ライフサイエンスコーパス: aHUS

1 aHUS episodes are often initiated or recur during inflam

2 aHUS patients frequently carry mutations in the inhibito

3 aHUS remains a clinical diagnosis without an objective l

4 aHUS-associated factor H mutations within this binding s

5 In this study, 23 aHUS-associated genetic changes in C3 were characterized

6 We studied 44 aHUS patients and their relatives to (1) test new assays

7 Acute aHUS serum, but not serum from remission, caused wider C

8 atient showed that she was homozygous for an aHUS CD46 at-risk haplotype.

9 ssociate with susceptibility to both C3G and aHUS.

10 Mechanistic studies of DGKE and aHUS are, therefore, essential to the design of appropri

11 teen patients were clinically categorized as aHUS based on the following criteria: (1) platelet count

12 the 19 patients clinically characterized as aHUS, suggesting that pretreatment measurements of compl

13 tients presenting with anti-FH Ab-associated aHUS.

14 ata strongly suggest that in DGKE-associated aHUS patients, thrombotic microangiopathy results from i

15 the molecular pathogenesis of FH-associated aHUS.

16 6%) were complicated by pregnancy-associated aHUS (p-aHUS), of which three appeared to be provoked by

17 It may be diarrheal-associated or atypical (aHUS).

18 deficiency in the pathogenesis of autoimmune aHUS.

19 ociation of CFHR1 deficiency with autoimmune aHUS could be due to the structural difference between C

20 nown why nearly all patients with autoimmune aHUS lack CFHR1 (CFH-related protein-1).

21 o the pathophysiological differences between aHUS and GP, demonstrating heterogeneity of anti-FH IgG.

22 Although both aHUS and acquired thrombotic thrombocytopenic purpura (T

23 In most cases, aHUS are caused by genetic mutations of components of th

24 s have at least one genetic mutation causing aHUS, including 4 with complement factor H mutations.

25 y, sensitivity, and specificity in detecting aHUS.

26 tivation in plasma and spontaneously develop aHUS but not MPGN2.

27 MCP may help predict the risk of developing aHUS in unaffected carriers of mutations.

28 c changes recently identified from different aHUS cohorts.

29 ns has improved our ability to differentiate aHUS from acquired TTP.

30 erum-based assay that helps to differentiate aHUS from other TMAs.

31 Differentiating aHUS from other TMAs, especially thrombotic thrombocytop

32 ught to develop a novel assay to distinguish aHUS from other TMAs based on the hypothesis that paroxy

33 ritical, but often difficult, to distinguish aHUS from other TMAs, such as thrombotic thrombocytopeni

34 lyanionic carbohydrates), we identified five aHUS-associated mutants with increased affinity for eith

35 ent complement inhibition on endothelium for aHUS treatment.

36 een the description of a new risk factor for aHUS in the form of mutations in thrombomodulin.

37 e a Cfh at-risk haplotype, the haplotype for aHUS was unique.

38 linical features and therapeutic options for aHUS.

39 he historically poor long-term prognosis for aHUS patients treated with plasma-based therapy.

40 s in the R1210C-independent overall risk for aHUS and AMD between mutation carriers developing one pa

41 Although we found four aHUS-linked fH mutations that decreased binding to C3b a

42 d anti-factor H autoantibodies isolated from aHUS patients inhibited the interaction between factor H

43 F-1 cells are more susceptible to serum from aHUS patients than parental EA.hy926 and TF-1 cells.

44 ed at least 1 previous renal transplant from aHUS.

45 NF2 mutations presenting with a TMA also had aHUS risk haplotypes, potentially accounting for the gen

46 Atypical HUS (aHUS) can result from genetic or autoimmune factors that

47 Atypical HUS (aHUS) is a disorder most commonly caused by inherited de

48 chia coli (STEC) infection, as atypical HUS (aHUS), usually caused by uncontrolled complement activat

49 otein (MCP;CD46) predispose to atypical HUS (aHUS), which is not associated with exposure to Shiga to

50 Complement mediated HUS (aHUS) has a worse prognosis compared with shiga toxin me

51 imilarities in the pathogenesis of STEC-HUS, aHUS, and secondary HUS are discussed.

52 he common pathogenetic features in STEC-HUS, aHUS, and secondary HUS are simultaneous damage to endot

53 In aHUS patients with an underlying overactive AP, addition

54 frequently associated with the anti-FH Ab in aHUS patients, were found in the GP patients.

55 reflecting ongoing complement activation in aHUS despite complete terminal complement blockade.

56 dentified, clearly implicating complement in aHUS.

57 , endothelial cell activation, and damage in aHUS.

58 characterization of the molecular defect in aHUS has allowed targeted therapy to be used.

59 lement overactivation have been described in aHUS.

60 This was exacerbated in aHUS by genetic abnormalities associated with AP overact

61 l ADAMTS13 deficiency is a common finding in aHUS patients and that genetic screening and functional

62 s been associated with impressive results in aHUS.

63 As with other genetic risk factors seen in aHUS, these mutations result in impaired regulation of c

64 lifying endothelial damage and thrombosis in aHUS.

65 and adolescent trials support its utility in aHUS, whereas retrospective data support the effectivene

66 utations per se are not sufficient to induce aHUS, and nonspecific primary triggers are required for

67 Subsequent analysis of the Newcastle aHUS cohort identified another family with a functionall

68 thrombocytopenic purpura (TTP) patients, no aHUS patients demonstrated ultralarge von Willebrand fac

69 tion and spontaneously develop MPGN2 but not aHUS.

70 To identify novel aHUS-associated genes, we completed a comprehensive scre

71 normalities account for approximately 50% of aHUS cases; however, mutations in the non-C gene diacylg

72 damage and thrombogenesis characteristic of aHUS.

73 ment genes and ADAMTS13 in a large cohort of aHUS patients.

74 knowledge of the functional consequences of aHUS-associated C3 mutations relative to the interaction

75 In this individual, the development of aHUS has been facilitated by the combination of a trigge

76 s C5a and C5b-9 may confirm the diagnosis of aHUS and differentiate it from TTP.

77 a more rapid identification and diagnosis of aHUS as the recovery of end-organ injury present appears

78 is pathway, and life-threatening episodes of aHUS can be provoked by pregnancy.

79 Early identification of aHUS is crucial so that plasma therapy can be initiated.

80 Our study expands the current knowledge of aHUS mechanisms and has implications for the treatment o

81 These animals represent the first model of aHUS and provide in vivo evidence that effective plasma

82 d in genes implicated in the pathogenesis of aHUS.

83 entified as important in the pathogenesis of aHUS.

84 We recommend that genetic screening of aHUS includes analysis of CFH and CFHR rearrangements, p

85 adducts is a common feature for triggers of aHUS and that failure of FH in protecting MDA-modified s

86 y can give rise to either spontaneous C3G or aHUS after a complement-activating trigger within the ki

87 A retrospective genetic analysis in our aHUS cohort (n=513) using multiple ligation probe amplif

88 ers, we identified FH-R1210C carriers in our aHUS, C3G, and AMD cohorts.

89 complicated by pregnancy-associated aHUS (p-aHUS), of which three appeared to be provoked by infecti

90 lasma infusions (one pregnancy resulted in p-aHUS, one intrauterine fetal death occurred, and seven p

91 yndrome before the definitive diagnosis of p-aHUS was made.

92 data support the effectiveness in paediatric aHUS.

93 ophysiology, diagnosis, and therapy for PNH, aHUS, and CAD.

94 s of successful prevention of posttransplant aHUS recurrence with eculizumab emerged a few years ago.

95 effective in preventing posttransplantation aHUS recurrence, yet may not fully block AMR pathogenesi

96 mab was effective in reversing or preventing aHUS whether or not genetic complement mutations were id

97 ckground differences could explain the R139W-aHUS incomplete penetrance.

98 otypes was significantly higher in the R139W-aHUS patients, compared with normal donors or to healthy

99 eculizumab and plasmapheresis for recurrent aHUS after kidney transplantation; two of them responded

100 ransplant that failed secondary to recurrent aHUS (75% of our patients).

101 ris within the eye and kidney, respectively, aHUS is characterized by renal endothelial injury.

102 ells and platelets, we now show that several aHUS-associated mutations, which have been predicted to

103 Here we report that several aHUS-related mutations alter the binding of FH19-20 to p

104 of the CFHR1 mutation presented with severe aHUS during adulthood; 57% of affected women in this coh

105 ation in binding of autoantibodies from some aHUS patients to CFH19-20 and CFHR14-5.

106 tioned by the puzzling observation that some aHUS-associated mutations markedly enhance FH binding to

107 Here, we report 14 sporadic aHUS patients carrying the same mutation, R139W, in the

108 lation pathways in 36 patients with sporadic aHUS using targeted genomic enrichment and massively par

109 ent of atypical haemolytic uraemic syndrome (aHUS) as well as the other complement-mediated renal dis

110 mplement mediated hemolytic uremic syndrome (aHUS) accounts for a significant proportion of non-shiga

111 ients to atypical hemolytic uremic syndrome (aHUS) and other disorders arising from inadequately regu

112 ted with atypical hemolytic uremic syndrome (aHUS) and related glomerulopathies.

113 nts with atypical hemolytic uremic syndrome (aHUS) are remarkable in contrast to the historically poo

114 rized in atypical hemolytic uremic syndrome (aHUS) but have been less well described in association w

115 nts with atypical hemolytic uremic syndrome (aHUS) develop a thrombotic microangiopathy (TMA) that in

116 convert atypical hemolytic uremic syndrome (aHUS) from a diagnosis of exclusion into a direct pathop

117 ies with atypical hemolytic uremic syndrome (aHUS) in the underlying pathomechanisms.

118 Atypical hemolytic uremic syndrome (aHUS) is a genetic ultrarare renal disease associated wi

119 Atypical hemolytic uremic syndrome (aHUS) is a genetic, life-threatening disease characteriz

120 Atypical hemolytic uremic syndrome (aHUS) is a rare disease with a high recurrence rate afte

121 Atypical hemolytic uremic syndrome (aHUS) is a rare renal thrombotic microangiopathy commonl

122 Atypical hemolytic uremic syndrome (aHUS) is a renal disease associated with complement alte

123 Atypical hemolytic uremic syndrome (aHUS) is a severe thrombotic microangiopathy characteriz

124 Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA) characterize

125 Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy caused by uncontro

126 Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy with severe renal

127 Atypical hemolytic uremic syndrome (aHUS) is an orphan disease with a high rate of recurrenc

128 Atypical hemolytic-uremic syndrome (aHUS) is associated with genetic complement abnormalitie

129 Atypical hemolytic uremic syndrome (aHUS) is characterized by complement attack against host

130 Atypical hemolytic uremic syndrome (aHUS) is characterized by dysregulated complement activi

131 Atypical hemolytic uremic syndrome (aHUS) is characterized by genetic and acquired abnormali

132 Atypical hemolytic uremic syndrome (aHUS) is classically described to result from a dysregul

133 nesis of atypical hemolytic uremic syndrome (aHUS) is strongly linked to dysregulation of the alterna

134 Atypical hemolytic uremic syndrome (aHUS) is usually characterized by uncontrolled complemen

135 ified in atypical hemolytic uremic syndrome (aHUS) patients cause dysregulation in the alternative pa

136 hy (TMA) atypical hemolytic uremic syndrome (aHUS) resulted in the successful introduction of the C i

137 C3G) and atypical hemolytic uremic syndrome (aHUS) strongly associate with inherited and acquired abn

138 ity, and atypical hemolytic uremic syndrome (aHUS), a disease of complement overactivation.

139 nts with atypical hemolytic uremic syndrome (aHUS), a rare condition characterized by microangiopathi

140 Atypical hemolytic uremic syndrome (aHUS), a rare form of thrombotic microangiopathy caused

141 ion with atypical hemolytic uremic syndrome (aHUS), also confers high risk of age-related macular deg

142 n (AMD), atypical hemolytic uremic syndrome (aHUS), and membranoproliferative glomerulonephritis type

143 ibute to atypical hemolytic uremic syndrome (aHUS), but incomplete penetrance suggests that additiona

144 In atypical hemolytic uremic syndrome (aHUS), mutations clustering toward the C terminus of fH

145 inked to atypical hemolytic uremic syndrome (aHUS), was defective in C3bBb decay-accelerating activit

146 leads to atypical hemolytic uremic syndrome (aHUS), while ADAMTS13 deficiency causes thrombotic throm

147 known as atypical hemolytic uremic syndrome (aHUS).

148 stpartum atypical hemolytic uremic syndrome (aHUS).

149 PNH) and atypical hemolytic uremic syndrome (aHUS).

150 nesis of atypical hemolytic uremic syndrome (aHUS).

151 The aHUS-linked CCP 19 mutant D1119G-CFH had virtually no CA

152 The aHUS-linked CCP 20 mutant S1191L/V1197A-CFH (LA-CFH) had

153 t correlate with the extent to which all the aHUS-associated mutants were found to be impaired in a m

154 revealed an absence of AMD phenotypes in the aHUS cohort and, vice versa, a lack of renal disease in

155 Moreover, the aHUS-associated CFHR1*B variant showed reduced binding t

156 In contrast to the aHUS patients, the GP patients had no circulating FH-con

157 ere treated with Eculizumab according to the aHUS therapeutic scheme.

158 hether hemolysis-derived heme contributes to aHUS pathogenesis.

159 mouse FH protein functionally equivalent to aHUS-associated human FH mutants, regulate C3 activation

160 r protein (CD46), and factor I predispose to aHUS development.

161 logical carbohydrate ligands, predisposes to aHUS.

162 In 8 eculizumab-treated aHUS patients, C3/SC5b-9 circulating levels did not chan

163 ts enrolled in the Ohio State University TTP/aHUS Registry presenting with an acute TMA.

164 nding of the genetic complexities underlying aHUS, illustrate the importance of performing functional

165 astrointestinal infection with STEC, whereas aHUS is associated primarily with mutations or autoantib

166 from 25 patients with TMAs, including 9 with aHUS and 12 with TTP.

167 r factor H (FH) are strongly associated with aHUS, but the mechanisms triggering disease onset have r

168 fying explanation for their association with aHUS.

169 ents whose diagnosis is most consistent with aHUS, and thus be more likely to benefit from therapy wi

170 However, recent findings in families with aHUS of mutations in the DGKE gene, which is not an inte

171 try on GPI-AP-deficient cells incubated with aHUS serum compared with heat-inactivated control, TTP,

172 e implications for treating individuals with aHUS.

173 plications for the treatment of infants with aHUS, who are increasingly treated with complement block

174 We screened 795 patients with aHUS and identified single mutations in 41% and combined

175 -function mutations in DGKE in patients with aHUS and normal complement levels challenged this observ

176 ent our data of 12 consecutive patients with aHUS and the outcome after kidney transplantation.

177 genetic changes identified in patients with aHUS are unrelated to disease pathogenesis.

178 Furthermore, screening patients with aHUS for all known disease-associated genes may inform d

179 r processes involved in TMA in patients with aHUS longitudinally, during up to 1 year of treatment, c

180 Serum from patients with aHUS resulted in a significant increase of nonviable PIG

181 est that mutation screening in patients with aHUS should be broadened to include genes in the coagula

182 he initial 25 MCP mutations in patients with aHUS were 2, R69W and A304V, that were expressed normall

183 ective study, we identified 12 patients with aHUS who were managed in our center since 2003.

184 complement inhibition in most patients with aHUS, but usually not those with a DGKepsilon mutation,

185 In addition to 3 patients with aHUS, the A304V mutation was identified in 1 patient eac

186 ctivity known to occur in some patients with aHUS.

187 een used successfully to treat patients with aHUS.

188 CFH and CFHR genes in 4.5% of patients with aHUS.

189 Affected individuals present with aHUS before age 1 year, have persistent hypertension, he

190 family in which the proposita presented with aHUS but did not respond to eculizumab.

191 Twelve renal transplant recipients with aHUS-related end-stage renal disease received eculizumab

192 l kinase varepsilon) that co-segregated with aHUS in nine unrelated kindreds, defining a distinctive

193 nd fetal pregnancy outcomes in 14 women with aHUS from the Vienna Thrombotic Microangiopathy Cohort.

194 ency of successful pregnancies in women with aHUS.