RESUMEN
Carnitine/organic cation transporter 1 (OCTN1) is the only known uptake transporter for ergothioneine which is a food-derived strong antioxidant amino acid that is absorbed by OCTN1. We previously reported the roles of OCTN1/ergothioneine in the progression of kidney fibrosis in ischemic kidney disease. In this study, we evaluated the roles of OCTN1 in the progression of diabetic kidney disease. A diabetic kidney disease model was induced in octn1 knockout and wild-type mice by streptozotocin (STZ). Oxidative stress, represented by urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG), were higher in the octn1 knockout mice. Azan- and Sirius red-positive areas increased significantly in the octn1 knockout mice. Gene expression was evaluated by cluster analysis, and shown to be different in the octn1 knockout mice compared with the wild-type mice. In a pathway analysis, the pathway associated with the cytoskeleton and cell adhesion increased. In accordance with interstitial fibrosis in octn1 knockout mice, gene expression of moesin in the injured kidney, known as an associated protein of cytoskeleton and cell membranes, was doubled 28 weeks after STZ injection. In addition, the moesin protein was expressed in a part of α-SMA-positive renal tubular epithelial cells. These findings were confirmed by cultured murine proximal tubular epithelial cells: The expression of moesin was induced under oxidative stress with hydrogen peroxide. These data indicate that OCTN1 would play some roles in progression of interstitial fibrosis under oxidative stress via moesin expression in diabetic kidney disease.
Asunto(s)
Nefropatías Diabéticas/patología , Riñón/patología , Proteínas de Transporte de Catión Orgánico/metabolismo , Simportadores/metabolismo , Animales , Diabetes Mellitus Experimental/complicaciones , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/metabolismo , Ergotioneína/metabolismo , Fibrosis , Regulación de la Expresión Génica , Riñón/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/metabolismo , Proteínas de Transporte de Catión Orgánico/genética , Estrés Oxidativo , Simportadores/genéticaRESUMEN
Peritoneal fibrosis (PF) is a severe complication of peritoneal dialysis, but there are few effective therapies for it. Recent studies have revealed a new biological function of trehalose as an autophagy inducer. Thus far, there are few reports regarding the therapeutic effects of trehalose on fibrotic diseases. Therefore, we examined whether trehalose has anti-fibrotic effects on PF. PF was induced by intraperitoneal injection of chlorhexidine gluconate (CG). CG challenges induced the increase of peritoneal thickness, ColIα1 mRNA expression and hydroxyproline content, all of which were significantly attenuated by trehalose. In addition, CG challenges induced a marked peritoneal accumulation of α-SMA+ myofibroblasts that was reduced by trehalose. The number of Wt1+ α-SMA+ cells in the peritoneum increased following CG challenges, suggesting that a part of α-SMA+ myofibroblasts were derived from peritoneal mesothelial cells (PMCs). The number of Wt1+ α-SMA+ cells was also suppressed by trehalose. Additionally, trehalose attenuated the increase of α-SMA and ColIα1 mRNA expression induced by TGF-ß1 through Snail protein degradation, which was dependent on autophagy in PMCs. These results suggest that trehalose might be a novel therapeutic agent for PF through the induction of autophagy and the suppression of mesothelial-to-mesenchymal transition in PMCs.
Asunto(s)
Transición Epitelial-Mesenquimal/efectos de los fármacos , Fibrosis Peritoneal/tratamiento farmacológico , Factores de Transcripción de la Familia Snail/metabolismo , Trehalosa/uso terapéutico , Animales , Clorhexidina/análogos & derivados , Clorhexidina/farmacología , Células Epiteliales/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Miofibroblastos/efectos de los fármacos , Miofibroblastos/metabolismo , Fibrosis Peritoneal/inducido químicamenteRESUMEN
BACKGROUND: A decreased response to erythropoiesis-stimulating agents (ESAs) leads to refractory anemia and worse prognosis in patients with chronic kidney disease. We examined the association between autoantibodies to the erythropoietin receptor (EPOR) and responsiveness to ESAs in patients on maintenance hemodialysis. METHODS: A total of 108 Japanese patients on maintenance hemodialysis at three institutions were enrolled. Sera from these patients were screened for anti-EPOR antibodies using an enzyme-linked immunosorbent assay. An ESA resistance index (ERI) was calculated, and patients in the highest ERI quartile were defined as ESA hyporesponsive. RESULTS: Anti-EPOR antibodies were detected in 11 patients (10%). Body mass index and hemoglobin, platelet, magnesium, and ferritin levels decreased with higher ERI levels. On the other hand, C-reactive protein (CRP) levels and the prevalence of anti-EPOR antibodies increased with higher ERI levels. In multivariate analysis, the presence of anti-EPOR antibodies together with CRP was a significant risk factor for ESA hyporesponsiveness. CONCLUSIONS: Anti-EPOR antibodies were detected in patients on maintenance hemodialysis, and these autoantibodies were independent factors for hyporesponsiveness to ESAs in these patients.
Asunto(s)
Anemia/tratamiento farmacológico , Autoanticuerpos/sangre , Hematínicos/uso terapéutico , Receptores de Eritropoyetina/inmunología , Diálisis Renal , Insuficiencia Renal Crónica/terapia , Anciano , Anciano de 80 o más Años , Anemia/sangre , Anemia/inmunología , Biomarcadores/sangre , Proteína C-Reactiva/análisis , Estudios Transversales , Resistencia a Medicamentos , Femenino , Hematínicos/efectos adversos , Humanos , Japón , Masculino , Persona de Mediana Edad , Diálisis Renal/efectos adversos , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/inmunología , Factores de Riesgo , Resultado del TratamientoRESUMEN
OBJECTIVES: Methicillin-resistant Staphylococcus aureus (MRSA) causes hospital- and community-acquired infections. It is not clear whether genetic characteristics of the bacteria contribute to disease pathogenesis in MRSA infection. We hypothesized that whole genome analysis of MRSA strains could reveal the key gene loci and/or the gene mutations that affect clinical manifestations of MRSA infection. METHODS: Whole genome sequences (WGS) of MRSA of 154 strains were analyzed with respect to clinical manifestations and data. Further, we evaluated the association between clinical manifestations in MRSA infection and genomic information. RESULTS: WGS revealed gene mutations that correlated with clinical manifestations of MRSA infection. Moreover, 12 mutations were selected as important mutations by Random Forest analysis. Cluster analysis revealed strains associated with a high frequency of bloodstream infection (BSI). Twenty seven out of 34 strains in this cluster caused BSI. These strains were all positive for collagen adhesion gene (cna) and have mutations in the locus, those were selected by Random Forest analysis. Univariate and multivariate analysis revealed that these gene mutations were the predictor for the incidence of BSI. Interestingly, mutant CNA protein showed lower attachment ability to collagen, suggesting that the mutant protein might contribute to the dissemination of bacteria. CONCLUSIONS: These findings suggest that the bacterial genotype affects the clinical characteristics of MRSA infection.
Asunto(s)
Adhesinas Bacterianas/genética , Bacteriemia/microbiología , Staphylococcus aureus Resistente a Meticilina/genética , Infecciones Estafilocócicas/microbiología , Adulto , Anciano , ADN Bacteriano , Femenino , Genoma Bacteriano , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Mutación , Secuenciación Completa del GenomaRESUMEN
AIM: High glucose (HG) induces endothelial injury in vasculature, leading to tissue injury in diabetic condition. Therefore, diabetes is one of the major cause of end-stage kidney disease as well as cardiovascular diseases. Chronic inflammation is involved in the progression of HG-induced cell injury. Recently, it has been reported that erythropoietin (EPO) protects the tissues from some kind of injury, such as hypoxia and mechanical stress. However, the contribution of EPO to HG-induced tissue injury remains to be explored. Therefore, we hypothesized that EPO protects endothelial cells from HG-induced injury via the regulation of inflammatory and anti-inflammatory balance. METHODS: We performed genome-wide transcriptome profiling in human umbilical vein endothelial cells (HUVEC), which were stimulated by HG with/without EPO treatment and detected the expression of inflammation associated genes. RESULTS: The expression pattern of mRNA expression in HG stimulated HUVEC with/without EPO were different in hieralchial clustering analysis. While inflammatory cytokines/chemokines mRNA expression were increased by the HG stimulation in HUVEC, Th2-related cytokine receptors and intracellular signaling molecules showed the reduced mRNA expression levels. EPO treatment reduced inflammatory cytokines/chemokines mRNA expression and increased Th2-related cytokine mRNA expression levels. Moreover, EPO stimulation increased mRNA expression of EPO receptor and ß-common receptor. CONCLUSION: EPO signaling protects HG-induced cell injury by the regulation of immune balance.
Asunto(s)
Eritropoyetina/farmacología , Glucosa/farmacología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Cultivadas , Quimiocinas/genética , Citocinas/genética , Citoprotección , Perfilación de la Expresión Génica , Células Endoteliales de la Vena Umbilical Humana/inmunología , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Receptores de Eritropoyetina/genética , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/fisiología , Células Th2/inmunologíaRESUMEN
Gut microbiota-derived metabolites play important roles in health and disease. D-amino acids and their L-forms are metabolites of gut microbiota with distinct functions. In this study, we show the pathophysiologic role of D-amino acids in association with gut microbiota in humans and mice with acute kidney injury (AKI). In a mouse kidney ischemia/reperfusion model, the gut microbiota protected against tubular injury. AKI-induced gut dysbiosis contributed to the altered metabolism of D-amino acids. Among the D-amino acids, only D-serine was detectable in the kidney. In injured kidneys, the activity of D-amino acid oxidase was decreased. Conversely, the activity of serine racemase was increased. The oral administration of D-serine mitigated the kidney injury in B6 mice and D-serine-depleted mice. D-serine suppressed hypoxia-induced tubular damage and promoted posthypoxic tubular cell proliferation. Finally, the D-serine levels in circulation were significantly correlated with the decrease in kidney function in AKI patients. These results demonstrate the renoprotective effects of gut-derived D-serine in AKI, shed light on the interactions between the gut microbiota and the kidney in both health and AKI, and highlight D-serine as a potential new therapeutic target and biomarker for AKI.
Asunto(s)
Lesión Renal Aguda/metabolismo , Disbiosis/metabolismo , Microbioma Gastrointestinal/fisiología , Daño por Reperfusión/metabolismo , Serina/metabolismo , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/patología , Administración Oral , Animales , Biomarcadores/metabolismo , Modelos Animales de Enfermedad , Disbiosis/microbiología , Femenino , Humanos , Túbulos Renales/patología , Masculino , Ratones , Racemasas y Epimerasas/metabolismo , Daño por Reperfusión/etiología , Serina/administración & dosificación , EstereoisomerismoRESUMEN
Mortality from infections has been reported to be higher in hemodialysis (HD) patients. Although dysfunction of neutrophils against bacterial infection was reported in HD patients, the precise mechanism remains to be clarified. We therefore examined the impacts of neutrophil inflammatory signaling on bactericidal activity in HD patients. Comprehensive analyses of intracellular signalings were performed in whole blood of HD patients and control using a microarray system. To confirm the contribution of the signaling to bactericidal activity in neutrophils, we examined the phosphorylation, bacterial killing function, reactive oxygen species (ROS) production, and myeloperoxidase (MPO) release in neutrophils against Staphylococcus aureus. RNA microarray analysis showed the suppression of p38 mitogen activated protein kinase (MAPK) signaling in HD patients. Neutrophils in HD patients showed the impairment of bactericidal activity against S. aureus compared to healthy subjects. Phosphorylation rate of p38MAPK of neutrophils in response to S. aureus was lower in HD patients than healthy subjects. The levels of ROS produced by neutrophils after co-culture with S. aureus were lower in HD patients, on the other hand, there was no difference of MPO release between HD patients and healthy subjects. A selective pharmacological inhibitor of p38MAPK suppressed bacterial killing function as well as ROS production in neutrophils of healthy subjects. Impairment of p38MAPK signaling pathway might contribute to the suppression of neutrophil bactericidal activity in HD patients through less production of ROS.
Asunto(s)
Neutrófilos/metabolismo , Diálisis Renal/métodos , Staphylococcus aureus/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Peroxidasa/metabolismo , Fosforilación/fisiología , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/fisiologíaRESUMEN
Carnitine/organic cation transporter 1 (OCTN1) is a specific transporter of the food-derived antioxidant ergothioneine. Ergothioneine is absorbed by intestinal OCTN1, distributed through the bloodstream, and incorporated into each organ by OCTN1. OCTN1 expression is upregulated in injured tissues, and promotes ergothioneine uptake to reduce further damage caused by oxidative stress. However, the role of the OCTN1-ergothioneine axis in kidney-intestine cross-talk and chronic kidney disease (CKD) progression remains unclear. Here we assessed ergothioneine uptake via intestinal OCTN1 and confirmed the expression of OCTN1. The ability of OCTN1 to absorb ergothioneine was diminished in mice with CKD. In combination with OCTN1 dysfunction, OCTN1 localization on the intestinal apical cellular membrane was disturbed in mice with CKD. Proteomic analysis, RT-PCR, Western blotting, and immunohistochemistry revealed that PDZ (PSD95, Dlg, and ZO1), a PDZK1 domain-containing protein that regulates the localization of transporters, was decreased in mice with CKD. Decreased intestinal ergothioneine uptake from food decreased ergothioneine levels in the blood of mice with CKD. Despite increased OCTN1 expression and ergothioneine uptake into the kidneys of mice with CKD, ergothioneine levels did not increase. To identify the role of the OCTN1-ergothioneine axis in CKD, we evaluated kidney damage and oxidative stress in OCTN1-knockout mice with CKD and found that kidney fibrosis worsened. Oxidative stress indicators were increased in OCTN1-knockout mice. Moreover, ergothioneine levels in the blood of patients with CKD decreased, which were restored after kidney transplantation. Thus, a novel inter-organ interaction mediated by transporters is associated with CKD progression.
Asunto(s)
Antioxidantes/metabolismo , Proteínas Portadoras/metabolismo , Ergotioneína/metabolismo , Mucosa Intestinal/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de la Membrana/metabolismo , Insuficiencia Renal Crónica/patología , Animales , Transporte Biológico , Proteínas Portadoras/genética , Línea Celular , Membrana Celular/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Regulación hacia Abajo , Ergotioneína/sangre , Humanos , Intestinos/citología , Túbulos Renales/citología , Túbulos Renales/patología , Masculino , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Transporte de Catión Orgánico , Estrés Oxidativo , Insuficiencia Renal Crónica/sangre , Simportadores , Regulación hacia ArribaRESUMEN
Peritoneal fibrosis (PF) is a serious complication in various clinical settings, but the mechanisms driving it remain to be fully determined. Connective tissue growth factor (CTGF) is known to regulate fibroblast activities. We therefore examined if CTGF inhibition has anti-fibrotic effects in PF. PF was induced by repetitive intraperitoneal injections of chlorhexidine gluconate (CG) in mice with type I pro-collagen promoter-driven green fluorescent protein (GFP) expression to identify fibroblasts. FG-3019, an anti-CTGF monoclonal antibody, was used to inhibit CTGF. CG-induced PF was significantly attenuated in FG-3019-treated mice. CG challenges induced marked accumulations of proliferating fibroblasts and of myofibroblasts, which were both reduced by FG-3019. Levels of peritoneal CTGF expression were increased by CG challenges, and suppressed in FG-3019-treated mice. FG-3019 treatment also reduced the number of CD31+ vessels and VEGF-A-positive cells in fibrotic peritoneum. In vitro studies using NIH 3T3 fibroblasts and peritoneal mesothelial cells (PMCs) showed that CTGF blockade suppressed TGF-ß1-induced fibroblast proliferation and myofibroblast differentiation, PMC mesothelial-to-mesenchymal transition, and VEGF-A production. These findings suggest that the inhibition of CTGF by FG-3019 might be a novel treatment for PF through the regulation of fibroblast and myofibroblast accumulation and angiogenesis.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Anticuerpos Monoclonales/farmacología , Factor de Crecimiento del Tejido Conjuntivo/genética , Neovascularización Patológica/prevención & control , Fibrosis Peritoneal/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular/genética , Animales , Anticuerpos Monoclonales Humanizados , Diferenciación Celular/efectos de los fármacos , Clorhexidina/análogos & derivados , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Factor de Crecimiento del Tejido Conjuntivo/antagonistas & inhibidores , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Modelos Animales de Enfermedad , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Regulación de la Expresión Génica , Genes Reporteros , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Ratones , Ratones Transgénicos , Miofibroblastos/efectos de los fármacos , Miofibroblastos/metabolismo , Miofibroblastos/patología , Células 3T3 NIH , Neovascularización Patológica/inducido químicamente , Neovascularización Patológica/genética , Neovascularización Patológica/patología , Fibrosis Peritoneal/inducido químicamente , Fibrosis Peritoneal/genética , Fibrosis Peritoneal/patología , Transducción de Señal , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismo , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND: Apoptosis inhibitor of macrophage (AIM) expressed on macrophages prolongs inflammation by protecting macrophages from apoptosis. Most circulating AIM co-exists with immunoglobulin M (IgM). AIM's pathophysiological role in relation to IgM remains unclear. Here we evaluated the glomerular expression/deposition of AIM and IgM in the kidney using immunohistochemistry and its associations with clinical manifestations in 43 patients with biopsy-confirmed kidney diseases. METHODS: Kidney biopsy tissue from all patients was immunostained for AIM and IgM. Staining patterns and percent stained areas within the glomeruli were determined. Cells expressing AIM were identified by co-staining with macrophage and endothelial cell surface markers. Correlations between staining results and clinical parameters were evaluated using univariate and multivariate analyses. RESULTS: AIM was deposited in various areas, such as mesangial and capillary area. A part of AIM expression was localized to CD68-positive macrophages in the glomerulus. Amount of glomerular expression was positively correlated with urinary protein in patients with severe proteinuria (urinary protein ≥0.5 g/day) and kidney dysfunction [estimated glomerular filtration ratio (eGFR) <60 ml/min/1.73 m2]. Urinary protein was higher in patients exhibiting overlapping glomerular expression of AIM and IgM. Annual eGFR decline rate negatively correlated with AIM-positive area. AIM-positive area and initial serum creatinine were independently associated with decreased kidney function. CONCLUSION: AIM expression in the kidney was associated with urinary protein and decline in kidney function. Co-expression with IgM appeared to exacerbate AIM's deleterious effects on kidney function. Combined glomerular AIM and IgM expression is a candidate prognostic index for kidney disease.
Asunto(s)
Enfermedades Renales/metabolismo , Glomérulos Renales/química , Proteinuria/metabolismo , Receptores Depuradores/análisis , Adulto , Anciano , Anciano de 80 o más Años , Proteínas Reguladoras de la Apoptosis , Biopsia , Células Endoteliales/química , Femenino , Tasa de Filtración Glomerular , Humanos , Inmunoglobulina M/análisis , Inmunohistoquímica , Enfermedades Renales/diagnóstico , Enfermedades Renales/fisiopatología , Glomérulos Renales/patología , Glomérulos Renales/fisiopatología , Macrófagos/química , Masculino , Persona de Mediana Edad , Análisis Multivariante , Proteinuria/diagnóstico , Proteinuria/fisiopatología , Estudios Retrospectivos , Adulto JovenRESUMEN
A 60-year-old male with end-stage kidney disease due to autosomal polycystic kidney disease began maintenance hemodialysis in 2005. A brain CT scan showed dilatation of left vertebral artery, basilar artery, bilateral post cerebral artery, and middle cerebral artery. At the time, he was diagnosed as vertebrobasilar dolichoectasia. He was once admitted to our hospital for ischemic stroke. After discharge, he was treated with anticoagulant agent from 2010 to 2012 without any new stroke events. In March, 2012, he was admitted to our hospital for an evaluation of diplopia and left hemiplegia. Brain MRI showed acute ischemia of bilateral pons and right temporal lobe. He was once recovered with urokinase and argatroban, but 3 months after admission, he died with sudden hypotension and impaired consciousness. Autopsy revealed that subarachnoid hemorrhage due to the rupture of basilar artery aneurysm was responsible for this event.
RESUMEN
BACKGROUND: Various sleep abnormalities, such as delayed sleep onset, frequent awakening and daytime sleepiness, deteriorate the quality of life in patients with chronic kidney disease (CKD), including those on haemodialysis (HD). Although there are some candidate causative molecules in the central nervous system, the contribution of peripheral blood cells (PBCs) remains unclear. In this study, we performed polysomnographic analysis in CKD patients and used PBCs to examine the expression of genes related to sleep and wakefulness states. METHODS: Polysomnographic analysis was performed in 9 CKD patients and 6 controls. Genes related to sleep and wakefulness were evaluated by RNA microarray in 19 subjects, including CKD patients and control subjects. RESULTS: Polysomnographic analysis revealed that the duration of the rapid eye movement (REM)/non-REM phases during total sleep time was different between CKD patients and healthy controls. In mRNA microarray evaluation, hierarchical clustering analysis showed different patterns of sleep-related gene expression in HD patients. mRNA expression levels of GABA receptor (GABBR2), noradrenaline receptor (ADRA1A), dopamine receptor (DRD1) and histamine receptor (HRH1) showed an inverse correlation with renal function. Moreover, the mRNA expression of orexin and its receptor (HCRTR1 and HCRTR2) was also inversely correlated with renal function. CONCLUSION: These data indicate that the expression of sleep-related genes in PBCs of CKD patients may be associated with sleep abnormalities.
Asunto(s)
Orexinas/metabolismo , Receptores de Neurotransmisores/metabolismo , Insuficiencia Renal Crónica/metabolismo , Sueño REM/fisiología , Ácido gamma-Aminobutírico/metabolismo , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Perfilación de la Expresión Génica , Humanos , Hipertensión/metabolismo , Leucocitos/metabolismo , Masculino , Persona de Mediana Edad , Polisomnografía , Insuficiencia Renal Crónica/fisiopatología , Transducción de SeñalRESUMEN
BACKGROUND: The prevention of relapse and infection complications during remission maintenance therapy is required to improve the prognosis of patients with microscopic polyangiitis (MPA) showing rapidly progressive glomerulonephritis (RPGN). The clinicopathological characteristics of patients with ANCA-positive MPA were examined to determine the risk factors for relapse or infectious complications after remission induction therapy. PATIENTS AND METHODS: The study population consisted of 52 patients diagnosed as ANCA-positive MPA showing RPGN from 2002 to 2012, after publication of the Japanese guideline for RPGN. The clinicopathological findings were examined between the presence and absence of relapse or infectious complications. RESULTS: The value of vasculitis damage index (VDI) was high for the relapse group and VDI value was identified as the leading factor associated with relapse [hazard ratio (HR) 3.36, 95 % confidence interval (CI) 1.58-7.12, P < 0.01]. On the other hand, the values of Birmingham Vasculitis Activity Score, clinical grade category of RPGN at diagnosis, and VDI at remission were high in the infectious group. Furthermore, clinical grade category of RPGN was the leading factor associated with infectious complications (HR 5.30, 95 % CI 1.41-19.9, P = 0.01). CONCLUSION: The disease activity at diagnosis and severity of organ damage at remission were associated with relapse and infectious complications during remission maintenance therapy and infectious complication affected kidney survival and all-cause mortality in patients with ANCA-positive MPA exhibiting RPGN.
Asunto(s)
Enfermedades Transmisibles/etiología , Glomerulonefritis/terapia , Inmunosupresores/uso terapéutico , Poliangitis Microscópica/terapia , Anciano , Enfermedades Transmisibles/diagnóstico , Enfermedades Transmisibles/mortalidad , Femenino , Glomerulonefritis/diagnóstico , Glomerulonefritis/etiología , Glomerulonefritis/mortalidad , Humanos , Inmunosupresores/efectos adversos , Japón , Estimación de Kaplan-Meier , Masculino , Poliangitis Microscópica/complicaciones , Poliangitis Microscópica/diagnóstico , Poliangitis Microscópica/mortalidad , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Recurrencia , Inducción de Remisión , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Renal coloboma syndrome (RCS) is characterized by renal anomalies and optic nerve colobomas. PAX2 mutations contribute to RCS. However, approximately half of the patients with RCS have no mutation in PAX2 gene. METHODS: To investigate the incidence and effects of mutations of PAX2 and 25 candidate genes, patient genes were screened using next-generation sequence analysis, and candidate mutations were confirmed using Sanger sequencing. The correlation between mutations and clinical manifestation was evaluated. RESULT: Thirty patients, including 26 patients (two families of five and two, 19 sporadic cases) with RCS, and 4 optic nerve coloboma only control cases were evaluated in the present study. Six PAX2 mutations in 21 probands [28%; two in family cohorts (n = 5 and n = 2) and in 4 out of 19 patients with sporadic disease] including four novel mutations were confirmed using Sanger sequencing. Moreover, four other sequence variants (CHD7, SALL4, KIF26B, and SIX4) were also confirmed, including a potentially pathogenic novel KIF26B mutation. Kidney function and proteinuria were more severe in patients with PAX2 mutations than in those without the mutation. Moreover, the coloboma score was significantly higher in patients with PAX2 gene mutations. Three out of five patients with PAX2 mutations had focal segmental glomerulosclerosis (FSGS) diagnosed from kidney biopsies. CONCLUSION: The results of this study identify several new mutations of PAX2, and sequence variants in four additional genes, including a novel potentially pathogenic mutation in KIF26B, which may play a role in the pathogenesis of RCS.
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Coloboma/genética , Coloboma/patología , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Mutación/genética , Factor de Transcripción PAX2/genética , Insuficiencia Renal/genética , Insuficiencia Renal/patología , Reflujo Vesicoureteral/genética , Reflujo Vesicoureteral/patología , Secuencia de Aminoácidos , Exones/genética , Familia , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Riñón/patología , Masculino , Datos de Secuencia Molecular , Nervio Óptico/anomalías , Factor de Transcripción PAX2/química , LinajeRESUMEN
BACKGROUND: Carotid echo indexes [intima-media thickness (IMT)] are commonly used surrogate markers for cardiovascular disease; however, the impacts of chronic kidney disease (CKD) on changes in IMT are unclear. We examined associations between CKD and IMT in participants with and without type 2 diabetes through longitudinal analysis. METHODS: In total, 424 subjects were enrolled in this study. IMT was measured as per carotid echo indexes. Relationships between IMT and risk factors were analyzed using multiple linear regression analysis, in which we defined IMT as the dependent variable and atherosclerosis-related factors (age, sex, systolic pressure, total cholesterol, body mass index, estimated glomerular filtration rate (eGFR), uric acid, smoking index, number of antihypertensive drugs, statin use, urinary protein levels, past cardiovascular event, glycated hemoglobin, and diabetes duration) as independent variables. RESULTS: The study population was composed of 70.3 % male subjects. Participants with diabetes accounted for 64.4 % of the total population. The mean follow-up duration was 2.2 ± 1.5 years. Alterations in IMT tended to be associated with systolic blood pressure (+10 mmHg) (ß = -0.0084, p = 0.09) and eGFR (+10 mL/min/1.73 m(2)) (ß = -0.0049, p = 0.06) in all participants. In participants without diabetes, alterations in IMT were associated with eGFR (+10 mL/min/1.73 m(2)) (ß = -0.0104, p = 0.03) and tended to be associated with systolic blood pressure (+10 mmHg) (ß = 0.0094, p = 0.06). No significant relationships were found in participants with diabetes. CONCLUSION: Low eGFR was associated with progression of carotid thickness independent of common cardiovascular risk factors in non-diabetic participants.
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Grosor Intima-Media Carotídeo/estadística & datos numéricos , Diabetes Mellitus Tipo 2/patología , Proteinuria/patología , Anciano , Pueblo Asiatico , Aterosclerosis/complicaciones , Presión Sanguínea , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/etiología , Diabetes Mellitus Tipo 2/diagnóstico por imagen , Diabetes Mellitus Tipo 2/orina , Nefropatías Diabéticas/diagnóstico por imagen , Nefropatías Diabéticas/patología , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
Calciphylaxis is a life-threatening complication of end-stage kidney disease (ESKD) and leads to cutaneous necrosis and gangrene. Various risk factors for calciphylaxis have been reported, and warfarin therapy is a particularly strong trigger. Here we report the case of 50-year-old woman with ESKD and systemic lupus erythematosus who developed calciphylaxis after anti-thrombotic therapy, including warfarin, for ischemic skin ulcers due to arteriosclerosis obliterans and anti-phospholipid antibody syndrome. Although warfarin improved the thrombotic skin ulcers, it might also be a trigger for calciphylaxis. Discontinuation of the warfarin and the addition of low-density lipoprotein apheresis and sodium thiosulfate infusion failed to improve the gangrene; eventually, her legs had to be amputated to prevent lethal infection. The histology of the dermal and soft tissue obtained from the amputated legs showed typical findings of calciphylaxis. Warfarin is a vitamin K antagonist with inhibitory effects on the calcification of regulatory proteins, such as matrix Gla protein and fetuin-A. Therefore, the warfarin therapy might have induced calciphylaxis in our patient.
RESUMEN
BACKGROUND: The prognosis in patients with idiopathic membranous nephropathy (IMN) is diverse. However, the prognosis after relapse and factors affecting relapse remain unclear. METHODS: A total of 146 Japanese patients with IMN who had been followed up for at least 3 years, or until end-stage renal failure or death were enrolled in this retrospective study. The initial clinicopathological factors were examined between the patients with and without relapse. The patients were assigned to two groups based on the electron microscopic findings: homogeneous type with synchronous electron-dense deposits and heterogeneous type with various phases of dense deposits. RESULTS: A total of 105 of the 146 patients (72 %) achieved complete remission (CR) or incomplete remission (ICR) I after initial treatment. Twenty-six of the 105 patients relapsed after CR or ICR I (25 %). There were no differences in initial clinical findings or data between the patients with and without relapse, except for the higher degree of proteinuria at onset in patients with relapse. The relapse rate of the heterogeneous group (43 %) was higher than that in the homogeneous group (20 %). There were no significant associations between relapse rate and immunosuppressive therapy at onset. Eleven of 26 patients showing relapse (42 %) achieved CR or ICR I, which was lower than the rate for patients with initial remission. CONCLUSION: Our results suggest that patients with relapse achieved CR or ICR I and that electron microscopic findings demonstrating heterogeneous type indicated susceptibility to relapse.
Asunto(s)
Glomerulonefritis Membranosa/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Femenino , Estudios de Seguimiento , Glomerulonefritis Membranosa/complicaciones , Glomerulonefritis Membranosa/tratamiento farmacológico , Humanos , Inmunosupresores/uso terapéutico , Japón , Masculino , Microscopía Electrónica , Persona de Mediana Edad , Proteinuria/etiología , Recurrencia , Inducción de Remisión , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
BACKGROUND: Although the cardiorenal relationship in chronic kidney disease has been investigated, information about the lung-kidney relationship is limited. Here, we investigated the impact of kidney function and urinary protein excretion on pulmonary dysfunction. METHODS: The data from pulmonary function tests and kidney function (estimated glomerular filtration rate [eGFR] and urinary protein) between 1 April 2005 and 30 June 2010 were selected from our laboratory database. Data were classified into 4 categories according to eGFR and proteinuria. Category 1, eGFR ≥60 ml/min/1.73 m(2) and urinary protein <0.3 g/gCr; category 2, eGFR <60 ml/min/1.73 m(2) and urinary protein <0.3 g/gCr; category 3, eGFR ≥60 ml/min/1.73 m(2) and urinary protein ≥0.3 g/gCr; and category 4, eGFR <60 ml/min/1.73 m(2) and urinary protein ≥0.3 g/gCr. Pulmonary function data were evaluated according to these 4 categories. RESULTS: A total of 133 participants without major respiratory disease, abnormal computed tomography and smoking history were enrolled. Hemoglobin (Hb)-adjusted percentage carbon monoxide diffusing capacity (%DLCO) in category 4 (46.2 ± 7.5) and category 2 (63.6 ± 17.8) were significantly lower than in category 1 (75.8 ± 18.9) (P < 0.05). In addition, Hb-adjusted %DLCO was weakly correlated with eGFR in participants with urinary protein <0.3 g/gCr (R = 0.30, P = 0.001). Hb-adjusted %DLCO was strongly correlated with eGFR in participants with urinary protein ≥0.3 g/gCr (R = 0.81, P < 0.001). Other pulmonary function test markers (percentage (%) vital capacity, % forced expiratory volume in one second (FEV1), FEV1/forced vital capacity, % total lung capacity, and % residual volume) were not significantly different between categories. CONCLUSION: This study suggests that decreased eGFR is associated with decreased %DLCO in proteinuric patients.
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Pulmón/fisiopatología , Proteinuria/fisiopatología , Insuficiencia Renal Crónica/fisiopatología , Adulto , Anciano , Femenino , Tasa de Filtración Glomerular , Humanos , Japón , Masculino , Persona de Mediana Edad , Pruebas de Función RespiratoriaRESUMEN
Diabetic nephropathy (DN) is a major cause of end stage kidney disease and a strong risk factor for cardiovascular diseases. Growing data show chronic inflammation plays an important role for the progression of DN. As for the immune cells, anti-inflammatory leukocytes as well as pro-inflammatory leukocytes play an important role in DN. In addition to leukocytes, renal resident cells contribute to the inflammatory process of DN. However, precise functions, phenotypes and immune balance of renal resident cells remain to be explored. Therefore, we hypothesized that the aberrant immune balance of renal resident cells contributes to the pathogenesis of DN. To explore this possibility, we performed genome-wide transcriptome profiling in mesangial cells and tubular epithelial cells (TECs), which were stimulated by high glucose (HG) and detected the expression of inflammation associated genes. HG increased the mRNA expression of oxidative stress, inflammasome and mammalian target of rapamycin (mTOR) related genes in mesangial cells. Pro-inflammatory/Th1 gene expression was upregulated, but Th2 related gene expression was downregulated in mesangial cells. In TECs, HG stimulation increased pro-inflammatory/Th1/Th2 gene expression. Phosphorylation of signaling proteins shifted towards pro-inflammatory phenotype with suppressed phosphorylation of Th2 related signaling in TECs. The data taken together indicate that HG shifts the immune balance toward pro-inflammatory/Th1 phenotype in mesangial cells and TECs, which might initiate and/or prolong inflammation, thereby resulting in diabetic nephropathy.