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1.
Mol Cell Endocrinol ; 592: 112318, 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38908427

RESUMO

INTRODUCTION: AMPK (AMP-activated protein kinase) is an enzyme that acts as a metabolic sensor and regulates multiple pathways via phosphorylating proteins in metabolic and proliferative pathways. The aim of this work was to study the activated cellular AMPK (phosphorylated-AMPK at Thr172, pAMPK) levels in pituitary tumor samples from patients with sporadic and familial acromegaly, as well as in samples from normal human pituitary gland. METHODS: We studied pituitary adenoma tissue from patients with sporadic somatotroph adenomas, familial acromegaly with heterozygote germline variants in the aryl hydrocarbon receptor interacting protein (AIP) gene (p.Q164*, p.R304* and p.F269_H275dup) and autopsy from normal pituitary glands without structural alterations. RESULTS: Cellular levels of pAMPK were significantly higher in patients with sporadic acromegaly compared to normal pituitary glands (p < 0.0001). Tissues samples from patients with germline AIP mutations also showed higher cellular levels of pAMPK compared to normal pituitary glands. We did not observe a significant difference in cellular levels of pAMPK according to the cytokeratin (CAM5.2) pattern (sparsely or densely granulated) for tumor samples of sporadic acromegaly. CONCLUSION: Our data show, for the first time in human cells, an increase of cellular levels of pAMPK in sporadic somatotropinomas, regardless of cytokeratin pattern, as well as in GH-secreting adenomas from patients with germline AIP mutations.

2.
Hepatol Commun ; 6(2): 270-280, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34520633

RESUMO

Liver test abnormalities are frequently observed in patients with coronavirus disease 2019 (COVID-19) and are associated with worse prognosis. However, information is limited about pathological changes in the liver in this infection, so the mechanism of liver injury is unclear. Here we describe liver histopathology and clinical correlates of 27 patients who died of COVID-19 in Manaus, Brazil. There was a high prevalence of liver injury (elevated alanine aminotransferase and aspartate aminotransferase in 44% and 48% of patients, respectively) in these patients. Histological analysis showed sinusoidal congestion and ischemic necrosis in more than 85% of the cases, but these appeared to be secondary to systemic rather than intrahepatic thrombotic events, as only 14% and 22% of samples were positive for CD61 (marker of platelet activation) and C4d (activated complement factor), respectively. Furthermore, the extent of these vascular findings did not correlate with the extent of transaminase elevations. Steatosis was present in 63% of patients, and portal inflammation was present in 52%. In most cases, hepatocytes expressed angiotensin-converting enzyme 2 (ACE2), which is responsible for binding and entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), even though this ectoenzyme was minimally expressed on hepatocytes in normal controls. However, SARS-CoV-2 staining was not observed. Most hepatocytes also expressed inositol 1,4,5-triphosphate receptor 3 (ITPR3), a calcium channel that becomes expressed in acute liver injury. Conclusion: The hepatocellular injury that commonly occurs in patients with severe COVID-19 is not due to the vascular events that contribute to pulmonary or cardiac damage. However, new expression of ACE2 and ITPR3 with concomitant inflammation and steatosis suggests that liver injury may result from inflammation, metabolic abnormalities, and perhaps direct viral injury.


Assuntos
COVID-19/complicações , Hepatopatias/patologia , Hepatopatias/virologia , Fígado/patologia , Fígado/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil , COVID-19/mortalidade , COVID-19/patologia , COVID-19/fisiopatologia , Feminino , Humanos , Fígado/fisiopatologia , Hepatopatias/diagnóstico , Hepatopatias/fisiopatologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade
3.
J. bras. nefrol ; 41(2): 252-265, Apr.-June 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1012537

RESUMO

Abstract Involvement of the kidneys by lupus nephritis (LN) is one of the most severe clinical manifestations seen in individuals with systemic lupus erythematosus (SLE). LN is more frequent and severe in pediatric patients and has been associated with higher morbidity and mortality rates. This narrative review aimed to describe the general aspects of LN and its particularities when affecting children and adolescents, while focusing on the disease's etiopathogenesis, clinical manifestations, renal tissue alterations, and treatment options.


Resumo A nefrite lúpica (NL) é caracterizada pelo acometimento dos rins no contexto das diversas manifestações clínicas do Lupus Eritematoso Sistêmico (LES), e representa uma das manifestações clínicas mais graves da doença. A NL é mais frequente e mais grave nos pacientes pediátricos, em comparação com os adultos, e causa maiores taxas de morbidade e mortalidade. O objetivo desta revisão narrativa foi descrever os aspectos gerais da NL e suas particularidades em crianças e adolescentes, com foco em sua etiopatogênese, nas manifestações clínicas, nas alterações histopatológicas renais e na abordagem terapêutica.


Assuntos
Humanos , Masculino , Feminino , Recém-Nascido , Lactente , Pré-Escolar , Criança , Adolescente , Nefrite Lúpica/patologia , Nefrite Lúpica/epidemiologia , Doenças Raras/patologia , Doenças Raras/epidemiologia , Nefrite Lúpica/diagnóstico , Nefrite Lúpica/tratamento farmacológico , Biomarcadores/urina , Biomarcadores/sangue , Prevalência , Doenças Raras/diagnóstico , Doenças Raras/tratamento farmacológico , Diagnóstico Precoce
4.
Front Pediatr ; 7: 114, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31001501

RESUMO

Background and Aim: Idiopathic nephrotic syndrome (INS) is classified according to the response to drug therapy in steroid-sensitive (SS), steroid-dependent (SD), and steroid-resistant (SR) categories. Previous studies showed changes in inflammatory activity of subpopulations of lymphocytes in INS. This study aimed to compare SS and SR patients in regard to subpopulations of leukocytes, profile of regulatory lymphocytes, and migratory activity of lymphocyte subpopulations. Results obtained in INS patients were also compared to age and sex-matched healthy controls. Methods: This is a cross-sectional study including SS patients (n = 30), SR patients (n = 14), and controls (n = 10). Peripheral blood samples were withdrawn for ex-vivo leukocyte flow cytometry analysis. Results: Percentage of B-lymphocytes and natural killer (NK) cells were significantly reduced in SR patients when compared to controls, while the percentage of NKT cells were decreased in SS patients in comparison to controls. Percentages of CD4+ expressing FoxP3 and CTLA4 were significantly higher in SS patients in comparison to SR patients and controls. The expression of integrin CD18 on the surface of T lymphocytes (CD3+) was reduced in SS patients if compared to controls. Conclusion: This study found that SS INS patients have higher levels of regulatory T-lymphocytes and lower expression of adhesion molecules than SR patients.

5.
J Bras Nefrol ; 41(2): 252-265, 2019.
Artigo em Inglês, Português | MEDLINE | ID: mdl-30465590

RESUMO

Involvement of the kidneys by lupus nephritis (LN) is one of the most severe clinical manifestations seen in individuals with systemic lupus erythematosus (SLE). LN is more frequent and severe in pediatric patients and has been associated with higher morbidity and mortality rates. This narrative review aimed to describe the general aspects of LN and its particularities when affecting children and adolescents, while focusing on the disease's etiopathogenesis, clinical manifestations, renal tissue alterations, and treatment options.


Assuntos
Nefrite Lúpica/epidemiologia , Nefrite Lúpica/patologia , Doenças Raras/epidemiologia , Doenças Raras/patologia , Adolescente , Biomarcadores/sangue , Biomarcadores/urina , Criança , Pré-Escolar , Diagnóstico Precoce , Feminino , Humanos , Lactente , Recém-Nascido , Nefrite Lúpica/diagnóstico , Nefrite Lúpica/tratamento farmacológico , Masculino , Prevalência , Doenças Raras/diagnóstico , Doenças Raras/tratamento farmacológico
6.
Biosci Rep ; 39(1)2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30514826

RESUMO

Introduction: Renin angiotensin system (RAS) plays a role in idiopathic nephrotic syndrome (INS). Most studies investigated only the classical RAS axis. Therefore, the aims of the present study were to evaluate urinary levels of RAS molecules related to classical and to counter-regulatory axes in pediatric patients with INS, to compare the measurements with levels in healthy controls and to search for associations with inflammatory molecules, proteinuria and disease treatment. Subjects and methods: This cross-sectional study included 31 patients with INS and 19 healthy controls, matched for age and sex. Patients and controls were submitted to urine collection for measurement of RAS molecules [Ang II, Ang-(1-7), ACE and ACE2] by enzyme immunoassay and cytokines by Cytometric Bead Array. Findings in INS patients were compared according to proteinuria: absent (<150 mg/dl, n = 15) and present (≥150 mg/dl, n = 16). Results: In comparison to controls, INS patients had increased Ang II, Ang-(1-7) and ACE, levels while ACE2 was reduced. INS patients with proteinuria had lower levels of ACE2 than those without proteinuria. ACE2 levels were negatively correlated with 24-h-proteinuria. Urinary concentrations of MCP-1/CCL2 were significantly higher in INS patients, positively correlated with Ang II and negatively with Ang-(1-7). ACE2 concentrations were negatively correlated with IP-10/CXCL-10 levels, which, in turn, were positively correlated with 24-h-proteinuria. Conclusion: INS patients exhibited changes in RAS molecules and in chemokines. Proteinuria was associated with low levels of ACE2 and high levels of inflammatory molecules.


Assuntos
Síndrome Nefrótica/genética , Peptidil Dipeptidase A/genética , Proteinúria/genética , Sistema Renina-Angiotensina/genética , Adolescente , Angiotensina I/genética , Angiotensina I/urina , Angiotensina II/genética , Angiotensina II/urina , Enzima de Conversão de Angiotensina 2 , Animais , Estudos de Casos e Controles , Quimiocina CCL2/genética , Quimiocina CCL2/urina , Quimiocina CXCL10/genética , Quimiocina CXCL10/urina , Criança , Estudos Transversais , Feminino , Expressão Gênica , Humanos , Masculino , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/patologia , Síndrome Nefrótica/urina , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/urina , Peptidil Dipeptidase A/urina , Proteinúria/diagnóstico , Proteinúria/patologia , Proteinúria/urina
7.
J. pediatr. (Rio J.) ; 94(5): 546-553, Sept.-Oct. 2018. tab, graf
Artigo em Inglês | LILACS | ID: biblio-975984

RESUMO

Abstract Objective: There is evidence of an important role of immune system changes in the triggering and maintenance of idiopathic nephrotic syndrome (INS). The aim of this study was to investigate the expression of cytokines in lymphocyte populations of patients with INS in comparison to healthy individuals, according to proteinuria. Methods: This cross-sectional study included 44 patients with INS and eight healthy children, matched for age and sex (controls). Patients were subdivided according to proteinuria: persistent proteinuria or partial remission (PP ≥ 300 mg/24 h, n = 17) and low proteinuria or complete remission (LP < 300 mg/24 h, n = 27). Ex vivo analysis of peripheral blood leukocytes by flow cytometry was performed using surface markers for T-lymphocytes, TCD4, TCD8, natural killer (NK) cells, NKT, and B-lymphocytes. Frequencies of intracellular cytokines were analyzed in these cells. Results: The frequencies of B-lymphocytes, NK cells, and NKT cells were lower in INS than in controls, whereas INS patients had a higher frequency of CD4+tumor necrosis factor (TNF)-α+ cells than controls. Cytotoxic-T-lymphocytes expressing IFN-γ were lower in INS than in controls. Patients with PP showed higher frequencies of CD4-T-lymphocytes expressing IFN-γ and TNF-α than controls. CD8-lymphocytes expressing TNF-α were increased in PP group when compared with LP and controls, while CD8+interferon (IFN)-γ+ cells were lower than in LP and in controls. Conclusion: Regardless the level of proteinuria, INS patients had increased expression of TNF-α in CD4-lymphocytes and reduced expression of IFN-γ in CD8-lymphocytes. Persistence of proteinuria was associated with higher levels of inflammatory markers.


Resumo Objetivo Há comprovação do importante papel das alterações no sistema imunológico no desencadeamento e manutenção da síndrome nefrótica idiopática (SNI). O objetivo deste estudo foi investigar a expressão das citocinas em populações de linfócitos de pacientes com SNI em comparação a indivíduos saudáveis e de acordo com a proteinúria. Métodos Este estudo transversal incluiu 44 pacientes com SNI e oito crianças saudáveis, pareados por idade e sexo (controles). Os pacientes foram subdivididos de acordo com a proteinúria: proteinúria persistente ou remissão parcial (PP ≥ 300 mg/24 h, n = 17) e proteinúria baixa ou remissão completa (PB < 300 mg/24 h, n = 27). A análise ex vivo de leucócitos no sangue periférico por citometria de fluxo foi feita utilizando marcadores de superfície para linfócitos T, TCD4, TCD8, células natural killer (NK), linfócitos NKT e B. As frequências das citocinas intracelulares foram analisadas nessas células. Resultados A frequência dos linfócitos B, células NK e células NKT foi menor em pacientes com SNI do que nos controles, ao passo que os pacientes com SNI apresentaram maior frequência de células CD4+fator de necrose tumoral (TNF)-α+ do que nos controles. Os linfócitos T citotóxicos que expressam interferon (IFN)-γ foram menores nos pacientes com SNI do que nos controles. Os pacientes com PP mostraram maiores frequências de linfócitos T CD4 que expressam IFN-γ e TNF-α que os controles. Os linfócitos CD8 que expressam TNF-α apresentaram aumento no grupo com PP, em comparação aos com PB e os controles, apesar de as células CD8+IFN-γ+ serem mais baixas nos pacientes com PB e nos controles. Conclusão Com relação ao nível de proteinúria, os pacientes com SNI apresentaram aumento na expressão de TNF-α nos linfócitos CD4 e expressão reduzida de IFN-γ nos linfócitos CD8. A persistência da proteinúria foi associada a maiores níveis de marcadores inflamatórios.


Assuntos
Humanos , Masculino , Feminino , Criança , Adolescente , Proteinúria/etiologia , Células Matadoras Naturais/imunologia , Linfócitos T/imunologia , Citocinas/imunologia , Síndrome Nefrótica/imunologia , Proteinúria/imunologia , Proteinúria/sangue , Biomarcadores , Estudos de Casos e Controles , Estudos Transversais , Citocinas/sangue , Progressão da Doença , Citometria de Fluxo , Contagem de Leucócitos , Síndrome Nefrótica/complicações , Síndrome Nefrótica/sangue
8.
Mol Cell Endocrinol ; 476: 103-109, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-29729370

RESUMO

Type 4 phosphodiesterases (PDE4s) of the large PDE enzyme superfamily have unique specificity for cAMP and may, therefore, be relevant for somatotroph tumorigenesis. Somatotroph adenomas typically overexpress PDEs probably as part of a compensatory mechanism to reduce cAMP levels. The rat PDE4A5 isoform (human homolog PDE4A4) interacts with the AIP protein, coded by a tumour suppressor gene mutated in a subgroup of familial isolated pituitary adenomas (FIPAs). PDE4A8 is the closest related isoform of PDE4A4. We aimed to evaluate the expression of both PDE4A4 and PDE4A8 in GH cells of AIP-mutated adenomas and compare their expression with that in GH cells from sporadic AIP-mutation negative GH-secreting adenomas, where we had shown previously that both PDE4A4 and PDE4A8 isoforms had been over-expressed. Confocal immunofluorescence analysis showed that both PDE4A8 and PDE4A4 had lower expression in AIP-mutated somatotropinoma samples compared to sporadic GH-secreting tumours (P < 0.0001 for both). Based on the association of low PDE4A4 and PDE4A8 expression with germline AIP-mutations positive samples we suggest that lack of AIP hinders the upregulation of PDE4A8 and PDE4A4 protein seen in sporadic somatotrophinomas. These data point to a unique disturbance of the cAMP-PDE pathway in AIP-mutation positive adenomas, which may help to explain their well-described poor response to somatostatin analogues.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Adenoma Hipofisário Secretor de Hormônio do Crescimento/enzimologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação/genética , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
9.
J Pediatr (Rio J) ; 94(5): 546-553, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28963877

RESUMO

OBJECTIVE: There is evidence of an important role of immune system changes in the triggering and maintenance of idiopathic nephrotic syndrome (INS). The aim of this study was to investigate the expression of cytokines in lymphocyte populations of patients with INS in comparison to healthy individuals, according to proteinuria. METHODS: This cross-sectional study included 44 patients with INS and eight healthy children, matched for age and sex (controls). Patients were subdivided according to proteinuria: persistent proteinuria or partial remission (PP≥300mg/24h, n=17) and low proteinuria or complete remission (LP<300mg/24h, n=27). Ex vivo analysis of peripheral blood leukocytes by flow cytometry was performed using surface markers for T-lymphocytes, TCD4, TCD8, natural killer (NK) cells, NKT, and B-lymphocytes. Frequencies of intracellular cytokines were analyzed in these cells. RESULTS: The frequencies of B-lymphocytes, NK cells, and NKT cells were lower in INS than in controls, whereas INS patients had a higher frequency of CD4+tumor necrosis factor (TNF)-α+ cells than controls. Cytotoxic-T-lymphocytes expressing IFN-γ were lower in INS than in controls. Patients with PP showed higher frequencies of CD4-T-lymphocytes expressing IFN-γ and TNF-α than controls. CD8-lymphocytes expressing TNF-α were increased in PP group when compared with LP and controls, while CD8+interferon (IFN)-γ+ cells were lower than in LP and in controls. CONCLUSION: Regardless the level of proteinuria, INS patients had increased expression of TNF-α in CD4-lymphocytes and reduced expression of IFN-γ in CD8-lymphocytes. Persistence of proteinuria was associated with higher levels of inflammatory markers.


Assuntos
Citocinas/imunologia , Células Matadoras Naturais/imunologia , Síndrome Nefrótica/imunologia , Proteinúria/etiologia , Linfócitos T/imunologia , Adolescente , Biomarcadores , Estudos de Casos e Controles , Criança , Estudos Transversais , Citocinas/sangue , Progressão da Doença , Feminino , Citometria de Fluxo , Humanos , Contagem de Leucócitos , Masculino , Síndrome Nefrótica/sangue , Síndrome Nefrótica/complicações , Proteinúria/sangue , Proteinúria/imunologia
10.
Pediatr Nephrol ; 32(11): 2165-2169, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28799058

RESUMO

BACKGROUND: The search for risk factors for chronic kidney disease in children with focal segmental glomerulosclerosis (FSGS) is important in defining prognosis and individualized treatment. This study preliminarily investigated whether CD44 immunostaining in glomerular parietal epithelial cells (PECs) is a prognostic marker in pediatric FSGS. METHODS: In this retrospective study, 26 patients with FSGS, biopsied from 1985 to 2010, were evaluated. Immunohistochemistry for CD44 was performed in all cases. For analysis purposes, patients were grouped according to whether or not they were positive for CD44 in PECs. The primary outcome was a decline in baseline estimated glomerular filtration rate (eGFR) of 50% or more. RESULTS: Median follow-up was 6.9 years. Median renal survival was 14.5 years and probability of a 50% decline of eGRF was 30% in 10 years. Nine children exhibited the primary outcome and 7 developed end-stage renal disease (ESRD). In comparison with PEC CD44-negative patients (n = 18), PEC CD44-positive patients (n = 8) presented lower baseline eGFR (99 ± 41 versus 141 ± 44 ml/min/1.73 m2, p = 0.035) and a significant decline in eGFR (-38.6 ± 39.5 versus -5.6 ± 25.3 ml/min/1.73 m2/year, p = 0.018). No difference was observed in FSGS subtypes or other glomerular features. Presence of CD44 staining in PECs was significantly associated with the decline in baseline eGFR of 50% or more. Renal survival was significantly reduced in PEC CD44-positive patients (3.8 vs 14.6 years in C4d-negative, p < 0.05). CONCLUSION: Our preliminary findings indicate, for the first time, that positivity for CD44 in PECs seems to be a pathological marker of renal function deterioration in pediatric patients with FSGS.


Assuntos
Biomarcadores/metabolismo , Glomerulosclerose Segmentar e Focal/patologia , Receptores de Hialuronatos/metabolismo , Glomérulos Renais/patologia , Adolescente , Criança , Pré-Escolar , Progressão da Doença , Células Epiteliais/metabolismo , Feminino , Taxa de Filtração Glomerular , Glomerulosclerose Segmentar e Focal/complicações , Glomerulosclerose Segmentar e Focal/metabolismo , Humanos , Imuno-Histoquímica , Falência Renal Crônica/etiologia , Glomérulos Renais/metabolismo , Masculino , Estudos Retrospectivos , Análise de Sobrevida
11.
Acta Cir Bras ; 32(5): 342-349, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28591363

RESUMO

PURPOSE:: To evaluate the effects of chronic consumption of green tea on body weight and distribution of visceral fat by Computed tomography in female Wistar rats. METHODS:: Wistar rats were divided into control group (n = 5), which received water and feed ad libitum, and green tea group (n = 8), in which water has been replaced by green tea. The animals were weighed weekly and Computed Tomography was used at the beginning (1st week) and end (18th week) of the experiment for evaluating the distribution of visceral fat. The animals were followed for 18 weeks. RESULTS:: There was no significant difference in body weight between the groups. However, there was significant difference in visceral fat area. The green tea group had less visceral fat area at the end of the experiment, 3.67 ± 1.2 cm2, while the control group showed an area of 6.25 ± 2.2 cm (p = 0.00). CONCLUSIONS:: Chronic consumption of green tea leads to decreased visceral adipose tissue area.


Assuntos
Distribuição da Gordura Corporal , Peso Corporal , Gordura Intra-Abdominal/anatomia & histologia , Chá , Animais , Feminino , Gordura Intra-Abdominal/diagnóstico por imagem , Modelos Animais , Distribuição Aleatória , Ratos Wistar , Tomografia Computadorizada de Emissão
12.
Acta cir. bras ; 32(5): 342-349, May 2017. graf
Artigo em Inglês | LILACS | ID: biblio-837707

RESUMO

Abstract Purpose: To evaluate the effects of chronic consumption of green tea on body weight and distribution of visceral fat by Computed tomography in female Wistar rats. Methods: Wistar rats were divided into control group (n = 5), which received water and feed ad libitum, and green tea group (n = 8), in which water has been replaced by green tea. The animals were weighed weekly and Computed Tomography was used at the beginning (1st week) and end (18th week) of the experiment for evaluating the distribution of visceral fat. The animals were followed for 18 weeks. Results: There was no significant difference in body weight between the groups. However, there was significant difference in visceral fat area. The green tea group had less visceral fat area at the end of the experiment, 3.67 ± 1.2 cm2, while the control group showed an area of 6.25 ± 2.2 cm (p = 0.00). Conclusions: Chronic consumption of green tea leads to decreased visceral adipose tissue area.


Assuntos
Animais , Feminino , Chá , Peso Corporal , Gordura Intra-Abdominal/anatomia & histologia , Distribuição da Gordura Corporal , Distribuição Aleatória , Tomografia Computadorizada de Emissão , Ratos Wistar , Modelos Animais , Gordura Intra-Abdominal/diagnóstico por imagem
14.
Pediatr Nephrol ; 32(7): 1211-1220, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28233100

RESUMO

BACKGROUND: Data on the risk factors for chronic kidney disease in children with immunoglobulin A nephropathy (IgAN) are scarce. This study was aimed at investigating whether glomerular C4d immunostaining is a prognostic marker in pediatric IgAN. METHODS: In this retrospective cohort study, 47 patients with IgAN biopsied from 1982 to 2010 were evaluated. Immunohistochemistry for C4d was performed in all cases. For analysis, patients were grouped according to positivity or not for C4d in the mesangial area. Primary outcome was a decline in baseline estimated glomerular filtration rate (eGFR) by 50% or more. RESULTS: Median follow-up was 8.3 years. Median renal survival was 13.7 years and the probability of a 50% decline in eGFR was 13% over 10 years. Nine children exhibited the primary outcome and 4 developed end-stage renal disease (ESRD). Compared with C4d-negative patients (n = 37), C4d-positive patients (n = 10) presented higher baseline proteinuria (1.66 ± 0.68 vs 0.47 ± 0.19 g/day/1.73 m2, p < 0.001), a progressive decline in eGFR (−10.04 ± 19.38 vs 1.70 ± 18.51 ml/min/1.73 m2/year; p = 0.045), and more frequently achieved the primary outcome (50.0 vs 10.8%, p = 0.013), and ESRD (30.0 vs 2.7%, p = 0.026). No difference was observed in Oxford classification variables. Baseline proteinuria, endocapillary hypercellularity and mesangial C4d deposition were associated with primary outcome in univariate analysis. Proteinuria and mesangial C4d deposition at baseline independently predicted the decline in eGFR. Renal survival was significantly reduced in C4d-positive patients (8.6 vs 15.1 years in C4d-negative patients, p < 0.001). CONCLUSIONS: In this exclusively pediatric cohort, positivity for C4d in the mesangial area was an independent predictor of renal function deterioration in IgAN.


Assuntos
Complemento C4b/análise , Mesângio Glomerular/patologia , Glomerulonefrite por IGA/patologia , Falência Renal Crônica/patologia , Fragmentos de Peptídeos/análise , Biomarcadores/análise , Biomarcadores/metabolismo , Biópsia , Criança , Complemento C4b/metabolismo , Progressão da Doença , Feminino , Seguimentos , Taxa de Filtração Glomerular , Mesângio Glomerular/metabolismo , Glomerulonefrite por IGA/urina , Humanos , Imuno-Histoquímica , Falência Renal Crônica/urina , Masculino , Fragmentos de Peptídeos/metabolismo , Prognóstico , Proteinúria/urina , Estudos Retrospectivos , Fatores de Risco
15.
Nephrology (Carlton) ; 21(12): 995-1002, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27414046

RESUMO

IgA nephropathy (IgAN) is one of the leading causes of glomerulonephritis characterized by the findings of IgA and IgG immune deposits in the mesangium of kidney biopsies from patients with persistent microscopic haematuria. IgAN is frequently detected among adolescents and young adults. IgAN presents a highly variable course that includes a spectrum from a very mild disease to end-stage renal disease (ESRD). There are several clinical and histological factors that strongly determined the final outcome of patients with IgAN. Pathological variables associated with unfavorable outcomes are mesangial hypercellularity, segmental glomerulosclerosis, endocapillary hypercellularity and interstitial fibrosis/tubular atrophy, according to the Oxford classification. Moreover, some studies also suggest a role for complement activation in the pathogenesis of IgAN. In this regard, staining for C4d may be an independent risk factor for the development of ESRD in IgAN. Despite the growing number of studies assessing IgAN risk factors, this kind of investigation in paediatric patients is still very limited. The aim of this article is to revise pathological markers related to deterioration of renal function in paediatric patients with IgAN, particularly those that can independently affect renal survival.


Assuntos
Glomerulonefrite por IGA/patologia , Glomerulosclerose Segmentar e Focal/patologia , Falência Renal Crônica/patologia , Glomérulos Renais/patologia , Adolescente , Fatores Etários , Atrofia , Biomarcadores/análise , Biópsia , Criança , Ativação do Complemento , Complemento C4b/análise , Progressão da Doença , Feminino , Fibrose , Glomerulonefrite por IGA/complicações , Glomerulonefrite por IGA/imunologia , Glomerulonefrite por IGA/fisiopatologia , Glomerulosclerose Segmentar e Focal/imunologia , Glomerulosclerose Segmentar e Focal/fisiopatologia , Humanos , Imunoglobulina A/análise , Imunoglobulina G/análise , Falência Renal Crônica/imunologia , Falência Renal Crônica/fisiopatologia , Testes de Função Renal , Glomérulos Renais/imunologia , Glomérulos Renais/fisiopatologia , Masculino , Fragmentos de Peptídeos/análise , Valor Preditivo dos Testes , Prognóstico , Fatores de Risco
16.
Inflamm Res ; 65(10): 757-70, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27351940

RESUMO

BACKGROUND AND AIM: IgA nephropathy is one of the leading causes of primary glomerulonephritis worldwide and an important etiology of renal disease in young adults. IgA nephropathy is considered an immune complex-mediated disease. METHODS: This review article summarizes recent evidence on the pathophysiology of IgA nephropathy. RESULTS: Current studies indicate an ordered sequence of multi-hits as fundamental to disease occurrence. Altered glycan structures in the hinge region of the heavy chains of IgA1 molecules act as auto-antigens, potentially triggering the production of glycan-specific autoantibodies. Recognition of novel epitopes by IgA and IgG antibodies leads to the formation of immune complexes galactose deficient-IgA1/anti-glycan IgG or IgA. Immune complexes of IgA combined with FcαRI/CD89 have also been implicated in disease exacerbation. These nephritogenic immune complexes are formed in the circulation and deposited in renal mesangium. Deposited immune complexes ultimately induce glomerular injury, through the release of pro-inflammatory cytokines, secretion of chemokines and the resultant migration of macrophages into the kidney. The TfR1/CD71 receptor has a pivotal role in mesangial cells. New signaling intracellular mechanisms have also been described. CONCLUSION: The knowledge of the whole pathophysiology of this disease could provide the rational bases for developing novel approaches for diagnosis, for monitoring disease activity, and for disease-specific treatment.


Assuntos
Glomerulonefrite por IGA , Animais , Glomerulonefrite por IGA/genética , Glomerulonefrite por IGA/imunologia , Humanos
17.
Pediatr Nephrol ; 30(11): 2011-20, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26084617

RESUMO

BACKGROUND: There are limited data on the risk factors for chronic kidney disease (CKD) in children with idiopathic nephrotic syndrome (INS). This retrospective cohort study aimed to develop a predictive model for CKD progression in children with INS. METHODS: Between 1970 and 2012, a total of 294 patients with INS were followed up. The primary outcome was progression to CKD stage 3 or higher. A predictive model was developed using a Cox proportional hazards model. A score was calculated using b-coefficients and summing up points assigned to each significant variable. Prognostic score was grouped into categories: low risk, medium risk, and high risk. RESULTS: Median follow-up was 6.9 years. Median renal survival was 26.1 years and probability of CKD stage 3 or higher was 8% in 10 years. Multivariate analysis showed that the most accurate model included initial age, hematuria, and steroid resistance. Accuracy was high with a c-statistic of 0.95 (95% confidence interval [CI] 0.91-0.99), 0.92 (95% CI 0.88-0.96), and 0.92 (95% CI 0.87-0.97) at 2, 5, and 10 years of follow-up respectively. By survival analysis, 10-year renal survival was 100% for the low-risk and 95% for the medium-risk group, while 40% of high-risk patients would exhibit CKD stage 3 or higher (P < 0.001). CONCLUSIONS: Our predictive model of CKD may contribute to the early identification of a subgroup of INS patients at a high risk of renal dysfunction.


Assuntos
Modelos Estatísticos , Síndrome Nefrótica/complicações , Insuficiência Renal Crônica/etiologia , Criança , Pré-Escolar , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Masculino , Estudos Retrospectivos , Fatores de Risco
18.
Int J Hypertens ; 2012: 414128, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22518283

RESUMO

In the past few years the understanding of the renin-angiotensin system (RAS) has improved, helping to better define the role of this system in physiological conditions and in human diseases. Besides Angiotensin (Ang) II, the biological importance of other Ang fragments was progressively evidenced. In this regard, Angiotensin- (Ang-) (1-7) was recognized as a biologically active product of the RAS cascade with a specific receptor, the G-protein-coupled receptor Mas, and that is mainly formed by the action of the angiotensin-converting enzyme (ACE) homolog enzyme, ACE2, which converts Ang II into Ang-(1-7). Taking into account the biological effects of these two mediators, Ang II and Ang-(1-7), the RAS can be envisioned as a dual function system in which the vasoconstrictor/proliferative or vasodilator/antiproliferative actions are primarily driven by the balance between Ang II and Ang-(1-7), respectively. In this paper, we will discuss our current understanding of the ACE2/Ang-(1-7)/Mas axis of the RAS in renal physiology and in the pathogenesis of primary hypertension and chronic kidney disease.

19.
FASEB J ; 25(9): 2987-95, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21628446

RESUMO

The family of angiotensin peptides has been steadily growing in recent years. Most are fragments of angiotensin II (Ang II) with different affinities to the known angiotensin receptors. Here, we describe a novel endogenous Ang II-like octapeptide in plasma from healthy humans and patients with end-stage renal failure, which acts as a stronger agonist at Mas receptors than Ang 1-7. Chromatographic purification and structural analysis by matrix-assisted laser desorption/ionization time-of-flight/time-of-flight (MALDI-TOF/TOF) revealed an Ang II-like octapeptide, angioprotectin, with the sequence Pro-Glu-Val-Tyr-Ile-His-Pro-Phe, which differs from Ang II in Pro¹ and Glu² instead of Asp¹ and Arg². Pro-Glu-Val-Tyr-Ile-His-Pro-Phe in angioprotectin is most likely generated enzymatically from Ang II. Angioprotectin antagonized the contractile actions of Ang II on rat aortic rings. The physiological antagonism of vasoconstrictor actions of Ang II by angioprotectin is mediated by the Mas receptor. Angioprotectin has a stronger affinity to the Mas receptor than Ang-1-7. Plasma concentrations were ~15% of plasma Ang II concentrations in healthy volunteers and up to 50% in patients with renal failure. A commercially available Ang II antibody did not discriminate between angioprotectin and Ang II; thus, angioprotectin can contribute to Ang II concentrations measured by antibody-based assays. This novel peptide is likely to be a relevant component of the human renin-angiotensin-system.


Assuntos
Angiotensina II/análogos & derivados , Vasodilatação/efeitos dos fármacos , Idoso , Angiotensina II/sangue , Angiotensina II/farmacologia , Animais , Aorta , Células CHO , Cricetinae , Cricetulus , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Ratos , Insuficiência Renal/sangue
20.
Rev. bras. hipertens ; 15(3): 134-143, jul.-set. 2008. ilus
Artigo em Português | LILACS | ID: lil-507879

RESUMO

Insuficiência cardíaca (IC) e doença renal crônica (DRC) freqüentemente coexistem. Essa combinação é denominada “síndrome cardiorrenal”. A intersecção entre as disfunções cardíaca e renal apresenta significativa implicação terapêutica e para o prognóstico de pacientes com IC ou com DRC. A coexistência das duas condições está associada com aumento significativo da morbidade e do risco de mortalidade. Os prováveis mecanismos que contribuem para a síndrome cardiorrenal incluem ativação do sistema renina-angiotensina (SRA) e do sistema nervoso simpático (SNS), bem como os efeitos de outros sistemas peptidérgicos, tais como os peptídeos natriuréticos e a vasopressina. Neste artigo, aspectos gerais dos mediadores do SRA, dos peptídeos natriuréticose da vasopressina serão revistos, focando no papel desses sistemas peptidérgicos nas disfunções cardíacas e renais.


Heart failure (HF) and chronic kidney disease (CKD) frequently coexist. This combination is commonly referred to as the “cardiorenal syndrome”. The intersection of cardiac and renal dysfunction has important therapeutic and prognostic implications in patients with HF or with CKD. The co-existence of both conditions is associated with significantly increased morbidity and mortality risk. The putative mechanisms that contribute to cardiorenal syndrome include activation of the renin angiotensin system (RAS) and sympathetic nervous system as well the effects of other petidergic systems such as natriuretic peptides and vasopressin. In this article, general aspects of RAS mediators, natriuretic peptides and vasopressin are reviewed, focusing on the role of these peptidergic systems in cardiac and renal dysfunctions.


Assuntos
Humanos , Angiotensina II , Fator Natriurético Atrial , Insuficiência Cardíaca , Insuficiência Renal Crônica , Vasopressinas
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