Txhim kho qhov kev ntsuam xyuas kev pheej hmoo ntawm kev tiv thaiv kab mob txhawm rau txhawm rau txhim kho caj ces-kev sib raug zoo thiab cov txiaj ntsig kho mob hauv cov menyuam yaus thiab cov tub ntxhais hluas tau txais Kev Pabcuam Niam Txiv Raum Hloov: Txoj Cai Rau Txoj Kev Kawm INCEPTION
Mar 27, 2022
Hu rau:joanna.jia@wecistanche.com/ WhatsApp: 008618081934791
Wai H. Lim1,2*, Brigitte Adams3, Stephen Alexander4,5, Antonia HM Bouts6, Frans Claas7, Michael Collins8,9, Elisabeth Cornelissen10, Heather Dunckley11, Huib de Jong12, Lloyd D'Orsogna13,14,15, Anna Francis 17, Sebastiaan Heidt7, Jean Herman18, Rhonda Holdsworth19, Joshua Kausman 20, 21, 22, Rabia Khalid 23, 24,
Jon Jin Kim 25,26,27, Siah Kim4, Noël Knops18,28, Vasilis Kosmoliaptsis29,30,31, Cynthia Kramer7, Dirk Kuypers32,33, Nicholas Larkins2,24,34, Suetonia C. Palmer35, Chanel Prestistidge3 Sharma 24,38, Meena Shingde39, Anne Taverniti24, Armando Teixeira-Pinto23, Peter Trnka 16,17, Francis Willis2,34,40,
Daniel Wong 2,41 thiab Germaine Wong 23,24,38
Cistanche tshuaj ntsuab tshuaj hmoovtuaj yeem txhim khoraum kev ua haujlwm
Abstract
Keeb kwm:Niam txiv pub raum hloov pauvyog qhov kev xaiv kho mob tshaj plaws rau cov menyuam yaus thiab cov tub ntxhais hluas nrograumua tsis tiav. Cov ntaub ntawv tshwm sim los ntawm kev soj ntsuam kev tshawb fawb tau tshaj tawm txhim kho cov txiaj ntsig luv luv thiab nruab nrab ntawm cov txiaj ntsig ntawm cov neeg tau txais txiaj ntsig ntawm leej txiv piv rau cov niam txiv pub dawb. Txoj kev tshawb fawb INCEPTION yog txhawm rau txheeb xyuas qhov sib txawv hauv kev tiv thaiv kab mob sib haum xeeb ntawm leej niam thiab leej txiv pub rau lub raum thiab paub tseeb tias qhov no cuam tshuam rau lub raum allograft cov txiaj ntsig hauv cov menyuam yaus thiab cov tub ntxhais hluas uas muaj lub raum tsis ua haujlwm.
Methods: Qhov kev tshawb nrhiav ntev ntev no yuav nrhiav taucov neeg tau txais kev hloov lub raumhnub nyoog qis dua los yog sib npaug li 18 xyoo uas tau txais kev pab niam txivraumKev hloov pauv thoob plaws 4 lub tebchaws (Australia, New Zealand, United Kingdom thiab Netherlands) thaum xyoo 1990 thiab 2020. Kev daws teeb meem ntawm tib neeg leukocyte antigen (HLA) ntaus ntawv ntawm ob tus neeg tau txais thiab cov niam txiv pub dawb yuav raug ua, muab kev ntsuam xyuas qhov tob ntawm immunological kev sib raug zoo. Cov txiaj ntsig tseem ceeb yog qhov sib xyaw ntawm de novo pub dawb tshwj xeeb los tiv thaiv-HLA antibody (DSA), biopsy-proven acute rejection lossis allograft poob mus txog 60-lub hlis tom qab hloov pauv. Cov txiaj ntsig thib ob yog de novo DSA, biopsy- proven acute rejection, acute or chronic antibody-mediated rejection or Chronic Allograft Damage Index (CADI) qhab nias ntawm> 1 ntawm allograft biopsy post-transplant, allograft function, proteinuria thiab allograft poob. Siv cov ntsiab lus tseem ceeb ntawm kev txheeb xyuas thiab Cox proportional hazards regression modelling, peb yuav txiav txim siab cov kev koom tes ntawm cov txheej txheem ntawm kev tiv thaiv kab mob thiab kev kho mob uas yuav txheeb xyuas qhov kev pheej hmoo stratifcation rau qhov kev ntsuas thawj thiab theem nrab ntawm cov tub ntxhais hluas lees txais niam txiv pub raum rau kev hloov pauv. Qhov kev tsim qauv no yuav tso cai rau peb tshawb xyuas qhov tseem ceeb ntawm kev lees txais niam txiv piv rau leej txiv pub dawb, rau cov tsev neeg txiav txim siab txog qhov kev xaiv zoo tshaj plaws rau kev pub dawb.
Kev Sib Tham: Qhov Kev Tshawb Fawb Kev Tshawb Fawb Kev Tshawb Fawb yuav tshawb nrhiav qhov muaj feem cuam tshuam txog kev tiv thaiv kab mob tiv thaiv kab mob ntawm leej niam thiab leej txiv pub dawblub raumrau kev hloov pauv ntawm cov menyuam yaus thiab cov tub ntxhais hluas. Peb txoj kev tshawb fawb yuav muab cov ntaub ntawv pov thawj los txhawb kev xaiv cov niam txiv pub dawb txhawm rau ua tiav qhov zoo tshaj plaws kev npaj mus sij hawm ntevraumKev hloov pauv thiab tag nrho cov txiaj ntsig kev noj qab haus huv rau cov menyuam yaus thiab cov tub ntxhais hluas, ib qho kev lees paub ntawm cov neeg tsis muaj zog.
Kev sau npe mus sib hais: Txoj kev kawm INCEPTION tau sau npe nrog Australian New Zealand Clinical Trials Registry, nrog rau tus lej sau npe ntawm ACTRN12620000911998 (14th Cuaj hlis 2020).
Keywords: hloov raum, menyuam, hluas, niam txiv pub, Immunological profle, Tib neeg leukocyte antigen, Antibody, Rejection, Allograft poob
Keeb kwm
Lub raumKev hloov pauv yog kev kho mob ntawm kev xaiv rau cov neeg mob raum tsis ua haujlwm, muab qhov tseem ceeb ntawm kev ciaj sia zoo dua piv rau cov neeg kho nrog kev lim ntshav mus sij hawm ntev [1]. Kev hloov pauv hauv lub raum nyob yog qhov xav tau vim tias cov neeg mob muaj sia nyob thiab cov khoom siv tau ntev dua nyob rau hauv kev sib piv nrog cov neeg hloov pauv cov neeg tuag [2–4]. Tsis tas li ntawd, nyob pub dawb pab txhawb kev hloov pauv ua ntej, zam qhov cuam tshuam tsis zoo rau kev noj qab haus huv, kev puas siab puas ntsws thiab kev kawm ntawm kev lim ntshav rau cov menyuam yaus thaum lub sijhawm tseem ceeb ntawm kev loj hlob thiab kev loj hlob [3].
Feem ntau cov menyuam yaus thiab cov hluasraumCov neeg tau txais kev hloov pauv yuav tsum tau hloov pauv tom qab thiab tom qab kev tsis ua haujlwm ntawm allograft feem ntau muaj kev nkag siab zoo (nrog kev txhim kho ntau yam tshuaj tiv thaiv tib neeg leukocyte antigen [HLA] cov tshuaj tiv thaiv uas tuaj yeem cuam tshuam kev hloov pauv yav tom ntej) thiab muaj kev pheej hmoo siab tuag [5]. Xaiv tus pub rau lub raum cuam tshuam nrog qhov ua tau zoo tshaj plaws nyob rau lub sijhawm ntev allograft yog qhov tseem ceeb. Cov niam txiv pub nyiaj rau ntau dua 60 feem pua ntawm cov neeg pub lub raum nyob rau cov neeg mob menyuam yaus thiab cov tub ntxhais hluas nrograumua tsis tiav hauv tebchaws United Kingdom, Australia thiab New Zealand [6, 7]. Txawm li cas los xij, nws tsis paub meej tias leej niam thiab leej txiv pub nyiaj pub dawb yog cuam tshuam nrog cov txiaj ntsig sib txawv. Kev tshawb fawb pej xeem tsis ntev los no qhia tau tiasraumKev hloov pauv los ntawm cov khoom pub rau lub raum tau cuam tshuam nrog txog li 60 feem pua kev pheej hmoo siab dua ntawm kev tsis lees paub thiab kev poob tag nrho piv rau leej txiv pub raum [8]. Txoj kev fnding yog qhov tsis sib haum xeeb rau yav dhau los qhov kev coj ua uas cuam tshuam rau cov niam txiv tsis tau txais txiaj ntsig antigen (NIMA) tuaj yeem ua rau muaj kev tiv thaiv kab mob tsawg dua piv rau kev kis tus txiv neej tsis tau txais txiaj ntsig (NIPA). Cov kev tshawb fawb yav dhau los thiab cov qauv kev sim tau qhia tias kev kis tus menyuam rau NIMA thaum cev xeeb tub tuaj yeem ua rau NIMA tshwj xeeb kam rau ua. Hauv ib txoj kev tshawb fawb, kev hloov pauv cov kwv tij uas qhia NIMA tau cuam tshuam nrog kev pheej hmoo tsawg dua ntawm kev tsis lees paub thiab cov txiaj ntsig zoo tshaj plaws uas tau sib piv rau cov kev hloov pauv uas qhia txog NIPA [9–11]. Muab hais tias cov niam txiv pub dawb yog qhov tseem ceeb ntawm cov neeg pub rau lub raum rau cov menyuam yaus thiab cov tub ntxhais hluas cov neeg mob lub raum tsis ua haujlwm, qhov kev tshawb fawb no yuav pab qhia seb HLA txuam ntawm cov epitope, amino acid thiab physiochemical zog qib yuav txhim khu kev nkag siab ntawm qhov sib txawv antigenicity thiab immunogenicity ntawm NIMA thiab NIPA ntawm allograft cov txiaj ntsig tom qab niam txiv pub raum hloov pauv. Te fndings los ntawm qhov kev tshawb fawb no tej zaum yuav muaj feem cuam tshuam rau kev kho mob tseem ceeb hauv kev xaiv cov niam txiv tsim nyog pub raum rau kev hloov pauv.
Lub hom phiaj tseem ceeb ntawm txoj kev tshawb fawb no yog los daws qhov kev paub tam sim no ntawm "NIMA paradox" los ntawm kev txheeb xyuas qhov sib txawv hauv kev tiv thaiv kab mob sib kis ntawm leej niam thiab leej txiv pub dawblub raumthiab yuav ua li cas qhov kev sib raug zoo no cuam tshuam rau allograft cov txiaj ntsig. Koj txoj kev kawm aims muaj xws li:
(i) Cov ncauj lus kom ntxaws txog kev tiv thaiv kab mob rau cov menyuam yaus thiab cov tub ntxhais hluas tau txais kev pab niam txivlub raumnrog thiab tsis muaj kev cuam tshuam cov txiaj ntsig ntawm kev txhim kho ntawm de novo tus neeg pub dawb tshwj xeeb los tiv thaiv HLA antibody (DSA), kev tsis lees paub lossis kev poob tag nrho;
(ii) Txiav txim siab txog kev sib koom ua ke ntawm cov kev pheej hmoo ntawm kev tiv thaiv kab mob sib txawv thiab cov txiaj ntsig tsis zoo; thiab
(iii) Txiav txim siab seb cov kev sib koom ua ke ntawm cov kev pheej hmoo ntawm kev tiv thaiv kab mob thiab cov txiaj ntsig tsis zoo yog hloov pauv los ntawm niam txiv thiab lwm yam kev kho mob.
cistanche ua tshuaj ntsuabraumob raum cov tsos mob
Methods/design
Kawm tsim thiab teeb tsa
Txoj kev kawm INCEPTION yog ib txoj kev tshawb nrhiav ntev uas yuav nrhiav cov neeg hloov pauv menyuam yaus thiab cov hluas uas muaj hnub nyoog qis dua lossis sib npaug li 18 xyoo uas tau txais cov niam txiv pub dawblub raumLub Ib Hlis 1990 txog Lub Kaum Ob Hlis 2020 (Daim duab 1). Cov niam txiv sib raug zoo kuj yuav yog
nrhiav neeg los koom nrog hauv txoj kev kawm. Neeg lausraumCov neeg tau txais kev cog qoob loo ntawm niam txiv pub raum hnub nyoog> 18 xyoo thaum lub sijhawm hloov pauv lossis cov neeg tau txais cov neeg pub dawb tuagraumkev hloov pauv yuav raug cais tawm. Cov nyiaj pab rau txoj kev kawm INCEPTION yog muab los ntawm National Health and Medical Research Council (NHMRC) Cov Tswv Yim Nyiaj Pab (Daim Ntawv Thov ID: APP1184595, nyiaj siv sijhawm 2020- 2023), Lub Tsev Haujlwm Saib Xyuas Kev Noj Qab Haus Huv Western Australia thiab Telethon-Perth Children's Hospital Research Fund (Lub sijhawm nyiaj txiag 2017-2020) thiab Starship Foundation Clinical Research Grant (Auckland, New Zealand). Te qhia thiab kev coj ua ntawm txoj kev kawm yuav ua raws li Te Strengthening the Reporting of Observational studies in Epidemiology (STROBE) cov lus qhia [12].
Txoj kev tshawb no yuav ua nyob thoob plaws 4 lub tebchaws suav nrog Australia (5 lub chaw hloov pauv), New Zealand (1 lub chaw hloov pauv), United Kingdom (UK, 13 lub chaw hloov pauv) thiab Netherlands (3 lub chaw hloov pauv). Te INCEPTION txoj kev tshawb fawb tau sau npe nrog Australian New Zealand Clinical Trials Registry (ANZCTR) ua ntej yuav nrhiav neeg ua haujlwm, nrog rau tus lej sau npe mus sib hais ntawm ACTRN12620000911998 (tso npe pom zoo 14th Cuaj hlis 2020).
Kawm nrhiav neeg ua haujlwm thiab khaws cov ntaub ntawv Hauv Australia thiab New Zealand, cov niam txiv pub dawb-tau txais cov khub uas ua tiav cov txheej txheem suav nrog yuav raug txheeb xyuas los ntawm Australia thiab New Zealand Dialysis and Transplant (ANZDATA) npe thiab xa mus rau cov neeg tshawb xyuas hauv zos. Tsuas yog ob tus neeg txais nyiaj pub dawb tau sau tseg hauv daim ntawv teev npe thaum nyob thiab nyob hauv Australia thiab New Zealand yuav raug hu kom tuaj koom. Txhua khub niam txiv-tus neeg txais yuav yuav muab kev tso cai sau ntawv lossis hais lus pom zoo lossis muaj hnub nyoog tsim nyog los ntawm cov neeg tshawb xyuas qhov chaw kawm lossis cov neeg sawv cev ua ntej koom. Te Sir Charles Gairdner Osborne Park Health Care Group Human Research Ethics Committee (Perth, Western Australia, Australia) tau pom zoo daim ntawv thov kev tshawb fawb nyob rau lub Kaum Ob Hlis 2018, nrog rau kev pom zoo ntawm kev coj ncaj ncees nyob rau txhua qhov chaw koom hauv Australia thiab New Zealand. Kev pom zoo rau New Zealand kev koom tes tau txais los ntawm New Zealand Health and Disability Ethics Committee (Ministry of Health, Wellington, New Zealand). Kev tso cai hais lus yuav raug siv thaum lub sijhawm muaj kev kis tus kabmob COVID{10}} kis thoob qhov txhia chaw, nrog rau HREC ntawm txhua qhov chaw koom nrog tso cai pom zoo rau qhov kev hloov kho no yog tias tsim nyog. Hauv tebchaws United Kingdom (kev pom zoo los ntawm United Kingdom National Health Service [NHS] hauv tebchaws Askiv thiab Wales) thiab Netherlands (kev pom zoo los ntawm Pawg Saib Xyuas Kev Noj Qab Haus Huv Kev Noj Qab Haus Huv ntawm Amsterdam Academic Medical Center), qhov haujlwm tshwj xeeb zam kev tso cai rau ntshav ntshav lossis deoxyribonucleic acid (DNA) biobanking thiab kev coj ua ntawm kev tshawb fawb kev tshawb fawb ntsig txograumCov txiaj ntsig tau hloov pauv tau raug tso cai, thiab kev coj ua ntawm txoj kev tshawb fawb no tau txais kev pom zoo tshiab ntawm kev coj ncaj ncees.
Txoj kev kawm
Hauv tebchaws Australia thiab New Zealand, txhua tus khub uas tau txais kev tso cai pub dawb yuav tuaj koom ib qho kev mus ntsib kom muaj 20 mL ntawm cov ntshav uas tau muab cais ua ntshav / ntshav thiab deoxyribonucleic acid (DNA) cais. Qhov kev kuaj ntshav no yuav raug muab coj los ntawm txhua tus neeg pub dawb-tus neeg txais khub txawm tias muaj cov khoom siv ua ntej khaws cia hauv ntshav / ntshav thiab DNA rau kev kuaj. Lub sij hawm ntawm qhov kev kuaj ntshav ntxiv rau cov neeg tau txais kev pab yuav zoo sib xws nrog lawv cov kev kho mob niaj hnub tshem tawm cov ntshav thaum ua tau. Cov neeg pub dawb thiab cov neeg tau txais txiaj ntsig tseem yuav tso cai tso cai nkag mus rau lawv cov ntaub ntawv kho mob los ntawm ANZDATA npe (lossis sib npaug kev sau npe kho mob hauv lwm lub tebchaws), Organ Matching (Australia-spe-cifc) thiab lwm lub tebchaws tshwj xeeb hauv Kev Pabcuam Ntshav (lub computer cov ntaub ntawv system uas khaws cov ntaub ntawv hais txog kev faib khoom nruab nrog cev thiab tus neeg pub dawbraumcov ntsiab lus, suav nrog cov ntaub ntawv ntawm tus neeg pub dawb thiab tus neeg txais HLA ntaus ntawv thiab hloov ua ntej thiab de novo DSA) thiab cov ntaub ntawv kho mob hauv zos los ntawm lawv lub tsev kho mob. Rau cov neeg txais kev pabcuam pub dawb hauv UK thiab Netherlands, kev pom zoo rau kev coj ncaj ncees yuav tso cai rau kev siv cov tshuaj khaws cia hauv ntshav / ntshav thiab DNA rau kev kuaj (qhov xav tau), tsis tas yuav tsum kuaj ntshav ntxiv los ntawm cov khub no.
Tiv thaiv cov ncauj lus kom ntxaws pub-tau txais kev tiv thaiv kab mob tiv thaiv kab mob
Kev daws teeb meem siab HLA ntaus ntawv
Hauv kaum xyoo dhau los, HLA-typing tau hloov zuj zus los ntawm sero-logical typing mus rau siab daws teeb meem molecular typing npog-ing HLA-A, −B, −C, −DRB1/3/4/5, −DPA1, −DPB1, −DQA1 thiab -DQB1 loci, muab kev ntsuas ntau dua thiab muaj tseeb ntawm cov ntaub so ntswg sib xws hauv kev hloov pauv. High-resolution molecular HLA typing rau 11 HLA-loci yuav ua tau siv lub Next Generation Sequencing (NGS) los yog lwm txoj kev daws teeb meem ntaus ntawv los ntawm cov chaw soj ntsuam cov ntaub so ntswg hauv txhua lub teb chaws. Muab NGS HLA-typing thoob plaws tag nrho HLA alleles yog suav tias yog kev coj ua qauv rau kev hloov pauv hloov pauv hloov pauv nyob hauv ntau lub chaw hloov pauv, rov sau cov neeg pub dawb / cov neeg txais yuav tsis raug ua tshwj tsis yog ntaus ntawv hla txhua HLA alleles ntawm qib siab daws teeb meem tsis muaj. .
Quantifying HLA-eplet tsis sib haum
Cov kev tshawb fawb txog kab mob kis tau tsis tu ncua tau pom tias muaj kev sib koom ua ke ntawm ntau tus epitope lossis eplet tsis sib haum thiab muaj kev pheej hmoo siab ntawm cov txiaj ntsig tsis zoo, suav nrog kev txhim kho ntawm de novo DSA, antibody mediated rejection (AMR), hloov pauv glomerulopathy (TG) thiab / lossis ntxov allograft. poob [13, 14]. High-resolution molecular typing muab lub cib fim rau kev ntsuam xyuas ntau dua thiab raug ntawm HLA compatibility hauv kev hloov pauv. Txawm li cas los xij, kev sib raug zoo raws li ntau txhiab tus HLA alleles yog qhov tsis yooj yim sua, tab sis qhov kev hloov pauv hauv HLA alleles tuaj yeem piav qhia los ntawm qhov sib txawv ntawm cov epitopes tsawg, uas yog ib feem ntawm HLA pro-tein, ua los ntawm polymorphic amino acid. cov seem. Eplets yog luv luv ntu ntu ntawm cov amino acid residues nyob rau hauv txhua HLA epitope uas muaj peev xwm theoretically elicit B-cell tsav lub cev tiv thaiv kab mob hauv cov neeg tau txais kev pab (imu- nogenicity) [15, 16]., terefore, compatibility kev ntsuam xyuas tsom rau eplet mismatches, xam siv. ib lub khoos phis tawj hu ua HLAMatchmaker [16, 17], yuav muaj peev xwm los txhim kho kev kwv yees ntawm cov txiaj ntsig tsis zoo ntawm cov txiaj ntsig [18]. Te identifcation thiab quantifcation ntawm qhov chaw thiab tus naj npawb ntawm eplet mismatches ntawm HLA chav kawm I (HLA-A, −B, −C) thiab chav II (HLA-DRB1/3/4/5, −DPA1, −DPB1, −DQA1 thiab -DQB1) loci yuav raug txiav txim los ntawm kev nkag mus rau 2-feld molecular HLA ntaus ntawv rau txhua tus neeg pub dawb thiab tus neeg txais khub rau hauv HLAMatchmaker kom muaj kev sib piv ntawm HLA eplet-profles ntawm txhua tus neeg pub dawb / tus neeg txais khub (HLA- ABC v2.0 and HLA-DRDQDP v2.1; http://www.eplets.net).
Tus pub-tau txais amino acid polymorphisms thiab physicochemical HLA incompatibility
Eplets yog theoretically defned (kev sib xyaw ntawm) amino acids uas tau hloov pauv, ua rau kev soj ntsuam kev koom ua ke ntawm txoj kev no nyuaj [19–21]. Kev soj ntsuam ntawm qhov sib txawv ntawm lub cev tsis sib xws ntawm tus neeg pub dawb thiab tus neeg txais HLA, ntxiv rau kev sib piv cov interlocus thiab intralocus amino acid polymorphisms hauv cov tshuaj tiv thaiv kab mob nkag mus tau ntawm HLA molecules tuaj yeem txhim kho kev pheej hmoo stratifcation thiab kwv yees qhov tshwm sim tsis zoo tom qab hloov pauv [22-24. ]. Te specifcity thiab stability ntawm antigen-antibody binding yog txiav txim los ntawm lub structural compatibility thiab cov electrostatic thiab hydrophobic kev sib tshuam ntawm ob molecules [25]. Cov neeg pub dawb thiab cov neeg txais HLA chav kawm I thiab chav kawm II tsis sib haum yuav raug muab piv rau qib theem kom tau txais tus lej thiab physicochemical tsis sib xws ntawm amino acid polymor-phims ntawm pub HLA molecules siv Cambridge HLA immunogenicity algorithm [22–24]. Te hnyav nkag tau ntawm cov amino acid polymorphisms kuj yuav raug soj ntsuam siv HLA Epitope Mismatch Algorithm (EMMA; https://hla-emma.com) thiab Cambridge HLA immunogenicity algorithm [24, 26]. Te electrostatic tsis zoo sib xws ntawm tus neeg pub dawb thiab tus neeg txais HLA molecules ntawm cov qauv txheej txheem yuav raug soj ntsuam siv cov qhab nia electrostatic tsis sib xws (EMS-3D) [27]. Tese cov qhab nia yuav muab cov txiaj ntsig kwv yees ntxiv rau cov lus teb hauv chav kawm I thiab II allo-antibody tab sis kev siv tshuaj kho mob ntawm ib lossis ntau dua ntawm cov qhab nia no tseem tsis meej [24, 27].
Quantifying lub luag hauj lwm ntawm T-cell pab nyob rau hauv DSA txoj kev loj hlob
Txog thaum tsis ntev los no, kev koom tes ntawm T hlwb rau DSA kev txhim kho tsis tau muaj nuj nqis. Kev pab T-cell yog qhov tseem ceeb hauv kev txhim kho immunoglobulin (Ig)-G DSA los ntawm kev txhawb nqa qhov sib txawv thiab kev loj hlob ntawm antigen- specifc naïve B hlwb rau hauv lub cim xeeb B-cells thiab ntshav plasma. Peptides muab tau los ntawm tus pub HLA molecules yog nthuav tawm los ntawm HLA chav kawm II molecules ntawm cov neeg tau txais B hlwb kom cognate pab T hlwb, uas tom qab ntawd muab cov cim thiab cytokines rau cov B hlwb kom dhau mus rau kev loj hlob, kev hloov hauv chav kawm thiab kev sib txawv rau hauv cov ntshav ntshav [28]. Peb yuav siv NetMHCIIpan software (www.cbs.dtu. dk/services/NetMHCII-2.3 thiab www.cbs.dtu.dk/servi ces/NetMHCIIpan-3.2) [29] rau txiav txim siab lub pan-spe-cifc binding ntawm peptides rau MHC chav kawm II alleles ntawm kev paub ua ntu zus uas siv cov kev qhia ua ntej tshwj xeeb afnity thresholds thiab pep-tide qeb duas thiab lwm yam hauv kev txhim kho los ntawm pab pawg kawm [22, 23, 30]. Tsis tas li ntawd, peb tseem yuav siv qhov kev kwv yees tsis pom kev lees paub HLA epitopes (PIRCHE) kev suav cov txheej txheem, uas yog tsim los kwv yees tsis ncaj qha lees paub HLA-derived pub peptides uas tuaj yeem ua rau T-cell allorecognition thiab ua rau kev tsim cov tshuaj tiv thaiv tshwj xeeb. -HLA IgG tiv thaiv lub cev (https://www.pirche.com/pirche/#/features/bioin formatics) kom paub qhov "nqi" ntawm T-cell pab [31]. Ntau tus lej ntawm PIRCHE, zoo li yuav sawv cev ntau dua ntawm "theoretical" T-cell epitopes uas tuaj yeem xa los ntawm tus neeg tau txais HLA chav kawm II molecules, tuaj yeem cuam tshuam nrog kev kho mob alloreactivity tab sis qhov tseem ceeb ntawm kev kho mob ntawm PIRCHE ntawm cov txiaj ntsig ntev ntev. tseem tsis tau txiav txim siab.
Cov txiaj ntsig ntsuas
Cov txiaj ntsig tseem ceeb yog qhov sib xyaw ntawm de novo DSA (defned as mean fuorescence intensity [MFI] ntau dua 500), lossis ib qho kev kuaj mob biopsy-proven acute rejection lossis allograft poob (defned as rov qab mus rau lim ntshav lossis tuag nrog func- tioning allograft) tom qab niam txiv pubraumtransplantation mus txog 60- hli tom qab hloov pauv. Cov txiaj ntsig thib ob yog ib qho ntawm cov txiaj ntsig ntawm cov txiaj ntsig tseem ceeb (kev txhim kho ntawm de novo DSA, ib qho kev tsis lees paub txog kev mob qog nqaij hlav, allograft poob ntawm 60- hli tom qab hloov pauv tab sis kuj txuas ntxiv mus rau 120- hli tom qab -transplant), mob hnyav lossis mob ntev AMR (xws li muaj TG) lossis Chronic Allograft Damage Index (CADI) tus qhab nia ntawm> 1 ntawm allograft biopsy post-transplant, allograft muaj nuj nqi (creatinine-derived kwv yees glomerular fltration rate [eGFR] siv ChronicLub raumKab Mob-Epidemiology Collaboration [CKD-EPI] kev sib npaug rau cov neeg tau txais hnub nyoog Ntau dua lossis sib npaug li 16 xyoo [32] lossis txaj txaj Schwartz sib npaug rau cov neeg tau txais hnub nyoog <16 xyoo [33–35]), thiab cov zis proteinuria.
De Novo DSA
Post-transplant sera ntawm tag nrho cov neeg tau txais kev kuaj mob ua ntej hloov pauv, thaum kuaj pom los yog niaj hnub ntawm lub sijhawm tshwj xeeb tom qab hloov pauv (hauv qee lub chaw) rau de novo DSA tau qhia tawm tsam leej niam lossis leej txiv pub HLA hla HLA-A, − B, −C, −DRB1, − DRB3/4/5, −DPA1, −DPB1, −DQA1 and -DQB1 alleles. Nyob rau hauv luv luv, ib tug aliquot ntawm ib tug tib antigen hlaws (SAB) sib tov yuav incubated nrog ib tug me me ntim ntawm cov neeg mob sera (kwv yees li 50 ul) uas muaj cov anti-HLA anti-lub cev raws li ib tug chaw tsim tshuaj paus cov lus qhia. Te tsom xam yuav tau ua nyob rau hauv Luminex (los yog sib npaug) platform thiab cov reactivity yuav raug txiav txim nrog lub chaw tsim tshuaj paus software thiab qhia raws li txhais tau tias fluorescence siv (MFI) rau txhua mismatched HLA. Antibod-ies rau cov HLA alleles nrog MFI ntawm qhov sib txawv ntawm qhov pib (los ntawm MFI Ntau dua lossis sib npaug rau 500) yuav raug suav tias yog "qhov txiaj ntsig zoo" vim tias peb thiab lwm tus tau pom muaj kev sib koom ua ke ntawm qhov muaj kev hloov pauv ua ntej DSA nrog MFI Ntau dua. tshaj los yog sib npaug rau 500 thiab muaj kev pheej hmoo siab ntawm kev tsis lees paub tom qab hloov lub raum [36, 37]. MFI tus nqi pib ntawm Ntau dua lossis sib npaug rau 500 yog txhais los ntawm Luminex platform. Lub sij hawm-cov ntsiab lus rau kev saib xyuas thiab kev sim rau kev hloov pauv ua ntej thiab de novo DSA yuav raug ua raws li cov qauv cai ntawm txhua qhov chaw koom; Feem ntau, kev hloov pauv ua ntej, txhua xyoo tom qab hloov pauv thiab / lossis thaum kho tau qhia (thaum lub sijhawm ua haujlwm ntawm allograft tsis ua haujlwm lossis kev tsis lees paub mob hnyav).
Kev soj ntsuam rau kev tsis lees paub mob hnyav thiab CADI
Cov ntu ntawm biopsy-pov thawj mob hnyav thiab mob ntev tsis lees paub (kuaj xyuas ntawm cov txheej txheem lossis kev soj ntsuam kuaj mob biopsies) tom qab hloov pauv yuav raug tshuaj xyuas thiab tshaj tawm raws li kev faib tawm Banf [38]. Raws li qhov no, txhua qhov kev tsis lees paub yuav raug cais raws li mob hnyav, mob ntev lossis mob ntev; thiab ntxiv stratifed rau cellular, vascular, antibody-mediated los yog mixed qauv rejections. Hom kev tsis lees paub ntau tshaj plaws hauv cov neeg uas muaj cov qauv sib xyaw yuav raug suav tias yog qhov tseem ceeb ntawm qhov txhab (xws li vascular lossis antibody-mediated> cellular rejections). TG (Banf cg 1-3) yuav raug coded raws li Banf classifcation thiab suav hais tias yog ib qho morphological manifestation ntawm chronic AMR [39].
Te CADI qhab nia quantifies tus nqi ntawm kev puas tsuaj rau lub allograft, nrog rau cov qhab nia xam los ntawm tag nrho ntawm rau qhov tsis muaj: (a) difuse los yog focal o thiab (b) fbrosis nyob rau hauv lub interstitium, (c) mesangial matrix nce thiab (d) ) sclerosis hauv glomeruli, (e) intimal proliferation ntawm cov hlab ntsha, thiab (f) tubular atrophy; nrog rau txhua tus parameter tau qhab nia nruab nrab ntawm 0 thiab 3 raws li tau piav qhia hauv lwm cov kev tshawb fawb [40]. Te CADI cov qhab nia yog qhov ntsuas thoob ntiaj teb tus qauv ntsuas raws li cov txheej txheem ua ntej tiv thaiv thiab suav tias yog ib feem ntawm cov qauv qhia hauv txhua lub chaw kuaj kab mob. Cov kev tshawb fawb yav dhau los tau pom zoo tias qhov qhab nia siab CADI cuam tshuam nrog kev tsis lees paub zoo nrog rau kev tsis lees paub ntev thiab kev poob qis txog li 4 xyoo tom qab hloov pauv, qhia tias CADI qhab nia muaj qhov tseem ceeb prognostic [41–45].
Lub raum allograft biopsies (cov txheej txheem los yog kev soj ntsuam kuaj mob biopsies) feem ntau ua tom qabraumtransplantation thiab feem ntau yog npaj rau hauv formalin-fxed parafn-embedded cov ntaub so ntswg los yog khaws cia ua cov ntaub so khov. Cov duab sawv cev lossis tag nrho cov duab swb (siv digital microscopy lossis site-specifc systems xws li Sysmex system raws li qhov chaw muaj) rau cov qhab nia histological 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 nws yuav tsum muaj cov txheej txheem kho mob (siv digital microscopy lossis site-specifc systems xws li Sysmex system raws li qhov chaw muaj) -Schif (PAS) thiab ib daim duab Trichrome-stained (qhov twg ua tau). Yog tias muaj ntau qhov kev kuaj mob biopsy muaj nyob rau hauv frst 12 lub hlis tom qab hloov pauv, tsuas yog cov ntaub so ntswg los ntawm ob qho ntawm cov khoom no (ib qho ntawm 0} thiab 6 lub hlis thiab lwm qhov ntawm > 6-12 hli yog tias muaj) yuav raug duab . Ib tus kws kho mob dig muag uas raug xaiv tsa yuav rov muab cov duab digital khaws cia (qhov twg muaj) raws li cov qauv CADI thiab Banf cov qauv rau kev tsis lees paub thiab ntev [41, 46].
Clinical thiab laboratory parameters
Ntxiv nrog rau kev ntsuas kev tiv thaiv kab mob thiab cov txiaj ntsig, ntau tus neeg pub dawb thiab tus neeg txais tus cwj pwm yuav raug muab rho tawm los ntawm cov npe, cov ntaub ntawv thiab cov ntaub ntawv kho mob hauv tsev kho mob hauv zos qhov tsim nyog thiab muaj. Cov ntaub ntawv yuav tsum tau muab rho tawm suav nrog tus neeg pub khoom muaj hnub nyoog, poj niam txiv neej, lub cev qhov hnyav, kev sib raug zoo pub dawb rau tus neeg tau txais, comorbid tej yam kev mob thiab haiv neeg; Cov neeg tau txais txiaj ntsig ntawm hnub nyoog, poj niam txiv neej, lub cev qhov hnyav, haiv neeg, kev noj qab haus huv-kev noj qab haus huv (SES; muab los ntawm post-code hauv Australia lossis lwm yam SES tsis nyob hauv lwm lub tebchaws), ntu ua ntej ntawm kev tsis ua raws li cov tshuaj tiv thaiv kab mob lossis tsis tau teem sijhawm. (raws li sau tseg rau hauv cov ntaub ntawv kho mob), comorbid tej yam kev mob (xws li complex syndrome, uro-logical, kab mob siab los yog mob plawv) thiab lub sij hawm dialysis; thiab kev hloov pauv cuam tshuam txog kev hloov pauv ntawm lub sijhawm, lub sijhawm ischemic, qhov kev xav ntawm qhov feem pua ntawm chav kawm I thiab II vaj huam sib luag reactive antibody (%), hom thiab intra-neeg mob hloov pauv ntawm qib calcineurin-inhibitor; tag nrho cov uas paub tias muaj feem xyuam nrog cov txiaj ntsig kev kho mob ntawm kev txaus siab. Cov ntaub ntawv hais txog kev ntsuas ntawm qhov muaj peev xwm nkag mus rau niam txiv antigens, suav nrog cov teeb meem hauv niam cev xeeb tub nrog rau kev kis kab mob, kev pub niam mis thiab kev xeeb tub ua ntej yuav raug nrhiav los ntawm cov neeg pub dawb (qhov twg muaj).
Specifc cov txiaj ntsig ntsuas suav nrog kev tsis lees paub mob hnyav (thiab Banf classifcation) txhua lub sijhawm taw qhia tom qab hloov pauv (hom, qhov hnyav thiab cov lus teb rau kev kho), allograft muaj nuj nqi (creatinine thiab eGFR ntawm 3 thiab 6 lub hlis, tom qab ntawd txhua xyoo tom qab hloov pauv), allograft tsis ua haujlwm ( suav nrog cov laj thawj ntawm allograft tsis ua haujlwm) thiab kev tuag (xws li ua rau tuag) yuav raug muab rho tawm los ntawm ANZDATA npe lossis cov peev txheej cuam tshuam hauv lwm lub tebchaws; thiabraumCov ntaub ntawv qhia txog biopsy, kev tsis lees paub txog kev kho mob thiab kev teb rau kev kho mob, kev siv tshuaj tiv thaiv kab mob (cov tshuaj kho mob rau calcineurin inhibitor [CNI] ntawm 3, 6, 12, 24, 36, 48, thiab 60 lub hlis tom qab hloov pauv), proteinuria ( urine protein / creatinine ratios ntawm 3, 6, 12, 24, 36, 48, thiab 60 lub hlis tom qab hloov pauv yog tias muaj) thiab tus naj npawb / sijhawm ntawm txhua qhov ua rau thiab ua rau hauv tsev kho mob tshwj xeeb yuav raug muab rho tawm los ntawm tsev kho mob hauv zos thiab chaw kuaj mob. cov ntaub ntawv. Te cov ntaub ntawv yuav raug nkag mus rau hauv cov ntaub ntawv tiv thaiv tus password (tshwj xeeb rau txhua qhov chaw) tsawg kawg yog mus txog 5- xyoo tom qab hloov pauv (lossis kom txog thaum allograft poob mus txog 10- xyoo tom qab hloov pauv siv cov ntaub ntawv txuas mus rau ANZDATA thiab lwm lub teb chaws-spe-cifc npe).
Kev xam qhov loj me
Kev ntsuas qhov loj me yog raws li cov txiaj ntsig tseem ceeb ntawm de novo DSA, txhua ntu ntawm kev tsis lees paub mob hnyav thiab kev poob tag nrho. Hauv peb ANZDATA kev sau npe kawm piv cov txiaj ntsig allograft ntawm leej niam thiab leej txiv pub dawbraumtransplants, ntau dua ntawmraumCov neeg tau txais kev hloov pauv uas tau txais niam txiv pub rau lub raum tau ntsib ib qho kev tsis lees paub thaum piv nrog cov neeg tau txais lub raum los ntawm leej txiv pub dawb (37 thiab 27 feem pua, raws li; p < 0.001)="" [4].="" cov="" ntaub="" ntawv="" hais="" txog="" kev="" txhim="" kho="" ntawm="" de="" novo="" dsa="" tsis="" muaj="" los="" ntawm="" anzdata="" npe.="" piv="" txwv="" tias="" txog="" li="" 40="" feem="" pua="" ntawm="" cov="" neeg="" tau="" txais="" kev="" pab="" tuaj="" yeem="" txhim="" kho="" de="" novo="" dsa,="" kev="" tsis="" lees="" paub="" lossis="" poob="" lawv="" cov="" allografts="" hauv="" 60="" lub="" hlis="" tom="" qab="" hloov="" pauv,="" tus="" qauv="" loj="" ntawm="" 479="" tus="" neeg="" pub="" dawb="" tus="" neeg="" txais="" khub="" (1:="" 1="" faib="" rau="" niam="" thiab="" txiv="" lub="" qhov="">lub raum) yuav tsum ua kom tiav lub zog ntawm 80 feem pua uas muaj qhov tseem ceeb ntawm ob sab ntawm 5 feem pua rau kev kuaj pom qhov sib txawv ntawm 0.10 ntawm marginal proportions tom qab siv kev kho txuas ntxiv (thiab cov qhab nias sib txuas ntawm 0.5 ntawm yam tsawg kawg yog 4 qhov kev soj ntsuam [rau cov txiaj ntsig kev ntsuas sib xyaw], thiab suav txog qhov muaj peev xwm ploj ntawm cov ntaub ntawv txog li 10 feem pua ) (Daim duab 2). Koj xav tau kev nrhiav neeg ua haujlwm ntawm 520 tus niam txiv pub dawb / tus neeg txais cov khub hauv qhov kev tshawb nrhiav rov qab yuav tsum muaj cov qauv tsim nyog thiab lub zog txaus los teb cov lus nug ntawm kev kawm. Kev ntsuas qhov loj me tau txiav txim siab siv qhov xav tau lub sijhawm nruab nrab qhov sib txawv (TAD) ntawm ob txhais tau tias los ntawm cov ntaub ntawv txuas ntxiv, sib raug zoo siv GEE txoj hauv kev PASS Sample Size Software.
Nyob nruab nrab ntawm 2015 thiab 2018, muaj 182 tus neeg mob menyuam yaus thiab cov tub ntxhais hluas hnub nyoog qis dua lossis sib npaug li 18 xyoo nrograumKev poob qis hauv Australia uas tau txais kev hloov raum, nrog rau niam txiv pub raum hloov pauv tau pab 40 feem pua ntawm tag nrho cov kev hloov pauv. Nws piv nrog 30 tus neeg mob hauv New
Zealand (67 feem pua ntawm niam txiv pub dawbraumhloov pauv) thiab 30 tus neeg mob hauv Netherlands (30-40 feem pua ntawm niam txiv pub raum hloov pauv) nyob rau tib lub sijhawm. Hauv tebchaws United Kingdom, muaj 760 tus neeg mob menyuam yaus thiab cov tub ntxhais hluas uas tau txais kev hloov pauv raum ntawm xyoo 2010 thiab 2015, nrog kwv yees li 340 (45 feem pua) cov niam txiv pub dawbraumhloov pauv. Tese tsis ntev los no fgures qhia tias lub hom phiaj qauv loj (kom nrhiav tau 520 tus neeg pub dawb / tus neeg tau txais khub ntawm 1990 thiab 2020) yog ua tiav.
Kev txheeb cais
Cov ntaub ntawv yuav raug nthuav tawm raws li qhov txhais tau tias ± tus qauv sib txawv (SD) lossis tus lej (feem ntau) rau qhov sib txawv thiab pawg sib txawv, raws li, nrog kev txhais tau tias thiab kev faib ua piv nrog siv t-test thiab qhov ntsuas chi-squared qhov tsim nyog. Peb yuav tsim qauv nrog ntau tus lej ntawm archetypes thiab xaiv qhov twg los siv raws li tus qauv fnal raws li cov seem ntawm cov squares siv "lub luj tshib" txoj kev [47]. Te archetypal qauv yuav muab cov qhab nia raws li kev sib xyaw ua ke ntawm kev hloov pauv kev tiv thaiv kab mob ua ntej thiab chaw kho mob (tus pub, tus neeg txais thiab hloov pauv) rau txhua tus neeg tau txais kev siv lub sijhawm los ntawm kev hloov pauv mus rau cov txiaj ntsig tseem ceeb ntawm de novo DSA, txhua ntu ntawm kev tsis lees paub mob hnyav thiab allograft. poob; nrog rau cov qhab nia tag nrho 1. Txhua qhov kev ntsuas yuav raug muab rau ib pawg archetype raws li qhov qhab nia siab tshaj plaws archetype (suav nrog "siab immunogenic txaus ntshai"profle, suav nrog kev pheej hmoo ntawm kev tiv thaiv kab mob). Cov qauv ntxiv uas suav nrog cov yam ntxwv ua ntej thiab tom qab hloov pauv (xws li hnub nyoog pub dawb, tsis ua raws) kuj tseem yuav tsim. Ib qho tseem ceeb ntawm kev tshuaj ntsuam xyuas yuav raug tsim los ua kom pom cov ntaub ntawv matrix siv los ua cov tswv yim rau kev tsom xam archetypal. Kev txheeb xyuas cov ntsiab lus tseem ceeb yuav ua rau ob qho txiaj ntsig tseem ceeb: (i) lub voj voog sib raug zoo, thiab (ii) qhov kev kwv yees ntawm cov tib neeg. Te correlation vajvoog tso cai rau ib tug graphical ntsuam xyuas ntawm cov kev sib raug zoo ntawm lub pre-transplant immunological thiab soj ntsuam tsis thiab lub graphical parameter contribution ntawm lub axes (zoo los yog tsis zoo contribution: vector direction; lub zog ntawm kev koom tes: vector length thaum projected ntawm axis). Peb yuav txheeb xyuas cov pab pawg sib txawv (xws li archetypes), txhua qhov uas muaj cov txheej txheem tiv thaiv kab mob tiv thaiv kab mob thiab kev kho mob zoo uas tuaj yeem txhim kho qhov kev pheej hmoo stratifcation rau "qhov tshwm sim tsis zoo" rau cov neeg txais kev pab niam txiv.raumrau kev hloov pauv, thiab cais rau cov uas tau txais niam lossis txiv pub pub dawblub raum. Te Australian thiab New Zealand cohorts yuav yog cov derivation cohort rau cov archetypes, uas yuav validated nyob rau hauv lub cohorts los ntawm lub tebchaws United Kingdom thiab lub Netherlands. Tom ntej no peb yuav nrhiav kev los tsim kom muaj tus qauv kev kwv yees (sib koom ua ke) los tshuaj xyuas cov kev sib koom ua ke ntawm pawg archetypes thiab lwm yam kev qhia tshwj xeeb ua ntej thiab cov txiaj ntsig tseem ceeb uas siv univariate Cox proportional hazards regression model. Tus qauv Cox multivariable yuav raug tsim los ntawm kev xaiv covariates los ntawm Pab Pawg Lasso thiab Doubly Robust Estimation (GLiDeR), ib txoj hauv kev ntawm kev xaiv sib txawv los txheeb xyuas cov neeg tsis sib haum xeeb uas siv cov kev hloov pauv ntawm pab pawg lasso txoj hauv kev uas ib txhij ua coefcient xaiv, tsis tu ncua, thiab kwv yees thoob plaws kev kho mob. thiab cov qauv tsim. Bootstrap resampling nrog hloov lossis subsampling yam tsis muaj kev hloov pauv yuav raug siv los tshawb xyuas thiab txheeb xyuas cov qauv kev ruaj ntseg. Cov qauv sib cais yuav raug tsim los rau txhua qhov kev tshwm sim thib ob. Te cov txiaj ntsig ntawm cov qauv thiab covariates yuav raug tshuaj xyuas kom ntseeg tau tias muaj feem cuam tshuam rau kev kho mob. Deviance thiab cov qhab nia seem yuav raug npaj los ntsuas rau cov tib neeg uas tau kwv yees tsis zoo lossis cov tib neeg uas tej zaum yuav muaj kev cuam tshuam loj ntawm cov qauv ntsuas. Te kev ua tau zoo ntawm cov qauv prognostic integrated yuav raug soj ntsuam los ntawm kev xam ib tug tsis-lub sij hawm-specifc cheeb tsam nyob rau hauv lub nkhaus (AUC) siv kev ntsuas ntawm concord-ance los ntawm Somer's Dxy statistic. Rau kev ntsuam xyuas ntawm tus qauv calibration, cov neeg mob yuav muaj kev pheej hmoo-stratifed nyob rau hauv lub hauv paus ntawm lawv cov kev kwv yees qhov ntsuas, uas yog cov linear ua ke ntawm cov khoom ntawm multivariate qauv coefcients thiab lawv tus kheej covariate qhov tseem ceeb. Kaplan-Meier txoj kev ciaj sia nyob tom qab yuav raug npaj rau cov neeg mob uas raug strati- pub rau hauv quintiles ntawm lawv qhov ntsuas ntsuas. Te valida-tion cohort's AUC yuav raug txiav txim thiab kwv yees thiab pom cov neeg tuag yuav raug muab piv. Kev sib koom ua ke ntawm cov archetypes thiab cov txiaj ntsig tsis zoo yuav raug tshuaj xyuas hauv pawg neeg yav tom ntej, thiab tshuaj xyuas seb qhov sib ntxiv ntawm lwm cov tshuaj tiv thaiv kab mob tshiab tshiab yuav ua li cas txhawm rau txhim kho qhov kev xeem ntawm cov qauv.
Kev sib tham
TE INCEPTION txoj kev kawm suav nrog cov niam txiv pub rau lub raum hloov pauv cov neeg tau txais txiaj ntsig thoob plaws 4 lub tebchaws cuam tshuam txog kev tshawb fawb ntawm ntau haiv neeg kev faib tawm, uas yuav tso cai rau kev nthuav dav ntawm fndings. Te muaj cov neeg tshawb xyuas qhov chaw hauv zos thiab kev siv cov txheej txheem kev kawm tshwj xeeb thiab cov txheej txheem yuav ua kom peb ua tiav lub hom phiaj nrhiav neeg ua haujlwm. Te investiga-tors/authors (thiab delegates) ntawm cov ntawv sau raws tu qauv thiab xaiv cov neeg siv khoom thiab cov neeg sawv cev sau npe ntawm txhua lub tebchaws yuav tsim pawg tswj hwm thiab cov ntaub ntawv saib xyuas, uas yuav sib tham ob xyoos ib zaug thiab hais txog cov teeb meem ntsig txog kev coj ua. ntawm kev tshawb fawb thiab ua raws li kev kawm raws tu qauv thiab txheej txheem. Txhua qhov kev hloov pauv hauv cov txheej txheem lossis kev ntes cov ntaub ntawv yuav tsum tau txais kev pom zoo los ntawm pawg tswj hwm thiab saib xyuas cov ntaub ntawv ua ntej kev nqis tes ua.
Kev khaws cia cov ntaub ntawv caj ces thiab cov ntshav qab zib rau cov haujlwm tshawb fawb yav tom ntej
Nrog rau cov kev txwv nyiaj txiag tam sim no rau txoj kev tshawb no, tsis yog tag nrho HLA thiab cov noob tsis-HLA lossis kev txheeb xyuas cov tshuaj tiv thaiv HLA thiab tsis-HLA cov tshuaj tiv thaiv yuav ua tau. Cov khoom siv noob caj noob ces thiab sera tau txais los ntawm cov neeg mob (thiab cov neeg pub dawb) yuav muab khaws cia rau lub sijhawm 15 xyoos tom qab ua tiav qhov kev kawm thawj zaug kom txog rau thaum muaj nyiaj txiag ntxiv rau cov haujlwm ntxiv. Pawg thawj coj saib xyuas thiab cov ntaub ntawv soj ntsuam ntawm qhov kev tshawb fawb no yuav muab kev saib xyuas cov kev tshawb fawb muaj peev xwm hais txog kev siv cov qauv no thiab cov ntaub ntawv qhia txog kev noj qab haus huv rau yav tom ntej.
Kev ceev ntiag tug, khaws cov ntaub ntawv thiab khaws cia
Tag nrho cov ntaub ntawv yuav raug tswj kom tsis pub leej twg paub. Cov ntaub ntawv yuav raug muab khaws cia rau hauv lub server ruaj ntseg thiab tsuas yog cov neeg soj ntsuam tau tso cai hauv pab pawg kawm lossis lawv cov neeg sawv cev tuaj yeem nkag mus rau cov ntaub ntawv. Cov ntaub ntawv ntsig txog kev noj qab haus huv yuav khaws cia tsawg kawg 15 xyoo tom qab ua tiav ntawm qhov project thiab cov ntawv tshaj tawm. Cov DNA ntxiv thiab cov sera uas tau muab rho tawm / cais thiab khaws cia yuav khaws cia rau hauv ib qho chaw hauv zos lossis hauv nruab nrab, uas yuav raug txheeb xyuas ua ntej ua ntej pib kawm. Yog tias cov neeg koom nrog tshem tawm kev pom zoo thaum lub sijhawm tshawb fawb, tus kws kho mob thiab cov neeg ua haujlwm tshawb fawb yuav tsis sau cov ntaub ntawv ntxiv, txawm hais tias tus kheej thiab lwm cov ntaub ntawv tseem ceeb uas twb tau sau tseg lawm yuav raug khaws cia kom ntseeg tau tias cov txiaj ntsig ntawm txoj haujlwm tshawb fawb tuaj yeem ntsuas tau zoo thiab rau ua raws li txoj cai. Cov khoom siv noob caj noob ces thiab sera tau txais rau lub hom phiaj ntawm txoj kev tshawb no yuav khaws cia hauv zos lossis hauv nruab nrab rau 15 xyoo tom qab ua tiav qhov kev tshawb fawb thawj zaug, tom qab ntawd cov qauv yuav raug rhuav tshem thiab muab pov tseg kom tsim nyog.
Kev nthuav tawm cov txiaj ntsig ntawm qhov project
Nws tau cia siab tias cov txiaj ntsig ntawm txoj haujlwm tshawb fawb no yuav raug tshaj tawm thiab / lossis nthuav tawm hauv ntau lub rooj sab laj, suav nrog cov rooj sib tham kho mob hauv tebchaws thiab thoob ntiaj teb. Hauv ib qho kev tshaj tawm thiab / lossis kev nthuav qhia, tsuas yog cov ntaub ntawv sau ua ke yuav raug muab rau hauv txoj hauv kev uas tsis muaj leej twg tuaj yeem txheeb xyuas tau. Cov txiaj ntsig ntawm cov txiaj ntsig no tseem yuav raug tshaj tawm los ntawm tsab ntawv xov xwm sau txog cov txiaj ntsig zoo rau txhua tus neeg tshawb nrhiav, cov neeg tshawb xyuas qhov chaw thiab lwm tus neeg cuam tshuam ncaj qha rau kev saib xyuas.raumcov neeg txais kev hloov pauv. Cov ntsiab lus ntawm qhov kev kawm fndings nyob rau hauv ib tug neeg cov lus yuav muab nthuav tawm rau cov neeg koom.
Te INCEPTION kev kawm fndings yuav muab pov thawj los txhawb lossis rov hais dua qhov pom tseeb tsis sib haum xeeb ntawm cov txiaj ntsig sib txawv cuam tshuam nrog niam thiab txiv hloov pauv, uas tuaj yeem qhia rau cov kws kho mob, cov kws kho mob, cov neeg mob thiab lawv tsev neeg ntawm kev pheej hmoo thiab xav tau mus ntev. - Cov txiaj ntsig graft tom qab lees txais niam txiv piv rau leej txiv pub dawblub raum. Raws li cov menyuam yaus thiab cov tub ntxhais hluas muaj kev xav tau ntau dua rau kev hloov pauv txoj sia nyob, txoj kev tshawb fawb INCEPTION yog qhov tseem ceeb rau kev txhawb nqa cov pov thawj los txhim kho kev ciaj sia tshwj xeeb rau cov menyuam yaus thiab cov tub ntxhais hluas nrograumua tsis tiav. Tsis tas li ntawd, kev hloov lub raum yog txuam nrog kev paub txog kev ua haujlwm zoo [48, 49], kev noj qab haus huv ntsig txog lub neej [50], kev kawm tau zoo thiab kev koom tes hauv lub neej [51]. Yog li kev ua kom muaj sia nyob frst allograft tau ua rau muaj txiaj ntsig los ntawm kev nce kev sib koom ua ke thiab kev ua haujlwm ntawm kev ua haujlwm hauv zej zog. Te INCEPTION kev kawm yog ib qho tseem ceeb los txhim kho kev nkag siab ntawm kev tiv thaiv kab mob sib txawv ntawm kev lees txais araumlos ntawm leej niam lossis leej txiv, uas tsis tuaj yeem ua tau kom txog thaum tsis ntev los no kev txhim kho thiab muaj cov cuab yeej siv thev naus laus zis. Qhov kev npaj ua haujlwm no yuav ua kom muaj kev txhim kho kev xaiv zoo tshaj plaws ntawm niam txiv pub raum rau cov menyuam yaus thiab cov tub ntxhais hluas uas muaj lub raum tsis ua haujlwm, nrog rau kev txhim kho tom ntej ntawm cov txiaj ntsig kev noj qab haus huv rau cov neeg muaj kev pheej hmoo. Tere yog qhov tsis paub meej txog kev siv hluav taws xob, kev siv tshuaj kho mob thiab qhov tseem ceeb ntawm qee yam ntawm cov txheej txheem no thiab qhov kev tshawb fawb no yuav ntsuas thiab ntsuas lub zog kwv yees ntawm kev sib txuas ntawm cov uas twb muaj lawm thiab tshiab ua ntej hloov B- thiab T cell molecular mismatch txoj hauv kev los tsim cov infuence ntawm genetic compatibility hauv kev txiav txim siab tsis zoo allograft tau tshwm sim.
Tsis tas li ntawd, cov peev txheej no yuav ntxiv dag zog rau kev tshawb fawb txog kev txaus siab hauv qhov no thiab lwm yam uas ua rau muaj kev txhim kho ntxiv hauvraumhloov pauv thiab tus neeg mob tawm-los rau qhov no thiab lwm tus neeg. Tshwj xeeb, cov no suav nrog:
1) Kev kwv yees tus nqi ntawm qhov kev ntsuas tshiab ntawm tus neeg pub dawb / tus neeg txais cov noob sib raug zoo rau cov txiaj ntsig tsis zoo thiab cov txiaj ntsig ntawm tus neeg mob xws li kev tsis lees paub, allograft poob, rov tshwm sim thawj zaugraumkab mob thiab lwm yam teeb meem tshwm sim tom qab hloov lub raum.
2) Koj muaj peev xwm rau tus kheej kev ntsuam xyuas kev pheej hmoo ntawm kev tiv thaiv kab mob kom txo tau cov txiaj ntsig tsis zoo nyob rau hauvraumcov neeg txais kev hloov pauv.
3) Kev tsim cov peev txheej tseem ceeb uas yuav suav nrog pawg loj tshaj plaws ntawm cov menyuam yaus thiab cov hluasraumCov neeg tau txais kev hloov pauv thoob ntiaj teb, nrog rau qhov muaj cov kev daws teeb meem siab HLA ntaus ntawv (siv cov txheej txheem ntaus ntawv siab tshaj plaws hauv NGS sequencing) thiab ua tiav cov ntaub ntawv allograft thiab cov neeg mob. Kev txhim kho cov txiaj ntsig hauv pawg neeg mob no yog qhov tseem ceeb vim tias lawv txoj sia nyob ntev, lub nra ntawm tus kab mob ntev thiab qhov tshwm sim uas cov neeg tau txais kev pab no yuav xav tau kev hloov pauv thiab txuas ntxiv mus siv cov peev txheej kho mob mus ntev hauv kev kho mob ntawm lawv lub nra.
Cov ntawv luv
AMR: Antibody-mediated rejection; AUC: Cheeb tsam nyob rau hauv lub cruve; ANZDATA: Australia thiab New Zealand Dialysis thiab Hloov; ANZCTR: Australian New Zealand Clinical Trials Registry; CADI: Chronic Allograft Damage Index; CKD- EPI: ChronicLub raumKab mob- Kab mob sib kis sib koom ua ke; DSA: De novo pub- specifc anti- HLA antibody; DNA: Deoxyribonucleic acid; EMS-3D: Electrostatic mismatch qhab nia; eGFR: kwv yees glomerular pom tus nqi; GLiDeR: Pab pawg Lasso thiab Doubly Robust kwv yees; HLA: Human leukocyte antigen; Ig: Immunoglobulin; MFI: Lub ntsiab lus fuorescence siv; NHMRC: National Health thiab Medical Research Council; NGS: Lwm tiam ua ntu zus; NIMA: Cov niam txiv tsis tau txais txiaj ntsig; NIPA: tsis yog los ntawm niam txiv antigen; PRA: Vaj huam sib luag reactive antibody; PAS: Periodic acid-Schif; PIRCHE: Kev kwv yees tsis ncaj qha los ntawm HLA epitopes; SES: Socioeconomic xwm txheej; STROBE: Txhim kho Kev Tshaj Tawm Txog Kev Tshawb Fawb Kev Tshawb Fawb hauv Kev Kab Mob Kab Mob; TG: Hloov glomerulopathies; UK: United Kingdom.
Kev lees paub
Peb xav lees paub Dr. Sean Kennedy, Dr. Hugh McCarthy thiab Dr. Fiona Mackie los ntawm Sydney Children's Hospital, Sydney, New South Wales rau kev koom tes hauv txoj kev tshawb no.
Cov neeg sau ntawv pab txhawb
WL thiab GW conceptualized thiab tsim txoj kev tshawb no thiab yog lub luag hauj lwm rau thawj tsab ntawv. FC, AF, SH, VK, CK, JK, PT, NL, AT, AT‑P pab tsim kev kawm. BA, SA, AB, FC, MC, EC, HD, HdJ, LD, AF, SH, JH, RH, JK, RK, JJK, SK, NK, VK, CK, DK, NL, SP, CP, AP, AS, MS, AT, AT-P, PT, FW, DW tau thuam thiab pab npaj cov qauv. WL thiab GW yog lub luag haujlwm rau daim ntawv kawg. Tus kws sau ntawv nyeem thiab pom zoo cov ntawv sau kawg.
Nyiaj txiag
Cov nyiaj pab rau txoj kev kawm INCEPTION yog muab los ntawm National Health and Medical Research Council (NHMRC) Ideas Grant (Application ID: APP1184595, funding duration 2020-2023), Department of Health Western Australia thiab Telethon- Perth Children's Hospital Research Fund (funding Lub sijhawm 2017-2020) thiab Starship Foundation Clinical Research Grant (Auckland, New Zealand). Tag nrho cov nyiaj tau los ntawm cov txheej txheem kev tshuaj xyuas sab nraud uas muaj zog heev.
Muaj cov ntaub ntawv thiab cov ntaub ntawv
Kev sib faib cov ntaub ntawv tsis muaj feem xyuam rau daim ntawv raws tu qauv. Cov ntaub ntawv kawm yav tom ntej yuav raug nthuav tawm hauv cov ntawv sau thiab cov ntaub ntawv txhawb nqa ntxiv (yog tias tsim nyog), tab sis qhov muaj cov ntaub ntawv no (hauv cov chaw khaws ntaub ntawv pej xeem) yuav yog raws li txhua lub teb chaws txoj kev tswj hwm tshwj xeeb.
Cov lus tshaj tawm
Kev pom zoo ntawm kev ncaj ncees thiab kev tso cai los koom
Kev pom zoo rau kev coj ncaj ncees tau tso cai los ntawm Sir Charles Gairdner Osborne Park Health Care Group Human Research Ethics Committee (PRN: RGS930), nrog rau kev pom zoo rau txhua qhov chaw hauv Australia. Kev sau ntawv lossis hais lus tso cai yuav tau txais los ntawm txhua tus neeg koom hauv Australia, nrog rau cov txheej txheem ntawm kev pom zoo los ntawm Pawg Neeg Saib Xyuas Kev Ncaj Ncees thaum lub sijhawm COVID-19 kis thoob qhov txhia chaw.
Tso cai rau kev tshaj tawm
Kev pom zoo yuav raug nrhiav nrog kev nrhiav neeg tuaj koom.
Kev nyiam sib tw
Cov kws sau ntawv tshaj tawm tias lawv tsis muaj kev sib tw nyiam.
Sau Paub meej
1 Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, Western Australia 6009, Australia. 2 Tsev Kawm Ntawv Kho Mob, University of Western Australia, Perth, Australia. 3 Department of Pediatric Nephrology, Hôpital Universitaire des Enfants— Reine Fabiola, Brussels, Belgium. 4 Department of Nephrology, Westmead Children's Hospital, Sydney, Australia. 5 Kws Qhia Tshuaj thiab Kev Noj Qab Haus Huv, University of Sydney, Sydney, Australia. 6 Department of Pediat-ric Nephrology, Emma Children's Hospital, Amsterdam University Medical Center, Amsterdam, Lub Netherlands. 7 Department of Immunology, Leiden University Medical Center, Leiden, Lub Netherlands. 8 Department of Renal Medicine, Auckland District Health Board, Auckland City Hospital, Auckland,
