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• W2593896229 abstract "Over the past 20 years, there has been an increase in chronic interstitial nephritis in agricultural communities (CINAC) not associated with traditional risk factors. This disease has become an important public health problem and is observed in several countries in Central America and Asia. CINAC predominantly affects young male farmers between the third and fifth decades of life with women, children, and adolescents less often affected. Clinically, CINAC behaves like a chronic tubulointerstitial nephropathy but with systemic manifestations not attributable to kidney disease. Kidney biopsy reveals chronic tubulointerstitial nephritis with variable glomerulosclerosis and mild chronic vascular damage, with the severity depending on sex, occupation, and CKD stage. The presence of toxicological, occupational, and environmental risk factors within these communities suggests a multifactorial etiology for CINAC. This may include exposure to agrochemicals, a contaminated environment, repeated episodes of dehydration with heat stress, and an underlying genetic predisposition. An understanding of these interacting factors using a multidisciplinary approach with international cooperation and the formulation of a comprehensive hypothesis are essential for the development of public health programs to prevent this devastating epidemic. Over the past 20 years, there has been an increase in chronic interstitial nephritis in agricultural communities (CINAC) not associated with traditional risk factors. This disease has become an important public health problem and is observed in several countries in Central America and Asia. CINAC predominantly affects young male farmers between the third and fifth decades of life with women, children, and adolescents less often affected. Clinically, CINAC behaves like a chronic tubulointerstitial nephropathy but with systemic manifestations not attributable to kidney disease. Kidney biopsy reveals chronic tubulointerstitial nephritis with variable glomerulosclerosis and mild chronic vascular damage, with the severity depending on sex, occupation, and CKD stage. The presence of toxicological, occupational, and environmental risk factors within these communities suggests a multifactorial etiology for CINAC. This may include exposure to agrochemicals, a contaminated environment, repeated episodes of dehydration with heat stress, and an underlying genetic predisposition. An understanding of these interacting factors using a multidisciplinary approach with international cooperation and the formulation of a comprehensive hypothesis are essential for the development of public health programs to prevent this devastating epidemic. Clinical Summary•Chronic interstitial nephritis in agricultural communities (CINAC) typically occurs in young to middle age male farmworkers in regions of Central America and Asia but also may occur in women and children.•CINAC is a form of tubulointerstitial nephritis and is a major public health crisis in affected countries.•There are genitourinary, neurologic, and vascular abnormalities in addition to the kidney disease.•The pathogenesis of CINAC likely is multifactorial including pesticide exposure, heat stress, dehydration, environmental contaminants, effects of low socioeconomic status, and genetic susceptibility. •Chronic interstitial nephritis in agricultural communities (CINAC) typically occurs in young to middle age male farmworkers in regions of Central America and Asia but also may occur in women and children.•CINAC is a form of tubulointerstitial nephritis and is a major public health crisis in affected countries.•There are genitourinary, neurologic, and vascular abnormalities in addition to the kidney disease.•The pathogenesis of CINAC likely is multifactorial including pesticide exposure, heat stress, dehydration, environmental contaminants, effects of low socioeconomic status, and genetic susceptibility. Diabetes mellitus and hypertension are the two leading causes of CKD across the globe, particularly in the developed world. In developing countries, these well-known etiologies of CKD can be accompanied or supplanted by other causes of glomerular and tubulointerstitial diseases such as infections or injury due to nephrotoxic drugs, herbal supplements, environmental toxins, and occupational exposure to pesticides. These factors all can contribute to the high burden of CKD in developing nations.1Jha V. Garcia-Garcia G. Iseki K. et al.Chronic kidney disease: global dimension and perspectives.Lancet. 2013; 382: 260-272Abstract Full Text Full Text PDF PubMed Scopus (2604) Google Scholar During the past two decades in certain locations in Latin America and Asia, there has been an increase in the prevalence of CKD affecting agricultural communities, specifically targeting young male agricultural workers who do not have the traditional risk factors of diabetes and hypertension. This recently recognized form of CKD has been termed chronic interstitial nephritis in agricultural communities (CINAC) and has become an important and devastating public health issue, particularly in Central America.2Almaguer M. Herrera R. Orantes C.M. Chronic kidney disease of unknown etiology in agricultural communities.MEDICC Rev. 2014; 16: 9-15PubMed Google Scholar, 3Orantes Navarro C.M. Herrera Valdés R. López M.A. et al.Epidemiological characteristics of chronic kidney disease of non-traditional causes in women of agricultural communities of El Salvador.Clin Nephrol. 2015; 83: 24-31Crossref PubMed Scopus (29) Google Scholar, 4Jayasumana C. Gajanayake R. Siribaddana S. Importance of arsenic and pesticides in epidemic chronic kidney disease in Sri Lanka.BMC Nephrol. 2014; 15: 124Crossref PubMed Scopus (37) Google Scholar, 5Jayasumana C. Gunatilake S. Senanayake P. Glyphosate, hard water and nephrotoxic metals: are they the culprits behind the epidemic of chronic kidney disease of unknown etiology in Sri Lanka?.Int J Environ Res Public Health. 2014; 11: 2125-2147Crossref PubMed Scopus (196) Google Scholar, 6Jayasumana C. Fonseka S. Fernando A. et al.Phosphate fertilizer is a main source of arsenic in areas affected with chronic kidney disease of unknown etiology in Sri Lanka.Springerplus. 2015; 4: 90Crossref PubMed Scopus (122) Google Scholar, 7Peraza S. Wesseling C. Aragon A. et al.Decreased kidney function among agricultural workers in El Salvador.Am J Kidney Dis. 2012; 59: 531-540Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar, 8Cerdas M. Chronic kidney disease in Costa Rica.Kidney Int Suppl. 2005; : S31-S33Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar In fact, according to The Pan American Health Organization, Nicaragua and El Salvador have CKD-related estimated mortality rates of 42.8 and 41.6 deaths per 100,000, respectively, which is fourfold higher than any other country in the world with respect to mortality due to kidney disease. In El Salvador, CKD is the second most common cause of death in men, with males affected at three times the rate of females.9Organization PAHO. Chronic kidney disease in agricultural communities in Central America. 2013:1–3.Google Scholar In El Salvador, a number of epidemiological studies have estimated the prevalence of CINAC in farming communities to be between 15% and 21% with a 9% to 13% prevalence of chronic renal failure. Less than half of those affected have diabetes mellitus or hypertension. While the disease predominates in men, it also affects women, children, and adolescents who live in these farming communities regardless of whether they work in agriculture, and evidence suggests that the kidney disease may begin in the early stages of life. This increased prevalence of CKD has been observed in farming communities both in the highlands and lowlands of El Salvador, suggesting there may be multiple factors involved.3Orantes Navarro C.M. Herrera Valdés R. López M.A. et al.Epidemiological characteristics of chronic kidney disease of non-traditional causes in women of agricultural communities of El Salvador.Clin Nephrol. 2015; 83: 24-31Crossref PubMed Scopus (29) Google Scholar, 10Orantes C.M. Herrera R. Almaguer M. et al.Chronic kidney disease in children and adolescents in Salvadoran farming communities: NefroSalva Pediatric Study (2009–2011).MEDICC Rev. 2016; 18: 15-21PubMed Google Scholar, 11Herrera Valdés R. Orantes C.M. Almaguer López M. et al.Clinical characteristics of chronic kidney disease of non-traditional causes in women of agricultural communities in El Salvador.Clin Nephrol. 2015; 83: 56-63Crossref PubMed Scopus (14) Google Scholar Interestingly, similar findings of CINAC have been reported worldwide, particularly in Sri Lanka, India, and Egypt. The etiology of this epidemic of CKD remains unclear but is thought to include exposure to toxins such as pesticides and herbicides and repeated episodes of dehydration which occur in all affected populations. Other similar risk factors that have been identified in those affected in differing locations include agricultural work, male sex, age, poverty, use of well water, over use of NSAIDs, and histories of snake bites and infections to a more limited degree.12Jayasumana C. Orantes C. Herrera R. et al.Chronic interstitial nephritis in agricultural communities: a worldwide epidemic with social, occupational and environmental determinants.Nephrol Dial Transplant. 2016; PubMed Google Scholar, 13Bandarage A. Political economy of epidemic kidney disease in Sri Lanka.SAGE Open. 2013; 3: 1-13Crossref Scopus (14) Google Scholar In farming communities, heavy metals (cadmium and arsenic) and pesticides are present in well water, floors in homes, and farmlands and are more concentrated in crop areas. These likely accumulate due to extensive use of pesticides, including those which have been banned in many developed countries, to improve crop yield. The increase in CKD incidence in Central America began approximately 20 years ago, concomitant with a significant increase in the use of toxic agricultural chemicals such as paraquat, glyphosate, triazines, methamidophos, and methyl parathion.4Jayasumana C. Gajanayake R. Siribaddana S. Importance of arsenic and pesticides in epidemic chronic kidney disease in Sri Lanka.BMC Nephrol. 2014; 15: 124Crossref PubMed Scopus (37) Google Scholar, 5Jayasumana C. Gunatilake S. Senanayake P. Glyphosate, hard water and nephrotoxic metals: are they the culprits behind the epidemic of chronic kidney disease of unknown etiology in Sri Lanka?.Int J Environ Res Public Health. 2014; 11: 2125-2147Crossref PubMed Scopus (196) Google Scholar The nephrotoxic potential of these compounds is known and has been described in the literature.14Chaumont A. Nickmilder M. Dumont X. Lundh T. Skerfving S. Bernard A. Associations between proteins and heavy metals in urine at low environmental exposures: evidence of reverse causality.Toxicol Lett. 2012; 210: 345-352Crossref PubMed Scopus (90) Google Scholar, 15Gonick H.C. Nephrotoxicity of cadmium & lead.Indian J Med Res. 2008; 128: 335-352PubMed Google Scholar, 16Edwards J.R. Prozialeck W.C. Cadmium, diabetes and chronic kidney disease.Toxicol Appl Pharmacol. 2009; 238: 289-293Crossref PubMed Scopus (242) Google Scholar, 17Järup L. Akesson A. Current status of cadmium as an environmental health problem.Toxicol Appl Pharmacol. 2009; 238: 201-208Crossref PubMed Scopus (1705) Google Scholar, 18Kalahasthi R.B. Rajmohan H. Rajan B. Kumar M.K. Urinary N-acetyl-beta -D-glucosaminidase and its isoenzymes A & B in workers exposed to cadmium at cadmium plating.J Occup Med Toxicol. 2007; 2: 5Crossref PubMed Scopus (10) Google Scholar, 19Sabath E. Robles-Osorio M.L. Medio ambiente y riñón: nefrotoxicidad por metales pesados (Renal health and the environment: heavy metal nephrotoxicity).Revista Nefrologia Organo. 2012; 32: 279-286PubMed Google Scholar Pesticide exposure occurs during farmland application and from pesticide storage in household facilities. During spraying, farmers may inhale or accidentally ingest pesticides and herbicides, and their skin may become contaminated with these toxins due to the lack of outer garment protection. There is an association between self-reported use of carbamate pesticides in a hot and humid environment with a change in kidney-related biomarkers and a reduction in GFR.20García-Trabanino R. Jarquín E. Wesseling C. et al.Heat stress, dehydration, and kidney function in sugarcane cutters in El Salvador–a cross-shift study of workers at risk of Mesoamerican nephropathy.Environ Res. 2015; 142: 746-755Crossref PubMed Scopus (183) Google Scholar In the United States, a cohort of 55,580 male licensed pesticide applicators showed a significant association of chronic exposure to specific pesticides with increased risk of developing end-stage kidney disease.21Lebov J.F. Engel L.S. Richardson D. Hogan S.L. Hoppin J.A. Sandler D.P. Pesticide use and risk of end-stage renal disease among licensed pesticide applicators in the Agricultural Health Study.Occup Environ Med. 2016; 73: 3-12Crossref PubMed Scopus (79) Google Scholar Further evidence for a role of toxin exposure is the presence of extrarenal symptoms associated with CINAC including urinary dribbling, abnormalities in arteries by ultrasound, myoclonus and sensorineural deafness.22Herrera R. Orantes C.M. Almaguer M. et al.Clinical characteristics of chronic kidney disease of nontraditional causes in Salvadoran farming communities.MEDICC Rev. 2014; 16: 39-48PubMed Google Scholar Volcanic soil and other natural contaminants such as arsenic and hard water also may play a role. Although a single metal cannot be linked to CINAC, heavy metals have been found in excessive amounts in the urine of agricultural workers. Jayasumana and associates5Jayasumana C. Gunatilake S. Senanayake P. Glyphosate, hard water and nephrotoxic metals: are they the culprits behind the epidemic of chronic kidney disease of unknown etiology in Sri Lanka?.Int J Environ Res Public Health. 2014; 11: 2125-2147Crossref PubMed Scopus (196) Google Scholar, 23Jayasumana M.A. Paranagama P. Amarasinghe M. et al.Possible link of chronic arsenic toxicity with chronic kidney disease of unknown etiology in Sri Lanka.J Nat Sci Res. 2013; 3: 64-73Google Scholar hypothesized that the use of glyphosate, an herbicide and strong metal chelater, in conjunction with arsenic and the consumption of hard water, might be a cause of kidney disease in Sri Lankan agricultural workers. When agricultural workers' clothes become contaminated with pesticides, family members subsequently may be exposed, particularly women while laundering the family clothing.24Ribó A, Quinteros E, Mejía R, Jovel R, López D. Contaminación de arsénico en suelos, sedimentos y agua en la región del Bajo Lempa, El Salvador. Paper presented at: Libro de Resumen. VII Congreso de la Red Latinoamericana de Ciencias Ambientales. San Carlos, CR: Universidad Nacional de Costa Rica 2013.Google Scholar, 25Mejía R. Quinteros E. López A. et al.Pesticide-handling practices in agriculture in El Salvador: an example from 42 patient farmers with chronic kidney disease in the Bajo Lempa region.Occup Dis Environ Med. 2014; 2: 56-70Crossref Google Scholar, 26VanDervort D.R. López D.L. Orantes C.M. Rodríguez D.S. Spatial distribution of unspecified chronic kidney disease in El Salvador by crop area cultivated and ambient temperature.MEDICC Rev. 2014; 16: 31-38PubMed Google Scholar In affected agricultural communities, family members may be exposed via inhalation or ingestion of these toxins due to contamination of household items or the surrounding water and soil. In three farming communities in El Salvador with a significant prevalence of CINAC, children and adolescents have been shown to have an increased incidence of CKD.10Orantes C.M. Herrera R. Almaguer M. et al.Chronic kidney disease in children and adolescents in Salvadoran farming communities: NefroSalva Pediatric Study (2009–2011).MEDICC Rev. 2016; 18: 15-21PubMed Google Scholar Ramirez-Rubio and associates27Ramírez-Rubio O. Amador J.J. Kaufman J.S. et al.Urine biomarkers of kidney injury among adolescents in Nicaragua, a region affected by an epidemic of chronic kidney disease of unknown aetiology.Nephrol Dial Transplant. 2016; 31: 424-432Crossref PubMed Scopus (47) Google Scholar showed that adolescents in an affected community in Nicaragua had increased tubular injury associated biomarkers despite no involvement with agricultural work. Other factors may contribute to childhood CKD in these regions such as poor maternal nutrition resulting in low birth weight or a genetic predisposition. In Sri Lanka, a genomewide association study demonstrated an SNP in the gene encoding sodium-dependent dicarboxylate transporter member 3, which conferred increased risk for CINAC with a population attributable fraction of 50% and odds ratio of 2.3.28Nanayakkara S. Senevirathna S.T. Abeysekera T. et al.An integrative study of the genetic, social and environmental determinants of chronic kidney disease characterized by tubulointerstitial damages in the North Central Region of Sri Lanka.J Occup Health. 2014; 56: 28-38Crossref PubMed Scopus (80) Google Scholar Repeated episodes of dehydration due to inadequate intake of fluids while engaged in manual labor in a hot humid climate have been proposed as a cause of CINAC, and undoubtedly repeated dehydration may produce kidney damage.29Torres C. Aragón A. González M. et al.Decreased kidney function of unknown cause in Nicaragua: a community-based survey.Am J Kidney Dis. 2010; 55: 485-496Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar Suggested pathogenetic mechanisms for dehydration-induced kidney injury include activation of the aldo reductase-fructokinase pathway in the proximal tubule with subsequent uric acid production resulting in proximal tubular injury; this has been replicated in an experimental model.30Roncal Jimenez C.A. Ishimoto T. Lanaspa M.A. et al.Fructokinase activity mediates dehydration-induced renal injury.Kidney Int. 2014; 86: 294-302Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar, 31Roncal-Jimenez C. García-Trabanino R. Barregard L. et al.Heat stress nephropathy from exercise-induced uric acid crystalluria: a perspective on mesoamerican nephropathy.Am J Kidney Dis. 2016; 67: 20-30Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar There also may be a role of rhabdomyolysis.12Jayasumana C. Orantes C. Herrera R. et al.Chronic interstitial nephritis in agricultural communities: a worldwide epidemic with social, occupational and environmental determinants.Nephrol Dial Transplant. 2016; PubMed Google Scholar Dehydration, caused by inadequate fluid intake in a hot environment, can affect elimination of toxic agents from the blood and increase the concentration of these agents in the kidney medulla, thus contributing to development of kidney injury. While there may be a role for dehydration in this epidemic of CKD, dehydration alone cannot explain the spectrum of this disease, which affects not only male farmworkers, but also men who are not farmworkers, men in the same geographic region who do not work in agriculture, women who are employed and not employed in agriculture, and school age children and adolescents. In the early stages of CINAC, patients may be asymptomatic or demonstrate urinary hesitancy, a thin urinary stream and dysuria. Symptoms become more common in CKD 2 and may include genitourinary abnormalities such as nocturia, dysuria, post void dribbling, hesitancy, and foamy urine, as well as systemic symptoms such as arthralgias, abnormal tendon reflexes, muscle cramps, asthenias, decreased libido, and fainting.22Herrera R. Orantes C.M. Almaguer M. et al.Clinical characteristics of chronic kidney disease of nontraditional causes in Salvadoran farming communities.MEDICC Rev. 2014; 16: 39-48PubMed Google Scholar At this time, there also may be polyuria with elevated urinary magnesium, sodium, calcium, and phosphorous, with resulting serum electrolyte abnormalities including hyponatremia, hypokalemia, hypomagnesemia and hypocalcemia, and metabolic alkalosis. As the disease progresses, these symptoms progressively intensify with worsening of the kidney disease. Urine analysis typically is unremarkable or shows mild proteinuria, likely of tubular origin with increased β2 microglobulin and tubular markers of injury including KIM-1 and NGAL.22Herrera R. Orantes C.M. Almaguer M. et al.Clinical characteristics of chronic kidney disease of nontraditional causes in Salvadoran farming communities.MEDICC Rev. 2014; 16: 39-48PubMed Google Scholar, 32De Silva P.M. Mohammed Abdul K.S. Eakanayake E.M. et al.Urinary biomarkers KIM-1 and NGAL for detection of chronic kidney disease of uncertain etiology (CKDu) among agricultural communities in Sri Lanka.PLoS Negl Trop Dis. 2016; 10: e0004979Crossref Scopus (42) Google Scholar, 33Cárdenas-González M. Osorio-Yáñez C. Gaspar-Ramírez O. et al.Environmental exposure to arsenic and chromium in children is associated with kidney injury molecule-1.Environ Res. 2016; 150: 653-662Crossref PubMed Scopus (71) Google Scholar Urine culture is negative. Kidney imaging shows changes of CKD and preserved kidney blood flow. No urinary bladder or prostate abnormalities are identified on ultrasound evaluation.22Herrera R. Orantes C.M. Almaguer M. et al.Clinical characteristics of chronic kidney disease of nontraditional causes in Salvadoran farming communities.MEDICC Rev. 2014; 16: 39-48PubMed Google Scholar As noted above, extrarenal symptoms involving the cardiovascular, peripheral vascular, and nervous systems may be present. Most patients are normotensive or have mildly elevated blood pressure, with a normal EKG and echocardiogram. On cardiac stress testing, patients typically have preserved physical capacity, and few have an abnormal pressor response. Peripheral arterial doppler studies show few abnormalities of the carotid and aortoiliac vessels; however, femoral and particularly tibial arteries demonstrate irregular walls and atherosclerosis.22Herrera R. Orantes C.M. Almaguer M. et al.Clinical characteristics of chronic kidney disease of nontraditional causes in Salvadoran farming communities.MEDICC Rev. 2014; 16: 39-48PubMed Google Scholar Sensorineural hearing loss is a common finding, while fundoscopic examination, intraocular pressure, and visual field testing are normal in the majority of patients, suggesting an absence of significant microvascular damage as is observed with diabetic or hypertensive retinopathy.22Herrera R. Orantes C.M. Almaguer M. et al.Clinical characteristics of chronic kidney disease of nontraditional causes in Salvadoran farming communities.MEDICC Rev. 2014; 16: 39-48PubMed Google Scholar Histologic findings are similar in cases of CINAC from different geographic areas.34López-Marín L. Chávez Y. García X.A. et al.Histopathology of chronic kidney disease of unknown etiology in Salvadoran agricultural communities.MEDICC Rev. 2014; 16: 49-54PubMed Google Scholar, 35Selvarajah M. Weeratunga P. Sivayoganthan S. Rathnatunga N. Rajapakse S. Clinicopathological correlates of chronic kidney disease of unknown etiology in Sri Lanka.Indian J Nephrol. 2016; 26: 357-363Crossref PubMed Scopus (16) Google Scholar, 36Wijkström J. Leiva R. Elinder C.G. et al.Clinical and pathological characterization of Mesoamerican nephropathy: a new kidney disease in Central America.Am J Kidney Dis. 2013; 62: 908-918Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar The predominant pattern is of a chronic tubulointerstitial nephritis characterized by tubular atrophy, interstitial fibrosis, and a variable interstitial mononuclear inflammatory infiltrate. There may be associated global glomerulosclerosis, glomerulomegaly, ischemic-appearing glomerular capillary wall corrugation, and features of vascular injury including muscular hypertrophy, smooth muscle vacuolization, and intimal proliferation within arteries and arterioles. Interestingly, there are some differences in the extent of interstitial inflammation and glomerular enlargement relative to the type of agricultural work; sugarcane workers demonstrate more tubulointerstitial scarring and inflammation and less glomerular enlargement compared with those working with other crops. Immunofluorescence shows no specific immune deposition in the glomeruli, tubules, or interstitium.34López-Marín L. Chávez Y. García X.A. et al.Histopathology of chronic kidney disease of unknown etiology in Salvadoran agricultural communities.MEDICC Rev. 2014; 16: 49-54PubMed Google Scholar Electron microscopy has revealed inclusions in proximal tubular epithelium, possibly secondary lysosomes or autophagic vacuoles; however, the pathogenesis of this feature is uncertain as similar structures are associated with quinine administration and their significance is unknown with respect to CINAC. The epidemic itself is defined as an increase in the number of cases of CKD in agricultural communities, which are characterized by three general conditions: poverty with all its repercussions, unhealthy working conditions, and a contaminated environment. These elements link the disease to deep rooted socioeconomic circumstances.22Herrera R. Orantes C.M. Almaguer M. et al.Clinical characteristics of chronic kidney disease of nontraditional causes in Salvadoran farming communities.MEDICC Rev. 2014; 16: 39-48PubMed Google Scholar This CKD epidemic has a double burden. The first is the presence of well-known traditional causes of CKD (diabetes mellitus, hypertension, glomerulopathies, and obstructive uropathy) which affect developed and developing countries, with an additional second burden due to as yet undetermined causes which result in a histopathological pattern of chronic tubulointerstitial nephritis impacting those in the targeted areas.2Almaguer M. Herrera R. Orantes C.M. Chronic kidney disease of unknown etiology in agricultural communities.MEDICC Rev. 2014; 16: 9-15PubMed Google Scholar Examples of cases and their inclusion as part of this epidemic are detailed below. A person who has lived or worked in agricultural communities with no known history of kidney disease and who demonstrates biomarkers of kidney damage in the urine and/or decreased glomerular filtration rate is considered to have a possible case of CINAC based on epidemiology.3Orantes Navarro C.M. Herrera Valdés R. López M.A. et al.Epidemiological characteristics of chronic kidney disease of non-traditional causes in women of agricultural communities of El Salvador.Clin Nephrol. 2015; 83: 24-31Crossref PubMed Scopus (29) Google Scholar, 37Orantes C.M. Herrera R. Almaguer M. et al.Epidemiology of chronic kidney disease in adults of Salvadoran agricultural communities.MEDICC Rev. 2014; 16: 23-30PubMed Google Scholar Additional information may further the diagnosis to a probable case of CINAC, which adds clinical criteria to the epidemiology. This would encompass a patient with possible CINAC in whom a primary or secondary cause of kidney disease has not been identified and who progresses from an early asymptomatic stage to exhibiting symptoms of fatigue, cramps, polyuria, nocturia, dysuria, foamy urine, fainting, joint pain and/or signs including occasional hypotension, mild cardiac disorders with predominant lower extremity peripheral vascular damage, a normal funduscopic examination, altered neurological reflexes, and sensorineural hearing loss. None of these findings should be a consequence of the stage of CKD. Additional findings may include no or minimal proteinuria, the presence of tubular injury markers such as β2 microglobulin, and abnormal urinary electrolyte excretion with associated hyponatremia, hypokalemia, hypomagnesemia, and/or hypocalcemia.3Orantes Navarro C.M. Herrera Valdés R. López M.A. et al.Epidemiological characteristics of chronic kidney disease of non-traditional causes in women of agricultural communities of El Salvador.Clin Nephrol. 2015; 83: 24-31Crossref PubMed Scopus (29) Google Scholar, 22Herrera R. Orantes C.M. Almaguer M. et al.Clinical characteristics of chronic kidney disease of nontraditional causes in Salvadoran farming communities.MEDICC Rev. 2014; 16: 39-48PubMed Google Scholar A confirmed case of CINAC fulfills the epidemiological and clinical criteria of CINAC denoted above and in whom a kidney biopsy demonstrates the histopathological pattern of chronic tubulointerstitial nephritis with or without secondary glomerulosclerosis and vascular damage.34López-Marín L. Chávez Y. García X.A. et al.Histopathology of chronic kidney disease of unknown etiology in Salvadoran agricultural communities.MEDICC Rev. 2014; 16: 49-54PubMed Google Scholar Figure 1 depicts how these case definitions fit within the broad diagnostic spectrum of CINAC from the community level to the individual. CINAC is a multifactorial disease, predominantly affecting young male farmers, and fewer numbers of nonfarming women, adolescents, and children. The widespread reach of CINAC within farming communities in Central America and Asia suggests the presence of environmental risk factors associated with the occupation of their residents. Those living in these agricultural communities are exposed to the same risk factors as the general population, with additional exposure occupational risks. Environmental natural or man-made toxic agents (heavy metals, pesticides, and chemicals and/or microbial substances) in the air, soil, or water may be subjected to transformation by climate, topography, and soil use.14Chaumont A. Nickmilder M. Dumont X. Lundh T. Skerfving S. Bernard A. Associations between proteins and heavy metals in urine at low environmental exposures: evidence of reverse causality.Toxicol Lett. 2012; 210: 345-352Crossref PubMed Scopus (90) Google Scholar, 15Gonick H.C. Nephrotoxicity of cadmium & lead.Indian J Med Res. 2008; 128: 335-352PubMed Google Scholar, 16Edwards J.R. Prozialeck W.C. Cadmium, diabetes and chronic kidney disease.Toxicol Appl Pharmacol. 2009; 238: 289-293Crossref PubMed Scopus (242) Google Scholar, 17Järup L. Akesson A. Current status of cadmium as an environmental health problem.Toxicol Appl Pharmacol. 2009; 238: 201-208Crossref PubMed Scopus (1705) Google Scholar, 24Ribó A, Quinteros E, Mejía R, Jovel R, López D. Contaminación de arsénico en suelos, sedimentos y agua en la región del Bajo Lempa, El Salvador. Paper presented at: Libro de Resumen. VII Congreso de la Red Latinoamericana de Ciencias Ambientales. San Carlos, CR: Universidad Nacional de Costa Rica 2013.Google Scholar, 33Cárdenas-González M. Osorio-Yáñez C. Gaspar-Ramírez O. et al.Environmental exposure to arsenic and chromium in children is associated with kidney injury molecule-1.Environ Res. 2016; 150: 653-662Crossref PubMed Scopus (71) Google Scholar, 36Wijkström J. Leiva R. Elinder C.G. et al.Clinical and pathological characterization of Mesoamerican nephropathy: a new kidney disease in Central America.Am J Kidney Dis. 2013; 62: 908-918Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar, 38Soderland P. Lovekar S. Weiner D.E. Brooks D.R. Kaufman J.S. Chronic kidney disease associated with environmental toxins and exposures.Adv Chronic Kidney Dis. 2010; 17: 254-264Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar These may spread to the wider farming community via air, water soil displacement, or absorption into the food chain. These toxic agents can then affect a susceptible subject who is exposed to unhealthy lifestyles and harsh working conditions such as dehydration and heat stress. Farmers likely have more concentrated and chronic exposure via drinking water, inhalation, ingestion, or skin contact while working in the fields. The intensity of the exposure may vary, ranging from high level (repeated exposure affecting primarily farmers) to a low level (chronic exposure affecting the general population) leading to repeated episodes of subclinical kidney injury. On a molecular level, toxins can affect the kidney tissue through direct tubular cell toxicity or alterations in intrarenal blood flow producing secondary tubular damage leading to CINAC.14Chaumont A. Nickmilder M. Dumont X. Lundh T. Skerfving S. Bernard A. Associations between proteins and heavy metals in urine at low environmental exposures: evidence of reverse causality.Toxicol Lett. 2012; 210: 345-352Crossref PubMed Scopus (90) Google Scholar, 23Jayasumana M.A. Paranagama P. Amarasinghe M. et al.Possible link of chronic arsenic toxicity with chronic kidney disease of unknown etiology in Sri Lanka.J Nat Sci Res. 2013; 3: 64-73Google Scholar Other factors putting this population at increased risk for CKD include low birth weight, infectious diseases, traditional risk factors, use of NSAIDs, and nephrotoxic medicinal herbs. Finally, there may be genetic susceptibility among the affected populations. A comprehensive hypothesis for the development of CINAC is summarized in Figure 2. The medical and scientific communities recognize CINAC as a public health crisis. The use of the unifying term CINAC in concert with our comprehensive hypothesis of its pathogenesis and proposed case definitions provides a framework for continued collection and analysis of risk factor data. Establishing a set of criteria for public health surveillance in different regions of the world with the same epidemic pattern (eg, El Salvador and Sri Lanka) will allow reporting from differing geographic locations with similar disease patterns.12Jayasumana C. Orantes C. Herrera R. et al.Chronic interstitial nephritis in agricultural communities: a worldwide epidemic with social, occupational and environmental determinants.Nephrol Dial Transplant. 2016; PubMed Google Scholar It is hoped that identification of multiple potential risk factors will provide public health officials and decision makers opportunities for early identification, intervention, and ultimately prevention of CINAC in socially vulnerable individuals in rural communities. In addition, there are social and environmental implications with regard to human rights in the context of adequate occupational health and safety." @default.
• W2593896229 created "2017-03-16" @default.
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• W2593896229 title "Toward a Comprehensive Hypothesis of Chronic Interstitial Nephritis in Agricultural Communities" @default.
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