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Epidemiology of Chronic Kidney Disease, With Special Emphasis on Chronic Kidney Disease of Uncertain Etiology, in the North Central Region of Sri Lanka

Epidemiology of Chronic Kidney Disease, With Special Emphasis on Chronic Kidney Disease of... J Epidemiol 2015;25(4):275-280 doi:10.2188/jea.JE20140074 Original Article Epidemiology of Chronic Kidney Disease, With Special Emphasis on Chronic Kidney Disease of Uncertain Etiology, in the North Central Region of Sri Lanka 1 2 3 Kithsiri Bandara Jayasekara , Dhammika Menike Dissanayake , Ramiah Sivakanesan , 4 4 Asanga Ranasinghe , Ranawaka Hewage Karunarathna , and Gardiye Waligamage Gamini Priyantha Kumara Senior Lecturer, Department of Medical Laboratory Sciences, General Sir John Kotelawala Defense University, Rathmalana, Sri Lanka Department of Pathology, Faculty of Medicine, University of Peradeniya, Peradeniya, Sri Lanka Department of Biochemistry, Faculty of Medicine, University of Peradeniya, Peradeniya, Sri Lanka Renal Unit, Provincial Director’sOffice, Anuradhapura, Sri Lanka Received April 11, 2014; accepted November 19, 2014; released online March 17, 2015 Copyright © 2015 Kithsiri Bandara Jayasekara et al. This is an open access article distributed under the terms of Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Background: The aim of the study was to identify the epidemiology of chronic kidney disease of uncertain etiology in Sri Lanka. Methods: A cross-sectional study was carried out by analyzing health statistics, and three cohort studies were conducted (n = 15 630, 3996, and 2809) to analyze the demographic information, age-specific prevalence, etiology, and stage of presentation. We screened 7604 individuals for chronic kidney disease of uncertain etiology. Results: The results showed that the male:female ratio was 2.4:1, the mean age of patients was 54.7 ± 8 years, 92% of the patients were farmers, and 93% consumed water from shallow dug wells. Familial occurrence was common (36%). The prevalence of chronic kidney disease in different age groups was 3% in those aged 30–40 years; 7% in those aged 41–50 years, 20% in those aged 51–60 years, and 29% in those older than 60 years. Chronic kidney disease of uncertain etiology was diagnosed in 70.2% of patients, while 15.7% and 9.6% were due to hypertension and diabetic mellitus, respectively. The majority of patients were stage 4 (40%) at first presentation, while 31.8% were stage 3 and 24.5% were stage 5. Stage 1 and 2 presentation accounted for only 3.4%. Conclusions: Low prevalence of CKDU was noticed (1.5%) among those who consumed water from natural springs. Prevalence was highest among males, rice farming communities, and those presenting at later disease stages. Key words: chronic kidney disease; uncertain etiology; epidemiology; North Central Province; male farmers; natural spring water leading to kidney failure in the United States are diabetes, INTRODUCTION hypertension, and glomerulonephritis, which account for 23.7 Chronic kidney disease (CKD) is increasingly recognized as a cases per million population. The study reported that 28% global public health problem. According to the World Health of the CKD patients who were greater than 65 years of Organization’s Global Burden of Disease (GBD) project, age were neither diabetic nor hypertensive, suggesting that kidney and urinary tract disease is the 12th most common cardiovascular disease is also an important cause. Couser cause of death and the 17th most common cause of et al reviewed CKD in developing countries and mentioned 1,2 disability. The total number of Americans living with that the percentage of CKD patients devoid of diabetes or CKD is now estimated to be 19.2 million, representing 11% of hypertension is considerably higher in developing countries the adult population in the U.S., and 0.22% of the population than in developed ones. Diabetes and hypertension account is estimated to have end-stage renal disease (ESRD) resulting for 30% and 21% of ESRD patients, respectively; however, from CKD. According to the 2008 United States Renal Data glomerulonephritis and CKD due to uncertain etiology System annual report Collins et al, the major causes of CKD account for a larger portion among younger patients in Address for correspondence. Jayasekara JMKB, PhD, Department of Medical Laboratory Sciences, Faculty of Allied Health Sciences, General Sir John Kotelawala Defense University, Rathmalana, Sri Lanka (e-mail: kbjayasekara@gmail.com). 275 276 Epidemiology of Chronic Kidney Disease of Uncertain Etiology in Sri Lanka 5,6 developing countries. A study involving International etiologies for CKDU in Sri Lanka. According to studies Society of Nephrology-sponsored screening programs in conducted in Sri Lanka, high concentration of fluoride in China, Mongolia, and Nepal revealed that 43% of people water and use of aluminum utensils for cooking have been 7 18 with CKD did not have diabetes or hypertension. The suggested as risk factors. Another study revealed that CKD estimated prevalence of moderate CKD in developed is distributed mainly in agricultural regions using reservoir countries is unclear but is generally thought to be between based cascade irrigation systems. Further, the study concluded 8–10 5% and 7% of the total adult population. that CKD in North Central Sri Lanka was a result of chronic One study reported that the epidemiology of CKD in India dietary intake of cadmium and high natural levels of fluoride 11 19 is different from that in European and Western populations. in drinking water. Unrecognized environmental toxins or Patients are approximately two decades younger on average, occupational exposures were also suggested to contribute and a substantial proportion present with small kidneys and to the increased prevalence of CKD in NCP. However, unclear CKD etiology. The study concluded that the absence contradictory findings identified by different scientists of nationwide reporting systems or registries makes it difficult indicated that the moderate to high levels of fluoride and to determine the true incidence and prevalence. cadmium in drinking water in the affected regions did not Chronic kidney disease of uncertain etiology (CKDU), contribute to CKDU. By considering the studies which a new type of nephropathy has been reported in several have been done so far, it is obvious that there is a need countries over the last few decades. The first outbreak of for a comprehensive study of CKDU in Sri Lanka. The one type of CKDU, Balkan endemic nephropathy was epidemiology of CKDU in Sri Lanka, including emergence reported between 1955 and 1957, initially in Serbia and of the disease, stages of presentation, and age-specific soon afterwards in Croatia, Bosnia-Herzegovina, and prevalence of the disease, is poorly explained by the literature. Yugoslavia. In Yugoslavia, six foci were identified along major rivers of the Danubian basin. The prevalence rate of METHODS the disease was reported to be between 2% and 10% in the Balkan region. A striking feature of BEN was the familial To identify the prevalence of CKD in each province of the occurrence of the disease; epidemiological studies have country, the number of CKD patients in all districts was suggested that the disease is abundant in family members. collected from the medical statistics division and analyzed Longer duration of exposure and close contact with water by province. CKDU is generally seen in three provinces: in affected areas have been postulated as risk factors for NCP, the northern parts of the UP (Mahiyanganaya and BEN. However, the precise etiology has still not been Girandurukotte), and some parts of the NWP (Nikawewa). 14,15 determined. These three areas together can be treated as special CKDU has also been observed along the Pacific border geographical terrain called the North Central Region (NCR), of the Central American region, including Nicaragua and and further information were collected only from these three El Salvador, which does not appear to follow the same provinces. epidemiological patterns demonstrated in CKDU in developed A large cohort study was conducted to identify the countries. In a study performed in the municipality of epidemiological characteristics of CKDU in Sri Lanka. Quezalguaque, Nicaragua in response to anecdotal reports of Information was collected, including basic demographic data a high prevalence of kidney disease in agricultural regions in (age, sex, occupation, and water source), from 15 630 CKD Northwestern Nicaragua, an overall prevalence of 12.7% for patients who attended hospitals and community renal clinics 2 16 decreased eGFR (<60 mL/min/1.73 m ) was observed. that were specifically established to follow up CKD patients A case-control study confirmed that the epidemiology of in all high prevalence areas in Sri Lanka, such as kidney disease in Nicaragua is different from that seen in the Madawachchiya, Kebithigolewa, Padaviya, Padavisripura, U.S. and other developed countries. However, Quezalguaque Girandurukotte, Pollonnaruwa, Medirigiriya, Ellahera, and residents with diabetes and hypertension accounted for only a Nikawewa, from 2004 to 2011. small portion of CKD. The majority of cases in this region A subset of recently diagnosed CKD patients (n = 3996; are in young adults. Researchers have found that working in diagnosed from 2009–2011) attending hospitals and the cotton and sugar cane industries, pesticide exposure, community renal clinics in NCP were further classified into living at lower altitude, alcoholism, and consumption of 13 age categories. Population information was collected commercially produced bulk rum known as ‘Guaro Lija’ are from Sri Lanka’s census and statistics department and risk factors for occurrence of the disease. Anuradhapura’s Survey Department, and age-specific CKDU, a new and predominant form of CKD in certain prevalence of the disease was calculated for the three areas parts of Sri Lanka, including North Central Province (NCP), that comprise the NCP. The prevalence of CKDU among Uva Province (UP), and a few areas of the North Western CKD patients in NCP was also analyzed. According to the Province (NWP), is threatening to reach epidemic guidelines provided by the Ministry of Health, the diagnostic proportions. Researchers have suggested different criteria used for CKDU include absence of diabetes mellitus, J Epidemiol 2015;25(4):275-280 Bandara JMK, et al. 277 Figure. Number of chronic kidney disease patients per 1000 population in all provinces in Sri Lanka between 2000 and 2010. hypertension, urinary tract infections, or other renal diseases RESULTS in the history; presence of proteinuria on two occasions; decreased eGFR (Modification of Diet in Renal Disease- Contribution of CKDU among CKD community in MDRD formula); and presence of radiological changes, NCP such as normal kidney in the early stage and reduction of Figure shows CKD cases reported in NCP, Northern (NP), kidney size, increased cortical echogenicity, and loss of Central (CP), Western (WP), Southern (SP), NWP, UP, cortico-medullary demarcation in the late stage. The earliest Sabaragamuwa (SAP), and Eastern Province (EP) in Sri pathological manifestation was interstitial inflammation Lanka from 2000 to 2010. The highest number of CKD and interstitial fibrosis, whereas tubular atrophy and patients was recorded in the NCP. The mean number of glomerulosclerosis were seen in later stages. CKD patients from 2000 to 2010 in NCP was 1.88 per 1000 Using the diagnostic criteria, CKDU patients (n = 2809) persons, while it was only 0.40 in other provinces (Figure). identified by health professionals in NCP (medical officers in a Renal Unit) in the above analysis were cautiously evaluated Demographic information of CKD patients in NCP for stage of CKDU at their first clinic visit and the number of Analysis of 15 630 CKD patients revealed a male:female ratio patients at each clinical stage was estimated for the period of 2.4:1. A total of 92% of the patients were farmers, 6% were 2009 to 2011. The stage of presentation of CKDU was military workers, and 2% were involved in other occupations. identified by analyzing biopsy reports and eGFR levels A total of 93% of the patients consumed water from shallow according to the KDOQI guidelines. We screened 7604 dug wells for at least five years before having the disease, individuals (3832 males and 3772 females, all aged >5 years) 6% of patients used tube wells, and only 1% consumed water in 14 Gramaniladhari divisions to identify proteinuria in the directly from reservoirs. community in one of the high-prevalence areas of the NCP, Kebithigollaewa, using a random cluster sampling method in Age-specific CKD distribution and etiology of the collaboration with medical officers in the NCP. Information on disease in high-prevalence areas in NCP drinking water sources used by participants was collected for The percentage of CKD patients (n = 3996) in the the preceding five years (such as natural spring, shallow dug Medawachchiya, Padaviya, and Kebithigollewa areas of wells, or other water sources). The urine standard dipstick NCP according to age, 3% aged 30–40 years, 7% aged method was used to detect proteinuria in early morning urine 41–50 years, 20% aged 51–60 years, and 29% aged >60 years. samples of the population. An individual with proteinuria on The male:female ratio was highest in the 40–44 years age two consecutive occasions was referred to a renal clinic for group and gradually decreased with increasing age (Table 1). further investigation of CKDU. Patients confirmed to have Patients were further analyzed for etiology of the disease. CKDU from the screening study and previously identified A total of 70% of CKD patients were identified as CKDU, patients were also included. Prevalence of CKDU among the while CKD was attributed to hypertension in 15.7% of screened population, including previously identified patients, patients and diabetic mellitus in 9.6% of patients (Table 2). was analyzed according to the drinking water sources used. The study was approved by the Provincial Director of Health Stage of presentation Services, NCP, Sri Lanka. We evaluated 2809 CKDU patients to identify the stage of presentation at the first day of diagnosis. The analysis was done according to eGFR levels and biopsy reports of the J Epidemiol 2015;25(4):275-280 278 Epidemiology of Chronic Kidney Disease of Uncertain Etiology in Sri Lanka Table 1. Age-specific prevalence of chronic kidney disease in North Central province at first diagnosis from 2009–2011 Age groups, Male CKD Male population Female CKD Female population Total CKD Male:female years patients (% CKD) patients (% CKD) patients (%) ratio 0–4 0 4282 (0%) 0 3978 (0%) 0 (0%) 0 5–9 6 4479 (0.1%) 5 4128 (0.1%) 11 (0.1%) 1.20 10–14 16 4126 (1%) 14 4021 (1%) 30 (0.5%) 1.14 15–19 34 4258 (1%) 24 4133 (1%) 58 (1%) 1.42 20–24 36 4968 (1%) 29 4721 (1%) 65 (1%) 1.24 25–29 40 3987 (1%) 29 3542 (1%) 69 (1%) 1.37 30–34 82 3564 (2%) 40 3561 (1%) 122 (2%) 2.05 35–39 189 3421 (5%) 45 3456 (2%) 234 (4%) 4.20 40–44 264 3129 (8%) 72 3456 (2%) 336 (5%) 3.66 45–49 381 2963 (13%) 125 2561 (5%) 506 (9%) 3.05 50–54 458 1986 (23%) 177 1689 (10%) 635 (17%) 2.58 55–59 366 1024 (35%) 134 1022 (13%) 500 (24%) 2.73 >60 949 2563 (37%) 481 2468 (20%) 1430 (29%) 2.19 Total 2821 44 750 (6%) 1175 42 736 (3%) 3996 (5%) 2.40 CKD, chronic kidney disease. Table 2. Etiology of chronic kidney disease in North Central Table 3. Prevalence of chronic kidney disease of uncertain Province from 2009–2011 etiology in the Kebithigollewa area from 2004–2011 Previously Number of Prevalence, Age, Male:female Drinking New Total Total Etiology Number diagnosed Odds ratio patients % mean ± SD ratio water CKDU CKDU prevalence screened CKDU (95% CI) source cases cases of CKDU cases CKDU 2809 70.2 54 ± 8 2.6:1 Hypertension 629 15.7 58 ± 12 1.6:1 Males Diabetic mellitus 384 9.6 56 ± 10 1.8:1 Natural springs 912 16 4 20 1 2% Others 174 4.4 44 ± 15 1.3:1 Shallow wells 2996 286 42 328 5.48 (3.46–8.66) 11% Total 3996 100 53 ± 12 2.4:1 Females CKDU, chronic kidney disease of uncertain etiology; SD, standard Natural springs 850 6 3 9 1 1% Shallow wells 2846 103 25 128 4.40 (2.23–8.68) 4.4% deviation. Total 7604 411 74 485 6.3% CKDU, chronic kidney disease of uncertain etiology; CI, confidence patients. The majority of the CKDU patients were at stage 4 interval. (40%), while 31.8% and 24.5% were in stages 3 and 5, respectively. Stages 1 or 2 accounted for only about 3.4% of patients. Biopsy reports showed interstitial fibrosis (IF) of any approximately 70% of the CKD population in NCP. A few degree, absent or mild interstitial inflammation (II), tubular CKDU clusters in Uva and North Western Province have also atrophy (TA) of any degree, with or without glomerular been identified ; however, CKDU patients in these clusters sclerosis (GS) in stage 1 and 2, moderate to severe IF and II did not comprise a large percentage of total CKD patients. and TA of any degree with or without GS in stage 3; and CKDU patients comprised only 25.6% of CKD patients in severe IF and II and TA in stages 4 and 5. WP. Other provinces of the country were also affected with CKD, though the etiologies of the disease were primarily Prevalence of CKDU in Kebithigollewa according to diabetes (30.6%) and hypertension (13.2%). It has also water source been reported that the difference in incidence of diabetic In the Kebithigollewa area, 1762 individuals consumed water nephropathy between WP and other provinces was not from natural springs and 5842 consumed water from shallow statistically significant (P > 0.05). wells. A low prevalence of CKDU (1.5%) was noticed among We observed a higher risk of developing CKD for male consumers of natural spring water, and a relatively high farmers engaged in agricultural activities in NCP, indicating prevalence (7.7%) was identified among consumers of water that this group may be exposed to an unidentified etiological from shallow wells (Table 3). agent. The increasing age-specific prevalence of CKD from the age of 35 years onwards indicates the possibility of long- term exposure to an etiological agent and/or contributory DISCUSSION factors present in the environment. The male:female ratio The present cross-sectional study was conducted in all 9 increased with age from the 30–34 years age group, indicating provinces of the country, and a remarkably higher number of that males were more susceptible than females at younger CKD patients was noticed only in NCP. Prevalence of CKD ages; however, with continued exposure, the number of in NCP was four times higher than in the other provinces females affected also increased (Table 1). One-third of the due to the high number of CKDU patients, who comprised population older than 60 years was affected with CKD in J Epidemiol 2015;25(4):275-280 Bandara JMK, et al. 279 NCP. A study conducted in the U.S. in 2003 also revealed that to be conducted to encourage use of spring water at least for the prevalence of CKD was 0.2% in the 20–39 years age drinking and cooking. A total of 92% of CKD patients in group, 1.8% in the 40–59 years age group, and 7.6% in the NCR consumed water from shallow dug wells; therefore, 60–69 years age group. Intense farming activities and it can be speculated that the etiology of CKDU is strongly exposure to pesticides were identified as risk factors for related to drinking water sources. Observations in Andhra CKDU in Nicaragua, and all of the affected CKD patients in Pradesh in India suggest that some elements present in ground the BEN cluster and in India’s Andhra Pradesh cluster were water (fluoride, calcium, magnesium, and sulfate) may be 27 31 farmers. Moreover, the affected patients were adults between contributing factors for CKDU. 30 and 50 years of age in both the BEN cluster, and in CKD in Central American countries. ACKNOWLEDGEMENTS A total of 70% of CKD patients in NCP were with unknown etiology (CKDU) and only 15.7% and 9.6% were The authors acknowledge the Provincial Director of Health diagnosed as hypertensive and diabetic mellitus patients, services and South Asian Clinical Toxicology Research respectively. However, diabetes and hypertension contributed Collaboration for providing partial support for the study. to over 60% of the CKD cases in the WP. CKDU patients Conflicts of interest: None declared. were relatively younger than patients with CKD due to hypertension and diabetes. In addition, the current study REFERENCES revealed that the male:female ratio of the other etiologies of 1. Murray CJ, Lopez AD, Mathers CD, Stein C. The Global CKD, such as diabetic nephropathy and hypertension, in NCP Burden of Disease 2000 project: aims, methods and data sources. was only about 1.5:1 (Table 2), while the male:female ratio of Global Programme on Evidence for Health Policy Discussion. 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J Environ Biol. 2013;58:6–10. 2012;33(4):689–93. 23. Wijetunge S, Ratnatunga NV, Abeysekera DT, Wazil AW, J Epidemiol 2015;25(4):275-280 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Epidemiology Pubmed Central

Epidemiology of Chronic Kidney Disease, With Special Emphasis on Chronic Kidney Disease of Uncertain Etiology, in the North Central Region of Sri Lanka

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J Epidemiol 2015;25(4):275-280 doi:10.2188/jea.JE20140074 Original Article Epidemiology of Chronic Kidney Disease, With Special Emphasis on Chronic Kidney Disease of Uncertain Etiology, in the North Central Region of Sri Lanka 1 2 3 Kithsiri Bandara Jayasekara , Dhammika Menike Dissanayake , Ramiah Sivakanesan , 4 4 Asanga Ranasinghe , Ranawaka Hewage Karunarathna , and Gardiye Waligamage Gamini Priyantha Kumara Senior Lecturer, Department of Medical Laboratory Sciences, General Sir John Kotelawala Defense University, Rathmalana, Sri Lanka Department of Pathology, Faculty of Medicine, University of Peradeniya, Peradeniya, Sri Lanka Department of Biochemistry, Faculty of Medicine, University of Peradeniya, Peradeniya, Sri Lanka Renal Unit, Provincial Director’sOffice, Anuradhapura, Sri Lanka Received April 11, 2014; accepted November 19, 2014; released online March 17, 2015 Copyright © 2015 Kithsiri Bandara Jayasekara et al. This is an open access article distributed under the terms of Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Background: The aim of the study was to identify the epidemiology of chronic kidney disease of uncertain etiology in Sri Lanka. Methods: A cross-sectional study was carried out by analyzing health statistics, and three cohort studies were conducted (n = 15 630, 3996, and 2809) to analyze the demographic information, age-specific prevalence, etiology, and stage of presentation. We screened 7604 individuals for chronic kidney disease of uncertain etiology. Results: The results showed that the male:female ratio was 2.4:1, the mean age of patients was 54.7 ± 8 years, 92% of the patients were farmers, and 93% consumed water from shallow dug wells. Familial occurrence was common (36%). The prevalence of chronic kidney disease in different age groups was 3% in those aged 30–40 years; 7% in those aged 41–50 years, 20% in those aged 51–60 years, and 29% in those older than 60 years. Chronic kidney disease of uncertain etiology was diagnosed in 70.2% of patients, while 15.7% and 9.6% were due to hypertension and diabetic mellitus, respectively. The majority of patients were stage 4 (40%) at first presentation, while 31.8% were stage 3 and 24.5% were stage 5. Stage 1 and 2 presentation accounted for only 3.4%. Conclusions: Low prevalence of CKDU was noticed (1.5%) among those who consumed water from natural springs. Prevalence was highest among males, rice farming communities, and those presenting at later disease stages. Key words: chronic kidney disease; uncertain etiology; epidemiology; North Central Province; male farmers; natural spring water leading to kidney failure in the United States are diabetes, INTRODUCTION hypertension, and glomerulonephritis, which account for 23.7 Chronic kidney disease (CKD) is increasingly recognized as a cases per million population. The study reported that 28% global public health problem. According to the World Health of the CKD patients who were greater than 65 years of Organization’s Global Burden of Disease (GBD) project, age were neither diabetic nor hypertensive, suggesting that kidney and urinary tract disease is the 12th most common cardiovascular disease is also an important cause. Couser cause of death and the 17th most common cause of et al reviewed CKD in developing countries and mentioned 1,2 disability. The total number of Americans living with that the percentage of CKD patients devoid of diabetes or CKD is now estimated to be 19.2 million, representing 11% of hypertension is considerably higher in developing countries the adult population in the U.S., and 0.22% of the population than in developed ones. Diabetes and hypertension account is estimated to have end-stage renal disease (ESRD) resulting for 30% and 21% of ESRD patients, respectively; however, from CKD. According to the 2008 United States Renal Data glomerulonephritis and CKD due to uncertain etiology System annual report Collins et al, the major causes of CKD account for a larger portion among younger patients in Address for correspondence. Jayasekara JMKB, PhD, Department of Medical Laboratory Sciences, Faculty of Allied Health Sciences, General Sir John Kotelawala Defense University, Rathmalana, Sri Lanka (e-mail: kbjayasekara@gmail.com). 275 276 Epidemiology of Chronic Kidney Disease of Uncertain Etiology in Sri Lanka 5,6 developing countries. A study involving International etiologies for CKDU in Sri Lanka. According to studies Society of Nephrology-sponsored screening programs in conducted in Sri Lanka, high concentration of fluoride in China, Mongolia, and Nepal revealed that 43% of people water and use of aluminum utensils for cooking have been 7 18 with CKD did not have diabetes or hypertension. The suggested as risk factors. Another study revealed that CKD estimated prevalence of moderate CKD in developed is distributed mainly in agricultural regions using reservoir countries is unclear but is generally thought to be between based cascade irrigation systems. Further, the study concluded 8–10 5% and 7% of the total adult population. that CKD in North Central Sri Lanka was a result of chronic One study reported that the epidemiology of CKD in India dietary intake of cadmium and high natural levels of fluoride 11 19 is different from that in European and Western populations. in drinking water. Unrecognized environmental toxins or Patients are approximately two decades younger on average, occupational exposures were also suggested to contribute and a substantial proportion present with small kidneys and to the increased prevalence of CKD in NCP. However, unclear CKD etiology. The study concluded that the absence contradictory findings identified by different scientists of nationwide reporting systems or registries makes it difficult indicated that the moderate to high levels of fluoride and to determine the true incidence and prevalence. cadmium in drinking water in the affected regions did not Chronic kidney disease of uncertain etiology (CKDU), contribute to CKDU. By considering the studies which a new type of nephropathy has been reported in several have been done so far, it is obvious that there is a need countries over the last few decades. The first outbreak of for a comprehensive study of CKDU in Sri Lanka. The one type of CKDU, Balkan endemic nephropathy was epidemiology of CKDU in Sri Lanka, including emergence reported between 1955 and 1957, initially in Serbia and of the disease, stages of presentation, and age-specific soon afterwards in Croatia, Bosnia-Herzegovina, and prevalence of the disease, is poorly explained by the literature. Yugoslavia. In Yugoslavia, six foci were identified along major rivers of the Danubian basin. The prevalence rate of METHODS the disease was reported to be between 2% and 10% in the Balkan region. A striking feature of BEN was the familial To identify the prevalence of CKD in each province of the occurrence of the disease; epidemiological studies have country, the number of CKD patients in all districts was suggested that the disease is abundant in family members. collected from the medical statistics division and analyzed Longer duration of exposure and close contact with water by province. CKDU is generally seen in three provinces: in affected areas have been postulated as risk factors for NCP, the northern parts of the UP (Mahiyanganaya and BEN. However, the precise etiology has still not been Girandurukotte), and some parts of the NWP (Nikawewa). 14,15 determined. These three areas together can be treated as special CKDU has also been observed along the Pacific border geographical terrain called the North Central Region (NCR), of the Central American region, including Nicaragua and and further information were collected only from these three El Salvador, which does not appear to follow the same provinces. epidemiological patterns demonstrated in CKDU in developed A large cohort study was conducted to identify the countries. In a study performed in the municipality of epidemiological characteristics of CKDU in Sri Lanka. Quezalguaque, Nicaragua in response to anecdotal reports of Information was collected, including basic demographic data a high prevalence of kidney disease in agricultural regions in (age, sex, occupation, and water source), from 15 630 CKD Northwestern Nicaragua, an overall prevalence of 12.7% for patients who attended hospitals and community renal clinics 2 16 decreased eGFR (<60 mL/min/1.73 m ) was observed. that were specifically established to follow up CKD patients A case-control study confirmed that the epidemiology of in all high prevalence areas in Sri Lanka, such as kidney disease in Nicaragua is different from that seen in the Madawachchiya, Kebithigolewa, Padaviya, Padavisripura, U.S. and other developed countries. However, Quezalguaque Girandurukotte, Pollonnaruwa, Medirigiriya, Ellahera, and residents with diabetes and hypertension accounted for only a Nikawewa, from 2004 to 2011. small portion of CKD. The majority of cases in this region A subset of recently diagnosed CKD patients (n = 3996; are in young adults. Researchers have found that working in diagnosed from 2009–2011) attending hospitals and the cotton and sugar cane industries, pesticide exposure, community renal clinics in NCP were further classified into living at lower altitude, alcoholism, and consumption of 13 age categories. Population information was collected commercially produced bulk rum known as ‘Guaro Lija’ are from Sri Lanka’s census and statistics department and risk factors for occurrence of the disease. Anuradhapura’s Survey Department, and age-specific CKDU, a new and predominant form of CKD in certain prevalence of the disease was calculated for the three areas parts of Sri Lanka, including North Central Province (NCP), that comprise the NCP. The prevalence of CKDU among Uva Province (UP), and a few areas of the North Western CKD patients in NCP was also analyzed. According to the Province (NWP), is threatening to reach epidemic guidelines provided by the Ministry of Health, the diagnostic proportions. Researchers have suggested different criteria used for CKDU include absence of diabetes mellitus, J Epidemiol 2015;25(4):275-280 Bandara JMK, et al. 277 Figure. Number of chronic kidney disease patients per 1000 population in all provinces in Sri Lanka between 2000 and 2010. hypertension, urinary tract infections, or other renal diseases RESULTS in the history; presence of proteinuria on two occasions; decreased eGFR (Modification of Diet in Renal Disease- Contribution of CKDU among CKD community in MDRD formula); and presence of radiological changes, NCP such as normal kidney in the early stage and reduction of Figure shows CKD cases reported in NCP, Northern (NP), kidney size, increased cortical echogenicity, and loss of Central (CP), Western (WP), Southern (SP), NWP, UP, cortico-medullary demarcation in the late stage. The earliest Sabaragamuwa (SAP), and Eastern Province (EP) in Sri pathological manifestation was interstitial inflammation Lanka from 2000 to 2010. The highest number of CKD and interstitial fibrosis, whereas tubular atrophy and patients was recorded in the NCP. The mean number of glomerulosclerosis were seen in later stages. CKD patients from 2000 to 2010 in NCP was 1.88 per 1000 Using the diagnostic criteria, CKDU patients (n = 2809) persons, while it was only 0.40 in other provinces (Figure). identified by health professionals in NCP (medical officers in a Renal Unit) in the above analysis were cautiously evaluated Demographic information of CKD patients in NCP for stage of CKDU at their first clinic visit and the number of Analysis of 15 630 CKD patients revealed a male:female ratio patients at each clinical stage was estimated for the period of 2.4:1. A total of 92% of the patients were farmers, 6% were 2009 to 2011. The stage of presentation of CKDU was military workers, and 2% were involved in other occupations. identified by analyzing biopsy reports and eGFR levels A total of 93% of the patients consumed water from shallow according to the KDOQI guidelines. We screened 7604 dug wells for at least five years before having the disease, individuals (3832 males and 3772 females, all aged >5 years) 6% of patients used tube wells, and only 1% consumed water in 14 Gramaniladhari divisions to identify proteinuria in the directly from reservoirs. community in one of the high-prevalence areas of the NCP, Kebithigollaewa, using a random cluster sampling method in Age-specific CKD distribution and etiology of the collaboration with medical officers in the NCP. Information on disease in high-prevalence areas in NCP drinking water sources used by participants was collected for The percentage of CKD patients (n = 3996) in the the preceding five years (such as natural spring, shallow dug Medawachchiya, Padaviya, and Kebithigollewa areas of wells, or other water sources). The urine standard dipstick NCP according to age, 3% aged 30–40 years, 7% aged method was used to detect proteinuria in early morning urine 41–50 years, 20% aged 51–60 years, and 29% aged >60 years. samples of the population. An individual with proteinuria on The male:female ratio was highest in the 40–44 years age two consecutive occasions was referred to a renal clinic for group and gradually decreased with increasing age (Table 1). further investigation of CKDU. Patients confirmed to have Patients were further analyzed for etiology of the disease. CKDU from the screening study and previously identified A total of 70% of CKD patients were identified as CKDU, patients were also included. Prevalence of CKDU among the while CKD was attributed to hypertension in 15.7% of screened population, including previously identified patients, patients and diabetic mellitus in 9.6% of patients (Table 2). was analyzed according to the drinking water sources used. The study was approved by the Provincial Director of Health Stage of presentation Services, NCP, Sri Lanka. We evaluated 2809 CKDU patients to identify the stage of presentation at the first day of diagnosis. The analysis was done according to eGFR levels and biopsy reports of the J Epidemiol 2015;25(4):275-280 278 Epidemiology of Chronic Kidney Disease of Uncertain Etiology in Sri Lanka Table 1. Age-specific prevalence of chronic kidney disease in North Central province at first diagnosis from 2009–2011 Age groups, Male CKD Male population Female CKD Female population Total CKD Male:female years patients (% CKD) patients (% CKD) patients (%) ratio 0–4 0 4282 (0%) 0 3978 (0%) 0 (0%) 0 5–9 6 4479 (0.1%) 5 4128 (0.1%) 11 (0.1%) 1.20 10–14 16 4126 (1%) 14 4021 (1%) 30 (0.5%) 1.14 15–19 34 4258 (1%) 24 4133 (1%) 58 (1%) 1.42 20–24 36 4968 (1%) 29 4721 (1%) 65 (1%) 1.24 25–29 40 3987 (1%) 29 3542 (1%) 69 (1%) 1.37 30–34 82 3564 (2%) 40 3561 (1%) 122 (2%) 2.05 35–39 189 3421 (5%) 45 3456 (2%) 234 (4%) 4.20 40–44 264 3129 (8%) 72 3456 (2%) 336 (5%) 3.66 45–49 381 2963 (13%) 125 2561 (5%) 506 (9%) 3.05 50–54 458 1986 (23%) 177 1689 (10%) 635 (17%) 2.58 55–59 366 1024 (35%) 134 1022 (13%) 500 (24%) 2.73 >60 949 2563 (37%) 481 2468 (20%) 1430 (29%) 2.19 Total 2821 44 750 (6%) 1175 42 736 (3%) 3996 (5%) 2.40 CKD, chronic kidney disease. Table 2. Etiology of chronic kidney disease in North Central Table 3. Prevalence of chronic kidney disease of uncertain Province from 2009–2011 etiology in the Kebithigollewa area from 2004–2011 Previously Number of Prevalence, Age, Male:female Drinking New Total Total Etiology Number diagnosed Odds ratio patients % mean ± SD ratio water CKDU CKDU prevalence screened CKDU (95% CI) source cases cases of CKDU cases CKDU 2809 70.2 54 ± 8 2.6:1 Hypertension 629 15.7 58 ± 12 1.6:1 Males Diabetic mellitus 384 9.6 56 ± 10 1.8:1 Natural springs 912 16 4 20 1 2% Others 174 4.4 44 ± 15 1.3:1 Shallow wells 2996 286 42 328 5.48 (3.46–8.66) 11% Total 3996 100 53 ± 12 2.4:1 Females CKDU, chronic kidney disease of uncertain etiology; SD, standard Natural springs 850 6 3 9 1 1% Shallow wells 2846 103 25 128 4.40 (2.23–8.68) 4.4% deviation. Total 7604 411 74 485 6.3% CKDU, chronic kidney disease of uncertain etiology; CI, confidence patients. The majority of the CKDU patients were at stage 4 interval. (40%), while 31.8% and 24.5% were in stages 3 and 5, respectively. Stages 1 or 2 accounted for only about 3.4% of patients. Biopsy reports showed interstitial fibrosis (IF) of any approximately 70% of the CKD population in NCP. A few degree, absent or mild interstitial inflammation (II), tubular CKDU clusters in Uva and North Western Province have also atrophy (TA) of any degree, with or without glomerular been identified ; however, CKDU patients in these clusters sclerosis (GS) in stage 1 and 2, moderate to severe IF and II did not comprise a large percentage of total CKD patients. and TA of any degree with or without GS in stage 3; and CKDU patients comprised only 25.6% of CKD patients in severe IF and II and TA in stages 4 and 5. WP. Other provinces of the country were also affected with CKD, though the etiologies of the disease were primarily Prevalence of CKDU in Kebithigollewa according to diabetes (30.6%) and hypertension (13.2%). It has also water source been reported that the difference in incidence of diabetic In the Kebithigollewa area, 1762 individuals consumed water nephropathy between WP and other provinces was not from natural springs and 5842 consumed water from shallow statistically significant (P > 0.05). wells. A low prevalence of CKDU (1.5%) was noticed among We observed a higher risk of developing CKD for male consumers of natural spring water, and a relatively high farmers engaged in agricultural activities in NCP, indicating prevalence (7.7%) was identified among consumers of water that this group may be exposed to an unidentified etiological from shallow wells (Table 3). agent. The increasing age-specific prevalence of CKD from the age of 35 years onwards indicates the possibility of long- term exposure to an etiological agent and/or contributory DISCUSSION factors present in the environment. The male:female ratio The present cross-sectional study was conducted in all 9 increased with age from the 30–34 years age group, indicating provinces of the country, and a remarkably higher number of that males were more susceptible than females at younger CKD patients was noticed only in NCP. Prevalence of CKD ages; however, with continued exposure, the number of in NCP was four times higher than in the other provinces females affected also increased (Table 1). One-third of the due to the high number of CKDU patients, who comprised population older than 60 years was affected with CKD in J Epidemiol 2015;25(4):275-280 Bandara JMK, et al. 279 NCP. A study conducted in the U.S. in 2003 also revealed that to be conducted to encourage use of spring water at least for the prevalence of CKD was 0.2% in the 20–39 years age drinking and cooking. A total of 92% of CKD patients in group, 1.8% in the 40–59 years age group, and 7.6% in the NCR consumed water from shallow dug wells; therefore, 60–69 years age group. Intense farming activities and it can be speculated that the etiology of CKDU is strongly exposure to pesticides were identified as risk factors for related to drinking water sources. Observations in Andhra CKDU in Nicaragua, and all of the affected CKD patients in Pradesh in India suggest that some elements present in ground the BEN cluster and in India’s Andhra Pradesh cluster were water (fluoride, calcium, magnesium, and sulfate) may be 27 31 farmers. Moreover, the affected patients were adults between contributing factors for CKDU. 30 and 50 years of age in both the BEN cluster, and in CKD in Central American countries. ACKNOWLEDGEMENTS A total of 70% of CKD patients in NCP were with unknown etiology (CKDU) and only 15.7% and 9.6% were The authors acknowledge the Provincial Director of Health diagnosed as hypertensive and diabetic mellitus patients, services and South Asian Clinical Toxicology Research respectively. However, diabetes and hypertension contributed Collaboration for providing partial support for the study. to over 60% of the CKD cases in the WP. CKDU patients Conflicts of interest: None declared. were relatively younger than patients with CKD due to hypertension and diabetes. In addition, the current study REFERENCES revealed that the male:female ratio of the other etiologies of 1. Murray CJ, Lopez AD, Mathers CD, Stein C. The Global CKD, such as diabetic nephropathy and hypertension, in NCP Burden of Disease 2000 project: aims, methods and data sources. was only about 1.5:1 (Table 2), while the male:female ratio of Global Programme on Evidence for Health Policy Discussion. 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Journal of EpidemiologyPubmed Central

Published: Apr 5, 2015

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