• CKDu: a perfect storm Editorial

  • CKDu ravages the Salvadoran countryside Feature

    MA, Conner Gorry
  • Chronic kidney disease of unknown etiology in agricultural communities Special Article

    Almaguer, Miguel; Herrera, Raúl; Orantes, Carlos M.

    Abstract in English:

    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.
  • Risk factors for reduced glomerular filtration rate in a Nicaraguan community affected by mesoamerican nephropathy Original Research

    Raines, Nathan; González, Marvin; Wyatt, Christina; Kurzrok, Mark; Pool, Christopher; Lemma, Tiziana; MPH, Ilana Weiss; Marín, Carlos; Prado, Valerio; Márquez, Eugenia; Mayorga, Karina; Morales, Jean Franco; Aragón, Aurora; Sheffield, Perry

    Abstract in English:

    INTRODUCTION: Mesoamerican nephropathy, also known as chronic kidney disease of unknown etiology, is widespread in Pacific coastal Central America. The cause of the epidemic is unknown, but the disease may be linked to multiple factors, including diet as well as environmental and occupational exposures. As many as 50% of men in some communities have Mesoamerican nephropathy. OBJECTIVE: Describe prevalence of reduced glomerular filtration rate in a region of Nicaragua suspected to harbor high rates of Mesoamerican nephropathy; and investigate potential risk factors for such reduction associated with agricultural work (such as pesticide exposure and specific agricultural tasks associated with increased heat stress); sugar consumption; and traditional factors such as age, sex, diabetes, hypertension and nephrotoxic medication use. METHODS: This study uses a cross-sectional design with nested case-control analysis. Cases were individuals with estimated glomerular filtration rates of <60mL/min/1.73m² and controls were individuals with those >90mL/min/1.73m², estimated using serum creatinine. Data on nutrition, past medical history, medication and substance use, and agricultural behaviors and exposures were collected using medical questionnaires from June through August, 2012. Venous blood and urine samples were collected to assess hemoglobin A1c, and dipstick proteinuria, respectively; anthropometry and blood pressure measurements were made using standard techniques. Analyses were conducted using chi square, and univariate and multiple logistic regression. RESULTS: Of 424 individuals in the study, 151 had an occupational history in agriculture. Prevalence of glomerular filtration rate <60mL/min/1.73m² was 9.8% among women and 41.9% among men (male to female ratio = 4.3, p<0.0001). Proteinuria ≥300 mg/dL was observed in <10% of participants with decreased glomerular filtration rate. Hemoglobin A1c and use of NSAIDs were not associated with decreased glomerular filtration rate. Although systolic and diastolic blood pressure was higher among participants with decreased glomerular filtration rate (p <0.001), hypertension was uncommon. Significant agricultural risk factors for reduced glomerular filtration rate included increased lifetime days cutting sugarcane during the dry season (OR 5.86, 95% CI 2.45 - 14.01), nondeliberate pesticide inhalation (OR 3.31, 95% CI 1.32 - 8.31), and sugarcane chewing (OR 3.24, 95% CI 1.39 - 7.58). CONCLUSIONS: Our findings demonstrate a high prevalence of chronic kidney disease not linked to traditional risk factors, and suggest it may be associated instead with occupational exposure to heat stress in conjunction with pesticide inhalation, sugarcane chewing and sugar intake during the workday.
  • Epidemiology of chronic kidney disease in adults of Salvadoran agricultural communities Original Research

    Orantes, Carlos M.; Herrera, Raúl; Almaguer, Miguel; Brizuela, Elsy G.; Núñez, Lilian; Alvarado, Nelly P.; Jackeline Fuentes, E.; Bayarre, Héctor D.; Amaya, Juan Carlos; Calero, Denis J.; Vela, Xavier F.; Zelaya, Susana M.; Granados, Delmy V.; Orellana, Patricia

    Abstract in English:

    INTRODUCTION: In El Salvador, chronic kidney disease is a serious and growing public health problem. Chronic renal failure was the first cause of hospital deaths in men and the fifth in women in 2011. OBJECTIVE: Determine prevalence of CKD, CKD risk factors (traditional and nontraditional) and renal damage markers in the adult population of specific rural areas in El Salvador; measure population distribution of renal function; and identify associated risk factors in CKD patients detected. METHODS: A cross-sectional analytical epidemiological study was conducted based on active screening for chronic kidney disease and risk factors in persons aged ≥18 years during 2009 - 2011. Epidemiological and clinical data were gathered through personal history, as well as urinalysis for renal and vascular damage markers, determinations of serum creatinine and glucose, and estimation of glomerular filtration rates. Chronic kidney disease cases were confirmed at three months. Multiple logistical regression was used for statistical analysis. RESULTS: Prevalence of chronic kidney disease was 18% (23.9% for men and 13.9% for women) in 2388 persons: 976 men and 1412 women from 1306 families studied. Chronic kidney disease with neither diabetes nor hypertension nor proteinuria ≥1 g/L (51.9%) predominated. Prevalence of chronic renal failure was 11% (17.1% in men and 6.8% in women). Prevalence of renal damage markers was 12.5% (higher in men): microalbuminuria, 6.9%; proteinuria (0.3 g/L), 1.7%; proteinuria (1g/L), 0.6%; proteinuria (2 g/L), 0.4 %; and hematuria, 1.5%. Prevalence of chronic kidney disease risk factors was: diabetes mellitus, 9%; hypertension, 20.9%; family history of chronic kidney disease, 16.5%; family history of diabetes mellitus, 18.5%; family history of hypertension, 30.6%; obesity, 21%; central obesity, 24.9%; NSAID use, 84.2%; smoking, 9.9%; alcohol use, 15%; agricultural occupation, 31.2%; and contact with agrochemicals, 46.7%. Chronic kidney disease was significantly associated with male sex, older age, hypertension, agricultural occupation, family history of chronic kidney disease and contact with the agrochemical methyl parathion. CONCLUSIONS: The results of this study support suggestions from other research that we are facing a new form of kidney disease that could be called agricultural nephropathy.
  • Spatial distribution of unspecified chronic kidney disease in El Salvador by crop area cultivated and ambient temperature Original Research

    VanDervort, Darcy R.; López, Dina L.; Orantes, Carlos M.; Rodríguez, David S.

    Abstract in English:

    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 fi elds), physical heat stress, and heavy metal exposure. OBJECTIVE: To evaluate the geographic relationship between unspecifi ed 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 signifi cant 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 signifi cant 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�fs 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�fs indices with relatively high positive values and statistical signifi cance (, 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 infl uence occurrence of unCKDu proxies. CKDu in El Salvador may arise from proximity to agriculture to which agrochemicals are applied, especially in sugarcane cultivation. The fi ndings of this preliminary ecological study suggest that more research is needed to assess and quantify presence of specifi c agrochemicals in high-CKDu areas.
  • Clinical characteristics of chronic kidney disease of nontraditional causes in Salvadoran farming communities Original Research

    Herrera, Raúl; Orantes, Carlos M.; Almaguer, Miguel; Alfonso, Pedro; Bayarre, Héctor D.; Leiva, Irma M.; Smith, Magaly J.; Cubias, Ricardo A.; MD, Carlos G. Torres; Almendárez, Walter O.; Cubias, Francisco R.; Morales, Fabrizio E.; Magaña, Salvador; Amaya, Juan C.; Perdomo, Edgard; Ventura, Mercedes C.; Villatoro, Juan F.; Vela, Xavier F.; Zelaya, Susana M.; Granados, Delmy V.; Vela, Eduardo; Orellana, Patricia; Hevia, Reynaldo; Fuentes, E. Jackeline; Mañalich, Reinaldo; Bacallao, Raymed; Ugarte, Mario; Arias, María I.; Chávez, Jackelin; Flores, Nelson E.; Aparicio, Claudia E.

    Abstract in English:

    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%), β2 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.
  • Histopathology of chronic kidney disease of unknown etiology in Salvadoran agricultural communities Original Research

    López-Marín, Laura; Chávez, Yudit; García, Xenia A.; Flores, Walter M.; García, Yesenia M.; Herrera, Raúl; Almaguer, Miguel; Orantes, Carlos M.; Calero, Denis; Bayarre, Héctor D.; Amaya, Juan Carlos; Magaña, Salvador; Espinoza, Paul A.; Serpas, Lisbeth

    Abstract in English:

    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.
  • Chronic kidney disease and associated risk factors in two Salvadoran farming communities, 2012 Original Research

    Vela, Xavier F.; Henríquez, David O.; Zelaya, Susana M.; Granados, Delmy V.; Hernández, Marcelo X.; Orantes, Carlos M.

    Abstract in English:

    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.
  • Update on uncertain etiology of chronic kidney disease in Sri Lanka's north-central dry zone Review Article

    Wanigasuriya, Kamani

    Abstract in English:

    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.
  • Chronic kidney disease in Central American agricultural communities: challenges for epidemiology and public health Perspective

    Silva, Luis Carlos; Ordúñez, Pedro

    Abstract in English:

    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.
  • Chronic kidney disease of unknown etiology should be renamed chronic agrochemical nephropathy Perspective

    FRCP, Saroj Jayasinghe MBBS MD

    Abstract in English:

    Epidemics of chronic kidney disease not attributable to common causes have recently been observed in Central America and Asia. Since the etiology is unclear, the disease is often known by terms such as chronic kidney disease of unknown etiology. There is growing evidence that risk factors include rural agricultural work and agrochemical exposure. The disease should be renamed chronic agrochemical nephropathy to highlight the most likely etiology and draw attention to the condition.
  • International society of nephrology's perspective on the emergence of chronic kidney diseases of unknown/undetermined etiology Viewpoint

    Remuzzi, Giuseppe; Perico, Norberto
  • Chronic kidney disease in our farming communities: implications of an epidemic Viewpoint

    Rodríguez, María Isabel
  • Chronic kidney disease of unknown etiology: a disease related to global warming? Viewpoint

    Johnson, Richard J.; Glaser, Jason; Sánchez-Lozada, Laura G.
  • CKDu: strategies for saving lives now Viewpoint

    Glaser, Jason; Weiss MA MPH, Ilana
  • Poverty: the common denominator of CKD's global threat Viewpoint

    García-García, Guillermo
Medical Education Cooperation with Cuba Oakland - California - United States
E-mail: editors@medicc.org