Chronic Kidney Disease (CKD) of unknown origin has caused serious public health problems in specific countries in the word, such as, Sri Lanka, India and Mesoamerica. Particularly in Costa Rica the pathology and linked mortality are concentrated in the north pacific region from the country. Affected people are found predominantly in rural agricultural areas with warm climate and low altitude and to a much lesser extent in hilly elevated areas; however, the full geographic extent of the disease is still unclear. The objective of this research is to determine a scenario of exposure to toxicants in populations with high numbers of cases of CKD. Explanatory variables for the high rate of CKD were determined by means of a Poisson multivariate regression analysis at a national level. The environmental variables included hectares of cultivated and burned sugarcane, atmospheric temperatures, relative humidity, arsenic in water for human consumption, speed and direction of winds, annual average precipitation, and geographical location with respect to alti- tude. Heavy metals, including transition metals and metalloids such as arsenic, cadmium, mercury, lead, vanadium, and silicon, which even at low concentrations have the potential to cause nephrotoxicity via chronic exposure, were quantified in the soils in areas with the highest prevalence of the disease in the country. According to this quantifica- tion and analysis, these metal(loid)s may have causal relevance in the pathology of CKD. The statistical, geographical and laboratory analy- ses determined that population exposure to environmental toxicants is seasonal, occurring under the convergence of annual climatic phenomena.
Research Article
Establishing a scenario of exposure to environmental toxins associated with nephropathies in agricultural areas of Costa Rica based on Geological Medicine
https://doi.org/10.21203/rs.3.rs-2146203/v1
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Mesoamerican nephropathy
geogenic contaminants
nephrotoxic heavy metals
accidental geophagy
exposure scenario
Humans live in close contact with geologically disrupted environments, which may have beneficial or hazardous impacts on their health. Many times, environ- mental influences on human health and wellbeing are underestimated. Natural exposure to geogenic contaminants (naturally occurring toxicants) such as: arsenic (As), fluoride (F), beryllium (Be), cadmium (Cd), mercury (Hg), lead (Pb), radon (Rn), selenium (Se), uranium (U) and their various chemical forms, affects human health (Bundschuh et al. 2017). Occurrence of these con- taminants in different geo-environments is the result of displacement from the source through different natural and anthropogenic processes. For example, their displacement can occur in the form of atmospheric dust or aerosols, thus affecting potable water, food, or air. The elements naturally occur in geogenic sources, such as rocks, soils, and minerals. They can impact human health through several mechanisms, including consumption of drinking water or by elemental bio magnification through the food chain (Bundschuh et al. 2017). Contact with geogenic contaminants may occur by several means including ingestion of contaminated water or solid geological matter, whether intentional (geophagy) or unintentional (soil or sand ingestion, which is a significant risk in the case of children) or by inhalation (atmospheric dust, aerosols) (Skin- ner 2007). These risks are studied in the field of Medical Geology, which is an interdisciplinary science that deals with the complex relationships among environmental factors related with the presence of geogenic contaminants in different geological environments, their mobility, geographic distribution and effects on human and animal health (Khandare 2012).
Chronic kidney diseases which cannot be explained by known traditional risk factors, or because their origin remains unknown, are increasingly recognized in specific geographic regions. Chronic Kidney Disease of Unknown Aetiology or non traditional (CKDu) is known in Mesoamerica as Mesoamer- ican Nephropathy (MeN). In other parts of the world, it is known as Chronic Interstitial Nephritis of Agricultural Communities (CINAC) or Kidney Disease of Unknown Causes in Agricultural Labourers (KDUCAL). This tubulointer- stitial pathology is primarily described as a chronic pattern strongly related to occupational exposure of agricultural workers and other manual workers. The burden of this disease falls on people living in poverty. Despite research advancements, aetiology of this disease continues to be unclear (Crowe et al. 2019). Additional details about the clinical differentiation of MeN can be found in Supplementary Text 1, in the ”Establishing a scenario of exposure to envi- ronmental toxins associated with nephropathies in agricultural areas of Costa Rica based on Geological Medicine: Supplementary Text” article.
CKDu appears to be a multifactorial disease. In some regions, but not in all of them, CKDu is more frequent among men than among women, which could reflect labour differences or some other variation regarding exposure. The pathology has remarkable similarities with what is observed in primary tubulointerstitial diseases leading to CKD, involving tubular atrophy and interstitial fibrosis, with limited morphological changes in the vasculature and glomeruli. On the other hand, genetic susceptibility, of populations or the influence of epigenetic factors on them, have not been adequately addressed (American Society of Nephrology 2018).
In Costa Rica, which is part of Mesoamerica, data from epidemiologic surveillance by the Costa Rican Social Security Fund (CCSS) reveal that the number of patients diagnosed with chronic kidney disease and are under dial- ysis therapy in the CCSS increased 317% in the last six years (Bustamante 2018). Research conducted in Costa Rica has addressed the disease from a causal point of view, considering only the effect of heat on sugarcane work- ers (Crowe et al. 2009, 2013, 2015; Wesseling et al. 2014, 2015). Mesoamerica is the region comprising the southern, eastern and central parts of Mexico, the whole of Guatemala and Belize, western Honduras, El Salvador, Costa Rica and Panama (Witschey and Brown 2012). In Costa Rica, tropical cli- mate is predominant in the region, although in the central and northern parts, a more temperate, warmer, and slightly humid climate is present. These climatic conditions provide the adequate conditions for growth and production of sugarcane.
The physical area comprising the place where toxicants are transported and released into the environment and where populations make contact with toxicants is called scenario of exposure. To determine the scenario of exposure of toxic agents in a population, established basic principles are applied, such as: problem formulation, hazard characterization, exposure characterization and risk characterization (Pen˜a 2001; United States Environmental Protection Agency 2016). Considerations for CKD include climatic and geological vari ables, as well as nephrotoxic causal agents such as heavy metals specifically arsenic, lead, cadmium. Additionally, minerals and metals, such as silica and vanadium are of consideration, as well as the toxicity of heavy metal mixtures in low concentrations. Additional information about the environmental variables that may influence CKD, including causal agents such as heavy metals and other nephrotoxic metals and metalloids (e.g., arsenic, lead, cadmium, mercury, silicon, and vanadium) can be found in Supplementary Text 1 and 2. Additionally, in Supplementary Text 3 is background information concerning heavy metals at low concentrations and potential risks of pesticides. The objective of this research was to establish a scenario of exposure to toxins in the population most affected by CKD in Costa Rica.
The following approach was employed:
- Determine the toxic kinetics of environmental contaminants: substances whose target organ is the kidney, particularly the renal tubules, and are related to an exposure scenario consistent with the socio-environmental dynamics of the area of study.
- Determine the statistical correlations and regressions at the national level (inferential statistics): determine whether, in principle, the environmental variables that support the exposure scenario can be related, especially under a Multivariate Regression model, which in these cases is generally met by the Distribution of Poisson. In addition, develop an equation using the Simplex method to determine the relationship between each environmental toxicological variable and the disease under study. Statistically significant counties where the study of the patients would be carried out in relation to their environment were defined.
- Quantify toxicants in the environmental matrices, such as soil and water, in the geographic area of research. Emphasis was given to whether the presence of toxicants in contact with the population was due to seasonal conditions or other specific environmental conditions of the zone.
- Quantify toxicants in human accumulator matrices such as hair and urine, as these are contact markers of toxicants in patients for the specific case of heavy metals. This was contrasted with chemical-clinical tests of target organs, and in our case of renal function, and compared to control popula- tions. Additionally, the specific effect of other cellular damage was explored for correlations or contributions that clarify the pathology of CKD, such as genotoxicity tests and other genetic damage.
After the analysis of the environmental factors involved in the pathology of CKD in Costa Rica, a scenario of exposure to toxins in the population was determined and is expressed in Figure 1. This figure highlights the pathways in which the sources of environmental toxicants in this region can lead to CKD. The Figure 1 was developed after obtaining results from multivariate regression statistical analysis. It was determined that for the specific area of the country that has the highest rates of the CKD, this population is exposed to geogenic sources of nephrotoxins. Mesoamerica belongs to an area of high volcanic influence in the world called the Pacific Ring of Fire (Figure 1 of the Supplementary Text). In Costa Rica, the population that has the highest incidence of CKD is the county called Can˜as, which is an area surrounded by volcanoes (5 active volcanoes, and 3 inactive), in addition is the area with the most wind-intense area to the country (Figure 2 of the Supplementary Text). The subsequent internal behavior of toxins in people was addressed in the theoretical approach of discussed below.
2.1 Correlation and regression analysis between environmental variables
This study was carried out between 2014 and 2022, and it utilizes data from state institutions. These data were used in statistical correlation and regression analysis and to create visual aids of statistical results, such as maps. Quantifi- cation of elements and metals in the soil was carried out in the Environmental Soil Chemistry laboratory at Texas Tech University. While the Statistical Unit of the CCSS (Costa Rican Social Security) did not maintain a (CKD) registry, the number of cases was estimated via annual hospital discharges of patients associated with CKD retrospectively by county between 2007 and 2014. The average rate of CKD between those years was used as a dependent variable and was calculated per 100,000 inhabitants. For the county population during that time period, the national census data from the INEC (National Institute of Statistics and Census) was used.
To evaluate the correlation between one or more explanatory variables, a Pearson Correlation test was carried out using the Minitab software. The test was carried using the following variables: (1) maximum average temper- ature, (2) altitude, (3) average relative humidity, (4) rate of planted acreage (hectares) of sugarcane, and (5) rate of burned hectares of sugarcane. The resulting values with respect to the rate of CKD are shown in Table 1. A correlation and regression analysis of the data for the environmental factors is presented in the Supplementary Text 4, in which the relationship of the variables is expressed under equation 1.
Table 1 Pearson Correlation test values using Minitab 18 with respect to the rate of CKD. All variables had a p-value of <0.05.
2.2 Analysis of environmental factors: disease rates
CKD presents marked geographic differences not only in Costa Rica but in other countries as well. One of the problems faced during this research was the lack of statistical data concerning the incidence and prevalence of CKD at a national level, and one of the most important statistical databases compiled was from the Ministry of Health for the cumulative mortality incidence rate for 2000-2016, which is expressed in Figure 2A. The county with the highest mortality rate is indicated with the darkest color, corresponding to the county of Can˜as. Figure 2B shows the location of the sugar cane crops according to the National Agriculture League of Sugar Cane, and Guanacaste province contains 45% of the country’s sugar cane production. It should also be noted that 55% of the sugarcane crops in the rest of the country are not related in any way to CKD. Figures 2C and 2D show the distribution of the districts in the county of Can˜as and the relationship between the percent of patients affected in Can˜as at different altitudes, respectively. Data concerning patients was provided by the CAIS for 2018, and the rates of CKD are compiled in Table 2.
Table 2 Rates of CKD distributed among districts of county Can˜as with respect to altitude.
According to Figure 2D, and specifically the county of Can˜as, the statistical correlation between altitude and affected populations corresponds to an R2 value of 0.52. If Porozal, which has a 0.27% affected population and is located at 35 masl, is removed from the correlation, the R2 value increases to 0.96. This implies that Porozal has conditions that make the population less vulnerable to CKD, such as its proximity to the Gulf of Nicoya or the Gulf of Colorado, as determined visually, the predominant soil in this area is a clayey soil. The data in Figure 2D indicate that there is a significant correlation between masl and CKD.
2.3 Agriculture
Figure 3 shows the relationship that sugarcane crops have with the areas with the highest incidence of CKD, especially the hectares of sugarcane that are burned during harvest. The statistical model indicated that sugarcane pro- duction and burning of sugarcane were the most important environmental variables related to CKD that for this model was run, but noticing that vari- ables are missing to be included in that model. The number of farms dedicated exclusively to agriculture in the country is shown in Figure 3, where in Can˜as, there are 50 – 300 parcels dedicated to sugarcane harvest. In Figure 3A, the number of hectares of sugarcane cultivation are shown, indicating that sug- arcane is a major crop in this area and throughout the country. Figure 3B shows the number of hectares of sugarcane that are burned in the country for every 10,000 hectares of land. These values are according to data issued by the MAG (Ministry of Agriculture and Livestock). The Figure 3 of the Sup- plementary Text shows variation in the rate of CKD due to variation in the rate of hectares burned and temperature.
2.4 Temperature
The Figure 4-A of the Supplementary Text shows the distribution of the max- imum annual average temperature by counties in Costa Rica according to Digital Atlas of Costa Rica. The Figure 4- B of the Supplementary Text shows relationship between the maximum annual average temperatures for the year 2020 in the meteorological stations (IMN - National Meteorological Institute) of the county of Can˜as and the height (masl) in the location stations. The Figure 5 of the Supplementary Text shows the temperature variation in degrees Celsius from 2003 to 2017 in the province of Guanacaste cause by the effects of El Nin˜o and La Nin˜a, this information is adapted from National Oceanic and Atmospheric Administration (NOAA 2018) and IMN. In Supplementary Text 5 other issues about environmental temperature are considered.
2.5 Altitude
Altitude represents one of the most important factors that determines the growth of sugarcane in agricultural regions, where growth is better at lower altitudes. Additionally, it is one of the factors related to CKD in the world (Crowe et al. 2019). Contour lines were made on a map of the Can˜as district with altitudes of 0 (masl) in the lowest parts of the Bebedero district (the district with the highest number of CKD cases in the country) to a maximum height of 2020 masl in the mountainous part, which is all presented in Figure 6 of the Supplementary Text, there is almost a direct relationship between the elevation of a district and the percentage of cases reported by CAIS.
2.6 Topography of the mountainous region
The location of the mountains according to the population is of critical impor- tance because this relationship affects the dispersion of particles by wind action. In the case of Can˜as, its location is in the middle of a pass between mountains and their slopes. In addition to this, the Can˜as and Bebedero dis- tricts are located in very low areas, less than 30 masl, between the volcanic mountain range of Guanacaste and the mountain range of Tilaran (Figure 2 of the Supplementary Text). This area is immediately below an important wind corridor in the country, mainly for Guanacaste province. In addition to specific considerations of topography, an analysis of the impact that environ- mental temperature, precipitation, and wind models of the research area have on CKD are considered in the Supplementary Text 4 and 5.
2.7 Analysis of heavy metals in the soil
Two soil sampling sets were carried out to complete the exposure scenario for the high rate of CKD in the population of Guanacaste province. Can˜as is the largest district with respect to the number of CKD cases, and Bebedero is the district with the highest proportion of patients with the disease. Thus, soil samples were collected from Bebedero, and another set was collected from the control area of El Guarco from the province of Cartago. Both places are influenced by volcanic activity, this geographical situation is shown in the Figure 7 of the Supplementary Text. In the case of county of Can˜as, there are five active volcanos, including Orosi, Miravalles, Tenorio, Rinc´on de la Vieja, and Arenal. For Cartago, the volcanos include Irazu´ and Turrialba. In total, 30 samples were taken from the Can˜as district and 15 samples from El Guarco district in Cartago. Results of the quantification of metals in soils are presented in Figure 4 of this article and Figure 8 of the Supplementary Text.
In order to evaluate the amounts of metals found in the soils of Can˜as, relate them to the exposure scenario, and compare them to important international regulatory limits for heavy metals in soils, Table 3 is presented. Table 3 also includes values from the 2019 Geochemical Atlas of Costa Rica, a comparison of the European regulation of heavy metals (Toth et al. 2016) and a comparison to US Environmental Protection Agency (US EPA) regulation values given by (He et al. 2015). According to T´oeth (T´oeth et al. 2016), in European countries there are different approaches to define the risk levels associated with heavy metal and metalloid concentrations in soils. The values in Table 3 correspond to those of the Ministry of the Environment of Finland, and the guideline values for soils in Europe are considered to be a risk for producing negative effects on plants and animals.
A determination of X-ray diffraction (XRD) patters for silica in the soil of sugar cane crop area was also carried out in order to determine if the difference between amorphous silica and crystalline silica was evident, this result is shown in Figure 9 of the Supplementary Text, a XRD spectra from samples from the sugar mill and Bebedero are shown. In both areas, silica has a crystalline pattern. Crystalline silica represents increased health risk than amorphous silica as a carcinogen and an immunogen (IARC 2020). Due to this finding, the risk scenario for the population in Bebedero is more relevant. The sample was taken from a sugar mill area and collected one week after sugar cane was burned. As can be seen in Table 3, the silica content of the soil in this area is very high, which is why this site is relevant to the positive exposure scenario of CKD in the local population.
Figure 10 of the Supplementary Text shows the values of the heavy metal concentrations in one of the soil cuts from Cerro Pelado in the mountain range of Tilaran. This region influences the wind patterns in Can˜as, and this was the place that had the highest concentration of heavy metals from the sam- ple areas in Guanacaste. This location and these values are important because they are relevant to the amount of metals that can be accidentally or inciden- tally ingested by populations affected by CKD in a process called involuntary geophagy or dust inhalation.
The hair stores metals that the normal human metabolism cannot elimi- nate, this is recognized as an environmental chronic marker of contact toxic metals in people. Three hair samples from people living in two areas with the highest number of cases of the disease were provided to the research group for preliminary analysis, (informed consents were filled out), however, only one of them was processed because the patients chronically consumed a large amounts of medications, which alters the result of this test. The sample was sent to the Wisconsin State Laboratory of Hygiene, Environmental Health Division
Table 3 Comparison of values of heavy metals, metalloids, and metals with toxicological significance in soils.
of the University of Wisconsin-Madison; requesting an analysis of the follow- ing metals to be carried out on the samples: Al, As, Cd, Pb, Hg, U, Ni, Sb, Ti, Cu, Zn, Cr, V, Sr, Rb and Co, using the SF-ICP-MS (Inductively Coupled Plasma-Mass Spectrometry), with oven digestion.
More information and results regarding hair analysis are shown in the 1.7 Supplementary Text 7: ”Analysis of heavy metals in hair as markers of chronic exposure in environmental toxicity and its effect of low doses”.
2.8 Wind effect
Monthly variation in a typical year (2018) of precipitation with respect to wind speed was measured and it show by Figure 11 of the Supplementary Text. The precipitation was measured at the La Pacifica meteorological station, Can˜as; wind speed was measured at the Mojica Station in Can˜as, Guanacaste about IMN data.
With respect to effect of wind on the area with the highest disease rate - Can˜as-, these winds reach high speeds in the area where the greatest number of cases of the disease occur. In addition, the wind, sugarcane burning during harvest occurs at the same time of the year. The wind and sugarcane burning were variables determined from the beginning of the model to be of significant importance. They gave the highest percentage rate of CKD in the country.
According to the geographical location of the study area and the effect of the wind on Can˜as, there are two wind-related components: one that crosses the mountain range between the Guanacaste range and the Tilaran range, whose effect is shown in Figure 12 of the Supplementary Text, and another horizontal component from the reanalysis model of North America Regional Reanalysis (NAAR), shown in Figure 13 of the Supplementary Text, both wind events occur in the same time period.
Relevant databases from corresponding authorities at the national level were consulted, and environmental variables that, in addition to having toxicological significance for CKD, also had public access records in Costa Rica were selected. Official data from state institutions regarding the counties were col- lected. Data were collected from Costa Rican Social Security (CCSS) regarding hospital discharges of CKD cases. These data were transformed into rates per 100,000 inhabitants per county, according to the information collected from 2007 to 2014, to determine the areas of population with the highest number of cases and respective control areas for comparison.
In addition, data were collected from the National Meteorological Insti- tute (IMN) for annual average temperature and relative humidity; from the National Geographic Institute (IGN) on altitude (masl) per county; hectares of cultivated sugarcane according to the Industrial Agricultural League of Sugar Cane (LAICA) were utilized. Land rated per ten thousand hectares and hectares of burned sugarcane crops was provided by the Sustainable Produc- tion Department of the National Directorate of Agricultural Extension, which is part of the Ministry of Agriculture and Livestock (MAG). In addition, the social development index of all counties was provided by the Ministry of Devel- opment and Planning (MIDEPLAN). CKD accumulated mortality incidence rates for 2000-2016 were obtained from the Ministry of Health data (MS), as well as the total population per county for the same period from the National Institute of Statistics and Censuses (INEC).
To include the presence of heavy metals into the model, such as geogenic contaminants where As is the only metal that has been looked for in drink- ing water, for this model, arsenic works as an environmental marker for the presence and measurement of heavy metals. This one was the year in which the National Water Laboratory included the first record on As in water sup- plies in Guanacaste and in the country. The information gathered for all the counties in the country allowed for collaboration with hospital discharges of CKD patients, with the aim of creating maps that would clarify the distribu- tion of the disease with respect to its geography. According to the models, the county of Can˜as had the greatest quantity of CKD patient cases recorded per number of inhabitants. Following this information, we contacted the Can˜as Integrated Health Assistance Center (CAIS) to know which district had the highest number of diagnosed cases. Maps of the disease were created respect to geography, soil topography, meteorology (temperature, precipitation and wind models), climatology and soil analyses for nephrotoxic heavy metals. In the present research we worked with the information provided by the district of Bebedero in the county of Can˜as; this county presented most cases according to the population.
Weather information recorded from the IMN stations closest to the CKD and control counties Can˜as for CKD and Esparza for control- was analysed. Graphs were made to visualize the information and compare the environmen- tal conditions of the study areas. Climate data was requested from the IMN meteorological stations La Pacifica in Can˜as, Guanacaste, Hacienda Mojica in Guanacaste, and San Miguelito in Barranca in the Puntarenas province.
As Can˜as is the county where proportionally most CKD cases were deter- mined with respect to the affected population, this county has the worst toxicological risk scenario. Thus, an analysis of the exposure scenario for this population was performed to understand the physical characteristics of the site and to describe the potential routes that toxicant agents were absorbed by individuals in the population. Lastly, the soil was sampled for analysis of nephrotoxic heavy metals (Hg, Pb, Cd, As, V) and silica (amorphous or crys- talline), in two areas: Can˜as in Guanacaste and El Guarco in Cartago. The samples were analyzed at the Department of Plant and Soil Sciences at Texas Tech University. Silicon was measured via portable X-ray fluorescence spec- trometry (Rouillon 2016). All soil samples for microwave assisted acid digestion with subsequent analysis via inductively coupled plasma – optical emission spectroscopy (ICP-OES) were analyzed in duplicate. Samples were weighed to
0.5 g and digested in a solution of 9 mL HNO3 and 3 mL HCl. Samples were digested in a Mars 6 microwave digestion system by CEM, using the method based on the US EPA 3051A for microwave assisted acid digestion of sedi- ments, sludge and oils. Post digestion, the solution was filtered to 0.22 microns. Five mL of filtered solution was diluted into 45 mL of 2% HNO3 in prepa- ration for analysis by (ICP-OES). All acids used were of trace metal grade. Analysis was done using an iCAP 7000 series ICP-OES by Thermo Scientific using the following wavelengths: As 193.759 nm, Cd 226.502 nm, Pb 220.353 nm, and V 292.464 nm. A standard curve was constructed using multi-element standard with concentrations of 0.1 ppm, 2.0 ppm, and 10 ppm. An internal standard of Y was run with each sample at 224.306 nm and 360.073 nm. Anal- ysis results were examined for elemental interferences before conversion from ppm to mg/kg and duplicates were averaged together.
According to the results, nephropathy can be a multifactorial disease. This has also been suggested by others (Garc´ıa-Trabanino et al. 2017; Johnson et al. 2019), where environmental variables can contribute to the problem. These findings are in line with the occurrence of CKD as found by nephrologist doctors in the Hospital of Liberia, Guanacaste. The doctors found that during the same time of the year (February, March, and April), the greatest number of cases of CKD occur, including exacerbations, progressions, and diagnoses of the disease.
According to the Costa Rican Meteorological Institute (Alvarado 2013), the principles of mass conservation play an important role specifically where the widening of the region from which the wind flows (i.e., out of the mountain pass) causes the flow to be distributed horizontally and become less dense. This change in land formation causes the pressure to decrease at lower altitudes and contributes to the formation of pressure differences at the outlet region of the wind. The difference in pressure causes an increase in flow velocity (i.e., higher wind speeds) due to the Venturi effect.
This increase in wind velocity is problematic when combined with the burn- ing of sugarcane. The locations when sugarcane is burned starts in Can˜as, but it also occurs in other areas of the Guanacaste province. The burning of sug- arcane, in addition to the added effects of wind and wind direction, implicates these factors in the transport and dispersal of particles found in the soil and air. This is particularly detrimental when the wind crosses the mountains and then increases in speed. The particles are then deposited according to their size, weight, and distance traveled in different areas in the southwest direc- tion. In addition to these effects due to the mountain range and increased wind velocity, there are other effects such as the Pacific decadal oscillations or the Madden-Julian variation (Zhao et al. 2019) which also cause differences in the variation of temperature within the country.
5.1 Environmental variables
It is also important to emphasize the understanding of environmental variabil- ity because the issues presented here are phenomena whose occurrence and effects have varied over the years. The case of high temperatures and drought in the Guanacaste area in different months and different years can be associated with the phenomenon of El Nin˜o, which causes such temperature variability effects in the pacific portion of Costa Rica.
The concentrations of heavy metals in the soils have been determined, and some of these metals will also be in the groundwater for human consumption. Groundwater was not measured in this work but has already been done by others; and the case of arsenic in the groundwater is generally known and has a notable contribution in the province of Guanacaste, with levels greater than 10 ug L−1 (Herrera et al. 2018). More information about the values of heavy metals is presented in Table 3. According to those data, which were sampled from Can˜as, when compared to the guideline values from the United States and
Europe, all of them have some relevance in pathology. Their presence should be considered particularly with respect to their potential impact on CKD and quantification in the people from that region.
Heavy metals in the soil, such as arsenic and cadmium along with others presented in Table 3, mainly present themselves as a hazard via a “mixed effect”. The metals are present in the soils of Can˜as and can carry out a toxic synergistic effect which will be mainly pronounced at certain times of the year. For example, during the high wind season, there is promotion of inhalation of toxicants through the mouth, which is toxicologically the most critical route called “involuntary geophagy”. This route is one of the most dangerous routes of entry of toxicants into the body since it forces absorption into the gastrointestinal system. This route is perhaps also mediated through the way in which the metals are complexed with the soil matrix and particle size, and particle size is linked to bio accessibility of contaminants to the body. Although it is important to determine the exact risk scenario to which the population is subjected, part of that scenario is to determine and quantify the amounts of individual toxicants that exposed populations and established control groups are experiencing. It is critical to understand how these groups are managing their interaction with the current exposure scenario and compare it with kidney function tests in affected patients. This should be done with respect to other population control groups from other areas for statistical significance.
In the case of the location El Guarco in Cartago, although most of these nephrotoxic metals are present in low concentrations in this area, this popula- tion is not impacted by the same exposure scenario that has been demonstrated for the Can˜as population. In the Cartago area, the soil remains humid almost all year, which prevents its dispersion as particles into the air for potential respiration by people. Some of the heavy metals found in the soil present a direct exposure risk to people, and they have the potential to be epigenetic inducers. Among those elements, arsenic has been highly studied. Arsenic is a known risk factor in the development of CKD and has been observed in sev- eral cases of patients in the studied area (Davey et al. 2008; Kile et al. 2014; Oxford University Press 2007; Reichard and Puga 2012; Skinner et al. 2010). Additionally, Bebedero has the lowest (masl) in comparison to other districts such as Palmira and Rio Naranjo (Figure 2D). There are very low to no cases of CKD in the latter two areas, and the sandy soil found in the lowlands of Bebedero allows it to be dispersed much more easily, constituting another risk factor for this specific population.
5.2 CKD progression
The temperature, soil, and wind effects do not entirely explain the large num- ber of CKD cases located in this region of the country; however, they are considered fundamental factors that together combined with physical exertion causes kidney disease in patients to progress slowly and continuously. This progression exacerbates the pathology in the kidneys affected by chronic toxic degenerative kidney disease. The patient realizes their state of health when they are in an advanced stage of 3, 4, or 5 of CKD and with deterioration of the glomerular filtration rate (GFR) from 3.8 to 4.4 mL/min/1.73 m2 annual. This results in the need to depend on permanent dialysis or a kidney trans- plant. CKD has a high mortality rate due to the challenges of accessing dialysis equipment in the affected regions and the late states of disease progress in patients (Correa-Rotter et al. 2014; Roncal-Jimenez et al. 2016).
Regarding the difference in CKD rates with respect to gender that have been reported, e.g., more men affected than women, but this result can be different depending on the site (PAHO 2019). There is still no evidence that constitutes this disease as a gender-linked disease, but rather linked to stren- uous occupations, particularly in agricultural operations. While the kidneys can collapse after chronic suffering, this difference between genders needs more study to be adequately quantified.
This study presents a comprehensive analysis for the occurrence of CKD in the northwestern province of Guanacaste, Costa Rica. Multiple variables were considered, including environmental variables such as wind, soil, water, and agricultural practices. Similar to the conditions found in Mesoamerica, this area is tropical with high temperatures for most of the year, and the region is suitable for the cultivation of extensive agricultural products, such as sugar- cane, cotton, and rice. Additionally, there is an important influence of volcanic activity, where heavy metals are present in the soil. Another factor of interest and important for future research studies, is the effect of long-range dust trans- port from the Sahara Desert, across the Atlantic, and into Mesoamerica (Figure 14 of the Supplementary Text) (AM&WFG 2021). Dust enters the country according to the predominant climatic phenomenon during the year, and the dust impacts the same area of this study which has augmented levels of CKD. Geographic and atmospheric wind patterns related to wind in areas affected by CKD could be repeated in other countries of Mesoamerica that includes areas surrounded by mountains but not near the Pacific coast, regarding the atmospheric movement of particles and the phenomenon of Sahara dust, this movement is also affected by what is known as the ”Intertropical Convergence Zone”, which describes the effect of wind circulation in the Mesoamerican zone (National Weather Service 2022).
The interdisciplinary approach to this problem is of a fundamental nature, and the problem is very complex. However, it is essential and urgent to mea- sure the toxicants in the patients to determine the degree that each will be affected and the stage of CKD they present. This can be done with kidney function tests. There are several important markers to measure, including hair, and then as a disease marker, genotoxic tests can be carried out so that com- munities and patients can receive early intervention before their kidneys have more been seriously impacted. This is especially important for children. If the disease can be diagnosed early in patients, it would allow for intervention with chelating agents, antioxidants, and specific and differentiated therapies to address the kidney problem. The urgency of this issue is critical for these com- munities to receive intervention as a priority, including policies for the transfer of people to other areas with less impact of the disease, or intervene in commu- nities with changes in the environment to reduce the impact of breathable soil particles, especially by children in spaces where they can play. Specific genetic determinations must also be carried out in affected populations in order to dis- criminate genotoxic and epigenetic damage, particularly with inheritable gene expression changes without DNA mutations. This will allow for some reverse in disease progression in the population. Children and pregnant women should have priority in the population management policies.
Acknowledgements: Thanks to Mr. Esteban Ramirez and Teodolito Guillen, PhD for their X-ray Diffraction (XRD) analysis for the determination of crystalline silica.
Dr. Diana Valles for her contributions in the statistics of patients from Can˜as Integrated Health Assistance Center (CAIS) in Can˜as.
Dr. Jorge Camacho and Lic. Eric Romero for their collaboration in the revision of the statistical data of the models.
To all the institutions that allowed use of data and data collection Costa Rican Social Security Fund (CCSS), Ministry of Agriculture and Livestock (MAG), Ministry of Health (MS), National Institute of Statistics and Census (INEC), National Meteorological Institute (IMN) specially Dr. Werner Stolz director of the IMN.
Dr. Enrique Sixel and Ms. Lucia Novoa for the design of several figures.
Department of Plant and Soil Science, Texas Tech University collaborated in the determination of all heavy metals in the soil samples.
To Mr. Michael Chac´on, for his time and help reviewing and editing the format of this written work.
Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflict of interest/Competing interests: The authors declare that they have no conflicts of interest.
Ethics approval: Not applicable.
Consent to participate: Not applicable.
Consent for publication: Not applicable.
Availability of data and materials: The datasets generated during and/or analysed during the current study are not publicly available, but are available from the corresponding author on reasonable request.
Code availability: Not applicable.
Authors’ contributions:
Virginia Montero: conceptualization, supervision, project admin, funding.
Oscar Ulloa, Marcela Quir´os: methodology, acquisition, analysis, and/or interpretation of data.
Sharon Ulate: visualization.
Javier Estrada: conceptualization.
Matthew G. Siebecker: methodology; acquisition, analysis, and/or interpre- tation of data; resources; writing—review and editing.
Amanda Jo Zimmerman: methodology; acquisition, analysis, and/or inter- pretation of data; resources.
David C. Weindorf: resources; methodology.
All authors read and approved the final manuscript.
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Table 1 Pearson Correlation test values using Minitab 18 with respect to the rate of CKD. All variables had a p-value of <0.05.
Table 2 Rates of CKD distributed among districts of county Can˜as with respect to altitude.
Table 3 Comparison of values of heavy metals, metalloids, and metals with toxicological significance in soils.
Supplementary Text 1-7 and Figures 1-14 are not available with this version