Eculizumab reduces complement activation, inflammation, endothelial damage, thrombosis, and renal injury markers in aHUS

Abstract

• This exploratory study describes the effect of eculizumab on multiple physiologic pathways affected by complement dysregulation in aHUS.• The results highlight the importance of sustained terminal complement blockade, even in patients with improved clinical laboratory values.Atypical hemolytic uremic syndrome (aHUS) is a genetic, life-threatening disease characterized by uncontrolled complement activation, systemic thrombotic microangiopathy (TMA), and vital organ damage. We evaluated the effect of terminal complement blockade with the anti-C5 monoclonal antibody eculizumab on biomarkers of cellular processes involved in TMA in patients with aHUS longitudinally, during up to 1 year of treatment, compared with in healthy volunteers. Biomarker levels were elevated at baseline in most patients, regardless of mutational status, plasma exchange/infusion use, platelet count, or lactate dehydrogenase or haptoglobin levels. Eculizumab reduced terminal complement activation (C5a and sC5b-9) and renal injury markers (clusterin, cystatin-C, b2-microglobulin, and liver fatty acid binding protein-1) to healthy volunteer levels and reduced inflammation (soluble tumor necrosis factor receptor-1), coagulation (prothrombin fragment F112 and D-dimer), and endothelial damage (thrombomodulin) markers to near-normal levels. Alternative pathway activation (Ba) and endothelial activation markers (soluble vascular cell adhesion molecule-1) decreased but remained elevated, reflecting ongoing complement activation in aHUS despite complete terminal complement blockade. These results highlight links between terminal complement activation and inflammation, endothelial damage, thrombosis, and renal injury and underscore ongoing risk for systemic TMA and progression to organ damage. Further research regarding underlying complement dysregulation is warranted. This trial was registered at www.clinicaltrials.gov as #NCT01194973. (Blood. 2015;125(21):3253-3262)

Atypical hemolytic uremic syndrome

“…The significantly increased levels of C5a and soluble C5b-9 (sC5b-9), markers of terminal complement activation, have been identified in the acute phase of aHUS compared with TTP or healthy controls [52,53]. Moreover, urine C5a, sC5b-9, and alternative pathway activation marker Ba are elevated in acute phase of aHUS, and these markers are decreased by eculizumab administration, with the exception of Ba [54]. However, Noris et al has reported that plasma C5a and sC5b-9 were not suitable markers for diagnosing aHUS, because these values were normal in 9 out of 19 cases even during the acute phase [55].…”

Thrombotic microangiophatic in the ICU, hemolytic uremic syndrome relate to pregnancy: case report and literature review

“…Los más frecuentes son los de tipo neurológico (48%), incluyendo irritabilidad, somnolencia, confusión, convulsiones, encefalopatía, accidente cerebrovascular, hemiparesias, hemiplejia o coma [12][13][14] , como ocurrió con esta paciente. El infarto agudo de miocardio se ha descrito hasta en un 3% de los pacientes con SHUa, pudiéndose relacionar con muerte súbita 12,15 . La variabilidad de la sintomatología dificulta el diagnóstico diferencial con otras causas de MAT.…”

“…A diferencia del SHU que se describió previamente, la trombosis intravascular en la PTT es consecuencia de una deficiencia severa de la actividad de la metaloproteasa ADAMST13, una enzima plasmática encargada de fragmentar los multímeros ultra largos de factor von Willebrand 15 . Actualmente, una deficiencia severa adquirida o congénita de ADAMTS13 (<5-10%) confirma el diagnóstico de Púrpura Trombocitopénica Trombótica (PTT).…”

“…Estudios recientes han demostrado que entre el 40-60% de pacientes con SHUa son portadores de mutaciones específicas en los genes del complemento, causando desregulación 15 de la vía alterna del complemento, en las más comunes se encuentran Factor H(CHF) (20-30%), MCP (5-15%), Factor I (4-10%), C3 (2-10%), Factor B (1-4%) y THBP (3-5%) 12 .…”

“…Según Roxanne y colaboradores 15 , en pacientes con SHUa, con y sin mutaciones del complemento identificados, se indica que el bloqueo del complemento terminal con Eculizumab interrumpe la progresión de la inflamación a la lesión renal y disfunción de órganos, a pesar de la evidencia de AP persistente y activación de células endoteliales.…”