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DOI: 10.1016/j.jhsb.2006.09.008 © 2007 The British Society for Surgery of the Hand
Hand Transplantation: The State-of-the-ArtFrom the Service d’Orthopédie-Traumatologie and Service de Néphrologie, Cliniques Universitaires de Bruxelles, Hôpital Erasme, 808 route de Lennik, B-1070, Brussels, Belgium and Department of Transplantation Surgery, University Hospital, Anichstrasse 35, Innsbruck, Austria Correspondence: Frédéric Schuind, Service d’Orthopédie-Traumatologie, Hôpital Erasme, Route de Lennik 808, 1070 Bruxelles, Belgium E-mail:Fschuind{at}ulb.ac.be
The feasibility of hand transplantation has been demonstrated, both surgically and immunologically. Levels of immunosuppression comparable to regimens used in solid organ transplantation are proving sufficient to prevent graft loss. Many patients have achieved discriminative sensibility and recovery of intrinsic muscle function. In addition to restoration of function, hand transplantation offers considerable psychological benefits. The recipient’s pre-operative psychological status, his motivation and his compliance with the intense rehabilitation programme are key issues. While the induction of graft specific tolerance represents a hope for the future, immunosuppression currently remains necessary and carries significant risks. Hand transplantation should, therefore, only be considered a therapeutic option for a carefully selected group of patients.
Key Words: hand transplantation • amputation • immunosuppression Hand transplantation remains controversial and raises serious ethical issues. Among hand and transplant surgeons, as in the general population, there are firm proponents and strong opponents to hand transplantation (Baumeister et al., 2004; Breidenbach et al., 2002; Brown, 2001; Cooney and Hentz, 2000, 2002; Dickenson and Widdershoven, 2001; Dubernard, 2002; Foucher, 1999, 2002; Francois et al., 2000; Herndon, 2000; Hettiaratchy et al., 2001, 2003; Hewitt, 1998; Hewitt et al., 1995; Hovius, 2001; Jones, 2002; Kann and Hewitt, 2001; Lanzetta et al., 2001; Lee, 2001, 2002; Lees and McCabe, 2002; Lübbe, 2003; Lundborg, 1999; Manske, 2001; Merle, 2001; Meyer, 2001; Pollard, 2001; Simmons, 2000; Tamai, 1999). Based on their personal experience (Margreiter et al., 2002; Schneeberger et al., 2004, 2006; Schuind et al., 2006a, b) and on the international experience, as recorded in the International Registry on Hand and Composite Tissue Transplantation (Lanzetta et al., 2005) and updated at the Seventh International Symposium on Composite Tissue Allotransplantation in Tucson, AZ, USA (January 2006), the authors review the indications/contraindications to hand transplantation and the organisation, surgical aspects and results of this novel therapeutic option. The article also discusses the risks of modern immunosuppression and future perspectives. Hand transplantation is a prime example of a composite tissue allograft, comprising skin, subcutaneous, neurovascular and mesenchymal tissues, such as bone, cartilage, muscle, fascia and skin (Black et al., 1983; Siemionow and Ozer, 2002). The potential benefits of composite tissue allografts for defects caused by trauma, resection of tumours or congenital deficiencies are immense. Complex reconstructions, presently performed using local or free flaps, never perfectly replicate the lost parts, whereas this can be accomplished by transplantation of matched tissues from a brain-dead donor (Barker et al., 2002; Black et al., 1983; Siemionow et al., 2002). By such procedures, donor site morbidity can be obviated and matched tissues used to replace missing tissues and severely scarred or irradiated defects (Lee and Mathes, 1999). Transplanted body parts with epiphyseal plates would maintain their growth potentials. Hence, composite tissue allografts could, ultimately, provide a therapeutic option also for innate defects (Guzman-Stein and Shons, 1987; Halloran et al., 1983; Hotokebuchi et al., 1989a, b; Zuker, 2006). In this respect, composite tissue allografts could perfectly fulfil Sir Harold Gillies’ concept of "replacing like with like" (Jones, 2002). Examples of composite tissue allografts, other than the hand performed successfully in the past decade include the larynx (Birchall et al., 2006), abdominal wall (Levi et al., 2003; Selvaggi et al., 2004) and knee/femur, the latter transplantation being indicated in patients with major post-traumatic destructions of the joint and quadriceps apparatus (Barker et al., 2002; Hofmann et al., 1998; Hofmann and Kirschner, 2000; Llull, 1998). The first attempt to transplant a human hand was undertaken in Ecuador in 1964 (Barker et al., 2002). As the immunosuppressants necessary, in particular calcineurin inhibitors, were not available at that time, the hand was rejected after 2 weeks. In parallel to this early attempt, much research has been conducted to establish a solid experimental model of limb transplantation (Arai et al., 1989; Benhaim et al., 1993; Black et al., 1982, 1983, 1988; Büttemeyer et al., 1996; Daniel et al., 1986; Doi, 1979; Furnas et al., 1983; Guzman-Stein and Shons, 1987; Halloran et al., 1983; Herndon, 2000; Hewitt et al., 1983, 1985, 1986, 1995; Hotokebuchi et al., 1989a; Hovius et al., 1992; Jones, 2002; Jones et al., 1999; Kann and Hewitt, 2001; Lance et al., 1971; Lee et al., 1991, 1995, Lipson et al., 1983a, b; Llull et al., 1992, 1995; Muramatsu et al., 1997; Nolan and Bowen, 1993; Poole et al., 1976; Porter and Lance, 1974; Press et al., 1983; Samulack et al., 1988; Siemionow et al., 2002; Siliski and Green, 1982; Stark et al., 1987; Tamai, 1999; Üstüner et al., 1998; van den Helder et al., 1994; Yeh et al., 1997). In most early experiments, the aim was to achieve limb survival using a single immunosuppressant and this was achieved using high, but toxic, doses of Cyclosporine A. The idea of utilising several immunosuppressants in combination to decrease the toxicity of the individual drugs is relatively recent. Perez-Abadia et al. (2003) used a low dose combination of tacrolimus with Mycophenolic Mofetil Acid (MMF) successfully in rats. However, single, or multiple, rejection episodes were observed in some animals; unfortunately, this model cannot easily be transposed to humans. It is interesting to note that, despite research efforts, the immunosuppressive regime actually used in most human hand transplant recipients has not been adequately studied. The first human hand transplantation of the "new era" was performed in Lyon in 1998 (Dubernard et al., 1999a, b) and the second transplantation was performed, a few months later in Louisville. This second graft is currently the longest surviving hand transplant in the world. These first two cases were unilateral transplants. The first bilateral hand transplant was carried out in France, followed by cases in Austria and China. As of December 2005, 23 hand transplantations in 17 adults with a 100%/91.3% patient/graft survival after a mean follow up of 45 months have been reported to the International Registry (www.handregistry.com, Lanzetta et al., 2005). In addition, two Chinese cases of thumb transplantation have been recorded. Little is known about the transplantation of hands between the neonate twins performed in Malaysia. Two hands have had to be reamputated, one as a consequence of progressive rejection in a non-compliant patient (the recipient of the first hand transplant in Lyon, France), the second in China for arterial thrombosis after steroid injection under somewhat unclear conditions. At the Seventh International Symposium on Composite Tissue Allotransplantation in Tucson, Arizona, USA in January 2006, Dr G.Pei surprised the audience with a summarising report of nine cases of hand transplantation (three bilateral, six unilateral) performed in different centres in China, several not reported to the International Registry. All nine patients were living in remote rural areas and, as most patients did not have health insurance, none of them could afford either regular medical follow-up or immunosuppression after the first postoperative year, when Government cover of this stopped. Not surprisingly, after good initial function, most hands became stiff and atrophic as a result of progressive rejection. Two of these hands had to be reamputated (including the case reported to the International Registry). Detailed reports on these cases, however, were not available to the authors. It is likely that there are other unrecorded cases of hand transplantation in China (Pei, 2006). It is difficult to understand why the guidelines of good clinical practice were not followed. It needs to be emphasised that the results obtained in these patients are not representative of the outcome after hand transplantation and only confirm that a transplanted hand is rejected when immunosuppression is omitted after the first postoperative year.
A hand transplantation programme should be designed with consideration of the ethical criteria of Moore (Siegler, 1998) in respect of (1) the scientific background of this relatively innovative surgery, (2) the skills and experience of the team, (3) ethical accuracy, (4) open display, (5) public evaluation and (6) public and scientific discussion. A hand transplant programme should only be started in a centre with sound experience in organ transplantation. The interdisciplinary consortium needs to include (1) hand surgeons with expertise in limb replantation, (2) transplant surgeons, (3) (and/or) specialists in internal medicine with a profound background in immunosuppression, (4) physiotherapists and occupational therapists specialised in hand rehabilitation and cortical reprogramming, (5) pathologists familiar with skin histology as well as with organ transplantation, (6) neurologists with a background in cortical activation patterns and coordination of hand function and (7) psychologists with experience in patients with post-traumatic/postoperative stress. The entire team should be familiar with the current data and recommendations for hand transplantation. The follow-up requires special attention. The contribution to the understanding of human hand transplantation from observations made in every single patient is particularly important. In addition, it is desirable that centres performing human hand transplantation are actively involved in experimental research on limb transplantation. Small animal models make it possible to investigate mechanisms contributing to pertinent topics such as rejection and provide the basis for the development of therapeutic strategies for unsolved problems.
Despite the frequency of upper limb amputations, only a few patients are good candidates for hand transplantation at this early stage. The ideal candidate is a highly motivated patient with a "clean-cut" bilateral mid- or distal-forearm amputation. In such a case, the extrinsic muscles are preserved, allowing early postoperative active mobilisation of the wrist and fingers. The vessels should be in good condition and the median, ulnar and radial sensory nerves intact. Distal neuromas allow for identification of nerves and these can be resected to appropriate lengths to obtain good microsuture without tension. However, according to the International Registry, only 33.3% of the patients transplanted fulfilled these criteria. A greater proportion of patients, namely 61.1%, received a transplant after unilateral loss of the dominant hand (transplantation of a non-dominant hand has only been performed once). A comparison of the outcomes after unilateral and bilateral hand transplantation has not yet been carried out. Among the cases published, or presented at various conferences, good results have been reported for single as well as for double hand transplantations. However, the inferiority of all transplant functional results when compared with the function of the patient’s own hand after single hand transplantation might influence satisfaction negatively. As for dominant, or non-dominant, hand transplantation, plasticity of the brain might be relevant. After dominant hand loss, the remaining non-dominant hand might well become "dominant". Again, however, a scientific evaluation of the difference in outcome after dominant- or non-dominant hand transplantation is missing from the literature. Transplantation was initially not considered to be indicated in patients with amputation at a very proximal level of the forearm, or above the elbow, because hand function would then depend entirely on nerve regeneration, as there are no remaining extrinsic muscles for early active wrist and finger motion. However, convincing results have been achieved with a bilateral transplantation of such a kind, performed in 2003 in Innsbruck (Schneeberger et al., manuscript in preparation). The level of amputation was just below the elbow and the entire forearm muscle mass was of donor origin and fixed to the recipient’s humerus. Despite an immunologically very difficult clinical course, hand function 3 years after transplantation is satisfactory. Not only have the forearm muscles regained function, providing good grip function, but also the intrinsic hand muscles have been reinnervated and allow for a certain degree of fine motor function. Given the risks of long-term immunosuppression and the alternate possibilities of reconstruction, isolated finger or thumb transplantation, or transplantation of hand components such as tendons+synovial sheath+-PIP joint are not considered reasonable, unless the patient is already on immunosuppression for a previous organ transplant. Reversibility of the intervention and re-establishment of the pre-transplant situation have been considered a prerequisite to transplantation. Patients with entirely stiff hands or left with almost no motor or sensory function as a result of, for example, a devastating war injury have requested a hand transplant. Indeed, bilateral amputation followed by transplantation could be considered a therapeutic option, but this has not yet been performed because, in the event of graft failure, the patient would be left with no hands. Although limb transplantation in children represents a theoretical approach for treatment of innate deformities and although growth of the transplanted limb would probably be observed, hand transplantation is not considered an option at present for such an indication. The main reasons for hesitancy are (1) the impossibility of obtaining informed consent, (2) the lack of knowledge of the integration of the "novel" limb(s) into the cerebral cortex and (3) the unclear long-term outcome. As for transplantation in adults, there is no clear limit to the recipient’s age, but there is a consensus, at this early stage, that hand transplantation should not be performed in patients over 55 years of age. The patient’s strong wish and his psychological stability represent an important – if not the most important – inclusion criterion. After the complex pretransplant evaluation has been accomplished and the patient is put on the waiting list, he/she has to wait for an unknown time until a suitable donor becomes available. After transplantation, the patient and his/her family and friends need to adapt to the novel situation and integrate the transplanted hands into what is considered "self". In some patients, additional surgical interventions, e.g. tenolysis, tendon transfer and/or removal of hardware, may become necessary. Furthermore, the need for pharmacological immunosuppression implies taking a considerable amount of medication according to a strict time schedule, probably for life. For determination of adequate trough levels, as well as to monitor side-effects such as nephrotoxicity, blood samples need to be taken frequently. Various medical investigations throughout follow-up are necessary. Even if an adequate immunosuppressive protocol is implemented, the risk of acute rejection remains high and the potential threat to long-term graft survival by chronic rejection unknown. The rehabilitation programme involves intensive daily training for 3 to 6 hours a day early after transplantation and should be continued at a lower intensity for years. For the patient, progress in hand function often seems to occur very slowly. Nevertheless, the patient needs to comply with the treatment protocol. Although, the initial overwhelming interest of the media is decreasing, patients still have to expect a certain amount of public exposure. For many of these reasons, hand transplantation should only be offered to highly motivated patients. Psychological stability, a strong socio-familial background and the ability to understand the complexity of the therapeutic programme in order to make appropriate decisions are necessary. Pre-operatively, thorough psychological investigation is indispensable and patients with weak personalities, or poor motivation, should not be kept on the transplant programme. One indicator of good motivation and compliance is the patient’s performance throughout the pre-operative evaluation, including in the use of prostheses. In this context, it is important to note that personality disorders are common among patients after severe trauma such as an amputation of the hands (Bachman and Burloux, 2001; Chin et al., 1999; Foucher, 1999; Meyer, 2003; Schweitzer et al., 1985; Sims, 1985). Postoperative psychological follow-up and support, therefore, also remain essential.
The pre-operative work-up is performed to rule out any pre-existent disease, which might be a contraindication to the surgical procedure or to chronic immunosuppression (Table 1). It is important to note that the cost of immunosuppression is enormous (up to 25,000 US $/year – Illdstad, 2006) and insurance companies do not routinely cover these expenses for a treatment that is still considered experimental. Therefore, clarification of funding needs to be established prior to enlisting the patient for hand transplantation. If financial support is not forthcoming, surgeons should not embark on hand transplantation.
The evaluation should include an angiogram of both forearms for detailed determination of the vessel status. In addition to radiomorphometric studies, MRI, ultrasound and EMG are useful tools for investigation of muscle morphology/function. Performance at functional cerebral MRI pre-operatively enables determination of post-transplant reactivation of the motor and sensory cortex. Reintegration of the hand into the brain has been demonstrated previously by different groups but the factors influencing the speed of cortical reactivation have not yet been clarified (Brenneis et al., 2005, Giraux et al., 2001, Neugroschl et al., 2005). An aesthetic prosthesis should be fabricated in advance so that it can be attached to the cadaver at the time of donation. Even more important than precise study of anatomical and medical prerequisites is the detailed education of the recipient candidate about all of the potential consequences of the surgical procedure and of chronic immunosuppression. This information should be given with special attention to the incompleteness of the current understanding of hand transplantation, including the unclear long-term outcome and its experimental nature (Jones, 2002). Repeated discussion with the recipient candidate seems useful, as the complexity of the procedure cannot be adequately described, or understood, in a single conversation and might well be underestimated. The patient’s written consent can only be given after time for reconsideration has been given. An independent Ethical Committee, competent to scrutinise all of the issues regarding the proposed transplantation, should be consulted and its recommendations for the planned intervention should be followed. In addition, national guidelines need to be obeyed.
The donor should be matched with the recipient in blood group, size, gender and cosmetic appearance. An X-ray of the forearm(s) should be performed for bone length measurements. As brain death in a young adult usually occurs as a consequence of trauma, forearm bone fractures need to be ruled out. A good immunological match is desirable. However, because of the limited number of potential donors and the anticipated limitations of consent for donation by the donor’s family, HLA matching cannot be taken into consideration at the present stage. Early reduction of immunosuppression under close observation is reasonable only in the very unlikely case of complete HLA matching (a "full house" match). Without any doubt, the pre-operative lymphocytotoxic crossmatch between donor and recipient should be negative. Cryopreservation of spleen cells should be performed to allow postoperative investigation of chimerism and anti-donor antibodies.
There are some technical differences between hand transplantation and hand replantation. Hand replantation is an emergency intervention and the patient is immediately referred to the operative room. Short ischaemia time, rapid revascularisation, stable bone fixation, careful nerve reconstruction and infection control are critical issues. Hand transplantation can be somewhat better planned. However, when the donor is situated in a hospital distant to the transplant centre, there is a risk of prolonged ischaemia time with unknown effects on short and long-term outcome. Ischaemia time influences muscle function and nerve regeneration critically. Muscle lesions occur after only 4 to 6 hours of ischaemia (Germann et al., 1989). In addition, ischaemia-reperfusion injury may have immunological consequences, with early onset and fast progression of chronic rejection, in addition to less clear effects on acute rejection and cytomegalovirus (CMV) replication, which has been shown for solid organ transplantation. Therefore, a short distance between the hospitals housing the donor and recipient, in conjunction with well-structured time planning, is desirable. Ideally, donor and recipient are operated on in adjacent theatres of the same institution. In addition, hands should be harvested prior to solid organs (Margreiter et al., 2002; Piza-Katzer, 2001; Schuind et al., 2006a, b). This can be done very quickly, under tourniquet, by elbow disarticulation – and the tourniquet may stay on the donor’s arm(s) until the end of harvesting other organs. Solid organ harvest prior to hand amputation results in impaired hand perfusion and prolongation of ischaemia time, which is less than ideal. Modern preservation solutions such as the University of Wisconsin solution (+ Depomedrol, Penicillin and Insulin) should be used for cold flush and hand preservation. After removal of excess tissues, bones, nerves, vessels and tendons are shortened to precisely match the recipient’s forearm(s); this is done on a side table(s), with ice under the operative drapes. A second team prepares the recipient’s stump(s). The transplant procedure itself is, then, similar to replantation, starting with osteosynthesis, followed by revascularisation, then tendon and nerve repair. Lanzetta recommended the use of a sentinel skin allograft to allow skin biopsies to be taken without affecting the hand transplant (Lanzetta et al., 2004). It is difficult to judge the relevance of his observation that rejection of the sentinel graft may occur prior to hand rejection and provide early warning. The sentinel graft can certainly not be compared with the hand in respect of its size and vascularisation. In addition, the site of implantation might be of relevance. Therefore, it is unclear if biopsies taken from the sentinel skin graft are representative of hand rejection.
Wide spectrum antibiotics together with prophylaxis for CMV and Pneumocystis Carinii infections are mandatory.
Different regimes of immunosuppression have been applied. Table 2 shows the immunosuppression pre-scribed to the first Belgian patient. Clear evidence of superiority of one immunosuppression protocol over another can only be derived from prospective, randomised clinical trials. For hand transplantation, such data will probably not be available for several decades. Therefore, the immunosuppressive regimen needs to be based on the limited experience in those patients transplanted to date, together with the advances learned from solid organ transplantation and data obtained from experimental limb transplantation. When designing the immunosuppressive protocol for hand transplantation, several differences to organ transplantation need to be taken into account: (1) hand amputees are otherwise healthy recipients and usually lack co-morbidities which might account for a higher risk of infection and malignancy in solid organ transplants; (2) transplantation of a hand is not life-saving; (3) in contrast to other transplants, the hand is constantly visible. Rejection episodes can, therefore, be detected very early by simple inspection; (4) in the cumulated International experience, most acute rejection episodes have occurred during the first postoperative year and the level of immunosuppression has to be adapted accordingly during that early period; (5) in addition to its superior efficiency in prevention of graft rejection when compared to other Calcineurin inhibitors, Tacrolimus seems to enhance nerve regeneration (Fansa et al., 1999; Francois et al., 2000; Kvist et al., 2003; Margreiter et al., 2002; Owen et al., 2001). Based on the experience in human hand transplantation, together with the arguments just mentioned, the following recommendations can be given: (1) for induction therapy to provide for potent early immunosuppression, there are two main options available: (a) either the use of antibody (Ab) preparations which induce profound lymphopoenia, such as the humanised monoclonal Ab Campath-1H, or the polyclonal rabbit anti-human ATG preparation, or (b) the use of monoclonal Abs which target the alpha-chain of the interleukin-2 receptor present on activated T cells, such as Basiliximab (Simulect®, Novartis) or Daclizumab (Zenapax®, Roche); (2) triple therapy during the first 2 to 3 years, including Tacrolimus, steroids and MMF; the steroids should be tapered to a dose of 4 to 6 mg/day of Methyl-prednisolone, possibly withdrawn if the patient develops significant toxicity such as diabetes mellitus; (3) at 2 to 3 years after transplantation, calcineurin inhibitors could, possibly, be replaced by mTOR-inhibitors, which have a low toxicity profile, protective effects on chronic rejection and anti-tumour properties (Kauffman et al., 2005).
Acute rejection episodes have occurred in almost all hand transplant recipients. Acute rejection not only represents an imminent danger to graft survival, but also has an unknown impact on the development of chronic rejection. It is, therefore, important to overcome acute rejection episodes quickly. The first line treatment is Methyl-prednisolone, given in doses of the order of 500 mg, three times daily for three consecutive days, although, in some cases, increasing the daily oral steroid dose has been sufficient. In addition to systemic treatment, topical application of immunosuppressant ointments has been used. Such an approach takes advantage of the unique possibility of treating rejection locally and is in keeping with current awareness that the skin is the primary target of hand rejection. However, the efficacy of topical immunosuppression has not been appropriately investigated and its clinical application is not based on scientific analysis (Barker et al., 2002; Cendales and Breidenbach, 2001; Dubernard et al., 1999a, b; 2000a, b; 2001a, b; 2002a, b, 2003; Francois et al., 2000; Jones et al., 2000; Kanitakis et al., 2000a; Lanzetta et al., 2004; Margreiter et al., 2002; Pei et al., 2001; Petruzzo et al., 2003, 2004; Piza-Katzer et al., 2002; Tobin et al., 2001). For second line treatment, application of ATG or IL-2 antibodies represents an expedient strategy. In a steroid- and ATG-resistant rejection, Campath-1H has been successfully used (Schneeberger et al., 2004).
We recommend the use of low-molecular subcutaneous heparin for 6 weeks and aspirin for at least 1 year for the postoperative prevention of vascular thrombosis.
Physiotherapy should be started early after transplantation, preferably on the first postoperative day, although this will depend on the quality of the tendon repairs. Physiotherapy is started with passive movements, but active mobilisation is encouraged as soon as possible. Between sessions of physiotherapy, the hand(s) should be kept in the intrinsic plus position by use of a thermoplastic splint. Sensory re-education and global motion pattern cortical reprogramming and, later, occupational therapy are indicated. Good results have been recorded using the specific cognitive exercise programme described by Perfetti, which was originally developed for the treatment of hemiplegia (Hummelsheim and Mauritz, 1993). Physiotherapy should be intense and prolonged: recent observations show that progress in hand function can still be achieved 5 years after transplantation (Schneeberger et al., 2006).
A comprehensive description of the monitoring of immunosuppression is beyond the scope of this review. For evaluation of bone healing, X-rays of hands and forearms should be performed at regular intervals, until solid bone healing has been achieved. Ultrasonography is valuable for investigation of the graft vessels, nerves, muscles and tendons. Angiography and CT angiography should be performed once a year and analysed with particular regard to graft vessel luminal narrowing/ occlusion as potential signs of chronic rejection. Monitoring for rejection is based on visual inspection of the allograft: hand transplantation offers a unique possibility to, virtually, see acute rejection happen. Rejection is characterised clinically by the development of erythematous papules and maculopapulous lesions, scattered irregularly over the allograft. Lesions can be restricted to a small area or can spread over the entire allograft. Upon progression, dermal/epidermal separation can result in erosions and, finally, necrosis, necessitating surgery. The patient complains usually of burning pain and dysaesthesiae. A decrease in sensitivity may be observed while motor function remains usually unaffected. Any skin lesions suggestive of rejection should be investigated by skin biopsy. Based on a lymphocytic and eosinophilic infiltrate, keratinocyte necrosis and dermal/epidermal separation, a grading system for rejection has been established (Schneeberger et al., 2004). As for tissues other than the skin, the data available are limited to a few rare occasions when respective tissue became available. Hence, a lymphocytic infiltrate might be present to a lesser extent also in the perineurium and in muscle, as well as connective tissue (Cendales et al., 2005; Wang et al., 2003). Immunohistochemical staining identified the majority of infiltrating cells as CD3-positive T lymphocytes with less than 5% CD20- and CD79a-positive B lymphocytes (Schneeberger et al., 2004). In the absence of clinical signs of rejection, it seems reasonable to perform skin biopsies on a regular basis every 3 months after the first year.
As is common after other hand surgery, the evaluation of results after hand transplantation is based on questionnaires, particularly the DASH (Hudak et al., 1996), on physical examination and on functional tests. The Brussels authors used the 400-points system (Schuind et al., 2003, 2006b) while others have preferred to use the Carroll test (Carroll, 1965). Specific score systems used in the evaluation of replantation, particularly Chen’s score, have also been recommended (Chen and Yu, 1987; Chen et al., 1981; Herzberg et al., 2003). However, Lanzetta et al. (2005) pointed out that a major difference between replantation and transplantation needs to be taken into account in the assessment. In replantation, the patients have not experienced the situation of being without a hand. Lanzetta et al. (2005) proposed a new grading system which considers this special situation of hand loss, the use of myoelectrical prosthesis before and the regained function after transplantation, as well as social reintegration, quality of life and aesthetic aspects.
When a patient is considered a good candidate for hand transplantation, the final decision to undergo the procedure needs to be made by the patient himself, based on his own perception of balance between the improved quality of life and the risks accepted to achieve this goal. Such a decision will – in part – be based on irrational elements (Edgell et al., 2001; Simmons, 2000). People make every day trade-offs with regard to their personal perception of balance between quality of life and risks. Hip arthroplasty, to overcome chronic pain and/or limited function, is such an intervention, just to name one less dramatic example (Siegler, 1998). In many ways, this is not different from renal transplantation. For decades, it remained unclear if patients’ survival would be improved by renal transplantation. According to Wolfe et al. (2004), patients placed on waiting lists for renal transplantation are much healthier, with an annual death rate 2.6 times lower, than the whole collective of patients on dialysis, although those who eventually undergo renal transplantation have to face lower short-term survival. However, survival at 8 months after transplantation is higher than in patients on dialysis. These data represent the first proof of what has been long assumed, namely that renal transplantation not only increases the quality of life but also the patients’ survival. However, for decades, kidney transplantation has been performed in order to relieve patients of the burden of dialysis and not to save, or prolong, their lives. Similarly, pancreatic transplantation improves the quality of life as ongoing routine measurement of blood glucose, as well as insulin injections, can be stopped. In addition, potentially life-threatening complications such as hypoglycaemia and diabetes-related diseases like nephropathy, atherosclerosis, retinopathy or neuropathy can be prevented. However, pancreas transplantation has not yet been shown to improve patients’ survival. Therefore, it would be a mistake to conclude that transplantations are only justified in situations in which individuals are at risk of death. In addition to life saving (heart and liver) transplantations, organ transplantations target other goals, such as improving quality of life and cost saving. These goals are essential elements in the full ethical justification of transplantation, although they receive little attention in the media. The question as to whether hand transplantation is justified might well be rephrased as ‘Is it justified to withhold this therapeutic option entirely from our patients? In this context, it is important to note that long-term results of hand transplantation are unknown. So far, all patients who have received a hand transplant are very grateful for their hand and would undergo transplantation again. Similar observations have been made after hand replantation: most patients are very satisfied to have regained body integrity, despite the fact that the hand function, in many cases, has remained rather poor (Russel et al., 1984; Schweitzer et al., 1985; Vanstraelen et al., 1993). However, it is known that patients with a replanted hand have more psychological problems than amputees (Hovius, 2001; Meyer, 2003). Hands are an essential part of our appearance and, over and above the functional and social impacts of the amputation, the psychological strain related to the amputation of the hand is underestimated by the majority of surgeons. The loss of body image has a disastrous psychological effect on many amputees (Bachman and Burloux, 2001; Brenner et al., 2002; Grant, 1980; Hovius, 2001; Jones, 2002; Meyer, 2003). It has been stated by Klapheke et al. (2000) that "amputation of the hand is a tremendous physical and psychological trauma that can precipitate powerful conflicts regarding loss of autonomy, guilt/ punishment and potency". Many patients are willing to accept certain risks to recover their body integrity and hand function. To be able to shake hands, to hug a partner, to recover independence by driving a car, etc. together with an improved self-esteem are significant factors in the patient satisfaction with hand transplantation. In addition, such changes relating to transplantation seem to help in mastering the stress caused by the initial trauma. In contrast to the constant psychological benefits of hand transplantation, functional gains vary from one patient to another. The mid-term functional results of hand transplantation seem to be superior to those reported after hand replantation (Axelrod and Buchler, 1991; Chen et al., 1981; Chen and Yu, 1987; Graham et al., 1998; Ipsen et al., 1990; Jones, 2002; Kann and Hewitt, 2001; Lee and Mathes, 1999; Meuli-Simmen et al., 1998; Meyer, 1985; Russell et al., 1984; Tamai, 1982; Vanstraelen et al., 1993). After hand transplantation, bimanual activity has been restored in most cases and many patients have regained protective sensation and intrinsic function (Francois et al., 2000; Lanzetta et al., 2005; Lee and Nguyen, 2005). For example, one recipient of a bilateral hand transplant in Innsbruck undertook a motorcycle expedition from Austria to the North Cape in the summer of 2002 and went on a trip through South America the following year. It has been stated that nerve regeneration after hand transplantation is faster than after replantation, possibly because of previously mentioned beneficial effect of Tacrolimus on nerve growth. In addition, the ability to perform nerve sutures without tension may contribute to the favourable results. For example, the first Brussels patient had excellent discriminative sensibility (two-point discrimination of 6 mm in the thumb and index finger pulps) and could localise each hand territory perfectly with his eyes shut. When outcome is compared to that with a myoelectrical prosthesis, sensitivity contributes very greatly to the superiority of a hand transplant over this alternative (Breidenbach et al., 2002; Graham et al., 1998; Lanzetta et al., 2001; Lundborg, 1999). This is also reflected in the fact that prostheses are frequently discarded by the patients because of the lack of sensation, at least in unilateral amputees (Herndon, 2000; Jones, 2002; Pinzur et al., 1994). Each tissue component of a hand transplantation is a target of the recipient’s immune response and different mechanisms for rejection of these components have been suggested (Brenner et al., 2002; Daniel et al., 1986; Herndon, 2000; Jones, 2002; Lee, 2001; Lee et al., 1991, 2001; Lee and Mathes, 1999; Llull, 1998; Petit et al., 2004; Petruzzo et al., 2001; Siemionow and Ozer, 2002). The skin has consistently been found to be the prime target of rejection (Büttemeyer et al., 1996; Daniel et al., 1986; Hewitt, 1998; Hotokebuchi et al., 1989a, b; Jones, 2002; Kanitakis et al., 2003; Lanzetta et al., 2001; Lee, 2001; Lee et al., 1991; Llull, 1998; Mathes et al., 2003; Stark et al., 1987; van den Helder et al., 1994). A clear reason has not yet been defined why this is, but it has been suggested that specific antigens could be present only in the epidermis (Halloran et al., 1999; Petit et al., 2004). The combination of different immunosuppressants allows for inhibition of the multiple pathways of the immune response. Application of two to four drugs allows the use of a lower dosage of each, resulting in lower toxicity and side-effects (Benhaim et al., 1993, 1996; Breidenbach et al., 2002; Daoud et al., 1998; Gorantla et al., 2000; Jones et al., 2001; Kahan and Ghobrial, 1994; Lanzetta et al., 2001, 2004; Lee and Mathes, 1999; Muramatsu et al., 1997; Siemionow et al., 2002). The risks of long-term immunosuppression in young, healthy patients undergoing hand transplantation, are unknown. According to the experience in solid organ transplantation, three categories of side-effects can be expected, viz. metabolic side-effects, opportunistic infections and malignancy. There is also a significant risk of non-compliance, especially with a graft which is not life sustaining. Non-compliance has been reported to occur in 10% to 30% of renal transplant recipients, causing many graft failures (Jones, 2002; Kouwenhoven et al., 2000; Lanzetta et al., 2001; Pollard, 2001). The Brussels hand-transplanted patient had no rejection for 44 months. He then reduced his immunosuppression by more than 50% on his own initiative, resulting in a serious rejection episode.
Metabolic side-effects
Opportunistic infections
Malignancy
Graft-Versus-Host Disease
Chronic rejection
The current need for immunosuppression to prevent rejection after hand transplantation keeps many surgeons from performing such an intervention. However, the true long-term risks of immunosuppression, as used in hand transplantation, are unknown. They certainly cannot be estimated on the basis of data collected from patients over 40 years of age, with organ failure and numerous co-morbidities such as osteomalacia, anaemia, bleeding diathesis, diabetes mellitus, arterial hypertension and cardiovascular problems, a fortiori if the data is based on old, immunosuppressive regimens. It can be assumed, that the risks of modern immunosuppression are lower in young and, otherwise, healthy hand transplant recipients than in most other organ transplant recipients (Breidenbach et al., 2002; Euvrard et al., 2003; Francois et al., 2000; Lanzetta et al., 2001). For example, resistance to infections should be higher than in kidney transplant recipients who have previously been on dialysis (Petruzzo et al., 2004). Should a life threatening opportunistic infection occur, or should the patient develop malignancy, which has not yet been observed after a hand transplantation, it is recommended that immunosuppression should be stopped and the hand amputated upon rejection (Baumeister et al., 2004; Breidenbach et al., 2002; Lees and McCabe, 2002). In solid organ transplantation, immunosuppression is increased whenever rejection is suspected. Monitoring of rejection, however, is difficult in many situations as elevations of functional parameters measured in the blood are neither sensitive nor specific. For instance, routine biopsies taken from grafted kidneys often show histological signs of rejection, although serum creatinine and urea remain unaltered. Therefore, the gold standard of confirmation and for ruling out rejection is to take a biopsy. However, taking a biopsy from solid organ transplants is associated with a relevant incidence of complications. In contrast, the detection of rejection is more evident in hand transplantation, as it primarily affects the skin. We, therefore, would suggest that immunosuppression should be reduced in order to determine the minimum immunosuppression required to prevent rejection and, thus, minimise the risks of side-effects and complications. In this context, it is fair to state that data on the level of immunosuppression required in hand transplant recipients have not been collected. It remains unknown if steroids can be withdrawn and calcineurin inhibitors reduced to low levels ("minimising protocols") in the long term. Single case observations suggest that levels of immunosuppression necessary to prevent rejection vary considerably between patients and that reduction of immunosuppression to levels with low toxicity is possible in some, but not all, patients. In one Austrian patient, steroids were withdrawn and Tacrolimus switched to Rapamycin during the fourth year after transplantation (Schneeberger et al., 2006). However, it is important to note that hand function was progressively lost after withdrawal of immunosuppression in several Chinese hand transplant recipients. In any case, the patients need to be followed very closely, in particular to early detect malignancy (including regular consultation with a dermatologist especially for patients much exposed to the sun) or infections. The ideal solution to prevent rejection would be the ability to induce specific tolerance (indefinite donor-specific allograft acceptance without the need for chronic immunosuppression). This has not been achieved so far. However, when a protocol for the induction of tolerance becomes a clinical reality, composite tissue allografts would certainly become a therapeutic option for multiple indications in a greater number of patients (Büttemeyer et al., 1996; Elster et al., 2000; Gorantla et al., 2003; Hettiaratchy, 2004; Hewitt, 1998; Jones, 2002; Kann and Hewitt, 2001; Llull, 1998; Orloff et al., 1995; Ozer et al., 2003; Rossini et al., 1999; Thomas et al., 2000; Werkele et al., 1998). There are several potential pathways towards what has been called the "holy grail" in transplantation. Tolerance can be attained by exposing the immature immune system of the recipient to donor cells (Butler et al., 2000; Lee and Mathes, 1999; Petit et al., 2004; Rossini et al., 1999; Schwind, 1962a, b; Siemionow and Ozer, 2002). Such an approach could potentially allow composite tissue allografts for certain congenital conditions. In mature animals, tolerance induction is more difficult (Lee, 2001; Lee et al., 2001), although questionable forms of tolerance towards a limb transplant in certain animal models were described decades ago (Black et al., 1985; Furnas et al., 1983; Hewitt et al., 1986; Lance et al., 1971). Especi |
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Abstract
REQUIREMENTS FOR ESTABLISHING A...