Figure 1: The distribution of drinking water sources in the North Central Province (NCP) in Sri Lanka (after Chandrajith et al. ).
Sunil J Wimalawansa*Professor of Medicine, Cardio-Metabolic Institute, Somerset, USA
*Corresponding author: Sunil J Wimalawansa, Professor, Department of Medicine & Endocrinology, Cardio Metabolic Institute, Somerset, NJ 08873, USA, Tel: 732-940-0811; E-mail: firstname.lastname@example.org
The contamination of food and water through waste and agricultural runoff poses serious threats to humans. Pollution with microbes causes noticeable diarrheal diseases, whereas agrochemicals and toxins cause insidious diseases and premature deaths. Chronic kidney disease of unknown origin (CKDuo) was first seen in dry-zonal agricultural regions in equatorial countries in the mid-1960s and in Sri Lanka in the mid- 1990s. A number of agents and toxins have been postulated as the cause of CKD of multi-factorial origin (CKDmfo/CKDuo), including heavy metals, agrochemicals, fungal and bacterial toxins, climate change; and a number of behavioural factors. Meanwhile, other potential causes have not been researched, including the indiscriminate use of non-steroidal anti-inflammatory drugs, illegal drugs/illicit alcohol, leptospirosis, chronic dehydration, and exposure to various combinations of toxic agrochemicals. The incidence of CKDmfo is doubling every 4 years in Sri Lanka, leading to more than 5,000 deaths annually, and more than 150,000 people currently are affected. Although a number of agents have been postulated, no single one has been identified as the cause of CKDmfo. To alleviate CKDmfo, it is essential to take a holistic approach: carry out a massive awareness campaign, prevent environmental pollution, lessen malnutrition, correct acquired unhealthy behaviours and habits, and provide clean water to all inhabitants in the affected communities. A sustained, coordinated, effective approach will decrease the disease incidence and premature deaths, and eventually eradicate CKDmfo. This review explores agrochemicals as a potential cause of this deadly disease.
Agribusiness; Agriculture; Behaviour; CKDu; Environment; Fluoride; Heavy metals; Premature death; Renal failure
CKD: Chronic Kidney Disease; CKDuo: CKD of unknown origin; CKDmfo: CKD of multifactorial origin; DoA: Department of Agriculture; EPA: Environmental Protection Agency;
NCP: North Central Province; TSP: Triple Superphosphate Fertilizers; WHO: World Health Organisation
The demand for fresh water for domestic, agricultural, and manufacturing use continues to increase worldwide . Because of its inherent chemical structure, water is easily polluted . Taken together
with the water scarecity, food and freshwater insecurity are increasingly a problem in many communities. Particularly in both, urban and rural, in emerging economies. This is aggravated by unpredictable weather patterns and prolonged dry seasons that are associated with recent climate change. Considering these factors, the lack of ready access to a safe supply of freshwater continues to be a serious threat to human health.
Over the past few decades, freshwater resources have been endangered, not only by over-exploitation, but also by neglect, poor management, ecological degradation, and man-made pollution . Naturally occurring and anthropogenic contaminations exhibit marked geographical variations , while unpredictable climate changes exacerbate ill health [5,6]. Degradation of watersheds and catchment areas in wooded and hilly country, deforestation, and the consequent soil erosion lead to harmful ecological changes and the need to dredge canals and reservoirs, which further contaminates the water and soil.
Water pollution secondary to expanding agricultural and human settlements, pollution related to the industrial sector and poor drainage, and inferior watershed management practices [7,8] all contribute to a shortage of clean water [9-11]. In addition, the failure to adopt proper soil and water conservation measures, irresponsible use of agrochemicals, lack of enforcement of environmental laws and a nationwide longterm sustainable water plan all add to scarcity of clean water [6,12] and escalating chronic human health conditions.
The kidney is one of the body organs receiving the highest blood flow and is highly metabolically active. Although somewhat more resilient than the liver, the kidneys are vulnerable to acute and chronic exposure to toxins and oxidative stress-induced damage. The two most common reasons for the development of chronic kidney disease (CKD) are hypertension and diabetes. However, kidneys can also injured by snake venom, and a number of other toxic agents and poisons entering the human body through oral, inhalational, or transdermal routes from the environment.
There are well-known associations between CKD and environmental agents, various disease conditions, immunological entities, and infections . Toxins, heavy metals, industrial chemicals and agrochemicals, immunogens, infections, and sometimes combinations of these can cause renal damage. In certain cases and conditions, the toxic effects of these agents are modulated by age, sex, genetic susceptibility, nutritional status, and existing comorbidities .
Associations between CKD of multi-factorial origin (CKDmfo), which predominantly affects the North Central Province (NCP) in Sri Lanka, and various components have been discussed previously [15,16]. Recent articles have focused on the excessive use of chemical fertilizer that contaminates water bodies and reservoirs [17-20], exposure of farmers to organophosphate pesticides , and pollution of drinking sources, including well water [16,22,23], with fluoride, heavy metals, and other agents [15,24,25]. Understanding the contamination of wellwater is relevant in the NCP because approximately 75% of NCP inhabitants drink from shallow wells  (Figure 1), and more than 85% of those with the disease consumed water from such wells.
Figure 1 show the Sources of drinking water supplies in the CKDmfo affected region.
The vast majority of people in the North Central Province (NCP) drink water from shallow wells and deep tube wells. Although surface water in shallow wells can be contaminated by agricultural runoff and other anthropogenic activities, tube wells are contaminated mostly by naturally occurring fluoride in groundwater . All published reports, including those from a group assembled by the department of health, Sri Lanka, through the World Health Organization (WHO), are inconclusive [15,16] with regard to discerning an aetiological factor; all studies have failed to clarify the situation [12,16,18, 20-23, 26, 27].
The data from extensive studies, such as the WHO-CKDu report [15,16] and collaborative Japanese studies and others [12,18,21,26,27], have failed to support any of the hypotheses regarding potential cause(s) of CKDmfo, including heavy metals, fluoride, ionicity and agrochemicals (including glyphosate, nitrates, or phosphates) [15,16,28]. Collectively the research data and commentaries of the last decade, however, have improved the understanding and knowledge of CKDmfo, but there is still much to learn.
During the past decade, the incidence of CKDmfo in the NCP has increased significantly , doubling every 4 years [21,29]. In addition, the disease continues to spread to adjacent and distant regions in the country [16,18]. However, it is unclear whether this increasing occurrence is attributable to a true increase in incidence of CKDmfo or better awareness and thus early diagnosis and greater reporting of the disease .
In Sri Lanka, CKDmfo causes the deaths of more than 5,000 per year, mostly male farmers (inlcuding significant number of suicides); numbers are increasing [15,21]. The victims are primarily from the agricultural areas in the dry zone. Only about 7% have access to a pipe-borne water supply; the rest rely on canals , tubewells, and dugwells for drinking water, and water for washing, bathing, and irrigation. Although there are a number of postulated causes, one specific cause of CKDmfo has not been established [15,20,30]. Many investigators have suggested that some substance(s) present in the water is likely to be responsible for the development of CKDmfo [18,31], but a specific factor(s) has not been identified [15,21].
Water Pollution and CKDmfo
The industrial development and colonization occurred since the 1950s in Sri Lanka. The vast majority of these new settlements occurred in areas that once were forested, particularly in the North Central Province (NCP). This was further complicated by a major irrigation project, the accelerated Mahaweli project that started in the mid-1970s. There is a possibility that the combination of these may have contributed to the genesis of the current epidemic of chronic kidney disease of multifactorial origin (CKDmfo); also knows as CKD of unknown origin/aetiology (CKDuo) [21,32]. Unless such projects are properly designed with due consideration given to human habitats and health, and longer-term needs and consequences, these developments can inflict tremendous pressure on the environment (and harm), creating adverse impacts on freshwater systems and humans.
One such example is the increasing incidence of non-communicable diseases in the region. A part of the problem is due to the surface water and groundwater contamination with the excessive plant nutrients use (phosphate, nitrate, and nitrites),organic matter, and excessive agrochemicals applied to farmlands locally, and in areas hundreds of miles upstream on the River Mahaweli [7,8,33,34]. There have been speculations for a while that water coming down from the Hill country brings many agrochemical-based pollutants through this river to the reservoirs in the dry zone, almost all of these reservoirs are located in the NCP [24,25,29,32,35,36]. Figure 2 illustrates the sectors and regions that are currently supplied by the water from River Mahaweli and the future expansion areas in the north of the country.
Because the geo-chemical parameters vary markedly from village to village, conclusions based on water quality data collected and analyzed from random samples can be misleading and thus cannot be generalized for the region. Nevertheless, available data suggest that environmental contamination and the unique hydro-geochemistry of the affected areas seem to play an important role in the development of CKDmfo [15,17,18,31,37]. However, none of the studies conducted to-date [15,18,27] reported levels higher than safe limits stipulated by the WHO and the United States Environmental Protection Agency (EPA) for any of the postulated causative agents in water samples.
Epidemiological Data and Spreading of Ckdmfo in Sri Lanka
The evidence suggests that CKDmfo is spreading from the NCP to other parts of the country, such as to Girandurukotte, Nagadeepa, Badulla District, Wilgamuwa in the Matale District, Nikawewa in the North Western Province, and recently into distant areas such as Jaffna, Udawalawa, Moneragala, and Hambantota districts (Figure 3). However, data available are insufficient to assess, whether this ‘spread’ outside the traditional NCP boundaries is attributable to enhanced awareness and thus increased diagnoses (yet diagnosed too late) because of the recently initiated population-based broader screening by the department of health and a number of volunteer organizations.
In addition to the insensitive and non-specific methods used for screening and diagnosis , there is high false-positive diagnosis made secondary to unstandardised urine samples collections, inlcuding poor urine collection methods (i.e., cross contamination with non-urinary proteins), that currently used by the department of health for screening and disgnosis. It is also possible that migration of significant numbers of families affected with the disease from the NCP into distant areas could be a factor. However, a true increase of the incidence (i.e., previously healthy people newly contracting the disease, in new localities) seems to be the primary reason for identifying new patients with CKDmfo in distant regions.
Figure 2: (A) Map of Sri Lanka illustrating major cities, and (B) a magnified geographical area, illustrating the regions fed by the water from the River Mahaweli and the areas that are covered by the Accelerated Mahaweli Developmenet Program in the North Central Province (NCP).
Agrochemicals and CKDmfo
In the late 19th century, agriculture began to change from the traditional, organic model to the green revolution. This was in part because of the increase in population that could not be supported using traditional methods that had been in use for centuries when the population was relativey static. The change started with the “nutrition/crop revolution,” which was followed by the green revolution in 20th century. The latter was characterized by a rapid increase in the use of synthetic agrochem-icals on which farmers quickly became dependent for growing crops.
Today, less than 10% of the world’s commercial farmlands use organic agricultural methods. 65% of these lands are exclusively use for generation of pastures for organic meat production. Other than hybrid cultivation, which uses traditional and modern agricultural methods, no method available today can replace the conventional agricultural methods that use agrochemicals to generate higher amounts of crops using the same arable land. Nevertheless, the overuse of agrochemicals is hazardous. However, such chemicals, when used correctly, based on the soil requirements are relatively safe and unlikely to generate health issues.
The presence of very smalll quantities of herbicide propanil [N(3,4- dichlorophenonyl) propanamide] and the insecticide chlorpyrifos [O,O-diethyl-O-(3,5,6-trichloro-2-pyridinyl) phosphorothioate] has been reported in certain water sources, including in shallow drinking wells in the affected areas [5,16,38,39], but other research has failed to detect these agrochemicals [17,18]. Small quantities of glyphosate [N-(phosphonomethyl)glycine]  (the major ingredient in the herbicide, Roundup) have been reported in only a very small number of water samples out of thousands tested to-date [40,41], including the WHO-CKDu study failed to detect meaningful quantities of glyphosate or any other agrochemicals in water sample analysed .
Agrochemicals by Themselves may not Cause the Disease Directly
Long-term exposure to propanil and chlorpyrifos, whether throught the contaminated water, by absorption via the skin, or inhalation during spraying, could cause liver and kidney disease . In addition, the massscale use of imported, poor-quality, triple superphosphate fertiliser and other toxic agrochemicals may have made the situation worse [19,43,44]. Meanwhile, some pesticides that are barred in industrialized countries continue to end up in emerging economies, in part because of the lack of enforcement of import safety regulations and quality controls .
Figure 3: The geographical distribution of patients with CKDmfo in relation to the climatic zones in Sri Lanka. (A) The three climatic zones are wet zone (pink), intermediate zone (red), and dry zone (orange), with the areas originally affected with CKDmfo shown in yellow. (B) A map of Sri Lanka illustrating the pattern of distribution and spread of the disease outside the NCP (NCP region is indicated in light green). Colour coding: The original CKDmfo hot spot areas (pink circles); the spread of the disease from 2008 through 2012 (blue circles), and the spread after 2012 (green circles). The climatic boundaries are illustrated with broken black lines. Figure A was modified after Smedley and Kinniburgh, 2002 and Figure B was modified from existing data, public domain, and from Wimalawansa et al (2014) with added new data .
Aforementioned chemicals and toxins are polluting the agricultural soils and water supplies , and some are likely to end up in the food chain. If this is the case, a portion of the food that is generated from these ‘chemically contaminated’ farmlands (e.g., in the NCP) are sent to other parts of Sri Lanka. Exportation of food to other countries, may even include the ones from which these contaminated fertiliser consingments sent to Sri Lanka. Overall, the proper use and management of agrochemicals, agricultural waste and petroleum spills, etc.  is essential to preventing pollution of water bodies and underground sources.
Such proactive steps could prevent degradation of water sources and perhaps decrease the incidence of CKDmfo in the long run. In addition, it is important to implement a broader pollution prevention educational program for farmers and the merchants who sell agrochemicals regarding the proper use of agrochemicals and water management to minimise environmental pollution. Among the large number of agrochemical components use in Sri Lanka, only glyphosate has been suggested to be associated with the CKDmfo by one group , but the evidence is scanty and no other scientific group has been able to verify it [15,18,44,48,49].
There is no evidence that Glyphosate causes CKDmfo
It has been hypothesised that glyphosate−heavy metal complexes may facilitate renal failure , but no scientific data exist to support this [20,21,43,50]. Demonstration of the mere presence of heavy metals and glyphosate in water samples, does not means it is associated with or causes CKDmfo. No other scientific group has been able to verify the reports [47,51]. There are potential metal complexes (Ca and Mg chelation) of glyphosate reported using computer modelling , but none reported for complexes of glyphosate with arsenic or cadmium. A number of scientists have pointed out that, based on chemical and thermodynamic variables, it is scientifically impossible for glyphosate molecules to act as a carrier for arsenic or cadmium, especially in the presence of Ca or Mg. Even if such complexes are made, they are insoluble and thus will not be dissolve in water.
The published literature suggests no adverse effect on human kidneys of glyphosate at the amounts that are recommended for farming activities [41,53] and glyphosate does not cause CKDmfo [21,50,54]. A number of regions in Sri Lanka have hard water, as indicated in Figure 2 (but generally with low fluoride content), and farmers in these regions were using similar or higher quantities of glyphosate. In these areas, the incidence of CKDmfo is not high. There are additional compelling epidemiological, chemical, and other scientific reasons to reject the hypothesis that glyphosate causes CKDmfo.
These reasons include, but not limited to: 1) the disease was prevalent in the NCP several years before this chemical was introduced to the region, 2) people who drink from shallow- and tube-wells are more susceptible to develop CKDmfo than those who drink water from tanks, but the chemical has not been found in either of these waters, 3) glyphosate binds tightly to the topsoil particles and makes relatively insoluble complexes with the abundant cationsin soil, such as calcium and magnesium, making little possibility of it leaching into the waterways, and 4) even if injested, it will bind tightly to cations in gut [43,44,50]. Currenlty, overall sciecne suggest that glyphosate plays no role in causing the CKDmfo epidemic in Sri Lanka [15,20,21].
Surfactants are Toxic and Harmful to Humans
Adjuvants and surfactants are routinely included in almost all pesticides and herbicides preparations to stabilise and enhance the intended effects of the activ ingredient. Very small quantities of the active ingredient (e.g., glyphosate) present in very few tested samples of water in certain locations that are not harmful to humans. However, acumulatiing evidence suggests that adjuvants and/or surfactants could be harmful to humans [55- 58]. Consequently, it is essential to protect water resources from these compounds. These include, Cosmo-Flux (in Roundup) and perfluorinated surfactants, and their precursors and adjuvants, if ingested in certain quantutues can cause ill health in human [58,59]. Thus, their presence in drinking waters and food must be minimised. This is where the right legal regulations are necessary to either limit or ban the importation (and local production) of products containing dangerous adjuvants, surfactants, and precursors; not banning the active ingredient.
Worldwide, there are several commonalities in the CKDuo/CKDmfoaffected countries, including poverty and drought-stricken nature and proximity to the equator (Bangladesh, Sri Lanka, southern China, India, South America, and certain eastern European countries). Affected nations all are predominantly agricultural countries and emerging economies. These communities and nations are economically disadvantaged, receiving aid from the West [21,60]. Although the European Union and the United States EPA banned the sale of certain manufactured agrochemicals , thousands of tons of some of these prohibited chemicals are sold as cheap agrochemical products to the aforementioned developing countries .
For example, when the EPA banned the sale of monosodium methyl arsenate (MSMA; sodium hydrogen methyl arsenate, an effective arsenicbased herbicide and fungicide) in the United States, the use of this chemical markedly increased in the developing countries . It is a less toxic form of arsenic that has replaced lead-hydrogen arsenate in agriculture, but still has the capacity, converting to toxic inorganic arsenite . Untill, replaced by glyphosate, it was one of the most commonly used herbicides on golf courses in developing countries .
Phosphate Eutrophication of Reservoir Water does not cause CKDmfo
Fertilisers containing rock-phosphate such as triple superphosphate fertilisers (TSPs)  are a source of cadmium and arsenic pollution in soil [25,32]. Overuse of TSP pollutes farm soil, and its runoff contaminates water bodies with excess phosphate [20,44]. Higher than acceptable levels of cadmium, arsenic, and lead are present in many pesticides and herbicides [66,67] as an active ingredient or as contaminants [68,69], and the overuse and exposure to such agents cause or agraviate chronic health issues. Because of the high governmental subsidy of fertilisers, many farmers overuse these products or use them carelessly with the misguided assumption that use of greater quantities than those recommended by the manufacturers and the Department of Agriculture (DoA) continue to increase agricultural output [20,21,44].
Excess fertiliser applied to the soil leaches into groundwater and run off via streams and rivers into reservoirs in the NCP, causing ecological changes and harming marine life. Excess phosphates and nitrates from the fertiliser facilitate algae blooms and cyanobacterial growth. As the nutrient increases, bacterial growth also increases and rapidly consumes dissolved oxygen in the water. This leads to suffocation of freshwater fish and retards their growth and propagation.
In addition, the release of nitrous oxide (from excessively used nitrates in fertilisers) into the atmosphere contributes to the reduction of ozone present in the stratosphere and adds to global climate change. The ozone layer absorbs much of the harmful ultraviolet radiation that comes from the sun. The erosion of this protective layer is known to cause additional harm to living beings, including an increase in cancer
The government provides a large fertiliser subsidy. For example, a 23- kg bag of fertiliser is sold for approximately for 350 rupees, at 10% of the real cost. Consequently, the government is spending more than 50 billion rupees a year on the fertiliser subsidy. Thus, a 10% reduction would save more than 5 billion rupees, which is adequate to eradicate the CKDmfo from the country and enriching the lives of farming communities in the region. These over usage of phosphate-fertiliser have led to phosphate eutrophication of water in all large reservoirs in the NCP region. Almost all of these reservoirs are in fact, fed by water coming from the hill country via the River Mahaweli.
The ranges of phosphate levels reported in these waterbodies in the NCP are between 0.07 and 0.15 mg/L (with an average of 0.12 mg/L) . This increase in water phosphate levels in reservoir suggests that over use of fertiliser in the upper terrains in the hill as the most likely cause for phosphate eutrophication of the RIver Mahaweli and reservoirs in the NCP . This is the regions that is also most affected by CKDmfo. These levels of phosphate (phosphorus) in water causes significant negative ecological effects on freshwater fauna and flora and cause algae blooms. However, there is no evidence that it is harmful to humans; especially, at these reported low levels in water. Even if water from these reservoirs is consumed by people, there is no evidence that it can harm kidneys or causing CKD.
Overuse of Pesticides and Lack of Precautions during Agrochemical use
In general, most famers do not take precautions when handling agrochemicals in developing countries , including in Sri Lanka . Nevertheless, this dangerous habit is no different from that in the CKDmfo-endemic and non-endemic areas, so this factor alone is unlikely to play a major role in the development of CKDmfo. It would be useful to gather comprehensive information about farmers’ social habits, dietetic patterns, storage of food and agrochemicals, the ways these chemical are used, advice on pest and plant-disease control measures, handling of pre-harvests and post-harvests, socioeconomic and cultural basis, case distribution, and so forth, and compare the information between the affected and non-affected communities. Such a comparison is likley to be productive on this issue.
Sicne the abolition of agricultural-extension advisory services, there is no established, reliable structure in communities for farmers to obtain proper information and advice on agricultural matters. In recent years, instead fo the DoA, farmers are relying on the vendors of agrochemicals for such information. The amount of fertiliser imported to Sri Lanka is approximately 8,000 metric tons per year (1 metric ton=1,000 kg). This can be quantitated into 2.5 ppm arsenic (~2.5 mg/kg of fertiliser) and 8 ppm cadmium (~8 mg/kg of fertiliser) to farm soil in the country every year. When excess fertiliser is applied to farmfields, what is not absorbed by soil and plants leaches out and finds its way into waterways. Therefore, the proper use of agrochemicals is one of the most important measures for the prevention of CKDmfo.
Sri Lanka had an effective and well-organized agricultural extension and advisory system that was dismantled three decades ago by the government with advice from the International Monetary Fund (IMF) and the World Bank. These extension workers had close relationship with farmers and were appointed and trained by the DoA. They provided an efficient and useful advisory services to farmers. This valuable scheme was replaced with the Provincial Council Administration System and Grama Niladhari (government-appointed “village headmen,” for whom agricultural training was not a prerequisite). This change led to a virtually complete breakdown of the nation’s valuable agricultural extension system.
Nevertheless, this Grama Niladharis were expected to provide the same services that previously provided by trained agricultural extension officers, creating a major vacuum of delivery of expertise and services across the country. The lack of extension workers was quickly filled by agrochemical agents and merchants. Desperate for money, a desire to increase crop output, lack of a proper agricultural advice and supervision, and highly subsidized fertilisers created a “perfect storm”; farmers began to overuse agrochemicals, which led to the current situation. It is essential that the Ministry of Agriculture re-establishing this valuable institution, similar to the cultivation committee handling paddy cultivation, and the use of fertiliser should be attended to by this entity.
Importance of Preventing CKDmfo
Chronic, non-communicable diseases have affected many areas in the NCP, and the incidences continue to escalate. The overall goals should be to minimize the incidence of CKDmfo by providing clean water and limiting environmental and water pollution at the source level so that watersheds and the environment are preserved; these are essential goals. In addition, the cascade of irrigation tanks should be restored for agriculture, bathing and other uses. In parallel, economical ways to collect rainwater should be encouraged to provide fresh water for domestic use.
Recent statistics indicate a doubling of the incidence of CKDmfo during the past 4 years . Although there is no causality established agrochemicals are one of the key suspects in causing this fatal disease. Therefore, it is of paramount importance to educate farmers and sellers to reduce the overuse of fertilisers and assure strict quality control on all locally manufactured and imported fertiliser consignments . This does not mean imposing a ban on agrochemicals. Instead, regulations should enforced, programs established to educate farmers of appropriate and responsible use of fertiliser based on soil testing data, while be able to maintain or even increase the agro-output but in a responsible manner.
This necessitates increasing the number of trained, quality assurance inspectors, empowering and allocating appropriate resources for pesticide regulation authorities, re-establishing large-scale agriculture extension services, and allowing unrestricted access for inspectors to all imported fertilisers and agrochemicals consingements to examine and assure the quality. To safeguard human health, enhancement of inspections and certification programs also would be useful with reference to all agricultural and fisheries products (food inspection) that come to the market.
Diversification of the economy to manufacturing, assembly, and other creative opportunities using locally available resources in the NCP region needs boosting, which should minimize future economic disasters caused by relying purely on agriculture. These value-added industries would improve the socioeconomic standard of residnents in the region, traditionally known to be poor.
Programs to be Implemented to Prevent CKDmfo
It is essential that environmental and customs officials impose strict quality control measures for all imported fertiliser and pesticide shipments at the ports of entry. It is ironic that industrialized or economically advantaged countries do not allow local distribution or importation of contaminated material yet allow dumping of such toxic “waste” in developing countries, many times using intermediaries. In addition, it is of paramount importance that a long-term plan for watershed management of the entire country be developed to stop the process of continuing water pollution . Preventing watershed degradation and associated soil erosion would improve agricultural output and decrease the burdens seen with CKDmfo and other chronic ill health problems.
To prevent any potential decrease of agricultural production, the gradual reduction of fertiliser subsidies should be tied to enhancing organic farming (and the use of hybrid methods), countrywide usae of soil fertility analysis, and strict use of fertiliser recommendations. This should automatically decrease the quantities of fertiliser released to farmers based on their actual need, as determined by the soil analysis data. The reduced fertiliser consumption would save the government millions of rupees and prevent soil pollution, while maintaining good quality agricultural output.
On the user end, the unwarranted practice of applying pesticides just before and after harvest must be banned. Instead, the Department of Health, EPA, and the Consumer Affairs Authority should be empowered and funded to analyse vegetables, fruits, rice, and other food items regularly, and educate farmers on the appropriate and responsible use of pesticides and fertilisers. An example of multi-pronged approach to curbing CKDmfo is illustrated in (Figure 4).
The need for a Mass-Media–Based Educational Campaign
Nationwide, a mass-media–based educational campaign on how to prevent environmental pollution and the steps needed to minimise the risk of developing CKDmfo is an essential part of the prevention program. Meaniwhile, ineffective approaches such as the ditribution of domestic water filtration systems should be stopped. The later has failed for a number of reasons, including (A) fewer than 10% of people who were provided the filters free of charge have actually used them; (B) the inefficiency of the removal of pollutants by water filtration systems; and (C) the systems are not cost-effective. The use of such systems should not be promoted.
While waiting for the National Water Supply and Drainage Board (NWS&DB) to provide a centrally purified, pipe-borne water supply for all municipalities, interim methods, such as reverse osmosis  or ozonisation of water , or at least larger-capacity, activated carbon filters that would adsorb organics and agrochemicals (but it does not remove heavy metals, fluoride, ions, etc.), must be implemented to give potable water to each house in the region.
To overcome CKDmfo, the country needs a broad, multidisciplinary approach to research and development, and implementation of programs with a focus on finding the disease’s root cause, prevention, and problem solving. The availability of clean and safe drinking water will have a profound impact on curbing the spread of waterborne pathogens and chemical and toxin-induced diseases. This should reduce the healthcare costs and morbidity and mortality associated with preventable diseases, including CKDmfo. All villagers have the right to access to clean water that is free from chemicals and toxins, just as has been provided to those who live in cities and urban areas. In addition, there should be regular testing of water, particularly in the affected areas.
Figure 4: Shown are the multi-pronged approach and the broader network of interconnected strategies needed to prevent and eradicate the occurrence of chronic kidney disease of multi-factorial origin (CKDmfo).
Proactive Actions are Needed
The provision of safe and clean water and sanitation saves more lives than all other medical advances and technologies put together. In addition, prevention costs only a fraction of the cost of the provision of acute medical care. In fact, it is ironic most countries do not allocate adequate resources for preventive health. The average healthcare funds spent for preventive healthcare in Southeast Asian countries is approximately 14% of the total health budget, which is greatly inadequate for disease prevention efforts.
Unhealthy behaviour, anthropogenic pollution, and climatic changes all contribute to human ill health and increase personal, public, and governmental costs. All citizens must take the responsible for minimising pollution and taking proper personal actions to ensure a better future for generations to come. Behavioural studies have taught us that current choices and incentives rule processes and the outcomes, so proper and fact-based education of farmers and consumers, and appropriate incentives are likely to decrease future unwanted issues.
The Importance of Protecting the Environment
In addition to education and environmental protection, it is necessary to provide basic safe amenities (such as access to potable water, safe sanitary facilities and shelter, affordable nutritious food, and basic healthcare) and then let the public decide which path to take. The government’s role should be to act as a referee, not as a player.
Fertiliser overuse because of a massive governmental subsidy program, expanding environmentally unfriendly technologies, unfair distribution of services and inequalities, and interfering politics are all externalities that change the course of the health and well-being of the population and disrupt the peace and prosperity of a country. These not only introduce negative health outcomes but also drive up expenses for individuals and the government. However, some externalities require governmental intervention, such as negotiations for putting together the correct policies, regulatory oversights, distribution of clean water and energy, and enforcement of law and order, etc. When done properly with longterm goals and good intentions, such interventions tremendously benefit society.
Collective evidence suggests that some substances present in the local water source likely is the reason for the genesis of CKDmfo. Therefore, the provision of safe, clean water must be given a high priority. Identification of the cause and mechanisms of renal failure in CKDmfo should be persue in papallel. Sri Lankan farmers uses excess amounts of chemical fertilisers and pesticides . In fact, per hectare of arable land, Sri Lanka is the highest user of chemical fertiliser and pesticides in Southeast Asia , approximately 284 kg of synthetic fertiliser per hectare of arable land, and that usage has increased by three- to four-fold during the past three decades; however, usage has plateaued over the past few years . More is not always better, so attempts must be directed to reducing the excessive use of fertiliser [29,44].
Many of the potential single-cause hypotheses tested was found not to be causative for CKDmfo in Sri Lanka, although they may be associated with the disease. However, multiple nephrotoxins, even at levels lower than those at which individual components can cause renal damage, may cause harm via additive or synergistic effects, especially if the toxins have different modes of actions that cause renal tubular damage [14,73-75]. Such multi-factorial effects have not been studied. With reference to the identification of causative factors, moving directly from the “hypothesis” to the “conclusions,” as has been done recently not only in Sri Lanka but also in other CKDuo-affected countries, including El Salvador and Nicaragua, hinders progress.
Fallacies related to competing to ‘prove’ his or her favourite hypothesis (instead of collaborating and testing it) and equating causality by mere demonstrating of an agent in water are other factors  that preventing scientific progress of identification of real cause(s) and finding practical solutions. Such inferior approaches, bypassing theory, experiments, and unbiased interpretation of data prevent the making of firm and practical conclusions and further delay the identification of the agent(s) causing CKDmfo.
Residents in the NCP who are older than 65 years have a higher incidence of CKD because of glomerular diseases, hypertension and diabetes , but have a lower incidence of renal failure due to tubular disease, CKDmfo [29,31]. This age disparity most likely is attributable to the high death rate associated with CKDmfo; deaths occur when patients are at younger ages. Overall, our data suggest that more than 10 to 15 years of regular exposure to causative agent(s) is necessary to develop CKDmfo. Thus, such exposures should have commenced between 30 and 35 years ago .
The geographical distribution of CKDmfo; having the disease in the absence of diabetes and hypertension; the prevalence of the disease among farming communities; and histopathologic findings of tubular pathology collectively suggest the involvement of hydro- geo-chemistry and environmental exposure to one or more nephrotoxins in the genesis of CKDmfo. “Multi-factorial” as a description of this environmentally acquired disease refers not only to multiple unknown chemicals, but also to potential combinations of multiple known and unknown physical phenomena, behaviours, and biological pathways.
CKDmfo has not been linked to a particular incident, event, habit, organism, or component. However, a combination of some of these factors could precipitate the disease, which is an environmentally acquired, chronic, occupational disease leading to premature death. Although evidence is mounting, the collective data fall short of confirming any agrochemical component as the causative factor for CKDmfo in Sri Lanka. Because origination of this disease likely is attributable to multiple causes, any single-cause, narrowly defined research is unlikely to generate meaningful data for implementing a program that will achieve an effective outcome. Prevention of CKDmfo is the only cure and the only way forward.
The author is grateful for constructive suggestions made in early verions of this mnauscript by Chamandika Warusavitharana, Geethanjalie Selvendran, and Dr. Douglas Olcott. For the past 17years, the author has been studying issues related to water contamination, escalating chronic diseases inlcuding CKDmfo, education and provision of clean water to prevent the propagation of CKD in Sri Lanka.
Conflicts of Interest
The author has no conflicts of interest.
- Writing Groups (1992). Environmental problems and developing countries. Finance Dev 29: 22-23. [Ref.]
- Wimalawansa SA, Wimalawansa SJ (2015) Clean water, healthy environment, and watershed preservation: Correct, enforceable policies are essential. Hydrology (in press)
- Burkart MR (2007) Diffuse pollution from intensive agriculture: sustainability, challenges, and opportunities. Water Sci Technol 55: 17-23 [Ref.]
- Anonymus (1979) Environmental geochemistry and health. Philos Trans R Soc Lond B Biol Sci 288:1-216
- Baumgarten A, Steinnes E, Friesl-Hanl W (2009) This special issue of “Environmental Geochemistry and Health,” compiles the output of the Symposium “Soils and their implication on Health.” Preface. Environ Geochem Health 31: 521-522. [Ref.]
- Mertens TE, Fernando MA, Marshall TF, Kirkwood BR, Cairncross S, et al. (1990) Determinants of water quality, availability and use in Kurunegala, Sri Lanka. Trop Med Parasitol 41: 89-97. [Ref.]
- Sarkar A, Patil S, Hugar LB, vanLoon G (2011) Sustainability of current agriculture practices, community perception, and implications for ecosystem health: an Indian study. EcoHealth 8: 418-431. [Ref.]
- Krauss J, Gallenberger I, Steffan-Dewenter I (2011) Decreased functional diversity and biological pest control in conventional compared to organic crop fields. PLoS One 6: e19502. [Ref.]
- Holt MS (2000) Sources of chemical contaminants and routes into the freshwater environment. Food Chem Toxicol 38: S21-S27. [Ref.]
- Jianguo J, Jun W, Xin X, Wei W, Zhou D, et al. (2004) Heavy metal stabilization in municipal solid waste incineration flyash using heavy metal chelating agents. J Hazard Mater 113: 141-146. [Ref.]
- Susset B, Grathwohl P (2011) Leaching standards for mineral recycling materials--a harmonized regulatory concept for the upcoming German Recycling Decree. Waste Manag 31: 201-214. [Ref.]
- Rathnamalala NK, Nagodavithana KC, Mihirini AT, Lanerolle RD (2011) Patient perceptions of risk factors for chronic kidney disease and methods of delaying progression of the disease in a tertiary care setting in Sri Lanka. Int J Clin Pract 65: 1108. [Ref.]
- Kalantar-Zadeh K, Stenvinkel P, Pillon L, Kopple JD (2003) Inflammation and nutrition in renal insufficiency. Adv Ren Replace Ther 10: 155-169. [Ref.]
- Soderland P, Lovekar S, Weiner DE, Brooks DR, Kaufman JS (2010) Chronic kidney disease associated with environmental toxins and exposures. Adv Chronic Kidney Dis 17: 254-264. [Ref.]
- WHO-CKDu Final Report (2013) WHO Sri Lanka CKDu report: Chronic kidney disease of unknown aetiology (CKDu): a new threat to health.
- WHO-Group, Jayathilaka NMP, Mendis S, Mehta FR, Dissanayake LJ, et al. (2013) Investigation and evaluaiton of chronic kidney disease of uncertain aetiology in Sri Lanka: Final Report. [Ref.]
- Chandrajith R, Dissanayake CB, Tobschall HJ (2005) The abundances of rarer trace elements in paddy (rice) soils of Sri Lanka. Chemosphere 58:1415-1420. [Ref.]
- Chandrajith R, Nanayakkara S, Itai K, Aturaliya TN, Dissanayake CB, et al. (2011) Chronic kidney diseases of uncertain etiology (CKDue) in Sri Lanka: geographic distribution and environmental implications. Environ Geochem Health 33: 267-278. [Ref.]
- Chen W, Krage N, Wu L, Pan G, Khosrivafard M, et al (2008) Arsenic, cadmium, and lead in California cropland soils: role of phosphate and micronutrient fertilizers. J Environ Qual 37: 689-695. [Ref.]
- Dharma-Wardana MW, Amarasiri SL, Dharmawardene N, Panabokke CR (2014) Chronic kidney disease of unknown aetiology and groundwater ionicity: study based on Sri Lanka. Environ Geochem Health 37: 221-231. [Ref.]
- Wimalawansa SJ (2015) Escalating Chronic Kidney Diseases in Sri Lanka: Causes, Solutions and recommendations. Environ health and prev med 19: 375-394. [Ref.]
- Warusavitharana CJ, Wimalawansa SJ (2015) Analysis of costeffective approaches to prevent chronic kidney disease of multifactorial origin (CKDmfo). Submitted to Scand J Work, Environ & Health.
- Athuraliya NT, Abeysekera TD, Amerasinghe PH, Kumarasiri R, Bandara P, et al. (2011). Uncertain etiologies of proteinuric-chronic kidney disease in rural Sri Lanka. Kidney Int 80: 1212-1221. [Ref.]
- Bandara JM, Senevirathna DM, Dasanayake DM, Herath V, Bandara JM, et al. (2008) Chronic renal failure among farm families in cascade irrigation systems in Sri Lanka associated with elevated dietary cadmium levels in rice and freshwater fish (Tilapia). Environ Geochem Health 30: 465-478. [Ref.]
- Wanigasuriya KP, Peiris-John RJ, Wickremasinghe R (2011) hronic kidney disease of unknown aetiology in Sri Lanka: is cadmium a likely cause? BMC Nephrol 12:32. [Ref.]
- Nanayakkara S, Komiya T, Ratnatunga N, Senevirathna ST, Harada KH, et al. (2012) Tubulointerstitial damage as the major pathological lesion in endemic chronic kidney disease among farmers in North Central Province of Sri Lanka. Environ Health Prev Med 17: 213-221. [Ref.]
- Nanayakkara S, Senevirathna ST, Abeysekera T, Chandrajith R, Ratnatunga N, et al. (2014) An integrative study of the genetic, social and environmental determinants of chronic kidney disease characterized by tubulointerstitial damages in the North Central Region of Sri Lanka. J Occup Health 56: 28-38. [Ref.]
- Nagarajah S, Emerson BN, Abeykoon V, Yogalingam S (1988) Water quality of some wells in Jaffna and Kilinochchi with special reference to nitrate pollution. Tropical Agriculturist 144: 61-78. [Ref.]
- Wimalawansa SA, Wimalawansa SJ (2014) Impact of changing agricultural practices on human health: Chronic kidney disease of multi-factorial origin in Sri Lanka. Wudpecker Journal of Agricultural Research 3: 110-124. [Ref.]
- Wimalawansa SJ (2013) Water pollution-associated ill health: Special emphasis on chronic kidney disease in Sri Lanka. Olcott Oration. [Ref.]
- Senevirathna L, Abeysekera T, Nanayakkara S, Chandrajith R, Ratnatunga N, et al. (2012) Risk factors associated with disease progression and mortality in chronic kidney disease of uncertain etiology: a cohort study in Medawachchiya, Sri Lanka. Environ health Prev Med 17: 191-198. [Ref.]
- Bandara JM, Wijewardena HV, Bandara YM, Jayasooriya RG, Rajapaksha H (2011) Pollution of River Mahaweli and farmlands under irrigation by cadmium from agricultural inputs leading to a chronic renal failure epidemic among farmers in NCP, Sri Lanka. Environ Geochem Health 33: 439-453. [Ref.]
- Paez-Osuna F (2001) The environmental impact of shrimp aquaculture: causes, effects, and mitigating alternatives. Environ Manage 28: 131-140. [Ref.]
- Nair PK (2011) Agroforestry systems and environmental quality: introduction. J Environ Qual 40: 784-790. [Ref.]
- Wanigasuriya K (2012) Aetiological factors of chronic kidney disease in the north central province of Sri Lanka: a review of evidence todate. J College Community Physicians Sri Lanka 17: 15-20. [Ref.]
- Wimalawansa SA, Wimalawansa SJ (2014) Protection of watersheds to prevent phosphate eutrophication and consequent environmental health hazards in Sri Lanka. Int J Res Environ Sci 1: 2s, 1-18.
- Dissanayake CB, Chandrajith R (2007) Medical geology in tropical countries with special reference to Sri Lanka. Environ Geochem Health 29: 155-162. [Ref.]
- van der Hoek W, Konradsen F (2005) Risk factors for acute pesticide poisoning in Sri Lanka. Trop Med Int Health 10: 589-596. [Ref.]
- Eddleston M, Rajapakshe M, Roberts D, Reginald K, Rezvi Sheriff MH, et al. (2002) Severe propanil [N-(3,4-dichlorophenyl) propanamide] pesticide self-poisoning. J Toxicol Clin Toxicol 40: 847-854. [Ref.]
- Franz JE, Mao MK, Sikorski JA (1997) Glyphosate: A unique global herbicide, American Chemical Society.
- Mink PJ MJ, Lundin JI, Sceurman BK (2011) Epidemiologic studies of glyphosate and non-cancer health outcomes: a review. Regul Toxicol Pharmacol 61: 172–184. [Ref.]
- Orantes CM, Herrera R, Almaguer M, Brizuela EG, Nunez L, et al. (2014) Epidemiology of chronic kidney disease in adults of Salvadoran agricultural communities. MEDICC Rev 16: 23-30. [Ref.]
- Wimalawansa SJ (2015) The role of ions, heavy metals, and fluoride in chronic kidney disease of multifactorial origin (CKDmfo/CKDuo) in Sri Lanka. Environ Geochem Health.
- Wimalawansa SA, Wimalawansa SJ (2014) Agrochemical-Related Environmental Pollution: Effects on Human Health. Global Journal of Biology, Agriculture and Health Sciences 3: 72-83. [Ref.]
- Pellow DN (2007) Transnational movements for environmental justice. Cambridge, MA: MIT Press
- Orisakwe OE, Njan AA, Afonne OJ, Akumka DD, Orish VN, et al (2004) Investigation into the nephrotoxicity of Nigerian bonny light crude oil in albino rats. Int J Environ Res Public Health 1:106-110. [Ref.]
- Jayasumana C, Gunatilake S, Senanayake P (2014) Glyphosate, hard water and nephrotoxic metals: are they the culprits behind the epidemic of chronic kidney disease of unknown etiology in sri lanka? Int J Environ Res Public Health 11:2125-2147. [Ref.]
- Wimalawansa SJ (2015) Escalating chronic kidney diseases of multi-factorial origin (CKD-mfo) in Sri Lanka: causes, solutions, and recommendations-update and responses. Environ health Prev Med 20:152-157. [Ref.]
- Jayatilake N, Mendis S, Maheepala P, Mehta FR (2013) Chronic kidney disease of uncertain aetiology: prevalence and causative factors in a developing country. BMC Nephrol 14:180. [Ref.]
- Multiple-Authors (2014) Glyphosate does not cause CKDu.
- Jayasumana M, Paranagama P, Amarasinghe M, Wijewardane K, Dahanayake K, et al. (2013) Possible link of chronic arsenic toxicity with chronic kidney disease of unknown etiology in Sri Lanka. J Nat Sci Res 3: 64-73. [Ref.]
- Caetano M, Ramalho T, Botrel D, da Cunha E, de Mello W (2012) Understanding the inactivation process of organophosphorus herbicides: A DFT study of glyphosate metallic complexes with Zn2+, Ca2+, Mg2+, Cu2+, Co3+, Fe3+, Cr3+, and Al3+. Int J Quantum Chem 112: 2752-2762. [Ref.]
- Wunnapuk K, Gobe G, Endre Z, Peake P, Grice JE, et al. (2014) Use of a glyphosate-based herbicide-induced nephrotoxicity model to investigate a panel of kidney injury biomarkers. Toxicol Lett 225:192- 200. [Ref.]
- The National Academies Collection: Reports funded by National Institutes of Health (1997) Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. [Ref.]
- Sachdev DP, Cameotra SS (2013) Biosurfactants in agriculture. Appl Microbiol Biotechnol 97:1005-1016.
- Coroi IG, De Wilde T, Cara MS, Jitareanu G, Steurbaut W (2011) Influence of surfactants on the sorption of two chloroacetanilide in an Romanian chernozem soil. Commun Agric Appl Biol Sci 76: 939-947. [Ref.]
- Brain RA, Solomon KR (2009) Comparison of the hazards posed to amphibians by the glyphosate spray control program versus the chemical and physical activities of coca production in Colombia. J Toxicol Environ Health A 72: 937-948. [Ref.]
- Garry VF, Burroughs B, Tarone R, Kesner JS (1999) Herbicides and adjuvants: an evolving view. Toxicol Ind Health 15:159-167. [Ref.]
- Skutlarek D, Exner M, Farber H (2006) Perfluorinated urfactants in surface and drinking waters. Environ Sci Pollut Res Int 13: 299-307. [Ref.]
- Hossain MP, Goyder EC, Rigby JE, El Nahas M (2009) CKD and poverty: a growing global challenge. Am J Kidney Dis 53:166-74 [Ref.]
- USA-EPA (2008) USEPA Office of Ground Water and Drinking Water Contaminant Candidate List 3 (CCL3). USEPA Office of Ground Water and Drinking Water.
- Bezirtzoglou C, Dekas K, Charvalos E (2011) Climate changes, environment and infection: facts, scenarios and growing awareness from the public health community within Europe. Anaerobe 17: 337-340. [Ref.]
- Schlenk D, Wolford L, Chelius M, Steevens J, Chan KM (1997) Effect of arsenite, arsenate, and the herbicide monosodium methyl arsonate (MSMA) on hepatic metallothionein expression and lipid peroxidation in channel catfish. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 118: 177-183. [Ref.]
- Shimizu M, Hochadel JF, Fulmer BA, Waalkes MP (1998) Effect of glutathione depletion and metallothionein gene expression on arsenic-induced cytotoxicity and c-myc expression in vitro. Toxicol Sci 45: 204-211. [Ref.]
- Topcu S, Incecik S, Unal YS (2003) The influence of meteorological conditions and stringent emission control on high TSP episodes in Istanbul. Environ Sci Pollut Res Int 10: 24-32. [Ref.]
- Zejda JE, McDuffie HH, Dosman JA (1993) Epidemiology of health and safety risks in agriculture and related industries. Practical applications for rural physicians. West J Med 158: 56-63. [Ref.]
- Damalas CA, Eleftherohorinos IG (2011) Pesticide exposure, safety issues, and risk assessment indicators. Int J Environ Res Public Health 8: 1402-1419.
- Company R, Serafim A, Lopes B, Cravo A, Shepherd TJ, et al. (2008) Using biochemical and isotope geochemistry to understand the environmental and public health implications of lead pollution in the lower Guadiana River, Iberia: a freshwater bivalve study. Sci Total Environ 405: 109-119. [Ref.]
- Divasta AD, Feldman HA, Brown JN, Giancaterino C, Gordon CM, Holick MF (2011) Bioavailability of vitamin D in malnourished adolescents with anorexia nervosa. J Clin Endocrinol Metab 96: 2575- 2580. [Ref.]
- Mejía R, Edgar Quinteros, E, López, A, Ribó, A, Cedillos, H, et al. (2014) Pesticide-handling practices in agriculture in El Salvador: An example from 42 patient farmers with chronic kidney disease in the Bajo Lempa region. Occupational Diseases and Environmental Medicine 2: 56-70. [Ref.]
- Wimalawansa SJ (2013) Purification of contaminated water with reverse osmosis: Effective solution of providing clean water for human needs in developing countries. Journal of Emerging Technology and Advanced Engineering 3: 75-89. [Ref.]
- WorldBank (2013) Fertilizer consumption (kilograms per hectare of arable land). [Ref.]
- Sabolic I (2006) Common mechanisms in nephropathy induced by toxic metals. Nephron Physiol 104: 107-114. [Ref.]
- Sabath E, Robles-Osorio ML (2012) Renal health and the environment: heavy metal nephrotoxicity. Nefrologia 32: 279-286. [Ref.]
- de Burbure C, Buchet JP, Leroyer A, Nisse C, Haguenoer JM, et al. (2006) Renal and neurologic effects of cadmium, lead, mercury, and arsenic in children: evidence of early effects and multiple interactions at environmental exposure levels. Environ Health Perspect 114: 584- 590. [Ref.]
- Jayasumana C, Gunatilake S, Siribaddana S (2015) Simultaneous exposure to multiple heavy metals and glyphosate may contribute to Sri Lankan agricultural nephropathy. BMC Nephrol 16:103. [Ref.]
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Citation: Wimalawansa SJ (2015) Agrochemicals and Chronic Kidney Disease of Multi-Factorial Origin: Environmentally Induced Occupational Exposure An Occupational Exposure Disease. Int J Nephrol Kidney Failure 1(3): doi http://dx.doi.org/10.16966/2380-5498.111
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