Methods for renal function determination

Abstract

A method for determining a glomerular filtration rate (GFR) in a patient includes administering to said patient a compound of Formula I and transdermally measuring spectral energy emitted by the compound of Formula I over a measurement time window. The spectral energy is emitted by the compound of Formula I in response to electromagnetic radiation delivered to the compound of Formula I. The method also includes determining the GFR in said patient based on the measured spectral energy emitted by the compound of Formula I over the measurement time window by fitting an exponential function to the spectral energy as a function of time or a linear function to the log of the spectral energy as a function of time to calculate a rate constant associated with renal clearance over the measurement time window and directly related to the GFR normalized to a body size metric of the patient.

What is claimed is: 
     
         1 . A method for determining a glomerular filtration rate (GFR) in a human patient, said method comprising:
 administering to said patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is configured to emit spectral energy when exposed to electromagnetic radiation;   transdermally measuring the spectral energy emitted by the compound of Formula I in said patient over a measurement time window using a sensor attached on a body of said patient, the body comprising skin, wherein the spectral energy is emitted by the compound of Formula I in response to electromagnetic radiation delivered to the compound of Formula I in said patient; and   determining, using a computing device in communication with the sensor, the GFR in said patient based on the measured spectral energy emitted by the compound of Formula I over the measurement time window, wherein the computing device determines the GFR by fitting an exponential function to the spectral energy as a function of time or a linear function to the log of the spectral energy as a function of time to calculate a rate constant associated with renal clearance over the measurement time window, wherein the rate constant is directly related to the GFR normalized to a body size metric of the patient;   wherein in the compound of Formula I,   
       
         
           
           
               
               
           
         
         each of X 1  and X 2  is independently —CO 2 R 1 , —CONR 1 R 2 , —CO(AA) or —CONH(PS); 
         each of Y 1  and Y 2  is independently selected from the group consisting of —NR 1 R 2  and 
       
       
         
           
           
               
               
           
         
         Z 1  is a single bond, —CR 1 R 2 —, —O—, —NR 1 —, —NCOR 1 —, —S—, —SO—, or —SO 2 —; 
         each of R 1  to R 2  are independently selected from the group consisting of H, —CH 2 (CHOH) a H, —CH 2 (CHOH) a CH 3 , —CH 2 (CHOH) a CO 2 H, —(CHCO 2 H) a CO 2 H, —(CH 2 CH 2 O) c H, —(CH 2 CH 2 O) c CH 3 , —(CH 2 ) a SO 3 H, —(CH 2 ) a SO 3   − , —(CH 2 ) a SO 2 H, —(CH 2 ) a SO 2   − , —(CH 2 ) a NHSO 3 H, —(CH 2 ) a NHSO 3   − , —(CH 2 ) a NHSO 2 H, —(CH 2 ) a NHSO 2   − , —(CH 2 ) a PO 4 H 3 , —(CH 2 ) a PO 4 H 2   − , —(CH 2 ) a PO 4 H 2− , —(CH 2 ) a PO 4   3− , —(CH 2 ) a PO 3 H 2 , —(CH 2 ) a PO 3 H − , and —(CH 2 ) a PO 3   2− ; 
         AA is a single amino acid or a peptide chain comprising two or more amino acids, each amino acid selected from the group consisting of natural and unnatural amino acids, wherein the two or more amino acids of the peptide chain are linked together by peptide or amide bonds and each instance of AA may be the same or different than each other instance; 
         PS is a sulfated or non-sulfated polysaccharide chain comprising one or more monosaccharide units connected by glycosidic linkages; and 
         a is a number from 1 to 10, c is a number from 1 to 100, and each of m and n are independently a number from 1 to 3. 
       
     
     
         2 . The method of  claim 1 , further comprising delivering electromagnetic radiation to the compound of Formula I in said patient using the sensor attached on the body of said patient. 
     
     
         3 . The method of  claim 1 , wherein the measurement time window is from about 15 minutes to about 168 hours. 
     
     
         4 . The method of  claim 1 , wherein both X 1  and X 2  are —CO(AA). 
     
     
         5 . The method of  claim 4 , wherein AA is D-serine, Y 1  and Y 2  are each —NR 1 R 2  and R 1 ═R 2  ═H. 
     
     
         6 . The method of  claim 1 , wherein the administering is done via a single intravenous or transdermal injection, and wherein the measuring is done via multiple measurements after the single injection, whereby determining the GFR is performed in real time. 
     
     
         7 . The method of  claim 1 , further comprising measuring a diffuse reflectance of the skin prior to and/or after administering the compound of Formula I. 
     
     
         8 . The method of  claim 1 , further comprising recording a baseline signal of fluorescence prior to administering the compound of Formula I. 
     
     
         9 . The method of  claim 1 , further comprising monitoring equilibration of the compound of Formula I after administering the compound of Formula I. 
     
     
         10 . The method of  claim 1 , wherein the body size metric is body surface area. 
     
     
         11 . A system for determining a glomerular filtration rate (GFR) in a human patient, said system comprising:
 an electromagnetic radiation source for delivering electromagnetic radiation to a compound of Formula I administered to said patient, wherein the compound of Formula I is configured to emit spectral energy when exposed to the electromagnetic radiation;   a sensor for transdermally measuring the spectral energy emitted by the compound of Formula I in said patient over a measurement time window, the sensor configured to be attached on a body of said patient, the body comprising skin; and   a computing device configured to be connected in communication with the sensor, wherein the computing device is configured to determine the GFR in said patient based on the spectral energy emitted by the compound of Formula I and measured by the sensor over the measurement time window, wherein the computing device is configured to determine the GFR by fitting an exponential function to the spectral energy as a function of time or a linear function to the log of the spectral energy as a function of time to calculate a rate constant associated with renal clearance over the measurement time window, wherein the rate constant is directly related to the GFR normalized to a body size metric of the patient;   wherein in the compound of Formula I,   
       
         
           
           
               
               
           
         
         each of X 1  and X 2  is independently —CO 2 R 1 , —CONR 1 R 2 , —CO(AA) or —CONH(PS); 
         each of Y 1  and Y 2  is independently selected from the group consisting of —NR 1 R 2  and 
       
       
         
           
           
               
               
           
         
         Z 1  is a single bond, —CR 1 R 2 —, —O—, —NR 1 —, —NCOR 1 —, —S—, —SO—, or —SO 2 —; 
         each of R 1  to R 2  are independently selected from the group consisting of H, —CH 2 (CHOH) a H, —CH 2 (CHOH) a CH 3 , —CH 2 (CHOH) a CO 2 H, —(CHCO 2 H) a CO 2 H, —(CH 2 CH 2 O) c H, —(CH 2 CH 2 O) c CH 3 , —(CH 2 ) a SO 3 H, —(CH 2 ) a SO 3   − , —(CH 2 ) a SO 2 H, —(CH 2 ) a SO 2   − , —(CH 2 ) a NHSO 3 H, —(CH 2 ) a NHSO 3   − , —(CH 2 ) a NHSO 2 H, —(CH 2 ) a NHSO 2   − , —(CH 2 ) a PO 4 H 3 , —(CH 2 ) a PO 4 H 2   − , —(CH 2 ) a PO 4 H 2− , —(CH 2 ) a PO 4   3− , —(CH 2 ) a PO 3 H 2 , —(CH 2 ) a PO 3 H − , and —(CH 2 ) a PO 3   2− ; 
         AA is a single amino acid or a peptide chain comprising two or more amino acids, each amino acid selected from the group consisting of natural and unnatural amino acids, wherein the two or more amino acids of the peptide chain are linked together by peptide or amide bonds and each instance of AA may be the same or different than each other instance; 
         PS is a sulfated or non-sulfated polysaccharide chain comprising one or more monosaccharide units connected by glycosidic linkages; and 
         a is a number from 1 to 10, c is a number from 1 to 100, and each of m and n are independently a number from 1 to 3. 
       
     
     
         12 . The system of  claim 11 , wherein the sensor comprises the electromagnetic radiation source, the sensor being configured to generate and deliver the electromagnetic radiation to the compound of Formula I administered to said patient. 
     
     
         13 . The system of  claim 11 , wherein the computing device is further configured to determine a diffuse reflectance of the skin of said patient and, based on the determined diffuse reflectance, cause at least one of an output level of the electromagnetic radiation source and a detector gain level of the sensor to be adjusted. 
     
     
         14 . The system of  claim 11 , wherein the computing device is further configured to record a baseline signal representative of fluorescence being emitted from the body of said patient before the compound of Formula I is administered to said patient. 
     
     
         15 . The system of  claim 11 , wherein the computing device is further configured to determine that equilibration of the compound of Formula I administered to said patient is complete and determine the GFR in said patient in response to determining that the equilibration is complete. 
     
     
         16 . A method for determining a glomerular filtration rate (GFR) in a human patient in real-time, said method comprising:
 administering to said patient a single injection of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is configured to emit spectral energy when exposed to electromagnetic radiation;   transdermally measuring the spectral energy emitted by the compound of Formula I in said patient over measurement time windows using a sensor attached on a body of said patient, the body comprising skin, wherein the spectral energy is emitted by the compound of Formula I in response to electromagnetic radiation delivered to the compound of Formula I in said patient; and   determining, using a computing device in communication with the sensor, the GFR in said patient based on the measured spectral energy emitted by the compound of Formula I over each measurement time window, wherein, for each measurement time window, the computing device determines the GFR by fitting an exponential function to the spectral energy as a function of time or a linear function to the log of the spectral energy as a function of time to calculate a rate constant associated with renal clearance over the respective measurement time window, wherein the rate constant is directly related to the GFR normalized to a body size metric of the patient;   wherein in the compound of Formula I,   
       
         
           
           
               
               
           
         
         each of X 1  and X 2  is independently —CO 2 R 1 , —CONR 1 R 2 , —CO(AA) or —CONH(PS); 
         each of Y 1  and Y 2  is independently selected from the group consisting of —NR 1 R 2  and 
       
       
         
           
           
               
               
           
         
         Z 1  is a single bond, —CR 1 R 2 —, —O—, —NR 1 —, —NCOR 1 —, —S—, —SO—, or —SO 2 —; 
         each of R 1  to R 2  are independently selected from the group consisting of H, —CH 2 (CHOH) a H, —CH 2 (CHOH) a CH 3 , —CH 2 (CHOH) a CO 2 H, —(CHCO 2 H) a CO 2 H, —(CH 2 CH 2 O) c H, —(CH 2 CH 2 O) c CH 3 , —(CH 2 ) a SO 3 H, —(CH 2 ) a SO 3   − , —(CH 2 ) a SO 2 H, —(CH 2 ) a SO 2   − , —(CH 2 ) a NHSO 3 H, —(CH 2 ) a NHSO 3   − , —(CH 2 ) a NHSO 2 H, —(CH 2 ) a NHSO 2   − , —(CH 2 ) a PO 4 H 3 , —(CH 2 ) a PO 4 H 2   − , —(CH 2 ) a PO 4 H 2− , —(CH 2 ) a PO 4   3− , —(CH 2 ) a PO 3 H 2 , —(CH 2 ) a PO 3 H − , and —(CH 2 ) a PO 3   2− ; 
         AA is a single amino acid or a peptide chain comprising two or more amino acids, each amino acid selected from the group consisting of natural and unnatural amino acids, wherein the two or more amino acids of the peptide chain are linked together by peptide or amide bonds and each instance of AA may be the same or different than each other instance; 
         PS is a sulfated or non-sulfated polysaccharide chain comprising one or more monosaccharide units connected by glycosidic linkages; and 
         a is a number from 1 to 10, c is a number from 1 to 100, and each of m and n are independently a number from 1 to 3. 
       
     
     
         17 . The method of  claim 16 , wherein each of said measurement time windows is from about 15 minutes to about 168 hours. 
     
     
         18 . The method of  claim 16 , wherein at least one pair of temporally adjacent measurement time windows overlap. 
     
     
         19 . The method of  claim 16 , further comprising adjusting at least one of said measurement time windows based on a quality metric associated with the transdermally measured spectral energy over the at least one of said measurement time windows. 
     
     
         20 . The method of  claim 16 , further comprising monitoring equilibration of the compound of Formula I after administering the compound of Formula I and prior to transdermally measuring the spectral energy emitted by the compound of Formula I in said patient over a first of said measurement time windows.