Cov qauv sib txawv ntawm lub raum Fibrosis yog qhov qhia txog kev raug mob rau lub raum sib txawv

edmund.chen@wecistanche.com

Abstract:Lub raum fifibrosis yog ib qho tshwm sim thiab pom ntawm ntau yam mob ntevmob raum(CKD) uas tshwm sim nyob rau hauv txawv morphological qauv, qhia txawv pathogenic ua rau. Loj macroscopically pom caws pliav yog cov sequelae ntawm kev raug mob loj focal thiab ua tiav parenchymal kev puas tsuaj, xav txog lub qhov txhab kho qhov txhab raws li qhov tshwm sim ntawm infarction. Hauvraum,mob glomerular raug mob ua rau atrophy ntawm cov tubule sib thooj, degeneration ntawm no tshwj xeeb nephron, thiab thaum kawg interstitial fifibrosis / tubular atrophy (IF / TA). Piv nrog rau qhov no glomerulus-induced focal hloov caws pliav, diffuse fifibrosis ywj siab ntawm tubular atrophy zoo li yog cov txheej txheem sib txawv.Lub raumfifibrosis zoo nkaus li txhim kho nyob rau hauv ib qho chaw tshwj xeeb, tab sis txawm tias focal thiab diffuse fifibrosis muaj cov yam ntxwv sib txawv cuam tshuam nrog lwm cov kab mob glomerular lossis tubulointerstitial tseem tsis pom. Hauv qhov kev tshawb fawb tam sim no, peb tsom los txheeb xyuas cov qauv ntawm lub raum fibrotic uas cuam tshuam rau lub raum qhov txhab, uas ncaj qha ua rau lub raum fibrogenesis, kom tshem tawm cov qauv fibrotic thiab tshwm sim ntawm kev puas tsuaj rau lub raum sib txawv. Cov qauv ntawmraumfifibrosis tau txheeb xyuas hauv cov qauv kev sim ntawm CKD thiab ntau lub raum pathologies hauv kev sib raug zoo nrog kev tshawb pom histopathological thiab ultrastructural. Tom qab induction ntawm cais crescentic glomerulonephritis (GN) nyob rau hauv nephrotoxic serum-nephritis (NTN), mob glomerular puas ua rau feem ntau focal fifibrosis nyob ib sab ntawm atrophic tubules. Los ntawm qhov sib txawv, siv unilateral ureteral obstruction (UUO) raws li tus qauv ntawm kev raug mob thawj zaug rau tubulointerstitial compartment qhia diffuse fifibrosis raws li tus qauv tseem ceeb ntawm cov kab mob ntev. Thaum kawg, folic acid-induced nephropathy (FAN) raws li tus qauv ntawm thawj tubular raug mob nrog sib law liag tubular atrophy ywj siab ntawm kev mob glomerular puas sib npaug induced predominant focal IF / TA. Los ntawm kev tshuaj xyuas ob peb lub raum pathologies, peb cov ntaub ntawv kuj qhia tias focal thiab diffuse fifibrosis tshwm sim los ua qhov mob ntev hauv feem ntau ntawm tib neeg lub raum kab mob, feem ntau muaj nyob rau hauv antineutrophil cytoplasmic antibodies (ANCA)-associated GN, lupus nephritis, thiab IgA nephropathy ( IgAN). Focal IF / TA cuam tshuam nrog kev puas tsuaj glomerular thiab kev raug mob tsis tuaj yeem rau nephrons, qhov sib txawv ntawm fifibrosis hauv ANCA GN tau cuam tshuam nrog kev cuam tshuam ntawm qhov mob tsis muaj kev puas tsuaj ntawm glomerular thiab nephron poob. Ultrastructural tsom xam ntawm focal IF / TA piv rau diffuse fifibrosis qhia txawv matrix compositions, ntxiv kev txhawb nqa los ntawm sib txawv collagen kos npe nyob rau hauv transcriptome datasets. Hais txog qhov tshwm sim ntawm lub raum mus ntev, tsuas yog qhov ntawm focal IF / TA cuam tshuam nrog kev txhim kho ntawm theem kawg.mob raum(ESKD) hauv ANCA GN. Nyob rau hauv sib piv, diffuseraumfifibrosis tsis cuam tshuam nrog lub raum mus ntev. Nyob rau hauv xaus, peb ntawm no muab pov thawj hais tias ib tug focal qauv ntawmraumfifibrosis zoo li cuam tshuam nrog nephron poob thiab hloov caws pliav. Nyob rau hauv sib piv, ib tug diffuse qauv ntawmraumfifibrosis zoo li tshwm sim los ntawm thawj qhov mob sib kis thiab raug mob.

Ntsiab lus:fibrosis qauv; raum fibrosis; mob raum; tubular atrophy; mob; kab mob vasculitis

CISTANCHE yuav txhim kho lub raum / raum kab mob

Taw qhia

Lub raum fifibrosis yog ib qho tshwm sim tshwm sim thiab cov cim ntawm ntau yam mob ntevkab mob raum(CKD) coj mus rau theem kawgmob raum(ESKD), tsis hais txog lub hauv paus etiology [1]. Feem ntau, lub raum fifibrosis (los yog tubulointerstitial fifibrosis) sawv cev rau histomorphology ntawm extracellular matrix (ECM) deposition nyob rau hauv tag nrho cov theem ntawm CKD.Lub raumfifibrosis tuaj yeem tshwm sim hauv cov qauv morphological sib txawv, qhia txog lwm yam kab mob ua rau [2]. Dav macroscopically pom caws pliav yog cov sequelae ntawm kev raug mob loj focal thiab ua tiav parenchymal kev puas tsuaj, xav txog qhov mob kho qhov txhab raws li qhov tshwm sim ntawm infarction [3]. Hauvraum, mob glomerular raug mob ua rau atrophy ntawm cov tubule sib raug zoo, degeneration ntawm no tshwj xeeb nephron, thiab thaum kawg interstitial fifibrosis / tubular atrophy (IF / TA) [4,5]. Piv nrog rau qhov no glomerulus-induced focal hloov caws pliav, fifibrosis ywj siab ntawm tubular atrophy (hauv qab no, hu ua diffuse fifibrosis) zoo li yog cov txheej txheem sib txawv [6,7]. Tubular atrophy txhais tau tias yog qhov poob ntawm kev thauj tshwj xeeb thiab cov peev txheej metabolic thiab feem ntau tshwm sim los ntawm cov tubules me, cov hlwb epithelial nrog daj ntseg cytoplasm, los yog dilated heev nyias tubules. Nyob rau hauv sib piv rau peb to taub txog fifibrosis li caws pliav nqaij sawv cev rau ib tug tsis tiav raum kho txheej txheem, diffuse fifibrosis yog suav hais tias yog ib tug active contributor ntawm CKD kev loj hlob, uas yog tseem ceeb raws li kev soj ntsuam hais tias kev poob ntawm lub raum ua hauj lwm correlates ntau ze nrog tubulointerstitial fifibrosis es. nrog glomerular puas [8–11]. Raws li cov ntsiab lus saum toj no,raumfifibrosis yog tham los yog ib tug mechanism ntawm tsis tiavraumkho lossis tus pab txhawb rau CKD kev nce qib [12,13].Lub raumfifibrosis zoo nkaus li txhim kho nyob rau hauv ib qho kev qhia tshwj xeeb, tab sis txawm tias focal IF / TA lossis diffuse fifibrosis muaj cov yam ntxwv sib txawv cuam tshuam nrog lwm cov kab mob glomerular lossis tubulointerstitial tseem tsis pom. Hauv qhov kev tshawb fawb tam sim no, peb tsom los txheeb xyuas cov qauv ntawm lub raum fibrotic cuam tshuam nrog rau cov kab mob hauv lub raum tau hais tseg (piv txwv li, glomerular, tubular, thiab interstitial lesions), uas ncaj qha ua rau lub raum fibrogenesis.

Cov ntaub ntawv thiab cov txheej txheem

2.1. TsiajTag nrho cov kev tshawb fawb tsiaj sim tau ua tiav nrog kev pom zoo los ntawm Pawg Saib Xyuas Tsiaj Tsiaj thiab Siv Pawg ntawm Beth Israel Deaconess Medical Center (BIDMC) thiab University Medical Center Göttingen ua raws li ARRIVE cov lus qhia [14]. Cov txheej txheem sim tau piav qhia hauv qab no. Ib qho piv txwv loj ntawm n=5 nas nyob rau hauv txhua pab pawg neeg tsis raug cai powered los yog prespecified. 2.2. Nephrotoxic Serum-Nephritis (NTN) Txhua tus nas yog thawj zaug txhaj tshuaj nrog 200 µg yaj IgG (Capralogics, Gilbertville, IA, USA) hauv 200 µL ua tiav Freund's adjuvant (Sigma, St. Louis, MO, USA) intravenously txhaj nrog 40 L. nephrotoxic ntshav nyob rau hnub 5, 6 thiab 7 tom qab txhaj tshuaj tiv thaiv ua ntej. Kev sim tau xaus 63 hnub tom qab txhaj tshuaj [15,16]. 2.3. Unilateral Ureteral Obstruction (UUO) Yim mus rau kaum ob lub lis piam hnub nyoog C57BL / 6 nas tau tshuaj loog nrog isoflurane inhalation, thiab analgesia tau ua los ntawm subcutaneous buprenorphine txhaj. Lub ureter tau muab cais los ntawm cov ntaub so ntswg nyob ib puag ncig, thiab ob txoj hlua khi tau muab tso rau hauv qhov sib nrug li 5 hli nyob rau sab sauv ob feem peb ntawm cov ureter ntawm lub raum sab laug kom tau txais kev cuam tshuam txhim khu kev qha. Kev sim ua tiav kaum hnub tom qab ureter ligation raws li tau piav qhia yav dhau los [17].

CISTANCHE yuav txhim kho rau lub raum/ raum mob

2.4. Folic Acid-Induced Nephropathy (FAN)Kev raug mob raum raug mob nrog kev txhaj tshuaj ib zaug hauv lub cev ntawm folic acid (250 mg / kg lub cev hnyav hauv PBS) hauv CD1 nas. Kev sim ua tiav 96 hnub tom qab txhaj tshuaj.

2.5. Kawm Pej Xeem Tag nrho ntawm 112 tus neeg mob ntawm ntau lub raum pathologies nrog rau mob interstitial nephritis (AIN), antineutrophil cytoplasmic antibody-associated txuam glomerulonephritis (ANCA GN), membranous GN, lupus nephritis, hypertensive nephropathy, IgA nephropathy (IgA nephropathy) glomerulosclerosis (FSGS), thiab ntshav qab zibmob raum(DKD) tau suav nrog. Txawm hais tias tsis muaj kev pom zoo raug cai rau kev siv cov ntaub ntawv kho mob niaj hnub, kev pom zoo tau tso cai los ntawm pawg neeg saib xyuas kev ncaj ncees ntawm University Medical Center Göttingen (no. 22/2/14 thiab 28/9/17). Tsis tas li ntawd, txhua tus neeg mob tau tso cai rau kev sau cov ntaub ntawv ua ib feem ntawm lawv cov kev kho mob tsis tu ncua. 2.6. Cov Lus Txhais Qhov kwv yees glomerular filtration rate (GFR) tau suav nrog siv ChronicKab mob raumEpidemiology Collaboration (CKD-EPI) equation [18]. Rau cov xwm txheej ntawm ANCA GN, Birmingham Vasculitis Activity Score (BVAS) version 3 raug xam raws li tau piav qhia yav dhau los [19]. BVAS raug ntsuas ntawm qhov ntsuas ntawm 0 txog 63, nrog rau 0 qhia tias tsis muaj kab mob ua haujlwm thiab cov qhab nia siab dua qhia tias muaj kab mob. 2.7. Masson's Trichrome Stain Formalin-fixed, paraffin-embedded raum tau muab faib rau ntawm 3 µm, thiab staining tau ua nyob rau ntawm BIDMC Histopathology Core thiab University Medical Center Göttingen. 2.8. Renal Histopathology Renal pathologists (LS, SH, thiab PS) tau soj ntsuam tag nrho cov biopsies thiab tau dig muag rau kev soj ntsuam cov ntaub ntawv sau thiab tshuaj xyuas. Analogously rau Banff cov qhab nia system, feem pua ​​​​ntawm cov cheeb tsam cortical cuam tshuam los ntawm tag nrhoraumfibrosis thiab focal interstitial fibrosis nyob rau hauv thaj tsam ntawm tubular atrophy (IF / TA) raug soj ntsuam nyob rau hauv tag nrho cov qauv. Diffuse fibrosis tsis cuam tshuam rau tubular atrophy tau suav los ntawm kev rho tawm [20]. Tsis tas li ntawd, txhua tus glomerulus tau qhab nia sib cais rau qhov muaj ntawm necrosis, crescents, thiab thoob ntiaj teb sclerosis. Yog li ntawd, qhov feem pua ​​​​ntawm glomeruli nrog ib qho ntawm cov yam ntxwv no tau suav ua ib feem ntawm tag nrho cov glomeruli hauv txhua lub raum biopsy. Raws li cov qhab nia no, histopathological subgrouping raws li Berden li al. (focal, crescentic, mix, lossis sclerotic class) thiab ARRS raws li Brix li al. (qis, nruab nrab, lossis siab txaus) tau ua [21,22].

2.9. Remission Induction TherapyGlucocorticoids (GCs) tau siv los ua kev kho mob hauv cov hlab ntshav lossis hauv qhov ncauj nrog lub sijhawm ua haujlwm. Plasma pauv (PEX) tau tswj hwm thaum lub sijhawm induction ntawm kev txiav txim siab ntawm cov kws kho mob. Rituximab (RTX) tau muab tshuaj hauv plaub koob tshuaj ntawm 375 mg / m2 txhua lub lim tiam; RTX tsis tau tswj hwm hauv 48 teev ua ntej kev kho PEX. Cyclophosphamide (CYC) tau muab tso rau hauv peb koob tshuaj mus txog 15 mg / kg txhua ob lub lis piam thiab txhua peb lub lis piam tom qab ntawd, hloov kho lub hnub nyoog thiab lub raum ua haujlwm. Kev sib xyaw ua ke tau muab rau hauv plaub koob txhaj tshuaj ntawm 375 mg / m2 RTX txhua lub lis piam thiab ob koob tshuaj ntawm 15 mg / kg CYC txhua ob lub lis piam. Raws li kev txiav txim siab ntawm kev kho cov kws kho mob, kev tshem tawm induction kev kho yog nyob ntawm cov txheej txheem yav dhau los thiab tus neeg mob yam xwm txheej. RTX nyiam nyob rau hauv cov neeg mob hluas, nrog rau toxicity yog qhov laj thawj tseem ceeb rau qhov kev xaiv no [23]. Prophylaxis los tiv thaiv Pneumocystis jiroveci kab mob tau muab raws li kev coj ua hauv zos.

CISTANCHE yuav txhim kho lub raum / raum tsis ua haujlwm

2.10. Kev tshuaj xyuas ntawm pej xeem muaj nyob Array DatasetsCov ntaub ntawv muaj nyob rau pej xeem tau txheeb xyuas raws li cov lus pom zoo [24]. Tib neeg cov ntaub ntawv transcriptome array tau pom tias yog log2 qhov nruab nrab nruab nrab siv zog muab rho tawm los ntawm Nephroseq database, suav nrog European Renal cDNA Biobank (ERCB) los ntawm 170 CKD cov neeg mob thiab 31 tus neeg noj qab haus huv pub dawb (tus lej nkag GSE69438) [25].

2.11. Cov txheej txheem txheeb caisCov kev hloov pauv tau raug sim rau kev faib tawm ib txwm siv Shapiro-Wilk test. Tsis yog ib txwm faib cov hloov pauv tsis tu ncua tau nthuav tawm raws li qhov nruab nrab thiab qhov sib txawv (IQR), categorical variables tau nthuav tawm raws li qhov zaus thiab feem pua. Kev sib piv ntawm cov lej tsis raug tsim los lossis ua ntej. Rau kev sib piv ntawm pab pawg, Kruskal-Wallis xeem tau siv. Rau kev sib piv pab pawg, Mann-Whitney U-test tau siv los txiav txim siab qhov sib txawv ntawm cov neeg nruab nrab. Tsis yog parametric ntawm pawg sib piv tau ua nrog Pearson's chi-square test. Kev sib raug zoo tau txheeb xyuas siv Spear txiv neej qhov sib txheeb coefficient (Spearman's ρ), thiab cov ntaub ntawv txheeb xyuas tau ua nrog GraphPad Prism (version 8.4.3 rau macOS, GraphPad Software, San Diego, CA, USA).

3. Cov txiaj ntsig

3.1. Kev raug mob rau lub raum sib txawv tau tshwm sim hauv cov qauv sib txawv ntawm lub raum FibrosisTxhawm rau kom paub meej txog cov kab mob hauv qab no hauv kev txhim kho ntawm focal IF / TA thiab diffuse fifibrosis los ntawm glomerular lossis tubular raug mob, peb thawj zaug sib tw nas nrog cov qauv kev sim ntawm thawj glomerular raug mob ua rau glomerular sclerosis tshwm sim los ntawm nephrotoxic serum-nephritis (NTN) , diffuse tubulointerstitial raug mob vim postrenal tsis ua hauj lwm nrog raum hemodynamic thiab metabolic hloov los ntawm unilateral ureteral obstruction (UUO), thiab ib tug tshwj xeeb qauv ntawm tubular raug mob ua rau tubular atrophy los ntawm folic acid-induced nephropathy (FAN, daim duab 1A) [26-28. ]. Lub raum nyob rau hauv cov kev sim ua qauv ntawmmob raumtau raug soj ntsuam los ntawm Masson's trichrome staining qhia tias qhov mob glomerular puas hauv NTN ua rau feem ntau focal IF / TA nyob ib sab ntawm atrophic tubules (Daim duab 1B, C thiab Table 1). Los ntawm qhov sib txawv, siv UUO ua tus qauv ntawm kev raug mob thawj zaug rau tubulointerstitial compartment nrog cov kab mob sib kis tau nthuav tawm cov kab mob fifibrosis ua tus qauv ntawm cov kab mob ntev (Daim duab 1B, C thiab Table 1). Interestingly, FAN raws li tus qauv ntawm thawj tubular raug mob nrog sib law liag tubular atrophy ywj siab ntawm ntev glomerular puas sib npaug induced predominant focal IF / TA (Daim duab 1B, C thiab Table 1), yog li underscoring lub luag hauj lwm ntawm tubular raug mob thiab tubular atrophy rau txoj kev loj hlob. ntawm no focal fifibrosis qauv.

3.2. Kev faib tawm ntawm Focal IF / TA thiab Diffuse Fibrosis hauv Tib Neeg PathologyTxhawm rau txheeb xyuas seb cov qauv sib txawv ntawm lub raum fifibrosis yog cov txheej txheem kev loj hlob ntawm cov kab mob hauv cov lus teb rau kev raug mob ntev thiab pom nyob rau hauv lub raum pathologies, peb txuas ntxiv txheeb xyuas qhov tshwm sim thiab kev faib tawm ntawm focal IF / TA thiab diffuse fifibrosis hauv ntau lwm tus neeg.kab mob raum.Hauv tag nrho 67 lub raum biopsies nrog rau lub raum pathologies sib txawv, suav nrog antineutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA GN), mob interstitial nephritis (AIN), membranous GN, lupus nephritis, hypertensive nephropathy, IgA nephropathy (IgA nephropathy) glomerulosclerosis (FSGS), thiab ntshav qab zibmob raum(DKD), focal IF/TA thiab diffuse fifibrosis tuaj yeem raug soj ntsuam rau qib sib txawv (Daim duab 2A–C thiab Table 2). Interestingly, diffuse fifibrosis feem ntau tshwm sim nyob rau hauv cov neeg mob ntawm ANCA GN, lupus nephritis, thiab IgAN li.kab mob raumnrog glomerular thiab interstitial raug mob (Daim duab 2C). Cov kev tshawb pom no qhia tias cov qauv sib txawv ntawm lub raum fifibrosis muaj nyob rau hauv ntau lub raum pathologies, suav nrog ANCA GN, thiab ANCA GN tuaj yeem ua tus qauv kab mob rau kev kawm inflammatory thiab degenerative raug mob mechanisms rau ntau lub raum sab hauv [29].

3.3. Focal IF / TA thiab Diffuse Fibrosis yog qhov qhia txog kev raug mob rau lub raum sib txawv hauv ANCA GNVim tias peb pom tias cov qauv sib txawv ntawm lub raum fifibrosis muaj nyob rau hauv ntau lub raum pathologies, suav nrog ANCA GN raws li kab mob raum nrog glomerular thiab inflammatory interstitial raug mob nrog kev sib npaug ntawm focal IF / TA thiab diffuse fifibrosis, peb txheeb xyuas cov qauv sib txawv ntawm lub raum fifibrosis hauv kev koom tes. nrog kev soj ntsuam, kuaj thiab kuaj histopathological nyob rau hauv tag nrho cov naj npawb ntawm 49 lub raum biopsies nrog paub tseeb ANCA GN (Table 3) [30–36]. Qhov loj ntawm tag nrho cov fifibrosis cuam tshuam nrog kev ua haujlwm ntawm lub raum tsis zoo, uas tau cuam tshuam los ntawm kev nce ntawm cov ntshav creatinine thiab poob ntawm glomerular filtration rate (GFR, Daim duab 3B). Los ntawm kev sib tw ANCA GN, tag nrho cov fifibrosis correlated nrog ib tug tsawg feem ntawm ib txwm glomeruli ntaus nqi rau ceev crescents thiab ntiaj teb no glomerular sclerosis (Daim duab 3C). Ntawm cov kab mob inflammatory, tag nrho cov fifibrosis correlated nrog tag nrho cov mob nyob rau hauv ANCA GN tsis meej vim hais tias ntawm interstitial o sab nraum cheeb tsam ntawm IF / TA los yog o nyob rau hauv cov cheeb tsam ntawm interstitial fifibrosis thiab tubular atrophy (i-IF / TA, daim duab 3C). Peb tom ntej no dissected raum fifibrosis rau hauv focal IF / TA thiab diffuse fifibrosis nyob ib ncig ntawm cov tubules uas tsis muaj cov cim tseem ceeb ntawm tubular atrophy rau kev tsom xam (Daim duab 3D). Qhov zoo siab, peb tau pom tsis muaj kev sib raug zoo ntawm focal IF / TA thiab diffuse fifibrosis (Daim duab 3E), cuam tshuam cov yam ntxwv ntawm txhua qhov txhab hauv ANCA GN. Raws li peb tau pom yav dhau los rau tag nrho cov fifibrosis, IF / TA correlated nrog ib feem tsawg ntawm cov glomeruli ib txwm, feem ntau yog vim lub ntiaj teb glomerular sclerosis (Daim duab 3E), lees paub cov txheej txheem tsim uas mob glomerular raug mob ua rau degeneration ntawm cov tubules sib raug nrog tubular atrophy thiab focal fibrotic caws pliav [4] Los ntawm qhov sib txawv, diffuse fifibrosis tsis cuam tshuam nrog kev puas tsuaj rau lub glomerular tab sis nrog crescentic glomeruli (Daim duab 3E), qhia tias diffuse fifibrosis (tsis hais txog tubular atrophy) tseem tsis tau paub txog cov txheej txheem uas tsis muaj kev ywj pheej ntawm kev raug mob glomerular thiab nephron poob. Kev ntsuam xyuas ntawm lub raum mob tau qhia tias diffuse fifibrosis tshwj xeeb yog txuam nrog interstitial o nyob rau hauv cov cheeb tsam uas tsis yog-fibrotic (Daim duab 3E), whereas focal IF / TA cortical nrog tag nrho cortical o uas tsis yog tshwj xeeb yog vim li cas rau interstitial o los yog i-IF / TA ( Daim duab 3E). Ntawm qhov kev ceeb toom, ob qho tib si kab mob cuam tshuam nrog kev ua rau lub raum ua haujlwm tsis zoo (Daim duab 3F), ntxiv kev txhawb nqa kev soj ntsuam tias txhua qhov txhab yog qhov tseem ceeb rau kev raug mob rau lub raum thiab cov txiaj ntsig.

Daim duab 3. Focal IF/TA thiab diffuse fifibrosis yog qhov qhia txog kev raug mob rau lub raum sib txawv hauv ANCA GN. (A) Tus neeg sawv cev photomicrograph ntawm Masson lub trichrome-stained raum seem hauv ANCA GN (scale bar: 200 µm). (B) Kev sib koom ua ke ntawm tag nrho lub raum fifibrosis, kev soj ntsuam thiab kev kuaj pom hauv ANCA GN tau qhia los ntawm daim ntawv qhia heatmap uas qhia txog qhov tseem ceeb ntawm Spearman's ρ, asterisks qhia p < 0.05.="" (c)="" kev="" sib="" koom="" ua="" ke="" ntawm="" tag="" nrho="" lub="" raum="" fifibrosis,="" glomerular="" thiab="" inflammatory="" kev="" tshawb="" pom="" nyob="" rau="" hauv="" anca="" gn="" yog="" qhia="" los="" ntawm="" heatmap="" qhia="" txog="" qhov="" tseem="" ceeb="" ntawm="" spearman's="" ρ,="" asterisks="" qhia="" p=""><0.05. (d)="" tus="" neeg="" sawv="" cev="" photomicrograph="" ntawm="" masson="" lub="" trichrome-stained="" raum="" seem="" hauv="" anca="" gn="" nrog="" focal="" if="" ta="" (sab="" saum="" toj="" vaj="" huam="" sib="" luag)="" thiab="" diffuse="" fifibrosis="" (qis="" vaj="" huam="" sib="" luag)="" tau="" qhia="" (="" nplai="" tuav:="" 40="" µm).="" (e)="" lub="" koom="" haum="" ntawm="" focal="" if="" ta="" thiab="" diffuse="" fifibrosis="" nrog="" glomerular="" thiab="" inflammatory="" kev="" tshawb="" pom="" yog="" qhia="" los="" ntawm="" heatmap="" qhia="" txog="" qhov="" tseem="" ceeb="" ntawm="" spearman's="" ρ,="" asterisks="" qhia="" p=""><0.05. (f)="" kev="" sib="" koom="" ua="" ke="" ntawm="" focal="" if="" ta="" thiab="" diffuse="" fifibrosis="" nrog="" kev="" soj="" ntsuam="" thiab="" kuaj="" pom="" hauv="" anca="" gn="" tau="" pom="" los="" ntawm="" daim="" duab="" qhia="" kev="" kub="" ntxhov="" uas="" qhia="" txog="" qhov="" tseem="" ceeb="" ntawm="" spearman's="" ρ,="" asterisks="" qhia="" p=""><0.05. cov="" ntawv="" luv:="" anca="" gn-antineutrophil="" cytoplasmic="" antibody="" glomerulonephritis;="" bvas-birmingham="" vasculitis="" cov="" qhab="" nia;="" crp-c="" reactive="" protein;="" gfr-glomerular="" pom="" tus="" nqi;="" if="" ta="" -="" interstitial="" fifibrosis="" tubular="" atrophy;="" iqr-interquartile="" ntau="" yam;="" mpo-myeloperoxidase;="" acr="" -="" tso="" zis="" albumin="" creatinine="" ration;="" upcr="" -="" zis="" protein="" creatinine="">

3.4. Kev soj ntsuam ntawm Focal IF / TA piv rau Diffuse Fibrosis nthuav tawm Cov Txheej Txheem MatrixTom ntej no, peb txheeb xyuas cov yam ntxwv morphological ntawm focal IF / TA thiab diffuse fifibrosis hauv ANCA GN kom ntxaws ntxiv. Semithin seem tau qhia tias focal IF / TA ib puag ncig atrophic tubules tau condensed ntau dua li cov ntaub so ntswg uas muaj fiber ntau nyob ib puag ncig khaws cia cov tubules (Daim duab 4A). Transmission electron microscopy (TEM) elucidated collagen bundles embedded in a densely packed stromal matrix (Daim duab 4B). Los ntawm qhov sib txawv, kev tsom xam ultrastructural ntawm diffuse fifibrosis pom yuav luag cov tubules uas nyob ib puag ncig los ntawm qhov dav dav edematous interiority nrog focal collagenous bundles nthuav tawm ib yam tsis tiav ntawm cov ntaub so ntswg fibrotic (Daim duab 4B). Cov kev soj ntsuam no cuam tshuam tias focal IF / TA thiab diffuse lub raum fifibrosis yuav txawv ntawm ECM muaj pes tsawg leeg thiab lub koom haum.

3.5. Tubulointerstitial Transcriptome nyob rau hauv koom haum nrog Tubular Atrophy nthuav tawm cov Collagen Kos Npe hauv raum FibrosisPeb tom ntej no tau txheeb xyuas ECM muaj pes tsawg leeg cuam tshuam los ntawm collagen kos npe hauv cov ntaub ntawv sau tseg los ntawm microdissected tubulointerstitial compartments hauv 170 CKD cov neeg mob thiab 31 tus neeg noj qab haus huv pub dawb (Nephroseq database) rau kev koom tes nrog cov cim tsim ntawm tubular atrophy, suav nrog cytokeratin -7 (encoded los ntawm KRT7), -18 (KRT18), thiab -19 (KRT19) [25,37]. Hauv tubulointerstitial compartments nrog kev qhia siab ntawm tubular raug mob cim, collagens COL1A1, COL1A2, COL3A1, COL4A1, COL4A2, COL5A2, COL6A3, COL16A1, thiab COL18A1 tau nthuav tawm ntau heev (Daim duab 5). Los ntawm qhov sib piv, kev sib cuam tshuam rov qab tau pom rau COL2A1, COL5A3, COL6A1, COL8A2, COL11A1, COL11A2, COL17A1, thiab COL19A1 (Daim duab 5). Cov txiaj ntsig no cuam tshuam tias lub raum fifibrosis tej zaum yuav muaj cov npe collagen tshwj xeeb hauv cov cim ntawm tubular raug mob.

3.6. Focal IF / TA cuam tshuam nrog cov txiaj ntsig ntev ntev hauv ANCA GNTxhawm rau kom nkag siab txog seb cov qauv sib txawv ntawm lub raum fifibrosis cuam tshuam nrog rau lub raum ua haujlwm ntev, peb txuas ntxiv piv rau tag nrho, focal IF / TA, thiab diffuse lub raum fifibrosis hauv ANCA GN nrog kev txhim kho ESKD. Tag nrho lub raum fifibrosis hauv ANCA GN cuam tshuam nrog rau lub raum mus sij hawm ntev (Table 4). Interestingly, tsuas yog qhov ntawm focal raum fifibrosis correlated nrog rau lub raum tshwm sim (Table 4). Piv txwv li, diffuse lub raum fifibrosis tsis koom nrog rau lub raum mus ntev (Table 4), qhia tias cov qauv fifibrosis txawv kuj tseem cuam tshuam rau kev loj hlob ntawm tus kab mob thiab muaj peev xwm kho tau.

Kev sib tham

Txog niaj hnub no, kev loj hlob ntawm lub raum fifibrosis tuaj yeem muab faib ua ob lub ntsiab lus: ntawm ib sab, cov ntaub ntawv muab cov ntaub ntawv pov thawj tias lub raum fifibrosis yog qhov tshwm sim yooj yim ntawm irreversible kev puas tsuaj rau lub nephron, xws li mob glomerular lossis tubular raug mob, ob qho tib si ua rau. nyob rau hauv tubular atrophy thiab focal interstitial fifibrosis ib puag ncig puas nephrons [12,13]. Yog li, focal IF / TA cuam tshuam nrog tubular atrophy pab txhawb rau lub raum kho los ntawm kev ua cov caws pliav, yog li hloov nephrons uas twb ploj lawm [12]. Ntawm qhov tod tes, lub raum fifibrosis yuav pom tau tias yog ib qho kev ua haujlwm, kev vam meej, thiab ua rau cov txheej txheem rov ua qauv ntawm lub raum interstitium. Hauv cov txheej txheem no, fibroblasts ncaj qha ua rau muaj kev raug mob ntawm epithelial, qhia txog kev sib cuam tshuam ntawm CKD kev loj hlob [13]. Rau peb txoj kev paub, qhov no yog thawj txoj kev tshawb fawb uas tau muab faib ua ob lub raum fifibrosis rau hauv ob qho tib si thiab muaj kev ywj pheej nrog focal lossis diffuse histomorphological qauv, yog li elucidating ob txoj kev sib txawv ntawm cov kab mob no. Txhawm rau muab kev nkag siab tshiab rau hauv thaj chaw ntawm lub raum fibrogenesis, kev txhim kho thiab txoj hmoo ntawm lub raum fifibrosis, peb tau tshuaj xyuas peb tus qauv nas sib txawv nrog cov chaw paub ntawm lub raum fifibrosis kom tshem tawm cov qauv fibrotic thiab tshwm sim thaum muaj kev puas tsuaj rau lub raum sib txawv. Induction ntawm ib qho kev sib cais Crescentic GN hauv NTN, thiab mob glomerular puas, ua rau feem ntau focal fifibrosis nyob ib sab ntawm atrophic tubules [26]. Cov kev soj ntsuam no txhawb lub tswv yim ntawm kev puas tsuaj nephron tsis tuaj yeem ua rau focal IF / TA ib puag ncig puas nephrons [12,13]. Los ntawm qhov sib txawv, siv UUO ua tus qauv ntawm kev raug mob thawj zaug rau tubulointerstitial compartment nrog cov kab mob sib kis tau nthuav tawm cov kab mob fifibrosis ua tus qauv ntawm cov kab mob ntev [27]. Lub raum fifibrosis hauv UUO nas yog tus cwj pwm los ntawm cov nqaij mos collagen fibers nyob ib puag ncig yuav luag cov tubules.

Interstitium ntawm UUO nas pom tsis tau tsuas yog diffuse fifibrosis tab sis kuj muaj ntau inflammatory hlwb. Txij li thaum o yog ib qho lus teb rau kev raug mob, nws yog ib qho tseem ceeb uas yuav tau tham txog seb puas muaj cov kab mob interstitial tshwm sim los ntawm kev puas tsuaj rau lub interstitial compartment ywj siab ntawm cov neeg nyob sib ze nephron. Yog li ntawd, diffuse fifibrosis tshwm sim los ntawm kev sib cais interstitial nephritis yam tsis muaj kev raug mob rau lub raum epithelial parenchyma, uas tuaj yeem tshwm sim nyob rau theem tom qab ntawm tus kab mob ua rau tubulointerstitial nephritis, thiab tej zaum yuav ua rau atrophic nephrons. Cov zis congestion nyob rau hauv lub tubular epithelial system yog thawj culprit nyob rau hauv lub UUO qauv, uas ua rau diffuse fifibrosis, raum hemodynamic, thiab metabolic hloov [27]. Txij li txhua qhov congestion ntawm parenchyma ua rau edema ntawm ib puag ncig interstitium, diffuse edematous raug mob ntawm lub raum interstitium tuaj yeem piav qhia txog qhov o thiab diffuse fifibrosis hauv UUO nas. Thaum kawg, FAN raws li tus qauv ntawm cov tubular raug mob nrog sib law liag tubular atrophy ywj siab ntawm kev puas tsuaj glomerular sib npaug sib npaug ntawm cov focal IF / TA, yog li underscoring lub luag hauj lwm ntawm tubular raug mob thiab tubular atrophy rau kev loj hlob ntawm focal IF / TA [28]. Nyob rau hauv cov qauv no, ntau tus neeg nyob sib ze nephrons tau tshwm sim los ntawm kev raug mob ntawm tubular toxicity, ua rau txuas mus rau tubular atrophy yam tsis muaj glomerular puas.

Ua raws li kev soj ntsuam ntawm ntau lub raum pathologies, peb cov ntaub ntawv kuj qhia tias focal IF / TA thiab diffuse fifibrosis tshwm sim los ua qhov mob ntev hauv feem ntau ntawm tib neeg lub raum kab mob. Focal IF / TA thiab diffuse fifibrosis yog tam sim no nyob rau hauv ANCA GN thiab underscore lub postulated mechanism ntawm ncaj qha interstitial raug mob raws li qhov ua rau ntawm diffuse fifibrosis. Hauv ANCA GN raws li kab mob hauv lub raum nrog kev raug mob glomerular (Crescent tsim, glomerular sclerosis, thiab nephron poob) thiab kev raug mob interstitial (vim o), peb ntawm no muab pov thawj tias tubulointerstitial fifibrosis yog txuam nrog nephron puas (nyob ntawm seb puas los yog ywj siab ntawm glomerular caws pliav) los yog thawj qhov kev raug mob interstitial (ua rau ib qho kev hloov kho fibrotic interstitial) [22,38–41]. Tsis tas li ntawd, peb cov ntaub ntawv qhia tias focal IF / TA hauv ANCA GN cuam tshuam nrog lub ntiaj teb glomerular sclerosis, ua rau glomerular sclerosis thiab nephron poob [26]. Ntawm no, peb tuaj yeem qhia tau tias focal raum caws pliav sawv cev rau lub hauv paus qauv ntawm lub raum fifibrosis, paub meej tias muaj ntau cov ntaub ntawv piav qhia tias kev puas tsuaj rau lub raum ua rau degeneration ntawm cov tubules sib raug nrog tubular atrophy, poob ntawm qhov tshwj xeeb nephron, thiab kho lub raum tsis tiav. los ntawm ib tug focal hloov caws pliav [12]. Yog li, peb cov ntaub ntawv lees paub tias focal IF / TA yog txuam nrog irreversible raug mob rau nephrons, txawm nyob los yog ywj siab ntawm glomerular raug mob. Cov qauv focal IF / TA hauv tib neeg biopsies zoo li muaj keeb kwm zoo sib xws, cuam tshuam rau lub raum kho. Los ntawm qhov sib txawv, diffuse fifibrosis hauv ANCA GN tshwj xeeb yog txuam nrog interstitial o. Semitin seem qhia cov ntaub so ntswg fibrotic nrog xoob txheej txheej collagen fibers nyob ib ncig ntawm yuav luag tag nrho cov tubules tsis muaj cov cim qhia ntawm qhov tseeb atrophy. Ntawm qhov kev ceeb toom, TEM tsom xam pom tau tias muaj cov pob txha pob txha pob txha pob txha nyob rau hauv ib qho kev sib koom ua ke tsis sib xws, qhia txog kev hloov pauv hloov pauv. Vim tias ANCA GN yog vasculitis cuam tshuam rau cov hlab ntsha me me, cov kab mob interstitial o thiab diffuse fifibrosis tuaj yeem piav qhia vim muaj cov vasculitis interstitial nrog rau cov hlab ntsha tawg; Yog li ntawd, edema thiab interstitial o aggravate diffuse interstitial fifibrosis [42].

CISTANCHE yuav txhim kho lub raum / raum mob ntshav qab zib

Cov ntaub ntawv sau tseg los ntawm microdissected tubulointerstitial compartments tau nthuav tawm cov npe sib txawv ntawm collagen cuam tshuam nrog focal IF / TA cuam tshuam nrog tubular atrophy thiab diffuse fifibrosis tsis cuam tshuam txog tubular atrophy, txhais tau tias focal IF / TA thiab diffuse raum fifibrosis yuav txawv hauv ECM muaj pes tsawg leeg. Collagen yog ib qho tseem ceeb ntawm fiber ntau cov protein nyob rau hauv lub extracellular matrix. Collagens tsim cov txheej txheem tseem ceeb ntawm ECM thiab muab lub zog tensile, tswj cell adhesion, txhawb chemotaxis thiab tsiv teb tsaws, thiab ncaj qha cov ntaub so ntswg kev loj hlob [43]. Txog niaj hnub no, 28 hom collagen tau piav qhia. Cov hom tseem ceeb ntawm collagen pom nyob rau hauv cov ntaub so ntswg yog hom I, II, III, V, thiab XI. Hauv microdissected tubulointerstitial compartments, focal fifibrosis cuam tshuam nrog cov cim ntawm tubular atrophy feem ntau muaj collagen hom I, III, IV, thiab V. Los ntawm qhov sib txawv, peb tau txheeb xyuas qhov sib cuam tshuam nrog collagen hom II thiab XI, txhais tau tias focal IF / TA thiab diffuse raum. fifibrosis tej zaum yuav txawv nyob rau hauv txawv kos npe collagen. Thaum kawg, peb ntawm no qhia tau hais tias tag nrho lub raum fifibrosis hauv ANCA GN cuam tshuam nrog cov txiaj ntsig ntawm lub raum mus ntev, raws li tau piav qhia yav dhau los [22]. Interestingly, tsuas yog qhov ntawm focal raum fifibrosis correlated nrog rau lub raum tshwm sim. Piv txwv li, diffuse raum fifibrosis tsis koom nrog rau lub raum mus ntev. Cov kev soj ntsuam no hais txog qhov txawv ntawm tus qauv fifibrosis kuj tseem tuaj yeem cuam tshuam txog kev kis kab mob thiab cov lus teb rau kev kho mob.

Ua ke, peb ntawm no muab pov thawj tias feem ntau ntawm lub raum fifibrosis zoo li cuam tshuam nrog nephron poob thiab hloov caws pliav, sawv cev rau cov ntaub so ntswg kho tsis tiav. Los ntawm qhov sib txawv, diffuse fifibrosis zoo li yog qhov tshwm sim ntawm thawj qhov kev mob sib kis thiab raug mob yam tsis muaj kev puas tsuaj rau lub raum epithelial compartment. Interestingly, ob qho tib si cov qauv ntawm fifibrosis correlated nrog ntau hnyav deterioration ntawm lub raum ua hauj lwm, implying tias txhua interstitial fibrotic lesion yog ib qho tseem ceeb contributor rau qhov tshwm sim. Nyob rau tib lub sijhawm, lub tswv yim ntawm kev poob ntawm kev ua haujlwm parenchyma ua rau focal hloov fifibrosis thiab diffuse fifibrosis hauv qab lwm cov txheej txheem tseem tsis tau piav qhia hauv lub raum. Cov txheej txheem zoo li no, txawm li cas los xij, tau tshaj tawm hauv plawv fifibrosis. Hloov fifibrosis (scar fifibrosis) yog focal thiab tshwm sim tom qab cardiomyocyte necrosis, piv txwv li, tom qab myocardial infarction, thiab suav hais tias tsis tuaj yeem tiv thaiv kev mob plawv tom qab infarction [44]. Ntawm qhov tod tes, diffuse fifibrosis tau cuam tshuam nrog kev sib kis ntawm cov cellular collagen yam tsis muaj cardiomyocyte necrosis thiab ntseeg tau tias yuav thim rov qab hauv txoj cai [45-48].

Cov kev txwv tseem ceeb ntawm peb txoj kev tshawb fawb yog qhov tsawg tsawg ntawm lub raum biopsies nyob rau hauv qee lub raum pathologies, nws qhov kev tsim rov qab, thiab kev txwv tsis pub hloov pauv ntawm cov qauv kev sim ntawm lub raum raug mob rau tib neeg. Txawm li cas los xij, peb qhov kev tshawb pom tseem ceeb uas focal IF / TA thiab diffuse fifibrosis yog cov qauv ywj pheej ntawm lub raum fifibrosis hauv ANCA GN (thiab lwm yam kab mob raum) txhais tau tias txhua qhov txhab muaj cov yam ntxwv sib txawv thiab, tej zaum, cov txheej txheem hauv ANCA GN. Tsis tas li ntawd, cov kev soj ntsuam no nthuav dav ntxiv rau peb cov kev paub tam sim no ntawm kev sib cuam tshuam ntawm qhov mob, lub raum raug mob, thiab fifibrosis, ua rau muaj kev nkag siab ntau dua ntawm cov lus teb inflammatory thiab muaj peev xwm kho tshiab cov tswv yim kho mob los hloov kho qhov txawv ntawm lub raum fifibrosis.

Cov lus xaus

Hauv kev xaus, peb ntawm no muab pov thawj tias cov qauv focal ntawm lub raum fifibrosis zoo li cuam tshuam nrog nephron poob thiab hloov caws pliav. Nyob rau hauv sib piv, tus qauv diffuse ntawm lub raum, fifibrosis tshwm sim los ntawm thawj interstitial o thiab raug mob.