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BACKGROUND: Clonal hematopoiesis (CH), which results from an array of nonmalignant driver gene mutations, can lead to altered immune cell function and chronic disease, and has been associated with worse outcomes in patients with heart failure (HF) with reduced ejection fraction. However, the role of CH in the prognosis of HF with preserved ejection fraction (HFpEF) has been understudied. This study aimed to characterize CH in patients with HFpEF and elucidate its causal role in a murine model. METHODS: Using a panel of 20 candidate CH driver genes and a variant allele fraction cutoff of 0.5%, ultradeep error-corrected sequencing identified CH in a cohort of 81 patients with HFpEF (mean age, 71±6 years; ejection fraction, 63±5%) and 36 controls without a diagnosis of HFpEF (mean age, 74±7 years; ejection fraction, 61.5±8%). CH was also evaluated in a replication cohort of 59 individuals with HFpEF. RESULTS: Compared with controls, there was an enrichment of TET2-mediated CH in the HFpEF patient cohort (12% versus 0%, respectively; P=0.02). In the HFpEF cohort, patients with CH exhibited exacerbated diastolic dysfunction in terms of E/e' (14.9 versus 11.7, respectively; P=0.0096) and E/A (1.69 versus 0.89, respectively; P=0.0206) compared with those without CH. The association of CH with exacerbated diastolic dysfunction was corroborated in a validation cohort of individuals with HFpEF. In accordance, patients with HFpEF, an age ≥70 years, and CH exhibited worse prognosis in terms of 5-year cardiovascular-related hospitalization rate (hazard ratio, 5.06; P=0.042) compared with patients with HFpEF and an age ≥70 years without CH. To investigate the causal role of CH in HFpEF, nonconditioned mice underwent adoptive transfer with Tet2-wild-type or Tet2-deficient bone marrow and were subsequently subjected to a high-fat diet/L-NAME (Nω-nitro-l-arginine methyl ester) combination treatment to induce features of HFpEF. This model of Tet2-CH exacerbated cardiac hypertrophy by heart weight/tibia length and cardiomyocyte size, diastolic dysfunction by E/e' and left ventricular end-diastolic pressure, and cardiac fibrosis compared with the Tet2-wild-type condition. CONCLUSIONS: CH is associated with worse heart function and prognosis in patients with HFpEF, and a murine experimental model of Tet2-mediated CH displays greater features of HFpEF.
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Insuficiencia Cardíaca , Disfunción Ventricular Izquierda , Humanos , Ratones , Animales , Anciano , Anciano de 80 o más Años , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/tratamiento farmacológico , Volumen Sistólico , Función Ventricular Izquierda , Hematopoyesis Clonal/genética , Disfunción Ventricular Izquierda/genéticaRESUMEN
The inappropriate over-activation of the with-no-lysine kinase (WNK)-STE20/SPS1-related proline/alanine-rich kinase (SPAK)-sodium chloride cotransporter (NCC) phosphorylation cascade increases sodium reabsorption in distal kidney nephrons, resulting in salt-sensitive hypertension. Although chronic kidney disease (CKD) is a common cause of salt-sensitive hypertension, the involvement of the WNK phosphorylation cascade is unknown. Moreover, the effect of immune systems on WNK kinases has not been investigated despite the fact that immune systems are important for salt sensitivity. Here we demonstrate that the protein abundance of WNK1, but not of WNK4, was increased at the distal convoluted tubules in the aristolochic acid nephropathy mouse model of CKD. Accordingly, the phosphorylation of both SPAK and NCC was also increased. Moreover, a high-salt diet did not adequately suppress activation of the WNK1-SPAK-NCC phosphorylation cascade in this model, leading to salt-sensitive hypertension. WNK1 also was increased in adenine nephropathy, but not in subtotal nephrectomy, models of CKD. By comparing the transcripts of these three models focusing on immune systems, we hypothesized that tumor necrosis factor (TNF)-α regulates WNK1 protein expression. In fact, TNF-α increased WNK1 protein expression in cultured renal tubular cells by reducing the transcription and protein levels of NEDD4-2 E3-ligase, which degrades WNK1 protein. Furthermore, the TNF-α inhibitor etanercept reversed the reduction of NEDD4-2 expression and upregulation of the WNK1-SPAK-NCC phosphorylation cascade in distal convoluted tubules in vivo in the aristolochic acid nephropathy model. Thus, salt-sensitive hypertension is induced in CKD via activation of the renal WNK1- SPAK-NCC phosphorylation cascade by TNF-α, reflecting a link with the immune system.
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Hipertensión , Insuficiencia Renal Crónica , Animales , Hipertensión/inducido químicamente , Ratones , Fosforilación , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Insuficiencia Renal Crónica/inducido químicamente , Factor de Necrosis Tumoral alfa , Proteína Quinasa Deficiente en Lisina WNK 1RESUMEN
With-no-lysine kinase (WNK) plays important roles in regulating electrolyte homeostasis, cell signaling, survival, and proliferation. It has been recently demonstrated that WNK1, a member of the WNK family, modifies the function of immune cells. Here we report that in macrophages, WNK1 has suppressive effects on lipopolysaccharide (LPS)-induced inflammatory responses via TGFß-activated kinase 1 (TAK1)-mediated activation of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathway. We found that WNK1 heterozygous (WNK1+/-) mice produced excessive proinflammatory cytokines in an experimental LPS-induced sepsis model, and peritoneal macrophages isolated from WNK1+/- mice produced higher levels of LPS-induced cytokines and NOS2 expression as canonical proinflammatory M1 macrophage markers. We confirmed that small hairpin RNA (shRNA)-mediated knockdown of WNK1 activated LPS-induced cytokine production and NOS2 expression in RAW 264.7 macrophages. Moreover, we demonstrated that WNK1 knockdown increased the nuclear translocation of NF-κB and activated the p38 and Jun N-terminal kinase (JNK) MAPK signaling pathway and that a TAK1 inhibitor diminished these effects of WNK1 knockdown. These results suggest that WNK1 acts as a physiologic immune modulator via interactions with TAK1. WNK1 may be a therapeutic target against the cytokine storm caused by sepsis.
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Citocinas/biosíntesis , Quinasas Quinasa Quinasa PAM/metabolismo , Activación de Macrófagos , Macrófagos/inmunología , Sepsis/inmunología , Proteína Quinasa Deficiente en Lisina WNK 1/metabolismo , Animales , Células Cultivadas , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Lipopolisacáridos , Quinasas Quinasa Quinasa PAM/fisiología , Sistema de Señalización de MAP Quinasas , Macrófagos/efectos de los fármacos , Macrófagos/enzimología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , FN-kappa B/metabolismo , Células RAW 264.7 , Sepsis/inducido químicamente , Sepsis/enzimología , Proteína Quinasa Deficiente en Lisina WNK 1/genética , Proteína Quinasa Deficiente en Lisina WNK 1/fisiología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Ac1PIM1 is a potential biosynthetic intermediate for phosphatidylinositol mannosides (PIMs) from Mycobacterium tuberculosis. We achieved the first synthesis of Ac1PIM1 by utilizing an allyl-type protecting group strategy and regioselective phosphorylation of inositol. A very potent agonist of an innate immune receptor DCAR, which is better than previously known agonists, is demonstrated.
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Inmunomodulación/efectos de los fármacos , Lectinas Tipo C/agonistas , Mycobacterium tuberculosis/química , Fosfatidilinositoles/farmacología , Receptores Inmunológicos/agonistas , Animales , Citocinas/biosíntesis , Lectinas Tipo C/inmunología , Ratones , Mycobacterium tuberculosis/inmunología , Fosfatidilinositoles/síntesis química , Fosfatidilinositoles/química , Fosforilación , Células RAW 264.7 , Receptores Inmunológicos/inmunologíaRESUMEN
BACKGROUND: Delirium is an independent predictor of death in patients undergoing dialysis for end-stage renal disease (ESRD). However, it is unknown whether delirium during hospitalization at the start of hemodialysis (HD) in elderly populations is associated with early mortality. METHODS: We conducted a retrospective cohort study to investigate the association between delirium and early mortality in the elderly after starting HD. The cohort consisted of patients ≥ 75 years who started dialysis for ESRD at the National Center for Global Health and Medicine from 2010 to 2017 and at Yokosuka Kyosai Hospital from 2007 to 2011. Delirium was defined as patients who showed new symptoms of transient confused thinking and reduced awareness of their environment and were prescribed antipsychotic medications. The primary outcome was death within 1 year. Data were analyzed using Cox proportional hazard models with adjustments for baseline characteristics. A multinomial logistic regression was used to identify the determinants of patients developing delirium. RESULTS: We enrolled 259 patients (males, 60%); 33 patients were diagnosed with delirium. The primary outcome was observed in 19 patients with delirium (58%) and 24 patients without delirium (11%) (p < 0.01). Delirium was independently associated with all-cause mortality within 1 year after starting HD (hazard ratio 7.82, 95% confidence interval 4.26-14.3; adjusted hazard ratio 7.16, 95% confidence interval 3.49-14.7). Delirium was positively correlated with "cognitive impairment" as well as "the use of steroids." CONCLUSION: Delirium is independently associated with early mortality in the elderly after starting HD.
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Delirio/mortalidad , Fallo Renal Crónico/mortalidad , Fallo Renal Crónico/terapia , Anciano , Anciano de 80 o más Años , Disfunción Cognitiva/epidemiología , Femenino , Hospitalización , Humanos , Japón/epidemiología , Estimación de Kaplan-Meier , Masculino , Modelos de Riesgos Proporcionales , Diálisis Renal , Estudios Retrospectivos , Esteroides/uso terapéuticoRESUMEN
BACKGROUND: Serum anion gap (AG) has recently been proven to represent a biomarker for predicting prognosis in patients with end-stage renal disease (ESRD). However, whether change in AG (ΔAG) at the time of starting hemodialysis predicts mortality after starting hemodialysis in elderly patients with ESRD remains unknown. METHODS: This retrospective cohort investigated the association between ΔAG and mortality after starting hemodialysis in the elderly. The cohort comprised patients ≥ 75 years old who started hemodialysis for ESRD at National Center for Global Health and Medicine between 2010 and 2017 and at Yokosuka Kyosai Hospital between 2007 and 2011. Patients were stratified into three groups (G1-3) based on ΔAG, calculated according to the equation: ΔAG = sodium - (chloride + bicarbonate) - 12. The primary outcome was death within 1 year of starting hemodialysis. Data were analyzed using Cox proportional hazard models with adjustments for baseline characteristics. RESULTS: We enrolled 254 patients (59% male). Median ΔAG was 2.6 (G1: > 3, n = 111; G2: 0-3, n = 103; G3: < 0, n = 40). The primary outcome was observed in 43 patients. Hazard ratios (HRs) were significantly higher for G1 and G3 than for G2 (G1: HR 2.47, 95% confidence interval 1.13-5.37; G3: HR 3.86, 95% confidence interval 1.62-9.16). Adjusted HRs (aHRs) were significantly higher for G1 and G3 than for G2 (G1: aHR 3.06, 95% confidence interval 1.23-7.62; G3: aHR 3.12, 95% confidence interval 1.10-8.78). CONCLUSIONS: A J-curve phenomenon is evident between ΔAG and early mortality after starting hemodialysis in the elderly.
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Equilibrio Ácido-Base , Fallo Renal Crónico/mortalidad , Fallo Renal Crónico/fisiopatología , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Cloruros/sangre , Femenino , Humanos , Hiperfosfatemia/epidemiología , Japón/epidemiología , Estimación de Kaplan-Meier , Fallo Renal Crónico/terapia , Masculino , Limitación de la Movilidad , Pronóstico , Modelos de Riesgos Proporcionales , Diálisis Renal , Estudios Retrospectivos , Factores de RiesgoRESUMEN
The kidneys consume a large amount of energy to regulate volume status and blood pressure and to excrete uremic toxins. The identification of factors that cause energy mismatch in the setting of chronic kidney disease (CKD) and the development of interventions aimed at improving this mismatch are key research imperatives. Although the critical cellular energy sensor 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK) is known to be inactivated in CKD, the mechanism of AMPK dysregulation is unknown. In a mouse model of CKD, metabolome analysis confirmed a decrease in AMPK activation in the kidneys despite a high AMP: ATP ratio, suggesting that AMPK did not sense energy depletion. Similar AMPK inactivation was found in heart and skeletal muscle in CKD mice. Several uremic factors were shown to inactivate AMPK in vitro and in ex vivo preparations of kidney tissue. The specific AMPK activator A-769662, which bypasses the AMP sensing mechanism, ameliorated fibrosis and improved energy status in the kidneys of CKD mice, whereas an AMP analog did not. We further demonstrated that a low-protein diet activated AMPK independent of the AMP sensing mechanism, leading to improvement in energy metabolism and kidney fibrosis. These results suggest that a failure to sense AMP is the key mechanism underlying the vicious cycle of energy depletion and CKD progression and direct AMPK activation may be a novel therapeutic approach in CKD.
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Proteínas Quinasas Activadas por AMP/metabolismo , Dieta con Restricción de Proteínas , Metabolismo Energético/fisiología , Riñón/patología , Insuficiencia Renal Crónica/patología , Adenosina Monofosfato/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Compuestos de Bifenilo , Modelos Animales de Enfermedad , Metabolismo Energético/efectos de los fármacos , Fibrosis/metabolismo , Humanos , Riñón/metabolismo , Masculino , Metabolómica , Ratones , Ratones Endogámicos C57BL , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Miocardio/metabolismo , Miocardio/patología , Pironas/farmacología , Insuficiencia Renal Crónica/dietoterapia , Insuficiencia Renal Crónica/etiología , Insuficiencia Renal Crónica/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Tiofenos/farmacologíaRESUMEN
Toll-like receptor 2 (TLR2), a member of the TLR innate immune receptor family, recognizes lipoproteins from bacteria and modulates the immune response by inducing the expression of various cytokines. TLR2 has a large hydrophobic pocket that recognizes long fatty acyl groups on TLR2 ligands. However, few studies have focused on the property of the hydrophobic TLR2 pocket. Based on the X-ray crystal structure of TLR2, small polar regions were found in the hydrophobic TLR2 pocket. Interactions between the polar residues and ligands were explored here by designing and synthesizing a Pam2CSK4 derivative of the TLR2 ligands, containing an amide group within the lipid moiety. We evaluated the binding affinities and immunomodulatory activities of these ligands. Results suggested that the amide groups in the lipid chain interacted with the polar residues in the hydrophobic lipid-binding pocket of TLR2.
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Adyuvantes Inmunológicos/farmacología , Lípidos/farmacología , Receptor Toll-Like 2/antagonistas & inhibidores , Adyuvantes Inmunológicos/síntesis química , Adyuvantes Inmunológicos/química , Animales , Citocinas/biosíntesis , Relación Dosis-Respuesta a Droga , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Ligandos , Lípidos/síntesis química , Lípidos/química , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Ratones , Estructura Molecular , Células RAW 264.7 , Relación Estructura-Actividad , Receptor Toll-Like 2/inmunologíaRESUMEN
As a mammalian toll-like receptor family member protein, TLR2 recognizes lipoproteins from bacteria and modulates the immune response by inducing the expression of various cytokines. We have developed fluorescence-labeled TLR2 ligands with either hydrophilic or hydrophobic fluorescence groups. The labeled ligands maintained the inflammatory IL-6 induction activity and enabled us to observe the internalization and colocalization of the TLR2 ligands using live-cell imaging. The time-lapse monitoring in the live-cell imaging of the fluorescence-labeled TLR2 ligand showed that TLR2/CD14 expression in the host cells enhanced the internalization of TLR2 ligand molecules.
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BACKGROUND: Elevated white blood cell (WBC) count is a well-known predictor of chronic kidney disease (CKD) progression. However, elderly patients commonly fail to develop a high WBC count in response to several diseased states and may instead present a low WBC count. Therefore, we hypothesized that low WBC count, in addition to high WBC count, is associated with CKD progression in the elderly. METHODS: We conducted a prospective cohort study using 3-year follow-up data from the CKD Research of Outcomes in Treatment and Epidemiology study. In the present study, participants aged over 60 years with pre-dialysis CKD stages G2-G5 were eligible. Patients were stratified into three groups according to WBC count using tertiles (T). The primary outcome was a composite of end-stage renal disease and a 50% reduction in estimated glomerular filtration rate. Data were analyzed using Cox proportional hazard models with adjustments for covariates. RESULTS: We enrolled 697 patients (males, 69%). The median WBC count was 6100 cells/µl (T1, <5400, n = 222; T2, 5400-6900, n = 235; T3, ≥6900, n = 240). During a median follow-up of 868 days, the primary outcome was observed in 170 patients, whereas 54 patients died. T1 and T3 had significantly higher hazard ratios (HR) than T2 (T1, HR 1.69, 95% confidence interval 1.14-2.51; T3, HR 1.63, 95% confidence interval 1.10-2.41). Moreover, T1 had a significantly higher adjusted HR (1.54, 95% confidence interval 1.00-2.37). CONCLUSION: Low WBC count is independently associated with CKD progression in the elderly.
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Leucocitos , Insuficiencia Renal Crónica/sangre , Factores de Edad , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Femenino , Tasa de Filtración Glomerular , Humanos , Japón/epidemiología , Estimación de Kaplan-Meier , Riñón/fisiopatología , Fallo Renal Crónico/sangre , Fallo Renal Crónico/mortalidad , Fallo Renal Crónico/fisiopatología , Recuento de Leucocitos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/mortalidad , Insuficiencia Renal Crónica/fisiopatología , Factores de Riesgo , Factores de TiempoRESUMEN
The Mycobacterium tuberculosis Ser/Thr kinase PknB is implicated in the regulation of bacterial cell growth and cell division. The intracellular kinase function of PknB is thought to be triggered by peptidoglycan (PGN) fragments that are recognized by the extracytoplasmic domain of PknB. The PGN in the cell wall of M.â tuberculosis has several unusual modifications, including the presence of N-glycolyl groups (in addition to N-acetyl groups) in the muramic acid residues and amidation of d-Glu in the peptide chains. Using synthetic PGN fragments incorporating these diverse PGN structures, we analyzed their binding characters through biolayer interferometry (BLI), NMR spectroscopy, and native mass spectrometry (nMS) techniques. The results of BLI showed that muropeptides containing 1,6-anhydro-MurNAc and longer glycan chains exhibited higher binding potency and that the fourth amino acid of the peptide stem, d-Ala, was crucial for protein recognition. Saturation transfer difference (STD) NMR spectroscopy indicated the major involvement of the stem peptide region in the PASTA-PGN fragment binding. nMS suggested that the binding stoichiometry was 1:1. The data provide the first molecular basis for the specific interaction of PGN with PknB and firmly establish PGNs as the effective ligands of PknB.
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Mycobacterium tuberculosis/enzimología , Peptidoglicano/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Conformación de Carbohidratos , Mycobacterium tuberculosis/metabolismo , Peptidoglicano/química , Proteínas Serina-Treonina Quinasas/químicaRESUMEN
BACKGROUND: Vitamin D analogs have generally been recommended for treatment of mineral bone disease in chronic kidney disease (CKD). However, the association between this treatment and CKD progression has not yet been established. METHODS: We designed a post hoc propensity score-matched cohort analysis derived from 3-year follow-up data of a prospective cohort. Adult participants with pre-dialysis CKD stages 4-5 who had newly been prescribed active vitamin D analogs during the observation period were eligible as matched cases. Then, matched controls were extracted from participants who had never been prescribed active vitamin D analogs. The primary outcome was a composite of end-stage renal disease or a 50 % reduction in estimated glomerular filtration rate (eGFR). A Cox proportional hazards model evaluated the association between the use of vitamin D analogs and the primary outcome. RESULTS: We enrolled 240 patients (males, 65 %). The number of matched cases and controls was 30 and 210, respectively. The primary outcome was observed in 94 patients, whereas 25 patients died. The mean ± standard deviation age and eGFR were 69 ± 12 years and 17 ± 5.7 ml/min/1.73 m2, respectively. In a Cox proportional hazard model, the use of vitamin D analogs was independently associated with a lower risk of the primary outcome (crude hazard ratio 0.41; 95 % confidence interval 0.19, 0.89; adjusted hazard ratio 0.38; 95 % confidence interval 0.17, 0.88). CONCLUSION: The use of vitamin D analogs is independently associated with the preservation of renal function in patients with pre-dialysis CKD stages 4-5.
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Tasa de Filtración Glomerular/efectos de los fármacos , Fallo Renal Crónico/prevención & control , Riñón/efectos de los fármacos , Insuficiencia Renal Crónica/tratamiento farmacológico , Vitamina D/uso terapéutico , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Progresión de la Enfermedad , Femenino , Humanos , Japón , Riñón/fisiopatología , Fallo Renal Crónico/fisiopatología , Masculino , Persona de Mediana Edad , Puntaje de Propensión , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Factores Protectores , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/fisiopatología , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Vitamina D/efectos adversos , Vitamina D/análogos & derivadosRESUMEN
AIM: Impaired mobility at the onset of dialysis is considered one of the most important risk factors for short-term mortality after initiation of dialysis in elderly patients. However, whether a decline in mobility after starting dialysis also affects mortality is unclear. METHODS: A total of 202 patients (age, >75 years; mean, 80.4 ± 4.3) were enrolled in this retrospective cohort study in Yokosuka, Japan. They were divided into three subgroups by mobility: independent mobility at onset of dialysis and preservation of mobility after starting dialysis (group 1, n = 104); independent mobility at onset of dialysis and decline in mobility after starting dialysis (group 2, n = 48); and impaired mobility at onset of dialysis (group 3, n = 50). They were followed for 6 months after starting dialysis. A Cox proportional hazards model was used to evaluate the association between mobility and mortality. RESULTS: A total of 24.8% of patients had impaired mobility at the start of dialysis, and 68.9% declined in mobility after starting dialysis. In multivariate Cox proportional hazards analysis, the adjusted hazard ratios of groups 2 and 3 compared with group 1 were 3.80 (95% confidence interval, 1.02-14.10) and 4.94 (95% confidence interval, 1.42-17.10), respectively. CONCLUSION: Not only impaired mobility at the start of dialysis but also a decline in mobility after starting dialysis is associated with short-term mortality after initiation of dialysis.
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Fallo Renal Crónico/terapia , Limitación de la Movilidad , Diálisis Peritoneal/mortalidad , Diálisis Renal/mortalidad , Factores de Edad , Anciano , Anciano de 80 o más Años , Distribución de Chi-Cuadrado , Femenino , Humanos , Japón , Estimación de Kaplan-Meier , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/mortalidad , Masculino , Análisis Multivariante , Diálisis Peritoneal/efectos adversos , Modelos de Riesgos Proporcionales , Diálisis Renal/efectos adversos , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Anti-centromere antibody (ACA), a typical autoantibody of systemic sclerosis, is also detected in primary biliary cirrhosis (PBC). However, its pathogenic role is not fully understood. The aim of this study was to determine the association between ACA and kidney function in PBC. METHODS: A cohort of 37 patients diagnosed as having PBC from July 2001 to November 2011 at Yokosuka Kyosai Hospital was retrospectively analyzed for a follow-up period of 12 months. The annual rate of estimated glomerular filtration rate (eGFR) decline within 1 year after the diagnosis was evaluated. The factors associated with eGFR decline were evaluated by linear regression analysis and logistic regression analysis. RESULTS: Overall, 37 PBC patients were included, of whom 12 (32%) had ACA. The patients with ACA had a lower eGFR (65.9 ± 19.9 vs. 80.3 ± 12.1 mL/min/1.73 m(2), P = 0.01), a higher likelihood of chronic kidney disease (CKD) (58 vs. 4%, P = 0.0005), and a higher rate of annual eGFR decline (-4.3 ± 5.1 vs. 0.2 ± 4.6 mL/min/year, P = 0.01) than those without ACA. Univariate regression analysis and multivariate regression analysis adjusted for potential cofounders including age, eGFR, sex, diabetes mellitus, and hypertension showed that ACA was associated with eGFR decline (P = 0.011 and 0.017, respectively). Multivariate logistic regression analysis adjusted for these cofounders showed that ACA was associated with eGFR decline less than -4 mL/min/year (odds ratio 7.21, 95% confidence interval 0.93-56.1, P = 0.059). CONCLUSIONS: ACA is an independent risk factor for CKD in PBC. Evaluation of ACA and kidney function is necessary to prevent CKD progression in PBC patients.
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Anticuerpos Antinucleares/análisis , Autoanticuerpos/análisis , Centrómero/inmunología , Cirrosis Hepática Biliar/complicaciones , Cirrosis Hepática Biliar/inmunología , Insuficiencia Renal Crónica/etiología , Anciano , Progresión de la Enfermedad , Femenino , Tasa de Filtración Glomerular , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de RiesgoRESUMEN
A 37-year-old man developed Henoch--Schönlein purpura nephritis (HSPN) with nephrotic syndrome and rapidly progressive glomerulonephritis after otitis media and externa due to methicillin-resistant Staphylococcus aureus infection. Despite resolution of the infection and prednisolone therapy, his kidney disease worsened. However, the addition of cyclosporine A finally resulted in complete remission of the nephrotic syndrome. A review of similar cases with post-Staphylococcal infection HSPN revealed strong similarities between this entity and immunoglobulin A-dominant postinfectious glomerulonephritis (IgA-PIGN), an increasingly recognized form of PIGN typically associated with Staphylococcal infection, in both clinical and morphological features. Post-Staphylococcal infection HSPN may constitute a subgroup of IgA-PIGN.
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Glomerulonefritis/etiología , Vasculitis por IgA/complicaciones , Staphylococcus aureus Resistente a Meticilina , Infecciones Estafilocócicas/complicaciones , Adulto , Ciclosporina/uso terapéutico , Glomerulonefritis/tratamiento farmacológico , Glomerulonefritis/microbiología , Glucocorticoides/uso terapéutico , Humanos , Vasculitis por IgA/microbiología , Inmunosupresores/uso terapéutico , Masculino , Prednisolona/uso terapéutico , Infecciones Estafilocócicas/microbiologíaRESUMEN
INTRODUCTION: Dialysis patients have a 10-25 times higher risk of reactivation of tuberculosis (TB). In this study, we investigated the diagnostic ability of QuantiFERON (QFT)-plus for TB in hemodialysis patients. QFT-plus, an interferon gamma release assay, is characterized by its use of CD4 and CD8 T cell signals. METHODS: Hemodialysis patients aged 20 years or older who underwent QFT-plus measurement in our hospital were included, inclusion criteria being fever above 37°C, high inflammatory response, and infiltrative pulmonary shadows. RESULTS: Forty-six patients were enrolled. Of these, 15% were QFT positive, 4% were diagnosed with active TB, 76% were QFT negative, 8% had inconclusive results. Sensitivity, specificity, positive predictive value, and negative predictive value were 100%, 87.5%, 28%, and 100%, respectively. CONCLUSIONS: QFT-plus may be useful for the diagnosis of active TB in dialysis patients. Further studies in cohorts with larger sample sizes are expected.
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Tuberculosis Latente , Tuberculosis , Humanos , Ensayos de Liberación de Interferón gamma , Interferón gamma , Tuberculosis Latente/diagnóstico , Tuberculosis/diagnóstico , Valor Predictivo de las PruebasRESUMEN
Various forms of cell death have been identified, and billions of cells die during development and daily in adult organisms. Clearing dead cells and associated cellular debris is an integral part of tissue homeostasis. While diverse types of phagocytes remove various forms of dying cells during acute kidney injury (AKI), it remains unknown whether boosting removal of a specific form of dying cell would provide a benefit and which cell type should be targeted for phagocytosis-mediated therapy. As there is a lack of viable strategies for the prevention and treatment of AKI, novel therapies and innovative approaches are required. There is a strong demand on developing and analyzing novel models to boost, monitor, and stop phagocytosis of dying cells.
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Lesión Renal Aguda , Apoptosis , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/terapia , Muerte Celular , Femenino , Humanos , Masculino , Fagocitos/metabolismo , Fagocitosis/fisiologíaRESUMEN
Objectives: Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) has been established in the management of peritoneal carcinomatosis. Although it is still necessary to take adequate measures against major postoperative complications including acute kidney injury (AKI), consensus is lacking on how to assess and stratify risk for patients with postoperative AKI after CRS-HIPEC. The aim of this retrospective cohort study was to investigate the association of intraoperative gross hematuria as a surrogate marker of ureter injury with postoperative AKI incidence. Methods: This retrospective cohort study investigated patients without impaired preoperative kidney function who underwent CRS-HIPEC at a single referral center, and evaluated the relationship between intraoperative gross hematuria and incidence of postoperative AKI as defined by the Kidney Disease Improving Global Outcomes practice guidelines. Logistic regression analysis was performed to calculate the odds ratio of intraoperative gross hematuria for AKI, adjusting for confounding factors and other risk factors for AKI. Results: We enrolled 185 patients (males, 37%). Twenty-five patients developed intraoperative gross hematuria. Postoperative AKI occurred in 10 (40%) of 25 patients with hematuria and 28 (17.5%) of 160 patients without hematuria. The crude odds ratio for exposure to hematuria was 3.14 (95% confidence interval, 1.30-7.60; p=0.020) for postoperative AKI. Adjusted odds ratio as estimated by multivariate logistic regression was 4.57 (95% confidence interval, 1.55-13.45; p=0.006). Conclusions: Intraoperative gross hematuria is significantly associated with postoperative AKI incidence after CRS-HIPEC.
RESUMEN
Hematopoietic mosaic loss of Y chromosome (mLOY) is associated with increased risk of mortality and age-related diseases in men, but the causal and mechanistic relationships have yet to be established. Here, we show that male mice reconstituted with bone marrow cells lacking the Y chromosome display increased mortality and age-related profibrotic pathologies including reduced cardiac function. Cardiac macrophages lacking the Y chromosome exhibited polarization toward a more fibrotic phenotype, and treatment with a transforming growth factor ß1-neutralizing antibody ameliorated cardiac dysfunction in mLOY mice. A prospective study revealed that mLOY in blood is associated with an increased risk for cardiovascular disease and heart failure-associated mortality. Together, these results indicate that hematopoietic mLOY causally contributes to fibrosis, cardiac dysfunction, and mortality in men.
Asunto(s)
Envejecimiento , Deleción Cromosómica , Insuficiencia Cardíaca , Células Madre Hematopoyéticas , Miocardio , Cromosoma Y , Envejecimiento/genética , Animales , Anticuerpos Neutralizantes/farmacología , Anticuerpos Neutralizantes/uso terapéutico , Fibrosis , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/terapia , Macrófagos , Masculino , Ratones , Mosaicismo , Miocardio/patología , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Cromosoma Y/genéticaRESUMEN
The first case of eosinophilic granulomatosis with polyangiitis (EGPA) simultaneously demonstrating various clinical manifestations, including retroperitoneal fibrosis (RPF) causing hydronephrosis and membranous nephropathy (MN) leading to nephrotic syndrome, is presented. There have been no previous case reports demonstrating the simultaneous onset of these three disease categories with significant complex pathologies. This case was successfully managed by providing adequate combination therapies according to each disease category, leading to complete remission (CR) of all three diseases. In conclusion, we believe this case is extremely rare and clinically suggestive, and that these findings can be applied to a future phenotype-tailored treatment strategy for EGPA.