CN111118142A - 血清赖氨酸氧化酶作为肾间质纤维化的分层诊断性生物标志物 - Google Patents
血清赖氨酸氧化酶作为肾间质纤维化的分层诊断性生物标志物 Download PDFInfo
- Publication number
- CN111118142A CN111118142A CN202010053338.9A CN202010053338A CN111118142A CN 111118142 A CN111118142 A CN 111118142A CN 202010053338 A CN202010053338 A CN 202010053338A CN 111118142 A CN111118142 A CN 111118142A
- Authority
- CN
- China
- Prior art keywords
- serum
- fibrosis
- renal
- lox
- interstitial fibrosis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 210000002966 serum Anatomy 0.000 title claims abstract description 59
- 206010023421 Kidney fibrosis Diseases 0.000 title claims abstract description 38
- 239000000104 diagnostic biomarker Substances 0.000 title abstract description 8
- 102000004669 Protein-Lysine 6-Oxidase Human genes 0.000 title abstract description 6
- 108010003894 Protein-Lysine 6-Oxidase Proteins 0.000 title abstract description 6
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000004472 Lysine Substances 0.000 claims abstract description 19
- 102000004316 Oxidoreductases Human genes 0.000 claims abstract description 18
- 108090000854 Oxidoreductases Proteins 0.000 claims abstract description 18
- 201000002793 renal fibrosis Diseases 0.000 claims description 35
- 108090000623 proteins and genes Proteins 0.000 claims description 24
- 239000003153 chemical reaction reagent Substances 0.000 claims description 14
- 238000003745 diagnosis Methods 0.000 claims description 9
- 238000012360 testing method Methods 0.000 claims description 6
- 238000001514 detection method Methods 0.000 claims description 3
- 239000000090 biomarker Substances 0.000 claims description 2
- 239000003550 marker Substances 0.000 claims description 2
- 238000009007 Diagnostic Kit Methods 0.000 claims 1
- 230000002596 correlated effect Effects 0.000 abstract description 6
- 206010016654 Fibrosis Diseases 0.000 description 26
- 230000004761 fibrosis Effects 0.000 description 24
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 18
- 102000004169 proteins and genes Human genes 0.000 description 15
- 210000003734 kidney Anatomy 0.000 description 12
- 235000018102 proteins Nutrition 0.000 description 12
- 102000008186 Collagen Human genes 0.000 description 9
- 108010035532 Collagen Proteins 0.000 description 9
- 229920001436 collagen Polymers 0.000 description 9
- 229940109239 creatinine Drugs 0.000 description 9
- 210000005084 renal tissue Anatomy 0.000 description 9
- 108010088751 Albumins Proteins 0.000 description 8
- 102000009027 Albumins Human genes 0.000 description 8
- 241000700159 Rattus Species 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 206010012601 diabetes mellitus Diseases 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 208000017169 kidney disease Diseases 0.000 description 6
- 230000001105 regulatory effect Effects 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 108010006654 Bleomycin Proteins 0.000 description 5
- 102000016942 Elastin Human genes 0.000 description 5
- 108010014258 Elastin Proteins 0.000 description 5
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 description 5
- 229960001561 bleomycin Drugs 0.000 description 5
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 238000004132 cross linking Methods 0.000 description 5
- 229920002549 elastin Polymers 0.000 description 5
- 238000001262 western blot Methods 0.000 description 5
- 102000012192 Cystatin C Human genes 0.000 description 4
- 108010061642 Cystatin C Proteins 0.000 description 4
- 208000002251 Dissecting Aneurysm Diseases 0.000 description 4
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 4
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 4
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 4
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 4
- 208000027418 Wounds and injury Diseases 0.000 description 4
- 206010002895 aortic dissection Diseases 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 210000002744 extracellular matrix Anatomy 0.000 description 4
- 210000002950 fibroblast Anatomy 0.000 description 4
- 230000003176 fibrotic effect Effects 0.000 description 4
- 208000014674 injury Diseases 0.000 description 4
- 230000003907 kidney function Effects 0.000 description 4
- 208000005069 pulmonary fibrosis Diseases 0.000 description 4
- 238000010186 staining Methods 0.000 description 4
- 229940116269 uric acid Drugs 0.000 description 4
- 108060006698 EGF receptor Proteins 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 3
- 102100034671 L-lactate dehydrogenase A chain Human genes 0.000 description 3
- 108010088350 Lactate Dehydrogenase 5 Proteins 0.000 description 3
- 108010071690 Prealbumin Proteins 0.000 description 3
- 102000007584 Prealbumin Human genes 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000035487 diastolic blood pressure Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000003364 immunohistochemistry Methods 0.000 description 3
- 238000012417 linear regression Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 230000002107 myocardial effect Effects 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 230000035945 sensitivity Effects 0.000 description 3
- 210000002700 urine Anatomy 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- HSTOKWSFWGCZMH-UHFFFAOYSA-N 3,3'-diaminobenzidine Chemical compound C1=C(N)C(N)=CC=C1C1=CC=C(N)C(N)=C1 HSTOKWSFWGCZMH-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 102000015833 Cystatin Human genes 0.000 description 2
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 206010018372 Glomerulonephritis membranous Diseases 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- 108090000279 Peptidyltransferases Proteins 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 208000020832 chronic kidney disease Diseases 0.000 description 2
- 108050004038 cystatin Proteins 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 208000033679 diabetic kidney disease Diseases 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 102000035122 glycosylated proteins Human genes 0.000 description 2
- 108091005608 glycosylated proteins Proteins 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 201000008350 membranous glomerulonephritis Diseases 0.000 description 2
- 231100000855 membranous nephropathy Toxicity 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000009456 molecular mechanism Effects 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 2
- 210000000626 ureter Anatomy 0.000 description 2
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 1
- 108010082126 Alanine transaminase Proteins 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 241001061264 Astragalus Species 0.000 description 1
- 238000000035 BCA protein assay Methods 0.000 description 1
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 101710088172 HTH-type transcriptional regulator RipA Proteins 0.000 description 1
- 206010019668 Hepatic fibrosis Diseases 0.000 description 1
- 101001011906 Homo sapiens Matrix metalloproteinase-14 Proteins 0.000 description 1
- 101000669513 Homo sapiens Metalloproteinase inhibitor 1 Proteins 0.000 description 1
- 101000990908 Homo sapiens Neutrophil collagenase Proteins 0.000 description 1
- 101000990915 Homo sapiens Stromelysin-1 Proteins 0.000 description 1
- 208000010159 IgA glomerulonephritis Diseases 0.000 description 1
- 206010021263 IgA nephropathy Diseases 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 238000000585 Mann–Whitney U test Methods 0.000 description 1
- 102100030216 Matrix metalloproteinase-14 Human genes 0.000 description 1
- 102100039364 Metalloproteinase inhibitor 1 Human genes 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010028594 Myocardial fibrosis Diseases 0.000 description 1
- 102100030411 Neutrophil collagenase Human genes 0.000 description 1
- 101150108126 PLAU gene Proteins 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 208000032056 Radiation Fibrosis Syndrome Diseases 0.000 description 1
- 206010067953 Radiation fibrosis Diseases 0.000 description 1
- 208000022639 SchC6pf-Schulz-Passarge syndrome Diseases 0.000 description 1
- 208000001364 Schopf-Schulz-Passarge syndrome Diseases 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 238000012352 Spearman correlation analysis Methods 0.000 description 1
- 102100030416 Stromelysin-1 Human genes 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 238000005882 aldol condensation reaction Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000006533 astragalus Nutrition 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 238000000546 chi-square test Methods 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000013480 data collection Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000000326 densiometry Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000009699 differential effect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 208000028208 end stage renal disease Diseases 0.000 description 1
- 201000000523 end stage renal failure Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 201000005206 focal segmental glomerulosclerosis Diseases 0.000 description 1
- 231100000854 focal segmental glomerulosclerosis Toxicity 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 230000024924 glomerular filtration Effects 0.000 description 1
- 108010012204 glutamate aminotransferase Proteins 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000002991 immunohistochemical analysis Methods 0.000 description 1
- 238000012151 immunohistochemical method Methods 0.000 description 1
- 238000011532 immunohistochemical staining Methods 0.000 description 1
- 239000003547 immunosorbent Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000010874 in vitro model Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000003331 infrared imaging Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 238000011862 kidney biopsy Methods 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 238000007833 oxidative deamination reaction Methods 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 239000013610 patient sample Substances 0.000 description 1
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- 238000010814 radioimmunoprecipitation assay Methods 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- 210000004233 talus Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/573—Immunoassay; Biospecific binding assay; Materials therefor for enzymes or isoenzymes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/112—Disease subtyping, staging or classification
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/158—Expression markers
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/90—Enzymes; Proenzymes
- G01N2333/902—Oxidoreductases (1.)
- G01N2333/90245—Oxidoreductases (1.) acting on paired donors with incorporation of molecular oxygen (1.14)
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/34—Genitourinary disorders
- G01N2800/347—Renal failures; Glomerular diseases; Tubulointerstitial diseases, e.g. nephritic syndrome, glomerulonephritis; Renovascular diseases, e.g. renal artery occlusion, nephropathy
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Analytical Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Physics & Mathematics (AREA)
- Biomedical Technology (AREA)
- Urology & Nephrology (AREA)
- Microbiology (AREA)
- Pathology (AREA)
- Genetics & Genomics (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Hematology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cell Biology (AREA)
- General Engineering & Computer Science (AREA)
- Biophysics (AREA)
- Food Science & Technology (AREA)
- Medicinal Chemistry (AREA)
- General Physics & Mathematics (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
本发明涉及血清赖氨酸氧化酶作为肾间质纤维化的分层诊断性生物标志物。本发明首次证实血清赖氨酸氧化酶与肾间质纤维化相关且呈正相关，赖氨酸氧化酶可作为肾脏间质纤维化的无创分层诊断性生物标志物，且具备准确度高的优势。
Description
技术领域
本发明涉及临床疾病诊断技术领域，具体地说，涉及血清赖氨酸氧化酶为肾间质纤维化的分层诊断性生物标志物。
背景技术
肾间质纤维化是各种慢性肾脏疾病发展为终末期肾病的共同病理特征，表现为细胞外基质(extracellular matrix，ECM)逐渐增多且发生过度交联。肾间质纤维化的范围和程度与肾功能减退具有高度相关性，但分子机制目前尚未阐明。
赖氨酸氧化酶(lysyl oxidase，LOX)是参与ECM交联的关键酶，最主要的功能是促进胶原和弹性蛋白发生交联，其交联机制如下：胶原和弹性蛋白富含赖氨酸，LOX使其赖氨酸残基ε-氨基发生氧化脱氨，产生AAS，通过Schiff’s碱或2个AAS相互作用形成分子间的醛醇缩合反应，使分子内和分子间交联，进而将胶原和弹性蛋白的可溶性单体转变为不溶性纤维，形成稳定的胶原纤维和纤维组织，使其具有强大的弹性与韧性，并能抵抗非特异性蛋白水解酶引起的弹性蛋白分解和胶原溶解。
目前有研究表明LOX与肝纤维化、心肌纤维化、肺纤维化、肾间质纤维化和肿瘤等多种疾病存在关系。
《中国循环杂志》2017年8月第32卷刊出的论文“赖氨酸氧化酶:一个潜在的急性主动脉夹层诊断指标”，探索了血液中LOX表达与急性期主动脉夹层的关系，证实LOX随着主动脉夹层发病时间延长而逐渐升高，是急性主动脉夹持的一个潜在诊断指标。
《广东医学》2011年9月第32卷第18期刊出的论文“博来霉素致大鼠肺纤维化模型中赖氨酰氧化酶蛋白表达与活性的动态变化”，研究了博来霉素(BLM)致大鼠肺纤维化模型中赖氨酰氧化酶(LOX)蛋白表达的变化，以及该变化与其活性的关系和对胶原沉积的影响。具体使用Western blot技术检测大鼠肺纤维化模型肺组织中的LOX蛋白表达变化，图谱中46、50、32kD 3个条带分别代表LOX的前蛋白(prepro-LOX)、糖基化蛋白(glycosylatedproLOX)和成熟蛋白(LOX)。与对照组比较，preproLOX在BLM处理后9、14d明显上调；糖基化蛋白在第9天开始上调，并在第14天达到高峰；两个前体蛋白在28d后恢复到基线水平；BLM对32kD LOX表达量影响较轻。
兰州大学2014年博士论文“X线诱导心肌成纤维细胞促纤维化损伤及黄芪注射液对其干预的实验研究”，观察了“X线对心肌成纤维细胞的促纤维化损伤效应”并构建纤维化损伤的细胞模型，在上述细胞模型上检测分析了X线对84个纤维化相关分子表达的影响，筛选出差异表达的基因，从分子水平初步探索放射促纤维化损伤的可能分子机制。结果表明PCR Array检测84个纤维化相关分子显示模型组(1Gy)和对照组(0Gy)相比有44个基因差异表达，30个基因表达上调，14个基因表达下调；细胞外基质两个基因Col-1A2和Col-3A1表达均上调；重构酶基因中MMP14、MMP3、MMP8、Plau(uPA)、Serpinala(al-antitrypsin)表达上调，Lox、Plat、Serpinel、TIMP1表达下调。
综上，可见LOX与疾病的关系非常复杂。目前未见血清赖氨酸氧化酶作为肾间质纤维化的分层诊断性生物标志物的报道。
发明内容
本发明的目的是针对现有技术中的不足，提供一种肾间质纤维化的分层诊断性生物标志物。
第一方面，本发明提供了血清赖氨酸氧化酶作为生物标志物在制备肾间质纤维化的分层诊断试剂或试剂盒中的应用。
作为一种优选实施方式，所述肾间质纤维化的分层诊断试剂或试剂盒其检测样品为血清。
第二方面，本发明提供了检测血清中赖氨酸氧化酶蛋白或基因含量的试剂在制备肾间质纤维化的分层诊断试剂或试剂盒中的应用。
作为一种优选实施方式，所述肾间质纤维化的分层诊断试剂或试剂盒其检测样品为血清。
第三方面，本发明提供了一种肾间质纤维化的分层诊断试剂盒，所述试剂盒包含检测血清中赖氨酸氧化酶蛋白或基因含量的试剂，以及操作说明书，所述操作说明书记载：检测样品为血清，预测肾脏纤维化时血清LOX的cutoff值为253.34pg/ml，分层诊断肾脏纤维化轻度和中-重度时血清LOX的cutoff值为306.56pg/ml。
作为一种优选实施方式，所述试剂盒还包含至少一种血清赖氨酸氧化酶以外的肾间质纤维化标志物的诊断试剂。
如本文所用，所述“肾间质纤维化”与“肾脏纤维化”含义相同。
所述赖氨酸氧化酶蛋白可参见GenBank：AAB23549.1。
所述“肾间质纤维化的分层诊断”是指肾间质纤维化程度的分级，通常地，如采用肾穿刺组织学病理检查的方法，则按照以下标准分级：
| 分级 | 标准(皮质区IFTA面积) |
| 0 | <10％ |
| 1 | 10-25％ |
| 2 | 26-50％ |
| 3 | >50％ |
本发明优点在于：
本研究首次证实血清赖氨酸氧化酶与肾间质纤维化相关且呈正相关，赖氨酸氧化酶可作为肾脏间质纤维化的无创分层诊断性生物标志物，具有较高的准确度。
附图说明
附图1：不同程度肾纤维化患者血清LOX的比较。A-B.非肾纤维化、肾纤维化患者血清赖氨酸氧化酶(LOX)浓度与轻度肾纤维化(A)、中重度肾纤维化患者血清LOX浓度的比较(B)。C.采用Spearman相关分析检验肾脏纤维化与血清LOX的相关性。D.肾纤维化患者低(25％)和高(25％)血清LOX水平的肾纤维化程度的比较。E.肾纤维化组血清LOX低表达(25％)和高表达(25％)与肾纤维化程度相关性比较。
附图2：根据血清LOX水平预测肾脏纤维化的ROC曲线。A.队列组。Cutoff值＝253.34pg/ml。AUC＝0.80,95％CI＝0.74-0.86。敏感性(95％CI)＝0.73(0.67-0.78)。特异性(95％CI)＝0.71(0.65-0.77)。B.肾纤维化组。Cutoff值＝306.56pg/ml。AUC＝0.88,95％CI＝0.82-0.95。敏感性(95％CI)＝0.82(0.76-0.89)。特异性(95％CI)＝0.85(0.79-0.92)。
附图3：LOX在肾脏中的表达与肾脏纤维化相关。A.肾纤维化和无纤维化肾组织标本LOX、Col3和Masson染色的免疫组化分析。B.肾纤维化患者肾组织LOX与Col3表达的相关性。采用Spearman秩系数相关性检验评估统计学意义。C.肾纤维化患者肾组织LOX与纤维化面积的相关性。采用Spearman秩系数相关性检验评估统计学意义。缩略词：MHA:轻度组织学异常；MN:膜性肾病；DN:糖尿病肾病；ANS:肾小动脉硬化；IgAN:IgA肾病。
附图4：LOX在肾纤维化的体内和体外肾脏纤维化模型中均上调。A-B.Westernblot分析经AngII处理的NRK-49F细胞中Col3和LOX的表达。C-D.Western blot分析UUO模型中Col3和LOX的肾脏表达。E.免疫组化显示UUO模型术后14天肾脏LOX蛋白表达及定位；肾脏切片用针对LOX、Col3的特异性抗体染色；肾切片用马松染色。
具体实施方式
下面结合附图对本发明提供的具体实施方式作详细说明。
实施例1
1实验材料和方法
1.1人肾脏组织采集及基线资料的收集
为了检测人肾脏和血清中赖氨酸氧化酶(LOX)的表达，我们收集了2016年1月1日至2019年10月30日在同济医院经肾穿刺的符合要求的258例肾脏疾病病人的血液和肾穿刺的蜡块组织及30例健康对照病人的电子病例资料(包括性别，年龄，肌酐，尿素氮，24h尿蛋白，肾小球滤过率等)(有3例病人基线资料缺失已排除)。202例患者中包括8例轻微的肾脏病理改变、20例微小病变、5例局灶性节段性肾小球硬化、41例Ig A肾病、24例糖尿病肾病、41例膜性肾病、21例肾小动脉硬化、8例狼疮性肾病、12例血管相关性肾病及22例其它肾脏疾病引起的纤维化患者。
使用了马松三色染色和免疫组化(LOX和Collagen III)对肾穿刺组织切片进行染色。两名独立的病理学家对肾脏纤维化标本进行病理评分(标准同发明内容部分所述)，并通过Image J软件进行系统评分。
1.2血样收集和LOX检测
采集血样，离心，-80℃保存，直至检测。根据制造商的说明，将冷冻的血清样品迅速解冻并置于室温下，使用商用酶联免疫吸附试剂盒检测血清LOX浓度。同济医院人类受试者委员会批准了本研究中使用患者样品的方案。所有参与者均已获得知情同意。
1.3UUO模型
Sprague-Dawley(SD)大鼠200-250g和8周龄C57Bl/6J小鼠，购自上海斯莱克实验动物有限公司。实验过程严格遵守美国国立卫生研究院《实验动物的护理和使用指南》，并得到同济大学医学院伦理委员会的批准。2.5％异氟烷进行麻醉，待大鼠和小鼠按捏尾巴无反应后，进行后续的手术。UUO模型：对大鼠进行单侧输尿管结扎(unilateral ureteralobstruction，UUO)手术。平行于腹部中线的纵向切口暴露左肾和输尿管。4-0丝结扎左输尿管，UUO手术后第14天处死大鼠，收集左肾。马松染色结果显示，UUO肾脏有明显胶原沉积，肾脏纤维化造模成功。
1.4细胞培养
将大鼠肾脏成纤维细胞系(NRK-49F)培养于含有10％的胎牛血清(FBS)(Gibco，#10100147)的DMEM(Gibco，#10569044)培养液中，将细胞置于37℃、5％CO2的细胞培养箱中培养并传代。定期传代并进行药物处理。
1.5蛋白质印迹检测
RIPA裂解肾脏组织或细胞后提取蛋白。利用BCA蛋白检测法对样品进行定量。蛋白在10％SDS-PAGE凝胶上电泳，并转移到PVDF膜上。5％脱脂奶粉封闭1小时。然后加入一抗孵育过夜，再加入辣根过氧化物酶标记的二抗孵育1小时。使用Odyssey红外成像系统对目的蛋白进行成像并使用Quantity One软件进行光密度测定。
1.6免疫组织化学
将石蜡包埋后的肾脏组织，制成3μm厚的石蜡肾切片，将切片抗原修复后，一抗4℃下孵育过夜，然后与生物素标记的第二抗体和辣根过氧化物酶(HRP)标记的第三抗体(DAKO)一起孵育。使用3,3'-二氨基联苯胺(DAB)试剂盒(Vector，#SK4100)进行显影，苏木精复染后显微镜下观察。一抗包括Col3a(Abcam，#ab-6310)，LOX(Abcam，#ab-31238)。
1.7数据处理与统计学分析
采用SPSS 21.0版(SSPS Inc.)进行统计分析。健康对照组经性别-年龄-病例对照配对证实。连续性变量正态分布用平均值±标准差、非正态分布用中位数及四分位数表示。分类变量以频率和百分比表示。连续变量比较采用学生t检验或Mann-Whitney U检验，分类变量比较采用卡方检验。用Spearman相关系数或Pearson chisquare检验两个变量之间的相关性。测定血清LOX和肌酐对间质纤维化的诊断效能，采用ROC曲线、敏感性、特异性、AUC、95％置信区间，计算最佳Cutoff值。以血清LOX水平为竞争事件的多变量线性回归分析将白蛋白和血清肌酐作为连续变量，糖尿病和高血压作为二元变量。p<0.05为差异有统计学意义。采用逐步多元线性回归分析方法建立预测模型。p<0.05为差异有统计学意义。
2结果
2.1病人基线资料
202例接受肾活检的肾脏疾病患者和30例健康对照患者被纳入研究。根据Image J评分系统将肾病患者分为两组：无纤维化组(NF)，评分＝0；纤维化组(F)，评分>0。研究人群的人口学和临床特征如表1所示。间质纤维化患者的收缩压、舒张压高于无纤维化患者，白蛋白、胆固醇水平低于间质纤维化患者(p<0.05)。各亚群在性别、年龄、前白蛋白、白蛋白、丙氨酸氨基转移酶、天冬酰胺酸、谷氨酰胺转肽酶、乳酸脱氢酶A、甘油三酯等方面无明显差异。
表1：肾脏纤维化患者与肾脏未发生纤维化患者的基线资料.
缩写词：NF：无纤维化组；F：纤维化组；DM：糖尿病；SBP：收缩压；DBP：舒张压；PA：前白蛋白；ALB：白蛋白；ALT：谷氨酸氨基转移酶；AST：天冬酰胺酸；GGT：谷氨酰胺转肽酶；LDHA：乳酸脱氢酶A；TCH：胆固醇；TG：甘油三酯。
来自队列的患者血清LOX和肾功能指标参数见表2。纤维化组血清LOX明显高于无纤维化组(356.12(238.74,479.40)vs 212.89(177.67,270.09)，p<0.0001)，健康对照组(356.12(238.74,479.40)vs 217.41±54.33，p<0.0001，)。两组间血清胱抑素、尿素氮、肌酐、eGFR差异有统计学意义(p<0.05)。
表2：肾脏纤维化患者与肾脏未发生纤维化患者的血清LOX水平及肾功能比较.
缩写词：NF：无纤维化组；F：纤维化组；Cys：胱抑素C；UA：尿酸；UPRO：24h尿蛋白；BUN：血尿素氮；sCr：肌酐。
为进一步分析血清LOX对肾纤维化的鉴别作用，将肾纤维化患者分为轻度纤维化组(MF)，评分<25％；中度(评分26-50％)和重度(评分>50％)纤维化组(MSF)，图像J评分系统评分26-100％。MSF组血清LOX明显高于MF组，而血清胱抑素、尿素氮、肌酐、eGFR等临床特征与MSF组无明显差异(表3)。
表3：轻度肾脏纤维化患者与中重度纤维化患者血清LOX及肾功能比较
缩写词：MF：轻度纤维化组；MSF：中-重度纤维化组；UPRO：24h尿蛋白；Cys：胱抑素C；UA：尿酸；BUN：血尿素氮；sCr：肌酐。
2.2血清LOX水平与间质纤维化的关系
与无肾纤维化患者相比，间质性纤维化(F)患者血清LOX水平较高(p<0.001，图1A)。MSF组血清LOX水平明显高于MF组(p<0.001，图1B)。血清LOX水平与肾间质纤维化面积呈正相关(r＝0.640，p<0.001，图1C)。
表4显示了间质纤维化面积的多变量预测因子。调整白蛋白、eGFR，糖尿病和高血压后，LOX仍与肾间质纤维化相关(β＝0.596，p<0.001)。
表4：肾纤维化患者血清LOX与其他变量的相关性的多元线性回归分析.
缩写词：ALB：白蛋白；DM：糖尿病；Hypertenstion：高血压。
间质性纤维化患者(n＝127)按血清LOX水平的四分位数分为四组。血清LOX水平最高者(前25％)肾间质纤维化面积显著高于血清LOX水平最低者(低25％)(图1D)。肾间质纤维化面积与血清LOX水平显著相关(r＝0.748，p<0.001)(图1E)。
为了进一步探讨血清LOX对间质纤维化的诊断价值，我们使用ROC分析LOX对肾脏纤维化的诊断水平。血清LOX预测肾脏纤维化的能力AUC-ROC为0.80(95％CI，0.74～0.86)，血清LOX的cutoff值为253.34pg/ml，分层诊断肾脏纤维化轻度和中-重度的能力AUC-ROC为0.88(95％CI，0.82～0.95)(图2A)。血清LOX的cutoff值为306.56pg/ml(图2B)。
2.3肾穿刺组织LOX的表达
采用免疫组化方法进行肾脏组织LOX染色，并根据Image J评分系统测量肾间质纤维化评分面积，评价LOX与肾脏切片间质纤维化程度的相关性。无纤维化肾组织(包括轻度组织学异常和微小改变疾病)LOX和Col3蛋白染色阳性较少，间质纤维化组织标本LOX蛋白表达水平较高(图3B)。LOX表达与Col3表达(r＝0.889，p＝0.002)及肾组织间质纤维化面积(r＝0.899，p<0.001)呈显著正相关，见图3C。
2.4肾间质纤维化诱导LOX的表达
我们通过体内外实验进一步证明肾间质纤维化与LOX水平的关系。AngII处理NRK-49F细胞12h、24h、36h、48h后，LOX蛋白表达增加2.3倍(图4A-B)。采用UUO大鼠模型检测肾脏LOX蛋白水平。进食14天后，Western blot(图4C-D)分析显示，14天后，UUO大鼠肾脏的LOX增加了6倍。免疫组化染色结果也在肾组织石蜡包埋切片中得到证实(图4E)。我们的结果显示肾纤维化与LOX表达增加呈正相关。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员，在不脱离本发明方法的前提下，还可以做出若干改进和补充，这些改进和补充也应视为本发明的保护范围。
Claims (6)
1.血清赖氨酸氧化酶作为生物标志物在制备肾间质纤维化的分层诊断试剂或试剂盒中的应用。
2.根据权利要求1所述的应用，其特征在于，所述肾间质纤维化的分层诊断试剂或试剂盒其检测样品为血清。
3.检测血清中赖氨酸氧化酶蛋白或基因含量的试剂在制备肾间质纤维化的分层诊断试剂或试剂盒中的应用。
4.根据权利要求3所述的应用，其特征在于，所述肾间质纤维化的分层诊断试剂或试剂盒其检测样品为血清。
5.一种肾间质纤维化的分层诊断试剂盒，其特征在于，所述试剂盒包含检测血清中赖氨酸氧化酶蛋白或基因含量的试剂，以及操作说明书，所述操作说明书记载：检测样品为血清；预测肾脏纤维化时血清LOX的cutoff值为253.34pg/ml，分层诊断肾脏纤维化轻度和中-重度时血清LOX的cutoff值为306.56pg/ml。
6.根据权利要求5所述的试剂盒，其特征在于，所述试剂盒还包含至少一种血清赖氨酸氧化酶以外的肾间质纤维化标志物的诊断试剂。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010053338.9A CN111118142A (zh) | 2020-01-17 | 2020-01-17 | 血清赖氨酸氧化酶作为肾间质纤维化的分层诊断性生物标志物 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010053338.9A CN111118142A (zh) | 2020-01-17 | 2020-01-17 | 血清赖氨酸氧化酶作为肾间质纤维化的分层诊断性生物标志物 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111118142A true CN111118142A (zh) | 2020-05-08 |
Family
ID=70489868
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010053338.9A Pending CN111118142A (zh) | 2020-01-17 | 2020-01-17 | 血清赖氨酸氧化酶作为肾间质纤维化的分层诊断性生物标志物 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111118142A (zh) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030114410A1 (en) * | 2000-08-08 | 2003-06-19 | Technion Research And Development Foundation Ltd. | Pharmaceutical compositions and methods useful for modulating angiogenesis and inhibiting metastasis and tumor fibrosis |
| CN101842114A (zh) * | 2007-08-02 | 2010-09-22 | 阿雷斯托生物科学股份有限公司 | 治疗和诊断纤维化、肿瘤侵入、血管生成和转移的方法和组合物 |
| CN104755501A (zh) * | 2012-10-30 | 2015-07-01 | 吉联亚科学公司 | 与赖氨酰氧化酶样蛋白2(loxl2)相关的治疗和诊断方法 |
| CN108728523A (zh) * | 2017-04-14 | 2018-11-02 | 中国科学院上海生命科学研究院 | Bcl-3作为诊断早期肾纤维化的标志物的应用 |
-
2020
- 2020-01-17 CN CN202010053338.9A patent/CN111118142A/zh active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030114410A1 (en) * | 2000-08-08 | 2003-06-19 | Technion Research And Development Foundation Ltd. | Pharmaceutical compositions and methods useful for modulating angiogenesis and inhibiting metastasis and tumor fibrosis |
| CN101842114A (zh) * | 2007-08-02 | 2010-09-22 | 阿雷斯托生物科学股份有限公司 | 治疗和诊断纤维化、肿瘤侵入、血管生成和转移的方法和组合物 |
| CN104755501A (zh) * | 2012-10-30 | 2015-07-01 | 吉联亚科学公司 | 与赖氨酰氧化酶样蛋白2(loxl2)相关的治疗和诊断方法 |
| CN108728523A (zh) * | 2017-04-14 | 2018-11-02 | 中国科学院上海生命科学研究院 | Bcl-3作为诊断早期肾纤维化的标志物的应用 |
Non-Patent Citations (2)
| Title |
|---|
| OMAR A MESARWI MD等: "Lysyl Oxidase as a Serum Biomarker of Liver Fibrosis in Patients with Severe Obesity and Obstructive Sleep Apnea", 《SLEEP》, 31 October 2015 (2015-10-31), pages 1585 * |
| 张晓琴等: "赖氨酸氧化酶与肾间质纤维化的关系研究进展", 《中华实用诊断与治疗杂志》, vol. 33, no. 1, 31 January 2019 (2019-01-31), pages 95 - 97 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Yuki et al. | Impaired tight junctions in atopic dermatitis skin and in a skin-equivalent model treated with interleukin-17 | |
| Miettinen et al. | Ten-year prognosis of Puumala hantavirus-induced acute interstitial nephritis | |
| EP3118624B1 (en) | Methods of diagnosing proliferative disorders | |
| Trnka et al. | Urinary biomarkers in obstructive nephropathy | |
| Deng et al. | AQP2 promotes astrocyte activation by modulating the TLR4/NFκB-p65 pathway following intracerebral hemorrhage | |
| CN116794330B (zh) | 用于酒精性肝病诊断的生物标志物及其应用 | |
| Huang et al. | Key role for EphB2 receptor in kidney fibrosis | |
| Watany et al. | Nephronectin (NPNT) and the prediction of nephrotic syndrome response to steroid treatment | |
| Rende et al. | Diagnostic and prognostic biomarkers for tubulointerstitial fibrosis | |
| WO2023197981A1 (zh) | Mmp19在早期诊断肾损伤中的应用及其产品和方法 | |
| CN111118142A (zh) | 血清赖氨酸氧化酶作为肾间质纤维化的分层诊断性生物标志物 | |
| KR102077987B1 (ko) | 신장 질환 진단용 바이오 마커 | |
| CN109891241B (zh) | 能够进行糖尿病性肾病的早期病情的特异性诊断的检查方法 | |
| Su et al. | The value of serial serum cell adhesion molecules in predicting acute kidney injury after severe sepsis in adults | |
| TW201030340A (en) | Method for renal disease diagnosis and prognosis using annexin a1 and rab23 as markers | |
| Morita et al. | Urinary autotaxin concentrations are associated with kidney injury | |
| Sabasiñska et al. | Laminin and transforming growth factor beta-1 in children with vesicoureteric reflux | |
| Ma et al. | Relationships of urinary VEGF/CR and IL-6/CR with glomerular pathological injury in asymptomatic hematuria patients | |
| CN111157741B (zh) | 髓系细胞触发受体1在制备胃炎诊断或治疗试剂中的应用及试剂盒 | |
| Mattii et al. | Kidney expression of RhoA, TGF-β1, and Fibronectin in Human IgA Nephropathy | |
| EP2817636B1 (en) | New method for rapid detection of hepatocyte growth factor in biological fluids | |
| Lai et al. | Abnormal glucose metabolism and galactose-deficient immunoglobulin A1 (IgA1) synthesis: a possible mechanism of IgA nephropathy | |
| Dogan et al. | Relation of serum spondin-2 levels with cardiac morphology and inflammatory parameters in hemodialysis patients | |
| Christiansen et al. | Increased urinary orosomucoid excretion is not related to impaired renal function in patients with type 2 diabetes | |
| Sun et al. | Associations between the concentrations of CD68, TGF‑β1, renal injury index and prognosis in glomerular diseases |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20200508 |
|
| RJ01 | Rejection of invention patent application after publication |