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Splenectomy Does Not Offer Immunological Benefits in ABO-Incompatible Liver Transplantation With a Preoperative Rituximab

Raut, Vikram; Mori, Akira; Kaido, Toshimi; Ogura, Yasuhiro; Taku, Iida; Nagai, Kazuyuki; Sasaki, Naoya; Endo, Kosuke; Hata, Toshiyuki; Yagi, Shintaro; Egawa, Hiroto; Uemoto, Shinji

doi: 10.1097/TP.0b013e318239e8e4
Clinical and Translational Research
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Background. Preformed anti-ABO antibodies are primarily responsible for antibody-mediated rejection (AMR) after ABO-incompatible (ABO-I) liver transplantation (LT) resulting in lethal hepatic necrosis and biliary complications. Splenectomy, an integral part of protocol for ABO-I LT, decreases anti-ABO antibodies. With the preoperative rituximab prophylaxis, role of the splenectomy for ABO-I LT is now under debate. We investigated the necessity of splenectomy by retrospective analyses of the short-term anti-ABO antibody response and long-term outcomes of ABO-I LT.

Methods. Thirty-seven ABO-I LTs performed from May 2006 through July 2009, at Kyoto University Hospital, Kyoto, Japan, were retrospectively analyzed. Twenty-seven patients who underwent splenectomy (splenectomy group) received 329.6±35.8 mg rituximab 17.7±11.9 days before living donor LT. Ten patients without splenectomy (nonsplenectomy group) received 320.0±10.3 mg rituximab 26.6±21.3 days before transplantation. All patients received a posttransplant hepatic artery infusion with prostaglandin E1 and methylprednisolone. Perioperative anti-ABO immunoglobulin M and immunoglobulin G antibody titers, rejections, biliary complications, infections, and survival results were compared.

Results. Preoperative rituximab with plasma exchange effectively reduced anti-ABO antibodies in both patient groups at the time of LT. There was no statistically significant difference observed in anti-ABO immunoglobulin M and immunoglobulin G antibody titers between the “splenectomy” and “nonsplenectomy” groups during the initial 8 weeks. The clinical outcomes, including AMR, biliary complications, infections, and survival, were similar in both the groups.

Conclusions. Preoperative rituximab effectively decreased the anti-ABO antibodies sufficiently to prevent the AMR irrespective of splenectomy. Splenectomy does not offer any immunological benefit in ABO-I LT with preoperative rituximab.

Department of Hepatobiliary-Pancreatic Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto, Japan.

This work was supported by “International Liver Transplantation Society” as “ILTS International Travel Scholar Award 2010” (V.R.).

The authors declare no conflicts of interest.

Address correspondence to: Vikram Raut, M.S., Department of Hepatobiliary-Pancreatic Surgery and Transplantation, Graduate School of Medicine, Kyoto University, 54, Kawara-cho, Shogoin, Sakyo-ku, Kyoto City, Kyoto, Japan 606-8507.

E-mail: drvikramraut@gmail.com

V.R. participated in research design, writing of the manuscript, and data analysis; A.M. and S.U. participated in research design and writing of the manuscript; T.K. participated in research design and data analysis; Y.O., N.S., and T.H. participated in the writing of the manuscript; I.T. and H.E. participated in research design; and K.N., K.E., and S.Y. participated in data analysis.

Received 14 June 2011. Revision requested 16 September 2011.

Accepted 26 September 2011.

Liver transplantation (LT) across the ABO blood-group barrier is generally contraindicated or only exceptionally performed due to the risks of lethal antibody-mediated rejection (AMR) (1–3). Experience of ABO-incompatible (ABO-I) kidney transplantation inspired Asian surgeons to develop innovative approaches to overcome the challenges of ABO-I LT and donor scarcity (4–6). Some liver transplant centers that used preoperative plasma exchange, splenectomy, and advanced immunosuppression have reported results of ABO-I LT comparable with those of ABO-compatible LT (7–10). Preformed antibodies are the first line of defense in humoral immunity responsible for AMR immediately after ABO-I LT. Splenectomy has been an integral part of the protocol for ABO-I LT at many centers (7, 9–13) as the spleen was considered to be the site of B-cell maturation and antibodies production. Apart from antibody production, spleen is an important site for other hematoimmunological functions that include filtration and storage of blood, phagocytosis and destruction of erythrocytes, antigen uptake, and potential hemopoiesis. Aggressive immunosuppression used in ABO-I LT precipitates postsplenectomy infections (14–17). Splenectomy induces a risk for postoperative portal vein thrombosis (18). Rituximab is an anti-CD-20 monoclonal antibody used for resistant B-cell lymphoma and has found increased use for ABO-I LT since 2003 (8, 9, 19–21, 22). The CD-20 antigen is expressed on B cells during all stages of its development except maturation. Consequently, rituximab depletes the CD-20-positive B cells from circulation and lymphoid tissues, including spleen, and is equivalent to a “chemical splenectomy.” In this era of ABO-I LT with preoperative rituximab prophylaxis, risks and benefits of the splenectomy need to be reevaluated. Some reports emphasize the need for splenectomy despite rituximab prophylaxis to eliminate a subpopulation of B cells that do not express the CD-20 antigen, while others show the persistence of CD20 markers in the spleen after rituximab therapy (23, 24). Spleen is not the only antibody-producing organ in the body and antibody production could possibly continue in the rest of the lymphoid tissues, even after splenectomy. It is important to examine an anti-ABO antibody response than CD-20 markers in the spleen after rituximab therapy. In this article, we investigated the necessity of splenectomy for ABO-I LT by retrospectively studying the anti-ABO antibodies in a recipient during the initial 8 weeks after transplantation, which is the crucial period for development of AMR along with the long-term outcomes.

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RESULTS

Thirty-seven ABO-I living donor liver transplantations (LDLTs) were performed in 16 men and 21 women. Table 1 describes sex, primary disease for transplantation, and relationship of a recipient with donor, donor–recipient blood groups, and type of graft used between “nonsplenectomy” and “splenectomy” groups. Age, body weight, model for end-stage liver disease scores of a recipient at transplantation, graft-recipient weight ratio, duration of operation, blood loss during the operation, and hospital stay of recipients between two groups are compared in Table 1. Table 2 shows the blood group combinations of recipient and donor.

TABLE 1

TABLE 1

TABLE 2

TABLE 2

Nonsplenectomy group received 320.0±10.3 mg (mean±standard deviation) of rituximab 26.6±21.3 days before LDLT, whereas splenectomy group received 329.6±35.8 mg rituximab 17.7±11.9 days before LDLT. The mean CD-19-positive B cells in blood in both the groups were 17.6±9.8% at the time of admission; with rituximab treatment, it was reduced to 1.1±3.1% at the time of LDLT (P=0.001; Fig. 1a). However, no difference was seen in the number of CD-19-positive B cells in nonsplenectomy group and splenectomy group at admission (13.9±7.2 and 20.3±11.5; P=0.129) and at LDLT (0.6±0.8 and 1.2±3.5; P=0.307).

FIGURE 1.

FIGURE 1.

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Anti-ABO Antibody Titers in Nonsplenectomy and Splenectomy Groups

Preoperative rituximab and plasma exchange reduced anti-ABO antibodies immunoglobulin M (IgM) from 1:128 (1:8–1:512 median and 5%–95% percentile) to 1:8 (1:1–1:32; P=<0.001; Fig. 1b) and immunoglobulin G (IgG) from 1:32 (1:8–1:1024) to 1:4 (1:1–1:128; P=0.002; Fig. 1c) at the time of LDLT. However, no difference was observed in nonsplenectomy and splenectomy groups; median IgM anti-ABO antibodies at the time of admission was 1:64 (1:8–1:512) and 1:128 (1:8–1:512, P=0.708), respectively, were reduced to 1:16 (1:1–1:16) and 1:8 (1:1–1:16, P=0.026) at the time of LDLT. Mean IgG anti-ABO antibody in nonsplenectomy and splenectomy groups, respectively, reduced from 1:16 (1:1–1:256) and 1:32 (1:2–1:256, P=0.061) to 1:2 (1:1–1:64) and 1:8 (1:1–1:64, P=0.162).

After LDLT, anti-ABO antibody titers of the nonsplenectomy and splenectomy groups were compared on postoperative days (PODs) 3, 9, 12, 15, 18, 21, 28, 35, 42, 49, and 56. During this period, anti-ABO titers in both groups remained low, irrespective of splenectomy. There was no statistically significant difference in postoperative anti-ABO IgM antibody titers in nonsplenectomy and splenectomy groups (Fig. 2a; P=0.920). Although anti-ABO IgG antibody titers remained high in splenectomy group, the difference was statistically not significant (Fig. 2b; P=0.991).

FIGURE 2.

FIGURE 2.

One patient in either group suffered AMR. AMR was treated with increasing the trough of tacrolimus, intravenous steroid therapy, and plasma exchange. Both groups had statistically insignificant differences in the incidence of acute cellular rejection (ACR), cholangitis, intrahepatic bile duct strictures, and viral and bacterial infections as shown in Table 3. Intrahepatic bile duct strictures developed in two patients from nonsplenectomy group.

TABLE 3

TABLE 3

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Hepatic Artery Infusion-Related Complications

Four patients required reexploration for bleeding, out of which two patients suffered from bleeding at the time of removal of hepatic artery catheter.

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Survival Difference

Four patients in both the groups died during the follow-up period (P=0.257). One- and 3-year survival rates after ABO-I LDLT in nonsplenectomy group were 60% and 60%, respectively. One- and 3-year survival rates in the splenectomy group were 88.9% and 84%, respectively. Deaths in patients from the nonsplenectomy group were related to hepatic artery catheter displacement and bleeding (two patients), perforation of bowel (one patient), and chronic renal failure (one patient). Deaths in the splenectomy group were related to sepsis (two patients), hepatitis C virus reinfection (one patient), and graft failure by AMR (one patient).

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DISCUSSION

Complications of ABO-I LT are closely related to the preformed anti-ABO antibodies in the recipient, which are primarily responsible for AMR. Current protocol of ABO-I LT that comprises plasma exchange, immunoglobulin, splenectomy, and mycophenolate mofetil is targeted toward reducing the anti-ABO antibody titers. Spleen was considered as a major site of antibody production. In 1985, Alexandre et al. (25) proposed splenectomy as a prerequisite for successful ABO-I kidney transplantation. This knowledge influenced the liver transplant surgeons who along with plasmapheresis and OKT-3 used splenectomy to reduce anti-ABO antibody titers (5). Splenectomy in ABO-I LT is often criticized for overwhelming postsplenectomy infections compounded by the aggressive immunosuppression used for ABO-I LT (14–17, 21). The introduction of rituximab for desensitization ABO-I LT prompted us to reevaluate the necessity of splenectomy for ABO-I LT.

In our study, rituximab was effective in the depletion of B cells from peripheral circulation as confirmed by decreased CD-19 B-positive cells in blood at the time of liver transplantation and is congruent to a previous report (26). Rituximab along with preoperative plasma exchange had effectively reduced the anti-ABO IgM and IgG antibodies. Sufficient elimination of B cells translated into an effective reduction of anti-ABO antibody titers to less than 1:16 during the first 8 weeks after LDLT, which is a crucial period for development of AMR. Splenectomy was performed at the time of LDLT; however, the anti-ABO antibody response was unrelated to splenectomy. Thus, this observation challenges the primary objective of splenectomy in ABO-I LDLT, which is to reduce the anti-ABO antibodies. Our study uniquely demonstrated that with 300 mg rituximab administered before transplantation, the anti-ABO antibody titers during initial 8 weeks after transplantation were almost similar in nonsplenectomy and splenectomy groups. Although rituximab does not completely eliminate B cells from the lymphoid tissue (24, 27), or mature B cells and plasma cells, which escape from the action of rituximab, preoperative single dose of rituximab had effectively eliminated B cells in the lymphoid tissue to keep anti-ABO antibodies sufficiently low to prevent AMR in most of the patients, irrespective of splenectomy. Spleen represents only 25% of total peripheral lymphoid tissue (28), and even after splenectomy, the antibody production could possibly continue in the rest of lymphoid tissue. This explains the similar anti-ABO antibody response in the nonsplenectomy and splenectomy groups. Thus, our study confirms that splenectomy has no advantage to reduce the anti-ABO antibodies in ABO-I LT with a preoperative use of rituximab.

This equivocal anti-ABO response translated into the almost similar postoperative outcomes. Incidence of AMR, ACR, cholangitis, bacterial, and viral infections in both groups was similar and statistically insignificant. Although splenectomy increases the risk of bacterial infections after liver transplantation, the incidence of bacterial infection in our study was similar in both groups possibly because the aggressive immunosuppression used in ABO-I liver transplantation could have masked the influence of splenectomy on infection. Notably, the patients in nonsplenectomy group had milder infections such as catheter-related sepsis (three patients), wound infection (two patients), and cholangitis (two patients), whereas the patients in the splenectomy group had more severe bacterial infections such as pneumonia (five patients), cholangitis (four patients), primary bacteriemia (three patients), and wound infection (two patients). Patients in the nonsplenectomy group had lower survival. However, most of the deaths in this group were related to the surgical complications of hepatic artery infusion and bowel perforation, whereas the deaths in splenectomy group were as a consequence of sepsis. Local infusion therapy had a significant contribution in improvement of survival of recipient and evolution of ABO-I LT; however, these results of hepatic artery infusion discouraged its use, and we stopped hepatic artery infusion since August 2009 at our center. The incidence of intrahepatic bile duct strictures, which is the milder form of AMR, was higher in splenectomy group. Higher IgG antibodies observed in splenectomy group possibly result in a low-grade antigen-antibody reaction leading to chronic inflammation and strictures (3).

Although this is the first study describing that splenectomy does not alter the outcomes of ABO-I LT with preoperative rituximab prophylaxis, similar results are described in the ABO-I kidney transplantation (29–31). In an era of ABO-I LT with rituximab prophylaxis, postoperative infections are the biggest challenge for liver transplant surgeons. To improve the safety of ABO-I LT, it is important that we understand the pharmacodynamics of rituximab in recipients. Single administration of rituximab at a dose of 375 mg/m2 can completely deplete a CD-20-positive B cell from peripheral circulation only after 3 weeks (27), although a single dose of rituximab is insufficient to remove B cells completely from lymph nodes (27) and spleen (23). However, the complete elimination of B cells from lymph node and spleen should be evaluated against the fear of the prolonged immunecompromised state for almost 8 to 12 months induced by a 375 mg/m2 dose of rituximab (27). As the initial 2 to 3 months are critical for development of AMR, such prolonged suppression of B cells is unnecessary in ABO-I LT. Moreover, such a large dose could possibly lead to the development of resistance to rituximab therapy because of “shaving reaction” associated with infusion of large amounts of rituximab in humans (32, 33). Rituximab was introduced for the treatment of resistant B-cell leukemia at a dose of 375 mg/m2 weekly for 4 weeks; however, such large dose is not desirable in ABO-I LT recipients to deplete normal B cells. Recently, Toki et al. (24) demonstrated that in the recipients of ABO-I kidney transplantation, as low as 15 mg/m2 dose of rituximab is sufficient to eliminate CD-20-positive B cell from the peripheral blood and recovery is seen after 3 to 6 months. Thus, smaller rituximab dose may be much more effective if sufficient time (minimum 3 weeks) is permitted for its action and consequently will increase the safety of ABO-I LT.

Thus, in this era with preoperative prophylaxis rituximab for ABO-I LT, splenectomy is unnecessary, as it does not affect the anti-ABO antibody production and immunological outcomes of ABO-I LT. In current scenario, rituximab 3 weeks before LDLT followed by plasma exchange is an effective protocol to decrease anti-ABO antibodies to prevent AMR.

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MATERIALS AND METHODS

During May 2006 to July 2009, 225 LDLTs were performed at Kyoto University Hospital, Kyoto, Japan: 126 were ABO identical, 42 were compatible, and 57 were ABO incompatible. Outcomes of ABO-I LDLT are unaltered in the pediatric age group (34); therefore, we do not use rituximab or splenectomy in pediatric ABO-I LDLT, and 16 pediatric ABO-I LDLTs were excluded from this study. Three LDLTs performed without preoperative rituximab prophylaxis were excluded from this study. One patient had cerebral hemorrhage on POD 3 and died on 14th day after transplantation and was excluded from this study. Thirty-seven patients with ABO-I LDLT, with preoperative prophylaxis of rituximab, were considered for this retrospective study. Apart from ABO-incompatibility, splenectomy with LDLT at Kyoto University Hospital is also performed for small-size graft with intraoperative portal vein pressure after reflow above 15 mm Hg (35) and hepatitis C infection (36) to prevent interferon-induced thrombocytopenia that is expected during treatment of hepatitis C virus recurrence. Twenty-seven patients who underwent splenectomy were grouped as splenectomy group, and splenectomy was not performed in 10 patients who were grouped as nonsplenectomy group. After approval from the Kyoto University ethics committee, data about demography, model for end-stage liver disease scores, CD-19 antigen assay, blood group of a recipient, operative records including duration of the surgery, blood loss, graft-recipient weight ratio, postoperative histopathological data including AMR, and ACR, were collected. Anti-ABO IgM and IgG antibody titers in recipients were measured at admission, transplantation, and on days 3, 6, 9, 12, 15, 18, 21, 28, 35, 42, 49, and 56 after transplantation. The operative procedure of LDLT and splenectomy at Kyoto University Hospital is described in detail elsewhere (37).

AMR was diagnosed histologically by periportal edema and endothelial C4d staining (38, 39) clinically correlating with increased anti-ABO antibody titers. ACR was diagnosed by Banff criteria (40). Biliary complications suspected clinically and histologically were confirmed by cholangiogram.

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Immunosuppression for ABO-I LDLT

Immunosuppression protocol for ABO-I LDLT at Kyoto University Hospital between May 2006 and July 2009 includes rituximab, plasma exchange, and hepatic artery infusion with prostaglandin E1 and methylprednisolone. All patients received rituximab intravenously before LDLT. We confirmed elimination of B cells from circulation by the study of a CD-19 marker (as expression of CD-19 almost corresponds with expression of CD-20) at the time of LDLT. Plasma exchange with blood group AB plasma was performed one to three times depending on anti-ABO antibody titers before transplantation, at a dose of 1 unit/kg body weight to reduce an anti-ABO antibody titer less than 1:16. Hepatic artery infusion started during operation after the reconstruction of hepatic artery, using prostaglandin E1 at the initial dose of 0.005 μg/kg/min and a maintenance dose of 0.01 μg/kg/min from POD 1 to 21 and 125 mg/day methylprednisolone for first 7 days. Cyclophosphamide 100 mg/day was administered intravenously for 7 days followed by oral mycophenolate mofetil 500 mg twice a day. Routine immunosuppression for LDLT at Kyoto University Hospital includes tacrolimus and steroid (41). Tacrolimus trough is maintained between 10 and 15 ng/mL during the first 2 weeks, 7 and 10 ng/mL during weeks 2 through 8, 5 and 7 ng/mL until 6 months, and below 5 ng/mL thereafter. Oral prednisolone started from POD 8 at a dose of 3 mg/kg is tapered to 1 mg/kg from the fourth week and stopped at 3 months.

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Statistical Method

Patient characteristics between splenectomy group and nonsplenectomy group were presented as mean±standard deviation, percentage, and compared using Levene's test for equality of variances and Pearson's chi-square by SPSS statistical software. General linear model with repeated measures was used to compare the mean anti-ABO titer between two groups. P value less than 0.05 was considered significant. Kaplan-Meier method is used to compare survival between two groups.

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ACKNOWLEDGMENTS

The authors thank Dr. Niansong Qian and Dr. Sang Geol Kim, M.D., for their critical reading and constructive suggestions for the manuscript.

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Keywords:

ABO incompatibility; Living donor liver transplantation; Anti-CD20 monoclonal antibody; Antibody-mediated rejection

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