Complement activation in secondary thrombotic microangiopathies

Nephrology Dialysis Transplantation, vol. 40, pp. 2193–2206

Abstract

Secondary thrombotic microangiopathies (TMAs) represent a heterogeneous group of diseases associated with a high risk of kidney failure and death despite available therapeutic strategies. Strong evidence implicates complement activation in the pathogenesis of secondary TMA, and emerging data increasingly suggest that pharmacological blockade of the complement improves the outcomes in patients with secondary TMA. Certain forms of secondary TMA, including postpartum TMA, TMA with coexisting hypertensive emergency and de novo TMA after kidney transplantation exhibit a high prevalence of pathogenic variants in complement genes, similar to those observed in primary atypical haemolytic uraemic syndrome. These conditions should be considered as complement-mediated TMA triggered by pregnancy or transplantation or in which severe hypertension represents a symptom rather than the aetiology of TMA. Their optimal management relies on early initiation of complement inhibition. Other aetiologies of secondary TMA (i.e. autoimmune diseases, haematopoietic stem cell transplantation, drugs, infections) are typically not linked with complement gene variants and their management primarily focuses on removal of the culprit trigger or treatment of the underlying condition. While well-designed trials are still awaited, a growing body of evidence suggests that complement activation is also involved in the pathophysiology of these diseases. Complement inhibitors, which have been associated with better outcomes, should be considered in patients with severe (life- or organ-threatening TMA) or refractory secondary TMA despite adequate management of the underlying condition. This review summarizes the current understanding and future directions in the management of secondary TMA, emphasizing the potential of complement inhibition as a therapeutic strategy.

Authors 15

1. Johann Morelle corresponding

   CHU Dinant Godinne UCL Namur · de Duve Institute · UCLouvain

   Affiliation as printed

   Division of Nephrology, University Hospitals Namur (CHU UCL Namur) , Namur ,

   de Duve Institute , UCLouvain, Brussels ,

   University Hospitals Namur (CHU UCL Namur) , Namur ,

2. Fernando Caravaca‐Fontán

   Research Institute Hospital 12 de Octubre · Hospital Universitario 12 De Octubre

   Affiliation as printed

   Instituto de Investigación Hospital ‘12 de Octubre’ (imas12) Department of Nephrology, , Madrid ,

3. Fádi Fakhouri

   Centre Hospitalier Universitaire Vaudois · University of Lausanne

   Affiliation as printed

   Division of Nephrology and Hypertension, CHUV, University of Lausanne , Lausanne ,

4. Eleni A. Frangou

   University of Nicosia · National and Kapodistrian University of Athens · Limassol General Hospital · Aretaeio Hospital

   Affiliation as printed

   Aretaieio Hospital, National and Kapodistrian University of Athens Medical School , Athens ,

   Limassol General Hospital Department of Nephrology, , State Health Services Organization, Limassol ,

   University of Nicosia Medical School Department of Basic and Clinical Sciences, , Nicosia ,

5. Annette N. Bruchfeld

   Linköping University · Karolinska University Hospital · Karolinska Institutet

   Affiliation as printed

   Karolinska University Hospital and CLINTEC Karolinska Institutet Department of Renal Medicine, , Stockholm ,

   Medicine and Caring Sciences, Linköping University Department of Health, , Linköping ,

   Linköping University Department of Health, Medicine and Caring Sciences, , Linköping ,

6. Jürgen Floege Aachen Division of Nephrology

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Division of Nephrology, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University Hospital , Aachen ,

7. Şafak Mirioğlu

   Bezmiâlem Vakıf Üniversitesi · Bezmiâlem Vakıf Üniversitesi Hastanesi · Istanbul University

   Affiliation as printed

   Aziz Sancar Institute of Experimental Medicine, Istanbul University Department of Immunology, , Istanbul ,

   Division of Nephrology, Bezmialem Vakif University Hospital , Istanbul ,

   Istanbul Faculty of Medicine, Istanbul University Division of Nephrology, Department of Internal Medicine, , Istanbul ,

   Division of Nephrology , Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul ,

8. Sarah Margaret Moran

   University College Cork · Cork University Hospital

   Affiliation as printed

   Cork University Hospital, University College Cork , Cork ,

9. Stefanie Steiger

   Ludwig-Maximilians-Universität München

   Affiliation as printed

   Ludwig-Maximilians-University Hospital Munich Division of Nephrology, Department of Medicine IV, , Munich ,

   Division of Nephrology , Department of Medicine IV, Ludwig-Maximilians-University Hospital Munich, Munich ,

10. Kate Stevens

    Queen Elizabeth University Hospital

    Affiliation as printed

    Queen Elizabeth University Hospital Glasgow Renal and Transplant Unit, , Glasgow ,

    Glasgow Renal and Transplant Unit, Queen Elizabeth University Hospital , Glasgow ,

11. Y K Onno Teng Aachen Department of Nephrology, Leiden Center of Expertise for Lupus, Vasculitis and Complement-mediated Systemic disease (LuVaCs) Department of Nephrology, Leiden University Medical Centre

    Leiden University · Leiden University Medical Center

    Affiliation as printed

    Leiden University Medical Center Center of Expertise for Lupus, Vasculitis and Complement-mediated Systemic disease (LuVaCs), Department of Nephrology, , Leiden ,

    Center of Expertise for Lupus, Vasculitis and Complement-mediated Systemic disease (LuVaCs) , Department of Nephrology, Leiden University Medical Center, Leiden ,

12. Selda Aydın

    Cliniques Universitaires Saint-Luc

    Affiliation as printed

    Cliniques Universitaires Saint-Luc Department of Pathology, , Brussels ,

    Cliniques universitaires Saint-Luc Department of Pathology, , Brussels ,

13. Anuja Java

    Washington University in St. Louis

    Affiliation as printed

    Division of Nephrology, Washington University School of Medicine Department of Medicine, , St. Louis, MO ,

    Division of Nephrology, Washington University School of Medicine Department of Medicine, , St. Louis, MO ;

14. Sjoerd A.M.E.G. Timmermans

    Maastricht University Medical Centre · Maastricht University

    Affiliation as printed

    Cardiovascular Research Institute Maastricht Department of Biochemistry, , Maastricht , and

    Expert Center for Immune-mediated Kidney Diseases and Vasculitis, Maastricht University Medical Center , Maastricht ,

    Cardiovascular Research Institute Maastricht Department of Biochemistry, , Maastricht ,

15. Andreas Kronbichler

    Linköping University · Innsbruck Medical University · Universität Innsbruck

    Affiliation as printed

    Linköping University Department of Health, Medicine and Caring Sciences, , Linköping ,

    Nephrology and Hypertension, Medical University of Innsbruck Department of Internal Medicine IV, , Innsbruck ,