Lub raum nyob rau hauv ib txwm laus Ib qho piv nrog rau mob raum mob
Mar 22, 2022
Hu rau: Audrey Hu Whatsapp / hp: 0086 13880143964 Email:audrey.hu@wecistanche.com
Aleksandar Denic, uas1Richard J. Glassock,2thiab Andrew D. Rule1
Feem ntau ntawm kev kuaj mob CKD yog siab ntawm cov neeg laus dua 65 xyoo. Txij li thaum GFR poob qis nrog kev laus ib txwm muaj, qhov tshwm sim no yog vim yog ib feem ntawm kev siv ib qho, qhov tseeb ntawm eGFR, 60 ml / min ib 1.73 m2 txuas ntxiv mus ntev li 3 lub hlis txhawm rau txheeb xyuas CKD tsis hais hnub nyoog li cas lossis qhov sib xyaw ua ke ntawm lwm yam cim ntawmraumraug mob, nrog rau qhov txawv txav albuminuria. Arguably, cov txheej txheem eGFR rau CKDdiagnosis yuav tsum tau hloov kho lub hnub nyoog, txhawm rau txhawm rau txhawm rau txhawm rau txhawm rau lub cev muaj hnub nyoog cuam tshuam txog kev poob qis hauv eGFR thiab zam dhau kev kuaj mob ntawm CKD hauv cov neeg laus (1). Ntau tus neeg laus uas muaj eGFR ruaj khov ntawm 45 txog 59 ml / min ib 1.73 m2 thiab tsis muaj qhov txawv txav ntawm albuminuria yog erroneously sau tias muaj CKD (1). Txawm li cas los xij, "bona-fife" CKD, ntawm ntau yam etiologies, tuaj yeem ua ke nrog kev hloov pauv ntawm lub raum los ntawm kev laus ib txwm muaj. Ntawm no, peb sim piav qhia txog cov kev hloov pauv ntawm cov laus hauv lub raum tshwm sim hauv lwm tus neeg noj qab haus huv piv nrog cov neeg muaj CKD.
Hauv kev teb rau kev ntxhov siab thiab / lossis kev puas tsuaj, cov hlwb tuaj yeem raug apoptosis lossis nkag mus rau hauv lub xeev ntawm senescence, pov thawj los ntawm kev hloov pauv hauv morphology thiab transcriptional profile, secretory phenotype, thiab tiv thaiv apoptosis. Txij li thaum muaj peev xwm rov tsim cov hlwb tshiab thiab cov ntaub so ntswg zoo li txo qis nrog kev laus, rov ua kom muaj kev sib npaug ntawm cov cellular ua haujlwm tsis zoo thiab kho cov kev loj hlob zuj zus thaum lub sijhawm laus. Superimposition ntawm ntau yam teeb meem xws li oxidative kev nyuaj siab (oxygen radicals thiab profibrogenic mediators) thiab mitochondrial raug mob raws li cov kev hloov hauv lub hnub nyoog, raws li tshwm sim nyob rau hauv cov kab mob, yuav ntxiv txhawb cellular thiab lub cev deterioration (2). Lwm cov kab mob tshwj xeeb raug mob, xws li o thiab ischemia, tuaj yeem ntxiv cov kev hloov pauv no. Yog li, physiologic aging thiab kab mob kev raug mob feem ntau sib koom ua ke, thiab lawv cov kev sib raug zoo yog complex thiab tsis yooj yim kawm. Yog li ntawd, ib tug ncauj lus kom ntxaws exposition ntawm lubraumKev hloov pauv hauv lub cev kev laus hauv cov neeg muaj kev noj qab haus huv yog qhov muaj txiaj ntsig zoo hauv kev nthuav tawm cov txiaj ntsig ntawm kev laus ntawm ib tus neeg saib xyuas kev hloov pauv mus koom CKD.
Ntau qhov kev tshawb fawb tau tshawb xyuas ntau yam ntawm micro-thiab macrostructural hloov pauv thiab kev ua haujlwm hloov pauv ntawm tib neeg.raumnyob rau hauv ib txwm, physiologic laus, txawm ntawm cov neeg noj qab haus huv. Noj qab nyob zoo nyob rau hauv lub raum pub poob mus txog ib nrab ntawm cov nephrons functional lawv yug los nrog (nephron endowment) los ntawm lub sij hawm lawv nyob rau hauv lawv cov seventies. Qhov no attrition ntawm nephrons yog nrog los ntawm kev nce hauv ntiaj teb glomerulosclerosis, tab sis tsis yog segmental glomerulosclerosis, thiab qhov nce hauv interstitial fibrosis / tubular atrophy (IF / TA) tsawg tsawg piv nrog CKD (3). Qhov kev poob nephron no thaum kawg ua rau txo qis hauv cortex ntim nrog kev laus. Tag nrho lub raum GFR ua tib zoo ua raws li qhov kev poob qis hauv nephron tus naj npawb, tuav ib leeg nephronGFR tsis hloov yam tsawg kawg ua ntej hnub nyoog 70 xyoo (4). Hypertrophy ntawm qhov seem ua haujlwm glomeruli tsis pom nyob rau hauv kev noj qab haus huv laus. Raws li txoj cai, albuminuria kuj tsis yog ib qho kev noj qab haus huv, tsis zoo li CKD.
Kev tshawb fawb hauv cov neeg mob uas tau txais nephrectomy rau lub raum mob cancer muab pov thawj rau kev poob tag nrhoraumGFR nrog cov laus dua 70 xyoo txawm tias tsawg kawg ntawm IF / TA (5). Thaum IF / TA zoo li tsis tshua muaj txiaj ntsig thaum vim nephron poob los ntawm kev laus dua li ntawm CKD, tus qauv ntawm IF / TA nrog kev laus kuj tseem ceeb. Kev tsom xam ntawm cov npoo loj ntawm cov tsis muaj kev cuam tshuamraumcov ntaub so ntswg los ntawm cov neeg mob uas tau txais radical nephrectomy rau cov qog qhia tau hais tias cov neeg mob laus muaj cov qauv tawg ntau ntawm IF / TA ntawm tib feem pua IF / TA cov neeg mob yau (6). Qhov no qhia: (1) IF / TA fociatrophy rau hauv me me IF / TA foci nrog kev cog lus ntawm lub cortex, uas ua rau kom lawv ceev; thiab (2) qhov atrophy no pab piav qhia qhov tsawg kawg nkaus ntawm feem pua IF / hauv cov neeg laus txawm tias poob ntawm nephrons tseem ceeb. Cov kev tshawb pom no kuj zoo ib yam nrog lub hnub nyoog ntsig txog lub ntiaj teb glomerulosclerosis qhov twg atrophy thiab ploj ntawm sclerosed glomeruli ua rau muaj kev tshawb pom ntawm nephron poob (3). Nce IF / TA qhov ntom ntom-yooj yim ntawm feem pua IF / TA kuj tseem muaj kev cuam tshuam rau kev nce qib CKD (6). Ua ke, ntawm tib feem pua IFTA, cov txheej txheem ntev ntev nrog ntau dua nephron poob muaj qhov tshwm sim tsis zoo dua li cov txheej txheem "mob" ntau dua nrog foci loj ntawm IF / TA (6)
Nyob rau hauv lub xyoo caum dhau los, muaj kev txaus siab rau podocyte dysfunction nyob rau hauvraumkev laus. Podocytes muaj kev sib txawv tag nrho, nyob ntev, cov hlwb tom qab mitotic, nrog lub peev xwm tsim dua tshiab. Hodgin thiab cov npoj yaig pom tias txo qis podocyte ntom nrog cov hnub nyoog laus, los ntawm .300 rau 106 mm3 hauv cov hluas.lub raumrau, 100 rau 106 mm3 hauv qublub raum(7). Tsis tas li ntawd, cov hnub nyoog laus dua podocytes tau ntxhov siab nrog ntau dua detachment tus nqi. Qhov tseem ceeb, lub raum kawm tsis txwv rau cov tib neeg noj qab haus huv thiab qhov cuam tshuam ntawm kev sib txuam nrog kev laus tuaj yeem cuam tshuam qhov kev tshawb pom no. Yog hais tias glomerular hyperfiltration yog superimposed raws li ib txwm muaj kev laus, ces podocyte detachment tus nqi yuav ceev, ua rau kom txo tau qhov tseem ceeb ntawm GFR thiab nce nyob rau hauv albuminuria.
Daim duab qhia txog cov txheej txheem uas cuam tshuam rau kev laus los yog ua rau kom ceev kev laus thiab nephron poob yog qhia nyob rau hauv daim duab 1. Ischemia thiab kev loj hlob ntawm cellular senescence yuav yog lwm yam tseem ceeb ntawmraumkev laus. Cov xwm txheej tseem ceeb hauv qab ntawm ischemia-txog hypothesis rauraumKev laus yog tias arterio- thiab arteriolosclerosis ua rau ischemia-driven vau ntawm glomerular architecture thiab, thaum kawg, ntiaj teb glomerulosclerosis. Raws li qhov tshwm sim ntawm kev mob ischemia, kev hloov pauv ntawm cov molecular tshwm sim, xws li kev hloov pauv ntawm p16, p19, thiab p21 qhia hauv tubular hlwb (8). Mesangial expansion thiab IF / TA hauv cov nas laus tuaj yeem txuas nrog o, apoptosis, thiab oxidative stress (9). Cov pov thawj rau oxidative kev nyuaj siab raws li qhov muaj peev xwm ua rau muaj txiaj ntsig tau txais kev txhawb nqa los ntawm kev txo qis ntawm Sirt1, PGC-1a, ERR-1a, PPARa, thiab klotho hauv cov nas laus tshaj plaws (24 lub hlis) . Nws tau raug pom zoo tias cov kev kho tshiab tshiab uas tsom rau cov teeb liab ntawm cov teeb meem no tuaj yeem txo cov txheej txheem uas cuam tshuam rau tus nqi ntawm kev laus hauv lub raum. Ntawm qhov tseem ceeb, ischemia-hais txog cellular senescence markers accumulate inhumanlub raummuab los ntawm stenotic raum cov hlab ntsha (8). Senolytic agents (dasatinib thiab quercetin) tuav cov lus cog tseg hauv kev txo qisraumatrophy, kev puas tsuaj, thiab kev ua haujlwm poob qis los ntawm kev tshem tawm p21-cov hlwb zoo (8). Cov kev tshawb fawb yav tom ntej tuaj yeem txiav txim siab lub luag haujlwm rau cov neeg ua haujlwm senolytic hauv kev kho hnub nyoog txog kev hloov pauv hauv lub raum (10).
Molecular pov thawj qhia tiasraumKev laus thiab qee qhov ua rau CKD qhia txog cov txheej txheem biologic. Proteomic profiling ntawm extracellular matrix muaj pes tsawg leeg nyob rau hauv nas thiab tib neeg lub raum tau qhia ib tug proteomic kos npe rau ob leeg.raumkev laus thiab kab mob (11). Qhov kev tshawb pom tseem ceeb yog txo qis hauv cov khoom hauv qab daus (xws li laminins, thiab collagens hom IV thiab VIII) thiab nce ntxiv ntawm cov cellular matrix proteins (collagen I, III, VI, thiab XV, thiab fibrinogens thiab nephronectin). Collagen VI tau nce thaum ntxov ntawm ob qho tib si kev laus thiab kab mob, tejzaum nws yog ib qho kev sim ntxiv dag zog rau cov tawv nqaij hauv qab daus hauv qab qhov kev loj hlob ntawm IF / TA.
Qhov tsis muaj albuminuria hauv ib txwm muaj hnub nyoog ntsig txog eGFRdecline qhia tias qhov kev ua haujlwm poob qis no tsis nruj thiab ua rau muaj kev cuam tshuam rau podocytopenia; Txawm li cas los xij, hauv cov txheej txheem kab mob uas ua rau glomerular hyperfiltration, lub xub ntiag ntawm albuminuria qhia ncaj qha mus rau podocyte dysbiosis. Kev ua haujlwm ntxiv yog xav tau los qhia meej txog cov kev sib txawv no raws li cov txheej txheem rau kev nce zuj zus ntawm tus lej nephron. Muaj ntau qhov kev sib tw, tab sis ntau qhov kev siv tshuaj kho mob kuj tseem tuaj yeem tshwm sim vim peb tau yooj yim dua rau kev paub qhov txawv hnub nyoog cuam tshuam los ntawm kev hloov pauv ntawm cov kab mob.raum. Overlap nyob rau hauv lub cellular biology ntawm ib txwm aging thiab tsawg kawg yog ib co hom ntawm kev loj hlob CKD yog pov thawj. Kev txhim kho ntawm cov tshuaj kho senolytic tuav cov lus cog tseg hauv kev cia siab tias yuav txo qis cov teebmeem ntawm kev laus ib se thiab cov ntaub ntawv nrawm ntawm kev laus uas tuaj yeem nrog qee hom CKD.
Qhia tawm
A. Denic qhia txog kev ua haujlwm nrog Mayo Clinic. RJ Glassock qhia txog kev pom zoo nrog American Journal of Nephrology, Anteris Bio, Aurinia, BioCryst, Bioscience, Calliditas, Chemo-Centryx, Equillium, Forsee Pharma, Horizon, Ionis, Karger Publications, NIH, Novartis, Omeros, Otsuka Pharma, RenaS ), River3Renal, Sentient, Therini Bio, Traverse (Retrophin), UpToDate (Wolters-Kluwer), Vertex, Vivace, thiab Walden; kev ua tswv cuab hauv Reata, Inc; tau txais kev qhuas los ntawm Aurinia, EcoR1, Karger Publications, thiab Wolters-Kluwer (UpToDate); ua tus kws pab tswv yim lossis tus tswv cuab ntawm American Journal of Nephrology, BioCryst, Calliditas, JASN, Novartis, Otsuka, Rena-Sight, Traverse, UniversityLub raumLub koom haum tshawb fawb, thiab UpToDate; hais lus bureau rau Aurinia; thiab lwm yam kev txaus siab/kev sib raug zoo nrog ASN-Open Forum Communities. AD Txoj Cai qhia txog kev ua haujlwm nrog Mayo Clinic; ua tus Thawj Saib Xyuas Haujlwm ntawm JASN thiab Tus Thawj Saib Xyuas Haujlwm ntawm Mayo Clinic Proceedings; ua tus kws pab tswv yim lossis tus tswv cuab ntawm NIDDK - CKD Biomarker Consortium Sab Nraud Kws Tshaj Lij Vaj Huam Sib Luag; thiab lwm yam kev txaus siab / kev sib raug zoo nrog UpToDate.
Nyiaj txiag
Txoj kev tshawb no tau txhawb nqa los ntawm US Department of Health thiab Human Services National Institutes of Health National Institute of Diabetes thiab Digestive thiabLub raumCov kab mob pub rau R01- DK90358.
Kev lees paub
Cov ntsiab lus ntawm tsab xov xwm no qhia txog kev paub txog tus kheej thiab kev xav ntawm tus kws sau ntawv thiab yuav tsum tsis txhob suav hais tias yog cov lus qhia lossis kev pom zoo. Cov ntsiab lus tsis cuam tshuam txog kev xav lossis kev xav ntawm American Society of Nephrology (ASN) lossis CJASN. Kev lav phib xaub rau cov ntaub ntawv thiab cov kev xav tau hais tawm ntawm no yog nyob nrog tus sau tag nrho.
Cov ntaub ntawv
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