Ib qho Kev Tsis Txaus Siab Ntawm Cov Kabmob Urinary Common Rejection Module (uCRM) Score For Non-invasive Kidney Transplant Monitoring
Mar 16, 2022
Hu rau: Audrey Hu Whatsapp / hp: 0086 13880143964 Email:audrey.hu@wecistanche.com
Abstract
Ib qho Kev Tsis Txaus Siab Module (CRM) uas muaj 11 cov noob tau nthuav tawm hauv allograft biopsies tau tshaj tawm yav dhau los los ua tus biomarker rau kev tsis lees paub mob hnyav (AR), cuam tshuam nrog kev raug mob graft, thiab kwv yees yav tom ntej allograft puas. Peb tau tshawb xyuas kev siv cov noob vaj huam sib luag ntawm cov zis cell pellet ntawm cov neeg mob raum hloov pauv. Cov kab mob hauv cov zis tau sau los ntawm cov neeg mob uas muaj kev tsis lees paub qhov mob biopsy, ciam teb AR (bAR), BK tus kab mob nephropathy (BKVN), thiab lub raum ruaj khov nrog cov txheej txheem biopsies (STA) tau txheeb xyuas rau kev qhia ntawm 11 cov noob no siv ntau cov khoom siv polymerase saw. cov tshuaj tiv thaiv (qPCR). Peb tau soj ntsuam 11 CRM noob no rau lawv cov kev nplua nuj, kev sib raug zoo ntawm tus kheej, thiab qib kev qhia ntawm tus kheej, Kev nthuav qhia ntawm 10/11 noob tau nce siab hauv AR thaum piv rau STA.Psmb9 thiab Cxcl10 tuaj yeem faib AR piv rau STA kom raug raws li 11- qauv qauv ( rhiab heev=93.6 feem pua, tshwj xeeb=97.6 feem pua ). Au CRM cov qhab nia, raws li qhov ntsuas geometric ntawm cov qib qhia, tuaj yeem paub qhov txawv ntawm AR los ntawm STA nrog qhov raug siab (AUC= 0.9886) thiab cuam tshuam tshwj xeeb nrog kev ntsuas histologic ntawm tubulitis thiab kev mob sib kis ntau dua li tubular atrophy, glomerulosclerosis, Intimal proliferation, tubular vacuolization, los yog mob glomerulitis. Cov zis gene qhia-raws li cov qhab nia no tuaj yeem ua rau tsis muaj kev cuam tshuam thiab kev saib xyuas ntau ntawm AR.
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Taw qhia
Lub raum hloov pauv (KTx) yog qhov kev hloov pauv zoo tshaj plaws rau kev kho mob ntawm lub raum tsis yooj yim (ESRD) los ntawm ib qho laj thawj [1]. Thaum txoj kev kho mob no tau dhau los ua kev coj ua niaj hnub thoob ntiaj teb, txhim kho tus neeg mob lub neej zoo thiab muaj sia nyob [2], cov txiaj ntsig ntawm lub raum mus sij hawm ntev tsis tau txhim kho raws li qhov xav tau txawm tias muaj kev nkag siab zoo ntawm lub cev tiv thaiv kab mob ntawm allograft tsis lees paub thiab qhov tshwm sim ntawm qhov tshiab. thiab ntau cov tshuaj tiv thaiv kab mob muaj zog [3]. Qhov laj thawj tseem ceeb rau kev muaj sia nyob tsis tu ncua thiab tsis zoo yog qhov tsis muaj peev xwm ua kom tsis muaj kev cuam tshuam txog lub nra ntawm lub cev tiv thaiv kab mob thiab kwv yees qhov kev tsis lees paub ua ntej kev ua haujlwm tsis zoo thiab kev raug mob histological. Tseeb tiag, thaum nws paub zoo tias cov neeg mob KTx tau txuas ntxiv mus rau lub cev tsis muaj zog thiab tsis muaj zog cuam tshuam txog kev raug mob [4, 5], kev saib xyuas KTx ib ntus yog nyob ntawm cov cim tsis txaus ntseeg ntawm allograft dysfunction xws li ntshav creatinine (6, Z] thiab kev saib xyuas KTx tsis sib xws. Raws li txoj cai allograft biopsies txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau tshuaj Nws muaj qhov tshwj xeeb tsawg rau kev kuaj mob ntawm qhov tsis lees paub (AR), vim tias qhov nce hauv cov ntshav creatinine tuaj yeem yog vim lwm yam laj thawj tsis ncaj qha cuam tshuam rau allograft rejection, xws li immunosuppressive (IS) tshuaj-txog nephrotoxicity, mob tubular necrosis, kab mob. , thiab interstitial fibrosis thiab tubular atrophy (IFTA). Tsis tas li ntawd, thaum siv kev soj ntsuam biopsies tau raug postulated ua tus qauv kub rau kev kuaj mob al. lograft lesions, qhov no mus kom ze yog kim, invasive, nrog cov txheej txheem morbidity (xws li los ntshav; txheej txheem yuav tsum tau sedation, tshwj xeeb tshaj yog rau cov me nyuam mos KTx cov neeg mob) [9], fraught nrog inter-operator nyeem variabilities, thiab feem ntau tsis zoo tus neeg sawv cev ntawm focal histological raug mob, Yog li ntawd, kev siv cov non-invasive biological markers uas yuav raug kwv yees thiab quantify lub nra ntawm Kev tiv thaiv kab mob hauv lub allograft yuav yog ib qho tseem ceeb ua ntej rau precision KTx saib xyuas [10-12].
Kev nug ntawm proteomic, RNA, thiab microRNA biomarkers nyob rau hauv cov zis ntawm KTx cov neeg mob tau pom los ntawm peb pab pawg thiab lwm tus neeg [13-17] los ua ib qho dej zoo tshaj plaws rau kev soj ntsuam ntawm lub raum allograft vim nws yog ib qho ultrafiltrate ntawm lub lub raum thiab tsom iav cov txheej txheem lom neeg thiab lub nra hnyav pom nyob rau hauv lub raum graft [18]. Txawm hais tias muaj ntau cov kev tshawb fawb uas yav dhau los tau soj ntsuam cov zis biomarkers raws li kev kuaj mob tsis muaj kev cuam tshuam rau kev soj ntsuam ntawm AR hauv lub raum hloov pauv, qhov tshwj xeeb tsom rau ib qho biomarkers xws li cov tshuaj chemokines thiab receptors xws li CXCR3, CXCL9, lossis CXCL10 [{{ 6}}] ua rau nws nyuaj rau kev ntes cov molecular complexity thiab heterogeneity ntawm AR hla cov neeg mob KTx sib txawv. Kev ntes no heterogeneity yog qhov tseem ceeb los ntsuas lub nra ntawm kev raug mob raws li qhov siv tau rau kev saib xyuas yav tom ntej ntawm AR thiab rov qab los ntawm kev raug mob graft tom qab kev kho mob [25, 26].
Nyob rau hauv txoj kev tshawb no, peb siv cov kev paub uas tau txais los ntawm harnessing ib tug Common Rejection Mod-ule (CRM) ntawm 11 noob [27], Ameslikas tsim siv tag nrho cov meta-analyses ntawm pej xeem muaj kev hloov cov ntaub so ntswg microarray datasets ntawm biopsy kuaj los ntawm plaub ntau yam khoom. lub cev. CRM noob hauv cov ntaub so ntswg (tCRM) tau tshaj tawm tag nrho ntawm cov neeg mob AR, tsis hais txog hom kab mob hauv nruab nrog cev, qhov sib txawv ntawm cov txheej txheem tiv thaiv kab mob, lossis qhov sib txawv hauv lub platform uas nug cov noob qhia. Ib qho kev txiav txim siab ntau yam txiav txim siab los ntawm kev txheeb xyuas cov qhab nia sib xyaw ua ke (cov qhab nia tCRM) tau kwv yees qhov muaj AR los ntawm kev sib tw ntawm cov ntaub so ntswg cov npe kos npe hauv 8 pawg neeg ywj pheej (n= 236 cov qauv) ntawm tib neeg lub raum allograft biopsies [27]. Qhov qhab nia tCRM tau raug lees paub ntxiv los ntawm qPCR hauv ib qho kev tshawb fawb cais ntawm KTx biopsy cov qauv kuaj pom ntawm ob qho tib si AR thiab mob ntev allograft raug mob (CAl) nrog cov noob sib txawv ntawm qhov pib [28]. Tsis tas li ntawd, cov txheej txheem CRM no tau raug lees paub nyob rau hauv ib qho kev ywj pheej ntawm cov ntaub so ntswg biopsied los ntawm cov neeg mob ntsws hloov cov neeg mob uas mob ntsws allograft dysfunction (CLAD) [29].
Hauv txoj kev tshawb no, peb ntsuas CRM gene teem rau kev siv cov zis kuaj los ntawm cov neeg mob KTx, ua ke nrog allograft biopsies nrog paub txog histology, rau kev kuaj mob tsis muaj kev cuam tshuam ntawm AR thiab lwm yam kev tiv thaiv kab mob. Ntxiv mus, peb tsim cov zis CRM (uCRM) cov qhab nia uas raug kev ntxub ntxaug ntawm STA thiab AR cov neeg mob. Peb ntsuas qhov kev soj ntsuam muaj peev xwm ntawm qhov qhab nia no hauv kev tshawb pom ntawm bAR los ntawm kev sib piv cov qhab nia no nrog cov qhab nia histology ntawm tubulitis thiab mob sib kis.
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Cov ntaub ntawv thiab cov txheej txheem
Cov qauv ntawm cov zis thiab cov kev tshawb fawb cohort
Biobank cov zis kuaj (n=1760) los ntawm KTx cov neeg tau txais kev tso npe hauv Stanford University thaum xyoo 2000 thiab 2011 thiab UCSF Medical Center tau tso npe rau xyoo 2014 thiab 2016 tau suav nrog hauv txoj kev tshawb no. Txoj kev tshawb no tau pom zoo los ntawm Pawg Saib Xyuas Kev Tshawb Fawb thiab Kev Ncaj Ncees ntawm University of California San Francisco, CA. Txhua tus neeg mob tau sau ntawv tso cai los koom nrog hauv kev tshawb fawb, ua raws li Kev Tshaj Tawm ntawm Helsinki. Cov haujlwm kho mob thiab kev tshawb fawb tau tshaj tawm yog ua raws li Cov Ntsiab Cai ntawm Kev Tshaj Tawm ntawm Istanbul raws li tau teev tseg hauv Kev Tshaj Tawm ntawm Istanbul ntawm Kev Lag Luam Kev Lag Luam thiab Kev Hloov Mus Los. Rau cov qauv tso zis siv los tsim qhov uCRM qhov pib rau AR, 178 cov zis kuaj tau txheeb xyuas nrog cov kab mob raum ua ke nrog rau cov kab mob uas tau hais meej meej ntawm Banff graded AR[30,31] lossis tsis muaj kev raug mob / ruaj khov (STA) grafts (Eig 1). Tsis tas li ntawd, peb kuj tau soj ntsuam qhov kos npe rau qhov kev ntsuam xyuas uCRM hauv BK kab mob nephropathy, uas yog ib qho tseem ceeb confounder rau kev kuaj mob ntawm AR thiab feem ntau tshwm sim nrog qhov mob tseem ceeb ntawm allograft biopsy. Zuag qhia tag nrho, 28 cov qauv raug muab pov tseg vim yog QC cov teeb meem ntsig txog cov ntsiab lus tsis zoo thiab tsis zoo RNA, uas ua rau muaj qhov kawg suav ntawm 150 cov qauv zis los ntawm 150 tus neeg rau kev txheeb xyuas ntu ntawm kev tiv thaiv kab mob KTx raug mob. Txhua tus qauv tso zis tau sib xyaw nrog kev kuaj ntshav thaum lub sijhawm sau cov zis uas tau soj ntsuam los ntawm tus kws kho mob hauv nruab nrab ntawm Stanford University (Richard Sibley) lossis ntawm UCSF (Zol-tan Laszik).
Cov yam ntxwv ntawm tus neeg mob
150 unique urine samples were assessed for the uCRM assay in 150 unique kidney transplant patients. Baseline clinical and demographic variables by AR, bAR, BKVN, or STA phenotype are shown in Table1, There were no significant differences between the groups in the demographic variables, except in recipient age (p= 0.025) and in donor-source (p=0.0008). These samples were used in cross-sectional analyses for modeling of gene expression data and subsequent development and validation of the uCRM threshold for biopsy-proven AR. Samples were collected from both pediatric (n=94) and adult (n=56)patients to enable a model-independent of recipient age or baseline immunosuppression. Based on the matched biopsy diagnosis, urine samples were categorized in the following categories: AR(n=64;45 biopsies met criteria for Banff confirmed AR with >i2,t2, and infiltration by >4 mononuclear hlwb /tubular cross-section, whereas 19 tau raws li cov qauv rau ciam teb AR nrog il / i2 thiab t0/t1 thiab infiltration los ntawm 1-4 mononuclear hlwb / tubular cross-section), STA (n { {8}}), BK kab mob nephritis(n =43), Cov neeg mob tau txais calcineurin-inhibitor ILS kev tswj hwm raws li tacrolimus thiab mycophenolate mofetil, nrog lossis tsis muaj steroids, thiab induction therapy nrog Thymoglobulin lossis anti-IL{{ 12}} receptor monoclonal antibody (daclizumab lossis basi. infliximab)[32]. Cov qauv zis tau txais ntawm qhov nruab nrab ntawm 731 hnub tom qab hloov pauv (ntau 169-1335 hnub).
Txhais kev raug mob phenotypes
All kidney biopsies were blindly and centrally analyzed at each institution by staff pathologists (RS and ZL)and were graded by the Banff dassification[31,33] for acute rejection.Intragraft C4d stains were performed [34] to assess for acute humoral rejection(AHR)[35]. Transplant injury was defined as>20 feem pua nce hauv cov ntshav creatinine los ntawm nws cov nqi hauv lub xeev tsis tu ncua thiab ib qho kev kuaj ntshav uas tau muab cais ua AR lossis BKVN.AR tau txhais tsawg kawg nkaus, raws li Banff schema, tubulitis tau ntau dua lossis sib npaug rau 1 nrog rau interstitial o tau qhab nia Ntau dua lossis sib npaug rau 1 nrog rau Cd thiab DSA tsis zoo. Ob leeg Tcell mediated AR (TCMR) thiab antibody-mediated rejection (ABMR) cov teeb meem raug ntxias, txawm hais tias tag nrho cov kev soj ntsuam ABMR muaj ib tug sib xyaw phenotype ntawm TCMR thiab ABMR, raws li kev soj ntsuam ntawm ntshiab ABMR yog tsis tshua pom nyob rau hauv uas tsis tshua muaj kev pheej hmoo, unsensitized cohorts. Kev hloov pauv ntawm ciam teb (bAR) tau pom nyob rau qee kis ntawm TCMR, tus cwj pwm los ntawm kev nkag mus ntawm cov hlwb mononuclear (<25% of="" the="" parenchyma)or="" foci="" of="" mild="" tubulitis(1-4="" mononuclear="" cells/tubular="" cross-section),="" and="" for="" purposes="" of="" molecular="" correlation="" analysis,="" these="" have="" been="" shown="" as="" bar,="" as="" the="" burden="" of="" histological="" inflammation="" was="" overall="" lower="" for="" these="" biopsy="" samples.="" bkvn="" was="" defined="" as="" the="" positivity="" of="" polyomavirus="" pcr="" in="" peripheral=""><1000-28,800,000), together="" with="" a="" positive="" sv40="" stain="" in="" the="" concomitant="" renal="" allograft="" biopsy.="" normal="" (sta)="" allografts="" were="" defined="" by="" an="" absence="" of="" significant="" injury="" pathology="" on="" the="" 6-month="" protocol="" biopsy,="" as="" defined="" by="" banff="" schema,="" stable="" graft="" function,="" no="" proteinuria,="" and="" no="">
Fig 1. Cov qauv xaiv thiab kawm schematic ntawm txoj kev kawm. 1,760 cov qauv zis tau sau los ntawm 2000 thiab 2016,
ntawm uas 643 muaj cov ntaub ntawv biopsy txuam. 178 ntawm cov 643 no muaj cov phenotypes zoo ntawm AR, bAR, BKVN, lossis STA.
Tom qab RNA rho tawm, cDNA synthesis, thiab qPCR kom muaj nuj nqis, 28 cov qauv tsis dhau QA / QC, tawm hauv 150
cov qauv rau kev txheeb xyuas thiab kev ua qauv.
Kev sau cov zis, ua, tag nrho RNA rho tawm, cDNA synthesis, thiab qPCR
Cov zis (50 mL; lub thawv tsis muaj menyuam) tau sau los ntawm cov neeg mob lub raum hloov ua ntej cov txheej txheem biopsy thiab ua ntej kev kho mob hnyav rau AR. RNA tau muab rho tawm los ntawm cov urinary cell sediment tom qab peb tau tshaj tawm raws tu qauv [36].Nyob rau hauv luv luv, cov zis hlwb tau los ntawm centrifuging tus 50-mL cov zis ntawm 2000xg rau 20 feeb.RNA tau muab rho tawm los ntawm cov zis cell pellets siv lub RNeasy Plus Micro Kit (Qiagen, Valencia, CA). RNA zoo tau raug soj ntsuam nrog NanoDrop ND-2000 spectrophotometer (ThermoFisher Scientific, Waltham, MA) nrog 260/280 piv. cDNA synthesis tau ua tiav siv 50ng ntawm RNA rho tawm siv SuperScript VILO"Master Mix (Invitrogen, Carlsbad, CA).qPCR tau ua ntawm cDNA synthesized los ntawm 50ng ntawm tag nrho RNA, tom qab ntawd 1.56ng ntawm cDNA tau ua tiav los ntawm cov phiaj xwm nthuav dav thiab cov qauv. dilution nrog lub pooled Taqman assays rau 1l uCRM noob nyob rau hauv multiplex, nrog Taqman PreAmp Master Mix (ABI) mus rau 5ul zaum kawg ntim, rau 18 cycles nyob rau hauv ib tug thermal cycler, ces diluted nrog DNA Suspension Buffer (TEKnova, CA). Microfluidic qPCR yog ua ntawm 96.96 dynamic arrays (Fluidigm, South San Francisco, CA) siv 2.25 ul ntawm cov qauv diluted los ntawm cov hom phiaj tshwj xeeb amplification, nrog rau Taqman Assays (ABI) rau txhua daim ntawv teev cov noob (S1Table), Taqman Universal master mix (Applied Biosystems, Foster City, CA) thiab Loading Reagent (Fluidigm), los ntawm priming thiab loading lub nti ntawm HX IFC Controller thiab ua qPCR nyob rau hauv lub BioMark (Fluidgm) system. Tus txheeb ze npaum li cas ntawm RNA qhia tau suav nrog kev sib piv cy. cle threshold (CT) txoj kev. Kev nthuav qhia qhov tseem ceeb tau normalized rau 18Susing ribosomal RNA endogenous reference thiab universal RNA (Agilent Inc., Santa Clara, CA).
Txheeb cais
Txhua qhov kev ntsuam xyuas qPCR tau khiav hauv qhov sib npaug. Tag nrho cov ntaub ntawv raug nthuav tawm raws li txhais tau tias ± SEM. Rau com-parisons ntawm CRM noob ib phenotype, ib qho kev sib xyaw ua ke nrog kev kho Geisser-Greenhouse tau siv, nrog ntau qhov kev sib piv kev kho tau ua los ntawm ob-theem linear-step txheej txheem ntawm Beniamini, Krieger, thiab Yekutieli. Pearson correlation thiab hierarchical dusting tau ua nyob rau hauv Morpheus (Broad Institute). Rau cov qauv kev kawm kev twv ua ntej, cov ntaub ntawv tau muab faib ua ib qho kev cob qhia (80 feem pua) thiab cov txheej txheem xeem (20 feem pua). Ib qho kev txiav txim siab txog kev faib cov qauv, tau lees paub ntawm cov txheej txheem sim, tau siv los txiav txim siab qhov tseeb tshaj plaws uCRM tau txiav tawm. Kev xaiv sib txawv Siv Random Forests (VSURF) tau siv los txheeb xyuas AR ys STA nrog rau kev ntsuas thiab ntsuas tus kheej cov noob tseem ceeb. Random Forest tsis paub meej qhov tseem ceeb tso zis yog txhais raws li qhov feem pua ntawm qhov tsis raug ntawm cov qauv ntawm qhov sib txawv (gene) raug tshem tawm (randomly permuted) los ntawm tus qauv. Unsupervised plua plav kom pom kev sib cais phenotype tau ua tiav siv cov neeg nyob sib ze stochastic embed-ding algorithm (t-SNE) hauv Mathematica 11.3 (Wolfram Research, Champaign. IL). Kev tsom xam network ntawm CRM noob tau ua los ntawm GeneMANIA [37]. Kev txheeb xyuas ntawm cov pej xeem sib txawv tau ua tiav siv Chi-square kev tshuaj ntsuam rau kev txiav txim siab thiab Kruskal-Wallis kev sim rau qhov sib txawv tsis tu ncua hauv IMP 14.2 (SASInstitute, Cary, NC). Tshwj tsis yog hais lwm yam. tag nrho lwm yam kev txheeb xyuas tau ua thiab pom pom nrog Prism 8.0.1 (GraphPad, Carlsbad, CA).
Kev pom zoo kawm
Txoj kev tshawb no tau pom zoo los ntawm Pawg Neeg Saib Xyuas Kev Ncaj Ncees ntawm Stanford University Medical School thiab UCSF Medical Center. Txhua tus neeg laus thiab cov niam txiv / cov neeg saib xyuas ntawm cov neeg mob uas tsis yog neeg laus tau sau ntawv tso cai los koom nrog hauv kev tshawb fawb, ua raws li Kev Tshaj Tawm ntawm Helsinki. Cov haujlwm kho mob thiab kev tshawb fawb tau tshaj tawm yog ua raws li Cov Ntsiab Cai ntawm Kev Tshaj Tawm ntawm Istanbul raws li tau teev tseg hauv Kev Tshaj Tawm ntawm Istanbul ntawm Kev Lag Luam Kev Lag Luam thiab Kev Hloov Mus Los.
TSEEM CEEB NTAWM CSITANCHE: IMPROVE Immunity
Cov txiaj ntsig
Lub hauv paus chaw kho mob thiab cov pej xeem sib txawv rau txhua tus 150 KTx tau txais nrog AR, bAR, BKVN, thiab STA phenotypes tau qhia hauv Table1.
Kev txheeb ze kev nplua nuj, thiab kev sib raug zoo ntawm CRM gene qhia hauv murine cell sediment
kwv tij nplua nuj. Txhawm rau txiav txim siab qhov txheeb ze ntawm CRM gene transcripts nyob rau hauv cov zis sediments, lub voj voog threshold (Ct) qhov tseem ceeb tau siv los ua ib qho metric ntawm abundance. Qhov qis dua tus nqi Ct, qhov siab dua nws qhov kev nplua nuj ntawm CRM noob. Ntawm 11 CRM genes, BASP1 yog cov ntawv sau ntau tshaj plaws nyob rau hauv cov zis cell sediment. BASP1 tau ua raws li TAP1, PSMB9, thiab ISG20 raws li 4 saum toj kawg nkaus transcripts.LCK thiab CD6 yog ib qho ntawm cov ntaub ntawv pov thawj tsawg tshaj plaws nyob rau hauv cov zis sediments hauv CRM gene-set. Txij li thaum Ct qhov tseem ceeb nyob ntawm qhov qis tshaj Ct tus nqi ntawm 14 mus rau qhov siab tshaj plaws Ct tus nqi ntawm 20, muaj ib qho 64-fold qhov sib txawv ntawm BASP1 thiab CD6 cov ntawv teev cov noob caj noob ces, nrog CD6 yog qhov tsawg tshaj plaws transcript.
Daim duab 2. Kev txheeb ze ntawm kev nplua nuj thiab kev sib raug zoo ntawm kev nplua nuj ntawm CRM noob nyob rau hauv cov zis thiab kev qhia ntawm CRM noob nyob rau ntau qhov chaw kho mob phenotypes ntawm lub raum hloov. A. Pearson correlation matrix qhia kev sib raug zoo ntawm 11 CRM noob nyob rau hauv lawv cov lus qhia nyob rau hauv urinary cell sediments. Qhov luaj li cas ntawm lub square ua hauj lwm raws li ib qho kev qhia pom ntawm lub zog ntawm kev sib raug zoo. B. Heatmap nrog saib xyuas pawg los ntawm phenotype qhia txog kev txheeb ze ntawm CRM noob hauv AR, bAR, BKVN, thiab STA. C. Violin plots depicting kev faib ntawm CRM noob nyob rau hauv AR, bAR, BKVN, thiab STA urine cell pellet. � qhia tias AR vs STA yog qhov tseem ceeb tom qab ntau qhov sib piv. # qhia tias bAR vs STA yog qhov tseem ceeb tom qab ntau qhov sib piv. Cov txheeb cais ntxiv muaj nyob rau hauv Table 2.
Kev sib raug zoo ntawm cov noob qhia ntawm CRM noob noob.
Tom ntej no, peb tau soj ntsuam qhov sib txheeb ntawm cov noob qhia ntawm 11 CRM noob. Qhov kev sib raug zoo sib txawv ntawm qhov tsis muaj zog heev (r=-0}.17 rau CXCL9 thiab NKG7 thiab r=-0.10 CXCL10 thiab RUNX3) mus rau qhov muaj zog heev (r=0}.77 rau INPP5D thiab TAP1 thiab cov tib tus nqi rau CD6 thiab LCK). Txawm hais tias CXCL9 thiab CXCL10 nyob rau hauv tib chav kawm ntawm chemokines, cov noob qhia kev sib raug zoo ntawm lawv tsuas yog nruab nrab (r=0.46). Daim duab qhia txog kev sib raug zoo matrix yog nthuav tawm hauv daim duab 2A. Daim ntawv qhia tshav kub uas tsim los siv kev saib xyuas pawg qhia pom qhov nce ntau ntawm cov noob qhia qhov tseem ceeb ntawm CRM genes hauv AR, bAR, thiab BKVN piv rau STA phenotype (Fig 2B).
uCRM noob qhia nyob rau hauv urinary sediments nrog biopsy-pom zoo AR thiab BKVN
Gene qhia ntawm CRMgenes hauv AR thiab bAR. Tom ntej no, peb tau soj ntsuam cov noob qhia ntawm txhua tus ntawm 11 CRM noob rau lawv cov txheeb ze qhia hauv AR, bAR, BKVN, thiab STA. Cov ntsiab lus ntawm cov txiaj ntsig ntawm kev tshuaj ntsuam tau nthuav tawm hauv Table 2 thiab Fig 2C.10 ntawm 11 cov noob tau nce ntau hauv AR cov zis sediments thaum piv rau cov zis sediments los ntawm STA. Txawm li cas los xij, tsuas yog tsib CRM genes (Cd6, Cxcll0, Cxd9, Nkg7, thiab Psmb9) tau raug tswj hwm zoo hauv cov qauv bAR piv rau STA thiab lawv cov lus qhia hauv pawg bAR kuj qis dua hauv Banff graded AR pawg, qhia tias uCRM noob tuaj yeem ua tau. qhia txog lub nra hnyav hauv lub allograft Eig 2C.
Table 2. Gene qhia theem ntawm CRM noob nyob rau txawv phenotypes
Gene qhia ntawm CRMgenes hauv BKVN. Kev nthuav qhia ntawm CD6, CXCL10, CXCL9, LCK, NKG7, thiab PSMB9 tau tswj hwm qhov sib txawv hauv cov qauv tso zis nrog cov neeg mob BKVN thaum piv rau cov qauv ntawm cov neeg mob STA. Tawm ntawm 6 lub noob nrog cov txheeb cais sib txawv ntawm cov noob qhia qhov tseem ceeb ntawm BKVN thiab STA cov qauv, kev qhia ntawm NKG7 tsuas yog qis dua hauv BKVN cov zis.
Kev txiav txim siab ntawm cov zis CRM (uCRM) gene qhia cov qhab nia txhawm rau txheeb xyuas qhov tsis lees txais lub raum hloov pauv
Vim hais tias kev qhia ntawm CRM gene-set tsis yog homogenous thoob plaws cov phenotypes hloov pauv thiab muaj ntau qhov kev sib tham ntawm lub cev sib txawv ntawm cov noob sib txawv (S1 Fig), peb siv cov kev saib xyuas uas tsis yog kab txuas ntxiv kom sib txawv thiab faib cov phenotypes. Unsupervised clustering ntawm t-SNE tau ua los txiav txim siab kev sib raug zoo ntawm uCRM noob thiab phenotypes. Daim duab 3A qhia txog t-SNE zajlus, qhia tias 11 CRM noob yuav luag tag nrho cais AR los ntawm STA cov qauv. Tus qauv VSURF, nyob ntawm Random Forests cov qhab nia tseem ceeb, txiav txim siab tias PSMB9 thiab CXCL10 yog ob lub noob tseem ceeb tshaj plaws hauv kev txaus siab AR los ntawm STA. Daim duab 3B qhia ntxiv txog qhov tseem ceeb ntawm 2 cov noob no. Cov phiaj xwm tseem ceeb ntawm cov noob hnyav txhais tau hais tias ib qho ntawm 2 cov noob yog cais tawm ntawm tus qauv, sib raug rau kwv yees li 20 feem pua ntawm qhov tsis raug ntawm tus qauv. Ob lub noob no tuaj yeem faib AR piv rau STA uas yuav luag muaj qhov tseeb raws li tus qauv 1l noob, nrog rau qhov rhiab heev ntawm 93.6 feem pua thiab qhov tshwj xeeb ntawm 97,6 feem pua. Gene qhia pib rau ob lub noob no tau txiav txim siab los ntawm kev txiav txim siab ntoo cais thiab cov log-scale qhov tseem ceeb ntawm ob lub noob no tau piav qhia hauv daim duab 3C. Ib qho chaw pib ntawm 28 rau CXCL10 thiab 3 rau PSMB9 raug cais tawm kom raug 86/88 AR & STA cov ntaub ntawv rau qhov tseeb tag nrho ntawm 97.7 feem pua. Qhov tseem ceeb, cov qauv bAR poob ntawm AR thiab STA pheno-hom, qhia txog kev ua kom tiav ntawm ob lub noob hauv qib ntawm allograft o.
Txhawm rau tshawb xyuas qhov kev faib tawm ntawm qhov qhab nia ntawm uCRM ntawm AR, ciam teb AR, thiab STA cov teeb meem, kev txiav txim siab ntoo cais tau tsim (Fig 4A). Cov ntoo txiav txim siab tau txiav txim siab qhov zoo tshaj plaws uCRM cov qhab nia rau txhua qhov phenotype. Qhov qhab nia siab dua 4 raug muab faib ua 44/49 AR rooj plaub; tus qhab nia tsawg dua 1.8 raug cais tawm 33/35 STA cov xwm txheej.14/23 cov kab mob ciam teb yog nyob nruab nrab ntawm ob qhov pib. Kev faib tawm ntawm uCRM cov qhab nia los ntawm phenotype yog piav qhia hauv Fig4B.Qhov nruab nrab uCRM cov qhab nia (SEM) rau AR, bAR, thiab STA yog 8.195 (0.631), 3.265 ({17}}.412{{21 }}), thiab 1.404(0.162) feem, thiab tag nrho cov kev sib piv yog qhov tseem ceeb tom qab ntau qhov kev sib piv kho. Tus qhab nia uCRM tuaj yeem paub qhov txawv ntawm AR thiab STA nrog qhov tseeb siab-ntawm qhov pib ntawm 3.63, qhov rhiab heev thiab qhov tshwj xeeb yog 95.35 feem pua thiab 97.78 feem pua ntawm qhov sib txawv (Eig 4C. Thaum qhov sib txawv ntawm AR thiab kev sib xyaw ntawm bAR thiab STA, uCRM tau khaws cia. qhov tseeb siab ntawm tib qhov pib, qhov rhiab heev thiab qhov tshwj xeeb yog 87.10 feem pua thiab 97.78 feem pua (S2A Fig).
Thaum suav nrog BKVN cov qauv, tag nrho cov phenotypes sib txawv ntawm ib leeg tom qab ntau qhov kev sib piv kev kho tshwj tsis yog bAR thiab BKVN (S2BFig). Thaum qhov sib txawv ntawm AR thiab kev sib xyaw ua ke ntawm bAR, STA, thiab BKVN, tus qhab nia uCRM tseem khaws tau qhov siab, tab sis qis dua. Siv tib yam 3.63 qhov pib, qhov rhiab heev thiab qhov tshwj xeeb yog 76.92 feem pua thiab 97.78 feem pua ntawm (S2CFig).
Lub ComScore cuam tshuam nrog AR-tshwj xeeb biopsy histological lesions Qhov tseem ceeb, qhov sib txawv ntawm kev nce tus qhab nia uCRM los ntawm STA mus rau bAR rau AR tau qhia tias tus qhab nia uCRM tuaj yeem kuaj pom qhov mob ntawm qhov chaw kho mob. Yog li ntawd, peb tau soj ntsuam seb qhov qhab nia ntawm uCRM puas cuam tshuam nrog qhov cuam tshuam ntawm histological AR lesions pom hauv kev sib tw biopsies los ntawm tib tus neeg mob, sau ib txhij. Raws li pom hauv daim duab 5A thiab 5B, cov qhab nia uCRM cuam tshuam nrog qhov twg ntawm tus kab mob tubulitis(t) thiab cov kab mob interstitial (i) cov qhab nia biopsy hauv AR(R=0.5479, P<0.0001 and="" r="0.4420,"><0.0001 for="" the="" ucrm="" score="" regarding="" t="" and="" ii,="" respectively).="" there="" was="" no="" correlation="" between="" the="" ucrm="" score="" and="" measures="" of="" tubular="" atrophy="" (ta),glomerulosclerosis="" (gs),mesangial="" matrix="" (mm),="" intimal="" proliferation="" (cv),="" medial="" arteriolar="" hyaline="" (ah),="" tubular="" vacuolization(tv),="" arteritis="" (v),="" or="" acute="" glomerulitis="">
TSEEM CEEB NTAWM CSITANCHE: ANTI-FATIGUE
Kev sib tham
Muaj kev xav tau ceev ceev hauv kev hloov tshuaj rau kev tsim cov cuab yeej saib xyuas kev ntseeg siab thiab tsis cuam tshuam uas yuav pab tau cov kws kho mob hloov pauv kwv yees qhov kev pheej hmoo ntawm kev raug mob ntawm allograft, tshwj xeeb tshaj yog ua ntej kev puas tsuaj allograft tau tsim. Thaum ib tug xov tooj ntawm transcriptional biomarkers tau txuam nrog AR, feem ntau ntawm cov kev tshawb fawb tau pib tsom rau ib tug tshwj xeeb los yog ib tug transcriptional yam tseem ceeb thiab tsis muaj kev cuam tshuam tag nrho cov molecular complexity ntawm cov txheej txheem lom ntawm allograft rejection [11,38]. Tsis tas li ntawd, thaum tus qauv kub tam sim no rau kev kuaj pom muaj kev tiv thaiv kab mob tiv thaiv kab mob allograft raug mob yog allograft biopsy, nws paub zoo tias cov txheej txheem muaj cov kev txwv tseem ceeb nyob rau hauv cov nqe lus ntawm cov qauv tsis tu ncua tsis tu ncua, nws tus nqi siab, thiab qhov tsis zoo rau kev rov ua dua. kev tshuaj ntsuam vim qhov invasive xwm ntawm cov txheej txheem.
Ntau cov ntawv tshaj tawm tau qhia txog qhov muaj txiaj ntsig ntawm kev kawm txawv biomarkers kwv yees AR hauv cov zis kuaj ntawm cov neeg tau txais kev hloov pauv raum [20-22]. Ua kom cov zis ntau ntxiv ntawm cov tshuaj tiv thaiv kab mob molecules thiab cov ntawv sau tseg xws li granzyme B. CXCL10.CXCL9.IFN-y, thiab CXCR3. tau pom tias muaj feem cuam tshuam nrog AR thiab qee zaum, txawm tias kwv yees qhov tshwm sim ntawm AR ua ntej [19,24,39-43]. Ua kom zoo dua ntawm cov ntaub ntawv tsis ntev los no tau tshaj tawm los ntawm peb pawg [2Z, 29,44] uas qhia txog kev tsis lees paub ntau yam ntawm cov noob qhia nyob rau hauv allograft biopsies thaum lub sij hawm AR, tsis hais hom ntaub so ntswg, lub hom phiaj tseem ceeb ntawm txoj kev tshawb no yog los tshawb xyuas seb qhov kev ntsuam xyuas. ntawm CRM nyob rau hauv cov zis ntawm lub raum hloov cov neeg mob yuav pab tau raws li ib tug zoo tagnrho non-invasive biomarker kwv yees lub advent ntawm AR.
Txawm hais tias ntau tus neeg CRM noob thiab cov khoom lag luam tau raug soj ntsuam ib tus zuj zus, qhov no yog thawj daim ntawv tshaj tawm ntawm kev sib sau ua ke, tsis muaj kev siv CRM noob hauv kev kwv yees ntawm AR hauv KTx. Piv txwv li, urinary CXCL9 mRNA thiab cov protein thiab CXCL10 mRNA yav dhau los tau raug soj ntsuam hauv ntau qhov kev tshawb fawb rau kev kuaj mob ntawm AR[13,45,46.PSMB9 cov ntaub ntawv pov thawj hauv lub raum biopsies kuj tau yav dhau los cuam tshuam nrog graft zoo thiab kev kwv yees ntawm kev tsis lees paub [ 47] ib.
Peb tau txheeb xyuas cov ntaub ntawv gene qhia ntawm cov zis tawm los ntawm cov neeg mob KTx rau cov txheeb ze ntau ntawm CRM cov ntaub ntawv pov thawj thiab lawv cov kev sib raug zoo ntawm kev qhia ntawm CRMgenes (Daim duab 2A).Raws li peb tau tshaj tawm txoj kev tshawb fawb yav dhau los soj ntsuam cov qhab nia CRM hauv cov ntaub so ntswg raum thiab lub ntsws allograft kuaj, CRMgenes tau nthuav tawm ntau ntxiv hauv AR thiab lwm yam kev raug mob xws li AR thiab BKVN (Fig 2B thiab 2C). Hauv tsab ntawv tshaj tawm no, peb kuj tau pom muaj kev sib raug zoo ntawm cov qhab nia uCRM uas tau tsim tshiab thiab cov qhab nia inflammatory (t thiab ii cov qhab nia ntawm lub raum biopsies). Txij li feem ntau ntawm cov CRM noob no tau nthuav tawm yuav luag tshwj xeeb hauv kev nkag mus rau hauv lub cev tiv thaiv kab mob, qhov kev nthuav qhia ntau ntxiv ntawm CRM noob hauv cov zis tso zis qhia tau tias muaj kev tso tawm ntau ntxiv ntawm cov kab mob hauv lub cev hauv cov zis ntawm lub raum hloov cov neeg tau txais kev raug mob graft.
Tom ntej no, peb siv cov qhab nia ua ke suav los ntawm tus kheej cov noob qhia qhov tseem ceeb ntawm tus kheej CRM genes, ComScore, raws li kev ntsuas los faib cov neeg mob raum hloov mus rau tus neeg mob uas tsis kam lees lossis tsis raug mob thiab txiav txim siab qhov pib rau AR. Cov txiaj ntsig los ntawm txoj kev tshawb fawb no qhia tau hais tias lub zog ntawm uCRM kev soj ntsuam tsis yog tsuas yog txheeb xyuas cov neeg mob nrog AR, tab sis kuj suav cov qib ntawm kev raug mob tshwm sim hauv allograft, raws li cov qhab nia nce los ntawm cov nqi qis hauv cov neeg mob STA, mus rau qhov nruab nrab ntawm cov neeg mob bAR, thiab rau cov txiaj ntsig siab hauv AR cov neeg mob, raws li tau pom hauv cov kab mob tubulitis thiab cov qhab nia ntawm cov kab mob sib kis. Peb ntseeg tias qhov qhab nia uCRM muaj peev xwm siv tau hauv kev saib xyuas kev hloov pauv thiab tuaj yeem ua haujlwm ntxiv rau lossis xa mus rau kev kuaj mob biopsies. Tus neeg mob uas tau qhab nia uCRM qis yuav tuaj yeem zam qhov tsis tsim nyog raws tu qauv biopsies thaum tus neeg mob uas tau qhab nia uCRM siab yuav xav tau kev soj ntsuam xyuas los yog ua rau biopsy los ntsuam xyuas graft.
Peb lees paub ntau qhov kev txwv ntawm txoj kev tshawb no uas suav nrog (i) txwv qhov loj me ntawm txoj kev tshawb no, (ii) tsis muaj lwm yam kev hloov pauv kev raug mob phenotypes xws li mob ntev allograft raug mob los yog tshuaj toxicity, thiab (i) tsis muaj kev ntsuam xyuas ntawm uCRM qhab nia nyob rau hauv ib tug longitudinal qauv nyob rau hauv loj cohort loj. Cov txiaj ntsig tau pom zoo no qhia tias cov kev tshawb fawb yav tom ntej yuav tsum tau ua kom muaj txiaj ntsig thiab ntsuas tag nrho cov txiaj ntsig muaj txiaj ntsig ntawm uCRM tus qhab nia hauv qhov chaw kho mob. Hauv cov ntsiab lus, peb nthuav qhia cov biomarker uas tsis muaj qhov tso zis tso zis tau tsim los ntawm Cov Txheej Txheem Kev Tsis Txaus Siab uas muaj 11 cov noob uas tuaj yeem txheeb xyuas qhov raug mob thiab tsis lees txais hauv cov neeg mob hloov lub raum.
TSEEM CEEB NTAWM CSITANCHE: Txhim kho nco
Cov ntaub ntawv
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