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1.
Medicina (Kaunas) ; 57(3)2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799854

RESUMO

Renal biopsy is useful to better understand the histological pattern of a lesion (glomerular, tubulointerstitial, and vascular) and the pathogenesis that leads to kidney failure. The potential impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the kidneys is still undetermined, and a variety of lesions are seen in the kidney tissue of coronavirus disease patients. This review is based on the morphological findings of patients described in case reports and a series of published cases. A search was conducted on MEDLINE and PubMed of case reports and case series of lesions in the presence of non-critical infection by SARS-CoV-2 published until 15/09/2020. We highlight the potential of the virus directly influencing the damage or the innate and adaptive immune response activating cytokine and procoagulant cascades, in addition to the genetic component triggering glomerular diseases, mainly collapsing focal segmental glomerulosclerosis, tubulointerstitial, and even vascular diseases. Kidney lesions caused by SARS-CoV-2 are frequent and have an impact on morbidity and mortality; thus, studies are needed to assess the morphological kidney changes and their mechanisms and may help define their spectrum and immediate or long-term impact.


Assuntos
Lesão Renal Aguda/patologia , Glomerulonefrite/patologia , Rim/patologia , Microangiopatias Trombóticas/patologia , Lesão Renal Aguda/sangue , Lesão Renal Aguda/imunologia , Imunidade Adaptativa/imunologia , Arteriosclerose/imunologia , Arteriosclerose/patologia , /imunologia , Citocinas/imunologia , Glomerulonefrite/imunologia , Glomerulonefrite por IGA/imunologia , Glomerulonefrite por IGA/patologia , Glomerulosclerose Segmentar e Focal/imunologia , Glomerulosclerose Segmentar e Focal/patologia , Humanos , Imunidade Inata/imunologia , Infarto/imunologia , Infarto/patologia , Rim/irrigação sanguínea , Rim/imunologia , Necrose do Córtex Renal/imunologia , Necrose do Córtex Renal/patologia , Nefrite Intersticial/imunologia , Nefrite Intersticial/patologia , Nefrose Lipoide/imunologia , Nefrose Lipoide/patologia , Rabdomiólise , Trombofilia/sangue , Microangiopatias Trombóticas/imunologia
2.
BMJ Case Rep ; 14(2)2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33547121

RESUMO

Renal involvement in mantle cell lymphoma (MCL) is rare. We present the case of a man followed for MCL presented with acute kidney injury and positive antineutrophil cytoplasmic antibody (ANCA) type anti proteinase 3 (PR3). He was treated as for a rapidly progressing glomerulonephritis with cyclophosphamide and methylprednisolone followed by oral prednisone. Renal biopsy revealed diffuse endocapillary proliferation and segmental extracapillary proliferation in four glomeruli. Immunohistochemistry confirmed the renal invasion of lymphomatous cells. He started improving his renal function shortly after starting treatment. The coexistence of renal MCL infiltration, extracapillary proliferation and ANCA positive is exceptional.


Assuntos
Glomerulonefrite/etiologia , Linfoma de Célula do Manto/complicações , Anticorpos Anticitoplasma de Neutrófilos/sangue , Protocolos de Quimioterapia Combinada Antineoplásica , Biomarcadores Tumorais/sangue , Biópsia , Ciclofosfamida , Diagnóstico Diferencial , Doxorrubicina , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/patologia , Humanos , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Prednisona , Rituximab , Vincristina
3.
JAMA Netw Open ; 4(1): e2030939, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33471115

RESUMO

Importance: A chronic shortage of donor kidneys is compounded by a high discard rate, and this rate is directly associated with biopsy specimen evaluation, which shows poor reproducibility among pathologists. A deep learning algorithm for measuring percent global glomerulosclerosis (an important predictor of outcome) on images of kidney biopsy specimens could enable pathologists to more reproducibly and accurately quantify percent global glomerulosclerosis, potentially saving organs that would have been discarded. Objective: To compare the performances of pathologists with a deep learning model on quantification of percent global glomerulosclerosis in whole-slide images of donor kidney biopsy specimens, and to determine the potential benefit of a deep learning model on organ discard rates. Design, Setting, and Participants: This prognostic study used whole-slide images acquired from 98 hematoxylin-eosin-stained frozen and 51 permanent donor biopsy specimen sections retrieved from 83 kidneys. Serial annotation by 3 board-certified pathologists served as ground truth for model training and for evaluation. Images of kidney biopsy specimens were obtained from the Washington University database (retrieved between June 2015 and June 2017). Cases were selected randomly from a database of more than 1000 cases to include biopsy specimens representing an equitable distribution within 0% to 5%, 6% to 10%, 11% to 15%, 16% to 20%, and more than 20% global glomerulosclerosis. Main Outcomes and Measures: Correlation coefficient (r) and root-mean-square error (RMSE) with respect to annotations were computed for cross-validated model predictions and on-call pathologists' estimates of percent global glomerulosclerosis when using individual and pooled slide results. Data were analyzed from March 2018 to August 2020. Results: The cross-validated model results of section images retrieved from 83 donor kidneys showed higher correlation with annotations (r = 0.916; 95% CI, 0.886-0.939) than on-call pathologists (r = 0.884; 95% CI, 0.825-0.923) that was enhanced when pooling glomeruli counts from multiple levels (r = 0.933; 95% CI, 0.898-0.956). Model prediction error for single levels (RMSE, 5.631; 95% CI, 4.735-6.517) was 14% lower than on-call pathologists (RMSE, 6.523; 95% CI, 5.191-7.783), improving to 22% with multiple levels (RMSE, 5.094; 95% CI, 3.972-6.301). The model decreased the likelihood of unnecessary organ discard by 37% compared with pathologists. Conclusions and Relevance: The findings of this prognostic study suggest that this deep learning model provided a scalable and robust method to quantify percent global glomerulosclerosis in whole-slide images of donor kidneys. The model performance improved by analyzing multiple levels of a section, surpassing the capacity of pathologists in the time-sensitive setting of examining donor biopsy specimens. The results indicate the potential of a deep learning model to prevent erroneous donor organ discard.


Assuntos
Biópsia/métodos , Aprendizado Profundo , Diagnóstico por Computador/métodos , Glomerulonefrite , Rim/patologia , Algoritmos , Glomerulonefrite/diagnóstico , Glomerulonefrite/patologia , Humanos , Patologistas , Reprodutibilidade dos Testes
4.
Pediatr Nephrol ; 36(4): 1019-1023, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33495896

RESUMO

BACKGROUND: Coronavirus disease 2019 (COVID-19) is thought to cause kidney injury via a variety of mechanisms. The most common reported kidney injury following COVID-19 infection is acute tubular injury (ATI); however, the procoagulant state induced by the virus may also damage the kidneys. CASE-DIAGNOSIS/TREATMENT: Herein, we report two cases of acute necrotizing glomerulonephritis (GN) with fibrinoid necrosis in the context of COVID-19 infection. The one with more chronic features in the kidney biopsy progressed to permanent kidney failure but the second one had an excellent response to glucocorticoid pulse therapy with subsequent normal kidney function at 2-month follow-up. CONCLUSIONS: Both reported cases had an acute presentation of kidney injury with positive nasopharyngeal PCR test for COVID-19. Based on the data review by the researchers, this is the first report of acute necrotizing GN associated with COVID-19 infection.


Assuntos
Lesão Renal Aguda/etiologia , Glomerulonefrite/etiologia , Glomérulos Renais/patologia , /patogenicidade , Lesão Renal Aguda/patologia , Lesão Renal Aguda/terapia , Adolescente , Biópsia , Coagulação Sanguínea , /diagnóstico , Glomerulonefrite/patologia , Glomerulonefrite/terapia , Glucocorticoides/administração & dosagem , Humanos , Glomérulos Renais/irrigação sanguínea , Masculino , Necrose/imunologia , Necrose/patologia , Contagem de Plaquetas , Pulsoterapia , Diálise Renal , Resultado do Tratamento
5.
BMJ Case Rep ; 14(1)2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33472800

RESUMO

Staphylococcus-associated glomerulonephritis (SAGN) occurs as a complication of staphylococcal infection elsewhere in the body. Dermatomyositis (DM) can be associated with glomerulonephritis due to the disease per se. We report a case of a 40-year-old male patient with DM who presented with acute kidney injury, and was initially pulsed with methylprednisolone for 3 days, followed by dexamethasone equivalent to 1 mg/kg/day prednisolone. He was subsequently found to have SAGN on kidney biopsy along with staphylococcus bacteraemia and left knee septic arthritis. With proof of definitive infection, intravenous immunoglobulin 2 g/kg over 2 days was given and steroids were reduced. He was treated with intravenous vancomycin. With treatment, the general condition of the patient improved. On day 38, he developed infective endocarditis and died of congestive heart failure subsequently. Undiagnosed staphylococcal sepsis complicating a rheumatological disease course can lead to complications like SAGN, infective endocarditis and contribute to increased morbidity and mortality, as is exemplified by our case.


Assuntos
Lesão Renal Aguda/diagnóstico , Artrite Infecciosa/diagnóstico , Bacteriemia/diagnóstico , Dermatomiosite/tratamento farmacológico , Glomerulonefrite/patologia , Glucocorticoides/uso terapêutico , Infecções Estafilocócicas/diagnóstico , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/terapia , Adulto , Antibacterianos/uso terapêutico , Artrite Infecciosa/tratamento farmacológico , Bacteriemia/tratamento farmacológico , Dermatomiosite/fisiopatologia , Endocardite Bacteriana , Evolução Fatal , Glomerulonefrite/etiologia , Glomerulonefrite/terapia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Masculino , Infecções Estafilocócicas/complicações , Infecções Estafilocócicas/tratamento farmacológico , Vancomicina/uso terapêutico
6.
BMJ Case Rep ; 14(1)2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33504520

RESUMO

Staphylococcus aureus is a troublesome pathogen, responsible for a broad range of clinical manifestations, ranging from benign skin infections to life-threatening conditions such as endocarditis and osteomyelitis. The kidney can be affected through a rapidly progressive glomerulonephritis mediated by an inflammatory reaction against a superantigen deposited in the glomerulus during the infection's course. This glomerulopathy has a poor prognosis, often leading to chronically impaired kidney function, eventually progressing to end-stage renal disease. Treatment rests on antibiotherapy. Despite the inflammatory role in this disease's pathophysiology, most authors discourage a simultaneous immunosuppressive approach given the concomitant infection. However, there are some reports of success after administration of systemic corticosteroids in these patients. We present a 66-year-old man with a staphylococcus-induced glomerulonephritis brought on by a vascular graft infection, with rapidly deteriorating kidney function despite extraction of the infected graft and 3 weeks of antibiotherapy with achievement of infection control. Kidney function improved after the introduction of corticosteroids. This case highlights the potential role of corticosteroids in selected cases of staphylococcus-induced glomerulonephritis, particularly those in which the infection is under control.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Antibacterianos/uso terapêutico , Prótese Vascular , Glomerulonefrite/tratamento farmacológico , Glucocorticoides/uso terapêutico , Infecções Relacionadas à Prótese/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológico , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/patologia , Idoso , Complexo Antígeno-Anticorpo/metabolismo , Hemocultura , Complemento C3/metabolismo , Remoção de Dispositivo , Progressão da Doença , Glomerulonefrite/etiologia , Glomerulonefrite/metabolismo , Glomerulonefrite/patologia , Humanos , Imunoglobulina A/metabolismo , Masculino , Metilprednisolona/uso terapêutico , Prednisolona/uso terapêutico , Infecções Relacionadas à Prótese/complicações , Infecções Estafilocócicas/complicações , Staphylococcus aureus
7.
Adv Chronic Kidney Dis ; 27(5): 365-376, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-33308501

RESUMO

Acute kidney injury (AKI) is common among hospitalized patients with Coronavirus Infectious Disease 2019 (COVID-19), with the occurrence of AKI ranging from 0.5% to 80%. The variability in the occurrence of AKI has been attributed to the difference in geographic locations, race/ethnicity, and severity of illness. AKI among hospitalized patients is associated with increased length of stay and in-hospital deaths. Even patients with AKI who survive to hospital discharge are at risk of developing chronic kidney disease or end-stage kidney disease. An improved knowledge of the pathophysiology of AKI in COVID-19 is crucial to mitigate and manage AKI and to improve the survival of patients who developed AKI during COVID-19. The goal of this article is to provide our current understanding of the etiology and the pathophysiology of AKI in the setting of COVID-19.


Assuntos
Lesão Renal Aguda/metabolismo , Citocinas/metabolismo , Glomerulonefrite/metabolismo , Microangiopatias Trombóticas/metabolismo , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/patologia , Lesão Renal Aguda/fisiopatologia , Antibacterianos/efeitos adversos , Antivirais/efeitos adversos , Apolipoproteína L1/genética , Ácido Ascórbico/efeitos adversos , Azotemia/metabolismo , Azotemia/patologia , Azotemia/fisiopatologia , /patologia , Progressão da Doença , Glomerulonefrite/patologia , Glomerulonefrite/fisiopatologia , Glomerulonefrite Membranosa/metabolismo , Glomerulonefrite Membranosa/patologia , Glomerulonefrite Membranosa/fisiopatologia , Mortalidade Hospitalar , Humanos , Túbulos Renais Proximais/lesões , Tempo de Internação , Mioglobina/metabolismo , Nefrite Intersticial/metabolismo , Nefrite Intersticial/patologia , Nefrite Intersticial/fisiopatologia , Nefrose Lipoide/metabolismo , Nefrose Lipoide/patologia , Nefrose Lipoide/fisiopatologia , Insuficiência Renal Crônica , Rabdomiólise/metabolismo , Índice de Gravidade de Doença , Microangiopatias Trombóticas/patologia , Microangiopatias Trombóticas/fisiopatologia , Vitaminas/efeitos adversos
9.
J Vis Exp ; (162)2020 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-32894262

RESUMO

Parietal epithelial cell (PEC) activation is one of the key factors involved in the development and progression of glomerulosclerosis. Inhibition of pathways involved in parietal epithelial cell activation could therefore be a tool to attenuate the progression of glomerular diseases. This article describes a method to culture and analyze parietal epithelial cell outgrowth of encapsulated glomeruli isolated from mouse kidney. After dissecting isolated mouse kidneys, the tissue is minced, and glomeruli are isolated by sieving. Encapsulated glomeruli are collected, and single glomeruli are cultured for 6 days to obtain glomerular outgrowth of parietal epithelial cells. During this period, parietal epithelial cell proliferation and migration can be analyzed by determining the cell number or the surface area of outgrowing cells. This assay can therefore be used as a tool to study the effects of an altered gene expression in transgenic- or knockout-mice or the effects of culture conditions on parietal epithelial cell growth characteristics and signaling. Using this method, important pathways involved in the process of parietal epithelial cell activation and consequently in glomerulosclerosis can be studied.


Assuntos
Células Epiteliais/citologia , Células Epiteliais/metabolismo , Glomérulos Renais/citologia , Animais , Movimento Celular , Proliferação de Células , Separação Celular , Células Cultivadas , Glomerulonefrite/patologia , Camundongos , Esclerose
10.
Am J Physiol Renal Physiol ; 319(4): F563-F570, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32799675

RESUMO

Acute kidney injury (AKI) frequently complicates major surgery and can be associated with hypertension and progress to chronic kidney disease, but reports on blood pressure normalization in AKI are conflicting. In the present study, we investigated the effects of an angiotensin-converting enzyme inhibitor, enalapril, and a soluble epoxide hydrolase inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), on renal inflammation, fibrosis, and glomerulosclerosis in a mouse model of ischemia-reperfusion injury (IRI)-induced AKI. Male CD1 mice underwent unilateral IRI for 35 min. Blood pressure was measured by tail cuff, and mesangial matrix expansion was quantified on methenamine silver-stained sections. Renal perfusion was assessed by functional MRI in vehicle- and TPPU-treated mice. Immunohistochemistry was performed to study the severity of AKI and inflammation. Leukocyte subsets were analyzed by flow cytometry, and proinflammatory cytokines were analyzed by quantitative PCR. Plasma and tissue levels of TPPU and lipid mediators were analyzed by liquid chromatography mass spectrometry. IRI resulted in a blood pressure increase of 20 mmHg in the vehicle-treated group. TPPU and enalapril normalized blood pressure and reduced mesangial matrix expansion. However, inflammation and progressive renal fibrosis were severe in all groups. TPPU further reduced renal perfusion on days 1 and 14. In conclusion, early antihypertensive treatment worsened renal outcome after AKI by further reducing renal perfusion despite reduced glomerulosclerosis.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Glomerulonefrite/prevenção & controle , Hipertensão/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Piperidinas/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/patologia , Lesão Renal Aguda/fisiopatologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Anti-Hipertensivos/toxicidade , Modelos Animais de Doenças , Progressão da Doença , Enalapril/farmacologia , Inibidores Enzimáticos/toxicidade , Epóxido Hidrolases/antagonistas & inibidores , Fibrose , Mesângio Glomerular/efeitos dos fármacos , Mesângio Glomerular/patologia , Mesângio Glomerular/fisiopatologia , Glomerulonefrite/etiologia , Glomerulonefrite/patologia , Glomerulonefrite/fisiopatologia , Hipertensão/etiologia , Hipertensão/fisiopatologia , Masculino , Camundongos , Compostos de Fenilureia/toxicidade , Piperidinas/toxicidade , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/fisiopatologia
11.
Transplantation ; 104(8): 1695-1702, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32732849

RESUMO

BACKGROUND: Reports about prognosis of adults receiving small pediatric-donor kidneys (PDK) as compared to those receiving elder pediatric or adult donor kidneys (ADKs) are controversial. This study aimed to examine the outcomes of adults receiving small PDK and possible prognostic factors. METHODS: The records of adults who received kidneys from donors < 10 years old at our center from July 1, 2011 to June 30, 2018 were reviewed. RESULTS: A total of 121 adults were small PDK recipients. Twenty-three patients received 29 biopsies or nephrectomy between 6 and 896 days posttransplantation days. Seven patients (30.4%) had pediatric donor glomerulopathy (PDG), which developed from 113 to 615 days posttransplantation. The incidence of proteinuria and hematuria was significantly higher in the PDG group. The characteristic pathological finding in PDG was irregular lamination and splintering of the glomerular basement membrane (GBM). Donor age, donor weight, and donor kidney volume were significantly less in PDG cases compared with the non-PDG cases. For the risk factors of PDG, increasing urinary RBC count during follow-up was an independent predictor, while increasing donor age and body weight were protective factors. PDG was not a significant risk factor for Scr increasing of PDKs. CONCLUSIONS: PDG is a potential cause of abnormal urinalysis in adults receiving small PDKs. The pathological characteristic change of PDG is splitting and lamination of GBM. Persistent hematuria after transplantation in recipients of PDK is a predictor of PDG development.


Assuntos
Glomerulonefrite/patologia , Hematúria/epidemiologia , Transplante de Rim/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Proteinúria/epidemiologia , Adolescente , Adulto , Fatores Etários , Aloenxertos/anatomia & histologia , Aloenxertos/patologia , Biópsia , Peso Corporal , Criança , Pré-Escolar , Feminino , Seguimentos , Membrana Basal Glomerular/patologia , Sobrevivência de Enxerto , Hematúria/etiologia , Hematúria/patologia , Hematúria/urina , Humanos , Lactente , Falência Renal Crônica/cirurgia , Transplante de Rim/métodos , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/patologia , Complicações Pós-Operatórias/urina , Prognóstico , Fatores de Proteção , Proteinúria/etiologia , Proteinúria/patologia , Proteinúria/urina , Estudos Retrospectivos , Fatores de Risco , Doadores de Tecidos , Resultado do Tratamento , Adulto Jovem
12.
Am J Physiol Renal Physiol ; 319(4): F636-F646, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32830536

RESUMO

Mitotic spindle assembly checkpoint protein 2 (MAD2B), a well-known anaphase-promoting complex/cyclosome (APC/C) inhibitor and a small subunit of DNA polymerase-ζ, is critical for mitotic control and DNA repair. Previously, we detected a strong increase of MAD2B in the glomeruli from patients with crescentic glomerulonephritis and anti-glomerular basement membrane (anti-GBM) rats, which predominantly originated from activated parietal epithelial cells (PECs). Consistently, in vitro MAD2B was increased in TNF-α-treated PECs, along with cell activation and proliferation, as well as extracellular matrix accumulation, which could be reversed by MAD2B genetic depletion. Furthermore, we found that expression of S phase kinase-associated protein 2 (Skp2), an APC/CCDH1 substrate, was increased in the glomeruli of anti-GBM rats, and TNF-α-stimulated PECs and could be suppressed by MAD2B depletion. Additionally, genetic deletion of Skp2 inhibited TNF-α-induced PEC activation and dysfunction. Finally, TNF-α blockade or glucocorticoid therapy administered to anti-GBM rats could ameliorate MAD2B and Skp2 accumulation as well as weaken PEC activation. Collectively, our data suggest that MAD2B has a pivotal role in the pathogenesis of glomerular PEC activation and crescent formation through induction of Skp2 expression.


Assuntos
Proliferação de Células , Células Epiteliais/metabolismo , Glomerulonefrite/enzimologia , Glomérulos Renais/metabolismo , Proteínas Mad2/metabolismo , Proteínas Quinases Associadas a Fase S/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Etanercepte/farmacologia , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Regulação da Expressão Gênica , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/genética , Glomerulonefrite/patologia , Glucocorticoides/farmacologia , Humanos , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/patologia , Proteínas Mad2/genética , Masculino , Camundongos , Prednisolona/análogos & derivados , Prednisolona/farmacologia , Células RAW 264.7 , Ratos Endogâmicos WKY , Proteínas Quinases Associadas a Fase S/genética , Transdução de Sinais
13.
Am J Physiol Renal Physiol ; 319(4): F571-F578, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32830537

RESUMO

(Pro)renin receptor [(P)RR] has multiple functions, but its regulation and role in the pathogenesis in glomerulonephritis (GN) are poorly defined. The aims of the present study were to determine the effects of direct renin inhibition (DRI) and demonstrate the role of (P)RR on the progression of crescentic GN. The anti-glomerular basement membrane nephritis rat model developed progressive proteinuria (83.64 ± 10.49 mg/day) and glomerular crescent formation (percent glomerular crescent: 62.1 ± 2.3%) accompanied by increased macrophage infiltration and glomerular expression of monocyte chemoattractant protein (MCP)-1, (P)RR, phospho-extracellular signal-regulated kinase (ERK)1/2, Wnt4, and active ß-catenin. Treatment with DRI ameliorated proteinuria (20.33 ± 5.88 mg/day) and markedly reduced glomerular crescent formation (20.9 ± 2.6%), induction of macrophage infiltration, (P)RR, phospho-ERK1/2, Wnt4, and active ß-catenin. Furthermore, primary cultured parietal epithelial cells stimulated by recombinant prorenin showed significant increases in cell proliferation. Notably, while the ERK1/2 inhibitor PD98059 or (P)RR-specific siRNA treatment abolished the elevation in cell proliferation, DRI treatment did not abrogate this elevation. Moreover, cultured mesangial cells showed an increase in prorenin-induced MCP-1 expression. Interestingly, (P)RR or Wnt4-specific siRNA treatment or the ß-catenin antagonist XAV939 inhibited the elevation of MCP-1 expression, whereas DRI did not. These results suggest that (P)RR regulates glomerular crescent formation via the ERK1/2 signaling and Wnt/ß-catenin pathways during the course of anti-glomerular basement membrane nephritis and that DRI mitigates the progression of crescentic GN through the reduction of (P)RR expression but not inhibition of prorenin binding to (P)RR.


Assuntos
Proliferação de Células , Glomerulonefrite/enzimologia , Células Mesangiais/enzimologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Receptores de Superfície Celular/metabolismo , Via de Sinalização Wnt , Amidas/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Fumaratos/farmacologia , Glomerulonefrite/patologia , Glomerulonefrite/prevenção & controle , Masculino , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/patologia , Fosforilação , Ratos Endogâmicos WKY , Via de Sinalização Wnt/efeitos dos fármacos , Proteína Wnt4/metabolismo , beta Catenina/metabolismo
14.
PLoS One ; 15(7): e0236051, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32716952

RESUMO

INTRODUCTION: Crescentic glomerulonephritis (CrGN) is a histologic feature of severe glomerular injury, clinically characterized by a rapid decline of renal function when not treated in a timely fashion. Factors associated with CrGN prognosis have not been thoroughly investigated. This study investigated the prognostic predictors of renal outcomes associated with CrGN, such as the histopathologic classification of anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, arteriosclerosis, and tertiary lymphoid organ (TLO) formation. METHODS: A total of 114 patients diagnosed with CrGN between 2010 and 2018 at two university-based hospitals has been retrospectively analyzed. Relationships between potential predictors and renal outcomes were analyzed using Cox proportional hazards model and linear regression analysis. RESULTS: The mean age was 61.0 ± 15.3 years, and 49.1% were male. Among them, 92 (80.7%) and 11 (9.6%) patients were positive for ANCA and for anti-glomerular basement membrane antibody, respectively. During the median follow-up of 458.0 days, 55 patients (48.2%) had advanced to end-stage renal disease (ESRD). Cox proportional hazards analysis revealed that patients under the mixed and sclerotic classes had worse renal survival compared to those in the focal class (mixed: hazard ratio [HR], 3.74; 95% confidence interval [CI], 1.18 to 11.82; P = 0.025; sclerotic: HR, 4.84; 95% CI, 1.44 to 16.32; P = 0.011). Severe arteriosclerosis was also associated with poor renal survival (HR, 2.44; 95% CI, 1.04 to 5.77; P = 0.042). TLOs were observed in 41 patients (36.0%). Moreover, TLO formation was also a prognostic factor for ESRD (HR, 1.82; 95% CI, 1.03 to 3.21; P = 0.040). In the multivariate linear regression analysis, age and sclerotic class were independent predictors for the change in estimated glomerular filtration rate during 1 year after biopsy. CONCLUSIONS: Specific histopathologic findings, histopathologic classification, severity of arteriosclerosis, and TLO formation provide helpful information in predicting renal outcomes associated with CrGN.


Assuntos
Glomerulonefrite/diagnóstico , Glomerulonefrite/patologia , Rim/patologia , Feminino , Glomerulonefrite/fisiopatologia , Humanos , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida
16.
Am J Kidney Dis ; 76(2): 295-297, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32362418
17.
PLoS One ; 15(5): e0233183, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32413078

RESUMO

Lupus is a debilitating multi-organ autoimmune disease clinically typified by periods of flare and remission. Exposing lupus-prone female NZBWF1 mice to crystalline silica (cSiO2), a known human autoimmune trigger, mimics flaring by inducing interferon-related gene (IRG) expression, inflammation, ectopic lymphoid structure (ELS) development, and autoantibody production in the lung that collectively accelerate glomerulonephritis. cSiO2-triggered flaring in this model can be prevented by supplementing mouse diet with the ω-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA). A limitation of previous studies was the use of purified diet that, although optimized for rodent health, does not reflect the high American intake of saturated fatty acid (SFA), ω-6 PUFAs, and total fat. To address this, we employed here a modified Total Western Diet (mTWD) emulating the 50th percentile U.S. macronutrient distribution to discern how DHA supplementation and/or SFA and ω-6 reduction influences cSiO2-triggered lupus flaring in female NZBWF1 mice. Six-week-old mice were fed isocaloric experimental diets for 2 wks, intranasally instilled with cSiO2 or saline vehicle weekly for 4 wks, and tissues assessed for lupus endpoints 11 wks following cSiO2 instillation. In mice fed basal mTWD, cSiO2 induced robust IRG expression, proinflammatory cytokine and chemokine elevation, leukocyte infiltration, ELS neogenesis, and autoantibody production in the lung, as well as early kidney nephritis onset compared to vehicle-treated mice fed mTWD. Consumption of mTWD containing DHA at the caloric equivalent to a human dose of 5 g/day dramatically suppressed induction of all lupus-associated endpoints. While decreasing SFA and ω-6 in mTWD modestly inhibited some disease markers, DHA addition to this diet was required for maximal protection against lupus development. Taken together, DHA supplementation at a translationally relevant dose was highly effective in preventing cSiO2-triggered lupus flaring in NZBWF1 mice, even against the background of a typical Western diet.


Assuntos
Dieta Ocidental/efeitos adversos , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-6/farmacologia , Lúpus Eritematoso Sistêmico/dietoterapia , Dióxido de Silício/toxicidade , Animais , Linfócitos B/imunologia , Citocinas/metabolismo , Suplementos Nutricionais , Modelos Animais de Doenças , Ácidos Graxos/farmacologia , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-6/metabolismo , Feminino , Glomerulonefrite/dietoterapia , Glomerulonefrite/metabolismo , Glomerulonefrite/patologia , Inflamação/imunologia , Interferon gama/metabolismo , Rim/metabolismo , Rim/patologia , Pulmão/metabolismo , Pulmão/patologia , Lúpus Eritematoso Sistêmico/induzido quimicamente , Camundongos , Linfócitos T/imunologia
18.
Am J Kidney Dis ; 76(4): 500-510, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32414663

RESUMO

RATIONALE & OBJECTIVE: Fibrillary glomerulonephritis (FGN) is a rare glomerular disease that often progresses to kidney failure requiring kidney replacement therapy. We have recently identified a novel biomarker of FGN, DnaJ homolog subfamily B member 9 (DNAJB9). In this study, we used sequential protocol allograft biopsies and DNAJB9 staining to help characterize a series of patients with native kidney FGN who underwent kidney transplantation. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: Between 1996 and 2016, kidney transplantation was performed on 19 patients with a reported diagnosis of FGN in their native/transplant kidneys. Using standard diagnostic criteria and DNAJB9 staining, we excluded 5 patients (4 atypical cases diagnosed as possible FGN and 1 donor-derived FGN). Protocol allograft biopsies had been performed at 4, 12, 24, 60, and 120 months posttransplantation. DNAJB9 immunohistochemistry was performed using an anti-DNAJB9 rabbit polyclonal antibody. Pre- and posttransplantation demographic and clinical characteristics were collected. Summary statistical analysis was performed, including nonparametric statistical tests. OBSERVATIONS: The 14 patients with FGN had a median posttransplantation follow-up of 5.7 (IQR, 2.9-13.8) years. 3 (21%) patients had recurrence of FGN, detected on the 5- (n=1) and 10-year (n=2) allograft biopsies. Median time to recurrence was 10.2 (IQR, 5-10.5) years. Median levels of proteinuria and iothalamate clearance at the time of recurrence were 243mg/d and 56mL/min. The remaining 11 patients had no evidence of histologic recurrence on the last posttransplantation biopsy, although the median time of follow-up was significantly less at 4.4 (IQR, 2.9-14.4) years. 3 (21%) patients had a monoclonal protein detectable in serum obtained pretransplantation; none of these patients had recurrent FGN. LIMITATIONS: Small study sample and shorter follow-up time in the nonrecurrent versus recurrent group. CONCLUSIONS: In this series, FGN had an indolent course in the kidney allograft in that detectable histologic recurrence did not appear for at least 5 years posttransplantation.


Assuntos
Glomerulonefrite/cirurgia , Proteínas de Choque Térmico HSP40/análise , Transplante de Rim , Rim/química , Proteínas de Membrana/análise , Chaperonas Moleculares/análise , Adulto , Idoso , Biomarcadores/análise , Biópsia , Feminino , Glomerulonefrite/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva
19.
Am J Physiol Renal Physiol ; 318(5): F1177-F1187, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32223311

RESUMO

Loss-of-function mutations in phospholipase C-ε1 (PLCE1) have been detected in patients with nephrotic syndrome, but other family members with the same mutation were asymptomatic, suggesting additional stressor are required to cause the full phenotype. Consistent with these observations, we determined that global Plce1-deficient mice have histologically normal glomeruli and no albuminuria at baseline. Angiotensin II (ANG II) is known to induce glomerular damage in genetically susceptible individuals. Therefore, we tested whether ANG II enhances glomerular damage in Plce1-deficient mice. ANG II increased blood pressure equally in Plce1-deficient and wild-type littermates. Additionally, it led to 20-fold increased albuminuria and significantly more sclerotic glomeruli in Plce1-deficient mice compared with wild-type littermates. Furthermore, Plce1-deficient mice demonstrated diffuse mesangial expansion, podocyte loss, and focal podocyte foot process effacement. To determine whether these effects are mediated by hypertension and hyperfiltration, rather than directly through ANG II, we raised blood pressure to a similar level using DOCA + salt + uninephrectomy and norepinephrine. This caused a fivefold increase in albuminuria in Plce1-deficient mice and a significant increase in the number of sclerotic glomeruli. Consistent with previous findings in mice, we detected strong PLCE1 transcript expression in podocytes using single cell sequencing of human kidney tissue. In hemagglutinin-tagged Plce1 transgenic mice, Plce1 was detected in podocytes and also in glomerular arterioles using immunohistochemistry. Our data demonstrate that Plce1 deficiency in mice predisposes to glomerular damage secondary to hypertensive insults.


Assuntos
Pressão Sanguínea , Glomerulonefrite/enzimologia , Hipertensão/enzimologia , Glomérulos Renais/enzimologia , Fosfoinositídeo Fosfolipase C/deficiência , Albuminúria/enzimologia , Albuminúria/genética , Albuminúria/fisiopatologia , Animais , Acetato de Desoxicorticosterona , Modelos Animais de Doenças , Feminino , Glomerulonefrite/genética , Glomerulonefrite/patologia , Glomerulonefrite/fisiopatologia , Hipertensão/genética , Hipertensão/fisiopatologia , Glomérulos Renais/patologia , Glomérulos Renais/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nefrectomia , Fosfoinositídeo Fosfolipase C/genética , Cloreto de Sódio na Dieta
20.
Adv Exp Med Biol ; 1221: 647-667, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32274730

RESUMO

The primary filtration of blood occurs in the glomerulus in the kidney. Destruction of any of the layers of the glomerular filtration barrier might result in proteinuric disease. The glomerular endothelial cells and especially its covering layer, the glycocalyx, play a pivotal role in development of albuminuria. One of the main sulfated glycosaminoglycans in the glomerular endothelial glycocalyx is heparan sulfate. The endoglycosidase heparanase degrades heparan sulfate, thereby affecting glomerular barrier function, immune reactivity and inflammation. Increased expression of glomerular heparanase correlates with loss of glomerular heparan sulfate in many glomerular diseases. Most importantly, heparanase knockout in mice prevented the development of albuminuria after induction of experimental diabetic nephropathy and experimental glomerulonephritis. Therefore, heparanase could serve as a pharmacological target for glomerular diseases. Several factors that regulate heparanase expression and activity have been identified and compounds aiming to inhibit heparanase activity are currently explored.


Assuntos
Glucuronidase/metabolismo , Nefropatias/enzimologia , Albuminúria/enzimologia , Albuminúria/patologia , Animais , Nefropatias Diabéticas/enzimologia , Nefropatias Diabéticas/patologia , Células Endoteliais/enzimologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Glomerulonefrite/enzimologia , Glomerulonefrite/patologia , Heparitina Sulfato , Humanos , Nefropatias/patologia , Glomérulos Renais/enzimologia , Glomérulos Renais/patologia
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