NMR-based serum metabolomics reveals diabetes-linked metabolic reprogramming in early-stage chronic kidney disease

Early-stage chronic kidney disease (CKD) is usually asymptomatic, and the presence of type 2 diabetes mellitus (T2DM) accelerates metabolic alterations long before conventional clinical markers detect changes. Despite their strong clinical association, the metabolic differences between early-stage non-diabetic CKD and diabetic CKD remain poorly understood, limiting early diagnosis and risk stratification. To identify disease-specific metabolic alterations and potential biomarkers, we employed quantitative proton NMR (¹H NMR) serum metabolomics (n = 100) in early-stage CKD (G1-G3B) patients, utilising untargeted polar metabolite profiling. Univariate and multivariate analyses (PCA, PLS-DA, Random Forest) clearly distinguished between diabetic CKD and non-diabetic CKD. Patients with diabetic CKD had lower levels of methionine, serine, and citrate, suggesting an early disturbance of energy and one-carbon metabolism. The ROC analysis (AUC = 0.77) showed a moderate level of diagnostic accuracy. Pathway enrichment analysis identified dysregulation of the tricarboxylic acid (TCA) cycle, pyruvate metabolism, glycine-serine-threonine metabolism, cysteine-methionine metabolism, and the one-carbon pool mediated by folate. Linear regression trend analyses across early-stage non-diabetic CKD, prediabetic CKD, and diabetic CKD revealed a gradual metabolic decline correlating with increasing glycemic burden. Collectively, these findings identify early metabolic signatures that elucidate the interplay between diabetic CKD and non- diabetic CKD, supporting improved patient stratification and targeted therapeutic strategies.