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The aim of the study was to assess trends in the relative use of dialysis modalities in the hospital-based pediatric cohort and to determine risk factors associated with in-hospital morality among pediatric patients receiving dialysis for acute kidney injury (AKI). Patients aged P P = 0.2411). Patients aged

Cheng-Kun Wu,1 Chien-Ning Hsu,2,3 Wei-Ru Cho,1 Shih-Cheng Yang,1 An-Che Liu,4 Wei-Chen Tai,1 Chen-Hsiang Lee,5 Yao-Hsu Yang,6– 8 Seng-Kee Chuah,1 Chih-Ming Liang1 1Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 2Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 3School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; 4Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 5Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 6Department of Traditional Chinese Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan; 7Health Information and Epidemiology Laboratory of Chang Gung Memorial Hospital, Chiayi, Taiwan; 8School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, TaiwanCorrespondence: Chih-Ming LiangDivision of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123, Dabi Road, Kaohsiung, 833, TaiwanTel +886-7-731-7123, ext. 8301Fax +886-7-732-2402Email gimy54861439@gmail.comBackground and Aim: Endoscopic sphincterotomy (ES) abolished the barrier between the hepatobiliary system and duodenum and might be at risk of pyogenic liver abscess (PLA). We aimed to identify the association factors of PLA in patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) procedures for treatment of choledocholithiasis.Methods: This study was based on the Chung Gung Research Database (CGRD) between January 1, 2001 and December 31, 2018. Those who had an International Classification of Diseases, Ninth and Tenth Revision (ICD9 and ICD10) codes of choledocholithiasis and received ERCP were enrolled. After strict exclusions, 11,697 patients were further divided into the endoscopic sphincterotomy (ES) group (n=7,111) and other ERCP group (n=4,586) for analysis.Results: Patients receiving ES had significantly higher rates of PLA than those of the other ERCP group (5-year cumulative incidence 2.4% versus 1.7%; 10-year cumulative incidence 3.9% versus 3.2%, log-rank p=0.0177). Aging, male gender, surgery for hepato-pancreato-biliary system and hepatobiliary malignancy were significant association factors of PLA. On multivariate analysis, the ES increased the risk of PLA (adjusted hazard ratio [aHR]=1.49; 95% CI=1.12– 1.98; p=0.0058) but decreased the risks for acute pancreatitis (aHR=0.72; 95% CI=0.60– 0.85; p=0.0002) and cholangitis (aHR= 0.91; 95% CI=0.84– 0.99; p=0.0259). There was no significant difference about recurrent choledocholithiasis between groups.Conclusion: This study demonstrated a significant risk of PLA after patients receiving ES compared with the other ERCP group. We should also carefully monitor the association factors of PLA after ERCP treatment of choledocholithiasis including aging, male gender, surgery for the hepato-pancreato-biliary system and hepatobiliary malignancy.Keywords: pyogenic liver abscess, endoscopic sphincterotomy, choledocholithiasis, endoscopic retrograde cholangiopancreatography

BACKGROUND AND AIM Clopidogrel is widely prescribed for patients with of aspirin-related upper gastrointestinal bleeding (UGIB) history. This study aimed to compare the risk of a major adverse cardiovascular event (MACE), UGIB, and mortality between aspirin and clopidogrel in patients at risk of bleeding. METHODS We analyzed adult patients at high risk of UGIB following aspirin-related bleeding for secondary MACE prevention between 2000 and 2012. Secondary prevention was for those patients who had ever been hospitalized for cardiovascular disease and reused aspirin or changed to clopidogrel after discharge. Study endpoints were recurrence of MACE, UGIB, and death in 90 days of follow-up. The associations between study outcomes and the use of clopidogrel (vs aspirin) were analyzed. RESULTS Among 947 eligible patients, 653 reused aspirin (in combination with a proton-pump inhibitor), and 294 were treated with clopidogrel (in combination with a proton-pump inhibitor) after discharge for UGIB. Compared with aspirin treatment, clopidogrel showed an increased risk of MACE (adjusted hazard ratio [aHR] 1.65; 95% confidence interval [CI] 0.87-3.12) and UGIB (aHR 1.25; 95% CI 0.66-2.36), but without statistical significance in 90 days' follow-up. Clopidogrel use was associated with greater than four times the risk of any cause of mortality (aHR 4.84; 95% CI 1.59-14.75), but the significance did not hold in propensity score-matched cohort analysis (P = 0.06). CONCLUSIONS A nonsignificant difference between clopidogrel and aspirin for short-term MACE prevention as well as UGIB recurrence was found in the present study. Further research to assess 90-day mortality would assist clinical decision making.

PURPOSE Using real-world data to support regulatory decision has become a global movement. However, a robust platform for active surveillance of medical product safety has not been established in Taiwan. METHODS Following the common data model structure of the U.S. Food and Drug Administration's Sentinel System, we built the Taiwan Sentinel Data Model (TSDM) using the National Health Insurance Research Database with longitudinal claims data from 23 million individuals, linked death and cause of death data from a national registry, and linked electronic health record data from a delivery system. We examined the conversion of the TSDM using the Sentinel Data Quality Review and Characterization Programs in a sample of sex- and age-stratified cohort of 3 million individuals. RESULTS The TSDM fulfilled the requirements of data quality assurance. Only about 6% of sex and 0.0007% of birth year were missing, and

ObjectiveThis study aimed to identify phenotypic clinical features associated with acute kidney injury (AKI) to predict non-recovery from AKI at hospital discharge using electronic health record data.MethodsData for hospitalized patients in the AKI Recovery Evaluation Study were derived from a large healthcare delivery system in Taiwan between January 2011 and December 2017. Living patients with AKI non-recovery were used to derive and validate multiple predictive models. In total, 64 candidates variables, such as demographic characteristics, comorbidities, healthcare services utilization, laboratory values, and nephrotoxic medication use, were measured within 1 year before the index admission and during hospitalization for AKI.ResultsAmong the top 20 important features in the predictive model, 8 features had a positive effect on AKI non-recovery prediction: AKI during hospitalization, serum creatinine (SCr) level at admission, receipt of dialysis during hospitalization, baseline comorbidity of cancer, AKI at admission, baseline lymphocyte count, baseline potassium, and low-density lipoprotein cholesterol levels. The predicted AKI non-recovery risk model using the eXtreme Gradient Boosting (XGBoost) algorithm achieved an area under the receiver operating characteristic (AUROC) curve statistic of 0.807, discrimination with a sensitivity of 0.724, and a specificity of 0.738 in the temporal validation cohort.ConclusionThe machine learning model approach can accurately predict AKI non-recovery using routinely collected health data in clinical practice. These results suggest that multifactorial risk factors are involved in AKI non-recovery, requiring patient-centered risk assessments and promotion of post-discharge AKI care to prevent AKI complications.

Glucocorticoid (GC)-induced bone loss is the most prevalent form of secondary osteoporosis. Previous studies demonstrated that long-term incubation of dexamethasone (DEX) induced oxidative stress and mitochondrial dysfunctions, consequently leading to apoptosis of differentiated osteoblasts. This DEX-induced cell death might be the main causes of bone loss. We previously described that DEX induced biphasic mitochondrial alternations. As GC affects mitochondrial physiology through several different possible routes, the short-term and long-term effects of GC treatment on mitochondria in the osteoblast have not been carefully characterized. Here, we examined the expression levels of genes that are associated with mitochondrial functions at several different time points after incubation with DEX. Mitochondrial biogenesis-mediated genes nuclear respiratory factor 1 (Nrf1) and Nrf2 were upregulated after 4-h incubation, and then declined after 24-h incubation, suggesting that mitochondrial biogenesis were transiently upregulated by DEX. In contrast, mitochondrial fusion gene optic atrophy 1 (Opa1) and mitofusin 2 (Mfn2) started to be elevated as the biogenesis started to decrease. Finally, the mitochondrial fission increased and apoptosis becomes prominent. Agree with the mitochondrial biphasic alterations hypothesis, the results suggested an early increase of mitochondrial activities and biogenesis upon DEX stimulation to the osteoblasts. The oxidative phosphorylation and inducible nitric oxide synthase levels increased results in oxidative stress accumulation, leading to mitochondrial fusion, and subsequently fission and triggering the apoptosis. Our results indicated that the primary effects of GC on mitochondria are promoting their functions and biogenesis. Mitochondrial breakdown and the activation of the apoptotic pathways appeared to be the secondary effect after long-term treatment.

Lipophilicity of statins has been linked to extrahepatic cell penetration and inhibition of isoprenoid synthesis and coenzyme Q10, which may affect myocardial contraction. Whether statins' lipophilicity affects the risk of cardiovascular disease development in patients under dialysis is unclear. This population-based study included 114,929 patients undergoing chronic dialysis, retrieved from the Registry for Catastrophic Illness Patients from the National Health Insurance Research Database in Taiwan from 2000 to 2013. Statins were initiated after dialysis and classified into hydrophilic and lipophilic by the duration of use. In total, 17,015 statin users and match controls were identified by using propensity score matching in 1:1 ratio. New statin use was associated with higher cardiovascular disease risk (adjusted hazard ratio (aHR): 1.2, 95% confidence interval (CI), 1.13-1.28) but lower all-cause mortality (aHR: 0.93, 95% CI, 0.89-0.96). Hydrophilic statins were significantly associated with lower risk of cardiovascular disease compared with lipophilic statins (aHR: 0.91, 95% CI, 0.85-0.97).

Background and aim Antibiotic prophylaxis should be instituted for cirrhotic patients with upper gastrointestinal bleeding (UGIB), but the benefit on compensated patients remains undetermined. We aimed to compare the clinical outcomes between cirrhotic patients without major complications with UGIB with and without antibiotic prophylaxis. Methods We conducted this population-based cohort study by using Taiwanese Longitudinal Health Insurance Database 2000 (LHID2000, between 1997 to 2013), aged 18 years or older with a hospital discharge diagnosis of cirrhosis (n = 64,506), UGIB (n = 7,784), and endoscopic therapy (n = 2,292). After strict exclusions, 1205 patients were enrolled and were divided into antibiotic exposure (n = 558) and non-exposure (n = 647) groups. The outcomes were rebleeding and mortality. Results After completing the analysis adjusted by death, the rebleeding rates within 4 weeks were significantly lower in patients with antibiotic prophylaxis (3.05% versus 6.03%, P = 0.0142) and those with endoscopic therapy (0.72% vs 3.09%, P = 0.0033) but not significant after 3 months and onwards. Male patients aged > 55, high CCI score ≧ 4, and UGIB of variceal etiologies were benefited from rebleeding. The use of antibiotics did not significantly impact 6-week mortality (adjusted hazard ratio: 1.07, 95%CI: 0.41~2.75; P = 0.8943). Old age, multiple comorbidities, and UGIB of variceal etiologies were risk factors of all-cause mortality. Conclusions The current study suggested that cirrhotic patients without major complications who suffered from UGIB were benefited by the use of antibiotics to prevent rebleeding within 4 weeks after endoscopic treatment of UGIB especially for those with age > 55, high CCI score ≧ 4, and UGIB of variceal etiologies.

One of the leading global public-health burdens is metabolic syndrome (MetS), despite the many advances in pharmacotherapies. MetS, now known as “developmental origins of health and disease” (DOHaD), can have its origins in early life. Offspring MetS can be programmed by various adverse early-life conditions, such as nutrition imbalance, maternal conditions or diseases, maternal chemical exposure, and medication use. Conversely, early interventions have shown potential to revoke programming processes to prevent MetS of developmental origins, namely reprogramming. In this review, we summarize what is currently known about adverse environmental insults implicated in MetS of developmental origins, including the fundamental underlying mechanisms. We also describe animal models that have been developed to study the developmental programming of MetS. This review extends previous research reviews by addressing implementation of reprogramming strategies to prevent the programming of MetS. These mechanism-targeted strategies include antioxidants, melatonin, resveratrol, probiotics/prebiotics, and amino acids. Much work remains to be accomplished to determine the insults that could induce MetS, to identify the mechanisms behind MetS programming, and to develop potential reprogramming strategies for clinical translation.

Background To assess the effect of sodium glucose cotransporter-2 inhibitors (SGLT-2is) for type 2 diabetes on kidney outcomes stratified by patient baseline estimated glomerular filtration rate (eGFR) levels (i.e., eGFR ≤ 60, 60 90 mL/min/1.73 m2). Methods Patients from three large healthcare delivery systems in Taiwan who had initiated SGLT-2is or other glucose-lowering drugs (oGLDs) between May 2016 and December 2017 were included. Main outcomes were the times to 30%, 40%, and 50% eGFR reduction after treatment initiation. One-to-one propensity score matching in the overall study cohort and in each eGFR subgroup between SGLT-2i and oGLD users was applied to ensure between-group comparability in baseline characteristics. Results There were 13,666 matched pairs of SGLT-2is and oGLD users in the overall cohort. While a sustained eGFR decline was revealed in oGLD-treated patients (mean values [standard errors] from 85.61 [0.43] to 82.49 [0.44] mL/min/1.73 m2 during the 12 months after treatment initiation), the mean eGFR values of SGLT-2i users decreased in the first 3 months (85.68 [0.37] to 79.71 [0.41] mL/min/1.73 m2) but then improved and sustained until the end of follow-up. There were 2300, 5705, and 5509 matched SGLT-2i and oGLD users in the eGFR ≤ 60, 60 90 subgroups, respectively. Using SGLT-2is versus oGLDs was significantly associated with slower eGFR declines; hazard ratios (HRs) were 0.51 (95% CI 0.37–0.69), 0.51 (0.37–0.70), and 0.47 (0.31–0.71) for 40% eGFR reduction in the eGFR ≤ 60, 60 90 subgroups, respectively. The renoprotective effect of SGLT-2is versus oGLDs was confirmed in the outcomes of 30% and 50% eGFR reduction across the three eGFR subgroups. Conclusions This study supports the renoprotective benefit of real-world SGLT-2i use irrespective of patient baseline kidney function.

Background and Objectives: Real-world evidence of apixaban treatment in patients with chronic kidney disease remains scarce. This study aimed to compare the relative risk of stroke or systemic embolism (SE) and major bleeding between apixaban and warfarin in atrial fibrillation (AF) patients with different degrees of kidney function.Design, Setting, Participants, and Measurements: We evaluated newly diagnosed AF patients between 2004 and 2018, who were receiving apixaban or warfarin. Electronic medical record data were collected from a large healthcare delivery network in Taiwan. The outcomes of hospitalization for stroke/SE and major bleeding were compared with propensity-score matched apixaban and warfarin cohorts. Stratified analyses according to initial apixaban dose (standard dose of 10 mg/day vs. lower dose of 2.5–5.0 mg/day) and baseline estimated glomerular filtration rate were performed.Results: Each cohort involved 1,625 matched patients. Apixaban was significantly associated with a lower risk of stroke/SE (adjusted hazard ratio [aHR]: 0.74; 95% confidence interval [CI]:0.57–0.97; p = 0.03). The risk of major bleeding was not increased whether in standard doses (aHR: 0.66; 95% CI: 0.45–0.96; p = 0.03) or reduced doses (aHR, 0.84; 95% CI, 0.63–1.12; p = 0.23) of apixaban. Regarding kidney function, apixaban reduced the risk of stroke/SE by 37% in those with an eGFR of 2 (aHR: 0.63; 95% CI: 0.40–0.98; p = 0.04).Conclusions: Compared to warfarin, apixaban is associated with a reduced risk of stroke/SE and is consistent with a subset of AF patients with eGFR 2. Both standard and reduced doses of apixaban showed lower risk of major bleeding than those of warfarin.

Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide (NO) synthase inhibitor, inhibits NO synthesis and contributes to the pathogenesis of many human diseases. In adults, ADMA has been identified as a biomarker for chronic kidney disease (CKD) progression and cardiovascular risk. However, little attention is given to translating the adult experience into the pediatric clinical setting. In the current review, we summarize circulating and urinary ADMA reported thus far in clinical studies relating to kidney disease in children and adolescents, as well as systematize the knowledge on pathophysiological role of ADMA in the kidneys. The aim of this review is also to show the various analytical methods for measuring ADMA and the issues tht need to be addressed before transforming to clinical practice in pediatric medicine. The last task is to suggest that ADMA may not only be suitable as a diagnostic or prognostic biomarker, but also a promising therapeutic strategy to treat pediatric kidney disease in the future.

Exposure to environmental chemicals during pregnancy and lactation is a contributing factor in gut microbiota dysbiosis and linked to programming of hypertension. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most toxic dioxin, induces toxic effects by mediating aryl hydrocarbon receptor (AHR). Resveratrol, a potent antioxidant with prebiotic properties, can possess high affinity for AHR and protect against TCDD-activated AHR attack. We examined whether perinatal resveratrol therapy prevents offspring hypertension programmed by maternal TCDD exposure and whether its beneficial effects are related to reshaping gut microbiota and antagonizing AHR-mediated T helper 17 (TH17) cells responses using a maternal TCDD exposure rat model. Pregnant Sprague-Dawley rats were given a weekly oral dose of TCDD 200 ng/kg for four doses (T), 50 mg/L of resveratrol in drinking water (CR), TCDD + resveratrol (TR), or vehicle (C) in pregnancy and lactation periods. Male offspring (n = 7–8/group) were sacrificed at the age of 12 weeks. Perinatal TCDD exposure caused elevated blood pressure in adult male offspring, which resveratrol supplementation prevented. Additionally, the TCDD-induced programming of hypertension is coincided with the activation of AHR signaling, TH17-induced renal inflammation, and alterations of gut microbiota compositions. Conversely, TCDD-mediated induction of AHR signaling and TH17 responses were restored by maternal resveratrol supplementation. Furthermore, maternal resveratrol supplementation prevented the programming of hypertension and was related to increased genera Bacteroides, ASF356, and Lachnoclostridium. Taken together, these results suggest that the interplay between gut microbiota, AHR-mediated TH17 responses, and renal inflammation in the gut and kidneys may play an important role in the action of resveratrol against TCDD-induced programming of hypertension.

Background: There is limited data on the relative survival rate of first-line therapy of gefitinib, erlotinib (first-generation epidermal growth factor receptor-tyrosine kinase inhibitor [EGFR-TKI]), and afatinib (second-generation EGFR-TKI) in patients with EGFR-mutated advanced lung adenocarcinoma in real-world data, especially in the Asian population. This study aimed to compare the relative survival rate of gefitinib, erlotinib, and afatinib in patients with EGFR-mutated advanced lung adenocarcinoma by real-world data in Taiwan.Methods: This retrospective cohort population-based study included untreated adult patients diagnosed with advanced lung adenocarcinoma who were identified in the Taiwan National Health Insurance Research Database between 2014 and 2017. The date of EGFR-mutated advanced lung adenocarcinoma diagnosis was referred as index date. This outcome evaluated overall survival (OS) and time to treatment failure (TTF) between gefitinib, erlotinib, and afatinib. Switching EGFR-TKIs or chemotherapy and new development of brain metastases were proxies of TTF. Estimated relative treatment effects on OS and TTF among EGFR-TKIs were adjusted by inverse probability of treatment weighting (IPTW) in Cox proportional hazards model. Propensity score (PS) matched pair analyses were performed as sensitivity analyses.Results: The study cohort included 3,695 patients initiated with gefitinib, 3,310 with erlotinib, and 3,041 with afatinib. The mean age among the three treatment groups was 70.4 (±11.6), 66.8 (±11.6), and 64.3 (±11.4) years, and the female percentage was 70.4, 58.6, and 57.7%, respectively. Afatinib showed longer median OS than gefitinib (23.9 vs. 21.3 months; adjusted hazard ratio (aHR), 0.87; p < 0.001) and erlotinib (23.9 vs. 21.8 months; aHR, 0.87; p = 0.001). Consistent results were observed with TTF outcomes. For patients with brain metastases at diagnosis, afatinib showed similar OS with erlotinib (p = 0.917) but superior to gefitinib (p = 0.028). PS matching had similar results with IPTW adjustment in the study population.Conclusion: Afatinib as first-line therapy had better survival outcomes for EGFR-mutated advanced lung adenocarcinoma than gefitinib and erlotinib in the Taiwan population. Both erlotinib and afatinib demonstrated superior treatment effect in patients with initial brain metastases than gefitinib.

Cardiovascular disease (CVD) is an evolving process that begins in the early stages of chronic kidney disease (CKD) in children. Several surrogate markers, such as ambulatory blood pressure monitoring (ABPM), left ventricular (LV) mass, and arterial stiffness assessment, allow for the early detection of subclinical CVD in pediatric CKD. Four groups of plasma samples (n = 3/group) from congenital anomalies of the kidney and urinary tract (CAKUT), as well as non-CAKUT patients with or without BP abnormalities, were studied to screen differentially expressed proteins using isobaric tags for relative and absolute protein quantification (iTRAQ)-based proteomics. As a result, 20 differentially expressed proteins associated with hypertension in children with CKD were discovered. Among them, apolipoprotein C-II (apoC-II) was found to have the highest abundance among the CKD patients with hypertension. As such, we hypothesized that apoC-II and apolipoprotein C-III (apoC-III) levels were related to BP abnormalities and CVD in children suffering from mild-to-moderate CKD. We examined their associations with surrogate markers of CV risk in 88 pediatric patients with CKD stages G1–G4. Children with CKD stages G2–G4 had a higher plasma apoC-II level than G1 patients (6.35 vs. 5.05 mg/dl, p < 0.05). We observed that ABPM abnormalities, LV mass, and arterial stiffness parameters were greater in CKD children who had stages G2–G4 than in those who had stage G1 (all p < 0.05). Plasma levels of apoC-II and apoC-III were positively correlated with total cholesterol, triglyceride, and low-density lipoprotein (LDL) (all p < 0.001). In multivariate linear regression analyses, apoC-II was correlated with a high LV mass index and an abnormal ABPM profile, and apoC-III was correlated with 24-h hypertension (r = 0.303, p = 0.003) and asleep hypertension (r = 0.379, p < 0.001). Early evaluations of apoC-II and apoC-III, ABPM, and surrogate markers of CV risk will aid in early preventative interventions to reduce the risk of CV in youths suffering from CKD.

Chronic kidney disease (CKD) and hypertension are becoming a global health challenge, despite developments in pharmacotherapy. Both diseases can begin in early life by so-called “developmental origins of health and disease” (DOHaD). Environmental chemical exposure during pregnancy can affect kidney development, resulting in renal programming. Here, we focus on environmental chemicals that pregnant mothers are likely to be exposed, including dioxins, bisphenol A (BPA), phthalates, per- and polyfluoroalkyl substances (PFAS), polycyclic aromatic hydrocarbons (PAH), heavy metals, and air pollution. We summarize current human evidence and animal models that supports the link between prenatal exposure to environmental chemicals and developmental origins of kidney disease and hypertension, with an emphasis on common mechanisms. These include oxidative stress, renin-angiotensin system, reduced nephron numbers, and aryl hydrocarbon receptor signaling pathway. Urgent action is required to identify toxic chemicals in the environment, avoid harmful chemicals exposure during pregnancy and lactation, and continue to discover other potentially harmful chemicals. Innovation is also needed to identify kidney disease and hypertension in the earliest stage, as well as translating effective reprogramming interventions from animal studies into clinical practice. Toward DOHaD approach, prohibiting toxic chemical exposure and better understanding of underlying mechanisms, we have the potential to reduce global burden of kidney disease and hypertension.

Maternal exposure to environmental pollutants affects fetal development, which can result in hypertension in adulthood. Gut microbiota-derived metabolite trimethylamine (TMA), trimethylamine-N-oxide (TMAO), and short chain fatty acids (SCFAs) have been associated with hypertension. We tested a hypothesis that maternal 3,3-Dimethyl-1-butanol (DMB, a TMA inhibitor) therapy prevents 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure-induced hypertension in adult offspring relevant to alterations of gut microbiota-derived metabolites, the mediation of aryl hydrocarbon receptor (AHR) signaling, and the renin-angiotensin system (RAS). Pregnant Sprague-Dawley rats were given weekly oral dose of TCDD 200 ng/kg for four doses (T), 1% DMB in drinking water (D), TCDD + DMB (TD), or vehicle (C) in pregnancy and lactation periods. Male progeny (n = 8/group) were sacrificed at the age of 12 weeks. Perinatal TCDD exposure caused hypertension in adult male offspring coinciding with reduced α-diversity, increased the Firmicutes to Bacteroidetes ratio, less abundant beneficial bacteria, impaired SCFA receptors’ expression, the activation of AHR signaling, and the aberrant activation of the RAS. Treatment with DMB during pregnancy and lactation rescued hypertension induced by perinatal TCDD exposure. This was accompanied by reshaping gut microbiota, mediating TMA-TMAO metabolic pathway, increasing acetic acid and its receptors, and restoring the AHR and RAS pathway. Our data provide new insights into the therapeutic potential of DMB, a microbiome-based metabolite treatment, for the prevention of hypertension of developmental origins.

Cardiovascular disease (CVD) risk factors are present early in life in children with chronic kidney disease (CKD), consequently cardiovascular morbidity presents in early adulthood. However, risk factors of CVD have been rarely addressed in children with early stage of CKD. This study included 63 children and adolescents aged 8- to 18 years-old with CKD stage G1–G4. Cardiovascular assessments consisted of 24-h ambulatory blood pressure monitoring (ABPM), arterial stiffness index, and echocardiography. We also applied dual-energy x-ray absorptiometry (DXA) scanning to analyze percentage body fat (PBF), lean body mass index (LBMI), fat mass index (FMI), and the android to gynoid fat ratio (A/G ratio). Up to 63.5% of CKD children had abnormal changes in BP detected by ABPM. CKD children with abnormal ABPM were older, had higher numbers of CKD stage G2 to G4, hyperuricemia, obesity, and higher FMI z-score and A/G ratio compared to individuals with normal ABPM (all p &lt, 0.05). Among these factors, only FMI z-score showed an independent association with abnormal ABPM using multivariate logistic regression analysis (p = 0.037). Our data highlight that body fat plays a key role for an abnormal ABPM in CKD children. The assessment of FMI may have clinical utility in discriminating CV risk in children and adolescents with early stages of CKD.

Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S), three major gasotransmitters, are involved in pleiotropic biofunctions. Research on their roles in hypertension and kidney disease has greatly expanded recently. The developing kidney can be programmed by various adverse in utero conditions by so-called renal programming, giving rise to hypertension and kidney disease in adulthood. Accordingly, early gasotransmitter-based interventions may have therapeutic potential to revoke programming processes, subsequently preventing hypertension and kidney disease of developmental origins. In this review, we describe the current knowledge of NO, CO, and H2S implicated in pregnancy, including in physiological and pathophysiological processes, highlighting their key roles in hypertension and kidney disease. We summarize current evidence of gasotransmitter-based interventions for prevention of hypertension and kidney disease in animal models. Continued study is required to assess the interplay among the gasotransmitters NO, CO, and H2S and renal programming, as well as a greater focus on further clinical translation.

Melatonin, a signaling hormone with pleiotropic biofunctions, has shown health benefits. Trimethylamine-N-oxide (TMAO) and asymmetric dimethylarginine (ADMA) are uremic toxins involved in the development of hypertension. TMAO originates from trimethylamine (TMA), a gut microbial product. ADMA is an endogenous nitric oxide (NO) synthase inhibitor. We examined whether melatonin therapy could prevent hypertension and kidney disease by mediating gut microbiota-derived metabolites and the NO pathway using an adenine-induced chronic kidney disease (CKD) young rat model. Six-week-old young Sprague Dawley rats of both sexes were fed a regular diet (C group), a diet supplemented with 0.5% adenine (CKD group), or adenine plus 0.01% melatonin in their drinking water (CKD + M group) for three weeks (N = 8/group). Adenine-fed rats developed renal dysfunction, hypertension, renal hypertrophy and increased uremic toxin levels of TMAO and ADMA. Melatonin therapy prevented hypertension in both sexes and attenuated kidney injury in males. Melatonin reversed the changes to the plasma TMAO-to-TMA ratio induced by CKD in both sexes. Besides, the protective effects of melatonin were associated with restoration of gut microbiota alterations, including increased α-diversity, and enhancement of the abundance of the phylum Proteobacteria and the genus Roseburia in male rats. Melatonin therapy also partially prevented the increases in ADMA in male CKD rats. Melatonin sex-specifically protected young rats against hypertension and kidney injury induced by CKD. The results of this study contribute toward a greater understanding of the interaction between melatonin, gut microbiota-derived metabolites, and the NO pathway that is behind CKD, which will help to prevent CKD-related disorders in children.

Cardiovascular diseases (CVDs) can originate from early life. Accumulating evidence suggests that gut microbiota in early life is linked to CVDs in later life. Gut microbiota-targeted therapy has gained significant importance in recent decades for its health-promoting role in the prevention (rather than just treatment) of CVDs. Thus far, available gut microbiota-based treatment modalities used as reprogramming interventions include probiotics, prebiotics, and postbiotics. The purpose of this review is, first, to highlight current studies that link dysbiotic gut microbiota to the developmental origins of CVD. This is followed by a summary of the connections between the gut microbiota and CVD behind cardiovascular programming, such as short chain fatty acids (SCFAs) and their receptors, trimethylamine-N-oxide (TMAO), uremic toxins, and aryl hydrocarbon receptor (AhR), and the renin-angiotensin system (RAS). This review also presents an overview of how gut microbiota-targeted reprogramming interventions can prevent the developmental origins of CVD from animal studies. Overall, this review reveals that recent advances in gut microbiota-targeted therapy might provide the answers to reduce the global burden of CVDs. Still, additional studies will be needed to put research findings into practice.

Background and Aims Perinatal high-fat (HF) diet programs high blood pressure (BP) in adult offspring. Hydrogen sulfide (H2S) has shown benefits in hypertension by restoration of nitric oxide (NO) bioavailability and alterations of gut microbiota. Garlic, a naturally dietary source of H2S donors, supplementation has shown benefits in hypertension. We aimed to examine whether maternal garlic oil supplementation can prevent hypertension programmed by maternal and post-weaning high-fat diet in adult offspring and whether its protective effects are related to mediation of H2S-genetaing system, alterations of gut microbiota composition, and microbiota metabolite short chain fatty acids (SCFAs). Method Pregnant rats received either a normal diet (ND) or HF diet (D12331, Research Diets, Inc.) Garlic oil (GO) or vesicle was administered daily by oral gavage at 100 mg/kg/day during pregnancy and lactation. Male offspring were weaned at 3 weeks of age, and onto either ND or HF diet to 16 weeks of age. Male offspring were assigned to four groups (n=8/group): ND, HF, ND+GO, and HF+GO. Garlic supplementation during pregnancy and lactation protected against programmed hypertension in adult male offspring fed with HF diet. All offspring were killed at 16 weeks of age. NO-related parameters were analyzed by HPLC. Plasma levels of SCFA were determined using GC-MS method. Fecal microbial community was analyzed using a combination of 16S rRNA gene and fecal metagenome sequence analysis. Results Garlic supplementation during pregnancy and lactation protected against programmed hypertension in adult male offspring fed with HF diet. Garlic oil supplementation caused a significant increase in plasma levels of acetate, propionate, and butyrate. NO bioavailability was augmented by garlic oil supplementation, represented by decreases of plasma levels of asymmetric and symmetric dimethylarginine (ADMA and SDMA) levels, and increased plasma L-arginine-to-ADMA ratio (AAR). HF intake associated with decreased α-diversity was quantified by Shannon diversity index. The Analysis of similarities (ANOSIM) demonstrated the difference in the gut microbiota among the four groups existed (All p < 0.05), indicating that four groups had distinct enterotypes. Additionally, garlic oil supplementation increased abundance of genus Lactobacillus, but decreased genera Turicibacter and Staphylococcus. Moreover, the linear discriminant analysis effect size (LEfSe) algorithm analysis identified several microbial markers including genera Lactobacillus, Staphylococcus, and Turicibacter. Conclusion The beneficial effects of garlic oil were associated with increased renal mRNA expression and activity of H2S-generating enzymes, increased NO bioavailability, increased plasma SCFA levels, and alterations of gut microbiota composition. Our data revealed associations between H2S-generating pathway in the gut and kidneys, NO system, gut microbiota, and microbiota-derived metabolites in hypertension programmed by HF intake and provided insight to garlic oil as a hypertension reprogramming strategy for further translational research.

Increasing evidence suggests that fetal programming through environmental exposure during a critical window of early life leads to long-term detrimental outcomes, by so-called developmental origins of health and disease (DOHaD). Hypertension can originate in early life. Animal models are essential for providing convincing evidence of a causal relationship between diverse early-life insults and the developmental programming of hypertension in later life. These insults include nutritional imbalances, maternal illnesses, exposure to environmental chemicals, and medication use. In addition to reviewing the various insults that contribute to hypertension of developmental origins, this review focuses on the benefits of animal models in addressing the underlying mechanisms by which early-life interventions can reprogram disease processes and prevent the development of hypertension. Our understanding of hypertension of developmental origins has been enhanced by each of these animal models, narrowing the knowledge gap between animal models and future clinical translation.

Background and Aims Renal function recovery after acute kidney injury (AKI) is associated with patient outcomes. The study objectives were to assess the patterns of AKI recovery within 6 months following discharge for AKI and subsequent incidence of chronic dialysis. Method A retrospective cohort of 234,867 hospitalized adult patients was examined for AKI between January 1, 2010, and December 31, 2017 in the largest healthcare delivery system in Taiwan. Renal function recovery at 3- and 6-month post discharge, incident chronic kidney disease and chronic dialysis initiation were analyzed over 7 years of follow-up. Renal recovery was defined by < 1.5× baseline SCr (prior to the hospitalization). Independent associations between renal function recovery patterns and renal outcomes was assessed by Cox proportional hazard model controlling for potential confounders, and subdistribution hazard ratio (SHR) with [95% CI] was analysed for competing risk of early death. Results Among 3 months AKI survivors (n=24,132), 14.28% (n=3,430) did not recovery back to baseline, and 16% of recovery did not sustain. Three distinct renal function recovery continuums at 6 months post hospital discharge were: persistent non-recovery (10.18%), non-recovery (14.33%), and recovery (75.5%). Comparing to survivors without AKI (n=50,387), the impact of renal recovery continuum on chronic dialysis initiation varied by patient’s baseline renal disease (SHR was 2.82 [95%CI, 2.42-3.28] in CKD, and 0.8 [95%CI, 0.27-2.38] for non-CKD. Persistent non-recovery was significantly associated with a greater increased risk of chronic dialysis than non-recovery in any patients with AKI. Comparing to patients with sustained AKI recovery, risk of CKD onset increased 5-fold in persistent non-recovery and 3-fold risk in non-recovery. Conclusion The continuum of AKI recovery post 6 months is associated with increased risk of chronic dialysis, particularly in patients with baseline CKD. These study results suggested that patients ever with AKI should receive close renal function monitoring for post-discharge management.

Background: With the promising outcomes of the pre-ESRD (end-stage renal disease) pay-for-performance (P4P) program, the National Health Insurance Administration (NHIA) of Taiwan launched a P4P program for patients with early chronic kidney disease (CKD) in 2011, targeting CKD patients at stages 1, 2, and 3a. This study aimed to examine the long-term effect of the early-CKD P4P program on CKD progression. Methods: We conducted a matched cohort study using electronic medical records from a large healthcare delivery system in Taiwan. The outcome of interest was CKD progression to estimated glomerular filtration rate (eGFR)

Purpose Steadily maintaining high intra-gastric PH is the major factor for successful Helicobacter pylori (H.pylori) eradication. It is important to search for a stronger PPI. Dexlansoprazole MR is a dual delayed release formulation PPI taken once daily which is capable of maintaining longer duration of high intra-gastric PH. It is very effective in treating gastroesophageal disease but reports on H, pylori eradication is very rare. This study sought to compare dexlansoprazole MR-based concomitant treatment and lansoprazole-based concomitant treatment in H. pylori infection and to investigate the factors that affect the eradication rates. Methods Two hundred two participants with H. pylori infection were included and randomly assigned to seven days of dexlansoprazole MR-based concomitant therapy (dexlansoprazole MR 60 mg once daily, clarithromycin 500 mg twice daily, amoxicillin 1 g twice daily and metronidazole 500 mg twice daily; DACM group) or a seven days of lansoprazole-based concomitant therapy (lansoprazole 30 mg twice daily, clarithromycin 500 mg twice daily, amoxicillin 1 g twice daily, and metronidazole 500 mg twice daily; LACM group). The participants were asked to perform urea breath tests eight weeks later. Results The eradication rates in the DACM group were 86.1% [95% confidence interval (CI): 77.8%-92.2%] in the ITT analysis and 90.6% (95% CI: 82.9%-95.6%) in the PP analysis, respectively, as compared with 90.1% (95% CI: 82.6%-95.2%) and 92.6% (95% CI: 85.5%-96.9%) (p=0.384 and p=0.572, respectively) in the LACM group for the same analyses. The adverse event rates were 11.5% in the DACM group and 10.2% in the LACM group (p=0.779). Conclusion As a first-line H. pylori treatment regimen, dexlansoprazole MR-based concomitant therapy attained a successful eradication rate of 90%, which was non inferior to that of lansoprazole-based concomitant treatment. Clinicaltrialsgov identifier NCT03829150.

Purpose: To assess the difference of the first-line therapy for Helicobacter pylori in patients with or without type 2 diabetes (DM) and to investigate the clinical factors influencing treatment outcomes. Patients and methods: In total, 719 patients with H. pylori infection were treated with 7-day standard first-line triple therapy, of whom 182 did and 537 did not have DM. Propensity score matched at a 1:2 ratio – for age, sex and body mass index was performed for the two groups, yielding a DM group with 147 patients and a non-DM group with 249 matched controls for analysis. Urea breath test was performed 6–8 weeks after treatment. Clinical and laboratory parameters were collected for identifying factors associated with failed eradication. Results: H. Pylori was eradicated in 74.1% (95% confidence interval [CI] =66.2–81.0) of the DM group and 85.3% (95% CI =80.8–89.4) of the non-DM group (p=0.005). Of 51 gastric biopsy samples cultured for H. pylori, 41 were positive. In the DM group, the rates of resistance to amoxicillin, clarithromycin, levofloxacin, and tetracycline were 0%, 50.0%, 50.0% and 0%, respectively. In the non-DM group, the comparable proportions were 2.9%, 17.1%, 22.9%, and 0%, respectively. Univariate analysis revealed that DM (Odds ratio [OR], 1.771, 95% CI, 1.167–2.668, p=0.006), clarithromycin resistance (OR, 15.273; 95% CI, 1.687–138.269; p=0.015), and amoxicillin resistance (OR, 4.672; 95% CI, 2.431–8.979; p90% eradication.