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Background: Clonal hematopoiesis of indeterminate potential (CHIP) is a common inflammatory condition of aging that causes myriad end-organ damage. We have recently shown associations for CHIP with acute kidney injury and with kidney function decline in the general population, with stronger associations for CHIP driven by mutations in genes other than DNMT3A (non- DNMT3A CHIP). Longitudinal kidney function endpoints in individuals with pre-existing chronic kidney disease (CKD) and CHIP have been examined in two previous studies, which reported conflicting findings and were limited by small sample sizes. Methods: In this study, we examined the prospective associations between CHIP and CKD progression events in four cohorts of CKD patients (total N = 5,772). The primary outcome was a composite of 50% kidney function decline or kidney failure. The slope of eGFR decline was examined as a secondary outcome. Mendelian randomization techniques were then used to investigate potential causal effects of CHIP on eGFR decline. Finally, kidney function was assessed in adenine-fed CKD model mice having received a bone marrow transplant recapitulating Tet2 -CHIP compared to controls transplanted wild-type bone marrow. Results: Across all cohorts, the average age was 66.4 years, the average baseline eGFR was 42.6 ml/min/1.73m 2 , and 24% had CHIP. Upon meta-analysis, non- DNMT3A CHIP was associated with a 59% higher relative risk of incident CKD progression (HR 1.59, 95% CI: 1.02-2.47). This association was more pronounced among individuals with diabetes (HR 1.29, 95% CI: 1.03-1.62) and with baseline eGFR ≥ 30 ml/min/1.73m (HR 1.80, 95% CI: 1.11-2.90). Additionally, the annualized slope of eGFR decline was steeper among non- DNMT3A CHIP carriers, relative to non-carriers (ß -0.61 ± 0.31 ml/min/1.73m 2 , p = 0.04). Mendelian randomization analyses suggested a causal role for CHIP in eGFR decline among individuals with diabetes. In a dietary adenine mouse model of CKD, Tet2 -CHIP was associated with lower GFR as well as greater kidney inflammation, tubular injury, and tubulointerstitial fibrosis. Conclusion: Non- DNMT3A CHIP is a potentially targetable novel risk factor for CKD progression.
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Peritoneal mesothelial cell senescence promotes the development of peritoneal dialysis (PD)-related peritoneal fibrosis. We previously revealed that Brahma-related gene 1 (BRG1) is increased in peritoneal fibrosis yet its role in modulating peritoneal mesothelial cell senescence is still unknown. This study evaluated the mechanism of BRG1 in peritoneal mesothelial cell senescence and peritoneal fibrosis using BRG1 knockdown mice, primary peritoneal mesothelial cells and human peritoneal samples from PD patients. The augmentation of BRG1 expression accelerated peritoneal mesothelial cell senescence, which attributed to mitochondrial dysfunction and mitophagy inhibition. Mitophagy activator salidroside rescued fibrotic responses and cellular senescence induced by BRG1. Mechanistically, BRG1 was recruited to oxidation resistance 1 (OXR1) promoter, where it suppressed transcription of OXR1 through interacting with forkhead box protein p2. Inhibition of OXR1 abrogated the improvement of BRG1 deficiency in mitophagy, fibrotic responses and cellular senescence. In a mouse PD model, BRG1 knockdown restored mitophagy, alleviated senescence and ameliorated peritoneal fibrosis. More importantly, the elevation level of BRG1 in human PD was associated with PD duration and D/P creatinine values. In conclusion, BRG1 accelerates mesothelial cell senescence and peritoneal fibrosis by inhibiting mitophagy through repression of OXR1. This indicates that modulating BRG1-OXR1-mitophagy signaling may represent an effective treatment for PD-related peritoneal fibrosis.
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Diálise Peritoneal , Fibrose Peritoneal , Animais , Humanos , Camundongos , Senescência Celular/genética , Proteínas Mitocondriais/metabolismo , Mitofagia/genética , Diálise Peritoneal/efeitos adversos , Fibrose Peritoneal/genética , Fibrose Peritoneal/metabolismo , Fibrose Peritoneal/patologia , Peritônio/metabolismo , Peritônio/patologiaRESUMO
OBJECTIVE: Malnutrition and inflammation are associated with mortality in peritoneal dialysis (PD) patients. Serum albumin and non-high-density lipoprotein cholesterol (non-HDL-C) are independently associated with mortality in PD patients. Combining albumin and non-HDL-C with mortality may be more plausible in clinical practice. METHODS: This retrospective cohort study included 1954 Chinese PD patients from 1 January 2009 to 31 December 2016. Kaplan-Meier curve was used to determine the relationship between albumin to non-HDL-C ratio and all-cause mortality. Cox regression analysis was applied to assess the independent predictive value while adjusting for confounding factors. Competitive risk analysis was used to examine the effects of other outcomes on all-cause mortality prognosis. RESULTS: In the 33-month follow-up period, there were 538 all-cause deaths. Kaplan-Meier analysis presented significant differences in all-cause mortality. Multivariate Cox regression showed that the risk of all-cause mortality was lower in the moderate group (9.36-12.79) (HR, 0.731; 95% CI, 0.593-0.902, p = 0.004) and the highest group (>12.79) (HR, 0.705; 95% CI, 0.565-0.879, p = 0.002) compared to the lowest group (≤9.36). Competitive risk analysis revealed significant differences for all-cause mortality (p < 0.001), while there was no statistical significance for other competing events. CONCLUSIONS: Low albumin to non-HDL-C ratio was associated with a high risk of all-cause mortality in PD patients. It may serve as a potential prognostic biomarker in PD patients.
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Diálise Peritoneal , Albumina Sérica , Humanos , Estudos Retrospectivos , ColesterolRESUMO
INTRODUCTION: To assess the relationship between the rate of residual renal function (RRF) decline in the first year and all-cause and cardiovascular mortality in peritoneal dialysis (PD) patients. METHODS: Incident PD patients were divided into two groups by the corresponding RRF decline value, when hazard ratio (HR) = 1 was found by the restricted cubic spline. The associations of rate of decline of RRF in the first year with mortality were evaluated. RESULTS: Of 497 PD patients, 122 patients died. After adjusting for confounding factors, patients in fast-decline group had a significant increase risk of all-cause and cardiovascular mortality (HR: 1.97 and 2.09, respectively). Each 0.1-mL/min/1.73 m2 /month decrease in RRF in the first year of PD was associated with a 19% and 20% higher risk of all-cause and cardiovascular mortality, respectively. CONCLUSIONS: Faster decline of RRF in the first year was independently associated with all-cause and cardiovascular mortality in PD patients.
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Doenças Cardiovasculares , Falência Renal Crônica , Diálise Peritoneal , Humanos , Taxa de Filtração Glomerular , Rim , Doenças Cardiovasculares/epidemiologiaRESUMO
Podocyte damage is the major cause of glomerular injury and proteinuria in multiple chronic kidney diseases. Metadherin (MTDH) is involved in podocyte apoptosis and promotes renal tubular injury in mouse models of diabetic nephropathy and renal fibrosis; however, its role in podocyte injury and proteinuria needs further exploration. Here, we show that MTDH was induced in the glomerular podocytes of patients with proteinuric chronic kidney disease and correlated with proteinuria. Podocyte-specific knockout of MTDH in mice reversed proteinuria, attenuated podocyte injury, and prevented glomerulosclerosis after advanced oxidation protein products challenge or adriamycin injury. Furthermore, specific knockout of MTDH in podocytes repressed ß-catenin phosphorylation at the Ser675 site and inhibited its downstream target gene transcription. Mechanistically, on the one hand, MTDH increased cAMP and then activated protein kinase A (PKA) to induce ß-catenin phosphorylation at the Ser675 site, facilitating the nuclear translocation of MTDH and ß-catenin; on the other hand, MTDH induced the deaggregation of pyruvate kinase M2 (PKM2) tetramers and promoted PKM2 monomers to enter the nucleus. This cascade of events leads to the formation of the MTDH/PKM2/ß-catenin/CBP/TCF4 transcription complex, thus triggering TCF4-dependent gene transcription. Inhibition of PKA activity by H-89 or blockade of PKM2 deaggregation by TEPP-46 abolished this cascade of events and disrupted transcription complex formation. These results suggest that MTDH induces podocyte injury and proteinuria by assembling the ß-catenin-mediated transcription complex by regulating PKA and PKM2 function.
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Nefropatias Diabéticas , Podócitos , Insuficiência Renal Crônica , Humanos , Camundongos , Animais , Podócitos/metabolismo , beta Catenina/genética , beta Catenina/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico , Fatores de Transcrição/genética , Proteinúria/genética , Proteinúria/metabolismo , Nefropatias Diabéticas/metabolismo , Insuficiência Renal Crônica/metabolismo , Proteínas de Membrana , Proteínas de Ligação a RNA/metabolismoRESUMO
OBJECTIVE: Inflammation and nutrition have been recognized as predicting mortality in patients receiving peritoneal dialysis (PD). Serum neutrophil and albumin are crucial factors in inflammation and nutrition status. Up until now, the synergistic effect of neutrophil and albumin on mortality prediction in PD patients is still being determined. Our study sought to assess the effect of the interaction between neutrophils and albumin on the risk of all-cause mortality and cardiovascular disease (CVD) mortality patients receiving PD. METHODS: A total of 1229 PD patients were recruited and divided into three categories in this cohort study. Their relationships with all-cause mortality and CVD mortality were analyzed in multivariable COX regression models adjusted for confounding factors. RESULTS: During the median follow-up of 34.2 months, 222 (18.1%) patients died, and 115 (51.8%) suffered from cardiovascular events. Patients with high neutrophil percentage-to-albumin ratio (NPAR) showed increased all-cause mortality and CVD mortality, with adjusted hazard ratios of 1.490 (95% confidence interval, 1.070-2.074, P = .018) and 1.633 (95% confidence interval, 1.041-2.561, P = .033), respectively, compared with those with low NPAR. Competitive risk models and sensitivity analyses further confirmed this association. In the receiver operating characteristic curve analysis, however, there was little evidence that NPAR is a better indicator than albumin and neutrophil count. CONCLUSIONS: Having a high NPAR is linked to a higher risk of mortality, especially when both high neutrophil and low albumin are present.
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BACKGROUND AND AIMS: Atherosclerosis, the main cause of cardiovascular disease (CVD), is prevalent in patients undergoing peritoneal dialysis (PD). Atherogenic index (AI) is a strong predictor of atherosclerosis. However, its prognostic value in CVD outcomes and all-cause mortality among patients undergoing PD remains uncertain. Therefore, we aimed to evaluate the association between AI and all-cause and CVD mortality in PD patients. METHODS: Calculated based on lipid profiles obtained through standard laboratory procedures, AI was evaluated in 2682 patients who underwent PD therapy between January 2006 and December 2017 and were followed up until December 2018. The study population was divided into four groups according to the quartile distribution of AI (Q1: <2.20, Q2: 2.20 to <2.97, Q3: 2.97 to <4.04, and Q4: ≥4.04). Multivariable Cox models were employed to explore the associations between AI and CVD and all-cause mortality was evaluated. RESULTS: During a median follow-up of 35.5 months (interquartile range, 20.9-57.2 months), 800 patients died, including 416 deaths from CVD. Restricted cubic splines showed non-linear relationship between AI and adverse clinical outcomes. The risks of all-cause and CVD mortality gradually increased across quartiles (log-rank, p < 0.001). After adjusting for potential confounders, the highest quartile (Q4) showed significantly elevated hazard ratio (HR) for both all-cause mortality (HR 1.54 [95% confidence interval (CI), 1.21-1.96]) and CVD mortality risk (HR 1.78 [95% CI, 1.26-2.52]), compared to the lowest quartile (Q1). CONCLUSIONS: AI was independently associated with all-cause and CVD mortality in patients undergoing PD, suggesting that AI might be a useful prognostic marker.
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Aterosclerose , Doenças Cardiovasculares , Diálise Peritoneal , Humanos , Diálise Peritoneal/efeitos adversos , Diálise Renal , Causas de Morte , Aterosclerose/diagnóstico , Aterosclerose/etiologia , Estudos RetrospectivosRESUMO
BACKGROUND: Serum uric acid to serum creatinine ratio (SUA/Scr) has emerged as a new biomarker, which is significantly associated with several metabolic diseases. However, no study has investigated the association between SUA/Scr and mortality among patients on continuous ambulatory peritoneal dialysis (CAPD). METHODS: In this multicenter retrospective cohort study, we enrolled CAPD patients in eight tertiary hospitals in China from 1 January 2005 to 31 May 2021. Cox proportional hazard models were used to determine the relationship between SUA/Scr and mortality. RESULTS: A total of 2480 patients were included; the mean age was 48.9 ± 13.9 years and 56.2% were males. During 12648.0 person-years of follow-up, 527 (21.3%) patients died, of which 267 (50.7%) deaths were caused by cardiovascular disease. After multivariable adjustment for covariates, per unit increase in SUA/Scr was associated with a 62.9% (HR, 1.629 (95% confidence interval (CI) 1.420-1.867)) and 73.0% (HR, 1.730 (95% CI 1.467-2.041)) higher risk of all-cause and cardiovascular mortality. Results were similar when categorized individuals by SUA/Scr quartiles. Compared with the lowest quartile of SUA/Scr, the highest and the second highest quartile of SUA/Scr had a 2.361-fold (95% CI 1.810-3.080) and 1.325-fold (95% CI 1.003-1.749) higher risk of all-cause mortality, as well as a 3.701-fold (95% CI 2.496-5.489) and 2.074-fold (95% CI 1.387-3.100) higher risk of cardiovascular mortality. Multivariable-adjusted spline regression models showed nonlinear association of SUA/Scr with mortality in CAPD patients. CONCLUSIONS: Higher levels of SUA/Scr were associated with higher risk of all-cause and cardiovascular mortality in CAPD patients.
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Doenças Cardiovasculares , Diálise Peritoneal Ambulatorial Contínua , Masculino , Humanos , Adulto , Pessoa de Meia-Idade , Feminino , Ácido Úrico , Creatinina , Estudos Retrospectivos , Diálise Peritoneal Ambulatorial Contínua/efeitos adversos , Fatores de RiscoRESUMO
BACKGROUND: Progressive peritoneal fibrosis is a worldwide public health concern impacting patients undergoing peritoneal dialysis (PD), yet there is no effective treatment. Our previous study revealed that a novel compound, micheliolide (MCL) inhibited peritoneal fibrosis in mice. However, its mechanism remains unclear. Brahma-related gene 1 (BRG1) is a key contributor to organ fibrosis, but its potential function in PD-related peritoneal fibrosis and the relationship between MCL and BRG1 remain unknown. METHODS: The effects of MCL on BRG1-induced fibrotic responses and TGF-ß1-Smads pathway were examined in a mouse PD model and in vitro peritoneal mesothelial cells. To investigate the targeting mechanism of MCL on BRG1, coimmunoprecipitation, MCL-biotin pulldown, molecular docking and cellular thermal shift assay were performed. RESULTS: BRG1 was markedly elevated in a mouse PD model and in peritoneal mesothelial cells cultured in TGF-ß1 or PD fluid condition. BRG1 overexpression in vitro augmented fibrotic responses and promoted TGF-ß1-increased-phosphorylation of Smad2 and Smad3. Meanwhile, knockdown of BRG1 diminished TGF-ß1-induced fibrotic responses and blocked TGF-ß1-Smad2/3 pathway. MCL ameliorated BRG1 overexpression-induced peritoneal fibrosis and impeded TGF-ß1-Smad2/3 signaling pathway both in a mouse PD model and in vitro. Mechanically, MCL impeded BRG1 from recognizing and attaching to histone H3 lysine 14 acetylation by binding to the asparagine (N1540) of BRG1, in thus restraining fibrotic responses and TGF-ß1-Smad2/3 signaling pathway. After the mutation of N1540 to alanine (N1540A), MCL was unable to bind to BRG1 and thus, unsuccessful in suppressing BRG1-induced fibrotic responses and TGF-ß1-Smad2/3 signaling pathway. CONCLUSION: Our research indicates that BRG1 may be a crucial mediator in peritoneal fibrosis and MCL targeting N1540 residue of BRG1 may be a novel therapeutic strategy to combat PD-related peritoneal fibrosis.
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Diálise Peritoneal , Fibrose Peritoneal , Animais , Camundongos , Modelos Animais de Doenças , Simulação de Acoplamento Molecular , Diálise Peritoneal/efeitos adversos , Fibrose Peritoneal/tratamento farmacológico , Fator de Crescimento Transformador beta1RESUMO
BACKGROUND: The glucose-to-lymphocyte ratio (GLR), a glucose metabolism and systemic inflammatory response parameter, is associated with an adverse prognosis for various diseases. However, the association between serum GLR and prognosis in patients undergoing peritoneal dialysis (PD) is poorly understood. METHODS: In this multi-center cohort study, 3236 PD patients were consecutively enrolled between 1 January 2009 and 31 December 2018. Patients were divided into four groups according to the quartiles of baseline GLR levels (Q1: GLR ≤ 2.91, Q2:2.91 < GLR ≤ 3.91, Q3:3.91 < GLR < 5.59 and Q4: GLR ≥ 5.59). The primary endpoint was all-cause and cardiovascular disease (CVD) related mortality. The correlation between GLR and mortality was examined using Kaplan-Meier and multivariable Cox proportional analyses. RESULTS: During the follow-up period of 45.93 ± 29.01 months, 25.53% (826/3236) patients died, of whom 31% (254/826) were in Q4 (GLR ≥ 5.59). Multivariable analysis revealed that GLR was significantly associated with all-cause mortality (adjusted HR 1.02; CI 1.00 â¼ 1.04, p = .019) and CVD mortality (adjusted HR 1.02; CI 1.00 â¼ 1.04, p = .04). Compared with the Q1 (GLR ≤ 2.91), placement in Q4 was associated with an increased risk of all-cause mortality (adjusted HR: 1.26, 95% CI: 1.02 â¼ 1.56, p = .03) and CVD mortality (adjusted HR 1.76; CI 1.31 â¼ 2.38, p < .001). A nonlinear relationship was found between GLR and all-cause or CVD mortality in patients undergoing PD (p = .032). CONCLUSION: A higher serum GLR level is an independent prognostic factor for all-cause and CVD mortality in patients undergoing PD, suggesting that more attention should be paid to GLR.
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Doenças Cardiovasculares , Diálise Peritoneal , Humanos , Estudos de Coortes , Prognóstico , Relevância Clínica , Estudos Retrospectivos , Diálise Peritoneal/efeitos adversos , Glucose , Modelos de Riscos ProporcionaisRESUMO
Peritoneal fibrosis (PF) is the main cause of peritoneal ultrafiltration failure in patients undergoing long-term peritoneal dialysis (PD). Epithelial-mesenchymal transition (EMT) is the key pathogenesis of PF. However, currently, no specific treatments are available to suppress PF. N-methylpiperazine-diepoxyovatodiolide (NMPDOva) is a newly synthesized compound that involves a chemical modification of ovatodiolide. In this study, we aimed to explore the antifibrotic effects of NMPDOva in PD-related PF and underlying mechanisms. A mouse model of PD-related PF was established via daily intraperitoneal injection of 4.25% glucose PD fluid. In vitro studies were performed using the transforming growth factor-beta1 (TGF-ß1)-stimulated HMrSV5 cell line. Pathological changes were observed, and fibrotic markers were significantly elevated in the peritoneal membrane in mice model of PD-related PF. However, NMPDOva treatment significantly alleviated PD-related PF by decreasing the extracellular matrix accumulation. NMPDOva treatment decreased the expression of fibronectin, collagen â , and alpha-smooth muscle actin (α-SMA) in mice with PD-related PF. Moreover, NMPDOva could alleviate TGF-ß1-induced EMT in HMrSV5 cells, inhibited phosphorylation and nuclear translocation of Smad2/3, and increased the expression of Smad7. Meanwhile, NMPDOva inhibited phosphorylation of JAK2 and STAT3. Collectively, these results indicated that NMPDOva prevents PD-related PF by inhibiting the TGF-ß1/Smad and JAK/STAT signaling pathway. Therefore, because of these antifibrotic effects, NMPDOva may be a promising therapeutic agent for PD-related PF.
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Fibrose Peritoneal , Camundongos , Animais , Fibrose Peritoneal/tratamento farmacológico , Fibrose Peritoneal/etiologia , Fibrose Peritoneal/patologia , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Transdução de Sinais , Peritônio/metabolismo , Peritônio/patologia , Transição Epitelial-Mesenquimal , FibroseRESUMO
BACKGROUND: Total cholesterol is inversely associated with mortality in dialysis patients, which seems implausible in real-world clinical practice. May there be an optimal range of total cholesterol associated with a lower mortality risk? We aimed to evaluate the optimal range for peritoneal dialysis (PD) patients. METHODS: We conducted a retrospective real-world cohort study of 3565 incident PD patients from five PD centers between January 1, 2005, and May 31, 2020. Baseline variables were collected within one week before the start of PD. The associations between total cholesterol and mortality were examined using cause-specific hazard models. RESULTS: 820 (23.0%) patients died, including 415 cardiovascular deaths, during the follow-up period. Restricted spline plots showed a U-curved association of total cholesterol with mortality. Compared with the reference range (4.10-4.50 mmol/L), high levels of total cholesterol (> 4.50 mmol/L) were associated with increased risks of all-cause (hazard ratio [HR] 1.35, 95% confidence index [CI] 1.08-1.67) and cardiovascular mortality (HR 1.38, 95% CI 1.09-1.87). Similarly, compared with the reference range, low levels of total cholesterol (< 4.10mmol/L) were also associated with high risks of all-cause (HR 1.62, 95% CI 1.31-1.95) and cardiovascular mortality (HR 1.72, 95% CI 1.27-2.34). CONCLUSION: Total cholesterol levels at the start of PD between 4.10 and 4.50 mmol/L (158.5 to 174.0 mg/dL), an optimal range, were associated with lower risks of death than higher or lower levels, resulting in a U-shaped association.
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Doenças Cardiovasculares , Diálise Peritoneal , Humanos , Diálise Renal , Estudos Retrospectivos , Estudos de Coortes , ColesterolRESUMO
BACKGROUND AND AIMS: Remnant cholesterol (RC) adversely contributes to cardiovascular disease (CVD) and overall survival in various diseases. However, its role in CVD outcomes and all-cause mortality in patients undergoing peritoneal dialysis (PD) is limited. Therefore, we aimed to investigate the association between RC and all-cause and CVD mortality in patients undergoing PD. METHODS AND RESULTS: Based on lipid profiles recorded using standard laboratory procedures, fasting RC levels were calculated in 2710 incident patients undergoing PD who were enrolled between January 2006 and December 2017 and followed up until December 2018. Patients were divided into four groups according to the quartile distribution of baseline RC levels (Q1: <0.40 mmol/L, Q2: 0.40 to <0.64 mmol/L, Q3: 0.64 to <1.03 mmol/L, and Q4: ≥1.03 mmol/L). Associations between RC and CVD and all-cause mortality were evaluated using multivariable Cox models. During the median follow-up period of 35.4 months (interquartile range, 20.9-57.2 months), 820 deaths were recorded, of which 438 were CVD-related. Smoothing plots showed non-linear relationships between RC and adverse outcomes. The risks of all-cause and CVD mortality increased progressively through the quartiles (log-rank, p < 0.001). Using adjusted proportional hazard models, a comparison of the highest (Q4) to lowest (Q1) quartiles revealed significant increases in the hazard ratio (HR) for all-cause mortality (HR 1.95 [95% confidence interval (CI), 1.51-2.51]) and CVD mortality risk (HR 2.60 [95% CI, 1.80-3.75]). CONCLUSION: An increased RC level was independently associated with all-cause and CVD mortality in patients undergoing PD, suggesting that RC was important clinically and required further research.
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Doenças Cardiovasculares , Diálise Peritoneal , Humanos , Estudos Retrospectivos , Diálise Peritoneal/efeitos adversos , Fatores de Risco , Colesterol , Modelos de Riscos ProporcionaisRESUMO
BACKGROUND: Immune-inflammatory biomarkers (IIBs) have been shown to be correlated with prognosis in patients undergoing peritoneal dialysis (PD). In this study, we aimed to evaluate the relationship between a novel comprehensive biomarker, the pan-immune-inflammation value (PIV), and the prognosis of patients undergoing PD. METHODS: We retrospectively analyzed data from a multicenter, large-sample PD database. PIV was calculated as (neutrophil count × platelet count × monocyte count)/lymphocyte count. The prognostic endpoints in this study were all-cause death all-cause, cardiovascular disease (CVD) and infection-related death. The Kaplan-Meier method, a Cox proportional hazards regression, Fine-Gray competing risk model, smooth curve, and subgroup analysis were used to analyze the independent relationship between PIV and the prognosis of patients undergoing PD. RESULTS: A total of 2796 cases of PD were included, and the study population was divided into Tertiles 1, 2, and 3, according to the tertiles of baseline PIVs. After adjusting for multiple model factors, patients in the Tertile 3 group had a significantly higher risk of all-cause death, CVD death and infection-related death compared with patients with PIV in the Tertile 1 group. Interaction tests showed no positive correlations for subgroup parameters. Regarding all-cause death, compared with the lowest tertile, the multivariable-adjusted hazard ratios (95% confidence intervals) of the highest and middle tertiles were 1.55 (1.25-1.94) and 1.77 (1.43-2.19), respectively; PIV (log2 processing) was associated with 17% excess of mortality in the continuous model. CONCLUSIONS: A high PIV at baseline was significantly associated with an increased risk of deaths due to all-causes, CVD and infection in patients undergoing PD.
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Doenças Cardiovasculares , Diálise Peritoneal , Humanos , Estudos Retrospectivos , Prognóstico , Inflamação , Biomarcadores , Doenças Cardiovasculares/etiologia , Modelos de Riscos ProporcionaisRESUMO
Lung cancer is one of the most malignant diseases and a major contributor to cancer-related deaths worldwide due to the deficiency of early diagnosis and effective therapy that are of great importance for patient prognosis and quality of life. Over the past decade, the advent of clustered regularly interspaced short palindromic repeats/CRISPR associated protein (CRISPR/Cas) system has significantly propelled the progress of both fundamental research and clinical trials of lung cancer. In this review, we review the current applications of the CRISPR/Cas system in diagnosis, target identification, and treatment resistance of lung cancer. Furthermore, we summarize the development of lung cancer animal models and delivery methods based on CRISPR system, providing novel insights into clinical diagnosis and treatment strategies of lung cancer.
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Background: Preexisting cardiovascular disease (CVD) and hypertension are each associated with poor prognosis in peritoneal dialysis (PD) patients. Joint associations of preexisting CVD and hypertension have not been comprehensively evaluated in this population. Methods: We conducted a retrospective cohort study of 3073 Chinese incident PD patients from five dialysis centres between January 1, 2005, and December 31, 2018. The joint associations between preexisting CVD, hypertension, and mortality were analysed using Cox regression models. Results: Over a median of 33.7 months of follow-up, 581 (18.6%) patients died, with 286 (9.3%) deaths due to CVD. After adjusting for confounding factors, the preexisting CVD coexisting with hypertension, preexisting CVD, and hypertension groups had higher risks of all-cause mortality (hazard ratio [HR]: 3.97, 95% confidence interval [CI]: 3.06 to 5.15; HR: 2.21, 95% CI: 1.29 to 3.79; and HR: 1.83, 95% CI: 1.47 to 2.29, respectively) and CVD mortality (HR: 4.68, 95% CI: 3.27 to 6.69; HR: 2.10, 95% CI: 0.95 to 4.62; and HR: 1.86, 95% CI: 1.36 to 2.54, respectively) than the control group without preexisting CVD or hypertension (p for trend < 0.001). There was no interaction between subgroup analyses (p > 0.05). The joint associations showed similar patterns using the Fine-Gray competing risk models. Conclusions: Preexisting CVD and hypertension at the start of PD were additive prognostic utilities for mortality, and preexisting CVD was more strongly associated with mortality than hypertension.
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OBJECTIVES: The global mortality rate from chronic kidney disease (CKD) has increased over the past two decades. Typically, peritoneal dialysis (PD) remains a useful alternative treatment for end-stage renal disease. Cardiovascular disease (CVD) is the main complication in PD patients. In terms of prognosis, it is reported that platelet distribution width (PDW) can predict adverse CVD events. However, the relationship between PDW and new-onset CVD in PD patients is not clear. This study aimed to explore the relationship between PDW and new-onset CVD in PD patients. METHODS: This was a retrospective cohort study, from 4 July 2005 to 31 December 2019, and a total of 1557 patients were recruited. PDW was respectively categorized into two groups: PDW ≤13.2 fL and PDW >13.2 fL. The primary outcome was a new-onset CVD event. Cox proportional hazards models were performed to assess the hazard ratio (HR). Receiver-operating characteristic (ROC) curves were applied to evaluate the predictive accuracy of the PDW on CVD events. RESULTS: During follow-up, 114 new-onset CVD events were recorded. Cox proportional hazards models showed a higher risk of CVD events in patients with high PDW (HR = 1.862 95%CI 1.205-2.877, p = 0.005). Kaplan-Meier cumulative incidence curves showed the risk of the first occurrence of CVD events was greater in the high PDW group (p = 0.006). CONCLUSIONS: High PDW is associated with new-onset cardiovascular disease events in PD patients.
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Doenças Cardiovasculares , Diálise Peritoneal , Humanos , Volume Plaquetário Médio , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Estudos Retrospectivos , Contagem de Plaquetas , Prognóstico , Diálise Peritoneal/efeitos adversos , Modelos de Riscos ProporcionaisRESUMO
BACKGROUND: New lipid-lowering therapy at the start of dialysis and measurement of lipid parameters over the follow-up period is not recommended in dialysis patients, which seems unappropriated in clinical practice. We aimed to examine the effect of hyperlipidemia on mortality in patients undergoing continuous ambulatory peritoneal dialysis (CAPD). METHODS: A retrospective cohort study was performed, including 2939 incident CAPD patients from five dialysis facilities between January 1, 2005, and December 31, 2018. The primary outcome was all-cause mortality. The association between hyperlipidemia at the start of CAPD and all-cause mortality was evaluated using Cox proportional hazards regression. RESULTS: Of 2939 with a median age of 50.0 (interquartile range, 39.0-61.0), 1697 (57.7%) were men, 533 (18.1%) had hyperlipidemia, 549 (18.7%) had diabetes mellitus, 1915 (65.2%) had hypertension, and 410 (14.0%) had a history of CVD. During the median follow-up period of 35.1 months, 519 (17.7%) died, including 402 (16.7%, 47.4/1000 patient-years) in the non-hyperlipidemia group and 117 (22.0%, 71.1/1000 patient-years) in the hyperlipidemia group. Over the overall follow-up period, patients with hyperlipidemia had an equally high risk of all-cause mortality throughout follow-up as those without hyperlipidemia ([HR] 1.04, 95% confidence interval [CI] 0.83 to 1.31). However, from the 48-month follow-up onwards, hyperlipidemia was associated with a 2.26 (95% CI 1.49 to 3.43)-time higher risk of all-cause mortality than non-hyperlipidemia. Hypertension modified the association between hyperlipidemia and all-cause mortality (P for interaction < 0.001). A significantly increased risk of all-cause mortality was observed among patients with hypertension (HR 2.27, 95%CI 1.44-3.58). CONCLUSION: Among CAPD patients, hyperlipidemia at the beginning of CAPD was associated with a high risk of long-term mortality. Hypertension may mediate the association. Our findings suggested that long-term lipid-lowering treatment should be used in those patients with hyperlipidemia.
Assuntos
Hiperlipidemias , Hipertensão , Falência Renal Crônica , Diálise Peritoneal , Masculino , Humanos , Feminino , Estudos Retrospectivos , Diálise Renal , Diálise Peritoneal/efeitos adversos , Hiperlipidemias/epidemiologia , Hipertensão/epidemiologia , Lipídeos , Modelos de Riscos Proporcionais , Falência Renal Crônica/terapiaRESUMO
BACKGROUND: A large number of studies have shown that proton pump inhibitors (PPIs) are associated with infection events. Therefore, we retrospectively evaluated the association of PPI therapy with the occurrence of first pneumonia and peritoneal dialysis(PD)-related peritonitis events in the maintenance PD patients. METHODS: We collected PD patients in two large hospitals from January 1, 2012 to December 31, 2016, and divided them into the PPI group and the non-PPI group. Multivariate Cox proportional hazards models were applied to evaluate the cumulative incidence and hazard ratios (HRs). Inverse probability of treatment weight (IPTW) method was used to adjust for covariate imbalance between the two groups and further confirm our findings. RESULTS: Finally, 656 PD patients were included for data analysis, and the results showed that PPI usage was associated with an increased risk of pneumonia [HR 1.71; 95% CI 1.06-2.76; p = 0.027] and peritonitis [HR 1.73; 95% CI 1.24-2.40; p = 0.001]. IPTW-adjusted HRs for the association of PPIs with pneumonia and peritonitis were 1.58 (95% CI:1.18-2.12; p = 0.002) and 2.33 (95% CI:1.91-2.85; p < 0.001), respectively. Moreover, the competitive risk model proved that under the conditions of competition for other events(including transfer to hemodialysis therapy, kidney transplant, transfer from our research center, loss to follow-up, and death), the differences in endpoints events between the two groups were still statistically significant (p = 0.009, p < 0.001, respectively). CONCLUSIONS: PPIs was associated with an increased risk of first pneumonia and PD-related peritonitis events in PD patients, which reminds clinicians to be cautious when prescribing acid-suppressing drugs for PD patients.
Assuntos
Falência Renal Crônica , Diálise Peritoneal , Peritonite , Pneumonia , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Diálise Peritoneal/efeitos adversos , Diálise Peritoneal/métodos , Peritonite/epidemiologia , Peritonite/etiologia , Pneumonia/epidemiologia , Pneumonia/etiologia , Modelos de Riscos Proporcionais , Inibidores da Bomba de Prótons/efeitos adversos , Estudos Retrospectivos , Fatores de RiscoRESUMO
Background: In dialysis patients, lowering low-density lipoprotein cholesterol (LDL-C) did not provide benefits, which seemed implausible in clinical practice. We hypothesized a U-shaped association between LDL-C and mortality in dialysis patients. Methods: In this multi-center retrospective real-world cohort study, 3,565 incident Chinese peritoneal dialysis (PD) patients between January 1, 2005, and May 31, 2020, were included. The associations between baseline LDL-C and mortality were examined using cause-specific hazard models. Results: Of 3,565 patients, 820 died, including 415 cardiovascular deaths. As compared with the reference range (2.26-2.60 mmol/L), both higher levels of LDL-C (> 2.60 mmol/L) and lower levels of LDL-C (< 2.26 mmol/L) were associated with increased risks of all-cause mortality (hazard ratio [HR],1.35, 95% confidence index [CI], 1.09-1.66; HR 1.36, 95%CI, 1.13-1.64) and cardiovascular mortality (HR, 1.31, 95% CI, 1.10-1.72; HR, 1.64; 95% CI, 1.22-2.19). Malnutrition (albumin < 36.0 g/L) modified the association between LDL-C and cardiovascular mortality (P for interaction = 0.01). A significantly increased risk of cardiovascular mortality was observed among patients with malnutrition and lower levels of LDL-C (HR 2.96, 95%CI 1.43-6.12) or higher levels of LDL-C (HR 2.81, 95%CI 1.38-5.72). Conclusion: Low and high levels of LDL-C at the start of PD procedure were associated with increased all-cause and cardiovascular mortality risks. Malnutrition may modify the association of LDL-C with cardiovascular mortality.