Silica Nephropathy and Chronic Kidney Disease of Unknown Etiology

Epidemics of chronic kidney disease of unknown etiology (CKDu) have emerged in Central America (Mesoamerican Nephropathy), in northern Sri Lanka (Sri Lankan nephropathy), in Andhra Pradesh and other regions of India (Uddanam Nephropathy), in Veracruz and Aguascalientes regions of Mexico and are emerging in the United States. In all cases, the primary histologic finding is chronic interstitial nephritis with variable degrees of glomerulosclerosis. To date a variety of causes have been considered, including heavy metals, agrochemicals, infectious diseases, and recurrent heat stress and dehydration. During the first cycle of this award, we evaluated the novel hypothesis that amorphous silica, released into the air during the burning of sugarcane and rice, may be a primary cause. Our findings demonstrated that: 1). Amorphous silica present in sugarcane and rice and is released when crops are burned as part of harvesting. 2). The particulate matter fraction (PM2.5) of burned sugarcane and rice contains 80-90 percent amorphous, nanoparticle sized silica. Workers at risk for CKDu are exposed to extremely high air borne concentrations 3). We reported that individuals with CKDu have higher levels of silica nanoparticles present in kidney biopsies than those with other kidney diseases 4). Sugarcane workers have increasing levels of silica in their urine across a harvest season. 5). Inhalation of amorphous nanoparticle sized silica or sugarcane ash in rats or mice leads to development of CKDu like pathology with minimal respiratory signs and the biopsies show chronic interstitial nephritis with silica particles present in kidney. Given our important findings during the first cycle of this award, we propose to 1) Characterize the exposure to silica in a cohort of sugarcane workers in Guatemala and examine levels of silica in urine, blood and nasal washes. 2) Develop a novel physiologically based toxicokinetic model in mice that can predict exposure to silica in humans and be extrapolated to workers at risk for CKDu. 3) better determine mechanisms of toxicity and identify novel biomarkers by using an integrated approach of redox proteomics and spatial transcriptomics in an animal model. Overall, these studies will improve our understanding of the role silica exposure has on development of CKDu, develop a novel predictive model to better determine risk associated with exposure and greatly improve environmental safety and human health.