Izražaj koštanih morfogenetskih proteina u kirurški odstranjenim presađenim bubrezima

Furić Čunko, Vesna (2012) Izražaj koštanih morfogenetskih proteina u kirurški odstranjenim presađenim bubrezima. PhD thesis, Sveučilište u Zagrebu.

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Abstract

INTRODUCTION: In Republic of Croatia around 450000 people has an increased risk or manifest chronic kidney disease. Kidney transplantation is method of choice in managing end stage kidney disease. Improvement in immunosuppressive therapy lowered the number of acute allograft rejection episodes, but long-term allograft function remains unchanged over the past 20 years. Finding key players involved in the process of chronic graft disfunction was one of the driving forces of this Thesis AIM: The aim of this Thesis was to investigate the connection between expression pattern of bone morphogenetic proteins in kidney allograft tissue and the cause of allograft dysfunction and the subsequent need for transplant nephrectomy. By performing this study our aim was to show a difference in bone morphogenetic protein expression pattern in normal and allograft kidney tissue, and that this difference is connected to the cause of allograft dysfunction that was the clinical indication for transplant nephrectomy. METHODS: A total of 50 kidney allografts were analyzed. They were obtained by transplant nephrectomy due to different clinical indication. Expression pattern of BMP-2, BMP-4. BMP-6 and BMP-7 in normal and allograft kidney tissue was shown by immunohistochemical staining. Normal kidney tissue was obtained from kidneys with localized kidney tumor that were surgically removed. Tissue that was taken from the most distant point from the tumor was analyzed. The difference in bone morphogenetic protein expression was calculated by Fisher exact test. RESULTS: In this study it has been shown that the most common indications for transplant nephrectomy in the first three months after transplantation were host infection that demanded reduction of immunosuppression, renal artery or vein thrombosis and surgical complications. In the second period after 12 months after transplantation, chronic allograft dysfunction was the most common indication for transplant nephrectomy. In kidney transplant tissue that was removed during the first 3 months BMP-6 expression was higher in comparison to BMP-6 expression in normal kidney tissue. In transplanted kidney tissue that was removed more than 12 months after transplantation BMP-4 and BMP-7 expression in tubular epithelial cells was significantly lower than in normal kidney tissue. In transplanted kidney tissue that was removed due to thrombosis of renal artery or vein BMP-6 expression was significantly higher in tubular epithelial cells than in normal kidney tissue. The expression of BMP-2, BMP-4 and BMP-7 did not differ between transplanted and normal kidney tissue in this group. In transplanted kidney tissue that was removed due to life threatening infection that demanded cessation of immunosuppressive therapy BMP-4 and BMP-6 expression was significantly higher in tubular epithelial cells than in normal kidney tissue. BMP-4 and BMP-7 expression was statistically lower in tubular epithelial cell of kidney transplants that were removed due to chronic allograft dysfunction in comparison to normal kidney tissue. Comparison of transplanted kidney tissue without signs of interstitial fibrosis and tubular atrophy (IFTA) with kidney tissue that displayed grade II and III of IFTA showed that BMP-4, BMP-6 and BMP-7 had statistically higher expression in tissue without IFTA. BMP-4 and BMP-7 had significantly lower expression in epithelial tubular cells of transplanted kidney tissue with IFTA II and IFTA III in comparison with normal kidney tissue. BMP-4 and BMP-6 had significantly higher expression in epithelial tubular cells in transplanted kidney tissue with acute T cell mediated rejection in comparison with normal kidney tissue. BMP-4 had significantly stronger expression in proximal tubular epithelial cells in comparison with distal and medullar epithelial cells in normal kidney tissue, in transplanted kidney tissue that was removed within first 3 months after transplantation, and in transplanted kidney tissue without IFTA. In kidney transplant specimens with IFTA II and III BMP-4 had uniform significantly lower expression in comparison with specimens without fibrosis. Loss of morphological characteristics of tubular epithelial cells brings a loss of BMP-4 expression diversity among different tubular epithelial cells. CONCLUSION: Intensity and expression pattern of bone morphogenetic proteins in transplanted kidney tissue is dependent upon the length of the transplanted period, clinical indication for transplant nephrectomy and signs of interstitial fibrosis and tubular atrophy in kidney tissue.

Abstract in Croatian

UVOD: U Republici Hrvatskoj oko 450000 osoba boluje od kronične bolesti bubrega ili ima povećani rizik za njezin razvoj. Transplantacija bubrega je metoda izbora u liječenju završnog stadija kroničnog zatajenja bubrega. Razvojem i usavršavanjem imunosupresivne terapije smanjen je broj epizoda akutnih odbacivanja presadaka, ali prosječno preživljenje presatka stagnira posljednjih 20 godina. Potraga za čimbenicima koji su uključeni u proces oštećenja i gubitka funkcije presatka jedan je od motiva istraživanja u ovoj disertaciji. CILJ ISTRAŽIVANJA: Cilj doktorskog rada bio je ispitati povezanost uzorka izražaja koštanih morfogenetskih proteina( BMP) i uzroka poremećaja funkcije presatka i posljedičnog kirurškog odstranjenja. Ovim istraživanjem željeli smo pokazati da postoji razlika uzorka izražaja koštanih morfogenetskih proteina u tkivu kirurški uklonjenog presatka i zdravom tkivu bubrega te da je ta razlika u izražaju povezana s uzrokom poremećaja funkcije presatka koji je bio indikacija za njegovo kirurško uklanjanje. ISPITANICI I METODE: Istraženo je tkivo 50 bubrežnih presadaka koji su kirurški uklonjeni iz bolesnika zbog različitih indikacija nakon transplantacije. Imunohistokemijskom metodom prikazan je izražaj proteina BMP-2, BMP-4. BMP-6 i BMP-7 u tkivu transplantiranih bubrega i u normalnom tkivu bubrega kontrolne skupine. Kontrolnu skupinu činili su uzorci normalnog tkiva bubrega, dobiveni nefrektomijom bolesnika s lokaliziranim tumorom bubrega. Za analizu je korišteno tkivo uzeto s najudaljenijeg mjesta od sijela tumora. Razlika u izražaju koštanih morfogenetskih proteina utvrđena je korištenjem Fisherovog testa. REZULTATI: Ovim istraživanjem je pokazano da su najčešće indikacije za kirurško uklanjanje presatka bubrega u prva tri mjeseca nakon transplantacije bile su infekcije primatelja zbog kojih je ukinuta imunosupresivna terapija, tromboza arterije ili vene bubrega i kirurške komplikacije. U razdoblju nakon 12 mjeseci najčešća indikacija za kirurško uklanjanje bila je kronična disfunkcija presatka. U tkivu transplantiranih bubrega uklonjenih u prva tri posttransplantacijska mjeseca izražaj BMP-6 u epitelnim stanicama kanalića bubrežnog parenhima je statistički značajno jači u odnosu na izražaj BMP-6 u epitelnim stanicama kanalića bubrežnog parenhima kontrolne skupine. U tkivu bubrega transplantiranom duže od 12 mjeseci postoji statistički značajno slabiji izražaj BMP-4 i BMP-7 u epitelnim stanicama kanalića bubrežnog parenhima u odnosu na izražaj u normalnom tkivu bubrega. U uzorcima tkiva transplantiranih bubrega koji su kirurški uklonjeni zbog tromboze velikih krvnih žila presatka BMP-6 je bio statistički značajno jače izražen u epitelnim stanicama kanalića bubrežnog parenhima u odnosu na kontrolnu skupinu. Izražaj BMP-2, BMP-4, BMP-7 se nije razlikovao u uzrocima transplantiranog tkiva bubrega i kontrolnoj skupni. U uzrocima tkiva transplantiranih bubrega uklonjenih zbog životno ugrožavajuće infekcije koja je zahtijevala ukidanje imunosupresije BMP-4 i BMP-6 su bili statistički značajno jače izraženi u epitelnim stanicama kanalića bubrežnog parenhima u odnosu na kontrolnu skupinu. Koštani morfogenetski proteini 4 i 7 su statistički značajno slabije izraženi u epitelnim stanicama kanalića bubrežnog parenhima tkiva presadaka bubrega uklonjenih zbog kronične insuficijencije presatka u odnosu na kontrolnu skupinu. Izražaj BMP-4, BMP-6 i BMP-7 statistički je značajno jače izražen u epitelnim stanicama kanalića bubrežnog parenhima tkiva transplantiranih bubrega bez znakova fibroze intersticija i tubularne atrofije u odnosu na uzorke transplantiranih bubrega sa znakovima fibroze intersticija i tubularne atrofije II i III stupnja. BMP-4 i BMP-7 statistički su značajno slabije izraženi u epitelnim stanicama kanalića tkiva bubrega sa intersticijskom fibrozom i tubularnom atrofijom II i III stupnja u odnosu na zdravo tkivo bubrega. BMP-4 i BMP-6 su statistički značajno jače izraženi u epitelnim stanicama bubrežnih kanalića uzoraka s T staničnim odbacivanjem u odnosu na kontrolnu skupinu. BMP-4 je statistički značajno jače izražen u epitelnim stanicama proksimalnih kanalića u odnosu na distalne i kanaliće srži u uzorcima zdravog tkiva bubrega i u tkivu presađenih bubrega uklonjenih u prva 3 mjeseca od transplantacije te u uzorcima presadaka bez znakova intersticijske fibroze i tubularne atrofije. U uzorcima presadaka bubrega s intersticijskom fibrozom i tubularnom atrofijom BMP-4 je jednolično statistički značajno slabije izražen u odnosu na uzorke bez intersticijske fibroze i tubularne atrofije. Gubitkom morfoloških karakteristika kanalića gubi se i razlika u izraženosti BMP-4 između pojedinih vrsta kanalića. ZAKLJUČAK: Jačina i uzorak izražaja koštanih morfogenetskih proteina u tkivu presađenog bubrega ovisi o vremenskom periodu koliko je presadak bio u primatelju bubrega, o kliničkoj indikaciji za kirurško uklanjanje presatka i o postojanju intersticijske fibroze i tubularne atrofije u tkivu presatka.

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