Association of albumin to non-high-density lipoprotein cholesterol ratio with mortality in peritoneal dialysis patients.

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.

Brahma-related gene 1 acts as a profibrotic mediator and targeting it by micheliolide ameliorates peritoneal fibrosis.

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.

Remnant cholesterol as a risk factor for all-cause and cardiovascular mortality in incident peritoneal dialysis patients.

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.

Total cholesterol and mortality in peritoneal dialysis: a retrospective cohort study.

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.

Association of Neutrophil and Albumin With Mortality Risk in Patients Receiving Peritoneal Dialysis.

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.

Pan-immune-inflammation value is associated with poor prognosis in patients undergoing peritoneal dialysis.

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.

Clinical significance of serum glucose to lymphocyte ratio as a prognostic marker in peritoneal dialysis patients.

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 ∼ 1.04, p = .019) and CVD mortality (adjusted HR 1.02; CI 1.00 ∼ 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 ∼ 1.56, p = .03) and CVD mortality (adjusted HR 1.76; CI 1.31 ∼ 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.

Serum uric acid to creatinine ratio as a risk factor for mortality among patients on continuous ambulatory peritoneal dialysis: a multi-center retrospective study.

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.

ACEi/ARBs associate with lower incidence of gastrointestinal bleeding in peritoneal dialysis patients.

BACKGROUND: Gastrointestinal bleeding (GIB) is widespread in patients with impaired renal function. Whether angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACEi/ARBs) potentially take a crucial role in avoiding GIB incidence among peritoneal dialysis (PD) patients is unknown. METHODS: Overall, 734 PD patients were enrolled after using propensity score matching. Kaplan-Meier analysis and COX regression were used to explore correlation between ACEi/ARBs and GIB. Competitive risk model was aimed to identify whether other events were confounding factors. Forest plot was applied to assess the influence of ACEI/ARBs on GIB incidence in different groups. RESULTS: During 8-year follow-up, 89 (12.13%) cases of GIB were recorded. Kaplan-Meier analysis revealed that the incidence of GIB among patients taking ACEi/ARBs was lower than those subjects who had not (log rank = 6.442, P = 0.011). After adjusted different confounding factors, administration of ACEi/ARBs was associated with lowered GIB incidence (adjusted HR = 0.49, 95% CI 0.32-0.77, P = 0.002). In competitive risk model, considering of other events, the incidence of GIB in two groups was still statistically significant (P = 0.010). Subgroup analysis showed ACEi/ARBs taking impeded GIB in the ≥ 60 age group (HR = 0.52, 95% CI 0.28-0.98, P = 0.040). CONCLUSION: PD patients who were submitted to ACEi/ARBs inclined to have a lower risk for GIB. In this regard, ACEi/ARBs offered a promising choice to GIB.

Hyperlipidemia and mortality in patients on peritoneal dialysis.

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.

Coexistence of diabetes mellitus and pre-existing cardiovascular disease and mortality in Chinese patients on peritoneal dialysis.

BACKGROUND: Little is known about the association between the coexistence of diabetes mellitus (DM) and pre-existing cardiovascular disease (CVD) and mortality in patients undergoing continuous ambulatory peritoneal dialysis (CAPD). METHODS: A retrospective cohort study of 2939 Chinese incident CAPD patients was conducted between January 1, 2005, and December 31, 2018. The primary and secondary outcomes were all-cause and CVD mortality. The association between the coexistence of DM and pre-existing CVD and mortality was evaluated using Cox proportional hazards regression. RESULTS: Over a median of 35.1 months of follow-up, 519 patients (17.7%) died, with 258 (8.8%) being CVD-related deaths. DM plus pre-existing CVD, DM, and pre-existing CVD were associated with a higher risk of all-cause mortality (adjusted hazard ratio [HR], 2.85; 95% confidence interval [CI], 2.18 to 3.72; adjusted HR, 1.89; 95% CI, 1.50 to 2.38; and HR, 1.43; 95% CI, 1.07 to 1.92; P for tend < 0.001) and CVD mortality (adjusted HR, 2.79; 95% CI, 1.91 to 4.08; HR, 1.88; 95% CI, 1.35 to 2.61; and HR, 1.82; 95% CI, 1.23 to 2.68; P for trend < 0.001) than no DM or pre-existing CVD. Subgroup analyses stratified by sex, hypertension status, and hyperlipidemia status showed a similar pattern. CONCLUSIONS: The coexistence of DM and pre-existing CVD at the start of CAPD was more strongly associated with a higher risk of all-cause and CVD mortality than DM or pre-existing CVD alone.

Proton pump inhibitor usage is associated with higher all-cause mortality and CV events in peritoneal dialysis patients.

OBJECTIVES: A long period of inappropriate proton pump inhibitors (PPI) treatment has been proved to be associated with adverse prognosis in general population and hemodialysis patients. This study was conducted to clarify the impact of PPI usage on mortality and adverse cardiovascular (CV) events in peritoneal dialysis (PD) patients. METHODS AND DESIGN: This is a retrospective study. A total of 905 patients were enrolled from two PD centers, including 211 patients on PPI treatment and 618 patients not on PPIs. Kaplan-Meier curves were used to identify the incidence of adverse outcomes. Multivariate Cox regression models and inverse probability of treatment weighting (IPTW) were applied to analyze hazard ratios (HRs) for adverse outcomes. RESULTS: During follow-up, 162 deaths and 102 CV events were recorded. Kaplan-Meier curve demonstrated all-cause mortality (log-rank test p = .018) and CV events (log-rank test p = .024) were significantly higher in PPI usage group. Multivariate Cox regression models and IPTW showed that PPI usage was an indicator for all-cause mortality (HR = 1.35, 95%CI = 1.09-1.67, p = .006) and CV events (HR = 1.78, 95%CI = 1.35-2.32, p < .001). CONCLUSIONS: PPI usage is associated with higher all-cause mortality and CV events in PD patients. Clinicians are supposed to be more careful when using PPI and need to master the indications more rigorously in patients receiving PD treatment.

Proton pump inhibitor usage associates with higher risk of first episodes of pneumonia and peritonitis in peritoneal dialysis patients.

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.

The relationship between platelet distribution width and new-onset cardiovascular disease events in patients with peritoneal dialysis.

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.

Brahma-related gene-1 promotes tubular senescence and renal fibrosis through Wnt/ß-catenin/autophagy axis.

Although accelerated cellular senescence is closely related to the progression of chronic kidney disease (CKD) and renal fibrosis, the underlying mechanisms remain largely unknown. Here, we reported that tubular aberrant expression of Brahma-related gene 1 (BRG1), an enzymatic subunit of the SWItch/Sucrose Non-Fermentable complex, is critically involved in tubular senescence and renal fibrosis. BRG1 was significantly up-regulated in the kidneys, predominantly in tubular epithelial cells, of both CKD patients and unilateral ureteral obstruction (UUO) mice. In vivo, shRNA-mediated knockdown of BRG1 significantly ameliorated renal fibrosis, improved tubular senescence, and inhibited UUO-induced activation of Wnt/ß-catenin pathway. In mouse renal tubular epithelial cells (mTECs) and primary renal tubular cells, inhibition of BRG1 diminished transforming growth factor-ß1 (TGF-ß1)-induced cellular senescence and fibrotic responses. Correspondingly, ectopic expression of BRG1 in mTECs or normal kidneys increased p16INK4a, p19ARF, and p21 expression and senescence-associated ß-galactosidase (SA-ß-gal) activity, indicating accelerated tubular senescence. Additionally, BRG1-mediated pro-fibrotic responses were largely abolished by small interfering RNA (siRNA)-mediated p16INK4a silencing in vitro or continuous senolytic treatment with ABT-263 in vivo. Moreover, BRG1 activated the Wnt/ß-catenin pathway, which further inhibited autophagy. Pharmacologic inhibition of the Wnt/ß-catenin pathway (ICG-001) or rapamycin (RAPA)-mediated activation of autophagy effectively blocked BRG1-induced tubular senescence and fibrotic responses, while bafilomycin A1 (Baf A1)-mediated inhibition of autophagy abolished the effects of ICG-001. Further, BRG1 altered the secretome of senescent tubular cells, which promoted proliferation and activation of fibroblasts. Taken together, our results indicate that BRG1 induces tubular senescence by inhibiting autophagy via the Wnt/ß-catenin pathway, which ultimately contributes to the development of renal fibrosis.

FOXO3a accumulation and activation accelerate oxidative stress-induced podocyte injury.

Podocyte injury is the primary cause of glomerular injury in diabetic nephropathy (DN). Advanced oxidation protein products (AOPPs), the triggers and markers of oxidative stress in DN, have been linked to podocyte damage. However, the underlying mechanism is not yet clear. Here, we investigated the potential role of FOXO3a, a key transcription factor in the response to stress, in mediating AOPPs-induced podocyte injury. We found that FOXO3a expression was increased in the glomeruli of kidney biopsies from patients with DN and it was positively correlated with proteinuria. The serum from patients with DN significantly increased FOXO3a and its downstream genes FasL and Bim, thereby inducing the high level of cleaved caspase3 and the loss of nephrin and podocin expressions in podocytes. Blockade of AOPPs signaling by a neutralizing antibody against the receptor of advanced glycation end products (αRAGE) abolished the effect of DN serum on podocytes, confirming the pathogenic role of AOPPs in DN serum. Downregulation of FOXO3a decreased AOPPs-induced podocyte apoptosis and restored the levels of podocyte markers nephrin and podocin, and upregulation of FOXO3a exacerbated these changes in podocytes after AOPPs treatment. Furthermore, FOXO3a specifically activated proapoptotic genes in podocytes only in the presence of AOPPs. Mechanistically, AOPPs increased the FOXO3a protein levels by inhibiting their autophagic degradation in a ROS/mTOR-dependent manner. Moreover AOPPs activated the accumulated FOXO3a by maintaining FOXO3a in the nucleus, and this process was dependent on ROS-mediated AKT signaling deactivation. These studies suggest that FOXO3a plays a critical role in mediating AOPPs-induced podocyte injury and reveal a new mechanistic linkage of oxidative stress, FOXO3a activation and podocyte injury in DN.

MicroRNA-145 promotes the epithelial-mesenchymal transition in peritoneal dialysis-associated fibrosis by suppressing fibroblast growth factor 10.

Peritoneal fibrosis is a common complication of long-term peritoneal dialysis (PD) and the principal cause of ultrafiltration failure during PD. The initial and reversible step in PD-associated peritoneal fibrosis is the epithelial-mesenchymal transition (EMT). Although the mechanisms in the EMT have been the focus of many studies, only limited information is currently available concerning microRNA (miRNA) regulation in peritoneal fibrosis. In this study, we aimed to characterize the roles of microRNA-145 (miR-145) and fibroblast growth factor 10 (FGF10) in peritoneal fibrosis. After inducing EMT with transforming growth factor-ß1 (TGF-ß1) in vitro, we found that miR-145 is significantly up-regulated, whereas FGF10 is markedly down-regulated, suggesting a close link between miR-145 and FGF10 in peritoneal fibrosis, further confirmed in luciferase reporter experiments. Furthermore, in human peritoneal mesothelial cells (i.e. HMrSV5 cells), miR-145 mimics induced EMT, whereas miR-145 inhibition suppressed EMT, and we also observed that miR-145 suppressed FGF10 expression. In vivo, we found that the exogenous delivery of an miR-145 expression plasmid both blocked FGF10 and intensified the EMT, whereas miR-145 inhibition promoted the expression of FGF10 and reversed the EMT. In conclusion, miR-145 promotes the EMT during the development of peritoneal fibrosis by suppressing FGF10 activity, suggesting that miR-145 represents a potential therapeutic target for managing peritoneal fibrosis.

Correction: Micheliolide ameliorates renal fibrosis by suppressing the Mtdh/BMP/MAPK pathway.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The relationship between neutrophil-to-lymphocyte ratio and the first occurrence of pneumonia in peritoneal dialysis patients.

BACKGROUND: Although neutrophil-to-lymphocyte ratio (NLR) is closely associated with pneumonia in the general population, its relationship is unclear in peritoneal dialysis (PD) patients. METHODS: This is a cohort study consisting of 739 PD patients and dividing into two groups. Kaplan-Meier curves were applied to observe the incidence of the first occurrence of pneumonia, competitive risk analysis was conducted to compare whether there was a significant difference in each NLR group in the presence of other competing events, multivariable COX regression analysis was used to evaluate the hazard ratios (HRs), as well as forest plot was used to analyze the relationship between NLR and the first occurrence of pneumonia in different subgroups. RESULTS: Of all the patients, 116 cases of first-time pneumonia were recorded. The first-time pneumonia incidence rate was 71.67/1000 patient-years in high NLR group, which was markedly higher than that of 45.81/1000 patient-years in low NLR group. Kaplan-Meier curves indicated significant differences in the incidence of the first occurrence of pneumonia between two groups (log-rank test p = 0.015). The competitive risk model suggested a significant difference in the cumulative incidence of first pneumonia between the two groups (p = 0.032). Compared to low NLR group, adjusted Cox model showed that high NLR group was associated with increased risk of pneumonia incidence (HR, 1.51; 95% CI 1.04-2.21; p = 0.031). Forest plot showed no interaction was found in subgroups. CONCLUSIONS: The risk of pneumonia was significantly increasing in PD patients with high NLR, which may have a certain guiding significance for the clinic.

Albumin-globulin ratio and mortality in patients on peritoneal dialysis: a retrospective study.

BACKGROUND: Albumin-globulin ratio (AGR), a variable based on serum albumin and non-albumin proteins, has been demonstrated as a predictor of mortality in patients with malignant neoplasm. The aim of this study was to evaluate the prognostic value of AGR on peritoneal dialysis (PD) patients. METHODS: We retrospectively analyzed 602 incident PD patients from January 1st, 2008, to December 31st, 2017, at our center and followed them until December 31st, 2018. Kaplan-Meier curves and multivariate Cox regression models were applied to analyze the association between AGR and all-cause of mortality and cardiovascular mortality. RESULTS: The median follow-up time was 32.17 (interquartile range = 32.80) months. During follow-up, 131 (21.8%) patients died, including 57 patients (43.5%) who died due to cardiovascular diseases. Kaplan-Meier curves showed that patients with AGR > 1.26 had better rates of survival than those with AGR ≤ 1.25 (p < 0.001). After adjusting for potential confounders, the lower AGR level was significantly associated with an increased all-cause and cardiovascular mortality [hazard ratio (HR): 1.57, 95% confidence interval (CI): 1.07-2.32, p = 0.022 and HR: 2.01, 95% CI: 1.10-3.69, p = 0.023 respectively]. CONCLUSIONS: Patients with a low AGR level had an increased all-cause and cardiovascular mortality. AGR may be a useful index in identifying patients on PD at risk for CVD and all-cause of mortality.