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National Institute of Environmental Health Sciences

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International Experts Share Insights into Chronic Kidney Disease of Uncertain Etiology

By Adeline Lopez

Workshop organizing committee and other collaborators

The workshop was an international collaborative effort between NIEHS, NIDDK, IRET, PAHO, SEARO, and CENCAM. Pictured here, members of the organizing committee and other collaborators from left to right: Brittany Trottier; Bonnie Joubert, Ph.D., NIEHS; Marvin González, M.D., Ph.D., CENCAM; Jennifer Crowe, Ph.D., IRET-SALTRA, CENCAM; Kristina Jakobsson, M.D., CENCAM; Agnes Soares da Silva, M.D., Ph.D., PAHO, José Escamilla, Ph.D., PAHO, Daniel Brooks, DSc., CENCAM; Nalika Gunawardena, M.D., SEARO. Not pictured are organizing committee members Kevin Abbott, M.D., NIDDK; Ricardo Correa-Rotter, M.D., CENCAM; Paul Kimmel, M.D., NIDDK; Ty Lawson, NIEHS; and Susan Mendley, M.D., NIDDK.
(Photo courtesy of Daylin Anchía, Universidad Nacional Costa Rica)

Many Names for CKDu

Referred to here as chronic kidney disease of uncertain etiology (CKDu), it is also known as Mesoamerican Nephropathy (MeN), Chronic Interstitial Nephritis of Agricultural Communities (CINAC), Kidney Disease of Unknown Cause in Agricultural Laborers (KDUCAL), Chronic Kidney Disease of Non-Traditional Etiology (CKDnt), Chronic Agricultural Nephropathy (CAN), and Chronic Kidney Disease with Multifactorial Origin (CKD-MFO).

The many names for the condition indicate the lack of certainty of the cause, since those affected do not have the traditional risk factors for kidney disease, such as diabetes, hypertension, and advanced age.

Scientific experts from around the world gathered March 20-22 to discuss various approaches for addressing a unique epidemic of chronic kidney disease that cannot be explained by traditional or known risk factors, referred to here as chronic kidney disease of uncertain etiology (CKDu). Held in San José, Costa Rica, the Third International Workshop on Chronic Kidney Diseases of Uncertain/Non-traditional Etiology in Mesoamerica and Other Regions focused on identifying critical research gaps and building collaborations to find solutions for this important public health problem.

CKDu is increasingly recognized in specific geographic or agricultural regions in countries including Nicaragua, El Salvador, Guatemala, Costa Rica, Sri Lanka, and India. It tends to be found in younger individuals than would be expected for traditional kidney disease. The greatest burden falls on individuals living in poverty, including predominantly male agricultural workers and other manual laborers, depending on the region. The underlying contributing factors are not fully understood, and although CKDu symptoms appear to be similar across affected regions, it is unclear whether the condition represents one common disease or related pathologies.

The workshop kicked off with an inaugural session, including National Institute of Environmental Health Sciences (NIEHS) and National Toxicology Program Director Linda Birnbaum, Ph.D., and dignitaries from the Costa Rican Ministry of Health, the Vice Rectory for Research of the Universidad Nacional in Costa Rica, the Consortium for the Epidemic of Nephropathy in Central America and Mexico (CENCAM), the Central American Institute for Studies on Toxic Substances (IRET), the Central American Program for Health Work and Environment (SALTRA), and World Health Organization (WHO) Regional Offices, Pan American Health Organization (PAHO), and South-East Asia Regional Office (SEARO).

Leveraging International Partnerships for a Global Perspective

The workshop expanded on existing partnerships to broaden international expertise and include greater representation of researchers from geographic CKDu hotspots. It also emphasized putting pen to paper to come up with strategies to move the field forward and continue collaborative efforts long after the conclusion of the workshop.

An International Collaborative Effort

The workshop built on previous efforts, including workshops in 2012 and 2015 led by CENCAM in Costa Rica, a workshop organized by SEARO in 2016 on chronic kidney disease in Sri Lanka, and a 2018 workshop on chronic kidney disease in agricultural communities organized by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and NIEHS. In support of the workshop in Costa Rica, NIDDK provided grant funding was provided for junior investigator travel to the workshop.

SEARO is particularly interested in CKDu as it relates to agricultural communities in Southeast Asia that are affected by the disease, like Sri Lanka and India. PAHO and CENCAM are focused on Central America and Mexico, where certain regions have experienced up to four times the global CKDu mortality rate.

SEARO, PAHO, and CENCAM are actively working within their respective regions to promote collaborations, research, and effective dissemination of information to address CKDu.

“It was very important to our organizing committee to bring together people from various impacted regions to share their perspectives,” noted NIEHS Scientific Program Director and member of the workshop organizing committee Bonnie Joubert, Ph.D. “It provided an opportunity to discuss the factors that may be contributing to CKDu in depth, and recognize the different data collected and methods applied by researchers working in communities impacted by CKDu.”

Over 135 participants from 15 countries representing academia, government agencies, and industry engaged in roundtable discussions where they had the opportunity to meet and exchange ideas with other leading experts in the field. They discussed clinical aspects and burden of the disease, possible biological mechanisms behind these clinical symptoms, factors that contribute to disease, and societal response.

Chronic Kidney Disease of Uncertain Etiology Group Photo
Third International Workshop on Chronic Kidney Diseases of Uncertain/Non-traditional Etiology in Mesoamerica and Other Regions meeting participants.
(Photo courtesy of Jennifer Crowe, Universidad Nacional Costa Rica / CENCAM)

Building Bridges and Working Towards Solutions

One of the unique features of the meeting was the World Café, which provided a discussion forum for small groups of about 10 participants. World Café facilitators represented countries around the world, including Guatemala, Mexico, Costa Rica, El Salvador, Nicaragua, Sri Lanka, and the United States.

“The World Café was a less formal and more intimate way to get people talking to each other despite coming from different countries and different areas of expertise,” said Jennifer Crowe, Ph.D., of SALTRA-IRET at the National University of Costa Rica. “It allowed everyone to have a voice in the meeting. The positive energy and active engagement of this process continued throughout the meeting so that discussions were very lively, productive, and positive.” Crowe is a member of CENCAM and was part of the workshop organizing committee.

NIEHS grantees

The meeting was attended by several NIEHS grantees, including (from left to right) Katherine James, Ph.D.; Alison Sanders, D.Ph.; and Andres Cardenas, Ph.D. Also pictured are Aurora Arragón, M.D., Ph.D., of the University of Nicaragua and NIH grantee Lesliam Quiros Alcala, Ph.D. This majority early stage and new investigator team led one of the morning training sessions, focused on the fundamentals of exposure assessment for pesticides, other agrochemicals, and metals.
(Photo courtesy of Jose Escamilla, PAHO)

During the meeting, eight working groups held focused sessions tackling different areas related to CKDu. Guided by extensive pre-meeting preparations, the working groups had an opportunity to dig into complex scientific topics. They talked about the state of the science, opportunities to expand collaborations, standardizing global research protocols, and recommendations for intervention and prevention strategies.

Topics included the combined effect of heat, dehydration, and work load; analytical epidemiology; biomarkers of renal function; surveillance and screening; clinical presentation and treatment; pathology; molecular approaches to CKDu; and assessing environmental exposures such as pesticides, agricultural chemicals, and metals.

One working group discussed advanced molecular approaches to learn more about CKDu, including using genetic and epigenetic approaches to identify factors that lead to CKDu. They considered how molecular tools can help understand the biology of the disease and make predictions about which individuals may be most susceptible.

The working group on clinical presentation and treatment of CKDu discussed the possibility that the CKDu epidemics in Southeast Asia and Central America and Mexico may have distinct etiologies. They described unique features of the disease in each participant’s region, and began developing a plan for early detection, preventive measures, and recommendations for treatment. The analytical epidemiology group discussed recommendations for study design. One of the key recommendations of this group was the need for simple ecological studies using standardized protocols to better understand CKDu prevalence in diverse parts of the world.

According to SEARO National Professional Officer Nalika Gunawardena, M.D., the recommendations to guide epidemiologists and researchers in generating valid and comparable data across the countries were a particularly important outcome of the workshop, because they will help inform early diagnosis and better treatment.

Focusing Collaboration and Cooperation to Address CKDu

Joubert moderated a panel discussion, in which participants discussed the current research landscape, ongoing collaborations, and barriers to effective collaborations. The panel, which included NIDDK program director Paul Kimmel, M.D., began with an overview of known and ongoing studies of CKDu, including the countries where studies are taking place, the epidemiological study designs being employed, and the primary investigators for each study. Different working groups met with each other throughout the meeting in collaborative efforts to leverage their combined multidisciplinary expertise and perspectives and identify opportunities to move the field forward.

What NIEHS is Doing

The workshop was a key activity related to NIEHS’ re-designation as a WHO Collaborating Centre for Environmental Health Sciences in 2017. One of the activities added under the 2017 – 2021 workplan involved exploring collaboration with WHO on understanding and preventing CKDu, particularly as it relates to environmental factors that may play a role.

The NIEHS-WHO Collaborating Centre served as the scientific and organizational hub, supporting the connection of all the interested parties, and gathering support inside and outside NIH for the meeting. The NIEHS-WHO Collaborating Centre also joined forces with another WHO Collaborating Centre, IRET, to leverage resources in a coordinated effort.

NIEHS also currently funds research to understand how the environment, genetics, and other factors are involved in CKDu. These efforts are relevant to several areas of the NIEHS Strategic Plan, including understanding differences in individual susceptibility, addressing emerging environmental health issues, reducing environmental health disparities, and building capacity in global health.

Agnes Soares da Silva, M.D., Ph.D., MPH

Soares speaks during the policy session. Brathwaite, right, served as a moderator.
(Photo courtesy of Daylin Anchía, Universidad Nacional Costa Rica)

Before the meeting adjourned, Agnes Soares da Silva, M.D., Ph.D., MPH, and Olivia Brathwaite of PAHO moderated a discussion related to policy. Discussions focused on the implications of some of the themes that emerged from the workshop for communities and health professionals, including challenges related to the complex social, economic, and cultural factors that shape responses to the epidemic in affected countries. The session also focused on strategies for communicating research findings to policymakers to better inform decision making.

Reactions from meeting participants were overwhelmingly positive. “It is clear evidence of how this collaboration with NIEHS strengthens the capacity of WHO, PAHO and SEARO to respond to emerging priority public health problems,” said Soares.

“People from different backgrounds and disciplines felt comfortable to have in-depth and often difficult discussions on a topic which has caused divisions in the past,” said Crowe. “We demonstrated that institutions can collaborate effectively to make that happen using diverse resources and abilities.”