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loss occurring in four. Despite the high documented rejection rate, graft survival rates hold at approximately
[38]
70% in patients with > 10 years of follow-up . A complex immunosuppressive regimen is necessary for
VCA that follows protocols well-established for solid organ transplantation. They typically involve
induction with mono- or poly-clonal antibody therapy followed by lifelong maintenance with triple-drug
combinations [19,42] . Such extensive immunosuppression can cause complications, including but not limited
to metabolic disturbances, opportunistic infections, malignancies, and thromboses - thereby carrying risks
for shortening life and creating harm for the recipients . These risks are exemplified by two of the four
[38]
cases of true lower extremity allotransplantation, which were complicated by the development of a primary
central nervous system lymphoma and disseminated aspergillosis with multi-organ failure and early
[26]
death . Interestingly, however, immunosuppressive medications have been shown to accelerate the rate of
nerve regeneration - although the implications for functional recovery are unclear [43,44] . Centers have also
reported using similar dosage and serum level requirements as those widely accepted for solid organ
transplantation . Other than medical consequences, the necessity for immunosuppression, along with
[45]
physiotherapy specific for limb transplantation, further generate substantial time and financial costs that
may create a burden on the patient’s behalf.

Additionally, the psychosocial burden for recipients and families must be considered. Experts note that
candidates often underestimate the difficulties experienced in the posttransplant period, especially since the
quality of life tends to decrease in the first three months after the procedure before improvement is seen, not
reaching baseline reported quality of life until approximately one year after hand transplantation [46-48] .
Recipients frequently develop mood changes and anxiety in this perioperative period and during episodes of
acute rejection . Moreover, a psychosocial challenge of extremity transplantation involves assimilation of
[46]
the new limb into the recipient’s body image. The visible nature of VCA of the extremity can result in body
image distortion and a disrupted sense of bodily integrity, leading to negative self-evaluation and a reduced
sense of well-being [49,50] . Inability to psychologically integrate the allograft may then lead to nonadherence
with medications and subsequent rejection. This process can exacerbate recipients’ emotional and physical
distress, as they would be faced with not only reexperiencing loss of a limb but also potential lesser function
than before the transplant from further amputation of the preexisting stump. Visibility of the transplant
may also lead to psychological regression, negative responses from family and friends, and acute distress .
[33]
Furthermore, caregivers of recipients must endure substantial burdens from balancing employment and
other responsibilities with the demands of long-term care, which are only amplified for family members
who are untrained and unprepared to perform the skilled medical tasks required of them .
[51]

The novelty of VCA means candidates must assume an inherent risk of uncertainty regarding outcomes and
complications of the procedure. Long-term data, while expanding for VCA of the hand, does not yet exist
for VCA of the lower extremity. Therefore, limb transplantation can cause harm to the patient that may or
may not be superseded by the benefits discussed earlier.

Finally, as previously discussed, there are differences in the functionality of upper and lower limb prostheses
and hence, distinctions in the ethical considerations for VCA. While upper extremity prosthetics provide
acceptable function, they have not yet been able to provide the dexterity needed to attain function similar to
baseline . Meanwhile, lower extremity constructs have shown an excellent return to the limb’s less
[52]
[3,4]
complex range of motion, with many patients able to achieve independent ambulation . Accordingly, the
risk for potential harm is higher for lower extremity VCA, as a meaningful alternative exists without the
risks of immunosuppression.