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Immunosuppression
The main argument against VCA is its requirement for lifelong immunosuppression that places recipients at
risk of adverse events, graft loss, and a shortened lifespan. Traditionally, extremity transplants have been
maintained with a triple-drug immunosuppressive regimen after antibody-based lymphocyte depleting
induction therapy - most commonly involving the use of polyclonal or monoclonal antibodies, tacrolimus,
mycophenolate mofetil and steroids, all of which have significant long-term side effects [19,42] .

Recent initiatives have sought to determine regimens that cause less morbidity with equal or greater
effectiveness in reducing the risk of rejection, to reduce or eliminate the need for lifelong
immunosuppression. At the forefront is an effort to induce donor-specific transplantation tolerance and
achieve chimerism, which refers to the coexistence of donor and recipient immune cells. Multiple strategies
have been proposed, including hematopoietic stem cell transplantation, costimulation blockade and cell-
[135]
based therapies . Topical immunosuppression may also help prevent rejection without the substantial
risks implicated with systemic immunosuppression. While tolerance has been induced in various protocols
[136]
for small animal models, large animal studies have largely been unsuccessful . Without consistent
evidence supporting immunomodulation in non-human models, the transition from bench to bedside
remains limited. Nevertheless, some centers have attempted the adoption of minimal immunosuppression
protocols. Of note, a joint team at the Johns Hopkins University School of Medicine and University of
Pittsburgh has achieved lower rates of morbidity with the use of hematopoietic stem cell transplantation
with low-dose tacrolimus monotherapy - although chimerism was not realized with this regimen [137,138] . At
two years follow-up, their five-patient cohort had no signs of chronic rejection, infrequent acute rejection
episodes, and an acceptable side effect profile. Elsewhere, the application of a minimal immunosuppression
protocol resulted in acute rejection necessitating explantation within one year of initial hand
transplantation . Therefore, the advent of more effective, less toxic immunosuppressive therapies has the
[136]
potential to reduce some of the ethical controversy surrounding VCA and create a more favorable risk-
benefit profile.

General advancements
Another key ethical consideration of VCA of the extremity is that it is a novel procedure, which limits the
data currently supporting decision-making. As time passes, a greater number of procedures will be
performed, transplant facilities will have more experience with allotransplantation, and more long-term
data will be available. Eventually, there will likely also be greater supervision and management of the
allocation process as well as fading media scrutiny. Correspondingly, compared with the current state of
VCA, future candidates may assume a lower risk of uncertainty regarding outcomes and complications of
the procedure. The concerns discussed previously surrounding patient selection, understanding, and
privacy may also be lessened with further development of the field.

CONCLUSION
VCA of the lower extremity is an emerging field with considerable ethical challenges, given it is being a life-
enhancing rather than lifesaving procedure. The primary ethical tension is between the principles of
beneficence and nonmaleficence, though there are also relevant concerns about informed consent. Experts
have been increasingly in favor of the ethicality of hand transplantation [139,140] , a shift in opinion which may
be partially influenced by advancements in immunosuppression that alter the risk-benefit profile [19,138] .
However, lower extremity transplantation is likely to remain controversial given the high function and
technological innovations of lower limb prosthetics - where a shortcoming for upper extremity alternatives
exists. Both are not currently and will unlikely become the best option for the majority of amputees, but
VCA is a good alternative for patients who fail other reconstructive treatments. Overall, the ethical
considerations surrounding VCA will continue to evolve with the data, particularly if advancements in