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INTRODUCTION: The blockade of the renin-angiotensin system (RAS) has a beneficial effect on reducing the levels of proteinuria and blood pressure in patients with chronic kidney disease (CKD) and reduces the risk of developing end-stage kidney disease in CKD patients. Nonetheless, a debate persists regarding the impact of RAS inhibitors on outcomes such as mortality and graft survival in renal transplant patients. To assess the effect of RAS inhibitors on graft recipients in the past decade, we conducted a systematic review and meta-analysis. METHODS: We searched Embase, PubMed, and the Cochrane Central Register of Clinical Trials from January 1, 2012, to August 1, 2022. We included 14 articles, comprising 5 randomized controlled trials (RCTs) and 9 cohort studies, including 45,377 patients. These studies compared patient or graft survival between an RAS inhibitor treatment arm and a control arm. RESULTS: The meta-analysis revealed that RAS blockade was significantly associated with lower mortality in cohort studies (risk ratio [RR] = 0.66, 95% confidence interval [CI]: 0.55-0.79), reduced allograft loss in cohort studies (RR = 0.62, 95% CI: 0.54-0.71), and significant changes in systolic blood pressure in RCTs. Subgroup analysis of the groups of interest (interventions involving RAS blockade, follow-up period of ≥5 years) showed consistently reduced mortality (RR = 0.67, 95% CI: 0.56-0.81) and reduced allograft loss (RR = 0.61, 95% CI: 0.54-0.70). CONCLUSIONS: Our results demonstrated that the application of RAS blockade among renal transplant recipients was associated with lower mortality and allograft loss in cohort studies but not in RCTs. More powered clinical trials are needed to evaluate the effects of RAS blockade in renal transplant recipients.
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BACKGROUND: Older patients are at risk for acute kidney injury and chronic kidney disease. Age-related increases in DNA methylation at CpG islands have been linked to aging-related diseases like cancer and cardiovascular disease, but the exact causal relationship between methylation in renal aging and other kidney diseases remains unclear. This study aimed to elucidate the methylation status of peripheral blood mononuclear cells (PBMCs) in the Asian population. Using human whole blood DNA methylation analysis from the Taiwan Biobank, we included participants with both whole blood genome-wide methylation data and follow-up data on serum creatinine. We investigated hyper- and hypomethylated genes in comparison of participants with higher and lower estimated glomerular filtration (eGFR) decline rate in overall cohort as well as in comparison of old and young participants in subgroup of participants with higher eGFR decline rate. Common genes and signaling pathways in both comparative analyses were identified. RESULTS: Among 1587 participants in the analysis, 187 participants had higher eGFR decline rate. According to the comparison of methylation in participants with different eGFR declines and at different ages, respectively, we identified common hypermethylated genes, including DNMT3A and GGACT, as well as hypomethylated genes such as ARL6IP5, CYB5D1, BCL6, RPRD2, ZNF451, and MIAT in both participants with higher eGFR decline and those of older age. We observed associations between the methylation status of signaling pathways and aging as well as renal function decline. These pathways notably included autophagy, p38 mitogen-activated protein kinases, and sirtuins, which were associated with autophagy process and cytokine production. CONCLUSIONS: Through methylation analysis of PBMCs, we identified genes and signaling pathways which could play crucial roles in the interplay of renal aging and renal function decline. These findings contribute to the development of novel biomarkers for identifying at-risk groups and even for therapeutic agent discovery.
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Envejecimiento , Islas de CpG , Metilación de ADN , Tasa de Filtración Glomerular , Humanos , Metilación de ADN/genética , Femenino , Masculino , Persona de Mediana Edad , Anciano , Taiwán , Envejecimiento/genética , Envejecimiento/sangre , Tasa de Filtración Glomerular/genética , Adulto , Islas de CpG/genética , Leucocitos Mononucleares/metabolismo , Riñón/fisiopatología , Epigénesis Genética/genética , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/fisiopatología , Estudio de Asociación del Genoma Completo/métodosRESUMEN
BACKGROUND: Albuminuria is common and associated with increased risks of end-stage kidney disease and cardiovascular diseases, yet its underlying mechanism remains obscure. Previous genome-wide association studies (GWAS) for albuminuria did not consider gene pleiotropy and primarily focused on European ancestry populations. This study adopted a multi-trait analysis of GWAS (MTAG) approach to jointly analyze two vital kidney traits, estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) to identify and prioritize the genes associated with UACR. METHODS: Data from the Taiwan Biobank from 2012 to 2023 were analyzed. GWAS of UACR and eGFR were performed separately and the summary statistics from these GWAS were jointly analyzed using MTAG. The polygenic risk scores (PRS) of UACR were constructed for validation. The UACR-associated loci were further fine-mapped and prioritized based on their deleteriousness, eQTL associations, and relatedness to Mendelian kidney diseases. RESULTS: MTAG analysis of the UACR revealed 15 genetic loci, including 12 novel loci. The PRS for UACR was significantly associated with urinary albumin level (P < 0.001) and microalbuminuria (P = 0.001 â¼ 0.045). A list of priority genes was generated. Twelve genes with high priority included the albumin endocytic receptor gene LRP2 and ciliary genes IFT172. CONCLUSIONS: The findings of this multi-trait GWAS suggest that primary cilia play a role in sensing mechanical stimuli, leading to albumin endocytosis. The priority list of genes warrants further translational investigation to reduce albuminuria.
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In the aged patients suffering from acute kidney injury, the risk for progression to chronic kidney disease and mortality is high. Aging accompanied by glomerulosclerosis, interstitial inflammation, and fibrosis might be one of the underlying mechanisms for vulnerability. In addition to sustained activation of the renin-angiotensin system, persistent chronic inflammation with tertiary lymphoid tissue formation is more common and is associated with disease progression in the aged kidney after acute injury. Based on recent laboratory evidence that young blood can rejuvenate the brain, muscle, and heart, we were intrigued by the possible protective effect of young plasma on acute kidney injury in aged mice. Here, we demonstrated that young plasma from 2-month-old mice could attenuate chronic kidney disease progression in 15-month-old mice subjected to acute kidney injury induced by ischemia-reperfusion. In the aged mice after acute kidney injury, young plasma administration decreased tubulointerstitial injury, fibrosis, and tertiary lymphoid tissue formation in kidneys assessed on day 28 after acute injury despite no significant beneficial effect on injury severity and survival. Mechanistically, young plasma inhibited angiotensin II-activated chemokines in pericytes that were responsible for tertiary lymphoid tissue formation. In summary, our data provide evidence that young plasma attenuates the transition from acute kidney injury to chronic kidney disease in aged mice. The therapeutic potential of young plasma infusion or exchange in the aged patients suffering acute kidney injury needs to be addressed in clinical trials.
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Studies have highlighted the significant involvement of kidney pericytes in renal fibrosis. Kidney pericytes, classified as interstitial mesenchymal cells, are extensively branched, collagen-producing cells that closely interact with endothelial cells. This article aims to provide an overview of the recent advancements in understanding the physiological functions of pericytes and their roles in kidney diseases. In a healthy kidney, pericytes have essential physiological function in angiogenesis, erythropoietin (EPO) production, and the regulation of renal blood flow. Nevertheless, pericyte-myofibroblast transition has been identified as the primary cause of disease progression in acute kidney injury (AKI)-to-chronic kidney disease (CKD) continuum. Our recent research has demonstrated that hypoxia-inducible factor-2α (HIF-2α) regulates erythropoietin production in pericytes. However, this production is repressed by EPO gene hypermethylation and HIF-2α downregulation which were induced by transforming growth factor-ß1-activated DNA methyltransferase and activin receptor-like kinase-5 signaling pathway during renal fibrosis, respectively. Additionally, AKI induces epigenetic modifications in pericytes, rendering them more prone to extracellular matrix production, cell migration and proliferation, thereby contributing to subsequent capillary rarefaction and renal fibrosis. Further investigation into the specific functions and roles of different subpopulations of pericytes may contribute for the development of targeted therapies aimed at attenuating kidney disease and mitigating their adverse effects.
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Lesión Renal Aguda , Eritropoyetina , Enfermedades Renales , Insuficiencia Renal Crónica , Humanos , Pericitos/metabolismo , Células Endoteliales/metabolismo , Riñón/patología , Eritropoyetina/genética , Lesión Renal Aguda/patología , Fibrosis , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismoRESUMEN
BACKGROUND/PURPOSE: Predictive modeling aids in identifying patients at high risk of adverse events. Using routinely collected data, we report a competing risk prediction model for kidney failure. METHODS: A total of 5138 patients with CKD stages 3b-5 were included and randomized into the development and validation cohorts at a ratio of 7:3. The outcome was end-stage kidney disease, defined as the initiation of dialysis or kidney transplantation. All patients were followed-up until December 31, 2020. A Fine and Gray model was applied to estimate the sub-hazard ratio of kidney failure, with death as a competing event. RESULTS: In the development cohort, the mean age was 67.6 ± 13.9 years and 60 % were male. The mean index eGFR and median urinary protein-creatinine ratio (UPCR) were 26.5 ± 12.8 mL/min/1.73 m2 and 1051 mg/g, respectively. The median follow-up duration was 1051 days. The proportion of patients with kidney failure and death was 25.4 % and 14.1 %, respectively. Four models were applied, including eGFR, age, sex, UPCR, systolic and diastolic blood pressure, serum albumin, phosphate, uric acid, haemoglobin, and potassium levels had the best goodness of fit. All models had good discrimination with time-to-event c statistics of 0.89-0.95 in the development cohort and 0.86-0.95 in the validation cohort. The prediction models showed excellent and fairly good calibration at 2 and 5-year risk, respectively. CONCLUSION: Using real-world data, our competing risk model can accurately predict progression to kidney failure over 2 years in patients with advanced CKD.
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BACKGROUND: Cancer cells promote glycolysis, which supports rapid cell growth and proliferation. Phosphofructokinase-fructose bisphosphatases (PFKFBs), a family of bidirectional glycolytic enzymes, play key roles in the regulation of glycolysis in many types of cancer. However, their roles in oral squamous cell carcinoma (OSCC), the most common type of oral cancer, are still unknown. METHODS: We compared the gene expression levels of PFKFB family members and analyzed their clinical significance in oral cancer patients, whose clinical data were obtained the Cancer Genome Atlas database. Moreover, real-time quantitative polymerase chain reaction, western blotting, assays for cell viability, cell cycle, cell migration and viability of cell spheroid were performed in scramble and PFKFB-silenced cells. RESULTS: We discovered that PFKFB3 expression in tumor tissues was slightly higher than that in tumor adjacent normal tissues but that PFKFB4 expression was significantly higher in the tumor tissues of oral cancer patients. High PFKFB3 and PFKFB4 expression had different effects on the prognosis of oral cancer patients with different clinicopathological outcomes. Our data showed that PFKFB3 and PFKFB4 play different roles; PFKFB3 is involved in cell viability, G2/M cell cycle progression, invasion, and migration, whereas PFKFB4 is involved in the drug resistance and cancer stemness of OSCC cells. Furthermore, oral cancer patients with co-expressions of PFKFB3/cell cycle or EMT markers and PFKFB4/stemness markers had poor prognosis. CONCLUSIONS: PFKFB3 and PFKFB4 play different biological roles in OSCC cells, which implying that they might be potential prognostic biomarkers for OSCC patients with certain clinicopathological outcomes.
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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
INTRODUCTION: Periodontitis is the main indication for dental extraction and often leads to peri-implantitis (PI). Alveolar ridge preservation (ARP) is an effective means of preserving ridge dimensions after extraction. However, whether PI prevalence is lower after ARP for extraction after periodontitis remains unclear. This study investigated PI after ARP in patients with periodontitis. MATERIALS AND METHODS: This study explored the 138 dental implants of 113 patients. The reasons for extraction were categorized as periodontitis or nonperiodontitis. All implants were placed at sites treated using ARP. PI was diagnosed on the basis of radiographic bone loss of ≥3 mm, as determined through comparison of standardized bitewing radiographs obtained immediately after insertion with those obtained after at least 6 months. Chi-square and two-sample t testing and generalized estimating equations (GEE) logistic regression model were employed to identify risk factors for PI. Statistical significance was indicated by p < 0.05. RESULTS: The overall PI prevalence was 24.6% (n = 34). The GEE univariate logistic regression demonstrated that implant sites and implant types were significantly associated with PI (premolar vs. molar: crude odds ratios [OR] = 5.27, 95% confidence intervals [CI] = 2.15-12.87, p = 0.0003; bone level vs. tissue level: crude OR = 5.08, 95% CI = 2.10-12.24; p = 0.003, respectively). After adjustment for confounding factors, the risks of PI were significantly associated with implant sites (premolar vs. molar: adjusted OR [AOR] = 4.62, 95% CI = 1.74-12.24; p = 0.002) and implant types (bone level vs. tissue level: AOR = 6.46, 95% CI = 1.67-25.02; p = 0.007). The reason for dental extraction-that is, periodontitis or nonperiodontitis-was not significantly associated with PI. CONCLUSION: ARP reduces the incidence of periodontitis-related PI at extraction sites. To address the limitations of our study, consistent and prospective randomized controlled trials are warranted.
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Pérdida de Hueso Alveolar , Implantes Dentales , Periimplantitis , Periodontitis , Humanos , Implantes Dentales/efectos adversos , Periimplantitis/epidemiología , Periimplantitis/etiología , Periimplantitis/prevención & control , Pérdida de Hueso Alveolar/etiología , Pérdida de Hueso Alveolar/inducido químicamente , Estudios Prospectivos , Prevalencia , Estudios Retrospectivos , Periodontitis/complicaciones , Proceso Alveolar/diagnóstico por imagenRESUMEN
PURPOSE: This study aimed to investigate changes in alveolar bone width around dental implants and identify the anterior nasal spine (ANS), posterior nasal spine (PNS), and floor of the nasal cavity that can be used as reference landmarks for standardizing the orientation of different cone-beam computed tomography (CBCT) scans. MATERIALS AND METHODS: We enrolled two groups that comprised 30 implants. Two CBCT scans from the same patient after implant surgery in the first group were obtained to determine differences in the relative distance and angle between the ANS and apex of the dental implant. Then we compared the second group of patients' presurgical and postsurgical CBCT images to evaluate changes in alveolar bone width after dental implant surgery by the aforementioned bony landmarks. RESULTS: In the first group, no statistically significant differences were detected in the mean distance between the ANS, PNS and implant tip in different directions. In the second group, bone width increased at 1 mm (p = 0.020) and decreased at 4 mm (p < 0.001) and 7 mm (p < 0.001) below the alveolar bone crest after implant surgery. CONCLUSIONS: Within the limitations of the present study, the ANS, PNS, and floor of the nasal cavity can be useful in standardizing the orientation of CBCT scans and alveolar bone remodeling after implant surgery varied depending on the height and direction from the alveolar bone crest based on the three landmarks.
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Implantes Dentales , Humanos , Maxilar/diagnóstico por imagen , Maxilar/cirugía , Proceso Alveolar/diagnóstico por imagen , Tomografía Computarizada de Haz Cónico/métodos , Remodelación ÓseaRESUMEN
Background: The glomerular filtration rate (GFR) decline varies in patients with advanced chronic kidney disease (CKD), and the concurrent changes in CKD-related biomarkers are unclear. Objectives: This study aimed to examine the changes in CKD-related biomarkers along with the kidney function decline in various GFR trajectory groups. Design: This study was a longitudinal cohort study originated from the pre-end-stage renal disease (pre-ESRD) care program in a single tertiary center between 2006 and 2019. Methods: We adopted a group-based trajectory model to categorize CKD patients into three trajectories according to estimated glomerular filtration rate (eGFR) changes. A repeated-measures linear mixed model was used to estimate the concurrent biomarker trends in a 2-year period before dialysis and to examine the differences among trajectory groups. A total of 15 biomarkers were analyzed, including urine protein, serum uric acid, albumin, lipid, electrolytes, and hematologic markers. Results: Using longitudinal data from 2 years before dialysis initiation, 1758 CKD patients were included. We identified three distinct eGFR trajectories: persistently low eGFR levels, progressive loss of eGFR, and accelerated loss of eGFR. Eight of the 15 biomarkers showed distinct patterns among the trajectory groups. Compared with the group with persistently low eGFR values, the other two groups were associated with a more rapid increase in the blood urea nitrogen (BUN) level and urine protein-creatinine ratio (UPCR), especially in the year before dialysis initiation, and a more rapid decline in hemoglobin and platelet counts. A rapid eGFR decline was associated with lower levels of albumin and potassium, and higher levels of mean corpuscular hemoglobin concentration (MCHC) and white blood cell (WBC). The albumin level in the group with an accelerated loss of eGFR was below the normal range. Conclusion: Using longitudinal data, we delineated the changes in CKD biomarkers with disease progression. The results provide information to clinicians and clues to elucidate the mechanism of CKD progression.
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Acute kidney injury (AKI) increases the risk of chronic kidney disease (CKD), and AKI and CKD are seen as interconnected syndromes. Acute kidney disease (AKD) is defined as subacute damage and/or loss of kidney function occurring 7 to 90 days after AKI, during which period key interventions may be initiated to hinder the development of CKD. While AKD is usually under-recognized, it is associated with high morbidity and mortality globally. This review article aims to summarize the current knowledge concerning the epidemiology, pathophysiology, and management of AKD with the aim to develop monitoring strategies and therapeutic agents of AKD. Generally, AKD tends to occur more frequently in the elderly and those with chronic diseases, such as hypertension, diabetes mellitus, and metabolic syndrome. In addition, the severity, duration, and frequency of AKI are independent risk factors for AKD. Investigations of several mechanisms of AKD, such as renal tubular epithelium cell-cycle arrest, epigenetic change, chronic inflammation, mitochondria dysfunction, failed regeneration of tubular cells, metabolic reprogramming, and renin-angiotensin system (RAS) activation, have identified additional potential pharmacotherapy targets. Management of AKD includes prevention of repeated AKI, early and regular follow-up by a nephrologist, resumption and adjustment of essential medication, optimization of blood pressure control and nutrition management, and development of new pharmaceutical agents including RAS inhibitors. Finally, we outline a care bundle for AKD patients based on important lessons learned from studies and registries and identify the need for clinical trials of RAS inhibitors or other novel agents to impede ensuing CKD development.
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OBJECTIVE: To evaluate the association between serum urate and risk of incident chronic kidney disease (CKD) and to assess whether serum urate plays a causal role in CKD. PATIENTS AND METHODS: We conducted a prospective cohort study and Mendelian randomization analysis that analyzed longitudinal data from the Taiwan Biobank between January 1, 2012, and December 31, 2021. RESULTS: A total of 34,831 individuals met the inclusion criteria, of which 4697 (13.5%) had hyperuricemia. After a median (interquartile range) follow-up of 4.1 (3.1-4.9) years, 429 participants developed CKD. After adjustment for age, sex, and comorbid conditions, each mg/dL increase in serum urate was associated with a 15% higher risk of incident CKD (HR, 1.15; 95% CI, 1.08 to 1.24; P<.001). The genetic risk score and seven Mendelian randomization methods revealed no significant association between serum urate levels and the risk of incident CKD (HR, 1.03; 95% CI, 0.72 to 1.46; P=0.89; all P>.05 for 7 Mendelian randomization methods). CONCLUSION: This prospective, population-based cohort study showed that elevated serum urate is a significant risk factor for incident CKD; however, Mendelian randomization analyses failed to provide evidence that serum urate had a causal effect on CKD in the East Asian population.
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Insuficiencia Renal Crónica , Ácido Úrico , Humanos , Estudios Prospectivos , Estudios de Cohortes , Análisis de la Aleatorización Mendeliana , Bancos de Muestras Biológicas , Taiwán , Factores de RiesgoRESUMEN
Single-atom catalysts (SACs) have shown potential for achieving an efficient electrochemical CO2 reduction reaction (CO2RR) despite challenges in their synthesis. Here, Ag2S/Ag nanowires provide initial anchoring sites for Cu SACs (Cu/Ag2S/Ag), then Cu/Ag(S) was synthesized by an electrochemical treatment resulting in complete sulfur removal, i.e., Cu SACs on a defective Ag surface. The CO2RR Faradaic efficiency (FECO2RR) of Cu/Ag(S) reaches 93.0% at a CO2RR partial current density (jCO2RR) of 2.9 mA/cm2 under -1.0 V vs RHE, which outperforms sulfur-removed Ag2S/Ag without Cu SACs (Ag(S), 78.5% FECO2RR with 1.8 mA/cm2jCO2RR). At -1.4 V vs RHE, both FECO2RR and jCO2RR over Cu/Ag(S) reached 78.6% and 6.1 mA/cm2, which tripled those over Ag(S), respectively. As revealed by in situ and ex situ characterizations together with theoretical calculations, the interacted Cu SACs and their neighboring defective Ag surface increase microstrain and downshift the d-band center of Cu/Ag(S), thus lowering the energy barrier by â¼0.5 eV for *CO formation, which accounts for the improved CO2RR activity and selectivity toward related products such as CO and C2+ products.
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INTRODUCTION: Old age has been considered as a positive modifier of chronic kidney disease (CKD), but the progression of CKD is often accelerated by acute kidney injury (AKI) in older adults. This study aimed to investigate this paradoxical interplay and identify age-specific predictors of end-stage kidney disease (ESKD). METHODS: This retrospective cohort included 6,101 patients with CKD stage 3B-5 followed at a single center during 2005-2018. Participants were stratified into four age groups to explore age-dependent influences on the risk of ESKD and all-cause mortality. Multivariate Cox proportional hazard regression model with competing risk analysis was used to identify predictors of outcomes. RESULTS: During a median follow-up of 2.68 years, 1,650 (27.0%) patients developed ESKD and 541 (8.9%) patients died. The rate of ESKD decreased with advancing age, being lowest in the very old-aged (>75 years) group who displayed the slowest rate of estimated glomerular filtration rate (eGFR) decline. Multivariate Cox proportional hazard regression adjusted for competing death showed that younger ages, compared with patients aged >75 years, together with AKI episodes and several traditional risk factors were identified as predictors for ESKD. The impact of AKI episodes on ESKD development was most prominent in patients aged >75 years. These results were confirmed with subgroup analyses in patients with outcomes of different ages. CONCLUSION: Older adults with CKD exhibited a slower decline rate of eGFR, yet they were more likely to develop ESKD following AKI episodes. These results suggest tackling AKI is needed to prevent accelerated initiation of renal replacement therapy in elderly patients with pre-existing CKD.
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Lesión Renal Aguda , Fallo Renal Crónico , Insuficiencia Renal Crónica , Anciano , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Progresión de la Enfermedad , Fallo Renal Crónico/terapia , Insuficiencia Renal Crónica/terapia , Tasa de Filtración Glomerular , Factores de RiesgoRESUMEN
Anemia is common in patients with chronic kidney disease (CKD) and is mainly caused by insufficient production of erythropoietin from fibrotic kidney. Because anemia impairs quality of life and overall prognosis, recombinant human erythropoietin-related products (erythropoiesis-stimulating agents, ESAs) have been developed to increase hemoglobin level for decades. However, many safety concerns have been announced regarding the use of ESAs, including an increased occurrence of cardiovascular events, vascular access thrombosis, cancer progression, and recurrence. Hypoxia-inducible factor (HIF) is crucial to erythropoietin production, as a result, prolyl hydroxylase domain (PHD) enzyme inhibitors have been new therapeutic agents for the treatment of anemia in CKD. They can be administered orally, which is a preferred route for patients not undergoing hemodialysis. In clinical trials, PHD inhibitor could induce noninferior effect on erythropoiesis and improve functional iron deficiency compared with ESAs. Although no serious adverse events were reported, safety is still a concern because HIF stabilization induced by PHD inhibitor has pleotropic effects, such as angiogenesis, metabolic change, and cell survival, which might lead to unwanted deleterious effects, including fibrosis, inflammation, cardiovascular risk, and tumor growth. More molecular mechanisms of PHD inhibition and long-term clinical trials are needed to observe these pleotropic effects for the confirmation of safety and efficacy of PHD inhibitors.
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Calorie restriction (CR) and fasting affect lifespan, disease susceptibility and response to acute injury across multiple animal models, including ischaemic injuries such as myocardial infarction or kidney hypoxia. The cargo and function of circulating extracellular vesicles (EV) respond to changes in host physiology, including exercise, injury, and other interventions. Thus, we hypothesised that EVs induced following CR may reflect some of the beneficial properties of CR itself. In a pilot study, EVs were isolated from mice following 21 days of 30 % CR, and from eight human donors after 72 h water-only fasting. EV size, concentration and morphology were profiled by NTA, western blot and cryoEM, and their function was assessed using multiple assays related to ischaemic diseases. We found that EVs from post-fasting samples better protected cardiac cells from hypoxia/reperfusion (H/R) injury compared to pre-fasting EVs. However, there was no difference when used to treat H/R-injured kidney epithelial cells. Post-fasting derived EVs slowed the rate of fibroblast migration and slightly reduced macrophage inflammatory gene expression compared to pre-fasting derived EVs. Lastly, we compared miRNA cargos of pre- and post-fasting human serum EVs and found significant changes in a small number of miRNAs. We conclude that fasting appears to influence EV cargo and function, with varied effects worthy of further exploration.
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Ischemia-reperfusion injury (IRI) contributes to acute kidney injury (AKI) and development of chronic kidney disease. We describe an IRI protocol for mice via flank incisions approach, using a pedicle clamp to cause ischemic injury. Compared with trans-abdominal approach, it is technically easier with lesser fluid loss and organ injury. Technical challenges during the dissection of renal pedicles are highlighted. For complete details on the execution of this protocol, please refer to Lai et al. (2014).
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Lesión Renal Aguda , Daño por Reperfusión , Ratones , Animales , Riñón , DisecciónRESUMEN
Rheumatoid arthritis (RA) and periodontitis are suggested to be closely linked based on microbial dysbiosis, but limited subgingival bacteria have been proven in the pathogenesis of RA. We enrolled 30 RA patients and 25 controls and divided them into three groups with matched age, gender, and diabetes statuses: group AM (all of the matched participants), group PD (periodontally diseased), and group PH (periodontally healthy). Their subgingival microbial composition was determined by V3-V4 16S rRNA gene sequencing. Significant differences in subgingival microbial clustering between the RA patients and controls were observed in groups AM and PD. Among the taxa enriched in RA, Aminipila butyrica and Peptococcus simiae were the only two species displaying positive correlation to the level of anti-citrullinated protein antibodies (ACPAs) in both of the groups. Surprisingly, the median of relative abundances of A. butyrica and P. simiae were 0% in the controls of group PD. Furthermore, a gene encoding arginine deiminase with the capability to produce citrulline was addressed in the complete genome sequence of A. butyrica. This is the first study to elucidate the important roles of A. butyrica and P. simiae as periodontal bacteria leading to RA possibly through the induction of ACPA production.