Hypomagnesemia Is a Risk Factor for Cardiovascular Disease- and Noncardiovascular Disease-Related Mortality in Peritoneal Dialysis Patients.

PURPOSE: Recent research has shown that hypomagnesemia is associated with increased all-cause mortality in hemodialysis patients. However, the relationship between the long-term prognosis of peritoneal dialysis (PD) and the study is not yet clear. This study will analyze the effects of hypomagnesemia on all-cause, cardiovascular diseases (CVD), and non-CVD mortality in PD patients. METHOD: In a retrospective cohort study, 1,004 samples were selected from 7 PD centers in China. Based on the baseline blood magnesium level at the beginning of stable dialysis, all patients were classified into blood magnesium <0.7 mmol/L group, 0.7-1.2 mmol/L group, and >1.2 mmol/L group (the end event was death). The Kaplan-Meier method was used to calculate the difference in cumulative survival rate; the Cox proportional hazard model was used to analyze the risk factors of all-cause, CVD, and non-CVD death causes. RESULTS: Cox multiple regression analysis results (reference comparison of 0.7-1.2 mmol/L group): patients with serum magnesium <0.7 mmol/L have a higher risk ratio of all-cause mortality (HR = 1.580, 95% CI: 1.222-2.042, p = 0.001), and it is also obvious after correction by multiple models (HR = 1.578, 95% CI: 1.196-2.083, p = 0.001). Subgroup analysis of the causes of death was as follows: CVD risk (HR = 1.628, 95% CI: 1.114-2.379, p = 0.012) and non-CVD risk (HR = 1.521, 95% CI: 1.011-2.288, p = 0.044). Further analysis of the causes of infection-related death in non-CVD is also significant (HR = 1.919, 95% CI: 1.131-3.1257, p = 0.016). On the other hand, the serum magnesium>1.2 mmol/L group had lower all-cause mortality after correction (HR = 0.687, 95% CI: 0.480-0.985, p = 0.041), and subgroup analysis of the cause of death had no statistical significance (p > 0.05). CONCLUSIONS: Hypomagnesemia (serum magnesium <0.7 mmol/L) during stable dialysis in PD patients is a risk factor for CVD- and non-CVD-related mortality, especially infection-related death causes.

Hyperlipidemia and mortality associated with diabetes mellitus co-existence in Chinese peritoneal dialysis patients.

BACKGROUND: To evaluate associations between diabetes mellitus (DM) coexisting with hyperlipidemia and mortality in peritoneal dialysis (PD) patients. METHODS: This was a retrospective cohort study with 2939 incident PD patients in China from January 2005 to December 2018. Associations between the DM coexisting with hyperlipidemia and mortality were evaluated using the Cox regression. RESULTS: Of 2939 patients, with a median age of 50.0 years, 519 (17.7%) died during the median of 35.1 months. DM coexisting with hyperlipidemia, DM, and hyperlipidemia were associated with 1.93 (95% CI 1.45 to 2.56), 1.86 (95% CI 1.49 to 2.32), and 0.90 (95% CI 0.66 to 1.24)-time higher risk of all-cause mortality, compared with without DM and hyperlipidemia, respectively (P for trend < 0.001). Subgroup analyses showed a similar pattern. Among DM patients, hyperlipidemia was as a high risk of mortality as non-hyperlipidemia (hazard ratio 1.02, 95%CI 0.73 to 1.43) during the overall follow-up period, but from 48-month follow-up onwards, hyperlipidemia patients had 3.60 (95%CI 1.62 to 8.01)-fold higher risk of all-cause mortality than those non-hyperlipidemia (P interaction = 1.000). CONCLUSIONS: PD patients with DM coexisting with hyperlipidemia were at the highest risk of all-cause mortality, followed by DM patients and hyperlipidemia patients, and hyperlipidemia may have an adverse effect on long-term survival in DM patients.

Association between aminotransferase/alanine aminotransferase ratio and cardiovascular disease mortality in patients on peritoneal dialysis: a multi-center retrospective study.

BACKGROUND: Elevated aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio is an independent risk factor for cardiovascular disease (CVD) among the general population. However, an association between AST/ALT ratio and CVD mortality in patients on peritoneal dialysis (PD) has received little attention. METHODS: A total of 2224 incident PD patients from multi-centers were enrolled from November 1, 2005, to June 30, 2017, in this retrospective cohort study. The primary endpoint was CVD mortality. Eligible patients were divided into high and normal groups according to the AST/ALT ratio cut-off for CVD mortality with the receiver operating characteristic (ROC) curve. The associations between the AST/ALT ratio and CVD mortality were evaluated by the Cox regression model. RESULTS: Of eligible 1579 patients with a mean age of 49.3 ± 14.6 years, 55.4% of patients were male, 18.1% of patients had diabetes, and 64.2% of patients had hypertension. The prevalence of a high AST/ALT ratio was 76.6% in the cohort population. During a follow-up period with 4659.6 patient-years, 316 patients died, of which 193 (61.1%) deaths were caused by CVD episodes. The incidence of CVD mortality in the high group was significantly higher than that in the normal group (13.1% versus 9.2%, P = 0.024). Cumulative CVD mortality rates were significantly different between the two groups by Kaplan-Meier analysis [hazards ratio (HR) = 1.50, 95% confidence index (CI) 1.09-2.07, P = 0.014]. After adjusting for confounding factors, a higher AST/ALT ratio was independently associated with an increased risk of CVD mortality compared with their counterparts (HR = 1.43, 95%CI 1.08-2.41, P = 0.002). CONCLUSIONS: PD patients with high baseline AST/ALT ratio levels may be at a significant risk of CVD mortality.

Corrigendum to "Irbesartan Ameliorates Diabetic Nephropathy by Suppressing the RANKL-RANK-NF-κB Pathway in Type 2 Diabetic db/db Mice".

[This corrects the article DOI: 10.1155/2016/1405924.].

Metadherin facilitates podocyte apoptosis in diabetic nephropathy.

Apoptosis, one of the major causes of podocyte loss, has been reported to have a vital role in diabetic nephropathy (DN) pathogenesis, and understanding the mechanisms underlying the regulation of podocyte apoptosis is crucial. Metadherin (MTDH) is an important oncogene, which is overexpressed in most cancers and responsible for apoptosis, metastasis, and poor patient survival. Here we show that the expression levels of Mtdh and phosphorylated p38 mitogen-activated protein kinase (MAPK) are significantly increased, whereas those of the microRNA-30 family members (miR-30s) are considerably reduced in the glomeruli of DN rat model and in high glucose (HG)-induced conditionally immortalized mouse podocytes (MPC5). These levels are positively correlated with podocyte apoptosis rate. The inhibition of Mtdh expression, using small interfering RNA, but not Mtdh overexpression, was shown to inhibit HG-induced MPC5 apoptosis and p38 MAPK pathway, and Bax and cleaved caspase 3 expression. This was shown to be similar to the effects of p38 MAPK inhibitor (SB203580). Furthermore, luciferase assay results demonstrated that Mtdh represents the target of miR-30s. Transient transfection experiments, using miR-30 microRNA (miRNA) inhibitors, led to the increase in Mtdh expression and induced the apoptosis of MPC5, whereas the treatment with miR-30 miRNA mimics led to the reduction in Mtdh expression and apoptosis of HG-induced MPC5 cells in comparison with their respective controls. Our results demonstrate that Mtdh is a potent modulator of podocyte apoptosis, and that it represents the target of miR-30 miRNAs, facilitating podocyte apoptosis through the activation of HG-induced p38 MAPK-dependent pathway.

Cyclopropanyldehydrocostunolide LJ attenuates high glucose-induced podocyte injury by suppressing RANKL/RANK-mediated NF-κB and MAPK signaling pathways.

AIMS: The aim of this research was to investigate the effects of cyclopropanyldehydrocostunolide (also named LJ), a derivative of sesquiterpene lactones (SLs), on high glucose (HG)-induced podocyte injury and the associated molecular mechanisms. METHODS: Differentiated mouse podocytes were incubated in different treatments. The migration and albumin filtration of podocytes were examined by Transwell filters. The protein and mRNA levels of MCP-1 were measured using enzyme-linked immunosorbent assay (ELISA) and quantitative real-time PCR (q-PCR). Protein expression and phosphorylation were detected by western blot, and the nuclear translocation of NF-κB was performed with a confocal microscope. The gene expression of the receptor activator for NF-κB (RANK) was silenced by small interfering RNA (siRNA). RESULTS: Our results showed that HG enhanced migration, albumin filtration and MCP-1 expression in podocytes. At the molecular level, HG promoted the phosphorylation of NF-κB/p65, IKKß, IκBα, mitogen-activated protein kinase (MAPK) and the nuclear translocation of p65. LJ reversed the effects of HG in a dose-dependent manner. Furthermore, our data provided the first demonstration that the receptor activator for NF-κB ligand (RANKL) and its cognate receptor RANK were overexpressed in HG-induced podocytes and were downregulated by LJ. RANK siRNA also attenuated HG-induced podocyte injury and markedly inhibited the activation of NF-κB and MAPK signaling pathways. CONCLUSIONS: LJ attenuates HG-induced podocyte injury by suppressing RANKL/RANK-mediated NF-κB and MAPK signaling pathways.

Irbesartan Ameliorates Diabetic Nephropathy by Suppressing the RANKL-RANK-NF-κB Pathway in Type 2 Diabetic db/db Mice.

The receptor activator of NF-κB ligand (RANKL) and its receptor RANK are overexpressed in focal segmental glomerular sclerosis (FSGS), IgA nephropathy (IgAN), and membranous nephropathy (MN). However, the expression and the potential roles of RANKL and RANK in diabetic nephropathy (DN) remain unclear. Irbesartan (Irb) has beneficial effects against diabetes-induced renal damage, but its mechanisms are poorly understood. Our present study investigated the effects of Irb in DN and whether the renal protective effects of Irb are mediated by RANKL/RANK and the downstream NF-κB pathway in db/db mice. Our results showed that db/db mice revealed severe metabolic abnormalities, renal dysfunction, podocyte injury, and increased MCP-1; these symptoms were reversed by Irb. At the molecular level, RANKL and RANK were overexpressed in the kidneys of db/db mice and Irb downregulated RANKL and RANK and inhibited the downstream NF-κB pathway. Our study suggests that Irb can ameliorate DN by suppressing the RANKL-RANK-NF-κB pathway.

Hypochlorite-Modified Albumin Upregulates ICAM-1 Expression via a MAPK-NF-κB Signaling Cascade: Protective Effects of Apocynin.

Hypochlorite-modified albumin (HOCl-alb) has been linked to endothelial dysfunction, which plays an important role in the development of hypertension, diabetes, and chronic kidney disease. However, whether HOCl-alb induces endothelial dysfunction via vascular inflammation and whether a signaling pathway is involved are unknown and have not been investigated. HOCl-alb was found to upregulate ICAM-1 expression in human umbilical vein endothelial cells (HUVECs) in a time- and dose-dependent manner. HOCl-alb time-dependently phosphorylated ERK1/2 and p38(MAPK). HOCl-alb also activated NF-κB. ICAM-1 expression was dose-dependently inhibited by U0126 (a specific inhibitor of MEK1/2, a signal upstream from ERK1/2), SB203580 (a specific inhibitor of p38(MAPK)), and SN50 (a specific inhibitor of NF-κB). U0126 and SB203580 both counteracted the activation of NF-κB, whereas the phosphorylation of ERK1/2 and p38(MAPK) was not blocked by SN50. ERK1/2 phosphorylation was blocked by U0126 but not by SB203580, and p38(MAPK) activity was reduced by SB203580 but not by U0126. Apocynin, a specific NADPH oxidase (NOX) inhibitor, inhibited ICAM-1 expression and the activity of ERK1/2, p38(MAPK), and NF-κB. These results indicate that HOCl-alb-induced ICAM-1 expression is caused by the activation of a redox-sensitive intracellular signal cascade involving ERK1/2 and p38(MAPK), culminating in the activation of NF-κB and involving NOXs among the upstream signals.

Optimization and evaluation of magnetic bead separation combined with matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy (MALDI-TOF MS) for proteins profiling of peritoneal dialysis effluent.

Peritoneal dialysis effluent (PDE) potentially carries an archive of peptides relevant to pathological processes in abdominal and surrounding tissues. Magnetic beads and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry is one such approach that offers a unique tool for profiling of peptides, but this approach has not been used in the PDE analysis. In this study, we developed a strategy for screening PDE proteins <15 kDa and applied this technique to identify potential biomarkers for peritonitis. We examined four kinds of magnetic beads, including a carbon series (C3, C8), weak cation exchange (WCX) and immobilized metal-affinity chromatography (IMAC-Cu) beads. Samples processed with IMAC-Cu magnetic beads consistently showed more MS signals across all beads within the measured mass range. Moreover, there was no difference in the number and morphology of MS signals between concentrated and unconcentrated samples. The PDE peptidome pattern, based on a panel of 15 peaks, accurately recognized peritonitis PD patients from peritonitis-free patients with sensitivity of 90.5% and specificity of 94.7% respectively. Therefore, IMAC-Cu magnetic beads and unconcentrated samples can be used as a fast and cost-effective approach for sample preparation prior to more in-depth discovery of predictive biomarkers of disease in patients on dialysis.