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1.
Pol Merkur Lekarski ; 49(293): 364-367, 2021 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-34800025

RESUMO

Secondary membranous - proliferative glomerulonephritis most often develops in the course of viral infections (HCV, HBV), autoimmune diseases, paraproteinemia, and also in the course of chronic bacterial infections. Infections with Pseudomonas stutzeri (P. stutzeri) are extremely rare and usually mildly symptomatic. The natural habitat of this bacterium is soil and water. Nevertheless, in the case of P. stutzeri infection, especially in patients frequently hospitalized or receiving immunosuppressive medications, environmental contamination in healthcare facilities should be taken into account when looking for the source of the infection. A CASE REPORT: A 60-year-old man with a previous history of nicotinism and arterial hypertension with a vascular port in the vena cava superior (VCS) after treatment for bladder cancer (stage G2/G3) several years ago was described. The patient underwent the TURBT procedure, and then received intravesical infusions with BCG for 3 years, followed by complications in the form of severe dysuria and lower abdominal pain. Due to severe nausea and the inability to take analgesics orally, the patient was ordered to insert a vascular port into the VCS in order to continue the analgesic and anti - inflammatory therapy. Several years later, after the onset of massive edema of lower limbs, the patient was subjected to a 24-hour urine collection, in which proteinuria amounted to approx. 13 g/day, followed by a diagnostic kidney biopsy. Histopathological examination described membranoproliferative glomerulonephritis (MPGN). Other renal parameters were also abnormal, i.e. serum creatinine concentration was 1.9 mg/ dl and serum urea concentration was 116 mg/dl. Immunosuppressive treatment was initiated. Patient received methylprednisolone intravenously followed by prednisone orally and cyclosporine orally. During the initial period of immunosuppressive therapy, the serum levels of cyclosporine were insufficient (starting from 26.34 ng/ml), which resulted in increasing its dose, ultimately reaching 175 mg/day. After several months of therapy, the patient was hospitalized again, due to infection of the respiratory tract that had lasted for several weeks and was not amenable to antibiotic therapy. Deterioration of renal parameters and increased inflammatory markers suggested diagnosis of catheter - related sepsis. P. stutzeri was grown from the material collected from the catheter and the patient's blood. Appropriate antibiotic therapy was initiated and after the patient's condition improved, cyclosporine therapy was restarted, which was discontinued after the diagnosis of bacteremia. Rapid remission was achieved, allowing the discontinuation of immunosuppressive drugs. CONCLUSIONS: Chronic, asymptomatic infection with a rare pathogen, like Pseudomonas stutzeri, was probably the cause of the glomerulonephritis. After removal of the port and antibiotic therapy, disease remission was achieved.


Assuntos
Bacteriemia , Glomerulonefrite Membranoproliferativa , Glomerulonefrite , Pseudomonas stutzeri , Bacteriemia/complicações , Bacteriemia/diagnóstico , Bacteriemia/tratamento farmacológico , Cateteres , Glomerulonefrite/diagnóstico , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/etiologia , Glomerulonefrite Membranoproliferativa/complicações , Glomerulonefrite Membranoproliferativa/diagnóstico , Glomerulonefrite Membranoproliferativa/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade
2.
Klin Lab Diagn ; 66(10): 610-617, 2021 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-34665947

RESUMO

The timely diagnosis and treatment of post-infectious glomerulonephritis (PIGN) is currently limited by the erased and low-symptom nature of the disease, which leads to the search for informative biological markers of the disease, which can be used as immunological indicators of blood and urine. The study was carried out in order to establish the characteristic changes in the immunological parameters of blood and urine in patients with PIGN. The study included 60 patients with PIGN from among the patients, hospitalized in the nephrology department of the Republican Clinical Hospital of Health Care Ministry of the Chuvash Republic in 2015-2018. In addition to the generally accepted research methods, the patients underwent: 1) the determination of indicators of innate and acquired immune response in the blood (CD3+ -, CD3+ CD4+-, CD3+CD8+-, CD4+CD25+-, CD95+-, CD20+-, CD14+CD282+-, CD14+CD284+- cells; levels of IgG, IgA, IgM, circulating immune complexes, C3, C4) and urine (levels of IgG, IgA, IgM, C3, C4); 2) the determination of the levels of cytokines - IL-1ß, Ra-IL-1ß, IL-2, IL-4, IL-8, IL-10, IL-17A in blood serum and urine. The data obtained were compared with those of the group of healthy individuals. The changes in blood immunological parameters, identified in the group of patients with PIGN, indicate the activation of innate immunity (the increase in the number of CD14+TLR2+- cells) and the humoral component of adaptive immunity (the increase in the number of B-lymphocytes, hyperimmunoglobulinemia - the increase in IgM and IgA levels) against the background of the decrease in the number of T (CD3+) - lymphocytes and regulatory (CD4+CD25high) - cells, hypocomplementemia (decreased levels of C3, C4). The increase in the content of C3, IgG and IgA was found in the urine. The cytokine profile of blood in patients with PIGN was characterized by the increase in the levels of pro- and anti-inflammatory cytokines IL-1ß, Ra-IL-1ß, IL-2, IL-8, IL-10, IL-17A, with the exception of IL-4, which remained on the levels of healthy individuals. The cytokine profile of urine in patients was characterized by the increase in the levels of pro-inflammatory cytokines IL-1ß, IL-2, IL-8, IL-17A and anti-inflammatory cytokine - IL-10, with no changes in the content of Ra-IL-1ß and IL-4. The revealed features of the immunological profile of blood and urine in patients with PIGN reflect the immunopathogenetic mechanisms of this disease.


Assuntos
Líquidos Corporais , Glomerulonefrite , Linfócitos B , Citocinas , Humanos
3.
Front Immunol ; 12: 762006, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34659268

RESUMO

As the coronavirus disease 2019 (COVID-19) pandemic is ongoing and new variants of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) are emerging, there is an urgent need for COVID-19 vaccines to control disease outbreaks by herd immunity. Surveillance of rare safety issues related to these vaccines is progressing, since more granular data emerge with regard to adverse events of COVID-19 vaccines during post-marketing surveillance. Interestingly, four cases of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) presenting with pauci-immune crescentic glomerulonephritis (GN) after COVID-19 mRNA vaccination have already been reported. We here expand our current knowledge of this rare but important association and report a case of AAV presenting with massive rhabdomyolysis and pauci-immune crescentic GN after Pfizer-BioNTech COVID-19 mRNA vaccination. As huge vaccination programs are ongoing worldwide, post-marketing surveillance systems must continue to assess vaccine safety important for the detection of any events associated with COVID-19 vaccination. This is especially relevant in complex diseases where diagnosis is often challenging, as in our patient with AAV presenting with massive rhabdomyolysis and pauci-immune crescentic GN.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/patologia , Vacinas contra COVID-19/efeitos adversos , Glomerulonefrite/patologia , Rabdomiólise/patologia , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Anticorpos Anticitoplasma de Neutrófilos/sangue , Anticorpos Anticitoplasma de Neutrófilos/imunologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/imunologia , Feminino , Glomerulonefrite/diagnóstico , Glomerulonefrite/imunologia , Humanos , RNA Mensageiro/imunologia , Rabdomiólise/diagnóstico , Rabdomiólise/imunologia
4.
Molecules ; 26(19)2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34641404

RESUMO

Tomatoes are widely consumed, however, studies on tomato seeds are limited. In this study, we isolated 11 compounds including saponins and flavonol glycosides from tomato seeds and evaluated their effects on epidermal hydration. Among the isolated compounds, tomato seed saponins (10 µM) significantly increased the mRNA expression of proteins related to epidermal hydration, including filaggrin, involucrin, and enzymes for ceramide synthesis, by 1.32- to 1.91-fold compared with the control in HaCaT cells. Tomato seed saponins (10 µM) also decreased transepidermal water loss by 7 to 13 g/m2·h in the reconstructed human epidermal keratinization (RHEK) models. Quantitative analysis of the ceramide content in the stratum corneum (SC) revealed that lycoperoside H (1-10 µM) is a promising candidate to stimulate ceramide synthesis via the upregulation of ceramide synthase-3, glucosylceramide synthase, and ß-glucocerebrosidase, which led to an increase in the total SC ceramides (approximately 1.5-fold) in concert with ceramide (NP) (approximately 2-fold) in the RHEK models. Evaluation of the anti-inflammatory and anti-allergic effects of lycoperoside H demonstrated that lycoperoside H is suggested to act as a partial agonist of the glucocorticoid receptor and exhibits anti-inflammatory effects (10 mg/kg in animal test). These findings indicate that lycoperoside H can improve epidermal dehydration and suppress inflammation by increasing SC ceramide and steroidal anti-inflammatory activity.


Assuntos
Anti-Inflamatórios/farmacologia , Ceramidas/metabolismo , Epiderme/efeitos dos fármacos , Glicosídeos/farmacologia , Queratinócitos/efeitos dos fármacos , Lycopersicon esculentum/química , Esteroides/farmacologia , Animais , Desidratação , Epiderme/metabolismo , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/metabolismo , Glomerulonefrite/patologia , Cobaias , Humanos , Queratinócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , Saponinas/farmacologia , Sementes/química
5.
Kidney int ; 100(4): 753-779, 20211001.
Artigo em Inglês | BIGG - guias GRADE | ID: biblio-1292240

RESUMO

The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Management of Glomerular Diseases is an update to the KDIGO 2012 guideline. The aim is to assist clinicians caring for individuals with glomerulonephritis (GN), both adults and children. The scope includes various glomerular diseases, including IgA nephropathy and IgA vasculitis, membranous nephropathy, nephrotic syndrome, minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), infection-related GN, antineutrophil cytoplasmic antibody (ANCA) vasculitis, lupus nephritis, and anti­glomerular basement membrane antibody GN. In addition, this guideline will be the first to address the subtype of complement-mediated diseases. Each chapter follows the same format providing guidance related to diagnosis, prognosis, treatment, and special situations. The goal of the guideline is to generate a useful resource for clinicians and patients by providing actionable recommendations based on evidence syntheses, with useful infographics incorporating views from experts in the field. Another aim is to propose research recommendations for areas where there are gaps in knowledge. The guideline targets a broad global audience of clinicians treating GN while being mindful of implications for policy and cost. Development of this guideline update followed an explicit process whereby treatment approaches and guideline recommendations are based on systematic reviews of relevant studies, and appraisal of the quality of the evidence and the strength of recommendations followed the "Grading of Recommendations Assessment, Development and Evaluation" (GRADE) approach. Limitations of the evidence are discussed, with areas of future research also presented


Assuntos
Humanos , Criança , Adulto , Glomerulonefrite/diagnóstico , Biomarcadores/análise , Imunossupressão/efeitos adversos , Glomerulonefrite/complicações , Glomerulonefrite/prevenção & controle
7.
Int J Mycobacteriol ; 10(2): 199-201, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34558475

RESUMO

Hansen's disease is one of the ancient skin diseases known to humankind, still foxes even trained physician leading to delay in its diagnosis and unusual health burden. India followed by Brazil constitutes the highest number in newly diagnosed cases. Even though the World Health Organization and individual country have done much to contain the spread of leprosy, the findings of systemic complications, grade 2 deformity, and childhood leprosy reflect some shortcomings of the worldwide public health program. Renal involvement, particularly glomerulonephritis, is a known common systemic complication of the leprosy, but introduction of multidrug therapy and early case detection have reduced the chances of systemic complication significantly over the last three decades. Here, we report a case who presented in the emergency department with rapidly progressive swelling of the body, on evaluation found to have leprosy and glomerulonephritis having tubuloreticular inclusions in glomerular endothelial cell cytoplasm on electron microscopy.


Assuntos
Glomerulonefrite , Hanseníase , Dermatopatias , Criança , Quimioterapia Combinada , Glomerulonefrite/diagnóstico , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/etiologia , Humanos , Hansenostáticos/uso terapêutico , Hanseníase/complicações , Hanseníase/diagnóstico , Hanseníase/tratamento farmacológico , Úlcera
8.
Kidney Int ; 100(4): 753-779, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34556300

RESUMO

The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Management of Glomerular Diseases is an update to the KDIGO 2012 guideline. The aim is to assist clinicians caring for individuals with glomerulonephritis (GN), both adults and children. The scope includes various glomerular diseases, including IgA nephropathy and IgA vasculitis, membranous nephropathy, nephrotic syndrome, minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), infection-related GN, antineutrophil cytoplasmic antibody (ANCA) vasculitis, lupus nephritis, and anti-glomerular basement membrane antibody GN. In addition, this guideline will be the first to address the subtype of complement-mediated diseases. Each chapter follows the same format providing guidance related to diagnosis, prognosis, treatment, and special situations. The goal of the guideline is to generate a useful resource for clinicians and patients by providing actionable recommendations based on evidence syntheses, with useful infographics incorporating views from experts in the field. Another aim is to propose research recommendations for areas where there are gaps in knowledge. The guideline targets a broad global audience of clinicians treating GN while being mindful of implications for policy and cost. Development of this guideline update followed an explicit process whereby treatment approaches and guideline recommendations are based on systematic reviews of relevant studies, and appraisal of the quality of the evidence and the strength of recommendations followed the "Grading of Recommendations Assessment, Development and Evaluation" (GRADE) approach. Limitations of the evidence are discussed, with areas of future research also presented.


Assuntos
Glomerulonefrite por IGA , Glomerulonefrite Membranosa , Glomerulonefrite , Nefrose Lipoide , Adulto , Criança , Glomerulonefrite/diagnóstico , Glomerulonefrite/terapia , Glomerulonefrite por IGA/diagnóstico , Glomerulonefrite por IGA/terapia , Glomerulonefrite Membranosa/diagnóstico , Glomerulonefrite Membranosa/tratamento farmacológico , Humanos , Rim
9.
PLoS One ; 16(9): e0257397, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34520493

RESUMO

The reclassification of membranoproliferative glomerulonephritis (MPGN) into immune-complex MPGN (IC-MPGN) and C3 glomerulopathy (C3G) based on immunofluorescence findings in kidney biopsies has provided insights into these two distinct diseases. C3G is further classified into dense deposit disease and C3 glomerulonephritis (C3GN) based on electron micrographic findings. Although these diseases have poor outcomes, limited Japanese literature confined to small, single-center cohorts exist on these diseases. We retrospectively analyzed 81 patients with MPGN type I and III from 15 hospitals in the Japan Renal Biopsy Registry to compare demographic, clinical characteristics and treatment outcomes of patients with IC-MPGN to those with C3GN. Of the 81 patients reviewed by immunofluorescence findings in kidney biopsies, 67 patients had IC-MPGN and 14 patients had C3GN. Age at diagnosis and systolic and diastolic pressure were higher and proteinuria and impaired renal function were significantly more prevalent in patients with IC-MPGN than those with C3GN. About 80% of the patients in both groups were treated with immunosuppressive therapy. At last follow-up (median 4.8 years), complete remission rate of proteinuria was significantly higher in patients with C3GN (64.3%) than in those with IC-MPGN (29.9%; P = 0.015). The renal survival rate was lower in patients with IC-MPGN when compared to C3GN (73.1% vs. 100%; log-rank, P = 0.031). Systolic blood pressure and renal function at baseline were independent predictors of progression to end-stage kidney disease. The overall prognosis of patients with C3GN is more favorable than for patients with IC-MPGN.


Assuntos
Demografia/métodos , Glomerulonefrite/diagnóstico , Glomerulonefrite/fisiopatologia , Adolescente , Adulto , Fatores Etários , Idoso , Complexo Antígeno-Anticorpo , Biópsia , Pressão Sanguínea , Feminino , Imunofluorescência , Seguimentos , Humanos , Japão , Rim , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Indução de Remissão , Estudos Retrospectivos , Resultado do Tratamento
10.
Cell Mol Life Sci ; 78(19-20): 6721-6734, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34568976

RESUMO

Myeloid cells and TLR4 play a critical role in acute kidney injury. This study investigated the regulatory role and mechanisms of myeloid TLR4 in experimental anti-glomerular basement membrane (GBM) glomerulonephritis (GN). Anti-GBM GN was induced in tlr4flox/flox and tlr4flox/flox-lysM-cre mice by intravenous injection of the sheep anti-mouse GBM antibody. Compared to control mice, conditional disruption of tlr4 from myeloid cells, largely macrophages (> 85%), suppressed glomerular crescent formation and attenuated progressive renal injury by lowering serum creatinine and 24-h urine protein excretion while improving creatinine clearance. Mechanistically, deletion of myeloid tlr4 markedly inhibited renal infiltration of macrophages and T cells and resulted in a shift of infiltrating macrophages from F4/80+iNOS+ M1 to F4/80+CD206+ M2 phenotype and inhibited the upregulation of renal proinflammatory cytokines IL-1ß and MCP-1. Importantly, deletion of myeloid tlr4 suppressed T cell-mediated immune injury by shifting Th1 (CD4+IFNγ+) and Th17 (CD4+IL-17a+) to Treg (CD4+CD25+FoxP3+) immune responses. Transcriptome analysis also revealed that disrupted myeloid TLR4 largely downregulated genes involving immune and cytokine-related pathways. Thus, myeloid TLR4 plays a pivotal role in anti-GBM GN by immunological switching from M1 to M2 and from Th1/Th17 to Treg and targeting myeloid TLR4 may be a novel therapeutic strategy for immune-mediated kidney diseases.


Assuntos
Membrana Basal/metabolismo , Glomerulonefrite/metabolismo , Glomérulos Renais/metabolismo , Células Mieloides/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Citocinas/metabolismo , Feminino , Rim/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Th1/metabolismo , Células Th17/metabolismo
11.
Am J Physiol Renal Physiol ; 321(5): F600-F616, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34541901

RESUMO

Following our previous reports on mesangial sclerosis and vascular proliferation in diabetic nephropathy (DN) (Kriz W, Löwen J, Federico G, van den Born J, Gröne E, Gröne HJ. Am J Physiol Renal Physiol 312: F1101-F1111, 2017; Löwen J, Gröne E, Gröne HJ, Kriz W. Am J Physiol Renal Physiol 317: F399-F410, 2019), we now describe the advanced stages of DN terminating in glomerular obsolescence and tubulointerstitial fibrosis based on a total of 918 biopsies. The structural aberrations emerged from two defects: 1) increased synthesis of glomerular basement membrane (GBM) components by podocytes and endothelial cells leading to an accumulation of GBM material in the mesangium and 2) a defect of glomerular vessels consisting of increased leakiness and an increased propensity to proliferate. Both defects may lead to glomerular degeneration. The progressing compaction of accumulated worn-out GBM material together with the retraction of podocytes out of the tuft and the collapse and hyalinosis of capillaries results in a shrunken tuft that fuses with Bowman's capsule (BC) to glomerular sclerosis. The most frequent pathway to glomerular decay starts with local tuft expansions that result in contacts of structurally intact podocytes to the parietal epithelium initiating the formation of tuft adhesions, which include the penetration of glomerular capillaries into BC. Exudation of plasma from such capillaries into the space between the parietal epithelium and its basement membrane causes the formation of insudative fluid accumulations within BC spreading around the glomerular circumference and, via the glomerulotubular junction, onto the tubule. Degeneration of the corresponding tubule develops secondarily to the glomerular damage, either due to cessation of filtration in cases of global sclerosis or due to encroachment of the insudative spaces. The degenerating tubules induce the proliferation of myofibroblasts resulting in interstitial fibrosis.NEW & NOTEWORTHY Based on analysis of 918 human biopsies, essential derangement in diabetic nephropathy consists of accumulation of worn-out glomerular basement membrane in the mesangium that may advance to global sclerosis. The most frequent pathway to nephron dropout starts with the penetration of glomerular capillaries into Bowman's capsule (BC), delivering an exudate into BC that spreads around the entire glomerular circumference and via the glomerulotubular junction onto the tubule, resulting in glomerular sclerosis and chronic tubulointerstitial damage.


Assuntos
Nefropatias Diabéticas/patologia , Glomerulonefrite/patologia , Néfrons/patologia , Biópsia , Cápsula Glomerular/patologia , Capilares/patologia , Permeabilidade Capilar , Nefropatias Diabéticas/metabolismo , Progressão da Doença , Células Endoteliais/patologia , Fibrose , Membrana Basal Glomerular/patologia , Glomerulonefrite/metabolismo , Humanos , Microscopia Eletrônica de Transmissão , Neovascularização Patológica , Néfrons/metabolismo , Néfrons/ultraestrutura , Podócitos/patologia
13.
Medicine (Baltimore) ; 100(32): e26905, 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34397922

RESUMO

RATIONALE: Several renal diseases are associated with infectious endocarditis. However, there are few reports on patients with granulomatosis with polyangiitis (GPA) associated with infectious endocarditis, and there is no consensus for appropriate treatment. PATIENTS CONCERNS: A 35 -years-old man with congenital ventricular septal defect presented severe anemia, hematuria and proteinuria. The blood and urine examinations showed elevated white blood cells (12,900 cells/µL), C-reactive protein level (13.1 mg/dL) and proteinase 3-anti-neutrophil cytoplasmic antibody (PR3-ANCA) level (11.0 IU/mL), severe anemia (hemoglobin: 6.1 g/dL) and renal dysfunction [estimated glomerular filtration rate (eGFR): 12.7 ml/min.1.78 m2 with hematuria and proteinuria]. DIAGNOSES: The patient was diagnosed with crescentic glomerulonephritis with histological features of GPA associated with infectious endocarditis by renal biopsy and transthoracic echocardiography. INTERVENTIONS: Antibacterial drugs (ampicillin-sulbactam) were administrated. No immunomodulating agents were used because immunosuppressive drugs may worsen infectious endocarditis. Subsequently, renal function and urinary findings improved. However, infectious endocarditis was not improved. Therefore, valve replacements and ventricular septal closure surgery were conducted. OUTCOMES: Thereafter, his postoperative course was uneventful, renal function improved (eGFR: 64.3 ml/min.1.78 m2), and PR3-ANCA level normalized. LESSONS: We reported a case report of PR3-ANCA positive glomerulonephritis with histological features of GPA associated with infectious endocarditis. Physicians might note this renal complication when they manage infectious endocarditis.


Assuntos
Anticorpos Anticitoplasma de Neutrófilos/imunologia , Endocardite Bacteriana Subaguda/complicações , Glomerulonefrite/etiologia , Granulomatose com Poliangiite/complicações , Adulto , Biópsia , Glomerulonefrite/diagnóstico , Glomerulonefrite/imunologia , Granulomatose com Poliangiite/diagnóstico , Granulomatose com Poliangiite/imunologia , Humanos , Rim/patologia , Masculino
14.
Am J Physiol Cell Physiol ; 321(2): C384-C393, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34232747

RESUMO

Inflammation of the kidney is a key contributor to proliferative glomerulonephritis, and kidney damage during glomerulonephritis can lead to renal failure. The immune response associated with glomerulonephritis episodes is a major determinant of patient outcomes, and understanding this response is paramount for effective therapeutic treatment. Neutrophils are the first responders to sites of infection or tissue injury and are a significant cellular infiltrate during proliferative glomerulonephritis. This immune cell was initially recognized as a "blunt" nonspecific effector cell that was recruited to kill pathogens and then die quickly. However, recent studies have shown that the behavior and function of neutrophils are substantially more complex. Neutrophil recruitment to inflammatory sites must be carefully regulated so that these potent cells accurately arrive at tissue sites and perform their functions without nonspecific injury to other locations. As the kidney contains unique microvasculature befitting their specialized role in blood filtration, the recruitment of neutrophils in the renal environment differs from other organs. This Mini-Review will describe how advances in live-animal (intravital) imaging led to the discovery of novel recruitment pathways in the kidney, particularly in the glomeruli, and highlight these differences to canonical neutrophil recruitment. In addition, molecular engagement of surface molecules that lead to intracellular signaling, which is followed by neutrophil capture in the glomeruli, is also briefly discussed. Finally, the contribution of other immune cells in renal neutrophil recruitment, the fate of the emigrated neutrophils after inflammation, and the relevance of mouse models compared with human glomerulonephritides will also be explored.


Assuntos
Glomerulonefrite/metabolismo , Glomérulos Renais/metabolismo , Rim/metabolismo , Infiltração de Neutrófilos/imunologia , Neutrófilos/metabolismo , Animais , Humanos , Inflamação/metabolismo
15.
Cell Death Dis ; 12(7): 687, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244474

RESUMO

Podocytes are a key component of the glomerular filtration barrier, and its dysfunction and eventual loss drive glomerular disease progression. Recent research has demonstrated the importance of podocyte cross-talk with other glomerular cells, such as glomerular endothelial cells (GECs), in both glomerular homeostasis and in disease settings. However, how GECs are affected globally by podocyte injury and loss in disease settings remains unclear. Therefore, to characterize the molecular changes occurring in GECs in response to the podocyte loss, we performed the transcriptomic profiling of isolated GECs after diphtheria toxin (DT)-mediated podocyte depletion in transgenic mice with podocyte-specific human DT receptor and endothelial-specific enhanced yellow fluorescent protein (EYFP) expression. DT administration led to nearly 40% of podocyte loss with the development of glomerulosclerosis. Differential gene expression analysis of isolated GECs in the diseased mice showed significant changes in pathways related to cell adhesion and actin cytoskeleton, proliferation, and angiogenesis, as well as apoptosis and cell death. However, quantification of EYFP + GECs indicated that there was a reduction in GECs in the diseased mice, suggesting that despite the ongoing proliferation, the concomitant injury and the activation of cell death program results in their overall net loss. The upstream regulator analysis strongly indicated the involvement of p53, TGF-ß1, and TNF-α as key mediators of the molecular changes occurring in GECs in the diseased mice. Our findings demonstrate significant molecular changes in GECs as a secondary consequence of podocyte loss and provide a valuable resource for further in-depth analysis of potential glomerular cross-talk mediators.


Assuntos
Células Endoteliais/metabolismo , Perfilação da Expressão Gênica , Glomerulonefrite/genética , Podócitos/patologia , Transcriptoma , Animais , Modelos Animais de Doenças , Células Endoteliais/patologia , Feminino , Redes Reguladoras de Genes , Glomerulonefrite/metabolismo , Glomerulonefrite/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transdução de Sinais , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
16.
Front Immunol ; 12: 645483, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220805

RESUMO

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic vasculitis, most frequently presenting as microscopic polyangiitis (MPA) or granulomatosis with polyangiitis (GPA). Pathogenic ANCAs trigger a deleterious immune response resulting in pauci-immune necrotizing and crescentic glomerulonephritis (GN). Standard therapeutical regimens include aggressive immunosuppressive therapy. Since some patients require renal replacement therapy (RRT) despite intensive immunosuppressive therapy, additional therapeutic plasma exchange (PEX) to deplete pathogenic ANCAs has been recommended but its value has recently been questioned. Because therapeutic decision making is crucial in these critically ill patients, we here aimed to identify inflammatory lesions in association with PEX consideration in a retrospective study from a single center tertiary hospital in a real-world population of 46 patients with severe AAV requiring intensive care treatment. The decision to consider PEX was more likely in patients with need for intensive care treatment and severe renal dysfunction. In contrast, short-term outcomes did not depend on clinical, or laboratory characteristics assessed at admission. Histopathological analysis confirmed active disease reflected by increased glomerular necrosis and crescents, but these histopathological findings did not associate with short-term outcome either. Interestingly, only increased global glomerular sclerosis in renal biopsies associated with a detrimental short-term outcome. In conclusion, our study investigated determinants for the consideration of therapeutic PEX in patients with severe AAV requiring intensive care treatment. This aspect underscores the need for renal biopsy and requires further investigation in a prospective controlled setting for therapeutic decision making especially in patients with severe AAV requiring intensive care treatment, especially important for treating intensivists.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/terapia , Glomerulonefrite/terapia , Troca Plasmática , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/sangue , Estado Terminal , Feminino , Glomerulonefrite/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
17.
Front Immunol ; 12: 681503, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220829

RESUMO

Systemic lupus erythematosus (SLE) is an autoimmune disorder disproportionally affecting women. A similar sex difference exists in the murine New Zealand Black/White hybrid model (NZBWF1) of SLE with all females, but only 30-40% of males, developing disease within the first year of life. Myeloid-derived suppressor cells (MDSCs) are prominent in NZBWF1 males and while depletion of these cells in males, but not females, promotes disease development, the mechanism of suppression remains unknown. S100a9, expressed by neutrophils and MDSCs, has previously been shown to exert immunosuppressive functions in cancer and inflammation. Here we investigated if S100a9 exerts immunosuppressive functions in NZBWF1 male and female mice. S100a9 +/+, S100a9 +/- and S100a9 -/- NZBWF1 mice were followed for disease development for up to 8 months of age. Serum autoantibody levels, splenomegaly, lymphocyte activation, glomerulonephritis and proteinuria were measured longitudinally or at the time of harvest. In accordance with an immunosuppressive function of MDSCs in male mice, S100a9-deficient male NZBWF1 mice developed accelerated autoimmunity as indicated by increased numbers of differentiated effector B and T cells, elevated serum autoantibody levels, increased immune-complex deposition and renal inflammation, and accelerated development of proteinuria. In contrast, female mice showed either no response to S100a9-deficiency or even a slight reduction in disease symptoms. Furthermore, male, but not female, S100a9-/- NZBWF1 mice displayed an elevated type I interferon-induced gene signature, suggesting that S100a9 may dampen a pathogenic type I interferon signal in male mice. Taken together, S100a9 exerts an immunosuppressive function in male NZBWF1 mice effectively moderating lupus-like disease development via inhibition of type I interferon production, lymphocyte activation, autoantibody production and the development of renal disease.


Assuntos
Calgranulina B/genética , Suscetibilidade a Doenças , Lúpus Eritematoso Sistêmico/etiologia , Animais , Autoanticorpos/imunologia , Calgranulina B/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças/imunologia , Expressão Gênica , Predisposição Genética para Doença , Glomerulonefrite/etiologia , Glomerulonefrite/metabolismo , Glomerulonefrite/patologia , Humanos , Imuno-Histoquímica , Imunofenotipagem , Lúpus Eritematoso Sistêmico/metabolismo , Lúpus Eritematoso Sistêmico/patologia , Ativação Linfocitária , Linfócitos/imunologia , Linfócitos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Infiltração de Neutrófilos , Fatores Sexuais , Baço/imunologia , Baço/metabolismo , Baço/patologia
18.
Cesk Patol ; 57(2): 109-112, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34275321

RESUMO

Inflammatory bowel disease (IBD) is a group of chronic relapsing intestinal inflammatory processes primarily represented by ulcerative colitis (UC) and Crohn´s disease (CD). Nearly half of IBD cases are followed by extraintestinal complications and renal involvement can occur independatly or along with other complications and are described with the patients sufferring from UC or CD. Most frequent renal involvement is nephrolithiasis, tubulointerstinal nephritis, different kinds of glomerulonephritis and AA amyloidosis. We are presenting an unusal form of renal involvement of a young female patient with a severe form of Crohn´s disease treated with recombinant monoclonal antibodies.


Assuntos
Colite Ulcerativa , Doença de Crohn , Glomerulonefrite , Doenças Inflamatórias Intestinais , Doença de Crohn/complicações , Feminino , Humanos , Recidiva
19.
Int J Mol Sci ; 22(12)2021 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-34205415

RESUMO

Acute kidney injury (AKI) is a common and severe complication of antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) causing progressive chronic kidney disease (CKD), end-stage renal disease (ESRD) or death. Pathogenic ANCAs, in particular proteinase 3 (PR3) and myeloperoxidase (MPO), trigger a deleterious immune response resulting in pauci-immune necrotizing and crescentic glomerulonephritis (GN), a common manifestation of glomerular injury in AAV. However, there is growing evidence that activation of the complement pathway contributes to the pathogenesis and progression of AAV. We here aimed to compare glomerular and tubulointerstitial lesions in ANCA GN and extrarenal manifestation of AAV in association with levels of circulating complement components C3c and C4. METHODS: Plasma levels of C3c and C4 in a total number of 53 kidney biopsies with ANCA GN were retrospectively included between 2015 and 2020. Glomerular and tubulointerstitial lesions were evaluated according to established scoring systems for ANCA GN and analogous to the Banff classification. RESULTS: We here show that circulating levels of C3c and C4 in ANCA GN were comparable to the majority of other renal pathologies. Furthermore, hypocomplementemia was only detectable in a minor subset of ANCA GN and not correlated with renal or extrarenal AAV manifestations. However, low levels of circulating C3c correlated with AKI severity in ANCA GN independent of systemic disease activity or extrarenal AAV manifestation. By systematic scoring of glomerular and tubulointerstitial lesions, we provide evidence that low levels of circulating C3c and C4 correlated with vasculitis manifestations to distinct renal compartments in ANCA GN. CONCLUSIONS: We here expand our current knowledge about distinct complement components in association with vasculitis manifestations to different renal compartments in ANCA GN. While low levels of C4 correlated with glomerulitis, our observation that low levels of circulating complement component C3c is associated with interstitial vasculitis manifestation reflected by intimal arteritis implicates that C3c contributes to tubulointerstitial injury in ANCA GN.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/sangue , Complemento C3c/metabolismo , Complemento C4/metabolismo , Glomerulonefrite/sangue , Glomérulos Renais/patologia , Túbulos Renais/patologia , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/patologia , Feminino , Glomerulonefrite/imunologia , Glomerulonefrite/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
20.
Clin Immunol ; 229: 108794, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34245915

RESUMO

C3 glomerulopathy (C3G) is a rare renal disease characterized by predominant glomerular C3 staining. Complement alternative pathway dysregulation due to inherited complement defects is associated with C3G. To identify novel C3G-related genes, we screened 86 genes in the complement, coagulation and endothelial systems in 35 C3G patients by targeted genomic enrichment and massively parallel sequencing. Surprisingly, the most frequently mutated gene was VWF. Patients with VWF variants had significantly higher proteinuria levels, higher crescent formation and lower factor H (FH) levels. We further selected two VWF variants to transiently express the von Willebrand factor (vWF) protein, we found that vWF expression from the c.1519A > G variant was significantly reduced. In vitro results further indicated that vWF could regulate complement activation, as it could bind to FH and C3b, act as a cofactor for factor I-mediated cleavage of C3b. Thus, we speculated that vWF might be involved in the pathogenesis of C3G.


Assuntos
Complemento C3/metabolismo , Glomerulonefrite Membranoproliferativa/genética , Glomerulonefrite/genética , Fator de von Willebrand/genética , Adolescente , Adulto , Estudos de Casos e Controles , China , Estudos de Coortes , Complemento C3b/metabolismo , Fator H do Complemento/metabolismo , Via Alternativa do Complemento , Feminino , Variação Genética , Glomerulonefrite/imunologia , Glomerulonefrite/patologia , Glomerulonefrite Membranoproliferativa/imunologia , Glomerulonefrite Membranoproliferativa/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Técnicas In Vitro , Glomérulos Renais/imunologia , Glomérulos Renais/patologia , Masculino , Pessoa de Meia-Idade , Modelos Imunológicos , Simulação de Dinâmica Molecular , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Análise de Sequência de DNA , Adulto Jovem , Fator de von Willebrand/química , Fator de von Willebrand/metabolismo
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