Tolerance is the Holy Grail of transplant for several reasons. First, harmful lifelong immunosuppression and related complications can be avoided. Second, the ultimate goal of "one transplant for life" can be achieved by improving the health of transplant recipients and the longevity of transplanted organs.1 However, tolerance is not yet a regular daily practice, and the induction of a successful tolerance may bring up important challenges and complications. Most importantly, it is known that different organs behave differently to the same tolerogenic protocols. Although abdominal organ transplants, such as kidney and liver allografts, are considered to be "tolerance-prone" organs due to their relatively weaker immunogenicity, thoracic organ transplants (ie, heart and lung allografts) are considered as "tolerance-resistant" organs due to their higher immunogenicity.2 In 2008, the Boston group reported that they stopped all maintenance immunosuppression therapy 9 to 14 mo after renal transplantation with the use of a nonmyeloablative preparative regimen, which included thymic irradiation and bone marrow transplant.3 Although the study was limited to 4 patients, renal function remained stable for 2 to 5 y without immunosuppression, and T cells from those 4 patients obtained after withdrawal of immunosuppressive therapy showed donor-specific unresponsiveness.3 In 2014, the same Boston group reported 10 tolerogenic renal transplant recipients with long-term outcomes.4 In an effort to use clinically applicable costimulation-based immunosuppressive regimen and delayed bone marrow transplant as a transient mixed hematopoietic chimerism protocol, Hotta et al5 showed long-term renal allograft tolerance in nonhuman primates. Other groups showed kidney allografts-induced tolerance of heart allografts through mixed hematopoietic chimerism when transplanted simultaneously in mice, swine, and nonhuman primates, which has been considered as "kidney-induced heart allograft tolerance."6 However, there was no successful report of tolerance of heart allografts when they were transplanted as heart transplants alone. In this issue of Transplantation, Chaban et al7 reported their experience in "heart" (alone) allograft tolerance in nonhuman primates using enhanced costimulation blockade regimen with anti-CD154 monoclonal antibody (mAb), anti-CD2 mAb, and anti-CD28 mAb. They transplanted 8 macaques with heterotopic hearts from major histocompatibility complex-mismatched donors. The regimen included intensive costimulation blockade-based immunosuppression as well as other powerful treatments, such as total body irradiation, thymic irradiation, and donor bone marrow transplantation. The authors concluded that intensive costimulation pathway blockade with anti-CD154 mAb, CD2 mAb, and anti-CD28 mAb promoted lymphocyte chimerism at the cost of high incidence of posttransplantation lymphoproliferative disease and opportunistic infections. Unfortunately, these serious complications prevented the assessment of the immunosuppressive regimen's long-term effectiveness to promote alloimmune tolerance.7 The study by Chaban et al has exciting new findings as well as certain limitations.7 First, the study used novel humanized anti-CD154 mAb that contains the hu5c8 Fab region and an engineered Fc region, which downregulates FcγR2 binding to reduce platelet activation, therefore anti-CD154 pathway-related prothrombotic events. Second, the study targeted the CD2 pathway on mature T cells, inhibiting T-cell proliferation and memory T cells, and the CD28 pathway reducing acute cellular rejection through the inhibition of different costimulation pathways, such as CD28/B7 and CD28-dependent CD154 blockade. In contrast, the study was limited because of (1) its small sample size, (2) high incidence of complications not enabling long-term follow-up, (3) variation in the quantity of viable bone marrow cells for each transplant, and (4) other immunological diversity, such as level of immunosuppression and amount of blood transfusion with cross-reactive antidonor antibodies. Despite all challenges and negative results, the preclinical tolerance induction study by Chaban et al in heart allotransplant alone in nonhuman primates showed us again that the Holy Grail of transplant is not easy to achieve, and more research needs to be done to reach the goal of "one transplant for life." Currently, the cost of achieving tolerance in heart allotransplant alone is too high that recipients pay the price with life-threatening complications, such as posttransplantation lymphoproliferative disease, lethal infections, or irreversible rejections. Therefore, it is crucial to understand and acknowledge that clinical heart transplantation is currently not ready to handle such a risk. However, with continued rigorous research into new tolerogenic protocols,8 the ultimate goal of having tolerance in heart allografts could be a clinical reality. We, therefore, acknowledge the importance of work by Chaban et al, which paves an important stone to the long but important road of tolerance.

Liver xenotransplantation has emerged as a potential solution to the shortage of deceased human donor organs and is now becoming a reality due to recent developments in genetic engineering and immunosuppressive therapy. Early efforts using non-human primates and genetically modified pigs faced significant challenges such as thrombocytopenia and graft rejection. Understanding the mechanism behind those challenges and using novel genetically engineered pigs enabled researchers to overcome some of the hurdles, but more research is needed. However, new advances might allow pig liver xenotransplantation to potentially serve as a bridge to liver allotransplantation or allow native liver regeneration in the near future.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths, with increasing incidence. There are different treatment options, but only 30%-40% of HCC cases are diagnosed at an early stage for curative treatment. With the implementation of Milan Criteria for liver transplantation (LT) in HCC cases and its use for organ allocation with successful outcomes, LT has become an optimal treatment. Seeking new criteria for LT and developing updated algorithms for HCC treatment has become a hot topic nowadays. With the experience in living donor liver transplantation (LDLT), especially in Asian countries, LDLT was established and adopted with different criteria for HCC treatment, especially including criteria beyond Milan's size and number of tumors. Living donor grafts are uniquely different than deceased donor grafts as they are not considered a public resource. A living donor graft is rather a private gift intended for a specific recipient. Living donor livers are not limited by organ allocation systems, and this significant advantage of LDLT has opened new frontiers in the treatment of HCC. Improvements in LDLT have had remarkable parallel effects in the successful treatment of HCC as supported by a growing body of literature in the past decade.

Smith-Lemli-Opitz syndrome is an autosomal recessive metabolic disease characterized by mental retardation and multiple congenital anomalies. The main pathology is the lack of the enzyme 3β-hydroxysterol Δ7-reductase, which is the last enzymatic step in cholesterol synthesis, ending with a low cholesterol level. Cholesterol is vitally important in cell membranes and myelination of the nervous system. The cholesterol level affects many systems of the body, especially the nervous system. The cause of liver involvement in Smith-Lemli-Opitz syndrome is unclear, and many hypotheses have been suggested. Here, we present the early results of a patient with Smith-Lemli-Opitz syndrome who underwent living-donor liver transplant due to cirrhosis. As a result of liver transplant, normal cholesterol levels were shown, as well as improvements in the patient's neurodevelopment and behavior. Early liver transplant may be considered for patients with a defect of cholesterol biosynthesis, even in the absence of cirrhosis, and may be a future treatment option to prevent risks of neurologic deterioration.

BACKGROUND:Complement activation in kidney transplantation is implicated in the pathogenesis of delayed graft function (DGF). This study evaluated the therapeutic efficacy of high-dose recombinant human C1 esterase inhibitor (rhC1INH) to prevent DGF in a nonhuman primate model of kidney transplantation after brain death and prolonged cold ischemia. METHODS:Brain death donors underwent 20 h of conventional management. Procured kidneys were stored on ice for 44-48 h, then transplanted into ABO-compatible major histocompatibility complex-mismatched recipients. Recipients were treated with vehicle (n = 5) or rhC1INH 500 U/kg plus heparin 40 U/kg (n = 8) before reperfusion, 12 h, and 24 h posttransplant. Recipients were followed up for 120 d. RESULTS:Of vehicle-treated recipients, 80% (4 of 5) developed DGF versus 12.5% (1 of 8) rhC1INH-treated recipients (P = 0.015). rhC1INH-treated recipients had faster creatinine recovery, superior urinary output, and reduced urinary neutrophil gelatinase-associated lipocalin and tissue inhibitor of metalloproteinases 2-insulin-like growth factor-binding protein 7 throughout the first week, indicating reduced allograft injury. Treated recipients presented lower postreperfusion plasma interleukin (IL)-6, IL-8, tumor necrosis factor-alpha, and IL-18, lower day 4 monocyte chemoattractant protein 1, and trended toward lower C5. Treated recipients exhibited less C3b/C5b-9 deposition on day 7 biopsies. rhC1INH-treated animals also trended toward prolonged mediated rejection-free survival. CONCLUSIONS:Our results recommend high-dose C1INH complement blockade in transplant recipients as an effective strategy to reduce kidney injury and inflammation, prevent DGF, delay antibody-mediated rejection development, and improve transplant outcomes.

OBJECTIVES The use of deceased after circulatory death liver allografts in patients with primary sclerosing cholangitis is controversial, given the increased risk of graft complications in patients with primary sclerosing cholangitis. We hypothesized that transplant of deceased after circulatory death livers into recipients with primary sclerosing cholangitis when appropriately selected using the UK deceased after circulatory death scoring system is not associated with increased graft failure and mortality. MATERIALS AND METHODS We analyzed 99 229 transplants (between January 2001 and December 2018) from the Organ Procurement and Transplantation Network database. Deceased after circulatory death transplants were stratified by the UK scoring system as low risk or high risk. We identified 3958 patients with primary sclerosing cholangitis who received deceased after brain death transplant and 95 patients with primary sclerosing cholangitis who received deceased after circulatory death transplant. RESULTS As expected, 5-year graft survival was lower in the circulatory death recipient group (69.0% vs 78.4%; P = .02). However, 5-year graft survival was significantly lower in the high-risk versus low-risk UK scoring system group (60.0% vs 75.4%; P = .02), with rate in the low-risk group similar to the brain death recipient group (78.4% vs 75.4%; P = .52). On multivariate analysis, the high-risk group had significantly increased risk of graft loss (hazard ratio of 1.92; P = .01). However, the low-risk group had equivalent graft survival to the brain death recipient group (hazard ratio of 1.23; P = .31). CONCLUSIONS Graft failure was higher in patients with primary sclerosing cholangitis who received livers from deceased after circulatory death donors; however, the risk of graft loss was abrogated using appropriately matched donor and recipient combinations.

Objective: Living liver and kidney donor surgeries are major surgical procedures applied to healthy people with mortality and morbidity risks not providing any direct therapeutic advantage to the donor. In this study, we aimed to share our simultaneous and sequential living liver-kidney donor experience under literature review in this worldwide rare practice. Material and Methods: Between January 2007 and February 2018, a total of 1109 living donor nephrectomies and 867 living liver donor hepatectomies were performed with no mortality to living-related donors. Eight donors who were simultaneous or sequential living liver-kidney donors in this time period were retrospectively reviewed and presented with their minimum 2-year follow-up. Results: Of the 8 donors, 3 of them were simultaneous and 5 of them were sequential liver-kidney donation. All of them were close relatives. Mean age was 39 (26-61) years and mean BMI was 25.7 (17.7-40). In 3 donors, right lobe, in 4 donors, left lateral sector, and in 1 donor, left lobe hepatectomy were performed. Median hospital stay was 9 (7-13) days. Two donors experienced early and late postoperative complications (Grade 3b and Grade 1). No mortality and no other long-term complication occurred. Conclusion: Expansion of the donor pool by utilizing grafts from living donors is a globally-accepted proposition since it provides safety and successful outcomes. Simultaneous or sequential liver and kidney donation from the same donor seems to be a reasonable option for combined liver-kidney transplant recipients in special circumstances with acceptable outcomes.

Background/aim: With the increased experience in living donor liver transplantation (LDLT), it has been adopted for the treatment of hepatocellular carcinoma (HCC), with emerging discussions of criteria beyond tumor size and number. In contrast to deceased donor liver transplantation (DDLT), recipient selection for LDLT is not limited by organ allocation systems. We discuss herein the assessment, criteria, and experience with liver transplantation (LT) in HCC cases at a high-volume LDLT center. Material and methods: Between August 2006 and December 2017, 191 adult LT HCC recipients with at least one-year follow-up were retrospectively analyzed. Results: In 191 patients, one-, three- and five-year survival rates were 87.2%, 81.6%, and 76.2%, respectively, including early postoperative mortality. In 174 patients with long-term follow-up, one-, three- and five-year disease-free survival rates were 91.6%, 87.7%, and 84.4%, respectively. When multivariate analysis was utilized, tumor differentiation was the only factor which statistically affected survival (p = 0.025). Conclusion: LDLT allows us to push the limits forward and the question "Are the criteria always right?" is always on the table. We can conclude that, with the advantage of LDLT, every HCC patient deserves a case-by-case basis discussion for LT under scientific literature support. In borderline cases, tumor biopsy might help determine the decision for LT.

Objectives Living liver donor surgery is a major surgical procedure applied to healthy people with mortality and morbidity risks and does not provide any direct therapeutic advantage to the donor. We retrospectively analyzed the postoperative complication of our living liver donors to figure out the risks of donation. Material and Methods Between November, 2006 and December, 2018, a total of 939 living liver donor hepatectomies were performed with no mortality to the living-related donors. Eight hundred and ninety donors with a minimum 1-year follow-up were analyzed retrospectively. Results Of the 890 donors, 519 (58.3%) were males and 371 (41.7%) were females. Mean age was 35 years (18-64) and mean body mass index was 25.7 kg/m2 (17.7-40). Right donor hepatectomy was performed to 601 (67.5%), left donor hepatectomy to 28 (3.2%) and left lateral sector hepatectomy to 261 (29.3%) of the donors. Of the 890 donors, 174 (19.5%) donors experienced a total of 204 early and late complications including life- threatening and nearly life- threatening complications in 26 (2.9%) of them. Intraoperative complication occurred in 4 (0.5%) donors. Right donors hepatectomy complication rate (23.3%) was higher than left donor (14.3%) and left lateral sector donor hepatectomy (11.5%). Conclusion All donor candidates should be well-informed not only on the details of early and late complications of living liver donation, also possible outcomes of the recipient. In addition to detailed physical evaluation, preoperative psychosocial evaluation is also mandatory. Comprehensive donor evaluation, surgical experience, surgical technique, close postoperative follow-up and establishing a good dialog with the donor allows better outcomes.

A 36-year-old female patient with end-stage liver failure from secondary sclerosing cholangitis was being evaluated for transplantation. She had a history of biliary atresia status post–Kasai portoenterostomy at five months of age. Over the past several years, her medical history was complicated by multiple episodes of recurrent cholangitis requiring prolonged courses of antibiotics and several hospitalizations. Despite her symptomatic disease, she had well-compensated liver function with a total serum bilirubin level at evaluation of 0.9 mg/dL, an international normalized ratio of 0.9, and an albumin level of 3.7 g/dL. She had normal renal function with a serum creatinine level of 0.69 mg/dL. Due to ongoing issues with debilitating fatigue, intermittent abdominal pain, and ascending cholangitis, she was awarded exception points for a Model for End-Stage Liver Disease score of 21. Preoperative, multiphase imaging was obtained during her evaluation process to aid in surgical planning. 1Biliary atresia is associated with which hepatic anatomic abnormalities?aAbsent portal vein, replaced hepatic artery system off the superior mesenteric artery, and absent extrahepatic bile ductsbPreduodenal portal vein, absent retrohepatic vena cava, and absent extrahepatic bile ductscAbsent hepatic artery, preduodenal portal vein, and absent extrahepatic bile ductsdCholedochal cysts and absent portal vein2Based on Figure 1, what is the patient’s anatomic abnormality?aAbsent right hepatic veinbAccessory right posterior hepatic veincShort confluence of the hepatic veins that drains into the right atriumdNo anatomic abnormality identifiedeLack of a common confluence of the left and middle hepatic veins3What anatomic abnormality associated with biliary atresia is shown in Figure 2?aSitus inversusbPolyspleniacPreduodenal portal veindMalrotation of the intestineseCardiac anomaliesFIGURE 2Computed tomography coronal images with intravenous contrastView Large Image Figure ViewerDownload Hi-res image Download (PPT)4If considering this patient’s candidacy to receive a living donor liver transplant, what potential operative planning is necessary to achieve a successful transplant?aAvailability of an interposition graft between the donor hepatic vein and recipient outflow vein for a right lobe graftbHaving banked vein available due to insufficient portal vein inflowcPlan to revise the roux limb from the prior portoenterostomy for biliary drainagedHaving banked artery available due to the lack of recipient hepatic arteryeA right lobe liver graft is the only consideration for live donation5In the described case, what are the option(s) for establishing venous outflow while performing a deceased donor transplant?aSide-to-side cavocavostomybCaval replacementcPiggyback hepatic vein anastomosisdSide-to-side cavocavostomy or caval replacement

Background/aim The progression of chronic kidney disease (CKD) in recipients of living-donor liver transplant (LDLT) compared to deceased-donor liver transplant (DDLT) has not been studied in the literature. We hypothesize that CKD stage progression in LDLT recipients is reduced compared to that of their DDLT counterparts. Materials and methods A retrospective study was undertaken including 999 adult, single-organ, primary liver transplant recipients (218 LDLT and 781 DDLT) at 2 centers between January 2003 and December 2012, in which CKD progression and regression were evaluated within the first 3 years after transplantation. Results Waiting time from evaluation to transplantation was significantly lower in LDLT patients compared to recipients of DDLT. CKD stage progression from preoperative transplant evaluation to transplantation was significantly greater in DDLT. Deceased-donor liver transplant recipients continued to have higher rates of clinically significant renal disease progression (from stage I–II to stage III–V) across multiple time points over the first 3 years posttransplant. Furthermore, a greater degree of CKD regression was observed in recipients of LDLT. Conclusion It can be concluded that LDLT provides excellent graft and patient survival, significantly reducing the overall incidence of clinically significant CKD stage progression when compared to DDLT. Moreover, there is a significantly higher incidence of CKD stage regression in LDLT compared to DDLT. These observations were maintained in both high and low model for end-stage liver disease(MELD)populations. This observation likely reflects earlier access to transplantation in LDLT as one of the contributing factors to preventing CKD progression.