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Hypertensive emergency and hemolytic uremic syndrome
ggaaac and CFH tgtgt haplotypes were significantly high- er in HE-aHUS patients than in controls (MCP ggaac 27% vs. 6.2%; CFH tgtgt 16% vs. 3.7%) (Table 2). Notably, 8/74 (11%) HE-aHUS patients were homozygous for both at-risk haplotypes, whereas none of the control pop- ulation was.
Among HE-aHUS patients, three rare variants were identified in six Afro-Caribbean patients, compared to 37 variants in 70 patients of other ethnic origin, defining a similar frequency of rare complement variants in both ethnic groups (50% vs. 53%, respectively). Only one of the six Afro-Caribbean patients was homozygote for the at-risk ApoL1 haplotype, a similar frequency as that in the general Afro-Caribbean population.16
Treatment of atypical hemolytic uremic syndrome with or without hypertensive emergency
All HE-aHUS patients were initially treated with anti- hypertensive therapy. Plasma infusion or plasma exchange (PLEX) was used in 39/57 HE-aHUS patients vs. 47/52 noHE-aHUS patients (68% vs. 90%; P=0.009). However, no difference was observed in prognosis according to PLEX treatment (Online Supplementary Tables S5 and S6, Online Supplementary Figure S3).
Eculizumab was used in 13/76 (17%) HE-aHUS patients and 17/61 (28%) noHE-aHUS patients. In HE- aHUS patients, eculizumab was usually proposed after failure of PLEX and anti-hypertensive therapy (median time between diagnosis and eculizumab, 10 days).
Overall, eculizumab provided a significant benefit in the whole cohort (HE-aHUS and noHE-aHUS patients), with a 5-year renal survival of 79% vs. 30% in patients treated or not with eculizumab, respectively (P<0.001) (Figure 4A, Online Supplementary Table S5A,B). Notably,
Figure 2. Renal survival in patients with atypical hemolytic uremic syndrome, with or without hypertensive emergency, not treated with eculizumab. Analysis of renal survival without end-stage renal disease or death in patients not treated with eculizumab. Log-rank test, P=0.1. Follow-up was not available for two patients with hypertensive emergency and atypical hemolytic uremic syndrome. HE: hypertensive emergency; aHUS: atypical hemolytic uremic syndrome.
Table 2. Genetic characteristics of patients with atypical hemolytic uremic syndrome with or without hypertensive emergency, and of French controls.
Individuals with rare variant
Individuals with at least one pathogenic variant CFH rare variant, n (%)
Pathogenic variant, n (% of CFH rare variants) MCP rare variant, n (%)
Pathogenic variant, n (% of MCP rare variants) CFI rare variant, n (%)
Pathogenic variant, n (% of CFI rare variants) C3 rare variant, n (%)
Pathogenic variant, n (% of C3 rare variants) CFB rare variant, n (%)
Pathogenic variant, n (% of C3 rare variants) THBD rare variant, n (%)
Pathogenic variant, n (% of THBD rare variants)
Two rare variants n (%)
Patients with at least one Pathogenic variant, n
(% of patients with 2 rare variants)
Anti-CFH antibodies n (%)
At-risk homozygous CFH tgtgt haplotype n (%) At-risk homozygous MCP ggaac haplotype n (%)
Both haplotypes n (%)
HE- aHUS n=76
39 (51.3)
30 (39.4) 17 (22.4) 15 (88) 2 (2.6) 2 (100) 9 (11.9) 7 (78) 4 (5.3) 2 (50) 1 (1.3) 0
1 (1.3) 0
5 (6.6)
4 (80)
2 (2.6) 12/74 (16) 20/74 (27)
8/74 (11)
noHE-aHUS n=61
41 (67)
38 (62) 21 (34.4) 20 (95) 3 (5) 3 (100) 5 (8.2) 4 (80) 7 (11.5) 6 (85)
French controls n=80
11 (13.7)
2 (2.5) 2 (2.5) 0 (0) 0
0 (0) 2 (2.5) 0 (0) 4 (5) 0 (0)
P (HE-aHUS vs. French controls)
<0.0001
<0.0001 0.0001
0.2 0.04 0.9 0.5 0.5 0.2
0.2 0.02 0.002 0.04
P (noHE-aHUS vs. French controls)
<0.0001
<0.0001 0.0003
0.07 0.07 0.17 0.2 0.6 0.45
0.2
0.1
0.001
0.2
P (HE-aHUS vs. no HE-aHUS)
0.06
0.008 0.12
0.6 0.4 0.5 0.6 0.4 0.4
0.3 0.3 0.9 0.2
2(3) 0
2 (100) 0 (0) 0
3 (5)
3 (100)
1(2) 0
0 (0) 1 (1.25) 1 (100) 2 (2.5)
1 (50)
6/56 (10.7)
15/50 (30)
2/50 (4)
3/80 (3.7)
5/80 (6,25)
0
HE: hypertensive emergency; aHUS: atypical hemolytic uremic syndrome; n: number of individuals; CFB: complement factor B; CFH: complement factor H; CFI: complement factor I; MCP: membrane cofactor protein; THBD: thrombomodulin. None of the patients carry two rare variants in the DGKE gene.
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