Introduction:
The present study aims to characterize the genetic predisposition for the development of Mesoamerican Nephropathy (MeN) in patients from Panama.
Methods:
We followed a cohort of 61 MeN patients, 30 exposed healthy donors to heat stress and agricultural work and 30 non-exposed healthy donors from Central Panama for more than six years diagnosed with a comprehensive clinical, laboratory, and genetics protocol. A Whole Exome Sequencing approach was performed in patients diagnosed with MeN using the criteria of the Pan American Health Organisation (PAHO).
Results:
We found a variant harbored in the APOE gene (rs429358 c.388T>C p.(Cys130Arg) belonging to the APOE4 haplotype, identified in 26% (16/61) of the patients, that exhibits an extraordinary and significant distortion of segregation (Hardy Weinberg Equilibrium of P= 0.001) when compared to unaffected populations from disparate regions around the world that was not found in the control groups. Blood uric acid levels in MeN patients carrying the APOE4 haplotype had a significantly higher concentration than non-carriers individuals. Even within the group of patients with MeN, elevated serum uric acid is associated with an APOE-mediated genetic predisposition. To follow these findings, we made a comparison with blood uric acid levels of a group of 60 MeN patients compared to those of 30 healthy controls exposed to high-temperature agricultural work and 30 unexposed healthy donors, finding significant differences between all these groups, highlighting that MeN patients showed the highest values, followed by the exposed healthy donors and then the unexposed healthy donors with the lowest values.
Conclusions:
These results may be key findings, as previous studies by our group and others suggested that uric acid metabolic dysfunction after exercise and heat stress associated with dehydration-induced hyperuricemia is frequently observed in MeN patients (Courville et al, 2022; Roncal-Jimenez et al, 2026). In earlier studies, the APOE4 has been associated with elevations in serum uric acid (Sun et al, 2015). Furthermore, previous studies have associated APOE variants with progression to CKD (Hsu et, 2005). Hyperuricemia is an independently predictive factor for CKD (Johnson et al, 2022). Heat stress-associated urate crystalluria is frequent in subjects with MEN, in whom it may be favouring renal damage, and uricosuria accompanies rhabdomyolysis, in which it has been strongly suspected to play a contributing role. Uric acid has been shown experimentally to cause endothelial dysfunction by both depleting biologically active nitric oxide and inducing oxidative stress. Serum uric acid also is correlated with significantly elevated afferent arteriolar resistance in humans (Johnson et al, 2022). We hypothesize that agricultural work at high temperatures elevates uric acid, even in healthy individuals, and that those with genetic predisposition, carriers of the APOE variant reported in this study, would be at increased risk of developing MeN. One limitation of the present study is the small sample of patients. The link between APOE variation and the finding of hyperuricemia, both associated with MeN, points to the fact that uric acid dysfunction may be at the core of the pathophysiology of MeN, which is crucial for defining new treatments for hyperuricemia, such as uric acid-lowering therapies in healthy exposed individuals as well as in those with MeN.
I have no potential conflict of interest to disclose.
I did not use generative AI and AI-assisted technologies in the writing process.