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Mesoamerican Nephropathy (MeN) is a chronic kidney disease (CKD) in Central America which may be caused by heat stress leading to recurrent episodes of acute kidney injury (AKI). Biopsy features of MeN are not sufficiently specific to identify a causal injury mechanism, but broadly demonstrate tubular injury with ischemic features and mononuclear cellular inflammation. AKI caused by ischemia and inflammation is characterized by deranged biosynthesis of nicotinamide adenine dinucleotide (NAD+), which can be assayed in vivo as a rise in the urinary quinolinate to tryptophan (Q/T) ratio. NAD+ biosynthetic derangement in AKI is of particular interest because it may be mitigated by administration of nutritional precursors such as nicotinamide to protect against injury.
Using a paired case-control design, we investigated differences in urinary Q/T and other NAD+ related metabolites in a male sugarcane worker population with high rates of MeN in Nicaragua. Hypotheses are presented in Table 1.
Among 327 sugarcane workers studied, we identified 45 individuals with serum creatinine (sCr) >1.3mg/dL present for <6 months as our “AKI” group, and matched them 1:1 based on age and job category with two comparison groups. Our primary comparison group, “no kidney injury,” had sCr <1.1mg/dL. Our secondary comparison group, “CKD,” had sCr >1.3mg/dL for >6 months, and were additionally matched 1:1 for sCr. We measured urine metabolites using liquid chromatography - coupled tandem mass spectrometry. Statistical comparisons were made using the Wilcoxon Signed Rank Test.
Workers at risk for MeN who develop AKI demonstrate elevated urine Q/T ratio compared to those with no kidney injury, consistent with NAD+ biosynthetic derangement and ischemic / inflammatory kidney injury. Lower urinary levels of nicotinamide, the main circulating NAD+ precursor in the body, along with its breakdown product methylnicotinamide suggest increased NAD+ demand in workers with AKI. Our finding that the directionality of differences in key metabolites between the AKI and NoKI groups persists between the AKI and CKD groups is evidence that these metabolites likely reflect metabolic features of AKI, and not just differences in clearance of these metabolites driven by decreased kidney function. Limitations include the cross-sectional nature of this study and limited generalizability beyond male sugarcane workers in Nicaragua. NAD+ biosynthetic derangement, as evidenced by increased urine Q/T ratio and alterations in other NAD+ precursor metabolites, is present during AKI among male sugarcane workers at risk for MeN. Therapeutic targeting with nicotinamide supplementation to boost NAD+ biosynthesis should be investigated to prevent AKI in this setting.