In El Salvador, chronic kidney disease had reached epidemic proportions towards the end of this century’s first decade. In 2011–2012, the Ministry of Health reported it was the leading cause of hospital deaths in men, the fifth in women, and the third overall in adult hospital fatalities. Farming was the most common occupation among men in dialysis (50.7%). By 2017, chronic kidney disease admissions had overwhelmed hospital capacity. In 2009, El Salvador’s Ministry of Health, Cuba’s Ministry of Public Health and PAHO launched a cooperative effort to comprehensively tackle the epidemic. The joint investigations revealed a total prevalence of chronic kidney disease in the adult population of farming communities higher than that reported internationally (18% vs.11%–14.8%), higher in men than in women (23.9% vs 13.9%) and higher in men who were farmers/farmworkers than in men who were not (31.3% vs. 14.8%). The disease was also detected in children. An association was found between chronic kidney disease and exposure to agrochemicals (OR 1.4–2.5). In 51.9% of all chronic kidney disease cases, traditional causes (diabetes, hypertension, glomerulopathies, obstructive nephropathies and cystic diseases) were ruled out and the existence of a particular form of chronic kidney disease of nontraditional etiology was confirmed (whose initial cases were reported as early as 2002). In the patients studied, functional alterations and histopathologic diagnosis confirmed a chronic tubulointerstitial nephritis; most presented with neurosensory hearing loss, altered tendon reflexes and tibial artery damage. The main results of this cooperation were the epidemiologic, physiopathologic, clinical and histopathologic characterization of chronic kidney disease of nontraditional etiology. This characterization facilitated case definition for the epidemic and led to the hypothesis of systemic toxicity from agrochemicals (e.g., paraquat, glyphosate), which particularly affect the kidneys and to which farmers/farmworkers (who may also become dehydrated in the fields) are most exposed. The research thus also laid the foundations for design of comprehensive intersectoral government actions to reduce cases and put an end to the epidemic. KEYWORDS Chronic kidney disease, chronic renal failure, tubulointerstitial nephritis, epidemiology, histopathology, international cooperation, agrochemicals, environmental pollutants, noxae, and pesticides, occupational health, PAHO; El Salvador, Cuba
ABSTRACT
INTRODUCTION Despite growing research interest in the epidemic of chronic kidney disease of nontraditional etiology (a distinct form of chronic kidney disease disproportionately affecting agricultural populations across Mesoamerica—Central America and southern Mexico), its etiology remains poorly understood.
OBJECTIVE Elucidate factors that impact researchers’ efforts to understand the epidemic of chronic kidney disease of nontraditional etiology.
METHODS Semistructured interviews were conducted with 39 international researchers, selected based on their publications and participation in conferences about chronic kidney disease of nontraditional etiology. Interviews were conducted from May through September of 2015 in English or Spanish by video conference, telephone or in person. Interviews were audio recorded, transcribed, and analyzed iteratively using content analysis.
RESULTS Of 39 researchers interviewed, 30.8% were women, 84.6% had a medical and/or doctoral degree and 74.3% had ≥6 years’ experience carrying out research on chronic kidney disease of nontraditional etiology. Three major themes were identified related to factors affecting research progress. The first, influence of state and private interests, concerned perceptions that sugar industry and some governments in Mesoamerica dismissed, hindered, intimidated and inaccurately represented research on chronic kidney disease of nontraditional etiology. The second, limited material and human resources, had to do with scarcity of stable, impartial funding and adequate in-country research infrastructure. Researchers were largely funded by nontraditional sources (charitable organizations, private donations, sugar industry in Mesoamerica, personal funds) or not funded at all. The third, logistical challenges across study lifetimes, referred to barriers such as unwieldy approval mechanisms, gang interference and publication hurdles.
CONCLUSIONS Producing high quality and clinically relevant studies to address chronic kidney disease of nontraditional etiology in the resource-scarce Mesoamerican research climate has been fraught with challenges. These findings contextualize the progress that has been made in understanding chronic kidney disease of nontraditional etiology to date and highlight the need for public health and biomedical organizations to support researchers’ ongoing efforts to engage all stakeholders in addressing the epidemic, disseminate their research findings and identify feasible strategies for addressing the community-wide suffering caused by chronic kidney disease of nontraditional etiology.
KEYWORDS Chronic kidney disease, chronic renal insufficiency, chronic renal failure, chronic kidney failure, interstitial nephritis, qualitative research, epidemiology, occupational health, Costa Rica, El Salvador, Guatemala, Mexico, Mesoamerica, Nicaragua
This paper contextualizes the chronic kidney disease epidemic and related burden of disease affecting Central American farming communities. It summarizes the two main causal hypotheses (heat stress and agrochemicals), draws attention to the consequences of dichotomous reasoning concerning causality, and warns of potential conflicts of interest and their role in “manufacturing doubt.” It describes some methodological errors that compromise past study findings and cautions against delaying public health actions until a conclusive understanding is reached about the epidemic’s causes and underlying mechanisms. It makes the case for a comprehensive approach to the historical, social and epidemiological facts of the epidemic, for critically assessing existing studies and for enhanced rigor in new research.
KEYWORDS Epidemiology, public health, chronic kidney disease, causality, epidemic, agriculture, environment, agrochemicals, pesticides, heat stress, social determinants of health, Central America
INTRODUCTION This manuscript updates a review previously published in a local journal in 2012, about a new form of chronic kidney disease that has emerged over the past two decades in the north-central dry zone of Sri Lanka, where the underlying causes remain undetermined. Disease burden is higher in this area, particularly North Central Province, and affects a rural and disadvantaged population involved in rice-paddy farming. Over the last decade several studies have been carried out to estimate prevalence and identify determinants of this chronic kidney disease of uncertain etiology.
OBJECTIVE Summarize the available evidence on prevalence, clinical profile and risk factors of chronic kidney disease of uncertain etiology in the north-central region of Sri Lanka.
METHODS PubMed search located 16 manuscripts published in peer-reviewed journals. Three peer-reviewed abstracts of presentations at national scientific conferences were also included in the review.
RESULTS Disease prevalence was 5.1%–16.9% with more severe disease seen in men than in women. Patients with mild to moderate stages of disease were asymptomatic or had nonspecific symptoms; urinary sediments were bland; 24-hour urine protein excretion was <1 g; and ultrasound demonstrated bilateral small kidneys. Interstitial fibrosis was the main pathological feature on renal biopsy. The possibility of environmental toxins affecting vulnerable population groups in a specific geographic area was considered in evaluating etiological factors. Pesticide residues were detected in affected patients’ urine, and mycotoxins detected in foods were below maximum statutory limits. Calcium-bicarbonate–type water with high levels of fluoride was predominant in endemic regions. Significantly high levels of cadmium in urine of cases compared to controls, as well as the disease’s dose-related response to these levels, has drawn attention to this element as a possible contributing factor. Familial clustering of patients is suggestive of a polygenic inheritance pattern comparable to that associated with diseases of multifactorial etiology.
CONCLUSIONS Available data suggest that chronic kidney disease of uncertain etiology is an environmentally acquired disease, but to date no definitive causal factor has been identified. Geographic distribution and research findings suggest a multifactorial etiology.
KEYWORDS Chronic kidney disease, uncertain etiology, prevalence, clinical profile, risk factors, rural communities, paddy farming, environmentally acquired disease, Sri Lanka
INTRODUCTION Chronic kidney disease is a global pandemic, affecting the majority of countries in the world. Its prevalence is approximately 10% and it is associated mainly with diabetes and high blood pressure. In El Salvador, it is the leading cause of hospital deaths among men.
OBJECTIVE Determine prevalence of chronic kidney disease and its risk factors in two Salvadoran farming communities.
METHODS From March through September 2012, a descriptive cross-sectional study was conducted in two Salvadoran farming communities: Dimas Rodríguez (El Paisnal municipality) and El Jícaro (San Agustín municipality). The research involved both epidemiological and clinical methods. An active search for chronic kidney disease and its risk factors was carried out in the population aged >15 years. House-to-house visits were carried out to take family and individual health histories and gather data on social conditions and risk factors. A physical examination was performed, along with laboratory tests (urinalysis and blood chemistry) to measure renal function and detect markers for renal damage.
RESULTS A total of 223 persons of both sexes were studied. Overall prevalence of chronic kidney disease was 50.2%. Prevalence of chronic renal failure was 16.1%, with slight variations between the sexes. In El Jícaro, 77.3% of participants reported contact with agrochemicals and 76.6% were farmworkers; the respective figures for Dimas Rodríguez were 75.8% and 73.7%. The next most frequently reported risk factor was NSAID use, at 61.7% in El Jícaro and 77.9% in Dimas Rodríguez.
CONCLUSIONS CKD prevalence is alarming in these communities, among both young and old, men and women, independently of occupation. Health services must cope with the increased CKD burden observed, and are challenged to implement preventive strategies.
KEYWORDS Chronic kidney disease, chronic renal failure, pesticides, El Salvador
INTRODUCTION For at least a decade, a chronic kidney disease unassociated with diabetes mellitus, hypertension or any of the more common traditional causes, has been reported in Salvadoran agricultural communities.
OBJECTIVE Characterize histopathology of chronic kidney disease of unknown etiology in patients from Salvadoran agricultural communities, describe renal damage associated with each disease stage, and assess associations between histopathological alterations and sociodemographic variables.
METHODS The study involved 46 patients of both sexes, aged =18 years. After clinical, laboratory and imaging examinations, kidney biopsies were performed and renal tissue assessed for interstitial fibrosis, tubular atrophy, interstitial inflammatory infiltration, sclerosis, increase in glomerular size and extraglomerular vascular lesions (according to the Banff 97 classification used for kidney transplant rejection). Special staining was done: Schiff periodic acid, Masson trichrome and methenamine silver. Immunofluorescence techniques were used to evaluate IgA, IgG, IgM, complement C1q and C3, fibrin, and kappa and lambda light chain deposits.
RESULTS The main findings were interstitial fibrosis and tubular atrophy with or without inflammatory monocyte infiltration. In addition, generalized sclerosis, increased glomerular size, collapse of some glomerular tufts, and lesions of extraglomerular blood vessels (such as intimal proliferation and thickening and vacuolization of the tunica media) were observed. Interstitial fibrosis and glomerulosclerosis were associated with male sex. Sugarcane workers showed more interstitial fibrosis and tubular atrophy and less glomerulomegaly than other occupational groups.
CONCLUSION The morphological pattern in all biopsies was one of chronic tubulointerstitial nephropathy with secondary glomerular and vascular damage, in different stages of evolution of chronic kidney disease, independent of age, sex or occupation.
KEYWORDS Chronic kidney disease, chronic tubulointerstitial nephropathy, tubulointerstitial nephritis, glomerulosclerosis, histopathology, El Salvador
INTRODUCTION Chronic kidney disease is a serious health problem in El Salvador. Since the 1990s, there has been an increase in cases unassociated with traditional risk factors. It is the second leading cause of death in men aged >18 years. In 2009, it was the first cause of in-hospital death for men and the fifth for women. The disease has not been thoroughly studied.
OBJECTIVE Characterize clinical manifestations (including extrarenal) and pathophysiology of chronic kidney disease of nontraditional causes in Salvadoran farming communities.
METHODS A descriptive clinical study was carried out in 46 participants (36 men, 10 women), identified through chronic kidney disease population screening of 5018 persons. Inclusion criteria were age 18–59 years; chronic kidney disease at stages 2, 3a and 3b, or at 3a and 3b with diabetes or hypertension and without proteinuria; normal fundoscopic exam; no structural abnormalities on renal ultrasound; and HIV-negative. Examinations included social determinants; psychological assessment; clinical exam of organs and systems; hematological and biochemical parameters in blood and urine; urine sediment analysis; markers of renal damage; glomerular and tubular function; and liver, pancreas and lung functions. Renal, prostate and gynecological ultrasound; and Doppler echocardiography and peripheral vascular and renal Doppler ultrasound were performed.
RESULTS Patient distribution by chronic kidney disease stages: 2 (32.6%), 3a (23.9%), 3b (43.5%). Poverty was the leading social determinant observed. Risk factor prevalence: agrochemical exposure (95.7%), agricultural work (78.3%), male sex (78.3%), profuse sweating during work (76.3%), malaria (43.5%), NSAID use (41.3%), hypertension (36.9%), diabetes (4.3%). General symptoms: arthralgia (54.3%), asthenia (52.2%), cramps (45.7%), fainting (30.4). Renal symptoms: nycturia (65.2%), dysuria (39.1%), foamy urine (63%). Markers of renal damage: macroalbuminuria (80.4%), ß2 microglobulin (78.2%), NGAL (26.1%). Renal function: hypermagnesuria (100%), hyperphosphaturia (50%), hypernatriuria (45.7%), hyperkaluria (23.9%), hypercalciuria (17.4%), electrolyte polyuria (43.5%), metabolic alkalosis (45.7%), hyponatremia (47.8%), hypocalcemia (39.1%), hypokalemia (30.4%), hypomagnesemia (19.6%). Imaging: Ultrasound showed fatty liver (93.5%) and vascular Doppler showed tibial artery damage (66.7%). Neurological symptoms: abnormal tendon reflexes (45.6%), Babinski sign and myoclonus (6.5%), sensorineural hearing loss (56.5%).
CONCLUSIONS This chronic kidney disease studied behaves clinically like chronic tubulointerstitial nephropathy, but with systemic manifestations not attributable to kidney disease. While male agricultural workers predominated, women and adolescents were also affected. Findings support a hypothesis of multifactorial etiology with a key role played by nephrotoxic environmental agents.
KEYWORDS Chronic kidney disease, occupational disease, chronic tubulointerstitial nephropathy, nephrotoxicity, renal ischemia, social determinants, El Salvador
INTRODUCTION Chronic kidney disease of unknown etiology is occurring in various geographic areas worldwide. Cases lack typical risk factors associated with chronic kidney disease, such as diabetes and hypertension. It is epidemic in El Salvador, Central America, where it is diagnosed with increasing frequency in young, otherwise-healthy male farmworkers. Suspected causes include agrochemical use (especially in sugarcane fields), physical heat stress, and heavy metal exposure.
OBJECTIVE To evaluate the geographic relationship between unspecified chronic kidney disease (unCKD) and nondiabetic chronic renal failure (ndESRD) hospital admissions in El Salvador with the proximity to cultivated crops and ambient temperatures.
METHODS Data on unCKD and ndESRD were compared with environmental variables, crop area cultivated (indicator of agrochemical use) and high ambient temperatures. Using geographically weighted regression analysis, two model sets were created using reported municipal hospital admission rates per ten thousand population for unCKD 2006–2010 and rates of ndESRD 2005–2010. These were assessed against local percent of land cultivated by crop (sugarcane, coffee, corn, cotton, sorghum, and beans) and mean maximum ambient temperature, with Moran’s indices determining data clustering. Two-dimensional geographic models illustrated parameter spatial distribution.
RESULTS Bivariate geographically weighted regressions showed statistically significant correlations between percent area of sugarcane, corn, cotton, coffee, and bean cultivation, as well as mean maximum ambient temperature with both unCKD and ndESRD hospital admission rates. Percent area of sugarcane cultivation had greatest statistical weight (p =0.001; Rp2 = 0.77 for unCKD). The most statistically significant multivariate geographically weighted regression model for unCKD included percent area of sugarcane, cotton and corn cultivation (p =0.001; Rp2 = 0.80), while, for ndESRD, it included the percent area of sugarcane, corn, cotton and coffee cultivation (Rp2 = 0.52). Univariate unCKD and ndESRD Moran’s I (0.20 and 0.33, respectively) indicated some degree of clustering. Ambient temperature did not improve multivariate geographically-weighted regression models for unCKD or ndESRD. Local bivariate Moran’s indices with relatively high positive values and statistical significance (0.3–1.0, p =0.05) indicated positive clustering between unCKD hospital admission rates and percent area of sugarcane as well as cotton cultivation. The greatest positive response for clustering values did not consistently plot near the highest temperatures; there were some positive clusters in regions of lower temperatures. Clusters of ndESRD were also observed, some in areas of relatively low chronic kidney disease incidence in western El Salvador.
CONCLUSIONS High temperatures do not appear to strongly influence occurrence of unCKDu proxies. CKDu in El Salvador may arise from proximity to agriculture to which agrochemicals are applied, especially in sugarcane cultivation. The findings of this preliminary ecological study suggest that more research is needed to assess and quantify presence of specific agrochemicals in high-CKDu areas.
KEYWORDS Chronic kidney disease, chronic renal failure, ESRD, geographically weighted regression, sugarcane, agrochemicals, El Salvador
In recent years, Central America, Egypt, India and Sri Lanka have reported a high prevalence of chronic kidney disease of unknown etiology in agricultural communities, predominantly among male farmworkers. This essay examines the disease’s case definitions, epidemiology (disease burden, demographics, associated risk factors) and causal hypotheses, by reviewing published findings from El Salvador, Nicaragua, Costa Rica, Sri Lanka, Egypt and India. The range of confirmed chronic kidney disease prevalence was 17.9%–21.1%. Prevalence of reduced glomerular filtration (<60 mL/min/1.73 m2 body surface area) based on a single serum creatinine measurement was 0%–67% men and 0%–57% women. Prevalence was generally higher in male farmworkers aged 20–50 years, and varied by community economic activity and altitude. Cause was unknown in 57.4%–66.7% of patients. The dominant histopathological diagnosis was chronic tubulointerstitial nephritis. Associations were reported with agricultural work, agrochemical exposure, dehydration, hypertension, homemade alcohol use and family history of chronic kidney disease. There is no strong evidence for a single cause, and multiple environmental, occupational and social factors are probably involved. Further etiological research is needed, plus interventions to reduce preventable risk factors.
KEYWORDS: Chronic kidney disease, prevalence, risk factors
INTRODUCTION Knowledge of prognostic factors in end-stage renal disease patients has improved dialysis management and methods for reducing morbidity and mortality, underlining the importance of identification, prevention and control of these factors.
OBJECTIVE Identify factors affecting prognosis (survival or death) in hemodialysis patients at the Medical-Surgical Research Center in Havana over a ten-year period.
METHODS Descriptive, prospective study of 81 end-stage renal disease patients who received hemodialysis at the Medical-Surgical Research Center from 1995 to 2004. Prognostic factors were identified at initiation of and during dialysis treatment, using chi square, t test, McNemar test, Kaplan Meier analysis, log-rank test and Cox regression model, with significance threshold set at p <0.05.
RESULTS Hypertension and diabetes were the leading causes of end-stage renal disease. Six patients were referred late. Mean survival was 4.4 years; with survival of 86.6%, 54.7% and 26.6% at one, three and five years respectively. Factors predictive of decreased survival that were most frequent at initiation of hemodialysis were hypertension and chronic anemia (both present in 95.9% of cases); malnutrition, hypoalbuminemia, cardiovascular disease and chronic liver disease increased during treatment while hypertension decreased. In multivariate analysis, prognostic factors that significantly predicted decreased survival were hypertension, inadequate vascular access and diabetes. Patients aged ≥60 years and those with malnutrition, hypoalbuminemia, anemia, cardiovascular disease or liver disease had lower survival figures at the end of the study period. Leading causes of death were infections (45.2%) and cardiovascular disease (41.9%); the latter was present in 93.5% of deaths, independent of underlying cause of death.
CONCLUSIONS Survival of hemodialysis patients diminished at five years. Some negative predictive factors are present at initiation of hemodialysis, such as diabetes, hypertension and chronic anemia; others increased later, including malnutrition, hypoalbuminemia, cardiovascular disease and liver disease.
KEYWORDS Hemodialysis, prognostic factors, survival, chronic kidney disease, end-stage renal disease, Cuba
INTRODUCTION The disease complex comprised of atherosclerosis, chronic kidney disease (CKD) and other associated chronic vascular diseases is the leading cause of mortality worldwide. Microalbuminuria is a marker for vascular damage in the heart, kidney and brain. This paper presents selected findings of the clinical-epidemiological Isle of Youth Study (ISYS) of markers for kidney and vascular damage from chronic vascular diseases and their common risk factors in total population, focusing on Phase 2 reassessment (in 2010) of Phase 1 (2004 to 2006) results.
OBJECTIVES (1) Update the prevalence of risk factors in the study population aged ≥20 years (adult population). (2) Confirm presence of microalbuminuria in at-risk adults diagnosed as presumptive positives in Phase I. (3) Evaluate association between microalbuminuria and selected risk factors.
METHODS Of 3779 adults positive for microalbuminuria in ISYS Phase 1, 73.1% were reevaluated. The risk-factor questionnaire was re-administered and blood pressure, weight and height were measured. Blood was tested for creatinine, glycemia, cholesterol and triglycerides. Glomerular filtration rate was calculated using the Modification of Diet in Renal Disease (MDRD) formula. Albuminuria was measured in urine using Micral-Test (Germany) and albumin/creatinine ratio (ACR) by nephelometry. This paper uses ACR as the reference for analyzing risk factor associations. Double-entry tables were developed to analyze association among microalbuminuria, risk factors and co-morbidities.
RESULTS Most prevalent risks were hypertension, consumption of nonsteroidal anti-inflammatory drugs (NSAIDs), excess weight and hypertriglyceridemia. Microalbuminuria was confirmed in 18% of cases, using the same test. Elevated prevalence of microalbuminuria was positively associated with advancing age, male sex, underweight, smoking, NSAID use, dyslipidemia, hypertension, diabetes, heart disease and stroke.
CONCLUSIONS The at-risk cohort studied presented low levels of confirmation for positive microalbuminuria. Positive microalbuminuria stratified individuals at greatest risk, except for obesity.
KEYWORDS Chronic kidney disease, cardiovascular disease, risk factors, damage markers, albuminuria, microalbuminuria, Cuba
Introduction Obesity is a social disease constituting a global pandemic. It is present in 90% of diabetic and 65% of hypertensive patients. It is associated with cardiometabolic syndrome and with damaging physiopathological mechanisms, particularly for the vascular system and the kidneys. On Cuba’s Isle of Youth, a community-based epidemiological study of chronic kidney disease (CKD), hypertension (HTN), diabetes mellitus (DM) and cardio-cerebral vascular disease was carried out in total population, including an examination of common risk factors.
Objective Based on the Isle of Youth Study (ISYS) data, determine prevalence of obesity and overweight, and their association with CKD, HTN, DM, and shared risk factors for all these conditions in total population of the Isle of Youth, Cuba.
Methods Phase 1: Population diagnosis (November 2004-April 2006): 96.6% of the Isle of Youth’s total population (80,117) was studied, including all ages and both sexes. Information was offered to the public, and written informed consent obtained. Screening was conducted by participant questionnaire including risk factors, physical measurements (weight, height, blood pressure and body mass index), and a single first-morning urine sample to determine the presence of vascular-renal damage markers – proteinuria and hematuria (Combur 10 Test, Roche), and microalbuminuria (Micral Test, Roche). When results were positive, serum creatinine was determined and glomerular filtration rate (GFR) estimated with Modification of Diet in Renal Disease (MDRD) formula for adults and Schwartz formula for children <15 years. Data obtained were analyzed to determine association of participants’ nutritional status with prevalence of chronic kidney disease, hypertension and diabetes mellitus, as well as a set of common risk factors.
Results Population <20 years: Obesity prevalence 3.2%; positive urine markers in 56.9% of obese and 8.9% of non-obese participants; positive albuminuria in 38% of obese and 3% of non-obese. Obese participants were found to be hyperfiltrating. DM prevalence was 9.5% in obese and 1.1% in non-obese participants. Population ≥20 years: Overweight, 31.3%; obese, 13.4%. Positive markers in normal-weight, overweight and obese individuals were 18.3%, 21.2% and 32.7%, respectively; microalbuminuria values increased with weight. Obese individuals were found to be hyperfiltrating. HTN prevalence in normal-weight, overweight and obese individuals was 18.3%, 31.5%, and 51.0% respectively; DM rates were 2.8%, 5.2% y 11.3%, respectively.
Conclusion In Cuba, obesity poses significant risk for vascular and renal damage and should be the focus of increased prevention efforts.
Keywords Vascular diseases, chronic kidney disease, CKD, chronic kidney insufficiency, hypertension, diabetes mellitus, risk factors, obesity, overweight, body mass index, glomerular filtration rate
