Abstract
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 language | English |
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Pages (from-to) | 1099-1109 |
Number of pages | 11 |
Journal | Kidney International Reports |
Volume | 6 |
Issue number | 4 |
DOIs | |
Publication status | Published - 1 Apr 2021 |
Keywords
- atypical hemolytic uremic syndrome
- complement
- eculizumab
- hypertensive emergency
- kidney transplantation
- pregnancy
- thrombotic microangiopathy
- HEMOLYTIC-UREMIC SYNDROME
- FACTOR-I
- INHIBITOR ECULIZUMAB
- ACTIVATION
- VARIANTS
- AHUS
- MUTATIONS
- DISEASE
- PREGNANCY
- DEFECTS