GB2512120A

GB2512120A - A novel Medical Device and Methods for determining Renal Function Levels in Mammals

Info

Publication number: GB2512120A
Application number: GB1305205.5A
Authority: GB
Inventors: Dario Veretnik; Vadim Lozansky; Daniel Weltman; Boaz Giron; Yonathan Wand
Original assignee: Individual
Current assignee: Individual
Priority date: 2013-03-21
Filing date: 2013-03-21
Publication date: 2014-09-24
Also published as: WO2014147615A1; GB2512120A8; GB201305205D0

Abstract

A medical device, a system, a method and a kit useful for the determination of renal function levels in a mammalian subject, comprising Creatinine and Urea labeled with 13C in a predetermined concentration; Creatinine and Urea labeled with 13C are administered to a subject and according to their concentration in the urine and/or blood the renal function levels are assessed.

Description

Title: A novel Medical Device and Methods for determining Renal Function Levels in Mammals

Field of the invention

[01] The present invention generally relates to a medical device,kit and system for determining renal function levels and a method for producing, using them as well as analyzing samples. More particularly, the present invention relates to 13C labeled Urea and 13C Creatinine for determining renal function by administering them to a subject and checking their concentration in blood and/or urine.

Background of the invention

[02] Renal function is an indication of the state of the kidney and its role in renal physiology.

glomerular filtration rate (GER), Creatinine clearance, blood Urea nitrogen (BUN), fractional excretion of Urca are all measures important in asscssing the excretory function of thc kidneys. It is very important to monitor rcnal functions of people suffcring from chronic kidney disease as well as people suffering from diabetes, hypertension and dehydration, [03] Creatinine and Urea concentrations in blood and urine are a major indication for determining the mentioned measurements and therefore are key players in assessing renal function. To date, only endogenous Creatinine and Urea are measured for assessing these functions.Both, Creatinine and Urea, concentrations in the blood are affected by many variables (e.g. age, race, gender, stress, diet, physical activity, general liver health etc.) and therefore are not a very reliable measure and it is difficult to set a universal standard that distinguishes between functioning and non-functioning kidneys.More accurate tests for assessing renal function exist but they are either very expensive or they utilize non-natural materials or radioisotopes which is disapproved of by large sections of the medical and patient communities. For example, patent EP 0063946, utilizes a complex of Technetium-99m. Another example is patent EP 2203743 that uses peptide biomarkers to assess renal function.

[04] It is thus a long-felt need to provide an improved novel diagnostic tool that will enable fast and inexpensive renal function assessment without introducing hazardous materials to the body of a patient.

Summary of the invention

[05] The present invention provides a medical device useful for the determination of renal function levels in a mammalian subject, comprising: (a) Crcatininc in a predetermined concentration; and (b) Urea in a predetermined concentration;whcrcin Creatininc and Urea are labeled with I3 [06] It is another object of the current invention to disclose the medical device as defined in any of the above, wherein Creatinine and Urea are alternatively labeled with a stable isotope selected from a group consisting of 2H, 15N, 180,and any combination thereof [07] It is another object of the current invention to disclose the medical device as defined in any of the above, wherein the labeled Creatinine and Urea are stored in a manner selected from a group consisting of administrable solution, lyophilized powder, dehydrated powder and any combination thereof [08] It is another object of the current invention to disclose the medical device as defined in any of the above, wherein the lyophilized powder and the dehydrated powder are diluted to a certain volume to give the predetermined concentration of the labeled Urea and Creatinine.

[09] It is another object of the current invention to disclose the medical device as defined in any of the above, wherein the administrable solution refers to a solution ready to be administered in a route selected from group consisting of intranasal, intravenous, intradermal, intramuscular and any combination thereof [10] It is another object of the current invention to disclose the medical device as defined in any of the above, wherein the medical device is additionally adapted to determine the effectiveness of treatments selected from a group consisting of dialysis, hemodialysis, peritoneal dialysis, hemofiltration, hemodiafiltration, intestinal dialysis and any combination thereof [11] It is another object of the current invention to disclose the medical device as defined in any of the above, wherein the medical device is adapted to assess renal frmnction in subjects suffering from diabetes, hypertension and hypotension and liquid imbalance.

[12] It is another object of the current invention to disclose the medical device as defined in any of the above, wherein the predefined concentration of Urea and Creatinine are determined according to bodyweight.

[13] It is another object of the current invention to disclose the medical device as defined in any of the above, wherein the predefined concentrations of Urea and Creatinine are adapted for specific populations selected from a group consisting of:premature babies, neonates, infants, children, pregnant women, adults, elderly and health compromised individuals.

[14] It is another object of the current invention to disclose the medical device as defined in any of the above, wherein the predefined concentration of Urea is A molar, where A is in the range of about 0 molar to about 100 molar.

[15] It is another object of the current invention to disclose the medical device as defined in any of the above, wherein the predefined concentration of Creatinine is B molar, where B is in the range of about 0 molar to about 100 molar.

[16] It is another object of the current invention to disclose the medical device as defined in any of the above, wherein the enrichment of the stable isotopes are A%, where A is substantially more than 0%.

[17] It is another object of the current invention to disclose a system adapted to determine renal function levels in a mammalian subject, comprising: (a) Creatinine and Urea in a predetermined concentration; (b) means for administrating Creatinine and Urea; and (c) means for detection of Creatinine and Urea from samples selected from a group consisting of (i) urine sample; (ii) blood samples and any combination thcrcof;whcrcin Creatinine and Urea are labeled with 3C adapted for detection by the means for detection.

[18] It is another object of the current invention to disclose the system as defined in any of the above, wherein Creatinine and Urea are alternatively labeled with a stable isotope sclcctcd from a group consisting of:2H,15N, 180,and any combination thereof [19] It is another object of the current invention to disclose the system as defined in any of the above, wherein the means of detection are selected from a group consisting of: (1) gas chromatography (2) liquid chromatography (3) mass spectroscopy; (4) nuclear magnetic resonance spectroscopy; (5) infrared spectroscopy; and any combination thereof.

[20] It is another object of the current invention to disclose the system as defined in any of the above, wherein the labeled Creatinine and Urea are storedin a manner selected from a group consisting of: administrable solution, lyophilized powder, dehydrated powder and any combination thereof [21] It is another object of the current invention to disclose the system as defined in any of the above, wherein the lyophilized powder and the dehydrated powder are diluted to a certain volume to give the predetermined concentration of the labeled Urea and Creatinine.

[22] It is another object of the current invention to disclose the system as defined in any of the above, wherein the administrable solution refers to a solution ready to be administered in a route selected from group consisting of: intranasal, intravenous, intradermal, intramuscular and any combination thereof [23] It is another object of the current invention to disclose the system as defined in any of the above, wherein the system is adapted for self-use.

[24] It is another object of the current invention to disclose a kit useful for the determination of renal function levels in a mammalian subject, comprising: (a) 13C labeled Creatinine in a predetermined concentration; and (b)13C labeled Urea in a predetermined eoneentration;wherein the injectable solution is enclosed in a pyrogenie container selected from a group consisting of ampule; syringe; sachet, vial; bottle; and any combination thereof [25] It is another object of the current invention to disclose the kit as defined in any of the above, whereinthe Creatinine and the Urea are ahematively labeled with a stable isotope selected from a group consisting of:2H,15N, 180,and any combination thereof [26] It is another object of the current invention to disclose the kit as defined in any of the above, wherein the container is sterile.

[27] It is another object of the current invention to disclose the kit as defined in any of the above, wherein thekit additionally comprises inactive ingredients.

[28] It is another object of the current invention to disclose a method for producing a medical device adapted for the determination of renal function levels (lOO),comprising steps of (a) providing Urea in a predefined concentration(1O1); (b) providing Creatinine in a predefined coneentration(102); (e) mixingtheUrea and theCreatinine (103); and (d) enclosing the mix of step (c) in containers(104); wherein, theUrea and Creatinine are labeled with13C.

[29] It is another object of the current invention to disclose the method as defined in any of the above, wherein Creatinine and Urea are alternatively labeled with a stable isotope selected from a group consisting of2H,13C, 15N, 80,and any combination thereof [30] It is another object of the current invention to disclose the method as defined in any of the above, additionally comprising step of mixing the mix of step (c) in an aqueous solution selected from a group consisting of: (a) saline; (b) water for injection and any combination thereof [31] It is another object of the current invention to disclose the method as defined in any of the above, additionally comprising step of lyophilizing the mix of step(c).

[32] It is another object of the current invention to disclose the method as defined in any of the above, additionally comprising step of sterilizing the mix of step (c).

[33] It is another object of the current invention to disclose the method as defined in any of the above, wherein the predefined concentration of Urea is A molar, where A is in the range of about 0 molar to about 100 molar.

[34] It is another object of the current invention to disclose the method as defined in any of the above, wherein the predefined concentration of Creatinine is B molar, where B is in the range of about 0 molar to about 100 molar.

[35] It is another object of the current invention to disclose the method as defined in any of the above, additionally comprising step of selecting the container from a group consisting of: ampule; syringe; sachet;vial; bottle; and any combination thereof [36] It is another object of the current invention to disclose the method as defined in any of the above, wherein additionally comprising the step of adding inactive ingredients.

[37] It is another object of the current invention to disclose a method for determining renal function levels in a mammalian subject(200), comprising steps of: (a) providing an administrable solution(201) comprising: U) Creatinine in a predetermined concentration; and (ii) Urea in a predetermined concentration; (b) administrating theadministrable solution to the mammalian subject(202); (c) determining the concentration of theCreatinine and Urea in at least one sample (204);whercin Creatinine and Urea are labeled with c that enables step (d) of determining their concentration.

[38] It is another object of the current invention to disclose the method as defined in any of the above, wherein Creatinine and Urea are alternatively labeled with a stable isotope selected from a group consisting of 2H,15N, 180,and any combination thereof [39] It is another object of the current invention to disclose the method as defined in any of the above, wherein the method additionally comprises step of determining the effectiveness of treatments selected from a group consisting of dialysis, hemodialysis, peritoneal dialysis, hemofiltration, hemodiafiltration, intestinal dialysis.

[40] It is another object of the current invention to disclose the method as defined in any of the above, wherein the method additionally comprises step of measuring renal function factors indicative of renal function selected from a group consisting of: (1) glomerular filtration rate (GER); (2) tubular reabsorption factor (TrAF); (3) Creatinine clearance rate; (4) Blood Urea Nitrogen (BTJN), fractional excretion of Urea; and any combination thereof.

[41] It is another object of the current invention to disclose thc mcthod as defined in any of the above, wherein step (c) of collecting the samples is conducted at at least one time point afterstep (b) of administrating the injectable solution.

[42] It is another object of the current invention to disclose the method as defined in any of the above, wherein step (d) of determiningconcentration is carried out by means selected from a group consisting of (a) gas chromatography; (b) liquid chromatography (c) mass spectroscopy; (d) nuclear magnetic resonance spectroscopy; (e) infrared spectroscopy; and any combination thereof [43] It is another object of the current invention to disclose the method as defined in any of the above, wherein step (b) of administrating is carried out in a manner selected from a group consisting of: (a) intra-muscular injection; (b)intra-venous injection; (c) sub-cutaneous injection; (d) intra-nasal administration and any combination thereof [44] It is another object of the current invention to disclose the method as defined in any of the above, wherein step (c) of collecting samples the urine samples are collected in a way selected from a group consisting of (a) one time point; (b); muhiple time points (c) continuously; and any combination thereof.

[45] It is another object of the current invention to disclose the method as defined in any of the above, wherein step (c) of collecting samples the blood sample is drawn from a source selected from a group consisting of: (a) vein; (b) artery; (c) capillary; and any combination thereof [46] It is another object of the current invention to disclose a standard of care protocol for accurately staging renal function within a patient(300), comprising steps of: (a) providing an administrable solution (301)comprising: (i) 3Clabeled Creatinine labeled in a predetermined concentration; and (ii) 3Clabeled Urea labeled with a stable isotope in a predetermined concentration; (b) administering the administrable solution to the subject(302); (c) collecting at least one sample from the subject(303); and (d) determining the concentration of Creatinine and Urea in the samples(304);wherein the concentrations of the labeled Creatinine and Urea in the samples are adapted to accurately determine GFR independently of gender, race and age, stress, diet, physical activity and general liver health.

[47] It is another object of the current invention to disclose the standard of care protocol as defined in any of the above, wherein Creatinine and Urea are alternatively labeled with a stable isotope selected from a group consisting of 2H,'5N, 180,and any combination thereof [48] It is another object of the current invention to disclose the standard of care protocol as defined in any of the above, wherein additionally comprising step of selecting the kind of sample from a group consisting of: (a) urine sample; (b) blood sample; and any combination thereof [49] It is another object of the current invention to disclose the standard of care protocol as defined in any of the above, wherein step (d) of determining concentration is carried out by means selected from a group consisting of (a) gas chromatography; (b) liquid chromatography; (c) mass spectroscopy; (d) nuclear magnetic resonance spectroscopy; (e) infrared spectroseopy; and any combination thereof.

[50] It is another object of the current invention to disclose the standard of care protocol as defined in any of the above, wherein step (b) of administrating is carried out in a manner selected from a group consisting of (a) intra-muscular injection; (b)intra-venous injection; (c)sub-cutaneous injection; (d) intra-nasal administration and any combination thereof [51] It is another object of the current invention to disclose the standard of care protocol as defined in any of the above, wherein step (c) of collecting the samples is conducted at at least one time point after step (b) of administrating the injectable solution.

[52] It is another object of the current invention to disclose a method for analyzing samples taken from a mammalian subject to determine the mammalian subject renal function (400), comprising steps of: (a) providing the samples (401); (b) treating the samples (402); (c) determining the concentrations of Urea and Creatinine (403); and (d) evaluating the renal function from the concentrations of Urea and Creatinine (404); wherein the Urea and Creatinine are labeled with 13i [53] It is another object of the current invention to disclose the method as defined in any of the above, wherein Creatinine and Urea are alternatively labeled with a stable isotope selected from a group consisting of:2H,15N, 180,and any combination thereof [54] It is another object of the current invention to disclose the method as defined in any of the above, wherein step (c) of determining the concentrations of Urea and Creatinine is carried out in a manner selected from a group consisting of: (a) gas chromatography; (b) liquid chromatography (c) mass spectroscopy; (d) nuclear magnetic resonance spectroscopy; (e) infrared spectroscopy; and any combination thereof [55] It is another object of the current invention to disclose the method as defined in any of the above, wherein the step of determining the concentration of Urea is done with no additional enzymatic reaction.

[56] It is another object of the current invention to disclose the method as defined in any of the above, wherein the step of determining the concentration of Creatinine additionally comprises the steps of: (a) dividing the sample to sample A and sample B; (b) measuring the concentration of Urea in the sample A; (c) enzymatically converting the Creatinine to Urea in sample B; (d) measuring the concentration of Urea in sample B; and (e) subtracting Urea concentration of step (b) from Urea concentration of step (c).

[57] It is another object of the current invention to disclose the method as defined in any of the above, wherein step (c) of enzymatically converting Creatinine to Urea is carried out by the Creatininase enzymatic treatment.

[58] Brief Description of the drawings

[59] In the following detailed description of the preferred embodiments, reference is made to the accompanying drawings that form a part hereof, and in which are shown by way of illustration specific embodiments in which the invention may be practiced. It is understood that other embodiments may be utilized and structural changes may be made without departing from the scope of the present invention. The present invention may be practiced according to the claims without some or all of these spccific details. For the purpose of clarity, technical material that is known in the technical fields related to the invention has not been described in detail so that the present invention is not unnecessarily obscurcd.Thc prcscnt invcntion provides means and methods of accuratcly measuring renal function that without the use of radioisotopes or other unstable compounds.

[60] In the accompanying drawing: [61] Figure 1 is a schematic flow diagram illustrating the method for producing a medical device adapted to determine renal function levels (190); [62] Figure 2 is a schematic flow diagram illustrating thc mcthod for detcrmining rcnal function levels in a mammalian subject (200); [63] Figure 3 is schematic flow diagram illustratthg the standard of care protocol for accurately staging renal function within a paticnt (300); and [64] Figure 4 is schematic flow diagram illustrating the method for analyzing samples taken from a mammalian subject to determine said mammalian subject renal function(400).

Detailed description of the invention

[65] In the following detailed description of the preferred embodiments, reference is made to the accompanying drawings that form a part hereof and in which are shown by way of illustration specific embodiments in which the invention may be practiced. It is understood that other embodiments may be utilized and structural changes may bc made without departing from the scope of the present invention. The present invention may be practiced according to the claims without some or all of these specific details. For the purpose of clarity, technical material that is known in the technical fields related to the invention has not been describcd in dctail so that thc prcsent invention is not unnecessarily obscured.

[66] The present invention provides a medical device, system, kit, method for use, method for producing and a standard of care for the determination of renal function levels in a mammalian subject.

[67] The term "2H (deuterium)" refers hereinafter to a natural, stable isotope of hydrogen and one of the environmental isotopes which makes up about 0.0156%of all natural hydrogen on Earth.

[68] The term "3C(Carbon-13)"refers hereinafter to a natural, stable isotope of carbon and one of the environmental isotopes which makes up about 1.1% of all natural carbon on Earth.

[69] The term "N (Nitrogen-15)" refers hereinafter to a rare stable isotope of nitrogen.

[70] The term 180 (oxygen-IS)' refers hereinafter to a natural, stable isotope of oxygen and one of the environmental isotopes.

[71] The term "administrable solution" refers hereinafter to a solution ready to be administered through a selected administration route.

[72] The term "renal function" refers hereinafter to any indication of the state of the kidney and its role in renal physiology.

[73] The term "mammalian subject" refers hereinafter toany of various warm-blooded vertebrate animals of the class Mammalia, characterized by a covering of hair on the skin and, in the female, milk-producing mammary glands for nourishing the young. More generally the term refers to: humans, horses, dogs, cats, cows, etc. [74] The term "GFR" refers hereinafter tothe glomerular filtration rate of volume of daily filtered fluid through the kidney.

[75] The term "intranasal administration" refers hereinafter to administration through thethin mueosa of the nasal cavity which is well vaseularized.

[76] The term "inactive ingredients" refers hereinafter toingredients added during the manufacturing process of pharmaceutical products and generally have no pharmacological effeetbinding materials (which may be excipients), dyes, preservatives, emulsiflers, antioxidants etc. [77] The term sterilizing refers hereinafter to the elimination of microbiological organisms to achieve a sterile microbial environment. More generally the term refers to heat sterilization, chemical sterilization, radiation sterilization, sterile filtration, etc. [78] The term "mass spectroscopy" refers hereinafter tothe science of displaying the spectra of the masses of the molecules comprising a sample of material.More generally the term refers to IAMS (Accelerator Mass Spectrometry), Gas Chromatography-MS, Liquid Chromatography-M S. ICP-MS (Inductively Coupled Plasma-Mass spectrometry), I RMS (Isotope Ratio Mass Spectrometry), Ion Mobility Spectrometry-MS, MAILDI-TOF, SELDI-TOF, Tandem MS, TIMS (Thermal Ionization-Mass Spectrometry), SSMS (Spark Source Mass Spectrometry).

[79] The term "nuclear magnetic resonancespectroscopy" refers hereinafter tothe research technique that exp'oits the magnetic properties of certain atomic nuclei and determines the physical and chemical properties of atoms or the molecules in which they are contained.

[80] The term "infrared spectroscopy" refers hereinafter tothe spectroscopy that deaLs with the infrared region of the electromagnetic spectrum. It covers a range of techniques, mostly based on absorption spectroscopy and is used to identi' and study chemicals.

[81] The term "Gas Chromatography" refers hereinafter to a common type of chromatography used in analytical chemistry for separating and analyzing compounds that can be vaporized without decomposition.

[82] The term "Liquid Chromatography" refers hereinafter toa separation technique in which the mobile phase is a liquid. Liquid chromatography can be carried out either in a column or a plane.

[83] The presented invention uses13C labeled Urea and Creatinine to determine renal function levels in a mammalian subject. The 3C isotope is stable, non-radioactive, non-ionizing and chemically indistinguishable from'2C, which is the major naturally occurring isotope.

The most common parameter used to assess renal function is GFR. To date, this parameter is determined by measuring endogenous concentrations of Urea and Creatinine in blood and urine. The results of these measurements are highly inaccurate and in orderforthem to have meaning, factors like age, race and gender has to be considered. By measuring exogenous labeled Creatinine and Urea rather than their endogenous counterparts, as suggested in this invention, results are much more accurate.The presented invention uses'3C labeled Urea and Creatinine to determine renal fUnction levels in a mammalian subject. The 5C isotope is stable, non-radioactive, non-ionizing and chemically indistinguishable from'2C, which is the major naturally occurring isotope.

The most common parameter used to assess renal function is GFR. To date, this parameter is determined by measuring endogenous concentrations of Urea and Creatinine in blood and urine. Thc results of these measuremcnts arc highly inaccurate and in ordcr for thcm to have meaning, factors like age, race and gender has to be considered. By measuring exogenous labeled Creatinine and Urea rather than their endogenous counterparts, as suggested in this invention, results arc much morc accuratc, the mentioned factors are eliminated and the whole process of sample collecting is much less cumbersome.

[84] It is according to one embodiment of the invention, wherein a medical device useful for the determination of renal function levels in a mammalian subject, comprising: (a) Creatinine in a predetermined concentration; and (b) Urea in a predetermined concentration; wherein said Creatnne and said Urea are labeled with -C. [85] In yet another embodiment of the invention, wherein said Creatinine and said Urea are alternatively labeled with a stable isotope selected from a group consisting of 2H, 1N, o and any combination thereof.

[86] In yet another embodiment of the invention, wherein said labeled Creatinine and Urea are stored in a manner selected from a group consisting of: administrable solution, lyophilized powder, dehydrated powder and any combination thereof [87] In yet another embodiment of the invention, wherein said lyophilized powder and said dchydrated powdcr arc diluted to a certain volumc to give said prcdctcrmined concentration of said labeled Urea and Creatinine.

[88] In yet another cmbodimcnt of the invcntion, whercin said administrablc solution refers to a solution ready to be administered in a route selected from group consisting of intranasal, intravenous, illtradermal, intramuscular and any combination thercof.

[89] In yet another embodiment of the invention, wherein said medical device is additionally adapted to determine the effectiveness of treatments selected from a group consisting of: dialysis, hemodialysis, peritoncal dialysis, hemofiltration, hemodiafiltration, intcstinal dialysis and any combination thereof [90] In yet another embodiment of the invention, wherein said medical device is adapted to assess renal function in subjects suffering from diabetes, hypertension and hypotension.

People suffering from the mentioned conditions are highly susceptible to suffer from decreased renal function and therefore their kidney function should be monitored closely.

[91] Tn yet another embodiment of the invention, wherein said predefined concentration of Urea and Creatinine are determined according to bodyweight.

[92] Tn yet another embodiment of the invention, wherein said predefined concentrations of Urea and Creatinine are adapted for specific populations selected from a group consisting of premature babies, neonates, infants, children, pregnant women, adults, elderly and health compromised individuals.

[93] Tn yet another embodiment of the invention, wherein said predefined concentration of Urea is A molar, where A is in the range of about 0 molar to about 100 molar.

[94] Tn yet another embodiment of the invention, wherein said predefined concentration of Creatinine is B molar, where B is in the range of about 0 molar to about 100 molar.

[95] Tn yet another embodiment of the invention, wherein the enrichment of said stable isotopes is A%, where A is substantially more than 0%.

[96] In yet another embodiment of the invention, a system adapted to determine renal function levels in a mammalian subject, comprising: (a) Creatinine and Urea in a predetermined concentration; (b)means for administrating said Creatinine and Urea; and (b) means for detection of said Creatinine and Ureafrom samples selected from a group consisting of: (i) urine samp1e (ii) blood samples and any combination thereofwherein said Creatinine and Urea are labeled with 3C adapted for detection by said means for detection.

[97] In yet another embodiment of the invention, wherein said Creatinine and said Urea are alternatively labeled with a stable isotope selected from a group consisting of 2H, 1N, 1g0 and any combination thereof.

[98] Tn yet another embodiment of the invention, wherein said means of detection are selected from a group consisting of: (1) gas chromatography (2) liquid chromatography (3) mass spectroseopy; (4) nuclear magnetic resonance speetroseopy; (5) infrared spectroscopy; and any combination thereof [99] In yet another embodiment of the invention, wherein said labeled Creatinine and Urea are stored in a manner selected from a group consisting of administrable solution, lyophilized powder, dehydrated powder and any combination thereof [100] In yet another embodiment of the invention, wherein said lyophilized powder and said dehydrated powder are diluted to a certain volume to give said predetermined concentration of said labeled Urea and Creatinine.

[101] In yet another embodiment of the invention, wherein said administrable solution refrrs to a solution rcady to be administered in a route selected fivm group consisting of intranasal, intravenous, intradermal, intramuscular and any combination thereof [102] In yet another embodiment of the invention, wherein said system is adapted for self-use.

Itisapossibilitythatthesystemwillbeadaptedtouseathome-theusercould administer the solution to himself and collect the samples (especially if they are urine samples. For analyses the patient would either deliver the samples to a lab or that the analyzing system will also be adapted to home-use.

[103] In yet another embodiment of the invention, a kit useful for the determination of renal function levels in a mammalian subject, comprisin (a) 3C labeled Creatinine in a predetermined concentration; and (b) 3C labeled Urea in a predetermined concentration; wherein said administrable solution is enclosed in a pyrogenic container selected from a group consisting of: ampoule; syringe; sachet, vial; bottle; and any combination thereof [104] In yet another embodiment of the invention, wherein said Creatinine and said Urea are alternatively labeled with a stable isotope selected from a group consisting of 2H, 5N, and any combination thereof [105] In yet another embodiment of the invention, wherein said container is sterile.

[106] In yet another embodiment of the invention, wherein said kit additionally comprises inactive ingredients. Inactive ingredients Active ingredients can be preservative, emulsifiers or dyes. They have no pharmaceutical effect but are essential for storage for storage.

[107] In yet another embodiment of the invention a method for producing a medical device adapted for the determination of renal function levels (100), comprising steps of (a) providing Urea in a predefined concentration (101); (b) providing Creatinine in a predefined concentration (102); (c) mixing said Urea and said Creatinine (203); and (d) enclosing said mix of step (c) in containers (104); wherein, said Urea and Creatinine are labeled with 13C.

[108] In yet another embodiment of the invention, wherein said Creatinine and said Urea are alternatively labeled with a stable isotope selected from a group consisting of: 2H, C, 15N, 180, and any combination thereof.

[109] In yet another embodiment of the invention, additionally comprising step of mixing said mix of step (c) in an aqueous solution selected from a group consisting of: (a) saline; (b) water for injection and any combination thereof [110] In yet another embodiment of the invention, additionally comprising step of lyophilizing said mix of step (c).

[111] In yet another embodiment of the invention, additionally comprising step of sterilizing said mix of step (c).

[112] In yet another embodiment of the invention, wherein said predefined concentration of Urea is A molar, where A is in the range of about 0 molar to about 100 molar.

[113] In yet another embodiment of the invention, wherein said predefined concentration of creatinine is B molar, where B is in the range of about 0 molar to about 100 molar.

[114] In yet another embodiment of the invention, additionally comprising step of selecting said container from a group consisting of: ampule; syringe; sachet; vial; boff Ic; and any combination thereof [115] In yet another embodiment of the invention, wherein additionally comprising the step of adding inactive ingredients.

[116] In yet another embodiment of the invention a method for determining renal function levels in a mammalian subject (200), comprising steps of: (a) providing an administrable solution (201) comprising: (i) Creatinine in a predetermined concentration; and (ii) Urea in a predetermined concentration; (b) administrating said administrable solution to said mammalian subject (202); (c) collecting at least one sample (203) selected from a group consisting of (D blood sample; (ii) urine sample; and any combination thereof; and (d) determining the concentration of said Creatinine and said Urea in said at least one sample (204); wherein said Creatinine and said Urea are labeled with 3C that enables step (d) of determining their concentration.

[117] In yet another embodiment of the invention, wherein said Creatinine and said Urea are alternatively labeled with a stable isotope selected from a group consisting of 2H, 15N, 18 and any combination thereof.

[118] In yet another embodiment of the invention, wherein said method additionally comprises step of determining the effectiveness of treatments selected from a group consisting of: dialysis, hemodialysis, peritoneal dialysis, hemoflltration, hemodiafiltration, intestinal dialysis.

[119] In yet another embodiment of thc invention, wherein said method additionally comprises step of measuring renal function factors indicative of renal function selected from a group consisting of: (1) glomerular filtration rate (GFR); (2) tubular reabsorption factor (TrAF); (3) Creatinine clearance rate; (4) Blood Urea Nitrogen (BUN), fractional excretion of Urea; and any combination thereof [120] In yet another embodiment of the invention, wherein said step (c) of collecting said samples is conducted at at least onc timc point aftcr said stcp (b) of administrating said

injectable solution.

[121] In yet another embodiment of the invention, wherein said step (d) of determining concentration is carried out by means selected from a group consisting of: (a) gas chromatography; (b) liquid chromatography (e) mass spectroscopy; (d) nuclear magnetic resonance spectroscopy; (e) infrared spectroscopy; and any combination thereof.

[122] In yet another embodiment of the invention, wherein said step (b) of administrating is carried out in a manner selected from a group consisting of (a) intra-muscular injection; (b) intra-venous injection; (c)sub-cutaneous injection; (d) intra-nasal administration and any combination thereof [123] In yet another embodiment of the invention, wherein said step (c) of collecting samples said urine samples are collected in a way selected from a group consisting of (a) one time point; (b); multiple time points (c) continuously; and any combination thereof [124] In yet anothcr embodiment of thc invcntion 0, wherein said step (c) of collecting samples said blood sample is drawn from a source selected from a group consisting of (a) vein; (b) artery; (c) capillary; and any combination thereof.

[125] A In yet another embodiment of the invention a standard of care protocol for accurately staging renal function within a patient (300), comprising steps of (a) providing an administrable solution (391) comprising: (i) 3C labeled Creatinine labeled in a predetermined concentration; and (ii)'3C labeled Urea labeled with a stable isotope in a predetermined concentration; (b) administering said administrable solution to said subject (302); (c) collecting at least one sample from said subject (303); and (d) determining the concentration of said Creatinine and said Urea in said samples (304); wherein said concentrations of said labcled Crcatinine and Urea in said samples arc adapted to accurately determine GFR indcpcndently of gender, race and age, stress, diet, physical activity and general liver hcalth.

[126] In yet another embodiment of the invention, wherein said Creatinine and said Urea are alternatively labeled with a stable isotope selected from a group consisting of: 2H, 1N, 1S and any combination thereof.

[127] Tn yet another embodiment of the invention, wherein additionally comprising step of selecting the kind of sample from a group consisting of: (a) urine sample; (b) blood sample; and any combination thereof [128] In yet another embodiment of the invention, wherein said step (d) of determining concentration is carried out by means selected from a group consisting of (a) gas chromatography; (b) liquid chromatography; (c) mass speetroscopy; (d) nudear magnetic resonance spectroscopy; (e) infrared spectroscopy; and any combination thereof.

[129] In yet another embodiment of the invention, wherein said step (b) of administrating is carried out in a manner selected from a group consisting of (a) intra-muscular injection; (b)intra-venous injection; (c)sub-cutaneous injection; (d) intra-nasal administration and any combination thereof [130] In yet another embodiment of the invention, wherein said step (c) of collecting said samples is conducted at at least one time point after said step (b) of administrating said

injectable solution.

[131] A In yet another embodiment of the invention a method for analyzing samples taken from a mammalian subject to determine said mammalian subject renal function (400), comprising steps of: (a) providing said samples (401); (b) treating said samples (402); (c) determining said concentrations of Urea and Creatinine (403); and (ci) evaluating said renal ifinction from said concentrations of Urea and Crcatininc (404); wherein said Urea and Creatinine are labeled with C. [132] In yet another embodiment of the invention, wherein said Creatinine and said Urea are alternatively labeled with a stable isotope selected from a group consisting of 2H, 15N, and any combination thereof.

[133] In yet another embodiment of the invention, wherein said step (e) of determining said concentrations of Urea and Creatinine is carried out in a manner selected from a group consisting of: (a) gas chromatography; (b) liquid chromatography (c) mass speetroscopy; (d) nuclear magnetic resonance spcctroscopy; (c) infrared speetroseopy; and any combination thereof [134] In yet another embodiment of the invention, wherein said step of determining the concentration of Urea is done with no additional enzymatic reaction. Urea concentration can be easily determined by gas chromatography. However, Creatinine concentration is more difficult to detect by gas chromatography and there for in order to determine its concentration it is enzymatically converted to Urea and according to the urea concentration the Creatinine concentration is determined.

[135] In yet another embodiment of the invention, wherein said step of determining the concentration of Creatinine additionally comprises the steps of (a) dividing said sample to sample A and sample B; (b) measuring said concentration of Urea in said sample A; (c) enzymatically converting said Creatinine to said Urea in sample B; d) measuring said concentration of Urea in said sample B; and (e) subtracting said Urea concentration of step (b) from said Urea concentration of step (c).

[136] In yet another embodiment of the invention, wherein said step c) of enzymatically converting said Creatinine to said Urea is carried out by the Creatininase enzymatic treatment.

[137] Reference is now made to figure 1,illustratingin a schematic flow diagram the method for producing a medical device adapted to determine renal fhnction lcvcls(100).Urca and Creatinine are provided (101,102)and are mixed together (103).The mixed solution is and enclosed in pyrogenic containers (104). If the medical device is intended for injection then an additional step of sterilizing the mix as well as the containers has to be added.

Other optional additional steps are: adding inactive ingredients, mixing with water for injection or saline and lyophilizing or drying the mix into a powder.

[138] Reference is now made to figure 2,illustrating a schematic flow diagram of the method for determining renal function levels in a mammalian subject(200). In the first step an administrable solution comprising'C labeled Creatinine and Urea in a predetermined concentration is provided (201). In the next step the administrable solution is administered to a mammalian subject (202) and then a least one sample of blood and/or urine is collected (203). More than one sample or continuous collection of urine is also optional. In the last step the concentration of Urea and Creatininc in the samples are determined (204)gas or liquid chromatography. This method is for assessing the effectiveness of treatments such as dialysis and artificial kidneys. It should be also used to assess kidney function in people with chronic renal diseases as well as in people with diabetes, hypertension or hypotension.

[139] Reference is now made to figure 3illustrating a schematic flow diagram of the standard of care for accurately staging renal function within a patient(300). In the first step an administrable solution comprising Creatinine and Urea labeled with 13C in a predetermined concentration is provided (301). The solution is then administered (302) to a subject followed by sample collection (303). The concentrations of Urea and Creatinine in the collected samples arc then determined (304).This standard of care enables accurate staging of the renal function without putting into consideration factors such as age, race, gender, etc. [140] Reference is now made to figure 4 illustrating a schematic flow diagram of the method for analyzing samples to determine renal function (400). First a sample is provided(401) from a mammalian subject to which 3C labcled Urea and Crcatininc was administcrcd to.

Samples can be either urine or blood. In the second step the samples are treated as required for clinical samples (402) followed by determining the concentration of Urea and Creatinine (403) by chromatographie mass spectral technique. According to the concentration of Urea and Crcatininc in the blood! urine the kidney function is evaluated (404).