Macroautophagy/autophagy protects against cellular stress. Renal sublethal injury-triggered tubular epithelial cell cycle arrest at G₂/M is associated with interstitial fibrosis. However, the role of autophagy in renal fibrosis is elusive. Here, we hypothesized that autophagy activity in tubular epithelial cells is pivotal for inhibition of cell cycle G₂/M arrest and subsequent fibrogenic response. In both renal epithelial cells stimulated by angiotensin II (AGT II) and the murine kidney after unilateral ureteral obstruction (UUO), we observed that occurrence of autophagy preceded increased production of COL1 (collagen, type I). Pharmacological enhancement of autophagy by rapamycin suppressed COL1 accumulation and renal fibrosis. In contrast, genetic ablation of autophagy by proximal tubular epithelial cell-specific deletion of Atg5, with reduction of the LC3-II protein level and degradation of SQSTM1/p62, showed marked cell cycle arrest at the G₂/M phase, robust COL1 deposition, and severe interstitial fibrosis in a UUO model, as compared with wild-type mice. In vitro, AGT II exposure triggered autophagy preferentially in the G₁/S phase, and increased COL1 expression in the G₂/M phase in renal epithelial cells. Stimulation of Atg5-deficient primary proximal tubular cells with AGT II also resulted in elevated G₂/M arrest and COL1 production. Pharmacological or genetic inhibition of autophagy increased AGT II-mediated G₂/M arrest. Enhanced expression of ATG5, but not the autophagy-deficient ATG5 mutant K130R, rescued the G₂/M arrest, suggesting the regulation of cell cycle progression by ATG5 is autophagy dependent. In conclusion, Atg5-mediated autophagy in proximal epithelial cells is a critical host-defense mechanism that prevents renal fibrosis by blocking G₂/M arrest.

Results concerning the association between peritoneal dialysis-related peritonitis and mortality in peritoneal dialysis patients are inconclusive, with one potential reason being that the time-dependent effect of peritonitis has rarely been considered in previous studies. This study aimed to evaluate whether peritonitis has a negative impact on mortality in a large cohort of peritoneal dialysis patients. We also assessed the changing impact of peritonitis on patient mortality with respect to duration of follow-up. This retrospective cohort study included incident patients who started peritoneal dialysis from 1 January 2006 to 31 December 2011. Episodes of peritonitis were recorded at the time of onset, and peritonitis was parameterized as a time-dependent variable for analysis. We used the Cox regression model to assess whether peritonitis has a negative impact on mortality. A total of 1321 patients were included. The mean age was 48.1 ± 15.3 years, 41.3% were female, and 23.5% with diabetes mellitus. The median (interquartile) follow-up time was 34 (21–48) months. After adjusting for confounders, peritonitis was independently associated with 95% increased risk of all-cause mortality (hazard ratio, 1.95; 95% confidence interval: 1.46–2.60), 90% increased risk of cardiovascular mortality (hazard ratio, 1.90; 95% confidence interval: 1.28–2.81) and near 4-fold increased risk of infection-related mortality (hazard ratio, 4.94; 95% confidence interval: 2.47–9.86). Further analyses showed that peritonitis was not significantly associated with mortality within 2 years of peritoneal dialysis initiation, but strongly influenced mortality in patients dialysed longer than 2 years. Peritonitis was independently associated with higher risk of all-cause, cardiovascular and infection-related mortality in peritoneal dialysis patients, and its impact on mortality was more significant in patients with longer peritoneal dialysis duration.

Abnormal serum potassium is associated with an increased risk of mortality in dialysis patients. However, the impacts of serum potassium levels on short- and long-term mortality and association of potassium variability with death in peritoneal dialysis (PD) patients are uncertain. We examined mortality-predictability of serum potassium at baseline and its variability in PD patients treated in our center January 2006 through December 2010 with follow-up through December 2012. The hazard ratios (HRs) were used to assess the relationship between baseline potassium levels and short-term (≤1 year) as well as long-term (>1 year) survival. Variability of serum potassium was defined as the coefficient of variation of serum potassium (CVSP) during the first year of PD. A total of 886 incident PD patients were enrolled, with 248 patients (27.9%) presented hypokalemia (serum potassium <3.5 mEq/L). During a median follow-up of 31 months (range: 0.5–81.0 months), adjusted all-cause mortality hazard ratio (HR) and 95% confidence interval (CI) for baseline serum potassium of <3.0, 3.0 to <3.5, 3.5 to <4.0, 4.5 to <5.0, and ≥5.0 mEq/L, compared with 4.0 to <4.5 (reference), were 1.79 (1.02–3.14), 1.15 (0.72–1.86), 1.31 (0.82–2.08), 1.33 (0.71–2.48), 1.28 (0.53–3.10), respectively. The increased risk of lower potassium with mortality was evident during the first year of follow-up, but vanished thereafter. Adjusted all-cause mortality HR for CVSP increments of 7.5% to <12.0%; 12.0% to <16.7% and ≥16.7%, compared with <7.5% (reference), were 1.35 (0.67–2.71), 2.00 (1.05–3.83) and 2.18 (1.18–4.05), respectively. Similar association was found between serum potassium levels and its variability and cardiovascular mortality. A lower serum potassium level was associated with all-cause and cardiovascular mortality during the first year of follow-up in incident PD patients. In addition, higher variability of serum potassium levels conferred an increased risk of death in this population.

♦ Background: The prognostic value of pulmonary hypertension at the start of peritoneal dialysis (PD) in patient survival is unclear. ♦ Methods: We conducted a retrospective study of incident patients who initiated PD therapy from January 2007 to December 2011, and followed up through June 2013. Pulmonary hypertension was defined as an estimated systolic pulmonary artery pressure (PAP) of ≥ 35 mm Hg using echocardiography. Clinical parameters and laboratory findings were compared between patients with and without pulmonary hypertension and a logistic regression model was elaborated. Patient outcomes (all-cause and cardiovascular mortality) were recorded during follow-up. Survival curves were constructed by the Kaplan-Meier method, and the influences of pulmonary hypertension on outcomes were analyzed by Cox regression models. ♦ Results: Pulmonary hypertension was prevalent in 99 (16.0%) of the 618 patients studied. The independent risk factors for pulmonary hypertension were female (odds ratio [OR] = 2.12; 95% confidence interval [CI]: 1.29 – 3.46), left atrial diameter (OR = 1.15; 95% CI: 1.10 – 1.20), left ventricular ejection fraction (OR = 0.97; 95% CI: 0.95 – 0.99), and serum sodium (OR = 0.94; 95% CI: 0.89 – 0.99). Over a median follow-up of 29.4 months, 93 patients (15.0%) died, 59.1% of them due to cardiovascular disease. Kaplan-Meier survival analysis showed that patients with pulmonary hypertension had worse overall rates of survival and cardiovascular death-free survival than those without pulmonary hypertension. After multivariate adjustment, pulmonary hypertension was independently associated with increased risk for both all-cause and cardiovascular mortality, with hazard ratios (HRs) of 2.10 (95% CI: 1.35 – 3.27) and 2.60 (95% CI: 1.48 – 4.56), respectively. ♦ Conclusions: The prevalence of pulmonary hypertension at the start of PD was common and associated with increased risk of both all-cause and cardiovascular mortality in incident PD patients.

Although high body mass index (BMI) appears to confer a survival advantage in hemodialysis patients, the association of BMI with mortality in continuous ambulatory peritoneal dialysis (CAPD) patients is uncertain. We enrolled incident CAPD patients and BMI was categorized according to World Health Organization classification for Asian population. BMI at baseline and one year after the initiation of peritoneal dialysis (PD) treatment was assessed to calculate the BMI change (∆BMI). Patients were split into four categories according quartiles of ∆BMI. Kaplan-Meier method and Cox regression proportional hazard analysis were performed to assess the association of BMI on outcomes. A total of 1263 CAPD patients were included, with a mean age of 47.8 ± 15.0 years, a mean BMI of 21.58 ± 3.13 kg/m². During a median follow-up of 25.3 months, obesity was associated with increased risk for cardiovascular diseases (CVD) death (adjusted hazard ratio (AHR) 2.01; 95% CI 1.14, 3.54), but not all-cause mortality. Additionally, patients with more BMI decline (>0.80%) during the first year after CAPD initiation had an elevated risk for both all-cause (AHR: 2.21, 95% CI 1.23–3.95) and CVD mortality (AHR 2.31, 95% CI 1.11, 4.84), which was independent of baseline BMI values.

High mobility group box 1 (HMGB1), a DNA-binding nuclear protein, has been implicated as an endogenous danger signal in the pathogenesis of infection diseases. However, the potential role and source of HMGB1 in the peritoneal dialysis (PD) effluence of patients with peritonitis are unknown. First, to evaluate HMDB1 levels in peritoneal dialysis effluence (PDE), a total of 61 PD patients were enrolled in this study, including 42 patients with peritonitis and 19 without peritonitis. Demographic characteristics, symptoms, physical examination findings and laboratory parameters were recorded. HMGB1 levels in PDE were determined by Western blot and ELISA. The concentrations of TNF-α and IL-6 in PDE were quantified by ELISA. By animal model, inhibition of HMGB1 with glycyrrhizin was performed to determine the effects of HMGB1 in LPS-induced mice peritonitis. In vitro, a human peritoneal mesothelial cell line (HMrSV5) was stimulated with lipopolysaccharide (LPS), HMGB1 extracellular content in the culture media and intracellular distribution in various cellular fractions were analyzed by Western blot or immunofluorescence. The results showed that the levels of HMGB1 in PDE were higher in patients with peritonitis than those in controls, and gradually declined during the period of effective antibiotic treatments. Furthermore, the levels of HMGB1 in PDE were positively correlated with white blood cells (WBCs) count, TNF-α and IL-6 levels. However, pretreatment with glycyrrhizin attenuated LPS-induced acute peritoneal inflammation and dysfunction in mice. In cultured HMrSV5 cells, LPS actively induced HMGB1 nuclear-cytoplasmic translocation and release in a time and dose-dependent fashion. Moreover, cytosolic HMGB1 was located in lysosomes and secreted via a lysosome-mediated secretory pathway following LPS stimulation. Our study demonstrates that elevated HMGB1 levels in PDE during PD-related peritonitis, at least partially, from peritoneal mesothelial cells, which may be involved in the process of PD-related peritonitis and play a critical role in acute peritoneal dysfunction.