Donor shortage in heart transplantations is a worldwide common issue. The revised organ transplantation law became effective in July 2010 to change the situation in which overseas transplantations were required for pediatric patients. Since then, the number of heart transplantations has increased to 30-40 cases per year, from 10 or less before the revised law. However, the number of patients on a waiting list is skyrocketing, and an expected waiting period is lengthening to far longer than 3 years. The medical consultant system, which is a Japanese unique system of brain-dead donor management, was started in 2002. It enabled us to procure and transplant hearts from marginal donors frequently. In this review, the results of marginal donor heart use in the United States and Europe and the present status of marginal donor use and influence on long-term results are examined.

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In Japan, because of the very limited number of cadaveric donors in the pediatric generation, a partial graft from a related living donor or a split graft from a cadaveric donor remains a popular modality. Reflecting this background, discussion about the marginal donor for the pediatric age group in Japan includes such factors as graft size, vascular anatomy, transmission of the genetically defined anomalies, HLA matching, and ABO incompatibility, instead of factors common in Western countries. Details are discussed in each.

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The severe scarcity of deceased donors is a critical issue in Japan, which leads to maximal effort to us limited brain-death donors for transplantations. The words “extended criterial donor graft" or “marginal donor graft" usually encompass the liver grafts from donors with known risk factors for primary nonfunction or graft dysfunction after liver transplantations. Steatosis of the graft, aged donors, cardiac death donors, hepatitis virus positive donors, split liver grafts, and grafts with long cold ischemic time are usually referred to as marginal grafts; however, there are no established criteria for the extended criteria liver graft so far. This article reviews the extended criteria (marginal) donor graft in deceased donor liver transplantations in Japan, with special reference to split liver transplantation.

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Kidney transplantation is among the most effective therapies for patients with end-stage renal disease (ESRD). However, dialysis therapy is more commonly used compared to kidney transplantation in ESRD patients because of the shortage of donors in Japan. The gap between the number of wait-listed patients for kidney transplantation and the number of donations has forced transplant institutions to consider kidneys that are normally not considered for transplantation. These so-called marginal donors include cadaveric donors whose kidneys are of suboptimal quality and elderly living donors who have one or all of these conditions: hypertension, obesity, and diabetes. The most common problems with the use of marginal donors in transplantation are slow and delayed graft functions and graft failure in the short and long terms after kidney transplantations, respectively. Because the acceptability of elderly living kidney donors remains controversial, we summarized the outcomes of kidney transplantations from these donors in our institute. The risk of slow, but not delayed, graft function was higher in the kidney transplant patients who received transplants from elderly living kidney donors than those who received transplants from young donors. No significant difference in death-censored long-term graft survival rate was observed between patients who received transplants from young donors and those who received transplants from elderly donors. However, patient survival rate was significantly lower among the latter than among the former. These findings support the use of grafts from elderly living donors for kidney transplantation. When both the recipient and marginal living donor are well informed of the potential risks, kidney transplantation with suboptimal kidneys can be a better choice for eligible patients with ESRD.

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Most studies reported from the world's high-volume centers demonstrated encouraging short- and long-term outcomes after extended criteria lung transplantations. Pushing the limit of donor selection is worth the effort in the current situation of a huge organ demand-supply gap. However, sensible risk-oriented management should be undertaken to alleviate the negative influence of donor lung qualities and to a secure feasible survival outcome in an extended criteria lung transplantation. The key factors to success include a best donor-recipient risk matching, surgery with minimal dependence on heart lung apparatus, and posttransplant recipient management with maximal care of protecting allograft from oedema. The current lung selection criteria can be safely relaxed on a case-by-case basis only if donor risk factors are accurately and specifically identified and the recipient is managed appropriately to be prepared to recondition extended lungs in the body after transplantation.

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In terms of absolute shortages of donors, organ transplantation in Japan is in a more serious position than in Europe or the United States. In Japan, a law allowing organ transplantation from brain-dead donors finally came into force in October 1997. The first pancreas transplantation (PTx) was successfully performed at Osaka University Hospital in April 2000. Since then, however, only 86 cases of procurement have occurred over the approximately 13 years after introduction of the law; it was very strict and limited to organ procurement from donors who had provided prior written consent. The law was eventually revised in July 2010 to more closely resemble laws in Europe and the U. S.
After this revision, the number of donations has increased approximately seven-fold. The number of such procedures totaled 146 (33.0/year, as of December 31, 2014) after the revision, compared to 64 (4.9/year) before the revision. However, the rate of marginal donors is 67.1%, which is still high.
Although the number of donors increased, donor shortages and severe environment surrounding donors still exist in our country. Transplant outcomes, however, are comparable to those in Europe and the U. S.
This report examines the present status and problems of PTx in Japan from the perspective of “marginal donors.”

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Although recent progress in the field of regenerative therapy for thin tissue, e.g., dermis or digestive tract mucosa, and tissue with simple construction and function, e.g., bone or cartilage, is advancing, the development of parenchymal organ regeneration is behind. The difficulties of understanding complicated structures and functions of three-dimensional organ are considered reasons for the delay. Especially, there is a strong demand for the investigation of novel therapeutic options for organs failure of such vital organs, e.g,. liver, kidney or pancreas, but it remains only halfway finished. Therefore, new methods to facilitate recovery from such organ failure are highly desirable. Recent progress in the field of tissue engineering has opened attractive approaches for clinical applications of regenerative medicine. Of these, tissue decellularization technology, which retains all the necessary cues for cell maintenance and homeostasis, has recently been applied to whole organs. In this review, we focus on tissue decellularization as a new therapeutic approach.

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Development of the ventricular assist device (VAD) started in the 1960s, and bridge use of VAD in heart transplantations (BTTs) started in the 1980s. Thereafter VAD spread widely in Western countries. The commercially available first generation of pulsatile-flow implantable left ventricular assist device became popular as a BTT device in the 1990s, and the second and third generations of continuous-flow implantable LVADs were introduced in the 2000s. The concept of destination therapy (DT) with implantable LVAD was proposed by a Columbia University team in 1997. According to the results of the REMATCH study and the HeartMate II DT study in the United States, DT indication of HeartMate VE was reimbursed in 2002 for patients ineligible to receive heart transplantations, and that of HeartMate II in 2010. A shortage of donor hearts is now serious even in the United States, where heart transplants have become popular as a standard treatment of severe heart failure. Therefore DT cases are rapidly increasing. The shortage of donor hearts in Japan is extreme, and the annual number of donor hearts to be the thirtieth of the US population ratio, heart transplants never gained the status of standard therapeutic strategy for severe heart failure in Japan. At the moment, implantable LVAD is reimbursed only for BTT indication. If we view the primary role of an implantable LVAD as an alternative treatment for a heart transplant, we should begin to discuss how to introduce DT into Japanese clinical fields as soon as possible.

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【Objective】The wide gap between the number of patients on the waiting list for pancreas transplantation and the insufficient number of organ donors results in the use of “critical" donors, so-called marginal or extended criteria donors (ECD).
【Methods】Thirty six pancreas transplantations from brain-dead donors were performed in our institute from 2001 to 2014. They were evaluated for the conventional criteria concerning ECD previously advocated and new criteria that we have recently proposed.
【Results】According to conventional criteria, most brain-dead donors were excluded from the application of a pancreas transplantation; however, they actually developed excellent primary organ functions.
【Conclusion】It appears that conventional criteria for ECD are too restrictive and that our criteria fit into the reality of Japan.

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【Objective】Although the reported incidence of medication non-adherence after pediatric liver transplantation (LT) is from 5.6% to 65.0%, and the reported incidence of graft failure due to medication nonadherence is 17.0%, the current state of medication non-adherence in Japan is unclear. In this study, we sought to clarify the current state of medication non-adherence in our institution and investigated measures to prevent medication nonadherence.
【Design】From June 1998 to February 2013, a total of 125 LTs were performed in our institution and others. All patients were beyond the age of junior high school students (geq 12 years old). The investigation period was January 2014 to January 2015.
【Methods】Data regarding the frequency of medication nonadherence and medication management were retrospectively collected based on the medical records by the attending physicians. The patients were classified in two groups, namely, the good-medication adherence group and the medication nonadherence group, and risk factors for medication nonadherence and factors related to medication management were evaluated. The rate of medication nonadherence was clarified by age at this investigation and at LT.
【Results】Medication nonadherence was observed in 42 cases (33.6%). The ages at this investigation and at LT were significantly higher in the medication nonadherence group than in the good-medication adherence group (p=0.05 and p＜0.01, respectively). The graft function was significantly worse in the medication nonadherence group than in the good-medication adherence group (p＜0.01), and more patients had graft failure (three (8.1%) vs. one (1.2%), respectively, p=0.12). In the 40 patients who received treatment with three types of immunosuppressants, the age at the start of medication tended to be higher in the medication nonadherence group than in the good-medication adherence group (p=0.11), and all patients with medication nonadherence had a graft dysfunction. With respect to social factors, the number of patients with ambulatory irregularities, and those, exhibiting medication self-management, changes in the home environment, and unpleasant experiences of medication were significantly higher in the medication nonadherence group than in the good-medication adherence group (p＜0.01, p＜0.01, p＜0.01, and p＜0.01, respectively).
【Conclusions】It is important to provide personal and continuous patient compliance instructions to patients shifting to medication self-management, such as patients beyond the age of junior high school students. It is necessary for self-managed patients to adhere to the patient compliance instructions, especially when immunosuppressant therapy is intensified. When the patient's family background or life situation changes, additional patient compliance instructions should therefore be provided despite the patient's age.

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【Objective】Living-donor liver transplantation (LDLT) outcomes have improved with advances in immunosuppression and surgical techniques. However, de novo malignancy after LDLT is a problem, and we aimed to examine its characteristics and surveillance.
【Methods】We retrospectively evaluated 164 recipients who survived for more than a year after undergoing LDLT at our department from July 1996 to October 2013. Postoperative surveillance included abdominal ultrasonography, abdominal computed tomography, gastrointestinal endoscopy, and fecal occult blood analysis.
【Results】Fifteen recipients (9.1%) had de novo malignancies. Lung cancer was the most common malignancy (n=3), followed by breast cancer (n=2). Skin, endometrial, bladder, kidney, tongue, gastric, colon, and pancreatic cancers; leukemia; and malignant lymphoma were also observed (n=1 each). The median duration and 10-year cumulative incidence of de novo malignancy after LDLT were 5.9 years （range, 0.3-10.6 years） and 17.7%, respectively. The incidence of cancer was higher in the LDLT recipients than in the general population (standard incidence ratio, 3.05). Routine surveillance identified de novo malignancy in only 5 patients (33.3%). The remaining patients (n=10) showed symptoms before diagnosis. Twelve cases (92.3%) of solid tumors, except advanced pancreatic cancer, were resected.
【Conclusions】The overall risk of malignancy was higher among LDLT recipients than among the general population. Early detection and treatment of de novo malignancy improved the long-term outcomes of LDLT. Therefore appropriate surveillance methods for de novo malignancy are required.

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【Objective】Donation after cardiac death (DCD) is internationally considered to be an encouraging source of organs for transplantation and has a potential to increase the number of organ donors. The purpose of this study is to clarify the current state of deceased kidney transplantations in Kanagawa Prefecture, Japan, and to assess the availability of DCD donors.
【Methods】From July 2010 to October 2013, thirty-six kidney transplantations from 24 deceased donors were performed in Kanagawa Prefecture. We retrospectively reviewed the clinical records of these donors and their recipients and compared the outcomes of deceased donor kidney transplantations between DCD and donation after brain death (DBD).
【Results】Comparisons of the donors between 12 DCD and 12 DBD revealed that the DBD donor group was younger (P＜0.01) and had a higher percentage of females (P=0.04). Also, the DCD donor group had longer warm ischemia times (P＜0.01) and longer durations of anuria before donation (P＜0.01). Significant differences were not found in other donor factors (cause of death, serum creatinine on the day of admission, history of hypertension, history of diabetes mellitus, and history of cardiac arrest before donation). In the recipients of deceased kidney transplants (21 from DCD and 15 from DBD), the DCD group had longer cold ischemia time (P＜0.01) and longer total ischemia time (P＜0.01), higher delayed graft function rate (P＜0.01), and longer duration requiring hemodialysis after transplantation (P=0.03). No significant differences were observed in serum creatinine levels (P=0.12) and other recipient factors (age, sex ratio, waiting period, and HLA mismatch) between the two groups. At a mean follow-up time of 376±260 days, 34 recipients were alive with functioning grafts; one DCD recipient was alive with primary graft nonfunction, and one DBD recipient had died with a functioning graft.
【Conclusions】Although based on a limited number of cases with short follow-up periods, our study suggests that the outcomes of kidney transplantation from DCD donors are comparable with those from DBD donors, and DCD transplantation has the potential to expand the donor pool.

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A 57-year-old woman with blood type A Rh-positive was referred to our hospital to receive a liver transplantation resulting from a diagnosis of acute liver failure. She received a deceased liver graft from a man with blood group O Rh-positive. The surgical procedure was carried out uneventfully. Her immunosuppressive regimen was composed of tacrolimus, steroids and mycophenolate mofetil. On day 6 after transplantation, contrast-enhanced computed tomography was performed to investigate the cause of anemia, but no evidence of bleeding was seen. Although 10 units of group A concentrated red blood cells were transfused in 6 days, the value of hematocrit decreased to 17.0%, from 20.8%. The value of haptoglobin was 5 mg/dl. Direct Coombs test showed positive results. The titer of anti-A antibodies was x8. The recipient's lymphocytes were separated from whole blood to perform Y-chromosome-specific in situ hybridization. Under the microscope, one lymphocyte with Y chromosome was seen in 500 lymphocytes. Taken together with these results, anti-A antibodies produced by donor lymphocytes were thought to be involved in the pathogenesis of this case. Following the previous reports, we started to use group O concentrated red blood cells, and the level of hematocrit was elevated. Direct Coombs test became negative on day 19 after transplantation, and the titer of anti-A antibodies became negative on day 107. She was discharged from our hospital on day 55, and remained in good health with no evidence of recurrence.

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For kidney transplant patients, cytomegalovirus (CMV) after a transplant is a major concern because replication of or reinfection with this virus can influence transplanted kidney function and patient prognosis. Results of the seroprevalence of CMV antibodies in recent years demonstrate an inclination toward an increase in CMV infections. Further, there have been cases refractory to treatment as a result of increasing CMV resistance to ganciclovir (GCV). In this study, we had two cases in which we were able to effectively treat CMV by revising the administration time for patients to 4 hours. In these patients, primary treatment according to the general GCV administration method (administered in 1 hour) was ineffective. The first case was a 39-year-old male patient whose GCV treatment was ineffective because of GCV-resistant CMV resulting from a UL97 variation. After an extended administration period of 4 hours, a quick recovery was achieved. The second case was also a primary CMV infection in which GCV was administered at its maximum dose; however, the patient still demonstrated poor recovery. Extension of the administration period to 4 hours also resulted in a quick recovery of CMV antigenemia assay. In cases of ineffective treatment for CMV infections with general GCV administration, prolonged administration times with the same amount of GCV have resulted in effective CMV treatment, although there was no effect on the GCV trough levels. Maintaining concentrations above GCV therapeutic levels for prolonged periods may provide effective treatment for difficult cases.

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