Organ transplantation remains the only fundamental treatment for end-stage organ failure. Immunosuppression therapy is the key to successful post-transplantation outcomes. Although the survival after organ transplantation has improved with the development of immunosuppressant, chronic rejection and side effects of long-term exposure to immunosuppression remain ongoing concerns. Immune tolerance is important for normal physiology, and occurs in two forms: central and peripheral. The regulatory T cell is the essential constituent in peripheral tolerance. Regulatory T cells specialize in suppressing immune responses, including autoimmune disease, allergy or alloreaction. Regulatory T-cell therapy in transplantation may be emerging as an alternative therapeutic choice.
Induced pluripotent stem cell (iPSC) -based technologies provide new opportunities in regenerative medicine to generate grafts for transplantation. The banking of iPSCs from donors with homozygous HLA haplotypes is planned in Japan, aiming to reduce immune reaction. Even though HLA-homozygous iPSCs are used, immune suppression would be inevitable because of minor antigen mismatches. A couple of studies concerning such immunological issues have been reported, including gene modification and immune regulatory cell induction from PSCs. Meanwhile, our research group has recently examined the concept that the recipient immune response against PSC-derived graft can be regulated by administration of immunoregulatory cells generated from the same PSC. This therapeutic approach prolonged the survival of PSC-derived allograft by suppressing host T cell proliferation and antibody production by B cells.
iPSC-based technologies provide us numerous benefits; however, considering their safety from an immunological point of view should be of great importance for the development and clinical translation of this novel techniques.
Induction of hematopoietic chimerism is thus far the only approach that was proven to be effective to induce allograft tolerance in nonhuman primates (NHP) and humans. In the United States, three centers have reported clinical trials for tolerance induction in recipients of living donor kidney transplants via donor hematopoietic stem cell transplantation. In these clinical trials, successful renal allograft tolerance induction has been achieved following induction of either transient mixed or persistent full donor chimerism. At Massachusetts General Hospital, based upon observations in murine models, we developed nonmyeloablative regimens to induce allograft tolerance through the mixed chimerism approach in NHP and humans. Despite detectable chimerism induced by our nonmyeloablative conditioning regimen typically disappears within 30-60 days, renal allograft tolerance was reproducibly achieved in MHC-mismatched kidney transplant recipients.
Improving the consistency of tolerance with less morbidity and extending the approach to deceased donor transplantation are critical next steps for wider clinical applications.
HLA haplotype-homozygous (HLA-homo) induced pluripotent stem cells (iPSCs) are being prepared as a national initiative referred to as the “iPSC Stock Project”, to be used for allogeneic transplantation of regenerated tissue into recipients carrying an identical haplotype in one of the alleles (HLA-hetero). In this article, we address the issue whether NK cells play any roles in graft rejection in this homo-to-hetero transplantation setting, and show our recent finding that NK cells from an HLA-hetero person can kill the cells regenerated from HLA-homo iPSCs when the KIR-ligand is mismatched, by the mechanism of missing-self response. Such cytotoxicity was cancelled when target cells were regenerated from iPSCs transduced with the “missing” HLA gene, providing the basis for an approach to prevent such NK cell-mediated rejection responses. We further discuss the frequency of KIR-ligand mismatch cases occurring in the iPSC Stock Project.
【Objective】 The frequency of pregnancies among kidney transplant recipients has increased due to improvement in kidney transplant health care. Marriage, pregnancy, and childbirth are important in a woman’s life, even for kidney transplant recipients. The goal of this study was to highlight the experience of childbearing for kidney transplant recipients and to investigate methods of nursing for that condition.
【Design】 Qualitative research.
【Methods】 Data collection was performed by conducting semi-structured interviews with three mothers who had experienced pregnancy and delivered their children after kidney transplantation.
The life history of each recipient was described according to the life history method, and we performed qualitative and inductive analysis.
【Results】 Four periods were considered in evaluating the experience of kidney transplantation subjects regarding pregnancy and childbirth. Recipients, who abandoned the possibility of motherhood before kidney transplantation, felt strongly that their purpose was to bear and rear children. On the other hand, since they suffered from anxiety resulting from the stress of rearing children since childbirth, it led to their poor health maintenance.
【Conclusion】 Recipients had abandoned the hope for bearing and rearing children before transplantation. However, the transplant enabled those women to experience childbirth and parenting; they appreciated such an experience and found something to live for. On the other hand, because health care gets neglected when one is busy with childcare, they were scared and afraid that their graft might get damaged. We concluded that it is necessary to transform their desire to be healthy for their child into self-health maintenance.
【Objective】 Significant improvements in survival and physical growth in infants following living donor liver transplantation (LDLT) for biliary atresia (BA) have been reported. However, cognitive and psychological development in infants after LDLT has not been well documented. We analyzed the physiological development of infantile transplant recipients with BA, especially those at one year post transplantation.
【Methods】 Eight BA patients younger than 1 year at the time of transplantation were enrolled between November 2013 and November 2014. All patients underwent physical therapy post transplantation. Psychophysical development was assessed using the Kyoto Scale of Psychological Development (KSPD) before the therapy, at the time of discharge, and one year after LDLT. The age of the patients ranged from 4 to 11 months. They had all received the diagnosis of type III BA and had undergone a Kasai portoenterostomy before age 5 months. The pediatric end-stage liver disease (PELD) score ranged from 6 to 21, and the Child-Pugh score was either grade B or C for all the patients.
【Results】 Five patients weighed less than −2SD preoperatively but approached the normal range in the following year. The height of one patient remained −2SD even one year after LDLT. All the patients had achieved head control and the ability to roll on the floor prior to the LDLT, and were able to walk within one year following the operation. The KSPD development quotient indicated that the postural-motor score was much lower than the cognitive-adaptive and language-social ability scores at the time of the LDLT and discharge but that it had improved one year later.
【Conclusion】 BA patients who received a LDLT in their infancy showed significant developmental delay even one year after the operation. These results suggest that perioperative management is necessary for normal psychosocial development in these patients.
【Objective】 Obesity may cause obesity-related nephropathy due to glomerular hyperfiltration and the like. There is concern that the risk of kidney injury may increase due to progression of glomerular hyperfiltration after nephrectomy of living kidney donors with obesity. We conducted a retrospective observational study on short-term renal prognosis of living kidney donors with obesity.
【Methods】 Between April 2003 and July 2013, 149 living kidney donors who were followed 3 years or more were treated as BMI<25.0 kg/m2 (normal group), 25.0 kg/m2≤BMI<30.0 kg/m2 (obese group), or 30.0 kg/m2≤BMI (maximum 33.1 kg/m2) (highly obese group), and eGFR and proteinuria were compared.
【Results】 Among the 149 donors, 100 normal subjects, 43 obese subjects and 6 highly obese subjects were included. There was no significant difference in the preoperative renal function or the observation period among the 3 groups. The eGFR after 1 year was 54.3±10.8 ml/min/1,73 m2, 51.3±10.3 ml/min/1,73 m2, and 57.3±12.2 ml/min/1,73 m2 (p=0.213), and the eGFR at the final examination was 55.0±11.8 ml/min/1,73 m2, 54.4±13.5 ml/min/1,73 m2, and 54.7±14.0 ml/min/1,73 m2 (p=0.978), and the protein urine appearance rates were 14.0%, 25.6% and 16.7% (p=0.223), respectively, and there was no significant difference.
【Conclusion】 In this study, obese living kidney donors were not significantly different from non-obese living kidney donors in short-term renal prognosis. Further long-term observation and examination of more cases are necessary.
【Objective】 Percutaneous and ultrasound-guided renal allograft biopsy (RAB) is the gold standard procedure with which to evaluate renal allograft dysfunction. Major complications after RAB include hematoma, hematuria, and arteriovenous fistula (AVF) in the graft. Since RAB is a relatively invasive test, we evaluated the risk of complications and subsequent prognosis of the graft.
【Methods】 This was a single center retrospective cohort analysis of 325 RABs carried out on 272 patients between 2013 and 2016. Biopsy was conducted percutaneously and with ultrasound-guidance using an 18G or 16G needle. We compared the medical background of patients with and without RAB complications, with special reference to renal functions after RAB in an AVF group and a non-AVF group.
【Results】 In total, we identified 40 complications (12.3%) in 325 RABs, including 1 hematoma (0.3%), 7 hematuria (2.2%), 30 AVF in 30 patients (9.2%), and 2 deep vein thromboses (DVT; 0.62%). Comparisons of patient backgrounds between those with complications (n=40) and those without (n=232) revealed that there was a significant difference in graft weight (205±55 g versus 177±46 g; p=0.023) and everolimus intake (p=0.047). In one case involving hematoma, a small mass had developed around the graft, which spontaneously disappeared over the course of a few days. Although one case presented macroscopic hematuria, this resolved spontaneously. Serum eGFR levels following biopsy were comparable between the AVF group (n=30) and the non-AVF group (n=242) with no graft loss by AVF. Two patients with symptomatic DVT required re-admission: both had a high BMI (>30). While one case developed pulmonary embolism, both were resolved with anticoagulant therapy.
【Conclusion】 Approximately one in every 10 RAB cases was associated with a complication. Graft weight and everolimus intake were significant risk factors for RAB complications. While AVF was the most frequent complication (9.2%), the subsequent function of the grafts was comparable with that of non-AVF cases. However, a life-threatening complication of pulmonary embolism occurred in one case, probably due to compression around the allograft and bed rest for a few hours after the procedure. Our data suggest that physicians need to consider the formation of thrombosis following RAB, particularly in obese patients.
We report a case of deceased donor liver transplantation (DDLT) to an HBc-antibody-positive patient with hepatitis C virus (HCV) and liver cirrhosis due to hemophilia. A 45-year-old man had been suffering from hemophilia from the age of two and was diagnosed with the hepatitis B virus (HBV) and HCV infection owing to frequent blood derivative administration. He was finally evaluated for decompensated liver cirrhosis, with medical urgency and MELD scores of 8 and 28 points, respectively. Therefore, he was registered on the DDLT waiting list. Since he agreed with the donor call on the 22nd day after registration, we performed a regular DDLT employing a venous bolus infusion of hepatitis B immune globulin for prophylaxis. Factor VIII activity rose to 20-30%, and the APTT was shortened to 40-50 sec after the DDLT. The HBs-antibody titer exceeded 100 mIU/mL, and the HBV-DNA was thoroughly negative without the administration of entecavir. He was discharged on the 94th postoperative day and is receiving anti-HCV treatment without hepatitis B virus reactivation. Unlike the usual coinfection of hemophilia is human immunodeficiency virus and HCV, we experienced an extremely rare case of coinfection of HBV and HCV. HBc-antibody-positive recipients are not well discussed in the literature, in contrast to HBc-antibody-positive donors, because it is naturally thought that HBV cannot live and replicate in extrahepatic cells. However, there is no obvious evidence regarding the impossibility of extrahepatic replication and reactivation in HBc-antibody-positive recipients at this time; therefore, a careful follow-up of HBV reactivation is needed for HBc-antibody-positive recipients.
【Introduction】 Hepatic artery pseudoaneurysm after liver transplantation is a rare but devastating complication with an incidence of 0.3-2.6%. Once the pseudoaneurysm ruptures, the mortality rate becomes very high. We present a case with the hepatic artery pseudoaneurysm after living donor liver transplantation, which was successfully treated with placement of a covered stent.
【Case】 A 50-year-old man with a diagnosis of alcoholic cirrhosis underwent living-donor liver transplantation (LDLT) using the left lobe of his daughter as a graft. Hepatic artery anastomosis was performed in end-to-end fashion by interrupted sutures with 8-0 nylon. A bump-like projection with a diameter of 5 mm at the hepatic artery anastomosis was detected with a computed tomography (CT) scan on post-operative day (POD) 12, which was initially considered a stump of the hepatic artery but was confirmed as a pseudoaneurysm because the size of the projection increased to 8 mm with a CT scan POD 16. An expanded-polytetrafluoroethlen (ePTFE) membrane-covered stent was inserted to the anastomotic site and placed by inflating the intraluminal balloon POD 17 after the confirmation of the diagnosis with angiography and intravascular ultrasound (IVUS). After the procedure, aspirin and clopidogrel were started as anticoagulant therapy. The hepatic arterial flow was well-maintained as shown by subsequent ultrasound and CT scans, and recurrence of the aneurysm was not seen. The patient was discharged POD 57 and is alive and well with no complications at 3 months after the operation.
【Conclusion】 Since the rupture of a hepatic artery pseudoaneurym is fatal, it is important to perform ultrasonography, CT scan, or magnetic resonance imaging periodically after transplantation to detect such a devastating complication early enough. As shown in the present case, a covered stent was considered to be effective in preventing a rupture.