Urinary biomarkers of diabetic kidney disease

Table 1 Biomarkers can be categorized based on the renal compartment or pathological process they primarily reflect

Biomarker	Source	Diagnostic accuracy	Clinical significance and validation status	Prospective	Contras and limitations
uACR/albuminuria	Glomerular capillary wall	AUC: 0.522[18]-0.933[19]; sensitivity 77% and specificity 92% for microabuminuria; sensitivity 88% and specificity 90% for macroalbuminuria[20]	Standard early marker for DKD; persistent elevation indicates nephropathy	Widely used; inexpensive, reproducible	Affected by blood pressure, exercise, and infections (risk of false positives). DKD may be normoalbuminuric normal uACR and albuminuria do not always exclude DKD
GPC-5	Podocyte injury	ROC curve of urinary GPC-5/creatinine ratio comparing T2DM without nephropathy and those with nephropathy reveals a sensitivity of 93.3% and a specificity of 80%[21]	Emerging marker of podocyte damage; may reflect early glomerular dysfunction in DKD; more studies needed to validate it as a diagnostic tool of incipient nephropathy	Potential early marker of podocyte injury; non-invasive detection in urine	Limited validation (small sample size studies); clinical utility and standardization not yet established
Transferrin	Large protein leakage from the glomerular wall	AUC: 0.846 (95%CI: 0.810-0.882); sensitivity 69.8%, specificity 90.1% (for a cut-off value of 1.15)[22]	Suggests early glomerular barrier compromise before albuminuria. Since significant transferrin levels have been found in normoalbuminuric T2DM patients, it could be suitable as a marker of early-stage DKD; nevertheless, very limited body of research	Earlier than macroalbuminuria; non-invasive	Limited specificity (false positives in primary glomerulonephritis and hypertension in nondiabetic populations; elevated in other proteinuric states)
Immunoglobulins (IgG and IgM)	Large protein leakage from the glomerular wall	AUC: 0.894 (95%CI: 0.848-0.930); sensitivity 75.53%, specificity 92.31% (for a cut-off value of 8.56)[23]	Indicates severe dysfunction. Limited body of evidence in T2DM	Indicative of more advanced damage; could be used in combination with transferrin to enhance diagnostic values	May be negative until late stages of disease (due to high molecular weight of IgG). Testing is more invasive on the one hand, and insufficiently standardized on the other
Nephrin	Podocyte injury	Not available for DKD	Promising marker for detection of early glomerular injury in multiple studies[24]	Specific to podocyte injury; early detection possible	It does not predict early renal dysfunction in DKD[40]. Requires specialized assays, limited availability
Type IV collagen	Matrix remodeling at the glomerular basement membrane	AUC not consistently reported; significantly elevated in early DKD[25]. More sensitive than microalbuminuria but exact percentages not uniformly available	Associated with structural glomerular damage and fibrosis. Validated in large multicentric cohort across DKD stages. Some promising data, but more investigation on larger scale is needed	Reflects chronic structural damage, therefore useful to detect fibrosis	Limited validation (small-to-moderate sample size studies; lack of ROC quantification and cut-offs)[26,30]. Limited utility in early DKD, overlaps with other markers
Podocalyxin	Podocyte injury	AUC: 0.86 (95%CI: 0.81-0.91) alone; combined with α2-MG: AUC: 0.88 (95%CI: 0.83-0.93)[27], in another small study, AUC: 0.996[29]. Sensitivity 73.3%, specificity 93.3% at cut-off 43.8 ng/mL[28]	Linked to detachment and loss of podocytes. Validated in cross-sectional and prospective cohorts of 42-200 patients[27]. Might be a highly accurate biomarker of early podocyte injury, but more studies on larger scale are needed	Sensitive for podocyte detachment, useful in active disease	Not widely validated (limited sample size studies)[27,29]; inter-assay variability; requires advanced laboratory methods

uACR: Urine albumin-to-creatinine ratio; GPC-5: Glypican-5; IgG: Immunoglobulins G; IgM: Immunoglobulins M; AUC: Area under the curve; ROC: Receiver operating characteristic; T2DM: Type 2 diabetes mellitus; CI: Confidence interval; DKD: Diabetic kidney disease; α2-MG: Alpha 2-microglobulin.