Fenotyp vaskulární rejekce po transplantaci ledviny a izolovaná v-léze

• Název práce v češtině: Fenotyp vaskulární rejekce po transplantaci ledviny a izolovaná v-léze
• Název v anglickém jazyce: Phenotype of vascular rejection after kidney transplantations and isolated v-lesion
• Klíčová slova: transplantace ledviny, rejekce, intimální arteritida, v-léze
• Klíčová slova anglicky: kidney transplantation, rejection, intimal arteritis, v-lesion
• Akademický rok vypsání: 2015/2016
• Typ práce: disertační práce
• Jazyk práce: čeština
• Ústav: Institut klinické a experimentální medicíny (11-00020)
• Vedoucí / školitel: prof. MUDr. Ondřej Viklický, CSc.
• Řešitel: skrytý - zadáno a potvrzeno stud. odd.
• Datum přihlášení: 02.11.2015
• Datum zadání: 02.11.2015
• Datum potvrzení stud. oddělením: 02.11.2015
• Datum a čas obhajoby: 17.10.2024 11:15
• Místo konání obhajoby: Fyziologický ústav 1. LF UK
• Datum odevzdání elektronické podoby: 26.04.2024
• Datum proběhlé obhajoby: 17.10.2024
• Předmět: Obhajoba dizertační práce (B90002)
• Oponenti: MUDr. Jan Havlín, Ph.D.
• Konzultanti: doc. MUDr. Mariana Wohlfahrtová, Ph.D.

Seznam odborné literatury

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Předběžná náplň práce

Úvod: Intimální arteritida, v léze (v), je morfologickým podkladem vaskulární rejekce. Je současně řazena mezi diagnostická kritéria buňkami zprostředkované rejekce (TCMR), protilátkami zprostředkované rejekce (ABMR) a také může být způsobena ischemicko reperfuzním poškozením s morfologií izolované v-léze (IV). Prognóza transplantovaných ledvin je v těchto případech významně odlišná. Správná diagnostika, ke které přispěly i metody transkriptomické analýzy, je nezbytná pro volbu terapie odpovídající druhu poškození.
Metody: Databázovou analýzou jsme identifikovali četnost a prognostický význam jednotlivých fenotypů vaskulární rejekce. V následné prospektivní části byly provedeny kontrolní biopsie ke zhodnocení reakce na terapii. Pomocí microarray analýzy bioptických vzorků jsme porovnávali rozdílně regulované transkripty u IV a TCMRV.
Výsledky: Ve dvou postupně analyzovaných souborech pacientů (celkový počet 1896 osob) transplantovaných v letech 2010-2014 a následně 2014-2017 bylo identifikováno 25 pacientů s IV, 44 TCMRV, 36 ABMRV a 65 suspektních z ABMRV. Tříleté přežívání transplantovaných ledvin ve skupině TCMRV bylo více než 90 % a ve skupině ABMRV méně než 70 %. Ve skupině ABMRV nebyl v kontrolních biopsiích pozorován signifikantní ústup zánětlivých změn po terapii. Skupina izolované v-léze vykazovala nejvyšší přežívání (96 % ve 3 letech) a signifikantně nižší expresi s rejekcí asociovaných transkriptů než TCMRV.
Závěr: Intimální arteritida se vyskytuje u obou fenotypů rejekce, ale má rozdílnou reakci na terapii a prognózu. Exprese transkriptů asociovaných s rejekcí je u fenotypu časné izolované v-léze srovnatelná s nerejekčními nálezy což podporuje hypotézu o vlivu ischemicko reperfuzního poškození intimy cév transplantované ledviny.

Předběžná náplň práce v anglickém jazyce

Introduction: Intimal arteritis (v-lesion) may be judged as a morphologic feature of both T cell-mediated (TCMR) and antibody-mediated (ABMR) vascular rejection. Ischemic reperfusion injury may cause endothelial damage leading to isolated v-lesion (IV). Objectives of our research are correct identification of damage origin by transcriptomic analysis, response to treatment and prognostic impact.
Methods: We analysed medical records to identify incidence and outcome of vascular rejection phenotypes. Patients consented to undergo surveillance biopsies to confirm treatment outcome. We performed microarray analysis in selected IV and TCMRV cases to identify inflammation related transcripts and compare their activity between groups.
Results: We found 170 patients with v-lesion between 1896 transplanted from 2010 to 2017. We divided them into phenotype categories IV (N=25), TCMRV (N=44), ABMRV (N=36) and suspicious for ABMRV (or ABMRV DSA-) (N=65). Graft survival of TCMRV exceeded 90 % in 3 years compared to less than 70 % in the ABMRV group. Despite treatment, we did not observe histologic resolution of inflammation in ABMRV group, while in other groups histologic changes significantly improved. Microarray analysis showed lower activation of rejection associated transcripts in IV in comparison with the TCMRV group.
Conclusions: Prognosis of intimal arteritis due to T cell-mediated rejection is significantly better than during antibody-mediated rejection. Expression of rejection associated transcripts is comparable between early isolated v-lesion and normal samples supporting hypotheses of its origin during ischemic reperfusion injury.