Contrast-induced acute kidney injury (CIAKI) is a leading cause of acute kidney injury following radiographic procedures. Intrarenal oxidative stress plays a critical role in CIAKI. Nicotinamide adenine dinucleotide 3-phosphate (NADPH) oxidases (Noxs) are important sources of reactive oxygen species (ROS). Among the various types of Noxs, Nox4 is expressed predominantly in the kidney in rodents. Here, we evaluated the role of Nox4 and benefit of Nox4 inhibition on CIAKI using in vivo and in vitro models. HK-2 cells were treated with iohexol, with or without Nox4 knockdown, or the most specific Nox1/4 inhibitor (GKT137831). Effects of Nox4 inhibition on CIAKI mice were examined. Expression of Nox4 in HK-2 cells was significantly increased following iohexol exposure. Silencing of Nox4 rescued the production of ROS, downregulated pro-inflammatory markers (particularly phospho-p38) implicated in CIAKI, and reduced Bax and caspase 3/7 activity, which resulted in increased cellular survival in iohexol-treated HK-2 cells. Pretreatment with GKT137831 replicated these effects by decreasing levels of phospho-p38. In a CIAKI mouse model, even though the improvement of plasma blood urea nitrogen was unclear, pretreatment with GKT137831 resulted in preserved structure, reduced expression of 8-hydroxy-2’-deoxyguanosine (8OHdG) and kidney injury molecule-1 (KIM-1), and reduced number of TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling)-positive cells. These results suggest Nox4 as a key source of reactive oxygen species responsible for CIAKI and provide a novel potential option for prevention of CIAKI.

Collectively, these findings identify Nox4 as a key source of reactive oxygen species responsible for kidney injury in colistin-induced nephrotoxicity and highlight a novel potential way to treat drug-related nephrotoxicity.

Because of increases in the elderly population and diabetic patients, the proportion of elderly among dialysis patients has rapidly increased during the last decades. The mortality and morbidity of these elderly dialysis patients are obviously much higher than those of young patients, but large analytic studies about elderly dialysis patients' characteristics have rarely been published. The registry committee of the Korean Society of Nephrology has collected data about dialysis therapy in Korea through an Internet online registry program and analyzed the characteristics. A survey on elderly dialysis patients showed that more than 50% of elderly (65 years and older) patients had diabetic nephropathy as the cause of end-stage renal disease, and approximately 21% of elderly dialysis patients had hypertensive nephrosclerosis. The proportion of elderly hemodialysis (HD) patients with native vessel arteriovenous fistula as vascular access for HD was lower than that of young (under 65 years) HD patients (69% vs. 80%). Although the vascular access was poor and small surface area dialyzers were used for the elderly HD patients, the dialysis adequacy data of elderly patients were better than those of young patients. The laboratory data of elderly dialysis patients were not very different from those of young patients, but poor nutrition factors were observed in the elderly dialysis patients. Although small surface area dialyzers were used for elderly HD patients, the urea reduction ratio and Kt/V were higher in elderly HD patients than in young patients.

Hypoxia is an important cause of acute kidney injury (AKI) in various conditions because kidneys are one of the most susceptible organs to hypoxia. In this study, we investigated whether nicotinamide adenine dinucleotide 3-phosphate (NADPH) oxidase 4 (Nox4) plays a role in hypoxia induced AKI in a cellular and animal model. Expression of Nox4 in cultured human renal proximal tubular epithelial cells (HK-2) was significantly increased by hypoxic stimulation. TGF-β1 was endogenously secreted by hypoxic HK-2 cells. SB4315432 (a TGF-β1 receptor I inhibitor) significantly inhibited Nox4 expression in HK-2 cells through the Smad-dependent cell signaling pathway. Silencing of Nox4 using Nox4 siRNA and pharmacologic inhibition with GKT137831 (a specific Nox1/4 inhibitor) reduced the production of ROS and attenuated the apoptotic pathway. In addition, knockdown of Nox4 increased cell survival in hypoxic HK-2 cells and pretreatment with GKT137831 reproduce these results. This study demonstrates that hypoxia induces HK-2 cell apoptosis through a signaling pathway involving TGF-β1 via Smad pathway induction of Nox4-dependent ROS generation. In an ischemia/reperfusion rat model, pretreatment of GKT137831 attenuated ischemia/reperfusion induced acute kidney injury as indicated by preserved kidney function, attenuated renal structural damage and reduced apoptotic cells. Therapies targeting Nox4 may be effective against hypoxia-induced AKI.

Background/Aims: The aim of this study was to evaluate the peritonitis-causing bacteria detected in peritoneal fluid using a blood culture bottle in patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Methods: One-hundred and eleven dialysates from 43 patients suspected of peritonitis related to CAPD were retrospectively evaluated between May 2000 and February 2008. In all cases, 5 to 10 mL of dialysate was inoculated into a pair of BacT/Alert blood culture bottles, and 50 mL of centrifuged dialysate was simultaneously inoculated into a solid culture media for conventional culture. The results were compared to those of the conventional culture method. Isolated microorganisms were compared between the two methods. Results: The blood culture method was positive in 78.6% (88 / 112) of dialysate specimens and the conventional culture method in 50% (56 / 112, p < 0.001). Conclusions:The blood culture method using the BacT/Alert system is useful for culturing dialysates and improves the positive culture rate in patients with suspected peritonitis compared to the conventional culture method. (Korean J Intern Med 2010;25:82-85)

Background: Various studies have indicated that malnutrition and chronic inflammation are strong predictors of morbidity and mortality in patients with chronic kidney disease (CKD). The purpose of this study was to investigate the relationship between pulmonary function, malnutrition and chronic inflammation in patients with CKD. Methods: One hundred and six consenting patients with CKD were enrolled in the study between 2005 and 2007. Pulmonary function was assessed by forced vital capacity (FVC), forced expiratory volume in the first second (FEV₁) and peak expiratory flow (PEF), expressed as the normal percentage of predicted values (%FEV₁, %FVC and %PEF, respectively). Nutritional status was evaluated by skeletal muscle index (SMI), subjective global nutritional assessment (SGA), lean body mass, body mass index and serum albumin. Inflammation was assessed by the serum measurement of high-sensitive C reactive protein (hsCRP) levels. Results: Malnutrition (defined as SMI ≥1) and inflammation (defined as hsCRP >2 mg/l) in ESRD patients had significant negative associations with percentage predicted values for pulmonary function tests except %PEF (SMI: %FEV₁, p = 0.009, %FVC, p = 0.001; hsCRP: %FEV₁, p = 0.025, %FVC, p = 0.022). Multivariate Cox analysis showed that the ejection fraction in echocardiography and SGA were associated with poor survival, but there was no association for %FEV₁. Conclusions: Impaired pulmonary function was associated with malnutrition and inflammation in these dialysis patients. We were not able to determine a significant relationship between pulmonary function and mortality.

Oxidative stress is one of the principal causes of hypoxia-induced kidney injury. The ceria nanoparticle (CNP) is known to exhibit free radical scavenger and catalytic activities. When zirconia is attached to CNPs (CZNPs), the ceria atom tends to remain in a Ce3+ form and its efficacy as a free radical scavenger thus increases. We determined the effectiveness of CNP and CZNP antioxidant activities against hypoxia-induced acute kidney injury (AKI) and observed that these nanoparticles suppress the apoptosis of hypoxic HK-2 cells by restoring autophagy flux and alleviating mitochondrial damage. In vivo experiments revealed that CZNPs effectively attenuate hypoxia-induced AKI by preserving renal structures and glomerulus function. These nanoparticles can successfully diffuse into HK-2 cells and effectively counteract reactive oxygen species (ROS) to block hypoxia-induced AKI. This suggests that these particles represent a novel approach to controlling this condition.

Background Fabry disease (FD) is a lysosome storage disease (LSD) characterized by significantly reduced intracellular autophagy function. This contributes to the progression of intracellular pathologic signaling and can lead to organ injury. Phospholipid–polyethyleneglycol-capped Ceria-Zirconia antioxidant nanoparticles (PEG-CZNPs) have been reported to enhance autophagy flux. We analyzed whether they suppress globotriaosylceramide (Gb3) accumulation by enhancing autophagy flux and thereby attenuate kidney injury in both cellular and animal models of FD. Results Gb3 was significantly increased in cultured human renal proximal tubular epithelial cells (HK-2) and human podocytes following the siRNA silencing of α galactosidase A (α-GLA). PEG-CZNPs effectively reduced the intracellular accumulation of Gb3 in both cell models of FD and improved both intracellular inflammation and apoptosis in the HK-2 cell model of FD. Moreover these particles attenuated pro fibrotic cytokines in the human podocyte model of FD. This effect was revealed through an improvement of the intracellular autophagy flux function and a reduction in reactive oxygen species (ROS). An FD animal model was generated in which 4-week-old male B6;129-Glatm1Kul/J mice were treated for 8 weeks with 10 mg/kg of PEG-CZNPs (twice weekly via intraperitoneal injection). Gb3 levels were reduced in the kidney tissues of these animals, and their podocyte characteristics and autophagy flux functions were preserved. Conclusions PEG-CZNPs alleviate FD associated kidney injury by enhancing autophagy function and thus provide a foundation for the development of new drugs to treat of storage disease. Graphical Abstract