Urinary metabolites associate with the presence of diabetic kidney disease in type 2 diabetes and mediate the effect of inflammation on kidney complication.

AIMS: Diabetic kidney disease (DKD) is the one of the leading causes of end-stage kidney disease. Unraveling novel biomarker signatures capable to identify patients with DKD is favorable for tackle the burden. Here, we investigated the possible association between urinary metabolites and the presence of DKD in type 2 diabetes (T2D), and further, whether the associated metabolites improve discrimination of DKD and mediate the effect of inflammation on kidney involvement was evaluated. METHODS: Two independent cohorts comprising 192 individuals (92 DKD) were analyzed. Urinary metabolites were analyzed by targeted metabolome profiling  and inflammatory cytokine IL-18 were measured by ELISA. Differentially expressed metabolites were selected and mediation analysis was carried out. RESULTS: Seven potential metabolite biomarkers (i.e., S-Adenosyl-L-homocysteine, propionic acid, oxoadipic acid, leucine, isovaleric acid, isobutyric acid, and indole-3-carboxylic acid) were identified using the discovery and validation design. In the pooled analysis, propionic acid, oxoadipic acid, leucine, isovaleric acid, isobutyric acid, and indole-3-carboxylic acid were markedly and independently associated with DKD. The composite index of 7 potential metabolite biomarkers (CMI) mediated 32.99% of the significant association between the inflammatory IL-18 and DKD. Adding the metabolite biomarkers improved the discrimination of DKD. CONCLUSIONS: In T2D, several associated urinary metabolites were identified to improve the prediction of DKD. Whether interventions aimed at reducing CMI also reduce the risk of DKD especially in patients with high IL-18 needs further investigations.