Compositions and methods for diagnosing and treating chronic kidney disease
The present invention relates to methods and compositions for diagnosing and enabling treatment of chronic kidney disease in a feline. In one embodiment, a method of diagnosing chronic kidney disease (CKD) in a feline can comprise measuring a normalized relative abundance or absolute quantification of a first serum biomarker and determining if the feline has CKD, early-stage CKD, or late-stage CKD based on the normalized relative abundance or absolute quantification.
1 . A method of enabling treatment or slowing progression of chronic kidney disease in a feline, the method comprising:
(a) diagnosing chronic kidney disease (CKD) in the feline by (i) measuring a first serum biomarker, selected from the serum biomarkers listed in Tables 1 or 3 in normalized relative abundance, or selected from the serum biomarkers listed in Table 2 in absolute quantification:
TABLE 1
Diagnostic Range
(measured as normalized relative abundance)
Early-
Indeter-
Late-
Non-
Stage
minate
Stage
Serum Biomarker
CKD
CKD
Stage
CKD
4-ureidobutyrate
<−0.37
−0.37 to 0.379
0.38 to 1.5
>1.5
erythronate
<−0.49
−0.49 to 0.8
—
>0.8
6-oxopiperidine-2-
<−0.5
−0.5 to 0.469
0.47 to 1.48
>1.48
carboxylate
N-acetyl-
<−0.24
−0.24 to 0.39
0.40 to 1.2
>1.2
isoputreanine
retinol (Vitamin A)
<−0.29
−0.29 to 0.18
0.181 to 1.3
>1.3
pseudouridine
<−0.49
−0.49 to 0.61
—
>0.61
homocitrulline
<−0.19
−0.19 to 0.78
0.78 to 1.2
>1.2
ribonate
<−0.29
−0.29 to 0.53
0.531 to 0.82
>0.82
1-methylhistidine
<−0.39
−0.39 to 0.8
0.81 to 1.03
>1.03
3-hydroxy-2-
<−0.56
−0.56 to 0.164
0.165 to 1.2
>1.2
ethylpropionate
5,6-dihydrouridine
<−0.49
−0.49 to 0.8
—
>0.8
3,4-dihydroxy-
<−0.29
−0.29 to 0.4
0.41 to 1.0
>1.0
butyrate
formiminoglutamate
<−0.39
−0.39 to 0.9
—
>0.9
gamma-
<−0.29
−0.29 to 0.74
0.741 to 1.0
>1.0
carboxyglutamate
(S)-3-
<−0.219
−0.219 to 0.11
0.111 to 0.97
>0.97
hydroxybutyry-
lcarnitine
hydroxyasparagine
<−0.18
−0.18 to 0.64
0.641 to 0.83
>0.83
palmitoylcarnitine
<−0.47
−0.47 to 0.28
0.281 to 0.97
>0.97
aconitate
<−0.29
−0.29 to 0.44
0.441 to 0.88
>0.88
[cis or trans]
N1-methylinosine
<−0.29
−0.29 to 0.74
—
>0.74
orotidine
<−0.29
−0.29 to 0.6
—
>0.6
7-methylguanine
<−0.19
−0.19 to 0.54
0.541 to 0.96
>0.96
N-acetylserine
<−0.29
−0.29 to 0.7
—
>0.7
succinylcarnitine
<−0.09
−0.09 to 0.65
—
>0.65
2R,3R-
<−0.419
−0.419 to 0.43
0.431 to 0.85
>0.85
dihydroxybutyrate
2-O-methylascorbic
<−0.299
−0.299 to 0.65
0.651 to 1.07
>1.07
acid
O-sulfo-L-tyrosine
<−0.39
−0.39 to 0.6
—
>0.6
N-acetyltaurine
<−0.29
−0.29 to 0.19
0.191 to 0.98
>0.98
5-
<−0.19
−0.19 to 0.74
0.75 to 0.91
>0.91
hydroxy-
methylcytidine
arabitol/xylitol
<−0.39
−0.39 to 0.76
0.77 to 1.04
>1.04
arachidoyl carnitine
<−0.29
−0.29 to 0.34
0.341 to 0.97
>0.97
lyxonate
<−0.39
−0.39 to 0.8
—
>0.8
N6,N6-
<−0.29
−0.29 to 0.41
0.42 to 1.17
>1.17
dimethyllysine
2,3-dihydroxy-5-
<−0.29
−0.29 to 0.56
0.561 to 0.65
>0.65
methylthio-4-
pentenoate
(DMTPA)
hexanoyltaurine
<−0.32
−0.32 to 0.79
—
>0.79
allantoin
<−0.39
−0.39 to 0.79
—
>0.79
3-hydroxy-3-
<−0.29
−0.29 to 0.05
0.051 to 0.92
>0.92
methylglutarate
allantoic acid
<−0.14
−0.14 to 0.6
—
>0.6
myo-inositol
<−0.29
−0.29 to 0.67
0.68 to 0.93
>0.93
urea
<−0.444
−0.444 to 0.59
0.6 to 0.72
>0.72
dimethylglycine
<−0.39
−0.39 to 0.77
0.771 to 0.96
>0.96
TABLE 2
Diagnostic Range
(measured as absolute quantification in μg/mL)
Indeter-
Late-
Early-Stage
minate
Stage
Serum Biomarker
Non-CKD
CKD
Stage
CKD
3-Methyl-L-
<0.92
0.92 to 1.22
—
>1.22
Histidine
Acetylserine
<0.1
0.1 to 0.16
—
>0.16
Acetylthreonine
<0.08
0.08 to 0.12
—
>0.12
Beta-Pseudouridine
<1.03
1.03 to 2.12
—
>2.12
D-Arabitol
<0.27
0.27 to 0.44
—
>0.44
Meso-Erythritol
<0.48
0.48 to 0.98
—
>0.98
Myo-Inositol
<10.33
10.33 to 16.58
—
>16.58
N-Acetylalanine
<0.09
0.09 to 0.11
—
>0.11
Phenylacetyl-
<0.015
0.015 to 0.02
—
>0.02
glutamine
Tryptophan
>9.14
9.14 to 7
—
<7
Urea
<707.4
707.4 to 1150.6
—
>1150.6
TABLE 3
Diagnostic Range
(measured as normalized
relative abundance)
Early-
Indeter-
Late-
Stage
minate
Stage
Serum Biomarker
Non-CKD
CKD
Stage
CKD
1-methylguanidine
<0.73
0.73 to 1.53
—
>1.53
1-methyl-5-
<0.75
0.75 to 1.36
—
>1.36
imidazolelactate
5-(galactosylhydroxy)-
<0.82
0.82 to 1.43
—
>1.43
lysine
methionine sulfone
<0.8
0.8 to 1.47
—
>1.47
5-methylthioadenosine
<0.85
0.85 to 1.43
—
>1.43
(MTA)
N-carbamoylputrescine
<0.81
0.81 to 1.29
—
>1.29
oxindolylalanine
<0.78
0.78 to 1.34
—
>1.34
N6-carboxymethyllysine
<0.82
0.82 to 1.44
—
>1.44
ascorbic acid 2-sulfate
<0.75
0.75 to 1.45
—
>1.45
ascorbic acid 3-sulfate
<0.81
0.81 to 1.34
—
>1.34
citrate
<0.8
0.8 to 1.5
—
>1.5
carnitine
<0.87
0.87 to 1.29
—
>1.29
3-hydroxyadipate
<0.82
0.82 to 1.42
—
>1.42
azelate (C9-DC)
<0.84
0.84 to 1.3
—
>1.3
2S,3R-dihydroxybutyrate
<0.92
0.92 to 1.32
—
>1.32
glycerol 3-phosphate
<0.86
0.86 to 1.46
—
>1.46
orotate
<0.88
0.88 to 1.32
—
>1.32
3-ureidoisobutyrate
<0.91
0.91 to 1.37
—
>1.37
gamma-glutamyl-epsilon-
<0.91
0.91 to 1.43
—
>1.43
lysine
gamma-glutamylhistidine
<0.91
0.91 to 1.35
—
>1.35
gamma-glutamylisoleucine
<0.93
0.93 to 1.37
—
>1.37
2,6-dihydroxybenzoic acid
<0.93
0.93 to 1.3
—
>1.3
mannonate
<0.77
0.77 to 1.44
—
>1.44
(ii) measuring a normalized relative abundance or absolute quantification of a second serum biomarker selected from the serum biomarkers listed in Tables 1 or 3 in normalized relative abundance, or selected from the serum biomarkers listed in Table 2 in absolute quantification;
(iii) determining that the feline has CKD if the normalized relative abundance or absolute quantification have values outside the range under the non-CKD column, determining that the feline has early-stage chronic kidney disease if the normalized relative abundance or absolute quantification of the first and second serum biomarkers have values in the range under the early-stage CKD column, or determining that the feline has late-stage CKD if the normalized relative abundance or absolute quantification of the first and second serum biomarkers have values in the range under the late-stage CKD column; and
(iv) if the first and second serum biomarkers do not fall under the same diagnosis, measuring a normalized relative abundance or absolute quantification of one or more additional biomarkers to achieve a simple majority such that a diagnosis can be made; and
(b) feeding a composition to the feline, wherein the composition treats or slows the progression of CKD in the feline.
2 . The method of claim 1 , wherein the composition includes a combination of glycine, methionine, cysteine, and glutamine.
3 . The method of claim 1 , wherein the composition comprises medium chain triglycerides.
4 . The method of claim 1 , wherein the composition comprises arginine, eicosapentaenoic acid, docosahexaenoic acid, vitamin E, and B vitamins.
5 . The method of claim 1 , wherein the composition contains less than 1% of potassium and contains less than 1% of phosphorous compounds and phosphate compounds.
6 . The method of claim 1 , wherein the composition has protein and phosphorus in a ratio between 5:1 and 15:1.
7 . The method of claim 1 , wherein the composition is a pet food composition or is administered in conjunction with a pet food composition.
8 . The method of claim 1 , further comprising measuring a normalized relative abundance or absolute quantification of a third serum biomarker selected from the serum biomarkers listed in Tables 1 or 3 in normalized relative abundance, or selected from the serum biomarkers listed in Table 2 in absolute quantification.
9 . The method of claim 8 , further comprising measuring a normalized relative abundance or absolute quantification of a fourth serum biomarker selected from the serum biomarkers listed in Tables 1 or 3 in normalized relative abundance, or selected from the serum biomarkers listed in Table 2 in absolute quantification.