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BACKGROUND: Exit-site infection (ESI) is a common recurring complication in patients undergoing peritoneal dialysis (PD). Sucrose and povidone-iodine (SPI) mixtures, antimicrobial ointments that promote wound healing, have been used for the treatment of ulcers and burns, but their efficacy in exit-site care is still unclear. METHODS: This single-center retrospective observational study included patients who underwent PD between May 2010 and June 2022 and presented with episodes of ESI. Patients were divided into SPI and non-SPI groups and followed up from initial ESI onset until PD cessation, death, transfer to another facility, or June 2023. RESULTS: Among the 82 patients (mean age 62, [54-72] years), 23 were treated with SPI. The median follow-up duration was 39 months (range, 14-64), with an overall ESI incidence of 0.70 episodes per patient-year. Additionally, 43.1% of second and 25.6% of third ESI were caused by the same pathogen as the first. The log-rank test demonstrated significantly better second and third ESI-free survival in the SPI group than that in the non-SPI group (p < 0.01 and p < 0.01, respectively). In a Cox regression analysis, adjusting for potential confounders, SPI use was a significant predictor of decreased second and third ESI episodes (hazard ratio [HR], 0.22; 95% confidence interval [CI], 0.10-0.52 and HR, 0.22; 95%CI, 0.07-0.73, respectively). CONCLUSIONS: Our results showed that the use of SPI may be a promising option for preventing the incidence of ESI in patients with PD. TRIAL REGISTRATION: This study was approved by the Keio University School of Medicine Ethics Committee (approval number 20231078) on August 28, 2023. Retrospectively registered.
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Antiinfecciosos Locales , Infecciones Relacionadas con Catéteres , Diálisis Peritoneal , Povidona Yodada , Sacarosa , Humanos , Povidona Yodada/uso terapéutico , Persona de Mediana Edad , Estudios Retrospectivos , Masculino , Femenino , Anciano , Antiinfecciosos Locales/uso terapéutico , Infecciones Relacionadas con Catéteres/prevención & control , Infecciones Relacionadas con Catéteres/etiología , Catéteres de Permanencia/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: The use of simulated patients (SPs) to assess medical students' clinical performance is gaining prominence, underscored by patient safety perspective. However, few reports have investigated the validity of such assessment. Here, we examined the validity and reliability of an assessment tool that serves as a standardized tool for SPs to assess medical students' medical interview. METHODS: This longitudinal survey was conducted at Keio University School of Medicine in Japan from 2014 to 2021. To establish content validity, the simulated patient assessment tool (SPAT) was developed by several medical education specialists from 2008 to 2013. A cohort of 36 SPs assessed the performance of 831 medical students in clinical practice medical interview sessions from April 2014 to December 2021. The assessment's internal structure was analyzed using descriptive statistics (maximum, minimum, median, mean, and standard deviation) for the SPAT's 13 item total scores. Structural validity was examined with exploratory factor analysis, and internal consistency with Cronbach's alpha coefficients. The mean SPAT total scores across different SPs and scenarios were compared using one way analysis of variance (ANOVA). Convergent validity was determined by correlating SPAT with the post-clinical clerkship obstructive structured clinical examination (post-CC OSCE) total scores using Pearson's correlation coefficient. RESULTS: Of the 831 assessment sheets, 36 with missing values were excluded, leaving 795 for analysis. Thirty-five SPs, excluding one SP who quit in 2014, completed 795 assessments, for a response rate of 95.6%. Exploratory factor analysis revealed two factors, communication and physician performance. The overall Cronbach's alpha coefficient was 0.929. Significant differences in SPAT total scores were observed across SPs and scenarios via one-way ANOVA. A moderate correlation (r =.212, p <.05) was found between SPAT and post-CC OSCE total scores, indicating convergent validity. CONCLUSIONS: Evidence for the validity of SPAT was examined. These findings may be useful in the standardization of SP assessment of the scenario-based clinical performance of medical students.
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Educación Médica , Estudiantes de Medicina , Humanos , Evaluación Educacional , Reproducibilidad de los Resultados , Comunicación , Competencia ClínicaRESUMEN
In this study, we developed and validated the Clinical Student Version of the Japanese Interprofessional Competency Self-Assessment Scale (C-JASSIC) for healthcare students in their clinical practice phase. Data obtained from 331 students (medical, 98; nursing, 99; pharmacy, 134) during orientation for interprofessional education (pre-IPE) and from 319 students (medical, 94; nursing, 93; pharmacy, 132) within a week following IPE (post-IPE) were analyzed. Exploratory pre-IPE and Confirmatory post-IPE factor analyses revealed a consistent 6-factor structure aligning with the Japanese Interprofessional Competency domains. The scale exhibited strong internal consistency, with Cronbach's α values exceeding 0.8 for all factors both pre- and post-IPE. Scores for overall competency and individual domains increased post-IPE in 234 matched cases. A notable significant pre vs post difference concerned "Understanding of Others," indicating enhanced interprofessional comprehension after clinical practice. There was a weak but significant positive correlation between IPE satisfaction and difference in pre- and post-IPE scores. However, no significant differences were observed among medical, nursing, and pharmacy students. Despite its strengths, such as its competency-based design and cultural relevance to Japan, a limitation of the study may be potential self-reporting bias. Nonetheless, C-JASSIC represents a valuable tool for seamless competency evaluations from student to professional stages, with implications for broader Asian contexts.
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Relaciones Interprofesionales , Autoevaluación (Psicología) , Humanos , Japón , Reproducibilidad de los Resultados , Estudiantes del Área de la Salud/psicología , Competencia Clínica , Femenino , Masculino , Psicometría , Pueblos del Este de AsiaRESUMEN
BACKGROUND: In the enhancement of allergy care involving multidisciplinary and multiple medical departments, there is a perceived need for education that targets not only specialists but also non-specialists. However, research on the need for and methods of such education remains inadequate. OBJECTIVE: To design a remote allergy care education program for all medical practitioners and to validate its necessity and utility. METHODS: The Empowering Next Generation Allergist/immunologist toward Global Excellence Task Force (ENGAGE-TF), supported by the Japanese Society of Allergology, initiated a virtual educational program called 'Outreach Lectures' in collaboration with Keio University and Fukui University. This initiative was widely promoted through social media and various institutions, and a survey was conducted through its mailing list. RESULTS: 1139 responses were obtained. More than half were physicians from non-allergy specialties, representing a diverse range of healthcare professions. Over 70% expressed being 'very satisfied,' and over 60% found the difficulty level 'appropriate.' Free-form feedback revealed differences in learning focus based on profession and learning approach based on years of experience. CONCLUSION: The high participation rate (90%) of non-specialist physicians underscores the demand for addressing allergic conditions in primary care. The effectiveness of virtual / recurrent education, particularly for healthcare professionals with over 11 years of experience, was implied. Further follow-up investigation focusing on quantitative and objective assessment of educational effectiveness is indispensable.
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Alergia e Inmunología , Hipersensibilidad , Encuestas y Cuestionarios , Humanos , Alergia e Inmunología/educación , Educación a DistanciaRESUMEN
BACKGROUND: microRNAs (miRNAs) are non-coding small RNAs that regulate embryonic development, cell differentiation and pathological processes via interaction with mRNA. Epithelial-mesenchymal transition (EMT) is pathological process that involves in a variety of diseases such as cancer or fibrosis. METHODS: In this study, we identified miR-363 as a potent inducer of EMT by microarray analysis in human kidney tubular cells, and analyzed the function and mechanisms of miR-363. RESULTS: Overexpression of miR-363 induced mesenchymal phenotypes with loss of epithelial phenotypes in human kidney tubular cells. In addition, in vitro scratch assay demonstrated that miR-363 promotes cell migration of primary culture of human kidney tubular cells. We identified TWIST/canonical WNT pathway as the downstream effecter of miR-363, and inhibition of canonical WNT by small molecule, IWR-1, attenuated EMT induced by miR-363. CONCLUSION: miR-363 induces transdifferentiation of human kidney tubular cells via upregulation of TWIST/canonical WNT pathway.
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Transdiferenciación Celular , Células Epiteliales/metabolismo , Transición Epitelial-Mesenquimal , Túbulos Renales/metabolismo , MicroARNs/metabolismo , Línea Celular , Movimiento Celular , Transdiferenciación Celular/efectos de los fármacos , ARN Helicasas DEAD-box/genética , ARN Helicasas DEAD-box/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Perfilación de la Expresión Génica/métodos , Humanos , Imidas/farmacología , Túbulos Renales/efectos de los fármacos , Túbulos Renales/patología , MicroARNs/efectos de los fármacos , MicroARNs/genética , Proteínas Nucleares/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Fenotipo , Cultivo Primario de Células , Quinolinas/farmacología , Interferencia de ARN , Ribonucleasa III/genética , Ribonucleasa III/metabolismo , Transfección , Factor de Crecimiento Transformador beta/farmacología , Proteína 1 Relacionada con Twist/metabolismo , Vía de Señalización WntRESUMEN
Over the past few decades, several cardiac autoantibodies have been reported in sera from patients with dilated cardiomyopathy (DCM). Immunoadsorption (IA) therapy is one of the therapeutic tools to remove such autoantibodies. The objective of this study was to investigate functional effects of IA therapy using a tryptophan column in severe DCM patients. Of 49 patients enrolled, 44 were randomized from 10 sites in Japan. IA therapy was conducted in 40 patients with DCM (refractory to standard therapy for heart failure, New York Heart Association [NYHA] class III/IV, left ventricular ejection fraction [LVEF] <30%). Mean echocardiographic LVEF was significantly improved (23.8 ± 1.3% to 25.9 ± 1.3%, P = 0.0015). However, mean radionuclide LVEF over 3 months of IA therapy was not significantly improved (20.8 ± 1.1% to 21.9 ± 1%, P = 0.0605). The cardiothoracic ratio was also significantly decreased (P = 0.0010). NYHA functional class (P < 0.0001), subjective symptoms assessed by a quality of life questionnaire (P = 0.0022), maximum oxygen consumption (P = 0.0074), and 6-minute walk distance (P = 0.0050) were improved after IA therapy. Subgroup analysis revealed improvement of echocardiographic LVEF in patients with higher baseline autoantibody scores but not in those with lower scores. IA therapy improved subjective symptoms and exercise capacity in patients with refractory heart failure resulting from DCM. Favorable effect on cardiac function was noted in patients with higher autoantibody scores. J. Clin. Apheresis 31:535-544, 2016. © 2015 Wiley Periodicals, Inc.
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Autoanticuerpos/sangre , Cardiomiopatía Dilatada/terapia , Técnicas de Inmunoadsorción/normas , Triptófano/uso terapéutico , Ejercicio Físico/fisiología , Humanos , Consumo de Oxígeno/fisiología , Seguridad del Paciente , Estudios Prospectivos , Calidad de Vida , Volumen Sistólico/fisiología , Resultado del TratamientoRESUMEN
BACKGROUND: Primary biliary cirrhosis (PBC) is an immune-mediated chronic cholestatic liver disease, characterized by increased concentrations of serum IgM and the presence of circulating anti-mitochondrial antibodies. Although bone diseases such as osteoporosis or osteodystrophy are commonly associated with PBC, osteomalacia which is caused by abnormal vitamin D metabolism, mineralization defects, and phosphate deficiency has not been recognized as a complication of PBC. CASE PRESENTATION: We report the case of a 49-year-old Japanese woman who complained of multiple fractures. Hypophosphatemic osteomalacia was diagnosed from a low serum phosphorus level, 1,25-dihydroxyvitamin D3 level, high levels of bone specific alkaline phosphatase and the findings of bone scintigraphy, although a bone biopsy was not performed. Twenty four hour urine demonstrated a low renal fractional tubular reabsorption of phosphate, increased fractional excretion of uric acid and generalized aminoaciduria. An intravenous bicarbonate loading test suggested the presence of proximal renal tubular acidosis (RTA). These biochemical data indicated Fanconi syndrome with proximal RTA. A kidney biopsy demonstrated the features of tubulointerstitial nephritis (TIN). The patient was also suspected as having primary biliary cirrhosis (PBC) because of high levels of alkaline phosphatase, IgM and the presence of anti-mitochondrial M2 antibody, though biochemical liver function was normal. Sequential liver biopsy was compatible with PBC and the diagnosis of PBC was definite. After administration of 1,25 dihydroxyvitamin D3, neutral potassium phosphate, sodium bicarbonate for osteomalacia and subsequent predonizolone for TIN, symptoms of fractures were relieved and renal function including Fanconi syndrome was ameliorated. CONCLUSION: In this case, asymptomatic PBC was shown to induce TIN with Fanconi syndrome with dysregulation of electrolytes and vitamin D metabolism, which in turn led to osteomalacia with multiple fractures. Osteomalacia has not been recognized as a result of the renal involvement of PBC. PBC and its rare complication of TIN with Fanconi syndrome should be considered in adult patients with unexplained osteomalacia even in the absence of liver dysfunction.
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Síndrome de Fanconi/diagnóstico , Fracturas Múltiples/etiología , Cirrosis Hepática Biliar/complicaciones , Nefritis Intersticial/complicaciones , Osteomalacia/diagnóstico , Osteomalacia/etiología , Diagnóstico Diferencial , Síndrome de Fanconi/complicaciones , Síndrome de Fanconi/terapia , Femenino , Fracturas Múltiples/diagnóstico , Fracturas Múltiples/terapia , Humanos , Cirrosis Hepática Biliar/diagnóstico , Cirrosis Hepática Biliar/terapia , Persona de Mediana Edad , Nefritis Intersticial/diagnóstico , Nefritis Intersticial/terapia , Osteomalacia/terapia , Resultado del TratamientoRESUMEN
Chronic kidney disease (CKD) is associated with multiple complications, with recent scholarly attention underscoring cognitive impairment as a salient manifestation. Considering societal aging, preserving cognitive function has emerged as an urgent medical concern. Prolonged dialysis, encompassing hemodialysis (HD) and peritoneal dialysis (PD), has been associated with a decline in cognitive function. Here, we present the cases of three patients undergoing PD who exhibited a noticeable improvement in cognitive function upon the initiation of HD. One patient had exhibited mild cognitive decline, whereas the remaining two presented more severe impairment. Apart from a mild tendency for fluid retention, none of the three patients exhibited abnormalities in physical or imaging examinations. Evaluation using the Japanese version of the Montreal Cognitive Assessment (MoCA-J) yielded decreased scores across multiple domains, notably in executive and attention functions. However, after HD initiation, all patients demonstrated a marked enhancement in multiple MoCA-J parameters, accompanied by a significant improvement in subjective symptoms. Moreover, improvements in anemia and hypoalbuminemia were observed in all three patients, whereas consistent trends in other parameters were absent. These clinical observations suggest that the integration of HD into the therapeutic regimen of patients undergoing PD may enhance cognitive function, highlighting the contributory roles of hemoglobin and albumin in CKD-associated cognitive impairment.
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Hyperkalemia is a well-recognized electrolyte abnormality in patients with chronic kidney disease (CKD). Potassium binders are often used to prevent and treat hyperkalemia. However, few studies have evaluated the difference in serum potassium (K+) level-lowering effect during the post-acute phase between the novel potassium binder, sodium zirconium cyclosilicate (ZSC), and conventional agents. This retrospective study included patients who received potassium binders (either ZSC or calcium polystyrene sulfonate [CPS]) in our hospital between May 2020 and July 2022. The patients were divided into the ZSC and CPS groups. After propensity score matching, we compared changes from baseline to the first follow-up point, at least 4 weeks after initiating potassium binders, in electrolytes including K+ level between the two groups. Of the 132 patients, ZSC and CPS were administered in 48 and 84 patients, respectively. After matching, 38 patients were allocated to each group. The ZSC group showed greater reduction in K+ levels than did the CPS group (P < 0.05). Moreover, a significant increase in serum sodium minus chloride levels, a surrogate marker for metabolic acidosis, was observed in the ZSC group (P < 0.05). Our results demonstrated that ZSC could potentially improve hyperkalemia and metabolic acidosis in patients with CKD.
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The common histopathology of antineutrophil cytoplasmic antibody-associated vasculitis comprises pauci-immune crescentic glomerulonephritis with concomitant tubulointerstitial nephritis. Tubulointerstitial nephritis in the absence of glomerular involvement in patients with antineutrophil cytoplasmic antibody-associated vasculitis is uncommon. We report a case of antineutrophil cytoplasmic antibody-associated vasculitis-associated acute kidney injury manifesting as tubulointerstitial nephritis without glomerulonephritis. A 75-year-old woman with fever, cough, and myalgia developed kidney dysfunction with inflammatory reactions and tubular-type proteinuria, without glomerular hematuria. A kidney biopsy revealed tubulointerstitial nephritis with arteritis. We ruled out important underlying etiologies of tubulointerstitial nephritis, including infection, drug reactions, and autoimmune diseases. Since chest high-resolution computed tomography demonstrated mild interstitial pneumonia in bilateral lower lung fields, myeloperoxidase antineutrophil cytoplasmic antibody was measured and found to be positive. Therefore, we diagnosed the patient with antineutrophil cytoplasmic antibody-associated vasculitis-associated tubulointerstitial nephritis but not glomerulonephritis, and interstitial pneumonia. The patient's kidney function and symptoms markedly improved with prednisolone treatment. Clinicians should maintain high-level vigilance for antineutrophil cytoplasmic antibody-associated vasculitis as a possible underlying component of tubulointerstitial nephritis, particularly when kidney function deteriorates with tubulointerstitial injuries without glomerular features.
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The proximal straight tubule (S3 segment) of the kidney is highly susceptible to ischemia and toxic insults but has a remarkable capacity to repair its structure and function. In response to such injuries, complex processes take place to regenerate the epithelial cells of the S3 segment; however, the precise molecular mechanisms of this regeneration are still being investigated. By applying the "toxin receptor mediated cell knockout" method under the control of the S3 segment-specific promoter/enhancer, Gsl5, which drives core 2 ß-1,6-N-acetylglucosaminyltransferase gene expression, we established a transgenic mouse line expressing the human diphtheria toxin (DT) receptor only in the S3 segment. The administration of DT to these transgenic mice caused the selective ablation of S3 segment cells in a dose-dependent manner, and transgenic mice exhibited polyuria containing serum albumin and subsequently developed oliguria. An increase in the concentration of blood urea nitrogen was also observed, and the peak BUN levels occurred 3-7 days after DT administration. Histological analysis revealed that the most severe injury occurred in the S3 segments of the proximal tubule, in which tubular cells were exfoliated into the tubular lumen. In addition, aquaporin 7, which is localized exclusively to the S3 segment, was diminished. These results indicate that this transgenic mouse can suffer acute kidney injury (AKI) caused by S3 segment-specific damage after DT administration. This transgenic line offers an excellent model to uncover the mechanisms of AKI and its rapid recovery.
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Lesión Renal Aguda/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Túbulos Renales Proximales/patología , Lesión Renal Aguda/patología , Secuencia de Aminoácidos , Animales , Toxina Diftérica/toxicidad , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Células Epiteliales/patología , Factor de Crecimiento Similar a EGF de Unión a Heparina , Humanos , Túbulos Renales Proximales/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Datos de Secuencia Molecular , N-Acetilglucosaminiltransferasas/genética , Regiones Promotoras Genéticas , Secuencias Reguladoras de Ácidos NucleicosRESUMEN
Idiopathic multicentric Castleman disease (iMCD) is a systemic and polyclonal lymphoproliferative disease involving multiple organs, including the kidneys, due to the overproduction of interleukin-6 (IL-6). Recently, several reports have suggested that excessive IL-6 actions in iMCD could have a causal relationship with the development of diverse histopathological renal manifestations that cause nephrotic syndrome. However, the treatment for such cases remains unclear. We report a series of three cases of nephrotic syndrome due to iMCD that helps to delineate the importance of early and continuous therapy with the anti-interleukin-6 receptor antibody tocilizumab. First, treatment was suspended for infectious control, and the patient presented with nephrotic syndrome due to diffuse mesangial and endocapillary hypercellularity without immune deposits complicating acute kidney injury. Second, iMCD was treated with prednisolone alone. The patient suddenly developed nephrotic syndrome due to immune-complex glomerulonephritis, not otherwise specified, complicated with acute kidney injury. In the third case, nephrotic syndrome secondary to membranous glomerulonephritis was diagnosed, with a skin rash and IgE antibodies to tocilizumab, and was therefore treated with prednisolone alone. In contrast to the first two cases, the third progressed to end-stage renal disease on hemodialysis. Taken together, this series suggests that clinicians should maintain clinical vigilance for iMCD as a possible underlying component of nephrotic syndrome, since iMCD presents with a variety of renal pathologies. Prompt initiation and continuous administration of tocilizumab are likely key determinants of renal outcomes in such cases. In particular, when tocilizumab is suspended due to infection or in the perioperative period, consideration of its expeditious resumption should be made, taking into account both the withdrawal period and systemic conditions.
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Although the majority of renal amyloidosis is caused by either acquired monoclonal immunoglobulin light-chain amyloidosis or reactive systemic amyloid A, some cases are caused by hereditary amyloidosis. Apolipoprotein A-II (apoAII) amyloidosis is a rare form of hereditary amyloidosis and cannot be diagnosed by a routine examination. Thus, the prevalence and etiology of apoAII amyloidosis are uncertain. In humans, a genetic mutation in the stop codon of apoAII is considered to be a cause of amyloid fibril formation. We report on a 68-year-old man who presented with proteinuria by apoAII amyloidosis without family history. His proteinuria gradually increased to 6 g/day within 1 year. A renal biopsy showed amyloid deposition in the glomeruli, however, acquired monoclonal immunoglobulin light-chain amyloidosis and reactive systemic amyloid A were ruled out. Immunohistochemistry revealed apoAII deposition in the glomeruli, but DNA sequencing did not identify any genetic mutation in the coding sequence of apoAII. Here, we report a case of apoAII amyloidosis without a genetic mutation in the coding sequence and discuss the etiology of apoAII amyloidosis.
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Amiloidosis/patología , Apolipoproteína A-II , Enfermedades Renales/patología , Anciano , Amiloidosis/genética , Apolipoproteína A-II/genética , Humanos , Inmunohistoquímica , Riñón/metabolismo , MasculinoRESUMEN
BACKGROUND: Certain cardiac-specific autoantibodies found in patients with dilated cardiomyopathy (DCM) play a role in mediating myocardial damage and fatal ventricular arrhythmias resulting in sudden cardiac death. Immunoadsorption therapy (IA) is one of the therapeutic tools to remove such autoantibodies. Clinical studies from Germany have shown that nonspecific IA using columns loaded by sheep antihuman IgG or protein A improved hemodynamic data and affected favorably cardiac function and survival in patients with heart failure (HF) due to DCM. The goal of this study is to determine if IA therapy using the high-profile tryptophan column, which has high affinity for IgG3 subclass, affects favorably cardiac function in patients with severe HF who are refractory to conventional therapy. METHODS AND RESULTS: IA therapy was conducted in 16 patients with DCM (age 53 ± 4, male 8, New York Heart Association functional class III/IV, mean ejection fraction 18 ± 2%). Study subjects had autoantibodies directed against either ß1-adrenergic or M2-muscarinic receptors. Plasma brain natriuretic peptide levels were significantly decreased after IA (P = 0.016). Plasma inflammatory cytokines including interleukin-6 and tumor necrosis factor-α did not change after each session of IA. Six-minute walk distance was significantly increased after IA (P = 0.01). Left ventricular ejection fraction increased by 3% 3 months after IA (P = 0.039). CONCLUSIONS: Our initial experience demonstrated safety and short-term efficacy of IA using a new IgG3-specific tryptophan column for patients with advanced HF due to DCM. Long-term follow-up is needed to confirm the effects on cardiac function and morbidity/mortality in such patients.
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Cardiomiopatía Dilatada/complicaciones , Insuficiencia Cardíaca/terapia , Inmunoglobulina G/inmunología , Técnicas de Inmunoadsorción , Triptófano/metabolismo , Adulto , Anciano , Secuencia de Aminoácidos , Femenino , Insuficiencia Cardíaca/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Péptido Natriurético Encefálico/sangre , Función Ventricular IzquierdaRESUMEN
It is not clear whether interstitial fibroblasts or tubular epithelial cells are primarily responsible for the profibrotic effects of NF-κB activation during renal fibrogenesis. Here, we crossed mice carrying a conditional IκB dominant-negative transgene (IκBdN) with mice transgenic for cell-specific FSP1.Cre (FSP1(+) fibroblasts) or γGT.Cre (proximal tubular epithelia) and challenged all progeny with unilateral ureteral obstruction. We determined NF-κB activation by nuclear localization of phosphorylated p65 ((p)p65) in renal tissues after 7 days. We observed inhibition of NF-κB activation in interstitial cells and tubular epithelia in obstructed kidneys of FSP1.Cre;IκBdN and γGT.Cre;IκBdN mice, respectively, compared with IκBdN controls (P < 0.05). Deposition of extracellular matrix, however, was significantly lower in the obstructed kidneys of FSP1.Cre;IκBdN mice but not in γGT.Cre;IκBdN mice (P < 0.05). In addition, levels of mRNA encoding the profibrotic PAI-1, fibronectin-EIIIA, and type I (α1) procollagen were significantly lower in obstructed kidneys of FSP1.Cre;IκBdN mice compared with γGT.Cre;IκBdN mice (P < 0.05). Taken together, these data support a profibrotic role for fibroblasts, but not proximal tubular epithelial cells, in modulating NF-κB activation during renal fibrogenesis.
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Fibroblastos/metabolismo , Regulación de la Expresión Génica , Proteínas I-kappa B/genética , Enfermedades Renales/genética , Enfermedades Renales/patología , Animales , Modelos Animales de Enfermedad , Fibroblastos/patología , Fibrosis/genética , Fibrosis/patología , Fibrosis/fisiopatología , Proteínas I-kappa B/metabolismo , Proteínas I-kappa B/farmacología , Inmunohistoquímica , Enfermedades Renales/fisiopatología , Masculino , Ratones , Ratones Transgénicos , Inhibidor NF-kappaB alfa , Reacción en Cadena de la Polimerasa , ARN Mensajero/análisis , Distribución Aleatoria , Valores de Referencia , Sensibilidad y Especificidad , TransgenesRESUMEN
The "preconditioning effect" in AKI is a phenomenon in which an episode of ischemia-reperfusion results in tolerance to subsequent ischemia-reperfusion injury. However, its relationship between DNA damage repair has not been elucidated. Here, we show the role of KAT5 in the preconditioning effect. Preconditioning attenuated DNA damage in proximal tubular cells with elevated KAT5 expression. Ischemia-reperfusion (IR) injuries were exacerbated, and preconditioning effect vanished in proximal tubular-cell-specific KAT5 knockout mice. Investigation of tubuloglomerular feedback (TGF) by MALDI-IMS and urinary adenosine revealed that preconditioning caused attenuated TGF at least in part via KAT5. In addition, K-Cl cotransporter 3 (KCC3) expression decreased in damaged proximal tubular cells, which may be involved in accelerated TGF following IR. Furthermore, KAT5 induced KCC3 expression by maintaining chromatin accessibility and binding to the KCC3 promoter. These results suggest a novel mechanism of the preconditioning effect mediated by the promotion of DNA repair and attenuation of TGF through KAT5.
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BACKGROUND: Cardiodepressant IgG3 autoantibodies (CD-Abs) can be targeted by apheresis. Using blinded measurements of CD-Abs before and after immunoadsorption (IA), the cardiac function of patients who did or did not achieve complete CD-Abs elimination was compared. METHODS AND RESULTS: Autoantibodies were completely removed from 18 patients with heart failure (New York Heart Association class 3 or 4, left ventricular ejection fraction (LVEF) <30%) using a selective IgG3 adsorption column. All patients had anti-beta1-adrenergic and/or M2-muscarinic autoantibodies before IA, and all LVEF were measured on radionuclide ventriculography. CD-Abs were measured before and after IA, and patient status was blinded until all measurements were collected. Treatment was defined as complete when CD-Abs status changed from positive to negative after IA. Other instances were defined as incomplete. Six-min walk test results and brain natriuretic peptide levels improved significantly after IA (P<0.01). The increase in LVEF 3 months after IA was significantly greater after complete treatment in comparison to the incomplete treatment group (19+/-8-29+/-9% vs 18+/-9-17+/-8%, P<0.01). Cardiac insufficiency events were also more frequent in the incomplete treatment group. CONCLUSIONS: Complete elimination of CD-Abs with apheresis may be related to improved cardiac function in the treatment of heart failure.
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Autoanticuerpos/aislamiento & purificación , Insuficiencia Cardíaca/terapia , Inmunoglobulina G/inmunología , Técnicas de Inmunoadsorción , Adulto , Anciano , Autoanticuerpos/inmunología , Eliminación de Componentes Sanguíneos , Femenino , Insuficiencia Cardíaca/inmunología , Humanos , Masculino , Persona de Mediana Edad , Receptor Muscarínico M2/inmunología , Receptores Adrenérgicos beta/inmunología , Volumen Sistólico/efectos de los fármacos , Resultado del Tratamiento , Adulto JovenRESUMEN
Embryonic stem (ES) cells which have the unlimited proliferative capacity and extensive differentiation potency can be an attractive source for kidney regeneration therapies. Recent breakthroughs in the generation of induced pluripotent stem (iPS) cells have provided with another potential source for the artificially-generated kidney. The purpose of this study is to know how to differentiate mouse ES and iPS cells into renal lineage. We used iPS cells from mouse fibroblasts by transfection of four transcription factors, namely Oct4, Sox2, c-Myc and Klf4. Real-time PCR showed that renal lineage markers were expressed in both ES and iPS cells after the induction of differentiation. It also showed that a tubular specific marker, KSP progressively increased to day 18, although the differentiation of iPS cells was slower than ES cells. The results indicated that renal lineage cells can be differentiated from both murine ES and iPS cells. Several inducing factors were tested whether they influenced on cell differentiation. In ES cells, both of GDNF and BMP7 enhanced the differentiation to metanephric mesenchyme, and Activin enhanced the differentiation of ES cells to tubular cells. Activin also enhanced the differentiation of iPS cells to tubular cells, although the enhancement was lower than in ES cells. ES and iPS cells have a potential to differentiate to renal lineage cells, and they will be an attractive resource of kidney regeneration therapy. This differentiation is enhanced by Activin in both ES and iPS cells.
Asunto(s)
Diferenciación Celular , Linaje de la Célula , Células Madre Embrionarias/fisiología , Túbulos Renales/citología , Células Madre Pluripotentes/fisiología , Activinas/farmacología , Animales , Proteína Morfogenética Ósea 7/farmacología , Células Madre Embrionarias/efectos de los fármacos , Factor Neurotrófico Derivado de la Línea Celular Glial/farmacología , Túbulos Renales/fisiología , Factor 4 Similar a Kruppel , Ratones , Células Madre Pluripotentes/efectos de los fármacos , RegeneraciónRESUMEN
The derivation of kidney tissues from human pluripotent stem cells (hPSCs) and its application for replacement therapy in end-stage renal disease have been widely discussed. Here we report that consecutive transfections of two sets of synthetic mRNAs encoding transcription factors can induce rapid and efficient differentiation of hPSCs into kidney tissues, termed induced nephron-like organoids (iNephLOs). The first set - FIGLA, PITX2, ASCL1 and TFAP2C, differentiated hPSCs into SIX2+SALL1+ nephron progenitor cells with 92% efficiency within 2 days. Subsequently, the second set - HNF1A, GATA3, GATA1 and EMX2, differentiated these cells into PAX8+LHX1+ pretubular aggregates in another 2 days. Further culture in both 2-dimensional and 3-dimensional conditions produced iNephLOs containing cells characterized as podocytes, proximal tubules, and distal tubules in an additional 10 days. Global gene expression profiles showed similarities between iNephLOs and the human adult kidney, suggesting possible uses of iNephLOs as in vitro models for kidneys.