Early diagnosis and early treatment are important for the antibody-mediated rejection (AMR) to account for 10%-20% of the rejection after heart transplantation because of poor prognosis and the onset extension risk of the cardiac allograft vasculopathy (CAV).
More than 90% of patients have been waitng for heart transplantations with a ventricular assist device for approximately 1,000 days in our country, and anti-HLA antidodies, which cause AMR extension to the next CAV after the transplant, have been paid attention to.
The development of the test to detect advances for anti-HLA antibodies in recent years, and there are CDC-XM (complement-dependency-related cytotoxic tests), AHG-XM, FCXM (flowcyte cross-match), Solid-phase Assay (ELISA, FCM, Luminex), make it necessary to know that each characteristic by a target specific antibody, the sensitivity, of the effect of the drug in each to be different.
It is recommended that the examination for AMR by the measurement of anti-HLA antibodies and C4d-immunostaining in the posttransplant myocardial biopsy in two and four weeks, and subsequently in 3, 6, 12 months posttransplant, and when clinical AMR is suspected. About AMR caused by the non-HLA antibodies, we soon expect the development of a non-HLA antibody method for measurement.
As for the AMR treatment, plasmapheresis, a large amount of intravenous immunoglobulin (IVIG), anti-CD20 monoclonal antibody (rituximab), use of corticosteroid and/or cyclophosphamide, and switching from cyclosporine to tacrolimus for the immunosuppressive therapy are considered.
The knowledge of antibody-mediated rejections in lung transplantations is quite limited compared with those in liver and kidney transplantations. In lung transplantation, an ABO-incompatible transplantation is basically contraindicated, and crossmatch-positive transplantations are also not widely performed. However, the importance of antibody-mediated rejections has been currently recognized by physicians and surgeons involved in lung transplantation. In the current international consensus statements, the monitoring of donor-specific antibodies and accumulation of diagnoses of antibody-mediated rejections have been recommended in lung transplant centers. These practices would soon clarify the true mechanism of antibody-mediated rejections including donor-specific antibodies, which will also pave the path to the establishment of their treatment.
Donor-specific Antibodies (DSAs) are risk factors for rejection and graft loss in solid organ transplantation, especially associated with all HLA (Human Leukocyte Antigen) loci and class II in case of pre- and post-transplantation, respectively. It is recognized that the reactivity of HLA antigens varies according to the difference in HLA allele in the same HLA serotype. Therefore, epitope analysis becomes the useful method for evaluation of the HLA antibody specificity. Thus, HLA allele matching is more useful than HLA serotype matching, because it is possible that the same epitope in different HLA allele of patients and donors possessing the same HLA serotype is not shared. According to analysis of the association with epitope mismatch and rejection or graft loss reported by Wiebe et al, more numbers of HLA epitope mismatch causes worse outcome. The reason is attributed to the higher opportunity of de novo DSA production.
When the focus is on HLA antibodies detection, LCT (Lymphocyte Cytotoxicity Test), FCM (Flowcytometry), and Luminex method are widely used. The characteristics of these three methods are different. The LCT and FCM methods are based on the reaction of panel lymphocyte mixed with patient's serum but they are considered unsuitable for the identification of HLA antibodies specificities as this requires various kinds of panel lymphocytes. The Luminex method is based on solid phase assay, which uses the polystyrene bead coated with purified HLA antigen prepared by two different methods. One of them is the PRA (panel reactive antibody) method that utilizes HLA antigen extracted from a lymphocyte, and the other one is the SAB (single antigen bead) method, which utilizes HLA antigen prepared through gene-recombination technology. Interpretation of HLA antibodies specificity is difficult because of dissimilarity of beads made in two methods.
Two ways are considered for crossmatch test. One way is called the "direct crossmatch", in which test is made to determine whether donor lymphocytes in added patient serum are living or dying, similar to the LCT or FCM method. Another way is called the "virtual crossmatch", in which test is made to determine whether HLA type of donor and HLA antibodies specificity of the patient are same or different. The "virtual crossmatch" is more useful when not using donor lymphocytes and high sensitivity, but this is not so close to reaction in the body. The most ideal strategy is to conduct the "virtual crossmatch" test first because of high sensitivity, followed by the secondary "direct crossmatch" test if the result in the first test is positive, for more closer reaction of the body. Recently, ICFA method has been shown to be a more sensitive "direct crossmatch" test. We must choose the best way for crossmatch according to the situation.
Advances in immunosuppressants, such as rituximab, basiliximab, and others, enable organ transplantation for sensitized patients. In fact, an adequate desensitization protocol would lead to acceptable outcomes in the acute phase. However, it is true that the management of acute or, in particular, chronic antibody-mediated rejection resulting from donor-specific antihuman leukocyte antigens (HLA) antibodies, is still an important issue to improve better long-term graft survival. Thus DSAs seem to be a central research topic in the field of organ transplantation. In the 1960s, the introduction of azathioprine brought the beginning of contemporary renal transplantation. Following this, the barrier of anti-AB antigens and anti-HLA antibodies was recognized: incompatibilities were considered as a high risk factor for renal transplantation. In the next half-century, the main attention was paid to T cell-mediated rejection. This led to the development of calcineurin inhibitors and several antibody drugs: a depletion of lymphocytes that enabled the control of T cell-mediated rejection. DSAs have finally received much attention in the 21st century because controlling them brings better outcomes in renal transplantations. This manuscript refers to examination, diagnoses, management, treatment, and outcomes in DSA-positive renal transplantation.
The impact of donor-specific anti-HLA antibodies (DSA) on liver allograft remains elusive. The impact of DSA may cause two types of antibody-mediated rejection (AMR) : one is acute AMR resulting in adverse consequences during the perioperative period, and the other is chronic AMR causing progressive fibrosis in the late liver allograft.
Because acute AMR does not necessarily occur even in patients with preformed DSA, to some extent the liver is considered to be resistant to AMR. However, evidence has accumulated that preformed DSA will cause liver graft injury. We previously experienced that the one-year survival rate of the crossmatch-positive patients was 60% without taking any measures. To clarify the impact of DSA, we examined DSA in the sera by Luminex solid-phase detection assay and retrospectively analyzed the influence on the outcome. And then, we have adopted the new strategy for DSA-positive recipients to prevent acute AMR. A one-year survival rate has become similar among DSA-positive and negative recipients.
The features of chronic AMR have not been well defined. We have reported that DSA are significantly correlated with progressive centrilobular fibrosis in the late allograft liver biopsies, especially in the pediatric recipients. The similar phenomena have been observed in the adult recipients. The impact of DSA on long-term prognosis is unclear from our experience, even through poor prognosis of patients with DSA was reported.
The impact of preformed DSA on the survival has been emerged. However, our current strategy to prevent fatal acute AMR to occur in DSA-positive patients significantly improved the survival rate. De novo DSA may cause progressive fibrosis, but the influence on prognosis of the graft in DSA-positive patients should be revealed through long-term observation.
Demographic data and the outcomes of pediatric kidney transplantations in Japan were reviewed based on the Japanese Renal Transplant Registry data from the Japanese Society for Clinical Renal Transplantation and the Japanese Society for Transplantation. The children were defined as patients who had not yet attained their 20th birthday at the time of transplant. A total of 2,876 kidney transplantations have been performed on children in Japan from 1964 to 2014. Transplants were categorized into four time periods (1964-1985, 1986-1995, 1996-2001, and 2002-2014) to reflect changes in immunosuppression practices over time (in general, introduction of cyclosporine, tacrolimus, mycophenolate mofetil, and basiliximab). Patient demographics have changed over time with an increase in the percentage of younger recipients, preemptive kidney transplantations and ABO-incompatible kidney transplantations. Patient survival and graft survival have also improved tremendously. The 5- and 10-year Kaplan-Meier estimates of patient/graft survival in living-donor recipients were 98.9/96.4% and 98.1/92.3% in the 2002-2014 cohorts. Also, the 5- and 10-year Kaplan-Meier estimates of patient/graft survival in deceased-donor recipients were 98.1/83.5% and 96.6/68.0% in the 2002-2014 cohorts. More efforts to define the clinical features and outcomes of pediatric kidney transplant patients are essential for better treatments for children with end-stage renal disease.
After the Act on Organ Transplant was revised to include an opting-in system by agreement from donors' family members without their antemortem consent and to permit the donation from pediatric donors younger than 15 years in July 2010, the number of deceased donor transplants was expected to increase dramatically. But the total number of liver transplants from deceased donors did not change significantly, and the majority of pediatric recipients still must rely on living donors. On the other hand, split-liver transplantation is an option for the expansion of the donor organ pool and enables the possibility of liver transplantation for two recipients with end-stage liver disease. Although an initial experience of split-liver transplantation in Japan had acceptable outcomes, further considerations of the techniques and indications are needed to expand its application. This is a report on the current status and issues of deceased-donor split-liver transplantations in Japan.
【Objective】Kidney transplant recipients are at increased risk of developing cancer in comparison with the general population. To effectively manage post-transplant malignancies, it is essential to proactively monitor patients. A long-term intensive screening program was associated with a reduced incidence of cancer after transplantation. This study evaluated the usefulness of the gene expression profiling of peripheral blood samples obtained kidney transplant patients and adopted a screening test for detecting cancer of the digestive system (gastric, colon, pancreas and biliary tract cancer). 【Methods】Nineteen patients were included in this study, and a total of fifty-three gene expression screening tests were performed. The gene expression profiles of blood-delivered total RNA and whole genome human gene expression profiles were obtained. We investigated the expression levels of 2,665 genes associated with digestive cancers and counted the number of genes in which expression was altered. A hierarchical clustering analysis was also performed. The final prediction of the cancer possibility was determined according to an algorithm. 【Results】The number of genes in which expression was altered was significantly increased in the kidney transplant recipients in comparison to the general population (1,091±63 vs. 823±94, p=0.0024). The number of genes with altered expression decreased after the induction of mTOR inhibitor (1,484±227 vs. 883±154, p=0.0439). No cases of possible digestive cancer were detected in this study period. 【Conclusion】The gene expression profiling of peripheral blood samples may be a useful and non-invasive diagnostic tool that allows for the early detection of cancer of the digestive system.
A 46-year-old male with a history of type 1 diabetes mellitus since he was 20 years old underwent a simultaneous pancreas and kidney transplantation. However, he required allograft pancreatectomy on day 2 after the transplantation as a result of venous thrombosis. One year later, he underwent pancreas retransplantation from a deceased donor. Because an intimal dissection of the right iliac artery was noted during the operation, he underwent surgical reconstruction of the external iliac artery with an e-PTFE graft. The postoperative clinical course was uneventful, and the pancreas graft functioned well. Candidates of pancreas and/or renal transplantation often have severe arteriosclerosis and vascular calcification. We must carefully select the position of anastomosis in the patient with severe arteriosclerosis, thus avoiding intraoperative arterial injuries.
Although the number of simultaneous liver and kidney transplantations from cadaveric donors has been increasing in Europe and the United States, removing organs from living donors for sequential liver and kidney transplantations (SeqLKT) is still rare. We present our experience using living-donor organs for not only the first SeqLKT but also a second kidney transplantation (KT). The patient is a 20-year-old woman with primary hyperoxaluria type1. When she was fifteen months old, SeqLKT was performed be removal from her father. Unfortunately, the renal graft loss was caused by chronic antibody-mediated rejection. Subsequently, a second KT was performed by removal from her mother. We believe this is a very rare case and a valuable experience considering the present situation of severe organ shortage.
With the aging of end-stage renal disease (ESRD) patients, transplant recipients are also aging. In the case of the elderly recipient, senescence of body function, donor selection, increased susceptibility to infection, and malignancy should be under consideration and immunosuppression protocol may play important role for elderly recipients. We report a case of an elderly kidney transplant recipient maintaining good graft function with everolimus and steroid withdrawing calcineurin inhibitor and mycophenolate mofetil. The patient is a 76-years-old man. Hemodialysis was introduced on February 12, 2010 in chronic renal failure resulting from diabetic nephropathy. On October 17, 2012, he received the kidney from his wife, who was incompatible with his ABO blood type. Plasma exchange was performed and rituximab was administered before transplantation. Tacrolimus, mycophenolate mofetil, and steroid were used for maintainance immunosuppression. A small inflammatory change was pointed out in the left lung by chest computed tomography before transplantation. After the transplantation, the inflammatory lesion gradually increased and was diagnosed as lung cancer. Surgical resection of the lesion was carried out on March 27, 2013, and everolimus was administered. Severe and prolonged pneumonia developed after the operation, and MMF and tacrolimus were then withdrawn.Everolimus and steroid have continued to be administered for 2 years and good graft function is maintained.