Functional and Genetic Landscape of Complement Dysregulation Along the Spectrum of Thrombotic Microangiopathy and its Potential Implications on Clinical Outcomes

S.A.M.E.G. Timmermans, J.G.M.C. Damoiseaux, A. Werion, C.P. Reutelingsperger, J. Morelle, P. van Paassen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Introduction: The syndromes of thrombotic microangiopathy (TMA) are diverse and represent severe endothelial damage caused by various mechanisms. The complement system plays a major role in a subset of patients with TMA, and its recognition is of clinical importance because it guides choice and duration of treatment.

Methods: We studied a well-defined cohort of patients with TMA and hypothesized that assessment of serum-induced ex vivo C5b9 formation on the endothelium and screening for rare variants in complement genes can better categorize TMA.

Results: Massive ex vivo C5b9 formation was found in all patients with primary atypical hemolytic uremic syndrome (n/N = 11/11) and in 59% of patients with TMA and coexisting conditions (n/N = 30/51). Massive ex vivo C5b9 formation was associated with rare genetic variants (45% [n/N = 20/44] vs. 0% [n/N = 0/21] patients with normal ex vivo C5b9 formation; P < 0.001). Massive ex vivo C5b9 formation was associated with favorable renal response to therapeutic complement inhibition in patients with TMA and coexisting conditions (86% [n/N = 12/14] vs. 31% [n/N = 5/16] of untreated patients; P < 0.001), indicating complementmediated TMA rather than secondary disease. Among treated patients, the odds ratio for 1-year kidney survival was 12.0 (95% confidence interval 1.2-115.4). TMA recurrence was linked to rare genetic variants in all cases. Patients with normal ex vivo C5b9 formation had an acute, nonrelapsing form of TMA.

Conclusions: Ex vivo C5b9 formation and genetic testing appears to categorize TMAs into different groups because it identifies complement as a driving factor of disease, with potential therapeutic and prognostic implications.

Original languageEnglish
Pages (from-to)1099-1109
Number of pages11
JournalKidney International Reports
Issue number4
Publication statusPublished - 1 Apr 2021


  • atypical hemolytic uremic syndrome
  • complement
  • eculizumab
  • hypertensive emergency
  • kidney transplantation
  • pregnancy
  • thrombotic microangiopathy
  • AHUS

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