Back to Table of Contents | May 2011

Clinical and Health Affairs

Hand Transplantation

By Hatem Amer, M.D., Brian T. Carlsen, M.D., Jennifer L. Dusso, Brooks S. Edwards, M.D., and Steven L. Moran, M.D.

■ The first successful hand transplant was performed in 1998, opening up a new possibility for patients who have suffered mutilating hand injuries. Since then, more than 60 such procedures have been performed throughout the world. This article describes the evolution of hand transplantation, outcomes of patients listed in the International Registry of Hand and Composite Tissue Transplantation, and ethical issues involved in hand transplantation. It also describes the hand transplantation program at Mayo Clinic, which was established in 2010.

Hand and upper limb injuries account for approximately 10% of all emergency department visits.¹ Such injuries are not uncommon in agricultural states such as Minnesota, and many times they can be devastating. In the case of mutilating hand injuries, surgeons often cannot replant the severed parts, requiring patients to be treated with amputation and fitted for a prosthetic limb. Because upper-limb prostheses do not provide sensation and fine motor control, they are an inadequate replacement for the lost hand or arm for many patients, particularly those with bilateral amputations. Hand transplantation is a new option for patients in which the missing part is replaced, allowing for re-establishment of sensation and fine-motor control.

Over the past decade, hand transplantation has become an established means of limb reconstruction for patients with severe injuries to the hand and forearm. Since 1998, more than 60 hand transplants have been performed successfully around the world. Mayo Clinic established the first nonexperimental hand transplantation program in the United States last year (see “Mayo Clinic’s Hand Transplantation Program”). Hand transplantation, like face

transplantation, is a form of vascularized composite allotransplantation (VCA). Similar to solid-organ transplantation, VCA involves the transfer of living tissue from a donor to a recipient. In the case of a hand transplant, the transplanted hand requires a vascular connection in order to survive, and the patient requires standard immunosuppression to prevent rejection. Nerve regeneration into the transplanted tissue is required for sensation within the skin and reanimation of muscles within the transplanted tissue. VCA should be differentiated from acellular allografts such as tendon grafts and bone allografts, which have been used in orthopedic surgery for years, as those grafts are only structural in nature.

This article provides a brief overview of the current state of hand transplantation and the development of Mayo Clinic’s hand transplantation program.

History of Hand Transplantation
Hand surgeons are often called upon to reattach severed parts. Fingers, thumbs, hands, and forearms have all been successfully replanted since the initial reports of arm replantation by Malt and McKhann in 1962 ^2,3 and thumb replantation by Kamatsu and Tamai in 1968.⁴ Hand transplantation was a natural extension of this technical procedure for those patients who were not candidates for reattachment.

The first attempt at hand transplantation was made in Ecuador in 1964 but failed because of problems with inadequate immunosuppression.^5,6 During the past three decades, immunosuppressive medications substantially improved with the development of the calcineurin inhibitors cyclosporine and FK-506 (tacrolimus) as well as the potent antimetabolite mycophenolate mofetil (MMF). These medications have allowed for improvement in solid-organ transplantation and for long-term survival of limb transplants in animal models.^7-9

The biggest obstacle to hand and face transplantation has been the perception that the skin is one of the most antigenic organs.10 The idea that skin rejection would be an insurmountable barrier to hand and face transplant was proposed by Dr. Joseph Murray, a plastic surgeon noted for performing the first kidney transplant in identical twins and who later won the Nobel prize for his work in transplantation medicine.¹⁰ Ironically, it would be Murray’s own research fellow, Dr. Jean- Michel Dubernard, who would perform the first successful hand transplant in 1998 and show that rejection could be controlled with the use of standard immunosuppression.¹¹ A worldwide voluntary registry was created in 2002 to track patient progress following VCA and report outcomes.¹²

Hand Transplant Outcomes
The International Registry of Hand and Composite Tissue Transplantation (IRHCTT) published the most extensive and comprehensive outcomes data regarding hand transplantation in 2008 and 2010.^13,14 Follow-up was available on 33 patients who had undergone 49 hand transplants (17 unilateral and 16 bilateral) and two digit transplants. Patients who have elected to undergo hand transplantation have tended to be younger, with an average age of 32 years (range 19 to 54 years), and male. Follow-up within the IRHCTT reports extend from one month to 11 years.^13,14 Time from injury to transplant varied from two months to 34 years.¹³ Patient survival following hand transplantation stands at 100% within the United States.

Current long-term graft survival among patients in Europe and the United States is better than 94%. Immune-mediated rejection has been the primary cause of graft loss.^12,14 The first case of graft loss occurred in 1998 in Lyon, France, with the first unilateral hand transplant patient; pathologic specimens of the rejected hand showed evidence of lichenoid-like lesions, which can also be seen in cases of graft versus host disease.^12,13 Rejection occurred after the patient stopped taking his immunosuppression medications. The only case of graft loss in a U.S. patient was the result of ischemia caused by fibro-intimal hyperplasia. Fibro-intimal hyperplasia is thought to be a form of chronic rejection similar to that which has been described in heart transplant recipients.¹⁵

There has been debate over what is the best choice for immunosuppression for hand transplant patients. The majority of procedures have involved an induction process consisting of antithymocyte globulin, tacrolimus, MMF, and corticosteroids. Maintenance therapy for most patients has involved continuation of MMF, tacrolimus, and corticosteroids; this drug combination is similar to that which is currently considered standard treatment in solid-organ transplantation.^12,16,17 Modifications of this regimen have been reported, and in the IRHCTT study, 21.7% of recipients received only steroids and tacrolimus for maintenance therapy, whereas 8.7% were switched to sirolimus; 8.7% of recipients received corticosteroids, low-dose tacrolimus, and everolimus; 4.3% received sirolimus and MMF. Thirteen percent of patients underwent withdrawal of corticosteroids at some point during the follow-up period.^12,13 The reason for switching from tacrolimus to sirolimus or everlimus is usually the patient’s inability to tolerate the medication. There has been an effort to minimize corticosteroid dosing because of the medications’ side effects. Cushing syndrome, weight gain, dermatitis, and mood swings have been observed. Metabolic complications have been seen in up to 50% of patients and have included hyperglycemia and increased creatinine values. Most of these adverse effects have been transient and reversible. One patient required bilateral hip replacements as a result of corticosteroid use; and one has developed end-stage renal disease requiring dialysis eight years after transplant.¹⁴

The majority of patients in the IRHCTT study (87%) have developed opportunistic infections, including cytomegalovirus, Clostridium, and herpetic infections. The incidence of metabolic complications and opportunistic infections in hand transplant patients appears to be similar to that of solid-organ transplant patients. Newer corticosteroid-tapering protocols or corticosteroid-sparing therapies have been tried in addition to new antilymphocyte agents as well as tolerance-inducing protocols; but it is still too early to assess the benefit of these protocols over standard immunosuppression or evaluate their long-term safety.^12,18

Despite immunosuppression, acute rejection episodes occurred in 85% of patients within the first year; however all episodes of acute rejection were controlled with modification of immunosuppressive medications. Acute rejection, in cases of hand transplantation, is evaluated through skin biopsies. Rejection episodes are usually heralded by the development of a rash or dermatitis. Skin biopsies show evidence of lymphocytic infiltration in cases of acute rejection. Management of rejection episodes in hand transplant patients is similar to the management of rejection in solid-organ transplant patients. Hand transplant patients appear to have better survival rates than patients who have received solid organs when immunosuppressive protocols are followed properly.^18,19 The majority of acute rejection episodes may be managed with topical or systemic cortiocsteroids and topical tacrolimus.¹² Deterioration in hand function has not been noted following rejection episodes.^12,17

Functional outcomes have been very encouraging, with all patients recovering protective sensibility, 90% recovering tactile sensibility, and 82.3% recovering discriminative sensibility.¹⁴ Muscle recovery begins with the extrinsic flexor and extensor groups, allowing some patients to perform grasp-and-pinch activities shortly after transplantation. Recovery of intrinsic muscles can take up to 15 months. Recovery of intrinsic muscle function has been confirmed by electromyographic studies in several hands.^16,19 Extrinsic and intrinsic muscle function has allowed patients to perform most daily activities, including eating, driving, grasping objects, riding a bicycle or motorbike, shaving, using the telephone, and writing. In addition, functional MRI has demonstrated that after transplantation, hand representation is regained within the sensory and motor cortex of the brain.^20,21

Brandacher and colleagues reported that the most significant clinical improvements occur during the first three years following transplant, with minor improvements occurring after that. Discriminative sensation has been identified in all forearm transplantations; this gives great hope to patients with extremely disabling injuries.¹⁷ Nerve recovery is thought to take place at a rate of 1 mm a day from the point of traumatic injury. Thus, the more proximal the transplantation, the longer it takes to recover sensation within the hand. Interestingly, it has been noted that tacrolimus, one of the immunosuppressive medications commonly used in hand transplantation, has been able to accelerate nerve recovery, potentially shortening the period of time necessary for sensory return within the hand.²²

The IRHCTT study also found patient quality-of-life scores improved significantly in more than 75% of transplant recipients. Bilateral hand transplant recipients were only slightly more satisfied than unilateral hand transplant patients. In addition, the majority of patients have been able to return to work following surgery.^13,14,17

In summary, the IRHCTT report shows that after 11 years of clinical follow-up, hand transplantation is technically feasible and that results are encouraging as long as patients adhere to their immunosuppressive regimen and receive adequate physical therapy. Immunosuppressive protocols currently used in solid organ transplantation have proved to be sufficient to prevent rejection after hand transplantation. From a functional point of view, a remarkably good recovery of sensibility has been documented in all transplanted hands. In particular, protective sensation was achieved in all patients within 12 months. As time progressed, 90% showed tactile and 72% discriminative sensibility, thus providing a true benefit over prosthetics.^12,13

The Transplant Procedure
Any patient in good health between the ages of 25 and 60 who has suffered unilateral or bilateral arm, forearm, or hand loss may be a transplant candidate. Exclusion criteria are the same as for solid organ transplantation: active hepatitis B or C, viral encephalitis, or active malignancy. Additional exclusion criteria include autoimmune inflammatory arthritis; extensive or severe osteoarthritis; and any neuropathy that could adversely affect the recovery of sensation and motor function within the hand such as inherited peripheral neuropathy, inflammatory (axonal or demyelinating) neuropathy, systemic disease with associated neuropathy (diabetes, alcoholism, amyloidosis), and toxic neuropathy (heavy metal poisoning, drug toxicity, industrial agent exposure).

The organ donation and retrieval process is coordinated through LifeSource, the organ procurement organization for Minnesota and North and South Dakota. Donor hands are matched for sex, size, skin color, and blood type. Of the 49 limbs reported in the 2010 IRHCTT study, 28% had six HLA mismatches, 20% had five, 12% had four, and 32% had three. No zero-mismatch transplants were reported.¹⁴

Donor arms are usually removed at the level of the distal humerus. This provides additional tissue that may be used for nerve grafting or tendon grafting during surgery. In addition, it minimizes procurement time so as not to interfere with the retrieval of other solid organs.

The surgery involves preparation of the recipient’s stump or injured extremity by identifying the bones, tendons, nerves, and blood vessels. The first step is attachment of the bones using standard plates and screws used in the management of forearm fractures (Figure 1). Blood flow is then re-established in the limb by anastomosis of the arteries and veins (Figure 2). Muscle and tendon repair is then carried out, followed by nerve repair. Finally, the skin is closed. Cold ischemia time has ranged from 50 minutes to 12 hours (mean: six hours, 12 minutes) and is largely dependent on the geographic distance between donor and recipient hospitals.¹³ More than five surgeons are typically involved in hand transplants, and the procedures last between 12 and 24 hours.

Following surgery, hand therapists perform daily sessions. Rigorous on-site hand therapy can continue for up to three months following surgery in cases of bilateral above-elbow transplantation. Maintenance of passive joint motion and prevention of contracture are essential to preserving normal motion as nerve function slowly recovers. Medical monitoring following transplantation includes doing routine skin biopsies from the transplanted hand to check for signs of rejection, as well as routine blood work to ensure appropriate levels of immunosuppressive medications.

Ethical, Psychological, and Financial Considerations
Ethical issues are a foremost consideration in hand transplantation. Hand transplantation is considered life-enhancing as opposed to life-saving; thus extreme care must be taken when explaining to the patient the risks associated with the procedure and the necessity for long-term compliance with the immunosuppressive regimen. Ensuring patients will have life-long access to appropriate immunosuppressive drugs prior to transplantation is necessary in the planning process.

It has been well-established that successful outcomes depend on a healthy doctor-patient relationship. Klapheke, who published the psychiatric results and observations associated with the lone U.S. hand transplant failure, has noted that the key indicators for success are the patient’s ability to form alliances with his or her health care team, intellectual and emotional development, and body image, and whether he or she has untreated or ongoing post-traumatic stress disorder.^23,24 During a transition period, the hand must be successfully integrated into the patient’s sense of self, and ongoing psychiatric and social support are provided.^25,26

Hand transplant procedures performed in the United States have been supported by philanthropic grants, NIH funding, and grants through the Department of Defense. As hand and face transplant procedures become more common, portions of the procedure may be covered under some insurance plans. MM

Hatem Amer is assistant professor of medicine and medical director of the vascularized composite allotransplantation program; Brian Carlsen is an assistant professor of plastic surgery; Jennifer Dusso is operations manager of the William J. von Liebig Transplant Center; Brooks Edwards is professor of medicine and director of the William J. von Liebig Transplant Center; and Steven Moran is professor and chair of plastic surgery, professor of orthopedics, and surgical director of the VCA program. All are at Mayo Clinic in Rochester.
 

References
1. Clark DP, Scott RN, Anderson IW. Hand problems in an accident and emergency department. J Hand Surg Br. 1985;10(3):297-9.
2. Malt RA ,McKhann CF. Replantation of several arms. JAMA. 1964;189:716-22.
3. Tamai S. Twenty years’ experience of limb replantation—review of 293 upper extremity replants. J Hand Surg Am. 1982;7(6):549-56.
4. Kamatsu S,Tamai S. Successful replantation of a completely cut-off thumb: case report. Plast Reconstr Surg. 1968;42:374.
5. Gilbert R. Transplant is successful with a cadaver forearm. Med Trib Med News. 1964;5:20-2.
6. Gilbert R. Hand transplanted from cadaver is reampuated. Med Trib Med News. 1964;5:23-5.
7. Goto T, Kino T, Hatanaka H, et al. Discovery of FK-506, a novel immunosuppressant isolated from Streptomyces tsukubaensis. Transplant Proc. 1987;19 (5 Suppl 6):4-8.
8. Allison AC, Eugui EM. Immunosuppressive and other effects of mycophenolic acid and an ester prodrug, mycophenolate mofetil. Immunol Rev. 1993;136:5-28.
9. Jones JW Jr, Ustuner ET, Zdichavsky M, et al. Long-term survival of an extremity composite tissue allograft with FK506-mycophenolate mofetil therapy. Surgery. 1999;126(2):384-8.
10. Murray JE. Organ transplantation (skin, kidney, heart) and the plastic surgeon. Plast Reconstr Surg. 1971;47(5):425-31.
11. Dubernard JM, Owen E, Herzberg G, et al. Human hand allograft: report on first 6 months. Lancet. 1999;353(9161):1315-20.
12. Lanzetta M, Petruzzo P, Dubernard JM, et al. Second report (1998–2006) of the International Registry of Hand and Composite Tissue Transplantation. Transplant Immunol. 2008;18(1):1-6.
13. Petruzzo P, Lanzetta M, Dubernard JM, et al. The International Registry on Hand and Composite Tissue Transplantation. Transplantation 2008;86(4):487-92.
14. Petruzzo P, Lanzetta M, Dubernard JM., et al. The International Registry on Hand and Composite Tissue Transplantation. Transplantation. 2010;90(12):1590-4.
15. Michaels PJ, Espejo ML, Kobashigawa J, et al. Humoral rejection in cardiac transplantation: risk factors, hemodynamic consequences and relationship to transplant coronary artery disease. J Heart Lung Transplant. 2005;22:58-69.
16. Dubernard JM, Petruzzo P, Lanzetta M, et al. al. Functional results of the first human double-hand transplantation. Ann Surg. 2003;238(1):128-36.
17. Brandacher G, Ninkovic M, Piza-Katzer H, et al. The Innsbruck hand transplant program: update at 8 years after the first transplant. Transplantation Proc. 2009;41(2):491-4.
18. Breidenbach WC, Tobin GR, Gorantla VS, et al. A position statement in support of hand transplantation. J Hand Surg Am. 2002;27(5):760-70.
19. Breidenbach WC, Gonzales NR, Kaufman CL, et al. Outcomes of the first 2 American hand transplants at 8 and 6 years posttransplant. J Hand Surg Am. 2008;33(7):1039-47.
20. Giraux P, Sirigu A, Schneider F, et al. Cortical reorganization in motor cortex after graft of both hands. Nat Neurosci. 2001;4(7):691-2.
21. Vargas CD, Aballéa A, Rodrigues EC, et al. Re-emergence of hand-muscle representations in human motor cortex after hand allograft. Proc Natl Acad Sci USA. 2009;106(17):7197-202.
22. Gold BG. FK506 and the role of immunophilins in nerve regeneration. Mol Neurobiol. 1997;15(3):285-306.
23. Klapheke M. The role of the psychiatrist in organ transplantation. Bull Menninger Clin. 1999;63(1):13-39.
24. Klapheke, M., Transplantation of the human hand: psychiatric considerations. Bull Menninger Clin. 1999;63:159-73.
25. Siegler M. Ethical issues in innovative surgery:should we attempt a cadaveric hand transplantation in a human subject? Transplant Proc. 1998;309(6):2779-82.
26. Simmons PD. Ethical considerations in composite tissue allotransplantation. Microsurgery. 2000;20(8):458-65.