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ABSTRACT INTRODUCTION Chronic kidney disease of unknown etiology is occurring in various geographic areas worldwide. Cases lack typical risk factors associated with chronic kidney disease, such as diabetes and hypertension. It is epidemic in El Salvador, Central America, where it is diagnosed with increasing frequency in young, otherwise-healthy male farmworkers. Suspected causes include agrochemical use (especially in sugarcane ¿ elds), physical heat stress, and heavy metal exposure. OBJECTIVE To evaluate the geographic relationship between unspeci¿ ed chronic kidney disease (unCKD) and nondiabetic chronic renal failure (ndESRD) hospital admissions in El Salvador with the proximity to cultivated crops and ambient temperatures. METHODS Data on unCKD and ndESRD were compared with environmental variables, crop area cultivated (indicator of agrochemical use) and high ambient temperatures. Using geographically weighted regression analysis, two model sets were created using reported municipal hospital admission rates per ten thousand population for unCKD 2006-2010 and rates of ndESRD 2005-2010. These were assessed against local percent of land cultivated by crop (sugarcane, coffee, corn, cotton, sorghum, and beans) and mean maximum ambient temperature, with Moran's indices determining data clustering. Two-dimensional geographic models illustrated parameter spatial distribution. RESULTS Bivariate geographically weighted regressions showed statistically signi¿ cant correlations between percent area of sugarcane, corn, cotton, coffee, and bean cultivation, as well as mean maximum ambient temperature with both unCKD and ndESRD hospital admission rates. Percent area of sugarcane cultivation had greatest statistical weight (p 0.001; R p 2 = 0.77 for unCKD). The most statistically signi¿ cant multivariate geographically weighted regression model for unCKD included percent area of sugarcane, cotton and corn cultivation (p 0.001; R p 2 = 0.80), while, for ndESRD, it included the percent area of sugarcane, corn, cotton and coffee cultivation (R p 2 = 0.52). Univariate unCKD and ndESRD Moran's I (0.20 and 0.33, respectively) indicated some degree of clustering. Ambient temperature did not improve multivariate geographically-weighted regression models for unCKD or ndESRD. Local bivariate Moran's indices with relatively high positive values and statistical signi¿ cance (0.3-1.0, p 0.05) indicated positive clustering between unCKD hospital admission rates and percent area of sugarcane as well as cotton cultivation. The greatest positive response for clustering values did not consistently plot near the highest temperatures; there were some positive clusters in regions of lower temperatures. Clusters of ndESRD were also observed, some in areas of relatively low chronic kidney disease incidence in western El Salvador. CONCLUSIONS High temperatures do not appear to strongly inÀ uence occurrence of unCKDu proxies. CKDu in El Salvador may arise from proximity to agriculture to which agrochemicals are applied, especially in sugarcane cultivation. The ¿ ndings of this preliminary ecological study suggest that more research is needed to assess and quantify presence of speci¿ c agrochemicals in high-CKDu areas

Chronic interstitial nephritis in agricultural communities is a toxin induced proximal tubular nephropathy

Almost 30 years after the detection of chronic interstitial nephritis in agricultural communities (CINAC) its etiology remains unknown. To help define this we examined 34 renal biopsies from Sri Lanka, El Salvador, India and France of patients with chronic kidney disease 2-3 and diagnosed with CINAC by light and electron microscopy. In addition to known histopathology, we identified a unique constellation of proximal tubular cell findings including large dysmorphic lysosomes with a light-medium electron-dense matrix containing dispersed dark electron-dense non-membrane bound "aggregates". These aggregates associated with varying degrees of cellular/tubular atrophy, apparent cell fragment shedding and no-weak proximal tubular cell proliferative capacity. Identical lysosomal lesions, identifiable by electron microscopy, were observed in 9% of renal transplant implantation biopsies, but were more prevalent in six month (50%) and 12 month (67%) protocol biopsies and in indication biopsies (76%) of calcineurin inhibitor treated transplant patients. The phenotype was also found associated with nephrotoxic drugs (lomustine, clomiphene, lithium, cocaine) and in some patients with light chain tubulopathy, all conditions that can be directly or indirectly linked to calcineurin pathway inhibition or modulation. One hundred biopsies of normal kidneys, drug/toxin induced nephropathies, and overt proteinuric patients of different etiologies to some extent could demonstrate the light microscopic proximal tubular cell changes, but rarely the electron microscopic lysosomal features. Rats treated with the calcineurin inhibitor cyclosporine for four weeks developed similar proximal tubular cell lysosomal alterations, which were absent in a dehydration group. Overall, the finding of an identical proximal tubular cell (lysosomal) lesion in CINAC and calcineurin inhibitor nephrotoxicity in different geographic regions suggests a common paradigm where CINAC patients undergo a tubulotoxic mechanism similar to calcineurin inhibitor nephrotoxicity