A silent killer and its unknown cause

With an increasing demand for kidney transplants, scientific uncertainty in what causes kidney diseases remains a serious dilemma :

by Rhitu Chatterjee

A small crowd of villagers waits at a low-slung concrete school building in Pedda Srirampuram, a village in the south Indian state of Andhra Pradesh. The early morning air is crisp and the men and women are dressed in light shawls and sweaters. Each holds two plastic bags-one with their medical records, the other with a clear plastic container of their urine. They line up to be seen by one of four young men at two large wooden tables.

A researcher named Srinivas Rao sits at the first table. "What's your name?" he asks a short, wiry man who is next in line. "D. Kesava Rao," the man replies, handing over his medical records. Rao, the researcher, flips through the pages, noting down details. "His kidneys are not functioning at all," Rao remarks. "Both his kidneys."

Kesava Rao, 45, has chronic kidney disease of unknown etiology (CKDu) and depends on dialysis to survive. "Every week I undergo dialysis, four weeks a month," Rao says. A soft-spoken man with a ready smile, Rao has worked all his life on construction sites or coconut farms. He lived a healthy life and hardly ever saw a doctor, he says, until a fever led to an exam and his diagnosis. Rao didn't have diabetes or, until his kidneys failed, hypertension, the two main causes of chronic kidney disease worldwide. Nor do most of the other villagers who have gathered here, all chronic kidney disease patients, waiting to get a free blood test for creatinine, a metabolite and a proxy for kidney function, and give samples of urine and blood for research.

Rural disease

This region in coastal Andhra Pradesh is at the heart of what local doctors and media are calling a 'CKDu epidemic.' There is little rigorous prevalence data, but unpublished studies by Gangadhar Taduri, a nephrologist at the Nizam's Institute of Medical Sciences in Hyderabad, in the neighbouring state of Telangana, suggest the disease affects 15% to 18% of the population in this agricultural region, known for rice, cashews, and coconuts.

Unlike the more common kind of CKD, seen mostly in the elderly in urban areas, CKDu appears to be a rural disease, affecting farm workers, the majority of them men between their 30s and 50s. "It is a problem of disadvantaged populations," says Taduri, who is leading the team of researchers in the village.

A rash of similar outbreaks in other countries has underscored that it is a global problem. Some rice-growing regions of Sri Lanka have their own epidemic, and the disease is rampant in sugar-producing regions of Mexico and Central America. It has also been reported in Egypt. Just about everywhere, prevalence numbers are scarce and uncertain, but "there is a great deal of concern," says Virginia Weaver, an epidemiologist at Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland. "This is an illness that has substantial mortality. People who would otherwise be working, raising families, are dying. It's quite extraordinary."

Public health experts and researchers are alarmed and baffled. In Central America, which has been hit the hardest, the leading hypothesis is that this is an occupational disease, caused by chronic exposure to heat and dehydration in the cane fields.

Here in Andhra Pradesh, Taduri and his colleagues think natural toxins in the drinking water-lithium, for example-could contribute. Using the blood and urine samples from Pedda Srirampuram, "we're going to evaluate whether [trace elements] are really present in the body or not," says C. Prabhakar Reddy, one of the researchers collecting the samples.

But in India, as in Sri Lanka and Central America, researchers trying to explain CKDu are pursuing a wide range of ideas, including excessive use of over-the- counter painkillers and exposure to pesticides.

Nephrologist Ajay Singh of Harvard Medical School in Boston has found high levels of silica, present in some pesticides, in the region's drinking water, and thinks it could be responsible. "There's a smoking gun," he says, though he concedes: "I don't know whether the smoking gun is responsible."

As the global scale of the disease becomes clear, the search for answers is accelerating. The beginnings of an international scientific network to study CKDu are taking shape, and researchers are working on simple, accurate diagnostics so that they can map incidence around the globe-and try to correlate it with potential causes.

Two Indian kidney donors (Hindu)

Like most places where CKDu is rampant, India doesn't have a good idea how many people have the disease (also known as CKDnT, for non-traditional causes). But the anecdotal evidence from Andhra Pradesh is sobering. We have "almost 126 widows" of men who have died from CKD, says Rajni Kumar Dolai, the chief of the village of Balliputtuga. The total population of his village is 3270, which implies that almost 4% of its inhabitants have died of the disease.

By screening village populations in a van equipped with an ultrasound machine and other diagnostic equipment, Taduri and his colleagues came up with their estimated incidence of 15% or more in this region. Most people diagnosed with CKDu "didn't have any complaints that suggested a kidney problem," Taduri says. "But ... their creatinine was high." Ultrasound exams revealed that they had "shrunken" kidneys.

Shrunken kidneys

CKDu is so deadly in part because it is hard to detect. "It is a silent killer," says A. K. Chakravarthy, a nephrologist in Nellore, Andhra Pradesh. In the disease's early stages, people show no symptoms. "By the time they find out, it is too late," he says. Their kidneys are already beyond repair, leading to high blood pressure, weakness and other symptoms. Access to dialysis here remains limited, even though the state government of Andhra Pradesh has added facilities in recent years. For many patients, death comes not long after their diagnosis.

Those lucky enough to get dialysis survive for several years, but are unable to earn a living, pushing their families deeper into poverty. His strength and endurance sapped by the disease and dialysis, Kesava Rao can no longer provide for his family of five. His eldest son, now 20, has had to step into his father's shoes. "He finished high school, and then stopped studying," Rao says. "He's the primary breadwinner of the family now."

In India, several research groups are on the trail of a cause. But each team has used its own methods and tools, often in isolation, making it hard to compare findings. Taduri and Singh, for example, have both worked in Andhra Pradesh for years, and both have pursued the hypothesis that the high levels of silica in drinking water could be responsible. Silica dust is known to damage lungs and kidneys when inhaled, but no one knows what it does when ingested.

Yet the two researchers had never met until recently. "I wasn't even aware that this work was going on," Singh says about Taduri's work. Whereas Singh thinks the silica comes from pesticides, Taduri believes it leaches into the groundwater from bedrock. Singh admits the researchers could have benefitted from a collaboration. "We need to develop a coordinated approach."

Collaborative research

Credit for image: G. Grullón/Science

That is true beyond India. As scientists and public health experts realize that CKDu is a global disease or set of diseases, they are casting a wider net for possible causes. "We need to look at this from a global perspective," Weaver says.

Some 30 Indian and international scientists, physicians, and public health experts sit at a round table in a nondescript conference room at The Energy and Resources Institute in New Delhi. The group is here for a CKD workshop spearheaded by the La Isla Foundation, a non-profit group that works with affected communities in Central America. The goal of the January meeting: to create a global network of scientists studying the disease.

The first task for the network is to determine prevalence, says Ben Caplin, a nephrologist at University College London who works in Nicaragua. "We need to know where are the hot spots of CKDnT," he says. "Are there common environmental, occupational, and social factors shared between CKDnT hot spots?"

But participants differ about how to define the disease. Caplin proposes a working definition: "no alternative cause of CKD diagnosed by medical professional, absence of diabetes, absence of hypertension." But Singh says that the condition may well be a collection of diseases caused by different factors in different places. By insisting on a single definition, we are "already starting to have a bias on what the causes may be."

Neil Pearce of the London School of Hygiene & Tropical Medicine, the only epidemiologist in the room, says screening for impaired kidney function can be done without making assumptions about causes. "We're trying to find populations with high prevalence and low prevalence. This says nothing about the individual."

Getting a handle on prevalence will require a standard screening test, however. Caplin, Pearce, and their colleagues are developing a protocol that can be adapted for different populations: a blood test for kidney function, a urine test, and a basic questionnaire recording the participant's age, sex, occupation and income. The team is trying to keep it simple and inexpensive, Caplin says. "We don't want to make it too complicated and put people off."

The team hopes to publish the protocol in a peer-reviewed journal, so that scientists in any country can use it to screen local or regional populations with their own funds.

"I think that using a simple protocol that will be affordable in different settings would really shed light on the extent and global distribution of the disease," says Catharina Wesseling, an occupational and environmental health expert at the Karolinska Institute in Stockholm.

Silent killer

Wesseling studies CKDnT in Central America, where it takes an even heavier toll than in India. "Just look at the mortality numbers," says Jason Glaser of La Isla. In Chichigalpa, Nicaragua, for example, "46% of all male deaths are due to CKD," he says. "Seventy-five percent of deaths of men between 35 and 55 years are due to CKD." By some estimates, the disease has already killed at least 20,000 people in the region.

If the disease hitting India is identical, research in Central America could narrow the search for a cause. Recent studies there have bolstered the hypothesis that CKDu results from long hours of work in the heat with too little drinking water, leading to chronic dehydration.

Last year, for example, a study by Wesseling and her colleagues showed that the disease has existed in Costa Rica at least since the 1970s, but that the death rate in Guanacaste Province has shot up from 4.4 per 100,000 men between 1970 and 1972 to 38.5 in 2008 to 2012 with the expansion of industrial-scale sugarcane farms.

In another study, the same group showed that the kidney function of cane cutters in one Nicaraguan community declined through a single harvest period. "These people have a very scary deterioration of kidney function over the harvest time," Wesseling says.

A pilot study she and her colleagues did last year hinted at how chronic dehydration does its damage. They found high levels of uric acid crystals in cane cutters' urine, especially at the ends of their shifts. Those crystals could be injuring the kidneys, the researchers proposed. "This is an important mechanism we hadn't thought about," says Richard Johnson, a nephrologist at the University of Colorado, Denver, and an author on the study.

But the case is far from closed. "I absolutely don't think that heat stress and dehydration are the only part of the story," Glaser says. "You see different severity [of the disease] in different places." Like him, most scientists are not yet ruling out other factors.

Even before scientists know for sure what causes the disease, Taduri says communities can take steps to reduce the risks. Providing clean surface water sources for drinking, urging people to drink more water at work, and advising them to stay away from pain- killers will improve their health anyway, he contends. In El Salvador, Glaser and his colleagues are working to expand a pilot study called the Worker Health and Efficiency program, which prescribes frequent rest and hydration for workers.

Fears and frustrations

Meanwhile, in CKDu-affected communities in southern India, fear and frustration are on the rise. Now, says Taduri, villagers in Andhra Pradesh refuse to come for screening, fearing stigma. When a man is diagnosed with the kidney condition, "his entire family will feel him as a burden," explains Dolai, the village chief in Balliputtuga.

On a nearby farm, a group of men stand in a circle peeling coconuts. Most are sweating in the midmorning sun. Each stands over a blade longer than his forearm, its wooden handle planted firmly in the soil. They pluck coconuts from a pile and swiftly pull each one over the blade, peeling the thick husk away from the hard, brown inner shell.

The men talk as they work, and the conversation turns to their creatinine levels. "Mine is 1.4," says a young man in his 30s. "Mine is 1.3," another says. "One point nine."

"Two." For half the men, the levels are either borderline or high. All work long hours under the sun, with too little water to drink.

Their legs and backs often hurt when they return home in the evenings, and they turn to painkillers or alcohol, even though they know both are bad for their kidneys.

The men understand they are at risk of chronic kidney disease, but believe they can do little to stop it from progressing. Rest is not an option, one says. "We have the disease, but we still have to work to earn a living."

- sciencemag.org