In Mesoamerica, an increasing number of cases have been reported over the years –and it is therefore considered endemic to the region, being called Mesoamerican endemic nephropathy (MeN). In Sri Lanka it is called Sri Lankan nephropathy, and in India, Uddanam nephropathy.13 Although its cause has not been elucidated to date, it is designated by the term of its geographic referent.1 It occurs mainly in specific areas below 500 m above sea level (MASL), associated with the Pacific Ocean coast, in warm climates with sandy soils, which suggests ease of airborne particle transport and entry into the human body through accidental geophagy and inhalation.2,14–17 The case of Aguascalientes and Calvillo, in Mexico, breaks with this premise as cases have been reported at over 1600 MASL and the ambient temperature in that area averages around 19 °C,18 suggesting other environmental causes.

El Salvador and Nicaragua are among the 10 countries with the highest CKD mortality worldwide, and it is the leading cause of mortality among working-age people in El Salvador.19 This region has experienced a >50% decline in age-standardized disability-adjusted life years (DALYs) attributable to CKD from 1990 to 2017, deviating from the global trend in that country.20

All regional nephropathies share the following social attributes: a) they affect low- to middle-income countries with tropical climates, b) they predominantly involve rural agricultural communities, c) the disease manifests mostly in men, d) in most cases there is a significant absence of proteinuria and hypertension, and e) they present chronic tubulointerstitial nephritis in kidney biopsies.13

According to what was stated by García-Trabanino and Correa-Rotter, a meta-analysis showed that the disease is positively associated with male sex and family history of CKD,1 low fluid intake and low altitude above sea level, but no significant association was found with pesticide exposure, nonsteroidal anti-inflammatory drug use, heat stress, or alcohol consumption.3 In general, to date and despite many studies conducted, none of the proposed etiological hypotheses has been scientifically proven, so the cause of the disease could be multifactorial, requiring a combination of more than one of the aforementioned elements or at least one causal agent and other facilitating factors to manifest.2,3

In Mesoamerica, it has been associated with workers in sugarcane, cotton, corn, and rice crops, construction workers, mining, fishing industry, shrimp farms, and brick factories.21–23 The disease is more common among those who work at low altitude and sea level, on plantations related to low-altitude extensive crops, and nearly absent among coffee plantation workers at higher elevations.24–26 Milder and less frequent manifestations of kidney disease have also been observed in women and children living in these regions.27,28

Those who have considered heat stress to play an important role in CKD have suggested that the increased prevalence may be due to climate change with even higher temperatures, which could suggest that this disease could become more common over time; however, acute kidney injury associated with manual labor in the heat has been reported in Florida and California29,30; nevertheless, in this case there was no documentation of an associated increase in CKD rates.

A limitation of the heat stress hypothesis is the fact that there are many warm regions in the world associated with agricultural activity where this type of kidney disease is uncommon or has not been reported at all.31 Previous work has also suggested that this CKDu may be caused by agrochemicals, heavy metals, or contaminated water; however, the considerable regional disparities make it difficult to establish a common causal link in the investigation of the disease.13

Furthermore, it is known that CKDu occurs among miners, construction workers, brick manufacturers, etc., in whom there is no occupational exposure to glyphosate or other pesticides. A systematic review and meta-analysis of epidemiological studies in 2018 also found no association between CKDu and pesticides.13 It is now concluded that exposure to higher ambient temperature is associated with a more rapid decline in renal function in patients already carrying CKD.1,32

According to what was established by Ramachandra et al., who cited works by Ordunez et al.,33 they suggested in a temporal trend analysis and mortality pattern in Central America from 1997 to 2013 that the heat stress hypothesis could not fully explain the MeN epidemic.33 Similarly, VanDervort et al. reported a lack of association between high ambient temperature and the occurrence of CKDu in El Salvador.34 The lack of a high prevalence of the disease among agricultural communities in other areas with a similar climate also does not support this hypothesis31; the case of Aguascalientes, Mexico, also does not correlate with this premise as the average temperature in this location is 19 °C.18

Furthermore, hyperuricemia, although reported to be common in some studies, is not a consistent finding, and given that uric acid is excreted by the kidneys, elevated urate levels could simply be an effect of reduced estimated glomerular filtration rate (eGFR), rather than the cause. Therefore, some authors hypothesize that although heat stress may be an important contributing factor to CKDu progression, it is unlikely to be the sole cause31; moreover, there is insufficient published literature studying its statistical association with other forms of endemic nephropathy.13

Among the most important heavy metals in toxicological terms that the literature associates in water and soil with CKD are: arsenic (As), cadmium (Cd), and lead (Pb). Currently, the literature establishes them as nephrotoxic, mentioning chronic low- to moderate-dose exposures that contribute to CKD35–38; in the case of Aguascalientes, Mexico, arsenic was also found in the population's drinking water.18 The Agency for Toxic Substances and Disease Registry (ATSDR fact sheets) details the potential effects on human health of these elements in the environment and describes in detail the effect of these metals on each organ of the human body.39–41

Within the framework of this review, vanadium (V) is also mentioned, as it presents effects compatible with the cellular lesions found in CKDu40; additionally, this review presents an analysis of the specific contribution of silica to the disease. The genotoxic role of heavy metals involves several pathways through which they can cause damage to the body, with special attention to renal cells.42 Among the different ways heavy metals can affect DNA are direct oxidation of the molecule, causing strand breaks and its methylation,43 which may lead to alterations in gene expression, including the activation of oncogenes and the silencing of tumor suppressor genes.44

DNA methylation can be identified as epigenetic damage, which is an alteration in gene expression that can be inherited and is reversible. Ways to reverse epigenetic damage include stopping the patient's exposure to the toxic substance45 and the use of demethylating drugs,5,46 thus potentially reversing it with such therapies,47 which would be highly beneficial for these populations.

There are not many histological studies that have been able to relate histological alterations between MeN patients and other Asian patients, but a study by Vervaet et al.48 in 34 renal biopsies from patients diagnosed with chronic interstitial nephritis in agricultural communities (CINAC) in stages 2 and 3, found that rats treated with cyclosporine, a calcineurin inhibitor, compared with a control group of rats subjected to dehydration for four weeks, developed lysosomal alterations in proximal tubular cells that were absent in the dehydration group rats.48

Furthermore, the finding of an identical lesion in the proximal tubular cells –lysosomes– in CINAC nephrotoxicity and calcineurin inhibitor nephrotoxicity in different geographic regions, such as in El Salvador, Sri Lanka and India, suggests a common paradigm in which CINAC patients experience a tubulotoxic mechanism similar to calcineurin inhibition nephrotoxicity; the lysosomal alteration was also found associated with nephrotoxic drugs (lomustine, clomiphene, lithium, cocaine).48 However, As as As2O3 has also been described as exerting a cellular effect via calcineurin NFAT inhibition,49,50 which also suggests the specific toxic role of As at the renal cell level. These lysosomal alterations could be considered what is known in toxicology as a “nonspecific toxicological marker,” but a very important one given that it has been found in both geographic regions. Table 1 tbl1 presents a summary of the main cellular damage mechanisms caused by nephrotoxic metals in relation to this pathology.

It is of great importance to identify the most reliable effect biomarkers for identifying heavy metal exposure that can be used in human biomonitoring studies.100–104 Most mammals metabolize inorganic arsenic (iAs) by reducing it to trivalence, followed by oxidative methylation to pentavalence, and it is excreted primarily in urine within 4–5 days in most species.105 Intra- and interindividual differences in iAs methylation may affect the adverse health effects of arsenic. The most common exposure biomarker for iAs is the measurement of total urinary arsenic; however, this biomarker cannot predict arsenic concentrations in target tissues, nor can it be used to assess possible damage from chronic exposure.106

Total urinary arsenic levels (24-h), hair and nail levels could be short-term internal dose biomarkers, while skin hyperpigmentation and palmoplantar hyperkeratosis could be long-term internal dose biomarkers (years).107

Regarding Cd, β-2-microglobulin and N-acetyl-β-d-glucosaminidase are well-established, sensitive (but less specific for causality of damage) renal tubular damage biomarkers and the most common for relating Cd exposure to renal tubular dysfunction in exposed patients. Biomarkers based on omics analyses, that is, changes in the epigenome, transcriptome, proteome and metabolome associated with metal exposure, are considered effect biomarkers; that is, of disease.108 This means that exposure biomarkers should not be used to establish a disease diagnosis; moreover, they may be negative and the individuals may already be affected, because they are also short-term biomarkers but may have already caused cellular toxicity changes in the tissues. Monitoring based on exposure biomarkers for CKDu should be evaluated in conjunction with renal function tests and be based on toxic exposure scenarios in the population investigated.

Internationally, a discrepancy has been reported between sex-specific treatment of renal failure by dialysis (higher in men) and the prevalence of chronic kidney disease in the general population (higher in women); however, men are more frequent in nephrology services,109,110 who also have a higher prevalence of end-stage kidney disease.111

Studies have shown that women have a more efficient arsenic methylation profile (higher proportion of dimethylated species resulting from their cellular metabolism) and more easily eliminate the incorporated arsenical load.52,60 In general terms, the literature describes a lower rate of arsenic-associated cancer in women60; gender differences in arsenic metabolism enzymes may affect its biotransformation in the liver, which may be one of the important mechanisms of arsenic toxicity in different sexes and different target organs.112–116

Poverty can increase the population's susceptibility to illness from exposure to one or more environmental toxicants.39,57–59,117,118 Likewise, reduced access to timely medical care makes poverty a vulnerability factor, increasing the risk of mortality.119–123

Regional and local differences in socioeconomic context have been described in the Americas, which is directly related to arsenic content in water. Research has found lower educational levels associated with higher arsenic concentrations in public water supplies in the United States,124,125 to which different predictive models were applied.126,127

An inherited cause has been postulated since familial recurrence has been observed in the disease in endemic areas, more common in men, even within the same family.1,128

Genetic testing has revolutionized the diagnosis of many diseases, including CKD. Recent studies indicate that genetic testing can diagnose the cause in approximately 10%–40% of CKDu cases.129–136

It has been considered that genetics also plays a role as an important risk factor, since not all workers exposed to the same metabolic and heat stress conditions develop this disease; furthermore, it occurs in families, pointing to the possibility that heredity could play a role of interest, and that environmental and genetic factors play an important role in predisposition to CKDu. In the case of Aguascalientes, Mexico, the inbreeding relationship maintained in that population has been well studied.18

The association of single nucleotide polymorphisms in genes with CKDu susceptibility in the KCNA10 and SLC13A3 genes has been analyzed in patients from central India with susceptibility to increased serum uric acid.135

A possible genetic basis for CKDu has also been postulated, based on the finding of familial clustering in some cases. Genome-wide association studies from the North Central Province in Sri Lanka have revealed a significant association between CKDu and the SLC13A3 and KCNA10 genes, while in India a role for CYP1A1 polymorphism has been suggested.13,93,137,138

Adults with low birth weight (LBW) have a higher prevalence of kidneys with a congenital nephron deficit whose glomeruli are enlarged (oligomeganephronia). These findings, moreover, are accompanied throughout their clinical history by a greater presence of microalbuminuria and accelerated loss of renal function, which translate into CKDu. This has a significant impact on morbidity and mortality, and is strongly associated with LBW, fetal growth restriction and prematurity as risk factors for CKDu. Although a low number of nephrons does not always determine that CKDu will develop in the future, this characteristic reduces the kidneys' ability to withstand subsequent damage (such as in diabetes and arterial hypertension) and is thus proposed as a marker for renal pathology in adult life.139,140

CKD in our endemic area is treated following the guidelines for CKD in general, where earlier stages have lower morbidity and mortality and a lower risk of progression to more advanced stages. The earlier the treatment is initiated and environmental exposure to other nephrotoxicants is avoided, the better the patient's survival and the lower the probability of advancing to other stages of CKD, including the end stage (KDIGO, SLANH).

To date, there is no specific treatment for the disease, although as with any other nephropathy, early detection and adequate management may help improve the evolution and prognosis of the disease, delaying the initiation of renal replacement therapy, which is of limited access in the affected countries.

Universal salt restriction is not recommended in these patients due to the possibility of hyponatremia, nor is restriction of the amount of fluids the patient ingests, since the endemic areas of the disease are located in hot regions. Similarly, consumption of fructose-rich carbonated beverages is discouraged.141 In many cases, hypokalemia persists despite dietary reinforcement and the use of oral potassium supplements and a potassium-sparing diuretic (expert recommendation not yet demonstrated with evidence) such as spironolactone at the minimum necessary dose is required, particularly in early stages of the disease or in moderately advanced stages.141