TOPK inhibits TNF-α-induced granulosa cell apoptosis via regulation of SIRT1/p53.

T-LAK cell originated protein kinase (TOPK) has been shown to regulate proliferation, invasion or migration of various cancer cells. However, the role of TOPK in follicle environments remains unknown. Here we reveal that TOPK inhibits TNF-α-induced human granulosa COV434 cell apoptosis. The expression of TOPK were increased in COV434 cells in response to TNF-α. TOPK inhibition also decreased TNF-α-induced SIRT1 expression but promoted TNF-α-induced p53 acetylation and expression of PUMA or NOXA. Accordingly, TOPK inhibition attenuated TNF-α-mediated SIRT1 transcriptional activity. In addition, SIRT1 inhibition augmented acetylation of p53 or expression of PUMA and NOXA in response to TNF-α, leading to COV434 cell apoptosis. We conclude that TOPK suppresses TNF-α-induced COV434 granulosa cell apoptosis via regulation of p53/SIRT1 axis, suggesting a potential role of TOPK in regulation of ovarian follicular development.

Efficacy and Safety of Plastic Cannulae Compared with Metal Needles in the Initial Use of an Arteriovenous Fistulae in Incident Hemodialysis Patients: A Randomized Controlled Study.

INTRODUCTION: Successful cannulation of an arteriovenous fistula (AVF) is important in patients starting hemodialysis (HD). Metal needles have been used for decades, but the usefulness of plastic cannulae has recently been demonstrated as a new technique. METHODS: This was a prospective, randomized, open-label study of incident HD patients. Eligible patients were randomized into 2 groups in a 1:1 ratio (n = 45/group). Maturation of the AVF was confirmed using Doppler ultrasound prior to first needling, and 2 well-trained nurses implemented the AVF cannulation. The primary endpoint was the initial cannulation failure rate, defined as the failure of successful completion of 3 consecutive dialysis sessions. The secondary endpoints were time for hemostasis at the end of HD, degree of patients' pain, degree of cannulation difficulty felt by the nursing staffs, and achieving optimal HD adequacy. RESULTS: The mean elapsed time from AVF creation to the first cannulation was 48.1 ± 16.7 days. A total of 17 cases of cannulation failure occurred, and the failure risk tended to be higher in the metal needle group than the plastic cannula group (hazard ratio 2.6, 95% confidence interval 0.95-7.41) after adjusting for age, gender, comorbidities, and AVF location. The overall incidence of vessel injury was higher and time for hemostasis was significantly longer in the metal group than the plastic group. The use of plastic cannula was associated with a better HD adequacy compared to a metal needle. However, the patients' pain score (p = 0.004) and nursing staff's cannulation difficulty score (p = 0.084) were higher in the plastic group, emphasizing the great importance of practice using plastic cannulae. CONCLUSION: The vascular outcomes of plastic cannulae were much favorable compared to metal needles in incident HD patients. The use of plastic cannulae could be a new and innovative way to improve the quality of dialysis.

Effectiveness of Flow Volume Measurement Training Using a Custom-Made Doppler Flow Simulator.

INTRODUCTION: This study was conducted to analyze the effectiveness of a custom-made Doppler ultrasound (DUS) flow simulator, vascular phantom, and Doppler test fluid in the training of dialysis staff in flow volume (FV) measurements for arteriovenous (AV) access in hemodialysis (HD) patients. METHODS: A DUS flow simulator was constructed using a continuous renal replacement therapy machine. Vascular phantoms were constructed using a rubber enema tube and keyboard cleaning gel. The Doppler test fluid consisted of freeze-dried instant coffee granules and 0.9% saline. This easy and affordable simulator was used to train 12 dialysis staff members, with no previous experience in DUS FV measurement. After a 3-day lecture course, the staff members performed DUS analyses on the AV access of HD patients. Thereafter, they underwent a 3-day training course using the simulator and then performed the DUS analyses of the AV access again. Each staff member assessed the FV 3 times, and the mean values of the measurements pretraining and posttraining were analyzed using paired t tests. RESULTS: The difference in the mean value of FV measurements and the reference value decreased from 131.6 mL/min to 62.5 mL/min (95% confidence interval = 30.0-108.0, P = 0.002), and the standard deviation of the FV measurements decreased from 96.9 mL/min to 47.0 mL/min (95% confidence interval = 7.9-91.8, P = 0.023) after DUS training with the simulator. CONCLUSIONS: The accuracy and reproducibility of FV measurements markedly improved after training with the simulator; it may be helpful for medical practitioners involved in AV access for HD treatment.

Comparison of dynamic arterial and venous pressure between metal needles and plastic cannulas in incident hemodialysis patients with arteriovenous graft.

BACKGROUND AND OBJECTS: We hypothesized that plastic cannulae with 17-gauge inner needle compared to 16-gauge metal needles can have stable dynamic venous and arterial pressure maintaining prescribed blood flow safely during a hemodialysis treatment. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: A single-center, prospective, randomized, open-label clinical trial was conducted involving 16 incident hemodialysis patients who had arteriovenous graft placed as their first arteriovenous access. Subjects were randomized to metal needle group (n = 8) versus plastic cannula group (n = 8). We measured serial dynamic pre-pump arterial and venous pressure under five different blood pump flow rates (150, 200, 250, 300, and 350 mL/min). RESULTS: The mean age of patients was 67.6 ± 8.5 (range: 51-81) years, and six patients (37.5%) were male. Patients with plastic cannula showed less negative arterial pre-pump pressures and lower venous pressures than those with metal needles at all prescribed blood flow rates, and the difference was statistically significant (P < 0.001). CONCLUSION: The plastic cannula had more stable arterial and venous pressures at prescribed blood pump flow rates than those pressures of the metal needle in incident patients with arteriovenous graft during hemodialysis.

Role of the SIRT1/p53 regulatory axis in oxidative stress­mediated granulosa cell apoptosis.

Oxidative stress has been suggested to induce granulosa cell apoptosis, which contributes to follicular atresia. However, the mechanism via which oxidative stress mediates granulosa cell apoptosis remains elusive. Therefore, the aim of this study was to elucidate the molecular mechanisms regulating oxidative stress­induced granulosa cell apoptosis. The present study demonstrated that reactive oxygen species induced by H2O2 resulted in human granulosa COV434 cell apoptosis via the regulation of sirtuin 1 (SIRT1)­mediated p53 activity. Endogenous SIRT1 expression was alleviated by H2O2 treatment of COV434 cells in a time­dependent manner. In addition, knockdown or inhibition of SIRT1 promoted H2O2­induced poly(ADP­ribose) polymerase (PARP) cleavage and p53 acetylation, which led to an increase in COV434 cell apoptosis. Treatment with H2O2 enhanced the expression levels of the p53­dependent proteins, p53­upregulated modulator of apoptosis (PUMA) and phorbol­12­myristate­13­acetate­induced protein 1 (PMAIP1), as well as those of p53; however, knockdown of p53 decreased cleaved PARP, PUMA and PMAIP1 expression levels induced by H2O2 treatment. Moreover, knockdown of PUMA or PMAIP1 attenuated the H2O2 induction of PARP cleavage and COV434 cell apoptosis. In conclusion, the present findings suggested that H2O2­induced oxidative stress causes granulosa COV434 cell apoptosis via the upregulation of p53 activity by SIRT1 suppression, indicating a mechanistic role of the SIRT1/p53 axis in H2O2­induced granulosa cell apoptosis.

Acute Hydronephrosis owing to A Giant Fecaloma in an Older Patient.

Hydroureteronephrosis with acute urinary tract obstruction can lead to serious complications such as obstructive nephropathy or pyelonephritis. We report the first case of hydroureteronephrosis caused by a giant fecaloma in an 83-year-old woman accompanied with chronic constipation in Korea. The patient with a fever presented to the emergency room and was diagnosed with right hydronephrosis. Computed tomography revealed a markedly dilated rectum with a giant fecaloma compressing the right vesicoureteric junction. Hydroureteronephrosis was resolved through manual disimpaction of the fecaloma and simultaneous lavage with rectal tubes, which improved the acute pyelonephritis and renal function. Chronic constipation can lead to giant fecaloma threatening urinary tract patency, especially in older patients with immobility or dehydration. Therefore, clinicians should consider this condition as a rare but possible cause of hydronephrosis in older adult patients with chronic constipation.

TOPK inhibition accelerates oxidative stress­induced granulosa cell apoptosis via the p53/SIRT1 axis.

It has been suggested that oxidative stress involving reactive oxygen species (ROS) induces granulosa cell apoptosis, leading to follicular atresia, and that T­lymphokine­activated killer cell­originated protein kinase (TOPK) suppresses cancer cell apoptosis induced by several stimuli. However, it remains to be determined whether TOPK affects oxidative stress­induced granulosa cell apoptosis. The present study demonstrates that TOPK inhibition increases human granulosa COV434 cell apoptosis induced by hydrogen peroxide (H2O2). Co­treatment with the TOPK inhibitor, OTS514, in combination with H2O2 increased p53 acetylation and its expression, whereas it decreased Sirtuin 1 (SIRT1) expression, contributing to the promotion of apoptosis. In addition, the SIRT1 activator, resveratrol, or the SIRT1 inhibitor, Ex527, reduced or elevated H2O2­induced COV434 cell apoptosis, respectively. Furthermore, the p53 inhibitor, Pifithrin­µ, diminished the augmentation in poly(ADP­ribose) polymerase (PARP) cleavage induced by OTS514 plus H2O2, while the Mdm2 antagonist, Nutlin 3, increased PARP cleavage. Moreover, OTS514 further decreased the SIRT1 transcriptional activity decreased by H2O2, but promoted the H2O2­induced p53 or p21 transcriptional activity. Notably, the expression of exogenous p53 reduced SIRT1 transcriptional activity. Taken together, the findings of the present study demonstrate that TOPK inhibition promotes p53­mediated granulosa cell apoptosis through SIRT1 downregulation in response to H2O2. Therefore, it can be concluded that TOPK suppresses H2O2­induced apoptosis through the modulation of the p53/SIRT1 axis, suggesting a potential role of TOPK in the regulation of human granulosa cell apoptosis, leading to the promotion of abnormal follicular development.

Role of peribrachial fat as a key determinant of brachial artery dilatation for successful arteriovenous fistula maturation in hemodialysis patients.

The functional quality of the inflow artery is one of the most important determinants of arteriovenous fistula (AVF) success. We evaluated the association of early optimal brachial arterial dilatation with a successful AVF maturation and assessed the role of peribrachial adipose tissue in determining brachial arterial distensibility. All patients underwent a preoperative vascular mapping with Doppler ultrasound (US), and only patients who had suitable vessels for AVF creation were enrolled (n = 162). Peribrachial fat thickness was measured using US. To evaluate the degree of brachial dilatation, follow-up US was performed at 1 month after surgery, and early brachial artery dilation was defined as the change in postoperative arterial diameter compared to the preoperative value. The primary outcome was failure to achieve a clinically functional AVF within 8 weeks. Nonfunctional AVF occurred in 21 (13.0%) patients, and they had a significantly lower brachial dilatation than patients with successful AVF during early period after surgery (0.85 vs. 0.43 mm, p = 0.003). Patients with a brachial dilatation greater than median level showed a 1.8-times higher rate of achieving a successful AVF than those without. Interestingly, the early brachial dilatation showed significant correlations with diabetes (r = -0.260, p = 0.001), peribrachial fat thickness (r = -0.301, p = 0.008), and the presence of brachial artery calcification (r = -0.178, p = 0.036). Even after adjustments for demographic factors, comorbidities, and baseline brachial flow volume, peribrachial fat thickness was an independent determinant for early brachial dilatation (ß = -0.286, p = 0.013). A close interplay between the peri-brachial fat and brachial dilatation can be translated into novel clinical tools to predict successful AVF maturation.

Prognostic role of circulating neutrophil extracellular traps levels for long-term mortality in new end-stage renal disease patients.

Dysregulation of innate immunity has been proposed as an important contributing factor for advanced atherosclerosis and resultant high mortality in hemodialysis (HD) patients. To evaluate the long-term prognostic role of in vivo neutrophil extracellular traps (NETs), we measured circulating serum nucleosome, myeloperoxidase (MPO), and DNase I levels in 281 incident HD patients. Circulating nucleosome level was significantly higher in HD patients compared to controls, and it was closely associated with MPO levels, suggesting increased in vivo NETs in uremia. Patients in the nucleosome Q4 group had significantly increased all-cause and adverse CV mortality compared to those in the Q1-3 group even after adjusting traditional risk factors Also, serum DNase I level was significantly higher in HD patients than controls (2.76 ±â€¯1.02 ng/ml and 1.93 ±â€¯0.85 ng/ml), but it had no correlation with NETs. Interestingly, it serves an additive biomarker for predicting poor CV outcomes. The two novel biomarkers might provide an importance independent prognostic significance in incident HD patients.

Outcomes of vascular access in hemodialysis patients: Analysis based on the Korean National Health Insurance Database from 2008 to 2016.

BACKGROUND: Controversies exist whether arteriovenous fistula (AVF) placement is preferred over arteriovenous graft (AVG) for elderly patients. Current guidelines did not offer specific recommendations. Thus, this study was conducted to analyze the all-cause mortality and primary patency associated with various vascular access (VA) types according to age group. METHODS: This retrospective observational study investigated the Korean insurance claims data of chronic kidney disease patients who began hemodialysis between January 2008 and December 2016. We investigated all-cause mortality associated with initial VA in incident hemodialysis patients and primary patency between AVF and AVG according to age group. RESULTS: The proportion of patients with a tunneled dialysis catheter (TDC) that was first placed for VA increased from 18.4% in 2008 to 52.3% in 2016. Incident hemodialysis patients with a TDC or AVG for the initial VA had significantly higher mortality risk than patients with an AVF, except for patients over 85 years, who showed no significant difference in all-cause mortality regardless of VA type. In the patency analysis on initial AV access, AVG had significantly poorer primary patency than AVF in all age groups. CONCLUSION: AVF had better patency than AVG in all age groups; however, the benefit of AVF attenuated in the older age groups. The mortality rate between AVF and AVG was not significantly different in patients over 85 years. Therefore, a "patient-first" approach should be emphasized over a "fistula-first" approach in AV access creation for incident hemodialysis patients older than 85 years.

Custom-made Doppler ultrasound flow simulator for dialysis access using continuous renal replacement therapy machine.

The purpose of this article was to introduce an easy and inexpensive way of making a simulator for training in Doppler ultrasound flow rate measurement using a continuous renal replacement therapy machine and home-made phantoms. A Doppler ultrasound flow simulator was made using a continuous renal replacement therapy machine and vascular phantoms for flow rate assessment of dialysis access with readily accessible components including rubber tube, keyboard cleaning gel, and freeze-dried instant coffee granules. The simulator is an affordable and easy method of Doppler ultrasound flow rate measurement training for dialysis staff using materials readily available in dialysis centers.

Anatomical variants of upper arm veins on preoperative mapping venography for hemodialysis access in Korean adults.

INTRODUCTION: The number of elderly patients requiring hemodialysis has increased, along with the need for multiple vascular access placements. Thus, the frequency of access creation using the upper arm veins, including transposed basilic arteriovenous fistula, has also increased. The purpose of this study was to identify the prevalence of anatomical variations in the upper arm veins on preoperative mapping venography and to investigate the implications of such variants on access creation. METHODS: A total of 494 venograms were performed on 251 patients for primary access creation from June 2014 to June 2017 in this single-center, retrospective study. The venograms were classified into eight subtypes, based on the anatomical relationship between the basilic and brachial veins. The presence of bifid cephalic arches and brachial-basilic ladders was also examined. RESULTS: The presence of bifid cephalic arches and brachial-basilic ladders was identified in 8.7% and 14.0% of cases, respectively. Paired brachial veins joined separately with the basilic vein in 67.4% of venograms, whereas these veins merged into a common brachial vein before connecting to the basilic vein in 13.1% of cases. A single brachial vein was present in 19.3% of cases. 15.7% of cases were considered unsuitable for basilic vein transposition due to the early confluence of the brachial-basilic vein, posing a risk of obliterating the deep venous drainage if transposed. CONCLUSION: There are significant anatomical variations of upper arm veins, and the recognition of certain variants can affect surgical planning and outcomes of access placement. It is important to identify anatomical variants of the upper arm veins during preoperative vein mapping.

Current treatment status and medical costs for hemodialysis vascular access based on analysis of the Korean Health Insurance Database.

BACKGROUND/AIMS: The Republic of Korea is a country where the hemodialysis population is growing rapidly. It is believed that the numbers of treatments related to vascular access-related complications are also increasing. This study investigated the current status of treatment and medical expenses for vascular access in Korean patients on hemodialysis. METHODS: This was a descriptive observational study. We inspected the insurance claims of patients with chronic kidney disease who underwent hemodialysis between January 2008 and December 2016. We calculated descriptive statistics of the frequencies and medical expenses of procedures for vascular access. RESULTS: The national medical expenses for access-related treatment were 7.12 billion KRW (equivalent to 6.36 million USD) in 2008, and these expenses increased to 42.12 billion KRW (equivalent to 37.67 million USD) in 2016. The population of hemodialysis patients, the annual frequency of access-related procedures, and the total medical cost for access-related procedures increased by 1.6-, 2.6-, and 5.9-fold, respectively, over the past 9 years. The frequency and costs of access care increased as the number of patients on hemodialysis increased. The increase in vascular access-related costs has largely been driven by increased numbers of percutaneous angioplasty. CONCLUSION: The increasing proportion of medical costs for percutaneous angioplasty represents a challenge in the management of end-stage renal disease in Korea. It is essential to identify the clinical and physiological aspects as well as anatomical abnormalities before planning angioplasty. A timely surgical correction could be a viable option to control the rapid growth of access-related medical expenses.

KLOTHO gene polymorphism is associated with coronary artery stenosis but not with coronary calcification in a Korean population.

Experimental studies have demonstrated KLOTHO gene polymorphism might be associated with vascular atherosclerosis and calcification. However, the impact of this genetic variant on human coronary arteries still remains to be elucidated. We investigated the effect of a KLOTHO gene variant on coronary artery stenosis and calcification. Four hundred and thirty-four patients referred for chest pain were enrolled. All the patients underwent coronary angiography and were investigated for polymorphism of the KLOTHO G395A gene. Coronary artery disease (CAD) was defined as > or = 50% diameter stenosis in at least one coronary artery. The other patients were considered to be controls. Homozygotes or heterozygotes for G395A were significantly more common in the CAD patients than in the controls (30.2% versus 21.5%, P = 0.039). In the subgroup aged < 60 years, the G395A mutant was more frequent in CAD than in control (35.3% versus 18.8%, P = 0.016), but in patients > or = 60 years, there was no difference (28.0% versus 24.1%, P = 0.473). Using multivariate analysis, we identified the KLOTHO gene G395A mutant as an independent risk factor of CAD (OR 1.712, 95% CI [1.066-2.749], P = 0.026). The frequency of the KLOTHO gene G395A mutant was not different between the calcified and noncalcified coronary artery groups (25.7%, 26.4%, respectively, P = 0.861) and an A allele carrier state was not an independent risk factor of coronary artery calcification. In conclusion, the KLOTHO gene G395A allele carrier state may be associated with CAD but not with coronary artery calcification in this Korean population.