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Atypical femoral fracture (AFF) is generally a rare complication of long-term use of bisphosphonate (BP); glucocorticoid (GC) use and Asian race are also risk factors. Femoral localized periosteal thickening (LPT, also termed "beaking") of the lateral cortex often precedes AFF. This cohort study investigated the incidence of LPT and AFF and their clinical courses over 10 yr in patients with autoimmune inflammatory rheumatic diseases (AIRDs) treated with BP and GC. The study population consisted of 121 patients with AIRDs taking BP and GC. LPT was screened by X-ray, and the LPT shape was evaluated. Prednisolone (PSL) dose was 10 (8-12) mg/d at enrollment and 9 (6-10) mg/d at the last observation. LPT was evident in 10 patients at enrollment and increased linearly to 31 patients (26%) at the last observation. AFF occurred in 9 femurs of 5 patients with LPT. All patients with AFF had bilateral LPT, and the prevalence of pointed type and LPT height were higher in the AFF-positive group than in the AFF-negative group. AFF occurred before BP discontinuation in 2 patients, 1 yr after BP discontinuation in 1, after BP discontinuation followed by 7 yr of alfacalcidol use in 1, and after switching from alfacalcidol to denosumab in 1. The prevalence rates of AFF and LPT associated with long-term BP use with concomitant use of GC (mostly PSL ≥ 6 mg/d) in Japanese patients with AIRD increased over time. The selection of long-term osteoporosis treatment for LPT-positive patients is difficult in some cases.
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Adult-onset Still's disease (AOSD) causes fever, rash, pharyngalgia, and arthralgia through autoinflammation. Its complement titer has not previously received attention because this usually increases during the inflammatory process. Our female patient in her 60s was admitted to the hospital with fever, rash, arthralgia, and pharyngalgia. Her white blood cell count was 19,130/µL, hemoglobin was 11.0 g/dL, platelet count was 26.0 × 104/µL, and ferritin titer was 6,175 ng/mL. Anti-nuclear antibodies and anti-neutrophil cytoplasmic antibodies were negative. The presence of infectious diseases and malignancies was excluded. She was diagnosed with hypocomplementemia at the onset of AOSD because of her low complement component 4 (C4) titer (<5.0 mg/dL). Her complement component 3 (C3) titer was 104.5 mg/dL, which was within normal limits. There was no sign of thrombotic microangiopathy (TMA) or hemophagocytosis. She was treated with high-dose corticosteroids, including pulse methylprednisolone therapy, cyclosporine, methotrexate, and intravenous immunoglobulin, but was resistant to these, and her disease repeatedly flared up. Treatment with intravenous cyclophosphamide eventually led to remission. Post-treatment, her C4 titer increased to within the normal range. Although hypocomplementemia with TMA or hemophagocytosis has been reported in AOSD patients, our patient showed no sign of either at disease onset. Hypocomplementemia of AOSD may be a sign of high disease activity and could be a predictive marker for resistance to standard therapy.
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OBJECTIVES: We evaluated the association between anti-ribosomal P antibody (anti-RibP) titres and disease activity in Japanese systemic lupus erythematosus (SLE) patients. METHODS: Eighty patients admitted and treated in Niigata University Hospital for new-onset or flare-up of SLE were included in this retrospective cross-sectional study. Clinical data were obtained from medical records at admission. Anti-RibP index, and cytokine and tryptophan metabolite levels were determined by ELISA. RESULTS: Of the 80 SLE patients, 30 had anti-RibP. Anti-RibP presence was associated with a greater prevalence of skin rash and more severe inflammatory responses, demonstrated by higher inflammatory cytokine levels, hypocomplementemia, and accelerated tryptophan metabolism, in younger patients. The serum anti-RibP index correlated with age at diagnosis, clinical indicators, initial prednisolone dose, and cytokines and tryptophan metabolite levels in univariate analysis. Multivariate analysis showed the anti-RibP index was independently associated with initial prednisolone dose and prevalence of skin rash. Anti-RibP IgG were mainly IgG2 and IgG3 subclasses, and anti-RibP IgG3 was associated with hypocomplementemia, higher disease activity score, accelerated kynurenine pathway activity, and higher proinflammatory cytokine production. The coexistence of anti-dsDNA IgG and anti-RibP IgG2 or IgG3 accompanied higher IL-10 and IFN-α2 levels; furthermore, anti-RibP IgG3 coexistence with anti-dsDNA antibody contributed to the requirement for higher initial prednisolone doses and accelerated kynurenine pathway activity. CONCLUSION: Anti-RibP was associated with clinical manifestations and parameters in SLE, and its index might be a useful indicator of disease severity. Anti-RibP IgG3 was the IgG subclass most strongly associated with the pathogenesis of SLE.
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OBJECTIVES: The incidence of femoral localized periosteal thickening (LPT), which can precede atypical femoral fracture (AFF), is not low (1-10%) in Japanese patients with autoimmune inflammatory rheumatic diseases (AIRDs). We explored the associations between underlying AIRDs and the prevalence of LPT. METHODS: We conducted post hoc analyses of two cohorts that included a total of 280 Japanese women, 105 of whom had AIRDs and had been taking bisphosphonate (BP) and prednisolone (PSL) and 175 of whom had rheumatoid arthritis (RA). RESULTS: LPT was detected in a total of 18 patients (6.4%) and 3 (1.1%) developed AFFs. RA was negatively correlated with LPT. A disease other than RA requiring glucocorticoid treatment, BP use ≥5 years, PSL use ≥7 years, and a PSL dose ≥5.5 mg/day were positively correlated with LPT. After adjusting for age, diabetes mellitus, and BP duration or daily PSL dose, RA was no longer associated with LPT. CONCLUSIONS: LPT in Japanese patients with AIRDs was associated with BP and glucocorticoid treatment rather than underlying AIRDs. When PSL dose ≥5.5 mg/day is required long-term [typically combined with long-term BP treatment (≥5 years)], clinicians need to pay particular attention in cases LPT and AFF as well as glucocorticoid-induced osteoporosis.
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Artrite Reumatoide , Conservadores da Densidade Óssea , Fraturas do Fêmur , Humanos , Feminino , Conservadores da Densidade Óssea/uso terapêutico , Fraturas do Fêmur/induzido quimicamente , Fraturas do Fêmur/tratamento farmacológico , Fraturas do Fêmur/epidemiologia , Glucocorticoides/efeitos adversos , Difosfonatos/uso terapêutico , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/tratamento farmacológico , Prednisolona/efeitos adversosRESUMO
A 68-year-old man presented with right buccal ulceration along the facial artery, temporal pain, lagophthalmos, diplopia, and tongue deviation to the right. Contrast-enhanced computed tomography showed bilateral temporal artery and right maxillary artery wall thickening, and a diagnosis of giant cell arteritis (GCA) was made according to the American College of Rheumatology 1990 criteria. Treatment with corticosteroids ameliorated his symptoms. This is the first report of GCA with buccal skin ulceration along a facial artery. Because a delayed diagnosis can lead to irreversible damage, it is essential to notice rare symptoms, such as skin ulceration and multiple cranial neuropathy-like symptoms.
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Arterite de Células Gigantes , Úlcera Cutânea , Masculino , Humanos , Idoso , Arterite de Células Gigantes/diagnóstico , Arterite de Células Gigantes/diagnóstico por imagem , Artérias Temporais/diagnóstico por imagem , Artérias , Tomografia Computadorizada por Raios X , Úlcera Cutânea/etiologiaRESUMO
We describe the case of a 78-year-old man presenting with multiple oedematous erythemas, fever, and arthralgia who subsequently developed neutrophil infiltration into the cartilage of the bilateral auricularis, consistent with relapsing polychondritis. A skin biopsy of the erythema on his right arm showed dense neutrophilic infiltration into the dermis, while a bone marrow aspirate revealed myelodysplastic syndromes with characteristic vacuoles in myeloid precursor cells. Although the patient achieved remission with high-dose oral prednisolone, the inflammatory symptoms relapsed, and he was resistant to colchicine and cyclosporine. The patient spontaneously developed left leg oedema and high-output cardiac failure caused by an arteriovenous fistula with a common iliac artery aneurysm. We successfully performed a two-stage surgery using internal iliac artery coil embolisation and endovascular aortic repair of the iliac aneurysm. We assumed the patient was suffering from large-vessel vasculitis such as giant cell arteritis or Takayasu's arteritis. We treated him with tocilizumab in addition to prednisolone, and the febrile events and elevated C-reactive protein levels improved. One year later, sequencing of ubiquitylation-initiating E1 enzyme using peripheral blood leucocytes revealed somatic variants (c.121A>C p.Met41Leu), confirming the diagnosis of vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome. This case suggests that arteriovenous fistula could be a complication of VEXAS syndrome with large-vessel vasculitis, and adequate surgical intervention and prompt diagnosis are essential for rescue. Although arteriovenous fistula is a rare complication of VEXAS syndrome, physicians should be aware of this complication to ensure prompt diagnosis and timely surgical intervention.
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Fístula Arteriovenosa , Insuficiência Cardíaca , Aneurisma Ilíaco , Vasculite , Masculino , Humanos , Idoso , Fístula Arteriovenosa/complicações , Fístula Arteriovenosa/diagnóstico , Aneurisma Ilíaco/complicações , Aneurisma Ilíaco/cirurgia , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/terapia , Vasculite/complicaçõesRESUMO
INTRODUCTION: Femoral localized periosteal thickening (LPT, also termed "beaking") of the lateral cortex often precedes an atypical femoral fracture (AFF). Bisphosphonate (BP) use, glucocorticoid use, and Asian race are major risk factors for developing such fractures. The aim of this study was to determine whether the trabecular bone score (TBS) reflecting the lumbar trabecular microarchitecture was related to LPT in glucocorticoid-treated Japanese patients with autoimmune diseases. MATERIALS AND METHODS: We retrospectively investigated 111 women with autoimmune diseases treated with prednisolone (PSL) who had undergone both femoral X-ray and dual-energy X-ray absorptiometry of the L1 - L4 lumbar vertebrae and for whom TBS could be evaluated for two or more of these. RESULTS: Femoral LPT was evident in the X-rays of 18 of 111 patients (16.2%). Higher body mass index (BMI), longer duration of PSL use and longer duration of BP use were significant in patients with LPT compared to those without. The TBS was significantly lower in patients with LPT than in those without (1.314 ± 0.092 vs. 1.365 ± 0.100, p = 0.044); however, the lumbar bone mineral density did not differ significantly (0.892 ± 0.141 vs. 0.897 ± 0.154 g/cm2, p = 0.897). TBS was significantly associated with LPT (odds ratio, 0.004; 95% CI, 0 - 0.96; p = 0.048), but not in the multivariate analysis including BMI, duration of PSL use and duration of BP use. CONCLUSIONS: The TBS was lower in glucocorticoid-treated Japanese women with autoimmune diseases with LPT than in those without LPT, and deteriorated trabecular microarchitecture influenced by longer use of BP and glucocorticoid might be associated with the development of LPT.
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Osso Esponjoso , Fraturas por Osteoporose , Absorciometria de Fóton , Densidade Óssea , Osso Esponjoso/diagnóstico por imagem , Feminino , Humanos , Incidência , Vértebras Lombares/diagnóstico por imagem , Estudos RetrospectivosRESUMO
Antiribosomal P protein (anti-P) autoantibodies commonly develop in patients with systemic lupus erythematosus. We have previously established hybridoma clones producing anti-P mAbs. In this study, we explored the pathogenesis of behavioral disorders induced by anti-P Abs using these mAbs. New Zealand Black × New Zealand White F1, New Zealand White, C57BL/6, and BALB/c mice were treated with 1 mg of anti-P Abs once every 2 wk. The behavioral disorder was evaluated by the tail suspension test, forced swim test, and open field test. Following administration of anti-P Abs, New Zealand Black × New Zealand White F1 and C57BL/6 mice developed depressive behavior and showed increased anxiety with elevated serum TNF-α and IL-6 levels. Anti-P Abs were not deposited in the affected brain tissue; instead, this mood disorder was associated with lower serum and brain tryptophan concentrations. Tryptophan supplementation recovered serum tryptophan levels and prevented the behavioral disorder. TNF-α and IL-6 were essential for the decreased serum tryptophan and disease development, which were ameliorated by treatment with anti-TNF-α neutralizing Abs or dexamethasone. Peritoneal macrophages from C57BL/6 mice produced TNF-α, IL-6, and IDO-1 via interaction with anti-P Abs through activating FcγRs, which were required for disease development. IVIg, which has an immunosuppressive effect partly through the regulation of FcγR expression, also prevented the decrease in serum tryptophan and disease development. Furthermore, serum tryptophan concentrations were decreased in the sera of systemic lupus erythematosus patients with anti-P Abs, and lower tryptophan levels correlated with disease activity. Our study revealed some of the molecular mechanisms of mood disorder induced by anti-P Abs.
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Complexo Antígeno-Anticorpo/metabolismo , Encéfalo/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Macrófagos/imunologia , Transtornos do Humor/prevenção & controle , Soro/metabolismo , Triptofano/metabolismo , Animais , Anticorpos Monoclonais/metabolismo , Autoanticorpos/metabolismo , Suplementos Nutricionais , Humanos , Hibridomas , Lúpus Eritematoso Sistêmico/complicações , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Transtornos do Humor/etiologia , Fosfoproteínas/imunologia , Receptores de IgG/metabolismo , Proteínas Ribossômicas/imunologia , Triptofano/administração & dosagem , Fator de Necrose Tumoral alfa/metabolismoRESUMO
OBJECTIVES: Anti-ribosomal P protein autoantibodies (anti-P) specifically develop in patients with systemic lupus erythematosus. Associations of anti-P with lupus nephritis (LN) histological subclass and renal outcome remain inconclusive. We sought to determine the association of anti-P and anti-double-stranded DNA antibody (anti-dsDNA) with renal histology and prognosis in LN patients. METHODS: Thirty-four patients with LN, having undergone kidney biopsy, were included. The 2018 revised ISN/RPS classification system was used for pathophysiological evaluation. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate < 60 mL/min/1.73 m2 for > 3 months. RESULTS: Six patients (17.6%) were positive for anti-P and 26 (76.5%) for anti-dsDNA. Among the six patients with anti-P, one did not have anti-dsDNA, but did have anti-Sm antibody, and showed a histological subtype of class V. This patient maintained good renal function for over 14 years. The remaining five patients, who had both anti-P and anti-dsDNA, exhibited proliferative nephritis and were associated with prolonged hypocomplementemia, and the incidence of CKD did not differ from patients without anti-P. CONCLUSION: Although this study included a small number of patients, the results indicated that histology class and renal prognosis associated with anti-P depend on the coexistence of anti-dsDNA. Further studies with a large number of patients are required to confirm this conclusion.
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Anticorpos Antinucleares/imunologia , Nefrite Lúpica/imunologia , Adolescente , Adulto , Anticorpos Antinucleares/análise , Biomarcadores/análise , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
Hepcidin, a major regulator of iron metabolism and homeostasis, is regulated by inflammation. Recent studies have suggested that hepcidin and iron metabolism are involved in osteoporosis, and the aim of this study was to determine whether serum hepcidin levels are correlated with the degree of osteoporosis in patients with rheumatoid arthritis (RA). A total of 262 patients with RA (67.5 ± 11.4 years; 77.5% female) were enrolled. Serum iron, ferritin, and hepcidin levels were positively correlated each other. Multiple regression analyses revealed that the serum iron level was positively correlated with femoral T and Z scores, whereas the serum hepcidin level was not. Serum hepcidin level was correlated with the serum 25-hydroxy vitamin D level, which was in turn positively related to the femoral Z score. Serum hepcidin and serum iron were indirectly and directly related to osteoporosis in patients with RA.
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Artrite Reumatoide/patologia , Hepcidinas/sangue , Ferro/metabolismo , Osteoporose/patologia , Idoso , Artrite Reumatoide/complicações , Artrite Reumatoide/metabolismo , Calcifediol/sangue , Feminino , Ferritinas/sangue , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Inflamação/metabolismo , Inflamação/patologia , Ferro/sangue , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Osteoporose/complicações , Índice de Gravidade de DoençaRESUMO
Treatment of systemic lupus erythematosus (SLE) often continues with moderate-to-low doses of glucocorticoids for the long term. Bisphosphonates aid in the prevention and management of glucocorticoid-induced osteoporosis (GIOP). However, long-term use of bisphosphonates increases the relative risk of atypical femoral fracture (AFF) and the incidence is typically 16 or 113 per 100,000 person-years in patients treated with bisphosphonates for 5 or 10 years, respectively. Here, we explored bisphosphonate prescription rate and prevalence of AFF in patients with SLE. In total, 270 patients with SLE were enrolled. The Japanese Society for Bone and Mineral Research Guideline 2014 for GIOP management and treatment was used. We also explored AFF history through medical records. Most (n = 251) patients were recommended to treat by the GIOP guideline (scores ≥ 3); bisphosphonates, denosumab, teriparatide, or active vitamin D was prescribed for 85.7%. Bisphosphonates were currently used by 66.1% of the patients, and 65% had used them for ≥ 5 years. Of all patients, 76.7% had a history of bisphosphonate use, 5 of 270 (1.9%) had histories of AFF. Four of five patients with AFF had taken bisphosphonates for ≥ 3.5 years, in addition to moderate doses (≥ 10 mg/day) of glucocorticoids. For the SLE patients with a history of bisphosphonate use, the incidence of AFF was calculated to be 278 per 100,000 person-years. Our single-center study found that bisphosphonates were commonly used long term by Japanese patients with SLE. As AFF is not rare, AFF should be cared in patients with SLE.
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Conservadores da Densidade Óssea/efeitos adversos , Difosfonatos/efeitos adversos , Fraturas do Fêmur/induzido quimicamente , Glucocorticoides/efeitos adversos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Osteoporose/prevenção & controle , Adulto , Idoso , Idoso de 80 Anos ou mais , Conservadores da Densidade Óssea/administração & dosagem , Difosfonatos/administração & dosagem , Esquema de Medicação , Feminino , Fraturas do Fêmur/diagnóstico por imagem , Fraturas do Fêmur/epidemiologia , Glucocorticoides/administração & dosagem , Humanos , Incidência , Japão/epidemiologia , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/epidemiologia , Masculino , Pessoa de Meia-Idade , Osteoporose/induzido quimicamente , Osteoporose/diagnóstico por imagem , Osteoporose/epidemiologia , Prevalência , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Patients with rheumatoid arthritis (RA) often have reduced muscle mass. Estimated glomerular filtration ratio using the serum cystatin C concentration (eGFRcys) is more accurate than eGFR using the serum creatinine (eGFRcreat) because cystatin C is not influenced by muscle mass, but glucocorticoid therapy may affect serum cystatin C concentration. METHODS: Fifty patients with RA were included in this study. Renal inulin clearance (Cin) was measured and compared with eGFRcreat, eGFRcys, or the mean of eGFRcreat and eGFRcys (eGFRavg). RESULTS: The mean creatine kinase (CK) concentration was low (36.8⯱â¯24.4â¯U/l).The eGFRcreat and eGFRcys regression lines were significantly different from yâ¯=â¯x. The mean eGFRcreat value was significantly higher than Cin and that of eGFRcys was lower than Cin. The difference between eGFRcys and Cin was negatively correlated with daily PSL dose. The mean eGFRcys value of patients taking <10â¯mg PSL was not different from Cin and the eGFRcys regression line was not different from yâ¯=â¯x. CONCLUSION: eGFRcys of patients taking a daily PSL dose ≥10â¯mg was inaccurate, while eGFRcys was underestimated. eGFRcys was more accurate than eGFRcreat or eGFRavg for patients taking a daily PSL dose of <10â¯mg.
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Artrite Reumatoide/tratamento farmacológico , Cistatina C/sangue , Taxa de Filtração Glomerular , Glucocorticoides/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/sangue , Creatinina/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The kidney is a major target organ for systemic amyloidosis, which results in proteinuria and an elevated serum creatinine level. The clinical manifestations and precursor proteins of amyloid A (AA) and light-chain (AL) amyloidosis are different, and the renal damage due to amyloid deposition also seems to differ. The purpose of this study was to clarify haw the difference in clinical features between AA and AL amyloidosis are explained by the difference in the amount and distribution of amyloid deposition in the renal tissues. A total of 119 patients participated: 58 patients with an established diagnosis of AA amyloidosis (AA group) and 61 with AL amyloidosis (AL group). We retrospectively investigated the correlation between clinical data, pathological manifestations, and the area occupied by amyloid in renal biopsy specimens. In most of the renal specimens the percentage area occupied by amyloid was less than 10%. For statistical analyses, the percentage area of amyloid deposition was transformed to a common logarithmic value (Log10%amyloid). The results of sex-, age-, and Log10%amyloid-adjusted analyses showed that systolic blood pressure (SBP) was higher in the AA group. In terms of renal function parameters, serum creatinine, creatinine clearance (Ccr) and estimated glomerular filtration rate (eGFR) indicated significant renal impairment in the AA group, whereas urinary protein indicated significant renal impairment in the AL group. Pathological examinations revealed amyloid was predominantly deposited at glomerular basement membrane (GBM) and easily transferred to the mesangial area in the AA group, and it was predominantly deposited at in the AL group. The degree of amyloid deposition in the glomerular capillary was significantly more severe in AL group. The frequency of amyloid deposits in extraglomerular mesangium was not significantly different between the two groups, but in AA group, the degree amyloid deposition was significantly more severe, and the deposition pattern in the glomerulus was nodular. Nodular deposition in extraglomerular mesangium leads to renal impairment in AA group. There are significant differences between AA and AL amyloidosis with regard to the renal function, especially in terms of Ccr, eGFR and urinary protein, even after Log10%amyloid was adjusted; showing that these inter-group differences in renal function would not be depend on the amount of renal amyloid deposits. These differences could be explained by the difference in distribution and morphological pattern of amyloid deposition in the renal tissue.
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Pressão Sanguínea , Taxa de Filtração Glomerular , Rim , Proteinúria , Febre Reumática , Proteína Amiloide A Sérica , Idoso , Biópsia , Feminino , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/complicações , Amiloidose de Cadeia Leve de Imunoglobulina/patologia , Amiloidose de Cadeia Leve de Imunoglobulina/fisiopatologia , Amiloidose de Cadeia Leve de Imunoglobulina/urina , Rim/metabolismo , Rim/patologia , Rim/fisiopatologia , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Proteinúria/complicações , Proteinúria/patologia , Proteinúria/fisiopatologia , Proteinúria/urina , Febre Reumática/complicações , Febre Reumática/patologia , Febre Reumática/fisiopatologia , Febre Reumática/urina , Proteína Amiloide A Sérica/metabolismoRESUMO
Although calcineurin (CN) is distributed in many cell types and functions in regulating cell functions, the precise roles ofCNremained in each type of the cells are not well understood yet. ACNinhibitor (CNI) has been used for steroid-resistant nephrotic syndrome. ACNIis assumed to ameliorate proteinuria by preventing the overproduction of T-cell cytokines. However, recent reports suggest thatCNIhas a direct effect on podocyte. It is accepted that a slit diaphragm (SD), a unique cell-cell junction of podocytes, is a critical barrier preventing a leak of plasma protein into urine. Therefore, we hypothesized thatCNIhas an effect on theSD In this study, we analyzed the expression ofCNin physiological and in the nephrotic model caused by the antibody against nephrin, a critical component of theSD We observed thatCNis expressed at theSDin normal rat and human kidney sections and has an interaction with nephrin. The staining ofCNat theSDwas reduced in the nephrotic model, whileCNactivity in glomeruli was increased. We also observed that the treatment with tacrolimus, aCNI, in this nephrotic model suppressed the redistribution ofCN, nephrin, and otherSDcomponents and ameliorated proteinuria. These observations suggested that the redistribution and the activation ofCNmay participate in the development of theSDinjury.
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Inibidores de Calcineurina/farmacologia , Calcineurina/metabolismo , Junções Intercelulares/efeitos dos fármacos , Síndrome Nefrótica/tratamento farmacológico , Podócitos/efeitos dos fármacos , Proteinúria/tratamento farmacológico , Tacrolimo/farmacologia , Animais , Anticorpos Monoclonais , Linhagem Celular , Criança , Modelos Animais de Doenças , Feminino , Humanos , Junções Intercelulares/enzimologia , Junções Intercelulares/patologia , Masculino , Proteínas de Membrana/imunologia , Proteínas de Membrana/metabolismo , Camundongos , Síndrome Nefrótica/induzido quimicamente , Síndrome Nefrótica/congênito , Síndrome Nefrótica/enzimologia , Síndrome Nefrótica/patologia , Podócitos/enzimologia , Podócitos/patologia , Transporte Proteico , Proteinúria/induzido quimicamente , Proteinúria/enzimologia , Proteinúria/patologia , Ratos Wistar , Fatores de TempoRESUMO
The purpose of this study was to clarify the factors related to silent osteonecrosis of the femoral head (ONFH) in patients with systemic lupus erythematosus (SLE). Seventy-eight patients with SLE were selected on the basis of having been newly diagnosed and requiring high-dose prednisolone, including pulse therapy with methylprednisolone, as the initial treatment. All the patients initially underwent MRI at 3 months after the start of corticosteroid treatment to detect any early changes in the femoral head. These examinations were then performed again 3 months later. Laboratory parameters were evaluated at the start of steroid treatment and at 1 month thereafter. By 3 months after the start of corticosteroid treatment, silent ONFH was diagnosed by MRI in 21 patients (26.9 %), being bilateral in 11 patients and unilateral in 10. The occurrence of silent ONFH was not related to SLE disease activity index, serological activity, or renal function; it was also unrelated to body mass index (BMI), body surface area (BSA), and the initial dose of prednisolone per unit body weight. However, the total cholesterol level at 4 weeks after the start of steroid treatment tended to be higher in patients with silent ONFH. Patients with a higher triglyceride level showed a significantly higher frequency of silent ONFH both before (p = 0.002) and 4 weeks after (p = 0.036) steroid initiation.A high triglyceride level is an important risk factor for silent ONFH in patients with SLE, and large-scale epidemiologic surveys of such early events are needed in this patient population.
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Doenças Assintomáticas/epidemiologia , Necrose da Cabeça do Fêmur/epidemiologia , Hipertrigliceridemia/epidemiologia , Lúpus Eritematoso Sistêmico/epidemiologia , Adolescente , Adulto , Idoso , Índice de Massa Corporal , Superfície Corporal , Feminino , Necrose da Cabeça do Fêmur/sangue , Necrose da Cabeça do Fêmur/patologia , Glucocorticoides/uso terapêutico , Humanos , Hipertrigliceridemia/sangue , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Imageamento por Ressonância Magnética , Masculino , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Prednisolona/uso terapêutico , Estudos Prospectivos , Fatores de Risco , Triglicerídeos/sangue , Adulto JovemRESUMO
The glomerular visceral epithelial cell (podocyte) is characterized as a specialized structure of the interdigitating foot processes, covering the outer side of the glomerular basement membrane (GBM). The neighboring foot processes are connected by a slit diaphragm, which is a key structure regulating the barrier function of the glomerular capillary wall to prevent proteinuria. We have previously reported that synaptic vesicle protein 2 B (SV2B) is expressed in the podocyte and that the expression is clearly decreased in nephrotic models. However, the precise function of SV2B in the podocyte is unclear. To investigate the role of SV2B in maintaining the podocyte function and to better understand the function of the neuron-like vesicle expressing SV2B in the podocyte, we analyzed them with SV2B knockout (KO) mice. An increase in the amount of proteinuria, effacement of the foot process of the podocyte, and alterations of the GBM were detected in SV2B KO mice. It was also found that the expression of CD2AP, nephrin, and NEPH1, the functional molecules of the slit diaphragm, and laminin, a critical component of the GBM, is clearly altered in SV2B KO mice. Synaptotagmin and neurexin, which have a role in the synaptic vesicle docking in neurons, are downregulated in the kidney cortex of SV2B KO mice. We have previously reported that neurexin interacts with CD2AP, and the present study shows that SV2B interacts with CD2AP. These findings suggest that the SV2B-neurexin complex is involved in the formation and maintenance of the slit diaphragm. In addition, SV2B is densely expressed close to the cell surface in the presumptive podocyte in the early stage of glomerulogenesis. These results suggest that SV2B has an essential role in the formation and maintenance of the glomerular capillary wall.