Cov txiaj ntsig tau los ntawm German Chronic Kidney Disease (GCKD) Kev Kawm Txhawb Kev Koom Tes Ntawm Cov txheeb ze Telomere Length nrog kev tuag nyob rau hauv ib pawg loj ntawm cov neeg mob uas muaj mob raum mob ntev
Mar 12, 2022
Hu rau: Audrey Hu Whatsapp / hp: 0086 13880143964 Email:audrey.hu@wecistanche.com
Federica Fazzini1, Claudia Lamina1, Julia Raschenberger & et al.
Raum International (2020) 98, 488–497; https://doi.org/10.1016/j.kint.2020.02.034
Copyright ª 2020, International Society of Nephrology. Tshaj tawm los ntawm Elsevier Inc. Qhov no yog ib tsab xov xwm qhib-access nyob rau hauv daim ntawv tso cai CC BY
Telomere ntev yog paub tias muaj kev cuam tshuam nrog kev laus thiab tau raug pom zoo ua tus cim rau cov kab mob kev laus. Telomere attrition tuaj yeem ua kom nrawm los ntawm oxidative kev nyuaj siab thiab o, ob qho tib si feem ntau tshwm sim hauv cov neeg mob raum mob. Ntawm no, peb tau tshawb xyuas seb qhov ntev ntawm telomere muaj feem cuam tshuam nrog kev tuag nyob rau hauv ib pawg loj ntawm cov neeg mob uas muaj kab mob raum ntev G3 thiab A1-3 lossis G1-2 nrog rau cov proteinuria (A3) thaum tso npe. Tus txheeb ze telomere ntev tau ntsuas nyob rau hauv cov ntshav peripheral los ntawm ntau PCR txoj kev hauv 4,955 tus neeg mob los ntawm GCKD txoj kev tshawb fawb, ib qho kev soj ntsuam txuas ntxiv mus. Ua tiav plaub xyoos kev soj ntsuam tau muaj los ntawm 4,926 tus neeg mob uas peb tau sau 354 tus neeg tuag. Cov kwv tij telomere ntev yog qhov muaj zog thiab muaj kev ywj pheej kwv yees ntawm txhua qhov kev tuag. Txhua qhov kev txo qis ntawm 0.1 qhov txheeb ze telomere ntev chav tsev tau cuam tshuam nrog 14 feem pua nce kev pheej hmoo ntawm kev tuag (kev phom sij piv 1.14 [95 feem pua ntawm kev ntseeg siab 1.06-1.22]) hauv cov qauv hloov kho Rau hnub nyoog, poj niam txiv neej, hauv paus eGFR, zis albumin / creatinine piv, ntshav qab zib mellitus, kab mob plawv, LDL-cholesterol, HDL-cholesterol, haus luam yeeb, lub cev qhov ntsuas, systolic thiab diastolic ntshav siab, C-reactive protein thiab serum albumin. Qhov no txhais ua 75 feem pua siab dua rau cov neeg nyob hauv qis tshaj piv rau qhov siab tshaj plaws quartile ntawm kwv tij telomere ntev. Lub koom haum feem ntau yog tsav los ntawm 117 lub plawv tuag (1.20 [1.05-1.35]) nrog rau 67 tus neeg tuag vim muaj kab mob (1.27 [1.07-1.50]). Yog li, peb qhov kev tshawb pom txhawb nqa kev sib koom ua ke ntawm luv telomere ntev nrog txhua qhov ua rau tuag, kev tuag ntawm cov hlab plawv, thiab kev tuag vim kev kis kab mob hauv cov neeg mob uas mob raum mob.
KEYWORDS:mob raum mob; kab mob; kev tuag; txheeb ze telomere ntev
Mob raum mob(CKD) yog ib yam kab mob nyuaj, thiab nws cov cuab yeej cuab tam tau kwv yees li 30 feem pua – 70 feem pua .9–12 Nyob rau xyoo tas los no, cov kev tshawb fawb genome-wide koom haum tau txheeb xyuas ntau yam genetic loci txuam nrog raum ua haujlwm thiab CKD.13–17.
Txawm li cas los xij, qhov ntsuas ib leeg nucleotide polymorphisms ntawm qhov txheeb xyuas loci piav qhia tsuas yog ib feem me ntawm cov cuab yeej cuab tam, thiab cov neeg koom nrog caj ces ntxiv yuav ploj mus. Txog rau tam sim no, tsuas yog qee qhov kev tshawb fawb me me tau tshawb xyuas qhov sib koom ntawm TL thiab kab mob raum. Qee qhov kev tshawb fawb pom tias luv luv TL cuam tshuam nrog rau lub raum tsis zoo hauv cov pej xeem, 18,19 nrog rau cov neeg mob plawv tsis ua hauj lwm.20 Peb nyuam qhuav piav qhia luv luv ntawm cov txheeb ze TL (RTL) rau cov neeg mob uas mob hnyav CKD uas muaj kab mob plawv ( CVD), 21 nrog rau kev koom tes nrog ntev 22 thiab kev loj hlob ntawm CKD.23 Cov neeg mob uas tau mus txog raum tsis ua haujlwm kho los ntawm hemodialysis tau piav qhia tias tau txo TL hauv kev sib piv nrog kev noj qab haus huv, 24-27 thiab txo TL yog cuam tshuam nrog kev tuag. 28 Tsuas yog ob peb qhov kev tshawb fawb tau ua nyob rau hauv cov neeg mob lub raum tsis-dialysis-dependent.21–23,29,30 Rau peb txoj kev paub, txoj kev tshawb fawb tam sim no yog thawj txoj kev tshawb fawb yav tom ntej uas tshawb xyuas kev koom tes ntawm leukocyte RTL thiab ua rau muaj kev tuag hauv ib qho loj. Tsis-dialysis-dependent CKD cohort.
Cistanche txiaj ntsig: txhim kho lub raum ua haujlwm
TSEEM CEEB
Cov yam ntxwv tseem ceeb ntawm cov neeg kawm
RTL tau suav nrog cov ntshav peripheral los ntawm kev ua kom muaj nuj nqis polymerase cov tshuaj tiv thaiv kab mob hauv 4955 tus neeg mob los ntawm GermanMob raum mobkawm. Ib qho ua tiav {{0}} xyoo rov qab los ntawm 4926 tus neeg mob. Cov yam ntxwv tseem ceeb ntawm cov neeg mob 4926 no raws li quartiles ntawm RTL tau muab rau hauv Table 1. RTL muaj txij li qhov tsawg kawg nkaus ntawm {{10}}.40 mus rau qhov siab tshaj ntawm 2.31 (Cov duab ntxiv S1 ), nrog qhov nruab nrab ± SD ntawm 0.95 ±{22}}.19 thiab nruab nrab ntawm 0.92 (1st quartile ¼ 0.82; 3rd quartile ¼ 1 . 05). RTL tau cuam tshuam tsis zoo nrog lub hnub nyoog (r ¼ -{{30}}}.36, P < 0.001)="" thiab="" muaj="" kev="" cuam="" tshuam="" zoo="" nrog="" kwv="" yees="" glomerular="" pom="" tus="" nqi="" (egfr;="" r="" ¼="" 0.17,="" p="">< 0.001)="" thiab="" zis="" albumin–="" creatinine="" piv="" (r="" ¼="" 0.05,="" p=""><0.001). thaum="" peb="" hloov="" rtl="" rau="" hnub="" nyoog="" thiab="" poj="" niam="" txiv="" neej,="" peb="" tsis="" pom="" muaj="" kev="" sib="" raug="" zoo="" nrog="" egfr="" thiab="" cov="" zis="" albumin-creatinine="">
Kev soj ntsuam yav tom ntej thiab kev tuag
Tag nrho ntawm 354 tus neeg tuag tau tshwm sim thaum lub sijhawm nruab nrab ntawm 4 xyoo (1483 hnub). Cov ua rau tuag yog CVD suav nrog myocardial infarction, kab mob plawv, mob plawv tuag, mob plawv tsis ua hauj lwm, pulmonary embolism, kab mob plawv thiab ischemic stroke (117 tus neeg mob, 33.1 feem pua), kab mob (67 cov neeg mob, 18.9 feem pua), nonischemic cerebrovascular ua rau (9 tus neeg mob, 2.5 feem pua), kab mob peripheral vascular (7 tus neeg mob, 2.0 feem pua), raum tsis ua haujlwm (8 tus neeg mob, 2.3 feem pua), ntau yam ua rau (103 tus neeg mob, 29.1 feem pua) thiab tsis paub ua rau ( 43 tus neeg mob, 12.1 feem pua).
Cov xwm txheej sib sau ua ke qhia tias qhov xwm txheej ntawm txhua qhov ua rau tuag (Daim duab 1a) nce nrog luv RTL, nrog qhov xwm txheej siab tshaj plaws nrog qis RTL quartile. Nyob rau hauv cov xwm txheej tshwm sim ua haujlwm nkhaus ntawm cov hlab plawv (Daim duab 1b) thiab kev tuag ntawm cov kab mob (Daim duab 1c), qhov sib txawv ntawm cov quartiles tau hais tsawg dua, tab sis qhov kev txiav txim ntawm cov quartiles yog tib yam.
Daim duab 1|Cov xwm txheej tshwm sim rau (a) tag nrho-ua rau kev tuag, (b) kab mob plawv (CVD) kev tuag, thiab (c) tuag vim muaj kab mob, los ntawm quartiles (Q) ntawm kwv tij telomere ntev (RTL). Q1 yog quartile suav nrog cov neeg mob uas luv tshaj RTL.
Cov txiaj ntsig ntawm Cox regression qauv siv cov kev hloov pauv sib txawv tau muab rau hauv Table 2 thiab pom tias muaj kev koom tes tseem ceeb ntawm luv luv RTL thiab kev pheej hmoo ntawm txhua qhov kev tuag. Kev ntsuas tsis tu ncua, txhua qhov txo qis ntawm 0.1 RTL units tau cuam tshuam nrog 16 feem pua ntawm kev pheej hmoo ntawm kev tuag nyob rau hauv tus qauv hloov kho rau hnub nyoog thiab poj niam txiv neej (kev phom sij piv [HR], 1.16; 95 feem pua ntawm kev ntseeg siab [CI], 1. 08–1.24; P ¼ 1.7e{14}}). Lub koom haum tseem ceeb tom qab ncua kev hloov kho rau eGFR, tso zis albumin-creatinine piv, ntshav qab zib mellitus, thiab kab mob plawv (mob 2: HR, 1.16; 95 feem pua CI, 1.08–1.24) thiab ntxiv CVD cov kev pheej hmoo tsawg-qhov ntom ntom. lipoprotein cholesterol, high-density lipoprotein cholesterol, haus luam yeeb, lub cev hnyav Performance index, systolic ntshav siab, diastolic ntshav siab, C-reactive protein, thiab serum albumin ntawm lub hauv paus ( qauv 3: HR, 1.14; 95 feem pua CI, 1.06–1.22; P ¼ 3.5e-04). Nonlinear P spline tsom xam yog muab nyob rau hauv daim duab 2 thiab qhia ib tug yuav luag linear koom haum RTL nrog tag nrho cov-ua rau tuag. Cov neeg mob uas luv tshaj RTL (1st quartile) muaj 75 feem pua kev pheej hmoo siab dua rau tag nrho cov neeg tuag piv rau cov nyob rau hauv lub quartile nrog ntev RTL (Sab Ntxiv Table S1, tag nrho cov qauv: HR, 1.75; 95 feem pua CI, 1.22–2.50 ; P 0.0024).
Tom ntej no, peb txheeb xyuas dab tsi yog tsav lub koom haum ntawm RTL nrog txhua qhov ua rau tuag (Table 2). Peb tau soj ntsuam 2 feem ntau tshwj xeeb ua rau kev tuag thiab pom tias txhua qhov txo qis ntawm 0.1 RTL units tau cuam tshuam nrog 20 feem pua ua rau muaj kev pheej hmoo ntawm CVD tuag nyob rau hauv cov qauv kho tag nrho (HR, 1.2 0; 95% CI, 1.05–1.35; P ¼ 0.0052). Txo RTL kuj tseem cuam tshuam nrog kev tuag vim muaj kab mob. Txhua qhov 0.1 chav tsev txo qis ntawm RTL yog txuam nrog 1.27-fold muaj kev pheej hmoo ntau dua rau kev tuag vim kev kis kab mob (HR, 1.27; 95% CI, 1.07–1.50; P ¼ 0.0051). Saib ntawm kev kwv yees rau ntau lub quartiles hauv Supplementary Table S1 qhia txog kev tuag vim kev kis kab mob uas qhov kev kwv yees rau txhua lub quartiles 1, 2, thiab 3 tau zoo sib xws rau cov quartile 4. Kev tsom xam nrog rau lwm yam ua rau tuag li. zoo li tsis paub ua rau kev tuag tau pom tseeb dhau lawm thiab tsis tau qhia txog kev koom tes nrog RTL (cov ntaub ntawv tsis qhia).
Daim duab ntawm Schoenfeld residuals scaled thiab ntsuam xyuas ntawm proportional txaus ntshai assumption tsis qhia tej lub sij hawm sib txawv los rau RTL rau ib yam ntawm cov kev soj ntsuam tshwm sim. Lub subdistribution HRs rau ob lub plawv thiab kab mob kev tuag, qhia nyob rau hauv Ntxiv Table S2, tsuas yog me ntsis attenuated piv rau qhov ua rau HRs.
We also evaluated whether the effect of RTL on the 3 different outcomes differed between men and women and for patients with and without diabetes mellitus, but we did not detect a significant interaction for these variables, or for age (all P values of interaction >0.1 hauv cov qauv hloov kho tag nrho). Muab hais tias peb tsis ntev los no tau pom U-zoo li lub koom haum ntawm lub sijhawm ntawm CKD thiab RTL, 22 peb tau ua qhov kev soj ntsuam rhiab heev ntxiv rau kev hloov kho rau lub sijhawm ntawm CKD ntawm lub hauv paus uas txhais tau tias tsawg dua 6 lub hlis, nruab nrab ntawm 6 lub hlis thiab 5 xyoo, thiab ntau dua 5. xyoo. Qhov kev hloov kho ntxiv no ua rau tsuas yog qhov kev hloov pauv ntawm HRs tau txais rau tag nrho 3 qhov kawg (Table Ntxiv S3).
Cistanche txiaj ntsig: txhim kho lub raum ua haujlwm
Kev sib tham
Cov txiaj ntsig ntawm txoj kev tshawb fawb no tau pom tias muaj kev sib koom ua ke tseem ceeb ntawm RTL nrog txhua qhov ua rau tuag hauv ib pawg neeg tsis-dialysis-dependent CKD. Shorter RTL tau cuam tshuam nrog kev pheej hmoo siab ntawm kev tuag ntawm nws tus kheej los ntawm lub raum ua haujlwm thiab ib txwm muaj kev pheej hmoo CVD. Lub koom haum no tau tsav los ntawm kev tuag vim CVD nrog rau kev tuag vim kev kis kab mob.
Kev koom tes nrog txhua qhov ua rau tuag
Kev tshawb fawb ua ntej,5,6,31–35nrog qee qhov kev zam,36,37 tau pom tias muaj kev cuam tshuam tsis zoo ntawm RTL thiab txhua qhov ua rau tuag hauv cov pej xeem. Txoj kev tshawb fawb loj tshaj plaws kom deb li deb (n ¼ 64,637) tau ua los ntawm Rode li al., nrog rau kev hloov kho HR rau kev tuag ntawm 1.40 rau cov decile nrog luv tshaj piv rau cov decile nrog ntev RTL.35Raws li cov txiaj ntsig no, peb txoj kev tshawb fawb tau pom nrog txhua qhov txo qis ntawm 0.1 RTL units muaj 14 feem pua kev pheej hmoo siab dua rau tag nrho cov neeg tuag, uas txhais tau hais tias 75 feem pua siab dua rau cov neeg qis tshaj piv rau qhov siab tshaj. quartile ntawm RTL. Rau peb txoj kev paub, tsuas yog Carrero li al.28tau tshawb xyuas kev sib raug zoo ntawm RTL thiab kev pheej hmoo tuag hauv cov neeg mob CKD. Lawv tau kawm 175 tus neeg mob uas muaj kab mob raum kawg uas kho los ntawm hemodialysis, ntawm lawv 70 tuag thaum lub sijhawm nruab nrab ntawm 31 lub hlis ntawm kev soj ntsuam. Cov kws sau ntawv tau pom tias TL tus kheej kwv yees tus neeg mob muaj sia nyob tom qab hloov kho ntxiv rau hnub nyoog, poj niam txiv neej, thiab mob. Txoj kev tshawb fawb tam sim no txuas ntxiv cov kev soj ntsuam no rau cov neeg coob coob uas muaj CKD uas tsis tas yuav lim ntshav.
Daim duab 2|Kho cov nonlinear splines (thiab 95 feem pua kev ntseeg siab bands) rau kev sib koom ua ke ntawm cov txheeb ze telomere ntev (RTL) thiab kev phom sij (HR) ntawm (a) tag nrho cov neeg tuag, (b) mob plawv tuag, thiab (c) tuag vim muaj kab mob. . HR yog muab raws li teev-scale ntawm cov se. Greyline: hloov qauv 1 (hloov rau hnub nyoog thiab poj niam txiv neej). Blueline: hloov qauv 3 (hloov rau hnub nyoog, poj niam txiv neej, kwv yees [txuas ntxiv]
Koom nrog CVD kev tuag
Tsis muaj kev tshawb fawb tau tshawb xyuas lub koom haum ntawm RTL nrog CVD kev tuag hauv cov neeg mob CKD txog tam sim no, txawm hais tias qhov no yog qhov ua rau tuag rau cov neeg mob no. Raws li kev tshawb nrhiav haiv neeg thiab ntawm cov qauv kev hloov kho cov ntaub ntawv, qee qhov, tab sis tsis yog tag nrho, cov kev tshawb fawb hauv cov pej xeem tau tshaj tawm txog kev koom tes ntawm cov txiaj ntsig qis RTL thiab CVD.33,38–41Kev txhawb zog rau lub koom haum ua rau muaj kev cuam tshuam los ntawm kev tshawb fawb Mendelian randomization nyob rau hauv uas cov noob caj noob ces cuam tshuam nrog luv luv RTL tau pom tias muaj feem cuam tshuam nrog cov kab mob plawv ischemic.40Hauv txoj kev tshawb fawb tam sim no, peb tau txheeb xyuas qhov kev koom tes tseem ceeb ntawm RTL nrog kev tuag ntawm cov hlab plawv, nrog 20 feem pua siab dua nrog rau txhua qhov txo qis ntawm RTL los ntawm 0.1 units, lossis 75 feem pua kev pheej hmoo siab dua rau cov cov neeg mob hauv lub quartile nrog qhov luv tshaj TL piv rau lub quartile nrog qhov ntev tshaj plaws TLs. Qhov kev tshawb pom no yog ua raws li peb tsab ntawv tshaj tawm ua ntej ntawm kev koom tes nrog cov xwm txheej ntawm cov hlab plawv hauv cov neeg mob no: txhua qhov txo qis ntawm RTL los ntawm 0.1 units tau cuam tshuam nrog 6 feem pua siab dua qhov txawv ntawm CVD nyob rau hauv tus qauv kho hnub nyoog, poj niam txiv neej, tam sim no. Kev haus luam yeeb, ntshav siab, ntshav qab zib mellitus, cov roj lipoprotein tsawg ntom ntom, siab ntom ntom
Lipoprotein cholesterol, C-reactive protein, eGFR, thiab lub cev qhov hnyav.21Cov kev soj ntsuam yav tom ntej hauv cov neeg mob hauv qhov kev tshawb xyuas tam sim no tau qhia tias tshwj xeeb tshaj yog qhov qis tshaj plaws ntawm RTL tau cuam tshuam nrog kev pheej hmoo ntau ntxiv, thaum lwm qhov 3 quartiles tau pom qhov kwv yees zoo sib xws (Daim duab 1b).
Koom nrog kev tuag vim muaj kab mob
Txawm hais tias kev sim ua pov thawj txhawb nqa lub luag haujlwm ntawm cell senescence thiab luv TL hauv kev tiv thaiv kab mob tsis zoo, kev tshawb fawb txog kab mob kis tau qis, tshwj xeeb tshaj yog hauv cov neeg mob CKD. Helby et al. tau ua qhov loj tshaj plaws (n ¼ 75,309) yav tom ntej cov pej xeem-raws li kev tshawb nrhiav RTL thiab kev pheej hmoo ntawm kev mus pw hauv tsev kho mob rau cov kab mob sib kis thiab kev pheej hmoo ntawm kev kis kab mob tuag. Thaum lub sij hawm 7 xyoo ntawm kev soj ntsuam, lawv tau pom muaj kev pheej hmoo siab dua ntawm kev kis kab mob hauv quartile nrog luv tshaj piv nrog lub quartile nrog qhov ntev tshaj RTL.42 Cov kev tshawb fawb yav dhau los nrog cov qauv me me qhia txog qhov tsis sib haum xeeb.32,43,44Peb qhov kev tshawb pom hauv cov neeg mob CKD piav qhia thawj zaug ntawm kev sib koom ua ke ntawm RTL luv luv thiab muaj kev pheej hmoo siab dua rau kev tuag vim muaj kab mob hauv cov neeg muaj kev pheej hmoo siab no.
Cistanche txiaj ntsig: txhim kho lub raum ua haujlwm
Muaj peev xwm mechanism
Cov txheej txheem lom neeg hauv qab ntawm kev sib raug zoo ntawm RTL thiab kev tuag tseem tsis tau paub meej. Lub koom haum txheeb xyuas los ntawm peb txoj kev tshawb fawb tsis qhia meej seb RTL shortening puas cuam tshuam txog kab mob plawv thiab kab mob. Txawm li cas los xij, txoj kev tshawb fawb genome-wide koom nrog ua raws li kev soj ntsuam cov qhab nia ntawm kev pheej hmoo ntawm noob caj noob ces sib xyaw ua ke ntawm 7 genetic loci tau pom tias muaj kev koom tes ntawm cov alleles cuam tshuam nrog luv luv RTL nrog kev pheej hmoo ntawm cov kab mob plawv. Qhov kev tshawb pom no muab kev txhawb nqa muaj peev xwm ua rau lub luag haujlwm ntawm RTL hauv CVD.45,46Tsis tas li ntawd, cellular senescence tshwm sim los ntawm telomere attrition tuaj yeem ua rau mob atherosclerosis thiab arteriosclerosis. Kev sib sau ntawm cov hlwb senescent hauv lub nkoj ua rau muaj kev tsim cov atherosclerotic plaques thiab media calcifications uas ua rau muaj zog ntawm cov hlab ntsha uas ua rau muaj qhov tseem ceeb ntawm cov kab mob uremic arterial.47Feem ntau ntawm cov kev tshawb fawb tau ntsuas RTL hauv DNA los ntawm peripheral leukocytes. Txawm li cas los xij, ib qho kev sib raug zoo tau pom ntawm leukocyte thiab aortic phab ntsa TL.48Yog li, cellular senescence tuaj yeem cuam tshuam rau cov hlwb endothelial ua rau kev ua haujlwm tsis zoo hauv cov phab ntsa vascular thiab txhawb kev ua kom lub cev tiv thaiv kab mob, qhov tshwm sim tseem ceeb hauv atherosclerosis. Tsis tas li ntawd, luv telomeres qhib p53 thiab autophagy nyob rau hauv lub plawv progenitor hlwb, destabilizing qhov seem ntawm quiescence thiab proliferation mus rau txawv thiab senescence, ua rau ib tug qaug zog ntawm lub plawv progenitor hlwb.49Telomere dysfunction tau pom tias ua rau muaj kev cuam tshuam loj heev p53- nyob ntawm kev tsim txom ntawm tus tswv tswj hwm ntawm mitochondrial biogenesis thiab kev ua haujlwm, uas ua rau muaj kev cuam tshuam bioenergetic vim tsis muaj oxidative phosphorylation thiab adenosine triphosphate tiam.50,51
Kuj tseem muaj ntau qhov txuas ntawm RTL thiab kab mob. Kev poob ntawm telomeres tau pom thaum lub sijhawm T cell sib txawv,52nyob rau hauv cov kab mob viral ntev,53thiab nrog hnub nyoog.54Tsis tas li ntawd, luv leukocyte TL tau raug tshaj tawm tias yog ib qho kev pheej hmoo ntawm ntau yam kab mob tiv thaiv kab mob.55thiab ntshav qab zib.56Leukocyte luv TL ua rau cell senescence uas ua raws li kev txo qis ntawm lub cev tiv thaiv kab mob hauv lub cev. TL kuj tseem tuaj yeem koom nrog hauv kev poob qis hauv lub hnub nyoog ntawm kev tiv thaiv kab mob ntsig txog cov lus teb tsis txaus rau cov tshuaj tiv thaiv thiab kev kis mob hnyav.57–59Lub luag haujlwm muaj peev xwm ntawm TL hauv kev kis kab mob kuj tau txais kev txhawb nqa los ntawm kev tshawb fawb genome-wide nyob rau hauv Suav cov pej xeem. Dorjee thiab cov npoj yaig tau soj ntsuam kev sib koom ua ke ntawm TL-txo cov allele thiab kev tuag vim muaj kab mob ua pa.60RTL attrition tej zaum yuav tshwm sim los ntawm qhov muaj siab oxidative kev nyuaj siab, ib qho mob hauv CKD.61 Ntau qhov kev tshawb fawb hauv vitro thiab hauv vivo tau pom tias oxidative kev nyuaj siab ua rau telomere attrition.62,63Tseeb tiag, telomeres, nrog lawv cov ntsiab lus guanine siab, muaj kev cuam tshuam rau oxidative puas tsuaj,64thiab ib leeg-strand DNA tawg vim yog oxidative kev nyuaj siab yuav yog ib qho tseem ceeb rau telomere shortening thaum DNA replication.65
Cistanche txiaj ntsig: txhim kho lub raum ua haujlwm
Muaj zog thiab kev txwv
Lub zog ntawm qhov kev tshawb fawb no suav nrog cov qauv loj ntawm cov neeg uas tau hais tseg zoo nrog qhov nruab nrab ntawm kev soj ntsuam ntawm 4 xyoo uas yuav luag tsis muaj kev poob rau kev soj ntsuam, kev sib raug zoo ntawm cov neeg kawm, thiab kev ntsuam xyuas hauv nruab nrab ntawm TL thiab cov txiaj ntsig ntsuas. Kev ntsuas ntawm RTL tshwj xeeb yog qhov tseem ceeb tshaj plaws vim tias kev tsim qauv ntawm lub chaw soj nstuam tsis yooj yim ua kom tiav thiab yog li cov txheej txheem yuav tsum tau ua nyob rau hauv tib lub chaw soj nstuam raws li cov xwm txheej zoo ib yam ntawm cov txheej txheem, siv cov noob, ntsuas, cov neeg ua haujlwm, 66, thiab DNA. txheej txheem extraction.67
Muaj qee qhov kev txwv rau txoj kev tshawb no. Ua ntej, RTL tau ntsuas hauv peripheral leukocytes. Nws paub tias tus nqi ntawm kev nce mus rau senescence txawv ntawm lymphocyte subsets. 59Hmoov tsis zoo, tsis muaj cov ntaub ntawv hais txog cov ntshav cell muaj pes tsawg leeg hauv GermanMob raum mobkawm thiab yog li ntawd tsis tuaj yeem tshawb xyuas qhov no. Paub RTL los ntawm ntau hom kab mob raum yuav muaj kev txaus siab, tab sis nws tsis tuaj yeem tau txais hauv kev tshawb fawb txog kev kis kabmob loj vim qhov no yuav xav tau cov ntaub so ntswg los ntawm biopsies. Qhov kev txwv thib ob suav nrog kev soj ntsuam kev tsim qauv ntawm txoj kev tshawb fawb, uas tsis tso cai rau kev nthuav dav ntawm causality lossis biological mechanism. Qhov thib peb, txoj kev tshawb no nrhiav cov neeg mob CKD feem ntau nyob rau theem G3 lossis A3, thiab qhov kev tshawb pom yuav tsis tuaj yeem ua rau lwm theem ntawm CKD. Plaub, kev koom tes nrog cov laj thawj tshwj xeeb ntawm kev tuag tej zaum yuav raug txwv los ntawm kev suav lub zog tab sis tseem muaj nyob rau 2 qhov tseem ceeb ntawm kev tuag. Thaum kawg, txawm hais tias peb cov kev tshuaj ntsuam xyuas tau raug kho rau cov kab mob plawv thiab cov kab mob hauv lub raum, peb tsis tuaj yeem tshem tawm qhov tshwm sim ntawm qhov tsis txaus ntseeg los ntawm qhov tsis paub lossis tsis ntsuas.
sib txawv. Txawm li cas los xij, nws yog qhov nthuav heev kom pom tias qhov kev kwv yees ntawm lub hnub nyoog thiab kev sib deev hloov pauv ntawm RTL rau ntau qhov txiaj ntsig tau ruaj khov nrog kev hloov kho ntxiv rau lwm qhov sib txawv, qhia tias RTL muaj kev ywj pheej ntawm lwm qhov sib txawv thaum cov ntaub ntawv raug kho rau hnub nyoog thiab poj niam txiv neej.
Cov lus xaus
Cov txheeb ze luv luv TL suav los ntawm cov ntshav peripheral leukocytes ntawm nws tus kheej cuam tshuam nrog tag nrho cov neeg tuag thaum lub sij hawm 4 xyoo ntawm kev soj ntsuam hauv cov neeg mob uas mob hnyav CKD. Lub koom haum no tau tsav los ntawm kev tuag vim CVD nrog rau kev tuag vim kev kis kab mob.
Cistanche txiaj ntsig: txhim kho lub raum ua haujlwm
Txoj kev
Kawm cov pej xeem
Lub GermanMob raum mob study is an ongoing prospective multicenter observational cohort. A detailed description of the study has been published previously.68 Briefly, 5217 patients under regular care by nephrologists were enrolled. Inclusion criteria were moderately reduced kidney function defined as eGFR of 30–60 ml/min per 1.73 m2 (stage G3, A1–A3) or an eGFR >60 ml / min ib 1.73 m2 nyob rau hauv lub xub ntiag ntawm overt proteinuria (theem G1-G2, A3). Cov txheej txheem cais tawm yog cov haiv neeg tsis yog neeg Caucasian, cov khoom siv hauv nruab nrog cev lossis cov pob txha hloov pauv, mob qog noj ntshav tsis pub dhau 24 lub hlis ua ntej kev tshuaj ntsuam, New York Heart Association Theem IV lub plawv tsis ua haujlwm, thiab tuaj koom kev cai lij choj lossis tsis muaj peev xwm muab kev pom zoo. Laboratory parameters uas tau nthuav tawm yog txhua yam ntsuas los ntawm kev sau biosamples nyob rau hauv lub hauv paus chaw soj nstuam raws li tau piav yav dhau los.68 Cov ntaub ntawv hais txog kev noj qab haus huv cov xwm txheej, kev kho mob thiab tsev neeg keeb kwm, tshuaj, thiab kev noj qab haus huv ntawm lub neej tau txais los ntawm cov neeg ua haujlwm tau txais kev cob qhia los ntawm cov qauv lus nug. Cov kab mob plawv uas muaj nyob hauv lub hauv paus tau txhais tau tias yog keeb kwm ntawm kev tsis tuag myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, stroke, thiab kev cuam tshuam ntawm cov hlab ntsha carotid (carotid endarterectomy thiab / lossis carotid balloon angioplasty lossis stent implantation).
Txhua tus neeg tuaj koom tau txais kev pom zoo sau tseg, thiab txoj kev tshawb fawb tau pom zoo los ntawm Pawg Neeg Saib Xyuas Kev Ncaj Ncees ntawm txhua lub koom haum koom nrog thiab tau sau npe rau hauv lub teb chaws sau npe rau kev tshawb fawb soj ntsuam (DRKS 00003971). Txhua txoj hauv kev tau ua raws li cov txheej txheem pom zoo thiab Tshaj Tawm ntawm Helsinki. Cov ntaub ntawv raug sau thiab tswj hwm siv Askimed (https://www.askimed.com) raws li huab-based web platform rau kev sau thiab tswj cov ntaub ntawv tshaj tawm cov ntaub ntawv thiab cov ntaub ntawv kuaj.
Clinical endpoints thaum lub sij hawm tom ntej
Raws li tau piav qhia tsis ntev los no, 69 tus neeg mob tau ua raws txhua xyoo los ntawm cov neeg ua haujlwm tau txais kev cob qhia hloov kev sib ntsib tim ntsej tim muag nrog kev mus ntsib hauv xov tooj. Thaum mus ntsib no, cov ntaub ntawv ntawm kev mus pw hauv tsev kho mob, cov xwm txheej tau tshwm sim, thiab keeb kwm kev kho mob tau hloov kho raws li ib feem ntawm kev xam phaj. Cov ntawv ceeb toom tawm hauv tsev kho mob raug sau los ntawm cov kws kho mob thiab / lossis tsev kho mob. Cov ntsiab lus xaus tsis tu ncua los ntawm cov ntawv ceeb toom no los ntawm pawg neeg cob qhia thiab saib xyuas qhov kawg uas muaj 3 tus kws kho mob ywj pheej raws li daim ntawv teev npe kawg uas tau teev tseg. Cov ntaub ntawv hais txog qhov ua rau tuag yog muab los ntawm cov ntawv ceeb toom no nrog rau cov ntawv pov thawj kev tuag uas tau sau los ntawm cov chaw lis haujlwm pej xeem sau npe thaum twg cov neeg ua haujlwm raug ceeb toom txog kev tuag ntawm tus neeg koom nrog kev kawm.
Kev tshuaj xyuas tam sim no suav nrog tag nrho cov ntsiab lus kawg uas tau tshwm sim txog rau thaum 4- xyoo rov qab. Yog tias tus neeg mob tsis tuaj yeem mus ntsib 4- xyoo tom qab, peb suav tag nrho cov ntsiab lus xaus mus txog 4.5 xyoo tom qab kev mus ntsib hauv paus. Yog li ntawd, lub sij hawm censoring yog 4- xyoo rov qab hnub los yog 4.5 xyoo tom qab lub hauv paus. Thawj qhov tshwm sim yog tag nrho cov neeg tuag. Txhawm rau soj ntsuam seb puas muaj cov koom haum txheeb xyuas tuaj yeem raug suav tias yog qhov ua rau tuag, kev tuag los ntawm cov kab mob plawv thiab cov kab mob sib kis tau suav tias yog qhov tshwm sim thib ob. Cov pab pawg ntawm CVD tuag suav nrog myocardial infarction, kab mob plawv, mob plawv tuag, mob plawv tsis ua hauj lwm, pulmonary embolism, kab mob plawv, thiab ischemic stroke. Lwm qhov laj thawj ntawm kev tuag kuj tau sau tseg, tab sis cov pab pawg no tsis loj txaus los ua cov kev soj ntsuam tshwj xeeb ntxiv.
Kev ntsuas RTL
Genomic DNA tau muab rho tawm los ntawm tag nrho cov ntshav hauv lub hauv paus chaw kuaj mob nrog Chemagic Sib Nqus Sib Nqus Module I (PerkinElmer chromagen Technologie GmbH, Baesweiler, Lub teb chaws Yelemees). Kev tshuaj xyuas tam sim no yog ua raws li 4926 tus neeg mob uas ntsuas RTL hauv cov qauv ntshav hauv qab thiab cov ntaub ntawv ntawm kev tuag muaj. RTL tau ntsuas nyob rau hauv quadruplicate siv ib tug quantitative polymerase chain reaction-based assay tsim los ntawm Cawthon70 thiab hloov kho raws li tau piav qhia yav dhau los.71 DNA kuaj tau khiav hauv 15-ml cov tshuaj tiv thaiv uas muaj 1x Quantifast TM SYBR Green PCR master mix (Qiagen, Hilden, Lub teb chaws Yelemees), 10 ng ntawm DNA, 1 mM ntawm telomere primer, los yog 250 nm ntawm vaj tsev tu noob 36B4 primer. Peb tau txiav txim siab qhov txheeb ze ntawm telomere rov luam tus lej (T) rau ib daim ntawv luam gene luam tus lej (36B4 noob, encoding ribosomal phosphoprotein PO, nyob ntawm chromosome 12; S). T / S piv yog proportional rau tus kheej RTL. Lub automation ntawm no high throughput txheej txheem ua nyob rau hauv zoo heev zoo-tswj ntsuas nrog ib tug tsawg inter-assay coefficient ntawm variation ntawm lub T / S ratios. Ib qho kev lag luam DNA uas muaj nyob rau hauv tag nrho cov txheej txheem polymerase saw cov tshuaj tiv thaiv daim hlau tau siv los tshuaj xyuas qhov ua tau zoo ntawm qhov kev soj ntsuam ntawm tag nrho cov kev tshawb fawb. Lub interassay coefficient ntawm variation ntawm T / S piv ntawm cov qauv no soj ntsuam nyob rau hauv 112 kev sim ywj siab yog 9.6 feem pua ua ntej normalization thiab txo mus rau 4.0 feem pua tom qab normalization (Ntxiv daim duab S2).
Kev txheeb cais
Peb piv cov yam ntxwv ntawm cov neeg koom nrog (Table 1) siv Kruskal–Wallis xeem rau kev sib txawv tsis tu ncua thiab chi-squared xeem rau categorical variables. Cov xwm txheej ua haujlwm nkhaus tau siv los kwv yees cov xwm txheej sib txawv ntawm qhov sib txawv ntawm kev tuag suav nrog kev pheej hmoo sib tw.72 Cox proportional hazards regression qauv tau ua los ntsuas cov koom haum ntawm RTL nrog 3 qhov tshwm sim: (i) tag nrho-ua rau kev tuag, ( ii) tuag vim CVD, thiab (iii) tuag vim muaj kab mob. Rau ob qho laj thawj tshwj xeeb qhov kawg (ii thiab iii), cov neeg mob tau raug censored, yog tias kev tuag tshwm sim los ntawm lwm qhov laj thawj. Tsis tas li ntawd, cov koom haum nrog cov laj thawj tshwj xeeb ntawm qhov kawg no tau raug tshuaj xyuas los ntawm kev sib tw-kev pheej hmoo ntawm kev muaj sia nyob regression, txiav txim siab tag nrho cov neeg tuag los ntawm lwm yam ua rau muaj kev sib tw. Yog li, ob qho tib si ua rau HRs thiab subdivision HRs tau tshaj tawm txog kev tuag vim CVD lossis kab mob. Cox proportional txaus ntshai qauv tau haum siv 3 theem sib txawv ntawm kev hloov: qauv 1 hloov kho rau hnub nyoog thiab poj niam txiv neej; qauv 2 kuj tau hloov kho rau lub hauv paus eGFR, zis albumin-creatinine piv, CVD ntau, thiab ntshav qab zib; Qauv 3 txuas ntxiv kho rau cov kev pheej hmoo CVD, cov roj cholesterol, kev haus luam yeeb hauv lub cev, kev haus luam yeeb hauv lub cev, kev haus luam yeeb hauv lub cev, C-Realive Protein, thiab albumin. Kev xaiv ntawm cov hloov pauv hloov kho rau hauv ntau cov qauv yog raws li qhov sib txawv ntawm cov yam ntxwv kho mob ntawm cov quartiles ntawm RTL nyob rau hauv Table 1. Nyob rau hauv cov qauv regression, RTL tau soj ntsuam tsis tu ncua thiab raws li categorical kwv yees (hauv quartiles ntawm RTL). Muab cov txiaj ntsig thawj zaug tau qhia tias muaj kev pheej hmoo siab dua, tshwj xeeb tshaj yog rau cov nqi qis ntawm RTL, qhov (ua rau tshwj xeeb) HR kuj tau tshaj tawm rau quartiles 1, 2, thiab 3 piv rau quartile 4 raws li kev siv (Table Ntxiv S1). Kev soj ntsuam ntxiv hauv qab yog ua raws li kev soj ntsuam pom ntawm P-spline kom muab cov duab ntawm kev sib raug zoo ntawm RTL thiab kev pheej hmoo tuag. Peb tau siv Spearman qhov kev sib raug zoo coefficient los ntsuas kev sib koom ntawm kev kawm sib txawv. Txhua qhov kev txheeb xyuas txheeb cais tau ua tiav siv R 3.3.2 (https://www.r-project.org); P-tus nqi<0.05 were="" considered="" statistically="">
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