American Society of Transplantation Executive Summary on Pediatric Lung Transplantation

Lung transplantation in children poses distinctly different challenges from those seen in the adult population. This consensus statement reviews the experience in the field of pediatric lung transplantation and highlights areas that deserve further investigation.     

Comparison of Sirolimus with Low-Dose Tacrolimus Versus Sirolimus-based Calcineurin Inhibitor-Free Regimen in Live Donor Renal Transplantation

Between May 2001 and January 2003, 132 live donor renal allotransplant recipients were included in a prospective, randomized controlled trial where they were divided into two groups. All patients received steroids and basiliximab induction therapy. For maintenance immunosuppression, tacrolimus and sirolimus were used in group A. In group B, mycophenolate mofetil (MMF) and sirolimus were utilized. Patients were followed up for a minimum of 24 months. One-year patient and graft survival rates were not significantly different between group A (96.9%, 92.3%) and group B (100%, 98.4%), respectively. However, the incidence of biopsy-proven acute rejection was less in group B but the difference was not statistically significant (13.5% vs. 18.5% in group A). Statistically significant better renal function was encountered among group B patients at two years post-transplantation as measured by serum creatinine (1.25 vs. 1.43 mg/dl; P = 0.017) and calculated glomerular filtration rate (GFR) (94.9 vs. 79.6 ml/min; P = 0.005). One year protocol biopsies showed insignificant differences relative to chronic allograft damage index (CADI) between either group (Group A: 2.41 vs. Group B: 2.69; P = 0.436). Conclusion: Similar outcome was noted among patients in whom calcineurin inhibitors were not included in their immunosuppressive regimen. The long term impact of this observation on graft survival and function needs longer follow up.     

Monozygotic Transplantation: Concerns and Opportunities

We describe the case of a 24‐year‐old female with end‐stage renal disease from focal segmental glomerulosclerosis (FSGS) diagnosed at age 16, who underwent monozygotic triplet transplantation at age 21 from her sister. Monozygosity was established by buccal smear DNA PCR amplification using short tandem repeat ( 1 ) profiling for 16 genetic alleles. All immunosuppression was discontinued by 1 month posttransplant. To evaluate the use of immunosuppression in HLA identical monozygotic transplantation, we interrogated the OPTN (Organ Procurement Transplant Network) database for all transplants conducted from 1987 to 2006. We identified 194 probable identical twin transplantations based on age, gender, race, ethnic category, blood type and HLA match. We evaluated the use of various immunosuppressive agents at discharge, 6 months and 1, 2 and 3 years after transplantation. Seventy‐one percent of these patients at discharge and 34% at the end of 1 year were on immunosuppression. At discharge 61% received steroids and 30% received calcineurin inhibitors and 66% of these remained on calcineurin inhibitors at 1 year. Renal function was superior among those not maintained on immunosuppression. Thus, monozygotic transplantation confers an immunologic advantage that allows immunosuppression elimination despite a risk of recurrent glomerular disease such as FSGS with appropriate evaluation and management.     

Alemtuzumab Pre-Conditioning With Tacrolimus Monotherapy in Pediatric Renal Transplantation

We employed antibody pre-conditioning with alemtuzumab and posttransplant immunosuppression with low-dose tacrolimus monotherapy in 26 consecutive pediatric kidney transplant recipients between January 2004 and December 2005. Mean recipient age was 10.7 +/- 5.8 years, 7.7% were undergoing retransplantation, and 3.8% were sensitized, with a PRA >20%. Mean donor age was 32.8 +/- 9.2 years. Living donors were utilized in 65% of the transplants. Mean cold ischemia time was 27.6 +/- 6.4 h. The mean number of HLA mismatches was 3.3 +/- 1.3. Mean follow-up was 25 +/- 8 months. One and 2 year patient survival was 100% and 96%. One and 2 year graft survival was 96% and 88%. Mean serum creatinine was 1.1 +/- 0.6 mg/dL, and calculated creatinine clearance was 82.3 +/- 29.4 mL/min/1.73 m(2). The incidence of pre-weaning acute rejection was 11.5%; the incidence of delayed graft function was 7.7%. Eighteen (69%) of the children were tapered to spaced tacrolimus monotherapy, 10.5 +/- 2.2 months after transplantation. The incidence of CMV, PTLD and BK virus was 0%; the incidence of posttransplant diabetes was 7.7%. Although more follow-up is clearly needed, antibody pre-conditioning with alemtuzumab and tacrolimus monotherapy may be a safe and effective regimen in pediatric renal transplantation.     

Efficacy of Extracorporeal Photopheresis in Patients With Bronchiolitis Obliterans Syndrome After Lung Transplantation

Background

Lung transplantation (LT) is only therapeutic option for patients affected by chronic respiratory failure. Chronic rejection, also known as bronchiolitis obliterans syndrome (BOS), is still the main cause of death and the most important factor that influences post-transplantation quality of life. Currently available therapies have not been proven to result in significant benefit in the prevention or treatment of BOS. Extracorporeal photopheresis (ECP) seems to reduce the rate of lung function decline in transplant recipients with progressive BOS.

What's in the Pipeline? New Immunosuppressive Drugs in Transplantation

In the pipeline, there are a number of novel immunosuppressive drugs in preclinical development or in early clinical trials. The major target of new agents are cell-surface molecules important in immune cell interactions (especially the costimulatory pathway), signaling pathways that activate T cells, T-cell proliferation and trafficking and recruitment of immune cells responsible for rejection. The most promising biologic agents include a humanized anti-CD11a (anti-LFA1), humanized anti-B7.1/B7.2, a second-generation CTLA4Ig (LEA29Y) and a humanized antibody to anti-CD45 RB. Inhibitors of T-cell activation and signaling are still in preclinical development. The most interesting inhibitors of T-cell proliferation include inhibitors of the Janus protein tyrosine kinase, JAK3, and FK778, a leflunomide analog. Chemokines play an important role in rejection by virtue of their critical role as regulator of trafficking and activation of lymphocytes. Early trials of FTY720, a synthetic small molecule with functional homology to sphingosine-1 phosphate leading to lymphocyte sequestration, appear very promising; however, enthusiasm for this drug is mitigated by its potential cardiac side-effects. Antagonists to several chemokine receptors, including CCR1, CXCR3 and CCR5, have been shown to be effective in experimental transplantation and are likely to be considered for clinical development.     

气管移植的研究进展

气管移植目前仍处于动物实验阶段，影响气管移植应用主要因素在于移植气管的再血管化、有效的免疫抑制及供者气管的保存、带蒂大网膜包裹移植 管是移植体再血管化的有效方法。先期将气管移植体置于大网膜内，再将带蒂大网膜气管移植能明显提高移植体的再血管化，并降低移植体的感染率，气管的再血管化仍受到气管移植长度的限制，为解决这一问题，近年利用分段气管移植能有效延长气管移植开度，动物实验表明，气楠样存在移植排斥反应     

活体肝移植术3例报道

目的：报告３例活体肝部分移植术的临床体会。方法：回顾性分析一例弥漫性肝内胆管囊性扩张症、一例肝豆状核变性和一例原发性胆汁性肝硬化病人活体部分肝移植的临床经过。结果：供肝分别取自病人父亲（２例）或健康志愿者（一例）的肝左外叶,切取肝脏２６０～３００ｇ,供体术后恢复良好。受体手术历时１１～１３ｈ,出血２００～１５００ｍｌ。例１,女,１０岁,因术后肝断面和剥离面出血２次进腹止血,术后第１１天出现急性排斥反应,经激素冲击治疗而愈;一直采用环孢素Ａ为主的免疫抑制治疗,术后还出现胸水、腹水、切口裂开、输血反应等并发症,都经治而愈,现已健康生存４年。例２,女,２０岁,因供体为Ａ型血,受体为Ｏ型血,术中切除脾脏;手术前后采用环磷酰胺、ＦＫ５０６、霉酚酸脂和肾上腺皮质激素联合免疫抑制治疗,术后第１５天出现肝动脉及第三段肝静脉栓塞,溶栓治疗后又出现腹腔出血,术后第１７天再次开腹后恢复顺利,现已健康生存一年。例３,男,３岁,手术及术后恢复均顺利,现已健康生存近２月。结论：严格选择手术适应证、在病人全身状况良好时施行手术、做好围手术期管理的每一个环节,是确保肝移植手术取得成功的关键。     

心脏移植术后的免疫抑制治疗和免疫监测

心脏移植是治疗终末期心脏疾病的有效手段。以钙调磷酸酶抑制剂(CsA或FK506)为基础的免疫抑制治疗是心脏移植术后最常用的免疫抑制方案,许多心脏移植受者在移植前或/和移植后同时使用单克隆抗体进行诱导治疗。雷帕霉素和Everolimus等新型免疫抑制剂在有效抑制急性排斥反应的同时还可预防移植物心血管病变,显示出较好的应用前景。应用免疫学指标、心肌标记物和其它血清标记物等相对无创的指标预测和估计排斥反应的发生及其程度,有助于尽早发现和控制移植排斥反应,以提高心脏移植的效果。     

What's New and Hot in Clinical Organ Transplantation: Report From American Transplant Congress 2012

Innovative and exciting advances in the clinical sciences in organ transplantation were presented at the American Transplant Congress 2012. The full spectrum of transplantation was covered with important advancements in many topics. Key areas covered by presentations included living donor outcomes, organ preservation, optimal allocation of deceased donors, new immunosuppression regimens, antibody mediated rejection and the regulatory environment. This review will highlight some of the most interesting and innovative clinical presentations from the meeting.     

Prospective, Randomized, Multi-Center Trial of Antibody Induction Therapy in Simultaneous Pancreas-Kidney Transplantation

A randomized, multicenter, prospective study was conducted at 18 pancreas transplant centers in the United States to determine the role of induction therapy in simultaneous pancreas-kidney (SPK) transplantation. One hundred and 74 recipients were enrolled: 87 recipients each in the induction and noninduction treatment arms. Maintenance immunosuppression consisted of tacrolimus, mycophenolate mofetil, and corticosteroids. There were no statistically significant differences between treatment groups for patient, kidney, and pancreas graft survival at 1-year. The 1-year cumulative incidence of any treated biopsy-confirmed or presumptive rejection episodes (kidney or pancreas) in the induction and noninduction treatment arms was 24.6% and 31.2% (p = 0.28), respectively. The 1-year cumulative incidence of biopsy-confirmed, treated, acute kidney allograft rejection in the induction and noninduction treatment arms was 13.1% and 23.0% (p = 0.08), respectively. Biopsy-confirmed kidney allograft rejection occurred later post-transplant and appeared to be less severe among recipients that received induction therapy. The highest rate of Cytomegalovirus (CMV) viremia/syndrome was observed in the subgroup of recipients who received T-cell depleting antibody induction and received organs from CMV serologically positive donors. Decisions regarding the routine use of induction therapy in SPK transplantation must take into consideration its differential effects on risk of rejection and infection.     

Nerve Allotransplantation as it Pertains to Composite Tissue Transplantation

Nerve allografts provide a temporary scaffold for host nerve regeneration and allow for the repair of significant segmental nerve injuries. From rodent, large animal, and nonhuman primate studies, as well as clinical experience, nerve allografts, with the use of immunosuppression, have the capacity to provide equal regeneration and function to that of an autograft. In contrast to solid organ transplantation and composite tissue transfers, nerve allograft transplantation requires only temporary immunosuppression. Furthermore, nerve allograft rejection is difficult to assess, as the nerves are surgically buried and are without an immediate functional endpoint to monitor. In this article, we review what we know about peripheral nerve allograft transplantation from three decades of experience and apply our current understanding of nerve regeneration to the emerging field of composite tissue transplantation. No benefit of any kind will be received either directly or indirectly by the authors. Grant Funding: National Institute of Health 5RO1NS033406-14.     

Review of Immunomodulation by Photopheresis: Treatment of Cutaneous T–Cell Lymphoma, Autoimmune Disease, and Allograft Rejection

Abstract: Photopheresis is an apheresis–based therapy that is currently available at approximately 70 medical centers worldwide. Recent evidence indicates that extracorporeal photopheresis can significantly prolong life as well as induce a 60–75% response rate among individuals with advanced cutaneous T–cell lymphoma (CTCL). Moreover, a 10–15% cure rate, in response to photopheresis alone, or in combination with interferon–a, has been obtained at our institution. These complete responses have been characterized by the complete disappearance of morphologically atypical cells from the skin and blood. Southern blot analysis of peripheral blood specimens has also confirmed the indefinite disappearance of the malignant T–cell clone from the blood of patients with complete responses. Current immunological data obtained from in vitro human studies and from animal models suggest that the basis for the responses of CTCL patients are related to activation of treated macrophages resulting in release of cytokines, including substantial levels of tumor necrosis factor a (TNF-α), and perhaps, to the induction of anticlonotypic immunity directed against pathogenic clones of T lymphocytes. In addition to the treatment of CTCL, a potential role for photopheresis in the therapy of autoimmune disease has been suggested by recent pilot studies of pemphigus vulgaris, rheumatoid arthritis, and systemic lupus erythematosus. Furthermore, a randomized, single–blinded trial involving 79 patients with early onset, aggressive systemic sclerosis suggested that photopheresis could beneficially affect the course of the cutaneous thickening in this form of the disease. Lastly, two independent pilot studies of cardiac transplantation have indicated that photopheresis can reverse acute cardiac allograft rejection and potentially suppress ongoing chronic rejection. Randomized, controlled trials for these new indications for photopheresis therapy are currently in the early stages of implementation.     

Intestinal Transplantation: An Unexpected Journey

The development of pediatric intestine transplantation has required continuous refinements in the management of intestinal failure, surgical technique, and perioperative care. The development of better immunosuppressive management (cyclosporine in 1978 and tacrolimus in 1989) and enhancements in our understanding of the relationship between recipient and host immune systems have resulted in better long-term survival. Paralleling this, advancements in the organ procurement techniques and organ preservation solutions have made possible the procurement and transplantation of various types of intestine containing grafts tailored to the needs of the various indications for which intestine transplantation is being performed.