Serum biomarkers in diabetic kidney disease: A comprehensive narrative review

Table 1 Serum biomarkers for early detection of diabetic kidney disease

Biomarker	Diagnostic accuracy	Main limitations	Validation status
Creatinine[1,34,39]	AUC = 0.66 for early DKD in T2DM; sensitivity = 60%; specificity = 70%	Low sensitivity in early DKD; influenced by muscle mass, age, sex, diet, ethnicity, drugs; does not reflect tubular damage or albuminuria	Routinely used worldwide; clinically established but inadequate alone for early diagnosis
Cystatin C[45-50]	CKD: Sensitivity = 0.85, specificity = 0.87, AUC = 0.92; DKD meta-analysis: AUC = 0.94; T2DM cohort: AUC = 0.914	Assay variability; cut-offs vary by age and ethnicity; limited long-term outcome validation	Widely validated and recommended; incomplete global assay standardization
NGAL[5,53-57]	Sensitivity = 0.79, specificity = 0.87; sNGAL: AUC = 0.973	Lack of standardized cut-offs; assay heterogeneity; optimal in biomarker panels	Promising; requires large multicenter longitudinal studies
KIM-1[104,128]	No quantitative AUC, sensitivity or specificity reported	Poor specificity; assay heterogeneity; lack of standardized cut-offs	Insufficient validation; prospective multicenter studies required
Heparanase[56-63]	No quantitative diagnostic performance data	Multifactorial regulation; limited clinical validation	Potential early-stage biomarker; not validated for routine use
Uromodulin[77-84]	No AUC, sensitivity or specificity reported	Lack of standardized assays; genetic variability	Clinical implementation pending
β2-microglobulin[86-96]	AUC = 0.925 (high); AUC = 0.792 (moderate in T2DM cohort)	Influenced by inflammation; assay variability; no reference ranges	Promising diagnostic and prognostic marker; further validation needed
β-trace protein[98-103]	Plasma BTP: Sensitivity = 82%, specificity = 78%, AUC = 0.86	Small cohorts; assay variability; no standardized cut-offs	Potentially useful; insufficient evidence for widespread clinical use

This table summarizes the main serum biomarkers investigated for the early detection of diabetic kidney disease, highlighting their diagnostic performance, principal limitations, and current validation status in clinical research and practice. AUC: Area under the curve; KIM-1: Kidney injury molecule-1; NGAL: Neutrophil gelatinase-associated lipocalin; sNGAL: Serum neutrophil gelatinase-associated lipocalin; DKD: Diabetic kidney disease; CKD: Chronic kidney disease; T2DM: Type 2 diabetes mellitus; BTP: Beta-trace protein.