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.

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.

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.

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.

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.

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.

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.

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.

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.

Maternal Phthalates Exposure and Blood Pressure during and after Pregnancy in the PROGRESS Study.

BACKGROUND: Phthalate exposure is ubiquitous and may affect biological pathways related to regulators of blood pressure. Given the profound changes in vasculature during pregnancy, pregnant women may be particularly susceptible to the potential effects of phthalates on blood pressure. OBJECTIVES: We examined associations of phthalate exposure during pregnancy with maternal blood pressure trajectories from mid-pregnancy through 72 months postpartum. METHODS: Women with singleton pregnancies delivering a live birth in Mexico City were enrolled during the second trimester (n=892). Spot urine samples from the second and third trimesters were analyzed for 15 phthalate metabolites. Blood pressure and covariate data were collected over nine visits through 72 months postpartum. We used linear, logistic, and linear mixed models; latent class growth models (LCGMs); and Bayesian kernel machine regression to estimate the relationship of urinary phthalate biomarkers with maternal blood pressure. RESULTS: As a joint mixture, phthalate biomarker concentrations during pregnancy were associated with higher blood pressure rise during mid-to-late gestation. With respect to individual biomarkers, second trimester concentrations of monobenzyl phthalate (MBzP) and di(2-ethylhexyl) phthalate biomarkers (ΣDEHP) were associated with higher third trimester blood pressure. Two trajectory classes were identified by LCGM, characterized by increasing blood pressure through 72 months postpartum ("increase-increase") or decreased blood pressure through 18 months postpartum with a gradual increase thereafter ("decrease-increase"). Increasing exposure to phthalate mixtures during pregnancy was associated with higher odds of being in the increase-increase class. Similar associations were observed for mono-2-ethyl-5-carboxypentyl terephthalate (MECPTP) and dibutyl phthalate (ΣDBP) biomarkers. When specific time periods were examined, we observed specific temporal relationships were observed for ΣDEHP, MECPTP, MBzP, and ΣDBP. DISCUSSION: In our cohort of pregnant women from Mexico City, exposure to phthalates and phthalate biomarkers was associated with higher blood pressure during late pregnancy, as well as with long-term changes in blood pressure trajectories. https://doi.org/10.1289/EHP8562.

Prenatal and Early Childhood Exposure to Lead and Repeated Measures of Metabolic Syndrome Risk Indicators From Childhood to Preadolescence.

Background: Exposure to lead (Pb) during the early life stages has been associated with the development of metabolic syndrome (MetS). Longitudinal studies of Pb exposure in critical developmental windows in children are limited. Methods: Our study included 601 mother-child dyads from the PROGRESS (Programming Research in Obesity, Growth, Environment and Social Stressors) birth cohort. Blood lead levels (BLLs) were assessed during the second and third gestational trimesters, in cord blood at delivery, and at ages 1, 2, and 4 years. Bone lead levels in the patella and tibia were assessed at 1 month postpartum and evaluated in separate models. To account for cumulative exposure (prenatal, postnatal, and cumulative), we dichotomized the BLLs at each stage visit and determined the following: "higher" if a BLL was at least once above the median (HPb) and "lower" if all BLLs were below the median (LPb). We analyzed fasting glucose, HbA1c, triglycerides (TGs), total cholesterol (TC), high-density lipoprotein cholesterol (cHDL), low-density lipoprotein cholesterol (cLDL), body mass index, waist circumference (WC), body fat percentage, and systolic (SBP) and diastolic blood pressure (DBP) at two study visits between 6 and 12 years of age and created cutoff points based on the clinical guidelines for each indicator. Mixed effects models were used to analyze each outcome longitudinally for each BLL score, adjusting for child's sex, size for gestational age, child's age, maternal parity, mother's age, and socioeconomic status. Results: We observed associations for HPb exposure and TC in all stages (OR = 0.53, 95%CI = 0.32-0.86) and postnatally (OR = 0.59, 95%CI = 0.36-0.94) and for prenatal HPb and TGs (OR = 0.65, 95%CI = 0.44-0.95). HPb at all stages was associated with WC (OR = 0.27, 95%CI = 0.08-0.86), BMI (OR = 0.33, 95%CI = 0.11-0.99), SBP (OR = 0.53, 95%CI = 0.32-0.85), and DBP (OR = 0.57, 95%CI = 0.34-0.95). Pb levels in the patella were associated with cHDL (OR = 1.03, 95%CI = 1.00-1.07) and those in the tibia with TGs (OR = 0.95, 95%CI = 0.91-0.99). Conclusion: Early life exposure to Pb may alter early indicators of MetS. A follow-up of these children will allow for more definition on the impact of longer-term exposures.

Association of Manganese Biomarker Concentrations with Blood Pressure and Kidney Parameters among Healthy Adolescents: NHANES 2013-2018.

Deficiency or excess exposure to manganese (Mn), an essential mineral, may have potentially adverse health effects. The kidneys are a major organ of Mn site-specific toxicity because of their unique role in filtration, metabolism, and excretion of xenobiotics. We hypothesized that Mn concentrations were associated with poorer blood pressure (BP) and kidney parameters such as estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN), and albumin creatinine ratio (ACR). We conducted a cross-sectional analysis of 1931 healthy U.S. adolescents aged 12-19 years participating in National Health and Nutrition Examination Survey cycles 2013-2014, 2015-2016, and 2017-2018. Blood and urine Mn concentrations were measured using inductively coupled plasma mass spectrometry. Systolic and diastolic BP were calculated as the average of available readings. eGFR was calculated from serum creatinine using the Bedside Schwartz equation. We performed multiple linear regression, adjusting for age, sex, body mass index, race/ethnicity, and poverty income ratio. We observed null relationships between blood Mn concentrations with eGFR, ACR, BUN, and BP. In a subset of 691 participants, we observed that a 10-fold increase in urine Mn was associated with a 16.4 mL/min higher eGFR (95% Confidence Interval: 11.1, 21.7). These exploratory findings should be interpreted cautiously and warrant investigation in longitudinal studies.

The impact of the COVID-19 pandemic on patterns of attendance at emergency departments in two large London hospitals: an observational study.

BACKGROUND: Hospitals in England have undergone considerable change to address the surge in demand imposed by the COVID-19 pandemic. The impact of this on emergency department (ED) attendances is unknown, especially for non-COVID-19 related emergencies. METHODS: This analysis is an observational study of ED attendances at the Imperial College Healthcare NHS Trust (ICHNT). We calibrated auto-regressive integrated moving average time-series models of ED attendances using historic (2015-2019) data. Forecasted trends were compared to present year ICHNT data for the period between March 12, 2020 (when England implemented the first COVID-19 public health measure) and May 31, 2020. We compared ICHTN trends with publicly available regional and national data. Lastly, we compared hospital admissions made via the ED and in-hospital mortality at ICHNT during the present year to the historic 5-year average. RESULTS: ED attendances at ICHNT decreased by 35% during the period after the first lockdown was imposed on March 12, 2020 and before May 31, 2020, reflecting broader trends seen for ED attendances across all England regions, which fell by approximately 50% for the same time frame. For ICHNT, the decrease in attendances was mainly amongst those aged < 65 years and those arriving by their own means (e.g. personal or public transport) and not correlated with any of the spatial dependencies analysed such as increasing distance from postcode of residence to the hospital. Emergency admissions of patients without COVID-19 after March 12, 2020 fell by 48%; we did not observe a significant change to the crude mortality risk in patients without COVID-19 (RR 1.13, 95%CI 0.94-1.37, p = 0.19). CONCLUSIONS: Our study findings reflect broader trends seen across England and give an indication how emergency healthcare seeking has drastically changed. At ICHNT, we find that a larger proportion arrived by ambulance and that hospitalisation outcomes of patients without COVID-19 did not differ from previous years. The extent to which these findings relate to ED avoidance behaviours compared to having sought alternative emergency health services outside of hospital remains unknown. National analyses and strategies to streamline emergency services in England going forward are urgently needed.

A Scoping Review of Life-Course Psychosocial Stress and Kidney Function.

Increased exposure to maternal psychosocial stress during gestation and adverse neonatal environments has been linked to alterations in developmental programming and health consequences in offspring. A programmed low nephron endowment, among other altered pathways of susceptibility, likely increases the vulnerability to develop chronic kidney disease in later life. Our aim in this scoping review was to identify gaps in the literature by focusing on understanding the association between life-course exposure to psychosocial stress, and the risk of reduced kidney function. A systematic search in four databases (PubMed, ProQuest, Wed of Science, and Scopus) was performed, yielding 609 articles. Following abstract and full-text review, we identified 19 articles meeting our inclusion criteria, reporting associations between different psychosocial stressors and an increase in the prevalence of kidney disease or decline in kidney function, mainly in adulthood. There are a lack of studies that specifically evaluated the association between gestational exposure to psychosocial stress and measures of kidney function or disease in early life, despite the overall evidence consistent with the independent effects of prenatal stress on other perinatal and postnatal outcomes. Further research will establish epidemiological studies with clear and more comparable psychosocial stressors to solve this critical research gap.

Nephrotoxic Metal Mixtures and Preadolescent Kidney Function.

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 longitudinal cohort study. We estimated the mixture effects of these metals, using weighted quantile sum regression (WQS) applied to urine biomarkers (Umix), blood biomarkers (Bmix), and MMBs, on the cystatin C-based estimated glomerular filtration rate (eGFR) and serum cystatin C assessed at 8-10 years of age, adjusted for covariates. Quartile increases in Umix and the MMB mixture were associated with 2.5% (95%CI: 0.1, 5.0) and 3.0% (95%CI: 0.2, 5.7) increased eGFR and -2.6% (95% CI: -5.1%, -0.1%) and -3.3% (95% CI: -6.5%, -0.1%) decreased cystatin C, respectively. Weights indicate that the strongest contributors to the associations with eGFR and serum cystatin C were Cd and Pb, respectively. MMBs detected mixture effects distinct from associations with individual metals or media-type, highlighting the benefits of incorporating information from multiple exposure media in mixtures analyses.

Metal exposure and bone remodeling during pregnancy: Results from the PROGRESS cohort study.

Pregnancy is characterized by high bone remodeling and might be a window of susceptibility to the toxic effects of metals on bone tissue. The aim of this study was to assess associations between metals in blood [lead (Pb), cadmium (Cd)and arsenic (As)] and bone remodeling during pregnancy. We studied pregnant woman from the PROGRESS Cohort (Programming Research in Obesity, Growth, and Environment and Social Stress). We measured concentrations of metals in blood and obtained measures of bone remodeling by quantitative ultrasound (QUS) at the radius in the second and third trimester of pregnancy. To account for chronic lead exposure, we measured lead in tibia and patella one-month postpartum with K-shell X-ray fluorescence. We assessed cross-sectional and longitudinal associations between multiple-metal concentrations and QUS z-scores using linear regression models and linear mixed models adjusted for potential confounders. Third trimester blood Cd concentrations were marginal associated with lower QUS z-scores [-0.16 (95% CI: -0.33, 0.007); P-Value = 0.06]. Mixed models showed that blood Cd was longitudinally and marginally associated with an average of -0.10 z-score (95% CI: -0.21, 0.002; P-Value = 0.06) over the course of pregnancy. Associations for Pb and As were all inverse however none reached significance. Additionally, bone Pb concentrations in patella, an index of cumulative exposure, were significantly associated with -0.06 z-score at radius (95% CI: -0.10, -0.01; P-Value = 0.03) during pregnancy. Pb and Cd blood levels are associated with lower QUS distal radius z-scores in pregnant women. Bone Pb concentrations in patella were negatively associated with z-score at radius showing the long-term effects of Pb on bone tissue. However, we cannot exclude the possibility of reverse causality for patella Pb and radius z-score associations. Our results support the importance of reducing women's metal exposure during pregnancy, as metals exposure during pregnancy may have consequences for bone strength later in life. The main finding of our study is the association between Cd blood levels and radius z-score during pregnancy. Bone lead in patella was also negatively associated with radius z-scores.

Prenatal blood lead levels and reduced preadolescent glomerular filtration rate: Modification by body mass index.

BACKGROUND: For the developing kidney, the prenatal period may represent a critical window of vulnerability to environmental insults resulting in permanent nephron loss. Given that the majority of nephron formation is complete in the 3rd trimester, we set out to test whether 1) prenatal lead exposure is associated with decreased preadolescent kidney function and 2) whether preadolescent obesity acts synergistically with early life lead exposure to reduce kidney function. METHODS: Our study included 453 mother-child pairs participating in the PROGRESS birth cohort. We assessed prenatal blood lead levels (BLLs) in samples collected in the 2nd and 3rd trimesters and at delivery, as well as tibial and patellar bone lead measures assessed one-month postpartum. Preadolescent estimated glomerular filtration rate (eGFR) was derived from serum levels of creatinine and/or cystatin C measured at age 8-12 years. We applied linear regression to assess the relationship between prenatal bone and BLL with preadolescent eGFR, and adjusted for covariates including age, sex, BMI z-score, indoor tobacco smoke exposure, and socioeconomic status. We also examined sex-specific associations and tested for effect modification by BMI status. RESULTS: We observed null associations between prenatal lead exposure and eGFR. However, in interaction analyses we found that among overweight children, there was an inverse association between BLL (assessed at 2nd and 3rd trimester and at delivery) and preadolescent eGFR. For example, among overweight participants, a one ln-unit increase in 2nd trimester BLL was associated with a 10.5 unit decrease in cystatin C-based eGFR (95% CI: -18.1, -2.8; p = 0.008). Regardless of lead exposure, we also observed null relationships between BMI z-score and eGFR overall, as well as among overweight participants. However, among participants with preadolescent obesity, we observed a significant 5.9-unit decrease in eGFR. We observed no evidence of sex-specific effects. CONCLUSIONS: Our findings, if confirmed in other studies, suggest a complex interplay between the combined adverse effects of adiposity and perinatal lead exposure as they relate to adolescent kidney function. Future studies will assess kidney function and adiposity trajectories through adolescence to better understand environmental risk factors for kidney function decline.

Exosomal miRNAs in urine associated with children's cardiorenal parameters: a cross-sectional study.

Aims: The authors sought to examine associations between urinary exosomal miRNAs (exo-miRs), emerging biomarkers of renal health, and cardiorenal outcomes in early childhood. Materials & methods: The authors extracted exo-miRs in urine from 88 healthy Mexican children aged 4-6 years. The authors measured associations between 193 exo-miRs and cardiorenal outcomes: systolic/diastolic blood pressure, estimated glomerular filtration rate and urinary sodium and potassium levels. The authors adjusted for age, sex, BMI, socioeconomic status, indoor tobacco smoke exposure and urine specific gravity. Results: Multiple exo-miRs were identified meeting a false discovery rate threshold of q < 0.1. Specifically, three exo-miRs had increased expression with urinary sodium, 17 with urinary sodium-to-potassium ratio and one with decreased estimated glomerular filtration rate. Conclusions: These results highlight urinary exo-miRs as early-life biomarkers of children's cardiorenal health.