Clearing the air: a review of the effects of air pollution on dialysis outcomes.

PURPOSE OF REVIEW: An evolving body of literature indicates exposure to air pollutants is associated with adverse health outcomes in dialysis patients. As the prevalence of kidney disease increases, understanding the role of environmental agents on the health of dialysis patients is critical to reducing global morbidity and mortality. RECENT FINDINGS: We identified 16 publications that investigated associations between pollutants including particulate matter (PM 2.5 and PM 10 ), carbon monoxide (CO), nitrogen dioxide (NO 2 ), sulfur dioxide (SO 2 ), and ozone (O 3 ) and health outcomes among dialysis patients. Eight studies examined the effects of particulate matter (PM) and four studies examined the effects CO exposure on dialysis patients. Exposure to PM was consistently associated with outcomes including all-cause mortality and a smaller body of literature suggested relationships with subclinical outcomes. Exposure to CO was associated with all-cause mortality, generalized inflammation, and uremic pruritus. An additional four studies examined multiple pollutant exposures including NO 2 , SO 2 , and O 3 and reported associations with all-cause mortality in dialysis patients. SUMMARY: This review emphasized the nascent literature that demonstrates consistent relationships between air pollutant exposure and adverse outcomes among dialysis patients. Further research is needed to assess the impact of air pollutants, including how co-exposures will impact dialysis patient health.

Non-essential and essential trace element mixtures and kidney function in early pregnancy - A cross-sectional analysis in project viva.

Some trace elements are established nephrotoxicants, yet their associations with kidney function remain understudied in the context of pregnancy, a time of substantial change in kidney physiology and function. We aimed to estimate the individual and joint associations of trace element mixtures with maternal kidney function during the 1st trimester of pregnancy (mean 9.7 gestational weeks). 1040 women from Project Viva contributed blood samples which were assessed for erythrocyte non-essential [arsenic (As), cadmium (Cd), cesium (Cs), mercury (Hg), lead (Pb)] and essential [barium (Ba), magnesium (Mg), manganese (Mn), selenium (Se), and Zinc (Zn)] trace elements, and plasma creatinine for kidney function. We estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration (eGFRCKD-EPI) equation without race-adjustment factors. We examined associations of eGFRCKD-EPI with individual trace elements using multivariable linear regression and their mixtures using quantile-based g-computation, adjusting for sociodemographics, pregnancy characteristics, and diet. Participants in our study were predominantly White (75%), college graduates (72%), and had household income >$70,000/year (63%). After adjusting for covariates, higher Pb (ß -3.51 ml/min/1.73 m2; 95% CI -5.83, -1.18) concentrations were associated with lower eGFRCKD-EPI, while higher Mg (ß 10.53 ml/min/1.73 m2; 95% CI 5.35, 15.71), Se (ß 5.56 ml/min/1.73 m2; 95% CI 0.82, 10.31), and Zn (ß 5.88 ml/min/1.73 m2; 95% CI 0.51, 11.26) concentrations were associated with higher eGFRCKD-EPI. In mixture analyses, higher non-essential trace elements mixture concentration was associated with reduced eGFRCKD-EPI (Ψ -1.03 ml/min/1.73 m2; 95% CI: 1.92, -0.14). Conversely, higher essential trace elements mixture concentration was associated with higher eGFR (Ψ 1.42; 95% CI: 0.48, 2.37). Exposure to trace elements in early pregnancy may influence women's kidney function although reverse causation cannot be eliminated in this cross-sectional analysis. These findings have important implications for long-term cardiovascular and postpartum kidney health that warrant additional studies.

A cross-validation based approach for estimating specific gravity in elementary-school aged children using a nonlinear model.

Environmental research often relies on urinary biomarkers which require dilution correction to accurately measure exposures. Specific gravity (SG) and creatinine (UCr) are commonly measured urinary dilution factors. Epidemiologic studies may assess only one of these measures, making it difficult to pool studies that may otherwise be able to be combined. Participants from the National Health and Nutrition Examination Survey 2007-2008 cycle were used to perform k-fold validation of a nonlinear model estimating SG from UCr. The final estimated model was applied to participants from the School Inner-City Asthma Intervention Study, who submitted urinary samples to the Children's Health Exposure Analysis Resource. Model performance was evaluated using calibration metrics to determine how closely the average estimated SG was to the measured SG. Additional models, with interaction terms for age, sex, body mass index, race/ethnicity, relative time of day when sample was collected, log transformed 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), and asthma status were estimated and assessed for improvement. The association between monobenzyl phthalate (MBZP) and asthma symptom days, controlling for measured UCr, measured SG, and each estimated SG were compared to assess validity of the estimated SG. The model estimating SG from UCr alone, resulted in a beta estimate of 1.10 (95% CI: 1.01, 1.19), indicating agreement between model-predicted SG and measured SG. Inclusion of age and sex in the model improved estimation (ß = 1.06, 95% CI: 0.98, 1.15). The full model accounting for all interaction terms with UCr resulted in the best agreement (ß = 1.01, 95% CI: 0.93,1.09). Associations between MBZP and asthma symptoms days, controlling for each estimated SG, were within the range of effect estimates when controlling for measured SG and measured UCr (Rate ratios = 1.28-1.34). Our nonlinear modeling provides opportunities to estimate SG in studies that measure UCr or vice versa, enabling data pooling despite differences in urine dilution factors.

Early childhood fluoride exposure and preadolescent kidney function.

BACKGROUND: Early-life renal maturation is susceptible to nephrotoxic environmental chemicals. Given the widespread consumption of fluoride and the global obesity epidemic, our main aim was to determine whether childhood fluoride exposure adversely affects kidney function in preadolescence, and if adiposity status modifies this association. METHODS: Our study included 438 children from the PROGRESS cohort. Urinary fluoride (uF) was assessed at age 4 by diffusion analysis; outcomes studied included estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN), selected kidney proteins and blood pressure measured at age 8-12 years. We modeled the relationship between uF and outcomes, and adjusted for body mass index (BMI), age, sex, and socioeconomic status. RESULTS: The median uF concentration was 0.67 µg/mL. We observed null associations between 4-year uF and preadolescent eGFR, although effect estimates were in the expected inverse direction. A single unit increase in ln-transformed uF was associated with a 2.2 mL/min decrease in cystatin C-based eGFR (95% CI: 5.8, 1.4; p = 0.23). We observed no evidence of sex-specific effects or effect modification by BMI status. Although uF was not associated with BMI, among children with obesity, we observed an inverse association (ß: 4.8; 95% CI: 10.2, 0.6; p = 0.08) between uF and eGFR. CONCLUSIONS: Low-level fluoride exposure in early childhood was not associated with renal function in preadolescence. However, given the adverse outcomes of chronic fluoride consumption it is possible that the preadolescent age was too young to observe any effects. Longitudinal follow-up in this cohort and others is an important next step.

Critical windows of perinatal particulate matter (PM2.5) exposure and preadolescent kidney function.

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.

Secondhand smoke exposure and higher blood pressure in children and adolescents participating in NHANES.

We assessed the relationship between acute and intermittent secondhand tobacco smoke (SHS) exposure with child and adolescent blood pressure (BP). We analyzed cross-sectional data from 3579 children and adolescents aged 8-17 years participating in the National Health and Nutrition Examination Survey (NHANES) collected between 2007 and 2012, with SHS exposure assessed via serum cotinine (a biomarker for acute exposures) and urine NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, a biomarker for intermittent exposures). BP percentiles and z-scores were calculated according to the 2017 guidelines established by the American Academy of Pediatrics. We used weighted linear regression accounting for the complex sampling weights from NHANES and adjusting for socio-demographic and clinical characteristics. Overall, 56% of the children were non-Hispanic white with a mean age of 12.6 years. There was approximately equal representation of boys and girls. Approximately 15.9% of participants lived in homes where smoking was present. In adjusted models, an interquartile range (IQR) increase in urinary NNAL was associated with 0.099 (95% CI: 0.033, 0.16) higher diastolic blood pressure (DBP) z-score, and with a 0.094 (95% CI: 0.011, 0.18) higher systolic blood pressure (SBP) z-score. The odds of being in the hypertensive range was 1.966 (95% CI: 1.31, 2.951) times greater among children with high NNAL exposures compared to those with undetectable NNAL. For serum cotinine, an IQR increase was associated with 0.097 (95% CI: 0.020, 0.17) higher DBP z-scores, but was not significantly associated with SBP z-scores. The associations of cotinine and NNAL with BP also differed by sex. Our findings provide the first characterization of the relationship between a major tobacco-specific metabolite, NNAL, and BP z-scores in a nationally representative population of US children.

Identifying critical windows of prenatal particulate matter (PM2.5) exposure and early childhood blood pressure.

BACKGROUND: Exposure to air pollution is associated with increased blood pressure (BP) in adults and children. Some evidence suggests that air pollution exposure during the prenatal period may contribute to adverse cardiorenal health later in life. Here we apply a distributed lag model (DLM) approach to identify critical windows that may underlie the association between prenatal particulate matter ≤ 2.5 µm in diameter (PM2.5) exposure and children's BP at ages 4-6 years. METHODS: Participants included 537 mother-child dyads enrolled in the Programming Research in Obesity, GRowth Environment, and Social Stress (PROGRESS) longitudinal birth cohort study based in Mexico City. Prenatal daily PM2.5 exposure was estimated using a validated satellite-based spatio-temporal model and BP was measured using the automated Spacelabs system with a sized cuff. We used distributed lag models (DLMs) to examine associations between daily PM2.5 exposure and systolic and diastolic BP (SBP and DBP), adjusting for child's age, sex and BMI, as well as maternal education, preeclampsia and indoor smoking report during the second and third trimester, seasonality and average postnatal year 1 PM2.5 exposure. RESULTS: We found that PM2.5 exposure between weeks 11-32 of gestation (days 80-226) was significantly associated with children's increased SBP. Similarly, PM2.5 exposure between weeks 9-25 of gestation (days 63-176) was significantly associated with increased DBP. To place this into context, a constant 10 µg/m3 increase in PM2.5 sustained throughout this critical window would predict a cumulative increase of 2.6 mmHg (CI: 0.5, 4.6) in SBP and 0.88 mmHg (CI: 0.1, 1.6) in DBP at ages 4-6 years. In a stratified analysis by sex, this association persisted in boys but not in girls. CONCLUSIONS: Second and third trimester PM2.5 exposure may increase children's BP in early life. Further work investigating PM2.5 exposure with BP trajectories later in childhood will be important to understanding cardiorenal trajectories that may predict adult disease. Our results underscore the importance of reducing air pollution exposure among susceptible populations, including pregnant women.

Developmental Origins of Common Disease: Epigenetic Contributions to Obesity.

The perinatal period is a window of susceptibility for later life disease. Recent epigenetic findings are beginning to increase our understanding of the molecular mechanisms that may contribute to the programming of obesity. This review summarizes recent evidence that supports the role of epigenetically mediated early life programming in the later onset of obesity. Establishing such links between environmental exposures and modifiable molecular changes ultimately holds promise to inform interventional efforts toward alleviating the environmentally mediated onset of obesity.

Prenatal Metal Concentrations and Childhood Cardiometabolic Risk Using Bayesian Kernel Machine Regression to Assess Mixture and Interaction Effects.

BACKGROUND: Trace metal concentrations may affect cardiometabolic risk, but the role of prenatal exposure is unclear. We examined (1) the relation between blood metal concentrations during pregnancy and child cardiometabolic risk factors; (2) overall effects of metals mixture (essential vs. nonessential); and (3) interactions between metals. METHODS: We measured 11 metals in maternal second-trimester whole blood in a prospective birth cohort in Mexico City. In children 4-6 years old, we measured body mass index (BMI), percent body fat, and blood pressure (N = 609); and plasma hemoglobin A1C (HbA1c), non-high-density lipoprotein (HDL) cholesterol, triglycerides, leptin, and adiponectin (N = 411). We constructed cardiometabolic component scores using age- and sex-adjusted z scores and averaged five scores to create a global risk score. We estimated linear associations of each metal with individual z scores and used Bayesian Kernel Machine Regression to assess metal mixtures and interactions. RESULTS: Higher total metals were associated with lower HbA1c, leptin, and systolic blood pressure, and with higher adiponectin and non-HDL cholesterol. We observed no interactions between metals. Higher selenium was associated with lower triglycerides in linear (ß = -1.01 z score units per 1 unit ln(Se), 95% CI = -1.84, -0.18) and Bayesian Kernel Machine Regression models. Manganese was associated with decreased HbA1c in linear models (ß = -0.32 and 95% CI = -0.61, -0.03). Antimony and arsenic were associated with lower leptin in Bayesian Kernel Machine Regression models. Essential metals were more strongly associated with cardiometabolic risk than were nonessential metals. CONCLUSIONS: Low essential metals during pregnancy were associated with increased cardiometabolic risk factors in childhood.

Maternal blood arsenic levels and associations with birth weight-for-gestational age.

BACKGROUND: Among highly exposed populations, arsenic exposure in utero may be associated with decreased birth weight, however less is known about potential effects of arsenic exposure in urban communities without contaminated sources such as drinking water. OBJECTIVE: Investigate the association of blood arsenic levels with birth weight-for-gestational age categories within a prospective birth cohort study. DESIGN/METHODS: We analyzed 730 mother-infant dyads within the Programming Research in Obesity, GRowth, Environment and Social Stressors (PROGRESS) cohort in Mexico City. Total arsenic was measured in maternal blood samples from the 2nd and 3rd trimesters, at delivery, as well as from infant umbilical cord blood samples. Multivariable, multinomial logistic regression models adjusting for maternal age at enrollment, pre-pregnancy body mass index, parity, infant sex, socioeconomic position, and prenatal environmental tobacco smoke exposure were used to calculate odds ratios of small-for-gestational age (<10th percentile, SGA) and large-for-gestational age (>90th percentile, LGA) compared to appropriate-for-gestational age (AGA) per unit increase of log-transformed arsenic. RESULTS: Median (IQR) blood arsenic levels for maternal second trimester were 0.72 (0.33) µg/L, maternal third trimester 0.75 (0.41) µg/L, maternal at delivery 0.85 (0.70) µg/L, and infant cord 0.78 (0.65) µg/L. Maternal delivery and infant cord blood samples were most strongly correlated (spearman r = 0.65, p < 0.0001). Maternal arsenic levels at delivery were associated with significantly higher odds of both SGA (adj. OR = 1.44, 95% CI: 1.08-1.93) and LGA (adj. OR = 2.03, 95% CI: 1.12-3.67) compared to AGA. Results were similar for cord blood. There were 130 SGA infants and 22 LGA infants. Earlier in pregnancy, there were no significant associations of arsenic and birth weight-for-gestational age. However, we observed non-significantly higher odds of LGA among women with higher arsenic levels in the 3rd trimester (adj. OR = 1.46, 95% CI: 0.67-3.12). CONCLUSION: We found that in a Mexico City birth cohort, higher maternal blood arsenic levels at delivery were associated with higher odds of both SGA and LGA. However, sources and species of arsenic were not known and the number of LGA infants was small, limiting the interpretation of this finding and highlighting the importance of future large studies to incorporate arsenic speciation. If our findings were confirmed in studies that addressed these limitations, determining modifiable factors that could be mitigated, such as sources of arsenic exposure, may be important for optimizing fetal growth to improve long-term health of children.

Perinatal and childhood exposure to environmental chemicals and blood pressure in children: a review of literature 2007-2017.

Exposure to environmental chemicals during periods of renal development from embryogenesis to birth and through childhood can inform critical windows of nephrotoxicity, including changes in childhood blood pressure. This review assessed recent studies that examined the relationship of air pollution, metals, and other organic pollutants with children's blood pressure outcomes. We restricted this review to peer-reviewed studies published in English between January 2007 and July 2017. We identified a total of 36 articles that estimated associations with childhood blood pressure, of which 14 studies examined the effects of air pollution, 10 examined metals, and 12 examined other organic pollutants including phthalates (n = 4), Bisphenol A (n = 3), polychlorinated biphenols (n = 2), organophosphate pesticides (n = 2), or perfluoroalkyl acids (n = 1). Similar to the established relationship between tobacco smoke exposure and childhood blood pressure, the majority of studies that examined air pollutants, particularly exposure to PM10 and PM2.5, reported associations with increased childhood blood pressure. The literature reported conflicting evidence for metals, and putative evidence of the effects of exposure to phthalates, Bisphenol A, polychlorinated biphenols, and pesticides. Overall, our review underscores the need for additional studies that assess the impact of nephrotoxicant exposure during early life, particularly the perinatal period, and blood pressure in childhood.

Environmental exposures and pediatric kidney function and disease: A systematic review.

BACKGROUND: Environmental chemical exposures have been implicated in pediatric kidney disease. No appraisal of the available evidence has been conducted on this topic. METHODS: We performed a systematic review of the epidemiologic studies that assessed association of environmental exposures with measures of kidney function and disease in pediatric populations. The search period went through July 2016. RESULTS: We found 50 studies that met the search criteria and were included in this systematic review. Environmental exposures reviewed herein included lead, cadmium, mercury, arsenic, fluoride, aflatoxin, melamine, environmental tobacco, bisphenol A, dental procedures, phthalates, ferfluorooctanoic acid, triclosan, and thallium/uranium. Most studies assessed environmental chemical exposure via biomarkers but four studies assessed exposure via proximity to emission source. There was mixed evidence of association between metal exposures, and other non-metal environmental exposures and pediatric kidney disease and other kidney disease biomarkers. The evaluation of causality is hampered by the small numbers of studies for each type of environmental exposure, as well as lack of study quality and limited prospective evidence. CONCLUSION: There is a need for well-designed epidemiologic studies of environmental chemical exposures and kidney disease outcomes.

Maternal residential exposure to agricultural pesticides and birth defects in a 2003 to 2005 North Carolina birth cohort.

BACKGROUND: Birth defects are responsible for a large proportion of disability and infant mortality. Exposure to a variety of pesticides have been linked to increased risk of birth defects. METHODS: We conducted a case-control study to estimate the associations between a residence-based metric of agricultural pesticide exposure and birth defects. We linked singleton live birth records for 2003 to 2005 from the North Carolina (NC) State Center for Health Statistics to data from the NC Birth Defects Monitoring Program. Included women had residence at delivery inside NC and infants with gestational ages from 20 to 44 weeks (n = 304,906). Pesticide exposure was assigned using a previously constructed metric, estimating total chemical exposure (pounds of active ingredient) based on crops within 500 meters of maternal residence, specific dates of pregnancy, and chemical application dates based on the planting/harvesting dates of each crop. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals for four categories of exposure (<10(th) , 10-50(th) , 50-90(th) , and >90(th) percentiles) compared with unexposed. Models were adjusted for maternal race, age at delivery, education, marital status, and smoking status. RESULTS: We observed elevated ORs for congenital heart defects and certain structural defects affecting the gastrointestinal, genitourinary and musculoskeletal systems (e.g., OR [95% confidence interval] [highest exposure vs. unexposed] for tracheal esophageal fistula/esophageal atresia = 1.98 [0.69, 5.66], and OR for atrial septal defects: 1.70 [1.34, 2.14]). CONCLUSION: Our results provide some evidence of associations between residential exposure to agricultural pesticides and several birth defects phenotypes. Birth Defects Research (Part A) 106:240-249, 2016. © 2016 Wiley Periodicals, Inc.

Toxic metal levels in children residing in a smelting craft village in Vietnam: a pilot biomonitoring study.

BACKGROUND: In Vietnam, environmental pollution caused by small-scale domestic smelting of automobile batteries into lead ingot is a growing concern. The village of Nghia Lo is a smelting craft village located roughly 25 km southeast of Hanoi in the Red River Delta. Despite the concern of toxic metal exposure in the village, biomonitoring among susceptible populations, such as children, has not been previously conducted. The aim of this study was to determine the body burden of toxic metals in children residing in a smelting craft village. METHODS: Twenty children from Nghia Lo, Vietnam, ages 18 months to four years were selected for capillary whole blood and toenail biomonitoring. Whole blood lead levels (BLLs) were measured using a portable lead analyzer, and toenail levels of arsenic, cadmium, chromium, lead, manganese, and mercury were analyzed with inductively coupled plasma-mass spectrometry. RESULTS: The findings show that all of the 20 children had detectable BLLs, and every child had levels that exceeded the Centers for Disease Control and Prevention guideline level of 5 µg/dL. Eighty percent of tested subjects had BLLs higher than 10 µg/dL. Five children (25%) had BLLs greater than 45 µg/dL, the level of recommended medical intervention. In addition to blood lead, all of the children had detectable levels of arsenic, cadmium, chromium, lead, manganese, and mercury in toenail samples. Notably, average toenail lead, manganese, and mercury levels were 157 µg/g, 7.41 µg/g, and 2.63 µg/g respectively, well above levels previously reported in children. Significant Spearman's rank correlations showed that there were relationships between blood and toenail lead levels (r = 0.65, p < 0.05), toenail levels of lead and cadmium (r = 0.66, p < 0.05), and toenail levels of manganese and chromium (r = 0.72, p < 0.001). Linear regression showed that reducing the distance to the nearest active smelter by half was associated with a 116% increase in BLL (p < 0.05). CONCLUSIONS: The results suggest that children in battery recycling and smelting craft villages in Vietnam are co-exposed to toxic metals. There is an urgent need for mitigation to control metal exposure related to domestic smelting.

Association between arsenic, cadmium, manganese, and lead levels in private wells and birth defects prevalence in North Carolina: a semi-ecologic study.

BACKGROUND: Toxic metals including arsenic, cadmium, manganese, and lead are known human developmental toxicants that are able to cross the placental barrier from mother to fetus. In this population-based study, we assess the association between metal concentrations in private well water and birth defect prevalence in North Carolina. METHODS: A semi-ecologic study was conducted including 20,151 infants born between 2003 and 2008 with selected birth defects (cases) identified by the North Carolina Birth Defects Monitoring Program, and 668,381 non-malformed infants (controls). Maternal residences at delivery and over 10,000 well locations measured for metals by the North Carolina Division of Public Health were geocoded. The average level of each metal was calculated among wells sampled within North Carolina census tracts. Individual exposure was assigned as the average metal level of the census tract that contained the geocoded maternal residence. Prevalence ratios (PR) with 95% confidence intervals (CI) were calculated to estimate the association between the prevalence of birth defects in the highest category (≥90th percentile) of average census tract metal levels and compared to the lowest category (≤50th percentile). RESULTS: Statewide, private well metal levels exceeded the EPA Maximum Contaminant Level (MCL) or secondary MCL for arsenic, cadmium, manganese, and lead in 2.4, 0.1, 20.5, and 3.1 percent of wells tested. Elevated manganese levels were statistically significantly associated with a higher prevalence of conotruncal heart defects (PR: 1.6 95% CI: 1.1-2.5). CONCLUSIONS: These findings suggest an ecologic association between higher manganese concentrations in drinking water and the prevalence of conotruncal heart defects.

Associations of salivary aldosterone levels during pregnancy with maternal blood pressure and birth weight-for-gestational age in a Mexico City birth cohort.

OBJECTIVE: To determine associations of maternal salivary aldosterone with blood pressure (BP) in pregnancy and infant birth weight-for-gestational age (BWGA). METHODS: We measured maternal salivary aldosterone, BP and BWGA z-scores in 471 Mexico City pregnancy cohort participants and performed multivariable linear regression of BP and BWGA on log-aldosterone levels. RESULTS: Log-aldosterone was positively associated with diastolic BP (ß = 0.12 95% CI: 0.04, 0.21). There were no main effects of log-aldosterone on BWGA. However, we detected an interaction between log-aldosterone and BP in association with BWGA; higher log-aldosterone was associated with lower BWGA in the lowest (ß = -0.12, 95% CI: -0.26, 0.02) and highest (ß = -0.12, 95% CI: -0.29, 0.06) BP tertiles. In contrast, in the middle BP tertile the association was positive (ß = 0.09, 95% CI: -0.02, 0.20), p for interaction = 0.03. CONCLUSION: Higher maternal salivary aldosterone is positively associated with diastolic BP and may affect fetal growth differently depending on concurrent maternal blood pressure.

Recent ambient temperature and fine particulate matter (PM2.5) exposure is associated with urinary kidney injury biomarkers in children.

BACKGROUND: Limited research has examined associations between exposure to ambient temperature, air pollution, and kidney function or injury during the preadolescent period. We examined associations between exposure to ambient temperature and particulate matter with aerodynamic diameter ≤ 2.5 µm (PM2.5) with preadolescent estimated glomerular filtration rate (eGFR) and urinary kidney injury biomarkers. METHODS: Participants included 437 children without cardiovascular or kidney disease enrolled in the Programming Research in Obesity, Growth, Environment and Social Stressors birth cohort study in Mexico City. eGFR and urinary kidney injury biomarkers were assessed at 8-12 years. Validated satellite-based spatio-temporal models were used to estimate mean daily temperature and PM2.5 levels at each participant's residence 7- and 30-days prior to the date of visit. Linear regression and distributed lag nonlinear models (DLNM) were used to examine associations between daily mean temperature and PM2.5 exposure and kidney outcomes, adjusted for covariates. RESULTS: In single linear regressions, higher seven-day average PM2.5 was associated with higher urinary alpha-1-microglobulin and eGFR. In DLNM analyses, higher temperature exposure in the seven days prior to date of visit was associated with a decrease in urinary cystatin C of -0.56 ng/mL (95 % confidence interval (CI): -1.08, -0.04) and in osteopontin of -0.08 ng/mL (95 % CI: -0.15, -0.001). PM2.5 exposure over the seven days prior to date of visit was associated with an increase in eGFR of 1.77 mL/min/1.73m2 (95 % CI: 0.55, 2.99) and urinary cystatin C of 0.19 ng/mL (95 % CI: 0.03, 0.35). CONCLUSIONS: Recent exposure to ambient temperature and PM2.5 were associated with increased and decreased urinary kidney injury biomarkers that may reflect subclinical glomerular or tubular injury in children. Further research is required to assess environmental exposures and worsening subclinical kidney injury across development.

A State-of-the-Science Review of Interactions of Per- and Polyfluoroalkyl Substances (PFAS) with Renal Transporters in Health and Disease: Implications for Population Variability in PFAS Toxicokinetics.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are ubiquitous in the environment and have been shown to cause various adverse health impacts. In animals, sex- and species-specific differences in PFAS elimination half-lives have been linked to the activity of kidney transporters. However, PFAS molecular interactions with kidney transporters are still not fully understood. Moreover, the impact of kidney disease on PFAS elimination remains unclear. OBJECTIVES: This state-of-the-science review integrated current knowledge to assess how changes in kidney function and transporter expression from health to disease could affect PFAS toxicokinetics and identified priority research gaps that should be addressed to advance knowledge. METHODS: We searched for studies that measured PFAS uptake by kidney transporters, quantified transporter-level changes associated with kidney disease status, and developed PFAS pharmacokinetic models. We then used two databases to identify untested kidney transporters that have the potential for PFAS transport based on their endogenous substrates. Finally, we used an existing pharmacokinetic model for perfluorooctanoic acid (PFOA) in male rats to explore the influence of transporter expression levels, glomerular filtration rate (GFR), and serum albumin on serum half-lives. RESULTS: The literature search identified nine human and eight rat kidney transporters that were previously investigated for their ability to transport PFAS, as well as seven human and three rat transporters that were confirmed to transport specific PFAS. We proposed a candidate list of seven untested kidney transporters with the potential for PFAS transport. Model results indicated PFOA toxicokinetics were more influenced by changes in GFR than in transporter expression. DISCUSSION: Studies on additional transporters, particularly efflux transporters, and on more PFAS, especially current-use PFAS, are needed to better cover the role of transporters across the PFAS class. Remaining research gaps in transporter expression changes in specific kidney disease states could limit the effectiveness of risk assessment and prevent identification of vulnerable populations. https://doi.org/10.1289/EHP11885.

Prenatal and early childhood critical windows for the association of nephrotoxic metal and metalloid mixtures with kidney function.

INTRODUCTION: As 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. METHODS: Participants 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. RESULTS: We 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. CONCLUSIONS: Using tooth-matrix biomarkers, we identified discrete developmental exposure windows wherein Pb and metal(loid) mixtures were associated with altered preadolescent kidney function.

Prenatal Metal Exposures and Associations with Kidney Injury Biomarkers in Children.

Prenatal exposure to arsenic (As), cadmium (Cd), mercury (Hg), and lead (Pb) may be nephrotoxic, yet limited studies have examined subclinical kidney injury biomarkers in children. We assessed whether metal exposure in the second trimester (2T), a crucial time of kidney development, is associated with altered urine kidney injury and function biomarkers in preadolescent children. Analyses included 494 children participating in a birth cohort study in Mexico City. Concentrations of As, Cd, and Pb were measured from pregnant women in 2T blood and urine, and Hg in urine only. Kidney biomarkers were measured from children in urine at age 8-12 years. We assessed the associations between individual metals and (1) kidney biomarkers using linear regression and (2) a multi-protein kidney mixture using weighted quantile sum (WQS) regression. Associations of separate urine and blood metal mixtures with individual kidney biomarkers were assessed via WQS. Within the multi-protein mixture, the association with increased urinary As was predominated by urine alpha-1-microglobulin (A1M), interferon gamma-induced protein 10 (IP10), and fatty acid binding protein 1; the association with increased urinary Cd was predominated by A1M, clusterin, and albumin. The urine metal mixture was associated with increased albumin (0.23 ng/mL; 95% confidence interval (CI): 0.10, 0.37), IP10 (0.15 ng/mL; 95% CI: 0.02, 0.28), and cystatin C (0.17 ng/mL; 95% CI: 0.04, 0.31); these associations were mainly driven by urinary As and Cd. We observed null associations between prenatal blood or urine metal mixtures and estimated glomerular filtration rate. Higher prenatal urinary metals, individually and as a mixture were associated with altered kidney injury biomarkers in children. Further research and longer participant follow-up are required to ascertain the risk of kidney disease later in life.