Project Summary There is an epidemic of chronic kidney disease (CKD) in Central America, and the prevalence has been increasing over the past 20 years. El Salvador has the highest overall mortality rate from kidney disease in the world, and CKD is the second leading cause of mortality among men of working age. Due to its unique characteristics, the disease is referred to as Mesoamerican Nephropathy (MeN). In the US and Europe, CKD is common in older populations (age>60), affects men and women equally, and is primarily due to diabetes and hypertension. In contrast, CKD in certain regions of Central America disproportionately affects younger men and appears to be unrelated to diabetes or hypertension. Agricultural workers are the most affected, but the specific cause(s) remains unknown. The goal of the proposed research is to investigate the potential roles of exposure to the herbicide glyphosate, heavy metals and heat stress on the risk of MeN among sugarcane and corn workers in El Salvador. The proposed study aims to determine whether glyphosate, heat stress and/or nephrotoxic metals, alone or in combination, cause kidney injury. We will also investigate whether biomarkers of kidney injury lead to decreased kidney function over time. Results of the study may contribute to occupational and environmental heath interventions related to these three exposures, as well as contribute to the understanding of kidney injury biomarkers, which may be used for early detection and treatment to mitigate kidney injury and CKD risk. Results may also inform other CKD epidemics with similar characteristics that have been described in our countries including India and Sri Lanka. Our aims are: (1) Recruit and establish a cohort of 300 sugarcane and corn workers in El Salvador; (2) Measure heat, conduct physical examinations of workers, and collect urine and blood samples to characterize exposure to metals and glyphosate at baseline, biomarkers of kidney injury, and exposure to heat stress and muscle damage, pre- and post-shift over three consecutive workdays; (3) Investigate industry, job task, duration of employment, metals, glyphosate and heat stress, as predictors of kidney function (eGFR) over a 30-month period; (4) Bank biological samples for future analysis of additional hypotheses as they emerge; and (5) Communicate individual kidney function results to cohort participants, and overall study results to cohort participants, the scientific community, public health officials and the general public. The research team has been planning this longitudinal cohort study for nearly a year, coordinating with sugar mills, the sugar producers association, a community center (and leader) in the most affected coastal region of the country where corn cooperatives are highly concentrated, the leading El Salvadoran nephrologist who first published on this epidemic in 2002, a well-respected occupational health physician who trains and supports agricultural workers in El Salvador to lead the field team, and the University of El Salvador program on work, health and the environment.