Table 2 Prognostic application of liquid biopsy in recent 5 years

CTC

Italy

2021

Enumeration

Peripheral blood

CellSearch System

195 metastasis RCC patients

Predicting patients' survival

Patients with at least 3 CTCs had a shorter OS of 13.8 months versus 52.8 months in those with fewer than 3 CTCs

Patients had at least 3 CTCs, with a median PFS of 5.8 versus 15 months in the remaining patients

[184]

China

2019

Beclin-1

Peripheral blood

Can Patrol CTC enrichment technique,

RNA ISH

58 metastasis-free RCC patients

11 metastasis RCC patients

Predicting patients' metastasis

The number of preoperative Beclin1-positive CTCs in the metastatic group was significantly higher than the number of Beclin1-negative CTCs (P < 0.05)

The difference between the number of Beclin1-positive CTCs and Beclin1-negative CTCs in the metastasis-free group was not statistically significant (P > 0.05)

[25]

ctDNA/

cfDNA

Japan

2019

Status and fragment size

of cfDNA

or ctDNA

Plasma

NGS

ddPCR

53 RCC patients

Predicting patients' survivals

ctDNA status was associated with PFS and CSS (P = 0.061, P < 0.01, respectively)

cfDNA fragment size was significantly associated with PFS and CSS (p = 0.004, p = 0.011, respectively)

[50]

Japan

2018

Plasma cfDNA fragment size

Plasma

qPCR

Microfluidics-based platform

92 RCC patients

41 healthy controls

Predicting patients' survivals

Shorter cfDNA fragment size was negatively associated with progression-free survival (p = 0.006)

[41]

cfRNA

Canada

2020

miR-328-3p

Urine

qPCR

30 oncocytomas patients

26 progressive ccRCC-SRM patients

24 non-progressive ccRCC-SRM patients

Predicting patients' survivals

Patients with high miR-328-3p expression levels had significantly longer OS (HR = 0.29, p = 0.042) compared to patients with low miR-328-3p expression levels

[79]

Germany

2018

miR-122-5p

miR-206

Serum

qPCR

86 ccRCC patients

55 benign renal tumor patients

28 healthy controls

Predicting patients' grade and metastasis

miR-122-5p levels were significantly increased in metastasized ccRCCs (cM0 vs. cM1; p = 0.045) and advanced Fuhrman Grade (G1/2 vs. G3/4; p = 0.001)

Serum miR-206 expression was significantly increased in advanced pT-stage (pT1/2 vs. pT3/4; p = 0.006) and metastasized ccRCC (cM0 vs. cM1; p = 0.002)

[165]

Predicting patients' survivals

Univariate Cox Regression analysis showed that elevated miR-122-5p and miR-206 serum levels were correlated with a shorter period of progression-free, cancer-specific, and overall survival (all P < 0.005)

Protein

India

2021

GRP78

Serum

Elisa

60 RCC patients

60 non-tumor controls

Predicting the metastasis of RCC

GRP78 expression was significantly higher in RCC patients with metastatic than in those without metastasis (P < 0.001). Predicting ability of metastasis or non-metastasis RCC: AUC 0.954, sensitivity 100%, specificity 90.4%

[179]

Predicting the grade of RCC

Median level of serum GRP78 increases with higher grade of RCC (P < 0.001). Predicting ability of high or low-grade RCC: AUC 0.948, sensitivity 92%, specificity 83%

Norway

2021

IL-6, IL-27, IL-31, OSM, CNT-f, IL-6Rα, gp130

Serum

Luminex immune-bead technology and

a high-sensitivity kit

159 RCC patients with nephron sparing surgery, a radical nephrectomy or a cyto-reductive nephrectomy

Predicting patients' recurrence

Kaplan–Meier analysis showed IL-27 had a significantly predictive ability of recurrence (P = 0.026)

Cox multivariate regression consisted of IL-6 and IL-27 showed that IL-6 had a significantly predictive ability of recurrence (P = 0.004) but not IL-27 (P = 0.082)

Kaplan–Meier analysis showed both of IL-27 and IL-6 had significantly predictive abilities of recurrence for ccRCC patients withlarge tumors (diameter > 7.0 cm) (P = 0.014, P = 0.026, respectively)

[117]

Predicting patients' survivals

Kaplan–Meier analysis and multivariate regression analysis showed IL-6 had a significantly predictive ability of disease-specific survival (DSS) (P < 0.026, P = 0.001, respectively)

Kaplan–Meier analysis showed IL-6 could predict DSS for patients with a tumor diameter from a 4 to 7 cm and > 7 cm (P = 0.001, P = 0.02, respectively), and IL-27 could predict DSS for patients with a tumor diameter > 7 cm (P = 0.025)

Kaplan–Meier analysis showed IL-6 could predict OS for ccRCC patients (P = 0.001) but not IL-27 (P = 0.066)

Kaplan–Meier analysis showed IL-6 could predict DSS for patients with a tumor diameter from a 4 to 7 cm but not > 7 cm (P = 0.018, P = 0.063, respectively), while gp130 could only predict DSS for patients with a tumor diameter > 7 cm (P = 0.001)

USA

2021

Hpg80

Plasma

Elisa

89 RCC patients

Refining IMDC prognostic scores

Patients with high hPG80 levels (> 4.5 pM) had a shorter OS than other patients (12 vs. 31.2 months, respectively; p = 0.0031)

Adding hPG80 levels > 4.5 pM in the IMDC risk scores showed better significance slightly and more refined discriminating ability (p = 0.0046)

[180]

France

2021

SAA2, CFB

Plasma

Elisa

59 mRCC

patients with sunitinib or bevacizumab treatment

Predicting the metastasis of RCC

Combination of Fuhrman grade and levels of SAA2 and CFB showed better ability of predicting time to relapse. The model combining Fuhrman grade and CFB showed the best C-Index (C-Index = 0.7273), followed by the three covariates together (C-Index = 0.7163) and Fuhrman grade alone (C-Index = 0.6948)

[186]

France

2021

NGAL

Urine

ARCHITECT C4100

50 RCC patients

Evaluating post-operative risk of progression and death

ccRCC patients with NGAL level above 2.19 ng/mmol had a 5-time fold higher risk of progression than patients with NGAL level below the threshold (HR = 5.5, p = 0.005). The HR of cancer specific death for patients with a level of NGAL above 2.19 ng/mmol was of 7.2 (p = 0.001)

[185]

Italy

2020

PD-1, PD-L1, BTN3A1

Plasma

Elisa

Testing cohort:

21 mccRCC

patients with nivolumab treatment

Validating cohort:

20 mccRCC

patients with nivolumab treatment

15 localized ccRCC patients

Predicting metastasis of ccRCC patients

The mean levels of plasma immune checkpoint levels in metastatic ccRCC patients were significantly higher than localized RCC patients (PD-1: 2.79 vs. 1.54 ng/mL, p = 0.003; PD-L1: 0.62 vs. 0.49 ng/mL, p = 0.03)

Plasma immune checkpoint levels were correlated to number and localization of metastatic sites

[187]

USA

2019

PLIN-2

Urine

Plasmonic biosensor

20 RCC patients

20 healthy controls

8 BLCA patients

10 diabetic nephropathy patients

Predicting the size

of RCC tumor

The urine PLIN-2 concentrations were associated to tumor size which Spearman correlation coefficient is 0.59 (P < 0.009)

[128]

Metabolites

Japan

2022

5 urinary metabolites

Urine

LC–MS/MS

56 ccRCC patients

10 benign urological tumor

Predicting the recurrence

A model consisting of 5 metabolites (lactic acid, glycine, 2-HG, succinic acid, and kynurenic acid) showed significant predicting value for ccRCC recurrence (AUC 0.894, sensitivity 88.9%, specificity 88.0%) and T3 ccRCC patients (AUC 0.903, sensitivity 88.9%, and specificity 100%)

[100]

Japan

2020

9 urinary metabolites

Urine

LC–MS

69 stage I-II RCC patients

18 stage III-IV RCC patients

60 benign renal tumor patients

Predicting the clinical stage

A model consisting of 4 metabolites (L-kynurenine, L-glutamine, fructose 6-phosphate and butyrylcarnitine) was used for predicting III-IV stage of RCC patients: AUC 0.837, sensitivity 88.5%, specificity 75.4%

[176]

Exosome

Spain

2021

Exosome mtDNA

VH1, CγB, HBB

Plasma

Differential ultracentrifugation,

qPCR,

NGS,

dPCR

13 RCC patients

15 healthy controls

Predicting the metastasis of RCC

qPCR showed that VH1-short, VH1-long and CγB-short (B phase) were of a significant difference in metastatic group and non-metastatic group (p = 0.020, p = 0.035, p = 0.078, respectively)

dPCR showed that VH1-short (B phase) and CγB-short (C phase) were of a significant difference in metastatic group and non-metastatic group (p = 0.069, p = 0.037, respectively)

dPCR and qPCR showed that HBB-long were of a more significant difference in metastatic group and non-metastatic group in most phases

[183]