Solid organ transplantation (SOT) was invented in the 20th century. It was long felt that transplantation of vascularized tissue and vascularized skin in particular is impossible because stringent rejection of the skin cannot be overcome. More than 100 cases of human hand, forearm, arm, face, abdominal wall, and leg transplantations have proven otherwise and broadened the surgical, immunologic, and scientific plethora in transplantation (1, 2). Conventional treatment for patients with an amputated upper limb includes therapies such as the Krukenberg procedure for patients with an amputated hand and aesthetic or functional prostheses for patients with an amputated forearm and arm. In many cases, surgical treatment may help to improve function but often results in unsatisfactory appearance (3). Lately, hand transplantation has become an alternative for patients with an amputated upper limb. Although the first clinical cases have displayed good functional outcomes, the clinical courses were not free from complications (1). Only those patients who poorly adapted to amputation can accept the risks of chronic immunosuppression in exchange for a functional improvement.
In their forum article, Cendales et al. have addressed the need for regulations and allocation in vascularized composite allograft (VCA) and summarized the current status in the United States and Europe. As described, the definition of VCA and the nomenclature require further attention and work with the competent authorities. For the many reasons mentioned, regulations as currently developed for SOT would be suitable for VCA, whereas regulations for tissue retrieval and transplantation would make VCA impracticable. Using SOT regulations for VCA provides a basis and helps to define the legislative framework. Adequate adjustments for VCA, however, should be carefully considered. As mentioned in the forum article by Cendales et al., psychologic and social implications and differences to SOT require attention. VCA donation and allocation imply additional elements such as donor identification, race, and bone length/size, which need to be worked into an allocation system. Furthermore, retrieval of limbs, faces, and possibly other body parts in the future demands algorithms for the sequence of steps during the donor operation to guarantee the operation to be a well-coordinated process. With the increasing number of surgical teams participating in a donor operation and the nature of VCAs differing from SOT, this should be clarified, and regulations should be installed.
For the purpose of initiating the steps following the definition of legislation and oversight, we herein further elaborate on the current understanding and some of the critical aspects for this process.
DIFFERENCES BETWEEN THE UNITED STATES AND EUROPE
The oversight for organ transplants lays with the Organ Procurement and Transplantation Network, as contracted by the Health Resources and Services Administration for the United States. In Europe, nations have individual regulations and overseeing bodies, whereas the European Union (EU) provides only a “directive.” In a recent meeting of competent authorities of tissue and cells, it was discussed that the EU Tissue and Cells Directives are not suitable for VCA and that VCAs do not fulfill the requirements for an organ as “lifesaving.” Hence, at this point, it remains unclear if VCA in the European legislative framework falls under solid organs or tissue. This leaves room for interpretation and complicates any attempt to find uniform regulations for VCA in the EU. The American Society for Reconstructive Transplantation has initiated a task force to provide information and support for the definition of VCAs as organs. This effort has substantiated the proposal that VCA falls under the same regulatory oversight as solid organ transplants. To promote such a process in the EU, a similar effort has been initiated by the European Society for Organ Transplantation – Composite Tissue Allotransplantation Committee. Because of the different overseeing bodies and structure, the primary goal of this organization is to develop and communicate a uniform proposal for regulations with the national organizations. This could then lead to a more decisive and meaningful EU directive—feeding back to further modifications of national regulations.
Regulations for allocation follow a similar pattern. Whereas United Network for Organ Sharing (UNOS) may (in case of a decision as indicated previously and a subsequent mandate) form a working group for the definition of the allocation for VCA, the national and multinational bodies such as Eurotransplant, Scandiatransplant, and Swisstransplant will establish regulations for allocation together with national representatives. Again, it would be desirable if such regulations would follow a uniform pattern and if the development of any regulations would include advisors with firsthand experience in the field.
Oversight by UNOS mandates data submission to the UNOS registry, ensuring recording of events and quality control. Although multinational registries such as the European Liver Transplant Registry are established also in Europe, mandatory data submission exists only in some states of the EU. For example, in France, data need to be sent to the Agence de la Biomédecine, an agency overseeing organ exchange. The only multinational registry for VCA is currently the International Registry on Hand and Composite Tissue Transplantation. Although this registry is essential and valuable for the assessment of the overall outcome in VCA, data submission is voluntary, and the data set therefore is not complete.
ALLOCATION OF VCA IN EUROPE
To date, none of the VCA transplantations performed have been matched for human leukocyte antigen (HLA). This is a result of the urgency of the procedure and the limited number of available donors with adequate skin color, gender, and age match. Extrapolating from the experience in SOT, matching for HLA could be considered once donor allocation is embedded in national and multinational organizations, and a larger number of donors may become available. This initiative is supported by the results from a recent systematic review, where the number of acute rejections correlated with HLA mismatches (3.07 vs. 1.8, P=0.079) (4). As the pool of available donors expands, HLA matching may be of relevance in the donor selection process. Despite evidence indicating that the antibody-mediated immune response has a less prominent impact on graft survival when compared with kidney transplantation, donors with an HLA allele for which a VCA recipient has an unacceptably high level of donor-specific antibodies should be excluded to avoid the possible risk of graft vasculopathy in the long term.
Several aspects require attention and may factor into VCA allocation:
- - Size match/mismatch: With the limited number of donors available, it is important to develop guidelines for acceptable size, color, texture, and gender match/mismatch in hand and face transplantation. A gender mismatch might be more acceptable for hand than for face transplantation. Age should also be taken into account. In France, a maximum of a 10-year difference between donors and recipients was accepted as a criterion for allocation. In some centers, hand donors were required to be within a ±10% limit for height and weight.
- - Arterial lines: It should be addressed if an arterial line on the graft was acceptable or a contraindication for hand transplantation. Although there were different opinions, it seemed reasonable to remove the arterial line, and see if vessel/perfusion is patent. In addition, an angiogram could be performed for clarification.
- - Another aspect that warrants attention is the tolerable ischemia time and ischemia-reperfusion (I/R) injury in VCA. It has been demonstrated that tissue exposed to cold ischemia suffers significant damage and is subject to degeneration and fibrosis in forearm transplantation (5). A systematic analysis of injury of the individual tissues in VCA is currently being conducted (S.S., unpublished data, 2012). Some reports have shown good functional outcomes after 12 hr of ischemia in hand transplantation, but preliminary data from the systematic analysis (6) and studies on injury of individual tissues in response to ischemia and the limited data available from human hand transplants have indicated that ischemia time should be kept short. At this point, local and regional attribution should be favored. Once donor allocation over long distance can be realized and better understanding of the maximum ischemia time has been established, a clearer definition of the geographic radius for the donor search can be defined.
Despite the fact that VCA has not been considered a routine practice in France, the following criteria for allocation have been established in 2009:
- The donor selection is based on skin color, gender, age, ABO group, and HLA typing.
- VCAs should be performed between ABO-identical or ABO-compatible donors and recipients.
- National priority is defined for hypersensitized and sensitized recipients, urgent cases (arteriovenous malformation with severe bleeding for face transplantation), and combined face and arm transplantation.
- Allocation within a region/province is given priority in the absence of national priority. For local allocation, the transplant team is free to select the most suitable recipient.
- For national allocation, priorities are defined as (1) age difference of less than 10 years between donor and recipient and (2) time on the waiting list.
Bone marrow retrieval for immunomodulation in VCA: Vascularized bone marrow is a component of some but not all VCAs. Whereas a clear proof of the immunologic advantage deriving form vascularized bone marrow remains to be shown in human, experimental evidence strengthens this believe. Furthermore, to vascularized bone marrow, bone marrow or stem-cell infusions have recently become popular for the effect of immunomodulation and reduction/elimination of maintenance immunosuppression. Bone retrieval for the purpose of immunomodulation in SOT and VCA poses further technical and logistical challenges, which need to be addressed if the use of bone marrow and stem cells is widened. Vertebral body retrieval should be performed after VCA and organ procurement to limit cold ischemic time for organ transplantation.
Blood loss in a brain-dead donor may potentially destabilize the donor, and this could impact on the retrieval process and the quality of organs and tissue retrieved. For this reason, the sequence of events for concurrent VCA and organ donor should be carefully planned. At the current stage, planning is performed individually or per center preference. A VCA retrieval negatively impacting on SOT retrieval has not been reported to date. In many centers, hand and face retrieval have preceded SOT retrieval, and blood loss was kept at a minimum. Whereas arguments for decision making may also include, for example, muscle mass, velocity of retrieval, and the ability to apply external cooling between cross-clamping and dissection, a uniform standard should be worked out and established together with SOT surgeons. An algorithm could be based on the donor’s hemodynamic stability: stable donor, VCA retrieval first; and unstable donor, solid organ retrieval first. In all cases, VCAs and organs should be procured before tissue retrieval.
Ischemia time should be kept as short as possible to avoid significant I/R injury, which may increase the risk of edema and arterial thrombosis in the short term and fibrosis in the long term. The acceptable ischemia time has not been clearly defined. A cold ischemia time between 4 and 9 hr has been associated with good results in the French experience. Other teams have reported acceptable results with 12 hr of ischemia time. As an upper limit, a cold ischemia time of 10 hr seems reasonable at this point.
STANDARDIZATION OF POSTOPERATIVE FOLLOW-UP
Randomized clinical trials in VCA should be designed to elucidate if any given immunosuppressive protocol has any advantage over another. In VCA, this could be better realized with cohort studies, in which random allocation is possible but blinding is not. However, it is unlikely that a randomized clinical trial can be performed in VCA because the prevalence of upper limb amputation or facial defects requiring transplantation remains low. A solution could be the introduction of Zelen double randomized consent design, where patients are randomized to intervention or control but are allowed to choose their final allocation (7). Although such design is less efficient mathematically and inherits a bias, it allows for a new randomized trial to be evaluated in an intention-to-treat analysis. Finally, comparing the current protocols with historical cohorts or historical case series is worthwhile but provides very limited evidence.
Reports on hand allograft transplantation have mostly included annual outcome assessments. Most of them have been measured using the Hand Transplant Score System, the Chen functional grade, and the disabilities of the arm, shoulder, and hand (DASH) questionnaire. Lately, the SF-36 questionnaire has been used by some groups to report their outcomes. Other groups have used different instruments, such as the Carroll test or the Tamai-Ipsen test. Gathering information from a growing number of programs around the globe is challenging, and drawing significant conclusions may be impossible because of the overall limited number of cases reported using any of the instruments described in the literature. In addition, some instruments are not suitable to measure the functional status before transplantation, which hampers the evaluation of the functional improvement after transplantation.
Patients undergoing limb transplantation should undergo a critical evaluation of their outcomes using validated instruments. The benefit of a hand transplant in comparison with the pretransplantation situation should be systematically analyzed and numerically depicted. Outcome instruments that attempt to assess the function and quality of life of patients subject to limb surgery are available. The quality of the outcome can be described by both the clinician and the patient. With results classically described by the clinician as “good” or “excellent,” reproducibility is very limited. Clinician-based outcome measures do not express all necessary information about what the patient is able or unable to do. Efforts are being made to measure the outcomes of VCAs more objectively and independent from the surgeon’s perspective. Patient-reported outcome measures (PROMs) are being introduced in addition to clinician-based outcomes. To date, the DASH score is the only tool that has been used for this purpose. The DASH is a PROM and expresses the outcomes numerically. It has been tested for longitudinal observations and proven adequate for assessment after surgery in patients with a variety of musculoskeletal disorders. Furthermore, the outcome may change over time, and although function is usually improving during the first 2 years, little improvement is seen after 5 years. A recent systematic review was able to demonstrate a statistically significant improvement in the disabilities of the upper limb after hand transplantation (2). For face transplants, a comparison has been made to a paralyzed face where recovery is expected. In a fashion similar to the DASH, the Facial Disability Index is a PROM that evaluates the disabilities of the face caused by facial nerve paralysis. Although the Facial Disability Index has been included in the International Registry on Hand and Composite Tissue Transplantation (http://www.handregistry.com), there are no data available confirming the suitability of this instrument in transplantation at this point, and it may take long before outcomes of face transplants can be homogeneously reported and interpreted.
Whereas the legislative framework for VCA remains to be completed in some areas, work toward a balanced allocation system for VCA is an important task for national and international organizations and competent authorities. Definition of an allocation system together with collection of outcome data will help to further progress in this novel field.
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