Nephrotoxic Metal Mixtures and Preadolescent Kidney Function.
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ABSTRACT:
SUBMITTER: Levin-Schwartz Y
PROVIDER: S-EPMC8391795 | biostudies-literature | 2021 Aug
REPOSITORIES: biostudies-literature
Publications
Nephrotoxic Metal Mixtures and Preadolescent Kidney Function.
Levin-Schwartz Yuri Y Politis Maria D MD Gennings Chris C Tamayo-Ortiz Marcela M Flores Daniel D Amarasiriwardena Chitra C Pantic Ivan I Tolentino Mari Cruz MC Estrada-Gutierrez Guadalupe G Lamadrid-Figueroa Hector H Tellez-Rojo Martha M MM Baccarelli Andrea A AA Wright Robert O RO Sanders Alison P AP
Children (Basel, Switzerland) 20210802 8
Exposure to metals including lead (Pb), cadmium (Cd), and arsenic (As), may impair kidney function as individual toxicants or in mixtures. However, no single medium is ideal to study multiple metals simultaneously. We hypothesized that multi-media biomarkers (MMBs), integrated indices combining information across biomarkers, are informative of adverse kidney function. Levels of Pb, Cd, and As were quantified in blood and urine in 4-6-year-old Mexican children (n = 300) in the PROGRESS longitudin ...[more]
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Project description:IntroductionAs renal development and maturation processes begin in utero and continue through early childhood, sensitive developmental periods arise during which metal exposures can program subclinical nephrotoxicity that manifests later in life. We used novel dentine biomarkers of established nephrotoxicants including arsenic (As), cadmium (Cd), lead (Pb), chromium (Cr), and lithium (Li), and their mixtures, to identify critical windows of exposure-associated kidney function alterations in preadolescents.MethodsParticipants included 353 children in the Programming Research in Obesity Growth, Environment and Social Stressors (PROGRESS) longitudinal birth cohort study based in Mexico City. Estimated glomerular filtration rate (eGFR) was assessed in 8-12 year old children using serum cystatin C measures. Pre- and postnatal metal(loid) concentrations were assessed in weekly increments by analyzing deciduous teeth with laser ablation-inductively coupled plasma-mass spectrometry. We used reverse distributed lag models (rDLMs) and lagged Weighted Quantile Sum (L-WQS) regression to examine time-varying associations between weekly perinatal metal(loid) exposure or metal(loid) mixtures and preadolescent eGFR while adjusting for age, sex, BMI z-score, SES and prenatal tobacco smoke exposure.ResultsWe identified a critical window of susceptibility to Pb exposure, in the late 3rd trimester (5 weeks prior to birth) during which higher Pb exposure was associated with children's increased eGFR. When all elements were assessed as a mixture, we identified late 2nd/early 3rd trimester (weeks 8-17 of gestation) as a window of vulnerability associated with decreased eGFR, with Li and Cr contributing the greatest weights to the association. When stratified by sex, we observed stronger effects among boys than girls.ConclusionsUsing tooth-matrix biomarkers, we identified discrete developmental exposure windows wherein Pb and metal(loid) mixtures were associated with altered preadolescent kidney function.
| S-EPMC9792626 | biostudies-literature
Project description:Air pollution exposure, especially particulate matter ≤2.5 μm in diameter (PM2.5), is associated with poorer kidney function in adults and children. Perinatal exposure may occur during susceptible periods of nephron development. We used distributed lag nonlinear models (DLNMs) to examine time-varying associations between early life daily PM2.5 exposure (periconceptional through age 8 years) and kidney parameters in preadolescent children aged 8-10 years. Participants included 427 mother-child dyads enrolled in the PROGRESS birth cohort study based in Mexico City. Daily PM2.5 exposure was estimated at each participant's residence using a validated satellite-based spatio-temporal model. Kidney function parameters included estimated glomerular filtration rate (eGFR), serum cystatin C, and blood urea nitrogen (BUN). Models were adjusted for child's age, sex and body mass index (BMI) z-score, as well as maternal education, indoor smoking report and seasonality (prenatal models were additionally adjusted for average first year of life PM2.5 exposure). We also tested for sex-specific effects. Average perinatal PM2.5 was 22.7 μg/m3 and ranged 16.4-29.3 μg/m3. Early pregnancy PM2.5 exposures were associated with higher eGFR in preadolescence. Specifically, we found that PM2.5 exposure between weeks 1-18 of gestation was associated with increased preadolescent eGFR, whereas exposure in the first 14 months of life after birth were associated with decreased eGFR. Specifically, a 5 μg/m3 increase in PM2.5 during the detected prenatal window was associated with a cumulative increase in eGFR of 4.44 mL/min/1.732 (95%CI: 1.37, 7.52), and during the postnatal window we report a cumulative eGFR decrease of -10.36 mL/min/1.732 (95%CI: -17.68, -3.04). We identified perinatal windows of susceptibility to PM2.5 exposure with preadolescent kidney function parameters. Follow-up investigating PM2.5 exposure with peripubertal kidney function trajectories and risk of kidney disease in adulthood will be critical.
| S-EPMC8678189 | biostudies-literature
Project description:BackgroundDue to these changes in kidney function, aging kidneys are more prone to drug-induced impairments in renal properties. Diabetes has been associated with the declined kidney function and an elevated risk of renal failure. The aim of this study is to compare kidney function and potentially nephrotoxic drug use among home-dwelling older persons with or without diabetes.MethodsA total of 259 persons with and 259 persons without diabetes and aged ≥65 years were randomly selected to participate in a health examination with complete data gathered from 363 individuals (187 with diabetes and 176 without diabetes). The estimated glomerular filtration rate (eGFR) was calculated using CKD-EPI equation. Each participant was categorized based on the nephrotoxic profile of their medications.ResultsThere were no differences in mean eGFR values (77.5 ± 18.8 vs. 80.5 ± 14.8 ml/min/1.73m2, p = 0.089) or in the proportion of participants with eGFR < 60 ml/min/1.73m2 among persons with diabetes (16% vs. 10%, p = 0.070), compared to persons without diabetes. Potentially nephrotoxic drug use was similar between the groups. The mean number of potentially nephrotoxic drugs was 1.06 ± 0.88 in those with and 0.97 ± 1.05 in those without diabetes (p = 0.39).ConclusionsThe kidney function of older persons with diabetes does not differ from that of older persons without diabetes and furthermore potentially nephrotoxic drug use seem to play only a minor role in the decline in kidney function among home-dwelling persons in the Inner-Savo district.
| S-EPMC6954600 | biostudies-literature
Project description:Using the nonaccelerated murine nephrotoxic nephritis (NTN) as a model of chronic kidney disease (CKD) could provide an easily inducible model that enables a rapid test of treatments. Originally, the NTN model was developed as an acute model of glomerulonephritis, but in this study we evaluate the model as a CKD model and compare CD1 and C57BL/6 female and male mice. CD1 mice have previously showed an increased susceptibility to CKD in other CKD models. NTN was induced by injecting nephrotoxic serum (NTS) and evaluated by CKD parameters including albuminuria, glomerular filtration rate (GFR), mesangial expansion, and renal fibrosis. Both strains showed significant albuminuria on days 2-3 which remained significant until the last time point on days 36-37 supporting dysfunctional filtration also observed by a significantly declined GFR on days 5-6, 15-17, and 34-37. Both strains showed early progressive mesangial expansion and significant renal fibrosis within three weeks suggesting CKD development. CD1 and C57BL/6 females showed a similar disease progression, but female mice seemed more susceptible to NTS compared to male mice. The presence of albuminuria, GFR decline, mesangial expansion, and fibrosis showed that the NTN model is a relevant CKD model both in C57BL/6 and in CD1 mice.
| S-EPMC5859794 | biostudies-literature
Project description:The recent development of a custom cDNA microarray platform for one of thé standard organisms in aquatic toxicology, Daphnia magna, opened up new ways to mechanistic insights of toxicological responses. In this study, gene expression and (sub)organismal responses (Cellular Energy Allocation, growth) were assayed after short-term waterborne metal exposure. Microarray analysis of Ni-exposed daphnids revealed several affected functional gene classes, of which the largest ones were involved in different metabolic processes (mainly protein and chitin related processes), cuticula turnover, transport and signal transduction. Furthermore, genes involved in oxygen transport and heme metabolism (hemoglobin, δ-aminolevilunate synthase) were down-regulated. Applying a Partial Least Squares regression on nickel fingerprints and biochemical (sub)organismal parameters revealed a set of co-varying genes (hemoglobin, RNA terminal phosphate cyclase, a ribosomal protein and an “unknown” gene fragment). An inverse relationship was seen between the mRNA expression levels of different cuticula proteins and available energy reserves. In addition to the nickel exposure, daphnids were exposed to binary mixtures of nickel and cadmium or nickel and lead. Using multivariate analysis techniques, the mixture gene expression fingerprints (Ni2++Cd2+, Ni2++Pb2+) were compared to those of the single metal treatments (Ni2+, Cd2+, Pb2+). It was hypothesized that the molecular fingerprints of the mixtures would be additive combinations of the gene expression profiles of the individual compounds present in the mixture. However, our results clearly showed additionally affected pathways after mixture treatment (e.g. additional affected genes involved in carbohydrate catabolic processes and proteolysis), indicating interactive molecular responses which are not merely the additive sum of the individual metals. These findings, although indicative of the complex nature of mixture toxicity evaluation, underline the potential of a toxicogenomics approach in gaining more mechanistic information on the effects of single compounds and mixtures.
2009-02-27 | GSE13866 | GEO
Project description:Nephrotoxic medication (NTM) avoidance may prevent further kidney damage in children with acute kidney injury (AKI). We compared outpatient NTM prescriptions in children with or without AKI during pediatric intensive care (PICU) hospitalization. We hypothesize that children with AKI are prescribed NTMs at the same rate as those without it. This was a retrospective administrative data study of children <18 years, admitted to two PICUs in Montreal, Canada, from 2003 to 2005, with ≥30 days of provincial drug coverage. We evaluated the presence of ≥3 outpatient NTM prescriptions during the first year and 5 years after PICU discharge. Of 970 children, 23% had PICU AKI. In the 1st-5th years after discharge, 18% AKI vs. 10% non-AKI and 13% AKI vs. 4% non-AKI patients received ≥3 NTM prescriptions, respectively. There was no association between PICU AKI and prescription of ≥3 NTMs during the first year (adjusted RR 1.02 [95% CI 0.95-1.10]) nor in the first 5 years post-discharge (adjusted RR 1.04 [95%CI 0.96-1.12]). By offering a better understanding of the current state of outpatient NTM prescription to children with AKI, our study is a step toward considering strategies such as knowledge translation interventions for decreasing NTM exposure and improving outcomes in children with AKI.
| S-EPMC8618325 | biostudies-literature
Project description:BackgroundMetal(oid)s have been cross-sectionally associated with lung function outcomes in childhood but there is limited data on their combined effects starting in utero. Child sex may further modify these effects.ObjectiveExamine associations between in utero and early life exposure to metals assessed via novel dentine biomarkers and childhood lung function and explore effect modification by child sex.MethodsAnalyses included 291 children enrolled in the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) study, a longitudinal birth cohort study in Mexico City. Weekly dentine levels of arsenic (As), cadmium (Cd), cobalt (Co), copper (Cu), manganese (Mn), nickel (Ni), and lead (Pb) were measured from 15 weeks pre-birth to 15 weeks post birth in deciduous children's teeth. Lung function was tested at ages 8-14 years and then modeled as age, height and sex adjusted z-scores. Associations were modeled using lagged weighted quantile sum (LWQS) regression to evaluate the potential for a time-varying mixture effect adjusting for maternal age and education at enrollment and exposure to environmental tobacco smoke in pregnancy. Models were also stratified by sex.ResultsWe identified a window of susceptibility at 12-15 weeks pre-birth in which the metal mixture was associated with lower FVC z-scores in children aged 8-14 years. Cd and Mn were the largest contributors to the mixture effect (70 %). There was also some evidence of effect modification by sex, in which the mean weights and weighted correlations over the identified window was more evident in males when compared to females. In the male stratum, Cd, Mn and additionally Pb also dominated the mixture association.ConclusionsPrenatal metal(oid) exposure was associated with lower lung function in childhood. These findings underscore the need to consider both mixtures and windows of susceptibility to fully elucidate effects of prenatal metal(oid) exposure on childhood lung function.
| S-EPMC11238599 | biostudies-literature
Project description:The recent development of a custom cDNA microarray platform for one of thé standard organisms in aquatic toxicology, Daphnia magna, opened up new ways to mechanistic insights of toxicological responses. In this study, gene expression and (sub)organismal responses (Cellular Energy Allocation, growth) were assayed after short-term waterborne metal exposure. Microarray analysis of Ni-exposed daphnids revealed several affected functional gene classes, of which the largest ones were involved in different metabolic processes (mainly protein and chitin related processes), cuticula turnover, transport and signal transduction. Furthermore, genes involved in oxygen transport and heme metabolism (hemoglobin, δ-aminolevilunate synthase) were down-regulated. Applying a Partial Least Squares regression on nickel fingerprints and biochemical (sub)organismal parameters revealed a set of co-varying genes (hemoglobin, RNA terminal phosphate cyclase, a ribosomal protein and an âunknownâ gene fragment). An inverse relationship was seen between the mRNA expression levels of different cuticula proteins and available energy reserves. In addition to the nickel exposure, daphnids were exposed to binary mixtures of nickel and cadmium or nickel and lead. Using multivariate analysis techniques, the mixture gene expression fingerprints (Ni2++Cd2+, Ni2++Pb2+) were compared to those of the single metal treatments (Ni2+, Cd2+, Pb2+). It was hypothesized that the molecular fingerprints of the mixtures would be additive combinations of the gene expression profiles of the individual compounds present in the mixture. However, our results clearly showed additionally affected pathways after mixture treatment (e.g. additional affected genes involved in carbohydrate catabolic processes and proteolysis), indicating interactive molecular responses which are not merely the additive sum of the individual metals. These findings, although indicative of the complex nature of mixture toxicity evaluation, underline the potential of a toxicogenomics approach in gaining more mechanistic information on the effects of single compounds and mixtures. In general, a universal reference design was used. The following analysis (normalization and statistical analysis) was performed. Spots were identified and ratioâs quantified by means of the Genepix software 5.0 (Axon Instruments). Subsequently, a MIAME compliant platform, the BioArray Software Environment Database (BASE 1.2.12, http://www.islab.ua.ac.be/base/) was used for storage, further evaluation and succeeding statistical analysis of the microarray datasets. After a local background correction, spots with a foreground larger than the mean local background +2 standard deviations for one or both colours were selected for further analysis. The Log2 transformed Cy3/Cy5 ratio data were normalized by implementation of a Locally Weighed Scatterplot Smoothing (Lowess) (Yang et al., 2002) step, which is an intensity-based method. Significant vertical cut-off values of log -0.85 and 0.85 were determined through multiple self-self hybridizations. These were performed by labelling the same biological material with both Cy3 and Cy5 dyes and hybridizing them simultaneously on a microarray slide. To statistically evaluate the microarray results, Significance Analysis of Microarrays (SAM) described by Tusher et al. (2001) was applied on the Lowess normalized datasets. With this SAM approach a false discovery rate (FDR) below 5% was applied. As a result genes with log2 ratios outside the confidence interval of -0.85 and 0.85 were considered as differentially expressed gene fragments when FDR was below 5%.
2010-05-22 | E-GEOD-13866 | biostudies-arrayexpress
Project description:Vancomycin is a glycopeptide antibiotic used against multi-drug resistant gram-positive bacteria such as Staphylococcus aureus (MRSA). Although invaluable against resistant bacteria, vancomycin harbors adverse drug reactions including cytopenia, ototoxicity, as well as nephrotoxicity. Since nephrotoxicity is a rarely occurring side effect, its mechanism is incompletely understood. Only recently, the actual clinically relevant concentration the in kidneys of patients receiving vancomycin was investigated and were found to exceed plasma concentrations by far. We applied these clinically relevant vancomycin concentrations to murine and canine renal epithelial cell lines and assessed metabolic and lipidomic alterations by untargeted and targeted gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry analyses. Despite marked differences in the lipidome, both cell lines increased anabolic glucose reactions, resulting in higher sorbitol and lactate levels. To the best of our knowledge, this is the first endometabolic profiling of kidney cells exposed to clinically relevant vancomycin concentrations. The presented study will provide a valuable dataset to nephrotoxicity researchers and might add to unveiling the nephrotoxic mechanism of vancomycin.
| S-EPMC8466248 | biostudies-literature
Project description:BackgroundExposure to environmental metals can cause nephrotoxicity. There is an international epidemic of chronic kidney disease of unknown cause (CKDu). Whether metal exposures contribute to kidney dysfunction in populations at risk for CKDu remains unresolved.ObjectiveUrinary metals (arsenic, cadmium, nickel, and uranium) were examined in 222 sugarcane cutters in Guatemala at three time points over 1 year.MethodsWe explored the relationships between metal concentrations and markers of kidney function using multivariable linear mixed-effect models.ResultsArsenic, cadmium, and nickel were detected in the majority of the 340 urine samples and were generally within limits previously considered to be nonnephrotoxic. Nevertheless, higher urine cadmium was inversely associated with estimated glomerular filtration rate (eGFR) (β: -4.23, 95% confidence interval [CI]: -6.92, -1.54) and positively associated with neutrophil gelatinase-associated lipocalin (NGAL) (β: 2.92, 95% CI: 1.20, 4.64). Higher urine arsenic was also inversely associated with eGFR (β: -4.36, 95% CI: -7.07, -1.64).SignificanceOur findings suggest that exposures to metals, including cadmium and arsenic, might contribute to kidney toxicity seen in workers at risk for CKDu. These findings are consistent with the potential for metal nephrotoxicity at lower than expected levels in the setting of manual work in a very hot environment.
| S-EPMC8371072 | biostudies-literature