Early tacrolimus exposure does not impact long-term outcomes after liver transplantation

Table 1 Donors and recipients characteristics

	≤ 10 ng/mL, n = 98	> 10 ng/mL, n = 57	P value
Donors
Age, year (mean ± SD)	54.7 ± 17.5	54.7 ± 17.5	0.002
Male	58 (59.2%)	35 (61.4%)	0.786
Cause of death			0.004
Stroke	57 (58.2%)	48 (84.2%)
Trauma	27 (27.6%)	6 (10.5%)
Other	14 (14.3%)	3 (5.3%)
Graft steatosis	19 (19.6%)	12 (21.1%)	0.827
Recipients
Age, years (mean ± SD)	55.3 ± 8.4	53.2 ± 9.8	0.227
Male	81 (82.7%)	48 (84.2%)	0.802
MELD (mean ± SD)	13.1 ± 5.6	12.7 ± 5.3	0.618
Hepatocellular carcinoma	45 (45.9%)	29 (50.9%)	0.551
Cause of liver disease			0.283
Alcohol abuse	45 (45.9%)	24 (42.1%)
HCV	40 (40.8%)	18 (31.6%)
HBV	3 (3.1%)	5 (8.8%)
Cho/estatic liver disease	3 (3.1%)	4 (7%)
Other	7 (7.1%)	6 (10.5%)
Medical history (pre LT)
MDRD-4 (mean ± SD)	107.8 ± 35.7	16.7 ± 33.7	0.223
Diabetes mellitus	18 (18.4%)	9 (15.8%)	0.683
Arterial hypertension	12 (12.2%)	10 (17.5%)	0.362
Mean tacrolimus trough levels 1 mo (ng/mL)	7.38 ± 1.68	12.62 ± 2.25	NA
Corticosteroids	80 (82.5%)	49 (86.0%)	0.571
Mycophenolate mofetil	32 (32.7%)	9 (15.8%)	0.024

MELD: Model for end-stage liver disease; MDRD-4: Modification of diet in renal disease; HCV: Hepatitis C virus; HCC: Hepatocellular carcinoma; LT: Liver transplantation.

Table 2 Recipients outcomes after liver transplantation

	≤ 10 ng/mL, n = 98	> 10 ng/mL, n = 57	P value
Biopsy-proven acute rejection	12 (12.2%)	5(8.8%)	0.505
Arterial complications	12 (12.2%)	7(12.3%)	0.995
Biliary complications	13 (13.3%)	8 (14%)	0.893
Infection (any)	49(50.0%)	26 (45.6%)	0.598
Cytomegalovirus infection	26 (26.5%)	12 (21.1%)	0.445
Retransplantation	5 (5.1%)	5 (8.8%)	0.500
HCC recurrence1	1 (2.3%)	0	0.999
HCV recurrence2	35 (87.5%)	14 (77.8%)	0.438
De novo tumor	10 (10.2%)	5 (8.8%)	0.771
New-onset arterial hypertension	35(36.1%)	19 (36.5%)	0.827
New-onset diabetes	21 (21.6%)	6 (12.7%)	0.127
Tacrolimus withdrawal. Causes:	18 (18.4%)	8 (14.0%)	0.486
Kidney failure	7	1
Neurotoxicity	1	2
Metabolic syndrome	6	4
Metabolic synd + kidney failure	1	-
Other	3	1
MDRD-4 at 5 yr (mean ± SD)	82.5 ± 19.4	80.32 ± 14.7	0.686
Deaths. Causes:	10 (10.2%)	8 (14.0%)	0.827
HCV recurrence	5	3
De novo tumor	1	2
Sepsis	2	1
Stroke	0	1
Other	2	1

¹Including variables with P < 0.2 in univariate analysis, highlighted in bold.

²Renal dysfunction during hospitalization. HCC: Hepatocellular carcinoma; HCV: Hepatitis C virus; MDRD-4 stands for: Modification of Diet in Renal Disease.

Table 3 Univariate and multivariate analysis of factors associated with patient mortality

	Univariate analysis		Multivariate analysis1
	P value	HR (95%CI)	P value	HR (95%CI)
Age of donor ≥ 70 years	0.55	0.73 (0.26-2.05)
Recipient
Liver steatosis	0.1	0.408 (0.09-1.79)
Age ≥ 60 years	0.94	1.04 (0.39-2.78)
HCV infection as cause of liver disease	0.02	3.02 (1.17-7.81)	0.003	4.94 (1.72-14.17)
Presence of hepatocellular carcinoma	0.57	1.31 (0.52-3.34)
MELD score ≥ 20	0.02	3.16 (1.12-8.91)	0.003	6.06 (1.88-19.56)
Diabetes before transplantation	0.63	1.32(0.43-4.01)
Hypertension before transplantation	0.05	2.78 (0.98-7.90)	-	-
MDRD-4 at baseline	0.35	0.99 (0.97-1.01)
Mycophenolate mofetil at initial therapy	0.89	1.07 (0.38-3.02)
Outcomes and complications
BPAR	0.20	2.08 (0.67-6.43)
Arterial complications	0.06	2.91 (0.94-9.06)	0.03	3.76 (1.12-12.62)
Biliary complications	0.59	1.41 (0.40-4.92)
Renal dysfunction early after transplant2	0.08	2.40 (0.90-6.38)	-	-
Renal hypertension	0.82	1.12 (0.42-3.02)
De novo diabetes	0.02	3.25 (1.24-8.55)	-	-
Cardiovascular	0.14
Arterial hypertension	0.08	0.32 (0.09-1.15)	-	-
Heart failure	0.26	0.31 (0.04-2.37)
De novo tumor	0.005	4.20 (1.56-11.32)	< 0.001	13.82 (4.06-46.98)
HCV recurrence	0.22	1.79 (0.70-4.53)
HCC recurrence	0.008	16.61 (2.10-131.07)	-	-
Any infection	0.71	1.12 (0.47-3.03)
Bacterial infection	0.04	2.71 (1.04-7.07)	-	-
Viral infection	0.39	0.61 (0.20-1.87)
Fungal infection	0.87	1.19 (0.16-9.03)
Cytomegalovirus infection	0.79	0.86 (0.28-2.62)
Normal renal function at last visit (MDRD-4 ≥ 60 mL/min/1.73 m2)	0.92	1.08 (0.23-5.08)
Mean tacrolimus levels at days 1-30 after LT
> 10 ng/mL vs ≤ 10 ng/mL	0.44	1.44 (0.57-3.65)
< 7 ng/mL (reference)3	0.32
7-10 ng/mL	0.31	0.49 (0.12-1.96)
> 10 ng/mL	0.59	1.33 (0.47-3.73)
> 8 ng/mL vs < 8 ng/mL3	0.78	1.14 (0.44-2.95)
Early graft dysfunction	0.08	2.44 (0.890-6.63)	< 0.001	6.02 (2.34-15.49)

¹Including variables with P < 0.2 in univariate analysis, highlighted in bold.

²Renal dysfunction during hospitalization.

³Additional analysis modifying cut-off values. MELD: Model for end-stage liver disease; HCV: Hepatitis C virus; HCC: Hepatocellular carcinoma; BPAR: Biopsy-proven acute rejection; MDRD-4 stands for: Modification of Diet in Renal Disease; LT: Liver transplantation.