Reply: We still need to deal with antibody-mediated rejection in living donor liver transplantation

Abstract

We thank Dr. Furukawa and colleagues for their interest in our recent publication. [1] We demonstrated that a lower Model for End-stage Liver Disease score ≤ 13 and a higher pretreatment anti-ABO IgM-titer ≥ 128 were significant pretransplant risk factors for antibody-mediated rejection (AMR) after ABO-incompatible (ABOi) living donor liver transplantation (LDLT). Patients fulfilling both factors showed significantly worse graft/recipient survival than those without. Further, high-titer (sum-mean fluorescence intensity of HLA class-I+II ≥ 10,000) and multiloci preformed donor-specific antibodies (pDSAs) were significant pretransplant risk factors for pDSA-AMR. [1] Regarding our patient survival after ABOi-LDLT, [1] which they described as "unacceptable," our study cohort included many older cases performed in the era of local infusion therapies. The recent 1-/3-/5-year survival rates for adult ABOi-LDLT patients ( ≥ 18 y, 2013-2019) with the current protocol using rituximab without local infusion therapies are 100%/96%/96%, which rival or surpass 95%/91%/91% after ABO-identical/-compatible LDLT, respectively (Figure 1). When limited to the era of rituximab 500 mg/individual (2015-2019, n = 15), 1-/3-/5-year recipient survival rates after adult ABOi-LDLT reached 100%/100%/100%, respectively. These outcomes are considered "acceptable" compared with the results from another high-volume center. [2] Once ABOi-AMR developed however, 10 of 19 patients (52.6%) suffered AMR-related death or graft loss. [1] In contrast, one patient with pDSA-AMR died of complications unrelated to AMR, but the other 4 have long been fine postoperatively, reaching 0% AMR-related death or graft loss. The causes of graft loss and AMR treatments they requested were detailed in Supplemental Tables and Patients and Methods [1] and our previous paper, [3] respectively. Please review them again. Collectively, ABOi-AMR significantly deteriorated graft/recipient survival, whereas pDSA-AMR, if properly treated, did not significantly affect patient survival with slower/milder onset than ABOi-AMR. [1] A recent large-cohort study also reported no significant impact of pDSAs on post-LT recipient survival. [4] However, we never underestimate DSA-related complications. As shown, [1] 5 of 10 patients with summean fluorescence intensity ≥ 10,000 developed AMR with long-lasting high-titer DSAs. Our experience since the 1990s revealed that persistent humoral alloreactivity and its long-term exposure can cause chronic graft fibrosis, [5] which likely affects long-term prognosis.

Anti-complement 5 antibody ameliorates antibody-mediated rejection after liver transplantation in rats

“…Antibody-mediated rejection (AMR) is a refractory rejection after donor-specific antibody (DSA)-positive or blood-type incompatible organ transplantation (1). Pre-transplant desensitization with rituximab has dramatically improved the outcome of ABOincompatible living-donor LT (ABOi-LDLT) by eliminating antibodyproducing B lymphocytes, leading to a significant reduction in AMR (2)(3)(4)(5). However, once AMR develops, it is still challenging to effectively treat AMR (4,6), and preformed and de novo DSAs aggravate liver transplantation (LT) outcomes (7,8).…”