Predictive biomarkers of early allograft dysfunction after liver transplantation: A prospective pilot study

Table 1 Baseline characteristics of static cold storage recipients by early allograft dysfunction status, n (%)

Variable	Subset	Non-EAD (n = 16)	EAD (n = 8)
Donor age	Median (IQR)	41.5 (30.5, 52)	55.5 (38, 61.5)
Donor mode of death	DCD	2 (13)	1 (13)
	ECD	2 (13)	1 (13)
	SCD	12 (74)	6 (74)
Recipient age	Median (IQR)	58 (43, 64)	59 (51.5, 63.5)
Recipient gender	Female	8 (50)	3 (38)
	Male	8 (50)	6 (62)
BMI	Median (IQR)	25.5 (23.5, 30)	34 (32.5, 36)
MELD score	Median (IQR)	24.5 (18, 35)	28 (27, 35)
Primary ESLD etiology	Acute liver failure	2 (12)	1 (12)
	Alcohol-related cirrhosis	5 (32)	0
	Autoimmune	0 (0)	1 (12)
	Graft failure	1 (6)	0
	HCC	1 (6)	0
	HCV	0	3 (38)
	MASH	4 (25)	3 (38)
	PBC	1 (6)	0
	PSC	2 (12)	0
Comorbidities	No	2 (12)	2 (25)
Hepatic encephalopathy	Yes	14 (88)	6 (75)
Hepatopulmonary syndrome	No	12 (75)	7 (88)
	Yes	4 (25)	1 (12)
Non-obstructive CAD	No	11 (69)	5 (63)
	Yes	5 (31)	3 (37)
Obstructive CAD	No	16 (100)	7 (88)
	Yes	0	1 (12)
Hepatorenal syndrome	No	10 (63)	5 (63)
	Yes	6 (37)	3 (37)
Esophageal varices	No	5 (31)	4 (50)
	Yes	11 (69)	4 (50)
Ascites	No	4 (25)	3 (38)
	Yes	12 (75)	5 (62)
Hypertension	No	0	0
	Yes	16 (100)	8 (100)
Pre-operative laboratory values:
Creatinine (mg/dL)	Median (IQR)	0.95 (0.72, 1.33)	1.11 (0.84, 1.53)
INR	Median (IQR)	1.72 (1.48, 2.76)	1.36 (1.1, 2.25)
Hemoglobin (g/dL)	Median (IQR)	9.45 (8.9, 12.25)	10.9 (8.7, 13.05)
Platelets (109/L)	Median (IQR)	82 (62, 118)	88 (62.5, 127.5)
Fibrinogen (mg/dL)	Median (IQR)	169 (137, 138)	204.5 (122.5, 301.5)
Total ischemia time (hours)	Median (IQR)	6.42 (5.17, 7.18)	6.17 (4.64, 8.07)
Cold ischemia (hours)	Median (IQR)	5.81 (4.59, 6.69)	5.71 (3.9, 7.49)
Warm ischemia (minutes)	Median (IQR)	32.5 (29, 37.5)	35 (28, 48)
Inferior vena cava clamp type	Piggyback	16 (100)	6 (75)
	Total cross clamp	0	2 (25)
Day 7 INR	Median (IQR)	1.03 (0.94, 1.1)	1.17 (1.05, 1.47)
Day 7 total bilirubin (mg/dL)	Median (IQR)	2.05 (0.85, 4.25)	2.55 (2.1, 5.1)
Peak 7-day AST (U/L)	Median (IQR)	997 (609, 1509.5)	3215 (2413, 6318)
Peak 7-day ALT (U/L)	Median (IQR)	482 (230, 957.5)	1304 (543, 1948)
Methylprednisolone exposure (relative to T2)	Before	6 (38)	3 (38)
	After	10 (62)	5 (62)
Received basiliximab		8 (50)	4 (50)
Basiliximab exposure (relative to T2)	Before	3 (37)	1 (25)
	After	5 (62)	3 (75)

AST: Aspartate transaminase; ALT: Alanine transaminase; INR: International normalized ratio; SCDs: Standard criteria donors; ESLD: End-stage liver disease; MASH: Metabolic dysfunction-associated steatohepatitis; HCC: Hepatocellular carcinoma; HCV: Hepatitis C virus; MELD: Model for end-stage liver disease; EAD: Early allograft dysfunction; IQR: Interquartile ranges; DCD: Donation after circulatory death; ECD: Extended criteria donor; BMI: Body mass index; PBC: Primary biliary cirrhosis; PSC: Primary sclerosing cholangitis; CAD: Coronary artery disease.

Table 2 Serum immunomodulatory protein levels at each timepoint for early allograft dysfunction and non-early allograft dysfunction groups among static cold storage recipients

Biomarker	Timepoint	No EAD (n = 16)	EAD (n = 8)	P value
HIF-1α	T1	341.2 (88.1, 855.8)	588.3 (76.4, 1285.7)	0.7133
	T2	520.7 (415.6, 1007.6)	1087 (608.7, 1758)	0.2207
	T3	157.9 (110, 273)	611.2 (384.7, 869.9)	0.0095
	T2-T1	171.2 (-25.8, 423.8)	430.6 (86.3, 739.7)	0.1590
IL-2Rα	T1	2492 (1684, 4685)	2080 (1357, 2781)	0.1984
	T2	1158 (803, 2226)	1402 (737.7, 1674)	0.5403
	T3	3614 (3426, 4495)	3068 (2719, 5631)	0.3798
	T2-T1	-888.9 (-3419.4, 227.7)	-654.9 (-1659.3, -267.4)	0.7133
IP-10	T1	946.8 (369.2, 1304.5)	616.6 (381.2, 716.8)	0.3272
	T2	469.5 (383.7, 686.1)	871.1 (491.2, 1897)	0.1779
	T3	920.6 (644.5, 2371)	976.8 (449.4, 1212)	0.4945
	T2-T1	-181.5 (-452.4, 145.9)	386.7 (-26.7, 1280.7)	0.0200
MCP-1	T1	476.9 (330.1, 644.9)	390.6 (352.1, 497.5)	0.4624
	T2	3251 (1276, 5205)	3317 (2136, 5470)	0.6242
	T3	451.3 (386.2, 628.9)	725.3 (517.4, 1089)	0.2046
	T2-T1	2742.4 (939.7, 4605.5)	2967 (1473, 5074)	0.5815
RANTES	T1	2258 (1108, 4669)	4557 (1407, 13462)	0.2207
	T2	3002 (765, 4140)	2209 (1284, 7100)	0.4624
	T3	525.8 (417.7, 1124.5)	349.5 (222.4, 613.8)	0.4945
	T2-T1	-486.5 (-2029.5, 1915.7)	-188.2 (-3805, 2191)	0.9512
IL-1β	T1	0.59 (0.43, 0.82)	0.42 (0.3, 0.58)	0.2724
	T2	2.6 (1.1, 4.2)	2.3 (1.2, 5.5)	0.5815
	T3	0.5 (0.47, 1.02)	0.59 (0.43, 0.82)	0.8453
	T2-T1	2.14 (0.57, 3.61)	1.74 (0.75, 4.96)	0.6056
TNF-α	T1	2.21 (1.48, 4.07)	2.3 (1.8, 2.8)	1.000
	T2	4.1 (2.6, 17.1)	5.4 (3.3, 8.2)	0.6682
	T3	3.8 (2.2, 8.7)	3.9 (2.3, 6.1)	0.9223
	T2-T1	1.3 (0.35, 11.3)	2.59 (0.96, 5.6)	0.8065
MIG	T1	162.6 (95.5, 224.5)	127.1 (90.5, 142.4)	0.3272
	T2	320.5 (221.4, 501.5)	511.2 (348.1, 1022.5)	0.1258
	T3	473.3 (193.7, 593.4)	578.9 (194.1, 1269)	0.5582
	T2-T1	171.5 (83.6, 313.4)	414.7 (239.9, 898)	0.0662
IL-8	T1	28.1 (19.7, 123.9)	75.3 (11.5, 126.4)	0.8065
	T2	375.7 (79.9, 731.8)	457.9 (274.5, 1708)	0.2446
	T3	40.9 (29, 58.5)	117.7 (46.4, 164.8)	0.1432
	T2-T1	348.2 (60.5, 677.5)	387.7 (164.4, 1613.3)	0.2207
IL-6	T1	15.4 (8.7, 24.9)	6.3 (3.7, 12.9)	0.0433
	T2	95.1 (57.7, 168.3)	130.6 (96, 434.1)	0.1258
	T3	6.8 (5.9, 12.2)	8.4 (7.9, 12)	0.1432
	T2-T1	82.7 (52.1, 152.5)	121.7 (92.8, 430.3)	0.0982
PTX3	T1	26350 (16282, 46843)	19700 (13195, 74614)	0.5815
	T2	93788 (74749, 118562)	95021 (42785, 121719)	0.6242
	T3	98274 (56929, 138102)	139127 (85375, 263959)	0.0971
	T2-T1	52611 (42493, 73971)	58756.5 (16182.5, 78433.9)	0.6682
IFN-γ	T1	9.4 (5.4, 26.1)	9.6 (4.2, 11.8)	0.3745
	T2	20.2 (8.8, 38.2)	23.9 (7.3, 44.4)	0.9512
	T3	8.7 (3.4, 52.8)	9.1 (4.5, 11.1)	1.000
	T2-T1	2.8 (-1.9, 11.3)	13.14 (3.2, 29.6)	0.0982

HIF-1α: Hypoxia inducible factor-1 alpha; IL: Interleukin; IP-10: Interferon-gamma-inducible protein 10; MCP-1: Monocyte chemoattractant protein-1; RANTES: Regulated upon activation, normal T-cell expressed and secreted; IL-1β: Interleukin-1 beta; TNF-α: Tumor necrosis factor-α; MIG: Monokine induced by gamma interferon; PTX3: Pentraxin 3; IFN-γ: Interferon-gamma.