The issue of chronic kidney disease of unknown etiology (CKDu) dominates the research arena as well as the media; and has raised the specter of determining the causal factor(s) that contribute to its development. There is evidence to support the notion that the majority of the patients diagnosed with CKDu are farmers, and arguments have been presented to suggest the possibility of water resources being the main contributor to the development of the disease. Thus IWMI became interested in exploring these linkages with the chronic kidney disease that is prevalent in some parts of Sri Lanka, especially in the North Central Province. What we know about the disease: • CKDu patients are characterized by non-conformation/association to the known risk factors such as diabetes, hypertension or chronic glomerulonephritis. The onset of the disease appears to be asymptomatic, and by the time the patient seeks treatment the kidneys have reached a stage of irreversible damage -- end stage renal disease (ESRD). • Over the past 12 years numerous studies have been undertaken by a range of institutions in relation to the problem and, as a result, a body of research has been established. They range from hospital cohort and community level studies; water resource studies; assessments of food sources; and studies into possible genetic linkages. Several of these studies have been published in peer-reviewed journals along with a substantial quantity of material in 'grey literature'. • The disease is predominantly confined to male farmers in the North Central Province (NCP) of Sri Lanka, who are over the age of 40. Patients are predominantly subsistence farmers and/or agricultural laborers. The ratio of male to females affected by the disease ranges from 3:1 to 2.4:1. There is evidence to suggest that the age of patients diagnosed with the disease is gradually lowering (with community screening); suggesting it is occurring even among younger cohorts of the population as well. • According to current estimates, CKDu appears to be 3-4 times higher in the NCP than that of most other provinces, except the NP. As early as 2002, three times the national average of CKD patients were found in the NCP. It is not clear whether the progressive increase in patients being diagnosed with CKDu with time is due to increased awareness of the disease, improved diagnostic techniques or to an increase in patients manifesting signs of Coda. • The occurrence of the CKDu has been reported from outside Sri Lanka as well, including India and Central America. A hypothesis that has been put forward as to why the multitude of farmers is predisposed to the disease, is that they undertake strenuous labor under hot climatic conditions that may lead to chronic dehydration and greater/lesser consumption of water. The literature indicates that under these conditions the disease could occur due to an inadequate intake of water that places stress on the kidneys; or people drinking greater amounts of water that may contain the causal agent(s) that affect the kidneys. This would suggest that water and its constituents may in part play a role in the etiology of the disease, a view that is held by several parties investigating this problem in Sri Lanka who we have contacted. • There is very little supporting evidence to infer aflotoxin contamination as a significant causal factor responsible for the development of the disease in Sri Lanka. • Arsenic (As) has been implicated, however, all but one of the materials reviewed were in the category of non-peer reviewed publications hence, making it difficult to verify the veracity of these assertions. While elevated levels of (As) are reported to have been measured in groundwater samples collected by groups working on the issue, the strongest endorsement that (As) is not viewed as a candidate for the development of the disease comes from the World Health Organization (WHO). In their study of groundwater samples collected from the areas identified as hotspots for CKDu, arsenic (As) levels were found to be 'normal'. However, a recently published article has implicated (As), and offers heavy metals in conjunction with water quality (hardness of water) as causal factors in the development of the disease. The agro-chemicals that are routinely used in rice production systems have been identified as the source of (As). Since (As) being associated with agro-chemicals has been suggested as the possible source, it is difficult to reconcile why the disease does not afflict all rice growing areas of Sri Lanka, where these chemicals are routinely used in the rice production systems. • Cadmium (Cd) has been implicated as a causal factor contributing to the disease, and the source of contamination being identified as triple super phosphate (TSP). Elevated levels of Cd were reported in waters from the reservoirs within the Mahaweli diversion scheme, soils, and in a range of foods commonly consumed by rural communities. Cadmium levels measured in soils and rice samples by one of the groups appeared to be elevated, although they were not as high as those measured in Thailand, where known Cd-related kidney disease had been identified. Further studies have questioned the veracity of these results. It is difficult to reconcile the role of Cd in the disease, as TSP use is widespread throughout the agricultural sector in Sri Lanka and elsewhere. One would, therefore, expect to find the incidence of the disease more common throughout Sri Lanka, which is not the case. Hence, it is unlikely that Cd plays a significant role in the development of the disease. • Toxicity associated with the formation of aluminum (Al) fluoride by the reaction between fluorides in water with the aluminum found in low-quality utensils, which are in wide use in these areas has been suggested as a possible causal factor. Although the usage of lowquality aluminum utensils has been discouraged by the government in CKDu endemic areas, it is not clear whether there is any clinical evidence to support this hypothesis. • What does appear as a potential causal factor in the development of the disease is, the fluoride (F) in the groundwater and its interaction with other ionic constituents that are present namely, Ca, Na and possibly Mg. There is evidence to suggest that the disease is confined to areas where high levels of F are present in the groundwater, and that it is not the concentration of F per se, but rather the interaction of F with constituent ions in the solution. • There is a growing body of knowledge that would suggest a genetic link to the problem that predisposes certain individuals to the disease. We are aware that a peer-reviewed article is currently being prepared that supports this hypothesis. There is evidence to suggest that water quality plays a role in the development of the disease. In discussions with our colleagues in the Water Board, it was revealed that in villages where there was a high incidence of the disease, the provision of safe drinking water has reversed that situation. However, this has not been verified through controlled studies, but does offer insights into the possible role of water in the development of the disease. This review was undertaken in response to growing concerns over the occurrence of chronic kidney disease of unknown etiology (CKDu) in Sri Lanka, and the potential role that agriculture and water resources may play as causal factors in the development of the disease. The content describes a review of current published information on CKDu in Sri Lanka; an assessment and commentary on potential environmentally-induced causal factors that have been implicated in the development of the disease, and identifies the gaps in research and recommends potential areas of research where IWMI could contribute to addressing the current impasse. © 2012, by IWMI.
