Everolimus immunosuppression reduces the serum expression of fibrosis markers in liver transplant recipients

Table 1 Demographic and clinical characteristics of patients before liver transplantation

	Everolimuspatients(n = 30)	CNI patients(n = 30)	P value
Male	24 (80)	24 (80)	1.000
Age (yr)	46 (44-60)	51 (44-59)	0.760
Etiology of liver disease
EtOH	16 (53.3)	13 (43.3)	0.541
HCV	11 (36.7)	10 (33.3)
HBV	0	2 (6.7)
Autoimmune	1 (3.3)	2 (6.7)
Hemochromatosis	1 (3.3)	2 (6.7)
Cholestatic disorders	1 (3.3)	0
Cryptogenic	0	1 (3.3)
Time from LT (mo)	75 (16-113)	72 (17-108)	0.859
Indication for LT
HCC	2 (6.7)	4 (13. 3)	0.041
Decompensated cirrhosis	16 (53.3)	21 (70)
Decompensated cirrhosis and HCC	12 (40)	4 (13.3)
Acute liver Failure	0	1 (3.3)
Donor age (yr)	55 (34-72)	49 (31-63)	0.521
Early allograft dysfunction	5 (16.7 )	2 (6.7)	0.212

Categorical variables are expressed as absolute n (%), continuous variables are expressed as medians and interquartillic range. CNI: Calcineurin inhibitors; HCV: Hepatitis C virus; HBV: Hepatitis B virus; LT: Liver transplantation; HCC: Hepatocarcinoma.

Table 2 Clinical characteristics of patients after liver transplantation

	Everolimus patients(n = 30)	CNI patients(n = 30)	P value
Age	60 (49-64.5)	54 (46.5- 60.5)	0.756
BMI (kg/m2)	26.2 (23.3-28.2)	27.9 (25.2-31.3)	0.211
Dyslipemia	10 (33.3)	12 (40)	0.789
Diabetes mellitus	9 (30)	13 (43.3)	0.284
HTA	18 (60)	18 (60)	1.000
Neoplasia
HCC	8 (26.7)	1 (3.3)	0.026
Solid non-hepatic neoplasia	2 (6.7)	0
Skin neoplasia	4 (13.3)	1 (3.3)
Hematological neoplasia	2 (6.7)	0
Recurrent HCV	11 (36.7)	10 (33.3)	1.000
AST (IU/L)	23 (18-53)	35 (25-66)	0.081
ALT (IU/L)	43 (18- 65)	24 (18-62)	0.260
Bilirubin (mg/dL)	0.5 (0.37-0.7)	0.85 (0.5–1.1)	0.002
Cholesterol (mg/dL)	188.5 (167-220.75)	158 (141.25-178.25)	0.002
Acute rejection	7 (23.3)	9 (30)	0.771
Chronic rejection	2 (6.7)	1 (3.3)	1.000
Biliary complications	10 (33.3)	12 (40)	0.789
APRI	0.74 (0.48-2)	0.47 (0.34-1.4)	0.135
Liver stiffness (kPa)	7.6 (5.1-8.6)	8.4 (5.6-10.7)	0.134
Concomitant steroids	6 (20)	6 (20)	1.000
Concomitant	1 (3.3)	8 (26.7)	0.026
Mycophenolate mofetil

Categorical variables are expressed as absolute n (%), continuous variables are expressed as medians and interquartillic range. HCV: Hepatitis C virus; HBV: Hepatitis B virus; LT: Liver transplantation; HCC: Hepatocarcinoma; HTA: Arterial hypertension; APRI: APRI score.

Table 3 Serum levels of liver fibrosis mediators

	Everolimus patients(n = 30)	CNI patients(n = 30)	P value
VCAM (ng/mL)	68.25 (25.98-135.17)	58.88 (35.30-115.52)	0.668
PIIINP (ng/mL)	172.4 (119.75-1195.90)	879.40 (140.10-1555.15)	0.193
IP-10 (pg/mL)	86.01 (51.10-210.91)	79.61 (59.2-172.64)	0.669
HGF (pg/mL)	225.17 (163.30-320.17)	205.53 (152.59-297.86)	0.363
Angiopoietin (ng/mL)	26.97 (19.58-32.25)	30.108 (24.60-38.8)	0.122
TNF-α (ng/mL)	41.12 (38.35-44.8)	42.70 (40.20-45.07)	0.435
IL-10 (pg/mL)	8.52 (6.07-9.23)	8.66 (6.95-9.40)	0.856
TGF-β (ng/mL)	12.7 (3.7-133.6)	152.5 (14.4-333.2)	0.009
HA (ng/mL)	702.89 (329.4-838.2)	1513.6 (691.9-1951.4)	0.001
PDGF (ng/mL)	1.5630 (1.4663-1.6369)	1.5630 (1.4616-1.6369)	0.720

Variables are expressed as medians and interquartillic range. VCAM: Vascular cell adhesion molecule; PIIINP: Amino-terminal propeptide of type III procollagen; IP10: Interferon-inducible protein 10 calcineurin inhibitor; TNF-α: Transforming necrosis factor alpha; TGF: Tissue growth factor; HGF: Hepatocyte growth factor; HA: Hyaluronic acid; PDGF: Platelet derived growth factor.

Table 4 Stratified analysis according to factors that could influence liver fibrosis

	TGF-β(ng/mL)	P value	HA (ng/mL)	P value
All patients
E (n = 30)	12.7 (3.7-133.6)	0.009	702.89 (329.4-838.2)	0.001
CNI (n = 30)	152.5 (14.4-333.2)		1513.6 (691.9-1951.4)
Free of neoplasia
E (n = 29)	11.1 (3.2-22.4)	0.005	754.8 (351.3-837)	0.030
CNI (n = 22)	137.5 (14.4-333.2)		1296.7 (703.7-1936.1)
Time from LT > 5 yr
E (n = 17)	16.5 (7.6-264.6)	0.010	462.0 (351.3-770.3)	0.002
CNI (n = 16)	296.8 (125.4-337.1)		1084.7 (523.7-1665.8)
Donor age > 50 yr
E (n = 12)	14.0 (6.0-67.1)	0.06	910.0 (589.2-1510.8)	0.005
CNI (n = 15)	96.0 (14.5-297.1)		1897.0 (1519-2136.5)
Biliary complications
E (n = 12)	20.6 (7.6-265)	0.110	516.75 (235.6-1079.4)	0.010
CNI (n = 10)	272.3 (16.5-403.4)		1545.37 (1085.8-1888.7)
Recurrent HCV
E (n = 10)	6.5 (1.6-15.3)	0.260	914.55 (768.8-1513.6)	0.410
CNI (n = 11)	14.5 ( 6.1-225)		1991.17 (1532.4-2168.9)

Variables are expressed as medians and interquartillic range. TGF-β: Transforming growth factor-β; HA: Hyaluronic acid; E: Everolimus; CNI: Calcineurin inhibitors.