Hye Yun Jeong

PGC1α Activators Mitigate Diabetic Tubulopathy by Improving Mitochondrial Dynamics and Quality Control

Purpose. In this study, we investigated the effect of PGC1α activators on mitochondrial fusion, fission, and autophagic quality control in renal tubular cells in a diabetic environment in vivo and in vitro. We also examined whether the upregulation of PGC1α attenuates diabetic tubulopathy by normalizing mitochondrial homeostasis. Methods. HKC8 cells were subjected to high-glucose conditions (30 mM D-glucose). Diabetes was induced with streptozotocin (STZ, 50 mg/kg i.p. for 5 days) in male C57/BL6J mice. AICAR or metformin was used as a PGC1α activator. Results. Treatment with the PGC1α activators AICAR and metformin improved functional mitochondrial mass in HKC8 cells in high-glucose conditions. Moreover, in renal proximal tubular cells, increased PGC1α activity correlated with the reversal of changes in Drp1, Mfn1, and LC3-II protein expression in a high-glucose environment. Normalized mitochondrial life cycles resulted in low ROS production and reduced apoptosis. AICAR and metformin treatment effectively mitigated albuminuria and renal histopathology and decreased the expression of TGFβ1 and αSMA in the kidneys of diabetic mice. Conclusions. Our results demonstrate that increases in PGC1α activity improve diabetic tubulopathy by modulating mitochondrial dynamics and autophagy.

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.

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.

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.

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.

Chloroquine and amodiaquine enhance AMPK phosphorylation and improve mitochondrial fragmentation in diabetic tubulopathy

We investigated the effects of chloroquine (CQ) and amodiaquine (AQ) on AMPK phosphorylation in renal tubular cells in a diabetic environment in vivo and in vitro. We also examined whether CQ- or AQ-mediated AMPK activity restoration attenuated diabetic tubulopathy by normalizing mitochondrial fragmentation. Human renal proximal epithelial cells (HKC8) were incubated in high-glucose conditions. Diabetes was induced with streptozotocin in male C57/BL6J mice. Treatment with CQ or AQ abolished high-glucose-induced phospho-AMPK and phosph-PGC1α down-regulation in HKC8 cells. Improvements in functional mitochondrial mass and balanced fusion/fission protein expression were observed in HKC8 cells after treatment with CQ or AQ in high-glucose conditions. Moreover, decreased mitochondrial ROS production and reduced apoptotic and fibrotic protein expression were noted in HKC8 cells after treatment with CQ or AQ, even in high-glucose conditions. CQ and AQ treatment effectively mitigated albuminuria and renal histopathologic changes and increased AMPK activity in the kidneys of diabetic mice. Electron microscopy analysis showed that mitochondrial fragmentation was decreased, and 8-OHdG content was low in the renal tubular cells of the CQ and AQ treatment groups compared with those of the diabetic control group. Our results suggest that CQ and AQ may be useful treatments for patients with diabetic kidney disease.

Beneficial effect of statins in patients receiving chronic hemodialysis following percutaneous coronary intervention: A nationwide retrospective cohort study

The cardiovascular diseases are the leading cause of mortality in end-stage renal disease (ESRD) patients. However, roles of statins are still controversial in dialysis-dependent ESRD patients regardless of having proven coronary artery occlusive disease. The aim of this study was to examine the benefit of statin following percutaneous coronary intervention (PCI) in ESRD patients who have proven coronary artery occlusive disease. This study was based on the National Health Insurance Service-National Sample Cohort in South Korea. We included 150 ESRD patients on chronic hemodialysis who underwent PCI with stenting between 2002 and 2013. The primary outcome was a composite of myocardial infarction, stroke, and all-cause mortality. Multivariate time-dependent Cox regression analysis were performed, and statin therapy after PCI was treated as a time-dependent variable. During 3.15 ± 2.71 (mean ± standard deviation) years of follow-up, there were 82 patients with primary outcome. The adjusted hazard ratio for statin use was 0.54 [0.33–0.90] compared to no statin use. This study showed that statin has significant benefit on reducing adverse events risk in dialysis-dependent ESRD patients after PCI.

LINCS L1000 dataset-based repositioning of CGP-60474 as a highly potent anti-endotoxemic agent

Sepsis is one of the most common clinical syndromes that causes death and disability. Although many studies have developed drugs for sepsis treatment, none have decreased the mortality rate. The aim of this study was to identify a novel treatment option for sepsis using the library of integrated network-based cellular signatures (LINCS) L1000 perturbation dataset based on an in vitro and in vivo sepsis model. Sepsis-related microarray studies of early-stage inflammatory processes in patients and innate immune cells were collected from the Gene Expression Omnibus (GEO) data repository and used for candidate drug selection based on the LINCS L1000 perturbation dataset. The anti-inflammatory effects of the selected candidate drugs were analyzed using activated macrophage cell lines. CGP-60474, an inhibitor of cyclin-dependent kinase, was the most potent drug. It alleviated tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in activated macrophages by downregulating the NF-κB activity, and it reduced the mortality rate in LPS induced endotoxemia mice. This study shows that CGP-60474 could be a potential therapeutic candidate to attenuate the endotoxemic process. Additionally, the virtual screening strategy using the LINCS L1000 perturbation dataset could be a cost and time effective tool in the early stages of drug development.

The Clinical Significance of Physical Activity in Maintenance Dialysis Patients

Background: The aim of the present study was to evaluate the effects of physical activity on various aspects in Asian dialysis patients. Methods: This was a retrospective cohort study. Study participants were recruited from 27 hospitals or dialysis centers in Korea (n = 1611). The participants were divided into 3 groups according to the degree of regular exercise: Inactive group, Intermediate group, and Active group. Results: The proportions of patients with frailty and the presence of each component decreased as physical activity increased. The presence and numbers of disabilities decreased as physical activity increased. The number of participants with a history of fall during the last 12 months was 149 (20.5%) in the Inactive group, 88 (16.9%) in the Intermediate group, and 48 (13.2%) in the Active group. Physical component scale and mental component scale scores increased as physical activity increased. The survival rate for all-cause death at 500 days was 95.5% in the Active group, 95.2% in the Intermediate group, and 93.5% in the Inactive group. Conclusion: High physical activity was associated with favorable results for most health-related quality of life scale scores, including frailty, disability, and exhaustion, in Korean dialysis patients.