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Chronic kidney disease of unknown aetiology in Sri Lanka: is cadmium a likely cause?

Chronic kidney disease of unknown aetiology in Sri Lanka: is cadmium a likely cause? Background: The rising prevalence of chronic kidney disease (CKD) and subsequent end stage renal failure necessitating renal replacement therapy has profound consequences for affected individuals and health care resources. This community based study was conducted to identify potential predictors of microalbuminuria in a randomly selected sample of adults from the North Central Province (NCP) of Sri Lanka, where the burden of CKD is pronounced and the underlying cause still unknown. Methods: Exposures to possible risk factors were determined in randomly recruited subjects (425 females and 461 males) from selected areas of the NCP of Sri Lanka using an interviewer administered questionnaire. Sulphosalicylic acid and the Light Dependent Resister microalbumin gel filtration method was used for initial screening for microalbuminuria and reconfirmed by the Micral strip test. Results: Microalbumnuria was detected in 6.1% of the females and 8.5% of the males. Smoking (p < 0.001), alcohol use (p = 0.003), hypertension (p < 0.001), diabetes (p < 0.001), urinary tract infection (UTI) (p = 0.034) and consumption of water from wells in the fields (p = 0.025) were associated with microalbuminuria. In the binary logistic regression analysis, hypertension, diabetes mellitus, UTI, drinking well water in the fields, smoking and pesticide spraying were found to be significant predictors of microalbuminuria. Conclusions: Hypertension, diabetes mellitus, UTI, and smoking are known risk factors for microalbuminuria. The association between microalbuminuria and consumption of well water suggests an environmental aetiology to CKD in NCP. The causative agent is yet to be identified. Investigations for cadmium as a potential causative agent needs to be initiated. Keywords: Chronic kidney disease, aetiology, cadmium Background culture, NCP has been a fertile ground for infectious There is an increasing trend in mortality and morbidity diseases such as malaria and Japanese encephalitis in the due to chronic kidney disease (CKD) in Sri Lanka. past. CKD is a major health problem in the province at Although epidemiological data are lacking at present, present. this burden is even more pronounced in the North Cen- There may be unrecognized environmental toxins or tral Province (NCP) of Sri Lanka where the underlying occupational exposures giving rise to CKD in the region, cause of CKD remains unrecognized [1]. but this remains unproven. Chronic kidney disease of The NCP was the seat of Sri Lanka’s ancient king- uncertain aetiology (CKDu) in this region mainly affects doms and the centre of civilization and Buddhism. The males from poor socio-economic backgrounds who are province extends over 10 530 m in the dry zone of the involved in paddy farming raising the possibility of agro- country and has a sophisticated irrigation system of chemical exposure as a cause for CKDu. Renal biopsy water storage reservoirs. Despite its unique history and studies revealing a tubulo-interstitial nephritis with minimum inflammation and early fibrosis in patients with early CKDu also favours a common aetiological * Correspondence: kamaniw@sltnet.lk factor and possibly a toxin mediated renal disease [2]. Department of Medicine, University of Sri Jayewardenepura, Nugegoda, Sri Recent work done by us indicates an environmental Lanka Full list of author information is available at the end of the article © 2011 Wanigasuriya et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Wanigasuriya et al. BMC Nephrology 2011, 12:32 Page 2 of 7 http://www.biomedcentral.com/1471-2369/12/32 aetiology. In the case-control study, being a farmer (p < Binary logistic regression analysis was done to control 0.001), using pesticides (p < 0.001), drinking well water for confounding factors. (p < 0.001), having a family history of renal dysfunction Ethical clearance was obtained from the Ethical (p = 0.001), use of ayurvedic treatment (p < 0.001) and Review Committee of the Faculty of Medical Sciences, a history of snake bite (p < 0.001) were found to be risk University of Sri Jayewardenepura. Written informed factors for CKDu [3]. The present study examines these consent was obtained using an approved consent form. risk factors further in the community setting through All participants with microalbuminuria were referred to detection of microalbuminuria, an early indicator of medical clinics conducted at Teaching Hospital, Anur- renal damage. adhapura or Medawachchiya hospital. Methods Results Anuradhapura, the main district in the NCP of Sri The sample comprised 425 females and 461 males. The Lanka, is subdivided in to 25 divisional secretariat areas. males were significantly older (p = 0.016), taller (p < The district population was 745 693 according to the 0.001) and heavier (p < 0.001) as compared to the last census in 2001. Based on statistics from the Anur- females (Table 1). adhapura Teaching Hospital, subjects were selected A significantly higher percentage of males were from three divisional secretary areas namely, Medawach- involved in agriculture (p = 0.001) and pesticide spray chiya and Padaviya which had the highest reported cases activities (p < 0.001) as compared to the females. The of CKDu and Rajanganaya which had a relatively low source of drinking water at home was similar in the incidence of CKDu. females and the males. However, females used water From each divisional secretary area, 3 grama-niladari from home in the field more often than the males (p = divisions, the smallest administrative units in the coun- 0.003). A higher percentage of males consumed water try that typically have approximately 200-250 house- from wells in the fields as compared to the females (p = holds and a population of 800-1000, were randomly 0.001). selected. From each grama-niladari division, 60 house- Micro-albuminuria was detected in 6.1% of the holds were randomly selected from the voters register. females (n = 26) and 8.5% of the males (n = 39) who All adults over 18 years were requested to participate in participated in the study. A significantly higher percen- the study and attend the special clinic conducted in tage of subjects with microalbuminuria had previously each area. Of the total 1110 adults in the selected smoked (p < 0.001), consumed alcohol (p = 0.003), pre- households, 886 participated in the study. viously been treated for hypertension (p < 0.001), dia- Blood pressure measurements were taken using stan- betes (p < 0.001) and urinary tract infection (UTI) (p = dard procedures and a physical examination conducted 0.034) and consumed water from wells situated in fields on all subjects by a physician. A structured pre-tested (p = 0.025) as compared to those with no microalbumi- interviewer-administered questionnaire was used to nuria (Table 2). obtain personal data and information on risk factors and In the binary logistic regression analysis the significant past medical history. The farmers were questioned predictors of microalbuminuria were history of hyper- further to find out details regarding the use of pesticides. tension, diabetes mellitus, UTI, drinking well water in A spot urine sample was collected and urinary microal- the fields, history of smoking and involvement of pesti- bumin was estimated by precipitating with 25% sulphosa- cide spraying (Table 3). Subjects with a history of hyper- licylic acid using the Light Dependent Resister micro- tension, diabetes mellitus and smoking were over three- albumin gel filtration method. This test detects albumin and-a half times more likely to have microalbuminuria concentrations in the range of 10-200 mg/L with 83% as compared to those who had no such history. Subjects sensitivity and 73% specificity [4]. Positive results were who drank well water in the field were approximately reconfirmed for microalbuminuria by the Micral strip twice as more likely to have microalbuminuria as com- test (Roche diagnostics) in an early morning urine sam- pared to those who did not. Significantly, pesticide ple. Those who were found to have positive results for spraying was found to be protective. both were considered as having microalbuminuria. Data were double entered and analyzed using SPSS Discussion (Statistical Products and Service Solutions, Chicago, Diabetes mellitus, hypertension, smoking, past history of USA) version 13.0. Associations between variables were urinary tract infections, pesticide spraying and consump- tested using independent sample t-tests, chi square tests, tion of water from a well situated in the field were sig- Fisher’s exact tests and Odds ratios. Ninety-five percent nificant predictors of microalbuminuria in the study confidence intervals were calculated for the Odds ratios. population. Wanigasuriya et al. BMC Nephrology 2011, 12:32 Page 3 of 7 http://www.biomedcentral.com/1471-2369/12/32 Table 1 Demographic characteristics of sample population Variable Females (n = 425) Males (n = 461) p-value Mean (SD) age (years) 30.53 (20.60) 33.63 (17.4) 0.016 Mean (SD) height (cm) 62.68 (75.15) 81.90 (81.23) < 0.001 Mean (SD) weight (kg) 25.68 (24.87) 37.09 (24.81) < 0.001 Number (%) by occupation Agriculture based 302 (71.1) 393 (85.2) 0.001 Other 123 (28.9) 68 (14.8) < 0.001 Number (%) involved in pesticide spraying 45 (14.8) 321 (81.7) < 0.001 Number (%) by source of drinking water at home Well 388 (93.9) 425 (93.0) 0.572 Stream 9 (2.2) 19 (4.2) 0.099 Pipe 24 (5.8) 19 (4.2) 0.261 Tube well 17 (4.1) 22 (4.8) 0.619 Other 0 (0.0) 1 (0.2) 0.525 Number (%) by source of drinking water in the field From home 252 (79.7) 286 (69.9) 0.003 Well in the field 105 (33.2) 187 (45.7) 0.001 Other 19 (6.0) 36 (8.8) 0.160 Estimation of microalbuminuria is recommended as a microalbuminuria is common, even among persons screening test to detect patients at an early stage of without diabetes or hypertension. CKD. Currently, microalbuminuria is defined as urinary Although diabetes mellitus and hypertension are albumin excretion between 20-200 mg/g in men and 30- known to cause CKD, it is likely that these conditions 300 mg/g in women, using the urinary albumin-to-crea- are associated with CKD in some populations, rather tinine ratio in a random urine sample; 30-300 mg/24 h, than being its cause. The high prevalence of microalbu- if measured in a 24 h urine collection; or 20-200 micro- minuria and its strong association with diabetes mellitus grams/min, if measured in a timed (e.g. 4 h or over- and hypertension in areas of high prevalence of CKDu night) urine collection [5]. A urinary albumin investigated by us maybedue to theinvolvement of a concentration below these limits is considered as normal common aetiological factor which may be implicated in excretion. The sulphosalicylic acid test was used as a the occurrence of CKDu, hypertension and an increased cost effective screening test to detect microalbuminuria susceptibility to renal damage in diabetes mellitus. and the micral test was used for confirmation. Microal- Deficiencies or excesses of trace element compounds in buminuria is an independent predictor for end stage water or soil is known to have an impact on the health of the inhabitants of the terrain. This is particularly evident renal disease in patients with diabetes mellitus or hyper- tension and, is used as an index of renal involvement. In in certain areas of the dry zone of Sri Lanka where a high this study, microalbuminuria was detected in 6.1% of prevalence of dental fluorosis is found due to the high the females and 8.5% of the males. Similar findings were fluoride content in ground water [8] and a high preva- reported from USA in which microalbuminuria was lence of endemic goitre is found in the wet zone due to detected in 6.1% of men and 9.7% of women in the gen- iodine deficiency [9]. Reservoirs are the main source of eral population [6]. In 19 848 elderly South-East Asians, irrigation for paddy lands in the NCP of Sri Lanka while proteinuria (defined as ≥1+ protein on urine dipstick drinking water in the rural areas is obtained mainly from analysis) was found in 8.5% of previously undetected wells. Other investigators have found high levels of Cd, Singaporeans, after excluding the 1.1% who had pre- Fe and Pb in five reservoirs in the same study area [10]. existing renal disease [7]. In the Third National Health Dissolved Cd in reservoir water and sediment was 0.03 to and Nutrition Examination Survey conducted in the 0.06 mg/L and 1.78 mg/L, respectively. This is much USA, the prevalence of microalbuminuria was 28.8% in higher than the Maximum Contaminant Level Goal of persons with previously diagnosed diabetes, 16.0% in 0.005 mg/L or 5 ppb recommended by the US Environ- those with hypertension, and 5.1% in those without dia- ment Protection Agency. Cd content in lotus rhizomes betes, hypertension, cardiovascular disease, or elevated was 253.82 mg/kg. The Provisional Tolerable Weekly serum creatinine levels [6]. The authors concluded that intake of Cd, based on the extreme exposure by rice and Wanigasuriya et al. BMC Nephrology 2011, 12:32 Page 4 of 7 http://www.biomedcentral.com/1471-2369/12/32 Table 2 Exposure to possible risk factors and the presence of albuminuria Variable Number (%) of subjects with Odds ratio (95% CI) p-value no albuminuria albuminuria n n Farmers Yes 814 630 (77.4) 63 52 (82.5) 1.381 0.344 No 184 (22.6) 11 (17.5) (0.706-2.701) Involved in pesticide spraying Yes 812 330 (40.6) 61 25 (41.0) 1.014 0.958 No 482 (59.4) 36 (59.0) (0.598-1.722) History of pesticide poisoning Yes 813 38 (4.7) 63 2 (3.2) 0.669 0.439 No 775 (95.3) 61 (96.8) (0.158-2.838) History of smoking Yes 813 176 (21.6) 63 29 (46.0) 3.087 < 0.001 No 637 (78.4) 34 (54.0) (1.830-5.207) History of alcohol use Yes 814 220 (27.0) 63 28 (44.4) 3.087 0.003 No 594 (73.0) 35 (55.6) (1.830-5.207) Treated for Hypertension Yes 813 114 (14.0) 63 27 (42.9) 2.160 < 0.001 No 699 (86.0) 36 (57.1) (1.284-3.635) Treated for Diabetes Mellitus Yes 812 41 (5.0) 63 13 (20.6) 4.889 < 0.001 No 771 (95.0) 50 (79.4) (2.461-9.712) Acute Glomerular Nephritis Yes 814 2(0.2) 62 0 (0.0) 0.929 0.863 No 812 (99.8) 62 (100.0) (0.912-0.946) Renal stones Yes 814 32 (3.9) 63 1 (1.6) 0.394 0.298 No 782 (96.1) 62 (98.4) (0.053-2.933) Urinary Tract Infection Yes 814 199 (24.4) 63 8 (12.7) 0.450 0.034 No 615 (75.6) 55 (87.3) (0.211-0.960) Chronic drug use Yes 813 43 (5.3) 62 5 (8.1) 1.571 0.248 No 770 (94.7) 57 (91.9) (0.599-4.120) Use of Ayurvedic Treatment Yes 814 551 (67.7) 27 45 (71.4) 1.193 0.540 No 263 (32.3) 18 (28.6) (0.678-2.102) Snake bite in the past Yes 813 95 (11.7) 63 10 (15.9) 1.426 0.324 No 718 (88.3) 53 (84.1) (0.702-2.897) Drinking water source a) at home Well Yes 799 732 (91.6) 63 61 (96.8) 2.792 0.102 No 67 (8.4) 2 (3.2) (0.668-1.671) Stream Yes 799 27 (3.4) 63 0 (0.0) 0.925 0.125 No 772 (96.6) 63 (100.0) (0.907-0.943) Pipe borne Yes 799 40 (5.0) 63 2 (3.2) 0.622 0.393 No 759 (95.0) 61 (6.8) (0.147-2.636) Tube well Yes 799 35 (4.4) 63 2 (3.2) 0.716 0.483 No 764 (95.6) 61 (96.8) (0.168-3.047) Other Yes 799 1 (0.1) 63 0 (0.0) 0.927 0.927 No 798 (99.9) 63 (100.0) (0.910-0.944) b) in the field From home Yes 814 496 (60.9) 63 37 (58.7) 0.912 0.730 No 318 (39.1) 26 (41.3) (0.542-1.536) Well Yes 814 251 (30.8) 63 28 (44.4) 1.794 0.025 No 563 (69.2) 35 (55.6) (1.068-3.014) Other Yes 814 51 (6.3) 63 1 (1.6) 0.241 0.097 No 763 (93.7) 62 (98.4) (0.033-1.776) Chi square test. Fishers exact test. Wanigasuriya et al. BMC Nephrology 2011, 12:32 Page 5 of 7 http://www.biomedcentral.com/1471-2369/12/32 Table 3 Summary results of logistic regression analysis (both male and female participants included) Variable Regression coefficient p-value Odds Ratio 95% confidence interval of odds ratio Intercept -3.492 History of hypertension 1.539 < 0.001 4.658 2.578 - 8.414 History of Diabetes mellitus 1.343 0.001 3.832 1.735 - 8.465 History of urinary tract infection -0.706 0.098 0.493 0.214 - 1.138 Drinking well water at the field 0.650 0.037 1.916 1.041 - 3.527 History of smoking 1.638 < 0.001 5.147 2.568 - 10.314 Involved in pesticide spraying -0.835 0.024 0.434 0.210 - 0.898 Reference category is no history of hypertension. Reference category is no history of diabetes mellitus. Reference category is no history of urinary tract infection. Reference category is not using drinking water from a well in the field. Reference category is no history of smoking. Reference category is not involved in pesticide spraying. fish, was also found to be high in the region [10]. Rice, toxic compounds than wells situated in home gardens, the staple food, fish and lotus rhizomes are frequently due to the extensive use of pesticides and fertilizers in consumed by the local community. In Southeast China, a paddy cultivation in the study area, a possible source of major source of cadmium exposure in the general popu- Cd. Whether fertilizers and pesticides used in this pri- lation is the consumption of cereals, particularly rice, marily agricultural setting are the sources of Cd in soil vegetables and shellfish [11]. and reservoirs is not known. The concentrations of Cd In this study, subjects with a history of smoking were and other heavy metals in different inorganic fertilizers five times more likely to have microalbuminuria as com- and in pesticides have been evaluated together with the pared to those who had no such history. It is known contribution of these metals in soils from their use in that smoking increases the risk of nephropathy in dia- rice farming areas in Spain [15]. Fertilizer (superpho- betic individuals. The Multiple Risk Factor Intervention sphate) and the three pesticides analyzed contained high Trial found an increased risk for end-stage renal disease amounts of Cd. A study on the potential impact of in smokers as compared to non-smokers which was heavy metals on groundwater as a result of fertilizer use independent of age, ethnicity, income, blood pressure, suggests significant potential groundwater pollution diabetes mellitus or a history of ischaemic heart disease from Cd, Se, Mo and U caused as a result of long-term [12]. use of phosphate fertilizers. The possibility for Cd From the findings of this study, it may be postulated reaching the groundwater system through soil-compart- that ground water in the fields and cigarettes (and possi- ments is indicated. Poor de-silting of reservoirs in NCP bly certain food items consumed by this population), are could lead to progressive rise in Cd levels in water likely sources of an environmental toxin. There is an which in turn feed the paddy cultivation [16]. It is also urgent need for studies to identify the toxin for effective possible that high levels of cadmium could be concen- interventions to be tested. Although we cannot implicate trated in well water in polluted locations. In addition, a particular toxin based on findings of the present study farmers clean contaminated spraying equipment near we postulate that Cd may well be the toxin in question the field well after spraying pesticides. Heavy metal con- and propose that further work be done to test this centrations in well water in the study area, however, are hypothesis. Nephrotoxicity in humans caused by high yet to be estimated. level exposure to Cd is known. Itai-itai disease following In a review that focused on studies of the prevalence mass Cd poisoning due to contaminated water in of Cd-related kidney dysfunction among population Toyama Prefecture, Japan is documented [13,14]. In the groups residing in Cd contaminated areas in China, next section, we present reasons for generating this dose-response relationships are shown between urinary hypothesis. Cd and the prevalence of increased levels of biomarkers of renal damage. Biomarkers of renal tubular dysfunc- Cd as a likely cause of CKDu tion such as urinary beta-2-microglobulin or N-acetyl- This studyreconfirms previousfindingsofdrinking beta-D-glucosaminidase and of glomerular kidney dys- water from wells situated in the field being a significant function (urinary albumin) were found to be associated predictor of early CKDu [3]. The wells situated in the with Cd exposure [17]. The factors that influenced these fields could have high concentrations of Cd and other dose-response relationships included metallothionein Wanigasuriya et al. BMC Nephrology 2011, 12:32 Page 6 of 7 http://www.biomedcentral.com/1471-2369/12/32 mRNA levels, increased levels of auto antibodies in these risk factors microalbuminuria is associated with blood/plasma against metallothionein and Type II drinking well water from agricultural fields in the NCP diabetes. of Sri Lanka. Although it is not possible to draw firm Increased susceptibility to Cd-induced renal damage in causal conclusions from this study due to the cross-sec- diabetes has been shown in population groups in China tional nature of it, the findings are helpful in directing and Australia [18,19]. Diabetes mellitus may increase future longitudinal and interventional studies that are the risk of Cd-induced kidney damage. Metallothionein urgently needed to establish definitive causality and plays a critical role in protecting animals and humans identify relevant protective measures. We propose against Cd-induced nephrotoxictiy [20-22]. The pre- further work be done to test Cd as a possible toxin in sence of metallothionein antibody (MT-Ab) increases the occurrence of CKDu in the NCP of Sri Lanka. the susceptibility for tubular damage among Cd workers. In persons with type II diabetes, increased levels of auto Abbreviations antibodies against metallothionein in blood plasma was CKD: Chronic Kidney Disease; NCP: North Central Province; CKDu: Chronic observed at urinary Cd levels around 1 microgram/g Kidney Disease of uncertain aetiology; UTI: Urinary Tract Infection; MT-Ab: Metallothionein Antibody creatinine [18]. The authors claim that the presence of MT-Ab can potentiate tubular dysfunction among dia- Acknowledgements betic subjects and that patients with high MT-Ab levels This work was supported by the University of Sri Jayewardenepura, Sri Lanka. are more prone to development of tubular damage. Author details Whether MT-Abs is found in the current study popula- 1 Department of Medicine, University of Sri Jayewardenepura, Nugegoda, Sri tion is not known. If Cd exposure is found to be signifi- Lanka. Department of Physiology, University of Sri Jayewardenepura, Nugegoda, Sri Lanka. Section of Epidemiology and Biostatistics, University of cant in the study area, susceptibility for renal damage is Auckland, Auckland, New Zealand. Department of Public health, University more likely in the presence of MT-Ab. Moreover, it is of Kelaniya, Ragama, Sri Lanka. possible that diabetes mellitus in the study population Authors’ contributions may increase the risk of Cd-induced kidney damage as KPW conceived of the study, participated in the design and coordination, reported previously. These postulations need to be carried out the data collection and helped draft the manuscript. RJPJ investigated before a definitive cause of CKDu can be participated in the design of the study, performed the statistical analysis and drafted the manuscript. ARW participated in the design of the study, established in the NCP of Sri Lanka. A recent review on performed the statistical analysis and helped draft the manuscript. All Cd, diabetes and CKD concludes that Cd may be a fac- authors read and approved the final manuscript. tor in the development of some types of diabetes and Competing interests the authors raise the possibility that Cd and diabetes- The authors declare that they have no competing interests. related hyperglycaemia may act synergistically to damage the kidney [23]. Received: 20 December 2010 Accepted: 5 July 2011 Published: 5 July 2011 Further, cigarette tobacco is known to contain appre- ciable amounts of cadmium with the accumulation of References cadmium in smokers being related to the number of 1. Hittarage A: Chronic renal disease in North Central Province of Sri Lanka. pack-years smoked [24]. Studies have demonstrated Anuradhapura Medical Journal 2004, 3-5. 2. Athuraliya TNC, Abeysekera DTDJ, Amerasinghe PH: Chronic renal failure, early low-level cadmium exposure in smokers to have towards understanding the current trend. 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Kobayashi E, Suwazono Y, Dochi M, Honda R, Kido T: Influence of consumption of cadmium-polluted rice or Jinzu River water on occurrence of renal tubular dysfunction and/or Itai-itai disease. Biol Trace Elem Res 2009, 127:257-68. 14. Kobayashi E, Suwazono Y, Dochi M, Honda R, Kido T, Nakagawa H: Influence of drinking and/or cooking with Jinzu River water on the development of Itai-itai disease. Biol Trace Elem Res 2008, 129:46-57. 15. Gimeno-García E, Andreu V, Boluda R: Heavy metals incidence in the application of inorganic fertilizers and pesticides to rice farming soils. Environ Pollut 1996, 92(1):19-25. 16. Bandara JMRS, Wijewardena HVP, Liyanege J, Upul MA, Bandara JMUA: Chronic renal failure in Sri Lanka caused by elevated dietary cadmium: Trojan horse of the green revolution. Toxicol Lett 2010, 198(1):33-39. 17. Nordberg GF, Jin T, Wu X, Lu J, Chen L, Lei L, Hong F, Nordberg M: Prevalence of kidney dysfunction in humans - relationship to cadmium dose, metallothionein, immunological and metabolic factors. Biochimie 2009, 91:1282-5. 18. Chen L, Lei L, Jin T, Nordberg M, Nordberg GF: Plasma Metallothion antibody, urinary cadmium and renal dysfunction in a Chinese Type 2 Diabetic population. Diabetes care 2006, 29(12):2682-9. 19. O’Rourke P, Moore M, Ng J, Magrath V, Walmby M: Stricking association between urinary cadmium level and albuminuria among Torres Strait Islander people with diabetes. Environ Res 2008, 106(3):379-383. 20. Nordberg M, Nordberg GF: Toxicological aspects of metallothionein. Cell Mol Biol 2000, 46:451-63. 21. Nordberg M, Jin T, Nordberg GF: Cadmium, metallothionein and renal tubular toxicity. IARC Sci Publ 1992, 118:293-7. 22. Jin T, Lu J, Nordberg M: Toxicokinetics and biochemistry of cadmium with special emphasis on the role of metallothionein. Neurotoxicology 1998, 19:529-35. 23. Edwards JR, Prozialeck WC: Cadmium, diabetes and chronic kidney disease. Toxicol Appl Pharmacol 2009, 238:289-93. 24. Lewis PG, Coughlin Linda L, Jusko William J, Stuart Hartz: Contribution of cigarette smoking to cadmium accumulation in man. Lancet 1972, 299(7745):291-2. 25. El-Safty IA, Shouman AE, Anwar S: Early detection of nephrotoxic effects due to low-dose exposure of cadmium among cigarette smokers. J Egypt Public Health Association 1996, 71(1-2):9-29. Pre-publication history The pre-publication history for this paper can be accessed here: http://www.biomedcentral.com/1471-2369/12/32/prepub doi:10.1186/1471-2369-12-32 Cite this article as: Wanigasuriya et al.: Chronic kidney disease of unknown aetiology in Sri Lanka: is cadmium a likely cause? BMC Nephrology 2011 12:32. 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Chronic kidney disease of unknown aetiology in Sri Lanka: is cadmium a likely cause?

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Springer Journals
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Copyright © 2011 by Wanigasuriya et al; licensee BioMed Central Ltd.
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Medicine & Public Health; Nephrology; Internal Medicine
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10.1186/1471-2369-12-32
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21726464
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Abstract

Background: The rising prevalence of chronic kidney disease (CKD) and subsequent end stage renal failure necessitating renal replacement therapy has profound consequences for affected individuals and health care resources. This community based study was conducted to identify potential predictors of microalbuminuria in a randomly selected sample of adults from the North Central Province (NCP) of Sri Lanka, where the burden of CKD is pronounced and the underlying cause still unknown. Methods: Exposures to possible risk factors were determined in randomly recruited subjects (425 females and 461 males) from selected areas of the NCP of Sri Lanka using an interviewer administered questionnaire. Sulphosalicylic acid and the Light Dependent Resister microalbumin gel filtration method was used for initial screening for microalbuminuria and reconfirmed by the Micral strip test. Results: Microalbumnuria was detected in 6.1% of the females and 8.5% of the males. Smoking (p < 0.001), alcohol use (p = 0.003), hypertension (p < 0.001), diabetes (p < 0.001), urinary tract infection (UTI) (p = 0.034) and consumption of water from wells in the fields (p = 0.025) were associated with microalbuminuria. In the binary logistic regression analysis, hypertension, diabetes mellitus, UTI, drinking well water in the fields, smoking and pesticide spraying were found to be significant predictors of microalbuminuria. Conclusions: Hypertension, diabetes mellitus, UTI, and smoking are known risk factors for microalbuminuria. The association between microalbuminuria and consumption of well water suggests an environmental aetiology to CKD in NCP. The causative agent is yet to be identified. Investigations for cadmium as a potential causative agent needs to be initiated. Keywords: Chronic kidney disease, aetiology, cadmium Background culture, NCP has been a fertile ground for infectious There is an increasing trend in mortality and morbidity diseases such as malaria and Japanese encephalitis in the due to chronic kidney disease (CKD) in Sri Lanka. past. CKD is a major health problem in the province at Although epidemiological data are lacking at present, present. this burden is even more pronounced in the North Cen- There may be unrecognized environmental toxins or tral Province (NCP) of Sri Lanka where the underlying occupational exposures giving rise to CKD in the region, cause of CKD remains unrecognized [1]. but this remains unproven. Chronic kidney disease of The NCP was the seat of Sri Lanka’s ancient king- uncertain aetiology (CKDu) in this region mainly affects doms and the centre of civilization and Buddhism. The males from poor socio-economic backgrounds who are province extends over 10 530 m in the dry zone of the involved in paddy farming raising the possibility of agro- country and has a sophisticated irrigation system of chemical exposure as a cause for CKDu. Renal biopsy water storage reservoirs. Despite its unique history and studies revealing a tubulo-interstitial nephritis with minimum inflammation and early fibrosis in patients with early CKDu also favours a common aetiological * Correspondence: kamaniw@sltnet.lk factor and possibly a toxin mediated renal disease [2]. Department of Medicine, University of Sri Jayewardenepura, Nugegoda, Sri Recent work done by us indicates an environmental Lanka Full list of author information is available at the end of the article © 2011 Wanigasuriya et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Wanigasuriya et al. BMC Nephrology 2011, 12:32 Page 2 of 7 http://www.biomedcentral.com/1471-2369/12/32 aetiology. In the case-control study, being a farmer (p < Binary logistic regression analysis was done to control 0.001), using pesticides (p < 0.001), drinking well water for confounding factors. (p < 0.001), having a family history of renal dysfunction Ethical clearance was obtained from the Ethical (p = 0.001), use of ayurvedic treatment (p < 0.001) and Review Committee of the Faculty of Medical Sciences, a history of snake bite (p < 0.001) were found to be risk University of Sri Jayewardenepura. Written informed factors for CKDu [3]. The present study examines these consent was obtained using an approved consent form. risk factors further in the community setting through All participants with microalbuminuria were referred to detection of microalbuminuria, an early indicator of medical clinics conducted at Teaching Hospital, Anur- renal damage. adhapura or Medawachchiya hospital. Methods Results Anuradhapura, the main district in the NCP of Sri The sample comprised 425 females and 461 males. The Lanka, is subdivided in to 25 divisional secretariat areas. males were significantly older (p = 0.016), taller (p < The district population was 745 693 according to the 0.001) and heavier (p < 0.001) as compared to the last census in 2001. Based on statistics from the Anur- females (Table 1). adhapura Teaching Hospital, subjects were selected A significantly higher percentage of males were from three divisional secretary areas namely, Medawach- involved in agriculture (p = 0.001) and pesticide spray chiya and Padaviya which had the highest reported cases activities (p < 0.001) as compared to the females. The of CKDu and Rajanganaya which had a relatively low source of drinking water at home was similar in the incidence of CKDu. females and the males. However, females used water From each divisional secretary area, 3 grama-niladari from home in the field more often than the males (p = divisions, the smallest administrative units in the coun- 0.003). A higher percentage of males consumed water try that typically have approximately 200-250 house- from wells in the fields as compared to the females (p = holds and a population of 800-1000, were randomly 0.001). selected. From each grama-niladari division, 60 house- Micro-albuminuria was detected in 6.1% of the holds were randomly selected from the voters register. females (n = 26) and 8.5% of the males (n = 39) who All adults over 18 years were requested to participate in participated in the study. A significantly higher percen- the study and attend the special clinic conducted in tage of subjects with microalbuminuria had previously each area. Of the total 1110 adults in the selected smoked (p < 0.001), consumed alcohol (p = 0.003), pre- households, 886 participated in the study. viously been treated for hypertension (p < 0.001), dia- Blood pressure measurements were taken using stan- betes (p < 0.001) and urinary tract infection (UTI) (p = dard procedures and a physical examination conducted 0.034) and consumed water from wells situated in fields on all subjects by a physician. A structured pre-tested (p = 0.025) as compared to those with no microalbumi- interviewer-administered questionnaire was used to nuria (Table 2). obtain personal data and information on risk factors and In the binary logistic regression analysis the significant past medical history. The farmers were questioned predictors of microalbuminuria were history of hyper- further to find out details regarding the use of pesticides. tension, diabetes mellitus, UTI, drinking well water in A spot urine sample was collected and urinary microal- the fields, history of smoking and involvement of pesti- bumin was estimated by precipitating with 25% sulphosa- cide spraying (Table 3). Subjects with a history of hyper- licylic acid using the Light Dependent Resister micro- tension, diabetes mellitus and smoking were over three- albumin gel filtration method. This test detects albumin and-a half times more likely to have microalbuminuria concentrations in the range of 10-200 mg/L with 83% as compared to those who had no such history. Subjects sensitivity and 73% specificity [4]. Positive results were who drank well water in the field were approximately reconfirmed for microalbuminuria by the Micral strip twice as more likely to have microalbuminuria as com- test (Roche diagnostics) in an early morning urine sam- pared to those who did not. Significantly, pesticide ple. Those who were found to have positive results for spraying was found to be protective. both were considered as having microalbuminuria. Data were double entered and analyzed using SPSS Discussion (Statistical Products and Service Solutions, Chicago, Diabetes mellitus, hypertension, smoking, past history of USA) version 13.0. Associations between variables were urinary tract infections, pesticide spraying and consump- tested using independent sample t-tests, chi square tests, tion of water from a well situated in the field were sig- Fisher’s exact tests and Odds ratios. Ninety-five percent nificant predictors of microalbuminuria in the study confidence intervals were calculated for the Odds ratios. population. Wanigasuriya et al. BMC Nephrology 2011, 12:32 Page 3 of 7 http://www.biomedcentral.com/1471-2369/12/32 Table 1 Demographic characteristics of sample population Variable Females (n = 425) Males (n = 461) p-value Mean (SD) age (years) 30.53 (20.60) 33.63 (17.4) 0.016 Mean (SD) height (cm) 62.68 (75.15) 81.90 (81.23) < 0.001 Mean (SD) weight (kg) 25.68 (24.87) 37.09 (24.81) < 0.001 Number (%) by occupation Agriculture based 302 (71.1) 393 (85.2) 0.001 Other 123 (28.9) 68 (14.8) < 0.001 Number (%) involved in pesticide spraying 45 (14.8) 321 (81.7) < 0.001 Number (%) by source of drinking water at home Well 388 (93.9) 425 (93.0) 0.572 Stream 9 (2.2) 19 (4.2) 0.099 Pipe 24 (5.8) 19 (4.2) 0.261 Tube well 17 (4.1) 22 (4.8) 0.619 Other 0 (0.0) 1 (0.2) 0.525 Number (%) by source of drinking water in the field From home 252 (79.7) 286 (69.9) 0.003 Well in the field 105 (33.2) 187 (45.7) 0.001 Other 19 (6.0) 36 (8.8) 0.160 Estimation of microalbuminuria is recommended as a microalbuminuria is common, even among persons screening test to detect patients at an early stage of without diabetes or hypertension. CKD. Currently, microalbuminuria is defined as urinary Although diabetes mellitus and hypertension are albumin excretion between 20-200 mg/g in men and 30- known to cause CKD, it is likely that these conditions 300 mg/g in women, using the urinary albumin-to-crea- are associated with CKD in some populations, rather tinine ratio in a random urine sample; 30-300 mg/24 h, than being its cause. The high prevalence of microalbu- if measured in a 24 h urine collection; or 20-200 micro- minuria and its strong association with diabetes mellitus grams/min, if measured in a timed (e.g. 4 h or over- and hypertension in areas of high prevalence of CKDu night) urine collection [5]. A urinary albumin investigated by us maybedue to theinvolvement of a concentration below these limits is considered as normal common aetiological factor which may be implicated in excretion. The sulphosalicylic acid test was used as a the occurrence of CKDu, hypertension and an increased cost effective screening test to detect microalbuminuria susceptibility to renal damage in diabetes mellitus. and the micral test was used for confirmation. Microal- Deficiencies or excesses of trace element compounds in buminuria is an independent predictor for end stage water or soil is known to have an impact on the health of the inhabitants of the terrain. This is particularly evident renal disease in patients with diabetes mellitus or hyper- tension and, is used as an index of renal involvement. In in certain areas of the dry zone of Sri Lanka where a high this study, microalbuminuria was detected in 6.1% of prevalence of dental fluorosis is found due to the high the females and 8.5% of the males. Similar findings were fluoride content in ground water [8] and a high preva- reported from USA in which microalbuminuria was lence of endemic goitre is found in the wet zone due to detected in 6.1% of men and 9.7% of women in the gen- iodine deficiency [9]. Reservoirs are the main source of eral population [6]. In 19 848 elderly South-East Asians, irrigation for paddy lands in the NCP of Sri Lanka while proteinuria (defined as ≥1+ protein on urine dipstick drinking water in the rural areas is obtained mainly from analysis) was found in 8.5% of previously undetected wells. Other investigators have found high levels of Cd, Singaporeans, after excluding the 1.1% who had pre- Fe and Pb in five reservoirs in the same study area [10]. existing renal disease [7]. In the Third National Health Dissolved Cd in reservoir water and sediment was 0.03 to and Nutrition Examination Survey conducted in the 0.06 mg/L and 1.78 mg/L, respectively. This is much USA, the prevalence of microalbuminuria was 28.8% in higher than the Maximum Contaminant Level Goal of persons with previously diagnosed diabetes, 16.0% in 0.005 mg/L or 5 ppb recommended by the US Environ- those with hypertension, and 5.1% in those without dia- ment Protection Agency. Cd content in lotus rhizomes betes, hypertension, cardiovascular disease, or elevated was 253.82 mg/kg. The Provisional Tolerable Weekly serum creatinine levels [6]. The authors concluded that intake of Cd, based on the extreme exposure by rice and Wanigasuriya et al. BMC Nephrology 2011, 12:32 Page 4 of 7 http://www.biomedcentral.com/1471-2369/12/32 Table 2 Exposure to possible risk factors and the presence of albuminuria Variable Number (%) of subjects with Odds ratio (95% CI) p-value no albuminuria albuminuria n n Farmers Yes 814 630 (77.4) 63 52 (82.5) 1.381 0.344 No 184 (22.6) 11 (17.5) (0.706-2.701) Involved in pesticide spraying Yes 812 330 (40.6) 61 25 (41.0) 1.014 0.958 No 482 (59.4) 36 (59.0) (0.598-1.722) History of pesticide poisoning Yes 813 38 (4.7) 63 2 (3.2) 0.669 0.439 No 775 (95.3) 61 (96.8) (0.158-2.838) History of smoking Yes 813 176 (21.6) 63 29 (46.0) 3.087 < 0.001 No 637 (78.4) 34 (54.0) (1.830-5.207) History of alcohol use Yes 814 220 (27.0) 63 28 (44.4) 3.087 0.003 No 594 (73.0) 35 (55.6) (1.830-5.207) Treated for Hypertension Yes 813 114 (14.0) 63 27 (42.9) 2.160 < 0.001 No 699 (86.0) 36 (57.1) (1.284-3.635) Treated for Diabetes Mellitus Yes 812 41 (5.0) 63 13 (20.6) 4.889 < 0.001 No 771 (95.0) 50 (79.4) (2.461-9.712) Acute Glomerular Nephritis Yes 814 2(0.2) 62 0 (0.0) 0.929 0.863 No 812 (99.8) 62 (100.0) (0.912-0.946) Renal stones Yes 814 32 (3.9) 63 1 (1.6) 0.394 0.298 No 782 (96.1) 62 (98.4) (0.053-2.933) Urinary Tract Infection Yes 814 199 (24.4) 63 8 (12.7) 0.450 0.034 No 615 (75.6) 55 (87.3) (0.211-0.960) Chronic drug use Yes 813 43 (5.3) 62 5 (8.1) 1.571 0.248 No 770 (94.7) 57 (91.9) (0.599-4.120) Use of Ayurvedic Treatment Yes 814 551 (67.7) 27 45 (71.4) 1.193 0.540 No 263 (32.3) 18 (28.6) (0.678-2.102) Snake bite in the past Yes 813 95 (11.7) 63 10 (15.9) 1.426 0.324 No 718 (88.3) 53 (84.1) (0.702-2.897) Drinking water source a) at home Well Yes 799 732 (91.6) 63 61 (96.8) 2.792 0.102 No 67 (8.4) 2 (3.2) (0.668-1.671) Stream Yes 799 27 (3.4) 63 0 (0.0) 0.925 0.125 No 772 (96.6) 63 (100.0) (0.907-0.943) Pipe borne Yes 799 40 (5.0) 63 2 (3.2) 0.622 0.393 No 759 (95.0) 61 (6.8) (0.147-2.636) Tube well Yes 799 35 (4.4) 63 2 (3.2) 0.716 0.483 No 764 (95.6) 61 (96.8) (0.168-3.047) Other Yes 799 1 (0.1) 63 0 (0.0) 0.927 0.927 No 798 (99.9) 63 (100.0) (0.910-0.944) b) in the field From home Yes 814 496 (60.9) 63 37 (58.7) 0.912 0.730 No 318 (39.1) 26 (41.3) (0.542-1.536) Well Yes 814 251 (30.8) 63 28 (44.4) 1.794 0.025 No 563 (69.2) 35 (55.6) (1.068-3.014) Other Yes 814 51 (6.3) 63 1 (1.6) 0.241 0.097 No 763 (93.7) 62 (98.4) (0.033-1.776) Chi square test. Fishers exact test. Wanigasuriya et al. BMC Nephrology 2011, 12:32 Page 5 of 7 http://www.biomedcentral.com/1471-2369/12/32 Table 3 Summary results of logistic regression analysis (both male and female participants included) Variable Regression coefficient p-value Odds Ratio 95% confidence interval of odds ratio Intercept -3.492 History of hypertension 1.539 < 0.001 4.658 2.578 - 8.414 History of Diabetes mellitus 1.343 0.001 3.832 1.735 - 8.465 History of urinary tract infection -0.706 0.098 0.493 0.214 - 1.138 Drinking well water at the field 0.650 0.037 1.916 1.041 - 3.527 History of smoking 1.638 < 0.001 5.147 2.568 - 10.314 Involved in pesticide spraying -0.835 0.024 0.434 0.210 - 0.898 Reference category is no history of hypertension. Reference category is no history of diabetes mellitus. Reference category is no history of urinary tract infection. Reference category is not using drinking water from a well in the field. Reference category is no history of smoking. Reference category is not involved in pesticide spraying. fish, was also found to be high in the region [10]. Rice, toxic compounds than wells situated in home gardens, the staple food, fish and lotus rhizomes are frequently due to the extensive use of pesticides and fertilizers in consumed by the local community. In Southeast China, a paddy cultivation in the study area, a possible source of major source of cadmium exposure in the general popu- Cd. Whether fertilizers and pesticides used in this pri- lation is the consumption of cereals, particularly rice, marily agricultural setting are the sources of Cd in soil vegetables and shellfish [11]. and reservoirs is not known. The concentrations of Cd In this study, subjects with a history of smoking were and other heavy metals in different inorganic fertilizers five times more likely to have microalbuminuria as com- and in pesticides have been evaluated together with the pared to those who had no such history. It is known contribution of these metals in soils from their use in that smoking increases the risk of nephropathy in dia- rice farming areas in Spain [15]. Fertilizer (superpho- betic individuals. The Multiple Risk Factor Intervention sphate) and the three pesticides analyzed contained high Trial found an increased risk for end-stage renal disease amounts of Cd. A study on the potential impact of in smokers as compared to non-smokers which was heavy metals on groundwater as a result of fertilizer use independent of age, ethnicity, income, blood pressure, suggests significant potential groundwater pollution diabetes mellitus or a history of ischaemic heart disease from Cd, Se, Mo and U caused as a result of long-term [12]. use of phosphate fertilizers. The possibility for Cd From the findings of this study, it may be postulated reaching the groundwater system through soil-compart- that ground water in the fields and cigarettes (and possi- ments is indicated. Poor de-silting of reservoirs in NCP bly certain food items consumed by this population), are could lead to progressive rise in Cd levels in water likely sources of an environmental toxin. There is an which in turn feed the paddy cultivation [16]. It is also urgent need for studies to identify the toxin for effective possible that high levels of cadmium could be concen- interventions to be tested. Although we cannot implicate trated in well water in polluted locations. In addition, a particular toxin based on findings of the present study farmers clean contaminated spraying equipment near we postulate that Cd may well be the toxin in question the field well after spraying pesticides. Heavy metal con- and propose that further work be done to test this centrations in well water in the study area, however, are hypothesis. Nephrotoxicity in humans caused by high yet to be estimated. level exposure to Cd is known. Itai-itai disease following In a review that focused on studies of the prevalence mass Cd poisoning due to contaminated water in of Cd-related kidney dysfunction among population Toyama Prefecture, Japan is documented [13,14]. In the groups residing in Cd contaminated areas in China, next section, we present reasons for generating this dose-response relationships are shown between urinary hypothesis. Cd and the prevalence of increased levels of biomarkers of renal damage. Biomarkers of renal tubular dysfunc- Cd as a likely cause of CKDu tion such as urinary beta-2-microglobulin or N-acetyl- This studyreconfirms previousfindingsofdrinking beta-D-glucosaminidase and of glomerular kidney dys- water from wells situated in the field being a significant function (urinary albumin) were found to be associated predictor of early CKDu [3]. The wells situated in the with Cd exposure [17]. The factors that influenced these fields could have high concentrations of Cd and other dose-response relationships included metallothionein Wanigasuriya et al. BMC Nephrology 2011, 12:32 Page 6 of 7 http://www.biomedcentral.com/1471-2369/12/32 mRNA levels, increased levels of auto antibodies in these risk factors microalbuminuria is associated with blood/plasma against metallothionein and Type II drinking well water from agricultural fields in the NCP diabetes. of Sri Lanka. Although it is not possible to draw firm Increased susceptibility to Cd-induced renal damage in causal conclusions from this study due to the cross-sec- diabetes has been shown in population groups in China tional nature of it, the findings are helpful in directing and Australia [18,19]. Diabetes mellitus may increase future longitudinal and interventional studies that are the risk of Cd-induced kidney damage. Metallothionein urgently needed to establish definitive causality and plays a critical role in protecting animals and humans identify relevant protective measures. We propose against Cd-induced nephrotoxictiy [20-22]. The pre- further work be done to test Cd as a possible toxin in sence of metallothionein antibody (MT-Ab) increases the occurrence of CKDu in the NCP of Sri Lanka. the susceptibility for tubular damage among Cd workers. In persons with type II diabetes, increased levels of auto Abbreviations antibodies against metallothionein in blood plasma was CKD: Chronic Kidney Disease; NCP: North Central Province; CKDu: Chronic observed at urinary Cd levels around 1 microgram/g Kidney Disease of uncertain aetiology; UTI: Urinary Tract Infection; MT-Ab: Metallothionein Antibody creatinine [18]. The authors claim that the presence of MT-Ab can potentiate tubular dysfunction among dia- Acknowledgements betic subjects and that patients with high MT-Ab levels This work was supported by the University of Sri Jayewardenepura, Sri Lanka. are more prone to development of tubular damage. Author details Whether MT-Abs is found in the current study popula- 1 Department of Medicine, University of Sri Jayewardenepura, Nugegoda, Sri tion is not known. If Cd exposure is found to be signifi- Lanka. Department of Physiology, University of Sri Jayewardenepura, Nugegoda, Sri Lanka. Section of Epidemiology and Biostatistics, University of cant in the study area, susceptibility for renal damage is Auckland, Auckland, New Zealand. Department of Public health, University more likely in the presence of MT-Ab. Moreover, it is of Kelaniya, Ragama, Sri Lanka. possible that diabetes mellitus in the study population Authors’ contributions may increase the risk of Cd-induced kidney damage as KPW conceived of the study, participated in the design and coordination, reported previously. These postulations need to be carried out the data collection and helped draft the manuscript. RJPJ investigated before a definitive cause of CKDu can be participated in the design of the study, performed the statistical analysis and drafted the manuscript. ARW participated in the design of the study, established in the NCP of Sri Lanka. A recent review on performed the statistical analysis and helped draft the manuscript. All Cd, diabetes and CKD concludes that Cd may be a fac- authors read and approved the final manuscript. tor in the development of some types of diabetes and Competing interests the authors raise the possibility that Cd and diabetes- The authors declare that they have no competing interests. related hyperglycaemia may act synergistically to damage the kidney [23]. Received: 20 December 2010 Accepted: 5 July 2011 Published: 5 July 2011 Further, cigarette tobacco is known to contain appre- ciable amounts of cadmium with the accumulation of References cadmium in smokers being related to the number of 1. Hittarage A: Chronic renal disease in North Central Province of Sri Lanka. pack-years smoked [24]. Studies have demonstrated Anuradhapura Medical Journal 2004, 3-5. 2. Athuraliya TNC, Abeysekera DTDJ, Amerasinghe PH: Chronic renal failure, early low-level cadmium exposure in smokers to have towards understanding the current trend. 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Nordberg GF, Jin T, Wu X, Lu J, Chen L, Lei L, Hong F, Nordberg M: Prevalence of kidney dysfunction in humans - relationship to cadmium dose, metallothionein, immunological and metabolic factors. Biochimie 2009, 91:1282-5. 18. Chen L, Lei L, Jin T, Nordberg M, Nordberg GF: Plasma Metallothion antibody, urinary cadmium and renal dysfunction in a Chinese Type 2 Diabetic population. Diabetes care 2006, 29(12):2682-9. 19. O’Rourke P, Moore M, Ng J, Magrath V, Walmby M: Stricking association between urinary cadmium level and albuminuria among Torres Strait Islander people with diabetes. Environ Res 2008, 106(3):379-383. 20. Nordberg M, Nordberg GF: Toxicological aspects of metallothionein. Cell Mol Biol 2000, 46:451-63. 21. Nordberg M, Jin T, Nordberg GF: Cadmium, metallothionein and renal tubular toxicity. IARC Sci Publ 1992, 118:293-7. 22. Jin T, Lu J, Nordberg M: Toxicokinetics and biochemistry of cadmium with special emphasis on the role of metallothionein. Neurotoxicology 1998, 19:529-35. 23. Edwards JR, Prozialeck WC: Cadmium, diabetes and chronic kidney disease. Toxicol Appl Pharmacol 2009, 238:289-93. 24. Lewis PG, Coughlin Linda L, Jusko William J, Stuart Hartz: Contribution of cigarette smoking to cadmium accumulation in man. Lancet 1972, 299(7745):291-2. 25. El-Safty IA, Shouman AE, Anwar S: Early detection of nephrotoxic effects due to low-dose exposure of cadmium among cigarette smokers. J Egypt Public Health Association 1996, 71(1-2):9-29. Pre-publication history The pre-publication history for this paper can be accessed here: http://www.biomedcentral.com/1471-2369/12/32/prepub doi:10.1186/1471-2369-12-32 Cite this article as: Wanigasuriya et al.: Chronic kidney disease of unknown aetiology in Sri Lanka: is cadmium a likely cause? BMC Nephrology 2011 12:32. 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