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Volume: 17 Issue: 1 February 2019

FULL TEXT

REVIEW
Hand Transplantation: Current Status and Immunologic Obstacles

Hand transplantation is the most common form of modern composite tissue allotransplantation, with 89 cases reported worldwide since 1998. The procedure is a treatment option for complex injuries that leave patients with structural, functional, and aesthetic deficits that cannot be addressed by other means. Successful application of this technology requires a multidisciplinary approach, incorporating not only skilled hand surgeons, transplant surgeons, and transplant immunologists, but also hand therapists, psychiatrists, medical specialists, anesthesiologists, and so on. Its long-term results depend on proper patient selection, a technically successful operation, postoperative rehabilitation, and an immunotherapy protocol that prevents rejection. Recent advances in transplant immunology are shifting the focus from immunosuppression to immunoregulation. Despite the enormous antigen load associated with composite tissue allografts, hand transplant has become a clinical reality, with immunosuppression comparable to that of solid-organ transplants. Our understanding of hand transplantation is still evolving, and ongoing research is needed to improve functional outcomes and to decrease the morbidity associated with long-term immunosup­pression. This review discusses the current protocols for upper extremity donation, transplant receipt, surgical techniques, postoperative rehabilitation and immuno­suppression, nerve regeneration, functional outcomes, ethical issues, and financial considerations.


Key words : Allograft, Composite tissue allotransplantation, Immunosuppression, Rehabilitation

Introduction

Hand transplantation is a form of composite tissue allotransplantation (CTA), which is defined as the transfer of vascularized or nonvascularized hetero­geneous tissues (skin, fat, muscle, nerve, bone, etc.) with different antigenicities from one person to another. It is a treatment option for complex injuries that leave patients with structural, functional, and aesthetic deficits that cannot be addressed by other means. Composite tissue allotransplantation repre­sents the highest state of the reconstructive ladder because of the complex technical and immunologic aspects associated with it.1 As of 2018, there have been approximately 100 hands transplanted on more than 60 patients around the world.

The first hand transplant was performed in 1964 in Ecuador by Dr. Gilbert.2 However, the transplant was amputated 3 weeks later due to acute rejection. A 30-year period of stagnation followed, during which developments in immunosuppressive drug therapy for solid-organ transplant occurred in the 1980s and 1990s.3 Surgeons in Lyon, France, performed the world’s second unilateral hand transplant on September 23, 1998, by an international team of surgeons.4 The patient was a 48-year-old male who had sustained a traumatic circular saw amputation at the mid-forearm level. Since then, hand transplant programs have been launched in the United States, Belgium, Poland, Turkey, China, Australia, the United Kingdom, Iran, Mexico, and Taiwan.5-14 Representative cases of hand transplants are listed in Table 1. Currently, there are 19 hand transplant centers registered with the International Registry of the Hand and Composite Tissue Transplantation (IRHCTT) society.

The surgical procedures involved in hand trans­plants are time intensive and technically demanding but less so compared with the efforts needed to manage the immune responses to the allograft and the postoperative functional recovery. The development of new, potent, and specific immuno­suppressive drugs to study CTA, as well as the use of animal models, has set the stage for bench-to-bedside translation. The current immunosuppressive pro­tocols applied to hand transplant have been extrapolated from regimens used in solid-organ transplant.15 Most hand transplant patients receive polyclonal or monoclonal antibody preparations for induction therapy followed by triple-drug com­binations for maintenance therapy, which include tacrolimus, mycophenolate mofetil, and steroids, although the doses and trough levels of each drug may differ between centers.

The desire of reconstructive surgeons to replace "like with like" is best approximated with CTA. Until doctors are capable of regenerating composite autografts from a patient’s own stem cells, hand transplant offers the best opportunity for recon­structing absent, damaged, or nonfunctional portions of the body. Once the upper extremity CTA has shown technical success, the patient begins an intensive and lengthy recovery with postoperative therapy. The appropriate surgical and ethical indications for this operation continue to evolve as advances in immunotherapy protocols catch up to current surgical capabilities. This review summarizes the current protocols for patient assessment, ethical issues, extremity donation, transplant receipt, surgical process, postoperative rehabilitation and immunosuppression, and functional outcomes.

Ethical considerations
The ethical debates surrounding hand transplant have continued for over a decade. Because of the need for lifelong immunosuppression and the risk of graft loss, there has been significant discussion regarding the ethics of the procedure. Today, most, if not all, solid-organ transplants are considered life-saving enterprises, which are well worth the risk of chronic immunosuppression or even potential acute graft loss. In terms of long-term risks versus benefits, most hand surgeons will agree that transplant for bilateral amputees is a worthwhile endeavor that may justify the risks of immunosuppression. Therefore, the risk of the procedure has to be measured against the quality-of-life benefits.16,17 The arguments against transplant based on immuno­suppressive risk, however, could be challenged by the development of immunoregulatory protocols with decreased toxicity from systemic immunosuppression. These advances require the development of laboratory models for limb and complex multipart transplantations that can demonstrate the efficacy of novel immunotherapies.18

Patient selection and preoperative planning
The current challenges of hand transplant relate to the selection of proper recipients with regard to anatomic, medical, and psychosocial factors. The surgical indications in hand transplant are still being debated and defined. Given that hand transplant is an elective procedure, proper patient selection and preoperative education have been emphasized to maximize clinical success.19 The overall success of CTA relies on many factors. One could argue that it is the technical expertise of the team and effective postoperative care of the recipient that plays a significant role in transplant outcomes. However, it is the proper evaluation, selection, and management of donors and potential recipients that is probably more important.15 Although patient selection for CTA is critical, parameters for inclusion and exclusion of donors and recipients have not yet been conclusively defined or standardized. Whereas absolute contra­indications are more easily defined (Table 2), there are no set indications for hand transplants at this time.17,20

The mandatory requirements for limb donation are family consent, age between 18 and 65 years, limb matched for size with recipient, same blood type as recipient, negative cross-match, and, importantly, accurate matching for sex and skin tone. Recipient selection criteria include age, no serious coexisting medical (eg, coronary artery disease, diabetes) or psychosocial problems (including alcoholism, drug abuse), negative history for malignancy or human immunodeficiency virus infection, negative cross-match with donor, and negative pregnancy test in female recipients.21 The patient’s compliance is necessary for both long-term immunotherapy monitoring and long-term hand therapy. Without the patient’s cooperation, graft function and survival may be severely compromised.22

Distal amputations are preferred, as there is less distance needed for nerve regeneration to target muscles. If a patient meets the inclusion criteria, additional information (sex, handedness, type and level of injury, date of injury, complete medical and surgical history, photos of limb, and rehabilitation and prosthesis history) is requested before the face-to-face visit with the transplant team. Once this visit has been completed and all parties have expressed interest in pursuing a possible transplant, an institutional review board-approved evaluation begins, after which the transplant committee makes a final decision regarding patient eligibility for the transplant list. Hand transplant is an experimental procedure, supported by grants and individual institutions, that uses large amounts of resources in terms of upfront hospital and physician costs. Therefore, careful consideration must be given to the financial burden imposed, and financial support must be assessed individually.23

Transplant surgical procedures
The surgical approach to a hand transplant is based on modified replantation techniques. The added benefit of having an excess of available tissue without a zone of traumatic injury from the donor is a great advantage over traditional replantation. The operation is completed under tourniquet, using general anesthesia with regional block administration for vasodilatation and pain control. Two surgical teams, each consisting of 1 main transplant surgeon and 1 assistant transplant surgeon, are used. One team prepares the recipient site, while the other team prepares the donor limb. Ideally, the recipient and donor teams are in the same room for better coordination. The donor team prepares the donor limb on the back table, tailoring the forearm to the needs of the recipient.24

Retrieval of life-saving organs should take priority; however, if possible, the limb should be retrieved before the compromising peripheral perfusion. In 50% of transplants, limbs were retrieved before solid organs, whereas the remaining 50% were procured after extraction of solid organs. Limb dissection is started before cross-clamping of the aorta and before organ retrieval. Fish-mouth skin incisions are made approximately 3 cm above the elbow, and the vessels are identified and ligated. The volar incision is extended to allow for release of the carpal tunnel. Subcutaneous dissection from proximal to distal is completed on iced sponges to minimize the warm ischemia time. All structures are left longer than the anticipated need. Each structure is individually tagged with a piece of Esmarch bandage labeled
with indelible ink and secured using 2-0 silk. The donor radius and ulna are provisionally plated. A brachial artery cannula should be placed, and the composite graft should be immediately perfused with University of Wisconsin perfusion solution. The remainder of the limb is then transected and removed from the donor, wrapped in moist gauze, placed in a sterile triple-organ transplant transport bag, and then bathed in an ice water solution at 4°C to 6°C for transport.

During transport, the preservation solution-infused graft should be continuously perfused through the brachial artery cannula for its entire period of ischemia. Upon completion of retrieval, the donor site should be sutured, and a cosmetic prosthetic limb should be applied if requested by the donor’s family.24,25

Recipient stump preparation can begin once the donor limb is procured and the logistics of travel are settled. Tissue requirements from the donor should have been identified based on preoperative as­sessment of the recipient, and the recipient team must have clearly identified the amount of nerves, arteries, and veins required from the donor for transplant. Mid-lateral incisions are made, and subcutaneous dissection is performed, with care to preserve the superficial veins. Each structure is also tagged using a piece of Esmarch bandage labeled with indelible ink and secured using 2-0 silk. After all structures have been prepared and labeled, osteosynthesis is performed, for which the 2 surgical teams are consolidated into one and the standard surgical sequence of replantation commences.

Tendon repairs can be completed by the surgeon’s method of choice. A Pulvertaft weave is used by many because it provides a strong repair that is amenable to early motion. For both extensors and flexors, proximal muscle repairs are usually limited to the epimysium and perimysium. The repair sequence of the different tissues varies considerably. When possible, all tendon and nerve repairs are performed in a bloodless field before arterial and venous reconstruction. After completion of bone fixation and arterial anastomosis, venous anas­tomoses and reperfusion follow in most cases. The most technically challenging aspect of the procedure is usually the reestablishment of venous outflow through multiple venous microanastomoses. Median and ulnar nerves are always repaired, whereas
the radial nerve is reconstructed in selected cases. The wound is closed with skin flaps of the donor and recipient interdigitating to prevent creation of a circumferential scar contracture. The patient is then transported to the transplant or surgical intensive care unit where close graft monitoring is performed.26,27

Immune monitoring
Recent advances in transplant immunology are driving a paradigm shift, from one of immuno­suppression to one of immunoregulation. Transplant rejection, which can be classified as acute or chronic rejection, occurs when a recipient’s immune system attacks and attempts to destroy transplanted tissue. The difficulty with preventing rejection in CTA, especially in a complex graft such as the upper extremity, is the presence of multiple tissues with different antigenicities. Relative antigenicities of tissues are skin > muscle > bone > cartilage > nerve, and so on.20 Because hand transplants are visible to the patient and surgeon, whereas solid organs are not, acute rejections can be visually detected immediately, and topical agents can focus added immunosuppressive efforts locally to the effected tissue without added systemic effects.

Acute rejection is focused in the skin, which is the initial site of rejection. It is usually a cell-mediated response (predominantly lymphocytic) but may be accompanied by antibody-mediated rejection. Characterization of acute rejection is based on the Banff 2007 classification system, which has been developed for scoring, grading, and reporting acute rejections in CTA.28 Cellular rejection of hand transplants is focused in the skin, which is the most antigenic tissue, owing to an increased concentration of local immune cells and tissue-specific antigens, and is thus the site of initial rejection and has the most cellular infiltrates of all the tissues in established rejections. Skin is currently considered the sentinel tissue and the target of acute rejection, which is usually manifested as a recognizable local or diffuse erythematous maculopapular rash, edema, vesiculation, desquamation, and/or ulceration. Thus, skin biopsy is the criterion standard for diagnosis of an acute rejection.20 However, atypical presentations may also occur, usually on palm or nail (Figure 1).29 These differences provide advantages for monitoring and treatment of acute rejections of CTA over solid-organ transplants.30 Important clinical characteristics of an acute rejection include edema, erythema, eschar, and necrosis. The incidence of having 1 episode of acute rejection is 85%, and 56% of recipients experience multiple episodes of rejection. This is significantly higher than the rates seen for solid-organ transplants (10% for kidney transplants in the first year) and is thought to be secondary to ease of surveillance.31,32

Chronic rejection is the long-term loss of graft function due to damage from a persistent immu­nologic response to the graft. The factors cont­ributing to chronic rejection are thought to be similar to those for solid-organ transplants. Immunologic factors include the timing of acute rejection, severe or repetitive humoral acute rejection, greater human leukocyte antigen mismatch, higher recipient panel reactive antibodies, cytomegalovirus-positive donor to cytomegalovirus-negative recipient, steroid-resistant acute rejection, and C4d.33 Nonimmunologic factors include older donor, unstable donor, donor athe­rosclerosis, prolonged cold ischemia, recipient comorbidities (hypertension, diabetes, obesity, high cholesterol), and recipient immunosuppressant noncompliance. Hand transplants are currently monitored for chronic rejection with clinical and functional examinations, skin biopsies, donor-specific antibody screening, and standard vascular imaging.20 Although cellular rejection is well characterized, the relevance of antibody-mediated rejection and C4d complement deposition is not well defined.34 Graft-skin biopsies are routinely per­formed whenever clinically indicated and are examined for evidence of chronic rejection, including intimal hyperplasia, subintimal foamy histiocytes in the vessels, and tissue fibrosis. Immunohistochemistry (staining for CD3, CD4, CD8, CD20, and CD68) is carried out for quantification and characterization of a potential cellular infiltrate.

Immunotherapy and chimerism
Immunosuppressant medications modulate various aspects of the immune response. Most hand trans­plants received worldwide have been successfully maintained using traditional triple-drug immuno­suppressive treatment after an antibody-based lymphocyte-depleting induction therapy as developed for solid-organ transplant procedures.15 The most commonly used treatments include polyclonal or monoclonal antibodies, tacrolimus, mycophenolate mofetil, and steroids, which must be taken by patients multiple times per day indefinitely. The widely used tacrolimus enhances nerve regeneration but causes nephrotoxicity, diabetes, hypertension, and posttransplant lymphoproliferative disorder. Sirolimus (an inhibitor of the mechanistic target of rapamycin) can be used instead of tacrolimus to limit renal toxicity, improve glycemic control, and lessen neurotoxicity. Mycophenolate mofetil is an anti­metabolite that prevents synthesis of nucleotides needed for lymphocyte proliferation. It causes bone marrow suppression and gastrointestinal side effects. Steroids have varied uses but are being replaced with induction (lympho-depleting) agents because of the cardiovascular morbidity and infection risk associated with long-term steroid use. Table 3 shows dosages and adverse effects of immunotherapy drugs.14,20,35-37

Immunologic challenges continue to be addressed as immunosuppressive regimens are sought that cause less morbidity but are equally or more effective with regard to prevention of rejection. The post­transplant goal is to create a chimeric immune system. Chimerism involves the coexistence of donor and recipient immune cells, thereby inducing tolerance and limiting rejection. There needs to be the existence of approximately 1% of donor immune precursor cells in the recipient to induce tolerance.38,39 Chimerism may be promoted in hand transplant patients by giving the recipient donor bone marrow or via the production of immune precursor cells in vascularized donor bone marrow. As our under-standing of the immune system, mechanisms of graft rejection, and immunosuppression have improved, strategies to induce donor-specific immune tolerance have evolved. The goal of achieving tolerance offers the possibility of a greatly reduced need for long-term immunosuppressive drugs and even the possibility of eliminating such need.40

Functional outcomes
In general, functional outcomes after hand transplant have been good in reported series. All viable hands presented normal skin color and texture and normal hair and nail growth. Arterial blood supply and venous outflow have been satisfactory in all patients, who were also reported to have sufficient extrinsic motor function to perform grip and pinch activities. On average, patients showed the ability to perform a number of daily manual activities, including eating, driving, grasping objects, riding a bicycle or a motorcycle, shaving, using the telephone, and writing (Figure 2). Notably, bilateral hand transplant patients showed symmetric use of their hands. Improved manual skills have allowed them not only to resume their previous jobs but also, in some cases, to find more suitable employment.41 Protective sensation recovery like the ability to detect pain, thermal stimuli, and gross tactile sensation have occurred in all grafted hands. Nerve regeneration has allowed a certain degree of discriminative sensation, although this was not to the same degree for all parts of the graft. Some patients have shown continued improvement in motility, even after several years. Functional magnetic resonance imaging have shown that sensorimotor activation of the brain cortex progressively regained the classic hand area within 6 months postoperatively.42

Complications

Hand transplant has been complicated by both early and late problems. Early complications have been as extreme as the loss of limb. Early common surgical complications include vessel thrombosis, hematoma, skin necrosis, arteriovenous fistula, acute limb loss, and death.43 Early medical complications include pneumonia, sepsis, other nonsurgical infections, and adverse medication reactions. Immunosuppression-related complications appear to dominate the late medical complications and have included serum sickness, opportunistic infections, hyperglycemia and diabetes mellitus, end-stage renal disease, hyper­tension, Cushing syndrome, avascular necrosis of the femoral heads, skin cancer, and hyperparathyroidism. In the United States and Europe, 6 hands have been amputated postoperatively. One was the result of an acute postoperative thrombosis, one was from a bacterial infection within the first 2 postoperative months, and the others were secondary to rejection. At least 7 transplanted hands have been removed in China. Most recently in the United States, the world’s second attempt at a combined bilateral hand and face transplant resulted in survival of the face but early loss of both hands.44

Rehabilitation
All patients have followed a rehabilitation program in addition to immunosuppressive therapy post­transplant. The goal of postoperative rehabilitation is to improve function, quality of life, and self-esteem of the transplant patient. Rehabilitation includes physiotherapy, electrostimulation, and occupational therapy. Important principles include a consistent well-trained team of therapists (including physical therapists, occupational therapists, and hand therapists) and starting therapy as early as possible to decrease finger swelling, prevent ligament and capsular contractures, and maintain flexor and extensor balance. Sensory reeducation is included to help recreate and organize the sensorimotor cortex projection of the hand, desensitize hypersensitive areas, and improve muscle strength and dexterity, with consistent use of standardized measures of objective. Special splints (eg, dynamic extension splints) and casting and bracing are used to ap­propriately position the hand and allow for initiation of exercise.45 From 8 to 12 weeks posttransplant, biofeedback training and cognitive therapy are added, depending on the level of healing and usage gained at that time. In bilateral hand transplant patients, motor and sensory representations have been used to reintegrate motor function involving not only extrinsic but also intrinsic cortical repre­sentations. Functional benefits to hand transplant recipients cannot occur without adequate nerve regeneration into the trans­planted limb, as well as reintegration of regenerated nerves into soma­tosensory and motor cortices of the brain. Sensory and motor deprivation from ampu­tation results in a recognized cortical reorganization. Patient compliance is important for achievement of postoperative goals, as sustained and intensive rehabilitation can improve function for years after transplant.46

Summary

Although CTA may not produce life-saving results, it certainly affects quality of life sufficiently that patients have demonstrated a willingness to accept a certain level of risk. The midterm and long-term results of upper extremity allotransplant are certainly promising and support the indication of these procedures for restoration of form and function in patients with upper limb amputations. With com­pletion of the first successful hand trans­plantation 18 years ago, our understanding of the procedure has continued to evolve. Ongoing research is needed to improve functional outcomes and to decrease the morbidity associated with long-term immunosup­pression. As immunologic advances, ethical debate, economic analysis, and access to this technology continue to progress, hand transplantation has ushered in a new era in the treatment of limb loss. Hand transplantation definitely remains an inno­vative solution that can greatly enhance the lives of well-selected amputees. With each successful trans­plant procedure, the collective lessons learned from worldwide experience, and continued laboratory research advancements, CTA offers to advance both transplant medicine and reconstructive surgery. Furthermore, as immunosuppression gives way to immunoregulation with less morbid medical regimens required for graft survival, the future for this technology will continue to expand.


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Volume : 17
Issue : 1
Pages : 97 - 104
DOI : 10.6002/ect.2018.0163


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From the 1Department of Plastic and Reconstructive Surgery, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Korea; and the 2Department of Plastic and Reconstructive Surgery, Seoul National University College of Medicine, Seoul, Korea
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare.
Corresponding author: Seok-chan Eun, Department of Plastic and Reconstructive Surgery, Seoul National University College of Medicine, Seoul National University Bundang Hospital, 82, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam-si Gyeonggi-do 13620, Republic of Korea
Phone: +82 31 787 7223
E-mail: sceun@snu.ac.kr