Chronic Kidney Disease of Uncertain Origin in the Dry Zone (CKDu)



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By Ranjit Mullriyawa


My interest in the above subject stems from association with the dry zone and dry zone farmers for more than thirty years – as a farmer myself personally operating a small farm in the Mahiyangana area for ten years(1969-78), and subsequently, as a researcher in the Dept. of Agriculture, and NGO activist spotlighting problems of dry zone farmers. I have read with considerable interest many articles pertaining to CKDu appearing in the local press as well as those appearing ‘on line’. I have also interviewed some of the principal researchers and proponents of key hypotheses pertaining to CKDu. This article attempts to summarize current information/knowledge gleaned from these sources as well as discuss the pros and cons of various theories advanced by our scientists with an open mind. Its main purpose is to inform the general public about a major health problem afflicting farming communities in the dry zone- Sri Lanka’s ‘rice bowl’.


Symptoms of the disease


Clinical symptoms of CKDu are: Fatigue, panting, lack of appetite, nausea, anemia and swelling of feet and face( towards the later stages). The disease is said to be ‘chronic’ because it takes many years for symptoms to develop.


A significant observation with respect to CKDu is that some patients afflicted with the disease do not manifest any abnormal symptoms until their kidneys have been seriously damaged. The following case history narrated by Dr. Lishanthe Gunarathne, Medical Officer in Charge of the Renal Unit at Girandurukotte Hospital clearly illustrates this point : "A 36 year old unmarried male patient came to me recently with a history of headache for five days. He appeared quite healthy. However a blood test revealed serious kidney damage – his GFR (Glomerular Filtration Rate) was 2ml/min/1.73 m2.( In a normal healthy adult,GFR is over 90) I helped him obtain immediate treatment at the nephrology unit of Kandy Hospital, but I heard that he had died after a few weeks."


Kidney damage caused by diabetes and hypertension manifests similar clinical symptoms, but CKDu patients have not had a prior history of diabetes, hyper tension or urinary tract infection. Post mortem studies of kidneys (histo-pathological studies) of CKDu patients reveals damage to urinary ‘tubules’, where as diabetes and hypertension induced kidney damage is said to mainly affect blood vessels. Damage to urinary tubules is frequently associated with nephro toxins (toxic to the kidneys).


What exactly causes CKDu is still unknown. It is therefore referred to as Chronic kidney disease of unknown ‘etiology’ (cause).


History and Geographical Distribution


An ‘Assistant Government Agent’ (AGA) working in Padaviya (North Central Province) around 1990 -92, was alarmed by many mysterious deaths occurring in his area, and accordingly, drew the attention of doctors at Anuradhapura hospital to this problem. However, credit for the first detection and diagnosis of CKDu is due to Dr. Thilak Abeysekere, a Nephrologist attached to Anuradhapura hospital in early 2000-2002.


A few years later, the disease was also reported from villages in Medirigiriya in Polonnaruwa district. All the above areas fall within the North Central Province (NCP). As such, many persons began to refer to the disease as CKDu in the NCP. Still later, The same disease was also observed to occur among farmers in Girandurukotte and Mahiyangana (Uva Province) and Dehiattakandiya (Eastern Province). Recently (2007) Nikawewa, (in the North-Western Province) also began to report cases of CKDu. All the above areas fall within the ‘dry zone’ of Sri Lanka. It would therefore seem more appropriate to refer to the problem as CKDu in the dry zone.


Area Province CKDu Detected


Madawachchiya NCP 1990


Padaviya NCP 1992


Girandurukote Uva 1998


Medirigiriya NCP 2002


Nikawewa NWP 2007


Common features of affected villages(endemic areas) and CKDu patients


- These villages tend to be clustered around dry zone tanks and irrigation canals.


- Population mainly engaged in farming (rice/paddy farmers)


- Low socio-economic status appears to be a distinguishing feature of many CKDu patients.


- Disease begins to appear in older people. Most affected age group -55-60yrs.


- More men than women affected by disease. Men out number women by a factor of 2.5


- Alcohol consumption (illicit brew-"kassipu") high among men.


- Increased number of CKDu cases reported during land preparation for paddy cultivation.


- People obtain drinking water mainly from open(dug)wells. This water tends to have a high content of fluoride(2-5 parts per million – ppm). ‘Hardness’ ( due to dissolved Calcium and Magnesium salts) also appears to be a common characteristic of such water.


Magnitude and gravity of the problem


Exact number of people affected by CKDu is not known. However, it is believed that over 8000 people are currently undergoing treatment in different parts of the country. At Girandurukotte hospital alone about 2600 patients are undergoing treatment at present.


A recent WHO investigation estimates prevalence of the disease at 15.3 % of the population in endemic areas (North-central region of the country).


CKDu is a serious problem because there is very little hope for people suffering from the disease. By the time clinical symptoms begin to appear, the kidneys have already been seriously damaged. Only a kidney transplant will enable such people to lead a relatively normal life. Frequent dialysis (once every three days) may help prolong life up to a point, but this is troublesome and expensive - a single round of dialysis costs the government approximately Rs. 7,000 at present and the increasing number of CKDu patients exerts a severe strain on government resources.


The social dimension of CKDu, and its impact on poverty stricken dry zone farming communities has not received the attention that it deserves. The illness has a direct impact on patients’ daily life including livelihood activities, domestic tasks, consumption patterns and their participation in social activities at community level. As the disease advances, patients become too ill to continue in gainful employment, and, as the most vulnerable individuals tend to be middle-aged men, many families are deprived of their principal ‘bread winner’. Medical expenses- frequent lab tests at private clinics, and transport to and fro from ‘renal clinics’ at government hospitals, creates further strain on family budgets. Families affected by CKDu are pathetic – driven to despair and impoverishment. In some families more than one person may be affected by the disease. Besides free treatment at government hospitals, the only assistance provided to patients by the State at present is a meager 500-1000 rupees per month (depending on severity of the disease).


Many Questions – Few Convincing Answers


The following questions need to be answered in discussing this subject:


=What is/are the nephro-toxic substance/s?


=How does the toxic substance enter the human body?


=Why is the disease confined to the ‘dry zone’ and farmers?


=Some dry zone areas (eg. Dambulla, Ampara, Moneragala, Udawalawe and Hambantota) do not seem to be affected by the disease. Why?


=CKDu has emerged as a major health problem only during the past 20-25 years. Why?


=Why does the incidence of CKDu increase with age –older people (55-60yrs most affected )


=Why does the disease affect more men than women?


Entry of Toxic Substances


Toxic substances (toxins) can enter the body through food, drinking water, air, or skin contact. However, the specific toxic substance/s causing CKDu is still unknown although it is widely believed that drinking water and the food chain may be the main mode of entry of toxins into the body.


Few Convincing Answers


Fluoride Hypothesis -2004


Professor Oliver Illeperuma, (Dept. of Chemistry, University of Peradeniya) and his research team consisting of Geologists and Chemists, attributed CKDu to high Fluoride content (2-5 parts per million) in drinking water and the use of low quality aluminum utensils for cooking and storing water. They observed a close positive correlation between Fluoride content in ground water (well water) and distribution of CKDu patients. The WHO permissible limit for Fluoride in drinking water is said to be 0.6 ppm.


Fluoride in water was believed to react with Aluminum in utensils (cooking utensils and Aluminum pots used for water storage) forming aluminum-fluoro complexes which enhances the entry of fluoride into the human body. High fluoride content has been shown to result in kidney damage in rats. However, the nephro-toxic effects of fluoride in humans does not seem to have been firmly established as yet.


If fluoride is indeed the main "culprit" responsible for CKDu, why has CKDu not been detected in other areas (Moneragala, Ampara and Hambantota) having even higher levels of fluoride in ground water? Illeperuma’s contention is that people in these areas prefer to drink water from irrigation canals since well water tends to manifest high salinity. "Canal water has less fluoride and salt".


Heavy Metals (Cadmium and Arsenic)


Other researchers- Bandara, Indrajith, Nalin de Silva and Jayasumana et.al. began to focus their attention on proven nephro-toxins such as Cadmium and Arsenic.


Bandara et. al. from Peradeniya University(2008), reported high levels(3-6 ppm) of dissolved Cadmium (Cd) in water samples collected from five reservoirs in CKDu endemic areas. This finding was contradicted by another group of scientists (Chandrajith et. al.) in 2011. Analysing water samples from the same reservoirs, these scientists claimed that Cd levels were much lower than what was reported by Bandara and his researchers. Chandrajith’s team also analysed well water in CKDu endemic areas and concluded that Cd levels were within normal levels specified by WHO.


Arsenic scare


A group of scientists lead by Professor Nalin de Silva from Kelaniya University and Dr. Jayasumana, attached to Rajarata University (medical faculty), were the first to report Arsenic (As) as the main cause of CKDu. Their contention is that As in drinking water reacts with Calcium in the same water (hard water-a common feature in the dry zone) forming Calcium arsenate. When people drink this water, the As in Calcium arsenate causes kidney damage. Arsenic is a well known nephro toxin. Pesticides and fertilizers used by farmers were believed to be the main source of As contamination.


The above researchers also claimed that rice and vegetables consumed by farmers in CKDu endemic areas contained high levels of Arsenic. They reported that As content in drinking water was 2-10 times (20-200 parts per billion-ppb) the WHO permissible standard (10ppb).


Significantly, no other researcher or research group has been able to confirm, or replicate the results arrived at by the Kelaniya and Rajarata scientists. Even the high powered WHO investigation which analyzed 118 water samples from CKDu endemic areas in Anuradhapura, Polonnaruwa and Badulla districts did not find raised Arsenic values above WHO standard.


Arsenic and Cadmium in food chain


The WHO study tested a wide variety of food (rice, vegetables, locally grown pulses, fresh water fish etc.) for Cadmium, and Arsenic. Cadmium levels in rice, in both CKDu endemic and non endemic areas were found to be less than the maximum permissible limit. They found only three items (viz. Lotus rhizomes, Tobacco and Tilapia fish) that contained Cd levels above the maximum permissible level. No mention is made of the Arsenic content in food.


The Department of Agriculture tested 28 rice samples from CKDu endemic areas, and detected As content of any significance only in three samples.


In the light of the above findings, fears of Arsenic poisoning through drinking water and locally grown food would seem to be unwarranted, and the role of Arsenic as a causative factor of CKDu would appear to be speculative.


Algal Toxins


A unique feature of Sri Lanka’s ‘dry zone’, is the presence of a large number of man made reservoirs (‘tanks’). These water bodies have been subjected to considerable eutrophication (nutrient enrichment) resulting from intensification of agriculture (excessive fertilizer use – phosphate fertilizers in particular) and poor water management practices in recent years. Eutrophication has promoted the rapid growth of blue-green algae ( Cyanobacteria) which are known to produce toxic substances (algal toxins or ’). Researchers at Peradeniya University(medical faculty), and the Institute of Fundamental Studies, Hantana, Kandy have identified several species of toxin producing cyanobacteria from these dry zone tanks and wells providing drinking water. Cyanotoxins can not be destroyed/inactivated by boiling water. They are also water soluble, and can easily enter the ground water table and contaminate drinking water sources (wells). Many farmers bathe in dry zone tanks, while some even drink water from ’. These observations have raised the possibility of cyanotoxins playing a role in the development of CKDu. Cyanotoxins can enter the body through oral and skin contact. However, research on this subject is still in its early stages, and lack of adequate funding is a major impediment encountered by both research groups at present.


Genetic Factors


Some families affected by CKDu have been observed to contain several family members manifesting symptoms of the same disease, while their immediate neighbours appear to be healthy. This observation has raised the possibility of a genetic aetiology to the disease.


 


W.H.O. Investigation


In 2010 the Sri Lanka government (GOSL) sought the assistance of the World Health Organisation(WHO) in investigating the CKDu problem. It requested WHO to "coordinate a multi-sectoral multidisciplinary research effort which built upon existing information." This study was expected to generate conclusive evidence within a specified time frame (2 years) to make prevention of CKDu an option. Total budget for the study was estimated at 100 million rupees – 70 million rupees provided by GOSL through the National Science Foundation, and 30 million as WHO contribution.


In December, 2012, WHO released its report titled : ‘Investigation and Evaluation of Chronic Kidney Disease of Uncertain Aetiology in Sri Lanka. Final Report. December 31st 2012’.


Significant Findings of WHO Investigation


1. Population prevalence study of endemic areas (Norh Central Region – including NCP, NWP and Girandurukotte in Uva province) indicated 15.3 % of the people to be affected by CKDu.


2. "Being male reduced the risk of CKDu". This contradicted an earlier report (WHO country newsletter, Dec.2009) which stated that 72% male and 28 % females were affected by CKDu).


3. Cadmium(Cd) content in urine of CKDu patients was more than that of healthy adults from the same location (endemic area). "These results indicate a higher exposure of people in the endemic area to Cd".


"Chronic exposure to low levels of Cadmium(Cd) may be playing a role in the causation of CKDu".


4. Cadmium(Cd) content in all drinking water samples analyzed was within normal limits.


5. Analysis for Cd in a variety of food items ( rice, locally grown pulses, leafy vegetables, lotus rhizomes, tobacco, betel leaf and fresh water fish-‘Tilapia’ and ‘Lula’) collected from households of 606 CKDu patients, revealed that only Lotus rhizomes,Tobacco and Tilapia fish had any significant Cd content.


6. The same food samples were also analysed for Arsenic, but the report makes no mention of their Arsenic content.


7. Arsenic content in drinking water was within normal limits specified by WHO (10 parts per billion).


"Drinking water is unlikely to be the source of Arsenic and Cadmium exposure", concluded the WHO report.


8. Concentration of Arsenic (As) in the urine of CKDu patients was less than that excreted by healthy adults in the same (endemic) area.


9. Arsenic levels in the hair of CKDu subjects was significantly higher than in healthy subjects from the same (endemic) area, but there was no significant difference in As concentration in nails of CKDu subjects compared to controls.


10. "Pesticide residues were detected in the urine of people with CKDu as well as those in the control area." Where was the control area?


"One or more pesticide residues were above reference levels in 31.6 % of people with CKDu". The herbicide 2,4- D is mentioned as one of the pesticides detected in urine analysis of CKDu patients, but 2,4-D has not been in use in Sri Lanka for over ten years!


Propanil – a herbicide widely used by rice farmers, is claimed to be nephro toxic. But this is challenged by local researchers (Dhammika Menike et. al.) who state that Propanil is not a nephrotoxin.


Likewise, the insecticide chloropyrifos is referred to as a nephrotoxin in the WHO report, but it is believed to be a neurotoxin (Pesticide Action Network)


The contention that Cd contained in lotus rhizomes and Tilapia fish is a likely cause of CKDu does not seem very convincing.


Surely, dry zone farmers are no mere lotus eaters and Tilapia consumers! Fish caught in dry zone tanks, and lotus rhizomes also find their way to urban markets such as Anuradhapura . Why don’t urban consumers (in Anuradhapura town )suffer from CKDu (if Cadmium is causing the disease)? There are no convincing answers.


As the end product of a hundred million rupee investment in research, the ‘WHO final report’ is disappointing. It is inconclusive, lacks clarity, has many contradictions, and the presentation of data and discussion do not meet the high standards that one would expect from a reputed International organization such as WHO.


Summing Up


Despite over a decade of research involving scientists (local and foreign), the exact cause of CKDu is still unknown. However, available evidence would strongly suggest that CKDu is probably multifactorial involving one or more environmental factors and a possible genetic predisposition in vulnerable populations. Occurrence of the disease only among dry zone farmers, would seem to indicate a link to the lifestyle of these farmers. Could the hot dry zone climate and long hours of work (often exceeding ten hours a day) in the field by farmers, and consequent dehydration, be a predisposing factor to kidney damage? It has been observed that traders and rural elites who cultivate rice fields using hired labour, do not suffer from CKDu despite drinking the same water and eating virtually the same food. Detection of more CKDu patients during land preparation prior to sowing rice (an extremely stressful period for farmers), observed by Dr.Dhammika Menike and her researchers, may seem to further confirm the role of stressful physical work as a possible predisposing factor leading to dehydration resulting in the kidneys becoming more susceptible to damage by nephrotoxins.


Indiscriminate pesticide use and careless application of pesticides by farmers is a well known problem that has not been effectively addressed by agricultural extension workers. This matter needs to be urgently addressed by the Dept.of Agriculture.


Widespread alcoholism evident among male farmers may be yet another predisposing factor to kidney damage.


Application of pesticides is essentially a task performed by males; male workers tend to carry out most of the heavy work out in the rice paddies, and alcoholism is predominantly a male entertainment. These three factors may explain why more men than women farmers tend to be afflicted by CKDu. (All local researchers confirm that more men tend to be affected by CKDu than women – men out number women by a factor of two or more. (Only the WHO final report contradicts this observation.)


A significant positive outcome resulting from widespread media publicity to toxic effects of pesticides and excessive application of inorganic fertilizers, has resulted in heightened awareness and recognition of the urgent need to strengthen regulatory mechanisms pertaining to the import and distribution of agro-chemicals (pesticides and fertilizers).


* The writer wishes to thank the following persons for their technical input- discussing and sharing the results of their research and experience with him:


Dr.Lishantha Gunaratne, Medical Officer In Charge, Renal Unit, D.H. Girandurukotte ; Prof.Oliver Illeperuma, Head, Dept.of Chemistry, University of Peradeniya; Prof. Ananda Kulasooriya, Emeritus Prof. Botany, University of Peradeniya ; Dr.Dhammika Magana-Arachchi, Research Fellow, Institute of Fundamental Studies, Hantana, Kandy; Prof.Dhammika Menike, Prof. in Haematology, Faculty of Medicine, Uni. Of Peradeniya ; Mr. J.P.Padmasiri, Senior Chemist (Retired) National Water Supply and Drainage Board and Visiting Scientist, IFS, Hantana; and Dr. Anura Wijesekara, Registrar of Pesticides.


* The writer may be contacted at the following e-mail address : rangoviya2013@gmail.com


 
 
 
 
 
 
 
 
 
 
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