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Paired exchange Living donor Liver Transplantation: Indications, stumbling blocks, and future considerations

  • Dhiraj Agrawal
    Affiliations
    Department of Gastroenterology and Hepatology, PACE Hospitals, Hitec City, Hyderabad, India 500081
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    Subhash Gupta
    Footnotes
    a +917838660172, +918527166415, +919891052970, +919717721446.
    Affiliations
    Centre for Liver and Biliary Sciences, Max Saket Hospital 1 Press Enclave Road New Delhi, India 110 017
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    1 Contact details. Max Super Speciality Hospital (West Block), Saket, Press Enclave Road, Saket, New Delhi – 110017.
    Sanjiv Saigal
    Correspondence
    Corresponding author. .
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    1 Contact details. Max Super Speciality Hospital (West Block), Saket, Press Enclave Road, Saket, New Delhi – 110017.
    Affiliations
    Hepatology and Liver Transplant, Centre for Liver & Biliary Sciences, Centre of Gastroenterology, Hepatology & Endoscopy, Max Super Speciality Hospital, Saket, New Delhi, India 110017
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    1 Contact details. Max Super Speciality Hospital (West Block), Saket, Press Enclave Road, Saket, New Delhi – 110017.
Published:October 28, 2022DOI:https://doi.org/10.1016/j.jhep.2022.10.019

      Abstract

      The last decade has seen Liver Paired exchange (LPE) as an increasingly used modality across the transplant community by which pairs of incompatible living Liver donors and their intended recipients swap Livers resulting in compatible transplants. The feasibility and benefit of LPE in providing excellent recipient outcomes and robust donor safety have been proven in uncomplicated swaps. Began initially as single-centre two-way or three-way exchanges, LPE has tremendous potential to grow into more complicated chains over days and over multiple centres. Also, LPE is associated with unique technical, logistical, ethical and legislative challenges. This review discusses the indications, potential types of LPE, unique solutions to stumbling blocks in performing LPE, and future considerations on how LPE can expand the living donor liver pool and the armamentarium of living donor liver transplantation (LDLT).

      Keywords

      Abbreviations

      ABOi
      ABO blood group incompatible
      ABOc
      ABO blood group incompatible
      AMR
      Antibody-mediated rejection
      CIT
      Cold ischemia time
      EAD
      Early graft dysfunction
      ESLD
      End-stage liver disease
      GRWR
      Graft-to-recipient weight ratio
      GIM
      Graft inflow modulation
      HCC
      Hepatocellular carcinoma
      KPE
      Kidney paired exchange
      LDLT
      Living-donor liver transplantation
      LPE
      Liver Paired exchange
      LL
      Left lobe
      LLS
      Left lateral segment
      MELD
      Model for end-stage liver disease
      ND-LLD
      Non-directed living liver donor
      NEAD
      Non-simultaneous extended altruistic donor
      PVF
      Portal vein flow
      PVP
      Portal vein pressure
      RL
      Right lobe
      SFSG
      Small for size graft
      SFGS
      Small for size graft syndrome
      UNOS
      United Network for Organ Sharing
      UCSF
      University of California San Francisco
      WIT
      Warm ischemia time

      Conflict of Interest

      None.

      Financial support

      None.

      Authors contributions

      DA Initial draft, revision, and editing.
      SS Revision and editing.
      SG Revision and editing.
      • 1.
        Liver paired exchange (LPE) is a fair and legal way to increase the living donor liver organ pool in cases of ABO blood group incompatibility and donor allograft size mismatch.
      • 2.
        LPE is associated with excellent donor and recipient outcomes at high-volume LDLT centres.
      • 3.
        Both LPE and ABO-i LDLT are feasible options to overcome blood group barriers.
      • 4.
        The merits of LPE include no desensitization, lower infection risk‚, excellent graft outcomes, cost savings‚ the ability to benefit multiple recipients simultaneously.
      • 5.
        LPE is associated with unique technical, logistical, ethical and legislative challenges.
      • 6.
        The necessary infrastructure to support a robust LPE program would include a central registry, strengthening matching algorithms, monitoring outcomes, and developing logistical support.

      Introduction

      The last decade has seen Liver Paired exchange (LPE) or paired exchange, living donor liver transplantation (LDLT) as an increasingly used modality by the transplant community by which pairs of incompatible living Liver donors and their intended recipients swap Livers resulting in compatible transplants. The two transplant recipients can be removed from the deceased donor waiting list, shortening the list for remaining patients. The potential number of living donor and recipient pairs suitable for LPE is largely unexplored. Based on our prior experience
      • Agrawal D.
      • Saigal S.
      • Jadaun S.S.
      • Singh S.A.
      • Agrawal S.
      • Gupta S.
      Paired Exchange Living Donor Liver Transplantation: A Nine-year Experience From North India.
      and literature review, we aim to discuss the indications, potential types of LPE, unique solutions to stumbling blocks in performing LPE, and future considerations on how LPE can expand the living donor liver pool and the armamentarium of living donor liver transplantation (LDLT).

      LPE experience worldwide to date

      The published literature on LPE has nine reports (5 original articles and 4 case reports), including 74 LPEs from Asia and North America.
      • Agrawal D.
      • Saigal S.
      • Jadaun S.S.
      • Singh S.A.
      • Agrawal S.
      • Gupta S.
      Paired Exchange Living Donor Liver Transplantation: A Nine-year Experience From North India.
      • Hwang S.
      • Lee S.G.
      • Moon D.B.
      • Song G.W.
      • Ahn C.S.
      • Kim K.H.
      • et al.
      Exchange living donor liver transplantation to overcome ABO incompatibility in adult patients.
      • Jung D.H.
      • Hwang S.
      • Ahn C.S.
      • Kim K.H.
      • Moon D.B.
      • Lee S.G.
      • et al.
      Section 16. Update on experience in paired-exchange donors in living donor liver transplantation for adult patients at ASAN Medical Center.
      • Gunabushanam V.
      • Ganesh S.
      • Soltys K.
      • Mazariegos G.
      • Ganoza A.
      • Molinari M.
      • et al.
      Increasing Living Donor Liver Transplantation Using Liver Paired Exchange.
      • Kaplan A.
      • Rosenblatt R.
      • Jackson W.
      • Samstein B.
      • Brown Jr., R.S.
      Practices and Perceptions of Living Donor Liver Transplantation, Non-directed Donation, and Liver Paired Exchange: A National Survey.
      • Braun H.J.
      • Torres A.M.
      • Louie F.
      • Weinberg S.D.
      • Kang S.M.
      • Ascher N.L.
      • et al.
      Expanding living donor liver transplantation: Report of first US living donor liver transplant chain.
      • Patel M.S.
      • Mohamed Z.
      • Ghanekar A.
      • Sapisochin G.
      • McGilvray I.
      • Selzner N.
      • et al.
      Living donor liver paired exchange: A North American first.
      • Chan S.C.
      • Lo C.M.
      • Yong B.H.
      • Tsui W.J.
      • Ng K.K.
      • Fan S.T.
      Paired donor interchange to avoid ABO-incompatible living donor liver transplantation.
      • Chan S.C.
      • KSh Chok
      • Sharr W.W.
      • Chan A.C.
      • Tsang S.H.
      • Dai W.C.
      • et al.
      Samaritan donor interchange in living donor liver transplantation.
      LPE constitutes approximately 1.2 to 8.3 % of the total LDLTs performed at the individual centre
      • Agrawal D.
      • Saigal S.
      • Jadaun S.S.
      • Singh S.A.
      • Agrawal S.
      • Gupta S.
      Paired Exchange Living Donor Liver Transplantation: A Nine-year Experience From North India.
      • Hwang S.
      • Lee S.G.
      • Moon D.B.
      • Song G.W.
      • Ahn C.S.
      • Kim K.H.
      • et al.
      Exchange living donor liver transplantation to overcome ABO incompatibility in adult patients.
      • Jung D.H.
      • Hwang S.
      • Ahn C.S.
      • Kim K.H.
      • Moon D.B.
      • Lee S.G.
      • et al.
      Section 16. Update on experience in paired-exchange donors in living donor liver transplantation for adult patients at ASAN Medical Center.
      • Gunabushanam V.
      • Ganesh S.
      • Soltys K.
      • Mazariegos G.
      • Ganoza A.
      • Molinari M.
      • et al.
      Increasing Living Donor Liver Transplantation Using Liver Paired Exchange.
      , signifying a substantial potential of this form of LDLT to mitigate the liver allograft shortage. Table 1 compares the data on LPE from major published series to date.
      Table. 1Major published series on Liver paired exchange (LPE) worldwide.
      CountryKorea2,3India1United States of America4
      Type of StudyOriginal articleOriginal articleOriginal article
      Year201420222022
      AuthorDong-Hwan Jung et alDhiraj Agrawal et alVikraman Gunabushanam, et al
      Single-centreSingle-centreSingle centreSingle centre
      N (pairs/% of total LDLTs)26 (1.2%)34 (1.45%)10 (8.3%)
      Study duration2003 – 20112012 -20212019-2021
      Indications for LPE
      ABO-incompatible22 pairs34 pairs9 pairs
      ABO compatible2 pairs cascade allocationNil1 pair
      2 pairs small graft volume
      Recipients263420
      Donors28 (2 pairs 3x2)3420
      Relationship
      Blood-related263413
      Unrelated207
      Donation
      Directed donation273413
      Non-directed donation107
      Type of exchangeSimultaneous/single-centreSimultaneous/single-centreSequential (4.8 days)/single-centre
      Graft used
      Right liver graft18 (69.2%)33 (97%)19 (95%)
      Left liver graft6 (23.1%)1 (3%)1 (5%)
      Dual grafts2 (7.7%)00
      Recipient properties
      AetiologyHepatitis B 17 (65.4%)ALD 17 (50 %)NASH (45%)
      Standard MELD score19.1 ± 9.821 (10-36)15.85 (9 -30)
      GRWR1.05 ± 0.151.04 (0.63 -2.2)0.97 (0.55 -1.6)
      Recipient Outcome
      1-year survival96.20%85.3% (n=29)85%
      5-year survival90.10%NANA
      Donor outcome100%100%100%
      It is interesting to observe the reasons behind the variable growth of LPE programmes across various time points in different regions of the world. The world’s first LPE program was established at Asan medical centre in 2003 to avoid ABO-incompatible (ABOi) LDLT in adults. They reported their initial experience in 2010
      • Hwang S.
      • Lee S.G.
      • Moon D.B.
      • Song G.W.
      • Ahn C.S.
      • Kim K.H.
      • et al.
      Exchange living donor liver transplantation to overcome ABO incompatibility in adult patients.
      and an updated experience of 26 LPEs (1.2% of 2,182 adult LDLT) in 2014
      • Jung D.H.
      • Hwang S.
      • Ahn C.S.
      • Kim K.H.
      • Moon D.B.
      • Lee S.G.
      • et al.
      Section 16. Update on experience in paired-exchange donors in living donor liver transplantation for adult patients at ASAN Medical Center.
      . Subsequently, they launched an ABO-i LDLT program in 2009. After introducing these two mutually supplementary programs, they saw an initial increase in the matching rate for LPE. However, with the improved outcomes of ABO-i LDLT, the weight of the LPE donation soon shifted toward ABO-i LDLTs. The author concluded that donor exchange and ABO-i transplantation are feasible options to overcome ABOi. The decision to choose donor exchange or ABOi LDLT should be left to individual patients.
      Another study from the University of Pittsburgh Medical Center (PMC) reviewed their experience with 10 LPEs over three years with excellent donor (100%) and recipient survival (85%).
      • Gunabushanam V.
      • Ganesh S.
      • Soltys K.
      • Mazariegos G.
      • Ganoza A.
      • Molinari M.
      • et al.
      Increasing Living Donor Liver Transplantation Using Liver Paired Exchange.
      At PMC, the sequential algorithm in case of ABOi or size mismatch involves offering all donors an option of paired exchange with another incompatible pair, or with an ABO compatible (ABOc) pair, or initiating a pair with a non-directed donor, and lastly, the option of undergoing ABOi transplantation. During their study period, 46 (19.2%) of the total 239 LDLTs were initiated from non-directed liver donors. Of 46, seven initiated LPE, and the LDLTs were completed within 1–14 days (mean 4.8 days) of each other. The other three of the ten incompatible pairs were matched with a compatible pair. The authors concluded that the availability of non-directed O blood group donors is critical in initiating and completing paired exchanges.
      A recent prospective study by Agrawal et al. reported
      • Agrawal D.
      • Saigal S.
      • Jadaun S.S.
      • Singh S.A.
      • Agrawal S.
      • Gupta S.
      Paired Exchange Living Donor Liver Transplantation: A Nine-year Experience From North India.
      17 simultaneous Liver paired exchanges of 2 dyads, leading to 34 (1.45% of 2340) LDLT transplants over nine years. This centre from India adopted an ABO-i and LPE program in 2012. However, till 2016, LPE s constituted less than 1% of overall transplants. As their program matured, the number of both ABO-i and paired donor exchange LDLTs rapidly increased, and LPE constituted as much as 5.3% of total transplants in 2021. The authors concluded that LPE is a fair and legal way to increase the living donor liver organ pool.
      A recent study surveyed 56 LDLT programs in the US.
      • Kaplan A.
      • Rosenblatt R.
      • Jackson W.
      • Samstein B.
      • Brown Jr., R.S.
      Practices and Perceptions of Living Donor Liver Transplantation, Non-directed Donation, and Liver Paired Exchange: A National Survey.
      Only six (12%) reported doing LPE, of which 75% performed LPEs within a single institution. Of the remaining 50 centres, 92% would consider starting an LPE programme, of which 78% would be open to multicentric LPE.
      These recent reports looking at outcomes and the role of non-directed donation, sequential donations, and multicentric LPE are highly encouraging.

      Indications of LPE

      For patients with end-stage liver disease (ESLD) considering LDLT, the foremost requirement is having an eligible donor. There are several reasons to reject an otherwise willing and fit donor, such as ABO incompatibility (ABOi), inadequate graft-to-recipient weight ratio (GRWR), poor graft quality, complex liver anatomy, and low remnant liver volume. The strategies to overcome these barriers to donations include graft inflow modulation (GIM) or dual-lobe LDLT for low GRWR
      • Kwon J.H.
      • Song G.W.
      • Hwang S.
      • Kim K.H.
      • Ahn C.S.
      • Lee S.G.
      • et al.
      Dual-graft adult living donor liver transplantation with ABO-incompatible graft: short-term and long-term outcomes.
      ; a stringent weight loss regimen to improve donor liver steatosis
      • Trakroo S.
      • Bhardwaj N.
      • Garg R.
      • Modaresi Esfeh J.
      Weight loss interventions in living donor liver transplantation as a tool in expanding the donor pool: A systematic review and meta-analysis.
      and ABO-i LDLT or LPE for ABOi donors
      • Kang Z.Y.
      • Liu W.
      • Li D.H.
      Comparison of clinical outcomes between ABO-incompatible and ABO-compatible pediatric liver transplantation: a systematic literature review and meta-analysis.
      ,
      • Kim J.M.
      Increasing Living Liver Donor Pools: Liver Paired Exchange Versus ABO-incompatible Living Donor Liver Transplantation.
      . With increasing experience, transplant surgeons increasingly accept donors with complex liver anatomy.
      • Yaprak O.
      • Dayangac M.
      • Akyildiz M.
      • Demirbas T.
      • Guler N.
      • Bulutcu F.
      • et al.
      Biliary complications after right lobe living donor liver transplantation: a single-centre experience.
      In recent times, all these advances have facilitated more significant numbers of LDLTs.
      The LPE program aims to increase LDLT for a subgroup of prospective recipients who cannot receive donor liver organs from their intended potentially healthy, willing, first-degree relatives due to ABO incompatibility and other factors such as suboptimal hepatic mass or anatomical considerations. In the most extensive series of LPEs from north India, ABOi was the indication for LPE in all 34 (100%) recipients transplanted.
      • Agrawal D.
      • Saigal S.
      • Jadaun S.S.
      • Singh S.A.
      • Agrawal S.
      • Gupta S.
      Paired Exchange Living Donor Liver Transplantation: A Nine-year Experience From North India.
      Jung et al. from South Korea reported that 4 out of 26 LPE cases over nine years (2182 LDLTs) were performed for non-blood group indications and the rest were for ABOi.
      • Jung D.H.
      • Hwang S.
      • Ahn C.S.
      • Kim K.H.
      • Moon D.B.
      • Lee S.G.
      • et al.
      Section 16. Update on experience in paired-exchange donors in living donor liver transplantation for adult patients at ASAN Medical Center.
      Alike any LDLT, the survival benefit of LPE arises from reduced waitlist mortality and hence can be advocated for any prospective liver recipient with an ineligible donor, regardless of disease aetiology, United nations organ sharing (UNOS) status, or Model for end-stage liver disease (MELD) score.

      ABO blood group incompatibility

      ABO incompatibility is the most recognized reason for donor rejection during the initial screening of adult patients for LDLT. In all the prior published reports on LPE, ABOi was the most common reason for conducting LPE.
      Since the early 2000s, numerous interventions have been attempted to reduce the risk of antibody-mediated rejection (AMR) in ABO-incompatible LT (ABOi), of which the introduction of rituximab has revolutionized this field.
      • Ikegami T.
      • Taketomi A.
      • Soejima Y.
      • Yoshizumi T.
      • Uchiyama H.
      • Harada N.
      • et al.
      Rituximab, IVIG, and plasma exchange without graft local infusion treatment: a new protocol in ABO incompatible living donor liver transplantation.
      Strategies to prevent AMR after ABO-i LDLT was established in Japan in 2014 and then expanded to Asia.
      • 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.
      A simplified protocol of desensitization for ABOi with rituximab, along with plasma exchange and the occasional need for IVIG, use of mycophenolate pre-LDLT, and induction with IL-2 receptor antagonists has succeeded in making ABOi adult LDLT safe by avoiding post-ABOi LT AMR.
      • Lee C.F.
      • Cheng C.H.
      • Wang Y.C.
      • Soong R.S.
      • Wu T.H.
      • Chou H.S.
      • et al.
      Adult living donor liver transplantation across ABOIncompatibility.
      • Song G.W.
      • Lee S.G.
      • Hwang S.
      • Kim K.H.
      • Ahn C.S.
      • Moon D.B.
      • et al.
      ABO-Incompatible Adult Living Donor Liver Transplantation Under the Desensitization Protocol With Rituximab.
      • Kim S.H.
      • Lee E.C.
      • Shim J.R.
      • Park S.J.
      A simplified protocol using rituximab and immunoglobulin for ABO-incompatible low-titre living donor liver transplantation.
      Several studies in ABOi LDLT have reported comparable graft and patient survivals without significant differences in bile duct complications, infection, or hepatocellular carcinoma recurrence compared with ABO-compatible LDLT.
      • Kim J.M.
      • Kwon C.H.
      • Joh J.W.
      • Han S.B.
      • Sinn D.H.
      • Choi G.S.
      • et al.
      Case-matched comparison of ABO-incompatible and ABO-compatible living donor liver transplantation.
      ,
      • Yoon Y.I.
      • Song G.W.
      • Lee S.G.
      • Hwang S.
      • Kim K.H.
      • Kim S.H.
      • et al.
      Outcome of ABO-incompatible adult living-donor liver transplantation for patients with hepatocellular carcinoma.
      A systematic review and meta-analysis including 2137 ABOi-LTs and the 8646 ABOc-LTs found no significant difference at 1-year, 3-year, and 5-year in all-cause mortality, death-censored graft survival and complication incidence rate between ABOi-LDLT group and ABOc-LDLT group.
      • Gan K.
      • Li Z.
      • Bao S.
      • Fang Y.
      • Wang T.
      • Huang H.
      • et al.
      Clinical outcomes after ABO-incompatible liver transplantation: A systematic review and meta-analysis.
      Today, ABOi LDLT accounts for the vast majority of LDLT in cases of ABO incompatibility. An ABOi LDLT programme can successfully function in an isolated resource-rich hospital, while a successful LPE program must meet a unique set of logistical and ethical challenges. Hence the drive to promote LPE has not been as vigorous. The merits of LPE include no desensitization, lower infection risk‚, comparable graft outcomes, cost savings‚ the ability to benefit multiple recipients and the potential to utilize non-directed donors. All these factors have probably led to a resurgence of LPEs in the West. Thus, despite being conceptually different, ABOi and paired exchange LDLT have addressed the conundrum of overcoming blood group barriers by developing standardized procedures. Naturally, each has its proponents, but a practical way forward would be to amalgamate the two programmes in a mutually complementary manner.

      Donor allograft size mismatch

      A living liver donor may be incompatible with his intended recipient because of size mismatch. Donor allograft size may be too small or large relative to recipient weight and size or may leave the donor with inadequate hepatic volume reserve. In LDLT, donor safety is a priority. Therefore, a substantial proportion of patients with end-stage liver disease give up the opportunity for LDLT due to concern about donor safety. Of 16 donor/recipient pairs matched through LPE at the Asan Medical Center, two were for a better size match.
      • Jung D.H.
      • Hwang S.
      • Ahn C.S.
      • Kim K.H.
      • Moon D.B.
      • Lee S.G.
      • et al.
      Section 16. Update on experience in paired-exchange donors in living donor liver transplantation for adult patients at ASAN Medical Center.
      Most LDLT centres consider a graft with a GRWR of 0.8 or GV/SLV of 40% as SFSG. When the grafts are smaller, the excess portal flow/pressure transmitted to the graft in the post-perfusion setting results in early graft dysfunction (EAD). The risk of EAD is based on multiple factors such as graft size, donor age, and recipient disease severity
      • Pomposelli J.J.
      • Goodrich N.P.
      • Emond J.C.
      • Humar A.
      • Baker T.B.
      • Grant D.R.
      • et al.
      Patterns of early allograft dysfunction in adult live donor liver transplantation: the A2ALL experience.
      , each of them may influence the decision concerning GRWR and any potential benefit of participation in LPE.
      In LDLT with SFSG, the excessive portal flow can be modulated via various portal inflow modulation (PIM) techniques.
      • Cheng P.
      • Li Z.
      • Fu Z.
      • Jian Q.
      • Deng R.
      • Ma Y.
      Small-for-size syndrome and graft inflow modulation techniques in liver transplantation.
      ,
      • Ikegami T.
      • Onda S.
      • Furukawa K.
      • Haruki K.
      • Shirai Y.
      • Gocho T.
      Small-for-size graft, small-for-size syndrome and inflow modulation in living donor liver transplantation.
      Splenic artery ligation is a widely performed and the least morbid of the PIM techniques, which reduces not only the portal flow but also increases hepatic arterial pressures. Simultaneous splenectomy during LDLT has been well-documented in Japan but not globally due to higher associated morbidity from bleeding, splanchnic vein thrombosis, infections and pancreatic leak.
      • Fujiki M.
      • Hashimoto K.
      • Quintini C.
      • Aucejo F.
      • Kwon C.H.D.
      • Matsushima H.
      • et al.
      Living Donor Liver Transplantation with Augmented Venous Outflow and Splenectomy: A Promised Land for Small Left Lobe Grafts.
      Instead of splenectomy, splenic devascularization has been shown to decompress the portal system with lesser complications. For SFSS after LDLT, splenic artery embolization (SAE) is the treatment of choice. Hemiportocaval shunt (HPCS) is a more commonly performed portosystemic shunt surgery, which reduces portal hyperperfusion without causing portal vein steal syndrome. The pharmacological PIM measures are less validated and include terlipressin, octreotide, somatostatin, prostaglandin E1 and adenosine.
      The various PIM techniques are associated with varying degrees of success and have varying levels of evidence to support their use in preventing SFSS. Hence, there is no consensus on the optimal PIM method to facilitate improved outcomes with SFSG. With this in mind, an LT surgeon should apply these techniques on a case-by-case basis. A recent systematic review of GIM techniques in LDLT with SFSG grafts has shown that GIM is associated with improved outcomes.
      • Rammohan A.
      • Rela M.
      • Kim D.S.
      • Soejima Y.
      • Kasahara M.
      • Ikegami T.
      • et al.
      Does modification of portal pressure and flow enhance recovery of the recipient after living donor liver transplantation? - A systematic review of literature and expert panel recommendations.
      ,
      • Gavriilidis P.
      • Azoulay D.
      Graft Inflow Modulation in Living Donor Liver Transplantation with a Small-for-Size Graft: A Systematic Review and Meta-Analysis.
      To overcome small for size syndrome (SFSG), Lee et al.
      • Lee S.G.
      • Hwang S.
      • Park K.M.
      • Kim K.H.
      • Ahn C.S.
      • Lee Y.J.
      • et al.
      Seventeen adult-to-adult living donor liver transplantations using dual grafts.
      in 2001 advocated using dual liver grafts from two left livers to reduce the donor risk while balancing the risk of a small-for-size syndrome in the recipient. Since then, close to 400 dual-graft (DG) LDLTs have been reported worldwide. Lee et al. reported the most extensive series of 346 patients over 15 years with 1, 5- and 10-year patient survival rates of 89.2%, 85.5% and 80.2%, respectively. However, a statistically significant longer operative time (18.7vs13.9 h), greater need for blood transfusion (18.2vs11.4 units), higher surgical complication rate (53.7vs28.5%) and higher in-hospital mortality rate (7.0%vs4.0%) was noted in dual lobe grafts group
      • Song G.W.
      • Lee S.G.
      • Moon D.B.
      • Ahn C.S.
      • Hwang S.
      • Jung D.H.
      • et al.
      Dual-graft Adult Living Donor Liver Transplantation: An Innovative Surgical Procedure for Live Liver Donor Pool Expansion.
      Similarly, another article reported comparable short-term and long-term outcomes in 43 patients who have received dual graft LDLT.
      • Xu Y.
      • Chen H.
      • Yeh H.
      • Wang H.
      • Leng J.
      • Dong J.
      Living donor liver transplantation using dual grafts: Experience and lessons learned from cases worldwide.
      The major limitation of DG ALDLT is its technical complexity due to the heterotopic implantation and increased rates of surgical complications due to double the number of complex vascular and biliary reconstructions. The heterotopically implanted minor graft can undergo atrophy due to “portal inflow steal” by the larger graft. Also, in DG-LDLT, there is the risk of rejection between two grafts and the graft and recipient. Also, DG- LDLT puts two donors at risk for one recipient. Thus dual graft LDLT is a technically complex procedure that can be feasible only at a high volume LDLT centre.
      It will be interesting to study what constitutes a better graft for the recipient; a low GRWR-graft with portal inflow modulation, vs Dual graft LDLT, vs a graft from LPE, vs an ABOi incompatible graft.

      Variant liver anatomy

      Hepatic arterial and biliary anatomy demonstrates a large number of variations. Therefore, donors with multiple arteries or multiple ducts to 1 hepatic lobe may not be good candidates as multiple arterial, and biliary reconstructions in the recipient entail more significant recipient morbidity and rarely mortality.
      • Watson C.J.
      • Harper S.J.
      Anatomical variation and its management in transplantation.
      In such cases, the contralateral lobe could be considered to avoid complex reconstructions. However, the contralateral lobe can be size inappropriate for the intended recipient. In such circumstances, LPE offers better donor and recipient matching and possibly minimizes post-transplant complications. Additionally, compatible pairs who seek something other than a donor of the correct blood type can be included in the paired donation.

      Potential types of paired liver exchanges

      Rapaport was envisaged in 1986 for kidney paired exchange (KPE) transplantation. Began initially as simple exchanges, swaps in kidney transplantations have grown into more complicated chains. Similarly, LPEs are being conducted as single-centre simple two-way or three-way exchanges but have tremendous potential to grow into more complicated chains over days and multiple centres. The potential types of Liver paired exchanges have been diagrammatically illustrated in Fig. 1.
      • 1.
        Two-way directed swap: Simple swaps between two ABOi pairs where two recipients exchange donors circumventing the blood group barrier in two pairs (Fig. 1A.).
      • 2.
        Three-way swap: Clinical situations where one donor’s right lobe (RL) is too small for a large-sized recipient and another donor with a small left lobe (LL) or RL is also ABOi, are not uncommon. In such situations, three ways swaps are done to overcome two difficult obstacles, graft size disparity and ABO incompatibility. (Fig. 1B.).
      • 3.
        Non-directed extended living donor chains: Non-directed altruistic living liver donors can initiate the non-directed extended altruistic donor (NEAD) chains without the reciprocity requirement of the LPE match (Fig. 1C.).
      Figure thumbnail gr1
      Figure. 1Shows indications and types of Liver paired exchanges (LPE) (A.). Demonstrates a two-way exchange in which D1-R1 and D2-R2 pairs are ABOi pairs, and LPE makes them ABO identical. Second, a shows that the D2-R2 pair is ABOi, while the D1-R1 pair has low GRWR. Two-way directed exchanges, in this case, circumvents both the barriers to donation (B.). Demonstrates a three-way swap in which D1-R1 is ABOc but has low GRWR; the D2-R2 pair is ABOi, but the graft size is large for the pediatric recipient, and the D3-R3 pair is ABOi (C.). Demonstrates that ‘non-directed altruistic living liver donor’ or ‘domino liver donor’ initiates the non-directed extended altruistic donor (NEAD) chains without the reciprocity requirement of the LPE match. The donor of the first incompatible pair can donate to the recipient of the next pair, and so on.

      Simultaneous vs Sequential LPE - Timing of the exchange

      Simultaneous LPE

      The simplest form of exchange would be single-centre two-way directed simultaneous swaps. In the few studies published, all the donor and recipient operations were performed in four operating rooms simultaneously on the same day. The logistics involved in performing four simultaneous operations of LPE at a single institution are extensive. For a single LDLT operation, it is estimated that more than 18 skilled team members, including two sets of teams, each consisting of anaesthetists, transplant surgeons, nurses, and technicians, may be needed, and in LPE, this number is doubled. In addition, the blood bank must be equipped with requirements for significant surges. These constraints limit the LPE to a few high-volume centres.
      Further, any unanticipated difficulty due to operative anatomical variations may impact both recipients’ outcomes. So the centres doing LPE must have a large experienced team, or else the senior surgeons will often have to rotate from one operating room to another to ensure the smooth conduct of all four operations. The most extensive swap series published from India
      • Agrawal D.
      • Saigal S.
      • Jadaun S.S.
      • Singh S.A.
      • Agrawal S.
      • Gupta S.
      Paired Exchange Living Donor Liver Transplantation: A Nine-year Experience From North India.
      determined the outcome in the two simultaneous donor-recipient pairs of 34 swaps. The authors found that Cold ischemia time (CIT 109.7vs112.6 minutes) and warm ischemia time (WIT 32.7vs36.1 minutes) in both pairs were comparable, suggesting that neither pair had an inferior operation. The donor morbidity was 8.8% (n=3) and donor survival was 100%. The one-year recipient’s survival was 85.3% (n = 29). The excellent donor and recipient outcomes were not influenced by the logistical and technical challenges encountered in simultaneously performing two LDLT operations. Single-centre simultaneous swap has another advantage of decreasing the chances of an incomplete exchange due to the donor reneging post-operatively.

      Sequential or staged LPE

      Some authors have proposed that LPE be done sequentially on the same day or staged on different days. This approach would be more straightforward as most centres do not have large teams, and logistic issues constitute a significant limitation with simultaneous LPE. However, LDLT being a long-duration surgery over 16 hours, it might not be logistically possible to do it on the same day. The literature on staged LPE for LDLT consists of a single case report
      • Braun H.J.
      • Torres A.M.
      • Louie F.
      • Weinberg S.D.
      • Kang S.M.
      • Ascher N.L.
      • et al.
      Expanding living donor liver transplantation: Report of first US living donor liver transplant chain.
      in which the operations were performed on two sequential days and relied on the use and compliance of a bridge donor.
      The contextualization of sequential LPE is mainly based upon extrapolation from the KPE experience. A review of 344 KPE chains
      • Cowan N.
      • Gritsch H.A.
      • Nassiri N.
      • Sinacore J.
      • Veale J.
      Broken Chains and Reneging: A Review of 1748 Kidney Paired Donation Transplants.
      between 2008 and 2016 revealed that almost 5.6% of bridge donors broke the chain due to a medical issue that prohibited them from completing donations. Thus in sequential LPE, there is a chance of an incomplete exchange, as bridge donors might opt out of living donation at the last moment and break the chain without legal recourse.

      Multicentric LPE

      Multi-centric LPE can be another potential option to overcome the logistical issue in simultaneous single-centre LPE and the risk of donor revocation in sequential LPE. In the initial phase, LPE could start between 2 experienced LDLT centres within geographic proximity and whose surgical teams have an established relationship. In a recent report by Yu et al.
      • Yu Y.D.
      • Hwang R.
      • Halazun K.J.
      • Griesemer A.
      • Kato T.
      • Emond J.
      • et al.
      Whose Liver Is It Anyway? Two Centers Participating in One Living Donor Transplantation.
      , a successful LDLT was performed where the donor hepatectomy was performed at one transplant centre, and the partial liver graft was shipped to the recipient transplant centre. The usual principles of LDLT were followed, and the ischemia time was acceptable. This finding provides a stepping stone for developing an LPE program involving different institutions within geographic proximity.
      For a multicentric LPE to be successful, establishing an understanding between donor and recipient centres is crucial. The other centre must thoroughly review the donor workup to confirm that the donor is adequate for their recipient. The timing of the donor hepatectomy and recipient operations should be matched, and the two teams should communicate intraoperatively. Unexpected anatomy, steatotic graft, metastatic hepatocellular carcinoma (HCC), or hemodynamic instability may arise during the intraoperative course. In such times, mutual decisions should be taken, as any irreversible steps in a donor or recipient surgery can impact the successful completion of the swap. Another option would be for one surgeon from the recipient’s team can participate in the donor surgery and transport the donor allograft back to the recipient hospital. The liver grafts tolerate less cold ischemia than kidney grafts. Hence, an expeditious transport of Liver grafts must be ensured between the geographically distant centres. Another consideration can be moving the donor (or recipient) rather than the organ. However, patients might be reluctant to get reassigned to an unfamiliar surgical team. Hence moving the organ rather than the donor (or recipient) would engender a wider acceptance.

      Role of Non-directed altruistic living liver donors in LPE

      In LPE, appropriately matched altruistic donors can trigger a successful LPE chain. A non-directed living liver donor does not have a genetic or emotional relationship with the potential recipient but effectively donates a portion of their Liver to the pool of patients on the transplant waiting list. Transplant centres can often select willing donors based on their commitment and unwavering interest. A domino LPE chain initiated by an altruistic non-directed donor may be conducted simultaneously on the same day or over a few days
      • Rees M.A.
      • Kopke J.E.
      • Pelletier R.P.
      • Segev D.L.
      • Rutter M.E.
      • Fabrega A.J.
      • et al.
      A nonsimultaneous, extended, altruistic-donor chain.
      , also called ‘non-simultaneous extended altruistic donor (NEAD) chain.’ In NEAD chains, additional pairs are added to the chain over days to months, thus enabling multiple transplantations without the burden of performing these procedures simultaneously. Thus non-directed altruistic donations have a tremendous potential to expand the donor pool in LPE.
      However, the rate of altruistic non-directed donation in LDLT is likely much lower in most countries. In a report from Jung et al.,
      • Jung D.H.
      • Hwang S.
      • Ahn C.S.
      • Kim K.H.
      • Moon D.B.
      • Lee S.G.
      • et al.
      Section 16. Update on experience in paired-exchange donors in living donor liver transplantation for adult patients at ASAN Medical Center.
      one donor of 26 LPE cases over nine years was an unrelated non-directed donor. In its early LPE experience, the centre has seen the advantages of 1 non-directed donor facilitating a domino LPE. Recently, in the report of the first LPE in North America, a non-directed anonymous living liver donor initiated the LPE chain, alleviating an ABO incompatibility in the other donor-recipient pair.
      • Patel M.S.
      • Mohamed Z.
      • Ghanekar A.
      • Sapisochin G.
      • McGilvray I.
      • Selzner N.
      • et al.
      Living donor liver paired exchange: A North American first.
      A recent study examined the safety and feasibility of anonymous living liver donation, where 50 anonymous adult LDLTs were performed over 12 years with excellent outcomes.
      • Goldaracena N.
      • Jung J.
      • Aravinthan A.D.
      • Abbey S.E.
      • Krause S.
      • Pritlove C.
      • et al.
      Donor outcomes in anonymous live liver donation.
      Between 1998 and 2018, 105 non-directed living donor liver transplants were reported in the United States, with the annual number increasing annually.
      • Raza M.H.
      • Aziz H.
      • Kaur N.
      • Lo M.
      • Sher L.
      • Genyk Y.
      • et al.
      Global experience and perspective on anonymous non-directed live donation in living donor liver transplantation.
      According to to publicly available OPTN data, in liver donations, non-directed donors made up 3.2% of all living donor transplants in 2017 and increased to 11.8% by 2020, although this has mainly been concentrated at particular centres
      • Kim W.R.
      • Lake J.R.
      • Smith J.M.
      • Schladt D.P.
      • Skeans M.A.
      • Noreen S.M.
      • et al.
      OPTN/SRTR 2017 Annual Data Report: Liver.
      . If this trend continues, adding non-directed living liver donors (ND-LLD) can reasonably increase total LDLT numbers. Measures to increase the pool of Non-directed living liver donors (ND-LLD) are outlined in Table 2.
      Table 2Measures to increase the pool of Non-directed living liver donors (ND-LLD).
      • 1.
        Financial neutrality
        • a.
          Alleviating the financial burden associated with transportation, accommodation, parking, donor assessment, surgery, and long-term care by modifying reimbursement policies
        • b.
          Employee-friendly workplace regulations - reimbursement for lost wages encountered from the donation process
        • c.
          Ensured access for NDDs to health and life insurance
      • 2.
        Appropriate system (regulatory and legal) facilitators
        • a.
          National regulations should endorse the use of anonymous LD
        • b.
          Expanding the number of centres with non-directed living liver donor (ND-LLD) programmes.
        • c.
          Optimize existing ND-LLD programs and standards and increase collaboration amongst organ-sharing organizations, practitioners and societies
        • d.
          The transplant community should conduct a consensus conference on this topic and come up with consensus meetings guidelines regarding the components of the medical and psychosocial donor evaluation, recipient selection, and ethical best practice
        • e.
          The ND-LLD Registry should be established, and transplant centres must report their experience to a registry
        • f.
          Transplant centres should publish the long-term follow-up data to provide visibility to the program and its results, both to citizens and professionals
        • g.
          Future prospective studies should compare the outcome of directed vs non-directed donors
      • 3.
        Address the ethical concerns surrounding ND-LLD
        • a.
          Anonymity vs conditional anonymity and Donor-recipient disclosure
        • b.
          Donor coercion, organ trafficking, and Repetitive donor disorder
        • c.
          A utilization-centric approach facilitating higher utility of ND-LLD within the bounds of non-futility
        • d.
          Development of a donor-centric, expertise-based multidisciplinary approach to ensure sound ethical decision-making
        • e.
          Transplant programs that refuse to consider ND-LLD should refer these patients to another centre which agrees to consider them
        • f.
          Expansion of laparoscopic and robotic techniques in ND-LLD decreases the harm associated with RL donation.
      • 4.
        Public awareness
        • a.
          Media solicitations and Social media testimonials by transplant institutions or prospective recipients through newsletters, websites, and social media platforms within an ethical context
        • b.
          Education through organ donation and transplantation awareness campaigns
        • c.
          Scrutinizing the perception of general populations across various socio-cultural conditions to assess the potential for anonymous LDLT objectively
      • 5.
        Increasing the utility of an NDD through LPE
        • a.
          Directed donors can be evaluated as an NDD for an alternative recipient if they are incompatible with their intended recipient or if their intended recipient has found an alternative match

      Stumbling blocks in the promotion of LPE

      The challenges involved in LPE or swap LDLT are too distinct compared to KPE, whether technical, logistical, or ethical.
      • Mishra A.
      • Lo A.
      • Lee G.S.
      • Samstein B.
      • Yoo P.S.
      • Levine M.H.
      • et al.
      Liver paired exchange: Can the Liver emulate the kidney?.
      Participants in LPE are exposed to the usual hazard associated with an LDLT and the additional risks that can arise directly from an exchange. Hence pairs who wish to pursue this route to donation and transplantation should receive specific education about these additional risks. This section discusses the challenges to performing LPE.

      Ethical challenges

      The goal of LPE is to ethically increase the donor liver pool available for transplantation. However, there are some unique ethical concerns associated with it.
      Coercion: Coercion is one of the most significant ethical concerns while evaluating living donors. LPE may inadvertently expose ambivalent donors because a reluctant donor may no longer be able to make a reasonable and acceptable excuse for opting out. Therefore, with the introduction of LPE, the transplant centres will have to evaluate the donation process more robustly.
      Donor reigning: If LPE aspires to maintain long chains to maximize the number of matches and transplants, the issue of donor revocation will have to be addressed. One can only imagine a situation where the donor backs out of exchange after his intended recipient has received a transplant, leaving the recipient of the opposite pair un-transplanted. One can also imagine a policy in which recipients whose donor drops out are prioritized for transplant with a deceased donor through UNOS, although no such policy exists to date. Thus, rectifying an incomplete swap is a potentially complicated subject requiring future consideration.
      Equity and Double equipoise: The prerequisites for participation in LPE include the anticipation of comparably good outcomes in both pairs after donor exchange. Double equipoise is the balance between the interplay of need, donor safety, and recipient’s survival benefit from LDLT.
      • Cronin 2nd, D.C.
      • Millis J.M.
      • Siegler M.
      Transplantation of liver grafts from living donors into adults--too much, too soon.
      In LPE, to balance relative donor risk and optimize recipient’s outcomes, the swaps should be equal concerning GRWR and per cent of the future liver remnant (FLR), graft quality, anatomical difficulty, and the recipient’s MELD score. In LPE, both donor operations should be of similar magnitude and not pose a higher risk to one of the donors. The GRWR of less than 0.8 entails a higher risk of SFSS. Recipients with high MELD scores can have a favourable outcome with timely LDLT
      • Sundaram V.
      • Jalan R.
      • Wu T.
      • Volk M.L.
      • Asrani S.K.
      • Klein A.S.
      • et al.
      Factors Associated with Survival of Patients With Severe Acute-On-Chronic Liver Failure Before and After Liver Transplantation.
      , and with this background, they can participate in LPE, provided they have sufficient hepatic reserve and time for another matching pair to become available. In a recent study, three of 68 LPE participants had HCC within UCSF criteria.
      • Agrawal D.
      • Saigal S.
      • Jadaun S.S.
      • Singh S.A.
      • Agrawal S.
      • Gupta S.
      Paired Exchange Living Donor Liver Transplantation: A Nine-year Experience From North India.
      Transplants are often considered for HCC outside the UCSF criteria in the LDLT setting; however, this might not be suitable in LPE to provide similar outcomes in both pairs.
      Hence in LPE, a multidisciplinary forum comprising transplant hepatologists, surgeons, bioethicists, and psychiatrists should discuss the suitability of each donor and recipient pair and the equity of the exchange. LDLT case volume, clinical experience, and institutional outcomes are significant factors in this decision process. Each pair should be informed about the structure of the exchange and alternative options like DDLT and ABOi transplant. Although a poor outcome is possible in any LDLT, if one of the recipients is anticipated to have higher mortality for any reason, this should be conveyed to all four parties beforehand so none of them feels the guilt of a poor outcome.
      Allocation principles: In LPE, when a non-directed liver donor or a deceased donor initiates the chain, there is the potential to advantage one of the recipients unfairly. There are no data on the best practice for allocating such liver donor organs. Hence an essential consideration in LPE initiated by such a donor is selecting the final recipient in the chain. Priority should be given to recipients who do not have a compatible match but are likely to have a good outcome. One might consider a waiting list candidate with high MELD scores, cases where disease severity is under-represented in the MELD-based allocation system, or a pediatric waitlist candidate. A multidisciplinary committee should make the selection of such recipients.

      Legislative challenges

      LPE is transplantation between unrelated people and is therefore liable for exploitation. However, the Transplant Act in India has some built-in safety features like it allows only blood relatives to donate and bars exchanges between national and foreigners. For swap operations, permission for transplant is given to only one centre. Hence multicentric LPE would require legislative changes and clearance from the government agency. With the involvement of non-directed donors in LPE, the ethical tensions and insecurities surrounding historical organ trafficking and coercive donation by vulnerable populations should be revisited, as non-directed donors do not necessarily have a clear incentive to donate. Living donation can also impact disability and life insurance policies, so donors should talk to their insurers before donating. As an incentive to donate, we propose a policy change where lifelong health insurance is provided to all organ donors to cover all health care costs that may or may not be related to the donation.
      When multiple institutions are involved in LPE, the financial management of these exchanges becomes complex and can potentially impede the implementation of LPE.

      Future Considerations

      The feasibility and benefit of LPE in providing excellent recipient outcomes and robust donor safety have been proven in uncomplicated swaps. To date, most centres report doing LPE as simultaneous single centre 2-way exchanges. The disadvantage of the single-centre approach is that incompatible pairs will have only limited exposure to potential matches. In the future, LPE can be conducted between a coalition of centres within geographic proximity where many incompatible pairs can participate in an exchange. A compatible pair can also be enrolled in an LPE program if there is some benefit to the recipient, primarily better anatomy or size match or an organ from a younger donor. The participation of compatible pairs will increase the donor organ pool and the match frequency for an incompatible pair.
      The necessary infrastructure to support a robust LPE program would include a central registry, strengthening matching algorithms, monitoring outcomes, and developing logistical support. Hence we propose to create an LPE consortium to manage participating pairs and centres. The participating centres will need to upload all data into a centralized computer system the consortia runs, providing secure online access to harmonized data to all centres participating in an exchange. In this respect, we suggest that the description of the partial liver graft must be standardized. All this will certainly, ensure better donor-recipient matching. In future, prospective multicenter registry data regarding the safety and outcomes of LPE will shed excellent light on this modality of transplant.
      One of the most challenging issues to be resolved would be establishing a matching algorithm to determine transplant priority. The factors that should be considered are MELD score, pediatric recipients, recipients more challenging to match based on blood type or size, or those with complications of liver disease not well measured by MELD. As new pairs are added, the matching algorithm is rerun to yield the best match for their intended recipient. Thus, a robust pool of donor and recipient pairs through geographic expansion and mathematical optimization will increase the likelihood of matching hard-to-match pairs and facilitate a more significant number of transplants.

      Conclusion

      LPE is a fair and legal way to increase the liver organ donor pool and seems feasible at centres with significant LDLT experience to offer LDLT in cases of ABO incompatibility and inadequate graft volumes. Favourable outcomes in LPE require balancing donor risks with excellent survival in both recipients and simultaneous operations to avoid the risk of revocation. Simultaneous LPE allows more control over logistical issues and better coordination between donor and recipient teams. The participation of multiple institutions in paired exchange will increase the chance of receiving a better-matched organ for the recipient on the waiting list. Incorporating altruistic donors to initiate the chains and the usage of bridge donors will need to be explored. To date, pending the multicenter registry data regarding the safety and outcomes of LPE, an LPE network could be the platform to enhance collaboration amongst the countries so that strategic planning for the future of LPE can be achieved holistically. Continuous refinement and progress in alternatives like LPE and ABOi programs should be pursued for liver recipients with incompatible donors. Looking at current trends, LPE will probably be an essential component of any LDLT program armamentarium in the coming future.

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