Version July 2025
INTRODUCTION —
In the early 21st century, clinicians in Central America observed a high burden of unexplained chronic kidney disease (CKD) affecting agricultural workers in Costa Rica, El Salvador, and Nicaragua [1-4]. Initially named Mesoamerican Nephropathy (MeN), this kidney disease is now referred to as chronic kidney disease of unknown cause (CKDu), since it occurs in the absence of clear CKD etiologies such as diabetes or hypertension [5]. Other proposed terms for CKDu include chronic kidney disease of non-traditional origin (CKDnt), chronic interstitial nephritis in agricultural communities (CINAC) [6,7], and heat-induced kidney disease [1]. Though the cause of CKDu remains a matter of debate, and multiple exposures and conditions may contribute, many investigators consider heat stress as the driving factor [8,9]. There is no specific treatment of CKDu, other than that for nonproteinuric CKD from any other cause, but prevention programs may be beneficial [8-12].
This topic reviews the epidemiology, pathogenesis, clinical presentation, diagnosis, and treatment of CKDu. Overviews of the evaluation and treatment of CKD are presented elsewhere:
●(See "Chronic kidney disease (newly identified): Clinical presentation and diagnostic approach in adults".)
●(See "Overview of the management of chronic kidney disease in adults".)
EPIDEMIOLOGY
Prevalence — The entity of chronic kidney disease of unknown etiology (CKDu) 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) [13,14].
●Central America – A high prevalence of CKD and CKD-related mortality has been observed in several regions of El Salvador, Nicaragua, Guatemala, Costa Rica, and Mexico that have hot climates and active sugarcane plantations [14-19]. Representative estimates are as follows:
•In Nicaragua and El Salvador, the prevalence of CKD among males engaged in farming and agricultural work, and exposed to heat during strenuous work (eg, sugarcane cutting), ranged from approximately 10 to 40 percent [20-25].
•In a community near the town of Chichigalpa in Nicaragua, referred to as the ‘village of widows’ because so many workers die from CKDu, the prevalence of CKD was 42 percent in males and 10 percent in females [26].
•In the Guanacaste province, on the northwest Pacific coast of Costa Rica, the age-standardized CKD-associated mortality rate increased from 5.8 per 100,000 in the early 1970s to 75.0 per 100,000 between 2007 and 2012 [27], in conjunction with rising regional temperatures.
•In Central American males aged 50 to 54 years, the CKD-associated mortality rate between 2000 and 2009 was approximately 110 per 100,000 population in countries with high levels of sugarcane production (eg, Nicaragua and El Salvador) compared with less than 40 per 100,000 population in countries with relatively low levels of sugarcane production (eg, Panama) [28].
•Compared with other workers, rice production workers in Costa Rica exposed to heat above recommended limits for occupational heat exposure experienced kidney injury (defined as a serum creatinine increase ≥0.3 mg/dL) more frequently (26 percent versus 2 percent) and had lower baseline long term eGFR [29].
In both El Salvador and Nicaragua, CKDu appears to be most prevalent in warmer, low-altitude regions [23,30]. For example, in a study that included 256 males from five agricultural communities in El Salvador, the prevalence of CKD in low altitude areas was approximately 20 percent [23]. By contrast, the prevalence in cooler, high altitude areas was <2 percent.
●Other regions – The prevalence of CKDu in regions outside Central America is unclear. However, clusters of CKDu have been reported in other agricultural populations and in heat-exposed manual workers in hot climates, such as Sri Lanka [6,31-37] and India [19,33,38]. CKDu also has been reported among Nepalese migrants working in Gulf countries [39]. Unlike CKDu in Central America, CKDu in other regions appears to be common in females and individuals of older age [40-42].
Risk factors — Although multiple possible risk factors for CKDu have been suggested, many experts consider heat stress as the major contributor to the development CKDu.
●Heat stress – Hard, physical work in hot climates is an important underlying risk factor for CKDu [1,15,21,23,43-45]. There is a dose-effect and dose-response relationship between the intensity and duration of heat exposure and the prevalence and severity of CKD [23,26,46-48]. Representative studies are as follows:
•In a two-year longitudinal study that included 263 males from rural communities in northwestern Nicaragua who did not have CKD, diabetes, or hypertension at baseline, the odds of a rapid decline in eGFR (defined as an annual decrease of >18 mL/min/1.73 m2) were over three times higher in agricultural workers compared with non-agricultural workers, and nearly four times higher in workers with available shade during breaks compared with those without available shade [49].
•In a study of 427 sugarcane workers in Nicaragua, the mean decrease in eGFR from pre-harvest to post-harvest was 0 mL/min/1.73 m2 in those with low-moderate workload, 5 mL/min/1.73 m2 in those with high workload, and 9 mL/min/1.73 m2 in those with very high workload [50].
●Pesticides or other agrochemicals – Contact with pesticides or other agrochemicals, which is common in agricultural communities with high CKD prevalence [21], has been proposed as a risk factor for CKDu [28,31]. However, associations between agrochemicals/pesticides and CKD have not been consistently observed. A meta-analysis of 25 observational studies of CKDu in Central America found no significant association between pesticide exposure and CKDu [51]. Although pesticides are known to cause acute and chronic health diseases in humans [52], they have not been conclusively demonstrated to cause nephrotoxicity [25,53,54].
●Genetics – Genetic factors may play a role in CKDu. In a genome-wide association study of 1458 individuals in Northwestern Nicaragua, Native American ancestry was strongly associated with increased risk of CKDu [2]. This study also identified associations between OPCML gene mutations and increased risk of CKDu. Protective OPCML variants were associated with increased urine osmolality, suggesting greater ability to defend against hypovolemia.
Other possible risk factors for CKDu include consumption of sugar-containing rehydration drinks, lower socioeconomic class or poverty, excessive use of nonsteroidal anti-inflammatory drugs (NSAIDs), infections (possibly with an unknown virus), low body mass index, exposure to toxic substances and metals, and exposure to silica [15,21,23,26,43-45,51,55-60]. However, evidence for these putative risk factors is relatively weak [1,61,62].
PATHOGENESIS AND HISTOLOGY —
Many investigators believe that the most likely cause of chronic kidney disease of unknown etiology (CKDu) is repeated episodes of acute kidney injury (AKI) related to heat stress and dehydration [15,43,44,63-65] (see 'Risk factors' above). The pathogenesis and histology of CKDu are discussed below:
●Pathogenesis – The pathogenesis of CKDu is unknown. However, prolonged and repeated heat stress may cause recurrent episodes of AKI that eventually lead to CKD (CKDu) [8,9,66-74]. Although the mechanism whereby repeated bouts of hemodynamic AKI may cause CKD is unclear, severe volume depletion and/or potassium losses from excessive sweating may play a role [3,75]. These factors may stimulate renal hormonal systems (eg, renin-angiotensin-aldosterone system and vasopressin) that result in constriction of glomerular arterioles with glomerular ischemia and a mix of chronic glomerular and tubulointerstitial changes.
Tubulointerstitial nephritis also appears to contribute to CKDu. In active surveillance studies performed in a high-risk area of Nicaragua [76,77], individuals who met proposed criteria for an early acute form of Mesoamerican nephropathy (MeN) had laboratory studies [76] and biopsy findings [77] typical for tubulointerstitial nephritis. The cause of tubulointerstitial nephritis in patients with CKDu is unknown. It is possible that heat stress and concomitant sugar consumption, such as from sugarcane or drinking fructose-containing rehydration drinks, upregulate pro-inflammatory stimuli such as fructose, uric acid, endotoxins, and a variety of cytokines. Alternatively, some investigators have suggested that pesticides or other agrochemicals may act as a tubulointerstitial antigen [78].
●Histology – Our knowledge of the histologic features of CKDu are primarily based on kidney biopsy series from Nicaragua and El Salvador [75,77,79,80]. Additional kidney histopathologic findings of patients with CKDu are from Sri Lanka [81] and India [4,82].
Biopsies of patients who presented with CKDu showed tubular atrophy and fibrosis coupled with widespread chronic glomerular changes, including glomerulosclerosis and hypertrophy of the glomerular tufts [75,79,80]. Chronic glomerular ischemia was suggested by wrinkling of glomerular capillaries and thickening of Bowman's capsule [75]. Prominent vascular lesions were not present, but intimal fibrosis and thickening of the tunica media of extraglomerular blood vessels were observed [75,79,80]. The mesangial matrix was increased, but there was no mesangial proliferation (picture 1).
One biopsy report suggests that the early stages of CKDu are consistent with acute tubulointerstitial nephritis [77]. In this study, biopsies were performed on 11 individuals in a high-risk area of Nicaragua who met proposed criteria for acute MeN [76]. 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 [77] differ from previously described series [75,79,80,83] in which interstitial inflammation was not prominent and glomerular changes were observed. The observed histologic differences may reflect differences in the patient case mix. Patients with a putative diagnosis of acute MeN had leukocyturia and leucocytosis and/or neutrophilia, suggesting acute inflammation [77], whereas patients included in the earlier biopsy series had established CKD [75,79]. This suggests that the chronic glomerular changes of chronic MeN (ie, CKDu) may be preceded by acute interstitial inflammation [71].
In addition to acute and chronic interstitial nephritis, proximal tubular dysmorphic lysosomes and aggregates have been reported in kidney biopsies of patients with CKDu [78]. 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 CKDu is controversial [84] since similar types of dysmorphic lysosomes are seen in kidney biopsies from patients with non-CKDu diagnoses [85].
Patients with CKDu from outside Mesoamerica may have more interstitial inflammation and vascular changes on histopathology compared with patients with CKDu from Mesoamerica [40,81,86]. The histopathologic changes in CKDu outside Mesoamerica also appear to be more severe.
CLINICAL FEATURES —
Most patients with chronic kidney disease of unknown etiology (CKDu) are otherwise healthy, young or middle-aged males who have a history of physically demanding work in a hot climate [13,87,88] (see 'Pathogenesis and histology' above).
●Symptoms – Patients with CKDu are usually asymptomatic, until or unless they develop symptoms of uremia. However, among patients with CKDu, clinicians may elicit a history of a variety of symptoms that occur (or occurred) during or around periods of strenuous agricultural work, including weakness, arthralgias, muscle cramps, fainting during work, nocturia, dysuria associated with back or flank pain ("chistata"), episodic headache, tachycardia, fever, nausea, difficulty breathing, dizziness, and swelling of the hands/feet [87-89].
●Physical examination, laboratory tests, and radiographic findings – CKDu is usually characterized by the following features:
•Body mass index in the normal or low range.
•Normotension or only mild hypertension, and no evidence of edema [83].
•A benign urinalysis. Patients generally do not have hematuria, and proteinuria is usually absent or present at only low levels [15,75,83].
•Ultrasound examination of kidneys often shows somewhat small kidneys with decreased cortical thickness, consistent with chronic kidney disease (CKD) of almost any cause.
In addition, the serum concentrations of magnesium and potassium may be low [87]. In a study from Nicaragua low magnesium and low potassium were observed in 37 and 21 percent of patients, respectively [79,83]. Though not routinely measured, urine markers of tubular injury, including monocyte chemoattractant protein-1 (MCP-1) and kidney injury molecule-1 (KIM-1), are increased [64].
DIAGNOSIS
When to suspect CKDu — The diagnosis of chronic kidney disease of unknown etiology (CKDu) should be suspected in at-risk patients who present with chronic kidney disease (CKD) without proteinuria or hematuria and without apparent cause. At-risk individuals are agricultural workers who perform (or have performed) physically demanding work for long hours in conditions with substantial heat exposure, especially in regions with an increased incidence of nonproteinuric CKD such as Central America and Sri Lanka.
CKD is defined as a decreased estimated glomerular filtration rate (eGFR) that persists for three months or longer. (See "Chronic kidney disease (newly identified): Clinical presentation and diagnostic approach in adults".)
Establishing the diagnosis
●Initial evaluation – For patients with suspected CKDu (see 'When to suspect CKDu' above), a careful evaluation should be performed to exclude other, potentially treatable causes of CKD. The evaluation of CKD is discussed elsewhere. (See "Chronic kidney disease (newly identified): Clinical presentation and diagnostic approach in adults".)
●Role of kidney biopsy – A kidney biopsy is required to confirm the diagnosis of CKDu and to exclude other causes of kidney disease [90,91]. However, we generally do not biopsy patients with chronic, irreversible disease as suggested by one or both of the following:
•eGFR <30 mL/min/1.73 m2
•Small (eg, <9 cm) hyperechoic kidneys on ultrasound
●Diagnostic criteria – Although various case definitions for CKDu have been proposed [92,93], generally accepted and validated criteria for the diagnosis of CKDu do not exist. We make the diagnosis of CKDu in patients who have risk factors for CKDu (see 'When to suspect CKDu' above) and who meet the following criteria:
•Kidney biopsy findings consistent with CKDu. 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. Wrinkling of glomerular capillaries suggesting chronic glomerular ischemia in kidney biopsies without arteriosclerosis or signs of hypertension is indicative of CKDu [79]. (See 'Pathogenesis and histology' above.)
•In patients with early stages of CKDu, kidney biopsies may display interstitial inflammation [77] (see 'Pathogenesis and histology' above). In such patients, other etiologies of interstitial neрhritiѕ must be excluded before a diagnosis of CKDu is made. (See "Clinical manifestations and diagnosis of acute interstitial nephritis", section on 'Establishing the cause'.)
Differential diagnosis — The urinalysis, quantitation of proteinuria, and ultrasound are similar to other tubulointerstitial forms of CKD (see 'Clinical features' above). As such, 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 'Evaluation'.)
TREATMENT —
There is no specific treatment of chronic kidney disease of unknown etiology (CKDu). The treatment is supportive care, directed at preventing the progression and treating the signs and symptoms of chronic kidney disease (CKD). Continued exposure to heat stress and exposure to potentially nephrotoxic substances and/or drugs should be avoided. (See "Overview of the management of chronic kidney disease in adults".)
PROGNOSIS
●Progression of chronic kidney disease – Chronic kidney disease of unknown etiology (CKDu) tends to progress, and end-stage kidney disease (ESKD) may eventually develop. However, 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 [51,79,80,94]. 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.
In one representative study, 26 patients with biopsy-confirmed CKDu 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 [94]. Faster decline was associated with moderate to severe interstitial fibrosis by biopsy.
●Increased mortality – CKDu is associated with high mortality [16,95,96]. This is largely attributed to the prevalence of CKDu 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 [16].
PREVENTION —
For individuals at risk of chronic kidney disease of unknown etiology (CKDu), our approach to prevention is based upon risk factors for, and the putative pathogenesis of, CKDu. At-risk individuals are defined as agricultural workers who perform physically demanding work for long hours in conditions of extreme heat. (See 'Pathogenesis and histology' above and 'Risk factors' above.)
Preventive measures include the following:
●Avoidance of heat stress – Excessive exposure to heat in connection with hard, physical work performed over many hours daily should be avoided [88]. Individuals who are at risk for CKDu should be advised to drink adequate fluids that contain sufficient amounts of sodium and potassium [75]. It has been suggested that fructose-containing fluids should be avoided [97]; 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).
In El Salvador, an interventional program modeled after the United States Occupational Safety and Health Administration (OSHA)'s Water-Rest-Shade program may reduce the impact of heat stress on at-risk workers [98]. 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. The decrease in eGFR over the five-month harvest was smaller in the intervention group than in the control group [99]. Similarly, improved hydration, rest, and access to shade also attenuated the decline in eGFR among sugarcane harvest workers in Nicaragua [11]. Another intervention in Nicaragua, characterized by acclimatization, rest periods, shade, and water and electrolyte solutions, was associated with a lower incidence of acute kidney injury (AKI) (7 versus 27 percent) and hospitalization for AKI (1 versus 9 percent) [12].
●Other measures – Even if pesticides may not cause CKDu, any potential hazards associated with their use should be minimized, and sustainable, nontoxic pest control methods should be encouraged [15].
Although some clinicians have advocated inhibition of the renin-angiotensin-aldosterone system to prevent CKDu in at risk individuals, we do not use angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) for this purpose. Although no studies have suggested an association between ACE inhibitor or ARB use and the development of CKDu, blockade of the renin-angiotensin system (RAS) may predispose individuals to AKI in the setting of hypovolemia, thus increasing the risk of CKDu [100]. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Effect of renin-angiotensin system inhibitors on progression of CKD'.)
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
●Overview – Chronic kidney disease (CKD) of unknown cause (CKDu) is also called Mesoamerican nephropathy (MeN), CKD of non-traditional origin (CKDnt), chronic interstitial nephritis in agricultural communities (CINAC), and heat-induced kidney disease. CKDu refers to a type of nonproteinuric CKD that typically presents in agricultural workers in the absence of any common etiology for CKD. (See 'Introduction' above and 'Epidemiology' above.)
●Epidemiology – CKDu is highly prevalent in low-altitude, coastal regions of Central America, especially El Salvador and Nicaragua. CKDu also occurs in Sri Lanka and India. The major risk factor for CKDu is agricultural work in a hot climate. (See 'Epidemiology' above.)
●Pathogenesis and histology – CKDu may be caused by repeated episodes of acute kidney injury (AKI) related to heat stress and volume depletion. 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 CKDu may show findings of acute tubulointerstitial nephritis. (See 'Pathogenesis and histology' above.)
●Clinical features – Most patients with CKDu are otherwise healthy, young or middle-aged males who have a history of physically demanding work in a hot climate. CKDu is usually characterized by the following features (see 'Clinical features' above):
•Body mass index in the normal or low range.
•Normotension or only mild hypertension, and no evidence of edema.
•A benign urinalysis. Patients generally do not have hematuria, and proteinuria is usually absent or present at only low levels.
•Ultrasound examination of kidneys often shows somewhat small kidneys with decreased cortical thickness, consistent with CKD of almost any cause.
●Diagnosis – CKDu should be considered in at-risk patients who present with CKD without proteinuria or hematuria and without other causes of CKD. A careful evaluation should be performed to exclude other, potentially treatable causes of CKD. A kidney biopsy is required to confirm the diagnosis of CKDu and to exclude other causes of kidney disease. However, we generally do not biopsy patients with chronic, irreversible disease. (See 'Diagnosis' above.)
●Treatment – There is no specific treatment of CKDu. The treatment is supportive care, directed at preventing the progression and treating the signs and symptoms of CKD. Continued exposure to heat stress and exposure to potentially nephrotoxic substances and/or drugs should be avoided. (See "Overview of the management of chronic kidney disease in adults".)
●Prevention – Excessive exposure to heat in connection with hard, physical work performed over many hours daily should be avoided. Interventions modeled after the United States Occupational Safety and Health Administration (OSHA)'s Water-Rest-Shade program may help prevent CKDu. (See 'Prevention' above.)
