There is no clinically applicable biomarker for surveillance of hepatocellular carcinoma (HCC), because the sensitivity of serum alpha‐fetoprotein (AFP) is too low for this purpose. Here, we ...determined the diagnostic performance of a panel of urinary metabolites of HCC patients from West Africa. Urine samples were collected from Nigerian and Gambian patients recruited on the case‐control platform of the Prevention of Liver Fibrosis and Cancer in Africa (PROLIFICA) program. Urinary proton nuclear magnetic resonance (1H‐NMR) spectroscopy was used to metabolically phenotype 290 subjects: 63 with HCC; 32 with cirrhosis (Cir); 107 with noncirrhotic liver disease (DC); and 88 normal control (NC) healthy volunteers. Urine samples from a further cohort of 463 subjects (141 HCC, 56 Cir, 178 DC, and 88 NC) were analyzed, the results of which validated the initial cohort. The urinary metabotype of patients with HCC was distinct from those with Cir, DC, and NC with areas under the receiver operating characteristic (AUROC) curves of 0.86 (0.78‐0.94), 0.93 (0.89‐0.97), and 0.89 (0.80‐0.98) in the training set and 0.81 (0.73‐0.89), 0.96 (0.94‐0.99), and 0.90 (0.85‐0.96), respectively, in the validation cohort. A urinary metabolite panel, comprising inosine, indole‐3‐acetate, galactose, and an N‐acetylated amino acid (NAA), showed a high sensitivity (86.9% 75.8‐94.2) and specificity (90.3% 74.2‐98.0) in the discrimination of HCC from cirrhosis, a finding that was corroborated in a validation cohort (AUROC: urinary panel = 0.72; AFP = 0.58). Metabolites that were significantly increased in urine of HCC patients, and which correlated with clinical stage of HCC, were NAA, dimethylglycine, 1‐methylnicotinamide, methionine, acetylcarnitine, 2‐oxoglutarate, choline, and creatine. Conclusion: The urinary metabotyping of this West African cohort identified and validated a metabolite panel that diagnostically outperforms serum AFP. (Hepatology 2014;60:1291–1301)
Limited knowledge regarding the reproducibility of biomarkers in 24-h urine samples has hindered the collection and use of the samples in epidemiologic studies.
We aimed to evaluate the ...reproducibility of various markers in repeat 24-h urine samples.
We calculated intraclass correlation coefficients (ICCs) of biomarkers measured in 24-h urine samples that were collected in 3168 participants in the NHS (Nurses' Health Study), NHSII (Nurses' Health Study II), and Health Professionals Follow-Up Study.
In 742 women with 4 samples each collected over the course of 1 y, ICCs for sodium were 0.32 in the NHS and 0.34 in the NHSII. In 2439 men and women with 2 samples each collected over 1 wk to ≥1 mo, the ICCs ranged from 0.33 to 0.68 for sodium at various intervals between collections. The urinary excretion of potassium, calcium, magnesium, phosphate, sulfate, and other urinary markers showed generally higher reproducibility (ICCs >0.4). In 47 women with two 24-h urine samples, ICCs ranged from 0.15 (catechin) to 0.75 (enterolactone) for polyphenol metabolites. For phthalates, ICCs were generally ≤0.26 except for monobenzyl phthalate (ICC: 0.55), whereas the ICC was 0.39 for bisphenol A (BPA). We further estimated that, for the large majority of the biomarkers, the mean of three 24-h urine samples could provide a correlation of ≥0.8 with true long-term urinary excretion.
These data suggest that the urinary excretion of various biomarkers, such as minerals, electrolytes, most polyphenols, and BPA, is reasonably reproducible in 24-h urine samples that are collected within a few days or ≤1 y. Our findings show that three 24-h samples are sufficient for the measurement of long-term exposure status in epidemiologic studies.
Clinicians have access to limited tools that predict which patients with early AKI will progress to more severe stages. In early AKI, urine output after a furosemide stress test (FST), which involves ...intravenous administration of furosemide (1.0 or 1.5 mg/kg), can predict the development of stage 3 AKI. We measured several AKI biomarkers in our previously published cohort of 77 patients with early AKI who received an FST and evaluated the ability of FST urine output and biomarkers to predict the development of stage 3 AKI (n=25 32.5%), receipt of RRT (n=11 14.2%), or inpatient mortality (n=16 20.7%). With an area under the curve (AUC)±SEM of 0.87±0.09 (P<0.0001), 2-hour urine output after FST was significantly better than each urinary biomarker tested in predicting progression to stage 3 (P<0.05). FST urine output was the only biomarker to significantly predict RRT (0.86±0.08; P=0.001). Regardless of the end point, combining FST urine output with individual biomarkers using logistic regression did not significantly improve risk stratification (ΔAUC, P>0.10 for all). When FST urine output was assessed in patients with increased biomarker levels, the AUC for progression to stage 3 improved to 0.90±0.06 and the AUC for receipt of RRT improved to 0.91±0.08. Overall, in the setting of early AKI, FST urine output outperformed biochemical biomarkers for prediction of progressive AKI, need for RRT, and inpatient mortality. Using a FST in patients with increased biomarker levels improves risk stratification, although further research is needed.
Our objective was to evaluate the relationship of urine metals including barium, cadmium, cobalt, cesium, molybdenum, lead, antimony, thallium, tungsten, and uranium with diabetes prevalence. Data ...were from a cross-sectional study of 9,447 participants of the 1999-2010 National Health and Nutrition Examination Survey, a representative sample of the U.S. civilian noninstitutionalized population. Metals were measured in a spot urine sample, and diabetes status was determined based on a previous diagnosis or an A1C ≥6.5% (48 mmol/mol). After multivariable adjustment, the odds ratios of diabetes associated with the highest quartile of metal, compared with the lowest quartile, were 0.86 (95% CI 0.66-1.12) for barium (Ptrend = 0.13), 0.74 (0.51-1.09) for cadmium (Ptrend = 0.35), 1.21 (0.85-1.72) for cobalt (Ptrend = 0.59), 1.31 (0.90-1.91) for cesium (Ptrend = 0.29), 1.76 (1.24-2.50) for molybdenum (Ptrend = 0.01), 0.79 (0.56-1.13) for lead (Ptrend = 0.10), 1.72 (1.27-2.33) for antimony (Ptrend < 0.01), 0.76 (0.51-1.13) for thallium (Ptrend = 0.13), 2.18 (1.51-3.15) for tungsten (Ptrend < 0.01), and 1.46 (1.09-1.96) for uranium (Ptrend = 0.02). Higher quartiles of barium, molybdenum, and antimony were associated with greater HOMA of insulin resistance after adjustment. Molybdenum, antimony, tungsten, and uranium were positively associated with diabetes, even at the relatively low levels seen in the U.S.
Prospective studies should further evaluate metals as risk factors for diabetes.
Autism spectrum disorder (ASD) is still diagnosed through behavioral observation, due to a lack of laboratory biomarkers, which could greatly aid clinicians in providing earlier and more reliable ...diagnoses. Metabolomics on human biofluids provides a sensitive tool to identify metabolite profiles potentially usable as biomarkers for ASD. Initial metabolomic studies, analyzing urines and plasma of ASD and control individuals, suggested that autistic patients may share some metabolic abnormalities, despite several inconsistencies stemming from differences in technology, ethnicity, age range, and definition of "control" status.
ASD-specific urinary metabolomic patterns were explored at an early age in 30 ASD children and 30 matched controls (age range 2-7, M:F = 22:8) using hydrophilic interaction chromatography (HILIC)-UHPLC and mass spectrometry, a highly sensitive, accurate, and unbiased approach. Metabolites were then subjected to multivariate statistical analysis and grouped by metabolic pathway.
Urinary metabolites displaying the largest differences between young ASD and control children belonged to the tryptophan and purine metabolic pathways. Also, vitamin B
, riboflavin, phenylalanine-tyrosine-tryptophan biosynthesis, pantothenate and CoA, and pyrimidine metabolism differed significantly. ASD children preferentially transform tryptophan into xanthurenic acid and quinolinic acid (two catabolites of the kynurenine pathway), at the expense of kynurenic acid and especially of melatonin. Also, the gut microbiome contributes to altered tryptophan metabolism, yielding increased levels of indolyl 3-acetic acid and indolyl lactate.
The metabolic pathways most distinctive of young Italian autistic children largely overlap with those found in rodent models of ASD following maternal immune activation or genetic manipulations. These results are consistent with the proposal of a purine-driven cell danger response, accompanied by overproduction of epileptogenic and excitotoxic quinolinic acid, large reductions in melatonin synthesis, and gut dysbiosis. These metabolic abnormalities could underlie several comorbidities frequently associated to ASD, such as seizures, sleep disorders, and gastrointestinal symptoms, and could contribute to autism severity. Their diagnostic sensitivity, disease-specificity, and interethnic variability will merit further investigation.
To examine the long-term stability and validity of analyte concentrations of 21 clinical biochemistry parameters in 24-h urine samples stored for 12 or 15yr at −22°C and preservative free.
Healthy ...children's 24-h urine samples in which the respective analytes had been measured shortly after sample collection (baseline) were reanalyzed. Second measurement was performed after 12yr (organic acids) and 15yr (creatinine, urea, osmolality, iodine, nitrogen, anions, cations, acid–base parameters) with the same analytical methodology. Paired comparisons and correlations between the baseline and repeated measurements were done. Recovery rates were calculated.
More than half of the analytes (creatinine, urea, iodine, nitrogen, sodium, potassium, magnesium, calcium, ammonium, bicarbonate, citric & uric acid) showed measurement values after >10yr of storage not significantly different from baseline. 15 of the 21 parameters were highly correlated (r=0.99) between baseline and second measurement. Poorest correlation was r=0.77 for oxalate. Recovery ranged from 73% (oxalate) to 105% (phosphate).
Our results suggest high long-term stability and measurement validity for numerous clinical chemistry parameters stored at −22°C without addition of any urine preservative. Prospective storage of urine aliquots at −22°C for periods even exceeding 10yr, appears to be an acceptable and valid tool in epidemiological settings for later quantification of several urine analytes.
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•We examined long-term stability of select urine analytes stored >10yr at −22°C.•Urine samples were both collected and stored preservative-free.•Repeat measurements of more than half of the analytes did not differ from baseline.•E.g., creatinine, iodine, nitrogen, various minerals proved as stable biomarkers.•Results suggest high long-term stability for relevant clinical chemical parameters.
Aberrant fetal programming in gestational diabetes mellitus seems to increase the risk of obesity, type 2 diabetes, and cardiovascular disease. The inability to accurately identify gestational ...diabetes mellitus in the first trimester of pregnancy has thwarted ascertaining whether early therapeutic interventions reduce the predisposition to these prevalent medical disorders.
A metabolomics study was conducted to determine whether advanced analytical methods could identify accurate predictors of gestational diabetes mellitus in early pregnancy.
This nested observational case-control study was composed of 92 gravidas (46 in the gestational diabetes mellitus group and 46 in the control group) in early pregnancy, who were matched by maternal age, body mass index, and gestational age at urine collection. Gestational diabetes mellitus was diagnosed according to community standards. A comprehensive metabolomics platform measured 626 endogenous metabolites in randomly collected urine. Consensus multivariate criteria or the most important by 1 method identified low–molecular weight metabolites independently associated with gestational diabetes mellitus, and a classification tree selected a subset most predictive of gestational diabetes mellitus.
Urine for both groups was collected at a mean gestational age of 12 weeks (range, 6–19 weeks’ gestation). Consensus multivariate analysis identified 11 metabolites independently linked to gestational diabetes mellitus. Classification tree analysis selected a 7-metabolite subset that predicted gestational diabetes mellitus with an accuracy of 96.7%, independent of maternal age, body mass index, and time of urine collection.
Validation of this high-accuracy model by a larger study is now needed to support future studies to determine whether therapeutic interventions in the first trimester of pregnancy for gestational diabetes mellitus reduce short- and long-term morbidity.
Over the last two decades, usage of neonicotinoid (NEO) insecticides has increased due to their high selectivity for insects versus mammals and their effectiveness for extermination of insects ...resistant to conventional pesticides such as pyrethroids and organophosphates (OPs). However, historical change of the NEO exposure level in humans is poorly understood. The aim of this study is to reveal changes in the levels of NEO and OP exposure in the human body over the last two decades using biomonitoring technique. We quantified urinary concentrations of 7 NEOs (acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid, and thiamethoxam) and 4 metabolites of OPs (dimethylphosphate, dimethylthiophosphate, diethylphosphate, and diethylthiophosphate) in 95 adult females aged 45–75 in 1994, 2000, 2003, 2009, and 2011 (n = 17–20 different individuals in each year). The results show that the detection rates of urinary NEOs in Japanese women increased significantly between 1994 and 2011, suggesting that intakes of NEOs into the human body rose during that period. In contrast, exposure to OPs having O,O-dimethyl moieties decreased steadily according to a finding that geometric means of urinary dimethylphosphate concentrations kept diminishing considerably. These changes may reflect the amounts of NEOs and OPs used as insecticides in Japan.
Neonicotinoids are systemic insecticides used since the 1990's , that possess renal tubular toxicity. We conducted a field-based descriptive study in the North Central Dry-zone of Sri Lanka, where ...chronic kidney disease (CKD) of unknown etiology has been increasing since the 1990's. To elucidate the relationship between renal tubular dysfunctions and urinary neonicotinoids concentrations, we collected spot urine samples from15 CKD patients, 15 family members, and 62 neighbors in 2015, analyzed two renal tubular biomarkers, Cystatin-C and L-FABP, quantified seven neonicotinoids and a metabolite N-desmethyl-acetamiprid by LC-MS/MS; and we investigated their symptoms using a questionnaire. Cystatin-C and L-FABP had a positive correlation (p < 0.001). N-Desmethyl-acetamiprid was detected in 92.4% of the urine samples, followed by dinotefuran (17.4%), thiamethoxam (17.4%), clothianidin (9.8%), thiacloprid and imidacloprid. Dinotefuran and thiacloprid have never been registered in Sri Lanka. In High Cystatin-C group (> 70 μg/gCre, n = 7), higher urinary concentration of dinotefuran (p = 0.009), and in Zero Cystatin-C group (< LOQ, n = 7), higher N-desmethyl-acetamiprid (p = 0.013), dinotefuran (p = 0.049), and thiacloprid (p = 0.035), and more complaints of chest pains, stomachache, skin eruption and diarrhea (p < 0.05) were found than in Normal Cystatin-C group (n = 78). Urinary neonicotinoids may be one of the potential risk factors for renal tubular dysfunction in this area.
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