Until the Japanese Organ Transplantation Act was revised on 17 July 2010, only persons who had a written consent for organ donation after brain death could donate their organs in Japan, and children under 15 years of age could not donate their hearts after brain death. Therefore small children could not undergo a heart transplantation (HTx) in Japan, and many Japanese children traveled abroad to undergo HTx. After revision of the Act, small children were able to donate organs if their family agreed; ultimately, six children (one younger than 6 years, three from 10 to 14 years, and two from 15 to 17 years) donated their hearts through 2014. In this review, the current status and issues of pediatric HTx in Japan and indication of pediatric HTx and management before and after HTx are described. Briefly, most indications of HTx were dilated cardiomyopathy (DCM) and restrictive cardiomyopathy in Japan, and in Japan many candidates with DCM required a left ventricular assist device (LVAS) for bridge to HTx. The immunosuppressive regimen was calcineurin inhibitor and mycophenolate mofetil, and steroid was discontinued within 6 months in most children. Patient survival at 10 years after HTX was 100% in children transplanted in Japan and 87.6% in children transplanted abroad. Posttransplant lymphoproliferative disorder and various infections were major morbidity and mortality. Non adherence should be paid attention, especially to take care of adolescent patients.
In July 2010, the domestic law for organ transplants was revised to enable children under 15-year of age to donate their organs if the parents had given consent in the case of brain death. After this revision, the substantial number of pediatric heart transplantations was expected to increase; however only 7 cases were performed during these 5 years. The problems related to the shortage of organ donors and long waiting times for orthotopic heart transplantations have not yet been resolved. As a result, new treatment strategies including innovative mechanical devices and regenerative therapies for pediatric heart failure, are critically needed. Accumulated evidence of cardiac regeneration strategies using various types of somatic stem cells have revealed the efficacy of stem cell therapies for heart failure. Initial results of the Transcoronary Infusion of Cardiac Progenitor cell infusion in patients with single ventricle physiology (TICAP) phase I study (NCT01273857) conducted at Okayama University (2011-2013) have shown that intracoronary infusion of cardiosphere-derived cells (CDCs) following staged palliation was feasible and safe to treat children with hypoplastic left heart syndrome. Currently, a randomized phase II trial (Cardiac Progenitor Cell Infusion to treat Univentricular Heart Disease: PERSEUS, NCT01829750) is ongoing at our institution to verify the therapeutic efficacy of CDC infusion in patients with univentricular heart diseases. From 2016, we will conduct a countrywide sponsor-initiated multicenter clinical trial to construct this therapeutic strategy for children with heart failure as an insurance coverage treatment. In this review, we discuss the problems involved with end-stage pediatric heart failure and the current status of stem cell therapy for heart failure in children.
Lung transplantation is now an acceptable therapeutic option in patients with end-stage lung disease. In pediatric lung transplantation, living-donor lung transplantation remains important with the current shortage of suitable cadaveric donor lungs. Especially for infants and small children, technical innovation of living lung transplant with adult middle lobe or lung segment instead of lower lobe is important because the adult lower lobe is too large to fit in to the small recipient chest. Five-year survivals of pediatric lung transplants at Okayama University and the world average are 89% and 51%, respectively. However, when it comes to lung growing, a size- and age-matched brain-dead pediatric donor remains ideal.
Even with a recent increase in the number of donors, a remarkable donor shortage remains in pediatric lung transplantation. Moreover, lung transplantation in pediatrics is still challenging in its perioperative management.
In preoperative time, it is difficult to determine an exact normal range for the pediatric population. In anesthetic induction, residual respiratory function must be carefully considered. In severe cases, extra corporeal support should be prepared. Because hemilateral lung transplantation is common in children, their induction is normally safe. Prevention of hyperinflation associated with permissive hypercapnia must be considered. Sometimes nitric oxide is useful to control pulmonary hypertension and severe hypoxemia. It normally takes over 30 minutes to wean from a cardiopulmonary bypass for the prevention of ischemia-reperfusion injury. At weaning time, we always use nitric oxide.
After operation, primary graft dysfunction, anastomosis leakage, acute rejection, and infectious complications must be considered. We try to wean mechanical ventilation as soon as possible. It normally takes 2-3 days on average. Unnecessary hyperinflation should be avoided. In some cases, vasoactive drugs such as milrinone were used.
There are huge variations in patients' conditions and underlying diseases. We must pay special attention to patient status in each case. Bronchiolitis obliterans and primary pulmonary hypertension are the most common underlying diseases, and special care is necessary for these types of recipients.
Among a total number of 7,474 liver transplants, 2,639 pediatric liver transplants were performed until the end of 2013. The Japanese Liver Transplant Registry revealed excellent outcomes of pediatric liver transplantations, 91.8% at 5-year patient survival rate, as a result of recent advances not only in surgical procedures, but also in perioperative management. The indication of pediatric liver transplantation has been widely expanded; especially small children suffering from critical liver disease in infancy can now undergo living donor liver transplantation (LDLT) by using monosegmental grafts. Although the number of deceased donor liver transplantation is still low in Japan, split liver transplantation is a promising way to expand the donor pool. Domino liver transplantation, using the liver from maple syrup urine disease, has also recently been launched as another therapeutic option of LDLT.
Kidney transplantation (KT) is the preferred treatment for end-stage renal disease in children. Compared to dialysis, it confers improved survival, skeletal growth, health-related quality of life, and neuropsychological development.
In Japan, 3.5～4.7 per million children start renal replacement therapy every year. Compared with adults, there is greater use of peritoneal dialysis (PD) or KT as primary therapy. When considering children younger than 5 years of age who began dialysis as their primary mode of renal replacement therapy from 2009 to 2013, we find that 87% were treated with PD, and 22% have received KT preemptively.
The number of pediatric KTs has remained steady at approximately 90 over the past several years. Because of the severe shortage of suitable deceased donor (DD) allograft, most children (85% to 90%) have received kidneys from their living relatives. However, the number of DD KTs has gradually increased since 2002 because the policy was changed for children under the age of 15 to receive priority points.
Graft survival has continued to improve over the past decade. The 5- and 10- year graft survival rate from 1996 to 2009 are 90.1% and 81.1%. Graft survival estimates were 90.1% at 5 years and 81.1% at 10 years for transplants in the same period.
A greater pediatric priority might be associated with a significant decrease in waiting time for DD KTs and a significant increase in the pediatric KT rate.
More action should be extended to increase the total number of DD kidneys. Further, we should increase discussion the new allocation policy concerning kidneys from pediatric donor.
Hepatocyte transplantation (HT) has been indicated in patients with metabolic liver diseases and acute liver failure as a bridge or an alternative to liver transplantation. HT has the benefit of non-invasive treatment, availability of hepatocyte isolated from marginal donors and cryopreserved hepatocytes at the time of need. On the other hand, HT has the disadvantages of injury of hepatocytes after thawing, difficulty of monitoring acute cellular rejection after HT, and few supplies of hepatocytes for HT. Approximately 100 cases of HT have been reported, and infused hepatocytes were derived from deceased donors or nonheart-beating donors in all cases. In our study, hepatocytes were isolated from the remnant liver of reduced left-lateral segment graft from a living-donor. We experienced two cases of HT using hepatocytes from a living-donor for the first time worldwide. One case was neonatal ornithine transcarbamylase (OTC) deficiency, and the other was neonatal carbamoyl phosphate synthetase 1 deficiency (CPS1D). HT was performed successfully in both. In the case of OTC deficiency, the patient underwent living-donor liver transplantation from his mother 5 months after HT. In the CPS1D case, 4 months have passed since HT, and the patient is waiting for a living-donor liver transplantation. In this manuscript, we review the current situation of HT and our experience of HT using hepatocytes from the remnant liver of a reduced left-lateral segment graft in a living-donor liver transplantation.
Since the Organ Transplantation Act was issued in 1997, confirmation of a recipient's intent has been carried out after the sentence of brain death to the donor family by two steps of its determination in Japan. Therefore, transplant centers could prepare organ procurement and transplantation for the recipient once this has been done. This prolonged the total period of procurement process between a donor call to the Japanese Organ Transplant Network and end of the procurement operation. After many years of requests by emergency physicians, a new rule was accepted by the government on 14 February 2015 to settle the recipient's intent earlier than the second determination of the donor's brain death.
A donor is evaluated by medical consultants to determine which organ can be transplanted and the method of donor management, during the period between two steps of determination of brain death. Also, lymphocytes cross match is also done at that time. These processes are essential for the transplant center to decide whether to transplant the particular organ to their recipient. Therefore we should consider these things to renew the process of organ procurements from brain-dead donors in Japan.
【Objective】Pregnancy after renal transplantation sometimes severely affects function of a grafted kidney. The aim of this study is to reveal the influence of pregnancy on kidney grafts. 【Design】Retrospective study of 4 cases. 【Methods】From Apr. 2004 to Nov. 2014, a total 371 cases were followed for immunosuppressive therapy after renal transplantation. Among them, 4 cases experienced 5 pregnancies. The course of the 5 pregnancies was reviewed and the deterioration of the graft function analyzed. 【Results】Primary renal diseases were IgA nephropathy (n=3) and chronic glomerulonephritis (n=1). The maintenance immunosuppressive agents consisted of calcineurin inhibitor (cyclosporine A n=3; tacrolimus n=1), antimetabolite (mycophenolate mofetil was changed to azathioprine), and prednisolone. Pregnancies in 2 cases had no trouble in the graft kidneys. In another case, function of the graft kidney deteriorated after the delivery. The rate of increase in serum creatinine was 11%. The 4th case, which had a recurrence of IgA nephropathy, had a normal course in her first pregnancy and labor at term after transplantation, but she developed a complication of preeclampsia during the second pregnancy. This caused severe activation of the recurrent IgA nephropathy, which necessitated reintroduction to dialysis therapy within half a year. 【Conclusion】In cases with potential deleterious effects on kidney grafts, more detailed informed consent is required, as shown here, with the risk involved in pregnancy after renal transplantation, which, however is minimal if the graft condition is good. If a transplant patient is determined to have a child in spite of the risk of kidney dysfunction, more rigorous control is required of general conditions, especially of blood pressure.
【Objective】Tacrolimus is a potent immunosuppressive drug. But because of its narrow therapeutic range, the monitoring of blood level is necessary. Various methods of measurement are available. We evaluated two immunoassay methods: affinity column mediated immunoassay (ACMIA) and chemiluminescent enzyme immunoassay (CLIA) using identical blood samples. 【Methods】We tested 2074 blood samples obtained from 196 patients from June 2010 to February 2012. The mean age of patients was 58.9 (range 22.5-88.9) years. Primary diseases included rheumatism, lupus nephritis, inflammatory bowel disease, polymyositis, dermatomyositis and myasthenia gravis. Treatments included hematopoietic stem-cell transplantation, renal transplantation and liver transplantation. ACMIA and CLIA were carried out according to manufacturer instructions using Dimension™ Xpand-HM and ARCHITECT™ i1000SR, respectively. 【Results】Mean blood concentrations of tacrolimus (in ng/mL) were 6.0 (ACMIA) and 7.2 (CLIA), and this difference was significant (p＜0.01). Excellent linear correlation (R2 = 0.92) was observed, but the blood concentration measured by ACMIA was 19% lower than that obtained by CLIA for all samples. At low concentrations of CLIA (＜5 ng/mL), the discrepancy was more than 40%. 【Conclusion】Tacrolimus concentration in blood as measured by ACMIA was significantly lower than that measured by CLIA. It is clinically important to understand the characteristics of the two methods.
【Objective】In the Shizuoka area, we have managed kidney transplant recipients on the initiative of nephrologists in collaboration with urologists. We carried out this study to assess whether we had performed living-donor kidney transplantations (LDKTs), including preemptive kidney transplantations (PEKTs) adequately, and to detect tasks for future promotion of them in the Shizuoka area. 【Design】Case-series 【Methods】We retrospectively reviewed all planned LDKTs at Shizuoka General Hospital from January 1, 2008, to May 31, 2015. Factors associated with the performance of PEKTs were analyzed, and we compared our number of LDKTs and executing rate of PEKTs with the national average and the average in Aichi Prefecture. 【Results】Fifty-five patients were referred to our division of transplantation from 22 hospitals in Shizuoka Prefecture. Fifty LDKTs were performed. The estimated glomerular filtration rate (eGFR) value of all 20 patients without dialysis treatment when introduced was lower than 15 ml/min, and we could perform PEKT on 8 recipients. The lower creatinine and the higher eGFR value were associated with the performance of PEKT (p＜0.05), but referral from our own facility and diabetic nephropathy were not associated (p＞0.05). 【Conclusions】We identified the characteristics of LDKTs including PEKTs in the Shizuoka area. Compared with the averages of Japan and Aichi Prefecture, the numbers of LDKTs and PEKTs were obviously low. Despite the initiative of nephrologists, we ourselves could not perform PEKTs appropriately because of late referral. We believe that appropriate explanations of transplantations by nephrologist at earlier stages are associated with subsequent promotions of LDKT and PEKT.
【Objective】Although the annual number of deceased organ donations in Japan has been slightly increasing, the number per million citizens was much lower than in other countries. To find the attitude toward organ transplantation among hospital employees, a cross-sectional questionnaire survey was conducted. 【Design】A cross-sectional questionnaire survey of general hospital employee. 【Methods】The questionnaire form used was the public opinion poll conducted by the Cabinet Office in August 2012. Questionnaires were distributed to 532 employees at the Japan Baptist Hospital, and the results were summarized and compared with the report of a current opinion poll. 【Results】The number of respondents was 401 (75.3%). Eighty-percent were female, and 30% were age 30 to 39 years. Nine percent were physicians and 42% were nurses. Sixty-five percent of respondents had interest in organ transplantations, and 51% had talked about organ transplantations with their family members. Responses to questions regarding knowledge on the amended organ transplant law were as follows: 63.0% understood that a child under 15 years old could become an organ donor, and 62.8% understood that family members could give permission for donation when a brain-dead person had not shown his living will. These percentages were lower than those of a public opinion poll (70.2%, 66.9%). As compared to the poll results (12.6%), a higher number of respondents had signed their organ donor cards (25.9%). 【Conclusion】High interest in organ transplantations was observed through a questionnaire survey of general hospital employees. Continuing medical education on up-to-date knowledge of organ transplantations may be needed for medical professions
Fibrin degradation products, D-dimer (FDP-DD), and soluble fibrin (SF) are useful markers for the diagnosis of thrombosis. Among them, SF is relatively new, so the dynamics of SF during thrombolytic therapy for portal vein thrombosis (PVT) have not been well known.
A 9-month-old girl underwent living-donor liver transplantation at her 7 months as a result of biliary cirrhosis after Kasai's procedure. The clinical course after transplantation was uneventful, and she was discharged on postoperative day 42. Six days after discharge, because of cholangitis with high fever, she entered our hospital, and ultrasound revealed PVT in the umbilical portion. At the time of diagnosis, the values of SF and FDP-DD were 12.5μg/ml, and 11.9μg/ml respectively. Five days after the initiation of thrombolytic therapy, PVT had disappeared. The value of SF was below the measurement sensitivity, but that of FDP-DD was 9.6μg/ml. The FDP-DD value fell to normal 27 days after the initiation of thrombolytic therapy. She now shows no signs of recurrence of PVT after an 11-month follow-up.
Imaging study and measurement of FDP-DD are essential to diagnose PVT. Because this case shows the possibility of SF as a useful surrogate maker to estimate thrombosis and thrombolysis in PVT after LT, further investigation is expected.
Severe pulmonary arterial hypertension (PAH) is a fatal disease, although lung transplantation is an option when medical therapy is exhausted. In Japan, the most common approach is living-donor lobar lung transplantation (LDLT). Outcomes after LDLT are steadily improving but remain poorer than those for heart transplantation, mainly because of the high incidence of post transplant bronchiolitis obliterans syndrome (BOS), which sometimes occurs later than 10 years after surgery. BOS is rare in LDLT, and the symptoms are milder than those associated with cadaveric lung transplantation as a result of hemilateral lung rejection of donor tissue. Furthermore, onset is usually insidious.
Here, we report a case of a 27-year-old woman with BOS that developed 15 years after LDLT for severe heart failure (New York Heart Association functional class IV) caused by idiopathic PAH. The ABO blood type-compatible donors were the parents of the patient, who received subsequent treatment with cyclosporin A, mycophenolate mofetil, and low-dose prednisolone. She had been well and working full-time, but her trough cyclosporin A level had decreased to ＜150 mg/dL because of poor drug compliance 1 year before admission. Fifteen years after transplantation, the patient reported mild dyspnea while walking up stairways. A pulmonary function test showed reductions in forced expiratory volume in one second (FEV1) (＜70%) and maximum midexpiratory flow (＜25%). Lung perfusion scintigraphy revealed BOS of the right lung (her father's right lower lung). Aggressive treatment included intravenous methylprednisolone, oral azithromycin, inhalation of bronchodilators, tiotropium bromide, and beclomethasone as well as dose adjustment of cyclosporin A and mycophenolate mofetil. Because of these treatment modifications, her status remained unchanged (Hugh-Jones I) and did not worsen. In conclusion, even 15 years after LDLT, BOS manifesting as chronic allograft rejection may occur if anti–graft rejection medication is not properly administered.