LATE ACUTE REJECTION IN LIVER TRANSPLANT: A SYSTEMATIC REVIEW

To analyze the reported results published in recent years by leading transplant centers in evaluating late acute rejection and update the clinical manifestations, diagnosis and treatment of liver transplantation.

Method:

Systematic literature review through Medline-PubMed database with headings related to late acute rejection in articles published until November 2013 was done. Were analyzed demographics, immunosuppression, rejection, infection and graft and patient survival rates.

Results:

Late acute rejection in liver transplantation showed poor results mainly regarding patient and graft survival. Almost all of these cohort studies were retrospective and descriptive. The incidence of late acute rejection varied from 7-40% in these studies. Late acute rejection was one cause for graft loss and resulted in different outcomes with worse patient and graft survival after liver transplant. Late acute rejection has been variably defined and may be a cause of chronic rejection with worse prognosis. Late acute rejection occurs during a period in which the goal is to maintain lower immunosuppression after liver transplantation.

Conclusion:

The current articles show the importance of late acute rejection. The real benefit is based on early diagnosis and adequate treatment at the onset until late follow up after liver transplantation.

Transplante de fígado; Rejeição; Revisão sistemática

Colégio Brasileiro de Cirurgia Digestiva Av. Brigadeiro Luiz Antonio, 278 - 6° - Salas 10 e 11, 01318-901 São Paulo/SP Brasil, Tel.: (11) 3288-8174/3289-0741 - São Paulo - SP - Brazil
E-mail: revistaabcd@gmail.com

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[1] Correspondence: Lucas Souto Nacif E-mail: lucasnacif@usp.br

Studies	Type /Time	LAR definition (histologically)	Incidence /Factor	outcomes
Wang, G.Y. et al. 2013 10	Retrospective; 40 biopsies performed on 37 patients	Six months after LT	ACR (n=24) Relative eosinophil count was higher than non-ACR	>blood eosinophil count was a valuable biomarker for predicting LAR after LT
Uemura, T. et al. 2008 9	Retrospective; 1604 adult LT; from 1985 to 2003.	> Six months after LT	19.0% (305 /1604)	Patient (p=0.0083) and graft survival (p=0.0075) were significantly lower in the LAR
Ramji, A. et al. 2002 6	Retrospective; 524 LT performed from 1989 to 2000.	Six months after LT	23% (97/415); median 402 days post LT (range, 180 to 3137 days)	> CR in patients developed LAR (p= 0.04) 79% mild 5% ST resistant
Thurairajah, P.H. et al. 2013 7	Retrospective; 970 adult LT from 2000 to 2010.	Three months after LT	11% (103/970), mean time of 565 days (median, 311 days; range, 90-2922 days)	Graft survival (10 years) was 74% in LAR vs 81% in those without AR (p=0.01)
Akamatsu, N. et al. 2006 1	247 adult LDLT from January 1996 to March 2005.	> Six months after LDLT	7% (15 cases) Median time 302 day (range:182-1490)	Survival based on immunosuppression: tacrolimus (n=166) vs cyclosporine (n =38) (p< 0.0001)
Florman, S. et al. 2004 2	Total of 532 recipients; more than 1000 days follow-up	33 months after LT	8,1% (43) mean time 1545 ± 441 d post-LT. 38 of the 43 (88.4%) patients with LAR had EAR episodes before 1000 days post-LT vs. only 295 of the 488 patients (60.5%) that did not have LAR (p< 0.01)	Overall patient survival for LAR (n=43) is 81.4% vs 82.0% without LAR (n=488) (p =ns).
Junge, G. et al. 2005 3	1426 LT performed from 1988 till April 2002.	> Three months after LT	AR in 5% (52) among 47 patients. LAR 79% demonstrated previous EAR	CR was 3.7%. No significant difference in patient survival (with or without LAR)
Neil, D.A.H. et al. 2001 5	Prospective; evaluated the delay on diagnoses of Bx	> One month post LT	40.7% (11) LAR. Incidence in LAR is much greater at 25%.	No difference in severity and RAI p>0.05 (EAR vs LAR); worse prognosis of LAR
Wiesner, R.H. et al. 2006 11	9646 adult LT from June 1995 to April 2004	≥ Six months post- LT	LAR independent risk factor for late graft loss (HR=1.99, p<0.001) and for late death (HR=1.98, p=0.001)	MMF with TAC and ST decreased risk of LAR, in patients with HCV, HBV and nonviral disease

Studies	Immunosuppression regimen	Therapeutic LAR episode
Ramji, A. et al. 2002⁶	32 patients (33%) were ST tapered within the previous 8 weeks, 15 patients (16%) were not on any ST, 48 (50%) had ST dose of prednisone 5 mg or less daily. 17 patients (18%) had sub therapeutic CsA or TAC levels at least once during the preceding eight weeks: four in TAC (≤5 ng/mL) and 13 in the CsA group (level ≤100 ng/mL)	73% of LAR episodes were treated with pulse intravenous ST. The remaining rejection episodes were treated with an increase in oral prednisone or a change in calcineurin inhibitor agent (CsA to TAC). 6% of LAR episodes were ST resistant and required OKT3. LAR treated with maintenance cyclosporine compared with tacrolimus, 28% vs 14%, respectively (p=0.006).
Junge, G. et al. 2005³	N/A	Corticoid bolus therapy was prescribed in 39 patients (81%). Of all the patients with grade 0.5 rejections, 28% (n=7) received a modification of their immunosuppression. AR higher than grade 1 was treated with ST bolus therapy (11%) or a modification of their immunosuppression (30%).
Florman, S. et al. 2004²	CsA target levels (ng/dL) were routinely maintained post-LT between 300 and 400 the first month, 250 and 350 the second and third months, 200 and 300 between months 3 and 12, and 100 and 200 after 1 year. TAC target levels (ng/dL) were routinely maintained post-LT between 15 and 20 the first month, 10 and 15 between the second and third months, approximately 10 between 3 and 12 months, and between 5 and 10 after 1 year.	Intravenous ST boluses ± intravenous ST recycle; Over five days (50 mg, then 40 mg, then 30 mg, then 20 mg, then 20 mg, then changed to 20 mg daily orally) for this initial LAR. OKT3 in few cases.
Uemura, T. et al. 2008 ⁹	TAC or CsA with ST. Renal dysfunction or other calcineurin toxicity received azathioprine at 1-2 mg/kg/d (1984-1994) or MMF at 0.5-2 g/d (1995-2004). ST taper was used in all patients. Induction therapy with OKT3 was used in only patients with pre-existing renal failure at the time of transplant. CsA target levels (ng/mL) were routinely maintained post-LT between 250 and 350 in the first month and tapered down to 100 and 200 after one year.	Intravenous bolus of 1 g of methylprednisolone daily for two days followed by recycles of prednisolone. If clinical and histological evidence of persistent acute rejection remained, OKT3 or thymoglobulin was administered intravenously for a total of seven to 14 day followed by a liver biopsy.
Thurairajah, P.H. et al. 2013 ⁷	24 patients (24%) were on monotherapy with a calcineurin inhibitor (21 on TAC and 3 on CsA), 56 patients (57%) were on two immunosuppressors, with the most common combination consisting of an antimetabolite and a CNI (19 azathioprine and TAC, 16 TAC and MMF), 9 patients were on prednisolone and TAC and 18 patients (18%) were on a triple-therapy regimen of CNI, antimetabolites, and corticosteroids.	Pulsed high-dose corticosteroids prednisolone 200 mg/day for three days.
Akamatsu, N. et al. 2006 ¹	ST and TAC strictly controlled with therapeutic drug monitoring. More than 6 months after LDLT, TAC and CsA were maintained at 5 to 10 μg/L and 100 to 150 μg/L, respectively.	High-dose methylprednisolone (20 mg/kg per day) followed by recycling. Patients with steroid-resistant cellular rejection were treated with MMF and OKT3.