Environmental exposures and markers of early disease among young people at risk of chronic kidney disease of uncertain etiology
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Abstract
Prevalence of Chronic Kidney Disease (CKD), the ninth leading cause of death globally, is rising, and mortality rates from unexplained CKD epidemics are among the highest in the world. Chronic kidney disease of uncertain etiology (CKDu) is an ongoing epidemic concentrated in rural communities across tropical regions and is not caused by traditional CKD risk factors. Compared to the United States and Canada, male CKD mortality is 5–10 times higher in parts of Central America, where the disease is termed Mesoamerican Nephropathy (MeN). After disease emergence in the late 1990s–early 2000s among Salvadoran agricultural workers, epidemiological investigations have assessed MeN risk in relation to exposures to heat stress, agrichemicals, heavy metals and metalloids, silica, and a genetic susceptibility, though full disease causality remains uncertain. Repeated kidney injury from heat stress exposure in physically intense occupational settings is the leading hypothesized causal risk factor; however, communities across the globe with similar heat stress exposure profiles do not display CKDu, supporting a multifactorial disease etiology. Previous investigations of children and adolescents born in communities with high CKDu prevalence have demonstrated elevated kidney injury biomarkers, which suggests early life exposures may play a role in disease incidence in adulthood. Despite notable occupational research on working-age males, epidemiological investigation of kidney health among youth in Central America at risk of MeN remains scarce, and to date, there is limited research on females.
In this dissertation, I present novel analyses which contribute to the knowledge of environmental exposures and MeN-related kidney function among young people in Central America, including males and females of varying work status. All analyses use data sourced from an ongoing, NIH-funded prospective cohort study, Estudio Jovenes-Nica (EJN), composed of nearly 500 Nicaraguan individuals followed across childhood, adolescence, and young adulthood. In this dissertation, I apply complex and high-dimensional statistical and exposure assessment methods to evaluate urinary metabolomic markers, estimate heat stress, and quantify metal exposures in relation to kidney health.
Chapter One provides important contextual background on disease epidemiology of CKDu and MeN, disease history in the context of the Central American sugarcane industry, and key components of kidney physiology and measurement. Chapter Two details an untargeted urinary metabolomics analysis in which I evaluated metabolomic profiles in relation to CKDu risk factors. This work contributes to knowledge regarding early CKDu processes and subclinical monitoring efforts. In Chapter Three, I evaluate longitudinal kidney function against the leading hypothesized MeN risk factor, occupational heat stress, through detailed occupational history questionnaire data. Here, I integrate advanced epidemiological model building with local expertise from our community-based field team leaders. Last, in Chapter Four, I describe toenail metal concentrations and their association with cross-sectional kidney function in a subset of EJN participants. Traditional regression models and novel mixtures methods are used to evaluate single and co-metal exposures, as well as any joint effect, higher-order interactions, and nonlinearities.
In Chapter Five, I discuss strengths and limitations of the analyses and areas for continued investigation. I highlight the importance of implementing causal methods, refining disease definitions, and understanding the social and commercial determinants of health within MeN-endemic communities.
Description
2026
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Attribution 4.0 International