WO2024017853A1

WO2024017853A1 - Haemodialysis method and machine with a bicarbonate-buffered dialysate without acidifier

Info

Publication number: WO2024017853A1
Application number: PCT/EP2023/069842
Authority: WO
Inventors: Bernard Bene; Laurent JUILLARD
Original assignee: Bernard Bene; Juillard Laurent
Priority date: 2022-07-18
Filing date: 2023-07-17
Publication date: 2024-01-25
Also published as: FR3137840A1; FR3137840B1

Abstract

Machine (1) for renal replacement therapy by haemodialysis, the machine comprising a haemodialyser (2), the machine being provided with an ultrafilter (17) and a first pumping means (18), the ultrafilter being disposed on the dialysate inlet tube and the first pumping means being disposed on the dialysate inlet tube, the machine comprising a second pumping means (32) for dialysate evacuation and a third pumping means (31) for dialysate evacuation, the second and third pumping and evacuating means being disposed in series on the outlet tube, the machine being provided with means for controlling the ultrafiltration, the machine comprising a first injection station (12) for injecting a first dialysate component (13), into the inlet tube, upstream of the first pumping means, and a second injection station (19) for injecting a second dialysate component (20), into the inlet tube, downstream of the first pumping means.

Description

Hemodialysis process and machine with bicarbonate-buffered dialysate without acidifier

Technical area

The invention relates to the technical field of extrarenal purification.

State of the art

Extrarenal purification is used in cases of end-stage chronic renal failure (ESRD).

“Renal failure” refers to the partial or total, transient or permanent loss of overall renal function. By “chronic renal failure”, we designate the consequence of a progressive irreversible destruction of the nephrons, with a reduction in glomerular filtration, assessed by clearance. In France, the High Authority for Health (HAS) indicates that the glomerular filtration rate is estimated from serum creatinine, using the CKD-EPI equation (Chronic Kidney Disease Epidemiology Collaboration, Levey et al, Ann Intern Med. May 5; 150(9): 604-612. 2009), the agreed threshold to define the drop in glomerular filtration rate (GFR) being 60 ml/min/1.73 m ² .

Chronic renal failure progresses slowly over several months, or even several years, with renal function declining until it no longer exists at all, this state being called “end-stage chronic renal failure”, and corresponding to stage 5 of the disease. chronic kidney disease, with a glomerular filtration rate less than 15 ml/min/1.73 m ² , according to the N FK-KDOKI classification (National Kidney Foundation - Kidney Disease Quality Initiative).

In France, the number of people treated for chronic end-stage renal failure is estimated at 92,000, including approximately 50,000 receiving extrarenal purification treatment and approximately 42,000 transplant recipients, the mortality rate being 10.4%. Hypertensive and vascular nephropathy, diabetic nephropathy represent more than half of I RCT treatment cases (Biomedicine Agency, 2019 annual report, REIN, French Registry of replacement treatments).

It is estimated that kidney disease affects nearly 600 million people worldwide. Apart from kidney transplant which concerns around 3200 patients in France each year, the treatment of chronic end-stage renal failure is carried out by chronic replacement hemodialysis, according to different modalities: peritoneal dialysis, hemodialysis (at home, autodialysis, medical dialysis , in-center hemodialysis). These treatments concern around 1,100 new patients in France each year.

By “dialysis” we mean a technique allowing exchanges between two liquids of different compositions, separated by a semi-permeable membrane. The term "chronic replacement hemodialysis" refers to the extrarenal purification techniques used for the treatment of chronic renal insufficiency, these techniques based on exchanges, through a semi-permeable membrane, between the constituents of the plasma and those of an electrolytic solution called dialysis liquid or dialysate, of composition generally close to that of a normal extracellular liquid.

A general state of the hemodialysis technique is presented for example in the documents Petitclerc Hémodialysis: news and perspectives, ITBM-RBM, 2001; Merlo et al. Hemodialysis generators: state of the French market, ITBM-RBM 28, 150-168, 2007; Sirshendu De et al. Hemodialysis Membranes: for Engineers to Medical Practitioners, ISBN 9780367573737, 230 pages, 2020.

Three main types of extrarenal purification are implemented in commercially available dialysis machines: hemodialysis, hemofiltration, peritoneal dialysis, as well as their variants: hemodiafiltration, biofiltration.

Peritoneal dialysis uses the peritoneum as a semi-permeable membrane. Other dialysis techniques use artificial membranes.

In peritoneal dialysis, water transfer is osmotic. Peritoneal dialysis has several advantages. Almost always, peritoneal dialysis is performed at home, avoiding fatigue and travel time to a dialysis center. Peritoneal dialysis can be continuous ambulatory, performed during the day, or automated and performed at night. Peritoneal dialysis does not require the use of coagulants, and does not require an extracorporeal blood circuit. Peritoneal dialysis, however, has disadvantages and is little used, particularly in France where around 6% of patients treated for chronic end-stage renal failure use peritoneal dialysis, this ratio having remained without notable change since 2012.

Peritoneal dialysis remains perceived as risky, particularly with regard to peritoneal infections, or sclerosing and encapsulating peritonitis (see Rottembourg et al, The reality of peritoneal dialysis: 40 years later, Nephro ther, 2018).

Unlike the different hemodialysis techniques in which an arteriovenous fistula or a port are commonly used as a vascular access, as an alternative to a central venous catheter, peritoneal dialysis requires the use of a catheter. Training of the patient, caregiver or home nurse is necessary for the care of the catheter exit port, essential in trying to avoid peritoneal infection and maintaining aseptic conditions during connections and catheter disconnections. This risk is all the higher as these connections and disconnections are frequent, particularly in continuous ambulatory peritoneal dialysis. This risk of infection, which can lead to peritonitis, is increased by age, diabetes, and a high body mass index. Peritoneal infection can cause damage to the peritoneal membrane, or even death of the patient.

For peritoneal dialysis, storage space for dialysate bags and dialysis equipment is necessary in the patient's home. In addition to the risk of infection, peritoneal dialysis can fail due to catheter malfunction, or psychological problems related to acceptance of the treatment. The proportion of patients having to interrupt peritoneal dialysis in France is around 50% at three years.

Autodialysis (or autonomous hemodialysis) is rarely used in France. Autodialysis centers allow patients residing in the same area to come together, with a nurse taking care of the patients but only intervening if necessary. Autodialysis can be assisted, the patient being trained in hemodialysis and being partially autonomous.

Medical dialysis is carried out in a unit welcoming patients who cannot or do not want to be treated at at home or in an autodialysis unit and who require intermittent medical care.

Most patients carry out their dialysis sessions in a hemodialysis center (in France 82% of new patients, and 56% of hemodialysis patients as of December 31, 2018). This state of affairs has negative consequences on the patient's quality of life: hemodialysis requires three sessions per week, during the day, each lasting between 4 and 6 hours most often. To this session time, the patient must add a round trip travel time.

The invention relates more particularly to hemodialysis using an artificial, extracorporeal membrane, whether this hemodialysis is carried out at home, in an autodialysis unit, or in a medical center. Three types of transfer can exist through an extrarenal purification machine membrane: migration, convection, diffusion. These transfer mechanisms are for example presented by Jungers et al, Chronic renal failure, prevention and treatment ISBN 2-257-17556-5, 2004.

Diffusion (sometimes called conduction) is a passive transfer of solutes without the passage of water, under the effect of a concentration gradient on either side of a membrane, between the blood compartment to be purified and the dialysate compartment . This passive transfer allows the transfer of urea, creatine, potassium and phosphorus.

Convection, or ultrafiltration, is an active transfer of water accompanied by solutes, under the effect of a pressure gradient between the blood compartment and the dialysate compartment. This active transfer allows the elimination of excess water in the patient.

Certain molecules contained in the patient's blood can also be adsorbed to the membrane, potentially forming a biofilm on the membrane.

In hemodialysis, the transfer of molecules is essentially obtained by diffusion, under the effect of a concentration gradient, with water and sodium being eliminated by ultrafiltration.

In the so-called hemofiltration variant, the transfer of molecules is convective, through a high permeability membrane, and the patient's water balance is ensured by injecting into the blood circuit a substitution solution, of composition close to that of a normal plasma ultrafiltrate. In the so-called hemodiafiltration variant, the transfer of solutes is diffusive (for low molecular weight substances) and convective (for high molar mass solutes), hemodiafiltration requiring both a dialysate and a replacement solution. Just as in hemofiltration, the substitution solution must be sterile and non-pyrogenic.

Hemofiltration and hemodiafiltration can be performed online.

As noted in the document Methods and Techniques for Improving the Removal of High Molecular Weight Solutes in Hemodialysis, ITBM-RBM 2001, filtration at a hemodialyzer can be forced by increasing the transmembrane pressure (TMP) between the blood compartment and the dialysate compartment, this increase in PTM being ensured by an ultrafiltration master of the hemodialysis generator. This increase in PTM leads to a significant loss of plasma water, compensated by the provision of a replacement fluid (stored in external bags, or prepared online from the dialysate), predilution and postdilution.

Examples of hemodiafiltration machines can be found in documents US10821216 (Nephros, 2020), EP1351756 (Nephros, 2013), EP2295092 (Bellco, 201 1), US6843779 (M irmedical, 2005), EP692269 (Fresenius, 2000) , US5194157 (Sorin, 1993), US501 1607 (Toru, 1991).

In hemodialysis, the purification of uremic toxins is obtained by exchanges between plasma and dialysis fluids (dialysate and/or reinjection fluids) devoid of these toxins. In order to maintain or restore the electrolyte balance of the internal environment, these dialysis liquids must contain the four quantitatively most important cations in the extracellular environment (Na ⁺ , K ⁺ , Ca ²⁺ , Mg ²⁺ ) as well as the two quantitatively most important anions (bicarbonate HCO3" and chloride Cl").

In addition to the purification of uremic toxins, hemodialysis aims to adjust the concentrations of ionized substances in the plasma to values close to physiological levels.

This is achieved by diffusive and convective exchange processes through a semi-permeable membrane, where the blood is brought into contact with the dialysate, having a composition close to the values to be achieved in the patient's blood at the end of the dialysis session. . The body needs mineral substances such as sodium, potassium, calcium, magnesium, chlorine and phosphorus, the excess or absence of any of these elements can lead to serious health problems, particularly in dialysis patients.

For example, a reduction in dietary sodium intake is recommended for patients suffering from chronic renal failure, the expected benefit being on progression to end-stage renal failure and cardiovascular mortality (Keller et al , Sodium, hypertension, chronic kidney diseases, and public health, Nephrology & Therapeutics, April 2018 pages S93-S98).

With regard to potassium, renal insufficiency is generally responsible for hyperkalemia (>5mmol/l), itself responsible for heart rhythm disorders which are life-threatening (Dussol, Potassium physiology, hypokalaemia and hyperkalaemia, Nephrology & Therapeutics, June 3, 2010, pages 180-199).

State of the art concerning dialysates

A usual dialysate composition (in mmol/l) is close to the following values:

Table 1 - Conventional composition of dialysate

These values may vary slightly, depending on specific prescriptions depending on the patient's needs.

When dialysis is carried out in a center, the dialysate is conventionally produced by diluting concentrated solutions.

The manufacture of dialysate from concentrated solutions must follow detailed regulatory requirements, see in particular European Pharmacopoeia No. 1167: water for dilution of concentrated solutions for hemodialysis; see also for example standard NFS 93-310 of December 2004, relating to design requirements, performance and safety operation of water treatment and distribution systems for dilution of concentrated solutions for hemodialysis, and the NFS 93-315 standard of November 2008, relating to the requirements and recommendations for users of fluids for hemodialysis.

In practice, when dialysis is carried out outside the patient's home, in dedicated structures, the dialysate is produced continuously by a generator, during the dialysis session, from ultrapure water and concentrates: most often a bicarbonate concentrate and an acid concentrate. The acid concentrate is usually delivered in cans of around five liters, or in liquid bags. The bicarbonate concentrate is used in addition to the acid concentrate and is usually delivered in powder cartridges, allowing the production of buffer for a dialysis session, typically 650g for four hours of dialysis to 1kg for eight hours of dialysis.

In recent years, dialysis techniques have been developed to allow the treatment of patients at home with simplified equipment, adapted to an extra-hospital environment.

These techniques use machines that do not generate dialysate from treated water and concentrates, but use sterile dialysate, at final dilution, in bags, ready to use. Such simplified machines for home dialysis are, for example, known under the brands NxStage ® and Physidia ®.

The dialysate in the NxStage machines is lactate-based, and is supplied in five liter bags, with four to five bags required per dialysis session.

The dialysate from Physidia machines is offered with a bicarbonate and lactate buffer, in five liter bags. Dialysate bags with bicarbonate buffer are two-compartment, extemporaneous mixing must be done before starting the dialysis session, and dialysate bags with lactate buffer are ready to use.

Document US2005/098500 (Collins, 2005) describes an extrarenal purification machine by hemodiafiltration, the machine comprising two cartridges in series, the pH of the dialysate entering the first filtration cartridge being modified by introducing a strong base or of a salt of a weak acid, the second cartridge correcting variations in blood pH occurring in the first cartridge. The machine comprises means for determining the pH of the dialysate of the second cartridge necessary to return the blood treated in the first cartridge to a normal level, an acid pump and/or a bicarbonate pump which can be used to adjust the pH of the dialysate to provide a pretreated dialysate at the inlet of the second cartridge. A portion of the pretreated dialysate is injected by a pump into an ultrafiltration means, and is mixed with the blood leaving the first cartridge, before entering the second cartridge.

Technical issues

An important problem encountered during the manufacture of dialysis liquids is to make divalent cations (calcium and magnesium) and bicarbonate coexist in solution. At neutral pH, bicarbonate ions precipitate with divalent cations (Ca ²⁺ and Mg ²⁺ ) and form insoluble precipitates of calcium and magnesium carbonate.

In the presence of bicarbonate, these divalent cations tend to produce precipitates of calcium and magnesium carbonate.

The HCOs' ion being in large excess compared to the divalent cations, this precipitation is responsible for a reduction in the concentration, or even a disappearance, of these divalent cations normally dissolved in the dialysis liquids.

Indeed, the bicarbonate ion in the presence of the calcium ion and the magnesium ion forms insoluble precipitates, which do not cross the semi-permeable membrane, thus reducing the available concentration of these elements to ensure ionic balance in the patient.

Precipitation of calcium carbonate in bicarbonate dialysate circuits has been a long-known problem, see for example Klein et al. Calcium carbonate precipitation in bicarbonate hemodialysis, Artificial Organ Vol 10 No. 3, 1986.

To take this difficulty into account, it has been proposed: to use stabilizing agents, for example glycylglycine, as described in document EP 277868 (Pierre Fabre, 1988); placing the bicarbonate dialysate in a gas-tight one-compartment bag, as presented in document US 2003/0232093 (Baxter, 2003); to place the bicarbonate dialysate in a bag with two compartments, one containing the bicarbonate, the other the calcium and magnesium, as presented in document US2003138501 (Baxter, 2003).

When two-compartment bags are used, these two compartments must be mixed before the start of the session, which requires additional handling by the patient or caregiver.

In addition, the two-compartment bag represents a significant additional cost compared to a single-compartment bag of the same volume of sterile liquid.

To resolve this problem of formation of insoluble precipitates, several methods have successively appeared (see Petitclerc et al, Hemodialysis without acetate, what is it really? Nephrology & Therapeutics 7, 2011, pages 92-98; Dao et al, New dialysates: what acid in the dialysis bath, Nephrology and Therapeutics, Elsevier Masson, 2019. bubbling of gaseous CO2 in the tank containing the dialysate; replacement of bicarbonate with sodium acetate (acetate hemodialysis); addition of acid acetic, acidifying a concentrate containing the ions Na ⁺ , K ⁺ , Ca ²⁺ , Mg ²⁺ : hemodialysis with bicarbonate; replacement of acetic acid with hydrochloric acid or citric acid; biofiltration without acetate or AFB , with dialysate without buffers, the divalent ions being in the dialysate and the bicarbonate in the substitution liquid;

Duo-Cart-Biofiltration, with a dialysate containing only bicarbonate, sodium and chlorine, the substitution liquid containing potassium, calcium and magnesium chlorides, as well as glucose.

Each of these methods has drawbacks, and the great diversity of the solutions proposed illustrates that no solution is to date considered fully satisfactory.

Bubbing gaseous CO2 is an old technique which is not suitable for dialysates contained in bags, as indicated for example in document FR 2753099 (Aguettant, 1998). Acetate hemodialysis has proven to be unsuitable for thin, diabetic or elderly people. After an acetate hemodialysis session, acetemia can rise up to 15 mmol/L, which is much higher than its physiological concentration (<0.15 mmol/L). The clinical consequences of this hyperacetemia are numerous: hemodynamic instability linked to peripheral vasodilation and an alteration of myocardial contractility, bio-incompatibility and inflammation, acidosis.

The acidification of solutions with mineral (hydrochloric acid) or organic (acetic acid, lactic acid) acids leads to different disadvantages, depending on the acid used: the addition of acetic acid leads to the production of acetate, with the known negative effects of acetate hemodialysis, including drop in blood pressure, muscular impatience, post-dialytic asthenia; the addition of a strong acid such as hydrochloric acid requires the use of corrosion-resistant materials, for example stainless steel, for tanks and pipes and storage containers, and the hydraulic circuits of certain monitors hemodialysis do not tolerate the use of a strong acid such as hydrochloric acid; the addition of citric acid could lead to a reduction in the patient's ionic calcium level, a source of hypotension.

There are also disadvantages to adding lactate.

An example of dialysate composition using lactate is presented in the table below (composition in mmol/l).

Table 2- Conventional composition of a lactate dialysate

The lactate transferred to the patient is transformed into bicarbonate, making it possible to obtain the desired correction of the acid-base balance.

But this transformation is not immediate or complete and depends on the patient's liver function and muscle mass. This is the reason why the lactate level is generally higher than the bicarbonate level usually used in the dialysate.

Furthermore, a minority of patients with deficient lactate metabolism show signs of intolerance during the session, which force them to return to bicarbonate dialysate, with the disadvantages presented above.

Despite the addition of acid, the deposition of calcium carbonate in the circuits is presented as inevitable, requiring a decalcification treatment, see for example US6080321 (Fresenius, 2000), US10155077 (Fresenius, 2018).

The document WO2021 169042 (Bené, 2021) describes a method of operating a dialysis machine comprising the alternating circulation of two dialysates in a dialysate compartment of a dialysis machine, a first dialysate comprising solutes different from a second dialysate, the process comprising at least one operating cycle formed by a first phase of circulation of the first dialysate in the dialysate compartment, this first phase being directly followed by a second phase of circulation of the second dialysate in the dialysate compartment. The second dialysate comprises, for example, bicarbonate. The first dialysate comprises, for example, calcium and magnesium.

Objects of the invention

The invention aims to overcome the problems of hemodialysis machines and processes proposed in the prior art.

An object of the invention is to provide a method and a machine for hemodialysis with a dialysate buffered with bicarbonate, without risk of precipitation of carbonates.

Another object of the invention is to provide a method and a hemodialysis machine with a dialysate devoid of acidifier.

Another object of the invention is to provide a method and a hemodialysis machine meeting at least one of the above objects, and allowing the use of a conventional bicarbonate dialysate, the composition of which is for example close to that presented below (in mmol/l):

Another object of the invention is to provide a method and a machine meeting at least one of the above objects, and allowing emergency extrarenal purification, or chronic replacement hemodialysis.

Another object of the invention is to provide a method and a machine meeting at least one of the above objects, and allowing hemodialysis at home, or autodialysis, or medical dialysis.

General presentation of the invention

For these purposes, according to a first aspect, a machine for extrarenal purification by hemodialysis is proposed, the machine comprising a hemodialyzer divided by a semi-permeable membrane into a dialysate chamber (or dialysate compartment) and a chamber intended for blood. (or blood compartment), the machine comprising a dialysate circuit which has a source and an outlet, an inlet pipe connecting the source to the dialysate chamber, an outlet pipe connecting the dialysate chamber to the outlet, the machine being provided with a means of ultrafiltration of the dialysate, the ultrafiltration means comprising an ultrafilter and a first pumping means, the ultrafi Itre being arranged on the dialysate inlet pipe and the first pumping means being arranged on the dialysate inlet tube, the machine comprising a second dialysate pumping and evacuation means and a third dialysate pumping and evacuation means, the second and third pumping and evacuation means being arranged in series on the outlet tubing, the machine being provided with means for controlling ultrafiltration, the machine comprising an injection station, in the inlet tubing, of a first dialysate component, upstream of the first means of pumping, and a second injection station, in the inlet tubing, of a second dialysate component, downstream of the first pumping means.

The dialysate is thus formed by mixing the first component and the second component, in the inlet tubing of the hemodialyzer.

In certain implementations, the ultrafilter is placed between the second injection station and the hemodialyzer.

In other implementations, the ultrafilter is placed between the first pumping means and the second injection station.

Advantageously, the first injection station is arranged upstream of the first pumping means.

The first pumping means thus only circulates the first dialysate component, comprising for example only sodium bicarbonate.

Advantageously, the first injection station comprises connections for a bag containing the first dialysate component, the first injection station comprising means for pumping the first dialysate component.

Advantageously, the second injection station comprises connections for a bag containing the second dialysate component, the second injection station comprising means for pumping the second dialysate component.

In one implementation, the second injection station is in the form of a module that can be attached to a hemodialyzer inlet circuit, for example of an existing machine.

In certain implementations, the first dialysate component comprises a bicarbonate concentrate, forming, after dilution in a dialysate production line, a first diluted component containing in particular between 25 and 40 mmol/l of sodium bicarbonate.

Advantageously, the first dialysate component does not include calcium and does not contain magnesium.

In some implementations, the second dialysate component comprises an electrolyte concentrate and advantageously does not include bicarbonates, does not include acetate, does not include acid or acidifying substance.

In some implementations, the second dialysate component comprises, after dilution in a dialysate production line, 130 to 160 mmol/l sodium, 0 mmol/l to 2.0 mmol calcium, 0 mmol to 1.5 mmol/l of magnesium, up to 5 mmol/l of potassium, from 0 to 3 g/l of glucose.

In certain particular implementations, the second dialysate component comprises, after dilution in a dialysate production line, 140 mmol/l of sodium, from 1.2 mmol/l to 1.75 mmol of calcium, from 0.5 mmol to 1 mmol/l of magnesium, 1.5 to 3 mm ol/l of potassium, 0 to 3 g/l of glucose.

Advantageously, the machine includes means for heating the dialysate, on the inlet circuit, upstream of the injection station of the first dialysate component.

Advantageously, no pumping means is positioned on a portion of the dialysate circuit in which the dialysate resulting from the mixture of the first constituent and the second constituent circulates, before entering the hemodialyzer.

According to a second aspect, a hemodialysis process is proposed using a machine as presented above, the process comprising counter-current circulation of the blood and the dialysate in the hemodialyzer.

Description of embodiments

Other objects and advantages of the invention will appear in the light of the description of an embodiment, given below with reference to the appended figure.

- Figure 1 is a schematic representation of a hydraulic circuit of a dialysis machine, according to one embodiment of the invention;

- Figure 2 is a schematic representation of a hydraulic circuit of a dialysis machine, according to another embodiment of the invention

In the remainder of this description, the terms "upstream", "downstream" are used with reference to the direction of circulation of the fluid concerned, the directions of circulation of the fluids being represented by arrows in the appended figures.

In Figure 1 a dialysis machine 1 is shown schematically, comprising at least one hemodialyzer 2 and a generator monitor 3.

By hemodialyzer, we designate here an exchange module placed at the interface between a patient (not shown) and the dialysis machine 1, this module comprising a membrane separating a dialysate compartment 4 (or dialysate chamber) of a blood compartment 5 (or chamber intended for blood).

The membrane of hemodialyzer 2 is semi-permeable: it allows the passage of water, electrolytes and solutes of molecular weight lower than that of albumin, i.e. approximately 69 kDa, but does not allow the passage of proteins and figured elements of the blood.

The membrane is advantageously formed by a large number of capillaries, the internal diameter of a capillary being comprised for example between 180 and 220 microns, and the wall thickness of a capillary being comprised between for example 35 and 40 microns, the total surface area of these capillaries being of the order of 1 to 1.5 square meters. The hemodialyzer 2 is advantageously in the form of a cartridge containing dialysate circulation capillaries and blood circulation capillaries. Advantageously, the dialysate and the blood to be purified circulate in the capillaries against the current.

The membrane of the hemodialyzer has a permeability chosen in particular according to the type of hemodialysis prescribed for the patient. This permeability is evaluated by the value of the ultrafiltration coefficient, in m L/h.

According to different embodiments, the membrane of the hemodialyzer 2 is made of a material chosen from the group comprising polyacrylonitriles, polysulfones, polyethersulfones, ethylene vinyl alcohol copolymers, polymethylmethacrylates, cellulose acetates, in particular triacetate cellulose, mixtures of polyethylene glycol and polycarbonate.

In advantageous implementations, the membrane is made of a copolymer of polyacrylonitrile and sodium methallyl sulfonate, and is sold for example under the brand AN69 ®, or AN69 ST, the membrane being covered with heparin.

The hemodialyzer 2 is connected to the patient by an arterial line 6 and a venous line 7. The vascular access can be an arteriovenous fistula, a port, a graft, or a central venous catheter, in particular a tunnelled catheter.

A blood pump 8 is placed on the arterial line 6, upstream of the blood compartment 5 of the hemodialyzer 2, the flow rate of this blood pump 8 being for example between 200 and 400 ml/min. A anticoagulant is advantageously injected into the arterial line 6, upstream of the hemodialyzer 2, for example downstream of the blood pump 8. An air sensor 9 is advantageously placed on the venous line 7, downstream of the blood compartment 5 of the hemodialyzer 2.

The dialysis machine 1 allows the elimination of uremic toxins, the correction of hydro-electrolytic, phospho-calcic and acid-base disorders, by exchanges of sol utes and water between the patient's blood and the dialysate, the composition of which is close to that of normal extracellular fluid.

By “uremic toxin” we mean water-soluble substances of low molecular weight (for example creatinine), substances linked to proteins (for example melatonin), substances of medium molecular weight (for example beta2-microglobulin). A classification of uremic toxins with their normal concentration values is proposed by the European Uremic Toxin Work Group (EUTox).

The generator monitor 3 is capable of continuously and extemporaneously producing an electrolytic exchange solution, namely a dialysate and possibly a substitution liquid.

The generator monitor 3 is also capable of ensuring extracorporeal blood circulation. The generator monitor 3 also monitors the progress of dialysis sessions, with an evaluation of purification performance and hemodynamic performance.

The generator monitor 3 includes a dialysate production line 10.

This production line 10 is connected to a water source 11, advantageously osmosis or ultrapure water.

In the dialysate production line 10, a first component of the dialysate is injected in concentrated form, and is diluted in the osmosis water coming from the source 11.

In the dialysate production line 10, a second component of the dialysate is then injected in concentrated form, and is mixed in the production line 10 with the first component which has been previously diluted in osmosis water.

More precisely, downstream of the source 11, the production line 10 comprises a first injection station 12, for the injection of a first component 13 of dialysate. In certain implementations, the first injection station 12 comprises connections for connecting a bag 14, for example a flexible bag, containing the first component 13 in concentrated form. Downstream of this pocket 14, the first injection station 12 comprises a pumping means 15.

The pumping means 15 is for example a pump whose flow rate is between 0 and 1 liter per hour, and advantageously between 0.6 and 1 liter per hour.

On the dialysate production line 10, downstream of the first injection station 12, the generator monitor 3 comprises an ultrafiltration means 16.

The ultrafiltration means 16 comprises an ultrafilter 17 and a first pumping means 18, the flow rate of which is of the order of 300 to 700 ml per minute.

In the embodiment shown, the first pumping means 18 is arranged between the ultrafilter 17 and the first injection station 12 of the first dialysate component 13.

In other embodiments, the first pumping means 18 is arranged downstream of the first injection station 12 and upstream of the ultrafilter 17.

Downstream of the ultrafilter 17, the dialysate production line 10 comprises a second injection station 19 of a second dialysate component 20.

In certain implementations, the second injection station 19 comprises connections for connecting a bag 21, for example a flexible bag, containing the second component 20 in concentrated form. Downstream of this pocket 21, the second injection station 19 comprises a pumping means 22.

The pumping means 22 is for example a pump whose flow rate is between 0 and 1 liter per hour, advantageously between 0.6 and 1 liter per hour.

The second injection station 19 can advantageously be in the form of a module that can be attached to a production line of a dialysis machine, for example an existing machine.

The ultrafilter 17 is capable of retaining bacterial products. In certain implementations, the ultrafilter 17 is positioned between the pumping means 22 of the second component 20 and the dialysate compartment 4 of the hemodialyzer 2, the ultrafilter 17 being advantageously formed of materials, in particular polymeric materials, which do not adsorb noticeably no calcium carbonate.

In other implementations, the ultrafilter 17 is positioned between the first pumping means 18 and the pumping means 22 of the second dialysate component 20.

The generator monitor 3 includes an evacuation line 30 for the used dialysate, downstream of the hemodialyzer 2.

The evacuation line 30 comprises an ultrafiltration pump 31 and a dialysate pump 32 forming a second pumping means.

In an advantageous implementation, the first pumping means 18 arranged on the dialysate production line 10 and the second pumping means 32 (dialysate pump) arranged on the evacuation line 30 of the used dialysate are pumps whose flow rates are equal and between 300 and 700 ml per minute.

Advantageously, the pumping means 18, 32 are arranged at the inlet and outlet of an ultrafiltration monitor.

The pumping means 32 flushes the used dialysate from the ultrafiltration master towards a sewer.

The function of the ultrafiltration monitor is notably to guarantee the accuracy of the patient's weight loss during the hemodialysis session. The desired weight loss for the patient is defined at the start of the hemodialysis session. Conventionally, the total quantity of fluid to be subtracted is equal to the difference between the initial weight and the base weight (dry weight) reached at the end of the previous hemodialysis sessions and for which the patient is normotensive. The extracted volume takes into account the consumption of drinks during the duration of dialysis.

Advantageously, during a hemodialysis session, the flow rates of the pumping means 18, 32 are substantially identical, and the flow rate of the ultrafiltration pump 31 is substantially equal to the hourly weight loss of the patient, increased by the flow rate of the injection pump 22 of the second component 20.

The pumping means 31 achieves weight loss for the patient. Downstream of the injection station 19 of the second component 20, the dialysate production line 10 circulates sterile and apyrogenic dialysate towards the dialysate compartment 4 of the hemodialyzer 2.

Advantageously, the first component 13 of the dialysate comprises a bicarbonate concentrate, and makes it possible to obtain, after dilution with osmosis water in the production line 10, a first diluted component containing between 25 and 40 mmol/l of bicarbonate of sodium. The value of the sodium bicarbonate concentration, by dilution of the concentrate in osmosis water, depends on the medical prescription.

The sodium bicarbonate concentration is adjusted, for example, by conductimetry measurement and feedback control.

The first dialysate component 13 is thus manufactured by dilution, from a liquid solution or a soluble powder contained in a bag 14, for example a flexible bag.

Advantageously, the first dialysate component 13 does not comprise calcium and does not contain magnesium.

Advantageously, the second dialysate component 20 comprises an electrolyte concentrate.

Advantageously, the second dialysate component 20 does not include bicarbonates, does not include acetate and does not include acid.

In certain implementations, the second dialysate component 20 comprises, after dilution in the production line 10, from 130 to 160 mmol/l of sodium, from 0 mmol/l to 2.0 mmol of calcium, from 0 mmol to 1 mmol. 5 mmol/l magnesium, up to 5 mmol/l potassium, 0 to 3 g/l glucose.

In certain particular implementations, the second dialysate component 20 comprises, after dilution in the production line 10, 140 mmol/l of sodium, from 1.2 mmol/l to 1.75 mmol of calcium, from 0.5 mmol to 1 mmol/l of magnesium, 1.5 to 3 mmol/l of potassium, 0 to 3 g/l of glucose.

The second component 20 of dialysate is for example manufactured by dilution ^1/35 or ^1/45 of a concentrate contained in a bag 21, for example a flexible bag.

The sodium concentration in the dialysate obtained can be monitored, to take into account the medical prescription, for example by feedback control and conductometry measurement. The dialysate circuits of machine 1 are advantageously free of dead arms and dead ends, the dialysate circulating in the circuits without stagnating or remaining there longer than a limited time.

The absence of dead arms and dead ends ensures contact of the entire circuit with the disinfection agents, between two hemodialysis sessions.

Advantageously, the heating of the dialysate is positioned on the osmosis water inlet, upstream of the injection of the first component 13 of the dialysate. Heating the dialysate makes it possible to obtain dialysate heated to approximately 37° at the inlet of hemodialyzer 2.

Advantageously, the inlet pump 18 in the ultrafiltration master only circulates the first dialysate component 13, and the pump 22 which injects the second dialysate component 20 is positioned inside the ultrafiltrati on master, downstream of the inlet pump 18.

Advantageously, no pumping means is passed through by the dialysate upstream of the hemodialyzer 2. The dialysate containing both bicarbonate and calcium and/or magnesium chloride only travels the length of tubing separating the second station injection 19 of the second component 20 and the inlet of the hemodialyzer 2, before coming into contact with the membrane. The length of this tubing is advantageously reduced and has no pumping system.

Advantageously, at the end of a hemodialysis session, a scaling step is implemented, for example with sodium citrate. Advantageously, this descaling step is launched immediately after disconnection of the venous and arterial lines on 6, 7, without stopping the circulation of fluid in the dialysate supply and evacuation circuit.

Experimental results have shown that in a machine according to the invention, the bicarbonate dialysate remains stable for more than twenty minutes, without any detectable presence of insoluble particles of calcium carbonate.

The total volume of the dialysate circuit representing less than two liters, and the dialysate circulating at a flow rate of around 500 ml per minute, the passage time of the dialysate in the circuit of machine 1 is less than five minutes. During operation for four hours of a machine 1 according to the attached Figure 1, a production of dialysate was obtained from osmosis water, a first component 13 (bicarbonate concentrate) and a second component 20 (without acidifier), with dialysate circulation at a flow rate of 500 ml per minute. No variation in the transfer of calcium, bicarbonate and other substances dissolved in the dialysate was observed.

The hydraulic circuit of the dialysis machine shown schematically in Figure 1 can be presented in three parts.

A first part of the hydraulic circuit comprises the source 11 of osmosis water, the first injection station 12 and its pumping means 15, the means 18 for pumping the mixture of the first component 13 with the osmosis water, and the supply conduit for this mixture of the first component 13 with the osmosis water to the point of junction with the second injection station 19.

Advantageously, the first component 13 is in the form of a concentrate, placed in a bag, in particular a flexible bag 14. Advantageously, the first component 13 contains all of the bicarbonate, and contains neither calcium nor magnesium.

Advantageously, a conductivity probe allows the flow rate of the pumping means 15 to be controlled, a control being carried out in particular according to the setpoint value fixed by medical prescription. The conductivity probe is preferably placed between the first injection station 12 and the pumping means 18.

Advantageously, the mixture of the concentrate of the first component 13 with the osmosis water has a bicarbonate concentration less than or equal to 38 mmol/L

Advantageously, the flow rate of the pumping means 18 is less than or equal to 95% of the flow rate of the final dialysate entering the hemodialyzer 2.

A second part of the hydraulic circuit includes the second injection station 19 with its pumping means 22.

Advantageously, the second component 20 is in the form of a concentrate, placed in a bag, in particular a flexible bag 21. Advantageously, the second component 20 contains all of the calcium and magnesium.

Advantageously, the second component 20 contains neither bicarbonate nor acidifying substance. The pumping means 22 ensures the circulation of the second component at a flow rate advantageously less than or equal to 5% of the flow rate of the final dialysate entering the hemodialyzer 2.

A third part of the hydraulic circuit includes the tubing connecting the inlet of the hemodialyzer 2 to the junction point between the first part and the second part of the hydraulic circuit.

In the third part of the hydraulic circuit, the final dialysate circulates, a conductivity probe being advantageously placed on this third part of the circuit, for controlling the pumping means 22, a control being ensured according to a set value, in particular from medical prescription.

The flow rate Q3 of the final dialysate in the third part of the circuit is equal to Q1 +Q2, where Q1 is the flow rate of the pumping means 18 of the first part of the circuit, and Q2 is the flow rate of the pumping means 22 of the second part part of the circuit.

The final dialysate contains calcium, magnesium and bicarbonate. The concentration Cf of a substance in the final dialysate is

((C1*Q1) + (C2*Q2))/(Q1 +Q2), where C1 and C2 are respectively the concentration of the substance in the fluid displaced in the first and second part of the hydraulic circuit.

Advantageously, the concentrations C1 and C2 are determined so that the concentration Cf in the final dialysate is equal to the following values (in mmol/l), with the ranges of values below:

Advantageously, the glucose concentration in the final dialysate is between 0 and 3 g/l, preferably close to 1 g/l.

As has been indicated, all of the bicarbonate contained in the final dialysate advantageously comes from the first component 13, the all of the calcium and magnesium contained in the final dialysate advantageously coming from the second component 20.

According to various implementations, the other components of the final dialysate, in particular sodium, potassium and glucose, can be distributed between the first component 13 and the second component 20, according to any intermediate between the two following distributions: the first component 13 contains all of the sodium bicarbonate and potassium chlorides, as well as glucose, the second component 20 containing all of the calcium and magnesium chlorides; the first component 13 contains all of the sodium bicarbonate and the second component 20 contains all of the sodium, potassium, calcium and magnesium chlorides, as well as glucose.

Advantageously, the third part of the hydraulic circuit is of reduced length, and does not include any pumping means.

We now refer to Figure 2, which illustrates a second embodiment.

Embodiment of Figure 2.

The embodiment of Figure 2 is similar to that of Figure 1, with the following differences.

In the first part of the circuit, an injection station 40 of a sodium chloride concentrate is placed downstream of the first station 12 of the sodium bicarbonate concentrate injection.

Advantageously, all of the sodium chloride and bicarbonate in the final dialysate comes from the mixture, in osmosis water, of the first component injected at the first station 12 and the sodium chloride concentrate injected at the injection station 40.

Sodium chloride concentrate is in liquid or powder form. The same applies to the sodium bicarbonate concentrate, and to the concentrate from the second injection station 19. These concentrates are advantageously contained in bags, in particular flexible bags.

At the sodium chloride injection station, a pumping means 41 ensures a flow rate of between 0.5 and 1 l/h. Control of the pumping means 15 of the first injection station 12 is ensured on the basis of signals coming from a conductivity probe 42.

Likewise, control of the pumping means 41 of the injection station 40 is ensured on the basis of signals coming from a conductivity probe 43.

Control of the pumping means 22 of the second injection station 19 is ensured on the basis of signals coming from a conductivity probe 44.

The substances administered by injection station 19 are the substances of the final dialysate other than sodium and bicarbonate, that is to say calcium, magnesium, potassium and glucose. Taking into account the possible concentration of these substances in a liquid concentrate, a flow rate of between 100 and 200 ml/h is sufficient for injection station 19.

No pumping means is positioned on the circuit portion between the injection station 19 and the entry of the dialysate into the hemodialyzer.

The invention has many advantages.

A method and a hemodialysis machine are proposed with a bicarbonate-buffered dialysate, without risk of carbonate precipitation. Scaling of the machine is thus avoided, as is clogging of the membrane.

A method and a hemodialysis machine are proposed with a dialysate devoid of acidifier. The dialysate advantageously contains neither acetic acid, nor citric acid, nor lactic acid, nor hydrochloric acid. Acidification of the dialysate is thus avoided, with the associated risks of hypercapnia. Side effects of acidifiers on the patient are also avoided.

The dialysate is advantageously bicarbonate and of composition close to that presented below:

The process and the machine allow emergency extrarenal purification, or chronic replacement hemodialysis, at home, or in autodialysis, or medical dialysis. The process and the machine allow the treatment of patients at home with simplified equipment, adapted to an extra-hospital environment, the machine using sterile components, in a bag, ready to use.

Claims

1. Machine (1) for extrarenal purification by hemodialysis, the machine (1) comprising a hemodialyzer (2) divided by a semi-permeable membrane into a dialysate chamber (4) and a chamber intended for blood (5), the machine (1) comprising a dialysate circuit (10, 30) which has a source and an outlet, an inlet tube connecting the source to the dialysate chamber (4), an outlet tube connecting the dialysate chamber (4) upon evacuation, the machine (1) being provided with a means of ultrafiltration (16) of the dialysate, the ultrafiltration means (16) comprising an ultrafilter (17) and a first pumping means (18), the the ultrafilter (17) being arranged on the dialysate inlet pipe and the first pumping means (18) being arranged on the dialysate inlet pipe, the machine (1) comprising a second pumping means (32) and dialysate evacuation and a third means for pumping (31) and evacuating dialysate, the second and third pumping means (31, 32) and evacuation being arranged in series on the outlet pipe, the machine ( 1) being provided with means for controlling ultrafiltration, the machine (1) being characterized in that it comprises a first injection station (12), in the inlet pipe, of a first component (13 ) of dialysate, upstream of the first pumping means (18), and a second injection station (19), in the inlet tubing, of a second component (20) of dialysate, downstream of the first means of pumping (18).

2. Machine (1) according to claim 1, characterized in that the ultrafilter (17) is arranged between the second injection station (19) and the hemodialyzer (2).

3. Machine (1) according to claim 1, characterized in that the ultrafilter (17) is arranged between the first pumping means (18) and the second injection station (19).

4. Machine (1) according to any one of claims 1 to 3, characterized in that the first injection station (12) comprises connections for a bag (14) containing the first component (13) dialysate, the first injection station (12) comprising means (15) for pumping the first dialysate component (13).

5. Machine (1) according to any one of claims 1 to 4, characterized in that the second injection station (19) comprises a connection for a bag (21) containing the second component (20) of dialysate, the second injection station (19) comprising means (22) for pumping the second dialysate component (20).

6. Machine (1) according to any one of claims 1 to 5, characterized in that it comprises means for heating the dialysate, on the inlet circuit, upstream of the first injection station (12) of the first component (13) of dialysate.

7. Machine (1) according to any one of claims 1 to 6, characterized in that no pumping means is positioned on a portion of the dialysate circuit in which the dialysate resulting from the mixture of the first component (13) circulates. ) and the second dialysate component (20).