Methods and compositions for diagnosis and prognosis of renal injury and renal failure

Patent metadata

Field	Value
Publication number	US-11099194-B2
Application number	US-201715641203-A
Country	US
Kind code	B2
Filing date	Jul 3, 2017
Priority date	Jan 17, 2013
Publication date	Aug 24, 2021
Grant date	Aug 24, 2021

Abstract

The present invention relates to methods and compositions for monitoring, diagnosis, prognosis, and determination of treatment regimens in subjects suffering from or suspected of having a renal injury. In particular, the invention relates to using a measured urine concentration of one or more of TIMP2 and IGFBP7 in combination with one or more of a measured serum creatinine and a measured urine output, which results are correlated to the renal status of the subject, and can be used for diagnosis, prognosis, risk stratification, staging, monitoring, categorizing and determination of further diagnosis and treatment regimens in subjects suffering or at risk of suffering from an injury to renal function, reduced renal function, and/or acute renal failure.

First claim

We claim:

1. A method of treating an individual at risk of progressing to future stage I (Injury) or stage F (Failure) acute kidney injury under the RIFLE (Risk, Injury, Failure, Loss, End stage renal disease) classification system, based on a decision tree analysis, comprising:
obtaining a urine sample from the individual and using the urine sample,
determining a measure value for a urine Metalloproteinase inhibitor 2 (TIMP2) concentration,
determining a measured value for a urine Insulin-like growth factor-binding protein 7 (IGFBP7) concentration, and
determining a measured value for weight-adjusted urine output;

obtaining a serum sample from the individual and using the serum sample, determining a measured value for a serum creatnine concentration;
performing the decision tree analysis based on each of (i)-(iv):
(i) determine whether the product of the Insulin-like growth factor-binding protein 7 value and the Metalloproteinase inhibitor 2 value is above a predetermined threshold selected from a population study of subjects known to be at RIFLE stage R, the threshold separating the population into a first subpopulation above the threshold which is at an increased predisposition for progressing to future RIFLE stage I or F acute kidney injury within 48 hours relative to a second subpopulation not above the threshold,
(ii) determine whether the serum creatnine value is greater than or equal to 0.3 mg/dL or increased to greater than or equal to 150% (1.5-fold) of a baseline serum creatnine value for the individual,
(iii) determine whether the weight-adjusted urine output value is less than 0.5 mL/kg per hour for more than 6 hours, and
(iv) determine that (i) and either (ii) or (iii) are true;

correlating the result of the decision tree analysis to the individual's renal status, wherein (i) and either (ii) or (iii) are determined to be true for the individual, by assigning to the individual in which (i) and either (ii) or (iii) are true an increased likelihood of progressing to future RIFLE stage I or stage F within 48 hours, relative to an individual for which (i) and (ii) are not both true and for which (i) and (iii) are not both true; and
treating the individual based on the individual's assignment of an increased likelihood of progressing to future RIFLE stage I or stage F within 48 hours with a compatible treatment, wherein the compatible treatment comprises one or more of initiating renal replacement therapy, withdrawing delivery of compounds that are known to be damaging to the kidney, delaying procedures that are known to be damaging to the kidney, and modifying diuretic administration.

2. The method of claim 1 , wherein step (iv) of the decision tree analysis comprises determining that step (ii) is true.

3. The method of claim 1 , wherein step (iv) of the decision tree analysis comprises determining that step (iii) is true.

4. The method of claim 1 , wherein step (iv) of the decision tree analysis comprises determining that steps (ii) and (iii) are true.

5. The method of claim 1 , wherein the compatible treatment comprises initiating renal replacement therapy.

6. The method of claim 5 , wherein initiating renal replacement therapy comprises initiating dialysis.

7. The method of claim 1 , wherein the compatible treatment comprises withdrawing delivery of compounds that are known to be damaging to the kidney.

8. The method of claim 1 , wherein the compatible treatment comprises delaying procedures that are known to be damaging to the kidney.

9. The method of claim 1 , wherein the compatible treatment comprises modifying diuretic administration.

10. The method of claim 1 , further comprising assigning the individual a likelihood of progressing to future RIFLE stage I or F acute kidney injury within 30 days.

11. The method of claim 1 , further comprising assigning the individual a likelihood of progressing to future RIFLE stage I or F acute kidney injury within 24 hours.

12. The method of claim 1 , wherein the individual is selected for evaluation of renal status based on the pre-existence in the individual of one or more known risk factors for prerenal, intrinsic renal, or postrenal acute kidney injury.

13. The method of claim 1 , wherein the individual is selected for evaluation of renal status based on an existing diagnosis of one or more of congestive heart failure, preeclampsia, eclampsia, diabetes mellitus, hypertension, coronary artery disease, proteinuria, renal insufficiency, glomerular filtration below the normal range, cirrhosis, serum creatnine above the normal range, sepsis, injury to renal function, reduced renal function, or ARF, or based on undergoing or having undergone major vascular surgery, coronary artery bypass or other cardiac surgery, or based on exposure to NSAIDs, cyclosporines, tacrolimus, aminoglycosides, foscarnet, ethylene glycol, hemoglobin, myoglobin, ifosfamide, heavy metals, methotrexate, radiopaque contrast agents, or streptozotocin.

14. The method of claim 1 , further comprising assigning the individual a likelihood of progressing to future RIFLE stage F acute kidney injury within 48 hours.

15. The method of claim 1 , further comprising assigning the individual a likelihood of progressing to future RIFLE stage F acute kidney injury within 24 hours.

16. The method of claim 1 , wherein the increased predisposition for progressing to future RIFLE stage I or F acute kidney injury within 48 hours is an increased predisposition for progressing to future RIFLE stage I or F within 24 hours.

Assignees

• Astute Medical Inc

Inventors

• Anderberg Joseph
• Gray Jeff
• Mcpherson Paul
• Nakamura Kevin
• Kampf James Patrick

Classifications

• G01N33/6893 Primary

  related to diseases not provided for elsewhere · CPC title

• G01N33/70

  involving creatine or creatinine · CPC title

• G01N2800/347

  Renal failures; Glomerular diseases; Tubulointerstitial diseases, e.g. nephritic syndrome, glomerulonephritis; Renovascular diseases, e.g. renal artery occlusion, nephropathy · CPC title

• G01N2333/4745

  Insulin-like growth factor binding protein · CPC title

• G16B40/20

  Supervised data analysis · CPC title