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

Background CKD 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 young Nicaraguan participants 12-23 years without CKDnt (n=136) were analyzed by proton nuclear magnetic resonance spectroscopy for 50 metabolites associated with kidney dysfunction. Urinary metabolite levels were compared by, 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 (/3=0.82, [95% confidence interval, 0.16 to 1.85]; P = 0.01). Pyruvate concentrations were lower among youth with low eGFR (/3= -0.36 [95% confidence interval, -0.57 to -0.04]; P = 0.03), and concentrations of other citric acid 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, such as 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.

Automated summary

The urine analysis of young Nicaraguan participants revealed that glycine concentration was higher in high-risk regions of CKDnt, possibly due to greater heat exposure or renal stress; low eGFR was associated with decreased pyruvate concentration, and citric acid cycle metabolites were likely related to mitochondrial respiration rates in the kidneys; participants with low eGFR experienced a decline in the concentration of 1-methylnicotinamide, an anti-fibrosis metabolite in tubule cells. These findings are important for understanding the origins of CKDnt.