Mesoamerican Nephropathy

Mesoamerican nephropathy (MeN) is a currently unexplained epidemic of chronic kidney disease of unknown origin (CKDu), 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.

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, it has been estimated that this largely unknown epidemic has caused the premature death of at least 20,000 men in the region. 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".

The people affected by the epidemic are mainly young and middle-aged male laborers in the agricultural sector, particularly sugarcane workers. 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) in the high temperatures of the coastlands. The epidemic appears to affect particular Pacific coastal regions of Nicaragua, El Salvador, Costa Rica, and Guatemala.

Causes

The cause of MeN is unclear, but it is certainly not explained by conventional causes such as diabetes mellitus or hypertension. 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.

Multifactorial disease

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.”

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 CKD but only to acute kidney injury. Mesoamerican volcanic soils, for instance, are rich in arsenic and cadmium (e.g. CKDu miners).

Alcoholism and self-medication

Alcoholism and self-medication are also common features in these populations. NSAIDs self-prescription is particularly widespread, 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.

Clinical manifestations

Clinical manifestations, and biopsy findings 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. A recent study 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.

Heatstress and dehydration

The same position supported by the authors of one study developed in El Salvador, 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, 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, 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 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.

Published evidence in 2016 suggest heat stress and strenuous activity-induced cyclic uricosuria and crystalluria as a possible mechanism for the tubular lesion.

Agrochemicals

A relationship between CKDu and people working in agriculture can be found in El Salvador in areas with high pesticide use. 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. In a Latin American country high creatinine levels of workers can likely be attributed to the use of the nematicide DBCP. Also a relationship between increased blood levels of certain organochlorine pesticides and the occurrence of chronic kidney disease was observed in India. 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.

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

• 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 of occupational heat stress and Kidney Disease from Thailand in 2012 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.

Diagnosis

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".

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, 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. 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.

Clinically, MeN presents as a tubular-interstitial disease: patients have low-range or no proteinuria, electrolyte abnormalities -mainly low serum potassium and sodium-, and high levels of uric acid, but no hypertension. Also, many patients show uricosuria, and urate crystals are seen on fresh urine samples.

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

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.

• ${\displaystyle \mathrm{\varnothing }}$ 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.

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.

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 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.

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 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, also from El Salvador, reported some field efforts on trying to identify the cause of the disease, and confirmed its curious epidemiological pattern.

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.” 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.

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

See also

• Precautionary Principle