Perspectives of pediatric liver and kidney transplantation in Japan

In Japan, around one hundred and thirty pediatric living donor liver transplantations (LDLT) have been done every year, while cadaveric transplants are only 11 in the past 10 years. The indication has been extended to newborn babies as small as 2.5 kg of body weight. Five-year patient-survival of pediatric LDLT in Japan is 84.4%. Seventy pediatric kidney transplantations were done in 2008, 59 from living and 11 from cadaveric donors. Ten-year graft survival is improving in recent cases, and it is 79.4% in cases done after 1992. Living donor kidney transplantation has been possible in children as small as 7 or 8 kg of body weight. With such a technical success, discussion to enhance the preemptive renal transplantation has been started in Japan.     

Immunological factors in organ transplantation

Several immunological factors affect the outcome of human kidney transplants. HLA-A,-B and-DR matching improves kidney graft survival rate, especially matching for HLA-DR antigens. The beneficial effect of pretransplant blood transfusion has been confirmed although the mechanisms of the beneficial effect are not clear. Donor specific transfusion prior to living related donor kidney transplantation improve graft survival but some 30% of potential recipients become sensitized to the donor during the transfusion process. Major improvements in the results of organ transplantation have been achieved during the past few years with the use of new immunosuppressive agents, namely cyclosporin and monoclonal antibodies reacting with T lymphocytes. Both agents act selectively on T lymphocytes. However, nephrotoxicity of cyclosporin may limit its use.     

Pediatric kidney transplantation

Recently we achieved good outcomes in pediatric renal transplantation under basiliximab induction steroid withdrawal regimen including ciclosporin and mycophenolate mofetil (1 and 2 years patient/graft survival rates; 100%/96.6%). Steroid was withdrawn in 3 children and was given alternatively in 18 among 30 children under this regimen. Height standard deviation scores were significantly improved 1 year post-transplantation (-1.7+/-0.26 (mean+/-SE)), compared with those at transplantation (-2.1+/-0.23 (mean+/-SE)). Viral infection is still one of serious complications. Children tend to have symptomatic viral infection as a prime infection because of sero-negative antibodies against Cytomegalovirus (CMV) and Epstein-Barr virus(EBV). CMV was safely controlled with preemptive treatment monitoring with CMV antigenemia. EBV infection may result in posttransplant lymphoproliferative disease (PTLD). Ganciclovir for CMV and rituximab for EBV are useful. ABO blood group incompatible kidney transplantation demonstrated long-term better outcomes in children than adult. Pneumococcal infection was unexpectedly rare despite of splenectomy. Preemptive transplantation should be recommended to avoid dialysis for children regarding of good outcomes. Cadaver donor transplantation for a small child resulted in poor outcomes. Therefore living donor kidney transplantation for a small child is preferred. Management of cardiovascular monitoring with Swan-Ganz catheter and transesophageal ultrasound is important to overcome size mismatch between small body and a large kidney. It improves cardiac output and keeps good recirculation in an adult renal allograft. Kidney transplantation for children with end stage renal disease should be considered earlier and preemptively to improve growth retardation and provide better quality of life.     

ABO-incompatibility in solid organ transplantation

The most important transplantation antigen system in solid organ transplantation is the ABO histo-blood group system. Crossing the ABO barrier in solid organ transplantation is usually not done except for emergency liver transplantations. Early experiences of crossing the ABO barrier in renal transplantation were very disappointing. In the 1970s, clinical trials were started transplanting kidneys of subgroup A2 into blood group O recipients. The tissues of the A2 subgroup expresses reduced amount of A antigens compared to subgroup A1 and the recipients had no special pretreatment and standard immunosuppression. A number of early graft losses were experienced but the trial also resulted in several long time surviving grafts. A few centres have adapted the concept of A2 to non A kidney transplantations with successful results, when the recipient anti-A titres are low or reduced prior to transplantation. In the early 1980s one group successfully transplanted A1 and B kidneys from living related donors across the ABO-barrier using an immunosuppressive protocol consisting of quadruple drugs and splenectomy and this protocol was adapted by a few other groups. In Japan, where cadaver donors are available in very limited number, the largest number of ABO-incompatible transplantations have been performed. Altogether more than 300 ABO-incompatible kidney transplantations have been performed in more than 40 centres since 1989. ABO-incompatible liver transplantations have been performed mainly in emergency cases and the results have generally been inferior to ABO-compatible grafts. In children below the age of three years, liver transplantations across the ABO-barrier have been quite successful especially with living related donors. Very few ABO-incompatible heart/heart-lung/lung-transplantations have been reported with a few successful cases, but the majority have been failures. Recently a series of ABO-incompatible heart transplants performed in small children have been reported with a high success rate.     

心脏移植手术的围手术期处理

目的：总结心脏移植围手术期处理的初步经验。方法：2例终末期扩张性心肌病和1例复杂性先心病人进行了同种源位心脏移植术，围手术期分别在受体和供体的选择、供心的保护、循环和呼吸的支持治疗、免疫治疗和监测、预防感染这五方面着重进行了处理。结果：所有病人均存活，心功能由Ⅳ级提升至I－Ⅱ级；术前EF平均27.6%，术后提高到69．3％；未发生循环和呼吸系统并发症，亦未发生排异和严重感染等并发症，顺利出院。随访1年多，3例患者均生活质量良好。结论：心脏移植手术的成功除了熟练的手术技术外，选择恰当的供体和受体、良好的供心保护、适当的循环和呼吸的支持治疗、正确的免疫治疗和监测、有效的防感染措施是心脏移植围手术期处理的重点，是确保手术成功的关键。     

Tacrolimus: immunosuppression following liver and kidney transplant

Advances in transplantation have been impressive since the introduction of cyclosporin, however, there is still considerable debate on the most suitable immunosuppressant regimen. Tacrolimus, a new macrolide immunosuppressant, was marketed in the U. K. in 1994. Open studies have demonstrated its equal efficacy to cyclosporin in terms of patient and graft survival rates when used for primary immunosuppression following both liver and kidney transplantations. Tacrolimus also provides a valuable alternative for patients experiencing rejection in whom re-transplantation is often the only alternative. Unfortunately, in the studies to date, tacrolimus use was associated with increased nephrotoxicity and neurotoxicity compared to cyclosporin. Further trials are therefore required to define tacrolimus' true value in this complex field.     

实体器官移植患者接受心脏外科手术的围术期分析

目的评估实体器官移植患者接受心脏外科手术的安全性和预后。 方法回顾性收集2010年1月至2019年8月期间复旦大学附属中山医院收治的实体器官移植术后接受心脏外科手术患者的临床资料,包括年龄、性别、基础疾病、器官移植种类、器官移植至本次心脏外科手术时间、辅助检查、手术情况、围术期并发症、重症监护病房住院时间、总住院时间,并对存活患者进行随访。 结果共纳入14例实体器官移植患者,其中12例（85.7%）为肾移植,1例（7.1%）为肝移植,1例（7.1%）为心脏移植。患者平均年龄（57.5±6.0）岁,移植至本次心脏外科手术平均时间（11.4±5.5）年。平均重症监护病房住院时间（3.6±4.3）天,平均住医院时间（18.4±8.4）天。围术期并发症包括急性肾损伤2例（14.3%）,其中1例（7.1%）需要行连续性肾脏替代治;新发心房颤动1例（7.1%）;术后感染3例（21.4%）,均为肺部感染。30 d内死亡患者2例（14.3%）。存活患者随访3~124个月,平均（38.7±40.3）个月,随访期间无患者死亡,均未出现再住院治疗。 结论实体器官移植患者接受心脏外科手术具有良好的短期及长期预后。然而,围术期的感染风险、术后急性肾损伤的发生仍需密切关注。     

大鼠异位心脏移植动物模型制作的外科技巧

目的：探讨大鼠异位心脏移植动物模型制作的外科技巧。方法：制作80例Wistar-SD大鼠腹腔异位心脏移植动物模型，在供心的切取、受体的肝素化、腹腔血管的准备、心肌的灌注和保护及血管的吻合上有较多的改进。结果：应用改进的方法，制作心脏移植动物模型成功率为92．5％。结论：提高外科技能是保证大鼠异位心脏移植成功率的关键。     

小鼠腹腔异位心脏移植模型的建立及移植心功能监测

目的探讨小鼠腹部异位心脏移植手术的技术改进及移植心功能监测。方法采用供心主动脉与受体腹主动脉、供心肺动脉与受体下腔静脉端侧吻合方法对120只小鼠进行腹部心脏移植术。术后采用腹部触诊的方法 ,监测移植心功能。结果手术成功率91.67%(110/120)。供心修取时间(13.4±1.1)min,受体手术时间(40.2±2.8)min,其中吻合时间(25.6±2.5)min。同系异基因组移植心平均存活时间为7天(MST=7天),而同系同基因组移植心均长期存活(MST100天)。结论改进的小鼠腹部异位心脏移植技术稳定可靠,并可通过腹部触诊的方法评价移植物功能,适用于移植免疫学方面的研究。     

Current status and future of clinical kidney transplantation in Japan

Kidney transplantation has been established to be the therapy for an end-stage renal disease. In Japan, living donor kidney transplantation is frequently performed (> 80%) because of a shortage of the deceased donors. The graft survival has been improved to 93.4% (5-year graft survival in living donor kidney transplantation after 2001). ABO-incompatible cases are increasing and more than 20% are ABO-incompatible in Japan (30% in our institution). In our institution, 225 kidney transplantations (182: living donors, 43: deceased donors) have been performed from 2004.4 to 2010.6. Although the graft survival is excellent, posttransplant infections including cytomegalovirus, EB virus and BK virus are problems which should be solved. For the safety of the recipients, we should use kidney grafts from brain-dead donors.     

Immunological factors in organ transplantation

Several immunological factors affect the outcome of human kidney transplants. HLA-A,-B and-DR matching improves kidney graft survival rate, especially matching for HLA-DR antigens. The beneficial effect of pretransplant blood transfusion has been confirmed although the mechanisms of the beneficial effect are not clear. Donor specific transfusion prior to living related donor kidney transplantation improve graft survival but some 30% of potential recipients become sensitized to the donor during the transfusion process. Major improvements in the results of organ transplantation have been achieved during the past few years with the use of new immunosuppressive agents, namely cyclosporin and monoclonal antibodies reacting with T lymphocytes. Both agents act selectively on T lymphocytes. However, nephrotoxicity of cyclosporin may limit its use.     

大鼠肝移植不同供肝切取技术对供肝质量的影响

目的:探讨在大鼠肝移植供肝切取过程中不同方法对供肝质量的影响。方法:SD大鼠120只,随机分成3组,即标准法组(A组)、快速法组(B组)和改良快速法组(C组),每组各行20对大鼠原位肝移植,观察术中资料和术后3周存活率及冷灌洗后肝脏形态学改变。结果:在供肝切取手术时间上C组明显较A、B两组为短(P<0.05),其术后3周存活率也高于A组(P<0.05)。光镜下C组与A、B两组相比肝窦内未见红细胞。结论:标准法和快速法适合于刚建立大鼠肝移植模型的单位,为提高供肝质量、改善术后存活率应选择改良快速法。     

Retrospective analysis of renal transplantation outcomes in children admitted to a paediatric intensive care unit in Brazil

Renal transplantation has been described as the main treatment for children with end-stage renal disease. Traditionally, infants and small children represented a high-risk group with poor allograft survival. However, studies conducted mainly in developed countries have been demonstrated improvements in allograft survival rates. The aim of this study was to identify demographic characteristics of recipients and kidney donors and to analyse the outcomes of children who received postoperative care following renal transplantation in one Paediatric Intensive Care Unit (PICU). This retrospective study was carried out in a university hospital in Brazil. The data were collected through reviewing the follow up of medical records of recipients and kidney donors between 1988 and 2002. Chi-square or Fisher exact tests were used to analyse differences in outcome between living and donor transplants, whereas Mann-Whitney and Kruskal-Wallis tests were used to compare differences in outcome by age groups and by the number of complications affecting recipients. A total of 44 children were admitted for renal transplantation. Within this group, the median age was 10.1(+/-3.2) years, 63.6% were men and 38% were non-Caucasians. In contrast, the donor group had a median age of 17.5(+/-12.5) years, of which 51.3% were male, 56.8% were Caucasian and 70.5% were cadaver donors. The average length of PICU stay was 31.4 h, with complications being identified in the majority of the transplanted children. The occurrence of four or more complications was significantly associated with acute rejection (p= 0.009). In conclusion, the main outcomes of this study were similar to those observed in developed countries, in terms of acute rejections (52.3%), dialysis resumption (31.8%), graft loss (29.5%), chronic rejections (9.1%) and death (4.5%). Complications during PICU stay were significantly linked to the occurrence of acute rejection.     

供心保存研究中大鼠心脏异位移植模型的制作

目的 为探索心脏移植中供心保护快速可靠的研究方法。方法 快速摘取供体心肺，采用离体供心灌注停跳；在松弛的状态下结扎静脉，将其胸主动脉与受者的腹主动脉、肺动脉与受者的下腔静脉端侧吻合，采取间断+连续的缝合方法；开放血流时，先开放远心端再开放近心端，同时按摩心脏。结果 预实验组(n=20)成功14只，动脉吻合口出血2只、心脏复跳失败2只、吻合口狭窄2只；正式实验组(n=20)成功18只，2只死于吻合口出血。预实验组手术成功率为70％，正式实验组为90％(p>0.05)。结论 （1）快速摘取心肺，然后再进行离体心脏灌注保护，操作简单，热缺血时间很短，灌注效果肯定，对供心的保护效果好。（2）离体心肺组织结扎静脉，对心房、冠脉影响非常小。（3）采取间断+连续的缝合方法，因吻合口狭窄造成手术失败的可能性很低，（4）合理定位，避免吻合完毕供心动脉扭曲，从而影响复跳。（5）注意受体鼠的保温、消毒及血容量丧失非常关键。（6）利用心外膜起搏导线获得了供心的动态心电图。     

Selection of patients for kidney organ transplantation.

Renal transplantation is a viable alternative for most patients with end-stage renal disease, either before or after the institution of dialysis. Evaluation of potential recipients is necessary before transplantation and is mandatory to exclude patients who are likely to have a poor outcome. Such evaluation also may identify special problems and conditions in patients with end-stage renal disease who will require intervention before transplantation. Identification and evaluation of each transplant donor is also very important. Although organs from related living donors usually have better long-term function, survival, and fewer complications, most efforts in the transplantation community are spent attempting to extend the survival of cadaver kidney transplants. This goal could be accomplished by increasing availability of cadaver organs, improving histocompatibility of donor-recipient pairs, and improving available immunosuppressive therapy.     

Organ sharing network for organ transplantation from heart-beating deceased donors

Organ sharing network is indispensable for ensuring the fair, smooth and rapid shipping transplant organs. In Japan, Kidney Transplant Network was founded in 1995, and thereafter reformed to Organ Transplant Network following the legislation and enforcement of Organ Transplant Act. Under these circumstances, 36 cases of the organ donation from heart-beating deceased donor have been realized, and consequently 27 cases of cardiac transplants, 22 cases of lung transplants, 28 cases of liver transplants and 20 cases of combined pancreas and kidney transplants were done as for March of 2005. Clinical outcomes of these transplantations can be compared favorably to those of the West countries. The number of death on the waiting list, however, amounted to 70 for cardiac transplant, 67 for lung transplant, 134 for liver transplant, which would be 2.5 to 5 times as much as those who underwent transplantation. To make a breakthrough in issues on the organ shortage, the public enlightenment, the promotion of donor cards/seals, the amendment of Organ Transplant Act and related regulations and the insurance coverage of the cost of organ donation/transplantation are urgent challenges today.     

Removal of anti-A/B antibodies with plasmapheresis in ABO-incompatible kidney transplantation.

Because of a shortage of cadaver donors in Japan, ABO-incompatible living kidney transplantation has been carried out. Sixty-seven ABO-incompatible living kidney transplantations (LKT) were performed between January 1989 and December 1995 at our institution. In our previous report on the long-term results of ABO-incompatible LKT, graft survival of ABO-incompatible LKT up to 3 years was significantly lower than that of ABO-compatible LKT, but no significant difference was seen from 4 to 8 years. We removed anti-A/B antibodies by immunoadsorption and/or double filtration plasmapheresis before kidney transplantation. There was a significant difference between the anti-A/B antibody titers before and after plasmapheresis. The anti-A/B antibody titers also were well suppressed over the long term after transplantation.     

Organs shortage in the United States

Since the law pertaining to deceased transplantation was legalized in October 1997 in Japan, 140 cases of deceased transplants have been performed through March 2005. Patients on waiting lists, however, are increasing every year. Meanwhile patients traveling abroad in desperations to require donors also increase. In the United States, over 25,000 transplantations are performed annually. The number of patients on waiting list exceeded 86,000 in 2003. Organ shortages are a serious problem, even in the United States. Expanded criteria donor(ECD) and Model for endstage liver disease (MELD) scoring systems were implemented to improve some problems in kidney and liver allocation systems, respectively in 2002. Utilization of donated organs for non-citizens is limited in the United States. Japan must independently increase deceased donor transplantations.     

Apheresis therapy for living-donor liver transplantation: experience for apheresis use for living-donor liver transplantation at Kyoto University.

Liver transplantation is a fundamental treatment for patients with end-stage hepatic failure. In order to perform living-donor liver transplantations under safer conditions, apheresis plays a major role in Japan due to the prevalence of living-donor liver transplantation wherein later retransplantation is difficult. In our department, the roles of apheresis in liver transplantation are as follows: as bridge therapy to liver transplantation (n = 45); as a supplement to the graft liver until the recovery of hepatic function (n = 77); as treatment for multiple organ failure including posttransplantation renal failure (n = 15); and as a means with which to reduce antibody titers for antibodies such as anti-A or anti-B in persons with ABO blood type = incompatible liver transplantation (n = 23). In our department, we have performed 822 liver transplantations at present. Of those cases, 183 were selected wherein apheresis was performed around the time of the operation. In all cases, transplantation with sufficient apheresis was performed before the surgical operation, however, 22 patients (48.9%) died after undergoing surgery. Among the patients who underwent the postoperative apheresis, those in the nonsurvivor group had lower grafted liver weights compared to those of the survivor group. The kidney was the organ that most frequently failed due to postoperative complications. In cases of ABO blood type-incompatible liver transplantations, patients with high preoperative anti-A/B IgM antibody titers sustained bile duct complications, patients with high preoperative anti-IgG antibody titers sustained hepatic necrosis, and patients with high postoperative anti-A/B IgM and anti-IgG antibody titers sustained hepatic necrosis most frequently.     

40例亲属活体肾移植临床报告

目的：总结我中心4年40例亲属活体肾移植的经验.方法：40例患者中3例为夫妻间供肾,其余为血缘亲属供肾.术前均行HLA配型、PRA及淋巴毒试验检查.手术全为开放手术取肾,取左肾32例,右肾8例;受者均为第一次接受肾移植手术.术后以环孢素A（或他克莫司）、霉酚酸酯及泼尼松三联抗排斥反应治疗.结果：供者术后1周内出院,随访至今,肾功能均正常.受者术后36 d内出院,出院时肾功能正常,随访2～48月,未见肾功能异常病例. 结论：术前对供、受者的正确评价及成熟的手术技术是手术成功的保证,术后坚持随访和合理应用免疫抑制剂是受者长期存活的关键.亲属活体肾移植组织配型好,术前可充分准备,术后用药量少,手术成功率和长期存活率高,是一种安全可靠经济的治疗手段.