Strategies for ABO Incompatible Liver Transplantation

Abstract

Liver transplantation (LT) is a definitive treatment for the decompensated liver cirrhosis and fulminant liver failure. With limited availability of cadaveric liver allograft, ABO incompatible (ABOi) living donor liver transplantation (LDLT) plays an important part in further expansion of donor pool. Over the years, with the introduction of Rituximab and improving desensitisation protocol, outcomes of ABOi LDLT are on par with ABO compatible LT. However, ABOi LDLT protocol varies markedly from centre to centre. Intravenous Rituximab followed by plasmapheresis or immunoadsorption effectively reduce ABO isoagglutinins titre before transplant, thereby reducing the risk of antibody mediated rejection in the post-transplant period. Local infusion therapy and splenectomy are not used routinely at most of the centres in Rituximab era. Post-transplant immunosuppression usually consists of standard triple drug regime, and tacrolimus trough levels are targeted at higher level compared to ABO compatible LT. Introduction of newer therapies like Belatacept and Obinutuzumab hold promise to further improve outcomes and reduce the risk of antibody mediated rejection related complications. ABOi LT in emergency situations like acute liver failure and deceased donor LT is challenging due to limited time period for desensitisation protocol before transplant, and available evidence are still limited but encouraging.

Liver transplantation (LT) has become an established treatment for liver cirrhosis, acute liver failure and other end stage liver diseases. With growing cases of liver cirrhosis, gap between the demand and availability of liver allograft is continuing to rise. Because of limited availability of cadaveric graft, in many countries living donor liver transplantation (LDLT) has been the predominant form of liver transplant. The use of ABO incompatible (ABOi) grafts has led to further expansion of the donor pool. In geographical areas with scarcity of deceased donor organs, ABOi liver allograft may be the only potential option for sick patients who require urgent liver transplant. ABOi LDLT is now an important form of LT in East and Southeast Asia, contributing up to 10% or more in some of these countries.1, 2, 3

Crossing of ABO barrier in human solid organ transplantation was first attempted by Dr. GP Alexandre in renal transplant in 1985.⁴ Initial success rates of ABOi liver transplants in adults were low, and outcomes were disappointing. High mortality was mostly related with hyperacute rejection, antibody mediated rejection (AMR) related allograft loss and infections due to overimmunosuppression.^5,6 Initial successful results of ABOi LDLT involved the use of multiple plasmapheresis, splenectomy, local infusion therapy along with higher doses of multiple immunosuppressive drugs. Addition of Rituximab further improved the graft rejection rates.7, 8, 9 Over the years, with improving immunosuppression and introduction of various desensitisation protocols, outcomes of ABOi have improved markedly. Currently, graft survival and long-term outcomes of ABOi liver transplant are almost similar to the ABO compatible (ABOc) transplant.^10,11 Desensitization protocols differ markedly from centre to centre. In this review, we will discuss pre- and peri transplant desensitisation protocols and strategies being used in ABOi liver transplant to minimise the risk of AMR.

PATHOPHYSIOLOGY OF REJECTION IN AMR

ABOi liver transplant has the risk of AMR that can manifest as graft dysfunction, rapid graft loss due to hepatic necrosis and non-anastomotic biliary strictures. ABO antigens are oligosaccharide structures, which are expressed on a wide variety of human tissues in addition to red blood cells, and are present on most epithelial and endothelial cells.^12,13 ABO blood antigens are primarily expressed over red blood cells, vascular endothelium and biliary epithelium.¹⁴ Preformed ABO antibodies present in recipient blood bind ABO antigens, expressing on donor tissue cells in allograft liver. Antigen antibody binding along with complement activation leads to inflammatory cascade with recruitment of platelets, neutrophils, macrophages and release of various cytokines and chemokines. This results in injury to vascular endothelium and vascular thrombi formation within the grafted liver. Impairment of blood circulation results in graft tissue and biliary ducts ischaemia, leading to liver necrosis, biliary strictures, cholestasis and ultimately graft loss.¹⁵

AMR histopathology is characterised by endothelial cells injury within portal tract vasculature with periportal oedema, microvasculitis, endothelitis and microthrombi, with the development of parenchymal and biliary necrosis in more severe cases in later stage. After complement activation, C4d binds to endothelial tissues, and diffuse microvascular C4d deposition seen on immunohistochemical staining is one of the hall marks of AMR16, 17, 18

PRE-TRANSPLANT STRATEGIES TO DECREASE THE RISK OF ANTIBODY MEDIATED COMPLICATIONS

Post-transplant outcomes and graft survival primarily depend on the removal of preformed anti ABO antibodies in recipients before the liver transplant. Risk of post-transplant AMR, graft necrosis and biliary complications increased with high perioperative titre of anti A and anti B antibodies. Desensitization strategies aim to significantly reduce the titre of these anti ABO antibodies in recipients, leading to minimisation of graft rejection and related complications.^19,20

Rituximab

Rituximab is an anti CD-20 chimeric murine monoclonal antibody, which is primarily being used in lymphomas, autoimmune and rheumatoid disorders. One of the first successful uses of Rituximab in ABOi solid organ transplant was reported by Tyden et al. in kidney transplantation.²¹ After the success in kidney transplant, it was used in ABOi liver transplant. First reported use of Rituximab was by Monterio et al. in liver transplant.⁷ Rituximab binds selectively to CD-20, which is expressed by most of the human B lymphocytes. CD 20 expression is not seen on stem cells, pro B cells and plasma cells, but stimulated plasma cells and plasma blast cells may express CD20. Binding of Rituximab on CD 20 positive cells results in cell injury and death via direct signalling, complement-dependent cellular toxicity and antibody-dependent cellular toxicity , leading to depletion of B cell population.^22,23

B cells play multiple roles in the immune system like antibody production, cytokines productions as well as antigen producing cells. So, B cell depletions not only interrupt humoral but also T cells-mediated immune response.^24,25

Rituximab is given as intravenous formulation in the standard dose of 375 mg/m². Single dose is usually sufficient, and multiple administrations can increase the risk of infections.¹⁰ Doses lower than 375 mg/m² have also been used recently in some studies. In a small study by Egawa et al., Rituximab dose of 200 mg/m² was not associated with the increased risk of AMR.²⁶ Lower dose can be considered in sick patients who have higher risk of infections. Rituximab has a long elimination half-life of about 3 weeks. Drug is usually given 2–3 weeks before the planned transplant surgery. Recent studies have shown that it can be given as early as 7 days before liver transplant with optimal outcomes. In emergency conditions, it has been given even within 72 h of surgery.^10,27,28 B cell depletion in peripheral blood starts within 48–72 h, however, complete depletion may take up to three weeks. The effect of Rituximab after single dose usually lasts for several months. Early administration has the advantage that dose can be repeated in case of inadequate response. Also, Rituximab can be eliminated by plasmapheresis when performed within 3 days of Rituximab administration.^15,29

Administration of a single dose of Rituximab usually results in complete long-term elimination of B cells and memory B cells in peripheral blood, spleen and lymph nodes; however, B cells elimination in lymph nodes is not complete.^27,30 The use of Rituximab in ABOi LDLT has resulted in significant reduction in AMR episodes, and markedly improved graft survival.³¹ In a multicentre study conducted in Japan, absence of Rituximab prophylaxis was the only significant factor associated with AMR. Incidence of AMR in Rituximab and non-Rituximab group was 6% and 23%, respectively. Local infusion therapy, IVIG and splenectomy had no impact on AMR and overall survival.^10,28 Table 1.

Table 1.

Studies Showing ABOi LDLT Outcomes in Post- Rituximab Era.

Study	LT type	Number of patients	Graft survival rates	Patient survival rates
Kim JM et al. 201877	Adult ABOi LDLT	59	1-, 2- and 3-years survival rates– 90.3%, 79.7% and 73.3%	1-, 2- and 3-years survival rates– 90.6%, 85.0% and 81.9%
Song et al. 20165	Adult ABOi LDLT	235	1, 3-years survival rates– 93.3% and 89.2%	1, 3-years survival rates– 96.5% and 92.3%
Kim SH et al. 201778	Adult ABOi LDLT	43	NA	3-years survival rate- 82.4%
Lee CF et al. 201548	Adult ABOi LDLT	46	1,3- and 5-years survival rates– 81.7%, 75.7% and 71.0%	1,3- and 5-years survival rates– 81.7%, 75.7% and 71.0%
Ikegami T et al. 201679	Adult ABOi LDLT	19	1- and 5-years survival rates– 94.7% and 87.9%	NA
Honda et al. 201880	Paediatric ABOi LDLT	29	1,3- and 5-years survival rates −82.8%, 82.8%, 78.2%	NA

ABOi, ABO incompatible; LDLT, Living donor liver transplant; NA, not available.

Rituximab has also been used as a standalone desensitisation measure before transplant. In a small study of 40 patients, Yamamoto et al. showed similar survival and AMR rates between patients who received Rituximab with or without plasmapheresis (PP). Patients who did not receive PP had lower fungal and viral infection rates.³² Lee et al. compared ABOi LDLT outcomes in two groups who received single dose of Rituximab 2 weeks before transplant. Plasmapheresis was done only in one of the two groups. ABOi related complications and survival rates were similar in both groups. Authors concluded that Rituximab alone was sufficient to achieve desensitisation. ABO antibody titre at the time of LDLT for most of the patients was below 1:16.³³ Whether or not these Rituximab monotherapy protocols are applicable for the patients with high pre-operative titres need further evidences. Long-term biliary complications and graft survival data is also limited for these shorter regimes.

Plasma Exchange Therapy And Immunoadsorption

The presence of preformed anti A and anti B isoagglutinin in recipients is responsible for AMR and related complications after transplant, and risk of these complications increase with higher agglutinins titres.^6,20 Plasmapheresis is an effective method to remove iso agglutinins and bring down the titres within acceptable limit. As plasmapheresis only removes the preformed antibodies without affecting the synthesis, titre may rise again, and patients usually require more than one session.³⁴

Pre-transplant target ABO isoagglutinin titre differs from centre to centre, and may varies from less than 1:8 to 1:64 in immediate pre-transplant period. As discussed earlier, those patients who have achieved the target titres with Rituximab administration may not need plasmapheresis.^32,33 A single session of plasmapheresis usually result in 50–60% reduction in IgG and Ig M levels.^19,35 A recipient may require more than one session to achieve the target isoagglutinin titres. Plasmapheresis involves exchange of large volume of patient plasma, along with removal of plasma proteins, immunoglobulins in addition to ABO antibodies. Side effects can include hypersensitivity, haemodynamic stress and citrate toxicity.³⁶ Plasmapheresis is also used to bring down post-liver transplant rebound of ABO isoagglutinins.

Double filtration plasmapheresis is a variation of plasma exchange therapy, which contains separate system of plasma separator and fractionator. It effectively removes large proteins like immunoglobulins, but low molecular weight proteins like coagulation factors and albumin are transfused back to the recipients. In comparison to regular plasma exchange, in double filtration plasmapheresis requirement of replacement albumin and fresh frozen plasma is reduced. This method is mainly used in Asian countries, and experience is limited in other parts of the world.^36,37

Immunoadsorption (IA) works in the same way as plasmapheresis by removing ABO isoagglutinins, however it differs from plasmapheresis as it removes only specific antibodies. Antigen specific columns of immunoadsorption adsorb ABO antibodies, and rest of immunoglobulins and plasma components are returned to recipients. Adverse effects profile of IA is relatively better than nonselective plasmapheresis.³⁸ Many studies in ABOi kidney transplantation have showed the efficacy of IA, however there is limited published data in liver transplant recipients.^31,39,40

Local Infusion Therapy

Post-operative local infusion therapy (LIT) in portal vein using Gabexate mesylate, methylprednisolone or prostaglandin E1 has been used in the past. The use of LIT prevents microangiopathy by ameliorating the inflammatory response triggered by preformed antibodies and donor antigen interaction.¹⁵ Their use has resulted in improved survival outcomes in liver transplant, and 2-year adult recipient survival in Japan increased from 60% to 80% in ABOi LDLT.^14,19 Infusion therapy is given through catheter insertion in portal vein or hepatic artery. Catheter related complications like bleeding, infection and thrombosis can be seen in 16% and 37% cases in hepatic artery and portal vein infusion therapy, respectively.⁴¹ With the introduction of Rituximab, LIT does not seem to have any additional advantage in the prevention of AMR or survival outcomes. Song et al. showed no difference in AMR incidence and survival outcomes in patients with or without LIT.⁴² LIT also had high adverse events rate leading to discontinuation in many patients.⁵ However, in case of emergency ABOi LDLT and DDLT when Rituximab may not lead to significant B cell depletion due to limited time, use of LIT can be considered.^10,15,43

INTRA OPERATIVE STRATEGIES

Splenectomy

Spleen is a major lymphoid organ of the body, representing about 1/4th of peripheral lymphoid tissues. Being a reservoir of plasma cells, it is also a site of antibodies production. Splenectomy during transplant surgery helps in eliminating the plasma cells that persist even after Rituximab and plasmapheresis. Splenectomy has been a part of the protocol for ABOi LDLT at most of the centres during pre-Rituximab era. Some centres still prefer to perform splenectomy in addition to Rituximab and plasmapheresis.¹⁹ However, with the pre-transplant Rituximab, splenectomy is unlikely to add any further benefit. Splenectomy also increases the risk of infections in already immunocompromised recipients.^14,41,44 Rout et al. reported similar ABO isoagglutinins titre, the AMR rate and survival outcome in patients with or without splenectomy. Both groups in his study received pre-operative Rituximab.⁴⁵

POST-TRANSPLANT STRATEGIES

Intravenous Immunoglobulins (IVIG)

Intravenous immunoglobulin (IVIG) primarily consisted of polyspecific IgG, and is prepared by using plasma of multiple healthy blood donors. It has been used in immunodeficiency disorders and systemic inflammatory syndromes.²⁸ High dose of IVIG has been used for the treatment of steroid resistant severe acute rejection in kidney and liver transplant, although the experience has been limited.⁴⁶ IVIG has also been used in ABOi LDLT for post-transplant rebound of ABO antibodies titres.² IVIG acts as an immunomodulator, and has a multifactorial action in solid organ transplant recipients that include inhibition of alloreactive T cells, blocking of CD19 expression on activated B cells, blockade and neutralisation of allo-antibodies. It also blocks Fc receptors on mononuclear phagocytes, and causes compliment inhibition.^19,47 The use of IVIG as a part of desensitisation protocol in ABOi LDLT has been reported in few studies. Kim et al. used a simplified protocol without plasmapheresis in 43 patients. After receiving Rituximab before transplant, patients were give IVIG (0.8 gm/kg) on post-operative day 1 and 4 along with triple drug immunosuppression. No patients had AMR, but 30% patients had biliary strictures. ABO antibody titres were below 1:16 at the time of transplant in all patients. Limited experience, absence of long-term outcomes data along with high treatment cost and adverse reactions are the limiting factors for the routine use of IVIG as a part of desensitisation protocol.

Target Abo Isoagglutinins Titres In Pre-Transplant And Post-Transplant Period

Still no consensus has been reached regarding the safe levels of anti A and anti B titres, at which the risk of AMR and other related complications is minimal and target level varies from centre to centre.³¹ Target pre-transplant level antibodies vary from ≤1:64 to ≤1:8 in various studies.^5,48 In a study of 381 adult ABOi LDLT patients, Egawa et al. showed that the risk of AMR increased at the level of ≥1:16 and ≥1:64 in pre-transplant and post-transplant period, respectively. The use of Rituximab significantly decreased the risk of AMR in this study.¹⁰ Although many evidences suggest that pre-transplant ABO isoagglutinins titre directly correlate with the risk of AMR, some studies have shown contrary results. Some researchers have suggested that anti A and B titres may not affect the incidence of AMR in liver transplant recipients.^6,49,50 Sometime non-anastomotic intrahepatic biliary strictures, a complication of AMR, can occur without obvious rebound in isoagglutinin titres.⁴³ Daily monitoring of isoagglutinin titres is recommended for the first 4 weeks in the post-transplant period to detect early rise in titres. Beyond 8 weeks isoagglutinin titre rebound is rare and usually do not affect the outcomes, so routine monitoring not required.¹⁹

Post-Transplant Immunosuppression

In ABOi LDLT, post-transplant immunosuppression protocol consists of a standard triple drug regime similar to the ABOc LDLT protocol. Initial 500 mg–1000 mg dose of IV Methylprednisolone is given intra operatively during the anhepatic phase. Intravenous Methyl prednisolone 100 mg is given on post op day 1 followed by slow tapering over a week. Oral prednisolone is started at the end of the first week and continued usually for the next three months and then stopped after slow tapering. Tacrolimus and mycophenolate are started on post-operative day 1 and tacrolimus trough levels are maintained between 10 and 12 ng/ml for the initial few weeks. Mycophenolate Mofetil (MMF) is given in the dose of 500–1000 mg per day, and a higher dose can be used in patients with renal dysfunction to allow a lower dose of tacrolimus.^28,51 The use of Basiliximab as a post-transplant induction agent in patients with renal dysfunction helps delay the use of Calcineurin inhibitors (CNIs), but it's use has been associated with an increasing risk of infection, and experience in ABOi LDLT settings is currently limited.^52,53 Post-transplant management after the first 8–12 weeks is similar to ABOc LDLT. In the absence of any rejection episode, steroids can be gradually stopped after three months, while CNIs and Mycophenolate should be continued. Further management and follow-up of these patients, including immunosuppression, is similar to the ABOc LDLT.

ABOI LDLT IN PAEDIATRIC POPULATION

Studies have reported better outcomes in children as compared to adult in ABOi LDLT. In a retrospective analysis of national registry database by Stewart et al., paediatric (<17years) ABOi DDLT graft survival was similar to ABOc DDLT.⁵⁴ Children under 2 years have the best outcomes in paediatric ABOi LDLT, and 11 months is the minimum age at which antibody mediated complications have been reported. Immature immune system and resulted decreased risk of AMR are likely the possible reasons for better outcomes in children.^20,55, 56, 57 Mysore et al. devised a new strategy for ABOi DDLT based on pre-transplant ABO antibody titres. Children with pre-transplant titre of ≥1:32 received Rituximab and plasmapheresis before transplant, followed by standard triple drug immunosuppression in post-transplant period. Children with pre-transplant isoagglutinins titre of <1:16 received only steroids and tacrolimus. Authors reported 100% graft survival rate over a 3.3 year follow up. However, in this study only ten patients underwent ABOi liver transplant.⁵⁸ Given the absence of AMR and AMR related complications in children below 1 year, the use of Rituximab and plasmapheresis is avoided in this group of patients at many centres. Anti AB isoagglutinins titres in small children can be below the pre-transplant target level, without any desensitization method because development of these antibodies is age dependent. Post-transplant immunosuppression protocol usually consists of three drug regimens as in adult patients including CNIs, MMF and steroids. In a retrospective analysis by Markiewicz-Kijewska et al., IVIg was used in 30% children in the post-transplant period as a part of desensitisation protocol or in treatment of severe AMR. This study involved paediatric ABOi LT and was conducted at eight European centres.⁵⁹

ABOI LT IN EMERGENCY INDICATIONS

ABOi LT has many challenges in emergency situations like DDLT, ALF and critically sick ACLF patients when clinical condition does not allow waiting for a compatible allograft. The risk of infection-associated mortality is increased with the use of B cells depleting agents and immunosuppressive regimens in these critically sick patients.^28,60 Because of the limited time available for desensitization protocol, the risk of AMR is increased in the post-transplant period. Although, early studies reported suboptimal results in emergency ABOi LT, more recent evidences are encouraging.^61,62 Dahlgren et al. have reported their successful experience of ABOi LT in DDLT. They developed a protocol in which single dose of Rituximab was administered on day 0 before transplant and PP or IA was started as soon as DDLT was scheduled. IA or PP was also done in the post-transplant period on day 2, 5 and 8, regardless of ABO antibody titre levels. Graft and patient survival rates were similar to the ABOc control group, and only one patient developed AMR.⁶³ In another study, Shen et al. used Rituximab, IVIG and Basiliximab based protocol in ABOi DDLT with 83% graft survival rates at 3 years.⁶⁴ In a small case series of eight patients, Lee et al. used Bortezomib, Rituximab and PP in ABOi LDLT for ALF patients. The desensitization protocol took 4.75 days of mean time to prepare these patients. Six months graft survival rate was 87.5%, and one patient developed AMR after 6 months.⁶⁵ Published studies on ABOi LDLT in emergency settings are mostly small case series only, and data regarding efficacy and safety is very limited currently. Further evidences are needed to establish an effective desensitisation protocol in emergency ABOi LDLT.

PROTOCOL AT OUR CENTRE

ABOi LDLT at our centre steadily increasing in last 4–5 years, and constitute about 3% of total liver transplants. We start desensitization protocol with the administration of Rituximab two weeks before the liver transplant surgery (Figure 1). The dose is usually 350 mg, and a lower dose (300 mg) is used in patients with acute on chronic liver failure or who have been in ICU for a prolonged period as risk of infection is increased in these patients. CD 19+ and CD 20+ mononuclear cells are used to assess the response to Rituximab, and the presence of less than 1% of these cells is considered as satisfactory response. The use of good quality allograft with greater volume and easy biliary reconstruction is preferable. Biliary complications increase the risk of sepsis, and small for size syndrome is difficult to distinguish from AMR in the post-operative period. The pre-transplant plasmapheresis or IA is done to achieve the target ABO antibody titre of ≤1:16 before the transplant surgery. We do not use splenectomy, LIT or IVIG in our protocol. Anti IL-2 agent like Basiliximab is not used routinely for induction. Recipients receive intravenous methyl prednisolone (500–1000 mg) intraoperatively during anhepatic phase. Post-transplant immunosuppression consists of standard triple drugs including CNIs, MMF and steroids. Tacrolimus trough levels are maintained between 10 and 12 ng/ml for the first 2–3 weeks. MMF is usually started at a dose of 500 mg twice a day and then increased to 750–1000 mg twice a day. ABO antibody titres are measured twice a day for the first two weeks and then once a day till the discharge of patient. Indication of plasmapheresis in post-transplant period includes two logs rise in titres or rise in titre to 1:64 or more, unexplained rise in bilirubin and liver transaminases. Liver biopsy is used for diagnosis of AMR in selected cases only. Acute rejection episodes are managed with plasmapheresis, steroid pulse therapy and modulation of doses of CNIs and MMF. As these patients have high risk of post-transplant infections, broad spectrum antibiotics are routinely used in the early post-transplant period. In addition, these patients receive prophylactic antifungal therapy and pre-emptive treatment for cytomegalovirus infection. Colour doppler for portal vein and hepatic vessels is done twice a day in early post- operative period. Patients also receive low molecular weight heparin (Enoxaparin) for the first 3–4 weeks to decrease the risk of hepatic artery thrombosis. We have performed 95 ABOi LDLT at our centre that include both adult and paediatric patients. Overall, one year survival rate in ABOi LDLT was 82.1% (17/95) at our centre. Biliary complications requiring intervention were seen in 16.8% (16/95) patients. Graft rejection including AMR and ACR was present in 26.3% (25/95) cases, of which most patients could recover with medical treatment and graft loss was rare.

Figure 1.

Algorithm of ABO incompatible liver transplantation protocol.

CMV, Cytomegalovirus.

FUTURE DIRECTIONS

In a recently published systemic review and metanalysis short-term and long-term graft survival, complications and mortality were similar in ABOi and ABOc LDLT. One year and three survival rates of more than 93% and 89% have been reported in ABOi LDLT.^36,43,66 Although ABOi LDLT is being performed routinely and the outcome has improved significantly, there are many areas that need improvement and warrant further studies. Early diagnosis and management of AMR is one of the critical factors to improve graft survival rate and outcomes in ABOi LDLT. Validation of potential biomarkers and laboratory tests for early diagnosis of AMR before pathological changes in liver biopsy is one potential area for future research. Treatment of AMR is still not standardised, and severe AMR cases not responding to steroids pulses and conventional immunosuppression are usually managed byplasmapheresis and IVIG.¹⁸ Proteasome inhibitor Bortezomib and complement inhibitor Eculizumab in refractory AMR have been used in limited studies only and need more evidence for their regular use.67, 68, 69 Other emerging therapies for AMR include IL-6 receptor antagonist Tocilizumab and T cell costimulating agent Belatacept. Experience with these newer agents is very limited but preliminary data seems promising.^28,70,71 Newer anti CD20 drug, Obinutuzumab, has been used in Rituximab refractory cases of B cell lymphomas. Obinutuzumab has more potent B cell depletion effect compared to Rituximab. It can be used in ABOi transplant as an alternative to Rituximab, and a small study showed its safety and tolerability in kidney transplant patients.72, 73, 74 Another important issue is the management of perioperative infection. Rituximab significantly increases the risk of infections in transplant recipients. Sakai et al. demonstrated that IgG Fc receptor single nucleotide polymorphism affects the Rituximab B cells depleting effect and risk of infections in transplant recipients.⁷⁵ Egawa et al. found that the presence of high percentage of pre-existing effector CD8+ T cells in ABOi LDLT recipients is associated with severe infectious complications and poor outcomes.⁷⁶ Further studies in this area will be helpful in better risk prediction and management of infectious complications. Table 2.

Table 2.

Newer Drugs in ABO Incompatible Liver Transplantation.

Drug	Class	Indication
Obinutuzumab	Anti CD20 monoclonal antibody	Pre-transplant desensitization
Imlifidase	IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS)	Pre-transplant desensitization
Tocilizumab	Anti-IL-6 monoclonal antibody	Pre-transplant desensitization, Chronic AMR, GVHD
Bortezomib, Carfilzomib	Proteosome inhibitors	Acute AMR
Eculizumab	Compliment inhibitor	Acute AMR
Belimumab, Tabalumab, atacicept	Anti-BAFF monoclonal antibody	Pre-transplant desensitization, AMR
Belatacept	Anti-CD80/CD86 monoclonal antibody	Post-transplant immunosuppression

Adapted from Cheng et al., Current Pharmaceutical Design, 2020 (Reference 30).

AMR, Antibody mediated rejection; BAFF, B-cell activating factor; GVHD, Graft versus host disease.

In conclusion, ABOi LDLT is an important tool to expand liver donor pools, and with the use of newer desensitisation protocols consisting of Rituximab, graft and patient survival is comparable to ABOc LDLT. The management of severe AMR, prevention of biliary and infectious complications are the challenges that affect survival outcomes. Regular monitoring with liver biochemistry and imaging for graft function and vigilance for infectious complications are important for the prevention and management of complications in these patients.

Credit authorship contribution statement

1. Shekhar Singh Jadaun, MD, DM; Draft writing.

2. Shaleen Agarwal, MS, MCh; Revision.

3. Subhash Gupta, MS, FRCSED, FRCS; Revision.

4. Sanjiv Saigal, MD, DM; Revision.

Conflicts of interest

All authors have none to declare.

AcknowledgementS

We would like to thank Ms. Nishu Pundir for the help in figures and tables.

Funding

No grant or funding was taken for this research.