Is an Environmental Nephrotoxin the Primary Cause of CKDu (Mesoamerican Nephropathy)? PRO.

Abstract

Chronic interstitial nephritis in agricultural communities (CINAC), also named CKD of unknown origin (CKDu) or Mesoamerican nephropathy (MeN), is defined as a form of CKD affecting young men and—less often—women. Its etiology is unrelated to diabetes, GN, hypertension, or other known causes of CKD. Patients with CINAC live and work mainly in poor agricultural communities, often in hot tropical regions, and are exposed to potentially toxic agrochemicals through work by ingestion of contaminated food and water, and/or by inhalation (1,2). The epidemic dimension of CINAC was first observed in the 1990s in Sri Lanka and Central America and has since been found to be an important cause of CKD-related deaths in an increasing number of countries (3,4). Patients with CINAC have bilateral, small, irregularly contoured kidneys with mutual size discrepancy of <1.5 cm on ultrasound, as observed in advanced cases of analgesic nephropathy and aristolochic nephropathy (5,6). Almost all patients with CINAC exhibit a proximal tubular lesion: tubular cell atrophy, basement membrane thickening, deficient proximal tubular cell (PTC) regeneration, loss of function, distal tubular proliferation/hypertrophy, and variable extents of interstitial fibrosis and cellular infiltration. Overt glomerular injury is rare in the early stages, whereas secondary glomerulosclerosis develops in later CKD stages. By electron microscopy, PTCs demonstrate enlarged dysmorphic lysosomes (≥1.2 µ m) containing homogenous nonmembrane-bound, electron-dense, rounded/irregular “aggregates” dispersed throughout the light-to-medium, uniform, electron-dense lysosomal matrix (7) (Figure 1). These features are also observed in a number of toxin-induced nephropathies. Figure 1. Overview of the constellation of proximal tubular lesions observed in patients with chronic interstitial nephritis in agricultural communities/CKD of unknown origin. (A) Proximal tubular cells containing many enlarged argyrophilic granules, demonstrated to be lysosomes (arrowheads) (7) (Periodic acid–Schiff methenamine [PASM] staining). (B) Affected proximal tubule demonstrating enlarged lysosomes, flattened atrophic epithelial cells with …