Potential Mechanisms Involved in Chronic Kidney Disease of Unclear Etiology

Abstract

Background and objectivesThe etiology of chronic kidney disease of unclear etiology, also known as Mesoamerican nephropathy, remains unclear. We investigated potential etiologies for Mesoamerican nephropathy in an immigrant dialysis population.Design, setting, participants, & measurementsMigrants with Mesoamerican nephropathy kidney failure (n=52) were identified by exclusion of known causes of kidney disease and compared using a cross-sectional survey with demographically similar patients with kidney failure from other causes (n=63) and age/sex/place of origin–matched healthy participants (n=16). Survey results were extended to the bench; C57BL/6 mice (n=73) received 10–15 weekly intraperitoneal injections of paraquat (a reactive oxygen species–generating herbicide) or vehicle. Kidney function, histology, and expression of organic cation transporter-2 (proximal tubule entry for paraquat) and multidrug and toxin extrusion 1 (extrusion pathway) were examined. Kidney biopsies from Nicaraguan patients with acute Mesoamerican nephropathy were stained for the above transporters and compared with patients with tubulointerstitial nephritis and without Mesoamerican nephropathy.ResultsPatients with Mesoamerican nephropathy and kidney failure were young agricultural workers, almost exclusively men; the majority were from Mexico and El Salvador; and they had prior exposures to agrochemicals, including paraquat (27%). After adjustment for age/sex, exposure to any agrochemical or paraquat was associated with Mesoamerican nephropathy kidney failure (odds ratio, 4.86; 95% confidence interval, 1.82 to 12.96; P=0.002 and odds ratio, 12.25; 95% confidence interval, 1.51 to 99.36; P=0.02, respectively). Adjusted for age/sex and other covariates, 1 year of agrochemical exposure was associated with Mesoamerican nephropathy kidney failure (odds ratio, 1.23; 95% confidence interval, 1.04 to 1.44; P=0.02). Compared with 16 matched healthy controls, Mesoamerican nephropathy kidney failure was significantly associated with exposure to paraquat and agrochemicals. Paraquat-treated male mice developed kidney failure and tubulointerstitial nephritis consistent with Mesoamerican nephropathy. Organic cation transporter-2 expression was higher in male kidneys versus female kidneys. Paraquat treatment increased organic cation transporter-2 expression and decreased multidrug and toxin extrusion 1 expression in male kidneys; similar results were observed in the kidneys of Nicaraguan patients with Mesoamerican nephropathy.ConclusionsExposure to agrochemicals is associated with Mesoamerican nephropathy, and chronic exposure of mice to paraquat, a prototypical oxidant, induced kidney failure similar to Mesoamerican nephropathy.

Chronic kidney disease with unknown cause across the global spectrum

“…Evidence for nephrotoxin-induced injury is present in Central America, where 1 year of agrochemical exposure was significantly associated with CKDu, with OR 4.86, P less than 0.002 and OR 12.25, P less than 0.02 for agrochemical and paraquat exposure, respectively [28 ▪▪ ]. Longer and more frequent exposures resulted in higher risk with or without PPE use.…”

“…Longer and more frequent exposures resulted in higher risk with or without PPE use. Similarly, Central American migrants in the United States showed an association between chronic intermittent agrochemical exposure, particularly paraquat, and kidney failure [28 ▪▪ ]. In Mexico, agrochemicals have been potentially associated with impaired kidney function and proteinuria [29].…”

Unraveling the Mysteries of CKD of Uncertain Etiology

“…In this issue of CJASN , Holliday et al . (4) attempt to investigate a specific agrochemical, paraquat, as a potential etiologic agent for CKDu using a clinic-to-benchside approach. Their approach is reminiscent of the approach that ultimately identified Balkan endemic nephropathy, the closest historical corollary of CKDu, as resulting from aristolochic acid exposure.…”

“…Similarly, although in reverse order, Holliday et al (4) first identified 52 patients matching the case definition of Mesoamerican nephropathy receiving dialysis care at the Harris Health System in Houston, and two sets of Latin American immigrant participants serving as controls. The first control set of 63 patients was also receiving dialysis and had a specific cause of kidney disease identified; a second set of 16 participants were matched for age and country of origin but did not have kidney disease.…”

“…Given the signal for higher self-reported paraquat exposure (even compared with other self-reported agrochemicals), Holliday et al (4) tested the effects of chronic low-dose paraquat exposure in the kidneys of mice and determined the expression of organic cation transporter-2 and multidrug and toxin extrusion 1 in paraquat-treated mice and Nicaraguan patients with acute Mesoamerican nephropathy ( n =8 for biopsies available for staining for both transporters). After 15 weeks of intraperitoneal paraquat injections, male mice demonstrated increases in serum creatinine, with kidney tissue showing fibrosis, and T cell and macrophage infiltration; the findings were less pronounced among female mice.…”