Table 4.
The results of potential biomarkers of DN in 13 eligible studies.
| Potential biomarkers | Refence | Results | Method |
|---|---|---|---|
| AMBP | Zubiri, 2014 (39) Kaminska,2016 (13) |
AMBP was increased in DN group. | LC–MS/MS SRM Nano-LC-MALDI-TOF/TOF MS |
| OPG | Benito-Martin, 2013 (44) | OPG in urinary EV was expressed higher in CKD (DN, IgAN and CAKUT) patients, compared with healthy control. | WB ELISA |
| C-Megalin | Shankhajit De, 2017 (45) | The excretion of C-megalin per urinary EV and C-megalin of total urinary EV were increased with the progression of DN and also positive correlated with UACR. The declined eGFR was negatively correlated with excretion of C-megalin per Urinary EV, while positive correlated with C-megalin of total urinary EV. | WB |
| MMP MMP2 |
Gudehithlu, 2015 (47) Luca Musante, 2015 (37) |
MMP significantly decreased in DN patients compared with healthy control. MMP2 showed a progressive decrease trend from T1DM patients to DN patients with macroalbuminuria. |
ELISA Gel Electrophoresis, WB |
| CP | Gudehithlu, 2015 (47) | CP in urinary EV significantly increased, compared with healthy control. | ELISA |
| WT1 | Kalani, 2013 (36) | The detection rate of WT1 in urinary EV was significantly higher than diabetic patients than healthy control. The levels of WT1 were significantly higher in DN patients than diabetic patients, and the level of WT1 were associated with a significant increase in UACR and Scr, as well as a decline in eGFR. ROC analysis showed that WT1 effectively predict GFR< 60 ml. min-1/1.73 m2. | WB |
| Elf3 | Sakurai, 2019 (46) | Elf3 in urinary EV was only detected in DN patients, and can be a biomarker for podocyte injuries and predict the decline in eGFR in the coming years. | WB |
| DPP4 | Sun, 2012 (40) | The levels of DPP4 in urinary EV were significantly higher in T2DM and DN patients than healthy control group. And macroalbuminuria DN patients were detected higher level of DPP4 than other groups. | ELISA |
| Chen, 2021 (43) | The levels of DPP4 in urinary EV: healthy control < T2DM < DN with microalbuminuria <DN with macroalbuminuria. | ELISA | |
| Luca Musante, 2015 (37) | The T1DM and DN with microalbuminuria patients showed significantly lower level of DPP4 in urinary EV compared with healthy control. Macroalbuminuria patients had higher level and lower functional activity of it compared with healthy control. | Gel Electrophoresis, WB Spectrophotometric Assay |
|
| RGN | Zubiri, 2015 (38) | RGN was undetectable in DN patients. | WB |
| MLL3 VDAC1 |
Zubiri, 2014 (39) | MLL3 were increased and VDAC1 decreased in DN group. Setting a minimum of 2 assigned peptides per protein, 562 proteins in urinary EV were identified. |
LC–MS/MS SRM |
| CD59 MASP2 |
Kaminska,2016 (13) | CD59 and MASP2 were found in DN patients. | Nano-LC-MALDI-TOF/TOF MS |
| CTSA CTSC CTSD CTSE CTSL1 CTSZ KLK10 KLIK13 MME PRTN3 ADAM9 |
Luca Musante, 2015 (37) | The cathepsin family of A, C, D, L, and Z appeared to progressively increase from T1DM patients to DN patients with macroalbuminuria, while only cathepsin E decreased following trend. PRTN3 has an opposite trend with a marked increase in the normoalbuminuric and microalbuminuria group to reach a normal level in the macroalbuminuric group, and it significantly higher than healthy control. Whereas the level of KLK10 showed same trend with increased albuminuria from T1DM patients to DN patients with macroalbuminuria. MME was detected lower in T1DM and DN patients compared with healthy control. And KLK13in T1DM and DN patients was higher and ADAM9 lower than healthy control. | Gel Electrophoresis WB |
| PODXL | Wu, 2018 (41) | The level of PODXL in urinary EV showed significantly higher in DN patients, compared with healthy control, T2DM and other glomerular nephropathy patients. | ELISA |
| IL1B CDH1 |
Wang, 2020 (42) | The level of IL1B in urinary EV: healthy control < T2DM < DN with microalbuminuria <DN with macroalbuminuria. CDH1 in urinary EV showed markedly lower in T2DM and DN patients compared with healthy control, while it showed no significant differences in T2DM and DN groups. | WB, ELISA |
ADAM9, a disintegrin and a metalloprotease 9; AMBP, Alpha-1-Microglobulin/Bikunin Precursor; CAKUT, congenital anomalies of the kidney and urinary tract; CD59, inhibitor of the complement membrane attack complex; CDH1, E-cadherin; CKD: chronic kidney disease; CP, ceruloplasmin; CTSA, cathepsin A; CTSC, cathepsin C; CTSD, cathepsin D; CTSE, cathepsin E; CTSL1, cathepsin L; CTSZ, cathepsin X/Z/P; DN, diabetic nephropathy; DPP4, dipeptidyl peptidase-IV; eGFR, estamited glomerular filtration rate; Elf3, eukaryotic initiation factor 3; EV, extracellular vesicles; HC, healthy control; IgAN, IgA Nephropathy; IL1B, Interleukin-1 beta; KLK10, Kallikrein Related Peptidase 10; KLK13, Kallikrein Related Peptidase 13; MASP2, mannan-binding lectin serine protease 2; MLL3, Myeloid-lineage leukemia protein 3 homolog; MME, Neprilysin; MMP, Gelatinase; MMP2, matrix metallopeptidase 2; OPG, Osteoprotegerin; PODXL, Podocalyxin; PRTN3, proteinase 3; RGN, Regucalcin; ROC, receiver operating characteristic curve; Scr, serum creatinine; UACR, urine albumin-to-creatinine ratio; VDAC1, Voltage Dependent Anion Channel 1; WB, Western blotting; WT1, Wilm’s Tumor-1.