Compositions comprising insulin and ketones bodies to treat cancer

Abstract

A dialysis fluid comprising between 5 pmol / L and 350 pmol / L insulin or pharmaceutically acceptable salts and esters of insulin is provided. The dialysis fluid is suitable for being used in connection with dialysis treatment of cancer. Furthermore, infusion compositions for treatment of cancer, methods for treating cancer, and extracorporeal blood treatment systems are provided.

Description

[0001] DIALYSIS FLUID FOR THE TREATMENT OF CANCER The disclosure herein relates to extracorporeal blood treatment. More specifically, the disclosure relates to the use of extracorporeal blood treatments such as hemodialysis, hemodiafiltration, and hemofiltration in the treatment of cancer. Most specifically, the disclosure relates to dialysis fluids for use in hemodialysis therapy treatment methods of cancer. Technical background Most human cancer cells show an altered energy metabolism that distinguishes them from normal cells. Normal cells acquire most of their energy through mitochondrial oxidative phosphorylation, an aerobic process in which glucose is oxidized, firstly through the glycolysis and subsequently through the tricarboxylic acid (TCA) cycle to produce adenosine triphosphate. This pathway is, on the contrary, only secondary in cancer cells. This was first observed in the 1920s by Warburg. He noted that after cancer cells have metabolized glucose by the glycolysis, lactate is produced from puruvate. In normal cells, this only occurs under anaerobic conditions, but in cancer cells, this alternative pathway is increased even in the presence of abundant oxygen. This phenomenon was named as “aerobic glycolysis” or “Warburg effect” (Warburg et al., 1927, Gen Physiol 8: 519-530). The presence of a characteristic glycolytic phenotype in cancer cells was confirmed by subsequent studies that have also observed overexpression of enzymes involved in glycolysis in most of cancer cells. The above metabolic transformation confers to cancer cells a selective growth advantage and contributes to the ability to resist to hypoxia and apoptosis. Since the rate of tumor cell proliferation exceeds the rate of new blood vessel formation, many tumors grow in a low- oxygen environment. Various metabolic alterations in cancer cells exist and the most common and the most well-known is their habit to produce energy through aerobic glycolysis. Furthermore, many intermediates of glycolysis, such as, for example, ribose, glycerol and serine, are also intermediates of biosynthetic and anabolic pathways that are essential during cancer cell growth and proliferation. Also, glycolysis produces ATP from ADP which allows to sustain cell growth in the tumor. However, glycolysis is much less efficient than oxidative phosphorylation, and therefore requires a high amount of glucose to produce sufficient amounts of ATP. Therefore, this metabolic pathway requires a high amount of glucose. Many cancer cells become addicted to glucose as their main energy supplier. Owing to multiple reasons, glycolytic tumor cells become vulnerable if their glucose supply is targeted. Further, many cancer cells also display addiction to glutamine. The high rate of glutamine uptake exhibited by glutamine-dependent cells is not only a result from its role as a nitrogen source in nucleotide and amino acid biosynthesis, but also, glutamine is the primary mitochondrial substrate in cancer and is required to produce NADPH for redox control and macromolecular synthesis. Other metabolic alterations exist in cancers that have an important role in survival and, Importantly, many cancers show a surprisingly good ability to change their metabolic profile. This plasticity to withstand environmental challenges such as when glucose, glutamine, or oxygen get low is crucial for the survival of the cancer cell. Many metabolic alterations exist in cancers and various amino acids such as glutamine have important roles in cancer metabolism to control redox balance and to produce building blocks for continued proliferation and further, many cancers show a surprisingly good ability to utilize those alternative pathways to change their metabolic profile when needed to adopt to new metabolic limitations. This quality (ability) is an important feature for cancers and their ability to withstand environmental challenges when metabolic energy resources such as glucose, glutamine, or oxygen become scarce. Therefore, to effectively affect cancer through a metabolic approach it is important to affect their metabolic system from more than one direction. Reduced glucose can by most cancer cells be readily handled, but if several metabolic possibilities are affected at the same time (as reducing glucose and amino acids, such as glutamine) the sum of these changes becomes much more devastating than the individual parts. Beside glucose and glutamine, which are global energy sources for many cancers, serine cysteine and glycine meet important specific needs to sustain cell growth and proliferation in cancer, for example through the one-carbon metabolism. In addition to a large energy requirement, cancer cells must also accumulate building blocks for the construction of new cellular components, including nucleic acids, proteins, and lipids, as well as equally important cofactors for the maintenance of their cellular redox status (Amelio et al.: Trends. Biochem.Sci. (2014), vol. 39(4): 191-198)). Studies have demonstrated that arginine is necessary for cellular growth and can become limiting in states of rapid growth and if deprived from the cancer cells also effect survival (Albaugh et al., J.Surg. Oncol. (2017), vol. 115(3), 273-280). In view of the above, it has been suggested that reduced glycaemia may serve as a strategy to target a broad range of glycolysis dependent tumors. In low glycaemia conditions, fats and especially ketone bodies can replace glucose as a primary metabolic fuel for normal cells. Many tumors, however, have abnormalities in the genes and enzymes needed to metabolize lipids and ketone bodies for energy. Therefore, a transition from carbohydrate to ketones for energy specifically targets the energy metabolism in glycolysis-dependent tumor cells (Seyfried et al, 2010, Nutrition and Metabolism, 7:7). In accordance with this approach, for example, WO2011070527 discloses a method of treatment of a proliferative disorder, cancerous or non-cancerous, in an individual wherein a hemodialysis apparatus is used to reduce blood glucose concentration. The use of a hemodialysis apparatus for reducing glycemia has the advantage that the glucose concentration in the blood can be reduced and thereby decreased in a more controlled and effective way compared to diet glucose deprivation. However, the method and apparatus disclosed in WO2011070527 require blood glucose sensors and blood glutamine sensors connected to the blood intake-flow, the blood return flow and the dialysate, which sensors all are connected to the central control unit of the hemodialysis machine. Moreover, the central control unit of WO2011070527 is also connected to an electroencephalograph (EEG) in order to provide the central unit with information pertaining to spontaneous electro-cerebral activity to initiate raising of glucose and glutamine levels. Such a large number of sensors and instruments leads to a high level of complexity and associated high cost. Further, patients undergoing this treatment must consume only a glucose restricted diet for several days prior to undertaking the treatment. This is not an insignificant burden on the patient. Moreover, the inventors have identified that even when hemodialysis is deployed to reduce glycemia it can be challenging to keep a patient’s blood glucose concentration consistently low over an extended period. Without wishing to be bound by any particular theory, it is postulated that the production of glucose in the liver via the process of gluconeogenesis may have an effect in this regard. WO2023 / 099346 A1 relates to compositions for peritoneal dialysis in connection with treating cancer (not hemodialysis) which may comprise ketones and small amounts of non- essential amino acids. The document is silent regarding insulin. Weber et al., Biochemistry 1965, Vol. 53, pp. 96-104, discloses the influence of insulin on biosynthesis of hepatic gluconeogenetic enzymes. The article as silent about dialysis as well as treatment of cancer. WO2021 / 245040 A1 relates to treatment of cancer by dialysis. Nothing is mentioned about using insulin. US2017 / 281607 A1 discloses a pharmaceutical substance and composition for increasing production of insulin. The document is silent regarding treatment of cancer. EP1872812 relates to treatment of diabetes patients that also suffer from end stage renal disease. Nothing is disclosed about treatment of cancer. WO 98 / 06421 A1 discloses dialysis treatment of cancer with a dialysis solution containing a low amount of essential amino acids as well as insulin. Nothing is mentioned about ketones. WO 82 / 03773 A1 describes a dialysis solution containing glucose, amino acids and insulin. Nothing is mentioned about treatment of cancer. There is a constant need for improved ways of treating cancer. More specifically, there is a need for a dialysis fluid that could be in used hemodialysis therapy treatment methods for treating cancer. SUMMARY The present invention provides a dialysis fluid comprising between 5 pmol / L and 350 pmol / L of insulin or pharmaceutically acceptable salts or esters thereof. In an embodiment, the dialysis fluid comprises a concentration of insulin or pharmaceutically acceptable salts or esters thereof within the range of 158 pmol / L – 175 pmol / L. It has been surprisingly found that the inclusion of insulin in the dialysis fluid can, in use, suppress the process of gluconeogenesis while having little perceivable effect on the equivalent ketoneogenesis process, that being the production of nutritional ketones by the liver. This means that the production of glucose may be inhibited alongside its removal by dialysis, while production of ketones is maintained and an energy source for the patient is provided. In preferred embodiments, the dialysis fluid comprises less than 4 mM, and preferably 0.5 – 3 mmol / L glucose or a hydrolysis equivalent concentration thereof. In preferred embodiments, the dialysis fluid comprises between 0.5 mmol / L and 30 mmol / L of a ketone body, such as acetoacetate, beta-hydroxybutyrate or pharmaceutically acceptable derivatives, esters and salts thereof. In some embodiments, the ketone bodies are provided in salt form. More preferably, the concentration of ketone bodies amounts to 2 - 12 mM. In some embodiments, dialysis fluid may contain bicarbonate ions. The concentration of those bicarbonate ions preferably amounts to 15 - 50 mM. More preferably, the concentration of those bicarbonate ions amounts to 20 - 40 mM. The dialysis fluid may contain one or more compounds selected from the group of glucose, pyruvic acid, and amino acids selected from the group of serine, cysteine, glycine, alanine, glutamic acid, glutamine, proline, aspartic acid, asparagine, threonine or pharmaceutically acceptable derivates thereof. Such derivatives could be salts or oligopeptides. In case the dialysis fluid contains a certain concentration of an oligopeptide, the concentration of the participating amino acids after hydrolysis of the peptide is given (This concentration is referred to herein as “hydrolysis-equivalent concentration”). Examples of such oligopeptides, typically dipeptides where at least one of the amino acid residues is glutamine are L-alanyl-L-glutamine, and L-glycyl-L-glutamine. In case the concentration of the dipeptide L-alanyl-L-glutamine would be 1 mM, the hydrolysis-equivalent concentration of the alanine and glutamine parts, respectively, of this oligopeptide would be 1 mM alanine and 1 mM glutamine. The hydrolysisequivalent concentration of an amino acid which is not part of an oligopeptide is simply the concentration of the amino acid or amino acid derivative. Glutamine-containing oligopeptides, also referred to herein as glutamine-containing compounds, are typically used instead of glutamine in liquid compositions in order to enhance stability and solubility. Preferably, the dialysate fluid does not contain any pyruvic acid, serine, cysteine, glutamic acid, proline, aspartic acid, asparagine, threonine, or derivatives thereof. Preferably, the dialysis fluid contains a hydrolysis-equivalent concentration of at most 0.3 mM of glutamine or derivatives thereof. In preferred embodiments the fluid is substantially free from glutamine or derivatives thereof. Indeed, the fluid may be substantially free from pyruvic acid, serine, cysteine, glutamic acid, proline aspartic acid, asparagine, threonine or derivatives thereof. In preferred embodiments the dialysis fluid contains a pharmaceutically acceptable amount of a pharmaceutically acceptable cytostatic agent. In a further aspect, the invention provides a premix for a dialysis fluid as described above. A premix may comprise a powder premix, where the components are provided in ratios such that when diluted with a suitable quantity of water or saline, it forms a dialysis fluid as described above. Alternatively, a premix may comprise a liquid premix, where the components are provided in a concentrated solution in ratios such that when diluted with a suitable quantity of water or saline, it forms a dialysis fluid as described above. In a further aspect of the invention there is provided a composition for delivery to a patient as an infusion, the composition comprising insulin or pharmaceutically acceptable salts or esters of insulin; and either one or more medium chain triglycerides or one or more ketone bodies selected from the group acetoacetate, beta-hydroxybutarate, acetone and pharmaceutically acceptable derivatives thereof; wherein the composition is substantially free from glucose or derivatives thereof and / or glutamine or derivatives thereof. This composition is preferably for use in the treatment of cancer. In this regard, it is noted that insulin may be provided to a subject patient via an infusion provided either to an extracorporeal circuit of a dialysis machine, downstream of a dialyser, or directly to the subject patient. Insulin so provided would replace insulin which may have been removed by the dialyser and / or provide an increased concentration of insulin in the blood of the patient. In a further aspect, there is provided a composition for use in the treatment of cancer by delivery to a patient as an infusion, the composition comprising insulin or pharmaceutically acceptable salts or esters of insulin, the composition being substantially free from glucose or derivatives thereof and / or glutamine or derivatives thereof; the composition being for use in the treatment of cancer in patients undergoing dialysis to reduce blood plasma concentrations of glucose and / or glutamine. In a further aspect, there is provided a method of treating cancer comprising performing dialysis on a patient to reduce blood plasma concentrations of glucose and / or glutamine and administering to the patient a composition comprising insulin or pharmaceutically acceptable salts or esters of insulin, the composition being substantially free from glucose or derivatives thereof and / or glutamine or derivatives thereof. The cancer may be a cancer with metabolic alteration that makes the cancer dependent on glucose and / or glutamine, for example a cancer selected from human colon carcinoma, glioblastoma, prostate, breast and liver cancer. In a further aspect, the invention provides a kit comprising: a composition for delivery to a patient as an infusion, the composition comprising insulin or pharmaceutically acceptable salts or esters of insulin; and either one or more medium chain triglycerides or one or more ketone bodies selected from the group acetoacetate, beta-hydroxybutarate, acetone and pharmaceutically acceptable derivatives thereof; wherein the composition is substantially free from glucose or derivatives thereof and / or glutamine or derivatives thereof; and a dialysis fluid containing less than 4 mmoml / L glucose or a hydrolysis equivalent concentration thereof. Preferably, the dialysis fluid comprises less than 2 mmol / L glucose or less than 1 mmol.L glucose. In a further aspect, the invention provides an extracorporeal blood treatment system for treating a subject suffering from cancer, the system comprising: an extracorporeal blood circuit; a dialysate fluid circuit; said extracorporeal blood circuit and dialysate fluid circuit being divided by a membrane of a filtration unit; at least one blood pump for controlling the flow of blood through the blood circuit; at least one dialysate fluid pump for controlling the flow of dialysate fluid through the dialysate fluid circuit; one or more infusion lines, each infusion line being connected to the extracorporeal blood circuit or adapted for being directly connected to the vascular system of the subject to be treated, each infusion line comprising an infusion pump; a system computing unit operatively connected to the blood pump and the dialysate fluid pump and optionally to the one or more infusion pumps of the one or more infusion lines; said system computing unit having a user interface including an input means and a display means; wherein the system computing unit is adapted for receiving a desired blood concentration value GLNbof glutamine within the range of 0.1 and 0.5 mM; the system computing unit is adapted for receiving a desired blood concentration value GLUCOSEbof glucose within the range of 1 to 4 mM; the system computing unit is adapted for receiving a concentration value GLNp representing the concentration of glutamine or pharmaceutically acceptable glutamine- containing compounds in fresh dialysate fluid; the system computing unit is adapted for receiving a concentration value GLUCOSEprepresenting the concentration of glucose in fresh dialysate fluid; the system computing unit is adapted for receiving a concentration value INSULIN, representing the concentration of insulin or a pharmaceutically acceptable derivative thereof in an infusion liquid to be infused into the extracorporeal blood line or directly into the vascular system of said subject to be treated, through one of said one or more infusion lines; the system computing unit is adapted for receiving an actual concentration value GLNa of glutamine in blood from said treated subject and receiving an actual concentration value GLUCOSEaof glucose in blood from said treated subject; the system computing unit being adapted for controlling said blood pump and said dialysate fluid pump in such a way that the actual blood concentration value GLNa of glutamine is driven towards or below GLNband the actual blood concentration value GLUCOSEaof glucose is driven towards or below GLUCOSEb; and the system is adapted for infusing said infusion liquid into the extracorporeal blood line or directly into the vascular system of said subject to be treated, the system computing unit is adapted for controlling said infusion pump of said infusion line in such a way that when the actual blood concentration value GLUCOSEaof glucose is at or below GLUCOSEb, the infusion is delivered at a first flow rate INSULINfand when the actual blood concentration value GLUCOSEa of glucose is greater than GLUCOSEb, the infusion is delivered at a flow rate INSULINg, INSULINg being greater than INSULINf. Preferably, the system computing unit is adapted for receiving a desired blood concentration value KETONEb of a ketone body, such as acetoacetate, beta- hydroxybutyrate or pharmaceutically acceptable derivatives, esters and salts thereof within the range of 1 - 15 mM; the system computing unit is adapted for receiving the concentration value of ketone bodies, such as acetoacetate, beta-hydroxybutyrate or pharmaceutically acceptable derivatives, esters and salts thereof, in a dialysis fluid to be used, KETONEn ;and the system computing unit is adapted for receiving an actual concentration value KETONEa of a ketone body such as acetoacetate and / or beta-hydroxybutyrate. It is preferred that the system computing unit is configured to drive KETONEa towards KETONEb. Preferably, the system computing unit is adapted for comparing KETONEa and KETONEb, and if KETONEa ^ KETONEb, displaying a message on said display informing that the treated subject should consume a further amount of ketone bodies or medium chain triglycerides. Preferably, the or a second infusion liquid contains ketone bodies or medium chain triglycerides and wherein the system computing unit is configured to deliver the ketone bodies or medium chain triglycerides when KETONEa^ KETONEb. Preferably, the desired blood glucose concentration GLUCOSEb is 1mmol / L to 2 mmol / L, preferably wherein the desired blood glucose concentration GLUCOSEb is 1mmol / L to 1.5 mmol / L, for example around 1 mmol / L. In this disclosure the term “subject” relates to a human or animal patient in need of treatment. The term “ketone bodies” relates to water-soluble molecules containing the ketone group that may be produced by the liver from fatty acids. Typically, a ketone body in accordance with the present invention is beta-hydroxybuturate or a pharmaceutically acceptable derivative thereof, such as its enantiomer (R) — beta-hydroxybutyric acid, (S)-beta- hydroxybutyrate, or enantiomeric mixture, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof, as well as acetoacetate. Medium chain triglycerides are also considered to be derivatives of a ketone body in accordance with the present invention. The term “medium chain triglycerides” or “MCT oils” are triglycerides with two or three fatty acids having an aliphatic tail of 6 - 12 carbon atoms. Such medium chain triglycerides or MCT oils may be transformed into ketone bodies in the human body. Examples of infusion liquids containing ketone bodies or ketone body derivatives are Lipofundin ® MCT / LCT 20 % (B. Braun) or SMOFlipid ® 20 % (Fresenius Kabi). Further examples can be found in WO2018 / 114309 A1. Preferably, the cancer is a cancer with metabolic alteration that makes the cancer dependent on glucose and / or glutamine. Typically, the cancer is selected from human colon carcinoma and glioblastoma, as well prostate, breast and liver cancer. In one embodiment, the dialysis fluid contains a pharmaceutically acceptable amount of a pharmaceutically acceptable cytostatic agent. The above summary of the present disclosure is not intended to describe each embodiment or every implementation thereof. Advantages, together with a more complete understanding of the present disclosure, will become apparent and appreciated by referring to the following detailed description and claims taken in conjunction with the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic block diagram of an exemplary extracorporeal blood treatment system that can be used for treating cancer by hemodialysis using a dialysis fluid according to the present invention. FIG. 2A, 2B and 2C illustrate the treatment goals in accordance with the present invention. FIGS 2D and 2E illustrate possible pH shifts in vicinity of normal cells and cancer cells in connection with dialysis using a dialysis fluid according to the present application. FIG. 2F illustrate the hypothesis that hemodialysis using a dialysate fluid according to the present invention renders cancer cells more sensitive to cytostatic agents and healthy cells more resilient to the cytotoxic drug. Figure 3 A-B show schematic diagrams of the experimental setup (A) in Reference Example 1. Hemodialysis was performed in anesthetized ketotic Sprague-Dawley rats using a blood flow rate of 1 mL / min and a dialysate flow rate of 1 mL / min. In the schematic diagram of the simulational setup (B). Hemodialysis was simulated for a patient using a blood flow rate of 300 mL / min and a dialysate flow rate of 500 mL / min. Figure 4 shows violin plots of blood ketones (A), plasma glucose (B), plasma urea (C), and standard base excess (D) immediately before, during, and 30 min after the dialysis session. Figure 5 shows the simulated glycogen, glucose, insulin, and ketone levels without dialysis (broken lines) and before, during, and after an 8-hour dialysis session started before glycogen stores have been depleted (continuous lines). Scale numbers for glucose and ketones are both in black. Figure 6 shows the simulated glycogen, glucose, insulin, and ketone levels without dialysis (broken lines) and before, during, and after an 8-hour dialysis session started after glycogen stores have been depleted (continuous lines). Scale numbers for glucose and ketones are both in black. Figure 7 shows the simulated glycogen, glucose, insulin, and ketone levels before, during and after an 8-hour dialysis with zero insulin clearance. Scale numbers for glucose and ketones are both in black. Figure 8 A-C show the simulated flow rates of ketones (A), glucose (B), and insulin (C) to and from blood and removed by dialysis for the cases of continued starvation without dialysis (black) and with dialysis (red). Figure 9 A-C show the flow rates of ketones (A), glucose (B), and insulin (C) to and from blood and removed by dialysis for the cases of continued starvation without dialysis (black) and dialysis with zero insulin clearance (red). DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS The present invention relates to a new dialysis fluid for use in a hemodialysis therapy method of treating cancer. In particular, it relates to fluids for use in dialysis treatments which involve the introduction of insulin to the subject. The inventors have surprisingly found that providing insulin to a subject when glucose is being removed by a dialysis treatment appears to suppress the onset of gluconeogenesis more than glucose usage is changed, allowing glycemia to be reduced to a very low level as desired. In contrast, it is surprisingly found that the impact of insulin on ketogenesis in this context appears to be limited by comparison. In a first embodiment, the dialysis fluid for the treatment contains insulin or a pharmaceutically acceptable salt or ester in a concentration between 5 pmol / L and 350 pmol / L (e.g. between 15 pmol / L and 175 pmol / L) insulin or pharmaceutically acceptable salts or esters of insulin. The dialysis fluid also contains less than 4 mmol / L (e.g. between 1 mmol / L and 2 mmol / L) glucose or a hydrolysis equivalent concentration thereof and may also include ketone bodies (such as acetoacetate, beta-hydroxybutyrate or pharmaceutically acceptable derivatives, esters and salts thereof) in a concentration between 0.5 mmol / L and 30 mmol / L. In other embodiments, especially those where the dialysis fluid does not contain one or both of insulin or ketone bodies, one or more infusions are also provided. A first infusion comprises a composition comprising insulin or pharmaceutically acceptable salts or esters of insulin and being substantially free from glucose or derivatives thereof and / or glutamine or derivatives thereof. This infusion may also contain ketone bodies, including MCTs. In further embodiments, especially where there are no ketone bodies provided in the insulin containing infusion, an additional infusion is provided which comprises such ketone bodies. Exemplary systems for extracorporeal blood treatment that could be used together with the dialysis fluids disclosed herein are described in patent application PCT / EP2021 / 064592. Furthermore, non-limiting examples of systems and devices for carrying out extracorporeal blood treatment can be found in EP1668556, US 5,679,245, US 5,762,805, US 5,776,345 and US5, 910,252. In the schematic view of FIG. 1, the exemplary extracorporeal blood treatment system 50 generally includes a blood tubing circuit 52 which includes an arterial line 52a and a venous line 52b which are connectable to a patient’s vascular system. The apparatus comprises a filtration unit 58 having a primary chamber (blood chamber) and a secondary chamber (dialysate chamber) separated by a semi-permeable filtration membrane 59. The inlet of the primary chamber is connected to the blood withdrawal line or arterial line 52a. Likewise, the outlet of the primary chamber is connected to the blood return line or venous line 52b. The inlet of the secondary chamber is connected to a fresh dialysate fluid supply line 54b, which in turn is connected to a source 74 for providing a fresh dialysis solution. The outlet of the secondary chamber of the filtration unit 58 is connected to a dialysis solution or spent dialysate line 54a, which conveys a spent dialysis solution to an effluent connector 73. In the present invention, the filtration unit 58 comprises a membrane 59 which is configured to remove relatively small compounds from blood in the blood tubing circuit 112. The membrane is configured to have a molecular weight cut off (MWCO) of 50 kDa or less or even 40 kDa or less (such as 30 kDa or less, or 10 kDa or less). Flow of blood through the blood line 52a, 52b and filtration unit 58 is governed by a blood pump 60 positioned in the arterial line 52a. Likewise, flow of fresh dialysate fluid from the source 74 through the filtration unit 58 to the effluent collector 73 by a dialysate fluid pump 68 in the supply line 54b, while pressure in dialysate fluid line 54 is governed by a pressure release valve in the spent dialysate line 54a. Alternatively, a second pump 62 could be included in the spent dialysate line 54a instead of a pressure release valve. There could also be one or more infusion lines 66, 80, 81, 82 that are connected to the venous portion of the blood line 52b. In some embodiments, one or more of these infusion lines are adapted to be directly connected to the vascular system of a patient (not shown in the figures). Each of the one or more infusion lines 66, 80, 81, 82 may comprise separate pumps. In one embodiment, an infusion liquid containing ketone bodies or ketone body derivatives could be infused by such an infusion line. A system computing unit 64 is provided in communication with the blood pump 60, the dialysate fluid pump 68, and the one or more pumps of the one or more infusion lines 66, 80, 81 , 82 and the pressure release valve or additional dialysate pump 68 so as to provide control over those devices in use. In an alternative embodiment, the system computing unit 64 provides the user with suitable settings data via a graphical user interface for the pumps in the one or more infusion lines 66, 80, 81 , 82. The system computing unit is also in communication with an input means for the provision of information and instruction to the system processing unit 64. The input means may comprise a graphical user interface such as one which may be controlled by the use of a touch screen arrangement. In some embodiments, the input means may comprise a keyboard. In some embodiments, the input means may include one or more sensors for detecting the concentration of various substances or conditions in the patient’s blood and / or in the spent dialysate. As already mentioned, the present invention provides a dialysis fluid for use in a hemodialysis method. The basic idea behind dialysis treatments is to change the composition of a body fluid by using a semipermeable membrane and a dialysate fluid. The term “body fluid” typically relates to blood but may also be an intracellular fluid of a subject to be treated. The body fluid is separated from the dialysate fluid by the membrane. The membrane is permeable for small molecules but impermeable for larger molecules. Small body fluid components may therefore pass the membrane whereas larger entities are retained where they are. The result is that the concentrations of the body fluid as well as the dialysate fluid change. The driving forces of these changes are diffusion and pressure. As aerobic glycolysis or the Wartburg effect is common in many cancer cells, the following therapeutic goals may be set up: a) reduction of the concentration of glucose as well as amino acids, such as pyruvic acid, serine, cysteine, glycine, alanine, glutamic acid, glutamine, proline, aspartic acid, asparagine, threonine and derivatives thereof, in the body fluid. This can, among all, be obtained by administrating insulin; b) maintenance of physiological pH (pH within the range of 7.2 - 7.6) in the body fluid as lactic acid formed during aerobic glycolysis may locally reduce pH; c) adding ketone bodies in order to provide a source of energy that tumors dependent on aerobic glycolysis cannot rely upon. FIGS. 2A, 2B and 2C illustrate examples of some of the therapy goals and principles of the present invention. Each diagram discloses examples of normal conditions regarding concentration of a specific blood component. FIG. 2A shows that the patient at the onset of the treatment typically has an actual blood concentration of glutamine GLNawithin the range of 0.20 - 0.8 mmol / L. During treatment in which a dialysate fluid with no glutamine or a very low glutamine content, the actual blood concentration of glutamine is reduced to a desired value GLNb, which is within the range of 0.1 - 0.5 mmol / L, and for example within the range of 0.15 - 0.3 mM. FIG. 2B shows that the patient at the onset of the treatment typically has an actual blood concentration of glucose GLUCOSEawithin the range of 4 - 8 mmol / L. During treatment, with a dialysate fluid containing no or a low amount of glucose, the actual blood concentration of glucose is reduced to a desired value GLUCOSEb, which typically is within the range of 0.5 - 4 mmol / L and more preferably in the range 0.5 -3 mmol / L. In embodiments where insulin is provided in the dialysis fluid, the blood concentration of insulin in the patient is not lowered (and may be increased) by the dialysis treatment. This is intended to provide for the suppression of gluconeogenesis, which has been found to take place when a subject’s blood glucose concentration has been reduced to low levels for an extended period. In embodiments where little or no insulin is provided in the dialysis fluid, insulin may be introduced as an infusion through an infusion line 66. In Figure 1, the infusion line 66 is shown as being introduced to the extracorporeal circuit, although it may also be introduced directly to the patient. In such embodiments, the infusion line 66 is in communication with the system computing unit 64. When the actual blood concentration of glucose GLUCOSEais above the a desired value GLUCOSEb, the system computing unit 64 actuates the infusion line 66 to introduce insulin to the subject. Finally, FIG. 2C shows that the blood initially hardly contains any ketone body such as beta-hydroxy-butyric acid or physiologically acceptable salt or ester thereof, such as the sodium salt. Accordingly, the actual value of concentration of ketone bodies in the patient’s blood KETONEa is about 0. Typically, the initially used fresh dialysate does not contain any ketone bodies or only small amounts. During treatment, the blood concentration of such ketones may rise to a desired value KETONEbwithin the range of 1 - 15 mmol / l such as within the range of 2 - 12 mM, by using a second dialysate fluid containing ketone bodies. The dialysate may contain a buffer component such as bicarbonate in order to facilitate maintenance of physiological pH in vicinity of a cancer tumor. As in relation to insulin, ketone bodies may be provided in the dialysis fluid. Additionally or alternatively, they may be provided to the subject as an infusion, either alongside insulin via the same infusion line 66 or via an alternative infusion line 80, 81, 82. In either case, the system computing unit 64 is configured such that when the actual value of concentration of ketone bodies in the patient’s blood KETONEais below the desired value KETONEb, additional ketones or MCTs are provided to the subject via the infusion line 66, 80, 81, 82. FIG. 2D illustrates pH in the vicinity of normal healthy cells as well as cancer cells under normal conditions. It should be noted that a normal healthy cell is surrounded by a neutral to slightly alkaline pH, whereas a cancer cell, due to production of lactic acid as a consequence of aerobic glycolysis is surrounded by a weak acid pH. Such a pH may have an immunosuppressing effect protecting the cancer cell. Such cancer acidity has been described in Huber et al., Seminars in Cancer Biology, vol. 43 (2017), pp. 74- 89. FIG. 2E shows possible effects of dialysis using the present dialysis fluid on such normal healthy cells and cancer cells. In both cases, the pH values in vicinity of the cells have increased in the so called Tumor Micro Environment (TME). This increase is caused by two different mechanisms. Firstly, the present dialysis fluid contains no or a very reduced amount of fuel for aerobic glycolysis. Accordingly, less lactic acid id produced. Secondly, the present dialysis fluid also contains buffering and slightly alkaline bicarbonate ions which also increases pH. Bicarbonate is a commonly used buffering substance in dialysis liquids for treatment of end stage renal disease. As a result of the treatment, the cancer cell in FIG. 2E is not surrounded by an acid TME, and therefore not protected by any immunosuppressing layer. Accordingly, we have arrived at the following conclusions: 1. A particular cancer cell in an environment containing low amounts of fuel for aerobic glycolysis having a non-immunosuppressing pH should be more vulnerable toward our inherent immune system than a corresponding cancer cell would be under normal conditions. 2. Cancer cells have a high demand for glucose and glutamine to support their rapid growth and proliferation. When glucose and glutamine are withdrawn, cancer cells become vulnerable to oxidative stress due to a reduction in their capacity to form NADPH. NADPH is an essential cofactor that helps to maintain the redox balance in cells by neutralizing reactive oxidative species (ROS). Glucose and glutamine are metabolized through glycolysis and the tricarbocyclic acid (TCA) cycle, respectively, to produce NADPH. When glucose and glutamine are limited, cancer cells switch to alternative metabolic pathways, such as fatty acid oxidation and autophagy to generate energy and maintain redox homeostasis. However, these pathways are less efficient in generating NADPH, leading to an accumulation of ROS and oxidative stress. To sum it up, cancer cells are vulnerable to glucose and glutamine withdrawal due to increased oxidative stress caused by a reduction their capacity to form NADPH. This vulnerability can be exploited to develop new therapeutic strategies for cancer treatment. 3. Epigenetic changes most known to be induced by an increase in histone deacetylases (HDAC) are linked to oncogenesis and HDACs have pleiotropic effects and promote many oncogenes. Reducing increased HDACs in cancer through HDAC inhibitors can improve therapeutic efficacy of targeted cancer therapies. As dialysis treatment with the present dialysis fluid therefore should weaken such cancer cells, it is postulated that cancer cells treated accordingly should be more sensitive to cytostatic agents. FIG. 2F illustrates this postulate. The two diagrams show death rate for cancer cells as well as different non-cancer cells. As cancer cells grow fast, they are more sensitive to cytostatic agents that typical non-cancer cells. The left diagram outlines the situation without dialysis and the right diagram should show the situation when a dialysis treatment is run using a dialysis fluid according the present invention. Reference Example 1 A study was made of experimental hemodialysis in Sprague-Dawley rats pre-treated with ketogenic diet for five days. A theoretical model was also applied to mimic a similar treatment in humans, and to elucidate the mechanisms involved. METHODS Animals Experiments were performed in six male Sprague-Dawley rats having an average body weight of 316 g (305−318 g) given water and ketogenic food (Kliba-Nafag 2201 Ketogenic diet XL75:XP10) five days prior to experiments. The animals were treated according to the guidelines of the National Institutes of Health for Care and Use of Laboratory animals. The Ethics Committee for Animal Research at Lund University approved of the experiments (Dnr 5.8.18-08386 / 2022). Results are reported in compliance with the ARRIVE guidelines. No specific exclusion or inclusion criteria were used. The rat was carefully placed into a covered glass container to which a continuous supply of 5% isoflurane in air (Isoban, Abbot Stockholm, Sweden) was connected. After fully anesthetized, the rat was gently lifted from the container. Anesthesia was maintained using 1.6-1.8% isoflurane in air delivered in a small mask. Following tracheostomy, the rat was connected to a volume-controlled ventilator (Ugo Basile; Biological Research Apparatus, Comerio, Italy) using a positive end- expiratory pressure of 4 cm H2O. Body temperature was kept between 37.1°C to 37.3°C by using a feedback-controlled heating pad. End-tidal pCO2was maintained between 4.8 and 5.5 kPa (Capstar-100, CWE, Ardmore, Pa). The right femoral artery was cannulated for continuous monitoring of heart rate and mean arterial pressure (MAP); and for obtaining blood samples (95 μL) for measurement of glucose, urea, electrolytes, hemoglobin, and hematocrit (I-STAT, Abbott, Abbott Park, IL), and blood ketones (FreeStyle Precision Neo, Abbott, Abbott Park, IL). The right femoral vein was cannulated and connected to the dialyzer using plastic tubing. The right femoral artery was also cannulated and connected both to a pressure transducer to continuously monitor arterial line pressure, and to a blood pump (Masterflex Ismatec, Cole-Parmer, IL) connected to the dialyzer via plastic tubing. Before connection, the blood circuit was primed with 4% albumin (Albunorm, Octapharma Nordic AB, Sweden) to which heparin 50 IE (Heparin LEO 5000 IE / ml, Leo Pharma AB, Sweden) had been added. The right internal jugular vein was cannulated for infusion of maintenance fluid containing51Cr-EDTA. Hematocrit was determined by centrifugating thin capillary glass tubes. After the experiment, animals were euthanized with an intravenous bolus injection of potassium chloride. Experimental protocol The dialysis circuit inlet was connected via a pump to a glass cylinder containing fresh dialysis fluid (Hemosol B0, Baxter Healthcare, IL). The outlet from the dialyzer was also connected to a peristaltic pump which pumped spent dialysate to a glass cylinder. Both glass cylinders were placed on the same scale to ensure that no fluid was removed from the animal (Figure 3 A). A three-hour hemodialysis session was performed using a mini- capillary dialyzer device obtained from Baxter Healthcare (Hechingen, Germany), comprising a high-flux membrane (Polyflux Revaclear®, HF-Revaclear®). The membrane had a total surface area of 318 cm2with a total number of 355 fibers, each of which with an inner diameter of 190 μm, and a wall thickness of 35 μm (total intracapillary volume: 1.50 mL). Arterial blood samples were obtained before and 30 min after dialysis, and at 60, 90, 120, and 180 min during HD. Dialysate samples were collected before dialysis and at 10, 20, 40, 60, 90, 120, 150, and 180 min and analyzed on a gamma counter (Wizard 1480, LKP Wallac, Turku, Finland) to determine51Cr-EDTA activity. Statistical methods Data are shown as median (interquartile range) unless otherwise specified. Significant differences were assessed using an asymptotic Friedman omnibus test (coin package) which, if significant, was followed by a Wilcoxon-Nemenyi-McDonald-Thompson post hoc test. Two blood ketone values were above the range of measurement (8.0 mmol / L). Before statistical analysis they were set to 8.0 mmol / L. Since they were the highest values in the dataset, a value of 8 mmol / L ensures that (i) the median (IQR) is unaffected, and (ii) that the datapoints will get the highest and the same rank. P-values below 5% were considered significant. A simple power analysis (pwr.t.test, pwr package) showed that a group size of six animals has 80% power to detect an effect size (Cohen's d) of 1.4. For example, for blood ketones, if assuming a SD of 1 mM, such an effect size would correspond to a difference of 1.4 mM. Calculations were performed using R for mac version 4.1.1. Simulations To simulate the effects of dialysis on the systemic blood composition, the model developed by Todd8,9was used, in which the evolution of forty-six substances in human blood, liver, fat and muscle tissue was simulated during varying glucose feeding. Even though this is a rodent model, weadapted the volumes and flow rates to human conditions. The differential equations for blood concentrations of glucose, insulin, free fatty acids (FFA), ketones, and alanine were modified by introducing a dialysis clearing effect proportional to the concentration difference between blood and dialysis fluid. Although glucose is distributed into erythrocytes10,11, the transport is rather slow so that almost only plasma water will be cleared during the blood passage along the dialyzer fibers12. Dialyzer plasma water clearance was calculated assuming a plasma water flow rate of 180 mL / min in a blood flow rate of 300 mL / min and a dialysis fluid flow rate of 500 mL / min for a large dialyzer with a mass transfer area coefficient (K0A) for urea at 1500 mL / min (see Figure 3B). The K0A value for FFA (KoAFFA) was determined in relation to that of phosphate (K0APhos = 0.547 * K0Aurea) based on the ratio of molecular weights for phosphate (MWPhos = 95) and FFA (MWFFA= 256) according to the equation All other K0A values were determined using the same equation, but relating to K0A for creatinine (K0Acrea= 0.638 * K0Aurea) and MWcrea= 113. The distribution volumes were assumed to be whole blood for glucose12and plasma water for all other substances. Simulations were performed under the assumption of no intake of nutrients. RESULTS Baseline parameters Six Sprague-Dawley rats were given ketogenic diet for five days and gained between (min- max) 10 to 37 g in body weight. Before dialysis, median arterial pH was 7.43 (7.42 to 7.44), actual bicarbonate was 20.4 mmol / L (19.8 to 21.3), standard base excess was –3.5 mmol / L (–4.0 to –2.2), pO2 was 12.4 kPa (12.2 to 12.7), and pCO2 was 4.0 kPa (4.0 to 4.3). Dialysis was performed for three hours after which blood was returned to the animal, followed by a 30 min rest period before termination of the experiment. Treatment and baseline parameters are shown in Table 1. Table 1 A. Baseline parameters. Parameter Value Mean arterial pressure, mmHg 69 (62-73) Heart rate 329 (315-356) Arterial oxygen saturation (SO2) % 98 (97-98) Plasma sodium, mmol / L 138.5 (138.0 − 139.8) Plasma potassium, mmol / L 3.8 (3.8 − 3.9) Plasma chloride, mmol / L 103 (103 − 103) Plasma ionized calcium, mmol / L 1.28 (1.27 − 1.34) Plasma lactate, mmol / L 2.9 (2.1-3.9) Table 1 B. Treatment parameters. Parameter Value Blood flow (Qb), mL / min 1.0 Dialysate flow (Qd), mL / min 5 Dialysate sodium, mMa140 Dialysate potassium, mMb4 Dialysate bicarbonate, mMa32 Dialysate calcium, mMa1.75 Dialysate lactate, mMa3aNominal values from the manufacturer (Hemosol B0, Baxter Healthcare, IL)bApproximate value, 20 mmol potassium (Addex-Kalium, Fresenius Kabi, Sweden) was added to 5 L of fresh dialysis fluid Hemodialysis does not significantly reduce blood ketone levels Blood ketone levels before and after 180 min dialysis were similar, being 3.5 mmol / L (2.2- 5.6) and 3.8 mmol / L (2.2-5.1), respectively (P=0.53), with no significant differences in ketone concentrations during dialysis (Figure 4 A) (Table 2). Urea reduction ratio (URR) was 38% (25-42) and glucose reduction ratio was 36% (29-43), with concentrations decreasing over the course of the treatment (Figure 4 B and 4 C) (Table 3). The blood to dialysate clearance of51Cr-EDTA was stable during the entire dialysis session being 1.0 mL / min (0.7-1.1). Single-pool Kt / V urea was 0.57 (0.52-0.63), calculated as follows Kt / V = –log(1–URR-0.024). Assuming a total body water of 70% of body weight, this implies a urea clearance of 0.67 mL / min (0.62 to 0.80). Table 2. Effects of dialysis on blood ketones, lactate, and actual HCO3Group Ketones Lactate Actual Bicarbonate mmol L−1mmol L−1mmol L−1Before dialysis 3.5 (2.2 − 5.6) 2.9 (2.0 − 3.9) 20.4 (19.8 − 21.3) 90 min 3.5 (2.0 − 5.5) 1.9 (1.3 − 2.8) 22.8 (22.4 − 24.2) 180 min 3.8 (2.2 − 5.1) 2.0 (1.9 − 2.2) 23.5 (21.4 − 24.9) 30 min after dialysis 3.7 (2.2 − 5.6) 1.6 (1.5 − 1.8) 23.5 (22.1 − 25.0) Asymptotic Friedman Test P-value 0.49 0.39 0.02 95% CI for dialysis effect [-0.2 to 0.4] [-0.3 to 0.5] [0.3 to 0.6]

[0002] Effects on acid-base and blood chemistry during dialysis Plasma base excess increased during dialysis (Figure 4 D). In line with this, arterial pH increased from 7.42 (7.42-7.44) to 7.51 (7.49-7.52) after 180 min dialysis (P=0.005). Arterial pCO2 was not significantly different after 180 min hemodialysis, being 4.0 (4.0- 4.3) kPa before, and 4.0 (3.7-4.2) kPa after dialysis, respectively (P=0.81). Blood hemoglobin levels were not significantly different before versus after dialysis, being 113 g / L (106-118) and 116 g / L (111-118), respectively (P=1.00). Plasma potassium increased from 3.8 mmol / L (3.8-3.9) before dialysis to 4.5 mmol / L after 180 min (P=0.03), whereas there was no significant difference in plasma sodium (Table 3). In-silico modeling The simulation in Figure 5 showed that a significant lowering of the blood glucose level by dialysis can only be achieved after the glycogen stores in the liver have been depleted, which occurred about 3 hours after the start of dialysis at time 0. Dialysis was continued for 8 hours. We therefore suggest delaying the start of dialysis until this occurs, as seen in Figure 6, where the effect of dialysis (continuous lines) was compared to the case of continued starvation without dialysis (broken lines). Dialysis reduced blood glucose and insulin levels, while the ketone levels were slightly increased. In order to understand why ketone levels were increased despite the removal by dialysis a second simulation was performed where insulin clearance was set to zero. This could be approximated in the clinic by adding a suitable amount of insulin to the dialysis fluid. The results are shown in Figure 7. Without removal by dialysis the insulin level was raised significantly, which resulted in a dramatic decrease of the glucose level. The ketone levels were slightly decreased but were higher than without dialysis. Further insight was gained by studying the transport patterns of the key substances involved. Figure 8 A shows the delivery of ketones to blood (continuous lines), the removal by dialysis (broken line), and the disappearance rate from the blood (dotted lines) for the cases of no dialysis (black), and normal dialysis (red). The removal by dialysis constituted only a small fraction of the other effects, hardly visible in Figure 8 A. Also, delivery to and removal from the blood balanced each other to a large extent, being much larger than the resulting change in the blood concentration. For glucose and insulin, shown in Figure 8 B and Figure 8 C, the delivery to blood was nearly unaffected by dialysis, but the removal by dialysis constituted a large fraction of the delivery to blood and the consumption was considerably reduced. When insulin clearance was set to zero, Figure 9 A shows that the delivery and consumption of ketones were both slightly reduced, but were still larger than without dialysis. During these conditions, the turnover of glucose in Figure 9 B was very low, whereas the turnover of insulin in Figure 9 C was close to, but slightly lower than for the case with no dialysis. These experiments show that blood ketone levels in rats fed with ketogenic diet were relatively unaffected by hemodialysis, despite the fact that the low molecular weight of ketones (β-hydroxybutyrate, acetoacetate, and acetone) means that they will be removed efficiently by dialysis. Indeed, molecules of the same approximate size as keto-acids were clearly effectively removed (e.g., urea), and even bigger molecules like51Cr-EDTA were effectively cleared from blood. Furthermore, using a theoretical model we show that the removal of blood ketones by dialysis is most likely very small compared to the production by the liver which needs to satisfy the energy need of the entire body. The dialysate blood flow rate (Qb) was here set to 1 mL / min, which is similar to other experimental models of hemodialysis in rats13. Pre-filter arterial pressures were stable and positive at this blood flow rate, with 40-50 mmHg being a typical value. In order to elucidate how this blood flow rate would correspond to a human undergoing hemodialysis it may be set in relation to the distribution volume. For example, for urea the distribution volume is approximately equal to total body water (TBW), being about 70% of body weight in rats, which is roughly three times the extracellular volume14. Thus, a 300-g rat has a TBW of 210 mL, meaning that a blood flow rate of 1 mL / min clears ∼0.47% of the TBW from urea. For a 70-kg adult having a TBW of 42 L this corresponds to a blood flow of 42 x 0.47% = 200 mL / min. Nowadays, blood flow rates are usually 250 mL / min or higher, especially in patients treated with hemodiafiltration. On the other hand, we used a dialyzerwith a K0A of about 30 mL / min and a dialysate flow rate of 5 mL / min which are far higherthan Qb meaning that solute transport will be limited by the blood flow rather than the dialyzer membrane or dialysate flow. Indeed, in line with this, the estimated clearance of urea and the dialyzer plasma to dialysate clearance of51Cr-EDTA (a much larger molecule than urea) was nearly identical, being 0.67 mL / min for urea and 0.66 mL / min for51Cr- EDTA. It is reasonable to assume a very similar dialyzer clearance for glucose and ketones. It was also found that ketogenic diet leads to mild metabolic acidosis in rats; also, there was a very mild increase in plasma lactate. A slightly elevated lactate level has previously been observed in cows fed with ketogenic diet15. Also, potassium levels were increased during dialysis to 4.5 mmol / L. This may possibly be due to the fact that potassium 20 mmol was added to a 5-L bag of fresh dialysate manually, which due to tolerances in volume and composition of the potassium solution may cause the actual dialysate concentration to differ from 4 mmol / L. Another possible explanation may be the lower insulin levels caused by dialysis, leading to a shift of potassium from the intra-cellular space to the circulation16,17. Lastly, we observed a slight hyperglycemia before dialysis which is in line with previous studies in mice18in which they also noted lower insulin levels following ketogenic diet18. The experimental results were corroborated by the simulations shown in Figure 6, where ketone levels are even higher with dialysis than without. One explanation could be that the lower insulin levels caused by dialysis trigger an increased production of ketones that outweighs the removal by dialysis. This hypothesis was tested by a simulation where the insulin clearance was set to zero. Figure 7 shows that the insulin level is then almost as high as without dialysis, and the glucose level is dramatically reduced. The ketone level is slightly decreased (but still higher than without dialysis), probably due to the higher insulin level. Unexpectedly, the model also predicts an increase in glycogen. The simulation model also allows the calculation of the flow rates of ketones, glucose, and insulin to and from the blood compartment and their removal by dialysis, which are shown in Figure 8 A-C. For ketones, the removal by dialysis is smaller than the transports to and from the blood which almost balance each other. Therefore, relatively small changes in production and / or utilization of ketones will outweigh any removal by dialysis. This explains why ketone levels can increase despite dialytic removal. On the other hand, for insulin and glucose the production is almost unaffected by dialysis, but the removal by dialysis is a significant fraction of the inflow to blood and their concentrations are therefore to a large extent affected by dialysis. Setting insulin clearance to zero had a small effect on the flows of ketones (Figure 9 A), whereas both inflow and outflow of glucose (Figure 9 B) were dramatically reduced. The inflow of insulin (Figure 9 C) was almost unchanged, but the outflow was roughly restored to the non-dialysis value. It should be noted that the simulated flow rates to blood of ketones and glucose are higher than previously reported human production capacities of the liver, which are about 120 mg / min for ketones and 81 mg / min for glucose19. AQnother study by Balasse resulted in ketone production of 91 mg / min after 15 – 20h fasting that increased to a steady level of 197 mg / min after 3 days20. The high simulated values could be a result of using a rodent model with human flow rates and volumes, since reference values for insulin are known to be higher for rodents than for humans. We still believe that the simulations indicate the qualitative behavior and effects of dialysis using the proposed solutions. We have shown that it ispossible to induce a shift in metabolic conditions within minutes using dialysis. This shift can further be augmented by adding ketones and / or insulin during the dialysis session and make the shift faster and more pronounced. References 1 Mattiuzzi, C. & Lippi, G. Current Cancer Epidemiology. J Epidemiol Glob Health 9, 217-222, doi:10.2991 / jegh.k.191008.001 (2019). 2 Hobro, S. et al. Dialysis as a Novel Adjuvant Treatment for Malignant Cancers. Cancers 14, 5054 (2022). 3 Weber, D. D. et al. Ketogenic diet in the treatment of cancer - Where do we stand? Mol Metab 33, 102-121, doi:10.1016 / j.molmet.2019.06.026 (2020). 4 Abe, M., Kaizu, K. & Matsumoto, K. Plasma insulin is removed by hemodialysis: evaluation of the relation between plasma insulin and glucose by using a dialysate with or without glucose. Therapeutic Apheresis and Dialysis 11, 280-287 (2007). 5 Wathen, R. L., Keshaviah, P., Hommeyer, P., Cadwell, K. & Comty, C. M. The metabolic effects of hemodialysis with and without glucose in the dialysate. Am J Clin Nutr 31, 1870-1875, doi:10.1093 / ajcn / 31.10.1870 (1978). 6 Axelsson, J., Öberg, C. M., Rippe, A., Krause, B. & Rippe, B. Size-selectivity of a synthetic high-flux and a high cut-off dialyzing membrane compared to that of the rat glomerular filtration barrier. Journal of membrane science 413, 29-37 (2012). 7 Rippe, B. & Oberg, C. M. Albumin Turnover in Peritoneal and Hemodialysis. Semin Dial 29, 458-462, doi:10.1111 / sdi.12534 (2016). 8 Todd, A. J. Inclusion of a glycogen regulation mathematical model into a contextual metabolic framework, The University of North Carolina at Chapel Hill, (2008). 9 Xu, K., Morgan, K. T., Todd Gehris, A., Elston, T. C. & Gomez, S. M. A whole-body model for glycogen regulation reveals a critical role for substrate cycling in maintaining blood glucose homeostasis. PLoS Comput Biol 7, e1002272, doi:10.1371 / journal.pcbi.1002272 (2011). 10 Fogh-Andersen, N. & D'Orazio, P. Proposal for standardizing direct-reading biosensors for blood glucose. Clin Chem 44, 655-659 (1998). 11 Fogh-Andersen, N. et al. Recommendation on Reporting Results for Blood Glucose (From an IFCC Stage 1 Document) IFCC Scientific Division Working Group on Selective Electrodes. EJIFCC 12, 114-116 (2000). 12 Schneditz, D., Zierler, E., Martinelli, E., Czabak-Garbacz, R. & Hoehlein, M. Clearance, distribution volume, and dialyzer mass area transport coefficient of glucose in whole blood. ASAIO J 58, 137-142, doi:10.1097 / MAT.0b013e3182452b57 (2012). 13 Fukunaga, M. et al. In vivo evaluation of drug dialyzability in a rat model of hemodialysis. PLoS One 15, e0233925, doi:10.1371 / journal.pone.0233925 (2020). 14 Helman, J. & Öberg, C. M. High versus low ultrafiltration rates during experimental peritoneal dialysis in rats: Acute effects on plasma volume and systemic haemodynamics. Perit Dial Int, 8968608211069224, doi:10.1177 / 08968608211069224 (2022). 15 Zhang, G. S. et al. Dairy cows affected by ketosis show alterations in innate immunity and lipid and carbohydrate metabolism during the dry off period and postpartum. Res Vet Sci 107, 246-256, doi:10.1016 / j.rvsc.2016.06.012 (2016). 16 Apel, J., Reutrakul, S. & Baldwin, D. Hypoglycemia in the treatment of hyperkalemia with insulin in patients with end-stage renal disease. Clin Kidney J 7, 248-250, doi:10.1093 / ckj / sfu026 (2014). 17 McDonough, A. A. & Fenton, R. A. Potassium homeostasis: sensors, mediators, and targets. Pflugers Arch 474, 853-867, doi:10.1007 / s00424-022-02718-3 (2022). 18 Meidenbauer, J., Ta, N. & Seyfried, T. Influence of Dietary Intake on Plasma Metabolites and Lipids in C57BL / 6J Mice. Faseb J 27 (2013). 19 Garber, A. J., Menzel, P. H., Boden, G. & Owen, O. E. Hepatic ketogenesis and gluconeogenesis in humans. J Clin Invest 54, 981-989, doi:10.1172 / JCI107839 (1974). 20 Balasse, E. O. Kinetics of ketone body metabolism in fasting humans. Metabolism 28, 41-50, doi:10.1016 / 0026-0495(79)90166-5 (1979).

Claims

CLAIMS 1. A dialysis fluid comprising between 5 pmol / L and 350 pmol / L insulin or pharmaceutically acceptable salts or esters of insulin, which comprises between 0.5 mmol / L and 30 mmol / L ketone bodies such as such as acetoacetate, beta- hydroxybutyrate or pharmaceutically acceptable derivatives, esters and salts thereof.

2. A dialysis fluid according to claim 1 which comprises less than 4 mmol / L and preferably 0.5 – 3 mmol / L glucose, or a hydrolysis equivalent concentration thereof 3. A dialysis fluid according to any of claims 1 or 2 comprising between 15 pmol / L and 175 pmol / L insulin or pharmaceutically acceptable salts or esters of insulin.

4. A dialysis fluid according to any one of claims 1 - 3 , wherein the ketone bodies are provided in salt form, for example acetoacetate ions or beta-hydroxybutarate ions.

5. A dialysis fluid according to any preceding claim, wherein said fluid contains a hydrolysis equivalent concentration of at most 0.3 mmol / L glutamine or derivatives thereof.

6. A dialysis fluid according to claim 5, wherein said fluid is substantially free from glutamine or derivatives thereof.

7. A dialysis fluid according to claim 6, wherein the fluid is substantially free from pyruvic acid, serine, cysteine, glutamic acid, proline aspartic acid, asparagine, threonine or derivatives thereof.

8. A dialysis fluid according to any one of claims 1 to 7, wherein said fluid also contains a pharmaceutically acceptable amount of a pharmaceutically acceptable cytostatic agent.

9. A dialysis fluid according to any one of claims 1 to 8, wherein the liquid also contains an osmotic agent, selected from the group of polyethylene glycols and albumin.

10. A premix for a composition according to any of claims 1 to 9.

11. A composition for delivery to a patient as an infusion, the composition comprising insulin or pharmaceutically acceptable salts or esters of insulin; and either one or more medium chain triglycerides or one or more ketone bodies selected from the group acetoacetate, beta-hydroxybutarate, acetone and pharmaceutically acceptable derivatives thereof; wherein the composition is substantially free from glucose or derivatives thereof and / or glutamine or derivatives thereof.

12. A composition according to claim 11 which is for use in the treatment of cancer.

13. A composition for use in the treatment of cancer by delivery to a patient as an infusion, the composition comprising insulin or pharmaceutically acceptable salts or esters of insulin and ketone bodies such as such as acetoacetate, beta-hydroxybutyrate or pharmaceutically acceptable derivatives, esters and salts thereof, the compositionbeing substantially free from glucose or derivatives thereof and / or glutamine or derivatives thereof; the composition being for use in the treatment of cancer in patients undergoing dialysis to reduce blood plasma concentrations of glucose and / or glutamine.

14. A method of treating cancer comprising performing dialysis on a patient to reduce blood plasma concentrations of glucose and / or glutamine and administering to the patient a composition comprising insulin or pharmaceutically acceptable salts or esters of insulin and ketone bodies such as such as acetoacetate, beta-hydroxybutyrate or pharmaceutically acceptable derivatives, esters and salts thereof, the composition being substantially free from glucose or derivatives thereof and / or glutamine or derivatives thereof.

15. A composition of claim 12 or 13 or the method of claim 14 wherein the cancer is a cancer with metabolic alteration that makes the cancer dependent on glucose and / or glutamine, for example a cancer selected from human colon carcinoma, glioblastoma, prostate, breast and lung cancer.

16. An extracorporeal blood treatment system for treating a subject suffering from cancer, the system comprising: an extracorporeal blood circuit; a dialysate fluid circuit; said extracorporeal blood circuit and dialysate fluid circuit being divided by a membrane of a filtration unit; at least one blood pump for controlling the flow of blood through the blood circuit; at least one dialysate fluid pump for controlling the flow of dialysate fluid through the dialysate fluid circuit; one or more infusion lines, each infusion line being connected to the extracorporeal blood circuit or adapted for being directly connected to the vascular system of the subject to be treated, each infusion line comprising an infusion pump; a system computing unit operatively connected to the blood pump and the dialysate fluid pump and optionally to the one or more infusion pumps of the one or more infusion lines; said system computing unit having a user interface including an input means and a display means; wherein the system computing unit is adapted for receiving a desired blood concentration value GLNb of glutamine within the range of 0.1 and 0.5 mM; the system computing unit is adapted for receiving a desired blood concentration value GLUCOSEbof glucose within the range of 0.5 to 4 mM; the system computing unit is adapted for receiving a concentration value GLNp representing the concentration of glutamine or pharmaceutically acceptable glutamine- containing compounds in fresh dialysate fluid;the system computing unit is adapted for receiving a concentration value GLUCOSEp representing the concentration of glucose in fresh dialysate fluid; the system computing unit is adapted for receiving a concentration value INSULIN, representing the concentration of insulin or a pharmaceutically acceptable derivative thereof in an infusion liquid to be infused into the extracorporeal blood line or directly into the vascular system of said subject to be treated, through one of said one or more infusion lines; the system computing unit is adapted for receiving an actual concentration value GLNaof glutamine in blood from said treated subject and receiving an actual concentration value GLUCOSEa of glucose in blood from said treated subject; the system computing unit being adapted for controlling said blood pump and said dialysate fluid pump in such a way that the actual blood concentration value GLNaof glutamine is driven towards or below GLNband the actual blood concentration value GLUCOSEa of glucose is driven towards or below GLUCOSEb; and the system is adapted for infusing said infusion liquid into the extracorporeal blood line or directly into the vascular system of said subject to be treated, the system computing unit is adapted for controlling said infusion pump of said infusion line in such a way that when the actual blood concentration value GLUCOSEaof glucose is at or below GLUCOSEb, the infusion is delivered at a first flow rate INSULINf and when the actual blood concentration value GLUCOSEa of glucose is greater than GLUCOSEb, the infusion is delivered at a flow rate INSULINg, INSULINgbeing greater than INSULINf. wherein the system computing unit is adapted for receiving a desired blood concentration value KETONEb of a ketone body, such as acetoacetate, beta- hydroxybutyrate or pharmaceutically acceptable derivatives, esters and salts thereof within the range of 0.5 - 30 mM; the system computing unit is adapted for receiving the concentration value of ketone bodies, such as acetoacetate, beta-hydroxybutyrate or pharmaceutically acceptable derivatives, esters and salts thereof, in a dialysis fluid to be used, KETONEn; and the system computing unit is adapted for receiving an actual concentration value KETONEa of a ketone body such as acetoacetate and / or beta-hydroxybutyrate, in blood from said treated subject; and wherein KETONEais driven towards KETONEb.

17. A system according to claim 16, wherein the or a second infusion liquid contains ketone bodies or medium chain triglycerides and wherein the system computing unit is configured to deliver the ketone bodies or medium chain triglycerides when KETONEa ^ KETONEb.

18. A system according to any claim of claims 16 to 17, wherein the desired blood glucose concentration GLUCOSEb is 1mmol / L to 2 mmol / L, preferably wherein the desired blood glucose concentration GLUCOSEbis 1mmol / L to 1.5 mmol / L, for example around 1 mmol / L.

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