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.
