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 has been established as a prototypic disease result

3 aHUS patients frequently carry mutations in the inhibito

4 aHUS remains a clinical diagnosis without an objective l

5 aHUS-associated factor H mutations within this binding s

6 aHUS-associated FHR-1 mutants are pathogenic because the

7 expressed and functionally characterized 105 aHUS-associated FH variants.

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

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

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

11 dialysis during a previous episode of acute aHUS was not.

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

13 , we show that, when transferred to mice, an aHUS-associated gain-of-function change (D1115N) to the

14 n into sera samples of patients with C3G and aHUS does not enhance complement activity in either the

15 ssociate with susceptibility to both C3G and aHUS.

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

17 3KI mice from thrombotic microangiopathy and aHUS.

18 ting blood cells and the glomerulus, PNH and aHUS remarkably share several features in their etiology

19 Next to PNH and aHUS, germline-encoded CD59 or CD55 deficiency (the latt

20 and pathogenic distinctions between TTP and aHUS are often quite challenging.

21 Although they are rare, diagnosing TTP and aHUS associated with pregnancy, and postpartum, is param

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

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

24 otic microangiopathy clinically presented as aHUS, we searched for anti-factor H autoantibodies of th

25 with thrombotic microangiopathy presented as aHUS.

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

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

28 the molecular pathogenesis of FH-associated aHUS.

29 6%) were complicated by pregnancy-associated aHUS (p-aHUS), of which three appeared to be provoked by

30 e clinical diagnosis of pregnancy-associated aHUS/CM-TMA and assisted in guiding patient management,

31 ch in the management of pregnancy-associated aHUS/CM-TMA.

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

33 deficiency in the pathogenesis of autoimmune aHUS.

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

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

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

37 Although both aHUS and acquired thrombotic thrombocytopenic purpura (T

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

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

40 y, sensitivity, and specificity in detecting aHUS.

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

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

43 It can be difficult to diagnose aHUS/CM-TMA in pregnancy due to overlapping clinical fea

44 c changes recently identified from different aHUS cohorts.

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

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

47 Differentiating aHUS from other TMAs, especially thrombotic thrombocytop

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

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

50 n-of-function changes in complement C3 drive aHUS.

51 s (23%; 6 children and 7 adults) experienced aHUS relapse.

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

53 management, yet investigations assessing for aHUS/CM-TMA remained abnormal 6 months postpartum consis

54 s Ab could serve as a potential new drug for aHUS patients and alternative to C5 blockade by eculizum

55 ent complement inhibition on endothelium for aHUS treatment.

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

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

58 linical features and therapeutic options for aHUS.

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

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

61 regulatory proteins, and genetic testing for aHUS/CM-TMA, we describe how these results aided in the

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

63 Most frequently, aHUS is caused by complement dysregulation due to pathog

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

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

66 ed at least 1 previous renal transplant from aHUS.

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

68 The patient was diagnosed with atypical HUS (aHUS) and started on plasmapheresis, together with eculi

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

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

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

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

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

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

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

76 In aHUS patients with an underlying overactive AP, addition

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

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

79 dentified, clearly implicating complement in aHUS.

80 , endothelial cell activation, and damage in aHUS.

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

82 lement overactivation have been described in aHUS.

83 A strategy of eculizumab discontinuation in aHUS patients based on complement genetics is reasonable

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

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

86 rmined that 9 genetic variants identified in aHUS (N151S, G162D, G188A, V230E, A240G, G243R, C247G, A

87 ansplantation a viable therapeutic option in aHUS.

88 complement-activation protein C3 results in aHUS.

89 s been associated with impressive results in aHUS.

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

91 lifying endothelial damage and thrombosis in aHUS.

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

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

94 n C3, is associated with complement mediated aHUS in man, allowing us to study the clinical disease i

95 ive disease pathology in complement-mediated aHUS.

96 plement-mediated thrombotic microangiopathy (aHUS/CM-TMA), which has severe, life-threatening consequ

97 enhance both WT FH function as well as most aHUS-associated FH variants tested in this study.

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

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

100 RNA exosome, cause eculizumab nonresponsive aHUS.

101 tion and spontaneously develop MPGN2 but not aHUS.

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

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

104 damage and thrombogenesis characteristic of aHUS.

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

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

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

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

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

110 nt difficulties in the positive diagnosis of aHUS, and the latter remains, to date, a diagnosis by ex

111 recipients who had a confirmed diagnosis of aHUS.

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

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

114 The incidence of aHUS recurrence is determined by the underlying genetic

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

116 Nevertheless, long-term management of aHUS is increasingly individualized and lifelong C5 bloc

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

118 d in genes implicated in the pathogenesis of aHUS.

119 entified as important in the pathogenesis of aHUS.

120 ssion and continues eculizumab prevention of aHUS (1 infusion every 21 days).

121 quality of life of a sizeable proportion of aHUS patients while reducing the cost of treatment.

122 nuation was associated with a higher risk of aHUS relapse in all patients and in the subset of carrie

123 ne were associated with an increased risk of aHUS relapse, whereas requirement for dialysis during a

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

125 s become the cornerstone of the treatment of aHUS.

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

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

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

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

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

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

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

133 data support the effectiveness in paediatric aHUS.

134 he agonistic Ab in the context of pathogenic aHUS-related FH mutant proteins was investigated.

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

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

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

138 course of steroids and eculizumab to prevent aHUS relapse.

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

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

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

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

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

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

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

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

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

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

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

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

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

152 lement-mediated atypical hemolytic syndrome (aHUS).

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

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

155 such as atypical hemolytic uremic syndrome (aHUS) and age-related macular degeneration.

156 diseases atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy.

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

158 ion with atypical hemolytic uremic syndrome (aHUS) and other important diseases.

159 odels of atypical hemolytic uremic syndrome (aHUS) and paroxysmal nocturnal hemoglobinuria (PNH) as w

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

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

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

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

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

165 ement of atypical hemolytic uremic syndrome (aHUS) have dramatically improved in the last decade.

166 story of atypical hemolytic uremic syndrome (aHUS) in the native kidneys.

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

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

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

170 Atypical hemolytic uremic syndrome (aHUS) is a life-threatening thrombotic microangiopathy t

171 Atypical hemolytic uremic syndrome (aHUS) is a rare cause of end-stage kidney disease and as

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

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

174 Atypical hemolytic uremic syndrome (aHUS) is a rare thrombotic microangiopathy.

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

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

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

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

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

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

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

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

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

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

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

186 Atypical hemolytic uremic syndrome (aHUS) is frequently associated in humans with loss-of-fu

187 Atypical hemolytic uremic syndrome (aHUS) is life-threatening condition particularly when co

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

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

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

191 nts with atypical hemolytic uremic syndrome (aHUS) remains poorly defined.

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

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

194 econdary atypical hemolytic uremic syndrome (aHUS) through unknown mechanisms.

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

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

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

198 Atypical hemolytic uremic syndrome (aHUS), a severe thrombotic microangiopathy, is often rel

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

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

201 a (PNH), atypical hemolytic uremic syndrome (aHUS), and various glomerular diseases.

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

203 C3G) and atypical Hemolytic Uremic Syndrome (aHUS), implying that serum C3 consumption is not increas

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

205 es (PNH, atypical hemolytic uremic syndrome (aHUS), myasthenia gravis (MG), and anti-aquaporin-4 (AQP

206 sults in atypical hemolytic uremic syndrome (aHUS), the prototypes of thrombotic microangiopathy (TMA

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

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

209 known as atypical hemolytic uremic syndrome (aHUS).

210 stpartum atypical hemolytic uremic syndrome (aHUS).

211 nts with atypical hemolytic uremic syndrome (aHUS).

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

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

214 nesis of atypical hemolytic uremic syndrome (aHUS).

215 mediated atypical hemolytic uremic syndrome (aHUS; a diagnosis of exclusion).

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

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

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

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

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

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

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

223 Thus, aHUS provides an archetypal complement-mediated disease

224 hether hemolysis-derived heme contributes to aHUS pathogenesis.

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

226 3b-binding competition with FH is limited to aHUS-associated mutants, all surface-bound FHR-1 promote

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

228 logical carbohydrate ligands, predisposes to aHUS.

229 Similar to aHUS anthrax patients, PGN induces an initial hematocrit

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

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

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

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

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

235 discontinuation in children and adults with aHUS.

236 f FHR-1 mutants (including 2 associated with aHUS) and unraveled the molecular bases of the so-called

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

238 fying explanation for their association with aHUS.

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

240 n the first trimester who was diagnosed with aHUS/CM-TMA and treated with eculizumab from 19 weeks' g

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

242 We describe a peculiar case of a girl with aHUS complicating HSCT and her subsequent successful KTx

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

244 e implications for treating individuals with aHUS.

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

246 showing retinal ischemia can be linked with aHUS.

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

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

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

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

251 e UK cohort included all adult patients with aHUS at moderate or high risk of recurrence, transplante

252 r H of the IgG class in 10% of patients with aHUS but have not reported anti-factor H autoantibodies

253 Studies have shown that some patients with aHUS carry genetic abnormalities that affect genes that

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

255 accurately if clinical care of patients with aHUS is to be individualized and optimized.

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

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

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

259 cribing transplant outcomes in patients with aHUS transplanted between 1978 and 2017, including those

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

261 erlands, we selected all adult patients with aHUS who received a kidney transplant between 2010 and 2

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

263 he IgM class may be present in patients with aHUS, and their frequency is six-fold higher in thrombot

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

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

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

267 ctivity known to occur in some patients with aHUS.

268 een used successfully to treat patients with aHUS.

269 plantation is used in selected patients with aHUS.

270 gM autoantibodies versus other patients with aHUS: three of 20 (15%) versus four of 166 (2.4%), respe

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

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

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

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

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

276 ency of successful pregnancies in women with aHUS.