CKD in Central America: A Hot Issue
2012; Elsevier BV; Volume: 59; Issue: 4 Linguagem: Inglês
10.1053/j.ajkd.2012.01.005
ISSN1523-6838
AutoresDaniel R. Brooks, Oriana Ramírez‐Rubio, Juan José Amador,
Tópico(s)Acute Kidney Injury Research
ResumoRelated Article, p. 531For at least 2 decades, Central America has experienced a puzzling excess of chronic kidney disease (CKD), resulting in many thousands of deaths.1Ministry of Health of NicaraguaNorma y Protocolo para el Abordaje de la Enfermedad Renal Crónica. 2009http://www.minsa.gob.ni/index.php?option=com_remository&Itemid=52&func=fileinfo&id=6008Google Scholar, 2Ministry of Public Health and Social Assistance, El Salvador¿De qué se mueren y enferman los salvadoreños?.in: Memoria de Labores 2009-2010. 2011http://www.salud.gob.sv/index.php/servicios/descargas/documentos/Documentación-Institucional/Memorias-de-Labores/Memoria-de-Labores-2009-2010/Capítulo-II.-¿De-qué-se-enferma-y-muere-la-población-salvadoreña/Google Scholar Unlike previous outbreaks in areas such as the Balkans, Tunisia, and Japan, the epidemic in Central America has been under-reported in the scientific literature. Recently, more studies of this epidemic have been published, with the investigation by Peraza et al3Peraza S. Wesseling C. Aragon A. et al.Decreased kidney function among agriculture workers in El Salvador.Am J Kidney Dis. 2012; 59: 531-540Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar in this issue of the American Journal of Kidney Diseases the most recent exploration of CKD in this region.Although increases in the prevalence of CKD in high-income countries and many low- and middle-income nations are largely the result of increasing rates of obesity, diabetes, and hypertension, these factors appear to have little role in the Central American epidemic. Overall, CKD in this region has a number of distinguishing characteristics: (1) geographic areas of apparent excess disease are not equally distributed, but rather are centered on the Pacific coast of Central America (Fig 1); (2) men predominantly are affected, often by ratios greater than 3:1, and are diagnosed at a relatively young age, frequently in their 30s; and (3) significant proteinuria is uncommon, with the clinical profile and few biopsies that have been conducted appearing most consistent with a tubulointerstitial process characterized by small fibrotic kidneys.5García-Trabanino R. Dominguez J. Jansa J.M. Oliver A. Proteinuria and chronic renal failure in the coast of El Salvador: detection with low cost methods and associated factors.Nefrologia. 2005; 25: 31-38PubMed Google Scholar, 6Orantes C.M. Herrera R. Almaguer M. et al.Chronic kidney disease and associated risk factors in the Bajo Lempa region of El Salvador: nefrolempa study, 2009.MEDICC Rev. 2011; 13: 14-22PubMed Google Scholar, 7Trabanino R.G. Aguilar R. Silva C.R. Mercado M.O. Merino R.L. End-stage renal disease among patients in a referral hospital in El Salvador.Rev Panam Salud Publica. 2002; 12: 202-206Crossref PubMed Scopus (111) Google Scholar, 8Cerdas M. Chronic kidney disease in Costa Rica.Kidney Int Suppl. 2005; 97: S31-S33Crossref PubMed Scopus (62) Google Scholar, 9Laux TS, Bert PJ, Barreto Ruiz GM, et al. Nicaragua revisited: evidence of lower prevalence of chronic kidney disease in a high-altitude, coffee-growing village [published online ahead of print September 23, 2011]. J Nephrol. doi:10.5301/jn.5000028.Google Scholar, 10O'Donnell J.K. Tobey M. Weiner D.E. et al.Prevalence of and risk factors for chronic kidney disease in rural Nicaragua.Nephrol Dial Transplant. 2011; 26: 2798-2805Crossref PubMed Scopus (109) Google Scholar, 11Sanoff S.L. Callejas L. Alonso C.D. et al.Positive association of renal insufficiency with agriculture employment and unregulated alcohol consumption in Nicaragua.Ren Fail. 2010; 32: 766-777Crossref PubMed Scopus (67) Google Scholar, 12Torres C. Aragon A. Gonzalez 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 (166) Google ScholarIn their study, Peraza et al3Peraza S. Wesseling C. Aragon A. et al.Decreased kidney function among agriculture workers in El Salvador.Am J Kidney Dis. 2012; 59: 531-540Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar measured serum creatinine in presumed healthy adults aged 20-60 years in 5 communities in El Salvador: 2 were located at sea level, with sugarcane (and previously cotton) cultivation and harvesting the dominant industry, and the other 3 were located at higher altitudes, with economies based on sugarcane, coffee, and services. The prevalence of CKD, defined as estimated glomerular filtration rate 1.2 mg/dL) and women (OR, 2.3 [95% CI, 1.4-3.7] for creatinine >0.9 mg/dL) who spent 10 or more years in coastal sugarcane or cotton work compared with those who had never worked in either of those settings.To appreciate the significance of these findings, it is helpful to describe factors that have been considered as causes of the CKD epidemic. Although heavy metals, medications, diet, leptospirosis or other infections, and genetic and developmental susceptibility factors have all been proposed as possible causes, suspicion has centered mainly on factors that are disproportionately present in men, with occupational exposure to agrichemicals and consumption of alcohol in a form that, although not home distilled, was susceptible to accidental or intentional contamination during distribution and storage, receiving most of the early attention.11Sanoff S.L. Callejas L. Alonso C.D. et al.Positive association of renal insufficiency with agriculture employment and unregulated alcohol consumption in Nicaragua.Ren Fail. 2010; 32: 766-777Crossref PubMed Scopus (67) Google Scholar However, given the tropical climate and challenging working conditions in the region, investigators also have proposed heat stress as a potential mechanism.13Brooks D. Final scoping study report: epidemiology of chronic kidney disease in Nicaragua.2009http://www.cao-ombudsman.org/cases/document-links/documents/03H_BU_FINAL_report_scopestudyCRI_18.Dec.2009.pdfGoogle Scholar, 14Cuadra S.N. Jakobsson K. Hogstedt C. Wesseling C. Chronic kidney disease: assessment of current knowledge and feasibility for regional research collaboration in Central America. Vol 2. SALTRA, Work & Health Series, Heredia, Costa Rica2006http://www.saltra.info/images/articles/seriesaludytrabajo/seriesaludytrabajo2.pdfGoogle Scholar, 15Crowe J. Moya-Bonilla J.M. Roman-Solano B. Robles-Ramirez A. Heat exposure in sugarcane workers in Costa Rica during the non-harvest season.Glob Health Action. 2010 Nov 29; 3https://doi.org/10.3402/gha.v3i0.5619Crossref PubMed Google Scholar, 16Crowe J. van Wendel de Joode B. Wesseling C. A pilot field evaluation on heat stress in sugarcane workers in Costa Rica: what to do next?.Glob Health Action. 2009 Nov 11; 2https://doi.org/10.3402/gha.v2i0.2062Crossref PubMed Scopus (37) Google Scholar, 17Delgado Cortez O. Heat stress assessment among workers in a Nicaraguan sugarcane farm.Glob Health Action. 2009 Nov 11; 2https://doi.org/10.3402/gha.v2i0.2069Crossref PubMed Scopus (48) Google Scholar, 18Kjellstrom T. Crowe J. Climate change, workplace heat exposure, and occupational health and productivity in Central America.Int J Occup Environ Health. 2011; 17: 270-281Crossref PubMed Google Scholar, 19McClean M. Laws R. Ramirez Rubio O. Brooks D. Industrial hygiene/occupational health assesment: evaluating potential hazards associated with chemicals and work practices at the Ingenio San Antonio (Chichigalpa, Nicaragua).2010http://www.cao-ombudsman.org/documents/FINALIHReport-AUG302010-ENGLISH.pdfGoogle Scholar, 20Soderland 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 (163) Google ScholarHeat stress with subsequent volume depletion, if severe, can cause acute kidney injury (AKI) even in healthy adults, particularly in the presence of potential nephrotoxins, such as nonsteroidal anti-inflammatory drugs. Although it generally had been held that AKI leads to CKD only in the absence of functional recovery from the initial injury, recent evidence suggests that residual subclinical damage may increase the risk of CKD.21Venkatachalam M.A. Griffin K.A. Lan R. Geng H. Saikumar P. Bidani A.K. Acute kidney injury: a springboard for progression in chronic kidney disease.Am J Physiol Renal Physiol. 2010; 298: F1078-F1094Crossref PubMed Scopus (389) Google Scholar, 22Yang L. Humphreys B.D. Bonventre J.V. Pathophysiology of acute kidney injury to chronic kidney disease: maladaptive repair.Contrib Nephrol. 2011; 174: 149-155Crossref PubMed Scopus (104) Google Scholar, 23Coca S.G. Peixoto A.J. Garg A.X. Krumholz H.M. Parikh C.R. The prognostic importance of a small acute decrement in kidney function in hospitalized patients: a systematic review and meta-analysis.Am J Kidney Dis. 2007; 50: 712-720Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar, 24Coca SG, Singanamala S, Parikh CR. Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis [published online ahead of print November 23, 2011]. Kidney Int. doi:10.1038/ki.2011.379.Google Scholar, 25Levin A. Kellum J.A. Mehta R.L. Acute kidney injury: toward an integrated understanding through development of a research agenda.Clin J Am Soc Nephrol. 2008; 3: 862-863Crossref PubMed Scopus (24) Google Scholar Although overt AKI caused by extreme heat exhaustion and heat stroke are known to occur in the region and may explain a portion of the epidemic, it seems unlikely that such incidents could account for the majority of cases. Investigators have instead postulated that a chronic state of volume depletion leaves individuals susceptible to accumulation of damage to the kidneys from repeated subclinical insults, which eventually develops into CKD.Epidemiologic studies in the region during the last few years have provided some evidence supporting this hypothesis. With few exceptions, these investigations consist of cross-sectional studies that analyze serum creatinine and urine dipstick results in conjunction with questionnaires designed to explore associations between kidney function and putative risk factors. Despite their limitations, at least 2 consistent results have emerged. First, there are clear differences in risks of CKD according to type of industry and occupation. Workers in the sugarcane cultivation, mining, and fishing or shipping industries have higher prevalence rates, whereas areas in which coffee growing and services dominate show no evidence of excess disease.6Orantes C.M. Herrera R. Almaguer M. et al.Chronic kidney disease and associated risk factors in the Bajo Lempa region of El Salvador: nefrolempa study, 2009.MEDICC Rev. 2011; 13: 14-22PubMed Google Scholar, 9Laux TS, Bert PJ, Barreto Ruiz GM, et al. Nicaragua revisited: evidence of lower prevalence of chronic kidney disease in a high-altitude, coffee-growing village [published online ahead of print September 23, 2011]. J Nephrol. doi:10.5301/jn.5000028.Google Scholar, 10O'Donnell J.K. Tobey M. Weiner D.E. et al.Prevalence of and risk factors for chronic kidney disease in rural Nicaragua.Nephrol Dial Transplant. 2011; 26: 2798-2805Crossref PubMed Scopus (109) Google Scholar, 11Sanoff S.L. Callejas L. Alonso C.D. et al.Positive association of renal insufficiency with agriculture employment and unregulated alcohol consumption in Nicaragua.Ren Fail. 2010; 32: 766-777Crossref PubMed Scopus (67) Google Scholar, 12Torres C. Aragon A. Gonzalez 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 (166) Google Scholar Second, persons living at low altitudes are more likely to have CKD than those living at higher elevations.9Laux TS, Bert PJ, Barreto Ruiz GM, et al. Nicaragua revisited: evidence of lower prevalence of chronic kidney disease in a high-altitude, coffee-growing village [published online ahead of print September 23, 2011]. J Nephrol. doi:10.5301/jn.5000028.Google Scholar, 10O'Donnell J.K. Tobey M. Weiner D.E. et al.Prevalence of and risk factors for chronic kidney disease in rural Nicaragua.Nephrol Dial Transplant. 2011; 26: 2798-2805Crossref PubMed Scopus (109) Google Scholar, 12Torres C. Aragon A. Gonzalez 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 (166) Google ScholarThese 2 findings are consistent with the hypothesis that heat stress contributes to the development of kidney disease in the region because temperatures at lower elevation are significantly higher than at higher altitudes18Kjellstrom T. Crowe J. Climate change, workplace heat exposure, and occupational health and productivity in Central America.Int J Occup Environ Health. 2011; 17: 270-281Crossref PubMed Google Scholar and the pattern of industries with high and low prevalences is more consistent with heat stress than with agrichemical exposure. However, it has been difficult to distinguish among hypotheses because the type of industry typically also varies with elevation. For example, in Nicaragua, where most studies have been conducted to date, sugarcane is grown at low altitudes while coffee is grown at higher altitudes. Therefore, it can be difficult to clearly identify whether differences in prevalence are the result of differences in temperature and work intensity or in the type of agrichemicals used in each industry.Peraza et al3Peraza S. Wesseling C. Aragon A. et al.Decreased kidney function among agriculture workers in El Salvador.Am J Kidney Dis. 2012; 59: 531-540Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar recognized this issue and took advantage of the presence of sugarcane cultivation in both low- and high-altitude settings to provide the strongest contrast to date between the agrichemical and heat stress hypotheses. Their study shows for the first time that workers involved in sugarcane cultivation have a higher prevalence of elevated serum creatinine level (and lower estimated glomerular filtration rate) if they lived and worked at low elevations, but experienced no such effects at higher elevations despite similarities in the nature and organization of work and agrichemical use. This finding strongly suggests that differences in the environment in which the work is carried out, rather than in exposure to agrichemicals, are the main factor impacting on the prevalence of elevated serum creatinine level. They also reported that individuals engaged in subsistence farming at low elevations showed no increased prevalence of higher serum creatinine levels in contrast to lowland sugarcane workers. They attribute this difference to lower exposure to heat stress because of greater control over working conditions, although this conclusion may be premature given the very small number of subsistence farmers in the study. Nevertheless, the observation is an interesting one and warrants further investigation.One possible objection to the heat stress hypothesis is the fact that people engage in strenuous work in hot climates all around the globe. However, excesses of CKD with characteristics similar to the Central American epidemic have been reported in specific regions in Sri Lanka, India, and Egypt, all of which also have very warm climates, and the possibility that the disease is occurring in yet other areas should not be ruled out.26Athuraliya N.T. Abeysekera T.D. Amerasinghe P.H. et al.Uncertain etiologies of proteinuric-chronic kidney disease in rural Sri Lanka.Kidney Int. 2009; 80: 1212-1221Crossref Scopus (154) Google Scholar, 27Athuraliya T.N. Abeysekera D.T. Amerasinghe P.H. Kumarasiri P.V. Dissanayake V. Prevalence of chronic kidney disease in two tertiary care hospitals: high proportion of cases with uncertain aetiology.Ceylon Med J. 2009; 54: 23-25Crossref PubMed Scopus (56) Google Scholar, 28Nanayakkara S, Senevirathna ST, Karunaratne U, et al. Evidence of tubular damage in the very early stage of chronic kidney disease of uncertain etiology in the North Central Province of Sri Lanka: a cross-sectional study [published online ahead of print June 28, 2011]. Environ Health Prev Med. doi:10.1007/s12199-011-0224-z.Google Scholar, 29Siva G. 'Cursed' Uddanam cries for help.The Times of India. August 10, 2009; (Accessed December 23, 2011)http://articles.timesofindia.indiatimes.com/2009-08-10/hyderabad/28181811_1_mandals-villagers-kidneyGoogle Scholar, 30Machiraju R.S. Yaradi K. Gowrishankar S. et al.Epidemiology of Udhanam endemic nephropathy.J Am Soc Nephrol. 2009; 20 ([abstract]): 643AGoogle Scholar, 31Kamel E.G. El-Minshawy O. Environmental factors incriminated in the development of end stage renal disease in El-Minia Governorate, Upper Egypt.Int J Nephrol Urol. 2010; 2: 431-437Google Scholar It is possible that individuals in regions with a CKD excess also are exposed to other nephrotoxic factor(s) present in these particular locations, which could be potentiated in a setting in which individuals have been rendered more susceptible to kidney disease due to heat stress. A third possibility is that some form of increased susceptibility is present at birth or acquired during childhood, leading to subtle kidney damage, and the effects of heat stress speed the progression to overt disease.Based on the evidence accumulated by Peraza et al3Peraza S. Wesseling C. Aragon A. et al.Decreased kidney function among agriculture workers in El Salvador.Am J Kidney Dis. 2012; 59: 531-540Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar and others, as well as the recent understanding that AKI may be associated more closely with CKD than previously believed, the possibility that repeated episodes of subclinical kidney damage in the absence of overt AKI could cause CKD seems plausible and worthy of further study. Although it remains important to continue to pursue other hypotheses concerning the cause of the excess of CKD in Central America, it is time for more rigorous studies of heat stress. These studies should specifically investigate whether there are significant differences in volume depletion and muscle damage by type of work and hydration practices outside the work setting that are correlated with subclinical kidney damage, as well as whether that damage eventually accumulates over time to cause CKD. If heat stress is shown to cause CKD, either in isolation or in combination with other factors, this knowledge would benefit not only those living in areas with a current excess of CKD, but may have far wider implications for a world that is projected to grow warmer over the next century. Related Article, p. 531 Related Article, p. 531 Related Article, p. 531 For at least 2 decades, Central America has experienced a puzzling excess of chronic kidney disease (CKD), resulting in many thousands of deaths.1Ministry of Health of NicaraguaNorma y Protocolo para el Abordaje de la Enfermedad Renal Crónica. 2009http://www.minsa.gob.ni/index.php?option=com_remository&Itemid=52&func=fileinfo&id=6008Google Scholar, 2Ministry of Public Health and Social Assistance, El Salvador¿De qué se mueren y enferman los salvadoreños?.in: Memoria de Labores 2009-2010. 2011http://www.salud.gob.sv/index.php/servicios/descargas/documentos/Documentación-Institucional/Memorias-de-Labores/Memoria-de-Labores-2009-2010/Capítulo-II.-¿De-qué-se-enferma-y-muere-la-población-salvadoreña/Google Scholar Unlike previous outbreaks in areas such as the Balkans, Tunisia, and Japan, the epidemic in Central America has been under-reported in the scientific literature. Recently, more studies of this epidemic have been published, with the investigation by Peraza et al3Peraza S. Wesseling C. Aragon A. et al.Decreased kidney function among agriculture workers in El Salvador.Am J Kidney Dis. 2012; 59: 531-540Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar in this issue of the American Journal of Kidney Diseases the most recent exploration of CKD in this region. Although increases in the prevalence of CKD in high-income countries and many low- and middle-income nations are largely the result of increasing rates of obesity, diabetes, and hypertension, these factors appear to have little role in the Central American epidemic. Overall, CKD in this region has a number of distinguishing characteristics: (1) geographic areas of apparent excess disease are not equally distributed, but rather are centered on the Pacific coast of Central America (Fig 1); (2) men predominantly are affected, often by ratios greater than 3:1, and are diagnosed at a relatively young age, frequently in their 30s; and (3) significant proteinuria is uncommon, with the clinical profile and few biopsies that have been conducted appearing most consistent with a tubulointerstitial process characterized by small fibrotic kidneys.5García-Trabanino R. Dominguez J. Jansa J.M. Oliver A. Proteinuria and chronic renal failure in the coast of El Salvador: detection with low cost methods and associated factors.Nefrologia. 2005; 25: 31-38PubMed Google Scholar, 6Orantes C.M. Herrera R. Almaguer M. et al.Chronic kidney disease and associated risk factors in the Bajo Lempa region of El Salvador: nefrolempa study, 2009.MEDICC Rev. 2011; 13: 14-22PubMed Google Scholar, 7Trabanino R.G. Aguilar R. Silva C.R. Mercado M.O. Merino R.L. End-stage renal disease among patients in a referral hospital in El Salvador.Rev Panam Salud Publica. 2002; 12: 202-206Crossref PubMed Scopus (111) Google Scholar, 8Cerdas M. Chronic kidney disease in Costa Rica.Kidney Int Suppl. 2005; 97: S31-S33Crossref PubMed Scopus (62) Google Scholar, 9Laux TS, Bert PJ, Barreto Ruiz GM, et al. Nicaragua revisited: evidence of lower prevalence of chronic kidney disease in a high-altitude, coffee-growing village [published online ahead of print September 23, 2011]. J Nephrol. doi:10.5301/jn.5000028.Google Scholar, 10O'Donnell J.K. Tobey M. Weiner D.E. et al.Prevalence of and risk factors for chronic kidney disease in rural Nicaragua.Nephrol Dial Transplant. 2011; 26: 2798-2805Crossref PubMed Scopus (109) Google Scholar, 11Sanoff S.L. Callejas L. Alonso C.D. et al.Positive association of renal insufficiency with agriculture employment and unregulated alcohol consumption in Nicaragua.Ren Fail. 2010; 32: 766-777Crossref PubMed Scopus (67) Google Scholar, 12Torres C. Aragon A. Gonzalez 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 (166) Google Scholar In their study, Peraza et al3Peraza S. Wesseling C. Aragon A. et al.Decreased kidney function among agriculture workers in El Salvador.Am J Kidney Dis. 2012; 59: 531-540Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar measured serum creatinine in presumed healthy adults aged 20-60 years in 5 communities in El Salvador: 2 were located at sea level, with sugarcane (and previously cotton) cultivation and harvesting the dominant industry, and the other 3 were located at higher altitudes, with economies based on sugarcane, coffee, and services. The prevalence of CKD, defined as estimated glomerular filtration rate 1.2 mg/dL) and women (OR, 2.3 [95% CI, 1.4-3.7] for creatinine >0.9 mg/dL) who spent 10 or more years in coastal sugarcane or cotton work compared with those who had never worked in either of those settings. To appreciate the significance of these findings, it is helpful to describe factors that have been considered as causes of the CKD epidemic. Although heavy metals, medications, diet, leptospirosis or other infections, and genetic and developmental susceptibility factors have all been proposed as possible causes, suspicion has centered mainly on factors that are disproportionately present in men, with occupational exposure to agrichemicals and consumption of alcohol in a form that, although not home distilled, was susceptible to accidental or intentional contamination during distribution and storage, receiving most of the early attention.11Sanoff S.L. Callejas L. Alonso C.D. et al.Positive association of renal insufficiency with agriculture employment and unregulated alcohol consumption in Nicaragua.Ren Fail. 2010; 32: 766-777Crossref PubMed Scopus (67) Google Scholar However, given the tropical climate and challenging working conditions in the region, investigators also have proposed heat stress as a potential mechanism.13Brooks D. Final scoping study report: epidemiology of chronic kidney disease in Nicaragua.2009http://www.cao-ombudsman.org/cases/document-links/documents/03H_BU_FINAL_report_scopestudyCRI_18.Dec.2009.pdfGoogle Scholar, 14Cuadra S.N. Jakobsson K. Hogstedt C. Wesseling C. Chronic kidney disease: assessment of current knowledge and feasibility for regional research collaboration in Central America. Vol 2. SALTRA, Work & Health Series, Heredia, Costa Rica2006http://www.saltra.info/images/articles/seriesaludytrabajo/seriesaludytrabajo2.pdfGoogle Scholar, 15Crowe J. Moya-Bonilla J.M. Roman-Solano B. Robles-Ramirez A. Heat exposure in sugarcane workers in Costa Rica during the non-harvest season.Glob Health Action. 2010 Nov 29; 3https://doi.org/10.3402/gha.v3i0.5619Crossref PubMed Google Scholar, 16Crowe J. van Wendel de Joode B. Wesseling C. A pilot field evaluation on heat stress in sugarcane workers in Costa Rica: what to do next?.Glob Health Action. 2009 Nov 11; 2https://doi.org/10.3402/gha.v2i0.2062Crossref PubMed Scopus (37) Google Scholar, 17Delgado Cortez O. Heat stress assessment among workers in a Nicaraguan sugarcane farm.Glob Health Action. 2009 Nov 11; 2https://doi.org/10.3402/gha.v2i0.2069Crossref PubMed Scopus (48) Google Scholar, 18Kjellstrom T. Crowe J. Climate change, workplace heat exposure, and occupational health and productivity in Central America.Int J Occup Environ Health. 2011; 17: 270-281Crossref PubMed Google Scholar, 19McClean M. Laws R. Ramirez Rubio O. Brooks D. Industrial hygiene/occupational health assesment: evaluating potential hazards associated with chemicals and work practices at the Ingenio San Antonio (Chichigalpa, Nicaragua).2010http://www.cao-ombudsman.org/documents/FINALIHReport-AUG302010-ENGLISH.pdfGoogle Scholar, 20Soderland 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 (163) Google Scholar Heat stress with subsequent volume depletion, if severe, can cause acute kidney injury (AKI) even in healthy adults, particularly in the presence of potential nephrotoxins, such as nonsteroidal anti-inflammatory drugs. Although it generally had been held that AKI leads to CKD only in the absence of functional recovery from the initial injury, recent evidence suggests that residual subclinical damage may increase the risk of CKD.21Venkatachalam M.A. Griffin K.A. Lan R. Geng H. Saikumar P. Bidani A.K. Acute kidney injury: a springboard for progression in chronic kidney disease.Am J Physiol Renal Physiol. 2010; 298: F1078-F1094Crossref PubMed Scopus (389) Google Scholar, 22Yang L. Humphreys B.D. Bonventre J.V. Pathophysiology of acute kidney injury to chronic kidney disease: maladaptive repair.Contrib Nephrol. 2011; 174: 149-155Crossref PubMed Scopus (104) Google Scholar, 23Coca S.G. Peixoto A.J. Garg A.X. Krumholz H.M. Parikh C.R. The prognostic importance of a small acute decrement in kidney function in hospitalized patients: a systematic review and meta-analysis.Am J Kidney Dis. 2007; 50: 712-720Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar, 24Coca SG, Singanamala S, Parikh CR. Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis [published online ahead of print November 23, 2011]. Kidney Int. doi:10.1038/ki.2011.379.Google Scholar, 25Levin A. Kellum J.A. Mehta R.L. Acute kidney injury: toward an integrated understanding through development of a research agenda.Clin J Am Soc Nephrol. 2008; 3: 862-863Crossref PubMed Scopus (24) Google Scholar Although overt AKI caused by extreme heat exhaustion and heat stroke are known to occur in the region and may explain a portion of the epidemic, it seems unlikely that such incidents could account for the majority of cases. Investigators have instead postulated that a chronic state of volume depletion leaves individuals susceptible to accumulation of damage to the kidneys from repeated subclinical insults, which eventually develops into CKD. Epidemiologic studies in the region during the last few years have provided some evidence supporting this hypothesis. With few exceptions, these investigations consist of cross-sectional studies that analyze serum creatinine and urine dipstick results in conjunction with questionnaires designed to explore associations between kidney function and putative risk factors. Despite their limitations, at least 2 consistent results have emerged. First, there are clear differences in risks of CKD according to type of industry and occupation. Workers in the sugarcane cultivation, mining, and fishing or shipping industries have higher prevalence rates, whereas areas in which coffee growing and services dominate show no evidence of excess disease.6Orantes C.M. Herrera R. Almaguer M. et al.Chronic kidney disease and associated risk factors in the Bajo Lempa region of El Salvador: nefrolempa study, 2009.MEDICC Rev. 2011; 13: 14-22PubMed Google Scholar, 9Laux TS, Bert PJ, Barreto Ruiz GM, et al. Nicaragua revisited: evidence of lower prevalence of chronic kidney disease in a high-altitude, coffee-growing village [published online ahead of print September 23, 2011]. J Nephrol. doi:10.5301/jn.5000028.Google Scholar, 10O'Donnell J.K. Tobey M. Weiner D.E. et al.Prevalence of and risk factors for chronic kidney disease in rural Nicaragua.Nephrol Dial Transplant. 2011; 26: 2798-2805Crossref PubMed Scopus (109) Google Scholar, 11Sanoff S.L. Callejas L. Alonso C.D. et al.Positive association of renal insufficiency with agriculture employment and unregulated alcohol consumption in Nicaragua.Ren Fail. 2010; 32: 766-777Crossref PubMed Scopus (67) Google Scholar, 12Torres C. Aragon A. Gonzalez 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 (166) Google Scholar Second, persons living at low altitudes are more likely to have CKD than those living at higher elevations.9Laux TS, Bert PJ, Barreto Ruiz GM, et al. Nicaragua revisited: evidence of lower prevalence of chronic kidney disease in a high-altitude, coffee-growing village [published online ahead of print September 23, 2011]. J Nephrol. doi:10.5301/jn.5000028.Google Scholar, 10O'Donnell J.K. Tobey M. Weiner D.E. et al.Prevalence of and risk factors for chronic kidney disease in rural Nicaragua.Nephrol Dial Transplant. 2011; 26: 2798-2805Crossref PubMed Scopus (109) Google Scholar, 12Torres C. Aragon A. Gonzalez 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 (166) Google Scholar These 2 findings are consistent with the hypothesis that heat stress contributes to the development of kidney disease in the region because temperatures at lower elevation are significantly higher than at higher altitudes18Kjellstrom T. Crowe J. Climate change, workplace heat exposure, and occupational health and productivity in Central America.Int J Occup Environ Health. 2011; 17: 270-281Crossref PubMed Google Scholar and the pattern of industries with high and low prevalences is more consistent with heat stress than with agrichemical exposure. However, it has been difficult to distinguish among hypotheses because the type of industry typically also varies with elevation. For example, in Nicaragua, where most studies have been conducted to date, sugarcane is grown at low altitudes while coffee is grown at higher altitudes. Therefore, it can be difficult to clearly identify whether differences in prevalence are the result of differences in temperature and work intensity or in the type of agrichemicals used in each industry. Peraza et al3Peraza S. Wesseling C. Aragon A. et al.Decreased kidney function among agriculture workers in El Salvador.Am J Kidney Dis. 2012; 59: 531-540Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar recognized this issue and took advantage of the presence of sugarcane cultivation in both low- and high-altitude settings to provide the strongest contrast to date between the agrichemical and heat stress hypotheses. Their study shows for the first time that workers involved in sugarcane cultivation have a higher prevalence of elevated serum creatinine level (and lower estimated glomerular filtration rate) if they lived and worked at low elevations, but experienced no such effects at higher elevations despite similarities in the nature and organization of work and agrichemical use. This finding strongly suggests that differences in the environment in which the work is carried out, rather than in exposure to agrichemicals, are the main factor impacting on the prevalence of elevated serum creatinine level. They also reported that individuals engaged in subsistence farming at low elevations showed no increased prevalence of higher serum creatinine levels in contrast to lowland sugarcane workers. They attribute this difference to lower exposure to heat stress because of greater control over working conditions, although this conclusion may be premature given the very small number of subsistence farmers in the study. Nevertheless, the observation is an interesting one and warrants further investigation. One possible objection to the heat stress hypothesis is the fact that people engage in strenuous work in hot climates all around the globe. However, excesses of CKD with characteristics similar to the Central American epidemic have been reported in specific regions in Sri Lanka, India, and Egypt, all of which also have very warm climates, and the possibility that the disease is occurring in yet other areas should not be ruled out.26Athuraliya N.T. Abeysekera T.D. Amerasinghe P.H. et al.Uncertain etiologies of proteinuric-chronic kidney disease in rural Sri Lanka.Kidney Int. 2009; 80: 1212-1221Crossref Scopus (154) Google Scholar, 27Athuraliya T.N. Abeysekera D.T. Amerasinghe P.H. Kumarasiri P.V. Dissanayake V. Prevalence of chronic kidney disease in two tertiary care hospitals: high proportion of cases with uncertain aetiology.Ceylon Med J. 2009; 54: 23-25Crossref PubMed Scopus (56) Google Scholar, 28Nanayakkara S, Senevirathna ST, Karunaratne U, et al. Evidence of tubular damage in the very early stage of chronic kidney disease of uncertain etiology in the North Central Province of Sri Lanka: a cross-sectional study [published online ahead of print June 28, 2011]. Environ Health Prev Med. doi:10.1007/s12199-011-0224-z.Google Scholar, 29Siva G. 'Cursed' Uddanam cries for help.The Times of India. August 10, 2009; (Accessed December 23, 2011)http://articles.timesofindia.indiatimes.com/2009-08-10/hyderabad/28181811_1_mandals-villagers-kidneyGoogle Scholar, 30Machiraju R.S. Yaradi K. Gowrishankar S. et al.Epidemiology of Udhanam endemic nephropathy.J Am Soc Nephrol. 2009; 20 ([abstract]): 643AGoogle Scholar, 31Kamel E.G. El-Minshawy O. Environmental factors incriminated in the development of end stage renal disease in El-Minia Governorate, Upper Egypt.Int J Nephrol Urol. 2010; 2: 431-437Google Scholar It is possible that individuals in regions with a CKD excess also are exposed to other nephrotoxic factor(s) present in these particular locations, which could be potentiated in a setting in which individuals have been rendered more susceptible to kidney disease due to heat stress. A third possibility is that some form of increased susceptibility is present at birth or acquired during childhood, leading to subtle kidney damage, and the effects of heat stress speed the progression to overt disease. Based on the evidence accumulated by Peraza et al3Peraza S. Wesseling C. Aragon A. et al.Decreased kidney function among agriculture workers in El Salvador.Am J Kidney Dis. 2012; 59: 531-540Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar and others, as well as the recent understanding that AKI may be associated more closely with CKD than previously believed, the possibility that repeated episodes of subclinical kidney damage in the absence of overt AKI could cause CKD seems plausible and worthy of further study. Although it remains important to continue to pursue other hypotheses concerning the cause of the excess of CKD in Central America, it is time for more rigorous studies of heat stress. These studies should specifically investigate whether there are significant differences in volume depletion and muscle damage by type of work and hydration practices outside the work setting that are correlated with subclinical kidney damage, as well as whether that damage eventually accumulates over time to cause CKD. If heat stress is shown to cause CKD, either in isolation or in combination with other factors, this knowledge would benefit not only those living in areas with a current excess of CKD, but may have far wider implications for a world that is projected to grow warmer over the next century. The authors thank Daniel E. Weiner and James S. Kaufman for review and comments on earlier drafts of the manuscript. All authors are supported through a contract with the Office of the Compliance Advisor/Ombudsman, the independent accountability mechanism for social and environmental concerns of the International Finance Corporation/Multilateral Investment Guarantee Agency, World Bank Group. Oriana Ramirez-Rubio is partially funded by the "Enrique Nájera" predoctoral grant awarded by the Spanish Society of Epidemiology and the ISCIII (Spain′s Ministry of Health) . The views expressed in this article do not necessarily represent those of the World Bank or any other body. Financial Disclosure: The authors declare that they have no other relevant financial interests. Decreased Kidney Function Among Agricultural Workers in El SalvadorAmerican Journal of Kidney DiseasesVol. 59Issue 4PreviewAn epidemic of chronic kidney disease of unknown cause has emerged along the Pacific coast of Central America, particularly in relatively young male sugarcane workers. In El Salvador, we examined residence and occupations at different altitudes as surrogate risk factors for heat stress. Full-Text PDF
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