0 m² In another embodiment of the invention, two or more commercially available dialysers may be connected in a hemodialysis circuit using normal conditions of a hemolysis operation in order to obtain a total surface area of at least 3 0 m² Although the invention is not limited to any particular configuration, preferably, the two or more dialysers are connected in parallel

According to one aspect of the invention, there is provided a method for reducing phosphate levels in the blood of a patient by hemodialysis, comprising

• withdrawing and bypassing the blood from the patient in a continuous flow into contact with one face of an hemodialysis membrane, the hemodialysis membrane having a total surface area of at least 3 0 m² , • simultaneously passing dialysate solution in a continuous flow on an opposite face of the hemodialysis membrane to the side of the hemodialysis membrane in contact with the blood, the flow of the dialysate solution being countercurrent to the direction of flow of blood, and • returning the blood from which the phosphate levels have been reduced into the patient

According to another aspect of the invention, there is provided a dialyser for reducing phosphate levels in blood of a patient, comprising

• two compartments divided by a hemodialysis membrane having a total surface area of at least 3 0 m², one of said compartments for receiving continuous flow of blood that is in contact with one face of the hemodialysis membrane, another of said compartments for receiving a continuous flow of dialysate solution that is in contact with an opposite face of the hemodialysis membrane, the dialysate solution and the blood being completely separated from each other, • a blood inlet and a blood outlet of said dialyser for flowing the blood through said compartment for receiving blood, and

• a dialysate inlet and a dialysate outlet of said dialyser for flowing dialysate solution through said compartment for receiving dialysate solution

According to another aspect of the invention, there is provided an apparatus for reducing phosphate levels in blood of a patient, comprising

• a dialyser divided into two compartments by a hemodialysis membrane having a total surface area of at least 3 0 m²,

• a blood inlet line and a blood outlet line connected to a blood inlet and blood outlet of said dialyser for flowing the blood from the patient, through said blood compartment and back to the patient,

• a dialysate inlet line and a dialysate outlet line connected to a dialysate inlet and outlet of said dialyser for flowing dialysate solution through said dialysate compartment, • means for pumping the blood withdrawn from the patient through the dialyser and returning the dialysized blood having reduced phosphate levels back to the patient, and

• means for pumping the dialysate solution through the compartment receiving the dialysate solution, the flow of the dialysate solution in a direction countercurrent to the direction of the flow of the blood

According to another aspect of the invention, there is provided a method of treating a patient in need of phosphate reduction by hemodialysis comprising

• removing and bypassing the blood from the patient in a continuous flow into

contact with one side of an hemodialysis membrane, the hemodialysis membrane having a total surface area of at least 3 0 m²,

• passing dialysate solution in a continuous flow on an opposite side of the

hemodialysis membrane to the side of the hemodialysis membrane in contact with the blood, the flow of the dialysate solution being countercurrent to the direction of flow of blood, and

• returning the blood from which the phosphate levels have been reduced into the patient

It was discovered by the inventors that the use of a dialyser having a total surface area of at least 3 0 m² for a six week period led to better phosphate control among large hemodialysis patients, as reflected by an approximately 0 44 mmol/l reduction in predialysis serum phosphate as compared to conventional hemodialysis In contrast, increasing dialysate flow or prolonging dialysis treatment by 30 minutes did not lead to significantly better phosphate clearance or control

Accordingly, the use of a dialyser having a total surface area of at least 3 0 m² as described and shown herein for six weeks in overweight hemodialysis patients led to substantially lower levels of predialysis phosphate than those associated with conventional hemodialysis

Brief Description of the Drawings

In the figures, which illustrate, by way of example only, embodiments of the present invention Figure 1 is a partially cut-away view of a hollow fiber dialyser of the present invention,

Figure 2A is a longitudinal view of a section of the hollow fiber dialyser and Figure 2B is a diagrammatic cross-sectional view of the hollow fiber dialyser,

Figure 3 shows the trial flow of 18 study participants, Figure 4 show the effect of dialysis modality on pre- and postdialysis serum phosphate, and

Figure 5 shows the effect of dialysis modality on phosphate clearance and phosphate removal

Detailed Description The principle of hemodialysis is well known Dialysers are available in a variety of forms A conventional diayser contains a large plurality of semipermeable hollow fiber membranes to greatly increase the surface area, which helps to facilitate diffusion across the membrane and the removal of wastes and toxins

Typically, a dialyser contains essentially a blood compartment and a dialysate compartment separated from one another by semipermeable membrane having appropriate selective filtering properties Blood is perfused through the blood compartment and returned to the patient A dialysate solution is simultaneously circulated through the dialysate compartment A concentration gradient is thereby established which causes toxins and other wastes contained in the blood to migrate through the semipermeable membrane and into the dialysate solution

Dialyser

Reference is made to FIG 1 which schematically illustrates a perspective view of a dialyser 10 in accordance with an embodiment of the invention

The dialyser 10 is comprised of a nearly cylindrical jacket 12 which is preferably formed of a rigid plastic material Disposed in the jacket 12 is a hollow fiber bundle 5 made of a plurality of longitudinal semi-permeable hollow fibers 9, which are small bore capillaries arranged in parallel The semi-permeable hollow fibers 9 serve as a means for transferring toxins and other wastes being filtered from blood The hollow fiber membranes 9 are composed of a material which permits high flux dialysis, for example polymethylmethacrylate, polyacetylnitrile, cellulose acetate, cellulose triacetate, polyacrylonitrile, polysulfone, polyether sulfone, polyamide, polyethylene or

polypropylene. The hollow fibers 9 are bundled together in a manner which allows the blood to flow in a parallel manner through the lumina of the fibers while a dialysate solution is simultaneously passed through the dialyser 10 so as to bathe the exterior surfaces of the hollow fibers 9 with the solution. The bundle 5 of hollow fiber membranes 9 disposed in the jacket 12 is sealed at each end by a potting agent 7, e.g. polyurethane resin (Fig. 2A). The effective total surface area of the hollow fiber membranes 9 in the dialyser 10 is at least 3.0 m², preferably at least 3.3 m², and more preferably at least 3.6 m². For the bundle 5 of hollow fibers 9, the total surface area will depend on the fiber length, inner diameter, and overall number. Other considerations are the spacing of the fibers 9 within the bundle 5 and the degree to which the dialyser jacket 12 is packed with the fibers 9. The packing density of the dialyser 10 is the ratio of the area comprised of fibers 9 to the total area based on a transverse cut through the dialyser 10 (Fig. 2B). The manufacturing of a dialyser having a hollow fiber bundle having a hemodialysis membrane with a particular surface area is known in the art. See, for example,

U.S. Patent No. 5,139,668 (Pan et a/.), U.S. Patent No. 5,531 ,848 (Brinda et a/.) and U.S. Patent No. 6,478,960 (Saruhashi et a/.), all of which are incorporated herein by reference.

The jacket 12 has an arterial header cap 30 and a venous header cap 32 mounted on opposite ends, each of which are firmly connected to the jacket 12 by a collar 15,17. The arterial header cap 30 is provided with a blood inlet 23 and the venous header cap 32 is provided with a blood outlet 25. The jacket 12 is further provided with a dialysate inlet 18 and a dialysate outlet 22. The jacket 12 and the caps 30 and 32 are typically made of a hard resin such as, for example, polyethylene, polypropylene, polycarbonate, acrylic resin such as polymethyl methacrylate, hard polyvinyl chloride, styrene-butadiene copolymer or polystyrene.

Tubing is connected to the blood inlet 23 and 25 to remove and bypass blood from the patient into the dialyser and return the dialysed blood back to the patient. Likewise, tubing connected to the dialysate inlet 18 and outlet 22 allow the dialysate solution to pass through the dialyser. The dialysate flow path between the dialysate inlet 18 and the dialysate outlet 22 is formed by gaps between the hollow fiber membranes 9 and between the inner wall of the jacket 12. Dialysate solution enters the dialyser 10 thus perfuses and flows through the internal compartment around the outside of the bundle 5 of semipermeable hollow fibers 9. The blood flow path 13 between the blood inlet 23 and the blood outlet 25 is formed by the lumens of the hollow fiber membranes 9. For greater efficiency, the flow of the dialysate solution runs in a direction counter-current to the flow of blood through the hollow fiber membranes 9.

Examples of dialysers of this construction are illustrated in U.S. Patent No. 4,283,284 (Schnell), U.S. Patent No. 4,289,623 (Lee), U.S. Pat. No. 4,600,512 (Aid) and U.S. Patent No. 6,478,960 (Saruhashi, et a/.), all of which are incorporated by reference herein. Dialysers having other configurations may be used in the practice of the invention provided a total effective hemodialysis membrane surface area of at least 3.0 m² is provided.

Dialysis Conditions Pump assisted movement of blood through the dialyser 10 is typically required in order to displace a sufficient volume for effective cleansing within a treatment time of less than six hours. The dialysis delivery system pumps the dialysate solution through the dialysate compartment and also regulates the proper mixing of the dialysate concentrate and water, as well as monitors electrolyte concentrations. In use, the patient blood is pumped through the hollow fiber bundle 5 of the dialyser 10. The dialysate solution is pumped through the dialysate compartment of the dialyser 10 by the dialysis delivery system so that dialysis solution continuously bathes the exterior surface of the hollow fibers 9.

The dialysate flow rate, blood flow rate and connections are similar to those in standard dialysis processes. The dialysate blood flow should be chosen so as to allow for complete saturation of the dialysate fluid with the hollow fibers and selective solute removal but preventing backfiltration of fluid to the blood compartment. In an embodiment of the invention, the dialysate flow rate is about 500 to 1000 mL/min, preferably from about 800 to 1000 ml/min. More preferably, the dialysate flow rate is 800 mL/min to increase the efficiency of dialysis. The blood flow rate is about 200 to 500 ml/min, preferably from about 300 to 400 ml/min.

Apparatus

This apparatus is composed essentially of a dialyser with a hemodialysis membrane having a total surface area of at least 3.0 m² as described herein, and a volumetric controlled dialysis delivery system (e.g. Fresenius 2008H). In a preferred embodiment of the invention, a single dialyser having a total effective hemodialysis membrane surface area of at least 3.0 m² is used. In another embodiment, two or more commercially available dialysers may be connected to the dialysis delivery system, as long as the combined total surface area of the membranes of the dialysers is at least 3.0 m². An example of such a dialyser is the Fresinius F-80, a high flux dialyser which has a polysulfone membrane and a surface area of 2.1 m². In an apparatus intended to achieve the results of the present invention, the blood flow compartments of two or more dialysers are connected together in a parallel or series configuration, as are the dialysate compartments giving a total surface area of at least 3.0 m². Therefore, the present invention can be practiced with any conventional type dialysers and dialysis delivery system without requiring extensive modifications. According to one such embodiment, two F80A dialysers are connected by a Y-connector in a parallel configuration during each run using the method described by Powers et al (21 ), incorporated herein by reference. Dialysate flow was 800 ml/min and blood flow was 300 to 400 ml/min.

Although the present invention has been described in connection with two Fresinius F-80 dialysers, it will be readily apparent to those skilled in the art that other known dialysers (and dialysis delivery systems) may also be used to practice the present invention.

The present invention is further described by the following example. The example is provided solely to illustrate the invention by reference to specific embodiments. These examples, while illustrating certain specific aspects of the invention, do not portray the limitations or circumscribe the scope of the disclosed invention. Indeed, many modifications and variations of the invention will be apparent to those skilled in the art upon reading this specification and can be made without departing from its spirit and scope.

The following study was conducted in order to test the method and apparatus of the present invention using two dialysers in parallel configuration.

The inventors analyzed data from a previously reported randomized crossover trial to determine whether more intensive hemodialysis would improve phosphate clearance and reduce serum phosphate concentrations in hemodialysis patients. The effect of using two high flux dialysers in parallel for 4 hours on serum phosphate were compared with three other dialysis modalities (4 hours of standard HD, 4.5 hours of HD, and 4 hours of HD with increased dialysate flow). The study population consisted of large dialysis patients (>80kg) who could not achieve adequate Kt/V during a standard 4 hour thrice weekly prescription. Mean baseline pre-dialysis serum phosphate was 1.92 ± 0.63 mmol/l and mean pre-study calcium x phosphate product was 4.34 ± 1.55 mmol²/!². Using two dialysers in parallel was associated with a significant decrease in predialysis serum phosphate compared to standard hemodialysis (0 43 mmol/l lower, p=0 017) Mean serum postdialysis serum phosphate during the last treatment of the double dialyser period was also lower by 0 14 and 0 24 mmol/l than during the last treatment of the standard hemodialysis (p=0 046) and increased dialysate flow (p=0 0009) periods, respectively The double dialyser strategy was also associated with higher phosphate clearance than the other three strategies (113 7 (95% Cl 94 4,133 1 ) vs 83 1 (95%CI 73 5, 92 8), 86 1 (95%CI 74 4, 97 9) and 82 9 (95% CI73 2, 92 6) ml/mm, respectively)

The following examples are offered by way of illustration and not by way of limitation EXAMPLES

Data from a previously conducted randomized trial was used to test the hypothesis that more intensive hemodialysis would improve phosphate clearance and reduce serum phosphate concentrations in large hemodialysis patients Three methods of intensifying a thrice weekly hemodialysis regimen were considered higher dialysate flow (18, 19), extended dialysis duration, and the use of two dialysers in parallel (20, 21 ), all compared with standard thrice weekly hemodialysis

Patients

A randomized cross-over study was performed in 6 dialysis units affiliated with the University of Calgary and the University of Alberta The protocol was approved by the health ethics review boards at each institution Inclusion criteria were as follows patients on a stable regimen of hemodialysis =3 months, dry weight = 80kg, Kt/V =1 2 on two occasions in the previous 6 months or requirement for >12 hours of hemodialysis per week because of a history of inadequate dialysis, and blood flow rate = 350ml/mιn through a well functioning access Patients were excluded if they had a scheduled renal transplant in the next six months, had a contraindication to intradialytic anticoagulation, required >4 5 hours of hemodialysis three times per week for the purpose of volume removal due to excessive interdialytic weight gains or intradialytic hypotension / cramping, and failure to provide informed consent All patients who met inclusion / exclusion criteria and were not already receiving a hemodialysis regimen consisting of four hours, three times per week were switched to this modality for 4 weeks prior to entry into the active treatment part of the study Study Design

During the study period each patient received four different hemodialysis regimens in a randomized cross-over fashion, each lasting six weeks in duration To permit blinding of patients to dialysis treatment modality, all dialysis sessions were 4 5h, for the three strategies that included active dialysis for only 4h, dialysate flow was stopped and no dialysis occurred for the last 30 minutes of the run The "standard hemodialysis" prescription consisted of four hours of hemodialysis three times per week Hemodialysis was undertaken using the same high flux, high efficiency polysulfone dialyser during the entire study period (/ e F80A dialyser [Fresenius, Inc, Walnut Creek, CA] or equivalent), with a blood flow of 350-400 ml/mm and a dialysate flow of 500 ml/mm During "increased dialysate flow" treatment, patients received standard dialysis for four hours three times per week but the dialysate flow rate was 800 ml/mm rather than 500 ml/min The third modality was "increased dialysis duration" at 4 5h, 3 times per week, using dialysate flow of 500 ml/mm Lastly, in the final dialysis modality consisting of "two dialysers in parallel', patients received hemodialysis for four hours three times per week with two F80A dialysers connected by a Y-connector in a parallel configuration during each run using the method described by Powers et al (21 ) Dialysate flow was 800 ml/mm Previous research has shown that using this setup, the blood and dialysate flows are split almost equally between the dialysers (21 ) During all study dialysis sessions, the dialysis machines were sequestered behind a curtain in an attempt to blind patients to the dialysis strategy they were receiving Patients unable to reach their target weight within 4h due to excessive weight gam and/or intradialytic hypotension / cramping were permitted to receive ultrafiltration during the last half hour of the run (reassessed each run) This was unlikely to significantly improve small solute clearance, since the expected increase in delivered Kt/V would be <0 5% To assess the extent to which blinding was successful, participants were asked to state which type of dialysis they believe they received after each six-week period

Study Measures

The primary outcome of the original study was health-related quality of life The current manuscript reports a pre-specified secondary analysis that assessed the impact of the different dialytic strategies on the following indices of serum phosphate control and phosphate removal 1 ) Pre-dialysis serum phosphate (primary outcome), 2) Post-dialysis phosphate, 3) Phosphate clearance (22), and 4) Phosphate removal (23) Each of these outcomes was assessed during the last midweek session for each of the 4 different modalities. Therefore, for each participant there were 4 measures of each outcome (one for each of the four modalities). All measurements were done on the midweek dialysis sessions. Pre and postdialysis serum phosphate samples were drawn from the arterial needle. Postdialysis blood samples were drawn two minutes after decreasing the pump speed to 50 ml/min (i.e. at 4h for three of the strategies and at 4.5h for the increased dialysis time strategy). Serum phosphate measurements were obtained from two central laboratories (Calgary Laboratory Services and Alberta Provincial Laboratory in

Edmonton).

Statistical Analysis Sample size calculations were based on the primary study outcome, which required 18 patients to show a clinically relevant improvement in quality of life. Baseline characteristics are presented as means and 95% confidence intervals (or medians and interquartile range (IQR), where appropriate) for continuous variables and proportions for dichotomous variables. To determine the association between dialysis treatment regimens and serum phosphate/phosphate clearance/phosphate removal, a linear mixed effects model was used which takes into account the correlation of data due to repeated measurements for each subject given the crossover design of the study (24, 25). This analysis provides an assessment of within subject treatment comparisons (to determine the effect of the treatment), and also permits an assessment of between subject sequence comparisons (to determine the influence of the order of the treatments) and subject-by-sequence effects (to assess for potential carry-over effects).

The assumption that the response variables were normally distributed was tested and met. Initially, the treatment, treatment period, and treatment sequence were modeled as fixed effects with subjects modeled as random effects. Least-squares means were computed for each treatment, adjusting for other effects in the model. There was no evidence of period or carry-over effects therefore the primary analysis did not include terms for treatment period or treatment sequence. All analyses adjusted for the level of pre-dialysis serum phosphate obtained during the previous treatment period ("rolling baseline" serum phosphate) as a fixed effect. All analyses were performed using SAS software version 9.1.3 (SAS Institute Inc, Cary, NC).

Results

Baseline characteristics of the 18 study participants are shown in Table 1 with trial flow in Figure 3. The mean baseline pre-dialysis serum phosphate for patients who were receiving 4 hours of hemodialysis three times per week before enrollment was 1 92 ± 0 63 mmol/l Mean pre-study serum calcium was 2 26 ± 0 23 mmol/l, and mean pre-study calcium x phosphate product was 4 34 ± 1 55 mmol²/!²

Table 1 : Characteristics of participants

Characteristic n = 18

Age (years), median (IQR) 58 0 (44, 66)

Male, n (%) 17 (94 4)

Caucasian, n (%) 13 (72 2)

BMI (kg/m²), median (IQR) 32 0 (30 1 , 36 1 )

Duration on dialysis (months), median (IQR) 21 5 (16 0, 30 0)

Baseline Kt/V for patients while receiving 4hr dialysis, mean 1 23 (0 10)

(SD) (n=13)

Baseline pre-dialysis serum phosphate for patients while 1 92 (0 63) receiving 4hr dialysis, mmol/L, mean (SD)

Etiology of ESRD

Diabetes, n (%) 11 (61 1 )

Glomerulonephritis, n (%) 4 (22 2)

Polycystic kidney disease, n (%) 1 (5 6)

Transplant failure, n (%) 1 (5 6)

Charlson comorbidity score, median (IQR) 4 (3, 7)

Diabetes Mellitus, n(%) 14 (77 8)

Coronary Artery Disease, n (%) 8 (44 4)

Congestive heart failure, n (%) 5 (27 8)

Cerebral vascular disease, n (%) 3 (16 7)

Peripheral vascular disease, n(%) 4 (22 2)

BMI body mass index, ESRD end stage renal disease, IQR interquartile range, SD Standard deviation

As previously reported (REF), both increased dialysis duration (1 41 , 95% Cl 1 32, 1 50) and using two dialysers in parallel (1 41 , 95% Cl 1 33, 1 49) led to significantly greater Kt/V than standard dialysis (1 27, 95% Cl 1 19, 1 35) Mean Kt/V delivered in treatments with increased dialysate flow (1 31 , 95% Cl 1 22, 1 39) was similar to that for standard dialysis

Using two dialysers in parallel was associated with a significant decrease in predialysis serum phosphate compared to standard hemodialysis (Figure 4) Mean predialysis serum phosphate while using two dialysers in parallel was approximately 0 4 mmol/l lower than with standard hemodialysis (p=0 017) (Table 2) Table 2: Serum phosphate (mmol/l) by dialytic regimen

Characteristic Predialysis serum Postdialysis serum

phosphate phosphate

Baseline (pre-randomization) 1 92 (1 61 , 2 23)

Standard hemodialysis 2 11 (1 83, 2 39) 0 87 (0 71 , 1 02)

Increased dialysis time 1 87 (1 46, 2 29) 0 82 (0 62, 1 02)

Increased dialysate flow 2 03 (1 56, 2 50) 0 96 (0 74, 1 18)

Two dialysers in parallel 1 69 (1 34, 2 05) 0 70 (0 52, 0 87)

Mean (95% Cl)

Mean serum postdialysis serum phosphate as measured while using two dialysers in parallel was also lower by 0 14 and 0 24 mmol/l than with the standard hemodialysis (p=0 046) and increased dialysate flow (p=0 0009) strategies, respectively Longer dialysis time of 4 5h also significantly reduced postdialysis serum phosphate by

0 15 mmol/l, compared to the increased dialysate flow modality (p=0 04)

Using two dialysers in parallel was also associated with higher phosphate clearance than the other three strategies (Figure 5, Table 3) However, total phosphate removal was not significantly different between treatments

Table 3: Phosphate clearance (mL/min) and phosphate removal (mmol/l) by dialytic regimen

Characteristic Phosphate clearance Phosphate removal

Standard hemodialysis 83 1 (73 5, 92 8) 44 8 (39 0, 50 5)

Increased dialysis time 86 1 (74 4, 97 9) 46 6 (37 6, 55 6)

Increased dialysate flow 82 9 (73 2, 92 6) 44 6 (35 0, 54 2)

Two dialysers in parallel 113 7 (94 4, 133 1 ) 46 5 (35 4, 57 7)

Mean (95% Cl)

Results were similar in sensitivity analyses which adjusted for the pre-randomization predialysis serum phosphate rather than the rolling baseline measure of predialysis serum (data not shown) REFERENCES

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All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention

As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural reference unless the context clearly dictates otherwise Unless defined otherwise all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention belongs

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims

Claims

1 A method for reducing phosphate levels in the blood of a patient by hemodialysis, comprising withdrawing and bypassing the blood from the patient in a continuous flow into contact with one face of an hemodialysis membrane, the hemodialysis membrane having a total surface area of at least 3 0 m², simultaneously passing dialysate solution in a continuous flow on an opposite face of the hemodialysis membrane to the side of the hemodialysis membrane in contact with the blood, the flow of the dialysate solution being countercurrent to the direction of flow of blood, and returning the blood from which the phosphate levels have been reduced into the patient

2 The method of claim 1 , wherein the flow rate of the blood is from about 350 to 400 ml/mm 3 The method of claim 1 , wherein the flow rate of the dialysate solution is from about 500 ml/mm to 800 ml/mm

4 The method of any one of claims 1 to 3, wherein dialysis of the patient is for a period of 4 hours, 3 times per week, or for 4 5 hours, 3 times per week

5 The method of any one of claims 1 to 4, wherein the patient has a body mass of 80 kilograms or greater

6 The method of any one of claims 1 to 5, wherein the hemodialysis membrane having a total surface area of at least 3 0 m² is in the form of a plurality of hollow fibre tubes contained in a single dialyser

7 The method of any one of claims 1 to 5, wherein the hemodialysis membrane having a total surface area of at least 3 0 m² is in the form of a plurality of hollow fibre tubes contained in two or more dialysers

8 The method of claim 7, wherein the two or more dialysers are connected in a parallel configuration 9 The method of claim 8, wherein dialysis of the patient is for a period of 4 hours, 3 times per week and the flow rate of the dialysate soution is 800 ml/mm

10 The method of any one of claims 1 to 9, wherein the patient's predialysis blood phosphate levels are consistently lower between dialysis sessions compared to conventional hemodialysis treatment

11 The method of any one of claims 1 to 9, wherein the patient's predialysis blook phosphate levels are reduced by up to 0 44 mmol/l compared to conventional hemodialysis treatment

12 A dialyser for reducing phosphate levels in blood of a patient, comprising two compartments divided by means of a hemodialysis membrane having a total surface area of at least 3 0 m², one of said compartments for receiving continuous flow of blood that is in contact with one face of the hemodialysis membrane, another of said compartments for receiving a continuous flow of dialysate solution that is in contact with an opposite face of the hemodialysis membrane, the dialysate solution and the blood being completely separated from each other, a blood inlet and a blood outlet of said dialyser for flowing the blood through said blood compartment, and a dialysate inlet and a dialysate outlet of said dialyser for flowing dialysate solution through said dialysate solution compartment 13 The dialyser according to claim 12, wherein the hemodialysis membrane having a total surface area of at least 3 0 m² is in the form of a plurality of hollow fiber tubes

14 An apparatus for reducing phosphate levels in blood of a patient, comprising a dialyser divided into a blood compartment and a dialysate compartment by means of a hemodialysis membrane having a total surface area of at least 3 0 m² , a blood inlet line and a blood outlet line connected to a blood inlet and blood outlet of said dialyser for flowing the blood from the patient, through said blood compartment and back to the patient, a dialysate inlet line and a dialysate outlet line connected to a dialysate inlet and outlet of said dialyser for flowing dialysate solution through said dialysate compartment, means for pumping the blood withdrawn from the patient through the dialyser and returning the dialysized blood having reduced phosphate levels back to the patient, and means for pumping the dialysate solution through the dialysate compartment, the flow of the dialysate solution in a direction countercurrent to the direction of the flow of the blood 15 The apparatus of claim 14, wherein the hemodialysis membrane having a total surface area of at least 3 0 m² is in the form of a plurality of hollow fiber tubes

16 The apparatus of claim 15, wherein the hemodialysis membrane having a total surface area of at least 3 0 m² is contained in a single dialyser

17 A method of treating a patient in need of phosphate reduction by hemodialysis comprising removing and bypassing the blood from the patient in a continuous flow into contact with one side of an hemodialysis membrane, the hemodialysis membrane having a total surface area of at least 3 0 m², passing dialysate solution in a continuous flow on an opposite side of the hemodialysis membrane to the side of the hemodialysis membrane in contact with the blood, the flow of the dialysate solution being countercurrent to the direction of flow of blood, and returning the blood from which the phosphate levels have been reduced back to the patient 18 The method of claim 17, wherein the flow rate of the blood is from about

350 to 400 ml/mm

19 The method of claim 17, wherein the flow rate of the dialysate solution is from about 500 ml/min to 800 ml/mm

20 The method of any one of claims 17 to 19, wherein the patient has a body mass of 80 kilograms or greater

21. The method of any one of claims 17 to 20, wherein dialysis of the patient is for a period of 4 hours, 3 times per week and the flow rate of the dialysate soution is 800 ml/min.

22. The method of any one of claims 17 to 21 , wherein the patient's predialysis blood phosphate levels are consistently lower between dialysis sessions compared to conventional hemodialysis treatment.

23. The method of any one of claims 17 to 21 , wherein the patient's predialysis blook phosphate levels are reduced by up to 0.44 mmol/l compared to conventional hemodialysis treatment.