Faktè kwasans epidèm urin: Yon pwomèt "pwochen jenerasyon" biomarker nan maladi ren

Mo kleBiomarker · Faktè kwasans epidèm ·Maladi ren· Pipi

Abstract background:

LaFaktè kwasans epidèm (EGF)se yon pwoteyin globilè ki pwodui nan ren an, espesyalman nan bouk Henle ak tibil konvolute distal la. Pandan ke EGF pa egziste oswa diman detekte nan plasma, li prezan nan pipi moun nòmal. Jiska kounye a, risk stratifikasyon akmaladi ren kwonik (CKD)dyagnostik yo te konte sou estimasyond to filtraj glomerulèr (eGFR) ak rapò albumin / kreyatinin pipi (ACR), tou de ki reflete fonksyon glomerulèr oswa andikap. Malfonksyònman tubulaires, nan lòt men an, ka tou asosye ak ensifizans ren.

NOUVO FORMULASYON ÈRBAL POUMALADI REN KRONIK

Rezime: Paske diminye EGF pipi (uEGF) endike atrofi tubulaires ak fibwoz entèstisyèl, biomarker sa a, ansanm ak eGFR ak uACR, ka itilize nan popilasyon jeneral la pou evalyasyon risk ak dyagnostik CKD. Nivo uEGF yo te montre korelasyon ak ekspresyon intrarenal EGF mRNA epi yo te jwenn diminye nan yon varyete de maladi ren glomerulaire ak ki pa glomerulaire.

Mesaj kle: uEGF, uEGF/kreyatinin, oswa uEGF/monosit chemotaktik peptide-1 se posib "nouvo jenerasyon" byomarkè ki lye ak yon varyete maladi ren ki merite plis envestigasyon kòm yon sèl biomarker oswa kòm yon pati nan yon milti biomarker. panèl.

Entwodiksyon

Lafaktè kwasans epidèm(EGF) te premye dekouvri pa Stanley Cohen nan kòmansman ane 1950 yo [1]. Yon gwo konplèks pwa molekilè (MW) (MW: apeprè 74,000 Da) te idantifye prèske antyèman nan yon omojene brit nan glann submaxillary sourit gason an, revèsiblman disosyab nan EGF (MW: 6,045 Da) ak yon EGF- pwoteyin obligatwa (MW: 29, 000 Da) ak aktivite arginyl-esterase [2]. Anplis de sa, yo te jwenn EGF nan anpil tisi imen ak likid kò, ki gen ladan ren yo (espesyalman bouk Henle a ak tubul konvolutè distal) ak pipi [3], saliv [4], glann parotid [5], lèt, dlo nan je, epi sèlman. nan yon konsantrasyon minim nan plasma [4]. Plakèt yo se sous prensipal EGF san nan imen, epi konsantrasyon an ogmante piti piti pandan koagulasyon apre koleksyon echantiyon [6].

Fig. 1. yon EGF se yon 53-polipèptid yon sèl chèn asid amine ak yon MW relatif apeprè 6,000 Da. b Kwomozòm 4 (q25–q27) gen ladan jèn EGF, ki se apeprè 120 kb nan gwosè. c Estrikti EGFR a, yon manm nan fanmi reseptè ErbB la: domèn ekstraselilè ak kat subdomains, rejyon transmembran lipofil la, ak yon domèn entraselilè fòme EGFR la. d Chemen siyal ki anba deklanchman EGFR yo enkli chemen JAK-STAT, chemen PI3K/Akt/NF-B, chemen PI3K/Akt/PTEN/mTOR, ak rezo MAPK RAS-RAF-MEKERK. EGFR, reseptè faktè kwasans epidèm; PI3K, fosfoinozitid 3-kinaz; JAK-STAT, Janus kinaz-siyal transducer ak aktivateur nan transcription; ERK, kinaz ekstraselilè ki kontwole siyal.

EGF se yon polypeptide imen ki pa diyalize, kontra enfòmèl ant, chalè ki estab [7] ki gen 53 asid amine ak twa lyezon disulfid intramolekilè (Fig. 1a) [8]. Tout asid amine yo prezan eksepte fenilalanin, alanin, ak lizin, epi li gen yon rezidi arjinin C-terminal [2]. Jèn EGF a gen 24 ekson ak 23 entron epi li jwenn sou kwomozòm 4q25-q27 (Fig. 1b) [9].

EGF ankouraje pwopagasyon selilè, diferansyasyon, ak siviv pa obligatwa 1: 1 nan domèn nan ekstraselilè idrosolubl nan reseptè a EGF, sa ki lakòz yon konplèks nan 2EGF: 2 idrosolubl domèn ekstraselilè nan reseptè a EGF (Fig. 1c) [10, 11]. Dimerization ligand-induit sa a aktive aktivite intrinsèque pwoteyin-tirozin kinaz reseptè a (Fig. 1d), deklanche yon kaskad siyal nan selil la ak sa ki lakòz yon varyete de chanjman byochimik. Sa a evantyèlman mennen nan sentèz ADN ak pwopagasyon selil [12]. Nan ren an, EGF egzèse plizyè fonksyon byolojik tankou règleman metabolis selilè ak emodinamik glomerulèr, modulasyon kwasans selil, ak reparasyon ren apre aksidan [13]. Yon modèl eksperimantal nan ensifizans ren egi te montre ke EGF te ede ak rekiperasyon jiri tubulaires pa aktive chemen rejenerasyon, sa ki lakòz reepitelyalizasyon nan tib yo blese [14]. Atravè crosstalk ak fosfoinositide 3-kinaz, Janus kinaz-siyal transducer ak activateur nan transcription, ak ekstraselilè siyal ki reglemante chemen kinaz [15, 16], pi wo nivo urin EGF (uEGF) yo panse yo reflete mas fonksyonèl tubulèr ak potansyèl rejenerasyon [17]. Kontrèman, pi ba konsantrasyon uEGF yo asosye ak fibwoz entèrstisyèl ak atrofi tubulaires (IFTA) [18]. Anplis de sa, pwoteyin EGF detekte nan pipi pasyan maladi ren yo epi rapòte nan plizyè etid ka proEGF [19].

Nan revizyon sa a, nou pral bay yon apèsi sou aspè nalitik yo ak valè potansyèl uEGF pou evalye fonksyon ren nan popilasyon jeneral la ak nan pasyan adilt ki gen maladi ren kwonik (CKD; maladi ren dyabetik [DKD], glomerulonefrit prensipal,). transplantasyon ren, maladi ren polikistik). Anplis, nou mete aksan sou bezwen potansyèl ki pa satisfè nan domèn rechèch sa a.

Aspè analitik

Plizyè metòd yo te devlope pou mezire konsantrasyon EGF nan likid kò moun ki baze sou diferan prensip tankou radyo-immunoassay [20-22], radyo-reseptè tès [23], immunoassay anzim [24-26], tès imunosorban ki lye ak anzim (ELISAs). ) [27-30], ak ultramicro ELISA tès [31]. Tablo 1 bay yon apèsi sou karakteristik divès kalite teknik yo

Because of serum protein matrix effects, the sensitivity of radioimmunoassays and radioreceptor assays for EGF analysis in the blood is insufficient without sample pretreatment (gel filtration or immunoaffinity chromatography) [33, 34]. Although no sample preparation is required for enzyme immunoassays, routine usage of these tests is problematic due to the fluorogenic substrates for the enzyme reaction [24–26]. ELISA is the gold standard for measuring EGF because of its great sensitivity and specificity. The effect of various storage conditions on uEGF stability, as well as other preanalytical techniques, has been investigated. VEGF concentrations were steady at 4°C for 48 h, as did variability as the standard deviation of mean uEGF values. Long-term storage at −80°C for 1 and 2 months did not affect the observed uEGF concentrations. However, after 6 months, there was an increase in VEGF levels in both participants and quality control samples. The mean VEGF levels were unaffected by repeated freeze-thaw cycles [35]. There is no diurnal variation in uEGF excretion, and its rate of excretion is similar when sampled on consecutive days, supporting its measurement in spot urine samples [32]. With age, the concentration of VEGF declines [36]. So, age should always be taken into account when investigating uEGF concentration [37]. EGF concentration is less likely than serum creatinine and albuminuria to be confounded by extrarenal factors, which may contribute to its evaluation and sensitivity as a biomarker for kidney failure [38]. In patients with very low or very high muscle mass, serum creatinine and estimated glomerular filtration rate (eGFR) do not correctly reflect renal function. EGF/Cr may provide a more realistic picture of the amount of chronic kidney impairment in such circumstances. When monitoring the uEGF/Cr ratio in the same individual over time, changes are considered significant when there is a difference of >30% konpare ak valè anvan yo [19].

Popilasyon Jeneral

Tubular atrophy, interstitial fibrosis, and nephron loss define age-related glomerular filtration rate (GFR) reduction in seemingly healthy persons [39]. The amounts of mRNA EGF expressed by distal tubular epithelial cells are an indication of functional tubular mass and regeneration capability and are connected to GFR [17]. Aside from the traditional kidney damage indicators (eGFR and albuminutia), additional urine biomarkers of acute tubular injury have been identified [40]. However, only a few indicators reveal the persistent tubular injury. In population-level settings, uEGF could be a clinically applicable biomarker because it is stable over extended periods and can be reliably detected with just a few microliters of urine. In a prospective longitudinal study (follow-up of >5 years), the association between uEGF and rapid eGFR loss in subjects without diabetes mellitus (DM) or established CKD was investigated [38]. Because well-defined endpoints for CKD progression such as the incidence of end-stage kidney disease (ESKD), a doubling of serum creatinine, or a 30–40% decrease in eGFR are unlikely to occur in healthy subjects within a limited follow-up period [41], a fast eGFR decline was defined as a loss >3.0 mL/min/1.73 m2 pa ane. Lower uEGF te asosye endepandamman ak n bès rapid fonksyon ren ak ensidan CKD nan de kowòt popilasyon Ewopeyen an (Renal Iohexol Clearance Survey [RENIS], ki te gen ladan 1,249 pasyan, ak Prevansyon nan ren ak vaskilè nan Etap Maladi [PREVEND], ki enkli ladan li. 4,534 pasyan). Konsantrasyon VEGF yo te trè asosye ak ensidan an nan CKD, kèlkeswa lòt faktè risk (Tablo 2). Lyen an te rete (borderline) enpòtan apre yo fin kontwole laj, sèks, kòwòt, eGFR debaz, ak rapò albumin / kreatinin pipi (ACR). Nan modèl ajiste, konsantrasyon uEGFR te gen sèlman yon relasyon majinal ak rediksyon eGFR vle di nan RENIS la. Nan rechèch PREVENT, gwoup laj ki pi piti a te wè yon ti gout nan pousantaj chanjman eGFR la. Rezilta yo ta ka afekte pa yon presizyon ki pi ba nan eGFR nan seri nòmal la ak, nan sèten ka, yon elevasyon nòmal nan eGFR nan subpopulations akòz prefiltrasyon. VEGF ka yon gwo faktè risk kontribye pou CKD lè yo konbine avèk lòt varyab jenetik oswa anviwònman [38]. Yo te jwenn yon sèl SNP (rs11569017) nan jèn EGF ki asosye ak ESKD nan yon popilasyon Koreyen [9]. Paske esè RENIS ak PREVENT yo sitou enplike patisipan blan Ewopeyen yo, nou kwè rechèch nan lavni ta dwe evalye efikasite uEGF nan kowòt popilasyon miltietnik [38].

Tablo 2. Relasyon ant uEGF ak fonksyon ren nan popilasyon jeneral la