Risk factors for antibody-mediated rejection in ABO blood-type incompatible and donor-specific antibody-positive liver transplantation

Abstract

Antibody-mediated rejection (AMR) is a refractory rejection after ABO blood-type incompatible (ABOi) or donor-specific antibody (DSA)-positive liver transplantation (LT). Pretransplant rituximab desensitization dramatically reduced posttransplant AMR development; however, risk factors for AMR in the rituximab era remain unclear in both ABOi living-donor LT (ABOi-LDLT) and preformed DSA-positive LT (pDSA-LT). Of our 596 adult LDLTs (≥18 y) after rituximab introduction (2004–2019), 136 were ABOi-LDLT (22.8%). After excluding retransplants (9), acute liver failure (7), and protocol deviations (16), 104 ABOi-LDLTs were finally enrolled. Of these, 19 recipients developed AMR, 18 of which occurred within 2 weeks after transplantation (95%). ABOi-AMR significantly worsened graft and recipient survival than those without (p=0.02 and 0.04, respectively). Model for End-stage Liver Disease (MELD) ≤13 (OR: 5.15 [1.63–16.3], p=0.005) and pre-rituximab anti-ABO IgM-titer ≥128 (OR: 3.25 [1.05–10.0], p=0.03) were identified as independent risk factors for ABOi-AMR development. Recipients fulfilling both factors showed significantly worse survival rates than those who did not (p=0.003). Of 352 adult LTs, after introducing the LABScreen Single Ag method (2009–2019), pDSA with mean fluorescence intensity (MFI) ≥500 was detected in 50 cases (14.2%). After excluding 10 ABOi-LDLTs, 40 pDSA-LTs were finally analyzed, of which 5 developed AMR. The combination of high-titer (sum-MFI ≥10,000) and multi-loci pDSAs was a significant risk factor for pDSA-AMR development (p <0.001); however, it did not affect the 5-year recipient survival compared with those without (p=0.56). In conclusion, preoperative MELD ≤13 and pre-rituximab anti-ABO IgM-titer ≥128 for ABOi-LDLT, and the combination of sum-MFI ≥10,000 and multi-loci pDSAs for pDSA-LT, are risk factors for AMR in the era of rituximab desensitization. Characteristically, ABOi-AMR significantly deteriorated graft and recipient survival, whereas pDSA-AMR did not.

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

“…However, we never underestimate DSA-related complications. As shown, 1 5 of 10 patients with sum-mean 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.…”

“…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.…”

“…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.…”

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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.

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“…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 …”