National Institute of Environmental Health Sciences

By Eddy Ball

Chronic kidney disease of unknown origin (CKDu) has become a widespread threat to health among the agricultural populations of developing countries in South Asia and along the Pacific Coast of Central America, most notably in the equatorial regions of Sri Lanka, India, El Salvador, and Nicaragua.

Incidence of the disease has increased dramatically since reports of the first cases in the 1990s. According to a La Isla Foundation report, in the town of Chichigalpa, Nicaragua, which is considered the epicenter of CKDu in Central America, 46 percent of all male deaths between the years 2002-2012 were due to the disease. Locals have come to refer to the town as La Isla de Viudas or “The Island of Widows.”

In Sri Lanka alone, the government estimates the number of people at risk is as great as 2.5 million. A 2014 RTI International press briefing reported that the total number of cases was expected to reach as many as 25,000 by the end of 2013.

In the face of what is fast becoming an epidemic of this mysterious disease, the NIEHS Global Environmental Health (GEH) Program is giving CKDu increasing priority as a global health issue. “I think this [CKDu] is a very important topic for NIEHS to weigh in on, at the nexus of climate change and toxicology,” wrote NIEHS and National Toxicology Program Director Linda Birnbaum, Ph.D. “[It is] certainly a growing and very serious, but probably highly preventable, GEH problem.”

An insidious non-communicable disease

CKDu in South Asia and what some scientists are calling Mesoamerican Nephropathy (MeN) or CKD of non-traditional causes (CKDnT) in Central America are especially insidious because they are unrelated to traditional causes of kidney failure, such as diabetes and hypertension, and tend to cause fatalities in people ages 30-50 after years and even decades of gradual progression. In contrast, the form of CKD common in developed countries tends to be a disease of aging.

Suspected environmental causes include heat exposure and drinking water contamination producing heat stress and dehydration; metals, such as arsenic and cadmium, which accumulate in rice and other grasses; hard water with high fluoride content from shallow wells; and glyphosphate pesticides, which may draw out or chelate otherwise dormant metals (see LWMI Working Paper). With global temperatures increasing steadily, there are concerns that more severe heat stress in agricultural workers will continue to raise rates of CKDu.

NIH funding targets CKDu

Research specifically targeting CKDu is just beginning to gain momentum, but NIEHS has contributed by funding ongoing basic research, population studies, and workshop planning grants.

In partnership with the National Science Foundation, the NIEHS Superfund Research Program (SRP) provided support to Tissa Illangasekare, Ph.D., of the Colorado School of Mines for planning a multi-disciplinary workshop on CKDu in North Central Province, Sri Lanka in August. The workshop brought together experts in hydrology, engineering, occupational medicine, social sciences, and environmental health sciences for discussions and site visits at what is arguably ground zero in the country’s epidemic.

“CKDu is a pernicious, pervasive disease,” said NIEHS SRP Director William Suk, Ph.D.,“and there is no cure for it.” Because it occurs in specific geographical areas and the cause is probably an overlap of several factors, Suk continued, a multi-disciplinary approach is absolutely essential to unravelling the mystery of this complex disease. The NIEHS SRP has funded interventions in Bangladesh, Thailand, Vietnam, and Mexico to reduce arsenic exposures in drinking water. SRP also supports a number of research groups examining the connection between environmental exposures and kidney disease.

NIEHS has provided grant support to a number of researchers studying the connection between environmental exposures and CKD in adult and pediatric populations. Johns Hopkins University physician scientist Jeffrey Fadrowski, M.D., has studied the increased rates of kidney failure among children and adults exposed to lead and cadmium, even at levels considered non-toxic by current government standards. Last year, Fadrowski was part of a team that published a review of CKDu discussing the need for increase in etiological research.

Boston University SRP environmental scientist Madeleine Scammell, D.Sc., is presently a co-investigator on a study of the epidemic of chronic kidney disease in Central America and a member of the Consortium for the Epidemic of Nephropathy in Central America and Mexico. With a grant from NIEHS, she led planning for the November 2015 Second International Workshop on Mesoamerican Nephropathy held in San Jose, Costa Rica.

NIH sister institute, the National Institute of Diabetes and Kidney Diseases (NIDDK), has a wealth of data and samples from major clinical studies supported by NIDDK on chronic kidney disease.

A clinical trial sponsored by NIDDK on the pathogenesis of glomerulosclerosis is now recruiting patients who have been residents of the North or North Central Province in Sri Lanka for at least 15 years. Requirements for enrollment also include a negative history of prior renal disease or conditions, such as hypertension, associated with conventional CKD.

Researchers conducting the clinical trial, led by NIDDK Senior Investigator Jeffrey Kopp, M.D., plan to perform metabolomic and genetic analysis of samples from 50 cases and controls. Along with consultation with attending physicians in Sri Lanka to help support patient care, a subset of subjects with CKDu may be treated with either conventional agents, or, under separate consent, with a novel combination of conventional therapies as part of pilot studies that would involve long-term follow-up care at the NIH.

John Balbus, M.D., director of the NIEHS-WHO Collaborating Centre for Environmental Health Sciences, believes that NIEHS’ work with international partners to promote more research into causes of the disease and effective interventions will help prevent CKDu: (see text box) “By raising awareness of CKDu and its environmental causes, including its linkages to climate change, we hope to increase research to understand this worsening disease and save lives.”