Interplay between maternal nutrition and epigenetic programming on offspring hypertension.

Recent human and animal studies have delineated hypertension can develop in the earliest stage of life. A lack or excess of particular nutrients in the maternal diet may impact the expression of genes associated with BP, leading to an increased risk of hypertension in adulthood. Modulations in gene expression could be caused by epigenetic mechanisms through aberrant DNA methylation, histone modification, and microRNAs (miRNAs). Several molecular mechanisms for the developmental programming of hypertension, including oxidative stress, dysregulated nutrient-sensing signal, aberrant renin-angiotensin system, and dysbiotic gut microbiota have been associated with epigenetic programming. Conversely, maternal nutritional interventions such as amino acids, melatonin, polyphenols, resveratrol or short chain fatty acids may work as epigenetic modifiers to trigger protective epigenetic modifications and prevent offspring hypertension. We present a current perspective of maternal malnutrition that can cause fetal programming and the potential of epigenetic mechanisms lead to offspring hypertension. We also discuss the opportunities of dietary nutrients or nutraceuticals as epigenetic modifiers to counteract those adverse programming actions for hypertension prevention. The extent to which aberrant epigenetic changes can be reprogrammed or reversed by maternal dietary interventions in order to prevent human hypertension remains to be established. Continued research is necessary to evaluate the interaction between maternal malnutrition and epigenetic programming, as well as a greater focus on nutritional interventions for hypertension prevention towards their use in clinical translation.

Sulfur-Containing Amino Acids, Hydrogen Sulfide, and Sulfur Compounds on Kidney Health and Disease.

Hydrogen sulfide (H2S) plays a decisive role in kidney health and disease. H2S can ben synthesized via enzymatic and non-enzymatic pathways, as well as gut microbial origins. Kidney disease can originate in early life induced by various maternal insults throughout the process, namely renal programming. Sulfur-containing amino acids and sulfate are essential in normal pregnancy and fetal development. Dysregulated H2S signaling behind renal programming is linked to deficient nitric oxide, oxidative stress, the aberrant renin-angiotensin-aldosterone system, and gut microbiota dysbiosis. In animal models of renal programming, treatment with sulfur-containing amino acids, N-acetylcysteine, H2S donors, and organosulfur compounds during gestation and lactation could improve offspring's renal outcomes. In this review, we summarize current knowledge regarding sulfide/sulfate implicated in pregnancy and kidney development, current evidence supporting the interactions between H2S signaling and underlying mechanisms of renal programming, and recent advances in the beneficial actions of sulfide-related interventions on the prevention of kidney disease. Modifying H2S signaling is the novel therapeutic and preventive approach to reduce the global burden of kidney disease; however, more work is required to translate this into clinical practice.

Dietary Resveratrol Butyrate Monoester Supplement Improves Hypertension and Kidney Dysfunction in a Young Rat Chronic Kidney Disease Model.

Chronic kidney disease (CKD) remains a public health problem. Certain dietary supplements can assist in the prevention of CKD progression. In this regard, resveratrol is a polyphenol and has a potential therapeutic role in alleviating CKD. We previously utilized butyrate in order to improve the bioavailability of resveratrol via esterification and generated a resveratrol butyrate monoester (RBM). In this study, the hypothesis that RBM supplementation is able to protect against kidney dysfunction and hypertension was tested by using an adenine-induced CKD model. For this purpose, three-week-old male Sprague Dawley rats (n = 40) were equally categorized into: group 1-CN (sham control); group 2-CKD (adenine-fed rats); group 3-REV (CKD rats treated with 50 mg/L resveratrol); group 4-MEL (CKD rats treated with 25 mg/L RBM); and group 5-MEH (CKD rats treated with 50 mg/L RBM). At the end of a 12-week period, the rats were then euthanized. The adenine-fed rats displayed hypertension and kidney dysfunction, which were attenuated by dietary supplementation with RBM. The CKD-induced hypertension coincided with: decreased nitric oxide (NO) bioavailability; augmented renal protein expression of a (pro)renin receptor and angiotensin II type 1 receptor; and increased oxidative stress damage. Additionally, RBM and resveratrol supplementation shaped distinct gut microbiota profiles in the adenine-treated CKD rats. The positive effect of high-dose RBM was shown together with an increased abundance of the genera Duncaniella, Ligilactobacillus, and Monoglobus, as well as a decrease in Eubacterium and Schaedierella. Importantly, the mechanism of action of the RBM supplementation may be related to the restoration of NO, rebalancing of the RAS, a reduction in oxidative stress, and alterations to the gut microbiota. Moreover, RBM supplementation shows promise for the purposes of improving CKD outcomes and hypertension. As such, further translation to human studies is warranted.

Resveratrol Butyrate Ester Supplementation Blunts the Development of Offspring Hypertension in a Maternal Di-2-ethylhexyl Phthalate Exposure Rat Model.

Resveratrol (REV) is a plant polyphenol with a plethora of beneficial properties. We previously enhanced the efficacy of REV via esterification of REV with butyrate to form resveratrol butyrate ester (RBE). Compared with REV, RBE exhibits higher bioavailability and better antioxidant effects. Hypertension can originate in early life because of maternal toxic chemical exposure. This study aims to examine the effectiveness of RBE in the protection of offspring hypertension induced by maternal di-2-ethylhexylphthalate (DEHP) exposure and to explore the underlying mechanisms. DEHP (10 mg/kg/day) was used as oral gavage to pregnant rats during gestation and lactation. The control group received the vehicle. Three groups of DEHP-exposed dams received REV (6.67 mg/kg/day), or low-dose (3.33 mg/kg/day) or high-dose (6.67 mg/kg/day) RBE in drinking water during gestation and lactation. Perinatal DEHP exposure resulted in hypertension and bodyweight gain in adult male offspring, which was prevented by high-dose RBE. REV supplementation attenuated DEHP exposure-induced increases in blood pressure but not bodyweight. High-dose RBE decreased renal oxidative damage, increased plasma butyrate concentrations, and altered short chain fatty acid receptor (SCFA) expression. Low-dose RBE treatment reduced downstream mediators of the acryl hydrocarbon receptor (AHR) signaling pathway. Moreover, DEHP exposure, REV and RBE treatment differentially shaped the offspring's gut microbiota. In particular, high-dose RBE increased the abundance of the genus Duncaniella. The beneficial effects of RBE treatment were related to reducing oxidative damage, increasing plasma butyrate concentrations, downregulating SCFA receptor expression, antagonizing AHR signaling, and altering the gut microbiota. This study provides the first evidence of RBE as a novel plant polyphenol bioproduct targeting the oxidative stress and gut microbiota to protect against maternal DEHP exposure-primed offspring hypertension.

Maternal Metformin Treatment Reprograms Maternal High-Fat Diet-Induced Hepatic Steatosis in Offspring Associated with Placental Glucose Transporter Modifications.

Maternal high-fat (HF) diet exposure in utero may affect fetal development and cause metabolic problems throughout life due to lipid dysmetabolism and oxidative damage. Metformin has been suggested as a potential treatment for body weight reduction and nonalcoholic fatty liver disease, but its reprogramming effect on offspring is undetermined. This study assesses the effects of maternal metformin treatment on hepatic steatosis in offspring caused by maternal HF diet. Female rats were fed either a control or an HF diet before conception, with or without metformin treatment during gestation, and placenta and fetal liver tissues were collected. In another experiment, the offspring were fed a control diet until 120 d (adult stage). Metformin treatment during pregnancy ameliorates placental oxidative stress and enhances placental glucose transporter 1 (GLUT1), GLUT3, and GLUT4 expression levels through 5' adenosine monophosphate-activated protein kinase (AMPK) activation. Maternal metformin treatment was shown to reprogram maternal HF diet-induced changes in offspring fatty liver with the effects observed in adulthood as well. Further validation is required to develop maternal metformin therapy for clinical applications.

Perinatal Garlic Oil Supplementation Averts Rat Offspring Hypertension Programmed by Maternal Chronic Kidney Disease.

Garlic (Allium sativum) is a functional food, having hydrogen sulfide (H2S)-releasing capacity, which exhibits considerable effects on hypertension and gut microbiota. H2S is strongly associated with hypertension and chronic kidney disease (CKD). Maternal CKD leads to hypertension in adult rat progeny, which was linked to disruption of the gut microbiota. This study validated the benefits of perinatal garlic oil supplementation against offspring hypertension induced by maternal CKD via modulation of H2S signaling, nitric oxide (NO), and the gut microbiota. Before pregnancy, female rats received a 0.5% adenine diet for 3 weeks to develop an animal model to mimic human CKD. Garlic oil (100 mg/kg/day) or vehicle was administered to pregnant rats by oral gavage during gestation and lactation. Perinatal garlic oil supplementation protected against maternal CKD-induced hypertension in offspring at 12 weeks of age. The beneficial effects of garlic oil are associated with enhanced H2S signaling, increased NO bioavailability, and shifts in gut microbiota. Perinatal garlic oil supplementation reduces abundance of genera Variovorax, Nocardia, Sphingomonas, and Rhodococcus. Our findings provide insight into the role of early H2S-targeted intervention as a preventive strategy in hypertension for further translational research.

Novel Insights on Dietary Polyphenols for Prevention in Early-Life Origins of Hypertension: A Review Focusing on Preclinical Animal Models.

Polyphenols are the largest group of phytochemicals with health benefits. Early life appears to offer a critical window of opportunity for launching interventions focused on preventing hypertension, as increasing evidence supports the supposition that hypertension can originate in early life. Although polyphenols have antihypertensive actions, knowledge of the potential beneficial action of the early use of polyphenols to avert the development of hypertension is limited. Thus, in this review, we first provide a brief summary of the chemistry and biological function of polyphenols. Then, we present the current epidemiological and experimental evidence supporting the early-life origins of hypertension. We also document animal data on the use of specific polyphenols as an early-life intervention to protect offspring against hypertension in adulthood and discuss underlying mechanisms. Continued research into the use of polyphenols to prevent hypertension from starting early in life will have far-reaching implications for future health.

Dietary Supplementation with Cysteine during Pregnancy Rescues Maternal Chronic Kidney Disease-Induced Hypertension in Male Rat Offspring: The Impact of Hydrogen Sulfide and Microbiota-Derived Tryptophan Metabolites.

Maternal chronic kidney disease (CKD) is linked to offspring hypertension. The gut microbiome and its tryptophan metabolites, nitric oxide (NO), and renin-angiotensin system (RAS) are closely related to the development of hypertension. Hydrogen sulfide (H2S) has shown an anti-hypertensive effect. Our objective was to test whether l- or d-cysteine supplementation in pregnancy can prevent hypertension programmed by maternal CKD in adult offspring and to explore the protective mechanisms. CKD was induced in pregnant Sprague Dawley rats by a 0.5% adenine diet for 3 weeks. l- or d-cysteine was supplemented at 8 mmol/kg body weight/day during pregnancy. Male offspring were sacrificed at the age of 12 weeks (n = 8 per group). Maternal CKD-induced hypertension was similarly prevented by l- or d-cysteine supplementation. The protective effects of l- and d-cysteine are related to reducing oxidative stress, rebalancing the RAS, and reshaping the gut microbiome. l-cysteine therapy protected adult offspring against hypertension and was associated with enhanced H2S production, restoration of NO bioavailability, enhancement of beneficial genera Oscillibacter and Butyricicoccus, depletion of indole-producing genera Alistipes and Akkermansia, and the reduction of several indole metabolites. d-cysteine treatment increased kynurenic acid, 3-hydroxykynurenine, and xanthurenic acid in the kynurenine pathway, decreased 5-hydroxytryptophan and serotonin in the serotonin pathway, and enriched genera Bacteroides and Odoribacter abundance. In summary, these results suggest that l- and d-cysteine protect against maternal CKD-induced offspring hypertension, likely by enhancing H2S production, modulating gut microbiota and its derived metabolites, and the restoration of NO and RAS.

Separation and Identification of Resveratrol Butyrate Ester Complexes and Their Bioactivity in HepG2 Cell Models.

Resveratrol butyrate ester (RBE) complexes have demonstrated higher antioxidant capacity and anti-fat accumulation activity in previous studies. In this study, silica gel, high-performance liquid chromatography, and 1H nuclear magnetic resonance were used for separation and identification of RBE complex components. With the exception of resveratrol, five different structures of ester derivatives were separated from silica gel: 3,4'-di-O-butanoylresveratrol (ED2, 18.8%), 3-O-butanoylresveratrol (ED4, 35.7%), 4'-O-butanoylresveratrol (ED5, 4.4%), 3,5,4'-tri-O-butanoylresveratrol (ED6, 1.5%), and 3,5-di-O-butanoylresveratrol (ED7, 0.7%). Among the ester derivatives obtained, ED2 and ED4 were the main ester derivatives in the RBE complex. Thus, the cellular antioxidant activities of the RBE mixture, ED2, and ED4 were evaluated. Results showed that the antioxidant capacity of ED2 and ED4 was higher than that of the RBE mixture, demonstrating that the number and position of butyrate esterification sites are related to cell survival rate and antioxidant capacity. This study is the first to report the successful isolation, structural identification, and cellular biological antioxidant activity of RBE complex derivatives, which are key characteristics for the potential practical application of RBE complexes.

Renoprotective effect of SGLT-2 inhibitors among type 2 diabetes patients with different baseline kidney function: a multi-center study.

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 < eGFR ≤ 90, and eGFR > 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 < eGFR ≤ 90, and eGFR > 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 < eGFR ≤ 90, and eGFR > 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.

Association of EGFR Tyrosine Kinase Inhibitor Treatment With Progression-Free Survival Among Taiwanese Patients With Advanced Lung Adenocarcinoma and EGFR Mutation.

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.

Increased Risk of Pyogenic Liver Abscess after Endoscopic Sphincterotomy for Treatment of Choledocholithiasis.

BACKGROUND 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.

Preventive Aspects of Early Resveratrol Supplementation in Cardiovascular and Kidney Disease of Developmental Origins.

The increase in the incidence of cardiovascular diseases (CVDs) and kidney disease has stimulated research for strategies that could prevent, rather than just treat, both interconnected disorders. Resveratrol, a polyphenolic compound with pleiotropic biofunctions, has shown health benefits. Emerging epidemiological data supports that early life environmental insults are regarded as increased risks of developing CVDs and kidney disease in adulthood. Conversely, both disorders could be reversed or postponed by shifting interventions from adulthood to earlier stage by so-called reprogramming. The purpose of this review is first to highlight current epidemiological studies linking cardiovascular and renal programming to resulting CVD and kidney disease of developmental origins. This will be followed by a summary of how resveratrol could exert a positive influence on CVDs and kidney disease. This review also presents an overview of the evidence documenting resveratrol as a reprogramming agent to protect against CVD and kidney disease of developmental origins from animal studies and to outline the advances in understanding the underlying molecular mechanisms. Overall, this review reveals the need for future research to further clarify the reprogramming effects of resveratrol before clinical translation.

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.

Preventing Developmental Origins of Cardiovascular Disease: Hydrogen Sulfide as a Potential Target?

The cardiovascular system can be programmed by a diversity of early-life insults, leading to cardiovascular disease (CVD) in adulthood. This notion is now termed developmental origins of health and disease (DOHaD). Emerging evidence indicates hydrogen sulfide (H2S), a crucial regulator of cardiovascular homeostasis, plays a pathogenetic role in CVD of developmental origins. Conversely, early H2S-based interventions have proved beneficial in preventing adult-onset CVD in animal studies via reversing programming processes by so-called reprogramming. The focus of this review will first summarize the current knowledge on H2S implicated in cardiovascular programming. This will be followed by supporting evidence for the links between H2S signaling and underlying mechanisms of cardiovascular programming, such as oxidative stress, nitric oxide deficiency, dysregulated nutrient-sensing signals, activation of the renin-angiotensin system, and gut microbiota dysbiosis. It will also provide an overview from animal models regarding how H2S-based reprogramming interventions, such as precursors of H2S and H2S donors, may prevent CVD of developmental origins. A better understanding of cardiovascular programming and recent advances in H2S-based interventions might provide the answers to bring down the global burden of CVD.

Maternal Garlic Oil Supplementation Prevents High-Fat Diet-Induced Hypertension in Adult Rat Offspring: Implications of H2S-Generating Pathway in the Gut and Kidneys.

SCOPE: Perinatal high-fat (HF) diet induces hypertension in adult offspring. Garlic, a naturally dietary source of Hydrogen sulfide (H2 S) donor, has been shown benefits in hypertension. The article examines whether maternal garlic oil supplementation can prevent hypertension induced by HF diet and elucidate its protective effects. METHODS AND RESULTS: Pregnant rats are given either a normal diet or HF diet. Rat dams are given garlic oil or vehicle daily by oral gavage at 100 mg kg-1 day-1 during pregnancy and lactation. Male offspring are sacrificed at 16 weeks of age. Garlic oil supplementation during pregnancy and lactation protected against hypertension induced by HF diet in adult male offspring. The beneficial effects of garlic oil are associated with increased renal mRNA expression and activity of H2 S-generating enzymes, increased NO bioavailability, increased plasma short chain fatty acid levels, and alterations of gut microbiota composition. Garlic oil supplementation increases abundance of genus Lactobacillus, but decreases genera Turicibacter and Staphylococcus. CONCLUSION: The data reveals associations between H2 S-generating pathway in the gut and kidneys, NO system, gut microbiota, and microbiota-derived metabolites in hypertension induced by HF intake and provide insight to garlic oil as a hypertension reprogramming strategy for further translational research.

Prediction and Clinically Important Factors of Acute Kidney Injury Non-recovery.

OBJECTIVE: This 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. METHODS: Data 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. RESULTS: Among 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. CONCLUSION: The 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.

Comparison of Adverse Kidney Outcomes With Empagliflozin and Linagliptin Use in Patients With Type 2 Diabetic Patients in a Real-World Setting.

Background: To compare the effects of empagliflozin and linagliptin use on kidney outcomes of type 2 diabetes mellitus (T2DM) patients in a real-world setting. Methods: The study involved a propensity score-matched cohort comprising new users of empagliflozin or linagliptin with T2DM between January 1, 2013 and December 31, 2018 from a large healthcare delivery system in Taiwan. Clinical outcomes assessed: acute kidney injury (AKI), post-AKI dialysis, and mortality. Cox proportional hazard model was used to estimate the relative risk of empagliflozin or linagliptin use; a linear mixed model was used to compare the average change in estimated glomerular filtration rate (eGFR) over time. Results: Of the 7,042 individuals, 67 of 3,521 (1.9%) in the empagliflozin group and 144 of 3,521 (4.1%) in the linagliptin group developed AKI during the 2 years follow-up. Patients in the empagliflozin group were at a 40% lower risk of developing AKI compared to those in the linagliptin group (adjusted hazard ratio [aHR], 0.60; 95% confidence interval [CI], 0.45-0.82, p = 0.001). Stratified analysis showed that empagliflozin users ≥65 years of age (aHR, 0.70; 95% CI, 0.43-1.13, p = 0.148), or with a baseline eGFR <60 ml/min/1.73 m2 (aHR, 0.97; 95% CI, 0.57-1.65, p = 0.899), or with a baseline glycohemoglobin ≦7% (aHR, 1.01; 95% CI, 0.51-2.00, p =0.973) experienced attenuated benefits with respect to AKI risk. A smaller decline in eGFR was observed in empagliflozin users compared to linagliptin users regardless of AKI occurrence (adjusted ß = 1.51; 95% CI, 0.30-2.72 ml/min/1.73 m2, p = 0.014). Conclusion: Empagliflozin users were at a lower risk of developing AKI and exhibited a smaller eGFR decline than linagliptin users. Thus, empagliflozin may be a safer alternative to linagliptin for T2DM patients.

Building an active medical product safety surveillance system in Taiwan: Adaptation of the U.S. Sentinel System common data model structure to the National Health Insurance Research Database in Taiwan.

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 <0.001% of date data had illogical values. CONCLUSIONS: The TSDM-converted database could be a valuable data resource for domestic pharmacovigilance analysis in Taiwan and cross-country evaluation.

Maternal N-Acetylcysteine Therapy Prevents Hypertension in Spontaneously Hypertensive Rat Offspring: Implications of Hydrogen Sulfide-Generating Pathway and Gut Microbiota.

Hypertension can come from early life. N-acetylcysteine (NAC), a hydrogen sulfide (H2S) precursor as well as an antioxidant, has antihypertensive effect. We investigated whether maternal NAC therapy can protect spontaneously hypertensive rats (SHR) male offspring against hypertension. The pregnant rats were assigned to four groups: SHRs without treatment; Wistar Kyoto (WKY) without treatment; SHR+NAC, SHRs received 1% NAC in drinking water throughout pregnancy and lactation; and, WKY+NAC, WKY rats received 1% NAC in drinking water during pregnancy and lactation. Male offspring (n = 8/group) were killed at 12 weeks of age. Maternal NAC therapy prevented the rise in systolic blood pressure (BP) in male SHR offspring at 12 weeks of age. Renal cystathionine ß-synthase (CBS) and 3-mercaptopyruvate sulphurtransferase (3MST) protein levels and H2S-releasing activity were increased in the SHR+NAC offspring. Maternal NAC therapy increased fecal H2S and thiosulfate levels in the SHR+NAC group. Additionally, maternal NAC therapy differentially shaped gut microbiota and caused a distinct enterotype in each group. The protective effect of maternal NAC therapy against hypertension in SHR offspring is related to increased phylum Actinobacteria and genera Bifidobacterium and Allobaculum, but decreased phylum Verrucomicrobia, genera Turicibacter, and Akkermansia. Several microbes were identified as microbial markers, including genera Bifidobacterium, Allobaculum, Holdemania, and Turicibacter. Our results indicated that antioxidant therapy by NAC in pregnant SHRs can prevent the developmental programming of hypertension in male adult offspring. Our findings highlight the interrelationships among H2S-generating pathway in the kidneys and gut, gut microbiota, and hypertension. The implications of maternal NAC therapy elicited long-term protective effects on hypertension in later life that still await further clinical translation.