With a rising death toll from chronic kidney disease of unknown origin (CKDu) – also known in Central America as Mesoamerican nephropathy – and with greenhouse gas emissions driving global temperature increases, we are woefully short of early screening tools and treatment options for tens of thousands of patients. CKDu was first described in El Salvador in the 1990s, when unusually large numbers of agricultural workers began dying from irreversible renal failure. It quickly became evident that the phenomenon was pervasive among innumerable agricultural communities in hot, humid regions of Central America. CKDu’s presence is now potentially global, with similar disease patterns observed in North America, South America, the Middle East, Africa, and India. In Central America, CKD has become a leading cause of hospitalization and death, owing in large part to CKDu. Over the past decade, the death toll from CKD rose 83% in Guatemala, and CKD is now the second leading cause of death in both Nicaragua and El Salvador. Though these statistics are alarming, the true global burden of disease is unknown, because affected areas tend to have a poor health care infrastructure, which leaves cases undetected or underreported.

After nearly three decades, the causation of CKDu remains enigmatic, involving factors that do not align with those of classic kidney disease (i.e., diabetes and hypertension). Our knowledge gap hampers efforts to prevent new cases, slow disease progression, and treat late-stage disease. What we do know for certain is that CKDu is related to heat exposure and dehydration, although exposure to agrochemicals, heavy metals, and infectious agents, as well as genetic factors and risk factors related to poverty, malnutrition, and other social determinants of health may also contribute.

Sugarcane workers in Central America have been found to have very high rates of CKDu and have become a focus of investigation. Typically, workers harvest five to six tons of sugarcane per day, while heavily clothed, in temperatures that frequently surpass 40°C (104°F). There is increasing evidence that such heat exposure can cause daily subclinical acute kidney injury (ischemia, temperature-induced oxidative stress, and decreasing intracellular energy stores), which may cumulatively impair kidney function and result in CKD either directly or by exacerbating renal insults caused by other environmental exposures – or both. Indeed, recurrent exposure to heat stress and dehydration induces chronic inflammation and tubular injury in mice, similar to that seen in CKDu.

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