Project Summary/Abstract The overarching goals of this proposal are to contribute to the understanding of the causes, mechanisms, and potential strategies for prevention of the international epidemic of chronic kidney disease of unknown origin (CKDu). Our central hypothesis is that exposure to high concentrations of air contaminants will be associated with acute kidney injury in agricultural workers and that heat stress and dehydration will produce adverse effects on kidney biomarkers. We further hypothesize that this damage occurs through a vasopressin-mediated injury pathway. Access to a population of sugarcane workers in cooperation with a major Guatemalan agribusiness will allow for a study that characterizes sugarcane worker exposure to particulate matter (PM) and it constituents (silica, glyphosate, and metals) in conjunction with personal factors, including dehydration and heat stress. We will examine the individual contribution of air contaminant exposure, as well as the combined contribution of exposure and personal risk factors, on kidney dysfunction. In addition, we will investigate the mechanistic role of the vasopressin pathway to pathogenesis of CKDu. This research will: a) investigate an unexplored exposure pathway to identify inhalation exposures that may place agricultural workers at risk for the development of kidney dysfunction by conducting a robust personal exposure assessment, b) evaluate the relationship between exposure(s) and acute kidney injury, and c) examine underlying mechanisms by which dehydration and heat stress contribute to increased risk of CKDu in conjunction with nephrotoxicant exposures. To address this hypothesis, three aims are proposed: Aim 1 focuses on characterizing exposure to PM, silica, metals, and glyphosate in Guatemalan sugarcane workers and examining the impact of meteorological factors on personal exposure. We will use prospective, quantitative personal measurements in workers. Aim 2 will evaluate the relationship between occupational air contaminant exposure and kidney biomarkers of effect to identify workers with increased risk of cross-shift worsening renal function and inflammation. Aim 3 will evaluate the potential mechanism by which environmental and individual risk factors induce kidney injury. The proposed panel study will collect repeat respirable PM personal air samples across two 6-month harvest seasons in two groups of 60 workers, totaling 120 workers. First, we will collect baseline questionnaire and clinical data and biological samples from participants at the time of hire at a sugarcane plantation in Guatemala. Next, we will collect personal air measurements for each participant during the entire work shift to estimate daily airborne exposure to silica, glyphosate, and heavy metals, as well as urine and blood biomarkers pre- and post-shift at three time points for each worker during the two seasons. Results of this research will lead to large-scale intervention trials that will hel...