Risk Factors Associated with Chronic Kidney Disease of Unknown Origin (Ckdu) in North Central Province (NCP) of Sri Lanka: An Analysis of Evidence to Date

and are credited. Abstract Chronic kidney disease of unknown origin (CKDu) is a global burden among the agricultural communities, this is a non-communicable disease (NCD) which is asymptomatic and irreversible until latter stages of the disease. The disease has no common features unlike chronic kidney diseases (CKD’s) making early detection impossible in the patients. The most recent form of CKDu was reported in India, known as the Indian CKDu in late 2010’s. In Sri Lanka, CKDu is highly prevalent in the north central province of the country with nearly15.1%-22.9% presented with the disease. This region is a dry-zone in which agricultural and farming activities are carried out as the main occupation. Several studies have been carried out linking CKDu to various factors such as heavy metals in water, agrochemicals, heat, dehydration and socio-demographics in NCP. Despite several researches being conducted none of them were able to prove the root cause and causative factors of the disease. Using the available articles online, studies from countries such as India, Nicaragua, Sri Lanka and South America were chosen in which heat stress, dehydration, heavy metal involvement, agrochemicals were common causative factors reported in these geographical locations. Several studies analyzed indicate that the affected CKDu population were part of the agricultural community in rural areas with less or no proper high school education and family history with CKDu. Recent findings do suggest that a combination study involving socio-demographical data and geographical data will help to end the CKDu debate worldwide and provide new insights into early diagnosis.


Socio-demographical Factors
The region has agriculture as the main occupation, hence more male workers are heavily involved than the females. The working age group in the region lies around second decade and upwards in general with a minimum of 6-8 hours of paddy harvesting and ploughing taking place during the seasonal period. Impact of agrochemicals on CKDu Agrochemicals are widely used in most South Asian countries to provide a better yield in crop production, Sri Lanka also uses different forms of these such as pesticides, herbicides, insecticides and fertilizers commonly. The dry zone of Sri Lanka uses agrochemicals in high yields, where a study conducted by [8], the efficiency of cost-usage ratio was 0.37 in this region indicating an overuse of agrochemicals. In Sri Lanka, fertilizers are subsidized at high levels making it available for a cheaper rate for many farmers to use higher than recommended amounts. Due to this excessive usage of agrochemicals, the water cycle and the food chain patterns in the region also undergo changes [9,10].
Most farmers lack education and training to create awareness about the use of agrochemicals, this results in majority of them being directly exposed to the chemicals without any protection. Studies conducted previously has shown agrochemicals can enter the body through nails and hairs leading to skin diseases and cause damage to various organs in the body due to high metal content [11].
Excessive agrochemicals get washed away from the soil leading to excessive nutrients available for micro-organisms such as algae, bacteria and fungi to grow and incorporate themselves on the crops which can directly affect the food cycle chain of humans. Lack of water available in the region leads to farmers relying on well and spring water sources for consumption, the agrochemicals washed away from the soil can leech into the waterway pathways leading to groundwater consumption being contaminated. Phosphorus is identified as one of the key elements that causes "eutrophication" of the water quality and increases the risk of water drying out in the region [12].Nitrogen is another element that harms the ecosystem, excessive nitrogen can lead to over stimulation of aquatic plants and algae formation which competes for oxygen with other organisms. Several studies have shown that many fish species are contaminated with high heavy metal content and unable to be consumed by the residents of the NCP, with increasing damage to the ecosystem the quantity of fish present in the region will begin to reach its extinction with time [13]. Excessive nitrogen can also cause increase in pollutants present in the region; ammonia is one of the greenhouse gases formed due to excessive nitrogen present and this decreases the air quality leading to problems such as asthma and respiratory tract infections [14].
Potassium is the most important element needed for plant growth, where it allows movement of nutrients and water into the plants and needed for ATP production to regulate photosynthesis. Lack of potassium can lead to plant defects being visible and also can affect the growth of the plant, most farmers use "potash" a type of potassium fertilizer that is expensive and needed as an essential component during harvesting. As the subsidies are lowered in South Asian countries, the potassium fertilizers are used excessively causing draining of potassium into groundwater.
This could lead to hyperkalemia, which is a common condition presented among CKD individuals and lead to kidney dysfunction with time [15].
A combination of three essential elements can lead to long-term harm to the ecosystem, environment and human health, the impact of agrochemicals could be a probable cause of CKDu which has not been proven yet.
Heavy metals involvement in CKDu Several heavy metals have been linked to be causative agents for CKDu, these heavy metals are present as constituents and waste products of the agrochemicals. Arsenic is one of main heavymetals present in triple super phosphate (TSP) which is a common fertilizer used by farmers for the cultivation of rice. As stated by Rawat [16] nearly 2100kg of arsenic is imported yearly in the form of TSP fertilizers.
Despite the fact that the WHO considered pesticides containing arsenic as hazardous many farmers still continue to use them as they are unaware of the harm caused by these heavy metals [17].
Chronic arsenic toxicity (CAT) is a common feature presented among CKDu affected patients, where long term exposure can lead to cancer and impacts cognitive development in young adults. Arsenic contaminated ground water and food can lead to ingestion of these carcinogenic particles that can lead to long term effects as kidneys acts as the organs that helps to remove the waste products from the body. This can lead to long term irreversible damage caused to the kidneys leading to fibrosis and increased proteinuria levels in the patients' blood leading to nephrotoxin build up inside the body [18].
Cadmium is another heavy metal that is present in phosphorous fertilizers which is a carcinogenic compound for human health. Several countries have banned fertilizers containing cadmium due to the direct impact it has on the kidneys.
European Union passed a bill to limit the use of cadmium containing fertilizers as its adverse effects were causing increased reported incidents of kidney and respiratory system failures due to cadmium exposure [19]. Renal tubular dysfunction and increased creatinine levels in blood and urine are the main features observed in individuals with increased cadmium exposure. This is proven in the NCP of Sri Lanka, where excessive amount of cadmium was presented in ingested food and water which could probably be one of the causes of CKDu in these individuals [20,21]. Rice being the staple food consumed by the residents of the NCP and the cadmium levels found in rice in this region is well above the international limits set by the WHO indicating the excessive usage of agrochemicals in the region. Facts and theories states cadmium has a major impact like arsenic on the kidneys, but till date there has been no evidence that link cadmium to be the direct causative agent of SL-CKDu unlike in "Itai-itai disease"

[22].
Glyphosate is another widely used herbicide which has been identified as one of the probable causative factors of CKDu. Exposure to glyphosate in minimal amounts has no or less impact on the body organs or immune system, whereas excessive exposure could lead to severe complications such as DNA damage in exposed individuals. Glyphosate unlike arsenic and cadmium shows minimum levels of the heavy metal presence in the blood or urine and makes slow cellular damage inside the body. Regardless of the fact the WHO deemed glyphosate as "probably carcinogenic", the damage caused by the heavy metal can significantly impact the growth and metabolism in individuals when exposed for a long period Arsenic and cadmium are released into the environment by the phosphorous fertilizers and glyphosate is released through herbicides added for the harvesting process. Three of these heavy metals are released from the use of agrochemicals and play a significant part in proliferating damage to the kidneys. The chief contributing causative agent might be unknown, nonetheless the effect of heavy metals on kidneys can be understood. Water contamination as a source of CKDu outbreak Due to the cumulative accumulation of agrochemicals in the region the overall groundwater quality has impacted the overall quality of water. Ions such as