First live birth after uterus transplantation in the United States.

Uterus transplantation has proven to be a successful treatment for women with absolute uterine infertility, caused either by the absence of a uterus or the presence of a nonfunctioning uterus. We report the first birth of a healthy child following uterus transplantation in the United States, from a recipient of a uterus allograft procured from an altruistic living donor. Two major modifications from the previously reported live births characterized this uterus transplant. First, the transplanted uterus relied upon and sustained the pregnancy while having only the utero-ovarian vein as venous outflow. The implication is a significantly simplified living donor surgery that paves the way for minimally invasive laparoscopic or robot-assisted techniques for the donor hysterectomy. Second, the time from transplantation to embryo transfer was significantly shortened from prior protocols, allowing for an overall shorter exposure to immunosuppression by the recipient and lowering the risk for potential adverse effects from these medications.

Live nondirected uterus donors: Psychological characteristics and motivation for donation.

Emerging research suggests that uterus transplantation is a viable option for women without a uterus who want to become pregnant and carry a child to term. Currently, no knowledge exists regarding nondirected uterus donors. This study (NCT 02656550) explored the baseline psychological characteristics of nondirected uterus donors at a single study site. Of the 62 potential donors who underwent initial screening, 6 nondirected donors were chosen and participated in uterus donation. Participants received a comprehensive evaluation, which included clinical history and psychological assessments. The mean age of the donors was 42 years; most (83%) were white/not Hispanic, and all had a college degree. Current depression was reported by 2 participants, past depression was reported in 2 participants, and past anxiety was reported in 3 participants. Based on several different psychological measures, donors had a higher general well-being than the normative sample, and none of the participants' scores indicated psychological distress. All 6 women indicated that giving another woman an opportunity to carry her own child was a motivation for pursuing uterus donation. Further research on potential psychological motives and gains for the donor as well as long-term effects on donors is crucial for ethical practice.

Deceased donor uterus retrieval: A novel technique and workflow.

Uterus transplantation has proven successful when performed with a living donor. Subsequently, interest in the novel field of reproductive transplantation is growing. The procedure is still considered experimental, with fewer than 25 cases performed worldwide, and the techniques of both uterus procurement and transplantation are still developing. We detail a new approach to deceased donor uterus procurement. In contrast to reported techniques and our own initial experience, in which the deceased donor uterus was procured post cross-clamp and after other organs were procured, our approach now is to perform the uterus procurement prior to the procurement of other organs in a multiorgan donor and hence prior to cross-clamp. We describe our practical experience in developing and implementing the logistical workflow for deceased donor uterus procurement in a deceased multiorgan donor setting.

The American Society of Transplantation Consensus Conference on the Use of Hepatitis C Viremic Donors in Solid Organ Transplantation.

The availability of direct-acting antiviral agents for the treatment of hepatitis C virus (HCV) infection has resulted in a profound shift in the approach to the management of this infection. These changes have affected the practice of solid organ transplantation by altering the framework by which patients with end-stage organ disease are managed and receive organ transplants. The high level of safety and efficacy of these medications in patients with chronic HCV infection provides the opportunity to explore their use in the setting of transplanting organs from HCV-viremic patients into non-HCV-viremic recipients. Because these organs are frequently discarded and typically come from younger donors, this approach has the potential to save lives on the solid organ transplant waitlist. Therefore, an urgent need exists for prospective research protocols that study the risk versus benefit of using organs for hepatitis C-infected donors. In response to this rapidly changing practice and the need for scientific study and consensus, the American Society of Transplantation convened a meeting of experts to review current data and develop the framework for the study of using HCV viremic organs in solid organ transplantation.

Living Donor Uterus Transplantation: A Single Center's Observations and Lessons Learned From Early Setbacks to Technical Success.

Uterus transplantation is a vascularized composite allograft transplantation. It allows women who do not have a uterus to become pregnant and deliver a baby. In this paper, we analyze the first five cases of living donor uterus transplantation performed in the United States. The first three recipients lost their uterus grafts at days 14, 12, and 6, respectively, after transplant. Vascular complications, related to both inflow and outflow problems, were identified as the primary reason for the graft losses. Two recipients, at 6 and 3 mo, respectively, after transplant, have functioning grafts with regular menstrual cycles. Ultimate success will be claimed only after a live birth. This paper is an in-depth analysis of evaluation, surgical technique, and follow-up of these five living donor uterus transplants. The lessons learned were instrumental in allowing us to evolve from failure to technical and functional success. We aim to share our conclusions and build on knowledge in the evolving field of uterus transplantation.

Liver transplantation for "very early" intrahepatic cholangiocarcinoma: International retrospective study supporting a prospective assessment.

UNLABELLED: The presence of an intrahepatic cholangiocarcinoma (iCCA) in a cirrhotic liver is a contraindication for liver transplantation in most centers worldwide. Recent investigations have shown that "very early" iCCA (single tumors ≤2 cm) may have acceptable results after liver transplantation. This study further evaluates this finding in a larger international multicenter cohort. The study group was composed of those patients who were transplanted for hepatocellular carcinoma or decompensated cirrhosis and found to have an iCCA at explant pathology. Patients were divided into those with "very early" iCCA and those with "advanced" disease (single tumor >2 cm or multifocal disease). Between January 2000 and December 2013, 81 patients were found to have an iCCA at explant; 33 had separate nodules of iCCA and hepatocellular carcinoma, and 48 had only iCCA (study group). Within the study group, 15/48 (31%) constituted the "very early" iCCA group and 33/48 (69%) the "advanced" group. There were no significant differences between groups in preoperative characteristics. At explant, the median size of the largest tumor was larger in the "advanced" group (3.1 [2.5-4.4] versus 1.6 [1.5-1.8]). After a median follow-up of 35 (13.5-76.4) months, the 1-year, 3-year, and 5-year cumulative risks of recurrence were, respectively, 7%, 18%, and 18% in the very early iCCA group versus 30%, 47%, and 61% in the advanced iCCA group, P = 0.01. The 1-year, 3-year, and 5-year actuarial survival rates were, respectively, 93%, 84%, and 65% in the very early iCCA group versus 79%, 50%, and 45% in the advanced iCCA group, P = 0.02. CONCLUSION: Patients with cirrhosis and very early iCCA may become candidates for liver transplantation; a prospective multicenter clinical trial is needed to further confirm these results. (Hepatology 2016;64:1178-1188).

2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology: Introduction of Antibody-Mediated Rejection.

The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.

Proposed Diagnostic Criteria for Chronic Antibody-Mediated Rejection in Liver Allografts.

Donor-specific alloantibodies (DSA) can cause acute antibody-mediated rejection (AMR) in all solid organ allografts. However, long-term outcome in patients with posttransplant DSA needs further study. We retrospectively evaluated prospectively collected paired serum, tissue, and data on 45 matched DSA- positive [DSA+; mean florescence intensity (MFI) ≥10,000] and -negative (DSA-) recipients of a primary liver-only allograft from January 2000 to April 2009. Blinded histopathologic evaluation demonstrated that DSA+ versus DSA- patients were more likely to have subtle inflammation and unique patterns of fibrosis, despite normal or near-normal liver function tests. Stepwise multivariable modeling developed a score (putatively named the chronic AMR [cAMR] score) that included interface activity, lobular inflammation, portal tract collagenization, portal venopathy, sinusoidal fibrosis, and hepatitis C virus status. The score was developed (c = 0.811) and cross-validated (c = 0.704) to predict allograft failure. Two cutoffs were employed to optimize sensitivity and specificity (80% each); a value >27.5 predicted 50% 10-year allograft failure. We propose chronic AMR as a potential new entity defined by (1) a high cAMR score, (2) DSA, and (3) elimination of other potential causes of a similar injury pattern. In conclusion, cAMR score calculation identified liver allograft recipients with DSA at highest risk for allograft loss, although independent validation is needed.

Impact of IgG3 subclass and C1q-fixing donor-specific HLA alloantibodies on rejection and survival in liver transplantation.

Recent literature confirms donor-specific HLA alloantibodies (DSA) impair 5-year survival in some but not all liver transplant recipients. In an effort to improve DSA testing's association with rejection and death, we retrospectively evaluated 1270 liver transplant recipients for the presence of IgG3 and C1q-fixing DSA. In patients with preformed DSA, 29 and 51% had IgG3 and C1q-fixing DSA, respectively. In patients with de novo DSA, 62% and 67% had IgG3 and C1q-fixing DSA, respectively. When different types of DSA positive patients were compared to DSA negative patients, multivariable analysis showed that IgG3 DSA positivity had the highest numerical hazard ratio for death (IgG3: HR = 2.4, p < 0.001; C1q: HR = 1.9, p < 0.001; standard DSA: HR = 1.6, p < 0.001). Similarly, multivariable analysis demonstrated de novo IgG3 DSA positivity compared to no DSA had the highest hazard ratio for death (IgG3: HR = 2.1, p = 0.004; C1q: HR = 1.9, p = 0.02; standard DSA: HR = 1.8, p = 0.007). Preformed C1q-fixing class II DSA showed the strongest correlation with early rejection. In conclusion, preformed and de novo IgG3 subclass DSA positive patients had the highest absolute HR for death in side-by-side comparison with C1q and standard DSA positive versus DSA negative patients; however, IgG3 negative DSA positive patients still had inferior outcomes compared to DSA negative patients.

Belatacept-based immunosuppression in de novo liver transplant recipients: 1-year experience from a phase II randomized study.

This exploratory phase II study evaluated the safety and efficacy of belatacept in de novo adult liver transplant recipients. Patients were randomized (N = 260) to one of the following immunosuppressive regimens: (i) basiliximab + belatacept high dose [HD] + mycophenolate mofetil (MMF), (ii) belatacept HD + MMF, (iii) belatacept low dose [LD] + MMF, (iv) tacrolimus + MMF, or (v) tacrolimus alone. All received corticosteroids. Demographic characteristics were similar among groups. The proportion of patients who met the primary end point (composite of acute rejection, graft loss, death by month 6) was higher in the belatacept groups (42­48%) versus tacrolimus groups (15­38%), with the highest number of deaths and grafts losses in the belatacept LD group. By month 12, the proportion surviving with a functioning graft was higher with tacrolimus + MMF (93%) and lower with belatacept LD (67%) versus other groups (90%: basiliximab + belatacept HD; 83%: belatacept HD; 88%: tacrolimus). Mean calculated GFR was 15­34 mL/min higher in belatacept-treated patients at 1 year. Two cases of posttransplant lymphoproliferative disease and one case of progressive multifocal leukoencephalopathy occurred in belatacept-treated patients. Follow-up beyond month 12 revealed an increase in death and graft loss in another belatacept group (belatacept HD), after which the study was terminated.

The role of donor-specific HLA alloantibodies in liver transplantation.

The impact of donor-specific HLA alloantibodies (DSA) on short- and long-term liver transplant outcome is not clearly defined. While it is clear that not all levels of allosensitization produce overt clinical injury, and that liver allografts possess some degree of alloantibody resistance, alloantibody-mediated adverse consequences are increasingly being recognized. To better define the current state of this topic, we assembled experts to provide insights, explore controversies and develop recommendations for future research on the consequences of DSA in liver transplantation. This article summarizes the proceedings of this inaugural meeting. Several insights emerged. Acute antibody-mediated rejection (AMR), although rarely diagnosed, is increasingly understood to overlap with T cell-mediated rejection. Isolated liver allograft recipients are at increased risk of early allograft immunologic injury when preformed DSA are high titer and persist posttransplantation. Persons who undergo simultaneous liver-kidney transplantation are at risk of renal AMR when Class II DSA persist posttransplantation. Other under-appreciated DSA associations include ductopenia and fibrosis, plasma cell hepatitis, biliary strictures and accelerated fibrosis associated with recurrent liver disease. Standardized DSA testing and diagnostic criteria for both acute and chronic AMR are needed to distil existing associations into etiological processes in order to develop responsive therapeutic strategies.

De novo sirolimus and reduced-dose tacrolimus versus standard-dose tacrolimus after liver transplantation: the 2000-2003 phase II prospective randomized trial.

We studied whether the use of sirolimus with reduced-dose tacrolimus, as compared to standard-dose tacrolimus, after liver transplantation is safe, tolerated and efficacious. In an international multicenter, open-label, active-controlled randomized trial (2000-2003), adult primary liver transplant recipients (n=222) were randomly assigned immediately after transplantation to conventional-dose tacrolimus (trough: 7-15 ng/mL) or sirolimus (loading dose: 15 mg, initial dose: 5 mg titrated to a trough of 4-11 ng/mL) and reduced-dose tacrolimus (trough: 3-7 ng/mL). The study was terminated after 21 months due to imbalance in adverse events. The 24-month cumulative incidence of graft loss (26.4% vs. 12.5%, p=0.009) and patient death (20% vs. 8%, p=0.010) was higher in subjects receiving sirolimus. A numerically higher rate of hepatic artery thrombosis/portal vein thrombosis was observed in the sirolimus arm (8% vs. 3%, p=0.065). The incidence of sepsis was higher in the sirolimus arm (20.4% vs. 7.2%, p=0.006). Rates of acute cellular rejection were similar between the two groups. Early use of sirolimus using a loading dose followed by maintenance doses and reduced-dose tacrolimus in de novo liver transplant recipients is associated with higher rates of graft loss, death and sepsis when compared to the use of conventional-dose tacrolimus alone.

REFINE: a randomized trial comparing cyclosporine A and tacrolimus on fibrosis after liver transplantation for hepatitis C.

REFINE was a 12-month, prospective, open-label study in 356 patients receiving de novo liver transplantation for hepatitis C virus (HCV) cirrhosis, randomized to cyclosporine A (CsA) or tacrolimus with (i) no steroids, IL-2 receptor antibody induction and mycophenolic acid, or (ii) slow steroid tapering. The primary analysis population based on availability of liver biopsies comprised 165 patients (88 CsA, 77 tacrolimus). There was no difference in the primary endpoint, fibrosis stage ≥2 at 12 months, which occurred in 63/88 CsA-treated patients (71.6%) and 52/77 tacrolimus-treated patients (67.5%) (odds ratio [OR] 1.11; 95% CI 0.56, 2.21; p = 0.759). Similarly, no significant between-group difference occurred at month 24 (OR 1.15; 95% CI 0.47, 2.80; p = 0.767). Among steroid-free patients, fibrosis score ≥2 was significantly less frequent with CsA versus tacrolimus at month 12 (7/37 [18.9%] vs. 16/38 [42.1%]; p = 0.029). HCV viral load was similar in both the tacrolimus- and CsA-treated cohorts. Mean blood glucose was significantly higher with tacrolimus from day 15 onward. Biopsy-proven acute rejection, graft loss and death were similar. These results showed no differences in posttransplant HCV-induced liver fibrosis between patients treated with CsA or tacrolimus in steroid-containing regimens, whereas CsA in steroid-free protocols was associated with reduced severity of fibrosis progression at 1 year posttransplant.

De novo donor-specific HLA antibodies decrease patient and graft survival in liver transplant recipients.

The role of de novo donor-specific HLA antibodies (DSA) in liver transplantation remains unknown as most of the previous studies have only focused on preformed HLA antibodies. To understand the significance of de novo DSA, we designed a retrospective cohort study of 749 adult liver transplant recipients with pre- and posttransplant serum samples that were analyzed for DSA. We found that 8.1% of patients developed de novo DSA 1 year after transplant; almost all de novo DSAs were against HLA class II antigens, and the majority were against DQ antigens. In multivariable modeling, the use of cyclosporine (as opposed to tacrolimus) and low calcineurin inhibitor levels increased the risk of de novo DSA formation, while a calculated MELD score >15 at transplant and recipient age >60 years old reduced the risk. Multivariable analysis also demonstrated that patients with de novo DSA at 1-year had significantly lower patient and graft survival. In conclusion, we demonstrate that de novo DSA development after liver transplantation is an independent risk factor for patient death and graft loss.

Class II alloantibody and mortality in simultaneous liver-kidney transplantation.

Hyperacute kidney rejection is unusual in crossmatch positive recipients of simultaneous liver-kidney transplants (SLKT). However, recent data suggest that these patients remain at risk for antibody-mediated kidney rejection. To further investigate the risk associated with donor-specific alloantibodies (DSA) in SLKT, we studied 86 consecutive SLKT patients with an available pre-SLKT serum sample. Serum samples were analyzed in a blinded fashion for HLA DSA using single antigen beads (median florescence intensity≥2,000=positive). Post-SLKT samples were analyzed when available (76%). Thirty patients had preformed DSA, and nine developed de novo DSA. Preformed class I DSA did not change the risk of rejection, patient or allograft survival. In contrast, preformed class II DSA was associated with a markedly increased risk of renal antibody mediated rejection (AMR) (p=0.006), liver allograft rejection (p=0.002), patient death (p=0.02), liver allograft loss (p=0.02) and renal allograft loss (p=0.045). Multivariable modeling showed class II DSA (preformed or de novo) to be an independent predictor of patient death (HR=2.2; p=0.043) and liver allograft loss (HR=2.2; p=0.044). These data warrant reconsideration of the approach to DSA in SLKT.

Transplant organizational structures: viewpoints from established centers.

This personal viewpoint report summarizes the responses of a survey targeting established transplant programs with a structured framework, such as center, institute, or department, and stability of leadership to assure valuable experiential observations. The 18-item survey was sent to 20 US institutions that met inclusion criteria. The response rate was 100%. Seventeen institutions had a distinct transplant governance structure. A majority of respondents perceived that their type of transplant structure was associated with enhanced recognition within their institution (85%), improved regulatory compliance (85%), transplant volume growth (75%), improved quality outcomes (75%) and increased funding for transplant-related research (75%). The prevailing themes in respondents' remarks were the perceived need for autonomy of the transplant entity, alignment among services and finances and alignment of authority with responsibility. Many respondents suggested that a dialogue be opened about effective transplant infrastructure that overcomes the boundaries of traditional academic department silos.

Bortezomib for acute antibody-mediated rejection in liver transplantation.

Antibody-mediated rejection (AMR) is an uncommon, but challenging type of rejection after solid organ transplantation. We review three cases of AMR in ABO-compatible liver transplant recipients. These cases were characterized by severe acute rejection resistant to steroids and antithymocyte globulin, histologic evidence of plasma cell infiltrates, C4d positivity and high serum anti-HLA donor-specific antibodies. All three patients were treated with bortezomib, a proteasome inhibitor effective in depleting plasma cells. After treatment, all patients had improved or normal liver function tests, resolution of C4d deposition and significant decline in their HLA donor-specific antibodies.

Limiting hepatitis C virus progression in liver transplant recipients using sirolimus-based immunosuppression.

Hepatitis C virus (HCV) causes progressive liver fibrosis in liver transplant recipients and is the principal cause of long-term allograft failure. The antifibrotic effects of sirolimus are seen in animal models but have not been described in liver transplant recipients. We reviewed 1274 liver recipients from 2002 to 2010 and identified a cohort of HCV recipients exposed to sirolimus as primary immunosuppression (SRL Cohort) and an HCV Control Group of recipients who had never received sirolimus. Yearly protocol biopsies were done recording fibrosis stage (METAVIR score) with biopsy compliance of >80% at both year one and two. In an intent-to-treat analysis, the SRL Cohort had significantly less advanced fibrosis (stage ≥2) compared to the HCV Control Group at year one (15.3% vs. 36.2%, p < 0.0001) and year two (30.1% vs. 50.5%, p = 0.001). Because sirolimus is sometimes discontinued for side effects, the SRL Cohort was subgroup stratified for sirolimus duration, showing progressively less fibrosis with longer sirolimus duration. Multivariate analysis demonstrated sirolimus as an independent predictor of minimal fibrosis at year one, and year two. This is the first study among liver transplant recipients with recurrent HCV to describe the positive impact of sirolimus in respect of reduced fibrosis extent and rate of progression.