Perspective
Heat Stress Nephropathy From Exercise-Induced Uric Acid Crystalluria: A Perspective on Mesoamerican Nephropathy

https://doi.org/10.1053/j.ajkd.2015.08.021Get rights and content

Mesoamerican nephropathy (MeN), an epidemic in Central America, is a chronic kidney disease of unknown cause. In this article, we argue that MeN may be a uric acid disorder. Individuals at risk for developing the disease are primarily male workers exposed to heat stress and physical exertion that predisposes to recurrent water and volume depletion, often accompanied by urinary concentration and acidification. Uric acid is generated during heat stress, in part consequent to nucleotide release from muscles. We hypothesize that working in the sugarcane fields may result in cyclic uricosuria in which uric acid concentrations exceed solubility, leading to the formation of dihydrate urate crystals and local injury. Consistent with this hypothesis, we present pilot data documenting the common presence of urate crystals in the urine of sugarcane workers from El Salvador. High end-of-workday urinary uric acid concentrations were common in a pilot study, particularly if urine pH was corrected to 7. Hyperuricemia may induce glomerular hypertension, whereas the increased urinary uric acid may directly injure renal tubules. Thus, MeN may result from exercise and heat stress associated with dehydration-induced hyperuricemia and uricosuria. Increased hydration with water and salt, urinary alkalinization, reduction in sugary beverage intake, and inhibitors of uric acid synthesis should be tested for disease prevention.

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Could MeN Be a Uric Acid Disorder?

In 1974, Knochel et al13 suggested that hyperuricemia and uricosuria might have an etiologic role in the condition of “heat stress” nephropathy. Serum uric acid levels commonly increase after exercise in hot conditions, such as from marathon running and off-road motocross, often in association with acute kidney injury (AKI).14, 15, 16, 17 Despite such studies, the pathologic mechanism has not been further explored. Here, we revisit the hypothesis that hyperuricemia and cyclical uricosuria

Why Is There an Epidemic of MeN Now?

There is evidence that CKD due to MeN has been present for more than 30 years, but that its prevalence has been progressively increasing over recent decades.12, 49 This increase may be related to better awareness and improved diagnosis of the disease; however, additional factors should be considered. The first is global warming, which increases the risk for dehydration.50 Temperatures have been progressively increasing in El Salvador over the last century, with an average increase of 0.5°C

Acute Kidney Injury

Cyclic uricosuria may be also relevant to other types of AKI. Table 2 shows several types of AKI in which hyperuricemia and/or uricosuria are common.14, 43, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79 An increase in serum and urinary uric acid values with crystal formation can cause tumor lysis syndrome–associated AKI.80 In addition, there is a condition of hypouricemia and chronic uricosuria due to mutations in the genes encoding the proximal tubule urate

Limitations of the Hyperuricemia-Uricosuria Hypothesis

Although we show that uricosuria and urate crystalluria are not uncommon in sugarcane workers, there are nevertheless individuals who do not develop crystalluria. A key epidemiologic question is whether those who develop significant crystalluria are the same as those who develop CKD. However, answering this question will likely require longitudinal studies.

Likewise, it will be important to determine whether the development of kidney disease in this population may be predicted by the presence of

Proposal for Action

We present the hypothesis that MeN is a uric acid disorder. We propose that uric acid microcrystals (mainly sodium urate) develop when urinary uric acid concentrations are high and that these crystals may drive tubular injury, eventually causing the lesions observed in MeN. Elevated serum uric acid levels may also have a role in inducing some glomerulosclerosis.93, 112 A key action item is to improve the work conditions and hydration practices among the Central American sugarcane workers at

Acknowledgments

We thank Brandi Hunter for help analyzing blood samples for the pilot study; Ahsan Ejaz, Diana Jalal, Duk-Hee Kang, Enrique Perez-Pozo, and Ricardo Correa-Rotter for comments and suggestions; and the Agencia para el Desarrollo y la Salud Agropecuaria (AGDYSA; Agency for Development and Agricultural Health), which was involved in the El Salvador sugar cane workers study.20

Support: This article was supported by a grant from the Dutch National Postcode Lottery to the Solidaridad Network.

Financial

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    C.R.-J. and R.G.-T. contributed equally to this work.

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