Josep Carreras Leukaemia Research Institute.
Hematopathology, Department of Pathology, Centre de Diagnostic Biomedic (CDB), Hospital Clinic de Barcelona, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.
Clin J Am Soc Nephrol. 2019 Dec 6;14(12):1719-1732. doi: 10.2215/CJN.05830519. Epub 2019 Nov 6.
Atypical 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, & MEASUREMENTS: Complement 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 (=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 (=10), and malignant hypertension (=5) were included.
Acute 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.
The 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.
非典型溶血性尿毒症综合征是一种由替代补体途径失调引起的血栓性微血管病。有证据表明其他血栓性微血管病中存在补体激活。本研究旨在评估不同血栓性微血管病中的补体激活，并监测治疗反应。
设计、设置、参与者和测量方法：通过将内皮细胞暴露于血清或激活的患者血浆-柠檬酸化血浆与对照血清池（1:1）混合，来评估补体激活，并用免疫荧光法分析 C5b-9 沉积物。纳入不同疾病阶段的非典型溶血性尿毒症综合征患者（=34）、HELLP 综合征（一种以溶血、肝酶升高和血小板计数低为特征的妊娠并发症）或严重先兆子痫（=10）和恶性高血压（=5）。
急性非典型溶血性尿毒症综合征激活的血浆诱导内皮细胞上 C5b-9 沉积物增加。标准和低剂量的依库珠单抗抑制所有非典型溶血性尿毒症综合征患者的 C5b-9 沉积，除了两名患者显示部分缓解和临床复发。观察到与 C5b-9 沉积一起的显著纤维蛋白形成。使用激活的血浆样本获得的结果比使用血清样本获得的结果更明显且更具重现性。在疾病发作时，HELLP（所有病例）和先兆子痫（90%）患者的样本中 C5b-9 沉积也增加。在 HELLP 患者中，这种增加持续 40 天后，HELLP 和先兆子痫患者在 6-9 个月后水平恢复正常。恶性高血压患者的补体激活处于对照水平。
所提出的方法可识别急性非典型溶血性尿毒症综合征患者和其他疾病（如 HELLP 综合征和先兆子痫）中的补体过度激活。此外，它足够灵敏，可以单独评估 C5 抑制治疗的效果。
