Excellent outcome following emergency deceased donor ABO-incompatible liver transplantation using rituximab and antigen specific immunoadsorption

Figures & data

Table 1. Patient and donor characteristics for ABO-incompatible deceased donor liver transplant recipients.

Pat	Indication	MELD/ PELD	Waiting time (days)	CIT (h:m)	Recipient		Donor
					Age (years)	Blood group	Age (years)	Blood group
1	ACLF^a (HCV)	18	86	6:30	57	A	57	B
2	ACLF (PSC)	40	48	9:40	66	O	40	B
3	ALF (HLH)	38	1	6:09	19	O	31	A1
4	ALF (unknown)	36	1	5:30	31	O	64	A2
5	ALF (HBV)	40	3	9:00	31	O	64	A1
6	Re-tx ACLF (PLD)	37	14	6:00	35	O	39	A2
7	ALF (unknown)	40	2	8:49	46	O	49	A1
8	ALF (Wilson)	40	4	3:19	17	B	67	A2
9	Rescue re-tx HAT, PVT (AIH)	35	1	5:54	59	O	50	A2
10	ACLF (HBV)	34	1	3:35	56	O	74	A1
11	Rescue re-tx HAT (biliary atresia)	21	2	10:42	3	O	51	A1
12	Re-tx ACLF (ALF-first transplant)	39	14	3:38	28	O	31	A1B
13	ACLF (AAT /AIH)	40	0	4:40	54	O	37	A1
14	Hepatoblastoma^b	8	4	7:01	7mo	O	10	A2
15	ALF (mushroom)	40	4	8:30	46	O	73	A2
16	Rescue re-tx caval thrombosis (PBC)	38	3	7:33	64	B	70	A2
17	ACLF (PBC)	40	1	6:30	63	O	35	B
18	ACLF (ALC)	36	19	13:07	68	B	26	A1
19	ALF (HBV)	40	1	9:47	55	O	69	A1
20	ACLF (unknown)	40	1	7:41	68	O	49	A2

Pat: patient; No: number; MELD: model of end stage liver disease; PELD: pediatric end stage liver disease; CIT: cold ischemia time; ACLF: Acute-on-chronic liver failure [45]; HCV: hepatitis C; PSC: primary sclerosing cholangitis; ALF: Acute liver failure; HLH: hemophagocytic lymfohistiocytosis; HBV: Hepatitis B; PLD: polycystic liver disease; Re-tx: re-transplantation; HAT: hepatic artery thrombosis; PVT: portal vein thrombosis; AIH: autoimmune hepatitis; AAT: α1-antitrypsin deficiency; Mo: months; PBC: primary biliary cirrhosis; ALC: alcohol cirrhosis.

^aUncontrollable esophageal bleeding.

^bPre-transplant diagnosed with a large hepatoblastoma; however, the histopathological examination of the explanted liver revealed a hepatic rhabdomyoid tumor. The tumor was growing rapidly compressing the heart and lungs, hence the urgent indication for LT.

Table 2. Comparison of patient and donor characteristics between ABO-incompatible and ABO-identical/compatible deceased donor liver transplant recipients.

Characteristics	ABOi (n = 18)	ABOid/c (n = 72)	p Value
Recipient age (years)	54 [IQR 31,63]	52 [IQR 40,59]	.64
Recipient gender male	6 (33%)	40 (56%)	.12
MELD-score at tx	40 [IQR 36,40]	39[IQR 34,40]	.87
ICU pre-tx	17 (94%)	44 (61%)	.009
ALF	7 (39%)	26 (36%)	1.0
HCC	0	2 (3%)	1.0
Donor age (years)	50 [IQR 36,68]	62 [IQR 44,69]	.49
CIT (min) (0/2)^a	390 [IQR 318,532]	444 [IQR 371,506]	.79
Liver re-transplantation	4 (22%)	16 (22%)
Blood group matching	ABOi n = 18 (100%)	ABOid n = 58 (81%)
		ABOc n = 14 (19%)

ABOi: ABO-incompatible; ABOid: ABO-identical; ABOc: ABO-compatible; IQR: interquartile range; MELD: Model of end stage liver disease score; ICU: intensive-care unit; ALF: Acute liver failure; HCC: hepatocellular carcinoma; CIT: Cold ischemia time.

Recipent age, MELD-score, donor age and CIT are presented as median and interquartile range and compared with Mann-Whitney U test. Gender, ALF, HCC, liver re-transplantation and blood group combinations are presented as numbers (%). Gender, ALF and HCC were compared with Fisher’s exact test.

^aNumber of missing information in the two groups, respectively.

Table 3. Anti-A/B IgM/IgG antibody titers and HLA-antibodies for ABO-incompatible deceased donor liver transplant recipients.

Pat	IgM/IgG-titers			No. of IA/PP sessions		Crossmatch (CDC)	PRA (HLA-Ab)	DSA (HLA-Ab)
	Baseline	Pre-LT after IA/PP	Peak post-LT	Pre-LT	Post-LT
1	0/2	ND	1/4	0	4	Neg	No HLA-ab	ND
2	16/32	ND	0/2	1	0	Neg	No HLA-ab	ND
3	8/32	4/16	1/8	1	2	Pos #	No HLA-ab	ND
4	16/32	ND	256/512	0	8	Neg	No HLA-ab	ND
5	4/16	ND	1/4	0	0	Pos (B-cells) #	No HLA-ab	ND
6	32/128	ND	2/16	0	2 (IA + PF)	Neg	No HLA-ab	ND
7	32/64	8/32	4/32	2	6	Neg	Class I 10%, Class II 44%	Pre-LT Class I, MFI 1208
8	16/16	2/4	16/8	1	4	Neg	No HLA-ab	ND
9	4/8	0/1	2/2	1	3	Neg	No HLA-ab	ND
10	32/128	8/32	8/8	1	4	Neg	Class I 0%, Class II 60%	Pre-LT no DSA
11	1/2		8/8	0	6	Neg	No HLA-ab	ND
12	8/16^anti-A	4/4^anti-A	128/128^anti-A	1	11 (IA + PF)	Pos (B-cells)	Class I 0%, Class II 99%	Pre-LT ND
	4/8^anti-B	1/2^anti-B	32/32^anti-B					Post-LT Class II, MFI 12201
13	4/16	1/4	8/8	1	2	Pos #	No HLA-ab	ND
14	4/2	0/1	1/1	1	1	Neg	No HLA-ab	ND
15	8/16	4/8	8/32	1	3	Neg	No HLA-ab	ND
16	4/8	4/4	2/4	1	3	Neg	No HLA-ab	ND
17	64/256	4/16	1/4	1	3 (IA + PF)	Neg	No HLA-ab	ND
18	8/8	1/2	2/4	1	4	Neg	No HLA-ab	ND
19	32/256	0/8	8/32	3 (IA + PF)	6	Neg	Class I 0%, Class II 36%	ND
20	64/64	16/16	128/512	1	11	Neg	No HLA-ab	ND

No: number; CDC: complement dependent cytotoxicity; PRA: panel reactive antibody; HLA-ab: HLA-antibodies; DSA: donor specific antibodies Pre-LT: before liver transplantation; Post-LT: after liver transplantation; IA: immunoadsorption; PP: plasmapheresis; ND: not done.

# unspecific, no HLA antibodies detected.

Figure 1. Kaplan-Meier plot comparing patient (A) and graft survival (B) after ABO-incompatible (n = 18) and ABO-identical/compatible (n = 72) deceased donor liver transplantation (log-rank test).

Table 4. Survival and post-transplant clinical complications after ABO-incompatible deceased donor liver transplantation.

Pat	Follow up			Cause of graft loss	BPAR	Vascular complications	Biliary strictures
	Follow up time (m)	Alive	Functioning graft				NAS	AS
1	134	Yes	Yes	–	–	–	–	Yes^a
2	131	Yes	Yes	–	–	–	–	–
3	0.25	–	–	Death (HLH)	–	–	–	–
4	122	Yes	Yes	–	–	–	–	–
5	88	Yes	Yes	–	TCMR (RAI 4)	–	–	–
6	111	Yes	Yes	–	–	–	–	–
7	93	Yes	Yes	–	TCMR (RAI 7)^a	–	–	–
8	90	Yes	Yes	–	–	–	–	–
9	51	–	–	Death (Sepsis/MOF)	–	–	–	–
10	72	Yes	Yes	–	–	–	–	–
11	71	Yes	Yes	–	–	–	–	–
12	4	–	–	Death (Sepsis/MOF)	AMR	Partial arterial thrombosis	Yes	–
13	54	Yes	Yes	–	–	–	–	–
14	10	–	–	Death (hepatic rhabdomyoid ca)	TCMR (RAI 3)	–	–	–
15	52	Yes	Yes	–	–	–	–	–
16	51	Yes	Yes	–	–	–	–	–
17	49	Yes	Yes	–	–	PVT^a	–	–
18	48	Yes	Yes	–	–	–	–	–
19	31	Yes	Yes	–	TCMR (RAI 4)	Partial arterial thrombosis	Yes	–
20	22	Yes	Yes	–	–	–	–	–

Pat: patient; BPAR: biopsy proven acute rejection; NAS: non anastomotic biliary strictures; AS: anastomotic biliary stricture; Re-tx: re-transplantation; HCV: hepatitis C; HLH: hemophagocytic lymphohistiocytosis; HAT: hepatic artery thrombosis; PVT: portal vein thrombosis; TCMR: T-cell mediated rejection; RAI: rejection activity index. Ca: cancer; MOF: multiorgan failure; AMR: antibody-mediated rejection.

^aOccurred more than 12 months post-transplant.

Figure 2. Plots of anti-A/B antibody titers, IgM (A) and IgG (B), pre-, and post ABO-incompatible liver transplantation (n = 20).

Figure 3. Light microscopy of liver biopsies 9 days (A: Pat #13) and 12 days (B and C: Pat #12) post-transplant. A. Portal area with endothelialitis and minimal microvascular inflammation possible but no definitive proof of AMR. B. Slightly dilated vessel, enlarged endothelial nucleus (arrowhead) and microvascular inflammation dominated by neutrophils (arrow) suggesting AMR grade 2. C. Immunohistochemistry for C4d is diffusely positive in this specimen.

Table 5. Comparison of post-transplant complications occurring within one year after ABO-incompatible and ABO-identical/compatible deceased donor liver transplantation.

Complication	ABOi DDLT (n = 18)	ABOid/c DDLT (n = 72)	p Value
AMR	1 (6%)	0	.2
TCMR	2 (11%)	17 (24%)	.34
HAT	2^a (11%)	3^a (4%)	.26
PVT	0	0
AS	0	8 (11%)	.35
NAS	2 (10%)	5 (7%)	.62

ABOi: ABO-incompatible; DD: deceased donor; LT: liver transplantation; ABOid: ABO-identical; ABOc: ABO-compatible; AMR: antibody-mediated rejection; TCMR: T-cell mediated rejection; HAT: hepatic artery thrombosis; PVT: portal vein thrombosis; AS: anastomotic biliary stricture; NAS: non-anastomotic biliary strictures.

Fisher’s exact test was used for the comparison.

^aNone of the ABOi recipients developed complete HAT, however two patients had partial arterial thrombosis. In the ABOc group, all three patients with HAT were re-operated due to complete HAT.

Figure 4. Image of MRCP showing diffuse intrahepatic biliary strictures (Pat #16).

Table 6. Radiological findings with MRI/MRCP after ABO-incompatible deceased donor liver transplantation.

No	Clinical or protocol MRI/MRCP (days post LT)	Radiological findings		Clinical outcome
		Non anastomotic biliary strictures	Arterial thrombosis
1	Clinical MRI (633)	–	–	Functioning graft
2	ND			Functioning graft
3	ND			Death with functioning graft
4	ND			Functioning graft
5	ND			Functioning graft
6	ND			Functioning graft
7	Protocol MRI (1285)	Short stricture in the right bile duct	–	Functioning graft
8	Protocol MRI (2003)	Short stricture in the right bile duct	–	Functioning graft
9	Clinical MRI (908)	–	–	MOF, death
10	Protocol MRI (426)	–	–	Functioning graft
11	Protocol MRI (471)	–	–	Functioning graft
12	Clinical MRI (120)	Multiple intrahepatic strictures	Partial thrombosis in the hepatic artery proper and infarctions in both right and left liver lobe.	MOF, death
13	Protocol MRI (339)	–	–	Functioning graft
14	ND			Death with functioning graft
15	Protocol MRI (860)	–	–	Functioning graft
16	Protocol MRI (308)	Multiple intrahepatic biliary strictures, DIHBS	–	Functioning graft
17	ND			Functioning graft
18	Protocol MRI (88)	–	–	Functioning graft
19	Clinical MRI (49,392)	20 mm long stricture in the right bile duct (POD 49), multiple intrahepatic biliary strictures (POD 392)	Stenosis and partial thrombosis of the main arterial anastomosis. Partial thrombosis in a stenosed reconstructed aberrant right artery.	Functioning graft
20	Protocol MRI (50)	–	–	Functioning graft

MRI: magnetic resonance imaging; CT: computed tomography; LT: liver transplantation; ND: not done; Re-tx: re-transplantation; HAT: hepatic artery thrombosis; MOF: multiorgan failure; PVT: portal vein thrombosis.

Table 7. Protocol biopsies after ABO-incompatible deceased donor liver transplantation.

No	Post tx day	Morphology	C4d (0-3)	AMR (1-3)	TCMR	Antirejection treatment following protocol biopsy
7	7	Minimal sustained preservation injury	–	–	–	–
8	7	TCMR	ND	–	RAI 4	–
9	9	Normal histology	–	–	–	–
10	9	Minimal sustained preservation injury	–	–	–	–
11	9	Cholestatis	1	–	–	–
12	7	Possible	3	1	–	IA, PP
13	9	Possible AMR	2	1	–	–
14	19	TCMR	–	–	RAI 3	Solu-Medrol
15	12	Minimal sustained preservation injury	ND	–	–	–
16	26	TCMR	–	–	RAI 3	–
17	8	TCMR	3	–	RAI 6	–
18	10	Minimal sustained preservation injury and inflammation	3	–	–	–
19	7	TCMR	1	–	RAI 4	Solu-Medrol
20	12	Minimal unspecific inflammation	1	–	–	–

AMR: antibody-mediated rejection; TCMR: T-cell mediated rejection; ND: not done; IA: antigen specific immunoadsorption; PP: plasmapheresis.

C4d, AMR-, and TCMR-scoring was performed according to the 2016 comprehensive update of the Banff working group on liver allograft pathology.

Moreau R, Jalan R, Gines P, et al. Acute-on-chronic liver failure is a distinct syndrome that developed in patients with acute decompensation of cirrhosis. Gastroenterology. 2013;144(7):1426–1437.

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