Urinary oxygen and uses thereof in adaptive therapies for kidney function

Abstract

Methods and systems for preventing and / or inhibiting the progression of kidney renal injury in a subject are provided. A negative pressure treatment therapy having a dosing regimen tailored to a subject's urinary oxygen levels and risk assessment value is disclosed, and serves to prevent and / or reduce the progression of kidney renal injury through modification / adjustment of dose administered responsive to changes in a subject's urinary oxygen levels.

Description

URINARY OXYGEN AND USES THEREOF IN ADAPTIVE THERAPIES FOR KIDNEY FUNCTIONCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 547,388, filed November 5, 2023, which is incorporated herein in its entirety.FIELD OF THE INVENTION

[0002] Technical FieldThe present invention relates to the technical fields of methods, systems and devices for assessing urinary oxygen levels, treating and / or preventing impaired renal function and / or kidney renal injury, and the use of negative pressure therapy in treatment plans to control and / or protect against renal insufficiency and / or kidney renal injury. The present disclosure also relates to the field of methods for collecting and assessing urinary oxygen levels in a subject, and to methods for delivering negative pressure treatment to a subject.BACKGROUND OF THE INVENTION

[0002] Impaired Renal FunctionThe renal or urinary system includes a pair of kidneys, each kidney being connected by a ureter to the bladder, and a urethra for draining fluid or urine produced by the kidneys from the bladder. The kidneys perform several vital functions for the human body including, for example, filtering the blood to eliminate waste in the form of urine. The kidneys also regulate electrolytes (e.g., sodium, potassium and calcium) and metabolites, blood volume, blood pressure, blood pH, fluid volume, production of red blood cells, and bone metabolism. Adequate understanding of the anatomy and physiology of the kidneys is useful for understanding the impact that altered hemodynamics and other fluid overload conditions have on their function.

[0003] In normal anatomy, the two kidneys are located retroperitoneally in the abdominalcavity. The kidneys are bean-shaped encapsulated organs. Urine is formed by nephrons, the functional unit of the kidney, and then flows through a system of converging tubules called collecting ducts. The collecting ducts join together to form minor calyces, then major calyces, which ultimately join near the concave portion of the kidney (renal pelvis). A major function of the renal pelvis is to direct urine flow to the ureter. Urine flows from the renal pelvis into the ureter, a tube-like structure that carries the urine from the kidneys into the bladder. The outer layer of the kidney is called the cortex, and is a rigid fibrous encapsulation. The interior of the kidney is called the medulla. The medulla structures are arranged in pyramids.

[0004] Each kidney is made up of approximately one million nephrons. Each nephron includes the glomerulus, Bowman's capsule, and tubules. The tubules include the proximal convoluted tubule, the loop of Henle, the distal convoluted tubule, and the collecting duct. The nephrons contained in the cortex layer of the kidney are distinct from the anatomy of those contained in the medulla. The principal difference is the length of the loop of Henle. Medullary nephrons contain a longer loop of Henle, which, under normal circumstances, allows greater regulation of water and sodium reabsorption than in the cortex nephrons.

[0005] The glomerulus is the beginning of the nephron, and is responsible for the initial filtration of blood. Afferent arterioles pass blood into the glomerular capillaries, where hydrostatic pressure pushes water and solutes into Bowman's capsule. Net filtration pressure is expressed as the hydrostatic pressure in the afferent arteriole minus the hydrostatic pressure in Bowman's space minus the osmotic pressure in the efferent arteriole.

[0006] Net Filtration Pressure = Hydrostatic Pressure (Afferent Arteriole) - Hydrostatic Pressure (Bowman's Space) - Osmotic Pressure (Efferent Arteriole) [Equation 1]

[0007] The magnitude of this net filtration pressure defined by Equation 1 determines how much ultra-filtrate is formed in Bowman's space and delivered to the tubules. The remaining blood exits the glomerulus via the efferent arteriole. Normal glomerular filtration, or delivery of ultrafiltrate into the tubules, is about 90 ml / min / 1.73m2'

[0008] The glomerulus has a three-layer filtration structure, which includes the vascular endothelium, a glomerular basement membrane, and podocytes. Normally, large proteins such as albumin and red blood cells, are not filtered into Bowman's space. However, elevated glomerular pressures and mesangial expansion create surface area changes on the basement membrane and larger fenestrations between the podocytes allowing larger proteins to pass into Bowman's space.

[0009] Ultra-filtrate collected in Bowman's space is delivered first to the proximal convoluted tubule. Re-absorption and secretion of water and solutes in the tubules is performed by a mix of active transport channels and passive pressure gradients. The proximal convoluted tubules normally reabsorb a majority of the sodium chloride and water, and nearly all glucose and amino acids that were filtered by the glomerulus. The loop of Henle has two components that are designed to concentrate wastes in the urine. The descending limb is highly water permeable and reabsorbs most of the remaining water. The ascending limb reabsorbs 25% of the remaining sodium chloride, creating a concentrated urine, for example, in terms of urea and creatinine. The distal convoluted tubule normally reabsorbs a small proportion of sodium chloride, and the osmotic gradient creates conditions for the water to follow.

[0010] Under normal conditions, there is a net filtration of approximately 14 mmHg. The impact of venous congestion can be a significant decrease in net filtration, down to approximately 4 mmHg. See Jessup M. , The cardiorenal syndrome: Do we need a change of strategy or a change of tactics?, JACC 53(7):597-600, 2009 (hereinafter "Jessup"). The second filtration stage occurs at the proximal tubules. Most of the secretion and absorption from urine occurs in tubules in the medullary nephrons. Active transport of sodium from the tubule into the interstitial space initiates this process. However, the hydrostatic forces dominate the net exchange of solutes and water. Under normal circumstances, it is believed that 75% of the sodium is reabsorbed back into lymphatic or venous circulation. However, because the kidney is encapsulated, it is sensitive to changes in hydrostatic pressures from both venous and lymphatic congestion. During venous congestion the retention of sodium and water can exceed 85%, further perpetuating the renal congestion. See Verbrugge et al., The kidney in congestive heart failure: Are natriuresis, sodium, and diuretics really the good, the bad and the ugly? European Journal of Heart Failure 2014: 16,133-42 (hereinafter "Verbrugge").

[0011] Venous congestion can lead to a prerenal form of acute kidney injury (AKI). Prerenal AKI is due to a loss of perfusion (or loss of blood flow) through the kidney. While there has been focus on the lack of flow into the kidney due to shock, there is also evidence that a lack of blood flow out of the organ due to venous congestion can be a clinically important sustaining injury. See Damman K., Importance of venous congestion for worsening renal function in advanced decompensated heart failure, JACC 17:589-96, 2009 (hereinafter "Damman").

[0012] Prerenal AKI occurs across a wide variety of diagnoses requiring critical care admissions. The most prominent admissions are for sepsis and Acute Decompensated Heart Failure (ADHF). Additional admissions include cardiovascular surgery, general surgery, cirrhosis, trauma, bums, and pancreatitis. While there is wide clinical variability in the presentation of these disease states, a common denominator is an elevated central venous pressure. In the case of ADHF, the elevated central venous pressure caused by heart failure leads to pulmonary edema, and, subsequently, dyspnea in turn precipitating the admission. In the case of sepsis, the elevated central venous pressure is largely a result of aggressive fluid resuscitation. Whether the primary insult was low perfusion due to hypovolemia or sodium and fluid retention, the sustaining injury is the venous congestion resulting in inadequate perfusion.

[0013] Hypertension is another widely recognized state that creates perturbations within the active and passive transport systems of the kidney(s). Hypertension directly impacts afferent arteriole pressure and results in a proportional increase in net filtration pressure within the glomerulus. The increased filtration fraction also elevates the peritubular capillary pressure, which stimulates sodium and water re-absorption. See Verbrugge.

[0014] Because the kidney is an encapsulated organ, it is sensitive to pressure changes in the medullary pyramids. The elevated renal venous pressure creates congestion that leads to a rise in the interstitial pressures. The elevated interstitial pressures exert forces upon both the glomerulus and tubules. See Verbrugge. In the glomerulus, the elevated interstitial pressures directly oppose filtration. The increased pressures increase the interstitial fluid, thereby increasing the hydrostatic pressures in the interstitial fluid and peritubular capillaries in the medulla of the kidney. In both instances, hypoxia can ensue leading to cellular injury and further loss of perfusion.The net result is a further exacerbation of the sodium and water re-absorption creating a negative feedback. See Verbrugge, 133-42. Fluid overload, particularly in the abdominal cavity is associated with many diseases and conditions, including elevated intraabdominal pressure, abdominal compartment syndrome, and acute renal failure. Fluid overload can be addressed through renal replacement therapy. See Peters, C D., Short and Long-Term Effects of the Angiotensin II Receptor Blocker Irbesartanon Intradialytic Central Hemodynamics: A Randomized Double-Blind Placebo-Controlled One-Year Intervention Trial (the SAFIR Study), PLoS ONE (2015) 10(6): e0126882. doi:I0.1371 / joumal.pone.0126882 (hereinafter "Peters"). However, such a clinical strategy provides no improvement in renal function for patients with the cardiorenal syndrome. See Bart B., Ultrafiltration in decompensated heart failure with cardiorenal syndrome, NEJM 2012;367:2296-2304 (hereinafter "Bart").

[0015] In view of such problematic effects of fluid retention, systems and methods for improving removal of fluid such as urine from the patient and, specifically for increasing quantity and quality of fluid output from the kidneys, are needed. Before addressing appropriate methods of treatment, it is helpful to understand how physicians diagnose the risk of renal injury at any given point in time, and to distinguish this risk from the extent of renal impairment due to the progression of diseases such as acute kidney injury (AKI), chronic kidney disease (CKD) and others.

[0016] As any kidney disease progresses, kidney function may decline over time (particularly absent treatment). Discrete events along the way, such as a heart attack or cardiac surgery, may increase the risk of further renal injury on a temporary basis, as well as contribute to the rate of decline of kidney function.

[0017] Among various diagnostic factors, a patient’s medullary oxygen concentration is a recognized risk factor for AKI. For example, U.S. Pat. No. 11,660,032, issued on May 30, 2023 (“Silverton” patent), discusses methods of diagnosing AKI in cardiac surgery patients, and notes that “[m]edullary hypoxia is a recognized associated risk factor for AKI during cardiac surgery and may be a consequence of decreased oxygen delivery or increased oxygen consumption and is a major determinant of AKI and chronic kidney disease” [column 2, lines 35-49], It goes on tonote that “medullary oxygen tension is more closely related to urinary oxygen tension than renal venous oxygenation. In addition to determining the risk of AKI, the condition of the kidney may be related to the renal medullary oxygen concentration.”

[0018] Silverton offers no solution with regard to methods of modifying urinary oxygen levels, let alone treating AKI and impaired renal function generally, nor does it address correlating specific urinary oxygen levels to particular aspects of a treatment plan.

[0019] U.S. Pat. No. 10,772,998, issued on September 15, 2020 (“Luxon” patent) relates to “Taking measurements of multiple urine parameters as described, such as conductance, specific gravity, urine output and oxygen tension,” and “detecting AKI and UTI using the described parameters.” While the Luxon patent notes that “different causes of AKI have different effective therapies” (column 20, lines 34-39), it offers no insight into how any particular form of AKI (whether its cause was prerenal, postrenal, intrinsic, septic or otherwise) would be treated, much less any suggestion as to the value of correlating specific urinary oxygen levels with particular aspects of any such treatment plan.

[0020] It should be noted that the underlying pathophysiology for low oxygen levels is poorly understood.SUMMARY OF THE INVENTION

[0021] The present invention addresses shortcomings in prior systems and research relating to urinary oxygen levels and AKI. Prior systems and research have generally focused on diagnostic methods of employing urinary oxygen and other sensors to identify and quantify that risk. The present disclosure provides solutions in the form of methods of modifying urinary oxygen levels in a subject, correlating specific urinary oxygen levels to the subject’s risk of renal injury, correlating risk to particular aspects of a therapeutic treatment plan, and adapting the therapeutic tools of treating impaired renal function and improving renal oxygen handling to the relative degree of injury or risk of further kidney injury at any given point in time.

[0022] Generally, prior research and systems have contemplated that low oxygen is the result of decreased delivery of oxygen to the organ. In contrast, the present invention is based inpart on the recognition that the increased consumption of oxygen in the kidney appears to play a more important role than poor oxygen delivery to the kidney. The relationship between Na+ reabsorption and oxygen consumption has been shown to be linear. See Mandel, L.J., et.al., Stoichiometry and coupling of active transport to oxidative metabolism in epithelial tissues, Am, J. Physiol. 240 (Renal Fluid Electrolyte Physiol. 9): F357-F371,1981. Decreased delivery of oxygen to the kidney is a clinical challenge. Poor delivery can be associated with low cardiac output (including cardiogenic shock) and / or low hematocrit (including anemia). Low cardiac output, below the autoregulatory range, is associated with decreased glomerular fdtration rate. Interestingly, the kidney does not expend energy to filter the blood. The kidney expends energy, and therefore consumes oxygen, to reabsorb sodium, glucose and other critical solutes that require active transport, rather than diffusion. Therefore, increasing blood flow to the kidney results in an augmented glomerular filtration rate which increases the electrolyte load delivered to the tubules. The increased solute delivery into the tubules increases the demand for oxygen in the kidney to be able to reabsorb these critical solutes. When the increase in metabolic demand outpaces the delivery of oxygen to support the organ, this dynamic leads to sustained hypoxia. This hypoxia is a key process in the development of acute kidney injury following cardiac surgery and other forms of acute kidney injury. The energy consumption from elevated solute reabsorption is a common theme across not only acute kidney injury, but also progression of chronic kidney disease as well. The three primary risk factors for chronic kidney disease and its progression are hypertension, diabetes and heart failure. Chronic hypertension can often exceed the kidneys’ autoregulatory range - meaning that the kidney cannot maintain a constant glomerular filtration rate. That drives solute delivery to the kidney creating the same solute energy demand. Likewise, the poor glycemic control due to diabetes leads to an increase in glucose delivered to the tubules. Finally, heart failure is often associated with challenges in maintaining total body volume. The excessive volume leads to greater sodium filtration and reabsorption.

[0023] The present invention includes techniques that improve kidney function by decreasing the consumption of oxygen by decreasing the demand on the kidneys to reabsorb critical solutes. Such techniques also result in increased delivery of oxygen to the kidneys as kidney function improves.

[0024] Treatment for impaired kidney function and protection from acute renal insults hold promise to decelerate or even reverse the natural progression of the disease. It is therefore important when treating renal impairment to distinguish the risk of kidney injury (which may ebb and flow) at any given point in time from the current extent of progression of an underlying kidney disease. By doing so, as will be discussed in greater detail below, one can correlate aspects of a treatment plan with the current risk of kidney injury, as well as with the patient’s current condition (e.g., stages of CKD).100251 The present invention addresses shortcomings in prior systems for treating impaired renal function (including AKI, CKD and other renal diseases) by offering a treatment plan designed to improve kidney function (decelerating and even reversing the natural progression of the disease) that adapts to continually monitored oxygen levels by modifying aspects of the treatment plan to correlate treatment with the risk of kidney injury (represented by such monitored urinary oxygen levels, and potentially other factors). Embodiments include acute, sub-acute and chronic negative pressure treatment plans, ureteral, bladder and other urinary catheters (including percutaneous kidney catheters), oxygen and other sensors (e.g., sodium sensors), and external and indwelling pumps, among various other features.|0026] It should be noted that the term “oxygen levels” as used herein is meant to encompass a wide variety of types of oxygen measurements, including measuring oxygen content or concentration in different fluids (urine, blood, etc ), partial pressure of oxygen, oxygen tension, oxygen values and various other terms employed to denote the measurement of oxygen levels. References to “urinary oxygen levels” in the following disclosure is not meant to be limited to any particular type of oxygen measurement.

[0027] Moreover, the use of particular types of oxygen sensors at particular locations within and outside the human body is also not intended to be limited to any particular type of oxygen sensor or location (including the renal pelvis or other regions of the kidney, in-line or external to ureteral and other urinary catheters, at catheter connection ports, as well as internal and external sample or fluid collection chambers and at connections to external or indwelling pumps, among other locations). Finally, the use of other sensors in addition to oxygen sensors (e.g.,sodium sensors) is not intended to be foreclosed as a means of providing additional data on which treatment decisions are based.

[0028] The negative pressure treatment therapies disclosed herein are also not intended to represent the only type of treatments in the context of the present invention that are designed to improve kidney function and facilitate urine output from a patient’s kidneys. The embodiments described herein employ urine oxygen sensors (among other types of sensors) to provide continual measurements of urinary oxygen levels, which are iteratively correlated over time with specific aspects of negative pressure therapy (e.g., a particular magnitude of negative pressure). By calibrating the “dose” of negative pressure therapy (delivered to the kidney collecting system) to the current risk of kidney injury (represented by the monitored urinary oxygen levels), the present invention protects the kidneys from hypoxic injury while both improving oxygen delivery to the kidneys and decreasing the kidneys’ consumption of oxygen required to reabsorb critical solutes. In some embodiments, machine learning is employed to correlate particular aspects of a treatment plan to urinary oxygen levels.

[0029] In one embodiment, upon beginning a “standard dose” of treatment with urinary oxygen levels above a “baseline” threshold, the present invention detects a reduction in urinary oxygen levels, which eventually drop below that baseline threshold as demand for oxygen outpaces supply. At that point, in which the risk of kidney injury is rising, the present invention responds by employing an “enhanced dose” of treatment in an effort at least to decelerate the reduction in urinary oxygen levels. Should such values continue to decrease further despite enhanced treatment, the present invention modifies the treatment plan by employing a “further enhanced dose” (and perhaps eventually a “maximum dose”) of treatment.

[0030] In another embodiment, a “standard dose” of treatment may be altered to an “enhanced dose” of treatment in response to a duration of reduced low urinary oxygen levels, or even a frequency of transient intervals of reduced low urinary oxygen levels. The dual contribution of both magnitude and duration of kidney hypoxia are critical to the risk of kidney injury.

[0031] In yet another aspect, a method of preventing renal injury or reducing progression of renal injury in a subject having or at risk of renal insufficiency, is provided. In someembodiments, the method comprises comparing a urinary oxygen level of a subject having or at risk of developing renal insufficiency to a reference urinary oxygen level to provide a renal injury risk assessment value for the subject; categorizing the subject’s renal injury risk assessment value as no risk, low risk, moderate risk or high risk of renal injury or progression of renal injury administering a negative pressure treatment therapy to the subj ecf s kidney at a dose commensurate with the subject’s renal injury risk assessment value; and preventing renal injury or reducing the progression of renal injury in the subject, wherein continuously monitoring the subject’s urinary oxygen levels and administering to the kidney a dose of negative pressure treatment therapy commensurate to the subject’s renal injury risk assessment value, prevents or reduces the progression of renal injury in the subject.

[0032] In other embodiments the commensurate dose of negative pressure therapy administered to the kidney of a subject having a high renal injury risk assessment value is a dose of about -25 mmHG or a dose otherwise suitable for providing urinary oxygen levels in the subject at a clinically acceptable urinary oxygen reference level; a commensurate dose of negative pressure therapy administered to the kidney of a subject having a low or moderate renal injury risk assessment value is a dose of about -20 to about -15 mmHG or a dose suitable for otherwise providing urinary oxygen levels in the subject at a clinically acceptable urinary oxygen reference level; and a subject having a low renal injury risk assessment value is commensurate with the subject’s renal insufficiency or a dose suitable for otherwise providing urinary oxygen levels in the subject at a clinically acceptable urinary oxygen reference level.

[0033] Generally, and in some embodiments, a subject has a low risk of renal injury or progression of renal injury where the subject urinary oxygen level is about 80 mmHg or higher; the subject has a moderate risk of renal injury or progression of renal injury where the subject urinary oxygen level is greater than about 40 to less than about 80 mmHg; and the subject has a high risk of renal injury or progression of real injury where the subject urinary oxygen levels are below a hypoxia urinary oxygen threshold level, wherein a hypoxia urinary oxygen threshold level is between about 30 mmHg and about 40 mmHg.[0034| The actual dosage of negative pressure therapy to be administered, the range of urinary oxygen levels for each risk category for progression or onset of renal injury in the riskassessment categories described herein, may be adjusted up or down, or have a greater overlap between categories, than those levels and ranges identified here, and may be determined or modified, such as by the attending health care professional, in view of a particular subject’s physiological and / or physical needs, and the subject’s treatment tolerances.

[0035] As the adaptive negative pressure therapy begins to have a significant effect on the subjects urinary oxygen levels, as evidenced by observing a deceleration and eventual reversal of low urinary oxygen levels, the dose of negative pressure treatment may be reverted to a standard dose, and continued at a dose from to prior levels, and eventually back to the standard dose of treatment until no further treatment is warranted. As described below in the detailed description of various embodiments of the present invention illustrated in the following Figures, the present invention addresses the above-described deficiencies by providing an adaptive therapy that treats impaired kidney function while responding to low urinary oxygen levels encountered during the course of treatment by modifying aspects of the treatment plan in response to and in correlation with changing urinary oxygen levels.DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0036] FIG. 1 is a block diagram illustrating one embodiment of key components of the present invention.

[0037] FIG. 2 is a flowchart illustrating one embodiment of a key process of the present invention for generating an adaptive treatment plan over time correlated with urinary oxygen levels.

[0038] FIG. 3 is a graph illustrating one embodiment of adaptive negative pressure therapy of the present invention administered over time to two different patients during the course of treatment for impaired renal function.

[0039] FIG. 4 is a table illustrating one embodiment of different aspects of an adaptive negative pressure treatment plan of the present invention that are modified to correlate with urinary oxygen levels of two different patients (representing differing degrees of risk of kidney injury at a particular point in time).

[0040] FIG. 5 is a diagram illustrating the location of catheters, sensors and other physical components of one embodiment of a negative pressure therapy system of the present invention.

[0041] FIG. 6 presents an Oxygen Concentration Threshold Analysis.

[0042] FIG. 7 presents Urinary oxygen partial pressure (puO?) measures from bilateral ureteral catheters in a swine cardiac surgery model with cardiopulmonary bypass (CPB) demonstrate animals receiving 15mmHg continuous renal pelvis negative pressure (rpNP) have significantly reduced overall intraoperative low puO2burden (mmHg. min below 40mmHg), a marker for post-cardiac surgery acute kidney injury (CS-AKI) risk. Subanalyses reveal the effect to be significant during the period following CPB (postCPB), a time coincident with low puO2episodes observed in clinical cardiac surgery settings.

[0043] FIG 8 presents Raw urinary oxygen partial pressure (puO2) data is presented for left and right ureteral catheters for all animals in a swine mock cardiac surgery study with cardiopulmonary bypass (CPB), assigned to receive either -15mmHg renal pelvis negative pressure (rpNP Group) or no negative renal pelvis pressure (Control Group). Notable observations include: 1) reduced cumulative degree-duration of low saturation episodes (puO2less than 40mmHg, hatched horizontal line, see Figure 1) in the rpNP compared to the Control Group, 2) the heterogeneity of low saturation episodes, ranging from distinctly bilateral, involving left and right kidneys equivalently (e.g., animal 4, rpNP Group) to distinctly unilateral, involving one kidney only (e.g., right kidney only, animal 1, Control Group), and 3) the generally reduced between-catheter puO2differences (left vs. right) evident in the rpNP Group compared to the Control Group.DETAILED DESCRIPTION OF THE INVENTION

[0044] The following examples present a description of various specific aspects of the intended invention, and are not presented to limit the intended invention in any way.

[0045] In the following description, for purposes of explanation, specific numbers, materials and configurations are set forth in order to provide a thorough understanding of the invention. It will be apparent, however, to one having ordinary skill in the art that the inventionmay be practiced without these specific details. In some instances, well-known features may be omitted or simplified so as not to obscure the present invention. Furthermore, reference in the specification to phrases such as “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the invention. The appearances of phrases such as “in one embodiment” in various places in the specification are not necessarily all referring to the same embodiment.

[0046] Turning to FIG. 1, block diagram 100 illustrates one embodiment of key components of the present invention. While a physician 102 makes the final determination with respect to the details of a particular adaptive treatment plan 105 administered to a patient 101, the system 110 of the present invention facilitates the ultimate decisions made by the physician 102, including the iterative generation over time of an adaptive treatment plan 105 (via Treatment Plan Generator 150).

[0047] The components of system 110 may be implemented in any combination of hardware and / or software, and functionality of the components may be combined, divided or otherwise allocated differently than shown in FIG. 1, without departing from the spirit of the present invention. In the embodiment illustrated in FIG. 1, system 110 includes standard computer hardware 115, such as a server, desktop or laptop computer with one or more CPUs and an operating system and various peripheral memory, storage and I / O devices. Engineering tradeoffs may dictate the use of mobile or other computing devices and peripherals.

[0048] In this embodiment, the remaining components of system 110 are implemented in software, and embodied in permanent or transitory physical memory of computer hardware 115 (e g., stored as software instructions and / or data). Such software is interpreted, compiled, executed or otherwise processed by CPUs, GPUs and / or other physical processing units of computer hardware 115.|0049] In the context of negative pressure treatment for a patient 101 with impaired renal function, system 110 includes a system controller 120 which manages the overall process of receiving data 108 (including urinary oxygen levels) collected from patient 101 at various pointsin time (e.g., in between treatments and / or individual treatment sessions), and iteratively generating adaptive treatment plans 105 during each “treatment period.”|0050] Treatment periods differ in duration depending upon the type of negative pressure treatment being performed. For example, a treatment may involve one or more “treatment sessions” (e.g., weekly, daily or multiple times per day), each of which may last for minutes or hours at a time. After each treatment of one or more sessions, a subsequent treatment may occur after a specified (predetermined or data-based) period of time, during which data 108 are collected for the next iteration - i.e., regenerating an adaptive treatment plan 105 based upon urinary oxygen levels as well as other data. As discussed in greater detail below, this process continues until data 108 indicate that no further treatment is warranted.[00511 System 110 stores collected data levels in database 125, which includes current and historical data for each patient 101 (including urinary oxygen levels from oxygen sensors and, in other embodiments, sodium levels from sodium sensors, and data from other sensors), as well as demographic data, treatment history and other relevant data. Patient Data Manager 128 manages the collection and processing of data 108, which is obtained by medical practitioners via various manual and automated means, including sensors, in-person evaluation of symptoms and diagnostic techniques, serology, collection and analysis of fluids, imaging and others (e.g., stress tests, sweat tests, spectroscopy, etc.).

[0052] During each iteration, Treatment Plan Generator 150 regenerates a treatment plan 105 and / or modifies a prior treatment plan 105 based upon collected data 108 and, in one embodiment, correlated with urinary oxygen levels. In another embodiment, Treatment Plan Generator 150 employs machine learning techniques to train a neural network to correlate specific urinary oxygen levels to particular aspects of treatment plan 105, as discussed in greater detail below. Once trained, Treatment Plan Generator 150 effectively classifies urinary oxygen levels into categories and values of different aspects of a treatment plan 105, such as the negative pressure treatment plan components discussed below with respect to FIG. 4. While physician 102 may override or otherwise modify the treatment plan 105 generated by Treatment Plan Generator 150, these “recommendations” greatly facilitate what is otherwise a purely manual process.

[0053] As explained in greater detail below, Treatment Plan Generator 150 generates an “adaptive” treatment plan 105 by regenerating its recommended treatment plan 105 at multiple points in time (time periods) between which physician 102 administers a treatment plan 105 consisting of one or more sessions. In one embodiment, after each treatment, current data 108 is obtained from patient 101, and Treatment Plan Generator 150 generates an updated (adaptive) recommended treatment plan 105 to be administered by physician 102 during the upcoming time period.

[0054] In one embodiment, physician 102 administers a negative pressure treatment plan 105 for a patient 101 experiencing a particular stage of chronic kidney disease (CKD). In this embodiment, explained in greater detail below, negative pressure treatment plan 105 includes a general category or type of therapy (e.g., acute, sub-acute or chronic). For example, an acute therapy is typically administered in the hospital after a discrete event, such as heart failure. A subacute therapy is employed for a persistent, but less severe, condition, and is administered, for example, at home via a wearable system. Finally, a chronic condition is treated by a longer-term therapy, such as an implantable negative-pressure device that administers negative pressure therapy at various times over a relatively long period.

[0055] Each treatment plan 105 involves one or more sessions of negative pressure therapy, each of which may differ in various respects. For example, treatment plans 105 may differ in the “magnitude” of negative pressure applied (e.g., -20 mmHg) and / or the “mode” in which that negative pressure is applied (e.g., pulsatile, continuous, sinuous wave, etc.). Moreover, the “duration” of each session (e.g., 6 hours), as well as the “frequency” of sessions (e.g., daily) may also differ among treatment plans 105, as explained in greater detail below with respect to FIG. 4. In one embodiment, during each iteration, Treatment Plan Generator 150 generates these component details by correlating them with the degree of risk of kidney injury, which is represented by specific urinary oxygen levels collected during the most recent iteration (or, in other embodiments, during one or more prior iterations).

[0056] Turning to FIG. 2, flowchart 200 illustrates one embodiment of a key process of the present invention for generating an adaptive treatment plan 105 over time. As this processiterates over time, we can assume it starts at time “To” before any treatments have occurred. Beginning with step 202, system 110 collects current and historical patient data 108, including data obtained from oxygen and other sensors (such as urinary oxygen levels) as well as data obtained with the assistance of medical practitioners (symptoms, diagnostics, serology, fluids, imaging, etc ). In future iterations, data relating to prior treatments is also included.

[0057] In step 205, system 110 determines whether the patient’s current condition falls within a “treatable range” warranting treatment. In one embodiment, system 110 determines whether it is too early for such treatment to be effective or too late (e.g., if the patient’s impaired renal function has progressed so far that treatment is not likely to make a difference).

[0058] If the patient is not within a treatable range, then system 110 determines, in step 215, whether treatment has been completed. For example, if system 110 determines at time To that the patient’s renal function is not yet sufficiently impaired to benefit from negative pressure therapy, then treatment is not completed, as it has yet to be initiated. In that case, processing returns to step 202 and process 200 remains at time period To. In one embodiment, step 202 is repeated after a predetermined period of time. In other embodiments (not shown), process 200 may be suspended and reinitiated only after the patient’s condition warrants resumption. In other embodiments, even if process 200 is at a subsequent time period (e.g., time period T3 after one or more treatments have been performed), a pause in treatments may be justified before step 202 resumes.

[0059] If, however, system 110 determines in step 215 that all treatments have been completed (e.g., after time period T5 in one embodiment), then process 200 terminates. Alternatively, system 110 may determine that the patient has benefitted sufficiently from one or more negative pressure treatments (e.g., at Ti , T2, and T3) to warrant discontinuing further negative pressure therapy. Conversely, system 110 may determine that the patient’ s impaired renal function has progressed to the point where no further negative pressure therapy will prevent the inevitable progression of the patient’s disease, in which case no further therapy is warranted.

[0060] If system 110 determines in step 205 that the patient falls within a treatable range, then process 200 continues to step 210 for the purpose of generating (or regenerating - e.g., insubsequent time periods after therapy has begun) a treatment plan. Treatment Plan Generator 150 then generates a treatment plan 105 to be performed by physician 102.

[0061] After each treatment (i.e., one or more sessions of negative pressure therapy) has been performed, process 200 returns to step 202 for a subsequent iteration (e.g., moving to the next time period, from To to Ti, Ti to T2, and so forth). As noted above, Treatment Plan Generator 150 then regenerates the patient’s “adaptive” treatment plan during each subsequent time period - i.e., correlating particular aspects of that treatment plan to specific urinary oxygen levels.

[0062] In this manner, these adaptive treatments are designed to decelerate or reverse the progression of the patient’s impaired renal function or disease, in particular taking into account the effects of each treatment on the patient’s condition and, in particular, on urinary oxygen levels.Example 1 - Porcine Study

[0063] Applicants performed a scientific study on female swine to demonstrate the benefits of one embodiment of a negative pressure therapy treatment plan of the present invention - in particular the benefit of decelerating and reversing decreasing urinary oxygen levels in connection with cardiopulmonary bypass (CPB) surgery. In short, the study revealed significant differences between treatment and control groups at different hypoxia threshold levels. The treatment group experienced less time under each hypoxia threshold than did the control group, and this difference between the two groups increased at lower hypoxia thresholds.Method

[0064] Twelve female swine (50 - 65 kgs) were anesthetized and placed in a supine position for the placement of JuxtaFlow® catheters. Transurethral cystoscopy was performed on each animal to guide insertion of an 0.032” guidewire into each ureter. JuxtaFlow® catheters were then advanced over the wire to the ureter-renal junction of both kidneys. Placement in the renal pelvis was confirmed using fluoroscopy.

[0065] Following placement of the JuxtaFlow® catheters, each animal had a transurethral Foley catheter inserted into the urinary bladder. The JuxtaFlow® catheters were secured to the Foley catheter.

[0066] A needle port was connected between both JuxtaFlow® catheters and the JuxtaFlow® manifold. A urine 02 sensor was inserted through each port into the lumen of the catheter to allow continuous measurement of the partial pressure of oxygen in the urine produced by both kidneys independently.

[0067] An arterial sheath was placed in the femoral artery at the groin for temporary blood pressure monitoring without disrupting the JuxtaFlow® or Foley catheters.|0068] The animals were then randomized to treatment with the JuxtaFlow® Renal Assist Device (RAD) or control. The six animals that were assigned to the treatment group had their catheters connected to the JuxtaFlow® pump and treatment with -15 mmHg was initiated. The six animals that were assigned to the control group had their JuxtaFlow® catheters terminate in unsealed suction canisters.

[0069] The experiment included a two-hour baseline period, a one hour of cardiopulmonary bypass (CPB) followed by a two-hour post-surgery observation. During the initial two-hour baseline period, animals were monitored for vitals, blood and urine collections.

[0070] Animals were then placed onto their right side to prepare them for CPB. Intravenous paralytic was administered, then an incision was made between the left 3rd and 4th rib. The ribs were gently spread until the heart and lung were exposed. A sheath was placed in the internal mammary artery for more accurate blood pressure monitoring and secured with suture. The lung was pushed aside with a wet lap sponge to expose the pericardial sac. Once the heart was exposed, two purse strings were placed on the aorta using a pledgeted suture. The superior vena cava was then exposed, and one purse string was placed using a non-pledgeted suture. Topical lidocaine was used to prevent fibrillation and heparin anticoagulant administered IV in preparation for vascular cannulation. After bleeding times were achieved, a 24 Fr arterial cannula was placed in the middle of the aortic purse string and secured down with a rummel tourniquet and the pursestring. A 40 Fr venous cannula was placed in the superior vena cava and secured down. Extra suture ties were used to secure the rummels to the cannulas and secured to the skin until they were hooked up to the bypass pump. The bypass tubing was set up, flushed, and secured to the table. The tubing was connected to the cannulas and secured to the animal.

[0071] CPB was initiated and the heart was drained of blood and stopped for 1 hour during aortic cross clamp. During the CPB period, anesthesia and gas exchange were managed via the CPB circuit.

[0072] After successful separation from CPB, the venous cannula was removed, and the site closed using the purse string. The remaining blood was returned to the animal and arterial cannula removed and closed. The lung was returned to its original position and oxygen was recruited by sighing the animal. Heparin anti coagulation was then reversed using IV protamine. A chest tube was placed, and the incision closed.

[0073] The animal was returned to supine position and allowed to remain under anesthesia for the duration of the 2-hour post-CPB period.

[0074] Once the Post CPB period was completed, the animal was euthanized and the kidneys were harvested for gross examination.Results

[0075] Cardiopulmonary bypass was associated with a modest (5%) reduction in the creatinine clearance in the control group. Treatment with JuxtaFlow® RAD was associated with a modest (3%) increase during the bypass run. During the recovery period the creatinine clearance returned to pre-surgical values.

[0076] Urine output increased in both treatment and control groups during the bypass procedure. Treatment with the JuxtaFlow® RAD had a 20% greater urine output than the control.

[0077] Hematocrit values are known to fluctuate during bypass procedures; however, no differences in this trend were noted between treatment and control.

[0078] There were significant differences in the urinary oxygen levels between treatment and control. When using a hypoxia threshold of below 40 mmHg, the treatment group experienced 52% less time under the hypoxia threshold than control. When a lower hypoxia threshold of 35 mmHg was used, the treatment group experienced 80% less time under the threshold than control. When an extreme hypoxia threshold of 30 mmHg was used, only the control group had any time under the threshold.

[0079] Chi square analysis indicates that the treatment group had a greater proportion of urinary oxygen levels where both kidneys were above the hypoxia threshold (40mmHg) than control (chi sq 82.72, p<0.001) and a smaller proportion of urinary oxygen levels where both kidneys were below the hypoxia threshold than control (chi sq 142.62, p<0.001).

[0080] The present invention improves upon previous systems by providing a means of targeting and adapting therapy based upon in-line, intermittent as well as continuous, assessment of urine oxygen and other sensors. In one embodiment, the present invention incorporates the use of in-line oxygen sensors to determine the dose of negative pressure treatment being delivered to the collecting system. As demand outpaces supply of oxygen, the partial pressure of oxygen in the urine decreases.

[0081] The experiment described above suggests that the energy consumption from active reabsorption of solutes is the primary driver of the hypoxia leading to acute kidney injury. In a prior clinical study of JuxtaFlow® RAD (VOID-HF), 24 hours of treatment was associated with a doubling of sodium excretion, relative to control. In a prior animal model, the magnitude of negative pressure was associated with a dose response on the improvement of creatinine clearance. Therefore, negative pressure delivered to the collecting system of the kidney can improve oxygen delivery to the kidney and dramatically reduce the oxygen consumption by the kidney in a dose dependent manner - thus protecting the kidney from hypoxic injury.

[0082] Turning to FIG. 3, graph 300 illustrates one embodiment of the present invention in which urinary oxygen levels (in this case, partial pressure of oxygen in urine) 302 are monitored over time (ranging roughly from 60 mmHg down to 20 mmHg), and negative pressure therapy is administered to the patient’s renal pelvis on a dose-dependent basis correlated to particular levelsof urinary oxygen levels. Each treatment (of one or more sessions) is administered iteratively over the course of subsequent time periods 304 (starting with time To, following by Ti, T2, etc.).

[0083] In this embodiment, each treatment differs only in the magnitude of negative pressure applied - e.g., -15 mmHg 310 (a standard dose), -20 mmHg 315 (an increased dose) or - 25 mmHg 320 (a maximum dose). The increased dose 315 of negative pressure is applied when a patient’s urinary oxygen level 302 drops below an initial threshold of “low oxygen” 312 (in this case, 40 mmHg). The maximum dose 320 is applied when the patient’s urinary oxygen level 302 drops below a secondary threshold of “very low oxygen” 318 (in this case, 30 mmHg). In other embodiments, discussed with respect to FIG. 4 below, other aspects of a negative pressure treatment plan (beyond just the magnitude of negative pressure) are correlated with specific urinary oxygen levels (and ranges thereof) 302.

[0084] Graph 300 illustrates the monitored urinary oxygen levels 302 at subsequent time periods 304 for two different patients - patient A 330 and patient B 340. At time To, a standard dose 310 of negative pressure therapy is administered to patient A 330 who has a urinary oxygen level of 57 mmHg and patient B 340 who has a urinary oxygen level of 60 mmHg (both well above the initial low oxygen threshold 312 of 40 mmHg).

[0085] At time Ti, however, the urinary oxygen level 302 of patient B 340 drops to 38 mmHg, which is now below the initial low oxygen threshold 312 of 40 mmHg, resulting in a change to the increased dose 315 of negative pressure. The urinary oxygen level 302 of patient A 330 drops only to 50 mmHg, which is still above the initial low oxygen threshold 312 of 40 mmHg, resulting in no change to the standard dose 310 of negative pressure.

[0086] At time T2, the urinary oxygen level 302 of patient B 340 drops to 27 mmHg, which is now below the very low oxygen threshold 318 of 30 mmHg, resulting in another change to the maximum dose 320 of negative pressure. The urinary oxygen level 302 of patient A 330 drops only to 45 mmHg, which is still above the initial low oxygen threshold 312 of 40 mmHg, resulting in no change to the standard dose 310 of negative pressure.

[0087] By time T3, the urinary oxygen levels 302 of both patient A 330 and patient B 340 are now beginning to rise, indicating that the negative pressure therapy is having a positive effect, decelerating and even reversing the decline in urinary oxygen levels 302. No change in treatment results, however, as the urinary oxygen level of patient A 330 has risen only to 46 mmHg, still above the initial low oxygen threshold 312 of 40 mmHg, warranting no change to the standard dose 310 of negative pressure. Similarly, the urinary oxygen level of patient B 340 has risen only to 29 mmHg, still below the very low oxygen threshold 318 of 30 mmHg, warranting no change from the maximum dose 320 of negative pressure.

[0088] By time T4, the urinary oxygen levels 302 of both patient A 330 and patient B 340 continue to rise, indicating that the negative pressure therapy is in fact reversing the decline in urinary oxygen levels 302. The urinary oxygen level of patient A 330 has now risen back to 50 mmHg (where it was at time Ti), now comfortably above the initial low oxygen threshold 312 of 40 mmHg, warranting no change to the standard dose 310 of negative pressure. The urinary oxygen level of patient B 340 has now risen to 32 mmHg, above the very low oxygen threshold 318 of 30 mmHg, warranting a change back to the merely increased dose 315 of negative pressure.

[0089] The embodiment illustrated by graph 300 of FIG. 3 illustrates that, by correlating the “dose” of negative pressure therapy to particular ranges of urinary oxygen levels 302, the present invention enables a deceleration and then reversal of declining low oxygen levels (which had resulted from a patient’s impaired renal function, a discrete event such as a heart attack or cardiac surgery, or kidney diseases such as AKI or CKD), and an “adaptive” treatment plan that, iteratively over time, provides an appropriate “dose” of therapy necessary to address the patient’s condition over time. Without such an iterative adaptive approach to therapy, the patient could be at greater risk of kidney injury (e.g., due to an insufficient dose of therapy relative to renal oxygen supply and demand) or risk of “over-treatment” effects (e.g., administering therapy at a dose that provides no additional benefit to the patient relative to their therapeutic needs may increase risk of undue metabolic demand on the kidney).

[0090] In other embodiments, the relationship between urinary oxygen levels and magnitude of negative pressure applied to the renal pelvis (or other aspects of negative pressuretherapy) may be linear, curvilinear, exponential, or any number of different relationships. In all of these cases, the treatment plan is adaptive in that it iteratively modifies aspects of the therapy in correlation with the relative risk of kidney injury, as represented by changing urinary oxygen levels.

[0091] Turning to FIG. 4, table 400 illustrates one embodiment of different aspects of an adaptive negative pressure treatment plan 410 of the present invention. These components of treatment plan 410 are modified (by Treatment Plan Generator 150) to correlate more precisely with the patient’s current level of risk of kidney injury, as reflected by changing urinary oxygen levels.

[0092] Table 400 of FIG. 4 illustrates one embodiment of different aspects of an adaptive negative pressure treatment plan of the present invention that are modified to correlate with urinary oxygen levels of two different patients (representing differing degrees of risk of kidney injury at a given point in time). Treatment Plan 410 includes multiple different categories of negative pressure therapy, including the magnitude 418 of negative pressure applied, the mode 416 of therapy (e.g., “on” for 6 hours and then “off’ for 1 hour), the duration 414 of an individual therapy session and the frequency 412 of sessions over the course of a single treatment (which may be administered iteratively over time - e.g., at time To, then Ti, etc.).

[0093] In this embodiment, a standard treatment plan 420 includes particular values associated with each of these categories. For example, if a patient’s urinary oxygen levels equal or exceed 50 mmHg, then -20 mmHg of negative pressure is applied to the patient’s renal pelvis for a period of 72 hours (e g., 10 iterations of therapy each consisting of 6 hours on, followed by 1 hour off) for a single session. In other embodiments, this standard treatment plan 420 consists of a different type of therapy entirely (as opposed to negative pressure therapy), and includes other categories of treatment (or perhaps only a subset of these listed categories), as well as a different magnitude, mode and duration of negative pressure for a different frequency of sessions during a given iteration of therapy at a particular point in time.

[0094] As alluded to above, therapy is initiated on a particular patient, patient A 430 (e.g., at time To), employing this standard treatment plan 420. However, in a subsequent iteration (e.g.,time Ti), the urinary oxygen levels of patient A 430 decline (e.g., to 35 mmHg). At that point, a moderately more aggressive treatment plan is administered. In this embodiment, the magnitude 418 of negative pressure is not increased, which remains at -20 mmHg, as does the mode 416 of treatment (6 hours on, followed by 1 hour off). While still limited to a single session of treatment, the duration 414 of this session is increased from 72 to 96 hours.

[0095] By calibrating these particular aspects of treatment plan 410 to the changing urinary oxygen levels of patient A 430 over time, Treatment Plan Generator 150 can more accurately employ a treatment plan 410 at any given point in time that is most appropriate to the changing risk of kidney injury reflected by these changing urinary oxygen levels. In another embodiment, Treatment Plan Generator 150 employs machine learning to train (via extensive data samples) a neural network to classify more precisely the different aspects of treatment plan 410 to different patterns of changing urinary oxygen levels. In other embodiments, different ranges of urinary oxygen levels are employed to more or less precisely calibrate the different aspects of treatment plan 410.

[0096] Therapy is also initiated at time To on another patient, patient B 440, who also starts with the standard treatment plan 420. However, in a subsequent iteration (e.g., time Ti), the urinary oxygen levels of patient B 440 decline more rapidly than did those of patient A 430 (e.g., down to 25 mmHg rather than 35 mmHg). At that point, a significantly more aggressive treatment plan is administered. In this embodiment, the magnitude 418 of negative pressure is increased in a different mode 416 for a period of 8 hours (4 hours at -20 mmHg, followed by another 4 hours at -25 mmHg). While still limited to a single session of treatment, the duration 414 of this session is increased from 72 to 120 hours.

[0097] Because the urinary oxygen levels of patient B 440 are declining more rapidly than those of patient A 430, a significantly more aggressive treatment plan 410 is warranted. In this manner, patient B 440 is protected against a greater risk of kidney injury during the course of treatment. As noted above, urinary oxygen levels ebb and flow over time for a variety of reasons relating to a patient’s condition. The adaptive treatment plan of the present invention accommodates these changes and applies the appropriate “dose” of treatment at the appropriatetime - i.e., by correlating the detailed variables of the treatment plan to the current degree of risk evidenced by the patient’s urinary oxygen levels and their temporality (among other factors).

[0098] In other embodiments, the devices employed to administer treatment plan 410 also reflect the nature of the patient’s impaired renal condition which led to the need for treatment. For example, the JuxtaFlow® device (inserting a ureteral catheter with an external bedside pump) is employed in “acute” (in hospital) scenarios, such as heart failure. Such scenarios are relatively severe, but short term, and may include patients with no prior kidney-related symptoms. Once released from the hospital, further treatment may not be required.

[0099] In other scenarios, such as a “sub-acute” scenario, a different device may be more appropriate. For example, if the patient’s condition is less severe (e.g., semi-urgent), but more persistent, then they may continue treatment outside of the hospital for an extended period of time. In this scenario, a wearable device (such as a nephrostomy-deployed catheter, inserted percutaneously into the kidney, with an external wearable pump and bag) may be more appropriate. It could be worn for long periods of time (activated and deactivated as appropriate), and removed in between long sessions.

[0100] Finally, for “chronic” scenarios, an implantable device may be appropriate for more severe chronic conditions over relatively long periods of time (e.g., to prevent lifelong dialysis or even death). In this scenario, a fully implantable catheter and pump system (i.e., a “pacemaker for the kidney”) may be employed.

[0101] Turning to FIG. 5, diagram 500 illustrates different locations of oxygen and other sensors in these and other scenarios. Diagram 500 shows the patient’s kidneys 505, ureters 510 and bladder 512. The urinary catheters 515 are shown for the application of negative pressure into the patient’s renal pelvis.

[0102] Oxygen and other sensors 550 (including, for example, sodium sensors) can be deployed in various locations inside and outside the patient’s body. The selected location may depend on a variety of factors, including the efficacy of the sensor in measuring urinary oxygenlevels in different parts of the anatomy, as well as the ease and safety of inserting and removing them from different locations.

[0103] In one embodiment, sensors 550 are deployed internally to (in-line) or externally to catheters (outer surface) 515, which in this example is shown in the renal pelvis. In another embodiment, sensors 550 are deployed at catheter connection ports 516 where catheters 515 connect to connection tubing 518 used to transport negative pressure into the patient’s renal pelvis through catheters 515, as well as deliver urine from the patient’s bladder 512 back to sample collection chamber 520 and fluid collection container 530 (ultimately connecting to external pump 540).

[0104] In other embodiments, sensors 550 are deployed in-line inside connection tubing 518, inside sample collection chamber 520 or fluid collection container 530, or even within pump 540. In still other embodiments, sensors 550 are deployed in more than one of these locations (e.g., to take multiple different measurements at different locations to be used to calculate the most representative value or values. Moreover, the relative locations of these different components (sample collection chamber 520, fluid collection container 530 and pump 540) may vary, providing additional potential locations for deployment of sensors 550.

[0105] Finally, it should be noted that different devices (e.g., for acute, sub-acute and chronic scenarios) warrant different locations for delivering negative pressure into the patient’s renal pelvis, and thus provide different potential locations for deployment of sensors 550. In any event, the result is similar, in that iterative measurements of a patient’s urinary oxygen levels are enabled over time, and such urinary oxygen levels are correlated with different aspects of an adaptive treatment plan to provide the appropriate “dose” of treatment warranted by the relative risk of kidney injury reflected by such urinary oxygen levels. Use of additional sensors (e.g., a sodium sensor) or other measurements in determining the specific aspects of an adaptive treatment plan remain within the spirit of the present invention.

[0106] Background: Acute kidney injury commonly complicates cardiac surgery (CS- AKI) and is associated with low intraoperative urine oxygen partial pressure (puO2). Continuous renal pelvis negative pressure (rpNP) may provide renoprotection in patients with cardiorenalsyndrome but its relationship with CS-AKI is unknown. Therefore, using low puO2burden as a CS-AKI biomarker, in a swine cardiopulmonary bypass (CPB) model we assessed the renoprotective potential of continuous intraoperative rpNP treatment.

[0107] Methods: With IACUC approval, eight pigs with bilateral ureteral catheters received either continuous -15 mm Hg (rpNP group) or no negative pressure (control group). After a baseline period, CPB with heparin was initiated per left lateral thoracotomy including crossclamp and cardioplegia. CPB separation was followed by protamine and chest closure. Kidney function measures included urine output, creatinine clearance, sodium excretion, and q60sec left and right ureteral catheter puO2. Since low puO2consensus CS-AKI risk criteria are not available, a degreeduration threshold (mmHg. min below 40mmHg) was developed from unbiased analysis of all collected primary data and used to compare low puO2burden between rpNP and control groups; p< 0.05 considered significant.

[0109] Results: Procedural measures were similar between groups (rpNP -4, control-4), including hemodynamic, CPB perfusion, lowest hematocrit, serum electrolytes, IL6, and blood gas variables. Low puO2episodes were most frequent after CPB. The rpNP group had a significantly reduced low puO2burden vs. the control group (14.6 vs. 41.7mmHg.min per catheter; p< 0.02); episodes were shorter (average 30 vs. 57min) and less extreme (nadir puO2average 36 vs. 33mmHg). Increased renal function trends were also evident in rpNP compared to control animals (urine output, creatinine clearance, sodium excretion).

[0109] Conclusions: In a swine mock cardiac surgery model, rpNP treatment significantly reduced low puO2burden, a biomarker for CS-AKI risk. Such intriguing findings support more investigation into the renoprotective potential of rpNP treatment in cardiac surgery patients.Introduction

[0110] Cardiac surgery-associated acute kidney injury (CS-AKI) complicates 30 to 50% of procedures (1-5), and is associated with longer postoperative hospital stays, more readmissions, higher mortality and cost, and increased long term kidney disease. (6-11) Despite considerableresearch efforts, advances in prevention and therapy of CS-AKI and other types of AKI have been limited. (12) Therefore, novel interventions with renoprotection potential are of interest.

[0111] In the setting of cardiorenal syndrome Type 1 (CRS1; acute heart failure-related AKI) technologies that target AKI pathophysiology, so called “renal assist devices”, have shown promise. (13) One recent innovation involves continuous negative pressure (e.g., 15mmHg) delivered through ureteral catheters to each renal pelvis (rpNP). (14, 15) Potential benefits of rpNP in swine and humans CRS1 studies include increased glomerular filtration, sodium clearance and urine output that may be due, at least in part, to improved transglomerular gradients (14, 15). However, despite potential overlap between CRS1- and CS-AKI pathophysiology (e.g., renal arterial hypoperfusion, intra-renal venous congestion, and interstitial overload), the value of such renal assist devices in cardiac surgery (and feasibility) remains unexplored (16).

[0112] Effects of rpNP on CS-AKI and renal function during cardiac surgery are unknown. Therefore, in a mock-cardiac surgery swine cardiopulmonary bypass (CPB) model, with and without continuous rpNP, we measured renal function and used burden of low urine oxygen partial pressure (puO2), a biomarker reflecting CS-AKI risk, (17-19) (20) (21) to assess the renoprotective potential of rpNP in the setting of cardiac surgery with CPB.Materials and Methods

[0113] With IACUC approval, eight 50-65kg female Yorkshire pigs had identical mock cardiac surgery procedures involving bilateral ureteral catheter placement and urine oxygen partial pressure monitoring, left thoracotomy, CPB with aortic cross-clamping and cardioplegia administration. All procedures included three data collection periods; baseline (120minutes), cardiopulmonary bypass (CPB; estimated 120minutes), and post-CPB (120minutes). All procedures were conducted at Synchrony Labs, LLC located in Durham, NC, and animals were alternately allocated to one of two study protocol groups, “rpNP Group” or “Control Group”.Study ProtocolThe pre-cardiopulmonary bypass (CPB) phase (including baseline period)

[0114] Each animal received intramuscular tiletamine and zolazepam (4mg / kg), followed by induction of general endotracheal anesthesia (inhaled isoflurane 1-3% with intravenous propofol titrated to maintain immobility) and anesthesia maintenance (inhaled isoflurane 1-3%, titrated to maintain immobility, and blood pressure between 60-80mHg). A left femoral artery catheter was inserted, urinary tract catheters placed (bilateral renal pelvis ureteral catheters and a urinary bladder Foley catheter, details below) and urine collection initiated. Mild continuous bilateral rpNP was achieved per the ureteral catheters in the rpNP Group (-15 mm Hg) and puO2monitoring of urine exiting each ureteral catheter was established, while Control catheters were similarly connected and puO2monitoring initiated but without suction (see below). The baseline period for data recording was then initiated (120minute).

[0115] When baseline data recording was complete, animals were moved from supine to right lateral decubitus position, succinyl choline was administered intravenously (0.5mg / kg) and a left lateral thoracotomy performed. A left internal mammary artery catheter was then placed for ongoing monitoring and blood draws, and intravenous heparin administered (initial bolus 300units / kg and supplemental boluses 50 units / kg to achieve a target activated clotting time exceeding 300 seconds). Once satisfactory anticoagulation was achieved and descending aorta and right atrial cannulas placed (24 and 40 Fr, respectively), CPB was initiated, and pulmonary ventilation discontinued.The CPB Period[0116| Mild hypothermic CPB was employed in a standard fashion conducted by certified perfusionists. Briefly, target CPB flow rate was 2.2L / min / m2and temperature 34°C, with volatile anesthesia delivery (isoflurane 1-3%) titrated to maintain immobility and arterial blood pressure between 60-80mmHg. Desired arterial pCh and pCCh values were between 200-300 and 35-45 mmHg, respectively, achieved by air-oxygen mixture and fresh gas flow adjustments, respectively. CPB technology included the Stockert (Munich, Germany) Heart-Lung machine (Sill Roller Pump, 24V, max 160w), and LivaNova (London, UK) Perfusion pack, including a DHF 02 hemoconcentrator, Continuous Autotransfusion System, Haemonetics Cell Saver Collection Reservoir, Sechrist 3500 Low Flow Air-Oxygen Mixer, and Stockert DesignationHeater-Cooler. CPB monitoring was per routine perfusion standards, including pump flow, Ch / air flows and isoflurane setting, blood pressure, blood temperature and continuous arterial and venous oxygen saturation. During CPB, cardiac arrest was achieved with ascending aortic cross clamp placement and antegrade cardioplegia administration (500 - 1000 ml of 4°C IL lactated Ringer's solution, with 20 mEq potassium chloride, 32 mEq magnesium chloride, 10g mannitol 20%, 6.5 mEq sodium bicarbonate 8.4%, and 100 mg lidocaine). When cardiac standstill occurred cardioplegia was discontinued and the aortic crossclamp was removed, and after an approximately lOminute rewarming and reperfusion period pulmonary ventilation was re-initiated, and separation from CPB achieved. The CPB period was anticipated to last approximately 120minutes.Post CPB Period

[0117] Separation from CPB marked the beginning of the post-CPB period (120minutes). During this phase anesthesia was maintained with inhaled isoflurane (1-2%), aortic and right atrial cannulas were removed, protamine was administered intravenously, the thoracotomy incision was closed and a chest tube inserted. Finally, the animal was returned to supine position and euthanized, and both kidneys were harvested for examination of ureteral catheter placement and gross renal inspection.Ureteral and Foley Catheter Placement and Usage (Treatment v.s. Control Group)

[0118] Bilateral renal pelvis ureteral catheter placement was guided by cystoscopy and fluoroscopy, followed by Foley urinary bladder catheter placement in the standard fashion, combined procedures taking 20-30 minutes. (22) Briefly, with cystoscopic guidance 0.032inch guidewires were placed in each ureter. A ureteral catheter with a pre-formed coil (JuxtaFlow® catheter; 3ive Labs, LLC., Roswell, GA), (14, 15) was threaded over each guidewire and advanced to the respective ureter-renal pelvis junction using fluoroscopy. Wire removal caused the helical coil to re-form and anchor in the renal pelvis allowing negative pressure application without collapse; a radiopaque marker just proximal to the coil confirmed placement. Finally, ureteral catheters were secured to the Foley catheter for stability.

[0119] For purposes of the current study, a Luer lock primed with urine was inserted at the end of each collection tubing to permit continuous Ch partial pressure assessment from the stream exiting each ureteral catheter (see below). For each animal, both ureteral catheters were connected to a single manifold for combined urine collection. Only the rpNP Group ureteral catheters received controlled continuous 15 mm Hg negative pressure, urine drainage in Control Group animals was passive. Foley catheter urine collection was separate and passive. At the end of the study, direct confirmation of correct renal pelvis placement of each ureteral catheter was confirmed with kidney necropsy.Urine oxygen partial pressure (puCh.) monitoring

[0120] P11O2 monitoring was conducted using the OxyLite™ Pro monitoring system(Oxford Optronix, Oxford, UK). For each animal, left and right ureteral catheters were connected to separate NX-L.AS-I / O / E sensors (pO?. Large Area Sensor) and recorded every' 60 seconds through 2 channels of the OxyLite system on the LabChart program throughout the study. For study purposes, values were documented every 5 minutes.Standard additional monitoring

[0121] As outlined below, data recording resembled perioperative monitoring regimens during cardiac surgical procedures, with added measures of renal function. In addition to point of care assessments, laboratory analysis of samples was at two sites; blood and urine analysis were conducted by Quality Veterinary Labs (Davis, CA), and IL-6 analysis was performed by Creative Proteomics (Shirley, NY).

[0122] Blood pressure, heart rate and core temperature monitoring were continuous for each animal. Point of care arterial blood gas and hemoglobin assessments occurred at baseline, early CPB, late CPB and postCPB. Cumulative urine output (combined ureteral and Foley catheters), and urine protein and hematuria assessments were scheduled for the end of baseline, CPB, and postCPB periods.

[0123] Glomerular fdtration rate was calculated using Creatinine Clearance for each study period (baseline, CPB, and postCPB), using plasma and urine values of creatinine and combinedurine output (ureteral and Foley catheters). Urinary protein and red blood cell levels were determined for each animal (baseline, CPB, and postCPB), and IL6 clearance was estimated for each animal using urine and plasma IL6 levels and urine flow.Statistical Analysis|O124| Standard univariate comparisons for continuous variables including animal, procedural and outcome characteristics and standard renal function observations were made between groups using Student’s t-tests. Where appropriate, summary data was per animal (not counted separately for each catheter), but no statistical adjustment was made for correlation of data from each of two ureteral catheters in the same animal.|0125| Regarding the primary analysis, while the strong relationship of low puO2with CS- AKI is well established in general, (17-19) (20) (21) in the absence of consensus low puO2criteria to reflect CS-AKI risk a priori sample size calculation was not possible. Notably, even “normal” puO2values (e.g., baseline) could not be anticipated, given the unique features of the CPB swine model, and characteristics of the “urine column”, such as catheter length and selected location for puO2monitoring. An unbiased approach was therefore adopted to develop low puO2criteria from the available study data for group-comparisons. To generate a CS-AKI risk biomarker for the primary analysis, stepwise 5mmHg reductions were modeled for all puO2data to identify a threshold that provided sufficient “risk” data below the threshold to permit statistical comparisons. A degree-duration burden criteria (mmHg. min) was preferred over a nadir puO2approach due to the presumed increased sensitivity of the latter, characterizing desaturation periods by duration as well as depth of low puO2. Using a threshold cutoff below 40 mmHg identified 14.6% of total observations (195 / 1334) as “low”. This included measures from baseline, CPB and postCPB periods, 2.1% (8 / 384), 9.5% (54 / 566), and 34.6% (133 / 384) observations, respectively. Reassuringly, most puO2desaturation datapoints occurred during the postCPB period, consistent with low puO2timing observed in other reports. (23) The primary analysis was conducted by comparison of puO2burden below 40mmHg (mmHg. min) between the rpNP and Control Groups. Statistical significance was set at p <0.05.Results

[0126] Protocol completion was successful for all 8 animals, although CPB durations were longer than anticipated, but similar between groups (rpNP vs. Control Group, average 162 vs. 168min, p=0.72). Broadly, other basic procedural and physiologic measures were as expected, and similar between groups (Table 1), including body weight, blood pressure, heart rate, temperature, hemoglobin, and serum sodium levels.Table 1: Animal, Procedural and Laboratory variablesAbbreviations: CPB - cardiopulmonary bypass, rpNP - renal pelvis negative pressure

[0127] Renal function measures by study period and group are presented in tables 2 and 3. Group differences were limited to trends in urine output flow. Although higher in the rpNP Group at all timepoints, urine output did not significantly differ between groups (Table 3; rpNP vs Control: baseline, 1.97 vs. 1.07, p=0.36; CPB 4.96 vs. 3.95 p=0.71; postCPB 1.62 vs. 0.80 ml / kg / h, p=0.25). Additionally, during all periods ureteral relative to Foley flow was higher in the rpNP Group (Table 2; rpNP vs control: whole study, 91 vs. 71%, p=0.07; baseline 100 vs. 96%, p=0.36; CPB 87 vs 62%, p=0.08; postCPB 100 vs. 97%, p=0.36). Urine flow was greatest during CPB, and primarily ureteral, with apparent Foley catheter recruitment for overflow only, making Foley flow in many cases insufficient for sampling (Table 2).

[0128] Other renal function measures were not significantly different between the rpNP and Control Groups at any timepoint (Table 2). Nonetheless, at all timepoints throughout the study period measures of urine output, creatinine and IL6 clearance and sodium excretion were greater in the rpNP Group, suggesting a trend towards augmented renal function similar to that observed in a swine heart failure model. (14) In contrast, blood urea nitrogen measures were similar between the groups throughout the study period.Table 2: Urinary AssessmentsA. Urine Volume, Source and Collection TimeUrine Volume (ml) Duration (min)Abbreviations: CPB - cardiopulmonary bypass, HPF - high power field, QNS - urine quantity not sufficient, RBC - red blood cell, rpNP - renal pelvis negative pressure.

[0129] Urine protein and urine red cell analyses were separate for ureteral and Foley catheter samples (Table 2). As previously highlighted, Foley catheter sampling was insufficient for analysis in several animals (Table 3).Table 3: Renal Function MeasuresAbbreviations: CPB - cardiopulmonary bypass, IL-6 - interleukin 6, rpNP - renal pelvis negative pressure.

[0130] Relative to CS-AKI risk, the overall burden of low puO2episodes was significantly reduced in the rpNP Group (14.6 vs. 41.7mmHg.min per catheter, p<0.02; Figures 7 & 8); episodes were both shorter (average 30 vs. 57min), and their nadir puO2values higher (average 36 vs. 33mmHg). In sub-analyses by study period, low puO2burden was significantly reduced in therpNP Group only during the postCPB period (11.6 vs.37.6 mmHg. min per catheter, p<0.05; Figure 7).10131] Overall, low puO2episodes were distributed between unilateral and bilateral, and most frequent in the postCPB period with no apparent left / right catheter predilection (left 44, right 56%; Figure 8). There were eighteen total episodes (Control 9, Treatment 9) involving mostly paired declines in the same animal, although six were notably unilateral (Control 3, Treatment 3) including two moderate- severe prolonged postCPB desaturation episodes (Control 1, Treatment 1). By time period, baseline period low puO2episodes were infrequent, brief (<10minutes) and mild (nadir value 36-40mmHg) (3; Treatment group only). During CPB, episodes were more frequent, relatively brief (5-25 minutes) and mild-moderate (Control 5, Treatment 3; nadir value 33-40mmHg) although two Control group CPB episodes were recurrent and became severe (nadir value below 33mmHg) as they extended into the postCPB phase. In the postCPB phase there were 9 episodes (Control 6, Treatment 3), including all severe episodes with longer durations (longer than 35min) and lowest puO2values (nadir value below 33mmHg) (Control 4, Treatment 1).

[0132] In this exploratory study of swine undergoing mock-cardiac surgery with bilateral ureteral catheterization, animals receiving continuous 15mmHg renal pelvis negative pressure had a significantly reduced burden of low puO2(degree-duration less than 40mmHg), episodes were both shorter and less extreme, suggesting a reduced risk for CS-AKI. This effect was particularly notable following CPB, a period when the frequency and severity of low puO2episodes was highest in both groups. Separately, left and right kidney low puO2episodes were often concurrent but, interestingly in terms of CS-AKI pathophysiology, several were notably unilateral. Although no other between-group differences in renal function met significance at any timepoint, variables reflecting renal function (creatinine clearance, sodium excretion and urine output) trended higher in animals receiving continuous rpNP treatment. Urine flow was mostly through ureteral catheters with an apparent ceiling rate beyond which Foley catheter ‘overflow’ occurred.

[0133] No studies have explored the effects of continuous rpNP during cardiac surgery with CPB, relative to CS-AKI risk or renal function. However, studies in other settings have separately characterized the effects of rpNP (14, 15) and CPB (24, 25) on renal function. Broadly,standard measures and CPB-related factors from the current study were similar to other hypothermic CPB studies (Table 1 & 3), (24-26) validating the model, and reducing concern over effects on basic renal functions from ureteral catheter placement or rpNP. Notably, trends towards increased renal function with rpNP treatment (creatinine clearance, sodium excretion and urine output) parallel reported effects of rpNP in non-cardiac surgery settings, including a swine model of heart failure, (14) and humans with diuretic-resistant acute cardiorenal syndrome (15).

[0134] Regarding the validity of low puO2burden as the study risk biomarker for CS-AKI. Human studies consistently report excess low puO2in patients who subsequently manifest CS- AKI. (17-19) (20) (21) Intraoperative low puO2burden is also positively associated with poorer long-term renal outcomes and 1-year postoperative mortality. (27) puO2measures in the current study resemble observations from human studies, particularly the timing of the most severe low puO2episodes in the postCPB period. (23, 28) Unfortunately, low puO2burden consensus criteria are lacking, requiring an unbiased approach to develop criteria for the current analysis, and preventing a priori sample size estimates. Consequently the exact relationship of the study low puO2burden criteria (degree. duration lower than 40mmHg) with CS-AKI risk is unknown. Nonetheless, we believe the supportive evidence, and in the absence of superior biomarkers to reflect CS-AKI risk, puO2burden criteria as developed is a reasonable approach to such a dilemma. Accepting this, the study demonstrates a significant difference between study groups in low puO2burden suggestive of a benefit from rpNP treatment.

[0135] Notably, some factors can misleadingly depress puO2levels without proven renal risk, including furosemide, and general anesthesia with N2O-O2 sevoflurane / isoflurane, whereas dopamine and prostaglandin El may reverse such effects. (29, 30) Low urine flow rate can also produce artifactual puO2data. (23, 31) However, such concerns are not relevant to the current study given the absence of oliguria and such agents, with exception of a standardized anesthesia plan used in both groups (Table 2). It is unknown but possible that rpNP itself has spurious effects on low puO2burden, however this is unlikely in the absence of important between-group differences in puO2episodes during the baseline period. Notably, no preferable immediate intraoperative early biomarker candidates are available to contrast with low puO2burden in exploring CS-AKI risk.

[0136] Regarding feasibility of rpNP and cardiac surgery, the practical safety of ureteral catheterization with heparin anticoagulation can only be superficially assessed by the current study. Foley catheter placement is standard during cardiac surgery regardless of anti coagulation status. As highlighted above, while ureteral sampling for urinalysis was complete, several Foley samples were inadequate due to drainage patterns; nonetheless, analysis did reveal microscopic hematuria in some animals, although no gross hematuria was noted (Table 2; 8 animals, 16 paired ureteral catheters). In the patient setting, transient hematuria was noted following similar prophylactic unilateral or bilateral ureteral catheterization in 11 / 89 patients (12.3%) during “routine” laparoscopic colorectal surgery procedures (used to guide ureteral injury avoidance), admittedly in the absence of anti coagulation. (22) As in the current study use of a ureteral guidewire has been recommended in these practices to reduce the risk of complications (32).|0137] Among novel study findings, the most pertinent is that low continuous rpNP appears to reduce CS-AKI risk, as reflected by reductions in low puO2burden in this animal model. In future investigations, should rpNP reduce low puO2burden and subsequent CS-AKI in humans, such evidence would also endorse exploring the intriguing potential for renal real-time puO2monitoring with an effective, potentially titratable, intervention and feedback loop. Interesting secondary observations from the current study suggest that such monitoring and intervention could even be targeted unilaterally. To our knowledge no other studies have separately monitored left and right kidney function related to cardiac surgery with CPB, or otherwise explored uneven involvement of renal tissue (beyond gross occlusive phenomena) in clinical CS-AKI pathophysiology. Notably, if paired low puO2episodes are considered single episodes (i.e., 12 catheters equals 6 episodes), then the observed six unilateral episodes become half of the study total, such a mix was seen in both groups including one unilateral episode in each group that was severe.[0138) Although the primary focus of the current study is the effect of rpNP on low puO2episodes, interesting effects of continuous rpNP were also evident in the “normal” range of puO2measures. Most evident from gross data inspection, wide puO2differences between kidneys in the same animal are considerably reduced with rpNP treatment (Figure 8). To clarify, an arbitrary puO2between-kidney difference greater than 20mmHg is useful; in the combined data from therpNP group only 14% paired observations met such criteria (48 / 332), in contrast to 86% in the control group (287 / 335). In the rpNP Group almost all such between-kidney differences were during the CPB period (45 / 48), always involving higher puO2values in the left (dependent) kidney, and none overlapping with CS-AKI risk episodes. In contrast, Control Group differences were frequent throughout all study periods, without sidedness (higher puO2: left vs right, 41 vs. 59%) and episodes overlapped considerably with CS-AKI risk episodes. While the significance of such observations is unclear, the sense that rpNP influences renal physiology beyond simple burden reduction of low puO2episodes is interesting and highlights the need for better understanding of this intervention, and the potential significance of such observations.

[0139] In summary, in this exploratory study in a swine model of cardiac surgery with CPB and bilateral ureteral catheter placement, animals treated with continuous 15mmHg rpNP had lower CS-AKI risk, reflected by the reduced degree-duration burden of low puO2episodes below 40mmHg. Otherwise, no major differences in standard measures of renal function were evident with rpNP throughout the study period, although interesting differences in between-kidney puO2measures that did not meet CS-AKI risk criteria were also evident. Findings of the current investigation support further study of rpNP to explore its potential to prevent and / or treat CS-AKI. Also worthy of study, the combination of rpNP therapy with puO2monitoring, including the role of separate left-right kidney observation as a potential new approach to understanding CS-AKI, and the possibility of more targeted renal protection monitoring and intervention.BIBLIOGRAPHYThe following references are incorporated herein in their entirety.1. Malou Friederich-Persson, et al., ''Kidney Hypoxia, Attributable to Increased Oxygen Consumption, Induced Nephropathy Independently of Hyperglycemia and Oxidative Stress, ” Hypertension (Online Data Supplement) 2013, 62:914-919.2. Laurent Julliard, et al., Hypertension, 2007, 50:242-0247.3. Robert G. Evans, et al., Am J Physiol Renal Physiol, 2008, 295:F1259-F1270.4. Peter Hansell, et al., Clin Exp Pharmacol Physiol., 2013 February, 40(2): 123-127.5. Carla Carvalho, Uppsala Universitet, Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1581, 2019, pp 56.6. John R. Erbey, II, et al., U.S. Patent No. 9,744,331, August 29, 2017.7. Natalie A. Silverton, et al., U.S. Patent No. 11,660,032, May 30, 2023.8. Evan S. Luxon, et al., U.S. Patent No. 10,772,998, September 15, 2020.9. Englberger, L., et al., Crit Care. 2011 ; 15(1):R16.10. Bastin, A.J., et al., J Crit Care. 2013;28(4):389-96.11. Lagny, M.G., et al., BMC Nephrol. 2015;16:76.12. Arnaoutakis, G.J., et al., J Thorac Cardiovasc Surg. 2007;134(6): 1554-60; discussion 60-1.13. Haase, M., et al., J Thorac Cardiovasc Surg. 2009.14. Brown, J.R., et al., Ann Thorac Surg. 2014;97(1): 111-7.15. Brown, J.R., et al., Circulation. 2006;114(l Suppl):I409-13.16. Hobson, C.E., et al., Circulation. 2009;119(18):2444-53.17. Dasta, J.F., et al., Nephrol Dial Transplant. 2008;23(6): 1970-4.18. Coca, S.G., et al., Kidney Int. 2012;81(5):442-8.19. Cho, J.S., et al., J Thorac Cardiovasc Surg. 2021 ; 161 (2):681 -8 e3.20. Wang, Y., et al., Nat Rev Nephrol. 2017;13(l 1):697-711.21. Martens, P., et al., JACC Heart Fail. 2023;l l(10): 1289-303.22. Rao, V.S., et al., Am J Physiol Regul Integr Comp Physiol. 2021;321(4):R588-R94.23. Parker, A.M., et al., Heart Failure Society of America Annual Meeting; Sept 11, 2021; Denver, CO2021. pp 71.24. Kopitko, C , et al., J Clin Med. 2022; 11(10).25. Noe, K.M., et al., Clin Exp Pharmacol Physiol. 2022;49(2):228-41.

Claims

AMENDED CLAIMS received by the International Bureau on 11 April 2025 (11.04.2025)What is claimed is:

1. A method of generating and administering an adaptive treatment plan for a subject having a disease associated with renal insufficiency, the method comprising:(a) collecting values of current and historical subject data relating to the subject’s disease, wherein the values include urine oxygen levels;(b) generating a treatment plan for the subject’s disease, wherein the treatment plan is a function of the values of the subject data; and(c) administering a session of the treatment plan to the subject.

2. The method of claim 1, wherein steps (a), (b) and (c) above are performed during a first time interval, and are iteratively repeated during one or more time intervals subsequent to the first time interval, and wherein a change in urine oxygen levels over time serves as an indicator of a degree of risk of renal injury to the subject.

3. An adaptive treatment plan for a subject having a disease associated with renal insufficiency comprising:(a) collecting values, during a first time interval, of current and historical subject data relating to the subject’s disease, wherein the values include urine oxygen levels;(b) generating, during the first time interval, a treatment plan for the subject’s disease, wherein the treatment plan is a function of the values of the subject data collected during the first time interval;(c) administering a session of the treatment plan to the subject; and(d) iteratively repeating steps (a), (b) and (c) above during one or more time intervals subsequent to the first time interval, wherein a change in urine oxygen levels over time serves as an indicator of the degree of risk of injury to the subject, thereby generating an adaptive treatment plan over time.

4. The method of claim 1 wherein the urine oxygen levels represent urinary oxygen tension.

5. The method of claim 1 wherein the urine oxygen levels represent oxygen concentration in urine.

6. The method of claim 1 wherein negative pressure therapy is delivered to the subject’s kidney, renal pelvis, ureter or a combination thereof, through a ureteral catheter.

7. The method of claim 1 wherein negative pressure therapy is delivered to the subject’s kidney and / or renal pelvis.

8. The method of claim 1 wherein the urine oxygen levels are determined with one or more oxygen sensors.

9. The method of claim 8, wherein at least one of the oxygen sensors is located in the subject’s renal pelvis or kidney.

10. The method of claim 8, wherein at least one of the oxygen sensors is located in the subject’s body on an external surface of a device.

11. The method of claim 8, wherein at least one of the oxygen sensors is located inside a ureteral catheter, wherein the urethral catheter is capable of delivering negative pressure to a subject’s renal pelvis or kidney.

12. The method of claim 8, wherein at least one of the oxygen sensors is located outside the subject’s body.

13. The method of claim 12, wherein at least one of the oxygen sensors is located between the subject and an external pump.

14. The method of claim 13, wherein at least one of the oxygen sensors is located downstream from an external pump used to deliver negative pressure therapy to a subject’s renal pelvis or kidney.

15. The method of claim 2 wherein the adaptive treatment plan comprises one or more categories of treatment, wherein one category of treatment comprises a session of negative pressure, wherein each session is defined by a value for magnitude, mode, duration and frequency, and wherein each value is correlated with the subject’s urinary oxygen level at one or more of the time intervals during the adaptive treatment plan, wherein the adaptive treatment plan is commensurate with the risk of kidney injury to the subject.

16. A system of reducing risk of acute kidney injury in a subject comprising(a) continuously measuring a subject’s rate of kidney oxygen consumption for a period of time sufficient to establish a pattern of kidney oxygen consumption in the subject;(b) determining the subject’s risk of impaired renal function from the subject’s kidney oxygen consumption, wherein the subject’s risk of impaired renal function is categorized as low, moderate or high; c) selecting a treatment plan for the subject correlated with the subject’s risk of impaired renal function; and d) administering a treatment plan to the subject associated with the subject’s relative risk of impaired renal function, wherein the subject’s risk of impaired renal function is reduced compared to the risk of impaired kidney function without the treatment plan.

17. The system of claim 16 wherein the kidney of a subject having a high risk of impaired kidney function is administered a treatment plan comprising a dose of about -25 mmHg, and 17, and wherein the kidney of a subject having a low or moderate risk of renal injury is administered a treatment plan comprising a dose of about -20 to about -15 mmHG.

18. The system of claim 16 wherein the kidney of a subject having a low risk of renal injury is administered a dose of negative pressure therapy suitable for providing urinary oxygen levels in the subject at a clinically acceptable urinary oxygen reference level.

19. The system of claim 16 wherein: the subject has a low risk of renal injury or progression of renal injury where the subject urinary oxygen level is about 80 mmHg or higher; the subject has a moderate risk of renal injury or progression of renal injury where the subject urinary oxygen level is greater than about 40 to less than about 80 mmHg; and the subject has a high risk of renal injury or progression of real injury where the subject urinary oxygen levels are below a hypoxia urinary oxygen threshold level, wherein a hypoxia urinary oxygen threshold level is between about 30 mmHg and about 40 mmHg.

20. A system of reducing risk of acute kidney injury in a subject comprising(a) continuously measuring a subject’s rate of kidney oxygen consumption for a period of time sufficient to establish a pattern of kidney oxygen consumption in the subject;(b) determining the subject’s risk of impaired renal function from the subject’s kidney oxygen consumption, wherein the subject’s risk of impaired renal function is categorized as low, moderate or high; c) selecting a treatment plan for the subject correlated with the subject’s risk of impaired renal function; and d) administering a treatment plan to the subject associated with the subject’s relative risk of impaired renal function, wherein the subject’s risk of impaired renal function is reduced compared to the risk of impaired kidney function without the treatment plan. wherein the kidney of a subject having a low risk of renal injury is administered a dose of negative pressure therapy suitable for providing urinary oxygen levels in the subject at a clinically acceptable urinary oxygen reference level.

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