Future of non-invasive graft evaluation: A systematic review of proteomics in kidney transplantation

Table 1 Characteristics of the included studies

Ref.	Year of publication	Biomarker name	Type of fluid	Method of quantification	No. of samples	Condition evaluated	Data availability
Buscher et al[35]	2023	HGF, IGFB, P6, CD40, CX3CL1, SPARCL1	Plasma	Mass cytometry, PEA	39	Allograft function and rejection status	Yes
Başak Oktay et al[20]	2022	CXCL10	Urine	LC-MS/MS, ELISA	18	Chronic allograft dysfunction	No
Jeon et al[26]	2022	RBP4	Urine	LC-MS/MS, ELISA	49	Evaluation of renal graft function	On request
Carreras-Planella et al[24]	2021	Vitronectin	Urine	LC-MS/MS, ELISA	59	Assessment of fibrosis in kidney graft	No
Navarrete et al[22]	2020	Proteinase 3	Urine	Serine hydrolase ABPP with Nano-RP LC–MS/MS	32	Subclinical rejection
Braun et al[36]	2020	PCK2	Urine	(Western blot, SDS-PAGE, IHC validation), nano-LC-MS/MS - both untargeted and targeted using PRM	22	Prediction of long-term graft outcome	Yes
Thorne et al[33]	2020	S-troponin and S-myoglobin	Plasma	LC-MS/MS, ELISA	225	Subclinical effects of remote ischemic reconditioning	On request
Bank et al[31]	2019	TIMP2	Urine	sandwich ELISA	83	Prediction of the occurrence and duration of functionally defined delayed graft function	Yes
Al-Nedawi et al[25]	2019	TFIID subunit 1, 3-hydroxy-3-methylglutaryl coenzyme A reductase, FN1 protein, Spectrin beta chain, Protein AMBP, Alpha-1-acid glycoprotein 2, Dynein heavy chain 3, axonemal, Insulin receptor substrate 1, Prothrombin, Alpha-1-acid glycoprotein 1, Melanotransferrin, Catalase, DIS3-like exonuclease 1, Kinetochore-associated protein 1, Keratin, type II cuticular Hb6, Neuroblast differentiation-associated protein AHNAK, Apolipoprotein E, Angiotensinogen, Vitamin D-binding protein, EGF-containing fibulin-like extracellular matrix protein 1, Keratin, type II cytoskeletal 3, DNA repair protein RAD50, Receptor-type tyrosine-protein phosphatase, Apolipoprotein A-II, Transthyretin, Hemoglobin subunit beta	Plasma	(SDS-PAGE), MS/MS	30	eGFR correlation and graft function evaluation	No
Mockler et al[29]	2018	CXCL10	Urine	LC-MS/MS (to measure creatinine), sandwich ELISA (to measure CXCL10 and CCL2)	59	Correlation with eGFR and long term renal graft outcome	No
Williams et al[32]	2017	C4BPA, alpha, guanylin, immunoglob- ulin superfamily member 8, and serum amyloid P- component.	Urine	TUPA (scheduled LC-MRM this is a type of MS), sandwich ELISA	52	Diagnosis of Delayed graft function	Yes
Hirt-Minkowski et al[27]	2016	CCL2, CXCL10	Urine	ELISA	185	Prediction of long-term renal graft outcome	Yes
Hirt-Minkowski et al[28]	2015	CXCL10	Urine	sandwich ELISA	154	Long-term renal allograft outcome evaluation	Yes
Ho et al[23]	2016	MMP7	Urine	LC-MS/MS, ELISA	17	Subclinical graft injury and inflammation	Yes
Sigdel et al[21]	2013	ACAN, CLEC14A, GLB1, LGALS9B, LMAN2, MRC2 SEL, CD27, DPEP1, and F2	Urine	iTRAQ labeling, LC-MS/MS, ELISA	142	Evaluation of chronic allograft injury	Yes
Welberry Smith et al[30]	2013	Aminoacylase-1	Serum	LC-MS/MS, sandwich ELISA	194	Prediction of long-term outcome in patients with delayed graft function	Yes
Schmidt et al[34]	2013	Chitinase-3-like protein 1	Urine	MS	78	Evaluation of delayed graft injury and prediction of long-term renal graft outcome	Yes

LC-MS/MS: Liquid chromatography - tandem mass spectrometry; MRM: Targeted; ELISA: Enzyme-linked immunosorbent assay; HGF: Hepatocyte growth factor; CX3CL1: Fractalkine; IGFBP6: Insulin growth factor binding protein 6; CXCL10: C-X-C motif chemokine 10; SPARCL1: SPARC-like protein 1; RBP4: Retinol-binding protein 4; PCK2: Phosphoenolpyruvate carboxykinase 2; TIMP2: Tissue inhibitor of metalloproteinases-2; TFIID: Transcription initiation factor; C4BPA: C4b-binding protein alpha chain; CCL2: Chemokine ligand 2 ; MMP7: Matrix Metalloproteinase-7.

Table 2 The table contains the protein's name, UniProt number, cellular location, and code gene

Name	UniProt code	Cellular location	Sample type	Status	Code gene
Hepatocyte growth factor	P14210	Membrane, extracellular space	Plasma	Elevated	HGF
Insulin growth factor binding protein 6	P24592	Secreted	Plasma	Elevated	IGFBP6
CD40	P25942	Cell membrane and secreted	Plasma	Elevated	CD40
Fractalkine	P78423	Cell membrane	Plasma	Elevated	CX3CL1
SPARC-like protein 1	Q14515	Secreted, extracellular space and extracellular matrix	Plasma	Elevated	SPARCL1
C-X-C motif chemokine 10	P02778	Secreted, plasma membrane	Urine	Elevated	CXCL10
Retinol-binding protein 4	P02766	Cell wall, organelle, Secreted	Urine	Elevated	RBP4
Phosphoenolpyruvate carboxykinase 2	Q16822	Mitochondrion, ribosome	Urine	Elevated	PCK2
S troponin	P19429	Cytosol and sarcomere	Serum	Elevated	TNNI3
S myoglobin	P02144	Cytoplams and sarcoplasm	Serum	Elevated	MB
TIMP2	P16035	cytoplasmic vesicle, organelle, Secreted	Urine	Elevated	TIMP2
CCL2	P13500	Secreted	Urine	Elevated	CCL2
MMP7	P09237	Secreted, extracellular space, extracellular matrix	Urine	Elevated	MMP7
Aminoacylase-1	Q03154	Cytoplasm	Serum	Elevated	ACY1
Chitinase-3-like protein 1	P36222	Cytoplasm, endoplasmic reticulum, secreted	Urine	Elevated	CHI3 L1
Protein AMBP	P02760	Extracellular region, secreted	Plasma	Elevated	AMBP
Alpha-1-acid glycoprotein 2	P19652	Extracellular region, secreted	Plasma	Elevated	ORM2
Dynein heavy chain 3	Q8TD57	Cytoskeleton, cilium axoneme	Plasma	Elevated	DNAH3
Insulin receptor substrate 1	P06213	Cytosol, nucleus, plasma membrane, caveola	Plasma	Elevated	INSR
Catalase	P04040	Peroxisome	Plasma	Elevated	CAT
DIS3-like exonuclease 1	Q8TF46	Cytoplasm	Plasma	Elevated	DIS3 L
Kinetochore-associated protein 1	P50748	Cytoskeleton, spindle, nucleus, cytoplasm	Plasma	Elevated	KNTC1
Apolipoprotein E	P02649	Extracellular region, secreted	Plasma	Elevated	APOE
Angiotensinogen	P01019	Extracellular region, secreted	Plasma	Elevated	AGT
Vitamin D-binding protein	P02774	Extracellular region, secreted	Plasma	Elevated	GC
EGF-containing fibulin-like extracellular matrix protein 1	Q580Q6	Extracellular region, secreted	Plasma	Elevated	EFEMP1
C4b-binding protein alpha chain	P04003	Secreted	Urine	Elevated	C4BPA
Serum amyloid P-component	P02743	Secreted	Urine	Elevated	APCS
Aggrecan core protein	P16112	Secreted, extracellular space, extracellular matrix	Urine	Elevated	ACAN
C-type lectin domain family 14 member A	Q86T13	Membrane	Urine	Elevated	CLEC14A
Beta-galactosidase	P54803	Cytoplasm, lysosome	Urine	Elevated	GLB1
Galectin-9B	Q3B8N2	Cytosol, nucleus	Urine	Elevated	LGALS9B
Vesicular integral-membrane protein VIP36	Q12907	Endoplasmic reticulum, golgi apparatus, membrane	Urine	Elevated	LMAN2
C-type mannose receptor 2	Q9UBG0	Membrane	Urine	Elevated	MRC2
Protein sel-1 homolog 1	Q9UBV2	Endoplasmic reticulum membrane	Urine	Elevated	SEL1 L
CD27 antigen	P26842	Membrane	Urine	Elevated	CD27
Dipeptidase 1	Q9H4A9	Cell projection, microvillus membrane, cell membrane	Urine	Elevated	DPEP1
Transcription factor E2F2	Q14209	Nucleus	Urine	Elevated	E2F2
Keratin, type II cytoskeletal 3	P12035	Intermediate filament, keratin filament cytosol, exosome	Plasma	Decreased immediately, elevated 1 month after	KRT3
DNA repair protein RAD50	Q92878	Nucleus	Plasma	Decreased immediately, elevated 1 month after	RAD50
Receptor-type tyrosine-protein phosphatase	P23469	Integral component of membrane	Plasma	Decreased immediately po, elevated 1 month after	PTPRE
Vitronectin	P04004	Endoplasmic reticulum, golgi apparatus, organelles, secreted	Urine	Detected only in fibrotic grafts	VTN
proteinase 3	P24158	Lysosome, cytosol, plasma membrane, cytoplasmic vesicle, organelle, secreted	Urine	Increased activity	PRTN3
Transcription initiation factor TFIID subunit 1	P21675	Nucleus	Plasma	Decreased	TAF1
3-hydroxy-3-methylglutaryl coenzyme A reductase	P04035	Endoplasmic reticulum, ER membrane	Plasma	Decreased	HMGCR
Fibronectin	P02751	Extracellular region, secreted	Plasma	Decreased	FN1
Spectrin beta chain, non-erythrocytic 1	Q01082	Cytoskeleton	Plasma	Decreased	SPTBN1
Apolipoprotein A-II	V9GYM3	Extracellular region, secreted	Plasma	Decreased	APOA2
Transthyretin	E9KL36	Extracellular region, secreted	Plasma	Decreased	HEL111
Hemoglobin subunit beta	P68871	Cytosol, extracellular or secreted: Blood microparticle, exosome	Plasma	Decreased	HBB
Guanylin	Q02747	Secreted	Urine	Decreased	GUCA2A
Immunoglobulin superfamily member 8	Q969P0	Cell membrane	Urine	Decreased	IGSF8
Prothrombin	P00734	Extracellular region, secreted	Plasma	Elevated in good prognosis recipients	F2
Alpha-1-acid glycoprotein 1	P02763	Secreted	Plasma	Elevated in good prognosis recipients	ORM1
Melanotransferrin Isoform 1	P08582	Plasma membrane, GPI-anchor	Plasma	Elevated in good prognosis recipients	MELTF
Apolipoprotein A-I	P02647	Extracellular region, secreted	Plasma	Elevated in good prognosis recipients	APOA1
Keratin, type II cuticular Hb6	O43790	Cytoskeleton, keratin filament, cytosol extracellular region or secreted, exosome	Plasma	Elevated in good prognosis recipients	KRT86
Neuroblast differentiation-associated protein AHNAK	Q09666	Cytoskeleton, centrosome	Plasma	Elevated in good prognosis recipients	AHNAK

HGF: Hepatocyte growth factor; CX3CL1: fractalkine; IGFBP6: Insulin growth factor binding protein 6; CXCL10: C-X-C motif chemokine 10; SPARCL1: SPARC-like protein 1; RBP4: Retinol-binding protein 4; PCK2: Phosphoenolpyruvate carboxykinase 2; TIMP2: Tissue inhibitor of metalloproteinases-2; C4BPA: C4b-binding protein alpha chain; CCL2: Chemokine ligand 2; MMP7: Matrix Metalloproteinase-7.