CN102998436A - 以生物样品中的氧及氢同位素诊断肾脏失调或肿瘤疾病 - Google Patents
以生物样品中的氧及氢同位素诊断肾脏失调或肿瘤疾病 Download PDFInfo
- Publication number
- CN102998436A CN102998436A CN2012103335474A CN201210333547A CN102998436A CN 102998436 A CN102998436 A CN 102998436A CN 2012103335474 A CN2012103335474 A CN 2012103335474A CN 201210333547 A CN201210333547 A CN 201210333547A CN 102998436 A CN102998436 A CN 102998436A
- Authority
- CN
- China
- Prior art keywords
- delta
- disease
- renal
- kidney
- water
- 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.)
- Granted
Links
- 208000017169 kidney disease Diseases 0.000 title claims abstract description 81
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 47
- 239000012472 biological sample Substances 0.000 title claims abstract description 23
- 238000003745 diagnosis Methods 0.000 title claims description 9
- 201000006370 kidney failure Diseases 0.000 title claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 title description 14
- 239000001257 hydrogen Substances 0.000 title description 13
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 title description 11
- 229910052760 oxygen Inorganic materials 0.000 title description 11
- 239000001301 oxygen Substances 0.000 title description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 title description 7
- 238000000034 method Methods 0.000 claims abstract description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 68
- 208000020832 chronic kidney disease Diseases 0.000 claims description 51
- 210000002381 plasma Anatomy 0.000 claims description 46
- 201000010099 disease Diseases 0.000 claims description 32
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 32
- 230000001613 neoplastic effect Effects 0.000 claims description 28
- 210000004369 blood Anatomy 0.000 claims description 23
- 239000008280 blood Substances 0.000 claims description 23
- 239000000523 sample Substances 0.000 claims description 14
- 210000001124 body fluid Anatomy 0.000 claims description 12
- 239000002274 desiccant Substances 0.000 claims description 12
- 239000010839 body fluid Substances 0.000 claims description 8
- 210000002700 urine Anatomy 0.000 claims description 8
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 6
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 6
- 208000001647 Renal Insufficiency Diseases 0.000 claims description 5
- 201000011040 acute kidney failure Diseases 0.000 claims description 5
- 210000003722 extracellular fluid Anatomy 0.000 claims description 5
- 210000002966 serum Anatomy 0.000 claims description 5
- 208000009304 Acute Kidney Injury Diseases 0.000 claims description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 206010018364 Glomerulonephritis Diseases 0.000 claims description 4
- 208000033626 Renal failure acute Diseases 0.000 claims description 4
- 239000001110 calcium chloride Substances 0.000 claims description 4
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 4
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 4
- 239000012530 fluid Substances 0.000 claims description 4
- 230000000302 ischemic effect Effects 0.000 claims description 4
- 206010003445 Ascites Diseases 0.000 claims description 3
- 210000000941 bile Anatomy 0.000 claims description 3
- 210000001175 cerebrospinal fluid Anatomy 0.000 claims description 3
- 238000004821 distillation Methods 0.000 claims description 3
- 210000003608 fece Anatomy 0.000 claims description 3
- 210000002751 lymph Anatomy 0.000 claims description 3
- 238000001223 reverse osmosis Methods 0.000 claims description 3
- 210000003296 saliva Anatomy 0.000 claims description 3
- 238000005292 vacuum distillation Methods 0.000 claims description 3
- 201000001431 Hyperuricemia Diseases 0.000 claims description 2
- 206010037601 Pyelonephritis chronic Diseases 0.000 claims description 2
- 206010061481 Renal injury Diseases 0.000 claims description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- 208000012998 acute renal failure Diseases 0.000 claims description 2
- 201000006368 chronic pyelonephritis Diseases 0.000 claims description 2
- 208000022831 chronic renal failure syndrome Diseases 0.000 claims description 2
- GUJOJGAPFQRJSV-UHFFFAOYSA-N dialuminum;dioxosilane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[O-2].[Al+3].[Al+3].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O GUJOJGAPFQRJSV-UHFFFAOYSA-N 0.000 claims description 2
- 239000002808 molecular sieve Substances 0.000 claims description 2
- 208000030761 polycystic kidney disease Diseases 0.000 claims description 2
- 239000000741 silica gel Substances 0.000 claims description 2
- 229910002027 silica gel Inorganic materials 0.000 claims description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 2
- 231100000331 toxic Toxicity 0.000 claims description 2
- 230000002588 toxic effect Effects 0.000 claims description 2
- 229960001866 silicon dioxide Drugs 0.000 claims 1
- 201000000523 end stage renal failure Diseases 0.000 description 49
- 208000028208 end stage renal disease Diseases 0.000 description 44
- 206010012601 diabetes mellitus Diseases 0.000 description 30
- 210000003734 kidney Anatomy 0.000 description 15
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 14
- 102000010637 Aquaporins Human genes 0.000 description 13
- 230000003907 kidney function Effects 0.000 description 12
- 108010063290 Aquaporins Proteins 0.000 description 10
- 238000001631 haemodialysis Methods 0.000 description 9
- 230000000322 hemodialysis Effects 0.000 description 9
- 230000008085 renal dysfunction Effects 0.000 description 8
- 102000004888 Aquaporin 1 Human genes 0.000 description 7
- 102100034221 Growth-regulated alpha protein Human genes 0.000 description 7
- 101001069921 Homo sapiens Growth-regulated alpha protein Proteins 0.000 description 7
- 229940109239 creatinine Drugs 0.000 description 7
- 235000013305 food Nutrition 0.000 description 7
- 238000001556 precipitation Methods 0.000 description 7
- 108090001004 Aquaporin 1 Proteins 0.000 description 6
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 6
- 235000005911 diet Nutrition 0.000 description 6
- GXBMIBRIOWHPDT-UHFFFAOYSA-N Vasopressin Natural products N1C(=O)C(CC=2C=C(O)C=CC=2)NC(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CCCN=C(N)N)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C1CC1=CC=CC=C1 GXBMIBRIOWHPDT-UHFFFAOYSA-N 0.000 description 5
- 102000002852 Vasopressins Human genes 0.000 description 5
- 108010004977 Vasopressins Proteins 0.000 description 5
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 description 5
- 150000002431 hydrogen Chemical class 0.000 description 5
- 210000000885 nephron Anatomy 0.000 description 5
- 238000012552 review Methods 0.000 description 5
- 229960003726 vasopressin Drugs 0.000 description 5
- 108010036221 Aquaporin 2 Proteins 0.000 description 4
- 102100034414 Aquaporin-2 Human genes 0.000 description 4
- 206010020772 Hypertension Diseases 0.000 description 4
- 230000032683 aging Effects 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 230000000378 dietary effect Effects 0.000 description 4
- 230000013632 homeostatic process Effects 0.000 description 4
- 230000000155 isotopic effect Effects 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- 230000035699 permeability Effects 0.000 description 4
- 230000035479 physiological effects, processes and functions Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 239000003053 toxin Substances 0.000 description 4
- 231100000765 toxin Toxicity 0.000 description 4
- 108700012359 toxins Proteins 0.000 description 4
- 210000003932 urinary bladder Anatomy 0.000 description 4
- 208000003200 Adenoma Diseases 0.000 description 3
- 206010001233 Adenoma benign Diseases 0.000 description 3
- 201000009030 Carcinoma Diseases 0.000 description 3
- 108060006698 EGF receptor Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 235000011148 calcium chloride Nutrition 0.000 description 3
- 239000004202 carbamide Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000000329 molecular dynamics simulation Methods 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000003174 Brain Neoplasms Diseases 0.000 description 2
- 102000016950 Chemokine CXCL1 Human genes 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- 208000017604 Hodgkin disease Diseases 0.000 description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 206010062237 Renal impairment Diseases 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- 238000000692 Student's t-test Methods 0.000 description 2
- 208000016025 Waldenstroem macroglobulinemia Diseases 0.000 description 2
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 208000009956 adenocarcinoma Diseases 0.000 description 2
- 238000000540 analysis of variance Methods 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 230000035622 drinking Effects 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000024924 glomerular filtration Effects 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 238000002307 isotope ratio mass spectrometry Methods 0.000 description 2
- 210000003246 kidney medulla Anatomy 0.000 description 2
- 210000000244 kidney pelvis Anatomy 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 208000012804 lymphangiosarcoma Diseases 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 230000001124 posttranscriptional effect Effects 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 210000002307 prostate Anatomy 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- SDWMVMBAKVYNMX-UHFFFAOYSA-N 11-(4-bromophenyl)-9-piperidin-1-ylnaphtho[2,1-b][1,10]phenanthroline-8-carbonitrile Chemical compound BrC1=CC=C(C=C1)C1=C2C=CC3=NC=4C=5N=CC=CC=5C=CC=4C=C3C2=C(C(=C1)N1CCCCC1)C#N SDWMVMBAKVYNMX-UHFFFAOYSA-N 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 201000003076 Angiosarcoma Diseases 0.000 description 1
- 102000004363 Aquaporin 3 Human genes 0.000 description 1
- 108090000991 Aquaporin 3 Proteins 0.000 description 1
- 108010036280 Aquaporin 4 Proteins 0.000 description 1
- 102100037276 Aquaporin-4 Human genes 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 208000008720 Bone Marrow Neoplasms Diseases 0.000 description 1
- 101001027327 Bos taurus Growth-regulated protein homolog alpha Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 206010006417 Bronchial carcinoma Diseases 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 108010014419 Chemokine CXCL1 Proteins 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- 201000009047 Chordoma Diseases 0.000 description 1
- 208000006332 Choriocarcinoma Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 208000009798 Craniopharyngioma Diseases 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 201000009051 Embryonal Carcinoma Diseases 0.000 description 1
- 206010014967 Ependymoma Diseases 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010018852 Haematoma Diseases 0.000 description 1
- 102000003810 Interleukin-18 Human genes 0.000 description 1
- 108090000171 Interleukin-18 Proteins 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 208000018142 Leiomyosarcoma Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 208000007054 Medullary Carcinoma Diseases 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 102000029749 Microtubule Human genes 0.000 description 1
- 108091022875 Microtubule Proteins 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- -1 Na + Chemical class 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 201000010133 Oligodendroglioma Diseases 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 102000043276 Oncogene Human genes 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 206010063897 Renal ischaemia Diseases 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 208000033781 Thyroid carcinoma Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 241000364021 Tulsa Species 0.000 description 1
- 102000044209 Tumor Suppressor Genes Human genes 0.000 description 1
- 108700025716 Tumor Suppressor Genes Proteins 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 208000014070 Vestibular schwannoma Diseases 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 208000004064 acoustic neuroma Diseases 0.000 description 1
- 208000017733 acquired polycythemia vera Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000009056 active transport Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 230000001174 ascending effect Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000000476 body water Anatomy 0.000 description 1
- 201000006491 bone marrow cancer Diseases 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 208000003362 bronchogenic carcinoma Diseases 0.000 description 1
- 239000001175 calcium sulphate Substances 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 238000011088 calibration curve Methods 0.000 description 1
- 208000035269 cancer or benign tumor Diseases 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 201000007455 central nervous system cancer Diseases 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- 208000024207 chronic leukemia Diseases 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- CVSVTCORWBXHQV-UHFFFAOYSA-N creatine Chemical class NC(=[NH2+])N(C)CC([O-])=O CVSVTCORWBXHQV-UHFFFAOYSA-N 0.000 description 1
- 208000031513 cyst Diseases 0.000 description 1
- 208000002445 cystadenocarcinoma Diseases 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 235000001434 dietary modification Nutrition 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 210000004696 endometrium Anatomy 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 201000005619 esophageal carcinoma Diseases 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000003861 general physiology Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 208000025750 heavy chain disease Diseases 0.000 description 1
- 201000002222 hemangioblastoma Diseases 0.000 description 1
- 208000006359 hepatoblastoma Diseases 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 238000003064 k means clustering Methods 0.000 description 1
- 230000005977 kidney dysfunction Effects 0.000 description 1
- 210000000738 kidney tubule Anatomy 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 230000009063 long-term regulation Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000000210 loop of henle Anatomy 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 1
- 206010027191 meningioma Diseases 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 210000004688 microtubule Anatomy 0.000 description 1
- 208000025113 myeloid leukemia Diseases 0.000 description 1
- 208000001611 myxosarcoma Diseases 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000008239 natural water Substances 0.000 description 1
- 208000025189 neoplasm of testis Diseases 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 208000004019 papillary adenocarcinoma Diseases 0.000 description 1
- 201000010198 papillary carcinoma Diseases 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 208000029255 peripheral nervous system cancer Diseases 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 208000037244 polycythemia vera Diseases 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 210000000512 proximal kidney tubule Anatomy 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 210000002254 renal artery Anatomy 0.000 description 1
- 230000008663 renal system process Effects 0.000 description 1
- 210000002796 renal vein Anatomy 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 201000008407 sebaceous adenocarcinoma Diseases 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000011699 spontaneously hypertensive rat Methods 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 201000010965 sweat gland carcinoma Diseases 0.000 description 1
- 210000001258 synovial membrane Anatomy 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 208000013077 thyroid gland carcinoma Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 102000006030 urea transporter Human genes 0.000 description 1
- 108020003234 urea transporter Proteins 0.000 description 1
- 210000000626 ureter Anatomy 0.000 description 1
- 210000003708 urethra Anatomy 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- 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
- G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
- G01N33/60—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances involving radioactive labelled substances
-
- 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
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
-
- 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
-
- G—PHYSICS
- G21—NUCLEAR PHYSICS; NUCLEAR ENGINEERING
- G21H—OBTAINING ENERGY FROM RADIOACTIVE SOURCES; APPLICATIONS OF RADIATION FROM RADIOACTIVE SOURCES, NOT OTHERWISE PROVIDED FOR; UTILISING COSMIC RADIATION
- G21H5/00—Applications of radiation from radioactive sources or arrangements therefor, not otherwise provided for
- G21H5/02—Applications of radiation from radioactive sources or arrangements therefor, not otherwise provided for as tracers
-
- 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)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Biomedical Technology (AREA)
- Hematology (AREA)
- Immunology (AREA)
- Urology & Nephrology (AREA)
- Physics & Mathematics (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Pathology (AREA)
- Food Science & Technology (AREA)
- Medicinal Chemistry (AREA)
- General Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Cell Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- General Engineering & Computer Science (AREA)
- High Energy & Nuclear Physics (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
Abstract
本发明提供一种在疑似肾脏疾病或肿瘤疾病的个体诊断肾脏疾病或肿瘤疾病可能性的方法，包括测定疑似肾脏疾病或肿瘤疾病的个体的生物样品中delta O-18(δ18O)和/或delta H-2(δ2H)的值，比较该测定的delta O-18(δ18O)和/或delta H-2(δ2H)值与没有肾脏疾病或肿瘤疾病的个体的delta O-18(δ18O)和/或delta H-2(δ2H)的参考值，基于该测定的delta O-18(δ18O)和/或delta H-2(δ2H)值与deltaO-18(δ18O)和/或delta H-2(δ2H)的参考值的比较诊断肾脏疾病或肿瘤疾病的可能性；其中当疑似肾脏疾病或肿瘤疾病的个体的生物样品中delta O-18(δ18O)和/或delta H-2(δ2H)的值低于没有肾脏疾病或肿瘤疾病的个体的delta O-18(δ18O)和/或delta H-2(δ2H)的参考值时，则诊断为有肾脏疾病或肿瘤疾病的可能性。本发明亦提供一种实施本发明方法的套组。
Description
技术领域
本发明是关于肾脏疾病或肿瘤疾病的诊断。具体而言，本发明使用生物样品中的δH-2(δ2H)和/或δO-18(δ18O)值作为肾脏疾病或肿瘤疾病的诊断基础。
背景技术
肾脏为位于脊椎动物腹腔的背侧的单个或成对的器官，其功能为维持适当的水及电解质平衡、调节酸碱浓度及过滤血中代谢废物并以尿液形式排出。因此，肾脏疾病的结果会导致生物整体不平衡。许多器官，如膀胱、肠、心脏、肺及前列腺依靠肾脏的能力滤出身体中的不需要的废物并维持整体平衡。
肾脏是清洁血液的器官。肾动脉将血液自心脏带到肾脏，并通过数百万含有肾元的肾小球网络清洁血液。肾元滤出毒素、过量营养物及体液；剩余的经清洁及过滤的血液接着通过肾静脉回到血液循环中。滤出的物质流经肾小管调整盐份、水及废物，并排出至尿液。肾盂收集尿液；尿液从肾盂经输尿管流到膀胱；尿液排出膀胱并经尿道排出身体。
肾脏疾病包括高血压、肾小球肾炎与囊肿。糖尿病影响身体调节血糖的能力，过量血糖会伤害肾脏肾元，降低血管过滤毒素的能力。高血压伤害肾元；而肾小球肾炎通常关于一类非肾脏感染的疾病。
如两个肾由于疾病丧失功能，病患经验末期肾失调(end stagerenal disease；ESRD)或肾衰竭。肾衰竭意指身体不再去除特定毒素且无法适当地调节血压及重要营养物。除非这些病患经过治疗，否则他们由于毒素及废液堆积在血液中而可能在数天内死亡。
糖尿病性肾病，已知为糖尿病肾病变，是第1型糖尿病(TIDM)患加速发病并提早死亡。约25%至40%的TID M病患会发展成糖尿病肾病变。糖尿病肾病变的最长期严重影响是肾衰竭导致末期肾脏病，一种永久及几乎完全失去肾功能的病况，仅有少于10%的肾基础功能。
已知诊断肾脏疾病的传统方法牵涉特定蛋白质的检测。US7,141,382关于检测样品中介白素18(interleukin 18)的方法，较佳为倾向如肾衰竭的个体的血清肌酸酐增加前。US7,935,495提供一种检测动物早期肾病的方法，包括下列步骤：(a)得到欲检测样品及(b)测定样品中白蛋白的量。US7,833,872关于新颖且有用的生物标记，GRO-alpha(即，CXCL1、趋化素(Chemokine)C-X-C配体1、GRO1、GROa、MGSA、MGSA alpha、MGSA-a、NAP-3、SCYB1)，针对急性肾伤害(即AKI)、肾缺血再灌注伤害(即IRI)、缺血性急性肾伤害和/或缺血性急性肾小管性肾炎。虽然已知许多测定尿液或血液样品中成份的诊断肾失调的方法，但此等方法的缺点是牵涉复杂的步骤以得到测定结果。
此外，肿瘤或癌症病况持续为最普遍引起死亡的疾病的一种疾病。肿瘤发生随老化增加。肿瘤或癌症由持续多种基因突变引起，导致致癌基因活化和/或肿瘤抑制基因不活化。肿瘤或癌症成为全球致死率的主要原因。虽然诊断及治疗的进步，总存活率并未显著提升。仍有需要较准确和灵敏的诊断肿瘤或癌症的检测方法，特别是早期阶段的肿瘤或癌症。
水是生命的基础，也是身体最重要且最丰富的物质，约占身体质量的70%。虽然注意到水的重要性，但水同位素的独特性通常被忽略。天然水含有微量的重同位素氢和氧原子，其中2H与18O是主要种类。1H对2H的比例约为6240比1，或在V-SMOW(ViennaStandard Mean Ocean Water)水标准中为约155ppm，和16O对18O的比例约为499比1或约2005ppm。水同位素的独特特性与质谱技术的快速进展，各种生物样品中氢(δH)与氧(δO)的安定比例已在古食物、气象学、人类学、生态学和现代食物链网中作为”原子化石或追踪者”。
安定的非放射活性的同位素水，2H2O，在人类生理和病理生理上扮演重要角色。数种使用动物和细胞培养研究已显示饮食水中2H2O的增加或缺乏在病理生理和生理上具有重要影响。例如，现有技术显示2H2O通过刺激微管蛋白次单元(tubulin subunit)的聚合可促进微小管(microtubule)的形成，并导致细胞死亡。此外，2H2O含量增加在自发性高血压鼠可预防高血压。换言之，培养基中水的重氢(deuterium)缺乏降低动物细胞株的生长率。未治疗的链佐霉素诱导的糖尿病(streptozotocin-induced diabetes mellitus)鼠的身体水中的氢(δ2H)与氧(δ18O)同位素比例与正常鼠显著不同。
然而，没有任何现有技术揭示、教示或建议水同位素与肾脏疾病与肿瘤间的关系。
发明内容
本发明惊讶地发现生物样品中delta H-2(δ2H)和/或delta O-18(δ18O)的值与肾脏疾病或肿瘤疾病有关。因此，本发明发展比较得自假定具有肾脏疾病可能的个体与没有肾脏疾病或肿瘤疾病的个体的生物样品中delta H-2(δ2H)和/或delta O-18(δ18O)的诊断肾脏疾病或肿瘤疾病的方法。
除非另有定义，本文中所有技术或科学用语具有本领域技术人员一般了解的意义。所有本文中提到的公开刊物、专利申请案、专利及其它参考数据均以其全文并入参考。此外，材料、方法及实施例仅做为说明，并非限制本发明。
用语”检测(detecting)”或”诊断(diagnosing)”是鉴定具肾脏疾病或肿瘤疾病的病患或罹患肾脏疾病或肿瘤疾病风险的病患。
用语”分析(assay)”指分析样品以测定样品中物质的存在和/或该物质的量。
用语”降低量(decreased amount)”指较预定量为低的量。用语”肾脏疾病(renal disease)”指一个体的肾脏功能失调、受损、异常或功能障碍。
用语”样品”指得自哺乳动物个体的体液或组织液样品。作为非限制性实例，用于本发明的体液或组织液样品可为尿液、血液、血清、血浆、唾液、淋巴液、脑脊髓液、囊性液(cystic fluid)、腹水、粪便、胆汁、组织液及任何其它的分离体液。
用语”肿瘤”或”癌症”包括，但不限于，源自乳房、前列腺、大肠、肺、胰脏、肝、胃、膀胱或生殖器官(子宫颈、卵巢、子宫内膜等)、脑和骨髓的肿瘤或癌症、黑色素瘤或淋巴癌。
本案引用的所有刊物与专利文件以其全部并入参考，其目的是如个别公开或专利文件指出的相同范围。文件中的各种参考数据的引用，申请人不承认任何特定文献为其发明的现有技术。
在一方面，本发明提供一种在疑似肾脏疾病或肿瘤疾病的个体诊断肾脏疾病或肿瘤疾病可能性的方法，包括测定疑似肾脏疾病或肿瘤疾病的个体的生物样品中delta O-18(δ18O)和/或delta H-2(δ2H)的值，比较该测定的delta O-18(δ18O)和/或delta H-2(δ2H)值与没有肾脏疾病或肿瘤疾病的个体的delta O-18(δ18O)和/或delta H-2(δ2H)的参考值，基于该测定的delta O-18(δ18O)和/或delta H-2(δ2H)值与delta O-18(δ18O)和/或delta H-2(δ2H)的参考值的比较诊断肾脏疾病或肿瘤疾病的可能性；其中当疑似肾脏疾病或肿瘤疾病的个体的生物样品中delta O-18(δ18O)和/或delta H-2(δ2H)的值低于没有肾脏疾病或肿瘤疾病的个体的delta O-18(δ18O)和/或delta H-2(δ2H)的参考值时，则诊断为有肾脏疾病或肿瘤疾病的可能性。
所有哺乳动物个体可使用本发明方法测试。典型地，受测个体(或病患)罹患肾功能障碍(例如末期肾失调、肾病变、肾衰竭、高尿酸血症、糖尿病性肾病变、缺血性或毒物诱导的肾伤害、慢性肾衰竭、急性肾衰竭、肾小球性肾炎、多囊性肾病或慢性肾盂肾炎)、或肿瘤(例如，赘瘤(neoplasm)、肿瘤(tumor)、癌瘤(carcinoma)、肉瘤(sarcoma)、腺瘤(adenoma)、骨髓白血病、肝细胞癌、肝母细胞瘤、横纹肌肉瘤、食管癌、甲状腺癌、神经节母细胞瘤、纤维肉瘤、黏液肉瘤、脂肪肉瘤、软骨肉瘤、骨肉瘤、脊索癌、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮肉瘤、滑膜瘤、间皮瘤、尤文氏瘤(ewing's sarcoma)、平滑肌肉瘤、rhabdotheliosarcoma、大肠癌、胰脏癌、肝癌、乳癌、卵巢癌、前列腺癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊腺癌、髓样癌、支气管肺癌、肾细胞癌、血肿、胆管癌、黑色素瘤、绒毛膜癌、精母细胞瘤、胚胎性癌、威尔姆氏肿瘤(Wilms'tumor)、子宫颈癌、睪丸肿瘤、肺癌、小细胞肺癌、膀胱癌、上皮癌、神经胶质瘤、星状细胞瘤、髓母细胞瘤、颅咽管瘤、室管膜瘤、松果腺瘤、血管母细胞瘤、视网膜母细胞肿瘤、白血病、急性成髓细胞性白血病、慢性白血病、真性红细胞增多症、淋巴瘤(何杰金氏症及非何杰金氏症)、多发性骨髓瘤、Waldenstro m氏巨蛋白血症(Waldenstrom macroglobulinemia)、直肠癌、头颈癌、脑癌、原发部位未明癌、周围神经系统癌、中枢神经系统癌、听神经瘤、少突胶质细胞瘤、脑膜瘤、神经母细胞瘤、重链病、癌转移、及以未控制或不正常细胞生长表征的任何疾病或病症组成的群组)。较佳地，哺乳动物个体为人类、猪、马、狗、绵羊、牛、山羊或猫。
本发明惊讶地发现健康个体的水同位素存在生物平衡(biological homeostasis)。健康个体中的水状态(δ18O与δ2H)与肾脏疾病或肿瘤疾病的体中的水状态显著不同。肾脏疾病或肿瘤疾病的体中的delta O-18和/或delta H-2是降低的。
样品中的delta O-18和/或delta H-2的值作为比较用的参考值者是得自没有肾脏疾病或肿瘤疾病的个体(健康病患)。肾脏疾病或肿瘤疾病可藉由得自个体(如疑似罹患肾脏疾病或肿瘤疾病的个体)的体液样品中delta O-18和/或delta H-2的值降低而诊断。
根据本发明的方法也适合于健康个体的例行分析，即实施年度分析以诊断非常早期阶段的肾脏疾病或肿瘤疾病。
”控制组”参考值为得自健康状态的相同或其它个体的参考值。具体而言，同位素表示为关于国际V-SNOW (Vienna Standard Meanocean Water)标准的δ-符号(‰)。根据本发明，没有肾脏疾病或肿瘤疾病的个体的delta O-18为-30/00至约-4.50/00。没有肾脏疾病或肿瘤疾病的个体的d elta H-2为-300/00至约-350/00。
根据本发明，水同位素降低诊断为肾脏疾病或肿瘤疾病。也就是说，罹患肾脏疾病或肿瘤疾病的个体中的delta O-18和/或delta H-2的值低于没有肾脏疾病或肿瘤疾病的个体中的值。根据本发明，罹患肾脏疾病或肿瘤疾病的个体的delta O-18值低于约-4.5‰、约-5.5‰、约-6.0‰、约-7.0‰、约-8.0‰、约-9.0‰、约-10.0‰、约-11.0‰、约-12.0‰、约-13.0‰、约-14.0‰、约-15.0‰、约-16.0‰、约-17.0‰、约-18.0‰、约-19.0‰、约-20.0‰、约-21.0‰、约-22.0‰、约-23.0‰、约-24.0‰、约-25.0‰、约-26.0‰、约-27.0‰、约-28.0‰、约-29.0‰或约-30.0‰。较佳地，delta O-18值约-4.5‰至约-30.0‰；较佳为-4.5‰至约-25.0‰、-4.5‰至约-22.0‰、-4.5‰至约-20.0‰、-4.5‰至约-18.0‰、-4.5‰至约-16.0‰、-4.5‰至约-14.0‰、-4.5‰至约-12.0‰、-4.5‰至约-10.0‰；更佳为肾脏疾病为-5.0‰至约-16.0‰、-5.0‰至约-14.0‰、-5.0‰至约-12.0‰或更佳为肿瘤疾病为-5.0‰至约-25.0‰、-5.0‰至约-22.0‰、-5.0‰至约-20.0‰、-5.0‰至约-18.0‰、-5.0‰至约-16.0‰、-5.0‰至约-14.0‰、-5.0‰至约-12.0‰、-5.0‰至约-10.0‰。更佳地，delta O-18值为约-5.0‰至约-28.0‰、-5.0‰至约-26.0‰、-5.0‰至约-25.0‰、-5.0‰至约-20.0‰、-5.0‰至约-18.0‰、-5.0‰至约-16.0‰、-5.0‰至约-14.0‰、-5.0‰至约-12.0‰或-5.0‰至约-10.0‰。
根据本发明，罹患肾脏疾病或肿瘤疾病的个体的delta H-2值低于约-35‰、约-36‰、约-37‰、约-38‰、约-39‰、约-40‰、约-42‰、约-44‰、约-48‰、约-50‰、约-55‰、约-60‰、约-65‰、约-70‰、约-75‰、约-80‰、约-85‰、约-90‰、约-95‰或约-100‰。较佳地，delta H-2值为约-35‰至约-100‰、约-35‰至约-95‰、约-35‰至约-90‰、约-35‰至约-85‰、约-35‰至约-80‰、约-35‰至约-75‰、约-35‰至约-70‰、约-35‰至约-65‰、约-35‰至约-60‰、约-35‰至约-55‰、约-35‰至约-50‰、约-35‰至约-45‰、约-35‰至约-40‰、约-40‰至约-100‰、约-40‰至约-90‰、约-40‰至约-85‰、约-40‰至约-80‰、约-40至约-75‰、约-40‰至约-70‰或约-40‰至约-65‰。较佳地，肾脏疾病的delta H-2值为约-40‰至约-80‰、约-40‰至约-75‰、约-40‰至约-80‰、约-40‰至约-75‰、约-40‰至约-70‰、约-40‰至约-65‰、约-40‰至约-60‰、约-40‰至约-55‰或约-40‰至约-50‰。较佳地，肿瘤疾病的delta H-2值为约-45‰至约-100‰、约-45‰至约-95‰、约-45‰至约-90‰、约-45‰至约-85‰、约-45‰至约-80‰、约-45‰至约-70‰或约-45‰至约-60‰。
根据本发明，生物样品为体液。较佳地，体液为尿液、血液、血清、血浆、唾液、淋巴液、脑脊髓液、囊性液(cystic fluid)、腹水、粪便、胆汁、组织液及任何其它的分离体液。任何已知得到作为同位素测定的水的方法均可用于本发明。根据本发明之一具体实施例，测定同位素的水是得自将体液样品置于含干燥剂的密闭容器使得样品中的水被干燥剂吸收以得到不含其它成份的纯水，并接着从含水(或水合)的干燥剂去除水分。较佳地，以蒸馏自含水(或水合)干燥剂去除水；较佳为真空蒸馏。根据本发明，干燥剂是选自硅胶(silica gel)、活性碳、硫酸钙、氯化钙、蒙脱黏土(montmorillonite clay)和分子筛(molecular sieve)的群组。根据本发明的另一具体实施例，用于测定同位素的水是经逆渗透(reverseosmosis)得到。
在另一方面，本发明是关于实施本发明的套组，该套组包括：一包含生物样品的容器或预定充填该样品的容器，该生物样品得自可能罹患肾脏疾病或肿瘤疾病的个体或罹患肾脏疾病或肿瘤疾病风险的个体，一测定生物样品中delta O-18和/或delta H-2的装置，和一参考值装置，用于诊断肾脏疾病或肿瘤疾病。较佳地，该套组另包含含有干燥剂的容器。较佳地，该套组另包含自样品得到其中的水的装置；例如，含干燥剂的密闭容器及蒸馏装置或逆渗透装置。
测定delta O-18和/或delta H-2的装置可选自提供/定量delta O-18和/或delta H-2的任何适合装置；例如，同位素质谱仪(Isotope-ratiomass spectrometry；IRMS)。
用于诊断肾脏疾病或肿瘤疾病的参考值的装置较佳选自得自含健康个体生物样品的容器。本发明套组可进一步包含校正曲线、套组使用说明书或其组合。较佳包含适当的说明书(如书面形式)，提供关于诊断肾脏疾病或肿瘤疾病的使用信息。
本发明研究生物样品中氢(δ2H)和氧(δ18O)的安定同位素比例，观察到生物样品中(如血液、血浆)的δ2H及δ18O与肾脏功能和肿瘤疾病有关。特别是，控制组个体及糖尿病组个体(没有肾功能障碍)血浆(blood plasma)中的δ18O较晚期肾失调个体分别高87%及160%。健康肾组个体(即控制组个体及糖尿病组个体)血浆(blood plasma)中的δ2H较肾失调组个体分别高72%及92%。然而，在控制组个体和糖尿病组个体血浆中的水含量(δ2H)及氧(δ18O)则没有差异。
具体实施方式
实例
虽然已参考特定实施例描述本发明，但熟习此项技术者应了解，在不悖离本发明的范畴的情况下可作出各种变化且可用等效物替代其组件以适于特定情况。提供以下实验性实例以展示及进一步说明本发明的某些实施例的各种形式且不应理解为限制其范畴。在以下实验性揭示内容中，使用下列材料及方法：
参与者.根据针对参与者的记录的生物化学参数及医生描述，将参与者分成三类：对照个体(CS)、诊断为末期肾脏失调(ESRD)的患者及患有糖尿病但无可侦测的肾脏功能障碍(DB)的个体。所有DB个体皆处于糖尿病控制下。所有48名个体(5个CS、32个ESRD及5个DB)皆为居住在台北市的本地台湾人。其在取样日期之前至少三个月未远足。因此，可消除由食物及水的地理同位素组成而造成的同位素比变化(Bowen GJ,Wilkinson B(2002)Spatial distribution ofdelta 0-18 in meteoric precipitation.Geology 30:315-318；HobsonKA,Atwell L,Wassenaar LI(1999)Influence of drinking water anddiet on the stable-hydrogen isotope ratios of animal tissue,.ProcNatl Acad Sci USA 96:8003-8006；Bowen GJ,Ehleringer JR,Chesson LA,Thompson AH,Podlesak DW等人(2009)Dietary andphysiological controls on the hydrogen and oxygen isotope ratios ofhair from mid-20th century indigenous populations.Am J PhysAnthropol 139:494-504；Ches son LA,Podlesak DW,Erkkila BR,Cerling TE,Ehleringer JR(2010)Isotopic con sequences of consumerfood choice:Hydrogen and oxygen stable isotope ratios in foods fromfost food restaurants versus supermarkets.Food Chemistry 119:1250-1256)。
水样.将3ml人类血浆样品储存于15ml法尔康管(falcon tube)中。随后将管置放于具有15g CaCl2颗粒(Sigma-Aldrich)的预干燥且抽真空的圆瓶烧瓶中。随后将圆瓶烧瓶封盖且小心地密封以确保空气中的水不会进入烧瓶中。在室温下保温烧瓶以使CaCl2自人类血浆样品中吸收水，持续七天。藉由真空蒸馏自水合CaCl2获得水样(约2ml)(Buchi Glass OvenB-585,Kugelrohr)。
测定人类血浆中的氢(δ2H)及氧(δ18O).如下进行水样中的氢(δ2H)及氧(δ18O)之评估。通过熟知CO2-H2O平衡方法来分析稳定氧同位素组成(Epstein S,Mayeda T(1953)Variation of O18 content ofwaters from natural sources.Geochimica et Cosmochimica Acta 4:213-224；Brenninkmeijer CAM,Morrison PD (1987)An automatedsystem for isotopic equilibration of CO2 and H2O for 18O analysis ofwater.Chemical Geology:Isotope Geoscience section 66:21-26)。由VG SIRA 10同位素比质谱仪量测平衡之CO2气体。在使用由印地安那大学(Indiana University)生物地球化学实验室制造的锌珠将水还原成H 2之后于VG MM602D同位素比质谱仪上测定氢同位素组成(Coleman ML,Shepherd TJ,Durham JJ,Rouse JE,Moore GR(1982)Reduction of water with zinc for hydrogen isotope analysis.Analytical Chemistry 54:993-995)。所有同位素比结果以相对于国际V-SMOW(维也纳标准平均海洋水(Vienna Standard Mean OceanWater))标准之δ表示法(‰)报导且按SLAP(标准轻南极降水(StandardLight Antarctic Precipitation))的δ18O及δ2H分别为-55.5‰及-428‰的标度进行校正(Gonfiantini R (1978)Standards for stable isotopemeasurements in natural compounds.Nature 271:534-536)。针对实验室标准表示为lσ的分析精确度分别优于1.3‰(对于δ2H)及0.08‰(对于δ18O)。水样的双重复分析的平均差异分别为±1.5‰(对于δ2H)及±0.11‰(对于δ18O)。
数据分析.通过使用STASTISTICA 8.0(StartSoft.Inc.,Tulsa,OK)进行ANO VA及史都登氏t检验(Student's t-test)。在MATLABR2011a(MathWorks.Inc.,Natick,MA)中进行k平均值丛聚，其将数据分配成四个丛集的预设集(preset)。量测欧几里德距离(Euclideandistance)以计算丛集的矩心，亦即彼丛集内数据点的平均值。进行总共10,000次重复丛聚过程，在各轮中给出初始丛集矩心位置的新集合。此程序传回四个丛集的最佳解答方案，其中各丛集的点-矩心距离的总和具有最低值。
实例1使用本发明方法诊断肾脏失调
量测来自42个人类血浆的水样的氢(δ2H)及氧(δ18O)的稳定同位素比。自以下四组参与者随机获得样品：空腹对照个体(CS，n=5)、未经血液透析处理的空腹末期肾脏失调个体(ESRDnHD，n=5)、经血液透析处理的空腹末期肾脏失调个体(ESRDHD，n=5)及空腹糖尿病个体(DB，n=5)。
对照个体组(CS).
如表1中所示，CS的δ2H及δ18O的平均值为-4.76‰及-35.2‰。
表1.对照个体的血浆的同位素值。
空腹样品(CS)h
a.自具有健康肾脏的对照个体收集5个人类血浆样品(CS-1至CS-5)。
b.所有对照个体在取样的前三个月待在本地区而不旅行。
c.血尿素氮(BUN)测试用以通过量测血液中呈尿素形式的氮的量来评估肾脏功能。血液中尿素的正常含量为7-20mg/dL。
d.肌酐为肌酸的代谢物。使用肌酐测试作为肾脏功能的指示物。血液中肌酐的正常含量对于男性为0.7-1.2mg/dL，且对于女性为0.5-1.9mg/dL[45]。
e.估算肾小球滤过率，肾脏功能的指针。基于MDRD(肾脏失调中的膳食修正)公式eGFR=186×血清肌酐-1154×年龄-0.203×(1.212(若为黑人))×(0.742(若为女性))计算eGFR值[46]。
f.比率以相对于国际V-SMOW(维也纳标准平均海洋水)标准的δ表示法(‰)报导且按SLAP(标准轻南极降水)的δ18O及δ2H分别为-55.5‰及-428‰的标度进行校正[44]。
i.圆括号中的数字为取各组所有数字而得的标准差。
末期肾脏失调组(ESRD).
δ2H及δ18O的平均值对于ESRDnHD为-11.89‰及-72.44‰，且对于ESRDHD为-10.37‰及-59.10‰(表2)。ESRDHD(标准差对于δ18O为2.9且对于δ2H为11.54)相比ESRDnHD(标准差对于δ18O为0.9且对于δ2H为4.9)较分散。就δ2H而言，ESRDHD与ESRDnHD之间的差异显著[t0.05;30=2.5且F 0.05;1,30=6.33]。然而，对于δ18O，差异不显著[t0.05;30=1.17且F0.05;l,30=1.37]。
表2.末期肾脏失调(ESRD)患者的血浆的同位素值。
未经血液透析处理(ESRnHD)j
经血液透析处理(ESRDHD)k
a.自空腹8小时的ESRD(末期肾脏失调)患者收集32个人类血浆样品，且将其分成两组：ESRDnHD(末期肾脏失调但未经血液透析处理)及ESRDHD(末期肾脏失调且接受血液透析处理)。
b.,c.,d.BUN、肌酐及eGFR测试，所有皆为肾脏功能的指示物；参见表1脚注c、d及e。
e.血液中钠的浓度。血液中钠的正常含量为135-140mmol/L。
f.血液中钾的浓度。正常血液钾含量为3.5-5mmol/L。
g.血液中氯离子的浓度。血液中氯离子的正常范围为98-108mmol/L。
h.,i.同位素比以δ表示法(‰)报导，参见表1脚注c及d中的详情。
j.自未经血液透析处理的E S RD患者收集ESRDnHD样品(ESRD-1至ESRD-5)。ESRDnHD不进行单价离子测试。
k.自接受6个月血液透析的ESRD患者收集ESRDHD样品(ESRD-6至ESRD-32)。恰在ESRD患者接受血液透析之前收集此等样品。
I.圆括号中的数字为取各组所有数字而得之标准差。
糖尿病组(D B)
在DB组中，血浆中δ2H的平均值为-4.04‰，且δ18O的平均值为-34.08‰(表3)。
表3.糖尿病(DB)患者的血浆的同位素值
平均值 68.4 0.7(0.2) 99.46(21.46) 160.8(36.7) -4.04 -34.08
(标准差)g (7.1) (0.3) (5.0)
a.自空腹8小时的糖尿病患者收集DB血浆样品(DB-1至DB-5)。
b.血浆肌酐浓度，肾脏功能的指示物。
c.估算肾小球滤过率，肾脏功能的指针。详情参见表1脚注e。
d.空腹血糖含量。
e.,f同位素比以δ表示法(‰)报导，参见表1脚注c及d中之详情。
g.圆括号中的数字为取DB的所有数字而得的标准差。
ESRD的水δ18O及δ2H值明显低于CS之δ18O及δ2H值。
ESRDnHD的血浆中的水δ18O及δ2H的值显示与CS的δ18O及δ2H的值不同的特征。通过将史都登氏t检验及ANOVA统计分析应用于ESRDnHD及CS数据集，ESRDnHD及CS中的血浆的水含量(δ18O及δ2H)显示显著差异[对于δ18O，t0.05;8=13.78且F0.05; 1,8=189.83；对于δ2H，t0.05;8=15.08且F0.05;1,8=227.47]。E S RDHD的血浆中的δ18O及δ2H分布分散于CS与ESRDnHD之间。ESRDHD的血浆水中的δ18O及δ2H亦显著低于CS的δ18O及δ2H。ESRD (包括ESRDnHD及ESRDHD)的血浆中的δ18O及δ2H比CS低87%及72%，且比DB低160%及92%。因此，在本研究中血浆中的δ18O及δ2H之值与肾脏功能相关联。ESRD患者的血浆中之水18O及2H之较低含量令人感兴趣，此系因为正常对照个体与肾脏患者共享相同来源之饮用水及膳食水。
似乎在具有肾脏功能障碍的患者中2H及18O同位素自血浆水中选择性地「移除」。肾脏的许多功能之一为水的再吸收，现已知其至少部分由不同类型的肾脏水通道蛋白(aquaporin，AQP)(一种形成水通道的质膜蛋白)介导(Nielsen S,Frokiaer J,Marples D,KwonTH,Agre P等人(2002)Aquaporins in the kidney:from moleculesto medicine.Physiological Reviews 82:205-244；King LS,KozonoD,Agre P(2004)From structure to disease:The evolving tale ofaquaporin biology.Nature Reviews Molecular Cell Biology 5:687-698；Borgnia M,Nielsen S,Engel A,Agre P(1999)Cellular andmolecular biology of the aquaporin water channels.Annual Reviewof Biochemistry 68:425-458)。举例而言，水通道蛋白1(AQP1)位于近端小管及增加透水性之下降细支处(Nielsen S,Smith BL,Christensen EI,Knepper MA,Agre P(1993)CHIP28 water channelsare localized in constitutively water-permeable segments of thenephron.The Journal of cell biology 120:371-383)。AQP2、AQP3及AQP4位于集合管处，其中AQP2为集合管处透水性的升压素调控标靶(Nielsen S,Knepper MA(1993)Vasopressin activatescollecting duct urea transporters and water channels by distinctphysical processes.The American journal of physiology 265:F204-213)。自然地产生如下问题：这些水信道蛋白是否涉及肾脏功能障碍患者的血浆中的18O及2H的较低含量。在现有研究中，原型AQP1的分子动力学(MD)仿真及溶液实验显示2H2O的渗透性类似于水的渗透性(Mamonov AB,Coalson RD,Zeidel ML,Mathai JC(2007)Water and deuterium oxide perm eability through aquaporin1:MD predictions and experimental verification.The Journal ofgeneral physiology 130:111-116)，而另一研究显示AQP1的芳族物/精胺酸区域中的点突变使得质子可通过其(BeitzE,Wu B,Holm LM,Schultz JE,Zeuthen T(2006)Point mutations in thearomatic/arginine region in aquaporin 1 allow passage of urea,glycerol,ammonia,and protons.Proceedings of the NationalAcademy of Sciences of the United States of America 103:269-274)。此外，在ESRD患者中，发现升压素的浓度较高(Argent NB,Baylis PH,Wilkinson R(1990)Immunoreactive vasopressin in endstage renal failure.Clinica chimica acta;international journal ofclinical chemistry 190:185-188)。升压素及水分剥夺伴随肾脏集合管中之AQP2上调(Terris J,Ecelbarger CA,Nielsen S,Knepper MA(1996)Long-term regulation of four renal aquaporins in rats.TheAmerican journal of physiology 271:F414-422；Combet S,GouraudS,Gobin R,Berthonaud V,Geelen G等人(2008)Aquaporin-2downregulation in kidney medulla of aging rats isposttranscriptional and is abolished by water deprivation.AmericanJournal of Physiology-Renal Physiology 294:F1408-F1414)，且老龄化过程中AQP2之下调为转录后的(Combet S,Gouraud S,GobinR,Berthonaud V,Geelen G 等人(2008)Aquaporin-2downregulation in kidney medulla of aging rats isposttranscriptional and is abolished by water deprivation.AmericanJournal of Physiology-Renal Physiology 294:F1408-F1414)。对ESRDHD的血浆中的单价离子(诸如Na+、K+及Cl-)的含量的进一步研究揭示，亨利氏环(loop of Henle)的上升支的主动输送的正常功能化(表2)，而肾元的此部分不含水通道蛋白(Nielsen S,Frokiaer J,Marples D,Kwon TH,Agre P等人(2002)Aquaporins in the kidney:from molecules to medicine.Physiological Reviews 82:205-244；King LS,Kozono D,Agre P(2004)From structure to disease:Theevolving tale of aquaporin biology.Nature Reviews Molecular CellBiology 5:687-698)。因此，在系统分辨率与原子分辨率下研究ESRD的水通道蛋白在稳定同位素中的生理作用可阐明肾脏功能障碍患者中的低重水。
血浆的18O及2H的动态平衡抵抗水源的18O及2H含量的波动。
降雨的δ2H及δ18O值季节性地波动。因为血浆中的大部分水2H及18O最终将来自降雨-饮用水及膳食水的来源，所以令人感兴趣的是检查雨水与血浆水中的δ2H及δ18O值之间的关系。
比较数据的δ2H及δ18O值与台北自2000年至2010年每月降水的δ2H及δ18O值(Peng T-R,Wang C-H,Huang C-C,Fei L-Y,ChenC-TA 等人(2010)Stable isotopic characteristic of Taiwan'sprecipitation:A case study of western Pacific monsoon region.Earth and Planetary Science Letters 289:357-366)。1月至5月，雨水的δ2H及δ18O值显示极小变化。此等值在6月开始下降，在7月及8月达至最小，且自9月至12月回升。另一方面，C S组中的血浆水同位素比始终低于1月至5月的降雨的同位素比。然而，血浆水的同位素比在7月至12月的降雨的标准误差内。因此，观测到CS组的血浆中的同位素δ2H及δ18O的动态平衡对抗每日摄入水的波动。
归因于7月台湾常见的台风，降雨的同位素含量最小，但在所有其它月份中变化极大。7月及3月的ESRDHD的血浆水的同位素比显著低于降水的同位素比，再次表明雨水的较强独立性。虽然9月的降水的同位素比接近于CS的同位素比，但在ESRDnHD中仍观测到相同样式，比降水的同位素比低约35%。对于DB组，血浆水的δ18O可与12月的降雨的δ18O相当[t0.05;14=0.27且F0.05; 1,14=0.07]，但血浆水的δ2H显示降雨的独立性[t0.05;14=3.03且F0.05; 1,14=9.21]。
DB及CS组中的水δ18O及δ2H值类似。
来自DB的δ18O及δ2H的值类似于CS的δ18O及δ2H的值。ANOVA分析表明DB及CS的血浆水含量(δ18O及δ2H)相当[对于δ18O，F0.05;1,8=4.63；对于δ2H，F0.05;1,8=0.20]。
似乎存在反映差异性肾脏状况的水同位素的生物动态平衡的微调。举例而言，ESRDnHD及正常肾脏组(CS及DB)具有不同动态平衡水平。应注意，具有正常肾脏功能的三组(表1及表3)，CS及DB的δ18O及δ2H含量类似。另外，我们注意到，CS个体的年龄(范围自27至67岁)独立于DB及ESRD个体(p=0)。ESRDHD组中18O及2H动态平衡的缺乏可归因于各血液透析的时间及持续时间以及不同ESRDHD个体的水合状态(Konings CJ,Kooman JP,Schonck M,Cox-Reijven PL,van Kreel B等人(2002)Assessment offluid status in peritoneal dialysis patients.Perit Dial Int 22:683-692)。
肾脏功能障碍的原因通常极其复杂，包括药物、糖尿病、高血压、败血症、个人生活方式等等。尽管如此，肾脏受损引起代谢物积聚，其导致2H替代1H且18O替代16O。此最终导致血浆的低同位素。在本研究中，我们表明肾脏功能障碍与人类血浆中大大减小的δ18O及δ2H相关。观测到血浆的低同位素的特性在肾脏功能障碍患者中显现，但在健康个人或糖尿病患者中不会显现。数据及结果表明，血浆的δ18O及δ2H对肾脏功能敏感但似乎对年龄、种族及膳食不敏感，此可能归因于生物同位素动态平衡。总之，此初步研究连同生物数据一起表明使用血浆中的δ18O及δ2H的含量作为肾脏功能障碍的潜在标记的可能性。
Claims (14)
1.一种在疑似肾脏疾病或肿瘤疾病的个体诊断肾脏疾病或肿瘤疾病可能性的方法，包括测定疑似肾脏疾病或肿瘤疾病的个体的生物样品中delta O-18(δ18O)和/或delta H-2(δ2H)的值，比较该测定的deltaO-18(δ18O)和/或delta H-2(δ2H)值与没有肾脏疾病或肿瘤疾病的个体的delta O-18(δ18O)和/或delta H-2(δ2H)的参考值，基于该测定的deltaO-18(δ18O)和/或delta H-2(δ2H)值与delta O-18(δ18O)和/或delta H-2(δ2H)的参考值的比较诊断肾脏疾病或肿瘤疾病的可能性；其中当疑似肾脏疾病或肿瘤疾病的个体的生物样品中delta O-18(δ18O)和/或delta H-2(δ2H)的值低于没有肾脏疾病或肿瘤疾病的个体的delta O-18(δ18O)和/或delta H-2(δ2H)的参考值时，则诊断为有肾脏疾病或肿瘤疾病的可能性。
2.如权利要求1所述的方法，其中得自没有肾脏疾病或肿瘤疾病的个体的delta O-18(δ18O)参考值范围为-3.0‰至-4.5‰。
3.如权利要求1所述的方法，其中得自没有肾脏疾病或肿瘤疾病的个体的delta H-2(δ2H)参考值范围为-30‰至-35‰。
4.如权利要求1所述的方法，其中所述肾脏疾病或肿瘤疾病的个体的生物样品中delta O-18(δ18O)低于约-5‰。
5.如权利要求1所述的方法，其中所述肾脏疾病或肿瘤疾病的个体的生物样品中delta H-2(δ2H)低于约-40‰。
6.如权利要求1所述的方法，其中所述生物样品为体液。
7.如权利要求6所述的方法，其中所述体液为尿液、血液、血清、血浆、唾液、淋巴液、脑脊髓液、囊性液(cystic fluid)、腹水、粪便、胆汁或组织液。
8.如权利要求6所述的方法，其中所述体液为血浆。
9.如权利要求1所述的方法，其中所述生物样品的处理是将所述样品置于含干燥剂的密闭容器，并接着从含水(或水合)的干燥剂去除水分以得到用于测定delta O-18(δ18O)和/或delta H-2(δ2H)的值的水，或所述生物样品经逆渗透处理得到所述水。
10.如权利要求9所述的方法，其中自含水(或水合)干燥剂去除水是经蒸馏或真空蒸馏。
11.如权利要求1所述的方法，其中所述肾脏疾病为末期肾失调、肾病变、肾衰竭、高尿酸血症、糖尿病性肾病变、缺血性或毒物诱导的肾伤害、慢性肾衰竭、急性肾衰竭、肾小球性肾炎、多囊性肾病或慢性肾盂肾炎。
12.一种套组，其包括一包含生物样品的容器或预定充填所述样品的容器，所述生物样品得自可能罹患肾脏疾病或肿瘤疾病的个体或罹患肾脏疾病或肿瘤疾病风险的个体，一测定生物样品中delta O-18和/或delta H-2的装置，和一参考值装置，用于诊断肾脏疾病或肿瘤疾病。
13.如权利要求12所述的套组，其另包含含有干燥剂的容器。
14.如权利要求12所述的套组，其中所述干燥剂是选自硅胶(silicagel)、活性碳、硫酸钙、氯化钙、蒙脱黏土(montmorilloniteclay)和分子筛(molecular sieve)的群组。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US13/229,305 US20130062516A1 (en) | 2011-09-09 | 2011-09-09 | Diganosis of a renal disease by oxygen and hydrogen isotopes in a biological sample |
| US13/229,305 | 2011-09-09 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102998436A true CN102998436A (zh) | 2013-03-27 |
| CN102998436B CN102998436B (zh) | 2015-02-25 |
Family
ID=47828974
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210333547.4A Expired - Fee Related CN102998436B (zh) | 2011-09-09 | 2012-09-10 | 以生物样品中的氧及氢同位素诊断肾脏失调或肿瘤疾病 |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US20130062516A1 (zh) |
| JP (1) | JP5662979B2 (zh) |
| KR (2) | KR101567627B1 (zh) |
| CN (1) | CN102998436B (zh) |
| TW (1) | TWI520747B (zh) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5861870B2 (ja) * | 2011-12-22 | 2016-02-16 | 国立大学法人 宮崎大学 | 終末期腎不全の検出方法 |
| CA3060647A1 (en) * | 2018-10-29 | 2020-04-29 | Mcmaster University | Carbonic anhydrase-catalyzed isotope equilibrium between co2-h2o for oxygen isotope analyses of aqueous samples |
| JP2021001876A (ja) * | 2019-05-23 | 2021-01-07 | ユエンハウ リン | 腎疾患にかかっている可能性の決定 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101027556A (zh) * | 2004-06-07 | 2007-08-29 | 儿童医院医疗中心 | 肾脏疾病和损伤的早期检测方法 |
| CN101163971A (zh) * | 2004-12-20 | 2008-04-16 | 免疫体公司 | 测定作为肾病诊断标记物的嗜中性粒细胞明胶酶相关性脂笼蛋白(ngal) |
| WO2008113363A1 (en) * | 2007-03-21 | 2008-09-25 | Bioporto Diagnostics A/S | Diagnostic test for renal injury |
| WO2008116867A1 (en) * | 2007-03-26 | 2008-10-02 | Novartis Ag | Predictive renal safety biomarkers and biomarker signatures to monitor kidney function |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002050560A2 (de) | 2000-12-21 | 2002-06-27 | Hanns-Ludwig Schmidt | Verfahren zur bestimmung der herkunft und authentizität biologisch, biochemisch und ernährungsphysiologisch relevanter stoffe durch messung ihrer position-sellen sauerstoff- bzw. wasserstoff-isotopenverhältnisse |
| EP1384075B1 (en) * | 2001-03-28 | 2009-12-16 | Heska Corporation | Methods of detecting early renal disease in animals |
| JP2005130755A (ja) | 2003-10-30 | 2005-05-26 | New Energy & Industrial Technology Development Organization | 農産物の植物種および植物栽培地域の特定方法 |
| JP4432780B2 (ja) | 2005-01-07 | 2010-03-17 | 三菱マテリアル株式会社 | 米の生産地特定方法 |
-
2011
- 2011-09-09 US US13/229,305 patent/US20130062516A1/en not_active Abandoned
-
2012
- 2012-09-10 TW TW101133083A patent/TWI520747B/zh not_active IP Right Cessation
- 2012-09-10 CN CN201210333547.4A patent/CN102998436B/zh not_active Expired - Fee Related
- 2012-09-10 KR KR1020120100024A patent/KR101567627B1/ko not_active Expired - Fee Related
- 2012-09-10 JP JP2012198704A patent/JP5662979B2/ja not_active Expired - Fee Related
-
2014
- 2014-12-30 KR KR1020140193007A patent/KR101537198B1/ko not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101027556A (zh) * | 2004-06-07 | 2007-08-29 | 儿童医院医疗中心 | 肾脏疾病和损伤的早期检测方法 |
| CN101163971A (zh) * | 2004-12-20 | 2008-04-16 | 免疫体公司 | 测定作为肾病诊断标记物的嗜中性粒细胞明胶酶相关性脂笼蛋白(ngal) |
| WO2008113363A1 (en) * | 2007-03-21 | 2008-09-25 | Bioporto Diagnostics A/S | Diagnostic test for renal injury |
| WO2008116867A1 (en) * | 2007-03-26 | 2008-10-02 | Novartis Ag | Predictive renal safety biomarkers and biomarker signatures to monitor kidney function |
Non-Patent Citations (2)
| Title |
|---|
| JOHS F. THOMSON ET AL.: "Changes in Renal Function in Rats Drinking Heavy Water", 《EXP BIOL MED (MAYWOOD)》 * |
| 曾文炳等: "13C-美沙西汀呼气法参数诊断肝脏疾病的研究", 《中国科学（B）辑》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20150006411A (ko) | 2015-01-16 |
| HK1184532A1 (zh) | 2014-01-24 |
| KR101537198B1 (ko) | 2015-07-15 |
| KR20130028697A (ko) | 2013-03-19 |
| US20130062516A1 (en) | 2013-03-14 |
| TW201311276A (zh) | 2013-03-16 |
| JP2013061334A (ja) | 2013-04-04 |
| KR101567627B1 (ko) | 2015-11-09 |
| CN102998436B (zh) | 2015-02-25 |
| JP5662979B2 (ja) | 2015-02-04 |
| TWI520747B (zh) | 2016-02-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| e Silva et al. | Assessment of kidney function in patients with cancer | |
| Hanifa et al. | Tissue, urine and blood metabolite signatures of chronic kidney disease in the 5/6 nephrectomy rat model | |
| Smith et al. | SIFT-MS and FA-MS methods for ambient gas phase analysis: developments and applications in the UK | |
| BRPI0924639A2 (pt) | novos biomarcadores para avaliação de doenças nos rins. | |
| Heo et al. | Serum heavy metals and lung function in a chronic obstructive pulmonary disease cohort | |
| CN102998436B (zh) | 以生物样品中的氧及氢同位素诊断肾脏失调或肿瘤疾病 | |
| Zhong et al. | Application of wastewater-based epidemiology to estimate the usage of beta-agonists in 31 cities in China | |
| Cheng et al. | Untargeted metabolomics reveals the role of AQP9 in nonalcoholic fatty liver disease in a mice model | |
| Capolongo et al. | Urinary metabolic profile of patients with transfusion-dependent β-thalassemia major undergoing deferasirox therapy | |
| Garamszegi et al. | Detection of β-N-methylamino-l-alanine in postmortem olfactory bulbs of Alzheimer’s disease patients using UHPLC-MS/MS: An autopsy case-series study | |
| Claudel et al. | Estimating kidney function in patients with cancer: a narrative review | |
| Sun et al. | A translational study of Galectin-3 as an early biomarker and potential therapeutic target for ischemic-reperfusion induced acute kidney injury | |
| Wang et al. | Development of a rat model of D-galactosamine/lipopolysaccharide induced hepatorenal syndrome | |
| Lu et al. | Gestational Exposure to PM2. 5 and Specific Constituents, Meconium Metabolites, and Neonatal Neurobehavioral Development: A Cohort Study | |
| Kang et al. | Initial lactate level and mortality in septic shock patients with hepatic dysfunction | |
| Kim et al. | Virtual diagnosis of diabetic nephropathy using metabolomics in place of kidney biopsy: the DIAMOND study | |
| Stolic et al. | Residual renal function and erectile dysfunction in patients on hemodialysis | |
| Negrei et al. | Investigation relevance of methotrexate polyglutamates in biological systems by high performance liquid chromatography | |
| CN106546754B (zh) | 伊木萨克片作用于异常黏液质证与阳痿病证模型靶点蛋白及其筛选方法 | |
| Kuo et al. | Assessment of renal function by the stable oxygen and hydrogen isotopes in human blood plasma | |
| Jiang et al. | Exploring the Muscle Metabolomics in the Mouse Model of Sepsis‐Induced Acquired Weakness | |
| Guo et al. | Perfluoroalkyl and polyfluoroalkyl substances crossing the blood-joint barrier: Their occurrence and distribution in synovial fluid | |
| HK1184532B (zh) | 以生物样品中的氧及氢同位素诊断肾脏失调或肿瘤疾病 | |
| Arinell et al. | Effect of prolonged standardized bed rest on cystatin C and other markers of cardiovascular risk | |
| Chen et al. | Harnessing nanotechnology for gout therapy: Colchicine-loaded nanoparticles regulate macrophage polarization and reduce inflammation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1184532 Country of ref document: HK |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1184532 Country of ref document: HK |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20150225 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |