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

Abstract

Background: Chronic kidney disease of a nontraditional etiology (CKDnt) is responsible for high mortality in Central America, although its causes remain unclear. Evidence of kidney dysfunction has been observed among youth, suggesting that early kidney damage contributing to CKDnt may initiate in childhood. Methods: Urine specimens of Nicaraguan adolescents 12-23 years without CKDnt (n=136) were analyzed by proton nuclear magnetic resonance (1H-NMR) spectroscopy for 50 metabolites associated with kidney dysfunction. Urinary metabolite levels were compared by CKiD U25 estimated glomerular filtration rate (eGFR), regional CKDnt prevalence, sex, age, and family history of CKDnt using supervised statistical methods and pathway analysis in MetaboAnalyst. Magnitude of associations and changes over time were assessed through multivariable linear regression. Results: In adjusted analyses, glycine concentrations were higher among youth from high-risk regions (β=0.82, (95% CI: 0.16, 1.85); p=0.01). Pyruvate concentrations were lower among youth with low eGFR (β= -0.36; (95% CI:-0.57, -0.04); p=0.03) and concentrations of other citric acid (TCA) cycle metabolites differed by key risk factors. Over four years, participants with low eGFR experienced greater declines in 1-methylnicotinamide and 2-oxoglutarate and greater increases in citrate and guanidinoacetate concentrations. Conclusion: Urinary concentration of glycine, a molecule associated with thermoregulation and kidney function preservation, was higher among youth in high-risk CKDnt regions, suggestive of greater heat exposure or renal stress. Lower pyruvate concentrations were associated with low eGFR, and citric acid cycle metabolites like pyruvate likely relate to mitochondrial respiration rates in the kidneys. Participants with low eGFR experienced longitudinal declines in concentrations of 1-methylnicotinamide, an anti-inflammatory metabolite associated with anti-fibrosis in tubule cells. These findings merit further consideration in research on the origins of CKDnt.

Derangement in Nicotinamide Adenine Dinucleotide Metabolism is Observed During Acute Kidney Injury Among Male Agricultural Workers at Risk for Mesoamerican Nephropathy

“… 19 , 20 Increased markers of systemic inflammation have been linked with kidney injury in a population at high risk for MeN. 21 , 22 Urine metabolomics and serum proteomics of individuals engaged in high risk sugarcane harvest and seed cutting have identified features consistent with inflammation and altered energy metabolism, possibly in the context of increased gut permeability. 23 , 24 …”