An APOE ε4–Uric Acid Axis Underpins Mesoamerican Nephropathy

Mesoamerican Nephropathy (MeN) is a form of chronic kidney disease of non-traditional origin that has become a major public health concern among agricultural workers in Central America, where extreme heat and dehydration are common occupational hazards. In this study, we combined long-term clinical follow-up with exome sequencing to explore the contribution of genetic susceptibility to MeN. We identified a significant interaction between the APOE ε4 allele and elevated serum uric acid (SUA) levels, which together markedly increased the risk of disease. Patients carrying APOE ε4 showed higher SUA concentrations, while SUA values followed a clear gradient—highest in MeN cases, intermediate in heat-exposed but unaffected workers, and lowest in unexposed controls. These results indicate that uric acid regulation is shaped by both genetic and environmental factors. The findings suggest that urate-lowering therapies already used in clinical practice could be repurposed as preventive interventions for heat-exposed populations at risk of MeN.