RESUMO
Patients with ESRD undergoing peritoneal dialysis develop progressive peritoneal fibrosis, which may lead to technique failure. Recent data point to Th17-mediated inflammation as a key contributor in peritoneal damage. The leukocyte antigen CD69 modulates the setting and progression of autoimmune and inflammatory diseases by controlling the balance between Th17 and regulatory T cells (Tregs). However, the relevance of CD69 in tissue fibrosis remains largely unknown. Thus, we explored the role of CD69 in fibroproliferative responses using a mouse model of peritoneal fibrosis induced by dialysis fluid exposure under either normal or uremic status. We found that cd69-/- mice compared with wild-type (WT) mice showed enhanced fibrosis, mesothelial to mesenchymal transition, IL-17 production, and Th17 cell infiltration in response to dialysis fluid treatment. Uremia contributed partially to peritoneal inflammatory and fibrotic responses. Additionally, antibody-mediated CD69 blockade in WT mice mimicked the fibrotic response of cd69-/- mice. Finally, IL-17 blockade in cd69-/- mice decreased peritoneal fibrosis to the WT levels, and mixed bone marrow from cd69-/- and Rag2-/-γc-/- mice transplanted into WT mice reproduced the severity of the response to dialysis fluid observed in cd69-/- mice, showing that CD69 exerts its regulatory function within the lymphocyte compartment. Overall, our results indicate that CD69 controls tissue fibrosis by regulating Th17-mediated inflammation.
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Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Lectinas Tipo C/imunologia , Fibrose Peritoneal/imunologia , Animais , Antígenos CD/fisiologia , Antígenos de Diferenciação de Linfócitos T/fisiologia , Feminino , Lectinas Tipo C/deficiência , Lectinas Tipo C/fisiologia , Camundongos , Células Th17/fisiologiaRESUMO
OBJECTIVE: Testosterone deficiency is a common finding in men with chronic kidney disease (CKD). Testosterone is thought to play an important anabolic role in muscle synthesis, and muscle wasting is an important and deleterious characteristic of protein-energy wasting (PEW) in CKD. It is presently unknown if reduced endogenous testosterone associates with features of muscle wasting in men with CKD. METHODS: This was a cross-sectional observational study of 267 men with CKD stages 2-4 (mean ± standard deviation age 67 ± 13 years, estimated glomerular filtration rate 42.9 [interquartile range 30.2-56.7] mL/min/1.73 m²) with measurements of endogenous testosterone and surrogates of PEW such as albumin, prealbumin, high-sensitivity C-reactive protein (CRP) and normalized protein nitrogen appearance (nPNA). Fat-free mass was estimated by bioelectrical impedance vector analysis (BIVA) and muscle strength by handgrip dynamometry. RESULTS: Across decreasing thirds of testosterone distribution, patients were incrementally older and CRP levels rose significantly. Prealbumin, hemoglobin, nPNA, handgrip strength, and BIVA estimated surrogates of muscle mass and nutritional status (fat-free mass, body cell mass, and phase angle) were progressively reduced (P < .05 for all). In multivariate regression analyses including age, renal function, and other important confounders, testosterone significantly and independently contributed to explain the variances of handgrip strength and fat-free mass (P < .05 for all). CONCLUSIONS: Endogenous testosterone independently associates with muscle strength and fat-free mass in men with moderate CKD. It is plausible that the reduction in testosterone levels that accompanies CKD may further contribute to the procatabolic environment leading to muscle wasting.
Assuntos
Índice de Massa Corporal , Força da Mão/fisiologia , Insuficiência Renal Crônica/sangue , Testosterona/sangue , Idoso , Idoso de 80 Anos ou mais , Peso Corporal , Proteína C-Reativa/metabolismo , Estudos Transversais , Impedância Elétrica , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estado Nutricional , Fenótipo , Estudos Prospectivos , Análise de Regressão , Insuficiência Renal Crônica/fisiopatologia , Fatores de Risco , Testosterona/deficiênciaRESUMO
During peritoneal dialysis (PD), mesothelial cells undergo mesothelial-to-mesenchymal transition (MMT), a process associated with peritoneal-membrane dysfunction. Because TGF-ß1 can induce MMT, we evaluated the efficacy of TGF-ß1-blocking peptides in modulating MMT and ameliorating peritoneal damage in a mouse model of PD. Exposure of the peritoneum to PD fluid induced fibrosis, angiogenesis, functional impairment, and the accumulation of fibroblasts. In addition to expressing fibroblast-specific protein-1 (FSP-1), some fibroblasts co-expressed cytokeratin, indicating their mesothelial origin. These intermediate-phenotype (Cyto(+)/FSP-1(+)) fibroblasts had features of myofibroblasts with fibrogenic capacity. PD fluid treatment triggered the appearance of CD31(+)/FSP-1(+) and CD45(+)/FSP-1(+) cells, suggesting that fibroblasts also originate from endothelial cells and from cells recruited from bone marrow. Administration of blocking peptides significantly ameliorated fibrosis and angiogenesis, improved peritoneal function, and reduced the number of FSP-1(+) cells, especially in the Cyto(+)/FSP-1(+) subpopulation. Conversely, overexpression of TGF-ß1 in the peritoneum by adenovirus-mediated gene transfer led to a marked accumulation of fibroblasts, most of which derived from the mesothelium. Taken together, these results demonstrate that TGF-ß1 drives the peritoneal deterioration induced by dialysis fluid and highlights a role of TGF-ß1-mediated MMT in the pathophysiology of peritoneal-membrane dysfunction.
Assuntos
Transdiferenciação Celular/efeitos dos fármacos , Diálise Peritoneal/efeitos adversos , Fibrose Peritoneal/etiologia , Peritônio/patologia , Fator de Crescimento Transformador beta1/metabolismo , Animais , Biomarcadores/metabolismo , Células Cultivadas , Soluções para Diálise/efeitos adversos , Feminino , Injeções Intraperitoneais , Queratinas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Fragmentos de Peptídeos/farmacologia , Fragmentos de Peptídeos/uso terapêutico , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Fibrose Peritoneal/metabolismo , Fibrose Peritoneal/patologia , Fibrose Peritoneal/prevenção & controle , Fenótipo , Receptores de Fatores de Crescimento Transformadores beta/uso terapêutico , Proteína A4 de Ligação a Cálcio da Família S100 , Proteínas S100/metabolismo , Fator de Crescimento Transformador beta1/antagonistas & inibidoresRESUMO
BACKGROUND: Peritoneal membrane deterioration during peritoneal dialysis (PD) is associated with epithelial-to-mesenchymal transition (EMT) of mesothelial cells (MC), which is believed to be mainly due to glucose degradation products (GDPs) present in PD solutions. Here we investigate the impact of GDPs in PD solutions on the EMT of MC in vitro and ex vivo. METHODS: For in vitro studies, omentum-derived MC were incubated with standard PD fluid or low-GDP solution diluted 1:1 with culture medium. For ex vivo studies, 33 patients, who were distributed at random to either the 'standard' or the 'low GDP' groups, were followed over 24 months. Effluents were collected every 6 months to determine EMT markers in effluent MC. RESULTS: Exposure of MC to standard fluid in vitro resulted in morphological change into a non-epitheloid shape, down-regulation of E-cadherin, indicative of EMT, and in a strong induction of vascular endothelial growth factor (VEGF) expression. In contrast, in vitro exposure of MC to low-GDP solution did not lead to these phenotype changes. This could be confirmed ex vivo, as the prevalence of non-epitheloid phenotype of MC in the standard group was significantly higher with increasing PD duration and MC isolated from this group showed significantly higher levels of EMT-associated molecules including fibronectin, collagen I, VEGF, IL-8 and TGF-ß levels when compared with the low-GDP group. Over time, the expression of E-cadherin also decreased in the standard but increased in the low-GDP group. In addition, the levels of EMT-associated molecules (fibronectin, VEGF and IL-8) increased in the standard but decreased in the low-GDP group. A similar trend was also observed for collagen I and for TGF-ß (for the first year), but did not reach global statistical significance. Accordingly, effluent MC with non-epitheloid morphology showed significantly lower levels of E-cadherin and greater levels of fibronectin, collagen I, VEGF and IL 8 when compared with MC with epitheloid phenotype. The incidence of peritonitis did not significantly influence these results. Drop-out due to technique failure was less in the 'balance' group. The functional, renal and peritoneal evaluation of patients being treated with either standard or 'balance' fluid did not show any significant difference over time. CONCLUSIONS: MC from PD effluent of patients treated with a PD fluid containing low GDP levels show fewer signs of EMT and the respective molecules than MC from patients treated with standard fluid, indicating a better preservation of the peritoneal membrane structure and a favourable outcome in patients using low-GDP fluid. It also confirms the hypothesis that the protection of EMT by GDP-reduced fluids is also present in vivo.
Assuntos
Soluções para Diálise/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Glucose/metabolismo , Mesoderma/citologia , Mesoderma/efeitos dos fármacos , Diálise Peritoneal , Western Blotting , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Exposure to non-physiological solutions during peritoneal dialysis (PD) produces structural alterations to the peritoneal membrane and ultrafiltration dysfunction. The high concentration of glucose and glucose degradation products in standard PD fluids induce a local diabetic environment, which leads to the formation of advanced glycation end products (AGEs) that have an important role in peritoneal membrane deterioration. Peroxisome proliferator-activated receptor γ (PPAR-γ) agonists are used to treat type II diabetes and they have beneficial effects on inflammation, fibrosis, and angiogenesis. Hence, we evaluated the efficacy of the PPAR-γ agonist rosiglitazone (RSG) in ameliorating peritoneal membrane damage in a mouse PD model, and we analyzed the mechanisms underlying the protection offered by RSG. Exposure of the peritoneum to PD fluid resulted in AGEs accumulation, an inflammatory response, the loss of mesothelial cell monolayer and invasion of the compact zone by mesothelial cells, fibrosis, angiogenesis, and functional impairment of the peritoneum. Administration of RSG diminished the accumulation of AGEs, preserved the mesothelial monolayer, decreased the number of invading mesothelial cells, reduced fibrosis and angiogenesis, and improved peritoneal function. Interestingly, instead of reducing the leukocyte recruitment, RSG administration enhanced this process and specifically, the recruitment of CD3+ lymphocytes. Furthermore, RSG treatment augmented the levels of the anti-inflammatory cytokine interleukin (IL)-10 and increased the recruitment of CD4+ CD25+ FoxP3+ cells, suggesting that regulatory T cells mediated the protection of the peritoneal membrane. In cell-culture experiments, RSG did not prevent or reverse the mesothelial to mesenchymal transition, although it decreased mesothelial cells apoptosis. Accordingly, RSG appears to produce pleiotropic protective effects on the peritoneal membrane by reducing the accumulation of AGEs and inflammation, and by preserving the mesothelial cells monolayer, highlighting the potential of PPAR-γ activation to ameliorate peritoneal deterioration in PD patients.
Assuntos
Soluções para Diálise/efeitos adversos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , PPAR gama/agonistas , Diálise Peritoneal/efeitos adversos , Peritônio/efeitos dos fármacos , Peritônio/patologia , Tiazolidinedionas/farmacologia , Animais , Células Epiteliais/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Epitélio/efeitos dos fármacos , Epitélio/patologia , Fibrose , Glucose/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Imunidade Celular/efeitos dos fármacos , Inflamação , Camundongos , PPAR gama/metabolismo , Peritônio/imunologia , Peritônio/metabolismo , Rosiglitazona , Linfócitos T/imunologiaRESUMO
BACKGROUND: During peritoneal dialysis (PD), mesothelial cells (MC) undergo an epithelial-to-mesenchymal transition (EMT), and this process is associated with peritoneal membrane (PM) damage. Bone morphogenic protein-7 (BMP-7) antagonizes transforming growth factor (TGF)-beta1, modulates EMT and protects against fibrosis. Herein, we analysed the modulating role of BMP-7 on EMT of MC in vitro and its protective effects in a rat PD model. METHODS: Epitheliod or non-epitheliod MC were analysed for the expression of BMP-7, TGF-beta1, activated Smads, epithelial cadherin (E-cadherin), collagen I, alpha smooth muscle cell actin (alpha-SMA) and vascular endothelial growth factor (VEGF) using standard procedures. Rats were daily instilled with PD fluid with or without BMP-7 during 5 weeks. Histological analyses were carried out in parietal peritoneum. Fibrosis was quantified with van Gieson or Masson's trichrome staining. Vasculature, activated macrophages and invading MC were quantified by immunofluorescence analysis. Quantification of infiltrating leukocytes and MC density in liver imprints was performed by May-Grünwald-Giemsa staining. Hyaluronic acid levels were determined by ELISA. RESULTS: MC constitutively expressed BMP-7, and its expression was downregulated during EMT. Treatment with recombinant BMP-7 resulted in blockade of TGF-beta1-induced EMT of MC. We provide evidence of a Smad-dependent mechanism for the blockade of EMT. Exposure of rat peritoneum to PD fluid resulted in inflammatory and regenerative responses, invasion of the compact zone by MC, fibrosis and angiogenesis. Administration of BMP-7 decreased the number of invading MC and reduced fibrosis and angiogenesis. In contrast, BMP-7 had no effect on inflammatory and regenerative responses, suggesting that these are EMT-independent, and probably upstream, processes. CONCLUSIONS: Data point to a balance between BMP-7 and TGF-beta1 in the control of EMT and indicate that blockade of EMT may be a therapeutic approach to ameliorate peritoneal membrane damage during PD.
Assuntos
Proteína Morfogenética Óssea 7/fisiologia , Epitélio/metabolismo , Mesoderma/metabolismo , Diálise Peritoneal , Peritônio/metabolismo , Actinas/metabolismo , Animais , Western Blotting , Caderinas/metabolismo , Diferenciação Celular , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Fibrose , Humanos , Técnicas Imunoenzimáticas , Masculino , Ratos , Ratos Wistar , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/antagonistas & inibidoresRESUMO
During peritoneal dialysis (PD), exposure of the peritoneal membrane to nonphysiologic solutions causes inflammation, ultimately leading to altered structure and function. Myofibroblasts, one of the cell types that contribute to dysfunction of the peritoneal membrane, can originate from mesothelial cells (MCs) by epithelial-to-mesenchymal transition (EMT), a process that has been associated with an increased rate of peritoneal transport. Because cyclooxygenase-2 (COX-2) is induced by inflammation, we studied the role of COX-2 in the deterioration of the peritoneal membrane. We observed that nonepithelioid MCs found in peritoneal effluent expressed higher levels of COX-2 than epithelioid MCs. The mass transfer coefficient for creatinine correlated with MC phenotype and with COX-2 levels. Although COX-2 was upregulated during EMT of MCs in vitro, COX-2 inhibition did not prevent EMT. In a mouse model of PD, however, COX-2 inhibition with Celecoxib resulted in reduced fibrosis and in partial recovery of ultrafiltration, outcomes that were associated with a reduction of inflammatory cells. Furthermore, PD fluid with a low content of glucose degradation products did not induce EMT or COX-2; the peritoneal membranes of mice treated with this fluid showed less worsening than mice exposed to standard fluid. In conclusion, upregulation of COX-2 during EMT may mediate peritoneal inflammation, suggesting COX-2 inhibition as a potential strategy to ameliorate peritoneal deterioration in PD patients.
Assuntos
Ciclo-Oxigenase 2/metabolismo , Soluções para Diálise/efeitos adversos , Diálise Peritoneal/efeitos adversos , Peritônio/enzimologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Transporte Biológico Ativo , Celecoxib , Células Cultivadas , Ciclo-Oxigenase 2/genética , Inibidores de Ciclo-Oxigenase 2/farmacologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/enzimologia , Células Epiteliais/patologia , Epitélio/efeitos dos fármacos , Epitélio/enzimologia , Epitélio/patologia , Feminino , Humanos , Inflamação/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Modelos Animais , Peritônio/efeitos dos fármacos , Peritônio/patologia , Peritônio/fisiopatologia , Pirazóis/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Transcrição da Família Snail , Sulfonamidas/farmacologia , Fatores de Transcrição/genética , Regulação para Cima , Adulto JovemRESUMO
Bowel bacterial overgrowth syndrome (BBOS) is an important cause of gastrointestinal (GI) abnormalities. Proinflammatory cytokines (PICs) are excessively produced and accumulate because of kidney failure in dialysis patients who experience chronic infections such as BBOS. We explored the association between GL function, BBOS, and the malnutrition, inflammation, and atherosclerosis (MIA) syndrome. We studied GI malabsorption and maldigestion by analyzing fecal starch, sugar, fat, and nitrogen; intestinal protein permeability (alpha1-antitrypsin fecal clearance); and fecal chymotrypsin. We evaluated BBOS by breath hydrogen test (BHT) after a 3-day fat-and-carbohydrate-overload diet. Positive BHT was present in 10 patients, showing a high prevalence of GI macronutrient malabsorption and maldigestion, and compared with the other patients, the highest plasma levels of tumor necrosis factor alpha and interleukin 6 and lower levels of albumin and prealbumin. Those 10 patients were treated with a combination of several antibiotics, including neomycin, amoxicillin-clavulanate, and quinolones. Between 2 and 3 months later, the BHT, markers of nutrition, and PIC were re-tested. All treated patients showed an improvement in nutrition status and a lesser inflammatory pattern. The BBOS infectious process is found frequently in dialysis patients in association with GI malabsorption and maldigestion, malnutrition, and systemic inflammation. Hyperproduction of PIC because of BBOS induces MIA through a double pathway: GI disorders and deleterious systemic effects.
Assuntos
Aterosclerose/etiologia , Síndrome da Alça Cega/complicações , Gastroenteropatias/complicações , Desnutrição/etiologia , Diálise Peritoneal , Adulto , Idoso , Antibacterianos/uso terapêutico , Síndrome da Alça Cega/diagnóstico , Síndrome da Alça Cega/tratamento farmacológico , Testes Respiratórios , Proteína C-Reativa/análise , Feminino , Gastroenteropatias/diagnóstico , Gastroenteropatias/tratamento farmacológico , Humanos , Inflamação/etiologia , Interleucina-6/sangue , Absorção Intestinal , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Diálise Peritoneal/efeitos adversos , Fator de Necrose Tumoral alfa/sangueRESUMO
Epithelial-to-mesenchymal transition (EMT) is a self-regulated physiological process required for tissue repair that, in non-controled conditions may lead to fibrosis, angiogenesis, loss of normal organ function or cancer. Although several molecular pathways involved in EMT regulation have been described, this process does not have any specific treatment. This article introduces a systematic review of effective natural plant compounds and their extract that modulates the pathological EMT or its deleterious effects, through acting on different cellular signal transduction pathways both in vivo and in vitro. Thereby, cryptotanshinone, resveratrol, oxymatrine, ligustrazine, osthole, codonolactone, betanin, tannic acid, gentiopicroside, curcumin, genistein, paeoniflorin, gambogic acid and Cinnamomum cassia extracts inhibit EMT acting on transforming growth factor-ß (TGF-ß)/Smads signaling pathways. Gedunin, carnosol, celastrol, black rice anthocyanins, Duchesnea indica, cordycepin and Celastrus orbiculatus extract downregulate vimectin, fibronectin and N-cadherin. Sulforaphane, luteolin, celastrol, curcumin, arctigenin inhibit ß-catenin signaling pathways. Salvianolic acid-A and plumbagin block oxidative stress, while honokiol, gallic acid, piperlongumine, brusatol and paeoniflorin inhibit EMT transcription factors such as SNAIL, TWIST and ZEB. Plectranthoic acid, resveratrol, genistein, baicalin, polyphyllin I, cairicoside E, luteolin, berberine, nimbolide, curcumin, withaferin-A, jatrophone, ginsenoside-Rb1, honokiol, parthenolide, phoyunnanin-E, epicatechin-3-gallate, gigantol, eupatolide, baicalin and baicalein and nitidine chloride inhibit EMT acting on other signaling pathways (SIRT1, p38 MAPK, NFAT1, SMAD, IL-6, STAT3, AQP5, notch 1, PI3K/Akt, Wnt/ß-catenin, NF-κB, FAK/AKT, Hh). Despite the huge amount of preclinical data regarding EMT modulation by the natural compounds of plant, clinical translation is poor. Additionally, this review highlights some relevant examples of clinical trials using natural plant compounds to modulate EMT and its deleterious effects. Overall, this opens up new therapeutic alternatives in cancer, inflammatory and fibrosing diseases through the control of EMT process.
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Background: Appetite disorders are frequent and scantly studied in peritoneal dialysis (PD) patients and are associated with malnutrition and cardiovascular complications. Objective: We investigated the relationship between uremic insulin resistance, pro-inflammatory cytokines, and appetite-related peptides release (ARPr) with eating-behavior disorders in PD patients. Methods: We included 42 PD patients (12 suffering anorexia, 12 obese with high food-intake, and 18 asymptomatic) and 10 controls. We measured blood levels of ARPr including orexigens [neuropeptide-Y (NPY), ghrelin, and nitric-oxide], anorexigens [cholecystokinin, insulin, corticotropin-releasing factor, leptin, and adiponectin (Ad)], and cytokines (TNF-α, sTNFα-R2, and IL-6) both at baseline and after administering a standard-food stimulus (SFS). We also measured the expression of TNF-α, leptin and Ad-encoding mRNAs in abdominal adipose tissue. We compared these markers with eating motivation measured by a Visual Analog Scale (VAS). Results: Anorexics showed both little appetite, measured by a VAS, and low levels of orexigens that remained constant after SFS, coupled with high levels of anorexigens at baseline and after SFS. Obeses showed higher appetite, increased baseline levels of orexigens, lower baseline levels of anorexigens and cytokines and two peaks of NPY after SFS. The different patterns of ARPr and cytokines pointed to a close relationship with uremic insulin resistance. In fact, the euglycemic-hyperglycemic clamp reproduced these disorders. In anorexics, TNF-α fat expression was increased. In obese patients, leptin expression in fat tissue was down-regulated and showed correlation with the appetite. Conclusion: In PD, appetite is governed by substances that are altered at baseline and abnormally released. Such modulators are controlled by insulin metabolism and cytokines and, while anorexics display inflammatory predominance, obese patients predominantly display insulin resistance.
RESUMO
Uremia is considered capable of inducing structural anomalies of the peritoneum, including hyalinizing vasculopathy (HV). To further elucidate the contribution of uremia to the severity of HV, we performed an autopsy study of peritoneal dialysis (PD) patients with severe peritoneal HV lesions. Uremia is a systemic condition and, if capable of inducing HV, it will be expected to be detected outside the peritoneum. Seven autopsy cases of PD patients showing prominent peritoneal HV lesions were selected. Histological slides from the peritoneum, abdominal organs, heart and pericardium, lungs, visceral pleura, and central nervous system were reviewed. Peritoneal lesions were intense in all patients with prominent HV, fibrosis, and a variable presence of inflammation, fibrin, and calcification. Except for focal HV lesions in the intestinal submucosa of one diabetic patient, HV lesions were limited to the peritoneal membrane. None of the other extraperitoneal tissues showed such lesions. In conclusion, extraperitoneal vessels of PD patients show no relevant HV lesions when compared to peritoneal ones. This observation suggests that PD-related factors are the main contributors to the severity of vasculopathy. Uremia may participate in the development of the lesion but it does not seem to be responsible for its severity.
Assuntos
Calcinose/patologia , Hialina/metabolismo , Diálise Peritoneal/efeitos adversos , Peritônio/irrigação sanguínea , Doenças Vasculares/patologia , Idoso , Autopsia , Calcinose/etiologia , Feminino , Fibrose , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Índice de Gravidade de Doença , Espanha , Uremia/complicações , Uremia/patologia , Doenças Vasculares/etiologia , Doenças Vasculares/metabolismoRESUMO
Patients with chronic kidney disease frequently experience loss of appetite (anorexia), which increases in severity during the progression of the disease and may lead to protein-energy wasting, morbidity, and mortality. Anorexia represents a multiple, complex, and multifactorial disorder that may have its origin in renal failure (contemplating not only retention of uremic toxins but also peptides and cytokines) but that later on also involves metabolic abnormalities not yet corrected by dialysis therapy. This paper reviews current knowledge about the clinical signs of uremic anorexia as well as mechanisms involved. Based on megestrol acetate interventions and the recent observation that sex may modulate uremic appetite behavior, the potential role of sex hormones in treating chronic kidney disease anorexia needs to be further explored.
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Anorexia/epidemiologia , Transtornos da Alimentação e da Ingestão de Alimentos/epidemiologia , Uremia/complicações , Apetite , Citocinas/sangue , Transtornos da Alimentação e da Ingestão de Alimentos/fisiopatologia , Homeostase , Humanos , Absorção Intestinal , Leptina/fisiologia , Óxido Nítrico/fisiologia , Uremia/fisiopatologiaRESUMO
BACKGROUND: During continuous ambulatory peritoneal dialysis, the peritoneum is exposed to bioincompatible dialysis fluids that cause denudation of mesothelial cells and, ultimately, tissue fibrosis and failure of ultrafiltration. However, the mechanism of this process has yet to be elucidated. METHODS: Mesothelial cells isolated from effluents in dialysis fluid from patients undergoing continuous ambulatory peritoneal dialysis were phenotypically characterized by flow cytometry, confocal immunofluorescence, Western blotting, and reverse-transcriptase polymerase chain reaction. These cells were compared with mesothelial cells from omentum and treated with various stimuli in vitro to mimic the transdifferentiation observed during continuous ambulatory peritoneal dialysis. Results were confirmed in vivo by immunohistochemical analysis performed on peritoneal-biopsy specimens. RESULTS: Soon after dialysis is initiated, peritoneal mesothelial cells undergo a transition from an epithelial phenotype to a mesenchymal phenotype with a progressive loss of epithelial morphology and a decrease in the expression of cytokeratins and E-cadherin through an induction of the transcriptional repressor snail. Mesothelial cells also acquire a migratory phenotype with the up-regulation of expression of alpha2 integrin. In vitro analyses point to wound repair and profibrotic and inflammatory cytokines as factors that initiate mesothelial transdifferentiation. Immunohistochemical studies of peritoneal-biopsy specimens from patients undergoing continuous ambulatory peritoneal dialysis demonstrate the expression of the mesothelial markers intercellular adhesion molecule 1 and cytokeratins in fibroblast-like cells entrapped in the stroma, suggesting that these cells stemmed from local conversion of mesothelial cells. CONCLUSIONS: Our results suggest that mesothelial cells have an active role in the structural and functional alteration of the peritoneum during peritoneal dialysis. The findings suggest potential targets for the design of new dialysis solutions and markers for the monitoring of patients.
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Células Epiteliais/citologia , Diálise Peritoneal Ambulatorial Contínua , Movimento Celular , Células Cultivadas , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Imuno-Histoquímica , Cadeias alfa de Integrinas/metabolismo , Interleucina-1/farmacologia , Microscopia de Vídeo , Omento/citologia , Reação em Cadeia da Polimerase , RNA Mensageiro/metabolismo , Fatores de Transcrição da Família Snail , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta/farmacologiaRESUMO
Hypoalbuminemia may be secondary to volume expansion conditions and an independent risk factor for cardiovascular disease. Bioelectrical impedance analysis (BIA) is an accurate, non-invasive method to measure body composition, especially the water compartments in humans. The aim of this cross-sectional study is to evaluate the relationship between serum albumin concentration (SA) and hydration state measured by whole BIA. The study investigated 108 non-selected patients (73 on hemodialysis, 35 on peritoneal dialysis) with a mean age of 61.4 +/- 15.6 years, 42.7% of whom were female. The patients were allotted to groups according to their SA: Group 1, < or = 3.5 g/dL; Group 2, 3.6-4.0 g/dL; and Group 3, >4.0 g/dL. The BIA parameters used included: total body water, intracellular water (ICW), extracellular water (ECW), phase angle (PA), body cell mass (BCM), ICW/ECW ratio and ICW/ECW ratio patients/controls (fluid index). Seventy-five healthy volunteers formed the control group. A strong positive correlation was found between the PA and fluid index (r (2) = 0.993, P < 0.001), as well as between the PA and SA (r = 0.386, P < 0.001), and the ICW/ECW ratio and SA (r = 0.227, P < 0.001). The ECW was negatively correlated with SA (r = -0.330, P < 0.001). Every 0.1 g/dL decrease in SA was associated with a 0.33 L increase in ECW. Group 1 patients had lower reactance (P = 0.006), PA (P < 0.001), BCM (P = 0.012), fluid index (P < 0.001) and ICW/ECW ratio (P = 0.015), and an increased ECW (NS) than groups 2 and 3. We conclude that hypoalbuminemia is also a marker of fluid excess. The SA is associated to the fluid index and the PA allows assessment of the dry weight and its variations in an individualized manner in dialysis patients.
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Compartimentos de Líquidos Corporais , Água Corporal , Impedância Elétrica , Hipoalbuminemia/sangue , Diálise Peritoneal , Diálise Renal , Idoso , Biomarcadores , Composição Corporal , Análise por Conglomerados , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
This article reviews current knowledge about mechanisms responsible for uremic events, especially those that involve the central nervous system (CNS). Anorexia is a frequent complication of the uremic syndrome that contributes to malnutrition in patients on dialysis. Uremic anorexia has been associated with many factors. Traditionally, anorexia in dialysis patients has been regarded as a sign of uremic toxicity; therefore, 2 hypotheses have been proposed: the "middle molecule" and "peak concentration" hypotheses; both of these remain unproved. Recently, our group has proposed the tryptophan-serotonin hypothesis, which is based on a disorder in the amino acid profile that may be acquired when the patient is in uremic status. It is characterized by low concentrations of large neutral and branched chain amino acids in the cerebrospinal fluid. This situation permits a high level of tryptophan transport across the blood-brain barrier and enhances the synthesis of serotonin (the final target responsible for inhibiting appetite). The role of inflammation in the genesis of anorexia-malnutrition is also emphasized. In summary, in the CNS, factors associated with uremic anorexia include high levels within the cerebrospinal fluid of proinflammatory cytokines, leptin, and free tryptophan and serotonin (hyperserotoninergic-like syndrome), along with deficiency of neural nitric oxide (nNO) and disorders in various receptors such as melanocortin receptor-4 (MC4-R). Uremic anorexia is a complex complication associated with malnutrition and high levels of morbidity and mortality. Several uremia-acquired disorders in the CNS such as high cerebrospinal fluid levels of anorexigen substances and disorders in appetite regulator receptors may explain the lack of appetite.
Assuntos
Anorexia/imunologia , Regulação do Apetite/fisiologia , Encéfalo/metabolismo , Uremia/fisiopatologia , Aminoácidos/metabolismo , Citocinas/imunologia , Humanos , Leptina/metabolismo , Óxido Nítrico/metabolismo , Serotonina/metabolismo , Uremia/complicaçõesRESUMO
Peritoneal dialysis (PD) is an effective renal replacement therapy, but a significant proportion of patients suffer PD-related complications, which limit the treatment duration. Mesothelial-to-mesenchymal transition (MMT) contributes to the PD-related peritoneal dysfunction. We analyzed the genetic reprograming of MMT to identify new biomarkers that may be tested in PD-patients. Microarray analysis revealed a partial overlapping between MMT induced in vitro and ex vivo in effluent-derived mesothelial cells, and that MMT is mainly a repression process being higher the number of genes that are down-regulated than those that are induced. Cellular morphology and number of altered genes showed that MMT ex vivo could be subdivided into two stages: early/epithelioid and advanced/non-epithelioid. RT-PCR array analysis demonstrated that a number of genes differentially expressed in effluent-derived non-epithelioid cells also showed significant differential expression when comparing standard versus low-GDP PD fluids. Thrombospondin-1 (TSP1), collagen-13 (COL13), vascular endothelial growth factor A (VEGFA), and gremlin-1 (GREM1) were measured in PD effluents, and except GREM1, showed significant differences between early and advanced stages of MMT, and their expression was associated with a high peritoneal transport status. The results establish a proof of concept about the feasibility of measuring MMT-associated secreted protein levels as potential biomarkers in PD.
Assuntos
Reprogramação Celular/genética , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Transição Epitelial-Mesenquimal/genética , Genômica , Diálise Peritoneal , Biomarcadores , Soluções para Diálise/química , Perfilação da Expressão Gênica , Genômica/métodos , Glicólise , Humanos , Diálise Peritoneal/efeitos adversos , TranscriptomaRESUMO
During peritoneal dialysis (PD), the peritoneum is exposed to bioincompatible dialysis fluids, which causes progressive fibrosis and angiogenesis and, ultimately, ultrafiltration failure. In addition, repeated episodes of peritonitis or hemoperitoneum may accelerate all these processes. Fibrosis has been classically considered the main cause of peritoneal membrane functional decline. However, in parallel with fibrosis, the peritoneum also displays increases in capillary number (angiogenesis) and vasculopathy in response to PD. Nowadays, there is emerging evidence pointing to peritoneal microvasculature as the main factor responsible for increased solute transport and ultrafiltration failure. However, the pathophysiologic mechanism(s) involved in starting and maintaining peritoneal fibrosis and angiogenesis remain(s) elusive. Peritoneal stromal fibroblasts have been considered (for many years) the cell type mainly involved in structural and functional alterations of the peritoneum; whereas mesothelial cells have been considered mere victims of peritoneal injury caused by PD. Recently, ex vivo cultures of effluent-derived mesothelial cells, in conjunction with immunohistochemical analysis of peritoneal biopsies from PD patients, have identified mesothelial cells as culprits, at least in part, in peritoneal membrane deterioration. This review discusses recent findings that suggest new peritoneal myofibroblastic cells may arise from local conversion of mesothelial cells by epithelial-to-mesenchymal transition during the repair responses that take place in PD. The transdifferentiated mesothelial cells may retain a permanent mesenchymal state, as long as initiating stimuli persist, and contribute to PD-induced fibrosis and angiogenesis, and hence to membrane failure. Future therapeutic interventions could be designated in order to prevent or reverse epithelial-to-mesenchymal transition of mesothelial cells, or its pernicious effects.
Assuntos
Células Epiteliais , Diálise Peritoneal/efeitos adversos , Peritônio/metabolismo , Transporte Biológico , Células Cultivadas , Soluções para Diálise/farmacocinética , Fibrose/etiologia , Fibrose/patologia , Humanos , Neovascularização Patológica/etiologia , Neovascularização Patológica/patologia , Peritônio/irrigação sanguínea , Peritônio/patologia , Falha de TratamentoRESUMO
Cardiovascular factors are one of the main causes of morbidity and mortality in patients with chronic kidney disease. Bone mineral metabolism disorders and inflammation are pathological conditions that involve increased cardiovascular risk in chronic kidney disease. The cardiovascular risk involvement of bone mineral metabolism classical biochemical parameters such as phosphorus, calcium, vitamin D and PTH is well known. The newest markers, FGF23 and klotho, could also be implicated in cardiovascular disease.
Assuntos
Distúrbio Mineral e Ósseo na Doença Renal Crônica , Animais , Biomarcadores , Osso e Ossos/metabolismo , Calcineurina/fisiologia , Doenças Cardiovasculares/etiologia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/complicações , Distúrbio Mineral e Ósseo na Doença Renal Crônica/metabolismo , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/fisiologia , Glucuronidase/fisiologia , Humanos , Proteínas Klotho , Camundongos , Minerais/metabolismo , Modelos Biológicos , Hormônio Paratireóideo/fisiologia , Fósforo/metabolismo , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/metabolismo , Fatores de Risco , Calcificação Vascular/etiologia , Calcificação Vascular/prevenção & controle , Vitamina D/metabolismoRESUMO
UNLABELLED: Peritoneal dialysis (PD) is a form of renal replacement treatment, which employs the peritoneal membrane (PM) to eliminate toxins that cannot be removed by the kidney. The procedure itself, however, contributes to the loss of the PM ultrafiltration capacity (UFC), leading consequently to the technique malfunction. ß-blockers have been considered deleterious for PM due to their association with loss of UFC and induction of fibrosis. Herein we analyzed the effects of Nebivolol, a new generation of ß1-blocker, on PM alterations induced by PD fluids (PDF).In vitro: We found that mesothelial cells (MCs) express ß1-adrenergic receptor. MCs were treated with TGF-ß to induce mesothelial-to-mesenchymal transition (MMT) and co-treated with Nebivolol. Nebivolol reversed the TGF-ß effects, decreasing extracellular matrix synthesis, and improved the fibrinolytic capacity, decreasing plasminogen activator inhibitor-1 (PAI-1) and increasing tissue-type plasminogen activator (tPA) supernatant levels. Moreover, Nebivolol partially inhibited MMT and decreased vascular endothelial growth factor (VEGF) and IL-6 levels in supernatants.In vivo: Twenty-one C57BL/6 mice were divided into 3 groups. Control group carried a catheter without PDF infusion. Study group received intraperitoneally PDF and oral Nebivolol during 30 days. PDF group received PDF alone. Nebivolol maintained the UFC and reduced PM thickness, MMT and angiogenesis promoted by PDF. It also improved the fibrinolytic capacity in PD effluents decreasing PAI-1 and IL-8 and increased tPA levels. CONCLUSION: Nebivolol protects PM from PDF-induced damage, promoting anti-fibrotic, anti-angiogenic, anti-inflammatory and pro-fibrinolytic effects.
Assuntos
Agonistas de Receptores Adrenérgicos beta 1/farmacologia , Soluções para Diálise/efeitos adversos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Nebivolol/farmacologia , Diálise Peritoneal/efeitos adversos , Peritônio/efeitos dos fármacos , Peritônio/patologia , Agonistas de Receptores Adrenérgicos beta 1/uso terapêutico , Animais , Células Cultivadas , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Feminino , Fibrinólise/efeitos dos fármacos , Fibrose , Humanos , Interleucina-8/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Nebivolol/uso terapêutico , Neovascularização Patológica/induzido quimicamente , Neovascularização Patológica/tratamento farmacológico , Peritônio/citologia , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Receptores Adrenérgicos beta 1/metabolismo , Serpina E2/metabolismo , Ativador de Plasminogênio Tecidual/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND: During peritoneal dialysis (PD), the peritoneum is exposed to bioincompatible dialysis fluids that cause epithelial-to-mesenchymal transition of mesothelial cells, fibrosis, and angiogenesis. Ultrafiltration failure is associated with high transport rates and increased vascular surface, indicating the implication of vascular endothelial growth factor (VEGF). Sources of VEGF in vivo in PD patients remain unclear. We analyzed the correlation between epithelial-to-mesenchymal transition of mesothelial cells and both VEGF level and peritoneal functional decline. METHODS: Effluent mesothelial cells were isolated from 37 PD patients and analyzed for mesenchymal conversion. Mass transfer coefficient for creatinine (Cr-MTC) was used to evaluate peritoneal function. VEGF concentration was measured by using standard procedures. Peritoneal biopsy specimens from 12 PD patients and 6 controls were analyzed immunohistochemically for VEGF and cytokeratin expression. RESULTS: Nonepithelioid mesothelial cells from effluent produced a greater amount of VEGF ex vivo than epithelial-like mesothelial cells (P < 0.001). Patients whose drainage contained nonepithelioid mesothelial cells had greater serum VEGF levels than those with epithelial-like mesothelial cells in their effluent (P < 0.01). VEGF production ex vivo by effluent mesothelial cells correlated with serum VEGF level (r = 0.6; P < 0.01). In addition, Cr-MTC correlated with VEGF levels in culture (r = 0.8; P < 0.001) and serum (r = 0.35; P < 0.05). Cr-MTC also was associated with mesothelial cell phenotype. VEGF expression in stromal cells, retaining mesothelial markers, was observed in peritoneal biopsy specimens from high-transporter patients. CONCLUSION: These results suggest that mesothelial cells that have undergone epithelial-to-mesenchymal transition are the main source of VEGF in PD patients and therefore may be responsible for a high peritoneal transport rate.