Chronic kidney disease at one year after liver transplantation: Role of changes in immunosuppression over three decades

Table 1 Characteristics of liver transplant recipients, n (%)/median (25^th-75^th percentiles)

Variables	Total patients, (n = 594)	Patients with CKD at 1 year, (n = 290)	Patients without CKD at 1 year, (n = 304)	P value
Pre-transplant variables
Age in years	52.9 (45-59.08)	54.61 (46.07-60)	52.17 (43.93-58.42)	0.009
Female sex	174 (29.3)	109 (37.6)	65 (21.4)	< 0.001
HTN	78 (13.1)	42 (14.5)	36 (11.8)	0.406
DM	106 (17.9)	52 (17.9)	54 (17.8)	0.972
BMI in kg/m2	25.2 (22.76-28)	24.61 (22.57-27.75)	25.64 (22.93-28.57)	0.023
LT indication				0.007
Cirrhosis without tumor	410 (69)	212 (73.1)	198 (65.1)
HCC	149 (25.1)	58 (20)	91 (29.9)
AFH	10 (1.7)	4 (1.4)	6 (2)
Other	15 (2.5)	12 (4.1)	3 (1)
Other tumors	10 (1.7)	4 (1.4)	6 (2)
Child-Pugh				0.113
A	102 (17.2)	37 (12.8)	65 (21.4)
B	277 (46.6)	141 (48.6)	136 (44.7)
C	194 (32.7)	100 (34.5)	94 (30.9)
No cirrhosis	21 (3.5)	12 (4.1)	9 (3)
Pre-transplant RD	105 (17.7)	75 (25.9)	30 (9.9)	< 0.001
Post-transplant variables
Immunosuppression				< 0.001
Tac	375 (63.1)	146 (50.3)	229 (75,3)
CsA	219 (36.9)	143 (49.3)	76 (25)
Steroids	397 (66.8)	223 (76.9)	174 (57.2)
AZA	158 (26.6)	109 (37.6)	49 (16.1)
MPA	243 (40.9)	87 (30)	156 (51.3)
BAX	246 (41.4)	91 (31,4)	155 (50.9)
HTN at 6 months	202 (34.8)	113 (39)	89 (30)	0.013
DM at 6 months	175 (29.6)	96 (33.1)	79 (26.2)	0.074
Renal dysfunction
At 1 month	218 (36.8)	157 (54.1)	61 (20.1)	< 0.001
At 6 months	261 (44.3)	219 (75.5)	42 (13.8)	< 0.001

AFH: Acute fulminant hepatitis; AZA: Azathioprine; BAX: Basiliximab; BMI: Body mass index; CsA: Cyclosporine A; CKD: Chronic kidney disease; DM: Diabetes mellitus; HCC: Hepatocellular carcinoma; HTN: Arterial hypertension; LT: Liver transplant; MPA: Mycophenolic acid; RD: Renal dysfunction; Tac: Tacrolimus.

Table 2 Multivariable analysis of risk factors for chronic kidney disease at 1 year after liver transplant in all patients

Variable	P value	OR	95%CI
Age	0.003	1.03	1.01-1.05
Female sex	0.028	1.88	1.23-2.89
BMI	0.020	0.96	0.91-1.01
Pre-transplant RD	0.044	2.69	1.58-4.58
HCC	0.007	0.80	0.49-1.29
CNI (CsA)	< 0.001	3.77	2.45-5.78
HTN at 6 months	0.489	0.77	0.51-1.15
DM at 6 months	0.078	1.49	0.97-2.29

BMI: Body mass index; CNI: Calcineurin inhibitor; CsA: Cyclosporine A; DM: Diabetes mellitus; HCC: Hepatocellular carcinoma; HTN: Arterial hypertension; OR: Odds ratio; RD: Renal dysfunction.

Table 3 Characteristics of liver transplant recipients classified by periods, n (%)/mean ± SD

Variables	Total patients, (n = 594)	P1 1987-1991, (n = 69)	P2 1992-1996, (n = 99)	P3 1997-2001, (n = 111)	P4 2002-2007, (n = 102)	P5 2008-2013, (n = 84)	P6 2014-2019, (n = 129)
Pre-transplant variables
Age in years	51.1 ± 10.9	42.9 ± 11.2	47.1 ± 11.8	50.5 ± 10.7	52.9 ± 9.9	54.6 ± 8.8	56 ± 8.4
Female sex	174 (29.3)	28 (40.6)	35 (35.4)	34 (30.6)	24 (23.5)	21 (25)	32 (24.8)
HTN	78 (13.1)	1 (1.4)	5 (5.1)	8 (7.2)	18 (17.6)	19 (22.6)	27 (20.9)
DM	106 (17.9)	5 (7.2)	9 (9.1)	18 (16.2)	23 (22.5)	14 (16.6)	37 (28.7)
BMI in kg/m2	25.6 ± 4.2	24.2 ± 3.8	25.1 ± 5.3	25.3 ± 3.9	25.4 ± 4.0	27 ± 3.6	26.2 ± 3.8
LT indication
Cirrhosis without tumor	410 (69)	62 (89.8)	86 (86.9)	91 (82)	68 (66.7)	40 (47.6)	63 (48.8)
HCC	149 (25.1)	3 (4.3)	9 (9.1)	13 (11.7)	32 (31.4)	37 (44)	55 (42.6)
AFH	10 (1.7)	2 (2.9)	0	2 (1.8)	1 (1)	1 (1.2)	4 (3.1)
Other	15 (2.5)	0	2 (2)	1 (0.9)	1 (1)	5 (6)	6 (4.7)
Other tumors	10 (1.7)	2 (2.9)	2 (2)	4 (3.6)	0	1 (1.2)	1 (0.8)
Child-Pugh
A	92 (15.5)	8 (11.6)	4 (4)	6 (5.4)	17 (15.7)	24 (28.6)	33 (25.6)
B	278 (46.8)	33 (47.8)	64 (64.6)	58 (52.3)	46 (45.1)	27 (32.1)	49 (38)
C	190 (32)	24 (34.8)	27 (27.3)	40 (36)	37 (36.3)	26 (31)	36 (27.9)
No cirrhosis	35 (5.9)	4 (5.8)	4 (4)	7 (6.3)	2 (2)	7 (8.3)	11 (8.5)
Pre-transplant RD	105 (17.7)	14 (20.3)	17 (17.2)	15 (13.5)	23 (22.5)	11 (13.1)	25 (19.4)
Post-transplant variables
Immunosuppression
Tac1	360 (60.6)	0	7 (7.1)	54 (48.6)	101 (99)	80 (95.2)	118 (91.5)
CsA	219 (36.9)	69 (100)	92 (92.9)	57 (51.4)	1 (1)	0	0
Steroids	397 (66.8)	69 (100)	99 (100)	102 (91.9)	72 (70.6)	19 (22.6)	35 (27.1)
AZA	152 (25.6)	11 (16)	92 (92.9)	48 (43.2)	1 (1)	0	0
MPA	243 (40.9)	0	0	19 (17.1)	44 (43.1)	68 (80.9)	112 (86.7)
BAX	246 (41.4)	0	6 (6)	9 (8.2)	25 (24.5)	77 (91.7)	129 (100)
HTN at 6 months	202 (34.8)	18 (26,1)	49 (49.5)	27 (24.3)	24 (23.5)	40 (47.6)	44 (34.1)
DM at 6 months	175 (29.6)	14 (20.3)	20 (20.2)	34 (30.9)	39 (38.2)	24 (28.9)	44 (34.4)
Renal dysfunction
At 1 month	218 (36.8)	22 (31.9)	48 (48.5)	52 (46.8)	46 (45.5)	21 (25)	29 (22.5)
At 6 months	261 (44.3)	28 (40.6)	63 (63.6)	61 (55)	43 (44.3)	29 (34.5)	37 (28.7)
CKD at 1 year	290 (48.8)	37 (53.6)	74 (74.7)	62 (55.9)	47 (46.1)	32 (38.1)	38 (29.5)

¹Corresponds to treatment with tacrolimus (Tac) in the first 7 days. In the P5 and P6 groups, Tac use was 100% from that point forward.

AFH: Acute fulminant hepatitis; AZA: Azathioprine; BAX: Basiliximab; BMI: Body mass index; CKD: Chronic kidney disease; CsA: Cyclosporine A; DM: Diabetes mellitus; HCC: Hepatocellular; HTN: Arterial hypertension; LT: Liver transplant; MPA: Mycophenolic acid; RD: Renal dysfunction; Tac: Tacrolimus.

Table 4 Liver transplant recipients classified according to the calcineurin inhibitor received, n (%)/median (25^th-75^th percentiles)

Variables	CsA group 1987-1998, (n = 219)	Tac group 1999-2019, (n = 375)	P value
Pre-transplant variables
Age in years	47.83 (38.27-56)	55.18 (48.2-60.45)	< 0.001
Female sex	78 (35.6)	96 (25.6)	0.011
HTN	11 (5)	67 (17.9)	< 0.001
DM	23 (10.5)	83 (22.1)	0.001
BMI (kg/m2)	24.34 (22.32-26.67)	25.89 (23.04-28.71)	< 0.001
LT indication			< 0.001
Cirrhosis without tumor	190 (86.8)	220 (58.7)
HCC	17 (7.8)	132 (35.2)
AFH	3 (1.4)	7 (1.9)
Other	3 (1.4)	12 (3.2)
Other tumors	5 (2.3)	5 (1.3)
Child-Pugh			< 0.001
A	16 (7.3)	75 (20)
B	122 (56)	155 (41.3)
C	69 (31.5)	120 (32)
No cirrhosis	11 (5)	26 (6.9)
Pre-transplant RD	39 (17.8)	66 (17.6)	0.917
Post-transplant variables
Immunosuppression
Steroids	218 (100)	179 (47.7)	< 0.001
AZA	141 (64.8)	17 (4.5)	< 0.001
MPA	7 (3.2)	236 (62.9)	< 0.001
BAX	6 (2.7)	240 (64)	< 0.001
HTN at 6 months	91 (41.6)	111 (29.6)	0.005
DM at 6 months	48 (21.9)	127 (33.9)	0.003
Renal dysfunction
At 1 month	92 (42)	126 (33.6)	0.045
At 6 months	121 (55.3)	149 (37.7)	< 0.001
CKD at 1 year	141 (64.4)	149 (39.7)	< 0.001

AFH: Acute fulminant hepatitis; AZA: Azathioprine; BAX: Basiliximab; BMI: Body mass index; CsA: Cyclosporine A; DM: Diabetes mellitus; HCC: Hepatocellular carcinoma; HTN: Arterial hypertension; LT: Liver transplant; MPA: Mycophenolic acid; RD: Renal dysfunction; Tac: Tacrolimus.

Table 5 Patients treated with tacrolimus classified according to whether they developed renal dysfunction at 1 year, n (%)/median (25^th-75^th percentiles)

Variables	Patients with RD at 1 year, (n = 149)	Patients without RD at 1 year, (n = 226)	P value
Pre-transplant variables
Age in years	57.41 (50.18-62.81)	53.28 (47.29-59.05)	< 0.001
Female sex	51 (34.2)	45 (19.9)	0.003
HTN	33 (22.1)	34 (15)	0.101
DM	33 (22.1)	50 (22.1)	0.978
BMI (kg/m2)	25.08 (22.96-27.99)	26.3 (23.51-29)	0.024
LT indication			0.063
Cirrhosis without tumor	89 (59.7)	131 (58)
HCC	45 (30.2)	87 (38.5)
AFH	4 (2.7)	3 (1.3)
Other	9 (6)	3 (1.3)
Other tumors	2 (1.3)	3 (1.3)
Child-Pugh			0.112
A	21 (14.1)	54 (23.9)
B	65 (43.6)	90 (39.8)
C	48 (32.2)	72 (31.8)
No cirrhosis	15 (10)	11 (4.9)
Pre-transplant RD	38 (26)	26 (11.5)	< 0.001
Post-transplant variables
Immunosuppression
Steroids	82 (55)	97 (42.9)	0.026
MPA	82 (55)	154 (68.1)	0.016
BAX	85 (57)	153 (67.7)	0.054
Tac levels (ng/mL)
At 1 month	8.7 (6.0-11.5)	8.1 (6.3-11.0)	0.596
At 6 months	8.5 (6.0-11.5)	7.9 (6.0-10.3)	0.716
At 1 year	7.3 (5.1-9.3)	6.7 (5.5-9.1)	0.876
HTN at 6 months	49 (34.3)	62 (27.4)	0.243
DM at 6 months	56 (37.6)	71 (31.4)	0.25
Renal dysfunction
At 1 month	75 (51.7)	47 (20.8)	< 0.001
At 6 months	110 (74.8)	30 (13.3)	< 0.001

AFH: Acute fulminant hepatitis; BAX: Basiliximab; BMI: Body mass index; DM: Diabetes mellitus; HCC: Hepatocellular carcinoma; HTN: Arterial hypertension; LT: Liver transplant; MPA: Mycophenolic acid; RD: Renal dysfunction; Tac: Tacrolimus.

Table 6 Multivariable analysis of risk factors for chronic kidney disease at 1 year after liver transplant in patients treated with tacrolimus

Variables	P value	OR	95%CI
Age	0.001	1.04	1.02-1.07
Female sex	0.114	1.55	0.90-2.65
BMI	0.024	0.92	0.87-1.00
HCC	0.299	0.75	0.44-1.28
Pre-transplant RD	0.012	2.21	1.19-4.08
Treatment without MPA	0.015	1.85	1.13-3.06

BMI: Body mass index; HCC: Hepatocellular carcinoma; MPA: Mycophenolic acid; OR: Odds ratio; RD: Renal dysfunction.

Table 7 Patients treated with tacrolimus classified according to whether they received induction treatment with basiliximab, n (%)/median (25^th-75^th percentiles)/mean ± SD

Variables	Without basiliximab, (n = 135)	With basiliximab, (n = 240)	P value
Pre-transplant variables
Age in years	52.7 (44.3-59.0)	56.2 (50.0-61.1)	< 0.001
Female sex	36 (26.5)	60 (25.2)	0.884
HTN	17 (12.5)	51 (21.4)	0.044
DM	20 (14.7)	60 (25.2)	0.024
BMI (kg/m2)	25.0 ± 3.8	26.4 ± 3.9	0.003
LT indication			0.001
Cirrhosis without tumor	97 (71.3)	123 (51.7)
HCC	33 (24.3)	97 (40.8)
AFH	2 (1.5)	6 (2.5)
Other	1 (0.7)	11 (4.6)
Other tumors	3 (2.2)	1 (0.4)
Child-Pugh			0.004
A	16 (11.8)	59 (24.8)
B	69 (50.7)	89 (37.4)
C	43 (31.6)	72 (30.3)
No cirrhosis	8 (5.9)	18 (7.6)
Pre-transplant RD	24 (17.6)	41 (17.2)	0.918
Post-transplant variables
Immunosuppression			< 0.001
Steroids	118 (86.8)	59 (24.8)
MPA	34 (25)	202 (84.8)
Tac levels (ng/mL)
At 1 month	9.55 (7.0-13.6)	8.1 (5.9-10.1)	< 0.001
At 6 months	10 (7.7-12.7)	7 (5.6-9.3)	< 0.001
At 1 year	8.2 (6.0-10.8)	7 (5.1-8.5)	< 0.001
HTN at 6 months	32 (23.7)	76 (33.2)	0.073
DM at 6 months	45 (33.3)	81 (34.3)	0.937
Renal dysfunction
At 1 month	62 (45.6)	61 (25.7)	< 0.001
At 6 months	57 (42.2)	78 (33.1)	0.078
CKD at 1 year	61 (44.9)	85 (35.71)	0.103

AFH: Acute fulminant hepatitis; BMI: Body mass index; CsA: Cyclosporine A; DM: Diabetes mellitus; HCC: Hepatocellular carcinoma; HTN: Arterial hypertension; LT: Liver transplant; MPA: Mycophenolic acid; RD: Renal dysfunction; Tac: Tacrolimus.