ATIPIČNI HEMOLITIČNI UREMIČNI SINDROM. Polona Novak Samo Zver Jože Pretnar
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1 + ATIPIČNI HEMOLITIČNI UREMIČNI SINDROM Polona Novak Samo Zver Jože Pretnar
2 + Hemolitični uremični sindrom (HUS) Urgentno stanje Pogostejši pri otrocih Triada: mikroangiopatska hemolitična anemija, trombocitopenija, akutna ledvična odpoved 2 tipa HUS: D+ in D- D+ HUS predstavlja 95% primerov pri otrocih Šiga in verotoksin: poškodba endotelija (E.coli O157:H7, S. pneumoniae, Shigella dysenteriae): izjeme! V 33% primerov prisotna nevrološka simptomatika Podporno zdravljenje
3 + Trombotična trombocitopenična purpura TTP: pentada v zelo nizkem odstotku Mikroangiopatska hemolitična anemija, trombocitopenija, z ali brez ledvične odpovedi, z ali brez nevrološke simptomatike, brez druge možne etiologije (sepsa, DIK, ) Ali ima nivo ADAMTS13 prognostično vlogo različne študije Otroci brez ledvične odpovedi Diagnoza TTP: plazmafereza Preživetje iz 10 na 80% George JN. How I treat patients with thrombotic thrombocytopenic purpura: Blood
4 +
5 + Atipični hemolitični uremični sindrom HUS brez diareje = ATIPIČNI HUS 5% HUS pri otrocih predvsem do 1. leta in polovica primerov ahus pri adolescentih in odraslih Incidenca 2/mio Ponovitve pogoste pri ahus, pri HUS ne Pomanjkanje ADAMTS13 kot pri TTP, a huda ALO pri ahus, aktivnost ADAMTS13 manj kot 5% pri TTP Nevrološka simptomatika pri 20% Mortaliteta: 25% Končna ledvična odpoved pri 50% Sanchez-Corral, Melgosa: Advances in understanding the aetiology of atypical Haemolytic Uraemic Syndrome. British journal of hematology 2010
6 + Mehanizmi Disregulacija alternativne poti komplementnega sistema pri več kot 50% primerov: mutacije proteinov komplementa Protitelesa proti komplementnemu faktorju H (CFH) (6-10%) Mutacije CD46 (10-15%) najboljša prognoza (80% brez dialize) CFI (4-19%) CFB (1-2%) in C3 Gen za trombomodulin (5%) Inkompletna penetranca (okužba 35-50%, kontracepcijske tablete 8-20%) Glomerulne kapilare zaradi fenestriranega endotelija bolj občutljive Ostala polovica primerov: idiopatska, druge motnje v komplementu, motnje v metabolizmu kobalamina, ADAMTS13
7 + Slika: Neustrezna regulacija alternativne poti komplementnega sistema vodi v trombotično mikroangiopatijo. (Noris, Remuzzi New England Journal of Medicine, 2009)
8 + Vzročni dejavniki Familiarna (20%) slaba prognoza in sporadična oblika Virusi (neenteralni), tumorji, transplantacija, nosečnost, skleroderma, antifosfolipidni sindrom, HIV, kontracepcijske tablete Protitumorska zdravila (mitomicin, cisplatin, bleomicin, gemcitabin) Imunosupresivi: ciklosporin, takrolimus Antiagregacijska zdravila: tiklopidin, klopidogrel 50 % sporadičnih je idiopatskih
9 + Diagnoza Klinična slika Krvni razmaz: shizociti Hemogram, DKS, testi hemostaze, elektroliti, LDH, indirektni bilirubin, sečnina, kreatinin, coombs test, ADAMTS13 antigen in protitelesa Koprokulura (izključitev šiga- in verotoksina) HIV, ANA, AFP glede na anamnezo DD: TTP, HUS, ITP, DIK, HELLP, SLE, AFS, sepsa, tumorji, maligna hipertenzija
10 + Specifična diagnostika Pred plazmaferezami ELISA za protitelesa proti faktorju H Nivo faktorjev I, B in H v krvi imunološki testi IMI (kvantitativno, kvalitativno več) Nivoji C3, C4 IMI CD46 mutacije pretočna citometrija Funkcionalno testiranje: faktor H Genetsko testiranje mutacij (več mesecev) dokončna diagnoza Nizek nivo C3 v serumu in normalen C4 kaže na porabo in aktivacijo alternativne poti komplementa pri CFH, CFI, CD46, (C3 je v 50% normalen ) C3 depoziti v glomerulih in arteriolah kažejo na aktivacijo komplementa
11 + Zdravljenje Guidelines European Working Group on HUS Začetek plazmaferez v prvih 24-urah (s sveže zamrznjeno plazmo): 1-2 volumna na dan, vzporedno podporna terapija (transfuzije, dializa, antihipertenzivi), čakanje izvida za toksine Kljub plazmaferezam možna končna ledvična odpoved (mortaliteta iz 50% na 25%) Remisija: Tr nad tedna, brez hemolize, Dokazana protitelesa proti faktorju H: kortikosteroidi, azatioprin, mikofenolat, rituximab, ciklofosfamid Refraktrane oblike: vinkristin, ciklosporin A Koncentrat faktorja H v razvoju (nadomestilo za plazmafereze) Transplantacija (30-100% ponovitev) Taylor CM et al: Clinical Practice Guidelines dor the management of atypical Hemolytic Uraemic Syndrome in UK, British journal of hematology 2009
12 Zdravljenje Eculizumab (FDA odobritev septembra 2011 za odrasle in otroke): monoklonsko protitelo - inhibira komplementni protein C5 Učinkovit za zdravljenje refraktarnega ahus Doziranje: 900 mg prve 4 tedne, 1200 mg 5. teden, 1200 mg na 2 tedna predvidoma 6 mesecev Kombinirano zdravljenje s plazmaferezami: mg do 60 min po plazmaferezah Neisseria meningitidis Waters AM, Licht C: Pediatr Nephrol 2011: ahus caused by complement dysregulation: new therapies on the horizon
13 + Indikacije za transplantacijo Transplantacija ledvic: ponovitve bolezni! Vedno skupaj z intenzivno perioperativno plazmaferezo, ali IVIG, rituximab Mutacije faktorja H ali I: kombinirana tx ledvice in jeter, tx ledvic le izjemoma Mutacije CD46: tx ledvic (učinkovito) Mutacije B ali C3: premalo izkušenj s kombinirano presaditvijo, veliko ponovitev pri izolinarni tx ledvic Kombinirane mutacije: premalo podatkov Protitelesa proti faktorju H izolirana tx ledvic, če je titer nizek
14 + Klinični primer: HUS, ahus, TTP? KO za nefrologijo UKC Ljubljana 26-letna bolnica: prehlad, kontracepcijske tablete, hudo poslabšanje zdravstvenega stanja Tr 58, Hb 116, shizociti 1.5%, LDH 8,6, bilirubin cel. 31, dir.7, sečnina 7,1, kreatinin 173, MCV 81,9, blaga nevrološka simptomatika, vročina, driska ADAMTS13 antigen: 1589 ( ng/ml) ADAMTS13 protitelesa: 29,7 (poz. nad 9,6 E/mL) Zdravljenje: po 3 plazmaferezah Tr 136, Hb 100, kreatinin 221, bilirubin cel. 25, dir. 8, LDH 3,18 Nivo faktorja H normalen Nato remisija Diagnoza ob odpustu: ahus
15 + Zaključek Imena so pomembna: različno zdravljenje in prognoza Velik napredek pri razumevanju etiologije, nove možnosti zdravljenja Izboljšanje diagnostike: registri ahus, objava primerov, delovna skupina, številne nove klinične študije Glede na učinkovitost Eculizumaba nove smernice za transplantacijo Eculizumab pri nas (emea) Izboljšanje diagnostike pri nas (aktivnost CF, protitelesa proti CFH, CD46, genetska analiza)
16 + Hvala za pozornost!
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