Unravelling Disrupted Metabolic Pathways in Albuminuric Patients and Normoalbuminuric Patients with Diabetic Kidney Disease

Background Diabetic Kidney Disease (DKD) leads to albuminuria and gradually progresses to renal insufficiency. However, 20–40% of DKD cases are normoalbuminuric DKD, namely impaired kidney function with normal albumin levels, limiting the accuracy of albuminuria as an early biomarker. With metabolomic approach, this study aimed to understand the distinctions in disrupted urinary metabolic pathways between normoalbuminuric DKD (NA-DKD) and albuminuric DKD (A-DKD) patients. Methods A cross-sectional study with total of 16 NA-DKD and 16 A-DKD patients with no discernible differences in demographic or clinical characteristics from Pasar Minggu District Health Center and Jati Padang Regional Hospital in Jakarta were asked to provide midstream morning urine samples. All subjects were analyzed using untargeted metabolomic analysis with Quadruple Time of Flight Liquid Chromatography-Mass Spectrometry. Signature metabolites were determined by Projections to Latent Structures Discriminant Analysis (PLS-DA) with Variable Importance for the Projection (VIP) >1.0, fold change >1.2, p-value <0.05, and Area Under the Receiver Operating Characteristic Curve >0.65. Results The PLS-DA score plot demonstrated a clear separation between the NA-DKD and A-DKD groups, indicating distinct urinary metabolic profiles. Twenty urinary metabolites differed significantly between the two groups. Pathway analysis revealed alterations in glycerophospholipid, ether lipid, phenylalanine, and tryptophan metabolism. Receiver operating characteristic (ROC) analysis identified three metabolites–glycerophosphocholine, hippuric acid, and 2-aminobenzoic acid–with an area under curve (AUC) >0.65. These metabolites were significantly reduced in the A-DKD group, indicating their potential discriminatory performance. Conclusions Glycerophosphocholine, hippuric acid, and 2-aminobenzoic acid may serve as potential biomarkers for distinguishing albuminuric from normoalbuminuric DKD. These findings provide insight into metabolic alterations associated with DKD and warrant further validation in larger cohorts using targeted metabolomic approaches.