Formulations and methods for direct removal of sodium in patients with heart failure and / or severe renal dysfunction

Abstract

A direct sodium removal ("DSR") infusion regimen and methods of use are provided for removing sodium and reducing liquid overload from a patient suffering from severe renal dysfunction and / or heart failure, where the patient has at least a first DSR period with a first DSR infusion with sodium free or low sodium, the first infusion is instilled into the patient's peritoneal cavity during a first residence period to cause sodium and excess liquid to migrate to the patient's peritoneal cavity, and then the patient may be subjected to conventional dialysis to rebalance the patient's liquid and sodium levels.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Patent Application Serial No. 18 / 157,741 filed on January 20, 2023 and U.S. Patent Application Serial No. 17 / 661,737 filed on May 2, 2022 (now U.S. Patent No. 11,559,618), the entire contents of which are incorporated herein by reference. This application also relates to U.S. Patent Application Serial No. 17 / 174,855 filed on February 12, 2021 (now U.S. Patent No. 11,602,583), which is a continuation of U.S. Patent Application Serial No. 15 / 985,598 filed on May 21, 2018 (now U.S. Patent No. 10,918,778), claiming priority to U.S. Provisional Application Serial No. 62 / 510,652 filed on May 24, 2017, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present invention generally relates to formulations and methods for use of low sodium or sodium-free infusates that are applied to the peritoneal cavity of a patient to remove sodium and excess fluid from the body to relieve fluid overload ("DSR therapy"). U.S. Pat. No. 10,918,778, the entire contents of which are incorporated herein by reference, describes such a solution for heart failure patients with residual renal function. The invention described herein extends DSR therapy to patients with severely impaired renal function. Background Art

[0004] U.S. Patent No. 10,918,778 B2 describes a DSR infusate and method of use for removing excess fluid by removing sodium from a heart failure patient with residual renal function. In particular, the DSR infusate is specifically formulated for instillation into the patient's peritoneal cavity to remove sodium and water by one or both of: 1) ultrafiltration and / or 2) diffusion of sodium ions downward along a steep concentration gradient between the infusate instilled into the patient's peritoneal cavity and the surrounding tissues and blood vessels. After sodium and ultrafiltrate accumulate in the peritoneal cavity, they can be drained according to conventional peritoneal dialysis methods, or more preferably, transferred to the patient's bladder by an implantable pump, which is then emptied.

[0005] The aforementioned patents describe the elimination of excess fluid from the body to maintain a relatively stable serum sodium concentration by one or both of: 1) inducing fluid migration from the patient's body to the peritoneal cavity, from which it is eliminated, and / or 2) enhancing the excretion of excess fluid via the kidneys through urination. Patients with renal failure are also prone to the accumulation of extra sodium in body tissues and suffer from increased fluid retention. Such excess fluid may lead to congestive heart failure, which in turn may lead to edema of the lungs or liver.

[0006] U.S. Patent No. 5,589,197 to Shockley et al. describes a dialysate for peritoneal dialysis in which the sodium concentration is between about 35 and 125 meq / L. As discussed in the patent, such solutions can be used to deliver sodium to the peritoneal cavity for subsequent removal. Problems encountered with the early use of such low sodium dialysates include symptomatic hypotension and dialysis disequilibrium syndrome, a potentially fatal complication that leads to cerebral edema, coma, and death. See, e.g., Nakayma, Clinical Effect of Low Na Concentration Dialysate (120 mEq / L) for CAPD Patients PD conference, San. See, e.g., Zepeda-Orozco D, Quigley R., Dialysis disequilibrium syndrome, Pediatric Nephrology (Berlin, Germany) 2012; 27 (12): 2205-2211.

[0007] According to the current standard of care, people with end-stage renal disease usually undergo dialysis regularly to optimize sodium and fluid levels. It is reported that the average concentration of sodium in the dialysate is currently about 132 mMol / L. See, for example, Hecking M, Kainz A, Horl WH, Herkner H, Sunder-Plassmann G., Sodium setpoint and sodium gradient: influence on plasma sodium change and weight gain). American Journal of Nephrology 2011; 33(1): 39-48; Mc Causland FR, Brunelli SM, Waikar SS., Dialysate sodium, serum sodium and mortality in maintenance hemodialysis. Nephrology Dialysis Transplantation 2012; 27(4): 1613-8.

[0008] As reported in, for example, Munoz Mendoza J, Sun S, Chertow G, Moran J, Doss S, Schiller B. Dialysate sodium and sodium gradient in maintenance hemodialysis: aneglected sodium restriction approach?, Nephrology Dialysis Transplantation 2011; 26(4): 1281-7, experience with dialysate sodium concentrations higher than the patient's blood sodium level shows that such dialysates often result in a net increase in sodium at the end of the dialysis session, which can lead to increased fluid consumption and hypertension. Therefore, patients who frequently undergo hemodialysis may develop chronic hypernatremia and fluid retention.

[0009] As described in the above-incorporated patents, applicants have observed that eliminating fluid overload is a key clinical goal in managing heart failure. Applicants have observed that achieving a steady reduction in fluid retention requires the elimination of sodium from the body. Within certain ranges, patients with residual renal function will automatically rebalance serum sodium concentrations to maintain a constant serum osmolality and maintain a steady sodium level, such as described in Guyton & Hall, Textbook of Medical Physiology. This is because in patients with residual renal function, the kidneys will remove excess water that may lead to hyponatremia.

[0010] As described in the above-incorporated patents, applicants believe that the use of sodium-free or low-sodium dialysates to reduce fluid and / or sodium overload requires at least some residual renal function to avoid undesirable blood pressure drops caused by hyponatremia and / or dialysis imbalance syndrome. Therefore, it is desirable to develop DSR formulations and methods of use for DSR therapy of patients with severe renal dysfunction. Desired DSR formulations and methods will help such patients achieve reductions in sodium and fluid overload that are currently unachievable with conventional dialysis techniques, while maintaining sodium serum levels in such patients.

[0011] Therefore, it would be desirable to provide compositions and methods of use for extending the benefits of DSR therapy to patients suffering from severe renal dysfunction. Summary of the invention

[0012] According to the present invention, DSR infusates and methods of use are provided for removing sodium and reducing fluid overload in patients with severe renal dysfunction while helping to maintain stable serum sodium levels. In the context of the present invention, such patient groups include patients exhibiting stage 4 or stage 5 chronic kidney disease ("CKD"), and in addition to renal disease, these patients may also exhibit any of several forms of heart failure that can be treated by fluid management.

[0013] The applicant has observed that the low sodium or sodium-free infusion is instilled into the peritoneal cavity of patients with residual renal function, which can significantly relieve the symptoms of heart failure by reducing fluid overload. For example, in the applicant's first human trial, a sterile glucose solution in the range of 5% by weight to 15% by weight, a DSR preparation with no sodium or low sodium concentration, resulted in a large amount of sodium (e.g., up to 2g) and liquid (e.g., up to 2 liters) being removed within a two-hour residence time. The applicant observed that the serum sodium level of those patients remained substantially constant. To a certain extent, the amount of sodium that migrates to the patient's peritoneal cavity causes a transient serum sodium imbalance, and the patient's kidney causes additional water excretion to rebalance the serum sodium level. The applicant reasoned that if sodium migrates to the peritoneal cavity and is removed from the peritoneal cavity, the serum sodium level is maintained by releasing the sodium stored outside the blood vessels (e.g., in the interstitium of the skin and skeletal muscle) into the blood.

[0014] For patients with severe renal disease (e.g., CKD stage 4 or 5), there is a potential risk that excessive sodium removal via a single peritoneal dialysis with the DSR infusates described in the above-incorporated patents may (without corresponding fluid reduction) lead to hyponatremia. This condition may occur because patients with severe renal dysfunction may be unable to remove excess water from the blood to maintain a stable serum sodium level. To meet the needs of this patient population, special DSR infusates and methods are needed.

[0015] The amount of sodium and water removed during a specified residence time will be a function of the concentration of sodium in the infusate, the osmotic concentration of the infusate, and the tendency of the infusate components to migrate across the peritoneum and into the patient's tissues and vascular system. For example, an infusate containing no sodium will produce a steep gradient that causes sodium to migrate into the peritoneal cavity, while an infusate in which the sodium concentration is close to equimolar to serum levels, such as 130 meq / ml, will produce a more gradual gradient. If the residence time is long enough, sodium will progressively move into the fluid in the peritoneal cavity until the gradient disappears and the sodium concentration in the fluid in the peritoneal cavity becomes isotonic.

[0016] Similarly, the osmotic concentration of the infusate will determine its ability to drive water into the peritoneal cavity, and will vary based on the components in the infusate and its ability to migrate across the peritoneum. For example, it is known that when an infusate containing glucose is instilled into the peritoneal cavity, glucose provides a high osmotic concentration. However, because the glucose molecules migrate rapidly from the peritoneal cavity, the ability of the infusate to drive ultrafiltrate into the peritoneal cavity will decline quite rapidly. In contrast, icodextrin solutions also provide a high initial osmotic concentration, which remains high during the entire stay period because the icodextrin molecules are not prone to migration. Therefore, the ability of the infusate to drive excess fluid into the peritoneal cavity of the patient will also determine the ability of the DSR infusate to move excess sodium and water to the peritoneal cavity for subsequent removal. In addition, the more water that is sucked into the peritoneal cavity, the more the amount of sodium that will migrate to the peritoneal cavity to make the sodium concentration isotonic.

[0017] According to one aspect of the invention, a regimen of DSR infusates with different compositions can be provided for continuous use in patients with severe renal dysfunction. The first infusate composition can have a first selected sodium-free or low sodium concentration, and can be instilled into the patient's peritoneal cavity in an amount of 0.25L to 1.5L or more to start DSR treatment to reduce fluid and sodium overload, thereby establishing a new fluid and sodium balance for the patient. Thereafter, a second infusate composition with a different composition can be instilled in an amount of 0.25L to 2.0L to remove additional amounts of fluid and sodium, thereby establishing a new fluid balance for the patient. Treatment with these solutions can be performed continuously with the patient's traditional hemodialysis or peritoneal dialysis regimen, or in conjunction with, and / or interspersed.

[0018] After the first DSR treatment period, the patient may undergo one or more conventional hemodialysis or peritoneal dialysis periods to remove toxins carried by the blood. For example, the patient may undergo a first DSR treatment period to reduce fluid overload, and then undergo conventional hemodialysis or peritoneal dialysis treatment after the DSR treatment period to restore any fluid / sodium imbalance. During the first DSR treatment period, an exemplary first DSR infusate may comprise a sodium-free or low sodium solution, preferably consisting of sterile water containing 5% by weight glucose and up to 40% by weight icodextrin. In particular, it is expected that higher concentrations of icodextrin are ideal for avoiding hyperglycemia.

[0019] Subsequently, the patient may undergo a second DSR treatment period during which additional sodium and / or excess fluid may be removed, but in a different ratio than the first treatment period. An exemplary composition used as a second DSR infusion may include a sodium-free or low sodium solution consisting of sterile water containing 5% by weight glucose and 15% by weight icodextrin. More generally, during a subsequent DSR treatment period, which may be continuous in time with the first treatment, an infusion of any range of different glucose and icodextrin concentrations between about 5% by weight and 40% by weight may be used, such as based on the indications of the patient's specific circumstances, with the goal of removing fluid or enhancing sodium purification. Optionally, during the stay of such a second infusion, serum sodium concentration may be sampled, such as by blood sampling, to confirm that serum sodium levels have not dropped dramatically. Shortly after or between the first and second DSR periods, conventional hemodialysis or peritoneal dialysis may be performed to further rebalance and stabilize the patient's serum sodium and fluid levels.

[0020] Methods of instilling and removing the DSR infusate of the present invention are also provided. In particular, the DSR infusate can be instilled into the peritoneal cavity using a conventional peritoneal dialysis tubing kit, and the ultrafiltrate can be removed from the peritoneal cavity. More preferably, the removal of the dialysate solution and the sodium-containing ultrafiltrate can be accomplished using an implantable pump system described in commonly assigned U.S. Patent No. 9,956,336, the contents of which are incorporated herein by reference. The patent describes a system for mobile peritoneal dialysis in which the dialysate is infused into the peritoneal cavity. After a predetermined time and / or a predetermined interval, the implantable pump transfers the fluid accumulated in the peritoneum to the patient's bladder, where the fluid can be excreted by urination. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Other features, properties and various advantages of the present invention will become more apparent from the accompanying drawings and the following detailed description of preferred embodiments, in which:

[0022] Figure 1 A perspective view of an exemplary protocol for an infusion having a composition selected in accordance with the principles of the present invention for reducing fluid and sodium overload in a patient with severe renal dysfunction.

[0023] Figure 2 is a plan view of exemplary components of an implantable pump system for use in conjunction with the infusate compositions and methods of the present invention.

[0024] Figure 3 For use Figure 2 Schematic diagram of an exemplary arrangement of an implantable device of a system for practicing the DSR treatment methods of the present invention.

[0025] Figure 4 The invention discloses the use of Figure 1An exemplary method step of a DSR scheme.

[0026] Figure 5A , Figure 5B and Figure 5C is a graph depicting the results of testing the DSR method of the present invention on an initial group of five animals.

[0027] 6A to 6F is a graph depicting the results of testing of a subsequent group of ten animals using the DSR method of the present invention.

[0028] 7A to 7C Graph depicting changes in blood volume, red blood cell count and plasma volume in a subset of the second group of animals following continued application of the DSR method of the present invention.

[0029] Fig. 8A and Figure 8B Shown separately are the amount of sodium removed as a function of residence time and a comparison of sodium removal per patient in a first in man ("FIM") trial of 10 patients using a single dose of a sodium-free 10 wt % glucose solution and a conventional peritoneal dialysis solution, sequentially administered via a conventional peritoneal dialysis catheter.

[0030] Fig. 9A and Fig. 9B Bar graphs comparing the mean observed changes in physiological parameters of 10 other human patients during a second trial in which patients underwent a three-weekly DSR period for six weeks with a DSR solution of a sodium-free 10 wt % glucose solution.

[0031] Fig. 10A , Fig. 10B and Fig. 10C Graphs showing the evolution of changes in physiological parameters observed in 10 patients during the second human trial, respectively.

[0032] Fig.11 Bar graph showing the improvement in diuretic response in the second trial.

[0033] Fig.12 Table showing the lasting effect following DSR treatment in patients who experienced a significant reduction in the need for diuretic medication after the second trial. DETAILED DESCRIPTION

[0034] The present invention relates to infusion compositions and methods for treating fluid and / or sodium overload in patients with severe renal dysfunction (e.g., CKD stage 5 or stage 6). Infusion compositions and methods of treatment are considered to be a supplement to traditional hemodialysis or peritoneal dialysis treatments and methods. U.S. Patent No. 10,918,778B2 describes methods and compositions for treating heart failure patients with fluid overload with residual renal function, which is incorporated herein by reference in its entirety. The present invention relates to methods and compositions that extend the benefits of direct sodium removal technology to patients with severe renal dysfunction. Based on data collected in the first human trials with exemplary DSR infusions as described in the patents incorporated above, it is expected that the methods and compositions of the present invention can not only improve sodium / fluid balance, but also improve renal function and the efficacy of loop diuretics for controlling fluid overload.

[0035] In accordance with the principles of the present invention, a regimen consisting of at least a first DSR infusate composition having a selected osmotic concentration and no or low sodium is provided. By way of non-limiting example, the first infusate may comprise sterile water, up to 40 wt% icodextrin, and up to 10 wt% glucose. The regimen may also include a second infusate composition having the same or different composition and sodium concentration. An exemplary second infusate that may be used for a subsequent DSR phase may comprise sterile water, 15 wt% icodextrin, and 5 wt% glucose. Other DSR infusates may omit glucose entirely and consist solely of a low sodium icodextrin concentration, or have other high molecular weight biocompatible polymers as ingredients.

[0036] In one embodiment, the first infusate can be configured such that when instilled into the patient's peritoneal cavity, it creates a gradient that causes a large amount of water and sodium to migrate into the infusate during a first dwell period. At the end of the first dwell period or a portion thereof, the infusate, ultrafiltrate, and sodium are removed from the peritoneal cavity using a conventional peritoneal drainage catheter, or more preferably, an implanted pump that transfers fluid to the patient's bladder.

[0037] Immediately following or for a period of time after the first DSR treatment, the second infusate for the subsequent DSR treatment can be constituted so that when instilled into the patient's peritoneal cavity, it creates a gradient that causes additional water and / or sodium to migrate into the peritoneal cavity during the second dwell period. At the end of the second dwell period, or a portion thereof, the second infusate, ultrafiltrate, and sodium can be removed from the peritoneal cavity using a conventional drainage catheter or implanted pump. The osmotic concentration, composition, and sodium concentration of the second infusate can be adjusted as needed based on the patient's specific circumstances to customize the relief desired by that patient.

[0038] As described in detail below, for patients with severe renal dysfunction, the DSR infusion regimen is designed to be used in conjunction with the patient's conventional hemodialysis or peritoneal dialysis regimen. Conventional dialysis treatment, whether hemodialysis or peritoneal dialysis, aims to remove toxins and waste byproducts carried by the blood. Although conventional dialysis techniques can remove some excess water from the patient's circulation, it is not uncommon for patients with severe renal dysfunction to suffer from fluid overload. However, according to the principles of the present invention, DSR therapy can be used in combination with conventional dialysis techniques to remove sodium, resolve fluid overload, and reduce congestion. Initial FIM results also show that DSR treatment can restore a certain degree of renal function, improve the efficacy of loop diuretics, and alleviate a certain degree of transient dialysis-induced renal damage.

[0039] As described in the above-incorporated patents, zero or low sodium concentrations in each infusate cause sodium and fluid (osmotic ultrafiltrate) to pass from the patient's body into the peritoneal cavity. The DSR infusate is allowed to remain or dwell in the peritoneal cavity for a specified period of time before being removed along with the extracted sodium and osmotic ultrafiltrate. Removal of sodium-containing DSR infusates and osmotic ultrafiltrate from the peritoneal cavity can be performed using an implantable system, such as the Alfapump commercialized by Sequana Medical NV of Zwijnaarde, Belgium.

[0040] As used in this disclosure, a sodium-free or low sodium DSR infusate has a sodium content of less than 120 meq / L, and more preferably less than 35 meq / L, and includes infusates with zero or trace amounts of sodium. The fluid overload treatment methods of the present invention specifically contemplate the use of the methods of the present invention in patients experiencing severe renal dysfunction (e.g., CKD stage 4 or 5), as well as heart failure patients with end-stage renal disease.

[0041] refer to Figure 1 , in accordance with the principles and methods of the present invention, describes an exemplary protocol 10 of a DSR infusion suitable for patients with severe renal dysfunction, and includes two formulations designed to be instilled into the peritoneal cavity of patients with different osmotic concentrations, intended for use in consecutive DSR phases. Specifically, Figure 1 Depicted are bags 12 of DSR Solution 1, which may be used for a first treatment period, and bags 14 of DSR Solution 2, which may be used for subsequent DSR treatments as described below. However, it should be understood that DSR Solution 1 and Solution 2 may consist of a single composition of DSR infusate. Figure 1 Also depicted is a conventional tubing set 16 for infusing the fluid from bag 12 or 14 into the peritoneal cavity of a patient using a conventional peritoneal dialysis catheter (not shown).

[0042] In one embodiment, DSR Solution 1 and DSR Solution 2 are infusates that may have different compositions and are intended for sequential use in patients with severe renal dysfunction. Preferably, such patients undergo conventional hemodialysis or peritoneal dialysis on a regular basis. DSR Solution 1 may have a sodium concentration and osmotic concentration selected to initiate DSR therapy to reduce fluid and sodium overload. DSR Solution 2 may have a different sodium concentration and osmotic concentration and may be used in subsequent DSR phases to further reduce the fluid and sodium levels achieved in the first DSR phase. It is expected that one or more DSR phases may be coordinated and / or interspersed with the patient's conventional hemodialysis or peritoneal dialysis regimen.

[0043] In one method of the invention, after a first DSR therapy session with DSR Solution 1, the patient may undergo one or more sessions of conventional hemodialysis or peritoneal dialysis to remove toxins carried by the blood. The patient may then undergo a subsequent session with DSR Solution 2 to further reduce fluid and / or stored sodium, or to maintain the fluid / sodium balance achieved after the session with DSR Solution 1.

[0044] In an exemplary embodiment of DSR therapy regimen 10, DSR Solution 1 may comprise a sodium-free or low sodium solution consisting of sterile water containing 5% to 10% by weight dextrose and up to 40% by weight icodextrin. Such exemplary compositions of DSR Solution 1 are expected to remove sodium and water. The patient may then undergo further DSR therapy with DSR Solution 2, such that the composition of DSR Solution 2 is selected to remove additional fluid and / or sodium, or to maintain a new fluid / sodium balance achieved after the first DSR period. An exemplary composition of DSR Solution 2 may comprise a sodium-free or low sodium solution consisting of sterile water containing 5% by weight dextrose and 15% by weight icodextrin. Relative to DSR Solution 1, such exemplary compositions of DSR Solution 2 are expected to preferentially remove more sodium than water.

[0045] According to one aspect of the invention, serum sodium concentration may be sampled periodically, e.g., via blood samples, to monitor the patient's serum sodium level. A conventional hemodialysis or peritoneal dialysis session may be performed after or between the first and any second DSR sessions, as is typically required for patients with severe renal dysfunction. Advantageously, it is contemplated that such conventional hemodialysis or peritoneal dialysis sessions may also be used to fine-tune and / or stabilize the patient's fluid management.

[0046] Typically, formulations suitable for the first and subsequent DSR phases may contain zero to 50 grams of glucose per 100 ml of aqueous solution, and for some applications, 5% to 10% by weight of glucose; 0.5 to 50 grams of icodextrin per 100 ml of aqueous solution, and more preferably 15% to 30% by weight of icodextrin. Suitable solutions may also employ high molecular weight biocompatible polymer solutions (weight average molecular weight Da>10,000) having 0.5 to 50 grams of high molecular weight polymer per 100 ml of aqueous solution, and combinations thereof. Other ingredients that may replace glucose and / or icodextrin include solutions containing 0.5 to 50 grams of one or more of the following per 100 ml of aqueous solution: xylitol, glycerol, hyperbranched polyglycerol, sorbitol, carnitine, taurine, amino acids, urea, polyacrylates, polyethyleneimine, and stevioside. Aqueous solutions contain at least purified water and may additionally include electrolytes, such as small amounts of magnesium or calcium salts, preservatives, ingredients with antimicrobial or antifungal properties, or buffer materials to control the pH of the infusate. Icodextrin compositions may generally be preferred over glucose compositions because icodextrin has been observed to have a lower absorption rate when used in a peritoneal dialysis setting and thus may better protect the peritoneum than glucose-based compositions.

[0047] Although the DSR infusion described in U.S. Patent No. 10,918,778B2 is not recommended for patients with fluid overload heart failure with severe renal dysfunction, the infusion regimen described herein can be specifically formulated to treat patients in CKD stage or stage 5, especially patients for whom loop diuretics are no longer effective. As discussed below, the initial human tests performed by the assignee with a sodium-free glucose solution showed that the DSR therapy phase was interspersed with a traditional hemodialysis or peritoneal dialysis phase, enabling the later phase to be advantageously used for monitoring and / or regulating fluid and sodium levels. Those preliminary studies also showed that removing excess fluid and sodium via the DSR phase allowed a lower dose of loop diuretics to maintain appropriate fluid balance in the patient. For some patients, loop diuretics can be completely disabled during the study. In theory, in such cases, DSR therapy allows the patient's kidneys to rest and / or recover certain functions, thereby enhancing the efficacy of loop diuretics.

[0048] The methods of the present invention using the DSR compositions of the present invention may optionally include monitoring the patient's serum sodium levels associated with the DSR period. For example, blood samples may be collected during or after the DSR period to monitor serum sodium levels. Depending on the desired results for a particular patient, use of a first DSR infusate may cause more sodium than water to migrate into the patient's peritoneal cavity, from which the ultrafiltrate, along with the infusate and sodium, may be drained via a conventional peritoneal dialysis catheter, or more preferably, using an implantable pump described in the above-incorporated patents. The patient may then undergo conventional hemodialysis or peritoneal dialysis, during which additional fluid may be removed to rebalance the patient's sodium metabolism.

[0049] At some later time, e.g., several weeks later, following one or more regularly scheduled dialysis sessions, the patient may undergo another DSR session with DSR Solution 1 or DSR Solution 2. Again the patient's serum sodium level may be monitored by taking blood samples during or after the DSR treatment. According to one aspect of the invention, the DSR session may be intended to mobilize additional water and / or sodium to the patient's peritoneal cavity. In theory, as observed in initial testing, the body may store excess sodium in extravascular spaces, such as in the interstices of blood vessel walls. It is believed that as sodium migrates from the blood into the infusate instilled into the peritoneal cavity during the DSR dwell period, the sodium that migrates into the infusate is replenished by non-osmotic sodium. Therefore, in theory, by reducing non-osmotic sodium, the patient's body will be able to achieve a lower and healthier fluid balance.

[0050] Although the methods and DSR protocols of the present invention can be performed using conventional peritoneal infusion and drainage catheters, it is expected that the use of an implantable pump system provided by the assignee of the present application may be particularly advantageous. Specifically, the Alfapump system provided by Sequana Medical NV is well suited for removing sodium-containing infusates and ultrafiltrates from a patient's peritoneal cavity. For example, after the DSR infusate has been instilled into the patient's peritoneal cavity and a desired residence time has elapsed, or after sodium concentration has been detected in the ultrafiltrate, the implantable pump can be activated according to the clinician's programmed instructions to pump the sodium-containing DSR infusate and ultrafiltrate into the patient's bladder for subsequent emptying. In addition, it is possible that after the DSR period, fluid may continue to accumulate in the peritoneal cavity, and the implantable pump can be programmed to periodically pump such fluid to the bladder.

[0051] Thus, the methods of the present invention provide a method of controlling fluid overload and edema in patients with severe renal dysfunction while allowing such patients to experience a more normal lifestyle rather than their regularly scheduled dialysis sessions. And because the methods and compositions of the present invention are expected to result in a reduction in fluid and / or sodium volume, patients can not only experience improved comfort and lifestyle, but can also delay the onset of other comorbidities, such as further development of chronic kidney disease and / or progressive heart failure.

[0052] Reference now Figure 2 , describes an exemplary system 100 for practicing the present invention. Figure 2 , the components of system 100 are not drawn to scale on a relative or absolute basis. System 100 includes an implantable pump 120 that is specifically configured to move fluid out of the peritoneal cavity and into the bladder, and includes a plurality of sensors for monitoring and recording operating parameters related to the patient's health. An external charging and communication system 130 is used to periodically charge and communicate with the implantable device 110 and download operating data from the device 110. The monitoring and control system 140 includes software installed on the treating physician's computer to receive operating data from the charging and communication system 130 and allow the physician to modify the operation of the implantable device 110 based on the physician's perception of the patient's health based on a review of the operating data uploaded from the device 110. Optionally, the monitoring and control system can be configured to alert the physician about the prediction or detection of infection, heart failure decompensation, or other clinical events based on the recorded operating parameters. The implantable device 110 may also optionally include one or more ultraviolet (UV) sources configured to inhibit infection.

[0053] During a patient visit, the charging and communication system 130 may be coupled to the monitoring and control system 140, either wirelessly or using a cable, to download data stored on the implantable device 120 for review, or to adjust operating parameters of the implantable device. The monitoring and control system 140 may also be configured to upload and store data retrieved from the charging and communication system 130 to a remote server (not shown) for later access by a physician or the charging and communication system 130.

[0054] Implantable device 120 includes an electromechanical pump having a housing 121 configured for subcutaneous implantation. Implantable device 120 preferably includes an electrically driven mechanical gear pump having connectors 122 and 124. A bladder catheter 125 is coupled to pump housing 121 via connector 124. A peritoneal catheter 123 is coupled to pump housing 121 via connector 122. Peritoneal catheter 123 includes a tube having a first (proximal) end configured to be coupled to pump housing 121 and a second (distal) end configured to be positioned in the peritoneal cavity. Bladder catheter 125 includes a tube having a first (proximal) end configured to be coupled to pump housing 121 and a second (distal) end configured to be inserted through the wall of a patient's bladder and secured within the patient's bladder. In a preferred embodiment, both catheters are made of medical grade silicone and include a polyester cuff (not shown) at their distal ends to maintain the catheters in place.

[0055] The implantable device 120 may also include a pressure sensor for monitoring the pressure in one or both of the peritoneal cavity and the bladder, so that if the intra-abdominal pressure exceeds a limit determined by the physician, fluid is pumped from the peritoneal cavity into the bladder. Alternatively or additionally, the output of the pressure sensor can interrupt the pumping of fluid to the bladder until it is determined that the bladder has sufficient space to accommodate the additional fluid. For the comfort of the patient, the implantable device 120 can optionally be programmed not to pump at night or when an accelerometer included in the implantable device indicates that the patient is asleep (thus, emptying the bladder is not possible). The implantable device 120 preferably includes multiple independent fail-safe mechanisms to ensure that urine does not enter the peritoneal cavity from the bladder through the pump, thereby reducing the risk of spreading infection.

[0056] The preferred form of the external charging and communication system 130 includes a base 131 and a handpiece 132. In this embodiment, the handpiece 132 contains a controller, a radio transceiver, an inductive charging circuit, a battery, a charge quality indicator, and a display, and is removably coupled to the base 131 to charge its battery. The base 131 may contain a transformer and circuitry for converting conventional 120V or 220-240V service into a suitable DC current to charge the handpiece 132 when coupled to the base 131. In an alternative embodiment, the handpiece 132 may include such circuitry and a detachable power cord, allowing the handpiece to be plugged directly into a wall outlet to charge the battery. In a preferred embodiment, each of the implantable device 120 and the handpiece 132 includes a device identifier stored in a memory so that the handpiece 132 provided to a patient is coded to operate only with the patient's specific implantable device 120.

[0057] Handpiece 132 preferably includes a housing 133 having a multifunction button 134, a display 135, a plurality of light emitting diodes (LEDs, not shown), and an inductive coil portion 136. Multifunction button 134 provides the patient with the ability to issue a limited number of commands to implantable device 120, while display 135 provides visual confirmation that the desired commands have been entered; it also displays battery status. Inductive coil portion 136 houses an inductive coil that is used to transfer energy from handpiece 132 to charge the battery of implantable device 120. The LEDs, which are visible through the material of housing 133 when illuminated, may be arranged in three rows of two LEDs each, and are coupled to control circuitry and inductive charging circuitry contained within handpiece 132. The LEDs may be arranged to illuminate to reflect the degree of inductive coupling achieved between handpiece 132 and implantable device 120 during recharging of implantable device 120. Optionally, the LEDs may be omitted, and an analog display may be provided on display 135 to indicate the quality of the inductive coupling.

[0058] The control circuitry contained within handpiece 132 is coupled to the inductive charging circuit, battery, LED, and radio transceiver, and includes a memory for storing information from implantable device 120. Handpiece 132 also preferably includes a data port, such as a USB port, that allows the handpiece to be coupled to monitoring and control system 140 during a patient visit to a physician's office. Alternatively, handpiece 132 may include a wireless chip, such as one that complies with Bluetooth or IEEE 802.11 wireless standards, thereby enabling the handpiece to communicate wirelessly with monitoring and control system 140, either directly or via the Internet.

[0059] The monitoring and control system 140 is intended primarily for use by physicians and includes a computer configured to run on a conventional computer (e.g., Figure 2 The software enables the physician to configure, monitor, and control the operation of the charging and communication system 130 and the implantable device 120. The software may include routines for configuring and controlling the operation of the pump, such as a target amount of fluid to be moved per day or per motor drive, intervals between pump actuations, and limits on peritoneal cavity pressure, bladder pressure, pump pressure, and battery temperature. The system 140 may also provide instructions to the implantable device 120 via the charging and control system 130 to control the operation of the implantable device 120 so that fluid is not moved during specific periods (e.g., at night), or if the patient is asleep, then pump actuation is delayed.

[0060] The system 140 may also be configured to, for example, send an immediate command to the implantable device to start or stop the pump, or to operate the pump in reverse or at high power to unclog the pump or associated catheter. The software of the system 140 may also be configured to download real-time data related to the operation of the pump, as well as event logs stored during the operation of the implantable device 120. Based on the downloaded data, for example, based on measurements of the patient's intra-abdominal pressure, respiratory rate and / or fluid accumulation, the software of the system 140 may optionally be configured to warn the doctor of changes in the patient's health that are predicted or detected, for which the flow rate, volume, time and / or frequency of the pump operation may need to be adjusted. Finally, the system 140 may optionally be configured to remotely receive raw or filtered operating data from the patient's handpiece 132 via a secure Internet channel. More details of the system 100 are described in the above-mentioned incorporated U.S. patents.

[0061] Figure 3An implantable device 110 is depicted implanted in the abdomen of a patient, with the distal end of a peritoneal catheter 123 positioned within the patient's peritoneal cavity PC, and the distal end of a bladder catheter 125 positioned within the patient's bladder B. A reservoir 150 of a first or second DSR solution is coupled to a peritoneal infusion catheter 152 to deliver the DSR solution from the reservoir 150 into the peritoneal cavity PC. An optional pump 148 may be coupled to the infusion catheter 152 to accelerate the instillation of the DSR solution into the peritoneal cavity PC, or the pump 148 may be omitted such that the solution is infused via gravity.

[0062] According to a preferred embodiment of the present invention, the implantable device 120 is configured to move sodium-containing DSR infusates and osmotic ultrafiltrate from the peritoneal cavity to the bladder, and the selection of the amount, interval and flow rate can provide sufficient time for the accumulation of the target amount of sodium and / or fluid in the DSR infusate. Treatment algorithms can be developed for different DSR formulations and instillation volumes, different residence time lengths and different bladder discharge rates to optimize serum sodium levels and patient comfort. In general, it is expected that short but frequent pumping of liquid from the peritoneal cavity inhibits material accumulation on the lumens of catheters 123 and 125 and reduces the risk of tissue ingrowth. The fluid circuit of the implantable device 120 can be configured to provide an average flow rate of about 1 to 2.5 liters / hour, but higher and lower flow rates are also possible if necessary. Pumping time, flow rate and volume, including the time allowed for the DSR infusate to remain in the peritoneal cavity, can be programmed by a physician using the monitoring and control system 40 according to the needs of a specific patient.

[0063] Reference now Figure 4 , describes a method of treating patients with severe renal dysfunction using the DSR regimen of the present invention. Figure 4 An initial or subsequent DSR period is described, for example, with a DSR solution or 2, which can be prescribed on a patient-specific basis. Method 200 begins in step 201 by pumping 0.25 liters to 1.5 liters or more of a DSR solution from a reservoir (e.g., Figure 1 The DSR solution is drip-infused into the patient's peritoneal cavity (infusion bag 12 or 14). At step 202, the DSR solution is allowed to remain in the peritoneal cavity for a specific residence time, such as 2 hours, to allow excess sodium and fluid to migrate from the patient's body to the peritoneal cavity. At step 203, during the residence time, the patient's serum sodium level may optionally be sampled to monitor the sodium level. Alternatively, the termination of the residence time may be determined if the patient experiences discomfort due to excessive abdominal distension.

[0064] At step 204, once the residence time is complete, the sodium DSR solution and ultrafiltrate are drained via a conventional peritoneal drainage catheter or by using Figure 2The implantable pump pumps it to the bladder to move it from the patient's body. If fluid and sodium are pumped to the bladder, it can be excreted when the bladder is empty. In any case, removing the DSR solution and ultrafiltrate reduces the amount of fluid and sodium in the body. In step 205, it can be a regularly scheduled dialysis period, and the patient undergoes traditional hemodialysis or peritoneal dialysis to remove accumulated metabolic waste and toxins. During this dialysis period, additional fluid or sodium can be removed to rebalance any residual fluid / sodium imbalance caused by the first DSR period. In step 206, the doctor can also reassess the patient's need for loop diuretics and make appropriate adjustments to the dosage, and make an overall assessment of the patient's health, including the reduction of edema or fluid overload, heart and kidney function, and serum sodium levels. In step 207, additional DSR periods can be performed using DSR solution 2, and steps 202 to 206 are repeated.

[0065] exist Figure 4 After the initial DSR period, the patient's health indicators are expected to stabilize, fluid overload is reduced, renal function is improved, and / or the efficacy of loop diuretics (if still used) is enhanced. In order to maintain these improvements, the patient can undergo one or more subsequent DSR periods at step 207. As discussed above, the goal of these periods can be to maintain the renal improvements obtained from the initial DSR period, and / or to reduce additional amounts of non-osmotic sodium.

[0066] It is further contemplated that additional DSR periods may be scheduled periodically to maintain the improvements in patient well-being produced by the first and any prior subsequent DSR periods. In addition, the physician may elect to modify the composition of the DSR infusion to titrate its ability to remove fluid and sodium to the specific needs of the patient. In this manner, it is contemplated that the physician will be able to prolong the benefits achieved during prior DSR treatment, including reduction of fluid overload, improved renal function, and / or improved efficacy of loop diuretics, if still necessary. It is further hypothesized that patients with end-stage renal disease who follow the above-described regimen may be able to arrest or even potentially reverse the progression of the disease.

[0067] While various illustrative embodiments of the invention have been described above, it will be apparent to those skilled in the art that various changes and modifications can be made thereto without departing from the invention.

[0068] Preliminary experimental observations

[0069] To date, the DSR infusions and methods of the present invention have been initially tested in a porcine model and in first-in-human trials. The results of this testing provided very successful and beneficial results, as described below, and further elucidated the physiological mechanisms involved.

[0070] Pig model testing

[0071] In the first group of five pigs ("protocol-improved pigs"), the effect of infusing 1 liter of sodium-free DSR infusate into the peritoneal cavity of each pig was measured. The DSR infusate typically contains purified water and glucose, such as 10 grams of glucose per 100 milliliters of water, and is allowed to reside in the peritoneal cavity for up to six hours. 5-25 microcuries of I-131 radiolabeled albumin are mixed into the infusate as a non-absorbable tracer to determine ultrafiltration kinetics without the need for continuous drainage of the abdomen. Throughout the residence period, the fluid in the peritoneal cavity is sampled to determine the total sodium removal as a function of time and the sodium concentration in the fluid accumulated in the peritoneal cavity, as well as blood samples. Specifically, within 1-1 / 2 hours after the infusion of the DSR infusate, 3 ml blood samples and 2.5 ml fluid samples are collected every 15 minutes and analyzed. Blood and fluid samples are collected every 1 / 2 hour over the next 1-1 / 2 hour period. And in the last 3 hours, additional blood and fluid samples are collected every hour. In addition, the total volume of fluid accumulated in the peritoneal cavity, consisting of the sodium-containing DSR infusate and the osmotic ultrafiltrate, was recorded as a function of time.

[0072] Figure 5A shows the total sodium removal as a function of residence time for the first group of pigs, and Figure 5B Shown is the sodium concentration in samples removed from the peritoneal cavity as a function of time. Figure 5C The total volume of fluid accumulated in the peritoneal cavity of the first group of pigs is depicted. Figure 5C As shown, after two hours, infusion of 1 liter of DSR infusate induced accumulation of approximately 1 liter of osmotic filtrate in the peritoneal cavity.

[0073] In a second group of ten pigs ("protocol pigs"), a 1 liter DSR infusion was infused into the peritoneal cavity of each pig for a two-hour dwell period. Serum sodium, serum osmotic concentration, plasma osmotic pressure, and glucose levels were measured regularly throughout the dwell period by collecting 6 ml blood samples every 1 / 2 hour. The total osmotic concentration, glucose osmotic concentration, and non-glucose osmotic concentration of the fluid accumulated in the peritoneal cavity were measured regularly during the dwell period using the aforementioned samples. After the dwell period, the total amount of fluid drained from the peritoneal cavity and the total amount of sodium drained were measured.

[0074] Fig. 6A Figure 2 is a graph showing the total fluid volume removed from the peritoneal cavity of each protocol pig after a two hour dwell. Figure 6B Shown is the total amount of sodium removed from the peritoneal cavity of pigs from each protocol after a 2-hour dwell. Figure 6C Shown are changes in total osmolality, glucose osmolality, and non-glucose osmolality of fluid samples from the peritoneal cavity of protocol pigs throughout the 2-hour dwell period. Fig.6D , Fig. 6E and Fig. 6FChanges in serum sodium, serum osmolality, and serum glucose are shown for the protocol pigs throughout the 2-hour dwell period, respectively. The foregoing results indicate that, with a single administration of 1 liter of DSR infusion and a 2-hour dwell, the DSR infusion can remove clinically relevant amounts of sodium, e.g., approximately 4 g, but with clinically negligible effects on serum sodium levels. The amount of sodium removed is typically equivalent to two days of recommended sodium consumption, which would result in excretion of stored fluid via urination and direct excretion of large amounts (1 liter at the parameters studied) of accumulated osmotic ultrafiltrate from the peritoneal cavity. And as Fig.6D , 6E As shown in 6F and 6F, a single administration of DSR infusion at a two-hour dwell was considered very safe because serum sodium levels and serum osmolality remained stable throughout the period, with only an expected and clinically manageable increase in serum glucose concentration.

[0075] Figure 7A-7C Depicted are the results of measurements of a number of blood volume markers in five subgroups of the protocol herd before and after repeated application of a 10 wt % glucose DSR solution. Fig. 7A It was shown that after five cycles of DSR treatment, the total blood volume of the protocol pigs was reduced by almost 1 / 2. As expected, Figure 7B The DSR method was shown to have little effect on the total volume of red blood cells. Figure 7C The plasma volume was shown to be reduced by approximately 60%. Figure 7A-7C As depicted, repeated use of DSR solution can achieve a significant reduction in blood volume by reducing plasma volume. This also shows that DSR solution can be used to eliminate different levels of fluid overload.

[0076] First human feasibility study

[0077] The assignee of the present invention sought and received approval from the Research Review Board to conduct a first trial to evaluate the feasibility of removing sodium from patients using a single dose of DSR solution and a second follow-up study to evaluate the safety and tolerability of serial DSR phases. The first trial was conducted on 10 patients with end-stage renal disease who were undergoing regular peritoneal dialysis using pre-existing peritoneal catheters. In the second follow-up study, the DSR solution was instilled via a subcutaneous port and, after a residence time, removed via an implantable pump, such as Figure 2 In both experiments, a 10 wt % DSR solution of glucose in sterile water was used as a peritoneal infusion. Fig.11 The details and results of these initial trials are described.

[0078] In the first study, patients undergoing peritoneal dialysis for end-stage renal disease with a functional peritoneal dialysis catheter were randomized and crossed over every 1 week to either an open-label DSR solution (10% dextrose without sodium) or a standard peritoneal dialysis solution (Dianeal low calcium solution with 4.25% dextrose; Baxter; Deerfield, IL). This phase 1 study was conducted in patients undergoing universal peritoneal dialysis rather than in normal subjects to avoid the risks of peritoneal dialysis catheter placement in normal subjects. Inclusion criteria were as follows: active peritoneal dialysis with a functional peritoneal dialysis catheter implanted for less than 3 years, patients were older than 18 years, and were judged by the treating nephrologist to be at or above optimal volume status (i.e., not dehydrated). Exclusion criteria were uncontrolled diabetes with frequent episodes of severe hyperglycemia; systolic blood pressure <100 mm Hg; serum sodium <130 mEq / L; one or more episodes of peritonitis or active infection of the peritoneal dialysis catheter within the previous 6 months; anemia with hemoglobin <8 g / dL; serum bicarbonate <18 mEq / L; anuric renal failure; inability to give written informed consent or comply with the study protocol; and pregnant or lactating women.

[0079] 4.25% glucose peritoneal dialysis solution was selected as the comparison solution because it is the most effective commercially available peritoneal dialysis solution for removing fluid / sodium and has a similar osmotic capacity to 10% glucose. Prior to the instillation of the study fluid, patients took a variety of positions for 30 minutes of abdominal drainage to ensure as complete drainage as possible. Considering that this is a dialysis population prone to acidosis, all patients took 30mEq sodium citrate / citric acid orally. Next, 1L of DSR solution or standard peritoneal dialysis solution was infused into the peritoneum and retained for 2 hours. In addition to direct measurement of drainage fluid at the end of the stay, the intraperitoneal volume was longitudinally measured using the indicator dilution technique of I-131-radiolabeled albumin (Daxor). Vital signs, blood (every 30 minutes), and peritoneal fluid (every 15 minutes) were continuously obtained throughout the protocol. Patients in the DSR group were given 50% of the ultrafiltration volume in the form of intravenous saline at the end of the stay to replace sodium / volume losses. The primary endpoint was safety / tolerability, defined as completion of a 2-hour stay without significant discomfort or adverse events. The secondary efficacy endpoint was the difference in sodium removal between the DSR solution and standard peritoneal dialysis solution.

[0080] Ten patients completed the crossover study. The baseline characteristics of these patients are shown in the following table.

[0081]

[0082]

[0083] All 10 patients met the primary endpoint, defined as completing a 2-hour stay without significant discomfort or adverse events. Overall, the treatment was well tolerated, with 2 of the 10 patients reporting mild and transient cramping during instillation of the 10% glucose solution; one of these patients experienced similar cramping during instillation of standard peritoneal dialysis solution. There were no significant differences in blood pressure or peak heart rate between the two groups. Glucose changes were greater with the 10% glucose solution compared with standard peritoneal dialysis solution, with the differences being most pronounced early in the stay. However, after the solution was drained, the differences in plasma glucose completely disappeared. No patient in either group experienced severe hyperglycemia at any time point. Relative glucose absorption was identical between 10% glucose and standard peritoneal dialysis solution; however, given the greater absolute amount of glucose in 10% glucose, the absolute amount of glucose absorbed was also greater with 10% glucose.

[0084] There were no differences in serum sodium between the groups. Off-target removal of non-sodium electrolytes such as potassium (5.5 ± 1.1 mmol), magnesium (1.7 ± 2.5 mmol), phosphorus (1.9 ± 0.6 mmol), and calcium (1.6 ± 0.3 mmol) by DSR was negligible, and plasma electrolyte and chemical parameters were stable throughout the stay. Fig. 8A As shown in Figure 2, the secondary efficacy outcome of sodium removal was met with sodium-free 10% dextrose (4.5 ± 0.4 g) compared with standard peritoneal dialysis solution (1.0 ± 0.3 g) (P < 0.001). In addition to the significantly higher mean sodium clearance, the consistency of sodium removal was also very good. Figure 8B As depicted, the absolute variability between individual patient sodium removal and mean sodium removal was similar between DSR and standard peritoneal dialysis fluids. However, because total sodium removal was significantly lower in standard peritoneal dialysis fluids, the relative variability between individuals was higher in standard peritoneal dialysis fluids, ranging from 8% to 75% of mean total sodium removal compared with 2% to 18% for patients receiving DSR. Fluid removal was also higher with sodium-free 10% dextrose, with greater agreement between patients.

[0085] The major finding of the first human trial was that large amounts of sodium removal via the peritoneum were feasible. Specifically, it was observed that >4 g of sodium could be removed in 2 hours using 1 liter of sodium-free 10% glucose solution, using diffusion and convection forces. DSR therapy was well tolerated, with limited effects on plasma electrolyte levels, minimal off-target solute removal, and no discomfort in most subjects. Sodium removal was scalable, with substantially greater amounts of sodium removed by increasing the volume of 10% glucose circulating into the peritoneal space.

[0086] In the second study, the main purpose was to evaluate the safety and tolerability of DSR therapy for serial treatment of patients with chronic stable diuretic-resistant heart failure. The second purpose of this study was to evaluate the effects of DSR therapy serial treatment on renal function parameters and diuretic response. In this study, DSR solution was drip-injected into the patient's peritoneal cavity via a subcutaneous port. An implantable pump system developed by the assignee of this application, Sequana Medical, NV, was used to move fluid from the patient's peritoneal cavity to their bladder. Ten patients were included in the second study according to the following criteria:

[0087] Inclusion criteria:

[0088] 1. eGFR>30ml / min / 14.73m2

[0089] 2. A diagnosis of heart failure with one of the following:

[0090] a.nt-proBNP>400pg / ml (or BNP>100pg / ml)

[0091] and oral diuretic dose ≥ 80 mg furosemide equivalent or

[0092] B. Oral diuretic dose ≥ 120 mg furosemide equivalent

[0093] 3.30 days of stable diuretic dose

[0094] 4. Systolic blood pressure ≥100 mmHg

[0095] 5. Be at optimal volume as determined by the treating provider

[0096] Exclusion criteria:

[0097] 1. Serum sodium <135 mEq / L

[0098] 2. Severe hyperkalemia or baseline plasma potassium > 4.5 mEq / L

[0099] 3. History of severe bladder dysfunction expected to affect the subject's ability to tolerate DSR pump delivery into the bladder

[0100] 4. Uncontrolled diabetes or type 1 diabetes with frequent high blood sugar levels

[0101] The second study lasted a total of 6 weeks, plus an additional 2 weeks of follow-up. After screening, approximately 2 weeks before the start of the trial, 10 patients were implanted with Figure 2 Described in Implantable pump. Three days before the start of the DSR trial, each patient received 40 mg of furosemide intravenously, followed by a 6-hour timed urine collection. At the start of the DSR trial, all loop diuretics were discontinued. During the next two weeks, the patients were hospitalized and their diet was controlled to 3 grams of sodium per day in the first week and 5 grams of sodium in the second week. The patients were then allowed to go home. During the two-week hospitalization and the following four weeks, the patients underwent DSR treatment three times a week using a 10 weight percent glucose DSR solution. At the end of the six-week DSR period, the patients underwent another diuretic challenge with 40 mg of furosemide intravenously, followed by a 6-hour timed urine collection.

[0102] The following table presents the baseline characteristics of the group:

[0103]

[0104]

[0105] At the end of the six-week study, all patients remained on loop diuretics throughout the study. Neutral sodium balance (-1.3 grams) was achieved during the 2-week hospital stay. Body weight was also stable throughout the study (75.6 to 75.5 kg). Most patients underwent a reduction in DSR therapy to maintain constant body weight; the volume of 10% glucose DSR solution averaged 750 ± 348 ml / treatment.

[0106] The results of the study are shown in Figures 9 to Fig.12 In particular, Fig. 9A and 9B As shown, study participants experienced significant reductions in measured N-terminal-pro B-type natriuretic peptide ("NT-proBNP") and creatinine levels, indicating improved cardiorenal function. Fig. 10A , Fig. 10B and Fig. 10C Temporal trends in the improvement of study patients over the six-week period are depicted. Fig.11 Improvements in the patient's response to loop diuretics were described at the start of the trial and after the six-week DSR period, showing a three-fold increase in urine output. Fig.12 is a table reporting the results of follow-up evaluations of the eight patients in the study and indicates that the effect of DSR therapy in reducing diuretic resistance was durable, with patients experiencing an 89% to 50% reduction in their daily diuretic dose 10 to 12 months after the last DSR treatment, with at least one patient completely discontinuing diuretic use.

[0107] Thus, the second human study showed that six weeks of DSR therapy using an implantable pump to remove DSR solution and ultrafiltrate was generally well tolerated and successfully maintained neutral sodium balance and stable body weight despite complete discontinuation of loop diuretics. The study also showed significant benefits on cardiorenal function, as observed by meaningful improvements in NT-proBNP and renal function. In addition, diuretic resistance was significantly and durably improved.

[0108] Based on the results of initial human trials using a single composition DSR infusion (e.g., 10% by weight glucose), it is theoretically possible that the use of multiple compositions in a regimen interspersed with the patient's regularly occurring dialysis sessions could significantly enhance the long-term efficacy of loop diuretics, allow for the administration of reduced doses, and prevent and potentially reverse renal disease and heart failure. As discussed above, the use of multiple DSR compositions could enable the patient's physician to gradually reduce fluid and sodium overload over a period of weeks to months, and thereby establish improved sodium and fluid metabolism for the patient, improving severe renal dysfunction and heart failure.

[0109] Although various illustrative embodiments of the present invention have been described above, it will be apparent to those skilled in the art that various changes and modifications may be made thereto without departing from the present invention. For example, the pump system 1 may be ordered differently and may include additional or fewer components of different sizes and combinations. The appended claims are intended to cover all such changes and modifications that fall within the true spirit and scope of the present invention.

Claims

1. An infusion regimen for removing excess sodium and fluid from a patient suffering from fluid overload or severe renal dysfunction, the infusion regimen comprising: A first direct sodium removal (DSR) infusion, formulated to be administered by infusion into and removal from the peritoneal cavity of a patient, the first DSR infusion having a first osmotic concentration, wherein the aqueous solution contains a sodium concentration equal to or less than 35 meq / L, and the solution contains any one or more of the following: 0.5 to 50 grams of xylitol, glycerol, hyperbranched polyglycerol, sorbitol, carnitine, taurine, amino acids, urea, polyacrylates, polyethyleneimine, or stevioside, or any combination thereof, per 100 ml of aqueous solution.

2. The infusion regimen of claim 1, further comprising: A second DSR infusion is formulated to be administered by infusion into and removal from the peritoneal cavity of the patient, the second DSR infusion having a second osmotic concentration, wherein the aqueous solution contains a sodium concentration equal to or less than 35 meq / L, and the solution contains any one or more of the following: 0.5 to 50 grams of xylitol, glycerol, hyperbranched polyglycerol, sorbitol, carnitine, taurine, amino acids, urea, polyacrylates, polyethyleneimine or stevioside, or any combination thereof, per 100 ml of aqueous solution, wherein the second osmotic concentration is different from the first osmotic concentration.

3. The infusion regimen of claim 1 or 2, wherein the first DSR infusion further comprises at least one of: zero to 50 grams of dextrose per 100 ml of aqueous solution, 0.5 to 50 grams of icodextrin per 100 ml of aqueous solution, or 0.5 to 50 grams of a high molecular weight biocompatible polymer having an average molecular weight greater than 10,000 Daltons per 100 ml of aqueous solution, or any combination thereof.

4. The infusion regimen of claim 2 or 3, wherein the second DSR infusion further comprises at least one of: zero to 50 grams of glucose per 100 ml of aqueous solution, 0.5 to 50 grams of icodextrin per 100 ml of aqueous solution, or 0.5 to 50 grams of a high molecular weight biocompatible polymer having an average molecular weight greater than 10,000 Daltons per 100 ml of aqueous solution, or any combination thereof.

5. An infusion regimen according to any of the preceding claims, wherein the first DSR infusion has an osmotic concentration and a sodium concentration selected to induce a steep sodium gradient between the patient's serum sodium level and the first DSR infusion when instilled into the peritoneal cavity during a first dwell period.

6. The infusion regimen of any one of claims 2 to 5, wherein the second DSR infusion has an osmotic concentration and a sodium concentration selected to induce a gentle sodium gradient between the patient's serum sodium level and the second DSR infusion when instilled into the peritoneal cavity during a second dwell period.

7. The infusion regimen of any one of the preceding claims, wherein the first DSR infusion contains no sodium.

8. The infusion regimen of any one of claims 2 to 7, wherein the first DSR infusion or the second DSR infusion further comprises an electrolyte selected from a magnesium salt and a calcium salt.

9. The infusion regimen of any one of claims 2 to 8, wherein the first DSR infusion or the second DSR infusion further comprises at least one of: an antimicrobial agent, an antifungal agent, and a buffer.

10. The infusion regimen of any of the preceding claims, wherein the first DSR infusion is formulated to be sufficiently non-viscous to enable instillation from a reservoir into the peritoneal cavity via gravity feed.

11. The infusion regimen of any one of claims 2 to 10, wherein the second DSR infusion is formulated to be sufficiently non-viscous to enable instillation from a reservoir into the peritoneal cavity via gravity feed.

12. The infusion regimen of any one of claims 2 to 11, wherein each of the first DSR infusion and the second DSR infusion is formulated to be instilled into the patient's peritoneal cavity in an amount of between 0.25 and 2.0 liters per DSR period.

13. The infusion regimen of any of the preceding claims, wherein the first DSR infusion is substantially free of sodium.

14. The infusion regimen of any one of the preceding claims, wherein the first DSR infusion comprises 0.5 to 50 grams of dextrose per 100 ml of aqueous solution and 0.5 to 50 grams of icodextrin per 100 ml of aqueous solution.

15. The infusion regimen of any of the preceding claims, wherein the first DSR infusion further comprises water.

16. The infusion regimen of any one of the preceding claims, wherein the first DSR infusion comprises 10 grams of glucose per 100 ml.

17. The infusion regimen of any of the preceding claims, wherein the first DSR infusion is configured to be administered to a patient requiring the infusion to treat fluid overload in the patient.

18. The infusion regimen of any of the preceding claims, wherein the first DSR infusion is configured to be administered to the patient in need of the infusion to treat heart failure in the patient.

19. The infusion regimen of any of the preceding claims, wherein the first DSR infusion is configured to be administered to the patient requiring the infusion to treat severe renal dysfunction in the patient.

20. The infusion regimen of any of the preceding claims, wherein the first DSR infusion consists essentially of: 0.5 to 50 grams of glucose per 100 ml of aqueous solution, 0.5 to 50 grams of icodextrin per 100 ml of aqueous solution, and water.

21. The infusion regimen according to any one of the preceding claims, wherein the 0.5 to 50 grams of glucose per 100 ml of aqueous solution is 10 grams of glucose per 100 ml of aqueous solution.

22. The infusion regimen according to any one of the preceding claims, wherein the 0.5 to 50 grams of icodextrin per 100 ml of aqueous solution is 15 to 30 wt% icodextrin.

23. The infusion regimen of any one of the preceding claims, wherein the 0.5 to 50 grams of glucose per 100 ml aqueous solution is 5 to 10 wt% glucose and the 0.5 to 50 grams of icodextrin per 100 ml aqueous solution is 15 to 30 wt% icodextrin.

24. The infusion regimen of any one of the preceding claims, wherein the first DSR infusion removes excess sodium to cause a reduction in fluid overload in the patient while maintaining serum sodium levels approximately unchanged.

25. The infusion regimen of any one of claims 2 to 24, wherein each of the first DSR infusion and the second DSR infusion is formulated to be instilled into the patient's peritoneal cavity in an amount of between 0.25 and 2.0 liters per DSR period.

26. The infusion regimen of any of the preceding claims, wherein the first DSR infusion is configured to be administered by infusion into the peritoneal cavity of the patient for a dwell period of at least two hours.

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