Table 2.

Potential Causes of Mesoamerican Nephropathy

Hypotheses	Pros	Cons	Comments	Conclusion	Priority for Research
Heat stress, dehydration, and volume depletion	Heat exposure affects kidney function through volume depletion; exertion can produce rhabdomyolysis with consequent AKI35; individuals most frequently affected by MeN, ie, sugarcane workers, are exposed to extreme heat and strenuous work36; in El Salvador, sugarcane work in lowlands, but not in highlands, was associated with decreased kidney function16	CKD has not been reported among sugarcane workers in other hot areas, such as in Brazil, Africa, and others	Subclinical injuries from repeated episodes of heat stress and dehydration may develop into CKD; ongoing experimental research in mice supports the hypothesis37	Heat stress and dehydration are likely causes of MeN, in combination with other unknown factors	High priority
Hypokalemia and hyperuricemia	Prolonged hypokalemia can cause tubulointerstitial fibrosis38; hyperuricemia has experimentally been shown to cause glomerulosclerosis and tubulointerstitial fibrosis39	Hypokalemia and hyperuricemia are not universally present in individuals presenting with MeN; hyperuricemia-associated kidney disease usually is associated with significant microvascular disease, which appears to be minimal in MeN	Both hyperuricemia and hypokalemia likely are a consequence of volume depletion and activation of the renin-angiotensin system	Hypokalemia and hyperuricemia are probably cofactors rather than primary causes	Low priority
Fructose/fructokinase	Recurrent dehydration in mice can induce CKD by the stimulation of aldose reductase with the production of fructose that causes tubular injury via fructokinase37; some sugarcane workers are also hydrating with drinks high in sugar	Animal studies do not always carry over to humans	Epidemiologic studies investigating the role of hydration with sugary solutions need to be performed	Activation of the fructokinase pathway may represent a potential mechanism for dehydration-associated CKD	High priority
Arsenic	Arsenic (inorganic) can cause AKI; low/moderate urinary levels of arsenic have been linked with albuminuria40; arsenic pollution occurs in regions of Central America with MeN: Guanacaste, Costa Rica,41 and Bajo Lempa, El Salvador42; highest 10th percentile of total urinary arsenic in sugarcane and mine workers was associated with a significant decrease in eGFR in Nicaragua23	Arsenic is not a recognized cause of CKD; arsenic in drinking water has been documented in regions of Central America, but widespread high levels have not been demonstrated in the MeN-affected areas in Nicaragua or El Salvador43; urinary levels of Nicaraguan sugarcane and mining workers exceeded WHO tolerances in only 3%23	Occupational exposure through contaminated pesticide formulations (as observed in Sri Lanka44) has not been evaluated in Mesoamerica	Arsenic is possibly a cofactor	Medium priority
Other heavy metals	In El Salvador cadmium has been detected in water sources in Nefrolempa42; lead and other heavy metals could be present in illegal alcohol20	High cadmium, mercury, or lead levels are not reported in areas affected by MeN45; blood lead and urinary cadmium & uranium levels in Nicaragua sugarcane and mining workers were less than internationally recommended maximum and similar to levels in US population23; clinical presentation does not resemble renal effects from cadmium, lead, or mercury45	Occupational exposure through cadmium-contaminated pesticide formulations (as observed in Sri Lanka44) has not been evaluated in Mesoamerica	Lead, cadmium, mercury, and uranium are unlikely causes of MeN	Low priority
Pesticides	CKD is more frequent in agricultural populations, who likely are exposed to pesticides; some widely used pesticides can cause AKI: paraquat, 2,4-D, glyphosate, and cypermethrin46; epidemiologic studies have found some evidence of an association between pesticides and CKD18, 20	No pesticide has been identified as a cause of CKD in the literature we have examined; pesticides is a large heterogeneous group of agents with different toxicities; pesticide use differs greatly between regions and countries; it seems unlikely that thousands of CKD victims spread over multiple countries would be exposed to the same nephrotoxic pesticide	Pesticide contamination of water sources is a community concern; obsolete nephrotoxic insecticide toxaphene may still be present in soil in sugarcane areas where cotton or rice was produced, but this has not been evaluated; occupational exposure through contaminated pesticide formulations (as observed in Sri Lanka44) has not been evaluated in Mesoamerica	An etiologic role of pesticides in MeN is not likely but cannot be completely ruled out	Medium priority
Nephrotoxic medications	Use of NSAIDs is widespread15, 16; anecdotally, this is the case in particular among sugarcane workers exposed to physically demanding tasks; to a lesser extent, aminoglycoside antibiotics are used for dysuria treated as UTI47	NSAIDs are rarely associated with CKD and AKI should be seen more frequently if NSAIDs were an important cause; aminoglycosides need prolonged treatment in order to cause CKD48	NSAIDs and aminoglycosides may worsen kidney injury from other causes	The use of nephrotoxic medications is a possible cofactor in the MeN epidemic	High priority
Infectious diseases: leptospirosis	Leptospirosis can cause AKI in humans and CKD in other mammals49; leptospirosis is endemic in MeN regions, more common among male agricultural workers, including sugarcane workers49	Leptospira is not an established cause of CKD	Key question: Could mild or subclinical leptospirosis lead to multiple episodes of acute interstitial nephritis, resulting in progressive kidney fibrosis and ultimately CKD?49	Leptospirosis is possibly a cofactor	Medium priority
Urinary tract diseases	Heat stress could contribute to the development of kidney stones, which can damage the kidney and lead to CKD35	Urine cultures among 50 male sugarcane workers with current symptoms of ‘chistate’ (dysuria) or white blood cells in their urine were uniformly negative23; nephrolithiasis is infrequent and does not explain the widespread epidemic of MeN	‘Chistata’ (or chistate) is dysuria and, in Central America, it is often wrongly diagnosed as UTI; kidney stones and dysuria may have their origin in dehydration and heat stress; dysuria may be a symptom for microcrystals in hypersaturated urine35	UTIs are not a cause of MeN; kidney stones could be associated with MeN in the context of heat stress and dehydration	Low priority for UTIs and medium priority for kidney stones
Aristolochic acid	Various Aristolochia spp grow in Mesoamerica	The histopathology in MeN differs from aristolochic nephropathy34; absence of urothelial cancers; widespread exposure is unlikely: sex difference in MeN argues against50	Urothelial cancer has a long latency, could appear later or not at all if affected men die young; an increase may go undetected in countries without a cancer registry	Aristolochia is an unlikely cause, but cannot be completely ruled out at this moment	Low priority
Genetic susceptibility	High local rates of a relatively uncommon disease need a powerful risk factor; family clustering has been reported51	—	No studies have been carried out; the main benefit of determining a genetic component from the etiologic perspective is if it helps elucidate the other cause(s) of MeN; virtually all diseases have some genetic component, but unless the genetic component is strong, it is unlikely to be useful	—	Medium priority
Low birth weight, prenatal, and childhood exposures	High prevalence of CKD at young age suggests initial damage may start during childhood; markers of tubular kidney damage, especially NAG, were highest among students aged 12-18 y in areas with highest occurrence of CKD52	Levels of biomarkers were higher among women than men52	A factor, so far unidentified, may act at early age and posterior occupational exposure among men may trigger the disease	Early child factors may possibly influence disease occurrence, yet seems not a very likely cause	Medium priority
Hard water	In Sri Lanka, hard water and CKD occurrence coincide; it has been hypothesized that hardness of water affects heavy metal toxicity at the cellular level53	No known health effects from hard water	In the MeN-affected area of Guanacaste in Costa Rica, hard water is a serious community concern (Jennifer Crowe, personal communication)	Hard water is an unlikely cause	Low priority
(Illegal) alcohol use	One study found an association between CKD and intake of illegal alcohol in Nicaragua20	Strong associations between alcohol and MeN have not been observed in other studies in the Mesoamerican region14, 15, 16, 17, 18, 19, 22	—	Illegal alcohol is not a likely cause	Low priority
Silica dust	Silica has been associated with CKD54, 55; sugarcane, construction, and mining workers may be exposed to silica dust	Most cases of CKD associated with exposure to silica have been reported to condition glomerulonephritis and clinically have significant hypertension and proteinuria56	Silica content in soils in MeN areas is unknown	Silica is a potential risk of unknown magnitude	Low priority
Social determinants	Extreme poverty forces young people to leave school early and begin working in sugarcane57; working conditions in sugarcane are extremely harsh: excessive working hours, few rest days, and physical exertion in extreme heat36, 57	Social factors are prone to generalizations and oversimplification; social determinants do not explain the pathophysiology of the disease	Working conditions underlying physiopathology of MeN can be changed as preventative action	Poverty is a known determinant of CKD, although a distal cause; working conditions contribute to heat stress and dehydration	High priority

Abbreviations: AKI, acute kidney injury; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; MeN, Mesoamerican nephropathy; NSAIDs, non-steroidal antiinflammatory drugs; UTI, urinary tract infection; WHO, World Health Organization.