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1.
Crit Care Resusc ; 22(2): 142-151, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32389106

RESUMEN

BACKGROUND: Frequent assessment of urine output (UO), serum creatinine (sCr) and urinary cell cycle arrest biomarkers (CCAB) may improve acute kidney injury (AKI) prediction. OBJECTIVE: To study the performance of UO, short term sCr changes and urinary CCAB to predict severe AKI. METHODS: We measured 6 hours of UO, 6-hourly sCr changes, and urinary CCABs in all critically ill patients with cardiovascular or respiratory failure or early signs of renal stress between February and October 2018. We studied the association of such measurements, and their combination, with the development of AKI Stage 2 or 3 of the Kidney Disease: Improving Global Outcomes (KDIGO) definition at 12 hours. We evaluated predictive performance with logistic regression, area under the receiver operating characteristic (AUROC) curve, and net reclassification indices. We computed an optimal cut-off value for each biomarker. RESULTS: We assessed 622 patients and, as per the exclusion criteria, we enrolled 105 critically ill patients. After 12 hours of enrolment, AKI occurred in 32 patients (30%). UO, sCr change over 6 hours and CCABs were significantly associated with severe AKI at 12 hours, with all variables achieving an AUROC > 0.7 after adjustment. Combination of any of the two or three variables achieved an AUROC > 0.7 for subsequent severe AKI at 12 hours. The optimal predictive high specificity cut-off values were ≤ 0.4 mL/kg/h for UO, variation of +15 µmol/L over 6 hours in sCr, and ≥ 1.5 (ng/mL)2/1000 for CCABs. CONCLUSION: In this prospective study, an integrative approach using UO, short term sCr change and/or urinary CCABs showed a satisfactory performance for the prediction of severe AKI development at 12 hours.


Asunto(s)
Lesión Renal Aguda , Biomarcadores/orina , Puntos de Control del Ciclo Celular/fisiología , Orina , Lesión Renal Aguda/sangre , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/orina , Creatinina/sangre , Enfermedad Crítica , Tasa de Filtración Glomerular , Humanos , Unidades de Cuidados Intensivos , Pruebas de Función Renal , Estudios Prospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Micción
2.
Crit Care ; 24(1): 144, 2020 04 10.
Artículo en Inglés | MEDLINE | ID: mdl-32276601

RESUMEN

BACKGROUND: Acute kidney injury (AKI) is a frequently occurring syndrome in critically ill patients and is associated with worse outcomes. Biomarkers allow early identification and therapy of AKI which may improve outcomes. Urine chitinase 3-like protein 1 (uCHI3L1) was recently identified as a promising urinary biomarker for AKI. In this multicenter study, we evaluated the diagnostic performance for AKI stage 2 or greater of uCHI3L1 in comparison with the urinary cell cycle arrest biomarkers urinary tissue inhibitor of metalloproteinases-2 (TIMP-2)•insulin-like growth factor-binding protein 7 (IGFBP7) measured by NephroCheck Risk®. METHODS: Post hoc laboratory study of the prospective observational FINNAKI study. Of this cohort, we included patients with stored admission urine samples and availability of serum creatinine at day 1 of admission. Patients who already had AKI stage 2 or 3 at ICU admission were excluded. AKI was defined and staged according to the KDIGO definition and staging system. The primary endpoint was AKI stage 2 or 3 at day 1. Biomarker performance was assessed by the area under the curve of the receiver operating characteristic curve (AUC). We assessed individual performance and different combinations of urine biomarkers. RESULTS: Of 660 included patients, 49 (7.4%) had AKI stages 2-3 at day 1. All urine biomarkers were increased at admission in AKI patients. All biomarkers and most combinations had AUCs < 0.700. The combination uCHI3L1•TIMP-2 was best with a fair AUC of 0.706 (0.670, 0.718). uCHI3L1 had a positive likelihood ratio (LR) of 2.25 which was comparable to that of the NephroCheck Risk® cutoff of 2.0, while the negative LR of 0.53 was comparable to that of the NephroCheck Risk® cutoff of 0.3. CONCLUSIONS: We found that uCHI3L1 and NephroCheck Risk® had a comparable diagnostic performance for diagnosis of AKI stage 2 or greater within a 24-h period in this multicenter FINNAKI cohort. In contrast to initial discovery and validation studies, the diagnostic performance was poor. Possible explanations for this observation are differences in patient populations, proportion of emergency admissions, proportion of functional AKI, rate of developing AKI, and observation periods for diagnosis of AKI.


Asunto(s)
Lesión Renal Aguda/diagnóstico , Puntos de Control del Ciclo Celular , Proteína 1 Similar a Quitinasa-3/orina , Riñón/metabolismo , Anciano , Biomarcadores/orina , Enfermedad Crítica , Femenino , Humanos , Riñón/patología , Masculino , Persona de Mediana Edad , Estudios Prospectivos
3.
Eur J Endocrinol ; 182(5): 499-509, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32187575

RESUMEN

Objective: Sympathoadrenal activity is decreased during overnight rest. This study assessed whether urinary-free normetanephrine, metanephrine and methoxytyramine in overnight/first-morning urine collections might offer an alternative to measurements in 24-h collections or plasma for diagnosis of pheochromocytoma and paraganglioma (PPGL). Design and methods: Prospective multicenter cross-sectional diagnostic study involving 706 patients tested for PPGL, in whom tumors were confirmed in 79 and excluded in 627 after follow-up. Another 335 age- and sex-matched volunteers were included for reference purposes. Catecholamines and their free O-methylated metabolites were measured in 24-h collections divided according to waking and sleeping hours and normalized to creatinine. Plasma metabolites from blood sampled after supine rest were measured for comparison. Results: Urinary outputs of norepinephrine, normetanephrine, epinephrine and metanephrine in the reference population were respectively 50 (48-52)%, 35 (32-37)%, 76 (74-78)% and 15 (12-17)% lower following overnight than daytime collections. Patients in whom PPGLs were excluded showed 28 (26-30)% and 6 (3-9)% day-to-night falls in normetanephrine and metanephrine, while patients with PPGLs showed no significant day-to-night falls in metabolites. Urinary methoxytyramine was consistently unchanged from day to night. According to receiver-operating characteristic curves, diagnostic accuracy of metabolite measurements in overnight/first-morning urine samples did not differ from measurements in 24-h urine collections, but was lower for both than for plasma. Using optimized reference intervals, diagnostic specificity was higher for overnight than daytime collections at similar sensitivities. Conclusions: Measurements of urinary-free catecholamine metabolites in first-morning/overnight urine collections offer an alternative for diagnosis of PPGL to 24-h collections but remain less accurate than plasma measurements.


Asunto(s)
Neoplasias de las Glándulas Suprarrenales/orina , Dopamina/análogos & derivados , Metanefrina/orina , Paraganglioma/orina , Feocromocitoma/orina , Adolescente , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/orina , Dopamina/orina , Femenino , Humanos , Masculino , Persona de Mediana Edad , Paraganglioma/diagnóstico , Feocromocitoma/diagnóstico , Adulto Joven
4.
Med. clín (Ed. impr.) ; 154(5): 171-174, mar. 2020. graf, tab
Artículo en Español | IBECS | ID: ibc-186629

RESUMEN

Introducción y objetivos: Los antidiabéticos orales inhibidores del cotransportador sodio-glucosa (iSGLT2) reducen la morbimortalidad cardiovascular en la DM2. El aumento de la rigidez arterial puede participar en esta morbimortalidad. El objetivo de este trabajo fue analizar el efecto de la administración de dapagliflozina en la rigidez arterial. Pacientes y métodos: Estudio observacional, prospectivo que incluyó a 32 pacientes con DM2. Antes del inicio de dapagliflozina y a los 6 y 12 meses, se analizaron parámetros bioquímicos en sangre y orina. Basalmente y a los 12 meses se determinó la velocidad de pulso carótida-femoral (VPc-f) mediante tonometría. El análisis de los cambios en las variables y su interrelación se hizo mediante ANOVA de datos repetidos, test de Wilcoxon y regresión múltiple. Resultados: Se objetivó un descenso significativo de la VPc-f. No se evidenció asociación entre descenso de VPc-f y cambios de la glucemia, la uricemia, la presión arterial ni del peso. Conclusiones: Dapagliflozina, en sujetos con DM2, produce, a medio-largo plazo, una disminución de la rigidez arterial


Introduction: Oral antidiabetic inhibitors of the sodium-glucose cotransporter (SGLT2i) reduce cardiovascular morbidity and mortality in DM2. The increase in arterial stiffness can participate in this morbidity and mortality. The aim of this study was to analyse the effect of the administration of dapagliflozin on arterial stiffness. Patients and methods: Prospective observational study that included 32 patients with DM2. Before starting dapagliflozin, and at 6 and 12 months, biochemical parameters in blood and urine were analysed. Before starting dapagliflozin and at 12 months the velocity of the carotid-femoral pulse (VPc-f) was determined by tonometry. Changes in the variables and their interrelation was analysed by repeated data ANOVA, Wilcoxon's test and multiple regression. Results: A significant decrease in the VPc-f was observed. There was no association between decreased VPc-f and changes in blood glucose, uric acid, blood pressure or weight. Conclusions: Dapagliflozin, in subjects with DM2, produces a medium to long-term decrease in arterial stiffness


Asunto(s)
Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Rigidez Vascular/efectos de los fármacos , Cardiotónicos/efectos adversos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/administración & dosificación , Cardiotónicos/uso terapéutico , Estudios Prospectivos , Análisis de Varianza , Biomarcadores/sangre , Biomarcadores/orina
5.
Int J Occup Environ Med ; 11(2): 72-84, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32218555

RESUMEN

BACKGROUND: Informal electronic waste (e-waste) recycling is an increasingly important industry worldwide. However, few studies have studied the health risks in this group of workers. OBJECTIVE: To assess the associations between occupational exposures to metals and genetic instability and renal markers among e-waste recycling workers. METHODS: We recruited informal e-waste recycling workers from a community in northeastern Thailand. Participants completed a questionnaire, several health measurements, and provided urine and blood samples, which we then analyzed for a number of metals including lead (Pb), cadmium (Cd), and manganese (Mn). Samples were analyzed for a marker of RNA and DNA damage (ie, oxidative stress), 8-hydroxy-2'-deoxyguanosine (8-OHdG). Glomerular filtration rate (GFR) and fractional excretion of calcium (FECa%) were measured as markers of renal function. Correlations and regression models were used to assess associations between these various factors. RESULTS: We found significantly higher levels of Cd and Pb in blood of men compared with those in women. Men who worked >48 hours/week had significantly higher levels of 8-OHdG compared with men who worked ≤48 hours/week. Smoking was significantly associated with higher blood Pb and Cd concentrations among men. CONCLUSION: Our results suggest gender differences in both blood concentrations of metals associated with e-waste recycling and smoking and highlight potentially elevated oxidative stress associated with longer work hours. Health promotion efforts are needed among informal e-waste recyclers to reduce possible risks of renal damage and cancer.


Asunto(s)
Biomarcadores/orina , Daño del ADN , Residuos Electrónicos/efectos adversos , Metales Pesados/química , Exposición Profesional/efectos adversos , Insuficiencia Renal/inducido químicamente , Adulto , Cadmio/análisis , Femenino , Humanos , Industrias , Masculino , Metales Pesados/toxicidad , Estrés Oxidativo , Reciclaje , Tailandia
6.
Toxicol Lett ; 326: 18-22, 2020 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-32145395

RESUMEN

Ethylene oxide (EO), a carcinogenic chemical used as an industrial intermediate and sterilant, forms covalent adducts with DNA and proteins. The adduct with N-terminal valine [N-(2-hydroxyethyl)-l-valine, HEV] in blood protein globin has been employed as a principal biomarker of cumulative exposures to EO. However, as sampling of blood is inconvenient in routine occupational health practice, a non-invasive alternative to globin analysis has been investigated. Following identification of N-(2-hydroxyethyl)-l-valyl-l-leucine (HEVL) as ultimate cleavage product of EO-adducted globin excreted in the rat urine, here we report for the first time on the presence of HEVL in the urine of humans. In 18 sterilization workers, urinary HEVL ranged from 0.67 to 11.98 µg/g creatinine (mean ± SD: 5.04 ± 3.14 µg/g creat) and correlated with HEV: HEVL (µg/g creat) = 0.833 HEV (nmol/g globin) + 1.19 (R2 = 0.45). As unexpectedly high levels of urinary HEVL were found also in controls (mean ± SD: 0.97 ± 0.37 µg/g creat, n = 32), HEVL is not proposed for the accurate assessment of sub-ppm exposures to EO. On the other hand, non-invasive sampling and facile work-up procedure predetermine HEVL for screening purposes to identify subjects approaching to or exceeding occupational exposure limit for EO (1.8 mg/m3) to be re-examined by the more sensitive reference analysis for HEV.


Asunto(s)
Monitoreo Biológico/métodos , Biomarcadores/orina , Carcinógenos/toxicidad , Óxido de Etileno/orina , Exposición Profesional/efectos adversos , Valina/orina , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad
7.
Toxicol Lett ; 324: 54-64, 2020 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-32007588

RESUMEN

The aims of this work were to assess the PAH exposure among roofers and to identify relevant biomarkers for monitoring occupational exposure. Several campaigns were conducted between 2004 and 2017, with 28 individual air samples and 240 urinary samples collected from 73 roofers. Seventeen parent PAHs and 14 urinary biomarkers, metabolites of pyrene (1-OHP), benzo(a)pyrene (3-OHBaP and TetraolBaP), naphthalene (1- and 2-naphtols), fluorene (1- 2- 3- 9-fluorenols) and phenanthrene (1- 2- 3- 4- 9-phenanthrols), were analysed. Three exposure groups were considered: soft-applied roofing using polymer-modified bitumen ("PMB"), hot-applied roofing using oxidized bitumen ("OB") and the tearing off of old roof coatings containing coal tar ("CT"). The PAHs containing 2-3 rings were much more abundant, and the highest airborne levels were observed in the "CT" group. The biomonitoring results were consistent with these results, with a large predominance of 2-3 ring PAH metabolites. 1-OHP, 3-fluorenol and 2-phenanthrol were better correlated with airborne levels and less influenced by smoking than the other metabolites. Conversely, 1-/2-naphtol levels were heavily influenced by smoking and not correlated with airborne naphthalene levels. Moreover, 3-OHBaP and TetraolBaP levels were very low when applying bitumen membranes, and much higher exposures were observed during tear-off activities. In this context, the recommended strategy for roofer biomonitoring should include 1-OHP, fluorenols and phenanthrols, as well as carcinogenic BaP metabolites (3-OHBaP or TetraolBaP) when evaluating the occupational exposure of roofers that are tearing off old roof coatings.


Asunto(s)
Monitoreo Biológico/métodos , Exposición Profesional/análisis , Hidrocarburos Policíclicos Aromáticos/orina , Adulto , Contaminantes Ocupacionales del Aire/análisis , Benzopirenos/metabolismo , Biomarcadores/orina , Femenino , Humanos , Masculino , Persona de Mediana Edad , Material Particulado/análisis , Pirenos/metabolismo , Adulto Joven
8.
Artículo en Inglés | MEDLINE | ID: mdl-32109750

RESUMEN

Di-n-butyl adipate (DnBA) is an alternative to the anti-androgenic and strictly regulated di-n-butyl phthalate (DnBP) used as a cosmetic ingredient, plasticizer, and in various articles of everyday life. Hence, exposures of the general population have to be expected. Currently, biomarkers of DnBA exposure and methods for their determination are not available. Here, we describe a sensitive, rugged and precise analytical method for the determination of the DnBA monoester metabolite mono-n-butyl adipate (MnBA), as well as its potential downstream metabolites 3-hydroxy-mono-n-butyl adipate (3OH-MnBA) and 3-carboxy-mono-n-propyl adipate (3cx-MnPrA) in human urine. Glucuronic acid conjugates present in urine were deconjugated using a pure ß-glucuronidase. The metabolites were then analyzed by liquid chromatography on a C18 column with superficially porous particles coupled to electrospray ionization-triple quadrupole-tandem mass spectrometry, applying online turbulent flow chromatography for analyte enrichment and matrix depletion (online-SPE-LC-MS/MS). The metabolites were quantified using stable isotope dilution analysis with limits of quantification of 0.05 µg/L (MnBA), 0.1 µg/L (3OH-MnBA), and 0.5 µg/L (3cx-MnPrA). Method imprecision in urinary matrix was below 7% (coefficient of variation) for all analytes. Mean relative recoveries were between 93% and 107%. The suitability of the DnBA metabolites as biomarkers of exposure was demonstrated after dermal application of a commercially available sunscreen containing DnBA. Maximum concentrations were reached 6.5 h after dose (219 µg/L 3cx-MnPrA, 91 µg/L MnBA, and 3.9 µg/L 3OH-MnBA). Elimination kinetics were similar for all three metabolites. We were able to quantify 3cx-MnPrA and MnBA until 4 d after sunscreen application. In a sample set of 35 urine samples from the general German population, 3cx-MnPrA was quantified in 94% (median 2.54 µg/L, maximum 78.3 µg/L) and MnBA in 3% (median < LOQ, maximum 0.18 µg/L) of the samples. The method will be applied in future human metabolism and human biomonitoring population studies.


Asunto(s)
Adipatos/orina , Cromatografía Líquida de Alta Presión/métodos , Extracción en Fase Sólida/métodos , Espectrometría de Masas en Tándem/métodos , Adipatos/aislamiento & purificación , Adulto , Biomarcadores/orina , Exposición a Riesgos Ambientales/análisis , Femenino , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Adulto Joven
9.
JAMA ; 323(5): 432-443, 2020 02 04.
Artículo en Inglés | MEDLINE | ID: mdl-32016310

RESUMEN

Importance: Intravenous iron enables rapid correction of iron-deficiency anemia, but certain formulations induce fibroblast growth factor 23-mediated hypophosphatemia. Objective: To compare risks of hypophosphatemia and effects on biomarkers of mineral and bone homeostasis of intravenous iron isomaltoside (now known as ferric derisomaltose) vs ferric carboxymaltose. Design, Setting, and Participants: Between October 2017 and June 2018, 245 patients aged 18 years and older with iron-deficiency anemia (hemoglobin level ≤11 g/dL; serum ferritin level ≤100 ng/mL) and intolerance or unresponsiveness to 1 month or more of oral iron were recruited from 30 outpatient clinic sites in the United States into 2 identically designed, open-label, randomized clinical trials. Patients with reduced kidney function were excluded. Serum phosphate and 12 additional biomarkers of mineral and bone homeostasis were measured on days 0, 1, 7, 8, 14, 21, and 35. The date of final follow-up was June 19, 2018, for trial A and May 29, 2018, for trial B. Interventions: Intravenous administration of iron isomaltoside, 1000 mg, on day 0 or ferric carboxymaltose, 750 mg, infused on days 0 and 7. Main Outcomes and Measures: The primary end point was the incidence of hypophosphatemia (serum phosphate level <2.0 mg/dL) between baseline and day 35. Results: In trial A, 123 patients were randomized (mean [SD] age, 45.1 [11.0] years; 95.9% women), including 62 to iron isomaltoside and 61 to ferric carboxymaltose; 95.1% completed the trial. In trial B, 122 patients were randomized (mean [SD] age, 42.6 [12.2] years; 94.1% women), including 61 to iron isomaltoside and 61 to ferric carboxymaltose; 93.4% completed the trial. The incidence of hypophosphatemia was significantly lower following iron isomaltoside vs ferric carboxymaltose (trial A: 7.9% vs 75.0% [adjusted rate difference, -67.0% {95% CI, -77.4% to -51.5%}], P < .001; trial B: 8.1% vs 73.7% [adjusted rate difference, -65.8% {95% CI, -76.6% to -49.8%}], P < .001). Beyond hypophosphatemia and increased parathyroid hormone, the most common adverse drug reactions (No./total No.) were nausea (iron isomaltoside: 1/125; ferric carboxymaltose: 8/117) and headache (iron isomaltoside: 4/125; ferric carboxymaltose: 5/117). Conclusions and Relevance: In 2 randomized trials of patients with iron-deficiency anemia who were intolerant of or unresponsive to oral iron, iron isomaltoside (now called ferric derisomaltose), compared with ferric carboxymaltose, resulted in lower incidence of hypophosphatemia over 35 days. However, further research is needed to determine the clinical importance of this difference. Trial Registration: ClinicalTrials.gov Identifiers: NCT03238911 and NCT03237065.


Asunto(s)
Anemia Ferropénica/tratamiento farmacológico , Disacáridos/efectos adversos , Compuestos Férricos/efectos adversos , Hematínicos/efectos adversos , Hipofosfatemia/inducido químicamente , Maltosa/análogos & derivados , Adulto , Anemia Ferropénica/complicaciones , Biomarcadores/sangre , Biomarcadores/orina , Disacáridos/uso terapéutico , Femenino , Compuestos Férricos/uso terapéutico , Cefalea/inducido químicamente , Hematínicos/uso terapéutico , Humanos , Hipofosfatemia/epidemiología , Incidencia , Masculino , Maltosa/efectos adversos , Maltosa/uso terapéutico , Persona de Mediana Edad , Náusea/inducido químicamente , Fosfatos/sangre , Fosfatos/orina
10.
PLoS One ; 15(2): e0228989, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32053695

RESUMEN

Prediction and early detection of kidney damage induced by nonsteroidal anti-inflammatories (NSAIDs) would provide the best chances of maximizing the anti-inflammatory effects while minimizing the risk of kidney damage. Unfortunately, biomarkers for detecting NSAID-induced kidney damage in cats remain to be discovered. To identify potential urinary biomarkers for monitoring NSAID-based treatments, we applied an untargeted metabolomics approach to urine collected from cats treated repeatedly with meloxicam or saline for up to 17 days. Applying multivariate analysis, this study identified a panel of seven metabolites that discriminate meloxicam treated from saline treated cats. Combining artificial intelligence machine learning algorithms and an independent testing urinary metabolome data set from cats with meloxicam-induced kidney damage, a panel of metabolites was identified and validated. The panel of metabolites including tryptophan, tyrosine, taurine, threonic acid, pseudouridine, xylitol and lyxitol, successfully distinguish meloxicam-treated and saline-treated cats with up to 75-100% sensitivity and specificity. This panel of urinary metabolites may prove a useful and non-invasive diagnostic tool for monitoring potential NSAID induced kidney injury in feline patients and may act as the framework for identifying urine biomarkers of NSAID induced injury in other species.


Asunto(s)
Antiinflamatorios no Esteroideos/administración & dosificación , Biomarcadores/orina , Animales , Antiinflamatorios no Esteroideos/orina , Inteligencia Artificial , Butiratos/orina , Gatos , Cromatografía , Análisis por Conglomerados , Femenino , Humanos , Espectrometría de Masas , Metabolómica/métodos , Seudouridina/orina , Curva ROC , Alcoholes del Azúcar/orina , Taurina/orina , Tirosina/orina , Xilitol/orina
11.
Artículo en Inglés | MEDLINE | ID: mdl-32058315

RESUMEN

Mitragyna speciosa (kratom) is a drug that is increasingly used recreationally and "therapeutically", in the absence of medical supervision. The drug has been associated with a growing number of fatalities, and although its medicinal properties as an atypical opioid require further study, there are legitimate concerns regarding its unregulated use. Mitragynine is the most widely reported alkaloid within the plant, although more than forty other alkaloids have been identified. 7-Hydroxymitragynine is reported to have greater abuse liability due to its increased potency relative to mitragynine. In this report, biomarkers for mitragynine were investigated using liquid chromatography-quadrupole/time of flight mass spectrometry (LC-Q/TOF-MS). Speciociliatine and speciogynine were identified as alternative biomarkers, often exceeding the concentration of mitragynine in unhydrolyzed urine. 9-O-Demethylmitragynine and 7-hydroxymitragynine were identified in unhydrolyzed urine in 75% and 63% of the cases. Deconjugation of phase II metabolites using chemical hydrolysis was not suitable due to degradation of the Mitragyna alkaloids. Enzymatic hydrolysis was evaluated using three traditional glucuronidases, four sulfatases and four recombinant enzymes. Although enzymatic hydrolysis increased the concentration of 16-carboxymitragynine, it had nominal benefit for other metabolites. Deconjugation of urine was not necessary due to the abundance of parent drug (mitragynine), its diastereoisomers (speciociliatine and speciogynine) or metabolites (9-O-demethylmitragynine and 7-hydroxymitragynine).


Asunto(s)
Biomarcadores/orina , Mitragyna/metabolismo , Oxindoles/orina , Extractos Vegetales/metabolismo , Alcaloides de Triptamina Secologanina/metabolismo , Cromatografía Líquida de Alta Presión , Glucurónidos/análisis , Glucurónidos/metabolismo , Hidrólisis , Metaboloma , Mitragyna/química , Extractos Vegetales/análisis , Alcaloides de Triptamina Secologanina/análisis , Sulfatasas/análisis , Sulfatasas/metabolismo , Espectrometría de Masas en Tándem
12.
Vet Clin North Am Equine Pract ; 36(1): 121-134, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32037140

RESUMEN

Clinicopathologic evaluation of renal function and renal disease in sick adult horses remains grounded in detection of azotemia, assessment of serum and urine electrolyte concentrations, and evaluation of urinalysis findings, including specific gravity, reagent strip analysis, and sediment examination. Because increases in serum or plasma urea nitrogen and creatinine concentrations are insensitive indicators of a decreased glomerular filtration rate, there is considerable interest in identifying novel biomarkers of renal function or injury in blood and urine, with serum symmetric dimethylarginine concentration being the most recent addition to the commercial market.


Asunto(s)
Enfermedades de los Caballos/patología , Enfermedades de los Caballos/orina , Enfermedades Renales/veterinaria , Animales , Biomarcadores/sangre , Biomarcadores/orina , Enfermedades de los Caballos/sangre , Caballos , Enfermedades Renales/patología , Enfermedades Renales/orina , Masculino , Urinálisis/veterinaria
13.
Cell Physiol Biochem ; 54(1): 88-109, 2020 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-31990489

RESUMEN

Extracellular vesicles (EVs) are important mediators of intercellular communication. Since EVs are also released during pathological conditions, there has been considerable interest in their potential as sensitive biomarkers of cellular stress and/or injury. In the context of kidney disease, urinary EVs are promising indicators of glomerular and tubular damage. In the present review we discuss the role of urinary EVs in kidney health and disease. Our focus is to explore urinary large EVs (lEVs, often referred to as microparticles or microvesicles) as direct and noninvasive early biomarkers of renal injury. In this regard, studies have been demonstrating altered levels of urinary lEVs, especially podocyte-derived lEVs, preceding the decrease of renal function assessed by classical markers. In addition, we discuss the role of small EVs (sEVs, often referred to as exosomes) and their contents in kidney pathophysiology. Even though results concerning the production of sEVs during diseased conditions are varied, there has been a consensus on the importance of urinary sEV content assessment in kidney disease. These mediators, including EV-released miRNAs and mRNAs, are responsible for EV-mediated signaling in the regulation of renal cellular homeostasis, pathogenesis and regeneration. Finally, steps necessary for the validation of EVs as reliable markers will be discussed.


Asunto(s)
Vesículas Extracelulares/patología , Enfermedades Renales/diagnóstico , Glomérulos Renales/patología , Túbulos Renales/patología , Animales , Biomarcadores/análisis , Biomarcadores/orina , Humanos , Enfermedades Renales/patología , Enfermedades Renales/orina
14.
PLoS One ; 15(1): e0227138, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31999746

RESUMEN

BACKGROUND: Tuberculosis (TB) is the leading cause of death among HIV-positive patients. We assessed the cost-effectiveness of including lateral-flow urine lipoarabinomannan (LF-LAM) in TB diagnostic algorithms for severely ill or immunosuppressed HIV-positive patients with symptoms of TB in Kenya. METHODS: From a decision-analysis tree, ten diagnostic algorithms were elaborated and compared. All algorithms included clinical exam. The costs of each algorithm were calculated using a 'micro-costing' method. The efficacy was estimated through a prospective study that included severely ill or immunosuppressed (CD4<200cells/µL) HIV-positive adults with symptoms of TB. The cost-effectiveness analysis was performed using the disability-adjusted life year (DALY) averted as effectiveness outcome. A 4% discount rate was applied. RESULTS: The algorithm that added LF-LAM alone to the clinical exam lead to the least average cost per TB case detected (€47) and was the most cost-effective with a cost/DALY averted of €4.6. The algorithms including LF-LAM, microscopy and X-ray, and LF-LAM and Xpert in sputum, detected a high number of TB cases with a cost/DALY averted of €6.1 for each of them. In the comparisons of the algorithms two by two, using LF-LAM instead of microscopy (clinic&LAM vs clinicµscopy) and using LF-LAM along with GeneXpert in sputum instead of GeneXpert in urine along with GeneXpert in sputum, (clinic&LAM&Xpert_sputum vs clinic&Xpert_sputum&Xpert_urine) led to the highest increase in the cost-effectiveness ratios (ICERs): €-7.2 and €-12.6 respectively. In these two comparisons, using LF-LAM increased the number of TB patients detected while reducing costs. Adding LF-LAM to smear microscopy alone or to smear microscopy and Xray led to the highest increase in the additional number of TB cases detected (31 and 25 respectively) with an incremental efficiency estimated at 134 and 344 DALYs respectively. The ICERs were €22.0 and €8.6 respectively. CONCLUSION: Including LF-LAM in TB diagnostic algorithms is cost-effective for severely ill or immunosuppressed HIV-positive patients.


Asunto(s)
Análisis Costo-Beneficio , Infecciones por VIH/complicaciones , Lipopolisacáridos/orina , Técnicas de Diagnóstico Molecular/economía , Tuberculosis/diagnóstico , Adulto , Biomarcadores/orina , Femenino , Humanos , Masculino , Tuberculosis/orina
15.
Arch Biochem Biophys ; 681: 108279, 2020 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-31982394

RESUMEN

Because long-term occupational exposure to low concentrations of acrylamide (ACR) has the potential to cause neurological damage, it is important to identify biomarkers that can be used to evaluate this risk. In the present study, urine metabolomics of the ACR-exposed and non-exposed groups to identify potential metabolites was carried out using ultra high performance liquid chromatography coupled with quadrupole time of flight mass spectrometry. Serum biochemical indexes of the exposed and non-exposed groups were also determined. Principal component analysis showed a differential separation between exposed group and non-exposed group and a total of 7 metabolites were identified in positive and negative ionization modes; Area under curve of anthranilic acid, ß-guanidinopropionic acid and mesobilirubinogen were 0.980, 0.843 and 0.801 respectively and these metabolites showed high sensitivity and specificity. The 13 biochemical indexes were divided into three classes based on physiological functions. Only biomarkers of dysregulated liver function including alanine aminotransferase, aspartic transaminase, total bilirubin, direct bilirubin and triglyceride were significantly higher in the exposed group than in the non-exposed group. This study identifies important related metabolic changes in the bodies of workers after long-term occupational exposure to low concentration ACR and suggests new biomarkers of nervous system injury caused by ACR. The study also provides a sound basis for exploring the biochemical mechanisms and metabolic pathways of nervous system toxicity caused by ACR.


Asunto(s)
Acrilamida/efectos adversos , Biomarcadores/orina , Metabolómica/métodos , Exposición Profesional/efectos adversos , Acrilamida/metabolismo , Adulto , Biomarcadores/metabolismo , Cromatografía Líquida de Alta Presión/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Espectrometría de Masas en Tándem/métodos , Urinálisis/métodos
16.
Z Gastroenterol ; 58(1): 30-38, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31931538

RESUMEN

BACKGROUND: In order to reduce alcohol relapse after liver transplantation (LT), the German national guidelines for waiting-list maintenance and organ allocation demand a minimum 6-month period of alcohol abstinence pre-LT, confirmed by measuring urinary ethyl glucuronide (uEtG). METHODS: Between January 2015 and June 2016, uEtG was measured at least once in 339 cirrhotic patients with an indication for LT at the University Medical Center Mainz. uEtG was measured with an enzyme-linked immunosorbent assay (ELISA) screening test (cutoff value: 500 µg/L). For uEtG values ≥ 500 µg/L, liquid chromatography-mass spectrometry (LC-MS/MS) was performed as a confirmatory assay. Data were collected prospectively in a transplant database. RESULTS: Of the 339 potential liver transplant candidates, uEtG was negative in 86.4 %. Most patients were male (64.3 %), with an average age of 56.42 ±â€Š10.1 years. In the multivariate analysis, mean corpuscular volume (p = 0.001), urinary creatinine (p = 0.001), gamma-glutamyl transferase (p = 0.001), and hemoglobin (p = 0.003) were significantly associated with a positive uEtG test result. The sensitivity of the ELISA screening test was 100 % for uEtG values > 2000 µg/L, as confirmed by LC-MS/MS. CONCLUSION: uEtG is an effective parameter to reveal alcohol consumption by patients on the waiting list for LT. The sensitivity of the ELISA is excellent for uEtG values > 2000 µg/L, for which LC-MS/MS confirmation could be omitted.


Asunto(s)
Consumo de Bebidas Alcohólicas , Glucuronatos/orina , Cirrosis Hepática Alcohólica/cirugía , Cirrosis Hepática Alcohólica/orina , Trasplante de Hígado , Tamizaje Masivo/métodos , Anciano , Biomarcadores/orina , Cromatografía Liquida , Estudios de Cohortes , Ensayo de Inmunoadsorción Enzimática , Etanol/sangre , Etanol/orina , Femenino , Humanos , Cirrosis Hepática Alcohólica/diagnóstico , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Sensibilidad y Especificidad , Espectrometría de Masas en Tándem , Listas de Espera
17.
Environ Pollut ; 259: 113854, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-31918135

RESUMEN

The main objectives of the present study were to investigate urinary monohydroxylated polycyclic aromatic hydrocarbons (OH-PAHs) in 77 primiparas who live in Shenzhen, Guangdong Province, China, and their association with 8-hydroxy-2'-deoxyguanosine (8-OHdG) and human health risks. High detection frequencies of OH-PAHs demonstrated the wide occurrence of chemicals in the human exposure to PAHs. The urinary concentrations of Σ7OH-PAHs ranged from 1.37 to 45.5 ng/mL, and the median concentrations of 1-hydroxynaphthalene (1-OHN), 2-hydroxynaphthalene (2-OHN), 2-hydoxyfluorene (2-OHF), ΣOHPhe (the sum of 1-, 2+ 3-hydroxyphenanthrene), and 1-hydroxypyrene (1-OHP) were 3.00, 2.58, 0.31, 0.44, and 0.51 ng/mL, respectively. In the sum concentration of seven OH-PAHs, 1-OHN accounted for the largest proportion (43.7% of Σ7OH-PAHs), followed by 2-OHN (37.1%), 2-OHF (4.94%), 1-OHP (8.01%), 1-OHPhe (4.79%), and 2+3-OHPhe (1.46%). The present results showed that vehicle exhaust and petrochemical emission are the main sources of PAHs in primiparas in Shenzhen, and inhalation is the most important exposure route. The living conditions have a significant influence on human exposure to PAHs. The concentrations of 8-OHdG were positively correlated with OH-PAH concentrations in urine because evidence suggested that urinary 8-OHdG levels can be considered as a biomarker of oxidative DNA damage. Hazard quotient was used to assess the human health risks from exposure to single compound, and hazard index was used to assess the cumulative risks of the compounds, which demonstrated that the exposure risks from PAHs in primiparas were relatively low.


Asunto(s)
Exposición a Riesgos Ambientales , Estrés Oxidativo , Hidrocarburos Policíclicos Aromáticos , Biomarcadores/orina , China , Exposición a Riesgos Ambientales/análisis , Femenino , Humanos , Hidrocarburos Policíclicos Aromáticos/orina , Embarazo , Factores de Riesgo , Emisiones de Vehículos
18.
Biomed Chromatogr ; 34(4): e4792, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-31907953

RESUMEN

Diabetic retinopathy (DR) is a common microvascular complication of diabetes and remains one of the leading causes of blindness worldwide. Previous studies have shown that Bushen Huoxue Prescription (BP) possesses an effect on preventing and treating DR, but the mechanisms of action are not entirely clear. In order to clarify the mechanisms, the pharmacodynamical assessments of BP were investigated. Combining the pharmacodynamical studies, it was found that BP could inhibit high expression of VEGF and HIF-1α, indicating significant therapeutic effects on DR. In order to further investigate the mechanism of BP in treating DR, a urine metabolomics method based on ultrahigh-performance liquid chromatography coupled with Q-exactive quadrupole-electrostatic field Orbitrap mass spectrometry was established to observe the metabolic variations in DR rats and investigate the therapeutic effect of BP on DR. As a result, nine potential biomarkers associated with DR were found. The metabolic pathways related to these compounds were explored, and the results showed that these biomarkers were mainly associated with gut microbial metabolism, lipid metabolism and tryptophan metabolism. The results for the pharmacodynamics and metabolomics provided a theoretical basis for clarifying the mechanism of BP in the treatment of DR.


Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Retinopatía Diabética/metabolismo , Medicamentos Herbarios Chinos/farmacología , Espectrometría de Masas/métodos , Metaboloma/efectos de los fármacos , Animales , Biomarcadores/orina , Diabetes Mellitus Experimental , Masculino , Redes y Vías Metabólicas , Metabolómica , Ratas , Ratas Sprague-Dawley
19.
Biomed Chromatogr ; 34(4): e4795, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-31967660

RESUMEN

In this study, we focused on studying the changes in urine metabolites in hyperlipidemic rats using ultra-performance liquid chromatography coupled with quadrupole time-of-fight mass spectrometry (UPLC-Q-TOF/MS) and metabolomics, as well as the effect of Citri Reticulatae Chachiensis Pericarpium (CRCP) on hyperlipidemia. These urine samples were examined by UPLC-Q-TOF/MS to obtain MS data. The MS data were analyzed by principal component analysis and partial least squares-discriminant analysis to identify the differential metabolites. CRCP reduced the body weight and levels of triglycerides, total cholesterol and low-density lipoprotein cholesterol and abnormally decreased high-density lipoprotein cholesterol in hyperlipidemic rats, which were significantly raised by a high-fat diet. Twenty-seven potential biomarkers were identified within the complex sample matrix of urine. Fourteen biomarkers increased in the hyperlipidemia rats compared with normal rats. Meanwhile, 13 biomarkers decreased. CRCP reversed abnormal changes in biomarkers, including 5-l-glutamyl-taurine, 5-aminopentanoic acid, cis-4-octenedioic acid and 2-octenedioic acid. These biomarkers show that hyperlipidemia is related to the metabolic pathways of taurine and hypotaurine metabolism, fatty acid biosynthesis, and arginine and proline metabolism. CRCP mainly prevents hyperlipidemia by intervening in these metabolic pathways.


Asunto(s)
Citrus/química , Dieta Alta en Grasa , Metaboloma/efectos de los fármacos , Preparaciones de Plantas , Sustancias Protectoras , Animales , Biomarcadores/orina , Frutas/química , Masculino , Metabolómica , Preparaciones de Plantas/química , Preparaciones de Plantas/farmacología , Sustancias Protectoras/química , Sustancias Protectoras/farmacología , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados
20.
Nat Genet ; 52(2): 167-176, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31959995

RESUMEN

The kidneys integrate information from continuous systemic processes related to the absorption, distribution, metabolism and excretion (ADME) of metabolites. To identify underlying molecular mechanisms, we performed genome-wide association studies of the urinary concentrations of 1,172 metabolites among 1,627 patients with reduced kidney function. The 240 unique metabolite-locus associations (metabolite quantitative trait loci, mQTLs) that were identified and replicated highlight novel candidate substrates for transport proteins. The identified genes are enriched in ADME-relevant tissues and cell types, and they reveal novel candidates for biotransformation and detoxification reactions. Fine mapping of mQTLs and integration with single-cell gene expression permitted the prioritization of causal genes, functional variants and target cell types. The combination of mQTLs with genetic and health information from 450,000 UK Biobank participants illuminated metabolic mediators, and hence, novel urinary biomarkers of disease risk. This comprehensive resource of genetic targets and their substrates is informative for ADME processes in humans and is relevant to basic science, clinical medicine and pharmaceutical research.


Asunto(s)
Biotransformación/genética , Riñón/metabolismo , Sitios de Carácter Cuantitativo , Insuficiencia Renal Crónica/orina , Acetiltransferasas/genética , Acetiltransferasas/metabolismo , Fosfatasa Alcalina/genética , Fosfatasa Alcalina/metabolismo , Biomarcadores/orina , Estudios de Cohortes , Citocromo P-450 CYP2D6/genética , Estudio de Asociación del Genoma Completo , Humanos , Inactivación Metabólica , Riñón/citología , Metoprolol/farmacocinética , Polimorfismo de Nucleótido Simple , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/metabolismo , Orina/fisiología , Xenobióticos/farmacocinética , Xenobióticos/orina
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