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Mesoamerican nephropathy

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Mesoamerican Nephropathy (MeN) is a currently unexplained epidemic of chronic kidney disease of unknown origin (CKDu),[1] prevalent in the Pacific ocean coastal low lands of the mesoamerican region, including southern Mexico, Guatemala, El Salvador, Nicaragua, Honduras and Costa Rica. In rural areas of Nicaragua the disease is colloquially called creatinina.[2]

This CKD epidemic in Central America spans along a nearly 1000 kilometer stretch of the Pacific coast. In El Salvador and Nicaragua alone, the reported number of men dying from this painful disease has risen five-fold in the last 20 years, although some researchers believe hidden cases have always been there and this increment in official data could be partially due to the recent increase in reports and improved case search, pushed by the growing social and political interest in the disease. In El Salvador, the disease has become the second leading cause of death among adult men, and according to a recent editorial,[3] it has been estimated that this largely unknown epidemic has caused the premature death of at least 20,000 men in the region.[4] Science Magazine reports: "In El Salvador alone, PAHO's latest figures say CKD of all causes kills at least 2,500 people in the country each year".[5][6]

The people affected by the epidemic are mainly young and middle-aged male laborers in the agricultural sector,[7][8] particularly sugarcane workers.[9][10] The disease has also been found to be prevalent in other occupations implying strenuous work (miners, construction, port and transportation workers)[9][10][11][12][13] in the high temperatures of the coastlands. The epidemic appears to affect particular Pacific coastal regions of Nicaragua,[9][11][13] El Salvador,[7][10][14] Costa Rica,[15][16] and Guatemala.[17]

History

The real timeline of the disease is unknown since most of the aforementioned countries did not have or still lack renal disease registries, and the affected regions are mainly poor farm lands. Nicaraguan health authorities have commented that they have been noting an increase of CKD cases in the Pacific ocean coastal regions since the 80s, but it was not until 2002 that a scientific paper from an El Salvadoran reference hospital[7] first communicated and described the existence of an important group of CKDu patients with a particular epidemiological pattern. In January 2005, a second scientific paper,[14] also from El Salvador, reported some field efforts on trying to identify the cause of the disease, and confirmed its curious epidemiological pattern.

In November 2005, SALTRA, a university-based Program on Work and Health in Central America (SALTRA), organized a regional interdisciplinary workshop in Leon, Nicaragua, attended by 17 researchers from the involved countries and international experts. There, the existence of the disease —also referred to as CKDu— was first acknowledged, and collaboration was established throughout the region.

In November 2012, the Consortium for the Epidemic of Nephropathy in Central America and Mexico (CENCAM) was established in a subsequent SALTRA organized workshop in San Jose, Costa Rica, to promote further research on the disease, in order to improve knowledge about the epidemic, and to use it to reduce CKDu prevalence and incidence in the region. The full Final Technical Report from the 2012 MeN workshop is available from www.regionalnephropathy.org.

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.”[18] This Declaration was subsequently endorsed by PAHO through the Resolution CD52.R1, adopted in the 52nd Directing Council, 65th Session of the Regional Committee of WHO for the Americas, in October 2013.[19]

Clinical and histopathological findings

A comprehensive review of the disease and its characteristics was published in the American Journal of Kidney Diseases in January 2014, describing it as "a medical enigma yet to be solved".[1]

MeN is silent during initial stages but appears to progress quite fast to end-stage renal disease; it is mainly prevalent in young and middle aged men, with rates varying from 1:3 to 1:10 when compared to women,[7][9][10] and has not been described in children.

The disease is only prevalent in the Pacific ocean's coastal lowlands, absent from coffee plantations at higher grounds.[10][20] Also, agricultural communities located at sea level in the coastlands have an 8 to 10 times greater risk (odds ratio) for presenting the disease, when compared to other agricultural communities working the same type of crops, but located at higher altitudes, away from the coastal low lands.[10][14]

Clinically, MeN presents as a tubular-interstitial disease: patients have low-range or no proteinuria,[9][10][11][13][14] electrolyte abnormalities -mainly low serum potassium and sodium-, and high levels of uric acid, but no hypertension.[7][10][14][21]

Histopathological findings of the disease were described in a recently published paper,[21] and include: Tubular atrophy, interstitial fibrosis, and global glomerulosclerosis, a curious finding considering the absence of important proteinuria.

Causes

The etiology of MeN is unclear, but it is certainly not explained by conventional causes such as diabetes mellitus or hypertension.[1][7] Many risk factors have been proposed but to date, the causes of the disease remain uncertain and controversial.

From the very first report,[7] pesticides, environmental toxins, well water contamination, heavy metals, arsenic and others have been proposed among possible causes of the disease. For instance, the above-mentioned declaration produced by the April 2013 International Conference which took place in San Salvador said that: “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.” However, agrochemicals and heavy metals are ubiquitous in endemic and non-endemic areas, feature proteinuria, or have not been related previously to CKD but only to acute kidney injury. Mesoamerican volcanic soils, for instance, are rich in arsenic and cadmium.

In Central America, it is a cultural pattern that men do the field work while women stay home to perform domestic chores; since the disease is mainly seen in men/workers, it has been speculated it may be related to occupation, heat-stress or agrochemicals (particularly pesticides). Any widespread-environmental or community well water contamination cannot explain this particular gender/labor pattern; agrochemicals traditionally have been widely used in these and other farming areas where the disease is not prevalent,[10][14] so a specific product -or products combination- not used elsewhere but only in the coastlands should be brought into consideration by the pesticides hypothesis to offer a plausible explanation as the main culprit.

Alcoholism and self-medication are also common features in these populations. NSAIDs self-prescription is particularly widespread,[22][23] possibly due to frequent agricultural work posture-related pains, and dysuria is commonly treated with aminoglycosides, often not related to urinary tract infections but perhaps associated with dehydration itself.[22]

Published evidence, clinical manifestations,[10][14][21][24] and biopsy findings[21] suggest MeN could be a new form of CKD, a new pathologic entity related to repeated heat stress, dehydration, salt depletion, and other contributing factors, like NSAIDs abuse.[1][3][4][12][21][25][26][27][28][29] A recent study[30] with Wild-type mice exposed to recurrent dehydration induced by heat stress produced a similar pattern of kidney injury, thus providing a potential etiological 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.

Adding elements to the debate, another recent study from Sri Lanka,[31] where a similar and apparently new form of CKDu has become a serious public health concern too,[32] suggests chronic arsenic toxicity could be an important etiological factor. The authors hypothesize that "Agrochemicals could be the possible source for this Arsenic contamination". Dr. Channa Jayasumana, a Sri Lankan researcher, member of the medical faculty of Rajarata University, has been a leading supporter of the pesticide hypothesis, always in connection to hard water consumption. He has said that research conducted by his university found that "pesticides and chemical fertilizers were responsible for the spike in kidney diseases",[33] the same position supported by the authors of one study developed in El Salvador,[23] 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,[34] 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,[35] waiting for direct evidence linking the disease to the use of agrochemicals in the Mesoamerican region.

In the other hand, contesting the dehydration hypothesis, some argue[who?] 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 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".

A large (nearly 38,000 workers, 5 year follow up) prospective study from Thailand in 2012[36] 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.

To date, CKDu (MeN) causes remain undetermined and debatable; nothing can be ruled out. There is space for further investigation, e.g.: Leptospirosis has been suggested as a possible contributing factor[1] and oceanic nephrotoxic algae have also been brought to the chart of possibilities as a culprit for this unusual form of kidney damage.[citation needed] Assessment of the two main hypotheses (and, especially, their possible synergism) will depend on more and better research.

References

  1. ^ a b c d e 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. PMID 24412050.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. ^ Landau, Elizabeth (June 11, 2014). "Mysterious kidney disease plagues Central America". CNN. Retrieved 13 June 2014.
  3. ^ a b Wesseling C, Crowe J, Hogstedt C, Jakobsson K, Lucas R, Wegman DH. (November 2013). "The epidemic of chronic kidney disease of unknown etiology in Mesoamerica: a call for interdisciplinary research and action". Am J Public Health. 103 (11): 1927–30. doi:10.2105/AJPH.2013.301594. PMID 24028232.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ a b Ramirez-Rubio O, McClean MD, Amador JJ, Brooks DR. (January 2013). "An epidemic of chronic kidney disease in Central America: an overview". J Epidemiol Community Health. 67 (1): 1–3. doi:10.1136/jech-2012-201141. PMID 23002432.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ Cohen, J. (April 2014). "Mesoamerica's Mystery Killer". Science. 344 (6180): 143–147. doi:10.1126/science.344.6180.143.
  6. ^ Phelan M, Linton M. (April 2014). "Science Magazine: Researchers Hunt Origin of an Enigmatic Kidney Disease". {{cite journal}}: Cite journal requires |journal= (help)
  7. ^ a b c d e f g García-Trabanino R, Aguilar R, Reyes Silva C, Ortiz Mercado M, Leiva Merino R. (September 2002). "[End-stage renal disease among patients in a referral hospital in El Salvador]". Rev Panam Salud Publica. 12 (3): 202–6. PMID 12396639.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ Sanoff SL, Callejas L, Alonso CD, Hu Y, Colindres RE, Chin H, Morgan DR, Hogan SL. (2010). "Positive association of renal insufficiency with agriculture employment and unregulated alcohol consumption in Nicaragua". Ren Fail. 32 (7): 766–77. doi:10.3109/0886022X.2010.494333. PMC 3699859. PMID 20662688.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ a b c d e Torres C, Aragón A, González M, López I, Jakobsson K, Elinder CG, Lundberg I, Wesseling C. (March 2010). "Decreased kidney function of unknown cause in Nicaragua: a community-based survey". Am J Kidney Dis. 55 (3): 485–96. doi:10.1053/j.ajkd.2009.12.012. PMID 20116154.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ a b c d e f g h i j Peraza S, Wesseling C, Aragon A, Leiva R, Garcia-Trabanino R, Torres C, Jakobsson K, Elinder CG, Hogstedt C. (April 2012). "Decreased kidney function among agricultural workers in El Salvador" (PDF). Am J Kidney Dis. 59 (4): 531–40. doi:10.1053/j.ajkd.2011.11.039. PMID 22300650.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ a b c O'Donnell JK, Tobey M, Weiner DE, Stevens LA, Johnson S, Stringham P, Cohen B, Brooks DR. (September 2011). "Prevalence of and risk factors for chronic kidney disease in rural Nicaragua". Nephrol Dial Transplant. 26 (9): 2798–805. doi:10.1093/ndt/gfq385. PMID 20615905.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ a b Brooks DR, Ramirez-Rubio O, Amador JJ. (April 2012). "CKD in Central America: a hot issue". Am J Kidney Dis. 59 (4): 481–4. doi:10.1053/j.ajkd.2012.01.005. PMID 22444491.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ a b c McClean MD, Amador J, Laws R, et al. (2012). "Biological sampling report: Investigating biomarkers of kidney injury and chronic kidney disease among workers in Western Nicaragua" (PDF). {{cite journal}}: Cite journal requires |journal= (help)
  14. ^ a b c d e f g García-Trabanino R, Domínguez J, Jansà JM, Oliver A. (January 2005). "[Proteinuria and chronic renal failure in the coast of El Salvador: detection with low cost methods and associated factors]". Nefrologia. 25 (1): 31–8. PMID 15789534.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ Cerdas M. (August 2005). "Chronic kidney disease in Costa Rica". Kidney Int Suppl. 97 (S): 31–35. doi:10.1111/j.1523-1755.2005.09705.x. PMID 16014096.
  16. ^ Wesseling C. (June 2014). "Mesoamerican nephropathy in Costa Rica: Geographical distribution and time trends of chronic kidney disease mortality between 1970 and 2012". Occup Environ Med. 71 (S): 27. doi:10.1136/oemed-2014-102362.83. PMID 25018302.
  17. ^ Laux T. (April 2015). "Dialysis enrollment patterns in Guatemala: evidence of the chronic kidney disease of non-traditional causes epidemic in Mesoamerica". BMC Nephrology. 16 (1): 54. doi:10.1186/s12882-015-0049-x. PMID 25881146.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  18. ^ 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: http://www.salud.gob.sv/archivos/comunicaciones/archivos_comunicados2013/pdf/Declaracion_San%20Salvador_ERCnT_26042013.pdf Accessed March 2, 2014.
  19. ^ 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
  20. ^ Laux TS, Bert PJ, Barreto Ruiz GM, González M, Unruh M, Aragon A, Torres Lacourt C. (July 2012). "Nicaragua revisited: evidence of lower prevalence of chronic kidney disease in a high-altitude, coffee-growing village". J Nephrol. 25 (4): 533–40. doi:10.5301/jn.5000028. PMID 21956767.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  21. ^ a b c d e Wijkström J, Leiva R, Elinder CG, Leiva S, Trujillo Z, Trujillo L, Söderberg M, Hultenby K, Wernerson A. (November 2013). "Clinical and Pathological Characterization of Mesoamerican Nephropathy: A New Kidney Disease in Central America". Am J Kidney Dis. 62 (5): 908–18. doi:10.1053/j.ajkd.2013.05.019. PMID 23850447.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  22. ^ a b Ramirez-Rubio O, Brooks DR, Amador JJ, Kaufman JS, Weiner DE, Scammell MK. (April 2013). "Chronic kidney disease in Nicaragua: a qualitative analysis of semi-structured interviews with physicians and pharmacists". BMC Public Health. 13 (13): 350. doi:10.1186/1471-2458-13-350. PMC 3637184. PMID 23590528.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  23. ^ a b Orantes CM, Herrera R, Almaguer M, et al. (October 2011). "Chronic kidney disease and associated risk factors in the Bajo Lempa region of El Salvador: Nefrolempa study, 2009" (PDF). MEDICC Rev. 13 (4): 14–22. PMID 22143603.
  24. ^ 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; 2013:209-210. http://www.saltra.una.ac.cr/index.php/sst-vol-10. Accessed April 13, 2014.
  25. ^ Tangri N (29 July 2013). "MesoAmerican Nephropathy: A New Entity". eAJKD. National Kidney Foundation.
  26. ^ Johnson RJ, Sánchez-Lozada LG (October 2013). "Chronic kidney disease: Mesoamerican nephropathy—new clues to the cause". Nat Rev Nephrol. 9 (10): 560–1. doi:10.1038/nrneph.2013.174. PMID 23999393.
  27. ^ 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. (March 2014). "Resolving the Enigma of the Mesoamerican Nephropathy: A Research Workshop Summary". Am J Kidney Dis. 63 (3): 396–404. doi:10.1053/j.ajkd.2013.08.014. PMID 24140367.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  28. ^ Weiner DE, McClean MD, Kaufman JS, Brooks DR. (March 2013). "The Central American Epidemic of CKD". Clin J Am Soc Nephrol. 8 (3): 504–11. doi:10.2215/CJN.05050512. PMID 23099656.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  29. ^ Wernerson A, Wijkström J, Elinder CG. (May 2014). "Update on endemic nephropathies". Curr Opin Nephrol Hypertens. 23 (3): 232–8. doi:10.1097/01.mnh.0000444911.32794.e7. PMID 24717833.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  30. ^ 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. (December 2013). "Fructokinase activity mediates dehydration-induced renal injury". Kidney Int. 86 (2): 294–302. doi:10.1038/ki.2013.492. PMC 4120672. PMID 24336030.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  31. ^ Jayasumana MA, et al. (2013). "Possible link of chronic Arsenic toxicity with chronic kidney disease of unknown etiology in Sri Lanka". Journal of Natural Science Research. 3 (1): 64–73.
  32. ^ Redmon JH, Elledge MF, Womack DS, Wickremashinghe R, Wanigasuriya KP, Peiris-John RJ, Lunyera J, Smith K, Raymer JH, Levine KE (2014). "Additional perspectives on chronic kidney disease of unknown aetiology (CKDu) in Sri Lanka—lessons learned from the WHO CKDu population prevalence study". BMC Nephrology. 15: 125. doi:10.1186/1471-2369-15-125. PMC 4120717. PMID 25069485.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  33. ^ "Activists demand FAO compensation for kidney disease". UCA News. December 18, 2013.
  34. ^ Jayatilake, Nihal; Mendis, Shanthi; Maheepala, Palitha; Mehta, Firdosi R (2013). "Chronic kidney disease of uncertain aetiology: prevalence and causative factors in a developing country". BMC Nephrology. 14 (1): 180. doi:10.1186/1471-2369-14-180.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  35. ^ Sasha Chavkin (11 April 2014). "Herbicide ban on hold in Sri Lanka, as source of deadly kidney disease remains elusive". The Center for Public Integrity. Retrieved 3 September 2014.
  36. ^ Benjawan Tawatsupa, Lynette L-Y Lim, Tord Kjellstrom, Sam-ang Seubsman, Adrian Sleigh, and the Thai Cohort Study Team (May 2012). "Association Between Occupational Heat Stress and Kidney Disease Among 37 816 Workers in the Thai Cohort Study (TCS)". J Epidemiol. 22 (3): 251–60. doi:10.2188/jea.JE20110082. PMC 3798627. PMID 22343327.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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