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1.
Ther Apher Dial ; 23(1): 4-21, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30294946

RESUMO

Atypical hemolytic uremic syndrome (aHUS), a rare variant of thrombotic microangiopathy, is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. The condition is associated with poor clinical outcomes with high morbidity and mortality. Atypical HUS predominantly affects the kidneys but has the potential to cause multi-organ system dysfunction. This uncommon disorder is caused by a genetic abnormality in the complement alternative pathway resulting in over-activation of the complement system and formation of microvascular thrombi. Abnormalities of the complement pathway may be in the form of mutations in key complement genes or autoantibodies against specific complement factors. We discuss the pathophysiology, clinical manifestations, diagnosis, complications, and management of aHUS. We also review the efficacy and safety of the novel therapeutic agent, eculizumab, in aHUS, pregnancy-associated aHUS, and aHUS in renal transplant patients.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Síndrome Hemolítico-Urêmica Atípica , Via Alternativa do Complemento , Síndrome Hemolítico-Urêmica Atípica/diagnóstico , Síndrome Hemolítico-Urêmica Atípica/etiologia , Síndrome Hemolítico-Urêmica Atípica/fisiopatologia , Síndrome Hemolítico-Urêmica Atípica/terapia , Via Alternativa do Complemento/efeitos dos fármacos , Via Alternativa do Complemento/genética , Via Alternativa do Complemento/imunologia , Gerenciamento Clínico , Humanos , Fatores Imunológicos/farmacologia
3.
Nephron ; 140(1): 63-73, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29940557

RESUMO

Thrombomodulin (TM) is an endothelial glycoprotein that is present in all blood vessels. Five percent of all patients with atypical hemolytic uremic syndrome (aHUS) have mutations in the gene coding for TM, with a peak presentation in young children. Mutations often translate into quantitative and qualitative abnormalities of this endothelial glycoprotein. Outcome of the TM-associated aHUS is relatively poor with frequent relapses after transplantation despite its membrane-bound character. We observed a woman presenting with malignant hypertension (MHT) and associated kidney, brain, cardiac, and hematological involvement with thrombotic microangiopathy on kidney biopsy. She had a documented mutation of the gene coding for TM, which was associated with both aHUS and an increased risk for venous and arterial thrombosis. As TM has anti-coagulant, anti-inflammatory, and cytoprotective properties and also attenuates alternative complement activation, this glycoprotein could play an active role in other diseases with endothelial involvement apart from aHUS. We discuss the potential role of TM in the pathophysiology of various endotheliopathies including MHT. We also provide a framework for future therapeutic options.


Assuntos
Síndrome Hemolítico-Urêmica Atípica/genética , Hipertensão Maligna/genética , Trombomodulina/genética , Microangiopatias Trombóticas/genética , Adulto , Síndrome Hemolítico-Urêmica Atípica/patologia , Síndrome Hemolítico-Urêmica Atípica/fisiopatologia , Criança , Pré-Escolar , Endotélio Vascular/patologia , Feminino , Humanos , Hipertensão Maligna/patologia , Hipertensão Maligna/fisiopatologia , Rim/patologia , Trombomodulina/metabolismo , Trombomodulina/uso terapêutico , Microangiopatias Trombóticas/complicações , Microangiopatias Trombóticas/patologia
4.
Clin Genet ; 94(3-4): 330-338, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29888403

RESUMO

Genetic alterations in the complement system have been linked to a variety of diseases, including atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G), and age-related macular degeneration (AMD). We performed sequence analysis of the complement genes complement factor H (CFH), complement factor I (CFI), and complement C3 (C3) in 866 aHUS/C3G and 697 AMD patients. In total, we identified 505 low-frequency alleles, representing 121 unique variants, of which 51 are novel. CFH contained the largest number of unique low-frequency variants (n = 64; 53%), followed by C3 (n = 32; 26%) and CFI (n = 25; 21%). A substantial number of variants were found in both patients groups (n = 48; 40%), while 41 (34%) variants were found only in aHUS/C3G and 32 (26%) variants were AMD specific. Genotype-phenotype correlations between the disease groups identified a higher frequency of protein altering alleles in short consensus repeat 20 (SCR20) of factor H (FH), and in the serine protease domain of factor I (FI) in aHUS/C3G patients. In AMD, a higher frequency of protein-altering alleles was observed in SCR3, SCR5, and SCR7 of FH, the SRCR domain of FI, and in the MG3 domain of C3. In conclusion, we observed a substantial overlap of variants between aHUS/C3G and AMD; however, there is a distinct clustering of variants within specific domains.


Assuntos
Síndrome Hemolítico-Urêmica Atípica/genética , Complemento C3/genética , Fator I do Complemento/genética , Genótipo , Glomerulonefrite Membranosa/genética , Degeneração Macular/genética , Fenótipo , Síndrome Hemolítico-Urêmica Atípica/metabolismo , Síndrome Hemolítico-Urêmica Atípica/fisiopatologia , Estudos de Coortes , Complemento C3/metabolismo , Fator H do Complemento/genética , Fator H do Complemento/metabolismo , Fator I do Complemento/metabolismo , Predisposição Genética para Doença , Glomerulonefrite Membranosa/metabolismo , Glomerulonefrite Membranosa/fisiopatologia , Humanos , Degeneração Macular/metabolismo , Degeneração Macular/fisiopatologia
5.
J Bras Nefrol ; 40(1): 77-81, 2018.
Artigo em Inglês, Português | MEDLINE | ID: mdl-29796581

RESUMO

Scleroderma is an autoimmune disease that affects multiple systems. While pathophysiologic mechanisms governing the development of scleroderma are relatively poorly understood, advances in our understanding of the complement system are clarifying the role of complement pathways in the development of atypical hemolytic uremic syndrome and scleroderma renal crisis. The abundant similarities in their presentation as well as the clinical course are raising the possibility of a common underlying pathogenesis. Recent reports are emphasizing that complement pathways appear to be the unifying link. This article reviews the role of complement system in the development of atypical hemolytic uremic syndrome and scleroderma renal crisis, and calls for heightened awareness to the development of thrombotic angiopathy in patients with scleroderma.


Assuntos
Lesão Renal Aguda/imunologia , Lesão Renal Aguda/fisiopatologia , Síndrome Hemolítico-Urêmica Atípica/imunologia , Síndrome Hemolítico-Urêmica Atípica/fisiopatologia , Ativação do Complemento , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/fisiopatologia , Humanos
6.
J. bras. nefrol ; 40(1): 77-81, Jan.-Mar. 2018. tab
Artigo em Inglês | LILACS | ID: biblio-893816

RESUMO

ABSTRACT Scleroderma is an autoimmune disease that affects multiple systems. While pathophysiologic mechanisms governing the development of scleroderma are relatively poorly understood, advances in our understanding of the complement system are clarifying the role of complement pathways in the development of atypical hemolytic uremic syndrome and scleroderma renal crisis. The abundant similarities in their presentation as well as the clinical course are raising the possibility of a common underlying pathogenesis. Recent reports are emphasizing that complement pathways appear to be the unifying link. This article reviews the role of complement system in the development of atypical hemolytic uremic syndrome and scleroderma renal crisis, and calls for heightened awareness to the development of thrombotic angiopathy in patients with scleroderma.


RESUMO A esclerodermia é uma doença autoimune que afeta múltiplos sistemas. Embora os mecanismos fisiopatológicos que regem o desenvolvimento da esclerodermia sejam relativamente pouco compreendidos, os avanços em nossa compreensão do sistema do complemento estão esclarecendo o papel das vias do complemento no desenvolvimento da síndrome urêmica hemolítica atípica e da crise renal da esclerodermia. As abundantes semelhanças em sua apresentação, bem como o curso clínico, estão aumentando a possibilidade de uma patogênese subjacente comum. Relatórios recentes estão enfatizando que as vias de complemento parecem ser o link unificador. Este artigo analisa o papel do sistema do complemento no desenvolvimento da síndrome urêmica hemolítica atípica e da crise renal na esclerodermia, e exige maior conscientização para com o desenvolvimento da angiopatia trombótica em pacientes com esclerodermia.


Assuntos
Humanos , Escleroderma Sistêmico/imunologia , Ativação do Complemento , Lesão Renal Aguda/fisiopatologia , Lesão Renal Aguda/imunologia , Síndrome Hemolítico-Urêmica Atípica/fisiopatologia , Síndrome Hemolítico-Urêmica Atípica/imunologia , Escleroderma Sistêmico/fisiopatologia
7.
Arch Dis Child ; 103(3): 285-291, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28899876

RESUMO

Haemolytic uraemic syndrome (HUS), comprising microangiopathic haemolytic anaemia, thrombocytopaenia and acute kidney injury, remains the leading cause of paediatric intrinsic acute kidney injury, with peak incidence in children aged under 5 years. HUS most commonly occurs following infection with Shiga toxin-producing Escherichia coli (STEC-HUS). Additionally, HUS can occur as a result of inherited or acquired dysregulation of the alternative complement cascade (atypical HUS or aHUS) and in the setting of invasive pneumococcal infection. The field of HUS has been transformed by the discovery of the central role of complement in aHUS and the dawn of therapeutic complement inhibition. Herein, we address these three major forms of HUS in children, review the latest evidence for their treatment and discuss the management of STEC infection from presentation with bloody diarrhoea, through to development of fulminant HUS.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome Hemolítico-Urêmica Atípica/terapia , Inativadores do Complemento/uso terapêutico , Diarreia/terapia , Infecções por Escherichia coli/complicações , Síndrome Hemolítico-Urêmica Atípica/diagnóstico , Síndrome Hemolítico-Urêmica Atípica/microbiologia , Síndrome Hemolítico-Urêmica Atípica/fisiopatologia , Criança , Diarreia/microbiologia , Guias como Assunto , Humanos , Resultado do Tratamento
8.
J Am Soc Nephrol ; 29(3): 1020-1029, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29282226

RESUMO

Atypical HUS (aHUS) is a disorder most commonly caused by inherited defects of the alternative pathway of complement, or the proteins that regulate this pathway, and life-threatening episodes of aHUS can be provoked by pregnancy. We retrospectively and prospectively investigated 27 maternal and fetal pregnancy outcomes in 14 women with aHUS from the Vienna Thrombotic Microangiopathy Cohort. Seven pregnancies (26%) were complicated by pregnancy-associated aHUS (p-aHUS), of which three appeared to be provoked by infection, bleeding, and curettage, and three individuals were considered to have preeclampsia/HELLP syndrome before the definitive diagnosis of p-aHUS was made. Mutations in genes that encode the complement alternative pathway proteins or the molecules that regulate this pathway were detected in 71% of the women, with no relationship to pregnancy outcome. Twenty-one pregnancies (78%) resulted in a live birth, two preterm infants were stillborn, and four pregnancies resulted in early spontaneous abortions. Although short-term renal outcome was good in most women, long-term renal outcome was poor; among the 14 women, four had CKD stage 1-4, five had received a renal allograft, and three were dialysis-dependent at study end. We prospectively followed nine pregnancies of four women and treated six of these pregnancies with prophylactic plasma infusions (one pregnancy resulted in p-aHUS, one intrauterine fetal death occurred, and seven pregancies were uneventful). Our study emphasizes the frequency of successful pregnancies in women with aHUS. Close monitoring of such pregnancies for episodes of thrombotic microangiopathy is essential but, the best strategy to prevent these episodes remains unclear.


Assuntos
Síndrome Hemolítico-Urêmica Atípica/complicações , Síndrome Hemolítico-Urêmica Atípica/fisiopatologia , Falência Renal Crônica/fisiopatologia , Complicações na Gravidez/etiologia , Microangiopatias Trombóticas/etiologia , Aborto Espontâneo/etiologia , Adulto , Síndrome Hemolítico-Urêmica Atípica/genética , Síndrome Hemolítico-Urêmica Atípica/terapia , Via Alternativa do Complemento/genética , Progressão da Doença , Feminino , Morte Fetal/etiologia , Humanos , Recém-Nascido , Falência Renal Crônica/etiologia , Falência Renal Crônica/terapia , Nascimento Vivo , Masculino , Pessoa de Meia-Idade , Mutação , Plasma , Gravidez , Complicações na Gravidez/genética , Complicações na Gravidez/terapia , Estudos Prospectivos , Estudos Retrospectivos , Natimorto , Adulto Jovem
9.
PLoS One ; 12(11): e0188155, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29136640

RESUMO

INTRODUCTION: The treatment of choice for Atypical Hemolytic Uremic Syndrome (aHUS) is the monoclonal antibody eculizumab. The objective of this study was to assess the efficacy and safety of eculizumab in a cohort of kidney transplant patients suffering from aHUS. METHODS: Description of the prospective cohort of all the patients primarily treated with eculizumab after transplantation and divided into the therapeutic (onset of aHUS after transplantation) and prophylactic use (patients with previous diagnosis of aHUS undergoing kidney transplantation). RESULTS: Seven cases were outlined: five of therapeutic use and two, prophylactic. From the five cases of therapeutic use, there was improvement of the thrombotic microangiopathy in the 48 hours following the start of the drug and no patient experienced relapse during an average follow-up of 21 months in the continuous use of eculizumab (minimum of 6 and maximum of 42 months). One patient died at 6 months, due to Aspergillus infection. From the two cases of prophylactic use, one patient experienced relapsed thrombotic microangiopathy after 4 months and another patient remained asymptomatic after 16 months of follow-up, both on chronic treatment. DISCUSSION: The therapeutic use of eculizumab showed to be effective, with improvement of the microangiopathy parameters and persisting up to the end of the follow-up, without relapses. The additional risk of immunosuppression, leading to opportunistic infections, was well tolerated. The prophylactic use showed to be effective and safe; however, the doses and intervals should be individualized in order to avoid relapsed microangiopathy, especially in patients with factor H mutation.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico , Síndrome Hemolítico-Urêmica Atípica/fisiopatologia , Brasil , Humanos , Estudos Prospectivos , Resultado do Tratamento
10.
Medicine (Baltimore) ; 96(43): e8284, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29068997

RESUMO

RATIONALE: Methylmalonic acidemia (MMA) is a common organic acidemia, mainly due to methylmalonyl-CoA mutase (MCM) or its coenzyme cobalamin (VitB12) metabolic disorders. Cobalamin C (CblC) type is the most frequent inborn error of cobalamin metabolism; it can develop symptoms in childhood and often combine multisystem damage, which leads to methylmalonic acid, propionic acid, methyl citrate, and other metabolites abnormal accumulation, causing nerve, liver, kidney, bone marrow, and other organ damage. PATIENT CONCERNS: A 4-year-old girl presented with paleness, fatigue, severe normochromic anemia, and acute kidney injury. DIAGNOSIS: Based on severe normochromic anemia and acute kidney injury, renal biopsy showed membranous proliferative glomerular lesions and thrombotic microvascular disease, supporting the diagnosis of aHUS. Although the serum vitamin B12 was normal, further investigation found the concentration of urinary methylmalonic acid and serum homocysteine increased obviously, genetic analysis revealed a heterozygous MMACHC mutation (exonl: c. 80A >G, c. 609G >A). The final diagnosis was aHUS induced by inherited methylmalonic acidemia (MMACHC heterozygous mutation exonl: c. 80A >G, c. 609G >A). INTERVENTIONS: The patient was treated with a 1mg vitamin B12 intramuscular injection daily for 4 days after which the dose was then adjusted to a 1mg intramuscular injection twice a week. At the same time, the girl was given levocarnitine, betaine, folic acid, along with supportive treatment. OUTCOMES: After treated by vitamin B12 for 10 days, the patient condition significantly improved, Follow-up results showed complete recovery of hemoglobin and renal function. LESSONS: Although the majority of MMA onset from neurological damage, our case illustrates that partial CblC-type MMA can onset with severe metabolic aHUS. On the basis of chronic thrombotic microangiopathy (TMA)-induced renal damage, it can be complicated by acute hemolytic lesions. MMA should be considered in those patients with unclear microangiopathic hemolytic anemia accompany significant megaloblastic degeneration in bone marrow. We should pay attention to the causes and adopt a reasonable treatment strategy.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Síndrome Hemolítico-Urêmica Atípica , Proteínas de Transporte/genética , Vitamina B 12 , Erros Inatos do Metabolismo dos Aminoácidos/sangue , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Erros Inatos do Metabolismo dos Aminoácidos/genética , Síndrome Hemolítico-Urêmica Atípica/diagnóstico , Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico , Síndrome Hemolítico-Urêmica Atípica/etiologia , Síndrome Hemolítico-Urêmica Atípica/fisiopatologia , Pré-Escolar , Feminino , Homocisteína/sangue , Humanos , Rim/patologia , Ácido Metilmalônico/sangue , Mutação , Oxirredutases , Resultado do Tratamento , Vitamina B 12/administração & dosagem , Vitamina B 12/sangue , Vitamina B 12/metabolismo , Complexo Vitamínico B/administração & dosagem
11.
Clin J Oncol Nurs ; 21(4): 481-487, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28738049

RESUMO

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS), a condition found in adult and pediatric populations, can be idiopathic or acquired as a result of major systemic changes. aHUS presents with a wide array of symptoms that can be attributed to other less dangerous conditions. Because of its complex nature and rare occurrence, it is typically diagnosed in later stages and with multiple organ involvement.
. OBJECTIVES: This article provides an overview of aHUS and available interventions. 
. METHODS: Current aHUS literature was reviewed, and implications for nursing care were identified.
. FINDINGS: Early diagnosis is crucial to achieve positive patient outcomes. The difference in pathology among the different thrombotic microangiopathies and their appropriate management must be understood. Although aHUS requires a multidisciplinary approach, nurses play a crucial role in assessing disease progression and identifying possible complications.


Assuntos
Síndrome Hemolítico-Urêmica Atípica/diagnóstico , Síndrome Hemolítico-Urêmica Atípica/terapia , Adulto , Síndrome Hemolítico-Urêmica Atípica/genética , Síndrome Hemolítico-Urêmica Atípica/fisiopatologia , Criança , Feminino , Humanos , Masculino , Fatores de Risco , Resultado do Tratamento
12.
Ther Apher Dial ; 21(4): 304-319, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28508588

RESUMO

Complement-mediated atypical hemolytic uremic syndrome (aHUS) is a rare disease associated with high mortality and morbidity. Renal biopsies often indicate thrombotic microangiopathy (TMA). The condition is caused by an excessive activation of the alternative pathway leading to depositions of membrane attack complexes (MAC) on host cells. It may depend on mutations in complement components and regulatory proteins, or the formation of complement-specific antibodies. Mainly, an environmental trigger (e.g. infection) is needed for the excessive response to develop. The clinical characteristics are more or less shared with a wide range of diseases manifesting with microangiopathic hemolytic anemia. Because of prior deficits in pathogenic understanding, associated nomenclature has been based on clinical symptoms. New knowledge challenges these symptomatic definitions; however, an outdated terminology is still being applied in clinical practice to various extents. With respect to gained insights, it is more advantageous to rebuild the concepts on etiological and pathogenic grounds. The need for more distinct definitions is even more urgent in the light of the effective treatment regimen with eculizumab for complement-mediated aHUS. This review presents an up-to-date summary of the field of investigation, addresses the need for faster differential diagnostics and proposes a revised nomenclature based on the current pathogenic understanding.


Assuntos
Síndrome Hemolítico-Urêmica Atípica/diagnóstico , Terminologia como Assunto , Microangiopatias Trombóticas/diagnóstico , Síndrome Hemolítico-Urêmica Atípica/fisiopatologia , Biópsia , Proteínas do Sistema Complemento/metabolismo , Diagnóstico Diferencial , Humanos , Microangiopatias Trombóticas/fisiopatologia
13.
Bone Marrow Transplant ; 52(10): 1355-1360, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28287636

RESUMO

Transplant-associated thrombotic microangiopathy (TA-TMA) is an early complication of hematopoietic cell transplantation (HCT). A high mortality rate is documented in patients who are refractory to calcineurin inhibitor cessation. Estimates of TA-TMA prevalence vary significantly and are higher in allogeneic compared with autologous HCT. Furthermore, our understanding of the pathophysiology that is strongly related to diagnosis and treatment options is limited. Recent evidence has linked TA-TMA with atypical hemolytic uremic syndrome, a disease of excessive activation of the alternative pathway of complement, opening the Pandora's box in treatment options. As conventional treatment management is highly inefficient, detection of complement activation may allow for early recognition of patients who will benefit from complement inhibition. Preliminary clinical results showing successful eculizumab administration in children and adults with TA-TMA need to be carefully evaluated. Therefore, realizing the unmet needs of better understanding TA-TMA in this complex setting, we aimed to summarize current knowledge focusing on (1) critical evaluation of diagnostic criteria, (2) epidemiology and prognosis, (3) recent evidence of complement activation and endothelial damage and (4) treatment options.


Assuntos
Síndrome Hemolítico-Urêmica Atípica , Ativação do Complemento , Transplante de Células-Tronco Hematopoéticas , Microangiopatias Trombóticas , Aloenxertos , Síndrome Hemolítico-Urêmica Atípica/etiologia , Síndrome Hemolítico-Urêmica Atípica/metabolismo , Síndrome Hemolítico-Urêmica Atípica/mortalidade , Síndrome Hemolítico-Urêmica Atípica/fisiopatologia , Autoenxertos , Humanos , Microangiopatias Trombóticas/etiologia , Microangiopatias Trombóticas/metabolismo , Microangiopatias Trombóticas/mortalidade , Microangiopatias Trombóticas/fisiopatologia
15.
Vestn Ross Akad Med Nauk ; 72(1): 42-52, 2017.
Artigo em Russo | MEDLINE | ID: mdl-29308852

RESUMO

Background: The role of the alternative complement pathway (AP) abnormalities in the pathogenesis of aHUS is well studied. Clinical and morphological manifestations of atypical HUS and catastrophic APS are often similar. However, studies on the state of AP in patients with CAPS are virtually absent. Aims: The aim of our study was to assess the state of AP in patients with CAPS and aHUS. Patients and methods: The study enrolled 67 patients (pts) with a diagnosis of CAPS (28 pts) and aHUS (39 pts). Studies of the complement system are made of 10 pts with CAPS and 20 aHUS. Factor H, I, B, D content, functional activity of factor H, and complement components C3, C4 was determined in serum by ELISA kit. Results: Patients with CAPS and aHUS showed similar changes in complement biomarkers. The factor H level in the serum was significantly higher than the standard value. However, the specific activity of factor H reduced, mean rate 59% for aHUS and 26% for CAPS. The median value of factor D was twice higher than the normal range in both groups, indicating the activation of the AP. Conclusions: There are indications of an AP activation not only in pts with aHUS but in CAPS pts too. We suppose that the activity of factor H is a more sensitive indicator of complement system changes than factor H level. Patients with CAPS and aHUS have similar clinical and laboratory characteristics. However, CAPS is more severe, with the involvement of a larger number of vascular beds. Perhaps this is due to the double damaging effects on the endothelium ­ of antiphospholipid antibodies (aPL) and activated complement. So we hypothesize that CAPS can be called aPL-mediated TMA in pts with a complement system defect.


Assuntos
Síndrome Antifosfolipídica , Síndrome Hemolítico-Urêmica Atípica , Fator H do Complemento , Proteínas do Sistema Complemento , Microangiopatias Trombóticas/metabolismo , Adulto , Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/diagnóstico , Síndrome Antifosfolipídica/metabolismo , Síndrome Antifosfolipídica/fisiopatologia , Síndrome Hemolítico-Urêmica Atípica/diagnóstico , Síndrome Hemolítico-Urêmica Atípica/metabolismo , Síndrome Hemolítico-Urêmica Atípica/fisiopatologia , Fator H do Complemento/análise , Fator H do Complemento/metabolismo , Via Alternativa do Complemento , Proteínas do Sistema Complemento/análise , Proteínas do Sistema Complemento/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Feminino , Humanos , Masculino , Estatística como Assunto
16.
J Nephrol ; 30(1): 127-134, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26995002

RESUMO

BACKGROUND: Eculizumab is approved for atypical hemolytic uremic syndrome (aHUS). Guidelines discuss the importance of prompt treatment. We report a post hoc analysis investigating the effect of baseline factors, including patient characteristics and time from the latest aHUS manifestation to eculizumab initiation, on change from baseline in estimated glomerular filtration rate (eGFR) and other outcomes. METHODS: Data were pooled from four phase 2, open-label, single-arm, prospective clinical studies of eculizumab for patients with aHUS. Multivariate regressions identified predictors of eGFR change from baseline. The proportion of patients achieving sustained eGFR increase (defined: ≥15 ml/min/1.73 m2 for ≥28 days) and platelet count normalization were evaluated 1 year post-treatment. Baseline characteristics and eGFR outcomes were summarized by time to treatment from last aHUS manifestation [≤7 days (n = 21) versus >7 days (n = 76)]. RESULTS: Baseline eGFR were similar between groups. Multivariate regression analysis demonstrated time from aHUS manifestation to eculizumab treatment, age, baseline lactate dehydrogenase (LDH) and baseline hemoglobin were independently predictive of eGFR change from baseline. Mean eGFR change from baseline at 1 year was significantly higher in patients treated in ≤7 days than >7 days (57 vs. 23 ml/min/1.73 m2, p = 0.0098). After 1 year, 17/21 and 36/76 patients in the ≤7 and >7 day groups, respectively, achieved a sustained increase in eGFR. Mean time to platelet count normalization was similar between groups. CONCLUSIONS: Younger age, higher baseline LDH and lower baseline hemoglobin were associated with greater eGFR improvements. Early eculizumab initiation led to improved renal recovery, demonstrating the importance of rapid diagnosis and treatment of patients with aHUS.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico , Taxa de Filtração Glomerular , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Síndrome Hemolítico-Urêmica Atípica/fisiopatologia , Criança , Pré-Escolar , Feminino , Hemoglobinas/análise , Humanos , Lactente , Recém-Nascido , L-Lactato Desidrogenase/sangue , Masculino , Pessoa de Meia-Idade , Análise de Regressão
17.
Annu Rev Pathol ; 12: 25-52, 2017 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-27959629

RESUMO

The vertebrate complement system consists of sequentially interacting proteins that provide for a rapid and powerful host defense. Nearly 60 proteins comprise three activation pathways (classical, alternative, and lectin) and a terminal cytolytic pathway common to all. Attesting to its potency, nearly half of the system's components are engaged in its regulation. An emerging theme over the past decade is that variations in these inhibitors predispose to two scourges of modern humans. One, occurring most often in childhood, is a rare but deadly thrombomicroangiopathy called atypical hemolytic uremic syndrome. The other, age-related macular degeneration, is the most common form of blindness in the elderly. Their seemingly unrelated clinical presentations and pathologies share the common theme of overactivity of the complement system's alternative pathway. This review summarizes insights gained from contemporary genetics for understanding how dysregulation of this powerful innate immune system leads to these human diseases.


Assuntos
Síndrome Hemolítico-Urêmica Atípica/fisiopatologia , Via Alternativa do Complemento/genética , Proteínas do Sistema Complemento/genética , Degeneração Macular/fisiopatologia , Genótipo , Humanos
18.
Clin J Am Soc Nephrol ; 12(1): 50-59, 2017 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-27799617

RESUMO

BACKGROUND AND OBJECTIVES: The complement inhibitor eculizumab has dramatically improved the outcome of atypical hemolytic uremic syndrome. However, the optimal duration of eculizumab treatment in atypical hemolytic uremic syndrome remains debated. We report on the French atypical hemolytic uremic syndrome working group's first 2-year experience with eculizumab discontinuation in patients with atypical hemolytic uremic syndrome. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: Using the French atypical hemolytic uremic syndrome registry database, we retrospectively identified all dialysis-free patients with atypical hemolytic uremic syndrome who discontinued eculizumab between 2010 and 2014 and reviewed their relevant clinical and biologic data. The decision to discontinue eculizumab was made by the clinician in charge of the patient. All patients were closely monitored by regular urine dipsticks and blood tests. Eculizumab was rapidly (24-48 hours) restarted in case of relapse. RESULTS: Among 108 patients treated with eculizumab, 38 patients (nine children and 29 adults) discontinued eculizumab (median treatment duration of 17.5 months). Twenty-one patients (55%) carried novel or rare complement genes variants. Renal recovery under eculizumab was equally good in patients with and those without complement gene variants detected. After a median follow-up of 22 months, 12 patients (31%) experienced atypical hemolytic uremic syndrome relapse. Eight of 11 patients (72%) with complement factor H variants, four of eight patients (50%) with membrane cofactor protein variants, and zero of 16 patients with no rare variant detected relapsed. In relapsing patients, early reintroduction (≤48 hours) of eculizumab led to rapid (<7 days) hematologic remission and a return of serum creatinine to baseline level in a median time of 26 days. At last follow-up, renal function remained unchanged in nonrelapsing and relapsing patients compared with baseline values before eculizumab discontinuation. CONCLUSIONS: Pathogenic variants in complement genes were associated with higher risk of atypical hemolytic uremic syndrome relapse after eculizumab discontinuation. Prospective studies are needed to identify biomarkers predictive of relapse and determine the best strategy of retreatment in relapsing patients.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico , Síndrome Hemolítico-Urêmica Atípica/genética , Proteínas do Sistema Complemento/genética , Adolescente , Adulto , Idoso , Síndrome Hemolítico-Urêmica Atípica/fisiopatologia , Criança , Pré-Escolar , Fator H do Complemento/genética , Feminino , Seguimentos , Humanos , Masculino , Proteína Cofatora de Membrana/genética , Pessoa de Meia-Idade , Recidiva , Suspensão de Tratamento , Adulto Jovem
19.
Hematology Am Soc Hematol Educ Program ; 2016(1): 217-225, 2016 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-27913483

RESUMO

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA) that affects multiple organs and the kidneys in particular. aHUS can be sporadic or familial and is most commonly caused by dysregulation of the alternative complement pathway. The initial attack of aHUS can occur at any age, and is associated with a high rate of progression to end stage renal disease. Many aHUS patients relapse in the native or transplanted kidneys, and require close monitoring and long-term management. Availability of anticomplement therapy has revolutionized the management of aHUS, and can change the natural course of aHUS by inducing hematologic remission, improving or stabilizing kidney functions, and preventing graft failure. As a result, it is important to succeed in the challenging task of differentiating aHUS from other TMAs and initiate adequate treatment early during the course of disease. Considering the high cost of currently available anticomplement therapy, it is important also from a financial point of view to accurately diagnose aHUS early during the course of disease and determine the necessary length of therapy. This highlights the need for development of precise complement functional and genetic studies with rapid turnaround time.


Assuntos
Síndrome Hemolítico-Urêmica Atípica , Síndrome Hemolítico-Urêmica Atípica/sangue , Síndrome Hemolítico-Urêmica Atípica/diagnóstico , Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico , Síndrome Hemolítico-Urêmica Atípica/fisiopatologia , Proteínas do Sistema Complemento/metabolismo , Humanos , Rim/metabolismo , Rim/fisiopatologia , Transplante de Rim/efeitos adversos , Recidiva
20.
J Clin Rheumatol ; 22(6): 320-3, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27556240

RESUMO

Atypical hemolytic uremic syndrome is characterized by the presence of thrombocytopenia, microangiopathic hemolytic anemia, and end-organ injury. In this report, we describe two patients with systemic lupus erythematosus who presented with findings compatible with atypical hemolytic uremic syndrome, complicated by acute kidney injury that was refractory to conventional therapies. Both patients exhibited a response to eculizumab, a monoclonal antibody to complement protein C5, with stabilization of their platelet count. On 1-year follow-up from their initial presentation, their hematologic disease remained in remission without recurrence.


Assuntos
Lesão Renal Aguda , Anticorpos Monoclonais Humanizados/administração & dosagem , Síndrome Hemolítico-Urêmica Atípica , Lúpus Eritematoso Sistêmico/complicações , Microangiopatias Trombóticas , Lesão Renal Aguda/diagnóstico , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/terapia , Adulto , Síndrome Hemolítico-Urêmica Atípica/diagnóstico , Síndrome Hemolítico-Urêmica Atípica/etiologia , Síndrome Hemolítico-Urêmica Atípica/fisiopatologia , Síndrome Hemolítico-Urêmica Atípica/terapia , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Masculino , Contagem de Plaquetas/métodos , Microangiopatias Trombóticas/diagnóstico , Microangiopatias Trombóticas/etiologia , Microangiopatias Trombóticas/terapia , Resultado do Tratamento
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