RESUMO
The transcription factor Foxp3 plays crucial roles for Treg cell development and function. Conserved non-coding sequences (CNSs) at the Foxp3 locus control Foxp3 transcription, but how they developmentally contribute to Treg cell lineage specification remains obscure. Here, we show that among Foxp3 CNSs, the promoter-upstream CNS0 and the intergenic CNS3, which bind distinct transcription factors, were activated at early stages of thymocyte differentiation prior to Foxp3 promoter activation, with sequential genomic looping bridging these regions and the promoter. While deletion of either CNS0 or CNS3 partially compromised thymic Treg cell generation, deletion of both completely abrogated the generation and impaired the stability of Foxp3 expression in residual Treg cells. As a result, CNS0 and CNS3 double-deleted mice succumbed to lethal systemic autoimmunity and inflammation. Thus, hierarchical and coordinated activation of Foxp3 CNS0 and CNS3 initiates and stabilizes Foxp3 gene expression, thereby crucially controlling Treg cell development, maintenance, and consequently immunological self-tolerance.
Assuntos
Elementos Facilitadores Genéticos/imunologia , Fatores de Transcrição Forkhead/imunologia , Linfócitos T Reguladores/imunologia , Animais , Diferenciação Celular/imunologia , Linhagem da Célula/imunologia , Regulação da Expressão Gênica/imunologia , Humanos , Tolerância Imunológica/imunologia , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Regiões Promotoras Genéticas/imunologia , Tolerância a Antígenos Próprios/imunologiaRESUMO
This corrects the article DOI: 10.1038/ni.3646.
RESUMO
Most Foxp3+ regulatory T (Treg) cells develop in the thymus as a functionally mature T cell subpopulation specialized for immune suppression. Their cell fate appears to be determined before Foxp3 expression; yet molecular events that prime Foxp3- Treg precursor cells are largely obscure. We found that Treg cell-specific super-enhancers (Treg-SEs), which were associated with Foxp3 and other Treg cell signature genes, began to be activated in Treg precursor cells. T cell-specific deficiency of the genome organizer Satb1 impaired Treg-SE activation and the subsequent expression of Treg signature genes, causing severe autoimmunity due to Treg cell deficiency. These results suggest that Satb1-dependent Treg-SE activation is crucial for Treg cell lineage specification in the thymus and that its perturbation is causative of autoimmune and other immunological diseases.
Assuntos
Diferenciação Celular/imunologia , Fatores de Transcrição Forkhead/metabolismo , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Linfócitos T Reguladores/fisiologia , Ativação Transcricional/imunologia , Animais , Autoimunidade , Linhagem da Célula , Células Cultivadas , Elementos Facilitadores Genéticos/genética , Epigênese Genética , Fatores de Transcrição Forkhead/genética , Tolerância Imunológica , Masculino , Proteínas de Ligação à Região de Interação com a Matriz/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Especificidade de Órgãos , Células Precursoras de Linfócitos T/fisiologiaRESUMO
Despite the importance of Th17 cells in autoimmune diseases, it remains unclear how they control other inflammatory cells in autoimmune tissue damage. Using a model of spontaneous autoimmune arthritis, we showed that arthritogenic Th17 cells stimulated fibroblast-like synoviocytes via interleukin-17 (IL-17) to secrete the cytokine GM-CSF and also expanded synovial-resident innate lymphoid cells (ILCs) in inflamed joints. Activated synovial ILCs, which expressed CD25, IL-33Ra, and TLR9, produced abundant GM-CSF upon stimulation by IL-2, IL-33, or CpG DNA. Loss of GM-CSF production by either ILCs or radio-resistant stromal cells prevented Th17 cell-mediated arthritis. GM-CSF production by Th17 cells augmented chronic inflammation but was dispensable for the initiation of arthritis. We showed that GM-CSF-producing ILCs were present in inflamed joints of rheumatoid arthritis patients. Thus, a cellular cascade of autoimmune Th17 cells, ILCs, and stromal cells, via IL-17 and GM-CSF, mediates chronic joint inflammation and can be a target for therapeutic intervention.
Assuntos
Artrite Reumatoide/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Linfócitos/imunologia , Células Estromais/imunologia , Células Th17/imunologia , Animais , Artrite Reumatoide/metabolismo , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/biossíntese , Humanos , Linfócitos/metabolismo , Camundongos , Células Estromais/metabolismo , Membrana Sinovial/imunologia , Membrana Sinovial/metabolismo , Células Th17/metabolismoRESUMO
Although mesangial cell-glomerular basement membrane (GBM) connections play a key role in maintaining the glomerular capillary loop structure, information remains limited about how these connections are formed during glomerulogenesis. We have previously shown that weakened podocyte-GBM interactions owing to tensin 2 (Tns2) deficiency lead to abnormal GBM maturation during postnatal glomerulogenesis. Here, we investigated whether abnormal GBM maturation affected mesangial cell-GBM connections and mesangial cell differentiation. Histological analysis of the outer cortical glomeruli in Tns2-deficient mice revealed that GBM materials overproduced by stressed immature podocytes accumulated in the mesangium and interrupted the formation of mesangial cell-GBM connections, resulting in fewer capillary loops compared with that of normal glomeruli. In addition, expression of α-smooth muscle actin, an immature mesangial cell marker, persisted in mesangial cells of Tns2-deficient outer cortical glomeruli even after glomerulogenesis was completed, resulting in mesangial expansion. Furthermore, analysis of mouse primary mesangial cells revealed that mesangial cell differentiation depended on the type of extracellular matrix components to which the cells adhered, suggesting the participation of mesangial cell-GBM connections in mesangial cell differentiation. These findings suggest that abnormal GBM maturation affects mesangial cell differentiation by impairing mesangial cell-GBM connections.NEW & NOTEWORTHY Mesangial cell-glomerular basement membrane (GBM) connections play an important role in maintaining the structural integrity of the glomerular tuft. However, information remains scarce about how GBM maturation affects the formation of these connections during glomerular development. Here, we show that abnormal GBM maturation due to tensin 2 deficiency affects mesangial cell differentiation by impairing mesangial cell-GBM connections during postnatal glomerulogenesis.
Assuntos
Membrana Basal Glomerular , Podócitos , Camundongos , Animais , Membrana Basal/metabolismo , Tensinas , Mesângio Glomerular , Podócitos/metabolismo , Diferenciação CelularRESUMO
Tensin2 (Tns2), an integrin-linked protein, is enriched in podocytes within the glomerulus. Previous studies have revealed that Tns2-deficient mice exhibit defects of the glomerular basement membrane (GBM) soon after birth in a strain-dependent manner. However, the mechanisms for the onset of defects caused by Tns2 deficiency remains unidentified. Here, we aimed to determine the role of Tns2 using newborn Tns2-deficient mice and murine primary podocytes. Ultrastructural analysis revealed that developing glomeruli during postnatal nephrogenesis exhibited abnormal GBM processing due to ectopic laminin-α2 accumulation followed by GBM thickening. In addition, analysis of primary podocytes revealed that Tns2 deficiency led to impaired podocyte-GBM interaction and massive expression of laminin-α2 in podocytes. Our study suggests that weakened podocyte-GBM interaction due to Tns2 deficiency causes increased mechanical stress on podocytes by continuous daily filtration after birth, resulting in stressed podocytes ectopically producing laminin-α2, which interrupts GBM processing. We conclude that Tns2 plays important roles in the podocyte-GBM interaction and maintenance of the glomerular filtration barrier.
Assuntos
Membrana Basal Glomerular/metabolismo , Taxa de Filtração Glomerular , Podócitos/metabolismo , Tensinas/metabolismo , Fatores Etários , Animais , Animais Recém-Nascidos , Adesão Celular , Células Cultivadas , Membrana Basal Glomerular/ultraestrutura , Laminina/genética , Laminina/metabolismo , Camundongos Knockout , Podócitos/ultraestrutura , Estresse Mecânico , Tensinas/deficiência , Tensinas/genéticaRESUMO
BACKGROUND: It is unclear whether asymptomatic elevation of brain natriuretic peptide (BNP) is associated with cardiovascular events (CVEs) or heart failure (HF) in predialysis chronic kidney disease (CKD) patients. METHODS: We measured BNP in 482 asymptomatic predialysis patients with CKD stages 2-5 at nephrology referral between August 2004 and October 2010, and followed them prospectively to investigate the prognostic significance of BNP using Cox models and receiver operating characteristic (ROC) analyses. The primary composite end point was the time to death or the first nonfatal CVEs. Secondary end points included CVEs including sudden death, HF and all-cause death. RESULTS: The median age was 67 years (male, 67.4%; diabetic nephropathy, 33.4%), and estimated glomerular filtration rate was 20.1 mL/min/1.73 m2. The primary end point occurred in 92 patients. CVEs including sudden death, HF and all-cause death occurred in 66, 35, and 54 patients, respectively during a median follow-up period of 37.7 months. Multivariate analyses showed that BNP level was significantly associated with the primary end point (hazard ratio [HR] 1.241; 95% CI 1.020-1.511; p = 0.031), CVEs (HR 1.337; 95% CI 1.067-1.675; p = 0.012) and HF (HR 1.489; 95% CI 1.059-2.091; p = 0.022), but not associated with all-cause death (HR 1.081; 95% CI 0.829-1.410; p = 0.565). The ROC curves showed that the optimal predictive BNP levels for the primary end point, CVEs and HF were 92.5, 127.0, and 274.6 (pg/mL) respectively. CONCLUSION: Asymptomatic elevation of BNP is strongly predictive for CVEs and HF, which might help to integrate cardio-renal risk stratification in predialysis CKD patients.
Assuntos
Doenças Cardiovasculares/diagnóstico , Peptídeo Natriurético Encefálico/sangue , Insuficiência Renal Crônica/sangue , Idoso , Doenças Assintomáticas/epidemiologia , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Causas de Morte , Ecocardiografia , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Curva ROC , Encaminhamento e Consulta , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/mortalidade , Medição de Risco/métodos , Fatores de RiscoRESUMO
BACKGROUND: It is not known whether asymptomatic cardiac troponin T (cTnT) elevation is associated with all-cause or cardiovascular mortality in non-diabetic and advanced chronic kidney disease (CKD) patients. METHODS: We measured cTnT in 248 consecutive patients at 1-2 weeks before dialysis initiation between March 2005 and August 2010 and followed them prospectively. A Cox proportional hazard model was used to investigate the relationship between cTnT and all-cause and cardiovascular mortality on dialysis. RESULTS: The median age of the patients was 67 years (male 59.3 %), and the prevalence of diabetic nephropathy (DN) was 38.3 %. Asymptomatic cTnT elevation (>0.01 ng/mL) was observed in 196 (79 %) and 111 (73 %) patients among the overall patients and among patients without DN, respectively. A total of 51 patients died during a median follow-up period of 31.6 months. The cTnT level was associated with all-cause [hazard ratio (HR) 1.453; 95 % confidence interval (CI) 1.093-1.931; P = 0.010] and cardiovascular mortality [HR 1.973; 95 % CI 1.127-3.454; P = 0.017] on dialysis after extensive adjustment in the overall patient population. Patients without DN showed similar associations as those for the overall patient population (all-cause mortality: HR 1.566; 95 % CI 1.048-2.339; P = 0.029 and cardiovascular mortality: HR 2.657; 95 % CI 1.115-6.328; P = 0.027). CONCLUSION: Asymptomatic cTnT elevation might be strongly associated with all-cause and cardiovascular mortality in patients without DN, as well as in the overall advanced CKD patients. We suggest that cardiovascular risk in patients with pre-dialysis CKD should be stratified according to cTnT levels.
Assuntos
Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/mortalidade , Diálise Renal/mortalidade , Insuficiência Renal Crônica/mortalidade , Insuficiência Renal Crônica/terapia , Troponina T/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico , Causas de Morte , Distribuição de Qui-Quadrado , Feminino , Humanos , Japão/epidemiologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Prevalência , Modelos de Riscos Proporcionais , Estudos Prospectivos , Diálise Renal/efeitos adversos , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/diagnóstico , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Regulação para CimaRESUMO
BACKGROUND: There is a paucity of studies on whether early referral (ER) to nephrologist could reduce cardiovascular mortality on dialysis, and the length of pre-dialysis nephrological care needed to reduce mortality on dialysis. METHODSâANDâRESULTS: A total of 604 consecutive patients who started dialysis between 2001 and 2009 in Senshu region, Osaka, Japan were analyzed. Non-linear associations between mortality and pre-dialysis duration of nephrological care were assessed using restricted cubic spline function, and predictors for death analyzed on Cox modeling. A total of 31.6%, 18.2%, 11.3% and 6.1% of patients had >12, 24, 36 and 48 months of pre-dialysis care, respectively. A total of 258 patients (42.7%) were categorized as ER (≥6 months pre-dialysis duration). During the follow-up period (median, 31.1 months), 218 patients died (cardiovascular, n=70; infection, n=69). Although patients with late referral (LR) had a proxy of inappropriate pre-dialysis care compared with the ER group, Cox multivariate analysis failed to show a favorable association between ER and cardiovascular outcome. In contrast, a deleterious effect of LR on overall survival was observed but was limited only to the first 12 months of dialysis (HR, 1.957; 95% CI: 1.104-3.469; P=0.021), but not observed thereafter. CONCLUSIONS: Current pre-dialysis nephrological care may reduce short-term mortality but may not improve cardiovascular mortality after dialysis initiation.
Assuntos
Doenças Cardiovasculares , Nefrologia , Encaminhamento e Consulta , Diálise Renal/efeitos adversos , Idoso , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/terapia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Although laparoscopy may provide more detailed morphological and histological information about peritoneal damage, its significance in patients with long vintage of peritoneal dialysis (PD) is not elucidated. METHODS: Findings in 12 patients with PD vintage of 7.3 (5.0-8.4) years who had undergone laparoscopy between 2007 and 2011 were reviewed. Macroscopic (peritoneal change, hypervascular change, adhesion, encapsulation) and histopathological peritoneal findings (interstitial fibrosis, microvascular change, fibrin deposition, inflammatory cell infiltration) were scored and summed as Macro-total score (Macro-TS) and Micro-total score (Micro-TS), respectively. Factors associated with these scores and the relationship between these scores were investigated. RESULTS: Neither Macro-TS nor Micro-TS were related to PD vintage (p = 0.069 and p = 0.769, respectively); moreover, Macro-TS varied from patient to patient regardless of similar PD vintage. However, Macro-TS showed a significant association with duration of acidic dialysate (p = 0.003). CONCLUSION: Macroscopic and microscopic findings via laparoscopy may help the assessment of peritoneal damage in patients with long PD vintage.
Assuntos
Falência Renal Crônica/terapia , Laparoscopia , Infiltração Leucêmica/diagnóstico , Diálise Peritoneal/efeitos adversos , Peritônio/patologia , Aderências Teciduais/diagnóstico , Idoso , Feminino , Fibrose/diagnóstico , Fibrose/etiologia , Fibrose/patologia , Humanos , Falência Renal Crônica/patologia , Falência Renal Crônica/cirurgia , Infiltração Leucêmica/etiologia , Infiltração Leucêmica/patologia , Masculino , Microcirculação , Pessoa de Meia-Idade , Peritônio/irrigação sanguínea , Peritônio/cirurgia , Fatores de Tempo , Aderências Teciduais/etiologia , Aderências Teciduais/patologiaRESUMO
Lipids interfere with absorbance measurements conducted using colorimetric methods. To monitor lipemia, some systems measure absorbance using an analyzer. This report describes a novel case of interference with the lipemia index without lipemia. A 64-year-old woman with giant basal cell carcinoma underwent resection and sentinel lymph node biopsy. The patient had been subcutaneously injected with patent blue during sentinel lymph node resection. After surgery, her serum and urine were yellow-green, and the lipemia index, calculated by measuring absorbance at 658 nm (main wavelength) and 694 nm (secondary wavelength) using a JCA-BM8040 chemistry analyzer, was high. The absorbance spectrum of the patient's serum and patent blue solution were compared to determine the cause of the high lipemia index. The patient's serum and the patent blue solution showed absorption at wavelengths between 540 and 698 nm. Moreover, the absorbance was concentration-dependent for patent blue. These results thus indicated that the patient's serum contained patent blue. Here, we report a case wherein patent blue affected the lipemia index. Thus, it must be noted that patent blue injection may yield inaccurate results when evaluating lipemia index.
RESUMO
BACKGROUND: Recent experimental studies suggest that erythropoietin promotes beneficial myocardial remodeling during left ventricular hypertrophy (LVH); however, such compensatory capacity may be limited due to insufficient erythropoietin production in chronic kidney disease patients. Thus, this study aimed to explore the effect of pre-dialysis erythropoiesis-stimulating agent (ESA) use on the prognostic significance of LVH in dialyzed patients. METHODS: This retrospective study included 404 consecutive patients who started dialysis between 2001 and 2009. The interaction of ESA with the association between left ventricular mass index (LVMI) observed at dialysis initiation and all-cause and cardiovascular mortality was analyzed at the end of 2010 using the Cox model. RESULTS: During a median follow-up of 36.5 months, 164 patients died, 31 of them from heart failure. The frequency of pre-dialysis ESA use was 58.7 % and median LVMI was 160.3 g/m(2). Of interest, patients with the lowest tertile of LVMI had worse survival compared with those with each subsequent tertile. LVMI was inversely associated with all-cause mortality [hazard ratio (HR) 0.991, 95 % confidence interval (CI) 0.988-0.995, P = 0.000] after extensive adjustment including ejection fraction, whereas the prognostic value of LVMI for cardiovascular mortality was dependent on pre-dialysis ESA use [adjusted HR 1.010, 95 % CI 0.999-1.020, P = 0.065 for pre-dialysis ESA(+) and 0.978, 95 % CI 0.967-0.989, P = 0.000 for pre-dialysis ESA(-), respectively]. CONCLUSIONS: Our results suggest that reverse epidemiology may exist between LVH and mortality and that pre-dialysis ESA use may modify the prognostic significance of LVH observed at dialysis initiation for cardiovascular mortality in dialyzed patients.
Assuntos
Hematínicos/farmacologia , Hipertrofia Ventricular Esquerda/diagnóstico , Falência Renal Crônica/patologia , Falência Renal Crônica/terapia , Diálise Renal , Fatores Etários , Idoso , Biomarcadores , Coleta de Dados , Neuropatias Diabéticas/terapia , Feminino , Seguimentos , Humanos , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Terapia de Substituição Renal , Estudos Retrospectivos , Fatores de Risco , Estimulação Química , Resultado do Tratamento , UltrassonografiaRESUMO
We report a rare case of rhabdomyolysis caused by peripheral T-cell lymphoma (PTCL) in skeletal muscle. A 62-year-old man was admitted with complaints of sudden muscle weakness. Laboratory abnormalities were identified including markedly elevated creatinine-phosphokinase, peaking at 62,640 IU/L and serum creatinine (Cr) at 5.0 mg/dL. Computed tomography scans revealed tumorous swelling of the right psoas major muscle and the obturator internus muscles. Consequently, he was diagnosed with acute renal failure caused by rhabdomyolysis and was treated with hydration and continuous hemodiafiltration, which resulted in significant improvement in renal function (Cr 1.79 mg/dL). However, the cause of the rhabdomyolysis remained unclear, and he suddenly developed a remittent fever and suffered from hemophagocytic syndrome. Serum ferritin level dramatically increased to 104,707.0 ng/mL and creatinine level to 4.09 mg/dL. We performed a biopsy of inguinal lymph nodes, leading to a diagnosis of PTCL. Finally, he was diagnosed with rhabdomyolysis caused by PTCL. Methylprednisolone pulse therapy markedly improved his general condition and renal function (Cr 1.48 mg/dL), and computed tomography scans revealed that tumorous swelling was greatly diminished. Except when the cause of rhabdomyolysis is readily apparent, such as in cases of trauma, drug and thrombophlebitis, one should consider that rhabdomyolysis may be a sequel of lymphoma.
Assuntos
Linfoma de Células T Periférico/complicações , Neoplasias Musculares/complicações , Rabdomiólise/etiologia , Humanos , Linfoma de Células T Periférico/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Neoplasias Musculares/diagnóstico por imagem , Debilidade Muscular/etiologia , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND AND AIMS: Patients with immunoglobulin G4 (IgG4)-related disease (IgG4-RD) have elevated immunoglobulin E (IgE) concentration compared to that in healthy individuals, which suggests the occurrence of IgE-mediated allergic reactions. We have previously shown that IgG4 and IgE form a complex in some patients with IgG4-RD. However, it is currently unknown whether and how the presence of the IgG4-IgE complex affects IgE concentration measurements by different assays. MATERIALS AND METHODS: Twenty patients with confirmed presence or absence of IgG4-IgE complex were evaluated. We compared IgE concentrations measured by ST AIA-PACK IgE II (AIA-PACK), Elecsys IgE II Immunoassay (Elecsys), and Iatroace IgE (Iatroace) and evaluated to what extent the IgG4-IgE complex interfered with these measurements. RESULTS: In patients with the IgG4-IgE complex, IgE concentrations measured using Iatroace were significantly lower than those measured using Elecsys and tended to be lower than those measured using AIA-PACK. IgE concentrations determined by Iatroace were significantly different in patients with and without the IgG4-IgE complex, whereas no significant differences between these groups were detected when IgE concentrations were measured by AIA-PACK or Elecsys. CONCLUSION: The formation of the IgG4-IgE complex underestimates measured IgE concentrations depending on the method used. Therefore, caution should be exercised when selecting a specific IgE assay for patients with IgG4-RD.
Assuntos
Imunoglobulina E , Doença Relacionada a Imunoglobulina G4 , Humanos , Imunoglobulina GRESUMO
OBJECTIVE: Presence of autoantibodies against troponin I (cTnI) or T (cTnT) has been reported to interfere with troponin assays. However, the extent of the interference with the measurement has not been explored sufficiently. The aims of this study were to examine the frequencies of autoantibodies against troponin I and troponin T and how much these antibodies would affect the measurement. METHODS: The study comprised 52 subjects who visited Hokkaido University Hospital with suspected ischemic heart diseases. To evaluate the presence of autoantibodies, we calculated the recoveries of cTnI or cTnT after immunoglobulin G depletion, and the distributions of peaks reactive with cTnI or cTnT by high-performance liquid chromatography were examined. RESULTS: Autoantibodies against cTnI and cTnT were identified in 8 subjects (15.4%) and 1 subject (1.9%), respectively. Although the greatest difference between cTnI and cTnT was 32-fold, the distributions of cTnI-to-cTnT ratios in groups with and without anti-cTnI were not statistically different. CONCLUSION: Autoantibodies against cTnI were more frequent by several fold than those against cTnT. Their presence did not significantly expand the discrepancy between cTnI and cTnT assays.
Assuntos
Autoanticorpos , Troponina I , Humanos , Troponina T , BiomarcadoresRESUMO
BACKGROUND: As a cardiorenal syndrome, there is a dynamic interplay between the heart and the kidney. We conducted a prospective study to evaluate the prognostic impact of plasma B-type natriuretic peptide (BNP) level, a cardiac biomarker, on the long-term kidney prognosis in chronic kidney disease (CKD) patients. METHODS: We prospectively enrolled 508 patients with CKD Stages 3, 4 and 5 not on dialysis, from a single nephrology department between 2004 and 2010. The exclusion criteria were over 90 years of age, malignancy, active infection, low cardiac ejection fraction and rapid progressive glomerulonephritis. Relationships between BNP and kidney end point [defined as doubling of baseline serum creatinine and end-stage kidney disease (ESKD) requiring kidney replacement therapy] were measured using Cox models for case-mix and laboratory variables. RESULTS: The final analysis covered 485 participants with no loss to follow-up. The median follow-up period was 3.2 years. Two hundred and twenty-eight of the 485 patients reached ESKD requiring dialysis, and baseline serum creatinine levels doubled in another 31. The kidney end point was significantly poorer among patients with plasma BNP levels above, compared with below a cut-off value of 86.1 pg/mL indicated from receiver operating characteristic analysis. Multivariable Cox regression analysis identified the common logarithm BNP as a predictor of kidney end point (adjusted hazard ratio 1.78, 95% CI: 1.28-2.46, P < 0.01). CONCLUSIONS: Elevation of BNP level is associated with an increased risk for accelerated progression of CKD ultimately to ESKD. Monitoring the BNP level could be helpful in the management of combined heart and kidney disease.
Assuntos
Peptídeo Natriurético Encefálico/sangue , Insuficiência Renal Crônica/sangue , Idoso , Biomarcadores/sangue , Progressão da Doença , Feminino , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/etiologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Diálise Renal , Fatores de RiscoRESUMO
Quinoline-based tetradentate ligands with glucose pendants, N,N'-bis[2-(ß-d-glucopyranosyloxy)ethyl]-N,N'-bis[(6-methoxyquinolin-2-yl)methyl]ethylenediamine (N,N'-6-MeOBQBGEN) and its N,N-counterpart, N,N-6-MeOBQBGEN, have been prepared, and their fluorescence-spectral changes upon Zn binding were investigated. Upon excitation at 336 nm, N,N'-6-MeOBQBGEN showed weak fluorescence (Ï ≈ 0.016) in HEPES buffer (HEPES 50 mM, KCl 100 mM, pH 7.5). In the presence of Zn, N,N'-6-MeOBQBGEN exhibited a significant increase in fluorescence (Ï = 0.096) at 414 nm. The fluorescence enhancement is specific for Zn and Cd (I(Cd) /I(Zn) of 50% at 414 nm). On the other hand, N,N-6-MeOBQBGEN exhibited a smaller fluorescence enhancement upon Zn complexation (Ï = 0.043, λ(ex) = 334 nm, λ(em) = 407 nm) compared with N,N'-6-MeOBQBGEN. Fluorescence microscopic analysis using PC-12 rat adrenal cells revealed that N,N'-6-MeOBQBGEN exhibits a 1.8-fold higher fluorescence-signal response to Zn ion concentration compared with sugar-depleted compound 2 (N,N'-bis[(6-methoxyquinolin-2-yl)methyl]ethylenediamine), due to its enhanced uptake into cells due to the targeting ability of the attached carbohydrates.
Assuntos
Corantes Fluorescentes/química , Glucose/química , Quinolinas/química , Zinco/química , Animais , Transporte Biológico/efeitos dos fármacos , Linhagem Celular , Corantes Fluorescentes/farmacocinética , Corantes Fluorescentes/farmacologia , Glucose/farmacocinética , Concentração Inibidora 50 , Estrutura Molecular , Quinolinas/farmacocinética , RatosRESUMO
A previously healthy black man presented with acute kidney injury wtih nephrotic syndrome. His serum creatinine and albumin concentrations were 8.0 mg/dL and 0.4 g/dL, respectively. Renal ultrasound demonstrated an enlarged kidney with an extremely high echogenic cortex. Human immunodeficiency virus (HIV) was serologically positive, and kidney biopsy revealed a collapsing variant of focal segmental glomerulosclerosis with interstitial nephritis. He was diagnosed as having HIV-associated nephropathy (HIVAN). Although there have been only a few cases with characteristic HIVAN features in Japan, the number of patients with HIVAN who need dialysis treatment is relatively high globally, and is expected to increase even in Japan. The rapid clinical course of HIVAN, along with its characteristic histology and the direct pathogenesis of HIV on podocytes, is noteworthy. We described this case with reference to some recent findings.
Assuntos
Injúria Renal Aguda/etiologia , Infecções por HIV/complicações , Síndrome Nefrótica/etiologia , Injúria Renal Aguda/patologia , Adulto , Glomerulosclerose Segmentar e Focal/etiologia , Glomerulosclerose Segmentar e Focal/patologia , Humanos , Masculino , Nefrite Intersticial/etiologia , Nefrite Intersticial/patologia , Síndrome Nefrótica/patologia , Podócitos/patologia , Podócitos/virologiaRESUMO
BACKGROUND: IgE concentrations are occasionally elevated in patients with IgG4-related disease (IgG4-RD). In this report, we describe a novel case of IgG4-RD in which IgE concentrations were discordant between measuring reagents. CASE: An 81-year-old man was diagnosed with IgG4-RD and histological autoimmune pancreatitis, which ensued without treatment. The IgE concentrations measured using Elecsys IgE II Immunoassay and Iatroace IgE were 1287.0 IU/mL and 60.9 IU/mL, respectively. IgG4 concentration was 675 mg/dL. METHODS: To identify IgG and IgG4 directly bound to IgE, purification using protein G and anti-IgG4 antibody-conjugated matrixes and size-exclusion high-performance liquid chromatography (HPLC) were performed. RESULTS: In purification analysis, the IgE concentration of the flow-through and bound fractions were 6.8 IU/mL (10.8%) and 56.2 IU/mL (89.2%) for IgG purification and 6.8 IU/mL (12.2%) and 49.0 IU/mL (87.8%) for IgG4 purification. IgE was eluted as a single peak (640 kDa) using size-exclusion HPLC. In the elution pattern of IgG4, a minor peak (640 kDa) and a major peak (170 kDa) were observed. These results indicate that IgG4 binds to IgE and forms a complex, resulting in a discrepancy between reagents. CONCLUSIONS: In this report, we present an IgG4-IgE complex in a patient with IgG4-RD, which affected the discrepancy in IgE concentrations between IgE reagents. This report points to the significance of increased IgE production in IgG4-RD.