Complement activation in secondary thrombotic microangiopathies
- PMID: 40372375
- PMCID: PMC12559796
- DOI: 10.1093/ndt/gfaf091
Complement activation in secondary thrombotic microangiopathies
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.
Keywords: acute kidney injury; complement inhibition; complement system; haemolytic uraemic syndrome; thrombotic microangiopathy.
© The Author(s) 2025. Published by Oxford University Press on behalf of the ERA.
Conflict of interest statement
J.M. reports consultancy for Alexion Pharmaceuticals, AstraZeneca, Bayer, CSL Vifor, EG Specialty Care, GSK, Novartis, Sanofi-Genzyme and Versantis; research funding from Alexion Pharmaceuticals, AstraZeneca; speaker honoraria from Alexion Pharmaceuticals, AstraZeneca and Novartis and travel grants from Alexion Pharmaceuticals, AstraZeneca, CSL Vifor and Sanofi-Genzyme, outside the submitted work. F.C.-F. has received consultancy and/or speaker honoraria from Novartis, Apellis, SOBI, Otsuka, Alexion and AstraZeneca, outside the submitted work. F.F. has received consulting fees and honoraria from Alexion, Apellis, Roche, AstraZeneca, Novartis, Sobi and Vifor. E.F. has received contracts and support from the State Health Services Organization of Cyprus and honoraria from AstraZeneca, outside the submitted work. A.B. has received consultancy fees from Alexion, Boehringer Ingelheim and CSL Vifor and payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing or educational events from AstraZeneca, Bayer, Boehringer Ingelheim, Chemocentryx, CSL Vifor, Fresenius, GSK and Otsuka. J.F. has received consultancy and/or speaker honoraria from Alexion, AstraZeneca, Boehringer Ingelheim, Biogen, CSL Vifor, Novartis, Otsuka, Roche, Travere and Vera Therapeutics. He is also a member of the data safety monitoring board in studies by Novo Nordisk and AstraZeneca and he coordinates the KDIGO glomerular disease guidelines. S.M. reports receiving support for attending meetings and travel from Amgen and Sanofi Genzyme. S.S. reports contracting fees from AstraZeneca. K.I.S. has received consultancy fees from Bayer, Boehringer Ingelheim and CSL Vifor, outside the submitted work. A.J. serves on scientific advisory boards for Alexion, AstraZeneca Rare Disease and Novartis Pharmaceuticals; is also a principal investigator for Novartis Pharmaceuticals and has served as a consultant for Dianthus Therapeutics and Aurinia Pharmaceuticals and as a principal investigator for Apellis Pharmaceuticals and receives royalties from UpToDate. S.A.M.E.G.T. reports research funding from the Dutch Kidney Foundation and has received speaker honoraria and travel grants from Alexion Pharmaceuticals. A.K. reports grants or contracting fees from CSL Vifor and Otsuka and consulting fees from Amgen, AstraZeneca, Boehringer Ingelheim, CSL Vifor, Delta4, GSK, Novartis, Novo Nordisk, Otsuka, Roche, Sobi and Walden Biosciences. All other authors have nothing to disclose.
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