Page 194 - 2019_12-Haematologica-web

K. El Karoui et al.
Table 3. Characteristics and outcome of patients with atypical hemolytic uremic syndrome according to the presence or absence of hypertensive emergency and rare complement variants.
A. Whole cohort
Categories
Number
Male gender n (%)
Age, mean (SD), years Hemoglobin, mean (SD) g/L Platelets, mean(SD) x109/L Elevated LDH, n (%)
Presence of schistocytes, n (%) Low C3, n (%)
Neurological impairment, n (%) Cardiac dysfunction, n (%) Dialysis at onset, n (%)
HE-aHUS/V
41
24(58.5) 40.2(12.19) 8.359(1.937) 89.631(46.550) 20(87) 23(82.1) 11 (20) 15(65) 9(24) 33(85)
HE-aHUS/noV
35
20(57.1) 33.7(10.11) 8.53(2.367) 109.520(38.888) 14(74)
18(72) 1 (3) 17(65) 7(29) 24(80)
noHE-aHUS/V
42
12(28.6) 34.2(11.35) 7.033(1.471) 98.828(56.834) 23(92) 26(93)
18 (40) 7(20) 5(15) 31(82)
noHE-aHUS/noV
19
5(26.3) 41.1(16.8) 8.394(1.27) 62.188(45.140) 10(83) 13(87)
1 (0) 5(28) 1(6) 10(53)
P P
HE-aHUS/V vs. HE-aHUS/noV
0.006 >0.9 0.02 0.01 0.01 0.7 0.02 0.05 0.4 0.4 0.23 0.5
<0.0001 0.004 0.0002 >0.9 0.19 0.8
0.04 0.75
B. Patients without hypertensive emergency and without rare complement variant vs. whole cohort excluding those without hyper- tensive emergency and without rare complement variants.
Categories
Number
Male gender, n(%)
Age, mean (SD), years
Hemoglobin, mean (SD) g/L
Platelets, mean (SD) x109/L
Elevated LDH, n (%)
Presence of schistocytes, n (%)
Low C3, n (%)
Neurological impairment, n(%)
Cardiac dysfunction, n (%)
Dialysis at onset, n (%)
noHE-aHUS/noV
19
5(26.3)
41.1(16.8)
8.394(1.27)
62188(45140)
10(83)
13(87)
0 (0)
5(28)
1(6)
10(53)
Whole cohort excluding noHE-aHUS/noV P 118
56(48)
36(11)
8,0(2) 0.490
0.0863 0.1065
70059
57(85) >0.9
67(82,5) >0.9 24(21) 0,02 39(46) 0.19 21(22) 0.19 88(82) 0.01
0.0391
HE/V: patients with hypertensive emergency (HE) and atypical hemolytic uremic syndrome (aHUS) with rare complement variants; HE/noV: patients with HE-aHUS without rare complement variants; noHE/V: patients with noHEaHUS with rare complement variants; noHE/noV: patients with noHE-aHUS and no rare complement variants; SD: stan- dard deviation; LDH: lactate dehydrogenase
Discussion
Here, we describe the first series of patients with HE- aHUS using the new definition of HE6 and compared vari- ant frequencies and clinical outcome in aHUS cases with and without HE. This study showed that a genetic predis- position accounts for half of the patients in both groups and provided data showing that response to treatment and long-term outcome are predicted by HE phenotype at onset and individual gene abnormalities.
In light of the recent advances in the understanding of the pathophysiology of HUS,2,17 pathogenic variants in complement genes are the hallmark of complement- mediated HUS, and have been found in 40-60% of patients classified as having aHUS.1 Currently, there are few data addressing individual susceptibility to aHUS with hypertensive crisis/HE.7 In this study, we performed extensive complement genetic screening to identify rare variants and at-risk haplotypes identified as the aHUS genetic background.18 We identified rare variants in one or
two complement genes in 51.3% of HE-aHUS patients. This frequency is similar to that recently reported in 8/17 patients with ‘hypertension-associated thrombotic microangiopathy’ and complement variant.12 The variant frequency in each gene was not significantly different between HE-aHUS and noHE-aHUS patients. The rare variants identified in noHE-aHUS (91%) and in HE-aHUS (66.6%) patients lead to quantitative or functional defi- ciency which impairs the protection of endothelial cells from complement damage and are, therefore, pathogenic.19 Interestingly, the frequency of individuals carrying at least one pathogenic variant was significantly higher in HE-aHUS patients than in controls, but signifi- cantly lower than in noHE-aHUS patients (control 2.5%, HE-aHUS 39%, noHE-aHUS 62%; P<0.001). We also observed a slightly increased frequency of the homozy- gous CFH at-risk haplotype in HE-aHUS patients com- pared to that in controls, but did not find any significant difference between controls and noHE-aHUS patients. This observation needs to be confirmed in larger cohorts
2508
haematologica | 2019; 104(12)