Gene analysis of the complement system in adult patients with elements of thrombotic microangiopathy – case series

Autori:

Dino Kasumović, Nikola Zagorec, Miroslav Tišljar, Ivica Horvatić, Petar Šenjug, Danica Galešić Ljubanović, Krešimir Galešić

Sažetak
Trombotična mikroangiopatija (TMA) je patohistološki entitet obilježen stvaranjem tromba u mikrocirkulaciji, a klinički se definira posljedičnom mikroangiopatskom hemolitičkom anemijom (MAHA) i trombocitopenijom uz oštećenje ciljnih organa, najčešće akutnim oštećenjem bubrega (ABO). Određivanje etiologije može biti složeno. Oblik bolesti trombotična trombocitopenična purpura (TTP) uzrokovan je smanjenom aktivnošću proteaze ADAMTS13. Većina drugih oblika tzv. sekundarne TMA, vezana je etiološki uz neki patogeni proces u organizmu, najčešće hipertenzivnu krizu. Međutim, i u tim stanjima moguć je poremećaj sustava komplementa, što je glavno etiološko obilježje primarnog atipičnog hemolitičko-uremijskog sindroma (aHUS). Zbog toga je važna serološka analiza sustava komplementa, a u nekim slučajevima i njegova genska analiza. Prikazujemo karakteristike deset pacijenata kod kojih su prisutni laboratorijski i/ili patohistološki elementi TMA i u kojih je učinjena i serološka i genska analiza sustava komplementa. U troje pacijenata nađene su patogene ili vjerojatno patogene genske varijante povezane s dijagnozom primarnog aHUS-a. Svi oni su imali MAHA i ABO te patohistološki dokazanu TMA. Kod druge skupine od troje pacijenata nađena je na biopsiji bubrega TMA, ali su svi ostali rezultati (uključujući gensku analizu sastavnica komplementa) bili neupadljivi. Radilo se o pacijentima koji su se prezentirali hipertenzivnom krizom, a testiranje je provedeno u svrhu predtransplantacijske obrade. Kod preostalih četvero pacijenata pronađene su rizične genetske varijante za razvoj aHUS-a. Svi ovi pacijenti (osim jednog) imali su MAHA + ABO. U dva pacijenta nije nađena TMA u tkivu bubrega, no biopsija je učinjena mjesec dana nakon akutne bolesti. Genetska analiza sustava komplementa preporučuje se učiniti ako nema jasnoga sekundarnog uzroka TMA ili ako je važna za određivanje terapije, odnosno za transplantaciju bubrega.
Summary

Thrombotic microangiopathy (TMA) is a pathohistological entity characterized by the formation of thrombi in microcirculation, with clinically defined consequent microangiopathic hemolytic anemia (MAHA) and thrombocytopenia with damage to target organs, most often acute kidney injury (AKI). Determining the etiology can be complex. Thrombotic thrombocytopenic purpura (TTP) is caused by reduced activity of the protease ADAMTS13. Most other forms, so-called secondary TMA, are etiologically linked to some pathogenic process in the body, most often a hypertensive crisis. Even in these conditions, a disorder of the complement system is possible, which is the main etiological feature of primary atypical hemolytic uremic syndrome (aHUS). This is why serological analysis of the complement system, and in some cases its genetic analysis, is important. We present the characteristics of ten patients in whom laboratory and/or pathohistological elements of TMA were present, and in whom both serological and gene analysis of the complement system were performed. Genetic pathogenic or likely pathogenic variants associated with the diagnosis of primary aHUS were found in three patients. All of them had MAHA and AKI and pathohistologically proven TMA. In another group of three patients, TMA was found on kidney biopsy, but all other results (including gene analysis of complement components) were unremarkable. These were patients who presented with hypertensive crisis, and the testing was done for the purpose of pretransplant workup. In the remaining four patients, genetic risk variants for the development of aHUS were found. All these patients (except one) had MAHA + AKI. In two patients no TMA was found in the kidney tissue – but the biopsy was done one month after the acute illness. Gene analysis of the complement system is recommended if there is no clear secondary cause of TMA or if it is important for determining therapy, or for kidney transplantation.