Biomarkers related to kidney function and methods using the same

Abstract

Biomarkers of kidney function and methods for using said biomarkers for assessing kidney function, monitoring kidney function, diagnosing acute kidney injury, and diagnosing chronic kidney disease are provided. Also provided are suites of small molecule entities as biomarkers for chronic kidney disease.

What is claimed is: 
     
         1 . A method of assessing kidney function in a subject, the method comprising:
 a) extracting small molecules from a biological sample obtained from the subject to produce an analytical sample;   b) performing or having performed an assay on the analytical sample to determine the level(s) of one or more biomarkers, wherein the one or more biomarkers are selected from the group consisting of the following biomarkers: N-acetylthreonine, N-acetylalanine, arabitol, N-acetylserine, erythronate, 4-acetamidobutanoate, N6-carbamoylthreonyladenosine, N-acetylcarnosine, arabonate, xylonate, N-formylmethionine, O-methylcatechol sulfate, N-acetylmethionine, N2,N5-diacetylornithine, ribose, pyroglutamine, 5-methylthioadenosine (MTA), 1-methylurate, pro-hydroxy-pro, N-acetyl-3-methylhistidine, 2,3-dihydroxyisovalerate, trigonelline (N′-methylnicotinate), X-11564, and X-17299; and   c) assessing kidney function in the subject by comparing the level(s) of the one or more biomarkers to kidney function reference levels of the one or more biomarkers in order to assess kidney function in the subject.   
     
     
         2 . The method of  claim 1 , further comprising
 performing or having performed an assay on the analytical sample to determine the level(s) of one or more additional biomarkers selected from the group consisting of the following biomarkers: trans-4-hydroxyproline, myo-inositol, kynurenine, tryptophan, 3-methylhistidine, erythritol, urea, 3-methylglutarylcarnitine (C6), S-adenosylhomocysteine (SAH), N1-methyladenosine, N2,N2-dimethylguanosine, p-cresol sulfate, succinylcarnitine, 2-methylbutyrylcarnitine (C5), N4-acetylcytidine, N1-Methyl-2-pyridone-5-carboxamide, 1-methylhistidine, tiglyl carnitine, isobutyrylcarnitine, indolelactate, glutarylcarnitine (C5), choline, hydroxyisovaleroyl carnitine, scyllo-inositol, quinate, salicyluric glucuronide, 2-mannopyranosyl tryptophan (2-MPT), creatinine, phenylacetyl-L-glutamine, 3-indoxylsulfate, pseudouridine, N6-acetyllysine, threitol and 2-hydroxyhippurate (salicylurate).   
     
     
         3 . The method of  claim 1 , further comprising using the determined levels of the one or more biomarkers in a mathematical model to calculate an estimated glomerular filtration rate (GFR) to determine kidney function impairment. 
     
     
         4 . The method of  claim 3 , wherein the sample is analyzed using one or more techniques selected from the group consisting of mass spectrometry, ELISA, and antibody linkage. 
     
     
         5 . The method of  claim 1 , wherein the sample is obtained from a subject that has no symptoms of impaired kidney function. 
     
     
         6 . The method of  claim 1 , wherein the subject has been previously diagnosed with hypertension and/or diabetes. 
     
     
         7 . The method of  claim 1 , wherein the subject has symptoms of impaired kidney function. 
     
     
         8 . The method of  claim 1 , wherein the subject is one for whom kidney function assessment using conventional methods is difficult. 
     
     
         9 . The method of  claim 8 , wherein the subject is selected from the group consisting of the following: obese, very lean, vegetarian, chronically ill, and elderly. 
     
     
         10 . The method of  claim 1 , wherein the subject is a candidate to be a kidney donor. 
     
     
         11 . The method of  claim 1 , further comprising performing additional analysis comprising BUN, serum creatinine (SCr), urine albumin measurements, family history of chronic kidney disease (CKD), β-2 microglobulin, or β-TRACE, and combining results of the additional analysis with the assessment results from the initial assessment steps. 
     
     
         12 . A method of preventing impaired kidney function in a subject being treated or considered for treatment with a composition, wherein the composition may have a toxic effect on the kidneys, the method comprising:
 a) extracting small molecules from a biological sample obtained from the subject to produce an analytical sample;   b) performing, or having performed, an assay on the analytical sample to determine the level(s) of one or more biomarkers, wherein the one or more biomarkers are selected from the group consisting of the following biomarkers: N-acetylthreonine, N-acetylalanine, arabitol, N-acetylserine, erythronate, 4-acetamidobutanoate, N6-carbamoylthreonyladenosine, N-acetylcarnosine, arabonate, xylonate, N-formylmethionine, O-methylcatechol sulfate, N-acetylmethionine, N2,N5-diacetylornithine, ribose, pyroglutamine, 5-methylthioadenosine (MTA), 1-methylurate, pro-hydroxy-pro, N-acetyl-3-methylhistidine, 2,3-dihydroxyisovalerate, trigonelline (N′-methylnicotinate), X-11564, and X-17299; and   c) performing or having performed an assay on the analytical sample to determine the level(s) of one or more additional biomarkers selected from the group consisting of the following biomarkers: trans-4-hydroxyproline, myo-inositol, kynurenine, tryptophan, 3-methylhistidine, erythritol, urea, 3-methylglutarylcarnitine (C6), S-adenosylhomocysteine (SAH), N1-methyladenosine, N2,N2-dimethylguanosine, p-cresol sulfate, succinylcarnitine, 2-methylbutyrylcarnitine (C5), N4-acetylcytidine, N1-Methyl-2-pyridone-5-carboxamide, 1-methylhistidine, tiglyl carnitine, isobutyrylcarnitine, indolelactate, glutarylcarnitine (C5), choline, hydroxyisovaleroyl carnitine, scyllo-inositol, quinate, salicyluric glucuronide, 2-mannopyranosyl tryptophan (2-MPT), creatinine, phenylacetyl-L-glutamine, 3-indoxylsulfate, pseudouridine, N6-acetyllysine, threitol and 2-hydroxyhippurate (salicylurate); and   d) using the determined levels of the one or more biomarkers and, optionally, the one or more additional biomarkers, in a mathematical model to calculate an estimated glomerular filtration rate (GFR); and   e) using the estimated GFR to assess kidney function in the subject being treated or considered for treatment with the composition.   
     
     
         13 . The method of  claim 12 , wherein the composition is selected from the group consisting of a contrast imaging agent, a chemotherapeutic agent, and an antibiotic. 
     
     
         14 . A method of monitoring kidney function to prevent impaired kidney function in a subject, the method comprising:
 a) extracting small molecules from a biological sample obtained from a subject;   b) performing or having performed an assay on a first biological sample from the subject to determine the level(s) of one or more biomarkers for kidney function, where the one or more biomarkers are selected from the group consisting of the following biomarkers: N-acetylthreonine, N-acetylalanine, arabitol, N-acetylserine, erythronate, 4-acetamidobutanoate, N6-carbamoylthreonyladenosine, N-acetylcarnosine, arabonate, xylonate, N-formylmethionine, O-methylcatechol sulfate, N-acetylmethionine, N2,N5-diacetylornithine, ribose, pyroglutamine, 5-methylthioadenosine (MTA), 1-methylurate, pro-hydroxy-pro, N-acetyl-3-methylhistidine, 2,3-dihydroxyisovalerate, trigonelline (N′-methylnicotinate), X-11564, and X-17299;   c) performing or having performed the assay on a second biological sample from the subject to determine the level(s) of the one or more biomarkers for kidney function, wherein the second sample is obtained from the subject at a second time point; and   d) monitoring kidney function in the subject by comparing the level(s) of one or more biomarkers in the second sample to the level(s) of the one or more biomarkers in (a) the first sample and/or (b) kidney function reference levels of the one or more biomarkers.   
     
     
         15 . The method of  claim 14 , further comprising
 performing or having performed an assay on the first biological sample and the second biological sample from the subject to determine the level(s) of one or more additional biomarkers selected from the group consisting of the following biomarkers: trans-4-hydroxyproline, myo-inositol, kynurenine, tryptophan, 3-methylhistidine, erythritol, urea, 3-methylglutarylcarnitine (C6), S-adenosylhomocysteine (SAH), N1-methyladenosine, N2,N2-dimethylguanosine, p-cresol sulfate, succinylcarnitine, 2-methylbutyrylcarnitine (C5), N4-acetylcytidine, N1-Methyl-2-pyridone-5-carboxamide, 1-methylhistidine, tiglyl carnitine, isobutyrylcarnitine, indolelactate, glutarylcarnitine (C5), choline, hydroxyisovaleroyl carnitine, scyllo-inositol, quinate, salicyluric glucuronide, 2-mannopyranosyl tryptophan (2-MPT), creatinine, phenylacetyl-L-glutamine, 3-indoxylsulfate, pseudouridine, N6-acetyllysine, threitol and 2-hydroxyhippurate (salicylurate).   
     
     
         16 . The method of  claim 14 , further comprising using the determined levels of the one or more biomarkers in a mathematical model to calculate an estimated glomerular filtration rate (GFR); and using the estimated GFR to monitor kidney function. 
     
     
         17 . The method of  claim 14 , wherein the subject is being treated with a composition that may have a toxic effect on the kidneys. 
     
     
         18 . The method of  claim 17 , wherein the composition is selected from the group consisting of a contrast imaging agent, a chemotherapeutic agent, or an antibiotic.