Emergency ABO-incompatible living donor liver transplantation in Wilson disease-induced acute liver failure

Joseph J Valamparampil; Deepti Sachan; Naresh Shanmugam; Srinivas Mettu Reddy; Mohamed Rela

doi:10.4103/ajts.ajts_55_21

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CASE REPORT

Year : 2023 | Volume : 17 | Issue : 1 | Page : 128-130

Emergency ABO-incompatible living donor liver transplantation in Wilson disease-induced acute liver failure

Joseph J Valamparampil¹, Deepti Sachan², Naresh Shanmugam¹, Srinivas Mettu Reddy³, Mohamed Rela¹
¹ Institute of Liver Disease and Transplantation, Chennai, Tamil Nadu, India
² Transfusion Medicine, Bharat Institute of Higher Education and Research, Dr. Rela Institute and Medical Centre, Chennai, Tamil Nadu, India
³ Department of Liver Transplantation and HPB Surgery, Gleneagles Global Hospital and Health City; Institute of Liver Disease and Transplantation, Chennai, Tamil Nadu, India

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Date of Submission	20-May-2021
Date of Decision	16-Jun-2021
Date of Acceptance	01-Aug-2021
Date of Web Publication	26-May-2022

Abstract

We report the clinical outcome of an emergency ABO incompatible-liver transplantation (LT) for an 8-year-old child with Wilson's disease-induced acute liver failure. The pretransplant anti-A antibody titer was 1:64, and hence he underwent three cycles of conventional plasma exchange as pretransplant liver supportive treatment for deranged coagulopathy and liver function followed by one cycle of immunoadsorption (IA) prior to LT. The posttransplant immunosuppression consisted of rituximab, tacrolimus, mycophenolate mofetil, and corticosteroid. The patient had anti-A isoagglutinin rebound with elevated aminotransferases levels from postoperative day 7 for which he was restarted on IA plasmapheresis, but antibody titers did not decrease. Hence, he was switched to conventional plasmapheresis (CP) with which anti-A antibody titers decreased. The total dose of rituximab (150 milligrams/square meter of body surface area) was given in two divided doses of 75 mg at D-1 and D + 8 which was much less than the dose conventionally advocated (375 milligrams/square meter of body surface area). He is clinically well with good graft function without rejection after 1 year of follow-up. This case illustrates that IA and CP in conjunction with adequate immunosuppression is a viable approach in emergency ABO-incompatible-LT in Wilson disease-induced acute liver failure.

Keywords: ABO-incompatible, immunoadsorption, liver transplantation, plasmapheresis, Wilson's disease

How to cite this article:
Valamparampil JJ, Sachan D, Shanmugam N, Reddy SM, Rela M. Emergency ABO-incompatible living donor liver transplantation in Wilson disease-induced acute liver failure. Asian J Transfus Sci 2023;17:128-30

How to cite this URL:
Valamparampil JJ, Sachan D, Shanmugam N, Reddy SM, Rela M. Emergency ABO-incompatible living donor liver transplantation in Wilson disease-induced acute liver failure. Asian J Transfus Sci [serial online] 2023 [cited 2023 Mar 27];17:128-30. Available from: https://www.ajts.org/text.asp?2023/17/1/128/345998

Introduction

Wilson disease-induced acute liver failure (WD-ALF) is associated with a high risk of mortality unless emergency liver transplantation (LT) is performed. If blood group compatible donor is unavailable, ABO-incompatible-LT (ABOI-LT) remains the only lifesaving option in such patients. Emergency ABOI-LT in ALF is complicated by lack of adequate time to induce immunosuppression, higher risk of infections, graft loss, and overall mortality.^[1] We report a child with WD-ALF who underwent emergency ABOI-LT and his perioperative management. His postoperative was complicated by rebound antibody elevation, unresponsiveness of antibody to immunoadsorption (IA) plasmapheresis, and response to conventional plasmapheresis (CP).

Case Report

An 8-year-old male child was brought with a history of jaundice for 1-month duration, progressive abdominal distension, irritability, breathlessness, and pedal edema of 5 days duration. Etiological evaluation was suggestive of WD-ALF.

Patient's immunohematological workup was performed using column agglutination method on fully automated analyzer (IH-500 Analyser, Biorad), his blood group was O Rh positive with no ABO discrepancy in forward and reverse grouping. Direct and indirect Coombs test were performed using polyspecific Liss/Coombs' card commercially available reagent cells (Diacell I-II-III panel Bio-Rad, Switzerland) and were negative. He deteriorated rapidly with the development of acute kidney injury requiring continuous renal replacement therapy, Coombs' negative hemolytic anemia, hepatic encephalopathy (Grade II-III), and decline of New Wilson Score to 20 over 48 h.

Since no group matched donors were available in family and the chance of receiving a cadaveric graft was minimal, ABOI-LT was considered with his elder brother being the donor (A1+–O+). ABO isoagglutination titers were performed by conventional tube method using doubling dilution technique with normal saline for anti-A IgM antibodies in saline phase and anti-A IgG antibodies in Anti Human Globulin (AHG) phase. His anti-A titers of IgM/IgG was 1:64/1:64.

The patient's bilirubin levels increased to 34 mg/dl (normal 0.7–1.2) with coagulopathy, he was started with conventional plasma exchange (CP) as liver supportive therapy with fresh frozen plasma as replacement fluid. Keeping the possibility for ABOiLT, he initially underwent CP (1.5 times the plasma volume) with A group plasma as replacement fluid for three consecutive days as a bridge to LT as well as to reduce anti-A antibody titers. Due to the delay in the availability of IA column and need for conventional plasma exchange as the supportive therapy and the urgent nature of the transplant, preconditioning as per unit protocol could not be done. His anti-A IgM/IgG titers reduced to 1:16/1:8 after CP [Figure 1]. On receiving IA column (Glycosorb^®-ABO column, Glycorex Transplantation AB, Lund, Sweden), he then underwent one cycle of IA plasmapheresis, followed by one dose of rituximab (75 mg) 1 day prior to LT (D-1). Postplasmapheresis anti-A antibody titers decreased to target levels of <1:16 (IgM-1:1, IgG-1:1).

Figure 1: Pre-, peri-, and postoperative anti-A antibody titers. (CP = Conventional plasmapheresis, LT = Liver transplantation, IA = Immunoadsorption)

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He underwent living donor LT with a left lobe graft with a graft recipient weight ratio of 1.3. He was started on triple immunosuppression regimen with tacrolimus (0.3 mg/kg/day in two divided doses), mycophenolate mofetil (MMF, 20 mg/kg/day in two divided doses), and methylprednisolone (MP) (1 mg/kg/day) on the day of transplant (D0). Trough tacrolimus levels were targeted between 10 and 12 nanogram/milliliter (ng/ml). CD-19+ lymphocyte counts were <2% (target <5%) of total lymphocytes on 5^th postoperative day (D + 5). Steroids were changed to equivalent dose of oral prednisone once oral intake started and tapered by 25% dose weekly until 5 mg/ day which was continued.

Although his anti-A antibody titers were within target levels initially, he had a 4-fold increase in isoagglutinin titer on D + 7 along with increase in aminotransferase levels [Figure 1]. His post-LT Direct Coombs' test and antibody screen were negative on postoperative days 3 and 7. He underwent one cycle of IA, but the anti-A titers were unchanged and increased next day (D + 8). Hence, IA was initiated using new column and received one more dose of rituximab (75 mg) on D + 8. IA plasmapheresis on D + 9 was also associated with rapidly increasing anti-A antibody titers (IgM-1:128, IgG-1:64) with further increase in aminotransferase levels. Patient blood samples were sent to Glycorex Transplantation AB, Research Laboratory, Sweden, where the possibility of low-frequency nonblood group related specificities toward red blood cells was kept which can be the cause of false titers. Due to the failure of reduction of titers, we switched to CP; four cycles of CP were performed from D + 10 to D + 13 [Figure 1]. His titers stabilized and reduced to <16 from D + 14 without need for further intervention. The child is clinically well with good graft function and no episodes of rejection at 1 year of follow-up.

Discussion

ABOI-LT in pediatric recipients >2 years of age has traditionally been considered to increase the risk of rejection, vascular and biliary complications resulting in decreased patient and graft survival in the short and long term.^[2] However, with the use of novel immunosuppressive techniques and effective plasmapheresis, outcomes comparable to ABO-compatible LT can be achieved.^[3],[4] ABOI-LT in ALF is complicated by lack of adequate time for preLT immunomodulation, increased risk of rejection posttransplant, higher frequency of infections, graft failure, and need for re-transplantation.^[1]

In elective ABOI-LT in children >18 months of age, immunosuppression protocol in our unit consists of rituximab (50–150 milligrams/square meter of body surface area [mg/m²]) is given as a single dose 14 days before LT, MMF (Cellcept^®; Roche Pharmaceuticals, Basel, Switzerland) 7 days prior to LT. Methylprednisolone (MP, 1 mg/kg/day) and tacrolimus (Prograf^®; Astellas Pharma, Tokyo, Japan) are started on the day of LT. Rituximab dose is always individualized balancing the patient's clinical condition, risk of infection with the probable risk of graft injury due to inadequate immunosuppression. The target tacrolimus level in the initial 2 months is 10–12 ng/ml, 8–10 ng/ml in the next 4 months, 5–7 ng/ml in 6–12 months, and 3–5 ng/ml after 1 year. Steroids are tapered to 1 mg/day after 6 months after transplantation.

Rituximab has been shown to decrease the incidence of antibody-mediated rejection (AMR, especially hepatic necrosis), but timing of rituximab administration has no significant effect on AMR incidence or patient survival.^[5] Rituximab was initiated in this patient only on D-1 due to the emergency LT and associated time constraints. Since there was persistent anti-A antibody titer elevation (IgM and IgG-1:64), we gave another dose on D + 8. Total dose administered was 150 mg/m² which is much less than the dose advocated (375 mg/m²).^[5] Since postoperative infections are a major cause of morbidity, mortality in ALF and the risk increases significantly in ABOI-LT due to the use of multiple immunosuppressive drugs, we believe that it is important to titrate the dose of rituximab in each patient based on the clinical status.

The patient underwent IA pre-LT to decrease the preformed anti-donor blood type isoagglutinin antibody titer to ≤1:16. In ALF, immunomodulation prior to LT is usually inadequate due urgency of the transplant. There was significant anti-donor blood type antibody titer rebound requiring multiple IA plasmapheresis in our patient. We aimed to keep the antibody titers ≤1:16 in the first 2 weeks after the transplant; beyond the period, intervention for high antibody titers were considered only if associated with increased aminotransferase levels since posttransplant antibody titers have poor positive predictive value in AMR.^[6]

IA is very effective in removing anti-donor antibodies with several advantages over CP; fewer number of procedures for preconditioning, no need for replacement fluid, and decreased risk of infections.^[7] However, selection of preconditioning method (CP or IA) is crucial and should be decided based on the urgency of LT, financial considerations, and need of concurrent plasmapheresis as bridging therapy. In our case, we switched from CP to IA (D-1) due to the urgency of transplant and later switched back to CP (D + 8) due to the antibody rebound in spite of changing columns. Core-chain-dependent antibodies which not are absorbed by the IA column have been reported in 6% of patients after ABOI kidney transplantation with an adequate response after CP.^[7] Analysis for core-chain-dependent antibodies was inconclusive in our patient, so the reason for the failure of IA is not clear.

Conclusion

We report successful ABOI-LT in pediatric ALF complicated by rebound rise in antibody titers, ineffectiveness of IA, effective use of CP, and use of lower dose of rituximab.

Acknowledgment

We would like to thank Glycorex Transplantation AB, Lund, Sweden, for their laboratory support.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Chan G, Taqi A, Marotta P, Levstik M, McAlister V, Wall W, et al. Long-term outcomes of emergency liver transplantation for acute liver failure. Liver Transpl 2009;15:1696-702.
2.	Egawa H, Oike F, Buhler L, Shapiro AM, Minamiguchi S, Haga H, et al. Impact of recipient age on outcome of ABO-incompatible living-donor liver transplantation. Transplantation 2004;77:403-11.
3.	Heffron T, Welch D, Pillen T, Asolati M, Smallwood G, Hagedorn P, et al. Successful ABO-incompatible pediatric liver transplantation utilizing standard immunosuppression with selective postoperative plasmapheresis. Liver Transpl 2006;12:972-8.
4.	Honda M, Sugawara Y, Kadohisa M, Shimata K, Sakisaka M, Yoshii D, et al. Long-term Outcomes of ABO-incompatible pediatric living donor liver transplantation. Transplantation 2018;102:1702-9.
5.	Egawa H, Teramukai S, Haga H, Tanabe M, Mori A, Ikegami T, et al. Impact of rituximab desensitization on blood-type-incompatible adult living donor liver transplantation: A Japanese multicenter study: Rituximab in ABO-incompatible adult LDLT. Am J Transplant 2014;14:102-14.
6.	Tobian AA, Shirey RS, Montgomery RA, Cai W, Haas M, Ness PM, et al. ABO antibody titer and risk of antibody-mediated rejection in ABO-incompatible renal transplantation. Am J Transplant 2010;10:1247-53.
7.	Genberg H, Kumlien G, Wennberg L, Tyden G. The efficacy of antigen-specific immunoadsorption and rebound of anti-A/B antibodies in ABO-incompatible kidney transplantation. Nephrol Dial Transplant 2011;26:2394-400.