Compositions and methods for diagnosing and treating kidney disorders in a feline

• US 9,255,296 B2
• Filed: 02/24/2011
• Issued: 02/09/2016
• Est. Priority Date: 02/24/2011
• Status: Active Grant

• Current Assignee: Hill's Pet Nutrition Incorporated (Colgate-Palmolive Company)
• Original Assignee: Hill's Pet Nutrition Incorporated (Colgate-Palmolive Company)
• Inventors: Al-Murrani, Samer Waleed, Gao, Xiangming, Malladi, Sukhaswami
• Primary Examiner(s): Hibbert, Catherine S
• Application Number:
  US13/985,917
• Publication Number:
  US 20130344196A1
• Time in Patent Office: 1,811 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A23K 50/40 for carnivorous animals, e.g. cats or dogs
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/112 Disease subtyping, staging or classification
• CPC Class Codes: G01N 2800/347 Renal failures; Glomerular diseases; Tubulointerstitial diseases, e.g. nephritic syndrome, glomerulonephritis; Renovascular diseases, e.g. renal artery occlusion, nephropathy
• CPC Class Codes: G01N 33/6893 related to diseases not provided for elsewhere

Abstract

The present invention provides a method of diagnosing the existence of a kidney disorder in a feline comprising measuring the level of expression of one or more biomarkers selected from the group consisting of lumican; collagen alpha 1 (111) chain, variant 12; decorin; secreted frizzled-related protein 2; retinol binding protein 5; MMP-2; MMP-7; and MMP-19, in a biological sample from the feline, wherein differences in expression of the one or more biomarkers in the sample relative to a control value for expression in a sample from a normal animal indicate the existence of a kidney disorder; a method of treating a feline so diagnosed; and compositions, reagents and kits for carrying out the specified methods.

Claims

1. A method of diagnosing the existence of a kidney disorder in a feline comprising measuring the level of expression of one or more biomarkers selected from the group consisting of lumican;

collagen alpha 1(III) chain, variant 12;

decorin;

secreted frizzled-related protein 2;

retinol binding protein 5;

MMP-2;

MMP-7; and

MMP-19, in a biological sample from the feline,

comparing the level of expression of the one or more biomarkers in the biological sample from the feline to a control value, and

diagnosing the existence of the kidney disorder in the feline, wherein differences in expression of the one or more biomarkers in the sample relative to the control value for expression in a sample from a normal animal indicate the existence of a kidney disorder,

wherein the level of expression of the one or more biomarkers is determined by measuring gene expression of the one or more biomarkers using a DNA microarray comprising one or more oligonucleotides complementary to mRNA or cDNA corresponding to the one or more biomarkers to be measured, and

wherein the oligonucleotides in the DNA microarray comprise one or more probes comprising sequences selected from one or more of SEQ ID NOS. 1-8.

2. The method of claim 1 comprising detecting expression levels of secreted frizzled-related protein-2 (SFRP2) and/or retinol binding protein 5 (rbp5) and, optionally, expression levels of at least one gene selected from the group consisting of:

lumican (LUM);

decorin (DCN);

collagen alpha 1 (III) chain, variant 12 (COL3A1));

matrix metalloproteinase-2 (MMP2);

matrix metalloproteinase-7 (MMPI, PUMP-1); and

matrix metalloproteinase-19 (MMP19).

3. The method of claim 1 wherein the step of measuring gene expression of one or more biomarkers comprises (i) isolating RNA from the tissue sample, (ii) reverse transcribing the RNA to obtain the corresponding cDNA, (iii) isolating and fragmenting the cDNA thus obtained, (iv) contacting the cDNA fragments with a DNA microarray comprising one or more oligonucleotides complementary to cDNA corresponding to the one or more biomarkers to be measured, and (v) detecting hybridization between the cDNA fragments and the one or more oligonucleotides in the DNA microarray.

4. The method of claim 1 wherein the biological sample is blood or a sample of renal tissue.

5. The method of claim 1 comprising detecting expression levels of secreted frizzled-related protein-2 (SFRP2) and/or retinol binding protein 5 (rbp5).

6. The method of claim 1 wherein the feline has essentially normal kidney function, as measured by one or more of the following:

normal glomerular filtration rate, creatinine clearance rate, urinary protein levels, serum creatinine levels, urinary creatinine levels, blood urea nitrogen (BUN) levels, radioisotope metabolic labeling, soft tissue imaging, including sonography, magnetic resonance imaging and/or computed tomography.

7. The method of claim 1 wherein the kidney disorder is a disorder characterized by an abnormal loss of renal function, renal failure, reduced glomerular filtration rate or glomerulonephritis.

8. The method of claim 1 wherein the kidney disorder is glomerulonephritis.

9. The method of claim 1 wherein the existence of a kidney disorder is indicated by a significant difference in expression of one or more of the following relative to control expression values wherein a “

significant difference”

in the case of increased expression is an increase of at least twofold and in the case of decreased expression is a decrease of at least 50%;

a. Lumican expression increased;

b. Collagen alpha 1(III) chain, variant 12 expression increased;

c. Decorin expression increased;

d. Secreted frizzled-related protein 2 expression increased;

e. Retinol Binding Protein 5 expression decreased;

f. MMP-2 expression increased;

g. MMP-7 expression increased; and

/or

h. MMP-19 expression increased.

10. A method of treating, ameliorating, or delaying the progression of a kidney disorder characterized by an abnormal loss of renal function, renal failure, reduced glomerular filtration rate or glomerulonephritis in a feline, comprising diagnosing the existence of a kidney disorder by the method of claim 1 and managing the disorder by a kidney protective diet and/or medication.

11. The method of claim 10 wherein the step of managing the disorder comprises providing a kidney protective diet as substantially the sole diet to the feline.

12. The method of claim 10 wherein the kidney protective diet comprises one or more of the following modifications relative to a standard feline diet:

a. Reduced phosphorus

b. Reduced levels of protein

c. Reduced sodium

d. Increased levels of omega-3 fatty acids

e. Increased levels of B-complex vitamins

f. Increased antioxidants.

13. The method of claim 10 wherein the kidney protective diet comprises from about 18% to about 40% protein, from about 0.2% to about 0.85% phosphorus, and from about 0.04% to about 0.35% sodium, on a dry matter basis.

14. The method according to claim 12 comprising detecting expression levels of secreted frizzled-related protein-2 (SFRP2) and/or retinol binding protein 5 (rbp5).