Table 1.
Urine proteome studies in different types of nephropathies.
| Nephropathy Types |
Method | Number of Patients | The Main Biomarkers | Functions of Proteins/Main Processes | References |
|---|---|---|---|---|---|
| Chronic kidney disease |
CE-MS | 4766 | CKD 273 classifier ↓ fragments of different collagens, ↑ A1AT, serum albumin, hemoglobin α chain, fibrinogen α chain, uromodulin, Na+/K+-ATPase γ chain, and membrane-associated progesterone receptor component 1 |
CKD progression and fibrosis accumulation |
Good et al., 2010 [45] |
| CE-ESI-TOF MS | 1028 | CKD 273 classifier validation | Puntillo et al., 2017 [46] | ||
| CE-ESI-TOF MS | 1990 | CKD 273 classifier validation | Schanstra et al., 2015 [18] | ||
| CE-MS | 435 | FPP_29BH classifier ↑ cathepsin D, MMP-2, collagenase 3, MMP-14, α-2-HS-glycoprotein, fetuin-A, and 19 different collagen peptide fragments |
Fibrosis accumulation |
Catanese et al., 2021 [47] | |
| FSGS/MCD | 2D-DIGE-MS | 49 | A1AT, transferrin histatin-3 39S ribosomal protein L17 ↓ (FSGS vs. MCD) calretinin ↑ (FSGS vs. MCD) |
Modulating immunity, inflammation and apoptosis; abnormal permeability of GBM, cell proliferation and differentiation |
Perez et al., 2017 [48] |
| 2D-LC-MS/MS | 30 FSGS 30- MCD |
↑ Ubiquitin-60S ribosomal protein L40 (UBA52) (FSGS vs. MCD) | Protein degradation, stress response, and overexpression of UBA52 ameliorated the cell-cycle arrest | Wang et al., 2017 [49] | |
| LC-MS/MS | 4 MCD 4 FSGS |
CD14, C9, and A1AT ↑ cadherin-like 26, RNase A Family 1, DIS3-like exonuclease 1 |
Complement activation, inflammation, apoptosis, cells adhesion, and cell death |
Choi et al., 2017 [50] | |
| nano-LC-MS/MS | 10 FSGS | ↑ Apolipoprotein 1 matrix-remodeling protein 8 (MXRA8) |
Lipid oxidation and matrix accumulation |
Kalantari et al., 2014 [51] | |
| nanoLC-MS/MS | 11 FSGS | ↑ DPEP1, CD59, CD44, insulin-like growth factor-binding protein 7, and roundabout homolog 4 |
DPEP1 activates TRPC6 in podocytes complement activation, PETs activation, cell–cell interactions, cell adhesion, and maintenance of endothelial barrier organization and function |
Nafar et al., 2014 [52] | |
| MALDI-MS imaging | 6 FSGS | A1AT | Marker of podocyte stress, excessive loss, and hypertrophy of podocytes and glomerulosclerosis | Smith et al. 2016 [53] | |
| CE-MS | 110 FSGS 35 MCD |
↑ Collagens, A1AT ↓ clusterin, uromodulin polymeric immunoglobulin receptor, Golgi-associated olfactory signaling regulator ↑ collagens, uromodulin, keratin apolipoprotein C-IV ↓ β-2-microglobulin, clusterin, complement C3 |
Siwy et al., 2017 [54] | ||
| CE-MS | MCD 14 DN 11 |
retinol-binding protein 4 and SH3 domain-binding glutamic acid-rich-like protein 3 | Proteins could distinguish between MCNS and DN | Araumi et al., 2021 [55] | |
| Membranous nephropathy | LC-MS/MS | 4 | SERPINA7 and CD44 | Cell–cell interactions, cell adhesion, and migration | Choi et al., 2017 [50] |
| iTRAQ and LC-MS/MS | 5 | Lysosome membrane protein-2 | Immune inflammation | Rood et al., 2015 [56] | |
| TMT1 and TMT2+nanoLC- MS/MS | 63 | A1ATafamin | Contribute to accumulation of mesangial matrix lipid metabolism |
Pang et al., 2018 [57] | |
| MALDI-TOF MS | 13 | ↑UMOD ↑A1AT |
Tubular dysfunction inflammation and apoptosis; matrix accumulation |
Navarro-Muñoz et al., 2012 [58] | |
| CE-MS | 77 | ↑ A1AT, uromodulin, α-1B-glycoprotein, plasminogen, keratin, apolipoprotein C-IV ↓Fibrinogen α-chain, zinc finger protein ZFPM2, E1A-binding protein Microtubule-associated protein tauAP-3 complex subunit delta-1 |
Siwy et al., 2017 [54] | ||
| CE-MS | 23 | The combination of urinary afamin and complement C3 urine/plasma ratio | Could distinguish between MN and DN | Araumi et al., 2021 [55] | |
| IgA nephropathy | iTRAQ-MS | 4 | Complement C9, Ig kappa chain C region, cytoskeletal keratins type I (10), and type 2 (1, 5) | Complement activation; glomerular filtration barrier damage |
Ning et al., 2017 [59] |
| 2D-LC-MS/MS and iTRAQ | 12 | ICAM 1, metalloproteinase inhibitor 1, antitrombin III, and adiponectin | Inflammation; urine proteins originated from serum leakage |
Guo et al., 2018 [60] | |
| MALDI-TOF/TOF MS | 20 | ↓ UMOD ↑ A1AT |
Accumulation of mesangial matrix | Prikryl et al., 2017 [61] | |
| CE-MS | 209 | ↓ Collagen I ↑ A1AT |
Matrix accumulation and glomerulosclerosis |
Rudnicki et al., 2020 [62] | |
| IEF/LC-MS/MS | 30 | ↑ α-2-macroglobulin, ceruloplasmin, complement C3, complement C4a, haptoglobin, prothrombin, and antithrombin-III | Coagulation, complement activation, and cell interaction in inflammation | Mucha et al., 2014 [63] | |
| 2D-DIGE-MALDI-TOF/TOF | 43 | Albumin fragments, A1AT, and α-1- β-glycoprotein ↓ laminin G-like 3 (LG3) fragment of endorepellin |
Matrix accumulation apoptosis of endothelial cells; extensive fibrosis |
Surin et al., 2013 [64] | |
| nanoLC-MS/MS | 13 | CD44, glycoprotein 2, vasorin, epidermal growth factor, CMRF35-like molecule 9, protocadherin, utreoglobin, dipeptidyl peptidase IV, NHL repeat-containing protein 3, SLAM family member 5 (CD84) | Activation of apoptosis, immune inflammation, coagulation, and complement | Samavat et al., 2015 [36] | |
| LC-MS/MS | 24 | ↓ Aminopeptidase N and vasorin precursor levels were higher on average in the urinary exosome samples ↑ A1AT and ceruloplasmin |
IgAN markers vs. thin basement membrane nephropathy | Moon et al., 2011 [65] | |
| CE-MS | 179 | ↑ Small proline-rich protein, leucine-rich repeat-containing protein, A1AT, sodium/potassium-transporting ATPase subunit gamma | Siwy et al., 2017 [54] | ||
| Lupus nephritis |
SELDI-TOF MS | 49 inactive 26 active |
Protein ions with m/z of 3340 and 3980 | Distinguished active from inactive LN | Mosley et al., 2006 [66] |
| SELDI-TOF MS | 19 active | Hepcidin, fragments of A1AT, and albumin | Infiltration interstitial leukocytes, cytokines production, and matrix accumulation | Zhang et al., 2008 [67] | |
| CE-MS | 92 | Collagens, uromodulin, protein S100-A9, clusterin, β-2-microglobulin, and α-2-HS-glycoprotein | Matrix accumulation | Siwy et al., 2017 [54] | |
| 2D- DIGE-MALDI-TOF MS/MS | 88 | Haptoglobin, α-1 anti-chymotrypsin, and retinol-binding protein | Effect on inflammation loss of proximal renal tubule function |
Aggarwal et al., 2017 [68] | |
| iTRAQ-MS | 61 | α1-antichymotrypsin (SERPINA3) | Marker of LN activity | Turnier et al., 2019 [69] | |
| CE-MS | 93 | CKD273 validation | It could not identify urinary biomarkers and predict active LN | Tailliar et al., 2021 [70] | |
| Diabetic nephropathy | 2D-DIGE-LC-MS/MS | 33 | ↑ α1B-Glycoprotein zinc-α2-glycoprotein, α2-HS-glycoprotein vitamin D–binding protein (VDBP), calgranulin B, A1AT, hemopexin ↓ Transthyretin, apolipoprotein A1, AMBP, and plasma retinol-binding protein |
Hyperglycosylated state and matrix accumulation |
Rao et al., 2007 [71] |
| CE-MS | 305 | ↓ Collagen type I and uromodulin fragments ↑albumin |
Increased synthesis of protease inhibitors diminishes excretion of collagen fragments | Rossing et al., 2008 [72] | |
| CE-MS | 126 | CKD 273 classifier | Good et al., 2010 [45] | ||
| CE-MS | 576 | ↑ Clusterin, apolipiprotein ↓ hemoglobin, uromodulin, small proline-rich protein 3, leucine-rich repeat-containing protein 25 |
Accumulation of proteins in the extracellular matrix chronic renal damage |
Siwy et al., 2017 [54] | |
| iTRAQ | 50 | 408 N-linked glycoproteins, A1AT, and ceruloplasmin | Different stage of DN | Jin et al., 2020 [73] | |
| 2D-DIGE-MALDI Q-TOF | 268 | Transthyretin/prealbumin and Ig kappa C chain region + cystatin C, and ubiquitin + α-1-acid glycoprotein 1, apolipoprotein A1, α-1 microglobulin/bikunin precursor, pigment epithelium-derived factor, zinc α-2 glycoprotein |
0–5 years of T2DM duration 5–10 years more than 10 years |
Patel and Kalia, 2019 [74] | |
| iTRAQ | 65 | ↑Haptoglobin and α-1-microglobulin/bikunin precursor | Liao et al., 2018 [75] | ||
| C18 plate–MALDI-TOF | 174 | ↑ β2-microglobulin and clara-cell protein | Proximal tubular dysfunction | Chen et al., 2018 [76] |
CE—capillary electrophoresis; DIGE—differential in-gel electrophoresis; ESI—electrospray ionization; IEF—isoelectric focusing; iTRAQ—isobaric tags for relative and absolute quantitation; MALDI—matrix-assisted laser desorption/ionization; SELDI—surface-enhanced matrix assisted laser desorption/ionization; TOF—time-of-flight; TMT—tandem mass tags.