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The incidence, prevalence and trends of Chronic Kidney Disease and Chronic Kidney Disease of uncertain aetiology (CKDu) in the North Central Province of Sri Lanka: an analysis of 30,566 patients

The incidence, prevalence and trends of Chronic Kidney Disease and Chronic Kidney Disease of... Background: Chronic Kidney Disease (CKD) of uncertain origin (CKDu) has affected North Central Province (Anuradhapura and Polonnaruwa districts) of Sri Lanka. The cause is still unknown. The objective of this study was to describe the incidence, prevalence and trend of CKD/CKDu in North Central Province of Sri Lanka. Methods: A cross sectional survey conducted in North Central Province with GPS mapping in CKDu highly affected areas. The diagnosis of CKD and staging were made according to the Kidney Disease: Improving Global Outcomes paper. Descriptive statistics used with chi-square test for evaluating dichotomous variables. Log rank test was used to compare survival rates. The population data was obtained from the 2011 Census. Results: There were 30,566 CKD/CKDu patients in the North Central Province. Incidence of 0.10 in 2009, 0.39 in 2016 in Anuradhapura district, decreased slightly to 0.29 in 2017. Incidence of 0.09 in 2009, 0.46 in 2016 in Polonnaruwa district, decreased slightly to 0.41 in 2017. The point prevalence in high incidence areas ranged from 2.44–4.35. The 5 year survival rate was 71.2 (Anuradhapura 72.4 and Polonnaruwa 68.3, p = 0.0212). More than 70, 40 and 33% of patients were over 50, 60 and 70 years of age respectively. A male preponderance was seen in all the divisional areas (ranging from 1.3:1 to 2.6:1) and in all the age groups. Farmers were the most affected (70.6% Anuradhapura district and 65.1% Polonnaruwa district). Majority in CKD stage I (4943, 69.6%). There were 1685 deaths (17.5% of total CKD/CKDu patients, 67.6% of total deaths in CKD/CKDu patients) occurring within the first 3 years of diagnosis. GPS mapping shows that there is a clustering of households with CKD/CKDu. (Continued on next page) * Correspondence: pubudu@nicslk.com Renal Disease Prevention and Research Unit, Ministry of Health, Colombo, Sri Lanka National Intensive Care Surveillance, Ministry of Health, Colombo, Sri Lanka Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ranasinghe et al. BMC Nephrology (2019) 20:338 Page 2 of 11 (Continued from previous page) Conclusions: The incidence of CKD/CKDu increased up to 2016 with a slight decrease in 2017. The most vulnerable age group was 40 to 60 years. There is a male preponderance. Farmers at a higher risk. Majority were in CKD stage 1. More than two thirds of the deaths of CKD/CKDu patients occurred within three years of diagnosis with disparities in 5 year survival rate among the two districts. There is clustering of cases. Keywords: Chronic kidney disease of uncertain origin (CKDu), CKD/CKDu incidence, CKD/CKDu prevalence, CKDu in Sri Lanka, CKD/CKDu survival rate Background Hospitals of Kabethigollawa, Padaviya, and Thambuththe- Chronic Kidney Disease of uncertain aetiology (CKDu) gama and Divisional Hospitals of Madawachchiya and was first reported in the North Central Province of Sri Kahatagasdigiliya in the Anuradhapura district and Dis- Lanka in the mid 90’s[1]. It is defined as occurrence of trict General Hospital Polonnaruwa, Base Hospital Madir- Chronic Kidney Disease (CKD) without a known under- igiriya and Divisional Hospital Hingurakgoda in the lying cause [2, 3]. In the affected provinces a significant Polonnaruwa district. During the second stage from 2011 association has been detected with a rural agricultural to 2016 a list of newly diagnosed patients was prospect- population [3, 4]. Most studies reported that males are ively collected from 11 sentinel sites (these included the more affected in numbers and severity [3, 5]. previously mentioned hospitals and Divisional Hospital Studies regarding histopathological features in early Kekirawa from Anuradhapura and Divisional Hospital and late CKDu in Sri Lanka have shown a predominant Bakamuna from Polonnaruwa) on a monthly basis. For all chronic tubulointerstitial nephritis associated with glom- cases from 2003 the diagnosis of CKD/CKDu and the sta- erular scarring, tubular atrophy, interstitial fibrosis and ging of the disease had been made by a Consultant Phys- varying degrees of inflammation [5–8]. Some have re- ician or a Nephrologist. This study does not distinguish ported Acute Kidney Injury [9–11]. Several hypotheses between CKD and CKDu. This is because definitive guide- were generated and studies have been conducted to find lines for distinguishing CKD from CKDu (in Sri Lanka) a possible aetiological cause for the disease. These in- according to WHO criteria became available only after clude pesticides [12, 13], fluoride [14], heavy metals such 2016 [16]. The diagnosis of chronic kidney disease (which as cadmium and arsenic [4, 12, 15], and hardness of includes CKD and CKDu) and staging of the disease in ground water [12, 14], but none have brought forth con- these hospitals had been made according to the Kidney vincing evidence regarding an aetiological factor. Disease: Improving Global Outcomes paper [17]. The Data regarding incidence, deaths and changing trends GFR estimations were derived using the CKD-EPI creatin- of CKD/CKDu in the highly affected areas is scanty. ine equation. (2009) [18]. Early studies showed a point prevalence of 3.7% in From 2009 onwards the grama niladhari division and Madawachchiya and 3.2% in Huruluwewa divisions [14] the residing village of the CKD/CKDu patients were in- but later evidence suggested this to be around 15–23% cluded in addition to the basic socio-demographic fea- in Anuradhapura and Polonnaruwa districts [4]. Because tures. The grama niladhari division which is the smallest of the wide discrepancy of these figures the objective of administrative division in Sri Lanka, comprises three to this study is to describe the incidence, prevalence and four villages. Several grama niladhari divisions are trend of CKD/CKDu in North Central Province of Sri grouped together to make a divisional secretariat area Lanka, which was the first province in which the disease (DS division). Several DS divisions together make a dis- was identified. trict. Anuradhapura district has 22 DS divisions while Polonnaruwa has 7 divisions. CKD/CKDu patients in the highly affected DS areas in Methods the Anuradhapura (6 DS divisions) and Polonnaruwa dis- This cross sectional survey of CKD/CKDu patients in tricts (4 DS divisions) were prospectively GPS mapped North Central Province (Anuradhapura and Polonnaruwa commencing from 2012 onwards using Garmin etrex 10 districts) was done in two stages. In the first stage data GPS receiver. In the Anuradhapura district these DS areas was retrieved retrospectively using in-ward patient regis- included Madawachchiya (2012), Kabethigollawa (2012), ters and clinic patient registers of the medical wards of the Padaviya (2013), Rambewa (2013), Horowpathana (2015) hospitals in the North Central Province for the period and Kahatagasdigiliya (2015). In the Polonnaruwa district from 2003 to 2010 (Anuradhapura district from 2003 to the DS areas included Madirigiriya (2013), Dimbulagala 2010 and Polonnaruwa district from 2006 to 2010). The (2013), Hingurakgoda (2014) and Elahara (2014). For this hospitals included Teaching Hospital Anuradhapura, Base Ranasinghe et al. BMC Nephrology (2019) 20:338 Page 3 of 11 purpose the list of patients diagnosed with CKD/CKDu from 2003 to 2008. The group from 2009 to 2012 was obtained from the relevant hospitals. As each DS div- had an exact date of diagnosis but had been diag- ision comprises several GN divisions, GPS mapping nosed at a time when community based CKD/CKDu process was focused on GN divisions. Apart from the list, screening was not organized properly. In 2013 orga- a snowballing method was used to include any CKD/ nized community based CKD/CKDu screening com- CKDu patients who may have not been identified by the menced in North Central Province. To calculate the hospital list. The identified CKD/CKDu patients and incidence, population data was obtained from the family members were asked whether they knew of any 2011 Census [19]. other residents with similar chronic kidney disease in the For the calculation of point prevalence and propor- neighborhood. The patients detected by this snowballing tion of CKD/CKDu deaths the total number of CKD/ method were included in the study only if they had med- CKDu patients obtained during the GPS mapping was ical documentation to confirm CKD/CKDu from any hos- used. Point prevalence was defined as the prevalence pital other than those listed previously. Both living as well of living CKD/CKDu patients identified at the time of as dead patients with confirmed medical documentation the GPS mapping in specified DS divisions. Period in- regarding CKD/CKDu were included for the mapping. cidence was defined as the total number of new During GPS mapping, by questioning the households and CKD/CKDu cases occurring during a specific number subsequently scrutinizing available hospital records (in- of years. Log rank test was used to compare survival cluding death certificates in some) an attempt was made rates. The population for each DS area was obtained to determine if complications of CKD/CKDu was respon- from the 2011 Census [19]. sible for the death. The exact cause of death was not de- termined as postmortems had not been done. Staging of Results CKD among the dead is unknown. The study includes a total of 30,566 CKD/CKDu patients The data collected from hospitals was statistically who had been diagnosed at eleven hospitals in the North analysed using SPSS version 10 and STATA 13 stu- Central Province from 2003 to 2017. dent version. Counts and percentages were used to The change of incidence from 2009 to 2017 is shown express discrete variables while mean and standard separately for the two districts in Fig. 1. Both districts deviation were used to express continuous variables. show a steady increase of CKD/CKDu incidence from In univariate analysis, chi-square test was used for 2009 to 2012. The increase was from 0.10 to 0.14 in the evaluating dichotomous variables. For analysis pur- Auradhapura district and 0.09 to 0.13 in the Polonna- poses we divided the study population into three ruwa district. From 2013 to 2016 there was a sharp in- groups; from years 2003 to 2008, 2009 to 2012, and crease with the incidence in 2016 being 0.39 in the 2013 to 2016. This was because the exact date of first Auradhapura district and 0.46 in the Polonnaruwa dis- diagnosiswas notavailable forthe patientpopulation trict. However in 2017 a decline in the incidence was Fig. 1 Incidence of CKD/CKDu patients in Anuradhapura and Polonnaruwa districts Ranasinghe et al. BMC Nephrology (2019) 20:338 Page 4 of 11 observed in both districts (Auradhapura 0.29 and Polon- Polonnaruwa). This male preponderance was seen in all naruwa 0.41). the DS divisions (ranging from 1.3:1 to 2.6:1) and in all Table 1 shows the distribution of patients in the three the age groups. It is lowest in the younger age groups time category periods from 2003 to 2008, 2009 to 2012 (male:female is 1.1:1 in 11–20 years age group in both and 2013 to 2017. The mean age of the CKD/CKDu pa- districts) and highest in 41–60 years age group (male:fe- tients was 57.2 years with SD ± 13.4 years (Anuradhapura male is 2:1 in Anuradhapura and 2.4:1 in Polonnaruwa). district 57.2 years with SD ± 13.1 years, Polonnaruwa dis- After 60 years, the male preponderance diminished but trict mean age was 57.4 years with SD ± 14.1 years). In still remained high (male:female is 1.8:1 in Anuradha- both districts more than 70, 40 and 33% of patients were pura and 2.2:1 in Polonnaruwa in > 70 years age over 50, 60 and 70 years of age respectively. Only a small category). percentage of patients (5.4–8.6%) were in the 31 to 40 Farmers were the most commonly affected occupation years age group. group (70.6% from Anuradhapura district and 65.1% There was a male preponderance in both districts from Polonnaruwa district). Details of the staging (Table (male:female ratio 1.8:1 in Anuradhapura; 2.2:1 in 1) was available only in a minority of the group (7103, Table 1 Socio-demographic characteristics of CKD/CKDu in North Central Province Characteristics Anuradhapura (n = 20,473) Polonnaruwa (n = 10,093) 2003 to 2008 2009 to 2012 2013 to 2017 2006 to 2008 2009 to 2012 2013 to 2017 (n = 4039) (n = 4157) (n = 12,277) (n = 1474) (n = 2011) (n = 6608) Number (%) Number (%) Number (%) Number (%) Number (%) Number (%) Period Incidence 0.47 0.48 1.43 0.36 0.49 1.63 Sex Male 2731 (67.6%) 2796 (67.3%) 7577 (61.7%) 1132 (76.8%) 1477 (73.4%) 4309 (65.2%) Female 1308 (32.4%) 1361 (32.7%) 4700 (38.3%) 342 (23.2%) 534 (26.6%) 2299 (34.8%) Age (years) Male mean (SD) 56.7 (±13.9) 56.9 (±12.8) 57.7 (±12.2) 56.3 (±14.9) 58.9 (±11.9) 58.0 (±13.6) Female mean (SD) 56.6 (±15.5) 56.8 (±13.5) 56.8 (±13.3) 53.8 (±17.8) 59.2 (±13.1) 56.0 (±15.3) Age groups (years) < 10 13 (0.3%) 13 (0.3%) 15 (0.1%) 15 (1.0%) 4 (0.2%) 17 (0.3%) 11–20 102 (2.5%) 48 (1.1%) 168 (1.4%) 38 (2.6%) 8 (0.4%) 123 (1.8%) 21–30 100 (2.5%) 95 (2.3%) 205 (1.7%) 45 (3.0%) 27 (1.3%) 176 (2.7%) 31–40 262 (6.5%) 242 (5.8%) 748 (6.1%) 118 (8.0%) 106 (5.3%) 482 (7.3%) 41–50 706 (17.5%) 768 (18.5%) 1989 (16.2%) 261 (17.7%) 307 (15.3%) 1025 (15.5%) 51–60 1229 (30.4%) 1330 (32.0%) 4000 (32.6%) 420 (28.5%) 613 (30.5%) 1890 (28.6%) 61–70 1018 (25.2%) 1118 (26.9%) 3665 (29.8%) 334 (22.7%) 625 (31.1%) 1797 (27.2%) > 70 609 (15.1%) 543 (13.1%) 1487 (12.1%) 243 (16.5%) 321 (15.9%) 1098 (16.6%) Occupation Farmer 3118 (77.2%) 3174 (76.4%) 5198 (42.3%) 950 (83.3%) 1439 (78.1%) 3116 (47.1%) Other 921 (22.8%) 983 (23.6%) 2872 (23.4%) 191 (16.7%) 403 (21.9%) 2363 (35.8%) Not available 0 0 4207 (34.3%) 333 (22.6%) 169 (8.4%) 1129 (17.1%) Staging of CKD (n = 7103) Stage I 6 379 3109 242 229 978 Stage II 0 15 108 0 1 44 Stage III 0 289 271 0 6 374 Stage IV 0 165 204 0 0 136 Stage V 0 154 256 0 10 127 Reported Deaths a a,b Institutions Not reported 599 (14.4%) 1194 (12.2%) Not reported Not reported Not reported Percentage was calculated by taking the total number of CKD/CKDu for the respective period as the denominator 2017 deaths were not available Ranasinghe et al. BMC Nephrology (2019) 20:338 Page 5 of 11 23.2%). Of this most CKD/CKDu patients were in stage I groups of DS divisions of the North Central Province (4943, 69.6%). Stages II, III, IV and V had 2160 (30.4%) (p < 0.001, 95% Confidence Interval for incidence > 2.40 with 547 (7.7%) patients in Stage V respectively. was 2.44–3.63, for incidence < 2.40 was 1.02–1.51). The incidence of CKD/CKDu from 2012 to 2017 in There were 9653 CKD/CKDu patients (6335 from the DS divisions of both districts is shown in Table 2. Anuradhapura and 3318 from Polonnaruwa districts) in Comparison of divisions with period incidence of over the 10 DS divisions with the highest incidence which 2.40 (six in Anuradhapura district and one in Polonna- were GPS mapped. The point prevalence of CKD/CKDu ruwa district) with those below two shows that there is a in these high incidence areas of Auradhapura ranged statistical difference of period incidence among the two from 1.52–3.35 while it was 0.67–1.25 in Polonnaruwa. Table 2 Newly reported CKD/CKDu patients and CKD/CKDu prevalence data Ranasinghe et al. BMC Nephrology (2019) 20:338 Page 6 of 11 The 5 year survival rate was 71.2 (Anuradhapura 72.4, steadily increasing provision of safe drinking water in 95% CI 71.10–73.7 and Polonnaruwa 68.3, 95% CI 66.1– the affected areas [20]. 70.4). Anuradhapura district has a significantly higher The Balkan Endemic Nephropathy (BEN) thought to survival rate compared to Polonnaruwa district (log-rank be caused by environmental contaminants has shown test p = 0.0212). fluctuating incidence rates since its discovery in 1956 Among 9653 patients who were GPS mapped, 2491 [21]. However its prevalence has remained 3–7% over (25.8%) were dead patients. This included 1655 deaths, the last five decades [22]. (26.1%) from Anuradhapura and 836 deaths (25.2%) In the present study the point prevalence from GPS from Polonnaruwa districts. Among these deaths 578 mapping ranged from 1.52 to 3.35 in Anuradhapura and (6% of total CKD/CKDu patients, 23.2% of total deaths 0.67 to 1.25 in Polonnaruwa. These results are in agree- in CKD/CKDu patients) occurred within one year of ment with the study done by Chandrajith et al. (2011) diagnosis (Anuradhapura 396, 23.9%, Polonnaruwa 182, which showed a point prevalence of 3.7% in Madawach- 21.8%) while 1685 (17.5% of total CKD/CKDu patients, chiya and 3.2% in Huruluwewa [14] but not with the 67.6% of total deaths in CKD/CKDu patients) occurred study done by Jayathilaka et al. (2013) which showed a within the first 3 years of diagnosis (1115, 67.4% from point prevalence of 15–23% [4]. A possible explanation Anuradhapura and 570, 68.2% from Polonnaruwa dis- for this is the flows in the design, interpretation and tricts). Within the first 5 years of diagnosis 2063 patients conclusion of the study as shown by Jayasumna et al. were dead (21.4% of total CKD/CKDu patients, 82.8% of (2013) [13]. total deaths in CKD/CKDu patients). This included Our data shows that in the three time categories 1362 deaths (82.3% of total deaths in CKD/CKDu pa- (2003–2008,2009-2012,2013–2017) the age groups that tients) from Anuradhapura and 701 deaths (83.9% of were most affected were older patients (50 to 60 years total deaths in CKD/CKDu patients) from Polonna- and > 60 years). There was no increase within different ruwa districts. It was observed that over 95% of the age groups during the time periods that were studied. As patients (approximately 2390) did not have identifi- this study does not distinguish between CKD and CKDu able other causes of deaths (such as road traffic acci- it could be argued that the increased incidence in elderly dents, cancer etc.). may be due to diabetic and hypertensive nephropathy. Figure 2 depicts the total number of CKD/CKDu pa- However previous studies have demonstrated that dia- tients in different DS divisions of Sri Lanka which had betes and hypertension contribute to only a minority of been collected using the same methodology as in the CKD in this region [3]. present study other than for GPS mapping. This figure If the majority of patients in this study had CKDu, shows the seven DS divisions with CKD/CKDu period possible explanations to the increased incidence in older incidence of > 2.40 in Anuradhapura and Polonnaruwa patients include an aetiological factor with a cumulative districts in North Central Province are clustered to- effect or an aetiological factor which had a prolonged gether. This figure also shows that adjacent DS divisions period of pathogenesis. However if this was true, in the of neighboring districts also have high numbers. later time periods between 2009 to 2012 and 2013 to Figures 3, 4 and 5 shows GPS mapping of CKD/CKDu 2017 there should have been some increase in the pro- patients in the two DS divisions with the highest preva- portion of CKD./CKDu in other age groups as well espe- lence in Anuradhapura and Polonnaruwa districts. This cially if a common environmental factor was responsible. shows that there is a clustering of households with The other possible explanation is that the elderly people CKD/CKDu within DS divisions with the highest are more susceptible to an aetiological factor or factors prevalence. due to the physiological reasons or co-morbidities. BEN shows a low incidence in younger age groups and Discussion higher incidence after 65 years with the onset between Our study shows that the incidence of CKD/CKDu in 40 to 60 years [22]. It has a long latent period and thus North Central Province increased upto 2016. One reason affects the exposed at a later part of their life [21]. Meso- for the rapid increase in the incidence of the disease in american Nephropathy also shows a high proportion of both districts in North Central Province after 2012 may affected individuals between 50 to 70 age group [23]. be the organized community based screening pro- Our study shows an increase proportion of male pa- grammes conducted by the health sector resulting in in- tients within the different age groups and in the different creased case detection. Other reasons include increased DS divisions. Explanation for this male preponderance exposure to aetiological factor or factors which have not includes predominant exposure to the risk factors such been convincingly identified as of yet. This study also as pesticides in farmers or presence of disease modifying shows that the incidence has declined slightly in 2017 in factors (eg. use of alcohol and smoking). The possibility both districts. A probable reason for this may be the of a protective role by female hormones is unlikely as Ranasinghe et al. BMC Nephrology (2019) 20:338 Page 7 of 11 Fig. 2 Total number of CKD/CKDu patients in divisional secretariat areas. The map is created based on the data from this study. (This data was collected from hospitals using the same methodology as in this study from other districts) the male:female is lower in the female reproductive age CKDu in Sri Lanka with the disease being commoner groups. In both districts majority of patients were among males and older age groups and agricultural farmers. However majority of the people residing in workers [23]. these areas are anyway farmers [19]. Explanation for Our study also shows that the incidence is not uniform farmers being more affected may be due to higher ex- among all DS divisions of the two affected districts in posure to aetiological agents such as pesticides. Figure 4 North Central Province. There were six DS divisions in confirms that patients are clustered around areas with Anuradhapura and one from Polonnaruwa that reported paddy fields. This is further confirmed in Figs. 3 and 5 a period incidence of over 2.4. These high incidence which shows that GN divisions with a high population areas are clustered closer to each other. This is also ap- density which are of urban settings do not have high parent from Fig. 2 which shows the geographical distri- number of CKD/CKDu patients. Thus clustering pattern bution of DS divisions that had reported more than within DS divisions is not related to population density. 1000 CKD/CKDu cases from 2003 to 2017. These high In BEN both males and females are equally effected incidence DS divisions in North Central Province border [21]. However similar to CKDu in Sri Lanka it was DS divisions with high number of CKD/CKDu patients seen among the rural farming population [22]. The in the adjoining districts. Figure 2 indicates that the Mesoamerican Nephropathy also has similarities to number of reported CKD/CKDu patients decrease steadily Ranasinghe et al. BMC Nephrology (2019) 20:338 Page 8 of 11 Fig. 3 GPS mapping of CKD/CKDu patients vs population density in Madawachchiya DS division of Anuradhapura district. The map is created based on the data from this study. *The high population density GN areas indicated in dark brown are urban settings beyond the high incident areas. Thus the effect of the Similar findings are seen in BEN which exhibit focal causative factor may be distributed in a gradient fashion occurrence with affected and spared households in close with high incidence areas having the most exposure to the proximity within the same village [25]. BEN was re- causative factor while the lower areas probably have lower ported to have numerous members of one or several exposure. The other explanation may be that the high inci- generations in a single household [26]. denceareas mayhaveother factorsthatcontributetothe To the best of our knowledge this is the first publica- causation of disease after initial exposure to a toxic agent. tion indicating death rates and 5 year survival rates of GPS mapping indicates clustering of cases in both high CKD/CKDu patients in CKDu affected areas in Sri and low incident areas. According to the maps there are Lanka. Results from the GPS mapping shows that a total high prevalent areas and low prevalent areas even within of 2491 (25.8%) out of 9653 CKD/CKDu patients died. a GN division. When the maps are superimposed with Although the exact cause of death was not explored in paddy fields and irrigation tanks as shown in Fig. 4, this detail, during the GPS mapping, on discussion with the clustering seems to be mainly among the farming com- households and scrutinizing available hospital records munities and around irrigation tanks. The irrigation (including death certificates in some), it was observed tanks form a cascading system with water flowing from that over 95% of the patients (approximately 2390) did higher levels to lower levels. While conducting the study not have identifiable other causes of deaths (such as road we noticed clustering of CKD/CKDu patients towards traffic accidents, cancer etc.) and therefore were pre- the lower part of the tanks. Previous studies have also sumed to have died of complications resulting from identified clustering of cases towards the lower altitude CKD/CKDu. In comparison hospital based data shows of the tanks [24]. 1793 deaths among 16,434 patients with a death rate of Ranasinghe et al. BMC Nephrology (2019) 20:338 Page 9 of 11 Fig. 4 GPS mapping of CKD/CKDu patients’ occupation with water & paddy areas in Madawachchiya DS division of Anuradhapura district. The map is created based on the data from this study 10% (refer Table 1). This highlights the fact that the im- region [3]. Another study has shown that the prevalence plications of CKDu in relation to mortality may be more of diabetes in North Central Province during the same serious than what is indicated in hospital based statistics. period was 9.6% [27]. Based on these previous documen- This study showed a significantly high (log-rank test tations it seems unlikely that diabetes and hypertension p = 0.0212) 5 year survival rate in Anuradhapura (71.2%) would have contributed to major proportion of CKD in compared to that of Polonnaruwa (68.3%). One possible the region. explanation is the lack of access to health care facilities in Polonnaruwa compared to Anuradhapura based on Conclusion the assumption that majority of patients died due to The incidence of CKD/CKDu in North Central Province CKD/CKDu related causes. has increased up to 2016 with a slight decrease in 2017. Results from the GPS mapping shows that 6% of total A possible explanation for this may be the provision of CKD/CKDu patients died within the first year of diagno- safe drinking water. The most vulnerable age groups are sis whilst 17.5% died within three years. This represents from 40 to 60 years. There is a male preponderance. 67.7% of total deaths in CKD/CKDu. This emphasizes Farmers seem to be at a higher risk. Limited data shows the immediate need for hospital with facilities for dialy- that majority of patients are in CKD stage 1. sis and ideally renal transplants. The 5 year survival rate was 71.2. Anuradhapura dis- This study is limited by the fact that a distinction was trict (5 year survival rate 72.4) has a significantly higher not made between CKD and CKDu as data on co-mor- survival rate compared to Polonnaruwa district (5 year bidities was not collected. However a previous study has survival rate 68.3). Among the deaths in CKD/CKDu pa- demonstrated that diabetes (2%) and hypertension (14%) tients 578 (6% of total CKD/CKDu patients, 23.2% of contribute to only a minority of CKD/CKDu in this total deaths in CKD/CKDu patients) occurred within Ranasinghe et al. BMC Nephrology (2019) 20:338 Page 10 of 11 Fig. 5 GPS mapping of CKD/CKDu patients vs population density in Madirigiriya DS division of Polonnaruwa district. The map is created based on the data from this study one year of diagnosis while 1685 (17.5% of total CKD/ GWGP, RHK, APDS, KGDS, JMCNG, SKCRK, MSFS, JSC and CDS all helped to write the manuscript. All authors read and approved the final manuscript. CKDu patients, 67.6% of total deaths in CKD/CKDu pa- tients) occurred within the first 3 years of diagnosis. Funding Within the first 5 years of diagnosis 2063 patients were None dead (21.4% of total CKD/CKDu patients, 82.8% of total Availability of data and materials deaths in CKD/CKDu patients). Some of the aggregated data are available at the renal registry https://nicst. Areas reporting higher incidence of CKD/CKDu are com/iframe-renal-dev/ while all aggregated data used for this study are available from the Renal Disease Prevention and Research Unit, Ministry of clustered together. GPS mapping shows that even within Health, Sri Lanka. The data can be obtained on reasonable request with the the high incidence areas there is geographic clustering. permission from the Director General of Health Services, Ministry of Health, The clustering was mainly around paddy fields and irri- Sri Lanka. gation tanks. Ethics approval and consent to participate Abbreviations The data used for this study are anonymised aggregated (routinely gathered BEN: Balkan Endemic Nephropathy; CKD: Chronic Kidney Disease; during service delivery) secondary data. We have obtained this secondary CKDu: Chronic Kidney Disease of uncertain aetiology; DS: Divisional data and conducted the analysis. Most of this data is also available in the Sri Secretariat Lanka Renal Registry. The aggregate data is accessible to any persons. The approval for this study was obtained from the Ministry of Health, Sri Lanka. Acknowledgements Hospital and field staff of North Central Province. Consent for publication Not applicable Authors’ contributions AVR, GWGP, RHK, APDS, KGDS, JMCNG, SKCRK, MSFS, JSC and CDS all helped to prepare the methodology. KGDS, JMCNG, SKCRK and MSFS extracted the Competing interests data from the secondary data sources. GWGP and RHK did the analysis. AVR, The authors declare that they have no competing interests. Ranasinghe et al. BMC Nephrology (2019) 20:338 Page 11 of 11 Author details 17. Levey AS, Eckardt KU, Tsukamoto Y, Levin A, Coresh J, Rossert J, et al. Renal Disease Prevention and Research Unit, Ministry of Health, Colombo, Definition and classification of chronic kidney disease: a position statement Sri Lanka. National Intensive Care Surveillance, Ministry of Health, Colombo, from kidney disease: improving global outcomes (KDIGO). Kidney Int. 2005; Sri Lanka. Office of Additional Secretary (Development), Ministry of Health, 67:2089–100. Colombo, Sri Lanka. Department of Pathology, Faculty of Medicine, 18. Levey AS, Stevens LA, Schmid CH, Zhang Y, Castro A III. New equation to University of Colombo, Colombo, Sri Lanka. estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604–12. 19. Department of Census and Statistics. Census of Populationn and Housing of Received: 2 October 2018 Accepted: 29 July 2019 Sri Lanka, 2012. Colombo; 2012. 20. Ranasinghe HRALN, Lokuge LDMN, Edirisinghe JC, Bandara L. Water treatment, preventive measures and the chronic kidney disease in the farming community in Sri Lanka. J Agric Sci-Sri Lanka. 2015;10:98–108. 21. Janković S, Bukvić D, Marinković J, Janković J, Marić I, Djukanović L. Time References trends in Balkan endemic nephropathy incidence in the most affected 1. Abeysekera DTDJ, Kaiyoom SAA, Dissanayake SU. Place of peritoneal dialysis region in Serbia, 1977-2009: the disease has not yet disappeared. Nephrol in the management of renal failure patients admitted to General Hospital Dial Transplant. 2011;26:3171–6. Kandy. In: Kandy Society of Medicine 18th Annual Academic Conference; 22. Stiborová M, Arlt VM, Schmeiser HH. Balkan endemic nephropathy: an update on its aetiology. Arch Toxicol. 2016;90:2595–615. 2. Redmon JH, Elledge MF, Womack DS, Wickremashinghe R, Wanigasuriya KP, 23. Lebov JF, Valladares E, Peña R, Peña EM, Sanoff SL, Cisneros EC, et al. A Peiris-John RJ, et al. Additional perspectives on chronic kidney disease of population-based study of prevalence and risk factors of chronic kidney unknown aetiology (CKDu) in Sri Lanka--lessons learned from the WHO disease in León, Nicaragua. Can J Kidney Heal Dis. 2015;2:1–14. CKDu population prevalence study. BMC Nephrol. 2014;15:125. 24. Jayasekara KB, Dissanayake DM, Adhikari SB, Bandara P. Geographical 3. Athuraliya TNC, Abeysekera DTDJ, Amerasinghe PH, Kumarasiri PVR, distribution of chronic kidney disease of unknown origin in North Central Dissanayake V. Prevalence of chronic kidney disease in two tertiary care Region of Sri Lanka. Ceylon Med J. 2013;58:6–10. hospitals: high proportion of cases with uncertain aetiology. Ceylon Med J. 25. Bamias G, Boletis J. Balkan nephropathy: evolution of our knowledge. Am J 2009;54:23–5. Kidney Dis. 2008;52:606–16. 4. Jayatilake N, Mendis S, Maheepala P, Mehta FR. Chronic kidney disease of 26. Stefanovic V, Cukuranovic R, Miljkovic S, Marinkovic D, Toncheva D. Fifty uncertain aetiology: prevalence and causative factors in a developing years of Balkan endemic nephropathy: challenges of study using country. BMC Nephrol. 2013;14:180. https://doi.org/10.1186/1471-2369-14-1 epidemiological method. Ren Fail. 2009;31:409–18. 27. Katulanda P, Rathnapala DAV, Sheriff R, Mathews DR. Province and ethinic 5. Wijetunge S, Ratnatunga NVI, Abeysekera DTDJ, Wazil AWM, Selvarajah M, specific prevalance of diabetes among Sri Lankan adults. Sri Lanka J Ratnatunga CN. Retrospective analysis of renal histology in asymptomatic Diabetes Endocrinol Metabolism. 2011;1:2–7. patients with probable chronic kidney disease of unknown aetiology in Sri Lanka. Ceylon Med J. 2013;58:142–7. 6. Selvarajah M, Weeratunga P, Sivayoganthan S, Rathnatunga N, Rajapakse S. Publisher’sNote Clinicopathological correlates of chronic kidney disease of unknown Springer Nature remains neutral with regard to jurisdictional claims in etiology in Sri Lanka. Indian J Nephrol. 2016;26:357–63. published maps and institutional affiliations. 7. Wijetunge S, Ratnatunga NVI, Abeysekera TDJ, Wazil AWM, Selvarajah M. Endemic chronic kidney disease of unknown etiology in Sri Lanka: correlation of pathology with clinical stages. Indian J Nephrol. 2015;25: 274–80. 8. Nanayakkara S, Komiya T, Ratnatunga N, Senevirathna STMLD, Harada KH, Hitomi T, et al. Tubulointerstitial damage as the major pathological lesion in endemic chronic kidney disease among farmers in North Central Province of Sri Lanka. Environ Health Prev Med. 2012;17:213–21. 9. Nanayakkara S, Senevirathna STMLD, Abeysekera T, Chandrajith R, Ratnatunga N, Gunarathne EDL, et al. An integrative study of the genetic, social and environmental determinants of chronic kidney disease characterized by tubulointerstitial damages in the North Central Region of Sri Lanka. J Occup Health. 2014;56:28–38. 10. Glaser J, Lemery J, Rajagopalan B, Diaz HF, García-Trabanino R, Taduri G, et al. Climate change and the emergent epidemic of CKD from heat stress in rural communities: the case for heat stress nephropathy. Clin J Am Soc Nephrol. 2016;11:1472–83. 11. Liaño F, Tenorio MT, Rodríguez-Mendiola N, Ponte B. Acute kidney injury as a risk factor for chronic kidney diseases in disadvantaged populations. Clin Nephrol. 2010;74(Suppl 1):S89–94. 12. Jayasumana C, Gunatilake S, Senanayake P. Glyphosate, hard water and nephrotoxic metals: are they the culprits behind the epidemic of chronic kidney disease of unknown etiology in Sri Lanka? Int J Environ Res Public Health. 2014;11:2125–47. 13. Jayasumana C, Gajanayake R, Siribaddana S. Importance of arsenic and pesticides in epidemic chronic kidney disease in Sri Lanka. BMC Nephrol. 2014;15:124. https://doi.org/10.1186/1471-2369-15-124. 14. Chandrajith R, Nanayakkara S, Itai K, Aturaliya TNC, Dissanayake CB, Abeysekera T, et al. Chronic kidney diseases of uncertain etiology (CKDue) in Sri Lanka: geographic distribution and environmental implications. Environ Geochem Health. 2011;33:267–78. 15. Wanigasuriya KP, Peiris-John RJ, Wickremasinghe R. Chronic kidney disease of unknown aetiology in Sri Lanka: is cadmium a likely cause? BMC Nephrol. 2011;12:32. https://doi.org/10.1186/1471-2369-12-32. 16. WHO. 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The incidence, prevalence and trends of Chronic Kidney Disease and Chronic Kidney Disease of uncertain aetiology (CKDu) in the North Central Province of Sri Lanka: an analysis of 30,566 patients

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Medicine & Public Health; Nephrology; Internal Medicine
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1471-2369
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10.1186/s12882-019-1501-0
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Abstract

Background: Chronic Kidney Disease (CKD) of uncertain origin (CKDu) has affected North Central Province (Anuradhapura and Polonnaruwa districts) of Sri Lanka. The cause is still unknown. The objective of this study was to describe the incidence, prevalence and trend of CKD/CKDu in North Central Province of Sri Lanka. Methods: A cross sectional survey conducted in North Central Province with GPS mapping in CKDu highly affected areas. The diagnosis of CKD and staging were made according to the Kidney Disease: Improving Global Outcomes paper. Descriptive statistics used with chi-square test for evaluating dichotomous variables. Log rank test was used to compare survival rates. The population data was obtained from the 2011 Census. Results: There were 30,566 CKD/CKDu patients in the North Central Province. Incidence of 0.10 in 2009, 0.39 in 2016 in Anuradhapura district, decreased slightly to 0.29 in 2017. Incidence of 0.09 in 2009, 0.46 in 2016 in Polonnaruwa district, decreased slightly to 0.41 in 2017. The point prevalence in high incidence areas ranged from 2.44–4.35. The 5 year survival rate was 71.2 (Anuradhapura 72.4 and Polonnaruwa 68.3, p = 0.0212). More than 70, 40 and 33% of patients were over 50, 60 and 70 years of age respectively. A male preponderance was seen in all the divisional areas (ranging from 1.3:1 to 2.6:1) and in all the age groups. Farmers were the most affected (70.6% Anuradhapura district and 65.1% Polonnaruwa district). Majority in CKD stage I (4943, 69.6%). There were 1685 deaths (17.5% of total CKD/CKDu patients, 67.6% of total deaths in CKD/CKDu patients) occurring within the first 3 years of diagnosis. GPS mapping shows that there is a clustering of households with CKD/CKDu. (Continued on next page) * Correspondence: pubudu@nicslk.com Renal Disease Prevention and Research Unit, Ministry of Health, Colombo, Sri Lanka National Intensive Care Surveillance, Ministry of Health, Colombo, Sri Lanka Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ranasinghe et al. BMC Nephrology (2019) 20:338 Page 2 of 11 (Continued from previous page) Conclusions: The incidence of CKD/CKDu increased up to 2016 with a slight decrease in 2017. The most vulnerable age group was 40 to 60 years. There is a male preponderance. Farmers at a higher risk. Majority were in CKD stage 1. More than two thirds of the deaths of CKD/CKDu patients occurred within three years of diagnosis with disparities in 5 year survival rate among the two districts. There is clustering of cases. Keywords: Chronic kidney disease of uncertain origin (CKDu), CKD/CKDu incidence, CKD/CKDu prevalence, CKDu in Sri Lanka, CKD/CKDu survival rate Background Hospitals of Kabethigollawa, Padaviya, and Thambuththe- Chronic Kidney Disease of uncertain aetiology (CKDu) gama and Divisional Hospitals of Madawachchiya and was first reported in the North Central Province of Sri Kahatagasdigiliya in the Anuradhapura district and Dis- Lanka in the mid 90’s[1]. It is defined as occurrence of trict General Hospital Polonnaruwa, Base Hospital Madir- Chronic Kidney Disease (CKD) without a known under- igiriya and Divisional Hospital Hingurakgoda in the lying cause [2, 3]. In the affected provinces a significant Polonnaruwa district. During the second stage from 2011 association has been detected with a rural agricultural to 2016 a list of newly diagnosed patients was prospect- population [3, 4]. Most studies reported that males are ively collected from 11 sentinel sites (these included the more affected in numbers and severity [3, 5]. previously mentioned hospitals and Divisional Hospital Studies regarding histopathological features in early Kekirawa from Anuradhapura and Divisional Hospital and late CKDu in Sri Lanka have shown a predominant Bakamuna from Polonnaruwa) on a monthly basis. For all chronic tubulointerstitial nephritis associated with glom- cases from 2003 the diagnosis of CKD/CKDu and the sta- erular scarring, tubular atrophy, interstitial fibrosis and ging of the disease had been made by a Consultant Phys- varying degrees of inflammation [5–8]. Some have re- ician or a Nephrologist. This study does not distinguish ported Acute Kidney Injury [9–11]. Several hypotheses between CKD and CKDu. This is because definitive guide- were generated and studies have been conducted to find lines for distinguishing CKD from CKDu (in Sri Lanka) a possible aetiological cause for the disease. These in- according to WHO criteria became available only after clude pesticides [12, 13], fluoride [14], heavy metals such 2016 [16]. The diagnosis of chronic kidney disease (which as cadmium and arsenic [4, 12, 15], and hardness of includes CKD and CKDu) and staging of the disease in ground water [12, 14], but none have brought forth con- these hospitals had been made according to the Kidney vincing evidence regarding an aetiological factor. Disease: Improving Global Outcomes paper [17]. The Data regarding incidence, deaths and changing trends GFR estimations were derived using the CKD-EPI creatin- of CKD/CKDu in the highly affected areas is scanty. ine equation. (2009) [18]. Early studies showed a point prevalence of 3.7% in From 2009 onwards the grama niladhari division and Madawachchiya and 3.2% in Huruluwewa divisions [14] the residing village of the CKD/CKDu patients were in- but later evidence suggested this to be around 15–23% cluded in addition to the basic socio-demographic fea- in Anuradhapura and Polonnaruwa districts [4]. Because tures. The grama niladhari division which is the smallest of the wide discrepancy of these figures the objective of administrative division in Sri Lanka, comprises three to this study is to describe the incidence, prevalence and four villages. Several grama niladhari divisions are trend of CKD/CKDu in North Central Province of Sri grouped together to make a divisional secretariat area Lanka, which was the first province in which the disease (DS division). Several DS divisions together make a dis- was identified. trict. Anuradhapura district has 22 DS divisions while Polonnaruwa has 7 divisions. CKD/CKDu patients in the highly affected DS areas in Methods the Anuradhapura (6 DS divisions) and Polonnaruwa dis- This cross sectional survey of CKD/CKDu patients in tricts (4 DS divisions) were prospectively GPS mapped North Central Province (Anuradhapura and Polonnaruwa commencing from 2012 onwards using Garmin etrex 10 districts) was done in two stages. In the first stage data GPS receiver. In the Anuradhapura district these DS areas was retrieved retrospectively using in-ward patient regis- included Madawachchiya (2012), Kabethigollawa (2012), ters and clinic patient registers of the medical wards of the Padaviya (2013), Rambewa (2013), Horowpathana (2015) hospitals in the North Central Province for the period and Kahatagasdigiliya (2015). In the Polonnaruwa district from 2003 to 2010 (Anuradhapura district from 2003 to the DS areas included Madirigiriya (2013), Dimbulagala 2010 and Polonnaruwa district from 2006 to 2010). The (2013), Hingurakgoda (2014) and Elahara (2014). For this hospitals included Teaching Hospital Anuradhapura, Base Ranasinghe et al. BMC Nephrology (2019) 20:338 Page 3 of 11 purpose the list of patients diagnosed with CKD/CKDu from 2003 to 2008. The group from 2009 to 2012 was obtained from the relevant hospitals. As each DS div- had an exact date of diagnosis but had been diag- ision comprises several GN divisions, GPS mapping nosed at a time when community based CKD/CKDu process was focused on GN divisions. Apart from the list, screening was not organized properly. In 2013 orga- a snowballing method was used to include any CKD/ nized community based CKD/CKDu screening com- CKDu patients who may have not been identified by the menced in North Central Province. To calculate the hospital list. The identified CKD/CKDu patients and incidence, population data was obtained from the family members were asked whether they knew of any 2011 Census [19]. other residents with similar chronic kidney disease in the For the calculation of point prevalence and propor- neighborhood. The patients detected by this snowballing tion of CKD/CKDu deaths the total number of CKD/ method were included in the study only if they had med- CKDu patients obtained during the GPS mapping was ical documentation to confirm CKD/CKDu from any hos- used. Point prevalence was defined as the prevalence pital other than those listed previously. Both living as well of living CKD/CKDu patients identified at the time of as dead patients with confirmed medical documentation the GPS mapping in specified DS divisions. Period in- regarding CKD/CKDu were included for the mapping. cidence was defined as the total number of new During GPS mapping, by questioning the households and CKD/CKDu cases occurring during a specific number subsequently scrutinizing available hospital records (in- of years. Log rank test was used to compare survival cluding death certificates in some) an attempt was made rates. The population for each DS area was obtained to determine if complications of CKD/CKDu was respon- from the 2011 Census [19]. sible for the death. The exact cause of death was not de- termined as postmortems had not been done. Staging of Results CKD among the dead is unknown. The study includes a total of 30,566 CKD/CKDu patients The data collected from hospitals was statistically who had been diagnosed at eleven hospitals in the North analysed using SPSS version 10 and STATA 13 stu- Central Province from 2003 to 2017. dent version. Counts and percentages were used to The change of incidence from 2009 to 2017 is shown express discrete variables while mean and standard separately for the two districts in Fig. 1. Both districts deviation were used to express continuous variables. show a steady increase of CKD/CKDu incidence from In univariate analysis, chi-square test was used for 2009 to 2012. The increase was from 0.10 to 0.14 in the evaluating dichotomous variables. For analysis pur- Auradhapura district and 0.09 to 0.13 in the Polonna- poses we divided the study population into three ruwa district. From 2013 to 2016 there was a sharp in- groups; from years 2003 to 2008, 2009 to 2012, and crease with the incidence in 2016 being 0.39 in the 2013 to 2016. This was because the exact date of first Auradhapura district and 0.46 in the Polonnaruwa dis- diagnosiswas notavailable forthe patientpopulation trict. However in 2017 a decline in the incidence was Fig. 1 Incidence of CKD/CKDu patients in Anuradhapura and Polonnaruwa districts Ranasinghe et al. BMC Nephrology (2019) 20:338 Page 4 of 11 observed in both districts (Auradhapura 0.29 and Polon- Polonnaruwa). This male preponderance was seen in all naruwa 0.41). the DS divisions (ranging from 1.3:1 to 2.6:1) and in all Table 1 shows the distribution of patients in the three the age groups. It is lowest in the younger age groups time category periods from 2003 to 2008, 2009 to 2012 (male:female is 1.1:1 in 11–20 years age group in both and 2013 to 2017. The mean age of the CKD/CKDu pa- districts) and highest in 41–60 years age group (male:fe- tients was 57.2 years with SD ± 13.4 years (Anuradhapura male is 2:1 in Anuradhapura and 2.4:1 in Polonnaruwa). district 57.2 years with SD ± 13.1 years, Polonnaruwa dis- After 60 years, the male preponderance diminished but trict mean age was 57.4 years with SD ± 14.1 years). In still remained high (male:female is 1.8:1 in Anuradha- both districts more than 70, 40 and 33% of patients were pura and 2.2:1 in Polonnaruwa in > 70 years age over 50, 60 and 70 years of age respectively. Only a small category). percentage of patients (5.4–8.6%) were in the 31 to 40 Farmers were the most commonly affected occupation years age group. group (70.6% from Anuradhapura district and 65.1% There was a male preponderance in both districts from Polonnaruwa district). Details of the staging (Table (male:female ratio 1.8:1 in Anuradhapura; 2.2:1 in 1) was available only in a minority of the group (7103, Table 1 Socio-demographic characteristics of CKD/CKDu in North Central Province Characteristics Anuradhapura (n = 20,473) Polonnaruwa (n = 10,093) 2003 to 2008 2009 to 2012 2013 to 2017 2006 to 2008 2009 to 2012 2013 to 2017 (n = 4039) (n = 4157) (n = 12,277) (n = 1474) (n = 2011) (n = 6608) Number (%) Number (%) Number (%) Number (%) Number (%) Number (%) Period Incidence 0.47 0.48 1.43 0.36 0.49 1.63 Sex Male 2731 (67.6%) 2796 (67.3%) 7577 (61.7%) 1132 (76.8%) 1477 (73.4%) 4309 (65.2%) Female 1308 (32.4%) 1361 (32.7%) 4700 (38.3%) 342 (23.2%) 534 (26.6%) 2299 (34.8%) Age (years) Male mean (SD) 56.7 (±13.9) 56.9 (±12.8) 57.7 (±12.2) 56.3 (±14.9) 58.9 (±11.9) 58.0 (±13.6) Female mean (SD) 56.6 (±15.5) 56.8 (±13.5) 56.8 (±13.3) 53.8 (±17.8) 59.2 (±13.1) 56.0 (±15.3) Age groups (years) < 10 13 (0.3%) 13 (0.3%) 15 (0.1%) 15 (1.0%) 4 (0.2%) 17 (0.3%) 11–20 102 (2.5%) 48 (1.1%) 168 (1.4%) 38 (2.6%) 8 (0.4%) 123 (1.8%) 21–30 100 (2.5%) 95 (2.3%) 205 (1.7%) 45 (3.0%) 27 (1.3%) 176 (2.7%) 31–40 262 (6.5%) 242 (5.8%) 748 (6.1%) 118 (8.0%) 106 (5.3%) 482 (7.3%) 41–50 706 (17.5%) 768 (18.5%) 1989 (16.2%) 261 (17.7%) 307 (15.3%) 1025 (15.5%) 51–60 1229 (30.4%) 1330 (32.0%) 4000 (32.6%) 420 (28.5%) 613 (30.5%) 1890 (28.6%) 61–70 1018 (25.2%) 1118 (26.9%) 3665 (29.8%) 334 (22.7%) 625 (31.1%) 1797 (27.2%) > 70 609 (15.1%) 543 (13.1%) 1487 (12.1%) 243 (16.5%) 321 (15.9%) 1098 (16.6%) Occupation Farmer 3118 (77.2%) 3174 (76.4%) 5198 (42.3%) 950 (83.3%) 1439 (78.1%) 3116 (47.1%) Other 921 (22.8%) 983 (23.6%) 2872 (23.4%) 191 (16.7%) 403 (21.9%) 2363 (35.8%) Not available 0 0 4207 (34.3%) 333 (22.6%) 169 (8.4%) 1129 (17.1%) Staging of CKD (n = 7103) Stage I 6 379 3109 242 229 978 Stage II 0 15 108 0 1 44 Stage III 0 289 271 0 6 374 Stage IV 0 165 204 0 0 136 Stage V 0 154 256 0 10 127 Reported Deaths a a,b Institutions Not reported 599 (14.4%) 1194 (12.2%) Not reported Not reported Not reported Percentage was calculated by taking the total number of CKD/CKDu for the respective period as the denominator 2017 deaths were not available Ranasinghe et al. BMC Nephrology (2019) 20:338 Page 5 of 11 23.2%). Of this most CKD/CKDu patients were in stage I groups of DS divisions of the North Central Province (4943, 69.6%). Stages II, III, IV and V had 2160 (30.4%) (p < 0.001, 95% Confidence Interval for incidence > 2.40 with 547 (7.7%) patients in Stage V respectively. was 2.44–3.63, for incidence < 2.40 was 1.02–1.51). The incidence of CKD/CKDu from 2012 to 2017 in There were 9653 CKD/CKDu patients (6335 from the DS divisions of both districts is shown in Table 2. Anuradhapura and 3318 from Polonnaruwa districts) in Comparison of divisions with period incidence of over the 10 DS divisions with the highest incidence which 2.40 (six in Anuradhapura district and one in Polonna- were GPS mapped. The point prevalence of CKD/CKDu ruwa district) with those below two shows that there is a in these high incidence areas of Auradhapura ranged statistical difference of period incidence among the two from 1.52–3.35 while it was 0.67–1.25 in Polonnaruwa. Table 2 Newly reported CKD/CKDu patients and CKD/CKDu prevalence data Ranasinghe et al. BMC Nephrology (2019) 20:338 Page 6 of 11 The 5 year survival rate was 71.2 (Anuradhapura 72.4, steadily increasing provision of safe drinking water in 95% CI 71.10–73.7 and Polonnaruwa 68.3, 95% CI 66.1– the affected areas [20]. 70.4). Anuradhapura district has a significantly higher The Balkan Endemic Nephropathy (BEN) thought to survival rate compared to Polonnaruwa district (log-rank be caused by environmental contaminants has shown test p = 0.0212). fluctuating incidence rates since its discovery in 1956 Among 9653 patients who were GPS mapped, 2491 [21]. However its prevalence has remained 3–7% over (25.8%) were dead patients. This included 1655 deaths, the last five decades [22]. (26.1%) from Anuradhapura and 836 deaths (25.2%) In the present study the point prevalence from GPS from Polonnaruwa districts. Among these deaths 578 mapping ranged from 1.52 to 3.35 in Anuradhapura and (6% of total CKD/CKDu patients, 23.2% of total deaths 0.67 to 1.25 in Polonnaruwa. These results are in agree- in CKD/CKDu patients) occurred within one year of ment with the study done by Chandrajith et al. (2011) diagnosis (Anuradhapura 396, 23.9%, Polonnaruwa 182, which showed a point prevalence of 3.7% in Madawach- 21.8%) while 1685 (17.5% of total CKD/CKDu patients, chiya and 3.2% in Huruluwewa [14] but not with the 67.6% of total deaths in CKD/CKDu patients) occurred study done by Jayathilaka et al. (2013) which showed a within the first 3 years of diagnosis (1115, 67.4% from point prevalence of 15–23% [4]. A possible explanation Anuradhapura and 570, 68.2% from Polonnaruwa dis- for this is the flows in the design, interpretation and tricts). Within the first 5 years of diagnosis 2063 patients conclusion of the study as shown by Jayasumna et al. were dead (21.4% of total CKD/CKDu patients, 82.8% of (2013) [13]. total deaths in CKD/CKDu patients). This included Our data shows that in the three time categories 1362 deaths (82.3% of total deaths in CKD/CKDu pa- (2003–2008,2009-2012,2013–2017) the age groups that tients) from Anuradhapura and 701 deaths (83.9% of were most affected were older patients (50 to 60 years total deaths in CKD/CKDu patients) from Polonna- and > 60 years). There was no increase within different ruwa districts. It was observed that over 95% of the age groups during the time periods that were studied. As patients (approximately 2390) did not have identifi- this study does not distinguish between CKD and CKDu able other causes of deaths (such as road traffic acci- it could be argued that the increased incidence in elderly dents, cancer etc.). may be due to diabetic and hypertensive nephropathy. Figure 2 depicts the total number of CKD/CKDu pa- However previous studies have demonstrated that dia- tients in different DS divisions of Sri Lanka which had betes and hypertension contribute to only a minority of been collected using the same methodology as in the CKD in this region [3]. present study other than for GPS mapping. This figure If the majority of patients in this study had CKDu, shows the seven DS divisions with CKD/CKDu period possible explanations to the increased incidence in older incidence of > 2.40 in Anuradhapura and Polonnaruwa patients include an aetiological factor with a cumulative districts in North Central Province are clustered to- effect or an aetiological factor which had a prolonged gether. This figure also shows that adjacent DS divisions period of pathogenesis. However if this was true, in the of neighboring districts also have high numbers. later time periods between 2009 to 2012 and 2013 to Figures 3, 4 and 5 shows GPS mapping of CKD/CKDu 2017 there should have been some increase in the pro- patients in the two DS divisions with the highest preva- portion of CKD./CKDu in other age groups as well espe- lence in Anuradhapura and Polonnaruwa districts. This cially if a common environmental factor was responsible. shows that there is a clustering of households with The other possible explanation is that the elderly people CKD/CKDu within DS divisions with the highest are more susceptible to an aetiological factor or factors prevalence. due to the physiological reasons or co-morbidities. BEN shows a low incidence in younger age groups and Discussion higher incidence after 65 years with the onset between Our study shows that the incidence of CKD/CKDu in 40 to 60 years [22]. It has a long latent period and thus North Central Province increased upto 2016. One reason affects the exposed at a later part of their life [21]. Meso- for the rapid increase in the incidence of the disease in american Nephropathy also shows a high proportion of both districts in North Central Province after 2012 may affected individuals between 50 to 70 age group [23]. be the organized community based screening pro- Our study shows an increase proportion of male pa- grammes conducted by the health sector resulting in in- tients within the different age groups and in the different creased case detection. Other reasons include increased DS divisions. Explanation for this male preponderance exposure to aetiological factor or factors which have not includes predominant exposure to the risk factors such been convincingly identified as of yet. This study also as pesticides in farmers or presence of disease modifying shows that the incidence has declined slightly in 2017 in factors (eg. use of alcohol and smoking). The possibility both districts. A probable reason for this may be the of a protective role by female hormones is unlikely as Ranasinghe et al. BMC Nephrology (2019) 20:338 Page 7 of 11 Fig. 2 Total number of CKD/CKDu patients in divisional secretariat areas. The map is created based on the data from this study. (This data was collected from hospitals using the same methodology as in this study from other districts) the male:female is lower in the female reproductive age CKDu in Sri Lanka with the disease being commoner groups. In both districts majority of patients were among males and older age groups and agricultural farmers. However majority of the people residing in workers [23]. these areas are anyway farmers [19]. Explanation for Our study also shows that the incidence is not uniform farmers being more affected may be due to higher ex- among all DS divisions of the two affected districts in posure to aetiological agents such as pesticides. Figure 4 North Central Province. There were six DS divisions in confirms that patients are clustered around areas with Anuradhapura and one from Polonnaruwa that reported paddy fields. This is further confirmed in Figs. 3 and 5 a period incidence of over 2.4. These high incidence which shows that GN divisions with a high population areas are clustered closer to each other. This is also ap- density which are of urban settings do not have high parent from Fig. 2 which shows the geographical distri- number of CKD/CKDu patients. Thus clustering pattern bution of DS divisions that had reported more than within DS divisions is not related to population density. 1000 CKD/CKDu cases from 2003 to 2017. These high In BEN both males and females are equally effected incidence DS divisions in North Central Province border [21]. However similar to CKDu in Sri Lanka it was DS divisions with high number of CKD/CKDu patients seen among the rural farming population [22]. The in the adjoining districts. Figure 2 indicates that the Mesoamerican Nephropathy also has similarities to number of reported CKD/CKDu patients decrease steadily Ranasinghe et al. BMC Nephrology (2019) 20:338 Page 8 of 11 Fig. 3 GPS mapping of CKD/CKDu patients vs population density in Madawachchiya DS division of Anuradhapura district. The map is created based on the data from this study. *The high population density GN areas indicated in dark brown are urban settings beyond the high incident areas. Thus the effect of the Similar findings are seen in BEN which exhibit focal causative factor may be distributed in a gradient fashion occurrence with affected and spared households in close with high incidence areas having the most exposure to the proximity within the same village [25]. BEN was re- causative factor while the lower areas probably have lower ported to have numerous members of one or several exposure. The other explanation may be that the high inci- generations in a single household [26]. denceareas mayhaveother factorsthatcontributetothe To the best of our knowledge this is the first publica- causation of disease after initial exposure to a toxic agent. tion indicating death rates and 5 year survival rates of GPS mapping indicates clustering of cases in both high CKD/CKDu patients in CKDu affected areas in Sri and low incident areas. According to the maps there are Lanka. Results from the GPS mapping shows that a total high prevalent areas and low prevalent areas even within of 2491 (25.8%) out of 9653 CKD/CKDu patients died. a GN division. When the maps are superimposed with Although the exact cause of death was not explored in paddy fields and irrigation tanks as shown in Fig. 4, this detail, during the GPS mapping, on discussion with the clustering seems to be mainly among the farming com- households and scrutinizing available hospital records munities and around irrigation tanks. The irrigation (including death certificates in some), it was observed tanks form a cascading system with water flowing from that over 95% of the patients (approximately 2390) did higher levels to lower levels. While conducting the study not have identifiable other causes of deaths (such as road we noticed clustering of CKD/CKDu patients towards traffic accidents, cancer etc.) and therefore were pre- the lower part of the tanks. Previous studies have also sumed to have died of complications resulting from identified clustering of cases towards the lower altitude CKD/CKDu. In comparison hospital based data shows of the tanks [24]. 1793 deaths among 16,434 patients with a death rate of Ranasinghe et al. BMC Nephrology (2019) 20:338 Page 9 of 11 Fig. 4 GPS mapping of CKD/CKDu patients’ occupation with water & paddy areas in Madawachchiya DS division of Anuradhapura district. The map is created based on the data from this study 10% (refer Table 1). This highlights the fact that the im- region [3]. Another study has shown that the prevalence plications of CKDu in relation to mortality may be more of diabetes in North Central Province during the same serious than what is indicated in hospital based statistics. period was 9.6% [27]. Based on these previous documen- This study showed a significantly high (log-rank test tations it seems unlikely that diabetes and hypertension p = 0.0212) 5 year survival rate in Anuradhapura (71.2%) would have contributed to major proportion of CKD in compared to that of Polonnaruwa (68.3%). One possible the region. explanation is the lack of access to health care facilities in Polonnaruwa compared to Anuradhapura based on Conclusion the assumption that majority of patients died due to The incidence of CKD/CKDu in North Central Province CKD/CKDu related causes. has increased up to 2016 with a slight decrease in 2017. Results from the GPS mapping shows that 6% of total A possible explanation for this may be the provision of CKD/CKDu patients died within the first year of diagno- safe drinking water. The most vulnerable age groups are sis whilst 17.5% died within three years. This represents from 40 to 60 years. There is a male preponderance. 67.7% of total deaths in CKD/CKDu. This emphasizes Farmers seem to be at a higher risk. Limited data shows the immediate need for hospital with facilities for dialy- that majority of patients are in CKD stage 1. sis and ideally renal transplants. The 5 year survival rate was 71.2. Anuradhapura dis- This study is limited by the fact that a distinction was trict (5 year survival rate 72.4) has a significantly higher not made between CKD and CKDu as data on co-mor- survival rate compared to Polonnaruwa district (5 year bidities was not collected. However a previous study has survival rate 68.3). Among the deaths in CKD/CKDu pa- demonstrated that diabetes (2%) and hypertension (14%) tients 578 (6% of total CKD/CKDu patients, 23.2% of contribute to only a minority of CKD/CKDu in this total deaths in CKD/CKDu patients) occurred within Ranasinghe et al. BMC Nephrology (2019) 20:338 Page 10 of 11 Fig. 5 GPS mapping of CKD/CKDu patients vs population density in Madirigiriya DS division of Polonnaruwa district. The map is created based on the data from this study one year of diagnosis while 1685 (17.5% of total CKD/ GWGP, RHK, APDS, KGDS, JMCNG, SKCRK, MSFS, JSC and CDS all helped to write the manuscript. All authors read and approved the final manuscript. CKDu patients, 67.6% of total deaths in CKD/CKDu pa- tients) occurred within the first 3 years of diagnosis. Funding Within the first 5 years of diagnosis 2063 patients were None dead (21.4% of total CKD/CKDu patients, 82.8% of total Availability of data and materials deaths in CKD/CKDu patients). Some of the aggregated data are available at the renal registry https://nicst. Areas reporting higher incidence of CKD/CKDu are com/iframe-renal-dev/ while all aggregated data used for this study are available from the Renal Disease Prevention and Research Unit, Ministry of clustered together. GPS mapping shows that even within Health, Sri Lanka. The data can be obtained on reasonable request with the the high incidence areas there is geographic clustering. permission from the Director General of Health Services, Ministry of Health, The clustering was mainly around paddy fields and irri- Sri Lanka. gation tanks. Ethics approval and consent to participate Abbreviations The data used for this study are anonymised aggregated (routinely gathered BEN: Balkan Endemic Nephropathy; CKD: Chronic Kidney Disease; during service delivery) secondary data. We have obtained this secondary CKDu: Chronic Kidney Disease of uncertain aetiology; DS: Divisional data and conducted the analysis. Most of this data is also available in the Sri Secretariat Lanka Renal Registry. The aggregate data is accessible to any persons. The approval for this study was obtained from the Ministry of Health, Sri Lanka. Acknowledgements Hospital and field staff of North Central Province. Consent for publication Not applicable Authors’ contributions AVR, GWGP, RHK, APDS, KGDS, JMCNG, SKCRK, MSFS, JSC and CDS all helped to prepare the methodology. KGDS, JMCNG, SKCRK and MSFS extracted the Competing interests data from the secondary data sources. GWGP and RHK did the analysis. AVR, The authors declare that they have no competing interests. Ranasinghe et al. BMC Nephrology (2019) 20:338 Page 11 of 11 Author details 17. Levey AS, Eckardt KU, Tsukamoto Y, Levin A, Coresh J, Rossert J, et al. Renal Disease Prevention and Research Unit, Ministry of Health, Colombo, Definition and classification of chronic kidney disease: a position statement Sri Lanka. National Intensive Care Surveillance, Ministry of Health, Colombo, from kidney disease: improving global outcomes (KDIGO). Kidney Int. 2005; Sri Lanka. Office of Additional Secretary (Development), Ministry of Health, 67:2089–100. Colombo, Sri Lanka. Department of Pathology, Faculty of Medicine, 18. 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Published: Aug 28, 2019

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