Complement Activation and Thrombotic Microangiopathies

Author:

Palomo Marta,Blasco MiquelORCID,Molina Patricia,Lozano Miquel,Praga Manuel,Torramade-Moix Sergi,Martinez-Sanchez Julia,Cid Joan,Escolar Gines,Carreras Enric,Paules Cristina,Crispi Fatima,Quintana Luis F.,Poch Esteban,Rodas Lida,Goma Emma,Morelle JohannORCID,Espinosa Mario,Morales Enrique,Avila Ana,Cabello Virginia,Ariceta GemaORCID,Chocron Sara,Manrique JoaquinORCID,Barros Xoana,Martin Nadia,Huerta Ana,Fraga-Rodriguez Gloria M.,Cao Mercedes,Martin Marisa,Romera Ana Maria,Moreso Francesc,Manonelles Anna,Gratacos Eduard,Pereira Arturo,Campistol Josep M.,Diaz-Ricart Maribel

Abstract

Background and objectivesAtypical hemolytic uremic syndrome is a form of thrombotic microangiopathy caused by dysregulation of the alternative complement pathway. There is evidence showing complement activation in other thrombotic microangiopathies. The aim of this study was to evaluate complement activation in different thrombotic microangiopathies and to monitor treatment response.Design, setting, participants, & measurementsComplement activation was assessed by exposing endothelial cells to sera or activated-patient plasma—citrated plasma mixed with a control sera pool (1:1)—to analyze C5b-9 deposits by immunofluorescence. Patients with atypical hemolytic uremic syndrome (n=34) at different stages of the disease, HELLP syndrome (a pregnancy complication characterized by hemolysis, elevated liver enzymes, and low platelet count) or severe preeclampsia (n=10), and malignant hypertension (n=5) were included.ResultsAcute phase atypical hemolytic uremic syndrome–activated plasma induced an increased C5b-9 deposition on endothelial cells. Standard and lower doses of eculizumab inhibited C5b-9 deposition in all patients with atypical hemolytic uremic syndrome, except in two who showed partial remission and clinical relapse. Significant fibrin formation was observed together with C5b-9 deposition. Results obtained using activated-plasma samples were more marked and reproducible than those obtained with sera. C5b-9 deposition was also increased with samples from patients with HELLP (all cases) and preeclampsia (90%) at disease onset. This increase was sustained in those with HELLP after 40 days, and levels normalized in patients with both HELLP and preeclampsia after 6–9 months. Complement activation in those with malignant hypertension was at control levels.ConclusionsThe proposed methodology identifies complement overactivation in patients with atypical hemolytic uremic syndrome at acute phase and in other diseases such as HELLP syndrome and preeclampsia. Moreover, it is sensitive enough to individually assess the efficiency of the C5 inhibition treatment.

Funder

Spanish Kidney Research Network

Instituto de Salud Carlos III

[ISCIII]-RETIC

Red de Investigación Renal [REDinREN]

Fundació Miarnau

Jazz Pharmaceuticals

German Jose Carreras Leukaemia Foundation

ISCIII

Fondo de Investigación en Salud

Integrated Project in Health Institutes

Technology Development Projects in Health 2016

Centres de Recerca de Catalunya Programme of the Generalitat de Catalunya

Generalitat de Catalunya

Fondo Europeo de Desarrollo Regional [FEDER]

FEDER

Autonomous Region of Madrid

RedInRen

“La Caixa” Foundation

Cerebra Foundation for the Brain Injured Child

L’Agència de Gestió d’Ajuts Universitaris i de Recerca

Fundació Dexeus Mujer

Publisher

American Society of Nephrology (ASN)

Subject

Transplantation,Nephrology,Critical Care and Intensive Care Medicine,Epidemiology

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