Noninvasive method to quantify kidney function and functional decline
View Patent ↗Disclose are methods, compositions and kits for the determination of kidney function that provide an alternative to the standard-of-cure used for eGFR calculations. Described herein are methods for quantitative measurement of ADMA and hydration markers in a urine sample, and process used to transform the input of these methods into a measure of kidney function. The methods allow ADMA and other biomarkers to be detected in urine samples from a subject using a simple and inexpensive assay that can be easily performed noninvasively and only require urine samples for the prediction of kidney function.
1. A method for determining kidney function of a subject from a urine sample, the method comprising:
detecting an amount of asymmetric dimethylarginine (ADMA) from a urine sample of a subject;
assaying the urine sample to determine a hydration status of the subject; and
generating a value indicative of the kidney function of the subject based on the amount of ADMA from the urine sample and the hydration status of the subject;
determining the kidney function of the subject based on the value.
2. The method of claim 1 , wherein generating a value indicative of the kidney function of the subject comprises inputting the amount of ADMA and the hydration status of the subject into an algorithm to produce the value.
3. The method of claim 2 , wherein the algorithm is implemented via a computer system.
4. The method of claim 3 , wherein determining the kidney function of the subject comprises comparing the value to a threshold and determining the kidney function of the subject based on the comparison.
5. The method of claim 4 , wherein generating the value indicative of the kidney function of the subject comprises inputting a determined amount of a hydration marker from the urine sample into the algorithm to produce the value.
6. The method of claim 5 , wherein the hydration marker is creatinine.
7. The method of claim 5 , wherein the hydration marker is SDMA.
8. The method of claim 4 , wherein generating the value indicative of the kidney function of the subject comprises inputting a density or specific gravity of the urine sample into the algorithm to produce the value.
9. The method of claim 2 , wherein generating the value indicative of the kidney function of the subject comprises inputting an amount of total protein from the sample into the algorithm.
10. The method of claim 2 , wherein generating the value indicative of the kidney function of the subject comprises inputting an age of the subject into the algorithm.
11. The method of claim 2 , wherein generating the value indicative of the kidney function of the subject comprises inputting a gender of the subject into the algorithm.
12. The method of claim 2 , wherein a race of the subject is not input into the algorithm.
13. The method of claim 1 , wherein the amount of urine ADMA from the urine sample of the subject positively correlates with glomerular filtration rate (GFR).
14. The method of claim 1 , wherein the value indicative of the kidney function of the subject is an estimated GFR.
15. The method of claim 1 , wherein the hydration status of the subject is an amount of a urinary marker that is indicative of a hydration level in the subject.
16. The method of claim 15 , wherein the urinary marker that is indicative of a hydration level in the subject is selected from the group consisting of urine SDMA or urine creatinine.
17. The method of claim 16 , wherein assaying the urine sample to determine the hydration status of the subject comprises determining a density of the urine sample.
18. The method of claim 17 , wherein the hydration status of the subject is represented by a specific gravity of the urine sample.
19. The method of claim 1 , further comprising coupling a reagent to ADMA prior to detecting the amount of ADMA from the urine sample.
20. The method of claim 19 , wherein the reagent is selected from N-hydrosuccinimido carbonic acid; (2,5-dioxopyrrolidin-1 yl) hydrogen carbonate (also known as succinimidocarbonate); N,N′-disuccinimidyl carbonate; carbonic acid (choloromethyl ester) (N-hydroxysuccinimide ester); or (2,5-dioxopyrrolidin-1-yl) prop-2-enyl carbonate.
21. The method of claim 20 , wherein the step of detecting the amount of ADMA from the urine sample of the subject comprises:
contacting the urine sample with an antibody that specifically binds to ADMA; and
detecting an amount of the antibody that is in a bound state.
22. The method of claim 21 , wherein the antibody that specifically binds ADMA has a reactivity for symmetric dimethylarginine (SDMA) that is less than 25%, less than 10%, less than 5%, or less than 1% of its reactivity for ADMA.
23. The method of claim 1 , wherein the subject is identified as having impaired kidney function when the ADMA is in the urine sample at a concentration of less than 19.4 μM.
24. The method of claim 1 , wherein the subject is identified as having impaired kidney function when an ADMA/creatinine ratio or ADMA/SDMA ratio is less than 0 . 3 μM/mg/dL or 0.7 μ/mg/dL, respectively.
25. The method of claim 1 , further comprising (1) identifying the subject as having impaired kidney function and (2) administering a treatment to the subject based on the identified impairment of kidney function.
26. A method of detecting an amount of asymmetric dimethylarginine (ADMA) from a urine sample of a subject, the method comprising:
a. obtaining a urine sample from the subject; and
b. contacting the urine sample with an antibody that specifically binds to ADMA and
detecting binding between the antibody and ADMA, wherein the subject is identified as having impaired kidney function when the ADMA is in the urine sample at a concentration of less than 19.4 μM.
27. A method of treating a disease or disorder associated with decreased kidney function or kidney disease in a subject, the method comprising:
i) selecting a subject with having an ADMA concentration of less than 19.421 μM; or
ii) selecting a subject having an ADMA/creatinine ratio less than 0.3 μM/mg/dL; or
iii) selecting a subject having an ADMA/SDMA ratio less than 0.7 μM/mg/dL; and
iv) treating the subject by administering a diabetic kidney disease-targeted drug, a SGLT-2 receptor inhibitor, a SIRT 1 agonist, a bromodomain inhibitor, a steroid, or dialysis to the subject.