What do epidemiological studies tell us about chronic kidney disease of undetermined cause in Meso-America? A systematic review and meta-analysis

What do epidemiological studies tell us about chronic kidney disease of undetermined cause in... Background: The aim of this systematic review is to examine the epidemiological knowledge and gaps in understanding of the potential causes of chronic kidney disease of undetermined cause (CKDu) in Meso-America. Methods: A systematic literature search of epidemiological studies of CKDu was conducted in PubMed, Embase and Web of Science from January 2000 to January 2017. Study quality was assessed by adapting the tool from Higgins et al. for observational studies. Where applicable, the summary prevalence odds ratio (POR) and 95% confidence interval (CI) were calculated using a random effects model. Results: Twenty-five epidemiological studies were included in the analysis of risk factors for CKDu. The quality assessment of each occupational and community study was medium. The PORs for CKDu were males versus females 2.42 (95% CI 1.76– 3.08), family history of CKD (versus none) 1.84 (95% CI 1.37–2.30), high water intake (versus low) 1.61 (95% CI 1.01–2.21) and low altitude (versus highland) 2.09 (95% CI 1.00–3.17). There were no significant associations between CKDu and pesticide exposure (versus no) 1.17 (95% CI 0.87–1.46), alcohol consumption (versus no) 1.34 (95% CI 0.84–1.84), non-steroidal anti- inflammatory drugs (versus no) 0.99 (95% CI 0.60–1.39) and heat stress (versus no) 1.52 (95% CI 0.91 – 3.95). Conclusion: Our meta-analysis showed positive associations for males (versus females) and family history of CKD, water intake, lowland altitude and CKDu. There were no significant associations with pesticide exposure, non-steroidal anti- inflammatory drugs intake, heat stress and alcohol consumption. Key words: CKDu, Meso-America, Meso-American nephropathy, meta-analysis, Nicaragua, risk factors, systematic review Received: August 5, 2017. Editorial decision: October 18, 2017 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/496/4708273 by Ed 'DeepDyve' Gillespie user on 07 August 2018 CKD of undetermined cause in Meso-America | 497 some marginal cases were discussed between M.G.-Q., B.C. and Introduction D.N. After review of the titles and abstract were independently Meso-American nephropathy (MeN), also known as chronic kid- reviewed by two authors (M.G.-Q. and D.N.). All full-text articles ney disease of undetermined aetiology (CKDu), is a growing were assessed independently using the same criteria and public health problem and young agricultural workers of the included if both reviewers recommended inclusion. A second Pacific coast of Meso-America have been the most affected reviewer (D.N.) checked a sample of 45 titles and abstracts group [1–3]. There was an increased recognition of this problem selected randomly after duplicated articles were removed. by researchers, universities and policymakers after 2000 due to Agreement between authors was quantified by j-statistic a marked increase in mortality and morbidity [4]. calculation. Three years later, the Program on Work and Health in Central America (SALTRA) organized the first regional workshop Data extraction and quality assessment on chronic kidney disease (CKD); this reviewed available data, including several studies that showed increased risks for CKD A standardized data extraction form was used by M.G.-Q. to among sugarcane workers and high mortality related to CKD in extract study characteristics: authors, study design, year, coun- particular areas in Nicaragua and El Salvador [4]. In 2014, the try, sample size, altitude, exposure and outcome definitions, Pan American Health Organization classified CKDu as a major main findings, strengths and limitations and confounding fac- public health problem in Central America that requires urgent, tors. Any difficulty in data extraction was discussed by joint effective and concerted multisectoral action [5]. review of the original papers. In the last 10 years, several narrative reviews about CKDu Quality was assessed for each selected study using standard have been published [6–9]. None of these have conducted a for- quality assessment tools for trials [10] that we adapted for mal meta-analysis and there was no systematic assessment of observational studies. Studies were assigned a high, low or the quality of the available evidence considering inherent limi- uncertain risk according to the following criteria: selection bias, tations within the design and analyses of available epidemio- non-differential measurement error for exposure and outcome, logical studies. The purpose of this study is therefore to information bias in exposure and outcome, confounding and formally examine the epidemiological knowledge and gaps in reverse causation. understanding of the potential causes of CKD of undetermined cause in Meso-America. Data synthesis and analysis We reviewed the exposure and outcome definitions and Materials and methods reported risk factors in each study. Where there were several studies with similar exposure definitions, data were included in Research strategy a random effects meta-analysis for the respective exposure and We searched on PubMed, MEDLINE, Embase and Web Science to CKDu and displayed in a forest plot. Funnel plot analysis identify all original research that had been published between and Egger’s test were performed to detect publication bias and January 2005 and January 2017 reporting prevalence and P < 0.05 was considered significant. mortality of CKDu in Meso-America. Search terms included a The across-study heterogeneity was estimated by using combination of text words and headings for ‘Meso-American Cochran’s Q-statistic and calculating the proportion of total var- nephropathy’, ‘decreased kidney function’, ‘chronic kidney dis- 2 iability explained by heterogeneity (I ) described by Higgins et al. eases of unknown cause’, ‘chronic kidney disease of non- [10]. All analyses were performed using Stata version 14 traditional cause’, ‘agricultural’, ‘pesticide exposure’, ‘heat stress’, (StataCorp, College Station, TX, USA). etc., were used. The full search strategy is outlined in the Supplementary Material (Supplementary data,TablesS1–S3). Results The two reviewers had excellent agreement (Cohen’ s j ¼ 1) on Inclusion and exclusion criteria study inclusion after review of abstracts and titles. We identi- The search was limited to ‘adolescent and adult human beings’ fied 131 epidemiological studies on CKDu, of which 43% (56 and only papers published in English and Spanish languages papers) were duplicate studies using the same dataset. In addi- were considered. The search was restricted to studies conducted tion, 53 studies did not meet the inclusion criteria and 3 were in Meso-America (Central America and Mexico). The exposures of included by manual search, leaving 25 studies for the present interest included heat stress, dehydration, pesticide, non-steroi- systematic review (3 longitudinal occupational studies, 2 cross- dal anti-inflammatory drugs (NSAIDs), workplace conditions, sectional occupational studies, 14 community cross-sectional environmental toxins and infectious diseases. The outcomes of studies, 3 case–control studies and 3 ecological studies) (Fig. 1). interest included the reduced estimated glomerular filtration rate The included studies were conducted from January 2000 to (eGFR), elevated serum creatinine (SCr) and CKD of undetermined January 2017. cause. A wide range of study designs were assessed, including Occupational studies mainly assessed how occupational risk cross-sectional studies, case–control studies, retrospective or pro- factors in the workplace were associated with an eGFR cross- spective cohort studies and ecological studies. We excluded ani- sectionally or a subsequent decline of eGFR across harvest or a mal studies, editorials, systematic reviews and case reports single cross-shift in younger sugarcane workers (Table 1). For (Supplementary data, Table S4). However, systematic reviews many risk factors there is only one estimate per risk factor in were used to manually search for references. each study (Supplementary data, Table S5). We identified only two longitudinal community studies. One Selection process involved follow-up of eGFR measurements in the subgroup that All titles and abstracts were examined by one reviewer (M.G.-Q.) previously had abnormal SCr results, thus incident disease was according to the above inclusion criteria. Any disagreement of not captured [16]. For the other study, only baseline data are Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/496/4708273 by Ed 'DeepDyve' Gillespie user on 07 August 2018 498 | M. Gonza ´ lez-Quiroz et al. Fig. 1. CKD of undetermined cause (eGFR <60 mL/min/1.73 m ), systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta- Analyses diagram. available [17]. Most of the community-based studies were of factors and within-regions variability in exposure and cross-sectional design and recruited participants from different disease classification (outcome) (Table 4 and rationale in age groups and explored a variety of exposures. Two-thirds of Supplementary data,Table S7). Sufficient data for meta-analysis were available for a subset these used a similar outcome definition for kidney function involving calculating an eGFR (<60 mL/min/1.73 m ) using the of risk factors: male sex, family history of CKD, water intake, Modification of Diet in Renal Disease [18–25] or CKD pesticide exposure, alcohol consumption, self-medication with NSAIDs, heat stress and altitude. These were from 10 cross- Epidemiology Collaboration formula to quantify the prevalence of CKDu in the most affected regions [11–15, 26–28] (Table 2). sectional community studies and 3 case–control community Prevalence data among 14 cross-sectional community studies studies. In the meta-analysis, eight cross-sectional community are confounded by age, as people with different ages were studies showed positive associations between male and included, but overall more men than women were affected (Fig. eGFR <60 mL/min/1.73 m {prevalence odds ratio [POR] 2.42 [95% 2). It was not possible to report an age-standardized CKDu prev- confidence interval (CI) 1.76–3.08]; Cochran’s Q-statistic P ¼ 0.056, I ¼ 49.0%}. Three studies showed strong associations alence because a breakdown of the findings by age was not available for most studies. between family history of kidney disease and eGFR <60 mL/ The quality of three longitudinal occupational studies was min/1.73 m [POR 1.84 (95% CI 1.37–2.30); Cochran’s Q-statistic affected by severe loss of follow-up (up to 50%) during the P ¼ 0.947, I ¼ 0.0%]. For high water intake and eGFR <60 mL/ study period, either due to changes in role or redundancy [11– min/1.73 m the POR was 1.61 (95% CI: 1.01–2.21; Cochran’s Q- 13] (Table 3 and rationale in Supplementary data, Table S6). statistic P ¼ 0.511, I ¼ 0.0%) and for lowland altitude (versus One cross-sectional occupational study [15]and cross- highland) it was 2.09 (95% CI 1.00–3.17; Cochran’s Q-statistic sectional community-based studies [23–25, 31, 32]had incom- P ¼ 0.272, I ¼ 23.3%). The pooled POR for pesticide exposure plete adjustment for confounding and reverse causation. One was 1.17 (95% CI 0.87–1.46; Cochran’s Q-statistic P ¼ 0.537, case–control study suffered from selection bias of participants, I ¼ 0.0%) (Fig. 3). The summary estimate for alcohol consump- because researchers used improper procedures for selecting tion (yes versus no) was 1.34 (95% CI 0.84–1.84; Cochran’s Q-sta- their cases and controls (volunteer participations at clinics) tistic P ¼ 0.088, I ¼ 45.5%), for NSAIDs intake (yes versus no) (Table 4). Many cross-sectional studies were limited to single and eGFR <60 mL/min it was close to 1 [POR 0.99 (95% CI 0.60– measurements of creatinine, thus not fulfiling the chronicity 1.39); Cochran’s Q-statistic P ¼ 0.399, I ¼ 0.0%] and for heat criterion for CKD. Furthermore, the quality of three ecological stress exposure (yes versus no) it was 1.52 (95% CI 0.91 to 3.95; studies was potentially affected by unmeasured confounding Cochran’s Q-statistic P ¼ 0.065, I ¼ 70.6%) (Supplementary data, Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/496/4708273 by Ed 'DeepDyve' Gillespie user on 07 August 2018 CKD of undetermined cause in Meso-America | 499 Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/496/4708273 by Ed 'DeepDyve' Gillespie user on 07 August 2018 Table 1. Characteristics of occupational studies included in the systematic review (n¼5) Sample size/sex Authors Year Design Country Region N Male Female Age (years) Exposures Outcome definition Wesseling et al. [11] 2016 Cohort Nicaragua Leo ´ n and Chinandega 54 54 – 17–38 Sugarcane cutters, anthropometrics Decline in eGFR over time measurements, fructose intake and uri- nary biomarkers Laws et al. [12] 2016 Cohort Nicaragua Chinandega 284 251 33 18–63 Job category of sugarcane harvesters, Kidney urinary biomarkers years worked at sugar mill, water and kidney function over intake, isotonic solution intake, age and harvest sex Laws et al. [13] 2015 Cohort Nicaragua Chinandega 284 251 33 18–63 Job category of sugarcane harvesters, Decline in eGFR over harvest years worked at sugar mill, water intake, isotonic solution intake, age and sex Wesseling et al. [14] 2016 Cross- Nicaragua Leo ´ n and Chinandega 194 194 – 17–39 Differences between three occupations, eGFR <80 mL/min/1.73 m sectional socioeconomic status, hydration, life- style and health risk factors Garcia-Trabanino 2015 Cross- El Salvador Suchitoto, El Paisnal 189 168 21 18–49 Sugarcane workers, workplace conditions, Cross-shift changes in eGFR et al. [15] sectional and San Luis Talpa dehydration, heat stress, pesticide exposure and anthropometric measurements The baseline sample was 1104 sugarcane workers, but at the end of the harvest it was 284. eGFR, estimated glomerular filtration rate. 500 | M. Gonza ´ lez-Quiroz et al. Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/496/4708273 by Ed 'DeepDyve' Gillespie user on 07 August 2018 Table 2. Characteristics of community-based studies included in the systematic review (n¼20) Sample size/sex Authors Year Design Country Region N Male Female Age (years) Exposures Outcome definition Nicaragua Gonza ´ lez- 2017 Cohort Nicaragua Leo ´ n and 350 263 87 18–30 Sociodemographic information, work his- eGFR <90 mL/min/1.73 m Quiroz et al. Chinandega tory, lifestyle, work conditions, liquid [17] intake and current diseases (hyperten- sion or diabetes) Minnings et al. 2016 Cohort Nicaragua Rivas 1242 537 705 18 Demographic data, household member- SCr >1.5 mg/dL if male and [16] ship, health symptoms, hydration prac- >1.2 mg/dL if female or tices, occupational and exposure eGFR <60 mL/min/ history and personal medical history 1.73 m Kupferman 2016 Cross-sectional Nicaragua Chichigalpa 226 178 88 18 Clinical and demographic characteristics SCr >1.5 mg/dL if male and et al. [27] >1.2 mg/dL if female or eGFR <60 mL/min/ 1.73 m Lebov et al. [29] 2015 Cross-sectional Nicaragua Leo ´ n 2275 1324 951 18–70 Demographic indicators, source of drink- eGFR <60 mL/min/1.73 m ing water, personal medical history, occupation and lifestyle b 2 Laux et al. [21] 2012 Cross-sectional Nicaragua Matagalpa 267 120 147 20–60 Demographic data, personal and family eGFR <60 mL/min/1.73 m medical history, medications, occupa- tion and lifestyle Torres et al. 2010 Cross-sectional Nicaragua Leo ´ n and 1096 479 617 20–60 Sociodemographic data, personal medical SCr >1.2 mg/dL if male and [18] Chinandega history (diabetes, hypertension, obesity >0.9 mg/dL if female or and renal lithiasis), NSAIDs and eGFR <60 mL/min/ occupation 1.73 m Gonza ´ lez- 2010 Cross-sectional Nicaragua Chichigalpa 704 237 467 20–60 Sociodemographic data, personal medical eGFR <60 mL/min/1.73 m Quiroz [30] history (diabetes, hypertension, obesity and renal lithiasis), alcohol, NSAIDs, occupation and pesticide exposure a 2 Raines et al. 2014 Case–control Nicaragua Chichigalpa 424 166 258 15–69 Demographic data, personal medical his- eGFR <60 mL/min/1.73 m [26] tory, lifestyle, NSAIDs, cane chewing, inhaled pesticides, water intake, sugar beverage intake, occupation and per- sonal protective equipment O’Donnell 2010 Case–control Nicaragua Quezalguaque 771 298 473 18 Age, sex, anthropometric measurements, eGFR <60 mL/min/1.73 m et al. [20] education level, work history, exposure to pesticides, alcohol, cigarrete use and family and personal medical history a 2 Sanoff et al. 2010 Case–control Nicaragua Chinandega 997 848 149 18 Demographic data, hypertension, diabe- eGFR <60 mL/min/1.73 m [19] tes, family history of kidney disease and occupational and non-occupational exposures El Salvador Orantes- 2016 Cross-sectional El Salvador Bajo Lempa, 2115 1058 1057 <18 Age, sex and region eGFR <60 mL/min/1.73 m , Navarro Guayapa, Las by a second measure- et al. [24] Brisas ment of SCr within 3 months’ difference (continued) CKD of undetermined cause in Meso-America | 501 Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/496/4708273 by Ed 'DeepDyve' Gillespie user on 07 August 2018 Table 2. Continued Sample size/sex Authors Year Design Country Region N Male Female Age (years) Exposures Outcome definition Orantes- 2015 Cross-sectional El Salvador Bajo Lempa, 1412 – 1412 18 Age, sex, clinical history (hypertension eGFR <60 mL/min/1.73 m , Navarro Guayapa, Las and diabetes), family history (CKD, dia- by a second measure- et al. [31] Brisas betes and hypertension), occupation, ment of SCr within agrochemicals exposure and physical 3 months’ difference examination (weight, height and blood pressure) d 2 Vela et al. [25] 2014 Cross-sectional El Salvador El Jicaro and 223 110 113 15 Age, sex, physical measurements (weight, eGFR <60 mL/min/1.73 m , Dimas height, abdominal circumference and by a second measure- Gutie ´ rrez blood pressure), personal and family ment of SCr within medical history, occupational and envi- 3 months’ difference ronmental exposures a,d 2 Orantes et al. 2014 Cross-sectional El Salvador Bajo Lempa, 2388 976 1412 18 Age, sex, physical measurements (weight, eGFR <60 mL/min/1.73 m , [23] Guayapa abajo, height, waist circumference and blood by a second measure- Las Brisas pressure), personal and family medical ment of SCr within history, occupational exposures and 3 months’ difference lifestyle Peraza et al. 2012 Cross-sectional El Salvador San Luis Talpa, 664 256 408 20–60 Demographic data, occupational expo- SCr >1.2 mg/dL if male and [28] Jiquilisco, sure, medical conditions and lifestyle >0.9 mg/dL if female or Apastepeque, eGFR <60 mL/min/ San Salvador 1.73 m and Ataco a,d 2 Orantes et al. 2011 Cross-sectional El Salvador Bajo Lempa 775 343 432 18 Age, sex, physical measurements (weight, eGFR <60 mL/min/1.73 m , [22] height, abdominal circumference and by a second measure- blood pressure), personal and family ment of SCr within medical history, occupational, environ- 3 months’ difference mental exposures and lifestyle Garcia- 2005 Cross-sectional El Salvador Jaquilisco 291 291 – 34–66 Age, place of residence, occupation in SCr >1.5 mg/dL Trabanino agricultural work, history of pesticides et al. [32] exposure, alcohol consumption and basic medical history Costa Rica, El Salvador and Guatemala Wesseling et al. 2015 Ecological Costa Rica Costa Rica 6295 3843 2452 20 Age, sex, region, altitude, climate and sug- CKD by death certificate [33] arcane production Laux et al. [34] 2015 Ecological Guatemala Guatemala 3105 1591 1514 Not reported Sex, sugarcane cultivation, temperature, CKD by medical records region, life expectancy, educational from an RRT programme level and wealth VanDervort 2014 Ecological El Salvador El Salvador 24 726 – – No reported Temperature, crops (sugarcane, sorghum, CKD by medical records et al. [35] corn, beans, cotton and coffee) from National Surveillance Health System Altitude: at sea level. More than 500 m above sea level. At sea level and >500 m above sea level. d 2 Five studies from El Salvador applied the CKD definition: persistence of renal damage markers for 3 months or GFR <60 mL/min/1.73 m . eGFR, estimated glomerular filtration rate; SCr, serum creatinine; CKD, chronic kidney disease; NSAIDs, non-steroidal antiinflammatory drugs; RRT, renal replacement therapy. 502 | M. Gonza ´ lez-Quiroz et al. Fig. 2. Forest plot of all prevalence of chronic kidney disease of undetermined cause (eGFR <60 mL/min/1.73 m ) by age group and sex from 14 cross-sectional commun- ity studies identified. Fig. S1). A forest plot of occupation was not included because incomplete adjustment for confounding factors and the use of a each study used different reference categories. single SCr measurement. Longitudinal occupational studies We tested for publication bias for sex, pesticide exposure and were affected by severe loss of follow-up. alcohol consumption risk factors. The funnel plot for studies that A major issue impacting the quality of all the studies exam- have assessed the above risk factors provides evidence for poten- ined is that CKDu prevalence was estimated using a single SCr tial publication bias for pesticide exposure and alcohol consump- measurement rather than two measurements at least 3 months tion (P < 0.014 and P < 0.048, respectively) (Supplementary data, apart [36]. In affluent countries, a single measurement is fre- Fig. 2). quently used to estimate the prevalence of CKD, as the intra- individual variability of creatinine under stable conditions is only a few percent. However, in a hot setting there is consider- Discussion able seasonal variation and variation depending on work pat- We found 25 epidemiological studies that estimated the preva- terns and dehydration status; therefore, depending on when lence and assessed risk factors for CKDu in Meso-America. Our people are measured, they may have short-term fluctuations of meta-analysis found a clear positive association between male creatinine that are far more pronounced than in cooler settings. sex, family history of CKD, high water intake, lowland altitude Also, creatinine elevation can occur due to variations in factors and reduced eGFR <60 mL/min/1.73 m . There was no evidence such as exercise, muscle mass and diet. These factors may not for associations with pesticide exposure, NSAIDs intake, alcohol only affect variability within individuals, but may also bias com- consumption and heat stress. The quality of cross-sectional parisons across populations studies, since each study may over- studies was medium due to the potential for reverse causality, or underestimate kidney function depending on the season and Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/496/4708273 by Ed 'DeepDyve' Gillespie user on 07 August 2018 CKD of undetermined cause in Meso-America | 503 Table 3. Quality assessment of occupational studies (n¼5) Selection Selection Non-differential Information Non-differential Information bias: bias: loss of misclassification bias of misclassification bias of Reverse Studies participation follow-up exposure exposure of outcome outcome Confounding causation Cohort studies Wesseling et al. [11] Laws et al. [12] Laws et al. [13] Cross-sectional studies Wesseling et al. [14] N/A Garcia-Trabanino et al. [15] N/A Green bars: low risk of bias; yellow bars: medium risk of bias; red bars: high risk of bias. N/A, not applicable. Table 4. Quality assessment of community-based studies (n¼20) Selection Selection Non-differential Information Non-differential Information bias: bias: loss of misclassification bias of misclassification bias of Reverse Studies participation follow-up exposure exposure of outcome outcome Confounding causation Cohort studies Gonza ´ lez-Quiroz et al. [17] N/A Minnings et al. [16] Cross-sectional studies Orantes-Navarro et al. [24] N/A N/R N/R N/R Kupferman et al. [27] N/A Orantes-Navarro et al. [31] N/A Lebov et al. [29] N/A Vela et al. [25] N/A Orantes et al. [23] N/A Peraza et al. [28] N/A Laux et al. [21] N/A Orantes et al. [22] N/A Torres et al. [18] N/A Gonzalez-Quiroz [30] N/A Garcia-Trabanino et al. [32] N/A Case–control studies Raines et al. [26] N/A O’Donnell et al. [20] N/A Sanoff et al. [19] N/A Ecological studies Wesseling et al. [33] N/A Laux et al. [34] N/A VanDervort et al. [35] N/A Green bars: low risk of bias; yellow bars: medium risk of bias; red bars: high risk of bias. N/A, not applicable; N/R, not reported. setting of fieldwork or biological variation in the production of that predispose young men to CKDu when they start working in creatinine. In addition, creatinine levels may also be affected by sugarcane. Overall, considering the differential loss to follow-up ‘fixed’ factors such as ethnicity, which may also bias compari- of occupational studies, community cohorts have many advan- sons between populations. tages compared with occupational studies since they represent The longitudinal occupational studies were affected by a the entire risk population (workers from all occupations and loss of follow-up of up to 50% of their participants. This severely both genders) and an assessment of environmental exposures compromises study validity because those with CKDu are more at home [17]. likely to not be followed up [11–13]. Occupational studies are Ecological studies may be affected by variability within used to increase the power of a study when it is thought that a regions in exposure and disease classification and by unmeas- particular occupational exposure causes a problem. However, in ured confounding factors [33–35]. CKD mortality rate may vary the context of CKDu, it is not yet entirely clear whether occupa- across regions because of misclassification either of the cause tion is the only risk factor or whether there are other risk factors reported by death certificate or by better case detection. Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/496/4708273 by Ed 'DeepDyve' Gillespie user on 07 August 2018 504 | M. Gonza ´ lez-Quiroz et al. Fig. 3. Forest plots of association with (A) sex, (B) family history of CKD, (C) water intake, (D) lowland altitude and (E) pesticide exposure estimates associated with CKD of undetermined caused (eGFR <60 mL/min/1.73 m ). Black diamond data markers express PORs; horizontal lines are the 95% CIs; grey square marker size indicating the statistical weight of the study using the random effects meta-analysis. A diamond data marker denotes the overall POR and 95% for the outcome of interest. Moreover, environmental temperature may be different association with male sex, none of the other suggested risk fac- within regions or areas due to variability in seasons and tors were sufficiently well studied to conclusively prove or dis- altitude. Finally, the lack of control for confounders have prove their role. The most commonly cited working hypothesis been an Achilles heel for ecological studies, even on the for this disease has been heat stress causing repetitive episodes assumption that all variables have been accurately measured of dehydration in agricultural and non-agricultural workers due for all groups at a national level, basically due to the analysis to working under heat stress and high humidity [15, 37], which may result in acute kidney injury (AKI) secondary to hypoperfu- strategy, which cannot completely remove bias due to the confounder. sion or rhabdomyolysis [38]. However, although this hypothesis Epidemiological studies have underlined many potential risk has been explored in an experimental study that suggested that factors for CKDu, including male sex, occupation, high ambient dehydration and hyperosmolarity may induce tubular injury via temperature, self-medication with NSAIDs, altitude, exposure activation of the polyolfructokinase pathway in the kidney [39], to heavy metals or pesticides and genetic susceptibility [11, 13– there have been no corresponding data in humans to support 15, 18, 28]. While our systematic review could confirm the this hypothesis. Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/496/4708273 by Ed 'DeepDyve' Gillespie user on 07 August 2018 CKD of undetermined cause in Meso-America | 505 Our meta-analysis has identified positive associations of as differential loss to follow-up (as per existing occupational high water intake and CKDu in two cross-sectional community studies). studies [29, 30] and one case–control study [19]. The study authors’ interpretation of these findings was that high water Authors’ contributions intake could be a proxy for exposure to heat stress and volume depletion during the workday secondary to high exertion and This study was conceived and designed by M.G.-Q., N.P., B.C. sweating [11, 14, 15, 40]. Some authors hypothesized that high and D.N. Data collection was performed by M.G.-Q. and B.C. The analysis and interpretation of the results were done by M.G.-Q., water intake means that study participants drank more water trying to compensate for fluid deprivation, but that this is not B.C. and D.N. The draft was written by M.G.-Q. and D.N. All enough to recover their hydration status [11, 14, 15]. Other authors read and approved the final manuscript. authors have suggested that these associations are driven by intake from contaminated water sources (with pesticides or Supplementary data heavy metals) in the affected areas [41, 42]. An alternative inter- Supplementary data are available at ckj online. pretation could be reverse causation due to underlying kidney damage, in that those with kidney damage are unable to con- centrate their urine and therefore need to drink more to not feel Funding thirsty. To address the issue, it will be important to conduct The study has been supported by a grant (CF/03/14) from the more longitudinal studies to gain better insight into this association. UK Colt Foundation. Pesticides are used extensively in Meso-America. Farmers in the cooler highland regions use pesticides similarly to farmers Conflict of interest statement in coastal regions, yet CKDu prevalence is much lower at higher altitudes [15, 20–23, 26, 30]. Most of the studies that suggest a None declared. possible association between AKI and exposure to organochlor- ides, paraquat, 2,4-diclorophenoxyacetic and glyphosate have References been conducted in animals [43, 44]. A single prospective cohort 1. Weiner DE, McClean MD, Kaufman JS et al. The Central study among male licensed pesticide applicators in the USA American epidemic of CKD. Clin J Am Soc Nephrol 2013; 8: reported an association between end-stage renal disease and 504–511 exposure–response and increasing accumulated lifetime days 2. Correa-Rotter R, Wesseling C, Johnson RJ. CKD of unknown in pesticide exposure and non-exposure for some herbicides origin in Central America: the case for a Mesoamerican such as alachlor, paraquat, pendimethalin, atrazine, permethrin nephropathy. Am J Kidney Dis 2014; 63: 506–520 and metolochlor [45]. The principal limitation of existing epide- 3. Wegman D, Crowe J, Hogstedt C et al. (eds). Mesoamerican miological studies is that exposure has been assessed using cat- nephropathy: report from the second international research work- egorical questions (yes and no) and not by quantifying the shop on MeN. ISBN 978-9968-924-33-7. Heredia, Costa Rica: pesticide residues in urine or blood [14, 19, 20, 26, 32]. Our find- SALTRA/IRET-UNA, 2016 ings suggest selective reporting of studies supporting an associ- 4. Cuadra SN, Kristina J, Christer H et al Chronic Kidney Disease: ation with CKDu. Overall, the evidence about pesticide exposure Assessment of Current Knowledge and Feasibility for Regional and CKDu is still inconclusive. Research Collaboration in Central America. Heredia, Costa Rica: Genetic predisposition may play a role in the CKDu epi- SALTRA, 2006 demic, as some studies, and our meta-analysis, have suggested 5. Pan American Health Organization–World Health a positive association between family history of CKD and CKDu. Organization. Resolution CD52.R1: Chronic Kidney Disease in Although CKD in general shows a high heritability of disease, Agricultural Communities in Central America.Washigton, DC: suggesting familial clustering of risk factors, these have not PAHO, 2014. http://www.paho.org/hq/index.php? option¼com_ been explained by genetic association studies [46, 47]. A positive content&view¼article&id¼8833&Itemid¼40033&lang¼en (last association with family history of CKDu may simply be due to accessed 10 June 2017) children who lost parents to CKDu or living in rural areas start- 6. Lunyera J, Mohottige D, Isenburg MV et al. CKD of uncertain ing to work earlier in sugarcane or agriculture to support their household income. etiology: a systematic review. Clin J Am Soc Nephrol 2016; 11: 379–385 Our systematic review has strengths and limitations. To our 7. Gifford FJ, Gifford RM, Eddleston M et al. Endemic nephrop- knowledge, this is the first systematic review that included a meta-analysis and evaluated the study quality of each epide- athy around the world. Kidney Int Rep 2017; 2: 282–292 8. Madero M, Garcı ´a-Arroyo FE, Sa ´ nchez-Lozada LG. Pathophy- miological study by using a pre-specified tool adapted from siologic insight into MesoAmerican nephropathy. Curr Opin Higgins et al.[10] for observational studies. Second, we included a broad definition of CKD of unknown aetiology and a variety of Nephrol Hypertens 2017; 26: 296–302 9. Elinder C-G, Wijkstro ¨ m A, Wijkstrom J. Mesoamerican exposures. The main limitations of the review are that the avail- nephropathy (MeN): a ‘new’ chronic kidney disease related able evidence on CKDu is overall patchy and inconclusive. In summary, apart from male sex, positive family history, to occupational heat exposure with repeated deprivation of high water intake and lowland altitude, existing studies have salts and water. Int J Nephrol Kidney Failure 2015; 1: 1–9 10. Higgins JP, Altman DG, Gøtzsche PC et al. The Cochrane been inconclusive with regards to potential risk factors for CKDu, such as pesticide use, NSAIDs, heavy metals, alcohol Collaboration’s tool for assessing risk of bias in randomised consumption, heat stress and dehydration. Longitudinal trials. BMJ 2011; 343: d5928 community-based studies are needed to address problems of 11. Wesseling C, Arago ´ n A, Gonza ´ lez M et al. Kidney function in reverse causality (as per existing cross-sectional studies) as well sugarcane cutters in Nicaragua—a longitudinal study of Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/496/4708273 by Ed 'DeepDyve' Gillespie user on 07 August 2018 506 | M. Gonza ´ lez-Quiroz et al. Chichigalpa [Tesis de postgrado]. Universidad Nacional workers at risk of Mesoamerican nephropathy. Environ Res 2016; 147: 125–132 Auto ´ noma de Nicaragua, Leo ´ n, 2010 12. Laws RL, Brooks DR, Amador JJ et al. Biomarkers of kidney 31. Orantes Navarro CM, Herrera Valde ´ s R, Lo ´ pez MA et al. injury among nicaraguan sugarcane workers. Am J Kidney Dis Epidemiological characteristics of chronic kidney disease of 2016; 67: 209–217 non-traditional causes in women of agricultural commun- 13. Laws RL, Brooks DR, Amador JJ et al. Changes in kidney func- ities of El Salvador. Clin Nephrol 2015; 83(Suppl 1): 24–31 tion among Nicaraguan sugarcane workers. Int J Occup 32. Gracia-Trabanino R, Dominguez J, Jansa JM et al. [Proteinuria Environ Health 2015; 21: 241–250 and chronic renal failure in the coast of El Salvador: detec- 14. Wesseling C, Arago ´ n A, Gonza ´ lez M et al. Heat stress, hydra- tion with low cost methods and associated factors]. tion and uric acid: a cross-sectional study in workers of three Nefrologia 2005; 25: 31–38 occupations in a hotspot of Mesoamerican nephropathy in 33. Wesseling C, van Wendel de Joode B, Crowe J et al. Nicaragua. BMJ Open 2016; 6: 1–12 Mesoamerican nephropathy: geographical distribution and 15. Garcı ´a-Trabanino R, Jarquı ´n E, Wesseling C et al. Heat stress, time trends of chronic kidney disease mortality between dehydration, and kidney function in sugarcane cutters in El 1970 and 2012 in Costa Rica. Occup Environ Med 2015; 72: Salvador—a cross-shift study of workers at risk of 714–721 Mesoamerican nephropathy. Environ Res 2015; 142: 746–755 34. Laux TS, Barnoya J, Guerrero DR et al. Dialysis enrollment 16. Minnings K, Fiore M, Mosco M et al. The Rivas Cohort Study: patterns in Guatemala: evidence of the chronic kidney dis- design and baseline characteristics of a Nicaraguan cohort. ease of non-traditional causes epidemic in Mesoamerica. BMC Nephrol 2016; 17: 93 BMC Nephrol 2015; 16: 54 17. Gonza ´ lez-Quiroz M, Camacho A, Faber D et al. Rationale, 35. VanDervort DR, Lopez DL, Orantes CM et al Spatial distribu- description and baseline findings of a community-based tion of unspecified chronic kidney disease in El Salvador by prospective cohort study of kidney function amongst the crop area cultivated and ambient temperature. MEDICC Rev young rural population of Northwest Nicaragua. BMC 2014; 16: 31–38 Nephrol 2017; 18: 16 36. KDIGO 2012 clinical practice guideline for the evaluation and 18. Torres C, Arago ´ n A, Gonza ´ lez M et al. Decreased kidney func- management of chronic kidney disease. Kidney Int Suppl tion of unknown cause in Nicaragua: a community-based 2013; 3: 1–150 survey. Am J Kidney Dis 2010; 55: 485–496 37. Crowe J, Wesseling C, Solano BR et al. Heat exposure in sugar- 19. Sanoff SL, Callejas L, Alonso CD et al. Positive association of cane harvesters in Costa Rica. Am J Ind Med 2013; 56: 1157–1164 renal insufficiency with agriculture employment and 38. Paula Santos U, Zanetta DM, Terra-Filho M et al Burnt sugar- unregulated alcohol consumption in Nicaragua. Ren Fail 2010; 32: 766–777 cane harvesting is associated with acute renal dysfunction. 20. O’Donnell JK, Tobey M, Weiner DE et al. Prevalence of and Kidney Int 2015; 87: 792–799 risk factors for chronic kidney disease in rural Nicaragua. 39. Roncal Jimenez CA, Ishimoto T, Lanaspa MA et al. Nephrol Dial Transplant 2011; 26: 2798–2805 Fructokinase activity mediates dehydration-induced renal 21. Laux TS, Bert PJ, Barreto Ruiz GM et al. Nicaragua revisited: evi- injury. Kidney Int 2014; 86: 294–302 dence of lower prevalence of chronic kidney disease in a high- 40. Lucas RA, Bodin T, Garcı ´a-Trabanino R et al. Heat stress and altitude, coffee-growing village. JNephrol 2012; 25: 533–540 workload associated with sugarcane cutting—an excessively 22. Orantes CM, Herrera R, Almaguer M et al. Chronic kidney dis- strenuous occupation! Extrem Physiol Med 2015; 4(Suppl 1): A23 ease and associated risk factors in the Bajo Lempa region of El 41. Jayasumana C, Gunatilake S, Senanayake P. Glyphosate, Salvador: Nefrolempa study, 2009. MEDICC Rev 2011; 13: 14–22 hard water and nephrotoxic metals: are they the culprits 23. Orantes CM, Herrera R, Almaguer M et al. Epidemiology of behind the epidemic of chronic kidney disease of unknown chronic kidney disease in adults of Salvadoran agricultural etiology in Sri Lanka? Int J Environ Res Public Health 2014; 11: communities. MEDICC Rev 2014; 16: 23–30 2125–2147 24. Orantes-Navarro CM, Herrera-Valdes R, Almaguer-Lopez M 42. Jayasumana C, Paranagama P, Agampodi S et al. Drinking et al. Chronic kidney disease in children and adolescents in well water and occupational exposure to Herbicides is asso- Salvadoran farming communities: NefroSalva Pediatric ciated with chronic kidney disease, in Padavi-Sripura, Sri Study (2009–2011). MEDICC Rev 2016; 18; 15 Lanka. Environ Health 2015; 14: 6 25. Vela XF, Henriquez DO, Zelaya SM et al. Chronic kidney dis- 43. Uyanikgil Y, Ates ¸ U, Baka M et al. Immunohistochemical and ease and associated risk factors in two Salvadoran farming histopathological evaluation of 2,4-dichlorophenoxyacetic communities, 2012. MEDICC Rev 2014; 16: 55–60 acid-induced changes in rat kidney cortex. Bull Environ 26. Raines N, Gonzalez M, Wyatt C et al. Risk factors for reduced Contam Toxicol 2009; 82: 749–755 glomerular filtration rate in a Nicaraguan community affected 44. Poovala VS, Huang H, Salahudeen AK. Role of reactive oxy- by Mesoamerican nephropathy. MEDICC Rev 2014; 16: 16–22 gen metabolites in organophosphate–bidrin-induced renal 27. Kupferman J, Amador JJ, Lynch KE et al. Characterization of tubular cytotoxicity. J Am Soc Nephrol 1999; 10: 1746–1752 Mesoamerican nephropathy in a kidney failure hotspot in 45. Lebov JF, Engel LS, Richardson D et al.Pesticide use and risk of Nicaragua. Am J Kidney Dis 2016; 68: 716–725 end-stage renal disease among licensed pesticide applicators in 28. Peraza S, Wesseling C, Aragon A et al. Decreased kidney the Agricultural Health Study. Occup Environ Med 2016; 73: 3–12 function among agricultural workers in El Salvador. Am J 46. Wuttke M, Kottgen A. Insights into kidney diseases from Kidney Dis 2012; 59: 531–540 ~ genome-wide association studies. Nat Rev Nephrol 2016; 12: 29. Lebov JF, Valladares E, Pena R et al. A population-based study 549–562 of prevalence and risk factors of chronic kidney disease in 47. Gorski M, van der Most PJ, Teumer A et al. 1000 Genomes- Leon, Nicaragua. Can J Kidney Health Dis 2015; 2: 6 based meta-analysis identifies 10 novel loci for kidney func- 30. Gonzalez-Quiroz M. Enfermedad Renal Cro ´ nica: prevalencia y factores de riesgo ocupacionales en el municipio de tion. Sci Rep 2017; 7: 45040 Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/496/4708273 by Ed 'DeepDyve' Gillespie user on 07 August 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Kidney Journal Oxford University Press

What do epidemiological studies tell us about chronic kidney disease of undetermined cause in Meso-America? A systematic review and meta-analysis

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European Renal Association - European Dialysis and Transplant Association
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© The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA.
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2048-8505
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Abstract

Background: The aim of this systematic review is to examine the epidemiological knowledge and gaps in understanding of the potential causes of chronic kidney disease of undetermined cause (CKDu) in Meso-America. Methods: A systematic literature search of epidemiological studies of CKDu was conducted in PubMed, Embase and Web of Science from January 2000 to January 2017. Study quality was assessed by adapting the tool from Higgins et al. for observational studies. Where applicable, the summary prevalence odds ratio (POR) and 95% confidence interval (CI) were calculated using a random effects model. Results: Twenty-five epidemiological studies were included in the analysis of risk factors for CKDu. The quality assessment of each occupational and community study was medium. The PORs for CKDu were males versus females 2.42 (95% CI 1.76– 3.08), family history of CKD (versus none) 1.84 (95% CI 1.37–2.30), high water intake (versus low) 1.61 (95% CI 1.01–2.21) and low altitude (versus highland) 2.09 (95% CI 1.00–3.17). There were no significant associations between CKDu and pesticide exposure (versus no) 1.17 (95% CI 0.87–1.46), alcohol consumption (versus no) 1.34 (95% CI 0.84–1.84), non-steroidal anti- inflammatory drugs (versus no) 0.99 (95% CI 0.60–1.39) and heat stress (versus no) 1.52 (95% CI 0.91 – 3.95). Conclusion: Our meta-analysis showed positive associations for males (versus females) and family history of CKD, water intake, lowland altitude and CKDu. There were no significant associations with pesticide exposure, non-steroidal anti- inflammatory drugs intake, heat stress and alcohol consumption. Key words: CKDu, Meso-America, Meso-American nephropathy, meta-analysis, Nicaragua, risk factors, systematic review Received: August 5, 2017. Editorial decision: October 18, 2017 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/496/4708273 by Ed 'DeepDyve' Gillespie user on 07 August 2018 CKD of undetermined cause in Meso-America | 497 some marginal cases were discussed between M.G.-Q., B.C. and Introduction D.N. After review of the titles and abstract were independently Meso-American nephropathy (MeN), also known as chronic kid- reviewed by two authors (M.G.-Q. and D.N.). All full-text articles ney disease of undetermined aetiology (CKDu), is a growing were assessed independently using the same criteria and public health problem and young agricultural workers of the included if both reviewers recommended inclusion. A second Pacific coast of Meso-America have been the most affected reviewer (D.N.) checked a sample of 45 titles and abstracts group [1–3]. There was an increased recognition of this problem selected randomly after duplicated articles were removed. by researchers, universities and policymakers after 2000 due to Agreement between authors was quantified by j-statistic a marked increase in mortality and morbidity [4]. calculation. Three years later, the Program on Work and Health in Central America (SALTRA) organized the first regional workshop Data extraction and quality assessment on chronic kidney disease (CKD); this reviewed available data, including several studies that showed increased risks for CKD A standardized data extraction form was used by M.G.-Q. to among sugarcane workers and high mortality related to CKD in extract study characteristics: authors, study design, year, coun- particular areas in Nicaragua and El Salvador [4]. In 2014, the try, sample size, altitude, exposure and outcome definitions, Pan American Health Organization classified CKDu as a major main findings, strengths and limitations and confounding fac- public health problem in Central America that requires urgent, tors. Any difficulty in data extraction was discussed by joint effective and concerted multisectoral action [5]. review of the original papers. In the last 10 years, several narrative reviews about CKDu Quality was assessed for each selected study using standard have been published [6–9]. None of these have conducted a for- quality assessment tools for trials [10] that we adapted for mal meta-analysis and there was no systematic assessment of observational studies. Studies were assigned a high, low or the quality of the available evidence considering inherent limi- uncertain risk according to the following criteria: selection bias, tations within the design and analyses of available epidemio- non-differential measurement error for exposure and outcome, logical studies. The purpose of this study is therefore to information bias in exposure and outcome, confounding and formally examine the epidemiological knowledge and gaps in reverse causation. understanding of the potential causes of CKD of undetermined cause in Meso-America. Data synthesis and analysis We reviewed the exposure and outcome definitions and Materials and methods reported risk factors in each study. Where there were several studies with similar exposure definitions, data were included in Research strategy a random effects meta-analysis for the respective exposure and We searched on PubMed, MEDLINE, Embase and Web Science to CKDu and displayed in a forest plot. Funnel plot analysis identify all original research that had been published between and Egger’s test were performed to detect publication bias and January 2005 and January 2017 reporting prevalence and P < 0.05 was considered significant. mortality of CKDu in Meso-America. Search terms included a The across-study heterogeneity was estimated by using combination of text words and headings for ‘Meso-American Cochran’s Q-statistic and calculating the proportion of total var- nephropathy’, ‘decreased kidney function’, ‘chronic kidney dis- 2 iability explained by heterogeneity (I ) described by Higgins et al. eases of unknown cause’, ‘chronic kidney disease of non- [10]. All analyses were performed using Stata version 14 traditional cause’, ‘agricultural’, ‘pesticide exposure’, ‘heat stress’, (StataCorp, College Station, TX, USA). etc., were used. The full search strategy is outlined in the Supplementary Material (Supplementary data,TablesS1–S3). Results The two reviewers had excellent agreement (Cohen’ s j ¼ 1) on Inclusion and exclusion criteria study inclusion after review of abstracts and titles. We identi- The search was limited to ‘adolescent and adult human beings’ fied 131 epidemiological studies on CKDu, of which 43% (56 and only papers published in English and Spanish languages papers) were duplicate studies using the same dataset. In addi- were considered. The search was restricted to studies conducted tion, 53 studies did not meet the inclusion criteria and 3 were in Meso-America (Central America and Mexico). The exposures of included by manual search, leaving 25 studies for the present interest included heat stress, dehydration, pesticide, non-steroi- systematic review (3 longitudinal occupational studies, 2 cross- dal anti-inflammatory drugs (NSAIDs), workplace conditions, sectional occupational studies, 14 community cross-sectional environmental toxins and infectious diseases. The outcomes of studies, 3 case–control studies and 3 ecological studies) (Fig. 1). interest included the reduced estimated glomerular filtration rate The included studies were conducted from January 2000 to (eGFR), elevated serum creatinine (SCr) and CKD of undetermined January 2017. cause. A wide range of study designs were assessed, including Occupational studies mainly assessed how occupational risk cross-sectional studies, case–control studies, retrospective or pro- factors in the workplace were associated with an eGFR cross- spective cohort studies and ecological studies. We excluded ani- sectionally or a subsequent decline of eGFR across harvest or a mal studies, editorials, systematic reviews and case reports single cross-shift in younger sugarcane workers (Table 1). For (Supplementary data, Table S4). However, systematic reviews many risk factors there is only one estimate per risk factor in were used to manually search for references. each study (Supplementary data, Table S5). We identified only two longitudinal community studies. One Selection process involved follow-up of eGFR measurements in the subgroup that All titles and abstracts were examined by one reviewer (M.G.-Q.) previously had abnormal SCr results, thus incident disease was according to the above inclusion criteria. Any disagreement of not captured [16]. For the other study, only baseline data are Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/496/4708273 by Ed 'DeepDyve' Gillespie user on 07 August 2018 498 | M. Gonza ´ lez-Quiroz et al. Fig. 1. CKD of undetermined cause (eGFR <60 mL/min/1.73 m ), systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta- Analyses diagram. available [17]. Most of the community-based studies were of factors and within-regions variability in exposure and cross-sectional design and recruited participants from different disease classification (outcome) (Table 4 and rationale in age groups and explored a variety of exposures. Two-thirds of Supplementary data,Table S7). Sufficient data for meta-analysis were available for a subset these used a similar outcome definition for kidney function involving calculating an eGFR (<60 mL/min/1.73 m ) using the of risk factors: male sex, family history of CKD, water intake, Modification of Diet in Renal Disease [18–25] or CKD pesticide exposure, alcohol consumption, self-medication with NSAIDs, heat stress and altitude. These were from 10 cross- Epidemiology Collaboration formula to quantify the prevalence of CKDu in the most affected regions [11–15, 26–28] (Table 2). sectional community studies and 3 case–control community Prevalence data among 14 cross-sectional community studies studies. In the meta-analysis, eight cross-sectional community are confounded by age, as people with different ages were studies showed positive associations between male and included, but overall more men than women were affected (Fig. eGFR <60 mL/min/1.73 m {prevalence odds ratio [POR] 2.42 [95% 2). It was not possible to report an age-standardized CKDu prev- confidence interval (CI) 1.76–3.08]; Cochran’s Q-statistic P ¼ 0.056, I ¼ 49.0%}. Three studies showed strong associations alence because a breakdown of the findings by age was not available for most studies. between family history of kidney disease and eGFR <60 mL/ The quality of three longitudinal occupational studies was min/1.73 m [POR 1.84 (95% CI 1.37–2.30); Cochran’s Q-statistic affected by severe loss of follow-up (up to 50%) during the P ¼ 0.947, I ¼ 0.0%]. For high water intake and eGFR <60 mL/ study period, either due to changes in role or redundancy [11– min/1.73 m the POR was 1.61 (95% CI: 1.01–2.21; Cochran’s Q- 13] (Table 3 and rationale in Supplementary data, Table S6). statistic P ¼ 0.511, I ¼ 0.0%) and for lowland altitude (versus One cross-sectional occupational study [15]and cross- highland) it was 2.09 (95% CI 1.00–3.17; Cochran’s Q-statistic sectional community-based studies [23–25, 31, 32]had incom- P ¼ 0.272, I ¼ 23.3%). The pooled POR for pesticide exposure plete adjustment for confounding and reverse causation. One was 1.17 (95% CI 0.87–1.46; Cochran’s Q-statistic P ¼ 0.537, case–control study suffered from selection bias of participants, I ¼ 0.0%) (Fig. 3). The summary estimate for alcohol consump- because researchers used improper procedures for selecting tion (yes versus no) was 1.34 (95% CI 0.84–1.84; Cochran’s Q-sta- their cases and controls (volunteer participations at clinics) tistic P ¼ 0.088, I ¼ 45.5%), for NSAIDs intake (yes versus no) (Table 4). Many cross-sectional studies were limited to single and eGFR <60 mL/min it was close to 1 [POR 0.99 (95% CI 0.60– measurements of creatinine, thus not fulfiling the chronicity 1.39); Cochran’s Q-statistic P ¼ 0.399, I ¼ 0.0%] and for heat criterion for CKD. Furthermore, the quality of three ecological stress exposure (yes versus no) it was 1.52 (95% CI 0.91 to 3.95; studies was potentially affected by unmeasured confounding Cochran’s Q-statistic P ¼ 0.065, I ¼ 70.6%) (Supplementary data, Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/496/4708273 by Ed 'DeepDyve' Gillespie user on 07 August 2018 CKD of undetermined cause in Meso-America | 499 Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/496/4708273 by Ed 'DeepDyve' Gillespie user on 07 August 2018 Table 1. Characteristics of occupational studies included in the systematic review (n¼5) Sample size/sex Authors Year Design Country Region N Male Female Age (years) Exposures Outcome definition Wesseling et al. [11] 2016 Cohort Nicaragua Leo ´ n and Chinandega 54 54 – 17–38 Sugarcane cutters, anthropometrics Decline in eGFR over time measurements, fructose intake and uri- nary biomarkers Laws et al. [12] 2016 Cohort Nicaragua Chinandega 284 251 33 18–63 Job category of sugarcane harvesters, Kidney urinary biomarkers years worked at sugar mill, water and kidney function over intake, isotonic solution intake, age and harvest sex Laws et al. [13] 2015 Cohort Nicaragua Chinandega 284 251 33 18–63 Job category of sugarcane harvesters, Decline in eGFR over harvest years worked at sugar mill, water intake, isotonic solution intake, age and sex Wesseling et al. [14] 2016 Cross- Nicaragua Leo ´ n and Chinandega 194 194 – 17–39 Differences between three occupations, eGFR <80 mL/min/1.73 m sectional socioeconomic status, hydration, life- style and health risk factors Garcia-Trabanino 2015 Cross- El Salvador Suchitoto, El Paisnal 189 168 21 18–49 Sugarcane workers, workplace conditions, Cross-shift changes in eGFR et al. [15] sectional and San Luis Talpa dehydration, heat stress, pesticide exposure and anthropometric measurements The baseline sample was 1104 sugarcane workers, but at the end of the harvest it was 284. eGFR, estimated glomerular filtration rate. 500 | M. Gonza ´ lez-Quiroz et al. Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/496/4708273 by Ed 'DeepDyve' Gillespie user on 07 August 2018 Table 2. Characteristics of community-based studies included in the systematic review (n¼20) Sample size/sex Authors Year Design Country Region N Male Female Age (years) Exposures Outcome definition Nicaragua Gonza ´ lez- 2017 Cohort Nicaragua Leo ´ n and 350 263 87 18–30 Sociodemographic information, work his- eGFR <90 mL/min/1.73 m Quiroz et al. Chinandega tory, lifestyle, work conditions, liquid [17] intake and current diseases (hyperten- sion or diabetes) Minnings et al. 2016 Cohort Nicaragua Rivas 1242 537 705 18 Demographic data, household member- SCr >1.5 mg/dL if male and [16] ship, health symptoms, hydration prac- >1.2 mg/dL if female or tices, occupational and exposure eGFR <60 mL/min/ history and personal medical history 1.73 m Kupferman 2016 Cross-sectional Nicaragua Chichigalpa 226 178 88 18 Clinical and demographic characteristics SCr >1.5 mg/dL if male and et al. [27] >1.2 mg/dL if female or eGFR <60 mL/min/ 1.73 m Lebov et al. [29] 2015 Cross-sectional Nicaragua Leo ´ n 2275 1324 951 18–70 Demographic indicators, source of drink- eGFR <60 mL/min/1.73 m ing water, personal medical history, occupation and lifestyle b 2 Laux et al. [21] 2012 Cross-sectional Nicaragua Matagalpa 267 120 147 20–60 Demographic data, personal and family eGFR <60 mL/min/1.73 m medical history, medications, occupa- tion and lifestyle Torres et al. 2010 Cross-sectional Nicaragua Leo ´ n and 1096 479 617 20–60 Sociodemographic data, personal medical SCr >1.2 mg/dL if male and [18] Chinandega history (diabetes, hypertension, obesity >0.9 mg/dL if female or and renal lithiasis), NSAIDs and eGFR <60 mL/min/ occupation 1.73 m Gonza ´ lez- 2010 Cross-sectional Nicaragua Chichigalpa 704 237 467 20–60 Sociodemographic data, personal medical eGFR <60 mL/min/1.73 m Quiroz [30] history (diabetes, hypertension, obesity and renal lithiasis), alcohol, NSAIDs, occupation and pesticide exposure a 2 Raines et al. 2014 Case–control Nicaragua Chichigalpa 424 166 258 15–69 Demographic data, personal medical his- eGFR <60 mL/min/1.73 m [26] tory, lifestyle, NSAIDs, cane chewing, inhaled pesticides, water intake, sugar beverage intake, occupation and per- sonal protective equipment O’Donnell 2010 Case–control Nicaragua Quezalguaque 771 298 473 18 Age, sex, anthropometric measurements, eGFR <60 mL/min/1.73 m et al. [20] education level, work history, exposure to pesticides, alcohol, cigarrete use and family and personal medical history a 2 Sanoff et al. 2010 Case–control Nicaragua Chinandega 997 848 149 18 Demographic data, hypertension, diabe- eGFR <60 mL/min/1.73 m [19] tes, family history of kidney disease and occupational and non-occupational exposures El Salvador Orantes- 2016 Cross-sectional El Salvador Bajo Lempa, 2115 1058 1057 <18 Age, sex and region eGFR <60 mL/min/1.73 m , Navarro Guayapa, Las by a second measure- et al. [24] Brisas ment of SCr within 3 months’ difference (continued) CKD of undetermined cause in Meso-America | 501 Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/496/4708273 by Ed 'DeepDyve' Gillespie user on 07 August 2018 Table 2. Continued Sample size/sex Authors Year Design Country Region N Male Female Age (years) Exposures Outcome definition Orantes- 2015 Cross-sectional El Salvador Bajo Lempa, 1412 – 1412 18 Age, sex, clinical history (hypertension eGFR <60 mL/min/1.73 m , Navarro Guayapa, Las and diabetes), family history (CKD, dia- by a second measure- et al. [31] Brisas betes and hypertension), occupation, ment of SCr within agrochemicals exposure and physical 3 months’ difference examination (weight, height and blood pressure) d 2 Vela et al. [25] 2014 Cross-sectional El Salvador El Jicaro and 223 110 113 15 Age, sex, physical measurements (weight, eGFR <60 mL/min/1.73 m , Dimas height, abdominal circumference and by a second measure- Gutie ´ rrez blood pressure), personal and family ment of SCr within medical history, occupational and envi- 3 months’ difference ronmental exposures a,d 2 Orantes et al. 2014 Cross-sectional El Salvador Bajo Lempa, 2388 976 1412 18 Age, sex, physical measurements (weight, eGFR <60 mL/min/1.73 m , [23] Guayapa abajo, height, waist circumference and blood by a second measure- Las Brisas pressure), personal and family medical ment of SCr within history, occupational exposures and 3 months’ difference lifestyle Peraza et al. 2012 Cross-sectional El Salvador San Luis Talpa, 664 256 408 20–60 Demographic data, occupational expo- SCr >1.2 mg/dL if male and [28] Jiquilisco, sure, medical conditions and lifestyle >0.9 mg/dL if female or Apastepeque, eGFR <60 mL/min/ San Salvador 1.73 m and Ataco a,d 2 Orantes et al. 2011 Cross-sectional El Salvador Bajo Lempa 775 343 432 18 Age, sex, physical measurements (weight, eGFR <60 mL/min/1.73 m , [22] height, abdominal circumference and by a second measure- blood pressure), personal and family ment of SCr within medical history, occupational, environ- 3 months’ difference mental exposures and lifestyle Garcia- 2005 Cross-sectional El Salvador Jaquilisco 291 291 – 34–66 Age, place of residence, occupation in SCr >1.5 mg/dL Trabanino agricultural work, history of pesticides et al. [32] exposure, alcohol consumption and basic medical history Costa Rica, El Salvador and Guatemala Wesseling et al. 2015 Ecological Costa Rica Costa Rica 6295 3843 2452 20 Age, sex, region, altitude, climate and sug- CKD by death certificate [33] arcane production Laux et al. [34] 2015 Ecological Guatemala Guatemala 3105 1591 1514 Not reported Sex, sugarcane cultivation, temperature, CKD by medical records region, life expectancy, educational from an RRT programme level and wealth VanDervort 2014 Ecological El Salvador El Salvador 24 726 – – No reported Temperature, crops (sugarcane, sorghum, CKD by medical records et al. [35] corn, beans, cotton and coffee) from National Surveillance Health System Altitude: at sea level. More than 500 m above sea level. At sea level and >500 m above sea level. d 2 Five studies from El Salvador applied the CKD definition: persistence of renal damage markers for 3 months or GFR <60 mL/min/1.73 m . eGFR, estimated glomerular filtration rate; SCr, serum creatinine; CKD, chronic kidney disease; NSAIDs, non-steroidal antiinflammatory drugs; RRT, renal replacement therapy. 502 | M. Gonza ´ lez-Quiroz et al. Fig. 2. Forest plot of all prevalence of chronic kidney disease of undetermined cause (eGFR <60 mL/min/1.73 m ) by age group and sex from 14 cross-sectional commun- ity studies identified. Fig. S1). A forest plot of occupation was not included because incomplete adjustment for confounding factors and the use of a each study used different reference categories. single SCr measurement. Longitudinal occupational studies We tested for publication bias for sex, pesticide exposure and were affected by severe loss of follow-up. alcohol consumption risk factors. The funnel plot for studies that A major issue impacting the quality of all the studies exam- have assessed the above risk factors provides evidence for poten- ined is that CKDu prevalence was estimated using a single SCr tial publication bias for pesticide exposure and alcohol consump- measurement rather than two measurements at least 3 months tion (P < 0.014 and P < 0.048, respectively) (Supplementary data, apart [36]. In affluent countries, a single measurement is fre- Fig. 2). quently used to estimate the prevalence of CKD, as the intra- individual variability of creatinine under stable conditions is only a few percent. However, in a hot setting there is consider- Discussion able seasonal variation and variation depending on work pat- We found 25 epidemiological studies that estimated the preva- terns and dehydration status; therefore, depending on when lence and assessed risk factors for CKDu in Meso-America. Our people are measured, they may have short-term fluctuations of meta-analysis found a clear positive association between male creatinine that are far more pronounced than in cooler settings. sex, family history of CKD, high water intake, lowland altitude Also, creatinine elevation can occur due to variations in factors and reduced eGFR <60 mL/min/1.73 m . There was no evidence such as exercise, muscle mass and diet. These factors may not for associations with pesticide exposure, NSAIDs intake, alcohol only affect variability within individuals, but may also bias com- consumption and heat stress. The quality of cross-sectional parisons across populations studies, since each study may over- studies was medium due to the potential for reverse causality, or underestimate kidney function depending on the season and Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/496/4708273 by Ed 'DeepDyve' Gillespie user on 07 August 2018 CKD of undetermined cause in Meso-America | 503 Table 3. Quality assessment of occupational studies (n¼5) Selection Selection Non-differential Information Non-differential Information bias: bias: loss of misclassification bias of misclassification bias of Reverse Studies participation follow-up exposure exposure of outcome outcome Confounding causation Cohort studies Wesseling et al. [11] Laws et al. [12] Laws et al. [13] Cross-sectional studies Wesseling et al. [14] N/A Garcia-Trabanino et al. [15] N/A Green bars: low risk of bias; yellow bars: medium risk of bias; red bars: high risk of bias. N/A, not applicable. Table 4. Quality assessment of community-based studies (n¼20) Selection Selection Non-differential Information Non-differential Information bias: bias: loss of misclassification bias of misclassification bias of Reverse Studies participation follow-up exposure exposure of outcome outcome Confounding causation Cohort studies Gonza ´ lez-Quiroz et al. [17] N/A Minnings et al. [16] Cross-sectional studies Orantes-Navarro et al. [24] N/A N/R N/R N/R Kupferman et al. [27] N/A Orantes-Navarro et al. [31] N/A Lebov et al. [29] N/A Vela et al. [25] N/A Orantes et al. [23] N/A Peraza et al. [28] N/A Laux et al. [21] N/A Orantes et al. [22] N/A Torres et al. [18] N/A Gonzalez-Quiroz [30] N/A Garcia-Trabanino et al. [32] N/A Case–control studies Raines et al. [26] N/A O’Donnell et al. [20] N/A Sanoff et al. [19] N/A Ecological studies Wesseling et al. [33] N/A Laux et al. [34] N/A VanDervort et al. [35] N/A Green bars: low risk of bias; yellow bars: medium risk of bias; red bars: high risk of bias. N/A, not applicable; N/R, not reported. setting of fieldwork or biological variation in the production of that predispose young men to CKDu when they start working in creatinine. In addition, creatinine levels may also be affected by sugarcane. Overall, considering the differential loss to follow-up ‘fixed’ factors such as ethnicity, which may also bias compari- of occupational studies, community cohorts have many advan- sons between populations. tages compared with occupational studies since they represent The longitudinal occupational studies were affected by a the entire risk population (workers from all occupations and loss of follow-up of up to 50% of their participants. This severely both genders) and an assessment of environmental exposures compromises study validity because those with CKDu are more at home [17]. likely to not be followed up [11–13]. Occupational studies are Ecological studies may be affected by variability within used to increase the power of a study when it is thought that a regions in exposure and disease classification and by unmeas- particular occupational exposure causes a problem. However, in ured confounding factors [33–35]. CKD mortality rate may vary the context of CKDu, it is not yet entirely clear whether occupa- across regions because of misclassification either of the cause tion is the only risk factor or whether there are other risk factors reported by death certificate or by better case detection. Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/496/4708273 by Ed 'DeepDyve' Gillespie user on 07 August 2018 504 | M. Gonza ´ lez-Quiroz et al. Fig. 3. Forest plots of association with (A) sex, (B) family history of CKD, (C) water intake, (D) lowland altitude and (E) pesticide exposure estimates associated with CKD of undetermined caused (eGFR <60 mL/min/1.73 m ). Black diamond data markers express PORs; horizontal lines are the 95% CIs; grey square marker size indicating the statistical weight of the study using the random effects meta-analysis. A diamond data marker denotes the overall POR and 95% for the outcome of interest. Moreover, environmental temperature may be different association with male sex, none of the other suggested risk fac- within regions or areas due to variability in seasons and tors were sufficiently well studied to conclusively prove or dis- altitude. Finally, the lack of control for confounders have prove their role. The most commonly cited working hypothesis been an Achilles heel for ecological studies, even on the for this disease has been heat stress causing repetitive episodes assumption that all variables have been accurately measured of dehydration in agricultural and non-agricultural workers due for all groups at a national level, basically due to the analysis to working under heat stress and high humidity [15, 37], which may result in acute kidney injury (AKI) secondary to hypoperfu- strategy, which cannot completely remove bias due to the confounder. sion or rhabdomyolysis [38]. However, although this hypothesis Epidemiological studies have underlined many potential risk has been explored in an experimental study that suggested that factors for CKDu, including male sex, occupation, high ambient dehydration and hyperosmolarity may induce tubular injury via temperature, self-medication with NSAIDs, altitude, exposure activation of the polyolfructokinase pathway in the kidney [39], to heavy metals or pesticides and genetic susceptibility [11, 13– there have been no corresponding data in humans to support 15, 18, 28]. While our systematic review could confirm the this hypothesis. Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/496/4708273 by Ed 'DeepDyve' Gillespie user on 07 August 2018 CKD of undetermined cause in Meso-America | 505 Our meta-analysis has identified positive associations of as differential loss to follow-up (as per existing occupational high water intake and CKDu in two cross-sectional community studies). studies [29, 30] and one case–control study [19]. The study authors’ interpretation of these findings was that high water Authors’ contributions intake could be a proxy for exposure to heat stress and volume depletion during the workday secondary to high exertion and This study was conceived and designed by M.G.-Q., N.P., B.C. sweating [11, 14, 15, 40]. Some authors hypothesized that high and D.N. Data collection was performed by M.G.-Q. and B.C. The analysis and interpretation of the results were done by M.G.-Q., water intake means that study participants drank more water trying to compensate for fluid deprivation, but that this is not B.C. and D.N. The draft was written by M.G.-Q. and D.N. All enough to recover their hydration status [11, 14, 15]. Other authors read and approved the final manuscript. authors have suggested that these associations are driven by intake from contaminated water sources (with pesticides or Supplementary data heavy metals) in the affected areas [41, 42]. An alternative inter- Supplementary data are available at ckj online. pretation could be reverse causation due to underlying kidney damage, in that those with kidney damage are unable to con- centrate their urine and therefore need to drink more to not feel Funding thirsty. To address the issue, it will be important to conduct The study has been supported by a grant (CF/03/14) from the more longitudinal studies to gain better insight into this association. UK Colt Foundation. Pesticides are used extensively in Meso-America. Farmers in the cooler highland regions use pesticides similarly to farmers Conflict of interest statement in coastal regions, yet CKDu prevalence is much lower at higher altitudes [15, 20–23, 26, 30]. Most of the studies that suggest a None declared. possible association between AKI and exposure to organochlor- ides, paraquat, 2,4-diclorophenoxyacetic and glyphosate have References been conducted in animals [43, 44]. A single prospective cohort 1. Weiner DE, McClean MD, Kaufman JS et al. The Central study among male licensed pesticide applicators in the USA American epidemic of CKD. Clin J Am Soc Nephrol 2013; 8: reported an association between end-stage renal disease and 504–511 exposure–response and increasing accumulated lifetime days 2. Correa-Rotter R, Wesseling C, Johnson RJ. CKD of unknown in pesticide exposure and non-exposure for some herbicides origin in Central America: the case for a Mesoamerican such as alachlor, paraquat, pendimethalin, atrazine, permethrin nephropathy. Am J Kidney Dis 2014; 63: 506–520 and metolochlor [45]. The principal limitation of existing epide- 3. Wegman D, Crowe J, Hogstedt C et al. (eds). Mesoamerican miological studies is that exposure has been assessed using cat- nephropathy: report from the second international research work- egorical questions (yes and no) and not by quantifying the shop on MeN. ISBN 978-9968-924-33-7. Heredia, Costa Rica: pesticide residues in urine or blood [14, 19, 20, 26, 32]. Our find- SALTRA/IRET-UNA, 2016 ings suggest selective reporting of studies supporting an associ- 4. Cuadra SN, Kristina J, Christer H et al Chronic Kidney Disease: ation with CKDu. Overall, the evidence about pesticide exposure Assessment of Current Knowledge and Feasibility for Regional and CKDu is still inconclusive. Research Collaboration in Central America. Heredia, Costa Rica: Genetic predisposition may play a role in the CKDu epi- SALTRA, 2006 demic, as some studies, and our meta-analysis, have suggested 5. Pan American Health Organization–World Health a positive association between family history of CKD and CKDu. Organization. Resolution CD52.R1: Chronic Kidney Disease in Although CKD in general shows a high heritability of disease, Agricultural Communities in Central America.Washigton, DC: suggesting familial clustering of risk factors, these have not PAHO, 2014. http://www.paho.org/hq/index.php? option¼com_ been explained by genetic association studies [46, 47]. A positive content&view¼article&id¼8833&Itemid¼40033&lang¼en (last association with family history of CKDu may simply be due to accessed 10 June 2017) children who lost parents to CKDu or living in rural areas start- 6. Lunyera J, Mohottige D, Isenburg MV et al. CKD of uncertain ing to work earlier in sugarcane or agriculture to support their household income. etiology: a systematic review. Clin J Am Soc Nephrol 2016; 11: 379–385 Our systematic review has strengths and limitations. To our 7. Gifford FJ, Gifford RM, Eddleston M et al. Endemic nephrop- knowledge, this is the first systematic review that included a meta-analysis and evaluated the study quality of each epide- athy around the world. Kidney Int Rep 2017; 2: 282–292 8. Madero M, Garcı ´a-Arroyo FE, Sa ´ nchez-Lozada LG. Pathophy- miological study by using a pre-specified tool adapted from siologic insight into MesoAmerican nephropathy. Curr Opin Higgins et al.[10] for observational studies. Second, we included a broad definition of CKD of unknown aetiology and a variety of Nephrol Hypertens 2017; 26: 296–302 9. Elinder C-G, Wijkstro ¨ m A, Wijkstrom J. Mesoamerican exposures. The main limitations of the review are that the avail- nephropathy (MeN): a ‘new’ chronic kidney disease related able evidence on CKDu is overall patchy and inconclusive. In summary, apart from male sex, positive family history, to occupational heat exposure with repeated deprivation of high water intake and lowland altitude, existing studies have salts and water. Int J Nephrol Kidney Failure 2015; 1: 1–9 10. Higgins JP, Altman DG, Gøtzsche PC et al. The Cochrane been inconclusive with regards to potential risk factors for CKDu, such as pesticide use, NSAIDs, heavy metals, alcohol Collaboration’s tool for assessing risk of bias in randomised consumption, heat stress and dehydration. Longitudinal trials. BMJ 2011; 343: d5928 community-based studies are needed to address problems of 11. Wesseling C, Arago ´ n A, Gonza ´ lez M et al. Kidney function in reverse causality (as per existing cross-sectional studies) as well sugarcane cutters in Nicaragua—a longitudinal study of Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/496/4708273 by Ed 'DeepDyve' Gillespie user on 07 August 2018 506 | M. Gonza ´ lez-Quiroz et al. Chichigalpa [Tesis de postgrado]. Universidad Nacional workers at risk of Mesoamerican nephropathy. Environ Res 2016; 147: 125–132 Auto ´ noma de Nicaragua, Leo ´ n, 2010 12. Laws RL, Brooks DR, Amador JJ et al. Biomarkers of kidney 31. Orantes Navarro CM, Herrera Valde ´ s R, Lo ´ pez MA et al. injury among nicaraguan sugarcane workers. Am J Kidney Dis Epidemiological characteristics of chronic kidney disease of 2016; 67: 209–217 non-traditional causes in women of agricultural commun- 13. Laws RL, Brooks DR, Amador JJ et al. Changes in kidney func- ities of El Salvador. Clin Nephrol 2015; 83(Suppl 1): 24–31 tion among Nicaraguan sugarcane workers. Int J Occup 32. Gracia-Trabanino R, Dominguez J, Jansa JM et al. [Proteinuria Environ Health 2015; 21: 241–250 and chronic renal failure in the coast of El Salvador: detec- 14. Wesseling C, Arago ´ n A, Gonza ´ lez M et al. Heat stress, hydra- tion with low cost methods and associated factors]. tion and uric acid: a cross-sectional study in workers of three Nefrologia 2005; 25: 31–38 occupations in a hotspot of Mesoamerican nephropathy in 33. Wesseling C, van Wendel de Joode B, Crowe J et al. Nicaragua. BMJ Open 2016; 6: 1–12 Mesoamerican nephropathy: geographical distribution and 15. Garcı ´a-Trabanino R, Jarquı ´n E, Wesseling C et al. Heat stress, time trends of chronic kidney disease mortality between dehydration, and kidney function in sugarcane cutters in El 1970 and 2012 in Costa Rica. Occup Environ Med 2015; 72: Salvador—a cross-shift study of workers at risk of 714–721 Mesoamerican nephropathy. Environ Res 2015; 142: 746–755 34. Laux TS, Barnoya J, Guerrero DR et al. Dialysis enrollment 16. Minnings K, Fiore M, Mosco M et al. The Rivas Cohort Study: patterns in Guatemala: evidence of the chronic kidney dis- design and baseline characteristics of a Nicaraguan cohort. ease of non-traditional causes epidemic in Mesoamerica. BMC Nephrol 2016; 17: 93 BMC Nephrol 2015; 16: 54 17. Gonza ´ lez-Quiroz M, Camacho A, Faber D et al. Rationale, 35. VanDervort DR, Lopez DL, Orantes CM et al Spatial distribu- description and baseline findings of a community-based tion of unspecified chronic kidney disease in El Salvador by prospective cohort study of kidney function amongst the crop area cultivated and ambient temperature. MEDICC Rev young rural population of Northwest Nicaragua. BMC 2014; 16: 31–38 Nephrol 2017; 18: 16 36. KDIGO 2012 clinical practice guideline for the evaluation and 18. Torres C, Arago ´ n A, Gonza ´ lez M et al. Decreased kidney func- management of chronic kidney disease. Kidney Int Suppl tion of unknown cause in Nicaragua: a community-based 2013; 3: 1–150 survey. Am J Kidney Dis 2010; 55: 485–496 37. Crowe J, Wesseling C, Solano BR et al. Heat exposure in sugar- 19. Sanoff SL, Callejas L, Alonso CD et al. Positive association of cane harvesters in Costa Rica. Am J Ind Med 2013; 56: 1157–1164 renal insufficiency with agriculture employment and 38. Paula Santos U, Zanetta DM, Terra-Filho M et al Burnt sugar- unregulated alcohol consumption in Nicaragua. Ren Fail 2010; 32: 766–777 cane harvesting is associated with acute renal dysfunction. 20. O’Donnell JK, Tobey M, Weiner DE et al. Prevalence of and Kidney Int 2015; 87: 792–799 risk factors for chronic kidney disease in rural Nicaragua. 39. Roncal Jimenez CA, Ishimoto T, Lanaspa MA et al. Nephrol Dial Transplant 2011; 26: 2798–2805 Fructokinase activity mediates dehydration-induced renal 21. Laux TS, Bert PJ, Barreto Ruiz GM et al. Nicaragua revisited: evi- injury. Kidney Int 2014; 86: 294–302 dence of lower prevalence of chronic kidney disease in a high- 40. Lucas RA, Bodin T, Garcı ´a-Trabanino R et al. Heat stress and altitude, coffee-growing village. JNephrol 2012; 25: 533–540 workload associated with sugarcane cutting—an excessively 22. Orantes CM, Herrera R, Almaguer M et al. Chronic kidney dis- strenuous occupation! Extrem Physiol Med 2015; 4(Suppl 1): A23 ease and associated risk factors in the Bajo Lempa region of El 41. Jayasumana C, Gunatilake S, Senanayake P. Glyphosate, Salvador: Nefrolempa study, 2009. MEDICC Rev 2011; 13: 14–22 hard water and nephrotoxic metals: are they the culprits 23. Orantes CM, Herrera R, Almaguer M et al. Epidemiology of behind the epidemic of chronic kidney disease of unknown chronic kidney disease in adults of Salvadoran agricultural etiology in Sri Lanka? Int J Environ Res Public Health 2014; 11: communities. MEDICC Rev 2014; 16: 23–30 2125–2147 24. Orantes-Navarro CM, Herrera-Valdes R, Almaguer-Lopez M 42. Jayasumana C, Paranagama P, Agampodi S et al. Drinking et al. Chronic kidney disease in children and adolescents in well water and occupational exposure to Herbicides is asso- Salvadoran farming communities: NefroSalva Pediatric ciated with chronic kidney disease, in Padavi-Sripura, Sri Study (2009–2011). MEDICC Rev 2016; 18; 15 Lanka. Environ Health 2015; 14: 6 25. Vela XF, Henriquez DO, Zelaya SM et al. Chronic kidney dis- 43. Uyanikgil Y, Ates ¸ U, Baka M et al. Immunohistochemical and ease and associated risk factors in two Salvadoran farming histopathological evaluation of 2,4-dichlorophenoxyacetic communities, 2012. MEDICC Rev 2014; 16: 55–60 acid-induced changes in rat kidney cortex. Bull Environ 26. Raines N, Gonzalez M, Wyatt C et al. Risk factors for reduced Contam Toxicol 2009; 82: 749–755 glomerular filtration rate in a Nicaraguan community affected 44. Poovala VS, Huang H, Salahudeen AK. Role of reactive oxy- by Mesoamerican nephropathy. MEDICC Rev 2014; 16: 16–22 gen metabolites in organophosphate–bidrin-induced renal 27. Kupferman J, Amador JJ, Lynch KE et al. Characterization of tubular cytotoxicity. J Am Soc Nephrol 1999; 10: 1746–1752 Mesoamerican nephropathy in a kidney failure hotspot in 45. Lebov JF, Engel LS, Richardson D et al.Pesticide use and risk of Nicaragua. Am J Kidney Dis 2016; 68: 716–725 end-stage renal disease among licensed pesticide applicators in 28. Peraza S, Wesseling C, Aragon A et al. Decreased kidney the Agricultural Health Study. Occup Environ Med 2016; 73: 3–12 function among agricultural workers in El Salvador. Am J 46. Wuttke M, Kottgen A. Insights into kidney diseases from Kidney Dis 2012; 59: 531–540 ~ genome-wide association studies. Nat Rev Nephrol 2016; 12: 29. Lebov JF, Valladares E, Pena R et al. A population-based study 549–562 of prevalence and risk factors of chronic kidney disease in 47. Gorski M, van der Most PJ, Teumer A et al. 1000 Genomes- Leon, Nicaragua. Can J Kidney Health Dis 2015; 2: 6 based meta-analysis identifies 10 novel loci for kidney func- 30. Gonzalez-Quiroz M. Enfermedad Renal Cro ´ nica: prevalencia y factores de riesgo ocupacionales en el municipio de tion. Sci Rep 2017; 7: 45040 Downloaded from https://academic.oup.com/ckj/article-abstract/11/4/496/4708273 by Ed 'DeepDyve' Gillespie user on 07 August 2018

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