RESUMO
RATIONALE: Immune-mediated vasculitis with 2 or more autoantibodies, for example, anti-proteinase-3, combined with anti-myeloperoxidase (MPO) or anti-glomerular basement membrane (GBM) antibodies, is extremely unusual. Furthermore, the coexistence of autoimmune vasculitis and hematological malignancies is uncommon. Herein, we describe a case of double-seropositive anti-neutrophil cytoplasmic antibody (ANCA) vasculitis with multiple myeloma. PATIENT CONCERNS: A 79-year-old Asian man presented with persistent leg edema and kidney dysfunction. His kidney function rapidly decreased, and serologic test results showed higher titers of the anti-MPO antibody (54.7 IU/mL) and anti-GBM antibodies (>200 IU/mL). Additionally, the clinical features showed the possibility of monoclonal gammopathy with anemia and hyperglobulinemia. We performed kidney and bone marrow biopsy. Serum protein electrophoresis and immunofixation revealed no significant differences, but the results of the bone marrow smear were compatible with those of myeloma with 15% plasmacytosis. However, kidney biopsy showed diffuse crescentic glomerulonephritis without deposition of the immune complex or kappa/lambda chain. DIAGNOSES AND INTERVENTIONS: Finally, the patient was diagnosed with double-seropositive ANCA-associated glomerulonephritis and multiple myeloma. Given the patient's performance status, we initiated low-dose steroid pulse therapy, followed by conservative management. OUTCOMES: While the pulmonary lesions showed improvement, the kidney function did not regain its previous state, prompting the initiation of kidney replacement therapy by hemodialysis. There has been a decrease in the levels of anti-GBM and anti-MPO antibodies since the initial diagnosis. LESSONS: This case elucidates the complex interplay between ANCA-associated glomerulonephritis and hematologic malignancy and emphasizes the need for a nuanced treatment strategy considering its multifaceted clinical presentation.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Autoanticorpos , Mieloma Múltiplo , Peroxidase , Humanos , Mieloma Múltiplo/complicações , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/diagnóstico , Masculino , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/sangue , Peroxidase/imunologia , Autoanticorpos/sangue , Anticorpos Anticitoplasma de Neutrófilos/sangue , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Glomerulonefrite/imunologia , Glomerulonefrite/complicações , Glomerulonefrite/tratamento farmacológicoRESUMO
Cardiotrophin-1 (CT-1), a member of the interleukin (IL)-6 cytokine family, has renoprotective effects in mouse models of acute kidney disease and tubulointerstitial fibrosis, but its role in glomerular disease is unknown. To address this, we used the mouse model of nephrotoxic nephritis to test the hypothesis that CT-1 also has a protective role in immune-mediated glomerular disease. Using immunohistochemistry and analysis of single-cell RNA-sequencing data of isolated glomeruli, we demonstrate that CT-1 is expressed in the glomerulus in male mice, predominantly in parietal epithelial cells and is downregulated in mice with nephrotoxic nephritis. Furthermore, analysis of data from patients revealed that human glomerular disease is also associated with reduced glomerular CT-1 transcript levels. In male mice with nephrotoxic nephritis and established proteinuria, administration of CT-1 resulted in reduced albuminuria, prevented podocyte loss, and sustained plasma creatinine, compared with mice administered saline. CT-1 treatment also reduced fibrosis in the kidney cortex, peri-glomerular macrophage accumulation and the kidney levels of the pro-inflammatory mediator complement component 5a. In conclusion, CT-1 intervention therapy delays the progression of glomerular disease in mice by preserving kidney function and inhibiting renal inflammation and fibrosis.
Assuntos
Citocinas , Glomérulos Renais , Camundongos Endogâmicos C57BL , Animais , Masculino , Citocinas/metabolismo , Citocinas/genética , Camundongos , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Modelos Animais de Doenças , Humanos , Fibrose , Glomerulonefrite/metabolismo , Glomerulonefrite/patologia , Glomerulonefrite/tratamento farmacológicoRESUMO
C3 glomerulopathy is a rare disease, characterized by an abnormal activation of the complement's alternative pathway that leads to the accumulation of the C3 component in the kidney. The disease recurs in more than half of kidney transplant recipients, with a significant impact on graft survival. Recurrence of the primary disease represents the second cause of graft loss after organ rejection. In C3 glomerulopathy, there are several risk factors which can promote a recurrence during transplantation, such as delayed graft function, infection and monoclonal gammopathy. All these events can trigger the alternative complement pathway. In this review, we summarize the impact of C3 glomerulopathy on kidney grafts and present the latest treatment options. The most widely used treatments for the disease include corticosteroids and mycophenolate mofetil, which are already used chronically by kidney transplant recipients; thus, additional treatments for C3 glomerulopathy are required. Currently, several studies using anti-complement drugs (i.e., eculizumab, Ravalizumab, avacopan) for C3 glomerulopathy in kidney transplant patients are ongoing with encouraging results.
Assuntos
Complemento C3 , Transplante de Rim , Humanos , Transplante de Rim/efeitos adversos , Complemento C3/metabolismo , Rejeição de Enxerto/etiologia , Glomerulonefrite/etiologia , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/terapia , Ácido Micofenólico/uso terapêuticoRESUMO
Proliferative glomerulonephritis is a severe condition that often leads to kidney failure. There is a significant lack of effective treatment for these disorders. Here, following the identification of a somatic PIK3CA gain-of-function mutation in podocytes of a patient, we demonstrate using multiple genetically engineered mouse models, single-cell RNA sequencing, and spatial transcriptomics the crucial role played by this pathway for proliferative glomerulonephritis development by promoting podocyte proliferation, dedifferentiation, and inflammation. Additionally, we show that alpelisib, a PI3Kα inhibitor, improves glomerular lesions and kidney function in different mouse models of proliferative glomerulonephritis and lupus nephritis by targeting podocytes. Surprisingly, we determined that pharmacological inhibition of PI3Kα affects B and T lymphocyte populations in lupus nephritis mouse models, with a decrease in the production of proinflammatory cytokines, autoantibodies, and glomerular complement deposition, which are all characteristic features of PI3Kδ inhibition, the primary PI3K isoform expressed in lymphocytes. Importantly, PI3Kα inhibition does not impact lymphocyte function under normal conditions. These findings were then confirmed in human lymphocytes isolated from patients with active lupus nephritis. In conclusion, we demonstrate the major role played by PI3Kα in proliferative glomerulonephritis and show that in this condition, alpelisib acts on both podocytes and the immune system.
Assuntos
Classe I de Fosfatidilinositol 3-Quinases , Modelos Animais de Doenças , Nefrite Lúpica , Podócitos , Animais , Feminino , Humanos , Camundongos , Linfócitos B/imunologia , Linfócitos B/patologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Glomerulonefrite/patologia , Glomerulonefrite/imunologia , Glomerulonefrite/genética , Glomerulonefrite/enzimologia , Glomerulonefrite/tratamento farmacológico , Nefrite Lúpica/patologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/genética , Nefrite Lúpica/enzimologia , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Podócitos/patologia , Podócitos/imunologia , Podócitos/metabolismo , Linfócitos T/imunologia , Linfócitos T/patologia , TiazóisRESUMO
Renal fibrosis plays a key role in the pathogenesis of chronic kidney disease (CKD), in which the persistent high expression of transforming growth factor ß1 (TGF-ß1) and α-smooth muscle actin (α-SMA) contributes to the progression of CKD to renal failure. In order to improve the solubility, bioavailability, and targeting of tanshinone IIA (Tan IIA), a novel targeting material, aminoethyl anisamide-polyethylene glycol-1,2-distearoyl-sn-glycero-3-phosphate ethanolamine (AEAA-PEG-DSPE, APD) modified Tan IIA liposomes (APD-Tan IIA-L) was constructed. An animal model of glomerulonephritis induced by doxorubicin in BALB/c mice was established. APD-Tan IIA-L significantly decreased blood urea nitrogen and serum creatinine (SCr), and the consequences of renal tissue oxidative stress indicators showed that APD-Tan IIA-L downregulated malondialdehyde, upregulated superoxide dismutase, catalase, and glutathione peroxidase. Masson's trichrome staining showed that the deposition of collagen in the APD-Tan IIA-L group decreased significantly. The pro-fibrotic factors (fibronectin, collagen I, TGF-ß1, and α-SMA) and epithelial-mesenchymal transition marker (N-cadherin) were significantly inhibited by APD-Tan IIA-L. By improving the microenvironment of fibrotic kidneys, APD-Tan IIA-L attenuated TGF-ß1-induced excessive proliferation of fibroblasts and alleviated oxidative stress damage to the kidney, providing a new strategy for the clinical treatment of renal fibrosis.
Assuntos
Abietanos , Doxorrubicina , Fibrose , Glomerulonefrite , Rim , Lipossomos , Camundongos Endogâmicos BALB C , Animais , Camundongos , Lipossomos/química , Abietanos/farmacologia , Abietanos/química , Fibrose/tratamento farmacológico , Rim/efeitos dos fármacos , Rim/patologia , Rim/metabolismo , Masculino , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/induzido quimicamente , Glomerulonefrite/patologia , Fator de Crescimento Transformador beta1/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Modelos Animais de Doenças , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/induzido quimicamenteRESUMO
The absence of stimulator of interferon genes (STING) in 129.B6.Fcgr2b-deficient mice rescue lupus phenotypes. The administration of a STING inhibitor (ISD017) into the young 129.B6.Fcgr2b-deficient mice prevents lupus nephritis development. This study mainly aimed to evaluate the effects of STING inhibition (ISD107) on established SLE in mice to prove that ISD017 could be a good therapeutic drug to reverse the already set-up autoimmunity and kidney impairment. Twenty-four-week-old Fcgr2b-deficient mice were treated with cyclophosphamide (25 mg/kg, intraperitoneal, once per week), ISD017 (10 mg/kg, intraperitoneal, three times per week), or control vehicle for 8 weeks, and were analyzed for phenotypes. Both ISD017 and cyclophosphamide treatment increased long-term survival and reduced the severity of glomerulonephritis in Fcgr2b-deficient mice. While cyclophosphamide reduced activated B cells (B220+GL-7+), ISD017 decreased activated T cells (CD4+CD69+) and neutrophils (Ly6c+Ly6g+) in Fcgr2b-deficient mice. In addition, ISD017 reduced IL-1ß and interferon-inducible genes. In summary, ISD017 treatment in symptomatic 129.B6.Fcgr2b-deficient mice reduced the severity of glomerulonephritis and increased long-term survival. ISD017 worked comparably to cyclophosphamide for treating lupus nephritis in 129.B6.Fcgr2b-deficient mice. ISD017 reduced activated T cells and neutrophils, while cyclophosphamide targeted activated B cells. These results suggested that STING inhibitors can potentially be a new therapeutic drug for treating lupus.
Assuntos
Ciclofosfamida , Proteínas de Membrana , Receptores de IgG , Animais , Camundongos , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Linfócitos B/imunologia , Ciclofosfamida/farmacologia , Modelos Animais de Doenças , Glomerulonefrite/tratamento farmacológico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/genética , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/patologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de IgG/genética , Receptores de IgG/metabolismoRESUMO
PURPOSE OF REVIEW: Pauci-immune crescentic glomerulonephritis is the hallmark finding in ANCA-associated vasculitis (AAV) when the kidneys are affected. The rationale for immunosuppression in AAV is based on the underlying autoimmune nature of the disease. Overall remission rates, kidney outcomes, and the burden of disease have greatly improved since the discovery of various immunosuppressive therapies, but relapses remain common, and a significant proportion of patients continue to progress to end-stage kidney disease. Here, we review the role of immunosuppressive therapies for the treatment of pauci-immune crescentic glomerulonephritis. RECENT FINDINGS: Besides the recognized role of B and T cells in the pathogenies of AAV, the focus on the contribution of inflammatory cytokines, neutrophil extracellular traps (NETs), and the complement system allowed the discovery of new therapies. Specifically, the C5a receptor blocker (avacopan) has been approved as a glucocorticoid-sparing agent. Additionally, based on observational data, more clinicians are now using combination therapies during the induction phase. There is also an evolving understanding of the role of plasma exchange in removing ANCA antibodies. Furthermore, the recent development of risk score systems provides physicians with valuable prognostic information that can influence decisions on immunosuppression, although future validation from larger cohorts is needed. The over-activation of various immune pathways plays a significant role in the pathogenesis of pauci-immune crescentic glomerulonephritis in AAV. Immunosuppression is, therefore, an important strategy to halt disease progression and improve overall outcomes. Relapse prevention while minimizing adverse events of immunosuppression is a major long-term goal in AAV management.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Glomerulonefrite , Imunossupressores , Humanos , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Glomerulonefrite/imunologia , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/terapia , Imunossupressores/uso terapêutico , Terapia de Imunossupressão/métodos , Insuficiência Renal/etiologiaRESUMO
OBJECTIVES: Rituximab is being increasingly prescribed for the treatment of autoimmune glomerular diseases. While it is highly effective for some diseases, the response is less predictable for others, which may be due to differing requirements in terms of the dosing according to the disease type and variations concerning exposure to the drug. METHODS: We compiled novel rituximab dosing schedules according to pharmacokinetic analysis of data gathered from rituximab treated patients in a tertiary referral nephrology centre between May 2020 and June 2023. The population-pharmacokinetic analysis was based on the rituximab dosing, the patients' characteristics, rituximab levels and anti-rituximab antibodies. RESULTS: The analysis, which was based on data from 185 patients, clearly highlighted differing rituximab dosing requirements for patients with ANCA associated vasculitis and minimal change disease compared to those with membranous nephropathy, focal-segmental glomerulosclerosis and lupus nephritis. This corresponded to the good treatment response of the first two diseases and the unreliable efficacy for the others. The model predicts the rituximab pharmacokinetics with high degree of accuracy when body weight, proteinuria, type of glomerulonephritis, treatment length and anti-rituximab antibodies formation are used as covariates. We proposed a dosing schedule with shortened dosing intervals for difficult-to-treat diagnoses with high proteinuria. CONCLUSION: In order to ensure reliable and comparable exposure of rituximab with respect to the full range of glomerular diseases, the dosing schedule should be adjusted for membranous nephropathy, focal-segmental glomerulosclerosis and lupus nephritis. This is largely, but not solely, due to the enhanced level of unselective proteinuria in these diseases.
Assuntos
Rituximab , Rituximab/farmacocinética , Rituximab/administração & dosagem , Rituximab/uso terapêutico , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Idoso , Glomerulonefrite/tratamento farmacológico , Modelos Biológicos , Esquema de Medicação , Adulto Jovem , Resultado do Tratamento , Glomerulonefrite Membranosa/tratamento farmacológico , Relação Dose-Resposta a DrogaRESUMO
IgG4-related disease (IgG4-RD) is a chronic systemic inflammatory disease, characterized by tissue infiltration of lymphocytes and IgG4-secreting plasma cells, presenting by fibrosis of different tissues, which is usually responsive only to oral steroids therapy. Kidneys are the most commonly involved organs, exhibiting renal insufficiency, tubulointerstitial nephritis, and glomerulonephritis. Here, we describe a patient with acute renal insufficiency who was presented with edema, weakness, anemia and multiple lymphadenopathies. Kidney and lymph node biopsy showed crescentic glomerulonephritis in kidneys and lymphoplasmacytic infiltration in lymph nodes. After a course of treatment with an intravenous pulse of corticosteroid and cyclophosphamide, the patient's symptoms subsided, and kidney function improved. DOI: 10.52547/ijkd.7788.
Assuntos
Ciclofosfamida , Glomerulonefrite , Doença Relacionada a Imunoglobulina G4 , Humanos , Doença Relacionada a Imunoglobulina G4/complicações , Doença Relacionada a Imunoglobulina G4/tratamento farmacológico , Doença Relacionada a Imunoglobulina G4/diagnóstico , Glomerulonefrite/imunologia , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/diagnóstico , Glomerulonefrite/patologia , Ciclofosfamida/uso terapêutico , Masculino , Linfonodos/patologia , Imunossupressores/uso terapêutico , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/imunologia , Rim/patologia , Biópsia , Imunoglobulina G/sangue , Glucocorticoides/uso terapêutico , Pessoa de Meia-Idade , Resultado do Tratamento , Linfadenopatia/etiologia , Plasmócitos/imunologia , Plasmócitos/patologiaRESUMO
Complement inhibitors have been approved for several immune-mediated diseases and they are considered the next paradigm-shifting approach in the treatment of glomerulonephritis. The hierarchical organization of the complement system offers numerous molecular targets for therapeutic intervention. However, complement is an integral element of host defense and therefore complement inhibition can be associated with serious infectious complications. Here we give a closer look to the hierarchical complement system and how interfering with proximal versus distal or selective versus unselective molecular targets could determine efficacy and safety. Furthermore, we propose to consider the type of disease, immunological activity, and patient immunocompetence when stratifying patients, e.g., proximal/unselective targets for highly active and potentially fatal diseases while distal and selective targets may suit more chronic disease conditions with low or moderate disease activity requiring persistent complement blockade in patients with concomitant immunodeficiency. Certainly, there exists substantial promise for anti-complement therapeutics. However, balancing efficacy and safety will be key to establish powerful treatment effects with minimal adverse events, especially when complement blockade is continued over longer periods of time in chronic disorders.
Assuntos
Ativação do Complemento , Inativadores do Complemento , Proteínas do Sistema Complemento , Humanos , Inativadores do Complemento/uso terapêutico , Inativadores do Complemento/efeitos adversos , Proteínas do Sistema Complemento/imunologia , Proteínas do Sistema Complemento/metabolismo , Ativação do Complemento/efeitos dos fármacos , Animais , Resultado do Tratamento , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/imunologiaRESUMO
Post-infectious glomerulonephritis (PIGN), an uncommon variety of glomerulonephritis (GN), is characterized by emergence of nephritic syndrome within a few weeks following an infectious event. PIGN typically presents as a mild condition and tends to resolve by the time of diagnosis for GN. Aggregatibacter actinomycetemcomitans belongs to the HACEK group of bacteria, which constitutes less than 3% of bacteria responsible for community-acquired infective endocarditis. We present a case of 29-year-old man suspected of lymphoma with B-symptoms along with severe splenomegaly and nephromegaly. Shortly after, he developed an episode of nephritic syndrome accompanied by acute kidney injury (AKI) and high titers of cytoplasmic ANCA (c-ANCA)-positivity. Kidney biopsy revealed PIGN with tubulointerstitial nephritis. Despite treatment with antibiotics and corticosteroid, he visited the emergency room due to worsening dyspnea and multi-organ failure. An echocardiogram showed a bicuspid aortic valve with vegetation unseen on previous echocardiogram. He underwent aortic valve replacement immediately without adverse events. Four months after valve replacement, his renal function and cardiac performance have remained stable. We report a case of PIGN with AKI and high titers of c-ANCA appearing later as an infective endocarditis due to Aggregatibacter actinomycetemcomitans. With careful clinical observation and appropriate and timely management, satisfactory outcomes for patient health are possible.
Assuntos
Aggregatibacter actinomycetemcomitans , Anticorpos Anticitoplasma de Neutrófilos , Endocardite Bacteriana , Glomerulonefrite , Humanos , Masculino , Adulto , Anticorpos Anticitoplasma de Neutrófilos/sangue , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Endocardite Bacteriana/diagnóstico , Endocardite Bacteriana/microbiologia , Endocardite Bacteriana/imunologia , Endocardite Bacteriana/complicações , Endocardite Bacteriana/tratamento farmacológico , Glomerulonefrite/imunologia , Glomerulonefrite/microbiologia , Glomerulonefrite/diagnóstico , Glomerulonefrite/etiologia , Glomerulonefrite/tratamento farmacológico , Aggregatibacter actinomycetemcomitans/isolamento & purificação , Aggregatibacter actinomycetemcomitans/imunologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/imunologia , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/microbiologia , Infecções por Pasteurellaceae/diagnóstico , Infecções por Pasteurellaceae/microbiologia , Resultado do Tratamento , Implante de Prótese de Valva Cardíaca , Biópsia , Antibacterianos/uso terapêutico , Biomarcadores/sangue , Nefrite Intersticial/imunologia , Nefrite Intersticial/diagnóstico , Nefrite Intersticial/microbiologia , Nefrite Intersticial/etiologia , Nefrite Intersticial/tratamento farmacológicoRESUMO
Crescentic glomerulonephritis has been associated with several solid tumour malignancies. Only a few cases of nephropathy have been reported in association with tubo-ovarian/peritoneal malignancies. We report a 55-year-old female patient who presented to a tertiary care centre, Muscat, Oman, in 2022. She developed combined immune complex-mediated glomerulonephritis and pauci-immune necrotising crescentic vasculitis simultaneously with the diagnosis of tubo-ovarian/peritoneal cancer. The baseline estimated glomerular filtration rate (eGFR) was 13 mL/min. The patient received two doses of rituximab and three doses of pulse corticosteroids, leading to significant improvement in renal function and the disappearance of her proteinuria. The eGFR improved to >60mL/min; her proteinuria gradually resolved after 10 weeks of treatment. She was then given a combination chemotherapy treatment for tubo-ovarian/peritoneal cancer leading to a normalisation of her CA-125 after three months of therapy.
Assuntos
Carcinoma , Glomerulonefrite , Feminino , Humanos , Pessoa de Meia-Idade , Pacientes , Glomerulonefrite/tratamento farmacológico , Antígeno Ca-125 , ProteinúriaRESUMO
OBJECTIVES: Several therapeutic agents have been developed and used for the clinical treatment of systemic lupus erythematosus (SLE). In cases where SLE is accompanied by severe organ failures, such as neuropsychiatric lupus erythematosus (NPSLE) and acute onset of lupus nephritis, the use of potent immunosuppressive drugs, such as cyclophosphamide, is necessary. However, potent immunosuppressive drugs are known to increase infection risks. Thus, the development of therapeutic agents with novel mechanisms is urgently required. Previously, we reported that treatment with lysophosphatidic acid (LPA) prevents depression-like behaviours by suppressing microglial activation in MRL/lpr mice. In this study, we examined whether the treatment with LPA improves glomerulonephritis by affecting systemic immunity in MRL/lpr mice. METHODS: Eighteen-week-old MRL/lpr mice were treated with a vehicle or LPA for 3 weeks. After treatment, the glomerular inflammation and damage parameters were compared between the 2 groups. Moreover, we examined the effects of LPA on immune cells by flow cytometry using isolated splenocytes. RESULTS: LPA treatment in MRL/lpr mice significantly reduced the daily urinary albumin content and suppressed the CD68-positive cells and Periodic acid-Schiff (PAS)-positive areas in the glomeruli. The treatment also suppressed plasma anti-dsDNA antibodies and inflammatory cytokines in MRL/lpr mice. Although LPA did not significantly affect the total number of splenocytes, the treatment significantly reduced CD11b+Ly6G-Ly6C- cells (mature macrophages), as well as CD11b+Ly6G-Ly6C-CD68+ cells (activated mature macrophages). CONCLUSIONS: These results suggest that LPA may improve glomerulonephritis by suppressing macrophage activation in MRL/lpr mice.
Assuntos
Glomerulonefrite , Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Lisofosfolipídeos , Animais , Camundongos , Modelos Animais de Doenças , Ativação de Macrófagos , Camundongos Endogâmicos MRL lpr , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/prevenção & controle , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/prevenção & controle , Imunossupressores/farmacologia , Imunossupressores/uso terapêuticoRESUMO
The concept of infection-related glomerulonephritis (IRGN) has been introduced as adults diagnosed with glomerulonephritis often have coexisting active infections. Furthermore, IgA-dominant IRGN is associated with staphylococcal infections in adults with comorbidities, which often progress to end-stage renal disease. Little is known about IgA-dominant IRGN in children, and no consensus for a management strategy of this condition has been reached. We describe the case of a 9-year-old boy with IgA-dominant IRGN that was diagnosed using specific staining for nephritis-associated plasmin receptor (NAPlr)/plasmin activity and galactose-deficient IgA1 (Gd-IgA1), a marker of IgA nephropathy. The patient was successfully treated using a combination of prednisolone, mizoribine (an immunosuppressive drug), and lisinopril (an angiotensin-converting enzyme inhibitor) and three courses of methylprednisolone pulse therapy. The patient was admitted to our hospital with generalized edema, gross hematuria, proteinuria, hypertension, and renal dysfunction. Hypocomplementemia contributed to a diagnosis of IRGN, although the causative organism was unknown. A renal biopsy performed when the patient presented with nephrotic syndrome showed IgA deposition, positive staining for NAPlr, and negative staining for Gd-IgA1, in addition to findings consistent with IRGN, leading to a pathologic diagnosis of IgA-dominant IRGN. The histological staining for NAPlr/plasmin activity and Gd-IgA1, together with clinical symptoms, could be helpful for diagnosing IgA-dominant IRGN. Our findings indicate that otherwise healthy children can also develop IgA-dominant IRGN. Therefore, early diagnosis and aggressive treatment should be considered when IgA-dominant IRGN is suspected to avoid the possibility of incomplete recovery of renal function.
Assuntos
Imunoglobulina A , Humanos , Masculino , Criança , Imunoglobulina A/sangue , Glomerulonefrite por IGA/complicações , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/complicações , Glomerulonefrite/diagnósticoRESUMO
In 2021, the Kidney Disease: Improving Global Outcomes (KDIGO) Guideline for the Management of Glomerular Diseases was published. KDIGO is committed to providing the nephrology community with periodic updates, based on new developments for each disease. For patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), avacopan received regulatory approval in late 2021, leading to this KDIGO guideline update. In addition, the evidence supporting a lower-dose glucocorticoid induction regimen or even complete replacement of glucocorticoids has become stronger. Herein, an executive summary of the most important guideline changes from the AAV chapter is provided as a quick reference.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Glomerulonefrite , Nefrologia , Humanos , Glomerulonefrite/diagnóstico , Glomerulonefrite/tratamento farmacológico , Rim , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Anticorpos Anticitoplasma de Neutrófilos , Glucocorticoides/uso terapêuticoRESUMO
INTRODUCTION: Pauci-immune crescentic glomerulonephritis (GN) is the most common cause of rapidly progressive GN in adults. The aim of this study was to determine the outcome of patients with pauci-immune crescentic GN and risk factors of the development of end-stage kidney disease (ESKD) in these patients. METHODS: This case series study was carried on 120 patients with pauci-immune crescentic GN biopsied in our center betwen 1998 and 2016. Inclusion criteria were age > 16 years, at least one crescentic glomerulus, maximally 1+ deposition of immunoglobulins and complement components at fluorescent microscopy, and at least 6 months follow-up. The main outcomes were ESKD and death. RESULTS: The study population included 120 patients with pauciimmune crescentic GN (mean age was 47 ± 17 years and 49.1% male). There was no significant difference in outcome between patients with diffuse or focal crescentic GN. Seventy-two patients (60%) developed ESKD and 31 patients (25.8%) died. The need for dialysis at admission, lower baseline hemoglobin and GFR and GFR at four months and high percentage of glomerulosclerosis and interstitial fibrosis had a significant relationship with low kidney survival (P < .05). The rate of ESKD was higher in patients who did not receive cyclophosphamide therapy, due to focal crescentic GN or high chronicity, compared to patients who received it (70.7 vs. 28.5%, P < .001). CONCLUSION: In our study, a high percentage of patients with pauciimmune crescentic GN developed ESKD. Low first GFR and high chronicity in biopsy were associated with lower kidney survival. Failure to administer cyclophosphamide in seemingly limited or advanced cases, together with late referral may have led to poor prognosis. DOI: 10.52547/ijkd.7545.
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Glomerulonefrite Membranoproliferativa , Glomerulonefrite , Falência Renal Crônica , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Adolescente , Feminino , Glomerulonefrite/tratamento farmacológico , Prognóstico , Rim/patologia , Glomérulos Renais/patologia , Falência Renal Crônica/complicações , Doença Aguda , Ciclofosfamida/uso terapêutico , Biópsia/efeitos adversosRESUMO
Glomerulonephritis (GN) is the most common cause of end-stage renal failure worldwide; in most cases, it cannot be cured and can only delay the progression of the disease. At present, the main treatment methods include symptomatic therapy, immunosuppressive therapy, and renal replacement therapy. However, effective treatment of GN is hindered by issues such as steroid resistance, serious side effects, low bioavailability, and lack of precise targeting. With the widespread application of nanoparticles in medical treatment, novel methods have emerged for the treatment of kidney diseases. Targeted transportation of drugs, nucleic acids, and other substances to kidney tissues and even kidney cells through nanodrug delivery systems can reduce the systemic effects and adverse reactions of drugs and improve treatment effectiveness. The high specificity of nanoparticles enables them to bind to ion channels and block or enhance channel gating, thus improving inflammation. This review briefly introduces the characteristics of GN, describes the treatment status of GN, systematically summarizes the research achievements of nanoparticles in the treatment of primary GN, diabetic nephropathy and lupus nephritis, analyzes recent therapeutic developments, and outlines promising research directions, such as gas signaling molecule nanodrug delivery systems and ultrasmall nanoparticles. The current application of nanoparticles in GN is summarized to provide a reference for better treatment of GN in the future.
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Nefropatias Diabéticas , Glomerulonefrite , Nefrite Lúpica , Humanos , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/metabolismo , Rim/metabolismo , NanotecnologiaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Qiteng Xiaozhuo Granules (QTXZG), a traditional Chinese medicine prescription, is widely acknowledged for its therapeutic efficacy and lack of discernible toxicity in clinical practice, substantiating its potential in the treatment of chronic glomerulonephritis (CGN). Nevertheless, the specific effectiveness and underlying mechanisms of QTXZG remain insufficiently explored. AIM OF THE STUDY: The purpose of this study was to explore the mechanism of the QTXZG in the treatment of CGN via targeting autophagy based on serum pharmacochemistry, network pharmacology, and experimental validation. METHODS: Serum samples from SD rats orally administered QTXZG were analyzed using UPLC-QE/MS to identify contained compounds. Network and functional enrichment analyses elucidated QTXZG's targets and biological mechanisms. Reliability was ensured through molecular docking, in vivo and in vitro experiments. RESULTS: After oral administration of QTXZG, 39 enriched compounds in serum samples collected 1 h later were identified as potential active agents, with 508 potential targets recognized as QTXZG-specific targets. Through integration of various databases, intersection analysis of QTXZG targets, CGN-related genes, and autophagy-related targets identified 10 core autophagy-related targets for QTXZG in CGN. GO and KEGG analyses emphasized their roles in autophagy, inflammation, and immune processes, particularly emphasizing the enrichment of the AMPK/mTOR signaling pathway. Molecular docking results demonstrated strong binding affinities between QTXZG's key compounds and the predicted core targets. In animal experiments, QTXZG was found to ameliorate renal tissue damage in CGN model mice, significantly reducing serum creatinine (Scr) and blood urea nitrogen (BUN) levels. Importantly, both animal and cell experiments revealed QTXZG's ability to decrease excessive ROS and inflammatory factor release in mesangial cells. Furthermore, in vitro and in vivo experiments confirmed QTXZG's capacity to upregulate Beclin1 and LC3II/I expression, decrease p62 expression, and induce CGN autophagy through modulation of the AMPK/mTOR pathway. CONCLUSIONS: This study indicated that QTXZG can induce autophagy in CGN by affecting the AMPK/mTOR pathway, and induction of autophagy may be one of the possible mechanisms of QTXZG's anti-CGN.
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Medicamentos de Ervas Chinesas , Glomerulonefrite , Animais , Camundongos , Ratos , Ratos Sprague-Dawley , Farmacologia em Rede , Proteínas Quinases Ativadas por AMP , Simulação de Acoplamento Molecular , Reprodutibilidade dos Testes , Glomerulonefrite/tratamento farmacológico , Autofagia , Doença Crônica , Serina-Treonina Quinases TOR , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêuticoRESUMO
A Japanese female in her twenties developed general edema with heavy proteinuria, and was referred to our hospital. She exhibited the common clinical manifestation of idiopathic nephrotic syndrome with massive proteinuria (20.37 g/day), hypoalbuminemia (1.8 g/dL), and hypercholesterolemia (300 mg/dL). Routine admission tests were positive results for both the rapid plasma reagin latex agglutination test for syphilis (RPR) and the Treponema pallidum particle agglutination assay (TPHA). As such, we made her a diagnosis of nephrotic syndrome due to secondary syphilis. Renal biopsy revealed "full-house" nephropathy. Following the commencement of penicillin treatment, she developed skin rash, indicating the Jarisch-Herxheimer reaction (JHR). Her nephrotic syndrome responded rapidly and she achieved complete remission with antibiotic therapy alone after 4 weeks. In light of the increasing incidence of syphilis in Japan, clinicians should consider syphilis as a reversible cause of nephrotic syndrome.