Table 1.

Summary of studies reporting data of the diagnostic value of uEV in kidney transplantation.

Authors	Year of Publication	Country of Origin	Outcomes and Population	Timing of uEV Measurement	Technique	Normalization	Marker in uEV	Diagnostic Information
Sonoda et al. [16]	2009	Japan	Early I/R after transplantation (n = 1)	Day 1 before and day 2, 6 after transplantation	Immunoblot analysis	No	AQP1	AQP1 was hardly detectable before transplantation and significantly increased on day 2 after transplantation; Decreased AQP1 on day 6 was likely caused by I/R, according to findings in animal I/R models.
Pisitkun et al. [17]	2012	USA	Nonspecific findings (n = 2); TI (n = 7); TCMR (n = 6); AMR (n = 3)	Biopsy after transplantation	Large-scale liquid chromatography-tandem mass spectrometry	No	Proteome	Compared to all KTR: Cotransporter family showed higher expression in TI; Proteins related to epithelial cell differentiation showed higher expression in TCMR; Proteins related to acute inflammatory response, or antigen processing and presentation showed higher expression in AMR.
Alvarez et al. [18]	2013	Chile	Non-DGF (n = 12); DGF (n = 3)	Day 1, 2, 3 after transplantation	Western blotting	No	NGAL	Deceased donors showed higher levels of NGAL than living donors; The DGF group showed higher levels of NGAL than the non-DGF group.
Dimuccio et al. [19]	2014	Italy	Early graft function (n = 13); DGF (n = 12)	Hour 6, day 1, 7, 30 after transplantation	Cytofluorimetric analysis & Western blotting	Ratio of the expression level in CD133+ uEV and in total uEV	CD133	The proportion of CD133+ uEVs was much higher in healthy controls than ESRD patients; CD133+ uEVs increased from day 1 to day 30 after transplantation; KTR with DGF showed a lower increase in CD133+ uEV at day 1; The lower level of CD133+ uEV were associated with worse graft vascular lesions.
Esteva-Font et al. [20]	2014	Spain	CsA-free (n = 8); CsA-treated (n = 39)	1 year after transplantation	Immunoblotting	24-h urine volume	NCC & NKCC2	NCC and NKCC2 was more highly expressed in the CsA-treated group, whereas the p-values of all were above 0.05 (NCC: 0.1315, NKCC2 0.0542); NCC and NKCC2 were positively associated with the blood concentration of CsA, with p values of 0.0152 and 0.0497, respectively.
Sigdel et al. [21]	2015	USA	No rejection (n = 20); acute rejection (n = 10)	Biopsy after transplantation	Isobaric tags for relative and absolute quantitation & nanoLC-MS/MS	No	Proteome	DEFA5, CD5L, APOM, A2M, APOA2, PROS1, IGHM, FGA, and FGB were significantly increased in the acute rejection group.
Kim et al. [22]	2017	South Korea	Normal (n = 15); BKVN (n = 13); TCMR (n = 27); acute AMR (n = 9); CAMR (n = 16)	Biopsy after transplantation	Quantitative real-time polymerase chain reaction	MiR-16	Viral microRNA	Increased bkv-miR-B1-5p could diagnose BKVN, with AUC value of 0.989 and cut-off value of 5.9 log10 copies/mL (sensitivity 100%; specificity 98.5%); Increased bkv-miR-B1-5p/miR-16 could diagnose BKVN, with AUC value of 0.985 and cut-off value of 1.2 log10 copies/mL (sensitivity 100%; specificity 98.5%).
Park et al. [23]	2017	USA	No rejection (n = 22); acute rejection (n = 22)	Biopsy after transplantation	Integrated kidney exosome analysis	No	CD3	Increased CD3 could diagnose acute rejection with AUC value of 0.911 and cut-off value of 0.298 μA (sensitivity 92.8%, specificity 87.5%) in discovery set, with AUC value of 0.837. (sensitivity 63.6%, specificity 100%) in validation set.
Tutakhel et al. [24]	2017	Netherlands	CNIs-free (n = 13); CsA-treated (n = 9); Tacrolimus-treated (n = 23)	At least 6 months after transplantation	Immunoblotting	Ratio of phosphorylated NCC and total NCC	NCC	The expression of total NCC or phosphorylated NCC (Thr60) in CNI-treated KTR was significantly higher.
Hinrichs et al. [25]	2018	Denmark	No albuminuria (n = 19); albuminuria (n = 18)	1 year after transplantation	Western blotting	Urinary creatinine	γENaC	The expression of furin-cleaved γENaC and protease-cleaved γENaC (not full-length γENaC) was significantly increased in KTR with albuminuria.
Lim et al. [26]	2018	South Korea	Normal (n = 22); TCMR (n = 25)	Biopsy after transplantation	nanoLC-MS/MS & Western blotting	No	Proteome	APOA1, complement C3, HPX, PIGR, RBP4, etc. were increased in acute TCMR; NEP, PROM1, LRP2, CD9, NAPSA, etc., were decreased in TCMR.
Carreras-Planella et al. [27]	2020	Spain	Normal (n = 7); CNIs nephrotoxicity (n = 5); IFTA (n = 5)	Biopsy after transplantation	Mass spectrometry	Ezrin	Proteome	Compared to IFTA: Uroplakin family (UPK1A, UPK1B, UPK2, UPK3A), RAB1B, etc. were more positive in CNIs nephrotoxity; Complement components (C3, C5, C7) etc. were more negative in CNIs nephrotoxity.
Jung et al. [28]	2020	South Korea	Long-term graft survival (n = 57); CAMR (n = 26)	Biopsy after transplantation	Liquid chromatography–mass spectrometry	No	Proteome	PODXL, MUC1, etc. were decreased in CAMR; TTR, APOA1, HPX, complement C3, C4a, C4b, etc., were increased in CAMR.
Takada et al. [29]	2020	Japan	Normal (n = 20); IFTA (n = 19); CNIs nephrotoxicity (n = 17); CAMR (n = 22)	Biopsy after transplantation	Western blotting	CD9	SYT17	The ratio of SYT17/CD9 could distinguish CAMR from other groups, with AUC value of 0.82 and cut-off value of 0.42 (sensitivity 77%; specificity 87%)
Fekih et al. [8]	2021	USA	No rejection (n = 133); acute AMR (n = 8); CAMR (n = 16); TCMR (n = 35); borderline TCMR (n = 23); BKVN (n = 5)	Biopsy after transplantation	Quantitative real-time polymerase chain reaction	No	Messenger RNA	15 mRNA (CXCL11, CD74, IL32, etc.) could discriminate rejection from non-rejection, with the AUC value of 0.93 (sensitivity 84.7%; specificity 94%); 5 mRNA (CD74, complement C3, CXCL11, CD44, and IFNAR2) could distinguish TCMR from ABMR, with AUC value of 0.87 (sensitivity 87.5%; specificity 82.9%).

I/R: ischemia-reperfusion injury; AQP1: aquaporin 1; TCMR: T cell-mediated rejection; AMR: antibody-mediated rejection; TI: tubular injury; KTR: kidney transplant recipients; HLA: human leukocyte antigen; DGF: delayed graft function; NGAL: neutrophil gelatinase-associated lipocalin; CsA: cyclosporine A; NCC: sodium-chloride cotransporter; NKCC2: Na-K-Cl cotransporter; nanoLC-MS/MS: nano-scale liquid chromatography-tandem mass spectrometry; DEFA5: defensin-alpha 5; CD5L: CD5 molecule-like; APOM: apolipoprotein M; A2M: alpha-2-macroglobulin; APOA2: apolipoprotein A2; PROS1: protein S; IGHM: immunoglobulin heavy constant mu; FGA: fibrinogen alpha chain; FGB: fibrinogen beta chain; BKVN: BK virus associated nephropathy; CAMR: chronic antibody-mediated rejection; AUC: area under the curve; CNIs: calcineurin inhibitors; ENaC: epithelial sodium channel; APOA1: apolipoprotein A1; HPX: hemopexin; PIGR: polymeric immunoglobulin receptor; RBP4: retinol binding protein 4; NEP: neprilysin; PROM1: prominin 1; LRP2: low density lipoprotein receptor-related protein 2; NAPSA: napsin A aspartic peptidase; IFTA: interstitial fibrosis and tubular atrophy; SYT17; synaptotagmin 17; PODXL: podocalyxin; MUC1: mucin 1; TTR: transthyretin; RAB1B: Ras-related protein rab-1B; CXCL11: C-X-C motif chemokine ligand 11; IL32: interleukin 32; IFNAR2: interferon alpha and beta receptor subunit 2.