Increased levels of urinary biomarkers of lipid peroxidation products among workers occupationally exposed to diesel engine exhaust.

PubMed

Bin, Ping; Shen, Meili; Li, Haibin; Sun, Xin; Niu, Yong; Meng, Tao; Yu, Tao; Zhang, Xiao; Dai, Yufei; Gao, Weimin; Gu, Guizhen; Yu, Shanfa; Zheng, Yuxin

2016-08-01

Diesel engine exhaust (DEE) was found to induce lipid peroxidation (LPO) in animal exposure studies. LPO is a class of oxidative stress and can be reflected by detecting the levels of its production, such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), and etheno-DNA adducts including 1,N(6)-etheno-2'-deoxyadenosine (ɛdA) and 3,N(4)-etheno-2'-deoxycytidine (ɛdC). However, the impact of DEE exposure on LPO has not been explored in humans. In this study, we evaluated urinary MDA, 4-HNE, ɛdA, and ɛdC levels as biomarkers of LPO among 108 workers with exclusive exposure to DEE and 109 non-DEE-exposed workers. Results showed that increased levels of urinary MDA and ɛdA were observed in subjects occupationally exposed to DEE before and after age, body mass index (BMI), smoking status, and alcohol use were adjusted (all p < 0.001). There was a statistically significant relationship between the internal exposure dose (urinary ΣOH-PAHs) and MDA, 4-HNE, and ɛdA (all p < 0.001). Furthermore, significant increased relations between urinary etheno-DNA adduct and MDA, 4-HNE were observed (all p < 0.05). The findings of this study suggested that the level of LPO products (MDA and ɛdA) was increased in DEE-exposed workers, and urinary MDA and ɛdA might be feasible biomarkers for DEE exposure. LPO induced DNA damage might be involved and further motivated the genomic instability could be one of the pathogeneses of cancer induced by DEE-exposure. However, additional investigations should be performed to understand these observations.

URINARY MUTAGENICITY: A BIOMARKER OF GENOTOXIC EXPOSURES VIA AIR, WATER, AND DIET

EPA Science Inventory

During the past 30 years, ~100 studies have evaluated human urine for mutagenic activity using the Salmonella (Ames) mutagenicity assay. Urinary mutagenicity has been shown to correlate well with other biomarkers, including DNA and hemoglobin adducts, urinary metabolites, and chr...

Urinary Biomarkers for Screening for Renal Scarring in Children with Febrile Urinary Tract Infection: Pilot Study.

PubMed

Kitao, Tetsuya; Kimata, Takahisa; Yamanouchi, Sohsaku; Kato, Shogo; Tsuji, Shoji; Kaneko, Kazunari

2015-09-01

Recurrent febrile urinary tract infections during infancy cause renal scarring, which is characterized by progressive focal interstitial fibrosis and may lead to renal failure. Renal scarring can be diagnosed through scintigraphy, although it seems impractical to perform renal scintigraphy for all infants with febrile urinary tract infections. Therefore, it is important to search for a biomarker to identify the presence of renal scarring. We hypothesized that urinary biomarkers of nephropathy may increase in infants with renal scarring following febrile urinary tract infections. A total of 49 infants who underwent renal scintigraphy for febrile urinary tract infections were enrolled in the study. Several measurements were performed using urine samples, including total proteins, beta2-microglobulins, N-acetyl-β-D-glucosaminidase, neutrophil gelatinase associated lipocalin, liver-type fatty acid binding protein and angiotensinogen. Values were corrected by creatinine and compared between patients with and without renal scarring. Among urinary biomarkers only angiotensinogen in patients with scarring (median 14.6 μg/gm creatinine) demonstrated significantly higher levels than in patients without scarring (3.6 μg/gm creatinine, p <0.001). Urinary angiotensinogen may be useful for diagnosing the presence of renal scarring. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Permethrin Exposure Dosimetry: Biomarkers and Modifiable Factors

DTIC Science & Technology

2016-08-01

the effect of body weight/ BMI and total energy expenditure on permethrin absorption and dose, as determined by measurement of urinary biomarkers...body weight/ BMI and total energy expenditure on permethrin absorption and dose, as determined by measurement of urinary biomarkers (3PBA and cis- and

Using urinary biomarkers to evaluate polycyclic hydrocarbon exposures in 126 preschool children in Ohio

EPA Science Inventory

Limited data exist on exposures of young children to polycyclic aromatic hydrocarbons (PAHs) in the United States (US). The urinary metabolite of pyrene, 1-hydroxypyrene (1-OHPyr), is widely used as a biomarker of total PAH exposure. Our objectives were to quantify urinary 1-OHPy...

Effects of Three Commonly-used Diuretics on the Urinary Proteome

PubMed Central

Li, Xundou; Zhao, Mindi; Li, Menglin; Jia, Lulu; Gao, Youhe

2014-01-01

Biomarker is the measurable change associated with a physiological or pathophysiological process. Unlike blood which has mechanisms to keep the internal environment homeostatic, urine is more likely to reflect changes of the body. As a result, urine is likely to be a better biomarker source than blood. However, since the urinary proteome is affected by many factors, including diuretics, careful evaluation of those effects is necessary if urinary proteomics is used for biomarker discovery. Here, we evaluated the effects of three commonly-used diuretics (furosemide, F; hydrochlorothiazide, H; and spirolactone, S) on the urinary proteome in rats. Urine samples were collected before and after intragastric administration of diuretics at therapeutic doses and the proteomes were analyzed using label-free liquid chromatography–tandem mass spectrometry (LC–MS/MS). Based on the criteria of P ⩽ 0.05, a fold change ⩾2, a spectral count ⩾5, and false positive rate (FDR) ⩽1%, 14 proteins (seven for F, five for H, and two for S) were identified by Progenesis LC–MS. The human orthologs of most of these 14 proteins are stable in the healthy human urinary proteome, and ten of them are reported as disease biomarkers. Thus, our results suggest that the effects of diuretics deserve more attention in future urinary protein biomarker studies. Moreover, the distinct effects of diuretics on the urinary proteome may provide clues to the mechanisms of diuretics. PMID:24508280

Dietary predictors of young children’s exposures to chlorpyrifos, permethrin, and 2,4-D using urinary biomonitoring

EPA Science Inventory

Few data exist on the association between dietary habits and urinary biomarker concentrations of pesticides in children. The objective was to examined the association between the weekly intake frequency of 65 food items and urinary biomarkers of exposure to chlorpyrifos (3,5,6-tr...

Biomarkers of Exposure to Polycyclic Aromatic Hydrocarbons and Cognitive Function among Elderly in the United States (National Health and Nutrition Examination Survey: 2001-2002)

PubMed Central

Best, Elizabeth A.; Juarez-Colunga, Elizabeth; James, Katherine; LeBlanc, William G.; Serdar, Berrin

2016-01-01

Recent studies report a link between common environmental exposures, such as particulate matter air pollution and tobacco smoke, and decline in cognitive function. The purpose of this study was to assess the association between exposure to polycyclic aromatic hydrocarbons (PAHs), a selected group of chemicals present in particulate matter and tobacco smoke, and measures of cognitive performance among elderly in the general population. This cross-sectional analysis involved data from 454 individuals aged 60 years and older from the 2001–2002 National Health and Nutrition Examination Survey. The association between PAH exposures (as measured by urinary biomarkers) and cognitive function (digit symbol substitution test (DSST)) was assessed using multiple linear regression analyses. After adjusting for age, socio-economic status and diabetes we observed a negative association between urinary 1-hydroxypyrene, the gold standard of PAH exposure biomarkers, and DSST score. A one percent increase in urinary 1-hydroxypyrene resulted in approximately a 1.8 percent poorer performance on the digit symbol substitution test. Our findings are consistent with previous publications and further suggest that PAHs, at least in part may be responsible for the adverse cognitive effects linked to tobacco smoke and particulate matter air pollution. PMID:26849365

Mechanism-Based Urinary Biomarkers to Identify the Potential for Aminoglycoside-Induced Nephrotoxicity in Premature Neonates: A Proof-of-Concept Study

PubMed Central

Sabbisetti, Venkata; Turner, Mark A.; Farragher, Tracey; Bonventre, Joseph V.; Park, B. Kevin; Smyth, Rosalind L.; Pirmohamed, Munir

2012-01-01

Premature infants are frequently exposed to aminoglycoside antibiotics. Novel urinary biomarkers may provide a non-invasive means for the early identification of aminoglycoside-related proximal tubule renal toxicity, to enable adjustment of treatment and identification of infants at risk of long-term renal impairment. In this proof-of-concept study, urine samples were collected from 41 premature neonates (≤32 weeks gestation) at least once per week, and daily during courses of gentamicin, and for 3 days afterwards. Significant increases were observed in the three urinary biomarkers measured (Kidney Injury Molecule-1 (KIM-1), Neutrophil Gelatinase-associated Lipocalin (NGAL), and N-acetyl-β-D-glucosaminidase (NAG)) during treatment with multiple courses of gentamicin. When adjusted for potential confounders, the treatment effect of gentamicin remained significant only for KIM-1 (mean difference from not treated, 1.35 ng/mg urinary creatinine; 95% CI 0.05–2.65). Our study shows that (a) it is possible to collect serial urine samples from premature neonates, and that (b) proximal tubule specific urinary biomarkers can act as indicators of aminoglycoside-associated nephrotoxicity in this age group. Further studies to investigate the clinical utility of novel urinary biomarkers in comparison to serum creatinine need to be undertaken. PMID:22937100

Urinary exosomal transcription factors, a new class of biomarkers for renal disease

PubMed Central

Zhou, Hua; Cheruvanky, Anita; Hu, Xuzhen; Matsumoto, Takayuki; Hiramatsu, Noriyuki; Cho, Monique E.; Berger, Alexandra; Leelahavanichkul, Asada; Doi, Kent; Chawla, Lakhmir S.; Illei, Gabor G.; Kopp, Jeffrey B.; Balow, James E.; Austin, Howard A.; Yuen, Peter S.T.; Star, Robert A.

2008-01-01

Urinary exosomes are excreted from all nephron segments and are a rich source of kidney injury biomarkers. Because exosomes contain intracellular proteins, we asked if transcription factors (TF) can be measured in urinary exosomes. We collected urine from two acute kidney injury (AKI) models (cisplatin or ischemia/reperfusion) and two podocyte injury models (puromycin-treated rats and podocin/Vpr transgenic mice). Human urine was obtained from patients with AKI, focal segmental glomerulosclerosis (FSGS), and matched controls. After isolating urine exosomes by differential centrifugation, activating transcription factor 3 (ATF3) and Wilms Tumor 1 (WT-1) were detected by western blot. ATF3 was continuously detected in urine exosomes 2–24 hr after ischemia/reperfusion and in a biphasic pattern after cisplatin. In both models, urinary ATF3 was detected earlier than serum creatinine. Urinary ATF3 was detected in AKI patients but not in normal subjects or patients with chronic kidney disease (CKD). Urinary WT-1 was detected in animal models before significant glomerular sclerosis. Urinary WT-1 was detected in 9/10 FSGS patients, but not in 8 controls. Transcription factors can be detected in urine exosomes, but not in whole urine. Urinary ATF3 may be a novel renal tubular cell injury biomarker for detecting early AKI, whereas urinary WT-1 may detect early podocyte injury. Urinary exosomal TFs represent a new class of biomarkers for acute and chronic renal diseases and may offer insight into cellular regulatory pathways. PMID:18509321

Biomarkers in lower urinary tract symptoms/overactive bladder: a critical overview.

PubMed

Antunes-Lopes, Tiago; Cruz, Célia D; Cruz, Francisco; Sievert, Karl D

2014-07-01

Biomarkers constitute objectively measurable characteristics that can be evaluated as indicators of physiological and pathogenic processes and might be used as diagnostic, prognostic or predictive tools in clinical care. This review examines the availability of biomarkers to treat the dynamic and complex symptoms of overactive bladder (OAB). OAB biomarkers may contribute to reveal the origin of storage symptoms in otherwise healthy individuals. The research encompassing the changes that occur in the bladder or in the peripheral (and central) nervous system might be determined through blood or urinary molecules (neurotrophins, ATP, prostaglandins, C-reactive protein and cytokines) or the measurement of events occurring in the bladder wall (bladder wall or detrusor wall thickness, oxyhemoglobin and deoxyhemoglobin concentration). These biomarkers might contribute to a better understanding of the pathophysiologic mechanisms underlying OAB. The word biomarker to name all the parameters described above, from bladder wall thickness to urinary molecules, has been introduced to call the attention to a field wherein objective noninvasive parameters were nonexistent. OAB treatment based on a biomarker, in comparison to the treatment based on a diagnosis made from a careful history and exclusion of urinary tract infection, is not supported by current literature.

Exosomal Fetuin-A identified by proteomics: a novel urinary biomarker for detecting acute kidney injury

PubMed Central

Zhou, Hua; Pisitkun, Trairak; Aponte, Angel; Yuen, Peter S.T.; Hoffert, Jason D.; Yasuda, Hideo; Hu, Xuzhen; Chawla, Lakhmir; Shen, Rong-Fong; Knepper, Mark A.; Star., Robert A.

2008-01-01

Urinary exosomes containing apical membrane and intracellular fluid are normally secreted into the urine from all nephron segments, and may carry protein markers of renal dysfunction and structural injury. We aimed to discover biomarkers in urinary exosomes to detect acute kidney injury (AKI) which has a high mortality and morbidity. Animals were injected intravenously with cisplatin. Urinary exosomes were isolated by differential centrifugation. Protein changes were evaluated by two-dimensional difference in gel electrophoresis and changed proteins were identified by MALDI-TOF-TOF or LC-MS/MS. The identified candidate biomarkers were validated by western blotting in individual urine samples from rats subjected to cisplatin injection; bilateral ischemia and reperfusion (I/R); volume depletion (VD); and ICU patients with and without AKI. We identified 18 proteins that were increased and 9 proteins that were decreased 8 hr after cisplatin. Most of the candidates could not be validated by western blotting. However, exosomal Fetuin-A increased 52.5-fold at day 2 (1 day before serum creatinine increase and tubule damage) and remained elevated 51.5-fold at day 5 (peak renal injury) after cisplatin injection. By immuno-electron microscopy and elution studies, Fetuin-A was located inside urinary exosomes. Urinary Fetuin-A was increased 31.6-fold in the early phase (2~8hr) of ischemia/reperfusion, but not in prerenal azotemia. Urinary exosomal Fetuin-A also increased in three ICU patients with AKI compared to the patients without AKI. We conclude that 1) Proteomic analysis of urinary exosomes can provide biomarker candidates for the diagnosis of AKI; 2) Urinary Fetuin-A might be a predictive biomarker of structural renal injury. PMID:17021608

Urinary angiotensinogen as a potential biomarker of intrarenal renin-angiotensin system activity in Chinese chronic kidney disease patients.

PubMed

Xu, Z; Xu, B; Xu, C

2015-06-01

Urinary angiotensinogen (AGT) mainly derives from the AGT produced in proximal tubular cells. Evidence exists that supports the correlation between urinary AGT and circulating AGT. To investigate the role of urinary AGT as a potential biomarker of intrarenal renin-angiotensin system activity in Chinese chronic kidney disease (CKD) patients. ELISA-based method used to quantify urinary AGT. Analyzed the relationship between urinary AGT and intrarenal angiotensin II (Ang II) activity in 128 CKD patients. ELISA was applied to measure the urinary and plasma renin activity, AGT, Ang II and aldosterone. Furthermore expression levels of intrarenal renin, AGT, Ang II and Ang II receptor were examined by immunohistochemistry staining (IHCS) in 72 CKD patients undergoing renal biopsy. The logarithmic transformation Log(urinary AGT/UCre) levels showed a normal distribution. Therefore, Log(urinary AGT/UCre) levels were used for the analyses. Average urinary AGT was 2.02 ± 0.55 ng/(mg Cr). Hypertension, urinary protein, urinary Ang II and urinary type IV collagen (Col IV) positively correlated with urinary AGT. Estimated glomerular filtration rate (eGFR), urinary sodium and serum AGT negatively correlated with urinary AGT. Multiple regression analysis indicated that low serum AGT, high urinary protein, urinary Ang II and urinary Col IV correlated significantly with high urinary AGT. We observed positive correlation between urinary AGT and positive IHCS area of AGT, Ang II and Ang II type 1 receptor in renal tissue. These data suggest that urinary AGT might be a potential biomarker of intrarenal Ang II activity in CKD patients.

Platelet-derived growth factor receptor beta: a novel urinary biomarker for recurrence of non-muscle-invasive bladder cancer.

PubMed

Feng, Jiayu; He, Weifeng; Song, Yajun; Wang, Ying; Simpson, Richard J; Zhang, Xiaorong; Luo, Gaoxing; Wu, Jun; Huang, Chibing

2014-01-01

Non-muscle-invasive bladder cancer (NMIBC) is one of the most common malignant tumors in the urological system with a high risk of recurrence, and effective non-invasive biomarkers for NMIBC relapse are still needed. The human urinary proteome can reflect the status of the microenvironment of the urinary system and is an ideal source for clinical diagnosis of urinary system diseases. Our previous work used proteomics to identify 1643 high-confidence urinary proteins in the urine from a healthy population. Here, we used bioinformatics to construct a cancer-associated protein-protein interaction (PPI) network comprising 16 high-abundance urinary proteins based on the urinary proteome database. As a result, platelet-derived growth factor receptor beta (PDGFRB) was selected for further validation as a candidate biomarker for NMIBC diagnosis and prognosis. Although the levels of urinary PDGFRB showed no significant difference between patients pre- and post-surgery (n = 185, P>0.05), over 3 years of follow-up, urinary PDGFRB was shown to be significantly higher in relapsed patients (n = 68) than in relapse-free patients (n = 117, P<0.001). The levels of urinary PDGFRB were significantly correlated with the risk of 3-year recurrence of NMIBC, and these levels improved the accuracy of a NMIBC recurrence risk prediction model that included age, tumor size, and tumor number (area under the curve, 0.862; 95% CI, 0.809 to 0.914) compared to PDGFR alone. Therefore, we surmise that urinary PDGFRB could serve as a non-invasive biomarker for predicting NMIBC recurrence.

Effects of three commonly-used diuretics on the urinary proteome.

PubMed

Li, Xundou; Zhao, Mindi; Li, Menglin; Jia, Lulu; Gao, Youhe

2014-06-01

Biomarker is the measurable change associated with a physiological or pathophysiological process. Unlike blood which has mechanisms to keep the internal environment homeostatic, urine is more likely to reflect changes of the body. As a result, urine is likely to be a better biomarker source than blood. However, since the urinary proteome is affected by many factors, including diuretics, careful evaluation of those effects is necessary if urinary proteomics is used for biomarker discovery. Here, we evaluated the effects of three commonly-used diuretics (furosemide, F; hydrochlorothiazide, H; and spirolactone, S) on the urinary proteome in rats. Urine samples were collected before and after intragastric administration of diuretics at therapeutic doses and the proteomes were analyzed using label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS). Based on the criteria of P≤0.05, a fold change ≥2, a spectral count ≥5, and false positive rate (FDR) ≤1%, 14 proteins (seven for F, five for H, and two for S) were identified by Progenesis LC-MS. The human orthologs of most of these 14 proteins are stable in the healthy human urinary proteome, and ten of them are reported as disease biomarkers. Thus, our results suggest that the effects of diuretics deserve more attention in future urinary protein biomarker studies. Moreover, the distinct effects of diuretics on the urinary proteome may provide clues to the mechanisms of diuretics. Copyright © 2014. Production and hosting by Elsevier Ltd.

Is ciprofloxacin safe in patients with solitary kidney and upper urinary tract infection?

PubMed

Gluhovschi, Gheorghe; Gadalean, Florica; Gluhovschi, Cristina; Velciov, Silvia; Petrica, Ligia; Bob, Flaviu; Bozdog, Gheorghe; Kaycsa, Adriana

2016-12-01

The solitary kidney (SK) undergoes adaptive phenomena of hyperfunction and hyperfiltration. These secondary adaptive phenomena can make it more vulnerable to potentially nephrotoxic therapies. Adverse reactions of the kidneys to ciprofloxacin are rare, but sometimes severe. Therefore, our study sought to assess the reactions to ciprofloxacin of patients with solitary kidney (SK) and urinary tract infection (UTI) by means of urinary biomarkers. We studied 19 patients with SK and urinary tract infection (UTI) who had been administered a 7-day treatment with intravenous ciprofloxacin. Urinary N-acetyl-beta-d-glucosaminidase, alpha 1-microglobulin, and estimated glomerular filtration rate (eGFR) of these patients were measured at the initiation and at the end of treatment. In 47.37% patients NAG diminished under ciprofloxacin treatment. This observation has the significance of favourable evolution of the tubulointerstitial lesions caused by UTI and lack of nephrotoxic effects; 52.63% cases presented an increase of urinary NAG, a fact that suggests a nephrotoxic effect of ciprofloxacin. The evolution of urinary alpha 1-microglobulin was similar to that one of urinary NAG. Only one of three cases with chronic kidney disease (CKD) stage 5 presented acute kidney injury, associated with increase in the tubular markers. In spite of the high variability of the urinary biomarkers, UTI evolved favourably in these cases; eGFR increased in 16 out of 19 patients, a fact which is indicative of a good outcome of renal function, even in patients with elevated levels of the tubular damage biomarkers. This observation supports the hypothesis that eGFR may be dissociated from the biomarkers which assess tubular injury. In SK patients the occurrence of AKI is not frequent, although the urinary biomarkers rise in some patients treated with ciprofloxacin. This is related not only to the nephrotoxic effect of the drug, but probably to the association of other factors (allergy, individual susceptibility). In SK patients, renal tubular biomarkers, especially NAG, allow monitoring of tubular injury and impose caution in prescribing ciprofloxacin treatment, mainly to patients at risk. Ciprofloxacin is relatively safe regarding its nephrotoxicity, while caution is required in vulnerable patients. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Biomarkers of mercury exposure at a mercury recycling facility in Ukraine

USGS Publications Warehouse

Gibb, H.J.; Kozlov, K.; Buckley, J.P.; Centeno, J.; Jurgenson, V.; Kolker, A.; Conko, K.; Landa, E.; Panov, B.; Panov, Y.; Xu, H.

2008-01-01

This study evaluates biomarkers of occupational mercury exposure among workers at a mercury recycling operation in Gorlovka, Ukraine. The 29 study participants were divided into three occupational categories for analysis: (1) those who worked in the mercury recycling operation (Group A, n = 8), (2) those who worked at the facility but not in the yard where the recycling was done (Group B, n = 14), and (3) those who did not work at the facility (Group C, n = 7). Urine, blood, hair, and nail samples were collected from the participants, and a questionnaire was administered to obtain data on age, gender, occupational history, smoking, alcohol consumption, fish consumption, tattoos, dental amalgams, home heating system, education, source of drinking water, and family employment in the former mercury mine/smelter located on the site of the recycling facility. Each factor was tested in a univariate regression with total mercury in urine, blood, hair, and nails. Median biomarker concentrations were 4.04 ??g/g-Cr (urine), 2.58 ??g/L (blood), 3.95 ??g/g (hair), and 1.16 ??g/g (nails). Occupational category was significantly correlated (p < 0.001) with both blood and urinary mercury concentrations but not with hair or nail mercury. Four individuals had urinary mercury concentrations in a range previously found to be associated with subtle neurological and subjective symptoms (e.g., fatigue, loss of appetite, irritability), and one worker had a urinary mercury concentration in a range associated with a high probability of neurological effects and proteinuria. Comparison of results by occupational category found that workers directly involved with the recycling operation had the highest blood and urinary mercury levels. Those who worked at the facility but were not directly involved with the recycling operation had higher levels than those who did not work at the facility. Copyright ?? 2008 JOEH, LLC.

Recommendations and Standardization of Biomarker Quantification Using NMR-Based Metabolomics with Particular Focus on Urinary Analysis.

PubMed

Emwas, Abdul-Hamid; Roy, Raja; McKay, Ryan T; Ryan, Danielle; Brennan, Lorraine; Tenori, Leonardo; Luchinat, Claudio; Gao, Xin; Zeri, Ana Carolina; Gowda, G A Nagana; Raftery, Daniel; Steinbeck, Christoph; Salek, Reza M; Wishart, David S

2016-02-05

NMR-based metabolomics has shown considerable promise in disease diagnosis and biomarker discovery because it allows one to nondestructively identify and quantify large numbers of novel metabolite biomarkers in both biofluids and tissues. Precise metabolite quantification is a prerequisite to move any chemical biomarker or biomarker panel from the lab to the clinic. Among the biofluids commonly used for disease diagnosis and prognosis, urine has several advantages. It is abundant, sterile, and easily obtained, needs little sample preparation, and does not require invasive medical procedures for collection. Furthermore, urine captures and concentrates many "unwanted" or "undesirable" compounds throughout the body, providing a rich source of potentially useful disease biomarkers; however, incredible variation in urine chemical concentrations makes analysis of urine and identification of useful urinary biomarkers by NMR challenging. We discuss a number of the most significant issues regarding NMR-based urinary metabolomics with specific emphasis on metabolite quantification for disease biomarker applications and propose data collection and instrumental recommendations regarding NMR pulse sequences, acceptable acquisition parameter ranges, relaxation effects on quantitation, proper handling of instrumental differences, sample preparation, and biomarker assessment.

Urinary Metabolomic Profiling to Identify Potential Biomarkers for the Diagnosis of Behcet's Disease by Gas Chromatography/Time-of-Flight-Mass Spectrometry.

PubMed

Ahn, Joong Kyong; Kim, Jungyeon; Hwang, Jiwon; Song, Juhwan; Kim, Kyoung Heon; Cha, Hoon-Suk

2017-11-02

Diagnosing Behcet's disease (BD) is challenging because of the lack of a diagnostic biomarker. The purposes of this study were to investigate distinctive metabolic changes in urine samples of BD patients and to identify urinary metabolic biomarkers for diagnosis of BD using gas chromatography/time-of-flight-mass spectrometry (GC/TOF-MS). Metabolomic profiling of urine samples from 44 BD patients and 41 healthy controls (HC) were assessed using GC/TOF-MS, in conjunction with multivariate statistical analysis. A total of 110 urinary metabolites were identified. The urine metabolite profiles obtained from GC/TOF-MS analysis could distinguish BD patients from the HC group in the discovery set. The parameter values of the orthogonal partial least squared-discrimination analysis (OPLS-DA) model were R ² X of 0.231, R ² Y of 0.804, and Q ² of 0.598. A biomarker panel composed of guanine, pyrrole-2-carboxylate, 3-hydroxypyridine, mannose, l-citrulline, galactonate, isothreonate, sedoheptuloses, hypoxanthine, and gluconic acid lactone were selected and adequately validated as putative biomarkers of BD (sensitivity 96.7%, specificity 93.3%, area under the curve 0.974). OPLS-DA showed clear discrimination of BD and HC groups by a biomarker panel of ten metabolites in the independent set (accuracy 88%). We demonstrated characteristic urinary metabolic profiles and potential urinary metabolite biomarkers that have clinical value in the diagnosis of BD using GC/TOF-MS.

Urothelial cancer of the upper urinary tract: emerging biomarkers and integrative models for risk stratification.

PubMed

Mathieu, Romain; Vartolomei, Mihai D; Mbeutcha, Aurélie; Karakiewicz, Pierre I; Briganti, Alberto; Roupret, Morgan; Shariat, Shahrokh F

2016-08-01

The aim of this review was to provide an overview of current biomarkers and risk stratification models in urothelial cancer of the upper urinary tract (UTUC). A non-systematic Medline/PubMed literature search was performed using the terms "biomarkers", "preoperative models", "postoperative models", "risk stratification", together with "upper tract urothelial carcinoma". Original articles published between January 2003 and August 2015 were included based on their clinical relevance. Additional references were collected by cross referencing the bibliography of the selected articles. Various promising predictive and prognostic biomarkers have been identified in UTUC thanks to the increasing knowledge of the different biological pathways involved in UTUC tumorigenesis. These biomarkers may help identify tumors with aggressive biology and worse outcomes. Current tools aim at predicting muscle invasive or non-organ confined disease, renal failure after radical nephroureterectomy and survival outcomes. These models are still mainly based on imaging and clinicopathological feature and none has integrated biomarkers. Risk stratification in UTUC is still suboptimal, especially in the preoperative setting due to current limitations in staging and grading. Identification of novel biomarkers and external validation of current prognostic models may help improve risk stratification to allow evidence-based counselling for kidney-sparing approaches, perioperative chemotherapy and/or risk-based surveillance. Despite growing understanding of the biology underlying UTUC, management of this disease remains difficult due to the lack of validated biomarkers and the limitations of current predictive and prognostic tools. Further efforts and collaborations are necessaryry to allow their integration in daily practice.

Molecular lipid species in urinary exosomes as potential prostate cancer biomarkers.

PubMed

Skotland, Tore; Ekroos, Kim; Kauhanen, Dimple; Simolin, Helena; Seierstad, Therese; Berge, Viktor; Sandvig, Kirsten; Llorente, Alicia

2017-01-01

Exosomes have recently appeared as a novel source of noninvasive cancer biomarkers, since these nanovesicles contain molecules from cancer cells and can be detected in biofluids. We have here investigated the potential use of lipids in urinary exosomes as prostate cancer biomarkers. A high-throughput mass spectrometry quantitative lipidomic analysis was performed to reveal the lipid composition of urinary exosomes in prostate cancer patients and healthy controls. Control samples were first analysed to characterise the lipidome of urinary exosomes and test the reproducibility of the method. In total, 107 lipid species were quantified in urinary exosomes. Several differences, for example, in cholesterol and phosphatidylcholine, were found between urinary exosomes and exosomes derived from cell lines, thus showing the importance of in vivo studies for biomarker analysis. The 36 most abundant lipid species in urinary exosomes were then quantified in 15 prostate cancer patients and 13 healthy controls. Interestingly, the levels of nine lipids species were found to be significantly different when the two groups were compared. The highest significance was shown for phosphatidylserine (PS) 18:1/18:1 and lactosylceramide (d18:1/16:0), the latter also showed the highest patient-to-control ratio. Furthermore, combinations of these lipid species and PS 18:0-18:2 distinguished the two groups with 93% sensitivity and 100% specificity. Finally, in agreement with the reported dysregulation of sphingolipid metabolism in cancer cells, alteration in specific sphingolipid lipid classes were observed. This study shows for the first time the potential use of exosomal lipid species in urine as prostate cancer biomarkers. Copyright © 2016 Elsevier Ltd. All rights reserved.

Urinary metabonomics elucidate the therapeutic mechanism of Orthosiphon stamineus in mouse crystal-induced kidney injury.

PubMed

Gao, Songyan; Chen, Wei; Peng, Zhongjiang; Li, Na; Su, Li; Lv, Diya; Li, Ling; Lin, Qishan; Dong, Xin; Guo, Zhiyong; Lou, Ziyang

2015-05-26

Orthosiphon stamineus (OS), a traditional Chinese herb, is often used for promoting urination and treating nephrolithiasis. Urolithiasis is a major worldwide public health burden due to its high incidence of recurrence and damage to renal function. However, the etiology for urolithiasis is not well understood. Metabonomics, the systematic study of small molecule metabolites present in biological samples, has become a valid and powerful tool for understanding disease phenotypes. In this study, a urinary metabolic profiling analysis was performed in a mouse model of renal calcium oxalate crystal deposition to identify potential biomarkers for crystal-induced renal damage and the anti-crystal mechanism of OS. Thirty six mice were randomly divided into six groups including Saline, Crystal, Cystone and OS at dosages of 0.5g/kg, 1g/kg, and 2g/kg. A metabonomics approach using ultra-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) was developed to perform the urinary metabolic profiling analysis. Principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were utilized to identify differences between the metabolic profiles of mice in the saline control group and crystal group. Using partial least squares-discriminant analysis, 30 metabolites were identified as potential biomarkers of crystal-induced renal damage. Most of them were primarily involved in amino acid metabolism, taurine and hypotaurine metabolism, purine metabolism, and the citrate cycle (TCA). After the treatment with OS, the levels of 20 biomarkers had returned to the levels of the control samples. Our results suggest that OS has a protective effect for mice with crystal-induced kidney injury via the regulation of multiple metabolic pathways primarily involving amino acid, energy and choline metabolism. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Urinary biomarkers of exposure to insecticides, herbicides, and one insect repellent among pregnant women in Puerto Rico.

PubMed

Lewis, Ryan C; Cantonwine, David E; Anzalota Del Toro, Liza V; Calafat, Antonia M; Valentin-Blasini, Liza; Davis, Mark D; Baker, Samuel E; Alshawabkeh, Akram N; Cordero, José F; Meeker, John D

2014-11-19

There are potential adverse health risks to the mother and fetus from exposure to pesticides. Thus, studies of exposure to pesticides among pregnant women are of interest as they will assist with understanding the potential burden of exposure globally, identifying sources of exposure, and designing epidemiology studies. We measured urinary concentrations of the insect repellent N-N-diethyl-meta-toluamide (DEET) and two of its metabolites [3-diethyl-carbamoyl benzoic acid (DCBA) and N,N-diethyl-3-hydroxymethylbenzamide (DHMB)], four pyrethroid insecticide metabolites [4-fluoro-3-phenoxybenzoic acid (4-F-3-PBA); 3-phenoxybenzoic acid (3-PBA); trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (trans-DCCA); and cis-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropane carboxylic acid (cis-DBCA)], and two chlorophenoxy herbicides [2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T)] in 54 pregnant women from Puerto Rico at three separate time points (20 ± 2 weeks, 24 ± 2 weeks, and 28 ± 2 weeks of gestation). We calculated the distributions of the biomarker concentrations and compared them to those of women of reproductive age from the general U.S. population where available, and estimated the within-subject temporal variability of these repeated measurements. We also collected questionnaire data on demographics, consumption of select fruits, vegetables, and legumes in the past 48-hr, and pest-related issues, and associations between these variables and biomarker concentrations were examined. We found that 95th percentile urinary concentrations of DEET, 3-PBA, trans-DCCA, and 2,4-D were lower than women of reproductive age on the U.S. mainland, whereas 95th percentile urinary concentrations of 4-F-3-PBA, cis-DBCA, and 2,4,5-T were similar. DCBA, the only urinary biomarker detected in >50% of the samples, showed fair to good reproducibility across pregnancy (intraclass correlation coefficient: 0.60). Women were more likely (p <0.05) to have greater urinary concentrations of pesticide biomarkers if they were less educated (DCBA and trans-DCCA), unemployed (DHMB), or married (2,4-D), had consumed collards or spinach in past 48-hr (2,4-D) or had been using insect repellent since becoming pregnant (DCBA), or were involved with residential applications of pesticides (trans-DCCA). We identified concentrations and predictors of several pesticides among pregnant women in Puerto Rico. Further research is needed to understand what aspects of the predictors identified lead to greater exposure, and whether exposure during pregnancy is associated with adverse health.

Biomarkers of IgA vasculitis nephritis in children

PubMed Central

Pillebout, Evangeline; Jamin, Agnès; Ayari, Hamza; Housset, Pierre; Pierre, Melissa; Sauvaget, Virginia; Viglietti, Denis; Deschenes, Georges

2017-01-01

Henoch–Schönlein purpura is a systemic vasculitis characterized by IgA deposits, which target the skin, joints, and kidneys, among other organs. In children, prognosis is often good but little is known about biomarkers of pediatric nephritis. We hypothesized that biological markers, including cytokines, immunoglobulins, IgA-immune complexes, IgA glycosylation and neutrophil gelatinase-associated lipocalin (NGAL), may discriminate IgA vasculitis (IgAV) pediatric patients with renal involvement from those without renal involvement. Fifty children at the time of IgAV rash between 2010 and 2015 were prospectively enrolled and compared to 21 controls. All patients were assessed for clinical and biological parameters at the time of diagnosis, including the levels of cytokines, immunoglobulins, immune complexes, IgA glycosylation and NGAL in serum and urine. Among IgAV patients, 33 patients exhibited nephritis (IgAV-N) and 17 children were without nephritis (IgAV-woN). The serum level of galactose-deficient (Gd)-IgA1 (p<0.01) and the urinary concentrations of IgA, IgG, IgM, IL-6, IL-8, IL-10, IgA-IgG complexes and IgA-sCD89 complexes (p<0.001 for all) were higher in the IgAV-N patients than in the IgAV-woN patients. Among those markers, urinary IgA and IgM had the highest AUC (0.86 and 0.87 respectively, p<0.0001). This prospective cohort study furthers our understanding of the pathophysiology of IgAV. We identified biomarkers that are able to distinguish patients initially with or without nephritis. To conclude, serum Gd-IgA1 and urinary IgA, IgG, IgM, IL-6, IL-8, IL-10, and IgA-IgG and IgA-sCD89 complexes could identify IgAV pediatric patients with renal involvement at the time of diagnosis. PMID:29190714

Variations in the GLA gene correlate with globotriaosylceramide and globotriaosylsphingosine analog levels in urine and plasma

PubMed Central

Ferreira, Susana; Auray-Blais, Christiane; Boutin, Michel; Lavoie, Pamela; Nunes, José Pedro; Martins, Elisabete; Garman, Scott; Oliveira, João Paulo

2016-01-01

Recent data have shown that lyso-Gb3, the deacylated derivative of globotriaosylceramide (Gb3), is possibly involved in the pathogenesis of Fabry disease (FD) and might be a clinically useful biomarker of its metabolic load. To test this hypothesis, we assayed Gb3 and lyso-Gb3 and related analogs in plasma and/or urine samples of 12 clinically well-characterized subjects carrying several different GLA variant alleles associated with a wide range of residual α-galactosidase A activities. Urinary Gb3 was measured by HPLC–MS/MS; plasma and urinary lyso-Gb3 and related analogs were measured by UPLC–MS/MS. Individual profiles of Gb3 and lyso-Gb3 and related analogs closely correlated with the phenotypic data for each subject, discerning the classical FD patient from the two patients carrying cardiac variants as well as these from all the others without FD. The lyso-Gb3 analog at m/z 836 was found at increased levels only in patients manifesting clinically severe heart disease, irrespective of the pathogenicity of the GLA variant they carried. This finding suggests that this lyso-Gb3 analog might be an earlier biomarker of progressive heart disease, non-specific of the FD cardiomyopathy. The possibility that urinary Gb3 is a specific marker of kidney involvement in FD deserves further study. PMID:26070511

Urinary levoglucosan as a biomarker for woodsmoke exposure in wildland firefighters.

PubMed

Naeher, Luke P; Barr, Dana Boyd; Adetona, Olorunfemi; Simpson, Christopher D

2013-01-01

Levoglucosan, a sugar anhydride and a combustion breakdown product of cellulose is a dominant organic constituent of particles in woodsmoke. After exposure, levoglucosan is excreted unmetabolized in urine. Urinary levoglucosan was assessed as a biomarker of occupational woodsmoke exposure among wildland firefighters. Urine samples were collected from wildland firefighters before and after their work-shifts on days when they worked at prescribed burns. A total of 97 pairs of pre- and post-shift urine samples were collected from 19 firefighters over 10 prescribed burn shifts. The urine samples were analyzed to determine whether there was an increase in the concentration of levoglucosan from pre- to post-shift after the firefighters had worked at the prescribed burns. Overall, there was an increase in both the urinary volume-based and creatinine corrected levoglucosan concentrations from pre- to post-shift (P < 0.05). However, the direction of change in the concentrations was not consistent. There were increases in urinary levoglucosan concentration from pre- to post-shift in 63% of the person-day samples, and in only 58% of the person-day samples for the creatinine corrected concentrations. Although there was an overall increase in urinary concentrations of levoglucosan, results suggest that other sources apart from woodsmoke affected the urinary levels of this biomarker in wildland firefighters. Therefore, urinary levoglucosan may not be effective as a biomarker of woodsmoke exposure in this setting.

Recommendations and Standardization of Biomarker Quantification Using NMR-Based Metabolomics with Particular Focus on Urinary Analysis

PubMed Central

2016-01-01

NMR-based metabolomics has shown considerable promise in disease diagnosis and biomarker discovery because it allows one to nondestructively identify and quantify large numbers of novel metabolite biomarkers in both biofluids and tissues. Precise metabolite quantification is a prerequisite to move any chemical biomarker or biomarker panel from the lab to the clinic. Among the biofluids commonly used for disease diagnosis and prognosis, urine has several advantages. It is abundant, sterile, and easily obtained, needs little sample preparation, and does not require invasive medical procedures for collection. Furthermore, urine captures and concentrates many “unwanted” or “undesirable” compounds throughout the body, providing a rich source of potentially useful disease biomarkers; however, incredible variation in urine chemical concentrations makes analysis of urine and identification of useful urinary biomarkers by NMR challenging. We discuss a number of the most significant issues regarding NMR-based urinary metabolomics with specific emphasis on metabolite quantification for disease biomarker applications and propose data collection and instrumental recommendations regarding NMR pulse sequences, acceptable acquisition parameter ranges, relaxation effects on quantitation, proper handling of instrumental differences, sample preparation, and biomarker assessment. PMID:26745651

Biomarkers of susceptibility following benzene exposure: influence of genetic polymorphisms on benzene metabolism and health effects.

PubMed

Carbonari, Damiano; Chiarella, Pieranna; Mansi, Antonella; Pigini, Daniela; Iavicoli, Sergio; Tranfo, Giovanna

2016-01-01

Benzene is a ubiquitous occupational and environmental pollutant. Improved industrial hygiene allowed airborne concentrations close to the environmental context (1-1000 µg/m(3)). Conversely, new limits for benzene levels in urban air were set (5 µg/m(3)). The biomonitoring of exposure to such low benzene concentrations are performed measuring specific and sensitive biomarkers such as S-phenylmercapturic acid, trans, trans-muconic acid and urinary benzene: many studies referred high variability in the levels of these biomarkers, suggesting the involvement of polymorphic metabolic genes in the individual susceptibility to benzene toxicity. We reviewed the influence of metabolic polymorphisms on the biomarkers levels of benzene exposure and effect, in order to understand the real impact of benzene exposure on subjects with increased susceptibility.

RELIABILITY OF BIOMARKERS OF PESTICIDE EXPOSURE AMONG CHILDREN AND ADULTS IN CTEPP OHIO

EPA Science Inventory

Urinary biomarkers offer the potential for providing an efficient tool for exposure classification by reflecting the aggregate of all exposure routes. Substantial variability observed in urinary pesticide metabolite concentrations over short periods of time, however, has cast so...

Detection of an endogenous urinary biomarker associated with CYP2D6 activity using global metabolomics.

PubMed

Tay-Sontheimer, Jessica; Shireman, Laura M; Beyer, Richard P; Senn, Taurence; Witten, Daniela; Pearce, Robin E; Gaedigk, Andrea; Gana Fomban, Cletus L; Lutz, Justin D; Isoherranen, Nina; Thummel, Kenneth E; Fiehn, Oliver; Leeder, J Steven; Lin, Yvonne S

2014-12-01

We sought to discover endogenous urinary biomarkers of human CYP2D6 activity. Healthy pediatric subjects (n = 189) were phenotyped using dextromethorphan and randomized for candidate biomarker selection and validation. Global urinary metabolomics was performed using liquid chromatography quadrupole time-of-flight mass spectrometry. Candidate biomarkers were tested in adults receiving fluoxetine, a CYP2D6 inhibitor. A biomarker, M1 (m/z 444.3102) was correlated with CYP2D6 activity in both the pediatric training and validation sets. Poor metabolizers had undetectable levels of M1, whereas it was present in subjects with other phenotypes. In adult subjects, a 9.56-fold decrease in M1 abundance was observed during CYP2D6 inhibition. Identification and validation of M1 may provide a noninvasive means of CYP2D6 phenotyping.

Determination of methyl-, 2-hydroxyethyl- and 2-cyanoethylmercapturic acids as biomarkers of exposure to alkylating agents in cigarette smoke.

PubMed

Scherer, Gerhard; Urban, Michael; Hagedorn, Heinz-Werner; Serafin, Richard; Feng, Shixia; Kapur, Sunil; Muhammad, Raheema; Jin, Yan; Sarkar, Mohamadi; Roethig, Hans-Juergen

2010-10-01

Alkylating agents occur in the environment and are formed endogenously. Tobacco smoke contains a variety of alkylating agents or precursors including, among others, N-nitrosodimethylamine (NDMA), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), acrylonitrile and ethylene oxide. We developed and validated a method for the simultaneous determination of methylmercapturic acid (MMA, biomarker for methylating agents such as NDMA and NNK), 2-hydroxyethylmercapturic acid (HEMA, biomarker for ethylene oxide) and 2-cyanoethylmercapturic acid (CEMA, biomarker for acrylonitrile) in human urine using deuterated internal standards of each compound. The method involves liquid/liquid extraction of the urine sample, solid phase extraction on anion exchange cartridges, derivatization with pentafluorobenzyl bromide (PFBBr), liquid/liquid extraction of the reaction mixture and LC-MS/MS analysis with positive electrospray ionization. The method was linear in the ranges of 5.00-600, 1.00-50.0 and 1.50-900 ng/ml for MMA, HEMA and CEMA, respectively. The method was applied to two clinical studies in adult smokers of conventional cigarettes who either continued smoking conventional cigarettes, were switched to test cigarettes consisting of either an electrically heated cigarette smoking system (EHCSS) or having a highly activated carbon granule filter that were shown to have reduced exposure to specific smoke constituents, or stopped smoking. Urinary excretion of MMA was found to be unaffected by switching to the test cigarettes or stop smoking. Urinary HEMA excretion decreased by 46 to 54% after switching to test cigarettes and by approximately 74% when stopping smoking. Urinary CEMA excretion decreased by 74-77% when switching to test cigarettes and by approximately 90% when stopping smoking. This validated method for urinary alkylmercapturic acids is suitable to distinguish differences in exposure not only between smokers and nonsmokers but also between smoking of conventional and the two test cigarettes investigated in this study. Copyright © 2010 Elsevier B.V. All rights reserved.

Physiologically-Based Toxicokinetic Modeling of Zearalenone and Its Metabolites: Application to the Jersey Girl Study

PubMed Central

Mukherjee, Dwaipayan; Royce, Steven G.; Alexander, Jocelyn A.; Buckley, Brian; Isukapalli, Sastry S.; Bandera, Elisa V.; Zarbl, Helmut; Georgopoulos, Panos G.

2014-01-01

Zearalenone (ZEA), a fungal mycotoxin, and its metabolite zeranol (ZAL) are known estrogen agonists in mammals, and are found as contaminants in food. Zeranol, which is more potent than ZEA and comparable in potency to estradiol, is also added as a growth additive in beef in the US and Canada. This article presents the development and application of a Physiologically-Based Toxicokinetic (PBTK) model for ZEA and ZAL and their primary metabolites, zearalenol, zearalanone, and their conjugated glucuronides, for rats and for human subjects. The PBTK modeling study explicitly simulates critical metabolic pathways in the gastrointestinal and hepatic systems. Metabolic events such as dehydrogenation and glucuronidation of the chemicals, which have direct effects on the accumulation and elimination of the toxic compounds, have been quantified. The PBTK model considers urinary and fecal excretion and biliary recirculation and compares the predicted biomarkers of blood, urinary and fecal concentrations with published in vivo measurements in rats and human subjects. Additionally, the toxicokinetic model has been coupled with a novel probabilistic dietary exposure model and applied to the Jersey Girl Study (JGS), which involved measurement of mycoestrogens as urinary biomarkers, in a cohort of young girls in New Jersey, USA. A probabilistic exposure characterization for the study population has been conducted and the predicted urinary concentrations have been compared to measurements considering inter-individual physiological and dietary variability. The in vivo measurements from the JGS fall within the high and low predicted distributions of biomarker values corresponding to dietary exposure estimates calculated by the probabilistic modeling system. The work described here is the first of its kind to present a comprehensive framework developing estimates of potential exposures to mycotoxins and linking them with biologically relevant doses and biomarker measurements, including a systematic characterization of uncertainties in exposure and dose estimation for a vulnerable population. PMID:25474635

IMAC fractionation in combination with LC-MS reveals H2B and NIF-1 peptides as potential bladder cancer biomarkers.

PubMed

Frantzi, Maria; Zoidakis, Jerome; Papadopoulos, Theofilos; Zürbig, Petra; Katafigiotis, Ioannis; Stravodimos, Konstantinos; Lazaris, Andreas; Giannopoulou, Ioanna; Ploumidis, Achilles; Mischak, Harald; Mullen, William; Vlahou, Antonia

2013-09-06

Improvement in bladder cancer (BC) management requires more effective diagnosis and prognosis of disease recurrence and progression. Urinary biomarkers attract special interest because of the noninvasive means of urine collection. Proteomic analysis of urine entails the adoption of a fractionation methodology to reduce sample complexity. In this study, we applied immobilized metal affinity chromatography in combination with high-resolution LC-MS/MS for the discovery of native urinary peptides potentially associated with BC aggressiveness. This approach was employed toward urine samples from patients with invasive BC, noninvasive BC, and benign urogenital diseases. A total of 1845 peptides were identified, corresponding to a total of 638 precursor proteins. Specific enrichment for proteins involved in nucleosome assembly and for zinc-finger transcription factors was observed. The differential expression of two candidate biomarkers, histone H2B and NIF-1 (zinc finger 335) in BC, was verified in independent sets of urine samples by ELISA and by immunohistochemical analysis of BC tissue. The results collectively support changes in the expression of both of these proteins with tumor progression, suggesting their potential role as markers for discriminating BC stages. In addition, the data indicate a possible involvement of NIF-1 in BC progression, likely as a suppressor and through interactions with Sox9 and HoxA1.

Are Urinary PAHs Biomarkers of Controlled Exposure to Diesel Exhaust?

EPA Science Inventory

Urinary polycyclic aromatic hydrocarbons (PAHs) were evaluated as possible biomarkers of exposure to diesel exhaust (DE) in two controlled-chamber studies. We report levels of 14 PAHs from 28 subjects in urine that were collected before, immediately after and the morning after ex...

Urinary Urea, Uric Acid and Hippuric Acid as Potential Biomarkers in Multiple Sclerosis Patients.

PubMed

Atya, Hanaa B; Ali, Sahar A; Hegazy, Mohamed I; El Sharkawi, Fathia Z

2018-04-01

Urine is a proven source of metabolite biomarkers and has the potential to be a rapid, noninvasive, inexpensive, and efficient diagnostic tool for various human diseases. Despite these advantages, urine is an under-investigated source of biomarkers for multiple sclerosis (MS). The objective was to investigate the level of some urinary metabolites (urea, uric acid and hippuric acid) in patients with MS and correlate their levels to the severity of the disease, MS subtypes and MS treatment. The urine samples were collected from 73 MS patients-48 with RRMS and 25 with SPMS- and age matched 75 healthy controls. The values of urinary urea, uric acid and hippuric acid in MS patients were significantly decreased, and these metabolites in SPMS pattern showed significantly decrease than RRMS pattern. Also showed significant inverse correlation with expanded disability status scale and number of relapses. Accordingly, they may act as a potential urinary biomarkers for MS, and correlate to disease progression.

Discovery of urine biomarkers for bladder cancer via global metabolomics.

PubMed

Shi, Hangchuan; Li, Xiang; Zhang, Qingyang; Yang, Hongmei; Zhang, Xiaoping

2016-11-01

Bladder cancer (BC) is latent in its early stage and lethal in its late stage. Therefore, early diagnosis and intervention are essential for successful BC treatment. Considering the limitations of current diagnostic tools, noninvasive biomarkers that are both highly sensitive and specific are needed to improve the overall survival and quality of life of patients. With the advent of systems biology, "-omics" technologies have been developed over the past few decades. As a promising member, global metabolomics has increasingly been found to have clear potential for biomarker discovery. However, urinary metabolomics studies related to BC have lagged behind those of other urinary cancers, and major findings have not been systematically reported. The objective of this review is to comprehensively list the currently identified potential urinary metabolite biomarkers for BC.

Urinary biomarkers may provide prognostic information for subclinical acute kidney injury after cardiac surgery.

PubMed

Albert, Christian; Albert, Annemarie; Kube, Johanna; Bellomo, Rinaldo; Wettersten, Nicholas; Kuppe, Hermann; Westphal, Sabine; Haase, Michael; Haase-Fielitz, Anja

2018-06-01

This study aimed to determine the biomarker-specific outcome patterns and short-and long-term prognosis of cardiac surgery-asoociated acute kidney injury (AKI) identified by standard criteria and/or urinary kidney biomarkers. Patients enrolled (N = 200), originated a German multicenter study (NCT00672334). Standard risk injury, failure, loss, and end-stage renal disease classification (RIFLE) criteria (including serum creatinine and urine output) and urinary kidney biomarker test result (neutrophil gelatinase-associated lipocalin, midkine, interleukin 6, and proteinuria) were used for diagnosis of postoperative AKI. Primary end point was acute renal replacement therapy or in-hospital mortality. Long-term end points among others included 5-year mortality. Patients with single-biomarker-positive subclinical AKI (RIFLE negative) were identified. We controlled for systemic inflammation using C-reactive protein test. Urinary biomarkers (neutrophil gelatinase-associated lipocalin, midkine, and interleukin 6) were identified as independent predictors of the primary end point. Neutrophil gelatinase-associated lipocalin, midkine, or interleukin 6 positivity or de novo/worsening proteinuria identified 21.1%, 16.9%, 30.5%, and 48.0% more cases, respectively, with likely subclinical AKI (biomarker positive/RIFLE negative) additionally to cases with RIFLE positivity alone. Patients with likely subclinical AKI (neutrophil gelatinase-associated lipocalin or interleukin 6 positive) had increased risk of primary end point (adjusted hazard ratio, 7.18; 95% confidence interval, 1.52-33.93 [P = .013] and hazard ratio, 6.27; 95% confidence interval, 1.12-35.21 [P = .037]), respectively. Compared with biomarker-negative/RIFLE-positive patients, neutrophil gelatinase-associated lipocalin positive/RIFLE-positive or midkine-positive/RIFLE-positive patients had increased risk of primary end point (odds ratio, 9.6; 95% confidence interval, 1.4-67.3 [P = .033] and odds ratio, 14.7; 95% confidence interval, 2.0-109.2 [P = .011], respectively). Three percent to 11% of patients appear to be influenced by single-biomarker-positive subclinical AKI. During follow-up, kidney biomarker-defined short-term outcomes appeared to translate into long-term outcomes. Urinary kidney biomarkers identified RIFLE-negative patients with high-risk subclinical AKI as well as a higher risk subgroup of patients among RIFLE-AKI-positive patients. These findings support the concept that urinary biomarkers define subclinical AKI and higher risk subpopulations with worse long-term prognosis among standard patients with AKI. Copyright © 2017 The American Association for Thoracic Surgery. All rights reserved.

Urinary Collagen Fragments Are Significantly Altered in Diabetes: A Link to Pathophysiology

PubMed Central

Argilés, Àngel; Cerna, Marie; Delles, Christian; Dominiczak, Anna F.; Gayrard, Nathalie; Iphöfer, Alexander; Jänsch, Lothar; Jerums, George; Medek, Karel; Mischak, Harald; Navis, Gerjan J.; Roob, Johannes M.; Rossing, Kasper; Rossing, Peter; Rychlík, Ivan; Schiffer, Eric; Schmieder, Roland E.; Wascher, Thomas C.; Winklhofer-Roob, Brigitte M.; Zimmerli, Lukas U.; Zürbig, Petra; Snell-Bergeon, Janet K.

2010-01-01

Background The pathogenesis of diabetes mellitus (DM) is variable, comprising different inflammatory and immune responses. Proteome analysis holds the promise of delivering insight into the pathophysiological changes associated with diabetes. Recently, we identified and validated urinary proteomics biomarkers for diabetes. Based on these initial findings, we aimed to further validate urinary proteomics biomarkers specific for diabetes in general, and particularity associated with either type 1 (T1D) or type 2 diabetes (T2D). Methodology/Principal Findings Therefore, the low-molecular-weight urinary proteome of 902 subjects from 10 different centers, 315 controls and 587 patients with T1D (n = 299) or T2D (n = 288), was analyzed using capillary-electrophoresis mass-spectrometry. The 261 urinary biomarkers (100 were sequenced) previously discovered in 205 subjects were validated in an additional 697 subjects to distinguish DM subjects (n = 382) from control subjects (n = 315) with 94% (95% CI: 92–95) accuracy in this study. To identify biomarkers that differentiate T1D from T2D, a subset of normoalbuminuric patients with T1D (n = 68) and T2D (n = 42) was employed, enabling identification of 131 biomarker candidates (40 were sequenced) differentially regulated between T1D and T2D. These biomarkers distinguished T1D from T2D in an independent validation set of normoalbuminuric patients (n = 108) with 88% (95% CI: 81–94%) accuracy, and in patients with impaired renal function (n = 369) with 85% (95% CI: 81–88%) accuracy. Specific collagen fragments were associated with diabetes and type of diabetes indicating changes in collagen turnover and extracellular matrix as one hallmark of the molecular pathophysiology of diabetes. Additional biomarkers including inflammatory processes and pro-thrombotic alterations were observed. Conclusions/Significance These findings, based on the largest proteomic study performed to date on subjects with DM, validate the previously described biomarkers for DM, and pinpoint differences in the urinary proteome of T1D and T2D, indicating significant differences in extracellular matrix remodeling. PMID:20927192

Biomarkers for acute kidney injury in decompensated cirrhosis: A Prospective Study.

PubMed

Jaques, David A; Spahr, Laurent; Berra, Gregory; Poffet, Vincent; Lescuyer, Pierre; Gerstel, Eric; Garin, Nicolas; Martin, Pierre-Yves; Ponte, Belen

2018-01-25

Acute kidney injury (AKI) is a frequent complication in cirrhotic patients. As serum creatinine is a poor marker of renal function in this population, we aimed to study the utility of several biomarkers in this context. A prospective study was conducted in hospitalized patients with decompensated cirrhosis. Serum creatinine (SCr), Cystatin C (CystC), NGAL and urinary NGAL, KIM-1, protein, albumin and sodium were measured on three separate occasions. Renal resistive index (RRI) was obtained. We analyzed the value of these biomarkers to determine the presence of AKI, its etiology [prerenal, acute tubular necrosis (ATN), or hepatorenal (HRS)], its severity and a composite clinical outcome at 30 days (death, dialysis and intensive care admission). We included 105 patients, of which 55 had AKI. SCr, CystC, NGAL (plasma and urinary), urinary sodium and RRI at inclusion were independently associated with the presence of AKI. SCr, CystC and plasma NGAL were able to predict the subsequent development of AKI. Pre-renal state showed lower levels of SCr, NGAL (plasma and urinary) and RRI. ATN patients had high levels of NGAL (plasma and urinary) as well as urinary protein and sodium. HRS patients presented an intermediate pattern. All biomarkers paralleled the severity of AKI. SCr, CystC and plasma NGAL predicted the development of the composite clinical outcome with the same performance as the MELD score. In patients with decompensated cirrhosis, early measurement of renal biomarkers provides valuable information on AKI etiology. It could also improve AKI diagnosis and prognosis. This article is protected by copyright. All rights reserved.

Urinary Excretion of Sodium, Nitrogen, and Sugar Amounts Are Valid Biomarkers of Dietary Sodium, Protein, and High Sugar Intake in Nonobese Adolescents.

PubMed

Moore, Lori B; Liu, Sarah V; Halliday, Tanya M; Neilson, Andrew P; Hedrick, Valisa E; Davy, Brenda M

2017-12-01

Background: Objective indicators of dietary intake (e.g., biomarkers) are needed to overcome the limitations of self-reported dietary intake assessment methods in adolescents. To our knowledge, no controlled feeding studies to date have evaluated the validity of urinary sodium, nitrogen, or sugar excretion as dietary biomarkers in adolescents. Objective: This investigation aimed to evaluate the validity of urinary sodium, nitrogen, and total sugars (TS) excretion as biomarkers for sodium, protein, and added sugars (AS) intake in nonobese adolescents. Methods: In a crossover controlled feeding study design, 33 adolescents [12-18 y of age, 47 ± 25th percentile (mean ± SD) of body mass index (BMI; in kg/m 2 ) for age] consumed 5% AS [low added sugars (LAS)] and 25% AS [high added sugars (HAS)] isocaloric, macronutrient-matched (55% carbohydrate, 30% fat, and 15% protein) diets for 7 d each, in a randomly assigned order, with a 4-wk washout period between diets. On the final 2 d of each diet period, 24-h urine samples were collected. Thirty-two adolescents completed all measurements (97% retention). Results: Urinary sodium was not different from the expected 90% recovery (mean ± SD: 88% ± 18%, P = 0.50). Urinary nitrogen was correlated with protein intake ( r = 0.69, P < 0.001), although it was below the 80% expected recovery (62% ± 7%, P < 0.001). Urinary TS values were correlated with AS intake during the HAS diet ( r = 0.77, P < 0.001) and had a higher R 2 value of 0.28 than did AS intake ( R 2 = 0.36). TS excretion differed between LAS (0.226 ± 0.09 mg/d) and HAS (0.365 ± 0.16 mg/d) feeding periods ( P < 0.001). Conclusions: Urinary sodium appears to be a valid biomarker for sodium intake in nonobese adolescents. Urinary nitrogen is associated with protein intake, but nitrogen excretion rates were less than previously reported for adults, possibly owing to adolescent growth rates. TS excretion reflects AS at 25% AS intake and was responsive to the change in AS intake. Thus, urinary biomarkers are promising objective indicators of dietary intake in adolescents, although larger-scale feeding trials are needed to confirm these findings. This trial was registered at clinicaltrials.gov as NCT02455388. © 2017 American Society for Nutrition.

Proteases and protease inhibitors of urinary extracellular vesicles in diabetic nephropathy.

PubMed

Musante, Luca; Tataruch, Dorota; Gu, Dongfeng; Liu, Xinyu; Forsblom, Carol; Groop, Per-Henrik; Holthofer, Harry

2015-01-01

Diabetic nephropathy (DN) is one of the major complications of diabetes mellitus (DM), leads to chronic kidney disease (CKD), and, ultimately, is the main cause for end-stage kidney disease (ESKD). Beyond urinary albumin, no reliable biomarkers are available for accurate early diagnostics. Urinary extracellular vesicles (UEVs) have recently emerged as an interesting source of diagnostic and prognostic disease biomarkers. Here we used a protease and respective protease inhibitor array to profile urines of type 1 diabetes patients at different stages of kidney involvement. Urine samples were divided into groups based on the level of albuminuria and UEVs isolated by hydrostatic dialysis and screened for relative changes of 34 different proteases and 32 protease inhibitors, respectively. Interestingly, myeloblastin and its natural inhibitor elafin showed an increase in the normo- and microalbuminuric groups. Similarly, a characteristic pattern was observed in the array of protease inhibitors, with a marked increase of cystatin B, natural inhibitor of cathepsins L, H, and B as well as of neutrophil gelatinase-associated Lipocalin (NGAL) in the normoalbuminuric group. This study shows for the first time the distinctive alterations in comprehensive protease profiles of UEVs in diabetic nephropathy and uncovers intriguing mechanistic, prognostic, and diagnostic features of kidney damage in diabetes.

Urinary vitamin D-binding protein, a novel biomarker for lupus nephritis, predicts the development of proteinuric flare.

PubMed

Go, D J; Lee, J Y; Kang, M J; Lee, E Y; Lee, E B; Yi, E C; Song, Y W

2018-01-01

Lupus nephritis (LN) is a major complication of systemic lupus erythematosus (SLE). Conventional biomarkers for assessing renal disease activity are imperfect in predicting clinical outcomes associated with LN. The aim of this study is to identify urinary protein biomarkers that reliably reflect the disease activity or predict clinical outcomes. A quantitative proteomic analysis was performed to identify protein biomarker candidates that can differentiate between SLE patients with and without LN. Selected biomarker candidates were further verified by enzyme-linked immunosorbent assay using urine samples from a larger cohort of SLE patients ( n = 121) to investigate their predictive values for LN activity measure. Furthermore, the association between urinary levels of a selected panel of potential biomarkers and prognosis of LN was assessed with a four-year follow-up study of renal outcomes. Urinary vitamin D-binding protein (VDBP), transthyretin (TTR), retinol binding protein 4 (RBP4), and prostaglandin D synthase (PTGDS) were significantly elevated in SLE patients with LN, especially in patients with active LN ( n = 21). Among them, VDBP well correlated with severity of proteinuria (rho = 0.661, p < 0.001) and renal SLE Disease Activity Index (renal SLEDAI) (rho = 0.520, p < 0.001). In the four-year follow-up, VDBP was a significant risk factor (hazard ratio 9.627, 95% confidence interval 1.698 to 54.571, p = 0.011) for the development of proteinuric flare in SLE patients without proteinuria ( n = 100) after adjustments for multiple confounders. Urinary VDBP correlated with proteinuria and renal SLEDAI, and predicted the development of proteinuria.

Associations between urinary biomarkers of oxidative stress and air pollutants observed in a randomized crossover exposure to steel mill emissions.

PubMed

Pelletier, Guillaume; Rigden, Marc; Kauri, Lisa Marie; Shutt, Robin; Mahmud, Mamun; Cakmak, Sabit; Kumarathasan, Premkumari; Thomson, Errol M; Vincent, Renaud; Broad, Gayle; Liu, Ling; Dales, Robert

2017-04-01

The effects of industrial air pollution on human health have not been as thoroughly investigated as those of urban air pollution which originates mostly from automotive transport. To better assess the health impacts of point sources of industrial air pollution, a randomized crossover exposure study was conducted. Sixty one young and healthy volunteers were randomly assigned to spend five consecutive eight-hour days near a steel mill or at a location five kilometres away. After a nine or sixteen-day washout period, volunteers spent another five consecutive days at the second site. Meteorological conditions and air pollutants were monitored at both exposure sites. On each exposure day, the first morning urine was collected along with a second urine sample obtained immediately before leaving the exposure site at the end of the day. Urinary levels of biomarkers of oxidative stress 8-hydroxy-2'-deoxyguanosine (8-OHdG, a biomarker of oxidative DNA damage), malondialdehyde (MDA, a biomarker of lipid peroxidation), 8-isoprostane (8-IsoP, a bioactive metabolite resulting from the peroxidation of arachidonic acid) and Vascular Endothelial Growth Factor (VEGF, involved in response to oxidative stress) were measured. According to mixed-effects linear regression models, intra-individual variations in 8-OHdG urinary levels were significantly associated with exposure site, but surprisingly, lower levels were observed at the steel mill site. Delayed, temporally-defined associations with specific air pollutants were observed for 8-OHdG, 8-IsoP and VEGF. However, these associations were subtle, presented complex patterns and their biological consequences remain unclear. Crown Copyright © 2016. Published by Elsevier GmbH. All rights reserved.

Urinary elimination of coproporphyrins is dependent on ABCC2 polymorphisms and represents a potential biomarker of MRP2 activity in humans.

PubMed

Benz-de Bretagne, Isabelle; Respaud, Renaud; Vourc'h, Patrick; Halimi, Jean-Michel; Caille, Agnès; Hulot, Jean-Sébastien; Andres, Christian R; Le Guellec, Chantal

2011-01-01

MRP2 encoded by ABCC2 gene is involved in the secretion of numerous drugs and endogenous substrates. Patients with Dubin-Johnson syndrome due to mutation in ABCC2 gene have elevated urinary coproporphyrin ratio (UCP I/(I + III)). Here we investigated whether this ratio could serve as a biomarker of MRP2 function. Phenotype-genotype relationships were studied in 74 healthy subjects by measuring individual UCP I/(I + III) ratio obtained on 24-hour urine and by analyzing five common SNPs in ABCC2 gene. The UCP I/(I + III) ratio varied from 14.7% to 46.0% in our population. Subjects with 3972TT genotype had a higher ratio (P = .04) than those carrying the C allele. This higher UCP I/(I + III) ratio was correlated with a higher level of isomer I excretion. This study provides a proof of concept that UCP I/(I + III) ratio can be used as a biomarker of MRP2 function in clinical studies as it provides quantitative information about the in vivo activity of MRP2 in a given patient.

Urinary Elimination of Coproporphyrins Is Dependent on ABCC2 Polymorphisms and Represents a Potential Biomarker of MRP2 Activity in Humans

PubMed Central

Benz-de Bretagne, Isabelle; Respaud, Renaud; Vourc'h, Patrick; Halimi, Jean-Michel; Caille, Agnès; Hulot, Jean-Sébastien; Andres, Christian R.; Le Guellec, Chantal

2011-01-01

MRP2 encoded by ABCC2 gene is involved in the secretion of numerous drugs and endogenous substrates. Patients with Dubin-Johnson syndrome due to mutation in ABCC2 gene have elevated urinary coproporphyrin ratio (UCP I/(I + III)). Here we investigated whether this ratio could serve as a biomarker of MRP2 function. Phenotype-genotype relationships were studied in 74 healthy subjects by measuring individual UCP I/(I + III) ratio obtained on 24-hour urine and by analyzing five common SNPs in ABCC2 gene. The UCP I/(I + III) ratio varied from 14.7% to 46.0% in our population. Subjects with 3972TT genotype had a higher ratio (P = .04) than those carrying the C allele. This higher UCP I/(I + III) ratio was correlated with a higher level of isomer I excretion. This study provides a proof of concept that UCP I/(I + III) ratio can be used as a biomarker of MRP2 function in clinical studies as it provides quantitative information about the in vivo activity of MRP2 in a given patient. PMID:21541183

Urinary biomarkers of smokers’ exposure to tobacco smoke constituents in tobacco products assessment: a fit for purpose approach

PubMed Central

Gregg, Evan O.; Minet, Emmanuel

2013-01-01

There are established guidelines for bioanalytical assay validation and qualification of biomarkers. In this review, they were applied to a panel of urinary biomarkers of tobacco smoke exposure as part of a “fit for purpose” approach to the assessment of smoke constituents exposure in groups of tobacco product smokers. Clinical studies have allowed the identification of a group of tobacco exposure biomarkers demonstrating a good doseresponse relationship whilst others such as dihydroxybutyl mercapturic acid and 2-carboxy-1-methylethylmercapturic acid – did not reproducibly discriminate smokers and non-smokers. Furthermore, there are currently no agreed common reference standards to measure absolute concentrations and few inter-laboratory trials have been performed to establish consensus values for interim standards. Thus, we also discuss in this review additional requirements for the generation of robust data on urinary biomarkers, including toxicant metabolism and disposition, method validation and qualification for use in tobacco products comparison studies. PMID:23902266

Novel urinary biomarkers and their association with urinary heavy metals in chronic kidney disease of unknown aetiology in Sri Lanka: a pilot study

PubMed

Wanigasuriya, K; Jayawardene, I; Amarasiriwardena, C; Wickremasinghe, R

2017-12-26

Chronic kidney disease of unknown etiology (CKDu) has emerged as a significant public health problem in Sri Lanka. The role of environmental exposure to cadmium and arsenic in the aetiology of CKDu is still unclear. Identification of a panel of novel urinary biomarkers would be invaluable in the study of toxin mediated damage postulated to be the aetiology of CKDu. The aims of this study were to evaluate the profile of novel urinary biomarkers in CKDu patients and identify any association with environmental exposure to heavy metals. Thirty seven randomly selected CKDu patients attending a renal clinic in the North Central Province and two control groups namely a farmer group (n=39) and a non-farmer group (n=40) from a non-endemic area were included in this comparative cross sectional study. Urine samples were analyzed for heavy metals and five urinary biomarkers. CKDu patients had significantly elevated urinary levels of fibrinogen (198.2 ng/mg creatinine p<0.001), clusterin (3479 ng/mg creatinine p<0.001), cystatin-C (5124.8 ng/mg creatinine p<0.001) and β2-microglobulin (9913.4 ng/mg creatinine p<0.001) compared to the control groups. Fibrinogen and β2-microglobulin were the best to discriminate CKDu patients from normal individuals with the receiver operator areas under the curve being 0.867 and 0.853, respectively. Urinary fibrinogen and KIM-1 levels correlated positively with urinary arsenic levels. KIM-1 levels correlated positively with urinary mercury and lead levels but no correlation was seen with urinary cadmium levels. Fibrinogen and β2-microglobulin have the potential of being a screening tool for detection of CKDu and may aid the early diagnosis of toxin mediated tubular injury in CKDu. Their usefulness need to be further validated in a larger epidemiological study of patients with early stages of CKDu.

YKL-40 Associates with Renal Recovery in Deceased Donor Kidney Transplantation

PubMed Central

Puthumana, Jeremy; Hall, Isaac E.; Reese, Peter P.; Schröppel, Bernd; Weng, Francis L.; Thiessen-Philbrook, Heather; Doshi, Mona D.; Rao, Veena; Lee, Chun Geun; Elias, Jack A.; Cantley, Lloyd G.

2017-01-01

Deceased donor kidneys with AKI are often discarded for fear of poor transplant outcomes. Donor biomarkers that predict post-transplant renal recovery could improve organ selection and reduce discard. We tested whether higher levels of donor urinary YKL-40, a repair phase protein, associate with improved recipient outcomes in a prospective cohort study involving deceased kidney donors from five organ procurement organizations. We measured urinary YKL-40 concentration in 1301 donors (111 had AKI, defined as doubling of serum creatinine) and ascertained outcomes in the corresponding 2435 recipients, 756 of whom experienced delayed graft function (DGF). Donors with AKI had higher urinary YKL-40 concentration (P<0.001) and acute tubular necrosis on procurement biopsies (P=0.05). In fully adjusted analyses, elevated donor urinary YKL-40 concentration associated with reduced risk of DGF in both recipients of AKI donor kidneys (adjusted relative risk, 0.51 [95% confidence interval (95% CI), 0.32 to 0.80] for highest versus lowest YKL-40 tertile) and recipients of non-AKI donor kidneys (adjusted relative risk, 0.79 [95% CI, 0.65 to 0.97]). Furthermore, in the event of DGF, elevated donor urinary YKL-40 concentration associated with higher 6-month eGFR (6.75 [95% CI, 1.49 to 12.02] ml/min per 1.73 m2) and lower risk of graft failure (adjusted hazard ratio, 0.50 [95% CI, 0.27 to 0.94]). These findings suggest that YKL-40 is produced in response to tubular injury and is independently associated with recovery from AKI and DGF. If ultimately validated as a prognostic biomarker, urinary YKL-40 should be considered in determining the suitability of donor kidneys for transplant. PMID:27451287

Urinary excretion ratio of xanthurenic acid/kynurenic acid as a functional biomarker of niacin nutritional status.

PubMed

Shibata, Katsumi; Yamazaki, Marika; Matsuyama, Yukiyo

2016-07-18

The present study was conducted to survey functional biomarkers for evaluation of niacin nutritional status. Over 500 enzymes require niacin as a coenzyme. Of these, we chose the tryptophan degradation pathway. To create niacin-deficient animals, quinolinic acid phosphoribosyltransferase-knock out mice were used in the present study because wild type mice can synthesize nicotinamide from tryptophan. When the mice were made niacin-deficient, the urinary excretion of xanthurenic acid (XA) was extremely low compared with control mice; however, it increased according to the recovery of niacin nutritional status. The urinary excretion of kynurenic acid (KA) was the reverse of XA. Kynurenine 3-monooxygenase, which needs NADPH, was thought to be suppressed by niacin deficiency. Thus, we calculated the urinary excretion ratio of XA:KA as a functional biomarker of niacin nutrition. The ratio increased according to recovering niacin nutritional status. Low values equate with low niacin nutritional status.

Current state of the art for enhancing urine biomarker discovery

PubMed Central

Harpole, Michael; Davis, Justin; Espina, Virginia

2016-01-01

Urine is a highly desirable biospecimen for biomarker analysis because it can be collected recurrently by non-invasive techniques, in relatively large volumes. Urine contains cellular elements, biochemicals, and proteins derived from glomerular filtration of plasma, renal tubule excretion, and urogenital tract secretions that reflect, at a given time point, an individual's metabolic and pathophysiologic state. High-resolution mass spectrometry, coupled with state of the art fractionation systems are revealing the plethora of diagnostic/prognostic proteomic information existing within urinary exosomes, glycoproteins, and proteins. Affinity capture pre-processing techniques such as combinatorial peptide ligand libraries and biomarker harvesting hydrogel nanoparticles are enabling measurement/identification of previously undetectable urinary proteins. Future challenges in the urinary proteomics field include a) defining either single or multiple, universally applicable data normalization methods for comparing results within and between individual patients/data sets, and b) defining expected urinary protein levels in healthy individuals. PMID:27232439

Urinary NGAL, KIM-1 and L-FABP concentrations in antenatal hydronephrosis.

PubMed

Noyan, Aytul; Parmaksiz, Gonul; Dursun, Hasan; Ezer, Semire Serin; Anarat, Ruksan; Cengiz, Nurcan

2015-10-01

The clinical tests currently in use for obstructive nephropathy (such as renal ultrasonography, differential radionuclide renal scans and urinary creatinine concentration data) are not efficient predictors of the subsequent clinical course. Novel and simple biomarkers are required which, if proven, could be clinically beneficial in determining if a patient is eligible for surgery or reno-protective therapy. More recently, the interest of clinicians has focused on the potential of urinary neutrophil gelatinase-associated lipocalin (uNGAL), urinary kidney injury molecule-1 (uKIM-1) and urinary liver-type fatty acid-binding proteins (uL-FABP) as biomarkers for renal function in children with hydronephrosis (HN). The purpose of this study was to investigate possible clinical applications of uNGAL, uKIM-1 and uL-FABP as beneficial non-invasive biomarkers to determine whether or not surgical intervention is required in children with HN. Renal ultrasonography and radionuclide renal scans were used as diagnostic tools to detect HN. Patients were divided into two groups based on the antero-posterior diameter of their renal pelvis and the presence of dysfunction. Group 1 included 26 children with severe HN (with dysfunction), and group 2 consisted of 36 children with mild HN (without dysfunction). Urine samples were collected from 62 children with HN and 20 healthy children. Hydronephrosis was more common in males than in females, with a male to female ratio of 9:1 in the study sample. The incidence of left kidney involvement (32 patients) was slightly higher than right kidney involvement (28 patients). Compared with controls and group 2, the ratio of uNGAL to creatinine was significantly higher in group 1 (p < 0.05). The biomarker uNGAL/Cr exhibited fairly good diagnostic accuracy, with an area under the curve of 0.68 [95% confidence interval 0.6-0.7] and an optimal cut-off value of 0.16 ng/mg Cr (sensitivity 58%, specificity 75%) (p < 0.05). There was a positive correlation between the uNGAL/Cr ratio and the uKIM-1/Cr ratio (r = 0.582, p < 0.05) and uL-FABP/Cr ratio (r = 0675, p < 0.05) in group 1. The results clearly demonstrated that children with hydronephrosis and dysfunction had significantly increased uNGAL, and uNGAL/Cr concentrations. However, uKIM-1, uKIM-1/Cr, uL-FABP and uL-FABP/Cr concentrations were not significantly different when compared with controls. These results support the use of uNGAL concentrations as an early marker for renal dysfunction in HN. The study clearly demonstrated that pediatric patients with hydronephrosis and dysfunction had significantly higher uNGAL to creatinine concentrations as compared with controls. Copyright © 2015 Journal of Pediatric Urology Company. All rights reserved.

An Evaluation of Collagen Metabolism in Non Human Primates Associated with the Bion 11 Space Program-Markers of Urinary Collagen Turnover and Muscle Connective Tissue

NASA Technical Reports Server (NTRS)

Vailas, Arthur C.; Martinez, Daniel A.

1999-01-01

Patients exhibiting changes in connective tissue and bone metabolism also show changes in urinary by-products of tissue metabolism. Furthermore, the changes in urinary connective tissue and bone metabolites precede alterations at the tissue macromolecular level. Astronauts and Cosmonauts have also shown suggestive increases in urinary by-products of mineralized and non-mineralized tissue degradation. Thus, the idea of assessing connective tissue and bone response in spaceflight monkeys by measurement of biomarkers in urine has merit. Other investigations of bone and connective histology, cytology and chemistry in the Bion 11 monkeys will allow for further validation of the relationship of urinary biomarkers and tissue response. In future flights the non-invasive procedure of urinary analysis may be useful in early detection of changes in these tissues. The purpose of this grant investigation was to evaluate mineralized and non-mineralized connective tissue responses of non-human primates to microgravity by the non-invasive analysis of urinary biomarkers. Secondly, we also wanted to assess muscle connective tissue adaptive changes in three weight-bearing skeletal muscles: the soleus, media] gastrocnemius and tibialis anterior by obtaining pre-flight and post-flight small biopsy specimens in collaboration with Dr. V. Reggie Edgerton's laboratory at the University of California at Los Angeles.

Multicollinearity may lead to artificial interaction: an example from a cross sectional study of biomarkers.

PubMed

Sithisarankul, P; Weaver, V M; Diener-West, M; Strickland, P T

1997-06-01

Collinearity is the situation which arises in multiple regression when some or all of the explanatory variables are so highly correlated with one another that it becomes very difficult, if not impossible, to disentangle their influences and obtain a reasonably precise estimate of their effects. Suppressor variable is one of the extreme situations of collinearity that one variable can substantially increase the multiple correlation when combined with a variable that is only modestly correlated with the response variable. In this study, we describe the process by which we disentangled and discovered multicollinearity and its consequences, namely artificial interaction, using the data from cross-sectional quantification of several biomarkers. We showed how the collinearity between one biomarker (blood lead level) and another (urinary trans, trans-muconic acid) and their interaction (blood lead level* urinary trans, trans-muconic acid) can lead to the observed artificial interaction on the third biomarker (urinary 5-aminolevulinic acid).

Utility of Urinary Biomarkers in Predicting Loss of Residual Renal Function: The balANZ Trial

PubMed Central

Cho, Yeoungjee; Johnson, David W.; Vesey, David A.; Hawley, Carmel M.; Clarke, Margaret; Topley, Nicholas

2015-01-01

♦ Background: The ability of urinary biomarkers to predict residual renal function (RRF) decline in peritoneal dialysis (PD) patients has not been defined. The present study aimed to explore the utility of established biomarkers from kidney injury models for predicting loss of RRF in incident PD patients, and to evaluate the impact on RRF of using neutral-pH PD solution low in glucose degradation products. ♦ Methods: The study included 50 randomly selected participants from the balANZ trial who had completed 24 months of follow-up. A change in glomerular filtration rate (GFR) was used as the primary clinical outcome measure. In a mixed-effects general linear model, baseline measurements of 18 novel urinary biomarkers and albumin were used to predict GFR change. The model was further used to evaluate the impact of biocompatible PD solution on RRF, adjusted for each biomarker. ♦ Results: Baseline albuminuria was not a useful predictor of change in RRF in PD patients (p = 0.84). Only clusterin was a significant predictor of GFR decline in the whole population (p = 0.04, adjusted for baseline GFR and albuminuria). However, the relationship was no longer apparent when albuminuria was removed from the model (p = 0.31). When the effect of the administered PD solutions was examined using a model adjusted for PD solution type, baseline albuminuria, and GFR, higher baseline urinary concentrations of trefoil factor 3 (TFF3, p = 0.02), kidney injury molecule 1 (KIM-1, p = 0.04), and interferon γ-induced protein 10 (IP-10, p = 0.03) were associated with more rapid decline of RRF in patients receiving conventional PD solution compared with biocompatible PD solution. ♦ Conclusions: Higher urinary levels of kidney injury biomarkers (TFF3, KIM-1, IP-10) at baseline predicted significantly slower RRF decline in patients receiving biocompatible PD solutions. Findings from the present investigation should help to guide future studies to validate the utility of urinary biomarkers as tools to predict RRF decline in PD patients. PMID:24711637

Urinary polycyclic aromatic hydrocarbon biomarkers and diabetes mellitus.

PubMed

Alshaarawy, Omayma; Zhu, Motao; Ducatman, Alan M; Conway, Baqiyyah; Andrew, Michael E

2014-06-01

The aim of the current study is to investigate the association of polycyclic aromatic hydrocarbons (PAHs), a group of environmental pollutants, with diabetes mellitus. Animal studies link PAHs to inflammation and subsequent development of diabetes mellitus. In addition, occupational studies suggest that exposure to other aromatic hydrocarbons such as dioxins may be associated with diabetes risk in humans. We examined participants from the merged National Health and Nutrition Examination Survey 2001-2002, 2003-2004 and 2005-2006. Exposures of interest were eight urinary monohydroxy-PAHs. Our outcome was diabetes mellitus defined as a glycohemoglobin level (HbA1c) ≥6.5%, a self-reported physician diagnosis of diabetes or use of oral hypoglycaemic medication or insulin. Analyses were adjusted for age, sex, body mass index, race, alcohol consumption, poverty-income ratio, total cholesterol and serum cotinine. We observed a positive association between urinary biomarkers of 1 and 2-hydroxynapthol, 2-hydroxyphenanthrene and summed low molecular weight (LMW) PAH biomarkers, and diabetes mellitus. Compared with participants with summed LMW PAH biomarkers in the lowest quartile, the multivariable-adjusted OR of diabetes mellitus among those in the highest quartile was 3.1 (95% CI 1.6 to 5.8). Urinary biomarkers of 1 and 2-hydroxynapthol, 2-hydroxyphenanthrene and summed LMW PAH biomarkers are associated with diabetes mellitus in US adults 20-65 years of age. The association of a one-time biomarker of PAH exposure has limitations commonly associated with cross-sectional studies, yet is consistent with experimental animal data and is worthy of additional consideration.

Urinary Biomarkers of Brain Diseases

PubMed Central

An, Manxia; Gao, Youhe

2016-01-01

Biomarkers are the measurable changes associated with a physiological or pathophysiological process. Unlike blood, urine is not subject to homeostatic mechanisms. Therefore, greater fluctuations could occur in urine than in blood, better reflecting the changes in human body. The roadmap of urine biomarker era was proposed. Although urine analysis has been attempted for clinical diagnosis, and urine has been monitored during the progression of many diseases, particularly urinary system diseases, whether urine can reflect brain disease status remains uncertain. As some biomarkers of brain diseases can be detected in the body fluids such as cerebrospinal fluid and blood, there is a possibility that urine also contain biomarkers of brain diseases. This review summarizes the clues of brain diseases reflected in the urine proteome and metabolome. PMID:26751805

Triggered Urine Interleukin-6 Correlates to Severity of Symptoms in Nonfebrile Lower Urinary Tract Infections.

PubMed

Sundén, Fredrik; Butler, Daniel; Wullt, Björn

2017-07-01

Objective diagnosis of symptomatic urinary tract infections in patients prone to asymptomatic bacteriuria is compromised by local host responses that are already present and the positive urine culture. We investigated interleukin-6 as a biomarker for nonfebrile urinary tract infection severity and diagnostic thresholds for interleukin-6 and 8, and neutrophils to differentiate between asymptomatic bacteriuria and urinary tract infection. Patients with residual urine and neurogenic bladders due to spinal lesions included in a long-term Escherichia coli 83972 asymptomatic bacteriuria inoculation trial were monitored for 2 years. Symptom scoring and urine sampling to estimate interleukin-6 and 8, and neutrophils were performed regularly monthly and at urinary tract infection episodes. Patients were followed in the complete study for a mean of 19 months (range 10 to 27) and those with asymptomatic bacteriuria with E. coli 83972 were followed a mean of 11 months (range 4 to 19). A total of 37 nonfebrile urinary tract infection episodes with complete data on interleukin-6 and 8, neutrophils and symptom scoring were documented. Interleukin-6 was the only marker that persistently increased during urinary tract infection compared to asymptomatic bacteriuria in pooled and paired intra-individual comparisons (p <0.05). Interleukin-6 above the threshold (greater than 25 ng/l) correlated to more severe urinary tract infection symptoms (p <0.05). The sensitivity and specificity of all biomarkers were poor/moderate when differentiating asymptomatic bacteriuria vs all urinary tract infection episodes. However, in urinary tract infections with worse symptoms interleukin-6 and neutrophils demonstrated equal good/excellent outcomes. Triggered interleukin-6 correlated to urinary tract infection symptom severity and demonstrated a promising differential diagnostic capacity to discriminate urinary tract infection from asymptomatic bacteriuria. Future studies should explore interleukin-6 as a biomarker of urinary tract infection severity and assess the treatment indication in nonfebrile urinary tract infections. Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

A Compendium of Urinary Biomarkers Indicative of Glomerular Podocytopathy

PubMed Central

2013-01-01

It is well known that glomerular podocyte injury and loss are present in numerous nephropathies and that the pathophysiologic consecution of disease hinges upon the fate of the podocyte. While multiple factors play a hand in glomerulopathy progression, basic logic lends that if one monitors the podocyte's status, that may reflect the status of disease. Recent investigations have focused on what one can elucidate from the noninvasive collection of urine, and have proven that certain, specific biomarkers of podocytes can be readily identified via varying techniques. This paper has brought together all described urinary biomarkers of podocyte injury and is made to provide a concise summary of their utility and testing in laboratory and clinical theatres. While promising in the potential that they hold as tools for clinicians and investigators, the described biomarkers require further comprehensive vetting in the form of larger clinical trials and studies that would give their value true weight. These urinary biomarkers are put forth as novel indicators of glomerular disease presence, disease progression, and therapeutic efficacy that in some cases may be more advantageous than the established parameters/measures currently used in practice. PMID:24327929

Role for urinary biomarkers in diagnosis of acute rejection in the transplanted kidney.

PubMed

Merhi, Basma; Bayliss, George; Gohh, Reginald Y

2015-12-24

Despite the introduction of potent immunosuppressive medications within recent decades, acute rejection still accounts for up to 12% of all graft losses, and is generally associated with an increased risk of late graft failure. Current detection of acute rejection relies on frequent monitoring of the serum creatinine followed by a diagnostic renal biopsy. This strategy is flawed since an alteration in the serum creatinine is a late clinical event and significant irreversible histologic damage has often already occurred. Furthermore, biopsies are invasive procedures that carry their own inherent risk. The discovery of non-invasive urinary biomarkers to help diagnose acute rejection has been the subject of a significant amount of investigation. We review the literature on urinary biomarkers here, focusing on specific markers perforin and granzyme B mRNAs, FOXP3 mRNA, CXCL9/CXCL10 and miRNAs. These and other biomarkers are not yet widely used in clinical settings, but our review of the literature suggests that biomarkers may correlate with biopsy findings and provide an important early indicator of rejection, allowing more rapid treatment and better graft survival.

Role for urinary biomarkers in diagnosis of acute rejection in the transplanted kidney

PubMed Central

Merhi, Basma; Bayliss, George; Gohh, Reginald Y

2015-01-01

Despite the introduction of potent immunosuppressive medications within recent decades, acute rejection still accounts for up to 12% of all graft losses, and is generally associated with an increased risk of late graft failure. Current detection of acute rejection relies on frequent monitoring of the serum creatinine followed by a diagnostic renal biopsy. This strategy is flawed since an alteration in the serum creatinine is a late clinical event and significant irreversible histologic damage has often already occurred. Furthermore, biopsies are invasive procedures that carry their own inherent risk. The discovery of non-invasive urinary biomarkers to help diagnose acute rejection has been the subject of a significant amount of investigation. We review the literature on urinary biomarkers here, focusing on specific markers perforin and granzyme B mRNAs, FOXP3 mRNA, CXCL9/CXCL10 and miRNAs. These and other biomarkers are not yet widely used in clinical settings, but our review of the literature suggests that biomarkers may correlate with biopsy findings and provide an important early indicator of rejection, allowing more rapid treatment and better graft survival. PMID:26722652

DEVELOPMENT OF URINARY METABOLITE BIOMARKERS TO ASSESS POPULATION EXPOSURE TO PM2.5 FROM VARIOUS COMBUSTION SOURCES

EPA Science Inventory

A primary goal of our research is to validate the use of urinary biomarkers to apportion the sources of human exposure to PM2.5. Organic source tracers have been used in source apportionment studies of ambient PM2.5 to distinguish a range of combustion sources. Both gas and par...

Original Research: Potential of urinary nephrin as a biomarker reflecting podocyte dysfunction in various kidney disease models

PubMed Central

Wada, Yusuke; Moritani, Hiroshi; Mitori, Hikaru; Kondo, Mitsuhiro; Tanaka-Amino, Keiko; Eguchi, Megumi; Imasato, Akira; Inoki, Yutaka; Kajiyama, Hiroshi; Mimura, Toshihide; Tomura, Yuichi

2016-01-01

Urinary nephrin is a potential non-invasive biomarker of disease. To date, however, most studies of urinary nephrin have been conducted in animal models of diabetic nephropathy, and correlations between urinary nephrin-to-creatinine ratio and other parameters have yet to be evaluated in animal models or patients of kidney disease with podocyte dysfunction. We hypothesized that urinary nephrin-to-creatinine ratio can be up-regulated and is negatively correlated with renal nephrin mRNA levels in animal models of kidney disease, and that increased urinary nephrin-to-creatinine ratio levels are attenuated following administration of glucocorticoids. In the present study, renal nephrin mRNA, urinary nephrin-to-creatinine ratio, urinary protein-to-creatinine ratio, and creatinine clearance ratio were measured in animal models of adriamycin nephropathy, puromycin aminonucleoside nephropathy, anti-glomerular basement membrane glomerulonephritis, and 5/6 nephrectomy. The effects of prednisolone on urinary nephrin-to-creatinine ratio and other parameters in puromycin aminonucleoside (single injection) nephropathy rats were also investigated. In all models tested, urinary nephrin-to-creatinine ratio and urinary protein-to-creatinine ratio increased, while renal nephrin mRNA and creatinine clearance ratio decreased. Urinary nephrin-to-creatinine ratio exhibited a significant negative correlation with renal nephrin mRNA in almost all models, as well as a significant positive correlation with urinary protein-to-creatinine ratio and a significant negative correlation with creatinine clearance ratio. Urinary protein-to-creatinine ratio exhibited a significant negative correlation with renal nephrin mRNA. Following the administration of prednisolone to puromycin aminonucleoside (single injection) nephropathy rats, urinary nephrin-to-creatinine ratio was significantly suppressed and exhibited a significant positive correlation with urinary protein-to-creatinine ratio. In addition, the decrease in number of glomerular Wilms tumor antigen-1-positive cells was attenuated, and urinary nephrin-to-creatinine ratio exhibited a significant negative correlation in these cells. In conclusion, these results suggest that urinary nephrin-to-creatinine ratio level is a useful and reliable biomarker for predicting the amelioration of podocyte dysfunction by candidate drugs in various kidney disease models with podocyte dysfunction. This suggestion will also be validated in a clinical setting in future studies. PMID:27216597

How well does urinary lyso-Gb3 function as a biomarker in Fabry disease?

PubMed

Auray-Blais, Christiane; Ntwari, Aimé; Clarke, Joe T R; Warnock, David G; Oliveira, João Paulo; Young, Sarah P; Millington, David S; Bichet, Daniel G; Sirrs, Sandra; West, Michael L; Casey, Robin; Hwu, Wuh-Liang; Keutzer, Joan M; Zhang, X Kate; Gagnon, René

2010-12-14

Fabry disease is characterized by accumulation of glycosphingolipids, such as globotriaosylceramide (Gb(3)), in many tissues and body fluids. A novel plasma biomarker, globotriaosylsphingosine (lyso-Gb(3)), is increased in patients with the disease. Until now, lyso-Gb(3) was not detectable in urine, possibly because of the presence of interfering compounds. We undertook to: 1) characterize lyso-Gb(3) in urine; 2) develop a method to quantitate urinary lyso-Gb(3) by mass spectrometry; 3) evaluate urinary lyso-Gb(3) as a potential biomarker for Fabry disease; and 4) determine whether lyso-Gb(3) is an inhibitor of α-galactosidase A activity. We analyzed urinary lyso-Gb(3) from 83 Fabry patients and 77 healthy age-matched controls. The intraday and interday bias and precision of the method were <15%. Increases in lyso-Gb(3)/creatinine correlated with the concentrations of Gb(3) (r(2)=0.43), type of mutations (p=0.0006), gender (p<0.0001) and enzyme replacement therapy status (p=0.0012). Urine from healthy controls contained no detectable lyso-Gb(3). Lyso-Gb(3) did not inhibit GLA activity in dried blood spots. Increased urinary excretion of lyso-Gb(3) of Fabry patients correlated well with a number of indicators of disease severity. Lyso-Gb(3) is a reliable independent biomarker for clinically important characteristics of Fabry disease. Copyright © 2010 Elsevier B.V. All rights reserved.

Proteases and Protease Inhibitors of Urinary Extracellular Vesicles in Diabetic Nephropathy

PubMed Central

Tataruch, Dorota; Gu, Dongfeng; Liu, Xinyu; Forsblom, Carol; Groop, Per-Henrik; Holthofer, Harry

2015-01-01

Diabetic nephropathy (DN) is one of the major complications of diabetes mellitus (DM), leads to chronic kidney disease (CKD), and, ultimately, is the main cause for end-stage kidney disease (ESKD). Beyond urinary albumin, no reliable biomarkers are available for accurate early diagnostics. Urinary extracellular vesicles (UEVs) have recently emerged as an interesting source of diagnostic and prognostic disease biomarkers. Here we used a protease and respective protease inhibitor array to profile urines of type 1 diabetes patients at different stages of kidney involvement. Urine samples were divided into groups based on the level of albuminuria and UEVs isolated by hydrostatic dialysis and screened for relative changes of 34 different proteases and 32 protease inhibitors, respectively. Interestingly, myeloblastin and its natural inhibitor elafin showed an increase in the normo- and microalbuminuric groups. Similarly, a characteristic pattern was observed in the array of protease inhibitors, with a marked increase of cystatin B, natural inhibitor of cathepsins L, H, and B as well as of neutrophil gelatinase-associated Lipocalin (NGAL) in the normoalbuminuric group. This study shows for the first time the distinctive alterations in comprehensive protease profiles of UEVs in diabetic nephropathy and uncovers intriguing mechanistic, prognostic, and diagnostic features of kidney damage in diabetes. PMID:25874235

An Evaluation of Collagen Metabolism in Non Human Primates Associated with the Bion 11 Space Program-Markers of Urinary Collagen Turnover and Muscle Connective Tissue

NASA Technical Reports Server (NTRS)

Vailas, Arthur C.; Martinez, Daniel A.

1999-01-01

Patients exhibiting changes in connective tissue and bone metabolism also show changes in urinary by-products of tissue metabolism. Furthermore, the changes in urinary connective tissue and bone metabolites precede alterations at the tissue macromolecular level. Astronauts and Cosmonauts have also shown suggestive increases in urinary by-products of mineralized and non-mineralized tissue degradation. Thus, the idea of assessing connective tissue and bone response in spaceflight monkeys by measurement of biomarkers in urine has merit. Other investigations of bone and connective histology, cytology and chemistry in the Bion 11 monkeys will allow for further validation of the relationship of urinary biomarkers and tissue response. In future flights the non-invasive procedure of urinary analysis may be useful in early detection of changes in these tissues. Purpose: The purpose of this grant investigation was to evaluate mineralized and non-mineralized connective tissue responses of non-human primates to microgravity by the non-invasive analysis of urinary biomarkers. Secondly, we also wanted to assess muscle connective tissue adaptive changes in three weight-bearing skeletal muscles: the soleus, medial gastrocnemius and tibialis anterior by obtaining pre-flight and post-flight small biopsy specimens in collaboration with Dr. V. Reggie Edgerton's laboratory at the University of California at Los Angeles.

Urinary MicroRNA as Biomarker in Renal Transplantation.

PubMed

van de Vrie, M; Deegens, J K; Eikmans, M; van der Vlag, J; Hilbrands, L B

2017-05-01

Urine represents a noninvasive source in which proteins and nucleic acids can be assessed. Such analytes may function as biomarkers to monitor kidney graft pathology at every desired frequency, thereby providing a time window to prevent graft damage by therapeutic intervention. Recently, several proteins have been measured in urine as markers of graft injury. However, the specificity is limited, and measuring urinary proteins generally lacks the potential to predict early kidney graft damage. Currently, urinary mRNA and microRNA are being investigated to evaluate the prognostic value of changes in gene expression during the initial stages of graft damage. At such time point, a change in treatment regimen and dosage is expected to have maximum potency to minimize future decline in graft function. Both mRNA and microRNAs have shown promising results in both detection and prediction of graft injury. An advantage of microRNAs compared to mRNA molecules is their stability, a characteristic that is beneficial when working with urine samples. In this review, we provide the current state of urinary biomarkers in renal transplantation, with a focus on urinary microRNA. In addition, we discuss the methods used to study urinary microRNA expression. © 2016 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of American Society of Transplant Surgeons.

Urinary Protein Biomarker Analysis

DTIC Science & Technology

2017-10-01

monitoring, in the case of low-risk cancers, to radiation or surgical procedures for higher risk cancers (Bill-Axelson et al., N. Engl. J. Med., 370:932...the methods can include administering at least one of watchful waiting, active surveillance, surgery, radiation , hormone therapy, chemotherapy...macrophage inflammatory protein 1-α (MIP1α), and tonsillar lymphocyte LD78 α Protein (LD78-α), CCL3 is a monokine involved in the acute inflammatory state

Urinary trans-trans muconic acid (exposure biomarker to benzene) and hippuric acid (exposure biomarker to toluene) concentrations in Mexican women living in high-risk scenarios of air pollution.

PubMed

Pruneda-Alvarez, Lucía G; Ruíz-Vera, Tania; Ochoa-Martínez, Angeles C; Pérez-Maldonado, Iván N

2017-11-02

This study aimed to determine t,t-muconic acid (t,t-MA; exposure biomarker for benzene) and hippuric acid (HA; exposure biomarker for toluene) concentrations in the urine of women living in Mexico. In a cross-sectional study, apparently healthy women (n = 104) were voluntarily recruited from localities with a high risk of air pollution; t,t-MA and HA in urine were quantified using a high-performance liquid chromatography (HPLC) technique. Mean urinary levels of t,t-MA ranged from 680 to 1,310 μg/g creatinine. Mean values of HA ranged from 0.38 to 0.87 g/g creatinine. In conclusion, compared to data recently reported in literature, we found high urinary levels of t,t-MA and HA in assessed women participating in this study. We therefore deem the implementation of a strategy aimed at the reduction of exposure as a necessary measure for the evaluated communities.

Reference intervals for urinary renal injury biomarkers KIM-1 and NGAL in healthy children

PubMed Central

McWilliam, Stephen J; Antoine, Daniel J; Sabbisetti, Venkata; Pearce, Robin E; Jorgensen, Andrea L; Lin, Yvonne; Leeder, J Steven; Bonventre, Joseph V; Smyth, Rosalind L; Pirmohamed, Munir

2014-01-01

Aim The aim of this study was to establish reference intervals in healthy children for two novel urinary biomarkers of acute kidney injury, kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Materials & Methods Urinary biomarkers were determined in samples from children in the UK (n = 120) and the USA (n = 171) using both Meso Scale Discovery (MSD) and Luminex-based analytical approaches. Results 95% reference intervals for each biomarker in each cohort are presented and stratified by sex or ethnicity where necessary, and age-related variability is explored using quantile regression. We identified consistently higher NGAL concentrations in females than males (p < 0.0001), and lower KIM-1 concentrations in African–Americans than Caucasians (p = 0.02). KIM-1 demonstrated diurnal variation, with higher concentrations in the morning (p < 0.001). Conclusion This is the first report of reference intervals for KIM-1 and NGAL using two analytical methods in a healthy pediatric population in both UK and US-based populations. PMID:24661102

Kidney Injury Molecule-1 Outperforms Traditional Biomarkers of Kidney Injury in Multi-site Preclinical Biomarker Qualification Studies

PubMed Central

Vaidya, Vishal S.; Ozer, Josef S.; Frank, Dieterle; Collings, Fitz B.; Ramirez, Victoria; Troth, Sean; Muniappa, Nagaraja; Thudium, Douglas; Gerhold, David; Holder, Daniel J.; Bobadilla, Norma A.; Marrer, Estelle; Perentes, Elias; Cordier, André; Vonderscher, Jacky; Maurer, Gérard; Goering, Peter L.; Sistare, Frank D.; Bonventre, Joseph V.

2010-01-01

Kidney toxicity accounts for a significant percentage of morbidity and drug candidate failure. Serum creatinine (SCr) and blood urea nitrogen (BUN) have been used to monitor kidney dysfunction for over a century but these markers are insensitive and non-specific. In multi-site preclinical rat toxicology studies the diagnostic performance of urinary kidney injury molecule-1 (Kim-1) was compared to traditional biomarkers as predictors of kidney tubular histopathologic changes, currently considered the “gold standard” of nephrotoxicity. In multiple models of kidney injury, urinary Kim-1 significantly outperformed SCr and BUN. The area under the receiver operating characteristic curve for Kim-1 was between 0.91 and 0.99 as compared to 0.79 to 0.9 for BUN and 0.73 to 0.85 for SCr. Thus urinary Kim-1 is the first injury biomarker of kidney toxicity qualified by the FDA and EMEA and is expected to significantly improve kidney safety monitoring. PMID:20458318

Reduction in the urinary aflatoxin M1 biomarker as an early indicator of the efficacy of dietary interventions to reduce exposure to aflatoxins.

PubMed

Mitchell, Nicole J; Kumi, Justice; Johnson, Natalie M; Dotse, Eunice; Marroquin-Cardona, Alicia; Wang, Jia-Sheng; Jolly, Pauline E; Ankrah, Nii-Ayi; Phillips, Timothy D

2013-08-01

Aflatoxin B1 is a persistent public health issue in Ghana. Assessment of AFB1 intervention efficacy is currently dependent on long-term biomarkers. This study was designed to determine whether daily AFM1 biomarker levels could be utilized as an early detection method for intervention efficacy. Participants were treated with a refined calcium montmorillonite clay (UPSN) or a placebo (calcium carbonate) in a crossover study. Urine samples were assessed for AFM1 levels daily. UPSN treatment reduced AFM1 biomarkers by 55% compared to the placebo. This is the first study to show that daily urinary AFM1 levels can be used as a biomarker of internal aflatoxin B1 exposure in short-term intervention trials to determine efficacy.

Exposure to organophosphate flame retardants in spray polyurethane foam applicators: Role of dermal exposure.

PubMed

Bello, Anila; Carignan, Courtney C; Xue, Yalong; Stapleton, Heather M; Bello, Dhimiter

2018-04-01

Spray polyurethane foam (SPF) is a highly effective thermal insulation material that has seen considerable market growth in the past decade. Organophosphate flame retardants (PFRs) are added to SPF formulations to meet fire code requirements. A common flame retardant used in SPF formulations is tris 1-chloro 2-propyl phosphate (TCIPP), a suspected endocrine disruptor. Exposure monitoring efforts during SPF applications have focused primarily on the isocyanate component, a potent respiratory and dermal sensitizer. However, to our knowledge, there is no monitoring data for TCIPP. To characterize occupational exposures to TCIPP and other flame retardants during SPF insulation. Workers at four SPF insulation sites and one foam removal site (total n = 14) were recruited as part of this pilot study. Personal inhalation exposure to TCIPP was monitored with a CIP-10MI inhalable sampler and potential dermal exposure was assessed through the use of a glove dosimeter. Biomarkers of TCIPP and three other PFRs were measured in urine collected from workers pre-and post-shift. Linear mixed effect models were used to analyze associations of urinary biomarkers with inhalation and dermal exposures and paired t-tests were used to examine the difference on the means of urinary biomarkers pre-and post-shift. Chemical analysis of all species was performed with liquid chromatography-electrospray ionization tandem mass spectrometry. Geometric mean (GM) concentrations of TCIPP in personal air monitors and glove dosimeters collected from SPF applicators, 294.7 μg/m 3 and 18.8 mg/pair respectively. Overall, GM concentrations of the two TCIPP urinary biomarkers BCIPP and BCIPHIPP and (6.2 and 88.8 μg/mL) were 26-35 times higher than reported in the general population. Post-shift levels of TCIPP biomarkers were higher than pre-shift even though workers at insulation sites wore supplied air respirators, gloves and coveralls. The urinary biomarkers for the other PFRs were not elevated post shift. Concentrations of TCIPP on glove dosimeters were positively associated with post-shift urinary TCIPP biomarkers (p < 0.05) whereas concentrations in personal air samples were not. High levels of urinary biomarkers for TCIPP among SPF applicators, including post-shift, points to absorption of TCIPP during the work shift, in spite of the use of best industry exposure control practices. Dermal exposure appears to be an important, if not the primary exposure pathway for TCIPP, although inhalation or incidental ingestion of foam particles post-SPF application cannot be ruled out in this pilot study. Copyright © 2018 Elsevier Ltd. All rights reserved.

Identification of a sensitive urinary biomarker, selenium-binding protein 1, for early detection of acute kidney injury.

PubMed

Kim, Kyeong Seok; Yang, Hun Yong; Song, Hosup; Kang, Ye Rim; Kwon, JiHoon; An, JiHye; Son, Ji Yeon; Kwack, Seung Jun; Kim, Young-Mi; Bae, Ok-Nam; Ahn, Mee-Young; Lee, Jaewon; Yoon, Sungpil; Lee, Byung Mu; Kim, Hyung Sik

2017-01-01

Acute kidney injury (AKI) is associated with increased mortality rate in patients but clinically available biomarkers for disease detection are currently not available. Recently, a new biomarker, selenium-binding protein 1 (SBP1), was identified for detection of nephrotoxicity using proteomic analysis. The aim of this study was to assess the sensitivity of urinary SBP1 levels as an early detection of AKI using animal models such as cisplatin or ischemia/reperfusion (I/R). Sprague-Dawley rats were injected with cisplatin (6 mg/kg, once i.p.) and sacrificed at 1, 3, or 5 days after treatment. Ischemia was achieved by bilaterally occluding both kidneys with a microvascular clamp for 45 min and verified visually by a change in tissue color. After post-reperfusion, urine samples were collected at 9, 24, and 48 hr intervals. Urinary excretion of protein-based biomarkers was measured by Western blot analysis. In cisplatin-treated rats, mild histopathologic alterations were noted at day 1 which became severe at day 3. Blood urea nitrogen (BUN) and serum creatinine (SCr) levels were significantly increased at day 3. Levels of urinary excretion of SBP1, neutrophil gelatinase-associated lipocalin (NGAL), and a tissue inhibitor of metalloproteinase-1 (TIMP-1) were markedly elevated at day 3 and 5 following drug treatment. In the vehicle-treated I/R group, serum levels of BUN and SCr and AST activity were significantly increased compared to sham. Urinary excretion of SBP1 and NGAL rose markedly following I/R. The urinary levels of SBP1, NGAL, TIMP-1, and KIM-1 proteins excreted by AKI patients and normal subjects were compared. Among these proteins, a marked rise in SBP1 was observed in urine of patients with AKI compared to normal subjects. Based upon receiver-operator curves (ROC), SBP1 displayed a higher area under the curve (AUC) scores than levels of SCr, BUN, total protein, and glucose. In particular, SBP1 protein was readily detected in small amounts of urine without purification. Data thus indicate that urinary excretion of SBP1 may be useful as a reliable biomarker for early diagnosis of AKI in patients.

Carcinogen derived biomarkers: applications in studies of human exposure to secondhand tobacco smoke

PubMed Central

Hecht, S

2004-01-01

Objective: To review the literature on carcinogen derived biomarkers of exposure to secondhand tobacco smoke (SHS). These biomarkers are specifically related to known carcinogens in tobacco smoke and include urinary metabolites, DNA adducts, and blood protein adducts. Method: Published reviews and the current literature were searched for relevant articles. Results: The most consistently elevated biomarker in people exposed to SHS was 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides (NNAL-Gluc), urinary metabolites of the tobacco specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The tobacco specificity of this biomarker as well as its clear relation to an established lung carcinogen are particularly appropriate for its application in studies of SHS exposure. Conclusion: The results of the available carcinogen derived biomarker studies provide biochemical data which support the conclusion, based on epidemiologic investigations, that SHS causes lung cancer in non-smokers. PMID:14985617

Short-term biomarkers of apple consumption.

PubMed

Saenger, Theresa; Hübner, Florian; Humpf, Hans-Ulrich

2017-03-01

Urinary biomarkers are used to estimate the nutritional intake of humans. The aim of this study was to distinguish between low, medium, and high apple consumption by quantifying possible intake biomarkers in urine samples after apple consumption by HPLC-MS/MS. Apples were chosen as they are the most consumed fruits in Germany. Thirty subjects took part in 7-day study. They abstained from apples and apple products except for one weighed apple portion resembling one, two, or four apples. Before apple consumption and during the following days spot urine samples were collected. These urine samples were incubated with β-glucuronidase, diluted, and directly measured by HPLC-MS/MS. Phloretin, epicatechin, procyanidin B2, and quercetin were detected in urine using Scheduled MRM TM mode. Phloretin was confirmed as a urinary biomarker of apple intake and had the ability to discriminate between low or medium (one or two apples) and high apple consumption (four apples). The groups also differ in the excretion of epicatechin and procyanidin B2. Apple consumption can be monitored by urinary biomarkers for a period of at least 12 h after consumption. Furthermore the amount of apples consumed can be estimated by the concentration of certain biomarkers. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Calcium-deficiency assessment and biomarker identification by an integrated urinary metabonomics analysis

PubMed Central

2013-01-01

Background Calcium deficiency is a global public-health problem. Although the initial stage of calcium deficiency can lead to metabolic alterations or potential pathological changes, calcium deficiency is difficult to diagnose accurately. Moreover, the details of the molecular mechanism of calcium deficiency remain somewhat elusive. To accurately assess and provide appropriate nutritional intervention, we carried out a global analysis of metabolic alterations in response to calcium deficiency. Methods The metabolic alterations associated with calcium deficiency were first investigated in a rat model, using urinary metabonomics based on ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry and multivariate statistical analysis. Correlations between dietary calcium intake and the biomarkers identified from the rat model were further analyzed to confirm the potential application of these biomarkers in humans. Results Urinary metabolic-profiling analysis could preliminarily distinguish between calcium-deficient and non-deficient rats after a 2-week low-calcium diet. We established an integrated metabonomics strategy for identifying reliable biomarkers of calcium deficiency using a time-course analysis of discriminating metabolites in a low-calcium diet experiment, repeating the low-calcium diet experiment and performing a calcium-supplement experiment. In total, 27 biomarkers were identified, including glycine, oxoglutaric acid, pyrophosphoric acid, sebacic acid, pseudouridine, indoxyl sulfate, taurine, and phenylacetylglycine. The integrated urinary metabonomics analysis, which combined biomarkers with regular trends of change (types A, B, and C), could accurately assess calcium-deficient rats at different stages and clarify the dynamic pathophysiological changes and molecular mechanism of calcium deficiency in detail. Significant correlations between calcium intake and two biomarkers, pseudouridine (Pearson correlation, r = 0.53, P = 0.0001) and citrate (Pearson correlation, r = -0.43, P = 0.001), were further confirmed in 70 women. Conclusions To our knowledge, this is the first report of reliable biomarkers of calcium deficiency, which were identified using an integrated strategy. The identified biomarkers give new insights into the pathophysiological changes and molecular mechanisms of calcium deficiency. The correlations between calcium intake and two of the biomarkers provide a rationale or potential for further assessment and elucidation of the metabolic responses of calcium deficiency in humans. PMID:23537001

Long-term Stability of Urinary Biomarkers of Acute Kidney Injury in Children.

PubMed

Schuh, Meredith P; Nehus, Edward; Ma, Qing; Haffner, Christopher; Bennett, Michael; Krawczeski, Catherine D; Devarajan, Prasad

2016-01-01

Recent meta-analyses support the utility of urinary biomarkers for the diagnosis and prognosis of acute kidney injury. It is critical to establish optimal sample handling conditions for short-term processing and long-term urinary storage prior to widespread clinical deployment and meaningful use in prospective clinical trials. Prospective study. 80 children (median age, 1.1 [IQR, 0.5-4.2] years) undergoing cardiac surgery with cardiopulmonary bypass at our center. 50% of patients had acute kidney injury (defined as ≥50% increase in serum creatinine from baseline). We tested the effect on biomarker concentrations of short-term urine storage in ambient, refrigerator, and freezer conditions. We also tested the effects of multiple freeze-thaw cycles, as well as prolonged storage for 5 years. Urine concentrations of neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), and interleukin 18 (IL-18). All biomarkers were measured using commercially available kits. All 3 biomarkers were stable in urine stored at 4°C for 24 hours, but showed significant degradation (5.6%-10.1% from baseline) when stored at 25°C. All 3 biomarkers showed only a small although significant decrease in concentration (0.77%-2.9% from baseline) after 3 freeze-thaw cycles. Similarly, all 3 biomarkers displayed only a small but significant decrease in concentration (0.84%-3.2%) after storage for 5 years. Only the 3 most widely studied biomarkers were tested. Protease inhibitors were not evaluated. Short-term storage of urine samples for measurement of NGAL, KIM-1, and IL-18 may be performed at 4°C for up to 24 hours, but not at room temperature. These urinary biomarkers are stable at -80°C for up to 5 years of storage. Our results are reassuring for the deployment of these assays as biomarkers in clinical practice, as well as in prospective clinical studies requiring long-term urine storage. Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Evaluation of novel biomarkers of nephrotoxicity in Cynomolgus monkeys treated with gentamicin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gautier, Jean-Charles, E-mail: jean-charles.gautie

Most studies to evaluate kidney safety biomarkers have been performed in rats. This study was conducted in Cynomolgus monkeys in order to evaluate the potential usefulness of novel biomarkers of nephrotoxicity in this species. Groups of 3 males were given daily intramuscular injections of gentamicin, a nephrotoxic agent known to produce lesions in proximal tubules, at dose-levels of 10, 25, or 50 mg/kg/day for 10 days. Blood and 16-h urine samples were collected on Days − 7, − 3, 2, 4, 7, and at the end of the dosing period. Several novel kidney safety biomarkers were evaluated, with single- andmore » multiplex immunoassays and in immunoprecipitation-LC/MS assays, in parallel to histopathology and conventional clinical pathology parameters. Treatment with gentamicin induced a dose-dependent increase in kidney tubular cell degeneration/necrosis, ranging from minimal to mild severity at 10 mg/kg/day, moderate at 25 mg/kg/day, and to severe at 50 mg/kg/day. The results showed that the novel urinary biomarkers, microalbumin, α1-microglobulin, clusterin, and osteopontin, together with the more traditional clinical pathology parameters, urinary total protein and N-acetyl-β-D-glucosaminidase (NAG), were more sensitive than blood urea nitrogen (BUN) and serum creatinine (sCr) to detect kidney injury in the monkeys given 10 mg/kg/day gentamicin for 10 days, a dose leading to an exposure which is slightly higher than the desired therapeutic exposure in clinics. Therefore, these urinary biomarkers represent non-invasive biomarkers of proximal tubule injury in Cynomolgus monkeys which may be potentially useful in humans. - Highlights: • Gentamicin induced kidney tubular cell degeneration/necrosis in Cynomolgus monkey • Urinary clusterin and osteopontin were sensitive biomarkers of kidney injury. • Microalbumin and α1-microglobulin in urine were also more sensitive than serum creatinine.« less

UPLC-ESI-MS/MS method for the quantitative measurement of aliphatic diamines, trimethylamine N-oxide, and β-methylamino-l-alanine in human urine.

PubMed

Bhandari, Deepak; Bowman, Brett A; Patel, Anish B; Chambers, David M; De Jesús, Víctor R; Blount, Benjamin C

2018-04-15

This work describes a quantitative high-throughput analytical method for the simultaneous measurement of small aliphatic nitrogenous biomarkers, i.e., 1,6-hexamethylenediamine (HDA), isophoronediamine (IPDA), β-methylamino-l-alanine (BMAA), and trimethylamine N-oxide (TMAO), in human urine. Urinary aliphatic diamines, HDA and IPDA, are potential biomarkers of environmental exposure to their corresponding diisocyanates. Urinary BMAA forms as a result of human exposure to blue-green algae contaminated food. And, TMAO is excreted in urine due to the consumption of carnitine- and choline-rich diets. These urinary biomarkers represent classes of small aliphatic nitrogen-containing compounds (N-compounds) that have a high aqueous solubility, low logP, and/or high basic pK a . Because of the highly polar characteristics, analysis of these compounds in complex sample matrices is often challenging. We report on the development of ion-pairing chemistry based ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS) method for the simultaneous measurement of these biomarkers in human urine. Chromatographic separation was optimized using heptafluorobutyric acid-(HFBA-) based mobile phase and a reversed-phase C18 column. All four analytes were baseline separated within 2.6 min with an overall run time of 5 min per sample injection. Sample preparation involved 4 h of acid hydrolysis followed by automated solid phase extraction (SPE) performed using strong cation exchange sorbent bed with 7 N ammonia solution in methanol as eluent. Limits of detection ranged from 0.05 ng/mL to 1.60 ng/mL. The inter-day and intra-day accuracy were within 10%, and reproducibility within 15%. The method is accurate, fast, and well-suited for biomonitoring studies within targeted groups, as well as larger population-based studies such as the U. S. National Health and Nutrition Examination Survey (NHANES). Published by Elsevier B.V.

Integrated exposure assessment of sewage workers to genotoxicants: an urinary biomarker approach and oxidative stress evaluation

PubMed Central

2011-01-01

Background Sewage workers are exposed to multiple chemicals among which many are suspected genotoxicants. Therefore, they might incur DNA damage and oxidative stress. We aimed to explore integrated urinary biomarkers, assessing the overall urine genotoxicity by in vitro comet and micronucleus assays and measuring urinary 8-oxo-2'-deoxyguanosine. Methods During three consecutive working days, polycyclic aromatic hydrocarbons and volatile organic compounds were sampled in workplace air of 34 sewage and 30 office workers, as indicators of airborne exposure. The last day, subjects collected their 24 hours urine. Genotoxicity of urinary extracts was assessed by comet and micronucleus assays on a HepG2 cell line. Using competitive enzymatic immunoassay we evaluated the 24 hours urinary 8-oxo-2'-deoxyguanosine excretion. Benzo(a)pyrene toxicity equivalent factors and inhalation unit risk for Benzo(a)pyrene and benzene were used to give an estimate of cancer risk levels. Results Workplace air concentrations of polycyclic aromatic hydrocarbons (e.g. 23.7 [range 2.4-104.6] ng.m-3 for fluoranthene) and volatile organic compounds (e.g. 19.1 ± 2.9 [standard error] μ.m-3 for benzene) were elevated in sewage compared to office workplaces (P < 0.01) and corresponded to an increased lifetime cancer risk. The urinary extracts of sewage workers showed higher genotoxicity (P < 0.001) than office workers. Conclusions The integrated and non-specific urinary biomarkers of exposure showed that sewage workers experience exposure to mixtures of genotoxicants in the workplace. PMID:21435260

Integrated exposure assessment of sewage workers to genotoxicants: an urinary biomarker approach and oxidative stress evaluation.

PubMed

Al Zabadi, Hamzeh; Ferrari, Luc; Sari-Minodier, Irène; Kerautret, Marie-Aude; Tiberguent, Aziz; Paris, Christophe; Zmirou-Navier, Denis

2011-03-24

Sewage workers are exposed to multiple chemicals among which many are suspected genotoxicants. Therefore, they might incur DNA damage and oxidative stress. We aimed to explore integrated urinary biomarkers, assessing the overall urine genotoxicity by in vitro comet and micronucleus assays and measuring urinary 8-oxo-2'-deoxyguanosine. During three consecutive working days, polycyclic aromatic hydrocarbons and volatile organic compounds were sampled in workplace air of 34 sewage and 30 office workers, as indicators of airborne exposure. The last day, subjects collected their 24 hours urine. Genotoxicity of urinary extracts was assessed by comet and micronucleus assays on a HepG2 cell line. Using competitive enzymatic immunoassay we evaluated the 24 hours urinary 8-oxo-2'-deoxyguanosine excretion. Benzo(a)pyrene toxicity equivalent factors and inhalation unit risk for Benzo(a)pyrene and benzene were used to give an estimate of cancer risk levels. Workplace air concentrations of polycyclic aromatic hydrocarbons (e.g. 23.7 [range 2.4-104.6] ng.m-3 for fluoranthene) and volatile organic compounds (e.g. 19.1 ± 2.9 [standard error] μ.m-3 for benzene) were elevated in sewage compared to office workplaces (P < 0.01) and corresponded to an increased lifetime cancer risk. The urinary extracts of sewage workers showed higher genotoxicity (P < 0.001) than office workers. The integrated and non-specific urinary biomarkers of exposure showed that sewage workers experience exposure to mixtures of genotoxicants in the workplace.

Early urinary biomarkers of acute kidney injury in preterm infants.

PubMed

Hanna, Mina; Brophy, Patrick D; Giannone, Peter J; Joshi, Mandar S; Bauer, John A; RamachandraRao, Satish

2016-08-01

Acute kidney injury (AKI) in the neonatal intensive care setting is multifactorial and is associated with significant morbidity and mortality. This study evaluates the utility of novel urinary biomarkers to predict the development and/or severity AKI in preterm infants. We performed a case-control study on a prospective cohort of preterm infants (<32 wk), to compare seven urine biomarkers between 25 infants with AKI and 20 infants without AKI. Infants with AKI had significantly higher neutrophil gelatinase-associated lipocalin (NGAL) (median, control (CTRL) vs. AKI; 0.598 vs. 4.24 µg/ml; P < 0.0001). In contrast, urinary epidermal growth factor (EGF) levels were significantly lower in infants who developed AKI compared to controls (median, CTRL vs. AKI; 0.016 vs. 0.006 µg/ml; P < 0.001). The area under the curve (AUC) for NGAL for prediction of stage I AKI on the day prior to AKI diagnosis (day-1) was 0.91, and for the prediction of stage II/III, AKI was 0.92. Similarly, urine EGF was a predictor of renal injury on day -1 (AUC: 0.97 for stage I and 0.86 for stage II/III AKI). Urinary biomarkers may be useful to predict AKI development prior to changes in serum creatinine (SCr) in preterm infants.

Biomarkers of early genotoxicity and oxidative stress for occupational risk assessment of exposure to styrene in the fibreglass reinforced plastic industry.

PubMed

Cavallo, Delia; Tranfo, Giovanna; Ursini, Cinzia Lucia; Fresegna, Anna Maria; Ciervo, Aureliano; Maiello, Raffaele; Paci, Enrico; Pigini, Daniela; Gherardi, Monica; Gatto, Maria Pia; Buresti, Giuliana; Iavicoli, Sergio

2018-06-10

This study aimed to identify sensitive and not-invasive biomarkers of early genotoxic/oxidative effect for exposure to styrene in the fibreglass reinforced plastic manufacture. We studied 11 workers of a plastic manufacture using open molding process (A), 16 workers of a manufacture using closed process (B) and 12 controls. We evaluated geno/cytotoxic effects on buccal cells by Buccal Micronucleus Cytome (BMCyt) assay and genotoxic/oxidative effects on lymphocytes by Fpg-comet test. On A workers we also evaluated urinary 8oxoGua, 8oxodGuo and 8oxoGuo to investigate oxidative stress. Personal inhalation exposure to styrene was monitored by passive air sampling and GC/MS. Biological monitoring included urinary metabolites mandelic acid (MA) and phenylglyoxylic acid (PGA). The findings show higher styrene exposure, urinary MA + PGA levels and micronucleus frequency in manufacture A. Higher buccal karyolytic cell frequency vs controls were found in both exposed populations. We found in exposed workers, no induction of direct DNA damage but oxidative DNA damage. Fpg-comet assay and urinary oxidized guanine seem to be sensitive biomarkers of oxidative stress and BMCyt assay a good-not invasive biomarker of cyto-genotoxicity at target organ. The study, although limited by the small number of studied subjects, shows the usefulness of used biomarkers in risk assessment of styrene-exposed workers. Copyright © 2018 Elsevier B.V. All rights reserved.

UroMark-a urinary biomarker assay for the detection of bladder cancer.

PubMed

Feber, Andrew; Dhami, Pawan; Dong, Liqin; de Winter, Patricia; Tan, Wei Shen; Martínez-Fernández, Mónica; Paul, Dirk S; Hynes-Allen, Antony; Rezaee, Sheida; Gurung, Pratik; Rodney, Simon; Mehmood, Ahmed; Villacampa, Felipe; de la Rosa, Federico; Jameson, Charles; Cheng, Kar Keung; Zeegers, Maurice P; Bryan, Richard T; James, Nicholas D; Paramio, Jesus M; Freeman, Alex; Beck, Stephan; Kelly, John D

2017-01-01

Bladder cancer (BC) is one of the most common cancers in the western world and ranks as the most expensive to manage, due to the need for cystoscopic examination. BC shows frequent changes in DNA methylation, and several studies have shown the potential utility of urinary biomarkers by detecting epigenetic alterations in voided urine. The aim of this study is to develop a targeted bisulfite next-generation sequencing assay to diagnose BC from urine with high sensitivity and specificity. We defined a 150 CpG loci biomarker panel from a cohort of 86 muscle-invasive bladder cancers and 30 normal urothelium. Based on this panel, we developed the UroMark assay, a next-generation bisulphite sequencing assay and analysis pipeline for the detection of bladder cancer from urinary sediment DNA. The 150 loci UroMark assay was validated in an independent cohort ( n  = 274, non-cancer ( n  = 167) and bladder cancer ( n  = 107)) voided urine samples with an AUC of 97%. The UroMark classifier sensitivity of 98%, specificity of 97% and NPV of 97% for the detection of primary BC was compared to non-BC urine. Epigenetic urinary biomarkers for detection of BC have the potential to revolutionise the management of this disease. In this proof of concept study, we show the development and utility of a novel high-throughput, next-generation sequencing-based biomarker for the detection of BC-specific epigenetic alterations in urine.

Urinary 3-hydroxypropyl mercapturic acid (3-HPMA) concentrations in dogs with acute spinal cord injury due to intervertebral disc herniation.

PubMed

Sangster, A M; Zheng, L; Bentley, R T; Shi, R; Packer, R A

2017-01-01

The aim of this study was to investigate urinary 3-hydroxypropyl mercapturic acid (3-HPMA), a metabolite of acrolein, as a novel biomarker in acute spinal cord injury (ASCI) due to intervertebral disc herniation in dogs. Urine from 10 client-owned dogs with ASCI collected at presentation and 10 control dogs was analyzed for 3-HPMA. The median urinary 3-HPMA concentration in ASCI dogs was significantly higher than in control dogs, but was not correlated with the severity of ASCI. The median urinary 3-HPMA concentration in intact dogs was higher than in neutered dogs. Higher urinary 3-HPMA concentrations in dogs after ASCI support a role for acrolein, a cytotoxic by-product of lipid peroxidation, in canine ASCI. Urinary 3-HPMA could be used as a biomarker in future clinical trials to measure the effect of therapeutic intervention of reducing acrolein after ASCI. Copyright © 2016. Published by Elsevier Ltd.

Original Research: Potential of urinary nephrin as a biomarker reflecting podocyte dysfunction in various kidney disease models.

PubMed

Wada, Yusuke; Abe, Masaki; Moritani, Hiroshi; Mitori, Hikaru; Kondo, Mitsuhiro; Tanaka-Amino, Keiko; Eguchi, Megumi; Imasato, Akira; Inoki, Yutaka; Kajiyama, Hiroshi; Mimura, Toshihide; Tomura, Yuichi

2016-10-01

Urinary nephrin is a potential non-invasive biomarker of disease. To date, however, most studies of urinary nephrin have been conducted in animal models of diabetic nephropathy, and correlations between urinary nephrin-to-creatinine ratio and other parameters have yet to be evaluated in animal models or patients of kidney disease with podocyte dysfunction. We hypothesized that urinary nephrin-to-creatinine ratio can be up-regulated and is negatively correlated with renal nephrin mRNA levels in animal models of kidney disease, and that increased urinary nephrin-to-creatinine ratio levels are attenuated following administration of glucocorticoids. In the present study, renal nephrin mRNA, urinary nephrin-to-creatinine ratio, urinary protein-to-creatinine ratio, and creatinine clearance ratio were measured in animal models of adriamycin nephropathy, puromycin aminonucleoside nephropathy, anti-glomerular basement membrane glomerulonephritis, and 5/6 nephrectomy. The effects of prednisolone on urinary nephrin-to-creatinine ratio and other parameters in puromycin aminonucleoside (single injection) nephropathy rats were also investigated. In all models tested, urinary nephrin-to-creatinine ratio and urinary protein-to-creatinine ratio increased, while renal nephrin mRNA and creatinine clearance ratio decreased. Urinary nephrin-to-creatinine ratio exhibited a significant negative correlation with renal nephrin mRNA in almost all models, as well as a significant positive correlation with urinary protein-to-creatinine ratio and a significant negative correlation with creatinine clearance ratio. Urinary protein-to-creatinine ratio exhibited a significant negative correlation with renal nephrin mRNA. Following the administration of prednisolone to puromycin aminonucleoside (single injection) nephropathy rats, urinary nephrin-to-creatinine ratio was significantly suppressed and exhibited a significant positive correlation with urinary protein-to-creatinine ratio. In addition, the decrease in number of glomerular Wilms tumor antigen-1-positive cells was attenuated, and urinary nephrin-to-creatinine ratio exhibited a significant negative correlation in these cells. In conclusion, these results suggest that urinary nephrin-to-creatinine ratio level is a useful and reliable biomarker for predicting the amelioration of podocyte dysfunction by candidate drugs in various kidney disease models with podocyte dysfunction. This suggestion will also be validated in a clinical setting in future studies. © 2016 by the Society for Experimental Biology and Medicine.

Urinary Biomarkers of Brain Diseases.

PubMed

An, Manxia; Gao, Youhe

2015-12-01

Biomarkers are the measurable changes associated with a physiological or pathophysiological process. Unlike blood, urine is not subject to homeostatic mechanisms. Therefore, greater fluctuations could occur in urine than in blood, better reflecting the changes in human body. The roadmap of urine biomarker era was proposed. Although urine analysis has been attempted for clinical diagnosis, and urine has been monitored during the progression of many diseases, particularly urinary system diseases, whether urine can reflect brain disease status remains uncertain. As some biomarkers of brain diseases can be detected in the body fluids such as cerebrospinal fluid and blood, there is a possibility that urine also contain biomarkers of brain diseases. This review summarizes the clues of brain diseases reflected in the urine proteome and metabolome. Copyright © 2016 The Authors. Production and hosting by Elsevier Ltd.. All rights reserved.

Polyphenols excreted in urine as biomarkers of total polyphenol intake.

PubMed

Medina-Remón, Alexander; Tresserra-Rimbau, Anna; Arranz, Sara; Estruch, Ramón; Lamuela-Raventos, Rosa M

2012-11-01

Nutritional biomarkers have several advantages in acquiring data for epidemiological and clinical studies over traditional dietary assessment tools, such as food frequency questionnaires. While food frequency questionnaires constitute a subjective methodology, biomarkers can provide a less biased and more accurate measure of specific nutritional intake. A precise estimation of polyphenol consumption requires blood or urine sample biomarkers, although their association is usually highly complex. This article reviews recent research on urinary polyphenols as potential biomarkers of polyphenol intake, focusing on clinical and epidemiological studies. We also report a potentially useful methodology to assess total polyphenols in urine samples, which allows a rapid, simultaneous determination of total phenols in a large number of samples. This methodology can be applied in studies evaluating the utility of urinary polyphenols as markers of polyphenol intake, bioavailability and accumulation in the body.

Salivary and Urinary Total Antioxidant Capacity as Biomarkers of Oxidative Stress in Humans

PubMed Central

Peluso, Ilaria; Raguzzini, Anna

2016-01-01

Total Antioxidant Capacity (TAC) is a biomarker often used in order to investigate oxidative stress in many pathological conditions. Saliva and urine can be collected noninvasively and represent attractive diagnostic fluids for detecting biomarkers of various pathological conditions. The reviewed case-control and intervention studies that measured salivary or urinary TAC revealed that diseases, antioxidant foods, or supplements and age, gender, and lifestyle factors influenced salivary or urinary TAC. Salivary and urinary TAC were particularly affected by oral or renal status, respectively, as well as by infection; therefore these factors must be taken into account in both case-control and intervention studies. Furthermore, some considerations on sample collection and normalization strategies could be made. In particular, unstimulated saliva could be the better approach to measure salivary TAC, whereas 24 h or spontaneous urine collection should be chosen on the basis of the study outcome and of the creatinine clearance. Finally, the uric acid-independent TAC could be the better approach to evaluate red-ox status of body, in particular after nutritional interventions and in diseases associated with hyperuricaemia. PMID:26966611

EVALUATION AND COMPARISON OF URINARY METABOLIC BIOMARKERS OF EXPOSURE FOR THE JET FUEL JP-8

PubMed Central

B’Hymer, Clayton; Krieg, Edward; Cheever, Kenneth L.; Toennis, Christine A.; Clark, John C.; Kesner, James S.; Gibson, Roger; Butler, Mary Ann

2015-01-01

A study of workers exposed to jet fuel propellant 8 (JP-8) was conducted at U.S. Air Force bases and included the evaluation of three biomarkers of exposure: S-benzylmercapturic acid (BMA), S-phenylmercapturic acid (PMA), and (2-methoxyethoxy)acetic acid (MEAA). Postshift urine specimens were collected from various personnel categorized as high (n = 98), moderate (n = 38) and low (n = 61) JP-8 exposure based on work activities. BMA and PMA urinary levels were determined by high-performance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS), and MEAA urinary levels were determined by gas chromatography–mass spectrometry (GC-MS). The numbers of samples determined as positive for the presence of the BMA biomarker (above the test method’s limit of detection [LOD = 0.5 ng/ml]) were 96 (98.0%), 37 (97.4%), and 58 (95.1%) for the high, moderate, and low (control) exposure workgroup categories, respectively. The numbers of samples determined as positive for the presence of the PMA biomarker (LOD = 0.5 ng/ml) were 33 (33.7%), 9 (23.7%), and 12 (19.7%) for the high, moderate, and low exposure categories. The numbers of samples determined as positive for the presence of the MEAA biomarker (LOD = 0.1 μg/ml) were 92 (93.4%), 13 (34.2%), and 2 (3.3%) for the high, moderate, and low exposure categories. Statistical analysis of the mean levels of the analytes demonstrated MEAA to be the most accurate or appropriate biomarker for JP-8 exposure using urinary concentrations either adjusted or not adjusted for creatinine; mean levels of BMA and PMA were not statistically significant between workgroup categories after adjusting for creatinine. PMID:22712851

Evaluation and comparison of urinary metabolic biomarkers of exposure for the jet fuel JP-8.

PubMed

B'Hymer, Clayton; Krieg, Edward; Cheever, Kenneth L; Toennis, Christine A; Clark, John C; Kesner, James S; Gibson, Roger; Butler, Mary Ann

2012-01-01

A study of workers exposed to jet fuel propellant 8 (JP-8) was conducted at U.S. Air Force bases and included the evaluation of three biomarkers of exposure: S-benzylmercapturic acid (BMA), S-phenylmercapturic acid (PMA), and (2-methoxyethoxy)acetic acid (MEAA). Postshift urine specimens were collected from various personnel categorized as high (n = 98), moderate (n = 38) and low (n = 61) JP-8 exposure based on work activities. BMA and PMA urinary levels were determined by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), and MEAA urinary levels were determined by gas chromatography-mass spectrometry (GC-MS). The numbers of samples determined as positive for the presence of the BMA biomarker (above the test method's limit of detection [LOD = 0.5 ng/ml]) were 96 (98.0%), 37 (97.4%), and 58 (95.1%) for the high, moderate, and low (control) exposure workgroup categories, respectively. The numbers of samples determined as positive for the presence of the PMA biomarker (LOD = 0.5 ng/ml) were 33 (33.7%), 9 (23.7%), and 12 (19.7%) for the high, moderate, and low exposure categories. The numbers of samples determined as positive for the presence of the MEAA biomarker (LOD = 0.1 μ g/ml) were 92 (93.4%), 13 (34.2%), and 2 (3.3%) for the high, moderate, and low exposure categories. Statistical analysis of the mean levels of the analytes demonstrated MEAA to be the most accurate or appropriate biomarker for JP-8 exposure using urinary concentrations either adjusted or not adjusted for creatinine; mean levels of BMA and PMA were not statistically significant between workgroup categories after adjusting for creatinine.

Selenium-binding protein 1: a sensitive urinary biomarker to detect heavy metal-induced nephrotoxicity.

PubMed

Lee, Eui Kyung; Shin, Young-Jun; Park, Eun Young; Kim, Nam Deuk; Moon, Aree; Kwack, Seung Jun; Son, Ji Yeon; Kacew, Sam; Lee, Byung Mu; Bae, Ok-Nam; Kim, Hyung Sik

2017-04-01

Identifying novel biomarkers to detect nephrotoxicity is clinically important. Here, we attempted to identify new biomarkers for mercury-induced nephrotoxicity and compared their sensitivity to that of traditional biomarkers in animal models. Comparative proteomics analysis was performed in kidney tissues of Sprague-Dawley rats after oral treatment with HgCl 2 (0.1, 1, or 5 mg/kg/day) for 21 days. Kidney cortex tissues were analyzed by two-dimensional gel electrophoresis/matrix-assisted laser desorption/ionization, and differentially expressed proteins were identified. The corresponding spots were quantitated by RT-PCR. Selenium-binding protein 1 (SBP1) was found to be the most markedly upregulated protein in the kidney cortex of rats after HgCl 2 administration. However, blood urea nitrogen, serum creatinine, and glucose levels increased significantly only in the 1 or 5 mg/kg HgCl 2 -treated groups. A number of urinary excretion proteins, including kidney injury molecule-1, clusterin, monocyte chemoattractant protein-1, and β-microglobulin, increased dose-dependently. Histopathological examination revealed severe proximal tubular damage in high-dose (5 mg/kg) HgCl 2 -exposed groups. In addition, urinary excretion of SBP1 significantly increased in a dose-dependent manner. To confirm the critical role of SBP1 as a biomarker for nephrotoxicity, normal kidney proximal tubular cells were treated with HgCl 2 , CdCl 2 , or cisplatin for 24 h. SBP1 levels significantly increased in conditioned media exposed to nephrotoxicants, but decreased in cell lysates. Our investigations suggest that SBP1 may play a critical role in the pathological processes underlying chemical-induced nephrotoxicity. Thus, urinary excretion of SBP1 might be a sensitive and specific biomarker to detect early stages of kidney injury.

Is Urinary Cadmium a Biomarker of Long-term Exposure in Humans? A Review

PubMed Central

Kruse, Danielle; Harrington, James; Levine, Keith; Meliker, Jaymie R.

2017-01-01

Cadmium is a naturally-occurring element, and humans are exposed from cigarettes, food, and industrial sources. Following exposure, cadmium accumulates in the kidney and is slowly released into the urine, usually proportionally to the levels found in the kidneys. Cadmium levels in a single spot urine sample have been considered indicative of long-term exposure to cadmium; however, such a potentially exceptional biomarker requires careful scrutiny. In this review, we report good to excellent temporal stability of urinary cadmium (intraclass correlation coefficient 0.66–0.81) regardless of spot urine or first morning void sampling. Factors such as changes in smoking habits and diseases characterized by increased excretion of proteins may produce short-term changes in urinary cadmium levels. We recommend that epidemiologists use this powerful biomarker in prospective studies stratified by smoking status, along with thoughtful consideration of additional factors that can influence renal physiology and cadmium excretion. PMID:27696280

Promising molecular targets and biomarkers for male BPH and LUTS.

PubMed

Gharaee-Kermani, Mehrnaz; Macoska, Jill A

2013-12-01

Benign prostatic hyperplasia (BPH) is a major health concern for aging men. BPH is associated with urinary voiding dysfunction and lower urinary tract symptoms (LUTS), which negatively affects quality of life. Surgical resection and medical approaches have proven effective for improving urinary flow and relieving LUTS but are not effective for all men and can produce adverse effects that require termination of the therapeutic regimen. Thus, there is a need to explore other therapeutic targets to treat BPH/LUTS. Complicating the treatment of BPH/LUTS is the lack of biomarkers to effectively identify pathobiologies contributing to BPH/LUTS or to gauge successful response to therapy. This review will briefly discuss current knowledge and will highlight new studies that illuminate the pathobiologies contributing to BPH/LUTS, potential new therapeutic strategies for successfully treating BPH/LUTS, and new approaches for better defining these pathobiologies and response to therapeutics through the development of biomarkers and phenotyping strategies.

Podocyturia parallels proximal tubule dysfunction in type 2 diabetes mellitus patients independently of albuminuria and renal function decline: A cross-sectional study.

PubMed

Petrica, Ligia; Vlad, Mihaela; Vlad, Adrian; Gluhovschi, Gheorghe; Gadalean, Florica; Dumitrascu, Victor; Popescu, Roxana; Gluhovschi, Cristina; Matusz, Petru; Velciov, Silvia; Bob, Flaviu; Ursoniu, Sorin; Vlad, Daliborca

2017-09-01

Detection of podocytes in the urine of patients with type 2 diabetes may indicate severe injury to the podocytes. In the course of type 2 diabetes the proximal tubule is involved in urinary albumin processing. We studied the significance of podocyturia in relation with proximal tubule dysfunction in type 2 diabetes. A total of 86 patients with type 2 diabetes (34-normoalbuminuria; 30-microalbuminuria; 22-macroalbuminuria) and 28 healthy subjects were enrolled in the study and assessed concerning urinary podocytes, podocyte-associated molecules, and biomarkers of proximal tubule dysfunction. Urinary podocytes were examined in cell cultures by utilizing monoclonal antibodies against podocalyxin and synaptopodin. Podocytes were detected in the urine of 10% of the healthy controls, 24% of the normoalbuminuric, 40% of the microalbuminuric, and 82% of the macroalbuminuric patients. In multivariate logistic regression analysis, urinary podocytes correlated with urinary albumin:creatinine ratio (p=0.006), urinary nephrin/creat (p=0.001), urinary vascular endothelial growth factor/creat (p=0.001), urinary kidney injury molecule-1/creat (p=0.003), cystatin C (p=0.001), urinary advanced glycation end-products (p=0.002), eGFR (p=0.001). In patients with type 2 diabetes podocyturia parallels proximal tubule dysfunction independently of albuminuria and renal function decline. Advanced glycation end-products may impact the podocytes and the proximal tubule. Copyright © 2017 Elsevier Inc. All rights reserved.

Identifying Urinary and Serum Exosome Biomarkers for Radiation Exposure Using a Data Dependent Acquisition and SWATH-MS Combined Workflow.

PubMed

Kulkarni, Shilpa; Koller, Antonius; Mani, Kartik M; Wen, Ruofeng; Alfieri, Alan; Saha, Subhrajit; Wang, Jian; Patel, Purvi; Bandeira, Nuno; Guha, Chandan; Chen, Emily I

2016-11-01

Early and accurate assessment of radiation injury by radiation-responsive biomarkers is critical for triage and early intervention. Biofluids such as urine and serum are convenient for such analysis. Recent research has also suggested that exosomes are a reliable source of biomarkers in disease progression. In the present study, we analyzed total urine proteome and exosomes isolated from urine or serum for potential biomarkers of acute and persistent radiation injury in mice exposed to lethal whole body irradiation (WBI). For feasibility studies, the mice were irradiated at 10.4 Gy WBI, and urine and serum samples were collected 24 and 72 hours after irradiation. Exosomes were isolated and analyzed using liquid chromatography mass spectrometry/mass spectrometry-based workflow for radiation exposure signatures. A data dependent acquisition and SWATH-MS combined workflow approach was used to identify significantly exosome biomarkers indicative of acute or persistent radiation-induced responses. For the validation studies, mice were exposed to 3, 6, 8, or 10 Gy WBI, and samples were analyzed for comparison. A comparison between total urine proteomics and urine exosome proteomics demonstrated that exosome proteomic analysis was superior in identifying radiation signatures. Feasibility studies identified 23 biomarkers from urine and 24 biomarkers from serum exosomes after WBI. Urinary exosome signatures identified different physiological parameters than the ones obtained in serum exosomes. Exosome signatures from urine indicated injury to the liver, gastrointestinal, and genitourinary tracts. In contrast, serum showed vascular injuries and acute inflammation in response to radiation. Selected urinary exosomal biomarkers also showed changes at lower radiation doses in validation studies. Exosome proteomics revealed radiation- and time-dependent protein signatures after WBI. A total of 47 differentially secreted proteins were identified in urinary and serum exosomes. Together, these data showed the feasibility of defining biomarkers that could elucidate tissue-associated and systemic response caused by high-dose ionizing radiation. This is the first report using an exosome proteomics approach to identify radiation signatures. Copyright © 2016 Elsevier Inc. All rights reserved.

Identifying Urinary and Serum Exosome Biomarkers for Radiation Exposure Using a Data Dependent Acquisition and SWATH-MS Combined Workflow

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kulkarni, Shilpa; Koller, Antonius; Proteomics Shared Resource, Herbert Irving Comprehensive Cancer Center, New York, New York

Purpose: Early and accurate assessment of radiation injury by radiation-responsive biomarkers is critical for triage and early intervention. Biofluids such as urine and serum are convenient for such analysis. Recent research has also suggested that exosomes are a reliable source of biomarkers in disease progression. In the present study, we analyzed total urine proteome and exosomes isolated from urine or serum for potential biomarkers of acute and persistent radiation injury in mice exposed to lethal whole body irradiation (WBI). Methods and Materials: For feasibility studies, the mice were irradiated at 10.4 Gy WBI, and urine and serum samples were collected 24more » and 72 hours after irradiation. Exosomes were isolated and analyzed using liquid chromatography mass spectrometry/mass spectrometry-based workflow for radiation exposure signatures. A data dependent acquisition and SWATH-MS combined workflow approach was used to identify significantly exosome biomarkers indicative of acute or persistent radiation-induced responses. For the validation studies, mice were exposed to 3, 6, 8, or 10 Gy WBI, and samples were analyzed for comparison. Results: A comparison between total urine proteomics and urine exosome proteomics demonstrated that exosome proteomic analysis was superior in identifying radiation signatures. Feasibility studies identified 23 biomarkers from urine and 24 biomarkers from serum exosomes after WBI. Urinary exosome signatures identified different physiological parameters than the ones obtained in serum exosomes. Exosome signatures from urine indicated injury to the liver, gastrointestinal, and genitourinary tracts. In contrast, serum showed vascular injuries and acute inflammation in response to radiation. Selected urinary exosomal biomarkers also showed changes at lower radiation doses in validation studies. Conclusions: Exosome proteomics revealed radiation- and time-dependent protein signatures after WBI. A total of 47 differentially secreted proteins were identified in urinary and serum exosomes. Together, these data showed the feasibility of defining biomarkers that could elucidate tissue-associated and systemic response caused by high-dose ionizing radiation. This is the first report using an exosome proteomics approach to identify radiation signatures.« less

Repulsive guidance cue semaphorin 3A in urine predicts the progression of acute kidney injury in adult patients from a mixed intensive care unit.

PubMed

Doi, Kent; Noiri, Eisei; Nangaku, Masaomi; Yahagi, Naoki; Jayakumar, Calpurnia; Ramesh, Ganesan

2014-01-01

Predicting the development of acute kidney injury (AKI) in the critical care setting is challenging. Although several biomarkers showed somewhat satisfactory performance for detecting established AKI even in a heterogeneous disease-oriented population, identification of new biomarkers that predict the development of AKI accurately is urgently required. A single-center prospective observational cohort study was undertaken to evaluate for the first time the reliability of the newly identified biomarker semaphorin 3A for AKI diagnosis in heterogeneous intensive care unit populations. In addition to five urinary biomarkers of L-type fatty acid-binding protein (L-FABP), neutrophil gelatinase-associated lipocalin (NGAL), IL-18, albumin and N-acetyl-β-d-glucosaminidase (NAG), urinary semaphorin 3A was measured at intensive care unit (ICU) admission. Three hundred thirty-nine critically ill adult patients were recruited for this study. Among them, 131 patients (39%) were diagnosed with AKI by the RIFLE criteria and 66 patients were diagnosed as AKI at post-ICU admission (later-onset AKI). Eighty-four AKI patients showed worsening severity during 1 week observation (AKI progression). Although L-FABP, NGAL and IL-18 showed significantly higher area under the curve (AUC)-receiver operating characteristic (ROC) values than semaphorin 3A in detecting established AKI, semaphorin 3A was able to detect later-onset AKI and AKI progression with similar AUC-ROC values compared with the other five biomarkers [AUC-ROC (95% CI) for established AKI 0.64 (0.56-0.71), later-onset AKI 0.71 (0.64-0.78), AKI progression 0.71 (0.64-0.77)]. Urinary semaphorin 3A was not increased in non-progressive established AKI, while the other biomarkers were elevated regardless of further progression. Finally, sepsis did not have any impact on semaphorin 3A while the other urinary biomarkers were increased with sepsis. Semaphorin 3A is a new biomarker of AKI which may have a distinct predictive use for AKI progression when compared with other AKI biomarkers.

Radiation Metabolomics. 4. UPLC-ESI-QTOFMS-Based Metabolomics for Urinary Biomarker Discovery in Gamma-Irradiated Rats

PubMed Central

Johnson, Caroline H.; Patterson, Andrew D.; Krausz, Kristopher W.; Lanz, Christian; Kang, Dong Wook; Luecke, Hans; Gonzalez, Frank J.; Idle, Jeffrey R.

2011-01-01

Radiation metabolomics has aided in the identification of a number of biomarkers in cells and mice by ultra-performance liquid chromatography-coupled time-of-flight mass spectrometry (UPLC-ESI-QTOFMS) and in rats by gas chromatography-coupled mass spectrometry (GCMS). These markers have been shown to be both dose- and time-dependent. Here UPLC-ESI-QTOFMS was used to analyze rat urine samples taken from 12 rats over 7 days; they were either sham-irradiated or γ-irradiated with 3 Gy after 4 days of metabolic cage acclimatization. Using multivariate data analysis, nine urinary biomarkers of γ radiation in rats were identified, including a novel mammalian metabolite, N-acetyltaurine. These upregulated urinary biomarkers were confirmed through tandem mass spectrometry and comparisons with authentic standards. They include thymidine, 2′-deoxyuridine, 2′deoxyxanthosine, N1-acetylspermidine, N-acetylglucosamine/galactosamine-6-sulfate, N-acetyltaurine, N-hexanoylglycine, taurine and, tentatively, isethionic acid. Of these metabolites, 2′-deoxyuridine and thymidine were previously identified in the rat by GCMS (observed as uridine and thymine) and in the mouse by UPLC-ESI-QTOFMS. 2′Deoxyxanthosine, taurine and N-hexanoylglycine were also seen in the mouse by UPLC-ESI-QTOFMS. These are now unequivocal cross-species biomarkers for ionizing radiation exposure. Downregulated biomarkers were shown to be related to food deprivation and starvation mechanisms. The UPLC-ESI-QTOFMS approach has aided in the advance for finding common biomarkers of ionizing radiation exposure. PMID:21309707

Urinary isoflavonoid excretion as a biomarker of dietary soy intake during two randomized soy trials

PubMed Central

Morimoto, Yukiko; Beckford, Fanchon; Franke, Adrian A.; Maskarinec, Gertraud

2014-01-01

We evaluated urinary isoflavonoid excretion as a biomarker of dietary isoflavone intake during two randomized soy trials (13–24 months) among 256 premenopausal women with a total of 1,385 repeated urine samples. Participants consumed a high-soy diet (2 servings/day) and a low-soy diet (<3 servings/week), completed 7 unannounced 24-hour dietary recalls, and donated repeated urine samples, which were analyzed for isoflavonoid excretion by liquid chromatography methods. We computed correlation coefficients and applied logistic regression to estimate the area under the curve. Median daily dietary isoflavone intakes at baseline, during low- and high-soy diet were 0.5, 0.2, and 67.7 mg aglycone equivalents, respectively. The corresponding urinary isoflavonoid excretion values were 0.9, 1.1, and 43.9 nmol/mg creatinine. Across diets, urinary isoflavonoid excretion was significantly associated with dietary isoflavone intake (rs=0.51, AUC=0.85; p<0.0001) but not within diet periods (rs=0.05–0.06, AUC=0.565–0.573). Urinary isoflavonoid excretion is an excellent biomarker to discriminate between low- and high-soy diets across populations, but the association with dietary isoflavone intake is weak when the range of soy intake is small. PMID:24901088

COMPARISON OF THE URINARY METABOLITES OF RATS, MICE, AND HUMANS AFTER ORAL ARSENIC EXPOSURE FOCUSING ON THIOARSENICALS

EPA Science Inventory

Urinary metabolites of arsenic are useful as biomarkers of exposure because ingested arsenic is excreted primarily in urine1. Complete urinary arsenic speciation can provide insight into possible metabolic pathways as well as potential exposure sources. The pattern of excreted me...

Evaluation of urinary speciated arsenic in NHANES: Issues in interpretation in the context of potential inorganic arsenic exposure

EPA Science Inventory

Urinary dimethylarsinic acid (DMA) and monomethylarsonic acid (MMA) are among the commonly used biomarkers for inorganic arsenic (iAs) exposure, but may also arise from seafood consumption and organoarsenical pesticide applications. We examined speciated urinary arsenic data from...

Performance of urinary and gene expression biomarkers in detecting the nephrotoxic effects of melamine and cyanuric acid following diverse scenarios of co-exposure

PubMed Central

Bandele, Omari; Camacho, Luísa; Ferguson, Martine; Reimschuessel, Renate; Stine, Cynthia; Black, Thomas; Olejnik, Nicholas; Keltner, Zachary; Scott, Michael; Gamboa da Costa, Gonçalo; Sprando, Robert

2013-01-01

Although standard nephrotoxicity assessments primarily detect impaired renal function, KIM-1, clusterin, NGAL, osteopontin and TIMP-1 were recently identified biomarkers proposed to indicate earlier perturbations in renal integrity. The recent adulteration of infant and pet food with melamine (MEL) and structurally-related compounds revealed that co-ingestion of MEL and cyanuric acid (CYA) could form melamine–cyanurate crystals which obstruct renal tubules and induce acute renal failure. This study concurrently evaluated the ability of multiplexed urinary biomarker immunoassays and biomarker gene expression analysis to detect nephrotoxicity in F344 rats co-administered 60 ppm each of MEL and CYA in feed or via gavage for 28 days. The biomarkers were also evaluated for the ability to differentiate the effects of the compounds when co-administered using diverse dosing schedules (i.e., consecutive vs. staggered gavage) and dosing matrixes (i.e., feed vs. gavage). Our results illustrate the ability of both methods to detect and differentiate the severity of adverse effects in the staggered and consecutive gavage groups at much lower doses than previously observed in animals co-exposed to the compounds in feed. We also demonstrate that these urinary biomarkers outperform traditional diagnostic methods and represent a powerful, non-invasive indicator of chemical-induced nephrotoxicity prior to the onset of renal dysfunction. PMID:23022069

MGMT hypomethylation is associated with DNA damage in workers exposed to low-dose benzene.

PubMed

Li, Jie; Zhang, Xinjie; He, Zhini; Sun, Qing; Qin, Fei; Huang, Zhenlie; Zhang, Xiao; Sun, Xin; Liu, Linhua; Chen, Liping; Gao, Chen; Wang, Shan; Wang, Fangping; Li, Daochuan; Zeng, Xiaowen; Deng, Qifei; Wang, Qing; Zhang, Bo; Tang, Huanwen; Chen, Wen; Xiao, Yongmei

2017-07-01

This study aims to assess the effects of low-dose benzene on DNA damage and O 6 -methylguanine-DNA methyltransferase (MGMT) methylation in occupational workers. We recruited 96 nonsmoking male petrochemical industry workers exposed to low-dose benzene and 100 matched control workers. Urinary S-phenylmercapturic acid (SPMA) and S-benzylmercapturic acid (SBMA) were measured for indicating internal exposure of benzene and toluene. The degree of DNA damage was determined by the Comet assay. The levels of MGMT methylation were detected quantitatively by bisulphite-PCR pyrosequencing assay. The benzene-exposed workers had significantly higher levels of urinary SPMA, degree of DNA damage but decreased MGMT methylation than the controls (all p < 0.05). In contrast, the level of urinary SBMA does not differ between benzene-exposed workers and the controls. In all participants, MGMT methylation was negatively associated with the urinary SPMA and the degree of DNA damage, indicating that epigenetic regulation might be involved in response to low-dose benzene exposure-induced genetic damage. MGMT methylation could be a potent biomarker associated with low-dose benzene exposure and benzene-induced DNA damage.

INTERPRETATION OF BENZENE URINARY BIOMARKER DATA FOR RISK ASSESSMENT: A CASE STUDY

EPA Science Inventory

Human biomonitoring is an effective tool in assessing exposure to hundreds of chemicals. Too often, however, biomarkers such as parent or metabolite concentrations in blood or urine are reported without information on doses associated with the biomarkers and implications for hum...

Environmental Chemicals in Urine and Blood: Improving Methods for Creatinine and Lipid Adjustment.

PubMed

O'Brien, Katie M; Upson, Kristen; Cook, Nancy R; Weinberg, Clarice R

2016-02-01

Investigators measuring exposure biomarkers in urine typically adjust for creatinine to account for dilution-dependent sample variation in urine concentrations. Similarly, it is standard to adjust for serum lipids when measuring lipophilic chemicals in serum. However, there is controversy regarding the best approach, and existing methods may not effectively correct for measurement error. We compared adjustment methods, including novel approaches, using simulated case-control data. Using a directed acyclic graph framework, we defined six causal scenarios for epidemiologic studies of environmental chemicals measured in urine or serum. The scenarios include variables known to influence creatinine (e.g., age and hydration) or serum lipid levels (e.g., body mass index and recent fat intake). Over a range of true effect sizes, we analyzed each scenario using seven adjustment approaches and estimated the corresponding bias and confidence interval coverage across 1,000 simulated studies. For urinary biomarker measurements, our novel method, which incorporates both covariate-adjusted standardization and the inclusion of creatinine as a covariate in the regression model, had low bias and possessed 95% confidence interval coverage of nearly 95% for most simulated scenarios. For serum biomarker measurements, a similar approach involving standardization plus serum lipid level adjustment generally performed well. To control measurement error bias caused by variations in serum lipids or by urinary diluteness, we recommend improved methods for standardizing exposure concentrations across individuals.

Detection of urinary biomarkers for early diagnosis of acute renal allograft rejection by proteomic analysis.

PubMed

Jia, Xiongfei; Gan, Chengjun; Xiao, Ke; He, Weifeng; Zhang, Tao; Huang, Cibing; Wu, Xiongfei; Luo, Gaoxing; Wang, Xiaojuan; Hu, Jie; Tan, Jiangling; Zhang, Xiaorong; Larsen, Peter Mose; Wu, Jun

2009-06-01

Acute allograft rejection has been recognized as a major impediment to improved success in renal transplantation. Timely detection and control of rejection are very important for the improvement in long-term renal allograft survival. Thus, biomarkers for early diagnosis of acute rejection are required urgently to clinical medication. This study seeks to search for such biomarker candidates by comparing patients' pre-treatment urinary protein profiling with their post-treatment urinary protein profiling. A total of 15 significantly and consistently down-regulated protein candidates were identified. Among them, alpha-1-antichymotrypsin precursor (AACT), tumor rejection antigen gp96 (GP96) and Zn-Alpha-2-Glycoprotein (ZAG) were selected for further analysis. The results indicated that Western Blot assay of AACT, GP96 and ZAG had advanced the diagnosis time of acute renal rejection by 3 days, compared with current standard clinical observation and laboratory examination. Furthermore, the double-blind detection revealed that the accuracy, sensitivity and specificity of the diagnosis of acute renal rejection of AACT, GP96 and ZAG were 66.67%/100%/60%, 83.33%/100%/80% and 66.67%/100%/60%, respectively, and 100%/100%/100% in combination. In conclusion, urinary protein AACT, GP96 and ZAG could be a set of potential biomarkers for early non-invasive diagnosis of the acute rejection after renal transplantation. Copyright © 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A Systematic Review of the Diagnostic and Prognostic Value of Urinary Protein Biomarkers in Urothelial Bladder Cancer

PubMed Central

D’Costa, Jamie J.; Goldsmith, James C.; Wilson, Jayne S.; Bryan, Richard T.; Ward, Douglas G.

2016-01-01

For over 80 years, cystoscopy has remained the gold-standard for detecting tumours of the urinary bladder. Since bladder tumours have a tendency to recur and progress, many patients are subjected to repeated cystoscopies during long-term surveillance, with the procedure being both unpleasant for the patient and expensive for healthcare providers. The identification and validation of bladder tumour specific molecular markers in urine could enable tumour detection and reduce reliance on cystoscopy, and numerous classes of biomarkers have been studied. Proteins represent the most intensively studied class of biomolecule in this setting. As an aid to researchers searching for better urinary biomarkers, we report a comprehensive systematic review of the literature and a searchable database of proteins that have been investigated to date. Our objective was to classify these proteins as: 1) those with robustly characterised sensitivity and specificity for bladder cancer detection; 2) those that show potential but further investigation is required; 3) those unlikely to warrant further investigation; and 4) those investigated as prognostic markers. This work should help to prioritise certain biomarkers for rigorous validation, whilst preventing wasted effort on proteins that have shown no association whatsoever with the disease, or only modest biomarker performance despite large-scale efforts at validation. PMID:27500198

Urinary angiostatin, CXCL4 and VCAM-1 as biomarkers of lupus nephritis.

PubMed

Mok, Chi Chiu; Soliman, Samar; Ho, Ling Yin; Mohamed, Fatma A; Mohamed, Faten Ismail; Mohan, Chandra

2018-01-11

The aim was to study urinary angiostatin, CXC chemokine ligand 4 (CXCL4) and vascular cell adhesion molecule-1 (VCAM-1) as biomarkers of renal disease in systemic lupus erythematosus (SLE). Patients who fulfilled ≥ 4 American College of Rheumatology (ACR) criteria for SLE with active renal, active non-renal or inactive disease, and a group of healthy controls were studied. Urine samples were assayed for angiostatin, CXCL4 and VCAM-1 by ELISA, and normalized by creatinine. Receiver operating characteristic analysis was performed to obtain the best cutoff values to calculate the performance of these markers in differentiating the different groups of patients as compared to anti-double-stranded DNA (anti-dsDNA) and complement C3. Correlation between these urinary biomarkers and various renal parameters was also tested. Patients with SLE (n = 227; 80 with inactive SLE, 67 with active non-renal disease and 80 with active renal disease; 94% women; age 39.2 ± 13.8 years) and 53 controls (96% women) were studied. All were ethnic Chinese. Urinary angiostatin, CXCL4 and VCAM-1 (normalized for creatinine) were significantly higher in patients with active renal disease than in patients with active non-renal disease, patients with inactive SLE and controls. These markers correlated significantly with total SLE disease activity index (SLEDAI) and renal SLEDAI scores, and with the urinary protein-to-creatinine ratio. Urine angiostatin exhibited higher specificity and sensitivity in differentiating active renal from active non-renal SLE (area under the curve (AUC) 0.87) than serum anti-dsDNA/C3. Urine CXCL4 (AUC 0.64) and VCAM-1 (AUC 0.73), on the other hand, performed similarly to anti-dsDNA/C3. All three markers performed comparably to anti-dsDNA/C3 in distinguishing active from inactive SLE. In a subgroup of 68 patients with paired renal biopsy, the urinary levels of these proteins did not differ significantly between the proliferative and non-proliferative types of lupus nephritis. Urinary CXCL4 and VCAM-1 correlated significantly with the histologic activity score, and urinary angiostatin correlated significantly with proteinuria in this subgroup. Urinary angiostatin, CXCL4 and VCAM-1 are potential biomarkers for SLE, in particular lupus nephritis. Further longitudinal studies are necessary to delineate the performance of these markers in predicting renal flares and prognosis in SLE patients.

Urinary microRNAs as potential biomarkers of pesticide exposure

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weldon, Brittany A.; Shubin, Sara Pacheco; Smith,

MicroRNAs (miRNAs) are post-transcriptional regulators that silence messenger RNAs. Because miRNAs are stable at room temperature and long-lived, they have been proposed as molecular biomarkers to monitor disease and exposure status. While urinary miRNAs have been used clinically as potential diagnostic markers for kidney and bladder cancers and other diseases, their utility in non-clinical settings has yet to be fully developed. Our goal was to investigate the potential for urinary miRNAs to act as biomarkers of pesticide exposure and early biological response by identifying the miRNAs present in urine from 27 parent/child, farmworker/non-farmworker pairs (16FW/11NFW) collected during two agricultural seasonsmore » (thinning and post-harvest) and characterizing the between- and within-individual variability of these miRNA epigenetic regulators. MiRNAs were isolated from archived urine samples and identified using PCR arrays. Comparisons were made between age, households, season, and occupation. Of 384 miRNAs investigated, 297 (77%) were detectable in at least one sample. Seven miRNAs were detected in at least 50% of the samples, and one miRNA was present in 96% of the samples. Principal components and hierarchical clustering analyses indicate significant differences in miRNA profiles between farmworker and non-farmworker adults as well as between seasons. Six miRNAs were observed to be positively associated with farmworkers status during the post-harvest season. Expression of five of these miRNA trended towards a positive dose response relationship with organophosphate pesticide metabolites in farmworkers. These results suggest that miRNAs may be novel biomarkers of pesticide exposure and early biological response. - Highlights: • A novel method to identify microRNA biomarkers in urinary samples is proposed. • Six miRNAs have been identified as associated with occupational farm work and pesticide exposure. • An observed seasonal difference suggests transient characteristics of urinary miRNAs.« less

Reproducibility of urinary biomarkers in multiple 24-h urine samples.

PubMed

Sun, Qi; Bertrand, Kimberly A; Franke, Adrian A; Rosner, Bernard; Curhan, Gary C; Willett, Walter C

2017-01-01

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. © 2017 American Society for Nutrition.

Reproducibility of urinary biomarkers in multiple 24-h urine samples123

PubMed Central

Sun, Qi; Bertrand, Kimberly A; Franke, Adrian A; Rosner, Bernard; Curhan, Gary C; Willett, Walter C

2017-01-01

Background: Limited knowledge regarding the reproducibility of biomarkers in 24-h urine samples has hindered the collection and use of the samples in epidemiologic studies. Objective: We aimed to evaluate the reproducibility of various markers in repeat 24-h urine samples. Design: 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. Results: 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. Conclusions: 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. PMID:28049663

Alpha C-telopeptide of type I collagen is associated with subchondral bone turnover and predicts progression of joint space narrowing and osteophytes in osteoarthritis.

PubMed

Huebner, Janet L; Bay-Jensen, Anne C; Huffman, Kim M; He, Yi; Leeming, Diana J; McDaniel, Gary E; Karsdal, Morten A; Kraus, Virginia B

2014-09-01

To evaluate joint tissue remodeling using the urinary collagen biomarkers urinary α-C-telopeptide of type I collagen (α-CTX) and urinary C-telopeptide of type II collagen (CTX-II) and to determine the association of these biomarkers with osteoarthritis (OA) severity, progression, and localized knee bone turnover. Participants (n = 149) with symptomatic and radiographic knee OA underwent fixed-flexion knee radiography at baseline and 3 years, and late-phase bone scintigraphy of both knees at baseline, which were scored semiquantitatively for osteophyte and joint space narrowing (JSN) severity and uptake intensity, with scores summed across knees. Urinary concentrations of α-CTX and CTX-II were determined by enzyme-linked immunosorbent assay. Immunohistochemical analysis of human OA knees was performed to localize the joint tissue origin of the biomarker epitopes. Urinary α-CTX concentrations correlated strongly with the intensity of bone scintigraphic uptake and with JSN progression (risk ratio 13.2) and osteophyte progression (risk ratio 3). Urinary CTX-II concentrations were strongly associated with intensity of bone scintigraphic uptake, with JSN and osteophyte severity, and with OA progression based on osteophyte score. Urinary α-CTX localized primarily to high bone turnover areas in subchondral bone. CTX-II localized to the bone-cartilage interface, the tidemark, and damaged articular cartilage. Baseline urinary α-CTX, which was localized to high turnover areas of subchondral bone, was associated with dynamic bone turnover of knees, as signified by scintigraphy, and progression of both osteophytes and JSN. Urinary CTX-II correlated with JSN and osteophyte severity and progression of osteophytes. To our knowledge, this represents the first report of serologic markers reflecting subchondral bone turnover. These collagen markers may be useful for noninvasive detection and quantification of active subchondral bone turnover and joint remodeling in knee OA. Copyright © 2014 by the American College of Rheumatology.

Evaluation of the usefulness of novel biomarkers for drug-induced acute kidney injury in beagle dogs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhou, Xiaobing; Graduate School of Peking Union Medical College, Dongcheng District, Beijing, 100730; Ma, Ben

As kidney is a major target organ affected by drug toxicity, early detection of renal injury is critical in preclinical drug development. In past decades, a series of novel biomarkers of drug-induced nephrotoxicity were discovered and verified in rats. However, limited data regarding the performance of novel biomarkers in non-rodent species are publicly available. To increase the applicability of these biomarkers, we evaluated the performance of 4 urinary biomarkers including neutrophil gelatinase-associated lipocalin (NGAL), clusterin, total protein, and N-acetyl-β-D-glucosaminidase (NAG), relative to histopathology and traditional clinical chemistry in beagle dogs with acute kidney injury (AKI) induced by gentamicin. The resultsmore » showed that urinary NGAL and clusterin levels were significantly elevated in dogs on days 1 and 3 after administration of gentamicin, respectively. Gene expression analysis further provided mechanistic evidence to support that NGAL and clusterin are potential biomarkers for the early assessment of drug-induced renal damage. Furthermore, the high area (both AUCs = 1.000) under receiver operator characteristics (ROC) curve also indicated that NGAL and clusterin were the most sensitive biomarkers for detection of gentamicin-induced renal proximal tubular toxicity. Our results also suggested that NAG may be used in routine toxicity testing due to its sensitivity and robustness for detection of tissue injury. The present data will provide insights into the preclinical use of these biomarkers for detection of drug-induced AKI in non-rodent species. - Highlights: • Urinary NGAL, clusterin and NAG levels were significantly elevated in canine AKI. • NGAL and clusterin gene expression were increased following treatment with gentamicin. • NGAL and clusterin have high specificity and sensitivity for detection of AKI.« less

The Potential Utility of Urinary Biomarkers for Risk Prediction in Combat Casualties: A Prospective Observational Cohort Study

DTIC Science & Technology

2015-06-16

are associated with poor outcomes, including death and the need for renal replacement therapy. Methods : We conducted a prospective, observational study...penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. 1. REPORT DATE 16 JUN 2015...2. REPORT TYPE N/A 3. DATES COVERED - 4. TITLE AND SUBTITLE The Potential Utility of Urinary Biomarkers for Risk Prediction in Combat

Urinary metallomics as a novel biomarker discovery platform: Breast cancer as a case study.

PubMed

Burton, Casey; Dan, Yongbo; Donovan, Ariel; Liu, Kun; Shi, Honglan; Ma, Yinfa; Bosnak, Cynthia P

2016-01-15

Urinary metallomics is presented here as a new "omics" approach that aims to facilitate personalized cancer screening and prevention by improving our understanding of urinary metals in disease. Twenty-two urinary metals were examined with inductively-coupled plasma-mass spectrometry in 138 women newly diagnosed with breast cancer and benign conditions. Urinary metals from spot urine samples were adjusted to renal dilution using urine specific gravity. Two urinary metals, copper (P-value=0.036) and lead (P-value=0.003), were significantly increased in the urine of breast cancer patients. A multivariate model that comprised copper, lead, and patient age afforded encouraging discriminatory power (AUC: 0.728, P-value<0.0005), while univariate models of copper (61.7% sensitivity, 50.0% specificity) and lead (76.6% sensitivity, 51.2% specificity) at optimized cutoff thresholds compared favorably with other breast cancer diagnostic modalities such as mammography. Correlations found among various metals suggested potential geographic and dietary influences on the urine metallome that warrant further investigation. This proof-of-concept work introduces urinary metallomics as a noninvasive, potentially transformative "omics" approach to early cancer detection. Urinary copper and lead have also been preliminarily identified as potential breast cancer biomarkers. Copyright © 2015 Elsevier B.V. All rights reserved.

ANALYSIS OF UNCERTAINTIES IN DOSE RECONSTRUCTION FROM BIOMARKERS: IMPACT ON STUDY DESIGN

EPA Science Inventory

The absorbed dose is defined as the quantity which has passed through the barriers (skin, GI tract, The absorbed dose of a pesticide can be estimated from its established urinary biomarker. ungs). For an exposure study, there are several options for biomarker collection, each w...

Urinary aminopeptidase activities as early and predictive biomarkers of renal dysfunction in cisplatin-treated rats.

PubMed

Quesada, Andrés; Vargas, Félix; Montoro-Molina, Sebastián; O'Valle, Francisco; Rodríguez-Martínez, María Dolores; Osuna, Antonio; Prieto, Isabel; Ramírez, Manuel; Wangensteen, Rosemary

2012-01-01

This study analyzes the fluorimetric determination of alanyl- (Ala), glutamyl- (Glu), leucyl-cystinyl- (Cys) and aspartyl-aminopeptidase (AspAp) urinary enzymatic activities as early and predictive biomarkers of renal dysfunction in cisplatin-treated rats. Male Wistar rats (n = 8 each group) received a single subcutaneous injection of either saline or cisplatin 3.5 or 7 mg/kg, and urine samples were taken at 0, 1, 2, 3 and 14 days after treatment. In urine samples we determined Ala, Glu, Cys and AspAp activities, proteinuria, N-acetyl-β-D-glucosaminidase (NAG), albumin, and neutrophil gelatinase-associated lipocalin (NGAL). Plasma creatinine, creatinine clearance and renal morphological variables were measured at the end of the experiment. CysAp, NAG and albumin were increased 48 hours after treatment in the cisplatin 3.5 mg/kg treated group. At 24 hours, all urinary aminopeptidase activities and albuminuria were significantly increased in the cisplatin 7 mg/kg treated group. Aminopeptidase urinary activities correlated (p<0.011; r(2)>0.259) with plasma creatinine, creatinine clearance and/or kidney weight/body weight ratio at the end of the experiment and they could be considered as predictive biomarkers of renal injury severity. ROC-AUC analysis was made to study their sensitivity and specificity to distinguish between treated and untreated rats at day 1. All aminopeptidase activities showed an AUC>0.633. We conclude that Ala, Cys, Glu and AspAp enzymatic activities are early and predictive urinary biomarkers of the renal dysfunction induced by cisplatin. These determinations can be very useful in the prognostic and diagnostic of renal dysfunction in preclinical research and clinical practice.

Biomarker and Drug Target Discovery Using Proteomics in a New Rat Model of Sepsis-Induced Acute Renal Failure

PubMed Central

Holly, Mikaela K.; Dear, James W.; Hu, Xuzhen; Schechter, Alan N.; Gladwin, Mark T.; Hewitt, Stephen M.; Yuen, Peter S.T.; Star, Robert A.

2008-01-01

Background Sepsis is one of the common causes of acute renal failure (ARF). The objective of this study was to identify new biomarkers and therapeutic targets. We present a new rat model of sepsis-induced ARF based on cecal ligation and puncture (CLP). We used this model to find urinary proteins which may be potential biomarkers and/or drug targets. Methods Aged rats were treated with fluids and antibiotics after CLP. Urinary proteins from septic rats without ARF and urinary proteins from septic rats with ARF were compared by difference in-gel electrophoresis (DIGE). Results CLP surgery elevated IL-6 and IL-10 serum cytokines and blood nitrite compared with sham-operated rats. However there was a range of serum creatinine values at 24 hrs (0.4–2.3 mg/dL) and only 24% developed ARF. Histology confirmed renal injury in these rats. 49% of rats did not develop ARF. Rats without ARF also had less liver injury. The mortality rate at 24 hrs was 27% but was increased by housing the post-surgery rats in metabolic cages. Creatinine clearance and urine output 2–8 hours after CLP was significantly reduced in rats which died within 24 hours. Using DIGE we identified changes in a number of urinary proteins including albumin, brush-border enzymes (eg., meprin-1-alpha) and serine protease inhibitors. The meprin-1-alpha inhibitor actinonin prevented ARF in aged mice. Conclusion In summary we describe a new rat model of sepsis-induced ARF which has a heterogeneous response similar to humans. This model allowed us to use DIGE to find changes in urinary proteins and this approach identified a potential biomarker and drug target – meprin-1-alpha. PMID:16760904

New markers of dietary added sugar intake.

PubMed

Davy, Brenda; Jahren, Hope

2016-07-01

Added sugar consumption is associated with adverse health outcomes, including weight gain and cardio-metabolic disease, yet the reliance on self-reported methods to determine added sugar intake continues to be a significant research limitation. The purpose of this review is to summarize recent advances in the development of two potential predictive biomarkers of added sugar intake: δC and urinary sugar excretion. The results of numerous cross-sectional investigations have indicated modest associations of the δC sugar biomarker measured in a variety of sample types (e.g., fingerstick blood, serum, red blood cells, and hair) with self-reported added sugar and sugar-sweetened beverage intake, and δC values have been reported to change over time with changes in reported sugar-sweetened beverage intake. Results from large-scale trials have suggested modest associations of urinary sugar excretion with reported sugar intake, and a dose-response relation has been demonstrated between urinary sugar excretion and actual sugar intake. Valid markers of sugar intake are urgently needed to more definitively determine the health consequences of added sugar intake. Adequately powered controlled feeding studies are needed to validate and compare these two biomarkers of sugar intake, and to determine what individual characteristics and conditions impact biomarker results.

Dose-response relationships of polycyclic aromatic hydrocarbons exposure and oxidative damage to DNA and lipid in coke oven workers.

PubMed

Kuang, Dan; Zhang, Wangzhen; Deng, Qifei; Zhang, Xiao; Huang, Kun; Guan, Lei; Hu, Die; Wu, Tangchun; Guo, Huan

2013-07-02

Polycyclic aromatic hydrocarbons (PAHs) are known to induce reactive oxygen species and oxidative stress, but the dose-response relationships between exposure to PAHs and oxidative stress levels have not been established. In this study, we recruited 1333 male coke oven workers, monitored the levels of environmental PAHs, and measured internal PAH exposure biomarkers including 12 urinary PAH metabolites and plasma benzo[a]pyrene-r-7,t-8,t-9,c-10-tetrahydotetrol-albumin (BPDE-Alb) adducts, as well as the two oxidative biomarkers urinary 8-hydroxydeoxyguanosine (8-OHdG) and 8-iso-prostaglandin-F2α (8-iso-PGF2α). We found that the total concentration of urinary PAH metabolites and plasma BPDE-Alb adducts were both significantly associated with increased 8-OHdG and 8-iso-PGF2α in both smokers and nonsmokers (all p < 0.05). This exposure-response effect was also observed for most PAH metabolites (all p(trend) < 0.01), except for 4-hydroxyphenanthrene and 8-OHdG (p(trend) = 0.108). Furthermore, it was shown that only urinary 1-hydroxypyrene has a significant positive association with both 8-OHdG and 8-iso-PGF2α after a Bonferroni correction (p < 0.005). Our results indicated that urinary ΣOH-PAHs and plasma BPDE-Alb adducts can result in significant dose-related increases in oxidative damage to DNA and lipids. Furthermore, when a multianalyte method is unavailable, our findings demonstrate that urinary 1-hydroxypyrene is a useful biomarker for evaluating total PAHs exposure and assessing oxidative damage in coke oven workers.

Increased Klk9 Urinary Excretion Is Associated to Hypertension-Induced Cardiovascular Damage and Renal Alterations.

PubMed

Blázquez-Medela, Ana M; García-Sánchez, Omar; Quirós, Yaremi; Blanco-Gozalo, Victor; Prieto-García, Laura; Sancho-Martínez, Sandra M; Romero, Miguel; Duarte, Juan M; López-Hernández, Francisco J; López-Novoa, José M; Martínez-Salgado, Carlos

2015-10-01

Early detection of hypertensive end-organ damage and secondary diseases are key determinants of cardiovascular prognosis in patients suffering from arterial hypertension. Presently, there are no biomarkers for the detection of hypertensive target organ damage, most outstandingly including blood vessels, the heart, and the kidneys.We aimed to validate the usefulness of the urinary excretion of the serine protease kallikrein-related peptidase 9 (KLK9) as a biomarker of hypertension-induced target organ damage.Urinary, plasma, and renal tissue levels of KLK9 were measured by the Western blot in different rat models of hypertension, including angiotensin-II infusion, DOCA-salt, L-NAME administration, and spontaneous hypertension. Urinary levels were associated to cardiovascular and renal injury, assessed by histopathology. The origin of urinary KLK9 was investigated through in situ renal perfusion experiments.The urinary excretion of KLK9 is increased in different experimental models of hypertension in rats. The ACE inhibitor trandolapril significantly reduced arterial pressure and the urinary level of KLK9. Hypertension did not increase kidney, heart, liver, lung, or plasma KLK9 levels. Hypertension-induced increased urinary excretion of KLK9 results from specific alterations in its tubular reabsorption, even in the absence of overt nephropathy. KLK9 urinary excretion strongly correlates with cardiac hypertrophy and aortic wall thickening.KLK9 appears in the urine in the presence of hypertension as a result of subtle renal handling alterations. Urinary KLK9 might be potentially used as an indicator of hypertensive cardiac and vascular damage.

Integration of 1H NMR and UPLC-Q-TOF/MS for a Comprehensive Urinary Metabonomics Study on a Rat Model of Depression Induced by Chronic Unpredictable Mild Stress

PubMed Central

Jia, Hong-mei; Feng, Yu-fei; Liu, Yue-tao; Chang, Xing; Chen, Lin; Zhang, Hong-wu; Ding, Gang; Zou, Zhong-mei

2013-01-01

Depression is a type of complex psychiatric disorder with long-term, recurrent bouts, and its etiology remains largely unknown. Here, an integrated approach utilizing 1H NMR and UPLC-Q-TOF/MS together was firstly used for a comprehensive urinary metabonomics study on chronic unpredictable mild stress (CUMS) treated rats. More than twenty-nine metabolic pathways were disturbed after CUMS treatment and thirty-six potential biomarkers were identified by using two complementary analytical technologies. Among the identified biomarkers, nineteen (10, 11, 16, 17, 21–25, and 27–36) were firstly reported as potential biomarkers of CUMS-induced depression. Obviously, this paper presented a comprehensive map of the metabolic pathways perturbed by CUMS and expanded on the multitude of potential biomarkers that have been previously reported in the CUMS model. Four metabolic pathways, including valine, leucine and isoleucine biosynthesis; phenylalanine, tyrosine and tryptophan biosynthesis; tryptophan metabolism; synthesis and degradation of ketone bodies had the deepest influence in the pathophysiologic process of depression. Fifteen potential biomarkers (1–2, 4–6, 15, 18, 20–23, 27, 32, 35–36) involved in the above four metabolic pathways might become the screening criteria in clinical diagnosis and predict the development of depression. Moreover, the results of Western blot analysis of aromatic L-amino acid decarboxylase (DDC) and indoleamine 2, 3-dioxygenase (IDO) in the hippocampus of CUMS-treated rats indicated that depletion of 5-HT and tryptophan, production of 5-MT and altered expression of DDC and IDO together played a key role in the initiation and progression of depression. In addition, none of the potential biomarkers were detected by NMR and LC-MS simultaneously which indicated the complementary of the two kinds of detection technologies. Therefore, the integration of 1H NMR and UPLC-Q-TOF/MS in metabonomics study provided an approach to identify the comprehensive potential depression-related biomarkers and helpful in further understanding the underlying molecular mechanisms of depression through the disturbance of metabolic pathways. PMID:23696839

A urinary metabolite of phenanthrene as a biomarker of polycyclic aromatic hydrocarbon metabolic activation in workers exposed to residual oil fly ash.

PubMed

Kim, Jee Young; Hecht, Stephen S; Mukherjee, Sutapa; Carmella, Steven G; Rodrigues, Ema G; Christiani, David C

2005-03-01

Residual oil fly ash is a chemically complex combustion product containing a significant component of potentially carcinogenic transition metals and polycyclic aromatic hydrocarbons (PAH). Various biomarkers of PAH exposure have been investigated previously, most notably 1-hydroxypyrene (1-OHP), in urine. In this study, we assessed the utility of r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (trans, anti-PheT), a metabolite of phenanthrene, to detect occupational PAH exposure. Urine samples collected across the workweek were analyzed for 1-OHP and trans, anti-PheT in boilermakers (n = 20) exposed to residual oil fly ash. Median baseline urinary trans, anti-PheT concentrations were 0.50 microg/g creatinine in current tobacco smokers and 0.39 microg/g creatinine in nonsmokers. Median baseline urinary 1-OHP concentrations in smokers and nonsmokers were 0.31 and 0.13 microg/g creatinine, respectively. To study further the effect of smoking exposure on the urinary PAH markers, urinary cotinine was used. Although urinary trans, anti-PheT and 1-OHP concentrations were correlated (Spearman r = 0.63; P < 0.001) for all subjects, the regression coefficient between log-transformed trans, anti-PheT and log 1-OHP was statistically significant only for subjects with low levels of urinary cotinine or for nonsmokers. Each 1-unit increase in log 1-OHP was associated with a 0.77-unit increase (95% confidence interval, 0.45-1.09) in log trans, anti-PheT in subjects with low levels of urinary cotinine (P < 0.001). In these subjects, dichotomized occupational exposure status was a significant predictor of log trans, anti-PheT (P = 0.02) but not of log 1-OHP (P = 0.2). In conclusion, we found that urinary trans, anti-PheT was detected in levels comparable with 1-OHP in occupationally exposed workers, particularly nonsmokers. This study shows that urinary trans, anti-PheT may be an effective biomarker of uptake and metabolic activation of PAHs.

Urinary biomarkers in hydronephrosis.

PubMed

Madsen, Mia Gebauer

2013-02-01

Hydronephrosis is diagnosed in 0.5-1% of all newborns, and ureteropelvic junction obstruction (UPJO) accounts for 35% of those cases. A urinary tract obstruction that occurs during early kidney development affects renal morphogenesis, maturation, and growth, and in the most severe cases, this will ultimately lead to progressive renal tubular atrophy and interstitial fibrosis with the loss of nephrons. The clinical management of these patients remains a controversial topic. The aim is to preserve renal function by identifying the 15-20% of children who require early surgical intervention from those for whom watchful waiting may be appropriate because of spontaneous resolving/stabilization without significant loss of renal function. Although the patients attend regular follow-ups, including repetitive blood tests, ultrasonographies, and the more invasive diuretic renograms, the surgeons still miss reliably biomarkers that could be used as predictors for renal parenchymal damage and decreased renal function, and thereby provide more clear indications for surgical intervention. The aim of this PhD thesis was to further elucidate the pathophysiology of obstructive nephropathy (study I) and to search for potential candidate biomarkers that may have a predictive and/or diagnostic value in the management of hydronephrosis (study II). Study I: Urine and kidney cytokine profiles in experimental unilateral acute and chronic hydronephrosis. To study the dynamics of the urinary secretion of cytokines after the release of unilateral ureteral obstruction, and to study whether the urinary concentrations of these compounds reliably reflects changes in the renal parenchyma. This was tested in 2 experimental rat models: an acute obstruction model and a chronic obstruction model. The acute obstruction model demonstrated significant differences in the renal levels of IL-1β, IL-6, TNF-α, and IL-10 in comparison with controls, and these differences were associated with similar differences in their urinary excretion. Such results were not obtained in the chronic obstruction model in which significant differences were only demonstrated in the urinary concentrations of IL-6. Study II: Candidate urinary biomarkers in hydronephrosis - a clinical study. To study the dynamics of the urinary excretion of selected potential biomarkers in children after the relief of UPJO, and to compare their findings with healthy controls. Twenty-eight children with UPJO were included in the study from 2007-2011 together with 13 healthy children. Pre-, peri- and post-operatively (1 year) urine samples were collected. The median age of the patients was 8.1 (3.5-14.5) years. Five proteins (EGF, IP-10, MCP-1, RANTES, and MIP-1α) were examined in study IIa, and 4 proteins (NGAL, CyC, βM-2, and OPN) were examined in study IIb. In brief, significantly increased urinary concentrations of EGF and MCP-1 were demonstrated in children with UPJO compared to controls, which was followed by a decline in the post-operative period to levels similar to the controls. This indicates that the urinary concentrations of EGF and MCP-1 are regulated as a response to the obstruction, suggesting that they may have a potential as urinary biomarkers in hydronephrosis. In general, urine from the obstructed kidney exhibited higher concentrations of the proteins compared to urine from the nonobstructed kidney. Furthermore, CyC, β-2M, and OPN were negatively correlated with age, and IP-10 and MCP-1 were negatively correlated with DRF. In conclusion, this PhD study confirmed increased concentrations of selected proteins in urine from kidneys suffering from obstruction. Interestingly, it was observed that some urinary proteins had an age-dependent excretion. Further investigations are required to test the ability of the examined proteins to identify an obstruction and reveal disease progression and, thereby, be useful clinical tools.

Elevated plasma and urinary concentrations of green tea catechins associated with improved plasma lipid profile in healthy Japanese women.

PubMed

Takechi, Ryusuke; Alfonso, Helman; Hiramatsu, Naoko; Ishisaka, Akari; Tanaka, Akira; Tan, La'Belle; Lee, Andy H

2016-03-01

This study investigated green tea catechins in plasma and urine and chronic disease biomarkers. We hypothesized that plasma and urinary concentration of green tea catechins are associated with cardiovascular disease and diabetes biomarkers. First void urine and fasting plasma samples were collected from 57 generally healthy females aged 38 to 73 years (mean, 52 ± 8 years) recruited in Himeji, Japan. The concentrations of plasma and urinary green tea catechins were determined by liquid chromatography coupled with mass tandem spectrometer. Low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, glucose, insulin, glycated hemoglobin, and C-reactive protein in plasma/serum samples were analyzed by a commercial diagnostic laboratory. Statistical associations were assessed using Spearman correlation coefficients. The results showed weak associations between plasma total catechin and triglyceride (r = -0.30) and LDL cholesterol (r = -0.28), whereas plasma (-)-epigallocatechin-3-gallate, (-)-epigallocatechin, (-)-epicatechin-3-gallate, and (-)-epicatechin exhibited weak to moderate associations with triglyceride or LDL cholesterol, but little associations with HDL cholesterol, body fat, and body mass index were evident. Urinary total catechin was weakly associated with triglyceride (r = -0.19) and LDL cholesterol (r = -0.15), whereas urinary (-)-epigallocatechin-3-gallate (r = -0.33), (-)-epigallocatechin (r = -0.23), and (-)-epicatechin-3-gallate (r = -0.33) had weak to moderate correlations with triglyceride and similarly with body fat and body mass index. Both plasma (r = -0.24) and urinary (r = -0.24) total catechin, as well as individual catechins, were weakly associated with glycated hemoglobin. Plasma total and individual catechins were weakly to moderately associated with C-reactive protein, but not the case for urinary catechins. In conclusion, we found weak to moderate associations between plasma and urinary green tea catechin concentrations and plasma biomarkers of cardiovascular disease and diabetes. Copyright © 2016 Elsevier Inc. All rights reserved.

Proximal tubule proteins are significantly elevated in bladder urine of patients with ureteropelvic junction obstruction and may represent novel biomarkers: A pilot study.

PubMed

Gerber, Claire; Harel, Miriam; Lynch, Miranda L; Herbst, Katherine W; Ferrer, Fernando A; Shapiro, Linda H

2016-04-01

Ureteropelvic junction obstruction (UPJO) is the major cause of hydronephrosis in children and may lead to renal injury and early renal dysfunction. However, diagnosis of the degree of obstruction and severity of renal injury relies on invasive and often inconclusive renal scans. Biomarkers from voided urine that detect early renal injury are highly desirable because of their noninvasive collection and their potential to assist in earlier and more reliable diagnosis of the severity of obstruction. Early in response to UPJO, increased intrarenal pressure directly impacts the proximal tubule brush border. We hypothesize that single-pass, apically expressed proximal tubule brush border proteins will be shed into the urine early and rapidly and will be reliable noninvasive urinary biomarkers, providing the tools for a more reliable stratification of UPJO patients. We performed a prospective cohort study at Connecticut Children's Medical Center. Bladder urine samples from 12 UPJO patients were obtained prior to surgical intervention. Control urine samples were collected from healthy pediatric patients presenting with primary nocturnal enuresis. We determined levels of NGAL, KIM-1 (previously identified biomarkers), CD10, CD13, and CD26 (potentially novel biomarkers) by ELISA in control and experimental urine samples. Urinary creatinine levels were used to normalize the urinary protein levels measured by ELISA. Each of the proximal tubule proteins outperformed the previously published biomarkers. No differences in urinary NGAL and KIM-1 levels were observed between control and obstructed patients (p = 0.932 and p = 0.799, respectively). However, levels of CD10, CD13, and CD26 were significantly higher in the voided urine of obstructed individuals when compared with controls (p = 0.002, p = 0.024, and p = 0.007, respectively) (Figure). Targeted identification of reliable, noninvasive biomarkers of renal injury is critical to aid in diagnosing patients at risk, guiding therapeutic decisions and monitoring treatment efficacy. Proximal tubule brush border proteins are reliably detected in the urine of obstructed patients and may be more effective at predicting UPJO. Copyright © 2015 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.

Inter- and intra-individual variation in urinary biomarker concentrations over a 6-day sampling period. Part 1: metals.

PubMed

Smolders, Roel; Koch, Holger M; Moos, Rebecca K; Cocker, John; Jones, Kate; Warren, Nick; Levy, Len; Bevan, Ruth; Hays, Sean M; Aylward, Lesa L

2014-12-01

The aim of the current HBM-study is to further the understanding of the impact of inter- and intra-individual variability in HBM surveys as it may have implications for the design and interpretation of the study outcomes. As spot samples only provide a snapshot in time of the concentrations of chemicals in an individual, it remains unclear to what extent intra-individual variability plays a role in the overall variability of population-wide HBM surveys. The current paper describes the results of an intensive biomonitoring study, in which all individual urine samples of 8 individuals were collected over a 6-day sampling period (a total of 352 unique samples). By analyzing different metals (As, Cd, Mn, Ni) in each individual sample, inter- and intra-individual variability for these four metals could be determined, and the relationships between exposure, internal dose, and sampling protocol assessed. Although the range of biomarker values for different metals was well within the normal range reported in large-scale population surveys, large intra-individual differences over a 6-day period could also be observed. Typically, measured biomarker values span at least an order of magnitude within an individual, and more if specific exposure episodes could be identified. Fish consumption for example caused a twenty- to thirty-fold increase in urinary As-levels over a period of 2-6h. Intra-class correlation coefficients (ICC) were typically low for uncorrected biomarker values (between 0.104 and 0.460 for the 4 metals), but improved when corrected for creatinine or specific gravity (SG). The results show that even though urine is a preferred matrix for HBM studies, there are certain methodological issues that need to be taken into account in the interpretation of urinary biomarker data, related to the intrinsic variability of the urination process itself, the relationship between exposure events and biomarker quantification, and the timing of sampling. When setting up HBM-projects, this expected relationship between individual exposure episode and urinary biomarker concentration needs to be taken into account. Copyright © 2014. Published by Elsevier Ireland Ltd.

Subclinical chronic kidney disease modifies the diagnosis of experimental acute kidney injury.

PubMed

Succar, Lena; Pianta, Timothy J; Davidson, Trent; Pickering, John W; Endre, Zoltán H

2017-09-01

Extensive structural damage within the kidney must be present before serum creatinine increases. However, a subclinical phase of chronic kidney disease (CKD) usually goes undetected. Here we tested whether experimental subclinical CKD would modify functional and damage biomarker profiles of acute kidney injury (AKI). Subclinical CKD was induced in rats by adenine or aristolochic acid models but without increasing serum creatinine. After prolonged recovery (three to six weeks), AKI was induced with a subnephrotoxic dose of cisplatin. Urinary levels of kidney injury molecule-1 (KIM-1), cytochrome C, monocyte chemotactic protein-1 (MCP-1), clusterin, and interleukin-18 increased during CKD induction, without an increase in serum creatinine. After AKI in adenine-induced CKD, serum creatinine increased more rapidly, while increased urinary KIM-1, clusterin, and MCP-1 were delayed and reduced. Increased serum creatinine and biomarker excretion were associated with diffuse tubulointerstitial injury in the outer stripe of outer medulla coupled with over 50% cortical damage. Following AKI in aristolochic acid-induced CKD, increased serum creatinine, urinary KIM-1, clusterin, MCP-1, cytochrome C, and interleukin-18 concentrations and excretion were greater at day 21 than day 42 and inversely correlated with cortical injury. Subclinical CKD modified functional and damage biomarker profiles in diametrically opposite ways. Functional biomarker profiles were more sensitive, while damage biomarker diagnostic thresholds and increases were diminished and delayed. Damage biomarker concentrations and excretion were inversely linked to the extent of prior cortical damage. Thus, thresholds for AKI biomarkers may need to be lower or sampling delayed in the known presence of CKD. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

Urinary Proteomic Biomarkers for Diagnosis and Risk Stratification of Autosomal Dominant Polycystic Kidney Disease: A Multicentric Study

PubMed Central

Kistler, Andreas D.; Serra, Andreas L.; Siwy, Justyna; Poster, Diane; Krauer, Fabienne; Torres, Vicente E.; Mrug, Michal; Grantham, Jared J.; Bae, Kyongtae T.; Bost, James E.; Mullen, William; Wüthrich, Rudolf P.; Mischak, Harald; Chapman, Arlene B.

2013-01-01

Treatment options for autosomal dominant polycystic kidney disease (ADPKD) will likely become available in the near future, hence reliable diagnostic and prognostic biomarkers for the disease are strongly needed. Here, we aimed to define urinary proteomic patterns in ADPKD patients, which aid diagnosis and risk stratification. By capillary electrophoresis online coupled to mass spectrometry (CE-MS), we compared the urinary peptidome of 41 ADPKD patients to 189 healthy controls and identified 657 peptides with significantly altered excretion, of which 209 could be sequenced using tandem mass spectrometry. A support-vector-machine based diagnostic biomarker model based on the 142 most consistent peptide markers achieved a diagnostic sensitivity of 84.5% and specificity of 94.2% in an independent validation cohort, consisting of 251 ADPKD patients from five different centers and 86 healthy controls. The proteomic alterations in ADPKD included, but were not limited to markers previously associated with acute kidney injury (AKI). The diagnostic biomarker model was highly specific for ADPKD when tested in a cohort consisting of 481 patients with a variety of renal and extrarenal diseases, including AKI. Similar to ultrasound, sensitivity and specificity of the diagnostic score depended on patient age and genotype. We were furthermore able to identify biomarkers for disease severity and progression. A proteomic severity score was developed to predict height adjusted total kidney volume (htTKV) based on proteomic analysis of 134 ADPKD patients and showed a correlation of r = 0.415 (p<0.0001) with htTKV in an independent validation cohort consisting of 158 ADPKD patients. In conclusion, the performance of peptidomic biomarker scores is superior to any other biochemical markers of ADPKD and the proteomic biomarker patterns are a promising tool for prognostic evaluation of ADPKD. PMID:23326375

Biomarker-predicted sugars intake compared with self-reported measures in US Hispanics/Latinos: results from the HCHS/SOL SOLNAS study.

PubMed

Beasley, J M; Jung, M; Tasevska, N; Wong, W W; Siega-Riz, A M; Sotres-Alvarez, D; Gellman, M D; Kizer, J R; Shaw, P A; Stamler, J; Stoutenberg, M; Van Horn, L; Franke, A A; Wylie-Rosett, J; Mossavar-Rahmani, Y

2016-12-01

Measurement error in self-reported total sugars intake may obscure associations between sugars consumption and health outcomes, and the sum of 24 h urinary sucrose and fructose may serve as a predictive biomarker of total sugars intake. The Study of Latinos: Nutrition & Physical Activity Assessment Study (SOLNAS) was an ancillary study to the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) cohort. Doubly labelled water and 24 h urinary sucrose and fructose were used as biomarkers of energy and sugars intake, respectively. Participants' diets were assessed by up to three 24 h recalls (88 % had two or more recalls). Procedures were repeated approximately 6 months after the initial visit among a subset of ninety-six participants. Four centres (Bronx, NY; Chicago, IL; Miami, FL; San Diego, CA) across the USA. Men and women (n 477) aged 18-74 years. The geometric mean of total sugars was 167·5 (95 % CI 154·4, 181·7) g/d for the biomarker-predicted and 90·6 (95 % CI 87·6, 93·6) g/d for the self-reported total sugars intake. Self-reported total sugars intake was not correlated with biomarker-predicted sugars intake (r=-0·06, P=0·20, n 450). Among the reliability sample (n 90), the reproducibility coefficient was 0·59 for biomarker-predicted and 0·20 for self-reported total sugars intake. Possible explanations for the lack of association between biomarker-predicted and self-reported sugars intake include measurement error in self-reported diet, high intra-individual variability in sugars intake, and/or urinary sucrose and fructose may not be a suitable proxy for total sugars intake in this study population.

Biomarker-predicted sugars intake compared with self-reported measures in US Hispanics/Latinos: Results from the HCHS/SOL SOLNAS Study

PubMed Central

Beasley, JM; Jung, M; Tasevska, N; Wong, WW; Siega-Riz, AM; Sotres-Alvarez, D; Gellman, MD; Kizer, JR; Shaw, PA; Stamler, J; Stoutenberg, M; Van Horn, L; Franke, AA; Wylie-Rosett, J; Mossavar-Rahmani, Y

2017-01-01

Objective Measurement error in self-reported total sugars intake may obscure associations between sugars consumption and health outcomes, and the sum of 24-hr urinary sucrose and fructose may serve as a predictive biomarker of total sugars intake. Design The Study of Latinos: Nutrition & Physical Activity Assessment Study (SOLNAS) was an ancillary study to the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) cohort. Doubly labeled water (DLW) and 24-hr urinary sucrose and fructose were used as biomarkers of energy and sugars intake, respectively. Participants’ diets were assessed by up to three 24-hr recalls (88% had two or more recalls). Procedures were repeated approximately six months after the initial visit among a subset of 96 participants. Setting Four centers (Bronx, NY; Chicago, IL; Miami, FL; San Diego, CA) across the United States Subjects 477 men and women aged 18–74 years. Results The geometric mean of total sugars intake was 167.5 (95% CI: 154.4–181.7) g/day for the biomarker-predicted and 90.6 (95% CI: 87.6–93.6) g/day for the self-reported total sugars intake. Self-reported total sugars intake was not correlated with biomarker-predicted sugars intake (r=−0.06, P=0.20, n=450). Among the reliability sample (n=90), the reproducibility coefficient was 0.59 for biomarker-predicted and 0.20 for self-reported total sugars intake. Conclusions Possible explanations for the lack of association between biomarker-predicted and self-reported sugars intake include measurement error in self-reported diet, high intra-individual variability in sugars intake, and/or urinary sucrose and fructose may not be a suitable proxy for total sugars intake in this study population. PMID:27339078

Permethrin exposure from fabric-treated military uniforms under different wear-time scenarios.

PubMed

Proctor, Susan P; Maule, Alexis L; Heaton, Kristin J; Adam, Gina E

2014-11-01

The objective of the project was to ascertain whether urinary biomarkers of permethrin exposure are detected after wearing post-tailored, fabric-treated military uniforms under two different wear-time exposure scenarios. Study A occurred over 3.5 days and involved six participants wearing treated uniforms continuously for 30-32 h. Urine collection occurred at scheduled time points before, during, and after wearing the uniform. Study B, conducted over 19 days, included 11 participants wearing treated uniforms for 3 consecutive days, 8 h each day (with urine collection before, during, and after wear). Urinary biomarkers of permethrin (3-phenoxybenzoic acid (3PBA), cis- 2,2-(dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid (cDCCA), trans- 2,2-(dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid (tDCCA)) were detected during and after wear. Biomarker detection generally occurred over the 10- to 12-h period after putting on the uniform and subsided 24 h following uniform removal (in both Study A and B scenarios). Those wearing permethrin-treated uniforms under the longer wear-time scenario (Study A) excreted significantly higher cumulative mean levels compared with those in Study B (3.29 times higher for 3PBA and 2.23 times higher for the sum of c/tDCCA (P≤0.001)). Findings suggest that wearing permethrin-treated clothing does increase absorbed, internal dose levels of permethrin above population levels and is significantly related to wear-time duration.

Clinical Utility of Urinary CD90 as a Biomarker for Prostate Cancer Detection — EDRN Public Portal

Cancer.gov

Tumor-associated stromal cells differ from normal gland-associated stromal cells in gene expression. Genes up-regulated in these stromal cells are potential cancer biomarkers, especially those encoding secreted or extracellular proteins. These proteins might be detected in urine. CD90/THY1 is one such candidate. A clinical test based on urinary CD90 would be useful in reducing the number of unnecessary biopsies done because of abnormal serum PSA and/or DRE finding. Elevated CD90 protein is found in tumor tissue and urine.

Determination of urinary aromatic amines in smokers and nonsmokers using a MIPs-SPE coupled with LC-MS/MS method.

PubMed

Yu, Jingjing; Wang, Sheng; Zhao, Ge; Wang, Bing; Ding, Li; Zhang, Xiaobing; Xie, Jianping; Xie, Fuwei

2014-05-01

Urinary aromatic amines (AAs) could be used as biomarkers for human exposure to AAs in cigarette smoke. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the determination of urinary AAs (i.e. 1-naphthylamine (1-NA), 2-naphthylamine (2-NA), 3-aminobiphenyl (3-ABP) and 4-aminobiphenyl (4-ABP)) in smokers and nonsmokers. A molecularly imprinted polymers (MIPs) solid phase extraction (SPE) cartridge was applied to purify urine samples and no derivatization reaction was involved. Each analytes used respective stable isotope internal standards, which could well compensate matrix effect. Lower limit of detections (LODs) for four AAs were obtained and in the range of 1.5-5ngL(-1). Recovery ranged from 87.7±4.5% to 111.3±6.4% and precision were less than 9.9%. The method was applied to analyze urine samples of 40 smokers and 10 nonsmokers. The 24h urinary excretion amounts of total AAs were higher for smokers compared with nonsmokers. What's more, 1-NA, 3-ABP and 4-ABP excretion amounts showed significant differences (p<0.05) between smokers and nonsmokers. Copyright © 2014 Elsevier B.V. All rights reserved.

Hydroxy-fipronil is a new urinary biomarker of exposure to fipronil

EPA Science Inventory

Occupational medical surveillance is highly desirable in manufacturing facilities where exposure to chemicals is significant. The insecticide fipronil is generally considered safe for humans but with increasing use, exposure to fipronil is of concern. Identification of urinary me...

Urinary Netrin-1: A New Biomarker for the Early Diagnosis of Renal Damage in Obese Children.

PubMed

Övünç Hacıhamdioğlu, Duygu; Hacıhamdioğlu, Bülent; Altun, Demet; Müftüoğlu, Tuba; Karademir, Ferhan; Süleymanoğlu, Selami

2016-09-01

Urinary netrin-1 is a new marker to demonstrate early tubular damage. The aim of this study was to determine whether urinary netrin-1 is increased in obese children. A total of 68 normoalbuminuric and normotensive obese patients and 65 controls were included in the study. Urine samples were collected for assessment of urinary phosphorus, sodium, potassium, creatinine, albumin, and netrin-1. Blood samples were collected for measurements of fasting glucose, insulin, lipid, phosphorus, sodium, potassium, and creatinine levels. Homeostatic model assessment insulin resistance index was calculated. Gender and age were similar between obese and control groups (12.01±3.03 vs. 11.7±3.2 years, p=0.568 and 33 vs. 35 girls, p=0.543, respectively). Obese patients had significantly higher netrin-1 excretion than the controls (841.68±673.17 vs. 228.94±137.25 pg/mg creatinine, p=0.000). Urinary netrin-1 level was significantly higher in obese subjects with insulin resistance compared to those without insulin resistance (1142±1181 vs. 604.9±589.91 pg/mg creatinine, p=0.001). In normotensive and normoalbuminuric obese children, urinary netrin-1 level can increase before onset of albuminuria. Urinary netrin-1 excretion appears to be affected predominantly by insulin resistance and hyperinsulinemia. Urinary netrin-1 may be a new biomarker for determining early tubular injury in obese children.

Impact of radiotherapy and chemotherapy on biomarkers of oxidative DNA damage in lung cancer patients.

PubMed

Crohns, Marika; Saarelainen, Seppo; Erhola, Marina; Alho, Hannu; Kellokumpu-Lehtinen, Pirkko

2009-07-01

To assess oxidative damage to DNA during lung cancer (LC) treatments. Urinary levels of 8-oxoguanine (8-oxoGua) and levels of 8-oxo-2'-deoxyguanosine (8-oxodG) from urine and whole blood were determined in 36 non-cancer controls and 65 LC patients before any treatments. Samples were also obtained of LC patients during and after radiotherapy (RT, n=33) and chemotherapy (CT, n=16). Stage IV LC patients had higher urinary 8-oxoGua and 8-oxodG levels than patients with stage I-III disease (p=0.044 and p=0.034, respectively). Urinary 8-oxodG levels increased during the first week of RT (p<0.001). Nuclear 8-oxodG increased during RT and 3 months after start of RT. Nuclear 8-oxodG levels also rose between the first two CT cycles (p=0.043), and urinary 8-oxodG levels during the sixth CT cycle (p=0.009). Urinary DNA damage biomarker levels may be associated with LC stage. Both RT and CT increase the parameters of DNA oxidation.

Predicting Severity of Acute Kidney Injury in Term Neonates with Perinatal Asphyxia Using Urinary Neutrophil Gelatinase Associated Lipocalin.

PubMed

Tanigasalam, Vasanthan; Bhat, Ballambattu Vishnu; Adhisivam, Bethou; Sridhar, Magadi Gopalakrishna; Harichandrakumar, Kottyen Thazath

2016-11-01

To evaluate the utility of urinary Neutrophil Gelatinase Associated Lipocalin (NGAL) as a biomarker for predicting Acute Kidney Injury (AKI) and its severity among neonates with perinatal asphyxia. This descriptive study included 120 term neonates with perinatal asphyxia. Renal parameters of neonates were monitored and AKI was ascertained as per Acute Kidney Injury Network criteria. Urinary NGAL was estimated and correlated with severity of AKI. Among the 120 neonates with perinatal asphyxia, 55(46 %) had AKI. The median urinary NGAL level was 165 ng/ml (88.8-245.8) in neonates with AKI compared to 58.97(42.8-74.7) in those without AKI. The median NGAL was 134.45(112.2-162.5), 301.2(255.5-361.2), 416.2(412.2-465.5) in AKI stages 1, 2 and 3 respectively. An NGAL cut off value of 86.82 ng/ml had 87 % sensitivity and 87.7 % specificity in predicting AKI. Urinary NGAL is a useful biomarker for predicting AKI and its severity among neonates with perinatal asphyxia.

Urinary metabonomics study on toxicity biomarker discovery in rats treated with Xanthii Fructus.

PubMed

Lu, Fang; Cao, Min; Wu, Bin; Li, Xu-zhao; Liu, Hong-yu; Chen, Da-zhong; Liu, Shu-min

2013-08-26

Xanthii Fructus (XF) is commonly called "Cang-Erzi" in traditional Chinese medicine (TCM) and widely used for the treatment of sinusitis, headache, rheumatism, and skin itching. However, the clinical utilization of XF is relatively restricted owing to its toxicity. To discover the characteristic potential biomarkers in rats treated with XF by urinary metabonomics. Ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) was applied in the study. The total ion chromatograms obtained from control and different dosage groups were distinguishable by a multivariate statistical analysis method. The greatest difference in metabolic profile was observed between high dosage group and control group, and the metabolic characters in rats treated with XF were perturbed in a dose-dependent manner. The metabolic changes in response for XF treatment were observed in urinary samples, which were revealed by orthogonal projection to latent structures discriminate analysis (OPLS-DA), and 10 metabolites could be served as the potential toxicity biomarkers. In addition, the mechanism associated with the damages of lipid per-oxidation and the metabolic disturbances of fatty acid oxidation were investigated. These results indicate that metabonomics analysis in urinary samples may be useful for predicting the toxicity induced by XF. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Protein shedding in urothelial bladder cancer: prognostic implications of soluble urinary EGFR and EpCAM.

PubMed

Bryan, R T; Regan, H L; Pirrie, S J; Devall, A J; Cheng, K K; Zeegers, M P; James, N D; Knowles, M A; Ward, D G

2015-03-17

Better biomarkers must be found to develop clinically useful urine tests for bladder cancer. Proteomics can be used to identify the proteins released by cancer cell lines and generate candidate markers for developing such tests. We used shotgun proteomics to identify proteins released into culture media by eight bladder cancer cell lines. These data were compared with protein expression data from the Human Protein Atlas. Epidermal growth factor receptor (EGFR) was identified as a candidate biomarker and measured by ELISA in urine from 60 noncancer control subjects and from 436 patients with bladder cancer and long-term clinical follow-up. Bladder cancer cell lines shed soluble EGFR ectodomain. Soluble EGFR is also detectable in urine and is highly elevated in some patients with high-grade bladder cancer. Urinary EGFR is an independent indicator of poor bladder cancer-specific survival with a hazard ratio of 2.89 (95% CI 1.81-4.62, P<0.001). In multivariable models including both urinary EGFR and EpCAM, both biomarkers are predictive of bladder cancer-specific survival and have prognostic value over and above that provided by standard clinical observations. Measuring urinary EGFR and EpCAM may represent a simple and useful approach for fast-tracking the investigation and treatment of patients with the most aggressive bladder cancers.

Matrix Metalloproteinase-7 Is a Urinary Biomarker and Pathogenic Mediator of Kidney Fibrosis

PubMed Central

Zhou, Dong; Tian, Yuan; Sun, Ling; Zhou, Lili; Xiao, Liangxiang; Tan, Roderick J.; Tian, Jianwei; Fu, Haiyan

2017-01-01

Matrix metalloproteinase-7 (MMP-7), a secreted zinc– and calcium–dependent endopeptidase, is a transcriptional target of canonical Wnt/β-catenin signaling. Because Wnt/β-catenin is activated in diseased kidney, we hypothesized that urinary MMP-7 level may be used as a noninvasive surrogate biomarker for fibrotic lesions. To test this hypothesis, we conducted a cross-sectional study, measuring urinary MMP-7 levels in a cohort of 102 patients with CKD. Compared with normal subjects, patients with various kidney disorders had markedly elevated urinary levels of MMP-7. Furthermore, urinary MMP-7 levels closely correlated with renal fibrosis scores in patients. In mice, knockout of MMP-7 ameliorated the fibrotic lesions and expression of matrix genes induced by obstructive injury. Genetic ablation of MMP-7 also preserved E-cadherin protein expression and substantially reduced the expression of total and dephosphorylated β-catenin and the de novo expression of vimentin and fibroblast-specific protein 1 in renal tubules of obstructed kidneys. In vitro, MMP-7 proteolytically degraded E-cadherin in proximal tubular cells, leading to β-catenin liberation and nuclear translocation and induction of β-catenin target genes by a mechanism independent of Wnt ligands. Finally, pharmacologic inhibition of MMP-7 immediately after obstructive injury reduced renal fibrosis in vivo. These results suggest that MMP-7 not only can serve as a noninvasive biomarker but also is an important pathogenic mediator of kidney fibrosis. PMID:27624489

Metabolomics Approach to Male Lower Urinary Tract Symptoms: Identification of Possible Biomarkers and Potential Targets for New Treatments.

PubMed

Mitsui, Takahiko; Kira, Satoru; Ihara, Tatsuya; Sawada, Norifumi; Nakagomi, Hiroshi; Miyamoto, Tatsuya; Shimura, Hiroshi; Yokomichi, Hiroshi; Takeda, Masayuki

2018-05-01

We identified metabolites using a metabolomics approach and investigated the association between these metabolites and lower urinary tract symptoms. We used a 24-hour bladder diary and I-PSS (International Prostate Symptom Score) to assess micturition behavior and lower urinary tract symptoms in 58 male patients without apparent neurological disease. Lower urinary tract symptoms were defined as a total I-PSS score of 8 or greater. Patients with a score of 7 or less were placed in the control group. A comprehensive study of plasma metabolites was also performed by capillary electrophoresis time-of-flight mass spectrometry. Metabolites were compared between the lower urinary tract symptoms and control groups using the Mann-Whitney U test. Biomarkers of male lower urinary tract symptoms from the metabolites were analyzed using multivariable logistic regression analysis to determine the OR. Of the 58 men 32 were in the lower urinary tract symptoms group and the remaining 26 were in the control group. The 24-hour bladder diary showed that nocturnal urine volume, 24-hour micturition frequency, nocturnal micturition frequency and the nocturia index were significantly higher in the lower urinary tract symptoms group. Metabolomics analysis identified 60 metabolites from patient plasma. Multivariate analysis revealed that increased glutamate and decreased arginine, asparagine and inosine monophosphate were significantly associated with lower urinary tract symptoms in males. Decreases in citrulline and glutamine could also be associated with male lower urinary tract symptoms. Male lower urinary tract symptoms may develop due to abnormal metabolic processes in some pathways. Potential new treatments for lower urinary tract symptoms can be developed by identifying changes in the amino acid profiles. Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Kidney injury biomarkers and urinary creatinine variability in nominally healthy adults

EPA Science Inventory

Environmental exposure diagnostics use creatinine concentrations in urine aliquots as the internal standard for dilution normalization of all other excreted metabolites when urinary excretion rate data are not available. This is a reasonable approach for healthy adults as creati...

New Markers of Dietary Added Sugar Intake

PubMed Central

Davy, Brenda; Jahren, Hope

2016-01-01

Purpose of review Added sugar (AS) consumption is associated with adverse health outcomes including weight gain and cardio-metabolic disease, yet the reliance on self-reported methods to determine AS intake continues to be a significant research limitation. The purpose of this review is to summarize recent advances in the development of two potential predictive biomarkers of added sugar intake: δ13C and urinary sugar excretion. Recent findings The results of numerous cross-sectional investigations have indicated modest associations of the δ13C sugar biomarker measured in a variety of sample types (e.g., fingerstick blood, serum, red blood cells, hair) with self-reported AS and sugar-sweetened beverage (SSB) intake, and δ13C values have been reported to change over time with changes in reported SSB intake. Results from large-scale trials have suggested modest associations of urinary sugar excretion with reported sugar intake, and a dose-response relation has been demonstrated between urinary sugar excretion and actual sugar intake. Summary Valid markers of sugar intake are urgently needed to more definitively determine the health consequences of AS intake. Adequately-powered controlled feeding studies are needed to validate and compare these two biomarkers of sugar intake, and to determine what individual characteristics and conditions impact biomarker results. PMID:27137898

Normal distribution of urinary polyphenol excretion among Egyptian males 7-14 years old and changes following nutritional intervention with tomato juice (Lycopersicon esculentum).

PubMed

Hussein, Laila; Medina, Alexander; Barrionnevo, Ana; Lammuela-Raventos, Rosa M; Andres-Lacueva, Cristina

2009-06-01

The urinary flavonoids are considered a reliable biomarker for the intake of polyphenol-rich foods. To assess the normal distribution of urinary polyphenol [PP] excretion among healthy male children and adolescents on a typical Egyptian diet. To follow up the impact of nutritional intervention with tomato juice on the urinary excretion of [PP]. Forty-nine male subjects 7-14 years old collected a 24-h urine sample and filled a dietary record during a 7-day period. A daily serving of 230 g fresh tomato juice was followed for 18 days in a subgroup. Total urinary [PP] excretions were measured before and after termination of the intervention program. The total urinary [PP] was analyzed after a clean-up solid-phase extraction step by the Folin-Ciocalteu reagent in the 96 micro plates. The results were expressed as gallic acid equivalents (GAE). The urinary [PP] excretion averaged 48.6+/-5.5 mg GAE/24 h, equivalent to 89.5+/-8.4 mg GAE/g creatinine. The mean urinary [PP] excretion increased significantly (P<0.05) following the intervention with tomato juice (287.4+/-64.3 mg GAE/g creatinine) compared with the respective mean baseline level (94.5+/-8.92 mg GAE/g creatinine). Clinical laboratory reference limits for urinary polyphenols are presented for Egyptian male children and adolescents. Measuring the urinary polyphenol excretion proved a good biomarker for the dietary polyphenol intake and the results demonstrated that tomato [PP] was highly bioavailable in the human body.

Diagnostic accuracy of urinary prostate protein glycosylation profiling in prostatitis diagnosis.

PubMed

Vermassen, Tijl; Van Praet, Charles; Poelaert, Filip; Lumen, Nicolaas; Decaestecker, Karel; Hoebeke, Piet; Van Belle, Simon; Rottey, Sylvie; Delanghe, Joris

2015-01-01

Although prostatitis is a common male urinary tract infection, clinical diagnosis of prostatitis is difficult. The developmental mechanism of prostatitis is not yet unraveled which led to the elaboration of various biomarkers. As changes in asparagine-linked-(N-)-glycosylation were observed between healthy volunteers (HV), patients with benign prostate hyperplasia and prostate cancer patients, a difference could exist in biochemical parameters and urinary N-glycosylation between HV and prostatitis patients. We therefore investigated if prostatic protein glycosylation could improve the diagnosis of prostatitis. Differences in serum and urine biochemical markers and in total urine N-glycosylation profile of prostatic proteins were determined between HV (N=66) and prostatitis patients (N=36). Additionally, diagnostic accuracy of significant biochemical markers and changes in N-glycosylation was assessed. Urinary white blood cell (WBC) count enabled discrimination of HV from prostatitis patients (P<0.001). Urinary bacteria count allowed for discriminating prostatitis patients from HV (P<0.001). Total amount of biantennary structures (urinary 2A/MA marker) was significantly lower in prostatitis patients compared to HV (P<0.001). Combining the urinary 2A/MA marker and urinary WBC count resulted in an AUC of 0.79, 95% confidence interval (CI)=(0.70-0.89) which was significantly better than urinary WBC count (AUC=0.70, 95% CI=[0.59-0.82], P=0.042) as isolated test. We have demonstrated the diagnostic value of urinary N-glycosylation profiling, which shows great potential as biomarker for prostatitis. Further research is required to unravel the developmental course of prostatic inflammation.

Diagnostic accuracy of urinary prostate protein glycosylation profiling in prostatitis diagnosis

PubMed Central

Vermassen, Tijl; Van Praet, Charles; Poelaert, Filip; Lumen, Nicolaas; Decaestecker, Karel; Hoebeke, Piet; Van Belle, Simon; Rottey, Sylvie

2015-01-01

Introduction Although prostatitis is a common male urinary tract infection, clinical diagnosis of prostatitis is difficult. The developmental mechanism of prostatitis is not yet unraveled which led to the elaboration of various biomarkers. As changes in asparagine-linked-(N-)-glycosylation were observed between healthy volunteers (HV), patients with benign prostate hyperplasia and prostate cancer patients, a difference could exist in biochemical parameters and urinary N-glycosylation between HV and prostatitis patients. We therefore investigated if prostatic protein glycosylation could improve the diagnosis of prostatitis. Materials and methods Differences in serum and urine biochemical markers and in total urine N-glycosylation profile of prostatic proteins were determined between HV (N = 66) and prostatitis patients (N = 36). Additionally, diagnostic accuracy of significant biochemical markers and changes in N-glycosylation was assessed. Results Urinary white blood cell (WBC) count enabled discrimination of HV from prostatitis patients (P < 0.001). Urinary bacteria count allowed for discriminating prostatitis patients from HV (P < 0.001). Total amount of biantennary structures (urinary 2A/MA marker) was significantly lower in prostatitis patients compared to HV (P < 0.001). Combining the urinary 2A/MA marker and urinary WBC count resulted in an AUC of 0.79, 95% confidence interval (CI) = (0.70–0.89) which was significantly better than urinary WBC count (AUC = 0.70, 95% CI = [0.59–0.82], P = 0.042) as isolated test. Conclusions We have demonstrated the diagnostic value of urinary N-glycosylation profiling, which shows great potential as biomarker for prostatitis. Further research is required to unravel the developmental course of prostatic inflammation. PMID:26526330

Increased Klk9 Urinary Excretion Is Associated to Hypertension-Induced Cardiovascular Damage and Renal Alterations

PubMed Central

Blázquez-Medela, Ana M.; García-Sánchez, Omar; Quirós, Yaremi; Blanco-Gozalo, Victor; Prieto-García, Laura; Sancho-Martínez, Sandra M.; Romero, Miguel; Duarte, Juan M.; López-Hernández, Francisco J.; López-Novoa, José M.; Martínez-Salgado, Carlos

2015-01-01

Abstract Early detection of hypertensive end-organ damage and secondary diseases are key determinants of cardiovascular prognosis in patients suffering from arterial hypertension. Presently, there are no biomarkers for the detection of hypertensive target organ damage, most outstandingly including blood vessels, the heart, and the kidneys. We aimed to validate the usefulness of the urinary excretion of the serine protease kallikrein-related peptidase 9 (KLK9) as a biomarker of hypertension-induced target organ damage. Urinary, plasma, and renal tissue levels of KLK9 were measured by the Western blot in different rat models of hypertension, including angiotensin-II infusion, DOCA-salt, L-NAME administration, and spontaneous hypertension. Urinary levels were associated to cardiovascular and renal injury, assessed by histopathology. The origin of urinary KLK9 was investigated through in situ renal perfusion experiments. The urinary excretion of KLK9 is increased in different experimental models of hypertension in rats. The ACE inhibitor trandolapril significantly reduced arterial pressure and the urinary level of KLK9. Hypertension did not increase kidney, heart, liver, lung, or plasma KLK9 levels. Hypertension-induced increased urinary excretion of KLK9 results from specific alterations in its tubular reabsorption, even in the absence of overt nephropathy. KLK9 urinary excretion strongly correlates with cardiac hypertrophy and aortic wall thickening. KLK9 appears in the urine in the presence of hypertension as a result of subtle renal handling alterations. Urinary KLK9 might be potentially used as an indicator of hypertensive cardiac and vascular damage. PMID:26469898

Urinary Sugars--A Biomarker of Total Sugars Intake.

PubMed

Tasevska, Natasha

2015-07-15

Measurement error in self-reported sugars intake may explain the lack of consistency in the epidemiologic evidence on the association between sugars and disease risk. This review describes the development and applications of a biomarker of sugars intake, informs its future use and recommends directions for future research. Recently, 24 h urinary sucrose and fructose were suggested as a predictive biomarker for total sugars intake, based on findings from three highly controlled feeding studies conducted in the United Kingdom. From this work, a calibration equation for the biomarker that provides an unbiased measure of sugars intake was generated that has since been used in two US-based studies with free-living individuals to assess measurement error in dietary self-reports and to develop regression calibration equations that could be used in future diet-disease analyses. Further applications of the biomarker include its use as a surrogate measure of intake in diet-disease association studies. Although this biomarker has great potential and exhibits favorable characteristics, available data come from a few controlled studies with limited sample sizes conducted in the UK. Larger feeding studies conducted in different populations are needed to further explore biomarker characteristics and stability of its biases, compare its performance, and generate a unique, or population-specific biomarker calibration equations to be applied in future studies. A validated sugars biomarker is critical for informed interpretation of sugars-disease association studies.

Urinary Sugars—A Biomarker of Total Sugars Intake

PubMed Central

Tasevska, Natasha

2015-01-01

Measurement error in self-reported sugars intake may explain the lack of consistency in the epidemiologic evidence on the association between sugars and disease risk. This review describes the development and applications of a biomarker of sugars intake, informs its future use and recommends directions for future research. Recently, 24 h urinary sucrose and fructose were suggested as a predictive biomarker for total sugars intake, based on findings from three highly controlled feeding studies conducted in the United Kingdom. From this work, a calibration equation for the biomarker that provides an unbiased measure of sugars intake was generated that has since been used in two US-based studies with free-living individuals to assess measurement error in dietary self-reports and to develop regression calibration equations that could be used in future diet-disease analyses. Further applications of the biomarker include its use as a surrogate measure of intake in diet-disease association studies. Although this biomarker has great potential and exhibits favorable characteristics, available data come from a few controlled studies with limited sample sizes conducted in the UK. Larger feeding studies conducted in different populations are needed to further explore biomarker characteristics and stability of its biases, compare its performance, and generate a unique, or population-specific biomarker calibration equations to be applied in future studies. A validated sugars biomarker is critical for informed interpretation of sugars-disease association studies. PMID:26184307

Estimation of Inorganic Arsenic Exposure in Populations With Frequent Seafood Intake: Evidence From MESA and NHANES

PubMed Central

Jones, Miranda R.; Tellez-Plaza, Maria; Vaidya, Dhananjay; Grau, Maria; Francesconi, Kevin A.; Goessler, Walter; Guallar, Eliseo; Post, Wendy S.; Kaufman, Joel D.; Navas-Acien, Ana

2016-01-01

The sum of urinary inorganic arsenic (iAs) and methylated arsenic (monomethylarsonate and dimethylarsinate (DMA)) species is the main biomarker of iAs exposure. Assessing iAs exposure, however, is difficult in populations with moderate-to-high seafood intakes. In the present study, we used subsamples from the Multi-Ethnic Study of Atherosclerosis (2000–2002) (n = 310) and the 2003–2006 National Health and Nutrition Examination Survey (n = 1,175). We calibrated urinary concentrations of non–seafood-derived iAs, DMA, and methylarsonate, as well as the sum of inorganic and methylated arsenic species, in the Multi-Ethnic Study of Atherosclerosis and of DMA in the National Health and Nutrition Examination Survey by regressing their original concentrations by arsenobetaine and extracting model residuals. To confirm that calibrated biomarkers reflected iAs exposure but not seafood intake, we compared urinary arsenic concentrations by levels of seafood and rice intakes. Self-reported seafood intakes, estimated n-3 polyunsaturated fatty acid levels, and measured n-3 polyunsaturated fatty acid levels were positively associated with the original urinary arsenic biomarkers. Using the calibrated arsenic biomarkers, we found a marked attenuation of the associations with self-reported seafood intake and estimated or measured n-3 fatty acids, whereas associations with self-reported rice intake remained similar. Our residual-based method provides estimates of iAs exposure and metabolism for each participant that no longer reflect seafood intake and can facilitate research about low-to-moderate levels of iAs exposure in populations with high seafood intakes. PMID:27702745

Evaluation of Temporal Changes in Urine-based Metabolomic and Kidney Injury Markers to Detect Compound Induced Acute Kidney Tubular Toxicity in Beagle Dogs.

PubMed

Wagoner, M P; Yang, Y; McDuffie, J E; Klapczynski, M; Buck, W; Cheatham, L; Eisinger, D; Sace, F; Lynch, K M; Sonee, M; Ma, J-Y; Chen, Y; Marshall, K; Damour, M; Stephen, L; Dragan, Y P; Fikes, J; Snook, S; Kinter, L B

2017-01-01

Urinary protein biomarkers and metabolomic markers have been leveraged to detect acute Drug Induced Kidney Injury (DIKI) in rats; however, the utility of these indicators to enable early detection of DIKI in canine models has not been well documented. Therefore, we evaluated temporal changes in biomarkers and metabolites in urine from male and female beagle dogs. Gentamicin- induced kidney lesions in male dogs were characterized by moderate to severe tubular epithelial cell degeneration/necrosis, epithelial cell regeneration and dilation; and a unique urinebased metabolomic fingerprint. These metabolite changes included time and treatment-dependent increases in lactate, taurine, glucose, lactate, alanine, and citrate as well as 9 other known metabolites. As early as 3 days post dose, gentamicin induced increases in urinary albumin, clusterin, neutrophil gelatinase associated protein (NGAL) and total protein concentrations. Urinary albumin, clusterin, and NGAL showed earlier and more robust elevations than traditional kidney safety biomarkers, blood urea nitrogen and serum creatinine. Elevations in urinary kidney injury molecule 1 (KIM-1) were less reliable for detection of gentamicin nephrotoxicity in dogs based on values generated utilizing multiple first-generation, canine-specific KIM-1 immunoassays. The metabolic fingerprint was further evaluated in male and female dogs that received Compound A which induced slightly reversible renal tubular alterations characterized as degeneration/necrosis and concurrent significant increases in urinary taurine amongst other markers. These data support further investigations to demonstrate the value of urinary metabolites, albumin, clusterin, NGAL and taurine as promising markers to enable early detection of DIKI in dogs. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Comparing Urinary Biomarkers of Airborne and Dermal Exposure to Polycyclic Aromatic Compounds in Asphalt-Exposed Workers

PubMed Central

Sobus, Jon R.; McClean, Michael D.; Herrick, Robert F.; Waidyanatha, Suramya; Nylander-French, Leena A.; Kupper, Lawrence L.; Rappaport, Stephen M.

2009-01-01

When working with hot mix asphalt, road pavers are exposed to polycyclic aromatic hydrocarbons (PAHs) through the inhalation of vapors and particulate matter (PM) and through dermal contact with PM and contaminated surfaces. Several PAHs with four to six rings are potent carcinogens which reside in these particulate emissions. Since urinary biomarkers of large PAHs are rarely detectable in asphalt workers, attention has focused upon urinary levels of the more volatile and abundant two-ring and three-ring PAHs as potential biomarkers of PAH exposure. Here, we compare levels of particulate polycyclic aromatic compounds (P-PACs, a group of aromatic hydrocarbons containing PAHs and heterocyclic compounds with four or more rings) in air and dermal patch samples from 20 road pavers to the corresponding urinary levels of naphthalene (U-Nap) (two rings), phenanthrene (U-Phe) (three rings), monohydroxylated metabolites of naphthalene (OH-Nap) and phenanthrene (OH-Phe), and 1-hydroxypyrene (OH-Pyr) (four rings), the most widely used biomarker of PAH exposure. For each worker, daily breathing-zone air (n = 55) and dermal patch samples (n = 56) were collected on three consecutive workdays along with postshift, bedtime, and morning urine samples (n = 149). Measured levels of P-PACs and the urinary analytes were used to statistically model exposure–biomarker relationships while controlling for urinary creatinine, smoking status, age, body mass index, and the timing of urine sampling. Levels of OH-Phe in urine collected postshift, at bedtime, and the following morning were all significantly associated with levels of P-PACs in air and dermal patch samples. For U-Nap, U-Phe, and OH-Pyr, both air and dermal patch measurements of P-PACs were significant predictors of postshift urine levels, and dermal patch measurements were significant predictors of bedtime urine levels (all three analytes) and morning urine levels (U-Nap and OH-Pyr only). Significant effects of creatinine concentration were observed for all analytes, and modest effects of smoking status and body mass index were observed for U-Phe and OH-Pyr, respectively. Levels of OH-Nap were not associated with P-PAC measurements in air or dermal patch samples but were significantly affected by smoking status, age, day of sample collection, and urinary creatinine. We conclude that U-Nap, U-Phe, OH-Phe, and OH-Pyr can be used as biomarkers of exposure to particulate asphalt emissions, with OH-Phe being the most promising candidate. Indications that levels of U-Nap, U-Phe, and OH-Pyr were significantly associated with dermal patch measurements well into the evening after a given work shift, combined with the small ratios of within-person variance components to between-person variance components at bedtime, suggest that bedtime measurements may be useful for investigating dermal PAH exposures. PMID:19602502

Increased levels of etheno-DNA adducts and genotoxicity biomarkers of long-term exposure to pure diesel engine exhaust.

PubMed

Shen, Meili; Bin, Ping; Li, Haibin; Zhang, Xiao; Sun, Xin; Duan, Huawei; Niu, Yong; Meng, Tao; Dai, Yufei; Gao, Weimin; Yu, Shanfa; Gu, Guizhen; Zheng, Yuxin

2016-02-01

Etheno-DNA adducts are biomarkers for assessing oxidative stress. In this study, the aim was to detect the level of etheno-DNA adducts and explore the relationship between the etheno-DNA adducts and genotoxicity biomarkers of the diesel engine exhaust (DEE)-exposed workers. We recruited 86 diesel engine testing workers with long-term exposure to DEE and 99 non-DEE-exposed workers. The urinary mono-hydroxylated polycyclic aromatic hydrocarbons (OH-PAHs) and etheno-DNA adducts (εdA and εdC) were detected by HPLC-MS/MS and UPLC-MS/MS, respectively. Genotoxicity biomarkers were also evaluated by comet assay and cytokinesis-block micronucleus assay. The results showed that urinary εdA was significantly higher in the DEE-exposed workers (p<0.001), exhibited 2.1-fold increase compared with the non-DEE-exposed workers. The levels of urinary OH-PAHs were positively correlated with the level of εdA among all the study subjects (p<0.001). Moreover, we found that the increasing level of εdA was significantly associated with the increased olive tail moment, percentage of tail DNA, or frequency of micronucleus in the study subjects (p<0.01). No significant association was observed between the εdC level and any measured genotoxicity biomarkers. In summary, εdA could serve as an indicator for DEE exposure in the human population. Copyright © 2015 Elsevier B.V. All rights reserved.

Methodologies for the quantitative estimation of toxicant dose to cigarette smokers using physical, chemical and bioanalytical data.

PubMed

St Charles, Frank Kelley; McAughey, John; Shepperd, Christopher J

2013-06-01

Methodologies have been developed, described and demonstrated that convert mouth exposure estimates of cigarette smoke constituents to dose by accounting for smoke spilled from the mouth prior to inhalation (mouth-spill (MS)) and the respiratory retention (RR) during the inhalation cycle. The methodologies are applicable to just about any chemical compound in cigarette smoke that can be measured analytically and can be used with ambulatory population studies. Conversion of exposure to dose improves the relevancy for risk assessment paradigms. Except for urinary nicotine plus metabolites, biomarkers generally do not provide quantitative exposure or dose estimates. In addition, many smoke constituents have no reliable biomarkers. We describe methods to estimate the RR of chemical compounds in smoke based on their vapor pressure (VP) and to estimate the MS for a given subject. Data from two clinical studies were used to demonstrate dose estimation for 13 compounds, of which only 3 have urinary biomarkers. Compounds with VP > 10(-5) Pa generally have RRs of 88% or greater, which do not vary appreciably with inhalation volume (IV). Compounds with VP < 10(-7) Pa generally have RRs dependent on IV and lung exposure time. For MS, mean subject values from both studies were slightly greater than 30%. For constituents with urinary biomarkers, correlations with the calculated dose were significantly improved over correlations with mouth exposure. Of toxicological importance is that the dose correlations provide an estimate of the metabolic conversion of a constituent to its respective biomarker.

Proteomic Candidate Biomarkers of Drug-Induced Nephrotoxicity in the Rat

PubMed Central

Rouse, Rodney; Siwy, Justyna; Mullen, William; Mischak, Harald; Metzger, Jochen; Hanig, Joseph

2012-01-01

Improved biomarkers of acute nephrotoxicity are coveted by the drug development industry, regulatory agencies, and clinicians. In an effort to identify such biomarkers, urinary peptide profiles of rats treated with two different nephrotoxins were investigated. 493 marker candidates were defined that showed a significant response to cis-platin comparing a cis-platin treated cohort to controls. Next, urine samples from rats that received three consecutive daily doses of 150 or 300 mg/kg gentamicin were examined. 557 potential biomarkers were initially identified; 108 of these gentamicin-response markers showed a clear temporal response to treatment. 39 of the cisplatin-response markers also displayed a clear response to gentamicin. Of the combined 147 peptides, 101 were similarly regulated by gentamicin or cis-platin and 54 could be identified by tandem mass spectrometry. Most were collagen type I and type III fragments up-regulated in response to gentamicin treatment. Based on these peptides, classification models were generated and validated in a longitudinal study. In agreement with histopathology, the observed changes in classification scores were transient, initiated after the first dose, and generally persistent over a period of 10–20 days before returning to control levels. The data support the hypothesis that gentamicin-induced renal toxicity up-regulates protease activity, resulting in an increase in several specific urinary collagen fragments. Urinary proteomic biomarkers identified here, especially those common to both nephrotoxins, may serve as a valuable tool to investigate potential new drug candidates for the risk of nephrotoxicity. PMID:22509332

A characteristic biosignature for discrimination of gastric cancer from healthy population by high throughput GC-MS analysis

PubMed Central

Guo, Lei; Liu, Lei; Wen, Jingran; Xu, Lu; Yan, Min; Li, Zuofeng; Zhang, Xiaoyan; Nan, Peng; Jiang, Jinling; Ji, Jun; Zhang, Jianian; Cai, Wei; Zhuang, Huisheng; Wang, Yan; Zhu, Zhenggang; Yu, Yingyan

2016-01-01

Early diagnosis of gastric cancer is crucial to improve patient′ outcome. A good biomarker will function in early diagnosis for gastric cancer. In order to find practical and cost-effective biomarkers, we used gas chromatography combined mass spectrometer (GC-MS) to profile urinary metabolites on 293 urine samples. Ninety-four samples are taken as training set, others for validating study. Orthogonal partial least squares discriminant analysis (OPLS-DA), significance analysis of microarray (SAM) and Mann-Whitney U test are used for data analysis. The diagnostic value of urinary metabolites was evaluated by ROC curve. As results, Seventeen metabolites are significantly different between patients and healthy controls in training set. Among them, 14 metabolites show diagnostic value better than classic blood biomarkers by quantitative assay on validation set. Ten of them are amino acids and four are organic metabolites. Importantly, proline, p-cresol and 4-hydroxybenzoic acid disclose outcome-prediction value by means of survival analysis. Therefore, the examination of urinary metabolites is a promising noninvasive strategy for gastric cancer screening. PMID:27589838

Evaluation of Urinary Btex, Nicotine, and Cotinine as Biomarkers of Airborne Pollutants in Nonsmokers and Smokers.

PubMed

Brajenović, Nataša; Karačonji, Irena Brčić; Bulog, Aleksandar

2015-01-01

Benzene, toluene, ethylbenzene, and isomeric xylenes (BTEX) are by-products of tobacco smoke and traffic emissions. The aim of this study was to determine the contribution of cigarette smoking to urinary levels of BTEX present in humans. Nicotine and cotinine, biomarkers of exposure to tobacco smoke, as well as BTEX, were measured in urine of smokers (n = 70) and nonsmokers (n = 65) using headspace solid-phase microextraction (HS-SPME) followed by gas chromatography-mass spectrometry (GC-MS). In smokers, a significant correlation was found between urinary BTEX levels and nicotine and cotinine. In addition, significant regression models with nicotine and cotinine as predictors showed that BTEX in smokers' urine was predominantly derived from exposure to tobacco smoke. In nonsmokers a weak correlation between BTEX and nicotine and cotinine was found in urine. Further, there was a lack of significant contribution of BTEX to urinary nicotine and cotinine concentrations in nonsmokers. Thus, it was presumed that vehicle exhaust was the main source of exposure to BTEX in nonsmokers.

Reliability and validity of urinary nerve growth factor measurement in women with lower urinary tract symptoms.

PubMed

Vijaya, Gopalan; Cartwright, Rufus; Bhide, Alka; Derpapas, Alexandros; Fernando, Ruwan; Khullar, Vik

2016-11-01

The validity and reliability of measurement of urinary NGF as a diagnostic biomarker in women with lower urinary tract dysfunction (LUTD) is uncertain. We aimed to evaluate both the diagnostic and discriminant validity, and the test-retest reliability of urinary NGF measurement in women with LUTD. Urinary NGF was measured in women with LUTD (n = 205) and asymptomatic subjects (n = 31). Urinary NGF was assayed using an ELISA method and normalized against urinary creatinine. NGF/creatinine ratios were compared between symptom subgroups using Mann-Whitney U test, and between different urodynamic diagnoses using the Kruskal-Wallis test. Receiver Operator Characteristic (ROC) analysis was employed to evaluate the diagnostic performance of urinary NGF. Test-retest reliability of NGF measurement was assessed using intra-class correlation (ICC). Urinary NGF was significantly but non-specifically increased in symptomatic patients when compared to controls (13.33 vs. 2.05 ng NGF/g Cr, P < 0.001). On multivariate logistic regression NGF was a good predictor of patients having OAB or not, however, the adjusted odds ratio only 1.006. ROC analysis demonstrated poor discriminant ability between different symptomatic groups and urodynamic groups. Using a cut off of 13.0 ng NGF/g creatinine the test provides a sensitivity of 81%, but a specificity of only 39% for overactive bladder. The assays demonstrated good test-retest reliability with ICC of 0.889. Although urinary NGF can be reliably assayed, and is increased in various LUTDs, it discriminates poorly between these disorders therefore has very limited potential as a biomarker. Neurourol. Urodynam. 35:944-948, 2016. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

Urinary Biomarkers KIM-1 and NGAL for Detection of Chronic Kidney Disease of Uncertain Etiology (CKDu) among Agricultural Communities in Sri Lanka.

PubMed

De Silva, Pallagae Mangala C S; Mohammed Abdul, Khaja Shameem; Eakanayake, Eakanayake M D V; Jayasinghe, Sudheera Sammanthi; Jayasumana, Channa; Asanthi, Hewa Bandulage; Perera, Hettiarachigae S D; Chaminda, Gamage G Tushara; Chandana, Ediriweera P S; Siribaddana, Sisira H

2016-09-01

Chronic Kidney Disease of uncertain etiology (CKDu) is an emerging epidemic among farming communities in rural Sri Lanka. Victims do not exhibit common causative factors, however, histopathological studies revealed that CKDu is a tubulointerstitial disease. Urine albumin or albumin-creatinine ratio is still being used as a traditional diagnostic tool to identify CKDu, but accuracy and prevalence data generated are questionable. Urinary biomarkers have been used in similar nephropathy and are widely recognised for their sensitivity, specificity and accuracy in determining CKDu and early renal injury. However, these biomarkers have never been used in diagnosing CKDu in Sri Lanka. Male farmers (n = 1734) were recruited from 4 regions in Sri Lanka i.e. Matara and Nuwara Eliya (farming locations with no CKDu prevalence) and two CKDu emerging locations from Hambantota District in Southern Sri Lanka; Angunakolapelessa (EL1) and Bandagiriya (EL2). Albuminuria (ACR ≥ 30mg/g); serum creatinine based estimation of glomerular filtration rate (eGFR); creatinine normalized urinary kidney injury molecule (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) were measured. Fourteen new CKDu cases (18%) from EL1 and nine CKDu cases (9%) from EL2 were recognized for the first time from EL1, EL2 locations, which were previously considered as non-endemic of the disease and associated with persistent albuminuria (ACR ≥ 30mg/g Cr). No CKDu cases were identified in non-endemic study locations in Matara (CM) and Nuwara Eliya (CN). Analysis of urinary biomarkers showed urinary KIM-1 and NGAL were significantly higher in new CKDu cases in EL1 and EL2. However, we also reported significantly higher KIM-1 and NGAL in apparently healthy farmers in EL 1 and EL 2 with comparison to both control groups. These observations may indicate possible early renal damage in absence of persistent albuminuria and potential capabilities of urinary KIM-1 and NGAL in early detection of renal injury among farming communities in Southern Sri Lanka.

Urinary Biomarkers KIM-1 and NGAL for Detection of Chronic Kidney Disease of Uncertain Etiology (CKDu) among Agricultural Communities in Sri Lanka

PubMed Central

Mohammed Abdul, Khaja Shameem; Eakanayake, Eakanayake M. D. V.; Jayasinghe, Sudheera Sammanthi; Jayasumana, Channa; Asanthi, Hewa Bandulage; Perera, Hettiarachigae S. D.; Chaminda, Gamage G. Tushara; Chandana, Ediriweera P. S.; Siribaddana, Sisira H.

2016-01-01

Chronic Kidney Disease of uncertain etiology (CKDu) is an emerging epidemic among farming communities in rural Sri Lanka. Victims do not exhibit common causative factors, however, histopathological studies revealed that CKDu is a tubulointerstitial disease. Urine albumin or albumin-creatinine ratio is still being used as a traditional diagnostic tool to identify CKDu, but accuracy and prevalence data generated are questionable. Urinary biomarkers have been used in similar nephropathy and are widely recognised for their sensitivity, specificity and accuracy in determining CKDu and early renal injury. However, these biomarkers have never been used in diagnosing CKDu in Sri Lanka. Male farmers (n = 1734) were recruited from 4 regions in Sri Lanka i.e. Matara and Nuwara Eliya (farming locations with no CKDu prevalence) and two CKDu emerging locations from Hambantota District in Southern Sri Lanka; Angunakolapelessa (EL1) and Bandagiriya (EL2). Albuminuria (ACR ≥ 30mg/g); serum creatinine based estimation of glomerular filtration rate (eGFR); creatinine normalized urinary kidney injury molecule (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) were measured. Fourteen new CKDu cases (18%) from EL1 and nine CKDu cases (9%) from EL2 were recognized for the first time from EL1, EL2 locations, which were previously considered as non-endemic of the disease and associated with persistent albuminuria (ACR ≥ 30mg/g Cr). No CKDu cases were identified in non-endemic study locations in Matara (CM) and Nuwara Eliya (CN). Analysis of urinary biomarkers showed urinary KIM-1 and NGAL were significantly higher in new CKDu cases in EL1 and EL2. However, we also reported significantly higher KIM-1 and NGAL in apparently healthy farmers in EL 1 and EL 2 with comparison to both control groups. These observations may indicate possible early renal damage in absence of persistent albuminuria and potential capabilities of urinary KIM-1 and NGAL in early detection of renal injury among farming communities in Southern Sri Lanka. PMID:27643785

Mycotoxin exposure in rural residents in northern Nigeria: a pilot study using multi-urinary biomarkers.

PubMed

Ezekiel, Chibundu N; Warth, Benedikt; Ogara, Isaac M; Abia, Wilfred A; Ezekiel, Victoria C; Atehnkeng, Joseph; Sulyok, Michael; Turner, Paul C; Tayo, Grace O; Krska, Rudolf; Bandyopadhyay, Ranajit

2014-05-01

A pilot, cross-sectional, correlational study was conducted in eight rural communities in northern Nigeria to investigate mycotoxin exposures in 120 volunteers (19 children, 20 adolescents and 81 adults) using a modern LC-MS/MS based multi-biomarker approach. First morning urine samples were analyzed and urinary biomarker levels correlated with mycotoxin levels in foods consumed the day before urine collection. A total of eight analytes were detected in 61/120 (50.8%) of studied urine samples, with ochratoxin A, aflatoxin M1 and fumonisin B1 being the most frequently occurring biomarkers of exposure. These mycotoxin biomarkers were present in samples from all age categories, suggestive of chronic (lifetime) exposures. Rough estimates of mycotoxin intake suggested some exposures were higher than the tolerable daily intake. Overall, rural consumer populations from Nasarawa were more exposed to several mixtures of mycotoxins in their diets relative to those from Kaduna as shown by food and urine biomarker data. This study has shown that mycotoxin co-exposure may be a major public health challenge in rural Nigeria; this calls for urgent intervention. Copyright © 2014 Elsevier Ltd. All rights reserved.

Urinary NGAL and hematic ADMA levels: an early sign of cardio-renal syndrome in young adults born preterm?

PubMed

Bassareo, Pier Paolo; Fanos, Vassilios; Mussap, Michele; Flore, Giovanna; Noto, Antonio; Puddu, Melania; Saba, Luca; Mercuro, Giuseppe

2013-10-01

Prematurity at birth is a known risk factor for the development of an early chronic renal disease. Urinary neutrophil gelatinase-associated lipocalin (NGAL) is a well established biomarker of kidney injury, while high blood levels of asymmetric dimethylarginine (ADMA) are associated with the future development of adverse cardiovascular events and cardiac death. (1) to verify the presence of statistically significant differences between urinary NGAL and hematic ADMA levels in young adults born preterm at extremely low birth weight (<1000 g; ex-ELBW) and those of a control group of healthy adults born at term (C) (2) to seek correlations between NGAL and ADMA levels, which would indicate the presence of an early cardio-renal involvement in ex-ELBW. Twelve ex-ELBW subjects (six males and six female, mean age: 23.9 ± 3.2 years) were compared with 12 C (six males and six female). Urinary NGAL and hematic ADMA levels were assessed. Urinary NGAL levels were higher in ex- ELBW subjects compared to C (p < 0.05), as well as hematic ADMA concentrations (p < 0.05). A statistically significant correlation was found between urinary NGAL and ADMA (r = -0.60, p < 0.04). Our preliminary findings support the hypothesis that in ex-ELBW subjects the development of an early chronic kidney disease contributes towards inducing an increase in the atherosclerotic process and in the risk of future adverse cardiovascular events.

Comparing older and younger Japanese primiparae: fatigue, depression and biomarkers of stress.

PubMed

Mori, Emi; Maehara, Kunie; Iwata, Hiroko; Sakajo, Akiko; Tsuchiya, Miyako; Ozawa, Harumi; Morita, Akiko; Maekawa, Tomoko; Saeki, Akiko

2015-03-01

This cohort study of primiparae was conducted to answer the following questions: Do older (≧ 35 years) and younger (20-29 years) Japanese primiparous mothers differ when comparing biomarkers of stress and measures of fatigue and depression? Are there changes in fatigue, depression and stress biomarkers when comparing older and younger mothers during the postpartum period? The Postnatal Accumulated Fatigue Scale and the Edinburgh Postnatal Depression Scale were administered in a time-series method four times: shortly after birth and monthly afterwards. Assays to measure biomarkers of stress, urinary 17-ketosteroids, urinary 17-hydroxycorticosteroids and salivary chromogranin-A, were collected shortly after delivery and at 1 month postpartum in both groups and a third time in older mothers at the 4th month. Statistical testing showed very little difference in fatigue, depression or stress biomarkers between older and younger mothers shortly after birth or 1 month later. Accumulated fatigue and depression scores of older mothers were highest 1 month after delivery. Additional cohort studies are required to characterize physical/psychological well-being of older Japanese primiparae. © 2015 Wiley Publishing Asia Pty Ltd.

Biomarkers of oxidative stress and its association with the urinary reducing capacity in bus maintenance workers.

PubMed

Sauvain, Jean-Jacques; Setyan, Ari; Wild, Pascal; Tacchini, Philippe; Lagger, Grégoire; Storti, Ferdinand; Deslarzes, Simon; Guillemin, Michel; Rossi, Michel J; Riediker, Michael

2011-05-30

Exposure to particles (PM) induces adverse health effects (cancer, cardiovascular and pulmonary diseases). A key-role in these adverse effects seems to be played by oxidative stress, which is an excess of reactive oxygen species relative to the amount of reducing species (including antioxidants), the first line of defense against reactive oxygen species. The aim of this study was to document the oxidative stress caused by exposure to respirable particles in vivo, and to test whether exposed workers presented changes in their urinary levels for reducing species. Bus depot workers (n = 32) exposed to particles and pollutants (respirable PM4, organic and elemental carbon, particulate metal content, polycyclic aromatic hydrocarbons, NOx, O3) were surveyed over two consecutive days. We collected urine samples before and after each shift, and quantified an oxidative stress biomarker (8-hydroxy-2'-deoxyguanosine), the reducing capacity and a biomarker of PAH exposure (1-hydroxypyrene). We used a linear mixed model to test for associations between the oxidative stress status of the workers and their particle exposure as well as with their urinary level of reducing species. Workers were exposed to low levels of respirable PM4 (range 25-71 μg/m3). However, urinary levels of 8-hydroxy-2'-deoxyguanosine increased significantly within each shift and between both days for non-smokers. The between-day increase was significantly correlated (p < 0.001) with the concentrations of organic carbon, NOx, and the particulate copper content. The within-shift increase in 8OHdG was highly correlated to an increase of the urinary reducing capacity (Spearman ρ = 0.59, p < 0.0001). These findings confirm that exposure to components associated to respirable particulate matter causes a systemic oxidative stress, as measured with the urinary 8OHdG. The strong association observed between urinary 8OHdG with the reducing capacity is suggestive of protective or other mechanisms, including circadian effects. Additional investigations should be performed to understand these observations.

Interpretation of Urinary and Blood Benzene biomarkers of Exposure for Non-Occupationally Exposed Individuals

EPA Science Inventory

Non-occupational exposure to benzene occurs primarily through inhalation ofair impacted by motor vehicle exhaust, fuel sources, and cigarette smoke. This study relates published measurements ofbenzene biomarkers to air exposure concentrations. Benzene has three reliable biomar...

DOSE RECONSTRUCTION FROM URINARY BIOMARKERS

EPA Science Inventory

The use of biomarkers for human health risk assessment is attractive because they are an indicator of the dose that actually entered the body by all mechanisms. This is an important consideration given the need to include aggregate exposures from diet and other pathways for pes...

Genetic and Epigenetic Biomarkers for Recurrent Prostate Cancer After Radiotherapy

DTIC Science & Technology

2013-05-01

prostatectomy are urinary incontinence , erectile dysfunction, and typical post-operative complications. Radiation therapy (RT) shows several distinct...includes a low risk of urinary incontinence . Major disadvantage of external beam RT include a treatment course of 8-9 weeks. -50% of patients have some...this treatment include the risk of acute urinary retention. Currently, the level of PSA, clinical stage and the Gleason score are used to

Urine biomarkers informative of human kidney allograft rejection and tolerance.

PubMed

Nissaisorakarn, Voravech; Lee, John Richard; Lubetzky, Michelle; Suthanthiran, Manikkam

2018-05-01

We developed urinary cell messenger RNA (mRNA) profiling to monitor in vivo status of human kidney allografts based on our conceptualization that the kidney allograft may function as an in vivo flow cell sorter allowing access of graft infiltrating cells to the glomerular ultrafiltrate and that interrogation of urinary cells is informative of allograft status. For the profiling urinary cells, we developed a two-step preamplification enhanced real-time quantitative PCR (RT-QPCR) assays with a customized amplicon; preamplification compensating for the low RNA yield from urine and the customized amplicon facilitating absolute quantification of mRNA and overcoming the inherent limitations of relative quantification widely used in RT-QPCR assays. Herein, we review our discovery and validation of urinary cell mRNAs as noninvasive biomarkers prognostic and diagnostic of acute cellular rejection (ACR) in kidney allografts. We summarize our results reflecting the utility of urinary cell mRNA profiling for predicting reversal of ACR with anti-rejection therapy; differential diagnosis of kidney allograft dysfunction; and noninvasive diagnosis and prognosis of BK virus nephropathy. Messenger RNA profiles associated with human kidney allograft tolerance are also summarized in this review. Altogether, data supporting the idea that urinary cell mRNA profiles are informative of kidney allograft status and tolerance are reviewed in this report. Copyright © 2018. Published by Elsevier Inc.

Biomarkers of oxidative stress in electroplating workers exposed to hexavalent chromium.

PubMed

Pan, Chih-Hong; Jeng, Hueiwang Anna; Lai, Ching-Huang

2018-01-01

This study evaluates levels of biomarkers of oxidative DNA damage and lipid peroxidation in 105 male workers at 16 electroplating companies who had been exposed to hexavalent chromium (Cr(VI)). The study participants were 230 non-smoking male workers, comprising 105 electroplating workers who had been exposed to chromium and 125 control subjects who performed office tasks. Personal air samples, spot urine samples, hair samples, fingernail samples and questionnaires were used to quantify exposure to Cr(VI), oxidative DNA damage, lipid peroxidation, and environmental pollutants. Both the geometric mean personal concentrations of Cr(VI) of the Cr-exposed workers and the total Cr concentrations in the air to which they were exposed significantly exceeded those for the control subjects. The geometric mean concentrations of Cr in urine, hair and fingernails, and the urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG), and malondialdehyde (MDA) levels in the Cr(VI) exposed workers exceeded those in the control subjects. Daily cumulative Cr(VI) exposure and urinary Cr were significantly correlated with urinary 8-OHdG levels following adjustments for covariates. A ten-fold increase in urinary Cr level was associated with a 1.73-fold increase in urinary 8-OHdG level. Daily cumulative Cr(VI) exposure and urinary Cr level were significantly correlated with urinary MDA level following adjustments for covariates. A ten-fold increase in urinary Cr was associated with a 1.45-fold increase in urinary MDA. Exposure to Cr(VI) increased oxidative DNA injury and the oxidative deterioration of lipids in electroplating workers.

First Post-Operative Urinary Kidney Injury Biomarkers and Association with the Duration of AKI in the TRIBE-AKI Cohort

PubMed Central

Coca, Steven G.; Nadkarni, Girish N.; Garg, Amit X.; Koyner, Jay; Thiessen-Philbrook, Heather; McArthur, Eric; Shlipak, Michael G.; Parikh, Chirag R.

2016-01-01

Background We previously demonstrated that assessment of the duration of AKI, in addition to magnitude of rise in creatinine alone, adds prognostic information for long-term survival. We evaluated whether post-operative kidney injury biomarkers in urine collected immediately after cardiac surgery associate with duration of serum creatinine elevation. Methods We studied 1199 adults undergoing cardiac surgery in a prospective cohort study (TRIBE-AKI) and examined the association between the levels of five urinary biomarkers individually at 0–6 hours after surgery: interleukin-18 (IL-18), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), liver fatty acid binding protein (L-FABP) and albumin with duration of serum creatinine-based AKIN criteria for AKI (0 (no AKI), 1–2, 3–6, ≥7 days). Results Overall, 407 (34%) patients had at least stage 1 AKI, of whom 251 (61.7%) had duration of 1–2 days, 118 (28.9%) had duration 3–6 days, and 38 (9.3%) had duration of ≥7 days. Higher concentrations of all biomarkers (per log increase) were independently associated with a greater odds of a longer duration of AKI; odds ratios and 95% confidence intervals using ordinal logistic regression were the following: IL-18: 1.22, 1.13–1.32; KIM-1: 1.36, 1.21–1.52; albumin 1.20, 1.09–1.32; L-FABP 1.11, 1.04–1.19; NGAL 1.06, 1.00–1.14). AKI duration of 7 days or longer was associated with a 5-fold adjusted risk of mortality at 3 years. Conclusions There was an independent dose-response association between urinary levels of injury biomarkers immediately after cardiac surgery and longer duration of AKI. Duration of AKI was also associated with long term mortality. Future studies should explore the potential utility of these urinary kidney injury biomarkers to enrich enrollment of patients at risk for longer duration of AKI into trials of interventions to prevent or treat post-operative AKI. PMID:27537050

Phytoestrogen Concentrations in Human Urine as Biomarkers for Dietary Phytoestrogen Intake in Mexican Women

PubMed Central

Chávez-Suárez, Karina M.; Ortega-Vélez, María I.; Valenzuela-Quintanar, Ana I.; Galván-Portillo, Marcia; López-Carrillo, Lizbeth; Esparza-Romero, Julián; Saucedo-Tamayo, María S.; Robles-Burgueño, María R.; Gutiérrez-Coronado, María L.; Campa-Siqueiros, Melissa M.; Grajeda-Cota, Patricia; Caire-Juvera, Graciela

2017-01-01

There has been substantial interest in phytoestrogens, because of their potential effect in reducing cancer and heart disease risk. Measuring concentrations of phytoestrogens in urine is an alternative method for conducting epidemiological studies. Our objective was to evaluate the urinary excretion of phytoestrogens as biomarkers for dietary phytoestrogen intake in Mexican women. Participants were 100 healthy women from 25 to 80 years of age. A food frequency questionnaire (FFQ) and a 24 h recall were used to estimate habitual and recent intakes of isoflavones, lignans, flavonols, coumestrol, resveratrol, naringenin, and luteolin. Urinary concentrations were measured by liquid chromatography (HPLC) coupled to mass spectrometry (MS) using the electrospray ionization interface (ESI) and diode array detector (DAD) (HPLC-DAD-ESI-MS). Spearman correlation coefficients were used to evaluate associations between dietary intake and urine concentrations. The habitual consumption (FFQ) of total phytoestrogens was 37.56 mg/day. In urine, the higher compounds were naringenin (60.1 µg/L) and enterolactone (41.7 µg/L). Recent intakes (24 h recall) of isoflavones (r = 0.460, p < 0.001), lignans (r = 0.550, p < 0.0001), flavonoids (r = 0.240, p < 0.05), and total phytoestrogens (r = 0.410, p < 0.001) were correlated to their urinary levels. Total phytoestrogen intakes estimated by the FFQ showed higher correlations to urinary levels (r = 0.730, p < 0.0001). Urinary phytoestrogens may be useful as biomarkers of phytoestrogen intake, and as a tool for evaluating the relationship of intake and disease risk in Mexican women. PMID:28961176

Intraluminal proteome and peptidome of human urinary extracellular vesicles.

PubMed

Liu, Xinyu; Chinello, Clizia; Musante, Luca; Cazzaniga, Marta; Tataruch, Dorota; Calzaferri, Giulio; James Smith, Andrew; De Sio, Gabriele; Magni, Fulvio; Zou, Hequn; Holthofer, Harry

2015-06-01

Urinary extracellular vesicles (UEVs) are a novel source for disease biomarker discovery. However, Tamm-Horsfall protein (THP) is still a challenge for proteomic analysis since it can inhibit detection of low-abundance proteins. Here, we introduce a new approach that does not involve an ultracentrifugation step to enrich vesicles and that reduces the amount of THP to manageable levels. UEVs were dialyzed and ultrafiltered after reduction and alkylation. The retained fraction was digested with trypsin to reduce the remaining THP and incubated with deoxycholate (DOC). The internal peptidome and internal proteome were analyzed by LC-ESI-MS. A total of 942 different proteins and 3115 unique endogenous peptide fragments deriving from 973 different protein isoforms were identified. Around 82% of the key endosomal sorting complex required for transport components of UEVs generation could be detected from the intraluminal content. Our UEVs preparation protocol provides a simplified way to investigate the intraluminal proteome and peptidome, in particular the subpopulation of UEVs of the trypsin-resistant class of exosomes (positive for tumor susceptibility gene101) and eliminates the majority of interfering proteins such as THP. This method allows the possibility to study endoproteome and endopeptidome of UEVs, thus greatly facilitating biomarker discovery. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Identification of novel non-invasive biomarkers of urinary chronic pelvic pain syndrome: findings from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network.

PubMed

Dagher, Adelle; Curatolo, Adam; Sachdev, Monisha; Stephens, Alisa J; Mullins, Chris; Landis, J Richard; van Bokhoven, Adrie; El-Hayek, Andrew; Froehlich, John W; Briscoe, Andrew C; Roy, Roopali; Yang, Jiang; Pontari, Michel A; Zurakowski, David; Lee, Richard S; Moses, Marsha A

2017-07-01

To examine a series of candidate markers for urological chronic pelvic pain syndrome (UCPPS), selected based on their proposed involvement in underlying biological processes so as to provide new insights into pathophysiology and suggest targets for expanded clinical and mechanistic studies. Baseline urine samples from Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network study participants with UCPPS (n = 259), positive controls (PCs; chronic pain without pelvic pain, n = 107) and healthy controls (HCs, n = 125) were analysed for the presence of proteins that are suggested in the literature to be associated with UCPPS. Matrix metalloproteinase (MMP)-2, MMP-9, MMP-9/neutrophil gelatinase-associated lipocalin (NGAL) complex (also known as Lipocalin 2), vascular endothelial growth factor (VEGF), VEGF receptor 1 (VEGF-R1) and NGAL were assayed and quantitated using mono-specific enzyme-linked immunosorbent assays for each protein. Log-transformed concentration (pg/mL or ng/mL) and concentration normalized to total protein (pg/μg) values were compared among the UCPPS, PC and HC groups within sex using the Student's t-test, with P values adjusted for multiple comparisons. Multivariable logistic regression and receiver-operating characteristic curves assessed the utility of the biomarkers in distinguishing participants with UCPPS and control participants. Associations of protein with symptom severity were assessed by linear regression. Significantly higher normalized concentrations (pg/μg) of VEGF, VEGF-R1 and MMP-9 in men and VEGF concentration (pg/mL) in women were associated with UCPPS vs HC. These proteins provided only marginal discrimination between UCPPS participants and HCs. In men with UCCPS, pain severity was significantly positively associated with concentrations of MMP-9 and MMP-9/NGAL complex, and urinary severity was significantly positively associated with MMP-9, MMP-9/NGAL complex and VEGF-R1. In women with UCPPS, pain and urinary symptom severity were associated with increased normalized concentrations of MMP-9/NGAL complex, while pain severity alone was associated with increased normalized concentrations of VEGF, and urinary severity alone was associated with increased normalized concentrations of MMP-2. Pain severity in women with UCPPS was significantly positively associated with concentrations of all biomarkers except NGAL, and urinary severity with all concentrations except VEGF-R1. Altered levels of MMP-9, MMP-9/NGAL complex and VEGF-R1 in men, and all biomarkers in women, were associated with clinical symptoms of UCPPS. None of the evaluated candidate markers usefully discriminated UCPPS patients from controls. Elevated VEGF, MMP-9 and VEGF-R1 levels in men and VEGF levels in women may provide potential new insights into the pathophysiology of UCPPS. © 2017 The Authors BJU International © 2017 BJU International Published by John Wiley & Sons Ltd.

Spot Sampling and Exposure Surrogate Selection as Sources of Bias in Environmental Epidemiology Studies

EPA Science Inventory

Spot measurements of chemical biomarkers are often used as quantitative exposure surrogates in environmental epidemiology studies. These measures can be expressed a number of different ways – for example, urinary biomarkers can be expressed in units of concentration (&micr...

Naturally Occurring Human Urinary Peptides for Use in Diagnosis of Chronic Kidney Disease*

PubMed Central

Good, David M.; Zürbig, Petra; Argilés, Àngel; Bauer, Hartwig W.; Behrens, Georg; Coon, Joshua J.; Dakna, Mohammed; Decramer, Stéphane; Delles, Christian; Dominiczak, Anna F.; Ehrich, Jochen H. H.; Eitner, Frank; Fliser, Danilo; Frommberger, Moritz; Ganser, Arnold; Girolami, Mark A.; Golovko, Igor; Gwinner, Wilfried; Haubitz, Marion; Herget-Rosenthal, Stefan; Jankowski, Joachim; Jahn, Holger; Jerums, George; Julian, Bruce A.; Kellmann, Markus; Kliem, Volker; Kolch, Walter; Krolewski, Andrzej S.; Luppi, Mario; Massy, Ziad; Melter, Michael; Neusüss, Christian; Novak, Jan; Peter, Karlheinz; Rossing, Kasper; Rupprecht, Harald; Schanstra, Joost P.; Schiffer, Eric; Stolzenburg, Jens-Uwe; Tarnow, Lise; Theodorescu, Dan; Thongboonkerd, Visith; Vanholder, Raymond; Weissinger, Eva M.; Mischak, Harald; Schmitt-Kopplin, Philippe

2010-01-01

Because of its availability, ease of collection, and correlation with physiology and pathology, urine is an attractive source for clinical proteomics/peptidomics. However, the lack of comparable data sets from large cohorts has greatly hindered the development of clinical proteomics. Here, we report the establishment of a reproducible, high resolution method for peptidome analysis of naturally occurring human urinary peptides and proteins, ranging from 800 to 17,000 Da, using samples from 3,600 individuals analyzed by capillary electrophoresis coupled to MS. All processed data were deposited in an Structured Query Language (SQL) database. This database currently contains 5,010 relevant unique urinary peptides that serve as a pool of potential classifiers for diagnosis and monitoring of various diseases. As an example, by using this source of information, we were able to define urinary peptide biomarkers for chronic kidney diseases, allowing diagnosis of these diseases with high accuracy. Application of the chronic kidney disease-specific biomarker set to an independent test cohort in the subsequent replication phase resulted in 85.5% sensitivity and 100% specificity. These results indicate the potential usefulness of capillary electrophoresis coupled to MS for clinical applications in the analysis of naturally occurring urinary peptides. PMID:20616184

INFLUENCE OF DIETARY ARSENIC ON URINARY ARSENIC METABOLITE EXCRETION

EPA Science Inventory

Influence of Dietary Arsenic on Urinary Arsenic Metabolite Excretion

Cara L. Carty, M.S., Edward E. Hudgens, B.Sc., Rebecca L. Calderon, Ph.D., M.S.P.H., Richard Kwok, M.S.P.H., Epidemiology and Biomarkers Branch/HSD, NHEERL/US EPA; David J. Thomas, Ph.D., Pharmacokinetics...

Urinary 8-hydroxy-2-deoxyguanosine and cognitive function in Puerto Rican adults

USDA-ARS?s Scientific Manuscript database

DNA oxidative stress has been suggested as an important pathogenic mechanism in cognitive impairment and dementia. We, therefore, examined whether urinary 8-hydroxy-2-deoxyguanosine (8-OHdG), a biomarker of global DNA oxidation, was associated with cognitive function in a sample of Puerto Rican adul...

RESIDENTIAL PESTICIDE USE AND URINARY ORGANOPHOSPHATE METABOLITES IN PRE-SCHOOL CHILDREN

EPA Science Inventory

Residential Pesticide Use and Urinary Organophosphate Metabolites in Pre-School Children
CL Carty1, P Mendola1, D Barr2, L Needham2, D Walsh1

1Epidemiology and Biomarkers Branch, Human Studies Division, National Health and Environmental Effects Research Laboratory, U.S....

Nicotine Dependence and Urinary Nicotine, Cotinine and Hydroxycotinine Levels in Daily Smokers.

PubMed

Van Overmeire, Ilse P I; De Smedt, Tom; Dendale, Paul; Nackaerts, Kristiaan; Vanacker, Hilde; Vanoeteren, Jan F A; Van Laethem, Danny M G; Van Loco, Joris; De Cremer, Koen A J

2016-09-01

Nicotine dependence and smoking frequency are critical factors for smoking cessation. The aims of this study are (1) to determine if nicotine dependence Fagerström Test for Nicotine Dependence (FTND) scores are associated with urinary levels of nicotine metabolites, (2) to assess the relationship of hydroxycotinine/cotinine ratio with FTND score and cigarettes smoked per day (CPD), and (3) to identify significant predictors of cigarettes per day among biomarker concentrations and individual FTND items. Urine samples and questionnaire data of 239 daily smokers were obtained. Nicotine, cotinine and hydroxycotinine urinary levels were determined by UPLC MS/MS.Multiple linear regression models were developed to explore the relationship between nicotine, cotinine, hydroxycotinine levels and separate FTND scores (for all six items). We found significant correlations between the different urinary biomarker concentrations, and the FTND score. The time before the first cigarette after waking (TTFC) was significantly associated with the nicotine, cotinine and hydroxycotinine concentrations. No association was found between the ratio of hydroxycotinine to cotinine and either the FTND or the CPD. A model including four FTND questions, sex, age, and the cotinine concentration, accounted for 45% of the variance of CPD. There are significant relationships between urinary levels of nicotine, cotinine, and hydroxycotinine and the FTND score. Especially the FTND question about TTFC is relevant for explaining the biomarker concentrations. CPD (below 15) was significantly explained by four FTND dependence items and urinary cotinine levels in a regression model. We investigated associations between urinary levels of nicotine, cotinine, and hydroxycotinine in daily smokers and the FTND scores for nicotine dependence. We did not find association between the hydroxycotinine/cotinine ratio and CPD. We developed a model that explains the cigarettes smoked daily (CPD) in a group of light smokers by combining FTND items, urinary cotinine levels, sex, and age. Our results might be of importance for clinical use or future studies on larger smoking populations. © The Author 2016. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Reductions in biomarkers of exposure (BoE) to harmful or potentially harmful constituents (HPHCs) following partial or complete substitution of cigarettes with electronic cigarettes in adult smokers

PubMed Central

O’Connell, Grant; Graff, Donald W.; D’Ruiz, Carl D.

2016-01-01

Abstract Changes in fifteen urine, blood and exhaled breath BoEs of HPHCs representing classes of compounds reported by FDA to be significant contributors to smoking-associated disease risks were measured in 105 clinical-confined subjects following randomization and a five-day forced-switch from usual brand conventional combustible cigarettes to: (i) exclusive commercial e-cigarette use; (ii) dual-use of commercial e-cigarettes and the subject’s usual cigarette brand; or (iii) discontinued use of all tobacco or nicotine products. Levels of urinary biomarkers in subjects that completely substituted their usual cigarette with e-cigarettes were significantly lower (29–95%) after 5 days. Percent reductions in eight of nine urinary BoEs were indistinguishable to smokers who had quit smoking, except for nicotine equivalents, which declined by 25–40%. Dual users who halved self-reported daily cigarette consumption with e-cigarettes exhibited reductions (7–38%) in eight of nine urinary biomarkers, but had increase (1–20%) in nicotine equivalents. Reductions were broadly proportional to the reduced numbers of cigarettes smoked. Dual user urinary nicotine equivalents were slightly higher, but not statistically significant. After 5 days, blood nicotine biomarker levels were lower in the cessation (75–96%) and exclusive use groups (11–83%); with dual users experiencing no significant reductions. All subjects experienced significant decreases in exhaled CO. Decreases in the cessation and exclusive groups ranged from 88–89% and 27–32% in dual users. Exhaled NO increased in the cessation and exclusive groups (46–63% respectively), whereas the dual users experienced minimal changes. Overall, smokers who completely or partially substituted conventional cigarettes with e-cigarettes over five days, experienced reductions in HPHCs. PMID:27401591

Reductions in biomarkers of exposure (BoE) to harmful or potentially harmful constituents (HPHCs) following partial or complete substitution of cigarettes with electronic cigarettes in adult smokers.

PubMed

O'Connell, Grant; Graff, Donald W; D'Ruiz, Carl D

2016-07-01

Changes in fifteen urine, blood and exhaled breath BoEs of HPHCs representing classes of compounds reported by FDA to be significant contributors to smoking-associated disease risks were measured in 105 clinical-confined subjects following randomization and a five-day forced-switch from usual brand conventional combustible cigarettes to: (i) exclusive commercial e-cigarette use; (ii) dual-use of commercial e-cigarettes and the subject's usual cigarette brand; or (iii) discontinued use of all tobacco or nicotine products. Levels of urinary biomarkers in subjects that completely substituted their usual cigarette with e-cigarettes were significantly lower (29-95%) after 5 days. Percent reductions in eight of nine urinary BoEs were indistinguishable to smokers who had quit smoking, except for nicotine equivalents, which declined by 25-40%. Dual users who halved self-reported daily cigarette consumption with e-cigarettes exhibited reductions (7-38%) in eight of nine urinary biomarkers, but had increase (1-20%) in nicotine equivalents. Reductions were broadly proportional to the reduced numbers of cigarettes smoked. Dual user urinary nicotine equivalents were slightly higher, but not statistically significant. After 5 days, blood nicotine biomarker levels were lower in the cessation (75-96%) and exclusive use groups (11-83%); with dual users experiencing no significant reductions. All subjects experienced significant decreases in exhaled CO. Decreases in the cessation and exclusive groups ranged from 88-89% and 27-32% in dual users. Exhaled NO increased in the cessation and exclusive groups (46-63% respectively), whereas the dual users experienced minimal changes. Overall, smokers who completely or partially substituted conventional cigarettes with e-cigarettes over five days, experienced reductions in HPHCs.

Beyond circulating microRNA biomarkers: Urinary microRNAs in ovarian and breast cancer.

PubMed

Gasparri, Maria Luisa; Casorelli, Assunta; Bardhi, Erlisa; Besharat, Aris Raad; Savone, Delia; Ruscito, Ilary; Farooqi, Ammad Ahmad; Papadia, Andrea; Mueller, Michael David; Ferretti, Elisabetta; Benedetti Panici, Pierluigi

2017-05-01

Breast cancer is the most common malignancy in women worldwide, and ovarian cancer is the most lethal gynecological malignancy. Women carrying a BRCA1/2 mutation have a very high lifetime risk of developing breast and ovarian cancer. The only effective risk-reducing strategy in BRCA-mutated women is a prophylactic surgery with bilateral mastectomy and bilateral salpingo-oophorectomy. However, many women are reluctant to undergo these prophylactic surgeries due to a consequent mutilated body perception, unfulfilled family planning, and precocious menopause. In these patients, an effective screening strategy is available only for breast cancer, but it only consists in close radiological exams with a significant burden for the health system and a significant distress to the patients. No biomarkers have been shown to effectively detect breast and ovarian cancer at an early stage. MicroRNAs (miRNAs) are key regulatory molecules operating in a post-transcriptional regulation of gene expression. Aberrant expression of miRNAs has been documented in several pathological conditions, including solid tumors, suggesting their involvement in tumorigenesis. miRNAs can be detected in blood and urine and could be used as biomarkers in solid tumors. Encouraging results are emerging in gynecological malignancy as well, and suggest a different pattern of expression of miRNAs in biological fluids of breast and ovarian cancer patients as compared to healthy control. Aim of this study is to highlight the role of the urinary miRNAs which are specifically associated with cancer and to investigate their role in early diagnosis and in determining the prognosis in breast and ovarian cancer.

[Tetra-saccharide glucose as a diagnostic biomarker for Pompe disease: a study with 35 patients].

PubMed

Bobillo Lobato, Joaquín; Durán Parejo, Pilar; Tejero Díez, Pedro; Jiménez Jiménez, Luis M

2013-08-04

Pompe disease is a disorder originating from an acid alpha-glycosidase (AAG) enzyme deficiency. This disease produces an accumulation of lysosomal glycogen in different tissues, whereby the skeletal and heart muscles are especially involved. The established diagnosis is achieved through the identification of the AAG deficiency. There are also other secondary diagnostic biomarkers, such as tetra-saccharide glucose (Glc4), which shows high levels in the urine of these patients. In this study it is highlighted the usefulness of Glc4 as a diagnostic biomarker for Pompe disease in its different forms of presentation, using a high-performance liquid chromatography with ultraviolet detection (HPLC/UV) adapted to the study. A total of 75 individuals have been analyzed: 40 healthy controls and 35 patients diagnosed with Pompe disease. Twenty-four hour samples of urine were collected from all of the patients and their Glc4 levels were determined by means of HPLC/UV. The evaluation of the urinary Glc4 shows a high discrimination ability between healthy/sick individuals. In addition, the results obtained have allowed to establish the most appropriate level of decision or cut-off point for the identification of sick people. Glc4 urinary levels are found to be high in patients suffering from Pompe disease and even though increased levels are also found in other conditions, the existence of a AAG deficiency together with a compatible clinical symptoms, prove very helpful for a correct diagnosis of this serious disease. Copyright © 2012 Elsevier España, S.L. All rights reserved.

Urinary volatile organic compounds as potential biomarkers for renal cell carcinoma

PubMed Central

WANG, DONGCHUN; WANG, CHANGSONG; PI, XIN; GUO, LEI; WANG, YUE; LI, MINGJUAN; FENG, YUE; LIN, ZIWEI; HOU, WEI; LI, ENYOU

2016-01-01

Currently, there is no adequate, sensitive, reproducible, specific and noninvasive biomarker that can reliably be used to detect renal cell carcinoma (RCC). Previous studies have elucidated the urinary non-volatile metabolic profile of RCC. However, whether urinary volatile organic compound (VOC) profiles are able to identify RCC remains to be elucidated. In the present study, urine was collected from 22 patients with RCC and 25 healthy subjects. Principal component analysis and orthogonal partial least square discriminant analysis were used to compare the data of patients and healthy subjects, and preoperative and postoperative patients undergoing radical nephrectomy. In total, 11 VOC biomarkers were elevated in the RCC patients compared to the healthy subjects, which were phenol; decanal; 1,6-dioxacyclododecane-7,12-dione; 1-bromo-1-(3-methyl-1-pentenylidene)-2,2,3,3-tetramethyl-cyclopropane; nonanal; 3-ethyl-3-methylheptane; isolongifolene-5-ol; 2,5-cyclohexadiene-1,4-dione, 2,6-bis(1,1-dimethylethyl); tetradecane; aniline; and 2,6,10,14-tetramethyl-pentadecane. Three biomarkers were decreased in RCC patients: styrene, 4-heptanone and dimethylsilanediol. In preoperative patients, 2-ethyl-1-hexanol and cyclohexanone were elevated, while 6-t-butyl-2,2,9,9-tetramethyl-3,5-decadien-7-yne were decreased when compared to postoperative patients. Compared with the healthy subjects, RCC has a unique VOC profile, suggesting that VOC profiles may be a useful diagnostic assay for RCC. PMID:27347408

Towards a biological monitoring guidance value for acrylamide.

PubMed

Sams, C; Jones, K; Warren, N; Cocker, J; Bell, S; Bull, P; Cain, M

2015-08-19

Acrylamide is classified as a potential human carcinogen and neurotoxicant. Biological monitoring is a useful tool for monitoring worker exposure. However, other sources of exposure to acrylamide (including cigarette smoke and diet) also need to be considered. This study has performed repeat measurements of the urinary mercapturic acids of acrylamide (AAMA) and its metabolite glycidamide (GAMA) and determined globin adducts in 20 production-plant workers at a UK acrylamide production facility. The relationship between biomarker levels and environmental monitoring data (air levels and hand washes) was investigated. Good correlations were found between all of the biomarkers (r(2)=0.86-0.91) and moderate correlations were found between the biomarkers and air levels (r(2) = 0.56-0.65). Our data show that urinary AAMA is a reliable biomarker of acrylamide exposure. Occupational hygiene data showed that acrylamide exposure at the company was well within the current UK Workplace Exposure Limit. The 90th percentile of urinary AAMA in non-smoking production-plant workers (537 μmol/mol creatinine (n = 59 samples)) is proposed as a possible biological monitoring guidance value. This 90th percentile increased to 798 μmol/mol if smokers were included (n = 72 samples). These values would be expected following an airborne exposure of less than 0.07 mg/m(3), well below the current UK workplace exposure limit of 0.3mg/m(3). Comparison of biomarker levels in non-occupationally exposed individuals suggests regional variations (between UK and Germany), possibly due to differences in diet. Crown Copyright © 2015. Published by Elsevier Ireland Ltd. All rights reserved.

Methodologies for the quantitative estimation of toxicant dose to cigarette smokers using physical, chemical and bioanalytical data

PubMed Central

McAughey, John; Shepperd, Christopher J.

2013-01-01

Methodologies have been developed, described and demonstrated that convert mouth exposure estimates of cigarette smoke constituents to dose by accounting for smoke spilled from the mouth prior to inhalation (mouth-spill (MS)) and the respiratory retention (RR) during the inhalation cycle. The methodologies are applicable to just about any chemical compound in cigarette smoke that can be measured analytically and can be used with ambulatory population studies. Conversion of exposure to dose improves the relevancy for risk assessment paradigms. Except for urinary nicotine plus metabolites, biomarkers generally do not provide quantitative exposure or dose estimates. In addition, many smoke constituents have no reliable biomarkers. We describe methods to estimate the RR of chemical compounds in smoke based on their vapor pressure (VP) and to estimate the MS for a given subject. Data from two clinical studies were used to demonstrate dose estimation for 13 compounds, of which only 3 have urinary biomarkers. Compounds with VP > 10−5 Pa generally have RRs of 88% or greater, which do not vary appreciably with inhalation volume (IV). Compounds with VP < 10−7 Pa generally have RRs dependent on IV and lung exposure time. For MS, mean subject values from both studies were slightly greater than 30%. For constituents with urinary biomarkers, correlations with the calculated dose were significantly improved over correlations with mouth exposure. Of toxicological importance is that the dose correlations provide an estimate of the metabolic conversion of a constituent to its respective biomarker. PMID:23742081

Nonylphenol Toxicity Evaluation and Discovery of Biomarkers in Rat Urine by a Metabolomics Strategy through HPLC-QTOF-MS.

PubMed

Zhang, Yan-Xin; Yang, Xin; Zou, Pan; Du, Peng-Fei; Wang, Jing; Jin, Fen; Jin, Mao-Jun; She, Yong-Xin

2016-05-14

Nonylphenol (NP) was quantified using liquid chromatography tandem mass spectrometry (LC-MS/MS) in the urine and plasma of rats treated with 0, 50, and 250 mg/kg/day of NP for four consecutive days. A urinary metabolomic strategy was originally implemented by high performance liquid chromatography time of flight mass spectrometry (HPLC-QTOF-MS) to explore the toxicological effects of NP and determine the overall alterations in the metabolite profiles so as to find potential biomarkers. It is essential to point out that from the observation, the metabolic data were clearly clustered and separated for the three groups. To further identify differentiated metabolites, multivariate analysis, including principal component analysis (PCA), orthogonal partial least-squares discriminant analysis (OPLS-DA), high-resolution MS/MS analysis, as well as searches of Metlin and Massbank databases, were conducted on a series of metabolites between the control and dose groups. Finally, five metabolites, including glycine, glycerophosphocholine, 5-hydroxytryptamine, malonaldehyde (showing an upward trend), and tryptophan (showing a downward trend), were identified as the potential urinary biomarkers of NP-induced toxicity. In order to validate the reliability of these potential biomarkers, an independent validation was performed by using the multiple reaction monitoring (MRM)-based targeted approach. The oxidative stress reflected by urinary 8-oxo-deoxyguanosine (8-oxodG) levels was elevated in individuals highly exposed to NP, supporting the hypothesis that mitochondrial dysfunction was a result of xenoestrogen accumulation. This study reveals a promising approach to find biomarkers to assist researchers in monitoring NP.

Nonylphenol Toxicity Evaluation and Discovery of Biomarkers in Rat Urine by a Metabolomics Strategy through HPLC-QTOF-MS

PubMed Central

Zhang, Yan-Xin; Yang, Xin; Zou, Pan; Du, Peng-Fei; Wang, Jing; Jin, Fen; Jin, Mao-Jun; She, Yong-Xin

2016-01-01

Nonylphenol (NP) was quantified using liquid chromatography tandem mass spectrometry (LC-MS/MS) in the urine and plasma of rats treated with 0, 50, and 250 mg/kg/day of NP for four consecutive days. A urinary metabolomic strategy was originally implemented by high performance liquid chromatography time of flight mass spectrometry (HPLC-QTOF-MS) to explore the toxicological effects of NP and determine the overall alterations in the metabolite profiles so as to find potential biomarkers. It is essential to point out that from the observation, the metabolic data were clearly clustered and separated for the three groups. To further identify differentiated metabolites, multivariate analysis, including principal component analysis (PCA), orthogonal partial least-squares discriminant analysis (OPLS-DA), high-resolution MS/MS analysis, as well as searches of Metlin and Massbank databases, were conducted on a series of metabolites between the control and dose groups. Finally, five metabolites, including glycine, glycerophosphocholine, 5-hydroxytryptamine, malonaldehyde (showing an upward trend), and tryptophan (showing a downward trend), were identified as the potential urinary biomarkers of NP-induced toxicity. In order to validate the reliability of these potential biomarkers, an independent validation was performed by using the multiple reaction monitoring (MRM)-based targeted approach. The oxidative stress reflected by urinary 8-oxo-deoxyguanosine (8-oxodG) levels was elevated in individuals highly exposed to NP, supporting the hypothesis that mitochondrial dysfunction was a result of xenoestrogen accumulation. This study reveals a promising approach to find biomarkers to assist researchers in monitoring NP. PMID:27187439

DOSE RECONSTRUCTION FROM URINARY BIOMARKERS USING PHARMACOKINETIC MODELS

EPA Science Inventory

The use of biomarkers for human health risk assessment is attractive because they are an indicator of the dose that actually entered the body by all mechanisms. This is an important consideration given the need to include aggregate exposures from diet and other pathways for pes...

Biomarker Levels of Toxic Metals among Asian Populations in the United States: NHANES 2011-2012.

PubMed

Awata, Hiroshi; Linder, Stephen; Mitchell, Laura E; Delclos, George L

2017-03-01

The Centers for Disease Control and Prevention (CDC) recently found that Asians have considerably higher biomarker levels of cadmium, lead, mercury, and arsenic than whites, blacks, Mexican Americans, and other Hispanics in the United States. Our goal was to further evaluate the higher metal biomarker levels among Asians. Biomarker data (blood cadmium, blood lead, blood mercury, urinary total arsenic, and urinary dimethylarsinic acic) from individuals ≥ 6 years of age were obtained from the 2011-2012 National Health and Nutrition Examination Survey (NHANES). We compared geometric mean levels of these five metal biomarkers in Asians with those of four other NHANES race/ethnic groups (white, black, Mexican American, and other Hispanic), and across three Asian subgroups (Chinese, Asian Indian, and other Asian). We also evaluated associations between biomarker levels and sociodemographic, physical, dietary, and behavioral covariates across the Asian subgroups. Asians had significantly higher levels of all five metal biomarkers than other race/ethnic groups ( p < 0.05), regardless of sociodemographic, physical, dietary, behavioral, or geographic characteristics. We also found variations in biomarker levels across the Asian subgroups. In general, Asian Indians had lower levels than the other two Asian subgroups, except for blood lead. The following characteristics were found to be significant predictors of several biomarker levels: sex, age, education, birthplace, smoking, and fish consumption. Overall, the Asian group had the highest geometric mean biomarker levels for all of the five metal variables. Furthermore, we provided evidence that significant variations in the biomarker levels are present across the Asian subgroups in the United States. Citation: Awata H, Linder S, Mitchell LE, Delclos GL. 2017. Biomarker levels of toxic metals among Asian populations in the United States: NHANES 2011-2012. Environ Health Perspect 125:306-313; http://dx.doi.org/10.1289/EHP27.

Biomarkers associated with obstructive sleep apnea: A scoping review

PubMed Central

De Luca Canto, Graziela; Pachêco-Pereira, Camila; Aydinoz, Secil; Major, Paul W.; Flores-Mir, Carlos; Gozal, David

2014-01-01

Summary The overall validity of biomarkers in the diagnosis of obstructive sleep apnea (OSA) remains unclear. We conducted a scoping review to provide assessments of biomarkers characteristics in the context of obstructive sleep apnea (OSA) and to identify gaps in the literature. A scoping review of studies in humans without age restriction that evaluated the potential diagnostic value of biological markers (blood, exhaled breath condensate, salivary, and urinary) in the OSA diagnosis was undertaken. Retained articles were those focused on the identification of biomarkers in subjects with OSA, the latter being confirmed with a full overnight or home-based polysomnography (PSG). Search strategies for six different databases were developed. The methodology of selected studies was classified using an adaptation of the evidence quality criteria from the American Academy of Pediatrics. Additionally the biomarkers were classified according to their potential clinical application. We identified 572 relevant studies, of which 117 met the inclusion criteria. Eighty-two studies were conducted in adults, 34 studies involved children, and one study had a sample composed of both adults and children. Most of the studies evaluated blood biomarkers. Potential diagnostic biomarkers were found in 9 pediatric studies and in 58 adults studies. Only 9 studies that reported sensitivity and specificity, which varied substantially from 43% to 100%, and from 45% to 100%, respectively. Thus, studies in adults have focused on the investigation of IL-6, TNF-α and hsCRP. There was not a specific biomarker that was tested by a majority of authors in pediatric studies, and combinatorial urine biomarker approaches have shown preliminary promising results. In adults IL-6 and IL-10 seem to have a favorable potential to become a good biomarker to identify OSA. PMID:25645128

(1)H-NMR analysis of the human urinary metabolome in response to an 18-month multi-component exercise program and calcium-vitamin-D3 supplementation in older men.

PubMed

Sheedy, John R; Gooley, Paul R; Nahid, Amsha; Tull, Dedreia L; McConville, Malcolm J; Kukuljan, Sonja; Nowson, Caryl A; Daly, Robin M; Ebeling, Peter R

2014-11-01

The musculoskeletal benefits of calcium and vitamin-D3 supplementation and exercise have been extensively studied, but the effect on metabolism remains contentious. Urine samples were analyzed by (1)H-NMR spectroscopy from participants recruited for an 18-month, randomized controlled trial of a multi-component exercise program and calcium and vitamin-D3 fortified milk consumption. It was shown previously that no increase in musculoskeletal composition was observed for participants assigned to the calcium and vitamin-D3 intervention, but exercise resulted in increased bone mineral density, total lean body mass, and muscle strength. Retrospective metabolomics analysis of urine samples from patients involved in this study revealed no distinct changes in the urinary metabolome in response to the calcium and vitamin-D3 intervention, but significant changes followed the exercise intervention, notably a reduction in creatinine and an increase in choline, guanidinoacetate, and hypoxanthine (p < 0.001, fold change > 1.5). These metabolites are intrinsically involved in anaerobic ATP synthesis, intracellular buffering, and methyl-balance regulation. The exercise intervention had a marked effect on the urine metabolome and markers of muscle turnover but none of these metabolites were obvious markers of bone turnover. Measurement of specific urinary exercise biomarkers may provide a basis for monitoring performance and metabolic response to exercise regimes.

Development of a Targeted Urine Proteome Assay for kidney diseases.

PubMed

Cantley, Lloyd G; Colangelo, Christopher M; Stone, Kathryn L; Chung, Lisa; Belcher, Justin; Abbott, Thomas; Cantley, Jennifer L; Williams, Kenneth R; Parikh, Chirag R

2016-01-01

Since human urine is the most readily available biofluid whose proteome changes in response to disease, it is a logical sample for identifying protein biomarkers for kidney diseases. Potential biomarkers were identified by using a multiproteomics workflow to compare urine proteomes of kidney transplant patients with immediate and delayed graft function. Differentially expressed proteins were identified, and corresponding stable isotope labeled internal peptide standards were synthesized for scheduled MRM. The Targeted Urine Proteome Assay (TUPA) was then developed by identifying those peptides for which there were at least two transitions for which interference in a urine matrix across 156 MRM runs was <30%. This resulted in an assay that monitors 224 peptides from 167 quantifiable proteins. TUPA opens the way for using a robust mass spectrometric technology, MRM, for quantifying and validating biomarkers from among 167 urinary proteins. This approach, while developed using differentially expressed urinary proteins from patients with delayed versus immediate graft function after kidney transplant, can be expanded to include differentially expressed urinary proteins in multiple kidney diseases. Thus, TUPA could provide a single assay to help diagnose, prognose, and manage many kidney diseases. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Performance of Serum Creatinine and Kidney Injury Biomarkers for Diagnosing Histologic Acute Tubular Injury.

PubMed

Moledina, Dennis G; Hall, Isaac E; Thiessen-Philbrook, Heather; Reese, Peter P; Weng, Francis L; Schröppel, Bernd; Doshi, Mona D; Wilson, F Perry; Coca, Steven G; Parikh, Chirag R

2017-12-01

The diagnosis of acute kidney injury (AKI), which is currently defined as an increase in serum creatinine (Scr) concentration, provides little information on the condition's actual cause. To improve phenotyping of AKI, many urinary biomarkers of tubular injury are being investigated. Because AKI cases are not frequently biopsied, the diagnostic accuracy of concentrations of Scr and urinary biomarkers for histologic acute tubular injury is unknown. Cross-sectional analysis from multicenter prospective cohort. Hospitalized deceased kidney donors on whom kidney biopsies were performed at the time of organ procurement for histologic evaluation. (1) AKI diagnosed by change in Scr concentration during donor hospitalization and (2) concentrations of urinary biomarkers (neutrophil gelatinase-associated lipocalin [NGAL], liver-type fatty acid-binding protein [L-FABP], interleukin 18 [IL-18], and kidney injury molecule 1 [KIM-1]) measured at organ procurement. Histologic acute tubular injury. Of 581 donors, 98 (17%) had mild acute tubular injury and 57 (10%) had severe acute tubular injury. Overall, Scr-based AKI had poor diagnostic performance for identifying histologic acute tubular injury and 49% of donors with severe acute tubular injury did not have AKI. The area under the receiver operating characteristic curve (AUROC) of change in Scr concentration for diagnosing severe acute tubular injury was 0.58 (95% CI, 0.49-0.67) and for any acute tubular injury was 0.52 (95% CI, 0.45-0.58). Compared with Scr concentration, NGAL concentration demonstrated higher AUROC for diagnosing both severe acute tubular injury (0.67; 95% CI, 0.60-0.74; P=0.03) and any acute tubular injury (0.60; 95% CI, 0.55-0.66; P=0.005). In donors who did not have Scr-based AKI, NGAL concentrations were higher with increasing severities of acute tubular injury (subclinical AKI). However, compared with Scr concentration, AUROCs for acute tubular injury diagnosis were not significantly higher for urinary L-FABP, IL-18, or KIM-1. The spectrum of AKI cause in deceased donors may be different from that of a general hospitalized population. Concentrations of Scr and kidney injury biomarkers (L-FABP, IL-18, and KIM-1) lack accuracy for diagnosing acute tubular injury in hospitalized deceased donors. Although urinary NGAL concentration had slightly higher discrimination for acute tubular injury than did Scr concentration, its overall AUROC was still modest. Published by Elsevier Inc.

Predictors of urinary levels of 2,4-dichlorophenoxyacetic acid, 3,5,6-trichloro-2-pyridinol, 3-phenoxybenzoic acid, and pentachlorophenol in 121 adults in Ohio.

PubMed

Morgan, Marsha K

2015-07-01

Limited data exist on the driving factors that influence the non-occupational exposures of adults to pesticides using urinary biomonitoring. In this work, the objectives were to quantify the urinary levels of 2,4-dichlorophenoxyacetic acid (2,4-D), 3,5,6-trichloro-2-pyridinol (TCP), 3-phenoxybenzoic acid (3-PBA), and pentachlorophenol (PCP) in 121 adults over a 48-h monitoring period and to examine the associations between selected sociodemographic and lifestyle factors and urinary levels of each pesticide biomarker. Adults, ages 20-49 years old, were recruited from six counties in Ohio (OH) in 2001. The participants collected 4-6 spot urine samples and completed questionnaires and diaries at home over a 48-h monitoring period. Urine samples were analyzed for 2,4-D, TCP, 3-PBA, and PCP by gas chromatography/mass spectrometry. Multiple regression modeling was used to determine the impact of selected sociodemographic and lifestyle factors on the log-transformed (ln) levels of each pesticide biomarker in adults. The pesticide biomarkers were detected in ≥ 89% of the urine samples, except for 3-PBA (66%). Median urinary levels of 2,4-D, TCP, 3-PBA, and PCP were 0.7, 3.4, 0.3, and 0.5 ng/mL, respectively. Results showed that 48-h sweet/salty snack consumption, 48-h time spend outside at home, and ln(creatinine) levels were significant predictors (p < 0.05), and race was a marginally significant predictor (p = 0.093) of the adults' ln(urinary 2,4-D) concentrations. Strong predictors (p < 0.05) of the adults' ln(urinary TCP) concentrations were urbanicity, employment status, sampling season, and ln(creatinine) levels. For 3-PBA, sampling season, pet ownership and removal of shoes before entering the home were significant predictors (p < 0.05) of the adults' ln(urinary 3-PBA) levels. Finally for PCP, removal of shoes before entering the home and ln(creatinine) levels were significant predictors (p < 0.05), and pet ownership was a marginally significant predictor (p = 0.056) of the adults' ln(urinary PCP) concentrations. In conclusion, specific sociodemographic and lifestyle factors were identified that increased the exposures of these adults to several different pesticides in their daily environments. Published by Elsevier GmbH.

HAND WIPE SUBSAMPLING METHOD FOR USE WITH BIOMARKER MEASUREMENTS IN THE AGRICULTURAL HEALTH STUDY/PESTICIDE EXPOSURE STUDY

EPA Science Inventory

Dermal exposure studies incorporating urinary biomarker measurements are complicated because dermal sampling may intercept or remove the target chemical before it is absorbed. A hand wipe subsampling method has been developed using polyurethane foam-tipped (PUF) swabs to minim...

Use of urinary biomarkers to characterize occupational exposure to BTEX in healthcare waste autoclave operators.

PubMed

Rafiee, Ata; Delgado-Saborit, Juana Maria; Gordi, Elham; Quémerais, Bernadette; Kazemi Moghadam, Vahid; Lu, Wenjing; Hashemi, Fallah; Hoseini, Mohammad

2018-08-01

Urinary benzene, toluene, ethylbenzene, and xylenes (BTEX) can be used as a reliable biomarker of exposure to these pollutants. This study was aimed to investigate the urinary BTEX concentration in operators of healthcare waste (HCW) autoclaves. This cross-sectional study was conducted in selected hospitals in Tehran, Iran between April and June 2017. Twenty operators (as the case group) and twenty control subjects were enrolled in the study. Personal urine samples were collected at the beginning and end of the work shift. Urinary BTEX were measured by a headspace gas chromatography-mass spectrometry (GC/MS). A detailed questionnaire was used to gather information from subjects. Results showed that the median of urinary benzene, toluene, ethylbenzene, m-p xylene, and o-xylene levels in the exposed group were 3.26, 3.36, 0.84, 3.94 and 4.48 μg/L, respectively. With the exception of ethylbenzene, subjects in the exposed group had significantly higher urinary BTEX levels than control group (p < 0.05). Urinary BTEX concentrations in the exposed case group were 2.5-fold higher than in the control group. There was a significant relationship between the amount of generated waste per day and the urinary BTEX in the exposed group. Smoking status and type of autoclave used were also identified as predictors of urinary BTEX concentrations. The healthcare waste treatment autoclaves can be considered as a significant BTEX exposure source for operators working with these treatment facilities. The appropriate personal protection equipment and control measures capable in reducing BTEX exposure should be provided to HCW workers to reduce their exposures to BTEX. Copyright © 2018 Elsevier B.V. All rights reserved.

Harnessing the Power of Cruciferous Vegetables: Developing a Biomarker for Brassica Vegetable Consumption Using Urinary 3,3'-Diindolylmethane.

PubMed

Fujioka, Naomi; Ransom, Benjamin W; Carmella, Steven G; Upadhyaya, Pramod; Lindgren, Bruce R; Roper-Batker, Astia; Hatsukami, Dorothy K; Fritz, Vincent A; Rohwer, Charles; Hecht, Stephen S

2016-10-01

Glucobrassicin in Brassica vegetables gives rise to indole-3-carbinol (I3C), a compound with potent anticancer effects in preclinical models. We previously showed that the urinary metabolite 3,3'-diindolylmethane (DIM) could discriminate between volunteers fed high and low doses of Brassica vegetables. However, the quantitative relationship between glucobrassicin exposure and urinary DIM level is unclear. We conducted a clinical trial to examine the hypotheses that a range of glucobrassicin exposure from Brassica vegetables is reflected in urinary DIM and that this effect plateaus. Forty-five subjects consumed vegetables, a mixture of brussels sprouts and/or cabbage, at one of seven discrete dose levels of glucobrassicin ranging from 25 to 500 μmol, once daily for 2 consecutive days. All urine was collected for 24 hours after each vegetable-eating session. Urinary DIM was measured using our published liquid chromatography-electrospray ionization-tandem mass spectrometry-selected reaction monitoring (LC/ESI-MS/MS-SRM) method. Urinary DIM excretion increased predictably with increasing glucobrassicin dose and plateaued between 200 and 300 μmol of glucobrassicin. The association between glucobrassicin dose and urinary DIM was strong and positive (R 2 = 0.68). The majority of DIM was excreted in the first 12 hours after vegetable consumption. We conclude that urinary DIM is a reliable biomarker of glucobrassicin exposure and I3C uptake and that feeding glucobrassicin beyond 200 μmol did not consistently lead to more urinary DIM, suggesting a plateau in potential chemopreventive benefit. Cancer Prev Res; 9(10); 788-93. ©2016 AACR. ©2016 American Association for Cancer Research.

Urinary Fluoride Concentration in Children with Disabilities Following Long-Term Fluoride Tablet Ingestion

ERIC Educational Resources Information Center

Liu, Hsiu-Yueh; Chen, Jung-Ren; Hung, Hsin-Chia; Hsiao, Szu-Yu; Huang, Shun-Te; Chen, Hong-Sen

2011-01-01

Urine is the most commonly utilized biomarker for fluoride excretion in public health and epidemiological studies. Approximately 30-50% of fluoride is excreted from urine in children. Urinary fluoride excretion reflects the total fluoride intake from multiple sources. After administering fluoride tablets to children with disabilities, urinary…

EVALUATION OF URINARY PAH METABOLITES AS BIOMARKERS OF EXPOSURE TO PM2.5 FROM COMBUSTION SOURCES

EPA Science Inventory

This study determined the relationship between daily personal exposure to airborne fine particles (PM2.5) and the excretion of urinary PAH metabolites over a 10-day period of repeated measurements. The samples (n=60) were selected from a large series of exposure and health pane...

Profiling of Kidney Injury Biomarkers in Patients Receiving Cisplatin: Time-Dependent Changes in the Absence of Clinical Nephrotoxicity

PubMed Central

George, Blessy; Wen, Xia; Mercke, Nickie; Gomez, Madeleine; O’Bryant, Cindy; Bowles, Daniel W.; Hu, Yichun; Hogan, Susan L.

2016-01-01

The success of cisplatin-containing regimens to treat solid tumors is limited, in part, by nephrotoxicity. In rodents, several urinary proteins have emerged as more sensitive indicators of cisplatin-induced kidney injury. We sought to characterize time-dependent changes in the urinary concentrations of 12 proteins including KIM-1, calbindin, β2M, and TFF3 after cisplatin therapy. Urine was collected at baseline, 3 (range: 2-5), and 10 (range: 9-11) days from 57 patients with solid tumors receiving outpatient cisplatin therapy (≥ 25 mg/m2). Serum creatinine was largely unchanged after cisplatin infusion. However, compared to baseline values, several novel biomarkers were significantly increased in the urine including β2M, which was 3-fold higher by day 3 (p<0.0001). Urinary KIM-1 and TFF3 were elevated 2-fold by day 10 (p=0.002 and p=0.002, respectively) whereas calbindin levels were increased 8-fold (p<0.0001). We report novel time-dependent changes in the urinary excretion of noninvasive markers of subclinical kidney injury after cisplatin treatment. PMID:28002630

Renal function in hepatosplenic schistosomiasis--an assessment of renal tubular disorders.

PubMed

Duarte, Daniella Bezerra; Vanderlei, Lucas Alexandre; Bispo, Raianne Kívia de Azevêdo; Pinheiro, Maria Eliete; da Silva, Geraldo Bezerra; Martins, Alice Maria Costa; Meneses, Gdayllon Cavalcante; Daher, Elizabeth De Francesco

2014-01-01

Renal involvement in Schistosoma mansoni infection is not well studied. The aim of this study is to investigate the occurrence of renal abnormalities in patients with hepatosplenic schistosomiasis (HSS), especially renal tubular disorders. This is a cross-sectional study with 20 consecutive patients with HSS followed in a medical center in Maceió, Alagoas, Brazil. Urinary acidification and concentration tests were performed using calcium chloride (CaCl2) after a 12-h period of water and food deprivation. The biomarker monocyte chemoattractant protein 1 (MCP-1) was quantified in urine. Fractional excretion of sodium (FENa+), transtubular potassium gradient (TTKG) and solute-free water reabsorption (TcH2O) were calculated. The HSS group was compared to a group of 17 healthy volunteers. Patients' mean age and gender were similar to controls. Urinary acidification deficit was found in 45% of HSS patients. Urinary osmolality was significantly lower in HSS patients (588 ± 112 vs. 764 ± 165 mOsm/kg, p = 0,001) after a 12-h period of water deprivation. TcH2O was lower in HSS patients (0.72 ± 0.5 vs. 1.1 ± 0.3, p = 0.04). Urinary concentration deficit was found in 85% of HSS patients. The values of MCP-1 were higher in HSS group than in control group (122 ± 134 vs. 40 ± 28 pg/mg-Cr, p = 0.01) and positively correlated with the values of microalbuminuria and proteinuria. HSS is associated with important kidney dysfunction. The main abnormalities found were urinary concentrating ability and incomplete distal acidification defect, demonstrating the occurrence of tubular dysfunction. There was also an increase in urinary MCP-1, which appears to be a more sensitive marker of renal damage than urinary albumin excretion rate.

Urinary biomarkers in hexachloro-1:3-butadiene-induced acute kidney injury in the female Hanover Wistar rat; correlation of α-glutathione S-transferase, albumin and kidney injury molecule-1 with histopathology and gene expression.

PubMed

Swain, Aubrey; Turton, John; Scudamore, Cheryl L; Pereira, Ines; Viswanathan, Neeti; Smyth, Rosemary; Munday, Michael; McClure, Fiona; Gandhi, Mitul; Sondh, Surjit; York, Malcolm

2011-05-01

Hexachloro-1:3-butadiene (HCBD) causes kidney injury specific to the pars recta of the proximal tubule. In the present studies, injury to the nephron was characterized at 24 h following a single dose of HCBD, using a range of quantitative urinary measurements, renal histopathology and gene expression. Multiplexed renal biomarker measurements were performed using both the Meso Scale Discovery (MSD) and Rules Based Medicine platforms. In a second study, rats were treated with a single nephrotoxic dose of HCBD and the time course release of a range of traditional and newer urinary biomarkers was followed over a 25 day period. Urinary albumin (a marker of both proximal tubular function and glomerular integrity) and α-glutathione S-transferase (α-GST, a proximal tubular cell marker of cytoplasmic leakage) showed the largest fold change at 24 h (day 1) after dosing. Most other markers measured on either the MSD or RBM platforms peaked on day 1 or 2 post-dosing, whereas levels of kidney injury molecule-1 (KIM-1), a marker of tubular regeneration, peaked on day 3/4. Therefore, in rat proximal tubular nephrotoxicity, the measurement of urinary albumin, α-GST and KIM-1 is recommended as they potentially provide useful information about the function, degree of damage and repair of the proximal tubule. Gene expression data provided useful confirmatory information regarding exposure of the kidney and liver to HCBD, and the response of these tissues to HCBD in terms of metabolism, oxidative stress, inflammation, and regeneration and repair. Copyright © 2011 John Wiley & Sons, Ltd.

Urinary cystatin C as a renal biomarker and its immunohistochemical localization in anti-GBM glomerulonephritis rats.

PubMed

Togashi, Yuko; Imura, Naoko; Miyamoto, Yohei

2013-11-01

The usefulness of urinary cystatin C for the early detection of renal damage in anti-glomerular basement membrane (GBM) glomerulonephritis rats was investigated and compared to other biomarkers (β2-microglobulin, calbindin, clusterin, epidermal growth factor (EGF), alpha-glutathione S-transferase (GST-α), mu-glutathione S-transferase (GST-μ), kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), osteopontin, tissue inhibitor of metalloprotease-1 (TIMP-1), and vascular endothelial growth factor (VEGF)). Urinary levels of cystatin C increased in anti-GBM glomerulonephritis rats, whereas the conventional markers, plasma creatinine and UN did not, demonstrating its usefulness for the early detection of renal damage associated with anti-GBM glomerulonephritis. As well as cystatin C, urinary β2-microglobulin, clusterin, GST-α, GST-μ, KIM-1, and NGAL also had the potential to detect renal damage associated with anti-GBM glomerulonephritis. Furthermore, the immunohistochemical localization of cystatin C in the kidney was examined. Cystatin C expression was mainly observed in the proximal renal tubules in anti-GBM glomerulonephritis rats, and its expression barely changed with the progression of glomerulonephritis. Cystatin C expression was also observed in the tubular lumen of the cortex and medulla when glomerulonephritis was marked, which was considered to be characteristic of renal damage. In conclusion, urinary cystatin C, β2-microglobulin, clusterin, GST-α, GST-μ, KIM-1, and NGAL could be useful biomarkers of renal damage in anti-GBM glomerulonephritis rats. Immunohistochemical cystatin C expression in the proximal renal tubules was barely changed by the progression of glomerulonephritis, but it was newly observed in the tubular lumen when renal damage was apparent. Crown Copyright © 2013. Published by Elsevier GmbH. All rights reserved.

Precise quantitation of 136 urinary proteins by LC/MRM-MS using stable isotope labeled peptides as internal standards for biomarker discovery and/or verification studies.

PubMed

Percy, Andrew J; Yang, Juncong; Hardie, Darryl B; Chambers, Andrew G; Tamura-Wells, Jessica; Borchers, Christoph H

2015-06-15

Spurred on by the growing demand for panels of validated disease biomarkers, increasing efforts have focused on advancing qualitative and quantitative tools for more highly multiplexed and sensitive analyses of a multitude of analytes in various human biofluids. In quantitative proteomics, evolving strategies involve the use of the targeted multiple reaction monitoring (MRM) mode of mass spectrometry (MS) with stable isotope-labeled standards (SIS) used for internal normalization. Using that preferred approach with non-invasive urine samples, we have systematically advanced and rigorously assessed the methodology toward the precise quantitation of the largest, multiplexed panel of candidate protein biomarkers in human urine to date. The concentrations of the 136 proteins span >5 orders of magnitude (from 8.6 μg/mL to 25 pg/mL), with average CVs of 8.6% over process triplicate. Detailed here is our quantitative method, the analysis strategy, a feasibility application to prostate cancer samples, and a discussion of the utility of this method in translational studies. Copyright © 2015 Elsevier Inc. All rights reserved.

Lung inflammation biomarkers and lung function in children chronically exposed to arsenic

DOE Office of Scientific and Technical Information (OSTI.GOV)

Olivas-Calderón, Edgar, E-mail: edgar_olivascalderon@hotmail.com; School of Medicine, University Juarez of Durango, Gomez Palacio, Durango; Recio-Vega, Rogelio, E-mail: rrecio@yahoo.com

Evidence suggests that exposure to arsenic in drinking water during early childhood or in utero has been associated with an increase in respiratory symptoms or diseases in the adulthood, however only a few studies have been carried out during those sensitive windows of exposure. Recently our group demonstrated that the exposure to arsenic during early childhood or in utero in children was associated with impairment in the lung function and suggested that this adverse effect could be due to a chronic inflammation response to the metalloid. Therefore, we designed this cross-sectional study in a cohort of children associating lung inflammatorymore » biomarkers and lung function with urinary As levels. A total of 275 healthy children were partitioned into four study groups according with their arsenic urinary levels. Inflammation biomarkers were measured in sputum by ELISA and the lung function was evaluated by spirometry. Fifty eight percent of the studied children were found to have a restrictive spirometric pattern. In the two highest exposed groups, the soluble receptor for advanced glycation end products' (sRAGE) sputum level was significantly lower and matrix metalloproteinase-9 (MMP-9) concentration was higher. When the biomarkers were correlated to the urinary arsenic species, negative associations were found between dimethylarsinic (DMA), monomethylarsonic percentage (%MMA) and dimethylarsinic percentage (%DMA) with sRAGE and positive associations between %DMA with MMP-9 and with the MMP-9/tissue inhibitor of metalloproteinase (TIMP-1) ratio. In conclusion, chronic arsenic exposure of children negatively correlates with sRAGE, and positively correlated with MMP-9 and MMP-9/TIMP-1 levels, and increases the frequency of an abnormal spirometric pattern. Arsenic-induced alterations in inflammatory biomarkers may contribute to the development of restrictive lung diseases. - Highlights: • First study in children evaluating lung inflammatory biomarkers and As levels • In 275 children chronically exposed to As, 3 biomarkers were measured. • Negative associations were found between DMA, %MMA and %DMA with sRAGE. • Positive associations were found between %DMA with MMP-9 and with the MMP-9/TIMP-1 ratio. • Chronic arsenic exposure-induced alterations in lung inflammatory biomarkers in children.« less

Urinary biomarkers of exposure to jet fuel (JP-8).

PubMed Central

Serdar, Berrin; Egeghy, Peter P; Waidyanatha, Suramya; Gibson, Roger; Rappaport, Stephen M

2003-01-01

Benzene, naphthalene, and 1- and 2-naphthol were measured in urine samples obtained from 322 U.S. Air Force personnel categorized a priori as likely to have low, moderate, or high exposure to jet fuel [jet propulsion fuel-8 (JP-8)]. In postexposure samples, levels of these analytes in the high-exposure group were 3- to 29-fold greater than in the low-exposure group and 2- to 12-fold greater than in the moderate-exposure group. Heavy exposure to JP-8 contributed roughly the same amount of benzene and more than three times the amount of naphthalene compared with cigarette smoking. Strong correlations were observed among postexposure levels of naphthalene-based biomarkers in urine and naphthalene in air and breath. We conclude that urinary naphthalene and the naphthols can serve as biomarkers of exposure to jet fuel. Of these, the naphthols are probably more useful because of their greater abundance and slower elimination kinetics. PMID:14594628

Association of increased urine brain derived neurotrophic factor with lower urinary tract symptoms in men with benign prostatic hyperplasia.

PubMed

Wang, Long-Wang; Li, Jian-Long; Yu, Yi; Xiao, Rui-Hai; Huang, Hong-Wei; Kuang, Ren-Rui; Hai, Bo

2017-08-01

Urinary brain-derived neurotrophic factor (BDNF), an ubiquitous neurotrophin, was found to rise in patients with benign prostatic hyperplasia (BPH). We hypothesized that the urinary level of BDNF could be a potential biomarker for lower urinary tract symptoms (LUTS) in patients with BPH. Totally, 76 patients with BPH-caused LUTS and 32 male control subjects without BPH were enrolled. International Prostate Symptom Score (IPSS) was applied to assess the symptom severity of LUTS. Urodynamic tests were performed for the diagnosis of underlying detrusor overactivity (DO) in the patients with BPH. Urine samples were collected from all subjects. Urinary BDNF levels were measured using enzyme-linked immunosorbent assays and normalized by urinary creatinine (Cr) levels. Seventy-six BPH patients were divided into moderate LUTS group (n=51, 720) according to the IPSS. Of the 76 BPH patients, DO was present in 34 (44.7%) according to the urodynamic test. The urinary BDNF/Cr levels were significantly higher in BPH patients with moderate LUTS (8.29±3.635, P<0.0001) and severe LUTS (11.8±6.44, P<0.0001) than normal controls (1.71±0.555). Patients with severe LUTS tended to have higher urinary BDNF/Cr levels than patients with moderate LUTS (11.8±6.44 vs. 8.29±3.635, P=0.000). The conditions of BPH with LUTS correlated with elevated urinary BDNF levels, and urinary BDNF levels were even higher in BPH-DO patients. The results of this study have provided evidence to suggest that urinary BDNF level test could evaluate the severity of LUTS in BPH patients, and BDNF level can be used as a biomarker for the diagnosis of DO in BPH patients.

Deoxynivalenol: rationale for development and application of a urinary biomarker.

PubMed

Turner, Paul C; Burley, Victoria J; Rothwell, Joseph A; White, Kay L M; Cade, Janet E; Wild, Christopher P

2008-07-01

Mycotoxins are common dietary contaminants in most regions of the world. The frequency of exposure to the various families of mycotoxins is often dependent on geographic location, national wealth and related agricultural and regulatory infrastructure, combined with diversity of diet and degree of food sufficiency. Deoxynivalenol (DON) is a Fusarium mycotoxin that frequently contaminates wheat, corn and barley in temperate regions. A number of acute poisoning incidences have been linked to DON-contaminated foods and chronic exposure to lower levels of DON has been predicted in many regions. DON is a potent animal toxin and exposure in humans may cause gastroenteritis, growth faltering and immune toxicity. An ability to conduct accurate exposure assessment at the individual level is required to fully understand the potential health consequences for humans. To date, such exposure biomarkers have been lacking for many important mycotoxins, including DON. To better assess exposure to DON at the individual level, we have developed a robust urinary assay, incorporating immunoaffinity column (IAC) enrichment and LC-MS detection. Further refinement of this urinary assay, by inclusion of (13)C-DON as an internal standard, was then undertaken and tested within the UK. DON was frequently observed in urine and was significantly associated with cereal intake. A dietary intervention study demonstrated that avoiding wheat in the diet markedly reduced urinary levels of DON. This biomarker requires further validation but our initial data suggest it may provide a useful tool in epidemiological investigations of the potential health consequences of this common environmental toxin.

Comparative differential proteomic analysis of minimal change disease and focal segmental glomerulosclerosis.

PubMed

Pérez, Vanessa; López, Dolores; Boixadera, Ester; Ibernón, Meritxell; Espinal, Anna; Bonet, Josep; Romero, Ramón

2017-02-03

Minimal change disease (MCD) and primary focal segmental glomerulosclerosis (FSGS) are glomerular diseases characterized by nephrotic syndrome. Their diagnosis requires a renal biopsy, but it is an invasive procedure with potential complications. In a small biopsy sample, where only normal glomeruli are observed, FSGS cannot be differentiated from MCD. The correct diagnosis is crucial to an effective treatment, as MCD is normally responsive to steroid therapy, whereas FSGS is usually resistant. The purpose of our study was to discover and validate novel early urinary biomarkers capable to differentiate between MCD and FSGS. Forty-nine patients biopsy-diagnosed of MCD and primary FSGS were randomly subdivided into a training set (10 MCD, 11 FSGS) and a validation set (14 MCD, 14 FSGS). The urinary proteome of the training set was analyzed by two-dimensional differential gel electrophoresis coupled with mass spectrometry. The proteins identified were quantified by enzyme-linked immunosorbent assay in urine samples from the validation set. Urinary concentration of alpha-1 antitrypsin, transferrin, histatin-3 and 39S ribosomal protein L17 was decreased and calretinin was increased in FSGS compared to MCD. These proteins were used to build a decision tree capable to predict patient's pathology. This preliminary study suggests a group of urinary proteins as possible non-invasive biomarkers with potential value in the differential diagnosis of MCD and FSGS. These biomarkers would reduce the number of misdiagnoses, avoiding unnecessary or inadequate treatments.

Identification of prostate cancer biomarkers in urinary exosomes

PubMed Central

Øverbye, Anders; Skotland, Tore; Koehler, Christian J.; Thiede, Bernd; Seierstad, Therese; Berge, Viktor; Sandvig, Kirsten; Llorente, Alicia

2015-01-01

Exosomes have recently appeared as a novel source of non-invasive cancer biomarkers since tumour-specific molecules can be found in exosomes isolated from biological fluids. We have here investigated the proteome of urinary exosomes by using mass spectrometry to identify proteins differentially expressed in prostate cancer patients compared to healthy male controls. In total, 15 control and 16 prostate cancer samples of urinary exosomes were analyzed. Importantly, 246 proteins were differentially expressed in the two groups. The majority of these proteins (221) were up-regulated in exosomes from prostate cancer patients. These proteins were analyzed according to specific criteria to create a focus list that contained 37 proteins. At 100% specificity, 17 of these proteins displayed individual sensitivities above 60%. Even though several of these proteins showed high sensitivity and specificity for prostate cancer as individual biomarkers, combining them in a multi-panel test has the potential for full differentiation of prostate cancer from non-disease controls. The highest sensitivity, 94%, was observed for transmembrane protein 256 (TM256; chromosome 17 open reading frame 61). LAMTOR proteins were also distinctly enriched with very high specificity for patient samples. TM256 and LAMTOR1 could be used to augment the sensitivity to 100%. Other prominent proteins were V-type proton ATPase 16 kDa proteolipid subunit (VATL), adipogenesis regulatory factor (ADIRF), and several Rab-class members and proteasomal proteins. In conclusion, this study clearly shows the potential of using urinary exosomes in the diagnosis and clinical management of prostate cancer. PMID:26196085

Identification of prostate cancer biomarkers in urinary exosomes.

PubMed

Øverbye, Anders; Skotland, Tore; Koehler, Christian J; Thiede, Bernd; Seierstad, Therese; Berge, Viktor; Sandvig, Kirsten; Llorente, Alicia

2015-10-06

Exosomes have recently appeared as a novel source of non-invasive cancer biomarkers since tumour-specific molecules can be found in exosomes isolated from biological fluids. We have here investigated the proteome of urinary exosomes by using mass spectrometry to identify proteins differentially expressed in prostate cancer patients compared to healthy male controls. In total, 15 control and 16 prostate cancer samples of urinary exosomes were analyzed. Importantly, 246 proteins were differentially expressed in the two groups. The majority of these proteins (221) were up-regulated in exosomes from prostate cancer patients. These proteins were analyzed according to specific criteria to create a focus list that contained 37 proteins. At 100% specificity, 17 of these proteins displayed individual sensitivities above 60%. Even though several of these proteins showed high sensitivity and specificity for prostate cancer as individual biomarkers, combining them in a multi-panel test has the potential for full differentiation of prostate cancer from non-disease controls. The highest sensitivity, 94%, was observed for transmembrane protein 256 (TM256; chromosome 17 open reading frame 61). LAMTOR proteins were also distinctly enriched with very high specificity for patient samples. TM256 and LAMTOR1 could be used to augment the sensitivity to 100%. Other prominent proteins were V-type proton ATPase 16 kDa proteolipid subunit (VATL), adipogenesis regulatory factor (ADIRF), and several Rab-class members and proteasomal proteins. In conclusion, this study clearly shows the potential of using urinary exosomes in the diagnosis and clinical management of prostate cancer.

Application of Liquid Chromatography-Tandem Mass Spectrometry To Determine Urinary Concentrations of Five Commonly Used Low-Calorie Sweeteners: A Novel Biomarker Approach for Assessing Recent Intakes?

PubMed

Logue, Caomhan; Dowey, Le Roy C; Strain, J J; Verhagen, Hans; McClean, Stephen; Gallagher, Alison M

2017-06-07

Although the use of low-calorie sweeteners (LCSs) is widespread, methods of assessing consumption within free-living populations have inherent limitations. Five commonly consumed LCSs, namely, acesulfame-K, saccharin, sucralose, cyclamate, and steviol glycosides, are excreted via the urine, and therefore a urinary biomarker approach may provide more objective LCS intake data. A LC-ESI-MS/MS method of simultaneously determining acesulfame-K, saccharin, sucralose, cyclamate, and the excretory metabolite of steviol glycosides, steviol glucuronide, in human urine was developed and validated. Linearity was observed over a concentration range of 10-1000 ng/mL with coefficients of determination ranging from 0.9969 to 0.9997. Accuracy ranged from 92 to 104%, and intrabatch and interday precisions were within acceptable limits with %CV below 8% for all compounds. A double-blind, randomized crossover dose-response study was conducted to assess the usefulness of urinary LCS excretions (from both fasting spot and a full 24-h urine collection) for investigating recent intakes. Both modes of sampling were useful for distinguishing between the three short-term intakes of acesulfame-K, saccharin, cyclamates, and steviol glycosides (p < 0.001), whereas for sucralose, urinary concentrations were useful for distinguishing between low (0.1% ADI) and high doses (10% ADI) only (p < 0.001). In summary, this biomarker approach may be useful for assessing intakes of five commonly consumed LCSs.

Urinary Tobacco Smoke Constituent Biomarkers for Assessing Risk of Lung Cancer

PubMed Central

Yuan, Jian-Min; Butler, Lesley M.; Stepanov, Irina; Hecht, Stephen S.

2014-01-01

Tobacco constituent biomarkers are metabolites of specific compounds present in tobacco or tobacco smoke. Highly reliable analytical methods, based mainly on mass spectrometry, have been developed for quantitation of these biomarkers in both urine and blood specimens. There is substantial inter-individual variation in smoking-related lung cancer risk that is determined in part by individual variability in the uptake and metabolism of tobacco smoke carcinogens. Thus, by incorporating these biomarkers in epidemiological studies we can potentially obtain a more valid and precise measure of in vivo carcinogen dose than by using self-reported smoking history, ultimately improving the estimation of smoking-related lung cancer risk. Indeed, we have demonstrated this by using a prospective study design comparing biomarker levels in urine samples collected from smokers many years prior to their development of cancer, versus those in their smoking counterparts without a cancer diagnosis. The following urinary metabolites were associated with lung cancer risk, independent of smoking intensity and duration: cotinine plus its glucuronide, a biomarker of nicotine uptake; 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total NNAL), a biomarker of the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK); and r-1-,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT), a biomarker of polycyclic aromatic hydrocarbons (PAH). These results provide several possible new directions for using tobacco smoke constituent biomarkers in lung cancer prevention, including improved lung cancer risk assessment, intermediate outcome determination in prevention trials and regulation of tobacco products. PMID:24408916

Urinary markers of acute kidney injury in newborns with perinatal asphyxia (.).

PubMed

Oncel, Mehmet Yekta; Canpolat, Fuat Emre; Arayici, Sema; Alyamac Dizdar, Evrim; Uras, Nurdan; Oguz, Serife Suna

2016-07-01

Acute kidney injury (AKI) affects up to 60% of severely asphyxiated neonates. The diagnosis of AKI can be and is further challenged by a lack of good biomarkers. We studied the role of novel markers for AKI, neutrophil gelatinase-associated lipocalin (NGAL), interleukin-8 (IL-18), Netrin-1 (NTN-1), and sodium hydrogen exchanger isoform 3 (NHE3) on development and early diagnosis of AKI in newborns with perinatal asphyxia (PA). Forty-one newborns with a diagnosis of PA (15 with AKI and 26 without AKI) and 20 healthy matched controls were involved to the study. Urinary samples were obtained on postnatal days 1 and 4 for patients with PA and on postnatal day 1 for the control subjects. AKI was defined using a serum creatinine-based modification of the acute kidney injury network criteria. The levels of NGAL, NTN-1, NHE3, and IL-18 on the first postnatal day urine samples were higher in patients compared to controls (p < 0.001, p <0.001, p  <0.02, p  <0.001, respectively). In patients with AKI, the levels of NGAL and IL-18 were higher when compared to patients without AKI (p = 0.002, p  <0.001, respectively). The levels of NTN-1 and NHE3 were similar in both groups. For the samples obtained on postnatal day 4, only NGAL levels were significantly higher in patients with AKI (p = 0.004) compared to those without AKI. To our knowledge, this is the largest study, which evaluated the utility of urinary biomarkers in the diagnosis of AKI in newborns with PA. First day, urine NGAL and IL-18 levels have an important diagnostic power in such patients.

Biomarkers of oxidative stress and its association with the urinary reducing capacity in bus maintenance workers

PubMed Central

2011-01-01

Background Exposure to particles (PM) induces adverse health effects (cancer, cardiovascular and pulmonary diseases). A key-role in these adverse effects seems to be played by oxidative stress, which is an excess of reactive oxygen species relative to the amount of reducing species (including antioxidants), the first line of defense against reactive oxygen species. The aim of this study was to document the oxidative stress caused by exposure to respirable particles in vivo, and to test whether exposed workers presented changes in their urinary levels for reducing species. Methods Bus depot workers (n = 32) exposed to particles and pollutants (respirable PM4, organic and elemental carbon, particulate metal content, polycyclic aromatic hydrocarbons, NOx, O3) were surveyed over two consecutive days. We collected urine samples before and after each shift, and quantified an oxidative stress biomarker (8-hydroxy-2'-deoxyguanosine), the reducing capacity and a biomarker of PAH exposure (1-hydroxypyrene). We used a linear mixed model to test for associations between the oxidative stress status of the workers and their particle exposure as well as with their urinary level of reducing species. Results Workers were exposed to low levels of respirable PM4 (range 25-71 μg/m3). However, urinary levels of 8-hydroxy-2'-deoxyguanosine increased significantly within each shift and between both days for non-smokers. The between-day increase was significantly correlated (p < 0.001) with the concentrations of organic carbon, NOx, and the particulate copper content. The within-shift increase in 8OHdG was highly correlated to an increase of the urinary reducing capacity (Spearman ρ = 0.59, p < 0.0001). Conclusions These findings confirm that exposure to components associated to respirable particulate matter causes a systemic oxidative stress, as measured with the urinary 8OHdG. The strong association observed between urinary 8OHdG with the reducing capacity is suggestive of protective or other mechanisms, including circadian effects. Additional investigations should be performed to understand these observations. PMID:21619715

Aronia berry polyphenol consumption reduces plasma total and low-density lipoprotein cholesterol in former smokers without lowering biomarkers of inflammation and oxidative stress: a randomized controlled trial.

PubMed

Xie, Liyang; Vance, Terrence; Kim, Bohkyung; Lee, Sang Gil; Caceres, Christian; Wang, Ying; Hubert, Patrice A; Lee, Ji-Young; Chun, Ock K; Bolling, Bradley W

2017-01-01

Former smokers are at increased risk for cardiovascular disease. We hypothesized that dietary aronia polyphenols would reduce biomarkers of cardiovascular disease risk, inflammation, and oxidative stress in former smokers. We also determined the extent these effects were associated with polyphenol bioavailability. A 12-week, randomized, placebo-controlled trial was conducted in 49 healthy adult former smokers (n = 24/placebo, n = 25/aronia) to evaluate if daily consumption of 500 mg aronia extract modulated plasma lipids, blood pressure, biomarkers of inflammation and oxidative stress, and lipid transport genes of peripheral blood mononuclear cells. The primary outcome was change in low-density lipoprotein cholesterol (LDL-C) from baseline, and multivariate correlation analysis was performed to determine if changes in lipids were associated with urinary polyphenol excretion. Aronia consumption reduced fasting plasma total cholesterol by 8% (P = .0140), LDL-C by 11% (P = .0285), and LDL receptor protein in peripheral blood mononuclear cells (P = .0036) at 12 weeks compared with the placebo group. Positive changes in the urinary polyphenol metabolites peonidin-3-O-galactoside, 3-(4-hydroxyphenyl) propionic acid, and unmetabolized anthocyanin cyanidin-3-O-galactoside were associated with lower plasma total cholesterol and LDL-C in the aronia group. Aronia consumption did not change blood pressure or biomarkers of inflammation and oxidative stress. Aronia polyphenols reduced total and LDL-C in former smokers but did not improve biomarkers of oxidative stress and chronic inflammation. The cholesterol-lowering activity of aronia extract was most closely associated with urinary levels of cyanidin-3-O-galactoside and peonidin-3-O-galactoside, its methylated metabolite. This trial was registered at ClinicalTrials.gov as NCT01541826. Copyright © 2016 Elsevier Inc. All rights reserved.

Associations between Deceased-Donor Urine Injury Biomarkers and Kidney Transplant Outcomes

PubMed Central

Reese, Peter P.; Hall, Isaac E.; Weng, Francis L.; Schröppel, Bernd; Doshi, Mona D.; Hasz, Rick D.; Thiessen-Philbrook, Heather; Ficek, Joseph; Rao, Veena; Murray, Patrick; Lin, Haiqun

2016-01-01

Assessment of deceased-donor organ quality is integral to transplant allocation practices, but tools to more precisely measure donor kidney injury and better predict outcomes are needed. In this study, we assessed associations between injury biomarkers in deceased-donor urine and the following outcomes: donor AKI (stage 2 or greater), recipient delayed graft function (defined as dialysis in first week post-transplant), and recipient 6-month eGFR. We measured urinary concentrations of microalbumin, neutrophil gelatinase–associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), IL-18, and liver-type fatty acid binding protein (L-FABP) from 1304 deceased donors at organ procurement, among whom 112 (9%) had AKI. Each biomarker strongly associated with AKI in adjusted analyses. Among 2441 kidney transplant recipients, 31% experienced delayed graft function, and mean±SD 6-month eGFR was 55.7±23.5 ml/min per 1.73 m2. In analyses adjusted for donor and recipient characteristics, higher donor urinary NGAL concentrations associated with recipient delayed graft function (highest versus lowest NGAL tertile relative risk, 1.21; 95% confidence interval, 1.02 to 1.43). Linear regression analyses of 6-month recipient renal function demonstrated that higher urinary NGAL and L-FABP concentrations associated with slightly lower 6-month eGFR only among recipients without delayed graft function. In summary, donor urine injury biomarkers strongly associate with donor AKI but provide limited value in predicting delayed graft function or early allograft function after transplant. PMID:26374609

(2-methoxyethoxy)acetic acid: a urinary biomarker of exposure for jet fuel JP-8.

PubMed

B'hymer, Clayton; Mathias, Patricia; Krieg, Edward; Cheever, Kenneth L; Toennis, Christine A; Clark, John C; Kesner, James S; Gibson, Roger L; Butler, Mary Ann

2012-05-01

To demonstrate the utility of the urinary metabolite (2-methoxyethoxy)acetic acid (MEAA) as a biomarker of exposure. 2-(2-methoxyethoxy)ethanol [diethylene glycol monomethyl ether] is an anti-icing agent used in the formulation of JP-8, and it is added at a known uniform 0.1% (v/v) concentration to each batch lot. JP-8 is a kerosene-based fuel containing different compounds that vary in the content of every batch/lot of fuel; thus, MEAA has the potential to be a more specific and a consistent quantitative biomarker for JP-8 exposure. MEAA was used to measure exposure of jet propulsion fuel 8 (JP-8) in United States Air Force (USAF) personnel working at six airbases within the United States. Post-shift urine specimens from various personnel including high (n = 98), moderate (n = 38), and low (n = 61) exposure workgroup categories were collected and analyzed by a gas chromatographic-mass spectrometric test method. The three exposure groups were evaluated for the number per group positive for MEAA, and a statistical analysis consisted of pair-wise t-tests for unequal variances was used to test for the differences in mean MEAA concentrations between the exposure groups. The number of samples detected as positive for MEAA exposure, that is, those above the test method's limit of detection (LOD = 0.1 μg/ml), were 92 (93.9%), 13 (34.2%), and 2 (3.3%) for the high, moderate, and low exposure workgroup categories, respectively. The mean urinary MEAA level was significantly greater in the high exposure category (6.8 μg/ml), compared to the moderate (0.42 μg/ml) and the low (0.07 μg/ml) exposure categories. The maximum concentration of urinary MEAA was 110 μg/ml for the high exposure category, while 4.8 μg/ml and 0.2 μg/ml maximum levels were found in the moderate and low exposure categories, respectively. This study demonstrated that urinary MEAA can be used as an accurate biomarker of exposure for JP-8 workers and clearly distinguished the differences in JP-8 exposure by workgroup category.

Metabolic profiling in Maturity-onset diabetes of the young (MODY) and young onset type 2 diabetes fails to detect robust urinary biomarkers.

PubMed

Gloyn, Anna L; Faber, Johan H; Malmodin, Daniel; Thanabalasingham, Gaya; Lam, Francis; Ueland, Per Magne; McCarthy, Mark I; Owen, Katharine R; Baunsgaard, Dorrit

2012-01-01

It is important to identify patients with Maturity-onset diabetes of the young (MODY) as a molecular diagnosis determines both treatment and prognosis. Genetic testing is currently expensive and many patients are therefore not assessed and are misclassified as having either type 1 or type 2 diabetes. Biomarkers could facilitate the prioritisation of patients for genetic testing. We hypothesised that patients with different underlying genetic aetiologies for their diabetes could have distinct metabolic profiles which may uncover novel biomarkers. The aim of this study was to perform metabolic profiling in urine from patients with MODY due to mutations in the genes encoding glucokinase (GCK) or hepatocyte nuclear factor 1 alpha (HNF1A), type 2 diabetes (T2D) and normoglycaemic control subjects. Urinary metabolic profiling by Nuclear Magnetic Resonance (NMR) and ultra performance liquid chromatography hyphenated to Q-TOF mass spectrometry (UPLC-MS) was performed in a Discovery set of subjects with HNF1A-MODY (n = 14), GCK-MODY (n = 17), T2D (n = 14) and normoglycaemic controls (n = 34). Data were used to build a valid partial least squares discriminate analysis (PLS-DA) model where HNF1A-MODY subjects could be separated from the other diabetes subtypes. No single metabolite contributed significantly to the separation of the patient groups. However, betaine, valine, glycine and glucose were elevated in the urine of HNF1A-MODY subjects compared to the other subgroups. Direct measurements of urinary amino acids and betaine in an extended dataset did not support differences between patients groups. Elevated urinary glucose in HNF1A-MODY is consistent with the previously reported low renal threshold for glucose in this genetic subtype. In conclusion, we report the first metabolic profiling study in monogenic diabetes and show that, despite the distinct biochemical pathways affected, there are unlikely to be robust urinary biomarkers which distinguish monogenic subtypes from T2D. Our results have implications for studies investigating metabolic profiles in complex traits including T2D.

Urinary metal and polycyclic aromatic hydrocarbon biomarkers in boilermakers exposed to metal fume and residual oil fly ash.

PubMed

Mukherjee, Sutapa; Rodrigues, Ema; Aeschliman, David B; Houk, R S; Palmer, Lyle J; Woodin, Mark A; Weker, Robert; Christiani, David C

2005-06-01

Boilermakers are occupationally exposed to known carcinogens. The association of urinary 1-hydroxy-pyrene (1-OHP), a biomarker of polycyclic aromatic hydrocarbon (PAH) exposure, with biomarkers of metal exposure (vanadium, chromium, manganese, nickel, copper, and lead) in boilermakers exposed to metal fume from welding and dust particulates from residual oil fly ash (ROFA) was examined. A repeated measures cohort study was conducted during the overhaul of an oil-fired boiler. Twice-daily urine samples were obtained for 5 days and analyzed for cotinine, 1-OHP, and metals. Generalized estimating equations (GEE) were used to model the multivariate relationship of 1-OHP to the explanatory variables. Metal and 1-OHP levels were determined for 165 urine samples from 20 boilermakers and these levels increased during the workweek. However, the 1-OHP level was not significantly associated with any individual metal level at any time point. This suggests that boilermakers were occupationally exposed to PAH and metals, but 1-OHP as a PAH biomarker was unable to serve as a surrogate marker of metal exposure for the metals measured in this study.

Effects of Ambient Coarse, Fine, and Ultrafine Particles and Their Biological Constituents on Systemic Biomarkers: A Controlled Human Exposure Study

PubMed Central

Urch, Bruce; Poon, Raymond; Szyszkowicz, Mieczyslaw; Speck, Mary; Gold, Diane R.; Wheeler, Amanda J.; Scott, James A.; Brook, Jeffrey R.; Thorne, Peter S.; Silverman, Frances S.

2015-01-01

Background Ambient coarse, fine, and ultrafine particles have been associated with mortality and morbidity. Few studies have compared how various particle size fractions affect systemic biomarkers. Objectives We examined changes of blood and urinary biomarkers following exposures to three particle sizes. Methods Fifty healthy nonsmoking volunteers, mean age of 28 years, were exposed to coarse (2.5–10 μm; mean, 213 μg/m3) and fine (0.15–2.5 μm; mean, 238 μg/m3) concentrated ambient particles (CAPs), and filtered ambient and/or medical air. Twenty-five participants were exposed to ultrafine CAP (< 0.3 μm; mean, 136 μg/m3) and filtered medical air. Exposures lasted 130 min, separated by ≥ 2 weeks. Blood/urine samples were collected preexposure and 1 hr and 21 hr postexposure to determine blood interleukin-6 and C-reactive protein (inflammation), endothelin-1 and vascular endothelial growth factor (VEGF; vascular mediators), and malondialdehyde (lipid peroxidation); as well as urinary VEGF, 8-hydroxy-deoxy-guanosine (DNA oxidation), and malondialdehyde. Mixed-model regressions assessed pre- and postexposure differences. Results One hour postexposure, for every 100-μg/m3 increase, coarse CAP was associated with increased blood VEGF (2.41 pg/mL; 95% CI: 0.41, 4.40) in models adjusted for O3, fine CAP with increased urinary malondialdehyde in single- (0.31 nmol/mg creatinine; 95% CI: 0.02, 0.60) and two-pollutant models, and ultrafine CAP with increased urinary 8-hydroxydeoxyguanosine in single- (0.69 ng/mg creatinine; 95% CI: 0.09, 1.29) and two-pollutant models, lasting < 21 hr. Endotoxin was significantly associated with biomarker changes similar to those found with CAPs. Conclusions Ambient particles with various sizes/constituents may influence systemic biomarkers differently. Endotoxin in ambient particles may contribute to vascular mediator changes and oxidative stress. Citation Liu L, Urch B, Poon R, Szyszkowicz M, Speck M, Gold DR, Wheeler AJ, Scott JA, Brook JR, Thorne PS, Silverman FS. 2015. Effects of ambient coarse, fine, and ultrafine particles and their biological constituents on systemic biomarkers: a controlled human exposure study. Environ Health Perspect 123:534–540; http://dx.doi.org/10.1289/ehp.1408387 PMID:25616223

Proximal renal tubular injury in rats sub-chronically exposed to low fluoride concentrations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cárdenas-González, Mariana C.; Del Razo, Luz M.; Barrera-Chimal, Jonatan

2013-11-01

Fluoride is usually found in groundwater at a very wide range of concentration between 0.5 and 25 ppm. At present, few studies have assessed the renal effects of fluoride at environmentally relevant concentrations. Furthermore, most of these studies have used insensitive and nonspecific biomarkers of kidney injury. The aim of this study was to use early and sensitive biomarkers to evaluate kidney injury after fluoride exposure to environmentally relevant concentrations. Recently weaned male Wistar rats were exposed to low (15 ppm) and high (50 ppm) fluoride concentrations in drinking water for a period of 40 days. At the end ofmore » the exposure period, kidney injury biomarkers were measured in urine and renal mRNA expression levels were assessed by real time RT-PCR. Our results showed that the urinary kidney injury molecule (Kim-1), clusterin (Clu), osteopontin (OPN) and heat shock protein 72 excretion rate significantly increased in the group exposed to the high fluoride concentration. Accordingly, fluoride exposure increased renal Kim-1, Clu and OPN mRNA expression levels. Moreover, there was a significant dose-dependent increase in urinary β-2-microglobulin and cystatin-C excretion rate. Additionally, a tendency towards a dose dependent increase of tubular damage in the histopathological light microscopy findings confirmed the preferential impact of fluoride on the tubular structure. All of these changes occurred at early stages in which, the renal function was not altered. In conclusion using early and sensitive biomarkers of kidney injury, we were able to found proximal tubular alterations in rats sub-chronically exposed to fluoride. - Highlights: • Exposure to low concentrations of fluoride induced proximal tubular injury • Increase in urinary Kim-1, Clu, OPN and Hsp72 in 50 ppm fluoride-exposed group • Increase in urinary B2M and CysC in 15 and 50 ppm fluoride-exposed groups • Fluoride exposure increased renal Kim, Clu and OPN mRNA expression levels. • Fluoride increased kidney injury biomarkers at stages where eGFR was unaltered.« less

Short-term markers of DNA damage among roofers who work with hot asphalt.

PubMed

Serdar, Berrin; Brindley, Stephen; Dooley, Greg; Volckens, John; Juarez-Colunga, Elizabeth; Gan, Ryan

2016-10-20

Roofers are at increased risk for various malignancies and their occupational exposures to polycyclic aromatic hydrocarbons (PAHs) have been considered as important risk factors. The overall goal of this project was to investigate the usefulness of phosphorylated histone H2AX (γH2AX) as a short-term biomarker of DNA damage among roofers. Blood, urine, and dermal wipe samples were collected from 20 roofers who work with hot asphalt before and after 6 h of work on Monday and Thursday of the same week (4 sampling periods). Particle-bound and gas-phase PAHs were collected using personal monitors during work hours. γH2AX was quantified in peripheral lymphocytes using flow cytometry and 8-hydroxy-2-deoxyguanosine (8-OHdG) was assessed in urine using ELISA. General linear mixed models were used to evaluate associations between DNA damage and possible predictors (such as sampling period, exposure levels, work- and life-style factors). Differences in mean biomarker and DNA damage levels were tested via ANOVA contrasts. Exposure measurements did not show an association with any of the urinary biomarkers or the measures of DNA damage. Naphthalene was the most abundant PAH in gas-phase, while benzo(e)pyrene was the most abundant particle-bound PAH. Post-shift levels of γH2AX and 8-OHdG were higher on both study days, when compared to pre-shift levels. Cigarette smoking was a predictor of γH2AX and urinary creatinine was a predictor of urinary 8-OHdG. Between-subject variance to total variance ratio was 35.3 % for γH2ax and 4.8 % for 8-OHdG. γH2AX is a promising biomarker of DNA damage in occupational epidemiology studies. It has a lower within-subject variation than urinary 8-OHdG and can easily be detected in large scale groups. Future studies that explore the kinetics of H2AX phosphorylation in relation to chemical exposures may reveal the transient and persistent nature of this sensitive biomarker of early DNA damage.

Environmental Chemicals in Urine and Blood: Improving Methods for Creatinine and Lipid Adjustment

PubMed Central

O’Brien, Katie M.; Upson, Kristen; Cook, Nancy R.; Weinberg, Clarice R.

2015-01-01

Background Investigators measuring exposure biomarkers in urine typically adjust for creatinine to account for dilution-dependent sample variation in urine concentrations. Similarly, it is standard to adjust for serum lipids when measuring lipophilic chemicals in serum. However, there is controversy regarding the best approach, and existing methods may not effectively correct for measurement error. Objectives We compared adjustment methods, including novel approaches, using simulated case–control data. Methods Using a directed acyclic graph framework, we defined six causal scenarios for epidemiologic studies of environmental chemicals measured in urine or serum. The scenarios include variables known to influence creatinine (e.g., age and hydration) or serum lipid levels (e.g., body mass index and recent fat intake). Over a range of true effect sizes, we analyzed each scenario using seven adjustment approaches and estimated the corresponding bias and confidence interval coverage across 1,000 simulated studies. Results For urinary biomarker measurements, our novel method, which incorporates both covariate-adjusted standardization and the inclusion of creatinine as a covariate in the regression model, had low bias and possessed 95% confidence interval coverage of nearly 95% for most simulated scenarios. For serum biomarker measurements, a similar approach involving standardization plus serum lipid level adjustment generally performed well. Conclusions To control measurement error bias caused by variations in serum lipids or by urinary diluteness, we recommend improved methods for standardizing exposure concentrations across individuals. Citation O’Brien KM, Upson K, Cook NR, Weinberg CR. 2016. Environmental chemicals in urine and blood: improving methods for creatinine and lipid adjustment. Environ Health Perspect 124:220–227; http://dx.doi.org/10.1289/ehp.1509693 PMID:26219104

Simultaneous detection of diagnostic biomarkers of alkaptonuria, ornithine carbamoyltransferase deficiency, and neuroblastoma disease by high-performance liquid chromatography/tandem mass spectrometry.

PubMed

Hsu, Wei-Yi; Chen, Ching-Ming; Tsai, Fuu-Jen; Lai, Chien-Chen

2013-05-01

Urinary homovanillic acid (HVA)/vanillylmandelic acid (VMA), orotic acid (OA), and homogentisic acid (HGA) are diagnostic biomarkers of neuroblastoma, ornithine carbamoyl transferase deficiency (OCTD), and alkaptonuria (AKU), respectively. In this study, a high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for simultaneous quantification of HVA, VMA, OA, and HGA in urine. After sample preparation, which involved only the dilution procedure, samples were quantified by LC-MS/MS. Full-scan MS/MS mode enabled the urinary markers to be quantified with a high degree of specificity and sensitivity. Rather than using a separate enzymatic method to normalize the concentration of creatinine in urine, we quantified the level of creatinine in urine in one LC-MS run. The limits of detection were 10 μg/l for HGA, 25 μg/l for HVA/VMA, and 50 μg/l for OA with a single-to-noise ratio of 3; the limits of quantification were 50 μg/l for HVA and HGA, 100 μg/l for VMA, and 250 μg/l for OA. The linear dynamic range for quantification of the analytes covered 2 to 3 orders of magnitude, depending on the analyte. The relative standard deviation of the developed LC-MS/MS method was less than 4% for the intra-day validation and 10% for the inter-day validation. The results show that our LC-MS/MS technique is a highly sensitive and rapid method for screening for biomarkers that are diagnostic of three metabolic diseases. Copyright © 2012 Elsevier B.V. All rights reserved.

What is the best biomarker to assess arsenic exposure via drinking water?

PubMed

Marchiset-Ferlay, Nathalie; Savanovitch, Chantal; Sauvant-Rochat, Marie-Pierre

2012-02-01

Arsenic (As) is a ubiquitous element. The current WHO guideline for As in drinking water is 10 μg/L. Furthermore, about 130 million people have only access to drinking water containing more than 10 g As/L. Although numerous studies have shown the related adverse effects of As, sensitive appropriate biomarkers are still required for studies of environmental epidemiology. A review of the literature has shown that various biomarkers are used for such research. Their limits and advantages are highlighted in this paper: (i) the detection of As or its derivatives in the blood is an indication of the dose ingested but it is not evidence of chronic intoxication. (ii) The detection of As in urine is an indispensible procedure because it is a good marker for internal dose. It has been demonstrated to correlate well for a number of chronic effects related to As levels in drinking water. However confounding factors must be taken into account to avoid misinterpretation and this may require As speciation. (iii) As in the hair and nails reflects the level of long term exposure but it is difficult to relate the level with the dose ingested. (iv) Some studies showed a correlation between urinary As and urinary and blood porphyrins. However, it is difficult to use only porphyrins as a biomarker in a population survey carried out without doing further studies. (v) Genotoxic effects are based on the characterization of these potential effects. Most studies have detected increases in DNA damage, sister chromatid exchange, micronuclei or chromosomal aberrations in populations exposed to As in drinking water. Micronuclei assay is the technique of choice to follow these populations, because it is sensitive and easy to use. To conclude, whatever epidemiological studies are, the urinary and toenail biomarkers are useful to provide indications of internal dose. Moreover, micronuclei assay can be complementary use as biomarker of early effects. Copyright © 2011 Elsevier Ltd. All rights reserved.

A novel reversed-phase HPLC method for the determination of urinary creatinine by pre-column derivatization with ethyl chloroformate: comparative studies with the standard Jaffé and isotope-dilution mass spectrometric assays.

PubMed

Leung, Elvis M K; Chan, Wan

2014-02-01

Creatinine is an important biomarker for renal function diagnosis and normalizing variations in urinary drug/metabolites concentration. Quantification of creatinine in biological fluids such as urine and plasma is important for clinical diagnosis as well as in biomonitoring programs and urinary metabolomics/metabonomics research. Current methods for creatinine determination either are nonselective or involve the use of expensive mass spectrometers. In this paper, a novel reversed-phase high-performance liquid chromatographic (HPLC) method for the determination of creatinine of high hydrophilicity by pre-column derivatization with ethyl chloroformate is presented. N-Ethyloxycarbonylation of creatinine significantly enhanced the hydrophobicity of creatinine, facilitating its chromatographic retention as well as quantification by HPLC. Factors governing the derivatization reaction were studied and optimized. The developed method was validated and applied for the determination of creatinine in rat urine samples. Comparative studies with isotope-dilution mass spectrometric method revealed that the two methods do not yield systematic differences in creatinine concentrations, indicating the HPLC method is suitable for the determination of creatinine in urine samples.

Assessment of urinary microparticles in normotensive patients with type 1 diabetes.

PubMed

Lytvyn, Yuliya; Xiao, Fengxia; Kennedy, Christopher R J; Perkins, Bruce A; Reich, Heather N; Scholey, James W; Cherney, David Z; Burger, Dylan

2017-03-01

Assessment of urinary extracellular vesicles including exosomes and microparticles (MPs) is an emerging approach for non-invasive detection of renal injury. We have previously reported that podocyte-derived MPs are increased in diabetic mice in advance of albuminuria. Here, we hypothesised that type 1 diabetes and acute hyperglycaemia would increase urinary podocyte MP levels in uncomplicated diabetes. In this post hoc exploratory analysis, we examined archived urine samples from normoalbuminuric patients with uncomplicated type 1 diabetes studied under clamped euglycaemia and hyperglycaemia and compared with healthy controls. Urinary vesicles were assessed by electron microscopy and nanoparticle tracking while podocyte MPs were assessed by flow cytometry. Neither vesicle size nor total number were significantly altered in type 1 diabetes or acute hyperglycaemia. By contrast, urinary podocyte MP levels were higher in type 1 diabetes (0.47 [0.00-3.42] MPs/μmol creatinine [Cr]) compared with healthy controls (0.00 [0.00-0.00] MPs/μmol Cr, p < 0.05) and increased under hyperglycaemic clamp (0.36 [0.00-4.15] MPs/μmol Cr during euglycaemia vs 2.70 [0.00-15.91] MPs/μmol Cr during hyperglycaemia, p < 0.05). Levels of urinary albumin to creatinine ratio and nephrin (surrogates of podocyte injury) were unchanged by type 1 diabetes or acute hyperglycaemia. Taken together, our data show that urinary podocyte MP levels are higher in patients with type 1 diabetes in advance of changes in other biomarkers (albuminuria, nephrin). Examination of podocyte MPs may serve as an early biomarker of glomerular injury in uncomplicated type 1 diabetes.

[Urinary L-type fatty acid binding protein (L-FABP) as a new urinary biomarker promulgated by the Ministry of Health, Labour and Welfare in Japan].

PubMed

Kamijo-Ikemori, Atsuko; Ichikawa, Daisuke; Matsui, Katsuomi; Yokoyama, Takeshi; Sugaya, Takeshi; Kimura, Kenjiro

2013-07-01

Liver-type fatty acid binding protein (L-FABP) is a 14kDa protein found in the cytoplasm of human renal proximal tubules. Fatty acids are bound with L-FABP and transported to the mitochondria or peroxisomes, where fatty acids are beta-oxidized, and this may play a role in fatty acid homeostasis. Moreover, L-FABP has high affinity and capacity to bind long-chain fatty acid oxidation products, and may be an effective endogenous antioxidant. Renal L-FABP is rarely expressed in the kidneys of rodents. In order to evaluate the pathological dynamics of renal L-FABP in kidney disease, human L-FABP chromosomal transgenic mice were generated. Various stress, such as massive proteinuria, hyperglycemia, hypertension, and toxins overloaded in the proximal tubules were revealed to up-regulate the gene expression of renal L-FABP and increase the excretion of L-FABP derived from the proximal tubules into urine. In clinical studies of chronic kidney disease (CKD), urinary L-FABP accurately reflected the degree of tubulointerstitial damage and correlated with the rate of CKD progression. Furthermore, a multicenter trial has shown that urinary L-FABP is more sensitive than urinary protein in predicting the progression of CKD. With respect to diabetic nephropathy and acute kidney disease (AKI), urinary L-FABP is an early diagnostic of kidney disease or a predictive marker for renal prognosis. After many clinical studies, urinary L-FABP was approved as a new tubular biomarker promulgated by the Ministry of Health, Labour and Welfare in Japan.

Urinary ATP May Be a Dynamic Biomarker of Detrusor Overactivity in Women with Overactive Bladder Syndrome

PubMed Central

Oliveira, Olga; Ferreira, Sónia; Reis, Maria Júlia; Oliveira, José Carlos; Correia-de-Sá, Paulo

2013-01-01

Background Nowadays, there is a considerable bulk of evidence showing that ATP has a prominent role in the regulation of human urinary bladder function and in the pathophysiology of detrusor overactivity. ATP mediates nonadrenergic-noncholinergic detrusor contractions in overactive bladders. In vitro studies have demonstrated that uroepithelial cells and cholinergic nerves from overactive human bladder samples (OAB) release more ATP than controls. Here, we compared the urinary ATP concentration in samples collected non-invasively from OAB women with detrusor overactivity and age-matched controls. Methods Patients with neurologic diseases, history of malignancy, urinary tract infections or renal impairment (creatinine clearance <70 ml/min) were excluded. All patients completed a 3-day voiding diary, a 24 h urine collection and blood sampling to evaluate creatinine clearance. Urine samples collected during voluntary voids were immediately freeze-preserved for ATP determination by the luciferin-luciferase bioluminescence assay; for comparison purposes, samples were also tested for urinary nerve growth factor (NGF) by ELISA. Results The urinary content of ATP, but not of NGF, normalized to patients’ urine creatinine levels (ATP/Cr) or urinary volume (ATP.Vol) were significantly (P<0.05) higher in OAB women with detrusor overactivity (n = 34) than in healthy controls (n = 30). Significant differences between the two groups were still observed by boosting urinary ATP/Cr content after water intake, but these were not detected for NGF/Cr. In OAB patients, urinary ATP/Cr levels correlated inversely with mean voided volumes determined in a 3-day voiding diary. Conclusion A high area under the receiver operator characteristics (ROC) curve (0.741; 95% CI 0.62–0.86; P<0.001) is consistent with urinary ATP/Cr being a highly sensitive dynamic biomarker for assessing detrusor overactivity in women with OAB syndrome. PMID:23741373

Helminths and Cancers From the Evolutionary Perspective.

PubMed

Scholte, Larissa L S; Pascoal-Xavier, Marcelo A; Nahum, Laila A

2018-01-01

Helminths include free-living and parasitic Platyhelminthes and Nematoda which infect millions of people worldwide. Some Platyhelminthes species of blood flukes ( Schistosoma haematobium, Schistosoma japonicum , and Schistosoma mansoni ) and liver flukes ( Clonorchis sinensis and Opisthorchis viverrini ) are known to be involved in human cancers. Other helminths are likely to be carcinogenic. Our main goals are to summarize the current knowledge of human cancers caused by Platyhelminthes, point out some helminth and human biomarkers identified so far, and highlight the potential contributions of phylogenetics and molecular evolution to cancer research. Human cancers caused by helminth infection include cholangiocarcinoma, colorectal hepatocellular carcinoma, squamous cell carcinoma, and urinary bladder cancer. Chronic inflammation is proposed as a common pathway for cancer initiation and development. Furthermore, different bacteria present in gastric, colorectal, and urogenital microbiomes might be responsible for enlarging inflammatory and fibrotic responses in cancers. Studies have suggested that different biomarkers are involved in helminth infection and human cancer development; although, the detailed mechanisms remain under debate. Different helminth proteins have been studied by different approaches. However, their evolutionary relationships remain unsolved. Here, we illustrate the strengths of homology identification and function prediction of uncharacterized proteins from genome sequencing projects based on an evolutionary framework. Together, these approaches may help identifying new biomarkers for disease diagnostics and intervention measures. This work has potential applications in the field of phylomedicine (evolutionary medicine) and may contribute to parasite and cancer research.

Biochemical and physical characterisation of urinary nanovesicles following CHAPS treatment.

PubMed

Musante, Luca; Saraswat, Mayank; Duriez, Elodie; Byrne, Barry; Ravidà, Alessandra; Domon, Bruno; Holthofer, Harry

2012-01-01

Urinary exosomes represent a precious source of potential biomarkers for disease biology. Currently, the methods for vesicle isolation are severely restricted by the tendency of vesicle entrapment, e.g. by the abundant Tamm-Horsfall protein (THP) polymers. Treatment by reducing agents such as dithiothreitol (DTT) releases entrapped vesicles, thus increasing the final yield. However, this harsh treatment can cause remodelling of all those proteins which feature extra-vesicular domains stabilized by internal disulfide bridges and have detrimental effects on their biological activity. In order to optimize exosomal yield, we explore two vesicle treatment protocols - dithiothreitol (DTT) and 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic (CHAPS) - applied to the differential centrifugation protocol for exosomal vesicle isolation. The results show that CHAPS treatment does not affect vesicle morphology or exosomal marker distribution, thus eliminating most of THP interference. Moreover, the recovery and preservation of catalytic activity of two trans-membrane proteases, dipeptidyl peptidase IV and nephrilysin, was examined and found to be clearly superior after CHAPS treatment compared to DTT. Finally, proteomic profiling by mass spectrometry (MS) revealed that 76.2% of proteins recovered by CHAPS are common to those seen for DTT treatment, which illustrates underlining similarities between the two approaches. In conclusion, we provide a major improvement to currently-utilized urinary vesicle isolation strategies to allow recovery of urinary vesicles without the deleterious interference of abundant urinary proteins, while preserving typical protein folding and, consequently, the precious biological activity of urinary proteins which serve as valuable biomarkers.

Fibroblast Growth Factor 23 Levels Associate with AKI and Death in Critical Illness.

PubMed

Leaf, David E; Jacob, Kirolos A; Srivastava, Anand; Chen, Margaret E; Christov, Marta; Jüppner, Harald; Sabbisetti, Venkata S; Martin, Aline; Wolf, Myles; Waikar, Sushrut S

2017-06-01

Elevated plasma levels of the osteocyte-derived hormone fibroblast growth factor 23 (FGF23) have emerged as a powerful biomarker of cardiovascular disease and death in patients with CKD. Whether elevated urinary or plasma FGF23 levels are prospectively associated with AKI and death in critically ill patients is unknown. We therefore conducted a prospective cohort study of 350 critically ill patients admitted to intensive care units at an academic medical center to investigate whether higher urinary FGF23 levels associate with the composite end point of AKI or in-hospital mortality (AKI/death). We measured urinary FGF23 levels within 24 hours of admission to the intensive care unit. In a subcohort ( n =131) we also measured plasma levels of FGF23, calcium, phosphate, parathyroid hormone, and vitamin D metabolites. Urinary and plasma FGF23 levels, but not other mineral metabolites, significantly associated with AKI/death. In multivariate analyses, patients in the highest compared with the lowest quartile of urinary FGF23 had a 3.9 greater odds (95% confidence interval, 1.6 to 9.5) of AKI/death. Higher urinary FGF23 levels also independently associated with greater hospital, 90-day, and 1-year mortality; longer length of stay; and several other important adverse outcomes. In conclusion, elevated FGF23 levels measured in the urine or plasma may be a promising novel biomarker of AKI, death, and other adverse outcomes in critically ill patients. Copyright © 2017 by the American Society of Nephrology.

Hebei Spirit Oil Spill Exposure and Subjective Symptoms in Residents Participating in Clean-Up Activities

PubMed Central

Cheong, Hae-Kwan; Lee, Jong Seong; Kwon, Hojang; Ha, Eun-Hee; Hong, Yun-Chul; Choi, Yeyong; Jeong, Woo-Chul; Hur, Jongil; Lee, Seung-Min; Kim, Eun-Jung; Im, Hosub

2011-01-01

Objectives This study was conducted to examine the relationship between crude oil exposure and physical symptoms among residents participating in clean-up work associated with the Hebei Spirit oil spill, 2007 in Korea. Methods A total of 288 residents responded to a questionnaire regarding subjective physical symptoms, sociodemographic characteristics and clean-up activities that occurred between two and eight weeks after the accident. Additionally, the urine of 154 of the respondents was analyzed for metabolites of volatile organic compounds (VOCs) and polycyclic aromatic hydrocarbons (PAHs) and heavy metals. To compare the urinary levels of exposure biomarkers, the urine of 39 inland residents who were not directly exposed to the oil spill were analyzed. Results Residents exposed to oil remnants through clean-up work showed associations between physical symptoms and the exposure levels defined in various ways, including days of work, degree of skin contamination, and levels of some urinary exposure biomarkers of VOCs, metabolites and metals, although no major abnormalities in urinary exposure biomarkers were observed. Conclusions This study provides evidence of a relationship between crude oil exposure and acute human health effects and suggests the need for follow-up to evaluate the exposure status and long-term health effects of clean-up participants. PMID:22125768

Urinary KIM-1, NGAL and L-FABP for the diagnosis of AKI in patients with acute coronary syndrome or heart failure undergoing coronary angiography.

PubMed

Torregrosa, Isidro; Montoliu, Carmina; Urios, Amparo; Andrés-Costa, María Jesús; Giménez-Garzó, Carla; Juan, Isabel; Puchades, María Jesús; Blasco, María Luisa; Carratalá, Arturo; Sanjuán, Rafael; Miguel, Alfonso

2015-11-01

Acute kidney injury (AKI) is a common complication after coronary angiography. Early biomarkers of this disease are needed since increase in serum creatinine levels is a late marker. To assess the usefulness of urinary kidney injury molecule-1 (uKIM-1), neutrophil gelatinase-associated lipocalin (uNGAL) and liver-type fatty acid-binding protein (uL-FABP) for early detection of AKI in these patients, comparing their performance with another group of cardiac surgery patients. Biomarkers were measured in 193 patients, 12 h after intervention. In the ROC analysis, AUC for KIM-1, NGAL and L-FABP was 0.713, 0.958 and 0.642, respectively, in the coronary angiography group, and 0.716, 0.916 and 0.743 in the cardiac surgery group. Urinary KIM-1 12 h after intervention is predictive of AKI in adult patients undergoing coronary angiography, but NGAL shows higher sensitivity and specificity. L-FABP provides inferior discrimination for AKI than KIM-1 or NGAL in contrast to its performance after cardiac surgery. This is the first study showing the predictive capacity of KIM-1 for AKI after coronary angiography. Further studies are still needed to answer relevant questions about the clinical utility of biomarkers for AKI in different clinical settings.

Biomarkers for oxidative stress: clinical application in pediatric medicine.

PubMed

Tsukahara, Hirokazu

2007-01-01

Loads of reactive oxygen species (ROS), including superoxide anion and nitric oxide, that overburden antioxidant systems induce oxidative stress in the body. Major cellular targets of ROS are membrane lipids, proteins, nucleic acids, and carbohydrates. Circumstantial evidence suggests that ROS play a crucial role in the initiation and progression of various diseases in children and adolescents. The involvement of ROS and oxidative stress in pediatric diseases is an important concern, but oxidative stress status in young subjects and appropriate methods for its measurement remain to be defined. Recently, specific biomarkers for oxidative damage and antioxidant defense have been introduced into the field of pediatric medicine. This review is intended to provide an overview of clinical applications of oxidative stress biomarkers in the field of pediatric medicine. First, this review presents the biochemistry and pathophysiology of ROS and antioxidant defense systems. Second, it presents a list of clinically applicable biomarkers, along with pediatric diseases in which enhanced oxidative stress might be involved. The discussion emphasizes that several reliable biomarkers are easily measurable using enzyme-linked immunosorbent assay. Third, this review presents age-related reference normal ranges of oxidative stress biomarkers, including urinary acrolein-lysine, 8-hydroxy-2'-deoxyguanosine, nitrite/nitrate, and pentosidine, and the changes of the parameters in several clinical conditions, including atopic dermatitis and diabetes mellitus. New and interesting data on oxidative stress and antioxidant defenses in neonatal biology are also presented. Fourth, this review discusses the ever-accumulating body of data linking oxidative stress to disturbances of the nitric oxide system and vascular endothelial activation/dysfunction. Finally, this review describes the reported clinical trials that have evaluated the efficacy of antioxidants for oxidative-stress related diseases. Suggestions are advanced for the direction of future trials using antioxidant therapies. Repeated measurement of appropriate parameters will enable us to discern the pathophysiological patterns of pediatric diseases and guide our therapies appropriately.

Biomarker Levels of Toxic Metals among Asian Populations in the United States: NHANES 2011–2012

PubMed Central

Awata, Hiroshi; Linder, Stephen; Mitchell, Laura E.; Delclos, George L.

2016-01-01

Introduction: The Centers for Disease Control and Prevention (CDC) recently found that Asians have considerably higher biomarker levels of cadmium, lead, mercury, and arsenic than whites, blacks, Mexican Americans, and other Hispanics in the United States. Objective: Our goal was to further evaluate the higher metal biomarker levels among Asians. Methods: Biomarker data (blood cadmium, blood lead, blood mercury, urinary total arsenic, and urinary dimethylarsinic acic) from individuals ≥ 6 years of age were obtained from the 2011–2012 National Health and Nutrition Examination Survey (NHANES). We compared geometric mean levels of these five metal biomarkers in Asians with those of four other NHANES race/ethnic groups (white, black, Mexican American, and other Hispanic), and across three Asian subgroups (Chinese, Asian Indian, and other Asian). We also evaluated associations between biomarker levels and sociodemographic, physical, dietary, and behavioral covariates across the Asian subgroups. Results: Asians had significantly higher levels of all five metal biomarkers than other race/ethnic groups (p < 0.05), regardless of sociodemographic, physical, dietary, behavioral, or geographic characteristics. We also found variations in biomarker levels across the Asian subgroups. In general, Asian Indians had lower levels than the other two Asian subgroups, except for blood lead. The following characteristics were found to be significant predictors of several biomarker levels: sex, age, education, birthplace, smoking, and fish consumption. Conclusions: Overall, the Asian group had the highest geometric mean biomarker levels for all of the five metal variables. Furthermore, we provided evidence that significant variations in the biomarker levels are present across the Asian subgroups in the United States. Citation: Awata H, Linder S, Mitchell LE, Delclos GL. 2017. Biomarker levels of toxic metals among Asian populations in the United States: NHANES 2011–2012. Environ Health Perspect 125:306–313; http://dx.doi.org/10.1289/EHP27 PMID:27517362

Characterization of renal biomarkers for use in clinical trials: biomarker evaluation in healthy volunteers

PubMed Central

Brott, David A; Adler, Scott H; Arani, Ramin; Lovick, Susan C; Pinches, Mark; Furlong, Stephen T

2014-01-01

Background Several preclinical urinary biomarkers have been qualified and accepted by the health authorities (US Food and Drug Administration, European Medicines Agency, and Pharmaceuticals and Medical Devices Agency) for detecting drug-induced kidney injury during preclinical toxicologic testing. Validated human assays for many of these biomarkers have become commercially available, and this study was designed to characterize some of the novel clinical renal biomarkers. The objective of this study was to evaluate clinical renal biomarkers in a typical Phase I healthy volunteer population to determine confidence intervals (pilot reference intervals), intersubject and intrasubject variability, effects of food intake, effect of sex, and vendor assay comparisons. Methods Spot urine samples from 20 male and 19 female healthy volunteers collected on multiple days were analyzed using single analyte and multiplex assays. The following analytes were measured: α-1-microglobulin, β-2-microglobulin, calbindin, clusterin, connective tissue growth factor, creatinine, cystatin C, glutathione S-transferase-α, kidney injury marker-1, microalbumin, N-acetyl-β-(D) glucosaminidase, neutrophil gelatinase-associated lipocalin, osteopontin, Tamm-Horsfall urinary glycoprotein, tissue inhibitor of metalloproteinase 1, trefoil factor 3, and vascular endothelial growth factor. Results Confidence intervals were determined from the single analyte and multiplex assays. Intersubject and intrasubject variability ranged from 38% to 299% and from 29% to 82% for biomarker concentration, and from 24% to 331% and from 10% to 67% for biomarker concentration normalized to creatinine, respectively. There was no major effect of food intake or sex. Single analyte and multiplex assays correlated with r2≥0.700 for five of six biomarkers when evaluating biomarker concentration, but for only two biomarkers when evaluating concentration normalized to creatinine. Conclusion Confidence intervals as well as intersubject and intrasubject variability were determined for novel clinical renal biomarkers/assays, which should be considered for evaluation in the next steps of the qualification process. PMID:24611000

Characterization of renal biomarkers for use in clinical trials: biomarker evaluation in healthy volunteers.

PubMed

Brott, David A; Adler, Scott H; Arani, Ramin; Lovick, Susan C; Pinches, Mark; Furlong, Stephen T

2014-01-01

Several preclinical urinary biomarkers have been qualified and accepted by the health authorities (US Food and Drug Administration, European Medicines Agency, and Pharmaceuticals and Medical Devices Agency) for detecting drug-induced kidney injury during preclinical toxicologic testing. Validated human assays for many of these biomarkers have become commercially available, and this study was designed to characterize some of the novel clinical renal biomarkers. The objective of this study was to evaluate clinical renal biomarkers in a typical Phase I healthy volunteer population to determine confidence intervals (pilot reference intervals), intersubject and intrasubject variability, effects of food intake, effect of sex, and vendor assay comparisons. Spot urine samples from 20 male and 19 female healthy volunteers collected on multiple days were analyzed using single analyte and multiplex assays. The following analytes were measured: α-1-microglobulin, β-2-microglobulin, calbindin, clusterin, connective tissue growth factor, creatinine, cystatin C, glutathione S-transferase-α, kidney injury marker-1, microalbumin, N-acetyl-β-(D) glucosaminidase, neutrophil gelatinase-associated lipocalin, osteopontin, Tamm-Horsfall urinary glycoprotein, tissue inhibitor of metalloproteinase 1, trefoil factor 3, and vascular endothelial growth factor. Confidence intervals were determined from the single analyte and multiplex assays. Intersubject and intrasubject variability ranged from 38% to 299% and from 29% to 82% for biomarker concentration, and from 24% to 331% and from 10% to 67% for biomarker concentration normalized to creatinine, respectively. There was no major effect of food intake or sex. Single analyte and multiplex assays correlated with r (2)≥0.700 for five of six biomarkers when evaluating biomarker concentration, but for only two biomarkers when evaluating concentration normalized to creatinine. Confidence intervals as well as intersubject and intrasubject variability were determined for novel clinical renal biomarkers/assays, which should be considered for evaluation in the next steps of the qualification process.

Biomarker-predicted sugars intake compared with self-reported measures in US Hispanics/Latinos: Results from the HCHS/SOL SOLNAS study

USDA-ARS?s Scientific Manuscript database

Measurement error in self-reported total sugars intake may obscure associations between sugars consumption and health outcomes, and the sum of 24 hour urinary sucrose and fructose may serve as a predictive biomarker of total sugars intake. The study of Latinos: Nutrition & Physical Activity Assessme...

Liquid chromatography with tandem mass spectrometry quantification of urinary proanthocyanin A2 dimer and its potential use as a biomarker of cranberry intake

USDA-ARS?s Scientific Manuscript database

The lack of a biomarker for the consumption of cranberries has confounded the interpretation of several studies investigating the effect of cranberry products, especially juices, on health outcomes. The objectives of this pilot study were to develop a liquid chromatography tandem mass spectrometric ...

KIM-1 Is a Potential Urinary Biomarker of Obstruction: Results from a Prospective Cohort Study.

PubMed

Olvera-Posada, Daniel; Dayarathna, Thamara; Dion, Marie; Alenezi, Husain; Sener, Alp; Denstedt, John D; Pautler, Stephen E; Razvi, Hassan

2017-02-01

Partial or complete obstruction of the urinary tract is a common and challenging urological condition that may occur in patients of any age. Serum creatinine is the most commonly used method to evaluate global renal function, although it has low sensitivity for early changes in the glomerular filtration rate or unilateral renal pathology. Hence, finding another measurable parameter that reflects the adaptation of the renal physiology to these circumstances is important. Several recent studies have assessed the use of new biomarkers of acute kidney injury (AKI), but the information among patients with stone disease and those with obstructive uropathy is limited. A prospective cohort study was conducted to determine the urinary levels of kidney injury molecule-1 (KIM-1), Total and Monomeric neutrophil gelatinase-associated lipocalin (NGAL) in patients with hydronephrosis secondary to renal stone disease, congenital ureteropelvic junction obstruction or ureteral stricture. Comparison between patients with hydronephrosis and no hydronephrosis was carried out along with correlation analysis to detect factors associated with biomarker expression. Urinary levels of KIM-1 significantly decreased after hydronephrosis treatment in patients with unilateral obstruction (1.19 ng/mL vs 0.76 ng/mL creatinine, p = 0.002), additionally KIM-1 was significantly higher in patients with hydronephrosis compared to stone disease patients without radiological evidence of obstruction (1.19 vs 0.64, p = 0.006). Total and Monomeric NGAL showed a moderate correlation with the presence of leukocyturia. We found that a KIM-1 value of 0.735 ng/mg creatinine had a sensitivity of 75% and specificity of 67% to predict the presence of hydronephrosis in preoperative studies (95% CI 0.58-0.87, p = 0.006). Our results show that KIM-1 is a promising biomarker of subclinical AKI associated with hydronephrosis in urological patients. NGAL values were influenced by the presence of leukocyturia, limiting its usefulness in this population.

MMP-1 and Pro-MMP-10 as potential urinary pharmacodynamic biomarkers of FGFR3-targeted therapy in patients with bladder cancer.

PubMed

Du, Xiangnan; Lin, Benjamin C; Wang, Qian-Rena; Li, Hao; Ingalla, Ellen; Tien, Janet; Rooney, Isabelle; Ashkenazi, Avi; Penuel, Elicia; Qing, Jing

2014-12-15

The aim of this study was to identify noninvasive pharmacodynamic biomarkers of FGFR3-targeted therapies in bladder cancer to facilitate the clinical development of experimental agent targeting FGFR3. Potential soluble pharmacodynamic biomarkers of FGFR3 were identified using a combination of transcriptional profiling and biochemical analyses in preclinical models. Two matrix metalloproteinases (MMP), MMP-1 and MMP-10, were selected for further studies in human bladder cancer xenograft models treated with a specific anti-FGFR3 monoclonal antibody, R3Mab. Serum and urinary levels of MMP-1 and MMP-10 were determined in healthy donors and patients with bladder cancer. The modulation of MMP-1 and MMP-10 by R3Mab in patients with bladder cancer was further evaluated in a phase I dose-escalation study. MMP-1 and MMP-10 mRNA and protein were downmodulated by FGFR3 shRNA and R3Mab in bladder cancer cell lines. FGFR3 signaling promoted the expression and secretion of MMP-1 and pro-MMP-10 in a MEK-dependent fashion. In bladder cancer xenograft models, R3Mab substantially blocked tumor progression and reduced the protein levels of human MMP-1 and pro-MMP-10 in tumor tissues as well as in mouse serum. Furthermore, both MMP-1 and pro-MMP-10 were elevated in the urine of patients with advanced bladder cancer. In a phase I dose-escalation trial, R3Mab administration resulted in an acute reduction of urinary MMP-1 and pro-MMP-10 levels in patients with bladder cancer. These findings reveal a critical role of FGFR3 in regulating MMP-1 and pro-MMP-10 expression and secretion, and identify urinary MMP-1 and pro-MMP-10 as potential pharmacodynamic biomarkers for R3Mab in patients with bladder cancer. ©2014 American Association for Cancer Research.

Urinary and Blood MicroRNA-126 and -770 are Potential Noninvasive Biomarker Candidates for Diabetic Nephropathy: a Meta-Analysis.

PubMed

Park, Sungjin; Moon, SeongRyeol; Lee, Kiyoung; Park, Ie Byung; Lee, Dae Ho; Nam, Seungyoon

2018-01-01

Diabetic nephropathy (DN), a major diabetic microvascular complication, has a long and growing list of biomarkers, including microRNA biomarkers, which have not been consistent across preclinical and clinical studies. This meta-analysis aims to identify significant blood- and urine-incident microRNAs as diagnostic/prognostic biomarker candidates for DN. PubMed, Web of Science, and Cochrane Library were searched from their earliest records through 12th Dec 2016. Relevant publications for the meta-analysis included (1) human participants; (2) microRNAs in blood and urine; (3) DN studies; and (4) English language. Four reviewers, including two physicians, independently and blindly extracted published data regarding microRNA profiles in blood and/or urine from subjects with diabetic nephropathy. A random-effect model was used to pool the data. Statistical associations between diabetic nephropathy and urinary or blood microRNA expression levels were assessed. Fourteen out of 327 studies (n=2,747 patients) were selected. Blood or urinary microRNA expression data of diabetic nephropathy were pooled for this analysis. The hsa-miR-126 family was significantly (OR: 0.57; 95% CI: 0.44-0.74; p-value < 0.0001) downregulated in blood from patients with diabetic kidney disease, while its urinary level was upregulated (OR: 2931.12; 95% CI: 9.96-862623.21; p-value = 0.0059). The hsa-miR-770 family microRNA were significantly (OR: 10.24; 95% CI: 2.37-44.25; p-value = 0.0018) upregulated in both blood and urine from patients with diabetic nephropathy. Our meta-analysis suggests that hsa-miR-126 and hsa-miR-770 family microRNA may have important diagnostic and pathogenetic implications for DN, which warrants further systematic clinical studies. © 2018 The Author(s). Published by S. Karger AG, Basel.

Serum Neutrophil Gelatinase-Associated Lipocalin and Urinary Kidney Injury Molecule-1 as Potential Biomarkers of Subclinical Nephrotoxicity After Gadolinium-Based and Iodinated-Based Contrast Media Exposure in Pediatric Patients with Normal Kidney Function

PubMed Central

Spasojević-Dimitrijeva, Brankica; Kotur-Stevuljević, Jelena; Đukić, Milan; Paripović, Dušan; Miloševski-Lomić, Gordana; Spasojević-Kalimanovska, Vesna; Pavićević, Polina; Mitrović, Jadranka; Kostić, Mirjana

2017-01-01

Background New renal biomarkers such as neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) show promise in early diagnosis of contrast media induced acute kidney injury (CI-AKI). The purpose of our study was to compare the subclinical nephrotoxicity (a condition without changes in standard renal biomarkers) of gadolinium-based contrast media (Gd-DTPA, gadopentetate dimeglumine) and iodinated-based contrast media (iopromide) in pediatric patients with normal kidney function. Material/Methods The first group (n=58) of patients included in the study were undergoing angiography with iopromide, and the second group (n=65) were undergoing magnetic resonance (MR) angiography/urography with Gd-DTPA administration. The concentrations of NGAL and KIM-1 were measured four times in the urine (pre-contrast, then at four hours, 24 hours, and 48 hours after contrast administration), and serum NGAL was measured at 0 (baseline), 24 hours, and 48 hours after contrast exposure. Results After 24 hours, serum NGAL increase of ≥25% was noticed in 32.6% of the patients in the iopromide group and in 25.45% of the patients in the gadolinium group, with significantly higher average percent of this increase in first group (62.23% vs. 36.44%, p=0.002). In the Gd-DTPA group, we observed a statistically significant increase in urinary KIM-1 24 hours after the procedure. Normalized urinary KIM-1, 24 hours after contrast exposure, was a better predictive factor for CI-AKI than other biomarkers (AUC 0.757, cut off 214 pg/mg, sensitivity 83.3%, specificity 54.2%, p=0.035). Conclusions In children with normal renal function, exposure to iodinated-based and gadolinium-based media might lead to subclinical nephrotoxicity, which could be detected using serum NGAL and urinary KIM-1. PMID:28874655

The Urine Proteome as a Biomarker of Radiation Injury: Submitted to Proteomics- Clinical Applications Special Issue: "Renal and Urinary Proteomics (Thongboonkerd)"

PubMed

Sharma, Mukut; Halligan, Brian D; Wakim, Bassam T; Savin, Virginia J; Cohen, Eric P; Moulder, John E

2008-06-18

Terrorist attacks or nuclear accidents could expose large numbers of people to ionizing radiation, and early biomarkers of radiation injury would be critical for triage, treatment and follow-up of such individuals. However, no such biomarkers have yet been proven to exist. We tested the potential of high throughput proteomics to identify protein biomarkers of radiation injury after total body X-ray irradiation in a rat model. Subtle functional changes in the kidney are suggested by an increased glomerular permeability for macromolecules measured within 24 hours after TBI. Ultrastructural changes in glomerular podocytes include partial loss of the interdigitating organization of foot processes. Analysis of urine by LC-MS/MS and 2D-GE showed significant changes in the urine proteome within 24 hours after TBI. Tissue kallikrein 1-related peptidase, cysteine proteinase inhibitor cystatin C and oxidized histidine were found to be increased while a number of proteinase inhibitors including kallikrein-binding protein and albumin were found to be decreased post-irradiation. Thus, TBI causes immediately detectable changes in renal structure and function and in the urinary protein profile. This suggests that both systemic and renal changes are induced by radiation and it may be possible to identify a set of biomarkers unique to radiation injury.

Review of Pesticide Urinary Biomarker Measurements from Selected US EPA Children’s Observational Exposure Studies

PubMed Central

Egeghy, Peter P.; Cohen Hubal, Elaine A.; Tulve, Nicolle S.; Melnyk, Lisa J.; Morgan, Marsha K.; Fortmann, Roy C.; Sheldon, Linda S.

2011-01-01

Children are exposed to a wide variety of pesticides originating from both outdoor and indoor sources. Several studies were conducted or funded by the EPA over the past decade to investigate children’s exposure to organophosphate and pyrethroid pesticides and the factors that impact their exposures. Urinary metabolite concentration measurements from these studies are consolidated here to identify trends, spatial and temporal patterns, and areas where further research is required. Namely, concentrations of the metabolites of chlorpyrifos (3,5,6-trichloro-2-pyridinol or TCPy), diazinon (2-isopropyl-6-methyl-4-pyrimidinol or IMP), and permethrin (3-phenoxybenzoic acid or 3-PBA) are presented. Information on the kinetic parameters describing absorption and elimination in humans is also presented to aid in interpretation. Metabolite concentrations varied more dramatically across studies for 3-PBA and IMP than for TCPy, with TCPy concentrations about an order of magnitude higher than the 3-PBA concentrations. Temporal variability was high for all metabolites with urinary 3-PBA concentrations slightly more consistent over time than the TCPy concentrations. Urinary biomarker levels provided only limited evidence of applications. The observed relationships between urinary metabolite levels and estimates of pesticide intake may be affected by differences in the contribution of each exposure route to total intake, which may vary with exposure intensity and across individuals. PMID:21655147

The Difference Quantity of Urinary Peptides between Two Groups of Type 2 Diabetic Patients with or without Coronary Artery Disease

PubMed Central

Fu, Guangzhen; Hu, Mei; Chu, Lina; Zhang, Man

2015-01-01

Objectives. We aim to explore urinary biomarkers that could monitor CAD in type 2 diabetic patients. Materials and Methods. Urine samples from two groups, twenty-eight type 2 diabetic patients with coexisting CAD and thirty type 2 diabetic patients without CAD, were purified by MB-WCX and then analyzed by MALDI-TOF-MS. Subsequently, we compared the urinary peptide signatures of the two groups by use of ClinProTools2.1 and evaluated the potential ability of the differently expressed peptides to distinguish type 2 diabetic patients with coexisting CAD from type 2 diabetic patients without CAD by ROC analysis. Finally, the differently expressed peptides were identified by nanoliquid chromatography-tandem mass spectrometry. Results. There were six differently expressed peptides (m/z 1305.2, 1743.9, 2184.9, 2756.1, 3223.2, and 6196.1) between the two groups of subjects, and they were identified as fragments of isoform 1 of fibrinogen alpha chain precursor, prothrombin precursor, and interalpha-trypsin inhibitor heavy chain H4. The diagnostic efficacy of m/z 2756.1 and m/z 3223.2 was better than the other peptides. Area under ROC of the m/z 2756.1, and m/z 3223.2 was 0.98 and 0.93, respectively. Conclusions. These urinary peptides are potential urinary biomarkers for monitoring of type 2 diabetic patients with CAD. PMID:26089891

Proteomic analysis of urine in patients with intestinal segments transposed into the urinary tract.

PubMed

Nabi, Ghulam; N'Dow, James; Hasan, Tahseen S; Booth, Ian R; Cash, Phil

2005-04-01

Intestinal segments are used to replace or reconstruct the urinary bladder when it has become dysfunctional or develops life-threatening disease such as cancer. The quality of life in patients with intestinal segments used to either enlarge or completely replace the native bladder is adversely affected by recurrent urinary tract infections, excessive mucus production and the occasional development of malignancy. At present, there is no reliable method of predicting or noninvasively monitoring these patients for the development of these complications. The characterisation of proteins secreted into urine from the transposed intestinal segments could serve as important indicators of these clinical complications. Urine is an ideal source of material in which to search for biomarkers, since it bathes the affected tissues and can be obtained relatively easily by noninvasive methods. The urinary proteome of patients with intestinal segments transposed into the urinary tract is unknown and we present the first global description of the urinary protein profile in these patients. Sample preparation is a critical step in achieving accurate and reliable data. We describe a method to prepare urinary proteins that was compatible with their subsequent analysis using two-dimensional polyacrylamide gel electrophoresis. This method helped to overcome some of the technical problems encountered in analysing urine from this patient cohort. The method was used to analyse urinary proteins recovered from five healthy controls and ten patients with intestinal segments transposed into the urinary tract. Four low molecular weight proteins were found to be present in nine out of ten for the patient group but for none of the healthy controls. The four proteins were identified as lithostathine-1 alpha precursor, pancreatitis associated protein-1 precursor, liver fatty acid binding protein and testis expressed protein-12. The role of these proteins as potential biomarkers of intestinal cell activity within the reconstructed bladder is discussed.

[Assessment of exposure to polycyclic aromatic hydrocarbons in asphalt workers by measurement of urinary 1-hydroxypyrene].

PubMed

Campo, Laura; Calisti, R; Polledri, Elisa; Barretta, F; Stopponi, Roberta; Massacesi, Stefania; Bertazzi, P A; Fustinoni, Silvia

2011-01-01

Asphalt workers are potentially exposed to polycyclic aromatic hydrocarbons (PAHs). As some PAHs are classified as carcinogenic, the assessment of occupational exposure to these agents is of the utmost importance in preventing toxic effects. To assess exposure to PAHs by urinary 1-hydroxypyrene (1-OHPyr). We studied 22 asphalt workers (14 smokers) and 5 control subjects (1 smoker). Multiple samples of urine (up to 4per subject) were collected at the end of the shift for the measurement of 1-OHPyr by LCMS/MS. Univariate and multivariate linear models for repeated measurements were used to evaluate the differences between groups and to identify the variables influencing of exposure. The median urinary excretion of 1-OHPyr in asphalt workers was low, but higher than that of control subjects (184 vs. <20 ng/L, or 106 vs. <20 ng/g creatinine, p < 0.001); cigarette smoking marginally increased 1-OHPyr in smoking asphalt workers in comparison to non-smokers (129 vs. 208 ng/L p= 0.09 or 94 vs. 121 ng/g creatinine, p = 0.06). The number of consecutive days at work significantly influenced the urinary excretion of l-OHPyr [+59% every day, CI: (2, 147), p = 0.04]. Subjects using paving machines had the highest exposure. A strong association between 1-OHPyr and urinary creatinine was observed. urinary 1-OHPyr is a useful indicator of occupational exposure to low levels of PAHs, such as those found in the subjects studied; in using this biomarker it is recommended to collect urine samples at the end of the working week and to express levels of the biomarker corrected for urinary creatinine.

Urinary 8-hydroxy-deoxyguanosine as a biomarker of oxidative DNA damage in employees of subway system.

PubMed

Mehrdad, Ramin; Aghdaei, Sara; Pouryaghoub, Gholamreza

2015-01-01

Exposure to air pollutants, steel dust or other occupational and environmental hazards as oxidative stress have adverse effects on subway workers' health. Oxidative stress generates an excessive amount of reactive oxygen species (ROS) and Oxygen Free Radicals during their work time in the tunnels. Once DNA is repaired, Urinary 8-hydroxy-deoxyguanosine (8-OHdG) is excreted in the urine. Therefore, urinary level of 8-OHdG can reflect the extent of oxidative DNA damage. The aim of this study was to document the oxidative stress caused by exposure to these hazards by measuring 8-OHdG in workers urine. We collected urine samples of 81 male subway workers after their working shift. The concentration of urinary 8-OHdG was measured by ELISA method. We used linear regression analysis to compare the level of urinary 8-OHdG as a biomarker of oxidative stress between workers in tunnels and other staff. The mean concentration of urinary 8-OHdG for workers in the tunnel was 58.05 (SD=28.83) ng/mg creatinine and for another staff was 54.16 (SD =26.98) ng/mg creatinine.  After adjustment for age, smoking, driving and a second job in a linear regression model, the concentration of 8-OHdG for the exposed group was significantly higher than unexposed group (P=0.038). These findings confirm that the concentration of urinary 8-OHdG for workers who work in tunnels was significantly higher than the other staff. Additional investigations should be performed to understand that which ones of occupational exposures are more important to cause oxidative stress.

URINARY MUTAGENESIS AS AN EXPOSURE BIOMARKER OF COOKED-MEAT-ASSOCIATED MUTAGENS: INFLUENCE OF COOKING TEMPERATURE, PHENOTYPE, AND GENOTYPE IN A CONTROLLED METABOLIC FEEDING STUDY

EPA Science Inventory

ABSTRACT
We evaluated urinary mutagenicity and selected phenotypes and genotypes in 60 subjects in a metabolic feeding study in which meat cooked at low temperature (100oC) was consumed for 1 week followed by meat cooked at high temperature (250oC) the second week. Meat coo...

Perturbations in the Urinary Exosome in Transplant Rejection

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sigdel, Tara K.; NG, Yolanda; Lee, Sangho

Background: Urine exosomes, vesicles exocytosed into urine by all renal epithelial cell types, occur under normal physiologic and disease states. Exosome contents may mirror disease-specific proteome perturbations in kidney injury. Analysis methodologies for the exosomal fraction of the urinary proteome were developed and for comparing the urinary exosomal fraction versus unfractionated proteome for biomarker discovery. Methods: Urine exosomes were isolated by centrifugal filtration from mid-stream, second morning void, urine samples collected from kidney transplant recipients with and without biopsy matched acute rejection. The proteomes of unfractionated whole urine (Uw) and urine exosomes (Uexo) underwent mass spectrometry-based quantitative proteomics analysis. Themore » proteome data were analyzed for significant differential protein abundances in acute rejection (AR). Results: Identifications of 1018 and 349 proteins, Uw and Uexo fractions, respectively, demonstrated a 279 protein overlap between the two urinary compartments with 25%(70) of overlapping proteins unique to Uexoand represented membrane bound proteins (p=9.31e-7). Of 349 urine exosomal proteins identified in transplant patients 220 were not previously identified in the normal urine exosomal fraction. Uexo proteins (11), functioning in the inflammatory / stress response, were more abundant in patients with biopsy-confirmed acute rejection, 3 of which were exclusive to Uexo. Uexo AR-specific biomarkers (8) were also detected in Uw, but since they were observed at significantly lower abundances in Uw, they were not significant for AR in Uw. Conclusions: A rapid urinary exosome isolation method and quantitative measurement of enriched Uexo proteins was applied. Urine proteins specific to the exosomal fraction were detected either in unfractionated urine (at low abundances) or by Uexo fraction analysis. Perturbed proteins in the exosomal compartment of urine collected from kidney transplant patients were specific to inflammatory responses, and were not observed in the Uexo fraction from normal healthy subjects. Uexo specific protein alterations in renal disease provide potential mechanistic insights and offer a unique panel of sensitive biomarkers for monitoring for acute transplant rejection.« less

Association between urinary 1-hydroxypyrene and genotoxic effects in coke oven workers

PubMed Central

Siwinska, E; Mielzynska, D; Kapka, L

2004-01-01

Methods: Blood and urine samples were collected immediately after a shift at the end of a working week from 50 coke oven workers and 50 control workers not exposed to PAHs. Methods included: (1) biomarkers of exposure: urinary 1-hydroxypyrene (HpU), urinary mutagenicity by the plate Salmonella test with strains TA98 and YG1024 after metabolic activation, expressed as mutagenic rate (MR98 and MR1024, respectively), urinary cotinine; and (2) biomarkers of biological effects in peripheral blood lymphocytes (PBL): sister chromatid exchanges (SCE/cell), cells of high frequency of SCE (% HFC), micronuclei (MN/1000 cells), chromosomal aberrations (CA/100 cells), and DNA damage by the Comet assay. Results: Occupational exposure to PAH resulted in significantly increased levels of HpU and mutagenic effect of urine. Median values of these biomarkers in coke oven workers were: 9.0 µmol/mol creatinine for HpU, 2.7 for MR98, and 8.2 for MR1024, compared to the controls: HpU = 0.6 µmol/mol creatinine, MR98 = 1.2, and MR1024 = 5.5. Occupational exposure caused significant induction of SCE, HFC, and MN in coke oven workers: median SCE = 5.9, HFC = 12.0%, MN = 6.0 compared to the controls: 3.9, 5.0%, and 3.0, respectively. No effect of occupational exposure was found in relation to CA and DNA damage measured with the Comet assay. HpU concentration was positively associated with SCE and HFC. The concentration of urinary 1-hydroxypyrene corresponding to a 5% probability of increased SCE was 1.0 µmol/mol creatinine. Conclusions: The occupational exposure to PAHs resulted in measurable biological effects (SCE, HFC, MN). In coke oven workers an increased level of SCE was not observed below the level of 1.0 µmol HpU/mol creatinine. PMID:14985527

Simultaneous Liquid Chromatography–Mass Spectrometry Quantification of Urinary Opiates, Cocaine, and Metabolites in Opiate-Dependent Pregnant Women in Methadone-Maintenance Treatment

PubMed Central

Shakleya, Diaa M.; Dams, Riet; Choo, Robin E.; Jones, Hendree; Huestis, Marilyn A.

2011-01-01

Opiates, cocaine, and metabolites were quantified by liquid chromatography–mass spectrometry (LC–MS) in 284 urine specimens, collected thrice weekly, to monitor possible drug relapse in 15 pregnant heroin-dependent women. Opiates were detected in 149 urine specimens (52%) with limits of quantification (LOQ) of 10–50 μg/L. Morphine, morphine-3-glucuronide, and/or morphine-6-glucuronide were positive in 121 specimens; 6-acetylmorphine, a biomarker of heroin ingestion, was quantifiable in only 7. No heroin, 6-acetylcodeine, papaverine, or noscapine were detected. One hundred and sixty-five urine specimens (58%) from all 15 participants were positive for one or more cocaine analytes (LOQ 10–100 μg/L). Ecgonine methylester (EME) and/or benzoylecgonine were the major cocaine biomarkers in 142. Anhydroecgonine methylester, a biomarker of smoked cocaine, was positive in six; cocaethylene and/or ecgonine ethylester, biomarkers of cocaine and ethanol co-ingestion, were found in 25. At the current Substance Abuse Mental Health Services Administration cutoffs for total morphine (2000 μg/L), codeine (2000 μg/L), 6-acetylmorphine (10 μg/L), and benzoylecgonine (100 μg/L), 16 opiate- and 29 cocaine-positive specimens were identified. Considering 100 μg/L EME as an additional urinary cocaine biomarker would identify 51 more positive cocaine specimens. Of interest is the differential pattern of opiate and cocaine biomarkers observed after LC–MS as compared to gas chromatography–mass spectrometry analysis. PMID:20109298

Elevated urinary level of vitamin D-binding protein as a novel biomarker for diabetic nephropathy

PubMed Central

TIAN, XIAO-QIN; ZHAO, LI-MIN; GE, JIA-PU; ZHANG, YAN; XU, YAN-CHENG

2014-01-01

Improving the early prediction and detection of diabetic nephropathy (DN) remains a great challenge in disease management. The aim of this study was to evaluate the early detection power of urinary vitamin D-binding protein (VDBP) for the diagnosis of DN. Urine samples were obtained from 45 healthy volunteers and 105 diabetic patients with normoalbuminuria (DM group), microalbuminuria (DN1 group) and macroalbuminuria (DN2 group) (n=35 per group). The VDBP expression patterns in urine from patients and controls were quantified by western blot analysis. The excretion levels of urinary VDBP were quantified with enzyme-linked immunosorbent assay. The quantification results were obtained by correcting for creatinine expression and showed that urinary VDBP levels were significantly elevated in the patients of the DN1 and DN2 groups compared with those of the DM group and normal controls (1,011.33±325.30 and 1,406.34±239.66 compared with 466.54±213.63 and 125.48±98.27 ng/mg, respectively) (P<0.001). Receiver operating characteristic analysis of urinary VDBP levels for the diagnosis of DN rendered an optimum cut-off value of 552.243 ng/mg corresponding to 92.86% sensitivity and 85.00% specificity, which also showed an area under the ROC curve of 0.966. In conclusion, the findings of the present study suggest that urinary VDBP may be a potential biomarker for the early detection and prevention of DN. Further studies are required to examine the pathogenic mechanisms of elevated VDBP levels and their role in the diagnosis of DN. PMID:24396416

Intraindividual stability of cortisol and cortisone and the ratio of cortisol to cortisone in saliva, urine and hair.

PubMed

Zhang, Quan; Chen, Zheng; Chen, Shenghuo; Xu, Youyun; Deng, Huihua

2017-02-01

Cortisol, cortisone and the ratio of cortisol to cortisone in saliva, urine and hair are acute, short-term and long-term biomarkers to reliably assess the activity of hypothalamic-pituitary-adrenal (HPA) axis and 11β-hydroxysteroid dehydrogenase (11β-HSD). One key issue is whether these biomarkers have intraindividual relative stability. Salivary, urinary and hair cortisol was proven to show considerable long-term intraindividual relative stability. However, currently unknown is whether cortisone and the ratio in saliva, urine and hair show intraindividual relative stability. The present study utilized a longitudinal design to validate long-term stability within two weeks of three biomarkers in saliva and urine, and long-term stability within twelve months of three hair biomarkers. Salivary, urinary and hair steroids were measured with high performance liquid chromatography tandem mass spectrometry. Three biomarkers in urine and hair showed moderate test-retest correlations with coefficient (r) ranging between 0.22 and 0.56 and good multiple-test consistencies with coefficient of intraclass correlation (ICC) ranging between 0.42 and 0.67. Three single-point salivary biomarkers showed weak to moderate test-retest correlations (r's between 0.01 and 0.38) and poor to fair multiple-test consistencies (ICC's between 0.29 and 0.53) within two weeks. Three single-day salivary biomarkers showed moderate test-retest correlations (r's between 0.23 and 0.53) and good multiple-test consistencies (ICC's between 0.56 and 0.66) within two weeks. Three biomarkers in urine and hair showed moderate long-term intraindividual relative stability. Three single-point salivary biomarkers showed weak to moderate short-term and long-term intraindividual relative stability, but three single-day salivary biomarkers showed moderate short-term and long-term intraindividual relative stability. Copyright © 2016 Elsevier Inc. All rights reserved.

Urinary biomarkers of acute kidney injury in deceased organ donors--kidney injury molecule-1 as an adjunct to predicting outcome.

PubMed

Field, Melanie; Dronavalli, Vamsi; Mistry, Punam; Drayson, Mark; Ready, Andrew; Cobbold, Mark; Inston, Nicholas

2014-07-01

Deceased kidney donors are increasingly "marginal," and many have risk factors for acute kidney injury (AKI) that may impact on subsequent renal transplant outcome. Despite this, determining the presence of AKI at the time of deceased organ donation remains difficult. Urine samples from 182 brainstem dead multi-organ donors (all of whom donated hearts that were transplanted) were analyzed for a Luminex(™) panel of biomarkers linked with AKI. This included KIM-1, NGAL, IFN-γ, TNF-α, cystatin C, Fractalkine and vascular endothelial growth factor. Levels were correlated to early renal transplant outcomes, most specifically delayed graft function. Donor urinary KIM-1 levels were significantly higher in donors whose kidneys displayed aberrant early function (p = 0.011). Fractalkine levels showed a trend toward elevation in such donors but uncorrected this did not attain significance. No correlation occurred with the remaining biomarkers. KIM-1 appears to show promise as a marker for AKI in deceased cardiac organ donors. The availability of a lateral flow device (Renastick(™) ) for KIM-1 that also demonstrates higher urinary KIM-1 levels in donors whose kidneys show aberrant initial function (p = 0.03), makes KIM-1 a potential indicator of AKI that may merit further evaluation for its application at the donor bedside. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Essential trace elements in amyotrophic lateral sclerosis (ALS): Results in a population of a risk area of Italy.

PubMed

Forte, Giovanni; Bocca, Beatrice; Oggiano, Riccardo; Clemente, Simonetta; Asara, Yolande; Sotgiu, Maria Alessandra; Farace, Cristiano; Montella, Andrea; Fois, Alessandro Giuseppe; Malaguarnera, Michele; Pirina, Pietro; Madeddu, Roberto

2017-09-01

Sardinian (Italy) island population has a uniquely high incidence of amyotrophic lateral sclerosis (ALS). Essential trace element levels in blood, hair, and urine of ALS Sardinian patients were investigated in search of valid biomarkers to recognize and predict ALS. Six elements (Ca, Cu, Fe, Mg, Se, and Zn) were measured in 34 patients compared to 30 age- and sex-matched healthy controls by a validated method. Levels of Ca and Cu in blood and of Se and Zn in hair were significantly higher in ALS than in controls, while urinary excretion of Mg and Se was significantly decreased. The selected cut-off concentrations for these biomarkers may distinguish patients with or without ALS with sufficient sensitivity and specificity. Many positive (as Se-Cu and Se-Zn) and negative associations (as Ca-Mg and Ca-Zn) between elements suggested that multiple metals involved in multiple mechanisms have a role in the ALS degeneration.

Interpreting biomarker data from the COPHES/DEMOCOPHES twin projects: Using external exposure data to understand biomarker differences among countries

DOE Office of Scientific and Technical Information (OSTI.GOV)

Smolders, R., E-mail: roel.smolders@vito.be; Den Hond, E.; Koppen, G.

In 2011 and 2012, the COPHES/DEMOCOPHES twin projects performed the first ever harmonized human biomonitoring survey in 17 European countries. In more than 1800 mother–child pairs, individual lifestyle data were collected and cadmium, cotinine and certain phthalate metabolites were measured in urine. Total mercury was determined in hair samples. While the main goal of the COPHES/DEMOCOPHES twin projects was to develop and test harmonized protocols and procedures, the goal of the current paper is to investigate whether the observed differences in biomarker values among the countries implementing DEMOCOPHES can be interpreted using information from external databases on environmental quality andmore » lifestyle. In general, 13 countries having implemented DEMOCOPHES provided high-quality data from external sources that were relevant for interpretation purposes. However, some data were not available for reporting or were not in line with predefined specifications. Therefore, only part of the external information could be included in the statistical analyses. Nonetheless, there was a highly significant correlation between national levels of fish consumption and mercury in hair, the strength of antismoking legislation was significantly related to urinary cotinine levels, and we were able to show indications that also urinary cadmium levels were associated with environmental quality and food quality. These results again show the potential of biomonitoring data to provide added value for (the evaluation of) evidence-informed policy making. - Highlights: • External data was collected to interpret HBM data from DEMOCOPHES. • Hg in hair could be related to fish consumption across different countries. • Urinary cotinine was related to strictness of anti-smoking legislation. • Urinary Cd was borderline significantly related to air and food quality. • Lack of comparable data among countries hampered the analysis.« less

The extracellular domain of neurotrophin receptor p75 as a candidate biomarker for amyotrophic lateral sclerosis.

PubMed

Shepheard, Stephanie R; Chataway, Tim; Schultz, David W; Rush, Robert A; Rogers, Mary-Louise

2014-01-01

Objective biomarkers for amyotrophic lateral sclerosis would facilitate the discovery of new treatments. The common neurotrophin receptor p75 is up regulated and the extracellular domain cleaved from injured neurons and peripheral glia in amyotrophic lateral sclerosis. We have tested the hypothesis that urinary levels of extracellular neurotrophin receptor p75 serve as a biomarker for both human motor amyotrophic lateral sclerosis and the SOD1(G93A) mouse model of the disease. The extracellular domain of neurotrophin receptor p75 was identified in the urine of amyotrophic lateral sclerosis patients by an immuno-precipitation/western blot procedure and confirmed by mass spectrometry. An ELISA was established to measure urinary extracellular neurotrophin receptor p75. The mean value for urinary extracellular neurotrophin receptor p75 from 28 amyotrophic lateral sclerosis patients measured by ELISA was 7.9±0.5 ng/mg creatinine and this was significantly higher (p<0.001) than 12 controls (2.6±0.2 ng/mg creatinine) and 19 patients with other neurological disease (Parkinson's disease and Multiple Sclerosis; 4.1±0.2 ng/mg creatinine). Pilot data of disease progression rates in 14 MND patients indicates that p75NTR(ECD) levels were significantly higher (p = 0.0041) in 7 rapidly progressing patients as compared to 7 with slowly progressing disease. Extracellular neurotrophin receptor p75 was also readily detected in SOD1(G93A) mice by immuno-precipitation/western blot before the onset of clinical symptoms. These findings indicate a significant relation between urinary extracellular neurotrophin receptor p75 levels and disease progression and suggests that it may be a useful marker of disease activity and progression in amyotrophic lateral sclerosis.

Urinary biomarkers of occupational jet fuel exposure among Air Force personnel.

PubMed

Smith, Kristen W; Proctor, Susan P; Ozonoff, A L; McClean, Michael D

2012-01-01

There is a potential for widespread occupational exposure to jet fuel among military and civilian personnel. Urinary metabolites of naphthalene have been suggested for use as short-term biomarkers of exposure to jet fuel (jet propulsion fuel 8 (JP8)). In this study, urinary biomarkers of JP8 were evaluated among US Air Force personnel. Personnel (n=24) were divided a priori into high, moderate, and low exposure groups. Pre- and post-shift urine samples were collected from each worker over three workdays and analyzed for metabolites of naphthalene (1- and 2-naphthol). Questionnaires and breathing-zone naphthalene samples were collected from each worker during the same workdays. Linear mixed-effects models were used to evaluate the exposure data. Post-shift levels of 1- and 2-naphthol varied significantly by a priori exposure group (levels in high group>moderate group>low group), and breathing-zone naphthalene was a significant predictor of post-shift levels of 1- and 2-naphthol, indicating that for every unit increase in breathing-zone naphthalene, there was an increase in naphthol levels. These results indicate that post-shift levels of urinary 1- and 2-naphthol reflect JP8 exposure during the work-shift and may be useful surrogates of JP8 exposure. Among the high exposed workers, significant job-related predictors of post-shift levels of 1- and 2-naphthol included entering the fuel tank, repairing leaks, direct skin contact with JP8, and not wearing gloves during the work-shift. The job-related predictors of 1- and 2-naphthol emphasize the importance of reducing inhalation and dermal exposure through the use of personal protective equipment while working in an environment with JP8.

Biological monitoring of smoke exposure among wildland firefighters: A pilot study comparing urinary methoxyphenols with personal exposures to carbon monoxide, particulate matter, and levoglucosan.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Neitzel, R.; Naeher, L., P.; Paulsen, M.

2009-04-01

Urinary methoxyphenols (MPs) have been proposed as biomarkers of woodsmoke exposure. However, few field studies have been undertaken to evaluate the relationship between woodsmoke exposure and urinary MP concentrations. We conducted a pilot study at the US Forest ServiceFSavannah River Site, in which carbon monoxide (CO), levoglucosan (LG), and particulate matter (PM2.5) exposures were measured in wildland firefighters on prescribedburn days. Pre- and post-shift urine samples were collected from each subject, and cross-shift changes in creatinine-corrected urinary MP concentrations were calculated. Correlations between exposure measures and creatine-adjusted urinary MP concentrations were explored, and regression models were developed relating changes inmore » urinary MP concentrations to measured exposure levels. Full-shift measurements were made on 13 firefighters over 20 work shifts in winter 2004 at the US Forest Service Savannah River site, a National Environmental Research Park. The average workshift length across the 20 measured shifts was 701±95 min. LG and CO exposures were significantly correlated for samples where the filter measurement captured at least 60% of the work shift (16 samples), as well as for the smaller set of full-shift exposure samples (n¼9). PM2.5 and CO exposures were not significantly correlated, and LG and PM2.5 exposures were only significantly correlated for samples representing at least 60% of the work shift. Creatinine-corrected urinary concentrations for 20 of the 22 MPs showed cross-shift increases, with 14 of these changes showing statistical significance. Individual and summed creatinine-adjusted guaiacol urinary MPs were highly associated with CO (and, to a lesser degree, LG) exposure levels, and random-effects regression models including CO and LG exposure levels explained up to 80% of the variance in cross-shift changes in summed creatinine-adjusted guaiacol urinary MP concentrations. Although limited by the small sample size, this pilot study demonstrates that urinary MP concentrations may be effective biomarkers of occupational exposure to wood smoke among wildland firefighters.« less

Biological monitoring of smoke exposure among wildland firefighters: Apilot study comparing urinary methoxyphenols with personal exposures to carbon monoxide, particulate matter, and levoglucosan.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Neitzel, R.; Naeher, L., P.; Paulsen, M.

2009-04-01

Urinary methoxyphenols (MPs) have been proposed as biomarkers of woodsmoke exposure. However, few field studies have been undertaken to evaluate the relationship between woodsmoke exposure and urinary MP concentrations. We conducted a pilot study at the US Forest Service Savannah River Site, in which carbon monoxide (CO), levoglucosan (LG), and particulate matter (PM2.5) exposures were measured in wildland firefighters on prescribed burn days. Pre- and post-shift urine samples were collected from each subject, and cross-shift changes in creatinine-corrected urinary MP concentrations were calculated. Correlations between exposure measures and creatine-adjusted urinary MP concentrations were explored, and regression models were developed relatingmore » changes in urinary MP concentrations to measured exposure levels. Full-shift measurements were made on 13 firefighters over 20 work shifts in winter 2004 at the US Forest Service Savannah River site, a National Environmental Research Park. The average workshift length across the 20 measured shifts was 701±95 min. LG and CO exposures were significantly correlated for samples where the filter measurement captured at least 60% of the work shift (16 samples), as well as for the smaller set of full-shift exposure samples (n¼9). PM2.5 and CO exposures were not significantly correlated, and LG and PM2.5 exposures were only significantly correlated for samples representing at least 60% of the work shift. Creatinine-corrected urinary concentrations for 20 of the 22 MPs showed cross-shift increases, with 14 of these changes showing statistical significance. Individual and summed creatinine-adjusted guaiacol urinary MPs were highly associated with CO (and, to a lesser degree, LG) exposure levels, and random-effects regression models including CO and LG exposure levels explained up to 80% of the variance in cross-shift changes in summed creatinine-adjusted guaiacol urinary MP concentrations. Although limited by the small sample size, this pilot study demonstrates that urinary MP concentrations may be effective biomarkers of occupational exposure to wood smoke among wildland firefighters.« less

Biological monitoring of smoke exposure among wildland firefighters: A pilot study comparing urinary methoxyphenols with personal exposures to carbon monoxide, particulate matter, and levoglucosan.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Neitzel, R.; Naeher, L., P.; Paulsen, M.

2009-04-01

Urinary methoxyphenols (MPs) have been proposed as biomarkers of woodsmoke exposure. However, few field studies have been undertaken to evaluate the relationship between woodsmoke exposure and urinary MP concentrations. We conducted a pilot study at the US Forest Service Savannah River Site, in which carbon monoxide (CO), levoglucosan (LG), and particulate matter (PM2.5) exposures were measured in wildland firefighters on prescribed burn days. Pre- and post-shift urine samples were collected from each subject, and cross-shift changes in creatinine-corrected urinary MP concentrations were calculated. Correlations between exposure measures and creatine-adjusted urinary MP concentrations were explored, and regression models were developed relatingmore » changes in urinary MP concentrations to measured exposure levels. Full-shift measurements were made on 13 firefighters over 20 work shifts in winter 2004 at the US Forest Service Savannah River site, a National Environmental Research Park. The average workshift length across the 20 measured shifts was 701±95 min. LG and CO exposures were significantly correlated for samples where the filter measurement captured at least 60% of the work shift (16 samples), as well as for the smaller set of full-shift exposure samples (n¼9). PM2.5 and CO exposures were not significantly correlated, and LG and PM2.5 exposures were only significantly correlated for samples representing at least 60% of the work shift. Creatinine-corrected urinary concentrations for 20 of the 22 MPs showed cross-shift increases, with 14 of these changes showing statistical significance. Individual and summed creatinine-adjusted guaiacol urinary MPs were highly associated with CO (and, to a lesser degree, LG) exposure levels, and random-effects regression models including CO and LG exposure levels explained up to 80% of the variance in cross-shift changes in summed creatinine-adjusted guaiacol urinary MP concentrations. Although limited by the small sample size, this pilot study demonstrates that urinary MP concentrations may be effective biomarkers of occupational exposure to wood smoke among wildland firefighters.« less

Biological monitoring of smoke exposure among wildland firefighters: Apilot study comparing urinary methoxyphenols with personal exposures to carbon monoxide, particulate matter, and levoglucosan.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Neitzel, R.; Naeher, L., P.; Paulsen, M.

2009-04-01

Urinary methoxyphenols (MPs) have been proposed as biomarkers of woodsmoke exposure. However, few field studies have been undertaken to evaluate the relationship between woodsmoke exposure and urinary MP concentrations. We conducted a pilot study at the US Forest ServiceFSavannah River Site, in which carbon monoxide (CO), levoglucosan (LG), and particulate matter (PM2.5) exposures were measured in wildland firefighters on prescribed burn days. Pre- and post-shift urine samples were collected from each subject, and cross-shift changes in creatinine-corrected urinary MP concentrations were calculated. Correlations between exposure measures and creatine-adjusted urinary MP concentrations were explored, and regression models were developed relating changesmore » in urinary MP concentrations to measured exposure levels. Full-shift measurements were made on 13 firefighters over 20 work shifts in winter 2004 at the US Forest Service Savannah River site, a National Environmental Research Park. The average workshift length across the 20 measured shifts was 701±95 min. LG and CO exposures were significantly correlated for samples where the filter measurement captured at least 60% of the work shift (16 samples), as well as for the smaller set of full-shift exposure samples (n¼9). PM2.5 and CO exposures were not significantly correlated, and LG and PM2.5 exposures were only significantly correlated for samples representing at least 60% of the work shift. Creatinine-corrected urinary concentrations for 20 of the 22 MPs showed cross-shift increases, with 14 of these changes showing statistical significance. Individual and summed creatinine-adjusted guaiacol urinary MPs were highly associated with CO (and, to a lesser degree, LG) exposure levels, and random-effects regression models including CO and LG exposure levels explained up to 80% of the variance in cross-shift changes in summed creatinine-adjusted guaiacol urinary MP concentrations. Although limited by the small sample size, this pilot study demonstrates that urinary MP concentrations may be effective biomarkers of occupational exposure to wood smoke among wildland firefighters.« less

Biological monitoring of smoke exposure among wildland firefighters: Apilot study comparing urinary methoxyphenols with personal exposures to carbon monoxide, particulate matter, and levoglucosan.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Neitzel, R.; Naeher, L., P.; Paulsen, M.

2008-04-01

Urinary methoxyphenols (MPs) have been proposed as biomarkers of woodsmoke exposure. However, few field studies have been undertaken to evaluate the relationship between woodsmoke exposure and urinary MP concentrations. We conducted a pilot study at the US Forest Service Savannah River Site, in which carbon monoxide (CO), levoglucosan (LG), and particulate matter (PM2.5) exposures were measured in wildland firefighters on prescribed burn days. Pre- and post-shift urine samples were collected from each subject, and cross-shift changes in creatinine-corrected urinary MP concentrations were calculated. Correlations between exposure measures and creatine-adjusted urinary MP concentrations were explored, and regression models were developed relatingmore » changes in urinary MP concentrations to measured exposure levels. Full-shift measurements were made on 13 firefighters over 20 work shifts in winter 2004 at the US Forest Service Savannah River site, a National Environmental Research Park. The average workshift length across the 20 measured shifts was 701±95 min. LG and CO exposures were significantly correlated for samples where the filter measurement captured at least 60% of the work shift (16 samples), as well as for the smaller set of full-shift exposure samples (n¼9). PM2.5 and CO exposures were not significantly correlated, and LG and PM2.5 exposures were only significantly correlated for samples representing at least 60% of the work shift. Creatinine-corrected urinary concentrations for 20 of the 22 MPs showed cross-shift increases, with 14 of these changes showing statistical significance. Individual and summed creatinine-adjusted guaiacol urinary MPs were highly associated with CO (and, to a lesser degree, LG) exposure levels, and random-effects regression models including CO and LG exposure levels explained up to 80% of the variance in cross-shift changes in summed creatinine-adjusted guaiacol urinary MP concentrations. Although limited by the small sample size, this pilot study demonstrates that urinary MP concentrations may be effective biomarkers of occupational exposure to wood smoke among wildland firefighters.« less

Increased Urinary Adenosine Triphosphate in Patients With Bladder Outlet Obstruction Due to Benign Prostate Hyperplasia.

PubMed

Silva-Ramos, Miguel; Silva, Isabel; Oliveira, José Carlos; Correia-de-Sá, Paulo

2016-11-01

Diagnosis of bladder outflow obstruction (BOO) in patients with lower urinary tract (LUT) symptoms is challenging without using invasive urodynamic tests. Recently, we showed in vitro that urothelial strips from patients with benign prostatic hyperplasia (BPH) release more ATP than controls. Here, we tested whether urinary ATP can be used as a wall tension transducer non-invasive biomarker to detect BOO in patients with BPH. 79 male patients with BOO and 22 asymptomatic controls were recruited prospectively. Patients were asked to complete the International Prostate Symptom Score (IPSS) questionnaire and to void at normal desire into a urinary flowmeter; the postvoid residual volume was determined by suprapubic ultrasonography. Urine samples from all individuals were examined for ATP, creatinine, and lactate dehydrogenase. BOO patients had significantly higher (P < 0.001) urinary ATP normalized by the voided volume (456 ± 36 nmol) than age-matched controls (209 ± 35 nmol). Urinary ATP amounts increased with the voided volume, but the slope of this rise was higher in BOO patients than in controls. A negative correlation was detected between urinary ATP and flow rate parameters, namely maximal flow rate (r = -0.310, P = 0.005), Siroky flow-volume normalization (r = -0.324, P = 0.004), and volume-normalized flow rate index (r = -0.320, P = 0.012). We found no correlation with LUT symptoms IPSS score. Areas under the receiver operator characteristics (ROC) curves were 0.91 (95%CI 0.86-0.96, P < 0.001) for ATP alone and 0.88 (95%CI 0.81-0.94, P < 0,001) when adjusted to urinary creatinine. Patients with BOO release higher amounts of ATP into the urine than the control group. The high area under the ROC curve suggests that urinary ATP can be a high-sensitive non-invasive biomarker of BOO, which may have a discriminative value of detrusor competence when comparing BPH patients with low urinary flow rates. Prostate 76:1353-1363, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

A Systematic Review of Biomarkers and Risk of Incident Type 2 Diabetes: An Overview of Epidemiological, Prediction and Aetiological Research Literature

PubMed Central

Sahlqvist, Anna-Stina; Lotta, Luca; Brosnan, Julia M.; Vollenweider, Peter; Giabbanelli, Philippe; Nunez, Derek J.; Waterworth, Dawn; Scott, Robert A.; Langenberg, Claudia; Wareham, Nicholas J.

2016-01-01

Background Blood-based or urinary biomarkers may play a role in quantifying the future risk of type 2 diabetes (T2D) and in understanding possible aetiological pathways to disease. However, no systematic review has been conducted that has identified and provided an overview of available biomarkers for incident T2D. We aimed to systematically review the associations of biomarkers with risk of developing T2D and to highlight evidence gaps in the existing literature regarding the predictive and aetiological value of these biomarkers and to direct future research in this field. Methods and Findings We systematically searched PubMed MEDLINE (January 2000 until March 2015) and Embase (until January 2016) databases for observational studies of biomarkers and incident T2D according to the 2009 PRISMA guidelines. We also searched availability of meta-analyses, Mendelian randomisation and prediction research for the identified biomarkers. We reviewed 3910 titles (705 abstracts) and 164 full papers and included 139 papers from 69 cohort studies that described the prospective relationships between 167 blood-based or urinary biomarkers and incident T2D. Only 35 biomarkers were reported in large scale studies with more than 1000 T2D cases, and thus the evidence for association was inconclusive for the majority of biomarkers. Fourteen biomarkers have been investigated using Mendelian randomisation approaches. Only for one biomarker was there strong observational evidence of association and evidence from genetic association studies that was compatible with an underlying causal association. In additional search for T2D prediction, we found only half of biomarkers were examined with formal evidence of predictive value for a minority of these biomarkers. Most biomarkers did not enhance the strength of prediction, but the strongest evidence for prediction was for biomarkers that quantify measures of glycaemia. Conclusions This study presents an extensive review of the current state of the literature to inform the strategy for future interrogation of existing and newly described biomarkers for T2D. Many biomarkers have been reported to be associated with the risk of developing T2D. The evidence of their value in adding to understanding of causal pathways to disease is very limited so far. The utility of most biomarkers remains largely unknown in clinical prediction. Future research should focus on providing good genetic instruments across consortia for possible biomarkers in Mendelian randomisation, prioritising biomarkers for measurement in large-scale cohort studies and examining predictive utility of biomarkers for a given context. PMID:27788146

Evaluation of Biomarkers of Exposure in Smokers Switching to a Carbon-Heated Tobacco Product: A Controlled, Randomized, Open-Label 5-Day Exposure Study

PubMed Central

Haziza, Christelle; Weitkunat, Rolf; Magnette, John

2016-01-01

Introduction: Tobacco harm reduction aims to provide reduced risk alternatives to adult smokers who would otherwise continue smoking combustible cigarettes (CCs). This randomized, open-label, three-arm, parallel-group, single-center, short-term confinement study aimed to investigate the effects of exposure to selected harmful and potentially harmful constituents (HPHCs) of cigarette smoke in adult smokers who switched to a carbon-heated tobacco product (CHTP) compared with adult smokers who continued to smoke CCs and those who abstained from smoking for 5 days. Methods: Biomarkers of exposure to HPHCs, including nicotine and urinary excretion of mutagenic material, were measured in 24-hour urine and blood samples in 112 male and female Caucasian smokers switching from CCs to the CHTP ad libitum use. Puffing topography was assessed during product use. Results: Switching to the CHTP or smoking abstinence (SA) resulted in marked decreases from baseline to Day 5 in all biomarkers of exposure measured, including carboxyhemoglobin (43% and 55% decrease in the CHTP and SA groups, respectively). The urinary excretion of mutagenic material was also markedly decreased on Day 5 compared with baseline (89% and 87% decrease in the CHTP and SA groups, respectively). No changes in biomarkers of exposure to HPHCs or urinary mutagenic material were observed between baseline and Day 5 in the CC group. Conclusions: Our results provide clear evidence supporting a reduction in the level of exposure to HPHCs of tobacco smoke in smokers who switch to CHTP under controlled conditions, similar to that observed in SA. Implications: The reductions observed in biomarkers of exposure to HPHCs of tobacco smoke in this short-term study could potentially also reduce the incidence of cancer, cardiovascular and respiratory diseases in those smokers who switch to a heated tobacco product. PMID:26817490

Urinary Metabolite Markers of Precocious Puberty*

PubMed Central

Qi, Ying; Li, Pin; Zhang, Yongyu; Cui, Lulu; Guo, Zi; Xie, Guoxiang; Su, Mingming; Li, Xin; Zheng, Xiaojiao; Qiu, Yunping; Liu, Yumin; Zhao, Aihua; Jia, Weiping; Jia, Wei

2012-01-01

The incidence of precocious puberty (PP, the appearance of signs of pubertal development at an abnormally early age), is rapidly rising, concurrent with changes of diet, lifestyles, and social environment. The current diagnostic methods are based on a hormone (gonadotropin-releasing hormone) stimulation test, which is costly, time-consuming, and uncomfortable for patients. The lack of molecular biomarkers to support simple laboratory tests, such as a blood or urine test, has been a long standing bottleneck in the clinical diagnosis and evaluation of PP. Here we report a metabolomic study using an ultra performance liquid chromatography-quadrupole time of flight mass spectrometry and gas chromatography-time of flight mass spectrometry. Urine metabolites from 163 individuals were profiled, and the metabolic alterations were analyzed after treatment of central precocious puberty (CPP) with triptorelin depot. A panel of biomarkers selected from >70 differentially expressed urinary metabolites by receiver operating characteristic and logistic regression analysis provided excellent predictive power with high sensitivity and specificity for PP. The altered metabolic profile of the PP patients was characterized by three major perturbed metabolic pathways: catecholamine, serotonin metabolism, and tricarboxylic acid cycle, presumably resulting from activation of the sympathetic nervous system and the hypothalamic-pituitary-gonadal axis. Treatment with triptorelin depot was able to normalize these three altered pathways. Additionally, significant changes in the urine levels of 4-hydroxyphenylacetic acid, 5-hydroxyindoleacetic acid, indoleacetic acid, 5-hydroxytryptophan, and 5-hydroxykynurenamine in the CPP group suggest that the development of CPP condition may involve an alteration in symbiotic gut microbial composition. PMID:22027199

What do the trace metal contents of urine and toenail samples from Qatar׳s farm workers bioindicate?

PubMed

Kuiper, Nora; Rowell, Candace; Nriagu, Jerome; Shomar, Basem

2014-05-01

Qatar׳s farm workers provide a unique population for exposure study: they are young, healthy males. This study combined trace element profiles in urine and toenail with survey information from 239 farm workers to assess the extent to which the biomarkers provide complementary exposure information. Urinary Mo levels (average=114 µg/L) were elevated; average urinary values (µg/L) for all other elements were: V (1.02), Cr (0.55), Mn (2.15), Fe (34.1), Co (0.47), Ni (2.95), Cu (15.0), As (47.8), Se (25.7), Cd (1.09), Ba (22.5), Pb (2.50) and U (0.15). Average toenail concentrations (mg/kg) were: Mn (2.48), Cu (4.43), As (0.26), Se (0.58), Mo (0.07), Cd (0.03), Ba (1.00), Pb (0.51) and U (0.02). No significant association was found between corresponding elements in urine and toenails. Elemental profiles suggest groundwater (with the exception of Mo) and soil-dust-crop exposure pathways cannot account for elemental variations. The main factors moderating trace element contents are related to depuration processes involving participants׳ trace element body burden prior to work in Qatar, and interactions of trace element metabolic cycles which over-ride the exposure footprint. Toenail and urine need to be carefully validated before reliable use as biomarkers of exposure in general populations for most elements in the study. Copyright © 2014 Elsevier Inc. All rights reserved.

Zinc Status Biomarkers and Cardiometabolic Risk Factors in Metabolic Syndrome: A Case Control Study

PubMed Central

Freitas, Erika P. S.; Cunha, Aline T. O.; Aquino, Sephora L. S.; Pedrosa, Lucia F. C.; Lima, Severina C. V. C.; Lima, Josivan G.; Almeida, Maria G.; Sena-Evangelista, Karine C. M.

2017-01-01

Metabolic syndrome (MS) involves pathophysiological alterations that might compromise zinc status. The aim of this study was to evaluate zinc status biomarkers and their associations with cardiometabolic factors in patients with MS. Our case control study included 88 patients with MS and 37 controls. We performed clinical and anthropometric assessments and obtained lipid, glycemic, and inflammatory profiles. We also evaluated zinc intake, plasma zinc, erythrocyte zinc, and 24-h urinary zinc excretion. The average zinc intake was significantly lower in the MS group (p < 0.001). Regression models indicated no significant differences in plasma zinc concentration (all p > 0.05) between the two groups. We found significantly higher erythrocyte zinc concentration in the MS group (p < 0.001) independent from co-variable adjustments. Twenty-four hour urinary zinc excretion was significantly higher in the MS group (p = 0.008), and adjustments for age and sex explained 21% of the difference (R2 = 0.21, p < 0.001). There were significant associations between zincuria and fasting blood glucose concentration (r = 0.479), waist circumference (r = 0.253), triglyceride concentration (r = 0.360), glycated hemoglobin concentration (r = 0.250), homeostatic model assessment—insulin resistance (r = 0.223), and high-sensitivity C-reactive protein concentration (r = 0.427) (all p < 0.05) in the MS group. Patients with MS had alterations in zinc metabolism mainly characterized by an increase in erythrocyte zinc and higher zincuria. PMID:28241426

Potential Role of Serum and Urinary Biomarkers in Diagnosis and Prognosis of Diabetic Nephropathy.

PubMed

Campion, Carole G; Sanchez-Ferras, Oraly; Batchu, Sri N

2017-01-01

Diabetic nephropathy (DN) is a progressive kidney disease caused by alterations in kidney architecture and function, and constitutes one of the leading causes of end-stage renal disease (ESRD). The purpose of this review is to summarize the state of the art of the DN-biomarker field with a focus on the new strategies that enhance the sensitivity of biomarkers to predict patients who will develop DN or are at risk of progressing to ESRD. In this review, we provide a description of the pathophysiology of DN and propose a panel of novel putative biomarkers associated with DN pathophysiology that have been increasingly investigated for diagnosis, to predict disease progression or to provide efficient personal treatment. We performed a review of the literature with PubMed and Google Scholar to collect baseline data about the pathophysiology of DN and biomarkers associated. We focused our research on new and emerging biomarkers of DN. In this review, we summarized the critical signaling pathways and biological processes involved in DN and highlighted the pathogenic mediators of this disease. We next proposed a large review of the major advances that have been made in identifying new biomarkers which are more sensitive and reliable compared with currently used biomarkers. This includes information about emergent biomarkers such as functional noncoding RNAs, microRNAs, long noncoding RNAs, exosomes, and microparticles. Despite intensive strategies and constant investigation, no current single treatment has been able to reverse or at least mitigate the progression of DN, or reduce the morbidity and mortality associated with this disease. Major difficulties probably come from the renal disease being heterogeneous among the patients. Expanding the proteomics screening, including oxidative stress and inflammatory markers, along with metabolomics approaches may further improve the prognostic value and help in identifying the patients with diabetes who are at high risk of developing kidney diseases.

In-Depth Characterization and Validation of Human Urine Metabolomes Reveal Novel Metabolic Signatures of Lower Urinary Tract Symptoms

NASA Astrophysics Data System (ADS)

Hao, Ling; Greer, Tyler; Page, David; Shi, Yatao; Vezina, Chad M.; Macoska, Jill A.; Marker, Paul C.; Bjorling, Dale E.; Bushman, Wade; Ricke, William A.; Li, Lingjun

2016-08-01

Lower urinary tract symptoms (LUTS) are a range of irritative or obstructive symptoms that commonly afflict aging population. The diagnosis is mostly based on patient-reported symptoms, and current medication often fails to completely eliminate these symptoms. There is a pressing need for objective non-invasive approaches to measure symptoms and understand disease mechanisms. We developed an in-depth workflow combining urine metabolomics analysis and machine learning bioinformatics to characterize metabolic alterations and support objective diagnosis of LUTS. Machine learning feature selection and statistical tests were combined to identify candidate biomarkers, which were statistically validated with leave-one-patient-out cross-validation and absolutely quantified by selected reaction monitoring assay. Receiver operating characteristic analysis showed highly-accurate prediction power of candidate biomarkers to stratify patients into disease or non-diseased categories. The key metabolites and pathways may be possibly correlated with smooth muscle tone changes, increased collagen content, and inflammation, which have been identified as potential contributors to urinary dysfunction in humans and rodents. Periurethral tissue staining revealed a significant increase in collagen content and tissue stiffness in men with LUTS. Together, our study provides the first characterization and validation of LUTS urinary metabolites and pathways to support the future development of a urine-based diagnostic test for LUTS.

Exploratory urinary metabolomics of type 1 leprosy reactions.

PubMed

Mayboroda, Oleg A; van Hooij, Anouk; Derks, Rico; van den Eeden, Susan J F; Dijkman, Karin; Khadge, Saraswoti; Thapa, Pratibha; Kunwar, Chhatra B; Hagge, Deanna A; Geluk, Annemieke

2016-04-01

Leprosy is an infectious disease caused by Mycobacterium leprae that affects the skin and nerves. Although curable with multidrug therapy, leprosy is complicated by acute inflammatory episodes called reactions, which are the major causes of irreversible neuropathy in leprosy that occur before, during, and even after treatment. Early diagnosis and prompt treatment of reactions reduces the risk of permanent disability. This exploratory study investigated whether urinary metabolic profiles could be identified that correlate with early signs of reversal reactions (RR). A prospective cohort of leprosy patients with and without reactions and endemic controls was recruited in Nepal. Urine-derived metabolic profiles were measured longitudinally. Thus, a conventional area of biomarker identification for leprosy was extended to non-invasive urine testing. It was found that the urinary metabolome could be used to discriminate endemic controls from untreated patients with mycobacterial disease. Moreover, metabolic signatures in the urine of patients developing RR were clearly different before RR onset compared to those at RR diagnosis. This study indicates that urinary metabolic profiles are promising host biomarkers for the detection of intra-individual changes during acute inflammation in leprosy and could contribute to early treatment and prevention of tissue damage. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Early Prediction of Lupus Nephritis Using Advanced Proteomics

DTIC Science & Technology

2008-06-01

Structure of the Conserved Hypothetical Protein Rv2302 from Mycobacterium tuberculosis ” 188, 5993-6001, J. Bacteriology, 2006. 11. T.A. Ramelot, A. Yee...currently elusive renal biomarkers crucial for the prognosis of SLE. A well-defined cohort of patients with SLE (n=150), disease and healthy...enhanced various TOF- MS, we discovered a set urinary lupus nephritis candidate biomarkers ; namely transferrin, ceruloplasmin, alpha1-acid

Differential urinary metabolites related with the severity of major depressive disorder.

PubMed

Chen, Jian-Jun; Zhou, Chan-Juan; Zheng, Peng; Cheng, Ke; Wang, Hai-Yang; Li, Juan; Zeng, Li; Xie, Peng

2017-08-14

Major depressive disorder (MDD) is a common mental disorder that affects a person's general health. However, there is still no objective laboratory test for diagnosing MDD. Here, an integrated analysis of data from our previous studies was performed to identify the differential metabolites in the urine of moderate and severe MDD patients. A dual platform approach (NMR spectroscopy and GC-MS) was used. Consequently, 14 and 22 differential metabolites responsible for separating moderate and severe MDD patients, respectively, from their respective healthy controls (HCs) were identified. Meanwhile, the moderate MDD-specific panel (N-Methylnicotinamide, Acetone, Choline, Citrate, vanillic acid and azelaic acid) and severe MDD-specific panel (indoxyl sulphate, Taurine, Citrate, 3-hydroxyphenylacetic acid, palmitic acid and Lactate) could discriminate moderate and severe MDD patients, respectively, from their respective HCs with high accuracy. Moreover, the differential metabolites in severe MDD were significantly involved in three metabolic pathways and some biofunctions. These results showed that there were divergent urinary metabolic phenotypes in moderate and severe MDD patients, and the identified potential urinary biomarkers might be useful for future developing objective diagnostic tests for MDD diagnosis. Our results could also be helpful for researchers to study the pathogenesis of MDD. Copyright © 2017 Elsevier B.V. All rights reserved.

Biomarkers of mercury exposure in two eastern Ukraine cities

USGS Publications Warehouse

Gibb, H.; Haver, C.; Kozlov, K.; Centeno, J.A.; Jurgenson, V.; Kolker, A.; Conko, K.M.; Landa, E.R.; Xu, H.

2011-01-01

This study evaluates biomarkers of mercury exposure among residents of Horlivka, a city in eastern Ukraine located in an area with geologic and industrial sources of environmental mercury, and residents of Artemivsk, a nearby comparison city outside the mercury-enriched area. Samples of urine, blood, hair, and nails were collected from study participants, and a questionnaire was administered to obtain data on age, gender, occupational history, smoking, alcohol consumption, fish consumption, tattoos, dental amalgams, home heating system, education, source of drinking water, and family employment in mines. Median biomarker mercury concentrations in Artemivsk were 0.26 ??g/g-Cr (urine), 0.92 ??g/L (blood), 0.42 ??g/g (hair), 0.11 ??g/g (toenails), and 0.09 ??g/g (fingernails); median concentrations in Horlivka were 0.15 ??g/g-Cr (urine), 1.01 ??g/L (blood), 0.14 ??g/g (hair), 0.31 ??g/g (toenails), and 0.31 ??g/g (fingernails). Biomarkers of mercury exposure for study participants from Horlivka and Artemivsk are low in comparison with occupationally exposed workers at a mercury recycling facility in Horlivka and in comparison with exposures known to be associated with clinical effects. Blood and urinary mercury did not suggest a higher mercury exposure among Horlivka residents as compared with Artemivsk; however, three individuals living in the immediate vicinity of the mercury mines had elevated blood and urinary mercury, relative to overall results for either city. For a limited number of residents from Horlivka (N = 7) and Artemivsk (N = 4), environmental samples (vacuum cleaner dust, dust wipes, soil) were collected from their residences. Mercury concentrations in vacuum cleaner dust and soil were good predictors of blood and urinary mercury. Copyright ?? 2011 JOEH, LLC.

Perspectives on using a multiplex human kidney safety biomarker panel to detect cisplatin-induced tubular toxicity in male and female Cynomolgus monkeys.

PubMed

Chen, Yafei; Dale Thurman, J; Kinter, Lewis B; Bialecki, Russell; Eric McDuffie, J

2017-12-01

Multiplex biomarker panel assays would enable early de-risking of discovery compound related kidney safety liabilities. The objective of this study was to evaluate the usefulness of the Myriad RBM Human KidneyMAP (Multi-Analyte Profile)® v.1.0 panel to detect experimental nephrotoxicity in Cynomolgus monkeys following a single intravenous administration of cisplatin (2.5mg/kg). Urine samples were collected at baseline on day -2; at approximately 4hr post-dose on day 1; and on days 4, 9, 15 and/or 20. Blood samples were collected at predose on day -2; at 4hr post-dose on day 1; and on days 2, 5, 10 and/or 21. Changes in toxicokinetic and biochemistry parameters in plasma, qualitative/quantitative urinalysis parameters, and urinary kidney safety biomarkers were assessed. Kidney tissues were collected on days 2, 5, 10 and 21 for routine microscopy. Cisplatin-induced tubular alterations were characterized by acute and progressive cortical tubular degeneration/necrosis, regeneration, tubular dilation and proteinaceous cast in the absence of statistically significant changes in traditional plasma biochemistry and urinalysis parameters. When normalized to urinary creatinine, cisplatin-induced significant increases in urinary levels of kidney injury molecule 1 (females on day 4), increases in calbindin D28k (males and females on day 4), decreases in Tamm-Horsfall glycoprotein (males on days 1, 4 and 9), and increases in clusterin (females and males on days 15 and 20, respectively), when compared to concurrent controls. This study revealed the usefulness of the Human KidneyMAP® multiplex panel when measuring changes in urine-based biomarkers to reliably detect cisplatin-induced acute/progressive cortical tubular injury in male and female Cynomolgus monkeys. Copyright © 2017 Elsevier Inc. All rights reserved.

Urinary peptidomics in a rodent model of diabetic nephropathy highlights epidermal growth factor as a biomarker for renal deterioration in patients with type 2 diabetes.

PubMed

Betz, Boris B; Jenks, Sara J; Cronshaw, Andrew D; Lamont, Douglas J; Cairns, Carolynn; Manning, Jonathan R; Goddard, Jane; Webb, David J; Mullins, John J; Hughes, Jeremy; McLachlan, Stela; Strachan, Mark W J; Price, Jackie F; Conway, Bryan R

2016-05-01

Many diabetic patients suffer from declining renal function without developing albuminuria. To identify alternative biomarkers for diabetic nephropathy (DN) we performed urinary peptidomic analysis in a rodent model in which hyperglycemia and hypertension synergize to promote renal pathologic changes consistent with human DN. We identified 297 increased and 15 decreased peptides in the urine of rats with DN compared with controls, including peptides derived from proteins associated with DN and novel candidate biomarkers. We confirmed by ELISA that one of the parent proteins, urinary epidermal growth factor (uEGF), was more than 2-fold reduced in rats with DN in comparison with controls. To assess the clinical utility of uEGF we examined renal outcomes in 642 participants from the Edinburgh Type 2 Diabetes Study who were normoalbuminuric and had preserved renal function at baseline. After adjustment for established renal risk factors, a lower uEGF to creatinine ratio was associated with new-onset estimated glomerular filtration rate less than 60 ml/min per 1.73m(2) (odds ratio 0.48; 95% confidence interval, 0.26-0.90), rapid (over 5% per annum) decline in renal function (odds ratio 0.44; 95% confidence interval, 0.27-0.72) or the composite of both outcomes (odds ratio 0.38; 95% confidence interval, 0.24-0.62). Thus, the utility of a low uEGF to creatinine ratio as a biomarker of progressive decline in renal function in normoalbuminuric patients should be assessed in additional populations. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Design and validation of an immunoaffinity LC-MS/MS assay for the quantification of a collagen type II neoepitope peptide in human urine: application as a biomarker of osteoarthritis.

PubMed

Nemirovskiy, Olga; Li, Wenlin Wendy; Szekely-Klepser, Gabriella

2010-01-01

Biomarkers play an increasingly important role for drug efficacy and safety evaluation in all stages of drug development. It is especially important to develop and validate sensitive and selective biomarkers for diseases where the onset of the disease is very slow and/or the disease progression is hard to follow, i.e., osteoarthritis (OA). The degradation of Type II collagen has been associated with the disease state of OA. Matrix metalloproteinases (MMPs) are enzymes that catalyze the degradation of collagen and therefore pursued as potential targets for the treatment of OA. Peptide biomarkers of MMP activity related to type II collagen degradation were identified and the presence of these peptides in MMP digests of human articular cartilage (HAC) explants and human urine were confirmed. An immunoaffinity LC/MS/MS assay for the quantification of the most abundant urinary type II collagen neoepitope (uTIINE) peptide, a 45-mer with 5 HO-proline residues was developed and clinically validated. The assay has subsequently been applied to analyze human urine samples from clinical studies. We have shown that the assay is able to differentiate between symptomatic OA and normal subjects, indicating that uTIINE can be used as potential biomarker for OA. This chapter discusses the assay procedure and provides information on the validation experiments used to evaluate the accuracy, precision, and selectivity data with attention to the specific challenges related to the quantification of endogenous protein/peptide biomarker analytes. The generalized approach can be used as a follow-up to studies whereby proteomics-based urinary biomarkers are identified and an assay needs to be developed. Considerations for the validation of such an assay are described.

Role of the intrarenal renin-angiotensin system in the progression of renal disease.

PubMed

Urushihara, Maki; Kagami, Shoji

2017-09-01

The intrarenal renin-angiotensin system (RAS) has many well-documented pathophysiologic functions in both blood pressure regulation and renal disease development. Angiotensin II (Ang II) is the major bioactive product of the RAS. It induces inflammation, renal cell growth, mitogenesis, apoptosis, migration, and differentiation. In addition, Ang II regulates the gene expression of bioactive substances and activates multiple intracellular signaling pathways that are involved in renal damage. Activation of the Ang II type 1 (AT1) receptor pathway results in the production of proinflammatory mediators, intracellular formation of reactive oxygen species, cell proliferation, and extracellular matrix synthesis, which in turn facilities renal injury. Involvement of angiotensinogen (AGT) in intrarenal RAS activation and development of renal disease has previously been reported. Moreover, studies have demonstrated that the urinary excretion rates of AGT provide a specific index of the intrarenal RAS status. Enhanced intrarenal AGT levels have been observed in experimental models of renal disease, supporting the concept that AGT plays an important role in the development and progression of renal disease. In this review, we focus on the role of intrarenal RAS activation in the pathophysiology of renal disease. Additionally, we explored the potential of urinary AGT as a novel biomarker of intrarenal RAS status in renal disease.

Measuring urinary N-acetyl-S-(4-hydroxy-2-methyl-2-buten-1-yl)-L-cysteine (IPMA3) as a potential biomarker of isoprene exposure.

PubMed

Alwis, K Udeni; Bailey, T Liz; Patel, Dhrusti; Wang, Liqun; Blount, Benjamin C

2016-10-19

Isoprene, the 2-methyl analog of 1,3-butadiene, is identified as a possible human carcinogen by the International Agency for Research on Cancer (IARC). Isoprene is ubiquitous in the environment with numerous natural and anthropogenic sources. Tobacco smoke is the main exogenous source of isoprene exposure in indoor environments. Among smoke constituents, isoprene is thought to contribute significantly to cancer risk; however, no selective urinary biomarkers of isoprene exposure have been identified for humans. In this manuscript, we measured the minor isoprene metabolite IPMA1 (mixture of N-acetyl-S-(1-[hydroxymethyl]-2-methyl-2-propen-1-yl)-L-cysteine and N-acetyl-S-(2-hydroxy-3-methyl-3-buten-1-yl)-L-cysteine), and we identified IPMA3 (N-acetyl-S-(4-hydroxy-2-methyl-2-buten-1-yl)-L-cysteine) as a major isoprene metabolite and novel isoprene exposure biomarker for humans. Urinary isoprene metabolites were measured using ultra high performance liquid chromatography coupled with electrospray ionization triple quad tandem mass spectrometry (UPLC/ESI-MSMS). The detection rates of IPMA1 and IPMA3 are <20% and 82%, respectively. The selectivity and abundance of IPMA3 make it a useful urinary biomarker of isoprene exposure. The limit of detection of IPMA3 in urine was 0.5 ng mL -1 . IPMA3 was stable under different storage temperatures and following ten freeze-thaw cycles. The average recovery of urine spiked with IPMA3 at three different levels was 99%. IPMA3 was measured in urine samples received from 75 anonymous subjects; the median (25th percentile, 75th percentile) IPMA3 level in smokers was 36.2 (18.2, 56.8) ng mL -1 and non-smokers 2.31 (2.31, 4.38) ng mL -1 . Application of this method to large population studies will help to characterize isoprene exposure and assess potential health impact. Published by Elsevier B.V.

Biomarkers of PAH exposure and hematologic effects in subjects exposed to combustion emission during residential (and professional) cooking practices in Pakistan.

PubMed

Kamal, Atif; Cincinelli, Alessandra; Martellini, Tania; Malik, Riffat Naseem

2016-01-01

The aim of this study was to evaluate and compare the exposure of household women and professional male workers to combustion emission in the indoor and semi-outdoor environments, respectively, by using biochemical parameters and the biomarkers of exposure to polycyclic aromatic hydrocarbon (PAH). Female (WR n = 60) and male "cooks" (WC n = 60) exposed to the combustion emission of fuel wood and coal in rural/suburban areas of Pakistan were recruited in this study and compared to non-exposed female (CF) and male (CM) groups (n = 32 and 34, respectively). Urinary biomarkers of PAH exposure including 1-hyroxypyrene (1-OHPyr), α-naphthol, and β-naphthol were analyzed together with the biomarkers of effect, including the serum c-reactive proteins (CRP), white blood cells (WBCs), hemoglobin (Hb), red blood cells (RBC), and platelet (PLT) count. In addition, blood superoxide dismutase (SOD) and urinary level of 8-hydroxydeoxyguanosine (8-OHdG) were evaluated to determine the oxidative stress and DNA damage, respectively. A questionnaire was used to document demographic-, health-, and exposure-related information. The results showed that urinary β-naphthol was almost 44% higher in WR subjects than WC (median 7.69 vs. 3.39 μmol/mol-Cr, respectively; p = 0.01) and respective controls (CF). Higher urinary 8-OHdG were observed in WR (71.1 ng/mg-Cr) than WC (56.37 ng/mg-Cr) (p < 0.001), and lower life status and higher degree of headache were observed in WR than WC. In WCs, however, a low Hb and high WBC (8.29 × 10(3) μL(-1), ranging between 6.1 and 10.6 × 10(3) μL(-1)) were observed in comparison with CM. The study shows that WC subjects used larger amount of fuel and were subjected to prolonged exposure. It was concluded that the role of ventilation is fundamental and WR were more exposed to PAHs despite the fact that WC spent more time in cooking (due to occupational requirement) than WR.

Assessment of aflatoxin exposure using serum and urinary biomarkers in São Paulo, Brazil: A pilot study.

PubMed

Jager, Alessandra V; Tonin, Fernando G; Baptista, Gabriela Z; Souto, Pollyana C M C; Oliveira, Carlos A F

2016-05-01

The aim of this study was to evaluate the human exposure of individuals from Pirassununga, Brazil, to dietary aflatoxins B1 (AFB1) and M1 (AFM1) by determination of serum AFB1-lysine and urinary aflatoxin biomarkers (AFM1 and AFB1-N(7)-guanine). The participants were recruited among employees from a Campus of the University of São Paulo, which provided food samples from their homes, as well as serum and urine samples four times every three months, from June 2011 until March 2012. The probable daily intake (PDI) of aflatoxin was estimated by using the results from analysis of food products collected by the time of samples collection, and data from a 24-hour dietary recall questionnaire. Analyses of AFB1 and AFM1 in food samples were conducted by high-performance liquid chromatography with fluorescence detection. Biomarkers in serum and urine were determined by tandem mass spectrometry. AFB1 and AFM1 were detected in 38 samples of cereals (28%, N=136) and 31 milk products (36%, N=86), respectively. AFB1-lysine and AFB1-N(7)-guanine and were not detected in serum or urine samples, respectively. However, AFM1 was found in 74 urine samples (65%), at mean levels in the 4 sampling times ranging from 0.37±0.23 to 1.70±2.88pg/mg creatinine. The mean PDI varied among different sampling times, ranging from 0.09±0.09 to 1.35±5.98ng/kg body weight/day. A modest though significant correlation (r=0.45; p=0.03; N=23) was found for the first time in Brazil between the AFM1 concentration in urine and the PDI for total aflatoxins (AFB1+AFM1) in sampling 1 (June 2011). Urinary AFM1 was confirmed as very sensitive for monitoring the human exposure to dietary aflatoxin. Further studies using serum and urinary biomarkers are needed to estimate the aflatoxin exposure of populations in higher risk areas in Brazil. Copyright © 2015 Elsevier GmbH. All rights reserved.

The physiological determinants of low-level urine cadmium: an assessment in a cross-sectional study among schoolchildren.

PubMed

Wang, Hongyu; Dumont, Xavier; Haufroid, Vincent; Bernard, Alfred

2017-09-12

Recent studies in children have reported associations of urinary cadmium (U-Cd), used as biomarker of Cd body burden, with renal dysfunction, retarded growth and impaired cognitive development in children. Little is known, however, about factors influencing U-Cd in children and likely to act as confounders. In a cross-sectional study involving 249 schoolchildren (mean age, 5.72 years; 138 boys), we measured the urine concentrations of cadmium, zinc, lead, albumin, alpha 1 -microglobulin (A1M), retinol-binding protein, β 2 -microglobulin and club cell protein (CC16). Determinants of U-Cd expressed per creatinine or adjusted to specific gravity were identified by multiple regression analyses. Girls and boys had similar median concentrations of U-Cd (0.22 and 0.24 μg/L, 0.33 and 0.35 μg/g creatinine, respectively). When models were run without including creatinine or specific gravity among independent variables, urinary zinc, urinary A1M and age emerged as the strongest predictors of U-Cd expressed per g creatinine or adjusted to SG. When adding creatinine among predictors, urinary creatinine emerged as an additional strong predictor correlating negatively with U-Cd per g creatinine. This strong residual influence of diuresis, not seen when adding specific gravity among predictors, linked U-Cd to U-A1M or U-CC16 through secondary associations mimicking those induced by Cd nephrotoxity. In young children U-Cd largely varies with diuresis, zinc metabolism and urinary A1M. These physiological determinants, unrelated to Cd body burden, may confound the child renal and developmental outcomes associated with low-level U-Cd.

Akt Links Insulin Signaling to Albumin Endocytosis in Proximal Tubule Epithelial Cells

PubMed Central

Coffey, Sam; Costacou, Tina; Orchard, Trevor; Erkan, Elif

2015-01-01

Diabetes mellitus (DM) has become an epidemic, causing a significant decline in quality of life of individuals due to its multisystem involvement. Kidney is an important target organ in DM accounting for the majority of patients requiring renal replacement therapy at dialysis units. Microalbuminuria (MA) has been a valuable tool to predict end-organ damage in DM but its low sensitivity has driven research efforts to seek other alternatives. Albumin is taken up by albumin receptors, megalin and cubilin in the proximal tubule epithelial cells. We demonstrated that insulin at physiological concentrations induce albumin endocytosis through activation of protein kinase B (Akt) in proximal tubule epithelial cells. Inhibition of Akt by a phosphorylation deficient construct abrogated insulin induced albumin endocytosis suggesting a role for Akt in insulin-induced albumin endocytosis. Furthermore we demonstrated a novel interaction between Akt substrate 160kDa (AS160) and cytoplasmic tail of megalin. Mice with type 1 DM (T1D) displayed decreased Akt, megalin, cubilin and AS160 expression in their kidneys in association with urinary cubilin shedding preceding significant MA. Patients with T1D who have developed MA in the EDC (The Pittsburgh Epidemiology of Diabetes Complications) study demonstrated urinary cubilin shedding prior to development of MA. We hypothesize that perturbed insulin-Akt cascade in DM leads to alterations in trafficking of megalin and cubilin, which results in urinary cubilin shedding as a prelude to MA in early diabetic nephropathy. We propose that utilization of urinary cubilin shedding, as a urinary biomarker, will allow us to detect and intervene in diabetic nephropathy (DN) at an earlier stage. PMID:26465605

Evaluation of urinary resveratrol as a biomarker of dietary resveratrol intake in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

PubMed

Zamora-Ros, Raul; Rothwell, Joseph A; Achaintre, David; Ferrari, Pietro; Boutron-Ruault, Marie-Christine; Mancini, Francesca R; Affret, Aurelie; Kühn, Tilman; Katzke, Verena; Boeing, Heiner; Küppel, Sven; Trichopoulou, Antonia; Lagiou, Pagona; La Vecchia, Carlo; Palli, Domenico; Contiero, Paolo; Panico, Salvatore; Tumino, Rosario; Ricceri, Fulvio; Noh, Hwayoung; Freisling, Heinz; Romieu, Isabelle; Scalbert, Augustin

2017-06-01

In vitro studies have shown several beneficial properties of resveratrol. Epidemiological evidence is still scarce, probably because of the difficulty in estimating resveratrol exposure accurately. The current study aimed to assess the relationships between acute and habitual dietary resveratrol and wine intake and urinary resveratrol excretion in a European population. A stratified random subsample of 475 men and women from four countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) cross-sectional study, who had provided 24-h urine samples and completed a 24-h dietary recall (24-HDR) on the same day, were included. Acute and habitual dietary data were collected using standardised 24-HDR software and a validated country-specific dietary questionnaire, respectively. Phenol-Explorer was used to estimate the intake of resveratrol and other stilbenes. Urinary resveratrol was analysed using tandem MS. Spearman's correlation coefficients between estimated dietary intakes of resveratrol and other stilbenes and consumption of wine, their main food source, were very high (r>0·9) when measured using dietary questionnaires and were slightly lower with 24-HDR (r>0·8). Partial Spearman's correlations between urinary resveratrol excretion and intake of resveratrol, total stilbenes or wine were found to be higher when using the 24-HDR (R 2 partial approximately 0·6) than when using the dietary questionnaires (R 2 partial approximately 0·5). Moderate to high correlations between dietary resveratrol, total stilbenes and wine, and urinary resveratrol concentrations were observed. These support the earlier findings that 24-h urinary resveratrol is an effective biomarker of both resveratrol and wine intakes. These correlations also support the validity of the estimation of resveratrol intake using the dietary questionnaire and Phenol-Explorer.

Activation of the Endogenous Renin-Angiotensin-Aldosterone System or Aldosterone Administration Increases Urinary Exosomal Sodium Channel Excretion.

PubMed

Qi, Ying; Wang, Xiaojing; Rose, Kristie L; MacDonald, W Hayes; Zhang, Bing; Schey, Kevin L; Luther, James M

2016-02-01

Urinary exosomes secreted by multiple cell types in the kidney may participate in intercellular signaling and provide an enriched source of kidney-specific proteins for biomarker discovery. Factors that alter the exosomal protein content remain unknown. To determine whether endogenous and exogenous hormones modify urinary exosomal protein content, we analyzed samples from 14 mildly hypertensive patients in a crossover study during a high-sodium (HS, 160 mmol/d) diet and low-sodium (LS, 20 mmol/d) diet to activate the endogenous renin-angiotensin-aldosterone system. We further analyzed selected exosomal protein content in a separate cohort of healthy persons receiving intravenous aldosterone (0.7 μg/kg per hour for 10 hours) versus vehicle infusion. The LS diet increased plasma renin activity and aldosterone concentration, whereas aldosterone infusion increased only aldosterone concentration. Protein analysis of paired urine exosome samples by liquid chromatography-tandem mass spectrometry-based multidimensional protein identification technology detected 2775 unique proteins, of which 316 exhibited significantly altered abundance during LS diet. Sodium chloride cotransporter (NCC) and α- and γ-epithelial sodium channel (ENaC) subunits from the discovery set were verified using targeted multiple reaction monitoring mass spectrometry quantified with isotope-labeled peptide standards. Dietary sodium restriction or acute aldosterone infusion similarly increased urine exosomal γENaC[112-122] peptide concentrations nearly 20-fold, which correlated with plasma aldosterone concentration and urinary Na/K ratio. Urine exosomal NCC and αENaC concentrations were relatively unchanged during these interventions. We conclude that urinary exosome content is altered by renin-angiotensin-aldosterone system activation. Urinary measurement of exosomal γENaC[112-122] concentration may provide a useful biomarker of ENaC activation in future clinical studies. Copyright © 2016 by the American Society of Nephrology.

Activation of the Endogenous Renin-Angiotensin-Aldosterone System or Aldosterone Administration Increases Urinary Exosomal Sodium Channel Excretion

PubMed Central

Qi, Ying; Wang, Xiaojing; Rose, Kristie L.; MacDonald, W. Hayes; Zhang, Bing; Schey, Kevin L.

2016-01-01

Urinary exosomes secreted by multiple cell types in the kidney may participate in intercellular signaling and provide an enriched source of kidney-specific proteins for biomarker discovery. Factors that alter the exosomal protein content remain unknown. To determine whether endogenous and exogenous hormones modify urinary exosomal protein content, we analyzed samples from 14 mildly hypertensive patients in a crossover study during a high-sodium (HS, 160 mmol/d) diet and low-sodium (LS, 20 mmol/d) diet to activate the endogenous renin-angiotensin-aldosterone system. We further analyzed selected exosomal protein content in a separate cohort of healthy persons receiving intravenous aldosterone (0.7 μg/kg per hour for 10 hours) versus vehicle infusion. The LS diet increased plasma renin activity and aldosterone concentration, whereas aldosterone infusion increased only aldosterone concentration. Protein analysis of paired urine exosome samples by liquid chromatography-tandem mass spectrometry–based multidimensional protein identification technology detected 2775 unique proteins, of which 316 exhibited significantly altered abundance during LS diet. Sodium chloride cotransporter (NCC) and α- and γ-epithelial sodium channel (ENaC) subunits from the discovery set were verified using targeted multiple reaction monitoring mass spectrometry quantified with isotope-labeled peptide standards. Dietary sodium restriction or acute aldosterone infusion similarly increased urine exosomal γENaC[112–122] peptide concentrations nearly 20-fold, which correlated with plasma aldosterone concentration and urinary Na/K ratio. Urine exosomal NCC and αENaC concentrations were relatively unchanged during these interventions. We conclude that urinary exosome content is altered by renin-angiotensin-aldosterone system activation. Urinary measurement of exosomal γENaC[112–122] concentration may provide a useful biomarker of ENaC activation in future clinical studies. PMID:26113616

Urinary potassium is a potential biomarker of disease activity in Ulcerative colitis and displays in vitro immunotolerant role.

PubMed

Goyal, Sandeep; Rampal, Ritika; Kedia, Saurabh; Mahajan, Sandeep; Bopanna, Sawan; Yadav, Devesh P; Jain, Saransh; Singh, Amit Kumar; Wari, Md Nahidul; Makharia, Govind; Awasthi, Amit; Ahuja, Vineet

2017-12-22

We evaluated the in-vitro effect of potassium on CD4 + T cells and the role of urinary potassium as a potential biomarker of disease activity in patients with ulcerative colitis (UC). This prospective observational cohort study included healthy controls (n = 18) and UC patients [n = 30, median age: 40 (IQR: 28-46) years, 17 males)] with active disease(assessed by Mayo score) from September 2015-May 2016. Twenty-four hours urinary potassium along with fecal calprotectin (FCP) were estimated in UC patients (at baseline and follow-up after 3-6 months) and controls. In healthy volunteers, we also assessed the effect of potassium on CD4 + T cells differentiated in the presence of Th17 polarizing condition. UC patients had significantly higher FCP (368.2 ± 443.04 vs 12.44 ± 27.51, p < 0.001) and significantly lower urinary potassium (26.6 ± 16.9 vs 46.89 ± 35.91, p = 0.01) levels than controls. At follow-up, a significant increase in urinary potassium among patients who had clinical response [n = 22, 21.4 (14.4-39.7) to 36.5 (20.5-61.6), p = 0.04] and remission [n = 12, 18.7 (9.1-34.3) to 36.5 (23.4-70.5), p = 0.05] was accompanied with a parallel decline in FCP. On in-vitro analysis, potassium under Th17 polarizing conditions significantly inhibited IL-17 and interferon-[Formula: see text] expression while favoring the induction of FoxP3 + T cells. Therefore, urinary potassium levels are inversely associated with disease activity in UC with in-vitro data supporting an immune-tolerant role of potassium.

High specificity of spot urinary free metanephrines in diagnosis and prognosis of pheochromocytomas and paragangliomas by HPLC with electrochemical detection.

PubMed

Zuo, Ming; Zhen, Qianna; Zhang, Xiaoqing; Zou, Wenbi; Yang, Xiangchun; Tian, Gang; Shi, Zhenghu; Li, Qifu; Ding, Min

2018-03-01

The metanephrines (MNs) in plasma and urine were proposed as biomarkers for the diagnosis of pheochromocytomas and paragangliomas (PPGLs). However, plasma free MNs and 24h urinary fractionated MNs were not satisfactory enough in specificity for the diagnosis of PPGLs. Moreover, the collection of 24h urine was inconvenient. This work examined the diagnostic and prognostic efficiency of free MNs in spot urine for PPGLs. We measured free MNs concentration in spot urine and plasma of 28 PPGLs patients and 155 control subjects by HPLC with electrochemical detection. Postoperative free MNs levels in spot urine and plasma of 14 PPGLs patients were also determined. Creatinine (Cr) concentration was used for the correction of urine volume. The specificity of spot urinary free MNs/Cr in the diagnosis of PPGLs was significantly higher than that of plasma free MNs [normetanephrine (NMN), 98.7% (95.4%-99.8%) vs 93.0% (87.4%-96.6%); metanephrine (MN), 93.6% (88.5%-96.9%) vs 84.5% (77.5%-90.0%)]. Meanwhile, the positive likelihood ratios for spot urinary free NMN/Cr and MN/Cr were 69.21 and 13.29, compared with 12.68 and 5.30 for plasma free NMN and MN, respectively. For the PPGLs patients underwent surgery, the plasma free MNs level appeared an abnormal elevation and yielded false-positive results for some patients. Our findings were validated in an independent cohort, resulting in the specificity of 100% for both urinary free NMN/Cr and MN/Cr, and 97.3% and 83.8% for plasma free NMN and MN, respectively. Spot urinary free MNs/Cr, superior to plasma free MNs, presented a promising biomarker for the diagnosis and prognosis of PPGLs. Copyright © 2017 Elsevier B.V. All rights reserved.

Biomarkers of Exposure to Toxic Substances: Volume 4: Metabonomics Biomarkers to Liver and Organ Damage

DTIC Science & Technology

2009-05-01

examined the urinary metabolite profiles from rats following a single exposure to the kidney toxicants D- serine, puromycin, hippuric acid and...15. SUBJECT TERMS Amphotericin B, bioinformatics, cell cycle regulation, clinical, clustering analysis, D-serine, glomerular injury, hippuric acid ...puromycin, hippuric acid and amphotericin B at various doses, and as a function of time post-dose. In toxicology, such dose-time metabonomics studies are

Developing Treatment, Treatment Validation, and Treatment Scope in the Setting of an Autism Clinical Trial

DTIC Science & Technology

2012-10-01

clinical phenotype. In addition polymorphic variants of genes of certain enzymes that synthesize and metabolize docosahexaenoic acid ( DHA ) may contribute...This project is to test to see if DHA treatment can beneficially affect excretion of urinary biomarkers of oxidative stress and the autism...excretion of the polyunsaturated fatty acid (PUFA) derived biomarkers of oxidative stress (isoprostanes and neuroprostanes) together with the changes in

Novel Biomarkers for the Diagnosis of Urinary Tract Infection—A Systematic Review

PubMed Central

Nanda, Neha; Juthani-Mehta, Manisha

2009-01-01

Urinary tract infections (UTIs) are associated with significant morbidity. We rely on clinical presentation, urinalysis, and urine culture to diagnose UTI. To differentiate between lower UTI and pyelonephritis, we depend on the clinical presentation. In the extremes of age and in immunocompromised individuals, clinical presentation is often atypical posing a challenge to diagnosis. In the elderly, the high prevalence of asymptomatic bacteriuria is another confounder. We conducted a search of publications to find novel biomarkers to diagnose UTI and to ascertain its severity. We searched PUBMED, MEDLINE and SCOPUS databases for studies pertaining to novel biomarkers and UTI. Two reviewers independently evaluated the methodology of the studies using the STARD (Standards for Reporting of Diagnostic Accuracy) criteria. We have identified procalcitonin as a biomarker to differentiate lower UTI from pyelonephritis in the pediatric age group. Elevated serum procalcitonin levels can result in early and aggressive treatment at the time of presentation. Interleukin 6 has also shown some promise in differentiating between lower UTI and pyelonephritis but needs further validation. Lastly, given the paucity of data in certain subgroups like diabetics, kidney transplant recipients, and individuals with spinal cord injury, further studies should be conducted in these populations to improve diagnostic criteria that will inform clinical management decisions. PMID:19707519

Novel urinary biomarkers and the early detection of acute kidney injury after open cardiac surgeries.

PubMed

Elmedany, Said M; Naga, Salah S; Elsharkawy, Rania; Mahrous, Rabab S; Elnaggar, Ahmed I

2017-08-01

Acute kidney injury (AKI) is a common complication after cardiac surgery, recently, several biomarkers have been used to facilitate early detection of AKI, including Neutrophil-gelatinase-associated-lipocalin (NGAL) and Kidney-injury-molecule-1 (KIM-1).This study was carried out to study the efficacy of urinary KIM-1 and NGAL separately and in combination in relation to early detection and assessment of severity of AKI after cardiac surgeries. This prospective study was carried out on 45 adult patients, of both sexes, Cleveland score(CCS) (0-5) and scheduled for elective coronary artery bypass graft (CABG) surgery in Alexandria Main University Hospital, after approval of the ethical committee and having an informed written consent from every patient. Patients were screened for renal function tests before surgery and every day for 3 day after surgery. Freshly urine samples were taken from all patients and centrifuged for microscopic examination of the sediment: preoperative, 2, 12, 24, and 48 hr after cardiopulmonary bypass (CPB) and for measurement of NGAL and KIM-1; after induction, 2, 6, 12, and 24 hr after CPB. The primary end point was the incidence of AKI defined by the AKIN criteria of serum creatinine. 11 patients developed AKI. Patients with AKI had a higher AKIN stages and CCS. CPB time and cross clamp time were significantly higher in the AKI group with a mean of (90.5±16.2) and (60.9±8.1) minutes respectively. Serum creatinine started to be significantly higher in AKI group from the second postoperative day with a mean value of 1.56±0.28 mg/dl compared to a mean value of 0.85±0.14 mg/dl in non-AKI group. Urine sediment score(USS) 1 and 2 were higher in the AKI group than in the non-AKI group 2 hrs after CPB and till the end of the 2nd day with area under the curve (AUC) average of (0.865). Urinary NGAL significantly rise in AKI patients 2 and 6 hr after CPB with corresponding AUC of (0.710 and 0.700) but uKIM-1 was higher in the AKI group 12 and 24 hr after CPB with AUC (0.725 and 0.703) respectively. Combination of urinary NGAL, KIM-1, and USS yielded AUC of 0.906. urinary NGAL is early sensitive but KIM-1which appears later than but is a more specific biomarker to ischemic renal injury. Urinary microscopic examination was found to be with very high sensitivity and specificity and injury site informative. The combination of more than one biomarker increases the accuracy of early detection of AKI after cardiac surgery. Copyright © 2017 Elsevier Inc. All rights reserved.

Identification of sex-specific urinary biomarkers for major depressive disorder by combined application of NMR- and GC-MS-based metabonomics.

PubMed

Zheng, P; Chen, J-J; Zhou, C-J; Zeng, L; Li, K-W; Sun, L; Liu, M-L; Zhu, D; Liang, Z-H; Xie, P

2016-11-15

Women are more vulnerable to major depressive disorder (MDD) than men. However, molecular biomarkers of sex differences are limited. Here we combined gas chromatography-mass spectrometry (GC-MS)- and nuclear magnetic resonance (NMR)-based metabonomics to investigate sex differences of urinary metabolite markers in MDD, and further explore their potential of diagnosing MDD. Consequently, the metabolite signatures of women and men MDD subjects were significantly different from of that in their respective healthy controls (HCs). Twenty seven women and 36 men related differentially expressed metabolites were identified in MDD. Fourteen metabolites were changed in both women and men MDD subjects. Significantly, the women-specific (m-Hydroxyphenylacetate, malonate, glycolate, hypoxanthine, isobutyrate and azelaic acid) and men-specific (tyrosine, N-acetyl-d-glucosamine, N-methylnicotinamide, indoxyl sulfate, citrate and succinate) marker panels were further identified, which could differentiate men and women MDD patients from their respective HCs with higher accuracy than previously reported sex-nonspecific marker panels. Our findings demonstrate that men and women MDD patients have distinct metabonomic signatures and sex-specific biomarkers have promising values in diagnosing MDD.

Discovery of human urinary biomarkers of aronia-citrus juice intake by HPLC-q-TOF-based metabolomic approach.

PubMed

Llorach, Rafael; Medina, Sonia; García-Viguera, Cristina; Zafrilla, Pilar; Abellán, José; Jauregui, Olga; Tomás-Barberán, Francisco A; Gil-Izquierdo, Angel; Andrés-Lacueva, Cristina

2014-06-01

Metabolomics has emerged in the field of food and nutrition sciences as a powerful tool for doing profiling approaches. In this context, HPLC-q-TOF-based metabolomics approach was applied to unveil changes in the urinary metabolome in human subjects (n = 51, 23 men and 28 women) after regular aronia-citrus juice (AC-juice) intake (250 mL/day) during 16 weeks compared to individuals given a placebo beverage. Samples were analyzed by HPLC-q-TOF followed by multivariate data analysis (orthogonal signal filtering-partial least square discriminant analysis) that discriminated relevant mass features related to AC-juice intake. The results showed that biomarkers of AC-juice intake including metabolites coming from metabolism of food components as proline betaine, ferulic acid, and two unknown mercapturate derivatives were identified. Discovery of new biomarkers of food intake will help in the building up of the food metabolome and facilitate future insights into the mechanisms of action of dietary components in population health. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Multiplexed targeted mass spectrometry assays for prostate cancer-associated urinary proteins

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shi, Tujin; Quek, Sue-Ing; Gao, Yuqian

Biomarkers for effective early diagnosis and prognosis of prostate cancer are still lacking. Multiplexed assays for cancer-associated proteins could be useful for identifying biomarkers for cancer detection and stratification. Herein, we report the development of sensitive targeted mass spectrometry assays for simultaneous quantification of 10 prostate cancer-associated proteins in urine. The diagnostic utility of these markers was evaluated with an initial cohort of 20 clinical urine samples. Individual marker concentration was normalized against the measured urinary prostate-specific antigen level as a reference of prostate-specific secretion. The areas under the receiver-operating characteristic curves for the 10 proteins ranged from 0.75 formore » CXCL14 to 0.87 for CEACAM5. Furthermore, MMP9 level was found to be significantly higher in patients with high Gleason scores, suggesting a potential of MMP9 as a marker for risk level assessment. Taken together, our work illustrated the feasibility of accurate multiplexed measurements of low-abundance cancer-associated proteins in urine and provided a viable path forward for preclinical verification of candidate biomarkers for prostate cancer.« less

Differentiating Medicated Patients Suffering from Major Depressive Disorder from Healthy Controls by Spot Urine Measurement of Monoamines and Steroid Hormones

PubMed Central

Wijaya, Chandra S.; Lee, Jovia J. Z.; Husain, Syeda F.; Ho, Cyrus S. H.; McIntyre, Roger S.; Tam, Wilson W.

2018-01-01

Introduction: Major Depressive Disorder (MDD) is a common psychiatric disorder. Currently, there is no objective, cost-effective and non-invasive method to measure biological markers related to the pathogenesis of MDD. Previous studies primarily focused on urinary metabolite markers which are not proximal to the pathogenesis of MDD. Herein, we compare urinary monoamines, steroid hormones and the derived ratios amongst MDD when compared to healthy controls. Methods: Morning urine samples of medicated patients suffering from MDD (n = 47) and healthy controls (n = 41) were collected. Enzyme-linked immunosorbent assay (ELISA) was performed to measure five biomarkers: cortisol, dopamine, noradrenaline, serotonin and sulphate derivative of dehydroepiandrosterone (DHEAS). The mean urinary levels and derived ratios of monoamines and steroid hormones were compared between patients and controls to identify potential biomarkers. The receiver operative characteristic curve (ROC) analysis was conducted to evaluate the diagnostic performance of potential biomarkers. Results: Medicated patients with MDD showed significantly higher spot urine ratio of DHEAS/serotonin (1.56 vs. 1.19, p = 0.004) and lower ratio of serotonin/dopamine (599.71 vs. 888.60, p = 0.008) than healthy controls. A spot urine serotonin/dopamine ratio cut-off of >667.38 had a sensitivity of 73.2% and specificity of 51.1%. Conclusions: Our results suggest that spot urine serotonin/dopamine ratio can be used as an objective diagnostic method for adults with MDD. PMID:29701669

Clinical Significance of Persistent Global and Focal Computed Tomography Nephrograms After Cardiac Catheterization and Their Relationships to Urinary Biomarkers of Kidney Damage and Procedural Factors: Pilot Study.

PubMed

Chu, Lisa L; Katzberg, Richard W; Solomon, Richard; Southard, Jeffrey; Evans, Scott J; Li, Chin-Shang; McDonald, Jennifer S; Payne, Catherine; Boone, John M; RamachandraRao, Satish P

2016-12-01

We evaluate the relationships between persistent computed tomography (CT) nephrograms and acute kidney injury after cardiac catheterization (CC). We compare changes in urinary biomarkers kidney injury molecule 1 (KIM-1), cystatin C, and serum creatinine to procedural factors. From 159 eligible patients without renal insufficiency (estimated glomerular filtration rate >60 mL/min), 40 random patients (age range, 42-81 years; mean age, 64 years; 25 men, 15 women) gave written informed consent to undergo unenhanced CT limited to their kidneys 24 hours after CC. Semiquantitative assessment for global nephrograms and quantitative assessment of focal nephrograms in each kidney was performed. Computed tomography attenuation (Hounsfield units) of the renal cortex was measured. Serum creatinine, KIM-1, and cystatin C were measured before and 24 hours after CC. Robust linear regression showed that both relative changes in KIM-1 and cystatin C had positive relationships with kidney CT attenuation (P = 0.012 and 0.002, respectively). Spearman rank correlation coefficient showed that both absolute changes and relative changes in KIM-1 and cystatin C had positive correlations with global nephrogram grades (P = 0.025 and 0.040, respectively, for KIM-1; P = 0.013 and 0.019, respectively, for cystatin C). Global nephrograms on unenhanced CT in patients who have undergone CC are significantly correlated with changes in urinary biomarkers for kidney damage.

An Intervention with Mineral Water Decreases Cardiometabolic Risk Biomarkers. A Crossover, Randomised, Controlled Trial with Two Mineral Waters in Moderately Hypercholesterolaemic Adults.

PubMed

Toxqui, Laura; Vaquero, M Pilar

2016-06-28

Water intake is essential for health maintenance and disease prevention. The effects of an intervention with two mineral waters, sodium-bicarbonated mineral water (BW) or control mineral water low in mineral content (CW), on cardiometabolic risk biomarkers were studied. In a randomised-controlled crossover-trial, sixty-four moderately hypercholesterolaemic adults were randomly assigned to consume 1 L/day of either BW (sodium, 1 g/L; bicarbonate, 2 g/L) or CW with the main meals for eight weeks, separated by an eight-week washout period. Blood lipids, lipid oxidation, glucose, insulin, aldosterone, urine pH, urinary electrolytes, blood pressure, body weight, fluid intake, energy, and nutrients from total diet and beverages were determined. Total cholesterol, LDL cholesterol, and glucose decreased (p < 0.01), oxidised LDL tended to decrease (p = 0.073), and apolipoprotein B increased during the intervention, without water type effect. Energy and carbohydrates from beverages decreased since soft drinks and fruit juice consumptions decreased throughout the trial. BW increased urinary pH (p = 0.006) and reduced calcium/creatinine excretion (p = 0.011). Urinary potassium/creatinine decreased with both waters. Consumption of 1 L/day of mineral water with the main meals reduces cardiometabolic risk biomarkers, likely to be attributed to a replacement of soft drinks by water. In addition, BW does not affect blood pressure and exerts a moderate alkalizing effect in the body.

Exposure to polycyclic aromatic hydrocarbons and volatile organic compounds among recently pregnant rural Guatemalan women cooking and heating with solid fuels.

PubMed

Weinstein, John R; Asteria-Peñaloza, Renée; Diaz-Artiga, Anaité; Davila, Gilberto; Hammond, S Katharine; Ryde, Ian T; Meyer, Joel N; Benowitz, Neal; Thompson, Lisa M

2017-06-01

Household air pollution is a major contributor to death and disability worldwide. Over 95% of rural Guatemalan households use woodstoves for cooking or heating. Woodsmoke contains carcinogenic or fetotoxic polycyclic aromatic hydrocarbons (PAHs) and volatile organic compounds (VOCs). Increased PAHs and VOCs have been shown to increase levels of oxidative stress. We examined PAH and VOC exposures among recently pregnant rural Guatemalan women exposed to woodsmoke and compared exposures to levels seen occupationally or among smokers. Urine was collected from 23 women who were 3 months post-partum three times over 72h: morning (fasting), after lunch, and following dinner or use of wood-fired traditional sauna baths (samples=68). Creatinine-adjusted urinary concentrations of metabolites of four PAHs and eight VOCs were analyzed by liquid chromatography-mass spectrometry. Creatinine-adjusted urinary biomarkers of oxidative stress, 8-isoprostane and 8-OHdG, were analyzed using enzyme-linked immunosorbent assays (ELISA). Long-term (pregnancy through 3 months prenatal) exposure to particulate matter and airborne PAHs were measured. Women using wood-fueled chimney stoves are exposed to high levels of particulate matter (median 48h PM 2.5 105.7μg/m 3 ; inter-quartile range (IQR): 77.6-130.4). Urinary PAH and VOC metabolites were significantly associated with woodsmoke exposures: 2-naphthol (median (IQR) in ng/mg creatinine: 295.9 (74.4-430.9) after sauna versus 23.9 (17.1-49.5) fasting; and acrolein: 571.7 (429.3-1040.7) after sauna versus 268.0 (178.3-398.6) fasting. Urinary PAH (total PAH: ρ=0.89, p<0.001) and VOC metabolites of benzene (ρ=0.80, p<0.001) and acrylonitrile (ρ=0.59, p<0.05) were strongly correlated with long-term exposure to particulate matter. However urinary biomarkers of oxidative stress were not correlated with particulate matter (ρ=0.01 to 0.05, p>0.85) or PAH and VOC biomarkers (ρ=-0.20 to 0.38, p>0.07). Urinary metabolite concentrations were significantly greater than those of heavy smokers (mean cigarettes/day=18) across all PAHs. In 15 (65%) women, maximum 1-hydroxypyrene concentrations exceeded the occupational exposure limit of coke-oven workers. The high concentrations of urinary PAH and VOC metabolites among recently pregnant women is alarming given the detrimental fetal and neonatal effects of prenatal PAH exposure. As most women used chimney woodstoves, cleaner fuels are critically needed to reduce smoke exposure. Copyright © 2017 Elsevier GmbH. All rights reserved.

Urinary Phenylacetylglutamine as Dosing Biomarker for Patients with Urea Cycle Disorders

PubMed Central

Mokhtarani, M; Diaz, GA; Rhead, W; Lichter-Konecki, U; Bartley, J; Feigenbaum, A; Longo, N; Berquist, W; Berry, SA; Gallagher, R; Bartholomew, D; Harding, CO; Korson, MS; McCandless, SE; Smith, W; Vockley, J; Bart, S; Kronn, D; Zori, R; Cederbaum, S; Dorrani, N; Merritt, JL; Sreenath-Nagamani, Sandesh; Summar, M; LeMons, C; Dickinson, K; Coakley, DF; Moors, TL; Lee, B; Scharschmidt, BF

2013-01-01

We have analyzed pharmacokinetic data for glycerol phenylbutyrate (also GT4P or HPN-100) and sodium phenylbutyrate with respect to possible dosing biomarkers in patients with urea cycle disorders (UCD). Study Design These analyses are based on over 3000 urine and plasma data points from 54 adult and 11 pediatric UCD patients (ages 6–17) who participated in three clinical studies comparing ammonia control and pharmacokinetics during steady state treatment with glycerol phenylbutyrate or sodium phenylbutyrate. All patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate or sodium phenylbutyrate in a cross over fashion and underwent 24-hour blood samples and urine sampling for phenylbutyric acid, phenylacetic acid and phenylacetylglutamine. Results Patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate ranging from 1.5–31.8 g/day and of sodium phenylbutyrate ranging from 1.3–31.7 g/day. Plasma metabolite levels varied widely, with average fluctuation indices ranging from 1979% –5690% for phenylbutyric acid, 843% to 3931% for phenylacetic acid, and 881% -to 1434% for phenylacetylglutamine. Mean percent recovery of phenylbutyric acid as urinary phenylacetylglutamine was 66.4 and 69.0 for pediatric patients and 68.7 and 71.4 for adult patients on glycerol phenylbutyrate and sodium phenylbutyrate, respectively. The correlation with dose was strongest for urinary phenylacetylglutamine excretion, either as morning spot urine (r=0.730, p<0.001) or as total 24-hour excretion (r=0.791 p<0.001), followed by plasma phenylacetylglutamine AUC24-hour, plasma phenylacetic acid AUC24-hour and phenylbutyric acid AUC24-hour. Plasma phenylacetic acid levels in adult and pediatric patients did not show a consistent relationship with either urinary phenylacetylglutamine or ammonia control. Conclusion The findings are collectively consistent with substantial yet variable pre-systemic (1st pass) conversion of phenylbutyric acid to phenylacetic acid and/or phenylacetylglutamine. The variability of blood metabolite levels during the day, their weaker correlation with dose, the need for multiple blood samples to capture trough and peak, and the inconsistency between phenylacetic acid and urinary phenylacetylglutamine as a marker of waste nitrogen scavenging limit the utility of plasma levels for therapeutic monitoring. By contrast, 24-hour urinary phenylacetylglutamine and morning spot urine phenylacetylglutamine correlate strongly with dose and appear to be clinically useful non-invasive biomarkers for compliance and therapeutic monitoring. PMID:22958974

Urinary phenylacetylglutamine as dosing biomarker for patients with urea cycle disorders.

PubMed

Mokhtarani, M; Diaz, G A; Rhead, W; Lichter-Konecki, U; Bartley, J; Feigenbaum, A; Longo, N; Berquist, W; Berry, S A; Gallagher, R; Bartholomew, D; Harding, C O; Korson, M S; McCandless, S E; Smith, W; Vockley, J; Bart, S; Kronn, D; Zori, R; Cederbaum, S; Dorrani, N; Merritt, J L; Sreenath-Nagamani, Sandesh; Summar, M; Lemons, C; Dickinson, K; Coakley, D F; Moors, T L; Lee, B; Scharschmidt, B F

2012-11-01

We have analyzed pharmacokinetic data for glycerol phenylbutyrate (also GT4P or HPN-100) and sodium phenylbutyrate with respect to possible dosing biomarkers in patients with urea cycle disorders (UCD). These analyses are based on over 3000 urine and plasma data points from 54 adult and 11 pediatric UCD patients (ages 6-17) who participated in three clinical studies comparing ammonia control and pharmacokinetics during steady state treatment with glycerol phenylbutyrate or sodium phenylbutyrate. All patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate or sodium phenylbutyrate in a cross over fashion and underwent 24-hour blood samples and urine sampling for phenylbutyric acid, phenylacetic acid and phenylacetylglutamine. Patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate ranging from 1.5 to 31.8 g/day and of sodium phenylbutyrate ranging from 1.3 to 31.7 g/day. Plasma metabolite levels varied widely, with average fluctuation indices ranging from 1979% to 5690% for phenylbutyric acid, 843% to 3931% for phenylacetic acid, and 881% to 1434% for phenylacetylglutamine. Mean percent recovery of phenylbutyric acid as urinary phenylacetylglutamine was 66.4 and 69.0 for pediatric patients and 68.7 and 71.4 for adult patients on glycerol phenylbutyrate and sodium phenylbutyrate, respectively. The correlation with dose was strongest for urinary phenylacetylglutamine excretion, either as morning spot urine (r = 0.730, p < 0.001) or as total 24-hour excretion (r = 0.791 p<0.001), followed by plasma phenylacetylglutamine AUC(24-hour), plasma phenylacetic acid AUC(24-hour) and phenylbutyric acid AUC(24-hour). Plasma phenylacetic acid levels in adult and pediatric patients did not show a consistent relationship with either urinary phenylacetylglutamine or ammonia control. The findings are collectively consistent with substantial yet variable pre-systemic (1st pass) conversion of phenylbutyric acid to phenylacetic acid and/or phenylacetylglutamine. The variability of blood metabolite levels during the day, their weaker correlation with dose, the need for multiple blood samples to capture trough and peak, and the inconsistency between phenylacetic acid and urinary phenylacetylglutamine as a marker of waste nitrogen scavenging limit the utility of plasma levels for therapeutic monitoring. By contrast, 24-hour urinary phenylacetylglutamine and morning spot urine phenylacetylglutamine correlate strongly with dose and appear to be clinically useful non-invasive biomarkers for compliance and therapeutic monitoring. Copyright © 2012 Elsevier Inc. All rights reserved.

Application of Sparse Linear Discriminant Analysis and Elastic Net for Diagnosis of IgA Nephropathy: Statistical and Biological Viewpoints

PubMed

Mohammadi Majd, Tahereh; Kalantari, Shiva; Raeisi Shahraki, Hadi; Nafar, Mohsen; Almasi, Afshin; Samavat, Shiva; Parvin, Mahmoud; Hashemian, Amirhossein

2018-03-10

IgA nephropathy (IgAN) is the most common primary glomerulonephritis diagnosed based on renal biopsy. Mesangial IgA deposits along with the proliferation of mesangial cells are the histologic hallmark of IgAN. Non-invasive diagnostic tools may help to prompt diagnosis and therapy. The discovery of potential and reliable urinary biomarkers for diagnosis of IgAN depends on applying robust and suitable models. Applying two multivariate modeling methods on a urine proteomic dataset obtained from IgAN patients, and comparison of the results of these methods were the purpose of this study. Two models were constructed for urinary protein profiles of 13 patients and 8 healthy individuals, based on sparse linear discriminant analysis (SLDA) and elastic net regression methods. A panel of selected biomarkers with the best coefficients were proposed and further analyzed for biological relevance using functional annotation and pathway analysis. Transferrin, α1-antitrypsin, and albumin fragments were the most important up-regulated biomarkers, while fibulin-5, YIP1 family member 3, prasoposin, and osteopontin were the most important down-regulated biomarkers. Pathway analysis revealed that complement and coagulation cascades and extracellular matrix-receptor interaction pathways impaired in the pathogenesis of IgAN. SLDA and elastic net had an equal importance for diagnosis of IgAN and were useful methods for exploring and processing proteomic data. In addition, the suggested biomarkers are reliable candidates for further validation to non-invasive diagnose of IgAN based on urine examination.

Utility of urinary biomarkers as a diagnostic tool for early diabetic nephropathy in patients with type 2 diabetes mellitus.

PubMed

Vijay, Soorampally; Hamide, Abdoul; Senthilkumar, Gandhipuram Periyasamy; Mehalingam, Vadivelan

2018-04-12

Renal tubulo-interstitial damage has an important role in the pathogenesis of early diabetic nephropathy. Urinary biomarkers can help in the detection of early nephropathy in type 2 diabetic patients. The aim of this study was to estimate the levels of urinary neutrophil gelatinase associated lipocalin (NGAL) and cystatin-C in type 2 diabetic patients with early diabetic nephropathy & to compare them with diabetic patients without nephropathy and to correlate urinary NGAL and cystatin-C levels with microalbuminuria in them. Cross-sectional comparative study. The study was conducted on 126 patients with type 2 diabetes along with 30 control subjects attending the outpatient care department of a tertiary care teaching hospital. There were 3 study groups-diabetic patients with microalbuminuria, diabetic patients without albuminuria and control subjects who were non-diabetic without any renal disease. Details on duration of diabetes and glycemic status were obtained from the patients. Urine examination was done for subjects in all the groups to look for microalbuminuria along with estimation of NGAL and cystatin-C levels. Samples were stored at -20 °C in the deep freezer. Urinary NGAL and cystatin-C levels were significantly elevated in patients with microalbuminuria (228.18 & 3.23 ng/ml) as compared to those without albuminuria (146.12 & 2.61 ng/ml) and in control subjects (26.56 & 0.30 ng/ml). Urinary NGAL and cystatin-C levels showed a linear correlation with microalbuminuria in diabetic patients. Urinary NGAL and cystatin-C levels were increased in type 2 diabetic patients with early diabetic nephropathy as compared to patients without nephropathy. Urine NGAL and cystatin-C levels also showed a positive correlation with microalbuminuria (urine albumin-creatinine ratio) in patients with type 2 diabetes mellitus. Copyright © 2018 Diabetes India. Published by Elsevier Ltd. All rights reserved.

Urinary porphyrins as biomarkers for arsenic exposure among susceptible populations in Guizhou Province, China

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ng, J.C.; Wang, J.P.; Zheng, B.S.

2005-08-07

Coal from some areas in Guizhou Province contains elevated levels of arsenic. This has caused arsenicosis in individuals who use arsenic-contaminated coal for the purposes of heating, cooking and drying of food in poorly ventilated dwellings. The population at risk has been estimated to be approximately 200,000 people. We analyzed the porphyrin excretion profile using a HPLC method in urine samples collected from 113 villagers who lived in Xing Ren district, a coal-borne arsenicosis endemic area and from 30 villagers from Xing Yi where arsenicosis is not prevalent. Urinary porphyrins were higher in the arsenic exposed group than those inmore » the control group. The correlation between urinary arsenic and porphyrin concentrations demonstrated the effect of arsenic on heme biosynthesis resulting in increased porphyrin excretion. Both uroporphyrin and coproporphyrin III showed significant increases in the excretion profile of the younger age ({lt} 20 years) arsenic-exposed group, suggesting that porphyrins could be used as early warning biomarkers of chronic arsenic exposure in humans. Greater increases of urinary arsenic and porphyrins in women, children and older age groups who spend much of their time indoors suggest that they might be at a higher risk. Whether elevated porphyrins could predict adverse health effects associated with both cancer and non-cancer end-points in chronically arsenic-exposed populations need further investigation.« less

Evaluation of the oxidative deoxyribonucleic acid damage biomarker 8-hydroxy-2'-deoxyguanosine in the urine of leukemic children by micellar electrokinetic capillary chromatography.

PubMed

Zhang, Pingping; Lian, Kaoqi; Wu, Xiaoli; Yao, Min; Lu, Xin; Kang, Weijun; Jiang, Lingling

2014-04-04

Determining the level of urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG), an oxidative DNA damage biomarker, is vital to the study of clinical pathogenesis and drug toxicity. The principal limitation of capillary electrophoresis (CE) with UV detection is its low sensitivity. To overcome this shortcoming, we developed a micellar electrokinetic capillary chromatography (MEKC) with solid-phase extraction (SPE) for urinary 8-OHdG analysis. The sensitivity of MEKC-UV was improved using a reasonable UV system, injection mode, and SPE. The parameters affecting MEKC and SPE were also optimized. The calibration curve was linear within the range from 1 to 500 μg L(-1). The limits of detection and quantification were 0.27 μg L(-1) and 0.82 μg L(-1), respectively. Interday and intraday precision were both <5.6%. The recovery of 8-OHdG in urine ranged from 94.5% to 103.2%. This method was used to measure urinary 8-OHdG from eight normal children, eight newly diagnosed leukemic children, and eight leukemic children undergoing chemotherapy. The results show that the proposed method can be used to assess oxidative stress in patients and the side effects of chemotherapeutic drugs by measuring urinary 8-OHdG. Copyright © 2014 Elsevier B.V. All rights reserved.

Exposure to Cooking Oil Fumes and Oxidative Damages: A Longitudinal Study in Chinese Military Cooks

PubMed Central

Lai, Ching-Huang; Jaakkola, Jouni J.K.; Chuang, Chien-Yi; Liou, Saou-Hsing; Lung, Shih-Chun; Loh, Ching-Hui; Yu, Dah-Shyong; Strickland, Paul T.

2014-01-01

Cooking oil fumes contain polycyclic aromatic hydrocarbons (PAHs), heterocyclic aromatic amines, benzene, and formaldehyde which may cause oxidative damages to DNA and lipids. We assessed the relations between exposure to cooking oil fumes (COF) and subsequent oxidative DNA damage and lipid peroxidation among military cooks and office-based soldiers. The study population, including 61 Taiwanese male military cooks and a reference group of 37 office soldiers, collected urine samples pre-shift of the first weekday and post-shift of the fifth workday. We measured airborne particulate PAHs in military kitchens and offices and concentrations of urinary 1-OHP, a biomarker of PAH exposure, urinary 8-hydroxydeoxyguanosine (8-OHdG), a biomarkers of oxidative DNA damage, and urinary isoprostane (Isop). Airborne particulate PAHs levels in kitchens significantly exceeded those in office areas. The concentrations of urinary 1-OHP among military cooks increased significantly after 5 days of exposure to COF. Using generalized estimating equation (GEE) analysis adjusting for confounding, a change in log(8-OHdG) and log(Isop) were statistically significantly related to a unit change in log(1-OHP) (regression coefficient [β], β= 0.06, 95% CI 0.001 to 0.12) and (β= 0.07, 95% CI 0.001 to 0.13), respectively. Exposure to PAHs, or other compounds in cooking-oil fumes, may cause both oxidative DNA damage and lipid peroxidation. PMID:22968348

New markers of urinary tract infection.

PubMed

Masajtis-Zagajewska, Anna; Nowicki, Michal

2017-08-01

Urinary tract infection (UTI) is the most common bacterial infection independent of age. It is also one of the most common causes of hospitalizations for infections among elderly people and the most common indication for antibiotic prescriptions in primary care. Both diagnostics and management of lower and upper urinary tract infections provide challenges in clinical practice due to their high prevalence and recurrence, and worldwide increase of antibiotic resistance. The clinical symptoms of UTI are often uncharacteristic or asymptomatic. The accurate diagnosis and early treatment are crucial due to risk of septicaemia and long-term consequences. Currently the diagnosis of urinary tract infection is based on the presence of clinical symptoms in combination with the results of nitrite strip test indicating the presence of bacteria in urine and semi-quantitative measurement of white blood cells count in urine. Although urine culture is the gold standard in UTI diagnostics it is both time-consuming and costly. Searching for novel biomarkers of UTI has attracted much attention in recent years. The article reviews several promising serum and urine biomarkers of UTI such as leukocyte esterase, C-reactive protein, procalcitonin, interleukins, elastase alpha (1)-proteinase inhibitor, lactofferin, secretory immunoglobulin A, heparin-binding protein, xanthine oxidase, myeloperoxidase, soluble triggering receptor expressed on myeloid cells-1, α-1 microglobulin (α1Mg) and tetrazolium nitroblue test (TNB). Copyright © 2017 Elsevier B.V. All rights reserved.

Recent advances in recurrent urinary tract infection from pathogenesis and biomarkers to prevention.

PubMed

Jhang, Jia-Fong; Kuo, Hann-Chorng

2017-01-01

Recurrent urinary tract infection (UTI) might be one of the most common problems in urological clinics. Recent research has revealed novel evidence about recurrent UTI and it should be considered a different disease from the first infection. The pathogenesis of recurrent UTI might include two mechanisms, bacterial factors and deficiencies in host defense. Bacterial survival in the urinary bladder after antibiotic treatment and progression to form intracellular bacterial communities might be the most important bacterial factors. In host defense deficiency, a defect in pathogen recognition and urothelial barrier function impairment play the most important roles. Immunodeficiency and urogenital tract anatomical abnormalities have been considered the essential risk factors for recurrent UTI. In healthy women, voiding dysfunction and behavioral factors also increase the risk of recurrent UTI. Sexual intercourse and estrogen deficiency in postmenopausal women might have the strongest association with recurrent UTI. Traditional lifestyle factors such as fluid intake and diet are not considered independent risk factors now. Serum and urine biomarkers to predict recurrent UTI from the first infection have also attracted a wide attention recently. Current clinical evidence suggests that serum macrophage colony-stimulating factor and urinary nerve growth factor have potential predictive value for recurrent UTI. Clinical trials have proven the efficacy of the oral immunoactive agent OM-89 for the prevention of UTI. Vaccines for recurrent UTI are recommended by the latest guidelines and are available on the market.

Exposure to cooking oil fumes and oxidative damages: a longitudinal study in Chinese military cooks.

PubMed

Lai, Ching-Huang; Jaakkola, Jouni J K; Chuang, Chien-Yi; Liou, Saou-Hsing; Lung, Shih-Chun; Loh, Ching-Hui; Yu, Dah-Shyong; Strickland, Paul T

2013-01-01

Cooking oil fumes (COF) contain polycyclic aromatic hydrocarbons (PAHs), heterocyclic aromatic amines, benzene, and formaldehyde, which may cause oxidative damages to DNA and lipids. We assessed the relations between exposure to COF and subsequent oxidative DNA damage and lipid peroxidation among military cooks and office-based soldiers. The study population, including 61 Taiwanese male military cooks and a reference group of 37 office soldiers, collected urine samples pre-shift of the first weekday and post-shift of the fifth workday. We measured airborne particulate PAHs in military kitchens and offices and concentrations of urinary 1-OHP, a biomarker of PAH exposure, urinary 8-hydroxydeoxyguanosine (8-OHdG), a biomarkers of oxidative DNA damage, and urinary isoprostane (Isop). Airborne particulate PAHs levels in kitchens significantly exceeded those in office areas. The concentrations of urinary 1-OHP among military cooks increased significantly after 5 days of exposure to COF. Using generalized estimating equation analysis adjusting for confounding, a change in log(8-OHdG) and log(Isop) were statistically significantly related to a unit change in log(1-OHP) (regression coefficient (β), β=0.06, 95% CI 0.001-0.12) and (β=0.07, 95% CI 0.001-0.13), respectively. Exposure to PAHs, or other compounds in cooking oil fumes, may cause both oxidative DNA damage and lipid peroxidation.

Maternal Arsenic Exposure, Arsenic Methylation Efficiency, and Birth Outcomes in the Biomarkers of Exposure to ARsenic (BEAR) Pregnancy Cohort in Mexico

PubMed Central

Laine, Jessica E.; Bailey, Kathryn A.; Rubio-Andrade, Marisela; Olshan, Andrew F.; Smeester, Lisa; Drobná, Zuzana; Herring, Amy H.; Stýblo, Miroslav; García-Vargas, Gonzalo G.

2014-01-01

Background: Exposure to inorganic arsenic (iAs) from drinking water is a global public health problem, yet much remains unknown about the extent of exposure in susceptible populations. Objectives: We aimed to establish the Biomarkers of Exposure to ARsenic (BEAR) prospective pregnancy cohort in Gómez Palacio, Mexico, to better understand the effects of iAs exposure on pregnant women and their children. Methods: Two hundred pregnant women were recruited for this study. Concentrations of iAs in drinking water (DW-iAs) and maternal urinary concentrations of iAs and its monomethylated and dimethylated metabolites (MMAs and DMAs, respectively) were determined. Birth outcomes were analyzed for their relationship to DW-iAs and to the concentrations and proportions of maternal urinary arsenicals. Results: DW-iAs for the study subjects ranged from < 0.5 to 236 μg As/L. More than half of the women (53%) had DW-iAs that exceeded the World Health Organization’s recommended guideline of 10 μg As/L. DW-iAs was significantly associated with the sum of the urinary arsenicals (U-tAs). Maternal urinary concentrations of MMAs were negatively associated with newborn birth weight and gestational age. Maternal urinary concentrations of iAs were associated with lower mean gestational age and newborn length. Conclusions: Biomonitoring results demonstrate that pregnant women in Gómez Palacio are exposed to potentially harmful levels of DW-iAs. The data support a relationship between iAs metabolism in pregnant women and adverse birth outcomes. The results underscore the risks associated with iAs exposure in vulnerable populations. Citation: Laine JE, Bailey KA, Rubio-Andrade M, Olshan AF, Smeester L, Drobná Z, Herring AH, Stýblo M, García-Vargas GG, Fry RC. 2015. Maternal arsenic exposure, arsenic methylation efficiency, and birth outcomes in the Biomarkers of Exposure to ARsenic (BEAR) pregnancy cohort in Mexico. Environ Health Perspect 123:186–192; http://dx.doi.org/10.1289/ehp.1307476 PMID:25325819

Variability of Urinary Phthalate Metabolite and Bisphenol A Concentrations before and during Pregnancy

PubMed Central

Braun, Joe M.; Smith, Kristen W.; Williams, Paige L.; Calafat, Antonia M.; Berry, Katharine; Ehrlich, Shelley

2012-01-01

Background: Gestational phthalate and bisphenol A (BPA) exposure may increase the risk of adverse maternal/child health outcomes, but there are few data on the variability of urinary biomarkers before and during pregnancy. Objective: We characterized the variability of urinary phthalate metabolite and BPA concentrations before and during pregnancy and the ability of a single spot urine sample to classify average gestational exposure. Methods: We collected 1,001 urine samples before and during pregnancy from 137 women who were partners in couples attending a Boston fertility clinic and who had a live birth. Women provided spot urine samples before (n ≥ 2) and during (n ≥ 2) pregnancy. We measured urinary concentrations of monoethyl phthalate (MEP), mono-n-butyl phthalate (MBP), mono-iso-butyl phthalate, monobenzyl phthalate (MBzP), four metabolites of di-(2-ethylhexyl) phthalate (DEHP), and BPA. After adjusting for specific gravity, we characterized biomarker variability using intraclass correlation coefficients (ICCs) and conducted several surrogate category analyses to determine whether a single spot urine sample could adequately classify average gestational exposure. Results: Absolute concentrations of phthalate metabolites and BPA were similar before and during pregnancy. Variability was higher during pregnancy than before pregnancy for BPA and MBzP, but similar during and before pregnancy for MBP, MEP, and ΣDEHP. During pregnancy, MEP (ICC = 0.50) and MBP (ICC = 0.45) were less variable than BPA (ICC = 0.12), MBzP (ICC = 0.25), and ΣDEHP metabolites (ICC = 0.08). Surrogate analyses suggested that a single spot urine sample may reasonably classify MEP and MBP concentrations during pregnancy, but more than one sample may be necessary for MBzP, DEHP, and BPA. Conclusions: Urinary phthalate metabolites and BPA concentrations were variable before and during pregnancy, but the magnitude of variability was biomarker specific. A single spot urine sample adequately classified MBP and MEP concentrations during pregnancy. The present results may be related to unique features of the women studied, and replication in other pregnancy cohorts is recommended. PMID:22262702

Preclinical evaluation of novel urinary biomarkers of cadmium nephrotoxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Prozialeck, Walter C.; Edwards, Joshua R.; Vaidya, Vishal S.

2009-08-01

As a result of the widespread use of Cd in industry and its extensive dissemination in the environment, there has been considerable interest in the identification of early biomarkers of Cd-induced kidney injury. Kim-1 is a transmembrane glycoprotein that is not detectable in normal kidney, but is up-regulated and shed into the urine following ischemic or nephrotoxic injury. Recent studies utilizing a sub-chronic model of Cd exposure in the rat have shown that Kim-1 is an early urinary marker of Cd-induced kidney injury. Kim-1 was detected in the urine 4-5 weeks before the onset of proteinuria and 1-3 weeks beforemore » the appearance of urinary metallothionein and Clara cell protein 16, which are standard markers of Cd nephrotoxicity. In the present study, we have compared the time course for the appearance of Kim-1 in the urine with the time course for the appearance of alpha glutathione-S-transferase ({alpha}-GST), N-acetyl-{beta}-D-glucose amidase (NAG) and Cd, each of which have been used or proposed as urinary markers of Cd nephrotoxicity. Adult male Sprague-Dawley rats were given daily subcutaneous injections of 0.6 mg (5.36 {mu}moles)/kg Cd, 5 days per week for up to 12 weeks. One day each week, 24 h urine samples were collected and analyzed for protein, creatinine and the various markers. The results showed that significant levels of Kim-1 appeared in the urine as early as 6 weeks into the treatment protocol and then continued to rise for the remainder of the 12 week treatment period. By contrast, significant levels of {alpha}-GST and NAG did not appear in the urine until 8 and 12 weeks, respectively, while proteinuria was not evident until 10 weeks. The urinary excretion of Cd was below the level of detection until week 4 and then showed a slow, linear increase over the next 6 weeks before increasing markedly between weeks 10 and 12. These results provide additional evidence that Kim-1 is a sensitive biomarker of the early stages of Cd-induced proximal tubule injury.« less

Occupational exposure to manganese-containing welding fumes and pulmonary function indices among natural gas transmission pipeline welders.

PubMed

Hassani, Hamid; Golbabaei, Farideh; Ghahri, Asghar; Hosseini, Mostafa; Shirkhanloo, Hamid; Dinari, Behnam; Eskandari, Davood; Fallahi, Majid

2012-01-01

The objectives of this study were to evaluate manganese (Mn)-containing welding fumes' exposure, assess urinary Mn as a biomarker for Mn exposure and investigate the correlation of Mn in air, total fumes and urinary Mn with pulmonary function indices in 118 welders and 37 unexposed controls from two regions in Iran, Assaluyeh and Borujen. Air samples were collected on mixed cellulose ester membrane filters in personal air samplers and then analyzed using inductively coupled plasma atomic emission spectroscopy (ICP-AES) (NIOSH Method 7300). For all participants, urine samples were collected during the entire work shift, and Mn in urine was determined by graphite furnace atomic absorption spectroscopy according to NIOSH Method 8310. Spirometric measurements were also done for participants. The maximum exposures to airborne Mn and total fumes were 0.304 ± 0.256 mg/m(3) and 21.52 ± 9.40 mg/m(3), respectively. The urine Mn levels in the various groups ranged between 0.77 to 7.58 μg/l. The correlation between airborne Mn and urinary Mn was significant for total whole participants. Some values of spirometric indices were statistically lower in welders rather than controls. Our results indicate that many welders have been exposed to higher concentrations of Mn-containing welding fumes. Urinary Mn can be used as a biomarker for Mn exposure. There were weak inverse correlations between Mn-containing welding fumes and pulmonary function indices, and the inverse correlation between urinary Mn with forced vital capacities (FVC) and forced expiratory volume in 1 s (FEV1) was significant.

Maternal arsenic exposure, arsenic methylation efficiency, and birth outcomes in the Biomarkers of Exposure to ARsenic (BEAR) pregnancy cohort in Mexico.

PubMed

Laine, Jessica E; Bailey, Kathryn A; Rubio-Andrade, Marisela; Olshan, Andrew F; Smeester, Lisa; Drobná, Zuzana; Herring, Amy H; Stýblo, Miroslav; García-Vargas, Gonzalo G; Fry, Rebecca C

2015-02-01

Exposure to inorganic arsenic (iAs) from drinking water is a global public health problem, yet much remains unknown about the extent of exposure in susceptible populations. We aimed to establish the Biomarkers of Exposure to ARsenic (BEAR) prospective pregnancy cohort in Gómez Palacio, Mexico, to better understand the effects of iAs exposure on pregnant women and their children. Two hundred pregnant women were recruited for this study. Concentrations of iAs in drinking water (DW-iAs) and maternal urinary concentrations of iAs and its monomethylated and dimethylated metabolites (MMAs and DMAs, respectively) were determined. Birth outcomes were analyzed for their relationship to DW-iAs and to the concentrations and proportions of maternal urinary arsenicals. DW-iAs for the study subjects ranged from < 0.5 to 236 μg As/L. More than half of the women (53%) had DW-iAs that exceeded the World Health Organization's recommended guideline of 10 μg As/L. DW-iAs was significantly associated with the sum of the urinary arsenicals (U-tAs). Maternal urinary concentrations of MMAs were negatively associated with newborn birth weight and gestational age. Maternal urinary concentrations of iAs were associated with lower mean gestational age and newborn length. Biomonitoring results demonstrate that pregnant women in Gómez Palacio are exposed to potentially harmful levels of DW-iAs. The data support a relationship between iAs metabolism in pregnant women and adverse birth outcomes. The results underscore the risks associated with iAs exposure in vulnerable populations.

Urinary neutrophil gelatinase-associated lipocalin, a biomarker for systemic inflammatory response syndrome in patients with nephrolithiasis.

PubMed

Zhu, Wei; Liu, Min; Wang, Guang-Chun; Che, Jian-Ping; Xu, Yun-Fei; Peng, Bo; Zheng, Jun-Hua

2014-03-01

The objective of this study was to determine the diagnostic value of neutrophil gelatinase-associated lipocalin (NGAL), C-reactive protein (CRP), and procalcitonin (PCT) in the prognosis of patients presenting with the systemic inflammatory response syndrome (SIRS) with nephrolithiasis. Urine NGAL protein levels were measured by enzyme-linked immunosorbent assay in 87 patients presenting with nephrolithiasis who were diagnosed as SIRS. Additionally, 52 patients presenting with nephrolithiasis but without urinary tract infection and 30 healthy controls were also included in the study. Levels of serum CRP and PCT were also taken into consideration. Median urinary NGAL levels were significantly increased in the SIRS cohorts compared with nephrolithiasis without urinary tract infection patients (4.28 ng/mL versus 2.69 ng/mL, P < 0.001), and NGAL was markedly elevated even in the early stage of SIRS (3.23 ng/mL versus 2.69 ng/mL, P < 0.001). According to the receiver-operating characteristic analysis, NGAL demonstrated a high diagnostic value compared with either PCT or CRP. In the later stage of SIRS, NGAL remained a highly sensitive (76.8%) and specific (86.5%) diagnostic marker compared with either PCT or CRP. Moreover, the area under the curves of NGAL (0.822) were also superior to those seen in either PCT (0.657) or CRP (0.761). Urinary NGAL is a highly sensitive and specific predictor of SIRS for patients presenting with nephrolithiasis. Further study of NGAL as a reliable biomarker of SIRS is required. Copyright © 2014 Elsevier Inc. All rights reserved.

Observing Protein & Energy Nutrition (OPEN) Study

Cancer.gov

The Observing Protein and Energy Nutrition (OPEN) Study was designed to assess dietary measurement error by comparing results from self-reported dietary intake data with four dietary biomarkers: doubly labeled water and urinary nitrogen, sodium, and potassium.

Chromium (VI) induced oxidative damage to DNA: increase of urinary 8-hydroxydeoxyguanosine concentrations (8-OHdG) among electroplating workers

PubMed Central

Kuo, H; Chang, S; Wu, K; Wu, F

2003-01-01

Aims: To investigate the concentration of urinary 8-hydroxydeoxyguanosine (8-OHdG) among electroplating workers in Taiwan. Methods: Fifty workers were selected from five chromium (Cr) electroplating plants in central Taiwan. The 20 control subjects were office workers with no previous exposure to Cr. Urinary 8-OHdG concentrations were determined using high performance liquid chromatography with electrochemical detection. Results: Urinary 8-OHdG concentrations among Cr workers (1149.5 pmol/kg/day) were higher than those in the control group (730.2 pmol/kg/day). There was a positive correlation between urinary 8-OHdG concentrations and urinary Cr concentration (r = 0.447, p < 0.01), and urinary 8-OHdG correlated positively with airborne Cr concentration (r = 0.285). Using multiple regression analysis, the factors that affected urinary 8-OHdG concentrations were alcohol, the common cold, and high urinary Cr concentration. There was a high correlation of urinary 8-OHdG with both smoking and drinking, but multiple regression analysis showed that smoking was not a significant factor. Age and gender were also non-significant factors. Conclusion: 8-OHdG, which is an indicator of oxidative DNA damage, was a sensitive biomarker for Cr exposure. PMID:12883020

Clinical utility of urinary soluble Fas in screening for bladder cancer.

PubMed

Srivastava, Anupam Kumar; Singh, Pankaj Kumar; Singh, Dhramveer; Dalela, Divakar; Rath, Srikanta Kumar; Bhatt, Madan Lal Brahma

2016-06-01

Early diagnosis of carcinoma of urinary bladder remains a challenge. Urine cytology, as an adjunct to cystoscopy, is less sensitive for low-grade tumors. Soluble Fas (sFas), a cell-surface receptor and member of the tumor necrosis factor superfamily, is frequently expressed in urinary bladder carcinoma. The objective of this study was to investigate the urinary sFas for diagnosis of transitional cell carcinoma (TCC) of urinary bladder. We examined urinary sFas concentration in 74 controls and 117 cases of TCC, both primary and recurrent disease, by using enzyme-linked immunosorbent assay and compared it with urinary cytology. Urinary sFas concentration was found to be significantly higher in the patient as compared to control group (P < 0.05). An optimal cutoff value of 174.0 pg/mL was proposed. The urinary sFas level was found to have an approximate sensitivity and specificity of 88.03% and 89.19% (P < 0.001), whereas urine cytology had sensitivity of 66.67% and specificity of 95.95%. sFas had better sensitivity in higher grade and both primary and recurrent cases of urinary bladder cancer in comparison with cytology. Out of 15 node positive bladder cancer cases, 13 had high urinary sFas levels, whereas 12 were urinary cytology positive for malignancy. Urinary sFas can be used as a non-invasive diagnostic biomarker for TCC of urinary bladder, both for primary and recurrent disease. © 2014 Wiley Publishing Asia Pty Ltd.

Nicotine and Toxicant Exposure Among US Smokeless Tobacco Users: Results from 1999-2012 National Health and Nutrition Examination Survey Data

PubMed Central

Rostron, Brian L.; Chang, Cindy M.; van Bemmel, Dana M.; Xia, Yang; Blount, Benjamin C.

2016-01-01

Background It has been suggested that smokeless tobacco users have high levels of exposure to nicotine and some toxic substances as measured by biomarker concentrations, but studies with nationally representative data have been limited. Methods We analyzed biomarkers of tobacco exposure for 23,684 adult participants from the National Health and Nutrition and Examination Survey (NHANES) from 1999-2012. The biomarkers analyzed were serum cotinine, urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), blood lead, blood cadmium, blood mercury, urinary arsenic, and urinary N-acetyl-S-(2-cyanoethyl)-L-cysteine (CYMA). We calculated geometric mean concentrations for each biomarker by tobacco use category (exclusive smokeless tobacco use, exclusive cigarette smoking, dual cigarette and smokeless tobacco use, and non-cigarette and smokeless tobacco use) and geometric mean ratios adjusting for demographic factors. Results Exclusive smokeless tobacco users had higher geometric mean concentrations of cotinine (178.9 ng/mL, 95% CI = 145.5, 220.0) and NNAL (583.0 pg/mg creatinine, 95% CI = 445.2, 763.5) than exclusive cigarette smokers, (130.6 ng/mL, 95% CI = 122.3, 139.6 and 217.6 pg/mg creatinine, 95% CI = 193.0, 245.2, respectively). Smokeless tobacco users also had higher concentrations of blood lead compared with non-tobacco users (adjusted geometric mean ratio = 1.30, 95% CI = 1.21, 1.38). Differences in concentrations of cadmium, mercury, and CYMA between smokeless tobacco users and non-tobacco users were not observed. Based on limited sample sizes, NNAL concentrations for smokeless tobacco users appear to have declined from 2007-2008 (geometric mean = 1013.7 pg/mg creatinine, 95% CI = 738.9, 1390.8) to 2011-2012 (geometric mean = 325.7 pg/mg creatinine, 95% CI = 159.6, 664.9). Conclusions Smokeless tobacco users have higher observed levels of exposure to nicotine and carcinogenic tobacco-specific nitrosamines, as measured by cotinine and NNAL biomarker concentrations, than cigarette smokers. Impact High levels of exposure to known harmful constituents for smokeless tobacco users is a cause of concern for individual and public health. PMID:26582044

The fate of sulfate in chronic heart failure

PubMed Central

Koning, Anne M.; Meijers, Wouter C.; Minović, Isidor; Post, Adrian; Feelisch, Martin; Pasch, Andreas; Leuvenink, Henri G. D.; de Boer, Rudolf A.; Bakker, Stephan J. L.

2017-01-01

New leads to advance our understanding of heart failure (HF) pathophysiology are urgently needed. Previous studies have linked urinary sulfate excretion to a favorable cardiovascular risk profile. Sulfate is not only the end product of hydrogen sulfide metabolism but is also directly involved in various (patho)physiological processes, provoking scientific interest in its renal handling. This study investigates sulfate clearance in chronic HF (CHF) patients and healthy individuals and considers its relationship with disease outcome. Parameters related to renal sulfate handling were determined in and compared between 96 previously characterized CHF patients and sex-matched healthy individuals. Among patients, sulfate clearance was analyzed for associations with clinical and outcome parameters. In CHF patients, plasma sulfate concentrations are significantly higher, whereas 24-h urinary excretion, fractional excretion, and clearance of sulfate are significantly lower, compared with healthy individuals. Among patients, sulfate clearance is independently associated with diuretics use, creatinine clearance and 24-h urinary sodium excretion. Sulfate clearance is associated with favorable disease outcome [hazard ratio per SD increase 0.38 (95% confidence interval 0.23–0.63), P < 0.001]. Although significance was lost after adjustment for creatinine clearance, the decrease of sulfate clearance in patients is independent of this parameter, indicating that sulfate clearance is not merely a reflection of renal function. This exploratory study reveals aberrant sulfate clearance as a potential contributor to CHF pathophysiology, with reduced levels in patients and a positive association with favorable disease outcome. Further research is needed to unravel the nature of its involvement and to determine its potential as a biomarker and target for therapy. NEW & NOTEWORTHY Sulfate clearance is decreased in chronic heart failure patients compared with healthy individuals. Among patients, sulfate clearance is positively associated with favorable disease outcome, i.e., a decreased rehospitalization rate and increased patient survival. Hence, decreased sulfate clearance may be involved in the pathophysiology of heart failure. PMID:27923792

Urinary excretion half life of trichloroacetic acid as a biomarker of exposure to chlorinated drinking water disinfection by-products

PubMed Central

Bader, E; Hrudey, S; Froese, K

2004-01-01

Methods: A longitudinal pilot exposure/intervention study measured the elimination half life of TCAA in urine. Beverage consumption was limited to a public water supply and bottled water of known TCAA concentration, and ingestion volume was managed. The five participants limited fluid consumption to only the water provided. Consumption journals were kept by each participant and their daily first morning urine (FMU) samples were analysed for TCAA and creatinine. TCAA elimination half life curves were generated from a two week washout period using TCAA-free bottled water. Results: Individual elimination half lives ranged from 2.1 to 6.3 days, for single compartment exponential decay, the model which fit the data. Conclusion: Urinary TCAA is persistent enough to be viable as a biomarker of medium term (days) exposure to drinking water TCAA ingestion within a range of realistic concentrations. PMID:15258281

Urinary phenylacetylglutamine (U-PAGN) concentration as biomarker for adherence in patients with urea cycle disorders (UCD) treated with glycerol phenylbutyrate.

PubMed

Mokhtarani, M; Diaz, G A; Lichter-Konecki, U; Berry, S A; Bartley, J; McCandless, S E; Smith, W; Harding, C; Le Mons, C; Coakley, D F; Lee, B; Scharschmidt, B F

2015-12-01

Urinary phenylacetylglutamine (U-PAGN) concentrations in spot urine samples were analyzed as a dosing biomarker during glycerol phenylbutyrate (GPB) dosing in 68 healthy adults and 66 adult and pediatric patients with urea cycle disorders who participated in GPB clinical trials. Age- and body surface area (BSA)-specific 25th percentile cutoff points for spot U-PAGN concentrations (<~9000 μg/mL for < 2 years old patients, < 7000 μg/mL for > 2 years with BSA ≤ 1.3 m 2 , and <~5000 μg/mL for > 2 years of age with BSA > 1.3 m 2 ) were determined as an approach to identify patients for whom increased dosing and/or adherence to prescribed dosing should be assessed.

Blood miRNAs as sensitive and specific biological indicators of environmental and occupational exposure to volatile organic compound (VOC).

PubMed

Song, Mi-Kyung; Ryu, Jae-Chun

2015-10-01

To date, there is still shortage of highly sensitive and specific minimally invasive biomarkers for assessment of environmental toxicants exposure. Because of the significance of microRNA (miRNA) in various diseases, circulating miRNAs in blood may be unique biomarkers for minimally invasive prediction of toxicants exposure. We identified and validated characteristic miRNA expression profiles of human whole blood in workers exposed to volatile organic compounds (VOCs) and compared the usefulness of miRNA indicator of VOCs with the effectiveness of the already used urinary biomarkers of occupational exposure. Using a microarray based approach we screened and detected deregulated miRNAs in their expression in workers exposed to VOCs (toluene [TOL], xylene [XYL] and ethylbenzene [EBZ]). Total 169 workers from four dockyards were enrolled in current study, and 50 subjects of them were used for miRNA microarray analysis. We identified 467 miRNAs for TOL, 211 miRNAs for XYL, and 695 miRNAs for XYL as characteristic discernible exposure indicator, which could discerned each VOC from the control group with higher accuracy, sensitivity, and specificity than urinary biomarkers. Current observations from this study point out that the altered levels of circulating miRNAs can be a reliable novel, minimally invasive biological indicator of occupational exposure to VOCs. Copyright © 2015 Elsevier GmbH. All rights reserved.

A metabolomics-driven approach to predict cocoa product consumption by designing a multimetabolite biomarker model in free-living subjects from the PREDIMED study.

PubMed

Garcia-Aloy, Mar; Llorach, Rafael; Urpi-Sarda, Mireia; Jáuregui, Olga; Corella, Dolores; Ruiz-Canela, Miguel; Salas-Salvadó, Jordi; Fitó, Montserrat; Ros, Emilio; Estruch, Ramon; Andres-Lacueva, Cristina

2015-02-01

The aim of the current study was to apply an untargeted metabolomics strategy to characterize a model of cocoa intake biomarkers in a free-living population. An untargeted HPLC-q-ToF-MS based metabolomics approach was applied to human urine from 32 consumers of cocoa or derived products (CC) and 32 matched control subjects with no consumption of cocoa products (NC). The multivariate statistical analysis (OSC-PLS-DA) showed clear differences between CC and NC groups. The discriminant biomarkers identified were mainly related to the metabolic pathways of theobromine and polyphenols, as well as to cocoa processing. Consumption of cocoa products was also associated with reduced urinary excretions of methylglutarylcarnitine, which could be related to effects of cocoa exposure on insulin resistance. To improve the prediction of cocoa consumption, a combined urinary metabolite model was constructed. ROC curves were performed to evaluate the model and individual metabolites. The AUC values (95% CI) for the model were 95.7% (89.8-100%) and 92.6% (81.9-100%) in training and validation sets, respectively, whereas the AUCs for individual metabolites were <90%. The metabolic signature of cocoa consumption in free-living subjects reveals that combining different metabolites as biomarker models improves prediction of dietary exposure to cocoa. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

High-performance liquid chromatographic method for profiling 2-oxo acids in urine and its application in evaluating vitamin status in rats.

PubMed

Shibata, Katsumi; Nakata, Chifumi; Fukuwatari, Tsutomu

2016-01-01

B-group vitamins are involved in the catabolism of 2-oxo acids. To identify the functional biomarkers of B-group vitamins, we developed a high-performance liquid chromatographic method for profiling 2-oxo acids in urine and applied this method to urine samples from rats deficient in vitamins B1 and B6 and pantothenic acid. 2-Oxo acids were reacted with 1,2-diamino-4,5-methylenebenzene to produce fluorescent derivatives, which were then separated using a TSKgel ODS-80Ts column with 30 mmol/L of KH2PO4 (pH 3.0):acetonitrile (7:3) at a flow rate of 1.0 mL/min. Vitamin B1 deficiency increased urinary levels of all 2-oxo acids, while vitamin B6 deficiency only increased levels of sum of 2-oxaloacetic acid and pyruvic acid, and pantothenic acid deficiency only increased levels of 2-oxoisovaleric acid. Profiles of 2-oxo acids in urine samples might be a non-invasive way of clarifying the functional biomarker of B-group vitamins.

Urine and plasma metabolomics study on potential hepatoxic biomarkers identification in rats induced by Gynura segetum.

PubMed

Qiu, Shoubei; Zhang, Haixia; Fei, Qianqian; Zhu, Fenxia; Wang, Jing; Jia, Xiaobin; Chen, Bin

2018-04-24

Gynura segetum (GS) is an herbal medicine containing Pyrrolizidine Alkaloids (PAs) that causes hepatic sinusoidal obstruction syndrome (HSOS). To discover potential biomarkers and metabolic mechanisms involved in the hepatotoxicity induced by GS. SD rats were randomly divided into 4 groups including Saline, the decoction of GS high, medium and low dosage at dosages of 3.75g • kg -1 , 7.5g • kg -1 and 15g • kg -1 . A metabolomics approach using Ultraperformance Liquid Chromatography -Quadrupole-Time-of-Flight / Mass Spectrometry (UPLC-Q-TOF/MS) was developed to perform the plasma and urinary metabolic profiling analysis, and identified differential metabolites by comparing the saline control group and decoction of GS groups. The herbal was presented dosage-dependent led to ingravescence of hepatotoxicity after the rats were consecutively given with the decoction of GS at varied dosages. A total of 18 differential metabolites of decoction of GS-induced hepatotoxicity were identified, while 10 of them including arginine, proline, glutamate, creatine, valine, linoleic acid, arachidonic acid, sphinganine, phytosphingosine, and citric acid could be discovered in urine and plasma, and primarily involved in Amino acid metabolism, Lipids metabolism and Energy metabolism. The results suggested that the differential metabolites of arginine, creatine, valine, glutamine and citric acid were verified as potential markers of GS-induced hepatotoxicity via the regulation of multiple metabolic pathways primarily involving in Amino acids metabolism and Energy metabolism. Copyright © 2018 Elsevier B.V. All rights reserved.

Assessing the metabolic effects of calcineurin inhibitors in renal transplant recipients by urine metabolic profiling.

PubMed

Diémé, Binta; Halimi, Jean Michel; Emond, Patrick; Büchler, Matthias; Nadal-Desbarat, Lydie; Blasco, Hélène; Le Guellec, Chantal

2014-07-27

Biomarkers that can predict graft function and/or renal side effects of calcineurin inhibitors (CNI) at each stage of treatment in kidney transplantation are still lacking. We report the first untargeted GC-MS-based metabolomic study on urines of renal transplant patients. This approach would bring insight in biomarkers useable for graft function monitoring. All consecutive patients receiving a kidney allograft in our transplantation department over a 6-month period were prospectively included and followed up for 12 months. We collected urine samples on the seventh day (D7) after transplantation, then at month 3 (M3) and month 12 (M12), and obtained mass-spectrometry-based urinary metabolic profiles. Multivariate analyses were conducted to compare metabolic profiles at the 3 different periods and to assess potential differences between cyclosporine and tacrolimus. Differences in metabolic signatures were also assessed according to graft function at D7 and renal function at M3 and M12. The urinary metabolic patterns varied over time in cyclosporine- and tacrolimus-treated patients and were somewhat different at D7, M3, and M12 between the 2 treatment groups. Principal metabolites that differed, regardless of the treatment used, were mainly sugars, inositol, and hippuric acid. Interestingly, among tacrolimus-treated patients, different metabolic signatures were found between patients with immediate or delayed graft function at D7. Urinary metabolomics represents a noninvasive way of monitoring immunosuppressive therapy in renal transplant patients. Although it is too early to consider it as a biomarker of CNI-induced injury or graft function, metabolomics appears a promising evaluation tool in this area.

Urinary biomarkers predict advanced acute kidney injury after cardiovascular surgery.

PubMed

Wang, Jian-Jhong; Chi, Nai-Hsin; Huang, Tao-Min; Connolly, Rory; Chen, Liang Wen; Chueh, Shih-Chieh Jeff; Kan, Wei-Chih; Lai, Chih-Cheng; Wu, Vin-Cent; Fang, Ji-Tseng; Chu, Tzong-Shinn; Wu, Kwan-Dun

2018-04-26

Acute kidney injury (AKI) after cardiovascular surgery is a serious complication. Little is known about the ability of novel biomarkers in combination with clinical risk scores for prediction of advanced AKI. In this prospectively conducted multicenter study, urine samples were collected from 149 adults at 0, 3, 6, 12 and 24 h after cardiovascular surgery. We measured urinary hemojuvelin (uHJV), kidney injury molecule-1 (uKIM-1), neutrophil gelatinase-associated lipocalin (uNGAL), α-glutathione S-transferase (uα-GST) and π-glutathione S-transferase (uπ-GST). The primary outcome was advanced AKI, under the definition of Kidney Disease: Improving Global Outcomes (KDIGO) stage 2, 3 and composite outcomes were KDIGO stage 2, 3 or 90-day mortality after hospital discharge. Patients with advanced AKI had significantly higher levels of uHJV and uKIM-1 at 3, 6 and 12 h after surgery. When normalized by urinary creatinine level, uKIM-1 in combination with uHJV at 3 h post-surgery had a high predictive ability for advanced AKI and composite outcome (AUC = 0.898 and 0.905, respectively). The combination of this biomarker panel (normalized uKIM-1, uHJV at 3 h post-operation) and Liano's score was superior in predicting advanced AKI (AUC = 0.931, category-free net reclassification improvement of 1.149, and p <  0.001). When added to Liano's score, normalized uHJV and uKIM-1 levels at 3 h after cardiovascular surgery enhanced the identification of patients at higher risk of progression to advanced AKI and composite outcomes.

Metabolomics study of human urinary metabolome modifications after intake of almond (Prunus dulcis (Mill.) D.A. Webb) skin polyphenols.

PubMed

Llorach, Rafael; Garrido, Ignacio; Monagas, Maria; Urpi-Sarda, Mireia; Tulipani, Sara; Bartolome, Begona; Andres-Lacueva, Cristina

2010-11-05

Almond, as a part of the nut family, is an important source of biological compounds, and specifically, almond skins have been considered an important source of polyphenols, including flavan-3-ols and flavonols. Polyphenol metabolism may produce several classes of metabolites that could often be more biologically active than their dietary precursor and could also become a robust new biomarker of almond polyphenol intake. In order to study urinary metabolome modifications during the 24 h after a single dose of almond skin extract, 24 volunteers (n = 24), who followed a polyphenol-free diet for 48 h before and during the study, ingested a dietary supplement of almond skin phenolic compounds (n = 12) or a placebo (n = 12). Urine samples were collected before ((-2)-0 h) and after (0-2 h, 2-6 h, 6-10 h, and 10-24 h) the intake and were analyzed by liquid chromatography-mass spectrometry (LC-q-TOF) and multivariate statistical analysis (principal component analysis (PCA) and orthogonal projection to latent structures (OPLS)). Putative identification of relevant biomarkers revealed a total of 34 metabolites associated with the single dose of almond extract, including host and, in particular, microbiota metabolites. As far as we know, this is the first time that conjugates of hydroxyphenylvaleric, hydroxyphenylpropionic, and hydroxyphenylacetic acids have been identified in human samples after the consumption of flavan-3-ols through a metabolomic approach. The results showed that this non-targeted approach could provide new intake biomarkers, contributing to the development of the food metabolome as an important part of the human urinary metabolome.

Identification of Urinary Polyphenol Metabolite Patterns Associated with Polyphenol-Rich Food Intake in Adults from Four European Countries.

PubMed

Noh, Hwayoung; Freisling, Heinz; Assi, Nada; Zamora-Ros, Raul; Achaintre, David; Affret, Aurélie; Mancini, Francesca; Boutron-Ruault, Marie-Christine; Flögel, Anna; Boeing, Heiner; Kühn, Tilman; Schübel, Ruth; Trichopoulou, Antonia; Naska, Androniki; Kritikou, Maria; Palli, Domenico; Pala, Valeria; Tumino, Rosario; Ricceri, Fulvio; Santucci de Magistris, Maria; Cross, Amanda; Slimani, Nadia; Scalbert, Augustin; Ferrari, Pietro

2017-07-25

We identified urinary polyphenol metabolite patterns by a novel algorithm that combines dimension reduction and variable selection methods to explain polyphenol-rich food intake, and compared their respective performance with that of single biomarkers in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The study included 475 adults from four European countries (Germany, France, Italy, and Greece). Dietary intakes were assessed with 24-h dietary recalls (24-HDR) and dietary questionnaires (DQ). Thirty-four polyphenols were measured by ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS-MS) in 24-h urine. Reduced rank regression-based variable importance in projection (RRR-VIP) and least absolute shrinkage and selection operator (LASSO) methods were used to select polyphenol metabolites. Reduced rank regression (RRR) was then used to identify patterns in these metabolites, maximizing the explained variability in intake of pre-selected polyphenol-rich foods. The performance of RRR models was evaluated using internal cross-validation to control for over-optimistic findings from over-fitting. High performance was observed for explaining recent intake (24-HDR) of red wine ( r = 0.65; AUC = 89.1%), coffee ( r = 0.51; AUC = 89.1%), and olives ( r = 0.35; AUC = 82.2%). These metabolite patterns performed better or equally well compared to single polyphenol biomarkers. Neither metabolite patterns nor single biomarkers performed well in explaining habitual intake (as reported in the DQ) of polyphenol-rich foods. This proposed strategy of biomarker pattern identification has the potential of expanding the currently still limited list of available dietary intake biomarkers.

Flow Cytometric Quantification of Peripheral Blood Cell β-Adrenergic Receptor Density and Urinary Endothelial Cell-Derived Microparticles in Pulmonary Arterial Hypertension.

PubMed

Rose, Jonathan A; Wanner, Nicholas; Cheong, Hoi I; Queisser, Kimberly; Barrett, Patrick; Park, Margaret; Hite, Corrine; Naga Prasad, Sathyamangla V; Erzurum, Serpil; Asosingh, Kewal

2016-01-01

Pulmonary arterial hypertension (PAH) is a heterogeneous disease characterized by severe angiogenic remodeling of the pulmonary artery wall and right ventricular hypertrophy. Thus, there is an increasing need for novel biomarkers to dissect disease heterogeneity, and predict treatment response. Although β-adrenergic receptor (βAR) dysfunction is well documented in left heart disease while endothelial cell-derived microparticles (Ec-MPs) are established biomarkers of angiogenic remodeling, methods for easy large clinical cohort analysis of these biomarkers are currently absent. Here we describe flow cytometric methods for quantification of βAR density on circulating white blood cells (WBC) and Ec-MPs in urine samples that can be used as potential biomarkers of right heart failure in PAH. Biotinylated β-blocker alprenolol was synthesized and validated as a βAR specific probe that was combined with immunophenotyping to quantify βAR density in circulating WBC subsets. Ec-MPs obtained from urine samples were stained for annexin-V and CD144, and analyzed by a micro flow cytometer. Flow cytometric detection of alprenolol showed that βAR density was decreased in most WBC subsets in PAH samples compared to healthy controls. Ec-MPs in urine was increased in PAH compared to controls. Furthermore, there was a direct correlation between Ec-MPs and Tricuspid annular plane systolic excursion (TAPSE) in PAH patients. Therefore, flow cytometric quantification of peripheral blood cell βAR density and urinary Ec-MPs may be useful as potential biomarkers of right ventricular function in PAH.

Flow Cytometric Quantification of Peripheral Blood Cell β-Adrenergic Receptor Density and Urinary Endothelial Cell-Derived Microparticles in Pulmonary Arterial Hypertension

PubMed Central

Rose, Jonathan A.; Wanner, Nicholas; Cheong, Hoi I.; Queisser, Kimberly; Barrett, Patrick; Park, Margaret; Hite, Corrine; Naga Prasad, Sathyamangla V.; Erzurum, Serpil; Asosingh, Kewal

2016-01-01

Pulmonary arterial hypertension (PAH) is a heterogeneous disease characterized by severe angiogenic remodeling of the pulmonary artery wall and right ventricular hypertrophy. Thus, there is an increasing need for novel biomarkers to dissect disease heterogeneity, and predict treatment response. Although β-adrenergic receptor (βAR) dysfunction is well documented in left heart disease while endothelial cell-derived microparticles (Ec-MPs) are established biomarkers of angiogenic remodeling, methods for easy large clinical cohort analysis of these biomarkers are currently absent. Here we describe flow cytometric methods for quantification of βAR density on circulating white blood cells (WBC) and Ec-MPs in urine samples that can be used as potential biomarkers of right heart failure in PAH. Biotinylated β-blocker alprenolol was synthesized and validated as a βAR specific probe that was combined with immunophenotyping to quantify βAR density in circulating WBC subsets. Ec-MPs obtained from urine samples were stained for annexin-V and CD144, and analyzed by a micro flow cytometer. Flow cytometric detection of alprenolol showed that βAR density was decreased in most WBC subsets in PAH samples compared to healthy controls. Ec-MPs in urine was increased in PAH compared to controls. Furthermore, there was a direct correlation between Ec-MPs and Tricuspid annular plane systolic excursion (TAPSE) in PAH patients. Therefore, flow cytometric quantification of peripheral blood cell βAR density and urinary Ec-MPs may be useful as potential biomarkers of right ventricular function in PAH. PMID:27270458

Lead concentration in plasma as a biomarker of exposure and risk, and modification of toxicity by δ-aminolevulinic acid dehydratase gene polymorphism.

PubMed

Tian, Liting; Zheng, Guang; Sommar, Johan Nilsson; Liang, Yihuai; Lundh, Tomas; Broberg, Karin; Lei, Lijian; Guo, Weijun; Li, Yulan; Tan, Mingguang; Skerfving, Staffan; Jin, Taiyi; Bergdahl, Ingvar A

2013-08-14

Blood lead concentration (B-Pb), the main biomarker of lead exposure and risk, is curvi-linearily related to exposure. We assessed plasma lead (P-Pb) as a marker for both lead exposure and toxic effects. We examined claims that δ-aminolevulinic acid dehydratase genotype (ALAD) can modify lead toxicity. In 290 lead-exposed and 91 unexposed Chinese workers, we determined P-Pb, B-Pb, urinary lead (U-Pb), ALAD polymorphism (rs1800435, ALAD1/2; TaqMan assay), and also toxic effects on heme synthesis (blood zinc protoporphyrin and hemoglobin, urinary δ-aminolevulic acid), on the kidneys (urinary albumin, β2-microglobulin and N-acetyl-β-d-glucosaminidase) and on the peripheral nervous system (sensory and motor conduction velocities). In exposed workers, median P-Pb was 4.10 (range 0.35-27)μg/L, B-Pb 401 (110-950)μg/L, and U-Pb 188 (22-590)μg/g creatinine. P-Pb had a higher ratio between exposed and unexposed workers (median 39, range 18-110) than B-Pb (19, 15-36; p<0.001) and U-Pb (28, 15-36; p<0.001). All three biomarkers were associated with all toxic effects (P-Pb: rS=-0.10 to 0.79; B-Pb: rS=-0.08 to 0.75; all p<0.05). In the exposed workers, B-Pb and U-Pb were significantly higher (p=0.04) in ALAD2 carriers (7% in the exposed population) than in ALAD1 homozygotes. P-Pb values were similar; ALAD1 homozygotes suffered higher kidney toxicity at the same P-Pb. (i) P-Pb has advantages over B-Pb as a biomarker of high Pb exposure, but it was not significantly better as an index of risk of toxicity. (ii) The ALAD genotype modifies toxicokinetics and toxicodynamics. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Pharmacogenomic Variants May Influence the Urinary Excretion of Novel Kidney Injury Biomarkers in Patients Receiving Cisplatin.

PubMed

Chang, Cara; Hu, Yichun; Hogan, Susan L; Mercke, Nickie; Gomez, Madeleine; O'Bryant, Cindy; Bowles, Daniel W; George, Blessy; Wen, Xia; Aleksunes, Lauren M; Joy, Melanie S

2017-06-22

Nephrotoxicity is a dose limiting side effect associated with the use of cisplatin in the treatment of solid tumors. The degree of nephrotoxicity is dictated by the selective accumulation of cisplatin in renal tubule cells due to: (1) uptake by organic cation transporter 2 (OCT2) and copper transporter 1 (CTR1); (2) metabolism by glutathione S-transferases (GSTs) and γ-glutamyltransferase 1 (GGT1); and (3) efflux by multidrug resistance-associated protein 2 (MRP2) and multidrug and toxin extrusion protein 1 (MATE1). The purpose of this study was to determine the significance of single nucleotide polymorphisms that regulate the expression and function of transporters and metabolism genes implicated in development of acute kidney injury (AKI) in cisplatin treated patients. Changes in the kidney function were assessed using novel urinary protein biomarkers and traditional markers. Genotyping was conducted by the QuantStudio 12K Flex Real-Time PCR System using a custom open array chip with metabolism, transport, and transcription factor polymorphisms of interest to cisplatin disposition and toxicity. Traditional and novel biomarker assays for kidney toxicity were assessed for differences according to genotype by ANOVA. Allele and genotype frequencies were determined based on Caucasian population frequencies. The polymorphisms rs596881 ( SLC22A2 /OCT2), and rs12686377 and rs7851395 ( SLC31A1 /CTR1) were associated with renoprotection and maintenance of estimated glomerular filtration rate (eGFR). Polymorphisms in SLC22A2 /OCT2, SLC31A1 /CTRI, SLC47A1 /MATE1, ABCC2 /MRP2, and GSTP1 were significantly associated with increases in the urinary excretion of novel AKI biomarkers: KIM-1, TFF3, MCP1, NGAL, clusterin, cystatin C, and calbindin. Knowledge concerning which genotypes in drug transporters are associated with cisplatin-induced nephrotoxicity may help to identify at-risk patients and initiate strategies, such as using lower or fractionated cisplatin doses or avoiding cisplatin altogether, in order to prevent AKI.

The endothelial lipase protein is promising urinary biomarker for diagnosis of gastric cancer.

PubMed

Dong, Xueyan; Wang, Guoqing; Zhang, Guoqing; Ni, Zhaohui; Suo, Jian; Cui, Juan; Cui, Ai; Yang, Qing; Xu, Ying; Li, Fan

2013-03-19

Gastric cancer is one of the most common malignant tumors in the world. Finding effective diagnostic biomarkers in urine or serum would represent the most ideal solution to detecting gastric cancer during annual physical examination. This study was to evaluate the potential of endothelial lipase (EL) as a urinary biomarker for diagnosis of gastric cancer. The expression levels of EL was measured using Western blotting and immunohistochemical staining experiments on (tissue, serum, and urine) samples of gastric cancer patients versus healthy people. We also checked the EL levels in the urine samples of other cancer types (lung, colon and rectum cancers) and benign lesions (gastritis and gastric leiomyoma) to check if EL was specific to gastric cancer. We observed a clear separation between the EL expression levels in the urine samples of 90 gastric cancer patients and of 57 healthy volunteers. It was approximately 9.9 fold average decrease of the EL expression levels in the urine samples of gastric cancer compared to the healthy controls (P <0.0001), achieving a 0.967 AUC value for the ROC (receiver operating characteristic) curve, demonstrating it's highly accurate as a diagnostic marker for gastric cancer. Interestingly, the expression levels of EL in tissue and serum samples were not nearly as discriminative as in urine samples (P = 0.90 and P = 0.79). In immunohistochemical experiments, positive expression of the EL protein was found in 67% (8/12) of gastric adjacent noncancerous and in 58% (7/12) of gastric cancer samples. There was no significant statistical in the expression levels of this protein between the gastric cancer and the matching noncancerous tissues (P =0.67). The urinary EL as a highly accurate gastric cancer biomarker that is potentially applicable to the general screening with high sensitivity and specificity. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/4527331618757552.

The endothelial lipase protein is promising urinary biomarker for diagnosis of gastric cancer

PubMed Central

2013-01-01

Background Gastric cancer is one of the most common malignant tumors in the world. Finding effective diagnostic biomarkers in urine or serum would represent the most ideal solution to detecting gastric cancer during annual physical examination. This study was to evaluate the potential of endothelial lipase (EL) as a urinary biomarker for diagnosis of gastric cancer. Methods The expression levels of EL was measured using Western blotting and immunohistochemical staining experiments on (tissue, serum, and urine) samples of gastric cancer patients versus healthy people. We also checked the EL levels in the urine samples of other cancer types (lung, colon and rectum cancers) and benign lesions (gastritis and gastric leiomyoma) to check if EL was specific to gastric cancer. Result We observed a clear separation between the EL expression levels in the urine samples of 90 gastric cancer patients and of 57 healthy volunteers. It was approximately 9.9 fold average decrease of the EL expression levels in the urine samples of gastric cancer compared to the healthy controls (P <0.0001), achieving a 0.967 AUC value for the ROC (receiver operating characteristic) curve, demonstrating it’s highly accurate as a diagnostic marker for gastric cancer. Interestingly, the expression levels of EL in tissue and serum samples were not nearly as discriminative as in urine samples (P = 0.90 and P = 0.79). In immunohistochemical experiments, positive expression of the EL protein was found in 67% (8/12) of gastric adjacent noncancerous and in 58% (7/12) of gastric cancer samples. There was no significant statistical in the expression levels of this protein between the gastric cancer and the matching noncancerous tissues (P =0.67). Conclusions The urinary EL as a highly accurate gastric cancer biomarker that is potentially applicable to the general screening with high sensitivity and specificity. Virtual Slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/4527331618757552 PMID:23510199

Crowdsourcing Disease Biomarker Discovery Research: The IP4IC Study.

PubMed

Chancellor, Michael B; Bartolone, Sarah N; Veerecke, Andrew; Lamb, Laura E

2018-05-01

Biomarker discovery is limited by readily assessable, cost efficient human samples available in large numbers that represent the entire heterogeneity of the disease. We developed a novel, active participation crowdsourcing method to determine BP-RS (Bladder Permeability Defect Risk Score). It is based on noninvasive urinary cytokines to discriminate patients with interstitial cystitis/bladder pain syndrome who had Hunner lesions from controls and patients with interstitial cystitis/bladder pain syndrome but without Hunner lesions. We performed a national crowdsourcing study in cooperation with the Interstitial Cystitis Association. Patients answered demographic, symptom severity and urinary frequency questionnaires on a HIPAA (Health Insurance Portability and Accountability Act) compliant website. Urine samples were collected at home, stabilized with a preservative and sent to Beaumont Hospital for analysis. The expression of 3 urinary cytokines was used in a machine learning algorithm to develop BP-RS. The IP4IC study collected a total of 448 urine samples, representing 153 patients (147 females and 6 males) with interstitial cystitis/bladder pain syndrome, of whom 54 (50 females and 4 males) had Hunner lesions. A total of 159 female and 136 male controls also participated, who were age matched. A defined BP-RS was calculated to predict interstitial cystitis/bladder pain syndrome with Hunner lesions or a bladder permeability defect etiology with 89% validity. In this novel participation crowdsourcing study we obtained a large number of urine samples from 46 states, which were collected at home, shipped and stored at room temperature. Using a machine learning algorithm we developed BP-RS to quantify the risk of interstitial cystitis/bladder pain syndrome with Hunner lesions, which is indicative of a bladder permeability defect etiology. To our knowledge BP-RS is the first validated urine biomarker assay for interstitial cystitis/bladder pain syndrome and one of the first biomarker assays to be developed using crowdsourcing. Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Urinary 1-Hydroxypyrene as a Biomarker to Carcinogenic Polycyclic Aromatic Hydrocarbon Exposure

PubMed Central

Ifegwu, Clinton; Osunjaye, Kayode; Fashogbon, Folasade; Oke, Kolawole; Adeniyi, Afolabi; Anyakora, Chimezie

2012-01-01

In order to capture the extent of exposure to polycyclic aromatic hydrocarbons (PAHs), various biomarkers have been employed. The biomarkers employed for PAHs include PAHs genetoxic end points in lymphocytes, urinary metabolites, PAH-DNA adducts, and PAH-Protein adducts. Of these, excretory 1-hydroxypyene, a metabolite of pyrene, has been used extensively as a biological monitoring indicator of exposure to PAHs. This study attempts to assess the level of this biomarker in the body fluid of 68 exposed subjects using high performance liquid chromatography HPLC. The subjects screened included auto mechanics, drivers, and fuel attendants. 1-hydroxypyrene was extracted from the urine of the subjects using solid phase extraction method. The HPLC analysis was done in isocratic mode using water:methanol (12:88 v/v) mobile phase. The stationary phase was XBridge C18 (150 × 4.6 mm) 5 μm column. The wavelength was 250 nm at a flow rate of 1.2 mL/min. The oven temperature was 30 ºC and the injection volume was 20 μL. The run time was 3 minutes. The level of urinary 1-hydroxypyrene detected varied for the different categories of occupation studied. About 27% of sampled fuel attendants and 22% of auto mechanics had detectable 1-hydroxypyrene in their urine samples. There was no detectable 1-hydroxypyene in the urine samples of commercial drivers or in the urine samples of students used as controls. The results of this study showed that fuel attendants and auto mechanics have significant exposures to PAHs. So far, there is no established benchmark for level of PAHs in urine, but our findings indicate the possibility of future cancer cases in this population as a result of their occupational exposure. The study was not able to link the level of 1-hydroxypyene with the smoking habits of the subjects. PMID:24179391

Urinary 1-hydroxypyrene as a biomarker to carcinogenic polycyclic aromatic hydrocarbon exposure.

PubMed

Ifegwu, Clinton; Osunjaye, Kayode; Fashogbon, Folasade; Oke, Kolawole; Adeniyi, Afolabi; Anyakora, Chimezie

2012-01-01

In order to capture the extent of exposure to polycyclic aromatic hydrocarbons (PAHs), various biomarkers have been employed. The biomarkers employed for PAHs include PAHs genetoxic end points in lymphocytes, urinary metabolites, PAH-DNA adducts, and PAH-Protein adducts. Of these, excretory 1-hydroxypyene, a metabolite of pyrene, has been used extensively as a biological monitoring indicator of exposure to PAHs. This study attempts to assess the level of this biomarker in the body fluid of 68 exposed subjects using high performance liquid chromatography HPLC. The subjects screened included auto mechanics, drivers, and fuel attendants. 1-hydroxypyrene was extracted from the urine of the subjects using solid phase extraction method. The HPLC analysis was done in isocratic mode using water:methanol (12:88 v/v) mobile phase. The stationary phase was XBridge C18 (150 × 4.6 mm) 5 μm column. The wavelength was 250 nm at a flow rate of 1.2 mL/min. The oven temperature was 30 ºC and the injection volume was 20 μL. The run time was 3 minutes. The level of urinary 1-hydroxypyrene detected varied for the different categories of occupation studied. About 27% of sampled fuel attendants and 22% of auto mechanics had detectable 1-hydroxypyrene in their urine samples. There was no detectable 1-hydroxypyene in the urine samples of commercial drivers or in the urine samples of students used as controls. The results of this study showed that fuel attendants and auto mechanics have significant exposures to PAHs. So far, there is no established benchmark for level of PAHs in urine, but our findings indicate the possibility of future cancer cases in this population as a result of their occupational exposure. The study was not able to link the level of 1-hydroxypyene with the smoking habits of the subjects.

Pharmacogenomic Variants May Influence the Urinary Excretion of Novel Kidney Injury Biomarkers in Patients Receiving Cisplatin

PubMed Central

Chang, Cara; Hu, Yichun; Hogan, Susan L.; Mercke, Nickie; Gomez, Madeleine; O’Bryant, Cindy; Bowles, Daniel W.; George, Blessy; Wen, Xia; Aleksunes, Lauren M.; Joy, Melanie S.

2017-01-01

Nephrotoxicity is a dose limiting side effect associated with the use of cisplatin in the treatment of solid tumors. The degree of nephrotoxicity is dictated by the selective accumulation of cisplatin in renal tubule cells due to: (1) uptake by organic cation transporter 2 (OCT2) and copper transporter 1 (CTR1); (2) metabolism by glutathione S-transferases (GSTs) and γ-glutamyltransferase 1 (GGT1); and (3) efflux by multidrug resistance-associated protein 2 (MRP2) and multidrug and toxin extrusion protein 1 (MATE1). The purpose of this study was to determine the significance of single nucleotide polymorphisms that regulate the expression and function of transporters and metabolism genes implicated in development of acute kidney injury (AKI) in cisplatin treated patients. Changes in the kidney function were assessed using novel urinary protein biomarkers and traditional markers. Genotyping was conducted by the QuantStudio 12K Flex Real-Time PCR System using a custom open array chip with metabolism, transport, and transcription factor polymorphisms of interest to cisplatin disposition and toxicity. Traditional and novel biomarker assays for kidney toxicity were assessed for differences according to genotype by ANOVA. Allele and genotype frequencies were determined based on Caucasian population frequencies. The polymorphisms rs596881 (SLC22A2/OCT2), and rs12686377 and rs7851395 (SLC31A1/CTR1) were associated with renoprotection and maintenance of estimated glomerular filtration rate (eGFR). Polymorphisms in SLC22A2/OCT2, SLC31A1/CTRI, SLC47A1/MATE1, ABCC2/MRP2, and GSTP1 were significantly associated with increases in the urinary excretion of novel AKI biomarkers: KIM-1, TFF3, MCP1, NGAL, clusterin, cystatin C, and calbindin. Knowledge concerning which genotypes in drug transporters are associated with cisplatin-induced nephrotoxicity may help to identify at-risk patients and initiate strategies, such as using lower or fractionated cisplatin doses or avoiding cisplatin altogether, in order to prevent AKI. PMID:28640195

Klotho and S100A8/A9 as Discriminative Markers between Pre-Renal and Intrinsic Acute Kidney Injury

PubMed Central

Kim, Ae Jin; Ro, Han; Kim, Hyunsook; Chang, Jae Hyun; Lee, Hyun Hee; Chung, Wookyung; Jung, Ji Yong

2016-01-01

Early detection and accurate differentiation of the cause of AKI may improve the prognosis of the patient. However, to date, there are few reliable biomarkers that can discriminate between pre-renal and intrinsic AKI. In this study, we determined whether AKI is associated with altered serum and urinary levels of Klotho, S100A8/A9 (an endogenous ligand of toll-like receptor 4), and neutrophil gelatinase-associated lipocalin (NGAL), which may allow differentiation between pre-renal and intrinsic AKI. A volume-depleted pre-renal AKI model was induced in male Sprague Dawley rats fed a low-salt diet (0.03%) without water 96 h before two intraperitoneal (IP) injections of furosemide (20 mg/kg) at a 24 h interval. In contrast, in the cisplatin-induced intrinsic AKI model, animals were given a single IP injection of cisplatin (5 mg/kg). All of the animals were euthanized 72 h after the first IP injection. Serum and urinary levels of Klotho, S100A8/A9, and NGAL were measured using an enzyme-linked immunosorbent assay. We also performed a proof-of-concept cross-sectional study to measure serum and urinary biomarkers in 61 hospitalized patients with established AKI. Compared to the intrinsic AKI group, the pre-renal AKI group showed a marked depression in urinary Klotho levels (13.21±17.32 vs. 72.97±17.96 pg/mL; P = 0.002). In addition, the intrinsic AKI group showed marked elevation of S100A8/A9 levels compared to the pre-renal AKI group (2629.97±598.05 ng/mL vs. 685.09±111.65 ng/mL; P = 0.002 in serum; 3361.11±250.86 ng/mL vs. 741.72±101.96 ng/mL; P = 0.003 in urine). There was no difference in serum and urinary NGAL levels between the pre-renal and intrinsic AKI groups. The proof-of-concept study with the hospitalized AKI patients also demonstrated decreased urinary Klotho in pre-renal AKI patients and increased urinary S100A8/A9 concentrations in intrinsic AKI patients. The attenuation of urinary Klotho and increase in urinary S100A8/A9 may allow differentiation between pre-renal and intrinsic AKI. PMID:26799323

Urinary and breast milk biomarkers to assess exposure to naphthalene in pregnant women: an investigation of personal and indoor air sources

PubMed Central

2014-01-01

Background Naphthalene exposures for most non-occupationally exposed individuals occur primarily indoors at home. Residential indoor sources include pest control products (specifically moth balls), incomplete combustion such as cigarette smoke, woodstoves and cooking, some consumer and building products, and emissions from gasoline sources found in attached garages. The study aim was to assess naphthalene exposure in pregnant women from Canada, using air measurements and biomarkers of exposure. Methods Pregnant women residing in Ottawa, Ontario completed personal and indoor air sampling, and questionnaires. During pregnancy, pooled urine voids were collected over two 24-hour periods on a weekday and a weekend day. At 2–3 months post-birth, they provided a spot urine sample and a breast milk sample following the 24-hour air monitoring. Urines were analyzed for 1-naphthol and 2-naphthol and breast milk for naphthalene. Simple linear regression models examined associations between known naphthalene sources, air and biomarker samples. Results Study recruitment rate was 11.2% resulting in 80 eligible women being included. Weekday and weekend samples were highly correlated for both personal (r = 0.83, p < 0.0001) and indoor air naphthalene (r = 0.91, p < 0.0001). Urine specific gravity (SG)-adjusted 2-naphthol concentrations collected on weekdays and weekends (r = 0.78, p < 0.001), and between pregnancy and postpartum samples (r = 0.54, p < 0.001) were correlated. Indoor and personal air naphthalene concentrations were significantly higher post-birth than during pregnancy (p < 0.0001 for signed rank tests); concurrent urine samples were not significantly different. Naphthalene in breast milk was associated with urinary 1-naphthol: a 10% increase in 1-naphthol was associated with a 1.6% increase in breast milk naphthalene (95% CI: 0.2%-3.1%). No significant associations were observed between naphthalene sources reported in self-administered questionnaires and the air or biomarker concentrations. Conclusions Median urinary concentrations of naphthalene metabolites tended to be similar to (1-naphthol) or lower (2-naphthol) than those reported in a Canadian survey of women of reproductive age. Only urinary 1-naphthol and naphthalene in breast milk were associated. Potential reasons for the lack of other associations include a lack of sources, varying biotransformation rates and behavioural differences over time. PMID:24767676

A pilot study of urinary fibroblast growth factor-2 and epithelial growth factor as potential biomarkers of acute kidney injury in critically ill children

PubMed Central

Wai, Kitman; Soler-García, Ángel A.; Perazzo, Sofia; Mattison, Parnell

2014-01-01

Background Acute kidney injury (AKI) increases the morbidity of critically ill children. Thus, it is necessary to identify better renal biomarkers to follow the outcome of these patients. This prospective case–control study explored the clinical value of a urinary biomarker profile comprised of neutrophil gelatinase lipocalin (uNGAL), fibroblast growth factor-2 (uFGF-2), and epidermal growth factor (uEGF) to follow these patients. Methods Urine samples were collected from 21 healthy children, and 39 critically ill children (mean age 7.5 years±6.97 SD) admitted to a pediatric intensive care unit with sepsis or requiring extra corporeal membrane oxygenation (ECMO). uNGAL, uFGF-2, and uEGF levels were measured using ELISA kits during the first 24 h of admission to PICU, at peak of illness, and upon resolution of the critical illness. Results On admission, the uNGAL and uFGF-2 levels were increased, and the uEGF levels were decreased, in critically ill children with AKI (n=19) compared to those without AKI (n=20), and healthy controls. A biomarker score using the combined cut-off values of uNGAL, uFGF-2, and uEGF (AUC=0.90) showed the highest specificity to identify children with AKI, relative to each biomarker alone. uNGAL and uFGF-2 on admission showed high sensitivity and specificity to predict mortality (AUC=0.82). Conclusions The biomarker profile comprised of uNGAL, uFGF-2, and uEGF increased the specificity to detect AKI in critically ill children, when compared to each biomarker used alone. uNGAL and uFGF-2 may also predict the risk of death. Further validation of these findings in a large sample size is warranted. PMID:23872928

A urinary peptide biomarker set predicts worsening of albuminuria in type 2 diabetes mellitus.

PubMed

Roscioni, S S; de Zeeuw, D; Hellemons, M E; Mischak, H; Zürbig, P; Bakker, S J L; Gansevoort, R T; Reinhard, H; Persson, F; Lajer, M; Rossing, P; Lambers Heerspink, H J

2013-02-01

Microalbuminuria is considered the first clinical sign of kidney dysfunction and is associated with a poor renal and cardiovascular prognosis in type 2 diabetes. Detection of patients who are prone to develop micro- or macroalbuminuria may represent an effective strategy to start or optimise therapeutic intervention. Here we assessed the value of a urinary proteomic-based risk score (classifier) in predicting the development and progression of microalbuminuria. We conducted a prospective case-control study. Cases (n = 44) and controls (n = 44) were selected from the PREVEND (Prevention of Renal and Vascular End-stage Disease) study and from the Steno Diabetes Center (Gentofte, Denmark). Cases were defined by transition from normo- to microalbuminuria or from micro- to macroalbuminuria over a follow-up of 3 years. Controls with no transitions in albuminuria were pair-matched for age, sex and albuminuria status. A model for the progression of albuminuria was built using a proteomic classifier based on 273 urinary peptides. The proteomic classifier was independently associated with transition to micro- or macroalbuminuria (OR 1.35 [95% CI 1.02, 1.79], p = 0.035). The classifier predicted the development and progression of albuminuria on top of albuminuria and estimated GFR (eGFR, area under the receiver operating characteristic [ROC] curve increase of 0.03, p = 0.002; integrated discrimination index [IDI]: 0.105, p = 0.002). Fragments of collagen and α-2-HS-glycoprotein showed significantly different expression between cases and controls. Although limited by the relatively small sample size, these results suggest that analysis of a urinary biomarker set enables early renal risk assessment in patients with diabetes. Further work is required to confirm the role of urinary proteomics in the prevention of renal failure in diabetes.

Simultaneous detection of six urinary pteridines and creatinine by high-performance liquid chromatography-tandem mass spectrometry for clinical breast cancer detection.

PubMed

Burton, Casey; Shi, Honglan; Ma, Yinfa

2013-11-19

Recent preliminary studies have implicated urinary pteridines as candidate biomarkers in a growing number of malignancies including breast cancer. While the developments of capillary electrophoresis-laser induced fluorescence (CE-LIF), high performance liquid chromatography (HPLC), and liquid chromatography-mass spectroscopy (LC-MS) pteridine urinalyses among others have helped to enable these findings, limitations including poor pteridine specificity, asynchronous or nonexistent renal dilution normalization, and a lack of information regarding adduct formation in mass spectrometry techniques utilizing electrospray ionization (ESI) have prevented application of these techniques to a larger clinical setting. In this study, a simple, rapid, specific, and sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method has been developed and optimized for simultaneous detection of six pteridines previously implicated in breast cancer and creatinine as a renal dilution factor in urine. In addition, this study reports cationic adduct formation of urinary pteridines under ESI-positive ionization for the first time. This newly developed technique separates and detects the following six urinary pteridines: 6-biopterin, 6-hydroxymethylpterin, d-neopterin, pterin, isoxanthopterin, and xanthopterin, as well as creatinine. The method detection limit for the pteridines is between 0.025 and 0.5 μg/L, and for creatinine, it is 0.15 μg/L. The method was also validated by spiked recoveries (81-105%), reproducibility (RSD: 1-6%), and application to 25 real urine samples from breast cancer positive and negative samples through a double-blind study. The proposed technique was finally compared directly with a previously reported CE-LIF technique, concluding that additional or alternative renal dilution factors are needed for proper investigation of urinary pteridines as breast cancer biomarkers.

Neutrophil Gelatinase-Associated Lipocalin Biomarker and Urinary Tract Infections: A Diagnostic Case-Control Study (NUTI Study).

PubMed

Price, Jameca Renee; Guran, Larissa; Lim, Jeong Youn; Megli, Christina J; Clark, Amanda L; Edwards, Sharon Renee; Denman, Mary Anna; Gregory, W Thomas

Acute uncomplicated urinary tract infection (UTI) in women is often treated based on symptoms alone. Urinary tract infection symptoms are highly sensitive but lack specificity and result in overuse of antibiotics. We sought to determine if urine neutrophil gelatinase-associated lipocalin (uNGAL) levels in urine can accurately discriminate between UTI and healthy women. We recruited adult women aged 18 to 85 years presenting in the ambulatory setting from November 2014 to January 2016. Cases were defined as women with Centers for Disease Control and Prevention-defined UTI symptoms and a positive urine culture of more than 10 organisms/mL on a midstream clean-catch specimen. Women without UTI symptoms were matched by age and menopausal status as control subjects. Exclusion criteria were no UTIs within 8 weeks, urinary tract anomalies, renal disease, pregnancy, or diabetes. Clean-catch urine samples were obtained for measuring uNGAL, prior to antibiotic treatment of cases. We used Mann-Whitney U test to compare the 2 groups. Receiver operating characteristic curves were plotted to compare the performance of uNGAL to established urinary markers. We enrolled 50 UTI cases and 50 control subjects. Urine NGAL levels were higher in the UTI group than in the control subjects (P < 0.0001). Using a cutoff of 23.9 ng/mL, NGAL achieved 98% sensitivity and 100% specificity. The receiver operating characteristic curve had an area under the curve of 0.97 (95% confidence interval, 0.93-1.00), which was significantly high and showed that uNGAL can identify UTI. Urine NGAL has the potential as a biomarker for diagnosing UTIs in adult women.

An association between urinary cadmium and urinary stone disease in persons living in cadmium-contaminated villages in northwestern Thailand: A population study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Swaddiwudhipong, Witaya, E-mail: swaddi@hotmail.com; Mahasakpan, Pranee; Limpatanachote, Pisit

Excessive urinary calcium excretion is the major risk of urinary stone formation. Very few population studies have been performed to determine the relationship between environmental cadmium exposure and urinary stone disease. This population-based study examined an association between urinary cadmium excretion, a good biomarker of long-term cadmium exposure, and prevalence of urinary stones in persons aged 15 years and older, who lived in the 12 cadmium-contaminated villages in the Mae Sot District, Tak Province, northwestern Thailand. A total of 6748 persons were interviewed and screened for urinary cadmium and urinary stone disease in 2009. To test a correlation between urinarymore » excretion of cadmium and calcium, we measured urinary calcium content in 1492 persons, who lived in 3 villages randomly selected from the 12 contaminated villages. The rate of urinary stones significantly increased from 4.3% among persons in the lowest quartile of urinary cadmium to 11.3% in the highest quartile. An increase in stone prevalence with increasing urinary cadmium levels was similarly observed in both genders. Multiple logistic regression analysis revealed a positive association between urinary cadmium levels and stone prevalence, after adjusting for other co-variables. The urinary calcium excretion significantly increased with increasing urinary cadmium levels in both genders, after adjusting for other co-variables. Elevated calciuria induced by cadmium might increase the risk of urinary stone formation in this environmentally exposed population. - Research highlights: {yields} Excessive calciuria is the major risk of urinary stone formation. {yields} We examine cadmium-exposed persons for urinary cadmium, calcium, and stones. {yields} The rate of urinary stones increases with increasing urinary cadmium. {yields} Urinary calcium excretion increases with increasing urinary cadmium. {yields} Elevated calciuria induced by cadmium may increase the risk of urinary stones.« less

Recent advances in recurrent urinary tract infection from pathogenesis and biomarkers to prevention

PubMed Central

Jhang, Jia-Fong; Kuo, Hann-Chorng

2017-01-01

Recurrent urinary tract infection (UTI) might be one of the most common problems in urological clinics. Recent research has revealed novel evidence about recurrent UTI and it should be considered a different disease from the first infection. The pathogenesis of recurrent UTI might include two mechanisms, bacterial factors and deficiencies in host defense. Bacterial survival in the urinary bladder after antibiotic treatment and progression to form intracellular bacterial communities might be the most important bacterial factors. In host defense deficiency, a defect in pathogen recognition and urothelial barrier function impairment play the most important roles. Immunodeficiency and urogenital tract anatomical abnormalities have been considered the essential risk factors for recurrent UTI. In healthy women, voiding dysfunction and behavioral factors also increase the risk of recurrent UTI. Sexual intercourse and estrogen deficiency in postmenopausal women might have the strongest association with recurrent UTI. Traditional lifestyle factors such as fluid intake and diet are not considered independent risk factors now. Serum and urine biomarkers to predict recurrent UTI from the first infection have also attracted a wide attention recently. Current clinical evidence suggests that serum macrophage colony-stimulating factor and urinary nerve growth factor have potential predictive value for recurrent UTI. Clinical trials have proven the efficacy of the oral immunoactive agent OM-89 for the prevention of UTI. Vaccines for recurrent UTI are recommended by the latest guidelines and are available on the market. PMID:28974905

Plasma asymmetric dimethylarginine (ADMA) levels in Mexican women exposed to polycyclic aromatic hydrocarbons (PAHs): A preliminary study.

PubMed

Pruneda-Alvarez, Lucía G; Ruíz-Vera, Tania; Ochoa-Martínez, Angeles C; Pérez-Vázquez, Francisco J; González Palomo, Ana K; Ilizaliturri-Hernández, Cesar A; Pérez-Maldonado, Iván N

2016-12-01

Recent studies indicate that exposure to environmental pollutants (as polycyclic aromatic hydrocarbons) is a very important risk factor for development of cardiovascular diseases (CVDs). Correspondingly, in recent times asymmetric dimethylarginine (ADMA) has been proposed as a new and meaningful biomarker predictor for the risk of CVDs. Therefore, the objective of this study was to evaluate plasma ADMA concentrations in Mexican women (n=155) exposed to polycyclic aromatic hydrocarbons (PAHs). Urinary 1-hydroxypyrene [(1-OHP), exposure biomarker for PAHs] levels were quantified using a high performance liquid chromatography (HPLC) technique and plasma ADMA concentrations were analyzed using a commercially available ELISA kit. Urinary 1-OHP levels in all women assessed ranged from

Association between Oxidative DNA Damage and Risk of Colorectal Cancer: Sensitive Determination of Urinary 8-Hydroxy-2′-deoxyguanosine by UPLC-MS/MS Analysis

PubMed Central

Guo, Cheng; Li, Xiaofen; Wang, Rong; Yu, Jiekai; Ye, Minfeng; Mao, Lingna; Zhang, Suzhan; Zheng, Shu

2016-01-01

Oxidative DNA damage plays crucial roles in the pathogenesis of numerous diseases including cancer. 8-hydroxy-2′-deoxyguanosine (8-OHdG) is the most representative product of oxidative modifications of DNA, and urinary 8-OHdG is potentially the best non-invasive biomarker of oxidative damage to DNA. Herein, we developed a sensitive, specific and accurate method for quantification of 8-OHdG in human urine. The urine samples were pretreated using off-line solid-phase extraction (SPE), followed by ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis. By the use of acetic acid as an additive to the mobile phase, we improved the UPLC-MS/MS detection of 8-OHdG by 2.7−5.3 times. Using the developed strategy, we measured the contents of 8-OHdG in urine samples from 142 healthy volunteers and 84 patients with colorectal cancer (CRC). We observed increased levels of urinary 8-OHdG in patients with CRC and patients with tumor metastasis, compared to healthy controls and patients without tumor metastasis, respectively. Additionally, logistic regression analysis and receiver operator characteristic (ROC) curve analysis were performed. Our findings implicate that oxidative stress plays important roles in the development of CRC and the marked increase of urinary 8-OHdG may serve as a potential liquid biomarker for the risk estimation, early warning and detection of CRC. PMID:27585556

Association between Oxidative DNA Damage and Risk of Colorectal Cancer: Sensitive Determination of Urinary 8-Hydroxy-2‧-deoxyguanosine by UPLC-MS/MS Analysis

NASA Astrophysics Data System (ADS)

Guo, Cheng; Li, Xiaofen; Wang, Rong; Yu, Jiekai; Ye, Minfeng; Mao, Lingna; Zhang, Suzhan; Zheng, Shu

2016-09-01

Oxidative DNA damage plays crucial roles in the pathogenesis of numerous diseases including cancer. 8-hydroxy-2‧-deoxyguanosine (8-OHdG) is the most representative product of oxidative modifications of DNA, and urinary 8-OHdG is potentially the best non-invasive biomarker of oxidative damage to DNA. Herein, we developed a sensitive, specific and accurate method for quantification of 8-OHdG in human urine. The urine samples were pretreated using off-line solid-phase extraction (SPE), followed by ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis. By the use of acetic acid as an additive to the mobile phase, we improved the UPLC-MS/MS detection of 8-OHdG by 2.7-5.3 times. Using the developed strategy, we measured the contents of 8-OHdG in urine samples from 142 healthy volunteers and 84 patients with colorectal cancer (CRC). We observed increased levels of urinary 8-OHdG in patients with CRC and patients with tumor metastasis, compared to healthy controls and patients without tumor metastasis, respectively. Additionally, logistic regression analysis and receiver operator characteristic (ROC) curve analysis were performed. Our findings implicate that oxidative stress plays important roles in the development of CRC and the marked increase of urinary 8-OHdG may serve as a potential liquid biomarker for the risk estimation, early warning and detection of CRC.

Dietary predictors of urinary environmental biomarkers in young girls, BCERP, 2004-7.

PubMed

Mervish, Nancy; McGovern, Kathleen J; Teitelbaum, Susan L; Pinney, Susan M; Windham, Gayle C; Biro, Frank M; Kushi, Lawrence H; Silva, Manori J; Ye, Xiaoyun; Calafat, Antonia M; Wolff, Mary S

2014-08-01

Exposures of children to phthalates, parabens, and bisphenol-A (BPA) are of concern because of their hormonal potential. These agents are found in a wide range of foods and packaging. We investigated whether intake of certain foods predict exposures to these chemicals in young girls. Among 1101 girls (6-8 years at enrollment) from the Breast Cancer and Environment Research Program (BCERP) study, we measured urinary exposure biomarkers for phthalates, parabens, and BPA and assessed dietary intake using 24-h recall 2-4 times. We examined the average daily servings of major and minor food groups categorized as 0 to <0.5, 0.5 to <1 and ≥ 1 servings per day. Items included dairy, eggs, fats, fish, fruit, single grains, meat, non-poultry meats, pasta, poultry and vegetables. Covariate-adjusted least squares geometric means and 95% confidence intervals of creatinine-corrected phthalate and phenol metabolite concentrations in urine were calculated in relation to food intake. Grains, flour and dry mixes and total fish consumption were positively associated with BPA and the sum of four di-2-ethylhexylphthalate (DEHP) urinary metabolite concentrations. Non-fresh vegetables and poultry were both positively associated with BPA and paraben urinary concentrations. Fats, oils and poultry consumption were positively associated with BPA. Whole-fat dairy consumption was associated with ΣDEHP. Some foods may contribute to child exposures to certain chemicals, and this may constitute modifiable means to reduce these environmental exposures. Copyright © 2014 Elsevier Inc. All rights reserved.

Ethion exposure and biological monitoring in vegetable farmers.

PubMed

Kongtip, Pornpimol; Changfuang, Sirinnapa; Yoosook, Witaya; Chantanakul, Suttinun; Sujirarat, Dusit

2011-03-01

To modify the method of analysis of urinary diethyl phosphate (DEP) in order to determine the relationship between atmospheric ethion concentration and urinary DEP concentration. A cross-sectional study was conducted by collecting atmospheric ethion in the breathing zone of 28 farmers following the NIOSH 5600 method. Urine samples were also collected to analyze urinary DEP concentrations by a modified method using a Gas Chromatography-Flame Photometric Detector (FPD). The average atmospheric ethion concentration in the breathing zone of farmers was 0.036 +/- 0.018 mg/m3. The average urinary DEP in pre-shift and post-shift was 0.030 +/- 0.06 and 0.851 +/- 1.80 mg/g of creatinine respectively. The average DEP during work shifts was 0.53 +/- 0.27, and ranged from 0.12 to 1.16 mg/g of creatinine. A high correlation coefficient (r = 0.645) was found between atmospheric ethion concentrations and urinary DEP concentrations at p < 0.001. The modified method provided a reliable result and the urinary DEP during work shifts was found to be a reliable biomarker of ethion exposure.

Tenofovir monotherapy for hepatitis B after 1 year does not produce renal dysfunction, but is associated with hyperparathyroidism not related to vitamin D.

PubMed

Patricio, Jose A; Lopes, Patricia F; Medeiros, Thalia; Mendes, Guilherme F; Silva, Andrea A; Esberard, Eliane B; Lugon, Jocemir R; Almeida, Jorge R

2016-01-01

Viral hepatitis B (VHB) represents a major public health problem. Studies from HIV multidrug patients have associated the use of tenofovir disoproxil fumarate (TDF) with renal dysfunction and phosphate wasting. The aim of this study was to examine the effect of year-long TDF monotherapy on renal function in VHB patients. We evaluated adult patients diagnosed with VHB before treatment initiation (T0), and after 3 and 12 months (T3 and T12) of TDF initiation. Estimated glomerular filtration rate (eGFR) was estimated by serum cystatin C and creatinine. In addition, urinary electrolytes and tubular biomarkers (cystatin C, β2-microglobulin and neutrophil gelatinase-associated lipocalin) were analyzed, as well as parathyroid hormone (PTH) and 25(OH)vitamin D levels. After 1 year, 32 patients completed the study, 22 (68.7%) men and 12 (37.5%) Whites, mean age 44.1±12.0 years. We found that serum electrolytes were similar at baseline and 3 or 12 months after initiation of TDF monotherapy. In addition, urinary fractional excretions of electrolytes as well as proteinuria, albuminuria, urinary β2-microglobulin, and urinary cystatin C showed no significant differences across the treatment timeline. There were also no statistical differences in the eGFR. There was a statistically significant increase in the PTH (Friedman's test, P=0.012), but the 25(OH)vitamin D levels were in the normal range in the beginning and did not change at the follow-up. Moreover, there was no correlation between the initial levels of vitamin D and the corresponding increases in the PTH values. If used as monotherapy in hepatitis B patients for a 12-month period, TDF is not associated with changes in either eGFR or a panel of urinary biomarkers. Serum and urinary electrolytes also remained unchanged. Of note, a significant increase in the PTH was found, although not related to the 25(OH)vitamin D initial status.

First-void urine: A potential biomarker source for triage of high-risk human papillomavirus infected women.

PubMed

Van Keer, Severien; Pattyn, Jade; Tjalma, Wiebren A A; Van Ostade, Xaveer; Ieven, Margareta; Van Damme, Pierre; Vorsters, Alex

2017-09-01

Great interest has been directed towards the use of first-void urine as a liquid biopsy for high-risk human papillomavirus DNA testing. Despite the high correlations established between urinary and cervical infections, human papillomavirus testing is unable to distinguish between productive and transforming high-risk infections that have the tendency to progress to cervical cancer. Thus far, investigations have been primarily confined to the identification of biomarkers for triage of high-risk human papillomavirus-positive women in cervicovaginal specimens and tissue biopsies. This paper reviews urinary biomarkers for cervical cancer and triage of high-risk human papillomavirus infections and elaborates on the opportunities and challenges that have emerged regarding the use of first-void urine as a liquid biopsy for the analysis of both morphological- (conventional cytology and novel immunohistochemical techniques) and molecular-based (HPV16/18 genotyping, host/viral gene methylation, RNA, and proteins) biomarkers. A literature search was performed in PubMed and Web of Science for studies investigating the use of urine as a biomarker source for cervical cancer screening. Five studies were identified reporting on biomarkers that are still in preclinical exploratory or clinical assay development phases and on assessments of non-invasive (urine) samples. Although large-scale validation studies are still needed, we conclude that methylation of both host and viral genes in urine has been proven feasible for use as a molecular cervical cancer triage and screening biomarker in phase two studies. This is especially promising and underscores our hypothesis that human papillomavirus DNA and candidate human and viral biomarkers are washed away with the initial, first-void urine, together with exfoliated cells, debris and impurities that line the urethra opening. Similar to the limitations of self-collected cervicovaginal samples, first-void urine will likely not fulfil the high-quality cellularity standards required for morphological biomarkers. Molecular biomarkers will likely overcome this issue to yield high-throughput, objective, and reproducible results. When using proper sampling, transport, storage, preanalytical biomarker concentration techniques, and clinically validated assays, first-void urine is expected to be a valuable source of molecular biomarkers for cervical cancer screening. Furthermore, as first-void urine can be easily and non-invasively collected, it is a highly preferred technique among women and offers the ability to test both primary high-risk human papillomavirus and biomarkers in the same sample. In addition, the use of first-void urine confers opportunities to reduce loss-to follow-up and non-adherence to screening subjects. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

Urinary metabonomic study of Panax ginseng in deficiency of vital energy rat using ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry.

PubMed

Lin, He; Pi, Zifeng; Men, Lihui; Chen, Weijia; Liu, Zhiqiang; Liu, Zhongying

2016-05-26

Deficiency of vital energy (DE) is called Qi-deficiency, a traditional Chinese medicine syndrome. It is an indicator of a disease emerging though fuzzy, dynamic, complex, nonspecific and subjective. Ginseng is regarded as the king of herbs. It is famous for the function of replenishing qi in traditional Chinese medicine. It has treatment potential for DE caused by various reasons. This study aimed to investigate the mechanism of ginseng treating symptom DE with the method of metabolomics. Thirty-five rats were randomly divided into three groups: normal control group, DE model group and ginseng treatment group. The DE model rats were administered daily with ginseng decoctiondecoctiondecoction intragastrically and others with water for 15 days. Urine was analyzed with ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Principal component analysis (PCA) and orthogonal projection to latent structures squares-discriminant analysis (OPLS-DA) were built to distinguish the three groups in this study and find potential biomarkers. The three groups are clearly separated and find out their metabolic distinction in PCA score plots. It showed that the metabolic profile of ginseng treatment group was changed to normal control group after administration of ginseng. Fifteen potential biomarkers are identified by OPLS-DA including Xanthurenic acid, kynurenic acid, Pantothenic acid, which are chiefly involved in tryptophan metabolism, taurine and hypotaurine metabolism, citric acid cycle, bile acid biosynthesis, alpha linolenic acid and linoleic acid metabolism. These biomarkers and the networks of their corresponding pathways will help to explain the mechanism of DE and ginseng treatment. The results of blood biochemical indicators routine and urinary metabonomic reveal that ginseng have good abilities to regulate the energy metabolism, immune function and antioxidant activities. And UPLC-Q-TOF-MS-based metabolomics can provide useful information for the understanding of metabolic changes in DE rats after administration of ginseng in urine. The biomarkers and their corresponding pathways will provide further information of the mechanisms of ginseng in treating DE. This work also proves that the method of metabonomics is effective in traditional Chinese medicinal research. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Urine proteome analysis in Dent's disease shows high selective changes potentially involved in chronic renal damage.

PubMed

Santucci, Laura; Candiano, Giovanni; Anglani, Franca; Bruschi, Maurizio; Tosetto, Enrica; Cremasco, Daniela; Murer, Luisa; D'Ambrosio, Chiara; Scaloni, Andrea; Petretto, Andrea; Caridi, Gianluca; Rossi, Roberta; Bonanni, Alice; Ghiggeri, Gian Marco

2016-01-01

Definition of the urinary protein composition would represent a potential tool for diagnosis in many clinical conditions. The use of new proteomic technologies allows detection of genetic and post-trasductional variants that increase sensitivity of the approach but complicates comparison within a heterogeneous patient population. Overall, this limits research of urinary biomarkers. Studying monogenic diseases are useful models to address this issue since genetic variability is reduced among first- and second-degree relatives of the same family. We applied this concept to Dent's disease, a monogenic condition characterised by low-molecular-weight proteinuria that is inherited following an X-linked trait. Results are presented here on a combined proteomic approach (LC-mass spectrometry, Western blot and zymograms for proteases and inhibitors) to characterise urine proteins in a large family (18 members, 6 hemizygous patients, 6 carrier females, and 6 normals) with Dent's diseases due to the 1070G>T mutation of the CLCN5. Gene ontology analysis on more than 1000 proteins showed that several clusters of proteins characterised urine of affected patients compared to carrier females and normal subjects: proteins involved in extracellular matrix remodelling were the major group. Specific analysis on metalloproteases and their inhibitors underscored unexpected mechanisms potentially involved in renal fibrosis. Studying with new-generation techniques for proteomic analysis of the members of a large family with Dent's disease sharing the same molecular defect allowed highly repetitive results that justify conclusions. Identification in urine of proteins actively involved in interstitial matrix remodelling poses the question of active anti-fibrotic drugs in Dent's patients. Copyright © 2015 Elsevier B.V. All rights reserved.

Metabolomics Based Dietary Biomarkers in Nutritional Epidemiology- Current Status and Future Opportunities.

PubMed

Brennan, Lorraine; Hu, Frank B

2018-04-24

The application of metabolomics in nutrition epidemiology holds great promise and there is a high expectation that it will play a leading role in deciphering the interactions between diet and health. However, while significant progress has been made in identification of putative biomarkers more work is needed to address the use of the biomarkers in dietary assessment. The aim of this review to critically evaluate progress in these areas and to identify challenges that need to be addressed going forward. The notable applications of dietary biomarkers in nutritional epidemiology include (1) Determination of food intake based on biomarkers levels and calibration equations from feeding studies (2) Classification of individuals into dietary patterns based on the urinary metabolic profile and (3) Application of metabolome-wide-association studies. Further work is needed to address some specific challenges to enable biomarkers to reach their full potential. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Temporal variability in urinary levels of drinking water disinfection byproducts dichloroacetic acid and trichloroacetic acid among men

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Yi-Xin; Zeng, Qiang; Wang, Le

Urinary haloacetic acids (HAAs), such as dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA), have been suggested as potential biomarkers of exposure to drinking water disinfection byproducts (DBPs). However, variable exposure to and the short elimination half-lives of these biomarkers can result in considerable variability in urinary measurements, leading to exposure misclassification. Here we examined the variability of DCAA and TCAA levels in the urine among eleven men who provided urine samples on 8 days over 3 months. The urinary concentrations of DCAA and TCAA were measured by gas chromatography coupled with electron capture detection. We calculated the intraclass correlation coefficientsmore » (ICCs) to characterize the within-person and between-person variances and computed the sensitivity and specificity to assess how well single or multiple urine collections accurately determined personal 3-month average DCAA and TCAA levels. The within-person variance was much higher than the between-person variance for all three sample types (spot, first morning, and 24-h urine samples) for DCAA (ICC=0.08–0.37) and TCAA (ICC=0.09–0.23), regardless of the sampling interval. A single-spot urinary sample predicted high (top 33%) 3-month average DCAA and TCAA levels with high specificity (0.79 and 0.78, respectively) but relatively low sensitivity (0.47 and 0.50, respectively). Collecting two or three urine samples from each participant improved the classification. The poor reproducibility of the measured urinary DCAA and TCAA concentrations indicate that a single measurement may not accurately reflect individual long-term exposure. Collection of multiple urine samples from one person is an option for reducing exposure classification errors in studies exploring the effects of DBP exposure on reproductive health. - Highlights: • We evaluated the variability of DCAA and TCAA levels in the urine among men. • Urinary DCAA and TCAA levels varied greatly over a 3-month period. • Single measurement may not accurately reflect personal long-term exposure levels. • Collecting multiple samples from one person improved the exposure classification.« less

Bisphenol A-associated epigenomic changes in prepubescent girls: a cross-sectional study in Gharbiah, Egypt

PubMed Central

2013-01-01

Background There is now compelling evidence that epigenetic modifications link adult disease susceptibility to environmental exposures during specific life stages, including pre-pubertal development. Animal studies indicate that bisphenol A (BPA), the monomer used in epoxy resins and polycarbonate plastics, may impact health through epigenetic mechanisms, and epidemiological data associate BPA levels with metabolic disorders, behavior changes, and reproductive effects. Thus, we conducted an environmental epidemiology study of BPA exposure and CpG methylation in pre-adolescent girls from Gharbiah, Egypt hypothesizing that methylation profiles exhibit exposure-dependent trends. Methods Urinary concentrations of total (free plus conjugated) species of BPA in spot samples were quantified for 60 girls aged 10 to 13. Genome-wide CpG methylation was concurrently measured in bisulfite-converted saliva DNA using the Infinium HumanMethylation27 BeadChip (N = 46). CpG sites from four candidate genes were validated via quantitative bisulfite pyrosequencing. Results CpG methylation varied widely among girls, and higher urinary BPA concentrations were generally associated with less genomic methylation. Based on pathway analyses, genes exhibiting reduced methylation with increasing urinary BPA were involved in immune function, transport activity, metabolism, and caspase activity. In particular, hypomethylation of CpG targets on chromosome X was associated with higher urinary BPA. Using the Comparative Toxicogenomics Database, we identified a number of candidate genes in our sample that previously have been associated with BPA-related expression change. Conclusions These data indicate that BPA may affect human health through specific epigenomic modification of genes in relevant pathways. Thus, epigenetic epidemiology holds promise for the identification of biomarkers from previous exposures and the development of epigenetic-based diagnostic strategies. PMID:23590724

Effect of calcium and vitamin D on growth, rickets and Kashin-Beck disease in 0- to 5-year-old children in a rural area of central Tibet.

PubMed

Rooze, Shancy; Mathieu, Françoise; Claus, William; Yangzom, Tashi; Yangzom, Dikki; Goyens, Philippe; de Maertelaer, Viviane

2016-06-01

To evaluate the effect of calcium (15 mmol/day) and vitamin D (625 μg/month), as single supplement or in combination, vs. no supplement on growth, clinical signs of rickets and Kashin-Beck disease (KBD) and dental health. Prospective controlled trial involving children aged 0-5 years living in four groups of villages in a KBD-endemic rural area of central Tibet who received either calcium and/or vitamin D or no supplement. The cohort was followed over 3 years. Primary outcome was the impact of the different supplementation regimes on KBD, rickets and growth; secondary outcomes were impact on urinary levels of calcium and phosphorus, biomarkers of bone and cartilage turnover, and dental health. No difference was observed between the four groups with regard to anthropometric data, rickets, KBD, urinary levels of CrossLaps(®) and CartiLaps(®) . Weight for height or age, mid-upper arm circumference and skinfold thickness decreased in the four groups. Height for age increased and the prevalence of KBD fell in the four groups. Dental health was better in the group receiving calcium and vitamin D. Urinary calcium levels increased after 3 years of follow-up in all groups; the group receiving vitamin D had a higher increase (P-value: 0.044). The same global increase was observed for urinary phosphorus levels; the group receiving calcium had a higher increase (P-value: 0.01). Calcium and vitamin D failed to improve growth and bone metabolism of children living in a KBD-endemic rural area. Calcium and vitamin D supplementation improved dental health. © 2016 John Wiley & Sons Ltd.

Urinary proteomic profiling reveals diclofenac-induced renal injury and hepatic regeneration in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Swelm, Rachel P.L. van; Laarakkers, Coby M.M.; Pertijs, Jeanne C.L.M.

Diclofenac (DF) is a widely used non-steroidal anti-inflammatory drug for the treatment of rheumatic disorders, but is often associated with liver injury. We applied urinary proteomic profiling using MALDI-TOF MS to identify biomarkers for DF-induced hepatotoxicity in mice. Female CH3/HeOUJIco mice were treated with 75 mg/kg bw DF by oral gavage and 24 h urine was collected. Proteins identified in urine of DF-treated mice included epidermal growth factor, transthyretin, kallikrein, clusterin, fatty acid binding protein 1 and urokinase, which are related to liver regeneration but also to kidney injury. Both organs showed enhanced levels of oxidative stress (TBARS, p

Exposure to BTEX and Ethers in Petrol Station Attendants and Proposal of Biological Exposure Equivalents for Urinary Benzene and MTBE.

PubMed

Campo, Laura; Rossella, Federica; Mercadante, Rosa; Fustinoni, Silvia

2016-04-01

To assess exposure to benzene (BEN) and other aromatic compounds (toluene, ethylbenzene, m+p-xylene, o-xylene) (BTEX), methyl tert-butyl ether (MTBE), and ethyl tert-butyl ether (ETBE) in petrol station workers using air sampling and biological monitoring and to propose biological equivalents to occupational limit values. Eighty-nine petrol station workers and 90 control subjects were investigated. Personal exposure to airborne BTEX and ethers was assessed during a mid-week shift; urine samples were collected at the beginning of the work week, prior to and at the end of air sampling. Petrol station workers had median airborne exposures to benzene and MTBE of 59 and 408 µg m(-3), respectively, with urinary benzene (BEN-U) and MTBE (MTBE-U) of 339 and 780 ng l(-1), respectively. Concentrations in petrol station workers were higher than in control subjects. There were significant positive correlations between airborne exposure and the corresponding biological marker, with Pearson's correlation coefficient (r) values of 0.437 and 0.865 for benzene and MTBE, respectively. There was also a strong correlation between airborne benzene and urinary MTBE (r = 0.835). Multiple linear regression analysis showed that the urinary levels of benzene were influenced by personal airborne exposure, urinary creatinine, and tobacco smoking [determination coefficient (R(2)) 0.572], while MTBE-U was influenced only by personal exposure (R(2) = 0.741). BEN-U and MTBE-U are sensitive and specific biomarkers of low occupational exposures. We propose using BEN-U as biomarker of exposure to benzene in nonsmokers and suggest 1457 ng l(-1) in end shift urine samples as biological exposure equivalent to the EU occupational limit value of 1 p.p.m.; for both smokers and nonsmokers, MTBE-U may be proposed as a surrogate biomarker of benzene exposure, with a biological exposure equivalent of 22 µg l(-1) in end shift samples. For MTBE exposure, we suggest the use of MTBE-U with a biological exposure equivalent of 22 µg l(-1) corresponding to the occupational limit value of 50 p.p.m. © The Author 2015. Published by Oxford University Press on behalf of the British Occupational Hygiene Society.

Urinary Biomarkers are Associated with Severity and Mechanism of Injury

PubMed Central

Janak, Jud C.; Stewart, Ian J.; Sosnov, Jonathan A.; Howard, Jeffrey T.; Siew, Edward D.; Chan, Mallory M.; Wickersham, Nancy; Ikizler, T. Alp; Chung, Kevin K.

2016-01-01

Combat-related blast trauma results in massive tissue injury and tends to involve multiple systems. Further, an acute measure of injury severity based on underlying biological mechanisms may be important for the triage and treatment of these types of patients. We hypothesized that urinary biomarkers (UBs) would reflect severity of injury and that they would be elevated for blast injuries compared to gunshot wounds (GSW) in a cohort of combat casualties. We also postulated that UBs would be higher in patients with burns compared to patients with non-burn trauma in a civilian cohort. Among 80 service members who sustained combat-related injuries, we performed generalized estimating equations to compare differences in log-transformed concentrations of the UBs by both (1) injury severity and (2) injury mechanism. Among 22 civilian patients, we performed Kruskal-Wallis tests to compare differences for the UBs stratified by burn and non-burn trauma. In the military cohort, with the exception of IL-18, all UBs were significantly (p<0.05) higher for patients with a severe combat-related injury (Injury Severity Score≥25). In addition, all crude UBs concentrations were significantly higher for blast vs. GSW patients (p<0.05). After adjusting for injury severity score and time of UB draw, KIM-1 (2.80 vs. 2.31; p=0.03) and LFABP (−1.11 vs. −1.92; p=0.02) were significantly higher for patients with a blast mechanism of injury. There were no significant differences in UBs between burn and non-burn civilian trauma patients. Future studies are needed to understand the physiologic response to trauma and the extent that UBs reflect these underlying processes. PMID:27798535

N-Acetyl-S-(n-Propyl)-L-Cysteine in Urine from Workers Exposed to 1-Bromopropane in Foam Cushion Spray Adhesives

PubMed Central

Hanley, Kevin W.; Petersen, Martin R.; Cheever, Kenneth L.; Luo, Lian

2009-01-01

1-Bromopropane (1-BP) has been marketed as an alternative for ozone depleting and other solvents; it is used in aerosol products, adhesives, metal, precision, and electronics cleaning solvents. Mechanisms of toxicity of 1-BP are not fully understood, but it may be a neurological and reproductive toxicant. Sparse exposure information prompted this study using 1-BP air sampling and urinary metabolites. Mercapturic acid conjugates are excreted in urine from 1-BP metabolism involving debromination. Research objectives were to evaluate the utility of urinary N-acetyl-S-(n-propyl)-L-cysteine (AcPrCys) for assessing exposure to 1-BP and compare it to urinary bromide [Br(−)] previously reported for these workers. Forty-eight-hour urine specimens were obtained from 30 workers at two factories where 1-BP spray adhesives were used to construct polyurethane foam seat cushions. Urine specimens were also obtained from 21 unexposed control subjects. All the workers' urine was collected into composite samples representing three time intervals: at work, after work but before bedtime, and upon awakening. Time-weighted average (TWA) geometric mean breathing zone concentrations were 92.4 and 10.5 p.p.m. for spraying and non-spraying jobs, respectively. Urinary AcPrCys showed the same trend as TWA exposures to 1-BP: higher levels were observed for sprayers. Associations of AcPrCys concentrations, adjusted for creatinine, with 1-BP TWA exposure were statistically significant for both sprayers (P < 0.05) and non-sprayers (P < 0.01). Spearman correlation coefficients for AcPrCys and Br(−) analyses determined from the same urine specimens were highly correlated (P < 0.0001). This study confirms that urinary AcPrCys is an important 1-BP metabolite and an effective biomarker for highly exposed foam cushion workers. PMID:19706636

USE OF PHARMACOKINETIC MODELS TO ASSESS OCCUPATIONAL AND RESIDENTIAL PESTICIDE EXPOSURE

EPA Science Inventory

Urinary biomarker measurements were analyzed using a dynamic pharmacokinetic model. The dynamic model provided the structure to link spot urine samples with corresponding exposure and absorbed dose. Data from both occupational and residential studies were analyzed. In the Agri...

[Effects on serum myelin proteins of n-hexane exposure].

PubMed

Yi, Juan; Zhou, Wei; He, Jia-xi; Liu, Qing-jun; Huang, Xian-qing

2011-02-01

Exploring the effects of n-hexane on expression of serum myelin proteins in occupational exposure workers, and finding the early biomarker of n-hexane exposure. In the study, 373 subjects were recruited, 269 exposure workers (work experience of more than1 year) and 104 non-exposure workers were selected. Firstly examined the level of urinary 2,5-hexanedione in the two groups, based on urinary 2,5-hexanedione biological limit value (4 mg/L), the exposed group was divided into high-exposed group and low-exposed group. And then collected blood samples and extracted serum. Human peripheral myelin protein zero (P0) antibody (IgG, IgM) and human peripheral myelin protein two (P2) antibody (IgG, IgM) analysis was performed according to ELISA kit. The concentration of urinary 2,5-hexanedione in the exposed group was (3.10 ± 1.35) mg/L. The level of P0 antibody (IgG, IgM) and P2 antibody (IgG, IgM) in the high-exposed group and low-exposed group were both higher than that in the controls (P < 0.01). P0 antibody and P2 antibody could be used as the early biomarkers of n-hexane exposure, which not only evaluate the occupational hazards in the early, but also provide the policy maker with scientific evidence.

Comparison of Intravenous and Oral Hydration in the Prevention of Contrast-Induced Acute Kidney Injury in Low-Risk Patients: A Randomized Trial.

PubMed

Martin-Moreno, Paloma L; Varo, Nerea; Martínez-Ansó, Eduardo; Martin-Calvo, Nerea; Sayón-Orea, Carmen; Bilbao, Jose I; Garcia-Fernandez, Nuria

2015-01-01

Contrast-induced acute kidney injury (CI-AKI) is a common cause of renal failure. We evaluated the effectiveness of oral sodium citrate versus intravenous (IV) sodium bicarbonate for CI-AKI prophylaxis as well as their influence on kidney injury biomarkers. A randomized, controlled, single-center study including 130 hospitalized patients (62.3% men), who were randomized to receive sodium bicarbonate (1/6 men, 3 ml/kg/h for 1 h; n = 43), oral sodium citrate (75 ml/10 kg divided into 4 doses; n = 43) or nonspecific hydration (n = 44) before contrast administration, was conducted. Serum creatinine and kidney injury biomarkers (cystatin C, neutrophil gelatinase-associated lipocalin, interleukin-8, F2-isoprostanes and cardiotrophin-1 [CT-1]) were assessed. Incidence of CI-AKI was 9.2% with no differences found between hydration groups: 7.0% in sodium bicarbonate group, 11.6% in oral sodium citrate group and 9.1% in the nonspecific hydration group. Urinary creatinine and urinary CT-1/creatinine ratio decreased 4 h after contrast infusion (p < 0.001), but none of the biomarkers assessed were affected by the treatments. There were no differences in hydration with oral sodium citrate and IV sodium bicarbonate for the prophylaxis of CI-AKI. Therefore, oral hydration represents a safe, inexpensive and practical method for preventing CI-AKI in low-risk patients. No effect on biomarkers for kidney injury could be demonstrated. © 2015 S. Karger AG, Basel.

The use of biomonitoring data in exposure and human health risk assessment: benzene case study.

PubMed

Arnold, Scott M; Angerer, Juergen; Boogaard, Peter J; Hughes, Michael F; O'Lone, Raegan B; Robison, Steven H; Schnatter, A Robert

2013-02-01

Abstract A framework of "Common Criteria" (i.e. a series of questions) has been developed to inform the use and evaluation of biomonitoring data in the context of human exposure and risk assessment. The data-rich chemical benzene was selected for use in a case study to assess whether refinement of the Common Criteria framework was necessary, and to gain additional perspective on approaches for integrating biomonitoring data into a risk-based context. The available data for benzene satisfied most of the Common Criteria and allowed for a risk-based evaluation of the benzene biomonitoring data. In general, biomarker (blood benzene, urinary benzene and urinary S-phenylmercapturic acid) central tendency (i.e. mean, median and geometric mean) concentrations for non-smokers are at or below the predicted blood or urine concentrations that would correspond to exposure at the US Environmental Protection Agency reference concentration (30 µg/m(3)), but greater than blood or urine concentrations relating to the air concentration at the 1 × 10(-5) excess cancer risk (2.9 µg/m(3)). Smokers clearly have higher levels of benzene exposure, and biomarker levels of benzene for non-smokers are generally consistent with ambient air monitoring results. While some biomarkers of benzene are specific indicators of exposure, the interpretation of benzene biomonitoring levels in a health-risk context are complicated by issues associated with short half-lives and gaps in knowledge regarding the relationship between the biomarkers and subsequent toxic effects.

Use of mass spectrometry fingerprinting to identify urinary metabolites after consumption of specific foods.

PubMed

Lloyd, Amanda J; Favé, Gaëlle; Beckmann, Manfred; Lin, Wanchang; Tailliart, Kathleen; Xie, Long; Mathers, John C; Draper, John

2011-10-01

The lack of robust biological markers of dietary exposure hinders the quantitative understanding of causal relations between diet and health. We aimed to develop an efficient procedure to discover metabolites in urine that may have future potential as biomarkers of acute exposure to foods of high public health importance. Twenty-four participants were provided with a test breakfast in which the cereal component of a standardized breakfast was replaced by 1 of 4 foods of high public health importance; 1.5-, 3-, and 4.5-h postprandial urine samples were collected. Flow infusion electrospray-ionization mass spectrometry followed by supervised multivariate data analysis was used to discover signals resulting from consumption of each test food. Fasted-state urine samples provided a universal comparator for food biomarker lead discovery in postprandial urine. The filtering of data features associated with consumption of the common components of the standardized breakfast improved discrimination models and readily identified metabolites that showed consumption of specific test foods. A combination of trimethylamine-N-oxide and 1-methylhistidine was associated with salmon consumption. Novel ascorbate derivatives were discovered in urine after consumption of either broccoli or raspberries. Sulphonated caffeic acid and sulphonated methyl-epicatechin concentrations increased dramatically after consumption of raspberries. This biomarker lead discovery strategy can identify urinary metabolites associated with acute exposure to individual foods. Future studies are required to validate the specificity and utility of potential biomarkers in an epidemiologic context.

Renal and blood pressure effects from environmental cadmium exposure in Thai children

DOE Office of Scientific and Technical Information (OSTI.GOV)

Swaddiwudhipong, Witaya, E-mail: swaddi@hotmail.com; Mahasakpan, Pranee; Jeekeeree, Wanpen

Very few studies have shown renal and blood pressure effects from environmental cadmium exposure in children. This population study examined associations between urinary cadmium excretion, a good biomarker of long-term cadmium exposure, and renal dysfunctions and blood pressure in environmentally exposed Thai children. Renal functions including urinary excretion of β{sub 2}-microglobulin, calcium (early renal effects), and total protein (late renal effect), and blood pressure were measured in 594 primary school children. Of the children studied, 19.0% had urinary cadmium ≥1 μg/g creatinine. The prevalence of urinary cadmium ≥1 μg/g creatinine was significantly higher in girls and in those consuming ricemore » grown in cadmium-contaminated areas. The geometric mean levels of urinary β{sub 2}-microglobulin, calcium, and total protein significantly increased with increasing tertiles of urinary cadmium. The analysis did not show increased blood pressure with increasing tertiles of urinary cadmium. After adjusting for age, sex, and blood lead levels, the analysis showed significant positive associations between urinary cadmium and urinary β{sub 2}-microglobulin and urinary calcium, but not urinary total protein nor blood pressure. Our findings provide evidence that environmental cadmium exposure can affect renal functions in children. A follow-up study is essential to assess the clinical significance and progress of renal effects in these children. - Highlights: • Few studies show renal effects from environmental cadmium exposure in children. • We report renal and blood pressure effects from cadmium exposure in Thai children. • Urinary β{sub 2}-microglobulin and calcium increased with increasing urinary cadmium. • The study found no association between urinary cadmium levels and blood pressure. • Environmental cadmium exposure can affect renal functions in children.« less

The diagnostic and prognostic importance of oxidative stress biomarkers and acute phase proteins in Urinary Tract Infection (UTI) in camels.

PubMed

El-Deeb, Wael M; Buczinski, Sébastien

2015-01-01

The present study aimed to investigate the diagnostic and prognostic importance of oxidative stress biomarkers and acute phase proteins in urinary tract infection (UTI) in camels. We describe the clinical, bacteriological and biochemical findings in 89 camels. Blood and urine samples from diseased (n = 74) and control camels (n = 15) were submitted to laboratory investigations. The urine analysis revealed high number of RBCS and pus cells. The concentrations of serum and erythrocytic malondialdehyde (sMDA & eMDA), Haptoglobin (Hp), serum amyloid A (SAA), Ceruloplasmin (Cp), fibrinogen (Fb), albumin, globulin and interleukin 6 (IL-6) were higher in diseased camels when compared to healthy ones. Catalase, super oxide dismutase and glutathione levels were lower in diseased camels when compared with control group. Forty one of 74 camels with UTI were successfully treated. The levels of malondialdehyde, catalase, super oxide dismutase, glutathione, Hp, SAA, Fb, total protein, globulin and IL-6 were associated with the odds of treatment failure. The MDA showed a great sensitivity (Se) and specificity (Sp) in predicting treatment failure (Se 85%/Sp 100%) as well as the SAA (Se 92%/Sp 87%) and globulin levels (Se 85%/Sp 100%) when using the cutoffs that maximizes the sum of Se + Sp. Multivariate logistic regression analysis revealed that two models had a high accuracy to predict failure with the first model including sex, sMDA and Hp as covariates (area under the receiver operating characteristic curve (AUC) = 0.92) and a second model using sex, SAA and Hp (AUC = 0.89). Conclusively, the oxidative stress biomarkers and acute phase proteins could be used as diagnostic and prognostic biomarkers in camel UTI management. Efforts should be forced to investigate such biomarkers in other species with UTI.

Randomized trial of glucosamine and chondroitin supplementation on inflammation and oxidative stress biomarkers and plasma proteomics profiles in healthy humans.

PubMed

Navarro, Sandi L; White, Emily; Kantor, Elizabeth D; Zhang, Yuzheng; Rho, Junghyun; Song, Xiaoling; Milne, Ginger L; Lampe, Paul D; Lampe, Johanna W

2015-01-01

Glucosamine and chondroitin are popular non-vitamin dietary supplements used for osteoarthritis. Long-term use is associated with lower incidence of colorectal and lung cancers and with lower mortality; however, the mechanism underlying these observations is unknown. In vitro and animal studies show that glucosamine and chondroitin inhibit NF-kB, a central mediator of inflammation, but no definitive trials have been done in healthy humans. We conducted a randomized, double-blind, placebo-controlled, cross-over study to assess the effects of glucosamine hydrochloride (1500 mg/d) plus chondroitin sulfate (1200 mg/d) for 28 days compared to placebo in 18 (9 men, 9 women) healthy, overweight (body mass index 25.0-32.5 kg/m2) adults, aged 20-55 y. We examined 4 serum inflammatory biomarkers: C-reactive protein (CRP), interleukin 6, and soluble tumor necrosis factor receptors I and II; a urinary inflammation biomarker: prostaglandin E2-metabolite; and a urinary oxidative stress biomarker: F2-isoprostane. Plasma proteomics on an antibody array was performed to explore other pathways modulated by glucosamine and chondroitin. Serum CRP concentrations were 23% lower after glucosamine and chondroitin compared to placebo (P = 0.048). There were no significant differences in other biomarkers. In the proteomics analyses, several pathways were significantly different between the interventions after Bonferroni correction, the most significant being a reduction in the "cytokine activity" pathway (P = 2.6 x 10-16), after glucosamine and chondroitin compared to placebo. Glucosamine and chondroitin supplementation may lower systemic inflammation and alter other pathways in healthy, overweight individuals. This study adds evidence for potential mechanisms supporting epidemiologic findings that glucosamine and chondroitin are associated with reduced risk of lung and colorectal cancer. ClinicalTrials.gov NCT01682694.

Variation of nephrotoxicity biomarkers by urinary storage condition in rats.

PubMed

Le, Jung-Min; Han, Young-Hwan; Choi, Su-Jeong; Park, Ju-Seong; Jang, Jeong-Jun; Bae, Re-Ji-Na; Lee, Mi Ju; Kim, Myoung Jun; Lee, Yong-Hoon; Kim, Duyeol; Lee, Hye-Young; Park, Sun-Hee; Park, Cheol-Beom; Kang, Jin Seok; Kang, Jong-Koo

2014-12-01

Recently, there has been an increase in the use of several nephrotoxicity biomarkers in preclinical experiments. In addition, it has been indicated that the result may have been influenced by secondary factors, such as sample storage condition or storage period. In this study, we have assessed the variation in urinary nephrotoxicity biomarkers as a result of urine storage conditions and storage period of the urine. Urine was sampled from specific pathogen-free Sprague-Dawley rats (19 weeks old), which were housed individually in hanged stainless steel wire mesh cages. Urine was stored at 20℃, at 4℃, or at -70℃ after sampling. The levels of the biomarkers such as beta-2 microglobulin (B2M), cystatin-C (Cys-C), N-acetyl-β- D-glucosaminidase (NAG), micro albumin (MA), micro protein (MP) were measured at 6, 24, 48 and 144 hr after sampling. The B2M level was significantly decreased at 6, 24, 48, and 144 hr compared to 0 hr at -70℃ (p < 0.05, p < 0.01, p < 0.05, and p < 0.05, respectively) and 24 and 144 hr at 20℃ (p < 0.01, p < 0.01, respectively). The Cys-C level was significantly decreased at 144 hr compared to 0 hr at 4℃ (p < 0.01), at 20℃ (p < 0.05) and at 70℃ (p < 0.01). MP and MA levels were not different for 144 hr in all storage conditions. Taken together, B2M and Cys-C levels were modulated by storage temperature and period. For the enhancement of test accuracy, it is suggested that strict protocols be established for samples to minimize the effects of the storage conditions on the detected levels of biomarkers.

Urinary sugars biomarker relates better to extrinsic than to intrinsic sugars intake in a metabolic study with volunteers consuming their normal diet.

PubMed

Tasevska, N; Runswick, S A; Welch, A A; McTaggart, A; Bingham, S A

2009-05-01

Sugars in diet are very difficult to measure because of the unreliability of self-reported dietary intake. Sucrose and fructose excreted in urine have been recently suggested as a biomarker for total sugars intake. To further characterize the use of this biomarker, we investigated whether urinary sugars correlated better to extrinsic compared to intrinsic sugars in the diet. Seven male and six female healthy participants were living for 30 days in a metabolic suite under strictly controlled conditions consuming their usual diet as assessed beforehand from four consecutive 7-day food diaries kept at home. During the 30-day study, all 24 h urine specimens were collected, validated for their completeness and analysed for sucrose and fructose. The mean total sugars intake in the group was 202+/-69 g day(-1). Daily intake of extrinsic, intrinsic and milk sugars contributed 60.1, 34.4 and 5.5%, to the total sugars intake, respectively. The individuals' 30-day mean sugars excretion levels were significantly correlated with the 30-day means of extrinsic sugars (r=0.84; P<0.001) but not with the intrinsic sugars intake (r=0.43; P=0.144). In the regression, only extrinsic sugars intake explained a significant proportion of the variability in sugars excretion (adjusted R(2)=0.64; P=0.001); daily excretion of 100 mg sucrose and fructose in urine predicted 124 g of extrinsic total sugars in the diet. Using fewer urinary and dietary measurements in the analysis did not change the overall trend of the findings. In this group of volunteers, sucrose and fructose in urine better correlated to extrinsic than to intrinsic sugars intake.

Analysis of Urinary Biomarkers for Smoking Crack Cocaine: Results of a Danish Laboratory Study.

PubMed

Jeppesen, Hans Henrik; Busch-Nielsen, Malthe; Larsen, Anders Nørgaard; Breindahl, Torben

2015-01-01

Crack cocaine (free-base cocaine) smokers belong to a subgroup of marginalized drug users exposed to severe health risks and great social harm. Detection of the urinary, pyrolytic biomarker methylecgonidine (MED) and its metabolite ecgonidine (ED) secures an unambiguous confirmation of crack cocaine smoking. Although prevalence studies of cocaine based upon self-reporting may not be accurate, laboratory analysis is seldom used for neither diagnostic purpose nor early identification of crack cocaine smoking, which is far more severe than snorting cocaine. A new analytical method was validated for MED, ED and other relevant cocaine metabolites using automated liquid handling and column switching coupled to liquid chromatography and tandem mass spectrometry. Limit of quantification was 30 ng/mL for ED and MED. This method was applied in a laboratory study of urine samples (n = 110) from cocaine users in Denmark subjected to routine drugs-of-abuse testing. Crack cocaine smoking was confirmed by the presence of MED and/or ED. Eighty-four samples (76.4%) were found positive for crack cocaine smoking in this group of problematic cocaine users. MED was only detected in 5.9% of the positive samples. The study shows a prevalence 3-fold higher to that recently suggested by European Monitoring Centre for Drugs and Drug Addiction. We therefore advocate that the urinary biomarkers MED and ED are included in routine testing methods for clinical toxicology. This may lead to an earlier identification of crack cocaine smoking and possibly prevent a more severe drug use. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Influence of Long-Distance Bicycle Riding on Serum/Urinary Biomarkers of Prostate Cancer

PubMed Central

Heger, Zbynek; Gumulec, Jaromir; Ondrak, Ales; Skoda, Jan; Zitka, Zdenek; Cernei, Natalia; Masarik, Michal; Zitka, Ondrej; Adam, Vojtech

2016-01-01

Herein, we present a study focused on the determination of the influence of long-distance (53 km) bicycle riding on levels of chosen biochemical urinary and serum prostate cancer (PCa) biomarkers total prostate-specific antigen (tPSA), free PSA (fPSA) and sarcosine. Fourteen healthy participants with no evidence of prostate diseases, in the age range from 49–57 years with a median of 52 years, underwent physical exercise (mean race time of 150 ± 20 min, elevation increase of 472 m) and pre- and post-ride blood/urine sampling. It was found that bicycle riding resulted in elevated serum uric acid (p = 0.001, median 271.76 vs. 308.44 µmol/L pre- and post-ride, respectively), lactate (p = 0.01, median 2.98 vs. 4.8 mmol/L) and C-reactive protein (p = 0.01, 0.0–0.01 mg/L). It is noteworthy that our work supports the studies demonstrating an increased PSA after mechanical manipulation of the prostate. The subjects exhibited either significantly higher post-ride tPSA (p = 0.002, median 0.69 vs. 1.1 ng/mL pre- and post-ride, respectively) and fPSA (p = 0.028, median 0.25 vs. 0.35 ng/mL). Contrary to that, sarcosine levels were not significantly affected by physical exercise (p = 0.20, median 1.64 vs. 1.92 µmol/mL for serum sarcosine, and p = 0.15, median 0.02 µmol/mmol of creatinine vs. 0.01 µmol/mmol of creatinine for urinary sarcosine). Taken together, our pilot study provides the first evidence that the potential biomarker of PCa—sarcosine does not have a drawback by means of a bicycle riding-induced false positivity, as was shown in the case of PSA. PMID:26999116

Metabolic Pathway Signatures Associated with Urinary Metabolite Biomarkers Differentiate Bladder Cancer Patients from Healthy Controls.

PubMed

Kim, Won Tae; Yun, Seok Joong; Yan, Chunri; Jeong, Pildu; Kim, Ye Hwan; Lee, Il Seok; Kang, Ho Won; Park, Sunghyouk; Moon, Sung Kwon; Choi, Yung Hyun; Choi, Young Deuk; Kim, Isaac Yi; Kim, Jayoung; Kim, Wun Jae

2016-07-01

Our previous high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry study identified bladder cancer (BCA)-specific urine metabolites, including carnitine, acylcarnitines, and melatonin. The objective of the current study was to determine which metabolic pathways are perturbed in BCA, based on our previously identified urinary metabolome. A total of 135 primary BCA samples and 26 control tissue samples from healthy volunteers were analyzed. The association between specific urinary metabolites and their related encoding genes was analyzed. Significant alterations in the carnitine-acylcarnitine and tryptophan metabolic pathways were detected in urine specimens from BCA patients compared to those of healthy controls. The expression of eight genes involved in the carnitine-acylcarnitine metabolic pathway (CPT1A, CPT1B, CPT1C, CPT2, SLC25A20, and CRAT) or tryptophan metabolism (TPH1 and IDO1) was assessed by RT-PCR in our BCA cohort (n=135). CPT1B, CPT1C, SLC25A20, CRAT, TPH1, and IOD1 were significantly downregulated in tumor tissues compared to normal bladder tissues (p<0.05 all) of patients with non-muscle invasive BCA, whereas CPT1B, CPT1C, CRAT, and TPH1 were downregulated in those with muscle invasive BCA (p<0.05), with no changes in IDO1 expression. Alterations in the expression of genes associated with the carnitine-acylcarnitine and tryptophan metabolic pathways, which were the most perturbed pathways in BCA, were determined.

The Urinary Tract Microbiome in Health and Disease.

PubMed

Aragón, Isabel M; Herrera-Imbroda, Bernardo; Queipo-Ortuño, María I; Castillo, Elisabeth; Del Moral, Julia Sequeira-García; Gómez-Millán, Jaime; Yucel, Gozde; Lara, María F

2016-11-14

The urinary tract, previously considered a sterile body niche, has emerged as the host of an array of bacteria in healthy individuals, revolutionizing the urology research field. To review the literature on microbiome implications in the urinary tract and the usefulness of probiotics/prebiotics and diet as treatment for urologic disorders. A systematic review was conducted using PubMed and Medline from inception until July 2016. The initial search identified 1419 studies and 89 were included in this systematic review. Specific bacterial communities have been found in the healthy urinary tract. Changes in this microbiome have been observed in certain urologic disorders such as urinary incontinence, urologic cancers, interstitial cystitis, neurogenic bladder dysfunction, sexually transmitted infections, and chronic prostatitis/chronic pelvic pain syndrome. The role of probiotics, prebiotics, and diet as treatment or preventive agents for urologic disorders requires further investigation. There is a microbiome associated with the healthy urinary tract that can change in urologic disorders. This represents a propitious context to identify new diagnostic, prognostic, and predictive microbiome-based biomarkers that could be used in clinical urology practice. In addition, probiotics, prebiotics, and diet modifications appear to represent an opportunity to regulate the urinary microbiome. We review the urinary microbiome of healthy individuals and its changes in relation to urinary disorders. The question to resolve is how we can modulate the microbiome to improve urinary tract health. Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Influence of body mass index status on urinary creatinine and specific gravity for epidemiological study of children.

PubMed

Wang, Bin; Tang, Chuanxi; Wang, Hexing; Zhou, Wei; Chen, Yue; Zhou, Ying; Jiang, Qingwu

2015-11-01

In epidemiological studies, urinary biomonitoring is a valid approach to assess the association between environmental chemical exposure and children's health. Many clinical biomarkers (e.g., endogenous metabolites) are also based on analysis of urine. Considering the variability in urinary output, urinary concentrations of chemicals are commonly adjusted by creatinine and specific gravity (SG). However, there is a lack of systematic evaluation of their appropriateness for children. Furthermore, urinary SG and creatinine excretion could be influenced by body mass index (BMI), but the effect of BMI status on the two correction factors is unknown. We measured SG and creatinine concentrations of repeated first morning urine samples collected from 243 primary school children (8-11 years) over 5 consecutive weekdays. Urinary SG presented a higher temporal consistency compared with creatinine. Urinary SG was associated with sex (p < 0.001), whereas sex (p =0.034) and BMI (p = 00.008) were associated with urinary creatinine levels. Inter-day collection time was not associated with SG or creatinine after excluding the effect of Monday as a confounder. When stratified by BMI status, none of the factors were associated with creatinine among the overweight and obese children. Generally, SG is preferable for correcting the variability in urinary output for children although creatinine correction may also perform well in overweight and obese children. SG correction is recommended for epidemiological exposure analysis in children based on urinary levels of exogenous or endogenous metabolites.

Obstructive renal injury: from fluid mechanics to molecular cell biology.

PubMed

Ucero, Alvaro C; Gonçalves, Sara; Benito-Martin, Alberto; Santamaría, Beatriz; Ramos, Adrian M; Berzal, Sergio; Ruiz-Ortega, Marta; Egido, Jesus; Ortiz, Alberto

2010-04-22

Urinary tract obstruction is a frequent cause of renal impairment. The physiopathology of obstructive nephropathy has long been viewed as a mere mechanical problem. However, recent advances in cell and systems biology have disclosed a complex physiopathology involving a high number of molecular mediators of injury that lead to cellular processes of apoptotic cell death, cell injury leading to inflammation and resultant fibrosis. Functional studies in animal models of ureteral obstruction using a variety of techniques that include genetically modified animals have disclosed an important role for the renin-angiotensin system, transforming growth factor-β1 (TGF-β1) and other mediators of inflammation in this process. In addition, high throughput techniques such as proteomics and transcriptomics have identified potential biomarkers that may guide clinical decision-making.

URINARY BIOMARKERS OF DI-ISONONYL PHTHALATE IN RATS

EPA Science Inventory

Commercial di-isononyl phthalate (DiNP) is a mixture of various branched-chain dialkyl phthalates mainly containing ninecarbon alkyl isomers. At high doses in rodents, DiNP is a carcinogen, and a developmental toxicant. After exposure, the diester isomers are de-esterified to for...

Estimation of caffeine intake from analysis of caffeine metabolites in wastewater.

PubMed

Gracia-Lor, Emma; Rousis, Nikolaos I; Zuccato, Ettore; Bade, Richard; Baz-Lomba, Jose Antonio; Castrignanò, Erika; Causanilles, Ana; Hernández, Félix; Kasprzyk-Hordern, Barbara; Kinyua, Juliet; McCall, Ann-Kathrin; van Nuijs, Alexander L N; Plósz, Benedek G; Ramin, Pedram; Ryu, Yeonsuk; Santos, Miguel M; Thomas, Kevin; de Voogt, Pim; Yang, Zhugen; Castiglioni, Sara

2017-12-31

Caffeine metabolites in wastewater were investigated as potential biomarkers for assessing caffeine intake in a population. The main human urinary metabolites of caffeine were measured in the urban wastewater of ten European cities and the metabolic profiles in wastewater were compared with the human urinary excretion profile. A good match was found for 1,7-dimethyluric acid, an exclusive caffeine metabolite, suggesting that might be a suitable biomarker in wastewater for assessing population-level caffeine consumption. A correction factor was developed considering the percentage of excretion of this metabolite in humans, according to published pharmacokinetic studies. Daily caffeine intake estimated from wastewater analysis was compared with the average daily intake calculated from the average amount of coffee consumed by country per capita. Good agreement was found in some cities but further information is needed to standardize this approach. Wastewater analysis proved useful to providing additional local information on caffeine use. Copyright © 2017 Elsevier B.V. All rights reserved.

Effects of environmental cadmium and lead exposure on adults neighboring a discharge: Evidences of adverse health effects.

PubMed

Cabral, Mathilde; Toure, Aminata; Garçon, Guillaume; Diop, Cheikh; Bouhsina, Saâd; Dewaele, Dorothée; Cazier, Fabrice; Courcot, Dominique; Tall-Dia, Anta; Shirali, Pirouz; Diouf, Amadou; Fall, Mamadou; Verdin, Anthony

2015-11-01

The purpose of the study was to determine Pb and Cd concentrations in humans and to assess the effect of co-exposure to these metals on biomarkers of oxidative stress and nephrotoxicity. Blood and urine levels of Pb and Cd, oxidative stress and urinary renal biomarkers were measured in 77 subjects neighboring a discharge and 52 in the control site. Exposed subjects showed significantly higher levels of lead and cadmium in blood and urine than the controls. Excessive production of reactive oxygen species induced by these metals in exposed subjects conducted to a decrease in antioxidant defense system (GPx, Selenium, GSH) and an increase in lipid peroxidation (MDA). Moreover, changes in markers of nephrotoxicity (high urinary concentrations of total protein, RBP and CC16, as well as GSTα and LDH increased activities) suggested the occurrence of discrete and early signs of impaired renal function for the discharge neighboring population. Copyright © 2015 Elsevier Ltd. All rights reserved.

Urinary microRNAs for prostate cancer diagnosis, prognosis, and treatment response: are we there yet?

PubMed

Balacescu, Ovidiu; Petrut, Bogdan; Tudoran, Oana; Feflea, Dragos; Balacescu, Loredana; Anghel, Andrei; Sirbu, Ioan O; Seclaman, Edward; Marian, Catalin

2017-11-01

Prostate cancer (PCa) remains one of the leading causes of cancer-related deaths in men. Despite the tremendous progress in research over the years, a suitable minimally invasive PCa biomarker is yet to be discovered. The recent advances regarding the roles of microRNAs as biomarkers has allowed for their study in PCa as well, especially as blood-based markers. However, there are several studies that used urine as biological sample to evaluate microRNAs as biomarkers for PCa diagnosis, prognosis, and treatment response, which were reviewed herein. A high degree of inconsistency among reports has been observed, which could be due to several analytical aspects, starting with different urinary fractions used for analysis and continuing with the employment of various analytical platforms and methods of statistical analysis. However, a few microRNAs were found to be dysregulated in the urine of PCa patients, which alone or together with serum prostate-specific antigen seem to improve diagnostic power even in the gray zone of PCa. These results warrant further confirmation by larger prospective studies, preferably using a standardized protocol for analysis. WIREs RNA 2017, 8:e1438. doi: 10.1002/wrna.1438 For further resources related to this article, please visit the WIREs website. © 2017 Wiley Periodicals, Inc.

High-throughput tandem mass spectrometry multiplex analysis for newborn urinary screening of creatine synthesis and transport disorders, Triple H syndrome and OTC deficiency.

PubMed

Auray-Blais, Christiane; Maranda, Bruno; Lavoie, Pamela

2014-09-25

Creatine synthesis and transport disorders, Triple H syndrome and ornithine transcarbamylase deficiency are treatable inborn errors of metabolism. Early screening of patients was found to be beneficial. Mass spectrometry analysis of specific urinary biomarkers might lead to early detection and treatment in the neonatal period. We developed a high-throughput mass spectrometry methodology applicable to newborn screening using dried urine on filter paper for these aforementioned diseases. A high-throughput methodology was devised for the simultaneous analysis of creatine, guanidineacetic acid, orotic acid, uracil, creatinine and respective internal standards, using both positive and negative electrospray ionization modes, depending on the compound. The precision and accuracy varied by <15%. Stability during storage at different temperatures was confirmed for three weeks. The limits of detection and quantification for each biomarker varied from 0.3 to 6.3 μmol/l and from 1.0 to 20.9 μmol/l, respectively. Analyses of urine specimens from affected patients revealed abnormal results. Targeted biomarkers in urine were detected in the first weeks of life. This rapid, simple and robust liquid chromatography/tandem mass spectrometry methodology is an efficient tool applicable to urine screening for inherited disorders by biochemical laboratories. Copyright © 2014 Elsevier B.V. All rights reserved.

Detection of new human metabolic urinary markers in chronic alcoholism and their reversal by aqueous extract of Tinospora cordifolia stem.

PubMed

Mittal, Ashwani; Dabur, Rajesh

2015-05-01

We have studied urine metabolic signature of chronic alcoholism (CA) before and after treatment with an Ayurvedic drug Tinospora cordifolia aqueous extract (TCE). Urinary metabolites of chronic alcoholics and apparently healthy subjects were profiled using HPLC-Q-TOF-MS. Discrimination models from the initial data sets were able to correctly assign the unknown samples to the CA, treated or healthy groups in validation sets with r(2) > 0.98. Metabolic signature in CA patients include changed tryptophan, fatty acids and pyrimidines metabolism. Several novel biomarkers of alcoholism were observed in urine for the first time which includes, 5-hydroxyindole, phenylacetic acid, picolinic acid, quinaldic acid, histidine, cystathionine, riboflavin, tetrahydrobiopterin and chenodeoxyglycocholic acid, in addition to previously reported biomarkers. Treatment of CA with TCE reverted the levels of most of the biomarkers except tetrahydrobiopterin levels. These results suggested that the measurement of these urine metabolites could be used as a non-invasive diagnostic method for the detection of CA. As TCE treatment significantly reversed the affected pathways without any side effect. Overall, the present data depicts that TCE may be used either alone or adjunct in reducing alcohol-induced disorders. © The Author 2015. Medical Council on Alcohol and Oxford University Press. All rights reserved.

A Fragment of the LG3 Peptide of Endorepellin Is Present in the Urine of Physically Active Mining Workers: A Potential Marker of Physical Activity

PubMed Central

Parker, Tony J.; Sampson, Dayle L.; Broszczak, Daniel; Chng, Yee L.; Carter, Shea L.; Leavesley, David I.; Parker, Anthony W.; Upton, Zee

2012-01-01

Biomarker analysis has been implemented in sports research in an attempt to monitor the effects of exertion and fatigue in athletes. This study proposed that while such biomarkers may be useful for monitoring injury risk in workers, proteomic approaches might also be utilised to identify novel exertion or injury markers. We found that urinary urea and cortisol levels were significantly elevated in mining workers following a 12 hour overnight shift. These levels failed to return to baseline over 24 h in the more active maintenance crew compared to truck drivers (operators) suggesting a lack of recovery between shifts. Use of a SELDI-TOF MS approach to detect novel exertion or injury markers revealed a spectral feature which was associated with workers in both work categories who were engaged in higher levels of physical activity. This feature was identified as the LG3 peptide, a C-terminal fragment of the anti-angiogenic/anti-tumourigenic protein endorepellin. This finding suggests that urinary LG3 peptide may be a biomarker of physical activity. It is also possible that the activity mediated release of LG3/endorepellin into the circulation may represent a biological mechanism for the known inverse association between physical activity and cancer risk/survival. PMID:22457785

A survey of liquid chromatographic-mass spectrometric analysis of mercapturic acid biomarkers in occupational and environmental exposure monitoring.

PubMed

Mathias, Patricia I; B'Hymer, Clayton

2014-08-01

High-performance liquid chromatography/mass spectrometry (HPLC/MS) is sensitive and specific for targeted quantitative analysis and is readily utilized for small molecules from biological matrices. This brief review describes recent selected HPLC/MS methods for the determination of urinary mercapturic acids (mercapturates) which are useful as biomarkers in characterizing human exposure to electrophilic industrial chemicals in occupational and environmental studies. Electrophilic compounds owing to their reactivity are used in chemical and industrial processes. They are present in industrial emissions, are combustion products of fossil fuels, and are components in tobacco smoke. Their presence in both the industrial and general environments are of concern for human and environmental health. Urinary mercapturates which are the products of metabolic detoxification of reactive chemicals provide a non-invasive tool to investigate human exposure to electrophilic toxicants. Selected recent mercapturate quantification methods are summarized and specific cases are presented. The biological formation of mercapturates is introduced and their use as biomarkers of metabolic processing of electrophilic compounds is discussed. Also, the use of liquid chromatography/tandem mass spectrometry in simultaneous determinations of the mercapturates of multiple parent compounds in a single determination is considered, as well as future trends and limitations in this area of research. Published by Elsevier B.V.

A fragment of the LG3 peptide of endorepellin is present in the urine of physically active mining workers: a potential marker of physical activity.

PubMed

Parker, Tony J; Sampson, Dayle L; Broszczak, Daniel; Chng, Yee L; Carter, Shea L; Leavesley, David I; Parker, Anthony W; Upton, Zee

2012-01-01

Biomarker analysis has been implemented in sports research in an attempt to monitor the effects of exertion and fatigue in athletes. This study proposed that while such biomarkers may be useful for monitoring injury risk in workers, proteomic approaches might also be utilised to identify novel exertion or injury markers. We found that urinary urea and cortisol levels were significantly elevated in mining workers following a 12 hour overnight shift. These levels failed to return to baseline over 24 h in the more active maintenance crew compared to truck drivers (operators) suggesting a lack of recovery between shifts. Use of a SELDI-TOF MS approach to detect novel exertion or injury markers revealed a spectral feature which was associated with workers in both work categories who were engaged in higher levels of physical activity. This feature was identified as the LG3 peptide, a C-terminal fragment of the anti-angiogenic/anti-tumourigenic protein endorepellin. This finding suggests that urinary LG3 peptide may be a biomarker of physical activity. It is also possible that the activity mediated release of LG3/endorepellin into the circulation may represent a biological mechanism for the known inverse association between physical activity and cancer risk/survival.

Development of Standard Reference Materials to support assessment of iodine status for nutritional and public health purposes.

PubMed

Long, Stephen E; Catron, Brittany L; Boggs, Ashley Sp; Tai, Susan Sc; Wise, Stephen A

2016-09-01

The use of urinary iodine as an indicator of iodine status relies in part on the accuracy of the analytical measurement of iodine in urine. Likewise, the use of dietary iodine intake as an indicator of iodine status relies in part on the accuracy of the analytical measurement of iodine in dietary sources, including foods and dietary supplements. Similarly, the use of specific serum biomarkers of thyroid function to screen for both iodine deficiency and iodine excess relies in part on the accuracy of the analytical measurement of those biomarkers. The National Institute of Standards and Technology has been working with the NIH Office of Dietary Supplements for several years to develop higher-order reference measurement procedures and Standard Reference Materials to support the validation of new routine analytical methods for iodine in foods and dietary supplements, for urinary iodine, and for several serum biomarkers of thyroid function including thyroid-stimulating hormone, thyroglobulin, total and free thyroxine, and total and free triiodothyronine. These materials and methods have the potential to improve the assessment of iodine status and thyroid function in observational studies and clinical trials, thereby promoting public health efforts related to iodine nutrition. © 2016 American Society for Nutrition.

Urinary 1H Nuclear Magnetic Resonance Metabolomic Fingerprinting Reveals Biomarkers of Pulse Consumption Related to Energy-Metabolism Modulation in a Subcohort from the PREDIMED study.

PubMed

Madrid-Gambin, Francisco; Llorach, Rafael; Vázquez-Fresno, Rosa; Urpi-Sarda, Mireia; Almanza-Aguilera, Enrique; Garcia-Aloy, Mar; Estruch, Ramon; Corella, Dolores; Andres-Lacueva, Cristina

2017-04-07

Little is known about the metabolome fingerprint of pulse consumption. The study of robust and accurate biomarkers for pulse dietary assessment has great value for nutritional epidemiology regarding health benefits and their mechanisms. To characterize the fingerprinting of dietary pulses (chickpeas, lentils, and beans), spot urine samples from a subcohort from the PREDIMED study were stratified using a validated food frequency questionnaire. Urine samples of nonpulse consumers (≤4 g/day of pulse intake) and habitual pulse consumers (≥25 g/day of pulse intake) were analyzed using a 1 H nuclear magnetic resonance (NMR) metabolomics approach combined with multi- and univariate data analysis. Pulse consumption showed differences through 16 metabolites coming from (i) choline metabolism, (ii) protein-related compounds, and (iii) energy metabolism (including lower urinary glucose). Stepwise logistic regression analysis was applied to design a combined model of pulse exposure, which resulted in glutamine, dimethylamine, and 3-methylhistidine. This model was evaluated by a receiver operating characteristic curve (AUC > 90% in both training and validation sets). The application of NMR-based metabolomics to reported pulse exposure highlighted new candidates for biomarkers of pulse consumption and the impact on energy metabolism, generating new hypotheses on energy modulation. Further intervention studies will confirm these findings.

Tomato Juice Consumption Modifies the Urinary Peptide Profile in Sprague-Dawley Rats with Induced Hepatic Steatosis

PubMed Central

Martín-Pozuelo, Gala; González-Barrio, Rocío; Barberá, Gonzalo G.; Albalat, Amaya; García-Alonso, Javier; Mullen, William; Mischak, Harald; Periago, María Jesús

2016-01-01

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in Western countries, with a high prevalence, and has been shown to increase the risk of type 2 diabetes, cardiovascular disease (CVD), etc. Tomato products contain several natural antioxidants, including lycopene—which has displayed a preventive effect on the development of steatosis and CVD. Accordingly, the aim of the present work was to evaluate the effect of tomato juice consumption on the urinary peptide profile in rats with NAFLD induced by an atherogenic diet and to identify potential peptide biomarkers for diagnosis. Urine samples, collected weekly for four weeks, were analyzed by capillary electrophoresis (CE) coupled to a mass spectrometer (MS). A partial least squares-discriminant analysis (PLS-DA) was carried out to explore the association between differential peptides and treatments. Among the 888 peptides initially identified, a total of 55 were obtained as potential biomarkers. Rats with steatosis after tomato juice intake showed a profile intermediate between that of healthy rats and that of rats with induced hepatic steatosis. Accordingly, tomato products could be considered as a dietary strategy for the impairment of NAFLD, although further research should be carried out to develop a specific biomarkers panel for NAFLD. PMID:27792191

Could Biomarkers of Bone, Cartilage or Synovium Turnover Be Used for Relapse Prediction in Rheumatoid Arthritis Patients?

PubMed Central

Dénarié, Delphine; Constant, Elodie; Thomas, Thierry

2014-01-01

Objective. The aim of this review is to clarify the usefulness of bone, cartilage, and synovial biomarker in the management of rheumatoid arthritis (RA) therapy in remission. Synovial Biomarkers. High MMP-3 levels are associated with joint progression in RA patients, but there is no data about their utility in clinical remission. IIINys and Glc-Gal-PYD seem to be more specific to synovium, but more studies are required. Cartilage Biomarkers. Unbalance between cartilage break-down biomarkers (urinary CTX II and COMP) and cartilage formation biomarker (PIIANP) was described. This unbalance is also associated with joint destruction and prognosis of destruction. No data are available on patients in remission. Bone Biomarkers. RA activity is correlated with an increase of bone resorption markers such as CTX I, PYD, and TRACP 5b and a decrease of bone formation markers such as OC and BALP. RA therapies seem to improve bone turnover in limiting bone resorption. There is no study about bone marker utility in remission. Conclusion. Biomarkers seem to correlate with RA activity and progression. They also could be used to manage RA therapies, but we need more data on RA remission to predict relapse. PMID:24744505

Exposure estimates to disinfection by-products of chlorinated drinking water.

PubMed

Weisel, C P; Kim, H; Haltmeier, P; Klotz, J B

1999-02-01

Exposure to disinfection by-products (DBPs) of drinking water is multiroute and occurs in households serviced by municipal water treatment facilities that disinfect the water as a necessary step to halt the spread of waterborne infectious diseases. Biomarkers of the two most abundant groups of DBPs of chlorination, exhaled breath levels of trihalomethanes (THMs) and urinary levels of two haloacetic acids, were compared to exposure estimates calculated from in-home tap water concentrations and responses to a questionnaire related to water usage. Background THM breath concentrations were uniformly low. Strong relationships were identified between the THM breath concentrations collected after a shower and both the THM water concentration and the THM exposure from a shower, after adjusting for the postshower delay time in collecting the breath sample. Urinary haloacetic acid excretion rates were not correlated to water concentrations. Urinary trichloroacetic acid excretion rates were correlated with ingestion exposure, and that correlation was stronger in a subset of individuals who consumed beverages primarily within their home where the concentration measurements were made. No correlation was observed between an average 48-hr exposure estimate and the urinary dichloroacetic acid excretion rate, presumably because of its short biological half-life. Valid biomarkers were identified for DBP exposures, but the time between the exposure and sample collection should be considered to account for different metabolic rates among the DBPs. Further, using water concentration as an exposure estimate can introduce misclassification of exposure for DBPs whose primary route is ingestion due to the great variability in the amount of water ingested across a population.

Assessment of Welders Exposure to Carcinogen Metals from Manual Metal Arc Welding in Gas Transmission Pipelines, Iran

PubMed Central

Golbabaei, F; Seyedsomea, M; Ghahri, A; Shirkhanloo, H; Khadem, M; Hassani, H; Sadeghi, N; Dinari, B

2012-01-01

Background: Welding can produce dangerous fumes containing various metals especially carcinogenic ones. Occupational exposure to welding fumes is associated with lung cancer. Therefore, welders in Gas Transmission Pipelines are known as a high-risk group. This study was designed to determinate the amounts of metals Cr, Ni, and Cd in breathing zone and urine of welders and to assess the possibility of introducing urinary metals as a biomarker due to occupational exposure. Methods: In this cross sectional study, 94 individuals from Gas Transmission Pipelines welders, Iran, Borujen in 2011 were selected and classified into 3 groups including Welders, Back Welders and Assistances. The sampling procedures were performed according to NIOSH 7300 for total chromium, nickel, and cadmium and NIOSH 7600 for Cr+6. For all participants urine samples were collected during the entire work shift and metals in urine were determined according to NIOSH 8310. Results: Back Welders and Assistances groups had maximum and minimum exposure to total fume and its elements, respectively. In addition, results showed that there are significant differences (P<0.05) between Welders and Back Welders with Assistances group in exposure with total fume and elements except Ni. Urinary concentrations of three metals including Cr, Cd and Ni among all welders were about 4.5, 12 and 14-fold greater than those detected in controls, respectively. Weak correlations were found between airborne and urinary metals concentrations (R2: Cr=0.45, Cd=0.298, Ni=0.362). Conclusion: Urinary metals concentrations could not be considerate as a biomarker for welders’ exposure assessment. PMID:23113226

Assessment of welders exposure to carcinogen metals from manual metal arc welding in gas transmission pipelines, iran.

PubMed

Golbabaei, F; Seyedsomea, M; Ghahri, A; Shirkhanloo, H; Khadem, M; Hassani, H; Sadeghi, N; Dinari, B

2012-01-01

Welding can produce dangerous fumes containing various metals especially carcinogenic ones. Occupational exposure to welding fumes is associated with lung cancer. Therefore, welders in Gas Transmission Pipelines are known as a high-risk group. This study was designed to determinate the amounts of metals Cr, Ni, and Cd in breathing zone and urine of welders and to assess the possibility of introducing urinary metals as a biomarker due to occupational exposure. In this cross sectional study, 94 individuals from Gas Transmission Pipelines welders, Iran, Borujen in 2011 were selected and classified into 3 groups including Welders, Back Welders and Assistances. The sampling procedures were performed according to NIOSH 7300 for total chromium, nickel, and cadmium and NIOSH 7600 for Cr+6. For all participants urine samples were collected during the entire work shift and metals in urine were determined according to NIOSH 8310. Back Welders and Assistances groups had maximum and minimum exposure to total fume and its elements, respectively. In addition, results showed that there are significant differences (P<0.05) between Welders and Back Welders with Assistances group in exposure with total fume and elements except Ni. Urinary concentrations of three metals including Cr, Cd and Ni among all welders were about 4.5, 12 and 14-fold greater than those detected in controls, respectively. Weak correlations were found between airborne and urinary metals concentrations (R2: Cr=0.45, Cd=0.298, Ni=0.362). Urinary metals concentrations could not be considerate as a biomarker for welders' exposure assessment.

Primary Bladder Neurofibroma: A Rare Case with Clinical Implications and Diagnostic Challenges.

PubMed

Umakanthan, Srikanth; Naik, Ramadas; Bukelo, Maryann Margaret; Rai, Sharada; Prabhu, Laxman

2015-09-01

Neurofibroma of the genito-urinary tract is rare. Urinary bladder is the commonest organ involved in cases of urinary tract involvement. Patients present early in life and there is male preponderance. We discuss here a case of primary neurofibroma of the urinary bladder in a 52-year-male presenting with haematuria, irritative bladder symptoms and pelvic mass. Cystoscopy showed a swelling in the left lateral wall. A transurethral biopsy revealed neurofibroma of the urinary bladder. Immunohistochemical studies confirmed the diagnosis.

Primary Bladder Neurofibroma: A Rare Case with Clinical Implications and Diagnostic Challenges

PubMed Central

Naik, Ramadas; Bukelo, Maryann Margaret; Rai, Sharada; Prabhu, Laxman

2015-01-01

Neurofibroma of the genito-urinary tract is rare. Urinary bladder is the commonest organ involved in cases of urinary tract involvement. Patients present early in life and there is male preponderance. We discuss here a case of primary neurofibroma of the urinary bladder in a 52-year-male presenting with haematuria, irritative bladder symptoms and pelvic mass. Cystoscopy showed a swelling in the left lateral wall. A transurethral biopsy revealed neurofibroma of the urinary bladder. Immunohistochemical studies confirmed the diagnosis. PMID:26500913

Domestic nitrogen oxide exposure, urinary nitrate, and asthma prevalence in preschool children.

PubMed

Ciuk, J; Volkmer, R E; Edwards, J W

2001-01-01

A South Australian preschool study carried out in 1993 showed that the prevalence of respiratory symptoms was significantly associated with use of unflued gas appliances for cooking and heating. The authors sought to determine an association between domestic exposure to nitrogen dioxide and the excretion of total urinary nitrate and nitrite, and their association with asthma prevalence. The results indicated that the geometric mean concentrations of nitrogen dioxide were much higher in homes that had natural gas appliance(s) and other types of appliances (i.e., electric and solid fuel). Higher levels of nitrogen dioxide were found in homes of suburban areas with higher prevalence of asthma and respiratory symptoms. Nitrogen dioxide levels were lower in the summer, and there was a higher level in kitchens than in bedrooms. Urinary nitrate excretion was evaluated in 1,335 preschool children from the same sampling areas. No association existed between nitrogen dioxide levels and urinary nitrates, nor was there a relationship between urinary nitrates and asthma prevalence. These findings confirm that there is a positive association between nitrogen dioxide exposure from gas appliances and the prevalence of respiratory symptoms, but urinary nitrate is not a useful biomarker of exposure at these levels.

Altered urinary porphyrins and mercury exposure as biomarkers for autism severity in Egyptian children with autism spectrum disorder.

PubMed

Khaled, Eman M; Meguid, Nagwa A; Bjørklund, Geir; Gouda, Amr; Bahary, Mohamed H; Hashish, Adel; Sallam, Nermin M; Chirumbolo, Salvatore; El-Bana, Mona A

2016-12-01

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that affects social, communication, and behavioral development. Recent evidence supported but also questioned the hypothetical role of compounds containing mercury (Hg) as contributors to the development of ASD. Specific alterations in the urinary excretion of porphyrin-containing ring catabolites have been associated with exposure to Hg in ASD patients. In the present study, the level of urinary porphyrins, as biomarkers of Hg toxicity in children with ASD, was evaluated, and its correlation with severity of the autistic behavior further explored. A total of 100 children was enrolled in the present study. They were classified into three groups: children with ASD (40), healthy controls (40), and healthy siblings of the ASD children (20). Children with ASD were diagnosed using DSM-IV-TR, ADI-R, and CARS tests. Urinary porphyrins were evaluated within the three groups using high-performance liquid chromatography (HPLC), after plasma evaluation of mercury (Hg) and lead (Pb) in the same groups. Results showed that children with ASD had significantly higher levels of Hg, Pb, and the porphyrins pentacarboxyporphyrin, coproporphyrin, precoproporphyrin, uroporphyrins, and hexacarboxyporphyrin compared to healthy controls and healthy siblings of the ASD children. However, there was no significant statistical difference in the level of heptacarboxyporphyrin among the three groups, while a significant positive correlation between the levels of coproporphyrin and precoproporphyrin and autism severity was observed. Mothers of ASD children showed a higher percentage of dental amalgam restorations compared to the mothers of healthy controls suggesting that high Hg levels in children with ASD may relate to the increased exposure to Hg from maternal dental amalgam during pregnancy and lactation. The results showed that the ASD children in the present study had increased blood Hg and Pb levels compared with healthy control children indicating that disordered porphyrin metabolism might interfere with the pathology associated with the autistic neurologic phenotype. The present study indicates that coproporphyrin and precoproporhyrin may be utilized as possible biomarkers for heavy metal exposure and autism severity in children with ASD.

Simultaneous Exposure to Heavy Metals among Residents in the Industrial Complex: Korean National Cohort Study

PubMed Central

Park, Heejin; Lee, Kyoungho; Moon, Chan-Seok; Woo, Kyungsook; Kang, Tack-Shin; Chung, Eun-Kyung; Son, Bu-Soon

2015-01-01

A survey was conducted to evaluate the multi-exposure level and correlation among toxic metal biomarkers (Cd, Pb, and Hg). A total of 592 individuals who participated in the survey were residents near an industrial complex in Gwangyang and Yeosu (exposed group) and of Hadong and Namhae (control group) in southern Korea from May 2007 to November 2010. The Gwangyang and Yeosu area exposed groups had slightly higher blood Pb (2.21 and 1.90 µg/dL), urinary Cd observed values (2.20 and 1.46 µg/L), urinary Cd with a urinary creatinine correction (1.43 and 1.25 µg/g Cr), and urinary Hg observed values (2.26 and 0.98 µg/L) in women participants than those in the Hadong and Namhae area (control group). Blood Pb (3.18 and 2.55 µg/dL), urinary Hg observed values (1.14 and 0.92 µg/L), and urinary Hg with a urinary creatinine correction (1.06 and 0.96 µg/L) for male participants were also slightly higher than those in the Hadong and Namhae area (control group). The correlation among urinary Cd, Hg and Pb concentrations in the blood was significant. We suggest that the exposed group of residents were simultaneously exposed to Pb, Cd, and Hg from contaminated ambient air originating from the iron manufacturing industrial complex. PMID:26024361

Urinary p-cresol is elevated in young French children with autism spectrum disorder: a replication study.

PubMed

Gabriele, Stefano; Sacco, Roberto; Cerullo, Sonia; Neri, Cristina; Urbani, Andrea; Tripi, Gabriele; Malvy, Joëlle; Barthelemy, Catherine; Bonnet-Brihault, Frédérique; Persico, Antonio M

2014-09-01

The aromatic compound p-cresol (4-methylphenol) has been found elevated in the urines of Italian autistic children up to 8 years of age. The present study aims at replicating these initial findings in an ethnically distinct sample and at extending them by measuring also the three components of urinary p-cresol, namely p-cresylsulfate, p-cresylglucuronate and free p-cresol. Total urinary p-cresol, p-cresylsulfate and p-cresylglucuronate were significantly elevated in 33 French autism spectrum disorder (ASD) cases compared with 33 sex- and age-matched controls (p < 0.05). This increase was limited to ASD children aged ≤8 years (p < 0.01), and not older (p = 0.17). Urinary levels of p-cresol and p-cresylsulfate were associated with stereotypic, compulsive/repetitive behaviors (p < 0.05), although not with overall autism severity. These results confirm the elevation of urinary p-cresol in a sizable set of small autistic children and spur interest into biomarker roles for p-cresol and p-cresylsulfate in autism.

Renal studies in safety pharmacology and toxicology: A survey conducted in the top 15 pharmaceutical companies.

PubMed

Benjamin, Amanda; Gallacher, David J; Greiter-Wilke, Andrea; Guillon, Jean-Michel; Kasai, Cheiko; Ledieu, David; Levesque, Paul; Prelle, Katja; Ratcliffe, Sian; Sannajust, Frederick; Valentin, Jean-Pierre

2015-01-01

With the recent development of more sensitive biomarkers to assess kidney injury preclinically, a survey was designed i) to investigate what strategies are used to investigate renal toxicity in both ICH S7A compliant Safety Pharmacology (SP) studies after a single dose of a compound and within repeat-dose toxicity studies by large pharmaceutical companies today; ii) to understand whether renal SP studies have impact or utility in drug development and/or if it may be more appropriate to assess renal effects after multiple doses of compounds; iii) to ascertain how much mechanistic work is performed by the top 15 largest pharmaceutical companies (as determined by R&D revenue size); iv) to gain an insight into the impact of the validation of DIKI biomarkers and their introduction in the safety evaluation paradigm; and v) to understand the impact of renal/urinary safety study data on progression of projects. Two short anonymous surveys were submitted to SP leaders of the top 15 pharmaceutical companies, as defined by 2012 R&D portfolio size. Fourteen multiple choice questions were designed to explore the strategies used to investigate renal effects in both ICH S7A compliant SP studies and within toxicology studies. A 67% and 60% response rate was obtained in the first and second surveys, respectively. Nine out of ten respondent companies conduct renal excretory measurements (eg. urine analysis) in toxicology studies whereas only five out of ten conduct specific renal SP studies; and all of those 5 also conduct the renal excretory measurements in toxicology studies. These companies measure and/or calculate a variety of parameters as part of these studies, and also on a case by case basis include regulatory qualified and non-qualified DIKI biomarkers. Finally, only one company has used renal/urinary functional data alone to stop a project, whereas the majority of respondents combine renal data with other target organ assessments to form an integrated decision-making set. These short surveys highlighted areas of similarity: a) urinary measurements are most commonly taken on repeat-dose toxicity studies, and b) renal SP studies are less often utilised. The two major differences are a) lack of consistent use of DIKI biomarkers in urinary safety studies and b) the way large pharmaceutical companies assess renal function. Finally, suggestions were made to improve the safety assessment methods for determining the safety of compounds with potential renal liability. Copyright © 2015 Elsevier Inc. All rights reserved.

Relationship between serum leptin concentrations and bone mineral density as well as biochemical markers of bone turnover in women with postmenopausal osteoporosis.

PubMed

Shaarawy, Mohamed; Abassi, Asmaa Farid; Hassan, Hany; Salem, Mahmoud E

2003-04-01

To determine whether leptin is involved in bone remodeling in patients with postmenopausal osteoporosis. Cross-sectional study. Department of Obstetrics and Gynecology, Faculty of Medicine, Cairo University. Ninety postmenopausal osteoporotic women (37 obese and 53 nonobese) and 30 healthy premenopausal women from the same clinic served as controls. Lumbar spine bone mineral density (LS-BMD) of osteoporotic patients was more than 2.5 SD below the normal mean of healthy premenopausal women. Serum levels of leptin, osteocalcin (OC), bone alkaline phosphatase (B-ALP), urinary deoxypyridinoline (DPyr), and N-telopeptide of type 1 collagen (NTX) as well as LS-BMD using dual energy X-ray absorptiometry (DEXA). The serum leptin level in obese postmenopausal osteoporotic patients was significantly increased compared with nonobese osteoporotic patients. There were no significant differences of bone formation markers (B-ALP, OC), bone resorption markers (DPyr, NTX), or LS-BMD between the obese and nonobese groups. There were no significant correlations between serum leptin and any biomarkers of bone turnover and BMD. In postmenopausal osteoporotic patients with increased bone turnover, serum leptin concentration is not correlated with BMD or with the biomarkers of bone formation or bone resorption.

Urinary YKL-40 as a Candidate Biomarker for Febrile Urinary Tract Infection in Young Children.

PubMed

Kim, Hyun Hee; Chung, Mi Hae; Bin, Joong Hyun; Cho, Kyoung Soon; Lee, Juyoung; Suh, Jin Soon

2018-01-01

Given that YKL-40 is a known marker of inflammation, we sought to determine its association with urinary tract infection (UTI) in febrile children. In total, 44 children aged 0 to 24 months with febrile UTI and 35 age- and sex-matched controls with fever from other causes were enrolled in the study. ELISA was performed to determine the level of YKL-40 in urine collected from each child. The ratio of urinary YKL-40 to creatinine (Cr) was higher in the children with a UTI than in the controls (P<0.001). The area under the ROC curve for detecting UTI was 0.88 for the urinary YKL-40/Cr ratio, 0.86 for pyuria, and 0.71 for positive nitrite on urinalysis. We applied a cut-off value of 125.23 pg/mg to urinary YKL-40/Cr for detecting UTI. Eight of nine children in the control group with pyuria had urinary YKL-40/Cr levels lower than 125.23 pg/mg, and the one child in the UTI group without pyuria or positive nitrite had a urinary YKL-40/Cr level greater than 125.23 pg/mg. Determining the levels of urinary YKL-40/Cr may help identify true cases of UTI in febrile young children, especially when they have pyuria but not nitrite, or have neither pyuria nor nitrite in the urine. © The Korean Society for Laboratory Medicine

Urinary YKL-40 as a Candidate Biomarker for Febrile Urinary Tract Infection in Young Children

PubMed Central

Kim, Hyun Hee; Chung, Mi Hae; Bin, Joong Hyun; Cho, Kyoung Soon; Lee, Juyoung

2018-01-01

Background Given that YKL-40 is a known marker of inflammation, we sought to determine its association with urinary tract infection (UTI) in febrile children. Methods In total, 44 children aged 0 to 24 months with febrile UTI and 35 age- and sex-matched controls with fever from other causes were enrolled in the study. ELISA was performed to determine the level of YKL-40 in urine collected from each child. Results The ratio of urinary YKL-40 to creatinine (Cr) was higher in the children with a UTI than in the controls (P<0.001). The area under the ROC curve for detecting UTI was 0.88 for the urinary YKL-40/Cr ratio, 0.86 for pyuria, and 0.71 for positive nitrite on urinalysis. We applied a cut-off value of 125.23 pg/mg to urinary YKL-40/Cr for detecting UTI. Eight of nine children in the control group with pyuria had urinary YKL-40/Cr levels lower than 125.23 pg/mg, and the one child in the UTI group without pyuria or positive nitrite had a urinary YKL-40/Cr level greater than 125.23 pg/mg. Conclusions Determining the levels of urinary YKL-40/Cr may help identify true cases of UTI in febrile young children, especially when they have pyuria but not nitrite, or have neither pyuria nor nitrite in the urine. PMID:29071817

Paired Serum and Urine Concentrations of Biomarkers of Diethyl Phthalate, Methyl Paraben, and Triclosan in Rats

PubMed Central

Teitelbaum, Susan L.; Li, Qian; Lambertini, Luca; Belpoggi, Fiorella; Manservisi, Fabiana; Falcioni, Laura; Bua, Luciano; Silva, Manori J.; Ye, Xiaoyun; Calafat, Antonia M.; Chen, Jia

2015-01-01

Background Exposure to environmental chemicals, including phthalates and phenols such as parabens and triclosan, is ubiquitous within the U.S. general population. Objective This proof-of-concept rodent study examined the relationship between oral doses of three widely used personal care product ingredients [diethyl phthalate (DEP), methyl paraben (MPB), and triclosan] and urine and serum concentrations of their respective biomarkers. Methods Using female Sprague-Dawley rats, we carried out two rounds of experiments with oral gavage doses selected in accordance with no observed adverse effect levels (NOAELs) derived from previous studies: 1,735 (DEP), 1,050 (MPB), 50 (triclosan) mg/kg/day. Administered doses ranged from 0.005 to 173 mg/kg/day, 10–100,000 times below the NOAEL for each chemical. Controls for the MPB and triclosan experiments were animals treated with olive oil (vehicle) only; controls for the DEP serum experiments were animals treated with the lowest doses of MPB and triclosan. Doses were administered for 5 days with five rats in each treatment group. Urine and blood serum, collected on the last day of exposure, were analyzed for biomarkers. Relationships between oral dose and biomarker concentrations were assessed using linear regression. Results Biomarkers were detected in all control urine samples at parts-per-billion levels, suggesting a low endemic environmental exposure to the three chemicals that could not be controlled even with all of the precautionary measures undertaken. Among the exposed animals, urinary concentrations of all three biomarkers were orders of magnitude higher than those in serum. A consistently positive linear relationship between oral dose and urinary concentration was observed (R2 > 0.80); this relationship was inconsistent in serum. Conclusions Our study highlights the importance of carefully considering the oral dose used in animal experiments and provides useful information in selecting doses for future studies. Citation Teitelbaum SL, Li Q, Lambertini L, Belpoggi F, Manservisi F, Falcioni L, Bua L, Silva MJ, Ye X, Calafat AM, Chen J. 2016. Paired serum and urine concentrations of biomarkers of diethyl phthalate, methyl paraben, and triclosan in rats. Environ Health Perspect 124:39–45; http://dx.doi.org/10.1289/ehp.1409586 PMID:26047088

Environmental exposure to arsenic and chromium in children is associated with kidney injury molecule-1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cárdenas-González, M.

Environmental hazards from natural or anthropological sources are widespread, especially in the north-central region of Mexico. Children represent a susceptible population due to their unique routes of exposure and special vulnerabilities. In this study we evaluated the association of exposure to environmental kidney toxicants with kidney injury biomarkers in children living in San Luis Potosi (SLP), Mexico. A cross-sectional study was conducted with 83 children (5–12 years of age) residents of Villa de Reyes, SLP. Exposure to arsenic, cadmium, chromium, fluoride and lead was assessed in urine, blood and drinking water samples. Almost all tap and well water samples hadmore » levels of arsenic (81.5%) and fluoride (100%) above the permissible levels recommended by the World Health Organization. Mean urine arsenic (45.6 ppb) and chromium (61.7 ppb) were higher than the biological exposure index, a reference value in occupational settings. Using multivariate adjusted models, we found a dose-dependent association between kidney injury molecule-1 (KIM-1) across chromium exposure tertiles [(T1: reference, T2: 467 pg/mL; T3: 615 pg/mL) (p-trend=0.001)]. Chromium upper tertile was also associated with higher urinary miR-200c (500 copies/μl) and miR-423 (189 copies/μL). Arsenic upper tertile was also associated with higher urinary KIM-1 (372 pg/mL). Other kidney injury/functional biomarkers such as serum creatinine, glomerular filtration rate, albuminuria, neutrophil gelatinase-associated lipocalin and miR-21 did not show any association with arsenic, chromium or any of the other toxicants evaluated. We conclude that KIM-1 might serve as a sensitive biomarker to screen children for kidney damage induced by environmental toxic agents. - Highlights: • Children living in Mexico had exceedingly high arsenic and chromium exposure. • Arsenic and chromium exposure was significantly associated with urinary KIM-1. • KIM-1 might serve as a sensitive biomarker to evaluate kidney injury in children.« less

[S1 Herpes zoster localization: acute urinary retention in woman].

PubMed

Vella, Marco; Mastrocinque, Giuseppe; Romeo, Salvatore; Giammanco, Giovanni; Melloni, Darwin

2011-01-01

Acute urinary retention in women is rare. The varicella-zoster virus causes inflammatory lesions of the sensory-root ganglions, meninges and, less frequently, spinal cord. Herpes zoster has been reported to affect, although rarely, lower urinary tract innervations, and acute urinary retention can be thought to occur in the presence of sacral dermatome involvement. Usually it is located in S2-4 dermatome and the prognosis for acute urinary retention is benign resolving in about 20 days. We present a case in which the S1 dermatome was involved and acute urinary retention developed. After 10 days of specific therapy and self-catheterization the problem resolved.

DTI-MRI biomarkers in the search for normal pressure hydrocephalus aetiology: a review.

PubMed

Hoza, David; Vlasák, Aleš; Hořínek, Daniel; Sameš, Martin; Alfieri, Alex

2015-04-01

Normal pressure hydrocephalus (NPH) is a clinical syndrome characterized by gait disturbances, urinary incontinence and dementia. Clinical presentation overlaps with Alzheimer disease (AD). Early recognition thus early intervention (shunting) is important for successful treatment, but lack of a diagnostic test with sufficient sensitivity and specificity complicates the diagnosis. We performed literature search and composed a structured review of imaging biomarkers of NPH. Morphometric studies are not sufficient to diagnose NPH. Hydrocephalus is a common finding in elderly people due to the symmetric brain atrophy and is even more pronounced in patients with AD. The key MRI biomarker seems to be diffusion tensor imaging (DTI). According to recent studies, the DTI analysis of the splenium corporis callosi, posterior limb of internal capsule, hippocampus and fornix combined with measurement of Evans index is a promising MRI biomarker of NPH and could be used for NPH diagnostics and in the differential diagnosis from AD and other dementias.

Biomarkers in patients treated with BCG: an update.

PubMed

Klap, Julia; Schmid, Marianne; Loughlin, Kevin R

2014-08-01

Bacillus Calmette-Guerin (BCG) instillations are the recommended treatment for non-muscle invasive bladder cancer but high recurrence and progression rates remain after treatment. Despite patients risk stratification, BCG effectiveness remains unpredictable. A close, invasive and expensive follow up is mandatory. To improve or even replace this heavy surveillance in this high risk population, validated biomarkers were developed. To identify the useful tools for the urologist in monitoring bladder cancer patients, we reviewed the literature focusing on plasma and urinary biomarkers of BCG-therapy outcome. Articles dated from 1988 to 2013 including specific keywords (urinary bladder neoplasm, biological markers, intravesical administration, recurrence) were examined and relevant papers were selected. Before treatment initiation, genetic polymorphisms of multiple agents (cytokines, matrix-metalloproteinases) were found to become very useful to tailor therapy and monitoring. Those biomarkers belong to personalized medicine which is a topic of great interest today, but still need to be validated in cohorts from different ethnicities. During instillations, cytokines (IL-2, IL-8, IL-6/IL-10) were reported to be reliable to determine treatment response and efficacy. Further studies are needed to confirm results and standardize thresholds. After treatment, UroVysion, the FDA-approved fluorescence in situ hybridization (FISH), appeared to be the most robust marker of all the clinical parameters reviewed; but is not yet validated for BCG-treated patients. No recommendations for everyday practice can be established today, but a combination of several markers and clinicopathological characteristics may be the future. As bladder cancer diagnosis and management are evolving, practicing urologists should be aware of and utilize bladder cancer markers in clinical practice.

Combined use of epithelial membrane antigen and nuclear matrix protein 52 as sensitive biomarkers for detection of bladder cancer.

PubMed

Attallah, Abdelfattah M; El-Far, Mohamed; Abdallah, Sanaa O; El-Waseef, Ahmed M; Omran, Mohamed M; Abdelrazek, Mohamed A; Attallah, Ahmed A; Saadh, Mohamed J; Radwan, Mohamed; El-waffaey, Kholoud A; Abol-Enei, Hassan

2015-11-11

The advent of noninvasive urine-based markers as well as other novel modalities has yielded improved diagnostic accuracy. However, the new markers failed to reach higher sensitivity and specificity. We therefore evaluated the potential role of epithelial membrane antigen (EMA) and nuclear matrix protein 52 (NMP-52) singly and combined as noninvasive biomarkers for the detection of bladder cancer (BC). A total of 160 individuals including 66 patients with BC, 54 patients with benign urologic disorders and 40 healthy volunteers were investigated. Urinary EMA at 130 kDa and NMP at 52 kDa were identified, purified and quantified by Western blot, electroelution and enzyme-linked immunosorbent assay (ELISA). The diagnostic performance of each biomarker and their combination were compared using area under receiver operating characteristic curves (AUC). Mean urinary EMA, 2.42 µg/mL, and NMP-52, 17.85 µg/mL, were significantly elevated in patients with BC compared to controls, 1.18 and 3.44 µg/mL, respectively (p<0.0001). The combined use of these markers yielded values which were increased 4.4- and 13.7-fold in the benign and malignant disease groups, respectively, with respect to the normal group. The values of EMA and NMP-52 were significantly higher in patients with higher-grade tumors than those with lower-grade tumors (p<0.0001). Moreover, this combination could predict all BC stages and grades with 0.91 AUC, 94% sensitivity and 80% specificity. EMA and NMP-52 in combination could be promising noninvasive biomarkers for BC detection.

Lung inflammation biomarkers and lung function in children chronically exposed to arsenic

PubMed Central

Olivas-Calderón, Edgar; Recio-Vega, Rogelio; Gandolfi, A. Jay; Lantz, R. Clark; González-Cortes, Tania; Alba, Cesar Gonzalez-De; Froines, John R.; Espinosa-Fematt, Jorge A.

2016-01-01

Evidence suggests that exposure to arsenic in drinking water during early childhood or in utero is associated with an increase in respiratory symptoms and diseases in adulthood, however only a few studies have been carried out during those sensitive windows of exposure. Recently our group demonstrated that exposure to arsenic during early childhood or in utero was associated with impairment in the lung function in children and suggested that this adverse effect could be due to a chronic inflammatory response to the metalloid. Therefore, a cross-sectional study was designed in a cohort of children associating lung inflammatory biomarkers and lung function with urinary As levels. A total of 275 healthy children were partitioned into four study groups according with their As levels. Inflammation biomarkers were measured in sputum by ELISA and the lung function was evaluated by spirometry. Fifty eight percent of the studied children were found to have a restrictive spirometric pattern. In the two highest exposed groups, the Soluble Receptor for Advanced Glycation Endproducts (sRAGE) sputum level was significantly lower and Matrix Metalloproteinase-9 (MMP-9) concentration was higher. When the biomarkers were correlated to the urinary arsenic species, negative associations were found between dimethylarsinic (DMA), monomethylarsenic percentage (%MMA) and dimethylarsinic percentage (%DMA) with sRAGE and positive associations between %DMA with MMP-9 and with the MMP-9/Tissue Inhibitor of Metalloproteinase (TIMP-1) ratio. In conclusion, chronic arsenic exposure of children negatively correlates with sRAGE, and positively correlated with MMP-9 and MMP-9/TIMP-1 levels, and increases the frequency of an abnormal spirometric pattern. PMID:26048584

The use of biomonitoring data in exposure and human health risk assessment: benzene case study

PubMed Central

Angerer, Juergen; Boogaard, Peter J.; Hughes, Michael F.; O’Lone, Raegan B.; Robison, Steven H.; Robert Schnatter, A.

2013-01-01

A framework of “Common Criteria” (i.e. a series of questions) has been developed to inform the use and evaluation of biomonitoring data in the context of human exposure and risk assessment. The data-rich chemical benzene was selected for use in a case study to assess whether refinement of the Common Criteria framework was necessary, and to gain additional perspective on approaches for integrating biomonitoring data into a risk-based context. The available data for benzene satisfied most of the Common Criteria and allowed for a risk-based evaluation of the benzene biomonitoring data. In general, biomarker (blood benzene, urinary benzene and urinary S-phenylmercapturic acid) central tendency (i.e. mean, median and geometric mean) concentrations for non-smokers are at or below the predicted blood or urine concentrations that would correspond to exposure at the US Environmental Protection Agency reference concentration (30 µg/m3), but greater than blood or urine concentrations relating to the air concentration at the 1 × 10−5 excess cancer risk (2.9 µg/m3). Smokers clearly have higher levels of benzene exposure, and biomarker levels of benzene for non-smokers are generally consistent with ambient air monitoring results. While some biomarkers of benzene are specific indicators of exposure, the interpretation of benzene biomonitoring levels in a health-risk context are complicated by issues associated with short half-lives and gaps in knowledge regarding the relationship between the biomarkers and subsequent toxic effects. PMID:23346981

Urinary Exosomes: The Potential for Biomarker Utility, Intercellular Signaling and Therapeutics in Urological Malignancy.

PubMed

Franzen, Carrie A; Blackwell, Robert H; Foreman, Kimberly E; Kuo, Paul C; Flanigan, Robert C; Gupta, Gopal N

2016-05-01

Exosomes are small secreted vesicles that contain proteins, mRNA and miRNA with the potential to alter signaling pathways in recipient cells. While exosome research has flourished, few publications have specifically considered the role of genitourinary cancer shed exosomes in urine, their implication in disease progression and their usefulness as noninvasive biomarkers. In this review we examined the current literature on the role of exosomes in intercellular communication and as biomarkers, and their potential as delivery vehicles for therapeutic applications in bladder, prostate and renal cancer. We searched PubMed® and Google® with the key words prostate cancer, bladder cancer, kidney cancer, exosomes, microvesicles and urine. Relevant articles, including original research studies and reviews, were selected based on contents. A review of this literature was generated. Cancer exosomes can be isolated from urine using various techniques. Cancer cells have been found to secrete more exosomes than normal cells. These exosomes have a role in cellular communication by interacting with and depositing their cargo in target cells. Bladder, prostate and renal cancer exosomes have been shown to enhance migration, invasion and angiogenesis. These exosomes have also been shown to increase proliferation, confer drug resistance and promote immune evasion. Urinary exosomes can be isolated from bladder, kidney and prostate cancer. They serve as a potential reservoir for biomarker identification. Exosomes also have potential for therapeutics as siRNA or pharmacological agents can be loaded into exosomes. Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

URINARY BIOMARKERS IN CHARCOAL WORKERS EXPOSED TO WOOD SMOKE IN BAHIA STATE, BRAZIL

EPA Science Inventory

Charcoal is an important source of energy for domestic and industrial use in many countries. In Brazil, the largest producer of charcoal in the world, approximately 350,000 workers are linked to the production and transportation of charcoal. In order to evaluate the occupationa...

The Reliability of Using Urinary Biomarkers to Estimate Human Exposures to Chlorpyrifos and Diazinon

EPA Science Inventory

A few studies have reported concurrent levels of chlorpyrifos (CPF) and diazinon (DZN) and their environmentally occurring metabolites, 3,5,6-trichloro-2-pyridinol (TCP) and 2-isopropyl-6-methyl-4-pyrimidinol (IMP), in food and in environmental media. This information raises ques...

Review of Pesticide Urinary Biomarker Measurements from Selected US EPA Children's Observational Exposure Studies

EPA Science Inventory

Children are exposed to a wide variety of pesticides originating from both outdoor and indoor sources. Several studies were conducted or funded by the EPA over the past decade to investigate children’s exposure to organophosphate and pyrethroid pesticides and the factors that im...

ARSENIC URINARY METABOLITES: BIOMARKER STUDY

EPA Science Inventory

A population of adults and children with ranges of 10 to 300 g/l of arsenic in their drinking water will have their urine analyzed for total and speciated arsenic. A sample of 30 families will be selected based on tap water analyses for arsenic. This sample will comprise 50% adul...

Genetic and Epigenetic Biomarkers for Recurrent Prostate Cancer After Radiotherapy

DTIC Science & Technology

2015-07-01

several distinct advantages over surgical treatment, such as no complications from surgery, and a low risk of urinary incontinence , RT treatment takes...Khorana, Tissue factor and VEGF expression in prostate carcinoma: a tissue microarray study. Cancer Invest, 2009. 27(4): p. 430-4. 7. Crawford, E.D

Using a physiologically based pharmacokinetic model to link urinary biomarker concentrations to dietary exposure of perchlorate

EPA Science Inventory

Exposure to perchlorate is widespread in the United States and many studies have attempted to character the perchlorate exposure by estimating the average daily intakes of perchlorate. These approaches provided population-based estimates, but did not provide individual-level exp...

Pyrethroid insecticides and their environmental degradates in repeated duplicate-diet solid food samples of 50 adults

EPA Science Inventory

Previous research has reported concurrent levels of pyrethroid insecticides and their environmental degradates in foods. These data raise concerns about using these same pyrethroid degradates found in the diet as urinary biomarkers of exposures in humans. The primary objective wa...

Correlation between urinary GAG and anti-idursulfase ERT neutralizing antibodies during treatment with NICIT immune tolerance regimen: A case report☆,☆☆

PubMed Central

Kim, Sarah; Whitley, Chester B.; Jarnes Utz, Jeanine R.

2018-01-01

Introduction Antibodies to intravenous idursulfase enzyme replacement therapy (ERT) for patients with Hunter syndrome (mucopolysaccharidosis type II, MPS II) can have a harmful clinical impact, including both increasing risk of infusion reactions and inhibiting therapeutic activity. Thus, failure to monitor anti-idursulfase antibodies and neutralizing antibodies, and delays in reporting results, may postpone critical clinical decisions. Hypothesis Urinary glycosaminoglycan (GAG) levels may be used as a biomarker for anti-idursulfase antibodies and neutralizing antibodies to improve timeliness in monitoring and managing ERT. Methods This is a case report describing a patient with MPS II with high levels of neutralizing antibodies and worsened clinical status who was treated for five years with a non-immunosuppressive and non-cytotoxic immune tolerance (NICIT) regimen, consisting of intravenous immune globulin and frequent infusions of idursulfase. Neutralizing antibodies and total anti-idursulfase antibodies were measured by two different methods, the direct 1,9-dimethylmethylene blue (DMB) assay and cetylpyridinium chloride carbazole-borate (CPC) assay. Results Neutralizing antibodies, measured as percent inhibition of enzyme activity and also by total neutralizing antibody titer, were correlated with quantitative urinary GAG measured by DMB assay (p = 0.026, p = 0.0067), and quantitative urinary GAG by CPC assay with percent inhibition of enzyme activity by neutralizing antibodies (p = 0.0475). The NICIT regimen showed a sustained immune tolerance after five years and was well-tolerated. Conclusions Urinary GAG, measured by DMB assay, may be a biomarker for anti-idursulfase neutralizing antibodies and is useful for managing immune tolerance regimens for patients with MPS II who have high levels of anti-idursulfase neutralizing antibodies. This study highlights the importance of regular and frequent monitoring of urinary GAG in patients with MPS II who are receiving ERT. The NICIT regimen, with less drug toxicities, may be preferred in patients with MPS who have a high risk of infections and whose disease progresses less rapidly than some other lysosomal storage diseases, such as infantile Pompe disease. PMID:28610913

Measurements of C-reactive protein (CRP) and nerve-growth-factor (NGF) concentrations in serum and urine samples of dogs with neurologic disorders.

PubMed

Kordass, Ulrike; Carlson, Regina; Stein, Veronika Maria; Tipold, Andrea

2016-01-08

The purpose of this study was to prove the hypothesis that C-reactive protein (CRP) and nerve growth factor (NGF) may be potential biomarkers for lower urinary tract disorders and may be able to distinguish between micturition dysfunctions of different origin in dogs with spinal cord diseases. NGF- and CRP- concentrations were measured in serum and urine samples using specific ELISA-Kits. Results in urine were standardized by urine-creatinine levels. CRP in serum was detectable in 32/76 and in urine samples in 40/76 patients. NGF could be measured in all serum and in 70/76 urine samples. Urinary CRP concentrations were significantly higher in dogs with micturition dysfunction (p = 0.0009) and in dogs with different neurological diseases (p = 0.0020) compared to the control group. However, comparing dogs with spinal cord disorders with and without associated micturition dysfunction no significant difference could be detected for NGF and CRP values in urine or serum samples. Additionally, levels did not decrease significantly, when measured at the time when the dogs regained the ability to urinate properly (urinary NGF p = 0.7962; urinary CRP p = 0.078). Urine samples with bacteria and/or leukocytes had no significant increase in urinary NGF (p = 0.1112) or CRP (p = 0.0534) concentrations, but higher CRP-levels in urine from dogs with cystitis were found compared to dogs without signs of cystitis. From these data we conclude that neither CRP nor NGF in urine or serum can be considered as reliable biomarkers for micturition disorders in dogs with spinal cord disorders in a clinical setting, but their production might be part of the pathogenesis of such disorders. Significantly higher levels of CRP could be found in the urine of dogs with micturition dysfunctions compared to control dogs. This phenomenon could potentially be explained by unspecific extrahepatic CRP production by smooth muscle cells in the dilated bladder.

Studies of a urinary biomarker of dietary inorganic sulphur in subjects on diets containing 1-38 mmol sulphur/day and of the half-life of ingested 34SO4(2-).

PubMed

Curno, R; Magee, E A; Edmond, L M; Cummings, J H

2008-09-01

Sulphites are widely used food additives that may damage health, hence limits are set on their use. They are excreted in urine as sulphate, along with sulphate derived from sulphur amino acids. Dietary intakes of sulphites are hard to determine, so we have tested the utility of urinary nitrogen:sulphate ratio as a biomarker of inorganic sulphur (IS) intake. Additionally we determined the half-life of ingested (34)SO(4)(2-) from its urinary excretion. Twenty healthy adult subjects were recruited by poster advertisement, for a 24-h study where they ate specified foods, which were high in IS, in addition to their normal diet. The half-life of ingested (34)SO(4)(2-) was assessed in five healthy volunteers, given 5.9 mmols of Na(2)(34)SO(4) as a single dose and collecting all urine specimens for 72-96 h. Urine and duplicate diets from three previously conducted studies were analysed for nitrogen and sulphate content, thus expanding the range of IS intakes for evaluation. Duplicate diets were analysed for IS content by ion exchange chromatography, while IS intake was predicted from urinary sulphate (g/day S)-(urinary nitrogen (g/day)/18.89). (32)S:(34)S ratios were determined by liquid chromatography mass spectrometry/mass spectrometry. The range of IS intake was 1.3-37.5 mmol S/day. Actual and predicted IS intakes were mmol/day+/-s.e. 9.2+/-0.65 and 7.0+/-0.45, respectively, and were correlated r=0.60 (n=108). The mean half-life of ingested (34)SO(4)(2-) was 8.2 h. From a 24-h urine collection, IS intake from the habitual diet can be determined for groups of individuals. To predict individual intakes of IS, which may include high sporadic amounts from beer and wine, at least 48 h of urine collection would be required.

The association between total phthalate concentration and non-communicable diseases and chronic inflammation in South Australian urban dwelling men.

PubMed

Bai, Peter Y; Wittert, Gary; Taylor, Anne W; Martin, Sean A; Milne, Robert W; Jenkins, Alicia J; Januszewski, Andrzej S; Shi, Zumin

2017-10-01

To investigate associations between urinary total phthalate concentration, chronic low-grade inflammation and non-communicable diseases in a cohort of South Australian men. 1504 men aged 39-84 years who provided a urinary sample at the follow-up visit of the Men Androgen Inflammation Lifestyle Environment and Stress (MAILES) study, a randomly-selected group of urban-dwelling, community-based men from Adelaide, Australia (n = 2038; study participation rate: 78.1%). Total phthalate concentration was quantified in fasting morning urine samples. Chronic diseases were assessed through self-report questionnaire or directly measured using standardised clinical and laboratory procedures. Inflammatory biomarkers were assayed by ELISA or spectroscopy. Multivariable linear and logistic regression models were applied to determine associations of log-transformed urinary phthalate concentration with inflammation and chronic disease. Total phthalates were detected in 99.6% of urinary samples; geometric mean (95% CI) was 114.1 (109.5-118.9)µg/g creatinine. Higher total phthalate levels were associated with higher levels of hs-CRP, IL-6 (all p < 0.05) and TNF-α but not MPO. Urinary total phthalate concentrations were positively associated with cardiovascular disease, type-2-diabetes and hypertension. Comparing extreme quartiles of total phthalate, prevalence ratios were 1.78 (95% CI 1.17 - 2.71, p-trend = 0.001) for cardiovascular disease and 1.84 (95%CI 1.34 - 2.51, p-trend = 0.001) for type-2-diabetes and 1.14 (95%CI 1.01 - 1.29, p-trend = 0.013) for hypertension. Total phthalates and asthma and depression were not significantly associated. A positive association between total phthalates and cardiovascular disease, type-2-diabetes, hypertension and increased levels of chronic low-grade inflammatory biomarkers was observed in urban-dwelling Australian men. Copyright © 2017 Elsevier Inc. All rights reserved.

Mass spectrometric measurement of urinary kynurenine-to-tryptophan ratio in children with and without urinary tract infection.

PubMed

Yarbrough, Melanie L; Briden, Kelleigh E; Mitsios, John V; Weindel, Annette L; Terrill, Cindy M; Hunstad, David A; Dietzen, Dennis J

2018-04-19

Indoleamine-2,3-dioxygenase (IDO) catalyzes the first step of tryptophan (Trp) catabolism, yielding kynurenine (Kyn) metabolites. The kynurenine-to-tryptophan (K/T) ratio is used as a surrogate for biological IDO enzyme activity. IDO expression is increased during Escherichia coli urinary tract infection (UTI). Thus, our objective was to develop a method for measurement of Kyn/Trp ratio in human blood and urine and evaluate its use as a biomarker of UTI. A mass spectrometric method was developed to measure Trp and Kyn in serum and urine specimens. The method was applied to clinical urine specimens from symptomatic pediatric patients with laboratory-confirmed UTI or other acute conditions and from healthy controls. The liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was linear to 500 μmol/L for both Trp and Kyn. Imprecision ranged from 5 to 15% for Trp and 6-20% for Kyn. Analytical recoveries of Trp and Kyn ranged from 96 to 119% in serum and 90-97% in urine. No correlation was found between the K/T ratio and circulating IDO mass (r = 0.110) in serum. Urinary Kyn and Trp in the pediatric test cohort demonstrated elevations in the K/T ratio in symptomatic patients with UTI (median 13.08) and without UTI (median 14.38) compared to healthy controls (median 4.93; p < 0.001 for both comparisons). No significant difference in K/T ratio was noted between symptomatic patients with and without UTI (p = 0.84). Measurement of Trp and Kyn by LC-MS/MS is accurate and precise in serum and urine specimens. While urinary K/T ratio is not a specific biomarker for UTI, it may represent a general indicator of a systemic inflammatory process. Copyright © 2018 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Urine Biomarkers and Perioperative Acute Kidney Injury: The Impact of Preoperative Estimated GFR

PubMed Central

Koyner, Jay L.; Coca, Steven G.; Thiessen-Philbrook, Heather; Patel, Uptal D.; Shlipak, Michael; Garg, Amit X.; Parikh, Chirag R.

2015-01-01

Background The interaction between baseline kidney function and the performance of biomarkers of acute kidney injury (AKI) on the development of AKI is unclear. Study Design Post-hoc analysis of prospective cohort study. Setting & Participants The 1,219 TRIBE-AKI Consortium adult cardiac surgery cohort participants. Predictor Unadjusted post-operative urinary biomarkers of AKI measured within 6 hours of surgery. Outcome AKI was defined as greater than or equal to AKI Network stage 1 (any AKI) as well as a doubling of serum creatinine from the pre-operative value or the need for emergent dialysis (severe AKI). Measurements Stratified analyses by a pre-operative eGFR ≤ 60 ml/min/1.73 m2 vs. > 60 ml/min/1.73 m2. Results 180 (42%) patients with a pre-operative eGFR ≤ 60 ml/min/1.73m2 developed clinical AKI compared to 246 (31%) in those with an eGFR >60 ml/min//1.73m2 (p<0.001). For log2-transformed biomarker concentrations there was a significant interaction between any AKI and baseline eGFR for interleukin 18 (IL-18; p=0.007) and borderline significance for liver-type fatty acid binding protein (p=0.06). For all biomarkers, the adjusted relative risk (RR) point estimates for the risk of any AKI were higher in those with elevated baseline eGFRs compared to those with an eGFR ≤ 60 ml/min/1.73m2. However the difference in magnitude of these risks were quite low (adjusted RRs were 1.04 [95% CI, 0.99–1.09] and 1.11 [95% CI, 1.07–1.15] for those with a pre-operative eGFR ≤ 60 ml/min/1.73 m2 and those with higher eGFRs, respectively). Although no biomarker displayed an interaction for baseline eGFR and severe AKI, log2-transformed IL-18 and kidney injury molecule 1 (KIM-1) had significant adjusted RRs for severe AKI in those with and without baseline eGFR ≤ 60 ml/min/1.73 m2. Limitations Limited numbers of patients with severe AKI and emergent dialysis. Conclusions The association between early post-operative AKI urinary biomarkers and AKI is modified by preoperative eGFR. The degree of this modification and its impact on the biomarker-AKI association is small across biomarkers. Our findings suggest that distinct biomarker cut-offs for those with and without a pre-operative eGFR ≤ 60 ml/min/1.73 m2 is not necessary. PMID:26386737

State-of-the-art nanoplatform-integrated MALDI-MS impacting resolutions in urinary proteomics.

PubMed

Gopal, Judy; Muthu, Manikandan; Chun, Se-Chul; Wu, Hui-Fen

2015-06-01

Urine proteomics has become a subject of interest, since it has led to a number of breakthroughs in disease diagnostics. Urine contains information not only from the kidney and the urinary tract but also from other organs, thus urinary proteome analysis allows for identification of biomarkers for both urogenital and systemic diseases. The following review gives a brief overview of the analytical techniques that have been in practice for urinary proteomics. MALDI-MS technique and its current application status in this area of clinical research have been discussed. The review comments on the challenges facing the conventional MALDI-MS technique and the upgradation of this technique with the introduction of nanotechnology. This review projects nano-based techniques such as nano-MALDI-MS, surface-assisted laser desorption/ionization, and nanostructure-initiator MS as the platforms that have the potential in trafficking MALDI-MS from the lab to the bedside. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Office evaluation of male patients with lower urinary tract symptoms.

PubMed

Tabatabaei, Shahin; Talab, Saman Shafaat; Zangi, Mahdi; Woo, Henry H

2012-12-01

Lower urinary tract symptoms due to benign prostatic hyperplasia (LUTS/BPH) are one of the most common urologic disorders in men. Accurate history-taking and focused physical examination allows us to diagnose the majority of cases. A better understanding of risk factors helps us tailor our treatment and predict outcomes more accurately. Population studies are crucial in our understanding of LUTS/BPH natural history. Temporary prostatic urethral stents that are used for the management of urinary retention may also be used for evaluation of patients with detrusor hypo-contractility. The use of ultrasound to measure intravesical prostatic protrusion (IPP) and the Doppler study for prostate capsular artery resistive index are promising. Near-infrared spectroscopy (NIRS) examines the tissue oxygenation that may be affected by bladder outlet obstruction. The mathematical algorithm needs some fine-tuning, and its reproducibility is debatable. Serum and urinary biomarkers may help us to diagnose the disorder, and more effectively monitor patients' response to therapy. Among all, IPP is clinically more applicable at this time.

Identification of Noninvasive Biomarkers for Alcohol-Induced Liver Disease Using Urinary Metabolomics and the Ppara-null Mouse

PubMed Central

Manna, Soumen K.; Patterson, Andrew D.; Yang, Qian; Krausz, Kristopher W.; Li, Henghong; Idle, Jeffrey R.; Fornace, Albert J.; Gonzalez, Frank J.

2010-01-01

Alcohol-induced liver disease (ALD) is a leading cause of non-accident-related deaths in the United States. Although liver damage caused by ALD is reversible when discovered at the earlier stages, current risk assessment tools are relatively non-specific. Identification of an early specific signature of ALD would aid in therapeutic intervention and recovery. In this study the metabolic changes associated with alcohol-induced liver disease were examined using alcohol-fed male Ppara-null mouse as a model of ALD. Principal components analysis of the mass spectrometry-based urinary metabolic profile showed that alcohol-treated wild-type and Ppara-null mice could be distinguished from control animals without information on history of alcohol consumption. The urinary excretion of ethyl-sulfate, ethyl-β-D-glucuronide, 4-hydroxyphenylacetic acid, and 4-hydroxyphenylacetic acid sulfate was elevated and that of the 2-hydroxyphenylacetic acid, adipic acid, and pimelic acid was depleted during alcohol treatment in both wild-type and the Ppara-null mice albeit to different extents. However, indole-3-lactic acid was exclusively elevated by alcohol exposure in Ppara-null mice. The elevation of indole-3-lactic acid is mechanistically related to the molecular events associated with development of ALD in alcohol-treated Ppara-null mice. This study demonstrated the ability of metabolomics approach to identify early, noninvasive biomarkers of ALD pathogenesis in Ppara-null mouse model. PMID:20540569

Increased levels of urinary PGE-M, a biomarker of inflammation, occur in association with obesity, aging and lung metastases in patients with breast cancer

PubMed Central

Morris, Patrick G.; Zhou, Xi Kathy; Milne, Ginger L.; Goldstein, Daniel; Hawks, Laura C.; Dang, Chau T.; Modi, Shanu; Fornier, Monica N.; Hudis, Clifford A.; Dannenberg, Andrew J.

2013-01-01

Elevated levels of cyclooxygenase (COX)-derived prostaglandin E2 (PGE2) occur in inflamed tissues. To evaluate the potential links between inflammation and breast cancer, levels of urinary prostaglandin E-metabolite (PGE-M), a stable end metabolite of PGE2, were quantified. We enrolled 400 patients with breast cancer: controls with early breast cancer (n=200), lung metastases (n=100) and metastases to other sites (n=100). Patients completed a questionnaire, provided urine and had measurements of height and weight. Urinary PGE-M was quantified by mass spectrometry. Ever smokers with lung metastasis who had not been exposed to NSAIDs had the highest PGE-M levels. PGE-M levels were increased in association with elevated BMI (p<0.001), aging (p<0.001), pack-year smoking history (p=0.02), lung metastases (p=0.02) and recent cytotoxic chemotherapy (p=0.03). Conversely, use of NSAIDs, prototypic inhibitors of COX activity, was associated with reduced PGE-M levels (p<0.001). Based on the current findings, PGE-M is likely to be a useful biomarker for the selection of high risk subgroups to determine the utility of interventions that aim to reduce inflammation and possibly the development and progression of breast cancer, especially in overweight and obese women. PMID:23531446

Biomonitoring of styrene occupational exposures: Biomarkers and determinants.

PubMed

Persoons, Renaud; Richard, Justine; Herve, Claire; Montlevier, Sarah; Marques, Marie; Maitre, Anne

2018-06-22

High styrene exposures are still experienced in various occupational settings, requesting regular exposure assessments. The aims of this study were to study occupational exposures in various industrial sectors and to determine factors influencing styrene urinary metabolites levels. Biomonitoring was conducted in 141 workers from fiberglass-reinforced plastic (FRP) manufacture, thermoplastic polymers production, vehicle repair shops and cured-in-place pipe lining (CIPP). Urinary styrene (StyU) as well as Mandelic (MA) / Phenyglyoxylic Acids (PGA) were quantified at the beginning and at the end of week, and multivariate linear regression models were used. StyU levels revealed very low, rarely exceeding 3 µg.L -1 . Highest concentrations of MA + PGA were observed in FRP sector, with levels reaching up to 1100 mg.g -1 of creatinine. Factors influencing end-of-week MA + PGA concentrations were levels at the beginning of week, open molding processes, proximity to the emission source, respiratory protection, styrene content in raw materials. Elevated levels were also observed during CIPP process, whereas thermoplastic injection and vehicle repair shop workers exhibited much lower exposures. Intervention on process (decreasing styrene proportion, using closed molding), protective equipment (local exhaust ventilation, respiratory protection) and individual practices (stringent safety rules) are expected to decrease occupational exposures. Urinary MA + PGA remain the most appropriate biomarkers for occupational biomonitoring. Copyright © 2018. Published by Elsevier B.V.

Evidence of uncoupling between renal dysfunction and injury in cardiorenal syndrome: insights from the BIONICS study.

PubMed

Legrand, Matthieu; De Berardinis, Benedetta; Gaggin, Hanna K; Magrini, Laura; Belcher, Arianna; Zancla, Benedetta; Femia, Alexandra; Simon, Mandy; Motiwala, Shweta; Sambhare, Rasika; Di Somma, Salvatore; Mebazaa, Alexandre; Vaidya, Vishal S; Januzzi, James L

2014-01-01

The objective of the study was to assess urinary biomarkers of renal injury for their individual or collective ability to predict Worsening renal function (WRF) in patients with acutely decompensated heart failure (ADHF). In a prospective, blinded international study, 87 emergency department (ED) patients with ADHF were evaluated with biomarkers of cardiac stretch (B type natriuretic peptide [BNP] and its amino terminal equivalent [NT-proBNP], ST2), biomarkers of renal function (creatinine, estimated glomerular filtration rate [eGFR]) and biomarkers of renal injury (plasma neutrophil gelatinase associated lipocalin [pNGAL], urine kidney injury molecule-1 [KIM-1], urine N-acetyl-beta-D-glucosaminidase [NAG], urine Cystatin C, urine fibrinogen). The primary endpoint was WRF. 26% developed WRF; baseline characteristics of subjects who developed WRF were generally comparable to those who did not. Biomarkers of renal function and urine biomarkers of renal injury were not correlated, while urine biomarkers of renal injury correlated between each other. Biomarker concentrations were similar between patients with and without WRF except for baseline BNP. Although plasma NGAL was associated with the combined endpoint, none of the biomarker showed predictive accuracy for WRF. In ED patients with ADHF, urine biomarkers of renal injury did not predict WRF. Our data suggest that a weak association exists between renal dysfunction and renal injury in this setting (Clinicaltrials.gov NCT#0150153).

Evidence of Uncoupling between Renal Dysfunction and Injury in Cardiorenal Syndrome: Insights from the BIONICS Study

PubMed Central

Legrand, Matthieu; De Berardinis, Benedetta; Gaggin, Hanna K.; Magrini, Laura; Belcher, Arianna; Zancla, Benedetta; Femia, Alexandra; Simon, Mandy; Motiwala, Shweta; Sambhare, Rasika; Di Somma, Salvatore; Mebazaa, Alexandre; Vaidya, Vishal S.; Januzzi, James L.; (GREAT), from the Global Research on Acute Conditions Team

2014-01-01

Objective The objective of the study was to assess urinary biomarkers of renal injury for their individual or collective ability to predict Worsening renal function (WRF) in patients with acutely decompensated heart failure (ADHF). Methods In a prospective, blinded international study, 87 emergency department (ED) patients with ADHF were evaluated with biomarkers of cardiac stretch (B type natriuretic peptide [BNP] and its amino terminal equivalent [NT-proBNP], ST2), biomarkers of renal function (creatinine, estimated glomerular filtration rate [eGFR]) and biomarkers of renal injury (plasma neutrophil gelatinase associated lipocalin [pNGAL], urine kidney injury molecule-1 [KIM-1], urine N-acetyl-beta-D-glucosaminidase [NAG], urine Cystatin C, urine fibrinogen). The primary endpoint was WRF. Results 26% developed WRF; baseline characteristics of subjects who developed WRF were generally comparable to those who did not. Biomarkers of renal function and urine biomarkers of renal injury were not correlated, while urine biomarkers of renal injury correlated between each other. Biomarker concentrations were similar between patients with and without WRF except for baseline BNP. Although plasma NGAL was associated with the combined endpoint, none of the biomarker showed predictive accuracy for WRF. Conclusions In ED patients with ADHF, urine biomarkers of renal injury did not predict WRF. Our data suggest that a weak association exists between renal dysfunction and renal injury in this setting (Clinicaltrials.gov NCT#0150153). PMID:25386851

Large-Scale SRM Screen of Urothelial Bladder Cancer Candidate Biomarkers in Urine.

PubMed

Duriez, Elodie; Masselon, Christophe D; Mesmin, Cédric; Court, Magali; Demeure, Kevin; Allory, Yves; Malats, Núria; Matondo, Mariette; Radvanyi, François; Garin, Jérôme; Domon, Bruno

2017-04-07

Urothelial bladder cancer is a condition associated with high recurrence and substantial morbidity and mortality. Noninvasive urinary tests that would detect bladder cancer and tumor recurrence are required to significantly improve patient care. Over the past decade, numerous bladder cancer candidate biomarkers have been identified in the context of extensive proteomics or transcriptomics studies. To translate these findings in clinically useful biomarkers, the systematic evaluation of these candidates remains the bottleneck. Such evaluation involves large-scale quantitative LC-SRM (liquid chromatography-selected reaction monitoring) measurements, targeting hundreds of signature peptides by monitoring thousands of transitions in a single analysis. The design of highly multiplexed SRM analyses is driven by several factors: throughput, robustness, selectivity and sensitivity. Because of the complexity of the samples to be analyzed, some measurements (transitions) can be interfered by coeluting isobaric species resulting in biased or inconsistent estimated peptide/protein levels. Thus the assessment of the quality of SRM data is critical to allow flagging these inconsistent data. We describe an efficient and robust method to process large SRM data sets, including the processing of the raw data, the detection of low-quality measurements, the normalization of the signals for each protein, and the estimation of protein levels. Using this methodology, a variety of proteins previously associated with bladder cancer have been assessed through the analysis of urine samples from a large cohort of cancer patients and corresponding controls in an effort to establish a priority list of most promising candidates to guide subsequent clinical validation studies.

Levels of prostaglandin E metabolite and leukotriene E(4) are increased in the urine of smokers: evidence that celecoxib shunts arachidonic acid into the 5-lipoxygenase pathway.

PubMed

Duffield-Lillico, Anna J; Boyle, Jay O; Zhou, Xi Kathy; Ghosh, Aradhana; Butala, Geera S; Subbaramaiah, Kotha; Newman, Robert A; Morrow, Jason D; Milne, Ginger L; Dannenberg, Andrew J

2009-04-01

Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO) play a role in inflammation and carcinogenesis. Biomarkers that reflect tobacco smoke-induced tissue injury are needed. In this study, levels of urinary prostaglandin E metabolite (PGE-M) and leukotriene E(4) (LTE(4)), biomarkers of the COX and 5-LO pathways, were compared in never smokers, former smokers, and current smokers. The effects of celecoxib, a selective COX-2 inhibitor, on levels of PGE-M and LTE(4) were determined. Baseline levels of PGE-M and LTE(4) were positively associated with smoking status; levels of PGE-M and LTE(4) were higher in current versus never smokers. Treatment with 200 mg celecoxib twice daily for 6 +/- 1 days led to a reduction in urinary PGE-M levels in all groups but exhibited the greatest effect among subjects with high baseline PGE-M levels. Thus, high baseline PGE-M levels in smokers reflected increased COX-2 activity. In individuals with high baseline PGE-M levels, treatment with celecoxib led to a significant increase in levels of urinary LTE(4), an effect that was not found in individuals with low baseline PGE-M levels. In conclusion, increased levels of urinary PGE-M and LTE(4) were found in human smokers, a result that may reflect subclinical lung inflammation. In individuals with high baseline levels of PGE-M (elevated COX-2 activity), celecoxib administration shunted arachidonic acid into the proinflammatory 5-LO pathway. Because 5-LO activity and LTE(4) have been suggested to play a role in cardiovascular disease, these results may help to explain the link between use of COX-2 inhibitors and cardiovascular complications.

Diagnostic accuracy of urinary biomarkers in infants younger than 3 months with urinary tract infection

PubMed Central

Jung, Nani; Byun, Hye Jin; Park, Jae Hyun; Kim, Joon Sik; Kim, Hae Won

2018-01-01

Purpose The aim of this study was to evaluate the diagnostic accuracy of urinary biomarkers, such as neutrophil gelatinase-associated lipocalin (uNGAL) and β-2 microglobulin (uB2MG), in early detection of urinary tract infection (UTI) in infants aged <3 months with fever. Methods A total of 422 infants aged <3 months (male:female=267:155; mean age, 56.4 days), who were admitted for fever, were retrospectively included in this study. We compared uNGAL and uB2MG between the UTI and non-UTI groups at the time of admission. The sensitivity, specificity, accuracy, and area under the curve (AUC) of uNGAL and uB2MG for use in diagnosing UTI were assessed. Results Among 422 patients, 102 (24.2%) were diagnosed with UTI. Levels of uNGAL were higher in the UTI group than in the non-UTI group (366.6 ng/mL vs. 26.9 ng/mL, P<0.001). Levels of uB2MG were not different between the 2 groups. Multivariate analysis revealed that uNGAL was an independent predictive factor for UTI (P=0.033). The sensitivity, specificity, and accuracy were 90.2%, 92.5%, and 91.9% for uNGAL, and 48.0%, 43.8%, and 44.8% for uB2MG, respectively. AUC of uNGAL was 0.942 and that of uB2MG was 0.407. Conclusion Accuracy of uNGAL in the diagnosis of UTI is high in febrile infants aged <3 months. uNGAL can help in the early diagnosis and treatment of UTI in infants. PMID:29441109

1H NMR spectroscopy-based metabolomics analysis for the diagnosis of symptomatic E. coli-associated urinary tract infection (UTI).

PubMed

Lussu, Milena; Camboni, Tania; Piras, Cristina; Serra, Corrado; Del Carratore, Francesco; Griffin, Julian; Atzori, Luigi; Manzin, Aldo

2017-09-21

Urinary tract infection (UTI) is one of the most common diagnoses in girls and women, and to a lesser extent in boys and men younger than 50 years. Escherichia coli, followed by Klebsiella spp. and Proteus spp., cause 75-90% of all infections. Infection of the urinary tract is identified by growth of a significant number of a single species in the urine, in the presence of symptoms. Urinary culture is an accurate diagnostic method but takes several hours or days to be carried out. Metabolomics analysis aims to identify biomarkers that are capable of speeding up diagnosis. Urine samples from 51 patients with a prior diagnosis of Escherichia coli-associated UTI, from 21 patients with UTI caused by other pathogens (bacteria and fungi), and from 61 healthy controls were analyzed. The 1 H-NMR spectra were acquired and processed. Multivariate statistical models were applied and their performance was validated using permutation test and ROC curve. Orthogonal Partial Least Squares-discriminant Analysis (OPLS-DA) showed good separation (R 2 Y = 0.76, Q2=0.45, p < 0.001) between UTI caused by Escherichia coli and healthy controls. Acetate and trimethylamine were identified as discriminant metabolites. The concentrations of both metabolites were calculated and used to build the ROC curves. The discriminant metabolites identified were also evaluated in urine samples from patients with other pathogens infections to test their specificity. Acetate and trimethylamine were identified as optimal candidates for biomarkers for UTI diagnosis. The conclusions support the possibility of a fast diagnostic test for Escherichia coli-associated UTI using acetate and trimethylamine concentrations.

Within- and between-child variation in repeated urinary pesticide metabolite measurements over a 1-year period.

PubMed

Attfield, Kathleen R; Hughes, Michael D; Spengler, John D; Lu, Chensheng

2014-02-01

Children are exposed to pesticides from many sources and routes, including dietary and incidental ingestion, dermal absorption, and inhalation. Linking health outcomes to these exposures using urinary metabolites requires understanding temporal variability within subjects to avoid exposure misclassification. We characterized the within- and between-child variability of urinary organophosphorus and pyrethroid metabolites in 23 participants of the Children's Pesticide Exposure Study-Washington over 1 year and examined the ability of one to four spot urine samples to categorize mean exposures. Each child provided urine samples twice daily over 7- to 16-day sessions in four seasons in 2003 and 2004. Samples were analyzed for five pyrethroid and five organophosphorus (OP) metabolites. After adjusting for specific gravity, we used a customized maximum likelihood estimation linear mixed-effects model that accounted for values below the limit of detection to calculate intraclass correlation coefficients (ICC) and conducted surrogate category analyses. Within-child variability was 2-11 times greater than between-child variability. When restricted to samples collected during a single season, ICCs were higher in the fall, winter, and spring than in summer for OPs, and higher in summer and winter for pyrethroids, indicating an increase in between-person variability relative to within-person variability during these seasons. Surrogate category analyses demonstrated that a single spot urine sample did not categorize metabolite concentrations well, and that four or more samples would be needed to categorize children into quartiles consistently. Urinary biomarkers of these short half-life pesticides exhibited substantial within-person variability in children observed over four seasons. Researchers investigating pesticides and health outcomes in children may need repeated biomarker measurements to derive accurate estimates of exposure and relative risks.

The physiological response to cold-water immersion following a mixed martial arts training session.

PubMed

Lindsay, Angus; Carr, Sam; Cross, Sean; Petersen, Carl; Lewis, John G; Gieseg, Steven P

2017-05-01

Combative sport is one of the most physically intense forms of exercise, yet the effect of recovery interventions has been largely unexplored. We investigated the effect of cold-water immersion on structural, inflammatory, and physiological stress biomarkers following a mixed martial arts (MMA) contest preparation training session in comparison with passive recovery. Semiprofessional MMA competitors (n = 15) were randomly assigned to a cold-water immersion (15 min at 10 °C) or passive recovery protocol (ambient air) completed immediately following a contest preparation training session. Markers of muscle damage (urinary myoglobin), inflammation/oxidative stress (urinary neopterin + total neopterin (neopterin + 7,8-dihydroneopterin)), and hypothalamic-pituitary axis (HPA) activation (saliva cortisol) were determined before, immediately after, and 1, 2, and 24 h postsession. Ratings of perceived soreness and fatigue, counter movement jump, and gastrointestinal temperature were also measured. Concentrations of all biomarkers increased significantly (p < 0.05) postsession. Cold water immersion attenuated increases in urinary neopterin (p < 0.05, d = 0.58), total neopterin (p < 0.05, d = 0.89), and saliva cortisol after 2 h (p < 0.05, d = 0.68) and urinary neopterin again at 24 h (p < 0.01, d = 0.57) in comparison with passive recovery. Perceived soreness, fatigue, and gastrointestinal temperatures were also lower for the cold-water immersion group at several time points postsession whilst counter movement jump did not differ. Combative sport athletes who are subjected to impact-induced stress may benefit from immediate cold-water immersion as a simple recovery intervention that reduces delayed onset muscle soreness as well as macrophage and HPA activation whilst not impairing functional performance.

Exposure estimates to disinfection by-products of chlorinated drinking water.

PubMed Central

Weisel, C P; Kim, H; Haltmeier, P; Klotz, J B

1999-01-01

Exposure to disinfection by-products (DBPs) of drinking water is multiroute and occurs in households serviced by municipal water treatment facilities that disinfect the water as a necessary step to halt the spread of waterborne infectious diseases. Biomarkers of the two most abundant groups of DBPs of chlorination, exhaled breath levels of trihalomethanes (THMs) and urinary levels of two haloacetic acids, were compared to exposure estimates calculated from in-home tap water concentrations and responses to a questionnaire related to water usage. Background THM breath concentrations were uniformly low. Strong relationships were identified between the THM breath concentrations collected after a shower and both the THM water concentration and the THM exposure from a shower, after adjusting for the postshower delay time in collecting the breath sample. Urinary haloacetic acid excretion rates were not correlated to water concentrations. Urinary trichloroacetic acid excretion rates were correlated with ingestion exposure, and that correlation was stronger in a subset of individuals who consumed beverages primarily within their home where the concentration measurements were made. No correlation was observed between an average 48-hr exposure estimate and the urinary dichloroacetic acid excretion rate, presumably because of its short biological half-life. Valid biomarkers were identified for DBP exposures, but the time between the exposure and sample collection should be considered to account for different metabolic rates among the DBPs. Further, using water concentration as an exposure estimate can introduce misclassification of exposure for DBPs whose primary route is ingestion due to the great variability in the amount of water ingested across a population. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:9924004

Predictors of Urinary 3-Phenoxybenzoic Acid Levels in 50 North Carolina Adults

PubMed Central

Morgan, Marsha; Jones, Paul; Sobus, Jon; Boyd Barr, Dana

2016-01-01

Limited data are available on the non-chemical stressors that impact adult exposures to pyrethroid insecticides based on urinary biomonitoring. The urinary metabolite, 3-phenoxybenzoic acid (3-PBA), is commonly used to assess human exposure to a number of pyrethroids. In a further analysis of published study data, we quantified urinary 3-PBA levels of 50 adults over a single, 24-h sampling period and examined the associations between the biomarker measurements and selected non-chemical stressors (demographic, lifestyle, and dietary factors). A convenience sample of 50 adults was recruited in North Carolina in 2009–2011. Participants collected individual urine voids (up to 11) and filled out activity, food, and pesticide use diaries over a 24-h sampling period. Urine voids (n = 326) were analyzed for 3-PBA concentrations using high-performance liquid chromatography-tandem mass spectrometry. 3-PBA was detected in 98% of the 24-h composited urine samples. The geometric mean urinary 3-PBA level was 1.68 ng/mL in adults. Time spent outside (p = 0.0006) was a highly significant predictor of natural log-transformed (ln) urinary 3-PBA levels, while consumption of coffee (p = 0.007) and breads (p = 0.019) and ln creatinine levels (p = 0.037) were significant predictors of urinary 3-PBA levels. In conclusion, we identified specific factors that substantially increased adult exposures to pyrethroids in their everyday environments. PMID:27886113

Analysis of the variability of human normal urine by 2D-GE reveals a "public" and a "private" proteome.

PubMed

Molina, Laurence; Salvetat, Nicolas; Ameur, Randa Ben; Peres, Sabine; Sommerer, Nicolas; Jarraya, Fayçal; Ayadi, Hammadi; Molina, Franck; Granier, Claude

2011-12-10

The characterization of the normal urinary proteome is steadily progressing and represents a major interest in the assessment of clinical urinary biomarkers. To estimate quantitatively the variability of the normal urinary proteome, urines of 20 healthy people were collected. We first evaluated the impact of the sample conservation temperature on urine proteome integrity. Keeping the urine sample at RT or at +4°C until storage at -80°C seems the best way for long-term storage of samples for 2D-GE analysis. The quantitative variability of the normal urinary proteome was estimated on the 20 urines mapped by 2D-GE. The occurrence of the 910 identified spots was analysed throughout the gels and represented in a virtual 2D gel. Sixteen percent of the spots were found to occur in all samples and 23% occurred in at least 90% of urines. About 13% of the protein spots were present only in 10% or less of the samples, thus representing the most variable part of the normal urinary proteome. Twenty proteins corresponding to a fraction of the fully conserved spots were identified by mass spectrometry. In conclusion, a "public" urinary proteome, common to healthy individuals, seems to coexist with a "private" urinary proteome, which is more specific to each individual. Copyright © 2011 Elsevier B.V. All rights reserved.

Cross-Classification of Human Urinary Lipidome by Sex, Age, and Body Mass Index.

PubMed

Okemoto, Kazuo; Maekawa, Keiko; Tajima, Yoko; Tohkin, Masahiro; Saito, Yoshiro

2016-01-01

Technological advancements in past decades have led to the development of integrative analytical approaches to lipidomics, such as liquid chromatography-mass spectrometry (LC/MS), and information about biogenic lipids is rapidly accumulating. Although several cohort-based studies have been conducted on the composition of urinary lipidome, the data on urinary lipids cross-classified by sex, age, and body mass index (BMI) are insufficient to screen for various abnormalities. To promote the development of urinary lipid metabolome-based diagnostic assay, we analyzed 60 urine samples from healthy white adults (young (c.a., 30 years) and old (c.a., 60 years) men/women) using LC/MS. Women had a higher urinary concentration of omega-3 12-lipoxygenase (LOX)-generated oxylipins with anti-inflammatory activity compared to men. In addition, young women showed increased abundance of poly-unsaturated fatty acids (PUFAs) and cytochrome P450 (P450)-produced oxylipins with anti-hypertensive activity compared with young men, whereas elderly women exhibited higher concentration of 5-LOX-generated anti-inflammatory oxylipins than elderly men. There were no significant differences in urinary oxylipin levels between young and old subjects or between subjects with low and high BMI. Our findings suggest that sex, but neither ages nor BMI could be a confounding factor for measuring the composition of urinary lipid metabolites in the healthy population. The information showed contribute to the development of reliable biomarker findings from urine.

Urinary level of nickel and acute leukaemia in Chinese children.

PubMed

Yang, Y; Jin, X M; Yan, C H; Tian, Y; Tang, J Y; Shen, X M

2008-10-01

The 8-hydroxy-2'-deoxyguanosine (8-OHdG), an oxidized nucleoside of DNA, not only is a widely used biomarker for the measurement of endogenous oxidative DNA damage but might also be a risk factor for many diseases including cancer. Metal exposure may play an important role in oxidative DNA damage among children. However, few studies on urinary 8-OHdG and metals have been conducted in children with acute leukemia. In the present study, urinary Ni and 8-OHdG were examined in 116 children with acute leukaemia (94 acute lymphoid leukaemia [ALL] and 22 acute myeloid leukaemia [AML]) and 51 healthy child controls. Our result showed that urinary Ni in acute leukaemia patients (ALL: 68.40 +/- 133.98, AML: 41.48 +/- 76.31 ng/mg creatinine) was significantly higher than that in controls (62.47 +/- 124.90 vs 17.63 +/- 46.17 ng/mg creatinine, P < 0.05). Similarly, the pretherapy level of urinary 8-OHdG in patients (ALL: 11.83 +/- 16.23, AML: 12.36 +/- 11.36 ng/mg creatinine) was significantly elevated compared with controls (11.92 +/- 15.42 vs 4.03 +/- 4.70 ng/mg creatinine, P < 0.05). Moreover, urinary 8-OHdG and urinary Ni showed a weak but significant association with increased risk of childhood leukaemia. The present study suggests that Ni may be an etiologic factor for childhood acute leukaemia by oxidative DNA damage.

Biomarker in Cisplatin-Based Chemotherapy for Urinary Bladder Cancer.

PubMed

Ecke, Thorsten H

2015-01-01

The treatment of metastasized bladder cancer has been evolving during recent years. Cisplatin based chemotherapy combinations are still gold standard in the treatment of advanced and metastasized bladder cancer. But new therapies are approaching. Based to this fact biological markers will become more important for decisions in bladder cancer treatment. A systematic MEDLINE search of the key words "cisplatin", "bladder cancer", "DNA marker", "protein marker", "methylation biomarker", "predictive marker", "prognostic marker" has been made. This review aims to highlight the most relevant clinical and experimental studies investigating markers for metastasized transitional carcinoma of the urothelium treated by cisplatin based regimens.

Assessment of DNA Damage and Telomerase Activity in Exfoliated Urinary Cells as Sensitive and Noninvasive Biomarkers for Early Diagnosis of Bladder Cancer in Ex-Workers of a Rubber Tyres Industry

PubMed Central

Pira, Enrico; Romano, Canzio; Fresegna, Anna Maria; Ciervo, Aureliano; Buresti, Giuliana; Zoli, Wainer; Calistri, Daniele

2014-01-01

The aim of the present study was to identify sensitive and noninvasive biomarkers of early carcinogenic effect at target organ to use in biomonitoring studies of workers at risk for previous occupational exposure to potential carcinogens. Standard urine cytology (Papanicolaou staining test), comet assay, and quantitative telomerase repeat amplification protocol (TRAP) assay were performed in 159 ex-rubber workers employed in tyres production and 97 unexposed subjects. In TRAP positive cases, a second level analysis using FISH (Urovysion) was done. Cystoscopy results were available for 11 individuals whose 6 FISH/TRAP/comet positive showed in 3 cases a dysplastic condition confirmed by biopsy, 1 comet positive resulted in infiltrating UBC to the biopsy and with hyperplasia and slight dysplasia to the urinary cytology, 1 comet positive resulted in papillary superficial UBC to the biopsy, 1 FISH/TRAP positive showed a normal condition, and 2 TRAP positive showed in one case a phlogosis condition. The results evidenced good concordance of TRAP, comet, and FISH assays as early biomarkers of procarcinogenic effect confirmed by the dysplastic condition and UBC found by cystoscopy-biopsy analysis. The analysis of these markers in urine cells could be potentially more accurate than conventional cytology in monitoring workers exposed to mixture of bladder potential carcinogens. PMID:24877087

Polycyclic aromatic hydrocarbons (PAHs), nitro-PAHs and related environmental compounds: biological markers of exposure and effects.

PubMed Central

Talaska, G; Underwood, P; Maier, A; Lewtas, J; Rothman, N; Jaeger, M

1996-01-01

Lung cancer caused by polycyclic aromatic hydrocarbons (PAHs), nitro-PAHs and related environmental agents is a major problem in industrialized nations. The high case-fatality rate of the disease, even with the best supportive treatment, underscores the importance of primary lung cancer prevention. Development of biomarkers of exposure and effects to PAHs and related compounds is now underway and includes measurement of urinary metabolites of specific PAHs as well as detection of protein and DNA adducts as indicators of effective dose. Validation of these markers in terms of total environmental dose requires that concurrent measures of air levels and potential dermal exposure be made. In addition, the interrelationships between PAH biomarkers must be determined, particularly when levels of the marker in surrogate molecules (e.g., protein) or markers from surrogate tissues (e.g., lymphocyte DNA) are used to assess the risk to the target organ, the lung. Two approaches to biomarker studies will be reviewed in this article: the progress made using blood lymphocytes as surrogates for lung tissues and the progress made developing noninvasive markers of carcinogen-DNA adduct levels in lung-derived cells available in bronchial-alveolar lavage and in sputum. Data are presented from studies in which exfoliated urothelial cells were used as a surrogate tissue to assess exposure to human urinary bladder carcinogens in occupational groups. PMID:8933032

Evaluation of KIM-1 as an early biomarker of snakebite-induced AKI in mice.

PubMed

Dantas, Rodrigo Tavares; Sampaio, Tiago Lima; Lima, Dânya Bandeira; Bezerra de Menezes, Ramon Róseo Paula Pessoa; Canuto, Jader Almeida; Toyama, Marcos Hikari; Evangelista, Janaína Serra Azul Monteiro; Martins, Alice Maria Costa

2018-06-14

Acute kidney injury (AKI) is one of the most important complications of bothropic poisoning and its early identification remains challenging. The nephrotoxicity of Bothrops insularis venom (BinsV) was previously described by our research group. In this study, we continued to evaluate the effect of BinsV on kidney function in mice and LLC-MK2 proximal tubule cells, evaluating KIM-1 protein as an early AKI biomarker. Male Swiss mice were inoculated with BinsV intramuscularly and observed for 24 h in a metabolic cage model. Urine and blood were collected for biochemical analyses and the kidneys were examined for oxide-reducing balance and submitted to histological analysis. LLC-MK2 cells incubated with BinsV were assessed for cell viability and cell death mechanism by flow cytometry. Histological analysis of the kidneys indicated AKI and the oxide-reducing analyses demonstrated a decreasing in reduced glutathione (GSH) levels and an increasing on Malondialdehyde (MDA) levels. BinsV was cytotoxic to LLC-MK2 and the cytometry analyses suggested necrosis. Within 24 h after the envenomation, urinary creatinine did not increase, but the urinary levels of KIM-1 increased. In conclusion, we found AKI evidence in the kidney tissue and the increase in the KIM-1 levels suggest it can be used as an early AKI biomarker. Copyright © 2018. Published by Elsevier Ltd.

Assessment of DNA damage and telomerase activity in exfoliated urinary cells as sensitive and noninvasive biomarkers for early diagnosis of bladder cancer in ex-workers of a rubber tyres industry.

PubMed

Cavallo, Delia; Casadio, Valentina; Bravaccini, Sara; Iavicoli, Sergio; Pira, Enrico; Romano, Canzio; Fresegna, Anna Maria; Maiello, Raffaele; Ciervo, Aureliano; Buresti, Giuliana; Zoli, Wainer; Calistri, Daniele

2014-01-01

The aim of the present study was to identify sensitive and noninvasive biomarkers of early carcinogenic effect at target organ to use in biomonitoring studies of workers at risk for previous occupational exposure to potential carcinogens. Standard urine cytology (Papanicolaou staining test), comet assay, and quantitative telomerase repeat amplification protocol (TRAP) assay were performed in 159 ex-rubber workers employed in tyres production and 97 unexposed subjects. In TRAP positive cases, a second level analysis using FISH (Urovysion) was done. Cystoscopy results were available for 11 individuals whose 6 FISH/TRAP/comet positive showed in 3 cases a dysplastic condition confirmed by biopsy, 1 comet positive resulted in infiltrating UBC to the biopsy and with hyperplasia and slight dysplasia to the urinary cytology, 1 comet positive resulted in papillary superficial UBC to the biopsy, 1 FISH/TRAP positive showed a normal condition, and 2 TRAP positive showed in one case a phlogosis condition. The results evidenced good concordance of TRAP, comet, and FISH assays as early biomarkers of procarcinogenic effect confirmed by the dysplastic condition and UBC found by cystoscopy-biopsy analysis. The analysis of these markers in urine cells could be potentially more accurate than conventional cytology in monitoring workers exposed to mixture of bladder potential carcinogens.

Conversion to Sirolimus Ameliorates Cyclosporine-Induced Nephropathy in the Rat: Focus on Serum, Urine, Gene, and Protein Renal Expression Biomarkers

PubMed Central

Sereno, José; Nunes, Sara; Rodrigues-Santos, Paulo; Rocha-Pereira, Petronila; Fernandes, João; Teixeira, Frederico; Reis, Flávio

2014-01-01

Protocols of conversion from cyclosporin A (CsA) to sirolimus (SRL) have been widely used in immunotherapy after transplantation to prevent CsA-induced nephropathy, but the molecular mechanisms underlying these protocols remain nuclear. This study aimed to identify the molecular pathways and putative biomarkers of CsA-to-SRL conversion in a rat model. Four animal groups (n = 6) were tested during 9 weeks: control, CsA, SRL, and conversion (CsA for 3 weeks followed by SRL for 6 weeks). Classical and emergent serum, urinary, and kidney tissue (gene and protein expression) markers were assessed. Renal lesions were analyzed in hematoxylin and eosin, periodic acid-Schiff, and Masson's trichrome stains. SRL-treated rats presented proteinuria and NGAL (serum and urinary) as the best markers of renal impairment. Short CsA treatment presented slight or even absent kidney lesions and TGF-β, NF-κ β, mTOR, PCNA, TP53, KIM-1, and CTGF as relevant gene and protein changes. Prolonged CsA exposure aggravated renal damage, without clear changes on the traditional markers, but with changes in serums TGF-β and IL-7, TBARs clearance, and kidney TGF-β and mTOR. Conversion to SRL prevented CsA-induced renal damage evolution (absent/mild grade lesions), while NGAL (serum versus urine) seems to be a feasible biomarker of CsA replacement to SRL. PMID:24971338

Urinary Angiotensinogen and Renin Excretion are Associated with Chronic Kidney Disease.

PubMed

Juretzko, Annett; Steinbach, Antje; Hannemann, Anke; Endlich, Karlhans; Endlich, Nicole; Friedrich, Nele; Lendeckel, Uwe; Stracke, Sylvia; Rettig, Rainer

2017-01-01

Several studies sought to identify new biomarkers for chronic kidney disease (CKD). As the renal renin-angiotensin system is activated in CKD, urinary angiotensinogen or renin excretion may be suitable candidates. We tested whether urinary angiotensinogen or renin excretion is elevated in CKD and whether these parameters are associated with estimated glomerular filtration rate (eGFR). We further tested whether urinary angiotensinogen or renin excretion may convey additional information beyond that provided by albuminuria. We measured urinary and plasma angiotensinogen, renin, albumin and creatinine in 177 CKD patients from the Greifswald Approach to Individualized Medicine project and in 283 healthy controls from the Study of Health in Pomerania. The urinary excretion of specific proteins is given as protein-to-creatinine ratio. Receiver operating characteristic (ROC) curves, spearman correlation coefficients and linear regression models were calculated. Urinary angiotensinogen [2,511 (196-31,909) vs. 18.6 (8.3-44.0) pmol/g, *P<0.01] and renin excretion [0.311 (0.135-1.155) vs. 0.069 (0.045-0.148) pmol/g, *P<0.01] were significantly higher in CKD patients than in healthy controls. The area under the ROC curve was significantly larger when urinary angiotensinogen, renin and albumin excretion were combined than with urinary albumin excretion alone. Urinary angiotensinogen (ß-coefficient -2.405, standard error 0.117, P<0.01) and renin excretion (ß-coefficient -0.793, standard error 0.061, P<0.01) were inversely associated with eGFR. Adjustment for albuminuria, age, sex, systolic blood pressure and body mass index did not significantly affect the results. Urinary angiotensinogen and renin excretion are elevated in CKD patients. Both parameters are negatively associated with eGFR and these associations are independent of urinary albumin excretion. In CKD patients urinary angiotensinogen and renin excretion may convey additional information beyond that provided by albuminuria. © 2017 The Author(s)Published by S. Karger AG, Basel.

Detection of urinary biomarkers in reservoir hosts of Leptospirosis by capillary electrophoresis mass spectrometry

USDA-ARS?s Scientific Manuscript database

Pathogenic leptospires colonize the renal tubules of reservoir hosts of infection and are excreted via urine into the environment. Reservoir hosts include a wide range of domestic and wild animal species and include cattle, dogs and rats which can persistently excrete large numbers of pathogenic lep...

THE TIME-COURSE AND SENSITIVITY OF MUCONIC ACID AS A BIOMARKER FOR HUMAN ENVIRONMENTAL EXPOSURE TO BENZENE

EPA Science Inventory

Preliminary results are presented that show the effect of an increased benzene exposure on the urinary elimination of trans,trans-muconic acid (MA) for an adult male. These results were generated from a controlled exposure experiment where by an individual was exposed to benzene ...

EXCRETION OF ARSENIC IN URINE AS A FUNCTION OF EXPOSURE TO ARSENIC IN DRINKING WATER

EPA Science Inventory

Urinary arsenic (As) concentrations were evaluated as a biomarker of exposure in a U.S. population chronically exposed to inorganic As (InAs) in their drinking water. Ninety-six individuals who consumed drinking water with As concentrations of 8-620 microg/L provided first mornin...

Urinary Biomarker, Dermal, and Air Measurement Results for 2,4-D and Chlorpyrifos Farm Applicators in the Agricultural Health Study

EPA Science Inventory

A subset of private pesticide applicators in the Agricultural Health Study (AHS) epidemiological cohort was monitored around the time of their agricultural use of 2,4-D and chlorpyrifos to assess exposure levels and potential determinants of exposure. Measurements included pre- a...

USE OF PHARMACOKINETIC MODEL TO ASSESS CHLORPYRIFOS EXPOSURE AND DOSE IN CHILDREN BASED ON URINARY BIOMARKER MEASUREMENTS

EPA Science Inventory

Chlorpyrifos is a common agricultural insecticide and has been used residentially in the United States until 2000 when this use was restricted by the U.S. Environmental Protection Agency (U.S. EPA). A chlorpyrifos metabolite, 3,5,6-trichloro-2-pyridinol (TCPy) has been found i...

EXPOSURE ASSESSMENT OF FOREST FIRE SMOKE IN SUSCEPTIBLE ADULTS, USING URINARY BIOMARKERS AND REAL-TIME AIR MONITORING DATA. (R827355C010)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

Urinary analysis reveals high deoxynivalenol exposure in pregnant women from Croatia.

PubMed

Sarkanj, Bojan; Warth, Benedikt; Uhlig, Silvio; Abia, Wilfred A; Sulyok, Michael; Klapec, Tomislav; Krska, Rudolf; Banjari, Ines

2013-12-01

In this pilot survey the levels of various mycotoxin biomarkers were determined in third trimester pregnant women from eastern Croatia. First void urine samples were collected and analysed using a "dilute and shoot" LC-ESI-MS/MS multi biomarker method. Deoxynivalenol (DON) and its metabolites: deoxynivalenol-15-glucuronide and deoxynivalenol-3-glucuronide were detected in 97.5% of the studied samples, partly at exceptionally high levels, while ochratoxin A was found in 10% of the samples. DON exposure was primarily reflected by the presence of deoxynivalenol-15-glucuronide with a mean concentration of 120 μg L(-1), while free DON was detected with a mean concentration of 18.3 μg L(-1). Several highly contaminated urine samples contained a third DON conjugate, tentatively identified as deoxynivalenol-7-glucuronide by MS/MS scans. The levels of urinary DON and its metabolites measured in this study are the highest ever reported, and 48% of subjects were estimated to exceed the provisional maximum tolerable daily intake (1 μg kg(-1) b.w.). Copyright © 2013 Elsevier Ltd. All rights reserved.

Are Treated Celiac Patients at Risk for Mycotoxins? An Italian Case-Study

PubMed Central

Cirlini, Martina; Mazzeo, Teresa; Roncoroni, Leda; Lombardo, Vincenza; Elli, Luca; Bardella, Maria T.; Agostoni, Carlo; Doneda, Luisa; Brighenti, Furio; Dall’Asta, Chiara; Pellegrini, Nicoletta

2016-01-01

Urinary biomarkers of mycotoxin exposure were evaluated in a group of celiac patients (n = 55) and in a control group of healthy subjects (n = 50) following their habitual diet. Deoxynivalenol (DON), zearalenone (ZEN), and fumonisin B1 (FB1) were monitored in 105 urinary samples collected from the two groups. Dietary habits were also recorded through compilation of a seven-day weighed dietary diary. Biomarkers of mycotoxin exposure were detected in 21 celiac patients and in 15 control subjects, corresponding to about 34% of total participants. In particular, ZEN was the most detected mycotoxin among all the studied subjects with a total of 19 positive cases. Results did not show a statistically significant difference in mycotoxin exposure between the two groups, and the presence of specific mycotoxins was not related to the intake of any particular food category. Our findings suggest little urgency of specific regulation for gluten free products, although the prevalence of exposure observed in free-living diets of both celiac and healthy subjects underlines the need of a constant surveillance on mycotoxins occurrence at large. PMID:28036017

A HPLC-Q-TOF-MS-based urinary metabolomic approach to identification of potential biomarkers of metabolic syndrome.

PubMed

Yu, Zhi-rui; Ning, Yu; Yu, Hao; Tang, Nai-jun

2014-04-01

Metabolic syndrome (MetS) is a serious threat to public health worldwide with an increased risk of developing type 2 diabetes, cardiovascular diseases and all-cause morbidity and mortality. In this study, a urinary metabolomic approach was performed on high performance liquid chromatography quadrupole time-of-flight mass spectrometry to discriminate 36 male MetS patients and 36 sex and age matched healthy controls. Pattern recognition analyses (principal component analysis and orthogonal projections to latent structures discriminate analysis) commonly demonstrated the difference between MetS patients and no-MetS subjects. This study found 8 metabolites that showed significant changes in patients with MetS, including branch-chain and aromatic amino acids (leucine, tyrosine, phenylalanine and tryptophan), short-chain acylcanitine (tiglylcarnitine), tricarboxylic acid (TCA) cycle intermediate (cis-aconitic acid) and glucuronidated products (cortolone-3-glucuronide and tetrahydroaldosterone-3-glucuronide). The candidate biomarkers revealed in this study could be useful in providing clues for further research focusing on the in-depth investigation of the cause of and cure for MetS.

Urinary C‑X‑C motif chemokine 13 is a noninvasive biomarker of antibody‑mediated renal allograft rejection.

PubMed

Chen, Dajin; Zhang, Jian; Peng, Wenhan; Weng, Chunhua; Chen, Jianghua

2018-06-22

Noninvasive monitoring methods of immune status are preferred by transplant recipients. The present study investigated whether urinary C‑X‑C motif chemokine 13 (CXCL13) had the potential to reflect ongoing immune processes within renal allografts. Using an ELISA assay, the level of urinary CXCL13 was quantified in a total of 146 renal allograft recipients and 40 healthy controls at scheduled intervals and at the time of the indicated or protocol biopsy. The results of the present study revealed that urinary CXCL13/creatinine (Cr) was lower in normal transplants compared with in those with acute tubular necrosis (ATN; P=0.001), chronic allograft nephropathy (CAN; P=0.01), and acute rejection (AR; P<0.0001), which was associated with a good diagnostic performance for AR [area under the curve (AUC)=0.818, P<0.0001). In addition, urinary CXCL13/Cr levels in patients with AR were also higher than that of patients with graft dysfunction but no rejection, including ATN and CAN (P=0.034). Notably, urinary CXCL13 distinguished between acute antibody‑mediated rejection (ABMR) and acute cellular rejection, with an AUC of 0.856. Furthermore, patients with steroid‑resistant AR exhibited significantly increased urinary CXCL13/Cr levels than patients with reversible AR (P=0.001). Additionally, elevated levels of urinary CXCL13/Cr within the first month of transplant were predictive of graft function at 3 and 6 months (P=0.044 and P=0.04, respectively). Collectively, the findings of the present study indicated that the noninvasive investigation of urinary CXCL13/Cr may be valuable for the detection of AR, particularly ABMR. In addition, high urinary CXCL13/Cr levels predicted a poor response to steroid treatment and compromised graft function.

Effects of exercise on the urinary proteome.

PubMed

Kohler, Maxie; Schänzer, Wilhelm; Thevis, Mario

2015-01-01

Exercise-induced proteinuria has been observed and studied for more than a century. It was found that different sport disciplines alter the urinary proteome in different ways. Moderate-intensity exercise results in increased glomerular filtration, meaning that medium-sized proteins are excreted in higher amounts, while high-intensity exercise of short duration also increases the excretion of low molecular weight proteins as a result of tubular dysfunction. Exhaustive exercise may lead to the excretion of hemoglobin or myoglobin, which changes the urinary proteome considerably. Studies comparing protein maps of different sport types compared to a control group showed that quality and quantity of urinary proteins are interindividually different. In addition, urine samples collected before and after exercise exhibit substantially different protein patterns even from the same person. Therefore, further studies investigating the urinary proteome are desirable. As the variation of protein content and composition in urine are generally much higher than in other matrices, respective studies need to be well controlled and homogenous groups of volunteers should be chosen. In addition to the sport-related physiological and biochemical interest, exercise-induced protein changes also need to be considered for biomarker measurements from urine samples for kidney or other diseases.

Urinary cortisol and psychopathology in obese binge eating subjects.

PubMed

Lavagnino, Luca; Amianto, Federico; Parasiliti Caprino, Mirko; Maccario, Mauro; Arvat, Emanuela; Ghigo, Ezio; Abbate Daga, Giovanni; Fassino, Secondo

2014-12-01

Investigations on the relationship between obesity, binge eating and the function of hypothalamic-pituitary-adrenal (HPA) axis have led to inconsistent results. General psychopathology affects HPA axis function. The present study aims to examine correlations between binge eating, general psychopathology and HPA axis function in obese binge eaters. Twenty-four hour urinary free cortisol (UFC/24 h) was measured in 71 obese binge eating women. The patients were administered psychometric tests investigating binge eating, psychopathology and clinical variables. The relationship between binge eating, psychopathology and urinary cortisol was investigated, controlling for age and BMI. We found an inverse correlation between UFC/24 h and binge eating, depression, obsessive-compusive symptoms, somatization and sensitivity. In a regression model a significant inverse correlation between urinary cortisol and psychopathology was confirmed. Urinary cortisol levels in obese patients with binge eating disorder show an inverse correlation with several dimensions of psychopathology which are considered to be typical of a cluster of psychiatric disorders characterized by low HPA axis function, and are very common in obese binge eating patients. If these results are confirmed, UFC/24 h might be considered a biomarker of psychopathology in obese binge eaters. Copyright © 2014 Elsevier Ltd. All rights reserved.

A HILIC-UHPLC-MS/MS untargeted urinary metabonomics combined with quantitative analysis of five polar biomarkers on osteoporosis rats after oral administration of Gushudan.

PubMed

Wu, Xiao; Huang, Yue; Sun, Jinghan; Wen, Yongqing; Qin, Feng; Zhao, Longshan; Xiong, Zhili

2018-01-01

A HILIC-UHPLC-MS/MS untargeted urinary metabonomic method combined with quantitative analysis of five potential polar biomarkers in rat urine was developed and validated, to further understand the anti-osteoporosis effect of Gushudan(GSD) and its mechanism on prednisolone-induced osteoporosis(OP) rats in this study. The metabolites were separated and identified on Waters BEH HILIC (2.1mm×100mm, 1.7μm) column using the Waters ACQUITY™ ultra performance liquid chromatography system (Waters Corporation, Milford, USA) coupled with a Micromass Quattro Micro™ API mass spectrometer (Waters Corp, Milford, MA, USA). Principal component analysis (PCA) was used to identify potential biomarkers. Primary potential polar biomarkers including creatinine, taurine, betaine, hypoxanthine and cytosine, which were related to energy metabolism, lipid metabolism and amino acid metabolism, were found in the untargeted metabonomic research. Moreover, these targeted biomarkers were further separated and quantified in multiple-reaction monitoring (MRM) with positive ionization mode, using tinidazole as internal standard (I.S.). Good linearities (r>0.99) were obtained for all the analytes with the low limit of quantification from 1.00 to 12.8μg/mL. The relative standard deviation (RSD) of the intra-day and inter-day precisions were within 15.0% and the accuracy ranged from -14.3% to 13.5%. The recovery was more than 85.0%. And the validated method was successfully applied to investigate the urine samples of the control group, prednisolone-induced osteoporosis model group and Gushudan-treatment group in rats. Compared to the control group, the level of creatinine, taurine, betaine, hypoxanthine and cytosine in the model group revealed a significant decrease trend (p<0.05), while the Gushudan-treatment group showed no statistically differences by an independent sample t-test. This paper provided a better understanding of the therapeutic effect and mechanism of GSD on prednisolone-induced osteoporosis rats. Copyright © 2017. Published by Elsevier B.V.

Randomized Trial of Glucosamine and Chondroitin Supplementation on Inflammation and Oxidative Stress Biomarkers and Plasma Proteomics Profiles in Healthy Humans

PubMed Central

Navarro, Sandi L.; White, Emily; Kantor, Elizabeth D.; Zhang, Yuzheng; Rho, Junghyun; Song, Xiaoling; Milne, Ginger L.; Lampe, Paul D.; Lampe, Johanna W.

2015-01-01

Background Glucosamine and chondroitin are popular non-vitamin dietary supplements used for osteoarthritis. Long-term use is associated with lower incidence of colorectal and lung cancers and with lower mortality; however, the mechanism underlying these observations is unknown. In vitro and animal studies show that glucosamine and chondroitin inhibit NF-kB, a central mediator of inflammation, but no definitive trials have been done in healthy humans. Methods We conducted a randomized, double-blind, placebo-controlled, cross-over study to assess the effects of glucosamine hydrochloride (1500 mg/d) plus chondroitin sulfate (1200 mg/d) for 28 days compared to placebo in 18 (9 men, 9 women) healthy, overweight (body mass index 25.0–32.5 kg/m2) adults, aged 20–55 y. We examined 4 serum inflammatory biomarkers: C-reactive protein (CRP), interleukin 6, and soluble tumor necrosis factor receptors I and II; a urinary inflammation biomarker: prostaglandin E2-metabolite; and a urinary oxidative stress biomarker: F2-isoprostane. Plasma proteomics on an antibody array was performed to explore other pathways modulated by glucosamine and chondroitin. Results Serum CRP concentrations were 23% lower after glucosamine and chondroitin compared to placebo (P = 0.048). There were no significant differences in other biomarkers. In the proteomics analyses, several pathways were significantly different between the interventions after Bonferroni correction, the most significant being a reduction in the “cytokine activity” pathway (P = 2.6 x 10-16), after glucosamine and chondroitin compared to placebo. Conclusion Glucosamine and chondroitin supplementation may lower systemic inflammation and alter other pathways in healthy, overweight individuals. This study adds evidence for potential mechanisms supporting epidemiologic findings that glucosamine and chondroitin are associated with reduced risk of lung and colorectal cancer. Trial Registration ClinicalTrials.gov NCT01682694 PMID:25719429

Impact of Τh1 and Τh2 cytokines in the progression of idiopathic nephrotic syndrome due to focal segmental glomerulosclerosis and minimal change disease.

PubMed

Stangou, Maria; Spartalis, Μichael; Daikidou, Dimitra-Vasilia; Kouloukourgiotou, Theodora; Sampani, Erasmia; Lambropoulou, Ioanna-Theologia; Pantzaki, Afroditi; Papagianni, Αikaterini; Efstratiadis, George

2017-07-01

Differential diagnosis between primary focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) is sometimes difficult as nephrotic syndrome is the main clinical symptom in both diseases. This study has attempted to evaluate the urinary excretion of Th1 and Th2 cytokines as potential biomarkers in distinguishing the two types of nephrotic syndrome, and predicting outcome of renal function. Thirty-six patients with FSGS (M/F 22/14, Age; 41.9 ± 17 years, SCr=1.7 ± 0.8 mg/dL, UProt=4.7 ± 5.5 g/24 h), and 21 with MCD (M/F 5/16, Age; 41.4 ± 15 years, SCr = 1 ± 0.4 mg/dL, UProt = 7.9 ± 9.3 g/24 h) were included in the study. Τh1 (IL-2, IL-12, GM-CSF, INF-γ, TNF-α) and Th2 cytokines (IL-4, IL-5, IL-10, IL-13) were measured by multiple cytokine assay, Luminex technology, in first morning urinary samples collected at the day of renal biopsy. No significant differences in urinary excretion of all cytokines were found between FSGS and MCD patients. In FSGS however, IL-12 urinary levels were independent factor correlated with both global sclerosis (R = 0.5, P = 0.009) and interstitial fibrosis (R = 0.5, P = 0.02). Th1 cytokines (IL-2 and GM-CSF) were significantly increased in FSGS patients who did not respond to treatment ( P = 0.03 and P = 0.007, respectively). Th2 cytokines (IL-4, IL-5, IL-10, IL-13) were significantly increased in MCD patients with frequent relapses ( P = 0.05, P = 0.001, P = 0.01, P = 0.03). Urinary excretion of Th1 and Th2 cytokines cannot discriminate FSGS from MCD. Th1 cytokines, especially IL-12, IL-2 and GM-CSF, may be involved in pathology and progression of FSGS, while Th2 cytokines are implicated in frequent relapses of nephrotic syndrome in MCD.

Exercise Training, NADPH Oxidase p22phox Gene Polymorphisms, and Hypertension

PubMed Central

FEAIRHELLER, DEBORAH L.; BROWN, MICHAEL D.; PARK, JOON-YOUNG; BRINKLEY, TINA E.; BASU, SAMAR; HAGBERG, JAMES M.; FERRELL, ROBERT E.; FENTY-STEWART, NICOLA M.

2010-01-01

Introduction Oxidative stress that is mediated through NADPH oxidase activity plays a role in the pathology of hypertension, and aerobic exercise training reduces NADPH oxidase activity. The involvement of genetic variation in the p22phox (CYBA) subunit genes in individual oxidative stress responses to aerobic exercise training has yet to be examined in Pre and Stage 1 hypertensives. Methods Ninety-four sedentary Pre and Stage 1 hypertensive adults underwent 6 months of aerobic exercise training at a level of 70% V̇O2max to determine whether the CYBA polymorphisms, C242T and A640G, were associated with changes in urinary 8-iso-prostaglandin F2α (8-iso-PGF2α), urinary nitric oxide metabolites (NOx), and plasma total antioxidant capacity (TAC). Results Demographic and subject characteristics were similar among genotype groups for both polymorphisms. At baseline, a significant (P = 0.03) difference among the C2424T genotype groups in 8-iso-PGF2α levels was detected, with the TT homozygotes having the lowest levels and the CC homozygotes having the highest levels. However, no differences were found at baseline between the A640G genotype groups. After 6 months of aerobic exercise training, there was a significant increase in V̇O2max (P < 0.0001) in the entire study population. In addition, there were significant increases in both urinary 8-iso-PGF2α (P = 0.002) and plasma TAC (P = 0.03) levels and a significant decrease in endogenous urinary NOx (P < 0.0001). Overall, aerobic exercise training elicited no significant differences among genotype groups in either CYBA variant for any of the oxidative stress variables. Conclusions We found that compared with CYBA polymorphisms C242T and A640G, it was aerobic exercise training that had the greatest influence on the selected biomarkers; furthermore, our results suggest that the C242T CYBA variant influences baseline levels of urinary 8-iso-PGF2α but not the aerobic exercise-induced responses. PMID:19516159

Urinary podocalyxin, the novel biomarker for detecting early renal change in obesity.

PubMed

Suwanpen, Chayanut; Nouanthong, Phonethipsavanh; Jaruvongvanich, Veeravich; Pongpirul, Krit; Pongpirul, Wannarat Amornnimit; Leelahavanichkul, Asada; Kanjanabuch, Talerngsak

2016-02-01

The prevalence of obesity is increasing during the past decade along with obesity-related glomerulopathy (ORG), glomeruli injury due to the obesity. The major pathogenesis of ORG is the shedding of podocytes from the glomerular cell barrier into urine. Podocalyxin (PCX), a main surface antigen of podocyte, correlates well with glomerulosclerosis progression and glomerular injury severity, and might be a potential biomarker for early renal alteration in obesity. In addition, vascular endothelial growth factor (VEGF) and alpha-smooth muscle actin (α-SMA) also play a role in promoting glomerulosclerosis. The aim of this study was to explore whether obese subjects without other diseases excrete more PCX-positive (PCX+) cells than non-obese individuals, in comparison with urine protein-creatinine ratio (UPCR) and glomerular filtration rate (GFR) as traditional renal markers. Moreover, the effect of body mass index (BMI) on urinary VEGF, PCX or α-SMA positive cells was also investigated. Forty-eight obese and 13 non-obese adults were included. Exfoliated cells from fresh first void morning urine were harvested, stained with PCX, VEGF, and α-SMA antibody, and quantified by flow cytometry. Correlation between interested urinary biomarkers (cells positive for PCX, VEGF plus PCX and α-SMA), UPCR and GFR with BMI and metabolic risk factors were analyzed. Obese patients had significantly higher PCX+ cells than non-obese [0.62 (0.00-13.13) vs. 0.15 (0.00-0.72) cells/ml × mg cr, p < 0.05]. There was no significant difference in GFR and UPCR between the groups. Of interest, BMI demonstrated a correlation with PCX+ cells (r = 0.343, p = 0.008) and cells positive for PCX plus VEGF (r = 0.374, p = 0.004). Obese subjects without other diseases and with normal UPCR and GFR showed evidence of renal alteration through the detection of a higher number of PCX+ cells. Increasing BMI also resulted in higher number of PCX+ cells.

Detection of inflammatory biomarkers in saliva and urine: Potential in diagnosis, prevention, and treatment for chronic diseases

PubMed Central

Tyagi, Amit K; Aggarwal, Bharat B

2016-01-01

Inflammation is a part of the complex biological response of inflammatory cells to harmful stimuli, such as pathogens, irritants, or damaged cells. This inflammation has been linked to several chronic diseases including cancer, atherosclerosis, rheumatoid arthritis, and multiple sclerosis. Major biomarkers of inflammation include tumor necrosis factor, interleukins (IL)-1, IL-6, IL-8, chemokines, cyclooxygenase, 5-lipooxygenase, and C-reactive protein, all of which are regulated by the transcription factor nuclear factor-kappaB. Although examining inflammatory biomarkers in blood is a standard practice, its identification in saliva and/or urine is more convenient and non-invasive. In this review, we aim to (1) discuss the detection of these inflammatory biomarkers in urine and saliva; (2) advantages of using salivary and urinary inflammatory biomarkers over blood, while also weighing on the challenges and/or limitations of their use; (3) examine their role(s) in connection with diagnosis, prevention, treatment, and drug development for several chronic diseases with inflammatory consequences, including cancer; and (4) explore the use of innovative salivary and urine based biosensor strategies that may permit the testing of biomarkers quickly, reliably, and cost-effectively, in a decentralized setting. PMID:27013544