High tacrolimus intra-patient variability is associated with graft rejection, and de novo donor-specific antibodies occurrence after liver transplantation

Table 1 Characteristics of the liver-transplant recipients

Variable	n = 116
Donors’ age at transplantation, yr (range)	53 (9-85)
Recipients’ age at transplantation, yr (range)	57 (18-72)
Recipients’ gender: male, n (%)	96 (83)
Initial liver disease, n (%)
Alcohol	49 (43)
Viral (HCV, HBV)	36 (31)
Autoimmune disease (AIH, PSC, PBC)	13 (11)
Other1	18 (17)
Median MELD score at transplantation (range) (%)	22 (6-40)
Positive HCV RNA at transplantation, n (%)	21 (18)
Re-transplantation, yes (%)	3 (3)
Induction therapy, yes: n (%)	87 (75)
Polyclonal antibodies, n (%)	9 (8)
Interleukin-2 receptor blocker, n (%)	78 (67)
Conversion during the follow-up from twice-daily to once daily tacrolimus, n (%)	42 (36)
Number of patients receiving tacrolimus once daily, n (%)	5 (4)
At discharge
Month 1	8 (7)
Month 3	9 (8)
Month 6	12 (10)
Month 9	18 (16)
Month 12	26 (31)
Month 18	39 (34)
Month 24	47 (41)
Tacrolimus trough level (ng/mL)	7.6 ± 3
At discharge
Month 1	8 ± 3
Month 3	8.4 ± 3
Month 6	8.4 ± 3
Month 9	7.4 ± 3
Month 12	7.8 ± 3
Month 18	7.5 ± 2
Month 24	6.9 ± 3
Mycophenolate mofetil dose (mg/d)	1700 ± 600
At discharge
Month 3	1250 ± 550
Month 6	1100 ± 450
Month 12	1000 ± 300
Month 24	1000 ± 300
Steroids (mg/d)
At discharge: Yes (%)	116 (100)
Dose (mg/d)	20 ± 12
Month 3: Yes (%)	114 (98)
Dose (mg/d)	8 ± 4
Month 6: Yes (%)	110 (95)
Dose (mg/d)	7 ± 5
Month 12: Yes (%)	104 (90)
Dose (mg/d)	6 ± 6
Month 24: Yes (%)	97 (84)
Dose (mg/d)	5 ± 2

¹Polycystic disease (n = 7), NASH syndrome (n = 4), Wilson disease (n = 2), bile duct atrophia (n = 1), drug intoxication (n = 2), and cryptogenic cirrhosis (n = 1). HBV: Hepatitis B virus; HCV: Hepatitis C virus; AIH: Auto-immune hepatitis; PSC: Primary sclerosing cholangitis; PBC: Primary biliary cirrhosis.

Table 2 Risk factors for a graft-rejection episode

Variable	Univariate analyses			Multivariate analyses
	OR	95%CI	P value	OR	95%CI	P value
MELD score > 30 (n = 31)	0.55	0.12-1.90	0.42	-
Initial liver disease
(1) Alcohol cirrhosis (n = 49) vs (2, 3, 4)	0.58	0.18-1.68	0.34	-
(2) Viral disease (n = 36) vs (1, 3, 4)	1.34	0.44-3.90	0.61	-
(3) Auto-immune ILD (n = 13) vs (1, 2,4)	3.12	0.71-12.47	0.07	1.00	0.51-1.15	0.210
(4) Other (n = 18) vs (1, 2, 3)	0.49	0.05-2.37	0.52	-
Induction therapy, yes (n = 87)	0.66	0.22-2.15	0.42	-
Polyclonal antibodies (vs other)	3.89	0.70-20.13	0.06	2.87	0.61-13.47	0.180
IL2R blockers (vs other)	0.40	0.14-1.70	0.08	0.52	0.185-1.50	0.230
Donors’ age > 50 yr (n = 69)	0.98	0.35-2.88	1.00	-
Recipients’ age > 50 yr (n = 92)	0.61	0.20-2.01	0.41	-
HCV-RNA + At transplantation (n = 21)	1.96	0.54-6.45	0.22	-
Steroid withdrawal during the FU (n = 19)	2.30	0.63-7.82	0.20	-
De novo DSAs during the FU (n = 13)	2.80	0.64-11.19	0.13	-
Tacrolimus trough level < 5 ng/mL (n = 34)	3.00	1.05-8.96	0.02	3.68	1.30-10.41	0.014
CV-IPV tacrolimus (continuous variable)	2.70	1.88-13.45	0.01	1.10	1.01-1.11	0.008
CV-IPV > 35%	3.05	1.05-8.96	0.03	3.07	1.14-8.24	0.030
CV-IPV > 0%	2.97	0.91-9.30	0.04	4.16	1.38-12.50	0.010
CV-C0/d-IPV	1.89	0.67-5.74	0.24	-

FU: Follow-up; ILD: Initial liver disease; HCV: Hepatitis C virus; CV-IPV: Coefficient of variability-intra-patient variability; CV-C₀/d-IPV: Coefficient of variability corrected for the corresponding daily dose-intra-patient variability.

Table 3 Risk factors for developing de novo donor-specific antibodies after liver transplantation.

Variable	Univariate analyses			Multivariate analyses
	OR	95%CI	P value	OR	95%CI	P value
MELD score > 30 (n = 31)	1.84	0.43-7.10	0.33	-
Initial liver disease
(1) Alcohol cirrhosis (n = 49) vs (2, 3, 4)	0.58	0.12-2.22	0.55	-
(2) Viral disease (n = 36) vs (1, 3, 4)	0.98	0.21-3.86	1.0	-
(3) Autoimmune ILD (n = 13) vs (1, 2, 4)	1.51	0.14-8.46	0.64	-
(4) Other (n = 18) vs (1, 2, 3)	2.79	0.55-11.83	0.64	-
Induction therapy, yes (n = 87)	1.61	0.41-7.61	0.55	-
Polyclonal antibodies (vs other)	0.59	0.70-18.00	0.60	-
IL2R blockers (vs other)	1.1	0.28-5.28	1.0	-
Donors’ age > 50 yr (n = 69)	0.78	0.20-3.00	0.77	-
Recipients’ age > 50 yr (n = 92)	0.36	0.09-1.58	0.10	0.2	0.07-0.85	0.3
HCV RNA + at transplantation (n = 21)	1.41	0.23-6.23	0.70	-
Steroid withdrawal during the FU (n = 19)	0.39	0.01-3.01	0.69	-
Tacrolimus trough level < 5 ng/mL (n = 34)	1.59	0.38-6.05	0.52	-
CV-IPV tacrolimus (continuous variable)	1.92	-1.28-21.39	0.08	1.1	1.0-1.12	0.006
CV-IPV > 35%	4.66	1.22-19.82	0.02	4.83	1.39-16.72	0.01
CV-IPV > 40%	9.10	2.28-40.63	< 0.001	9.73	2.65-35.76	0.001
CV-C0/d-IPV	3.15	5.47-27.31	0.005	1.0	0.97-1.02	0.09

FU: Follow-up; ILD: Initial liver disease; HCV: Hepatitis C virus; CV-IPV: Coefficient of variability-intra-patient variability; CV-C₀/d-IPV: Coefficient of variability corrected for the corresponding daily dose-intra-patient variability.