Machine learning approaches revealed metabolic signatures of incident chronic kidney disease in persons with pre-and type 2 diabetes

Early and precise identification of individuals with pre-diabetes and type 2 diabetes (T2D) at risk of progressing to chronic kidney disease (CKD) is essential to prevent complications of diabetes. Here, we identify and evaluate prospective metabolite biomarkers and the best set of predictors of CKD in the longitudinal, population-based Cooperative Health Research in the Region of Augsburg (KORA) cohort by targeted metabolomics and machine learning approaches. Out of 125 targeted metabolites, sphingomyelin (SM) C18:1 and phosphatidylcholine diacyl (PC aa) C38:0 were identified as candidate metabolite biomarkers of incident CKD specifically in hyperglycemic individuals followed during 6.5 years. Sets of predictors for incident CKD developed from 125 metabolites and 14 clinical variables showed highly stable performances in all three machine learning approaches and outperformed the currently established clinical algorithm for CKD. The two metabolites in combination with five clinical variables were identified as the best set of predictors and their predictive performance yielded a mean area value under the receiver operating characteristic curve of 0.857. The inclusion of metabolite variables in the clinical prediction of future CKD may thus improve the risk prediction in persons with pre- and T2D. The metabolite link with hyperglycemia-related early kidney dysfunction warrants further investigation.