Table 3.

Potential causes of endemic CKD in Central America

Possible CausesSupporting DataOpposing Data
 AgrichemicalsExtensively used in the regionNo single agrichemical linked to tubulointerstitial kidney disease without significant other organ involvement
High rates of CKD morbidity and mortality documented in areas with a high proportion of agricultural workersSimilar agrichemicals used at higher altitudes, but CKD does not seem highly prevalent (12)
With high volume of water intake, low concentrations of toxins still may yield high kidney exposureHigh frequency of reduced eGFR found in occupations with no exposure to agrichemicals: miners, stevedores, and construction workers (3)
High organophosphate exposure in El Salvador agricultural communities (35)
 Heavy metalsTypically manifests with indolent tubulointerstitial nephritisLimited evidence of high water levels of heavy metals, including cadmium, lead, arsenic, uranium, and 10 others in water samples tested one time in 2010 (3)
Lack of sophisticated water delivery systemsNo evidence of high urinary levels of cadmium, lead, or uranium or any association between these metals and reduced eGFR among 99 tested workers (3,11)
Active volcanic region
Arsenic common in water and soil in region (36,37)
Association between high urinary arsenic levels and low eGFR levels among 99 tested workers (3)
With high volumes of water intake, low concentrations of toxins still may yield high kidney exposure
 Aristolochic acidClinical course and manifestations consistent with Balkan endemic nephroathyLimited overall opposing data, including male predilection, no reported increased risk of genitourinary tract malignancies, and use of herbal remedies containing Aristolochia, were documented only in Eastern Nicaragua, which is not known to be affected by the CKD epidemic (38)
Multiple species of Aristolochia present in Nicaragua and used for herbal remedies (38)
 MedicationsWide, poorly regulated availability of antibiotics, including aminoglycosides (29)Unusual cause of CKD in the absence of other factors, particularly in otherwise healthy individuals, but many, including nonsteroidal anti-inflammatory drug use, would predispose to kidney failure in the setting of other toxins
Extensive use of nonsteroidal anti-inflammatory drugs (29)
 LeptospirosisExtremely common in Nicaragua (39)Insufficient number of diagnosed cases to account for epidemic; prevalence of a chronic carrier state unknown
Associated with AKIAcute severe disease not subtle
High seroprevalence (39)Uncertain link to CKD unless through AKI
Agricultural workers known to be a high-risk group (40)
 PyelonephritisPyuria and genitourinary symptoms common in local population, including menUrine cultures in the setting of leukocyte esterase positivity or symptoms showed no growth in all 50 male workers tested, whereas 3 of 11 female workers had positive cultures (3)
Genetic or developmentalLow birth weight (and therefore, low nephron mass) fairly commonAnecdotally, on clinically performed ultrasonography, no evidence of systemic developmental or anatomic abnormalities
Genes associated with protection against tropical diseases seem to increase the risk of CKD among persons with African ancestry allelic variation, including Hispanic populations (41,42)Nothing is known about the genetic admixture of the local population or the prevalence of alleles that have been shown to be associated with an increased risk of CKD
Recognized CKD anecdotally more common in persons with greater indigenous ancestryGreater indigenous ancestry associated with lower socioeconomic status, which is a risk factor for CKD in other populations
Volume depletion and heat-relatedLow-altitude Western Nicaragua is hot and humid, and it is considered the hottest region in NicaraguaHeat-associated AKI is not common in high-income countries and when present, tends to manifest coincident with multiorgan organ injury
CKD more common among workers engaged in heavy manual labor, typically consisting of menRequires that AKI, either recognized or subclinical, be the cause of CKD
CKD more common at lower altitudesNo documentation of frequent episodes of clinically recognized AKI caused by heat-related causes