Beyond Creatinine: D-Amino Acids as Emerging Indicators of Kidney Function and Disease

Despite decades of clinical use, serum creatinine and cystatin C remain imperfect indicators of kidney function, being influenced by muscle mass, age, sex, and inflammation and often showing limited sensitivity to early renal injury. D-amino acids (D-AAs), once largely regarded as by-products of microbial metabolism, have emerged as biologically active chiral metabolites with promising potential for improving the assessment of renal function and disease. This review synthesizes current mechanistic, analytical, and clinical evidence on D-AAs in chronic kidney disease, tracing their origins in diet, gut microbiota, and endogenous racemization through their stereoselective renal transport, tubular handling, and urinary excretion. Among these molecules, D-serine and D-asparagine have emerged as particularly promising biomarkers, showing strong associations with measured glomerular filtration rate and, in early studies, performance comparable or superior to conventional markers, though evidence remains limited to small or selected cohorts, while appearing less dependent on body composition across adult and pediatric populations. Beyond their biomarker potential, D-AAs participate in signaling and metabolic processes linking the gut, kidney, and brain, with altered D-AA homeostasis implicated in both renal injury and uremic neurological dysfunction. We critically examine the biological and clinical confounders, analytical challenges, and validation gaps that currently limit their translation into clinical practice and discuss how chiral metabolomics could contribute to a more precise assessment of kidney function and disease.