Science: Researchers Hunt Origin of an Enigmatic Kidney Disease

Scientists have come up with several hypotheses to explain an unusual epidemic affecting agricultural workers in Central America.

When nephrologist Ramón García Trabanino began working at San Salvador's Hospital Nacional Rosales as a medical student, the huge number of chronic kidney disease (CKD) patients startled him. So in 1999, he did a study and found that two-thirds of the patients did not have diabetes, hypertension, or any other common cause of CKD. Of those, 87% were men and most worked in agriculture. Today, he runs a San Salvador center for hemodialysis — which uses a machine to remove kidney wastes from the blood — that his father, also a nephrologist, started. | Malcolm Linton

In the hot lowlands of Central America, a mysterious kidney disease has been taking a deadly toll, particularly among agricultural workers who cut sugarcane.

"The international global health community needs to take this very seriously," Peter Hotez, a pediatrician at Baylor College of Medicine, told Science news reporter Jon Cohen. "What we're seeing is not business as usual. This is a serious outbreak and we need all hands on deck."

Referred to as chronic kidney disease of unknown etiology (CKDu), thousands of cases of this enigmatic ailment have been reported in El Salvador, Guatemala, Honduras, Nicaragua, Costa Rica, Panama and southern Mexico.

First reported in 2002, CKDu, which destroys the kidneys, is difficult to distinguish from other chronic renal diseases, and its cause has been very challenging to define as well. Amid the lack of hard data on CKDu's origin, several theories — ranging from pesticide exposure to infectious diseases to heat stress and chronic dehydration — have been proposed.

In his news article in the 11 April issue of Science, Jon Cohen explores the leading theories with their proponents.

View the slideshow, part of Science's coverage of the epidemic.

A young doctor in training named Ramón García Trabanino first uncovered the disease. In 1999 and 2000, García Trabanino interviewed more than 200 patients with end-stage renal disease at San Salvador's main public hospital. His report in the Pan American Journal of Public Health speculated that herbicides and insecticides were to blame for unusually high levels of kidney disease. The Pan American Health Organization took little interest in his report, however.

García Trabanino didn't give up. He went on to collaborate with others, only to find a mystifying pattern: El Salvadorans more frequently contracted CKDu if they labored in lowland regions than in a region 500 meters above sea level. Pesticide exposure was the same in both populations. With the only difference in the two populations being the heat (the lowlands are much hotter), García Trabanino began to suspect high temperatures played a role in driving CKDu.

Elsewhere in Central America, others thought so, too.

Researchers from several countries who were baffled by what seemed like a rising number of unexplained CKDu cases gathered in Nicaragua in November 2005, brought together by the Program on Health and Work in Central America (SALTRA). The meeting spawned studies that would ultimately measure physical indicators of kidney disease in nearly 2000 Central Americans. The results of these studies pointed not to pesticides, but to heat stress and chronic dehydration. These are common conditions among the region's agricultural workers, who endure long days in hot climates with little water.

"We think the evidence of heat stress and chronic dehydration is very strong," SALTRA founder and epidemiologist Catharina Wesseling told Cohen. Wesseling works at the Central American Institute for Studies on Toxic Substances at the National University in Heredia, Costa Rica.

She and other scientists still aren't sure why CKDu has yet to be found in parts of Latin America with climates a lot like El Salvador's, or with big sugarcane industries. Wesseling suspects it is either because those areas have better working conditions and better healthcare, or because the disease is there but has gone unreported.

Today, she is working with supporters of one of the newest "heat-plus" related hypotheses in the field, which contends that repeated dehydration in hot agricultural fields disrupts a metabolic pathway that leads to high levels of various kidney-damaging biochemicals, something published studies in mice bore out last December.

Cane cutters at this cooperative about an hour out of San Salvador stop cutting before noon, dodging the brutal afternoon sun. But other cane cutters work from sunup to almost sundown, and researchers worry that they may be particularly vulnerable to CKDu. | Malcolm Linton

Not everyone is convinced, however. Carlos Orantes, a nephrologist at the National Institute of Health in San Salvador, is skeptical of the heat-plus hypothesis. He collaborated on a study in 2009 that left him sure pesticides can't be dismissed. "We are not obsessed with pesticides, but we do believe they're at the center of the cause of the disease," Orantes told Cohen.

Meanwhile, adding to the controversy, a large study led by Boston University's Daniel Brooks and completed in 2012 evaluated the health effects of working conditions at a Nicaraguan sugarcane company and didn't find conclusive evidence for either pesticide or chronic heat stress and dehydration as a CKDu driver. The study explicitly stated that the causes of kidney trouble "were unknown," as was the relationship between the disease and that particular company's work practices.

Many researchers were startled by the conclusion, insisting that clear links exist between heat stress and dehydration and CKDu.

Today, researchers including Brooks have launched several new studies to conduct what they hope will be more sophisticated analyses of the potential causes.

Cohen writes that the search for the cause of a similarly mysterious kidney disease that first surfaced in the Balkans 60 years ago — and was finally pinned to a weed in 2012 — portends that it may take years to crack this case, and that research rivalries may complicate the hunt.