Pediatric liver transplantation

Table 1 Series of pediatric reduced-size liver transplantation

Series	Period	n	Survival (%)		ReTX (%)	Complications (%)
			Patient	Organ		HAT	PVT	BC	PNF
Broelsch et al[25]	1984-1987	9	44	33	11	0	0	11	11
Otte et al[26]	1984-1988	42	68	54	28	7	0	NA	5
Bismuth et al[22]	1984-1988	14	50	44	14	7	7	14	7
Houssin et al[27]	1986-1989	40	75	73	-	5	5	5	5
Kalayoglu et al[28]	1988-1989	12	83	67	25	16	8	0	0
Esquivel et al[29]	1988-1990	20	81	75	12	0	3	5	0
Langnas et al[30]	1988-1991	29	68	65	3	7	0	20	10

ReTX: Retransplantation; HAT: Hepatic artery thrombosis; PVT: Portal vein thrombosis; BC: Biliary complication; PNF: Primary non-function; NA: Not available.

Table 2 Series of pediatric living-related liver transplantation

Series	Period	n	Survival (%)		ReTX (%)	Complications (%)
			Patient	Organ		HAT	PVT	BC	PNF
Tanaka et al[33]	1990-1992	37	E 90 U 57	E 90 U 57	0	U 14	E 3	E 10	0
Emond et al[34]	1991-1992	18	94	84	16	11	6	16	0
Broelsch et al[35]	1991	20	85	75	20	25	20	35	0
Malagò et al[36]	1991-1994	36	72	72	8	2.8	3	25	-
Otte et al[37]	1993-1995	30	97	93	-			20
Haberal et al[38]	1990-1997	19	58	58	0	5	0	0	0
Darwish et al[39]	1993-2002	100	94	92	3	1	14	27	0

E: Elective cases; U: Urgent cases; ReTX: Retransplantation; HAT: Hepatic artery thrombosis; PVT: Portal vein thrombosis; BC: Biliary complication; PNF: Primary non-function.

Table 3 Series of ex situ split-liver transplantation

Series	Year	ADU (n)	PED (n)	Urgent (%)	Patient survival (%)		Graft survival (%)		Complications (%)
					ADU	PED	ADU	PED	HAT	PVT	BC	PNF
Pichlmayr et al[40]	1989	2	0	0	50	-	50	-	0	0	0	0
Bismuth et al[41]	1989	2	0	100	0	-	0	-	0	0	0	0
Otte et al[42]	1990	1	3	75	0	66	0	66	0	0	0	0
Emond et al[16]	1990	5	13	38	40	63	40	53	6	6	27	24
Broelsch et al[24]	1990	4	21	40	25	66	20	48	NA	NA	27	NA
Langnas et al[30]	1992	1	9	73	NA	NA	NA	NA	7	0	20	17
Houssin et al[43]	1993	6	10	50	83	70	83	60	13	25	25	0
Otte et al[44]	1994	11	18	27	NA	NA	NA	NA	10	0	17	10
Kalayoglu et al[45]	1996	5	7	8	100	85	80	71	8	0	17	0
Rogiers et al[46]	1996	5	7	44	57	100	42	100	15	0	15	0
Azoulay et al[47]	1996	26	1	14	80	100	76	100	15	0	22	4
Dunn et al[48]	1997	0	12	50		75		66	0	0	0	0
Rela et al[49]	1998	15	26	12	93	89	93	84	3	0	15	0
Mirza et al[50]	1998	10	14	58	80	78	NA	NA	8	0	8	16
Chardot et al[51]	1999	0	15	31	-	66	-	62	12	19	25	0
Reyes et al[52]	2000	13	12	66	69	66	61	50	12	0	8	NA
Deshpande et al[53]	2002	0	80	20	-	89	-	86	5	1	9	0
Noujaim et al[54]	2003	24	36	25	NA	NA	NA	NA	3	0	20	3
Oswari et al[55]	2005	0	30	13	-	70	-	67	2	5	7	NA

ADU: Adults; PED: Children.

Table 4 Series of in situ split-liver transplantation

Series	Year	ADU (n)	PED (n)	Urgent (%)	Patient survival (%)		Graft survival (%)		Complications (%)
					ADU	PED	ADU	PED	HAT	PVT	BC	PNF
Rogiers et al[56]	1996	7	7	35	100	85	85	71	0	0	0	0
Goss et al[57]	1997	14	12	58	85	100	78	91	0	0	14	11
Busuttil et al[58]	1999	NA	NA	66	85	96	86	75	3	1	3	8
Ghobrial et al[59]	2000	51	51	49	83	78	NA	NA	2	2	NA	8
Reyes et al[52]	2000	NA	NA	NA	93	100	79	83	3	0	3	7
Spada et al[60]	2000	36	35	25	84	85	79	76	5	10	28	2
Gridelli et al[61]	2003	0	90	28	-	90	-	80	7	6	33	1
Yersiz et al[62]	2003	57	104	-	78	75	69	64	13	11	19	26

Table 5 Banff grading of acute liver allograft rejection

Assessment	Criteria	RAI
Indeterminate	Portal inflammatory infiltrate that fails to meet criteria for the diagnosis of acute rejection	1-2
Mild	Rejection infiltrate in a minority of the triads that is generally mild and confined within the portal spaces	3-4
Moderate	Rejection infiltrate expanding most or all of the triads	5-6
Severe	As above for moderate, with spillover into the periportal areas and moderate to severe perivenular inflammation that extends into the hepatic perenchyma and is associated with perivenular hepatocyte necrosis	> 6

Table 6 Rejection activity index (RAI)

Category	Criteria	Score
Portal inflammation	Mostly lymphocytic inflammation involving, but not noticeably expanding, a minority of the triads	1
	Expansion of most or all of the triads by a mixed infiltrate containing lymphocytes with occasional blasts, neutrophils, and eosinophils	2
	Marked expansion of most or all of the triads by a mixed infiltrate containing numerous blasts and eosinophils with inflammatory spillover into the periportal parenchyma	3
Bile duct inflammation damage	A minority of the ducts are cuffed and infiltrated by inflammatory cells and show only mild reactive changes such as an increased nuclear-to-cytoplasmatic ratio of the epithelial cells	1
	Most or all of the ducts infiltrated by inflammatory cells. More than an occasional duct shows degenerative changes such as nuclear pleomorphism, disordered polarity, and cytoplasmatic vacuolization of the epithelium	2
	As above for the 2nd criterion, with most or all of the ducts showing degenerative changes or focal luminal disruption	3
Venous endothelial inflammation	Subendothelial lymphocytic infiltration involving some, but not a majority, of the portal and/or hepatic venules	1
	Subendothelial infiltration involving most or all of the portal and/or hepatic venules	2
	As above for the 2nd criterion, with moderate or severe perivenular inflammation that extends into the perivenular parenchyma and is associated with perivenular hepatocyte necrosis	3

Table 7 Literature review of immunosuppressive protocol with steroid weaning after pediatric liver transplantation

Author	Year	Patients (n)	Protocol	Weaning (%)		Graft loss	Rejection (%)
				Performed	Success		Acute	Chronic
Margarit et al[110]	1989	18	CsA+Aza	83	61	13%	27	13
Andrews et al[111]	1994	119	CsA+Aza1	44	67	No	13	No
Dunn et al[112]	1994	73	CsA+Aza	51	76	4%	7	4
McDiarmid et al[113]	1995	13	CsA+Aza			No	No	No
McKee et al[114]	1997	29	TAC	83	71		29
Martin et al[115]	1998	55	CsA+Aza	44	76	No	11	No
Reding et al[109116]	2000	375	CsA (n = 23)		21	No	No	No
			CsA-ME (n = 24)			No	No	No
			TAC (n = 31)			No	10	No
Atkison et al[117]	2002	94	CsA+Aza2	71	91		21
Toyoki et al[118]	2004	8	TAC	100	100	No	13	No

CsA: Cyclosporine; CsA-ME: Cyclosporine microemulsion; Aza: Azathioprine; TAC: Tacrolimus.

¹In 53% of the weaned children;

²Some patients received antilymphocyte globulin or OKT3 induction.

Table 8 Desired trough concentrations of calcineurin inhibitors after pediatric liver transplantation

Time post-transplant (mo)	Target level (mg/L)
	Cyclosporine	Tacrolimus
0-3	200-250	10-15
4-12	150-200	8-10
> 12	50-100	5-8

Table 9 Use of sirolimus in primary immunosuppressive regimens in liver transplantation

Author	Immunosuppression	No. of patients	Survival (%)		Acute rejection (%)	Follow-up (mo)
			Patient	Graft
McAlister et al[153]	TRL, SRL, STER1	32	92		3	8
McAlister et al[154]	TRL, SRL, STER1	56	93	91	14	23
Peltekian et al[155]	TRL, SRL, STER1	42	93	90	10	14
Pridöhl et al[156]	TRL, SRL, STER	22	91	78	14	14
Sindhi et al[157]	TRL, early SRL, STER	6			17	15
	TRL, late SRL, ATG	9			332	3

ATG: Antithymoglobulin; SRL: Sirolimus; STER: Corticosteroids; TRL: Tacrolimus;

¹Corticosteroids withdrawal 3 mo after transplantation;

²Rejection episodes observed before sirolimus was introduced in the immunosuppressive regimen.

Table 10 Use of IL-2 receptor antibodies in primary immunosuppressive regimens in pediatric liver transplantation

Author	Immunosuppression	No. of patients	Survival (%)		Acute rejection (%)	Follow-up (mo)
			Patient	Graft
Asensio et al[167]	TRL, STER	21	80	80	63	12
	TRL, STER, BAS	34	80	80	30
Strassburg et al[168]	TRL, STER	12			42	28
	CSA, STER, AZA	9			66
	CSA, STER	12			42
	CSA, STER, BAS	21			33
Heffron et al[169]	TRL, MMF, STER	20	85	88	50	24
	TRL,2 MMF, DAC, STER	61	93	73	15
Reding et al[119]	TRL, STER	20			50	12
	TRL, BAS, MMF1	20			25
Ganschow et al[170171]	CSA, STER	54	94		54	28-52
	CSA, STER, BAS	54	98		17
Schuller et al[172]	TRL, MMF, STER	12			66	14
	TRL, MMF, DAC, STER	18			0	6
Spada et al[120]	TRL, STER	36	91	86	32	24
	TRL, BAS	36	87	80	12

CSA: Cyclosporine; DAC: Daclizumab.

¹Mycophenolate mofetil was given in the first 9 patients.

²Tacrolimus was given starting from postoperative day 7.

Table 11 Common causes of late dysfunction in the pediatric population

	Incidence at 5 yr (%)	Risk factors
Acute rejection	Variable (< 30)	Inadequate immunosuppression
		Treatment with immune activating drugs (e.g. interferon)
		History of autoimmune liver disease
Chronic rejection	-3	Inadequate immunosuppression
		Treatment with immune-activating drugs (e.g. interferon)
		Refractory acute rejection
		Chronic rejection in a previous failed allograft
Recurrent AIH	-30	Suboptimal immunosuppression
		AIH type I
		Severe inflammation in native liver
		HLA DR3 or DR4
De novo AIH	< 5
Recurrent PBC	20-30	Tacrolimus as baseline immunosuppression
		Living-related donor
		Steroid and other immunosuppression withdrawal
Recurrent PSC	20-30	Male sex; donor-recipient gender mismatch
		Intact colon at time of transplantation
Idiopathic post-transplant hepatitis	5-60

AIH: Autoimmune hepatitis; PBC: Primary biliary cirrhosis; PSC: Primary sclerosing cholangitis.

Table 12 UNOS pediatric liver Kaplan-Meier patient and graft survival rates for transplants performed between 1997 and 2004

Recipient age (yr)	Patient survival (yr)			Graft survival (yr)
	1	3	5	1	3	5
< 1	89	82	78	81	70	63
1-5	86	80	77	78	71	67
6-10	91	86	86	84	76	75
11-17	93	87	81	87	77	67

One-year survival based on 2002-2004 transplants, 3-year survival based on 1999-2002 transplants, 5-year survival based on 1997-2000 transplants.