Table 1.
Summary of principal tubular biomarkers of DKD in clinical use.
| Tubular biomarkers | Clinical Importance | Sample | Ref. |
|---|---|---|---|
| NGAL | increased when acute tubular damage of various causes occurred; correlated with CKD progression | urine | (77, 78) |
| associated with urinary albumin excretion, rapid decline of eGFR, and increased serum creatinine | urine | (79–82) | |
| associated with renal progression to ESKD, progressive tubular structural and functional impairment | urine | (10, 83–85) | |
| best predictive cutoff value of urinary NGAL to creatine ratio (uNCR) for T2DKD diagnosis was 60.685 ng/mg; | urine | (82) | |
| 7.595 times higher risk of nephrotic-range proteinuria in T2DKD patients with uNCR >60.685 vs.≤60.685 ng/mg. | |||
| twofold or greater risk for CKD progression in patients with diabetes; | urine | (10) | |
| 1.5-fold or greater risk for CKD progression in patients without diabetes | |||
| KIM-1 | repaired injury by removing apoptotic bodies and cellular debris | urine | (8) |
| upregulated when kidney damages | urine | (86) | |
| largely restricted to tubular cells in areas with tubulointerstitial damage induced by overload proteinuria; upregulated in proteinuric nephropathy and associated with renal fibrosis and inflammation. | tissue | (55) (87) | |
| elevated in T2DM with normal or mildly increased albuminuria | urine | (88) | |
| increased in T1DM patients who developed from macroalbuminuria to late-stage CKD | urine | (89) | |
| elevated in the high-risk group which was stratified by both ACR and eGFR; decreased in the very high-risk group; not associated with either eGFR or albuminuria | urine | (84) | |
| no predictive value for progression to ESKD independently of albumin excretion rate (AER); no prognostic benefit to conventional biomarkers (AER, eGFR); causal impact of KIM-1 on the decrease of eGFR in T1DM by Mendelian randomization analysis | urine | (89) | |
| no association with uKIM-1-to-creatinine ratio and eGFR decline in patients with T2DM | urine | (13) | |
| contains most of the predictive information for eGFR progression in T1DM | urine | (90) | |
| predictive value for the rapid decline of renal function in DKD | urine/serum | (81, 91, 92) | |
| associated with DKD progression and yearly decline in eGFR | plasma | (9) | |
| the most important predictor by cross-omics technologies | urine | (93) | |
| YKL-40 | a marker of inflammation and endothelial dysfunction; an indicator of tubular injury severity | / | (94, 95) |
| associated with albuminuria in T1DM and in early stage of nephropathy in T2DM | plasma | (96) (13, 94, 97) | |
| elevated among macroalbuminuric T2DM patients | urine | (98) | |
| not associated with eGFR decline and varying levels of baseline eGFR and albuminuria in T2DM | plasma | (99) | |
| a plasma marker of DKD progression | plasma | (9) | |
| MCP-1 | upregulated and expressed in the diabetic glomerular and renal tubular epithelium | urine | (100) |
| correlated with the extent of interstitial inflammatory infiltrate | urine | (101, 102) | |
| associated with severity of proteinuria in DKD | urine | (103) | |
| elevation in renal tubuli contributes to renal tubular damage in DKD | tissue | (103) | |
| MCP-1-to-creatinine ratio concentrations were strongly associated with sustained renal decline, severity of kidney damage in T2DM | urine | (13) (84) | |
| associated with an increased risk of DKD progression only among patients with baseline eGFR<45 ml/min per 1.73 m2 | plasma | (9) | |
| Cubilin and megalin | increased in microalbuminuria groups compared with non-albuminuric groups in T1DM | urine | (104) |
| genetic association exists between a cubilin and a rare megalin variant with diabetes-associated ESKD in populations with recent African ancestry | gene | (105) | |
| upregulated renal megalin expression in early T2DM rats | tissue | (106) | |
| elevated in two models of insulin-deficient diabetes in drug-inducible megalin knockout mice | tissue | (107) | |
| megalin in both segment 1 and segment 2 participated in clearing the ultrafiltrate from proteins in both cortical and juxtamedullary nephrons under normal conditions | tissue | (108) | |
| megalin in segment 3 was inactive with regard to protein endocytosis; it was activated by the presence of proteins in the lumen of the tubule in normal physiology | tissue | (108) |
NGAL, neutrophil gelatinase-associated apolipoprotein; KIM-1, kidney injury molecule 1; YKL-40, chitinase-3-like protein 1; MCP-1, monocyte chemoattractant protein-1; T1DM/T2DM, type 1/2 diabetes mellitus; CKD, chronic kidney disease; ESKD, end-stage kidney disease; DKD, diabetic kidney disease; eGFR, estimated glomerular filtration rate; AER, albumin excretion rate; ESKD, end-stage of kidney disease; uNCR urinary NGAL to creatine ratio.