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RATIONALE & OBJECTIVE: The potential effects of antenatal glucocorticoid exposure on the health of children are unclear. We examined the association of gestational exposure to maternal systemic glucocorticoids and the risk of developing chronic kidney disease (CKD) in childhood. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Newborns cared for at the largest health care delivery system in Taiwan between 2004 and 2018. EXPOSURE: Maternal prescriptions for systemic glucocorticoids between the last menstrual period and birth as a proxy for gestational exposure. OUTCOME: Incidence of childhood CKD, including congenital anomalies of the kidney and urinary tract (CAKUT) and other kidney diseases (non-CAKUT), over 10 years. ANALYTICAL APPROACH: Cox proportional hazards models with stabilized inverse probability of treatment weighting and robust sandwich estimator were used to estimate the average association between systemic glucocorticoids and incident CKD after adjustment for offspring characteristics (adjusted HR: AHR). RESULTS: Among 23,363 singleton-born children, gestational systemic glucocorticoid exposure was significantly associated with a higher risk of childhood CKD (AHR, 1.69 [95% CI, 1.01-2.84]). Stratified analyses showed stronger associations between systemic glucocorticoids and childhood CKD within the strata of birth<37 weeks' gestational age (AHR, 2.38 [95% CI, 1.19-4.78]), male sex (AHR, 1.89 [95% CI, 1.00-3.55]), gestational exposure in the second trimester (AHR, 6.70 [95% CI, 2.17-20.64]), and total dose of>24mg hydrocortisone equivalent (AHR, 1.91 [95% CI, 1.05-3.47]). LIMITATIONS: Study was limited to the Taiwan health care delivery system and childhood CKD events through the age of 10 years. CONCLUSIONS: The findings of this study suggest that gestational exposure to systemic glucocorticoids is associated with the occurrence of kidney disease in childhood. If these findings are confirmed, they may inform clinicians who are considering prescribing systemic glucocorticoids during pregnancy. PLAIN-LANGUAGE SUMMARY: In a singleton-born cohort of neonates, maternal exposure to antenatal systemic glucocorticoids was significantly associated with a 1.7-fold increased risk of the children developing chronic kidney disease over the first 10 years of life. Children of mothers who received>24mg of hydrocortisone equivalent, systemic glucocorticoid treatment in second trimester of gestation, and children born at<37 weeks of gestational age had a higher risk of childhood kidney disease after gestational systemic glucocorticoid exposure. If these findings are confirmed, they may inform clinicians who are considering prescribing systemic glucocorticoids during pregnancy.
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Glucocorticoides , Efeitos Tardios da Exposição Pré-Natal , Insuficiência Renal Crônica , Humanos , Feminino , Gravidez , Glucocorticoides/efeitos adversos , Glucocorticoides/uso terapêutico , Insuficiência Renal Crônica/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Estudos Retrospectivos , Masculino , Taiwan/epidemiologia , Recém-Nascido , Criança , Adulto , Incidência , Pré-Escolar , Exposição Materna/efeitos adversos , Fatores de Risco , Lactente , Estudos de CoortesRESUMO
BACKGROUND: Statins may reduce the risk of recurrent gallstone disease by decreasing bile cholesterol saturation and pathogenicity. However, limited studies have investigated this issue. This study aimed to assess whether statin doses and serum cholesterol levels were associated with a decreased risk of recurrent biliary stone diseases after the first event index, with a follow-up time of 15 years. METHODS: Based on the Chang Gung Research Database (CGRD) between January 1, 2001, and December 31, 2020, we enrolled 68,384 patients with the International Classification of Diseases, Ninth and Tenth Revision codes of choledocholithiasis. After exclusions, 32,696 patients were divided into non-statin (<28 cDDD, cumulative defined daily doses) (n = 27,929) and statin (≥28 cDDD) (n = 4767) user groups for analysis. Serum cholesterol trajectories were estimated using group-based trajectory modeling (n = 8410). RESULTS: The statin users had higher Charlson Comorbidity Index (CCI) scores than the non-statin users. Time-dependent Cox regression analysis showed that statin use >365 cDDD was associated with a significantly lower risk of recurrent biliary stones (adjusted hazard ratio [aHR] = 0.28, 95% CI, 0.24-0.34; p < 00.0001), acute pancreatitis (aHR = 0.24, 95% CI, 0.17-0.32, p < 00.0001), and cholangitis (aHR = 0.28, 95% CI, 0.25-0.32, p < 00.0001). Cholecystectomy was also a protective factor for recurrent biliary stones (aHR = 0.41, 95% CI, 0.37-0.46; p < 00.0001). The higher trajectory serum cholesterol group (Group 3) had a lower risk trend for recurrent biliary stones (aHR = 0.79, p = 0.0700) and a lower risk of cholangitis (aHR = 0.79, p = 0.0071). CONCLUSION: This study supports the potential benefits of statin use and the role of cholecystectomy in reducing the risk of recurrent biliary stone diseases.
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The identification of pathological links among metabolic disorders, kidney ailments, and cardiovascular conditions has given rise to the concept of cardiovascular-kidney-metabolic (CKM) syndrome. Emerging prenatal risk factors seem to increase the likelihood of CKM syndrome across an individual's lifespan. The renin-angiotensin system (RAS) plays a crucial role in maternal-fetal health and maintaining homeostasis in cardiovascular, metabolic, and kidney functions. This review consolidates current preclinical evidence detailing how dysregulation of the RAS during pregnancy and lactation leads to CKM characteristics in offspring, elucidating the underlying mechanisms. The multi-organ effects of RAS, influencing fetal programming and triggering CKM traits in offspring, suggest it as a promising reprogramming strategy. Additionally, we present an overview of interventions targeting the RAS to prevent CKM traits. This comprehensive review of the potential role of the RAS in the early-life programming of CKM syndrome aims to expedite the clinical translation process, ultimately enhancing outcomes in cardiovascular-kidney-metabolic health.
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Sistema Cardiovascular , Hipertensão , Síndrome Metabólica , Gravidez , Feminino , Humanos , Sistema Renina-Angiotensina , Síndrome Metabólica/metabolismo , Rim/metabolismo , Sistema Cardiovascular/metabolismo , Coração , Hipertensão/metabolismoRESUMO
Early life exposure lays the groundwork for the risk of developing cardiovascular-kidney-metabolic (CKM) syndrome in adulthood. Various environmental chemicals to which pregnant mothers are commonly exposed can disrupt fetal programming, leading to a wide range of CKM phenotypes. The aryl hydrocarbon receptor (AHR) has a key role as a ligand-activated transcription factor in sensing these environmental chemicals. Activating AHR through exposure to environmental chemicals has been documented for its adverse impacts on cardiovascular diseases, hypertension, diabetes, obesity, kidney disease, and non-alcoholic fatty liver disease, as evidenced by both epidemiological and animal studies. In this review, we compile current human evidence and findings from animal models that support the connection between antenatal chemical exposures and CKM programming, focusing particularly on AHR signaling. Additionally, we explore potential AHR modulators aimed at preventing CKM syndrome. As the pioneering review to present evidence advocating for the avoidance of toxic chemical exposure during pregnancy and deepening our understanding of AHR signaling, this has the potential to mitigate the global burden of CKM syndrome in the future.
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Doenças Cardiovasculares , Efeitos Tardios da Exposição Pré-Natal , Receptores de Hidrocarboneto Arílico , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Humanos , Gravidez , Animais , Feminino , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/induzido quimicamente , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Nefropatias/etiologia , Exposição Materna/efeitos adversos , Transdução de Sinais/efeitos dos fármacos , Rim/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Desenvolvimento Fetal/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Poluentes Ambientais/efeitos adversos , Reprogramação MetabólicaRESUMO
The growing recognition of the association between maternal chronic kidney disease (CKD) and fetal programming highlights the increased vulnerability of hypertension in offspring. Potential mechanisms involve oxidative stress, dysbiosis in gut microbiota, and activation of the renin-angiotensin system (RAS). Our prior investigation showed that the administration of adenine to pregnant rats resulted in the development of CKD, ultimately causing hypertension in their adult offspring. Citrulline, known for enhancing nitric oxide (NO) production and possessing antioxidant and antihypertensive properties, was explored for its potential to reverse high blood pressure (BP) in offspring born to CKD dams. Male rat offspring, both from normal and adenine-induced CKD models, were randomly assigned to four groups (8 animals each): (1) control, (2) CKD, (3) citrulline-treated control rats, and (4) citrulline-treated CKD rats. Citrulline supplementation successfully reversed elevated BP in male progeny born to uremic mothers. The protective effects of perinatal citrulline supplementation were linked to an enhanced NO pathway, decreased expression of renal (pro)renin receptor, and changes in gut microbiota composition. Citrulline supplementation led to a reduction in the abundance of Monoglobus and Streptococcus genera and an increase in Agothobacterium Butyriciproducens. Citrulline's ability to influence taxa associated with hypertension may be linked to its protective effects against maternal CKD-induced offspring hypertension. In conclusion, perinatal citrulline treatment increased NO availability and mitigated elevated BP in rat offspring from uremic mother rats.
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Doenças do Sistema Nervoso Autônomo , Hipertensão , Pré-Eclâmpsia , Efeitos Tardios da Exposição Pré-Natal , Insuficiência Renal Crônica , Gravidez , Humanos , Feminino , Ratos , Animais , Masculino , Citrulina/farmacologia , Citrulina/uso terapêutico , Ratos Sprague-Dawley , Hipertensão/etiologia , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/complicações , Adenina/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamenteRESUMO
OBJECTIVE: To characterize longitudinal changes and correlations between the measures of EQ-5D-Y and generic PedsQL and their associations with clinical changes in children and adolescents with mild-to-moderate chronic kidney disease (CKD). METHODS: Participants were recruited from January 2017 to September 2021 in a medical center in Taiwan. Both instruments were administered in their initial visits and every 6-month subsequent visits. Spearman's Rho (ρ) was used to assess correlations between the scores of EQ-5D-Y and PedsQL measures in longitudinal changes. Cohen's effect size (ES) was used to evaluate the changes of scores/subscales over time. In addition, factors associated with longitudinal changes in the score/subscales were explored. RESULTS: A total of 121 participants were enrolled, and 83 with ≥ 3 HRQOL measures during the 3.5 years follow-up were assessed their changes of HRQOL measures. The correlations (ρ > 0.3) appeared between the changes in the visual analog scale (VAS) of EQ-5D-Y and emotional and social subscales of PedsQL. ES was small (< 0.5) in the VAS and level-sum-score (LSS) of EQ-5D-Y scores for the clinical changes in comorbidities, while some PedsQL subscales were medium to high (0.5-0.8 or > 0.8). Hypertension, mineral bone disorder/anemia, and hyperuricemia associated with the changes in both HRQOL scores were varied by their various domains. CONCLUSION: Both EQ-5D-Y and PedsQL of HRQOL measures were responsive to worsened childhood CKD-related comorbidities during the follow-up; however, convergent validity between them was limited in some domains. The LSS of EQ-5D-Y showed greater changes than the VAS by comorbidity status; further comparison with utility weight is needed to determine the better performance of EQ-5D-Y.
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Qualidade de Vida , Insuficiência Renal Crônica , Adolescente , Humanos , Criança , Qualidade de Vida/psicologia , Inquéritos e Questionários , Reprodutibilidade dos Testes , Comorbidade , PsicometriaRESUMO
BACKGROUND: Correlation between reports of children and parent for health-related quality of life (HRQOL) is not well studied. This study aims to assess the degree of agreement between child self- and parent proxy-rated HRQOL and to identify factors associated with discordance at baseline and during follow-up in Taiwanese children with chronic kidney disease (CKD). METHODS: This study includes pediatric patients aged 5-18 years with confirmed CKD. Participants completed the generic version of the Pediatric Quality of Life Inventory (PedsQL) at baseline and every 6 months during follow-up. Child-parent agreement on HRQOL reports was assessed using intraclass correlation coefficient (ICC). Multivariate regression models were used to determine factors associated with child-parent discordance. RESULTS: Of the 112 child-parent dyads included in the analysis, 97 dyads with 640 patient visits were assessed in 4.5 years. Children reported higher total scores on the physical and psychosocial domains as compared to their parent proxies. ICC was low (< 0.5) for the psychosocial domain and moderate for the physical health domain at initial assessment and slightly increased for the physical health (0.62) and for school functioning (0.51) during follow-up. Development of mineral bone disorder/anemia (ß, 11.75 [3.77-19.72]) and proteinuria (ß, 8.48 [1.15-15.81]) in the follow-up were associated with increased discordance in school functioning, and fathers with chronic disease were associated with increased discordance in social functioning (ß, 4.21 [0.68-7.74]). CONCLUSIONS: Parent proxy consistently estimated lower PedsQL score compared to self-reports of children. Child self-rated psychosocial health domains should be evaluated whenever possible to better elucidate treatment outcome over time. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Qualidade de Vida , Insuficiência Renal Crônica , Humanos , Criança , Qualidade de Vida/psicologia , Autorrelato , Pais/psicologia , Procurador , Inquéritos e QuestionáriosRESUMO
PURPOSE: The left censoring of values at -1 by design of the composite time trade-off (cTTO) tasks leads to excessive amount of -1 values in some EQ-5D-5L valuation studies. This study aimed to investigate whether a time-based willingness-to-accept (tWTA) question can be used to elicit values lower than -1 and improve the estimation of EQ-5D-5L values. METHODS: At the end of each cTTO task in the Taiwanese EQ-5D-5L valuation study, if the value of the health state was indicated to be lower than -1, a tWTA question eliciting the indifference point between a hypothetical life (i.e. x number of years in full health followed by 10 years in the health state) and immediate death was used to estimate its uncensored value. We compared the statistical characteristics of the censored and uncensored data. RESULTS: Four hundred and twenty-nine of 1,000 respondents were offered the tWTA question in a total of 1,071 cTTO tasks. In 79.55% of those tasks, indifference was not reached. Spearman's correlation with level summary score was -0.41 and -0.40 for negative uncensored and censored data, respectively. The logical inconsistency rates of the uncensored and censored data were 0.88% vs. 0.29%, respectively. Modelling of the uncensored data resulted in coefficients with greater uncertainty and much lower predictions. CONCLUSIONS: The elicitation of values lower than -1 using a tWTA question that grants more time for trading seems not a promising solution to the value censoring of the cTTO tasks. Other strategies for valuation of very poor health states should be explored.
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Apatia , Nível de Saúde , Humanos , Qualidade de Vida/psicologia , Inquéritos e QuestionáriosRESUMO
This study documented the prescribing patterns of methylphenidate and atomoxetine among patients aged 3 to 18 in Taiwan diagnosed with attention deficit hyperactivity disorder (ADHD) between 2004 and 2017. Initial treatment for ADHD, the time between the first diagnosis and the first prescription, and medication-switching patterns were investigated. The final cohort consisted of 256,882 patients, and 147,210 (57.3%) of them received medication treatment. Most of the patients (98.2%) received methylphenidate. Atomoxetine use increased from 0.1% in 2007 to 5.5% in 2017. The median time between the ADHD diagnosis and the first prescription was 21 days (IQR: 0-212 days). In patients who initiated methylphenidate, 12,406 (8.4%) patients switched to atomoxetine; 850 (31.3%) of the children began with atomoxetine and switched to methylphenidate. In conclusion, methylphenidate was the predominant treatment for ADHD in 2004-2017. However, the prevalence of pharmacotherapy for ADHD was relatively low. Further investigation on the reasons behind this pattern is recommended.
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Transtorno do Deficit de Atenção com Hiperatividade , Estimulantes do Sistema Nervoso Central , Metilfenidato , Humanos , Criança , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Cloridrato de Atomoxetina/uso terapêutico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Taiwan , Metilfenidato/uso terapêutico , Inibidores da Captação Adrenérgica/uso terapêutico , Inibidores da Captação Adrenérgica/efeitos adversosRESUMO
Melatonin, an endogenous hormone mainly released at night by the pineal gland, has multifaceted biofunctions. Emerging evidence points to melatonin having a crucial role in kidney health and disease. As the prevalence of chronic kidney disease (CKD) is still rising, a superior strategy to advance global kidney health is needed to not just treat CKD, but prevent it early on. Adult kidney disease can have its origins in early life. This review aims to evaluate the recent literature regarding melatonin's effect on kidney development, its clinical uses in the early stage of life, animal models documenting preventive applications of melatonin on offspring's kidney-related disease, and a thorough summary of therapeutic considerations concerning melatonin supplementation.
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Melatonina , Glândula Pineal , Insuficiência Renal Crônica , Animais , Melatonina/farmacologia , Melatonina/uso terapêutico , Rim , Insuficiência Renal Crônica/tratamento farmacológico , Modelos Animais , Ritmo CircadianoRESUMO
Chronic kidney disease (CKD) affects 10% of the global population, including pregnant women. Adverse maternal conditions determine the developmental programming of many diseases later in life. We previously demonstrated that adult rat offspring born to dams with CKD developed hypertension and renal hypertrophy. Trimethylamine-N-oxide (TMAO), a uremic toxin derived from the gut microbiota, has been linked to hypertension. This study assesses the effects of TMAO inhibition by iodomethylcholine (IMC) treatment on offspring hypertension programmed by maternal CKD. Female rats were fed either a control or a 0.5% adenine diet before conception, with or without IMC treatment during pregnancy and lactation. Maternal IMC treatment averted maternal CKD-primed offspring hypertension and renal hypertrophy in 12-week-old offspring. Offspring hypertension is associated with increases in the plasma TMAO concentration and oxidative stress and shifts in gut microbiota. The beneficial effects of IMC are related to a reduction in TMAO; increases in genera Acetatifactor, Bifidobacterium, and Eubacterium; and decreases in genera Phocacecola and Bacteroides. Our findings afford insights into the targeting of the gut microbiota to deplete TMAO production, with therapeutic potential for the prevention of offspring hypertension programmed by maternal CKD, although these results still need further clinical translation.
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Hipertensão , Insuficiência Renal Crônica , Feminino , Ratos , Humanos , Animais , Gravidez , Insuficiência Renal Crônica/tratamento farmacológico , Metilaminas , Hipertensão/prevenção & controle , Hipertrofia , Óxidos/uso terapêuticoRESUMO
The incidence of hypertension has increased to epidemic levels in the past decades. Increasing evidence reveals that maternal dietary habits play a crucial role in the development of hypertension in adult offspring. In humans, increased fat consumption has been considered responsible for obesity and associated diseases. Maternal diets rich in saturated fats have been widely employed in animal models to study various adverse offspring outcomes. In this review, we discussed current evidence linking maternal high-fat diet to offspring hypertension. We also provided an in-depth overview of the potential mechanisms underlying hypertension of developmental origins that are programmed by maternal high-fat intake from animal studies. Furthermore, this review also presented an overview of how reprogramming interventions can prevent maternal high-fat-diet-induced hypertension in adult offspring. Overall, recent advances in understanding mechanisms behind programming and reprogramming of maternal high-fat diet on hypertension of developmental origins might provide the answers to curtail this epidemic. Still, more research is needed to translate research findings into practice.
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Hipertensão , Efeitos Tardios da Exposição Pré-Natal , Animais , Dieta Hiperlipídica/efeitos adversos , Feminino , Humanos , Estresse Oxidativo , Efeitos Tardios da Exposição Pré-Natal/etiologia , Ratos , Ratos Sprague-DawleyRESUMO
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.
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Hipertensão , Polifenóis , Animais , Modelos Animais , Origem da Vida , Estresse Oxidativo , Polifenóis/farmacologia , Polifenóis/uso terapêuticoRESUMO
The gut-kidney interaction implicating chronic kidney disease (CKD) has been the focus of increasing interest in recent years. Gut microbiota-targeted therapies could prevent CKD and its comorbidities. Considering that CKD can originate in early life, its treatment and prevention should start in childhood or even earlier in fetal life. Therefore, a better understanding of how the early-life gut microbiome impacts CKD in later life and how to develop ideal early interventions are unmet needs to reduce CKD. The purpose of the current review is to summarize (1) the current evidence on the gut microbiota dysbiosis implicated in pediatric CKD; (2) current knowledge supporting the impact of the gut-kidney axis in CKD, including inflammation, immune response, alterations of microbiota compositions, short-chain fatty acids, and uremic toxins; and (3) an overview of the studies documenting early gut microbiota-targeted interventions in animal models of CKD of developmental origins. Treatment options include prebiotics, probiotics, postbiotics, etc. To accelerate the transition of gut microbiota-based therapies for early prevention of CKD, an extended comprehension of gut microbiota dysbiosis implicated in renal programming is needed, as well as a greater focus on pediatric CKD for further clinical translation.
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Microbioma Gastrointestinal , Probióticos , Insuficiência Renal Crônica , Animais , Criança , Disbiose , Microbioma Gastrointestinal/fisiologia , Humanos , Prebióticos , Probióticos/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológicoRESUMO
Metabolic syndrome (MetS) is an extremely prevalent complex trait and it can originate in early life. This concept is now being termed the developmental origins of health and disease (DOHaD). Increasing evidence supports that disturbance of gut microbiota influences various risk factors of MetS. The DOHaD theory provides an innovative strategy to prevent MetS through early intervention (i.e., reprogramming). In this review, we summarize the existing literature that supports how environmental cues induced MetS of developmental origins and the interplay between gut microbiota and other fundamental underlying mechanisms. We also present an overview of experimental animal models addressing implementation of gut microbiota-targeted reprogramming interventions to avert the programming of MetS. Even with growing evidence from animal studies supporting the uses of gut microbiota-targeted therapies start before birth to protect against MetS of developmental origins, their effects on pregnant women are still unknown and these results require further clinical translation.
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Microbioma Gastrointestinal , Síndrome Metabólica , Probióticos , Anormalidades Múltiplas , Animais , Feminino , Doenças Genéticas Ligadas ao Cromossomo X , Humanos , Eritrodermia Ictiosiforme Congênita , Deformidades Congênitas dos Membros , Síndrome Metabólica/tratamento farmacológico , Prebióticos , Gravidez , Probióticos/uso terapêuticoRESUMO
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.
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Metformina , Hepatopatia Gordurosa não Alcoólica , Feminino , Ratos , Gravidez , Animais , Dieta Hiperlipídica/efeitos adversos , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Placenta/metabolismo , Metformina/farmacologia , Metformina/uso terapêutico , Metformina/metabolismo , Gorduras na Dieta/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismoRESUMO
Emerging evidence supports that hypertension can be programmed or reprogrammed by maternal nutrition. Maternal exposures during pregnancy, such as maternal nutrition or antibiotic use, could alter the offspring's gut microbiota. Short-chain fatty acids (SCFAs) are the major gut microbiota-derived metabolites. Acetate, the most dominant SCFA, has shown its antihypertensive effect. Limited information exists regarding whether maternal acetate supplementation can prevent maternal minocycline-induced hypertension in adult offspring. We exposed pregnant Sprague Dawley rats to normal diet (ND), minocycline (MI, 50 mg/kg/day), magnesium acetate (AC, 200 mmol/L in drinking water), and MI + AC from gestation to lactation period. At 12 weeks of age, four groups (n = 8/group) of male progeny were sacrificed. Maternal acetate supplementation protected adult offspring against minocycline-induced hypertension. Minocycline administration reduced plasma acetic acid level, which maternal acetate supplementation prevented. Additionally, acetate supplementation increased the protein level of SCFA receptor G protein-coupled receptor 41 in the offspring kidneys. Further, minocycline administration and acetate supplementation significantly altered gut microbiota composition. Maternal acetate supplementation protected minocycline-induced hypertension accompanying by the increases in genera Roseburia, Bifidobacterium, and Coprococcus. In sum, our results cast new light on targeting gut microbial metabolites as early interventions to prevent the development of hypertension, which could help alleviate the global burden of hypertension.
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Hipertensão , Efeitos Tardios da Exposição Pré-Natal , Acetatos/farmacologia , Animais , Pressão Sanguínea , Suplementos Nutricionais , Feminino , Humanos , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Lactação , Masculino , Exposição Materna/efeitos adversos , Minociclina/farmacologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Ratos , Ratos Sprague-DawleyRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Taxa de Filtração Glomerular/efeitos dos fármacos , Nefropatias/tratamento farmacológico , Rim/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Adulto , Idoso , Bases de Dados Factuais , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Humanos , Rim/fisiopatologia , Nefropatias/diagnóstico , Nefropatias/epidemiologia , Nefropatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Taiwan/epidemiologia , Fatores de Tempo , Resultado do TratamentoRESUMO
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.
Assuntos
Aspirina/efeitos adversos , Doenças Cardiovasculares/prevenção & controle , Clopidogrel/efeitos adversos , Úlcera Péptica Hemorrágica/induzido quimicamente , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Bomba de Prótons/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Aspirina/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Clopidogrel/uso terapêutico , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Úlcera Péptica/complicações , Úlcera Péptica/tratamento farmacológico , Úlcera Péptica Hemorrágica/etiologia , Inibidores da Agregação Plaquetária/uso terapêutico , Inibidores da Bomba de Prótons/uso terapêutico , Medição de Risco , Fatores de Risco , Prevenção SecundáriaRESUMO
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.