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BACKGROUND: Alcohol consumption is associated with both beneficial and harmful effects, and the role of alcohol consumption in chronic kidney disease (CKD) remains inconclusive. This study aimed to investigate the relationship between alcohol consumption and CKD or estimated glomerular filtration rate (eGFR). METHODS: This study enrolled adults from the second Taiwanese Survey on Prevalences of Hypertension, Hyperglycemia, and Hyperlipidemia, conducted in 2007. Participants were categorized into frequent drinkers, occasional drinkers, and nondrinkers. The amount of alcohol consumption was assessed by standard drinks per week. The primary outcome was the presence of CKD, and the secondary outcome was the eGFR. RESULTS: Among 3967 participants with a mean age of 47.9 years and a CKD prevalence of 11.7%, 13.8% were frequent drinkers, and 23.1% were occasional drinkers. The average amount of alcohol consumed was 3.3 drinks per week. Frequent drinkers (odds ratio [OR] 0.622, 95% confidence interval [CI] 0.443-0.874) and occasional drinkers (OR 0.597 95% CI 0.434-0.821) showed a lower prevalence of CKD than nondrinkers. Consumption of a larger number of standard drinks was associated with a lower prevalence of CKD (OR 0.872, 95% CI 0.781-0.975). Frequent drinkers and those who consumed a larger number of standard drinks per week showed higher eGFRs. CONCLUSION: Within the range of moderate alcohol intake, those who consumed more alcohol had a higher eGFR and reduced prevalence of CKD. The potentially harmful effects of heavy drinking should be taken into consideration, and alcohol intake should be limited to less than light to moderate levels.
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Introduction: Postgraduate medical education assumes rising importance in the rapidly advancing field of medicine. Case-based learning (CBL), a learner-centered pedagogy employing clinical cases to improve decision-making, is widely embraced in postgraduate medical education, including nephrology. Studies suggest that learning self-efficacy (SE) was closely associated with learning motivation and academic performance; however, very few studies examined this association in postgraduate nephrology education. None evaluated whether there were interprofessional differences concerning such association. Methods: In 2022, we prospectively enrolled physicians and nurses participating in chronic kidney disease (CKD) care from institutions around Taiwan. They completed the Professional Medical Learning Self-efficacy (PMLS) questionnaire after attending >1 CBL session involving CKD care. We undertook confirmatory factor analysis (CFA), followed by structural equation modeling (SEM) to evaluate associations between 5 dimensions of learning SE (conceptual understanding [CU], higher-order cognitive skills [HC], practical work [PW], everyday application [EA], and medical science communication [MSC]) and their professional SE in nephrology according to participants' medical professions. Results: A total of 513 healthcare providers were surveyed. The convergent and construct validity of our questionnaire were satisfied after analyses. We found that better perceived professional performance in the form of higher professional SE in nephrology was significantly associated with all 5 dimensions of learning SE among physicians and nurses. Only CU and PW were significantly associated with physicians' professional performance; whereas among nurses, only HC and MSC were significantly associated. Conclusion: We showed that learning SE was an important determinant of nephrology professional performance. Different medical professions posed influences on major SE dimensions.
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This article underscores the importance of integrating comprehensive palliative care for noncancer patients who are undergoing hemodialysis, with an emphasis on the aging populations in Asian nations such as Taiwan, Japan, the Republic of Korea, and China. As the global demographic landscape shifts towards an aging society and healthcare continues to advance, a marked increase has been observed in patients undergoing hemodialysis who require palliative care. This necessitates an immediate paradigm shift to incorporate this care, addressing the intricate physical, psychosocial, and spiritual challenges faced by these individuals and their families. Numerous challenges impede the provision of effective palliative care, including difficulties in prognosis, delayed referrals, cultural misconceptions, lack of clinician confidence, and insufficient collaboration among healthcare professionals. The article proposes potential solutions, such as targeted training for clinicians, the use of telemedicine to facilitate shared decision-making, and the introduction of time-limited trials for dialysis to overcome these obstacles. The integration of palliative care into routine renal treatment and the promotion of transparent communication among healthcare professionals represent key strategies to enhance the quality of life and end-of-life care for people on hemodialysis. By embracing innovative strategies and fostering collaboration, healthcare providers can deliver more patient-centered, holistic care that meets the complex needs of seriously ill patients within an aging population undergoing hemodialysis.
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Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of end-stage kidney disease (ESKD) worldwide. Guidelines for the diagnosis and management of ADPKD in Taiwan remains unavailable. In this consensus statement, we summarize updated information on clinical features of international and domestic patients with ADPKD, followed by suggestions for optimal diagnosis and care in Taiwan. Specifically, counselling for at-risk minors and reproductive issues can be important, including ethical dilemmas surrounding prenatal diagnosis and pre-implantation genetic diagnosis. Studies reveal that ADPKD typically remains asymptomatic until the fourth decade of life, with symptoms resulting from cystic expansion with visceral compression, or rupture. The diagnosis can be made based on a detailed family history, followed by imaging studies (ultrasound, computed tomography, or magnetic resonance imaging). Genetic testing is reserved for atypical cases mostly. Common tools for prognosis prediction include total kidney volume, Mayo classification and PROPKD/genetic score. Screening and management of complications such as hypertension, proteinuria, urological infections, intracranial aneurysms, are also crucial for improving outcome. We suggest that the optimal management strategies of patients with ADPKD include general medical care, dietary recommendations and ADPKD-specific treatments. Key points include rigorous blood pressure control, dietary sodium restriction and Tolvaptan use, whereas the evidence for somatostatin analogues and mammalian target of rapamycin (mTOR) inhibitors remains limited. In summary, we outline an individualized care plan emphasizing careful monitoring of disease progression and highlight the need for shared decision-making among these patients.
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Fallo Renal Crónico , Riñón Poliquístico Autosómico Dominante , Humanos , Riñón Poliquístico Autosómico Dominante/diagnóstico , Riñón Poliquístico Autosómico Dominante/terapia , Riñón Poliquístico Autosómico Dominante/complicaciones , Taiwán/epidemiología , Tolvaptán , RiñónRESUMEN
BACKGROUND: Older adults have a higher risk of developing vascular calcification (VC). Circulating miRNAs can be potential risk indicators. However, prior studies used single miRNA mostly, whereas miRNA panels were rarely evaluated. We aimed to examine whether a miRNA panel outperformed each miRNA alone, and analyzed whether advanced age affected VC risk predictive performance offered by the miRNA panel. METHODS: We prospectively enrolled older adults (age ≥65 years) during their annual health checkup in 2017, and examined their VC severity followed by analyzing sera for VC regulatory miRNAs (miR-125b-5p, miR-125b-3p, and miR-378a-3p). We used multiple regression analyses to determine associations between each miRNA or a 3-combind panel and VC risk, followed by area under the receiver-operating-characteristics curve (AUROC) analysis. Participants were further divided to those of 65-75 and ≥75 years for comparison. RESULTS: From 199 older adults screened, 169 (median age, 73.3 years) with available calcification assessment were analyzed, among whom 74.6 % having VC. Those with VC had significantly lower circulating miR-125b-5p, miR-125b-3p, and miR-378a-3p levels than those without. Regression analyses showed that the 3-combined miRNA panel exhibited significant associations with VC risk, with significantly higher AUROC than those of models based on individual miRNA. Importantly, in those ≥75 years, the miRNA-predicted risk of VC was more prominent than that in the 65-75 years group. CONCLUSION: A miRNA panel for VC risk prediction might outperform individual miRNA alone in older adults, and advanced age modified the association between circulating miRNAs and the risk of VC.
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MicroARN Circulante , MicroARNs , Calcificación Vascular , Humanos , Anciano , MicroARN Circulante/genética , Vida Independiente , MicroARNs/genética , Calcificación Vascular/epidemiología , Calcificación Vascular/genética , Factores de RiesgoAsunto(s)
Nefrología , Humanos , Incertidumbre , Escolaridad , Inteligencia Artificial , Competencia ClínicaRESUMEN
The effects of lipid-lowering drugs (LLDs) on cardiovascular and renal outcomes in patients with advanced chronic kidney disease (CKD) and dyslipidemia are not completely understood. We conducted a retrospective cohort study to evaluate the effect of LLDs on end-stage kidney disease (ESKD), major adverse cardiovascular events (MACEs), and mortality in adult patients with CKD stage 3b, 4, or 5, and dyslipidemia. Participants were recruited between January 1, 2008, and December 31, 2018, and classified as LLD or non-LLD users; the final follow-up date was December 31, 2020. The primary outcome was time to ESKD or death due to renal failure. Sub-distribution hazard regression models adjusted for multivariables, including time-varying lipid profile covariates, were used for the analysis. Among the 6,740 participants, 4,280 patients with CKD and dyslipidemia, including 872 using LLDs and 3,408 not using LLDs, completed the primary analysis. The multivariable analyses showed that LLD users had a significantly lower risk of time to the composite renal outcome (adjusted hazard ratio [aHR], 0.76, 95% confidence interval [CI], 0.65-0.89), and MACE incidence (aHR, 0.75, 95% CI, 0.62-0.93) than did non-LLD users. After adjusting for time-varying covariates of the lipid profile, there was a significant difference in the composite renal outcome (aHR, 0.78, 95% CI, 0.65-0.93) and MACEs (aHR, 0.77, 95% CI, 0.60-0.98). Among adult patients with advanced CKD and dyslipidemia, LLD users had a significantly lower risk of composite renal outcomes and MACEs than non-LLD users. In addition to reducing lipid profile, the use of LLD is associated with renal and cardiovascular protective effects.
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Enfermedades Cardiovasculares , Dislipidemias , Fallo Renal Crónico , Insuficiencia Renal Crónica , Adulto , Humanos , Estudios Retrospectivos , Hipolipemiantes/uso terapéutico , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/epidemiología , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/tratamiento farmacológico , Fallo Renal Crónico/epidemiología , Dislipidemias/diagnóstico , Dislipidemias/tratamiento farmacológico , Dislipidemias/epidemiología , Lípidos , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & controlRESUMEN
Frailty describes the cumulative subtle health deficits leading to an increased vulnerability to insults among older individuals or disease-laden ones. The prevalence of frailty increases substantially and relentlessly over declining renal function. Frailty in patients with chronic kidney disease (CKD) carries kidney-specific risk factors, clinical correlates and outcomes associations, hence alternatively termed frail kidney phenotype by researchers. Pathogenetically, miRNAs participate extensively in the development and aggravation of frailty, including the occurrence of frail kidney phenotype in CKD patients. These understandings spark profound interest in discovering biomarkers for identifying this detrimental phenotype, and extracellular miRNAs emerge as potentially useful ones. Pilot studies identify promising miRNA candidates for evaluating intermediates and surrogates of frail kidney phenotype, and more are underway. Several potential miRNA species in biologic fluids, such as circulating miR-29b and miR-223 (as inflammatory markers), exosomal miR-16-5p, miR-17/92 cluster members, and miR-106-5p (for uremic vasculopathy), serum exosomal miR-203a-3p (for uremic sarcopenia) have been examined and can be promising choices. Nonetheless, there remains research gap in affirming the direct connections between specific miRNAs and frail kidney phenotype. This stems partially from multiple limitations less well acknowledged before. From this perspective, we further outline the limitations and precautions prior to validating specific extracellular miRNA(s) for this purpose, from the definition of frailty definition, the functional and tissue specificity of miRNAs, the severity of CKD, and various technical considerations. It is expected that more affirmative studies can be produced for extending the utility of extracellular miRNAs in predicting frail kidney phenotype.
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Infecciones por Mycobacterium no Tuberculosas , Diálisis Peritoneal , Peritonitis , Humanos , Diálisis Peritoneal/efectos adversos , Infecciones por Mycobacterium no Tuberculosas/diagnóstico , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Infecciones por Mycobacterium no Tuberculosas/etiología , Pruebas de Sensibilidad Microbiana , Peritonitis/diagnóstico , Peritonitis/tratamiento farmacológico , Peritonitis/etiologíaRESUMEN
BACKGROUND: As a part of natural disease progression, acute kidney injury (AKI) can develop into chronic kidney disease via renal fibrosis and inflammation. LTBP4 (latent transforming growth factor beta binding protein 4) regulates transforming growth factor beta, which plays a role in renal fibrosis pathogenesis. We previously investigated the role of LTBP4 in chronic kidney disease. Here, we examined the role of LTBP4 in AKI. METHODS: LTBP4 expression was evaluated in human renal tissues, obtained from healthy individuals and patients with AKI, using immunohistochemistry. LTBP4 was knocked down in both C57BL/6 mice and human renal proximal tubular cell line HK-2. AKI was induced in mice and HK-2 cells using ischemia-reperfusion injury and hypoxia, respectively. Mitochondrial division inhibitor 1, an inhibitor of DRP1 (dynamin-related protein 1), was used to reduce mitochondrial fragmentation. Gene and protein expression were then examined to assess inflammation and fibrosis. The results of bioenergetic studies for mitochondrial function, oxidative stress, and angiogenesis were assessed. RESULTS: LTBP4 expression was upregulated in the renal tissues of patients with AKI. Ltbp4-knockdown mice showed increased renal tissue injury and mitochondrial fragmentation after ischemia-reperfusion injury, as well as increased inflammation, oxidative stress, and fibrosis, and decreased angiogenesis. in vitro studies using HK-2 cells revealed similar results. The energy profiles of Ltbp4-deficient mice and LTBP4-deficient HK-2 cells indicated decreased ATP production. LTBP4-deficient HK-2 cells exhibited decreased mitochondrial respiration and glycolysis. Human aortic endothelial cells and human umbilical vein endothelial cells exhibited decreased angiogenesis when treated with LTBP4-knockdown conditioned media. Mitochondrial division inhibitor 1 treatment ameliorated inflammation, oxidative stress, and fibrosis in mice and decreased inflammation and oxidative stress in HK-2 cells. CONCLUSIONS: Our study is the first to demonstrate that LTBP4 deficiency increases AKI severity, consequently leading to chronic kidney disease. Potential therapies focusing on LTBP4-associated angiogenesis and LTBP4-regulated DRP1-dependent mitochondrial division are relevant to renal injury.
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Lesión Renal Aguda , Insuficiencia Renal Crónica , Daño por Reperfusión , Animales , Humanos , Ratones , Lesión Renal Aguda/prevención & control , Células Endoteliales/metabolismo , Fibrosis , Inflamación/metabolismo , Riñón/metabolismo , Proteínas de Unión a TGF-beta Latente , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Insuficiencia Renal Crónica/complicaciones , Daño por Reperfusión/complicaciones , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Low-intensity pulsed ultrasound (LIPUS) is a kind of therapeutic ultrasound. It can help improve bone fracture repair and soft tissue healing. Our previous study found that LIPUS treatment could halt the chronic kidney disease (CKD) progression in mice; unexpectedly, we observed the improvement of CKD-reduced muscle weights by LIPUS treatment. Here, we further tested the protective potential of LIPUS on CKD-associated muscle wasting/sarcopenia using the CKD mouse models. Mouse models of both unilateral renal ischemia/reperfusion injury (IRI) with nephrectomy and adenine administration were used to induce CKD. LIPUS with condition of 3 MHz, 100 mW/cm2, 20 min/day was applied to the kidney of CKD mice. LIPUS treatment significantly reversed the increased serum BUN/creatinine levels in CKD mice. LIPUS effectively prevented the decrease in grip strength, muscle weight (soleus, tibialis anterior, and gastrocnemius muscles), cross-section areas of muscle fibres, and muscular phosphorylated Akt protein expression by immunohistochemistry, and the increase in muscular atrogenes Atrogin1 and MuRF1 protein expression by immunohistochemistry in CKD mice. These results indicated that LIPUS could help improve weak muscle strength, muscle mass loss, muscle atrophy-related protein expression, and Akt inactivation. LIPUS application may be an alternative non-invasive therapeutic intervention on the management of CKD-associated muscle wasting.
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Insuficiencia Renal Crónica , Terapia por Ultrasonido , Ratones , Animales , Proteínas Proto-Oncogénicas c-akt/metabolismo , Terapia por Ultrasonido/métodos , Atrofia Muscular/etiología , Atrofia Muscular/prevención & control , Músculo Esquelético , Ondas Ultrasónicas , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/terapia , Insuficiencia Renal Crónica/metabolismoRESUMEN
Patients with diabetes mellitus (DM) have a higher risk of incident and aggravating frailty over time. Frailty-initiating risk factors have been identified, but modulators of frail severity over time remain poorly defined. We aimed to explore the influences of glucose-lowering drug (GLD) strategy on DM patients' risk of increasing frail severity. We retrospectively identified type 2 DM patients between 2008 and 2016, dividing them into "no GLD", oral GLD (oGLD) monotherapy, oGLD combination, and those receiving insulin without or with oGLD at baseline. Increasing frail severity, defined as ≥1 FRAIL component increase, was the outcome of interest. Cox proportional hazard regression was utilized to analyze the risk of increasing frail severity associated with GLD strategy, accounting for demographic, physical data, comorbidities, medication, and laboratory panel. After screening 82,208 patients with DM, 49,519 (no GLD, 42.7%; monotherapy, 24.0%; combination, 28.5%; and insulin user, 4.8%) were enrolled for analysis. After 4 years, 12,295 (24.8%) had increasing frail severity. After multivariate adjustment, oGLD combination group exhibited a significantly lower risk of increasing frail severity (hazard ratio (HR) 0.90, 95% confidence interval (CI) 0.86 - 0.94), while the risk of insulin users increased (HR 1.11, 95% CI 1.02 - 1.21) than no GLD group. Users receiving more oGLD exhibited a trend of less risk reduction relative to others. In conclusion, we discovered that the strategy of oral glucose lowering drugs combination might reduce the risk of frail severity increase. Accordingly, medication reconciliation in frail diabetic older adults should take into account their GLD regimens.
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Earlier detection of aortic calcification can facilitate subsequent cardiovascular care planning. Opportunistic screening based on plain chest radiography is potentially feasible in various population. We used multiple deep convolutional neural network (CNN) transfer learning by fine-tuning pre-trained models followed by ensemble technique for aortic arch calcification on chest radiographs from a derivation and two external databases with distinct features. Our ensemble approach achieved 84.12% precision, 84.70% recall, and an area under the receiver-operating-characteristic curve (AUC) of 0.85 in the general population/older adult's dataset. We also obtained 87.5% precision, 85.56% recall, and an AUC of 0.86 in the pre-end-stage kidney disease (pre-ESKD) cohort. We identified discriminative regions for identifying aortic arch calcification between patients without and with pre-ESKD. These findings are expected to optimize cardiovascular risk prediction if our model is incorporated into the process of routine care.
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Frailty is the incremental accumulation of minute defects that progressively impair health and performance. Frailty is commonly observed in older adults; however, secondary frailty may also occur in patients with metabolic disorders or major organ failure. In addition to physical frailty, several distinct types of frailty have been identified, including oral, cognitive, and social frailty, each of which is of practical importance. This nomenclature suggests that detailed descriptions of frailty can potentially advance relevant researches. In this narrative review, we first summarize the clinical value and plausible biological origin of frailty, as well as how to appropriately assess it using physical frailty phenotypes and frailty indexes. In the second part, we discuss the issue of vascular tissue as a relatively underappreciated organ whose pathologies contribute to the development of physical frailty. Moreover, when vascular tissue undergoes degeneration, it exhibits vulnerability to subtle injuries and manifests a unique phenotype amenable to clinical assessment prior to or accompanying physical frailty development. Finally, we propose that vascular frailty, based on an extensive set of experimental and clinical evidence, can be considered a new frailty type that requires our attention. We also outline potential methods for the operationalization of vascular frailty. Further studies are required to validate our claim and sharpen the spectrum of this degenerative phenotype.
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Sistema Cardiovascular , Fragilidad , Humanos , Fragilidad/complicaciones , Fragilidad/psicología , Sistema Cardiovascular/patologíaRESUMEN
Introduction: We aimed to substantiate the benefit of postoperative handgrip exercises (HGEs) in enhancing the maturation of an arteriovenous wrist fistula. Methods: We randomly assigned 119 patients aged 20 to 80 years who had wrist arteriovenous fistulas (AVFs) to undergo either a basic HGE program (group A), an advanced program (group B), or an advanced-plus upper arm banding program (group C). Outcomes were assessed by ultrasonographic evaluation of the diameter and flow at each follow-up. The attending nephrologist decided the clinical use of the fistula. Results: We identified no significant differences among the HGE groups in the mean diameter and blood flow 14, 30, 60, and 90 days after the creation of the wrist AVF (P = 0.55, 0.88, 0.21, and 0.19 for the diameter; 0.94, 0.81, 0.49, and 0.56 for the flow, respectively). The intent-to-treat analysis also found no difference in the clinical use of fistulas for hemodialysis (HD) (P = 0.997). Conclusion: In patients with a newly created wrist AVF, advancing frequency, with or without adding intensity using an upper arm tourniquet, of postoperative HGEs did not enhance the growth of the fistula or increase the rate of clinical use over 3 months. (ClinicalTrials.gov ID: NCT03077815).
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Liposomes have been used to improve therapeutic efficacy of drugs by increasing their bioavailability and altering biodistribution. The loading capacity of small molecules in liposomes remains a critical issue. Besides, the manufacturing process of liposomes requires multi-step procedures which hinders the clinical development. In this study, we developed a promising lipid-based nanocarriers (LN) delivery system for hydrophilic charged compounds using doxycycline (Doxy) as a model drug. This Doxy-loaded lipid nanocarrier (LN-Doxy) was fabricated by microfluidic technology. Design of experiments (DoE) was constructed to outline the interactions among the critical attributes of formulation, the parameters of microfluidic systems and excipient compositions. Response surface methodology (RSM) was furthered used for the optimization of LN-Doxy formulation. The LN-Doxy developed in this study showed high drug to lipid ratio and uniform distribution of particle size. Compared to Doxy solution, this LN-Doxy has reduced in vitro cellular toxicity and significant therapeutic efficacy which was verified in a peritonitis animal model. These results show the feasibility of using microfluidic technology combined with QbD approach to develop the LN formulation with high loading efficiency for ionizable hydrophilic drugs.
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Doxiciclina , Liposomas , Animales , Doxiciclina/uso terapéutico , Microfluídica/métodos , Distribución Tisular , Lípidos , Tamaño de la PartículaRESUMEN
Low-intensity pulsed ultrasound (LIPUS), a therapeutic type of ultrasound, is known to enhance bone fracture repair processes and help some tissues to heal. Here, we investigated the therapeutic potential of LIPUS for the treatment of chronic kidney disease (CKD) in two CKD mouse models. CKD mice were induced using both unilateral renal ischemia/reperfusion injury (IRI) with nephrectomy and adenine administration. The left kidneys of the CKD mice were treated using LIPUS with the parameters of 3 MHz, 100 mW/cm2, and 20 min/day, based on the preliminary experiments. The mice were euthanized 14 days after IRI or 28 days after the end of adenine administration. LIPUS treatment effectively alleviated the decreases in the body weight and albumin/globulin ratio and the increases in the serum renal functional markers, fibroblast growth factor-23, renal pathological changes, and renal fibrosis in the CKD mice. The parameters for epithelial-mesenchymal transition (EMT), senescence-related signal induction, and the inhibition of α-Klotho and endogenous antioxidant enzyme protein expression in the kidneys of the CKD mice were also significantly alleviated by LIPUS. These results suggest that LIPUS treatment reduces CKD progression through the inhibition of EMT and senescence-related signals. The application of LIPUS may be an alternative non-invasive therapeutic intervention for CKD therapy.
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Transición Epitelial-Mesenquimal , Insuficiencia Renal Crónica , Ratones , Animales , Riñón/metabolismo , Insuficiencia Renal Crónica/metabolismo , Fibrosis , Biomarcadores/metabolismo , Adenina/metabolismoRESUMEN
OBJECTIVES: To assess the cardiovascular and renal efficacy and safety of sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients without diabetes. METHODS: We searched PubMed, MEDLINE, Embase and Cochrane Library for publications up to 17 August 2022. Certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation approach. Random-effects meta-analyses were performed to pool effect measures across studies. Risk ratios (RRs) with 95% CIs are expressed for composite cardiovascular outcome of cardiovascular death or hospitalisation for heart failure, cardiovascular death, hospitalisation for heart failure, all-cause mortality and composite renal outcome of ≥50% reduction in estimated glomerular filtration rate (eGFR), end-stage kidney disease or renal death. Annual rate of change in eGFR is expressed as the mean difference with 95% CI. RESULTS: We identified four trials with 8927 patients with heart failure or chronic kidney disease (CKD). Compared with placebo, SGLT2 inhibitors showed favourable effects on the composite cardiovascular outcome (RR: 0.79, 95% CI: 0.71 to 0.87; moderate certainty), cardiovascular death (0.85, 0.74 to 0.99; moderate certainty), hospitalisation for heart failure (0.72, 0.62 to 0.82; moderate certainty), the composite renal outcome (0.64, 0.48 to 0.85; low certainty) and the annual rate of change in eGFR (mean difference: 0.99, 0.59 to 1.39 mL/min/1.73 m2/year; moderate certainty), while there was no significant difference in all-cause mortality (0.88, 0.77 to 1.01; very low certainty). Moderate certainty evidence indicated that SGLT2 inhibitors reduced the risk of serious adverse events and acute renal failure. Low certainty evidence suggested that SGLT2 inhibitors increased the risk of urinary tract infection and genital infection, while there were no differences in discontinuation due to adverse events, amputation, fracture, hypoglycaemia, ketoacidosis or volume depletion. CONCLUSIONS: Evidence of low to moderate certainty suggests that SGLT2 inhibitors provide cardiorenal benefits but have increased risk for urinary tract infection and genital infection in patients without diabetes and with heart failure or CKD. PROSPERO REGISTRATION NUMBER: CRD42021239807.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Insuficiencia Cardíaca , Insuficiencia Renal Crónica , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Enfermedades Cardiovasculares/tratamiento farmacológico , Diabetes Mellitus Tipo 2/inducido químicamente , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucosa/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/tratamiento farmacológico , Sodio/uso terapéutico , Transportador 2 de Sodio-Glucosa/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéuticoRESUMEN
BACKGROUND: The activation of the unfolded protein response (UPR) is closely linked to the pathogenesis of renal injuries. However, the role of XBP1, a crucial regulator of adaptive UPR, remains unclear during the transition from acute kidney injury (AKI) to chronic kidney disease (CKD). METHODS: We characterized XBP1 expressions in different mouse models of kidney injuries, including unilateral ischemia-reperfusion injury (UIRI), unilateral ureteral obstruction, and adenine-induced CKD, followed by generating proximal tubular XBP1 conditional knockout (XBP1cKO) mice for examining the influences of XBP1. Human proximal tubular epithelial cells (HK-2) were silenced of XBP1 to conduct proteomic analysis and investigate the underlying mechanism. RESULTS: We showed a tripartite activation of UPR in injured kidneys. XBP1 expressions were attenuated after AKI and inversely correlated with the severity of post-AKI renal fibrosis. XBP1cKO mice exhibited more severe renal fibrosis in the UIRI model than wide-type littermates. Silencing XBP1 induced HK-2 cell cycle arrest in G2M phase, inhibited cell proliferation, and promoted TGF-ß1 secretion. Proteomic analysis identified TNF receptor associated protein 1 (Trap1) as the potential downstream target transcriptionally regulated by XBP1s. Trap1 overexpression can alleviate silencing XBP1 induced profibrotic factor expressions and cell cycle arrest. CONCLUSION: The loss of XBP1 in kidney injury was profibrotic, and the process was mediated by autocrine and paracrine regulations in combination. The present study identified the XBP1-Trap1 axis as an instrumental mechanism responsible for post-AKI fibrosis, which is a novel regulatory pathway.
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Lesión Renal Aguda , Insuficiencia Renal Crónica , Daño por Reperfusión , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/genética , Animales , Regulación hacia Abajo , Fibrosis , Ratones , Proteómica , Insuficiencia Renal Crónica/genética , Respuesta de Proteína Desplegada/genéticaRESUMEN
Saturated free fatty acids (FFAs) strongly correlate with metabolic syndromes and are well-known risk factors for cardiovascular diseases (CVDs). The mechanism of palmitic acid (PA)-induced vascular lipotoxicity under endoplasmic reticulum (ER) stress is unknown. In the present paper, we investigate the roles of spliced form of X-box-binding protein 1 (XBP1s) target gene oxidative stress-induced growth inhibitor 1 (OSGIN1) in PA-induced vascular dysfunction. PA inhibited the tube formation assay of primary human umbilical vein endothelial cells (HUVECs). Simultaneously, PA treatment induced the XBP1s expression in HUVECs. Attenuate the induction of XBP1s by silencing the XBP1s retarded cell migration and diminished endothelial nitric oxide synthase (eNOS) expression. OSGIN1 is a target gene of XBP1s under PA treatment. The silencing of OSGIN1 inhibits cell migration by decreasing phospho-eNOS expression. PA activated autophagy in endothelial cells, inhibiting autophagy by 3-methyladenine (3-MA) decreased endothelial cell migration. Silencing XBP1s and OSGIN1 would reduce the induction of LC3 II; therefore, OSGIN1 could maintain autophagy to preserve endothelial cell migration. In conclusion, PA treatment induced ER stress and activated the inositol-requiring enzyme 1 alpha-spliced XBP1 (IRE1α-XBP1s) pathway. OSGIN1, a target gene of XBP1s, could protect endothelial cells from vascular lipotoxicity by regulating autophagy.