Table 1.
Details of the design of included studies/cohorts within. Studies are classified based on CKD model as: unilateral ureteral obstruction (UUO), hypertension, diabetes and other. Characteristic of the EV intervention, disease/animal model, timepoints evaluated, and main study findings are outlined
| CKD model |
Study | EV source | Dosing | Adm-route | Dose | CM | EV size | Markers | Species/Model | Sex | EV Adm |
End | Main findings |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| UUO | He [27] | MSCs (mouse) bone marrow | S | IV | 30 mg | UC | ~ 100 nm (TEM) | n.a. | C57BL6/J mouse (UUO), In vitro (human TECs, TGF-β1) | n.a. | 2d | 1w 2d | EVs alleviated EMT, and preserved renal function. |
| UUO | He [27] | MSCs (mouse) bone marrow | S | IV | 30 mg | UC | ~ 100 nm (TEM)* | n.a. | C57BL6/J mouse (UUO), In vitro (human TECs, TGF-β1) | n.a. | 2d | 2w 2d | EVs alleviated EMT, and preserved renal function. |
| UUO | Wang [39] | MSCs (mouse) bone marrow | S | IV | 30 μg | UC | n.a. |
n.a. (MSC-markers) |
C57BL/6 mouse, (UUO), In vitro (human TECs, TGF-β1) | n.a. | 1d | 1w | EVs improved fibrosis, reduced tubular damage, and preserved renal function. |
| UUO | Wang [39] | MSCs (mouse) bone marrow | S | IV | 30 μg | UC | n.a. |
n.a. (MSC-markers) |
C57BL/6 mouse, (UUO), In vitro (human TECs, TGF-β1) | n.a. | 1d | 2w | EVs improved fibrosis, reduced tubular damage, and preserved renal function. |
| UUO | Wang [38] | MSCs (rat) bone marrow,: younger rat | S | IV |
~30 μg* (from 3x10^5 cells) |
UC | n.a. |
n.a (MSC-markers) |
Fisher 344 rat (UUO), In vitro (h TECs, TGF-β1) | M | 1d | 1w | EVs improved tubulointerstitial injury. EVs failed to preserve SCr, preserved BUN. |
| UUO | Wang [38] | MSCs (rat) bone marrow: younger rat | S | IV | ~30 μg | UC | n.a. |
n.a. (MSC-markers) |
Fisher 344 rat (UUO), In vitro (h TECs, TGF-β1) | M | 1d | 2w | EVs improved tubulointerstitial injury, failed to preserve SCr, minimally decreased BUN. |
| UUO | Wang [38] | MSCs (rat) bone marrow, older rat | S | IV | ~30 μg | UC | n.a. |
n.a. (MSC-markers) |
Fisher 344 rat (UUO) | M | 1d | 1w | EVs failed to preserve tubulointerstitial injury, SCr and BUN. |
| UUO | Wang [38] | MSCs (rat) bone marrow, older rat | S | IV | ~30 μg | UC | n.a. |
n.a. (MSC-markers) |
Fisher 344 rat (UUO) | M | 1d | 2w | EVs failed to preserve tubulointerstitial injury, SCr and BUN. |
| UUO | Chen [10] | MSCs (human) adipose tissue | S | IV | 200 μg | UC | 30-150 nm (DLS) | CD9, CD63, CD81 | Nude mice* (UUO), In vitro (human EC) | M | 1d | 1w |
EVs improved kidney morphology and decreased fibrosis. However, EVs failed to preserve renal function. |
| UUO | Ji [28] | MSCs (human) umbilical cord | M (3) | IV |
~ 2.5 mg* (10 mg/kg body mass) |
UC | 32-180 nm (NTA) |
CD9, CD63, Alix. ,cyt C, calnexin (-) |
SD rat (UUO), In vitro (rat TECs, mechanical stress) | M | 6d | 2w | EVs attenuated the progression of renal functional decline and improved fibrosis. |
| UUO | Shi [37] | MSC (rat) bone marrow | S | IV |
~100 μg* (0.5 mg/kg body mass) |
UC | 50-600 nm (NTA) | CD9, CD63, HSP70 | SD rat (UUO), In vitro (human TECs, TGF-β1) | M | 1d | 2w | Histology: EVs improved renal fibrosis. EVs reduced inflammation, oxidative stress, apoptosis, and fibrosis in TECs stimulated with TGF-β1 |
| UUO | Yang [42] | EPCs (mouse) | M (3) | IV | ~20 μg* (from 2x10^5 cells) | UC | 100-1000 nm (TEM) | n.a. | C57BL/6 mouse, (UUO), In vitro (renal pericyte, TGF-β) | M | 1d | 5d | Histology: EVs improved EMT. |
| UUO | Choi [19] | MSCs (mouse) kidney | S | IV | 2×107 EVs | UC | n.a. | n.a. | FVB/N mice (UUO), In vitro (HUVECs, TGF-β) | n.a. | 1d | 1w | Histology: EVs improved EMT, decreased PTC loss and inflammatory cell infiltration. |
| Rodent HT | |||||||||||||
| HT | Cambier [17] | CPCs (human) | M (5) | IV | 350 μg |
Conc- entation & MF |
n.a. | * | C57BL/6J mouse (Ang II) | M | 2w | 4w |
EVs decreased albuminuria, ameliorated renal structural injury and inflammation . |
| HT | Lindoso [34] | MSCs (human) adipose tissue | M (8) | IV | ~20 μg (1.5x10^9 EVs) | UC | 96-132 nm (NTA) | CD63, CD81 | Wistar rat (DOCA-salt + UNX) | M | 1w | 8w | EVs improved renal function and ameliorated kidney damage by affecting kidney inflammation and EMT. |
| HT | Zou [47] | STC-like cells (pig) | S | IR | 30 μg | UC | 20-310 nm (NTA) | CD9, CD29, CD81, CD24 |
129-S1 mouse (RAS), In vitro (human TECs, AMA) |
M | 14 | ? | EVs improved renal function, alleviated tubular injury and restored mitochondrial function. |
| Porcine | |||||||||||||
| HT | Eirin [23] | MSCs (pig) adipose tissue | S | IR | ~100 μg (1x10^10 EVs) | UC | 20-400 nm (NTA) | CD9, CD40, CD81 | Domestic pig (obese diet + RAS) | F | 6w | 10w | EVs improved renal function, decreased inflammation, improved medullary oxygenation and kidney fibrosis. |
| HT | Eirin [24] | MSCs (pig), adipose lean-EVs | S | IR | ~100 μg (1x10^10 EVs) | UC | * | CD63, CD9, CD29, Beta1, MHCI, CD44 |
Domestic pig (obese diet + RAS) In vitro (human ECs) |
F | 6w | 9w | Lean-EVs improved GFR and RBF, and increased tube number and length, and EC migration. |
| HT | Eirin [24] | MSCs (pig), adipose MetS-EVs | S | IR | ~100 μg (1x10^10 EVs) | UC | * | CD63, CD9, CD29, Beta1, MHCI, CD44 |
Domestic pig (obese diet + RAS) In vitro (human ECs) |
F | 6w | 9w | The above effects were decreased for MetS-EVs. MetS-EVs failed to restore renal angiogenic factors, improve microvascular density, or fibrosis. |
| HT | Song [14] | MSCs (pig), adipose tissue lean-EVs | S | IR | ~100 μg (1x10^10 EVs) | UC | * | CD9, CD81, MSC markers | Domestic pig (obese diet + RAS), In vitro (activated T-cells) | F | 6w | 10w | Lean-EVs preserved GFR and improved kidney morhology by activating intrarenal regulatory T cells |
| HT | Song [14] | MSCs (pig), adipose tissue MetS-EVs | S | IR | ~100 μg (1x10^10 EVs) | UC | * | CD9, CD81, MSC-markers | Domestic pig (obese diet + RAS), In vitro (activated T-cells) | F | 6w | 10w | The protective effects were decreased for MetS-EVs. |
| HT | Zhao [45] | MSCs (pig) adipose tissue | S | IR | 1 x 10^11 EVs | UC | 100-200 nm (NTA) | CD9, CD29, CD69 | Domestic pig (obese diet + RAS) | F | 6w | 10w | EVs improved GFR and RBF and reduced fibrosis. Compared with MSC, EVs more significantly upregulated growth factor expression and decreased necroptosis. |
| DN, T1D | Duan [20] | SCs (human) urine | M (12) | IV | 100 μg | UC | 30–120 nm (TEM) | CD63, TSG101, HSP90B1 calnexin** |
SD rat (Streptozocin), In vitro (human podocyte, glucose) |
M | 3d | 12w | EVs preserved renal function and ameliorated glomerular damage. |
| DN, T1D | Jiang [29] | SCs (human), urine | M (12) | IV | 100 μg | UC-DG | 50–100 nm (TRPS) |
CD63, CD9, CD8, MSC-EV markers |
SD rat, (Streptozocin), In vitro (human podocyte, glucose) |
M | 3d | 12w | EVs ameliorated glomerular damage but failed to preserve renal function. |
| DN, T1D | Grange [25] | HLSCs (human) | M (5) | IV | ~100 μg (1x10^10 EVs) | UC | 44-280 nm (NTA) | * | NOD/SCID/iL2Ry KO NGS mouse (Streptozocin) | M | 5w | 7w | EVs partially improved SCr, BUN, and histological tubular and glomerular damage and improved fibrosis gene expression. |
| DN, T1D | Grange [25] | MSCs (human), bone marrow | M (5) | IV | ~100 μg (1x10^10 EVs) | UC | 44-280 nm (NTA) | * | NOD/SCID/iL2Ry KO NGS mouse (Streptozocin) | M | 5w | 7w | EVs partially improved SCr, BUN, and histological tubular and glomerular damage and improved fibrosis gene expression. |
| DN, T1D | Ebrahim [22] | MSCs (rat), bone marrow | M (56), M (2) | IV |
~30 ug* (100 μg/kg body mass) |
UC | 40–100 nm (TEM) | CD81, CD63 | Allbino rat (Streptozocin) | M | 8w 4d | 12w 4d | EVs markedly improved kidney function, and reduced histological tubular and glomerular damage and improved kidney fibrosis. |
| DN, T1D with HU | Zhong [46] | MSCs (human), umbilical cord | M (4) | IV |
~30 ug* (1.5 mg/kg body mass) |
UC | 30-500 nm (DLS) |
n.a. (MSC-markers) |
Balb/C mouse, (Streptozocin) with high UA In vitro (human PTCs) |
M | 2w | 6w | EVs markedly improved kidney function, and reduced EMT. |
| DN, T1D with HU | Zhong [46] | MSCs (human), umbilical cord | M (6) | IV |
~30 ug* (1.5 mg/kg body mass) |
UC | 30-500 nm (DLS) |
n.a. (MSC-markers) |
Balb/C mouse, (Streptozocin) with high UA In vitro (human PTCs) |
M | 2w | 8w | EVs markedly improved kidney function, and reduced EMT. |
| DN, T1D with HU | Zhong [46] | MSCs (human), umbilical cord | M (8) | IV |
~30 ug* (1.5 mg/kg body mass) |
UC | 30-500 nm (DLS) |
n.a. (MSC-markers) |
Balb/C mouse, (Streptozocin) with high UA In vitro (human PTCs) |
M | 2w | 10w | EVs markedly improved kidney function, and reduced EMT. |
| DN, T2D | Duan [21] | MSCs (mouse), adipose tissue | M (12) | IV | 100 μg | UC | 30-150 nm (DLS) | CD9, CD63, CD81, TSG101 | C57BL/KsJ db/db mouse, In vitro (mouse podocyte, glucose) | M | 13w | 25w | EVs decreased kidney structural damage and improved kidney function. |
| DN, T2D | Jin [30] | MSCs (mouse), adipose tissue | M (12) | IV | n.a. | Immun-P | 60-500 nm (NTA) | CD9, CD63, CD81 | C57BL/KsJ db/db mouse, In vitro (mouse podocyte, glucose) | M | 13w | 25w | EVs improved kidney function and reduced kidney structural damage. |
| DN | Nagaishi [35] | MSCs (rat), bone marrow | S | intra-renal | 5.3 × 10^7 EVs (CD9 ELISA) | UC | 40–100 nm (TEM) | HSP70, CD9, CD63 | Rat (Streptozocin), In vitro (rat TECs) | n.a. | 4w | 5 or 6w | EVs ameliorated renal histological damage induced by DM and decreased immune cell infiltrates. |
| DN | Jin [31] | MSCs (mouse), adipose tissue | n.a. | n.a. | n.a. | Immuno-P | <100 nm (TEM) | CD9, CD63, CD81 | In vitro (mice podocyte, glucose) | - | - | - | EVs protect against high glucose-induced EMT progression of podocytes. |
| (Other)Nx | He [26] | MSCs (mouse), bone marrow | M (3) | IV | 30 μg | UC | ~ 100 nm (TEM) | n.a. | C57BL6/J mouse (5/6 Nx) | n.a. | 2d | 1w 4d | EVs preserved renal function, decreased renal fibrosis, inflammation, and tubular damage. |
| (Other)Nx | Van Koppen [11] | MSCs (human), embryonic | M (4) | IV | 7 μg | UC-DG | n.a. | n.a. | Lewis rat (5/6 Nx + L-NNA + salt), In vitro (human endothelial cell) | M | 6w | 11w | EVs had no effect on kidney function and histology. EVs improved angiogenesis in vitro. |
| (Other)GN | Cantaluppi [18] | EPCs (human), blood | S | IV |
~60 μg* (30 μg/100g body mass) |
UC | 60-130 nm (NTA) | CD55, CD59 | Wistar rat (anti-Thy1.1 Ab), In vitro (rat mesangial cells, anti-Thy1.1 Ab) | F | 2d | 2w | EVs preserved renal function and morphology and decreased inflammatory cell infiltration. |
| (Other) Toxic | Kholia [32] | HLSCs | M (4) | IV |
100 μg* (1x10^10 EVs) |
UC-DG | 40-100 nm (TEM) | CD81, CD9, TSG101, CD81, CD107 | NGS mouse (Aristolochid acid), In vitro (mouse TECs, AA). | M | 3d | 4w | EVs preserved renal function and prevented kidney histological damage and decreased immune infiltrates in the kidney. |
| (Other) Toxic | Kholia [33] | MSCs (human), bone marrow | M (4) | IV |
100 μg* (1x10^10 EVs) |
UC | 80-500 nm (NTA) | CD9, CD63, CD81, GM130 (-) | NGS mouse (Aristolochid acid), In vitro (mouse TECs, AA). | M | 3d | 4w | EVs preserved renal function, prevented kidney histological damage, and decreased inflammatory infiltrates in the kidney. |
| (Other) Toxic | Ramirez-Bajo [12] | MSCs (mouse), bone marrow | M (2) | IV | 100 μg | UC | 22-370 nm (NTA) | CD63, CD9, MSC markers | C57BL/6 mouse (CyA) | M | 1d | 4w | EVs slightly improved BUN, did not improved morphology and failed to improve body weight. |
| (Other) Toxic | Ramirez-Bajo [12] | MSCs (mouse), bone marrow | M (2) | IV | 100 μg | UC | 22-370 nm (NTA) |
CD9, CD63, MSC-markers |
C57BL/6 mouse (CyA) | M | 2w | 4w | EVs reduced BUN slightly better than preventive intervention. Also, curative EVs decreased cyst formation and improved body weight. |
| (Other) Toxic | Zhang [44] | MSCs (human), umbilical cord | M (2) | IV | 100 μg | UC | 300-500 nm (EM) | MSC-markers | SD rat (CyA), In vitro (human TECs, CyA) | M | 1w | 4w | EVs improved renal function and ameliorated renal structural injury and oxidative stress. |
| (Other) Alport | Sedrakyan [36] | AFSC (mouse) | S | IC | 200 ug | UC | 50-500 nm (NTA) | CD9, CD63 , CD24, MSC-markers | Alport-TektdT mouse, In vitro (mice GEC) | n.d. | 8w | 36w | EVs improved renal function and decreased GEC damage. |
Cell of EV origin: AFSC amniotic fluid stem cell, CPC cardiac progenitor cell, EKC embryonic kidney cell, EPC endothelial progenitor cell, HLSC liver stem cell, MSC mesenchymal stem cell, SC satellite cell, STC STC-like cell, uSC urine mesenchymal stem cell. Methods of EV measurement: DLS dynamic light scattering, TEM transmission Electron Microscopy, NTA nanoparticle tracking analysis, TRPS tunable resistive pulse sensing. EV markers: CD cluster of Differentiation, HLA human leukocyte antigen, TSG101 tumor Susceptibility 101. CKD model: HT hypertension, DM diabetes, RAS renal artery steatosis, UUO unilateral ureteral obstruction, Nx nephrectomy, AMA Antimycin-A, CyA cyclosporine A, PTC peritubular capillary, TEC tubular epithelial cell, TGF-β1 transforming growth factor β, EMT epithelial to mesenchymal transition. Route of EV administration: IV intravenous, IC intra-cardiac, IR intra-renal
~data regarding single dosage were extrapolated for illustrative purposes, where dosage was recalculated based on μg per body mass or 100 μg protein was approximated as 1*10^10 EV particles or EVs from 1x10^6 SCs
*asterisk marks immunodeficient mice strain
#EA indicates start of EV administration (days since UUO procedure, or streptozocin injection for diabetes models, or RAS for hypertension). End indicates study end (days/weeks after induction)