Page 190 - 2019_12-Haematologica-web

K. El Karoui et al.
aHUS (1-year and 5-year renal survival rates 42% vs. 62% and 27% vs. 56%, respectively, P=0.002) (Online Supplementary Figure S1). Similar results were obtained when analyzing death-censored renal survival (Online Supplementary Figure S2A-F).
Complement evaluation
Results of the complement work-up in HE-aHUS and noHE-aHUS patients are presented in Tables 1 and 2. Low C3 levels were reported less frequently in patients with HE-aHUS than in those with noHE-aHUS (12/76 vs. 19/58, P=0.02). CFH autoantibodies with homozygous complement factor H-related protein 1 (CFHR1) deletion were detected in 2/76 patients with HE-aHUS (2/76) and 1/61 patients with noHE-aHUS.
At the individual level, a rare variant in the candidate genes was detected in 39/76 (51.3%) HE-aHUS patients, which was a slightly lower incidence that in noHE-aHUS patients (41/61, 67%, P=0.06), but significantly higher than in healthy donors (13.7%, P<0.0001). The distribu-
tion of each rare variant did not differ between HE-aHUS and noHE-aHUS patients: CFH 22% vs. 34% (P=ns), MCP 2.6% vs. 5% (P=ns), CFI 11.9% vs. 8.2% (P=ns), C3 5.3% vs. 11.5% (P=ns), CFB 1.3% vs. 3% (P=ns), THBD 1.3% vs. 0% (P=ns) and more than one variant 6.6% vs. 5% (P=ns), respectively (Table 2). We found genomic rearrangements involving CFH-CFHR1 in four HE-aHUS (5%) patients and two noHE-aHUS (3%) patients. To investigate the consequences of the rare variants on pro- tein expression and function, we analyzed the variant pathogenicity. Among the 45 rare variants identified in HE-aHUS patients, a total of 30/45 (66%) variants were pathogenic, and located in the coding regions of CFH (n=16), MCP (n=2), CFI (n=9) and C3 (n=3) (Figure 3 and Online Supplementary Tables S1-4).
In HE-aHUS patients, 30/76 (39.4%) carried at least one pathogenic variant, a frequency lower than that in noHE- aHUS patients (38/61, 62%; P=0.008) but higher than in controls (2/80, 2.5%; P<0.0001) (Table 2).
The frequencies of the homozygous at-risk MCP
Table 1. Clinical, biological and genetic characteristics of patients with atypical hemolytic uremic syndrome with or without hypertensive emer- gency.
P-value 0.003
SBP/DBP, mean, mmHg
Age, mean (SD), years
eGFR at onset, mean ( SD), mL/min/1.73 m2
Hemoglobin, mean (SD), g/dL
Platelets, mean (SD), x109/L
Elevated LDH, n (%)
Presence of schistocytes, n (%)
Neurologic impairment, n (%)
Cardiac dysfunction, n (%)
Dialysis at onset n(%)
At last follow up
Death 9450.5
Number
Male gender, n (%)
At diagnosis
Whole cohort
137
61(45)
HE-aHUS
76
44(58)
noHE-aHUS
61
17(28)
190/112 37(12) 14(14) 8(1.9) 97 (5) 67/79(84) 80/96(83) 44/102(43) 22/113(19) 98/126(78)
214/128 37(11) 12.9(12) 8.5(2) 104(5.5) 34/42(93) 41/53(77) 32/50(64) 16/61(26) 57/70(81)
154/90
<0.0001 0.2 0.3609 0.0112 0.11 0.4 0.11 <0.0001 0.059 0.28
36(13) 15.5(17) 7.5(1.5) 88(8.4) 33/37(95) 39/42(92) 12/52(23) 6/52(12) 41/56(73)
Dialysis n(%)
Age at dialysis, mean (SD), years Time until ESRD, mean (SD), m
Complement component assessment
C3 (660 to 1250 mg/L), median (Q1,Q3) Low C3 (<660mg/L) n (%)
C4 (93 to 380 mg/L)
Low factor H (<338 mg/L) n (%)
Low factor I (<42 mg/L) n (%)
Low CD46 (<12 MFI) n (%)
Positive anti-factor H Ab, n (%)
Rare variants in complement genes n (%)
97/126(77) 37.7(12) 21(51)
253 (206 ;312)
48/71(81) 37.3(12) 13(31)
841(692;976) 12/76 (15.7) 263 (215;314) 11/76 (14,5) 8/76 (10.5) 1/76 (1.3) 2/76 (2.6) 39 (51.3)
40/56(71) 0.01 37.9(12) 0.84 36(75) 0.07
768 (655;891) 0.04 19/58 (31) 0.02 246 (170 ;299) 0.05
13/58 (21.6) 0.2 7/58 (11.6) 0.8 3/58 (5) 0.2 1/47 (2) 0.8
41 (67) 0.06
817 (676;941) 31/134 (23)
24/134 (18) 16/134 (12)
4/134 (2.9) 3/123 (2.4) 80 (58.4)
HE: hypertensive emergency; aHUS: atypical hemolytic uremic syndrome; SBP: systolic blood pressure; DBP: diastolic blood pressure; SD: standard deviation; eGFR: estimated glomerular filtration rate; LDH: lactate dehydrogenase; ESRD: end-stage renal disease; Ab: antibodies. .
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