jerry.he@wecistanche.com

cistanche tuaj yeem txhim kho lub raum ua haujlwm

William T. McBride1, Mary Jo Kurth2, Anna Domanska2, Joanne Watt2, Gavin McLean1, Jijin Joseph1, John V. Lamont2, Peter Fitzgerald2 thiab Mark W. Ruddock2*

Abstract

Tom ntej: Nce perioperative pro-infammatory biomarkers, lub raum hypoperfusion thiab ischemia reperfusion raug mob (IRI) siab mob plawv mobraumraug mob (CS-AKI). Ua kom tso zis ntau ntxiv los tiv thaiv cytokines txo qis kev pheej hmoo. Peb tau soj ntsuam seb cov ntshav thiab cov urinary anti-infammatory biomarkers, thaum qhia raws li qhov piv nrog biomarkers ntawm infammation, hypoperfusion thiab IRI yog nce nyob rau hauv cov neeg mob CS-AKI.

Cov txheej txheem: Preoperative thiab 24-h postoperative ntshav thiab urinary pro-infammatory thiab anti-infammatory cytokines, ntshav VEGF thiab H-FABP (hypoperfusion biomarkers), thiab MK, biomarker rau IRI, tau ntsuas hauv 401 cov neeg mob phais plawv. Ua ntej thiab tom qab kev ua haujlwm siab ntawm biomarkers thiab xaiv qhov sib piv ntawm cov neeg mob uas tsis yog CS-AKI thiab CS-AKI.

Cov txiaj ntsig: Muab piv nrog cov uas tsis yog-CS-AKI, cov ntshav tsis zoo (ua ntej thiab tom qab-op TNF , IP-10, IL-12p40, MIP-1 , NGAL; pre-op IL-6; post-op IL-8, MK) thiab anti-infammatory (pre- thiab post-op sTNFsr1, sTNFsr2, IL-1RA) biomarkers ua ke nrog urinary pro-infammatory ( pre- thiab post-op uIL-12p40; post-op uIP-10, uNGAL) thiab anti-infammatory (pre- thiab post-op usTNFsr1, usTNFsr2, uIL-1RA) biomarkers , tau nce siab dua hauv cov neeg mob CS-AKI. Cov tshuaj tiv thaiv kab mob hauv cov zis, thaum qhia raws li qhov piv nrog biomarkers ntawm infammation (ntshav thiab zis), hypoperfusion (ntshav H-FABP thiab VEGF) thiab IRI (ntshav MK) tau txo qis hauv CS-AKI. Nyob rau hauv sib piv, cov ntshav anti-infammatory biomarkers qhia raws li zoo sib xws piv nrog cov ntshav biomarkers tau nce nyob rau hauv CS-AKI.

Cov ntsiab lus: Cov tshuaj tiv thaiv kab mob hauv cov zis tuaj yeem tiv thaiv kev raug mob ntawm perioperative infammation, hypoperfusion thiab IRI. Cov fnding no yuav muaj kev siv tshuaj kho mob hauv bioprediction thiab kev kuaj mob ua ntej ntawm CS-AKI thiab qhia txog cov tswv yim kho mob yav tom ntej rau cov neeg mob CS-AKI.

Keywords: Mob raum raug mob, Biomarkers, Cytokines, Cardiac phais, TNFsr2, IL-1RA, IL-12p40, H-FABP, Midkine

Keeb kwm

Peb qhov laj thawj tseem ceeb ntawm CS-AKI

Kev phais mob plawvraumKev raug mob (CS-AKI) postoperatively muaj peb txheej txheem loj. Ua ntej, hypop-erfusion uas tuaj yeem ua rau lub raum tsis ua haujlwm rau lub raum oxygen xa mus [1] pom nyob rau hauv ntau lub plawv-type fatty acid-binding protein (H-FABP) [2] thiab vascular endothelial.

* Cov ntawv sau: mark.ruddock@randox.com

2 Randox Laboratories Ltd, Clinical Studies Group, 55 Diamond Road, Crumlin, County Antrim BT29 4QY, Northern Ireland, UK

Daim ntawv teev cov ntaub ntawv sau tag nrho muaj nyob rau ntawm qhov kawg ntawm tsab xov xwm

Kev loj hlob zoo (VEGF) [3]. Thib ob, ischemia reperfusion raug mob (IRI) (refected nyob rau hauv nce midkine (MK) [4]) accentuates intrarenal infammatory txheej txheem [5], thiab MK defcient nas tau pom tias muaj kev tiv thaiv rau lub raum IRI [6]. Tirdly, ntxiv kev raug mob pro-infammatory tej zaum yuav tshwm sim los ntawm fltered reno-toxic pro-infammatory bio-markers tsim los ntawm kev phais mob thiab cov txheej txheem cardio-pulmonary bypass (CPB) [7]. Nws raug pom zoo los ntawm kev nce ntshav plasma qog necrosis factor soluble receptor 1 (pTNFsr1) thiab plasma qog necrosis factor solu- receptor 2 (pTNFsr2) [8] uas tej zaum yuav suav tau tias yog surrogate biomarkers rau cov ntshav hauv qab cov lus teb tsis txaus ntseeg [9 ]. Yog li, hauv kev tshuaj xyuas ua ntej ntawm cov qauv kuaj ntshav ntawm 401 tus neeg mob uas tau xaiv txoj kev phais mob plawv, kev soj ntsuam kev kho mob tau pom zoo tias biomarkers kwv yees ntawm lub raum tsis ua haujlwm tau sawv cev rau peb txoj hauv kev: hypoperfusion (H-FABP), IRI (MK) thiab pro-infam. - mation (serum qog necrosis factor soluble receptor 1 (sTNFsr1) thiab serum qog necrosis factor soluble receptor 2 (sTNFsr2)) [9].

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Mechanisms tiv thaiv CS-AKI

Raws li qhov sib txawv ntawm peb txoj kev raug mob loj uas tau txheeb xyuas hauv cov ntshav kuaj, muaj peev xwm tiv thaiv lub luag haujlwm tiv thaiv CS-AKI tau raug ntaus nqi los ntawm lub raum los tiv thaiv kev mob cytokine teb ntawm kev phais plawv, uas tshwm sim los ntawm perioperative nce hauv cov qog zis. necrosis factor soluble receptor 2 (uTNFsr2) thiab urinary interleukin-1 receptor antagonist (uIL-1RA) [7, 10–12]. Te urinary anti-infammatory uTNFsr2 cov lus teb ua ntej thiab zoo heev tshaj cov plasma anti- infammatory perioperative teb [10]. Ntxiv mus, qhov hnyav molecular ntawm uIL-1RA, urinary qog necrosis factor soluble receptor 1 (uTNFsr1) thiab uTNFsr2, yog ntau dua 20 kDa thiab yog li ntawd, lawv glomerular fltration yog qis dua lawv cov me me pro-infammatory counterparts [ 13]. Tese kev txiav txim siab taw qhia rau cov zis los tiv thaiv kab mob biomarkers feem ntau yog tsim nyob rau hauvraumnrog ib qho me me ntxiv los ntawm glomerular fltration [10, 11]. Yog li ntawd, plasma theem ntawm pTNFsr1, pTNFsr2 thiab plasma interleukin-1 receptor antagonist (pIL{5}}RA) yog constitutively siab dua li ib txwm kuaj pom cov qog necrosis factor (TNF) thiab interleukin{{7} } (IL-1) ​​uas tau nyeem- fltered. Yav dhau los McBride et al. [7] pom tau tias cov neeg mob tom qab ua haujlwm CS-AKI tau qis dua uIL- 1RA thiab uTNFsr2 cov lus teb dua li cov neeg mob uas tsis yog CS-AKI ua rau cov lus pom zoo ntawm qhov tsis txaus tso zis los tiv thaiv kab mob ua rau muaj qhov tsis zoo rau CS-AKI. Txawm li cas los xij, txoj kev tshawb no tsis tau soj ntsuam seb qhov tso zis los tiv thaiv kab mob tsis zoo / tsis txaus ntseeg tau cuam tshuam rau CS-AKI txoj kev loj hlob raws li qhov tseem ceeb fltered pro-infammatory biomarkers (interleukin{23}} (IL-1) thiab TNF) koom nrog hauv tubular. kev raug mob hauv vitro [14] tsis muaj lub ntsiab lus pom hauv cov zis ib txwm [15] vim tias lawv xav tias yuav nqus los ntawm cov tubules [16]. Urinary pro-infam-matory biomarkers tam sim no ntsuas tau xws li interferon gamma-induced protein-10 (IP-10), monocyte chemot-actic protein-1 (MCP-1) thiab macrophage infammatory protein-1δ (MIP-1δ) hauv cov neeg mob ntshav qab zib nephropathy [15]; neutrophil gelatinase-associated lipocalin (NGAL), macrophage infammatory protein-1 (MIP-1 ) thiab IP-10 hauv CS-AKI cov neeg mob [1, 3, 17]; MCP-1 hauv nas nrog AKI [18] thiab interleukin-12 subunit p40 (IL-12p40) hauv hom 1 ntshav qab zib [19]. Lub raum cuam tshuam ntawm urinary anti- thiab pro-infammatory tshuav nyiaj li cas tam sim no tsis paub.

Txawm hais tias hypoperfusion thiab IRI ncaj qha raug mob rau covlub raum[6], lawv muaj peev xwm ua rau raug moblub raumlos ntawm augmenting cov lus teb pro-infammatory [20, 21] tsa cov lus nug seb lub urinary anti-infamatory teb kuj tiv thaiv hypoperfusion thiab IRI. Yog li ntawd, peb tau tshawb xyuas seb cov urinary anti-infammatory biomarkers/hypoperfusion biomarkers thiab urinary anti-infammatory biomarkers/IRI biomarkers cuam tshuam CS-AKI txoj kev loj hlob.

Kawm aims

De novo kev ntsuas ntawm cov ntshav pro-infammatory bio-markers thiab urinary pro- thiab anti-infammatory bio-markers tau soj ntsuam ua ke nrog rau yav dhau los qhia cov ntaub ntawv nyob rau hauv cov ntshav biomarkers ntawm infammation, hypoperfusion thiab IRI [9] los txiav txim cov nram qab no hypothesis.

Paub meej hypothesis

Peb tau tshawb xyuas qhov kev xav thawj zaug uas CS-AKI kev txhim kho muaj xws li:

(Ia) Cov ntshav siab dua cov lus teb tsis txaus ntseeg nyob rau hauv sib npaug nrog

(Ib) Txo cov ntshav los tiv thaiv kab mob tsis zoo (Ic) Te piv ntawm cov ntshav tiv thaiv kab mob / pro-infam- matory biomarkers yuav qis dua hauv CS-AKI dua

tsis yog CS-AKI

Secondary hypothesis postulates tias:

(IIa) CS-AKI cov neeg mob pom cov zis ntau dua cov lus teb tsis zoo nyob rau tib lub sijhawm nrog

(IIb) Qis urinary anti-infammatory response (IIc) Te ratio of urinary anti-infammatory/pro- infammatory biomarkers thiab qhov piv ntawm

(IId) Urinary anti-infammatory/blood pro-infam- matory biomarkers yuav qis dua hauv CS-AKI dua li cov neeg mob uas tsis yog CS-AKI

Txij li thaum hypoperfusion yog ib qho tseem ceeb pab txhawb rau CS-AKI, H-FABP thiab VEGF tau ntsuas hauv txhua kis. Nws tau cia siab tias qhov kev thuam ntawm hypoperfusion yuav raug txo qis hauv cov neeg mob uas tau tswj hwm los ua kom txaus siab rau cov tshuaj tiv thaiv kab mob hauv lub cev. Raws li txoj cai, peb qhov kev xav thib peb yog:

(IIIa) Ua ntej thiab tom qab kev ua haujlwm H-FABP thiab VEGF yuav siab dua hauv CS-AKI cov neeg mob thiab (IIIb) Te piv ntawm cov tshuaj tiv thaiv kab mob urinary anti-infammatory biomarkers / serum hypoperfusion biomarkers (H-FABP thiab VEGF) yuav qis dua hauv CS - AKI cov neeg mob

Thaum kawg, txij li IRI yog ib qho tseem ceeb hauv CS- AKI, peb xav tias

(IVa) Midkine hauv ntshav thiab

(IVb) Cov zis, yuav siab dua hauv cov neeg mob CS-AKI thiab qhov sib piv ntawm cov tshuaj tiv thaiv kab mob hauv lub cev / cov ntshav midkine yuav qis dua hauv cov neeg mob CS-AKI.

Cov txheej txheem

Cov ntsiab lus ntawm kev nrhiav neeg mob, pej xeem, suav nrog thiab cais tawm, cov txheej txheem tshuaj loog, cov qauv sau thiab ua tiav, kev soj ntsuam kuaj ntawm biomarkers tau piav qhia yav dhau los [9]. Ntxiv nrog rau cov ntshav ntshav thiab ntshav, cov zis kuaj kuj tau sau los ntawm txhua tus neeg mob. Cov zis kuaj tau aliquoted thiab khov ntawm -80 degree. Cov neeg mob kuaj tau raug tshuaj xyuas siv Randox cytokine arrays thiab khiav ntawm Kev Tshawb Fawb Pov Thawj, raws li cov chaw tsim khoom cov lus qhia (Randox Laboratories Ltd., Crumlin, Northern Ireland).

Luv luv, 401 tus neeg mob sib law liag (n= 401) tau txais kev phais mob plawv tau suav nrog hauv txoj kev tshawb no. Cov neeg mob tau raug xaiv nyob rau hauv Lub Tsev Kho Mob Kho Mob ntawm Royal Victoria Tsev Kho Mob Belfast, Northern Ireland. Pawg neeg saib xyuas kev ncaj ncees hauv cheeb tsam thiab lub koom haum pom zoo tau txais thiab tau txais kev tso cai sau ntawv rau tus neeg mob. Cov txheej txheem tsis suav nrog suav nrog ua ntej kev lim ntshav-nyob ntawm lub raum tsis ua haujlwm lossis lub raum tsis zoo (kwv yees glomerular fltration tus nqi eGFR< 40)="" and="" diabetes="" mellitus.="" patients="" on="" preoperative="" angio-="" tensin="" conversion="" enzyme="" (ace)="" inhibitor="" therapy="" were="" not="" excluded.="" te="" anesthetic="" technique="" was="" based="" on="" the="" use="" of="" propofol="" and="" fentanyl.="" isofurane="" was="" used="" in="" most="" patients="" either="" as="" an="" adjunct="" anesthetic="" agent="" or="" to="" control="" blood="" pressure.="" pancuronium="" provided="" muscle="" relaxation.="" postoperative="" analgesia="" was="" with="" morphine="">

Cov lus txhais ntawm lub raum tsis ua haujlwm tau siv hauv kev tshawb fawb

Siv qhov kev pheej hmoo, raug mob, tsis ua hauj lwm, poob, theem kawg (RIFLE) Cri-teria of Renal Dysfunction [22, 23] CS-AKI tau tiv thaiv ib yam li hauv peb txoj kev tshawb fawb yav dhau los [7] raws li qhov poob ntawm cov hauv paus eGFR ntawm ntau dua 25. feem pua ​​(raws li xam los ntawm txoj kev hloov ntawm kev noj zaub mov hauv lub raum kab mob (MDRD) [24, 25] tshwm sim nyob rau hauv lub frst 24 thiab 48 teev tom qab phais (thaum ntxov lub raum tsis ua hauj lwm), nyob rau ffth postoperative hnub (lub raum dysfunction lig) los yog lub sijhawm twg los tau hauv lub sijhawm 5-hnub postoperative (thaum ntxov thiab lig ua ke).

Cytokine tsom xam

Cytokines uas tau kawm hauv cov ntshav thiab zis tau piav qhia nyob rau hauv Ntxiv fle 1.

Kev txheeb cais

Kev txheeb xyuas txheeb cais tau ua tiav siv SPSS ver. 25 (IBM). Mann Whitney U kuaj tau siv los txheeb xyuas cov cim biomarkers. Biomarkers nrog ap < 0.05="" tau="" suav="" tias="" yog="" qhov="" tseem="" ceeb.="" cheeb="" tsam="" hauv="" kev="" txais="" tus="" txheej="" txheem="" kev="" ua="" haujlwm="" (auroc)="" tau="" siv="" los="" ua="" qhov="" ntsuas="" rau="" kev="" muaj="" peev="" xwm="" ua="" ntej="" rau="" cytokine="" lossis="" cytokine="" piv="" piv="" rau="" cov="" neeg="" tsis="" yog="" cs-aki="" thiab="" cs-aki="" hauv="" txoj="" kev="" tshawb="" no.="" cytokine="" ratios="" tau="" xam="" thiab="" piv="" nrog="" qhov="" muaj="" peev="" xwm="" kwv="" yees="" siab="" tshaj="" plaws="" (auroc)="" los="" txheeb="" xyuas="" cov="" neeg="" mob="" uas="" muaj="" kev="" pheej="" hmoo="" ntawm="" kev="" tsim="" cs-aki="" txhua="" hnub,="" ua="" ntej,="" thiab="" tom="" qab="" phais="" plawv,="" raug="" tshawb="" xyuas.="" rov="" qab="" thiab="" forward="" wald="" thiab="" forced="" entry="" logistic="" regression="" tau="" siv="" los="" txheeb="" xyuas="" qhov="" sib="" piv="" ntawm="" kev="" sib="" txuas="" nrog="" lub="" peev="" xwm="" siab="" tshaj="" plaws="" (auroc)="" txhawm="" rau="" txheeb="" xyuas="" cov="" neeg="" mob="">

Cov txiaj ntsig

Tus neeg mob demographics

Tag nrho cov ntsiab lus ntawm cov ntaub ntawv pej xeem, kev faib tawm ntawm cov txheej txheem phais, kev tswj xyuas tom qab kev phais thiab kev tawm los loj tau piav qhia yav dhau los [9]. Cov yam ntxwv ntawm tus neeg mob tau piav qhia hauv Table 1.

Cov txiaj ntsig rau CS-AKI hauv kev sib piv nrog cov neeg mob uas tsis yog CS-AKI

Hypothesis I-a (blood pro-infammatory biomarkers)

Piv nrog rau cov neeg mob uas tsis yog CS-AKI, cov ntshav ua rau cov neeg mob ntshav qab zib tau nce ntxiv ob qho tib si ua ntej thiab tom qab kev kho mob hauv cov neeg mob uas muaj CS-AKI txheeb xyuas nyob rau ib hnub (Table 2) thiab Hnub 1, 2, 5 (Table 1. , 3, 5, ib.).

Hypothesis I-b (blood anti-infammatory biomarkers)

Pre- thiab postoperative sTNFsr1, sTNFsr2 thiab sIL-1ra tau qis dua hauv cov neeg mob uas tsis yog CS-AKI dua li CS-AKI identifed ntawm Txhua Hnub (Table 2), Hnub 1 thiab 2 (Ntxiv

Table 1 Cov yam ntxwv kho mob ntawm cov neeg mob kawm

Table 1 thiab 3). Qee cov cytokines tau nce nyob rau Hnub 5 (Cov Lus Ntxiv 5).

Hypothesis I-c (qhov sib piv ntawm cov ntshav tiv thaiv kab mob / cov ntshav ua rau tsis zoo rau biomarkers)

Kev sib piv tau siab dua hauv cov neeg mob ua ntej thiab tom qab kev ua haujlwm CS- AKI piv nrog cov neeg mob uas tsis yog CS-AKI tau txheeb xyuas nyob rau Hnub 1, 2, 5 thiab Txhua Hnub (Cov Lus Ntxiv 7, 13, 19, 25, raws li).

Hypothesis II-a (urinary pro-infammatory biomarkers)

Ua ntej thiab tom qab phais uIL-12p40; postoperative uIP-10 thiab uNGAL tau siab dua hauv Txhua Hnub CS-AKI cov neeg mob (Table 3). Ob peb cytokines tau tsa nyob rau Hnub 1, 2 thiab 5 cov neeg mob CS-AKI (Table Ntxiv 2, 4, 6, raws li).

Hypothesis II-b (urinary anti-infammatory biomarkers)

Pre- thiab postoperative uTNFsr1, uTNFsr2 thiab postop-erative uIL-1RA tau nce qhov tseem ceeb hauv Txhua Hnub CS-AKI cov neeg mob (Table 3). Hnub 1, tsuas yog tom qab kev phais uTNFsr2 tau nce ntxiv hauv cov neeg mob CS-AKI (Cov Lus Ntxiv 2) thaum hnub 2 ua ntej ua ntej uTNFsr1 tau nce ntxiv (Table 4). Hnub 5 tsis muaj qhov sib txawv tseem ceeb hauv qib ntawm urinary anti-infammatory cytokines ntawm cov neeg mob uas tsis yog CS-AKI thiab CS-AKI.

Hypothesis II-c (cov piv txwv ntawm urinary anti-infammatory/urinary pro-infammatory biomarkers)

Ntau qhov kev ua haujlwm tom qab tau qis dua hauv Ib Hnub, Hnub 1, 2 thiab 5 cov neeg mob CS-AKI (Supple- hlwb Table 8, 14, 20 thiab 26, feem).

Table 3 Urinary pro-infammatory thiab anti-infammatory cytokines