Re: As kidney disease kills thousands across continents, scientists scramble for answers
This ProMED massive summary may have inspired the other posts:
Published Date: 2012-09-21 10:47:12
Subject: PRO/EDR> Undiagnosed renal disease, men - multicountry: field workers
Archive Number: 20120921.1303309
UNDIAGNOSED RENAL DISEASE, MEN - MULTICOUNTRY: FIELD WORKERS
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Date: Mon 17 Sep 2012
Source: The Center for Public Integrity [edited]
http://www.publicintegrity.org/2012...across-continents-scientists-scramble-answers
In the tiny Sri Lankan village of Sandamalgama, rice farmer [WR] sits cross-legged on a wooden bed, peering out toward lush palm trees that surround his home. Listless and weak, the 46-year old father of 2 anxiously awaits word on whether his body can accept a kidney donation that offers his only chance of survival.
In Uddanam, India, a reed-thin farmer named [LN] prepares for the grueling 2-day journey he takes twice every week. For most of his 46 years, his job involved shimmying up palm trees to harvest coconuts at the top. He now spends most of his time negotiating the more than 100-mile [161 km] bus trips he takes to receive the dialysis treatments that keep him alive.
In the Nicaraguan community of La Isla, [MM] dreads returning to the rolling sugarcane fields where he spent most of his teenage years at work with a machete. Blood tests by the sugar company that employed him found that his kidneys were seriously damaged -- and exertion beneath the tropical sun could tip the 20-year-old's health into a lethal spiral.
In 3 countries on opposite ends of the world, these men face the same deadly mystery: their kidneys are failing, and no one knows why.
A mysterious form of chronic kidney disease -- CKD -- is afflicting thousands of people in rural, agricultural communities in Sri Lanka, India, and Central America. The struggle to identify its causes is baffling researchers across multiple continents and posing a lethal puzzle worthy of Sherlock Holmes.
The 3 epidemics have crucial threads in common. The victims are relatively young and mostly farm workers, and few suffer from diabetes and high blood pressure, the usual risk factors for renal disease. They experience a rare form of kidney damage, known as tubulo-interstitial disease, consistent with severe dehydration and toxic poisoning.
Other common links offer clues to a possible cause. The epidemics affect sharply defined geographic areas that are stunningly fertile and swelteringly hot. The victims mostly perform heavy manual labor, have little formal education and lack easy access to medical care. Pesticides are used heavily, and communities drink local groundwater. In each case, the disease began surging in the 1990s.
Despite a decade of research in each affected region -- and a potentially noteworthy discovery this year [2012] in Sri Lanka -- scientists have yet to prove a chemical at fault or a means of exposure. Researchers are convinced that if they could identify the culprit, the outbreaks could be stopped and the death toll reversed.
"I absolutely think that it's preventable," said Daniel Brooks, an epidemiologist at Boston University [BU] who is leading a study in Nicaragua of the new form of CKD. "I'm very convinced that what is happening to individuals is from some sort of exposure."
In a sense, researchers are waging a race against 3 parallel epidemics occurring across multiple continents. Yet the search for clues was slow to begin, with governments including the United States moving with little urgency despite warnings of the disease's toll. And separate groups of researchers -- each chasing clues to kidney epidemics across the globe -- have not fully explored whether they are linked together.
The new form of CKD is not officially recognized in the Americas even though kidney disease has killed more people in El Salvador and Nicaragua than diabetes, HIV/AIDS and leukemia combined in the last 5 years on record, the Center for Public Integrity found.
In a disease not yet formally recognized, researchers cannot say how many have fallen ill. But the death toll reaches tens of thousands.
More than 16 000 men died of kidney failure in Central America from 2005 to 2009, with annual deaths increasing more than 3-fold since 1990, according to an analysis of World Health Organization data. In Sri Lanka, the WHO says at least 8000 people suffer from chronic kidney disease of unknown cause, though other sources put the number more than double that. In the Indian state of Andhra Pradesh, more than 1500 have been treated for the ailment since 2007.
"There's a need to connect all the dots between these different outbreaks," said Dr Ajay Singh, a nephrologist at Harvard Medical School who is leading a study of the epidemic in India. "Our premise should be to first look for common causes."
The response has been fragmented in part because wealthy countries and international institutions have been reluctant to recognize the problem. Most CKD is caused by diabetes, obesity, or hypertension, all fast-growing problems in the developing world. Health officials have sometimes blamed the usual suspects of unhealthy diet and lifestyles for any increase in CKD in poor countries -- a diagnosis that neglects the possibility of environmental exposure.
"Nephrologists and public health professionals from wealthy countries are mostly either unfamiliar with the problem or skeptical whether it even exists," said Dr Catharina Wesseling, the regional director for the Program on Work and Health (SALTRA) in Central America, which pioneered the initial studies of the region's unsolved outbreak. "The response from the North and from international agencies must be much stronger."
In the meantime, thousands of villagers are dying each year from an ailment triggering as many questions as answers. Are tainted agrochemicals to blame? Dehydration in the fields, aggravated by dangerous working conditions? Or could multiple culprits exist, with different causes in each region?
From Sri Lanka to India to Central America, all the victims know is that something in their lush, hauntingly beautiful surroundings is wasting away their lives. In one patch of rural Nicaragua, so many men have died the community is called "The Island of the Widows." In the Indian region of Uddanam, a reverse trend has taken hold: couples decline to marry at all.
Sri Lanka
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[WR] has worked in the rice paddies since he was 20. He enjoyed good health until December 2011, when he began suffering an alarming array of pains. His head pounded, his knees ached at the joints, and his appetite deserted him.
He traveled from his home in Sandamalgama -- a village of 27 families -- to the doctor in the nearby town of Horowpathana. Tests revealed that his levels of creatinine, a chemical in the blood that indicates kidney function, were an astronomical 9.45 mg/dL -- more than 7 times higher than normal. He had chronic kidney disease, advanced into its late stages.
[WR's] illness is part of an epidemic sweeping northern Sri Lanka. The disease affects 3 provinces in the north central region of the country, and estimates of the number of patients range from 8000 by the World Health Organization to nearly 19 000 in a tally based on hospital records compiled by independent researchers. Prevalence in the affected region is 15 percent, according to unpublished results from a 3-year study by the Sri Lankan health ministry and WHO.
The government has even come up with a name for it: CKDu, chronic kidney disease of unknown etiology.
Since 2009, the health ministry and WHO have embarked on the world's largest and most comprehensive study of CKDu. They have sampled patients' blood and urine, tested the soil, water, and food, and surveyed and mapped the population of the affected region. "We need to do full-blown research on this and then find out the causative agents," said Dr Palitha Mahipala, additional secretary of health for Sri Lanka and the leader of the official study.
Still, despite growing public pressure and repeated promises of definitive answers just months away from release, the official program maintained complete silence about its findings for 3 years.
Finally, in June 2012, the health ministry and WHO publicly identified chemicals they said were an essential cause of the disease. The culprits: the heavy metals cadmium and arsenic, through low-level exposure likely occurring through the food chain. "It's not a mystery," said Dr Shanthi Mendis, the Coordinator and Senior Adviser of the WHO non-communicable disease program and the lead adviser of its efforts in Sri Lanka.
Cadmium and arsenic are both toxins with an array of human health effects that include kidney damage. Cadmium is often present in phosphate-based fertilizers, while arsenic has been detected in several Sri Lankan pesticides and also occurs naturally in some parts of South Asia.
The official findings in Sri Lanka represent a potential breakthrough, with implications in Central America and India. But the scientific program has not yet released any of its data behind its findings -- leaving questions unanswered and lingering doubts about its conclusions.
In sufficient quantities, cadmium and arsenic cause the same rare type of kidney damage found in the disease's victims. However, researchers Mahipala and Mendis said most of their patients' tests and environmental samples showed these chemicals at levels below the exposure limits set by United Nations agencies.
"It has not exceeded the limits," Mahipala said. "But now we are just thinking when somebody is exposed to these heavy metals over a long period of time," damage to the kidney tissue could result.
Mahipala acknowledged that "we can't really come to a conclusion" about the effects of specific exposures that remain within international limits. Neither he nor Mendis offered evidence to explain how these metals had entered the food chain or the bodies of victims at levels sufficient to cause CKD.
The WHO says it will release official study results in late October [2012] that will include hard data. The program is also embarking on research of dietary patterns in the affected region to better understand exposure levels.
Some evidence suggests that cadmium and arsenic have been disseminated through fertilizers and pesticides, whose import is financed by the Sri Lankan government. So, any definitive link between agrochemicals and public health failings would carry significant consequences.
Sri Lanka's agrochemical industry disputes the notion that its products are at fault. "We can guarantee that pesticides produced by many multinationals and international companies, they follow all the WHO and FAO [Food and Agriculture Organization] guidelines," said Rohitha Nanayakkara, secretary of Sri Lanka's National Agribusiness Council. "We believe that those are not in harmful levels."
In June 2011, Sri Lanka's Registrar of Pesticides briefly banned several leading pesticides such as glyphosate and carbofuran after tests found they were contaminated with small amounts of arsenic. A few months later, it reversed the ban after concluding that the arsenic levels were too low to pose a serious threat.
The ban was overturned even as the WHO's internal meeting notes in June 2011 called for stronger regulation of "nephrotoxic agrochemicals" -- and warned that any delay would cause "further accumulation of toxic agents in the environment and result in cumulative damage to the health of the people living in these areas."
As the fuller details of research remain undisclosed, Sri Lanka's well-regarded health service struggles to meet the massive need in the affected area. Local doctors say that as few as one of every 5 patients that need dialysis are approved to receive it. Public hospitals offer kidney transplants if patients can find their own donors and pay a substantial portion of the costs of necessary medications.
In [WR's] case, a friend of his family has offered to donate a kidney. As he awaits the result of blood tests to determine if he is a match, he travels more than 60 miles [97 km] twice a week to get dialysis, sleeping on the concrete floor of the hospital when his treatment goes too late for him to take the last bus home. He has no idea how he became so sick. "That's what I need to know," he said. "What happened to me?"
India
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[LN's] village, Gonaputtuga is part of a verdant rural belt along the India's eastern coast called Uddanam. Spanning less than 100 miles [161 km], this stretch of villages near the northern border of the Andhra Pradesh state has been suffering for 2 decades from a mysterious strain of CKD.
Healthy throughout his 46 years, [LN] began experiencing a painful series of ailments in late 2011. His body began to swell, he had difficulty urinating, and he found blood in his stool. He visited a doctor in the closest major city, Visakhapatnam, where he learned he had CKD.
Unable to work after decades spent harvesting coconuts from the top of palm trees, [LN] spends his days resting and traveling back and forth from dialysis in Visakhapatnam. "Now, I do nothing," he said. "I take medicines and be."
India's wave of CKD is smaller than the other outbreaks -- but highly concentrated. Unpublished results from a study by Harvard Medical School found that 37 percent of the population in the hardest hit village, Akkupalli, had the disease. From 2007 to 2012, 1520 patients from Uddanam received care for CKD from a state health insurance program for the poor. But this number significantly understates the burden of a disease that is latent until it reaches its advanced, deadly stages.
Unlike Sri Lanka and Central America, the illness affects men and women roughly equally, according to separate findings by researchers from Harvard and Stony Brook universities. The gender equality and geographic concentration of the illness have focused concentration on potential contamination, particularly in the drinking water.
"This seemed to be an exposure to the community as a whole," said Singh, of Harvard. Dr Ravi Raju Tatapudi, a leading nephrologist in Andhra Pradesh and the other study director, said heavy metals and pesticides running off from the fields into the groundwater were the group's primary suspects.
Despite years of attention to the disease, not one study has been published about Uddanam CKD. The Harvard group has conducted extensive tests of the groundwater and soil in the area, but the results have been delayed for months at a laboratory in Hyderabad.
For [LN], time is running out. At the Seven Hills Hospital, he smiles bravely and says he feels no pain, but his thin frame is dwarfed by the wide cot he rests on and the hulking hemodialysis machine attached by tubes to his arm.
"On dialysis people don't do well," said [LN's] doctor, Ravi Shankar Machiraju. "Holding on for a year would be just about it."
Central America
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[MM] started working in the cane fields at 14. His father had died of CKD 2 years before, and his family was struggling. After 3 years of work at the Ingenio San Antonio plantation, he was diagnosed with CKD at 17.
He continued to work -- providing false identification to contractors who looked past the fact that his permit carried a woman's name.
The epidemic in Central America spans 6 countries along a nearly 700-mile [1127 km] stretch of the Pacific coast. Across the region, kidney failure has killed more than 2800 men each year from 2005 to 2009, according to an analysis of data from the WHO. In El Salvador, the kidney disease has become the 2nd leading cause of death among adult men.
Groups of sick workers picket the gates of powerful sugar companies, demanding that the ailment be compensated as an occupational illness.
The Ingenio San Antonio sugar plantation is the epicenter of the fight. There, workers have been protesting for nearly a decade, alleging that the company's pesticides and labor practices caused the disease. After the World Bank provided the Ingenio San Antonio with a USD 55 million loan in 2006, workers complained to the Bank's ombudsman -- leading to an agreement that the company fund the ongoing Boston University study.
The BU team has pinpointed evidence suggesting that heat stress and dehydration are key contributing factors. Workers who performed strenuous labor in the sun, such as cane cutters, suffered significantly more kidney damage over the course of a single harvest season than those with less arduous job responsibilities, the researchers found.
However, recent tests of adolescents found that many had markers of kidney damage without ever having entered the fields -- suggesting a pre-existing exposure as well.
Brooks, the leader of the Boston University team, hypothesizes that a toxic exposure may render the population vulnerable but is not enough to trigger the disease by itself. "It doesn't actually go to chronic kidney disease until you get what I would call the 2nd hit, which would be the strenuous labor and the dehydration that may come from this difficult work," he said.
Researchers in El Salvador have also uncovered intriguing clues. A study published in April [2012] found that low-lying, coastal communities that grew sugarcane and cotton were both swamped by the disease, while a sugarcane community at a higher altitude was barely affected -- illustrating the vital role of geography. In Costa Rica, the government has launched a study that will seek to officially determine whether the illness is an occupational disease.
Workers like [MM] continue to place themselves at risk to support their families. At 20 years old, he is recently married and his wife is expecting a baby. "I feel like every day I work I'm taking away a little part of my life," he said. "We work there because the company is the only option we have."
Missed opportunities
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As the economic and human costs mount, governments have begun to fund studies and treatment programs. El Salvador has launched an initiative called "NefroLempa" that targets chronic kidney disease, the state of Andhra Pradesh has created a health insurance system for the poor and built new dialysis facilities, and Sri Lanka has worked closely with the WHO on research.
But international institutions and wealthy nations have repeatedly failed to connect the dots, let alone invest on a scale some experts say is necessary.
At a 2011 health summit in Mexico City, the United States beat back a proposal by Central American nations that would have listed CKD as a top priority for the Americas and adopted an official consensus that the Central American epidemic had distinct causes from most CKD.
"The idea was that to keep the focus on the key big risk factors that we could control and the major causes of death: heart disease, cancer, and diabetes," said David McQueen, a US delegate from the Centers for Disease Control and Prevention who has since retired from the agency. "And we felt, the position we were taking, that CKD was included."
McQueen's comments reflect the widely held view that any CKD in developing countries stems from diabetes and other diet-related risk factors rather than a new form of illness.
For its part, the WHO has not made any connections between the studies it is supporting in El Salvador and in Sri Lanka. In Central America, it has neither adopted a formal name for the disease nor considered whether it is related to the illness that it recognizes as "CKDu" in Sri Lanka.
The WHO has not kept a record of outbreaks similar to CKDu -- there have also been comparable reports in Egypt -- and believes that it is premature to extrapolate findings from Sri Lanka onto other regions.
CKD researchers are beginning to study each other's work independently. Scientists from Boston University, the Central American NGO SALTRA, and Sri Lanka have shared notes, and many will convene at a SALTRA-organized conference in Costa Rica in November [2012]. "We definitely need to see this as a global epidemic, but we must not forget that there may be important local causes and drivers," said Wesseling, the SALTRA director in Central America.
But so far, none of the scientists have systematically compared the epidemics or joined forces across regions to explore the broader phenomenon. The teams from Harvard and Boston University, based half an hour apart, have never met.
The medical mystery is so difficult to solve in part because the pieces do not fit together easily. It is possible that each epidemic has a different cause: pesticides in one place, hard labor in another, and an unexamined risk factor such as genetics in the 3rd.
Yet most on-the-ground researchers believe they are connected. "We're talking about these outbreaks that are happening among poor agrarian residents of these countries, mainly among men ... and that do not seem to be explained by diabetes or hypertension or any of the typical risk factors," said Boston University's Brooks. "So those things lead me to really think there's a good chance they are in fact connected."
[Byline: Anna Barry-Jester]
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[The article evokes great empathy for the human suffering at many levels. Cadmium (Cd) is a metal known to accumulate in the kidney. While arsenic (As) has been shown to accumulate in kidneys, it is much more of a liver problem and there does not seem to be a reported link to the liver in these cases. Furthermore, this article does not talk about kidney cancer but kidney failure. Arsenic is more likely to associated with cancer than kidney failure.
Cadmium concentrations in agricultural soil and wheat have increased continuously during the last century. At present, soil cadmium concentrations increase by about 0.2 percent per year. Cadmium accumulates in the kidneys. Human kidney concentrations of cadmium have increased several fold during the last century. Cadmium in pig kidney has been shown to have increased by about 2 percent per year from 1984-1992.
Cd is an important nephrotoxic pollutant, that poses increasing risks to populations in many parts of the world (Diawara et al, 2006; Kim et al, 2004; Cackovic et al, 2009; Yang et al, 2007, and Jarup, 2009). With chronic exposure, Cd accumulates in the epithelial cells of the proximal tubule of the kidney. When a threshold concentration of 150-200 microg/g tissue is reached, Cd causes a generalized dysfunction of the proximal tubule characterized by polyuria, low molecular weight proteinuria, and glucosuria (Jarup, 2002; Lauwerys et al, 1984; Satarug and Moore, 2004). As a result of the extensive use of Cd in industry and its extensive dissemination in the environment, numerous studies have focused on the identification of the early stages of Cd-induced kidney injury in exposed human populations (Prozialeck et al, 2007; Bernard, 2004; Prozialeck et al, 2009).
While the article does not indicate a connection to lead (Pb), it is known to cause kidney damage. A combination of lead and cadmium may be more damaging to the kidneys than either metal alone.
Studies of people in parts of Southeast Asia and South America with high levels of arsenic in their drinking water have found higher risks of cancers of the bladder, kidney, lung, skin, and, less consistently, colon and liver. In most of these studies, the levels of arsenic in the water were many times higher than those typically seen in the United States, even in US areas where arsenic levels are above normal.
Inorganic arsenic is found throughout the environment; it is released into the air by volcanoes, the weathering of arsenic-containing minerals and ores, and by commercial or industrial processes (1,2).
For most people, food is the largest source of arsenic exposure (about 25 to 50 micrograms per day [microg/d]), with lower amounts coming from drinking water and air. Among foods, some of the highest levels are found in fish and shellfish; however, this arsenic exists primarily as organic compounds, which are less toxic (1). Elevated levels of inorganic arsenic may be present in soil, either from natural mineral deposits or contamination from human activities, which may lead to dermal or ingestion exposure (1).
It is possible there are multiple factors in play here. Genetics, dehydration, metals or metal combinations, other chemicals, pesticides, and others may be factors that are combining in this process. While it seems there is definitely a problem, and it is wide spread over continents, the common factor of the environment these people are in does not seem to be well expressed. So the jury may be out on the epidemiology, but let's hope a cause is quickly found to reverse the horrible trend.
References
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1. Agency for Toxic Substances and Disease Registry (ATSDR). Toxicological Profile for Arsenic (Draft). US Public Health Service, US Department of Health and Human Services, Atlanta, GA. 1998 (
http://www.atsdr.cdc.gov/toxprofiles/tp.asp?id=22&tid=3)
2. Agency for Toxic Substances and Disease Registry (ATSDR). Case Studies in Environmental Medicine. Arsenic Toxicity. US Public Health Service, US Department of Health and Human Services, Atlanta, GA. 1990 (
http://www.atsdr.cdc.gov/csem/arsenic/docs/arsenic.pdf).
Portions of this comment were extracted from
Cadmium, Diabetes and Chronic Kidney Disease (
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2709710/),
Health effects of cadmium exposure--a review of the literature and a risk estimate (
http://www.ncbi.nlm.nih.gov/pubmed/9569444),
and American Cancer Society (
http://www.cancer.org/Cancer/CancerCauses/OtherCarcinogens/IntheWorkplace/arsenic). - Mod.TG
