Mitochondrial quality control and its emerging role in the pathogenesis of diabetic kidney disease

Most eukaryotic cells have mitochondrial networks that can change in shape, distribution, and size depending on cellular metabolic demands and environments. Mitochondrial quality control is critical for various mitochondrial functions including energy production, redox homeostasis, intracellular calcium handling, cell differentiation, proliferation, and cell death. Quality control mechanisms within mitochondria consist of antioxidant defenses, protein quality control, DNA damage repair systems, mitochondrial fusion and fission, mitophagy, and mitochondrial biogenesis. Defects in mitochondrial quality control and disruption of mitochondrial homeostasis are common characteristics of various kidney cell types under hyperglycemic conditions. Such defects contribute to diabetes-induced pathologies in renal tubular cells, podocytes, endothelial cells, and immune cells. In this review, we focus on the roles of mitochondrial quality control in diabetic kidney disease pathogenesis and discuss current research evidence and future directions.

Effects of online hemodiafiltration on anemia and nutritional status in chronic hemodialysis patients

Background@#Online hemodiafiltration (OL-HDF) offers considerable advantages in clearance of molecules of various sizes. However, evidence of clinical effects of OL-HDF is scarce in Korea. In this study, we investigated changes in laboratory values over more than 12 months after switching to OL-HDF. @*Methods@#Adult patients with end-stage renal disease undergoing hemodialysis (HD) were prospectively enrolled in a K-cohort (CRIS no. KCT0003281) from 6 tertiary hospitals in South Korea. We recruited 435 patients, 339 of whom were on HD at enrollment. One hundred eighty-two patients were followed for more than 24 months. Among them, 44 were switched to OL-HDF for more than 12 months without conversion to HD. We used a paired t test to compare baseline and 24-month follow-up results. @*Results@#The mean age of the subjects was 61.2 ± 12.2 years, and 62.6% were male. The baseline hemoglobin level was not significantly different between HD and OL-HDF group (10.61 ± 1.15 vs. 10.46 ± 1.03 g/dL, P = 0.437). However, the baseline serum protein and albumin levels were significantly lower in the OL-HDF group (6.82 ± 0.49 vs. 6.59 ± 0.48 g/dL, P = 0.006; 3.93 ± 0.28 vs. 3.73 ± 0.29 g/dL, P < 0.001). In patients switched to OL-HDF, levels of hemoglobin and serum albumin significantly increased (10.46 ± 1.03 vs. 11.08 ± 0.82 g/dL, P = 0.001; 3.73 ± 0.29 vs.

Anti-microbial and anti-inflammatory effects of Cheonwangbosim-dan against Helicobacter pylori-induced gastritis

Background@#There are various Helicobacter species colonizing the stomachs of animals. Although Helicobacter species usually cause asymptomatic infection in the hosts, clinical signs can occur due to gastritis associated with Helicobacter in animals. Among them, Helicobacter pylori is strongly associated with chronic gastritis, gastric ulcers, and gastric cancers. As the standard therapies used to treat H. pylori have proven insufficient, alternative options are needed to prevent and eradicate the diseases associated with this bacterium. Cheonwangbosim-dan (CBD), a traditional herbal formula that is popular in East Asia, has been commonly used for arterial or auricular flutter, neurosis, insomnia, and cardiac malfunction-induced disease. @*Objectives@#The present study investigated the antimicrobial effect of CBD on H. pylori-infected human gastric carcinoma AGS cells and model mice. @*Methods@#AGS cells were infected with H. pylori and treated with a variety of concentrations of CBD or antibiotics. Mice were given 3 oral inoculations with H. pylori and then dosed with CBD (100 or 500 mg/kg) for 4 weeks or with standard antibiotics for 1 week. One week after the last treatment, gastric samples were collected and examined by histopathological analysis, real-time quantitative polymerase chain reaction, and immunoblotting. @*Results@#Our results showed that CBD treatment of AGS cells significantly reduced the H. pylori-induced elevations of interleukin-8, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). In the animal model, CBD treatment inhibited the colonization of H. pylori and the levels of malondialdehyde, inflammation, proinflammatory cytokines, iNOS, and COX-2 in gastric tissues. CBD also decreased the phosphorylation levels of p38 mitogen-activated protein kinase family. @*Conclusions@#This study suggests that CBD might be a prospective candidate for treatingH. pylori-induced gastric injury.

Beneficial Effect of Chloroquine and Amodiaquine on Type 1 Diabetic Tubulopathy by Attenuating Mitochondrial Nox4 and Endoplasmic Reticulum Stress

Background@#Oxidative stress induced by chronic hyperglycemia is recognized as a significant mechanistic contributor to the development of diabetic kidney disease (DKD).Nonphagocytic nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) is a major source of reactive oxygen species (ROS) in many cell types and in the kidney tissue of diabetic animals. We designed this study to explore the therapeutic potential of chloroquine (CQ) and amodiaquine (AQ) for inhibiting mitochondrial Nox4 and diabetic tubular injury. @*Methods@#Human renal proximal tubular epithelial cells (hRPTCs) were cultured in highglucose media (30 mM D-glucose), and diabetes was induced with streptozotocin (STZ, 50 mg/kg i.p. for 5 days) in male C57BL/6J mice. CQ and AQ were administered to the mice via intraperitoneal injection for 14 weeks. @*Results@#CQ and AQ inhibited mitochondrial Nox4 and increased mitochondrial mass in hRPTCs under high-glucose conditions. Reduced mitochondrial ROS production after treatment with the drugs resulted in decreased endoplasmic reticulum (ER) stress, suppressed inflammatory protein expression and reduced cell apoptosis in hRPTCs under high-glucose conditions. Notably, CQ and AQ treatment diminished Nox4 activation and ER stress in the kidneys of STZ-induced diabetic mice. In addition, we observed attenuated inflammatory protein expression and albuminuria in STZ-induced diabetic mice after CQ and AQ treatment. @*Conclusion@#We substantiated the protective actions of CQ and AQ in diabetic tubulopathy associated with reduced mitochondrial Nox4 activation and ER stress alleviation. Further studies exploring the roles of mitochondrial Nox4 in the pathogenesis of DKD could suggest new therapeutic targets for patients with DKD.

Erratum: Association of serum uric acid level with coronary artery stenosis severity in Korean end-stage renal disease patients Volume 36, Issue 3, September 2017, Pages 282–289

Hye Yun Jeong and Hye Jeong Cho contributed equally to the above study as co-first authors.

Association of serum uric acid level with coronary artery stenosis severity in Korean end-stage renal disease patients

BACKGROUND: Hyperuricemia is common in end-stage renal disease (ESRD) patients, and many previous studies have reported the associations between hyperuricemia and adverse cardiovascular outcomes, which are the major cause of death in such patients. We investigated the relationship between serum uric acid level and the severity of coronary stenosis in ESRD patients on maintenance hemodialysis (MHD). METHODS: Among 721 patients who started MHD treatment, 102 underwent coronary angiographic tests complaining of chest discomfort that was new at initiation of MHD. We collected data on uric acid level and coronary artery luminal diameter, defining luminal diameter narrowing of more than 50% in any major coronary artery as critical-stenosis. RESULTS: We detected critical coronary artery stenosis in 52 (57.8%) patients. The mean uric acid level was 6.6 ± 2.2 mg/dL, and that was significantly higher in the critical-stenosis group (4.9 ± 1.4 mg/dL vs. 7.8 ± 2.0 mg/dL, P < 0.001). The only independent predictor of critical-stenosis in multivariate analysis was serum uric acid level (P < 0.001). CONCLUSION: High serum uric acid was associated with severe coronary artery stenosis in Korean ESRD patients. Hyperuricemia is a readily modifiable factor, and appropriately preventing it could provide significant benefits in ESRD patients.

Vitamin D and Hypertension

Vitamin D has the pleiotropic effects in multiple organ systems, and vitamin D deficiency was suggested to be associated with high blood pressure according to previous reports. Several interventional studies have examined the effect of vitamin D supplementation on high blood pressure patients, but the results have been inconsistent. In this article, we examined the literature that have proposed a mechanism involving vitamin D in the regulation of blood pressure and review previous observational and interventional studies that have shown the relationship between vitamin D and hypertension among various populations.

Administration of a High-Dose Erythropoietin-Stimulating Agent in Hemodialysis Patients is Associated with Late Arteriovenous Fistula Failure

PURPOSE: Investigating the risk of vascular access failure is critical for maintenance hemodialysis (MHD) patients. Erythropoietin stimulating agents (ESA) typically used for anemia of chronic kidney disease (CKD) may also stimulate neointimal hyperplasia, which is the most important factor in late arteriovenous fistula (AVF) failure. The aim of this study was to investigate whether ESA treatment is associated with late AVF failure. MATERIALS AND METHODS: The late AVF failure group comprised 51 patients who underwent percutaneous intervention or surgery for fistula revision after successful use for at least three months. There were 51 controls whose AVF had been patent for at least 24 months. RESULTS: The mean time from the first cannulation to late loss of AVF patency was 8.4±4.2 months. The average weekly dose of ESA was significantly higher in patients with AVF failure (4782.2±2360.5 IU/mL/wk vs. 7161.8±2775.2 IU/mL/wk, p<0.001). The only independent predictor of late AVF failure in multivariate analysis was high average ESA dose (odds ratio=1.015, 95% confidence interval=1.002–1.028, p=0.022). CONCLUSION: Patients with late AVF patency loss exhibit an association with a higher dose of ESA, although causality is unproven. Further study to elucidate potential mechanisms is warranted.

25-hydroxyvitamin D Levels was not Associated with Blood Pressure and Arterial Stiffness in Patients with Chronic Kidney Disease

BACKGROUND: We investigated the effect of vitamin D deficiency on cardiovascular risk profiles in an Asian population with chronic kidney disease (CKD). METHODS: A total of 210 participants (62 non-dialysis CKD patients and 148 hemodialysis [HD] patients) were enrolled between December 2009 and February 2010. Vitamin D deficiency was determined using the serum 25-hydroxyvitamin D [25(OH)D] concentration. Blood pressure and arterial stiffness were measured. Subjects were divided into groups according to 25(OH)D concentration based on a cut-off of 13.5 ng/mL in non-dialysis CKD patients and 11.3 ng/mL in HD patients. RESULTS: The mean age was 61.7±12.3 years in non-dialysis CKD patients and 57.0±12.7 years in HD patients. In the non-dialysis CKD group, mean estimated glomerular filtration rate (eGFR) was 29.7±15.4 mL/min/1.73 m2. Mean 25(OH)D concentration was 13.6±7.8 ng/mL in non-dialysis CKD patients and 11.3±6.7 ng/mL in HD patients. More than half of the subjects had vitamin D deficiency (67.6% in non-dialysis CKD patients and 80.4% in HD patients). There were no significant differences in systolic blood pressure, pulse pressure, and arterial stiffness between higher and lower 25(OH)D groups among non-dialysis CKD and HD patients. Multivariate analysis revealed that female sex (odds ratio [OR]: 5.890; 95% confidence interval [CI]: 2.597–13.387; p<0.001) and presence of diabetes (OR: 2.434; 95% CI: 1.103–5.370; p=0.028) were significantly associated with lower serum 25(OH)D levels in HD patients. CONCLUSION: The prevalence of vitamin D deficiency was high in both nondialysis CKD patients and HD patients. Serum 25(OH)D concentration was not a significant factor associated with blood pressure and arterial stiffness among non-dialysis CKD and HD patients.

Serum 25-hydroxyvitamin D as a predictor of hospitalization-free survival in predialysis and dialysis patients with chronic kidney disease: a single-center prospective observational analysis

BACKGROUND: Vitamin D has pleiotropic effects important for the proper functioning of multiple organ systems. We investigated whether serum 25-hydroxyvitamin D [25(OH)D] levels influenced hospitalization-free survival in patients with chronic kidney disease (CKD). METHODS: In this prospective study, serum levels of 25(OH)D were measured in 210 patients with CKD in the winter of 2009. Data regarding hospitalizations were collected over the subsequent 3 years. RESULTS: Vitamin D deficiency, as defined by a serum 25(OH)D level below 15 ng/mL, was observed in 76.7% of the patients. The mean 25(OH)D serum level was 13.6 ± 7.8 ng/mL in predialysis patients (n = 62) and 11.3 ± 6.7 ng/mL in dialysis patients (n = 148). During the follow-up, 107 patients (28 predialysis and 79 dialysis) were hospitalized because of infectious (33.6%) or cardiovascular diseases (23.4%). Predialysis and dialysis groups were divided into 2 subgroups based on the median 25(OH)D serum level. Kaplan-Meier analysis revealed that the risk of hospitalization was significantly lower in both predialysis and dialysis patients with above-median serum 25(OH)D levels (log-rank test; P = 0.043 and 0.002, respectively). Multivariate Cox proportional hazards models also demonstrated that the risk of hospitalization was significantly lower for patients with higher serum 25(OH)D levels in both the predialysis (hazard ratio, 0.963; 95% confidence interval, 0.93-0.99) and dialysis groups (hazard ratio, 0.955; 95% confidence interval, 0.91-0.99). CONCLUSION: A lower serum 25(OH)D level predicted poorer hospitalization-free survival in both predialysis and dialysis CKD patients.

Non-operative Treatment of Gastric Ulcer Perforation with Contrast Leakage in an Elderly Patient / 대한내과학회지

Peptic ulcer remains an important public health concern due to an aging society and the increasing use of non steroidal anti-inflammatory drugs (NSAIDs). Perforated peptic ulcer is a major life-threatening complication of peptic ulcer. While the preferred treatment is surgery, conservative treatment does not result in significantly different outcomes in young, hemodynamically stable patients. However, conservative treatment of perforated peptic ulcer is associated with high failure rates in elderly patients. We report a case of an 87-year-old patient with a perforated peptic ulcer with contrast agent leakage. The patient was treated conservatively without complications; the treatment included non per os (NPO), insertion of a Levin tube, intravenous antibiotics, and a proton pump inhibitor.

Metastatic Spermatic Cord Tumor From Colorectal Cancer

Metastatic tumors of the spermatic cord are extremely rare, and the prognosis for patients is typically poor. In the majority of cases, the primary tumor occurs in the gastrointestinal tract. We report a case of a 62-year-old man with a metastatic spermatic cord tumor. The patient complained of groin discomfort with a tender mass in the right inguinal area. An excisional biopsy was performed, and the pathologic finding was a metastatic mucinous adenocarcinoma. We performed a systemic evaluation including colonoscopy, abdominal computed tomography, and total-body positron emission tomography, and the primary tumor was confirmed to involve the total colon, including the cecum, sigmoid colon, and rectum. The pathologic finding for rectum revealed a mucinous adenocarcinoma compatible with a metastatic spermatic cord tumor.

Spinning-induced Rhabdomyolysis: Eleven Case Reports and Review of the Literature

Non-traumatic exertional rhabdomyolysis (exRML) occurs in individuals with normal muscles when the energy supplied to the muscle is insufficient. Here, we report 11 cases of spinning-induced rhabdomyolysis and review related literature. Spinning is a kind of indoor bicycle sport. The 11 patients who were diagnosed with exRML and admitted to CHA Bundang Medical Center were female and their ages ranged from 15 to 46 years. Two to three days prior to the presentation, the patients had attended a spinning class for the first time. All the patients had been otherwise healthy without any known medical illnesses. They were successfully treated without any complications, except mild non-symptomatic hypocalcemia. However, in the literature, severe complications such as compartment syndrome or acute kidney injury had been reported in relation to exRML including spinning-induced rhabdomyolysis. This spinning exercise needs prior guidelines and specific warnings to prevent exertional rhabdomyolysis.

A Case of Pulmonary Artery Sarcoma Presented as Cavitary Pulmonary Lesions / 결핵및호흡기질환

Pulmonary artery sarcoma (PAS) is a rare, poorly differentiated malignancy arising from the intimal layer of the pulmonary artery. Contrast-enhanced chest computed tomography (CT) is a good diagnostic modality that shows a low-attenuation filling defect of the pulmonary artery in PAS patients. An 18-year-old man was referred to our hospital for the evaluation and management of cavitary pulmonary lesions that did not respond to treatment. A contrast-enhanced CT of the chest was performed, which showed a filling defect within the right interlobar pulmonary artery. The patient underwent a curative right pneumonectomy after confirmation of PAS. Although lung parenchymal lesions of PAS are generally nonspecific, it can be presented as cavities indicate pulmonary infarcts. Clinicians must consider the possibility of PAS as well as pulmonary thromboembolism in patients with pulmonary infarcts. So, we report the case with PAS that was diagnosed during the evaluation of cavitary pulmonary lesions and reviewed the literatures.

Mesenchymal stem cells reciprocally regulate the M1/M2 balance in mouse bone marrow-derived macrophages

Mesenchymal stem cells (MSCs) have been widely studied for their applications in stem cell-based regeneration. During myocardial infarction (MI), infiltrated macrophages have pivotal roles in inflammation, angiogenesis and cardiac remodeling. We hypothesized that MSCs may modulate the immunologic environment to accelerate regeneration. This study was designed to assess the functional relationship between the macrophage phenotype and MSCs. MSCs isolated from bone marrow and bone marrow-derived macrophages (BMDMs) underwent differentiation induced by macrophage colony-stimulating factor. To determine the macrophage phenotype, classical M1 markers and alternative M2 markers were analyzed with or without co-culturing with MSCs in a transwell system. For animal studies, MI was induced by the ligation of the rat coronary artery. MSCs were injected within the infarct myocardium, and we analyzed the phenotype of the infiltrated macrophages by immunostaining. In the MSC-injected myocardium, the macrophages adjacent to the MSCs showed strong expression of arginase-1 (Arg1), an M2 marker. In BMDMs co-cultured with MSCs, the M1 markers such as interleukin-6 (IL-6), IL-1beta, monocyte chemoattractant protein-1 and inducible nitric oxide synthase (iNOS) were significantly reduced. In contrast, the M2 markers such as IL-10, IL-4, CD206 and Arg1 were markedly increased by co-culturing with MSCs. Specifically, the ratio of iNOS to Arg1 in BMDMs was notably downregulated by co-culturing with MSCs. These results suggest that the preferential shift of the macrophage phenotype from M1 to M2 may be related to the immune-modulating characteristics of MSCs that contribute to cardiac repair.

Vascular Calcification Scores are Associated with Arterial Stiffness, Inflammation, and Nutrition in Hemodialysis Patients / 대한내과학회지

BACKGROUND/AIMS: The vascular calcification (VC) score on a plain X-ray is associated with cardiovascular disease and mortality in hemodialysis (HD) patients. This study examined the correlations among the VC scores for the hands and pelvis X-rays, arterial stiffness, inflammation, and nutrition in HD patients. METHODS: VC was evaluated using plain x-rays of the hands and pelvis. Patients were categorized into the VC (+) (VC score > or = 3) or VC (-) (VC score < 3) groups. We measured the pulse wave velocity (PWV), ankle brachial index (ABI), and augmentation index (AI). RESULTS: The mean age of the patients was 55.6 +/- 13.2 years. The prevalence of diabetes mellitus (DM) was significantly higher in the VC (+) group than in the VC (-) group (87.5 vs. 34.2%, p < 0.05). The serum PTH (98.4 +/- 141.9 vs. 183.6 +/- 231.3 pg/mL, p < 0.05) and albumin (3.7 +/- 0.5 vs. 3.9 +/- 0.3 g/dL, p < 0.05) levels were significantly lower and PWV was significantly (p < 0.05) higher in the VC (+) group. In multiple linear regression analysis, only the presence of diabetes mellitus was significantly related to the VC score. CONCLUSIONS: The VC score was associated with the serum PTH and albumin, as well as with vascular stiffness. C-reactive protein did not show any significant association with the VC score.

Splenic Infarction as the Initial Manifestation of Antiphospholipid Syndrome in a Systemic Lupus Erythematosus Patient / 대한내과학회지

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease. In patients with SLE, the prevalence of antiphospholipid antibodies is considerably higher, and is largely responsible for thrombosis. Splenic infarction is a rare complication of arterial thrombosis in patients with SLE. It is important to consider splenic infarction in a patient with SLE complaining of left upper quadrant (LUQ) pain because of the possibility of severe infarction-related complications, such as subcapsular hemorrhage and splenic rupture. We report a case of solitary splenic infarction in a patient with SLE. The only symptom was LUQ pain of 3-day duration. Lupus anticoagulant activity was positive and abdominal-pelvic computed tomography (CT) was consistent with splenic infarction. She did not show any other evidence of thrombotic events. The patient was diagnosed with antiphospholipid syndrome that presented as a splenic infarction in a SLE patient.

A Case of Invasive Pulmonary Aspergillosis with Direct Invasion of the Mediastinum and the Left Atrium in an Immunocompetent Patient / 결핵및호흡기질환

We report a case of invasive pulmonary aspergillosis invading the mediastinum and the left atrium. A 70-year-old woman was hospitalized for dyspnea. She had been well controlled for her diabetes mellitus and hypertension. The chest X-ray disclosed mediastinal widening, and the computed tomography scan of the chest showed that there was a large mediastinal mass and this lesion extended into the left atrium and right bronchus. The cardiac echocardiography showed that a huge mediastinal cystic mass compressed in the right atrium and a hyperechoic polypoid lesion in the left. The pathology from the bronchoscopic biopsy observed abundant fungal hyphae which was stained with periodic acid-Schiff and Gomori's methenamine silver. Despite the treatment with antifungal agents, she died from cardiac tamponade after three months. Invasive pulmonary aspergillosis, which involves the mediastinum and the heart, is very rare in immunocompetent patients.

A Case of Invasive Pulmonary Aspergillosis with Direct Invasion of the Mediastinum and the Left Atrium in an Immunocompetent Patient / 결핵및호흡기질환

We report a case of invasive pulmonary aspergillosis invading the mediastinum and the left atrium. A 70-year-old woman was hospitalized for dyspnea. She had been well controlled for her diabetes mellitus and hypertension. The chest X-ray disclosed mediastinal widening, and the computed tomography scan of the chest showed that there was a large mediastinal mass and this lesion extended into the left atrium and right bronchus. The cardiac echocardiography showed that a huge mediastinal cystic mass compressed in the right atrium and a hyperechoic polypoid lesion in the left. The pathology from the bronchoscopic biopsy observed abundant fungal hyphae which was stained with periodic acid-Schiff and Gomori's methenamine silver. Despite the treatment with antifungal agents, she died from cardiac tamponade after three months. Invasive pulmonary aspergillosis, which involves the mediastinum and the heart, is very rare in immunocompetent patients.

Isolation and Characterization of Chicken NPAS3

Here we describe characterization of chicken neuronal Per-Arnt-Sim domain 3 (NPAS3) gene during embryogenesis including examinations of expression pattern and function of the gene. RTPCR assay showed that the primary tissue of expression for this gene is the central nervous system (CNS) while RNA in situ hybridization assay confirmed that NPAS3 was expressed in the ventricular zone of developing neural tube as early as Hamburger-Hamilton (HH) stage 20. Ectopic over-expression of the gene in ovo in the developing chicken neural tube by electroporation had little effect on stem cell population, overall neurogenesis, and motor neuron differentiation. We discuss the implications of our observation.