Deletion of NADPH oxidase 2 attenuates cisplatin-induced acute kidney injury through reducing ROS-induced proximal tubular cell injury and inflammation.

Backgrounds: Cisplatin is a commonly used chemotherapeutic agent in cancer treatment. However, its high nephrotoxicity limits its therapeutic application and efficacy. Cisplatin induces nephrotoxicity mainly through oxidative stress and inflammation. Reactive oxygen species (ROS) in the kidneys mainly arise from nicotinamide adenine dinucleotide phosphate (NADPH) oxidases 2 (NOX2), which is highly upregulated during ischemia-reperfusion injury and diabetes mellitus. However, its role in cisplatin-induced acute kidney injury (AKI) remains unknown. Methods: A 8-10-week-old NOX2 gene-knockout and wild-type mice were injected with 25 mg/kg cisplatin intraperitoneally for experiments. Results: We investigated the role of NOX2 in cisplatin-induced AKI and found that NOX2-mediated ROS production is a key inflammatory mediator of proximal tubular cell injury in cisplatin-induced AKI. NOX2 gene-knockout alleviated cisplatin-induced renal function decline, tubular injury score, kidney injury molecule-1(Kim-1) expression, and interleukin (IL)-6 and IL-1α levels with a reduction of ROS production. Moreover, in cisplatin-induced AKI, intercellular adhesion molecule 1 (ICAM-1) and the chemoattractant CXC ligand 1 (CXCL1) were highly expressed in association with neutrophil infiltration, which were all attenuated by deletion of NOX2. Conclusion: These data indicate that NOX2 aggravates cisplatin nephrotoxicity by promoting ROS-mediated tissue injury and neutrophil infiltration. Thus, appropriate targeting of NOX2/ROS pathway may minimize the risk of cisplatin-induced kidney injury in patients receiving cancer therapy.

Increasing Staphylococcus Species Resistance in Peritoneal Dialysis-Related Peritonitis over a 10-Year Period in a Single Taiwanese Center.

BACKGROUND: Peritonitis is a major complication of peritoneal dialysis (PD). Staphylococcus species are gram-positive bacteria that are most commonly associated with peritoneal peritonitis. The increasing antimicrobial resistance rate is a severe burden when considering the initial choice of antibiotics. This investigation examined the trends of staphylococcal infection as well as the resistance rate and clinical outcomes from 2006 to 2015 in southern Taiwan. METHODS: We retrospectively investigated all PD-related peritonitis episodes in southern Taiwan between January 2006 and December 2015 and evaluated the clinical characteristics of peritonitis, microbiological prevalence and resistance of Staphylococcus species, and outcomes in patients. RESULTS: Among 244 episodes of peritonitis, Staphylococcus species accounted for approximately 65% of the gram-positive bacteria that caused the infection. The methicillin resistance rate among Staphylococcus species substantially increased to 64% by 2015 in both Staphylococcus aureus and coagulase-negative staphylococci in southern Taiwan. Notably, patients with methicillin-resistant staphylococcal infection exhibited a significantly higher hospitalization rate than those with methicillin-sensitive staphylococcal infection. However, the catheter removal rate and transfer to hemodialysis exhibited no differences between the 2 groups. CONCLUSION: Peritonitis is the most serious complication in patients on PD, and microbiological trends have changed over the past 10 years at a single center in southern Taiwan. The number of methicillin-resistant Staphylococcus species has substantially increased. Empirical initial antibiotic therapy should be adapted on the basis of the growing microbiological resistance.

Vitamin D can ameliorate chlorhexidine gluconate-induced peritoneal fibrosis and functional deterioration through the inhibition of epithelial-to-mesenchymal transition of mesothelial cells.

BACKGROUND: Peritoneal dialysis (PD) can induce fibrosis and functional alterations in PD patients' peritoneal membranes, due to long-term unphysiological dialysate exposure, partially occurring via triggering of epithelial-to-mesenchymal transition (EMT) in peritoneal mesothelial cells (MCs). Vitamin D can ameliorate these negative effects; however, the mechanism remains unexplored. Therefore, we investigated its possible links to MCs EMT inhibition. METHODS: Peritoneal fibrosis was established in Sprague-Dawley rats by chlorhexidine gluconate (CG) intraperitoneal injection for 21 days, with and without 1α,25(OH)2D3 treatment. Morphological and functional evaluation and western blot analysis of EMT marker were performed upon peritoneum tissue. In vitro study was also performed in a primary human peritoneal MC culture system; MCs were incubated with transforming growth factor-ß1 (TGF-ß1) in the absence or presence of 1α,25(OH)2D3. EMT marker expression, migration activities, and cytoskeleton redistribution of MCs were determined. RESULTS: 1α,25(OH)2D3 ameliorated CG-induced morphological and functional deterioration in animal model, along with CG-induced upregulation of α-SMA and downregulation of E-cadherin expression. Meanwhile, 1α,25(OH)2D3 also ameliorated TGF-ß1-induced decrease in E-cadherin expression, increase in Snai1 and α-SMA expression, intracellular F-actin redistribution, and migration activity in vitro. CONCLUSION: 1α,25(OH)2D3 can ameliorate CG-induced peritoneal fibrosis and attenuate functional deterioration through inhibiting MC EMT.

Different Risk of Common Gastrointestinal Disease Between Groups Undergoing Hemodialysis or Peritoneal Dialysis or With Non-End Stage Renal Disease: A Nationwide Population-Based Cohort Study.

Peritoneal dialysis (PD) is one type of renal replacement therapy, but potential peritoneal damage and gastrointestinal (GI) tract adverse effects during long-term exposure to bio-incompatible dialysate remain a concern. Although GI disease frequently occurs in dialysis patients, whether the risk of GI diseases differs among PD and hemodialysis (HD) or non-uremic groups is still uncertain.In this retrospective cohort study, data were obtained from the National Health Insurance Research Database, which includes almost all dialysis patients in Taiwan. Between 2000 and 2009, a total of 1791 PD and 8955 HD incident patients were enrolled and matched for age and sex or for propensity score. In addition, a comparison cohort of 8955 non-uremic patients was also selected. Individuals were monitored for the occurrence of common GI diseases until 2010, and data were analyzed using several different models.Generally speaking, the results showed that the risk of gastroesophageal reflux, intestinal obstruction or adhesions, and abdominal hernia was significantly higher in the PD group, whereas the risk of peptic ulcer disease and lower GI diverticula and bleeding was significantly greater in the HD group. Meanwhile, the risk of mesenteric ischemia, liver cirrhosis, and acute pancreatitis was higher in dialysis patients, but was not significantly different between the PD and HD groups; moreover, the risk of appendicitis in the PD group appeared to be lower than that in the HD group.In conclusion, dialysis patients have a higher risk of most common GI diseases, and PD and HD modalities are associated with different GI diseases.

Hemoglobin variability does not predict mortality in peritoneal dialysis patients.

BACKGROUND: Hemoglobin variability in hemodialysis patients treated with erythropoiesis-stimulating agents has been used to evaluate mortality and comorbidity. Different outcomes have been reported in American and European hemodialysis patients. There are, however, few studies of the effects of hemoglobin variability in peritoneal dialysis patients. METHODS: We investigated hemoglobin variability in 363 peritoneal dialysis patients over 2 years to evaluate mortality and the association with comorbidity, peritonitis, and hospitalization. The hemoglobin of all patients selected for the study had been monitored for at least 6 months (April 2008 to September 2008). We assessed hemoglobin variability as fluctuations from the target hemoglobin level (11-12.5 g/dL). We defined the following 6 patient groups on the basis of hemoglobin patterns: consistently low (< 11 g/dL), consistently target range (11-12.5 g/dL), consistently high (> 12.5 g/dL), low-amplitude fluctuation with low hemoglobin levels, low-amplitude fluctuation with high hemoglobin levels, and high amplitude fluctuation. RESULTS: Only 2% of patients maintained a stable hemoglobin level within the target range and 46.8% of patients exhibited consistently low hemoglobin levels. After 2 years of observation, there was no difference in mortality as assessed by Kaplan-Meier analysis. There were also no differences in peritonitis and hospitalization between the 6 groups. However, the length of hospital stay was longer in the high amplitude fluctuation group (p = 0.008). CONCLUSION: Hemoglobin variability does not predict mortality in peritoneal dialysis patients.