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BACKGROUNDIt is unknown whether the risk of kidney disease progression and failure differs between patients with and without genetic kidney disorders.METHODSThree cohorts were evaluated: the prospective Cure Glomerulonephropathy Network (CureGN) and 2 retrospective cohorts from Columbia University, including 5,727 adults and children with kidney disease from any etiology who underwent whole-genome or exome sequencing. The effects of monogenic kidney disorders and APOL1 kidney-risk genotypes on the risk of kidney failure, estimated glomerular filtration rate (eGFR) decline, and disease remission rates were evaluated along with diagnostic yields and the impact of American College of Medical Genetics secondary findings (ACMG SFs).RESULTSMonogenic kidney disorders were identified in 371 patients (6.5%), high-risk APOL1 genotypes in 318 (5.5%), and ACMG SFs in 100 (5.2%). Family history of kidney disease was the strongest predictor of monogenic disorders. After adjustment for traditional risk factors, monogenic kidney disorders were associated with an increased risk of kidney failure (hazard ratio [HR] = 1.72), higher rate of eGFR decline (-3.06 vs. 0.25 mL/min/1.73 m2/year), and lower risk of complete remission (odds ratioNot achieving CR = 5.25). High-risk APOL1 genotypes were associated with an increased risk of kidney failure (HR = 1.67) and faster eGFR decline (-2.28 vs. 0.25 mL/min/1.73 m2), replicating prior findings. ACMG SFs were not associated with personal or family history of associated diseases, but were predicted to impact care in 70% of cases.CONCLUSIONSMonogenic kidney disorders were associated with an increased risk of kidney failure, faster eGFR decline, and lower rates of complete remission, suggesting opportunities for early identification and intervention based on molecular diagnosis.TRIAL REGISTRATIONNA.FUNDINGNational Institute of Diabetes and Digestive and Kidney Diseases grants U24DK100845 (formerly UM1DK100845), U01DK100846 (formerly UM1DK100846), U01DK100876 (formerly UM1DK100876), U01DK100866 (formerly UM1DK100866), U01DK100867 (formerly UM1DK100867), U24DK100845, DK081943, RC2DK116690, 2U01DK100876, 1R01DK136765, 5R01DK082753, and RC2-DK122397; NephCure Kidney International; Department of Defense Research Awards PR201425, W81XWH-16-1-0451, and W81XWH-22-1-0966; National Center for Advancing Translational Sciences grant UL1TR001873; National Library of Medicine grant R01LM013061; National Human Genome Research Institute grant 2U01HG008680.
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Apolipoproteína L1 , Tasa de Filtración Glomerular , Insuficiencia Renal , Humanos , Masculino , Femenino , Adulto , Apolipoproteína L1/genética , Persona de Mediana Edad , Insuficiencia Renal/genética , Factores de Riesgo , Niño , Estudios Retrospectivos , Adolescente , Estudios Prospectivos , Enfermedades Renales/genéticaRESUMEN
INTRODUCTION AND AIM: Hepatitis C virus infection and chronic kidney disease are major public health issues all over the world. It has been suggested a role of HCV as a risk factor for the development and progression of chronic kidney disease (defined by reduced glomerular filtration rate and/or detectable proteinuria) in the general population but conflicting findings have been given. MATERIAL AND METHODS: A systematic review of the published medical literature was conducted to assess whether positive HCV serologic status is associated with greater rate of proteinuria in the adult general population. We used a random-effect model to generate a summary estimate of the relative risk of proteinuria with HCV across the published studies. RESULTS: We identified 23 studies (n=198,967 unique patients) and performed separate meta-analyses according to the study design. Overall effect estimate was significant in cross-sectional (OR, 1.47, 95%CI, 1.3; 1.66) (P<0.001) and obvious between-study heterogeneity was observed (Q value by Chi-squared [χ2] test 27.3, P=0.02). The risk of proteinuria after exposure to HCV was also consistent among longitudinal studies (HR, 1.79, 95% CI, 1.17; 2.74) (P<0.001) and between-study heterogeneity occurred (Q value, 27.82 by X2 test, P=0.0001). Stratified analysis did not report heterogeneity in several comparisons-pooling studies based on urine protein/creatinine ratio (UACR) showed that the adjusted OR with HCV was 1.64 (95% CI, 1.41; 1.91, P<0.001) without heterogeneity (Q value by Chi-squared [χ2] test 9.98, P=NS). Meta-regression recorded a link between greater prevalence of proteinuria in males with HCV exposure (P=0.03). Studies based on univariate analysis (n=6, n=72, 551 unique patients) gave similar results, pooled OR 1.54 (95% CI, 1.08; 2.19) (P=0.0001). CONCLUSIONS: An important relationship between HCV infection and higher risk of proteinuria in the general population exists. Research aimed to understand the biological mechanisms underlying such association is under way. We encourage to screen all patients with HCV exposure for proteinuria.
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Hepatitis C , Proteinuria , Humanos , Proteinuria/etiología , Hepatitis C/complicaciones , Factores de RiesgoRESUMEN
The current trend in the European biogas industry is to shift away from electricity production towards the production of biomethane for the need to replace natural gas. The upgrading of biogas to biomethane is normally performed by separating the biogas in a stream containing natural gas grid quality methane and a stream containing mostly CO2. The CO2 stream is normally released into the atmosphere; however, part of the methane may still remain in it, and, if not oxidized, even a small fraction of methane released may jeopardise all the GHG emissions savings from producing the biomethane, being methane a powerful climate forcer. Scope of this work is to assess the opportunity cost of installing an Off Gas Combustion (OGC) device in biomethane upgrading plants. The currently available technologies for biogas upgrading to biomethane and the most common technology of OGC (the Regenerative Thermal Oxidisers, RTO) are described according to their performances and cost. Then the cost per tonne of CO2eq avoided associated to the adoption of RTO systems in relation to the upgrading performance is calculated to identify a potential threshold for an effective and efficient application of the RTO systems. It is found that, in case of upgrading technologies which can capture almost all biomethane in the upgrading off-gas (i.e. 99.9%), currently the adoption of an RTO to oxidise the methane left in the off-gas would add costs and need additional fuel to be operated, but would generate limited GHG emission savings, therefore the cost per tonne of CO2eq emissions avoided would result not competitive with other GHG emissions mitigation investments. While the installation of RTOs on upgrading systems with a methane slip of 0.3%, or higher, normally results cost competitive in reducing GHG emissions. The installation of an RTO on systems with a methane slip of 0.2% results in a cost per tonne of CO2eq emissions avoided of 50-100 euro, which is comparable to the current cost of CO2 emissions allowances in the EU ETS carbon market, representing therefore a reasonable choice for a threshold on methane slip regulation for biogas upgrading systems.
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Biocombustibles , Dióxido de Carbono , Gases de Efecto Invernadero , Metano , Gases de Efecto Invernadero/análisis , Dióxido de Carbono/análisis , Efecto Invernadero , Gas NaturalRESUMEN
BACKGROUND: Human kidneys are an important target of SARS-CoV-2 infection, and many renal abnormalities have been found in patients with SARS-CoV-2 infection, including proteinuria, hematuria, and acute kidney injury. Acute kidney injury is now considered a common complication of COVID-19, and the epidemiology of AKI in SARS-CoV-2-infected patients continues to be controversial. AIM AND METHODS: We have carried out a narrative review to evaluate the frequency and risk factors for AKI among patients hospitalized due to COVID-19, and the latest surveys on this topic have been included. The mechanisms by which AKI occurs in COVID-19 patients have also been reviewed. RESULTS: Multiple risk factors for the development of AKI in patients with SARS-CoV-2 infection have been identified; these have been classified in various groups (management and background factors, among others). SARS-CoV-2 targets the kidneys by indirect activity, but SARS-CoV-2 infects tubular epithelial cells and podocytes. We retrieved 24 reports (n = 502,593 unique patients with SARS-CoV-2 infection) and found an incidence of AKI of 31.8% (range, 0.5% to 56.9%). Only a minority (n = 2) of studies had a prospective design. We found that the AKI risk was greater in SARS-CoV-2 patients who underwent in-hospital deaths vs. those who survived; the summary estimate of the unadjusted RR of AKI was 2.63 (95% CI, 2.37; 2.93) (random-effects model). A stratified analysis showed that the incidence of AKI was greater in those reports where the frequency of COVID-19-positive patients having comorbidities (diabetes mellitus, arterial hypertension, and advanced age) was high. The unadjusted relative risk (aRR) of AKI was greater in SARS-CoV-2 patients who underwent ICU admission vs. those who did not; the pooled estimate of AKI risk was 2.64 (95% CI, 1.96; 3.56) according to the random-effects model. CONCLUSIONS: AKI is a common complication of hospitalized SARS-CoV-2-infected patients, and some comorbidities are important risk factors for it. The direct activity of the virus on the kidneys has been mentioned in the pathogenesis of AKI in SARS-CoV-2 patients. Further studies are ongoing in order to identify the mechanisms underlying the kidney injury in this population. The role of AKI on survival in SARS-CoV-2-infected patients is another area of active investigation.
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African American (AA) kidney recipients have a higher risk of allograft rejection and failure compared to non-AAs, but to what extent these outcomes are due to genetic versus environmental effects is currently unknown. Herein, we tested the effects of recipient self-reported race versus genetic proportion of African ancestry (pAFR), and neighborhood socioeconomic status (SES) on kidney allograft outcomes in multiethnic kidney transplant recipients from Columbia University (N = 1083) and the University of Pennsylvania (N = 738). All participants were genotyped with SNP arrays to estimate genetic admixture proportions. US census tract variables were used to analyze the effect of neighborhood factors. In both cohorts, self-reported recipient AA race and pAFR were individually associated with increased risk of rejection and failure after adjustment for known clinical risk factors and neighborhood SES factors. Joint analysis confirmed that self-reported recipient AA race and pAFR were both associated with a higher risk of allograft rejection (AA: HR 1.61 (1.31-1.96), P = 4.05E-06; pAFR: HR 1.90 (1.46-2.48), P = 2.40E-06) and allograft failure (AA: HR 1.52 (1.18-1.97), P = .001; pAFR: HR 1.70 (1.22-2.35), P = .002). Further research is needed to disentangle the role of genetics versus environmental, social, and structural factors contributing to poor transplantation outcomes in kidney recipients of African ancestry.
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Rechazo de Injerto , Supervivencia de Injerto , Trasplante de Riñón , Autoinforme , Humanos , Masculino , Femenino , Persona de Mediana Edad , Rechazo de Injerto/genética , Rechazo de Injerto/etiología , Supervivencia de Injerto/genética , Factores de Riesgo , Adulto , Pronóstico , Estudios de Seguimiento , Población Urbana , Negro o Afroamericano/genética , Fallo Renal Crónico/cirugía , Fallo Renal Crónico/genética , Receptores de Trasplantes , Etnicidad/genética , Características del Vecindario , Tasa de Filtración Glomerular , Pruebas de Función Renal , Estudios de CohortesRESUMEN
IgA Nephropathy (IgAN) and Membranous Nephropathy (MN) are primary immune-mediated glomerular diseases with highly variable prognosis. Current guidelines recommend that greater immunologic activity and worse prognosis should guide towards the best treatment in an individualized approach. Nevertheless, proteinuria and glomerular filtration rate, the current gold standards for prognosis assessment and treatment guidance in primary glomerular diseases, may be altered with chronic damage and nephron scarring, conditions that are not related to immune activity. In recent years, thanks to the development of new molecular technologies, among them genome-wide genotyping, RNA sequencing techniques, and mass spectrometry, we have witnessed an outstanding improvement in understanding the pathogenesis of IgAN and MN. In addition, recent genome-wide association studies have suggested potential targets for immunomodulating agents, stressing the need for the identification of specific biomarkers of immune activity. In this work, we aim to review current evidence and recent progress, including the more recent use of omics techniques, in the identification of potential biomarkers for immune monitoring in IgAN and MN.
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Glomerulonefritis por IGA , Glomerulonefritis Membranosa , Humanos , Glomerulonefritis por IGA/genética , Glomerulonefritis Membranosa/genética , Estudio de Asociación del Genoma Completo , Monitorización Inmunológica , Glomérulos RenalesRESUMEN
Kidney transplantation (KT) is the best treatment for end-stage kidney disease. However, early diagnosis of graft injury remains challenging, mainly because of the lack of accurate and noninvasive diagnostic techniques. Improving graft outcomes is equally demanding, as is the development of innovative therapies. Many research efforts are focusing on extracellular vesicles, cellular particles free in each body fluid that have shown promising results as precise markers of damage and potential therapeutic targets in many diseases, including the renal field. In fact, through their receptors and cargo, they act in damage response and immune modulation. In transplantation, they may be used to determine organ quality and aging, the presence of delayed graft function, rejection, and many other transplant-related pathologies. Moreover, their low immunogenicity and safe profile make them ideal for drug delivery and the development of therapies to improve KT outcomes. In this review, we summarize current evidence about extracellular vesicles in KT, starting with their characteristics and major laboratory techniques for isolation and characterization. Then, we discuss their use as potential markers of damage and as therapeutic targets, discussing their promising use in clinical practice as a form of liquid biopsy.
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Vesículas Extracelulares , Fallo Renal Crónico , Trasplante de Riñón , Humanos , Trasplante de Riñón/efectos adversos , Riñón , Fallo Renal Crónico/cirugía , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/etiología , Rechazo de Injerto/prevención & controlRESUMEN
IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. Here we performed a genome-wide association study of 10,146 kidney-biopsy-diagnosed IgAN cases and 28,751 controls across 17 international cohorts. We defined 30 genome-wide significant risk loci explaining 11% of disease risk. A total of 16 loci were new, including TNFSF4/TNFSF18, REL, CD28, PF4V1, LY86, LYN, ANXA3, TNFSF8/TNFSF15, REEP3, ZMIZ1, OVOL1/RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The risk loci were enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. We also observed a positive genetic correlation between IgAN and serum IgA levels. High polygenic score for IgAN was associated with earlier onset of kidney failure. In a comprehensive functional annotation analysis of candidate causal genes, we observed convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets.
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Glomerulonefritis por IGA , Animales , Ratones , Glomerulonefritis por IGA/tratamiento farmacológico , Glomerulonefritis por IGA/genética , Glomerulonefritis por IGA/diagnóstico , Estudio de Asociación del Genoma Completo , Inmunoglobulina A/genéticaRESUMEN
Pediatric steroid-sensitive nephrotic syndrome (pSSNS) is the most common childhood glomerular disease. Previous genome-wide association studies (GWAS) identified a risk locus in the HLA Class II region and three additional independent risk loci. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown. Here, we conduct a multi-population GWAS meta-analysis in 38,463 participants (2440 cases). We then conduct conditional analyses and population specific GWAS. We discover twelve significant associations-eight from the multi-population meta-analysis (four novel), two from the multi-population conditional analysis (one novel), and two additional novel loci from the European meta-analysis. Fine-mapping implicates specific amino acid haplotypes in HLA-DQA1 and HLA-DQB1 driving the HLA Class II risk locus. Non-HLA loci colocalize with eQTLs of monocytes and numerous T-cell subsets in independent datasets. Colocalization with kidney eQTLs is lacking but overlap with kidney cell open chromatin suggests an uncharacterized disease mechanism in kidney cells. A polygenic risk score (PRS) associates with earlier disease onset. Altogether, these discoveries expand our knowledge of pSSNS genetic architecture across populations and provide cell-specific insights into its molecular drivers. Evaluating these associations in additional cohorts will refine our understanding of population specificity, heterogeneity, and clinical and molecular associations.
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Estudio de Asociación del Genoma Completo , Síndrome Nefrótico , Humanos , Niño , Síndrome Nefrótico/genética , Predisposición Genética a la Enfermedad , Haplotipos , Factores de Riesgo , Polimorfismo de Nucleótido SimpleRESUMEN
Immunoglobulin A (IgA) mediates mucosal responses to food antigens and the intestinal microbiome and is involved in susceptibility to mucosal pathogens, celiac disease, inflammatory bowel disease, and IgA nephropathy. We performed a genome-wide association study of serum IgA levels in 41,263 individuals of diverse ancestries and identified 20 genome-wide significant loci, including 9 known and 11 novel loci. Co-localization analyses with expression QTLs prioritized candidate genes for 14 of 20 significant loci. Most loci encoded genes that produced immune defects and IgA abnormalities when genetically manipulated in mice. We also observed positive genetic correlations of serum IgA levels with IgA nephropathy, type 2 diabetes, and body mass index, and negative correlations with celiac disease, inflammatory bowel disease, and several infections. Mendelian randomization supported elevated serum IgA as a causal factor in IgA nephropathy. African ancestry was consistently associated with higher serum IgA levels and greater frequency of IgA-increasing alleles compared to other ancestries. Our findings provide novel insights into the genetic regulation of IgA levels and its potential role in human disease.
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Enfermedad Celíaca , Diabetes Mellitus Tipo 2 , Glomerulonefritis por IGA , Enfermedades Inflamatorias del Intestino , Humanos , Ratones , Animales , Glomerulonefritis por IGA/genética , Glomerulonefritis por IGA/complicaciones , Estudio de Asociación del Genoma Completo , Enfermedad Celíaca/genética , Predisposición Genética a la Enfermedad , Diabetes Mellitus Tipo 2/complicaciones , Inmunoglobulina A/genética , Riñón/metabolismoRESUMEN
Silver linden (Tilia tomentosa Moench, TtM) flowers possess several health-promoting properties, especially at the neurological level, such as intestinal relaxation activity associated with specific flavonols, particularly quercetin and kaempferol derivatives. However, such molecules are susceptible to degradation upon different triggers like heat, light and extreme pH values. To overcome the scarce stability of TtM flowers bioactive molecules and make them suitable for developing functional food and supplements, we applied microencapsulation. Spray-drying microencapsulation of TtM flowers extract was performed using three starch-derived wall materials: maltodextrin 12 DE (MD12) and 19 DE (MD19), and OSA-modified starch (OSA-S). The stability of total phenols, flavanols, and antioxidant capacity was monitored for 70 days under accelerated stress conditions (40 °C/70% RH) by HPLC and spectrophotometric methods, and the intestinal contractile activity was tested in a murine model. In comparison to MD12 and MD19, OSA-S stood out for the higher encapsulation efficiency of quercetin and kaempferol glycosides (+ 36-47% compared to MD12 and + 18-24% compared to MD19) and stability thereof (half-life on average + 30% compared to MD12 and + 51% compared to MD19). The intestinal contractile activity of OAS-S powders resulted comparable to the original extract, indicating that flavonols were biologically active and accessible. Our results underly the potential advantages of OSA-S encapsulated formulation as a functional ingredient for the development of nutraceutical products.
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Tilia , Animales , Ratones , Flores/química , Quempferoles/análisis , Extractos Vegetales/química , Quercetina/análisis , Almidón/química , Tilia/químicaRESUMEN
The continual development of potent immunosuppressive regimens has led to a decreased incidence of acute rejection and improvement of short-term kidney allograft survival. In contrast to acute rejection, glomerular diseases of the kidney allograft are being encountered more frequently and are emerging as leading causes of late kidney allograft failure. Although data on the pathogeneses of glomerular diseases in the kidney allograft are sparse, cumulative evidence suggests that post-transplant glomerular diseases may be the result of inherited predispositions and immunologic triggers. Although studying immunologic signals and performing genome-wide association studies are ideal approaches to tackle glomerular diseases in the kidney allograft, such studies are challenging because of the lack of adequately powered cohorts. In this review, we focus on the most commonly encountered recurrent and de novo glomerular diseases in the kidney allograft. We address the important advances made in understanding the immunopathology and genetic susceptibility of glomerular diseases in the native kidney and how to benefit from such knowledge to further our knowledge of post-transplant glomerular diseases. Defining genomic and immune predictors for glomerular diseases in the kidney allograft would support novel donor-recipient matching strategies and development of targeted therapies to ultimately improve long-term kidney allograft survival.
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Enfermedades Renales , Trasplante de Riñón , Aloinjertos , Estudio de Asociación del Genoma Completo , Humanos , Riñón , Enfermedades Renales/cirugía , Complicaciones Posoperatorias/epidemiología , Medicina de PrecisiónRESUMEN
Introduction: Although IgA nephropathy (IgAN) is the most common recurrent glomerulonephritis encountered in the kidney allograft, the clinical and immunogenetic characteristics remain poorly understood. We sought to study determinants and prognosis of recurrent IgAN with special focus on HLA antigens. Materials and Methods: Between 2005 and 2019, we identified 282 transplanted patients with failure secondary to IgAN from two North American and one European Medical Centers, including 80 with recurrent IgAN and 202 without recurrence. Prevalence of HLA antigens was compared to external healthy controls of European ancestry (n=15,740). Graft survival was assessed by Kaplan-Meier method and log rank test. Cox proportional hazards were used for multivariable analyses. Results: Compared to external controls of European ancestry, kidney transplant recipients of European ancestry with kidney failure secondary to IgAN had higher frequency of HLA-DQ5 (42% vs. 30%, OR=1.68, P=0.002) and lower frequency of HLA-DR15 (15% vs. 28%, OR=0.46, P<0.001) and HLA-DQ6 (32% vs. 45%, OR=0.59, P=0.003); however, the frequency of these HLA antigens were similar in recurrent versus non-recurring IgAN. Younger recipient age at transplantation was an independent predictor of recurrence. HLA-matching was an independent predictor for recurrent IgAN only in recipients of living-related but not deceased or living unrelated transplants. Recurrent IgAN was an independent predictor of allograft failure, along with acute rejection. In patients with recurrent IgAN, serum creatinine at biopsy, degree of proteinuria, and concurrent acute rejection were associated with inferior allograft survival. Discussion/ Conclusion: Recurrent IgAN negatively affects allograft survival. Younger recipient age at transplantation is an independent predictor of recurrent IgAN, while the presence of HLA antigens associated with IgAN in the native kidney and HLA-matching in recipients of deceased or living unrelated transplants are not.
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Radiation-induced fibrosis (RIF) is a serious, yet incurable, complication of external beam radiation therapy for the treatment of cancer. Macrophages are key cellular actors in RIF because of their ability to produce reactive oxidants, such as reactive oxygen species (ROS) and inflammatory cytokines that, in turn, are the drivers of pro-fibrotic pathways. In a previous work, we showed that phagocytosis could be exploited to deliver the potent natural antioxidant astaxanthin specifically to macrophages. For this purpose, astaxanthin encapsulated into µm-sized protein particles could specifically target macrophages that can uptake the particles by phagocytosis. In these cells, astaxanthin microparticles significantly reduced intracellular ROS levels and the secretion of bioactive TGFß and increased cell survival after radiation treatments. Here we show that pentoxifylline, a drug currently used for the treatment of muscle pain resulting from peripheral artery disease, amplifies the effects of astaxanthin microparticles on J774A.1 macrophages. Combination treatments with pentoxifylline and encapsulated astaxanthin might reduce the risk of RIF in cancer patients.
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Macrófagos/efectos de los fármacos , Microplásticos/química , Pentoxifilina/química , Pentoxifilina/farmacología , Especies Reactivas de Oxígeno/metabolismo , Antioxidantes/química , Antioxidantes/farmacología , Células Cultivadas , Fibrosis/tratamiento farmacológico , Fibrosis/metabolismo , Humanos , Macrófagos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fagocitosis/efectos de los fármacos , Tolerancia a Radiación/efectos de los fármacos , Factor de Crecimiento Transformador beta/metabolismo , Xantófilas/química , Xantófilas/farmacologíaRESUMEN
Sarcopenia is a prevalent condition in chronic kidney disease (CKD). We determined gut microbiota (gMB) composition in CKD patients with or without sarcopenia. Furthermore, we investigated whether in these patients, there was any association between gMB, uremic toxins, inflammation and oxidative stress. We analyzed gMB composition, uremic toxins (indoxyl sulphate and p-cresyl sulphate), inflammatory cytokines (interleukin 10, tumor necrosis factor α, interleukin 6, interleukin 17, interleukin 12 p70, monocyte chemoattractant protein-1 and fetuin-A) and oxidative stress (malondialdehyde) of 64 elderly CKD patients (10 < eGFR < 45 mL/min/1.73 m2, not on dialysis) categorized as sarcopenic and not-sarcopenic. Sarcopenia was defined according to European Working Group on Sarcopenia in Older People 2 criteria. Sarcopenic patients had a greater abundance of the Micrococcaceae and Verrucomicrobiaceae families and of Megasphaera, Rothia, Veillonella, Akkermansia and Coprobacillus genera. They had a lower abundance of the Gemellaceae and Veillonellaceae families and of Acidaminococcus and Gemella genera. GMB was associated with uremic toxins, inflammatory cytokines and MDA. However, uremic toxins, inflammatory cytokines and MDA were not different in sarcopenic compared with not-sarcopenic individuals, except for interleukin 10, which was higher in not-sarcopenic patients. In older CKD patients, gMB was different in sarcopenic than in not-sarcopenic ones. Several bacterial families and genera were associated with uremic toxins and inflammatory cytokines, although none of these latter substantially different in sarcopenic versus not-sarcopenic patients.
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Microbioma Gastrointestinal , Insuficiencia Renal Crónica/microbiología , Sarcopenia/epidemiología , Tóxinas Urémicas/metabolismo , Anciano , Bacterias , Humanos , Indicán , Inflamación , Interleucina-6 , Malondialdehído , Persona de Mediana Edad , Estrés Oxidativo , Diálisis Renal , Sarcopenia/metabolismo , Uremia , Tóxinas Urémicas/análisisRESUMEN
Radiation-induced fibrosis is a serious long-lasting side effect of radiation therapy. Central to this condition is the role of macrophages that, activated by radiation-induced reactive oxygen species and tissue cell damage, produce pro-inflammatory cytokines, such as transforming growth factor beta (TGFß). This, in turn, recruits fibroblasts at the site of the lesion that initiates fibrosis. We investigated whether astaxanthin, an antioxidant molecule extracted from marine and freshwater organisms, could help control macrophage activation. To this purpose, we encapsulated food-grade astaxanthin from Haematococcus pluvialis into micrometer-sized whey protein particles to specifically target macrophages that can uptake material within this size range by phagocytosis. The data show that astaxanthin-loaded microparticles are resistant to radiation, are well-tolerated by J774A.1 macrophages, induce in these cells a significant reduction of intracellular reactive oxygen species and inhibit the release of active TGFß as evaluated in a bioassay with transformed MFB-F11 fibroblasts. Micro-encapsulation of bioactive molecules is a promising strategy to specifically target phagocytic cells and modulate their own functions.
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Antioxidantes/farmacología , Macrófagos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Fagocitosis , Especies Reactivas de Oxígeno/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Proteína de Suero de Leche/metabolismo , Animales , Antioxidantes/metabolismo , Línea Celular , Portadores de Fármacos , Composición de Medicamentos , Macrófagos/metabolismo , Ratones , Tamaño de la Partícula , Xantófilas/metabolismo , Xantófilas/farmacologíaRESUMEN
Chronic Kidney Disease (CKD) represents a slowly progressive disorder that is typically silent until late stages, but early intervention can significantly delay its progression. We designed a portable and scalable electronic CKD phenotype to facilitate early disease recognition and empower large-scale observational and genetic studies of kidney traits. The algorithm uses a combination of rule-based and machine-learning methods to automatically place patients on the staging grid of albuminuria by glomerular filtration rate ("A-by-G" grid). We manually validated the algorithm by 451 chart reviews across three medical systems, demonstrating overall positive predictive value of 95% for CKD cases and 97% for healthy controls. Independent case-control validation using 2350 patient records demonstrated diagnostic specificity of 97% and sensitivity of 87%. Application of the phenotype to 1.3 million patients demonstrated that over 80% of CKD cases are undetected using ICD codes alone. We also demonstrated several large-scale applications of the phenotype, including identifying stage-specific kidney disease comorbidities, in silico estimation of kidney trait heritability in thousands of pedigrees reconstructed from medical records, and biobank-based multicenter genome-wide and phenome-wide association studies.
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The increasing global prevalence of SARS-CoV-2 and the resulting COVID-19 disease pandemic pose significant concerns for clinical management of solid organ transplant recipients (SOTR). Wearable devices that can measure physiologic changes in biometrics including heart rate, heart rate variability, body temperature, respiratory, activity (such as steps taken per day) and sleep patterns, and blood oxygen saturation show utility for the early detection of infection before clinical presentation of symptoms. Recent algorithms developed using preliminary wearable datasets show that SARS-CoV-2 is detectable before clinical symptoms in >80% of adults. Early detection of SARS-CoV-2, influenza, and other pathogens in SOTR, and their household members, could facilitate early interventions such as self-isolation and early clinical management of relevant infection(s). Ongoing studies testing the utility of wearable devices such as smartwatches for early detection of SARS-CoV-2 and other infections in the general population are reviewed here, along with the practical challenges to implementing these processes at scale in pediatric and adult SOTR, and their household members. The resources and logistics, including transplant-specific analyses pipelines to account for confounders such as polypharmacy and comorbidities, required in studies of pediatric and adult SOTR for the robust early detection of SARS-CoV-2, and other infections are also reviewed.