Mesoamerican nephropathy

INTRODUCTION — Mesoamerican nephropathy (MeN), sometimes also called chronic kidney disease (CKD) of unknown cause (CKDu) [1] or CKD of nontraditional cause (CKDnT) [2], refers to CKD that presents in young, agricultural workers, primarily in Central America, in the absence of any clear etiology [3-7]. Excessive heat stress, caused by physical exertion in the setting of high external temperatures, is the likely etiology of the Mesoamerican epidemic of CKDu [8-13]. There is no specific treatment of MeN, other than that for nonproteinuric CKD from any other cause, but prevention programs are beneficial [14-16].

This topic reviews the epidemiology, pathogenesis, clinical presentation, diagnosis, and treatment of MeN. An overview of the treatment of CKD is presented elsewhere. (See "Overview of the management of chronic kidney disease in adults".)

EPIDEMIOLOGY — The entity of MeN was first suggested when it was noted that a high percentage of patients initiated on dialysis in El Salvador had no obvious cause of chronic kidney disease (CKD) [17,18]. For instance, in a hospital-based study of 205 patients initiated on dialysis between 1999 and 2000, the cause of end-stage kidney disease (ESKD) was unknown in 135 patients [17].

Additional studies have revealed a high prevalence of CKD of unknown etiology (CKDu) and CKD-related mortality in specific regions of El Salvador, Nicaragua, Guatemala, Costa Rica, and Mexico [5,18-20]. A spatial disease mapping study of these five countries found that the incidence of CKDu is highest in municipalities with hot climates and heavy sugarcane cultivation [21].

●In one study of 291 males from the coastlands of El Salvador, the prevalence of previously undiagnosed CKD (defined by creatinine ≥1.5 mg/dL) was 13 percent [22]. Of these, only 38 percent had diabetes or hypertension (which are common causes of CKD in other areas), while the remainder did not appear to have a clear-cut cause for CKD. By contrast, the prevalence of CKD in the United States is approximately 5 percent [23]. (See "Epidemiology of chronic kidney disease".)

●In a study of 775 people (343 males) from the Bajo Lempa region of El Salvador, the prevalence of CKD (defined as estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m²) was 17 percent in males and 4 percent in females [24]. In most cases, diabetes, obesity, and hypertension had been excluded as causes, and the etiology was considered to be unknown.

●Among 2388 individuals from three agricultural communities in El Salvador (Bajo Lempa, Guayapa Abajo, and Las Brisas), the prevalence of CKD was 6.8 percent in females and 17 percent in males [25]. The prevalence of CKD (defined by eGFR <60 mL/min/1.73 m²) increased with age; among individuals age >60 years, 57 percent of males and 28 percent of females had CKD.

●In one report from one township in Nicaragua, the prevalence of CKD (defined by eGFR <60 mL/min/1.73 m²) was 42 percent among males and 9.8 percent among females [26].

●In a study from Quezalguaque, a municipality in Nicaragua, the prevalence of CKD (defined as eGFR <60 mL/min/1.73 m²) was 12.7 percent overall among 771 individuals tested and 53 percent among males aged 57 years or older. Among 98 individuals with a low eGFR who had their urine examined, 79 percent had no proteinuria detected by dipstick, and there were no associations with well-known risk factors for CKD such as hypertension or diabetes [27].

●Compared with construction workers and farmers, sugarcane cutters in Chinandega and Leon municipalities in Nicaragua had greater exposure to heat and consume more fluid on workdays but had less obesity, lower blood sugar, lower blood pressure, and a better lipid profile [28]. Reduced eGFR occurred in 16, 9, and 2 percent of sugarcane cutters, construction workers, and farmers, respectively. Serum uric acid levels related strongly and inversely to eGFR levels.

●In males aged 50 to 54 years, the CKD-associated mortality rate in Nicaragua and El Salvador between 2000 and 2009 was approximately 110/100,000 population compared with less than 40/100,000 population in countries such as Panama, Cuba, and Costa Rica [29].

●Between 2004 and 2013, the average annual incidence rate of ESKD in the Bajo Lempa region of El Salvador was 1410 per million population [19]. Most patients were male (9:1), and two-thirds of patients did not report diabetes or hypertension. Few received kidney replacement therapy (KRT), and patient mortality was high even with KRT.

●In a study of workers for a rice company in Costa Rica, CKD was more common among employees who worked in the field, both at baseline (19 versus 4 percent) and at follow-up (26 versus 7 percent) [30]. Excretion of a concentrated urine (urine specific gravity ≥1.025) was frequent in both groups, but field workers had greater exposure to heat and had high workloads.

Based on indirect data from diagnostic codes, the prevalence of CKD appears to be increasing in Nicaragua and El Salvador. In Nicaragua, CKD-related mortality increased from 4 to 10 per 100,000 inhabitants between 1992 and 2002 [18]. CKD-associated mortality rates were as high as 35 per 100,000 in regions close to the Pacific in this study [18]. Cross-sectional studies in these same regions reported a high prevalence of decreased eGFR.

The CKD mortality also appears to have increased in specific regions of Costa Rica [31]. In the Guanacaste province, at the northwest Pacific coast of Costa Rica, among males over 29 years of age, the age-standardized CKD-associated mortality rates per 100,000 increased from 5.8 in the early 1970s to 75.0 in years between 2007 and 2012 [31]. The rate increase in this region of Costa Rica is much higher than that observed in the rest of Costa Rica (which was from 5.9 in the early 1970s to 16.2 between 2007 and 2012). For females, rates increased from 4.5 to 20.7 in Guanacaste versus 4.2 to 9.7 in the rest of the country [31].

In both El Salvador and Nicaragua, MeN appears to be most prevalent in low-altitude, coastal regions. As an example, in a study of 664 individuals from five communities in El Salvador, the prevalence of CKD (defined as eGFR <60 mL/min/1.73 m²) among males from the two coastal communities was 19 and 18 percent [32]. By contrast, the prevalence in the high-altitude populations was below 2 percent. Similarly, in a study of five countries, municipalities in hot areas with much sugarcane cultivation had higher burdens of CKD

Regional differences in prevalence are also present in Nicaragua. In a study of 1096 people from five villages in northwestern Nicaragua, the prevalence of CKD was higher in villages located close to the coast and at a low altitude [33]. In addition, CKD defined by an elevated serum creatinine was highest among males in agricultural regions compared with nonagricultural regions. The pattern was similar for females. As noted above, in another study from Nicaragua, based on indirect data from diagnostic codes, CKD-related mortality varied between different regions, with rates up to 35 per 100,000 in regions close to the Pacific [18].

A high prevalence of CKD, similar to MeN, may exist among other agricultural populations in hot climates, such as Sri Lanka [9,34-36], and has been reported among Nepalese migrants working in Gulf countries [37]. Reports from certain areas of Sri Lanka describe a high prevalence of CKDu, with similar clinical characteristics and risk factors as MeN [38-40]. Even though some of the clinical characteristics between CKDu in Sri Lanka and MeN overlap, it is unclear if their pathogenesis is the same. In fact, patients with CKDu from outside Mesoamerica appear to have a higher degree of interstitial inflammation and vascular changes on histopathology compared with patients who have MeN [41-43]. The histopathologic changes in CKDu outside Mesoamerica appear to be more severe compared with MeN despite a less degree of heat exposure and strenuous work. CKDu is also more common in females and individuals of older age compared with that seen in MeN [42,44,45].

Risk factors — Multiple possible risk factors for MeN have been suggested, including [3-5,25,26,32,46-52]:

●Agricultural and physically demanding work in a hot climate

●Exposure to pesticides or agrochemicals

●Lower socioeconomic class or poverty

●Excessive use of nonsteroidal antiinflammatory drugs

●Male sex

●Infections, possibly resulting from an unknown virus

●Low body mass index

●Consumption of sugar-containing rehydration drinks

●Family history of CKD

●Exposure to silica

●Genetic factors

Hard, physical work in hot climates appears to be the most important underlying risk factor for MeN [3-5,25,32,47]. In a population study cited above, the prevalence of CKD increased with increasing number of years of work in the coastal sugarcane or cotton plantations [32]. In fact, work on sugarcane or cotton plantation was the strongest predictor for CKD among males for each 10-year period (figure 1).

In a study from El Salvador, the rates of hospital admissions for unspecified CKD and nondiabetic ESKD were highest in the southwestern municipalities of La Paz Department, which is the region of highest ambient temperatures (33 to 36ºC) in El Salvador [46]. Percent area of sugarcane cultivation was predictive of CKD by bivariate analysis; the strength of association with heat was less robust by multivariate analysis.

In another study from El Salvador, CKD was twice as common among male agricultural workers compared with nonagricultural workers [25].

Similar associations were reported from Nicaragua. In a case-control study from a Nicaraguan township with a high prevalence of CKD, in addition to age and male sex, the strongest independent association to CKD was lifetime hours cutting sugarcane, particularly during the dry season [26].

In a cross-sectional study of 2275 residents in Leon, Nicaragua, risk factors for CKD (eGFR <60 mL/min/1.73 m²) were older age, living in rural zone, lower education level, self-reported high blood pressure, years of agricultural work, alcohol consumption, and higher levels of daily water consumption. All were associated in a dose-response-related manner with increasing prevalence of CKD. The adjusted odds ratio (OR) for low eGFR increased from 1.3, 1.7, 2.6, and 2.9 with increasing five years of work in agriculture and likewise decreasing educational level [53].

The association between MeN and hard, physical labor in a warm climate ("heat stress") was supported in a study of 284 Nicaraguan sugarcane workers [54]. Workers included cane cutters (n = 51), seeders (n = 36), seed cutters (n = 19), agrochemical applicators (n = 29), irrigators (n = 49), drivers (n = 41), and factory workers (n = 59) [54]. The estimated GFR (eGFR) decreased during harvest in all groups exposed to heat stress but not in drivers and factory workers who were not exposed to heat stress. The changes in eGFR were small, however, and may have been affected by differences in muscle mass or diet and not reflective of true differences in clearance. Similar findings showing a decline in eGFR among agricultural workers after a harvest season have also been reported in other studies [55,56].

Contact with pesticides or other agrochemicals, which is common in agricultural communities with high CKD prevalence [25], has been proposed as a risk factor for MeN [9,29]. The Pan American Health Organization (PAHO) has hypothesized that exposure to agrochemicals and pesticides is an important contributing factor to the pathogenesis of MeN [9,29]. However, this association between CKD and agrochemicals/pesticides is mainly circumstantial and has not been clearly supported by the available evidence [26,50,57]. As an example, a meta-analysis of 25 epidemiologic studies on CKDu in Central America found no significant association between CKDu and pesticide exposure [50]. Overall, even though pesticides are known to cause acute and chronic health diseases in humans [58], they have not been conclusively demonstrated to cause nephrotoxicity [59-61].

Sugar-containing rehydration drinks have been suggested as a risk factor for MeN. In the study from Nicaragua, in models that adjusted for total hours cutting sugarcane during the dry season, MeN was associated with the consumption of a sugar-containing rehydration drink ("bolis") of borderline significance (OR 1.39, 95% CI 0.99–1.95) [26]. There was also a significant association between MeN and chewing sugarcane (OR 2.74, 95% CI 1.11–6.77) in this study.

Genetic factors may be of importance [51].

PATHOGENESIS — The cause of MeN is not known with total certainty. The most likely causes include repeated episodes of acute kidney injury (AKI) related to dehydration [3-5,62,63] and acute or chronic tubulointerstitial nephritis, which, if exposure is prolonged, may result in CKD. An infectious or toxic exposure may also contribute [64,65].

Dehydration-related AKI is suggested by a study of 28 healthy, Brazilian sugarcane workers in whom the plasma creatinine increased by the end of the workday (by an average of 0.24 mg/dL or 0.21 micromol/L), and 5 of the 28 examined males (18 percent) had AKI, defined as a 0.3 mg/dL or 1.5-fold increase in creatinine [66]. Significant dehydration was suggested by symptoms such as frequent muscle cramps during the cutting season and a high urine osmolality (average 890 mOsm/L). Repeated episodes of AKI may evolve into chronic kidney disease (CKD) [67,68].

Tubulointerstitial nephritis is suggested by active surveillance studies performed in a high-risk area of Nicaragua [64,65]. Selected individuals who met proposed criteria for an early acute form of MeN had laboratory studies [64] and biopsy findings [65] that are pathognomonic for tubulointerstitial nephritis. However, it is not clear yet whether the individuals who met the proposed criteria for acute MeN went on to develop the chronic form of MeN. The clinical presentation of these individuals and the biopsy findings are described below. (See 'Acute presentation' below and 'Pathology' below.)

A potential precipitant for tubulointerstitial nephritis has not been identified. Typically, acute tubulointerstitial nephritis is related to exposure to a drug or toxin or infection. (See "Clinical manifestations and diagnosis of acute interstitial nephritis" and "Clinical manifestations and diagnosis of acute interstitial nephritis", section on 'Etiology'.)

The excess use of nonsteroidal antiinflammatory drugs (NSAIDs) may contribute to MeN [4]. The role of NSAIDs is suggested by analysis of biopsies from MeN-affected individuals showing glomerular changes indicative of glomerular ischemia, despite only minor vascular changes [69]. Perturbations in the renin-angiotensin system (RAS) due to excessive and repeated losses of salts due to excessive sweating may also be involved in the pathogenesis [69].

Prolonged and repeated heat stress may cause recurrent AKI and CKD (MeN) [6,8,70-74]. Heat stress can result from strenuous physical activity (eg, agricultural work) performed in extreme heat, which leads to water and solute loss. Concomitant heat stress and sugar consumption, such as from sugarcane or drinking fructose-containing rehydration drinks, can be associated with higher pro-inflammatory stimuli including hypoxia, fructose, uric acid, endotoxins, and cytokines. These inflammatory stimuli ultimately result in AKI. Sugarcane cutters work in the field six to seven days per week for approximately six months (consecutively), allowing little opportunity for recuperative rest. Such a schedule can lead to recurrent AKI, fibrotic changes, and, ultimately, CKD.

Multiple other contributing factors have been suggested including inorganic arsenic, aristolochic acid, mycotoxins, leptospirosis, pesticides, hard water, trace and heavy metals, alcoholic drinks, hypokalemia, and hyperuricemia [3-5,75]. However, there are no data to support these possible contributors [7,76].

CLINICAL FEATURES — Most patients with MeN are otherwise healthy, young or middle-aged males who have a history of physically demanding agricultural work in a hot climate [17,77,78]. (See 'Pathogenesis' above.)

Patients describe weakness and arthralgias and/or muscle cramps [77]. These symptoms often cause them to take nonsteroidal antiinflammatory drugs (NSAIDs), which may contribute to the kidney disease. Some reports suggest that workers may be reluctant to hydrate because of perceptions of water contamination.

Other nonspecific symptoms including headache, tachycardia, fever, nausea, difficulty breathing, dizziness, swelling of hands/feet, and dysuria are often described as occurring weekly, particularly among harvesters [78].

Many patients describe fainting during work, nocturia, and dysuria associated with back or flank pain ("chistata"), which often leads to prescription of antibiotics for presumed urinary tract infection; in most cases, cultures are not performed, however [79].

Patients are usually normotensive or only mildly hypertensive and show no evidence of edema. In one study of 19 patients from Nicaragua with presumed MeN, all had blood pressure <140/90 mmHg [80].

Most patients are not obese.

Laboratory evaluation reveals an increased serum creatinine, with a reduced estimated glomerular filtration rate (eGFR). Patients generally do not have hematuria, and proteinuria is usually absent or present at only low levels [5,69,80]. Urinalysis is benign. The plasma concentrations of potassium, sodium, and magnesium are often low [77]. In a study from Nicaragua, low sodium, low magnesium, and low potassium were observed in 47, 37, and 21 percent of patients, respectively [80,81]. Uric acid may be elevated [5,28,80,82]. Urine markers of tubular injury, including monocyte chemoattractant protein-1 (MCP-1) and kidney injury molecule-1 (KIM-1), are increased [63]. As in other patients with CKD, patients with MeN may have anemia and low levels of erythropoietin.

Ultrasound examination of kidneys often shows somewhat small kidneys with decreased cortical thickness, both consistent with chronic kidney disease (CKD) of almost any cause.

CKD tends to progress, and end-stage kidney disease (ESKD) may eventually develop, although the timeframe of progression may vary and is not well defined. (See 'Prognosis' below.)

Acute presentation — Little is known about the early stages of MeN. In one study, early clinical and laboratory features were defined using active surveillance of workers who presented with acute or subacute kidney injury in a high-risk area of Nicaragua [64]. Patients were identified by local clinicians upon presentation to the hospital. Among 247 patients, symptoms began two days prior to the hospital visit. Almost all patients were normotensive, and 55 percent presented with fever, mostly low grade. Other symptoms included nausea, back pain, vomiting, headache, and muscle weakness in 59, 58, 50, 47, and 45 percent, respectively. Among 206 patients who had a baseline creatinine available, the creatinine increased twofold from baseline over 3.5 months.

The most striking laboratory finding was leukocyturia in 98 percent of patients; 75 percent had >15 white cells/high power field, and 34 percent had white cell casts.

Based on this study, the following criteria were proposed for a case definition of acute MeN in a high-risk setting:

●Elevated creatinine (>1.3 mg/dL for males and >1.1 mg/dL for females) or increased ≥0.3 mg/dL from documented baseline

●Leukocyturia

●At least two of the following symptoms including fever, nausea and vomiting, back pain, muscle weakness, headache, leukocytosis, or neutrophilia

Using the first two criteria plus either leukocytosis or neutrophilia, a biopsy study of 11 patients was subsequently performed [65]. All patients were young, male, and without diabetes or hypertension. Eighty-one percent of patients described a febrile illness. All 11 patients had tubulointerstitial nephritis. (See 'Pathology' below.)

However, the diagnostic criteria that were used to identify patients with acute MeN have not been validated, and it is not yet known whether individuals in this study progressed to the more classically described chronic stage of MeN.

PATHOLOGY — Our knowledge of the histologic features of MeN are primarily based on kidney biopsy series from Nicaragua and El Salvador [65,69,81,83]. Additional kidney histopathologic findings of patients with MeN who are from Sri Lanka, El Salvador, India, and France have also been reported [84].

Biopsies of patients who presented with chronic kidney disease (CKD) showed tubular atrophy and fibrosis coupled with widespread chronic glomerular changes, including glomerulosclerosis and hypertrophy of the glomerular tufts [69,81,83]. Chronic glomerular ischemia was suggested by wrinkling of glomerular capillaries and thickening of Bowman's capsule [69]. Prominent vascular lesions were not present, but intimal fibrosis and thickening of the tunica media of extraglomerular blood vessels were observed [69,81,83]. The mesangial matrix was increased, but there was no mesangial proliferation (picture 1).

One biopsy report suggests that the early stages of MeN are consistent with acute tubulointerstitial nephritis [65]. In this study, biopsies were performed on 11 individuals in a high-risk area of Nicaragua who met criteria for acute MeN (see 'Acute presentation' above). Histology showed interstitial inflammation with predominant mononuclear cell infiltrate. There was evidence of both acute injury (acute tubular cell injury, interstitial edema, early fibrosis) and chronic injury (tubular atrophy, interstitial fibrosis). Glomeruli and blood vessels were largely normal.

The morphologic findings in this kidney biopsy study [65] differ from previously described series [69,80,81,83] in which interstitial inflammation was not prominent and glomerular changes were observed. The observed histologic differences may reflect differences in the patient case mix. The study of acute MeN included patients with leukocyturia and leucocytosis and/or neutrophilia, suggesting acute inflammation [65], whereas patients included in the earlier biopsy series had established CKD [69,81]. This suggests that the chronic glomerular changes of MeN may be preceded by acute interstitial inflammation [73]. (See 'Pathogenesis' above.)

In addition to acute and chronic interstitial nephritis, proximal tubular dysmorphic lysosomes and aggregates have been reported in kidney biopsies of patients with MeN [84]. These findings are thought to be linked with toxic exposure to an unidentified agrochemical or pesticide. However, the specificity of such findings to a diagnosis of MeN has been debated [85].

DIAGNOSIS — The diagnosis of MeN should be considered in at-risk patients who present with a decreased estimated glomerular filtration rate (eGFR) without proteinuria or hematuria and without other causes of chronic kidney disease (CKD). (See "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting".)

At-risk individuals are defined as Central American agricultural workers who perform physically demanding work for long hours in conditions with heat exposure. The diagnosis of CKD is confirmed by a decreased eGFR that persists for three months or longer. (See "Chronic kidney disease (newly identified): Clinical presentation and diagnostic approach in adults".)

The urinalysis, quantitation of proteinuria, and ultrasound are similar to other tubulointerstitial forms of CKD. (See 'Clinical features' above.)

A careful evaluation for causes of CKD should be performed to exclude other, potentially treatable causes. The evaluation of CKD is discussed elsewhere. (See "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting".)

Kidney biopsies are required to confirm the diagnosis of MeN among individuals with the appropriate clinical presentation and to distinguish among different forms of endemic nephropathies [86]. The histologic features observed on biopsy include tubular atrophy and fibrosis coupled with chronic glomerular changes, including glomerulosclerosis, hypertrophy, and collapse of glomerular tufts indicative of glomerular ischemia. In early stages of MeN, kidney biopsies may display interstitial inflammation [65]. (See 'Pathology' above.)

Differential diagnosis — All other nonproteinuric causes of CKD should be considered. (See "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting", section on 'Intrinsic tubular and interstitial disease'.)

PREVENTION — It is not known with certainty how to prevent MeN, and the approach is based upon the suggested (but not proven) pathogenesis and risk factors. At-risk individuals are defined as Central American agricultural workers who perform physically demanding work for long hours in conditions of extreme heat. Also at risk are laborers who perform similar work in extreme heat in other geographic regions, such as Sri Lanka, where there is a similarly increased incidence of nonproteinuric chronic kidney disease (CKD). (See 'Pathogenesis' above and 'Risk factors' above.)

Excessive exposure to heat in connection with hard, physical work performed over many hours daily should be avoided [78]. Individuals who are at risk for MeN should be advised to drink adequate fluids that contain sufficient amounts of sodium and potassium [69]. It has been suggested that fructose-containing fluids should be avoided [87]; however, there are no clinical data that suggest that fructose-containing fluids are harmful in humans.

Workers should limit exposure to heat and, if possible, avoid nonsteroidal antiinflammatory drugs (NSAIDs), at least during the season of highest risk (ie, the harvesting season for sugarcane workers).

An interventional program modelled after the United States Occupational Safety and Health Administration (OSHA)'s Water-Rest-Shade program may reduce the impact of the heat stress conditions for the workforce in El Salvador [88]. The provision of water, shaded rest areas, scheduled rest periods, ergonomically improved machetes, and efficiency strategies increased self-reported water consumption by 25 percent and decreased symptoms associated with heat stress and dehydration. At the same time, the individual daily cut cane production increased. Cross-shift estimated glomerular filtration rate (eGFR) decrease was present in both intervention and control groups but smaller for the intervention group, and the decrease in eGFR over the five-month harvest was smaller in the intervention group than in the control group [89]. Similarly, improved hydration, rest, and access to shade also attenuated the decline in eGFR among sugarcane harvest workers in Nicaragua [15]. Another intervention in Nicaragua, characterized by acclimatization, rest periods, shade, and water and electrolyte solutions, was associated with a lower incidence of AKI (7 versus 27 percent) and hospitalization for AKI (1 versus 9 percent) [16].

Even if pesticides eventually are found not to cause CKD, there is no doubt that any potential hazards associated with their use should be minimized, and sustainable, nontoxic pest control methods should be encouraged [5].

We suggest not using angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) among individuals at risk for MeN, although these agents have been shown to be renoprotective in other forms of CKD and are effective antihypertensive agents. Although no studies have suggested an association between ACE inhibitor or ARB use and MeN, blockade of the renin-angiotensin system (RAS) may predispose individuals to AKI in the setting of hypovolemia, thus increasing the risk of MeN [69]. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Effect of renin-angiotensin system inhibitors on progression of CKD'.)

TREATMENT — There is no specific treatment of MeN. The treatment is supportive care, directed at preventing the progression and treating the signs and symptoms of chronic kidney disease (CKD). (See "Overview of the management of chronic kidney disease in adults".)

PROGNOSIS — Mesoamerican nephropathy (MeN) may progress in some patients, though the rate of progression can be highly variable. The average yearly decline in estimated glomerular filtration rate (eGFR) has ranged from 2 to 4 mL/min/1.73 m² in different studies; however, in a small proportion of patients, yearly decline in eGFR can be as high as 18 mL/min/1.73 m² [50,81,83,90]. Individuals with moderate to severe interstitial fibrosis in biopsies have a higher risk of progressive disease, and segmental sclerosis and albuminuria are more common in patients with rapid progression and may indicate a more active disease.

As an example, in a study of 26 patients with biopsy-confirmed MeN who were followed for five to seven years, half had stable or improved kidney function, a third had eGFR decline between 1 and 5 mL/min/1.73 m² per year, and approximately 15 percent progressed faster than 5 mL/min/1.73 m² per year [90]. Faster decline was associated with moderate to severe interstitial fibrosis by biopsy.

In another study of 586 agricultural workers in Nicaragua who presented with acute MeN, 8 percent progressed to CKD [91]. The strongest predictors for progression of MeN were the presence of anemia and paresthesias at presentation.

A study of rural communities in Nicaragua followed 263 males and 87 females between ages 18 and 30 for two years [92]. Baseline median eGFR among males and females was 116 and 110 mL/min/1.73 m², respectively. At two years, 10 percent of males and 3 percent of females had a rapid decline in their eGFR of 15 to 18 mL/min/1.73 m² per year, 81 percent of males and 97 percent of females had stable kidney function, and the remainder experienced a slower decline of 4 mL/min/1.73m² in their eGFR.

MeN is associated with high mortality [1,19,93]. This is largely attributed to the prevalence of MeN in regions with limited dialysis availability, therefore leading to premature death. However, a high mortality has also reported among patients who were able to initiate dialysis, suggesting that there may also be other factors contributing to death in these patients [19].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in adults".)

SUMMARY AND RECOMMENDATIONS

●Mesoamerican nephropathy (MeN), also called chronic kidney disease (CKD) of unknown cause (CKDu), or CKD of not traditional cause (CKDnT), refers to nonproteinuric CKD that presents in young, agricultural workers predominantly in Central America in the absence of any common etiology for CKD. (See 'Introduction' above.)

●MeN is highly prevalent in low-altitude, coastal regions of El Salvador and Nicaragua and possibly Guatemala and Costa Rica. A similar pathology may contribute to the high prevalence of nonproteinuric CKD in Sri Lanka and India, although this has not been proven. (See 'Epidemiology' above.)

●The major risk factor for MeN is agricultural work in a hot climate, specifically Central America, which likely causes dehydration and volume depletion and loss of minerals such as sodium and potassium. Other risk factors include male sex, poverty and, possibly, exposure to pesticides and agrochemicals, excessive use of nonsteroidal antiinflammatory drugs (NSAIDs), heavy metals, and consumption of sugar-containing rehydration drinks. (See 'Risk factors' above.)

●MeN is likely caused by repeated episodes of acute kidney injury (AKI) related to heat stress and dehydration, loss if minerals, and inflammation causing acute and chronic tubulointerstitial nephritis. (See 'Pathogenesis' above.)

●Patients present with nonspecific symptoms including weakness and/or fainting and arthralgias and/or muscle cramps during and after work. Some patients describe dysuria associated with back or flank pain (locally termed "chistata"). Symptoms often lead to use of NSAIDs and prescription of antibiotics for presumed urinary tract infection. (See 'Clinical features' above.)

●Patients are usually normotensive or only mildly hypertensive. Laboratory evaluation reveals an increased serum creatinine with a reduced estimated glomerular filtration rate (eGFR). Patients generally do not have hematuria, and proteinuria is usually absent or present at only low levels. Ultrasound examination of kidneys typically shows small kidneys with decreased cortical thickness, both consistent with CKD of almost any cause. (See 'Clinical features' above.)

●The histologic features observed on biopsy include tubular atrophy and fibrosis coupled with chronic glomerular changes, including glomerulosclerosis, hypertrophy, and collapse of glomerular tufts indicative of glomerular ischemia. Biopsies from early stages of MeN may show findings of acute tubulointerstitial nephritis. (See 'Pathology' above.)

●The diagnosis should be considered in at-risk patients who present with a decreased eGFR without proteinuria or hematuria and without other causes of CKD. The urinalysis, quantitation of proteinuria, and ultrasound are similar to other tubulointerstitial forms of CKD. A careful evaluation for causes of CKD should be performed to exclude other, potentially treatable causes. (See 'Diagnosis' above.)

●Individuals who are at risk for MeN should drink adequate fluids that contain sufficient amounts of sodium and potassium. Workers should limit exposure to heat and, if possible, avoid NSAIDs, at least during the season of highest risk. (See 'Prevention' above.)

●There is no specific treatment of MeN. Prevention is the key. Treatment includes supportive care, directed at preventing the progression and treating the signs and symptoms of CKD. MeN may progress to end-stage kidney disease (ESKD). (See 'Treatment' above and 'Prognosis' above.)