WO2014147615A1

WO2014147615A1 - Determination of renal function level using creatinine and urea labeled by a stable isotope

Info

Publication number: WO2014147615A1
Application number: PCT/IL2014/050294
Authority: WO
Inventors: Dario Veretnik; Vadim Lozansky; Daniel WELTMAN; Boaz Giron
Original assignee: Dario Veretnik; Vadim Lozansky; Weltman Daniel; Boaz Giron
Priority date: 2013-03-21
Filing date: 2014-03-17
Publication date: 2014-09-25
Also published as: GB2512120A; GB201305205D0; GB2512120A8

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; The 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

DETERMINATION OF RENAL FUNCTION LEVEL USING CREATININE AND UREA LABELED BY A STABLE ISOTOPE

Field of the invention

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 13 C labeled Creatinine and Urea for determining renal function by administering it to a subject and checking their concentration in blood and/or urine.

Background of the invention

Renal function is an indication of the state of the kidney and its role in renal physiology, glomerular filtration rate (GFR), Creatinine clearance, blood Urea nitrogen (BUN), fractional excretion of Urea are all measures important in assessing the excretory function of the kidneys. It is very important to monitor renal functions of people suffering from chronic kidney disease as well as people suffering from diabetes, hypertension and dehydration.

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 are 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.

Several scientific papers suggested the use of 1 ⁱ3³C labeled Urea for assessing the water balance of a patient. For example, Ikizler et al. recites the use 13 C labeled Urea for assessing V_urea, which is assumed to be the equivalent of total body water, in monitoring dialytic treatment. In another example, Kloppenburg et al, recites the use 13 C labeled Urea for assessing urea kinetic parameters. However, the use of labeled urea is not sufficient for providing elaborated data regarding renal function of a subject.

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

Summary of the invention

The present invention provides a medical device useful for the determination of renal function levels comprising a first predetermined amount of Creatinine configured to be administered to a mammalian subject; the Creatinine concentration obtainable from at least one sample selected from a group consisting of: urine sample, blood sample, and any combination thereof; wherein the Creatinine is labeled with at least one stable isotope.

It is another object of the current invention to disclose the medical as defined in any of the above, wherein the stable isotope is selected from a group consisting of: 13C, 2H, 15N, 180, and any combination thereof.

It is another object of the current invention to disclose the medical as defined in any of the above, wherein the medical device additionally comprises Urea in a second predetermined amount labeled by at least one stable isotope.

It is another object of the current invention to disclose the medical as defined in any of the above, wherein the first predetermined amount and the second predetermined amount are in a fixed molar ratio.

It is another object of the current invention to disclose the medical as defined in any of the above, wherein the molar ratio reflects the human physiological ratio of Creatinine to Urea in the plasma of a healthy mammalian subject.

It is another object of the current invention to disclose the medical as defined in any of the above, wherein the ratio is about 0.08.

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

It is another object of the current invention to disclose the medical 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.

It is another object of the current invention to disclose the medical 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.

It is another object of the current invention to disclose the medical as defined in any of the above, wherein the medical device is adapted to assess renal function in subjects suffering from diabetes, hypertension and hypotension liquid imbalance.

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

It is another object of the current invention to disclose the medical as defined in any of the above, wherein the first predefined amount is determined according to the mammalian subject body weight.

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

It is another object of the current invention to disclose the medical as defined in any of the above, wherein the renal function is determined according to at least one parameter selected from a group consisting of: glomerular filtration rate (GFR), tubular reabsorption rate, the difference of Urea absorption from Creatinine absorption; fractional excretion of urea and any combination thereof. It is another object of the current invention to disclose the medical as defined in any of the above, wherein at least one sample is collected in a manner selected from a group consisting of: (a) one time point; (b); multiple time points (c) continuously; and any combination thereof.

It is another object of the current invention to disclose the medical as defined in any of the above, wherein at least one sample is taken from the subject beginning at X minutes following administration of the first predetermined amount of Creatinine.

It is another object of the current invention to disclose the medical as defined in any of the above, wherein X has the value from about 30 minutes to about 180 minutes.

It is another object of the current invention to disclose a medical device useful for the determination of renal function levels comprising a first predetermined amount of Creatinine and a second predetermined amount of Urea (220B) configured to be administered to a mammalian subject (230); the Creatinine and the Urea concentration obtainable from at least one sample selected from a group consisting of: urine sample, blood sample, and any combination thereof; wherein the Creatinine and the Urea are labeled with at least one stable isotope; further wherein the first predetermined amount and the second predetermined amount are in a fixed molar ratio.

It is another object of the current invention to disclose the medical as defined in any of the above, wherein the Urea and the Creatinine are labeled with the same stable isotope.

It is another object of the current invention to disclose the medical as defined in any of the above, wherein the Urea and the Creatinine are labeled with different stable isotopes.

It is another object of the current invention to disclose the medical as defined in any of the above, wherein the ratio reflects the physiological ratio of Creatinine to Urea in the plasma of a healthy mammalian subject.

It is another object of the current invention to disclose the medical as defined in any of the above, wherein the labeled Creatinine and the labeled Urea are stored in a manner selected from a group consisting of: administrable solution, lyophilized powder, dehydrated powder and any combination thereof.

It is another object of the current invention to disclose the medical as defined in any of the above, wherein the lyophilized powder and the dehydrated powder are diluted to a certain volume to give a first predetermined concentration of the Creatinine and the Urea.

It is another object of the current invention to disclose the medical as defined in any of the above, wherein the first and the second predefined amount is determined according to the mammalian subject body weight.

It is another object of the current invention to disclose the medical as defined in any of the above, wherein the renal function is determined according to at least one parameter selected from a group consisting of: glomerular filtration rate (GFR), tubular reabsorption rate, the difference of Urea absorption from Creatinine absorption; fractional excretion of Urea; and any combination thereof. It is another object of the current invention to disclose the medical as defined in any of the above, wherein at least one sample is collected in a manner selected from a group consisting of: (a) one time point; (b); multiple time points (c) continuously; and any combination thereof.

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 in a first predetermined amount; (b) means for administrating the Creatinine; and (c) means for detecting the Creatinine from at least one sample selected from a group consisting of: urine sample; blood sample; and any combination thereof; wherein the Creatinine is labeled with at least one stable isotope adapted to be identified by the means for detection.

It is another object of the current invention to disclose the system as defined in any of the above, wherein the Creatinine and labeled with a stable isotope selected from a group consisting of: 13C, 2H, 15N, 180, and any combination thereof.

It is another object of the current invention to disclose the system as defined in any of the above, wherein the system additionally comprises Urea in a second predetermined amount labeled by at least one stable isotope.

It is another object of the current invention to disclose the system as defined in any of the above, wherein the first predetermined amount and the second predetermined amount are a in a fixed molar ratio.

It is another object of the current invention to disclose the system as defined in any of the above, wherein the molar ratio reflects the physiological ratio of Creatinine to Urea in the plasma of a healthy mammalian subject.

It is another object of the current invention to disclose the system as defined in any of the above, wherein the ratio is about 0.08. It is another object of the current invention to disclose the system as defined in any of the above, wherein the labeled Creatinine is stored in a manner selected from a group consisting of: administrable solution, lyophilized powder, dehydrated powder and any combination thereof.

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 a first predetermined concentration of the Creatinine.

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.

It is another object of the current invention to disclose the system as defined in any of the above, wherein the system is adapted to determine effectiveness of treatments selected from a group consisting of: dialysis, hemodialysis, peritoneal dialysis, hemofiltration, hemodiafiltration, intestinal dialysis and any combination thereof.

It is another object of the current invention to disclose the system as defined in any of the above, wherein the system is adapted to assess renal function in subjects suffering from diabetes, hypertension and hypotension liquid imbalance.

It is another object of the current invention to disclose the system as defined in any of the above, wherein the first predefined amount of Creatinine is adapted for specific populations selected from a group consisting of: premature babies, neonates, infants, children, pregnant women, adults, elderly and health compromised individuals.

It is another object of the current invention to disclose the system as defined in any of the above, wherein the first predefined amount is determined according to the mammalian subject body weight.

It is another object of the current invention to disclose the system as defined in any of the above, wherein the enrichment of the stable isotope is A%, where A is substantially more than 0%.

It is another object of the current invention to disclose the system as defined in any of the above, wherein the renal function is determined according to at least one parameter selected from a group consisting of: glomerular filtration rate (GFR), tubular reabsorption rate, the difference of Urea absorption from Creatinine absorption; fractional excretion of Urea, and any combination thereof. It is another object of the current invention to disclose the system as defined in any of the above, wherein at least one sample is collected in a manner selected from a group consisting of: one time point; multiple time points; continuously; and any combination thereof.

It is another object of the current invention to disclose the system as defined in any of the above, wherein at least one sample is taken from the subject beginning at X minutes following administration of the first predetermined amount of Creatinine.

It is another object of the current invention to disclose the system as defined in any of the above, wherein the X has the value from about 30 minutes to about 180 minutes.

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: gas chromatography; liquid chromatography; mass spectroscopy; nuclear magnetic resonance spectroscopy; infrared spectroscopy; and any combination thereof.

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.

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 in a first predetermined amount; (b) Urea in a second predetermined amount; (c) means for administrating the Creatinine and the Urea; and (d) means for detecting the Creatinine and the Urea from at least one sample selected from a group consisting of: urine sample; blood sample; and any combination thereof; wherein the Creatinine and the Urea are labeled with at least one stable isotope adapted to be identified by the means for detection; further wherein the first predetermined amount and the second predetermined amount are in a fixed molar ratio.

It is another object of the current invention to disclose the system as defined in any of the above, wherein the Creatinine and the Urea are labeled with a stable isotope selected from a group consisting of: 13C, 2H, 15N, 180, and any combination thereof.

It is another object of the current invention to disclose the system as defined in any of the above, wherein the Urea and the Creatinine are labeled with the same stable isotope.

It is another object of the current invention to disclose the system as defined in any of the above, wherein the Urea and the Creatinine are labeled with different stable isotopes. It is another object of the current invention to disclose the system as defined in any of the above, wherein the first predetermined amount and the second predetermined amount are a in a fixed molar ratio.

It is another object of the current invention to disclose the system as defined in any of the above, wherein the ratio is about 0.08.

It is another object of the current invention to disclose the system as defined in any of the above, wherein the labeled Creatinine and the labeled Urea is stored in a manner selected from a group consisting of: administrable solution, lyophilized powder, dehydrated powder and any combination thereof.

It is another object of the current invention to disclose the system as defined in any of the above, wherein the first predefined amount of Creatinine and the second predefined amount of Urea are adapted for specific populations selected from a group consisting of: premature babies, neonates, infants, children, pregnant women, adults, elderly and health compromised individuals. It is another object of the current invention to disclose the system as defined in any of the above, wherein the first and the second predefined amount are determined according to the mammalian subject body weight.

It is another object of the current invention to disclose the system as defined in any of the above, wherein the renal function is determined according to at least one parameter selected from a group consisting of: glomerular filtration rate (GFR), tubular reabsorption rate, the difference of Urea absorption from Creatinine absorption; fractional excretion of Urea; and any combination thereof.

It is another object of the current invention to disclose the system as defined in any of the above, wherein at least one sample is collected in a manner selected from a group consisting of: one time point; multiple time points; continuously; and any combination thereof.

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) an administrable solution comprising Creatinine in a first predetermined amount; the administrable solution is enclosed in a pyrogenic container selected from a group consisting of: ampule; syringe; sachet, vial; bottle; other conventional vessel and any combination thereof; (b) means for administering the administrable solution; and, (c) instructions for use; wherein the Creatinine is labeled with at least one stable isotope. It is another object of the current invention to disclose the kit as defined in any of the above, wherein the stable isotope is selected from a group consisting of: 13C, 2H, 15N, 180, and any combination thereof.

It is another object of the current invention to disclose the kit as defined in any of the above, wherein the container is sterile.

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

It is another object of the current invention to disclose the kit as defined in any of the above, wherein the kit additionally comprises Urea in a second predetermined amount labeled by at least one stable isotope.

It is another object of the current invention to disclose the kit as defined in any of the above, wherein the first predetermined amount and the second predetermined amount are a in a fixed molar ratio.

It is another object of the current invention to disclose the kit as defined in any of the above, wherein the molar ratio reflects the physiological ratio of Creatinine to Urea in the plasma of a healthy mammalian subject.

It is another object of the current invention to disclose the kit as defined in any of the above, wherein the ratio is about 0.08.

It is another object of the current invention to disclose the kit 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.

It is another object of the current invention to disclose the kit as defined in any of the above, wherein the kit is adapted to determine effectiveness of treatments selected from a group consisting of: dialysis, hemodialysis, peritoneal dialysis, hemofiltration, hemodiafiltration, intestinal dialysis and any combination thereof.

It is another object of the current invention to disclose the kit as defined in any of the above, wherein the kit is adapted to assess renal function in subjects suffering from diabetes, hypertension and hypotension liquid imbalance. It is another object of the current invention to disclose the kit as defined in any of the above, wherein the first predefined amount is adapted for specific populations selected from a group consisting of: premature babies, neonates, infants, children, pregnant women, adults, elderly and health compromised individuals.

It is another object of the current invention to disclose the kit as defined in any of the above, wherein the first predefined amount is determined according to the mammalian subject body weight.

It is another object of the current invention to disclose the kit as defined in any of the above, wherein the enrichment of the stable isotope is A%, where A is substantially more than 0%.

It is another object of the current invention to disclose the kit as defined in any of the above, wherein the renal function is determined according to at least one parameter selected from a group consisting of: glomerular filtration rate (GFR), tubular reabsorption rate, the difference of Urea absorption from Creatinine absorption; fractional excretion of Urea, and any combination thereof.

It is another object of the current invention to disclose the kit as defined in any of the above, wherein the kit is adapted for self-use.

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) an administrable solution comprising Creatinine in a first predetermined amount and Urea in a second predetermined amount; the administrable solution is enclosed in a pyrogenic container selected from a group consisting of: ampule; syringe; sachet, vial; bottle; and any combination thereof; (b) means for administering the administrable solution; and, (c) instructions for use; wherein the Creatinine and the Urea are labeled with at least one stable isotope; further wherein the first predetermined amount and the second predetermined amount are in a fixed molar ratio.

It is another object of the current invention to disclose the kit as defined in any of the above, wherein the stable isotope is selected from a group consisting of: 13C, 2H, 15N, 180, and any combination thereof.

It is another object of the current invention to disclose the kit as defined in any of the above, wherein the kit additionally comprises inactive ingredients. It is another object of the current invention to disclose the kit as defined in any of the above, wherein the molar ratio reflects the physiological ratio of Creatinine to Urea in the plasma of a healthy mammalian subject.

It is another object of the current invention to disclose the kit as defined in any of the above, wherein the kit is adapted to assess renal function in subjects suffering from diabetes, hypertension and hypotension liquid imbalance.

It is another object of the current invention to disclose the kit as defined in any of the above, wherein the first predefined amount is adapted for specific populations selected from a group consisting of: premature babies, neonates, infants, children, pregnant women, adults, elderly and health compromised individuals.

It is another object of the current invention to disclose the kit as defined in any of the above, wherein the first predefined amount and the second predetermined amount are determined according to the mammalian subject body weight.

It is another object of the current invention to disclose the kit as defined in any of the above, wherein the renal function is determined according to at least one parameter selected from a group consisting of: glomerular filtration rate (GFR), tubular reabsorption rate, the difference of Urea absorption from Creatinine absorption; fractional excretion of Urea; and any combination thereof. It is another object of the current invention to disclose the kit as defined in any of the above, wherein the kit is adapted for self-use.

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, comprising steps of: (a) providing Creatinine in a predetermined amount; (b) enclosing the Creatinine in containers; wherein, additionally comprising step of labeling the Creatinine with at least one stable isotope.

It is another object of the current invention to disclose the method as defined in any of the above, additionally comprising a step of selecting at least one stable isotope from a group consisting of: 13C, 2H, 13C, 15N, 180, and any combination thereof.

It is another object of the current invention to disclose the method as defined in any of the above, additionally comprising a step of mixing the Creatinine in an aqueous solution selected from a group consisting of: saline; water for injection; and any combination thereof.

It is another object of the current invention to disclose the method as defined in any of the above, additionally comprising a step of lyophilizing the Creatinine.

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 Creatinine.

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

It is another object of the current invention to disclose the method as defined in any of the above, additionally comprising a step of adding inactive ingredients.

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, comprising steps of: (a) providing Creatinine in a first predetermined amount; (b) providing Urea in a second predetermined amount; (c) enclosing the Creatinine and the Urea in containers; wherein additionally comprising step of labeling the Creatinine and the Urea with at least one stable isotope; further wherein additionally comprising a step of providing the first predetermined amount and the second predetermined amount in a fixed molar ratio. It is another object of the current invention to disclose the method as defined in any of the above, additionally comprising a step of selecting at least one stable isotope from a group consisting of: 13C, 2H, 13C, 15N, 180, and any combination thereof.

It is another object of the current invention to disclose the method as defined in any of the above, additionally comprising a step of mixing the Creatinine and the Urea in an aqueous solution selected from a group consisting of: saline; water for injection; and any combination thereof.

It is another object of the current invention to disclose the method as defined in any of the above, additionally comprising a step of lyophilizing the Creatinine and the Urea.

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 Creatinine and the Urea.

It is another object of the current invention to disclose s method for determining renal function levels in a mammalian subject, comprising steps of: (a) providing an administrable solution comprising Creatinine in a predetermined concentration; (b) administrating the administrable solution to the mammalian subject; (c) collecting at least one sample selected from a group consisting of: blood sample; urine sample; and any combination thereof; and, (d) determining the concentration of the Creatinine in at least one sample; wherein additionally comprising step of s labeling the Creatinine with at least one stable isotope, thus enabling step (d) of determining its concentration.

It is another object of the current invention to disclose the method as defined in any of the above, additionally comprising a step of determining the effectiveness of treatments selected from a group consisting of: dialysis, hemodialysis, peritoneal dialysis, hemofiltration, hemodiafiltration, intestinal dialysis. It is another object of the current invention to disclose the method as defined in any of the above, additionally comprising a step of measuring renal function factors indicative of renal function selected from a group consisting of: glomerular filtration rate (GFR); tubular reabsorption factor (TrAF); Creatinine clearance rate; Blood Urea Nitrogen (BUN), fractional excretion of Urea; and any combination thereof.

It is another object of the current invention to disclose the method as defined in any of the above, additionally comprising a step of collecting the samples in at least one time point after the step of administrating the injectable solution.

It is another object of the current invention to disclose the method as defined in any of the above, additionally comprising step of determining the concentration by means selected from a group consisting of: gas chromatography; liquid chromatography mass spectroscopy; nuclear magnetic resonance spectroscopy; infrared spectroscopy; and any combination thereof.

It is another object of the current invention to disclose the method as defined in any of the above, additionally comprising step of administrating in a manner selected from a group consisting of: intra-muscular injection; intra-venous injection; sub-cutaneous injection; intra-nasal administration; and any combination thereof.

It is another object of the current invention to disclose the method as defined in any of the above, additionally comprising step of collecting urine samples in a manner selected from a group consisting of: one time point; multiple time points; continuously; and any combination thereof.

It is another object of the current invention to disclose a method for determining renal function levels in a mammalian subject, comprising steps of: (a) providing an administrable solution comprising Creatinine in a first predetermined concentration and Urea in a second predetermined concentration; (b) administrating the administrable solution to the mammalian subject; (c) collecting at least one sample selected from a group consisting of: blood sample; urine sample; and any combination thereof; and (d) determining the concentration of the Creatinine and the Urea in at least one sample; wherein additionally comprising step of s labeling the Creatinine and the Urea with at least one stable isotope, thus enabling step (d) of determining its concentration; further wherein additionally comprising a step of providing the first predetermined concentration and the second predetermined concentration in a fixed molar ratio.

It is another object of the current invention to disclose the method as defined in any of the above, additionally comprising a step of selecting at least one stable isotope from a group consisting of:

13C, 2H, 13C, 15N, 180, and any combination thereof. It is another object of the current invention to disclose the method as defined in any of the above, additionally comprising a step of determining the effectiveness of treatments selected from a group consisting of: dialysis, hemodialysis, peritoneal dialysis, hemofiltration, hemodiafiltration, intestinal dialysis.

It is another object of the current invention to disclose the method as defined in any of the above, additionally comprising a step of measuring renal function factors indicative of renal function selected from a group consisting of: glomerular filtration rate (GFR); tubular reabsorption factor (TrAF); Creatinine clearance rate; Blood Urea Nitrogen (BUN), fractional excretion of Urea; and any combination thereof.

It is another object of the current invention to disclose the method as defined in any of the above, additionally comprising a step of administrating in a manner selected from a group consisting of: intra-muscular injection; intra-venous injection; sub-cutaneous injection; intra-nasal administration; and any combination thereof.

It is another object of the current invention to disclose the method as defined in any of the above, additionally comprising a step of collecting the blood sample from a source selected from a group consisting of: vein; artery; capillary; and any combination thereof.

It is another object of the current invention to disclose a standard of care protocol for accurately staging renal function failure within a patient, comprising steps of: (a) providing an administrable solution comprising Creatinine in a predetermined concentration labeled with at least one stable isotope; (b) administering the administrable solution to the subject; (c) collecting at least one sample from the subject; and (d) determining the concentration of the Creatinine in the samples; wherein the concentrations of the labeled Creatinine in the samples is adapted to accurately determine GFR independently of at least one selected from a group consisting of: gender, race and age, stress, diet, physical activity and general liver conditions.

It is another object of the current invention to disclose the standard of care as defined in any of the above, additionally comprising a step of selecting at least one stable isotope from a group consisting of: 13C, 2H, 13C, 15N, 180, and any combination thereof.

It is another object of the current invention to disclose the standard of care as defined in any of the above, additionally comprising a step of selecting the sample from a group consisting of: urine sample; blood sample; and any combination thereof.

It is another object of the current invention to disclose the standard of care as defined in any of the above, additionally comprising a step of determining the concentration by means selected from a group consisting of: gas chromatography; liquid chromatography; mass spectroscopy; nuclear magnetic resonance spectroscopy; infrared spectroscopy; and any combination thereof.

It is another object of the current invention to disclose the standard of care as defined in any of the above, additionally comprising a step of administrating in a manner selected from a group consisting of: intra-muscular injection; intra-venous injection; sub-cutaneous injection; intranasal administration; and any combination thereof.

It is another object of the current invention to disclose the standard of care as defined in any of the above, additionally comprising a step of collecting the samples in at least one time point after the step of administrating the injectable solution. is another object of the current invention to disclose a standard of care protocol for accurately staging renal function failure within a patient (300), comprising steps of: (a) providing an administrable solution comprising Creatinine in a first predetermined concentration and Urea in a second predetermined concentration; the Creatinine and the Urea are labeled with at least one stable isotope; the first predetermined concentration and the second predetermined concentration are in a fixed molar ratio; (b) administering the administrable solution to the subject ; (c) collecting at least one sample from the subject; and, (d) determining the concentration of the Creatinine and the Urea in the samples; wherein the concentrations of the labeled Creatinine and the labeled Urea in the samples are adapted to accurately determine GFR independently of at least one selected from a group consisting of: gender, race and age, stress, diet, physical activity and general liver conditions. It is another object of the current invention to disclose the standard of care as defined in any of the above, additionally comprising a step of selecting at least one stable isotope from a group consisting of: 13C, 2H, 13C, 15N, 180, and any combination thereof.

It is another object of the current invention to disclose the standard of care as defined in any of the above, additionally comprising a step of collecting the samples in at least one time point after the step of administrating the injectable solution.

Brief Description of the drawings

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 specific 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 obscured. The present invention provides means and methods of accurately measuring renal function that without the use of radioisotopes or other unstable compounds.

In the accompanying drawing: Figure 1 is a schematic illustration of a device useful for the determination of renal function levels (100);

Figure 2 is a schematic illustration of a device useful for the determination of renal function levels (200);

Figure 3 is schematic flow diagram illustrating a method for producing a medical device adapted for the determination of renal function levels (300);

Figure 4 is schematic flow diagram illustrating a method for determining renal function levels in a mammalian subject (400); and,

Figure 5 is a graph showing the time in which changes in creatinine concentration occur after an acute lowering of GFR.

Detailed description of the invention

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 specific 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 obscured.

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. More specifically the present invention recites a method in which creatinine labeled with a stable isotope ( 13 C in the preferred embodiment) is introduced to a mammalian subject. The labeled creatinine concentration in the urine and/or blood is then followed in order to assess the kidney function of the mammalian subject. This method has a unique advantage over the classic method of assessing endogenous creatinine since, due to the labelling, it is known how much Creatinine is administered. In the classic method there is no way to know how much Creatinine is synthesized within the body and therefore its excretion can only be estimated indirectly. In the method of the invention the exact amount that is introduced is known and it is simple to follow its excretion by measuring the labeled Creatinine concentration in the blood and/or urine. In a preferred embodiment the labeled Creatinine is administered together with labled Urea. They can be labeled with the same isotope or with different isotopes. This combination enables a more precise evaluation of the kidney function. Creatinine is fully excreted by the kidney while Urea at least partially reabsorbed. This combination can not only assess the renal function but can also pinpoint the failure in case there is one.

In a preferred embodiment, the combination of isotopically labeled Creatinine and Urea is given in a ratio mimicking the physiological ratio of a healthy person. This way the administration of the Creatinine-Urea combination will not interfere with the homeostasis of the body. The physiological ratio in humans is approximately 1/12 Creatinine to Urea.

The term " H (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.

The term " 13 C (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.

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

The term " 18 O (oxygen-18)" refers hereinafter to a natural, stable isotope of oxygen and one of the environmental isotopes.

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

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

The term "mammalian subject" refers hereinafter to any 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.

The term "intranasal administration" refers hereinafter to administration through the thin mucosa of the nasal cavity which is well vascularized.

The term "inactive ingredients" refers hereinafter to ingredients added during the manufacturing process of pharmaceutical products and generally have no pharmacological effect binding materials (which may be excipients), dyes, preservatives, emulsifiers, antioxidants etc. 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.

The term "mass spectroscopy" refers hereinafter to the science of displaying the spectra of the masses of the molecules comprising a sample of material. More generally the term refers to 1AMS (Accelerator Mass Spectrometry), Gas Chromatography-MS, Liquid Chromatography- MS, ICP-MS (Inductively Coupled Plasma-Mass spectrometry), IRMS (Isotope Ratio Mass Spectrometry), Ion Mobility Spectrometry-MS, MALDI-TOF, SELDI-TOF, Tandem MS, TIMS (Thermal Ionization-Mass Spectrometry), SSMS (Spark Source Mass Spectrometry).

The term "nuclear magnetic resonance spectroscopy" refers hereinafter to the research technique that exploits the magnetic properties of certain atomic nuclei and determines the physical and chemical properties of atoms or the molecules in which they are contained.

The term "infrared spectroscopy" refers hereinafter to the 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 identify and study chemicals.

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.

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

The term "Glomerular filtration rate (GFR)" refers hereinafter to the flow rate of filtered fluid through the kidney. Creatinine clearance rate is the volume of blood plasma that is cleared of creatinine per unit time and is a useful measure for approximating the GFR.

The term "Creatinine" refers hereinafter to a breakdown product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body (depending on muscle mass). Creatinine is removed from the blood chiefly by the kidneys, primarily by glomerular filtration, but also by proximal tubular secretion. Little or no tubular reabsorption of creatinine occurs. If the filtration in the kidney is deficient, creatinine blood levels rise. Therefore, creatinine levels in blood and urine may be used to calculate the creatinine clearance (CrCl), which correlates with the glomerular filtration rate (GFR). Blood creatinine levels may also be used alone to calculate the estimated GFR (eGFR). The term "Urea" refers hereinafter to an organic compound with the chemical formula CO(NH₂)₂- Urea plays a role in the countercurrent exchange system of the nephrons, that allows for re-absorption of water and critical ions from the excreted urine. Urea is reabsorbed in the inner medullary collecting ducts of the nephrons, thus raising the osmolality in the medullary interstitium surrounding the thin ascending limb of the loop of Henle, which in turn causes water to be reabsorbed. By action of the urea transporter 2, some of this reabsorbed urea will eventually flow back into the thin ascending limb of the tubule, through the collecting ducts, and into the excreted urine. This mechanism, which is controlled by the antidiuretic hormone, allows the body to create hyperosmotic urine, that has a higher concentration of dissolved substances than the blood plasma. This mechanism is important to prevent the loss of water, to maintain blood pressure, and to maintain a suitable concentration of sodium ions in the blood plasmas.

The presented invention uses 13 C labeled Urea and 13 C Creatinine to determine renal function levels in a mammalian subject. The 13 C isotope is stable, non-radioactive, non-ionizing and chemically indistinguishable from 12 C, 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 order for them 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 term "clearance" refers hereinafter to a pharmacokinetic measurement of the renal excretion ability. Every endogenous and exogenous substance has a specific clearance that depends on its filtration characteristics. Clearance is a function of glomerular filtration, secretion from the peritubular capillaries to the nephron, and reabsorption from the nephron back to the peritubular capillaries.

Reference is now made to Fig. 1 which is a schematic illustration of a device useful for the determination of renal function levels (100). The device comprises of Creatinine labeled with a stable isotope (120) to be administered to a mammalian subject (130). In a preferred embodiment the stable isotope is 13 C but it is also possible to label with 2 H, 15 N or 18 O. The enrichment of the stable isotope can be any concentration higher than its natural occurrence and that is high enough to detect. For example, in the 13 C urea breath test, in EU and in few countries use 13 C urea enriched by 50% approx. In the US, western EU and Israel they use 13 C-urea enriched in a 99% minimum. In a preferred embodiment the enrichment of 13 C in urea and creatinine will be in the range of about 50% to about 100%. The Creatinine is supplied in a known amount either in a dry form or as a solution. This way it is exactly known how much creatinine was administered and it can be assessed what part was excreted by the kidneys and by that assess the renal function (110). This way the GFR can be calculated accurately without adding factors of age, race, gender... The creatinine may be injected or introduced intravenously or intranasal.

Reference is still made to Fig. 1. Creatinine may either be supplied as a dry form or as a solution. The dry form may be lyophilized Creatinine that is diluted with water prior to its administration. A solution form will be sterile in the case it is injected. Other substances may be included in the device like preservatives, color ad any other substance usually present in solutions for injections or for intranasal administration.

Reference is still made to Fig. 1. The concentration of creatinine can be measured in the urine and/or the blood. Samples can be taken periodically or at a specific time point or continuously.

Reference is still made to Fig. 1. The Creatinine in the device can be in different amounts according to the patient. It can be determined according to the patient's body weight or according to his renal function. It may also be determined according to age, gender, race, etc.

Reference is still made to Fig. 1. The device may be used to assess the progress and the effectiveness of treatments such as dialysis, hemofiltration, hemodiafiltration and intestinal dialysis. The device has additional importance in assessing renal function in diabetic patients and patients suffering from hypertension, hypotension and liquid imbalance.

Reference is now made to Fig. 2 which is a schematic illustration of a device useful for the determination of renal function levels (200). The device is very similar to the device described in Fig. 1. The only difference from Fig. 1 is it comprises Creatinine (220A) and Urea (220B) in a fixed molar ratio. In a preferred embodiment the ratio mimics the Creatinine to Urea ratio in the plasma which is about 1/12. This way the administration of the urea and creatinine will not interfere with their physiological balance. Following the exogenous concentration of urea and Creatinine in blood and/or urine sample (240) enables a much more accurate assessment of renal function.

Reference is now made to Fig. 3, illustrating in a schematic flow diagram the method for producing a medical device adapted to determine renal function levels (300). Labeled Urea and

Creatinine are provided (310, 320) and are mixed together. The mixed solution is and enclosed in pyrogenic containers (330). 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. The solution may also be lyophilized and stored as a solid and diluted only prior to use. The method may also contain a step of labeling the creatinine and/or Urea either with the same isotope or by different isotopes. The labeling is most likely to happen by enrichment.

If the medical device comprises creatinine only then the only the Creatinine is stored in the pyrogenic containers.

Reference is now made to Fig. 4, illustrating a schematic flow diagram of the method for determining renal function levels in a mammalian subject (400). In the first step an administrable

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solution comprising C labeled Creatinine in a predetermined concentration is provided (410). In the next step the administrable solution is administered to a mammalian subject (420) and then a least one sample of blood and/or urine is collected (430). More than one sample or continuous collection of urine is optional. In the last step the concentration of Urea and Creatinine in the samples are determined (440) by gas or liquid chromatography. This method can be used for assessing the effectiveness of treatments such as dialysis and artificial kidneys. It may be also used to assess kidney function in people with chronic renal diseases as well as in people with diabetes, hypertension or hypotension.

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The same method may be applied for assessing renal function with a solution of C Creatinine and ¹³C Urea.

In a standard of care for accurately staging renal function within a patient an administrable

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solution comprising Creatinine (and Urea in some embodiments) labeled with C (or other stable isotope) in a predetermined concentration is provided. The solution is then administered to a subject followed by sample collection. The concentrations of Urea and Creatinine in the collected samples are then determined. This standard of care enables accurate staging of the renal function without putting into consideration factors such as age, race, gender, etc.

Example 1

Cl_x = clearance of substance X

P_x = plasma concentration of substance X

U_x = urine concentration of substance X

V_f = urine flow C1_X = U_X V_f/ P_x

Creatinine gives indication regarding the filtration rate of the kidney since it is known to be fully secreted.

Clurea gives indication regarding the reabsorption rate of the kidney since it is known to be at least partially reabsorbed.

From the clearance of both substance the hydration state of a patient can be assessed: Clurea- Cl_creatinine is proportional to the hydration state. Example 2

When for some reason the GFR decreases dramatically it takes a while until the exogenous creatinine concentrations may be detected.

Reference is now made to Fig. 5 is a graph showing the time in which changes in creatinine concentration occur after an acute lowering of GFR. It can be seen that it takes at least a day for the Creatinine production, balance and excretion to change in a manner that is detectable.

By using exogenous labeled Creatinine decrease in GFR can be much faster detected. The changes in the concentrations of the labeled Creatinine will appear much faster and in addition it will be possible to differentiate between a kidney problem and a problem caused by elevated Creatinine concentration in the blood as a result of massive muscle breakdown.

Claims

1. A medical device (100) useful for the determination of renal function levels (110) comprising a first predetermined amount of Creatinine (120) configured to be administered to a mammalian subject (130); said Creatinine concentration (140) obtainable from at least one sample selected from a group consisting of: urine sample, blood sample, and any combination thereof; wherein said Creatinine is labeled with at least one stable isotope.

2. The medical device according to claim 1, wherein said stable isotope is selected from a group consisting of: 13 C, 2 H, 15 N, 18 O, and any combination thereof.

3. The medical device according to claim 1, wherein said medical device additionally comprises Urea in a second predetermined amount labeled by said at least one stable isotope.

4. The medical device according to claim 3, wherein said first predetermined amount and said second predetermined amount are in a fixed molar ratio.

5. The medical device according to claim 4, wherein said molar ratio reflects the human physiological ratio of Creatinine to Urea in the plasma of a healthy mammalian subject.

6. The medical device according to claim 5, wherein said ratio is about 0.08.

7. The medical device according to claim 1, wherein said labeled Creatinine is stored in a manner selected from a group consisting of: administrable solution, lyophilized powder, dehydrated powder and any combination thereof.

8. The medical device according to claim 7, wherein said lyophilized powder and said dehydrated powder are diluted to a certain volume to give a first predetermined concentration of said Creatinine.

9. The medical device according to claim 7, wherein said 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. The medical device according to claim 1, wherein said 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. The medical device according to claim 1, wherein said medical device is adapted to assess renal function in subjects suffering from diabetes, hypertension and hypotension liquid imbalance.

12. The medical device according to claim 1, wherein said first predefined amount of Creatinine is adapted for specific populations selected from a group consisting of: premature babies, neonates, infants, children, pregnant women, adults, elderly and health compromised individuals.

13. The medical device according to claim 1, wherein said first predefined amount is determined according to said mammalian subject body weight.

14. The medical device according to claim 1, wherein the enrichment of said stable isotope is A%, where A is substantially more than 0%.

15. The medical device according to claim 1, wherein said renal function is determined according to at least one parameter selected from a group consisting of: glomerular filtration rate (GFR), tubular reabsorption rate, the difference of Urea absorption from Creatinine absorption; fractional excretion of urea and any combination thereof.

16. The medical device according to claim 1, wherein said at least one sample is collected in a manner selected from a group consisting of: (a) one time point; (b); multiple time points (c) continuously; and any combination thereof.

17. The medical device according to claim 16, wherein said at least one sample is taken from said subject beginning at X minutes following administration of said first predetermined amount of Creatinine.

18. The medical device according to claim 17, wherein X has the value from about 30 minutes to about 180 minutes.

19. A medical device (200) useful for the determination of renal function levels (210) comprising a first predetermined amount of Creatinine (220A) and a second predetermined amount of Urea (220B) configured to be administered to a mammalian subject (230); said Creatinine and said Urea concentration (240) obtainable from at least one sample selected from a group consisting of: urine sample, blood sample, and any combination thereof; wherein said Creatinine and said Urea are labeled with at least one stable isotope; further wherein said first predetermined amount and said second predetermined amount are in a fixed molar ratio.

20. The medical device according to claim 19, wherein said stable isotope is selected from a group consisting of: 13 C, 2 H, 15 N, 18 O, and any combination thereof.

21. The medical device according to claim 19, wherein said Urea and said Creatinine are labeled with the same stable isotope.

22. The medical device according to claim 19, wherein said Urea and said Creatinine are labeled with different stable isotopes.

23. The medical device according to claim 19, wherein said ratio reflects the physiological ratio of Creatinine to Urea in the plasma of a healthy mammalian subject.

24. The medical device according to claim 23, wherein said ratio is about 0.08.

25. The medical device according to claim 19, wherein said labeled Creatinine and said labeled Urea are stored in a manner selected from a group consisting of: administrable solution, lyophilized powder, dehydrated powder and any combination thereof.

26. The medical device according to claim 25, wherein said lyophilized powder and said dehydrated powder are diluted to a certain volume to give a first predetermined concentration of said Creatinine and said Urea.

27. The medical device according to claim 25, wherein said 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.

28. The medical device according to claim 19, wherein said 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.

29. The medical device according to claim 19, wherein said medical device is adapted to assess renal function in subjects suffering from diabetes, hypertension and hypotension liquid imbalance.

30. The medical device according to claim 19, wherein said first predefined amount of Creatinine is adapted for specific populations selected from a group consisting of: premature babies, neonates, infants, children, pregnant women, adults, elderly and health compromised individuals.

31. The medical device according to claim 19, wherein said first and said second predefined amount is determined according to said mammalian subject body weight.

32. The medical device according to claim 19, wherein the enrichment of said stable isotope is A%, where A is substantially more than 0%.

33. The medical device of claim 19, wherein said renal function is determined according to at least one parameter selected from a group consisting of: glomerular filtration rate (GFR), tubular reabsorption rate, the difference of Urea absorption from Creatinine absorption; fractional excretion of Urea; and any combination thereof.

34. The medical device according to claim 19, wherein said at least one sample is collected in a manner selected from a group consisting of: (a) one time point; (b); multiple time points (c) continuously; and any combination thereof.

35. The medical device according to claim 34, wherein said at least one sample is taken from said subject beginning at X minutes following administration of said first predetermined amount of Creatinine.

36. The medical device according to claim 35, wherein X has the value from about 30 minutes to about 180 minutes.

37. A system adapted to determine renal function levels in a mammalian subject, comprising: a. Creatinine in a first predetermined amount; b. means for administrating said Creatinine; and c. means for detecting said Creatinine from at least one sample selected from a group consisting of: urine sample; blood sample; and any combination thereof; wherein said Creatinine is labeled with at least one stable isotope adapted to be identified by said means for detection.

38. The system according to claim 37, wherein said Creatinine and labeled with a stable isotope selected from a group consisting of: 13 C, 2 H, 15 N, 18 O, and any combination thereof.

39. The system according to claim 37, wherein said system additionally comprises Urea in a second predetermined amount labeled by said at least one stable isotope.

40. The system according to claim 39, wherein said first predetermined amount and said second predetermined amount are a in a fixed molar ratio.

41. The system according to claim 40, wherein said molar ratio reflects the physiological ratio of Creatinine to Urea in the plasma of a healthy mammalian subject.

42. The system according to claim 41, wherein said ratio is about 0.08.

43. The system according to claim 37, wherein said labeled Creatinine is stored in a manner selected from a group consisting of: administrable solution, lyophilized powder, dehydrated powder and any combination thereof.

44. The system according to claim 43, wherein said lyophilized powder and said dehydrated powder are diluted to a certain volume to give a first predetermined concentration of said Creatinine.

45. The system according to claim 43, wherein said 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.

46. The system according to claim 37, wherein said system is adapted to determine effectiveness of treatments selected from a group consisting of: dialysis, hemodialysis, peritoneal dialysis, hemofiltration, hemodiafiltration, intestinal dialysis and any combination thereof.

47. The system according to claim 37, wherein said system is adapted to assess renal function in subjects suffering from diabetes, hypertension and hypotension liquid imbalance.

48. The system according to claim 37, wherein said first predefined amount of Creatinine is adapted for specific populations selected from a group consisting of: premature babies, neonates, infants, children, pregnant women, adults, elderly and health compromised individuals.

49. The system according to claim 37, wherein said first predefined amount is determined according to said mammalian subject body weight.

50. The system according to claim 37, wherein the enrichment of said stable isotope is A%, where A is substantially more than 0%.

51. The system according to claim 37, wherein said renal function is determined according to at least one parameter selected from a group consisting of: glomerular filtration rate (GFR), tubular reabsorption rate, the difference of Urea absorption from Creatinine absorption; fractional excretion of Urea, and any combination thereof.

52. The system according to claim 37, wherein said at least one sample is collected in a manner selected from a group consisting of: one time point; multiple time points; continuously; and any combination thereof.

53. The system according to claim 52, wherein said at least one sample is taken from said subject beginning at X minutes following administration of said first predetermined amount of Creatinine.

54. The system according to claim 53, wherein said X has the value from about 30 minutes to about 180 minutes.

55. The system according to claim 37, wherein said means of detection are selected from a group consisting of: gas chromatography; liquid chromatography; mass spectroscopy; nuclear magnetic resonance spectroscopy; infrared spectroscopy; and any combination thereof.

56. The system according to claim 37, wherein said system is adapted for self-use.

57. A system adapted to determine renal function levels in a mammalian subject, comprising: a. Creatinine in a first predetermined amount; b. Urea in a second predetermined amount; c. means for administrating said Creatinine and said Urea; and d. means for detecting said Creatinine and said Urea from at least one sample selected from a group consisting of: urine sample; blood sample; and any combination thereof; wherein said Creatinine and said Urea are labeled with at least one stable isotope adapted to be identified by said means for detection; further wherein said first predetermined amount and said second predetermined amount are in a fixed molar ratio.

58. The system according to claim 57, wherein said Creatinine and said Urea are labeled with a stable isotope selected from a group consisting of: 13 C, 2 H, 15 N, 18 O, and any combination thereof.

59. The system according to claim 58, wherein said Urea and said Creatinine are labeled with the same stable isotope.

60. The system according to claim 58, wherein said Urea and said Creatinine are labeled with different stable isotopes.

61. The system according to claim 57, wherein said first predetermined amount and said second predetermined amount are a in a fixed molar ratio.

62. The system according to claim 61, wherein said molar ratio reflects the physiological ratio of Creatinine to Urea in the plasma of a healthy mammalian subject.

63. The system according to claim 62, wherein said ratio is about 0.08.

64. The system according to claim 57, wherein said labeled Creatinine and said labeled Urea is stored in a manner selected from a group consisting of: administrable solution, lyophilized powder, dehydrated powder and any combination thereof.

65. The system according to claim 64, wherein said lyophilized powder and said dehydrated powder are diluted to a certain volume to give a first predetermined concentration of said Creatinine.

66. The system according to claim 64, wherein said 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.

67. The system according to claim 57, wherein said system is adapted to determine effectiveness of treatments selected from a group consisting of: dialysis, hemodialysis, peritoneal dialysis, hemofiltration, hemodiafiltration, intestinal dialysis and any combination thereof.

68. The system according to claim 57, wherein said system is adapted to assess renal function in subjects suffering from diabetes, hypertension and hypotension liquid imbalance.

69. The system according to claim 57, wherein said first predefined amount of Creatinine and said second predefined amount of Urea are adapted for specific populations selected from a group consisting of: premature babies, neonates, infants, children, pregnant women, adults, elderly and health compromised individuals.

70. The system according to claim 57, wherein said first and said second predefined amount are determined according to said mammalian subject body weight.

71. The system according to claim 57, wherein the enrichment of said stable isotope is A%, where A is substantially more than 0%.

72. The system according to claim 57, wherein said renal function is determined according to at least one parameter selected from a group consisting of: glomerular filtration rate (GFR), tubular reabsorption rate, the difference of Urea absorption from Creatinine absorption; fractional excretion of Urea; and any combination thereof.

73. The system according to claim 57, wherein said at least one sample is collected in a manner selected from a group consisting of: one time point; multiple time points; continuously; and any combination thereof.

74. The system according to claim 73, wherein said at least one sample is taken from said subject beginning at X minutes following administration of said first predetermined amount of Creatinine.

75. The system according to claim 74, wherein said X has the value from about 30 minutes to about 180 minutes.

76. The system according to claim 57, wherein said means of detection are selected from a group consisting of: gas chromatography; liquid chromatography; mass spectroscopy; nuclear magnetic resonance spectroscopy; infrared spectroscopy; and any combination thereof.

77. The system according to claim 57, wherein said system is adapted for self-use.

78. A kit useful for the determination of renal function levels in a mammalian subject, comprising: a. an administrable solution comprising Creatinine in a first predetermined amount; said administrable solution is enclosed in a pyrogenic container selected from a group consisting of: ampule; syringe; sachet, vial; bottle; other conventional vessel and any combination thereof; b. means for administering said administrable solution; and, c. instructions for use; wherein said Creatinine is labeled with at least one stable isotope.

79. The kit according to claim 78, wherein said stable isotope is selected from a group consisting of: 13 C, 2 H, 15 N, 18 O, and any combination thereof.

80. The kit according to claim 78, wherein said container is sterile.

81. The kit according to claim 78, wherein said kit additionally comprises inactive ingredients.

82. The kit according to claim 78, wherein said kit additionally comprises Urea in a second predetermined amount labeled by said at least one stable isotope.

83. The kit according to claim 82, wherein said first predetermined amount and said second predetermined amount are a in a fixed molar ratio.

84. The kit according to claim 83, wherein said molar ratio reflects the physiological ratio of Creatinine to Urea in the plasma of a healthy mammalian subject.

85. The kit according to claim 84, wherein said ratio is about 0.08.

86. The kit according to claim 86, wherein said 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.

87. The kit according to claim 78, wherein said kit is adapted to determine effectiveness of treatments selected from a group consisting of: dialysis, hemodialysis, peritoneal dialysis, hemofiltration, hemodiafiltration, intestinal dialysis and any combination thereof.

88. The kit according to claim 78, wherein said kit is adapted to assess renal function in subjects suffering from diabetes, hypertension and hypotension liquid imbalance.

89. The kit according to claim 78, wherein said first predefined amount is adapted for specific populations selected from a group consisting of: premature babies, neonates, infants, children, pregnant women, adults, elderly and health compromised individuals.

90. The kit according to claim 78, wherein said first predefined amount is determined according to said mammalian subject body weight.

91. The kit according to claim 78, wherein the enrichment of said stable isotope is A%, where A is substantially more than 0%.

92. The kit according to claim 78, wherein said renal function is determined according to at least one parameter selected from a group consisting of: glomerular filtration rate (GFR), tubular reabsorption rate, the difference of Urea absorption from Creatinine absorption; fractional excretion of Urea, and any combination thereof.

93. The kit according to claim 78, wherein said kit is adapted for self-use.

94. A kit useful for the determination of renal function levels in a mammalian subject, comprising: a. an administrable solution comprising Creatinine in a first predetermined amount and Urea in a second predetermined amount; said administrable solution is enclosed in a pyrogenic container selected from a group consisting of: ampule; syringe; sachet, vial; bottle; and any combination thereof; b. means for administering said administrable solution; and, c. instructions for use; wherein said Creatinine and said Urea are labeled with at least one stable isotope; further wherein said first predetermined amount and said second predetermined amount are in a fixed molar ratio.

95. The kit according to claim 94, wherein said stable isotope is selected from a group consisting of: 13 C, 2 H, 15 N, 18 O, and any combination thereof.

96. The kit according to claim 94, wherein said container is sterile.

97. The kit according to claim 94, wherein said kit additionally comprises inactive ingredients.

98. The kit according to claim 94, wherein said molar ratio reflects the physiological ratio of Creatinine to Urea in the plasma of a healthy mammalian subject.

99. The kit according to claim 98, wherein said ratio is about 0.08.

100. The kit according to claim 94, wherein said 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.

101. The kit according to claim 94, wherein said kit is adapted to determine effectiveness of treatments selected from a group consisting of: dialysis, hemodialysis, peritoneal dialysis, hemofiltration, hemodiafiltration, intestinal dialysis and any combination thereof.

102. The kit according to claim 94, wherein said kit is adapted to assess renal function in subjects suffering from diabetes, hypertension and hypotension liquid imbalance.

103. The kit according to claim 94, wherein said first predefined amount is adapted for specific populations selected from a group consisting of: premature babies, neonates, infants, children, pregnant women, adults, elderly and health compromised individuals.

104. The kit according to claim 94, wherein said first predefined amount and said second predetermined amount are determined according to said mammalian subject body weight.

105. The kit according to claim 94, wherein the enrichment of said stable isotope is A%, where A is substantially more than 0%.

106. The kit according to claim 94, wherein said renal function is determined according to at least one parameter selected from a group consisting of: glomerular filtration rate (GFR), tubular reabsorption rate, the difference of Urea absorption from Creatinine absorption; fractional excretion of Urea; and any combination thereof.

107. The kit according to claim 94, wherein said kit is adapted for self-use.

108. A method for producing a medical device adapted for the determination of renal function levels (300), comprising steps of: a. providing Creatinine in a predetermined amount (310); b. enclosing said Creatinine in containers (330); wherein, said method additionally comprising step of labeling said Creatinine with at least one stable isotope.

109. The method according to claim 108, additionally comprising a step of selecting said at least one stable isotope from a group consisting of: 13 C, 2 H, 13 C, 15 N, 18 O, and any combination thereof.

110. The method according to claim 108, additionally comprising a step of mixing said Creatinine in an aqueous solution selected from a group consisting of: saline; water for injection; and any combination thereof.

111. The method according to claim 108, additionally comprising a step of lyophilizing said Creatinine.

112. The method according to claim 108, additionally comprising step of sterilizing said Creatinine.

113. The method according to claim 108, additionally comprising a step of selecting said container from a group consisting of: ampule; syringe; sachet; vial; bottle; and any combination thereof.

114. The method according to claim 108, additionally comprising a step of adding inactive ingredients.

115. A method for producing a medical device adapted for the determination of renal function levels (300), comprising steps of: a. providing Creatinine in a first predetermined amount (310); b. providing Urea in a second predetermined amount (320); c. enclosing said Creatinine and said Urea in containers (330); wherein additionally comprising step of labeling said Creatinine and said Urea with at least one stable isotope; further wherein additionally comprising a step of providing said first predetermined amount and said second predetermined amount in a fixed molar ratio.

116. The method according to claim 115, additionally comprising a step of selecting said at least one stable isotope from a group consisting of: 13 C, 2 H, 13 C, 15 N, 18 O, and any combination thereof.

117. The method according to claim 115, additionally comprising a step of mixing said Creatinine and said Urea in an aqueous solution selected from a group consisting of: saline; water for injection; and any combination thereof.

118. The method according to claim 115, additionally comprising a step of lyophilizing said Creatinine and said Urea.

119. The method according to claim 115, additionally comprising step of sterilizing said Creatinine and said Urea.

120. The method according to claim 115, additionally comprising a step of selecting said container from a group consisting of: ampule; syringe; sachet; vial; bottle; and any combination thereof.

121. The method according to claim 115, additionally comprising a step of adding inactive ingredients.

122. A method for determining renal function levels in a mammalian subject (400), comprising steps of: a. providing an administrable solution comprising Creatinine in a predetermined concentration (410); b. administrating said administrable solution to said mammalian subject (420); c. collecting at least one sample selected from a group consisting of: blood sample; urine sample; and any combination thereof (430); and, d. determining the concentration of said Creatinine in said at least one sample (440); wherein additionally comprising step of s labeling said Creatinine with at least one stable isotope, thus enabling step (d) of determining its concentration.

123. The method according to claim 122, additionally comprising a step of selecting said at least one stable isotope from a group consisting of: 13 C, 2 H, 13 C, 15 N, 18 O, and any combination thereof.

124. The method according to claim 122, additionally comprising a step of determining the effectiveness of treatments selected from a group consisting of: dialysis, hemodialysis, peritoneal dialysis, hemofiltration, hemodiafiltration, intestinal dialysis.

125. The method according to claim 122, additionally comprising a step of measuring renal function factors indicative of renal function selected from a group consisting of: glomerular filtration rate (GFR); tubular reabsorption factor (TrAF); Creatinine clearance rate; Blood Urea Nitrogen (BUN), fractional excretion of Urea; and any combination thereof.

126. The method according to claim 122, additionally comprising a step of collecting said samples in at least one time point after said step of administrating said injectable solution.

127. The method according to claim 122, additionally comprising step of determining said concentration by means selected from a group consisting of: gas chromatography; liquid chromatography mass spectroscopy; nuclear magnetic resonance spectroscopy; infrared spectroscopy; and any combination thereof.

128. The method according to claim 122, additionally comprising step of administrating in a manner selected from a group consisting of: intra-muscular injection; intra-venous injection; sub-cutaneous injection; intra-nasal administration; and any combination thereof.

129. The method according to claim 122, additionally comprising step of collecting urine samples in a manner selected from a group consisting of: one time point; multiple time points; continuously; and any combination thereof.

130. A method for determining renal function levels in a mammalian subject (300), comprising steps of: a. providing an administrable solution comprising Creatinine in a first predetermined concentration and Urea in a second 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: blood sample; 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 additionally comprising step of s labeling said Creatinine and said Urea with at least one stable isotope, thus enabling step (d) of determining its concentration; further wherein additionally comprising a step of providing said first predetermined concentration and said second predetermined concentration in a fixed molar ratio.

1. The method according to claim 130, additionally comprising a step of selecting said at least one stable isotope from a group consisting of: 13 C, 2 H, 13 C, 15 N, 18 O, and any combination thereof.

The method according to claim 130, additionally comprising a step of determining the effectiveness of treatments selected from a group consisting of: dialysis, hemodialysis, peritoneal dialysis, hemofiltration, hemodiafiltration, intestinal dialysis.

The method according to claim 130, additionally comprising a step of measuring renal function factors indicative of renal function selected from a group consisting of: glomerular filtration rate (GFR); tubular reabsorption factor (TrAF); Creatinine clearance rate; Blood Urea Nitrogen (BUN), fractional excretion of Urea; and any combination thereof.

The method according to claim 130, additionally comprising a step of collecting said samples in at least one time point after said step of administrating said injectable solution.

The method according to claim 130, additionally comprising step of determining said concentration by means selected from a group consisting of: gas chromatography; liquid chromatography mass spectroscopy; nuclear magnetic resonance spectroscopy; infrared spectroscopy; and any combination thereof.

The method according to claim 130, additionally comprising a step of administrating in a manner selected from a group consisting of: intra-muscular injection; intra-venous injection; sub-cutaneous injection; intra-nasal administration; and any combination thereof.

137. The method according to claim 130, additionally comprising step of collecting urine samples in a manner selected from a group consisting of: one time point; multiple time points; continuously; and any combination thereof.

138. The method according to claim 130, additionally comprising a step of collecting said blood sample from a source selected from a group consisting of: vein; artery; capillary; and any combination thereof.

139. A standard of care protocol for accurately staging renal function failure within a patient, comprising steps of: a. providing an administrable solution comprising Creatinine in a predetermined concentration labeled with at least one stable isotope; b. administering said administrable solution to said subject; c. collecting at least one sample from said subject; and d. determining the concentration of said Creatinine in said samples; wherein said concentrations of said labeled Creatinine in said samples is adapted to accurately determine GFR independently of at least one selected from a group consisting of: gender, race and age, stress, diet, physical activity and general liver conditions.

140. The standard of care protocol according to claim 139, additionally comprising a step of selecting said at least one stable isotope from a group consisting of: 13 C, 2 H, 13 C, 15 N,

18 O, and any combination thereof.

141. The standard of care protocol according to claim 139, additionally comprising a step of selecting said sample from a group consisting of: urine sample; blood sample; and any combination thereof.

142. The standard of care protocol according to claim 139, additionally comprising a step of determining said concentration by means selected from a group consisting of: gas chromatography; liquid chromatography; mass spectroscopy; nuclear magnetic resonance spectroscopy; infrared spectroscopy; and any combination thereof.

143. The standard of care protocol according to claim 139, additionally comprising a step of administrating in a manner selected from a group consisting of: intra-muscular injection; intra-venous injection; sub-cutaneous injection; intra-nasal administration; and any combination thereof.

144. The standard of care protocol according to claim 139, additionally comprising a step of collecting said samples in at least one time point after said step of administrating said injectable solution.

145. A standard of care protocol for accurately staging renal function failure within a patient (300), comprising steps of: a. providing an administrable solution comprising Creatinine in a first predetermined concentration and Urea in a second predetermined concentration; said Creatinine and said Urea are labeled with at least one stable isotope; said first predetermined concentration and said second predetermined concentration are in a fixed molar ratio; b. administering said administrable solution to said subject ; c. collecting at least one sample from said subject; and d. determining the concentration of said Creatinine and said Urea in said samples; wherein said concentrations of said labeled Creatinine and said labeled Urea in said samples are adapted to accurately determine GFR independently of at least one selected from a group consisting of: gender, race and age, stress, diet, physical activity and general liver conditions.

146. The standard of care protocol according to claim 145, additionally comprising a step of selecting said at least one stable isotope from a group consisting of: 13 C, 2 H, 13 C, 15 N,

18 O, and any combination thereof.

147. The standard of care protocol according to claim 145, additionally comprising a step of selecting said sample from a group consisting of: urine sample; blood sample; and any combination thereof.

148. The standard of care protocol according to claim 145, additionally comprising a step of determining said concentration by means selected from a group consisting of: gas chromatography; liquid chromatography; mass spectroscopy; nuclear magnetic resonance spectroscopy; infrared spectroscopy; and any combination thereof.

149. The standard of care protocol according to claim 145, additionally comprising a step of administrating in a manner selected from a group consisting of: intra-muscular injection; intra-venous injection; sub-cutaneous injection; intra-nasal administration; and any combination thereof.

150. The standard of care protocol according to claim 145, additionally comprising a step of collecting said samples in at least one time point after said step of administrating said injectable solution.