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INTRODUCTION
The liver is considered an immune-privileged organ conducive to transplantation. However, ABO-incompatible (ABOi) liver transplantation often raises concerns about antibody-mediated rejection (AMR) [1]. The introduction of rituximab, an anti-CD20 antibody, has revolutionized the pretransplant preparation of ABOi recipients, reducing the incidence of AMR and making ABOi transplantation a more common strategy to address organ shortages [1]. For the prevention of AMR, various desensitization modalities have been described in the literature, including rituximab, plasmapheresis, splenectomy, intravenous immunoglobulin (IVIG), bortezomib, and newer therapies such as obinutuzumab and belatacept [2]. Ideally, 2 to 3 weeks of preparation are required before transplantation to reduce antibody titers to an acceptable level (<1:64) [3]. However, this timeframe may be unfeasible in emergency situations, such as acute liver failure, acute-on-chronic liver failure (ACLF), and primary nonfunction (PNF) following transplantation. In this series, we present three cases of emergency ABOi living donor liver transplantation (LDLT), performed in two patients with ACLF and one patient with PNF following previous LDLT, with perioperative management tailored to the needs of each patient.
ACLF is a syndrome characterized by acute deterioration of liver function and extrahepatic organ dysfunction in patients with established chronic liver disease (CLD). Its management remains a subject of debate [4]. However, liver transplantation has demonstrated superior overall survival compared to conservative management [5]. In our series, two patients with ACLF underwent ABOi LDLT due to a lack of compatible donors.
PNF is a rare and life-threatening complication that can occur following LDLT, necessitating immediate retransplantation to save the patient’s life [6]. While patients with PNF are assigned status I on the priority list for deceased donor liver transplantation, this option is often not feasible in countries with a scarcity of deceased donor transplants. However, obtaining an ABO-compatible living donor liver allograft is also challenging. In emergency cases, an ABOi liver allograft may be utilized as a stopgap measure with rapid preparation. In our series, one patient with PNF underwent urgent ABOi LDLT. Here, we report three cases of emergency ABOi LDLT utilizing a modified desensitization protocol tailored to each patient’s clinical status.
CASE REPORT
This report was prepared in accordance with the CARE guidelines, and written informed consent was obtained from all patients for publication of this study.
Case 1
A 54-year-old man with blood group O negative had been diagnosed with cryptogenic CLD, with a Child-Turcotte-Pugh (CTP) score of 11 and a Model for End-Stage Liver Disease (MELD) score of 29. He underwent ABO-compatible LDLT with his 29-year-old son (blood group O positive) as the donor. This transplant utilized a modified right lobe graft, weighing 693 g and with a graft-to-recipient weight ratio (GRWR) of 1.15. Following the transplant, the patient exhibited increased levels of bilirubin, transaminases, and serum ammonia (233 µg/dL), along with an unrecordable international normalized ratio (INR). Clinically, either AMR or acute cellular rejection (ACR) was suspected. The patient was managed with steroid therapy (methylprednisolone), a single dose of bortezomib (1.3 mg/m2), and therapeutic plasma exchange. Despite these interventions, his condition deteriorated, with an aspartate aminotransferase level exceeding 3,000 U/L, an INR greater than 18, a lactate level of 4.84, and an arterial pH of 7.16. Allograft Doppler ultrasonography was normal. The patient was diagnosed with PNF of the allograft according to the Organ Procurement and Transplantation Network definition [7]. To treat hyperammonemia and cerebral edema, a single session of continuous renal replacement therapy (CRRT) was performed. With the diagnosis of PNF, retransplantation was planned; however, only an ABOi donor, the patient’s wife, was available (specifically, blood group B to O negative). Fortunately, the patient had a low anti-B titer (IgG [immunoglobulin G] 1:4, IgM 1:2), and no pretransplant desensitization was performed. A modified right lobe graft, weighing 600 g and with a GRWR of 1.0, was used. Splenectomy was deferred due to low portal flow and a relatively low antibody level. Postoperatively, the patient developed acute renal failure (serum creatinine, 2.07 mg/dL) and required hemodialysis. Instead of the calcineurin inhibitor (CNI) tacrolimus, he received an injection of basiliximab (anti-CD25, 20 mg) on the first day after surgery. The postoperative immunosuppressive regimen included steroids, mycophenolate mofetil, and tacrolimus, introduced on the fifth day after retransplantation. The patient’s allograft function improved gradually following retransplantation, and he was discharged on postoperative day (POD) 15 in stable condition. At 20 months of follow-up, the patient was doing well, with a normally functioning allograft.
Case 2
A 30-year-old woman with cryptogenic CLD presented with a 2-month history of jaundice, which was complicated by encephalopathy of West Haven grade II. She was diagnosed with ACLF grade 3a according to the European Association for the Study of the Liver (EASL) criteria, with a CTP score categorized as class C, a MELD-sodium (MELD-Na) score of 41, and a Chronic Liver Failure Consortium (CLIF-C) score of 47 [4]. An ABOi donor was available, with the donor being A positive and the recipient O positive. The recipient’s anti-A antibody titers were IgG 1:1,024 and IgM 1:256. Two days before LDLT, she underwent eight cycles of plasmapheresis along with blood group-specific apheresis or immunoadsorption (SECORIM ABO, VitroSorb). This treatment reduced her anti-A titers to IgG 1:128 and IgM 1:128. However, a rebound increase in titers was observed on the day before transplantation (anti-A titer IgG 1:1,024, IgM 1:256); therefore, she received an additional eight cycles of plasmapheresis with the SECORIM ABO device and a single dose of rituximab (375 mg/m2), an anti-CD20 monoclonal antibody. Her pretransplant anti-A titers were IgG 1:512 and IgM 1:64. She received a modified right lobe graft with a GRWR of 0.91. Intraoperatively, splenectomy was deferred due to the prior administration of rituximab. Postoperatively, the patient was treated with IVIG (0.8 g/kg for 5 days), steroids, and tacrolimus. Due to severe neutropenia (absolute neutrophil count <500/μL) in the early postoperative period, mycophenolate mofetil was initiated on POD 4. On POD 1, the patient’s anti-A titers were IgG 1:128 and IgM 1:32, and these continued to gradually decline. On POD 7, an increase in serum bilirubin and transaminases was observed, despite normal antibody titers. ACR was suspected clinically and treated with methylprednisolone (750 mg), to which she responded well. She was discharged on POD 17. At 9 months of follow-up, the patient is doing well on a regimen of triple immunosuppressants.
Case 3
A 31-year-old man with blood group O positive and a history of ethanol-related CLD presented with a 4-week history of jaundice, followed by ascites, altered mental status, and decreased urine output. Clinically, he exhibited grade III/IV encephalopathy according to the West Haven criteria, as well as jaundice, pedal edema, and ascites. His biochemical parameters were abnormal upon presentation, with a total bilirubin of 23.5 mg/dL, corrected albumin of 2.6 g/dL, INR of 2.5, creatinine of 1.3 mg/dL, and Na of 140 mEq/L. He was diagnosed with grade 3b ACLF according to the EASL criteria, with a CLIF-C score of 60, a CTP score of 15, and a MELD-Na score of 32 [4]. Treatment included mechanical ventilation, inotropic support, and CRRT, and the patient was scheduled for LDLT. The donor was his sister, who had blood group B positive and was therefore ABOi. The patient had high anti-B antibody titers (IgM 1:256, IgG 1:4,096). He underwent eight cycles of blood-group-specific apheresis using SECORIM ABO as part of the desensitization protocol 1 day before the scheduled transplant. Despite this, his anti-B titers remained high (IgM 1:512, IgG 1:1,024) immediately before the liver transplant. Therapeutic plasma exchange was not conducted due to the risk of circulatory failure, while splenectomy was performed. The patient received IVIG intraoperatively and on PODs 1 and 3. The postoperative immunosuppressive regimen included tacrolimus, mycophenolate mofetil, and steroids. His anti-B titers gradually decreased, reaching IgG 1:8 and IgM 1:32 on POD 7. However, he developed acute kidney injury, necessitating discontinuation of the CNI tacrolimus and the initiation of intermittent sustained low-efficiency dialysis. He also developed graft dysfunction, which was managed conservatively. Long-term follow-up is pending.
Fig. 1 depicts trends in antibody levels and the perioperative management of the three patients.
DISCUSSION
The three case reports presented above illustrate the effectiveness of ABOi LDLT in emergency situations. For each of the three patients, the desensitization protocol deviated from the conventional approach, which typically involves assessment of CD19+/20+ cells, antibody titers, and administration of rituximab 2 to 3 weeks before transplantation. In our series, the patients exhibited variations in antibody titers, requiring individualized desensitization regimens. Additionally, postoperative kidney injury and leukopenia necessitated adjustments to the standard triple immunosuppression regimen.
PNF is a potentially life-threatening complication following liver transplantation, with retransplantation required for patient survival. Numerous factors may contribute to PNF, including ischemia-reperfusion (IR) injury, donor characteristics (such as advanced age, graft steatosis, and prolonged cold ischemia time), and recipient factors (like age, sex, MELD score, length of intensive care unit stay, and renal failure) [6]. In our first case, PNF was likely caused by an IR injury. The primary driver of AMR in ABOi liver transplantation is the level of antibodies against the blood group antigens. Elevated levels of IgG and IgM have been reported in patients with CLD; however, the underlying reasons remain unclear. Multiple theories have been proposed, including extensive collateralization and shunting of gut endotoxins and reduced clearance of immunoglobulins by the compromised liver [8].
On the contrary, studies have also reported impaired immunity, both innate and adaptive, in decompensated CLD. This impairment results from enhanced interleukin 2 signaling, which leads to an altered follicular T helper cell response, impaired B cell function, and disturbed IgG levels [9]. Consequently, a patient with CLD may exhibit hypergammaglobulinemia or hypogammaglobulinemia. Therefore, in case 1, the reduced immunoglobulin levels could be attributed to an impaired T cell response secondary to an acute liver failure-like clinical condition (PNF), the administration of high-dose steroids (injected methylprednisolone 500 mg), or the impact of CRRT. Nevertheless, the low levels of immunoglobulin were advantageous for our patient, for whom ABOi retransplantation was the only viable option. We administered bortezomib under suspicion of AMR, as this drug induces cell cycle arrest and programmed cell death in plasma cells. Researchers have explored the use of bortezomib for the rapid preparation of patients for ABOi liver transplantation, with a mean duration between dose and transplantation of 4.75±1.58 days [10]. In case 1 of the present series, the patient underwent liver transplantation 48 hours after the bortezomib injection, which was earlier than the expected onset of the drug’s effect.
In both cases 2 and 3, the patients presented with ACLF and multiorgan failure, necessitating urgent liver transplantation. Transplantation should be performed within the “golden window,” before the onset of sepsis or irreversible organ failure [15]. Unlike in the first case, both patients had high antibody titers before liver transplantation, posing a particular challenge. Few published reports are available regarding emergency ABOi in patients with high pretransplant antibody titers.
Selective immunoadsorption has been extensively studied in ABOi kidney transplantation as an effective method for removing specific antibodies. However, its role in ABOi LDLT has been less frequently explored [16]. In our series, the use of SECORIM ABO immunoadsorption resulted in an accelerated decrease in antibody levels. This facilitated successful ABOi liver transplantation in cases 2 and 3, with the transplant occurring within the window.
The spleen is the primary site for B cell maturation and antibody production. Consequently, splenectomy is a key intraoperative strategy for desensitization. Some centers routinely perform splenectomy for ABOi liver transplantation [1]. However, splenectomy can lead to reduced portal flow, forming the basis of portal flow modulation in LDLT [17]. In our first case, splenectomy was deemed unnecessary due to the low antibody level. In the second, rituximab was administered preoperatively, and low intraoperative portal flow precluded splenectomy. In contrast, the third patient had a high preoperative titer, prompting the performance of splenectomy regardless of portal flow.
Rituximab is an anti-CD20 monoclonal antibody that depletes B cells through complement-mediated cytotoxicity in the circulation and lymphoid tissue [18]. In a prior study, this drug was shown to reduce the incidence of AMR from 23.5% to 6.2% [19]. Additionally, its immunological benefits in the postoperative period are comparable to those of splenectomy. Conventionally, monitoring of immunoglobulin levels is recommended at specific intervals: 2 to 3 days following administration, after 1 week, and prior to surgery. In emergency ABOi transplantation, rituximab can be administered 1 day before the procedure, as supported by prior research and as demonstrated in our second patient (Table 1).
ABOi transplantation in the presence of high antibody titers is infrequently reported in the literature. One case report described ABOi LDLT conducted with a high titer (1:4,096), in which the patient received rituximab 14 days before the transplant, underwent plasmapheresis, and was treated with a triple immunosuppressive regimen preoperatively. Additionally, splenectomy was performed during surgery, and the patient continued on triple immunosuppressants after the transplant [20]. In our case 3, ABOi LDLT was expedited using immunoadsorption alone, a method not previously documented in the literature. Various authors have described accelerated desensitization protocols for urgent or semi-urgent ABOi liver transplantation in the contexts of acute liver failure, ACLF, drug-induced liver failure, and so on (Table 1).
ABOi liver transplantation carries a heightened concern for AMR during the postoperative period, along with increased risk of arterial thrombosis, biliary complications, sepsis, graft failure, and other issues. Fortunately, in our series, only one patient exhibited suspected cell-mediated rejection, which was successfully treated with pulse steroid therapy; no other complications were reported. The primary objective in achieving rejection-free liver transplantation is to lower antibody levels, which can be accomplished through both reduced antibody production (via rituximab, bortezomib, or splenectomy) and accelerated removal (through therapeutic plasma exchange, immunoadsorption, or immunoglobulin). Following transplantation, any elevation in liver enzymes warrants evaluation of antibody titers, assessment of donor-specific antibody levels, and graft biopsy with C4d staining to rule out AMR. According to our institutional policy, the antibody titer is monitored up to POD 7. While desensitization protocols vary internationally, the outcomes are generally satisfactory; thus, the overarching aim is to achieve a low titer before transplantation to prevent AMR. Nevertheless, in emergency situations, the urgency of transplantation outweighs the antibody level, given the availability of numerous methods to eliminate preformed antibodies and to treat AMR.
This case series reports the feasibility and successful outcomes of emergency ABOi transplants in three distinct clinical scenarios with different pretransplant antibody titers. With low titer levels, transplantation was possible without desensitization. Conversely, in a case involving high titer levels, transplantation was successfully performed using only immunoadsorption—a strategy not previously reported. Notably, however, these are individual case reports, and the chosen strategies were dictated by the urgent need for transplantation.
While emergency ABOi liver transplantation can represent a panacea for patients with liver failure, it often necessitates tailored desensitization protocols to prevent postoperative AMR. In certain cases, having a low level of antibodies may prove advantageous. Therefore, emergency ABOi LDLT can be safe and feasible with modifications to perioperative care in accordance with the patient’s needs. However, future studies with larger samples are necessary to validate our findings.
ARTICLE INFORMATION
Conflict of Interest:
No potential conflict of interest relevant to this article was reported.
Author Contributions
Conceptualization: NKG, KM, PS, AA, VV. Data curation: NKG, YY, TK. Formal analysis: NKG, YY, TK. Investigation: NKG, YY, TK. Methodology: NKG, YY, TK, AA. Visualization: NKG, YY, TK, AA. Writing–original draft: NKG, KM, PS, AA, VV. Writing–review & editing: NKG, KM, PS, AA, VV. All authors read and approved the final manuscript.
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