The Molecular Signature of Diabetic Kidney Disease: A Scoping Review of Emerging Biomarker Classes

Diabetic Kidney Disease (DKD) is the leading cause of end-stage renal disease worldwide, yet routine clinical biomarkers-albuminuria and creatinine-based estimated Glomerular Filtration Rate (eGFR)-often change only after substantial nephron loss, limiting opportunities for early intervention. This limitation is particularly important because an estimated 40-50% of people with type 2 diabetes may experience progressive renal dysfunction without albuminuria elevation (normoalbuminuric DKD), a phenotype frequently missed by conventional screening. This scoping review (PRISMA-ScR) synthesized evidence on emerging biomarkers that reflect distinct DKD pathogenic mechanisms and evaluated their diagnostic, prognostic, and implementation potential. PubMed/MEDLINE, Embase, Scopus, and Web of Science were searched for studies published from January 2005 to September 2025, yielding 37 eligible peer-reviewed studies. Evidence was organized into six biomarker domains: tubular injury (e.g., NGAL, KIM-1, L-FABP), glomerular filtration and tubular protein handling (e.g., cystatin C, low-molecular-weight proteins), inflammatory pathways (e.g., sTNFR1/2, IL-18, MCP-1), cell-cycle arrest (TIMP-2·IGFBP7), genomic/epigenetic signatures (microRNAs, exosomes), and multi-biomarker panels incorporating artificial intelligence. Across studies, novel biomarkers improved early detection (AUC ~0.75-0.90) and prognostication (hazard ratios up to ~5-6 for ESRD risk) relative to conventional measures; multi-marker approaches generally outperformed single biomarkers (AUC ~0.84-0.89 vs ~0.75-0.82). Implementation remains constrained by assay standardization, cost, and limited prospective outcomes evidence, underscoring the need for harmonized methods, large longitudinal cohorts, and biomarker-guided trials to enable precision risk stratification and earlier, targeted intervention.