Table 1.
Potential biomarkers for chronic rejection.
| Biomarker classification | Biomarker candidate | Sample type | AUC | Sensitivity/Specificity | Application | Ref |
|---|---|---|---|---|---|---|
| Transcriptomic biomarker | CD6, INPP5D, ISG20, NKG7, PSMB9, RUNX3, TAP1 (↑) | Kidney graft | n/a | n/a | Predict the development of progressive i-IFTA at 24 months | Sigdel TK, et al. (45) |
| vimentin, NKCC2, E-cadherin, 18S rRNA (↑) | Urine | 0.95 | 0.938/0.841 | As a 4-gene model diagnostic of i-IFTA | Lee JR, et al. (46) | |
| CHCHD10, KLHL13, FJX1, MET, SERINC5, RNF149, SPRY4, TGIF1, KAAG1, ST5, WNT9A, ASB15, RXRA | Kidney graft | 0.889 (average) | 0.81/0.79 (average) | Predict fibrosis and graft failure | O’Connell PJ, et al. (47) | |
| RSAD2, ETV7 (↑) | PBMC | 0.761 (RSAD2) 0.84 (ETV7) |
n/a | Diagnose of ABMR | Matz M, et al. (48) | |
| TIM-3 (↑) | PBMC | 0.71 | 0.83/0.75 | Predict CAD | Shahbaz SK, et al. (49) | |
| Urine | 0.75 | 0.83/0.75 | ||||
| TIM-3, KIM-1 (↑) | PBMC | 0.99 (TIM-3) | 1/0.98 (TIM-3) | Predict CAD | Shahbaz SK, et al. (50) | |
| 0.97 (KIM-1) | 1/0.7 (KIM-1) | |||||
| Urine | 0.95 (TIM-3) | 1/0.81 (TIM-3) | ||||
| 0.99 (KIM-1) | 1/0.93 (KIM-1) | |||||
| 0.95 (KIM-1 concentration) | 1/74 (KIM-1 concentration) | |||||
| CIITA (↓), CTLA-4 (↑) | PBMC | 0.902 (CIITA) | n/a | Predict dnDSA and chronic ABMR | Yamamoto T, et al. (51) | |
| 0.785 (CTLA4) | ||||||
| TLR-2, TLR-4, MyD88 (↑) | PBMC | 0.94 (TLR2) | 0.93/0.93 (TLR2) | Predict early and late CAD | Hosseinzadeh M, et al. (52) | |
| 0.95 (TLR4) | 0.93/0.93 (TLR4) | |||||
| 0.94 (MyD88) | 1/0.93 (MyD88) | |||||
| Kidney graft | 0.94 (TLR2) | 0.93/0.93 (TLR2) | ||||
| 0.95 (TLR4) | 0.93/1 (TLR4) | |||||
| 0.98 (MyD88) | 1/0.93 (MyD88) | |||||
| CASP3, FAS, IL-18 (↓) | PBMC | 0.79 (CASP3) | 0.71/0.88 (CASP3) | Predict graft function | Kaminska D, et al. (53) | |
| 0.75 (FAS) | 0.64/0.8 (FAS) | |||||
| 0.77 (IL-18) | 0.71/0.8 (IL-18) | |||||
| Epigenetic biomarkers | Foxp3 DNA demethylation | Kidney graft | n/a | n/a | Protector for long-term allograft outcome | Bestard O, et al. (54) |
| PD1 DNA methylation in memory CD8+ T cells (↑) | PBMC | n/a | n/a | PD1 DNA methylation increases in recipients with rejection | Karin Boer, et al. (55) | |
| miR-21, miR-200b (↑) | Urine | 0.89 (miR-21) | 0.85/0.8 (miR-21) | Corelate with renal allograft dysfunction and i-IFTA; diagnostic biomarkers for renal allograft monitoring | Zununi VS, et al. (56) | |
| 0.81 (miR-200b) | 0.84/0.95 (miR-200b) | |||||
| miR-150 (↑), miR-423-3p (↑), miR192 (↓), miR-200b (↓) | Plasma | 0.87 (all) | 0.78/0.91 | Predict graft outcome in recipients with CAD | Zununi VS, et al. (57) | |
| miR21, miR-155, miR-142-3p (↑) | Plasma | 0.82 (all) | 0.81/0.92 | Upregulate in recipients with i-IFTA; corelate with renal allograft dysfunction; can be used for graft monitoring | Zununi VS, et al. (58) | |
| miR-145-5p (↓) | Plasma | 0.891 | 0.933/0.731 | Diagnostic biomarker of i-IFTA | Matz M, e al (59) | |
| miR-148a (↓) | Plasma | 0.89 | 0.97/0.72 | Correlated with renal function and histological grades; biomarker of the progression to i-IFTA | Nariman-Saleh-Fam Z, et al. (60) | |
| miR-142-3p(↓), miR-204 (↑), miR-211 (↑) | Urine, kidney graft | 0.974 (miR-142-3p) | 0.89/1 (miR-142-3p) | As markers of CAD with i-IFTA and for monitoring graft function | Scian MJ, et al. (61) | |
| 0.967 (miR-204) | 0.95/1 (miR-204) | |||||
| 1 (miR-211) | 1/1 (miR-211) | |||||
| miR-142-5p (↓), miR-486-5p (↑) | PBMC | n/a | n/a | Predict chronic ABMR | Iwasaki K, et al. (62) | |
| Proteomic biomarker | V305_HUMAN_NTLYLNMNSLR, RL18_HUMAN_ILTFDQLALDSPK, F151A_HUMAN_AVGPSLDLLR, TGFR2_HUMAN_LTAQCVAER, LYAM1_HUMAN_AEIEYLEK, K2C8_HUMAN_LSELEAALQR, F151A_HUMAN_TYTQAMVEK, PLGB_Human_AFQYHSK, K1C19_HUMAN_ILGATIENSR, IBP7_HUMAN_GTCEQGPSIVTPPK, LV102_HUMAN_WYQQLPGTAPK DSRAD_Human_YLNTNPVGGLLEYAR, | Urine | 0.995 | n/a | Predict CAD | Sigdel TK, et al. (63) |
| PARP1 (↓) | Serum | 0.871 | n/a | Predict AR and chronic graft injury | Srivastava M, et al. (64) | |
| TNF-α, ANXA11, Integrin α3, Integrin β3 (↑) | Urine | 0.805 (TNFα) | n/a | Diagnose AR and CR | Srivastava M, et al. (65) | |
| 0.855 (Integrin α3) | ||||||
| 0.813 (integrin β3) | ||||||
| 0.963 (ANXA11) | ||||||
| CXCL9, CXCL10 (↑) CXCL9/Cr ratio (↑) CXCL10/Cr ratio (↑) |
Urine | 0.86 (CXCL9), 0.9 (CXCL9/Cr) | n/a | Predict TCMR | Rabant M, et al. (66) | |
| 0.8 (CXCL10), 0.82 (CXCL10/Cr) | n/a | Predict mixed rejection | ||||
| 0.7 (CXCL10), 0.7 (CXCL10/Cr) | n/a | Predict ABMR | ||||
| CXCL10/Cr ratio (↑) | Urine | 0.81 (sub-clinical TCMR) | 0.59/0.67 (subclinical TCMR) | Predict TCMR for pediatric recipients | Blydt-Hansen TD, et al. (67) | |
| 0.88 (clinical TCMR) | 0.77/0.6 (clinical TCMR) | |||||
| Vitronectin (↑) | Urine | 0.963 | n/a | Monitor fibrotic changes in kidney allograft | Carreras-Planella L, et al. (68) | |
| Properdin, sC5b-9 (↑) | Urine | n/a | n/a | As risk factors of graft failure | Lammerts R, et al. (69) | |
| AZGP1 (↑) | Urine | 0.946 | 0.846/0.8 | Predict and diagnose chronic ABMR | Jung HY, et al. (70) | |
| β2 microglobulin, NGAL, clusterin, KIM-1 (↑) | Urine | n/a | n/a | Predict chronic allograft nephropathy | Cassidy H, et al. (71) | |
| Metabolomic biomarkers | Newly Synthesized DNA and ATP | PBMC | n/a | n/a | Analyze lymphocyte subset activation responses | Sottong PR, et al. (72) |
| NAD, 1-MN, cholesterol sulfate, GABA, nicotinic acid, NADPH, proline, spermidine, alpha-hydroxyhippuric acid | Urine | n/a | n/a | Predict TCMR | Kalantari S, et al. (73) | |
| Alanine, Citrate, Lactate, combined with urea or glucose or glucutonate | Urine | 0.76 | n/a | Diagnose AR | Miriam B, et al. (74) | |
| threitol, inositol, glucose, xylono-1, 5-lactone, xylitol, xylopyranoside, 2,3-dihydroxybutanoic acid, glucitol, ribonic acid, octadecanoic acid, phosphate (↑) fructose, glycolic acid, 3-hydroxyisovaleric acid (↓) |
Urine | n/a | 0.867/0.677 | Diagnose AR | Long Zheng, et al. (75) | |
| guanidoacetic acid, methylimidazoleacetic acid, dopamine (↑) 4-guanidinobutyric acid, L-tryptophan (↓) |
Urine | 0.926 | 0.9/0.846 | Diagnose AR | Kim S, et al. (76) | |
| Itaconate, kynurenine (↑) | Kidney graft | n/a | n/a | Distinguish acute cellular rejection from IRI | Beier UH, et al. (77) | |
| glycine, glutaric acid, adipic acid, inulobiose, threose, sulfuric acid, taurine, N-methylalanine, asparagine, 5-aminovaleric acid lactam, myo-inositol | Urine | 0.985 | 0.929/0.963 | Diagnose AR | Sigdel TK, et al. (78) | |
| Cellular biomarker | TEMRA/EM CD8 T cell ratio (↑) | PBMC | 0.75 (8 year graft failure) | n/a | Predict graft failure | Jacquemont L, et al. (79) |
| 0.79 (11 year graft failure) | ||||||
| CD154+ T-cytotoxic memory cells (↑) | PBMC | 0.968 | 0.923/0.846 | Predict rejections (liver) | Ashokkumar C, et al. (80) | |
| PBMC | 0.938 | 1/0.88 | Predict AR (kidney) | Ashokkumar C, et al. (81) | ||
| alloreactive memory IFN-γ-producing T cells (↑) | PBMC | 0.725 | 0.8/0.64 | Predict subclinical TCMR and DSA | Crespo E, et al. (82) | |
| Ratio of T follicular helper cells and T follicular regulatory cells (Tfc/Tfr) (↑) | PBMC | n/a | n/a | Risk factor of CAD | Yan L, et al. (83) | |
| Myofibroblast | Kidney graft | n/a | n/a | Identify CR | Liu YG, et al. (84) |
NKCC2, Na-K-Cl cotransporter 2; CD6, cluster of differentiation 6; INPP5D, inositol polyphosphate-5-phosphatase D; ISG20, interferon-stimulated gene 20; NKG7, natural killer cell granule protein 7; PSMB9, proteasome subunit beta type-9; RUNX3, runt-related transcription factor 3; TAP1, transporter associated with antigen processing 1; CHCHD10, Coiled-coil-helix-coiled-coil-helix domain containing 10; KLHL13, Kelch-like family member 13; FJX1, Four jointed box 1; MET, Met proto-oncogene; SERINC5, Serine incorporator 5; RNF149, Ring finger protein 149; SPRY4, Sprouty homolog 4; TGIF1, TGFB-induced factor homeobox 1; KAAG1, Kidney associated antigen 1; ST5, Suppression of tumorigenicity 5; WNT9A, Wingless-type MMTV integration site family member 9A; ASB15, Ankyrin repeat and SOCS box-containing 15; RXRA, Retinoid X receptor alpha; TIM-3, T cell immunoglobulin and mucin domain 3; KIM-1, kidney injury molecule-1; CIITA, class II transactivator; CTLA-4, cytotoxic T-lymphocyte antigen; TLR, toll-like receptor; MyD88, myeloid differentiation factor 88; CASP3, caspase 3; FAS, first apoptotic signal; PD1, programmed death 1; miR, micro RNA; PARP1, Poly(ADP-ribose) polymerase 1; CXCL9, chemokine C-X-C motif ligand 9; CXCL10, chemokine C-X-C motif ligand 10; AZGP1, zinc-alpha-2-glycoprotein; NAD, nicotinamide adenine dinucleotide; 1-MN, 1-methylnicotinamide; GABA, gamma-aminobutyric acid; NADPH, nicotinamide adenine dinucleotide phosphate; IRI, ischemia reperfusion injury; NGAL, neutrophil gelatinase-associated lipocalin; TEMRA, terminally differentiated effector memory; EM, effector memory; PBMC, Peripheral blood mononuclear cell; AUC, area under curve; n/a, not available; I-IFTA, interstitial fibrosis and tubular atrophy; AR, acute rejection; CR, chronic rejection; ABMR, antibody-mediated rejection; TCMR, T cell-mediated rejection; CAD, chronic allograft dysfunction; dnDSA, de novo donor specific antibody.