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BACKGROUND: IgA nephropathy (IgAN) and IgA vasculitis with nephritis (IgAVN) are related glomerular diseases characterized by marked similarities in immunological and histological findings. We herein performed a comparative proteomic analysis of glomerular proteins in IgAN and IgAVN. METHODS: We used renal biopsy specimens from 6 IgAN patients without nephrotic syndrome (NS) (IgAN-I subgroup), 6 IgAN patients with NS (IgAN-II subgroup), 6 IgAVN patients with 0-8.0% of glomeruli with crescent formation (IgAVN-I subgroup), 6 IgAVN patients with 21.2-44.8% of glomeruli with crescent formation (IgAVN-II subgroup), 9 IgAVN patients without NS (IgAVN-III subgroup), 3 IgAVN patients with NS (IgAN-IV subgroup), and 5 control cases. Proteins were extracted from laser microdissected glomeruli and analyzed using mass spectrometry. The relative abundance of proteins was compared between groups. An immunohistochemical validation study was also performed. RESULTS: More than 850 proteins with high confidence were identified. A principal component analysis revealed a clear separation between IgAN and IgAVN patients and control cases. In further analyses, 546 proteins that were matched with ≥ 2 peptides were selected. The levels of immunoglobulins (IgA, IgG, and IgM), complements (C3, C4A, C5, and C9), complement factor H-related proteins (CFHR) 1 and 5, vitronectin, fibrinogen chains, and transforming growth factor-ß inducible gene-h3 were higher (> 2.6 fold) in the IgAN and IgAVN subgroups than in the control group, whereas hornerin levels were lower (< 0.3 fold). Furthermore, C9 and CFHR1 levels were significantly higher in the IgAN group than in the IgAVN group. The abundance of some podocyte-associated proteins and glomerular basement membrane (GBM) proteins was significantly less in the IgAN-II subgroup than in the IgAN-I subgroup as well as in the IgAVN-IV subgroup than in the IgAVN-III subgroup. Among the IgAN and IgAVN subgroups, talin 1 was not detected in the IgAN-II subgroup. This result was supported by immunohistochemical findings. CONCLUSIONS: The present results suggest shared molecular mechanisms for glomerular injury in IgAN and IgAVN, except for enhanced glomerular complement activation in IgAN. Differences in the protein abundance of podocyte-associated and GBM proteins between IgAN and IgAVN patients with and without NS may be associated with the severity of proteinuria.
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Monoclonal immunoglobulin (MIg)-associated glomerular diseases with non-organized deposits are rare disorders. They have recently been categorized into light chain deposit disease (LCDD), light and heavy chain deposit disease (LHCDD), heavy chain deposit disease (HCDD), proliferative glomerulonephritis with MIg deposits (PGNMID) and its light chain only variant (PGNMID-LC), and membranous glomerulopathy with light chain-restricted deposits (MG-LC). In our Japanese cohort of more than 9,500 patients who underwent renal biopsy (1979 - 2020), we evaluated clinicopathological features and long-term outcomes in 38 patients with MIg-associated glomerular diseases with non-organized deposits: LCDD (n = 9), LHCDD (n = 8), HCDD (n = 5), PGNMID-membranoproliferative glomerulonephritis (MPGN) (n = 7), PGNMID-LC (n = 2), and MG-LC (n = 7). In patients with LCDD, a low estimated glomerular filtration rate (eGFR) at biopsy, a high detection rate of urinary MIgs, a high incidence rate of multiple myeloma, and sever tubulointerstitial and vascular lesions were significant clinicopathological characteristics. Median duration of follow-up in each group was 42 - 114 months. Most patients were treated with steroid-based therapy. Patients with LCDD, LHCDD, HCDD, and MG-LC were recently treated with bortezomib-based therapy. Renal survival rate was significantly shorter for LCDD than of PGNMID and MG-LC. Patient survival rate was significantly longer for MG-LC than HCDD and PGNMID. Major causes of death were pulmonary and cardiovascular complications. Among disease groups, significant differences were observed in eGFR at biopsy, detection rates of urinary MIgs, incidence rates of multiple myeloma, severities of tubulointerstitial and vascular lesions, and long-term outcomes.
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Glomerulonefritis Membranoproliferativa , Glomerulonefritis , Enfermedades Renales , Mieloma Múltiple , Bortezomib , Glomerulonefritis/complicaciones , Glomerulonefritis/diagnóstico , Glomerulonefritis/tratamiento farmacológico , Glomerulonefritis Membranoproliferativa/patología , Humanos , Japón/epidemiología , Enfermedades Renales/patología , Mieloma Múltiple/complicaciones , Dibenzodioxinas Policloradas , Pronóstico , EsteroidesRESUMEN
BACKGROUND: We determined the usefulness and prognostic ability of the renal risk score (RRS), proposed in Europe, for Japanese patients with antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (AAGN) and high myeloperoxidase (MPO)-ANCA positivity; these aspects remain to be verified. METHODS: This retrospective study was conducted on 86 Japanese patients with new, biopsy-confirmed AAGN. We calculated the RRS and analyzed the relationship between this classification, and clinicopathological features and prognosis. We also compared the predictive values between RRS for endpoints including renal death and conventional prognostic tools for patients with AAGN. RESULTS: There were 33, 37, and 16 patients in the low-, medium-, and high-risk groups, respectively. All patients were MPO-ANCA positive. The median follow-up period was 33 months; 16 (18.6%) patients progressed to end-stage renal disease (ESRD). In the high-risk group, 9/16 (56.3%) patients progressed to ESRD, and renal prognosis was significantly poorer than that in other groups (low-risk group, P < 0.001; medium-risk group, P = 0.004). In Cox multivariate regression analysis, RRS was an independent, poor renal prognostic factor (hazard ratio 5.22; 95% confidence interval 2.20-12.40; P < 0.001). The receiver-operating characteristic curves of the RRS for each endpoint were comparable with those of the 2010 histological classification and those of the severity classification of Japanese rapidly progressive glomerulonephritis. CONCLUSIONS: This is the first study to report the usefulness of the RRS for predicting renal outcomes among Japanese patients with AAGN. Our predictive value of the RRS was comparable with that of conventional prognostic tools.
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Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Glomerulonefritis , Fallo Renal Crónico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/complicaciones , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/diagnóstico , Anticuerpos Anticitoplasma de Neutrófilos , Glomerulonefritis/patología , Humanos , Japón/epidemiología , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/etiología , Pronóstico , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: The prognostic significance of glomerular extracapillary hypercellularity (EXHC) in diabetic kidney disease (DKD) is unclear. The aim of this study was to investigate the clinicopathological features and outcomes of DKD patients with EXHC. METHODS: We studied 70 cases of renal biopsy-confirmed type 2 DKD that were diagnosed between 2004 and 2014 and compared the clinicopathological features and outcomes of 22 patients with EXHC (EXHC group) with those of 48 patients without EXHC (control group). All of the patients were Japanese. We assessed the renal biopsy specimens based on the Renal Pathology Society classification system. Clinical and laboratory data were collected at the time of the renal biopsy, and renal outcomes were assessed based on progression to end-stage renal disease (ESRD) requiring renal replacement therapy. The median duration of the observation period was 3 years. RESULTS: In pathological features, nodular sclerosis (Kimmelstiel-Wilson lesions) was observed more frequently in the EXHC group than in the control group (63.6% vs. 35.4%, P = 0.027). There were no significant intergroup differences in clinical features or renal outcomes. Univariate and multivariate Cox regression analyses of all patients showed that a high level of proteinuria, a low initial eGFR, and severe interstitial inflammation were poor prognostic factors. CONCLUSIONS: EXHC is related to nodular sclerosis, which is a known risk factor for ESRD. Careful observation is needed during the follow-up of DKD patients with EXHC, although there were no significant differences in renal outcomes between the EXHC and control groups.
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Nefropatías Diabéticas/patología , Membrana Basal Glomerular/patología , Mesangio Glomerular/patología , Fallo Renal Crónico/fisiopatología , Adulto , Anciano , Anciano de 80 o más Años , Nefropatías Diabéticas/complicaciones , Progresión de la Enfermedad , Femenino , Tasa de Filtración Glomerular , Humanos , Japón , Fallo Renal Crónico/etiología , Fallo Renal Crónico/terapia , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Nefritis/etiología , Pronóstico , Proteinuria/etiología , EsclerosisRESUMEN
BACKGROUND: High-IgA ddY (HIGA) mice, an animal model of human IgA nephropathy (IgAN), spontaneously develop nephropathy with glomerular IgA deposition and markedly elevated serum IgA levels from 25 weeks of age. METHODS: We performed a comparative proteomic analysis of the renal proteins collected from HIGA mice and control C57BL/6 mice at 5 or 38 weeks of age (the H5, H38, C5, and C38 groups) (n = 4 in each group). Proteins were extracted from the left whole kidney of each mouse and analyzed using nano-liquid chromatography-tandem mass spectrometry. The right kidneys were used for histopathological examinations. RESULTS: Immunohistochemical examinations showed glomerular deposition of IgA and the immunoglobulin joining (J) chain, and increased numbers of interstitial IgA- and J-chain-positive plasma cells in the H38 group. In the proteomic analysis, > 5000 proteins were identified, and 33 proteins with H38/H5 ratios of > 5.0, H38/C38 ratios of > 5.0, and C38/C5 ratios of < 1.5 were selected. Among them, there were various proteins that are known to be involved in human IgAN and/or animal IgAN models. Immunohistochemical examinations validated the proteomic results for some proteins. Furthermore, two proteins that are known to be associated with kidney disease displayed downregulated expression (H38/H5 ratio: 0.01) in the H38 group. CONCLUSIONS: The results of comparative proteomic analysis of renal proteins were consistent with previous histopathological and serological findings obtained in ddY and HIGA mice. Various proteins that are known to be involved in kidney disease, including IgAN, and potential disease marker proteins exhibited markedly altered levels in HIGA mice.
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Glomerulonefritis por IGA/metabolismo , Riñón/metabolismo , Proteoma , Animales , Estudios de Casos y Controles , Creatinina/sangre , Modelos Animales de Enfermedad , Femenino , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Three recent studies from the United States and China reported the clinicopathological features and short-term prognosis in patients with membranous nephropathy (MN) and crescents in the absence of secondary MN, anti-glomerular basement membrane (GBM) antibodies, and anti-neutrophil cytoplasmic antibodies (ANCA). METHODS: We compared clinicopathological and prognostic features in 16 MN patients with crescents (crescent group) and 38 MN patients without crescents (control group), in the absence of secondary MN, anti-GBM antibodies, and ANCA. Median follow-up periods in the crescent and control groups were 79 and 50 months, respectively. RESULTS: Decreased estimated glomerular filtration rates (<50 mL/min/1.73 m2), glomerulosclerosis, and moderate-to-severe interstitial fibrosis were more frequently observed in the crescent group than in the control group (P = 0.043, P = 0.004, and P = 0.035, respectively). Positive staining rates for glomerular IgG2 and IgG4 were significantly different between the 2 groups (P = 0.032, P = 0.006, respectively). Doubling of serum creatinine during follow-up was more frequently observed in the crescent group than in the control group (P = 0.002), although approximately two-thirds of patients in the crescent group were treated with immunosuppressive therapy. Crescent formation and interstitial fibrosis were risks for doubling of serum creatinine [hazard ratio (HR) = 10.506, P = 0.012; HR = 1.140, P = 0.009, respectively]. CONCLUSIONS: This is the first Japanese study demonstrating significant differences in clinicopathological and prognostic features between the 2 groups. Most patients in the crescent group may develop a long-term decline in renal function despite immunosuppressive therapy.
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Glomerulonefritis Membranosa , Riñón , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Anticitoplasma de Neutrófilos/sangre , Autoanticuerpos/sangre , Biomarcadores/sangre , Estudios de Casos y Controles , Creatinina/sangre , Progresión de la Enfermedad , Femenino , Fibrosis , Tasa de Filtración Glomerular , Glomerulonefritis Membranosa/sangre , Glomerulonefritis Membranosa/diagnóstico , Glomerulonefritis Membranosa/tratamiento farmacológico , Glomerulonefritis Membranosa/fisiopatología , Humanos , Inmunosupresores/uso terapéutico , Japón , Estimación de Kaplan-Meier , Riñón/efectos de los fármacos , Riñón/inmunología , Riñón/patología , Riñón/fisiopatología , Masculino , Persona de Mediana Edad , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
Mucosal immunity may play a key role in IgA nephropathy (IgAN) and IgA vasculitis with nephritis (IgAVN). IgAVN is characterized by the presence of non-thrombocytopenic palpable purpura, associated with glomerulonephritis with IgA-dominant immune deposits. Recent studies have shown the up-regulation of Toll-like receptors (TLRs) in patients with IgAN or IgAVN. Among TLRs that mediate innate immune reactions, TLR2, TLR4, and TRL5 recognize bacterial components, while TLR3, TLR7, and TLR9 recognize viral components. Here we compared the expression levels of TLR mRNAs in peripheral blood mononuclear cells (PBMCs) from 49 IgAN patients, 20 IgAVN patients, and 20 patients with thin basement membrane nephropathy (TBMN), unrelated to immune-mediated pathogenesis, as a control. The real-time RT-PCR analysis revealed the significantly higher expression levels of TLR2, TLR3, TLR5, TLR7, and TLR9 mRNAs in PBMCs of IgAN and IgAVN patients, compared to TBMN patients. Importantly, TLR4 mRNA levels were significantly higher in IgAN patients than in IgAVN patients, while its expression levels were comparable in IgAVN patients and TBMN patients. In contrast, TLR5 and TLR9 mRNA levels were significantly higher in IgAVN patients than in IgAN patients. In IgAN patients, expression levels of TLR2, TLR3, TLR5, or TLR9 mRNA were correlated with proteinuria levels, and TLR4 mRNA levels were correlated with serum IgA levels. In IgAVN patients, however, there was no such correlation. The up-regulated expression of TLR mRNAs in PBMCs may be related to the development of IgAN and IgAVN. The distinct expression patterns between these two diseases may reflect their different pathogenetic mechanisms.
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Regulación de la Expresión Génica , Glomerulonefritis por IGA/complicaciones , Glomerulonefritis por IGA/genética , Leucocitos Mononucleares/metabolismo , Receptores Toll-Like/genética , Vasculitis/complicaciones , Vasculitis/genética , Adulto , Femenino , Humanos , Interferón-alfa/genética , Interferón-alfa/metabolismo , Masculino , Persona de Mediana Edad , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores Toll-Like/metabolismoRESUMEN
We have been studying an easy bracket debonding method using heating of an orthodontic adhesive containing thermal expansion microcapsules. However, heating with a high-temperature heater brings obvious risks of burns around the oral cavity. Thus, we examined safer and more effective bracket debonding methods. The purpose of this in vitro study was to examine the reduction in debonding strength and the time taken using a bracket bonded with an orthodontic adhesive containing thermal expansion microcapsules and a CO2 laser as the heating method while maintaining safety. Ceramic brackets were bonded to bovine permanent mandibular incisors using bonding materials containing various microcapsule contents (0, 30, and 40 wt%), and the bond strengths were measured after laser irradiation for 4, 5, and 6 s and compared with nonlaser-treated groups. Subsequently, the temperature in the pulp chamber during laser irradiation was measured. After laser irradiation for 5 or 6 s, the bond strengths of the adhesive containing 40 wt% microcapsules were significantly decreased to â¼0.40 - 0.48-fold (4.6-5.5 MPa) compared with the nonlaser groups. The mean temperature rise of the pulp chamber was 4.3 °C with laser irradiation for 6 s, which was less than that required to induce pulp damage. Based on these results, we conclude that the combined use of a CO2 laser and an orthodontic adhesive containing thermal expansion microcapsules can be effective and safe for debonding ceramic brackets with less enamel damage or tooth pain.
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Recubrimiento Dental Adhesivo/métodos , Cementos Dentales/farmacología , Desconsolidación Dental/métodos , Porcelana Dental/farmacología , Calor , Láseres de Gas , Soportes Ortodóncicos , Animales , Cápsulas , Bovinos , Pulpa Dental/efectos de los fármacos , Pulpa Dental/efectos de la radiación , Resistencia al Corte , Factores de TiempoRESUMEN
Epstein-Barr virus (EBV) can rarely induce smooth muscle tumors (SMTs). A 20-year-old female patient underwent kidney transplantation for renal failure. Since then, she has been treated with immunosuppressants, including a calcineurin inhibitor, tacrolimus, and prednisolone, owing to the immunological rejection. Three years later, she developed large liver tumors (diameter >5 cm) and multiple small lung tumors that were identified as EBV-SMTs based on the results of liver biopsy/histopathology. No intervention was performed except for the addition of a mammalian target of the rapamycin inhibitor, everolimus, which inhibits both immune reaction and SMT growth. Finally, after 8 years, the transplanted kidney became nonfunctional, and immunosuppressant administration became unnecessary as urinary dialysis was started. Under these circumstances, SMT growth was observed despite the absence of immunosuppressant administration. Three months after the cessation of the immunosuppressants, EBV-SMTs in the liver and lungs shrank slightly. To the best of our knowledge, this is the first report on the genomic profile of this rare tumor. The clinical course of our patient indicates that EBV can induce SMTs, and immunological suppression of EBV may inhibit the activity of these tumors.
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Although the polymerization reaction in light-cured orthodontic adhesive continues for some time after light irradiation, it is unclear whether insufficiently irradiated adhesive develops sufficient bond strength. This in vitro study examined the maturation of bond strength after exposure of a variety of light doses. Large metal brackets were bonded to the enamel of 288 bovine mandibular incisors by irradiation at two light intensities (200 and 400 mW/cm(2)) and for three exposure times (3, 5, and 10 seconds) using three orthodontic adhesives (TB, OP, and BOB). Shear bond strengths and adhesive remnant indices (ARIs) were determined immediately (T1) and 24 hours after bonding (T2; n = 8 in each group). Comparisons were made using the Kruskal-Wallis H-test, the Bonferroni-corrected Mann-Whitney U-test, and the Yates-corrected chi-square test. Bond strengths of the adhesives that showed maturation at low light intensity (200 mW/cm(2)) increased by 1.4- to 2.0-fold in 24 hours. An increase in exposure time increased bond strength more than did an increase in light intensity for most orthodontic adhesives. With an exposure time of 3 seconds at 200 mW/cm(2), the ARI scores of TB and OP differed significantly between T1 and T2. Thus, the most acceptable procedure when applying low-dose light intensity to a bracket before the placement of a wire is to increase the exposure time and/or wait for sufficient maturation of bond strength.
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Recubrimiento Dental Adhesivo/métodos , Cementos Dentales/efectos de la radiación , Curación por Luz de Adhesivos Dentales/métodos , Soportes Ortodóncicos , Animales , Bovinos , Distribución de Chi-Cuadrado , Cementos Dentales/química , Luz , Ensayo de Materiales , Polimerizacion/efectos de la radiación , Estadísticas no ParamétricasRESUMEN
A 28-year-old woman exhibited a spiking fever, arthritis, and liver disfunction when she was 22 weeks pregnant. She was diagnosed with adult-onset Still's disease (AOSD). As her condition was resistant to corticosteroid therapy, tocilizumab (TCZ) was selected. The TCZ treatment was effective, and she delivered a healthy child while receiving TCZ treatment. Cases in which AOSD first arises during pregnancy are rare, and there have been no reports of TCZ treatment for AOSD being initiated during pregnancy. Although the safety of TCZ treatment during pregnancy has not been established, it may be effective against severe AOSD that develops during pregnancy.
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Anticuerpos Monoclonales Humanizados , Enfermedad de Still del Adulto , Corticoesteroides , Adulto , Anticuerpos Monoclonales Humanizados/uso terapéutico , Femenino , Humanos , Recién Nacido , Embarazo , Enfermedad de Still del Adulto/tratamiento farmacológico , Resultado del TratamientoRESUMEN
There are an increasing number of reports on the safe use of rituximab (RTX), a chimeric anti-CD20 monoclonal antibody, in pregnant women with hematological malignancies or refractory autoimmune diseases. In 2014, the use of RTX for patients with complicated steroid-dependent nephrotic syndrome (SDNS) was approved in Japan. We herein report a woman with childhood-onset complicated SDNS due to focal and segmental glomerulosclerosis, who had two successful pregnancies while receiving RTX maintenance therapy. No adverse complications were observed during the pregnancies, and she delivered healthy newborns. This case suggested that RTX may be used safely in pregnant women complicated with SDNS.
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Glomeruloesclerosis Focal y Segmentaria , Síndrome Nefrótico , Niño , Femenino , Humanos , Factores Inmunológicos/efectos adversos , Inmunosupresores , Recién Nacido , Japón , Síndrome Nefrótico/tratamiento farmacológico , Embarazo , Rituximab/efectos adversos , Esteroides , Resultado del TratamientoRESUMEN
A 60-year-old man presented with nephrotic syndrome (NS). Light microscopy of renal biopsy specimens showed minor glomerular abnormalities, while immunofluorescence microscopy revealed solitary polyclonal granular IgA deposition along the glomerular capillary walls. Electron microscopy showed small amounts of electron-dense deposits in the subepithelial area, but not in the mesangial area. In this patient, apparent underlying disease was not found during the 3-year follow-up, and low-dose prednisolone was effective in the treatment of NS. To our knowledge, there is only one case report of membranous nephropathy with clinicopathological features similar to our case.