Nicotinamide Adenine Dinucleotide (NAD+) Metabolism During Observational and Experimental Heat Stress and the Effect of Niacinamide Among Individuals at Risk for Mesoamerican Nephropathy - PROJECT SUMMARY Climate change has myriad health effects. An index condition of its impact on the kidneys appears to be Mesoamerican Nephropathy (MeN), a form of chronic kidney disease (CKD) found in individuals living in rural communities and working in agriculture along the Pacific coast of Central America. Its cause is unknown, but epidemiologic evidence suggests heat stress is a significant risk factor for disease. A potential mechanism linking heat stress and MeN may be recurrent subclinical ischemic or inflammatory injury to the kidney. Prior research shows that nicotinamide adenine dinucleotide (NAD+) biosynthetic derangement is an important diagnostic and pathophysiologic feature of ischemic and inflammatory kidney injury, and that administration of niacinamide boosts NAD+ biosynthesis and prevents injury. A key marker of NAD+ biosynthesis is the urine quinolinate to tryptophan (Q/T) ratio, which increases during injury. Across three parallel aims, this project will test the hypothesis that kidney injury and NAD+ biosynthetic derangement develop in individuals at risk for MeN when they are exposed to heat stress, and that both metabolic derangement and kidney injury may be mitigated by administration of niacinamide. Aim 1 will be observational, evaluating urinary Q/T ratio and kidney injury biomarkers in heat-stressed sugarcane cutters, a profession with very high rates of MeN. Aim 2 will define a dose-response curve between heat stress and kidney injury in a controlled human experimental setting, with parallel measurement of urine Q/T and other metabolic features to study the mechanisms connecting heat stress and injury. Participants will exercise in a heated environmental chamber under increasingly intense heat stress, modeling the spectrum experienced during sugarcane cutting. Aim 3 will be a randomized cross-over double-blind placebo-controlled trial of niacinamide during heat stress. Participants will exercise in a heated environmental chamber, at heat stress levels determined to elicit kidney strain and a rise in urine Q/T in Aim 2. Kidney injury biomarkers and Q/T will be compared between niacinamide and placebo groups. This project will (1) help isolate the role of heat stress in driving kidney injury in populations at risk for MeN; (2) develop an experimental protocol to study the mechanisms of heat stress-related kidney injury; and (3) evaluate a potential therapy to mitigate injury. It will also permit my further training in metabolomics; enable me to refine my skills in experimental physiology, clinical trials, and provocative testing; expand my capacity to work with vulnerable populations; and help me continue to develop my academic leadership within the supportive and well-resourced Beth Israel Deaconess / Harvard Medical School system. The proposed research Aims and career development plan will help me establish a career as an independent investigator, with expertise in uniting human trials and provocative testing with metabolomics to explore mechanisms connecting environmental exposures, kidney disease, and therapeutic response in vulnerable populations.
