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Clin J Am Soc Nephrol. 2019 Nov 6. pii: CJN.05830519. doi: 10.2215/CJN.05830519. [Epub ahead of print]

Complement Activation and Thrombotic Microangiopathies.

Author information

1
Josep Carreras Leukaemia Research Institute; mpalomo@carrerasresearch.org.
2
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.
3
Barcelona Endothelium Team, Barcelona, Spain.
4
Department of Nephrology and Renal Transplantation, Hospital Clinic de Barcelona, Universitat de Barcelona, Spain.
5
Group of nephro-urological diseases and renal transplantation (IDIBAPS), Barcelona, Spain.
6
Apheresis Unit, Department of Hemotherapy and Hemostasis, Institut Clinic de Malalties Hematologiques i Oncologiques (ICMHO), IDIBAPS, Hospital Clinic de Barcelona, Universitat de Barcelona, Barcelona, Spain.
7
Department of Nephrology, Hospital Universitario 12 de Octubre and Research Institute i+12, Madrid, Spain.
8
Department of Medicine, Universidad Complutense, Madrid, Spain.
9
Josep Carreras Leukaemia Research Institute.
10
Fetal i+D Fetal Medicine Research Center, BCNatal - Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clinic de Barcelona and Hospital Sant Joan de Deu), ICGON, IDIBAPS, Universitat de Barcelona and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER), Barcelona, Spain.
11
Division of Nephrology, Cliniques universitaires Saint-Luc, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.
12
Department of Nephrology, Hospital Universitario Reina Sofía e Instituto Maimonides de Investigaciones Biológicas de Córdoba (IMIBIC), Córdoba, Spain.
13
Department of Nephrology and Renal Transplantation, Hospital Universitario Dr Peset, Valencia, Spain.
14
Department of Nephrology, Hospital Virgen del Rocio, Sevilla, Spain.
15
Department of Pediatric Nephrology, Hospital Materno-Infantil, Vall d'Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain.
16
Department of Nephrology, Complejo Hospitalario de Navarra, Pamplona, Spain.
17
Department of Nephrology, Hospital Universitari Josep Trueta, Girona, Spain.
18
Department of Nephrology, Hospital Puerta de Hierro Majadahonda, Madrid, Spain.
19
Department of Pediatric Nephrology, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain.
20
Department of Nephrology, Complejo Hospitalario Universitario A Coruña, Coruña, Spain.
21
Department of Nephrology, Hospital Universitari Arnau de Vilanova, Lleida, Spain.
22
Department of Nephrology, Hospital General Universitario, Ciudad Real, Spain.
23
Department of Nephrology, Hospital Universitari Vall d'Hebron, Universitat Autonoma Barcelona, Barcelona, Spain.
24
Kidney Transplant Unit, Department of Nephrology, Hospital de Bellvitge, Universitat de Barcelona, Barcelona, Spain; and.
25
CDB, Barcelona, Spain.

Abstract

BACKGROUND AND OBJECTIVES:

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 (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.

RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

HELLP syndrome; alternative; antibodies; atypical hemolytic uremic syndrome; complement C9; complement activation; complement membrane; complement pathway; complement system proteins; eculizumab; endothelial cells; female; fibrin; fluorescent antibody technique; humanized; humans; hypertension; malignant; monoclonal; pre-eclampsia; pregnancy; recurrence; thrombotic microangiopathies

PMID:
31694864
DOI:
10.2215/CJN.05830519

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