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1.
Nat Commun ; 11(1): 4664, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938919

RESUMO

Cardiorenal syndrome type 4 (CRS4) is a common complication of chronic kidney disease (CKD), but the pathogenic mechanisms remain elusive. Here we report that morphological and functional changes in myocardial mitochondria are observed in CKD mice, especially decreases in oxidative phosphorylation and fatty acid metabolism. High phosphate (HP), a hallmark of CKD, contributes to myocardial energy metabolism dysfunction by downregulating peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α). Furthermore, the transcriptional factor interferon regulatory factor 1 (IRF1) is revealed as the key molecule upregulated by HP through histone H3K9 acetylation, and responsible for the HP-mediated transcriptional inhibition of PGC1α by directly binding to its promoter region. Conversely, restoration of PGC1α expression or genetic knockdown of IRF1 significantly attenuates HP-induced alterations in vitro and in vivo. These findings demonstrate that IRF1-PGC1α axis-mediated myocardial energy metabolism remodeling plays a crucial role in the pathogenesis of CRS4.


Assuntos
Síndrome Cardiorrenal/metabolismo , Fator Regulador 1 de Interferon/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Síndrome Cardiorrenal/patologia , Modelos Animais de Doenças , Regulação para Baixo , Metabolismo Energético , Técnicas de Silenciamento de Genes , Taxa de Filtração Glomerular , Glucuronidase/genética , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Humanos , Fator Regulador 1 de Interferon/genética , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Fosfatos/metabolismo , Regiões Promotoras Genéticas , Ratos , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/metabolismo , Adulto Jovem
2.
PLoS One ; 15(6): e0234712, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32603378

RESUMO

Chronic kidney disease is a common disease in dogs, and factors such as serum concentrations of creatinine, albumin, and phosphorus at the moment of diagnosis may influence the survival of these patients. The present retrospective study aimed to evaluate the relationship between survival in dogs with chronic kidney disease and laboratory parameters (creatinine, phosphorus, albumin, and hematocrit) and nutritional parameters (body condition score, muscle mass score, type of food, appetite and feeding method). A total of 116 dogs with chronic kidney disease stages 2 to 4 were included, and survival was calculated considering the time between diagnosis and death. Survival curves were configurated by Kaplan-Meier analysis and a comparison between survival curves was performed by the log-rank test. Factors related to survival were disease stage (p<0.0001), serum phosphorus concentration (p = 0.0005), hematocrit (0.0001), body condition score (p = 0.0391), muscle mass score (p = 0.0002), type of food (p = 0.0009), feeding method (p<0.0001) and appetite (p = 0.0007). Based on data obtained in this study, it is possible to conclude that early diagnosis, as well as nutritional evaluation and renal diet intake, are determinant strategies to increase survival in dogs with chronic kidney disease.


Assuntos
Doenças do Cão/metabolismo , Laboratórios , Estado Nutricional , Insuficiência Renal Crônica/veterinária , Animais , Doenças do Cão/sangue , Cães , Feminino , Estimativa de Kaplan-Meier , Masculino , Fósforo/sangue , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/metabolismo , Análise de Sobrevida
3.
PLoS One ; 15(7): e0232741, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32649699

RESUMO

INTRODUCTION: Inflammation plays a major role in the development of atherosclerosis and cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients. Toll-like receptor-4 (TLR4) is a major receptor for lipopolysaccharides (endotoxin) and other ligands involved in the pathogenesis of inflammation. We determined whether endotoxin levels and the presence of TLR4 polymorphisms are associated with markers of inflammation and atherosclerosis among South African CKD patients. MATERIALS AND METHODS: Endotoxin, lipopolysaccharide binding protein (LBP), serum CD14 (sCD14), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1) and carotid intima media thickness (CIMT) were measured in 160 participants (120 CKD patients and 40 controls). Associations between endotoxins and CIMT in the presence of sCD14, IL-8 and MCP-1, were assessed using odds ratios. Participants were screened for the presence of Asp299Gly and Thr399Ile TLR4 polymorphisms, and CIMT and inflammatory markers were compared between subjects with and without TLR4 polymorphisms. RESULTS: Endotoxin levels correlated with sCD14 (r = 0.441, p<0.001) and MCP-1 (r = 0.388, p<0.001) levels while increased CIMT was associated with MCP-1 (r = 0.448, p<0.001), sCD14 levels (r = 0.476, p<0.001), LBP (r = 0.340, p<0.001), and IL-8 (r = 0.395, p<0.001). Atherosclerosis was associated with endotoxin levels (odds ratio: 4.95; 95% confidence interval: 2.52-9.73; p<0.001), and was predicted by higher serum levels of inflammatory markers. Analysis of patients with TLR4 polymorphisms showed reduced serum levels of inflammatory markers and CIMT values compared with the patients carrying the wild type TLR4 alleles. CONCLUSION: The study demonstrated associations between circulating endotoxaemia, systemic inflammation and accelerated atherosclerosis among South African CKD patients, and showed that the atherogenic predictive power of endotoxaemia was significantly increased by the presence of elevated levels of inflammatory markers. Additional findings, which must be confirmed, suggest that TLR4 polymorphisms are associated with low levels of inflammatory markers and CIMT values.


Assuntos
Grupo com Ancestrais do Continente Africano/estatística & dados numéricos , Aterosclerose/complicações , Grupos Populacionais/estatística & dados numéricos , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/epidemiologia , Adulto , Espessura Intima-Media Carotídea , Estudos de Coortes , Suscetibilidade a Doenças , Feminino , Genótipo , Humanos , Inflamação/complicações , Masculino , Polimorfismo Genético , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/metabolismo , Risco , Receptor 4 Toll-Like/genética
4.
Am J Physiol Renal Physiol ; 319(2): F335-F344, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32657157

RESUMO

Human immunodeficiency virus (HIV) infection of kidney cells can lead to HIV-associated nephropathy (HIVAN) and aggravate the progression of other chronic kidney diseases. Thus, a better understanding of the mechanisms of HIV-induced kidney cell injury is needed for effective therapy against HIV-induced kidney disease progression. We have previously shown that the acetylation and activation of key inflammatory regulators, NF-κB p65 and STAT3, were increased in HIVAN kidneys. Here, we demonstrate the key role of sirtuin 1 (SIRT1) deacetylase in the regulation of NF-κB and STAT3 activity in HIVAN. We found that SIRT1 expression was reduced in the glomeruli of human and mouse HIVAN kidneys and that HIV-1 gene expression was associated with reduced SIRT1 expression and increased acetylation of NF-κB p65 and STAT3 in cultured podocytes. Interestingly, SIRT1 overexpression, in turn, reduced the expression of negative regulatory factor in podocytes stably expressing HIV-1 proviral genes, which was associated with inactivation of NF-κB p65 and a reduction in HIV-1 long terminal repeat promoter activity. In vivo, the administration of the small-molecule SIRT1 agonist BF175 or inducible overexpression of SIRT1 specifically in podocytes markedly attenuated albuminuria, kidney lesions, and expression of inflammatory markers in Tg26 mice. Finally, we showed that the reduction in SIRT1 expression by HIV-1 is in part mediated through miR-34a expression. Together, our data provide a new mechanism of SIRT1 regulation and its downstream effects in HIV-1-infected kidney cells and indicate that SIRT1/miR-34a are potential drug targets to treat HIV-related kidney disease.


Assuntos
Nefropatia Associada a AIDS/virologia , Insuficiência Renal Crônica/metabolismo , Sirtuína 1/metabolismo , Nefropatia Associada a AIDS/complicações , Nefropatia Associada a AIDS/metabolismo , Animais , Humanos , Rim/metabolismo , Glomérulos Renais/metabolismo , Glomérulos Renais/virologia , Camundongos , Podócitos/metabolismo , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/virologia , Fator de Transcrição RelA/metabolismo
5.
Eur Urol Focus ; 6(5): 1086-1096, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32540268

RESUMO

CONTEXT: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic that erupted in December 2019 has affected more than a million people from over 200 countries, claiming over 70 000 lives (by April 7, 2020). As the viral infection is driven by increased angiotensin-converting enzyme-2 (ACE2) expression, with the kidney exhibiting the highest expression, it is crucial to gain insights into the mechanisms underlying renal cell carcinoma (RCC) and coronavirus disease 2019 (COVID-19). OBJECTIVE: This study considers up-to-date information on the biological determinants shared by COVID-19 and renal disease, and aims to provide evidence-based recommendations for the clinical management of RCC patients with COVID-19. EVIDENCE ACQUISITION: A literature search was performed using all sources (MEDLINE, EMBASE, ScienceDirect, Cochrane Libraries, and Web of Science). As of March 31, 2020, the Center for Disease Control reported that of the adults hospitalized for COVID-19 with underlying conditions in the USA, 74.8% had chronic renal disease. EVIDENCE SYNTHESIS: Evidence is discussed from epidemiological studies on SARS-CoV-2 pandemic and molecular studies on the role of kidney in facilitating routes for SARS-CoV-2 entry, leading to increased virulence of SARS-CoV-2 and clinical manifestation of symptoms in RCC. CONCLUSIONS: This analysis will advance our understanding of (1) the molecular signatures shared by RCC and COVID-19 and (2) the clinical implications of overlapping signaling pathways in the therapeutic management of RCC and COVID-19 patients. PATIENT SUMMARY: Amid the coronavirus disease 2019 (COVID-19) pandemic, patients diagnosed with renal cell carcinoma and infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may receive complimentary treatment modalities to enhance therapeutic response.


Assuntos
Betacoronavirus/metabolismo , Carcinoma de Células Renais/metabolismo , Infecções por Coronavirus/metabolismo , Neoplasias Renais/metabolismo , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/metabolismo , Insuficiência Renal Crônica/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Lesão Renal Aguda/epidemiologia , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/terapia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Antivirais/uso terapêutico , Carcinoma de Células Renais/epidemiologia , Comorbidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/fisiopatologia , Antagonistas dos Receptores de Endotelina/uso terapêutico , Hospitalização , Humanos , Ipilimumab/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/epidemiologia , Biópsia Líquida , Nivolumabe/uso terapêutico , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Pneumonia Viral/fisiopatologia , Inibidores de Proteínas Quinases/uso terapêutico , Diálise Renal , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/terapia , Serina Endopeptidases/metabolismo , Índice de Gravidade de Doença , Sunitinibe/uso terapêutico
6.
Eur J Endocrinol ; 183(3): 233-244, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32508317

RESUMO

Background: Patients with chronic kidney disease (CKD) have a high risk of premature cardiovascular diseases (CVD) and show increased mortality. Pro-neurotensin (Pro-NT) was associated with metabolic diseases and predicted incident CVD and mortality. However, Pro-NT regulation in CKD and its potential role linking CKD and mortality have not been investigated, so far. Methods: In a central lab, circulating Pro-NT was quantified in three independent cohorts comprising 4715 participants (cohort 1: patients with CKD; cohort 2: general population study; and cohort 3: non-diabetic population study). Urinary Pro-NT was assessed in part of the patients from cohort 1. In a 4th independent cohort, serum Pro-NT was further related to mortality in patients with advanced CKD. Tissue-specific Nts expression was further investigated in two mouse models of diabetic CKD and compared to non-diabetic control mice. Results: Pro-NT significantly increased with deteriorating renal function (P < 0.001). In meta-analysis of cohorts 1-3, Pro-NT was significantly and independently associated with estimated glomerular filtration rate (P ≤ 0.002). Patients in the middle/high Pro-NT tertiles at baseline had a higher all-cause mortality compared to the low Pro-NT tertile (Hazard ratio: 2.11, P = 0.046). Mice with severe diabetic CKD did not show increased Nts mRNA expression in different tissues compared to control animals. Conclusions: Circulating Pro-NT is associated with impaired renal function in independent cohorts comprising 4715 subjects and is related to all-cause mortality in patients with end-stage kidney disease. Our human and rodent data are in accordance with the hypotheses that Pro-NT is eliminated by the kidneys and could potentially contribute to increased mortality observed in patients with CKD.


Assuntos
Neurotensina/metabolismo , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Estudos Transversais , Feminino , Taxa de Filtração Glomerular/fisiologia , Humanos , Rim/metabolismo , Rim/fisiopatologia , Estudos Longitudinais , Masculino , Metanálise como Assunto , Camundongos , Pessoa de Meia-Idade , Neurotensina/sangue , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/fisiopatologia
7.
Vasc Health Risk Manag ; 16: 167-180, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32494148

RESUMO

Vascular calcification (VC) is a life-threatening state in chronic kidney disease (CKD). High cardiovascular mortality and morbidity of CKD cases may root from medial VC promoted by hyperphosphatemia. Vascular calcification is an active, highly regulated, and complex biological process that is mediated by genetics, epigenetics, dysregulated form of matrix mineral metabolism, hormones, and the activation of cellular signaling pathways. Moreover, gut microbiome as a source of uremic toxins (eg, phosphate, advanced glycation end products and indoxyl-sulfate) can be regarded as a potential contributor to VC in CKD. Here, an update on different cellular and molecular processes involved in VC in CKD is discussed to elucidate the probable therapeutic pathways in the future.


Assuntos
Vasos Sanguíneos/metabolismo , Rim/metabolismo , Eliminação Renal , Insuficiência Renal Crônica/complicações , Calcificação Vascular/etiologia , Remodelação Vascular , Animais , Vasos Sanguíneos/patologia , Vasos Sanguíneos/fisiopatologia , Humanos , Rim/fisiopatologia , Prognóstico , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/mortalidade , Insuficiência Renal Crônica/fisiopatologia , Fatores de Risco , Calcificação Vascular/metabolismo , Calcificação Vascular/mortalidade , Calcificação Vascular/fisiopatologia
8.
Am J Physiol Renal Physiol ; 319(1): F84-F92, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32475130

RESUMO

Loss of muscle proteins increases the morbidity and mortality of patients with chronic kidney disease (CKD), and there are no reliable preventive treatments. We uncovered a STAT3/CCAAT-enhancer-binding protein-δ to myostatin signaling pathway that activates muscle protein degradation in mice with CKD or cancer; we also identified a small-molecule inhibitor of STAT3 (TTI-101) that blocks this pathway. To evaluate TTI-101 as a treatment for CKD-induced cachexia, we measured TTI-101 pharmacokinetics and pharmacodynamics in control and CKD rats that were orally administered TTI-101or its diluent. The following two groups of gavage-fed rats were studied: sham-operated control rats and CKD rats. Plasma was collected serially (0, 0.25, 0.5, 1, 2, 4, 8, and 24 h) following TTI-101 administration (at oral doses of 0, 10, 30, or 100 mg/kg). Plasma levels of TTI-101 were measured by LC-MS/MS, and pharmacokinetic results were analyzed with the PKSolver program. Plasma TTI-101 levels increased linearly with doses; the maximum plasma concentrations and time to maximal plasma levels (~1 h) were similar in sham-operated control rats and CKD rats. Notably, gavage treatment of TTI-101 for 3 days produced TTI-101 muscle levels in sham control rats and CKD rats that were not significantly different. CKD rats that received TTI-101 for 7 days had suppression of activated STAT3 and improved muscle grip strength; there also was a trend for increasing body and muscle weights. TTI-101 was tolerated at doses of 100 mg·kg-1·day-1 for 7 days. These results with TTI-101 in rats warrant its development as a treatment for cachexia in humans.


Assuntos
Inibidores Enzimáticos/farmacologia , Músculo Esquelético/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Insuficiência Renal Crônica/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Animais , Peso Corporal/efeitos dos fármacos , Cromatografia Líquida , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacocinética , Força da Mão , Músculo Esquelético/metabolismo , Ratos , Espectrometria de Massas em Tandem
9.
Am J Physiol Renal Physiol ; 319(1): F139-F148, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32538151

RESUMO

Inflammation is a major determinant for the progression of chronic kidney disease (CKD). NF-κB is a master transcription factor upregulated in CKD that promotes inflammation and regulates apoptosis and vascular remodeling. We aimed to modulate this pathway for CKD therapy in a swine model of CKD using a peptide inhibitor of the NF-κB p50 subunit (p50i) fused to a protein carrier [elastin-like polypeptide (ELP)] and equipped with a cell-penetrating peptide (SynB1). We hypothesized that intrarenal SynB1-ELP-p50i therapy would inhibit NF-κB-driven inflammation and induce renal recovery. CKD was induced in 14 pigs. After 6 wk, pigs received single intrarenal SynB1-ELP-p50i therapy (10 mg/kg) or placebo (n = 7 each). Renal hemodynamics were quantified in vivo using multidetector computed tomography before and 8 wk after treatment. Pigs were then euthanized. Ex vivo experiments were performed to quantify renal activation of NF-κB, expression of downstream mediators of NF-κB signaling, renal microvascular density, inflammation, and fibrosis. Fourteen weeks of CKD stimulated NF-κB signaling and downstream mediators (e.g., TNF-α, monocyte chemoattractant protein-1, and IL-6) accompanying loss of renal function, inflammation, fibrosis, and microvascular rarefaction versus controls. All of these were improved after SynB1-ELP-p50i therapy, accompanied by reduced circulating inflammatory cytokines as well, which were evident up to 8 wk after treatment. Current treatments for CKD are largely ineffective. Our study shows the feasibility of a new treatment to induce renal recovery by offsetting inflammation at a molecular level. It also supports the therapeutic potential of targeted inhibition of the NF-κB pathway using novel drug delivery technology in a translational model of CKD.


Assuntos
Rim/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Insuficiência Renal Crônica/tratamento farmacológico , Animais , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Fibrose/tratamento farmacológico , Fibrose/metabolismo , Fibrose/patologia , Rim/metabolismo , Rim/patologia , Circulação Renal/efeitos dos fármacos , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Transdução de Sinais/efeitos dos fármacos , Suínos
10.
PLoS One ; 15(5): e0233310, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32428014

RESUMO

BACKGROUND: No study has compared the clinical impact of indexation of left ventricular mass (LVM) on adverse clinical outcomes in pre-dialysis patients with chronic kidney disease (CKD). METHODS: We reviewed 2,101 patients from a large-scale multi-center prospective study that gathered anthropometric and echocardiographic measurements and clinical outcomes. The LVM was indexed as body surface area (LVMI-BSA) and height raised to the power of 2.7 (LVMI-H2.7). The main outcomes were composite renal and cardiovascular events and all-cause mortality. Left ventricular hypertrophy (LVH) was defined as the highest sex-specific quartile of LVMI-BSA or LVMI-H2.7. RESULTS: During a mean period of 3.5 years, 692 patients developed composite outcomes (32.9%). The area under the curve at 5 year of LVM (60.6%) for composite outcome was smaller than that for LVMI-BSA (63.2%, P <0.001) and LVMI-H2.7 (63.4%, P <0.001). The hazard ratio (HR) and 95% confidence interval (CI) per one unit increase in LVM (g), LVMI-BSA (g/m2), and LVMI-H2.7 (g/m2.7) for composite outcomes were 1.004 (1.002-1.005, P <0.001), 1.011 (1.006-1.016, P <0.001), and 1.023 (1.012-1.035, P <0.001), respectively. Patients with LVH determined by LVMI-BSA and LVMI-H2.7 (HR 1.352, 95% CI 1.123-1.626, P = 0.001) and LVH determined by only LVMI-BSA (HR 1.908, 95% CI 1.233-2.953, P = 0.004) showed an independent increase in the risk of composite-outcome development, when compared with patients without LVH, according to LVMI-BSA and LVMI-H2.7. CONCLUSION: Indexation of LVM improved the prediction of adverse outcomes. BSA may be as useful as height2.7 in indexing of LVM for predicting adverse outcomes in pre-dialysis patients with CKD.


Assuntos
Ventrículos do Coração/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Insuficiência Renal Crônica/metabolismo , Adulto , Pressão Sanguínea , Superfície Corporal , Estudos de Coortes , Diálise , Ecocardiografia/métodos , Feminino , Humanos , Hipertrofia Ventricular Esquerda/metabolismo , Masculino , Pessoa de Meia-Idade , Prevalência , Prognóstico , Estudos Prospectivos , Insuficiência Renal Crônica/complicações , República da Coreia
11.
PLoS One ; 15(5): e0232522, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32365131

RESUMO

Chronic Kidney Disease of uncertain etiology (CKDu) is an endemic, disease that mostly affects young agricultural workers in the rural dry zone of Sri Lanka. This study was designed to identify specific biochemical manifestations of CKDu cases. All (119) non-dialysis definite CKDu patients in Girandurukotte and Wilgamuwa were selected. Blood and urine samples were collected and measured biochemical parameters. All analyses were performed in IBM SPSS statistics version 23 (IBM Corp, USA). The median blood pressure was normal though nearly half of the patients (45.4%) who were in the advanced stages (Stage 3b, 4 and 5) of CKDu. Patients without a history of hypertension before the diagnosis of CKDu (100%) and minimal proteinuria (26%) are similar to the previous findings. Patients without a history of diabetes before the CKDu diagnosis had high percentages of diabetes (15.7%) and pre-diabetes (59.8%) and hence indicated the possibility of uremia induced impaired glucose intolerance in the rural areas of the country. There were 62.2% patients who had low vitamin D and only a minority had evidence of bone mineral diseases. Out of liver disease markers serum glutamic pyruvic transaminases (SGPT), serum glutamic oxaloacetic transaminases (SGOT), gamma-glutamyl transferase (GGT), and Lactic acid degydrogenase (LDH) had an inverse correlation with the advancement of the disease indicating subclinical liver disease. Osmolality in serum and urine showed a discrepancy despite > 50% of CKDu patients had increased their serum osmolality. The current study supports most of the previously described manifestations of CKDu. Moreover, some specific patterns have been identified which need to be validated in a larger group.


Assuntos
Insuficiência Renal Crônica/metabolismo , Adulto , Idoso , Biomarcadores/sangue , Biomarcadores/urina , Creatinina/sangue , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Concentração Osmolar , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/etiologia , Sódio/sangue , Sri Lanka/epidemiologia , Adulto Jovem
13.
Am J Clin Nutr ; 112(1): 129-137, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32453418

RESUMO

BACKGROUND: Advanced glycation end products (AGEs) accumulate in tissues with age and in conditions such as diabetes mellitus and chronic kidney disease (CKD), and they may be involved in age-related diseases. Skin AGEs measured as skin autofluorescence (SAF) are a noninvasive reflection of long-term AGE accumulation in tissues. Whether AGEs present in the diet (dAGEs) contribute to tissue AGEs is unclear. OBJECTIVES: Our aim was to investigate the association between dietary and skin AGEs in the Rotterdam Study, a population-based cohort of mainly European ancestry. METHODS: In 2515 participants, intake of 3 dAGEs [carboxymethyl-lysine (CML), N-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MGH1), and carboxyethyl-lysine (CEL)] was estimated using FFQs and the content of AGEs measured in commonly consumed foods. SAF was measured 5 y (median value) later using an AGE Reader. The association of dAGEs with SAF was analyzed in linear regression models and stratified for diabetes and chronic kidney disease (CKD, defined as estimated glomerular filtration rate ≤60 mL/min) status. RESULTS: Mean ± SD intake was 3.40 ±0.89 mg/d for CML, 28.98 ±7.87 mg/d for MGH1, and 3.11 ±0.89 mg/d for CEL. None of them was associated with SAF in the total study population. However, in stratified analyses, CML was positively associated with SAF after excluding both individuals with diabetes and individuals with CKD: 1 SD higher daily CML intake was associated with a 0.03 (95% CI: 0.009, 0.05) arbitrary units higher SAF. MGH1 and CEL intake were not significantly associated with SAF. Nevertheless, the associations were stronger when the time difference between dAGEs and SAF measurements was shorter. CONCLUSIONS: Higher dietary CML intake was associated with higher SAF only among participants with neither diabetes nor CKD, which may be explained by high AGE formation in diabetes and decreased excretion in CKD or by dietary modifications in these disease groups. The dAGE-SAF associations were also modified by the time difference between measurements. Our results suggest that dAGEs can influence tissue AGE accumulation and possibly thereby age-related diseases. This trial was registered at the Netherlands National Trial Register as NTR6831 (http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=6831) and at the WHO International Clinical Trials Registry Platform as NTR6831 (http://www.who.int/ictrp/network/primary/en/).


Assuntos
Produtos Finais de Glicação Avançada/metabolismo , Insuficiência Renal Crônica/metabolismo , Pele/metabolismo , Idoso , Estudos de Coortes , Feminino , Fluorescência , Produtos Finais de Glicação Avançada/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/etiologia , Pele/química
14.
Environ Toxicol ; 35(9): 1007-1014, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32441858

RESUMO

Arecoline, a component of betel nuts, is a known carcinogen that causes oral cancers among those who chew betel nuts. Betel nut chewing is also associated with an increased risk of chronic kidney disease (CKD), but the role of arecoline in this association is unclear. This in vitro study investigates the effects of arecoline on cultured human kidney (HK2) cells. We observed that arecoline had no effect on cell viability but increased cell migration in a dose-dependent manner. Western blot analysis showed that arecoline treatment caused a dose-dependent decrease in E-cadherin expression and dose-dependent increases in N-cadherin, vimentin, α-SMA, and collagen expression; reverse transcriptase-polymerase chain reaction analysis revealed dose-dependent increases in α-SMA and collagen mRNA. Arecoline treatment upregulated the expression of phosphorylated extracellular signal-regulated kinase through epithelial mesenchymal transition and renal fibrosis in HK2 cells. These findings demonstrate that arecoline plays a role in inducing the epithelial mesenchymal transition and fibrogenesis in renal tubule cells and suggest that arecoline promotes the progression of CKD.


Assuntos
Areca/toxicidade , Arecolina/toxicidade , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Túbulos Renais/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Actinas/genética , Actinas/metabolismo , Antígenos CD/genética , Antígenos CD/metabolismo , Areca/química , Caderinas/genética , Caderinas/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Transição Epitelial-Mesenquimal/genética , Fibrose , Humanos , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Sistema de Sinalização das MAP Quinases/genética , Fosforilação , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Regulação para Cima
15.
Mutat Res ; 852: 503167, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32265040

RESUMO

Chronic kidney disease (CKD) is a multifactorial disorder with an important genetic component, and several studies have demonstrated potential associations with allelic variants. In addition, CKD patients are also characterized by high levels of genomic damage. Nevertheless, no studies have established relationships between DNA damage, or genomic instability present in CKD patients, and gene polymorphisms. To fill in this gap, the potential role of polymorphisms in genes involved in base excision repair (OGG1, rs1052133; MUTYH, rs3219489; XRCC1, rs25487), nucleotide excision repair (ERCC2/XPD, rs1799793, rs171140, rs13181; ERCC4, rs3136166); phase II metabolism (GSTP1, rs749174; GSTO1, rs2164624; GSTO2, rs156697), and antioxidant enzymes (SOD1, rs17880135, rs1041740, rs202446; SOD2, rs4880; CAT, rs1001179; GPX1, rs17080528; GPX3, rs870406: GPX4, rs713041) were inquired. In addition, some genes involved in CKD (AGT, rs5050; GLO1, rs386572987; SHROOM3, rs17319721) were also evaluated. The genomic damage, the genomic instability, and oxidative damage were evaluated by using the micronucleus and the comet assay in 589 donors (415 CKD patients and 174 controls). Our results showed significant associations between genomic damage and genes directly involved in DNA repair pathways (XRCC1, and ERCC2), and with genes encoding for antioxidant enzymes (SOD1 and GPX1). GSTO2, as a gene involved in phase II metabolism, and MUTYH showed also an association with genomic instability. Interestingly, the three genes associated with CKD (AGT, GLO1, and SHROOM3) showed associations with both the high levels of oxidatively damaged DNA and genomic instability. These results support our view that genomic instability can be considered a biomarker of the CKD status.


Assuntos
Angiotensinogênio/genética , Reparo do DNA , Instabilidade Genômica , Lactoilglutationa Liase/genética , Proteínas dos Microfilamentos/genética , Insuficiência Renal Crônica/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Angiotensinogênio/metabolismo , Estudos de Casos e Controles , Ensaio Cometa , Dano ao DNA , DNA Glicosilases/genética , DNA Glicosilases/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Predisposição Genética para Doença , Genoma Humano , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Humanos , Lactoilglutationa Liase/metabolismo , Masculino , Proteínas dos Microfilamentos/metabolismo , Testes para Micronúcleos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/metabolismo , Proteína Grupo D do Xeroderma Pigmentoso/genética , Proteína Grupo D do Xeroderma Pigmentoso/metabolismo
16.
Am J Physiol Renal Physiol ; 318(5): F1229-F1236, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32249610

RESUMO

Metformin, an AMP-activated protein kinase (AMPK) activator, has been shown in previous studies to reduce kidney fibrosis in different models of experimental chronic kidney disease (CKD). However, in all of these studies, the administration of metformin was initiated before the establishment of renal disease, which is a condition that does not typically occur in clinical settings. The aim of the present study was to investigate whether the administration of metformin could arrest the progression of established renal disease in a well-recognized model of CKD, the subtotal kidney nephrectomy (Nx) model. Adult male Munich-Wistar rats underwent either Nx or sham operations. After the surgery (30 days), Nx rats that had systolic blood pressures of >170 mmHg and albuminuria levels of >40 mg/24 h were randomized to a no-treatment condition or to a treatment condition with metformin (300 mg·kg-1·day-1) for a period of either 60 or 120 days. After 60 days of treatment, we did not observe any differences in kidney disease parameters between Nx metformin-treated and untreated rats. However, after 120 days, Nx rats that had been treated with metformin displayed significant reductions in albuminuria levels and in markers of renal fibrosis. These effects were independent of any other effects on blood pressure or glycemia. In addition, treatment with metformin was also able to activate kidney AMPK and therefore improve mitochondrial biogenesis. It was concluded that metformin can arrest the progression of established kidney disease in the Nx model, likely via the activation of AMPK.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Ativadores de Enzimas/farmacologia , Rim/efeitos dos fármacos , Metformina/farmacologia , Nefrectomia , Insuficiência Renal Crônica/prevenção & controle , Albuminúria/etiologia , Albuminúria/metabolismo , Albuminúria/prevenção & controle , Animais , Modelos Animais de Doenças , Progressão da Doença , Ativação Enzimática , Fibrose , Hipertensão/etiologia , Hipertensão/metabolismo , Hipertensão/prevenção & controle , Rim/enzimologia , Rim/patologia , Rim/cirurgia , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Biogênese de Organelas , Ratos Wistar , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Fatores de Tempo
17.
PLoS One ; 15(4): e0230980, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32240223

RESUMO

OBJECTIVES: Anemia is highly prevalent in chronic kidney disease patients; however, its identification and management have been reported to be suboptimal. In this study we aimed to describe the prevalence, severity, risk factors, and treatment of anemia in different nephrology centers, among chronic kidney disease patients who were not given renal replacement therapy. MATERIALS AND METHODS: We performed a multicenter cross-sectional study in three different nephrology clinics. Adult (>18 years of age) chronic kidney disease patients with an estimated glomerular filtration rate (eGFR) below 60 ml/min, and who were not started dialysis were recruited. Demographic, clinical and laboratory data regarding anemia and its management were collected using a standard data form. Anemia was defined as a hemoglobin level below 12g/dL and severe anemia as a hemoglobin level below 10g/dl. RESULTS: A total of 1066 patients were enrolled in the study. Anemia and severe anemia were present in 55.9% and 14.9% of the patients, respectively. The mean hemoglobin level for the whole cohort was 11.8±1.8 g/dL. Univariate analyses revealed that the mean hemoglobin level was significantly different among the centers. Moreover, the frequency of the presence of anemia stratified by severity was also significantly different among the centers. According to binary logistic regression analysis, gender, levels of eGFR and iron, ferritin ≥ 100 ng/mL, and the nephrology center were independent determinants of severe anemia. CONCLUSIONS: We found a high prevalence of anemia among chronic kidney disease patients who were not on renal replacement therapy. Each center should determine the treatment strategy according to the patient's characteristics. According to our results, the center-specific management of anemia seems to be important.


Assuntos
Anemia/epidemiologia , Anemia/etiologia , Diálise Renal/efeitos adversos , Insuficiência Renal Crônica/complicações , Idoso , Estudos de Coortes , Estudos Transversais , Feminino , Ferritinas/metabolismo , Taxa de Filtração Glomerular/fisiologia , Hemoglobinas/metabolismo , Humanos , Ferro/metabolismo , Falência Renal Crônica/complicações , Falência Renal Crônica/metabolismo , Masculino , Pessoa de Meia-Idade , Nefrologia/métodos , Prevalência , Insuficiência Renal Crônica/metabolismo , Fatores de Risco
18.
Am J Kidney Dis ; 76(2): 174-183, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32305206

RESUMO

RATIONALE & OBJECTIVE: Persons with chronic kidney disease (CKD) are often unaware of their disease status. Efforts to improve CKD awareness may be most effective if focused on persons at highest risk for progression to kidney failure. STUDY DESIGN: Serial cross-sectional surveys. SETTING & PARTICIPANTS: Nonpregnant adults (aged≥20 years) with CKD glomerular filtration rate categories 3-4 (G3-G4) who participated in the National Health and Nutrition Examination Survey from 1999 to 2016 (n = 3,713). PREDICTOR: 5-year kidney failure risk, estimated using the Kidney Failure Risk Equation. Predicted risk was categorized as minimal (<2%), low (2%-<5%), intermediate (5%-<15%), or high (≥15%). OUTCOME: CKD awareness, defined by answering "yes" to the question "Have you ever been told by a doctor or other health professional that you had weak or failing kidneys?" ANALYTICAL APPROACH: Prevalence of CKD awareness was estimated within each risk group using complex sample survey methods. Associations between Kidney Failure Risk Equation risk and CKD awareness were assessed using multivariable logistic regression. CKD awareness was compared with awareness of hypertension and diabetes during the same period. RESULTS: In 2011 to 2016, unadjusted CKD awareness was 9.6%, 22.6%, 44.7%, and 49.0% in the minimal-, low-, intermediate-, and high-risk groups, respectively. In adjusted analyses, these proportions did not change over time. Awareness of CKD, including among the highest risk group, remains consistently below that of hypertension and diabetes and awareness of these conditions increased over time. LIMITATIONS: Imperfect sensitivity of the "weak or failing kidneys" question for ascertaining CKD awareness. CONCLUSIONS: Among adults with CKD G3-G4 who have 5-year estimated risks for kidney failure of 5%-<15% and≥15%, approximately half were unaware of their kidney disease, a gap that has persisted nearly 2 decades.


Assuntos
Conscientização , Taxa de Filtração Glomerular , Insuficiência Renal Crônica/metabolismo , Idoso , Revelação , Progressão da Doença , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/metabolismo , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Insuficiência Renal Crônica/epidemiologia , Medição de Risco , Índice de Gravidade de Doença , Estados Unidos/epidemiologia
19.
Am J Kidney Dis ; 76(2): 184-193, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32317121

RESUMO

RATIONALE & OBJECTIVE: Safe analgesic choices are limited in chronic kidney disease (CKD). We conducted a comparative analysis of harm from opioids versus nonsteroidal anti-inflammatory drugs (NSAIDs) in CKD. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 3,939 patients with CKD in the Chronic Renal Insufficiency Cohort (CRIC) Study. EXPOSURES: 30-day analgesic use reported at annual visits. OUTCOMES: A composite outcome of 50% glomerular filtration rate reduction and kidney failure requiring kidney replacement therapy (KRT), as well as the outcomes of kidney failure requiring KRT, hospitalization, and pre-kidney failure death. ANALYTICAL APPROACH: Marginal structural models with time-updated exposures. RESULTS: Participants were followed up for a median of 6.84 years, with 391 (9.9%) and 612 (15.5%) reporting baseline opioid and NSAID use, respectively. Time-updated opioid use was associated with the kidney disease composite outcome, kidney failure with KRT, death (HRs of 1.4 [95% CI, 1.2-1.7], 1.4 [95% CI, 1.1-1.7], and 1.5 [95% CI, 1.2-2.0], respectively), and hospitalization (rate ratio [RR], 1.7; 95% CI, 1.6-1.9) versus opioid nonusers. Similar results were found in an analysis restricted to a subcohort of participants reporting ever using other (nonopioid and non-NSAID) analgesics or tramadol. Time-updated NSAID use was associated with increased risk for the kidney disease composite (HR, 1.2; 95% CI, 1.0-1.5) and hospitalization (RR, 1.1; 95% CI, 1.0-1.3); however, these associations were not significant in the subcohort. The association of NSAID use with the kidney disease composite outcome varied by race, with a significant risk in blacks (HR, 1.3; 95% CI, 1.0-1.7). NSAID use was associated with lower risk for kidney failure with KRT in women and individuals with glomerular filtration rate<45mL/min/1.73m2 (HRs of 0.63 [95% CI, 0.45-0.88] and 0.77 [95% CI, 0.59-0.99], respectively). LIMITATIONS: Limited periods of recall of analgesic use and potential confounding by indication. CONCLUSIONS: Opioid use had a stronger association with adverse events than NSAIDs, with the latter's association with kidney disease outcomes limited to specific subgroups, notably those of black race.


Assuntos
Analgésicos Opioides/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Hospitalização/estatística & dados numéricos , Falência Renal Crônica/epidemiologia , Mortalidade , Dor/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , Adulto , Afro-Americanos , Idoso , Estudos de Coortes , Progressão da Doença , Grupo com Ancestrais do Continente Europeu , Feminino , Taxa de Filtração Glomerular , Humanos , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Dor/complicações , Modelos de Riscos Proporcionais , Estudos Prospectivos , Pirimidinas , Pirróis , Qualidade de Vida , Insuficiência Renal Crônica/complicações , Terapia de Substituição Renal/estatística & dados numéricos , Adulto Jovem
20.
Clin Chim Acta ; 505: 160-166, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32156608

RESUMO

Fibroblast growth factor can be measured in clinical practice using ELISA, with acceptable validity. Different from many metabolites and minerals, its value can differ by a thousand-fold between individuals, largely because of differences in kidney function and dietary habits. This wide range complicates the proper interpretation of the concentration of FGF23, both in terms of the appropriateness of a given value for a given estimated GFR, and in terms of estimating the magnitude of risk for clinical events, with which FGF23 is clearly associated. In this narrative review, the impact of kidney function, exposure to phosphate from diet, and novel emerging factors that influence FGF23 concentrations are discussed. These and yet to define determinants of FGF23 question the causality of the association of FGF23 with hard (cardiovascular) endpoints, as observed in several epidemiological studies.


Assuntos
Fatores de Crescimento de Fibroblastos/análise , Insuficiência Renal Crônica/metabolismo , Animais , Biomarcadores , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Testes de Função Renal , Insuficiência Renal Crônica/fisiopatologia
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