Mesoamerican nephropathy

# Overview
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. Reports in Science Magazine suggest that in El Salvador alone, PAHO's latest figures say CKD 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 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.

# 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.
- In 2002, 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 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.
- 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 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.
- The Declaration described CKD as having catastrophic effects associated with toxic-environmental and occupational factors, dehydration and behaviors harmful to renal health.

# 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".
MeN is silent during initial stages but appears to progress quite fast to end-stage renal disease.
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,
- Usually no hypertension.
Histopathological findings of the disease were described in a recently published paper, and include:
- Tubular atrophy
- Interstitial fibrosis
- 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. Many risk factors have been proposed but to date, the causes of the disease remain uncertain and controversial.
From the very first report, pesticides, environmental toxins, well water contamination, heavy metals, arsenic and others have been proposed among possible causes of the disease. For instance, in the April 2013 International Conference which took place in San Salvador it had been suggested that 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.
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, 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.

## Alcohol & Drugs
- 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.

## Agrochemicals
- It has been hypothesized that Agrochemicals could be the possible source for this Arsenic contamination. 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. Research done by this university, and also proved by many other studies, has found that pesticides and chemical fertilisers were responsible for the spike in kidney disease.
- 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.

## Heat stress & Dehydration
- In the other hand, supporting the dehydration hypothesis, 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 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.

# Pathophysiology
- Published evidence, 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 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 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.

# Clinical Features

# Differentiating Mesoamerican nephropathy from other Diseases
- Mesoamerican nephropathy must be differentiated from other endemic nephropathies, such as:
- Balkan or Aristolochic acid nephropathy
- Analgesic nephropathy
- Cadmium and lead nephropathy
- Nephropathy from ochratoxin and other moulds
These nephropathies can be differentiated histologically by microscopic examination of renal biopsies

# Epidemiology and Demographics
- The disease is only prevalent in the Pacific ocean's coastal lowlands, absent from coffee plantations at higher grounds.
- 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.

## Age
- Mesoamerican nephropathy is mainly prevalent in young and middle aged men
- It has not been described in children.

## Gender
- Mesoamerican nephropathy is seen in with rates varying from 1:3 to 1:10 when compared to women,
- 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).

# Risk Factors
- A significant risk factor in the development of Mesoamerican nephropathy is individuals who do strenuous work (miners, construction, port and transportation workers) in the high temperatures of the coastlands with inadequate water intake.
- Another risk factor is exposure to agrochemicals (particularly pesticides).
- Other risk factors include:
excessive NSAID use
male sex
Individuals with co-morbidities such as hypertension and diabetes
agricultural workers
- excessive NSAID use
- male sex
- Individuals with co-morbidities such as hypertension and diabetes
- agricultural workers

# Diagnosis

## Diagnostic Criteria
According to a study conducted in Nicaragua, the following diagnostic criteria was produced:
- A patient without hypertension or diabetes
- Serum creatinine that is elevated or increased from baseline
- Leukocyturia
- At least 2 of the following: Fever, nausea/vomiting, back pain, muscle weakness, headache, leukocytosis or neutrophilia

## Symptoms
- A patient with Mesoamerican nephropathy is usually asymptomatic until there is noticeable rise in serum creatinine and the patient lands in chronic kidney disease. However studies done in a private hospital in Nicaragua, located near the sugar cane estate, which provides primary health care to the families living their, has shown that their may be early symptoms that patients present with.
The patient may present with:
- Nausea
- Back pain
- Fever
- Vomiting
- Headache
- Muscle weakness

## Laboratory Findings
In the same study done in the private hospital in Nicaragua the following data was collected.

### Haematological and Blood Chemistry Findings
- The most prominent finding was leucocytosis and neutrophilia with elevated serum creatinine levels of more than 2-fold rise from the baseline.
- Other haematological findings include lymphopenia, depressed hemotocrit and haemoglobin, hypokalemia, hypomagnesia, and hyponatremia.

### Urinalysis
- Urine examination showed leukocyturia and leukocytic casts with possible low levels of proteinuria.

## Imaging Findings
- On ultrasonography, the kidneys may appear small and the cortex may be narrowed.

## Other Diagnostic Studies
- Mesoamerican nephropathy may also be diagnosed using renal biopsy.
- Findings on renal biopsy include glomerulosclerosis, glomerular hypertrophy, signs of chronic glomerular ischemia, mild to moderate tubulointerstitial damage and mild vascular changes were seen.

# Treatment

## Medical Therapy
- The mainstay of therapy for Mesoamerican nephropathy is hydration and rehydration.
- The idea is that, excessive work in heat stress, causes excessive sweating, which in turn causes loss of essential minerals such as sodium and potassium. Thus, proper hydration in addition with minerals could prevent this disease.
- Avoiding nephrotoxic drugs, mainly NSAID's, is another important preventive measure.
- Continuous insults may progress the disease to CKD, where the patient will eventually require dialysis.

## Prevention
- Considering the etiology of this disease the best possible preventive measure would be to avoid dehydration or provide adequate hydration and rehydration.
- Another preventive measure would be to avoid nephrotoxic drugs such as NSAID's, which have also been at fault for causing Mesoamerican nephropathy.