A medical resident in El Salvador’s suspicion that “normal” was anything but has led to what researchers believe to be an epidemic of heat-related kidney disease, one that kills thousands of people each year, and one that climate change could make far more lethal. University of Colorado School of Medicine researchers have played a key role in turning a young doctor’s hunch into a global research effort to understand and address the disease.

Richard Johnson, MD, who chairs the CU Department of Nephrology, is at the hub of the effort, which recently produced a paper that found evidence of heat-stress-related chronic kidney disease (CKD) manifesting in Central America, Southeast Asia, India and elsewhere. If Johnson and colleagues are right, their findings mark a watershed moment in our understanding of the health impacts of climate change.

Not only may vector-borne diseases like malaria, dengue and Zika creep out of the tropics with the poleward migration of the mosquitoes hosting them. Not only may more frequent heat waves contribute to spiking death rates among the ill and infirm as happened in Europe in 2003. But in the case of CKD, the heat and higher temperatures and the resulting dehydration may debilitate and ultimately kill otherwise healthy people.

‘Even in the kitchen’

The story began in 1998. Ramon Garcia-Trabanino, the medical resident, noted outsized numbers of rural patients with kidney disease coming through the doors of San Salvador’s Hospital Nacional Rosales, El Salvador’s premier hospital. Patients with failing kidneys seemed to be everywhere.

“I used to say metaphorically that renal patients were even in the kitchen. They were overwhelming the hospital,” Garcia-Trabanino said.

When he asked around, the usual answer was, “This is the way it has always been,” he said.

He led a small study to understand who these patients with failing kidneys were and where they came from. That study, published in 2000, found that two-thirds of them showed no signs of diabetes, hypertension or any other typical cause of CKD. Eighty-seven percent were men, and most worked in agriculture or did manual labor outdoors.

The paper won a national prize for medical research. That brought local and regional attention, which led to additional studies with collaborators in Central America and Mexico. By 2005, the disease had a name: Mesoamerican nephropathy, described as chronic kidney disease of unknown origin, or CKDu for short. The unknowns centered on the root causes of the disease: Was it pesticides? Something in the diet? Dehydration? Some combination? Something else entirely?

The effort to understand what was causing CKD moved forward slowly due to a lack of money and lab expertise. That changed in late 2012, in no small part because Johnson attended a conference in San Jose, Costa Rica.

In the lab

Among many other areas, Johnson’s research team had for years focused on understanding the kidney’s role in sugar metabolism and, by extension, obesity (his book, The Fat Switch, was part of a wave of research that has implicated fructose and other sugars – as opposed to fatty foods – as the principal villain in the obesity epidemic.) Johnson had been doing mouse-model research to understand the connection between dehydration and fructose metabolism. He and his team had found dehydrated animals to have suffered kidney damage similar to what Garcia-Trabanino and colleagues were seeing among sugarcane field workers and others in El Salvador, Nicaragua, Costa Rica, and Mexico.

As Garcia-Trabanino described it, Johnson “started assisting our little poor local research because we never had proper funding.” With Johnson’s interest and his CU lab now involved, “suddenly we had a big lab, one properly equipped to analyze blood samples and urine samples, and we had a great nephrologist with his experience and expertise.”

The aim was to understand the biology underlying CKD. While there’s still no definitive answer, Johnson and colleagues believe the kidney damage is a result of a dehydration-triggered chain of events involving the hormone vasopressin, which makes the body want to hold onto water. In the short term, it’s an effective survival tactic. Over time, the adaptation damages the kidneys and ultimately, without dialysis or transplant – neither of which are easy to come by in the places men work cane fields – kills you.

Global warming

The potential global-warming link came about through an insight of Johnson’s in May 2013. He and Carlos Roncal, a researcher in the Johnson Lab, got interested in whether heat might produce uric acid crystals in urine, which they had recently linked to CKD. They typically found about 20 percent of the Nicaraguan sugarcane workers being tested had the crystals in their urine – as compared to perhaps 1 percent among a typical population. After a particularly hot day in May, though, all the samples that came in had uric acid crystals. Johnson was convinced that heat stress had to be the cause.

He reached out to colleagues around the world via the International Society of Nephrology; they compared heat maps to CKD cases. They found overlap.

“Where the hottest days of the year are, that’s where the epidemics are,” Johnson said.

Johnson brought in other experts, including Jay Lemery, MD, a CU School of Medicine associate professor of Emergency Medicine and the department’s chief for wilderness and environmental medicine. Lemery wrote the book on climate change and health.

The result of the work, published in May, was “Climate Change and the Emergent Epidemic of CKD from Heat Stress in Rural Communities: The Case for Heat Stress Nephropathy.”

Lemery described his role as being “part of the group that pulled the story together, pulled the data together and wrote the narrative in a much larger context.”

That narrative makes a compelling case that heat-related CKD is not merely a Mesoamerican phenomenon, but rather a global phenomenon. What’s more, the heat waves that climate scientists consider to be an inevitable result of climate change are only going to make the problem worse.

“In our paper, whether it’s in Sri Lanka or El Salvador, the ultimate morbidity/mortality is kidney failure,” Lemery said. “But it’s really not. It’s chronic exposure to extreme heat events in combination with a paucity of potable water.”

The same idea applies to, say, heart failure patients who die during heat waves, he added.

“The take-home message is that it’s really important to articulate the clinical impact of climate change, because unless you’re teasing that out, it just may not show up in the data,” Lemery said.

Changing habits

These men with CKD – and for now, they’re mostly men – continue to toil through the heat in the fields or on construction sites or in open-air mines. They may or may not be drinking enough water, and they aren’t likely to adhere to U.S. Occupational Safety and Health Administration guidelines saying that one should rest in the shade for 15 minutes for each hour of humidity-adjusted temperatures over 79 degrees and take breaks of 45 minutes per hour if it’s hotter than 86 degrees.

“They have to work,” said Garcia-Trabanino. “So we teach them to drink enough water; to measure their level of hydration by looking at the color of their urine; and to take rests in the shade if they work in the sun.”

Garcia-Trabanino, now a nephrologist leading a San Salvador dialysis clinic his father founded, continues to research and publish on CKD. He says patients diagnosed early can also benefit from certain drugs.

“I still have patients alive we diagnosed in 2004-2005,” he said. “They still have CKD but we have slowed down the progression.”

The Johnson Lab at CU’s Anschutz Medical Campus has stayed on the CKD case, too. Other recent efforts include a closer look at the connection between the body’s reaction to dehydration and the kidney-damaging effects of Western diets high in fructose, salt and uric acid-producing purines. His team has also shown that rats exposed to 97-degree heat for an hour have much worse kidney damage if they rehydrate with a soft-drink-like solution than if they drink water or water with a sugar substitute. The work has major on-the-ground relevance: In places where the local population doesn’t trust the water (often because of suspicion that pesticides in the water are causing CKD), sugary drinks have become a substitute of choice.

The bottom line is that climate change impacts are about more than forest fires, floods and drought, Johnson said.

“We have not focused on the effects of water shortage and heat stress on the body itself,” he said. “The kidney is the great regulator. It can only do so much.”