Chronic Kidney Disease of unknown cause (CKDu) in disadvantaged communities in low-and-middle income countries (LMICs)

Lead Research Organisation: London Sch of Hygiene and Trop Medicine
Department Name: Epidemiology and Population Health

Abstract

There is an epidemic of primarily tubular-interstitial chronic kidney disease (CKD) clustering in agricultural communities in low-and-middle income countries (LMICs). This was featured recently in Science which reported previous work of some of the current applicants. Although it is currently unclear whether there is a unified underlying aetiology, these conditions have been collectively termed CKD of unknown cause (CKDu). CKDu is estimated to have led to the premature deaths of tens to hundreds of thousands of young men and women in LMICs over the last two decades. Thus, there is an urgent need to understand the aetiology and pathophysiology of these condition(s) and to develop preventive interventions.

Currently it is known that CKDu exists in Central America and mainly affects male rural agricultural workers. It may also be occurring in other tropical/subtropical parts of the world, but standardized data are not available for comparison, and also it is not known which population subgroups it affects. Obtaining this information is an essential step towards discovering the cause(s) of CKDu.

We have recently established a partnership involving a practical protocol to estimate distributions of renal function in disadvantaged communities: the Disadvantaged populations estimated glomerular filtration rate (eGFR) epidemiology study (DEGREE). This will provide key information to inform hypotheses and to guide further research into the causes of CKDu.

The Foundation Award will enable this partnership to make a step-change by implementing the prevalence survey protocol (and a related validation study) in four centres (India, Malawi, Peru, Mexico) in three tropical/subtropical regions (Asia, Africa, and Latin America) where the disease is likely to be endemic. This will provide the basis for developing further studies to discover the cause(s) of CKDu, and developing interventions to prevent it.

Technical Summary

There is an increasing recognition of epidemics of primarily tubular-interstitial chronic kidney disease (CKD) clustering in agricultural communities in low-and-middle income countries (LMICs). It is currently not possible to determine if the condition has similar characteristics or similar causes in different parts of the world. International comparisons are made more difficult because CKDu is usually clinically silent until it has progressed to advanced stages, so the diagnosis must be made by testing asymptomatic individuals.
There is a critical need for a more comprehensive and integrated approach to this problem, involving standardized validation, prevalence and risk factor studies, including comparisons between and within tropical/subtropical regions of the world.

We have recently established a collaboration involving a practical protocol to estimate distributions of renal function in disadvantaged communities: the Disadvantaged populations estimated glomerular filtration rate (eGFR) epidemiology study (DEGREE). This will provide key information to inform hypotheses and to guide further research into the causes of CKDu.

The Foundation Grant involves undertaking the DEGREE project in four centres (India, Malawi, Peru, Mexico) in three regions (South Asia, Latin America, Sub-Saharan Africa) where the disease is likely to be endemic. In each centre we will conduct a prevalence and risk factor survey in an urban and a rural area (the exception is Mexico where an urban survey is not possible because of the security situation), and we will also undertake a validation study to refine our approach to estimate GFR for cross-population comparisons.

Planned Impact

Chronic Kidney Disease of unknown cause (CKDu) affects vulnerable populations, many of whom are migrants. Impacted communities are so under resourced that the disease may have persisted for decades (goo.gl/7gQq3Y) without a functioning surveillance or treatment strategy in place, and may be more widespread than previously thought. It is essential to take a coordinated international approach to further understanding of this disease(goo.gl/dhLFX3)( goo.gl/EBV5LI), and the Foundation Award will enable this to be done for the first time.

The DEGREE study will enable standardized comparisons of impaired kidney function between and within tropical/subtropical regions of the world, in urban and rural areas. DEGREE will form the basis for further etiological research, surveillance of time trends, the implementation and evaluation of interventions. It will thereby aid countries, companies and development organizations in addressing the disease adequately.

Community organizations, research institutions and governments (Neil Pearce is an Advisor to the Sri Lankan government and WHO on CKDu), will be engaged to ensure that information on the DEGREE program, CKDu and appropriate treatment options are available. A DEGREE website will provide the protocol, research materials and information with which local researchers and other actors can empower themselves. Feedback and reporting of areas with endemic CKDu will allow us to build an international network both in terms of research, but also in terms of action on CKDu. Culture-specific written materials will also be distributed through on-the-ground community organizations so that relevant information can reach the affected populations.

Engagement with policy makers in impacted industries and within governments will be of high priority. We will assist the relevant authorities in establishing ongoing surveillance (Neil Pearce is already advising the Sri Lankan government on this), to understand 'who' is affected and 'where'. The La Isla Foundation has a track record of successfully working with governments to push policy forward as in Costa Rica (goo.gl/mpFn2e).

The potential burden of CKDu will undermine already tenuous economies in affected countries. Workers with CKDu produce goods consumed in Europe. Thus, knowledge about CKDu should inform foreign aid policy and help the UK to protect those along supply chains that support its economy. Communication materials developed by our team and excellent relationships with journalists and filmmakers from publications such as the Guardian (goo.gl/wOycrj),( goo.gl/aMDm1n) , Science(goo.gl/0lznPX) and National Geographic(goo.gl/1DxWg0) will inform a wide audience.

CKDu is potentially a global epidemic. DEGREE will support resource allocation and policy development to further assess the population burden, identify the causes, treat, and prevent this disease. This is the first strategic initiative with which to address CKDu and will impact actors along supply chains and throughout societal strata.

Publications

10 25 50

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Pearce N (2019) CKD of Unknown Cause: A Global Epidemic? in Kidney international reports

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Pearce N (2019) Causal Inference in Environmental Epidemiology: Old and New Approaches. in Epidemiology (Cambridge, Mass.)

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Pearce N (2019) Let's take the heat out of the CKDu debate: more evidence is needed. in Occupational and environmental medicine

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Pearce N (2020) Educational note: types of causes. in International journal of epidemiology

 
Description Our analyses of data from India have established that reduced eGFR not associated with traditional risk factors for chronic kidney disease (CKD) is common in rural settings of Southern India, which supports the hypothesis that CKD of undetermined aetiology (CKDu) is not confined to Central America.
Previous studies have suggested that CKDu might be found outside Central America and be common in Sri Lanka and India, but they had important limitations that challenged their conclusions. First, previous studies did not used population-based data and second, they did not used standardised methods to define CKDu. Our study is the first one to provide population based data on CKDu in India using methods standardised and used in the DEGREE protocol, that aims to enable international comparisons of prevalence of reduced eGFR and shed light in the risk factors for CKDu.
We analysed data from three population-based studies in urban and rural areas of Northern and Southern India, which included 12,500 individuals without known risk factors for chronic kidney disease. The findings show that the prevalence of reduced eGFR varied markedly between areas, being highest in rural areas of Southern Indian. In Northern India, age was the only risk factor significantly associated with reduced eGFR, whereas in Southern India, living in a rural area and education were also strongly associated with reduced eGFR.
We have also conducted the DEGREE survey in Malawi and Peru, which are also hot and involve heavy pesticide exposure in rural areas, but we found that CKDu was not common - indicating that heat and/or pesticide exposure on their own are not sufficient to cause CKDu.

The findings for India, Sri Lanka, Malawi and Peru have now all been published.
Exploitation Route Our analyses of data from India have established that reduced eGFR not associated with traditional risk factors for chronic kidney disease (CKD) is common in rural settings of Southern India, which supports the hypothesis that CKD of undetermined aetiology (CKDu) is not confined to Central America. This has major implications for South Asia, since we have established clearly, for the first time, that the condition is endemic there. This has important implications for researchers and policy makers.
We have now established cohort studies in Nicaragua, South India and Sri Lanka, three areas where we have established that CKDu is endemic. We are now planning to standardise and improve all three cohorts so that we can carry out joint analyses, and follow these population further. We applied to the MRC (PSMB) for this funding, but the application was scored well (8) but not funded. We have now revised the application and reapplied.
Sectors Agriculture, Food and Drink,Environment

URL https://www.lshtm.ac.uk/research/centres-projects-groups/degree-study
 
Description The governments of Sri Lanka, and of Andhra Pradesh (South India) are developing major new initiatives for research, screening and treatment of CKDu, and we are working with colleagues there to contribute to these initiatives. For example, there are plans to establish a major new CKDu Research Institute, and an associated CKDu hospital in Andhra Pradesh. One of us (NP) has met with the Chief Secretary of the State, and was invited to assist with these initiatives.
First Year Of Impact 2018
Sector Agriculture, Food and Drink,Healthcare
Impact Types Policy & public services

 
Description Advisory role on CKDu with Sri Lankan government
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Title DEGREE Study Database 
Description As the DEGREE study advances, we are recruiting an registering centres, which will eventually contribute data to the central DEGREE Study database. 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? No  
Impact The DEGREE study is just getting started - the MRC funding for the current project has been crucial in this regard. 
URL https://www.lshtm.ac.uk/degree-study
 
Description DEGREE Study 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Together with Dr Ben Caplin, University College, London, I have established the Disadvantaged populations eGFR epidemiology study (DEGREE). We have published the DEGREE protocol in BMC Nephrology, and we are now recruiting and registering DEGREE Study centres. This process has been facilitated by our MRC GCRF grant. The DEGREE Steering Committee has been established and comprises: Executive Neil Pearce (UK) (Chair) Ben Caplin (UK) (Co-chair) Jason Glaser (USA) Ricardo Correa-Rotter (Mexico) Kristina Jakobsson (Sweden) Ajay Singh (USA/India) Other Steering Committee members Antonio Bernabe-Ortiz (Peru) Emmanuel Burdmann (Brazil) Marvin Gonzales (Nicaragua) Vivekanand Jha (India) Rick Johnson (USA) Phabdheep Kaur (India) Pronpimolk Kongtip (Thailand) Hans Kromhout (Netherlands) Adeera Levin (Canada) Magdalena Madero Rovalo (Mexico) Dorothea Nitsch (UK) Moffat Nyirenda (Ugand/Malawi) Cristina O'Callaghan-Gordo (Spain) Pablo Perel (UK/Argentina) Dorairaj Prabhkaran (India) Narayan Prasad (India) Giuseppe Remuzzi (Italy) Rajiv Saran (USA) Liam Smeeth (UK) Vidhya Venugopal (India) Observers Nalika Gunawardenan (Sri Lanka)
Collaborator Contribution I have worked jointly with Dr Caplin to establish this study and the related international network. There are now 15 DEGREE Centres registered, another 5 which have done the survey and are about to register, and a number of more that are likely to register and undertake the study in the next year: https://www.lshtm.ac.uk/research/centres-projects-groups/degree-study#degree-centres The DEGREE Study Coordinating Centre is at LSHTM, headed by Dr Caplin and myself.
Impact We have published the DEGREE protocol in BMC Nephrology. We are about to submit a protocol for a CO-DEGREE study which can be developed after a DEGREE survey has been conducted and it is established that CKDu is endemic in an area.
Start Year 2017
 
Description DEGREE Study in Malawi 
Organisation Imperial College London
Department School of Public Health
Country United Kingdom 
Sector Academic/University 
PI Contribution I am co-supervising a PhD with Professor Paolo Vineis at Imperial College. The PhD study (Sophie Hamilton) is working on the DEGREE study in Malawi (which is funded by my MRC GCRF Grant), and adding on an environmental exposure module. Sophie has now completed and been awarded her PhD.
Collaborator Contribution I am co-supervising a PhD with Professor Paolo Vineis at Imperial College. The PhD study (Sophie Hamilton) is working on the DEGREE study in Malawi (which is funded by my MRC GCRF Grant), and adding on an environmental exposure module.
Impact Hamilton SA, Nakanga WP, Prynn JE, Crampin AC, Fecht D, Vineis P, Caplin B, Pearce N, Nyirenda MJ. Prevalence and risk factors for chronic kidney disease of unknown cause in Malawi: a cross-sectional analysis in a rural and urban population. BMC Nephrology 2020; 21: 387 [doi.org/10.1186/s12882-020-02034-x].
Start Year 2017
 
Description DEGREE Study in Peru 
Organisation Cayetano Heredia University
Country Peru 
Sector Academic/University 
PI Contribution I am working with colleagues in Peru who have followed the DEGREE study protocol and conducted the survey in two areas of Peru. This is part of the work in my MRC GCRF grant, uses a standardised protocol, and the data will eventually be analysed together. The Perudata have now been published.
Collaborator Contribution We have identified the Peru collaborators, and worked with them to establish and conduct the DEGREE protocol in an urban and a rural area of Peru, funded by the MRC GCRF grant. The study has now been completed and the first publication has appeared.
Impact Ruiz-Alejos AO, Caplin B, Miranda JJ, Pearce N, Bernabé-Ortiz A. CKD and CKDu in Northern Peru: a cross-sectional analysis under the DEGREE protocol. BMC Nephrology 2021; 22: 37. [doi.org/10.1186/s12882-021-02239-8].
Start Year 2017
 
Description DEGREE Study in South India 
Organisation Indian Council of Medical Research (ICMR)
Country India 
Sector Public 
PI Contribution I am working with colleagues in South India who have followed the DEGREE study protocol and are conducted the survey in two areas in Andhra Pradesh, South India. This is separate from the work in my MRC GCRF grant, but uses the same protocol, and the data will eventually be analysed together. The findings have now been published.
Collaborator Contribution I am working with colleagues in Sri Lanka who have followed the DEGREE study protocol and conducted the survey in two areas in Andhra Pradesh, South India. This is separate from the work in my MRC GCRF grant, but uses the same protocol, and the data will eventually be analysed together. I visited there in March 2018, and met with the State Minister of Health, and I have agreed to provide advice on CKDu research and policy.
Impact O'Callaghan-Gordo C, Shivashankar R, Anand S, Ghosh S, Glaser J, Gupta R, Jakobsson K, Kondal D, Krishnan A, Mohan S, Mohan V, Nitsch D, Praveen PA, Tandon N, Venkat Narayan V, Pearce N, Caplin B, Prabhakharan D. Chronic kidney disease of unknown aetiology in India: prevalence and risk factors. BMJ Open 2019;
Start Year 2017
 
Description DEGREE Study in Sri Lanka 
Organisation Ministry of Health, Nutrition and Indigenous Medicine
Country Sri Lanka 
Sector Public 
PI Contribution I am working with colleagues in Sri Lanka who have followed the DEGREE study protocol and conducted the survey in five areas of Sri Lanka. This is separate from the work in my MRC GCRF grant, but uses the same protocol, and the data will eventually be analysed together. The preliminary findings have been published.
Collaborator Contribution I am working with colleagues in Sri Lanka who have followed the DEGREE study protocol and conducted the survey in five areas of Sri Lanka. This is separate from the work in my MRC GCRF grant, but uses the same protocol, and the data will eventually be analysed together. The Sri Lanka work is being done by colleagues in the Ministry of Health and the WHO County office. I have visited and met with them three times to date. They have now worked with us to develop a cohort study protocol, based on a study that we are already doing in Nicaragua. This Sri Lankan cohort study is now under way, with funding from the Ministry of Health and the National Science Foundation, and the initial recruitment has been completed.
Impact Ruwanpathirana T, Senanayake S, Gunawardana N, Munasinghe A, Ginige S, Gamage D, Amarasekara J, Lokuketagoda B, Chulasiri P, Amunugama S, Palihawasana P, Caplin B, Pearce N. Prevalence and risk factors for impaired kidney function in the district of Anaradhapura, Sri Lanka. BMC Public Health 2019; 19: 763 [doi:10.1186/s12889-019-7117-2].
Start Year 2017
 
Description DEGREE Study in South India 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Policymakers/politicians
Results and Impact I am working with colleagues in South India who have followed the DEGREE study protocol and are conducting the survey in two areas in Andhra Pradesh. This is separate from the work in my MRC GCRF grant, but uses the same protocol, and the data will eventually be analysed together. The South India work is being done with colleagues in the Indian Council for Medical Research National Epidemiology Unit. In March 2018, I visited and met with practitioners and policy makers, and also with the State Minister of Health. I agreed to provide ongoing advice on CKDu research and policy.
Year(s) Of Engagement Activity 2018
 
Description DEGREE Study in Sri Lanka 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact I am working with colleagues in Sri Lanka who have followed the DEGREE study protocol and conducted the survey in five areas of Sri Lanka. This is separate from the work in my MRC GCRF grant, but uses the same protocol, and the data will eventually be analysed together. The Sri Lanka work is being done by colleagues in the Ministry of Health and the WHO County office. I have attended three meetings there, and a report on the surveys has been presented to the Ministry of Health.
Year(s) Of Engagement Activity 2017,2018