The impact of current immunosuppression strategies in renal transplantation on the field of reconstructive transplantation

Composite tissue allograft (CTA) transplantation, such as the clinical face and hand transplants, has now been performed in multiple centers across the world. The transplants have successfully treated complex injuries that have either failed conventional approaches or where autologous reconstruction could not restore both form and function. CTA transplantation has the potential to improve outcomes over traditional techniques. However, the widespread application of CTA transplantation continues to be limited by the need for chronic immunosuppression. Due to the small numbers of CTA transplants performed, any modification in the immunosuppression used will likely be based from the solid organ literature. The renal transplantation literature has served as the basis for the current selection of CTA drug regimens and in this article we review the evidence in the renal transplant literature for the selection of immunosuppressive regimens. The study then compares the regimens used in both the face and hand transplantation with those regimens currently used for renal transplantation.     

A modified model of hindlimb osteomyocutaneous flap for the study of tolerance to composite tissue allografts

Composite tissue allotransplantation (CTA) is the new frontier in transplantation. More than 25 hand allograft transplants have been performed worldwide, and the feasibility has been well established. The classical experimental model of CTA involves rat orthotopic hindlimb transplantation, a time-consuming procedure associated with high mortality and morbidity. We describe a rat heterotopic osteomyocutaneous flap that serves as a nonfunctional CTA, allowing the study of tolerance induction to a highly antigenic vascularized allograft of bone, muscle, and skin while minimizing the morbidity and mortality of full hind limb transplantation. In the present studies, we explored whether establishing chimerism by nonmyeloablative conditioning would induce tolerance to CTA. When compared with the classic hind limb transplantation model, these results demonstrate that our heterotopic hind limb flap is less morbid and as an effective experimental model for the study of CTA tolerance.     

Composite tissue transplantation: a rapidly advancing field

Composite tissue allotransplantation (CTA) is emerging as a potential treatment for complex tissue defects. It is currently being performed with increasing frequency in the clinic. The feasibility of the procedure has been confirmed through 30 hand transplantation, 3 facial reconstructions, and vascularized knee, esophageal, and tracheal allografts. A major drawback for CTA is the requirement for lifelong immunosuppression. The toxicity of these agents has limited the widespread application of CTA. Methods to reduce or eliminate the requirement for immunosuppression and promote CTA acceptance would represent a significant step forward in the field. Multiple studies suggest that mixed chimerism established by bone marrow transplantation promotes tolerance resulting in allograft acceptance. This overview focuses on the history and the exponentially expanding applications of the new frontier in CTA transplantation: immunology associated with CTA; preclinical animal models of CTA; clinical experience with CTA; and advances in mixed chimerism-induced tolerance in CTA. Additionally, some important hurdles that must be overcome in using bone marrow chimerism to induce tolerance to CTA are also discussed.     

Immunosuppression in an emerging field of plastic reconstructive surgery: composite tissue allotransplantation.

Composite tissue transplantation (CTA) refers to the transplantation of an allograft consisting of heterogeneous cadaveric tissues. It provides a means of restoring structural, functional and aesthetic form in severely injured patients. Recent progress in facial transplantation has highlighted the immense strides made in this field of reconstructive surgery. However the potential for improvements in quality of life must be offset by the need for life-long immunosuppression in adults with non life-threatening injuries. The benefits and difficulties of immunosuppressive drugs have been established in solid organ transplantation. Regimens derived from renal transplantation have been successfully applied to CTA. However the published incidence of complications seen in organ transplant recipients may not be easily extrapolated to potential CTA candidates and may be overstated. Accepted views that high dose immunosuppression would be needed to overcome highly antigenic tissues such as skin have not been borne out by clinical experience. It is therefore important to assess the current state of affairs, attempt to quantify the perceived risks and explore novel research methods being investigated. In doing so one can make a well-informed judgment of the potential benefit of this surgical modality as an integral part of the reconstructive ladder.     

Composite Tissue Allotransplantation: Past, Present and Future—The History and Expanding Applications of CTA as a New Frontier in Transplantation

Composite tissue allotransplantation (CTA) transplantation is currently being performed with increasing frequency in the clinic. The feasibility of the procedure has been confirmed in over 40 successful hand transplants, 3 facial reconstructions, and vascularized knee, esophageal, abdominal wall, and tracheal allografts. The toxicity of chronic, nonspecific immunosuppression remains a major limitation to the widespread availability of CTA and is associated with opportunistic infections, nephrotoxicity, end-organ damage, and an increased rate of malignancy. Methods to reduce or eliminate the requirement for immunosuppression would represent a significant step forward in the field. Mixed chimerism induces tolerance to solid organ and tissue allografts, including CTA. This overview focuses on the history and expanding applications of CTA as a new frontier in transplantation, and considers the important hurdles that must be overcome through research to allow widespread clinical application.     

同种异体复合组织移植Banff移植病理学诊断标准及进展

同种异体复合组织移植（CTA）是一门新兴的用于治疗功能性组织或肢体缺损的移植学科,由于绝大多数CTA移植物为带血管的移植物,因此也称为带血管的复合组织移植（VCA）。CTA/VCA的移植物包含同种异体的皮肤、皮下组织、骨骼、肌肉、神经和血管等两种或多种组织结构成分。由于大多数CTA/VCA移植物中带有皮肤组织,而皮肤组织是抗原性最强的免疫成分,移植术后的急性排斥反应是导致CTA/VCA移植失败及其移植物失功的首要障碍, 因此CTA/VCA移植物中的皮肤排斥反应的组织病理学特征成为首要的关注点。本文就CTA/VCA的排斥反应等病理学特征、2007年Banff诊断标准及其研究进展予以综述,以期为CTA/VCA的排斥反应及其他并发症的诊断及治疗提供参考。     

Strategies for tolerance induction in nonhuman primates

Recent advances in the field of reconstructive surgery and immunology resulted in increased interest in composite tissue allograft (CTA) transplantation. Up to date, more than 50 CTA transplants have been reported in humans. A significant number of experimental studies on CTA transplants under different protocols of tolerance-inducting strategies have been reported in small-animal models. There is however, a limited number of CTA transplants performed in nonhuman primates. To reach the ultimate clinical success in CTA transplantation, more experimental studies on tolerance induction in nonhuman primates are needed to apply these immunomodulatory protocols to CTA transplants in humans. In this review, strategies for tolerance induction in the nonhuman primate model in solid organ and CTA transplants are presented in 3 major categories: chimerism induction, T-cell depletion, and costimulatory receptor blockade.     

Predictive value and limitations of animal models for human transplantation: do we need more models for facial transplantation?

Animal models have traditionally provided the basis for preliminary investigation of new techniques prior to trials taking place in human subjects. The timing of when to proceed with human trials is difficult, as the accuracy of preclinical models can only be determined with hindsight. This review outlines the progression from transplantation in animal models to man. Now that many transplant procedures are well established, it is possible to assess the predictive value and limitations of animal models. These results are of great importance in the current debate about composite tissue allotransplantation (CTA) and in particular facial transplantation. This progression of CTA from animal models to man is outlined and compared with early renal, cardiac, and liver transplants. There is some evidence to suggest that animal models may have been misleading in CTA and that this has effectively delayed the transition to humans. The role for animal models in facial transplantation, which is currently making the step to clinical trials, is discussed.     

The surgeon's role and responsibility in facial tissue allograft transplantation

Facial composite tissue allograft (CTA) transplantation represents a novel frontier in the reconstruction of the human form. The face plays a central role in human interactions, with significant social ramifications resulting from facial disfigurement. The surgeon performing facial tissue transplantation bears additional responsibilities unique to plastic and reconstructive procedures. Reconstruction by facial tissue transplantation may immensely improve quality of life, provided the process of patient selection is conspicuous and appropriate and allograft rejection is prevented. However, facial CTA transplantation represents an elective procedure to reconstruct a non-life-threatening defect. Given the potential for organ failure, opportunistic infection, and malignancy resulting from long-term immunosuppression, the surgeon must carefully weigh the balance of risk to benefit for the individual patient. Pioneering surgeons developing this procedure must thoroughly evaluate its impact as it relates to clinical and social issues.     

The first (double) hand transplantation in Turkey

In September 2010, a bilateral hand allotransplantation was performed on a 28-year-old man who had suffered amputations at the level of 1/3 of the proximal forearm on the right and 1/3 of the distal forearm on the left 2 years previously. This was the first hand transplantation case in Turkey. Preoperative organization, legal difficulties, technical aspects of the operation, and immunosuppressive regimen are detailed herein. The early results of the first composite tissue allograft (CTA) transplantation are also reported. The results were encouraging for all future types of CTA transplantation, including hand and face. Following the early promising outcome of the first case of hand transplantation in Turkey, we have accelerated preparation of regulations for CTA transplantation, including hand and face allotransplantation.     

Impact of donor bone marrow on survival of composite tissue allografts

Composite tissue allotransplants (CTA) involves transplantation of various tissues including vessels, nerves, skin, and immune cells and bears significant antigenic load. Different immunosuppressive protocols are used for experimental and clinical CTA. Immunosuppressive agents maintain survival of the different components of composite tissue allografts. However, the potential side effects of chronic immunosuppression currently limit the widespread application of CTA transplants. Bone marrow therapy in many tolerance induction protocols therefore provides a guide to reaching the target of permanent immunotolerance. Multiple studies suggest that bone marrow is immunomodulatory and may facilitate allograft acceptance.In this review, bone marrow-based therapy protocols of experimental and clinical models are presented in composite tissue transplantation.     

Reconstruction of a severe facial defect by allotransplantation in neurofibromatosis type 1: a case report

Background

On January 26, 2010, our team performed a facial transplant for a patient with neurofibromatosis type 1. We detail the perioperative surgical strategies for the composite tissue allograft (CTA) of the lower parts of the face to restore a severe defect after excision of bilateral massive plexiform neurofibromas. The main distinctive feature included an innovative provisional heterotopic transplantation (PHT) technique of the facial allograft to the femoral vessels before its final orthotopic transplantation.

Case Report

A 35-year-old Caucasian man received a CTA of the lower two-thirds of the face, including a chin osseous segment. The face was obtained from a non–heart-beating donor. The sequence of microsurgical procedures began by performing a PHT of the CTA to the recipient's femoral vessels in the right thigh. Intraoperatively, he experienced considerable blood loss that required transfusion of 24 units of packed cells. Surgical revision was required at day 7 to remove an extensive hematoma in the right side of the CTA. The maintenance immunosuppressive regimen included steroids, mycophenolate mofetil, and tacrolimus.

Conclusion

We have reported a case of successful provisional transplantation of a human facial allograft onto the thigh as an alternative technique in human face transplantation. PHT was a reliable alternative procedure to obtain the facial allograft from a cadaveric donor.     

Past, present, and future research in the field of composite tissue allotransplantation

In September 1998, a surgical team in Lyon, France, performed the first successful hand transplant. After this historic event, in January 1999, the University of Louisville performed the first hand transplant in the United States. These events sparked interest and debate concerning the justification of performing limb allotransplantation. The field of composite tissue allotransplantation (CTA) has made significant advances in the past two decades, yet advancement of the applications of CTA into the clinical arena had been fairly limited to this point. The most inherent controversy in CTA involves the fact that the clinical applications for the most part involve restoration of function and/or structural integrity. These procedures are done essentially for quality-of-life concerns, not life-saving issues. Present concern involves subjecting CTA recipients to a lifetime of postoperative immunosuppressive therapy. We cannot fully understand where we stand at present and in what future directions the field is heading unless we have an understanding of where we have been in composite tissue transplantation. This article reviews the historical aspects of CTA, discusses the present state of CTA, and speculates on potential future applications of CTA.     

Experimental and clinical experience of composite tissues allotransplantation in reconstructive surgery

Composite tissue allotransplantation (CTA) is a new concept in reconstructive surgery to improve major physical defects with no current solution. Although not a life-saving procedure, tissue replacement by CTA offers great potential for improving quality of life but relies on lifelong immunotherapy. This new practice has become achievable with the refinement of microsurgical techniques, with experience gained from limb and scalp replantations, with the development of organ transplantation and the release of new immunosuppressive drugs. Experimental and clinical research made it possible. The first human cases of CTA proved the reality and the feasibility of the concept. While the early functional results of these allografts are encouraging, they will need to be assessed in the long-term, and development of less toxic - more efficient immonu-suppressive drugs will be a permanent requisite to the broadening of CTA. Although long-term outcome and potential adverse effects of chronic immunosuppression remain uncertain, as for organ transplantation, CTA is already a potential solution for some highly selected patients carrying physical disabilities such as large facial defects and bilateral hand amputation.     

Preoperative evaluation of living related kidney donor: which kidney to donate?

OBJECTIVES: As the number of cadaveric donor is far beyond the demand of the waiting list, living related kidney transplantation is important for the worldwide organ shortage. Besides, living related transplantation has advantages compared with cadaveric transplantation in terms of graft function and survival. However, the remaining kidney function of the living donor needs to be evaluated. METHODS: We collected 28 paired living kidney donations from March 2003 to March 2005. All patients underwent laparoscopic donor nephrectomy. The preoperative kidney evaluation included renal echography, renal nuclear scan, computed tomography angiography (CTA), and creatinine clearance (CCr). The renal function of the donor kidney was expressed as (donor kidney/both kidneys)%. The percentage renal function from renal echography, renal nuclear scan, and CTA were correlated with CCr. RESULTS: The mean percentage of donor kidney function according to renal echo, nuclear scan, and CTA were 49.77%, 51.83%, and 50.70%, respectively. The correlation coefficients for renal echography, nuclear scan, and CTA to CCr were -0.316, -0.201, and 0.123, respectively. The correlation coefficients for renal echography, nuclear scan, and CTA to postoperative serum creatinine of donor were 0.426, 0.036, and -0.119, respectively. CONCLUSION: From the viewpoint of donor postoperative residual renal function, preoperative renal sonography offered a better predictive value than nuclear scan or CTA.     

Current Indications for Hand and Face Allotransplantation

There is growing excitement centered on the possibilities of composite tissue allotransplantation (CTA) in many medical centers around the United States. As CTA programs begin to form, criteria to guide patient selection for these highly complex procedures is warranted. At this time the contraindications for CTA are more easily defined than the indications. What is clear is that a thorough multidisciplinary evaluation of each individual patient will be needed to determine the global impact and complexity of the defect. The role of the surgeon is to identify the feasibility of the CTA reconstruction and balance this with a complete knowledge of conventional reconstructive techniques. Conventional treatments may be used in place of CTA or as salvage for CTA failure.     

Preoperative vascular evaluation in living donor liver transplantation for biliary atresia

Background

Liver transplantation is an important treatment option in the management of end-stage liver disease. Preoperative vascular evaluation plays an important role for a safe and successful operation, especially in pediatric patients undergoing living donor liver transplantation (LDLT).

Purpose

The purpose of this study is to assess the usefulness and accuracy of Doppler ultrasound (US), computed tomographic angiography (CTA), and magnetic resonance angiography (MRA) in evaluating vascular anomalies in patients with biliary atresia (BA) undergoing LDLT.

Methods and Materials

Images of Doppler US, CTA, and MRA for preoperative vascular evaluation in 55 patients with BA undergoing LDLT were reviewed with the operative findings.

Results

All patients underwent preoperative US, CTA, and MRA. Pathologic portal vein (n = 18), interruption of the retrohepatic vena cava (n = 1), and aberrant right hepatic artery from the superior mesenteric artery (n = 2) were confirmed during the transplantation. The success rates of CTA and MRA in identifying vascular anomalies were 96% and 82%, respectively (P = .01). The sensitivity, specificity, and accuracy of Doppler US were 89%, 94%, and 92%, respectively. For CTA, it was 94%, 97%, and 96%, respectively; for MRA (including technical failure), it was 75%, 97%, and 89%, respectively.

Conclusion

Doppler US serves as an initial assessment for vascular evaluation and has the advantage in determining vascular flow quantities. CTA and MRA are used for precise surgical planning. However, MRA has lower success and accuracy rates when compared with CTA (P = .01). Doppler US with CTA can provide accurate preoperative vascular imaging in patients with BA undergoing LDLT.     

Establishing the case for CT angiography in the preoperative imaging of abdominal wall perforators

Preoperative imaging of the donor site vasculature for deep inferior epigastric artery (DIEA) perforator flaps and other abdominal wall reconstructive flaps has become more commonplace. Abdominal wall computed tomography angiography (CTA) has been described as the most accurate and reproducible modality available for demonstrating the location, size, and course of individual perforators. We drew on our experience of 75 consecutive patients planned for DIEA-based flap surgery undertaking CTA at a single institution. Seven of these cases have been reported to highlight the utility of CTA for preoperative planning, emphasizing the unique information supplied by CTA that may influence operative outcome. Among all cases that underwent preoperative imaging with CTA, there was 100% flap survival, with no partial or complete flap necrosis. We found that in three of the cases described, the choice of operation was necessarily selected based on CTA findings (DIEA perforator flap, transverse rectus abdominis myocutaneous flap, and superficial superior epigastric artery flap). In addition, three cases demonstrate that CTA findings may dictate the decision to operate at all, and one case demonstrates the utility of CTA for evaluating the entire abdominal contents for comorbid conditions. Our experience with CTA for abdominal wall perforator mapping has been highly beneficial. CTA may guide operative technique and improve perforator selection in uncomplicated cases, and in difficult cases it can guide the most appropriate operation or indeed if an operation is appropriate at all. This is particularly the case in the setting of comorbidities or previous abdominal surgery.     

Science of composite tissue allotransplantation

The science of composite tissue allotransplantation (CTA) is rooted in progressive thinking by surgeons, fueled by innovative solutions, and aided by understanding the immunology of tolerance and rejection. These three factors have allowed CTA to progress from science fiction to science fact. Research using preclinical animal models has allowed an understanding of the antigenicity of complex tissue transplants and mechanisms to promote graft acceptance. As a result, translation to the clinic has shown that CTA is a viable treatment option well on the way of becoming a standard of care for those who have lost extremities and suffered large tissue defects. The field of CTA has been progressing exponentially over the past decade. Transplantation of hands, larynx, vascularized knee, trachea, face, and abdominal wall has been performed. Several important observations have emerged from translation to the clinic. Although it was predicted that rejection would pose a major limitation, this has not proven true. In fact, steroid-sparing protocols for immunosuppression that have been successfully used in renal transplantation are sufficient to prevent rejection of limbs. Although skin is highly antigenic when transplanted alone in animal models, when part of a CTA, it has not proven to be. Chronic rejection has not been conclusively demonstrated in hand transplant recipients and is difficult to induce in rodent models of CTA. This review focuses on the science of CTA, provides a snapshot of where we are in the clinic, and discusses prospects for the future to make the procedures even more widely available.     

Advances in composite tissue allograft transplantation as related to the hand and upper extremity

The clinical transplantation of composite tissue allografts (CTA) such as human hand or larynx is stimulating discussions among surgeons at national and international forums on the indications, ethical aspects, toxic effects of immunosuppression, and functional results of the first reported cases of unilateral and bilateral hand transplantation. This Clinical Perspective article presents the latest advances in clinical and experimental research related to the field of CTAs. The article presents the historic aspects of CTA, a broad view of the current state of composite tissue transplantation, the mechanism of allograft rejection, current experimental and clinical protocols, and, finally, the future prospects of the standard use of CTAs. It is clear that there is a substantial demand for routine use of CTAs but the treatment protocols need to be optimized and the functional outcomes need to be improved.