Exposome and Metabolome Analysis of Sugarcane Workers Reveals Predictors of Kidney Injury.

Introduction: Sugarcane workers are exposed to potentially hazardous agrochemicals, including pesticides, heavy metals, and silica. Such occupational exposures present health risks and have been implicated in a high rate of kidney disease seen in these workers. Methods: To investigate potential biomarkers and mechanisms that could explain chronic kidney disease (CKD) among this worker population, paired urine samples were collected from sugarcane cutters at the beginning and end of a harvest season in Guatemala. Workers were then separated into 2 groups, namely those with or without kidney function decline (KFD) across the harvest season. Urine samples from these 2 groups underwent elemental analysis and untargeted metabolomics. Results: Urine profiles demonstrated increases in silicon, certain pesticides, and phosphorus levels in all workers, whereas heavy metals remained low. The KFD group had a reduction in estimated glomerular filtration rate (eGFR) across the harvest season; however, kidney injury marker 1 did not significantly change. Cross-harvest metabolomic analysis found trends of fatty acid accumulation, perturbed amino acid metabolism, presence of pesticides, and other known signs of impaired kidney function. Conclusion: Silica and certain pesticides were significantly elevated in the urine of sugarcane workers with or without KFD. Future work should determine whether long-term occupational exposure to silica and pesticides across multiple seasons contributes to CKD in these workers. Overall, these results confirmed that multiple exposures are occurring in sugarcane workers and may provide insight into early warning signs of kidney injury and may help explain the increased incidence of CKD among agricultural workers.

A longitudinal assessment of heat exposure and biomarkers of kidney function on heat shock protein 70 and antibodies among agricultural workers.

Background: Exposure to extreme heat impacts millions of people worldwide and outdoor workers are among the populations most affected by high temperatures. Heat stress induces several biological responses in humans, including the production of heat shock proteins (HSP) and antibodies against HSP (anti-HSP) which may play a central role in the body's cellular response to a hot environment. Objective: This longitudinal study investigated the impact of high temperatures and humidity on the presence of HSP70 and anti-HSP70 and examined relationships with markers of kidney function in an at-risk workforce under conditions of extreme heat and exertion in Guatemala. Methods: We collected ambient temperature and relative humidity data as well as biomarkers and clinical data from 40 sugarcane workers at the start and the end of a 6-month harvest. We used generalized mixed-effects models to estimate temperature effects on HSP70 and anti-HSP70 levels. In addition, we examined trends between HSP70 and anti-HSP70 levels and markers of kidney function across the harvest. Results: At the end of the harvest, temperatures were higher, and workers had, on average, higher levels of HSP70 and anti-HSP70 compared to the beginning of the season. We observed significant increasing trends with temperature indices and HSP70 levels. Maximum temperature was associated with HSP70 increments after controlling for age, systolic and diastolic blood pressure (ß: 0.21, 95% Confidence Interval: 0.09, 0.33). Kidney function decline across the harvest was associated with both higher levels of anti-HSP70 levels at the end of the harvest as well as greater increases in anti-HSP70 levels across the harvest. Conclusions: These results suggest that workplace heat exposure may increase the production of HSP70 and anti-HSP70 levels and that there may be a relationship between increasing anti-HSP70 antibodies and the development of renal injury. HSP70 holds promise as a biomarker of heat stress in exposed populations.

Intranasal Administration of Sugarcane Ash Causes Chronic Kidney Disease in Rats.

Background. Silica nanoparticles found in sugarcane ash have been postulated to be a toxicant contributing to chronic kidney disease of unknown etiology (CKDu). However, while the administration of manufactured silica nanoparticles is known to cause chronic tubulointerstitial disease in rats, the effect of administering sugarcane ash on kidney pathology remains unknown. Here we investigate whether sugarcane ash can induce CKD in rats. Methods. Sugarcane ash was administered for 13 weeks into the nares of rats (5 mg/day for 5d/week), and blood, urine and kidney tissues were collected at 13 weeks (at the end of ash administration) and in a separate group of rats at 24 weeks (11 weeks after stopping ash administration). Kidney histology was evaluated, and inflammation and fibrosis (collagen deposition) measured. Results. Sugarcane ash exposure led to the accumulation of silica in the kidneys, lungs, liver and spleen of rats. Mild proteinuria developed although renal function was largely maintained. However, biopsies showed focal glomeruli with segmental glomerulosclerosis, and tubulointerstitial inflammation and fibrosis that tended to worsen even after the ash administration had been stopped. Staining for the lysosomal marker, LAMP-1, showed decreased staining in ash administered rats consistent with lysosomal activation. Conclusion. Sugarcane ash containing silica nanoparticles can cause CKD in rats.

Point-of-Care Testing in Chronic Kidney Disease of Non-Traditional Origin: Considerations for Clinical, Epidemiological, and Health Surveillance Research and Practice.

Purpose: As the prevalence of chronic kidney disease of non-traditional origin (CKDnt) rises in low-resource settings, there is a need for reliable point-of-care creatinine testing. The purpose of this analysis was to assess the accuracy of two commonly used point-of-care creatinine devices, the i-STAT handheld (Abbott, Princeton, NJ, USA) and the StatSensor Creatinine (Nova Biomedical, Waltham, MA, USA) in comparison to venipuncture serum creatinine measures. The affordability, sensitivity, specificity, ease of use, and other considerations for each device are also presented. Methods: Three paired data sets were compared. We collected 213 paired i-STAT and venipuncture samples from a community study in Nicaragua in 2015-2016. We also collected 267 paired StatSensor Creatinine and venipuncture samples, including 158 from a community setting in Nicaragua in 2014-2015 and 109 from a Guatemala sugarcane worker cohort in 2017-2018. Pearson correlation coefficients, Bland-Altman plots, and no intercept linear regression models were used to assess agreement between point-of-care devices and blood samples. Results: The i-STAT performed the most accurately, overestimating creatinine by 0.07 mg/dL (95% CI: 0.02, 0.12) with no evidence of proportional bias. The StatSensor Creatinine performed well at low levels of creatinine (Mean (SD): 0.87 (0.19)). Due to proportional bias, the StatSensor Creatinine performed worse in the Nicaragua community setting where creatinine values ranged from 0.31 to 7.04 mg/dL. Discussion: Both devices provide acceptable sensitivity and specificity. Although adequate for routine surveillance, StatSensor Creatinine is less accurate as the values of measured creatinine increase, a consideration when using the point-of-care device for screening individuals at risk for CKDnt. Research, clinical, and screening objectives, cost, ease of use, and background prevalence of disease must all be carefully considered when selecting a point-of-care creatinine device. Conclusion: POC testing can be more accessible in resource-limited settings. The selection of the appropriate device will depend on the use-case.

Urinary concentrations of metals before and after volcanic eruption: a natural experiment surrounding the eruption of Volcán de Fuego, 2018.

Volcanic eruptions increase environmental heavy metal concentrations, yet little research has been performed on their extrapulmonary human health effects. We fortuitously collected biological samples in a cohort of Guatemalan sugarcane cutters in the area surrounding Volcán de Fuego before and after the June 2018 eruption. We sought to determine whether stratovolcanic activity was associated with changes in urinary concentrations of heavy metals in a cohort of sugarcane workers. In this exploratory analysis, we found significant increases in urinary arsenic, (ß = 1.46, P < 0.0001), cadmium (ß = 1.03, P < 0.0001), and lead (ß = 0.87, P = 0.003) in participants with residential proximity to Volcán de Fuego as compared to participants farther away, suggesting that volcanic activity could be associated with acute heavy metal exposures. This natural experiment is, to our knowledge, the first of its kind and suggests a need for more research into heavy metal exposure-related health impacts of volcanic eruptions.

Inhaled silica nanoparticles cause chronic kidney disease in rats.

Silica nanoparticles (SiNPs) released during the burning of sugarcane have been postulated to have a role in chronic kidney disease of unknown etiology. We tested the hypothesis that pristine SiNPs of the size present in sugarcane might cause chronic kidney injury when administered through the lung in rats. We administered 200- or 300-nm amorphous SiNPs twice weekly (4 mg/dose), or vehicle by oropharyngeal aspiration for 13 wk to rats followed by euthanasia after an additional 13 wk (26 wk total). Tissues were evaluated for the presence of SiNPs and evidence of histological injury. Both sizes of SiNPs caused kidney damage, with early tubular injury and inflammation (at week 13) that continued to inflammation and chronic fibrosis at week 26 despite discontinuation of the SiNP administration. Both sizes of SiNPs caused local inflammation in the lung and kidney and were detected in the serum and urine at week 13, and the 200-nm particles were also localized to the kidney with no evidence of retention of the 300-nm particles. At week 26, there was some clearance of the 200-nm silica from the kidneys, and urinary levels of SiNPs were reduced but still significant in both 200- and 300 nm-exposed rats. In conclusion, inhaled SiNPs cause chronic kidney injury that progresses despite stopping the SiNP administration. These findings support the hypothesis that human exposure to amorphous silica nanoparticles found in burned sugarcane fields could have a participatory role in chronic kidney disease of unknown etiology.NEW & NOTEWORTHY Inhalation of silica nanoparticles (SiNPs) released during the burning of sugarcane has been postulated to have a role in chronic kidney disease of unknown etiology (CKDu). We administered 200- and 300-nm amorphous SiNPs to rats by aspiration and observed kidney damage with tubular injury and inflammation that persisted even after stopping the SiNP exposure. These findings support the hypothesis that human exposure to SiNPs found in sugarcane ash could have a participatory role CKDu.

Latin American Agricultural Workers' Job Demands and Resources and the Association With Health Behaviors at Work and Overall Health.

In the present study, we describe the job demands and job resources (JD-R) experienced by agricultural workers in three Latin American countries and their relationship to proactive health behaviors at work and overall health. Following previous research on the JD-R model, we hypothesized that job demands (H1) would be negatively related to agricultural workers' self-reported overall health. On the other hand, we hypothesized that job resources (H2) would be positively related to agricultural workers' overall health. Furthermore, we hypothesized (H3) that workers' engagement in jobsite health promotion practices via their proactive health behaviors at work would partially mediate the relationship between workers' job resources and job demands and overall health. We also had a research question (R1) about whether there were differences by type of job held. The sample of workers who participated in this study (N = 1,861) worked in Mexico, Guatemala, and Nicaragua for one large agribusiness that produces sugar cane. They worked in two distinct areas: company administration and agricultural operations. We administered employee health and safety culture surveys using survey methods tailored to meet the needs of both types of workers. Stratified path analysis models were used to test study hypotheses. In general, we found support for hypotheses 1 and 2. For example, operations workers reported more physically demanding jobs and administrative workers reported more work-related stress. Regardless, the existence of high job demands was associated with poorer overall health amongst both types of workers. We found that workers in more health-supportive work environments perform more proactive health behaviors at work, regardless of their role within the organization. However, hypothesis 3 was not supported as proactive health behaviors at work was not associated with overall health. We discuss future research needs in terms of evaluating these hypotheses amongst workers employed by small- and medium-sized agribusinesses as well as those in the informal economy in Latin America. We also discuss important implications for agribusinesses seeking to develop health promotion programs that meet the needs of all workers.

Environmental metal exposures and kidney function of Guatemalan sugarcane workers.

BACKGROUND: Exposure 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. OBJECTIVE: Urinary metals (arsenic, cadmium, nickel, and uranium) were examined in 222 sugarcane cutters in Guatemala at three time points over 1 year. METHODS: We explored the relationships between metal concentrations and markers of kidney function using multivariable linear mixed-effect models. RESULTS: Arsenic, 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) (ß: -4.23, 95% confidence interval [CI]: -6.92, -1.54) and positively associated with neutrophil gelatinase-associated lipocalin (NGAL) (ß: 2.92, 95% CI: 1.20, 4.64). Higher urine arsenic was also inversely associated with eGFR (ß: -4.36, 95% CI: -7.07, -1.64). SIGNIFICANCE: Our 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.

Body Composition, Anemia, and Kidney Function among Guatemalan Sugarcane Workers.

Rates of anemia among agricultural workers, who are also at risk for kidney injury and chronic kidney disease of unknown cause (CKDu), are unknown. We evaluated body composition through the sum of three skinfolds among 203 male sugarcane cutters and assessed the relationship of variables related to nutrition, anemia (hemoglobin < 13 g/dL), and elevated hemoglobin A1c (HbA1c ≥ 5.7%) with estimated glomerular filtration rate (eGFR) using linear regression. Eleven percent of workers were at the level of essential body fat (2-5%). Anemia was present among 13% of workers, 70% of which were normochromic normocytic, a type of anemia suggesting potential underlying chronic disease. Anemia was more common among those with lower BMI and fat free mass. The prevalence of elevated HbA1c was 21%. A moderate negative correlation was found between hemoglobin and HbA1c (Pearson's r = -0.32, p <0.01) which suggests that HbA1c values should be interpreted with caution in populations that have high rates of anemia. Twelve percent of workers had reduced kidney function with an eGFR < 90 mL/min/1.73 m2. On average, the eGFR was 18 mL/min per 1.73 m2 lower [(95% CI:-24, -12), p <0.01)] for those with anemia than those without, and 8 mL/min per 1.73 m2 lower among those with elevated HbA1c [(95% CI: -13, -2), p < 0.01]. Results will inform future studies examining the role of anemia in the evaluation of CKDu and interventions to improve nutrition for workers in low-resource settings.

Cross-sectional study examining the accuracy of self-reported smoking status as compared to urinary cotinine levels among workers at risk for chronic kidney disease of unknown origin in Guatemala.

OBJECTIVES: There is a lack of information on cotinine levels in rural populations in low-income and middle-income countries like Guatemala. Therefore, there is a need to explore smoking status and biomarkers of tobacco use in epidemiological research in rural, low-income populations, in particular those at-risk for chronic kidney disease of unknown origin (CKDu). DESIGN: We evaluated self-reported smoking status against urinary cotinine levels, the gold standard biomarker of tobacco smoke exposure, among agricultural workers at four separate cross-sectional time points. SETTING: Guatemala. PARTICIPANTS: 283 sugarcane workers. PRIMARY OUTCOME MEASURES: Compared self-reported smoking status and urinary cotinine levels in two agricultural worker studies. RESULTS: Self-reported smoking prevalence was 12% among workers. According to cotinine levels (≥50 ng/mL), the smoking prevalence was 34%. Self-reported smoking status had 28% sensitivity and 96% specificity. Urinary cotinine levels show that smoking prevalence is underestimated in this worker population. CONCLUSIONS: According to our findings, smoking status should be objectively measured with biomarkers rather than self-reported in CKDu epidemiological research. Self-reported smoking status is likely an underestimate of the true smoking prevalence among agricultural workers. Research on the CKDu epidemic in Central America and other parts of the world might be underestimating tobacco exposure as a potential contributor to the development of CKDu.

Sugarcane Workweek Study: Risk Factors for Daily Changes in Creatinine.

INTRODUCTION: Agricultural workers laboring in thermally stressful environments are at increased risk for kidney injury and chronic kidney disease of unknown origin (CKDu), and their environmental and occupational exposures have been considered to be important risk factors. This study examined the effects of repeated kidney stress from the simultaneous strain of work and other factors experienced by workers in Guatemala during a typical workweek. METHODS: We collected data from 107 sugarcane workers across 7 consecutive work shifts. Data included information on daily occupational, meteorological, environmental, and lifestyle factors. We used multivariable linear mixed models to evaluate associations of these factors with percent change in creatinine. RESULTS: We observed that increasing wet bulb globe temperature (ß = 2.5%, 95% confidence interval [CI] = 0.3%, 4.7%) and increasing diastolic blood pressure (ß = 6.2%, 95% CI = 0.9%, 11.6%) were associated with increases in creatinine across the shift, whereas consumption of water from chlorinated dormitory tanks as compared to artesian well water (ß = -17.5%, 95% CI = -29.6%, -5.4%) and increasing number of rest breaks (ß = -5.8%, 95% CI = -9.0%, -2.6%) were found to be protective against increases in creatinine. Workers reporting drinking tank water had lower concentrations of urine creatinine-corrected arsenic, lead, uranium, and glyphosate compared to workers reporting the use of well water or municipal water. CONCLUSION: These results reinforce the need to focus on preventive actions that reduce kidney injury among this worker population, including strategies to reduce heat stress, managing blood pressure, and examining water sources of workers for nephrotoxic contaminants.

International Total Worker Health: Applicability to Agribusiness in Latin America.

Total Worker Health® (TWH) is a framework for integrating worker and workplace safety, health, and well-being, which has achieved success in European and US settings. However, the framework has not been implemented in Latin America or in agricultural sectors, leaving large and vulnerable populations underrepresented in the implementation and evaluation of these strategies to improve safety and promote health and well-being. This study presents a case study of how a TWH approach can be applied to a multinational Latin American agribusiness. We describe the process and adaptation strategy for conducting a TWH assessment at multiple organizational levels and in multiple countries. We follow this with a description of a TWH leadership training that was conducted based on the results of the assessment. Finally, we describe our methods to make corporate recommendations for TWH policies and programs that were informed by the TWH assessment and leadership trainings. With this case study we aim to demonstrate the importance and feasibility of conducting TWH in Latin America.

Workplace Screening Identifies Clinically Significant and Potentially Reversible Kidney Injury in Heat-Exposed Sugarcane Workers.

An epidemic of chronic kidney disease of unknown origin (CKDu) has emerged in the past two decades in agricultural communities, characterized by progressive renal failure with a dearth of early clinical symptoms. The aim of this study is to improve understanding of the natural history of this disease and to evaluate the impact of an educational and behavioral intervention on the trajectories of renal decline among a cohort of Guatemalan sugarcane workers. We identified groups of workers based on their kidney function during a longitudinal parent study conducted among sugarcane workers during the 2016-2017 harvest season. At the study's first time point in February 2017, workers who developed abnormal kidney function (AKF) (estimated glomerular filtration rate, eGFR, <60 mL/min per 1.73 m2) were placed in the AKF group, workers with reduced kidney function (RKF) (eGFR 60-89) were placed in the RKF group, and workers who maintained normal kidney function (NKF) (eGFR ≥ 90) were placed in the NKF group. As part of the study, a health promotion, behavioral and educational intervention centered on water, electrolytes, rest, and shade (WERS) was provided to all study participants. We then prospectively analyzed renal function at the three study time points in February, March, and April. Additional data collected from previous harvests allowed for retrospective analysis and we compared the rate of change in eGFR over the previous five years (2012 to 2016) for each identified group. Mixed effects linear regression with random intercepts for the workers was used to investigate the difference in rates of change for the three groups and to assess the impact of the intervention study on rate of change of kidney function during the study compared to each group's prior trajectory, utilizing the retrospective data collected during the five years prior to the study intervention. Between 2012 and 2016, eGFR declined at a rate of 0.18 mL/min per 1.73 m2 per year for the NKF group (95% CI: -0.66, 0.29, p = 0.45), 2.02 per year for the RKF group (95% CI: 1.00, 3.03, p = 0.0001) and 7.52 per year for the AKF group (95% CI: 6.01, 9.04, p < 0.0001). All study groups stabilized or improved their trajectory of decline during the intervention. This study supports the need to institute WERS interventions and to include mid-harvest screening protocols and longitudinal tracking of kidney function among sugarcane workers at high risk of CKDu. Early detection of rapid kidney function decline combined with appropriate interventions hold promise for stopping or slowing progression of renal insufficiency among these workers.

Wet Bulb Globe Temperature and Recorded Occupational Injury Rates among Sugarcane Harvesters in Southwest Guatemala.

As global temperatures continue to rise it is imperative to understand the adverse effects this will pose to workers laboring outdoors. The purpose of this study was to investigate the relationship between increases in wet bulb globe temperature (WBGT) and risk of occupational injury or dehydration among agricultural workers. We used data collected by an agribusiness in Southwest Guatemala over the course of four harvest seasons and Poisson generalized linear modelling for this analysis. Our analyses suggest a 3% increase in recorded injury risk with each degree increase in daily average WBGT above 30 °C (95% CI: -6%, 14%). Additionally, these data suggest that the relationship between WBGT and injury risk is non-linear with an additional 4% acceleration in risk for every degree increase in WBGT above 30 °C (95% CI: 0%, 8%). No relationship was found between daily average WBGT and risk of dehydration. Our results indicate that agricultural workers are at an increased risk of occupational injury in humid and hot environments and that businesses need to plan and adapt to increasing global temperatures by implementing and evaluating effective occupational safety and health programs to protect the health, safety, and well-being of their workers.

Electrolyte Beverage Intake to Promote Hydration and Maintain Kidney Function in Guatemalan Sugarcane Workers Laboring in Hot Conditions.

OBJECTIVES: To evaluate impact of electrolyte supplementation on hydration status and health outcomes in Guatemalan agricultural workers performing heavy work under hot climatic conditions. METHODS: A 3-week pragmatic trial was conducted with a group of 50 workers during the 2017 to 2018 sugarcane harvest. Workers received an electrolyte hydration intervention during 2 of the 3 weeks. Blood and urine samples were collected each week. RESULTS: Increased electrolyte intake resulted in less muscle injury. Kidney function was maintained across the intervention period. Workers were adequately hydrated and average electrolyte levels remained in normal ranges. Mild indications of hyponatremia occurred at higher levels of fluid intake. CONCLUSIONS: This trial demonstrates the feasibility of maintaining workers' electrolyte levels under extremely hot and humid conditions while mitigating muscle injury. Electrolyte supplementation should be added to standard workplace water, rest, and shade interventions to protect workers.

Creatinine Fluctuations Forecast Cross-Harvest Kidney Function Decline Among Sugarcane Workers in Guatemala.

BACKGROUND: Chronic kidney disease of unknown origin (CKDu) is an epidemic that disproportionately affects young agriculture workers in hot regions. It has been hypothesized that repeated acute kidney injury (AKI) may play a role in the development of disease. METHODS: Latent class mixed models were used to identify groups of Guatemalan sugarcane harvesters based on their daily changes in creatinine over 6 consecutive days in 2018. Exponential smoothing state space models were used to forecast end-of-season creatinine between the identified groups. Percent change in estimated glomerular filtration rate (eGFR) across the harvest was compared between groups. RESULTS: Twenty-nine percent (n = 30) of the 103 workers experienced repeated severe fluctuations in creatinine across shift. The model with multiplicative error, multiplicative trend, and multiplicative seasonality was able to accurately forecast end-of-season creatinine in the severe group (mean percentage error [MPE]: -4.7%). eGFR of workers in the severe group on average decreased 20% across season compared to 11% decline for those in the moderate group (95% confidence interval for difference: -17% to 0%). CONCLUSIONS: Daily fluctuations in creatinine can be used to forecast end-of-season creatinine in sugarcane harvesters. Workers who experience repeat severe daily fluctuations in creatinine, on average, experience a greater reduction in kidney function across the season.

A Pilot Study to Assess Inhalation Exposures among Sugarcane Workers in Guatemala: Implications for Chronic Kidney Disease of Unknown Origin.

BACKGROUND: Sugarcane workers in Central America experience a heavy burden of chronic kidney disease of unknown origin. We conducted a pilot study among worker proxies in Guatemala to characterize exposures to particulate matter, silica, heavy metals, and glyphosate, as well as to examine potential nephrotoxic exposures. METHODS: Air, soil, and ash samples were collected and analyzed using scanning electron microscopy, X-ray diffraction, inductively coupled plasma mass spectrometry, and an enzyme-linked immunosorbent assay. RESULTS: The average mass concentration for particulate matter (PM)2.5 and PM100 exposures were 360 µg/m3 (range: 32 to 1500 µg/m3) and 555 µg/m3 (range: 229 to 1170 µg/m3), respectively. The elemental composition of particles was largely silicon. The amount of crystalline silica was below 5 µg, yet the percentage of total silica was ~17% by weight. Putatively, the silica was in the amorphous form. Concentrations of aluminum and calcium ranged from 2-7 µg/m3. Glyphosate was not detectable in analyzed air samples but was detectable at concentrations ranging from 81-165 ppb in soil samples. CONCLUSION: Sugarcane workers are exposed to high concentrations of particulate matter. Future studies should investigate the potential role of silica, heavy metals, and agrochemicals in the etiology of chronic kidney disease in this population.