Mesoamerican nephropathy

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 with a high risk of heat stress, 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 during the 52nd Directing Council, 65th Session of the Regional Committee of WHO for the Americas, in October 2013.^[19]

In November 2015, a second CENCAM workshop was held in San Jose, Costa Rica. A statement and a report are under the works.

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. Only dysuria has been reported as an occasional early symptom of the disease.

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][21]

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][22][21][23]} Also, many patients show uricosuria, and urate crystals are seen on fresh urine samples.^[21][24]

Histopathological findings of the disease include tubular atrophy, interstitial fibrosis, and global glomerulosclerosis, a curious finding considering the absence of important proteinuria.^[22][25]

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.

As is often the case in such controversies, the affiliation of researchers plays a critical role in forming their opinions. Professor Collingridge explains:^[26]

The traditional view of expert opinion is . . . radically mistaken. An expert is traditionally seen as neutral, disinterested, unbiased. . . . On the view proposed here . . . an expert is best seen as a committed advocate. . . . It is notorious that the opinion of an expert . . . can often be predicted from knowledge of which group has his affiliation.

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,^[27][28] 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.^[27]

Published evidence, clinical manifestations,^{[10][14][21][22][29]} and biopsy findings^[22][25] 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.^{[1][3][4][12][21][22][24][30][31][32][33][34][35][36]} A recent study^[37] 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,^[38] where a similar and apparently new form of CKDu has become a serious public health concern too,^[39] suggests chronic synergestic exposure to multiple pesticide residues and heavy metal could be the main etiological factor. The authors hypothesize that “Agrochemicals are the essential factor for the disease“. 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”,^[40] Further he points out heat stress and dehydration is an important aggravating factor of the disease. The same position supported by the authors of one study developed in El Salvador,^[28] 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,^[41] 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,^[42] waiting for direct evidence linking the disease to the use of agrochemicals in the Mesoamerican region.

On the other hand, contesting the dehydration hypothesis, some argue 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^[43] 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.

Recently published evidence suggest heat stress and strenuous activity-induced cyclic uricosuria and crystalluria as a possible mechanism for the tubular lesion.^[21][24][30]

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][44][45] and oceanic nephrotoxic algae or agents have also been brought to the chart of possibilities as a culprit for this unusual form of kidney damage. Assessment of the two main hypotheses (and, especially, their possible synergism) will depend on more and better research.

References