WT1: The Hinge Between Anemia Correction and Cancer Development in Chronic Kidney Disease.

Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) emerge as promising agents to treat anemia in chronic kidney disease (CKD) but the major concern is their correlated risk of cancer development and progression. The Wilms' tumor gene, WT1, is transcriptionally regulated by HIF and is known to play a crucial role in tumorigenesis and invasiveness of certain types of cancers. From the mechanism of action of HIF-PHIs, to cancer hypoxia and the biological significance of WT1, this review will discuss the link between HIF, WT1, anemia correction, and cancer. We aimed to reveal the research gaps and offer a focused strategy to monitor the development and progression of specific types of cancer when using HIF-PHIs to treat anemia in CKD patients. In addition, to facilitate the long-term use of HIF-PHIs in anemic CKD patients, we will discuss the strategy of WT1 inhibition to reduce the development and progression of cancer.

High Induction of IL-6 Secretion From hUCMSCs Optimize the Potential of hUCMSCs and TCZ as Therapy for COVID-19-Related ARDS.

Biological and cellular interleukin-6 (IL-6)-related therapies have been used to treat severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure, which prompted further exploration of the role of IL-6 in human umbilical cord mesenchymal stem cell (hUCMSC) therapy. Peripheral blood mononuclear cells (PBMCs) were responders cocultured with hUCMSCs or exogenous IL-6. A PBMC suppression assay was used to analyze the anti-inflammatory effects via MTT assay. The IL-6 concentration in the supernatant was measured using ELISA. The correlation between the anti-inflammatory effect of hUCMSCs and IL-6 levels and the relevant roles of IL-6 and IL-6 mRNA expression was analyzed using the MetaCore functional network constructed from gene microarray data. The location of IL-6 and IL-6 receptor (IL-6R) expression was further evaluated. We reported that hUCMSCs did not initially exert any inhibitory effect on PHA-stimulated proliferation; however, a potent inhibitory effect on PHA-stimulated proliferation was observed, and the IL-6 concentration reached approximately 1000 ng/mL after 72 hours. Exogenous 1000 ng/mL IL-6 inhibited PHA-stimulated inflammation but less so than hUCMSCs. The inhibitory effects of hUCMSCs on PHA-stimulated PBMCs disappeared after adding an IL-6 neutralizing antibody or pretreatment with tocilizumab (TCZ), an IL-6R antagonist. hUCMSCs exert excellent anti-inflammatory effects by inducing higher IL-6 levels, which is different from TCZ. High concentration of IL-6 cytokine secretion plays an important role in the anti-inflammatory effect of hUCMSC therapy. Initial hUCMSC therapy, followed by TCZ, seems to optimize the therapeutic potential to treat COVID-19-related acute respiratory distress syndrome (ARDS).

The Perioperatively Altered Neutrophil-to-Lymphocyte Ratio Associates with Impaired DNA Damage Response in Liver Transplantation Recipients with Hepatocellular Carcinoma.

Increasing evidence has suggested that elevated systemic inflammation with a high neutrophil-lymphocyte ratio (NLR) is associated with poor prognosis after liver transplantation (LT). The ongoing molecular events involved in poor survival remain unclear. This retrospective study evaluated LT recipients whose data was collected at Kaohsiung Chang Gung Memorial Hospital between 2005 and 2014. Clinical records of 347 patients with hepatocellular carcinoma from seven days before LT to 30 days after LT illustrated that longitudinal values of lymphocytes, RBC, and hemoglobin were persistently low in patients with peritransplant high NLR (PTH-NLR, pre-LT ≥ 4 and post-LT ≥ 5), which indicated a significantly worse survival rate in association with increased RDW-CV and pancytopenia when compared to other patients (p = 0.008). We further found that PTH-NLR patients had decreased DNA damage response (DDR) genes and detoxifying enzymes of ADH and ALDH families, and increased mitochondrial stress response genes in their liver tissues. Reduced lineage markers of liver progenitor cells were also observed in PTH-NLR patients signifying the presence of unresolved impairments after LT. Our results demonstrate the association between hematopoietic deficiencies and lack of protection against DDR with PTH-NLR in LDLT recipients with HCC and may imply abnormal hematological and organismal defects in those patients.

Successful Modified Transoral Endoscopic Parathyroidectomy Vestibular Approach For Secondary Hyperparathyroidism With Ectopic Mediastinal Glands.

BACKGROUND: Transoral endoscopic parathyroidectomy vestibular approach for secondary hyperparathyroidism (SHPT) is controversial with regard to the time consumed, safety, and feasibility. We present our initial experience with modified transoral endoscopic parathyroidectomy vestibular approach (m-TOEPVA) procedure for SHPT using total parathyroidectomy with autotransplantation. MATERIALS AND METHODS: We retrospectively reviewed 10 patients with SHPT who underwent the m-TOEPVA procedure from December 2017 to April 2018 at our center. RESULTS: There were a total of 6 male individuals and 4 female individuals with a median age of 58.5 years. Among whom, 5 were on hemodialysis and 5 on peritoneal dialysis. The median length of hospital stay and operative time was 5 (4, 5) days, and 321.5 (302.75, 362.25) minutes, respectively. Successful removal of 4 parathyroid glands was achieved in 8 of 10 patients (80%) and, in 8 patients (8/10, 80%), the intact parathyroid hormone successfully dropped to <300 pg/mL at 3 months postoperatively. Two patients with ectopic parathyroid gland in the superior mediastinum were noted preoperatively by MIBI scan and subsequently had successful removal. Except for 1 patient with prolonged hospital stay (11 d) due to hungry bone syndrome, there were no other major complications. CONCLUSION: m-TOEPVA by total parathyroidectomy with autotransplantation for SHPT is feasible, safe, and offers optimal cosmetic results. The most valuable part is that m-TOEPVA provides direct visualization and successful removal of the ectopic parathyroid glands in the superior mediastinum.

Comparison of tunneled central venous catheters and native arteriovenous fistulae by evaluating the mortality and morbidity of patients with prevalent hemodialysis.

PURPOSE: We examined the association between catheter use for maintenance hemodialysis (HD) and mortality/hospitalization in a cohort of patients with prevalent HD. METHODS: In this study, 70 HD patients with tunneled cuffed central venous catheters (TCVCs) from a Taiwanese HD center during 2014-2016 were enrolled and compared with 70 matched HD patients with native arteriovenous fistulae (AVF). The compared variables included demographic parameters and laboratory and dialysis-related indices. Cox regression analysis was used to assess the risk of mortality/hospitalization within a year. RESULTS: Low baseline serum albumin levels were found in patients with TCVCs (3.64 g/dL vs 3.79 g/dL, p = 0.030). The mortality rates of patients with AVF and TCVCs were 14 per 1000 patients and 171 per 1000 patients, respectively. Infection was the leading cause of mortality/hospitalization in patients with TCVCs. Using multivariate analyses, the risk of death was found to be significantly higher in patients with TCVCs than in those with AVF (Hazard ratio [HR] 12.15, 95% CI 1.16-127.17; p = 0.037). Patients with TCVC also had a higher hospitalization rate (HR 1.33, 95% CI 0.71-2.49; p = 0.369) (not statistically significant). CONCLUSION: Catheter use for maintenance HD was associated with increased all-cause mortality.

Prediction of the Development of Persistent Massive Ascites After Living Donor Liver Transplantation Using a Perioperative Risk Score.

BACKGROUND: Persistent massive ascites (PMAS) longer than 14 days after living donor liver transplantation is not uncommon and associated with worse outcome. A predictive risk scoring system was constructed after analysis of recipient, graft, and surgery-related factors. METHODS: We retrospectively reviewed adult living donor liver transplantation recipients from 2005 to 2011 after excluding cases that experienced any intervention for perioperative vascular-related events. Two groups were identified, PMAS and non-PMAS. The score was constructed from significant factors using weighted odds ratios (OR). RESULTS: The study population included 439 recipients. Persistent massive ascites was evident in 74 cases (17%). Five significant risk predictors were identified in multivariate analysis: pretransplant serum creatinine greater than 1.5 mg/dL (OR, 5.693; weighted OR, 2), recipient spleen to graft volume ratio greater than 1.3 (OR, 4.466; weighted OR, 2), left lobe graft (OR, 3.196; weighted OR, 1), more than 1000 mL ascites at laparotomy (OR, 2.541; weighted OR, 1), and graft recipient weight ratio less than 0.8 (OR, 2.419; weighted OR, 1). The clinical scoring system was constructed and ranged from 0 to 7. Receiver operating characteristic analysis showed an area under the curve (0.778, P < 0.001). Internal validation of the score showed an area under the curve of 0.783. The 5- and 10-year survival rates for the non-PMAS versus the PMAS groups were 89% and 84% versus 81% and 48%, respectively (P = 0.001). CONCLUSIONS: The PMAS score is a predictive pretransplant clinical tool. A Clinical cutoff score of 4 might be decision-changing. Pretransplant correction of renal functions, deciding to harvest a large graft and/or consideration of splenic artery embolization could reduce the risk of PMAS.

Association between Helicobacter pylori eradication and the risk of coronary heart diseases.

The evidences on the association of Helicobacter pylori (H. pylori) to coronary heart diseases (CHD) are conflicting. In order to answer this important but yet unanswered clinical health issue, a large cohort study such as big data from the Taiwan National Health Insurance Research Database should be more convincing. Therefore, we aimed to make use of these big data source to analyze and clarify the relevance of H. pylori eradication and CHD risks. We looked through a total of 208196 patients with peptic ulcer diseases (PUD) from the years of 2000 to 2011. First, 3713 patients who received H. pylori eradication within 365 days of the index date were defined as the group A. We randomly selected the same number of patients as cohort A from 55249 non-eradication patients to be the comparison group B using propensity scores (including age, gender and comorbidity) so that we could control the confounding variables of CHD and mortality. Importantly, we perform sensitivity analysis for the time-dependent association between H. pylori eradication and risk of CHD, interactions between patient demographic characteristics and therapy by age (≥ or < 65 years old). The results showed that a trend of decreased association of CHD in patients with early eradication was observed compared to those without eradication (2.58% vs. 3.35%, p = 0.0905). The mortality rate was lower in early eradication subgroup compared to cohort B (2.86% vs. 4.43%, p = 0.0033). Interestingly, there was also significant difference observed in composite end-points for CHD and death in the early eradication subgroup (0.16% vs.0.57%, p = 0.0133). Further, the cumulative CHD rate was significantly lower in younger patients (< 65 years old) with H. pylori eradication therapy started < 1 year compared to those patients without eradication at all (p = 0.0384); the treatment did not appear to have an effect in older patients (≥ 65 years old) (p = 0.1963). Multivariate analysis showed that hypertension and renal diseases were risk factors for CHD in patients without eradication whilst younger age (< 65 years old) initiated with H. pylori therapy was a protective factor. In conclusion, the trend of decrease in CHD occurrence after early H. pylori eradication in addition to the significant decrease in composite end points for CHD and death, the significantly lower cumulative CHD rate in younger patients < 65 years old with H. pylori treated within 365 days suggested that there was positive association between H. pylori eradication and CHD.

First-Line Helicobacter pylori Eradication in Patients with Chronic Kidney Diseases in Taiwan.

AIMS: Patients with chronic kidney disease (CKD) and Helicobacter pylori (H. pylori) infection have a higher incidence of gastroduodenal diseases and therefore are recommended to receive eradication therapies. This study aimed to assess the efficacy of a 7-day standard triple therapy in patients with CKD (eGFR < 60 ml/min/1.73 m2) and to investigate the clinical factors influencing the success of eradication. METHODS: A total of 758 patients with H. pylori infection receiving a 7-day standard first-line triple therapy between January 1, 2013, and December 31, 2014, were recruited. Patients were divided into two groups: CKD group (N = 130) and non-CKD group (N = 628). RESULTS: The eradication rates attained by the CKD and non-CKD groups were 85.4% and 85.7%, respectively, in the per-protocol analysis (p = 0.933). The eradication rate in CKD stage 3 was 84.5% (82/97), in stage 4 was 88.2% (15/17), and in those who received hemodialysis was 87.5% (14/16). There were no significant differences in the various stages of CKD (p = 0.982). The adverse events were similar between the two groups (3.1% versus 4.6%, p = 0.433). Compliance between the two groups was good (100.0% versus 99.8%, p = 0.649). There was no significant clinical factor influencing the H. pylori eradication rate in the non-CKD and CKD groups. CONCLUSIONS: This study suggests that the H. pylori eradication rate and adverse rate in patients with CKD are comparable to those of non-CKD patients.

Mitochondrial Fission Increases Apoptosis and Decreases Autophagy in Renal Proximal Tubular Epithelial Cells Treated with High Glucose.

The aim of this study was to examine the effect of mitochondrial morphogenesis changes on apoptosis and autophagy of high-glucose-treated proximal tubular epithelial cells (HK2). Cell viability, apoptosis, and mitochondrial morphogenesis were examined using crystal violet, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL), and mitotracker staining, respectively. High glucose inhibited cell viability and induced mitochondrial fission in HK2 cells. After depleting mitofusin 1 (MFN1), the MFN1(-) HK2 cells (fission type) became more susceptible to high-glucose-induced apoptosis and mitochondrial fragmentation observed by TUNEL and mitotracker assays. In siMFN2 HK2 cells (fission type), mitochondria were highly fragmented (>80% fission rate) with or without high-glucose treatment; however, siFIS1 (mitochondrial fission protein 1) HK2 cells (fusion type) exhibited little fragmentation (<13%). High-glucose treatment induced autophagy, characterized by the formation of autophagosome and microtubule-associated protein light chain 3 (LC3) B-II, as observed by transmission electron microscopy and western blotting, respectively. LC3B-II levels decreased in both MFN1(-) and siMFN2 HK2 cells, but increased in siFIS1 HK2 cells. Moreover, autophagy displays a protective role against high-glucose-induced cell death based on cotreatment with autophagy inhibitors (3-methyladenine and chloroquine). Mitochondrial fission may increase apoptosis and decrease autophagy of high-glucose-treated HK2 cells.

Seven-Day Nonbismuth Containing Quadruple Therapy Could Achieve a Grade "A" Success Rate for First-Line Helicobacter pylori Eradication.

This prospective study was to assess the efficacy of nonbismuth containing quadruple therapy as first-line H. pylori treatment and to determine the clinical factors influencing patient outcome. We enrolled 200 H. pylori-infected naïve patients. They were prescribed either a 7-day nonbismuth containing quadruple therapy group (EACM, esomeprazole 40 mg twice daily, amoxicillin 1 g twice daily, metronidazole 500 mg twice daily, and clarithromycin 500 mg twice daily) or a 7-day standard triple therapy group (EAC, esomeprazole 40 mg twice daily, amoxicillin 1 g twice daily, and clarithromycin 500 mg twice daily). Follow-up studies to assess treatment responses were carried out 8 weeks later. The eradication rates attained by EACM and EAC groups were 95.6% (95% confidence interval [CI] = 89.4%-98.3%) and 79.3% (95% CI = 70%-86.4%) in the per-protocol analysis (P < 0.001) and 88% (95% CI = 80.2%-93.0%) and 73% (95% I = 63.6%-80.3%) in the intention-to-treat analysis (P = 0.007). Clarithromycin resistance, metronidazole resistance, and dual clarithromycin and metronidazole resistances were the clinical factors influencing H. pylori eradication in EACM group. Clarithromycin resistance and dual clarithromycin and metronidazole resistances were the influential factor for EAC treatment. In conclusion, the results suggest that 7-day nonbismuth containing quadruple therapy could achieve a grade "A" report card for first-line H. pylori treatment.

Nosocomial extended-spectrum beta-lactamase-producing Klebsiella pneumoniae bacteremia in hemodialysis patients and the implications for antibiotic therapy.

BACKGROUND: In the face of increasing treatment options for extended-spectrum beta-lactamase-producing Klebsiella pneumoniae (ESBL-Kp) hemodialysis (HD) access-related bacteremia, the difference in clinical effectiveness between ertapenem and flomoxef remains unclear. We conducted this retrospective study to determine their efficacies and treatment outcomes. METHODS: Patients on maintenance HD with fistula-, graft-, or catheter-related ESBL-Kp bacteremia were enrolled. Data related to clinical features and antibiotic treatments were collected. Outcome was determined by mortality resulting from bacteremia during the 14-day period after the collection of the first positive blood culture for flomoxef-susceptible ESBL-Kp. RESULTS: The 64 patients studied had severe septicemia as determined by the Pitt bacteremia score; 50% (32/64) were in the intensive care unit (ICU) at the time of bacteremia. Old age (>65 years; 57.8%), malnutrition (albumin<3.5g/dl; 92.2%), a history of severe illnesses (defined by shock, intubation, or ICU stay; 82.5%), and prolonged hospitalization prior to the onset of bacteremia (>30 days; 75%) were also highly prevalent. The study population comprised nine fistula-, 10 graft-, and 45 HD catheter-related bacteremia cases, and the mortality rate was high (38/64, 59.4%). The mortality rate was significantly higher in the flomoxef treatment group than in the ertapenem treatment group (22/30, 73% vs. 16/34, 47%, p<0.05). Among patients with catheter-related bacteremia, multivariate analyses revealed that flomoxef use (odds ratio (OR) 2.52, 95% confidence interval (CI) 1.34-35.17) and Pitt bacteremia score (OR 4.37, 95% CI 1.28-5.26) were independently associated with mortality. CONCLUSIONS: In accordance with our previous study, our results have demonstrated the inferiority of flomoxef to carbapenems in the treatment of HD access-related ESBL-Kp bacteremia and provide an insight into the possibility of using ertapenem rather than flomoxef as an initial or de-escalating therapy for infections caused by ESBL-producing bacteria.

The clinical and bacteriological factors for optimal levofloxacin-containing triple therapy in second-line Helicobacter pylori eradication.

Quinolone has the disadvantage of easily acquired drug resistance. It is important to prescribe it wisely for a high eradication rate. The current study aimed to determine the clinical and bacteriological factors for optimal levofloxacin-containing triple therapies in second-line H. pylori eradication. We enrolled a total of 158 H. pylori-infected patients who failed H. pylori eradication using the 7-day standard triple therapy (proton-pump inhibitor [PPI] twice daily, 500 mg clarithromycin twice daily, and 1 g amoxicillin twice daily). They were prescribed with either a 10-day (group A) or 14-day (group B) levofloxacin-containing triple therapy group (levofloxacin 500 mg once daily, amoxicillin 1 g twice daily, and esomeprazole 40 mg twice daily for 10 days) by their clinicians. Follow-up studies to assess treatment responses were carried out 8 weeks later. The eradication rates attained by groups A and B were 73.6% (95% confidence interval [CI]  = 63.9-85.3%) and 90.5% (95% CI = 84.5-98.1%), respectively in the per protocol analysis (P = 0.008 in the per protocol analysis) and 67.1% (95% CI = 56.6-78.5%) and 84.8% (95% CI = 76.8-93.4%), respectively, in the intention-to-treat analysis (P = 0.009). The subgroup analysis revealed that H. pylori eradication rates for group A patients with levofloxacin-susceptible strains were 92.9% (13/14) but it dropped to 12.5% (1/8) when levofloxacin-resistant strains existed. H. pylori was eradicated among all the group B patients with levofloxacin-susceptible strains, but only half of patients with levofloxacin-resistant strains were successfully eradicated. In conclusion, this study confirms the effectiveness of 14-day treatment. Importantly, the results imply that 10-day treatment duration should be optimal if a culture can be performed to confirm the existence of susceptible strains. The duration of H. pylori eradication and levofloxacin resistance were the influencing factors for successful treatment. This study suggests that tailored levofloxacin-containing therapy should be administered only for patients with susceptible strains because it can achieve >90% success rates.

Ten-Day versus 14-Day Levofloxacin-Containing Triple Therapy for Second-Line Anti-Helicobacter pylori Eradication in Taiwan.

Second-line Helicobacter pylori (H. pylori) eradication with fluoroquinolone-containing triple therapy is one of the recommended treatment options, but neither 7-day nor 10-day regimens provide >90% success rates. The current retrospective study aimed to clarify the effects of 10-day and 14-day levofloxacin-containing triple therapies for second-line H. pylori eradication in a Taiwanese cohort and to evaluate the potential clinical factors influencing eradication. A total of 200 patients who failed H. pylori eradication using the standard triple therapy were prescribed with either a 10-day (EAL-10) or a 14-day (EAL-14) levofloxacin-containing triple therapy group (levofloxacin 500 mg once daily, amoxicillin 1 g twice daily, and esomeprazole 40 mg twice daily). Follow-up studies to assess treatment response were carried out 8 weeks later. Eradication rates attained by EAL-10 and EAL-14 were 75.6%; 95% CI = 63.9-85.3% and 92.5%; 95% CI = 84.5-98.1%, P = 0.002 in the per protocol analysis and 68%; 95% CI = 56.6-78.5% and 86%; 95% CI = 76.8-93.4%, P = 0.002 in the intention-to-treat analysis. The duration of H. pylori therapy is the independent risk factor of H. pylori eradication (P = 0.003). In conclusion, 14-day levofloxacin-containing triple therapy can provide a >90% H. pylori eradication rate, but 10-day treatment duration may be suboptimal. The longer duration of H. pylori therapy (14 days) is the independent risk factor.

Current status in the treatment options for esophageal achalasia.

Recent advances in the treatment of achalasia include the use of high-resolution manometry to predict the outcome of patients and the introduction of peroral endoscopic myotomy (POEM). The first multicenter randomized, controlled, 2-year follow-up study conducted by the European Achalasia Trial group indicated that laparoscopic Heller myotomy (LHM) was not superior to pneumatic dilations (PD). Publications on the long-term success of laparoscopic surgery continue to emerge. In addition, laparoscopic single-site surgery is applicable to advanced laparoscopic operations such as LHM and anterior fundoplication. The optimal treatment option is an ongoing matter of debate. In this review, we provide an update of the current progress in the treatment of esophageal achalasia. Unless new conclusive data prove otherwise, LHM is considered the most durable treatment for achalasia at the expense of increased reflux-associated complications. However, PD is the first choice for non-surgical treatment and is more cost-effective. Repeated PD according to an "on-demand" strategy based on symptom recurrence can achieve long-term remission. Decision making should be based on clinical evidence that identifies a subcategory of patients who would benefit from specific treatment options. POEM has shown promise but its long-term efficacy and safety need to be assessed further.

Association of fatty liver disease with nonfatal cardiovascular events in patients undergoing maintenance hemodialysis.

BACKGROUND/AIMS: The prevalence of cardiovascular (CV) disease in patients undergoing maintenance hemodialysis (HD) is reportedly higher than that in healthy individuals. In the present study, we aimed to investigate whether ultrasonographically documented fatty liver disease (FLD) is an independent risk factor for nonfatal CV events in patients undergoing HD. METHODS: A retrospective cohort study was conducted in a medical center in southern Taiwan. The medical records of 490 patients undergoing HD who were enrolled between July 1998 and October 2012 were screened. Finally, 278 patients who had undergone hepatic ultrasonography and had available data were recruited in the present study. The patients included 130 men and 148 women; their mean age was 59.9 years. The primary endpoint was nonfatal CV events in the observation period. The comparable data included epidemiological, hematological, and biochemical profiles. A time-dependent statistical method was used to analyze the associated factors. RESULTS: The prevalence of nonfatal CV events was significantly increased in the patients with FLD compared with those without FLD (CV events: 32 vs. 18%, respectively; p = 0.008). After adjusting for associated risk factors (sex, age, body mass index, smoking, diabetes, hypertension, dyslipidemia, and Kt/V), multivariate analyses identified FLD (CV events: hazard ratio 2.84, 95% confidence interval 1.52-5.28, p = 0.001), advanced age, and diabetes to be independently associated with nonfatal CV events. CONCLUSION: The study suggests that FLD was an independent risk factor for nonfatal CV events in patients undergoing maintenance HD.