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Worldwide, the first case report of rituximab prophylaxis in kidney transplantation was published in Japan in 2002 ; many rituximab protocols for kidney transplantation have been reported since. Monteiro et al  reported the first case of ABO-I liver transplantation using rituximab in 2003, and Usuda et al  reported the first case of rituximab prophylaxis in ABO-I LDLT in 2005. In the Japanese registry, the first adult case of rituximab prophylaxis was reported in November 2003. In our previous multicenter study  of 291 patients who underwent ABO-I LDLT up to and including March 2006, 44 adult patients were administered rituximab. The current study includes 259 adult patients who underwent rituximab prophylaxis up to and including December 2011.
After 2000, the evolution of innovation in the treatment of small-for-size syndrome in adult LDLT and desensitization for DSA was achieved [11-13]. The era effect on overall survival is significant. In the total cohort of 381 adult patients, after adjustment for era effects in the multivariate analysis, only rituximab prophylaxis was a significant prognostic factor for AMR, but it was not a prognostic factor for overall survival. A prospective study is required to elucidate the effect of rituximab on patient survival; however, it would be difficult to remove rituximab prophylaxis when the current results are so much improved in the most recent era and when this may be attributable to rituximab.
To find the best regimen for rituximab, the impact of additional desensitization therapies and times and doses of rituximab were addressed. Splenectomy used to be considered an essential component of a successful ABO-I desensitization regimen for renal transplantation ; however, it has been reported that rituximab can be used in place of splenectomy with similar outcomes [15, 16]. The Kyoto group suggested that splenectomy should be avoided in 2007 [2, 17]. In LDLT, however, splenectomy is performed not only for desensitization but also for portal flow adjustment in patients with small-for-size syndrome and for future anti-viral treatment using interferon in hepatitis C patients. An assessment of the effects of preserving the spleen is required in patients without small-for-size syndrome or hepatitis C infection in future.
Plasma exchange is a standard procedure to reduce DSA titers, but the titer required to prevent AMR is not defined. If titers increase again after plasmapheresis, another plasmapheresis is often performed. When peak titer before transplantation is very low, plasmapheresis is not performed. In other words, the more times the plasmapheresis is performed, the greater the potential for an increase in DSA titer. However, we observed no significant relationship between the number of plasmapheresis procedures and clinical outcomes (Table 1).
IVIG is also a standard procedure, especially for human leukocyte antigen-related DSA in kidney transplantation, and the IVIG dose often ranged from 0.1 to 2 g/kg [18, 19]. In liver transplantation, Ikegami et al  reported a small series with desensitization by rituximab and IVIG (0.8 g/kg), and their cases were included here. We found no significant effect of IVIG on overall survival or AMR in the entire adult cohort (Table 1) and no additional effects in the rituximab group (Table 5). We analyzed the AMR incidence in each regimen with IVIG versus without IVIG (Figure 6). The AMR incidence was reduced from 26% to 9% in the local infusion and splenectomy (IS; no rituximab) regimen when IVIG was added, but this difference was not significant (p = 0.19). Among regimens with rituximab (R, RI, RIS and RS), the incidences were similar between with IVIG and without IVIG. IVIG is not approved in Japan and is not covered by insurance. IVIG costs 1.5–2.0 million yen per injection, whereas 500 mg of rituximab costs 0.3 million yen. A prospective study is required to elucidate the effects of IVIG in patients after rituximab prophylaxis.
Figure 6. Comparison of the incidences of antibody-mediated rejection (AMR) with and without intravenous immunoglobulin (IVIG) in each regimen. IS, local infusion with splenectomy without rituximab; R, rituximab without splenectomy or local infusion; RI, rituximab with infusion but without splenectomy; RIS, rituximab with both infusion and splenectomy; RS, rituximab with splenectomy but without infusion. There were no significant differences in the incidence of AMR.
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The incidence of adverse effects of rituximab was 1.6% (4/258), and all patients recovered and underwent LDLT. Rituximab prophylaxis could be tolerated by patients with end-stage liver diseases. The incidences of bacterial infections and CMV disease after transplantation were similar between the nonrituximab and rituximab groups, but the incidence of fungal infection was significantly lower in the rituximab group. Although data for the amount of steroid and trough levels of calcineurine inhibitors were not collected here, the total amount of conventional immunosuppressant might be reduced in light of the expected beneficial effects of rituximab. Lower amounts of conventional immunosuppressants might be a reason for the lower fungal infections.
In this study, half the patients were given 500 mg/body, a quarter were given 300 mg/body and a quarter were given 375 mg/m2 (corresponding to 430–762 mg/body; median, 600 mg/body). One reason for dose reduction could be concern about potential adverse effects in patients with end-stage liver diseases. In kidney transplantation, Shirakawa et al  reported a successful trial to reduce rituximab from 500 to 200 mg/body. Here, there was a tendency toward a higher incidence of AMR in patients treated with ≤300 mg/body compared with 500 mg/body or 375 mg/m2; however, three patients treated with 130 mg/body or 200 mg/body belonged to the same center, and one of them died from severe AMR. More evidence is needed before we can recommend reducing the rituximab dose below 300 mg/body in liver transplantation.
Multiple administrations of rituximab are standard in the treatment of B cell lymphoma. However, because the amount of targeted B cells is expected to be much smaller in transplant patients, a single dose is usually applied. A single dose is standard in kidney transplantation. Here, there were patients with two administrations in six centers and with three administrations in three centers, but the majority of these patients underwent transplantations in 2010 or earlier. All three centers changed their policy to one dose in 2012 on the basis of our data. The current study clearly demonstrates that multiple doses provide no significant benefit in terms of AMR incidence or survival, whereas they increase the incidences of fungal and CMV infections.
The Kyoto group recommended early administration of rituximab to deplete B cells, although the incidence of clinical AMR did not increase significantly in patients with late administration . Here, the timing of rituximab administration had no significant effect on AMR incidence on patient survival. Furthermore, 6 of 22 patients with FHF were given rituximab within 6 days before transplantation and survived without AMR. Hence, administration of rituximab immediately before transplantation is a promising therapeutic strategy.
The titers decrease after desensitization before transplantation and increase or do not change immediately after transplantation, and they usually decrease thereafter when patients survive . Hence, the optimum cut-off values vary among time points, between IgM and IgG. In rituximab-treated patients, peak IgG and IgM DSA titers posttransplantation were significantly greater in those with AMR, and the AMR incidence was significantly higher in patients with peak titers posttransplantation above optimum cut-off values calculated from ROC curves (i.e. IgM, ≥64; IgG, ≥128). Theoretically, it is an option to treat patients preemptively by using other desensitization methods such as IVIG and plasmapheresis when antibody titers are above the cut-off values; however, the decision is still difficult.
This study had limitations. It was an uncontrolled retrospective observational study with many confounders, some of which may have been nonrandom and unaccounted for, and thus despite the use of appropriate multivariate statistics unknown bias was possible. Because of the extent of co-linearity between rituximab and era, estimates of regression coefficients still might be unstable, although we tried to adjust era effects as much as possible. Prospective studies are required to examine the causality of the relationships found.
In conclusion, outcomes in adult ABO-I LDLT have significantly improved in the latest era coincident with the introduction of rituximab.
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We thank the institutions and members of The Japan Study Group for ABO-Blood-Type-Incompatible Transplantation: Asahikawa Medical University (Dr. Furukawa), Dokkyo University (Dr. Kubota), Ehime University (Dr. Takada), Fujijta Health University (Dr. Hibi), Hiroshima University (Dr. Ohdan), Iwate University (Drs. Takahara and Wakabayashi), Kanazawa University (Dr. Takamura), Hokkaido University (Drs. Shimamura and Taketomi), Jichi Medical University (Dr. Mizuta), Kanagawa Children's Hospital (Dr. Shinkai), Kanazawa Medical University (Dr. Ikawa), Kansai Medical University (Dr. Kaibori), Keio University (Dr. Tanabe), Kobe Municipal Hospital (Drs. Uryuhara and Kaihara), Kumamoto University (Drs. Yamamoto and Inomata), Kyoto University (Drs. Kaido and Uemoto), Kyoto Prefectural University (Drs. Okajima and Yoshimura), Kyushu University (Drs. Shirabe and Maehara), Mie University (Drs. Mizuno and Isaji), Nagasaki University (Drs. Soyama, Takatsuki and Eguchi), Nagoya City University (Dr. Suzuki), Nagoya University (Drs. Kiuchi and Ogura), Nara Medical University (Dr. Nakajima), National Center for Child Health and Development (Drs. Fukuda, Sakamoto and Kasahara), Niigata University (Dr. Sato), Okayama University (Dr. Yagi), Osaka University (Drs. Umeshita, Maruhashi and Nagano), Osaka City University (Dr. Kubo), Osaka Medical College (Dr. Hayashi), Shinshyu University (Dr. Miyagawa), Tokushima University (Dr. Shimada), Tsukuba University (Drs. Hori and Tanaka), Tokyo University (Dr. Sugawara), Tokyo Medical University (Dr. Shimazu), Tokyo Women's Medical University (Drs. Nakajima, Fuchinoue and Yamamoto), Tohoku University (Dr. Kawagishi), Yamaguchi University (Dr. Tamesa) and Yokohama City University (Drs. Takeda and Endo).