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

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.     

Bilateral Hand Transplantation: Six Years After the First Case

In this study we present our experience concerning bilateral hand transplantation. Two cases were performed: the first in January 2000 and the second in April 2003. Both recipients received the same immunosuppressive treatment, which was similar to those used in solid organ transplantation, including tacrolimus, prednisone and mycophenolate mofetil while antithymocyte globulins were added for induction. Both recipients presented two episodes of acute rejection (maculopapular lesions) in the first 3 months after transplantation; however, these were easily reversed after a few days increasing oral steroid doses and using topical immunosuppressants. The first recipient presented hyperglycemia and serum sickness while the second recipient suffered a thrombosis of the right ulnar artery and an osteomyelitis of left ulna. All the complications were successfully treated. Functional Magnetic Resonance Imaging (fMRI) showed that cortical hand representation progressively shifted from the lateral to the medial region in the motor cortex. After 6 and 2 years respectively, they showed a relevant sensorimotor recovery particularly of sensibility and activity of intrinsic muscles. They were able to perform the majority of daily activities and to lead a normal social life. The first recipient has been working since 2003. They are both satisfied with their grafted hands.     

Composite Tissue Allograft Extends a Helping Hand to Transplant Immunologists

The first successful human hand transplantation, performed on September 1998, has translated the scope of 'composite tissue allotransplantation' from research concepts into clinical practice. Beyond microsurgical problems that have been overcome several years ago, the main obstacle that still prevents the generalization of composite tissue allotransplantation is immunologic. This review, which summarizes the evidence obtained both from experimental animal models and from the first recipients of a hand transplant, is focused on the two immunological characteristics of composite allografts that set them apart from other solid organ allografts: (i) they contain skin tissue that elicits a strong immune response; and (ii) they contain lymphoid tissues (such as bone marrow and lymph nodes) that have the potential both to attack the recipient, and also to down-modulate the host immune response and induce tolerance. While on one hand, the composite tissue allografts raise new challenges to transplant immunologists, on the other they provide answers to questions that have remained unresolved for a long time. In this sense, composite tissue allografts extend a helping hand to transplant immunologists.     

Bilateral hand transplantation: bone healing under immunosuppression with tacrolimus, mycophenolate mofetil, and prednisolone

PURPOSE: Little is known about bone healing after composite tissue transplantation that requires pharmacologic immunosuppression. Bone integration and callus development were assessed in bilateral hand transplantation. METHODS: In this study the course of callus development and callus maturation were assessed by color Doppler sonography and radiography in a double hand transplant and compared with forearm replantation. RESULTS: After hand transplantation, ingrowth of small vessels at the bone junction was observed at week 3, calcified callus became visible at month 4, and bone union was completed at month 11. A similar time course of bone integration was observed after replantation. Plating offered sufficient stability. A recipient periostal flap is thought to have improved blood supply and favored development and induction of callus. CONCLUSIONS: Bone healing after hand transplantation under immunosuppression with tacrolimus, mycophenolate mofetil, and prednisolone is identical to that after forearm replantation.     

Infectious complications after kidney transplantation: current epidemiology and associated risk factors

BACKGROUND: The impact of newer immunosuppressive and antimicrobial prophylactic agents on the pattern of infectious complications following kidney transplantation has not been well studied. METHODS: This is an observational study in 127 adult recipients transplanted from 2001 to 2004. Patients received thymoglobulin (ATG) (50%) or basiliximab (50%) for induction and were maintained on mycophenolate mofetil, either tacrolimus (73%) or sirolimus (SRL) (27%), and prednisone (79%). Antimicrobial prophylaxis included perioperative cefazolin, trimethoprim/sulfamethaxazole for six months, valganciclovir for three months and nystatin for two months. Regression models were used to examine the association of various factors with infections. RESULTS: We observed 127 infections in 65 patients, consisting of urinary tract infection (UTI) (47%), viral infections (17%), pneumonia (8%) and surgical wound infections (7%). UTI was the most common infection in all post-transplant periods. Enterococcus spp. (33%) and Escherichia coli (21%) were the most prevalent uropathogens. Of six patients with cytomegalovirus infection, none had tissue-invasive disease. There were no cases of pneumocystis pneumonia or BK nephropathy. Six patients developed fungal infections. Two deaths due to disseminated Rhizopus and Candida albicans accounted for a 1.5% infection-related mortality. Retransplantation and ureteral stents were independently associated with UTI (OR=4.5 and 2.9, p=0.06 and 0.03, respectively), as were ATG and SRL with bacterial infections (OR=3.3 and 2.5, p=0.009 and 0.047, respectively). CONCLUSION: This study suggests that the use of newer immunosuppressive agents in recent years is associated with some changes in the epidemiology of post-transplant infections. Enterococci have become the predominant uropathogen. Invasive fungal infections, although rare, are often fatal.     

Minimization of immunosuppression after lung transplantation: current trends

This paper reviews efforts that have been made to minimize immunosuppression in lung transplant patients. A brief history of tolerance and its potential application to lung transplantation is also discussed.     

Principles in transplantation: immunology

The immune system has evolved to protect the body from disease-causing agents by using innate and adaptive systems. The innate system acts rapidly using non-specific processes to target a large variety of pathogens and prevent the spread of disease. The adaptive system works more slowly and uses lymphocytes to target specific pathogens. Prevention and treatment of rejection post-transplantation is achieved by controlling both these immune mechanisms pharmacologically.     

Report of the joint ESOT and TTS basic science meeting 2013: current concepts and discoveries in translational transplantation

A joint meeting organized by the European (ESOT) and The Transplantation (TTS) Societies for basic science research was organized in Paris, France, on November 7–9, 2013. Focused on new ideas and concepts in translational transplantation, the meeting served as a venue for state‐of‐the‐art developments in basic transplantation immunology, such as the potential for tolerance induction through regulation of T‐cell signaling. This meeting report summarizes important insights which were presented in Paris. It not only offers an overview of established aspects, such as the role of Tregs in transplantation, presented by Nobel laureate Rolf Zinkernagel, but also highlights novel facets in the field of transplantation, that is cell‐therapy‐based immunosuppression or composite tissue transplantation as presented by the emotional story given by Vasyly Rohovyy, who received two hand transplants. The ESOT/TTS joint meeting was an overall productive and enjoyable platform for basic science research in translational transplantation and fulfilled all expectations by giving a promising outlook for the future of research in the field of immunological transplantation research.     

The psychological assessment of candidates for reconstructive hand transplantation

Standardized psychological assessment of candidates for reconstructive hand transplantation (RHT) is a new approach in transplantation medicine. Currently, international guidelines and standardized criteria for the evaluation are not established. Patients suffering from the loss of a hand or an upper extremity have to cope with multiple challenges. For a selected group of patients, RHT represents an option for restoring natural function and for regaining daily living independence. The identification of at-risk patients and those requiring ongoing counseling due to poor coping or limited psychological resources are the primary focus of the psychological assessment. We have developed the 'Innsbruck Psychological Screening Program for Reconstructive Transplantation (iRT-PSP)' which utilizes a semi-structured interview and standardized psychological screening procedures and continuous follow-up ratings. Between January 2011 and October 2011, four candidates were evaluated using the iRT-PSP. Psychological impairments including social withdrawal, embarrassment, reduced self-esteem, and a depressive coping style were identified and poor quality of life was reported. The motivation for transplantation was diverse, depending on many factors such as bi- or unilateral impairment, native or accidental loss of hand, and social integration.     

Allograft vasculopathy after allogeneic vascularized knee transplantation

Composite tissue allotransplantation represents a new discipline in reconstructive surgery. Over the past 10 years, we have performed six human vascularized allogeneic knee transplantations. All of these grafts have been lost within the first 56 months. A histomorphologic assessment of the latest case resulted in the detection of diffuse concentric fibrous intimal thickening and occlusion of graft vessels. Findings are comparable with cardiac allograft vasculopathy. The lack of adequate tools for monitoring graft rejection might have allowed multiple untreated episodes of acute rejection, triggering myointimal proliferation and occlusion of graft vessels. Graft vasculopathy represents an obstacle to long‐term vascularized bone and joint allograft survival, and adequate tools for monitoring need to be developed.     

Sirolimus as the main immunosuppressant in the early postoperative period following liver transplantation: a report of six cases and review of the literature

The use of sirolimus as the main immunosuppressant in a calcineurin inhibitor-free regimen in the early postoperative period of liver transplantation (LT), when the incidence of rejection is the highest, has seldom been reported. We report six patients who received sirolimus in association with steroids only, at a median time of 10 days after LT (range 3-23). Tacrolimus, initially given as the standard immunosuppressant, was discontinued because of nephrotoxicity in three of these patients and neurotoxicity in the other three. Resolution of the neurological symptoms was observed in all cases and a marked improvement of the renal function in two of three patients. Two patients died, one of sepsis and the other of recurrent hepatitis C virus hepatitis, after 47 and 143 days respectively. Three patients developed acute rejection which responded to intravenous steroids. In this cohort of patients, the use of sirolimus appeared safe and provided an adequate prophylaxis against rejection, even though the drug was administered in the immediate postoperative period after LT.     

The effectiveness and safety of rituximab as induction therapy in ABO-compatible non-sensitized renal transplantation: a systematic review and meta-analysis of randomized controlled trials

Abstract

Background: The objective of this systematic review and meta-analysis was to evaluate the effectiveness and safety of rituximab as induction therapy in ABO-compatible, non-sensitized renal transplantation. Methods: A literature search for randomized controlled trials (RCTs) was performed from inception through February 2015. Studies that reported relative risks or hazard ratios comparing the risks of biopsy-proven acute rejection (BPAR), graft loss, leukopenia, infection or mortality in ABO-compatible, non-sensitized renal transplant recipients who received rituximab as induction therapy versus controls were included. Pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using a random-effect, generic inverse variance method. Results: Four RCTs with 480 patients were included in the meta-analysis. Pooled RR of BPAR in recipients with rituximab induction was 0.90 (95% CI 0.50–1.60). Compared to placebo, the risk of BPAR in rituximab group was 0.76 (95% CI 0.51–1.14, I²?=?0). The risk of leukopenia was increased in rituximab group with the pooled RR of 8.22 (95% CI 2.08–32.47). There were no statistical differences in the risks of infection, graft loss and mortality at 3–6 months after transplantation with pool RRs of 1.02 (95% CI 0.85–1.21), 0.55 (95% CI 0.21–1.48) and 0.58 (95% CI 0.17–1.99), respectively. Conclusion: This meta-analysis demonstrated insignificant reduced risks of BPAR, graft loss or mortality among in ABO-compatible, non-sensitized renal transplant recipients with rituximab induction. Although rituximab induction significantly increases risk of leukopenia, it appears to be safe with no significant risk of infection.     

Belatacept after kidney transplantation in adolescents: a retrospective study

Regardless of recipient age at kidney transplantation (KTx), patients are at greatest risk for graft loss in adolescence, partly due to nonadherence to an oral immunosuppressive regimen. Belatacept, a non‐nephrotoxic, first‐in‐class immunosuppressant that inhibits costimulation of T cells requires intravenous application only every 4 weeks, potentially leading to better adherence. However, it is only approved for use in adults. We report here the findings of the first study of belatacept in adolescents, comprising all patients in our department switched to belatacept post‐KTx. Six patients (median age 15.5 years) were switched after a median of 7.5 months (range 23 days to 12 years), treatment range 3–28 months (cumulative 83 months): Three patients switched early (<3 months after KTx) had increased estimated glomerular filtration rate (GFR); one patient switched 12 years post‐KTx has stable GFR; two patients were switched following rapid decline of and with markedly impaired GFR, changing slope in one patient. One patient had one acute rejection. In addition of two patients who received belatacept for other conditions, the only relevant adverse event was neutropenia (after a cumulative 109 months). Belatacept as primary immunosuppression is an option in Epstein–Barr virus‐seropositive nonadherent adolescents if administered sufficiently early before deterioration of graft function.     

肾移植术后并发恶性肿瘤6例报告

目的 提高肾移植术后发生恶性肿瘤的诊疗水平。方法 结合献回顾性分析我院肾移植术后发生的6例恶性肿瘤的诊疗资料。结果 1002例肾移植受术后共发生恶性肿瘤6例，发生时间于移植术后9～96(平均47．2)个月，其中左肾透明细胞癌1例、膀胱癌2例、食道癌1例、皮肤癌1例、肝癌1例。4例手术治疗，3例无瘤存活至今，1例术后肺广泛转移死亡。1例放疗，生存一年后癌转移死亡，1例未手术于短期内癌广泛转移死亡。结论 肾移植受术后免疫功能低下，容易发生恶性肿瘤，随诊时应引起足够的重视。早期发现、早期治疗，减少免疫抑制剂用量可取得较好疗效。     

Analysis of a single-center experience with mycophenolate mofetil based immunosuppression in renal transplantation

Purpose. Acute rejection continues to be a major clinical issue in renal transplantation. Three large multicenter trials have demonstrated a 50% decline in biopsy‐proven rejection when mycophenolate mofetil (MMF) was given to renal transplant recipients with corticosteroids and cyclosporine. The purpose of this study was to compare the 6‐month outcome of renal transplant recipients using MMF and non‐MMF based immunosuppression protocols over a 4‐year period at a single center.
Methods. This retrospective study analyzed three patient groups defined by their immunosuppression protocol. The first group included patients who received a quadruple immunosuppression regimen of antilymphocyte induction (ATG), cyclosporine (CYA), azathioprine (AZA), and corticosteroids (CCS), and were transplanted between October 1993 and May 1995 (AZA group). The second group included patients who received a triple immunosuppression regimen of CYA, MMF, and CCS, and were transplanted between June 1995 and May 1996 (MMF group). The third group included patients who were transplanted between January 1997 and December 1997, and received an immunosuppression regimen of CYA and MMF with a reduced CCS dosing schema (reduced steroid group (RST)). Data were collected from a retrospective review of inpatient and outpatient clinical records.
Results. A total of 325 patients were included in the study (106 AZA, 106 MMF, 113 RST). The demographic characteristics of the three groups were similar; however, the mean donor age for the AZA group was 40±15.1 years versus 33±14.1 years and 34±13.1 years for the MMF and RST groups, respectively (p<0.043). The incidence of acute, biopsy‐proven rejection at 6 months was significantly less in the MMF group when compared with the AZA group [16 (15.1%) versus 35 (33%) patients, p=0.002]. However, the incidence of acute, biopsy‐proven rejection in the RST group (35 patients, 31%) was similar to that of the AZA group. Kaplan–Meier estimates for the cumulative incidence of acute rejection demonstrated a significant difference between the MMF group and the other two groups (p=0.0059). The AZA group had more severe rejection as demonstrated by the more frequent use of antilymphocyte therapy for rejection treatment (68.4% episodes) compared with the MMF (38.9%) and RST (47.6%) groups. After 6 months of follow‐up, 11 patients had lost their grafts (8, AZA; 1, MMF; 2, RST). One patient died in each of the AZA and RST groups due to hemorrhage and a pulmonary embolus, respectively. Four AZA patients were diagnosed with a malignancy (three post‐transplant lymphoproliferative disorder, one squamous skin cell carcinoma) compared with 2 MMF patients (prostate cancer, basal skin cell carcinoma) and no RST patients. Herpes zoster was the only infection that occurred more frequently in the MMF group (p=0.03). No other differences in infection rates were noted among the three groups. The initial length of hospital stay declined significantly over the 4‐year study period [11±4.3 d (AZA), 7.0±4.0 d (MMF), 6.2±3.3 d (RST), p<0.001]. Total number of hospital days for the first 6 months also followed a similar declining pattern. Despite using intravenous cyclosporine immediately post‐transplant in the MMF and RST groups, the incidence of delayed graft function was similar among the three groups. Average serum creatinine at 1 month was significantly lower in the MMF group (p=0.008), but no difference was noted at 3 and 6 months when compared with the AZA and RST groups.
Conclusion. This retrospective analysis indicates that MMF is an effective immunosuppressant. Decreased length of stay and less steroid resistant rejections with MMF is favorable for decreased hospital costs. However, the rebound in rejection rate with the RST group suggests that further study is needed to define the optimal use of this agent in combination with others to maximize effectiveness and minimize negative side effects.