Mesoamerican nephropathy: Difference between revisions

Mesoamerican nephropathy
Mesoamerican nephropathy
Other names	Chronic Kidney Disease of Nontraditional Causes (CKDnt), Chronic Kidney Disease of Unknown Etiology / Uncertain Cause (CKDu), Creatinina (colloquial)
Specialty	Nephrology

Browse history interactively

← Previous edit Next edit →

Content deleted Content added

VisualWikitext

Inline

Revision as of 15:02, 29 October 2021

Mesoamerican nephropathy (MeN) is an endemic, non-diabetic, non-hypertensive chronic kidney disease (CKD) characterized by reduced glomerular filtration rate (GFR) with mild or no proteinuria and no features of known primary glomerular diseases. MeN is prevalent in agricultural communities along the Pacific Ocean coastal lowlands Mesoamerica, including southern Mexico, Guatemala, El Salvador, Nicaragua, Honduras and Costa Rica.^[1]^[2] Although most cases have been described among agricultural workers, MeN has also been described in other occupations, including miners, brick manufacturers, and fishermen.^[3]^[4] A common denominator among these occupations is that they are outdoor workers who reside in rural areas in hot and humid climates.^[5]

The MeN epidemic in Central America spans along a nearly 1000 kilometer stretch of the Pacific coast. Among the countries that this span encompasses, CKD is the second leading cause of death in El Salvador and Nicaragua, third leading cause in Costa Rica, and fourth leading cause in Panama.^[6] El Salvador and Nicaragua have the highest rates of kidney disease mortality in the world; among men, the mortality rate from CKD is approximately six-fold higher in El Salvador and five-fold higher in Nicaragua than the median global rate, and 1.5-2 times higher than the rate in Libya, the third-highest country on the list.^[7] The disease has devastated many of the communities where it exists and has overwhelmed healthcare systems in affected countries, causing unknown morbidity and tens of thousands of deaths over the last 20 years in Mesoamerica alone.^[8]

MeN is generally diagnosed in men in their third to fourth decade of life, and initially presents as a progressive decline in GFR without notable proteinuria. Traditional risk factors for CKD, including hypertension and diabetes mellitus, are generally absent. Despite international research efforts, the specific causes of the disease remain unknown, creating an enormous need for research, patient care and socioeconomic interventions that can only be appropriately addressed through international and interdisciplinary collaboration.^[9]^[10]^[11]

The term Mesoamerican Nephropathy has been in use in Central America and Mexico since 2012.^[12] Similar epidemics have been identified in both Sri Lanka and India, leading to the use of other terms that are not geographically-specific, including Chronic Kidney Disease of unknown etiology (CKDu) or of non-traditional origin (CKDnt) and Chronic Interstitial Nephritis in Agricultural Communities (CINAC).^[13] Although the diseases are clinically similar and affect similar populations in each country, whether these are all manifestations of the same disease or different diseases with superficial resemblance remains to be definitively demonstrated. High prevalence of CKD with similar characteristics to MeN may exist outside of Mesoamerica, India, and Sri Lanka, although evidence so far is limited to small studies and clinician reports.

History

High incidence of kidney disease in young agricultural workers, mostly in sugarcane, was first reported in communities in Nicaragua, El Salvador and Costa Rica in the 1990s, with the first published report appearing in 2002.^[14]^[15] Early studies suggested that MeN was most prevalent in communities with a large proportion of individuals working in sugarcane and other high-intensity agriculture, as well as in non-agricultural occupations involving heavy manual labor in hot environments at sea level, and was less prevalent among subsistence farmers and in communities located at higher altitudes.^[16]^[15]^[17]^[18]

A landmark international research meeting devoted to MeN, organized primarily by the Program on Work, Environment and Health in Central America (SALTRA), occurred in 2012. This workshop also led to the creation of the Consortium on the Epidemic of Nephropathy in Central America and Mexico (CENCAM), an international group of researchers and clinicians whose mission is to increase international collaboration for the exploration and research of MeN; contribute to a reduction in the overall prevalence and impact of MeN; and raise awareness and action about MeN in Central America and Mexico.^[19] Two additional international workshops were held in 2015 and 2019, and summaries of all three workshops are available.

In April 2013, a high-level meeting with regional health ministries, nongovernmental organizations, aid agencies, clinical specialists and researchers was held in San Salvador city, El Salvador, leading the Panamerican Health Organization (PAHO) to finally declare CKDu "a pressing and extremely serious health problem in the region". The Declaration described CKD as having “catastrophic effects associated with toxic-environmental and occupational factors, dehydration and behaviors harmful to renal health". In it, the Ministers of Health of the Central American Integration System [SICA, the Spanish acronym] declared their commitment to address CKDu comprehensively and to “strengthening scientific research in the framework of the prevention and control of chronic non-communicable diseases.”^[20] This Declaration was subsequently endorsed by PAHO through the Resolution CD52.R1, adopted during the 52nd Directing Council, 65th Session of the Regional Committee of WHO for the Americas, in October 2013.^[21]

Case definition, clinical manifestations, and histopathology

A challenging feature of MeN is that, because the pathophysiology of disease remains relatively poorly understood, the case definition remains broad and likely will include many cases of undiagnosed kidney diseases that ultimately prove to be unrelated to MeN. Recent efforts to provide a case definition have focused on the following features:^[22]^[23]

Suspected disease:
- Estimated GFR (eGFR) < 60 ml/min/1.73m²
- Absence of diabetes, hypertension, autoimmune disease, glomerular disease, congenital kidney disease, obstructive kidney disease as a clear cause of kidney disease (these comorbidities may be present but cannot account for disease development)
- Residing in a hotspot region
- Proteinuria < 2g/24h or 2g/g urine creatinine
Likely disease: All of the above, plus
- eGFR < 60 ml/min/1.73m² on 3 month or longer repeat measurement
- Relative hypokalemia and/or hyperuricemia
- Kidney ultrasound with loss of corticomedullary differentiation or bilateral small kidney size, without cystic disease or large stone burden
- Kidney biopsy showing primary tubulointerstitial disease without alternative cause of kidney disease in evidence

This case definition may not be as useful for disease outside of Mesoamerica; while there are many similarities between clinical aspects of CKDu in India, Sri Lanka, and MeN in Mesoamerica, there are some important differences as well. Individuals affected in Mesoamerica are younger (aged 20-40 as opposed to 20-60 at the age of onset of CKD). Both regions demonstrate a high male-to-female ratio and significant familial concordance, but the degree of male predominance appears to be greater in Mesoamerica. Most affected individuals in both regions live in rural poverty and work in occupations involving physical labor, including agriculture, fishing, and aquaculture. Hypokalemia, hyponatremia, minimal proteinuria, and sterile pyuria are highly prevalent. Individuals in Mesoamerica often have hyperuricemia and urate crystalluria, but this is observed less frequently India or Sri Lanka, .^[24]

Kidney biopsy in individuals with MeN demonstrates some consistent features across regions. Biopsies are generally chronic glomerular and tubulointerstitial damage with glomerulosclerosis and chronic glomerular ischemia, without positive findings on immunofluorescence or definitive evidence of primary glomerular lesions.^[25]^[26]^[27] Glomerular enlargement may be observed. Ultrastructural changes evaluated with electron microscopy were mostly consistent with the light microscopic observations. Large dysmorphic lysosomes within tubular epithelial cells have been proposed as a distinctive feature but at present are not considered pathognomonic.^[28] In kidney biopsies from individuals with acute kidney injury (AKI) among high-risk patients for MeN, considered possibly a contributing stage to disease, the main findings were described as tubulointerstitial nephritis with varying degrees of acute inflammation and chronic tubulointerstitial changes.^[29]^[30] In some cases, neutrophils have been found in the tubular lumen of both chronic and acute MeN/CKDu patients, but urine cultures from these patients have been negative.

Causes

Although many factors have been proposed as the cause of MeN, most attention has focused on heat stress due to a combination of strenuous work in a hot climate with insufficient hydration.^[31]^[32] Additional postulated contributing exposures include agrochemicals, metals, and pathogens.^[33]^[34]^[35] These factors are themselves a result of global and national economic and political systems that have led to poverty and social stratification.^[36] Discovery of the causes of MeN has been complicated by the fact that there are likely multiple factors that arise from different sources of exposure and/or different times of life. Until recently, progress has also been slowed by a lack of research funding, although more support has become available as awareness of the disease and its toll on the population has increased.

A review published in the New England Journal of Medicine in 2019^[37] summarizes a proposed mechanism in which heat exposure leads to dehydration and volume depletion and/or an increase in core temperature, which may cause kidney injury directly through tissue dysfunction or indirectly through hyperosmolarity or rhabdomyolysis. Similarly, it is possible that chronic sub-clinical undetected AKI leads to eventual CKD.^[38]^[39] Another proposed mechanism is increased kidney tubular toxin uptake resulting in direct tubular toxicity, which might also be amplified by heat-associated dehydration.^[40] Genetic factors are also likely to play a role.^[41] Regardless of what mechanisms are eventually proven to be involved, researchers agree that preventive measures should include measures to ensure safe drinking water, adequate hydration, rest, and shade for workers at risk, as well as to reduce exposure to toxins.^[37] A review of the state of knowledge on potential causes and mechanisms as of 2019 can be found in a summary of the Third International Workshop on Chronic Kidney Disease of Uncertain/Non-Traditional Etiology in Mesoamerica and Other Regions on Chronic Kidney Disease of Unknown Etiology held in March 2019.

Heat stress, dehydration and disturbances in water and mineral balance.

Heat strain and dehydration is in the spotlight globally due to emerging evidence of their association with adverse renal health issues including chronic kidney disease, especially in working populations.^[31] The probability of heat stress is greater when the temperature of the environment surpasses a persons core temperature, a situation common for outdoor workers in tropical settings where temperatures can easily surpass 37°C.^[42]

Although the specific mechanism by which heat, dehydration and workload contribute to the causal pathway for MeN remains to be definitively established, the association with MeN has been shown repeatedly. Epidemiological studies in Central America have reported adverse heat stress impacts in agricultural workers, particularly those in the sugarcane industry.^[43]^[44]^[45]^[46] In addition to exposure to high temperatures, evidence exists that high sweat rates and limited fluid intake can lead to functional and sub-clinical acute kidney injuries (AKI), and that repetitive AKI may lead to the development of CKD.^[47]^[48]

A well-conducted study on the relationship between workload and incidence of kidney injury in a fieldworker cohort with different levels of physically demanding work over a sugarcane harvest in Nicaragua was published in October 2019.^[45] The results provide evidence of dose-effect as well as dose-response relations between high-heat and high workload exposure and both increased episodes of incident acute kidney injury as well as progressive decline in GFR. The role of heat stress in the etiology of MeN is further supported by intervention studies showing mitigation of kidney function decline with efforts to improve rest, hydration, and access to shade among high-risk agricultural workers.^[49]^[50]^[51] Finally, there is evidence from animal models suggesting a potential mechanism or mechanisms for how heat stress may drive development of MeN.^[52]^[53]^[54]

Agrochemicals

Agrochemicals and pesticides have been frequently been proposed as a potential cause or contributor to the development of MeN,^[55]^[56]^[57]^[58] although the epidemiological and pathophysiologic evidence is somewhat limited and contradictory.^[45]^[59]^[60] The main limitations of both positive and negative studies remain poor specificity and quantification of pesticide exposure, as well as the cross-sectional nature of most studies and issues with confounding and selection bias. No study has directly investigated interactions between pesticides and other concomitant exposures in agricultural occupations, in particular heat stress and dehydration. Thus, existing studies provide scarce evidence for an association between pesticides and regional MeN epidemics, but a role of nephrotoxic agrochemicals nevertheless should not be conclusively discarded.

Exposure to metals

Exposure to metals such as cadmium, lead, nickel, and mercury has also been proposed as a cause or contributor to MeN,^[61]^[62] again with limited and contradictory evidence. A number of well conducted studies have shown no association with the development of MeN,^[63]^[60] although a recent study did show an association with nickel exposure.^[64] There may be regional variation with respect to the role of heavy metals, which appear unlikely to be an important contributor in Mesoamerica but which remain under more active investigation in India and Sri Lanka.

Alcohol and self-medication

Alcohol consumption, including consumption of home-brewed alcohol, as well as self-medication with NSAIDs and other nephrotoxic medications occurs in populations affected by MeN. To what extent such exposures contribute to the epidemic of MeN is not known, as evidence is again contradictory. Some studies have described an association between NSAID use^[43]^[65] or consumption of a home-brewed alcohol called "lija"^[66]^[67] and MeN, whereas others have found limited evidence that either is an important risk factor.^[59]

Infectious causes

The high density of infectious disease vectors and reservoirs, in the context of limited access to clean water, limited resources for detecting and controlling infectious disease outbreaks, and the continued emergence of new pathogens and pathogen variants, is an important consideration when addressing kidney health in tropical and low-resource settings. The presence of these factors in MeN burdened regions lend credence to the hypothesis of an infectious etiology, and there is some evidence in support of infection as a risk factor.^[68]^[69] However, other published studies investigating infectious agents as a causal factor in MeN have been negative.^[70] There may again exist regional variation between Mesoamerica and India / Sri Lanka with respect to the role of infectious causes in CKD development.

Summary of current scientific evidence

To date, CKDu (MeN) causes remain undetermined and debatable; nevertheless the number of cases could lead to the application of a precautionary principles from a humanitarian perspective. Due to the fact that the Mesoamerican nephropathy is regarded as a multifactorial disease the experimental design of comparative study should take following logical setting into account. Multifactorial problem. Assume that a disease is definitely caused by A, B, C and this example has no irrelevant risk factor for the disease. The disease will develop if at least 2 risk factors are present in a certain region.^{[citation needed]}

$\emptyset$ no prevalence of disease in region 1
A no prevalence of disease in region 2
B no prevalence of disease in region 3
C no prevalence of disease in region 4
A, B prevalence of disease in region 5
B, C prevalence of disease in region 6
C, A prevalence of disease in region 7
A, B, C prevalence of disease in region 8

Removing the risk factor A in the experimental group in comparison to control group will lead to changes in the outbreak of the disease in only 2 of 8 combinatorically possible regions, even if we define A as a relevant risk factor in this theoretical setting. The same is true if the experimental design adds in a comparative study the risk factor A to the regions in the experimental group in comparison to the control group. Because of the nature of a multifactorial disease, a single factor experimental design (e.g. "C") for one of the mentioned risk factors A, B and C will create a systematic underestimation of the risk for a single risk factor (e.g. "C") in this deterministic setting with relevant risk factors A, B and C only. Therefore the exclusion of a risk factor (e.g. "C") by not finding the evidence in the single factor experimental design cannot be performed even in a non-deterministic setting with uncertainties and irrelevant risk factors for the considered disease.^{[citation needed]}

If the difference in experimental and control are 2 risk factors (adding or removing two risk factor e.g. A, B in the control group), then 4 regions will show a differences in prevalence of the disease, with the disadvantage that the experimental design cannot clarify if one or both risk factors A and B are contributing to the progression and prevalence of the disease. The precautionary principles could lead to risk mitigation strategies for risk factor A and B until the etiology is clarified.^{[citation needed]}

Beside this logical analysis of a multifactorial setting there is space for further investigation, e.g.: Leptospirosis has been suggested as a possible contributing factor^[71]^[72]^[73] and oceanic nephrotoxic algae.

Risk factors associated with agents need evidence for the nephrotoxicity of the agent and evidence for the exposure assessment of a cohort to the risk factor. Assessment of the mentioned risk factors and their possible synergism will depend on more and better research.^{[citation needed]}

Prognosis, treatment and prevention

Evidence regarding the prognosis when MeN remains limited. One study suggests that there is substantial variety in progression of disease, with some individuals having slow or no further decline in kidney function following diagnosis, while others rapidly progress to end stage kidney disease (ESKD).^[74]

To date, there are no standard guidelines for the management of MeN patients, and treatment strategies employed by health care providers vary widely. Based on clinical consensus from the most recent CENCAM meeting, no specific treatment exists beyond improving access to shade, hydration, and rest among individuals engaging in work that places them at risk for heat stress, as well as emphasizing access to clean air and water and avoidance of nephrotoxic substances.^[75] Care of advanced CKD due to MeN should likely be similar to that employed in advanced CKD of other causes. There are anecdotal reports of response to allopurinol (in response to elevated uric acid levels), corticosteroids (in response to acute tubulointerstitial nephritis on kidney biopsy), and use of angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), but the consensus is that there is insufficient evidence to support any of these therapies at present.^[75]

References

^ Correa-Rotter, Ricardo; Wesseling, Catharina; Johnson, Richard J. (2014-03). "CKD of unknown origin in Central America: the case for a Mesoamerican nephropathy". American Journal of Kidney Diseases: The Official Journal of the National Kidney Foundation. 63 (3): 506–520. doi:10.1053/j.ajkd.2013.10.062. ISSN 1523-6838. PMC 7115712. PMID 24412050. {{cite journal}}: Check date values in: |date= (help)
^ Landau, Elizabeth (June 11, 2014). "Mysterious kidney disease plagues Central America". CNN. Retrieved 13 June 2014.
^ Torres, Cecilia; Aragón, Aurora; González, Marvin; López, Indiana; Jakobsson, Kristina; Elinder, Carl-Gustaf; Lundberg, Ingvar; Wesseling, Catharina (2010-03). "Decreased Kidney Function of Unknown Cause in Nicaragua: A Community-Based Survey". American Journal of Kidney Diseases. 55 (3): 485–496. doi:10.1053/j.ajkd.2009.12.012. ISSN 0272-6386. {{cite journal}}: Check date values in: |date= (help)
^ Gallo-Ruiz, Lyanne; Sennett, Caryn M.; Sánchez-Delgado, Mauricio; García-Urbina, Ana; Gámez-Altamirano, Tania; Basra, Komal; Laws, Rebecca L.; Amador, Juan José; Lopez-Pilarte, Damaris; Tripodis, Yorghos; Brooks, Daniel R. (2019-08). "Prevalence and Risk Factors for CKD Among Brickmaking Workers in La Paz Centro, Nicaragua". American Journal of Kidney Diseases: The Official Journal of the National Kidney Foundation. 74 (2): 239–247. doi:10.1053/j.ajkd.2019.01.017. ISSN 1523-6838. PMID 30826087. {{cite journal}}: Check date values in: |date= (help)
^ Wesseling, Catharina; Glaser, Jason; Rodríguez-Guzmán, Julieta; Weiss, Ilana; Lucas, Rebekah; Peraza, Sandra; da Silva, Agnes Soares; Hansson, Erik; Johnson, Richard J.; Hogstedt, Christer; Wegman, David H. (2020). "Chronic kidney disease of non-traditional origin in Mesoamerica: a disease primarily driven by occupational heat stress". Revista Panamericana De Salud Publica = Pan American Journal of Public Health. 44: e15. doi:10.26633/RPSP.2020.15. ISSN 1680-5348. PMC 6984407. PMID 31998376.
^ "Institute for Health Metrics and Evaluation". Retrieved 2.22.2021. {{cite web}}: Check date values in: |access-date= (help)CS1 maint: url-status (link)
^ "World Life Expectancy". Retrieved 2.22.2021. {{cite web}}: Check date values in: |access-date= (help)CS1 maint: url-status (link)
^ Ordunez, Pedro; Nieto, F Javier; Martinez, Ramon; Soliz, Patricia; Giraldo, Gloria P; Mott, Susan Anne; Hoy, Wendy E (2018-02-02). "Chronic kidney disease mortality trends in selected Central America countries, 1997–2013: clues to an epidemic of chronic interstitial nephritis of agricultural communities". Journal of Epidemiology and Community Health. 72 (4): 280–286. doi:10.1136/jech-2017-210023. ISSN 0143-005X.
^ Ramirez-Rubio, Oriana; McClean, Michael D.; Amador, Juan José; Brooks, Daniel R. (2013-01). "An epidemic of chronic kidney disease in Central America: an overview". Journal of Epidemiology and Community Health. 67 (1): 1–3. doi:10.1136/jech-2012-201141. ISSN 1470-2738. PMID 23002432. {{cite journal}}: Check date values in: |date= (help)
^ Johnson, Richard J.; Wesseling, Catharina; Newman, Lee S. (2019-05-09). "Chronic Kidney Disease of Unknown Cause in Agricultural Communities". New England Journal of Medicine. 380 (19): 1843–1852. doi:10.1056/nejmra1813869. ISSN 0028-4793.
^ Crowe, J., Joubert, B. R., & Brooks, D. R. (2020). Report from the Third International Workshop on Chronic Kidney Disease of Uncertain/Non-Traditional Etiology in Mesoamerica and Other Regions. Heredia: SALTRA-IRET, Universidad Nacional, Costa Rica.
^ Wesseling, Catharina; Crowe, Jennifer; Hogstedt, Christer; Jakobsson, Kristina; Lucas, Rebekah; Wegman, David H. (2013-11). "The epidemic of chronic kidney disease of unknown etiology in Mesoamerica: a call for interdisciplinary research and action". American Journal of Public Health. 103 (11): 1927–1930. doi:10.2105/AJPH.2013.301594. ISSN 1541-0048. PMC 3828726. PMID 24028232. {{cite journal}}: Check date values in: |date= (help)
^ Jayasumana, Channa; Orantes, Carlos; Herrera, Raul; Almaguer, Miguel; Lopez, Laura; Silva, Luis Carlos; Ordunez, Pedro; Siribaddana, Sisira; Gunatilake, Sarath; De Broe, Marc E. (2016-10-13). "Chronic interstitial nephritis in agricultural communities: a worldwide epidemic with social, occupational and environmental determinants". Nephrology Dialysis Transplantation: gfw346. doi:10.1093/ndt/gfw346. ISSN 0931-0509.
^ Cuadra SN, Jakobsson K, Hogstedt C, Wesseling C. Enfermedad renal crónica: Evaluación del conocimiento actual y la viabilidad para la colaboración de su investigación a nivel regional en América Central [Chronic Kidney Disease: Assessment of current knowledge and feasibility for regional research collab. Instituto Regional de Estudios en Sustancias Tóxicas (IRET-UNA), Serie Salud y Trabajo, No. 2; 2006. 76 p.
^ ^a ^b Trabanino, Ramón García; Aguilar, Raúl; Silva, Carlos Reyes; Mercado, Manuel Ortiz; Merino, Ricardo Leiva (2002-09). "[End-stage renal disease among patients in a referral hospital in El Salvador]". Revista Panamericana De Salud Publica = Pan American Journal of Public Health. 12 (3): 202–206. doi:10.1590/s1020-49892002000900009. ISSN 1020-4989. PMID 12396639. {{cite journal}}: Check date values in: |date= (help)
^ Torres, Cecilia; Aragón, Aurora; González, Marvin; López, Indiana; Jakobsson, Kristina; Elinder, Carl-Gustaf; Lundberg, Ingvar; Wesseling, Catharina (2010-03). "Decreased Kidney Function of Unknown Cause in Nicaragua: A Community-Based Survey". American Journal of Kidney Diseases. 55 (3): 485–496. doi:10.1053/j.ajkd.2009.12.012. ISSN 0272-6386. {{cite journal}}: Check date values in: |date= (help)
^ Peraza, Sandra; Wesseling, Catharina; Aragon, Aurora; Leiva, Ricardo; García-Trabanino, Ramón Antonio; Torres, Cecilia; Jakobsson, Kristina; Elinder, Carl Gustaf; Hogstedt, Christer (2012-04). "Decreased kidney function among agricultural workers in El Salvador". American Journal of Kidney Diseases: The Official Journal of the National Kidney Foundation. 59 (4): 531–540. doi:10.1053/j.ajkd.2011.11.039. ISSN 1523-6838. PMID 22300650. {{cite journal}}: Check date values in: |date= (help)
^ Sanoff, Scott L.; Callejas, Luis; Alonso, Carlos D.; Hu, Yichun; Colindres, Romulo E.; Chin, Hyunsook; Morgan, Douglas R.; Hogan, Susan L. (2010). "Positive association of renal insufficiency with agriculture employment and unregulated alcohol consumption in Nicaragua". Renal Failure. 32 (7): 766–777. doi:10.3109/0886022X.2010.494333. ISSN 1525-6049. PMC 3699859. PMID 20662688.
^ "CENCAM". Retrieved 10/26/2021. {{cite web}}: Check date values in: |access-date= (help)CS1 maint: url-status (link)
^ Declaración de San Salvador. Abordaje integral de la enfermedad renal túbulo-intersticial crónica de Centroamérica (ERTCC) que afecta predominantemente a las comunidades agrícolas. Available in: "Archived copy" (PDF). Archived from the original (PDF) on 2013-09-19. Retrieved 2014-04-04.{{cite web}}: CS1 maint: archived copy as title (link) Accessed March 2, 2014.
^ Pan American Health Organization. Resolution CD52.R1. Chronic kidney disease in agricultural communities in Central America. Washington, DC. 2013. Available at: http://www.paho.org/hq/index.php?option=com_content&view=article&id=8833&Itemid=40033&lang=en Accessed June 13, 2013
^ Mendley, Susan R.; Levin, Adeera; Correa-Rotter, Ricardo; Joubert, Bonnie R.; Whelan, Elizabeth A.; Curwin, Brian; Koritzinsky, Erik H.; Gaughan, Denise M.; Kimmel, Paul L.; Anand, Shuchi; Ordunez, Pedro (2019-11). "Chronic kidney diseases in agricultural communities: report from a workshop". Kidney International. 96 (5): 1071–1076. doi:10.1016/j.kint.2019.06.024. ISSN 1523-1755. PMC 7012362. PMID 31563333. {{cite journal}}: Check date values in: |date= (help)
^ Polo, Vicente Sanchez; Garcia-Trabanino, Ramon; Rodriguez, Guillermo; Madero, Magdalena (2020-10-22). "Mesoamerican Nephropathy (MeN): What We Know so Far". International Journal of Nephrology and Renovascular Disease. 13: 261–272. doi:10.2147/IJNRD.S270709. PMC 7588276. PMID 33116757.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
^ Raines NH, Hidalgo G, Herath CA, et al (2020). Clinical considerations surrounding Chronic Kidney Disease of Undetermined Etiology (CKDu). In Crowe J.L., Joubert B.R., Brooks. D.R. (Eds.). Report From the Third International Workshop on Chronic Kidney Diseases of Uncertain/Non-Traditional Etiology in Mesoamerica and Other Regions. Heredia, Costa Rica: SALTRA.
^ Wijkström, Julia; González-Quiroz, Marvin; Hernandez, Mario; Trujillo, Zulma; Hultenby, Kjell; Ring, Anneli; Söderberg, Magnus; Aragón, Aurora; Elinder, Carl-Gustaf; Wernerson, Annika (2017-05). "Renal Morphology, Clinical Findings, and Progression Rate in Mesoamerican Nephropathy". American Journal of Kidney Diseases. 69 (5): 626–636. doi:10.1053/j.ajkd.2016.10.036. ISSN 0272-6386. {{cite journal}}: Check date values in: |date= (help)
^ Nanayakkara, Shanika; Komiya, Toshiyuki; Ratnatunga, Neelakanthi; Senevirathna, S. T. M. L. D.; Harada, Kouji H.; Hitomi, Toshiaki; Gobe, Glenda; Muso, Eri; Abeysekera, Tilak; Koizumi, Akio (2012-05). "Tubulointerstitial damage as the major pathological lesion in endemic chronic kidney disease among farmers in North Central Province of Sri Lanka". Environmental Health and Preventive Medicine. 17 (3): 213–221. doi:10.1007/s12199-011-0243-9. ISSN 1347-4715. PMC 3348245. PMID 21993948. {{cite journal}}: Check date values in: |date= (help)
^ Wijkström, Julia; Jayasumana, Channa; Dassanayake, Rajeewa; Priyawardane, Nalin; Godakanda, Nimali; Siribaddana, Sisira; Ring, Anneli; Hultenby, Kjell; Söderberg, Magnus; Elinder, Carl-Gustaf; Wernerson, Annika (2018-03-07). "Morphological and clinical findings in Sri Lankan patients with chronic kidney disease of unknown cause (CKDu): Similarities and differences with Mesoamerican Nephropathy". PLOS ONE. 13 (3): e0193056. doi:10.1371/journal.pone.0193056. ISSN 1932-6203. PMC 5841753. PMID 29513702.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
^ Vervaet, Benjamin A.; Nast, Cynthia C.; Jayasumana, Channa; Schreurs, Gerd; Roels, Frank; Herath, Chula; Kojc, Nika; Samaee, Vahid; Rodrigo, Sonali; Gowrishankar, Swarnalata; Mousson, Christiane (2020-02). "Chronic interstitial nephritis in agricultural communities is a toxin-induced proximal tubular nephropathy". Kidney International. 97 (2): 350–369. doi:10.1016/j.kint.2019.11.009. ISSN 1523-1755. PMID 31892415. {{cite journal}}: Check date values in: |date= (help)
^ Fischer, Rebecca S. B.; Vangala, Chandan; Truong, Luan; Mandayam, Sreedhar; Chavarria, Denis; Granera Llanes, Orlando M.; Fonseca Laguna, Marcos U.; Guerra Baez, Alvaro; Garcia, Felix; García-Trabanino, Ramón; Murray, Kristy O. (2018-03). "Early detection of acute tubulointerstitial nephritis in the genesis of Mesoamerican nephropathy". Kidney International. 93 (3): 681–690. doi:10.1016/j.kint.2017.09.012. ISSN 1523-1755. PMID 29162294. {{cite journal}}: Check date values in: |date= (help)
^ Gunawardena, Sameera; Dayaratne, Maleesha; Wijesinghe, Harshima; Wijewickrama, Eranga (2021-04). "A Systematic Review of Renal Pathology in Chronic Kidney Disease of Uncertain Etiology". Kidney International Reports. doi:10.1016/j.ekir.2021.03.898. ISSN 2468-0249. PMC 8207327. PMID 34169213. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
^ ^a ^b Wesseling, Catharina; Glaser, Jason; Rodríguez-Guzmán, Julieta; Weiss, Ilana; Lucas, Rebekah; Peraza, Sandra; da Silva, Agnes Soares; Hansson, Erik; Johnson, Richard J.; Hogstedt, Christer; Wegman, David H. (2020). "Chronic kidney disease of non-traditional origin in Mesoamerica: a disease primarily driven by occupational heat stress". Revista Panamericana De Salud Publica = Pan American Journal of Public Health. 44: e15. doi:10.26633/RPSP.2020.15. ISSN 1680-5348. PMC 6984407. PMID 31998376.
^ Brooks DR, Ramirez-Rubio O, Amador JJ (April 2012). "CKD in Central America: a hot issue". Am J Kidney Dis. 59 (4): 481–84. doi:10.1053/j.ajkd.2012.01.005. PMID 22444491.
^ Valcke, Mathieu; Levasseur, Marie-Eve; Soares da Silva, Agnes; Wesseling, Catharina (2017-12). "Pesticide exposures and chronic kidney disease of unknown etiology: an epidemiologic review". Environmental Health. 16 (1): 49. doi:10.1186/s12940-017-0254-0. ISSN 1476-069X. {{cite journal}}: Check date values in: |date= (help)CS1 maint: unflagged free DOI (link)
^ Smpokou, Evangelia-Theano; González-Quiroz, Marvin; Martins, Carla; Alvito, Paula; Le Blond, Jennifer; Glaser, Jason; Aragón, Aurora; Wesseling, Catharina; Nitsch, Dorothea; Pearce, Neil; Norman, Jill (2019-12). "Environmental exposures in young adults with declining kidney function in a population at risk of Mesoamerican nephropathy". Occupational and Environmental Medicine. 76 (12): 920–926. doi:10.1136/oemed-2019-105772. ISSN 1351-0711. {{cite journal}}: Check date values in: |date= (help)
^ Yang, Chih-Wei (2018). "Leptospirosis Renal Disease: Emerging Culprit of Chronic Kidney Disease Unknown Etiology". Nephron. 138 (2): 129–136. doi:10.1159/000480691. ISSN 2235-3186. PMID 28926845.
^ Herrera, Raúl; Orantes, Carlos M.; Almaguer, Miguel; Alfonso, Pedro; Bayarre, Héctor D.; Leiva, Irma M.; Smith, Magaly J.; Cubias, Ricardo A.; Torres, Carlos G.; Almendárez, Walter O.; Cubias, Francisco R. (2014-04). "Clinical characteristics of chronic kidney disease of nontraditional causes in Salvadoran farming communities". MEDICC review. 16 (2): 39–48. doi:10.37757/MR2014.V16.N2.7. ISSN 1527-3172. PMID 24878648. {{cite journal}}: Check date values in: |date= (help)
^ ^a ^b Johnson, Richard J.; Wesseling, Catharina; Newman, Lee S. (2019-05-09). "Chronic Kidney Disease of Unknown Cause in Agricultural Communities". New England Journal of Medicine. 380 (19): 1843–1852. doi:10.1056/nejmra1813869. ISSN 0028-4793.
^ Kupferman, Joseph; Ramírez-Rubio, Oriana; Amador, Juan José; López-Pilarte, Damaris; Wilker, Elissa H.; Laws, Rebecca L.; Sennett, Caryn; Robles, Ninoska Violeta; Lau, Jorge Luis; Salinas, Alejandro José; Kaufman, James S. (2018-10). "Acute Kidney Injury in Sugarcane Workers at Risk for Mesoamerican Nephropathy". American Journal of Kidney Diseases: The Official Journal of the National Kidney Foundation. 72 (4): 475–482. doi:10.1053/j.ajkd.2018.04.014. ISSN 1523-6838. PMID 30042041. {{cite journal}}: Check date values in: |date= (help)
^ Fischer, Rebecca S. B.; Mandayam, Sreedhar; Chavarria, Denis; Vangala, Chandan; Nolan, Melissa S.; Garcia, Linda L.; Palma, Lesbia; Garcia, Felix; García-Trabanino, Ramón; Murray, Kristy O. (2017-10). "Clinical Evidence of Acute Mesoamerican Nephropathy". The American Journal of Tropical Medicine and Hygiene. 97 (4): 1247–1256. doi:10.4269/ajtmh.17-0260. ISSN 1476-1645. PMC 5637619. PMID 28722618. {{cite journal}}: Check date values in: |date= (help)
^ Jayasumana, Channa; Orantes, Carlos; Herrera, Raul; Almaguer, Miguel; Lopez, Laura; Silva, Luis Carlos; Ordunez, Pedro; Siribaddana, Sisira; Gunatilake, Sarath; De Broe, Marc E. (2016-10-13). "Chronic interstitial nephritis in agricultural communities: a worldwide epidemic with social, occupational and environmental determinants". Nephrology Dialysis Transplantation: gfw346. doi:10.1093/ndt/gfw346. ISSN 0931-0509.
^ Friedman, David J. (2019-01). "Genes and environment in chronic kidney disease hotspots". Current Opinion in Nephrology and Hypertension. 28 (1): 87–96. doi:10.1097/MNH.0000000000000470. ISSN 1473-6543. PMC 6763202. PMID 30451737. {{cite journal}}: Check date values in: |date= (help)
^ Crowe, Jennifer; Wesseling, Catharina; Solano, Bryan Román; Umaña, Manfred Pinto; Ramírez, Andrés Robles; Kjellstrom, Tord; Morales, David; Nilsson, Maria (2013-06-17). "Heat exposure in sugarcane harvesters in Costa Rica". American Journal of Industrial Medicine. 56 (10): 1157–1164. doi:10.1002/ajim.22204. ISSN 0271-3586.
^ ^a ^b Peraza, Sandra; Wesseling, Catharina; Aragon, Aurora; Leiva, Ricardo; García-Trabanino, Ramón Antonio; Torres, Cecilia; Jakobsson, Kristina; Elinder, Carl Gustaf; Hogstedt, Christer (2012-04). "Decreased kidney function among agricultural workers in El Salvador". American Journal of Kidney Diseases: The Official Journal of the National Kidney Foundation. 59 (4): 531–540. doi:10.1053/j.ajkd.2011.11.039. ISSN 1523-6838. PMID 22300650. {{cite journal}}: Check date values in: |date= (help)
^ Raines, Nathan; González, Marvin; Wyatt, Christina; Kurzrok, Mark; Pool, Christopher; Lemma, Tiziana; Weiss, Ilana; Marín, Carlos; Prado, Valerio; Marcas, Eugenia; Mayorga, Karina (2014-04). "Risk factors for reduced glomerular filtration rate in a Nicaraguan community affected by Mesoamerican nephropathy". MEDICC review. 16 (2): 16–22. doi:10.37757/MR2014.V16.N2.4. ISSN 1527-3172. PMID 24878645. {{cite journal}}: Check date values in: |date= (help)
^ ^a ^b ^c Hansson, Erik; Glaser, Jason; Weiss, Ilana; Ekström, Ulf; Apelqvist, Jenny; Hogstedt, Christer; Peraza, Sandra; Lucas, Rebekah; Jakobsson, Kristina; Wesseling, Catharina; Wegman, David H. (2019-11). "Workload and cross-harvest kidney injury in a Nicaraguan sugarcane worker cohort". Occupational and Environmental Medicine. 76 (11): 818–826. doi:10.1136/oemed-2019-105986. ISSN 1470-7926. PMC 6839725. PMID 31611303. {{cite journal}}: Check date values in: |date= (help)
^ Sorensen, Cecilia J.; Butler-Dawson, Jaime; Dally, Miranda; Krisher, Lyndsay; Griffin, Benjamin R.; Johnson, Richard J.; Lemery, Jay; Asensio, Claudia; Tenney, Liliana; Newman, Lee S. (2019-03). "Risk Factors and Mechanisms Underlying Cross-Shift Decline in Kidney Function in Guatemalan Sugarcane Workers". Journal of Occupational and Environmental Medicine. 61 (3): 239–250. doi:10.1097/JOM.0000000000001529. ISSN 1536-5948. PMC 6416034. PMID 30575695. {{cite journal}}: Check date values in: |date= (help)
^ García-Trabanino, Ramón; Jarquín, Emmanuel; Wesseling, Catharina; Johnson, Richard J.; González-Quiroz, Marvin; Weiss, Ilana; Glaser, Jason; José Vindell, Juan; Stockfelt, Leo; Roncal, Carlos; Harra, Tamara (2015-10). "Heat stress, dehydration, and kidney function in sugarcane cutters in El Salvador--A cross-shift study of workers at risk of Mesoamerican nephropathy". Environmental Research. 142: 746–755. doi:10.1016/j.envres.2015.07.007. ISSN 1096-0953. PMID 26209462. {{cite journal}}: Check date values in: |date= (help)
^ Wesseling, Catharina; Aragón, Aurora; González, Marvin; Weiss, Ilana; Glaser, Jason; Bobadilla, Norma A.; Roncal-Jiménez, Carlos; Correa-Rotter, Ricardo; Johnson, Richard J.; Barregard, Lars (2016-05). "Kidney function in sugarcane cutters in Nicaragua--A longitudinal study of workers at risk of Mesoamerican nephropathy". Environmental Research. 147: 125–132. doi:10.1016/j.envres.2016.02.002. ISSN 1096-0953. PMID 26866450. {{cite journal}}: Check date values in: |date= (help)
^ Wegman, David H.; Apelqvist, Jenny; Bottai, Matteo; Ekström, Ulf; García-Trabanino, Ramón; Glaser, Jason; Hogstedt, Christer; Jakobsson, Kristina; Jarquín, Emmanuel; Lucas, Rebekah A. I.; Weiss, Ilana (2018-01-01). "Intervention to diminish dehydration and kidney damage among sugarcane workers". Scandinavian Journal of Work, Environment & Health. 44 (1): 16–24. doi:10.5271/sjweh.3659. ISSN 1795-990X. PMID 28691728.
^ Glaser, Jason; Hansson, Erik; Weiss, Ilana; Wesseling, Catharina; Jakobsson, Kristina; Ekström, Ulf; Apelqvist, Jenny; Lucas, Rebekah; Arias Monge, Esteban; Peraza, Sandra; Hogstedt, Christer (2020-08). "Preventing kidney injury among sugarcane workers: promising evidence from enhanced workplace interventions". Occupational and Environmental Medicine. 77 (8): 527–534. doi:10.1136/oemed-2020-106406. ISSN 1470-7926. PMC 7402461. PMID 32404530. {{cite journal}}: Check date values in: |date= (help)
^ Sorensen, Cecilia J.; Krisher, Lyndsay; Butler-Dawson, Jaime; Dally, Miranda; Dexter, Lynn; Asensio, Claudia; Cruz, Alex; Newman, Lee S. (2020-11-18). "Workplace Screening Identifies Clinically Significant and Potentially Reversible Kidney Injury in Heat-Exposed Sugarcane Workers". International Journal of Environmental Research and Public Health. 17 (22): E8552. doi:10.3390/ijerph17228552. ISSN 1660-4601. PMC 7698805. PMID 33218070.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ Roncal Jimenez, Carlos A.; Ishimoto, Takuji; Lanaspa, Miguel A.; Rivard, Christopher J.; Nakagawa, Takahiko; Ejaz, A. Ahsan; Cicerchi, Christina; Inaba, Shinichiro; Le, MyPhuong; Miyazaki, Makoto; Glaser, Jason (2014-08). "Fructokinase activity mediates dehydration-induced renal injury". Kidney International. 86 (2): 294–302. doi:10.1038/ki.2013.492. ISSN 1523-1755. PMC 4120672. PMID 24336030. {{cite journal}}: Check date values in: |date= (help)
^ Roncal-Jimenez, Carlos A.; Milagres, Tamara; Andres-Hernando, Ana; Kuwabara, Masanari; Jensen, Thomas; Song, Zhilin; Bjornstad, Petter; Garcia, Gabriela E.; Sato, Yuka; Sanchez-Lozada, Laura G.; Lanaspa, Miguel A. (2017-03-01). "Effects of exogenous desmopressin on a model of heat stress nephropathy in mice". American Journal of Physiology. Renal Physiology. 312 (3): F418–F426. doi:10.1152/ajprenal.00495.2016. ISSN 1522-1466. PMC 5374310. PMID 28003190.
^ Sato, Yuka; Roncal-Jimenez, Carlos A.; Andres-Hernando, Ana; Jensen, Thomas; Tolan, Dean R.; Sanchez-Lozada, Laura G.; Newman, Lee S.; Butler-Dawson, Jaime; Sorensen, Cecilia; Glaser, Jason; Miyazaki, Makoto (2019-11-01). "Increase of core temperature affected the progression of kidney injury by repeated heat stress exposure". American Journal of Physiology. Renal Physiology. 317 (5): F1111–F1121. doi:10.1152/ajprenal.00259.2019. ISSN 1522-1466. PMC 6879947. PMID 31390229.
^ Orantes, Carlos M.; Herrera, Raúl; Almaguer, Miguel; Brizuela, Elsy G.; Núñez, Lilian; Alvarado, Nelly P.; Fuentes, E. Jackeline; Bayarre, Héctor D.; Amaya, Juan Carlos; Calero, Denis J.; Vela, Xavier F. (2014-04). "Epidemiology of chronic kidney disease in adults of Salvadoran agricultural communities". MEDICC review. 16 (2): 23–30. doi:10.37757/MR2014.V16.N2.5. ISSN 1527-3172. PMID 24878646. {{cite journal}}: Check date values in: |date= (help)
^ Vela, Xavier F.; Henríquez, David O.; Zelaya, Susana M.; Granados, Delmy V.; Hernández, Marcelo X.; Orantes, Carlos M. (2014-04). "Chronic kidney disease and associated risk factors in two Salvadoran farming communities, 2012". MEDICC review. 16 (2): 55–60. doi:10.37757/MR2014.V16.N2.9. ISSN 1527-3172. PMID 24878650. {{cite journal}}: Check date values in: |date= (help)
^ Chapman, Evelina; Haby, Michelle M.; Illanes, Eduardo; Sanchez-Viamonte, Julian; Elias, Vanessa; Reveiz, Ludovic (2019). "Risk factors for chronic kidney disease of non-traditional causes: a systematic review". Revista Panamericana De Salud Publica = Pan American Journal of Public Health. 43: e35. doi:10.26633/RPSP.2019.35. ISSN 1680-5348. PMC 6461065. PMID 31093259.
^ Vervaet, Benjamin A.; Nast, Cynthia C.; Jayasumana, Channa; Schreurs, Gerd; Roels, Frank; Herath, Chula; Kojc, Nika; Samaee, Vahid; Rodrigo, Sonali; Gowrishankar, Swarnalata; Mousson, Christiane (2020-02). "Chronic interstitial nephritis in agricultural communities is a toxin-induced proximal tubular nephropathy". Kidney International. 97 (2): 350–369. doi:10.1016/j.kint.2019.11.009. ISSN 1523-1755. PMID 31892415. {{cite journal}}: Check date values in: |date= (help)
^ ^a ^b González-Quiroz, Marvin; Pearce, Neil; Caplin, Ben; Nitsch, Dorothea (2018-08). "What do epidemiological studies tell us about chronic kidney disease of undetermined cause in Meso-America? A systematic review and meta-analysis". Clinical Kidney Journal. 11 (4): 496–506. doi:10.1093/ckj/sfx136. ISSN 2048-8505. PMC 6070103. PMID 30094014. {{cite journal}}: Check date values in: |date= (help)
^ ^a ^b Smpokou, Evangelia-Theano; González-Quiroz, Marvin; Martins, Carla; Alvito, Paula; Le Blond, Jennifer; Glaser, Jason; Aragón, Aurora; Wesseling, Catharina; Nitsch, Dorothea; Pearce, Neil; Norman, Jill (2019-12). "Environmental exposures in young adults with declining kidney function in a population at risk of Mesoamerican nephropathy". Occupational and Environmental Medicine. 76 (12): 920–926. doi:10.1136/oemed-2019-105772. ISSN 1470-7926. PMID 31562235. {{cite journal}}: Check date values in: |date= (help)
^ Lunyera, Joseph; Mohottige, Dinushika; Von Isenburg, Megan; Jeuland, Marc; Patel, Uptal D.; Stanifer, John W. (2016-03-07). "CKD of Uncertain Etiology: A Systematic Review". Clinical journal of the American Society of Nephrology: CJASN. 11 (3): 379–385. doi:10.2215/CJN.07500715. ISSN 1555-905X. PMC 4791820. PMID 26712810.
^ Kulathunga, M. R. D. L.; Ayanka Wijayawardena, M. A.; Naidu, Ravi; Wijeratne, A. W. (2019-02-27). "Chronic kidney disease of unknown aetiology in Sri Lanka and the exposure to environmental chemicals: a review of literature". Environmental Geochemistry and Health. 41 (5): 2329–2338. doi:10.1007/s10653-019-00264-z. ISSN 0269-4042.
^ Nanayakkara, Shanika; Senevirathna, STMLD; Abeysekera, Tilak; Chandrajith, Rohana; Ratnatunga, Neelakanthi; Gunarathne, EDL; Yan, Junxia; Hitomi, Toshiaki; Muso, Eri; Komiya, Toshiyuki; Harada, Kouji H. (2014-01). "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". Journal of Occupational Health. 56 (1): 28–38. doi:10.1539/joh.13-0172-oa. ISSN 1341-9145. {{cite journal}}: Check date values in: |date= (help)
^ Fischer, Rebecca S. B.; Unrine, Jason M.; Vangala, Chandan; Sanderson, Wayne T.; Mandayam, Sreedhar; Murray, Kristy O. (2020). "Evidence of nickel and other trace elements and their relationship to clinical findings in acute Mesoamerican Nephropathy: A case-control analysis". PloS One. 15 (11): e0240988. doi:10.1371/journal.pone.0240988. ISSN 1932-6203. PMC 7654766. PMID 33170853.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ Torres, Cecilia; Aragón, Aurora; González, Marvin; López, Indiana; Jakobsson, Kristina; Elinder, Carl-Gustaf; Lundberg, Ingvar; Wesseling, Catharina (2010-03). "Decreased kidney function of unknown cause in Nicaragua: a community-based survey". American Journal of Kidney Diseases: The Official Journal of the National Kidney Foundation. 55 (3): 485–496. doi:10.1053/j.ajkd.2009.12.012. ISSN 1523-6838. PMID 20116154. {{cite journal}}: Check date values in: |date= (help)
^ Sanoff, Scott L.; Callejas, Luis; Alonso, Carlos D.; Hu, Yichun; Colindres, Romulo E.; Chin, Hyunsook; Morgan, Douglas R.; Hogan, Susan L. (2010). "Positive association of renal insufficiency with agriculture employment and unregulated alcohol consumption in Nicaragua". Renal Failure. 32 (7): 766–777. doi:10.3109/0886022X.2010.494333. ISSN 1525-6049. PMC 3699859. PMID 20662688.
^ Lebov, Jill F.; Valladares, Eliette; Peña, Rodolfo; Peña, Edgar M.; Sanoff, Scott L.; Cisneros, Efren Castellón; Colindres, Romulo E.; Morgan, Douglas R.; Hogan, Susan L. (2015). "A population-based study of prevalence and risk factors of chronic kidney disease in León, Nicaragua". Canadian Journal of Kidney Health and Disease. 2: 6. doi:10.1186/s40697-015-0041-1. ISSN 2054-3581. PMC 4414463. PMID 25926994.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ Lokupathirage, Sithumini M.W.; Muthusinghe, Devinda S.; Shimizu, Kenta; Nishigami, Kumpei; Noda, Kisho; Tsuda, Yoshimi; Sarathkumara, Yomani D.; Gunawardana, Sirimevan; Arikawa, Jiro; Gamage, Chandika D.; Yoshimatsu, Kumiko (2019-11-01). "Serological Evidence of Thailand Orthohantavirus or Antigenically Related Virus Infection Among Rodents in a Chronic Kidney Disease of Unknown Etiology Endemic Area, Girandurukotte, Sri Lanka". Vector-Borne and Zoonotic Diseases. 19 (11): 859–866. doi:10.1089/vbz.2018.2429. ISSN 1530-3667.
^ Sunil-Chandra, N. P.; Jayaweera, J. A. A. S.; Kumbukgolla, W.; Jayasundara, M. V. M. L. (2020). "Association of Hantavirus Infections and Leptospirosis With the Occurrence of Chronic Kidney Disease of Uncertain Etiology in the North Central Province of Sri Lanka: A Prospective Study With Patients and Healthy Persons". Frontiers in Cellular and Infection Microbiology. 10: 544. doi:10.3389/fcimb.2020.556737. ISSN 2235-2988. PMC 7578220. PMID 33117726.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
^ Yih, W. Katherine; Kulldorff, Martin; Friedman, David J.; Leibler, Jessica H.; Amador, Juan José; López-Pilarte, Damaris; Galloway, Renee L.; Ramírez-Rubio, Oriana; Riefkohl, Alejandro; Brooks, Daniel R. (2019-09). "Investigating Possible Infectious Causes of Chronic Kidney Disease of Unknown Etiology in a Nicaraguan Mining Community". The American Journal of Tropical Medicine and Hygiene. 101 (3): 676–683. doi:10.4269/ajtmh.18-0856. ISSN 1476-1645. PMC 6726956. PMID 31309920. {{cite journal}}: Check date values in: |date= (help)
^ Correa-Rotter R, Wesseling C, Johnson RJ (March 2014). "CKD of unknown origin in Central America: the case for a Mesoamerican nephropathy". Am J Kidney Dis. 63 (3): 506–20. doi:10.1053/j.ajkd.2013.10.062. PMC 7115712. PMID 24412050.
^ Yang HY, Hung CC, Liu SH, Guo YG, Chen YC, Ko YC, Huang CT, Chou LF, Tian YC, Chang MY, Hsu HH, Lin MY, Hwang SJ, Yang CW (October 2015). "Overlooked Risk for Chronic Kidney Disease after Leptospiral Infection: A Population-Based Survey and Epidemiological Cohort Evidence". PLOS Neglected Tropical Diseases. 9 (10): e0004105. doi:10.1371/journal.pntd.0004105. PMC 4599860. PMID 26452161.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ Murray KO, Fischer RS, Chavarria D, Duttmann C, Garcia MN, Gorchakov R, Hotez PJ, Jiron W, Leibler JH, Lopez JE, Mandayam S, Marin A, Sheleby J (October 2015). "Mesoamerican nephropathy: a neglected tropical disease with an infectious etiology?". Microbes and Infection. 17 (10): 671–75. doi:10.1016/j.micinf.2015.08.005. PMID 26320026.
^ Gonzalez-Quiroz, Marvin; Smpokou, Evangelia-Theano; Silverwood, Richard J.; Camacho, Armando; Faber, Dorien; Garcia, Brenda La Rosa; Oomatia, Amin; Hill, Michael; Glaser, Jason; Le Blond, Jennifer; Wesseling, Catharina (2018-06-15). "Decline in Kidney Function among Apparently Healthy Young Adults at Risk of Mesoamerican Nephropathy". Journal of the American Society of Nephrology. 29 (8): 2200–2212. doi:10.1681/asn.2018020151. ISSN 1046-6673.
^ ^a ^b Raines NH, Hidalgo G, Herath CA, et al (2020). Clinical considerations surrounding Chronic Kidney Disease of Undetermined Etiology (CKDu). In Crowe J.L., Joubert B.R., Brooks. D.R. (Eds.). Report From the Third International Workshop on Chronic Kidney Diseases of Uncertain/Non-Traditional Etiology in Mesoamerica and Other Regions. Heredia, Costa Rica: SALTRA.

[1] Correa-Rotter, Ricardo; Wesseling, Catharina; Johnson, Richard J. (2014-03). "CKD of unknown origin in Central America: the case for a Mesoamerican nephropathy". American Journal of Kidney Diseases: The Official Journal of the National Kidney Foundation. 63 (3): 506–520. doi:10.1053/j.ajkd.2013.10.062. ISSN 1523-6838. PMC 7115712. PMID 24412050. {{cite journal}}: Check date values in: |date= (help)

[2] Landau, Elizabeth (June 11, 2014). "Mysterious kidney disease plagues Central America". CNN. Retrieved 13 June 2014.

[:02-3] Torres, Cecilia; Aragón, Aurora; González, Marvin; López, Indiana; Jakobsson, Kristina; Elinder, Carl-Gustaf; Lundberg, Ingvar; Wesseling, Catharina (2010-03). "Decreased Kidney Function of Unknown Cause in Nicaragua: A Community-Based Survey". American Journal of Kidney Diseases. 55 (3): 485–496. doi:10.1053/j.ajkd.2009.12.012. ISSN 0272-6386. {{cite journal}}: Check date values in: |date= (help)

[4] Gallo-Ruiz, Lyanne; Sennett, Caryn M.; Sánchez-Delgado, Mauricio; García-Urbina, Ana; Gámez-Altamirano, Tania; Basra, Komal; Laws, Rebecca L.; Amador, Juan José; Lopez-Pilarte, Damaris; Tripodis, Yorghos; Brooks, Daniel R. (2019-08). "Prevalence and Risk Factors for CKD Among Brickmaking Workers in La Paz Centro, Nicaragua". American Journal of Kidney Diseases: The Official Journal of the National Kidney Foundation. 74 (2): 239–247. doi:10.1053/j.ajkd.2019.01.017. ISSN 1523-6838. PMID 30826087. {{cite journal}}: Check date values in: |date= (help)

[:12-5] Wesseling, Catharina; Glaser, Jason; Rodríguez-Guzmán, Julieta; Weiss, Ilana; Lucas, Rebekah; Peraza, Sandra; da Silva, Agnes Soares; Hansson, Erik; Johnson, Richard J.; Hogstedt, Christer; Wegman, David H. (2020). "Chronic kidney disease of non-traditional origin in Mesoamerica: a disease primarily driven by occupational heat stress". Revista Panamericana De Salud Publica = Pan American Journal of Public Health. 44: e15. doi:10.26633/RPSP.2020.15. ISSN 1680-5348. PMC 6984407. PMID 31998376.

[6] "Institute for Health Metrics and Evaluation". Retrieved 2.22.2021. {{cite web}}: Check date values in: |access-date= (help)CS1 maint: url-status (link)

[7] "World Life Expectancy". Retrieved 2.22.2021. {{cite web}}: Check date values in: |access-date= (help)CS1 maint: url-status (link)

[8] Ordunez, Pedro; Nieto, F Javier; Martinez, Ramon; Soliz, Patricia; Giraldo, Gloria P; Mott, Susan Anne; Hoy, Wendy E (2018-02-02). "Chronic kidney disease mortality trends in selected Central America countries, 1997–2013: clues to an epidemic of chronic interstitial nephritis of agricultural communities". Journal of Epidemiology and Community Health. 72 (4): 280–286. doi:10.1136/jech-2017-210023. ISSN 0143-005X.

[9] Ramirez-Rubio, Oriana; McClean, Michael D.; Amador, Juan José; Brooks, Daniel R. (2013-01). "An epidemic of chronic kidney disease in Central America: an overview". Journal of Epidemiology and Community Health. 67 (1): 1–3. doi:10.1136/jech-2012-201141. ISSN 1470-2738. PMID 23002432. {{cite journal}}: Check date values in: |date= (help)

[10] Johnson, Richard J.; Wesseling, Catharina; Newman, Lee S. (2019-05-09). "Chronic Kidney Disease of Unknown Cause in Agricultural Communities". New England Journal of Medicine. 380 (19): 1843–1852. doi:10.1056/nejmra1813869. ISSN 0028-4793.

[11] Crowe, J., Joubert, B. R., & Brooks, D. R. (2020). Report from the Third International Workshop on Chronic Kidney Disease of Uncertain/Non-Traditional Etiology in Mesoamerica and Other Regions. Heredia: SALTRA-IRET, Universidad Nacional, Costa Rica.

[12] Wesseling, Catharina; Crowe, Jennifer; Hogstedt, Christer; Jakobsson, Kristina; Lucas, Rebekah; Wegman, David H. (2013-11). "The epidemic of chronic kidney disease of unknown etiology in Mesoamerica: a call for interdisciplinary research and action". American Journal of Public Health. 103 (11): 1927–1930. doi:10.2105/AJPH.2013.301594. ISSN 1541-0048. PMC 3828726. PMID 24028232. {{cite journal}}: Check date values in: |date= (help)

[13] Jayasumana, Channa; Orantes, Carlos; Herrera, Raul; Almaguer, Miguel; Lopez, Laura; Silva, Luis Carlos; Ordunez, Pedro; Siribaddana, Sisira; Gunatilake, Sarath; De Broe, Marc E. (2016-10-13). "Chronic interstitial nephritis in agricultural communities: a worldwide epidemic with social, occupational and environmental determinants". Nephrology Dialysis Transplantation: gfw346. doi:10.1093/ndt/gfw346. ISSN 0931-0509.

[14] Cuadra SN, Jakobsson K, Hogstedt C, Wesseling C. Enfermedad renal crónica: Evaluación del conocimiento actual y la viabilidad para la colaboración de su investigación a nivel regional en América Central [Chronic Kidney Disease: Assessment of current knowledge and feasibility for regional research collab. Instituto Regional de Estudios en Sustancias Tóxicas (IRET-UNA), Serie Salud y Trabajo, No. 2; 2006. 76 p.

[:22-15] Trabanino, Ramón García; Aguilar, Raúl; Silva, Carlos Reyes; Mercado, Manuel Ortiz; Merino, Ricardo Leiva (2002-09). "[End-stage renal disease among patients in a referral hospital in El Salvador]". Revista Panamericana De Salud Publica = Pan American Journal of Public Health. 12 (3): 202–206. doi:10.1590/s1020-49892002000900009. ISSN 1020-4989. PMID 12396639. {{cite journal}}: Check date values in: |date= (help)

[:022-16] Torres, Cecilia; Aragón, Aurora; González, Marvin; López, Indiana; Jakobsson, Kristina; Elinder, Carl-Gustaf; Lundberg, Ingvar; Wesseling, Catharina (2010-03). "Decreased Kidney Function of Unknown Cause in Nicaragua: A Community-Based Survey". American Journal of Kidney Diseases. 55 (3): 485–496. doi:10.1053/j.ajkd.2009.12.012. ISSN 0272-6386. {{cite journal}}: Check date values in: |date= (help)

[:32-17] Peraza, Sandra; Wesseling, Catharina; Aragon, Aurora; Leiva, Ricardo; García-Trabanino, Ramón Antonio; Torres, Cecilia; Jakobsson, Kristina; Elinder, Carl Gustaf; Hogstedt, Christer (2012-04). "Decreased kidney function among agricultural workers in El Salvador". American Journal of Kidney Diseases: The Official Journal of the National Kidney Foundation. 59 (4): 531–540. doi:10.1053/j.ajkd.2011.11.039. ISSN 1523-6838. PMID 22300650. {{cite journal}}: Check date values in: |date= (help)

[:42-18] Sanoff, Scott L.; Callejas, Luis; Alonso, Carlos D.; Hu, Yichun; Colindres, Romulo E.; Chin, Hyunsook; Morgan, Douglas R.; Hogan, Susan L. (2010). "Positive association of renal insufficiency with agriculture employment and unregulated alcohol consumption in Nicaragua". Renal Failure. 32 (7): 766–777. doi:10.3109/0886022X.2010.494333. ISSN 1525-6049. PMC 3699859. PMID 20662688.

[19] "CENCAM". Retrieved 10/26/2021. {{cite web}}: Check date values in: |access-date= (help)CS1 maint: url-status (link)

[SSDeclaration-20] Declaración de San Salvador. Abordaje integral de la enfermedad renal túbulo-intersticial crónica de Centroamérica (ERTCC) que afecta predominantemente a las comunidades agrícolas. Available in: "Archived copy" (PDF). Archived from the original (PDF) on 2013-09-19. Retrieved 2014-04-04.{{cite web}}: CS1 maint: archived copy as title (link) Accessed March 2, 2014.

[PAHOResolution-21] Pan American Health Organization. Resolution CD52.R1. Chronic kidney disease in agricultural communities in Central America. Washington, DC. 2013. Available at: http://www.paho.org/hq/index.php?option=com_content&view=article&id=8833&Itemid=40033&lang=en Accessed June 13, 2013

[22] Mendley, Susan R.; Levin, Adeera; Correa-Rotter, Ricardo; Joubert, Bonnie R.; Whelan, Elizabeth A.; Curwin, Brian; Koritzinsky, Erik H.; Gaughan, Denise M.; Kimmel, Paul L.; Anand, Shuchi; Ordunez, Pedro (2019-11). "Chronic kidney diseases in agricultural communities: report from a workshop". Kidney International. 96 (5): 1071–1076. doi:10.1016/j.kint.2019.06.024. ISSN 1523-1755. PMC 7012362. PMID 31563333. {{cite journal}}: Check date values in: |date= (help)

[23] Polo, Vicente Sanchez; Garcia-Trabanino, Ramon; Rodriguez, Guillermo; Madero, Magdalena (2020-10-22). "Mesoamerican Nephropathy (MeN): What We Know so Far". International Journal of Nephrology and Renovascular Disease. 13: 261–272. doi:10.2147/IJNRD.S270709. PMC 7588276. PMID 33116757.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)

[:52-24] Raines NH, Hidalgo G, Herath CA, et al (2020). Clinical considerations surrounding Chronic Kidney Disease of Undetermined Etiology (CKDu). In Crowe J.L., Joubert B.R., Brooks. D.R. (Eds.). Report From the Third International Workshop on Chronic Kidney Diseases of Uncertain/Non-Traditional Etiology in Mesoamerica and Other Regions. Heredia, Costa Rica: SALTRA.

[25] Wijkström, Julia; González-Quiroz, Marvin; Hernandez, Mario; Trujillo, Zulma; Hultenby, Kjell; Ring, Anneli; Söderberg, Magnus; Aragón, Aurora; Elinder, Carl-Gustaf; Wernerson, Annika (2017-05). "Renal Morphology, Clinical Findings, and Progression Rate in Mesoamerican Nephropathy". American Journal of Kidney Diseases. 69 (5): 626–636. doi:10.1053/j.ajkd.2016.10.036. ISSN 0272-6386. {{cite journal}}: Check date values in: |date= (help)

[26] Nanayakkara, Shanika; Komiya, Toshiyuki; Ratnatunga, Neelakanthi; Senevirathna, S. T. M. L. D.; Harada, Kouji H.; Hitomi, Toshiaki; Gobe, Glenda; Muso, Eri; Abeysekera, Tilak; Koizumi, Akio (2012-05). "Tubulointerstitial damage as the major pathological lesion in endemic chronic kidney disease among farmers in North Central Province of Sri Lanka". Environmental Health and Preventive Medicine. 17 (3): 213–221. doi:10.1007/s12199-011-0243-9. ISSN 1347-4715. PMC 3348245. PMID 21993948. {{cite journal}}: Check date values in: |date= (help)

[27] Wijkström, Julia; Jayasumana, Channa; Dassanayake, Rajeewa; Priyawardane, Nalin; Godakanda, Nimali; Siribaddana, Sisira; Ring, Anneli; Hultenby, Kjell; Söderberg, Magnus; Elinder, Carl-Gustaf; Wernerson, Annika (2018-03-07). "Morphological and clinical findings in Sri Lankan patients with chronic kidney disease of unknown cause (CKDu): Similarities and differences with Mesoamerican Nephropathy". PLOS ONE. 13 (3): e0193056. doi:10.1371/journal.pone.0193056. ISSN 1932-6203. PMC 5841753. PMID 29513702.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)

[:62-28] Vervaet, Benjamin A.; Nast, Cynthia C.; Jayasumana, Channa; Schreurs, Gerd; Roels, Frank; Herath, Chula; Kojc, Nika; Samaee, Vahid; Rodrigo, Sonali; Gowrishankar, Swarnalata; Mousson, Christiane (2020-02). "Chronic interstitial nephritis in agricultural communities is a toxin-induced proximal tubular nephropathy". Kidney International. 97 (2): 350–369. doi:10.1016/j.kint.2019.11.009. ISSN 1523-1755. PMID 31892415. {{cite journal}}: Check date values in: |date= (help)

[29] Fischer, Rebecca S. B.; Vangala, Chandan; Truong, Luan; Mandayam, Sreedhar; Chavarria, Denis; Granera Llanes, Orlando M.; Fonseca Laguna, Marcos U.; Guerra Baez, Alvaro; Garcia, Felix; García-Trabanino, Ramón; Murray, Kristy O. (2018-03). "Early detection of acute tubulointerstitial nephritis in the genesis of Mesoamerican nephropathy". Kidney International. 93 (3): 681–690. doi:10.1016/j.kint.2017.09.012. ISSN 1523-1755. PMID 29162294. {{cite journal}}: Check date values in: |date= (help)

[30] Gunawardena, Sameera; Dayaratne, Maleesha; Wijesinghe, Harshima; Wijewickrama, Eranga (2021-04). "A Systematic Review of Renal Pathology in Chronic Kidney Disease of Uncertain Etiology". Kidney International Reports. doi:10.1016/j.ekir.2021.03.898. ISSN 2468-0249. PMC 8207327. PMID 34169213. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)

[:122-31] Wesseling, Catharina; Glaser, Jason; Rodríguez-Guzmán, Julieta; Weiss, Ilana; Lucas, Rebekah; Peraza, Sandra; da Silva, Agnes Soares; Hansson, Erik; Johnson, Richard J.; Hogstedt, Christer; Wegman, David H. (2020). "Chronic kidney disease of non-traditional origin in Mesoamerica: a disease primarily driven by occupational heat stress". Revista Panamericana De Salud Publica = Pan American Journal of Public Health. 44: e15. doi:10.26633/RPSP.2020.15. ISSN 1680-5348. PMC 6984407. PMID 31998376.

[BrooksHot2-32] Brooks DR, Ramirez-Rubio O, Amador JJ (April 2012). "CKD in Central America: a hot issue". Am J Kidney Dis. 59 (4): 481–84. doi:10.1053/j.ajkd.2012.01.005. PMID 22444491.

[33] Valcke, Mathieu; Levasseur, Marie-Eve; Soares da Silva, Agnes; Wesseling, Catharina (2017-12). "Pesticide exposures and chronic kidney disease of unknown etiology: an epidemiologic review". Environmental Health. 16 (1): 49. doi:10.1186/s12940-017-0254-0. ISSN 1476-069X. {{cite journal}}: Check date values in: |date= (help)CS1 maint: unflagged free DOI (link)

[34] Smpokou, Evangelia-Theano; González-Quiroz, Marvin; Martins, Carla; Alvito, Paula; Le Blond, Jennifer; Glaser, Jason; Aragón, Aurora; Wesseling, Catharina; Nitsch, Dorothea; Pearce, Neil; Norman, Jill (2019-12). "Environmental exposures in young adults with declining kidney function in a population at risk of Mesoamerican nephropathy". Occupational and Environmental Medicine. 76 (12): 920–926. doi:10.1136/oemed-2019-105772. ISSN 1351-0711. {{cite journal}}: Check date values in: |date= (help)

[35] Yang, Chih-Wei (2018). "Leptospirosis Renal Disease: Emerging Culprit of Chronic Kidney Disease Unknown Etiology". Nephron. 138 (2): 129–136. doi:10.1159/000480691. ISSN 2235-3186. PMID 28926845.

[36] Herrera, Raúl; Orantes, Carlos M.; Almaguer, Miguel; Alfonso, Pedro; Bayarre, Héctor D.; Leiva, Irma M.; Smith, Magaly J.; Cubias, Ricardo A.; Torres, Carlos G.; Almendárez, Walter O.; Cubias, Francisco R. (2014-04). "Clinical characteristics of chronic kidney disease of nontraditional causes in Salvadoran farming communities". MEDICC review. 16 (2): 39–48. doi:10.37757/MR2014.V16.N2.7. ISSN 1527-3172. PMID 24878648. {{cite journal}}: Check date values in: |date= (help)

[:72-37] Johnson, Richard J.; Wesseling, Catharina; Newman, Lee S. (2019-05-09). "Chronic Kidney Disease of Unknown Cause in Agricultural Communities". New England Journal of Medicine. 380 (19): 1843–1852. doi:10.1056/nejmra1813869. ISSN 0028-4793.

[38] Kupferman, Joseph; Ramírez-Rubio, Oriana; Amador, Juan José; López-Pilarte, Damaris; Wilker, Elissa H.; Laws, Rebecca L.; Sennett, Caryn; Robles, Ninoska Violeta; Lau, Jorge Luis; Salinas, Alejandro José; Kaufman, James S. (2018-10). "Acute Kidney Injury in Sugarcane Workers at Risk for Mesoamerican Nephropathy". American Journal of Kidney Diseases: The Official Journal of the National Kidney Foundation. 72 (4): 475–482. doi:10.1053/j.ajkd.2018.04.014. ISSN 1523-6838. PMID 30042041. {{cite journal}}: Check date values in: |date= (help)

[39] Fischer, Rebecca S. B.; Mandayam, Sreedhar; Chavarria, Denis; Vangala, Chandan; Nolan, Melissa S.; Garcia, Linda L.; Palma, Lesbia; Garcia, Felix; García-Trabanino, Ramón; Murray, Kristy O. (2017-10). "Clinical Evidence of Acute Mesoamerican Nephropathy". The American Journal of Tropical Medicine and Hygiene. 97 (4): 1247–1256. doi:10.4269/ajtmh.17-0260. ISSN 1476-1645. PMC 5637619. PMID 28722618. {{cite journal}}: Check date values in: |date= (help)

[40] Jayasumana, Channa; Orantes, Carlos; Herrera, Raul; Almaguer, Miguel; Lopez, Laura; Silva, Luis Carlos; Ordunez, Pedro; Siribaddana, Sisira; Gunatilake, Sarath; De Broe, Marc E. (2016-10-13). "Chronic interstitial nephritis in agricultural communities: a worldwide epidemic with social, occupational and environmental determinants". Nephrology Dialysis Transplantation: gfw346. doi:10.1093/ndt/gfw346. ISSN 0931-0509.

[41] Friedman, David J. (2019-01). "Genes and environment in chronic kidney disease hotspots". Current Opinion in Nephrology and Hypertension. 28 (1): 87–96. doi:10.1097/MNH.0000000000000470. ISSN 1473-6543. PMC 6763202. PMID 30451737. {{cite journal}}: Check date values in: |date= (help)

[42] Crowe, Jennifer; Wesseling, Catharina; Solano, Bryan Román; Umaña, Manfred Pinto; Ramírez, Andrés Robles; Kjellstrom, Tord; Morales, David; Nilsson, Maria (2013-06-17). "Heat exposure in sugarcane harvesters in Costa Rica". American Journal of Industrial Medicine. 56 (10): 1157–1164. doi:10.1002/ajim.22204. ISSN 0271-3586.

[:322-43] Peraza, Sandra; Wesseling, Catharina; Aragon, Aurora; Leiva, Ricardo; García-Trabanino, Ramón Antonio; Torres, Cecilia; Jakobsson, Kristina; Elinder, Carl Gustaf; Hogstedt, Christer (2012-04). "Decreased kidney function among agricultural workers in El Salvador". American Journal of Kidney Diseases: The Official Journal of the National Kidney Foundation. 59 (4): 531–540. doi:10.1053/j.ajkd.2011.11.039. ISSN 1523-6838. PMID 22300650. {{cite journal}}: Check date values in: |date= (help)

[44] Raines, Nathan; González, Marvin; Wyatt, Christina; Kurzrok, Mark; Pool, Christopher; Lemma, Tiziana; Weiss, Ilana; Marín, Carlos; Prado, Valerio; Marcas, Eugenia; Mayorga, Karina (2014-04). "Risk factors for reduced glomerular filtration rate in a Nicaraguan community affected by Mesoamerican nephropathy". MEDICC review. 16 (2): 16–22. doi:10.37757/MR2014.V16.N2.4. ISSN 1527-3172. PMID 24878645. {{cite journal}}: Check date values in: |date= (help)

[:82-45] Hansson, Erik; Glaser, Jason; Weiss, Ilana; Ekström, Ulf; Apelqvist, Jenny; Hogstedt, Christer; Peraza, Sandra; Lucas, Rebekah; Jakobsson, Kristina; Wesseling, Catharina; Wegman, David H. (2019-11). "Workload and cross-harvest kidney injury in a Nicaraguan sugarcane worker cohort". Occupational and Environmental Medicine. 76 (11): 818–826. doi:10.1136/oemed-2019-105986. ISSN 1470-7926. PMC 6839725. PMID 31611303. {{cite journal}}: Check date values in: |date= (help)

[46] Sorensen, Cecilia J.; Butler-Dawson, Jaime; Dally, Miranda; Krisher, Lyndsay; Griffin, Benjamin R.; Johnson, Richard J.; Lemery, Jay; Asensio, Claudia; Tenney, Liliana; Newman, Lee S. (2019-03). "Risk Factors and Mechanisms Underlying Cross-Shift Decline in Kidney Function in Guatemalan Sugarcane Workers". Journal of Occupational and Environmental Medicine. 61 (3): 239–250. doi:10.1097/JOM.0000000000001529. ISSN 1536-5948. PMC 6416034. PMID 30575695. {{cite journal}}: Check date values in: |date= (help)

[47] García-Trabanino, Ramón; Jarquín, Emmanuel; Wesseling, Catharina; Johnson, Richard J.; González-Quiroz, Marvin; Weiss, Ilana; Glaser, Jason; José Vindell, Juan; Stockfelt, Leo; Roncal, Carlos; Harra, Tamara (2015-10). "Heat stress, dehydration, and kidney function in sugarcane cutters in El Salvador--A cross-shift study of workers at risk of Mesoamerican nephropathy". Environmental Research. 142: 746–755. doi:10.1016/j.envres.2015.07.007. ISSN 1096-0953. PMID 26209462. {{cite journal}}: Check date values in: |date= (help)

[48] Wesseling, Catharina; Aragón, Aurora; González, Marvin; Weiss, Ilana; Glaser, Jason; Bobadilla, Norma A.; Roncal-Jiménez, Carlos; Correa-Rotter, Ricardo; Johnson, Richard J.; Barregard, Lars (2016-05). "Kidney function in sugarcane cutters in Nicaragua--A longitudinal study of workers at risk of Mesoamerican nephropathy". Environmental Research. 147: 125–132. doi:10.1016/j.envres.2016.02.002. ISSN 1096-0953. PMID 26866450. {{cite journal}}: Check date values in: |date= (help)

[49] Wegman, David H.; Apelqvist, Jenny; Bottai, Matteo; Ekström, Ulf; García-Trabanino, Ramón; Glaser, Jason; Hogstedt, Christer; Jakobsson, Kristina; Jarquín, Emmanuel; Lucas, Rebekah A. I.; Weiss, Ilana (2018-01-01). "Intervention to diminish dehydration and kidney damage among sugarcane workers". Scandinavian Journal of Work, Environment & Health. 44 (1): 16–24. doi:10.5271/sjweh.3659. ISSN 1795-990X. PMID 28691728.

[50] Glaser, Jason; Hansson, Erik; Weiss, Ilana; Wesseling, Catharina; Jakobsson, Kristina; Ekström, Ulf; Apelqvist, Jenny; Lucas, Rebekah; Arias Monge, Esteban; Peraza, Sandra; Hogstedt, Christer (2020-08). "Preventing kidney injury among sugarcane workers: promising evidence from enhanced workplace interventions". Occupational and Environmental Medicine. 77 (8): 527–534. doi:10.1136/oemed-2020-106406. ISSN 1470-7926. PMC 7402461. PMID 32404530. {{cite journal}}: Check date values in: |date= (help)

[51] Sorensen, Cecilia J.; Krisher, Lyndsay; Butler-Dawson, Jaime; Dally, Miranda; Dexter, Lynn; Asensio, Claudia; Cruz, Alex; Newman, Lee S. (2020-11-18). "Workplace Screening Identifies Clinically Significant and Potentially Reversible Kidney Injury in Heat-Exposed Sugarcane Workers". International Journal of Environmental Research and Public Health. 17 (22): E8552. doi:10.3390/ijerph17228552. ISSN 1660-4601. PMC 7698805. PMID 33218070.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[52] Roncal Jimenez, Carlos A.; Ishimoto, Takuji; Lanaspa, Miguel A.; Rivard, Christopher J.; Nakagawa, Takahiko; Ejaz, A. Ahsan; Cicerchi, Christina; Inaba, Shinichiro; Le, MyPhuong; Miyazaki, Makoto; Glaser, Jason (2014-08). "Fructokinase activity mediates dehydration-induced renal injury". Kidney International. 86 (2): 294–302. doi:10.1038/ki.2013.492. ISSN 1523-1755. PMC 4120672. PMID 24336030. {{cite journal}}: Check date values in: |date= (help)

[53] Roncal-Jimenez, Carlos A.; Milagres, Tamara; Andres-Hernando, Ana; Kuwabara, Masanari; Jensen, Thomas; Song, Zhilin; Bjornstad, Petter; Garcia, Gabriela E.; Sato, Yuka; Sanchez-Lozada, Laura G.; Lanaspa, Miguel A. (2017-03-01). "Effects of exogenous desmopressin on a model of heat stress nephropathy in mice". American Journal of Physiology. Renal Physiology. 312 (3): F418–F426. doi:10.1152/ajprenal.00495.2016. ISSN 1522-1466. PMC 5374310. PMID 28003190.

[54] Sato, Yuka; Roncal-Jimenez, Carlos A.; Andres-Hernando, Ana; Jensen, Thomas; Tolan, Dean R.; Sanchez-Lozada, Laura G.; Newman, Lee S.; Butler-Dawson, Jaime; Sorensen, Cecilia; Glaser, Jason; Miyazaki, Makoto (2019-11-01). "Increase of core temperature affected the progression of kidney injury by repeated heat stress exposure". American Journal of Physiology. Renal Physiology. 317 (5): F1111–F1121. doi:10.1152/ajprenal.00259.2019. ISSN 1522-1466. PMC 6879947. PMID 31390229.

[55] Orantes, Carlos M.; Herrera, Raúl; Almaguer, Miguel; Brizuela, Elsy G.; Núñez, Lilian; Alvarado, Nelly P.; Fuentes, E. Jackeline; Bayarre, Héctor D.; Amaya, Juan Carlos; Calero, Denis J.; Vela, Xavier F. (2014-04). "Epidemiology of chronic kidney disease in adults of Salvadoran agricultural communities". MEDICC review. 16 (2): 23–30. doi:10.37757/MR2014.V16.N2.5. ISSN 1527-3172. PMID 24878646. {{cite journal}}: Check date values in: |date= (help)

[56] Vela, Xavier F.; Henríquez, David O.; Zelaya, Susana M.; Granados, Delmy V.; Hernández, Marcelo X.; Orantes, Carlos M. (2014-04). "Chronic kidney disease and associated risk factors in two Salvadoran farming communities, 2012". MEDICC review. 16 (2): 55–60. doi:10.37757/MR2014.V16.N2.9. ISSN 1527-3172. PMID 24878650. {{cite journal}}: Check date values in: |date= (help)

[57] Chapman, Evelina; Haby, Michelle M.; Illanes, Eduardo; Sanchez-Viamonte, Julian; Elias, Vanessa; Reveiz, Ludovic (2019). "Risk factors for chronic kidney disease of non-traditional causes: a systematic review". Revista Panamericana De Salud Publica = Pan American Journal of Public Health. 43: e35. doi:10.26633/RPSP.2019.35. ISSN 1680-5348. PMC 6461065. PMID 31093259.

[:622-58] Vervaet, Benjamin A.; Nast, Cynthia C.; Jayasumana, Channa; Schreurs, Gerd; Roels, Frank; Herath, Chula; Kojc, Nika; Samaee, Vahid; Rodrigo, Sonali; Gowrishankar, Swarnalata; Mousson, Christiane (2020-02). "Chronic interstitial nephritis in agricultural communities is a toxin-induced proximal tubular nephropathy". Kidney International. 97 (2): 350–369. doi:10.1016/j.kint.2019.11.009. ISSN 1523-1755. PMID 31892415. {{cite journal}}: Check date values in: |date= (help)

[:92-59] González-Quiroz, Marvin; Pearce, Neil; Caplin, Ben; Nitsch, Dorothea (2018-08). "What do epidemiological studies tell us about chronic kidney disease of undetermined cause in Meso-America? A systematic review and meta-analysis". Clinical Kidney Journal. 11 (4): 496–506. doi:10.1093/ckj/sfx136. ISSN 2048-8505. PMC 6070103. PMID 30094014. {{cite journal}}: Check date values in: |date= (help)

[:102-60] Smpokou, Evangelia-Theano; González-Quiroz, Marvin; Martins, Carla; Alvito, Paula; Le Blond, Jennifer; Glaser, Jason; Aragón, Aurora; Wesseling, Catharina; Nitsch, Dorothea; Pearce, Neil; Norman, Jill (2019-12). "Environmental exposures in young adults with declining kidney function in a population at risk of Mesoamerican nephropathy". Occupational and Environmental Medicine. 76 (12): 920–926. doi:10.1136/oemed-2019-105772. ISSN 1470-7926. PMID 31562235. {{cite journal}}: Check date values in: |date= (help)

[61] Lunyera, Joseph; Mohottige, Dinushika; Von Isenburg, Megan; Jeuland, Marc; Patel, Uptal D.; Stanifer, John W. (2016-03-07). "CKD of Uncertain Etiology: A Systematic Review". Clinical journal of the American Society of Nephrology: CJASN. 11 (3): 379–385. doi:10.2215/CJN.07500715. ISSN 1555-905X. PMC 4791820. PMID 26712810.

[62] Kulathunga, M. R. D. L.; Ayanka Wijayawardena, M. A.; Naidu, Ravi; Wijeratne, A. W. (2019-02-27). "Chronic kidney disease of unknown aetiology in Sri Lanka and the exposure to environmental chemicals: a review of literature". Environmental Geochemistry and Health. 41 (5): 2329–2338. doi:10.1007/s10653-019-00264-z. ISSN 0269-4042.

[63] Nanayakkara, Shanika; Senevirathna, STMLD; Abeysekera, Tilak; Chandrajith, Rohana; Ratnatunga, Neelakanthi; Gunarathne, EDL; Yan, Junxia; Hitomi, Toshiaki; Muso, Eri; Komiya, Toshiyuki; Harada, Kouji H. (2014-01). "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". Journal of Occupational Health. 56 (1): 28–38. doi:10.1539/joh.13-0172-oa. ISSN 1341-9145. {{cite journal}}: Check date values in: |date= (help)

[64] Fischer, Rebecca S. B.; Unrine, Jason M.; Vangala, Chandan; Sanderson, Wayne T.; Mandayam, Sreedhar; Murray, Kristy O. (2020). "Evidence of nickel and other trace elements and their relationship to clinical findings in acute Mesoamerican Nephropathy: A case-control analysis". PloS One. 15 (11): e0240988. doi:10.1371/journal.pone.0240988. ISSN 1932-6203. PMC 7654766. PMID 33170853.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[65] Torres, Cecilia; Aragón, Aurora; González, Marvin; López, Indiana; Jakobsson, Kristina; Elinder, Carl-Gustaf; Lundberg, Ingvar; Wesseling, Catharina (2010-03). "Decreased kidney function of unknown cause in Nicaragua: a community-based survey". American Journal of Kidney Diseases: The Official Journal of the National Kidney Foundation. 55 (3): 485–496. doi:10.1053/j.ajkd.2009.12.012. ISSN 1523-6838. PMID 20116154. {{cite journal}}: Check date values in: |date= (help)

[:422-66] Sanoff, Scott L.; Callejas, Luis; Alonso, Carlos D.; Hu, Yichun; Colindres, Romulo E.; Chin, Hyunsook; Morgan, Douglas R.; Hogan, Susan L. (2010). "Positive association of renal insufficiency with agriculture employment and unregulated alcohol consumption in Nicaragua". Renal Failure. 32 (7): 766–777. doi:10.3109/0886022X.2010.494333. ISSN 1525-6049. PMC 3699859. PMID 20662688.

[67] Lebov, Jill F.; Valladares, Eliette; Peña, Rodolfo; Peña, Edgar M.; Sanoff, Scott L.; Cisneros, Efren Castellón; Colindres, Romulo E.; Morgan, Douglas R.; Hogan, Susan L. (2015). "A population-based study of prevalence and risk factors of chronic kidney disease in León, Nicaragua". Canadian Journal of Kidney Health and Disease. 2: 6. doi:10.1186/s40697-015-0041-1. ISSN 2054-3581. PMC 4414463. PMID 25926994.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[68] Lokupathirage, Sithumini M.W.; Muthusinghe, Devinda S.; Shimizu, Kenta; Nishigami, Kumpei; Noda, Kisho; Tsuda, Yoshimi; Sarathkumara, Yomani D.; Gunawardana, Sirimevan; Arikawa, Jiro; Gamage, Chandika D.; Yoshimatsu, Kumiko (2019-11-01). "Serological Evidence of Thailand Orthohantavirus or Antigenically Related Virus Infection Among Rodents in a Chronic Kidney Disease of Unknown Etiology Endemic Area, Girandurukotte, Sri Lanka". Vector-Borne and Zoonotic Diseases. 19 (11): 859–866. doi:10.1089/vbz.2018.2429. ISSN 1530-3667.

[69] Sunil-Chandra, N. P.; Jayaweera, J. A. A. S.; Kumbukgolla, W.; Jayasundara, M. V. M. L. (2020). "Association of Hantavirus Infections and Leptospirosis With the Occurrence of Chronic Kidney Disease of Uncertain Etiology in the North Central Province of Sri Lanka: A Prospective Study With Patients and Healthy Persons". Frontiers in Cellular and Infection Microbiology. 10: 544. doi:10.3389/fcimb.2020.556737. ISSN 2235-2988. PMC 7578220. PMID 33117726.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)

[70] Yih, W. Katherine; Kulldorff, Martin; Friedman, David J.; Leibler, Jessica H.; Amador, Juan José; López-Pilarte, Damaris; Galloway, Renee L.; Ramírez-Rubio, Oriana; Riefkohl, Alejandro; Brooks, Daniel R. (2019-09). "Investigating Possible Infectious Causes of Chronic Kidney Disease of Unknown Etiology in a Nicaraguan Mining Community". The American Journal of Tropical Medicine and Hygiene. 101 (3): 676–683. doi:10.4269/ajtmh.18-0856. ISSN 1476-1645. PMC 6726956. PMID 31309920. {{cite journal}}: Check date values in: |date= (help)

[CorreaCase-71] Correa-Rotter R, Wesseling C, Johnson RJ (March 2014). "CKD of unknown origin in Central America: the case for a Mesoamerican nephropathy". Am J Kidney Dis. 63 (3): 506–20. doi:10.1053/j.ajkd.2013.10.062. PMC 7115712. PMID 24412050.

[Lepto1-72] Yang HY, Hung CC, Liu SH, Guo YG, Chen YC, Ko YC, Huang CT, Chou LF, Tian YC, Chang MY, Hsu HH, Lin MY, Hwang SJ, Yang CW (October 2015). "Overlooked Risk for Chronic Kidney Disease after Leptospiral Infection: A Population-Based Survey and Epidemiological Cohort Evidence". PLOS Neglected Tropical Diseases. 9 (10): e0004105. doi:10.1371/journal.pntd.0004105. PMC 4599860. PMID 26452161.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[Lepto2-73] Murray KO, Fischer RS, Chavarria D, Duttmann C, Garcia MN, Gorchakov R, Hotez PJ, Jiron W, Leibler JH, Lopez JE, Mandayam S, Marin A, Sheleby J (October 2015). "Mesoamerican nephropathy: a neglected tropical disease with an infectious etiology?". Microbes and Infection. 17 (10): 671–75. doi:10.1016/j.micinf.2015.08.005. PMID 26320026.

[74] Gonzalez-Quiroz, Marvin; Smpokou, Evangelia-Theano; Silverwood, Richard J.; Camacho, Armando; Faber, Dorien; Garcia, Brenda La Rosa; Oomatia, Amin; Hill, Michael; Glaser, Jason; Le Blond, Jennifer; Wesseling, Catharina (2018-06-15). "Decline in Kidney Function among Apparently Healthy Young Adults at Risk of Mesoamerican Nephropathy". Journal of the American Society of Nephrology. 29 (8): 2200–2212. doi:10.1681/asn.2018020151. ISSN 1046-6673.

[:522-75] Raines NH, Hidalgo G, Herath CA, et al (2020). Clinical considerations surrounding Chronic Kidney Disease of Undetermined Etiology (CKDu). In Crowe J.L., Joubert B.R., Brooks. D.R. (Eds.). Report From the Third International Workshop on Chronic Kidney Diseases of Uncertain/Non-Traditional Etiology in Mesoamerica and Other Regions. Heredia, Costa Rica: SALTRA.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

[30]

[31]

[32]

[33]

[34]

[35]

[36]

[37]

[38]

[39]

[40]

[41]

[42]

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50]

[51]

[52]

[53]

[54]

[55]

[56]

[57]

[58]

[59]

[60]

[61]

[62]

[63]

[64]

[65]

[66]

[67]

[68]

[69]

[70]

[71]

[72]

[73]

[74]

[75]

@@ Line 55: / Line 55: @@
 Kidney biopsy in individuals with MeN demonstrates some consistent features across regions. Biopsies are generally chronic glomerular and tubulointerstitial damage with glomerulosclerosis and chronic glomerular ischemia, without positive findings on immunofluorescence or definitive evidence of primary glomerular lesions.<ref>{{Cite journal|last=Wijkström|first=Julia|last2=González-Quiroz|first2=Marvin|last3=Hernandez|first3=Mario|last4=Trujillo|first4=Zulma|last5=Hultenby|first5=Kjell|last6=Ring|first6=Anneli|last7=Söderberg|first7=Magnus|last8=Aragón|first8=Aurora|last9=Elinder|first9=Carl-Gustaf|last10=Wernerson|first10=Annika|date=2017-05|title=Renal Morphology, Clinical Findings, and Progression Rate in Mesoamerican Nephropathy|url=http://dx.doi.org/10.1053/j.ajkd.2016.10.036|journal=American Journal of Kidney Diseases|volume=69|issue=5|pages=626–636|doi=10.1053/j.ajkd.2016.10.036|issn=0272-6386}}</ref><ref>{{Cite journal|last=Nanayakkara|first=Shanika|last2=Komiya|first2=Toshiyuki|last3=Ratnatunga|first3=Neelakanthi|last4=Senevirathna|first4=S. T. M. L. D.|last5=Harada|first5=Kouji H.|last6=Hitomi|first6=Toshiaki|last7=Gobe|first7=Glenda|last8=Muso|first8=Eri|last9=Abeysekera|first9=Tilak|last10=Koizumi|first10=Akio|date=2012-05|title=Tubulointerstitial damage as the major pathological lesion in endemic chronic kidney disease among farmers in North Central Province of Sri Lanka|url=https://pubmed.ncbi.nlm.nih.gov/21993948|journal=Environmental Health and Preventive Medicine|volume=17|issue=3|pages=213–221|doi=10.1007/s12199-011-0243-9|issn=1347-4715|pmc=3348245|pmid=21993948}}</ref><ref>{{Cite journal|last=Wijkström|first=Julia|last2=Jayasumana|first2=Channa|last3=Dassanayake|first3=Rajeewa|last4=Priyawardane|first4=Nalin|last5=Godakanda|first5=Nimali|last6=Siribaddana|first6=Sisira|last7=Ring|first7=Anneli|last8=Hultenby|first8=Kjell|last9=Söderberg|first9=Magnus|last10=Elinder|first10=Carl-Gustaf|last11=Wernerson|first11=Annika|date=2018-03-07|title=Morphological and clinical findings in Sri Lankan patients with chronic kidney disease of unknown cause (CKDu): Similarities and differences with Mesoamerican Nephropathy|url=https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193056|journal=PLOS ONE|language=en|volume=13|issue=3|pages=e0193056|doi=10.1371/journal.pone.0193056|issn=1932-6203|pmc=PMC5841753|pmid=29513702}}</ref> Glomerular enlargement may be observed. Ultrastructural changes evaluated with electron microscopy were mostly consistent with the light microscopic observations. Large dysmorphic lysosomes within tubular epithelial cells have been proposed as a distinctive feature but at present are not considered pathognomonic.<ref name=":62">{{Cite journal|last=Vervaet|first=Benjamin A.|last2=Nast|first2=Cynthia C.|last3=Jayasumana|first3=Channa|last4=Schreurs|first4=Gerd|last5=Roels|first5=Frank|last6=Herath|first6=Chula|last7=Kojc|first7=Nika|last8=Samaee|first8=Vahid|last9=Rodrigo|first9=Sonali|last10=Gowrishankar|first10=Swarnalata|last11=Mousson|first11=Christiane|date=2020-02|title=Chronic interstitial nephritis in agricultural communities is a toxin-induced proximal tubular nephropathy|url=https://pubmed.ncbi.nlm.nih.gov/31892415|journal=Kidney International|volume=97|issue=2|pages=350–369|doi=10.1016/j.kint.2019.11.009|issn=1523-1755|pmid=31892415}}</ref> In kidney biopsies from individuals with [[acute kidney injury]] (AKI) among high-risk patients for MeN, considered possibly a contributing stage to disease, the main findings were described as tubulointerstitial nephritis with varying degrees of acute inflammation and chronic tubulointerstitial changes.<ref>{{Cite journal|last=Fischer|first=Rebecca S. B.|last2=Vangala|first2=Chandan|last3=Truong|first3=Luan|last4=Mandayam|first4=Sreedhar|last5=Chavarria|first5=Denis|last6=Granera Llanes|first6=Orlando M.|last7=Fonseca Laguna|first7=Marcos U.|last8=Guerra Baez|first8=Alvaro|last9=Garcia|first9=Felix|last10=García-Trabanino|first10=Ramón|last11=Murray|first11=Kristy O.|date=2018-03|title=Early detection of acute tubulointerstitial nephritis in the genesis of Mesoamerican nephropathy|url=https://pubmed.ncbi.nlm.nih.gov/29162294|journal=Kidney International|volume=93|issue=3|pages=681–690|doi=10.1016/j.kint.2017.09.012|issn=1523-1755|pmid=29162294}}</ref><ref>{{Cite journal|last=Gunawardena|first=Sameera|last2=Dayaratne|first2=Maleesha|last3=Wijesinghe|first3=Harshima|last4=Wijewickrama|first4=Eranga|date=2021-04|title=A Systematic Review of Renal Pathology in Chronic Kidney Disease of Uncertain Etiology|url=https://doi.org/10.1016/j.ekir.2021.03.898|journal=Kidney International Reports|doi=10.1016/j.ekir.2021.03.898|issn=2468-0249|pmc=PMC8207327|pmid=34169213}}</ref> In some cases, neutrophils have been found in the tubular lumen of both chronic and acute MeN/CKDu patients, but urine cultures from these patients have been negative.
 ==Causes==
+Although many factors have been proposed as the cause of MeN, most attention has focused on heat stress due to a combination of strenuous work in a hot climate with insufficient hydration.<ref name=":122">{{Cite journal|last=Wesseling|first=Catharina|last2=Glaser|first2=Jason|last3=Rodríguez-Guzmán|first3=Julieta|last4=Weiss|first4=Ilana|last5=Lucas|first5=Rebekah|last6=Peraza|first6=Sandra|last7=da Silva|first7=Agnes Soares|last8=Hansson|first8=Erik|last9=Johnson|first9=Richard J.|last10=Hogstedt|first10=Christer|last11=Wegman|first11=David H.|date=2020|title=Chronic kidney disease of non-traditional origin in Mesoamerica: a disease primarily driven by occupational heat stress|url=https://pubmed.ncbi.nlm.nih.gov/31998376|journal=Revista Panamericana De Salud Publica = Pan American Journal of Public Health|volume=44|pages=e15|doi=10.26633/RPSP.2020.15|issn=1680-5348|pmc=6984407|pmid=31998376}}</ref><ref name="BrooksHot2">{{cite journal|vauthors=Brooks DR, Ramirez-Rubio O, Amador JJ|date=April 2012|title=CKD in Central America: a hot issue.|url=http://www.ajkd.org/article/S0272-6386(12)00029-7/abstract|journal=Am J Kidney Dis|volume=59|issue=4|pages=481–84|doi=10.1053/j.ajkd.2012.01.005|pmid=22444491}}</ref> Additional postulated contributing exposures include agrochemicals, metals, and pathogens.<ref>{{Cite journal|last=Valcke|first=Mathieu|last2=Levasseur|first2=Marie-Eve|last3=Soares da Silva|first3=Agnes|last4=Wesseling|first4=Catharina|date=2017-12|title=Pesticide exposures and chronic kidney disease of unknown etiology: an epidemiologic review|url=http://ehjournal.biomedcentral.com/articles/10.1186/s12940-017-0254-0|journal=Environmental Health|language=en|volume=16|issue=1|pages=49|doi=10.1186/s12940-017-0254-0|issn=1476-069X}}</ref><ref>{{Cite journal|last=Smpokou|first=Evangelia-Theano|last2=González-Quiroz|first2=Marvin|last3=Martins|first3=Carla|last4=Alvito|first4=Paula|last5=Le Blond|first5=Jennifer|last6=Glaser|first6=Jason|last7=Aragón|first7=Aurora|last8=Wesseling|first8=Catharina|last9=Nitsch|first9=Dorothea|last10=Pearce|first10=Neil|last11=Norman|first11=Jill|date=2019-12|title=Environmental exposures in young adults with declining kidney function in a population at risk of Mesoamerican nephropathy|url=https://oem.bmj.com/lookup/doi/10.1136/oemed-2019-105772|journal=Occupational and Environmental Medicine|language=en|volume=76|issue=12|pages=920–926|doi=10.1136/oemed-2019-105772|issn=1351-0711}}</ref><ref>{{Cite journal|last=Yang|first=Chih-Wei|date=2018|title=Leptospirosis Renal Disease: Emerging Culprit of Chronic Kidney Disease Unknown Etiology|url=https://pubmed.ncbi.nlm.nih.gov/28926845|journal=Nephron|volume=138|issue=2|pages=129–136|doi=10.1159/000480691|issn=2235-3186|pmid=28926845}}</ref> These factors are themselves a result of global and national economic and political systems that have led to poverty and social stratification.<ref>{{Cite journal|last=Herrera|first=Raúl|last2=Orantes|first2=Carlos M.|last3=Almaguer|first3=Miguel|last4=Alfonso|first4=Pedro|last5=Bayarre|first5=Héctor D.|last6=Leiva|first6=Irma M.|last7=Smith|first7=Magaly J.|last8=Cubias|first8=Ricardo A.|last9=Torres|first9=Carlos G.|last10=Almendárez|first10=Walter O.|last11=Cubias|first11=Francisco R.|date=2014-04|title=Clinical characteristics of chronic kidney disease of nontraditional causes in Salvadoran farming communities|url=https://pubmed.ncbi.nlm.nih.gov/24878648|journal=MEDICC review|volume=16|issue=2|pages=39–48|doi=10.37757/MR2014.V16.N2.7|issn=1527-3172|pmid=24878648}}</ref> Discovery of the causes of MeN has been complicated by the fact that there are likely multiple factors that arise from different sources of exposure and/or different times of life. Until recently, progress has also been slowed by a lack of research funding, although more support has become available as awareness of the disease and its toll on the population has increased.
-The cause of MeN is unclear, but it is certainly not explained by conventional causes such as [[diabetes mellitus]] or [[hypertension]].<ref name="CorreaCase">{{cite journal|vauthors=Correa-Rotter R, Wesseling C, Johnson RJ|date=March 2014|title=CKD of unknown origin in Central America: the case for a Mesoamerican nephropathy.|url=http://www.ajkd.org/article/S0272-6386(13)01568-0/abstract|journal=Am J Kidney Dis|volume=63|issue=3|pages=506–20|doi=10.1053/j.ajkd.2013.10.062|pmc=7115712|pmid=24412050}}<br /></ref><ref name="HNR">{{cite journal|vauthors=García-Trabanino R, Aguilar R, Reyes Silva C, Ortiz Mercado M, Leiva Merino R|date=September 2002|title=[End-stage renal disease among patients in a referral hospital in El Salvador].|journal=Rev Panam Salud Publica|volume=12|issue=3|pages=202–06|doi=10.1590/s1020-49892002000900009|pmid=12396639|doi-access=free}}<br /></ref> The cause of MeN is uncertain but many risk factors have been proposed, including repeated episodes of heat stress, dehydration, and long hours of work labor. <ref>Peraza, S., et al.(2012). Decreased Kidney Function Among Agricultural Workers in El Salvador. ''American Journal of Kidney Diseases'', DOI: 10.1053/j.ajkd.2011.11.039</ref>
+A review published in the [[The New England Journal of Medicine|New England Journal of Medicine]] in 2019<ref name=":72">{{Cite journal|last=Johnson|first=Richard J.|last2=Wesseling|first2=Catharina|last3=Newman|first3=Lee S.|date=2019-05-09|title=Chronic Kidney Disease of Unknown Cause in Agricultural Communities|url=http://dx.doi.org/10.1056/nejmra1813869|journal=New England Journal of Medicine|volume=380|issue=19|pages=1843–1852|doi=10.1056/nejmra1813869|issn=0028-4793}}</ref> summarizes a proposed mechanism in which heat exposure leads to dehydration and volume depletion and/or an increase in core temperature, which may cause kidney injury directly through tissue dysfunction or indirectly through hyperosmolarity or [[rhabdomyolysis]]. Similarly, it is possible that chronic sub-clinical undetected AKI leads to eventual CKD.<ref>{{Cite journal|last=Kupferman|first=Joseph|last2=Ramírez-Rubio|first2=Oriana|last3=Amador|first3=Juan José|last4=López-Pilarte|first4=Damaris|last5=Wilker|first5=Elissa H.|last6=Laws|first6=Rebecca L.|last7=Sennett|first7=Caryn|last8=Robles|first8=Ninoska Violeta|last9=Lau|first9=Jorge Luis|last10=Salinas|first10=Alejandro José|last11=Kaufman|first11=James S.|date=2018-10|title=Acute Kidney Injury in Sugarcane Workers at Risk for Mesoamerican Nephropathy|url=https://pubmed.ncbi.nlm.nih.gov/30042041|journal=American Journal of Kidney Diseases: The Official Journal of the National Kidney Foundation|volume=72|issue=4|pages=475–482|doi=10.1053/j.ajkd.2018.04.014|issn=1523-6838|pmid=30042041}}</ref><ref>{{Cite journal|last=Fischer|first=Rebecca S. B.|last2=Mandayam|first2=Sreedhar|last3=Chavarria|first3=Denis|last4=Vangala|first4=Chandan|last5=Nolan|first5=Melissa S.|last6=Garcia|first6=Linda L.|last7=Palma|first7=Lesbia|last8=Garcia|first8=Felix|last9=García-Trabanino|first9=Ramón|last10=Murray|first10=Kristy O.|date=2017-10|title=Clinical Evidence of Acute Mesoamerican Nephropathy|url=https://pubmed.ncbi.nlm.nih.gov/28722618|journal=The American Journal of Tropical Medicine and Hygiene|volume=97|issue=4|pages=1247–1256|doi=10.4269/ajtmh.17-0260|issn=1476-1645|pmc=5637619|pmid=28722618}}</ref> Another proposed mechanism is increased kidney tubular toxin uptake resulting in direct tubular toxicity, which might also be amplified by heat-associated dehydration.<ref>{{Cite journal|last=Jayasumana|first=Channa|last2=Orantes|first2=Carlos|last3=Herrera|first3=Raul|last4=Almaguer|first4=Miguel|last5=Lopez|first5=Laura|last6=Silva|first6=Luis Carlos|last7=Ordunez|first7=Pedro|last8=Siribaddana|first8=Sisira|last9=Gunatilake|first9=Sarath|last10=De Broe|first10=Marc E.|date=2016-10-13|title=Chronic interstitial nephritis in agricultural communities: a worldwide epidemic with social, occupational and environmental determinants|url=http://dx.doi.org/10.1093/ndt/gfw346|journal=Nephrology Dialysis Transplantation|pages=gfw346|doi=10.1093/ndt/gfw346|issn=0931-0509}}</ref> [[Genetics|Genetic]] factors are also likely to play a role.<ref>{{Cite journal|last=Friedman|first=David J.|date=2019-01|title=Genes and environment in chronic kidney disease hotspots|url=https://pubmed.ncbi.nlm.nih.gov/30451737|journal=Current Opinion in Nephrology and Hypertension|volume=28|issue=1|pages=87–96|doi=10.1097/MNH.0000000000000470|issn=1473-6543|pmc=6763202|pmid=30451737}}</ref> Regardless of what mechanisms are eventually proven to be involved, researchers agree that preventive measures should include measures to ensure safe drinking water, adequate hydration, rest, and shade for workers at risk, as well as to reduce exposure to toxins.<ref name=":72" />  A review of the state of knowledge on potential causes and mechanisms as of 2019 can be found in a [https://cencam.net/workshops-reports/ summary] of the Third International Workshop on Chronic Kidney Disease of Uncertain/Non-Traditional Etiology in Mesoamerica and Other Regions on Chronic Kidney Disease of Unknown Etiology held in March 2019.
-=== Multifactorial disease ===
-The above-mentioned declaration produced by the April 2013 International Conference which took place in San Salvador said that: {{cn|date=December 2020}}
-: “While there is consensus that this is a multifactorial disease, some of the main factors include exposure to agrochemicals, either through direct prolonged exposure over time or through residual long-standing contamination of the soil, water sources, and crops, compounded by difficult working conditions; exposure to high temperatures; and insufficient water intake, among others factors.”
-The nature of multifactorial problems is, that the observed disease can be caused from regionally different sets of risk factors, e.g. agrochemicals and heavy metals are ubiquitous in endemic and non-endemic areas, feature proteinuria, or have not been related previously to [[Chronic kidney disease|CKD]] but only to [[acute kidney injury]]. Mesoamerican volcanic soils, for instance, are rich in arsenic and cadmium (e.g. CKDu miners).
+=== Heat stress, dehydration and disturbances in water and mineral balance. ===
-=== Alcoholism and self-medication ===
+Heat strain and dehydration is in the spotlight globally due to emerging evidence of their association with adverse renal health issues including chronic kidney disease, especially in working populations.<ref name=":122" /> The probability of heat stress is greater when the temperature of the environment surpasses a persons core temperature, a situation common for outdoor workers in tropical settings where temperatures can easily surpass 37°C.<ref>{{Cite journal|last=Crowe|first=Jennifer|last2=Wesseling|first2=Catharina|last3=Solano|first3=Bryan Román|last4=Umaña|first4=Manfred Pinto|last5=Ramírez|first5=Andrés Robles|last6=Kjellstrom|first6=Tord|last7=Morales|first7=David|last8=Nilsson|first8=Maria|date=2013-06-17|title=Heat exposure in sugarcane harvesters in Costa Rica|url=http://dx.doi.org/10.1002/ajim.22204|journal=American Journal of Industrial Medicine|volume=56|issue=10|pages=1157–1164|doi=10.1002/ajim.22204|issn=0271-3586}}</ref>
-Alcoholism and self-medication are also common features in these populations. [[NSAID nephropathy|NSAID]]s self-prescription is particularly widespread,<ref name=RRPharmacy>{{cite journal |vauthors=Ramirez-Rubio O, Brooks DR, Amador JJ, Kaufman JS, Weiner DE, Scammell MK |title=Chronic kidney disease in Nicaragua: a qualitative analysis of semi-structured interviews with physicians and pharmacists. |journal=BMC Public Health |issue=1 |page=350 |date=April 2013 |pmid=23590528 |doi=10.1186/1471-2458-13-350 |pmc=3637184 |volume=13}}</ref><ref name=MEDICC>{{cite journal  |vauthors=Orantes CM, Herrera R, Almaguer M, etal |title=Chronic kidney disease and associated risk factors in the Bajo Lempa region of El Salvador: Nefrolempa study, 2009 |journal=MEDICC Rev |volume=13 |issue=4 |pages=14–22 |date=October 2011 |doi=10.37757/MR2011V13.N4.5 |pmid=22143603 |url=http://mediccreview.medicc.org/articles/mr_221.pdf |doi-access=free }}</ref> possibly due to frequent agricultural work posture-related pains, and [[dysuria]] is commonly treated with [[aminoglycoside]]s, often not related to urinary tract infections but perhaps associated with [[dehydration]] itself.<ref name=RRPharmacy/>
+Although the specific mechanism by which heat, dehydration and workload contribute to the causal pathway for MeN remains to be definitively established, the association with MeN has been shown repeatedly. Epidemiological studies in Central America have reported adverse heat stress impacts in agricultural workers, particularly those in the sugarcane industry.<ref name=":322">{{Cite journal|last=Peraza|first=Sandra|last2=Wesseling|first2=Catharina|last3=Aragon|first3=Aurora|last4=Leiva|first4=Ricardo|last5=García-Trabanino|first5=Ramón Antonio|last6=Torres|first6=Cecilia|last7=Jakobsson|first7=Kristina|last8=Elinder|first8=Carl Gustaf|last9=Hogstedt|first9=Christer|date=2012-04|title=Decreased kidney function among agricultural workers in El Salvador|url=https://pubmed.ncbi.nlm.nih.gov/22300650|journal=American Journal of Kidney Diseases: The Official Journal of the National Kidney Foundation|volume=59|issue=4|pages=531–540|doi=10.1053/j.ajkd.2011.11.039|issn=1523-6838|pmid=22300650}}</ref><ref>{{Cite journal|last=Raines|first=Nathan|last2=González|first2=Marvin|last3=Wyatt|first3=Christina|last4=Kurzrok|first4=Mark|last5=Pool|first5=Christopher|last6=Lemma|first6=Tiziana|last7=Weiss|first7=Ilana|last8=Marín|first8=Carlos|last9=Prado|first9=Valerio|last10=Marcas|first10=Eugenia|last11=Mayorga|first11=Karina|date=2014-04|title=Risk factors for reduced glomerular filtration rate in a Nicaraguan community affected by Mesoamerican nephropathy|url=https://pubmed.ncbi.nlm.nih.gov/24878645|journal=MEDICC review|volume=16|issue=2|pages=16–22|doi=10.37757/MR2014.V16.N2.4|issn=1527-3172|pmid=24878645}}</ref><ref name=":82">{{Cite journal|last=Hansson|first=Erik|last2=Glaser|first2=Jason|last3=Weiss|first3=Ilana|last4=Ekström|first4=Ulf|last5=Apelqvist|first5=Jenny|last6=Hogstedt|first6=Christer|last7=Peraza|first7=Sandra|last8=Lucas|first8=Rebekah|last9=Jakobsson|first9=Kristina|last10=Wesseling|first10=Catharina|last11=Wegman|first11=David H.|date=2019-11|title=Workload and cross-harvest kidney injury in a Nicaraguan sugarcane worker cohort|url=https://pubmed.ncbi.nlm.nih.gov/31611303|journal=Occupational and Environmental Medicine|volume=76|issue=11|pages=818–826|doi=10.1136/oemed-2019-105986|issn=1470-7926|pmc=6839725|pmid=31611303}}</ref><ref>{{Cite journal|last=Sorensen|first=Cecilia J.|last2=Butler-Dawson|first2=Jaime|last3=Dally|first3=Miranda|last4=Krisher|first4=Lyndsay|last5=Griffin|first5=Benjamin R.|last6=Johnson|first6=Richard J.|last7=Lemery|first7=Jay|last8=Asensio|first8=Claudia|last9=Tenney|first9=Liliana|last10=Newman|first10=Lee S.|date=2019-03|title=Risk Factors and Mechanisms Underlying Cross-Shift Decline in Kidney Function in Guatemalan Sugarcane Workers|url=https://pubmed.ncbi.nlm.nih.gov/30575695|journal=Journal of Occupational and Environmental Medicine|volume=61|issue=3|pages=239–250|doi=10.1097/JOM.0000000000001529|issn=1536-5948|pmc=6416034|pmid=30575695}}</ref> In addition to exposure to high temperatures, evidence exists that high sweat rates and limited fluid intake can lead to functional and sub-clinical acute kidney injuries (AKI), and that repetitive AKI may lead to the development of CKD.<ref>{{Cite journal|last=García-Trabanino|first=Ramón|last2=Jarquín|first2=Emmanuel|last3=Wesseling|first3=Catharina|last4=Johnson|first4=Richard J.|last5=González-Quiroz|first5=Marvin|last6=Weiss|first6=Ilana|last7=Glaser|first7=Jason|last8=José Vindell|first8=Juan|last9=Stockfelt|first9=Leo|last10=Roncal|first10=Carlos|last11=Harra|first11=Tamara|date=2015-10|title=Heat stress, dehydration, and kidney function in sugarcane cutters in El Salvador--A cross-shift study of workers at risk of Mesoamerican nephropathy|url=https://pubmed.ncbi.nlm.nih.gov/26209462|journal=Environmental Research|volume=142|pages=746–755|doi=10.1016/j.envres.2015.07.007|issn=1096-0953|pmid=26209462}}</ref><ref>{{Cite journal|last=Wesseling|first=Catharina|last2=Aragón|first2=Aurora|last3=González|first3=Marvin|last4=Weiss|first4=Ilana|last5=Glaser|first5=Jason|last6=Bobadilla|first6=Norma A.|last7=Roncal-Jiménez|first7=Carlos|last8=Correa-Rotter|first8=Ricardo|last9=Johnson|first9=Richard J.|last10=Barregard|first10=Lars|date=2016-05|title=Kidney function in sugarcane cutters in Nicaragua--A longitudinal study of workers at risk of Mesoamerican nephropathy|url=https://pubmed.ncbi.nlm.nih.gov/26866450|journal=Environmental Research|volume=147|pages=125–132|doi=10.1016/j.envres.2016.02.002|issn=1096-0953|pmid=26866450}}</ref>
-=== Clinical manifestations ===
-Clinical manifestations,<ref name="Peraza">{{cite journal|vauthors=Peraza S, Wesseling C, Aragon A, Leiva R, Garcia-Trabanino R, Torres C, Jakobsson K, Elinder CG, Hogstedt C|date=April 2012|title=Decreased kidney function among agricultural workers in El Salvador.|journal=Am J Kidney Dis|volume=59|issue=4|pages=531–40|doi=10.1053/j.ajkd.2011.11.039|pmid=22300650}}<br /></ref><ref name="Nefrologia">{{cite journal|vauthors=García-Trabanino R, Domínguez J, Jansà JM, Oliver A|date=January 2005|title=[Proteinuria and chronic renal failure in the coast of El Salvador: detection with low cost methods and associated factors].|url=http://www.paho.org/els/index.php?option=com_docman&task=doc_download&gid=546&Itemid=|journal=Nefrologia|volume=25|issue=1|pages=31–8|pmid=15789534}}<br /></ref><ref name="Cross-shift">{{cite journal|vauthors=García-Trabanino R, Jarquín E, Wesseling C, Johnson RJ, González-Quiroz M, Weiss I, Glaser J, Vindell JJ, Stockfelt L, Roncal C, Harra T, Barregard L|date=October 2015|title=Heat stress, dehydration, and kidney function in sugarcane cutters in El Salvador – a cross-shift study of workers at risk of Mesoamerican nephropathy.|journal=Environ Res|volume=142|issue=1|pages=746–55|bibcode=2015ER....142..746G|doi=10.1016/j.envres.2015.07.007|pmid=26209462|doi-access=free}}<br /></ref><ref name="Biopsies">{{cite journal|vauthors=Wijkström J, Leiva R, Elinder CG, Leiva S, Trujillo Z, Trujillo L, Söderberg M, Hultenby K, Wernerson A|date=November 2013|title=Clinical and Pathological Characterization of Mesoamerican Nephropathy: A New Kidney Disease in Central America.|url=http://www.ajkd.org/article/S0272-6386(13)00915-3/abstract|journal=Am J Kidney Dis|volume=62|issue=5|pages=908–18|doi=10.1053/j.ajkd.2013.05.019|pmid=23850447}}<br /></ref><ref name=Trujillo>Trujillo L, Cruz Z, Leiva R, Lazo S, Cruz V. Clinical characteristics and 3 year follow-up of patient with chronic kidney disease who live in Santa Clara sugarcane cooperative, department of La Paz, El Salvador. In: Wesseling C, Crowe J, Hogstedt C, Jakobsson K, Lucas R, Wegman D, eds. Mesoamerican Nephropathy: Report From the First International Research Workshop on MeN. Heredia, Costa Rica: SALTRA/IRET-UNA;  2013:209–10. http://www.saltra.una.ac.cr/index.php/sst-vol-10. Accessed April 13, 2014.</ref> and biopsy findings<ref name=Biopsies/><ref name="Biopsies2">{{cite journal|vauthors=Lopez-Marin L, Chavez Y, Garcia XA, Flores WM, Garcia YM, Herrera R, Almaguer M, Orantes CM, Calero D, Bayarre HD, Amaya JC, Magana S, Espinoza PA, Serpas L|date=April 2014|title=Histopathology of chronic kidney disease of unknown etiology in Salvadoran agricultural communities.|journal=MEDICC Rev|volume=16|issue=2|pages=49–54|doi=10.37757/MR2014.V16.N2.8|pmid=24878649|doi-access=free}}<br /></ref> suggest MeN could be a new form of CKD, a new pathologic entity related to repeated heat stress, dehydration, salt depletion, and possibly other contributing factors, like [[NSAIDs abuse]].<ref name=CorreaCase/><ref name="WesselingCall">{{cite journal|vauthors=Wesseling C, Crowe J, Hogstedt C, Jakobsson K, Lucas R, Wegman DH|date=November 2013|title=The epidemic of chronic kidney disease of unknown etiology in Mesoamerica: a call for interdisciplinary research and action|journal=Am J Public Health|volume=103|issue=11|pages=1927–30|doi=10.2105/AJPH.2013.301594|pmc=3828726|pmid=24028232}}<br /></ref><ref name="RROverview">{{cite journal|vauthors=Ramirez-Rubio O, McClean MD, Amador JJ, Brooks DR|date=January 2013|title=An epidemic of chronic kidney disease in Central America: an overview.|url=http://jech.bmj.com/content/67/1/1.extract|journal=J Epidemiol Community Health|volume=67|issue=1|pages=1–3|doi=10.1136/jech-2012-201141|pmid=23002432|s2cid=28456547}}<br /></ref><ref name="BrooksHot">{{cite journal|vauthors=Brooks DR, Ramirez-Rubio O, Amador JJ|date=April 2012|title=CKD in Central America: a hot issue.|url=http://www.ajkd.org/article/S0272-6386(12)00029-7/abstract|journal=Am J Kidney Dis|volume=59|issue=4|pages=481–84|doi=10.1053/j.ajkd.2012.01.005|pmid=22444491}}<br /></ref><ref name=Cross-shift/><ref name=Biopsies/><ref name="Crystalluria">{{cite journal|vauthors=Roncal-Jimenez C, García-Trabanino R, Barregard L, Lanaspa MA, Wesseling C, Harra T, Aragon A, Grases F, Jarquin ER, González MA, Weiss I, Glaser J, Sánchez-Lozada LG, Johnson RJ|date=January 2016|title=Heat Stress Nephropathy From Exercise-Induced Uric Acid Crystalluria: A Perspective on Mesoamerican Nephropathy.|url=http://www.ajkd.org/article/S0272-6386(15)01156-7/abstract|journal=Am J Kidney Dis|volume=67|issue=1|pages=20–30|doi=10.1053/j.ajkd.2015.08.021|pmid=26455995}}<br /></ref><ref name=GlobalWarming/><ref name=Tangri>{{cite web |author=Tangri N |title=MesoAmerican Nephropathy: A New Entity |date=29 July 2013 |work=eAJKD |publisher=National Kidney Foundation |url=http://ajkdblog.org/2013/07/29/mesoamerican-nephropathy-a-new-entity/}}<br /></ref><ref name=JohnsonClues>{{cite journal |vauthors=Johnson RJ, Sánchez-Lozada LG |title=Chronic kidney disease: Mesoamerican nephropathy – new clues to the cause |journal=Nat Rev Nephrol |volume=9 |issue=10 |pages=560–61 |date=October 2013 |pmid=23999393 |doi=10.1038/nrneph.2013.174 |s2cid=20611337 }}</ref><ref name=WesselingEnigma>{{cite journal |author=Wesseling C, Crowe J, Hogstedt C, Jakobsson K, Lucas R, Wegman DH; on behalf of the participants of the First International Research Workshop on the Mesoamerican Nephropathy. |title=Resolving the Enigma of the Mesoamerican Nephropathy: A Research Workshop Summary. |journal=Am J Kidney Dis |volume=63 |issue=3 |pages=396–404 |date=March 2014 |pmid=24140367 |doi=10.1053/j.ajkd.2013.08.014 |url=http://www.ajkd.org/article/S0272-6386(13)01200-6/abstract}}</ref><ref name=Weiner>{{cite journal |vauthors=Weiner DE, McClean MD, Kaufman JS, Brooks DR |title=The Central American Epidemic of CKD. |journal=Clin J Am Soc Nephrol |volume=8 |issue=3 |pages=504–11 |date=March 2013 |pmid=23099656 |doi=10.2215/CJN.05050512 |url=http://cjasn.asnjournals.org/content/8/3/504.long|doi-access=free }}</ref><ref name=Wernerson>{{cite journal |vauthors=Wernerson A, Wijkström J, Elinder CG |title=Update on endemic nephropathies. |journal=Curr Opin Nephrol Hypertens |volume=23 |issue=3 |pages=232–38 |date=May 2014 |doi=10.1097/01.mnh.0000444911.32794.e7 |pmid=24717833|s2cid=3023607 }}<br /></ref><ref name=Lucas>{{cite journal |vauthors=Lucas RA, Bodin T, García-Trabanino R, Wesseling C, Glaser J, Weiss I, Jarquin E, Jakobsson K, Wegman DH |title=Heat stress and workload associated with sugarcane cutting – an excessively strenuous occupation! |journal=Extrem Physiol Med |volume=4 |issue=Suppl 1 |page=A23 |date=2015 |doi=10.1186/2046-7648-4-S1-A23|pmc=4580831 }}<br /></ref>{{citation overkill|date=December 2020}} A recent study<ref name=JohnsonFructokinase>{{cite journal |vauthors=Roncal Jimenez CA, Ishimoto T, Lanaspa MA, Rivard CJ, Nakagawa T, Ejaz AA, Cicerchi C, Inaba S, Le M, Miyazaki M, Glaser J, Correa-Rotter R, González MA, Aragón A, Wesseling C, Sánchez-Lozada LG, Johnson RJ |title=Fructokinase activity mediates dehydration-induced renal injury. |journal=Kidney Int |date=December 2013 |pmid=24336030 |doi=10.1038/ki.2013.492 |url= |volume=86 |issue=2 |pages=294–302 |pmc=4120672}}</ref> with Wild-type mice exposed to recurrent dehydration induced by heat stress produced a similar pattern of kidney injury, thus providing a potential mechanism for MeN, by activation of the polyol pathway, via metabolism by fructokinase, resulting in generation of endogenous fructose and uric acid in the kidney that subsequently induces renal injury.{{cn|date=December 2020}}
+A well-conducted study on the relationship between workload and incidence of kidney injury in a fieldworker cohort with different levels of physically demanding work over a sugarcane harvest in Nicaragua was published in October 2019.<ref name=":82" /> The results provide evidence of dose-effect as well as dose-response relations between high-heat and high workload exposure and both increased episodes of incident acute kidney injury as well as progressive decline in GFR. The role of heat stress in the etiology of MeN is further supported by intervention studies showing mitigation of kidney function decline with efforts to improve rest, hydration, and access to shade among high-risk agricultural workers.<ref>{{Cite journal|last=Wegman|first=David H.|last2=Apelqvist|first2=Jenny|last3=Bottai|first3=Matteo|last4=Ekström|first4=Ulf|last5=García-Trabanino|first5=Ramón|last6=Glaser|first6=Jason|last7=Hogstedt|first7=Christer|last8=Jakobsson|first8=Kristina|last9=Jarquín|first9=Emmanuel|last10=Lucas|first10=Rebekah A. I.|last11=Weiss|first11=Ilana|date=2018-01-01|title=Intervention to diminish dehydration and kidney damage among sugarcane workers|url=https://pubmed.ncbi.nlm.nih.gov/28691728|journal=Scandinavian Journal of Work, Environment & Health|volume=44|issue=1|pages=16–24|doi=10.5271/sjweh.3659|issn=1795-990X|pmid=28691728}}</ref><ref>{{Cite journal|last=Glaser|first=Jason|last2=Hansson|first2=Erik|last3=Weiss|first3=Ilana|last4=Wesseling|first4=Catharina|last5=Jakobsson|first5=Kristina|last6=Ekström|first6=Ulf|last7=Apelqvist|first7=Jenny|last8=Lucas|first8=Rebekah|last9=Arias Monge|first9=Esteban|last10=Peraza|first10=Sandra|last11=Hogstedt|first11=Christer|date=2020-08|title=Preventing kidney injury among sugarcane workers: promising evidence from enhanced workplace interventions|url=https://pubmed.ncbi.nlm.nih.gov/32404530|journal=Occupational and Environmental Medicine|volume=77|issue=8|pages=527–534|doi=10.1136/oemed-2020-106406|issn=1470-7926|pmc=7402461|pmid=32404530}}</ref><ref>{{Cite journal|last=Sorensen|first=Cecilia J.|last2=Krisher|first2=Lyndsay|last3=Butler-Dawson|first3=Jaime|last4=Dally|first4=Miranda|last5=Dexter|first5=Lynn|last6=Asensio|first6=Claudia|last7=Cruz|first7=Alex|last8=Newman|first8=Lee S.|date=2020-11-18|title=Workplace Screening Identifies Clinically Significant and Potentially Reversible Kidney Injury in Heat-Exposed Sugarcane Workers|url=https://pubmed.ncbi.nlm.nih.gov/33218070|journal=International Journal of Environmental Research and Public Health|volume=17|issue=22|pages=E8552|doi=10.3390/ijerph17228552|issn=1660-4601|pmc=7698805|pmid=33218070}}</ref> Finally, there is evidence from animal models suggesting a potential mechanism or mechanisms for how heat stress may drive development of MeN.<ref>{{Cite journal|last=Roncal Jimenez|first=Carlos A.|last2=Ishimoto|first2=Takuji|last3=Lanaspa|first3=Miguel A.|last4=Rivard|first4=Christopher J.|last5=Nakagawa|first5=Takahiko|last6=Ejaz|first6=A. Ahsan|last7=Cicerchi|first7=Christina|last8=Inaba|first8=Shinichiro|last9=Le|first9=MyPhuong|last10=Miyazaki|first10=Makoto|last11=Glaser|first11=Jason|date=2014-08|title=Fructokinase activity mediates dehydration-induced renal injury|url=https://pubmed.ncbi.nlm.nih.gov/24336030|journal=Kidney International|volume=86|issue=2|pages=294–302|doi=10.1038/ki.2013.492|issn=1523-1755|pmc=4120672|pmid=24336030}}</ref><ref>{{Cite journal|last=Roncal-Jimenez|first=Carlos A.|last2=Milagres|first2=Tamara|last3=Andres-Hernando|first3=Ana|last4=Kuwabara|first4=Masanari|last5=Jensen|first5=Thomas|last6=Song|first6=Zhilin|last7=Bjornstad|first7=Petter|last8=Garcia|first8=Gabriela E.|last9=Sato|first9=Yuka|last10=Sanchez-Lozada|first10=Laura G.|last11=Lanaspa|first11=Miguel A.|date=2017-03-01|title=Effects of exogenous desmopressin on a model of heat stress nephropathy in mice|url=https://pubmed.ncbi.nlm.nih.gov/28003190|journal=American Journal of Physiology. Renal Physiology|volume=312|issue=3|pages=F418–F426|doi=10.1152/ajprenal.00495.2016|issn=1522-1466|pmc=5374310|pmid=28003190}}</ref><ref>{{Cite journal|last=Sato|first=Yuka|last2=Roncal-Jimenez|first2=Carlos A.|last3=Andres-Hernando|first3=Ana|last4=Jensen|first4=Thomas|last5=Tolan|first5=Dean R.|last6=Sanchez-Lozada|first6=Laura G.|last7=Newman|first7=Lee S.|last8=Butler-Dawson|first8=Jaime|last9=Sorensen|first9=Cecilia|last10=Glaser|first10=Jason|last11=Miyazaki|first11=Makoto|date=2019-11-01|title=Increase of core temperature affected the progression of kidney injury by repeated heat stress exposure|url=https://pubmed.ncbi.nlm.nih.gov/31390229|journal=American Journal of Physiology. Renal Physiology|volume=317|issue=5|pages=F1111–F1121|doi=10.1152/ajprenal.00259.2019|issn=1522-1466|pmc=6879947|pmid=31390229}}</ref>
-=== Heatstress and dehydration ===
-The same position supported by the authors of one study developed in El Salvador,<ref name="MEDICC" /> but the El Salvadoran study did not find an increased odds ratio for CKD in people exposed to agrochemical products, or direct evidence linking it to pesticides. Other studies from Sri Lanka have showed that chronic exposure of people in agrochemically laden fields to low levels of cadmium through the food chain and also to pesticides could be responsible for significantly higher urinary excretion of cadmium in individuals with CKDu,<ref name="JayatilakeCKDu">{{cite journal|last1=Jayatilake|first1=Nihal|last2=Mendis|first2=Shanthi|last3=Maheepala|first3=Palitha|last4=Mehta|first4=Firdosi R|title=Chronic kidney disease of uncertain aetiology: prevalence and causative factors in a developing country|journal=BMC Nephrology|date=2013|volume=14|issue=1|page=180|doi=10.1186/1471-2369-14-180|pmid=23981540|pmc=3765913}}</ref> but urinary cadmium excretion is increased in all forms of CKD, and cadmium nephropathy is highly proteinuric while MeN is not. Based on that hypothetical possibility, Sri Lanka has banned many of these chemicals, and El Salvador has similar legislation pending,<ref name="Chavkin">{{cite web |url=http://www.publicintegrity.org/2014/04/11/14551/herbicide-ban-hold-sri-lanka-source-deadly-kidney-disease-remains-elusive |title=Herbicide ban on hold in Sri Lanka, as source of deadly kidney disease remains elusive |author=Sasha Chavkin |date=11 April 2014 |access-date=3 September 2014 |publisher=The Center for Public Integrity}}</ref> waiting for direct evidence linking the disease to the use of agrochemicals in the [[Mesoamerican region]].
-A large (nearly 38,000 workers, 5 year follow up) prospective study from Thailand in 2012<ref name=TCSHeatStress>{{cite journal |author=Benjawan Tawatsupa, Lynette L-Y Lim, Tord Kjellstrom, Sam-ang Seubsman, Adrian Sleigh, and the Thai Cohort Study Team |title=Association Between Occupational Heat Stress and Kidney Disease Among 37 816 Workers in the Thai Cohort Study (TCS) |journal=J Epidemiol |volume=22 |issue=3 |pages=251–60 |date=May 2012 |doi=10.2188/jea.JE20110082 |pmid=22343327 |pmc=3798627}}<br /></ref> found a 5-fold increased risk (adjusted odds ratio) for CKD in heat stress exposed workers with physical jobs, so the disease could be more prevalent around the globe than first thought, and needs a closer look. The heat stress hypothesis needs to be more deeply considered and examined.{{cn|date=December 2020}}
-Published evidence in 2016 suggest heat stress and strenuous activity-induced cyclic uricosuria and crystalluria as a possible mechanism for the tubular lesion.<ref name=Cross-shift/><ref name=Crystalluria/><ref name=GlobalWarming>{{cite journal |vauthors=Roncal-Jimenez CA, García-Trabanino R, Wesseling C, Johnson RJ |title=Mesoamerican Nephropathy or Global Warming Nephropathy? |journal=Blood Purif |volume=41 |issue=1–3 |pages=135–38 |date=January 2016 |doi=10.1159/000441265 |pmid=26766409 |s2cid=342193 }}<br /></ref>
 === Agrochemicals ===
+Agrochemicals and pesticides have been frequently been proposed as a potential cause or contributor to the development of MeN,<ref>{{Cite journal|last=Orantes|first=Carlos M.|last2=Herrera|first2=Raúl|last3=Almaguer|first3=Miguel|last4=Brizuela|first4=Elsy G.|last5=Núñez|first5=Lilian|last6=Alvarado|first6=Nelly P.|last7=Fuentes|first7=E. Jackeline|last8=Bayarre|first8=Héctor D.|last9=Amaya|first9=Juan Carlos|last10=Calero|first10=Denis J.|last11=Vela|first11=Xavier F.|date=2014-04|title=Epidemiology of chronic kidney disease in adults of Salvadoran agricultural communities|url=https://pubmed.ncbi.nlm.nih.gov/24878646|journal=MEDICC review|volume=16|issue=2|pages=23–30|doi=10.37757/MR2014.V16.N2.5|issn=1527-3172|pmid=24878646}}</ref><ref>{{Cite journal|last=Vela|first=Xavier F.|last2=Henríquez|first2=David O.|last3=Zelaya|first3=Susana M.|last4=Granados|first4=Delmy V.|last5=Hernández|first5=Marcelo X.|last6=Orantes|first6=Carlos M.|date=2014-04|title=Chronic kidney disease and associated risk factors in two Salvadoran farming communities, 2012|url=https://pubmed.ncbi.nlm.nih.gov/24878650|journal=MEDICC review|volume=16|issue=2|pages=55–60|doi=10.37757/MR2014.V16.N2.9|issn=1527-3172|pmid=24878650}}</ref><ref>{{Cite journal|last=Chapman|first=Evelina|last2=Haby|first2=Michelle M.|last3=Illanes|first3=Eduardo|last4=Sanchez-Viamonte|first4=Julian|last5=Elias|first5=Vanessa|last6=Reveiz|first6=Ludovic|date=2019|title=Risk factors for chronic kidney disease of non-traditional causes: a systematic review|url=https://pubmed.ncbi.nlm.nih.gov/31093259|journal=Revista Panamericana De Salud Publica = Pan American Journal of Public Health|volume=43|pages=e35|doi=10.26633/RPSP.2019.35|issn=1680-5348|pmc=6461065|pmid=31093259}}</ref><ref name=":622">{{Cite journal|last=Vervaet|first=Benjamin A.|last2=Nast|first2=Cynthia C.|last3=Jayasumana|first3=Channa|last4=Schreurs|first4=Gerd|last5=Roels|first5=Frank|last6=Herath|first6=Chula|last7=Kojc|first7=Nika|last8=Samaee|first8=Vahid|last9=Rodrigo|first9=Sonali|last10=Gowrishankar|first10=Swarnalata|last11=Mousson|first11=Christiane|date=2020-02|title=Chronic interstitial nephritis in agricultural communities is a toxin-induced proximal tubular nephropathy|url=https://pubmed.ncbi.nlm.nih.gov/31892415|journal=Kidney International|volume=97|issue=2|pages=350–369|doi=10.1016/j.kint.2019.11.009|issn=1523-1755|pmid=31892415}}</ref> although the epidemiological and pathophysiologic evidence is somewhat limited and contradictory.<ref name=":82" /><ref name=":92">{{Cite journal|last=González-Quiroz|first=Marvin|last2=Pearce|first2=Neil|last3=Caplin|first3=Ben|last4=Nitsch|first4=Dorothea|date=2018-08|title=What do epidemiological studies tell us about chronic kidney disease of undetermined cause in Meso-America? A systematic review and meta-analysis|url=https://pubmed.ncbi.nlm.nih.gov/30094014|journal=Clinical Kidney Journal|volume=11|issue=4|pages=496–506|doi=10.1093/ckj/sfx136|issn=2048-8505|pmc=6070103|pmid=30094014}}</ref><ref name=":102">{{Cite journal|last=Smpokou|first=Evangelia-Theano|last2=González-Quiroz|first2=Marvin|last3=Martins|first3=Carla|last4=Alvito|first4=Paula|last5=Le Blond|first5=Jennifer|last6=Glaser|first6=Jason|last7=Aragón|first7=Aurora|last8=Wesseling|first8=Catharina|last9=Nitsch|first9=Dorothea|last10=Pearce|first10=Neil|last11=Norman|first11=Jill|date=2019-12|title=Environmental exposures in young adults with declining kidney function in a population at risk of Mesoamerican nephropathy|url=https://pubmed.ncbi.nlm.nih.gov/31562235|journal=Occupational and Environmental Medicine|volume=76|issue=12|pages=920–926|doi=10.1136/oemed-2019-105772|issn=1470-7926|pmid=31562235}}</ref> The main limitations of both positive and negative studies remain poor specificity and quantification of pesticide exposure, as well as the cross-sectional nature of most studies and issues with confounding and selection bias. No study has directly investigated interactions between pesticides and other concomitant exposures in agricultural occupations, in particular heat stress and dehydration. Thus, existing studies provide scarce evidence for an association between pesticides and regional MeN epidemics, but a role of nephrotoxic agrochemicals nevertheless should not be conclusively discarded.
-A relationship between CKDu and people working in agriculture can be found in El Salvador in areas with high [[pesticide]] use.<ref>Orantes, C. M., Herrera, R., Almaguer, M., Brizuela, E. G., Hernández, C. E., Bayarre, H., ... & Velázquez, M. E. (2011). Chronic kidney disease and associated risk factors in the Bajo Lempa region of El Salvador: Nefrolempa study, 2009. MEDICC review, 13, 14-22.</ref> The study did not find a direct cause for the etiology, but nephrotoxic environmental factors cannot be ruled out. In a rural area in Sri Lanca a possible association between CKD and a long term low- level exposure to OP pesticides was detected.<ref>Peiris-John, R., Wanigasuriya, J. K. P., Wickremasinghe, A. R., Dissanayake, W. P., & Hittarage, A. (2006). Exposure to acetylcholinesterase-inhibiting pesticides and chronic renal failure.
-</ref> In a Latin American country high creatinine levels of workers can likely be attributed to the use of the [[nematicide]] [[DBCP]].<ref>Yearout, R., Game, X., Krumpe, K., & McKenzie, C. (2008). Impacts of DBCP on participants in the agricultural industry in a third world nation (an industrial health, safety case study of a village at risk). International Journal of Industrial Ergonomics, 38(2), 127-134.</ref> Also a relationship between increased blood levels of certain organochlorine pesticides and the occurrence of chronic kidney disease was observed in India.<ref>Ghosh, R., Siddarth, M., Singh, N., Tyagi, V., Kare, P. K., Banerjee, B. D., ... & Tripathi, A. K. (2017). Organochlorine pesticide level in patients with chronic kidney disease of unknown etiology and its association with renal function. Environmental health and preventive medicine, 22(1), 49.
-</ref> In Nicaragua a non significant relation between pesticide use and the occurrence of CKDu was observed. The occurrence of CKDu was higher in person groups exposed to pesticides than in the control group.<ref>Sanoff, S. L., Callejas, L., Alonso, C. D., Hu, Y., Colindres, R. E., Chin, H., ... & Hogan, S. L. (2010). Positive association of renal insufficiency with agriculture employment and unregulated alcohol consumption in Nicaragua. Renal failure, 32(7), 766-777.</ref>
+=== Exposure to metals ===
-The import and production of agrochemicals can be quantified. In addition to the amount of agrochemicals the workflow in which agrochemicals are applied are relevant for the exposure of workers to agrochemical (application with tractor or manual work or application of self-protection measures). CKDu has not been reported among workers laboring under supposedly similar heat stress in other tropical areas of the world, such as [[Brazil]], [[Cuba]] or [[Jamaica]], where the same pesticides may not have been used in the same fashion or quantities as in Mesoamerica. However, heat stress measurements have not been assessed in these countries and cannot be compared, and CKD cases could be underreported, just like in the Mesoamerican region before the first description of the disease back in 2002. In any case, there are important differences between these Caribbean and Atlantic countries and the Mesoamerican Pacific coastlands, differences including {{cn|date=December 2020}}
+Exposure to metals such as cadmium, lead, nickel, and mercury has also been proposed as a cause or contributor to MeN,<ref>{{Cite journal|last=Lunyera|first=Joseph|last2=Mohottige|first2=Dinushika|last3=Von Isenburg|first3=Megan|last4=Jeuland|first4=Marc|last5=Patel|first5=Uptal D.|last6=Stanifer|first6=John W.|date=2016-03-07|title=CKD of Uncertain Etiology: A Systematic Review|url=https://pubmed.ncbi.nlm.nih.gov/26712810|journal=Clinical journal of the American Society of Nephrology: CJASN|volume=11|issue=3|pages=379–385|doi=10.2215/CJN.07500715|issn=1555-905X|pmc=4791820|pmid=26712810}}</ref><ref>{{Cite journal|last=Kulathunga|first=M. R. D. L.|last2=Ayanka Wijayawardena|first2=M. A.|last3=Naidu|first3=Ravi|last4=Wijeratne|first4=A. W.|date=2019-02-27|title=Chronic kidney disease of unknown aetiology in Sri Lanka and the exposure to environmental chemicals: a review of literature|url=http://dx.doi.org/10.1007/s10653-019-00264-z|journal=Environmental Geochemistry and Health|volume=41|issue=5|pages=2329–2338|doi=10.1007/s10653-019-00264-z|issn=0269-4042}}</ref> again with limited and contradictory evidence. A number of well conducted studies have shown no association with the development of MeN,<ref>{{Cite journal|last=Nanayakkara|first=Shanika|last2=Senevirathna|first2=STMLD|last3=Abeysekera|first3=Tilak|last4=Chandrajith|first4=Rohana|last5=Ratnatunga|first5=Neelakanthi|last6=Gunarathne|first6=EDL|last7=Yan|first7=Junxia|last8=Hitomi|first8=Toshiaki|last9=Muso|first9=Eri|last10=Komiya|first10=Toshiyuki|last11=Harada|first11=Kouji H.|date=2014-01|title=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|url=http://dx.doi.org/10.1539/joh.13-0172-oa|journal=Journal of Occupational Health|volume=56|issue=1|pages=28–38|doi=10.1539/joh.13-0172-oa|issn=1341-9145}}</ref><ref name=":102" /> although a recent study did show an association with nickel exposure.<ref>{{Cite journal|last=Fischer|first=Rebecca S. B.|last2=Unrine|first2=Jason M.|last3=Vangala|first3=Chandan|last4=Sanderson|first4=Wayne T.|last5=Mandayam|first5=Sreedhar|last6=Murray|first6=Kristy O.|date=2020|title=Evidence of nickel and other trace elements and their relationship to clinical findings in acute Mesoamerican Nephropathy: A case-control analysis|url=https://pubmed.ncbi.nlm.nih.gov/33170853|journal=PloS One|volume=15|issue=11|pages=e0240988|doi=10.1371/journal.pone.0240988|issn=1932-6203|pmc=7654766|pmid=33170853}}</ref> There may be regional variation with respect to the role of heavy metals, which appear unlikely to be an important contributor in Mesoamerica but which remain under more active investigation in India and Sri Lanka.
-* level of agroindustrial mechanization,
-* working conditions (access to drinking water and rest in shady spots),
-* easy access to NSAIDs without prescription,
-* and healthcare accessibility, and
-* marked ethnic differences - because the Mesoamerican Pacific Ocean coastland has little or no black ethnicity influence, being mainly Native American "mestizos".
+=== Alcohol and self-medication ===
-A large (nearly 38,000 workers, 5 year follow up) prospective study of occupational heat stress and Kidney Disease from Thailand in 2012<ref name=TCSHeatStress/> found a 5-fold increased risk (adjusted odds ratio) for CKD in heat stress exposed workers with physical jobs, so the disease could be more prevalent around the globe than first thought, and needs a closer look. The heat stress hypothesis needs to be more deeply considered and examined as contributing risk factor.{{cn|date=December 2020}}
+Alcohol consumption, including consumption of home-brewed alcohol, as well as self-medication with [[NSAID nephropathy|NSAIDs]] and other nephrotoxic medications occurs in populations affected by MeN. To what extent such exposures contribute to the epidemic of MeN is not known, as evidence is again contradictory. Some studies have described an association between NSAID use<ref name=":322" /><ref>{{Cite journal|last=Torres|first=Cecilia|last2=Aragón|first2=Aurora|last3=González|first3=Marvin|last4=López|first4=Indiana|last5=Jakobsson|first5=Kristina|last6=Elinder|first6=Carl-Gustaf|last7=Lundberg|first7=Ingvar|last8=Wesseling|first8=Catharina|date=2010-03|title=Decreased kidney function of unknown cause in Nicaragua: a community-based survey|url=https://pubmed.ncbi.nlm.nih.gov/20116154|journal=American Journal of Kidney Diseases: The Official Journal of the National Kidney Foundation|volume=55|issue=3|pages=485–496|doi=10.1053/j.ajkd.2009.12.012|issn=1523-6838|pmid=20116154}}</ref> or consumption of a home-brewed alcohol called "lija"<ref name=":422">{{Cite journal|last=Sanoff|first=Scott L.|last2=Callejas|first2=Luis|last3=Alonso|first3=Carlos D.|last4=Hu|first4=Yichun|last5=Colindres|first5=Romulo E.|last6=Chin|first6=Hyunsook|last7=Morgan|first7=Douglas R.|last8=Hogan|first8=Susan L.|date=2010|title=Positive association of renal insufficiency with agriculture employment and unregulated alcohol consumption in Nicaragua|url=https://pubmed.ncbi.nlm.nih.gov/20662688|journal=Renal Failure|volume=32|issue=7|pages=766–777|doi=10.3109/0886022X.2010.494333|issn=1525-6049|pmc=3699859|pmid=20662688}}</ref><ref>{{Cite journal|last=Lebov|first=Jill F.|last2=Valladares|first2=Eliette|last3=Peña|first3=Rodolfo|last4=Peña|first4=Edgar M.|last5=Sanoff|first5=Scott L.|last6=Cisneros|first6=Efren Castellón|last7=Colindres|first7=Romulo E.|last8=Morgan|first8=Douglas R.|last9=Hogan|first9=Susan L.|date=2015|title=A population-based study of prevalence and risk factors of chronic kidney disease in León, Nicaragua|url=https://pubmed.ncbi.nlm.nih.gov/25926994|journal=Canadian Journal of Kidney Health and Disease|volume=2|pages=6|doi=10.1186/s40697-015-0041-1|issn=2054-3581|pmc=4414463|pmid=25926994}}</ref> and MeN, whereas others have found limited evidence that either is an important risk factor.<ref name=":92" />
+=== Infectious causes ===
+The high density of infectious disease vectors and reservoirs, in the context of limited access to clean water, limited resources for detecting and controlling infectious disease outbreaks, and the continued emergence of new pathogens and pathogen variants, is an important consideration when addressing kidney health in tropical and low-resource settings. The presence of these factors in MeN burdened regions lend credence to the hypothesis of an infectious etiology, and there is some evidence in support of infection as a risk factor.<ref>{{Cite journal|last=Lokupathirage|first=Sithumini M.W.|last2=Muthusinghe|first2=Devinda S.|last3=Shimizu|first3=Kenta|last4=Nishigami|first4=Kumpei|last5=Noda|first5=Kisho|last6=Tsuda|first6=Yoshimi|last7=Sarathkumara|first7=Yomani D.|last8=Gunawardana|first8=Sirimevan|last9=Arikawa|first9=Jiro|last10=Gamage|first10=Chandika D.|last11=Yoshimatsu|first11=Kumiko|date=2019-11-01|title=Serological Evidence of Thailand Orthohantavirus or Antigenically Related Virus Infection Among Rodents in a Chronic Kidney Disease of Unknown Etiology Endemic Area, Girandurukotte, Sri Lanka|url=http://dx.doi.org/10.1089/vbz.2018.2429|journal=Vector-Borne and Zoonotic Diseases|volume=19|issue=11|pages=859–866|doi=10.1089/vbz.2018.2429|issn=1530-3667}}</ref><ref>{{Cite journal|last=Sunil-Chandra|first=N. P.|last2=Jayaweera|first2=J. A. A. S.|last3=Kumbukgolla|first3=W.|last4=Jayasundara|first4=M. V. M. L.|date=2020|title=Association of Hantavirus Infections and Leptospirosis With the Occurrence of Chronic Kidney Disease of Uncertain Etiology in the North Central Province of Sri Lanka: A Prospective Study With Patients and Healthy Persons|url=https://www.frontiersin.org/article/10.3389/fcimb.2020.556737|journal=Frontiers in Cellular and Infection Microbiology|volume=10|pages=544|doi=10.3389/fcimb.2020.556737|issn=2235-2988|pmc=PMC7578220|pmid=33117726}}</ref> However, other published studies investigating infectious agents as a causal factor in MeN have been negative.<ref>{{Cite journal|last=Yih|first=W. Katherine|last2=Kulldorff|first2=Martin|last3=Friedman|first3=David J.|last4=Leibler|first4=Jessica H.|last5=Amador|first5=Juan José|last6=López-Pilarte|first6=Damaris|last7=Galloway|first7=Renee L.|last8=Ramírez-Rubio|first8=Oriana|last9=Riefkohl|first9=Alejandro|last10=Brooks|first10=Daniel R.|date=2019-09|title=Investigating Possible Infectious Causes of Chronic Kidney Disease of Unknown Etiology in a Nicaraguan Mining Community|url=https://pubmed.ncbi.nlm.nih.gov/31309920|journal=The American Journal of Tropical Medicine and Hygiene|volume=101|issue=3|pages=676–683|doi=10.4269/ajtmh.18-0856|issn=1476-1645|pmc=6726956|pmid=31309920}}</ref> There may again exist regional variation between Mesoamerica and India / Sri Lanka with respect to the role of infectious causes in CKD development.
 === Summary of current scientific evidence ===
@@ Line 105: / Line 94: @@
 If the difference in experimental and control are 2 risk factors (adding or removing two risk factor e.g. A, B in the control group), then 4 regions will show a differences in prevalence of the disease, with the disadvantage that the experimental design cannot clarify if one or both risk factors A and B are contributing to the progression and prevalence of the disease. The precautionary principles could lead to risk mitigation strategies for risk factor A and B until the [[etiology]] is clarified.{{cn|date=December 2020}}
-Beside this logical analysis of a multifactorial setting there is space for further investigation, e.g.: [[Leptospirosis]] has been suggested as a possible contributing factor<ref name=CorreaCase/><ref name=Lepto1>{{cite journal |vauthors=Yang HY, Hung CC, Liu SH, Guo YG, Chen YC, Ko YC, Huang CT, Chou LF, Tian YC, Chang MY, Hsu HH, Lin MY, Hwang SJ, Yang CW |title=Overlooked Risk for Chronic Kidney Disease after Leptospiral Infection: A Population-Based Survey and Epidemiological Cohort Evidence. |journal=PLOS Neglected Tropical Diseases |volume=9 |issue=10 |pages=e0004105 |date=October 2015 |doi=10.1371/journal.pntd.0004105 |pmid=26452161 |pmc=4599860}}<br /></ref><ref name=Lepto2>{{cite journal |vauthors=Murray KO, Fischer RS, Chavarria D, Duttmann C, Garcia MN, Gorchakov R, Hotez PJ, Jiron W, Leibler JH, Lopez JE, Mandayam S, Marin A, Sheleby J |title=Mesoamerican nephropathy: a neglected tropical disease with an infectious etiology? |journal=Microbes and Infection |volume=17 |issue=10 |pages=671–75 |date=October 2015 |doi=10.1016/j.micinf.2015.08.005 |pmid=26320026 }}<br /></ref> and oceanic [[nephrotoxic]] [[algae]].
+Beside this logical analysis of a multifactorial setting there is space for further investigation, e.g.: [[Leptospirosis]] has been suggested as a possible contributing factor<ref name="CorreaCase">{{cite journal|vauthors=Correa-Rotter R, Wesseling C, Johnson RJ|date=March 2014|title=CKD of unknown origin in Central America: the case for a Mesoamerican nephropathy.|url=http://www.ajkd.org/article/S0272-6386(13)01568-0/abstract|journal=Am J Kidney Dis|volume=63|issue=3|pages=506–20|doi=10.1053/j.ajkd.2013.10.062|pmc=7115712|pmid=24412050}}<br /></ref><ref name=Lepto1>{{cite journal |vauthors=Yang HY, Hung CC, Liu SH, Guo YG, Chen YC, Ko YC, Huang CT, Chou LF, Tian YC, Chang MY, Hsu HH, Lin MY, Hwang SJ, Yang CW |title=Overlooked Risk for Chronic Kidney Disease after Leptospiral Infection: A Population-Based Survey and Epidemiological Cohort Evidence. |journal=PLOS Neglected Tropical Diseases |volume=9 |issue=10 |pages=e0004105 |date=October 2015 |doi=10.1371/journal.pntd.0004105 |pmid=26452161 |pmc=4599860}}<br /></ref><ref name=Lepto2>{{cite journal |vauthors=Murray KO, Fischer RS, Chavarria D, Duttmann C, Garcia MN, Gorchakov R, Hotez PJ, Jiron W, Leibler JH, Lopez JE, Mandayam S, Marin A, Sheleby J |title=Mesoamerican nephropathy: a neglected tropical disease with an infectious etiology? |journal=Microbes and Infection |volume=17 |issue=10 |pages=671–75 |date=October 2015 |doi=10.1016/j.micinf.2015.08.005 |pmid=26320026 }}<br /></ref> and oceanic [[nephrotoxic]] [[algae]].
 Risk factors associated with agents need evidence for the [[nephrotoxicity]] of the agent and evidence for the [[exposure assessment]] of a cohort to the risk factor. Assessment of the mentioned risk factors and their possible synergism will depend on more and better research.{{cn|date=December 2020}}
+== Prognosis, treatment and prevention ==
+Evidence regarding the prognosis when MeN remains limited. One study suggests that there is substantial variety in progression of disease, with some individuals having slow or no further decline in kidney function following diagnosis, while others rapidly progress to [[Kidney failure|end stage kidney disease]] (ESKD).<ref>{{Cite journal|last=Gonzalez-Quiroz|first=Marvin|last2=Smpokou|first2=Evangelia-Theano|last3=Silverwood|first3=Richard J.|last4=Camacho|first4=Armando|last5=Faber|first5=Dorien|last6=Garcia|first6=Brenda La Rosa|last7=Oomatia|first7=Amin|last8=Hill|first8=Michael|last9=Glaser|first9=Jason|last10=Le Blond|first10=Jennifer|last11=Wesseling|first11=Catharina|date=2018-06-15|title=Decline in Kidney Function among Apparently Healthy Young Adults at Risk of Mesoamerican Nephropathy|url=http://dx.doi.org/10.1681/asn.2018020151|journal=Journal of the American Society of Nephrology|volume=29|issue=8|pages=2200–2212|doi=10.1681/asn.2018020151|issn=1046-6673}}</ref>
+To date, there are no standard guidelines for the management of MeN patients, and treatment strategies employed by health care providers vary widely. Based on clinical consensus from the most recent CENCAM meeting, no specific treatment exists beyond improving access to shade, hydration, and rest among individuals engaging in work that places them at risk for heat stress, as well as emphasizing access to clean air and water and avoidance of nephrotoxic substances.<ref name=":522">Raines NH, Hidalgo G, Herath CA, et al (2020). Clinical considerations surrounding Chronic Kidney Disease of Undetermined Etiology (CKDu). In Crowe J.L., Joubert B.R., Brooks. D.R. (Eds.). Report From the Third International Workshop on Chronic Kidney Diseases of Uncertain/Non-Traditional Etiology in Mesoamerica and Other Regions. Heredia, Costa Rica: SALTRA.</ref> Care of advanced CKD due to MeN should likely be similar to that employed in advanced CKD of other causes. There are anecdotal reports of response to [[allopurinol]] (in response to elevated uric acid levels), [[Corticosteroid|corticosteroids]] (in response to acute tubulointerstitial nephritis on kidney biopsy), and use of [[ACE inhibitor|angiotensin converting enzyme inhibitors]] (ACEIs) and [[Angiotensin II receptor blocker|angiotensin II receptor blockers]] (ARBs), but the consensus is that there is insufficient evidence to support any of these therapies at present.<ref name=":522" />
 == See also ==

v t e Kidney disease
Glomerular disease	See Template:Glomerular disease
Tubules	Renal tubular acidosis proximal distal Acute tubular necrosis Genetic Fanconi syndrome Bartter syndrome Gitelman syndrome Liddle's syndrome
Interstitium	Interstitial nephritis Pyelonephritis Balkan endemic nephropathy
Vascular	Renal artery stenosis Renal ischemia Hypertensive nephropathy Renovascular hypertension Renal cortical necrosis
General syndromes	Nephritis Nephrosis Renal failure Acute renal failure Chronic kidney disease Uremia
Other	Analgesic nephropathy Renal osteodystrophy Nephroptosis Abderhalden–Kaufmann–Lignac syndrome Diabetes insipidus Nephrogenic Renal papilla Renal papillary necrosis Major calyx/pelvis Hydronephrosis Pyonephrosis Reflux nephropathy