Trimethylamine N-Oxide Combined with Phenylacetylglutamine as Potential Biomarkers for Diabetic Kidney Disease

Purpose: For diabetic kidney disease (DKD), a serious complication of diabetes mellitus, this study was designed to assess the potential utility of two gut microbiota-derived metabolites — trimethylamine N-oxide (TMAO) and phenylacetylglutamine (PAGln) — individually and in combination for identifying DKD. Methods: Plasma TMAO and PAGln levels were quantified by Liquid chromatography-tandem mass spectrometry (LC-MS/MS) in 165 patients with type 2 diabetes mellitus (T2DM) (63 without nephropathy and 102 with DKD). Spearman correlation analysis was performed to evaluate the associations between metabolite concentrations and renal function metrics. Multivariable logistic regression and Receiver operating characteristic (ROC) analyses were performed to evaluate independent risk associations and the potential of the metabolites to indicate DKD. Results: DKD patients showed significantly higher plasma TMAO and PAGln levels than T2DM subjects without nephropathy. Both metabolites correlated positively with blood urea nitrogen, serum creatinine, uric acid, microalbuminuria and urine albumin-to-creatinine ratio and negatively with estimated glomerular filtration rate, and each emerged as an independent correlate of DKD. ROC analysis gave area under the curve (AUC) values of 0.795 for TMAO and 0.832 for PAGln; combining the two metabolites raised the AUC to 0.846, with a substantial increase in sensitivity from 65.7% (TMAO alone) and 68.3% (PAGln alone) to 75.6%, while maintaining high specificity (85.2%). Conclusion: TMAO and PAGln are independent biomarkers of DKD. Their combined use significantly improved sensitivity while maintaining high specificity, offering a powerful, non-invasive strategy for identification of DKD. A flowchart illustrating a study on a population of 165 individuals with type 2 diabetes. It includes 63 individuals with type 2 diabetes mellitus and 102 with diabetic kidney disease. The chart outlines the process of collecting clinical data and fasting venous plasma. It specifies the collection of baseline characteristics and laboratory results, followed by the quantification of plasma trimethylamine N-oxide and phenylacetylglutamine using high-performance liquid chromatography-tandem mass spectrometry. The final step is data processing.Flowchart of study on 165 type 2 diabetes patients, detailing data collection and processing.