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1.
Kidney Int ; 98(5): 1084-1087, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33126970

RESUMO

Gain-of-function variants in CFB encoding factor B (FB), a component of the alternative pathway C3 convertase, have been reported in a minority of patients with aHUS and result in massive C3 activation. Zhang et al. describe the functional characterization of a novel FB variant (p.Ser367Arg) that they identified in 2 unrelated aHUS pedigrees who had undetectable C3 levels. The mutant FB caused strong C3 cleavage in fluid-phase but also C3 deposition on cell surface. This commentary addresses the implications of these findings for understanding the complexity of complement-related genetic renal diseases.


Assuntos
Síndrome Hemolítico-Urêmica Atípica , Fator B do Complemento , Síndrome Hemolítico-Urêmica Atípica/genética , Ativação do Complemento/genética , Fator B do Complemento/genética , Via Alternativa do Complemento/genética , Humanos , Mutação
2.
BMC Med Genet ; 21(1): 169, 2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32838746

RESUMO

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by microangiopathic hemolytic anemia caused by small vessel thrombosis, thrombocytopenia, and renal failure. The common cause of aHUS is a dysregulation in the alternative complement pathway. Mutations in none complement genes such as diacylglycerol kinase epsilon (DGKE) can also result in this syndrome. CASE PRESENTATION: Here, we report on a 19-year-old female with the clinical diagnosis of aHUS, who has unaffected consanguineous parents and an older sibling who was deceased from aHUS when she was seven months old. We performed whole exome sequencing (WES) followed by evaluation of detected variants for functional significance, using several online prediction tools. Next, in order to confirm the detected pathogenic variant in proband and segregation analysis in her family, Sanger sequencing was done. The novel variant was analyzed in terms of its impact on the protein 3-dimensional structure by computational structural modeling. The results revealed that the proband carried a novel homozygous missense variant in DGKE located in exon 6 of the gene (NM_003647.3, c.942C > G [p.Asn314Lys]), and in silico analysis anticipated it as damaging. Protein computational study confirmed the influence of potential pathogenic variant on structural stability and protein function. CONCLUSION: We suggest that some variations in the catalytic domain of DGKE like p.Asn314Lys which can cause alterations in secondary and 3-D structure of protein, might lead to aHUS.


Assuntos
Síndrome Hemolítico-Urêmica Atípica/genética , Diacilglicerol Quinase/genética , Mutação de Sentido Incorreto , Sequenciamento Completo do Exoma/métodos , Síndrome Hemolítico-Urêmica Atípica/diagnóstico , Domínio Catalítico , Consanguinidade , Diacilglicerol Quinase/química , Feminino , Homozigoto , Humanos , Masculino , Linhagem , Adulto Jovem
3.
Hematology ; 25(1): 101-107, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32091318

RESUMO

Objectives: DGKE mutations can lead to hemolysis and thrombus in patients with atypical hemolytic uremic syndrome (aHUS). However, the sequence variants of DGKE in Chinese patients with aHUS have not been reported, and the protein function and crystal structure of DGKE remain unresolved.Methods: Targeted exome sequencing was accomplished in one affected patient from each family using the Illumina NextSeq 500 platform. Protein modeling and functional analysis in DGKE were also performed to understand the impact of identified variants on the phenotype.Results: We report a novel compound heterozygous mutation in the DGKE gene in a Chinese consanguineous family in which a child was diagnosed with aHUS, which includes a c.231C>G missense mutation and a c.790_791delTG frameshift mutation derived from his father and mother, respectively. Our bioinformatic analysis suggested that the allelic mutations at different sites in DGKE yield abnormal crystal structures and conformations, leading to dysregulation of its downstream signaling.Conclusions: Our study further expands the spectrum of the sequence variants reported in the DGKE gene and also indicates that different races may have different DGKE variants. Moreover, the altered structures and conformations, caused by DGKE mutations, disrupt the binding of DGKE with its partners, and leading to the occurrence of aHUS.


Assuntos
Síndrome Hemolítico-Urêmica Atípica/genética , Diacilglicerol Quinase/genética , Sequência de Aminoácidos , Grupo com Ancestrais do Continente Asiático , Humanos , Masculino , Mutação
4.
J Am Soc Nephrol ; 31(2): 241-256, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31980588

RESUMO

Sequence and copy number variations in the human CFHR-Factor H gene cluster comprising the complement genes CFHR1, CFHR2, CFHR3, CFHR4, CFHR5, and Factor H are linked to the human kidney diseases atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy. Distinct genetic and chromosomal alterations, deletions, or duplications generate hybrid or mutant CFHR genes, as well as hybrid CFHR-Factor H genes, and alter the FHR and Factor H plasma repertoire. A clear association between the genetic modifications and the pathologic outcome is emerging: CFHR1, CFHR3, and Factor H gene alterations combined with intact CFHR2, CFHR4, and CFHR5 genes are reported in atypical hemolytic uremic syndrome. But alterations in each of the five CFHR genes in the context of an intact Factor H gene are described in C3 glomerulopathy. These genetic modifications influence complement function and the interplay of the five FHR proteins with each other and with Factor H. Understanding how mutant or hybrid FHR proteins, Factor H::FHR hybrid proteins, and altered Factor H, FHR plasma profiles cause pathology is of high interest for diagnosis and therapy.


Assuntos
Síndrome Hemolítico-Urêmica Atípica/genética , Complemento C3/análise , Glomerulonefrite Membranoproliferativa/genética , Síndrome Hemolítico-Urêmica Atípica/etiologia , Fator H do Complemento/química , Fator H do Complemento/genética , Fator H do Complemento/fisiologia , Variações do Número de Cópias de DNA , Predisposição Genética para Doença , Variação Genética , Glomerulonefrite Membranoproliferativa/etiologia , Humanos , Rim/patologia , Família Multigênica
5.
Clin Chim Acta ; 503: 61-69, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31945341

RESUMO

Pregnancy associated atypical hemolytic uremic syndrome (p-aHUS) is a disease with a triad of hemolytic anemia, thrombocytopenia and acute renal failure, which might be attributed to the uncontrolled complement activation. Herein, we sequenced a postpartum-aHUS patient and found the two missense variants of CD46, a novel mutation (c.403G > C, p.G135R) from her father and a once reported mutation (c.293C > T, p.T98I) without expressional and functional tests from her mother. The G135R mutation caused a significantly reduced membrane expression of CD46 in peripheral blood lymphocyte and renal cells. The T98I mutation caused a mild decrease membrane expression of CD46 in peripheral blood lymphocyte cells. Moreover, the expressed G135R protein was in precursor form, indicating that this mutant was retained intracellularly. The C3b binding ability of T98I mutant was slightly decreased while the C4b binding ability is not significantly changed. The cofactor ability of the two mutants for factor I in the degradation of C3b was demonstrated to be impaired. This study reported the first case of a four-generation postpartum-aHUS pedigree with isolated CD46 variants and the detailed disease progression, treatment, and prognosis provided more meaningful information for the understanding the disease.


Assuntos
Síndrome Hemolítico-Urêmica Atípica/genética , Proteína Cofatora de Membrana/genética , Mutação de Sentido Incorreto , Período Pós-Parto/genética , Adulto , Progressão da Doença , Feminino , Predisposição Genética para Doença , Humanos , Proteína Cofatora de Membrana/metabolismo , Linhagem , Gravidez , Prognóstico
6.
Iran J Kidney Dis ; 13(5): 316-321, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31705748

RESUMO

INTRODUCTION: Atypical hemolytic uremic syndrome (aHUS) is associated with mutations or antibodies that affect the regulation of the alternative complement pathway. In the recent years several studies have been published describing these mutations. In this study, the initial clinical findings, treatments and long-term follow-up results of 19 patients who were hospitalized with the diagnosis of aHUS were presented. MATERIALS AND METHODS: Nineteen patients who were diagnosed as aHUS were enrolled from January 2010 to March 2017. Initial clinical signs and clinical follow-up of patients with aHUS were evaluated. Disease causing complement factor H (CFH) mutations were determined.  Results. CFH mutations were detected in 5 of 19 aHUS cases. Of these, one was novel and 4 were previously reported. We reported here the clinical course of aHUS patients with CFH mutations (p.Glu936Asp, Val 1197Ala) and a novel mutation (Glu927Lys) which caused  previously defined aHUS. Two of the CFH mutation cases developed end stage kidney disease that required hemodialysis, 1 case developed chronic kidney disease. Two cases were in remission, one of them with supportive therapy and the other case was in remission with eculizumab treatment. CONCLUSIONS: Morbidity rate is higher in children with aHUS. The renal prognosis and morbidity rate is higher in children with CFH mutations than other children with aHUS. Poor prognosis in aHUS children with CFH mutation depends on the genetic background.


Assuntos
Síndrome Hemolítico-Urêmica Atípica/genética , Adolescente , Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome Hemolítico-Urêmica Atípica/etnologia , Síndrome Hemolítico-Urêmica Atípica/terapia , Criança , Pré-Escolar , Fator H do Complemento/genética , Inativadores do Complemento/uso terapêutico , Feminino , Humanos , Lactente , Falência Renal Crônica/etnologia , Falência Renal Crônica/genética , Falência Renal Crônica/terapia , Masculino , Diálise Renal , Estudos Retrospectivos , Resultado do Tratamento , Turquia/etnologia
7.
J Am Soc Nephrol ; 30(12): 2449-2463, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31575699

RESUMO

BACKGROUND: Atypical hemolytic uremic syndrome (HUS) is associated with high recurrence rates after kidney transplant, with devastating outcomes. In late 2011, experts in France recommended the use of highly individualized complement blockade-based prophylaxis with eculizumab to prevent post-transplant atypical HUS recurrence throughout the country. METHODS: To evaluate this strategy's effect on kidney transplant prognosis, we conducted a retrospective multicenter study from a large French nationwide registry, enrolling all adult patients with atypical HUS who had undergone complement analysis and a kidney transplant since January 1, 2007. To assess how atypical HUS epidemiology in France in the eculizumab era evolved, we undertook a population-based cohort study that included all adult patients with atypical HUS (n=397) between 2007 and 2016. RESULTS: The first study included 126 kidney transplants performed in 116 patients, 58.7% and 34.1% of which were considered to be at a high and moderate risk of atypical HUS recurrence, respectively. Eculizumab prophylaxis was used in 52 kidney transplants, including 39 at high risk of recurrence. Atypical HUS recurred after 43 (34.1%) of the transplants; in four cases, patients had received eculizumab prophylaxis and in 39 cases they did not. Use of prophylactic eculizumab was independently associated with a significantly reduced risk of recurrence and with significantly longer graft survival. In the second, population-based cohort study, the proportion of transplant recipients among patients with ESKD and atypical HUS sharply increased between 2012 and 2016, from 46.2% to 72.3%, and showed a close correlation with increasing eculizumab use among the transplant recipients. CONCLUSIONS: Results from this observational study are consistent with benefit from eculizumab prophylaxis based on pretransplant risk stratification and support the need for a rigorous randomized trial.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico , Inativadores do Complemento/uso terapêutico , Transplante de Rim , Adulto , Síndrome Hemolítico-Urêmica Atípica/epidemiologia , Síndrome Hemolítico-Urêmica Atípica/genética , Síndrome Hemolítico-Urêmica Atípica/cirurgia , Proteínas Inativadoras do Complemento C3b/genética , Proteínas do Sistema Complemento/análise , Feminino , França , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Proteínas Mutantes Quiméricas/genética , Cuidados Pré-Operatórios , Modelos de Riscos Proporcionais , Recidiva , Sistema de Registros , Estudos Retrospectivos , Prevenção Secundária
8.
Kidney Int ; 96(4): 995-1004, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31420192

RESUMO

Malignant hypertension is listed among the causes of secondary thrombotic microangiopathy, but pathogenic mutations in complement genes have been reported in patients with hypertension-induced thrombotic microangiopathy. Here we investigated the frequency and severity of hypertension in 55 patients with primary atypical hemolytic uremic syndrome (aHUS). A genetic analysis was performed in all patients, and funduscopic examination was performed in all the patients with Grades 2 and 3 hypertension. A cohort of 110 patients with malignant hypertension caused by diseases other than aHUS served as control. Thirty-six patients with aHUS presented Grade 2 or Grade 3 hypertension and funduscopic examination showed malignant hypertension in 19. Genetic abnormalities in complement were found in 19 patients (37% among patients with malignant hypertension). Plasmapheresis was performed in 46 patients and 26 received eculizumab. Renal and hematological responses were significantly lower after plasmapheresis (24%) than after eculizumab (81%). Renal survival was significantly higher in patients treated with eculizumab (85% at one, three and five years) compared to patients who did not receive this treatment (54%, 46% and 41%), respectively. Response to eculizumab was independent of hypertension severity and the presence of complement genetic abnormalities. Among patients with malignant hypertension caused by other diseases the prevalence of thrombotic microangiopathy was very low (5%). Thus, severe and malignant hypertension are common among patients with aHUS and eculizumab treatment leads to a higher renal survival when compared to plasmapheresis. However, thrombotic microangiopathy is uncommon among patients presenting with malignant hypertension caused by diseases other than aHUS.


Assuntos
Síndrome Hemolítico-Urêmica Atípica/complicações , Proteínas do Sistema Complemento/genética , Hipertensão Maligna/epidemiologia , Índice de Gravidade de Doença , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome Hemolítico-Urêmica Atípica/genética , Síndrome Hemolítico-Urêmica Atípica/terapia , Inativadores do Complemento/uso terapêutico , Feminino , Humanos , Hipertensão Maligna/diagnóstico , Hipertensão Maligna/genética , Hipertensão Maligna/terapia , Incidência , Masculino , Pessoa de Meia-Idade , Plasmaferese , Estudos Retrospectivos , Adulto Jovem
9.
Saudi J Kidney Dis Transpl ; 30(3): 701-705, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31249236

RESUMO

In evaluating a patient with thrombotic microangiopathy (TMA), it is necessary to rule out thrombotic thrombocytopenic purpura before a diagnosis of atypical hemolytic uremic syndrome (aHUS) is made. There have been reports that mutations of complement factors can coexist with partial A Disintegrin and Metalloproteinase with a ThromboSpondin type 1 motif, member 13 deficiency. Here, we report the case of a 6-year-old girl who was initially diagnosed as nephrotic syndrome and developed TMA after five years of onset of illness. She had poor response to treatment and had multiple relapses due to associated complement factor mutation. Hence, genetic evaluation has to be considered in all children presenting with aHUS.


Assuntos
Proteína ADAMTS13/genética , Síndrome Hemolítico-Urêmica Atípica/diagnóstico , Proteínas do Sistema Complemento/genética , Mutação , Púrpura Trombocitopênica Trombótica/diagnóstico , Proteína ADAMTS13/deficiência , Síndrome Hemolítico-Urêmica Atípica/genética , Síndrome Hemolítico-Urêmica Atípica/imunologia , Síndrome Hemolítico-Urêmica Atípica/terapia , Criança , Proteínas do Sistema Complemento/imunologia , Diagnóstico Diferencial , Evolução Fatal , Feminino , Predisposição Genética para Doença , Humanos , Fenótipo , Valor Preditivo dos Testes , Púrpura Trombocitopênica Trombótica/genética , Púrpura Trombocitopênica Trombótica/terapia , Resultado do Tratamento
10.
Pediatr Nephrol ; 34(11): 2339-2342, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31236666
11.
Front Immunol ; 10: 853, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31118930

RESUMO

Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by microangiopathic hemolytic anemia, thrombocytopenia and renal failure. It is caused by genetic or acquired defects of the complement alternative pathway. Factor H autoantibodies (anti-FHs) have been reported in 10% of aHUS patients and are associated with the deficiency of factor H-related 1 (FHR1). However, FHR1 deficiency is not enough to cause aHUS, since it is also present in about 5% of Caucasian healthy subjects. In this study we evaluated the prevalence of genetic variants in CFH, CD46, CFI, CFB, C3, and THBD in aHUS patients with anti-FHs, using healthy subjects with FHR1 deficiency, here defined "supercontrols," as a reference group. "Supercontrols" are more informative than general population because they share at least one risk factor (FHR1 deficiency) with aHUS patients. We analyzed anti-FHs in 305 patients and 30 were positive. The large majority were children (median age: 7.7 [IQR, 6.6-9.9] years) and 83% lacked FHR1 (n = 25, cases) due to the homozygous CFHR3-CFHR1 deletion (n = 20), or the compound heterozygous CFHR3-CFHR1 and CFHR1-CFHR4 deletions (n = 4), or the heterozygous CFHR3-CFHR1 deletion combined with a frameshift mutation in CFHR1 that generates a premature stop codon (n = 1). Of the 960 healthy adult subjects 48 had the FHR1 deficiency ("supercontrols"). Rare likely pathogenetic variants in CFH, THBD, and C3 were found in 24% of cases (n = 6) compared to 2.1% of the "supercontrols" (P-value = 0.005). We also found that the CFH H3 and the CD46 GGAAC haplotypes are not associated with anti-FHs aHUS, whereas these haplotypes are enriched in aHUS patients without anti-FHs, which highlights the differences in the genetic basis of the two forms of the disease. Finally, we confirm that common infections are environmental factors that contribute to the development of anti-FHs aHUS in genetically predisposed individuals, which fits with the sharp peak of incidence during scholar-age. Further studies are needed to fully elucidate the complex genetic and environmental factors underlying anti-FHs aHUS and to establish whether the combination of anti-FHs with likely pathogenetic variants or other risk factors influences disease outcome and response to therapies.


Assuntos
Síndrome Hemolítico-Urêmica Atípica/genética , Autoanticorpos/imunologia , Proteínas Sanguíneas/deficiência , Proteínas do Sistema Complemento/genética , Síndrome Hemolítico-Urêmica Atípica/imunologia , Autoantígenos/imunologia , Proteínas Sanguíneas/genética , Criança , Pré-Escolar , Fator H do Complemento/genética , Fator H do Complemento/imunologia , Feminino , Predisposição Genética para Doença , Variação Genética , Humanos , Masculino
12.
Kidney Int ; 95(6): 1443-1452, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30982675

RESUMO

Secondary hemolytic uremic syndrome (HUS) is a heterogeneous group of thrombotic microangiopathies associated with various underlying conditions. Whether it belongs to the spectrum of complement-mediated HUS remains controversial. We analysed the presentation, outcome, and frequency of complement gene rare variants in a cohort of 110 patients with secondary HUS attributed to drugs (29%), autoimmune diseases (24%), infections (17%), malignancies (10%), glomerulopathies (9%), extra-renal organ transplantation (8%), and pancreatitis (3%). The frequency of complement gene rare variants was similar in patients with secondary HUS (5%) and in healthy individuals (6% and 8% in French and European controls, respectively). At diagnosis, 40% of patients required dialysis and 18% had neurological manifestations. Fifty percent of patients received plasmatherapy and 35% were treated with eculizumab. Haematological and complete renal remission was achieved in 80% and 24% of patients, respectively. Thirty-nine percent of patients progressed to chronic kidney disease (stages 3-4) and an additional 37% reached end-stage renal disease. Eleven percent of patients died, most often from complications of the underlying cause of HUS. Only one patient experienced an HUS relapse. Patients treated with eculizumab presented with more severe HUS and were more likely to require dialysis at the time of diagnosis as compared to patients not treated with eculizumab. Rates of hematological remission, chronic kidney disease (stages 3-4), and end-stage renal disease were similar in the two groups. Secondary HUS is an acute nonrelapsing form of HUS, not related to complement dysregulation. The efficacy of eculizumab in this setting is not yet established.


Assuntos
Síndrome Hemolítico-Urêmica Atípica/genética , Proteínas do Sistema Complemento/genética , Síndrome Hemolítico-Urêmica/etiologia , Falência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome Hemolítico-Urêmica Atípica/mortalidade , Síndrome Hemolítico-Urêmica Atípica/patologia , Síndrome Hemolítico-Urêmica Atípica/terapia , Criança , Pré-Escolar , Ativação do Complemento/genética , Inativadores do Complemento/uso terapêutico , Proteínas do Sistema Complemento/imunologia , Progressão da Doença , Feminino , França/epidemiologia , Síndrome Hemolítico-Urêmica/mortalidade , Síndrome Hemolítico-Urêmica/patologia , Síndrome Hemolítico-Urêmica/terapia , Humanos , Rim/imunologia , Rim/patologia , Falência Renal Crônica/patologia , Masculino , Pessoa de Meia-Idade , Plasmaferese/estatística & dados numéricos , Sistema de Registros/estatística & dados numéricos , Diálise Renal/estatística & dados numéricos , Insuficiência Renal Crônica/patologia , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Adulto Jovem
13.
Clin Chim Acta ; 494: 143-150, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30905589

RESUMO

Although atypical hemolytic uremic syndrome (aHUS) is a genetic disorder, molecular defects are detected in only 60% of patients. We aim to dissect the genetic background by whole exome sequence and the clinical characteristics of pediatric patients with aHUS. Ten patients (6 male and 4 female) with mean age 5.2 ±â€¯5.0 years were enrolled. The age at onset ranged from 2 days to 11 years. Eighteen different mutations (17 missense, 2 nonsense, and 11 novel) on 7 complement and 3 coagulation genes were detected in all patients. The majority of mutation was heterozygous and S1191L on CFH were the recurrent mutation. Sixty percent of patients had multiple genetic mutations. Nine mutations were associated with genes known to be implicated in aHUS (CFH, CFI, CD46, CFHR5, and DGKE), while 4 and 5 mutations were detected on complement- (C8B, C9, and MASP1) and coagulation-associated (VWF and CD36) genes, respectively. CD36 may be a candidate gene act as disease modifier for aHUS through the contribution of thrombosis by impairing the interaction with TSP-1 and ADAMTS 13 shown in simulation model. Genetic defects on both complement and coagulation pathways play pathogenic roles on aHUS. CD36 may be a novel candidate gene act as disease modifier of aHUS.


Assuntos
Síndrome Hemolítico-Urêmica Atípica/genética , Mutação , Sequenciamento Completo do Exoma , Adolescente , Antígenos CD36/genética , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Taiwan
14.
Kidney Int ; 96(1): 67-79, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30910380

RESUMO

Atypical hemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy (TMA) caused by dysregulated complement activation. Clinically, aHUS is effectively treated by an anti-C5 monoclonal antibody (mAb) but whether the disease is mediated by the C5a receptor (C5aR) or C5b-9 pathway, or both, is unknown. Here we address this in a factor H mutant mouse (FHR/R) which developed complement-mediated TMA as well as macrovascular thrombosis caused by an aHUS-related factor H point mutation (mouse W1206R, corresponding to human W1183R). C5 deficiency and anti-C5 mAb treatment blocked all disease manifestations in FHR/R mice. C5aR1 gene deficiency prevented macrovascular thrombosis in various organs but did not improve survival or reduce renal TMA. Conversely, C6 or C9 deficiency significantly improved survival and markedly diminished renal TMA but did not prevent macrovascular thrombosis. Interestingly, as they aged both FHR/R C6-/- and FHR/R C9-/- mice developed glomerular disease reminiscent of C3 glomerulonephritis. Thus, C5aR and C5b-9 pathways drove different aspects of disease in FHR/R mice with the C5aR pathway being responsible for macrovascular thrombosis and chronic inflammatory injury while the C5b-9 pathway caused renal TMA. Our data provide new understanding of the pathogenesis of complement-mediated TMA and macrovascular thrombosis in FHR/R mice and suggest that C5 blockade is more effective for the treatment of aHUS than selectively targeting the C5aR or C5b-9 pathway alone.


Assuntos
Síndrome Hemolítico-Urêmica Atípica/imunologia , Fator H do Complemento/genética , Complexo de Ataque à Membrana do Sistema Complemento/imunologia , Glomérulos Renais/patologia , Receptor da Anafilatoxina C5a/imunologia , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico , Síndrome Hemolítico-Urêmica Atípica/genética , Síndrome Hemolítico-Urêmica Atípica/patologia , Ativação do Complemento/efeitos dos fármacos , Ativação do Complemento/genética , Ativação do Complemento/imunologia , Complemento C6/genética , Complemento C6/imunologia , Complemento C6/metabolismo , Fator H do Complemento/imunologia , Complexo de Ataque à Membrana do Sistema Complemento/genética , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Glomérulos Renais/irrigação sanguínea , Glomérulos Renais/ultraestrutura , Masculino , Camundongos , Camundongos Transgênicos , Microscopia Eletrônica , Mutação Puntual , Receptor da Anafilatoxina C5a/antagonistas & inibidores , Receptor da Anafilatoxina C5a/genética , Receptor da Anafilatoxina C5a/metabolismo
15.
G Ital Nefrol ; 36(1)2019 Feb.
Artigo em Italiano | MEDLINE | ID: mdl-30758152

RESUMO

Atypical hemolytic-uremic syndrome (aHUS) is a rare, potentially lethal (1-4) systemic disorder, capable of affecting both adults and children, causing thrombotic microangiopathy (TMA) (5) that leads to the formation of thrombus within small blood vessels with multiple organ failure. The pathogenesis of the aHUS is part of a sort of chronic and uncontrolled activation of the complement system by genetic mutation of some proteins usually responsible for its self-regulation (6,7). Today, the rapid diagnosis of the disease and the timely start of treatment with eculizumab, improve outcomes of renal failure, stroke and heart attack (8-10). Fabry disease is a rare tesaurismosis, X linked, due to the deficiency of the lysosomal enzyme alpha-galactosidase A (11-13), necessary for the physiological catabolism of glycosphingolipids. Multisystem clinical manifestations lead to a serious degenerative pathology. The diagnostic suspicion based on anamnesis and careful research of the symptoms and then confirmed by the enzymatic dosage of alpha galactosidase or by molecular analysis, allows the early treatment of the patient with enzyme replacement therapy, guaranteeing the resolution and/or slowing down the evolution of the disease, especially in the brain, heart and kidneys. In this report, we describe the clinical case of a patient who is a carrier of both rare diseases.


Assuntos
Síndrome Hemolítico-Urêmica Atípica/complicações , Doença de Fabry/complicações , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Insuficiência da Valva Aórtica/diagnóstico , Síndrome Hemolítico-Urêmica Atípica/genética , Síndrome Hemolítico-Urêmica Atípica/terapia , Terapia de Reposição de Enzimas , Doença de Fabry/diagnóstico , Doença de Fabry/genética , Doença de Fabry/terapia , Feminino , Humanos , Insuficiência da Valva Mitral/diagnóstico , Mutação , alfa-Galactosidase/análise , alfa-Galactosidase/fisiologia
16.
J Clin Invest ; 129(3): 1061-1075, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30714990

RESUMO

Atypical hemolytic uremic syndrome (aHUS) is frequently associated in humans with loss-of-function mutations in complement-regulating proteins or gain-of-function mutations in complement-activating proteins. Thus, aHUS provides an archetypal complement-mediated disease with which to model new therapeutic strategies and treatments. Herein, we show that, when transferred to mice, an aHUS-associated gain-of-function change (D1115N) to the complement-activation protein C3 results in aHUS. Homozygous C3 p.D1115N (C3KI) mice developed spontaneous chronic thrombotic microangiopathy together with hematuria, thrombocytopenia, elevated creatinine, and evidence of hemolysis. Mice with active disease had reduced plasma C3 with C3 fragment and C9 deposition within the kidney. Therapeutic blockade or genetic deletion of C5, a protein downstream of C3 in the complement cascade, protected homozygous C3KI mice from thrombotic microangiopathy and aHUS. Thus, our data provide in vivo modeling evidence that gain-of-function changes in complement C3 drive aHUS. They also show that long-term C5 deficiency is not accompanied by development of other renal complications (such as C3 glomerulopathy) despite sustained dysregulation of C3. Our results suggest that this preclinical model will allow testing of novel complement inhibitors with the aim of developing precisely targeted therapeutics that could have application in many complement-mediated diseases.


Assuntos
Síndrome Hemolítico-Urêmica Atípica , Ativação do Complemento , Complemento C3 , Complemento C5 , Rim , Mutação de Sentido Incorreto , Substituição de Aminoácidos , Animais , Síndrome Hemolítico-Urêmica Atípica/genética , Síndrome Hemolítico-Urêmica Atípica/imunologia , Síndrome Hemolítico-Urêmica Atípica/patologia , Complemento C3/genética , Complemento C3/imunologia , Complemento C5/genética , Complemento C5/imunologia , Complemento C9/genética , Complemento C9/imunologia , Modelos Animais de Doenças , Glomerulonefrite Membranosa/genética , Glomerulonefrite Membranosa/imunologia , Glomerulonefrite Membranosa/patologia , Rim/imunologia , Rim/patologia , Camundongos , Camundongos Transgênicos
17.
Curr Opin Nephrol Hypertens ; 28(2): 183-194, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30601180

RESUMO

PURPOSE OF REVIEW: The purpose of this review is to emphasize that single gene disorders are an important and sometimes unrecognized cause of progressive chronic kidney disease. We provide an overview of the benefits of making a genetic diagnosis, the currently available genetic testing methods and examples of diseases illustrating the impact of a genetic diagnosis. RECENT FINDINGS: Although there are now a number of monogenic renal diseases, only a few, such as autosomal dominant polycystic kidney disease (ADPKD), are generally diagnosable without genetic testing. Complicating clinical diagnosis is that many diseases that classically have characteristic renal or extrarenal findings, often present with an incomplete or overlapping phenotype that requires additional testing to be uncovered. Advances in sequencing technology and bioinformatic processing now give us the ability to screen the entire human genome or exome or an organ-limited subset of genes quickly and inexpensively permitting the unbiased interrogation of hundreds of genes, thus removing the need for precision in clinical diagnosis prior to testing. SUMMARY: We provide an overview of the principal phenotypes seen in chronic kidney disease with a focus on the cystic diseases and ciliopathies, the glomerular diseases, disorders of renal development and the tubulointerstitial diseases. In each of these phenotypes, we provide a listing of some of the important genes that have been identified to date, a brief discussion of the clinical diagnosis, the role of genetic testing and the differentiation of distinct genetic disorders from acquired and genetic phenocopies.


Assuntos
Testes Genéticos/métodos , Doenças Renais Císticas/genética , Insuficiência Renal Crônica/genética , Síndrome Hemolítico-Urêmica Atípica/genética , Anormalidades Congênitas/genética , Doença de Fabry/genética , Humanos , Nefrite Hereditária/genética , Fenótipo , Rim Policístico Autossômico Dominante/genética , Rim Policístico Autossômico Recessivo/genética , Insuficiência Renal Crônica/diagnóstico , Sistema Urinário/anormalidades
18.
Clin J Am Soc Nephrol ; 14(3): 364-377, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30674459

RESUMO

BACKGROUND AND OBJECTIVES: Inherited complement hyperactivation is critical for the pathogenesis of atypical hemolytic uremic syndrome (HUS) but undetermined in postdiarrheal HUS. Our aim was to investigate complement activation and variants of complement genes, and their association with disease severity in children with Shiga toxin-associated HUS. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Determination of complement biomarkers levels and next-generation sequencing for the six susceptibility genes for atypical HUS were performed in 108 children with a clinical diagnosis of post-diarrheal HUS (75 Shiga toxin-positive, and 33 Shiga toxin-negative) and 80 French controls. As an independent control cohort, we analyzed the genotypes in 503 European individuals from the 1000 Genomes Project. RESULTS: During the acute phase of HUS, plasma levels of C3 and sC5b-9 were increased, and half of patients had decreased membrane cofactor protein expression, which normalized after 2 weeks. Variants with minor allele frequency <1% were identified in 12 Shiga toxin-positive patients with HUS (12 out of 75, 16%), including pathogenic variants in four (four out of 75, 5%), with no significant differences compared with Shiga toxin-negative patients with HUS and controls. Pathogenic variants with minor allele frequency <0.1% were found in three Shiga toxin-positive patients with HUS (three out of 75, 4%) versus only four European controls (four out of 503, 0.8%) (odds ratio, 5.2; 95% confidence interval, 1.1 to 24; P=0.03). The genetic background did not significantly affect dialysis requirement, neurologic manifestations, and sC5b-9 level during the acute phase, and incident CKD during follow-up. However, the only patient who progressed to ESKD within 3 years carried a factor H pathogenic variant. CONCLUSIONS: Rare variants and complement activation biomarkers were not associated with severity of Shiga toxin-associated HUS. Only pathogenic variants with minor allele frequency <0.1% are more frequent in Shiga toxin-positive patients with HUS than in controls.


Assuntos
Síndrome Hemolítico-Urêmica Atípica/genética , Ativação do Complemento/genética , Proteínas do Sistema Complemento/genética , Infecções por Escherichia coli/genética , Variação Genética , Escherichia coli Shiga Toxigênica/patogenicidade , Fatores Etários , Síndrome Hemolítico-Urêmica Atípica/imunologia , Síndrome Hemolítico-Urêmica Atípica/microbiologia , Pré-Escolar , Progressão da Doença , Infecções por Escherichia coli/imunologia , Infecções por Escherichia coli/microbiologia , Feminino , França , Frequência do Gene , Predisposição Genética para Doença , Interações Hospedeiro-Patógeno , Humanos , Lactente , Falência Renal Crônica/genética , Falência Renal Crônica/imunologia , Falência Renal Crônica/microbiologia , Masculino , Fenótipo , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Escherichia coli Shiga Toxigênica/imunologia , Fatores de Tempo
19.
Nephrol Dial Transplant ; 34(3): 474-485, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30295827

RESUMO

BACKGROUND: Alport syndrome (AS) and atypical hemolytic-uremic syndrome (aHUS) are rare forms of chronic kidney disease (CKD) that can lead to a severe decline of renal function. Steroid-resistant nephrotic syndrome (SRNS) is more common than AS and aHUS and causes 10% of childhood-onset CKD. In recent years, multiple monogenic causes of AS, aHUS and SRNS have been identified, but their relative prevalence has yet to be studied together in a typical pediatric cohort of children with proteinuria and hematuria. We hypothesized that identification of causative mutations by whole exome sequencing (WES) in known monogenic nephritis and nephrosis genes would allow distinguishing nephritis from nephrosis in a typical pediatric group of patients with both proteinuria and hematuria at any level. METHODS: We therefore conducted an exon sequencing (WES) analysis for 11 AS, aHUS and thrombotic thrombocytopenic purpura-causing genes in an international cohort of 371 patients from 362 families presenting with both proteinuria and hematuria before age 25 years. In parallel, we conducted either WES or high-throughput exon sequencing for 23 SRNS-causing genes in all patients. RESULTS: We detected pathogenic mutations in 18 of the 34 genes analyzed, leading to a molecular diagnosis in 14.1% of families (51 of 362). Disease-causing mutations were detected in 3 AS-causing genes (4.7%), 3 aHUS-causing genes (1.4%) and 12 NS-causing genes (8.0%). We observed a much higher mutation detection rate for monogenic forms of CKD in consanguineous families (35.7% versus 10.1%). CONCLUSIONS: We present the first estimate of relative frequency of inherited AS, aHUS and NS in a typical pediatric cohort with proteinuria and hematuria. Important therapeutic and preventative measures may result from mutational analysis in individuals with proteinuria and hematuria.


Assuntos
Marcadores Genéticos , Mutação , Nefrite/diagnóstico , Nefrite/genética , Nefrose/diagnóstico , Nefrose/genética , Sequenciamento Completo do Exoma/métodos , Adolescente , Síndrome Hemolítico-Urêmica Atípica/diagnóstico , Síndrome Hemolítico-Urêmica Atípica/genética , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Nefrite Hereditária/diagnóstico , Nefrite Hereditária/genética , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/genética , Prognóstico
20.
Pediatr Nephrol ; 34(11): 2261-2277, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-30402748

RESUMO

With the introduction of the complement C5-inhibitor eculizumab, a new era was entered for patients with atypical hemolytic uremic syndrome (aHUS). Eculizumab therapy very effectively reversed thrombotic microangiopathy and reduced mortality and morbidity. Initial guidelines suggested lifelong treatment and recommended prophylactic use of eculizumab in aHUS patients receiving a kidney transplant. However, there is little evidence to support lifelong therapy or prophylactic treatment in kidney transplant recipients. Worldwide, there is an ongoing debate regarding the optimal dose and duration of treatment, particularly in view of the high costs and potential side effects of eculizumab. An increasing but still limited number of case reports and small cohort studies suggest that a restrictive treatment regimen is feasible. We review the current literature and focus on the safety and efficacy of restrictive use of eculizumab. Our current treatment protocol is based on restrictive use of eculizumab. Prospective monitoring will provide more definite proof of the feasibility of such restrictive treatment.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico , Complemento C5/antagonistas & inibidores , Inativadores do Complemento/efeitos adversos , Transplante de Rim/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Síndrome Hemolítico-Urêmica Atípica/genética , Síndrome Hemolítico-Urêmica Atípica/imunologia , Complemento C5/genética , Complemento C5/imunologia , Inativadores do Complemento/administração & dosagem , Progressão da Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Monitoramento de Medicamentos/normas , Estudos de Viabilidade , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Humanos , Falência Renal Crônica/genética , Falência Renal Crônica/cirurgia , Guias de Prática Clínica como Assunto , Prevenção Secundária/métodos , Prevenção Secundária/normas , Fatores de Tempo , Transplantados
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