51 Repeated agricultural dust exposure drives coordinated pulmonary and renal inflammation with implications for CKDu

Abstract Background Chronic kidney disease of unknown etiology (CKDu) is increasingly recognized worldwide among agricultural workers and is often associated with high particulate matter exposure, yet mechanisms linking inhaled particulates to renal inflammation remain poorly defined. Chronic respiratory exposure may trigger systemic immune activation, contributing to extrapulmonary injury, including kidneys. Objective Characterize pulmonary and renal inflammatory responses following repeated dust exposure and identify immune pathways contributing to CKDu pathogenesis. Methods Dust was collected from the San Luis Valley of Colorado, a rural agricultural region with ∼25% CKDu incidence. ICP-MS analysis revealed high levels of U, W, As, and Cd. Mice were exposed by oropharyngeal aspiration to 10 or 100 µg dust, five times per week for up to eight weeks. At four and eight weeks, bronchoalveolar lavage fluid (BALF) cellularity and immune cell profiling of lung and kidney digests were performed by flow cytometry. Histological and immunohistochemical analyses assessed tissue injury and inflammatory cell localization. Results BALF analysis demonstrated dose-dependent increases in total inflammatory cells, with significant neutrophil recruitment and decreased macrophages at 100 µg. Flow cytometry confirmed elevated interstitial macrophages, neutrophils, and cKit⁺ cells in lungs, and increased CD4⁺ and CD8⁺ T cells, neutrophils, and cDC1 in kidneys, accompanied by reduced patrolling monocytes and a shift toward naïve macrophages. Conclusions Repeated dust exposure induces coordinated pulmonary and renal inflammation, characterized by neutrophilic infiltration and macrophage remodelling. Ongoing histologic studies aim to define tissue-level alterations linking inhaled dust to CKDu-related injury, providing mechanistic insight into environmental contributions to kidney disease.