Nadey S. Hakim

Human hand allograft: report on first 6 months

BACKGROUND Long-term survival of animal limb allografts with new immunosuppressant combinations and encouraging results of autologous limb replantations led us to believe that clinical application of hand transplantation in human beings was viable. METHODS On Sept 23, 1998, we transplanted the right distal forearm and hand of a brain-dead man aged 41 years on to a man aged 48 years who had had traumatic amputation of the distal third of his right forearm. The donors arm was irrigated with UW organ preservation solution at 4 degrees C, amputated 5 cm above the elbow, and transported in a cool container. We dissected the donor limb and the recipients arm simultaneously to identify anatomical structures. Appropriate lengths of viable structures were matched. Transplantation involved bone fixation, arterial and venous anastomoses (ischaemic time 12.5 h), nerve sutures, joining of muscles and tendons, and skin closure. Immunosuppression included antithymocyte globulins, tacrolimus, mycophenolic acid, and prednisone. Maintenance therapy included tacrolimus, mycophenolic acid, and prednisone. Follow-up included routine post-transplant laboratory tests, skin biopsies, intensive physiotherapy, and psychological support. FINDINGS The initial postoperative course was uneventful. No surgical complications were seen. Immunosuppression was well tolerated. Mild clinical and histological signs of cutaneous rejection were seen at weeks 8-9 after surgery. These signs disappeared after prednisone dose was increased (from 20 mg/day to 40 mg/day) and topical application of immunosuppressive creams (tacrolimus, clobetasol). Intensive physiotherapy led to satisfactory progress of motor function. Sensory progress (Tinels sign) was excellent and reached the wrist crease (20 cm) on day 100 for the median and ulnar nerves, and at least 24 cm to the palm by 6 months when deep pressure, but not light touch sensation, could be felt at the mid palm. INTERPRETATION Hand allotransplantation is technically feasible. Currently available immunosuppression seems to prevent acute rejection. If no further episode of rejection occurs, the functional prognosis of this graft should be similar to if not better than that reported in large series of autoreconstruction.

Clinicopathologic features of graft rejection of the first human hand allograft

Background. The first human hand allograft, performed in Lyon, France, on September 23, 1998, was removed during month 29 posttransplantation as the result of rejection because the patient did not comply with the immunosuppressive treatment. Methods. The patient was regularly examined from the day of transplantation to amputation. Biopsies were taken from the skin of the allograft and examined immunohistologically. After amputation, various tissue specimens obtained from the allograft (including skin, tendons, bone, muscles, and joints) were studied. Results. From month 15 onward, the allografted skin presented lichenoid papules that progressively spread and coalesced into diffuse erythematous-scaly lesions over the allografted hand. Histologically, these showed an aspect of chronic lichenoid cutaneous graft-versus-host disease. At the time of amputation, erosive and necrotic areas over the skin were present. Pathologic examination of the allograft showed that the most severe changes were found in the skin. Mild inflammation was found in muscles and tendons. Bones (including bone marrow) and joints were spared. Conclusions. The skin is the main target of rejection in human hand allografts. Close clinicopathologic monitoring of the skin is the most reliable way to detect rejection in human composite tissue allografts.

Functional results of the first human double-hand transplantation

Objective Objective of this study was to analyze fifteen months after surgery the sensorimotor recovery of the first human double hand transplantation. Summary Background Data As for any organ transplantation the success of composite tissue allografts such as a double hand allograft depends on prevention of rejection and its functional recovery. Methods The recipient was a 33-year-old man with bilateral amputation. Surgery included procurement of the upper extremities from a multiorgan cadaveric donor, preparation of the graft and recipients stumps; then, bone fixation, arterial and venous anastomoses, nerve sutures, joining of tendons and muscles and skin closure. Rehabilitation program included physiotherapy, electrostimulation and occupational therapy. Immunosuppressive protocol included tacrolimus, prednisone and mycophenolate mofetil and, for induction, antithymocyte globulins and then CD25 monoclonal antibody were added. Sensorimotor recovery tests and functional magnetic resonance imaging (fMRI) were performed to assess functional return and cortical reorganization. All the results were classified according to Ipsens classification. Results No surgical complications occurred. Two episodes of skin acute rejection characterized by maculopapular lesions were completely reversed increasing steroid dose within 10 days. By fifteen months the sensorimotor recovery was encouraging and the life quality improved. fMRI showed that cortical hand representation progressively shifted from lateral to medial region in the motor cortex. Conclusion Even though at present this double hand allograft, treated using a conventional immunosuppression, allowed to obtain results at least as good as those achieved in replanted upper extremities, longer follow-up will be necessary to demonstrate the final functional restoration.

Mycophenolic acid 12-h trough level monitoring in renal transplantation: association with acute rejection and toxicity.

Studies of renal transplantation utilizing trough plasma level monitoring of mycophenolic acid (MPA) have shown inconsistent associations with toxicity and rejection.

First human double hand transplantation: efficacy of a conventional immunosuppressive protocol

Abstract: Based on the results achieved in single human hand transplantations, we decided to perform the first double hand transplantation with a conventional immunosuppressive protocol in a patient with a high potential for functional recovery. Two years after transplantation the efficacy and the safety of this immunosuppressive protocol are evaluated. The recipient was a 33‐yr‐old man suffering from a traumatic amputation of both hands in 1996. Five HLA‐A, ‐B, and ‐DR mismatches were present with the donor; T and B cell cross‐match was negative. Immunosuppressive protocol included tacrolimus, prednisone, mycophenolate mofetil and, for induction, antithymocyte globulins and then anti CD25 monoclonal antibody. Reconstitution of lymphocyte populations proceeded normally. Neither anti‐HLA antibodies nor chimerism in peripheral blood were detected. Two episodes of acute rejection characterized by maculopapular lesions occurred on days 53 and 82 after transplantation. Skin biopsies revealed a dermal lymphocytic infiltrate. Both episodes were completely and rapidly reversed by topical clobetasol and increased systemic corticosteroid therapy. The only side‐effects related to treatment were reversible serum sickness and hyperglycemia. No infectious complications and malignancies occurred. No signs of graft‐versus‐host disease have been detected. This case of double hand transplantation shows that conventional immunosuppression is effective and safe to ensure survival and functional recovery of the grafted limb.

HAND TRANSPLANTATION: ETHICS, IMMUNOSUPPRESSION AND INDICATIONS

Experimentation (. . .) is justified primarily by the individual’s and not by the community’s interest. However, this does not exclude that, provided that one’s own substantial integrity is preserved, the patient could legitimately bear a part of the risks to contribute with his/her initiative to the progress of medicine, and in this way, to the welfare of the community. Within the community, the purpose of medicine is to free the human being from the infirmities that block him, and from the psycho-somatic fragilities that humiliate him John Paul II From the address to the participants to two surgical meetings in Rome, Italy October 27, 1980

First human hand transplantation

Hand transplantation is a model of composite tissue allografting ( a A ) . The immunological issues in CTA are extremely complex, as different tissues are involved, each of which has to be considered both individually and as a part of a unit while each has a different time and intensity of rejection. Cartilage, ligaments and fat present low antigenicity, and consequently they lead to a weak rejection; bone, muscles, nerves and vessels show a moderate rejection profile in spite of various degrees of immunogenicity; skin, a complex immunological structure, is the component that develops the most severe rejection, because of the abundance of dentritic cells within epidermis and dermis. Finally, bone marrow, a source of immunocompetent cells, is a major target for rejection, but also a source of contaminating donor T cells that could induce a graft-versus-host disease in a strongly immunosuppressed recipient, and a source of stem cells that might contribute to the development of a microchimerism. Limb transplantation, the most common experimental model of CTA, has met with varying degrees of success; however, results have improved with the introduction of new immunosuppressants, especially tacrolimus and mycophenolic acid [l-71. In humans few cases of isolated muscle [8], bone, joint [9, lo], nerve [ l l ] or vascular allografts [12] have been reported. The first vascularized human hand transplantation was performed on 23 September 1998 in Lyon, and it is described in the present report [13].

Determinants of mycophenolic acid levels after renal transplantation.

There are data suggesting an association between mycophenolic acid (MPA) levels and acute rejection and toxicity in renal transplant recipients treated with mycophenolate mofetil (MMF), and therefore, knowledge of factors determining MPA levels may aid in accurate adjustment of MMF dosage. A total of 4970 samples taken 12 hours postdose were analyzed for MPA by immunoassay at regular intervals from the first week posttransplantation in 117 renal transplant patients immunosuppressed with MMF and tacrolimus in a steroid-sparing regimen (prednisolone for the first 7 days only). MPA levels rose in the first 3 months and stabilized thereafter; dose-normalized MPA levels rose throughout the first 12 months and subsequently stabilized. Multivariate analysis by means of a population-averaged linear regression showed positive associations between MPA level and total daily dose (P < 0.001) but not individual dose or total daily dose corrected for body weight. Positive associations were also seen with serum albumin (P = 0.01), tacrolimus trough level (P = 0.01), and female gender (P = 0.002). The association with tacrolimus levels diminished with time. Negative associations were seen between MPA level and higher estimated creatinine clearance (P < 0.001), and also with increasing alanine transaminase levels (P = 0.002), the use of oral antibiotics (P < 0.001), and infective diarrhea (P < 0.001). The latter findings may be related to changes in enterohepatic recirculation of MPA. Many clinical variables show associations with trough MPA levels. An understanding of these factors may aid therapeutic monitoring of MMF.

Première transplantation de main chez l'homme. Résultats précoces*

The first hand allograft was performed on September 23, 1998. The right distal forearm and hand of a brain dead donor was transplanted to a 48 year old recipient who had undergone a traumatic amputation of the distal third of his right forearm. The donors arm was irrigated with organ preservation solution (UW) and transported to Lyon in a cool container. Two teams simultaneously dissected the donors limb and the recipients stump to identify anatomical structures. Transplantation involved bone fixation, arterial and venous anastomoses, nerve sutures, joining of the muscles and tendons, and skin closure. Immunosuppression consisted of anti-lymphocyte, polyclonal and monoclonal antibodies, tacrolimus, mycophenolic acid, and prednisone. Mild clinical and histological signs of rejection occurred at week 9 after surgery. They disappeared with adjustments of the immunosuppressant doses. Seven months after surgery the patient was in good general condition. Intensive physiotherapy led to satisfactory progress of motor function. Sensory progress is excellent, reaching the fingertips. A longer follow-up is necessary to appreciate the final result. In the absence of further rejection, the functional prognosis of the graft should be similar to that reported after successful autoreconstruction.

Kidney Transplantation With Minimized Maintenance: Alemtuzumab Induction With Tacrolimus Monotherapy—an Open Label, Randomized Trial

Background. Immunosuppressive regimens for kidney transplantation which reduce the long-term burden of immunosuppression are attractive, but little data are available to judge the safety and efficacy of the different strategies used. We tested the hypothesis that the simple, cheap, regimen of alemtuzumab induction combined with tacrolimus monotherapy maintenance provided equivalent outcomes to the more commonly used combination of interleukin-2 receptor monoclonal antibody induction with tacrolimus and mycophenolate mofetil combination maintenance, both regimens using steroid withdrawal after 7 days. Methods. One hundred twenty-three live or deceased donor renal transplant recipients were randomized 2:1 to receive alemtuzumab/tacrolimus or daclizumab/tacrolimus/mycophenolate. The primary endpoint was survival with a functioning graft at 1 year. Results. Both regimens produced equivalent, excellent outcomes with the primary outcome measure of 97.6% in the alemtuzumab arm and 95.1% in the daclizumab arm at 1 year (95% confidence interval of difference 6.9% to −1.7%) and at 2 years 92.6% and 95.1%. Rejection was less frequent in the alemtuzumab arm with 1- and 2-year rejection-free survival of 91.2% and 89.9% compared with 82.3% and 82.3% in the daclizumab arm. There were no significant differences in terms of the occurrence of opportunistic infections. Conclusion. Alemtuzumab induction with tacrolimus maintenance monotherapy and short-course steroid use provides a simple, safe, and effective immunosuppressive regimen for renal transplantation.