Impact of comorbid renal dysfunction in patients with hepatocellular carcinoma on long-term outcomes after curative resection

Table 1 Characteristics of the patients with and without renal dysfunction

	RD (EGFR < 60), n = 128	Non-RD (EGFR ≥ 60), n = 672	P value
Age (yr)	69.5 ± 8.6	63.0 ± 10.4	< 0.0001
Sex
Male	111 (86.7)	549 (81.7)	0.17
Female	17 (13.3)	123 (18.3)	-
Etiology
HBV	29 (22.7)	263 (39.1)	< 0.001
HCV	41 (32.0)	218 (32.4)	0.93
NBNC	58 (45.3)	191 (28.5)	< 0.001
Child-Pugh grade
A	124 (96.9)	649 (96.6)	0.86
B	4 (3.1)	23 (3.4)	-
Laboratory data
Plt (×104/μL)	16.2 ± 6.2	15.5 ± 7.3	0.26
PT (%)	94.9 ± 13.7		0.08
Alb (g/dL)	4.0 ± 0.4	4.1 ± 0.4	0.32
T-bil (mg/dL)	0.7 ± 0.3	0.8 ± 0.4	< 0.001
AST (IU/L)	35.5 ± 31.2	43.0 ± 43.4	< 0.05
ALT (IU/L)	31.5 ± 30.0	40.0 ± 36.1	< 0.01
ChE (IU/L)	238.0 ± 89.8	245.0 ± 81.3	0.92
ICG15R (%)	14.4 ± 7.3	13.6 ± 10.6	0.61
HbA1c (%)	5.7 ± 1.1	5.3 ± 1.1	< 0.05
BUN (mg/dL)	20.0 ± 10.8	14.0 ± 4.0	< 0.0001
Cr (mg/dL)	1.1 ± 1.6	0.7 ± 0.1	< 0.0001
AFP (ng/mL)	10.3 (1.4-164321.4)	19.9 (0-5986980)	< 0.01
AFP-L3 (%)	0.0 ± 23.8	3.1 ± 24.4	< 0.05
PIVKA-II (mAU/mL)	11385.0 (0-436410)	136.0 (0-664680)	0.68

P values were determined by the χ² test or the Mann-Whitney U test. RD: Renal dysfunction; HBV: Hepatitis B virus; HCV: Hepatitis C virus; NBNC: Non-hepatitis B virus or hepatitis C virus; Plt: Platelet count; PT: Prothrombin time; Alb: Serum albumin; T-bil: Total bilirubin; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; ChE: Choline esterase; ICGR15: Indocyanine green rate at 15 min; HbA1c: Hemoglobin A1c; BUN: Blood urea nitrogen; Cr: Creatinine; AFP: Alpha-fetoprotein; AFP-L3: Alpha-fetoprotein isoform, lectin affinity; PIVKA-II: Protein-induced vitamin K absence-II; EGFR: Estimated glomerular filtration rate.

Table 2 Characteristics of the patients with severe and mild chronic kidney disease and without renal dysfunction

	CKD stage			P value
	Severe (EGFR < 30), n = 19	Mild (30 ≤ EGFR < 60), n = 109	Non-RD (EGFR ≥ 60), n = 672
Age (yr)	73.0 ± 8.9	69.0 ± 8.6	63.0 ± 10.4	< 0.0001
Sex
Male	13 (68.4)	98 (89.9)	549 (81.7)	< 0.05
Female	6 (31.6)	11 (10.1)	123 (18.3)	-
Etiology
HBV	5 (26.3)	24 (22.0)	263 (39.1)	< 0.01
HCV	8 (42.1)	33 (30.3)	218 (32.4)	0.59
NBNC	6 (31.6)	52 (47.7)	191 (28.5)	< 0.001
Child-Pugh grade
A	19 (100.0)	105 (96.3)	649 (96.6)	0.71
B	0 (0.0)	4 (3.7)	23 (3.4)	-
Laboratory data
Plt (×104/μL)	14.5 ± 5.2	16.3 ± 6.4	15.5 ± 7.3	0.76
PT (%)	94.9 ± 10.1	95.2 ± 14.3	91.7 ± 14.7	0.35
Alb (g/dL)	3.8 ± 0.3	4.1 ± 0.4	4.1 ± 0.4	< 0.01
T-bil (mg/dL)	0.4 ± 0.2	0.7 ± 0.3	0.8 ± 0.4	< 0.001
AST (IU/L)	27.0 ± 17.4	38.0 ± 32.5	43.0 ± 43.4	0.07
ALT (IU/L)	21.0 ± 19.0	34.0 ± 30.9	40.0 ± 36.1	< 0.05
ChE (IU/L)	181.0 ± 68.1	249.0 ± 90.0	245.0 ± 81.3	< 0.01
ICG15R (%)	10.5 ± 6.2	15.3 ± 7.3	13.6 ± 10.6	0.18
HbA1c (%)	5.5 ± 1.0	5.9 ± 1.1	5.3 ± 1.1	< 0.05
BUN (mg/dL)	38.0 ± 15.8	19.0 ± 5.2	14.0 ± 4.0	< 0.0001
Cr (mg/dL)	2.4 ± 3.2	1.0 ± 0.2	0.7 ± 0.1	< 0.0001
AFP (ng/mL)	51.5 (2.1-164321.4)	6.5 (1.4-37525.5)	19.9 (0-5986980)	0.61
AFP-L3 (%)	21.7 ± 30.6	0.0 ± 21.6	3.1 ± 24.4	< 0.05
PIVKA-II (mAU/mL)	1309.0 (10-167600)	105.0 (0-436410)	136.0 (0-664680)	0.93

P values were determined by the χ² test or by the Kruskal-Wallis U test. RD: Renal dysfunction; HBV: Hepatitis B virus; HCV: Hepatitis C virus; NBNC: Non-hepatitis B virus or hepatitis C virus; Plt: Platelet count; PT: Prothrombin time; Alb: Serum albumin; T-bil: Total bilirubin; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; ChE: Choline esterase; ICGR15: Indocyanine green rate at 15 min; HbA1c: Hemoglobin A1c; BUN: Blood urea nitrogen; Cr: Creatinine; AFP: Alpha-fetoprotein; AFP-L3: Alpha-fetoprotein isoform, lectin affinity; PIVKA-II: Protein-induced vitamin K absence-II; CKD: Chronic kidney disease; EGFR: Estimated glomerular filtration rate.

Table 3 Intraoperative parameters in the patients with and without renal dysfunction

	CKD stage		P value
	RD (EGFR < 60), n = 128	Non-RD (EGFR ≥ 60), n = 672
Intraoperative variables
Operative time (min)	323.0 ± 125.0	329.0 ± 108.0	0.70
Blood loss (mL)	380.0 ± 3230.1	425.0 ± 1577.3	0.42
Procedure of resection
Anatomical resection	99 (77.3)	498 (74.1)	0.44
Nonanatomical resection	29 (22.7)	174 (25.9)	-
Resected liver weight (g)	239.0 ± 459.3	252.0 ± 630.0	0.57
Curability
A + B	117 (91.4)	563 (83.8)	< 0.05
C	11 (8.6)	109 (16.2)	-
Tumor characteristics
Tumor size (cm)	4.5 ± 3.9	4.4 ± 4.6	0.85
Tumor number	1.0 ± 1.7	1.0 ± 2.8	0.55
PStage1
I	8 (6.3)	53 (7.9)	0.11
II	62 (48.4)	272 (40.5)	-
III	40 (31.3)	207 (30.8)	-
IV	18 (14.1)	140 (20.8)	-
Pathological grade
Well	24 (18.7)	95 (14.1)	0.29
Mod-por	104 (81.3)	577 (85.9)	-
Vascular invasion1
Yes	11 (8.6)	145 (21.6)	< 0.001
No	117 (91.4)	527 (78.4)	-
Liver fibrosis score2
0-1	44 (34.4)	143 (21.2)	< 0.0001
2	43 (33.6)	172 (25.6)	-
3	22 (17.2)	149 (22.2)	-
4	19 (14.8)	208 (31.0)	-

¹Liver Cancer Study Group of Japan, 6^th edition.

²Liver fibrosis was graded and staged according to the New Inuyama classification system as follows: F1 (periportal expansion), F2 (porto-portal septa), F3 (porto-central linkage or bridging fibrosis), and F4 (cirrhosis).

P values were determined by the χ² test or the Mann-Whitney U test. The liver fibrosis score was assessed by expert pathologists using a noncancerous lesion from the resected specimen. RD: Renal dysfunction; CKD: Chronic kidney disease; EGFR: Estimated glomerular filtration rate.

Table 4 Intraoperative parameters in the patients with severe and mild chronic kidney disease and without renal dysfunction

	CKD stage			P value
	Severe (EGFR < 30), n = 19	Mild (30 ≤ EGFR < 60), n = 109	Non-RD (EGFR ≥ 60), n = 672
Intraoperative variables
Operative time (min)	311.0 ± 112.0	331.0 ± 127.0	329.0 ± 108.0	0.52
Blood loss (mL)	389.0 ± 1254.1	380.0 ± 3464.9	425.0 ± 1577.3	0.64
Procedure of resection
Anatomical resection	13 (68.4)	86 (78.9)	498 (74.1)	0.46
Nonanatomical resection	6 (31.6)	23 (21.1)	174 (25.9)	-
Resected liver weight (g)	365.0 ± 388.5	222.0 ± 471.3	252.0 ± 630.0	0.24
Curability
A + B	19 (100.0)	98 (89.9)	563 (83.8)	< 0.05
C	0 (0.0)	11 (10.1)	109 (16.2)	-
Tumor characteristics
Tumor size (cm)	5.8 ± 4.0	4.5 ± 3.8	4.4 ± 4.6	0.41
Tumor number	1.0 ± 2.1	1.0 ± 1.6	1.0 ± 2.8	0.44
pStage1
I	1 (5.3)	7 (6.4)	53 (7.9)	0.45
II	8 (42.1)	54 (49.5)	272 (40.5)	-
III	7 (36.8)	33 (30.3)	207 (30.8)	-
IV	3 (15.8)	15 (13.8)	140 (20.8)	-
Pathological grade
Well	2 (10.5)	22 (20.2)	95 (14.1)	0.84
Mod-por	17 (89.5)	87 (79.8)	577 (85.9)	-
Vascular invasion1
Yes	2 (10.5)	9 (8.3)	145 (21.6)	< 0.01
No	17 (89.5)	100 (91.7)	527 (78.4)	-
Liver fibrosis score2
0-1	7 (36.8)	37 (34.0)	143 (21.2)	< 0.001
2	8 (42.1)	35 (32.1)	172 (25.6)	-
3	3 (15.8)	19 (17.4)	149 (22.2)	-
4	1 (5.3)	18 (16.5)	208 (31.0)	-

¹Liver Cancer Study Group of Japan, 6^th edition.

²Liver fibrosis was graded and staged according to the New Inuyama classification system as follows: F1 (periportal expansion), F2 (porto-portal septa), F3 (porto-central linkage or bridging fibrosis), and F4 (cirrhosis).

P values were determined by the χ² test or by the Kruskal-Wallis U test. The liver fibrosis score was assessed by expert pathologists using a noncancerous lesion from the resected specimen. RD: Renal dysfunction; CKD: Chronic kidney disease; EGFR: Estimated glomerular filtration rate.

Table 5 Postoperative complications in the patients with and without renal dysfunction

	CKD stage		P value
	RD (EGFR < 60), n = 128	Non-RD (EGFR ≥ 60), n = 672
All complications	33 (25.8)	169 (25.1)	0.96
Major complication (Grade ≥ 2)	20 (15.6)	112 (16.7)	0.91
Bile leakage	12 (9.8)	44 (6.5)	0.33
Ascites	6 (4.7)	27 (4.0)	0.90
Pleural effusion	4 (3.1)	37 (5.5)	0.41
Pneumonia	6 (5.3)	12 (1.8)	0.70
Bleeding	7 (5.5)	12 (1.8)	< 0.05
Liver failure	1 (0.8)	9 (1.3)	0.55
Surgical site infection	5 (3.9)	12 (1.8)	< 0.05
Duration of postoperative hospital stay (d)	16.0 ± 14.5	16.0 ± 19.3	0.17
Died during hospitalization	11 (0.8)	12 (0.1)	0.96

¹One patient in the renal dysfunction group died due to postoperative gastrointestinal perforation and an intraabdominal abscess.

²One patient in the non-renal dysfunction group died due to postoperative liver failure.

P values were determined by the χ² test or the Mann-Whitney U test. RD: Renal dysfunction; CKD: Chronic kidney disease; EGFR: Estimated glomerular filtration rate.

Table 6 Postoperative complications in the patients with severe and mild chronic kidney disease and without renal dysfunction

	CKD stage			P value
	Severe (EGFR < 30), n = 19	Mild (30 ≤ EGFR < 60), n = 109	Non-RD (EGFR ≥ 60), n = 672
All complications	5 (26.3)	28 (25.7)	169 (25.1)	0.99
Major complication (Grade ≥ 2)	3 (15.8)	17 (15.6)	112 (16.7)	0.98
Bile leakage	2 (10.5)	10 (9.2)	44 (6.5)	0.40
Ascites	2 (10.5)	4 (3.7)	27 (4.0)	0.45
Pleural effusion	0 (0.0)	4 (3.7)	37 (5.5)	0.68
Pneumonia	1 (5.3)	5 (4.6)	12 (1.8)	0.84
Bleeding	2 (10.5)	5 (4.6)	12 (1.8)	< 0.05
Liver failure	0 (0.0)	1 (0.9)	9 (1.3)	0.55
Surgical site infection	0 (0.0)	5 (4.6)	12 (1.8)	0.07
Duration of postoperative hospital stay (d)	16.0 ± 15.3	16.0 ± 14.4	16.0 ± 9.3	0.92
Died during hospitalization	0 (0.0)	11 (0.9)	12 (0.1)	0.96

¹One patient in the renal dysfunction group died due to postoperative gastrointestinal perforation and an intraabdominal abscess.

²One patient in the non-renal dysfunction group died due to postoperative liver failure.

P values were determined by the χ² test or the Mann-Whitney U test. RD: Renal dysfunction; CKD: Chronic kidney disease; EGFR: Estimated glomerular filtration rate.

Table 7 Prognostic factors for overall survival and relapse-free survival in the hepatocellular carcinoma patients with renal dysfunction

Variable (RD patients)	Univariate analysis (OS)		Multivariate analysis (OS)		Univariate analysis (RFS)		Multivariate analysis (RFS)
	HR (95%CI)	P value	HR (95%CI)	P value	HR (95%CI)	P value	HR (95%CI)	P value
Age > 60 yr	2.33 (1.14-5.63)	< 0.05	3.85 (0.81-22.53)	0.092	2.08 (1.01-5.01)	< 0.05	0.98 (0.26-4.76)	0.978
Male	1.37 (0.73-2.82)	0.371			1.66 (0.88-3.48)	0.122
HBV+	1.00 (0.56-1.67)	0.995			1.02 (0.57-1.73)	0.947
HCV+	0.97 (0.60-1.52)	0.899			1.03 (0.64-1.63)	0.889
NBNC	1.03 (0.66-1.60)	0.898			0.96 (0.61-1.50)	0.849
Child-Pugh grade B	2.16 (0.12-10.17)	0.44			0.90 (0.05-4.13)	0.919
Plt < 13.8	0.88 (0.54-1.40)	0.598			0.76 (0.46-1.22)	0.257
PT < 80	0.89 (0.47-1.57)	0.706			1.05 (0.57-1.81)	0.858
Alb < 4.0	1.25 (0.80-1.95)	0.321			1.23 (0.78-1.92)	0.376
T-bil > 1.2	0.87 (0.30-2.01)	0.772			1.03 (0.40-2.18)	0.95
AST > 38	1.15 (0.74-1.79)	0.534			1.31 (0.85-2.05)	0.223
ALT > 44	0.71 (0.43-1.14)	0.162			1.21 (0.76-1.90)	0.421
ChE < 168	2.40 (1.22-4.32)	< 0.01	1.06 (0.31-3.15)	0.921	3.15 (1.59-5.79)	< 0.01	2.21 (0.17-1.35)	0.147
ICGR15 > 15	0.94 (0.60-1.48)	0.800			1.36 (0.87-2.14)	0.176
HbA1c > 5.6	1.49 (0.87-2.55)	0.145			0.94 (0.57-1.56)	0.823
AFP > 10	1.51 (0.97-2.39)	0.068			2.07 (1.32-3.28)	< 0.01	0.79 (0.29-2.03)	0.634
AFP-L3 > 10	2.97 (1.74-5.01)	< 0.0001	2.57 (0.99-6.70)	0.051	2.21 (1.33-3.59)	< 0.01	2.22 (0.87-5.98)	0.095
PIVKA-II > 40	1.85 (1.17-3.00)	< 0.01	2.57 (0.64-11.50)	0.186	1.53 (0.97-2.46)	0.067
Operative time > Ave	0.96 (0.62-1.50)	0.868			0.98 (0.62-1.53)	0.916
Blood loss > Ave	1.31 (0.78-2.13)	0.282			1.17 (0.70-1.89)	0.533
Anatomical resection	1.06 (0.64-1.85)	0.833			0.79 (0.48-1.37)	0.391
Resected liver weight > Ave	2.05 (1.18-3.44)	< 0.01	0.99 (0.37-2.66)	0.978	1.53 (0.87-2.59)	0.137
Tumor size > Ave	1.94 (1.18-3.10)	< 0.01	1.06 (0.33-3.30)	0.918	1.88 (1.14-3.04)	< 0.05	1.86 (0.63-5.40)	0.258
Tumor number > 1	2.13 (1.30-3.45)	< 0.01	2.44 (1.04-5.75)	< 0.05	3.46 (2.04-5.85)	< 0.0001	3.77 (1.61-8.97)	< 0.01
Pathological grade (mod-por)	1.23 (0.70-2.34)	0.505			1.32 (0.76-2.47)	0.337
Vascular invasion (Vp+, Vv+)	4.92 (2.21-9.84)	< 0.0001	1.88 (0.61-5.14)	0.26	4.08 (1.86-8.00)	< 0.01	1.89 (0.70-4.60)	0.198
Liver fibrosis score 3, 4	1.29 (0.80-2.03)	0.278			1.37 (0.86-2.16)	0.186

OS: Overall survival; RFS: Recurrence-free survival; HR: Hazard ratio; CI: Confidence interval; RD: Renal dysfunction; HBV: Hepatitis B virus; HCV: Hepatitis C virus; NBNC: Non-hepatitis B virus or hepatitis C virus; Plt: Platelet counts; PT: Prothrombin time; Alb: Serum albumin; T-bil: Total bilirubin; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; ChE: Choline esterase; ICGR15: Indocyanine green rate at 15 min; HbA1c: Hemoglobin A1c; BUN: Blood urea nitrogen; Cr: Creatinine; AFP: Alpha-fetoprotein; AFP-L3: Alpha-fetoprotein isoform, lectin affinity; PIVKA-II: Protein-induced vitamin K absence-II; Ave: Average; Mod: Moderately differentiated; por: Poorly differentiated; Vp: Portal vein invasion; Vv: Hepatic vein invasion.