Oxidační a karbonylový stres, mikrozánět a kardiovaskulární riziko u pacientů s onemocněním ledvin.

• Název práce v češtině: Oxidační a karbonylový stres, mikrozánět a kardiovaskulární riziko u pacientů s onemocněním ledvin.
• Název v anglickém jazyce: Oxidative and carbonyl stress,microinflammation and cardiovascular risk in patiens with chronic kidney disease
• Klíčová slova: Biomarkery kardiovaskulárního rizika, diastolická funkce levé komory, echokardiografie, extracelulární nově identifikovaný RAGE-vazebný ligand (EN-RAGE/S100A12), fibroblastový růstový faktor 23 (FGF23), hmotnostní index levé komory (LVMI), hypertrofie levé komory (HLK), chronické onemocnění ledvin (CKD), placentární růstový faktor (PlGF), kardiovaskulární onemocnění, matrix-metaloproteinázy
• Klíčová slova anglicky: Biomarkers of cardiovascular risk, cardiovascular disease, chronic kidney disease (CKD), echocardiography, extracellular newly identified RAGE-ligand (EN-RAGE/S100A12), fibroblast growth factor 23 (FGF23), left ventricular diastolic function, left ventricular hypertrophy (LVH), left ventricular mass index (LVMI), placental growth factor (PlGF), matrix-metalloproteinases
• Akademický rok vypsání: 2013/2014
• Typ práce: disertační práce
• Jazyk práce: čeština
• Ústav: Ústav lékařské biochemie a laboratorní diagnostiky 1. LF UK a VFN (11-00410)
• Vedoucí / školitel: prof. MUDr. Marta Kalousová, Ph.D.
• Řešitel: skrytý - zadáno a potvrzeno stud. odd.
• Datum přihlášení: 11.08.2014
• Datum zadání: 11.08.2014
• Datum potvrzení stud. oddělením: 11.08.2014
• Datum a čas obhajoby: 16.06.2015 00:00
• Datum odevzdání elektronické podoby: 24.03.2015
• Datum proběhlé obhajoby: 16.06.2015
• Předmět: Obhajoba dizertační práce (B90002)
• Oponenti: prof. MUDr. Vladimír Teplan, DrSc.

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Předběžná náplň práce

Úvod:Vysoké kardiovaskulární riziko u pacientů s chronickým onemocněním ledvin je částečně způsobeno poruchou minerálové rovnováhy, mikrozánětem a oxidačním stresem. Pacienti s CKD kumulují tradiční i netradiční KV rizikové faktory. Mezi netradiční biomarkery spojené s KV rizikem patří i FGF23, matrix-metaloproteinázy a placentární růstový faktor. FGF23 je fosfaturický hormon a inhibitor syntézy kalcitriolu, je asociován s cévními kalcifikacemi. Matrix-metaloproteinázy ( MMP-2, MMP-9), jsou proteolytické a prozánětlivé enzymy, přispívající k remodelaci myokardu. Placentární růstový faktor (PlGF) je proangiogenní cytokin, který je ve zvířecím modelu spojen s hypertrofií levé komory. Hladiny FGF23, MMPs i PlGF jsou u CKD nemocných zvýšené.
Cíl:Cílem naší práce bylo popsat dynamiku změn vybraných nových biomarkerů KV rizika (FGF23, MMP-2, MMP-9 a PlGF) v různých stádiích CKD 1-5 a popsat jejich asociace s tradičními markery KV rizika. Dále jsme zjišťovali, zda existuje vztah mezi těmito markery a echokardiografickými parametry u nemocných s CKD stádia 2-4.
Metody:Do průřezové studie jsme zahrnuli 80 nemocných s CKD stádia 1-5 a 44 zdravých kontrol. V další, prospektivní studii, byl sledován vývoj echokardiografických parametrů u 62 subjektů s CKD 2-4, po průměrnou dobu 36±10 měsíců. Hladiny FGF23, MMP-2, MMP-9 a PlGF byly měřeny metodou ELISA. K detekci nezávislých korelací byla použita multivariantní regresní analýza.
Výsledky: V průřezové studii byly hladiny FGF23 a MMP-2 vyšší u CKD nemocných než u kontrol. Byly zjištěny nezávislé korelace mezi hladinou FGF23 a MMP-2, mezi FGF23 a parathormonem, mezi MMP-2 a fosfatémií, inverzní korelace mezi FGF23 a kalcitriolem. FGF23 bylo vyšší u osob s anamnézou KV onemocnění. V prospektivní studii byly počáteční vs. konečné parametry následující: zvýšení hmotnosti levé komory (LVMI) u 29% vs. 37,1% nemocných, diastolická dysfunkce LK u 74,1% vs. 75,8% nemocných. Byly zjištěny následující nezávislé korelace: LVMI s hladinou PlGF, cholesterolem, BNP, krevním tlakem a sérovým kreatininem. EN-RAGE s rozměrem levé síně a inverzně s poměrem E/A, jenž je korelátem diastolické funkce.
Závěry:Naše data svědčí pro asociaci markerů metabolické a kostní choroby se zánětem a KV rizikem u nemocných s CKD. Další výzkum by měl ukázat, zda jde o kauzální souvislost a zda terapeutická modulace hladin popsaných biomarkerů může zmírnit KV riziko u této populace.

Předběžná náplň práce v anglickém jazyce

Background:High cardiovascular risk in patients with chronic kidney disease is partly due to mineral dysbalance, microinflammation and oxidative stress. CKD patients accumulate traditional and non-traditional CV risk factors. FGF23, MMPs and PlGF belong among these non-traditional biomarkers of CV risk. FGF23 is a phosphaturic hormone and inhibitor of calcitriol synthesis. It is associated with vascular calcifications. Matrix-metalloproteinases (e.g. MMP-2, MMP-9) are proteolytic, proinflammatory enzymes, contributing to myocardial remodelation. Placental growth factor (PlGF) is a proangiogenic cytokine that is associated with LV hypertrophy in animal model. Plasmatic FGF23, MMPs and PlGF are elevated in CKD.
Aim:We aimed to describe dynamic changes between several novel biomarkers of CV risk (FGF23, MMP-2, MMP-9 and PlGF) in CKD stages 1-5, to describe their mutual correlations and possible association with traditional CV risk markers. We studied possible association of laboratory and echocardiographic parameters in patients with CKD stages 2-4.
Methods:In a cross-sectional study we evaluated 80 patiens with CKD 1-5 and 44 healthy controls. In a prospective study we evaluated echocardiographic and laboratory parameters in 62 patients with CKD 2–4 for an average study period of 36±10 months. FGF23, MMP-2, MMP-9 and PlGF serum levels were assessed by ELISA method.Multivariate regression analysis was used to detect independent correlations.
Results: In a cross-sectional study, plasmatic FGF23 and MMP-2 were higher in CKD patients versus controls. We detected following independent correlations: plasmatic FGF23 with MMP-2, plasmatic FGF23 with parathormone and inversely with calcitriol; MMP-2 with phosphate levels. Plasmatic FGF23 was higher in patients with CV disease history. In the prospective study, basic versus final measurement showed the following: increased left ventricular mass index (LVMI) in 29% versus 37,1% patients, LV diastolic dysfunction in 74,1% versus 75,8% patients. We detected the following independent correlations: LVMI was associated with PlGF levels, total cholesterol, BNP levels, systolic BP and serum creatinine levels. EN-RAGE was associated with left atrial diameter and inversely with E/A ratio.
Conclusions:Our data show an association of metabolic and bone disease with inflammation and CV risk in CKD patients. However, no data exist so far to prove causality of these associations. There is insufficient data about possible positive effect of therapeutic modulation of these biomarkers on CV risk in CKD population.