Water sources and kidney function: investigating chronic kidney disease of unknown etiology in a prospective study Penny Vlahos orcid.org/0000-0002-0034-60071, Stephen L. Schensul2, Shuchi Anand3, Emma Shipley1, Saranga Diyabalanage orcid.org/0000-0002-3268-73674, Chaoran Hu orcid.org/0000-0002-8966-62765, Toan Ha orcid.org/0000-0002-0574-08046, Allison Staniec1, Lalarukh Haider2, Jean J. Schensul7, Pasan Hewavitharane8, Tudor Silva9, Rohana Chandrajith orcid.org/0000-0003-3072-524010 & Nishantha Nanayakkara8 npj Clean Water 4, Article number: 50 (2021) Cite this article Environmental monitoringEnvironmental studiesWater resources A chronic Kidney Disease of unknown etiology (CKDu) has emerged with disproportionately high prevalence across dry lowland agricultural communities globally. Here we present the results of a prospective cohort of 293 patients with CKDu in the endemic region of Wilgamuwa, Sri Lanka, in whom we measured baseline kidney function and undertook quarterly follow up over 2 years. Well water was the primary historic drinking water source in the region, although a majority (68%) of participants reported switching to reverse osmosis water during study follow ups. Participants who reported ever drinking from well water had estimated glomerular filtration rates −6.7 (SD: 2.8) ml/min/1.73 m2 lower than participants who did not drink from well water historically (p = 0.0184) during the study period. Geospatial analysis identifies a cluster within the region where CKDu progression is significantly higher than the surrounding area. Samples of household wells (n = 262) indicated 68% had detectable agrochemical compounds with concentration above global water quality standards. It is expected that the detected contaminants compounds are indicators of poor water quality and that there is likely additional agrochemical exposure including commercial additives that may contribute to CKDu onset and/or progression. Thus, our study finds that well water exposure during a person’s lifetime in this region is associated with kidney function decline and identifies and quantifies putative nephrotoxic agrochemicals above safe drinking water concentrations in these wells. The rising global death toll from chronic kidney disease (CKD), now the world’s 12th leading cause of death, is considered a downstream consequence of the growing global prevalence of diabetes (4.7% of adults in 1980 and 8.5% in 2014) and hypertension (31.1% among adults, 90% increase from 1975–2015)1,2. In the same period, however, there has been a rapid increase in a ‘non-traditional’ type of CKD in rural lowland agricultural communities that is not associated with uncontrolled diabetes and hypertension, termed chronic kidney disease of ‘unknown etiology’ (CKDu) in South Asia3, also known as Mesoamerican Nephropathy (MeN) in Central and South America4 and the Central Valley of California5. While a majority of CKD is characterized as a primarily glomerular disease3,4, CKDu is a tubulointerstitial disease with varying degrees of interstitial fibrosis, interstitial inflammation, and tubular atrophy3,5. Both types move inevitably toward kidney failure and death unless there is intervention through hemodialysis or a kidney transplant.Sri Lanka is one of the world’s hot spots for CKDu with prevalence highest in the ‘dry zone’, North Central and Central Provinces6,7. In the post-world war-II (WWII) period, the emergence of the Green Revolution brought Sri Lanka and other low- and middle-income counties (LMICs) the promise of food self-sufficiency through high yield seeds, use of agrochemicals, reliable water sources, and increasing mechanization. The need for land and resources to implement the Green Revolution called for reestablishment of the irrigation system, known as the tank cascade irrigation systems developed in the fourth to sixth century (CE) and resettlement of farmers from the land-starved ‘wet zone’ into the dry8,9. From the 1950s to the end of the 1980s, funding from the World Bank and other international agencies resulted in the development of one of the largest irrigation projects in the world, involving the damming of Sri Lanka’s major river, the Mahaweli, and the development of reservoirs, spillways, and channels throughout the dry zone areas10.In the early 1990s, cases of kidney failure began to appear in health care facilities in the dry zone provinces, primarily among male and to a lesser extent among female farmers11. By the start of the new millennium, CKDu had become a major epidemic, especially for the poorest households, resulting in the loss of adult income earners, contributing to poverty, and increasing the cost of health care systems as a result of the expansion of hemodialysis and kidney transplant units. The current CKDu prevalence among 30- to 60-year-old men in dry zone districts is 15.1–22.9%6,7,11. The once valued occupation of farming has become stigmatized, contributing to the ill health, inability to work, and mortality of farmers12.Review of PubMed peer-review publications indicates over 110 publications during the last decade primarily focused on a search for the etiology of CKDu in Sri Lanka using cross-sectional or case-control approaches. The inability to generate conclusive results has left researchers and public health officials with little to communicate to the population at risk. Tracking progression of kidney disease in dry zone residents with CKDu may offer an alternative, complementary approach to investigating etiology.This paper examines the association between water source contamination and kidney function decline, drawing on data from the Kidney Progression Project (KiPP)13, a Sri Lanka-US collaboration of geochemists, anthropologists, and nephrologists, funded by the Fogarty International Center of the US National Institutes of Health. This transdisciplinary project explores the environmental, behavioral, and clinical factors associated with lower kidney function in a cohort of patients with established CKDu, generating data that allows us to examine the role of water consumption and kidney function.Table 1 summarizes the demographics, water use, and clinical data at baseline. Consistent with the known clinical and demographic characteristics of CKDu, 74% of our participants were men and 96% had 1+ urine protein or less but had substantial reduction in kidney function, with mean eGFR 37.5 ml/min/1.73 m2. Over half (53%) had lived in Wilgamuwa from birth, 92% of participants had farmed during their lifetime, and 66% reported that they were still engaged in farming for an average of 33 lifetime years.Table 1 General characteristics of participants in study cohort at baseline (Sept–Dec 2017)#.Drinking water sourcesHistoric drinking water source included well water for 89% of participants. All the wells in this study have been used as drinking water sources in the past. Water sources changed substantially during the study period. Figure 1 shows the water consumption patterns of participants over the KiPP study period, with a clear transition from the consumption of well water to RO water sources or other alternative sources. Supplemental Table 1a and Table 1b present demographic information stratified by baseline RO water use, versus not and by ever well water use versus not. A fewer proportion of participants with baseline RO water use were women, and a greater proportion owned farming land, compared with participants without baseline RO water use. Participants without any well water use were younger, and a greater proportion reported living in Wilgamuwa all their life.Fig. 1: Percent of KiPP participants reporting specific drinking water source prior to the study (past) and at each time point.Note the number of participants at each time point is specified as not all participants were available at each follow up.GIS analysisGIS analysis is summarized in Figs. 2 and 3. These identify key spatial trends including the spatial distribution of the baseline eGFR of the participants across the region (Fig. 2) and their rates of progression across the region. Figure 3 identifies two important clusters of low progression or improvement in the north–west region surrounding the medical clinic and a region just below this, also to the west where 24 participants have a significantly faster decline in eGFR relative to other participants. The average eGFR progression across the blue region is −1.2 ± w ml/min/1.73 m2/year and that of the relatively rapidly declining cluster (red region) is −2.1 ml/min/1.73 m2/year. Note, though both regions show decline in kidney function, this analysis identifies not the fastest rates of decline in the study, but rather individuals who are declining faster relative to their surrounding neighbors. It is also noteworthy that the blue region (slower CKDu progressors) is located at higher elevations in the drainage basin and upstream of the red regions (relatively faster CKDu progression) are located at lower elevations and downstream from the blue regions.Fig. 2: Spatial analysis of participant baseline eGFR (shaded circles) and CKDu progression over the study period (base map contours).Also illustrated on the map are the locations of reverse osmosis (RO) plants which ration free drinking water to residents as of late 2017 and the location of the three regional clinics/hospitals.Fig. 3: Hot Spot analysis of the region shows that there is a spatial cluster of fast progressors in the north–west region wherein CKDu progression is significantly faster than surrounding regions.The analysis also shows that participants in the uppermost north–west surrounding a medical clinic are performing significantly better (no progression or improvement) than surrounding regions.Water qualityDomestic well water for every participant in the sample was tested for inorganic metals, target complex ions and targeted organic agrochemicals14. Of the 26 inorganic metals that were quantified, all were within recommended water quality thresholds (Shipley et al. 2022). Of the 272 sampled wells, 68% yielded positive detections of the target agrochemical compounds (Table 2). All wells with positive detections had concentrations of at least one agrochemical that exceeded global drinking water guidelines and 40% had at least two. The wells with positive detections showed no discernable spatial patterns (Shipley et al., 2022).Table 2 Agrochemicals detected in domestic well in Wilgamuwa, Sri Lanka during 2018 water sampling from Shipley et al. (2022)24.Table 3 shows the relationship between ever consuming well water and eGFR. Participants who reported using well water during their lifetime had lower age- and sex-adjusted eGFR (−6.7 ± 2.8 ml/min/1.73 m2/year) over the study period, compared with participants not using any well water (p = 0.0184). Current water use at the time of study initiation was not associated with eGFR during the study period and of the 68% of the wells with high compound concentrations, <10% were still being used for drinking water by the end of the study period.Table 3 The relationship of water source to CKDu from linear mixed models on age- and sex-adjusted eGFR during the study period (18 months).Analysis of well water has established contamination that can contribute to nephrotoxicity. Diazinon, and organophosphate insecticide, is the most frequently detected agrochemical in this study. It is reported to induce nephrotoxicity in rats through depletion of antioxidant enzymes15 and the study proposes that oxidative stress could be used as an early intervention that may be beneficial in monitoring diazinon toxicity. DDT and its longer-lived metabolite p,p'-DDE are organochlorine insecticides and proven nephrotoxins in rats where sub-acute treatment leads to oxidative stress and apoptosis, the proposed mechanism of DDT-induced nephrotoxicity16. Propanil is a chlorinated herbicide and it too has been identified as a nephrotoxin in in-vivo studies wherein a metabolite resulting from propanil oxidation is suspected to contribute to propanil cytotoxicity17. Endosulfan II (banned by the Stochkholm Convention in 2011 though still in use in Asia) is an organochlorine insecticide. When introduced orally to rats, endosulfan II induced pathological alterations in the kidney including chronic glomerulonephritis, glomerulosclerosis, adenoma, and glomerulus deposits18.In addition to the agrochemicals, two other water quality parameters were high. These include water hardness, which has been weakly associated with incident kidney stones19,20 but not a feature of CKDu. Phosphate was higher than that recommended for drinking water samples based on US EPA standards in 80% of the wells. Though high dose phosphate preparations have been implicated in acute kidney dysfunction, kidney biopsy examinations of patients with CKDu have not supported this potential causative pathway21,22. To our knowledge, elevated phosphate levels have not been reported in other CKDu studies to date. Nonetheless, patients with CKD are at particular risk of further complications when exposed to high phosphate levels as the kidney's ability to regulate phosphate homeostasis is compromised21.While causation cannot be inferred from these results, there is strong evidence for concern about water contamination and CKDu both for the etiology of CKDu and the relative rapidity of progression. It is likely that there is no single compound of concern but rather a multiple stressor interactor effect across environmental and agrochemical exposure, behavior, and clinical factors. The detected compounds do show water contamination from nearby paddy agriculture and are indicators of numerous other possible substances that would be expected to be in the water including additives and uptake enhancers associated with the detected active compounds in commercial mixtures. In addition, since this is a single-time point analysis, prior exposure(s) to other compounds is likely, even among households in whose wells we did not detect compounds in the current study. As tube and dug wells are fed from aquifer systems, groundwater flow fields and direction are important considerations in local water quality, however, greater temporal sampling is required to examine this further.GIS analysis has revealed a cluster of participants in the western region which are progressing significantly faster than the surrounding participants. This cluster occurs at low relative elevations for the region where upstream waters are collected and stagnate. The resolution of the well sampling is not temporally robust to compare the water quality across this cluster (only single water samples collected at each location across the region). Thus, future sampling should focus on the synoptic sampling of water in this region across all seasons relative to controls. GIS analysis has also revealed a cluster of relatively lower disease progression that may be associated with proximity to clinical care though clusters surrounding the remaining two clinics do not show this consistently. Alternatively, this may be related to the direction of water flow as this cluster occurs at a higher elevation and upstream in the region. Proximity to RO water is another possible indicator of less CKDu progression however this cannot be assessed at this time. The RO plants are relatively new (all installed in late 2017 and early 2018 and are managed by the Sri Lankan Navy, providing free rations to residents). The impact of these plants is too recent to be captured in this baseline study; however the population will continue to be monitored in an ongoing study and these results are a critical reference point.This study has established a significant association between well water consumption and lower kidney function in patients with CKDu. The concern about drinking water contamination has led the Government of Sri Lanka to make a substantial investment in RO water and to explore alternatives for decontamination. While this approach may be effective in the short run, dependence on RO units with a limited running life is not a long-term solution. This study has strengths that include prospective data, that partici
https://www.nature.com/articles/s41545-021-00141-2
Water sources and kidney function: investigating chronic kidney disease of unknown etiology in a prospective study
