Furosemide Enhances the Sensitivity of Urinary Metabolomics for Assessment of Kidney Function

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The ability of urinary metabolomics to detect meaningful, tissue-specific, biological effects (i.e., toxicity, disease) is compounded by high background variability. We hypothesize that sensitivity can be enhanced by imposing a tissue-targeted metabolic stressor.


We tested whether the sensitivity of metabolomics to assess kidney function is improved under the diuretic stress of furosemide.


To mildly compromise kidney, rats were given a sub-acute dose of d-serine. Then at 24 h postdose, we administered vehicle solution (control) or the diuretic drug, furosemide, and conducted NMR-based urinary metabolomics.


Principal Components and OPLS discriminant analyses showed no effects on urinary profiles in rats receiving d-serine alone. However, the effects of d-serine were observable under furosemide-induced stress, as urinary profiles classified separately from rats receiving furosemide alone or vehicle-treated controls (p < 0.001). Furthermore, this profile was uniquely different from a co-treatment effect observed following co-administration of d-serine + furosemide. We identified 24 metabolites to classify the effects of furosemide in normal rats vs. d-serine-compromised rats. Most notably, a furosemide-induced increase in urinary excretion of α-ketoglutarate, creatinine, trigonelline, and tryptophan in control rats, was significantly reduced in d-serine exposed rats (p < 0.05). Interestingly, increased tryptophan metabolism has been shown to correlate with the severity of kidney transplant failure and chronic kidney disease.


We attribute these effects to differences in kidney function, which were only detectable under the stress imposed by furosemide. This technique may extend to other organ systems and may provide improved sensitivity for assessment of tissue function or early detection of disease.



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