Metabolic Features of Increased Gut Permeability, Inflammation, and Altered Energy Metabolism Distinguish Agricultural Workers at Risk for Mesoamerican Nephropathy

Abstract

Mesoamerican nephropathy (MeN) is a form of chronic kidney disease found predominantly in young men in Mesoamerica. Strenuous agricultural labor is a consistent risk factor for MeN, but the pathophysiologic mechanism leading to disease is poorly understood. We compared the urine metabolome among men in Nicaragua engaged in sugarcane harvest and seed cutting (n = 117), a group at high risk for MeN, against three referents: Nicaraguans working less strenuous jobs at the same sugarcane plantations (n = 78); Nicaraguans performing non-agricultural work (n = 102); and agricultural workers in Spain (n = 78). Using proton nuclear magnetic resonance, we identified 136 metabolites among participants. Our non-hypothesis-based approach identified distinguishing urine metabolic features in the high-risk group, revealing increased levels of hippurate and other gut-derived metabolites and decreased metabolites related to central energy metabolism when compared to referent groups. Our complementary hypothesis-based approach, focused on nicotinamide adenine dinucleotide (NAD+) related metabolites, and revealed a higher kynurenate/tryptophan ratio in the high-risk group (p = 0.001), consistent with a heightened inflammatory state. Workers in high-risk occupations are distinguishable by urinary metabolic features that suggest increased gut permeability, inflammation, and altered energy metabolism. Further study is needed to explore the pathophysiologic implications of these findings.

Urinary Metabolomic Profile of Youth at Risk of Chronic Kidney Disease in Nicaragua

“… 13 , 25 In our prior study, decreased TCA cycle metabolites are a urinary metabolic feature distinguishing adults engaged in agricultural work associated with high CKDnt risk in Central America. 26 These findings parallel those of the current study. Pyruvate is the end product of glycolysis and a key substrate for the TCA cycle.…”

Exposome and Metabolome Analysis of Sugarcane Workers Reveals Predictors of Kidney Injury

“…Alteration in energy metabolism is a hallmark of CKD, which has been found to occur in populations at high risk for CKDu. 28 The kidney is an extremely energy-intensive organ, requiring large amounts of functional mitochondria to remain healthy. 76 It is therefore highly sensitive to any changes in energy production, with disease states demonstrating pronounced shifts in energy metabolism.…”

“…Kidney disease is known to be associated with inflammatory renal tubular injury, altered redox state, fibrosis, and mitochondrial dysfunction. 27 , 28 Altered redox state, glycolytic shift, and accumulation of fatty acids are hallmarks of CKD that have also been demonstrated to occur in vitro following exposure to amorphous silica nanoparticles. 26 , 29 , 30 Such processes and pathways have many associated metabolites that can be quantified via metabolomics to help understand exposures and risk factors correlated with higher rates of kidney injury.…”

The Promise of Metabolomics and Exposomics in CKDu

“…The most well-established risk factor for CKDu development is exposure to heat stress. 1 Although metabolomics and exposomics may be used to indirectly assess potential downstream effects of heat stress such as increased gut permeability, 6 they do not directly assess heat stress. However, a number of other risk factors for CKDu development can be readily assessed by metabolomic and exposomic techniques to study them as independent entities and as important cofactors with heat stress.…”