Pathways underlying kidney vulnerability in outdoor workers

Trustees Of Indiana University, Bloomington IN

Investigators

Abstract

PROJECT SUMMARY Chronic kidney disease (CKD) is a leading cause of death worldwide. While traditionally associated with older age, hypertension, diabetes and obesity, a new CKD has emerged characterized by occupational origins and a nontraditional, multifactorial etiology. This CKD of nontraditional causes (CKDnt) already accounts for nearly 26 million cases of CKD worldwide. Despite often being attributed to concomitant factors like toxin, disease, and other environmental exposures, evidence supports that CKDnt is associated with work-related heat stress (WRHS) and the development of hyperthermia- (i.e., increased core (internal) body temperature). Hyperthermia exposure can cause clinical or subclinical acute kidney injury (AKI). Clinical AKI or repeated episodes of subclinical AKI (sAKI), defined as increases in AKI biomarkers, leads to a sustained fall in kidney function. Widespread acceptance of this hyperthermia-mediated etiological pathway is complicated by three factors. First, studies have largely been conducted in tropical occupational locations with limited seasonal temperature variation and in workforces mostly free of traditional CKD risk factors. Second, while clinical AKI is a likely cause of CKDnt, the role of sAKI is less certain. Third, hyperthermia appears to be common in workers at risk of CKDnt, but the role of repeated hyperthermia exposures is not well understood. Thus, the long-term goal of this research is to identify solutions that safeguard kidney health during WRHS. The objective of the proposed project is to identify the contribution of hyperthermia exposure to sAKI and CKDnt risk in a climate region with seasonal WRHS and in workers with a relatively high prevalence of traditional CKD risk factors. The central hypothesis is that hyperthermia exposure is a primary driver leading to increased sAKI risk and sustained declines in kidney function among outdoor workers. The central hypothesis will be tested by pursuing three independent specific aims in a project that will employ a longitudinal observational design in which markers of WRHS, hyperthermia exposure, sAKI risk, kidney function, and urinary metabolomic changes will be measured in the winter and late summer months in construction workers at high risk of WRHS associated AKI in the U.S. Aim 1 will identify the role of hyperthermia exposure on cross-shift sAKI risk. Aim 2 will characterize longitudinal changes in kidney function over the U.S. summer. Aim 3 will determine changes in the urinary metabolome in outdoor workers experiencing increased cross-shift sAKI risk. The proposed research is innovative because it will improve the hyperthermia-mediated sAKI-to-CKDnt model by including more varied climatic regions and CKD risk factors. This contribution is significant because the obtained information will provide strong support for a universal hyperthermia-mediated sAKI-to-CKDnt etiology and pave the way for therapies targeting metabolic pathways to prevent hyperthermia-mediated sAKI and, ultimately, CKDnt. It is expected that this contribution will provide the foundation for protecting outdoor workers against sAKI and CKDnt against a backdrop of increasingly hot global temperatures due to climate change.